0A4F4F9BD490A749D5437F821CF06DF1
Regulation No. 536/2014 of the European Parliament and of the Council on Clinical Trials on Medicinal Products for Human Use, Repealing Directive 2001/20/EC
https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf
http://leaux.net/URLS/ConvertAPI Text Files/6EEDD7F6C842FB3FEF08CD86626F6884.en.txt
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| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / Illegal Activity
Searching for indicator unlawful:
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p.(None):
p.(None): 2. The sponsor shall notify the Member States concerned, through the EU portal, of the event and
p.(None): the measures taken.
p.(None):
p.(None): That notification shall be made without undue delay but no later than seven days from the date the measures have been
p.(None): taken.
p.(None):
p.(None): 3. This Article is without prejudice to Chapters III and VII.
p.(None):
p.(None):
p.(None): Article 55
p.(None):
p.(None): Investigator's brochure
p.(None):
p.(None): 1. The sponsor shall provide the investigator with the investigator's brochure.
p.(None):
p.(None): 2. The investigator's brochure shall be updated where new and relevant safety information becomes
p.(None): available, and shall be reviewed by the sponsor at least once per year.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/41
p.(None):
p.(None): Article 56
p.(None):
p.(None): Recording, processing, handling and storage of information
p.(None):
p.(None): 1. All clinical trial information shall be recorded, processed, handled, and stored by the sponsor
p.(None): or investigator, as applicable, in such a way that it can be accurately reported, interpreted and
p.(None): verified while the confidentiality of records and the personal data of the subjects remain protected in
p.(None): accordance with the applicable law on personal data protec tion.
p.(None):
p.(None): 2. Appropriate technical and organisational measures shall be implemented to protect information and
p.(None): personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction
p.(None): or accidental loss, in particular where the processing involves the transmission over a network.
p.(None):
p.(None):
p.(None): Article 57
p.(None):
p.(None): Clinical trial master file
p.(None):
p.(None): The sponsor and the investigator shall keep a clinical trial master file. The clinical trial master
p.(None): file shall at all times contain the essential documents relating to that clinical trial which allow
p.(None): verification of the conduct of a clinical trial and the quality of the data generated, taking into
p.(None): account all characteristics of the clinical trial, including in particular whether the clinical trial is
p.(None): a low-intervention clinical trial. It shall be readily available, and directly accessible upon request, to
p.(None): the Member States.
p.(None):
p.(None): The clinical trial master file kept by the investigator and that kept by the sponsor may have a different
p.(None): content if this is justified by the different nature of the responsibilities of the investigator and the sponsor.
p.(None):
p.(None):
p.(None): Article 58
p.(None):
p.(None): Archiving of the clinical trial master file
p.(None):
p.(None): Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the
p.(None): content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the
p.(None): medical files of subjects shall be archived in accordance with national law.
p.(None):
p.(None): The content of the clinical trial master file shall be archived in a way that ensures that it is
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Political / criminal
Searching for indicator criminal:
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p.(None): jointly conduct a clinical trial. Those networks should be able to be co-sponsors of a clinical trial.
p.(None): In order not to weaken the
p.(None):
p.(None): (1) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code
p.(None): relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67).
p.(None): (2) Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community
p.(None): procedures for
p.(None): the authorisation and supervision of medicinal products for human and veterinary use and establishing a European
p.(None): Medicines Agency (OJ L 136, 30.4.2004, p. 1.)
p.(None):
p.(None): L 158/8 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): concept of responsibility in a clinical trial, where a clinical trial has several sponsors, they should all be subject
p.(None): to the obligations of a sponsor under this Regulation. However, the co-sponsors should be able to split
p.(None): up the responsibilities of the sponsor by contractual agreement.
p.(None):
p.(None):
p.(None): (60) In order to ensure that enforcement action may be taken by Member States and that legal
p.(None): proceedings may be brought in appropriate cases, it is appropriate to provide that sponsors that are not
p.(None): established in the Union should be represented by a legal representative in the Union. However in view of the
p.(None): divergent approaches of the Member States as regards civil and criminal liability, it is appropriate to leave to each
p.(None): Member State concerned, as regards its territory, the choice as to whether or not to require such a legal
p.(None): representative, provided that at least a contact person is established in the Union.
p.(None):
p.(None):
p.(None): (61) Where, in the course of a clinical trial, damage caused to the subject leads to the civil or
p.(None): criminal liability of the investigator or the sponsor, the conditions for liability in such cases, including issues
p.(None): of causality and the level of damages and sanctions, should remain governed by national law.
p.(None):
p.(None):
p.(None): (62) In clinical trials compensation should be ensured for damages successfully claimed in accordance with the
p.(None): applic able laws. Therefore Member States should ensure that systems for compensation for damages
p.(None): suffered by a subject are in place which are appropriate to the nature and the extent of the risk.
p.(None):
p.(None):
p.(None): (63) The Member State concerned should be given the power to revoke the authorisation of a clinical
p.(None): trial, suspend a clinical trial or require the sponsor to modify a clinical trial.
p.(None):
p.(None):
p.(None): (64) In order to ensure compliance with this Regulation, Member States should be able to conduct
p.(None): inspections and should have adequate inspection capacities.
p.(None):
p.(None):
p.(None): (65) The Commission should be able to control whether Member States correctly supervise compliance
p.(None): with this Regulation. Moreover, the Commission should be able to control whether regulatory systems of
p.(None): third countries ensure compliance with the specific provisions of this Regulation and Directive 2001/83/EC
p.(None): concerning clinical trials conducted in third countries.
p.(None):
p.(None):
p.(None): (66) In order to streamline and facilitate the flow of information between sponsors and Member
p.(None): States as well as between Member States, the Agency should, in collaboration with Member States and the
...
p.(None): legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant
p.(None): to this Regulation, and shall be the addressee for all communications with the sponsor provided for in
p.(None): this Regulation. Any communication to that legal representative shall be deemed to be a communication to the
p.(None): sponsor.
p.(None):
p.(None): 2. Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their
p.(None): terri tory, or on their territory and the territory of a third country, provided that they ensure that
p.(None): the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall
p.(None): be the addressee for all communications with the sponsor provided for in this Regulation.
p.(None):
p.(None): L 158/46 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. As regards clinical trials to be conducted in more than one Member State, all those Member States may choose
p.(None): not to apply paragraph 1 provided that they ensure that the sponsor establishes at least a contact
p.(None): person in the Union in respect of that clinical trial who shall be the addressee for all communications
p.(None): with the sponsor provided for in this Regulation.
p.(None):
p.(None):
p.(None): Article 75
p.(None):
p.(None): Liability
p.(None):
p.(None): This Chapter shall not affect the civil and criminal liability of the sponsor, investigator, or persons to whom the
p.(None): sponsor has delegated tasks.
p.(None):
p.(None):
p.(None): CHAPTER XII
p.(None):
p.(None): DAMAGE COMPENSATION
p.(None):
p.(None): Article 76
p.(None):
p.(None): Damage compensation
p.(None):
p.(None): 1. Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from
p.(None): par ticipation in a clinical trial conducted on their territory are in place in the form of insurance,
p.(None): a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the
p.(None): nature and the extent of the risk.
p.(None):
p.(None): 2. The sponsor and the investigator shall make use of the system referred to in paragraph 1 in
p.(None): the form appropriate for the Member State concerned where the clinical trial is conducted.
p.(None):
p.(None): 3. Member States shall not require any additional use of the system referred to in paragraph 1
p.(None): from the sponsor for low-intervention clinical trials, if any possible damage that could be suffered by
p.(None): a subject resulting from the use of the investigational medicinal product in accordance with the protocol
p.(None): of that specific clinical trial on the territory of that Member State is covered by the applicable
p.(None): compensation system already in place.
p.(None):
p.(None):
p.(None): CHAPTER XIII
p.(None):
p.(None): SUPERVISION BY MEMBER STATES, UNION INSPECTIONS AND CONTROLS
p.(None):
p.(None): Article 77
p.(None):
p.(None): Corrective measures to be taken by Member States
p.(None):
...
p.(None): Without prejudice to the Member States' competence for the definition of their health policy and for
p.(None): the organisation and delivery of health services and medical care, the costs for investigational medicinal
p.(None): products, auxiliary medicinal products, medical devices used for their administration and procedures
p.(None): specifically required by the protocol shall not be borne by the subject, unless the law of the Member State
p.(None): concerned provides otherwise.
p.(None):
p.(None): Article 93
p.(None): Data protection
p.(None): 1. Member States shall apply Directive 95/46/EC to the processing of personal data carried out in the
p.(None): Member States pursuant to this Regulation.
p.(None):
p.(None): 2. Regulation (EC) No 45/2001 shall apply to the processing of personal data carried out by the Commission and
p.(None): the Agency pursuant to this Regulation.
p.(None):
p.(None): Article 94
p.(None): Penalties
p.(None): 1. Member States shall lay down rules on penalties applicable to infringements of this Regulation
p.(None): and shall take all measures necessary to ensure that they are implemented. The penalties provided for shall be
p.(None): effective, proportionate and dissuasive.
p.(None): 2. The rules referred to in paragraph 1 shall address, inter alia, the following:
p.(None): (a) non-compliance with the provisions laid down in this Regulation on submission of information intended to be made
p.(None): publicly available to the EU database;
p.(None): (b) non-compliance with the provisions laid down in this Regulation on subject safety.
p.(None):
p.(None): Article 95
p.(None): Civil and criminal liability
p.(None):
p.(None): This Regulation is without prejudice to national and Union law on the civil and criminal liability of
p.(None): a sponsor or an investigator.
p.(None):
p.(None): CHAPTER XIX
p.(None):
p.(None): FINAL PROVISIONS
p.(None):
p.(None): Article 96
p.(None):
p.(None): Repeal
p.(None): 1. Directive 2001/20/EC is repealed as from the date referred to in the second paragraph of Article 99.
p.(None):
p.(None): 2. References to Directive 2001/20/EC shall be construed as references to this Regulation and shall be read in
p.(None): accord ance with the correlation table laid down in Annex VII.
p.(None):
p.(None): Article 97
p.(None): Review
p.(None): Five years after the date referred to in the second paragraph of Article 99, and every five years
p.(None): thereafter, the Commis sion shall present a report to the European Parliament and to the Council on
p.(None): the application of this Regulation. That report shall include an assessment of the impact that the
p.(None): Regulation has had on scientific and technological progress, comprehensive information on the different
p.(None): types of clinical trials authorised pursuant to this Regulation, and the measures required in order to
p.(None): maintain the competitiveness of European clinical research. The Commission shall, if appropriate, present a
p.(None): legislative proposal based on that report in order to update the provisions set out in this Regu
p.(None): lation.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/53
p.(None):
p.(None): Article 98
p.(None):
p.(None): Transitional provision
p.(None):
p.(None): 1. By way of derogation from Article 96(1) of this Regulation, where the request for authorisation
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Political / political affiliation
Searching for indicator party:
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p.(None):
p.(None): 29. For a multinational clinical trial where the medicinal product to be used in each Member State
p.(None): concerned is authorised at national level, and the SmPC varies among Member States concerned, the sponsor
p.(None): shall choose one SmPC for the whole clinical trial. This SmPC shall be the one best suited to ensure patient safety.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/59
p.(None):
p.(None): 30. If the IB is not an SmPC, it shall contain a clearly identifiable section called the ‘Reference
p.(None): Safety Information’ (RSI). In accordance with paragraphs 10 and 11 of Annex III, the RSI shall contain product
p.(None): information on the investigational medicinal product and on how to determine what adverse reactions are to
p.(None): be considered as expected adverse reactions, and on the frequency and nature of those adverse reactions.
p.(None):
p.(None):
p.(None): F. DOCUMENTATION RELATING TO COMPLIANCE WITH GOOD MANUFACTURING PRACTICE (GMP) FOR THE INVESTIGA
p.(None): TIONAL MEDICINAL PRODUCT
p.(None):
p.(None): 31. As regards documentation relating to GMP compliance, the following shall apply.
p.(None):
p.(None): 32. No documentation needs to be submitted where the investigational medicinal product is authorised and is
p.(None): not modified, whether or not it is manufactured in the Union.
p.(None):
p.(None): 33. If the investigational medicinal product is not authorised, and does not have a marketing authorisation
p.(None): from a third country that is party to the International Conference on Harmonisation of Technical
p.(None): Requirements for Registration of Pharmaceuticals for Human Use (ICH), and is not manufactured in the
p.(None): Union, the following documentation shall be submitted:
p.(None): (a) a copy of the authorisation referred to in Article 61; and
p.(None):
p.(None): (b) certification by the qualified person in the Union that the manufacturing complies with GMP at
p.(None): least equivalent to the GMP in the Union, unless there are specific arrangements provided for in mutual recogni tion
p.(None): agreements between the Union and third countries.
p.(None): 34. In all other cases, a copy of the authorisation referred to in Article 61 shall be submitted.
p.(None):
p.(None): 35. For processes related to investigational medicinal products set out in Article 61(5), which are not subject to an
p.(None): authorisation in accordance with Article 61, documentation to demonstrate compliance with the requirements referred
p.(None): to in Article 61(6) shall be submitted.
p.(None):
p.(None):
p.(None): G. INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER (IMPD)
p.(None):
p.(None): 36. The IMPD shall give information on the quality of any investigational medicinal product, the manufacture
p.(None): and control of the investigational medicinal product, and data from non-clinical studies and from its clinical use.
p.(None):
p.(None): 1.1. Data relating to the investigational medicinal product
p.(None):
p.(None): Introduction
p.(None):
p.(None): 37. Regarding data, the IMPD may be replaced by other documentation which may be submitted alone or
...
p.(None):
p.(None): B. SUBJECT DISPOSITION:
p.(None):
p.(None): 1. Recruitment (including information on the number of subjects screened, recruited and withdrawn;
p.(None): inclusion and exclusion criteria; randomisation and blinding details; investigational medicinal products used);
p.(None):
p.(None): 2. Pre-assignment Period;
p.(None):
p.(None): 3. Post Assignment Periods.
p.(None):
p.(None): C. BASELINE CHARACTERISTICS:
p.(None):
p.(None): 1. Baseline Characteristics (Required) Age;
p.(None):
p.(None): 2. Baseline Characteristics (Required) Gender;
p.(None):
p.(None): 3. Baseline Characteristics (Optional) Study Specific Characteristic.
p.(None):
p.(None): D. END POINTS:
p.(None):
p.(None): 1. End point definitions (*)
p.(None):
p.(None): 2. End Point #1 Statistical Analyses
p.(None): 3. End Point #2 Statistical Analyses
p.(None): (*) Information shall be provided for as many end points as defined in the protocol.
p.(None):
p.(None): L 158/70 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): E. ADVERSE EVENTS:
p.(None):
p.(None): 1. Adverse events information;
p.(None):
p.(None): 2. Adverse event reporting group;
p.(None):
p.(None): 3. Serious adverse event;
p.(None):
p.(None): 4. Non-serious adverse event.
p.(None):
p.(None): F. ADDITIONAL INFORMATION:
p.(None):
p.(None): 1. Global Substantial Modifications;
p.(None):
p.(None): 2. Global Interruptions and re-starts;
p.(None):
p.(None): 3. Limitations, addressing sources of potential bias and imprecisions and Caveats;
p.(None):
p.(None): 4. A declaration by the submitting party on the accuracy of the submitted information.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/71
p.(None):
p.(None): ANNEX V
p.(None):
p.(None): CONTENT OF THE SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL FOR LAYPERSONS
p.(None):
p.(None): The summary of the results of the clinical trial for laypersons shall contain information on the following elements:
p.(None): 1. Clinical trial identification (including title of the trial, protocol number, EU trial number and other
p.(None): identifiers);
p.(None): 2. Name and contact details of the sponsor;
p.(None): 3. General information about the clinical trial (including where and when the trial was conducted, the main
p.(None): objectives of the trial and an explanation of the reasons for conducting it);
p.(None): 4. Population of subjects (including information on the number of subjects included in the trial in
p.(None): the Member State concerned, in the Union and in third countries; age group breakdown and gender
p.(None): breakdown; inclusion and exclu sion criteria);
p.(None): 5. Investigational medicinal products used;
p.(None): 6. Description of adverse reactions and their frequency;
p.(None): 7. Overall results of the clinical trial;
p.(None): 8. Comments on the outcome of the clinical trial;
p.(None): 9. Indication if follow up clinical trials are foreseen;
p.(None): 10. Indication where additional information could be found.
p.(None):
p.(None): L 158/72 EN
p.(None): Official Journal of the European Union
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Political / vulnerable
Searching for indicator vulnerable:
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p.(None): the Governance of Clinical Trials of 10 December 2012 introduced different risk categories for clinical
p.(None): trials. Those categories are compatible with the categories of clinical trials defined in this Regulation as the OECD
p.(None): Categories A and B(1) correspond to the definition of a low-intervention clinical trial as set out in
p.(None): this Regulation, and the OECD Categories B(2) and C correspond to the definition of a clinical trial as set out in
p.(None): this Regulation.
p.(None):
p.(None):
p.(None): (13) The assessment of the application for a clinical trial should address in particular the
p.(None): anticipated therapeutic and public health benefits (relevance) and the risk and inconvenience for the
p.(None): subject. In respect of the relevance, various aspects should be taken into account, including whether the
p.(None): clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment of
p.(None): medicinal products and the authorisation of their placing on the market and whether surrogate end-points, when
p.(None): they are used, are justified.
p.(None):
p.(None):
p.(None): (14) Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent
p.(None): the popula tion groups, for example gender and age groups, that are likely to use the medicinal product
p.(None): investigated in the clinical trial.
p.(None):
p.(None):
p.(None): (15) In order to improve treatments available for vulnerable groups such as frail or older people,
p.(None): people suffering from multiple chronic conditions, and people affected by mental health disorders,
p.(None): medicinal products which are likely to be of significant clinical value should be fully and appropriately
p.(None): studied for their effects in these specific groups, including as regards requirements related to their
p.(None): specific characteristics and the protection of the health and well-being of subjects belonging to these groups.
p.(None):
p.(None):
p.(None): (16) The authorisation procedure should provide for the possibility to extend the timelines for the assessment
p.(None): in order to allow the sponsor to address questions or comments raised during the assessment of the
p.(None): application dossier. Moreover, it should be ensured that, within the extension period, there is always
p.(None): sufficient time for assessing the additional information submitted.
p.(None):
p.(None):
p.(None): (17) The authorisation to conduct a clinical trial should address all aspects of subject protection
p.(None): and data reliability and robustness. That authorisation should therefore be contained in a single
p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
p.(None): (18) It should be left to the Member State concerned to determine the appropriate body or bodies
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
...
p.(None): paragraph 1.
p.(None):
p.(None): 9. If no subject has been included in the clinical trial in a Member State concerned within two years from the
p.(None): notifica tion date of the authorisation, the authorisation shall expire in that Member State concerned
p.(None): unless an extension, on request of the sponsor, has been approved following the procedure set out in Chapter III.
p.(None):
p.(None):
p.(None): Article 9
p.(None):
p.(None): Persons assessing the application
p.(None):
p.(None): 1. Member States shall ensure that the persons validating and assessing the application do not have
p.(None): conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators
p.(None): involved and of persons financing the clinical trial, as well as free of any other undue influence.
p.(None):
p.(None): In order to guarantee independence and transparency, the Member States shall ensure that persons
p.(None): admitting and asses sing the application as regards the aspects addressed in Parts I and II of the
p.(None): assessment report have no financial or personal interests which could affect their impartiality. These persons
p.(None): shall make an annual declaration of their financial interests.
p.(None):
p.(None): 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who
p.(None): collectively have the necessary qualifications and experience.
p.(None):
p.(None): 3. At least one layperson shall participate in the assessment.
p.(None):
p.(None):
p.(None): Article 10
p.(None):
p.(None): Specific considerations for vulnerable populations
p.(None):
p.(None): 1. Where the subjects are minors, specific consideration shall be given to the assessment of the
p.(None): application for authorisation of a clinical trial on the basis of paediatric expertise or after taking
p.(None): advice on clinical, ethical and psycho social problems in the field of paediatrics.
p.(None):
p.(None): L 158/20 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the
p.(None): applica tion for authorisation of a clinical trial on the basis of expertise in the relevant disease
p.(None): and the patient population concerned or after taking advice on clinical, ethical and psychosocial
p.(None): questions in the field of the relevant disease and the patient population concerned.
p.(None):
p.(None): 3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the
p.(None): assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant
p.(None): condition and the population represented by the subject concerned.
p.(None):
p.(None): 4. If according to the protocol a clinical trial provides for the participation of specific groups
p.(None): or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of
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Health / Drug Dependence
Searching for indicator dependency:
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p.(None): for instance through audio or video recorders. Prior to obtaining informed consent, the potential subject
p.(None): should receive information in a prior interview in a language which is easily understood by him or her. The
p.(None): subject should have the opportunity to ask questions at any moment. Adequate time should be provided for
p.(None): the subject to consider his or her deci sion. In view of the fact that in certain Member States the only person
p.(None): qualified under national law to perform an interview with a potential subject is a medical doctor while in
p.(None): other Member States this is done by other profes sionals, it is appropriate to provide that the prior
p.(None): interview with a potential subject should be performed by a member of the investigating team qualified
p.(None): for this task under the national law of the Member State where the recruitment takes place.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/5
p.(None):
p.(None): (31) In order to certify that informed consent is given freely, the investigator should take into
p.(None): account all relevant circumstances which might influence the decision of a potential subject to participate in a
p.(None): clinical trial, in particu lar whether the potential subject belongs to an economically or socially
p.(None): disadvantaged group or is in a situation of institutional or hierarchical dependency that could inappropriately
p.(None): influence her or his decision to participate.
p.(None):
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
p.(None): pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior
p.(None): to the intervention. This Regulation should therefore set clear rules whereby such patients may be enrolled in the
p.(None): clinical trial under very strict condi tions. In addition, the said clinical trial should relate directly
p.(None): to the medical condition because of which it is not possible within the therapeutic window to obtain
p.(None): prior informed consent from the subject or from his or her legally designated representative. Any
p.(None): previously expressed objection by the patient should be respected, and informed consent from the subject
p.(None): or from his or her legally designated representative should be sought as soon as possible.
p.(None):
p.(None):
...
Health / Drug Usage
Searching for indicator influence:
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p.(None):
p.(None):
p.(None): (30) In accordance with international guidelines, the informed consent of a subject should be in
p.(None): writing. When the subject is unable to write, it may be recorded through appropriate alternative means,
p.(None): for instance through audio or video recorders. Prior to obtaining informed consent, the potential subject
p.(None): should receive information in a prior interview in a language which is easily understood by him or her. The
p.(None): subject should have the opportunity to ask questions at any moment. Adequate time should be provided for
p.(None): the subject to consider his or her deci sion. In view of the fact that in certain Member States the only person
p.(None): qualified under national law to perform an interview with a potential subject is a medical doctor while in
p.(None): other Member States this is done by other profes sionals, it is appropriate to provide that the prior
p.(None): interview with a potential subject should be performed by a member of the investigating team qualified
p.(None): for this task under the national law of the Member State where the recruitment takes place.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/5
p.(None):
p.(None): (31) In order to certify that informed consent is given freely, the investigator should take into
p.(None): account all relevant circumstances which might influence the decision of a potential subject to participate in a
p.(None): clinical trial, in particu lar whether the potential subject belongs to an economically or socially
p.(None): disadvantaged group or is in a situation of institutional or hierarchical dependency that could inappropriately
p.(None): influence her or his decision to participate.
p.(None):
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
...
p.(None):
p.(None):
p.(None): (45) The individuals involved in conducting a clinical trial, in particular investigators and other
p.(None): healthcare profes sionals, should be sufficiently qualified to perform their tasks, and the facilities
p.(None): where a clinical trial is to be conducted should be suitable for that clinical trial.
p.(None):
p.(None):
p.(None): (46) In order to ensure subject safety and the reliability and robustness of data from clinical trials,
p.(None): it is appropriate to provide that there should be arrangements for traceability, storage, return and destruction of
p.(None): investigational medi cinal products, depending on the nature of the clinical trial. For the same reasons,
p.(None): there should also be such arrangements for unauthorised auxiliary medicinal products.
p.(None):
p.(None):
p.(None): (47) During a clinical trial, a sponsor may become aware of serious breaches of the rules for the conduct of
p.(None): that clin ical trial. This should be reported to the Member States concerned in order for action to be
p.(None): taken by those Member States, where necessary.
p.(None):
p.(None):
p.(None): (48) Apart from the reporting of suspected unexpected serious adverse reactions, there may be other events which
p.(None): are relevant in terms of benefit-risk balance and which should be reported in a timely manner to the
p.(None): Member States concerned. It is important for subject safety that, in addition to serious adverse events
p.(None): and reactions, all unex pected events that might materially influence the benefit-risk assessment of the
p.(None): medicinal product or that would lead to changes in the administration of a medicinal product or in
p.(None): overall conduct of a clinical trial are notified to the Member States concerned. Examples of such
p.(None): unexpected events include an increase in the rate of occur rence of expected serious adverse reactions
p.(None): which may be clinically important, a significant hazard to the patient population, such as lack of efficacy
p.(None): of a medicinal product, or a major safety finding from a newly completed animal study (such as
p.(None): carcinogenicity).
p.(None):
p.(None):
p.(None): (49) Where unexpected events require an urgent modification of a clinical trial, it should be
p.(None): possible for the sponsor and the investigator to take urgent safety measures without awaiting prior authorisation.
p.(None): If such measures consti tute a temporary halt of the clinical trial, the sponsor should apply for a substantial
p.(None): modification before restarting the clinical trial.
p.(None):
p.(None):
p.(None): (50) In order to ensure compliance of the conduct of a clinical trial with the protocol, and in
p.(None): order for investigators to be informed about the investigational medicinal products they administer, the sponsor
p.(None): should supply the inves tigators with an investigator's brochure.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/7
p.(None):
p.(None): (51) The information generated in a clinical trial should be recorded, handled and stored adequately
...
p.(None): pro cedures followed to identify the urgency of the situation and to document it;
p.(None):
p.(None): (e) in the case of clinical trials where their methodology requires that groups of subjects rather than individual
p.(None): subjects are allocated to receive different investigational medicinal products, as referred to in Article
p.(None): 30, and where, as a consequence, simplified means for obtaining informed consent will be used, the simplified
p.(None): means shall be described.
p.(None):
p.(None): 63. In the cases set out in paragraph 62, the information given to the subject and to his or her
p.(None): legally designated representative shall be submitted.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/63
p.(None):
p.(None): M. SUITABILITY OF THE INVESTIGATOR (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 64. A list of the planned clinical trial sites, the name and position of the principal investigators
p.(None): and the planned number of subjects at the sites shall be submitted.
p.(None):
p.(None): 65. Description of the qualification of the investigators in a current curriculum vitae and other relevant
p.(None): documents shall be submitted. Any previous training in the principles of good clinical practice or
p.(None): experience obtained from work with clinical trials and patient care shall be described.
p.(None):
p.(None): 66. Any conditions, such as economic interests and institutional affiliations, that might influence the
p.(None): impartiality of the investigators shall be presented.
p.(None):
p.(None): N. SUITABILITY OF THE FACILITIES (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 67. A duly justified written statement on the suitability of the clinical trial sites adapted to the
p.(None): nature and use of the investigational medicinal product and including a description of the suitability of
p.(None): facilities, equipment, human resources and description of expertise, issued by the head of the
p.(None): clinic/institution at the clinical trial site or by some other responsible person, according to the
p.(None): system in the Member State concerned, shall be submitted.
p.(None):
p.(None): O. PROOF OF INSURANCE COVER OR INDEMNIFICATION (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 68. Proof of insurance, a guarantee, or a similar arrangement shall be submitted, if applicable.
p.(None):
p.(None): P. FINANCIAL AND OTHER ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 69. A brief description of the financing of the clinical trial.
p.(None):
p.(None): 70. Information on financial transactions and compensation paid to subjects and investigator/site for
p.(None): participating in the clinical trial shall be submitted.
p.(None):
p.(None): 71. Description of any other agreement between the sponsor and the site shall be submitted.
p.(None):
p.(None): Q. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 72. Proof of payment shall be submitted, if applicable.
p.(None):
p.(None): R. PROOF THAT DATA WILL BE PROCESSED IN COMPLIANCE WITH UNION LAW ON DATA PROTECTION
p.(None):
...
Searching for indicator substance:
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p.(None): the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send
p.(None): a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an
p.(None): impact on the benefit-risk balance of the clinical trial.
p.(None):
p.(None): 3. The sponsor shall keep detailed records of all adverse events reported to it by the investigator.
p.(None):
p.(None): 4. If the investigator becomes aware of a serious adverse event with a suspected causal
p.(None): relationship to the investiga tional medicinal product that occurs after the end of the clinical trial in a
p.(None): subject treated by him or her, the investigator shall, without undue delay, report the serious adverse event to the
p.(None): sponsor.
p.(None):
p.(None):
p.(None): Article 42
p.(None):
p.(None): Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency
p.(None):
p.(None): 1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without
p.(None): delay to the database referred to in Article 40(1) all relevant information about the following suspected
p.(None): unexpected serious adverse reactions.:
p.(None): (a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in
p.(None): that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred
p.(None): at a clinical trial site in the Union or in a third country;
p.(None): (b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of
p.(None): pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical
p.(None): trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:
p.(None): (i) by that sponsor, or
p.(None): (ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical
p.(None): trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the
p.(None): sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product
p.(None): or information to a future potential marketing authorisation holder on safety matters shall not be
p.(None): considered a joint development; and
p.(None): (c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in
p.(None): any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after
p.(None): the end of the clin ical trial.
p.(None): 2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency
p.(None): shall take account of the seriousness of the reaction and shall be as follows:
p.(None): (a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and
p.(None): in any event not later than seven days after the sponsor became aware of the reaction;
p.(None): (b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not
p.(None): later than 15 days after the sponsor became aware of the reaction;
...
p.(None): for specific clinical trials. It shall also facilitate the communication between sponsors and Member States
p.(None): concerned and enable sponsors to refer to previous submissions of an application for authorisation of a
p.(None): clinical trial or a substantial modification. It shall also enable citizens of the Union to have access
p.(None): to clinical information about medicinal products. To this end all data held in the EU database shall be
p.(None): in an easily searchable format, all related data shall be grouped together by way of the EU trial
p.(None): number, and hyperlinks shall be provided to link together related data and documents held on the EU
p.(None): database and other databases managed by the Agency.
p.(None):
p.(None): 3. The EU database shall support the recording and submission to the Medicinal Product Dictionary, contained in
p.(None): the Eudravigilance database, of all the data on medicinal products without a marketing authorisation in
p.(None): the Union and substances not authorised as part of a medicinal product in the Union, that are necessary
p.(None): for the maintenance of that dictionary. To this effect and also with the purpose of enabling the
p.(None): sponsor to cross-refer to prior applications, an EU medicinal product number shall be issued for every
p.(None): medicinal product without a marketing authorisation and an EU active substances code shall be issued for
p.(None): each new active substance not previously authorised as part of a medicinal product in the Union. This shall
p.(None): be done before or during the application for authorisation of the first clinical trial with that product or active
p.(None): substance submitted in accordance with this Regulation. Those numbers shall be mentioned in all subsequent applications
p.(None): for clinical trials and for substantial modifications.
p.(None):
p.(None): The data submitted, in accordance with the first subparagraph, describing medicinal products and
p.(None): substances shall comply with Union and international standards for the identification of medicinal products and
p.(None): active substances. When an investigational medicinal product which already has a marketing authorisation
p.(None): in the Union and/or an active substance which is part of a medicinal product with a marketing
p.(None): authorisation in the Union, is to be used in a clinical trial, the relevant product and active substance
p.(None): numbers shall be referred to in the application for that clinical trial.
p.(None):
p.(None): 4. The EU database shall be publicly accessible unless, for all or part of the data and
p.(None): information contained therein, confidentiality is justified on any of the following grounds:
p.(None):
p.(None): (a) protecting personal data in accordance with Regulation (EC) No 45/2001;
p.(None):
p.(None): (b) protecting commercially confidential information, in particular through taking into account the
p.(None): status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in
p.(None): disclosure;
p.(None):
p.(None): (c) protecting confidential communication between Member States in relation to the preparation of the
p.(None): assessment report;
p.(None):
p.(None): (d) ensuring effective supervision of the conduct of a clinical trial by Member States.
p.(None):
p.(None): 5. Without prejudice to paragraph 4, unless there is an overriding public interest in disclosure,
p.(None): data contained in the application dossier shall not be publicly accessible before the decision on the clinical trial
p.(None): has been made.
p.(None):
p.(None): 6. The EU database shall contain personal data only insofar as this is necessary for the purposes of paragraph
p.(None): 2.
p.(None):
p.(None): 7. No personal data of subjects shall be publicly accessible.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/49
p.(None):
p.(None): 8. The user interface of the EU database shall be available in all official languages of the Union.
p.(None):
...
p.(None):
p.(None): (b) the attached documents contain an accurate account of the information available;
p.(None):
p.(None): (c) the clinical trial is to be conducted in accordance with the protocol; and
p.(None):
p.(None): (d) the clinical trial is to be conducted in accordance with this Regulation.
p.(None):
p.(None): 4. The application dossier for an application limited to Part I of the assessment report referred to
p.(None): in Article 11 shall be limited to sections B to J and Q of this Annex.
p.(None):
p.(None): 5. Without prejudice to Article 26, the application dossier for an application limited to Part II of
p.(None): the assessment report referred to in Article 11 and the application dossier for an application referred to in
p.(None): Article 14 shall be limited to sections K to R of this Annex.
p.(None):
p.(None):
p.(None): B. COVER LETTER
p.(None):
p.(None): 6. The cover letter shall specify the EU trial number and the universal trial number and shall draw
p.(None): attention to any features which are particular to the clinical trial.
p.(None):
p.(None): 7. However, in the cover letter it is not necessary to reproduce information already contained in
p.(None): the EU applica tion form, with the following exceptions:
p.(None):
p.(None): (a) specific features of the clinical trial population, such as subjects not able to give informed consent,
p.(None): minors and pregnant or breastfeeding women;
p.(None):
p.(None): (b) whether the clinical trial involves the first administration of a new active substance to humans;
p.(None):
p.(None): (c) whether scientific advice relating to the clinical trial or the investigational medicinal product
p.(None): has been given by the Agency, a Member State or a third country;
p.(None):
p.(None): (d) whether the clinical trial is part or is intended to be part of a Paediatric Investigation Plan (PIP) as
p.(None): referred to in Title II, Chapter 3, of Regulation (EC) No 1901/2006 (if the Agency has already issued a
p.(None): decision on the PIP, the cover letter contains the link to the decision of the Agency on its website);
p.(None):
p.(None): (e) whether investigational medicinal products or auxiliary medicinal products are a narcotic,
p.(None): psychotropic or radiopharmaceutical;
p.(None):
p.(None): (f) whether the investigational medicinal products consist of or contain a genetically-modified organism
p.(None): or organisms;
p.(None):
p.(None): (g) whether the sponsor has obtained an orphan designation for the investigational medicinal product for
p.(None): an orphan condition;
p.(None):
p.(None): (h) a comprehensive list, including the regulatory status, of all investigational medicinal products and
p.(None): a list of all auxiliary medicinal products; and
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/55
p.(None):
p.(None): (i) a list of medical devices which are to be investigated in the clinical trial but which are not part of the
p.(None): inves tigational medicinal product or products, together with a statement as to whether the medical
p.(None): devices are CE-marked for the intended use.
...
p.(None): assessing, recording, and analysing these parameters;
p.(None):
p.(None): (ag) a description of ethical considerations relating to the clinical trial if those have not been
p.(None): described else where;
p.(None):
p.(None): (ah) a statement from the sponsor (either in the protocol or in a separate document) confirming that
p.(None): the investigators and institutions involved in the clinical trial are to permit clinical trial-related
p.(None): monitoring, audits and regulatory inspections, including provision of direct access to source data and documents;
p.(None):
p.(None): (ai) a description of the publication policy;
p.(None):
p.(None): (aj) duly substantiated reasons for the submission of the summary of the results of the clinical
p.(None): trials after more than one year;
p.(None):
p.(None): (ak) a description of the arrangements to comply with the applicable rules on the protection of personal data; in
p.(None): particular organisational and technical arrangements that will be implemented to avoid unauthorised access,
p.(None): disclosure, dissemination, alteration or loss of information and personal data processed;
p.(None):
p.(None): (al) a description of measures that will be implemented to ensure confidentiality of records and personal data of
p.(None): subjects;
p.(None):
p.(None): (am) a description of measures that will be implemented in case of data security breach in order to
p.(None): mitigate the possible adverse effects.
p.(None):
p.(None): 18. If a clinical trial is conducted with an active substance available in the Union under different
p.(None): trade names in a number of authorised medicinal products, the protocol may define the treatment in terms
p.(None): of the active substance or Anatomical Therapeutic Chemical (ATC) code (level 3-5) only and not specify
p.(None): the trade name of each product.
p.(None):
p.(None): L 158/58 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 19. With regard to the notification of adverse events, the protocol shall identify the categories of:
p.(None):
p.(None): (a) adverse events or laboratory anomalies that are critical to safety evaluations and must be reported
p.(None): by the investigator to the sponsor, and
p.(None):
p.(None): (b) serious adverse events which do not require immediate reporting by the investigator to the sponsor.
p.(None):
p.(None): 20. The protocol shall describe the procedures for:
p.(None):
p.(None): (a) eliciting and recording adverse events by the investigator, and the reporting of relevant adverse
p.(None): events by the investigator to the sponsor;
p.(None):
p.(None): (b) reporting by the investigator to the sponsor of those serious adverse events which have been
p.(None): identified in the protocol as not requiring immediate reporting;
p.(None):
p.(None): (c) reporting of suspected unexpected serious adverse reactions by the sponsor to the Eudravigilance database; and
p.(None):
p.(None): (d) follow-up of subjects after adverse reactions including the type and duration of follow-up.
p.(None):
p.(None): 21. In case the sponsor intends to submit a single safety report on all investigational medicinal
p.(None): products used in the clinical trial in accordance with Article 43(2), the protocol shall indicate the reasons
p.(None): thereof.
p.(None):
...
p.(None): international guidance, shall be submitted.
p.(None):
p.(None): 26. The purpose of the IB is to provide the investigators and others involved in the clinical trial
p.(None): with information to facilitate their understanding of the rationale for, and their compliance with, key
p.(None): features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety
p.(None): monitoring procedures.
p.(None):
p.(None): 27. The information in the IB shall be presented in a concise, simple, objective, balanced and
p.(None): non-promotional form that enables a clinician or investigator to understand it and make an unbiased
p.(None): risk-benefit assessment of the appropriateness of the proposed clinical trial. It shall be prepared from
p.(None): all available information and evidence that supports the rationale for the proposed clinical trial and the safe use
p.(None): of the investigational medi cinal product in the clinical trial and be presented in the form of summaries.
p.(None):
p.(None): 28. If the investigational medicinal product is authorised, and is used in accordance with the terms
p.(None): of the marketing authorisation, the approved summary of product characteristics (SmPC) shall be the IB. If the
p.(None): condi tions of use in the clinical trial differ from those authorised, the SmPC shall be supplemented with a summary
p.(None): of relevant non-clinical and clinical data that support the use of the investigational medicinal product
p.(None): in the clinical trial. Where the investigational medicinal product is identified in the protocol only by
p.(None): its active substance, the sponsor shall select one SmPC as equivalent to the IB for all medicinal
p.(None): products that contain that active substance and are used at any clinical trial site.
p.(None):
p.(None): 29. For a multinational clinical trial where the medicinal product to be used in each Member State
p.(None): concerned is authorised at national level, and the SmPC varies among Member States concerned, the sponsor
p.(None): shall choose one SmPC for the whole clinical trial. This SmPC shall be the one best suited to ensure patient safety.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/59
p.(None):
p.(None): 30. If the IB is not an SmPC, it shall contain a clearly identifiable section called the ‘Reference
p.(None): Safety Information’ (RSI). In accordance with paragraphs 10 and 11 of Annex III, the RSI shall contain product
p.(None): information on the investigational medicinal product and on how to determine what adverse reactions are to
p.(None): be considered as expected adverse reactions, and on the frequency and nature of those adverse reactions.
p.(None):
p.(None):
p.(None): F. DOCUMENTATION RELATING TO COMPLIANCE WITH GOOD MANUFACTURING PRACTICE (GMP) FOR THE INVESTIGA
p.(None): TIONAL MEDICINAL PRODUCT
p.(None):
p.(None): 31. As regards documentation relating to GMP compliance, the following shall apply.
p.(None):
p.(None): 32. No documentation needs to be submitted where the investigational medicinal product is authorised and is
p.(None): not modified, whether or not it is manufactured in the Union.
p.(None):
p.(None): 33. If the investigational medicinal product is not authorised, and does not have a marketing authorisation
...
p.(None): aspect of the pre-clinical data or clinical data that requires a detailed expert explanation or discussion beyond
p.(None): what would usually be included in the IB, the pre-clinical and clinical information shall be submitted as part of the
p.(None): IMPD.
p.(None):
p.(None):
p.(None): Possibility of referring to the SmPC
p.(None):
p.(None): 52. The applicant may submit the version of the SmPC valid at the time of application, as the IMPD if the
p.(None): investi gational medicinal product is authorised. The exact requirements are detailed in Table 1. Where
p.(None): new data are provided, it should be clearly identified.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/61
p.(None):
p.(None): Table 1: Content of the simplified IMPD
p.(None):
p.(None):
p.(None): Types of previous assessment
p.(None): The investigational medicinal product is authorised or has a marketing authorisation in an ICH country and is
p.(None): used in the clinical trial:
p.(None): — within the conditions of the SmPC
p.(None): — outside the conditions of the SmPC
p.(None): — after modification (for example blinding)
p.(None): Another pharmaceutical form or strength of the inves tigational medicinal product is authorised or
p.(None): has a marketing authorisation in an ICH country and the investigational medicinal product is
p.(None): supplied by the marketing authorisation holder
p.(None): The investigational medicinal product is not authorised and has no marketing authorisation in an ICH
p.(None): country but the active substance is contained in an authorised medicinal product, and
p.(None): — is supplied by the same manufacturer
p.(None): — is supplied by another manufacturer
p.(None): The investigational medicinal product was subject to a previous clinical trial application and authorised
p.(None): in the Member State concerned and has not been modified, and
p.(None): Quality data
p.(None):
p.(None):
p.(None):
p.(None): SmPC SmPC P+A
p.(None): SmPC+P+A
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): SmPC+P+A SmPC+S+P+A
p.(None): Non-clinical data
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): If appropriate SmPC
p.(None): Yes
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): Yes Yes
p.(None): Clinical data
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): If appropriate SmPC
p.(None): Yes
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): Yes Yes
p.(None):
p.(None): — no new data are available since last amendment to the clinical trial application,
p.(None): — new data are available since last amendment to the clinical trial application,
p.(None): — is used under different conditions
p.(None): Reference to previous submission
p.(None):
p.(None): New data New data New data
p.(None):
p.(None): If appropriate If appropriate If appropriate
p.(None):
p.(None): (S: Data relating to the active substance; P: Data relating to the investigational medicinal product; A: Additional
p.(None): information on Facilities and Equipment, Adventitious Agents Safety Evaluation, Novel Excipients, and Solvents for
p.(None): Reconstitution and Diluents)
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): 53. If the investigational medicinal product is defined in the protocol in terms of active substance or
p.(None): ATC code (see above, paragraph 18), the applicant may replace the IMPD by one representative SmPC for
p.(None): each active substance/active substance pertaining to that ATC group. Alternatively, the applicant may
p.(None): provide a collated document containing information equivalent to that in the representative SmPCs for each active
p.(None): substance that could be used as an investigational medicinal product in the clinical trial.
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): 1.3. IMPD in cases of placebo
p.(None):
p.(None):
p.(None):
p.(None): 54. If the investigational medicinal product is a placebo, the information requirements shall be limited
p.(None): to quality data. No additional documentation is required if the placebo has the same composition as the tested
p.(None): investiga tional medicinal product (with the exception of the active substance), is manufactured by the
p.(None): same manufac turer, and is not sterile.
p.(None):
p.(None): L 158/62 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): H. AUXILIARY MEDICINAL PRODUCT DOSSIER
p.(None):
p.(None): 55. Without prejudice to Article 65, the documentation requirements set out in sections F and G shall
p.(None): also apply to auxiliary medicinal products. However, where the auxiliary medicinal product is authorised
p.(None): in the Member State concerned, no additional information is required.
p.(None):
p.(None):
p.(None): I. SCIENTIFIC ADVICE AND PAEDIATRIC INVESTIGATION PLAN (PIP)
p.(None):
p.(None): 56. If available, a copy of the summary of scientific advice of the Agency, or of any Member State or third country,
p.(None): with regard to the clinical trial shall be submitted.
p.(None):
p.(None): 57. If the clinical trial is part of an agreed PIP, a copy of the Agency's decision on the agreement
p.(None): on the PIP, and the opinion of the Paediatric Committee, unless these documents are fully accessible
p.(None): via the internet shall be submitted. In the latter case, a link to this documentation in the cover letter is
p.(None): sufficient (see section B).
p.(None):
p.(None):
p.(None): J. CONTENT OF THE LABELLING OF THE INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): 58. A description of the content of the labelling of the investigational medicinal product in accordance
p.(None): with Annex VI shall be provided.
p.(None):
p.(None):
p.(None): K. RECRUITMENT ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
...
p.(None): and abuse of the product, shall be subject to the same obligation to report as adverse reactions.
p.(None):
p.(None): 3. In determining whether an adverse event is an adverse reaction, consideration shall be given to
p.(None): whether there is a reasonable possibility of establishing a causal relationship between the event and the
p.(None): investigational medi cinal product based on an analysis of available evidence.
p.(None):
p.(None): 4. In the absence of information on causality provided by the reporting investigator, the sponsor shall consult the
p.(None): reporting investigator and encourage him to express an opinion on this issue. The causality assessment
p.(None): given by the investigator shall not be downgraded by the sponsor. If the sponsor disagrees with the
p.(None): investigator's causality assessment, the opinion of both the investigator and the sponsor shall be provided with the
p.(None): report.
p.(None):
p.(None): 2.2. Expectedness, unexpectedness and the RSI
p.(None): 5. In determining whether an adverse event is unexpected, consideration shall be given to whether the event adds
p.(None): significant information on the specificity, increase of occurrence, or severity of a known, already
p.(None): documented serious adverse reaction.
p.(None):
p.(None): 6. The expectedness of an adverse reaction shall be set out by the sponsor in the RSI. Expectedness shall be deter
p.(None): mined on the basis of events previously observed with the active substance and not on the basis of the
p.(None): antici pated pharmacological properties of a medicinal product or events related to the subject's disease.
p.(None):
p.(None): 7. The RSI shall be contained in the SmPC or the IB. The covering letter shall refer to the
p.(None): location of the RSI in the application dossier. If the investigational medicinal product is
p.(None): authorised in several Member States concerned with different SmPCs, the sponsor shall select the most
p.(None): appropriate SmPC, with reference to subject safety, as the RSI.
p.(None):
p.(None): 8. The RSI may change during the conduct of a clinical trial. For the purpose of reporting SUSARs the version of
p.(None): the RSI at the moment of occurrence of the SUSAR shall apply. Thus, a change of the RSI impacts on
p.(None): the number of adverse reactions to be reported as SUSARs. Regarding the applicable RSI for the purpose
p.(None): of the annual safety report, see section 3 of this Annex.
p.(None):
p.(None): 9. If information on expectedness has been provided by the reporting investigator, this shall be taken into consid
p.(None): eration by the sponsor.
p.(None):
p.(None): 2.3. Information for the reporting of SUSARs
p.(None): 10. The information shall at least include:
p.(None): (a) a valid EU trial number;
p.(None): (b) a sponsor study number;
p.(None): (c) an identifiable coded subject;
p.(None): (d) an identifiable reporter;
p.(None): (e) a SUSAR;
p.(None): (f) a suspect investigational medicinal product (including active substance name-code);
p.(None): (g) a causality assessment.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/67
p.(None):
p.(None): 11. In addition, in order to properly process the report electronically, the following administrative
p.(None): information shall be provided:
p.(None): (a) the sender's (case) safety report unique identifier;
p.(None): (b) the receive date of the initial information from the primary source;
p.(None): (c) the receipt date of the most recent information;
p.(None): (d) the worldwide unique case identification number;
p.(None): (e) the sender identifier.
p.(None):
p.(None): 2.4. Follow-up reports of SUSARs
p.(None): 12. If the initial report of a SUSAR referred to in point (a) of Article 42(2) (fatal or
p.(None): life-threatening) is incomplete, for example if the sponsor has not provided all the information within
p.(None): seven days, the sponsor shall submit a completed report based on the initial information within an additional
p.(None): eight days.
p.(None):
p.(None): 13. The clock for initial reporting (day 0 = Di 0) starts as soon as the information containing the
p.(None): minimum reporting criteria has been received by the sponsor.
p.(None):
p.(None): 14. If significant new information on an already reported case is received by the sponsor, the clock
p.(None): starts again at day zero, that is the date of receipt of the new information. This information shall
p.(None): be reported as a follow-up report within 15 days.
p.(None):
p.(None): 15. If the initial report of a SUSAR referred to in Article 42(2)(c) (initially considered to be
...
p.(None): 4. Population of subjects (including information on the number of subjects included in the trial in
p.(None): the Member State concerned, in the Union and in third countries; age group breakdown and gender
p.(None): breakdown; inclusion and exclu sion criteria);
p.(None): 5. Investigational medicinal products used;
p.(None): 6. Description of adverse reactions and their frequency;
p.(None): 7. Overall results of the clinical trial;
p.(None): 8. Comments on the outcome of the clinical trial;
p.(None): 9. Indication if follow up clinical trials are foreseen;
p.(None): 10. Indication where additional information could be found.
p.(None):
p.(None): L 158/72 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX VI
p.(None):
p.(None): LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): A. UNAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): A.1. General rules
p.(None):
p.(None): 1. The following particulars shall appear on the immediate and the outer packaging:
p.(None):
p.(None): (a) name, address and telephone number of the main contact for information on the product, clinical
p.(None): trial and emergency unblinding; this may be the sponsor, contract research organisation or investigator (for the
p.(None): purpose of this Annex this is referred to as the 'main contact');
p.(None):
p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
p.(None): both the unauthorised investigational medicinal product and the comparator or placebo;
p.(None):
p.(None): (c) pharmaceutical form, route of administration, quantity of dosage units;
p.(None):
p.(None): (d) the batch or code number identifying the contents and packaging operation;
p.(None):
p.(None): (e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None):
p.(None): (f) the subject identification number and/or the treatment number and, where relevant, the visit number;
p.(None):
p.(None): (g) the name of the investigator (if not included in (a) or (e));
p.(None):
p.(None): (h) directions for use (reference may be made to a leaflet or other explanatory document intended for
p.(None): the subject or person administering the product);
p.(None):
p.(None): (i) 'For clinical trial use only' or similar wording;
p.(None):
p.(None): (j) the storage conditions;
p.(None):
p.(None): (k) period of use (expiry date or re-test date as applicable), in month and year format and in a
p.(None): manner that avoids any ambiguity; and
p.(None):
p.(None): (l) 'Keep out of reach of children', except when the product is for use in trials where the product is not taken
p.(None): home by subjects.
p.(None):
p.(None): 2. Symbols or pictograms may be included to clarify certain information mentioned above. Additional
p.(None): informa tion, warnings or handling instructions may be displayed.
p.(None):
...
Health / Healthy People
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p.(None): and risks to allow assessment in accordance with Article 6; for subjects in a clinical trial in an
p.(None): emer gency situation, the scientific grounds for expecting that the participation of the subjects has the potential to
p.(None): produce a direct clinically relevant benefit shall be documented;
p.(None): (e) where patients were involved in the design of the clinical trial, a description of their involvement;
p.(None):
p.(None): L 158/56 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (f) a description of, and justification for, the dosage, the dosage regime, the route and mode of
p.(None): administra tion, and the treatment period for all investigational medicinal products and auxiliary medicinal products;
p.(None):
p.(None): (g) a statement of whether the investigational medicinal products and auxiliary medicinal products
p.(None): used in the clinical trial are authorised; if authorised, whether they are to be used in the clinical
p.(None): trial in accord ance with the terms of their marketing authorisations, and, if not authorised, a justification for
p.(None): the use of non-authorised auxiliary medicinal products in the clinical trial;
p.(None):
p.(None): (h) a description of the groups and subgroups of the subjects participating in the clinical trial,
p.(None): including, where relevant, groups of subjects with specific needs, for example. age, gender, participation
p.(None): of healthy volunteers, subjects with rare and ultra rare diseases;
p.(None):
p.(None): (i) references to literature and data that are relevant to the clinical trial, and that provide background for
p.(None): the clinical trial;
p.(None):
p.(None): (j) a discussion of the relevance of the clinical trial in order to allow assessment in accordance with Article
p.(None): 6;
p.(None):
p.(None): (k) a description of the type of clinical trial to be conducted and a discussion of the trial design
p.(None): (including a schematic diagram of trial design, procedures and stages, if relevant);
p.(None):
p.(None): (l) a specification of the primary end-points and the secondary end-points, if any, to be measured during the
p.(None): clinical trial;
p.(None):
p.(None): (m) a description of the measures taken to minimise bias, including, if applicable,
p.(None): randomisation and blinding;
p.(None):
p.(None): (n) a description of the expected duration of subject participation and a description of the sequence and dur
p.(None): ation of all clinical trial periods, including follow-up, if relevant;
p.(None):
p.(None): (o) a clear and unambiguous definition of the end of the clinical trial in question and, if it is not the
p.(None): date of the last visit of the last subject, a specification of the estimated end date and a justification thereof;
p.(None):
p.(None): (p) a description of the criteria for discontinuing parts of the clinical trial or the entire clinical trial;
p.(None):
p.(None): (q) arrangements for the maintenance of clinical trial treatment randomisation codes and procedures
p.(None): for breaking codes, if relevant;
p.(None):
p.(None): (r) a description of procedures for the identification of data to be recorded directly on the Case
p.(None): Report Forms considered as source data;
p.(None):
...
Health / Mentally Disabled
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p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
p.(None): pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior
p.(None): to the intervention. This Regulation should therefore set clear rules whereby such patients may be enrolled in the
p.(None): clinical trial under very strict condi tions. In addition, the said clinical trial should relate directly
p.(None): to the medical condition because of which it is not possible within the therapeutic window to obtain
p.(None): prior informed consent from the subject or from his or her legally designated representative. Any
...
p.(None):
p.(None): (30) ‘Good clinical practice’ means a set of detailed ethical and scientific quality requirements for designing,
p.(None): conducting, performing, monitoring, auditing, recording, analysing and reporting clinical trials ensuring
p.(None): that the rights, safety and well-being of subjects are protected, and that the data generated in the clinical trial
p.(None): are reliable and robust;
p.(None):
p.(None): (31) ‘Inspection’ means the act by a competent authority of conducting an official review of documents,
p.(None): facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority
p.(None): to be related to the clinical trial and that may be located at the clinical trial site, at the sponsor's and/or
p.(None): contract research organisation's facilities, or at other establishments which the competent authority sees fit to
p.(None): inspect;
p.(None):
p.(None): L 158/14 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (32) ‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal product is
p.(None): administered and which does not necessarily have a causal relationship with this treatment;
p.(None): (33) ‘Serious adverse event’ means any untoward medical occurrence that at any dose requires inpatient
p.(None): hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability
p.(None): or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death;
p.(None): (34) ‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature, severity or outcome of which
p.(None): is not consistent with the reference safety information;
p.(None): (35) ‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
p.(None): format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
p.(None): accompanying an application for marketing authorisation.
p.(None): 3. For the purposes of this Regulation, a subject who falls under the definition of both ‘minor’
p.(None): and ‘incapacitated subject’ shall be deemed to be an incapacitated subject.
p.(None):
p.(None):
p.(None): Article 3
p.(None):
p.(None): General principle
p.(None):
p.(None): A clinical trial may be conducted only if:
p.(None): (a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and
p.(None): (b) it is designed to generate reliable and robust data.
p.(None):
p.(None):
p.(None): CHAPTER II
p.(None):
p.(None): AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL
p.(None):
p.(None): Article 4
p.(None):
p.(None): Prior authorisation
p.(None):
p.(None): A clinical trial shall be subject to scientific and ethical review and shall be authorised in accordance with this
p.(None): Regulation.
p.(None):
...
Health / Mentally Incapacitated
Searching for indicator incapable:
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p.(None): initiation, for the management and for setting up the financing of the clinical trial;
p.(None):
p.(None): (1) Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
p.(None): medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/13
p.(None):
p.(None): (15) ‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical trial site;
p.(None):
p.(None): (16) ‘Principal investigator’ means an investigator who is the responsible leader of a team of
p.(None): investigators who conduct a clinical trial at a clinical trial site;
p.(None):
p.(None): (17) ‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
p.(None): investigational medicinal product or as a control;
p.(None):
p.(None): (18) ‘Minor’ means a subject who is, according to the law of the Member State concerned, under the age of legal
p.(None): compe tence to give informed consent;
p.(None):
p.(None): (19) ‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal competence to give
p.(None): informed consent, incapable of giving informed consent according to the law of the Member State concerned;
p.(None):
p.(None): (20) ‘Legally designated representative’ means a natural or legal person, authority or body which,
p.(None): according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject
p.(None): who is an incapaci tated subject or a minor;
p.(None):
p.(None): (21) ‘Informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in
p.(None): a par ticular clinical trial, after having been informed of all aspects of the clinical trial that are
p.(None): relevant to the subject's decision to participate or, in case of minors and of incapacitated subjects, an
p.(None): authorisation or agreement from their legally designated representative to include them in the clinical trial;
p.(None):
p.(None): (22) ‘Protocol’ means a document that describes the objectives, design, methodology, statistical
p.(None): considerations and or ganisation of a clinical trial. The term ‘protocol’ encompasses successive versions
p.(None): of the protocol and protocol modifications;
p.(None):
p.(None): (23) ‘Investigator's brochure’ means a compilation of the clinical and non-clinical data on the
p.(None): investigational medicinal product or products which are relevant to the study of the product or products in humans;
p.(None):
...
p.(None): investigational medi cinal product and unauthorised auxiliary medicinal product in accordance with Article 51;
p.(None):
p.(None): (u) a description of the statistical methods to be employed, including, if relevant:
p.(None):
p.(None): — timing of any planned interim analysis and the number of subjects planned to be enrolled;
p.(None):
p.(None): — reasons for choice of sample size;
p.(None):
p.(None): — calculations of the power of the clinical trial and clinical relevance;
p.(None):
p.(None): — the level of significance to be used;
p.(None):
p.(None): — criteria for the termination of the clinical trial;
p.(None):
p.(None): — procedures for accounting for missing, unused, and spurious data and for reporting any deviation from
p.(None): the original statistical plan; and
p.(None):
p.(None): — the selection of subjects to be included in the analyses;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/57
p.(None):
p.(None): (v) a description of the subject inclusion and exclusion criteria, including criteria for withdrawing
p.(None): individual subjects from treatment or from the clinical trial;
p.(None):
p.(None): (w) a description of procedures relating to the withdrawal of subjects from treatment or from the
p.(None): clinical trial including procedures for the collection of data regarding withdrawn subjects, procedures for replace
p.(None): ment of subjects and the follow-up of subjects that have withdrawn from treatment or from the clinical
p.(None): trial;
p.(None):
p.(None): (x) a justification for including subjects who are incapable of giving informed consent or other special popu
p.(None): lations, such as minors;
p.(None):
p.(None): (y) a justification for the gender and age allocation of subjects and, if a specific gender or age
p.(None): group is excluded from or underrepresented in the clinical trials, an explanation of the reasons and
p.(None): justification for these exclusion criteria;
p.(None):
p.(None): (z) a detailed description of the recruitment and informed consent procedure, especially when subjects
p.(None): are incapable of giving informed consent;
p.(None):
p.(None): (aa) a description of the treatments, including medicinal products, which are permitted or not
p.(None): permitted, before or during the clinical trial;
p.(None):
p.(None): (ab) a description of the accountability procedures for the supply and administration of medicinal products to
p.(None): subjects including the maintenance of blinding, if applicable;
p.(None):
p.(None): (ac) a description of procedures for monitoring subject compliance, if applicable; (ad) a description of
p.(None): arrangements for monitoring the conduct of the clinical trial;
p.(None): (ae) a description of the arrangements for taking care of the subjects after their participation in
p.(None): the clinical trial has ended, where such additional care is necessary because of the subjects'
p.(None): participation in the clin ical trial and where it differs from that normally expected for the medical condition in
p.(None): question;
p.(None):
p.(None): (af) a specification of the efficacy and safety parameters as well as the methods and timing for
p.(None): assessing, recording, and analysing these parameters;
p.(None):
p.(None): (ag) a description of ethical considerations relating to the clinical trial if those have not been
p.(None): described else where;
p.(None):
p.(None): (ah) a statement from the sponsor (either in the protocol or in a separate document) confirming that
p.(None): the investigators and institutions involved in the clinical trial are to permit clinical trial-related
p.(None): monitoring, audits and regulatory inspections, including provision of direct access to source data and documents;
p.(None):
...
Health / Motherhood/Family
Searching for indicator family:
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p.(None): Regulation sets high standards of quality and safety for medicinal products by ensuring that data
p.(None): generated in clinical trials are reliable and robust, thus ensuring that treatments and medicines which
p.(None): are intended to be an improvement of a treatment of patients build on reliable and robust data.
p.(None): Moreover, this Regulation sets high standards of quality and safety of medicinal products used in the
p.(None): context of a clinical trial, thus ensuring the safety of subjects in a clinical trial.
p.(None):
p.(None): (1) Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of
p.(None): individuals with regard to the processing of personal data and on the free movement of such data (OJ L 281, 23.11.1995,
p.(None): p. 31).
p.(None): (2) Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of
p.(None): individuals with
p.(None): regard to the processing of personal data by the Community institutions and bodies and on the free movement of such
p.(None): data (OJ L 8, 12.1.2001, p. 1).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/11
p.(None):
p.(None): (83) This Regulation respects the fundamental rights and observes the principles recognised in
p.(None): particular by the Charter and notably human dignity, the integrity of the person, the rights of the
p.(None): child, respect for private and family life, the protection of personal data and the freedom of art and science.
p.(None): This Regulation should be applied by the Member States in accordance with those rights and principles.
p.(None):
p.(None): (84) The European Data Protection Supervisor has given an opinion (1) pursuant to Article 28(2) of
p.(None): Regulation (EC) No 45/2001.
p.(None):
p.(None): (85) Since the objective of this Regulation, namely to ensure that, throughout the Union, clinical trial data are
p.(None): reliable and robust while ensuring respect for the rights, safety, dignity and well-being of subjects,
p.(None): cannot be sufficiently achieved by the Member States but can rather, by reason of its scale, be better achieved at
p.(None): Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of
p.(None): the Treaty on Euro pean Union. In accordance with the principle of proportionality, as set out in that
p.(None): Article, this Regulation does not go beyond what is necessary in order to achieve that objective,
p.(None):
p.(None): HAVE ADOPTED THIS REGULATION:
p.(None):
p.(None): CHAPTER I
p.(None):
p.(None): GENERAL PROVISIONS
p.(None):
p.(None): Article 1
p.(None):
p.(None): Scope This Regulation applies to all clinical trials conducted in the Union. It does not apply to non-interventional
p.(None): studies.
p.(None):
p.(None): Article 2
p.(None):
...
Health / Pregnant
Searching for indicator pregnant:
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p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
p.(None): (18) It should be left to the Member State concerned to determine the appropriate body or bodies
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
p.(None): ethics committees within the timelines for the authorisation of that clinical trial as set out in this
p.(None): Regulation. Such decisions are a matter of internal organisation for each Member State. When determining
p.(None): the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular
p.(None): patients or patients' organisations. They should also ensure that the necessary expertise is available. In
p.(None): accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons
p.(None): who collectively have the necessary qualifi cations and experience. The persons assessing the application
p.(None): should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free
p.(None): from any other undue influence.
p.(None):
p.(None):
p.(None): (19) The assessment of applications for the authorisation of clinical trials should be conducted on
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
p.(None): trials involving subjects in emer gency situations, minors, incapacitated subjects, pregnant and breastfeeding
p.(None): women and, where appropriate, other identified specific population groups, such as elderly people or people suffering
p.(None): from rare and ultra rare diseases.
p.(None):
p.(None):
p.(None): (20) In practice, sponsors do not always have all the information needed for submitting a complete
p.(None): application for authorisation of a clinical trial in all of the Member States where a clinical trial is
p.(None): eventually going to be conducted. It should be possible for sponsors to submit an application solely on the
p.(None): basis of documents assessed jointly by those Member States where the clinical trial might be conducted.
p.(None):
p.(None):
p.(None): (21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure
p.(None): the reli able functioning of the assessment procedure, however, an application for authorisation of a
p.(None): clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the
p.(None): sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an
p.(None): application.
p.(None):
p.(None): L 158/4 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (22) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest in
p.(None): extending the clinical trial to an additional Member States after the initial authorisation of the clinical trial. An
...
p.(None): dossier. To ensure that the assessment of the application for authorisation of a clinical trial functions
p.(None): smoothly, Member States should consider accepting a commonly understood language in the medical field as
p.(None): the language for the docu mentation not destined for the subject.
p.(None):
p.(None):
p.(None): (27) Human dignity and the right to the integrity of the person are recognised in the Charter of
p.(None): Fundamental Rights of the European Union (the ‘Charter’). In particular, the Charter requires that any
p.(None): intervention in the field of biology and medicine cannot be performed without free and informed consent of the
p.(None): person concerned. Directive 2001/20/EC contains an extensive set of rules for the protection of subjects.
p.(None): These rules should be upheld. Regarding the rules concerning the determination of the legally
p.(None): designated representatives of incapacitated persons and minors, those rules diverge in Member States. It
p.(None): should therefore be left to Member States to deter mine the legally designated representatives of
p.(None): incapacitated persons and minors. Incapacitated subjects, minors, pregnant women and breastfeeding women require
p.(None): specific protection measures.
p.(None):
p.(None):
p.(None): (28) An appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner should be
p.(None): respon sible for all medical care provided to the subject, including the medical care provided by other medical staff.
p.(None):
p.(None):
p.(None): (29) It is appropriate that universities and other research institutions, under certain circumstances
p.(None): that are in accord ance with the applicable law on data protection, be able to collect data from
p.(None): clinical trials to be used for future scientific research, for example for medical, natural or social
p.(None): sciences research purposes. In order to collect data for such purposes it is necessary that the subject
p.(None): gives consent to use his or her data outside the protocol of the clinical trial and has the right to
p.(None): withdraw that consent at any time. It is also necessary that research projects based on such data be
p.(None): made subject to reviews that are appropriate for research on human data, for example on ethical aspects,
p.(None): before being conducted.
p.(None):
p.(None):
p.(None): (30) In accordance with international guidelines, the informed consent of a subject should be in
...
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
...
p.(None): assessment report have no financial or personal interests which could affect their impartiality. These persons
p.(None): shall make an annual declaration of their financial interests.
p.(None):
p.(None): 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who
p.(None): collectively have the necessary qualifications and experience.
p.(None):
p.(None): 3. At least one layperson shall participate in the assessment.
p.(None):
p.(None):
p.(None): Article 10
p.(None):
p.(None): Specific considerations for vulnerable populations
p.(None):
p.(None): 1. Where the subjects are minors, specific consideration shall be given to the assessment of the
p.(None): application for authorisation of a clinical trial on the basis of paediatric expertise or after taking
p.(None): advice on clinical, ethical and psycho social problems in the field of paediatrics.
p.(None):
p.(None): L 158/20 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the
p.(None): applica tion for authorisation of a clinical trial on the basis of expertise in the relevant disease
p.(None): and the patient population concerned or after taking advice on clinical, ethical and psychosocial
p.(None): questions in the field of the relevant disease and the patient population concerned.
p.(None):
p.(None): 3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the
p.(None): assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant
p.(None): condition and the population represented by the subject concerned.
p.(None):
p.(None): 4. If according to the protocol a clinical trial provides for the participation of specific groups
p.(None): or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of
p.(None): the application for authorisation of that clinical trial on the basis of expertise in the population represented by
p.(None): the subjects concerned.
p.(None):
p.(None): 5. In any application for authorisation of a clinical trial referred to in Article 35, specific consideration
p.(None): shall be given to the circumstances of the conduct of the clinical trial.
p.(None):
p.(None):
p.(None): Article 11
p.(None):
p.(None): Submission and assessment of applications limited to aspects covered by Part I or Part II of the
p.(None): assessment report
p.(None):
p.(None): Where the sponsor so requests, the application for authorisation of a clinical trial, its assessment and
p.(None): the conclusion shall be limited to the aspects covered by Part I of the assessment report.
p.(None):
p.(None): After the notification of the conclusion on the aspects covered by Part I of the assessment report,
p.(None): the sponsor may within two years apply for an authorisation limited to aspects covered by Part II of the
p.(None): assessment report. In that appli cation the sponsor shall declare that he is not aware of any new substantial
...
p.(None): of such a nature that it can only be carried out on minors;
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
p.(None): (ii) some benefit for the population represented by the minor concerned and such a clinical trial will
p.(None): pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with
p.(None): the standard treatment of the minor's condition.
p.(None): 2. The minor shall take part in the informed consent procedure in a way adapted to his or her
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
...
p.(None):
p.(None): 3. The application shall be signed by the sponsor or a representative of the sponsor. This signature confirms
p.(None): that the sponsor is satisfied that:
p.(None):
p.(None): (a) the information provided is complete;
p.(None):
p.(None): (b) the attached documents contain an accurate account of the information available;
p.(None):
p.(None): (c) the clinical trial is to be conducted in accordance with the protocol; and
p.(None):
p.(None): (d) the clinical trial is to be conducted in accordance with this Regulation.
p.(None):
p.(None): 4. The application dossier for an application limited to Part I of the assessment report referred to
p.(None): in Article 11 shall be limited to sections B to J and Q of this Annex.
p.(None):
p.(None): 5. Without prejudice to Article 26, the application dossier for an application limited to Part II of
p.(None): the assessment report referred to in Article 11 and the application dossier for an application referred to in
p.(None): Article 14 shall be limited to sections K to R of this Annex.
p.(None):
p.(None):
p.(None): B. COVER LETTER
p.(None):
p.(None): 6. The cover letter shall specify the EU trial number and the universal trial number and shall draw
p.(None): attention to any features which are particular to the clinical trial.
p.(None):
p.(None): 7. However, in the cover letter it is not necessary to reproduce information already contained in
p.(None): the EU applica tion form, with the following exceptions:
p.(None):
p.(None): (a) specific features of the clinical trial population, such as subjects not able to give informed consent,
p.(None): minors and pregnant or breastfeeding women;
p.(None):
p.(None): (b) whether the clinical trial involves the first administration of a new active substance to humans;
p.(None):
p.(None): (c) whether scientific advice relating to the clinical trial or the investigational medicinal product
p.(None): has been given by the Agency, a Member State or a third country;
p.(None):
p.(None): (d) whether the clinical trial is part or is intended to be part of a Paediatric Investigation Plan (PIP) as
p.(None): referred to in Title II, Chapter 3, of Regulation (EC) No 1901/2006 (if the Agency has already issued a
p.(None): decision on the PIP, the cover letter contains the link to the decision of the Agency on its website);
p.(None):
p.(None): (e) whether investigational medicinal products or auxiliary medicinal products are a narcotic,
p.(None): psychotropic or radiopharmaceutical;
p.(None):
p.(None): (f) whether the investigational medicinal products consist of or contain a genetically-modified organism
p.(None): or organisms;
p.(None):
p.(None): (g) whether the sponsor has obtained an orphan designation for the investigational medicinal product for
p.(None): an orphan condition;
p.(None):
p.(None): (h) a comprehensive list, including the regulatory status, of all investigational medicinal products and
p.(None): a list of all auxiliary medicinal products; and
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/55
p.(None):
...
Health / breastfeeding
Searching for indicator breastfeeding:
(return to top)
p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
p.(None): (18) It should be left to the Member State concerned to determine the appropriate body or bodies
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
p.(None): ethics committees within the timelines for the authorisation of that clinical trial as set out in this
p.(None): Regulation. Such decisions are a matter of internal organisation for each Member State. When determining
p.(None): the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular
p.(None): patients or patients' organisations. They should also ensure that the necessary expertise is available. In
p.(None): accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons
p.(None): who collectively have the necessary qualifi cations and experience. The persons assessing the application
p.(None): should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free
p.(None): from any other undue influence.
p.(None):
p.(None):
p.(None): (19) The assessment of applications for the authorisation of clinical trials should be conducted on
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
p.(None): trials involving subjects in emer gency situations, minors, incapacitated subjects, pregnant and breastfeeding
p.(None): women and, where appropriate, other identified specific population groups, such as elderly people or people suffering
p.(None): from rare and ultra rare diseases.
p.(None):
p.(None):
p.(None): (20) In practice, sponsors do not always have all the information needed for submitting a complete
p.(None): application for authorisation of a clinical trial in all of the Member States where a clinical trial is
p.(None): eventually going to be conducted. It should be possible for sponsors to submit an application solely on the
p.(None): basis of documents assessed jointly by those Member States where the clinical trial might be conducted.
p.(None):
p.(None):
p.(None): (21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure
p.(None): the reli able functioning of the assessment procedure, however, an application for authorisation of a
p.(None): clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the
p.(None): sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an
p.(None): application.
p.(None):
p.(None): L 158/4 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (22) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest in
p.(None): extending the clinical trial to an additional Member States after the initial authorisation of the clinical trial. An
p.(None): authorisation mechanism should be provided to allow for such extension, while avoiding the re-assessment
...
p.(None): smoothly, Member States should consider accepting a commonly understood language in the medical field as
p.(None): the language for the docu mentation not destined for the subject.
p.(None):
p.(None):
p.(None): (27) Human dignity and the right to the integrity of the person are recognised in the Charter of
p.(None): Fundamental Rights of the European Union (the ‘Charter’). In particular, the Charter requires that any
p.(None): intervention in the field of biology and medicine cannot be performed without free and informed consent of the
p.(None): person concerned. Directive 2001/20/EC contains an extensive set of rules for the protection of subjects.
p.(None): These rules should be upheld. Regarding the rules concerning the determination of the legally
p.(None): designated representatives of incapacitated persons and minors, those rules diverge in Member States. It
p.(None): should therefore be left to Member States to deter mine the legally designated representatives of
p.(None): incapacitated persons and minors. Incapacitated subjects, minors, pregnant women and breastfeeding women require
p.(None): specific protection measures.
p.(None):
p.(None):
p.(None): (28) An appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner should be
p.(None): respon sible for all medical care provided to the subject, including the medical care provided by other medical staff.
p.(None):
p.(None):
p.(None): (29) It is appropriate that universities and other research institutions, under certain circumstances
p.(None): that are in accord ance with the applicable law on data protection, be able to collect data from
p.(None): clinical trials to be used for future scientific research, for example for medical, natural or social
p.(None): sciences research purposes. In order to collect data for such purposes it is necessary that the subject
p.(None): gives consent to use his or her data outside the protocol of the clinical trial and has the right to
p.(None): withdraw that consent at any time. It is also necessary that research projects based on such data be
p.(None): made subject to reviews that are appropriate for research on human data, for example on ethical aspects,
p.(None): before being conducted.
p.(None):
p.(None):
p.(None): (30) In accordance with international guidelines, the informed consent of a subject should be in
p.(None): writing. When the subject is unable to write, it may be recorded through appropriate alternative means,
...
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
...
p.(None): assessment report have no financial or personal interests which could affect their impartiality. These persons
p.(None): shall make an annual declaration of their financial interests.
p.(None):
p.(None): 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who
p.(None): collectively have the necessary qualifications and experience.
p.(None):
p.(None): 3. At least one layperson shall participate in the assessment.
p.(None):
p.(None):
p.(None): Article 10
p.(None):
p.(None): Specific considerations for vulnerable populations
p.(None):
p.(None): 1. Where the subjects are minors, specific consideration shall be given to the assessment of the
p.(None): application for authorisation of a clinical trial on the basis of paediatric expertise or after taking
p.(None): advice on clinical, ethical and psycho social problems in the field of paediatrics.
p.(None):
p.(None): L 158/20 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the
p.(None): applica tion for authorisation of a clinical trial on the basis of expertise in the relevant disease
p.(None): and the patient population concerned or after taking advice on clinical, ethical and psychosocial
p.(None): questions in the field of the relevant disease and the patient population concerned.
p.(None):
p.(None): 3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the
p.(None): assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant
p.(None): condition and the population represented by the subject concerned.
p.(None):
p.(None): 4. If according to the protocol a clinical trial provides for the participation of specific groups
p.(None): or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of
p.(None): the application for authorisation of that clinical trial on the basis of expertise in the population represented by
p.(None): the subjects concerned.
p.(None):
p.(None): 5. In any application for authorisation of a clinical trial referred to in Article 35, specific consideration
p.(None): shall be given to the circumstances of the conduct of the clinical trial.
p.(None):
p.(None):
p.(None): Article 11
p.(None):
p.(None): Submission and assessment of applications limited to aspects covered by Part I or Part II of the
p.(None): assessment report
p.(None):
p.(None): Where the sponsor so requests, the application for authorisation of a clinical trial, its assessment and
p.(None): the conclusion shall be limited to the aspects covered by Part I of the assessment report.
p.(None):
p.(None): After the notification of the conclusion on the aspects covered by Part I of the assessment report,
p.(None): the sponsor may within two years apply for an authorisation limited to aspects covered by Part II of the
p.(None): assessment report. In that appli cation the sponsor shall declare that he is not aware of any new substantial
p.(None): scientific information that would change the validity of any item submitted in the application on the aspects
...
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
p.(None): (ii) some benefit for the population represented by the minor concerned and such a clinical trial will
p.(None): pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with
p.(None): the standard treatment of the minor's condition.
p.(None): 2. The minor shall take part in the informed consent procedure in a way adapted to his or her
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
p.(None): clinical trial may be obtained, and information on the clinical trial may be given, after the decision to
p.(None): include the subject in the clinical trial, provided that this decision is taken at the time of the first
...
p.(None): 3. The application shall be signed by the sponsor or a representative of the sponsor. This signature confirms
p.(None): that the sponsor is satisfied that:
p.(None):
p.(None): (a) the information provided is complete;
p.(None):
p.(None): (b) the attached documents contain an accurate account of the information available;
p.(None):
p.(None): (c) the clinical trial is to be conducted in accordance with the protocol; and
p.(None):
p.(None): (d) the clinical trial is to be conducted in accordance with this Regulation.
p.(None):
p.(None): 4. The application dossier for an application limited to Part I of the assessment report referred to
p.(None): in Article 11 shall be limited to sections B to J and Q of this Annex.
p.(None):
p.(None): 5. Without prejudice to Article 26, the application dossier for an application limited to Part II of
p.(None): the assessment report referred to in Article 11 and the application dossier for an application referred to in
p.(None): Article 14 shall be limited to sections K to R of this Annex.
p.(None):
p.(None):
p.(None): B. COVER LETTER
p.(None):
p.(None): 6. The cover letter shall specify the EU trial number and the universal trial number and shall draw
p.(None): attention to any features which are particular to the clinical trial.
p.(None):
p.(None): 7. However, in the cover letter it is not necessary to reproduce information already contained in
p.(None): the EU applica tion form, with the following exceptions:
p.(None):
p.(None): (a) specific features of the clinical trial population, such as subjects not able to give informed consent,
p.(None): minors and pregnant or breastfeeding women;
p.(None):
p.(None): (b) whether the clinical trial involves the first administration of a new active substance to humans;
p.(None):
p.(None): (c) whether scientific advice relating to the clinical trial or the investigational medicinal product
p.(None): has been given by the Agency, a Member State or a third country;
p.(None):
p.(None): (d) whether the clinical trial is part or is intended to be part of a Paediatric Investigation Plan (PIP) as
p.(None): referred to in Title II, Chapter 3, of Regulation (EC) No 1901/2006 (if the Agency has already issued a
p.(None): decision on the PIP, the cover letter contains the link to the decision of the Agency on its website);
p.(None):
p.(None): (e) whether investigational medicinal products or auxiliary medicinal products are a narcotic,
p.(None): psychotropic or radiopharmaceutical;
p.(None):
p.(None): (f) whether the investigational medicinal products consist of or contain a genetically-modified organism
p.(None): or organisms;
p.(None):
p.(None): (g) whether the sponsor has obtained an orphan designation for the investigational medicinal product for
p.(None): an orphan condition;
p.(None):
p.(None): (h) a comprehensive list, including the regulatory status, of all investigational medicinal products and
p.(None): a list of all auxiliary medicinal products; and
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/55
p.(None):
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.(None): through a single submission portal. Given that clinical trials carried out in a single Member State are equally
p.(None): important to European clinical research, the application dossier for such clinical trials should also be submitted
p.(None): through that single portal.
p.(None):
p.(None):
p.(None): (5) As regards Directive 2001/20/EC, experience also indicates that the legal form of a Regulation
p.(None): would present advantages for sponsors and investigators, for example in the context of clinical trials
p.(None): taking place in more than one Member State, since they will be able to rely on its provisions
p.(None): directly, but also in the context of safety reporting and labelling of investigational medicinal products.
p.(None): Divergences of approach among different Member States will be therefore kept to a minimum.
p.(None):
p.(None):
p.(None): (6) The Member States concerned should cooperate in assessing a request for authorisation of a clinical trial.
p.(None): This co operation should not include aspects of an intrinsically national nature, such as informed consent.
p.(None):
p.(None):
p.(None): (7) In order to avoid administrative delays for starting a clinical trial, the procedure to be used should be
p.(None): flexible and efficient, without compromising patient safety or public health.
p.(None):
p.(None):
p.(None): (8) The timelines for assessing an application dossier for clinical trials should be sufficient to
p.(None): assess the file while, at the same time, ensuring quick access to new, innovative treatments and
p.(None): ensuring that the Union remains an attractive place for conducting clinical trials. Against this
p.(None): background, Directive 2001/20/EC introduced the concept of tacit authorisation. This concept should be
p.(None): maintained in order to ensure that timelines are adhered to. In the event of a public health crisis, Member
p.(None): States should have the possibility to assess and authorise a clin ical trial application swiftly. No minimal timelines
p.(None): for approval should therefore be established.
p.(None):
p.(None):
p.(None): (9) Clinical trials for the development of orphan medicinal products as defined in Regulation (EC)
p.(None): No 141/2000 of the European Parliament and of the Council (1) and of medicinal products addressed to
p.(None): subjects affected by severe, debilitating and often life-threatening diseases affecting no more than one person
p.(None): in 50 000 in the Union (ultra-rare diseases) should be fostered.
p.(None):
p.(None):
p.(None): (10) Member States should efficiently assess all clinical trials applications within the given
p.(None): timelines. A rapid yet in- depth assessment is of particular importance for clinical trials concerning
p.(None): medical conditions which are severely debilitating and/or life threatening and for which therapeutic options are
p.(None): limited or non-existent, as in the case of rare and ultra-rare diseases.
p.(None):
p.(None):
p.(None): (11) The risk to subject safety in a clinical trial mainly stems from two sources: the
...
p.(None): United Nations. Member States should communicate those national provisions to the Commission.
p.(None):
p.(None):
p.(None): (75) Directive 2001/20/EC provides that no gene therapy trials may be carried out which result in
p.(None): modifications to the subject's germ line genetic identity. It is appropriate to maintain that provision.
p.(None):
p.(None): (1) Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011 laying down the
p.(None): rules and general principles concerning mechanisms for control by Member States of the Commission's exercise
p.(None): of implementing powers (OJ L 55, 28.2.2011, p. 13).
p.(None):
p.(None): L 158/10 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (76) Directive 95/46/EC of the European Parliament and of the Council (1) applies to the processing
p.(None): of personal data carried out in the Member States within the framework of this Regulation, under the
p.(None): supervision of the Member States competent authorities, in particular the public independent authorities
p.(None): designated by the Member States and Regulation (EC) No 45/2001 of the European Parliament and of the
p.(None): Council (2) applies to the processing of personal data carried out by the Commission and the Agency within the
p.(None): framework of this Regulation, under the supervision of the European Data Protection Supervisor. Those
p.(None): instruments strengthen personal data protection rights, encompassing the right to access, rectification and
p.(None): withdrawal, as well as specify the situations when restriction on those rights may be imposed. With a view to
p.(None): respecting those rights, while safeguarding the robust ness and reliability of data from clinical trials used
p.(None): for scientific purposes and the safety of subjects participating in clinical trials, it is appropriate to
p.(None): provide that, without prejudice to Directive 95/46/EC, the withdrawal of informed consent should not affect
p.(None): the results of activities already carried out, such as the storage and use of data obtained on the basis of informed
p.(None): consent before withdrawal.
p.(None):
p.(None):
p.(None): (77) Subjects should not have to pay for investigational medicinal products, auxiliary medicinal
p.(None): products, medical devices used for their administration and procedures specifically required by the
p.(None): protocol, unless the law of the Member State concerned provides otherwise.
p.(None):
p.(None):
p.(None): (78) The authorisation procedure set out in this Regulation should apply as soon as possible, in order for
p.(None): sponsors to reap the benefits of a streamlined authorisation procedure. However, in view of the importance
p.(None): of the extensive IT functionalities required for the authorisation procedure, it is appropriate to provide that
p.(None): this Regulation should only become applicable once it has been verified that the EU portal and the EU database are
p.(None): fully functional.
p.(None):
p.(None):
p.(None): (79) Directive 2001/20/EC should be repealed to ensure that only one set of rules applies to the
...
p.(None): the measures taken.
p.(None):
p.(None): That notification shall be made without undue delay but no later than seven days from the date the measures have been
p.(None): taken.
p.(None):
p.(None): 3. This Article is without prejudice to Chapters III and VII.
p.(None):
p.(None):
p.(None): Article 55
p.(None):
p.(None): Investigator's brochure
p.(None):
p.(None): 1. The sponsor shall provide the investigator with the investigator's brochure.
p.(None):
p.(None): 2. The investigator's brochure shall be updated where new and relevant safety information becomes
p.(None): available, and shall be reviewed by the sponsor at least once per year.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/41
p.(None):
p.(None): Article 56
p.(None):
p.(None): Recording, processing, handling and storage of information
p.(None):
p.(None): 1. All clinical trial information shall be recorded, processed, handled, and stored by the sponsor
p.(None): or investigator, as applicable, in such a way that it can be accurately reported, interpreted and
p.(None): verified while the confidentiality of records and the personal data of the subjects remain protected in
p.(None): accordance with the applicable law on personal data protec tion.
p.(None):
p.(None): 2. Appropriate technical and organisational measures shall be implemented to protect information and
p.(None): personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction
p.(None): or accidental loss, in particular where the processing involves the transmission over a network.
p.(None):
p.(None):
p.(None): Article 57
p.(None):
p.(None): Clinical trial master file
p.(None):
p.(None): The sponsor and the investigator shall keep a clinical trial master file. The clinical trial master
p.(None): file shall at all times contain the essential documents relating to that clinical trial which allow
p.(None): verification of the conduct of a clinical trial and the quality of the data generated, taking into
p.(None): account all characteristics of the clinical trial, including in particular whether the clinical trial is
p.(None): a low-intervention clinical trial. It shall be readily available, and directly accessible upon request, to
p.(None): the Member States.
p.(None):
p.(None): The clinical trial master file kept by the investigator and that kept by the sponsor may have a different
p.(None): content if this is justified by the different nature of the responsibilities of the investigator and the sponsor.
p.(None):
p.(None):
p.(None): Article 58
p.(None):
p.(None): Archiving of the clinical trial master file
p.(None):
p.(None): Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the
p.(None): content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the
p.(None): medical files of subjects shall be archived in accordance with national law.
p.(None):
p.(None): The content of the clinical trial master file shall be archived in a way that ensures that it is
p.(None): readily available and acces sible, upon request, to the competent authorities.
p.(None):
p.(None): Any transfer of ownership of the content of the clinical trial master file shall be documented. The
p.(None): new owner shall assume the responsibilities set out in this Article.
p.(None):
p.(None): The sponsor shall appoint individuals within its organisation to be responsible for archives. Access to
p.(None): archives shall be restricted to those individuals.
p.(None):
p.(None): The media used to archive the content of the clinical trial master file shall be such that the
p.(None): content remains complete and legible throughout the period referred to in the first paragraph.
p.(None):
p.(None): Any alteration to the content of the clinical trial master file shall be traceable.
p.(None):
p.(None):
p.(None): Article 59
p.(None):
p.(None): Auxiliary medicinal products
p.(None):
p.(None): 1. Only authorised auxiliary medicinal products may be used in a clinical trial.
p.(None):
p.(None): 2. Paragraph 1 shall not apply where no authorised auxiliary medicinal product is available in the
p.(None): Union or where the sponsor cannot reasonably be expected to use an authorised auxiliary medicinal product. A
p.(None): justification to this effect shall be included in the protocol.
p.(None):
p.(None): L 158/42 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Member States shall ensure that unauthorised auxiliary medicinal products may enter their
p.(None): territories for the purpose of their use in a clinical trial in accordance with paragraph 2.
p.(None):
p.(None):
p.(None): CHAPTER IX
p.(None):
p.(None): MANUFACTURING AND IMPORT OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): Article 60
p.(None):
p.(None): Scope of this Chapter
p.(None):
p.(None): This Chapter shall apply to the manufacture and import of investigational medicinal products and
p.(None): auxiliary medicinal products.
p.(None):
p.(None):
...
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Data and information submitted through the EU portal shall be stored in the EU database.
p.(None):
p.(None):
p.(None): Article 81
p.(None):
p.(None): EU database
p.(None):
p.(None): 1. The Agency shall, in collaboration with the Member States and the Commission, set up and
p.(None): maintain a EU data base at Union level. The Agency shall be considered to be the controller of the EU
p.(None): database and shall be responsible for avoiding unnecessary duplication between the EU database and the EudraCT and
p.(None): Eudravigilance databases.
p.(None):
p.(None): The EU database shall contain the data and information submitted in accordance with this Regulation.
p.(None):
p.(None): The EU database shall identify each clinical trial by a unique EU trial number. The sponsor shall
p.(None): refer to this EU trial number in any subsequent submission relating or referring to that clinical trial.
p.(None):
p.(None): 2. The EU database shall be established to enable cooperation between the competent authorities of
p.(None): the Member States concerned to the extent that it is necessary for the application of this Regulation and to search
p.(None): for specific clinical trials. It shall also facilitate the communication between sponsors and Member States
p.(None): concerned and enable sponsors to refer to previous submissions of an application for authorisation of a
p.(None): clinical trial or a substantial modification. It shall also enable citizens of the Union to have access
p.(None): to clinical information about medicinal products. To this end all data held in the EU database shall be
p.(None): in an easily searchable format, all related data shall be grouped together by way of the EU trial
p.(None): number, and hyperlinks shall be provided to link together related data and documents held on the EU
p.(None): database and other databases managed by the Agency.
p.(None):
p.(None): 3. The EU database shall support the recording and submission to the Medicinal Product Dictionary, contained in
p.(None): the Eudravigilance database, of all the data on medicinal products without a marketing authorisation in
p.(None): the Union and substances not authorised as part of a medicinal product in the Union, that are necessary
p.(None): for the maintenance of that dictionary. To this effect and also with the purpose of enabling the
p.(None): sponsor to cross-refer to prior applications, an EU medicinal product number shall be issued for every
p.(None): medicinal product without a marketing authorisation and an EU active substances code shall be issued for
p.(None): each new active substance not previously authorised as part of a medicinal product in the Union. This shall
p.(None): be done before or during the application for authorisation of the first clinical trial with that product or active
p.(None): substance submitted in accordance with this Regulation. Those numbers shall be mentioned in all subsequent applications
p.(None): for clinical trials and for substantial modifications.
...
p.(None): status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in
p.(None): disclosure;
p.(None):
p.(None): (c) protecting confidential communication between Member States in relation to the preparation of the
p.(None): assessment report;
p.(None):
p.(None): (d) ensuring effective supervision of the conduct of a clinical trial by Member States.
p.(None):
p.(None): 5. Without prejudice to paragraph 4, unless there is an overriding public interest in disclosure,
p.(None): data contained in the application dossier shall not be publicly accessible before the decision on the clinical trial
p.(None): has been made.
p.(None):
p.(None): 6. The EU database shall contain personal data only insofar as this is necessary for the purposes of paragraph
p.(None): 2.
p.(None):
p.(None): 7. No personal data of subjects shall be publicly accessible.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/49
p.(None):
p.(None): 8. The user interface of the EU database shall be available in all official languages of the Union.
p.(None):
p.(None): 9. The sponsor shall permanently update in the EU database information on any changes to the
p.(None): clinical trials which are not substantial modifications but are relevant for the supervision of
p.(None): the clinical trial by the Member States concerned.
p.(None):
p.(None): 10. The Agency, the Commission and Member States shall ensure that the data subject may effectively exercise
p.(None): his or her rights to information, to access, to rectify and to object in accordance with Regulation (EC)
p.(None): No 45/2001 and national data protection legislation implementing Directive 95/46/EC, respectively. They
p.(None): shall ensure that the data subject may effectively exercise the right of access to data relating to him
p.(None): or her, and the right to have inaccurate or incomplete data corrected or erased. Within their
p.(None): respective responsibilities, the Agency, the Commission and Member States shall ensure that inaccurate and
p.(None): unlawfully processed data are deleted, in accordance with the applicable law. Corrections and deletions shall
p.(None): be carried out as soon as possible, but no later than 60 days of a request being made by a data subject.
p.(None):
p.(None):
p.(None): Article 82
p.(None):
p.(None): Functionality of the EU portal and the EU database
p.(None):
p.(None): 1. The Agency shall, in collaboration with the Member States and the Commission, draw up the
p.(None): functional specifica tions for the EU portal and the EU database, together with the time frame for their
p.(None): implementation.
p.(None):
p.(None): 2. The Management Board of the Agency shall, on the basis of an independent audit report, inform
p.(None): the Commission when it has verified that the EU portal and the EU database have achieved full
p.(None): functionality and the systems meet the functional specifications drawn up pursuant to paragraph 1.
p.(None):
p.(None): 3. The Commission shall, when it is satisfied that the conditions referred to in paragraph 2 have
p.(None): been fulfilled, publish a notice to that effect in the Official Journal of the European Union.
p.(None):
p.(None):
p.(None): CHAPTER XV
p.(None):
p.(None): COOPERATION BETWEEN MEMBER STATES
p.(None):
p.(None): Article 83
p.(None):
p.(None): National contact points
p.(None):
p.(None): 1. Each Member State shall designate one national contact point in order to facilitate the
...
p.(None): are incapable of giving informed consent;
p.(None):
p.(None): (aa) a description of the treatments, including medicinal products, which are permitted or not
p.(None): permitted, before or during the clinical trial;
p.(None):
p.(None): (ab) a description of the accountability procedures for the supply and administration of medicinal products to
p.(None): subjects including the maintenance of blinding, if applicable;
p.(None):
p.(None): (ac) a description of procedures for monitoring subject compliance, if applicable; (ad) a description of
p.(None): arrangements for monitoring the conduct of the clinical trial;
p.(None): (ae) a description of the arrangements for taking care of the subjects after their participation in
p.(None): the clinical trial has ended, where such additional care is necessary because of the subjects'
p.(None): participation in the clin ical trial and where it differs from that normally expected for the medical condition in
p.(None): question;
p.(None):
p.(None): (af) a specification of the efficacy and safety parameters as well as the methods and timing for
p.(None): assessing, recording, and analysing these parameters;
p.(None):
p.(None): (ag) a description of ethical considerations relating to the clinical trial if those have not been
p.(None): described else where;
p.(None):
p.(None): (ah) a statement from the sponsor (either in the protocol or in a separate document) confirming that
p.(None): the investigators and institutions involved in the clinical trial are to permit clinical trial-related
p.(None): monitoring, audits and regulatory inspections, including provision of direct access to source data and documents;
p.(None):
p.(None): (ai) a description of the publication policy;
p.(None):
p.(None): (aj) duly substantiated reasons for the submission of the summary of the results of the clinical
p.(None): trials after more than one year;
p.(None):
p.(None): (ak) a description of the arrangements to comply with the applicable rules on the protection of personal data; in
p.(None): particular organisational and technical arrangements that will be implemented to avoid unauthorised access,
p.(None): disclosure, dissemination, alteration or loss of information and personal data processed;
p.(None):
p.(None): (al) a description of measures that will be implemented to ensure confidentiality of records and personal data of
p.(None): subjects;
p.(None):
p.(None): (am) a description of measures that will be implemented in case of data security breach in order to
p.(None): mitigate the possible adverse effects.
p.(None):
p.(None): 18. If a clinical trial is conducted with an active substance available in the Union under different
p.(None): trade names in a number of authorised medicinal products, the protocol may define the treatment in terms
p.(None): of the active substance or Anatomical Therapeutic Chemical (ATC) code (level 3-5) only and not specify
p.(None): the trade name of each product.
p.(None):
p.(None): L 158/58 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 19. With regard to the notification of adverse events, the protocol shall identify the categories of:
p.(None):
p.(None): (a) adverse events or laboratory anomalies that are critical to safety evaluations and must be reported
p.(None): by the investigator to the sponsor, and
p.(None):
p.(None): (b) serious adverse events which do not require immediate reporting by the investigator to the sponsor.
p.(None):
p.(None): 20. The protocol shall describe the procedures for:
p.(None):
p.(None): (a) eliciting and recording adverse events by the investigator, and the reporting of relevant adverse
...
Social / Age
Searching for indicator age:
(return to top)
p.(None): Official Journal of the European Union
p.(None): L 158/3
p.(None):
p.(None): (12) The Recommendation of the Organisation for Economic Cooperation and Development (OECD) Council on
p.(None): the Governance of Clinical Trials of 10 December 2012 introduced different risk categories for clinical
p.(None): trials. Those categories are compatible with the categories of clinical trials defined in this Regulation as the OECD
p.(None): Categories A and B(1) correspond to the definition of a low-intervention clinical trial as set out in
p.(None): this Regulation, and the OECD Categories B(2) and C correspond to the definition of a clinical trial as set out in
p.(None): this Regulation.
p.(None):
p.(None):
p.(None): (13) The assessment of the application for a clinical trial should address in particular the
p.(None): anticipated therapeutic and public health benefits (relevance) and the risk and inconvenience for the
p.(None): subject. In respect of the relevance, various aspects should be taken into account, including whether the
p.(None): clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment of
p.(None): medicinal products and the authorisation of their placing on the market and whether surrogate end-points, when
p.(None): they are used, are justified.
p.(None):
p.(None):
p.(None): (14) Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent
p.(None): the popula tion groups, for example gender and age groups, that are likely to use the medicinal product
p.(None): investigated in the clinical trial.
p.(None):
p.(None):
p.(None): (15) In order to improve treatments available for vulnerable groups such as frail or older people,
p.(None): people suffering from multiple chronic conditions, and people affected by mental health disorders,
p.(None): medicinal products which are likely to be of significant clinical value should be fully and appropriately
p.(None): studied for their effects in these specific groups, including as regards requirements related to their
p.(None): specific characteristics and the protection of the health and well-being of subjects belonging to these groups.
p.(None):
p.(None):
p.(None): (16) The authorisation procedure should provide for the possibility to extend the timelines for the assessment
p.(None): in order to allow the sponsor to address questions or comments raised during the assessment of the
p.(None): application dossier. Moreover, it should be ensured that, within the extension period, there is always
p.(None): sufficient time for assessing the additional information submitted.
p.(None):
p.(None):
p.(None): (17) The authorisation to conduct a clinical trial should address all aspects of subject protection
p.(None): and data reliability and robustness. That authorisation should therefore be contained in a single
p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
...
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
p.(None): pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior
p.(None): to the intervention. This Regulation should therefore set clear rules whereby such patients may be enrolled in the
p.(None): clinical trial under very strict condi tions. In addition, the said clinical trial should relate directly
p.(None): to the medical condition because of which it is not possible within the therapeutic window to obtain
...
p.(None):
p.(None): (13) ‘Substantial modification’ means any change to any aspect of the clinical trial which is made after
p.(None): notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to have a substantial
p.(None): impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the
p.(None): clinical trial;
p.(None):
p.(None): (14) ‘Sponsor’ means an individual, company, institution or organisation which takes responsibility for the
p.(None): initiation, for the management and for setting up the financing of the clinical trial;
p.(None):
p.(None): (1) Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
p.(None): medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/13
p.(None):
p.(None): (15) ‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical trial site;
p.(None):
p.(None): (16) ‘Principal investigator’ means an investigator who is the responsible leader of a team of
p.(None): investigators who conduct a clinical trial at a clinical trial site;
p.(None):
p.(None): (17) ‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
p.(None): investigational medicinal product or as a control;
p.(None):
p.(None): (18) ‘Minor’ means a subject who is, according to the law of the Member State concerned, under the age of legal
p.(None): compe tence to give informed consent;
p.(None):
p.(None): (19) ‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal competence to give
p.(None): informed consent, incapable of giving informed consent according to the law of the Member State concerned;
p.(None):
p.(None): (20) ‘Legally designated representative’ means a natural or legal person, authority or body which,
p.(None): according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject
p.(None): who is an incapaci tated subject or a minor;
p.(None):
p.(None): (21) ‘Informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in
p.(None): a par ticular clinical trial, after having been informed of all aspects of the clinical trial that are
p.(None): relevant to the subject's decision to participate or, in case of minors and of incapacitated subjects, an
p.(None): authorisation or agreement from their legally designated representative to include them in the clinical trial;
p.(None):
p.(None): (22) ‘Protocol’ means a document that describes the objectives, design, methodology, statistical
p.(None): considerations and or ganisation of a clinical trial. The term ‘protocol’ encompasses successive versions
p.(None): of the protocol and protocol modifications;
p.(None):
p.(None): (23) ‘Investigator's brochure’ means a compilation of the clinical and non-clinical data on the
...
p.(None): relates directly to the life-threatening or debilitating medical condition from which the subject suffers and such
p.(None): trial will pose only minimal risk to, and will impose minimal burden on, the incapacitated subject
p.(None): concerned in com parison with the standard treatment of the incapacitated subject's condition.
p.(None):
p.(None): 2. Point (g)(ii) of paragraph 1 shall be without prejudice to more stringent national rules
p.(None): prohibiting the conduct of those clinical trials on incapacitated subjects, where there are no scientific
p.(None): grounds to expect that participation in the clinical trial will produce a direct benefit to the subject
p.(None): outweighing the risks and burdens involved.
p.(None):
p.(None): 3. The subject shall as far as possible take part in the informed consent procedure.
p.(None):
p.(None):
p.(None): Article 32
p.(None):
p.(None): Clinical trials on minors
p.(None):
p.(None): 1. A clinical trial on minors may be conducted only where, in addition to the conditions set out in
p.(None): Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the minors have received the information referred to in Article 29(2) in a way adapted to their
p.(None): age and mental maturity and from investigators or members of the investigating team who are trained or
p.(None): experienced in working with children;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/33
p.(None):
p.(None): (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information
p.(None): referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is
p.(None): respected by the investi gator;
p.(None): (d) no incentives or financial inducements are given to the subject or his or her legally designated
p.(None): representative except for compensation for expenses and loss of earnings directly related to the participation in the
p.(None): clinical trial;
p.(None): (e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in
p.(None): minors or the clin ical trial is essential with respect to minors to validate data obtained in
p.(None): clinical trials on persons able to give informed consent or by other research methods;
p.(None): (f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is
p.(None): of such a nature that it can only be carried out on minors;
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
p.(None): (ii) some benefit for the population represented by the minor concerned and such a clinical trial will
p.(None): pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with
p.(None): the standard treatment of the minor's condition.
p.(None): 2. The minor shall take part in the informed consent procedure in a way adapted to his or her
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
...
p.(None): clinical trials that are relevant to the clinical trial;
p.(None): (d) a summary of the known and potential risks and benefits including an evaluation of the anticipated bene fits
p.(None): and risks to allow assessment in accordance with Article 6; for subjects in a clinical trial in an
p.(None): emer gency situation, the scientific grounds for expecting that the participation of the subjects has the potential to
p.(None): produce a direct clinically relevant benefit shall be documented;
p.(None): (e) where patients were involved in the design of the clinical trial, a description of their involvement;
p.(None):
p.(None): L 158/56 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (f) a description of, and justification for, the dosage, the dosage regime, the route and mode of
p.(None): administra tion, and the treatment period for all investigational medicinal products and auxiliary medicinal products;
p.(None):
p.(None): (g) a statement of whether the investigational medicinal products and auxiliary medicinal products
p.(None): used in the clinical trial are authorised; if authorised, whether they are to be used in the clinical
p.(None): trial in accord ance with the terms of their marketing authorisations, and, if not authorised, a justification for
p.(None): the use of non-authorised auxiliary medicinal products in the clinical trial;
p.(None):
p.(None): (h) a description of the groups and subgroups of the subjects participating in the clinical trial,
p.(None): including, where relevant, groups of subjects with specific needs, for example. age, gender, participation
p.(None): of healthy volunteers, subjects with rare and ultra rare diseases;
p.(None):
p.(None): (i) references to literature and data that are relevant to the clinical trial, and that provide background for
p.(None): the clinical trial;
p.(None):
p.(None): (j) a discussion of the relevance of the clinical trial in order to allow assessment in accordance with Article
p.(None): 6;
p.(None):
p.(None): (k) a description of the type of clinical trial to be conducted and a discussion of the trial design
p.(None): (including a schematic diagram of trial design, procedures and stages, if relevant);
p.(None):
p.(None): (l) a specification of the primary end-points and the secondary end-points, if any, to be measured during the
p.(None): clinical trial;
p.(None):
p.(None): (m) a description of the measures taken to minimise bias, including, if applicable,
p.(None): randomisation and blinding;
p.(None):
p.(None): (n) a description of the expected duration of subject participation and a description of the sequence and dur
p.(None): ation of all clinical trial periods, including follow-up, if relevant;
p.(None):
p.(None): (o) a clear and unambiguous definition of the end of the clinical trial in question and, if it is not the
p.(None): date of the last visit of the last subject, a specification of the estimated end date and a justification thereof;
p.(None):
p.(None): (p) a description of the criteria for discontinuing parts of the clinical trial or the entire clinical trial;
p.(None):
p.(None): (q) arrangements for the maintenance of clinical trial treatment randomisation codes and procedures
p.(None): for breaking codes, if relevant;
p.(None):
...
p.(None): — timing of any planned interim analysis and the number of subjects planned to be enrolled;
p.(None):
p.(None): — reasons for choice of sample size;
p.(None):
p.(None): — calculations of the power of the clinical trial and clinical relevance;
p.(None):
p.(None): — the level of significance to be used;
p.(None):
p.(None): — criteria for the termination of the clinical trial;
p.(None):
p.(None): — procedures for accounting for missing, unused, and spurious data and for reporting any deviation from
p.(None): the original statistical plan; and
p.(None):
p.(None): — the selection of subjects to be included in the analyses;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/57
p.(None):
p.(None): (v) a description of the subject inclusion and exclusion criteria, including criteria for withdrawing
p.(None): individual subjects from treatment or from the clinical trial;
p.(None):
p.(None): (w) a description of procedures relating to the withdrawal of subjects from treatment or from the
p.(None): clinical trial including procedures for the collection of data regarding withdrawn subjects, procedures for replace
p.(None): ment of subjects and the follow-up of subjects that have withdrawn from treatment or from the clinical
p.(None): trial;
p.(None):
p.(None): (x) a justification for including subjects who are incapable of giving informed consent or other special popu
p.(None): lations, such as minors;
p.(None):
p.(None): (y) a justification for the gender and age allocation of subjects and, if a specific gender or age
p.(None): group is excluded from or underrepresented in the clinical trials, an explanation of the reasons and
p.(None): justification for these exclusion criteria;
p.(None):
p.(None): (z) a detailed description of the recruitment and informed consent procedure, especially when subjects
p.(None): are incapable of giving informed consent;
p.(None):
p.(None): (aa) a description of the treatments, including medicinal products, which are permitted or not
p.(None): permitted, before or during the clinical trial;
p.(None):
p.(None): (ab) a description of the accountability procedures for the supply and administration of medicinal products to
p.(None): subjects including the maintenance of blinding, if applicable;
p.(None):
p.(None): (ac) a description of procedures for monitoring subject compliance, if applicable; (ad) a description of
p.(None): arrangements for monitoring the conduct of the clinical trial;
p.(None): (ae) a description of the arrangements for taking care of the subjects after their participation in
p.(None): the clinical trial has ended, where such additional care is necessary because of the subjects'
p.(None): participation in the clin ical trial and where it differs from that normally expected for the medical condition in
p.(None): question;
p.(None):
p.(None): (af) a specification of the efficacy and safety parameters as well as the methods and timing for
p.(None): assessing, recording, and analysing these parameters;
p.(None):
p.(None): (ag) a description of ethical considerations relating to the clinical trial if those have not been
p.(None): described else where;
p.(None):
...
p.(None):
p.(None):
p.(None): A. CLINICAL TRIAL INFORMATION:
p.(None):
p.(None): 1. Clinical trial identification (including title of the trial and protocol number);
p.(None):
p.(None): 2. Identifiers (including EU trial number, other identifiers);
p.(None):
p.(None): 3. Sponsor details (including scientific and public contact points);.
p.(None):
p.(None): 4. Paediatric regulatory details (including information whether the clinical trial is a part of a
p.(None): Paediatric Investigation Plan);
p.(None):
p.(None): 5. Result analysis stage (including information about intermediate data analysis date, interim or final
p.(None): analysis stage, date of global end of the clinical trial). For clinical trials replicating studies on
p.(None): already authorised investigational medicinal products and used in accordance with the terms of the
p.(None): marketing authorisation, the summary of the results should also indicate identified concerns in the overall
p.(None): results of the clinical trial relating to relevant aspects of the efficacy of the related medicinal product;
p.(None):
p.(None): 6. General information about the clinical trial (including information about main objectives of the
p.(None): trial, trial design, scientific background and explanation of rationale for the trial; date of the start
p.(None): of the trial, measures of protec tion of subjects taken, background therapy; and statistical methods used);
p.(None):
p.(None): 7. Population of subjects (including information with actual number of subjects included in the clinical
p.(None): trial in the Member State concerned, in the Union and in third countries; age group breakdown, gender breakdown).
p.(None):
p.(None): B. SUBJECT DISPOSITION:
p.(None):
p.(None): 1. Recruitment (including information on the number of subjects screened, recruited and withdrawn;
p.(None): inclusion and exclusion criteria; randomisation and blinding details; investigational medicinal products used);
p.(None):
p.(None): 2. Pre-assignment Period;
p.(None):
p.(None): 3. Post Assignment Periods.
p.(None):
p.(None): C. BASELINE CHARACTERISTICS:
p.(None):
p.(None): 1. Baseline Characteristics (Required) Age;
p.(None):
p.(None): 2. Baseline Characteristics (Required) Gender;
p.(None):
p.(None): 3. Baseline Characteristics (Optional) Study Specific Characteristic.
p.(None):
p.(None): D. END POINTS:
p.(None):
p.(None): 1. End point definitions (*)
p.(None):
p.(None): 2. End Point #1 Statistical Analyses
p.(None): 3. End Point #2 Statistical Analyses
p.(None): (*) Information shall be provided for as many end points as defined in the protocol.
p.(None):
p.(None): L 158/70 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): E. ADVERSE EVENTS:
p.(None):
p.(None): 1. Adverse events information;
p.(None):
p.(None): 2. Adverse event reporting group;
p.(None):
p.(None): 3. Serious adverse event;
p.(None):
p.(None): 4. Non-serious adverse event.
p.(None):
p.(None): F. ADDITIONAL INFORMATION:
p.(None):
p.(None): 1. Global Substantial Modifications;
p.(None):
p.(None): 2. Global Interruptions and re-starts;
p.(None):
p.(None): 3. Limitations, addressing sources of potential bias and imprecisions and Caveats;
p.(None):
p.(None): 4. A declaration by the submitting party on the accuracy of the submitted information.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/71
p.(None):
p.(None): ANNEX V
p.(None):
p.(None): CONTENT OF THE SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL FOR LAYPERSONS
p.(None):
p.(None): The summary of the results of the clinical trial for laypersons shall contain information on the following elements:
p.(None): 1. Clinical trial identification (including title of the trial, protocol number, EU trial number and other
p.(None): identifiers);
p.(None): 2. Name and contact details of the sponsor;
p.(None): 3. General information about the clinical trial (including where and when the trial was conducted, the main
p.(None): objectives of the trial and an explanation of the reasons for conducting it);
p.(None): 4. Population of subjects (including information on the number of subjects included in the trial in
p.(None): the Member State concerned, in the Union and in third countries; age group breakdown and gender
p.(None): breakdown; inclusion and exclu sion criteria);
p.(None): 5. Investigational medicinal products used;
p.(None): 6. Description of adverse reactions and their frequency;
p.(None): 7. Overall results of the clinical trial;
p.(None): 8. Comments on the outcome of the clinical trial;
p.(None): 9. Indication if follow up clinical trials are foreseen;
p.(None): 10. Indication where additional information could be found.
p.(None):
p.(None): L 158/72 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX VI
p.(None):
p.(None): LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): A. UNAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): A.1. General rules
p.(None):
p.(None): 1. The following particulars shall appear on the immediate and the outer packaging:
p.(None):
p.(None): (a) name, address and telephone number of the main contact for information on the product, clinical
p.(None): trial and emergency unblinding; this may be the sponsor, contract research organisation or investigator (for the
p.(None): purpose of this Annex this is referred to as the 'main contact');
p.(None):
p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
...
Social / Child
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p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
p.(None): pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior
...
p.(None): medicinal products used in the context of a clinical trial. Regarding Article 168(4)(c) TFEU, this
p.(None): Regulation sets high standards of quality and safety for medicinal products by ensuring that data
p.(None): generated in clinical trials are reliable and robust, thus ensuring that treatments and medicines which
p.(None): are intended to be an improvement of a treatment of patients build on reliable and robust data.
p.(None): Moreover, this Regulation sets high standards of quality and safety of medicinal products used in the
p.(None): context of a clinical trial, thus ensuring the safety of subjects in a clinical trial.
p.(None):
p.(None): (1) Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of
p.(None): individuals with regard to the processing of personal data and on the free movement of such data (OJ L 281, 23.11.1995,
p.(None): p. 31).
p.(None): (2) Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of
p.(None): individuals with
p.(None): regard to the processing of personal data by the Community institutions and bodies and on the free movement of such
p.(None): data (OJ L 8, 12.1.2001, p. 1).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/11
p.(None):
p.(None): (83) This Regulation respects the fundamental rights and observes the principles recognised in
p.(None): particular by the Charter and notably human dignity, the integrity of the person, the rights of the
p.(None): child, respect for private and family life, the protection of personal data and the freedom of art and science.
p.(None): This Regulation should be applied by the Member States in accordance with those rights and principles.
p.(None):
p.(None): (84) The European Data Protection Supervisor has given an opinion (1) pursuant to Article 28(2) of
p.(None): Regulation (EC) No 45/2001.
p.(None):
p.(None): (85) Since the objective of this Regulation, namely to ensure that, throughout the Union, clinical trial data are
p.(None): reliable and robust while ensuring respect for the rights, safety, dignity and well-being of subjects,
p.(None): cannot be sufficiently achieved by the Member States but can rather, by reason of its scale, be better achieved at
p.(None): Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of
p.(None): the Treaty on Euro pean Union. In accordance with the principle of proportionality, as set out in that
p.(None): Article, this Regulation does not go beyond what is necessary in order to achieve that objective,
p.(None):
p.(None): HAVE ADOPTED THIS REGULATION:
p.(None):
p.(None): CHAPTER I
p.(None):
p.(None): GENERAL PROVISIONS
p.(None):
p.(None): Article 1
p.(None):
...
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
p.(None): clinical trial may be obtained, and information on the clinical trial may be given, after the decision to
p.(None): include the subject in the clinical trial, provided that this decision is taken at the time of the first
p.(None): intervention on the subject, in accordance with the protocol for that clinical trial" and that all of the
p.(None): following conditions are fulfilled:
p.(None):
...
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p.(None): trial will pose only minimal risk to, and will impose minimal burden on, the incapacitated subject
p.(None): concerned in com parison with the standard treatment of the incapacitated subject's condition.
p.(None):
p.(None): 2. Point (g)(ii) of paragraph 1 shall be without prejudice to more stringent national rules
p.(None): prohibiting the conduct of those clinical trials on incapacitated subjects, where there are no scientific
p.(None): grounds to expect that participation in the clinical trial will produce a direct benefit to the subject
p.(None): outweighing the risks and burdens involved.
p.(None):
p.(None): 3. The subject shall as far as possible take part in the informed consent procedure.
p.(None):
p.(None):
p.(None): Article 32
p.(None):
p.(None): Clinical trials on minors
p.(None):
p.(None): 1. A clinical trial on minors may be conducted only where, in addition to the conditions set out in
p.(None): Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the minors have received the information referred to in Article 29(2) in a way adapted to their
p.(None): age and mental maturity and from investigators or members of the investigating team who are trained or
p.(None): experienced in working with children;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/33
p.(None):
p.(None): (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information
p.(None): referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is
p.(None): respected by the investi gator;
p.(None): (d) no incentives or financial inducements are given to the subject or his or her legally designated
p.(None): representative except for compensation for expenses and loss of earnings directly related to the participation in the
p.(None): clinical trial;
p.(None): (e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in
p.(None): minors or the clin ical trial is essential with respect to minors to validate data obtained in
p.(None): clinical trials on persons able to give informed consent or by other research methods;
p.(None): (f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is
p.(None): of such a nature that it can only be carried out on minors;
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
...
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
...
p.(None): purpose of this Annex this is referred to as the 'main contact');
p.(None):
p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
p.(None): both the unauthorised investigational medicinal product and the comparator or placebo;
p.(None):
p.(None): (c) pharmaceutical form, route of administration, quantity of dosage units;
p.(None):
p.(None): (d) the batch or code number identifying the contents and packaging operation;
p.(None):
p.(None): (e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None):
p.(None): (f) the subject identification number and/or the treatment number and, where relevant, the visit number;
p.(None):
p.(None): (g) the name of the investigator (if not included in (a) or (e));
p.(None):
p.(None): (h) directions for use (reference may be made to a leaflet or other explanatory document intended for
p.(None): the subject or person administering the product);
p.(None):
p.(None): (i) 'For clinical trial use only' or similar wording;
p.(None):
p.(None): (j) the storage conditions;
p.(None):
p.(None): (k) period of use (expiry date or re-test date as applicable), in month and year format and in a
p.(None): manner that avoids any ambiguity; and
p.(None):
p.(None): (l) 'Keep out of reach of children', except when the product is for use in trials where the product is not taken
p.(None): home by subjects.
p.(None):
p.(None): 2. Symbols or pictograms may be included to clarify certain information mentioned above. Additional
p.(None): informa tion, warnings or handling instructions may be displayed.
p.(None):
p.(None): 3. The address and telephone number of the main contact shall not be required to appear on the label if subjects have
p.(None): been given a leaflet or card which provides these details and have been instructed to keep this in
p.(None): their possession at all times.
p.(None):
p.(None):
p.(None): A.2. Limited labelling of immediate packaging
p.(None):
p.(None): A.2.1. Immediate and outer packaging provided together
p.(None):
p.(None): 4. When the product is provided to the subject or the person administering the medicinal product in
p.(None): an immediate packaging and outer packaging intended to remain together, and the outer packaging carries
p.(None): the particulars listed in section A.1., the following particulars shall appear on the immediate packaging
p.(None): (or any sealed dosing device that contains the immediate package):
p.(None):
p.(None): (a) name of the main contact;
p.(None):
p.(None): (b) pharmaceutical form, route of administration (may be excluded for oral solid dose forms), quantity
p.(None): of dosage units and, in the case of clinical trials which do not involve the blinding of the label,
p.(None): the name/ identifier and strength/potency;
p.(None):
p.(None): (c) batch and/or code number identifying the contents and packaging operation;
p.(None):
p.(None): 27.5.2014 EN
...
Social / Elderly
Searching for indicator elderly:
(return to top)
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
p.(None): ethics committees within the timelines for the authorisation of that clinical trial as set out in this
p.(None): Regulation. Such decisions are a matter of internal organisation for each Member State. When determining
p.(None): the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular
p.(None): patients or patients' organisations. They should also ensure that the necessary expertise is available. In
p.(None): accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons
p.(None): who collectively have the necessary qualifi cations and experience. The persons assessing the application
p.(None): should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free
p.(None): from any other undue influence.
p.(None):
p.(None):
p.(None): (19) The assessment of applications for the authorisation of clinical trials should be conducted on
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
p.(None): trials involving subjects in emer gency situations, minors, incapacitated subjects, pregnant and breastfeeding
p.(None): women and, where appropriate, other identified specific population groups, such as elderly people or people suffering
p.(None): from rare and ultra rare diseases.
p.(None):
p.(None):
p.(None): (20) In practice, sponsors do not always have all the information needed for submitting a complete
p.(None): application for authorisation of a clinical trial in all of the Member States where a clinical trial is
p.(None): eventually going to be conducted. It should be possible for sponsors to submit an application solely on the
p.(None): basis of documents assessed jointly by those Member States where the clinical trial might be conducted.
p.(None):
p.(None):
p.(None): (21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure
p.(None): the reli able functioning of the assessment procedure, however, an application for authorisation of a
p.(None): clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the
p.(None): sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an
p.(None): application.
p.(None):
p.(None): L 158/4 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (22) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest in
p.(None): extending the clinical trial to an additional Member States after the initial authorisation of the clinical trial. An
p.(None): authorisation mechanism should be provided to allow for such extension, while avoiding the re-assessment
p.(None): of the application by all the Member States concerned which were involved in the initial authorisation of the
p.(None): clinical trial.
p.(None):
p.(None):
...
Social / Fetus/Neonate
Searching for indicator foetus:
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p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
...
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
...
Searching for indicator foetuses:
(return to top)
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
...
Social / Incarcerated
Searching for indicator liberty:
(return to top)
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
p.(None): pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior
p.(None): to the intervention. This Regulation should therefore set clear rules whereby such patients may be enrolled in the
p.(None): clinical trial under very strict condi tions. In addition, the said clinical trial should relate directly
...
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
p.(None): clinical trial may be obtained, and information on the clinical trial may be given, after the decision to
p.(None): include the subject in the clinical trial, provided that this decision is taken at the time of the first
p.(None): intervention on the subject, in accordance with the protocol for that clinical trial" and that all of the
p.(None): following conditions are fulfilled:
p.(None):
p.(None): (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious
p.(None): medical condition, the subject is unable to provide prior informed consent and to receive prior information on the
p.(None): clinical trial;
p.(None):
p.(None): (b) there are scientific grounds to expect that participation of the subject in the clinical trial will
p.(None): have the potential to produce a direct clinically relevant benefit for the subject resulting in a
...
Searching for indicator restricted:
(return to top)
p.(None): subparagraph of paragraph 2 from the sponsor in accordance with the second and third subparagraph, the Member State
p.(None): concerned may extend the period referred to in the first subparagraph of paragraph 2 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from the receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the Member State
p.(None): concerned in accordance with the second subparagraph, the application shall be deemed to have lapsed in
p.(None): that Member State concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 8
p.(None):
p.(None): Decision on the clinical trial
p.(None):
p.(None): 1. Each Member State concerned shall notify the sponsor through the EU portal as to whether the
p.(None): clinical trial is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of one single decision within five days from the reporting date or from the last day
p.(None): of the assessment referred to in Article 7, whichever is later.
p.(None):
p.(None): An authorisation of a clinical trial subject to conditions is restricted to conditions which by their
p.(None): nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the
p.(None): conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions,
p.(None): that conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the
p.(None): reporting Member State as regards Part I of the assessment report only on the following grounds:
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 5 or 8 of Article 6.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/19
p.(None):
p.(None): Where a Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
p.(None): the Commission, to all Member States, and to the sponsor.
p.(None):
p.(None): 3. Where, regarding the aspects covered by Part I of the assessment report, the clinical trial is acceptable or
...
p.(None): This Chapter is without prejudice to the possibility for the sponsor to resubmit, following the refusal to grant an
p.(None): author isation or the withdrawal of an application, an application for authorisation to any intended
p.(None): Member State concerned. That application shall be deemed to be a new application for authorisation of another
p.(None): clinical trial.
p.(None):
p.(None):
p.(None): Article 14
p.(None):
p.(None): Subsequent addition of a Member State concerned
p.(None):
p.(None): 1. Where the sponsor wishes to extend an authorised clinical trial to another Member State (‘additional Member
p.(None): State concerned’), the sponsor shall submit an application dossier to that Member State through the EU portal.
p.(None):
p.(None): The application dossier may be submitted only after the notification date of the initial authorisation decision.
p.(None):
p.(None): 2. The reporting Member State for the application dossier referred to in paragraph 1 shall be the
p.(None): reporting Member State for the initial authorisation procedure.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/21
p.(None):
p.(None): 3. The additional Member State concerned shall notify the sponsor through the EU portal, within 52
p.(None): days from the date of submission of the application dossier referred to in paragraph 1, by way of one single
p.(None): decision as to whether the clinical trial is authorised, whether it is authorised subject to conditions, or whether
p.(None): the authorisation is refused.
p.(None):
p.(None): An authorisation of a clinical trial subject to conditions is restricted to conditions which by their
p.(None): nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 4. Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the
p.(None): conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions,
p.(None): that conclusion shall be deemed to be the conclusion of the additional Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, an additional Member State concerned may disagree with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None):
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under paragraph 5 or 6.
p.(None):
p.(None): Where an additional Member State concerned disagrees with the conclusion on the basis of the second
p.(None): subparagraph, it shall communicate its disagreement, together with a detailed justification, through the EU portal,
p.(None): to the Commission, to all Member States, and to the sponsor.
p.(None):
p.(None): 5. Between the date of submission of the application dossier referred to in paragraph 1 and five
p.(None): days before the expiry of the period referred to in paragraph 3, the additional Member State concerned
p.(None): may communicate to the reporting Member State and the other Member States concerned any considerations
...
p.(None): to the applica tion. The coordinated review shall be performed within a maximum of 12 days from receipt
p.(None): of the additional informa tion and the further consolidation shall be performed within a maximum of seven days from
p.(None): the end of the coordinated review. When finalising the assessment report, the reporting Member State shall
p.(None): take due account of the considerations of the other Member States concerned and shall record how all such
p.(None): considerations have been dealt with.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period determined by the reporting
p.(None): Member State in accordance with the third subparagraph, the application shall be deemed to have lapsed
p.(None): in all Member States concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 19
p.(None):
p.(None): Decision on the substantial modification of an aspect covered by Part I of the assessment report
p.(None):
p.(None): 1. Each Member State concerned shall notify the sponsor through the EU portal as to whether the substantial
p.(None): modifi cation is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within five days from the reporting date.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/25
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State is that the substantial modification is acceptable or
p.(None): acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the
p.(None): conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with that conclusion of the
p.(None): reporting Member State only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None):
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
p.(None): the Commission, to all Member States and to the sponsor.
p.(None):
p.(None): A Member State concerned shall refuse to authorise a substantial modification if it disagrees with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report on any of the
p.(None): grounds referred to in the second sub paragraph, or where an ethics committee has issued a negative
...
p.(None):
p.(None): L 158/26 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Where the Member State concerned has not notified the sponsor within the period referred to in the
p.(None): second sub paragraph, the substantial modification shall be deemed to concern an aspect covered by Part II of the
p.(None): assessment report and the application dossier shall be deemed to be complete.
p.(None):
p.(None): Where the sponsor has not provided comments nor completed the application dossier within the period
p.(None): referred to in the first subparagraph, the application shall be deemed to have lapsed in the Member State concerned.
p.(None):
p.(None): 4. For the purpose of this Article, the date on which the sponsor is notified in accordance with
p.(None): paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the
p.(None): validation date shall be the last day of the respective periods referred to in paragraphs 1 and 3.
p.(None):
p.(None): 5. The Member State concerned shall assess the application and shall submit to the sponsor, through
p.(None): the EU portal, Part II of the assessment report, including its conclusion, and the decision as to
p.(None): whether the substantial modification is authorised, whether it is authorised subject to conditions, or whether
p.(None): authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within 38 days from the validation date.
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 6. During the period referred to in the second subparagraph of paragraph 5, the Member State
p.(None): concerned may request, with justified reasons, additional information from the sponsor regarding the
p.(None): substantial modification as far as its territory is concerned.
p.(None):
p.(None): For the purpose of obtaining and reviewing this additional information from the sponsor, the Member
p.(None): State concerned may extend the period referred to in the second subparagraph of paragraph 5 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the Member State
p.(None): concerned in accordance with the third subparagraph, the application shall be deemed to have lapsed in that Member
p.(None): State.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None): 7. A Member State concerned shall refuse to authorise a substantial modification if it finds, on duly justified
p.(None): grounds, that the aspects covered by Part II of the assessment report are not complied with or where
...
p.(None): extend the period referred to paragraph 1 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from the receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide the requested additional information within the period set by the
p.(None): Member State concerned in accordance with the second subparagraph, the application shall be deemed to have
p.(None): lapsed in that Member State.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 23
p.(None):
p.(None): Decision on the substantial modification of aspects covered by Parts I and II of the assessment report
p.(None):
p.(None): 1. Each Member State concerned shall notify the sponsor through the EU portal as to whether the substantial
p.(None): modifi cation is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within five days from the reporting date or
p.(None): from the last day of the assessment period referred to in Article 22, whichever is later.
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State is that the substantial modification of
p.(None): aspects covered by Part I of the assessment report is acceptable or acceptable subject to compliance with specific
p.(None): conditions, that conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the
p.(None): reporting Member State only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards suject safety and data reliability and robustness submitted under paragraph
p.(None): 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion regarding the substantial modification of
p.(None): aspects covered by Part I of the assessment report on the basis of the second subparagraph, it shall
p.(None): communicate its disagree ment, together with a detailed justification through the EU portal to the
p.(None): Commission, to all Member States, and to the sponsor.
p.(None):
p.(None): L 158/28 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Where, regarding the substantial modification of aspects covered by Part I of the assessment report, the
...
p.(None): verification of the conduct of a clinical trial and the quality of the data generated, taking into
p.(None): account all characteristics of the clinical trial, including in particular whether the clinical trial is
p.(None): a low-intervention clinical trial. It shall be readily available, and directly accessible upon request, to
p.(None): the Member States.
p.(None):
p.(None): The clinical trial master file kept by the investigator and that kept by the sponsor may have a different
p.(None): content if this is justified by the different nature of the responsibilities of the investigator and the sponsor.
p.(None):
p.(None):
p.(None): Article 58
p.(None):
p.(None): Archiving of the clinical trial master file
p.(None):
p.(None): Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the
p.(None): content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the
p.(None): medical files of subjects shall be archived in accordance with national law.
p.(None):
p.(None): The content of the clinical trial master file shall be archived in a way that ensures that it is
p.(None): readily available and acces sible, upon request, to the competent authorities.
p.(None):
p.(None): Any transfer of ownership of the content of the clinical trial master file shall be documented. The
p.(None): new owner shall assume the responsibilities set out in this Article.
p.(None):
p.(None): The sponsor shall appoint individuals within its organisation to be responsible for archives. Access to
p.(None): archives shall be restricted to those individuals.
p.(None):
p.(None): The media used to archive the content of the clinical trial master file shall be such that the
p.(None): content remains complete and legible throughout the period referred to in the first paragraph.
p.(None):
p.(None): Any alteration to the content of the clinical trial master file shall be traceable.
p.(None):
p.(None):
p.(None): Article 59
p.(None):
p.(None): Auxiliary medicinal products
p.(None):
p.(None): 1. Only authorised auxiliary medicinal products may be used in a clinical trial.
p.(None):
p.(None): 2. Paragraph 1 shall not apply where no authorised auxiliary medicinal product is available in the
p.(None): Union or where the sponsor cannot reasonably be expected to use an authorised auxiliary medicinal product. A
p.(None): justification to this effect shall be included in the protocol.
p.(None):
p.(None): L 158/42 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Member States shall ensure that unauthorised auxiliary medicinal products may enter their
p.(None): territories for the purpose of their use in a clinical trial in accordance with paragraph 2.
p.(None):
p.(None):
p.(None): CHAPTER IX
p.(None):
p.(None): MANUFACTURING AND IMPORT OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): Article 60
p.(None):
p.(None): Scope of this Chapter
p.(None):
p.(None): This Chapter shall apply to the manufacture and import of investigational medicinal products and
p.(None): auxiliary medicinal products.
p.(None):
p.(None):
p.(None): Article 61
p.(None):
p.(None): Authorisation of manufacturing and import
p.(None):
...
Social / Linguistic Proficiency
Searching for indicator language:
(return to top)
p.(None): modifications may relate to the conduct, the design, the methodology, the investigational or auxiliary
p.(None): medicinal product, or the investigator or clinical trial site involved. Where those modifications have a
p.(None): substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data
p.(None): generated in the clinical trial, they should be subject to an authorisation procedure similar to the initial
p.(None): authorisation procedure.
p.(None):
p.(None):
p.(None): (24) The content of the application dossier for authorisation of a clinical trial should be
p.(None): harmonised in order to ensure that all Member States have the same information available and to simplify
p.(None): the application process for clinical trials.
p.(None):
p.(None):
p.(None): (25) In order to increase transparency in the area of clinical trials, data from a clinical trial
p.(None): should only be submitted in support of a clinical trial application if that clinical trial has been
p.(None): recorded in a publicly accessible and free of charge database which is a primary or partner registry
p.(None): of, or a data provider to, the international clinical trials registry platform of the World Health
p.(None): Organization (WHO ICTRP). Data providers to the WHO ICTRP create and manage clinical trial records in a manner
p.(None): that is consistent with the WHO registry criteria. Specific provision should be made for data from clinical
p.(None): trials started before the date of application of this Regulation.
p.(None):
p.(None):
p.(None): (26) It should be left to Member States to establish the language requirements for the application
p.(None): dossier. To ensure that the assessment of the application for authorisation of a clinical trial functions
p.(None): smoothly, Member States should consider accepting a commonly understood language in the medical field as
p.(None): the language for the docu mentation not destined for the subject.
p.(None):
p.(None):
p.(None): (27) Human dignity and the right to the integrity of the person are recognised in the Charter of
p.(None): Fundamental Rights of the European Union (the ‘Charter’). In particular, the Charter requires that any
p.(None): intervention in the field of biology and medicine cannot be performed without free and informed consent of the
p.(None): person concerned. Directive 2001/20/EC contains an extensive set of rules for the protection of subjects.
p.(None): These rules should be upheld. Regarding the rules concerning the determination of the legally
p.(None): designated representatives of incapacitated persons and minors, those rules diverge in Member States. It
p.(None): should therefore be left to Member States to deter mine the legally designated representatives of
p.(None): incapacitated persons and minors. Incapacitated subjects, minors, pregnant women and breastfeeding women require
p.(None): specific protection measures.
p.(None):
p.(None):
p.(None): (28) An appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner should be
p.(None): respon sible for all medical care provided to the subject, including the medical care provided by other medical staff.
p.(None):
p.(None):
p.(None): (29) It is appropriate that universities and other research institutions, under certain circumstances
p.(None): that are in accord ance with the applicable law on data protection, be able to collect data from
p.(None): clinical trials to be used for future scientific research, for example for medical, natural or social
p.(None): sciences research purposes. In order to collect data for such purposes it is necessary that the subject
p.(None): gives consent to use his or her data outside the protocol of the clinical trial and has the right to
p.(None): withdraw that consent at any time. It is also necessary that research projects based on such data be
p.(None): made subject to reviews that are appropriate for research on human data, for example on ethical aspects,
p.(None): before being conducted.
p.(None):
p.(None):
p.(None): (30) In accordance with international guidelines, the informed consent of a subject should be in
p.(None): writing. When the subject is unable to write, it may be recorded through appropriate alternative means,
p.(None): for instance through audio or video recorders. Prior to obtaining informed consent, the potential subject
p.(None): should receive information in a prior interview in a language which is easily understood by him or her. The
p.(None): subject should have the opportunity to ask questions at any moment. Adequate time should be provided for
p.(None): the subject to consider his or her deci sion. In view of the fact that in certain Member States the only person
p.(None): qualified under national law to perform an interview with a potential subject is a medical doctor while in
p.(None): other Member States this is done by other profes sionals, it is appropriate to provide that the prior
p.(None): interview with a potential subject should be performed by a member of the investigating team qualified
p.(None): for this task under the national law of the Member State where the recruitment takes place.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/5
p.(None):
p.(None): (31) In order to certify that informed consent is given freely, the investigator should take into
p.(None): account all relevant circumstances which might influence the decision of a potential subject to participate in a
p.(None): clinical trial, in particu lar whether the potential subject belongs to an economically or socially
p.(None): disadvantaged group or is in a situation of institutional or hierarchical dependency that could inappropriately
p.(None): influence her or his decision to participate.
p.(None):
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
...
p.(None): referred to in the second paragraph of Article 99, in accordance with Directive 2001/20/EC.
p.(None):
p.(None): 5. Where the clinical trial referred to in paragraph 4 has been conducted outside the Union, it
p.(None): shall have been conducted in accordance with principles equivalent to those of this Regulation as regards
p.(None): the rights and safety of the subject and the reliability and robustness of the data generated in the clinical
p.(None): trial.
p.(None):
p.(None): 6. Data from a clinical trial started as from the date referred to in the second paragraph of
p.(None): Article 99 shall only be submitted in an application dossier if that clinical trial has been registered
p.(None): prior to its start in a public register which is a primary or partner registry of, or a data provider to, the
p.(None): WHO ICTRP.
p.(None):
p.(None): Data from a clinical trial started before the date referred to in the second paragraph of Article 99 shall only be
p.(None): submitted in an application dossier if that clinical trial is registered in a public register which is a primary or
p.(None): partner registry of, or a data provider to, the WHO ICTRP or if the results of that clinical trial have
p.(None): been published in an independent peer- reviewed scientific publication.
p.(None):
p.(None): 7. Data submitted in an application dossier which do not comply with paragraphs 3 to 6 shall not
p.(None): be considered in the assessment of an application for authorisation of a clinical trial or of a substantial
p.(None): modification.
p.(None):
p.(None):
p.(None): Article 26
p.(None):
p.(None): Language requirements
p.(None):
p.(None): The language of the application dossier, or parts thereof, shall be determined by the Member State concerned.
p.(None):
p.(None): Member States, in applying the first paragraph, shall consider accepting, for the documentation not
p.(None): addressed to the subject, a commonly understood language in the medical field.
p.(None):
p.(None):
p.(None): Article 27
p.(None):
p.(None): Update by way of delegated acts
p.(None):
p.(None): The Commission shall be empowered to adopt delegated acts in accordance with Article 85 in respect of
p.(None): amending Annexes I and II in order to adapt them to technical progress or to take account of
p.(None): international regulatory develop ments in which the Union or the Member States are involved, in the field of
p.(None): clinical trials.
p.(None):
p.(None):
p.(None): CHAPTER V
p.(None):
p.(None): PROTECTION OF SUBJECTS AND INFORMED CONSENT
p.(None):
p.(None): Article 28
p.(None):
p.(None): General rules
p.(None):
p.(None): 1. A clinical trial may be conducted only where all of the following conditions are met:
p.(None): (a) the anticipated benefits to the subjects or to public health justify the foreseeable risks and
p.(None): inconveniences and compliance with this condition is constantly monitored;
p.(None): (b) the subjects, or where a subject is not able to give informed consent, his or her legally
p.(None): designated representative, have been informed in accordance with Article 29(2) to (6);
p.(None):
p.(None): L 158/30 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (c) the subjects, or where a subject is not able to give informed consent, his or her legally
...
p.(None): products referred to in paragraph 1 shall be contained in the application dossier.
p.(None):
p.(None):
p.(None): Article 52
p.(None):
p.(None): Reporting of serious breaches
p.(None):
p.(None): 1. The sponsor shall notify the Member States concerned about a serious breach of this Regulation
p.(None): or of the version of the protocol applicable at the time of the breach through the EU portal without undue delay
p.(None): but not later than seven days of becoming aware of that breach.
p.(None):
p.(None): 2. For the purposes of this Article, a ‘serious breach’ means a breach likely to affect to a
p.(None): significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the
p.(None): clinical trial.
p.(None):
p.(None):
p.(None): Article 53
p.(None):
p.(None): Other reporting obligations relevant for subject safety
p.(None):
p.(None): 1. The sponsor shall notify the Member States concerned through the EU portal of all unexpected events which
p.(None): affect the benefit-risk balance of the clinical trial, but are not suspected unexpected serious adverse
p.(None): reactions as referred to in Article 42. That notification shall be made without undue delay but no
p.(None): later than 15 days from the date the sponsor became aware of this event.
p.(None):
p.(None): 2. The sponsor shall submit to the Member States concerned, through the EU portal, all inspection
p.(None): reports of third country authorities concerning the clinical trial. When requested by a Member State concerned, the
p.(None): sponsor shall submit a translation of the report or of its summary in an official language of the Union indicated in
p.(None): the request.
p.(None):
p.(None):
p.(None): Article 54
p.(None):
p.(None): Urgent safety measures
p.(None):
p.(None): 1. Where an unexpected event is likely to seriously affect the benefit-risk balance, the sponsor
p.(None): and the investigator shall take appropriate urgent safety measures to protect the subjects.
p.(None):
p.(None): 2. The sponsor shall notify the Member States concerned, through the EU portal, of the event and
p.(None): the measures taken.
p.(None):
p.(None): That notification shall be made without undue delay but no later than seven days from the date the measures have been
p.(None): taken.
p.(None):
p.(None): 3. This Article is without prejudice to Chapters III and VII.
p.(None):
p.(None):
p.(None): Article 55
p.(None):
p.(None): Investigator's brochure
p.(None):
p.(None): 1. The sponsor shall provide the investigator with the investigator's brochure.
p.(None):
p.(None): 2. The investigator's brochure shall be updated where new and relevant safety information becomes
p.(None): available, and shall be reviewed by the sponsor at least once per year.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/41
p.(None):
p.(None): Article 56
p.(None):
p.(None): Recording, processing, handling and storage of information
p.(None):
p.(None): 1. All clinical trial information shall be recorded, processed, handled, and stored by the sponsor
p.(None): or investigator, as applicable, in such a way that it can be accurately reported, interpreted and
...
p.(None):
p.(None):
p.(None): Article 67
p.(None):
p.(None): Authorised investigational and authorised auxiliary medicinal products
p.(None):
p.(None): 1. Authorised investigational medicinal products and authorised auxiliary medicinal products shall be labelled:
p.(None):
p.(None): (a) in accordance with Article 66(1); or
p.(None):
p.(None): (b) in accordance with Title V of Directive 2001/83/EC.
p.(None):
p.(None): 2. Notwithstanding point (b) of paragraph 1, where the specific circumstances, provided for in the protocol, of a
p.(None): clin ical trial so require in order to ensure the safety of the subject or the reliability and
p.(None): robustness of data generated in a clinical trial, additional particulars relating to the identification of the
p.(None): clinical trial and of the contact person shall appear on the outer packaging and the immediate packaging of authorised
p.(None): investigational medicinal products. A list of these ad ditional particulars appearing on the outer packaging and
p.(None): immediate packaging is set out in section C of Annex VI.
p.(None):
p.(None):
p.(None): Article 68
p.(None):
p.(None): Radiopharmaceuticals used as investigational medicinal products or as auxiliary medicinal products for a
p.(None): medical diagnosis
p.(None):
p.(None): Articles 66 and 67 shall not apply to radiopharmaceuticals used as diagnostic investigational medicinal
p.(None): products or as diagnostic auxiliary medicinal products.
p.(None):
p.(None): The products referred to in the first paragraph shall be labelled appropriately in order to ensure the safety of the
p.(None): subject and the reliability and robustness of data generated in the clinical trial.
p.(None):
p.(None):
p.(None): Article 69
p.(None):
p.(None): Language
p.(None):
p.(None): The language of the information on the label shall be determined by the Member State concerned. The
p.(None): medicinal product may be labelled in several languages.
p.(None):
p.(None):
p.(None): Article 70
p.(None):
p.(None): Delegated act
p.(None):
p.(None): The Commission shall be empowered to adopt delegated acts in accordance with Article 89 in respect of
p.(None): amending Annex VI in order to ensure subject safety and the reliability and robustness of data generated
p.(None): in a clinical trial or to take account of technical progress.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/45
p.(None):
p.(None): CHAPTER XI
p.(None):
p.(None): SPONSOR AND INVESTIGATOR
p.(None):
p.(None): Article 71
p.(None):
p.(None): Sponsor
p.(None):
p.(None): A clinical trial may have one or several sponsors.
p.(None):
p.(None): Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution
p.(None): or an organisation. Such delegation shall be without prejudice to the responsibility of the sponsor, in
p.(None): particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical
p.(None): trial.
p.(None):
p.(None): The investigator and the sponsor may be the same person.
p.(None):
p.(None):
p.(None): Article 72
p.(None):
p.(None): Co-sponsorship
p.(None):
p.(None): 1. Without prejudice to Article 74, where a clinical trial has more than one sponsor, all sponsors
p.(None): shall have the responsibilities of a sponsor set out in this Regulation, unless the sponsors decide otherwise in a
...
Social / Marital Status
Searching for indicator single:
(return to top)
p.(None): clinical trials has only been partly achieved. This makes it in particular difficult to perform a given
p.(None): clinical trial in several Member
p.(None):
p.(None): (1) OJ C 44, 15.2.2013, p. 99.
p.(None): (2) Position of the European Parliament of 3 April 2014 (not yet published in the Official Journal) and decision of
p.(None): the Council of 14 April 2014.
p.(None): (3) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the
p.(None): laws, regulations and
p.(None): administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct
p.(None): of clinical trials on medicinal products for human use (OJ L 121, 1.5.2001, p. 34).
p.(None):
p.(None): L 158/2 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): States. Scientific development, however, suggests that future clinical trials will target more specific patient popula
p.(None): tions, such as subgroups identified through genomic information. In order to include a sufficient number
p.(None): of patients for such clinical trials it may be necessary to involve many, or all, Member States. The
p.(None): new procedures for the authorisation of clinical trials should stimulate the inclusion of as many Member States as
p.(None): possible. There fore, in order to simplify the procedures for the submission of an application dossier
p.(None): for the authorisation of a clinical trial, the multiple submission of largely identical information should
p.(None): be avoided and replaced by the submission of one application dossier to all the Member States concerned
p.(None): through a single submission portal. Given that clinical trials carried out in a single Member State are equally
p.(None): important to European clinical research, the application dossier for such clinical trials should also be submitted
p.(None): through that single portal.
p.(None):
p.(None):
p.(None): (5) As regards Directive 2001/20/EC, experience also indicates that the legal form of a Regulation
p.(None): would present advantages for sponsors and investigators, for example in the context of clinical trials
p.(None): taking place in more than one Member State, since they will be able to rely on its provisions
p.(None): directly, but also in the context of safety reporting and labelling of investigational medicinal products.
p.(None): Divergences of approach among different Member States will be therefore kept to a minimum.
p.(None):
p.(None):
p.(None): (6) The Member States concerned should cooperate in assessing a request for authorisation of a clinical trial.
p.(None): This co operation should not include aspects of an intrinsically national nature, such as informed consent.
p.(None):
p.(None):
p.(None): (7) In order to avoid administrative delays for starting a clinical trial, the procedure to be used should be
p.(None): flexible and efficient, without compromising patient safety or public health.
p.(None):
p.(None):
p.(None): (8) The timelines for assessing an application dossier for clinical trials should be sufficient to
p.(None): assess the file while, at the same time, ensuring quick access to new, innovative treatments and
p.(None): ensuring that the Union remains an attractive place for conducting clinical trials. Against this
p.(None): background, Directive 2001/20/EC introduced the concept of tacit authorisation. This concept should be
...
p.(None): the popula tion groups, for example gender and age groups, that are likely to use the medicinal product
p.(None): investigated in the clinical trial.
p.(None):
p.(None):
p.(None): (15) In order to improve treatments available for vulnerable groups such as frail or older people,
p.(None): people suffering from multiple chronic conditions, and people affected by mental health disorders,
p.(None): medicinal products which are likely to be of significant clinical value should be fully and appropriately
p.(None): studied for their effects in these specific groups, including as regards requirements related to their
p.(None): specific characteristics and the protection of the health and well-being of subjects belonging to these groups.
p.(None):
p.(None):
p.(None): (16) The authorisation procedure should provide for the possibility to extend the timelines for the assessment
p.(None): in order to allow the sponsor to address questions or comments raised during the assessment of the
p.(None): application dossier. Moreover, it should be ensured that, within the extension period, there is always
p.(None): sufficient time for assessing the additional information submitted.
p.(None):
p.(None):
p.(None): (17) The authorisation to conduct a clinical trial should address all aspects of subject protection
p.(None): and data reliability and robustness. That authorisation should therefore be contained in a single
p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
p.(None): (18) It should be left to the Member State concerned to determine the appropriate body or bodies
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
p.(None): ethics committees within the timelines for the authorisation of that clinical trial as set out in this
p.(None): Regulation. Such decisions are a matter of internal organisation for each Member State. When determining
p.(None): the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular
p.(None): patients or patients' organisations. They should also ensure that the necessary expertise is available. In
p.(None): accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons
p.(None): who collectively have the necessary qualifi cations and experience. The persons assessing the application
p.(None): should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free
p.(None): from any other undue influence.
p.(None):
p.(None):
p.(None): (19) The assessment of applications for the authorisation of clinical trials should be conducted on
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
...
p.(None): influence her or his decision to participate.
p.(None):
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
...
p.(None): arrangements for inspection for ensuring the quality of investiga tional medicinal products; the amendment
p.(None): of Annex VI in order to ensure subject safety and the reliability and robustness of data generated in
p.(None): a clinical trial or to take account of technical progress. It is of particular impor tance that the
p.(None): Commission carry out appropriate consultations during its preparatory work, including at expert level. The
p.(None): Commission, when preparing and drawing-up delegated acts, should ensure a simultaneous, timely and appropriate
p.(None): transmission of relevant documents to the European Parliament and to the Council.
p.(None):
p.(None):
p.(None): (74) Directive 2001/83/EC provides that that Directive does not affect the application of national
p.(None): legislation prohi biting or restricting the sale, supply or use of medicinal products as abortifacients. Directive
p.(None): 2001/83/EC provides that national legislation prohibiting or restricting the use of any specific type of
p.(None): human or animal cells is not, in principle, affected by either that Directive or any of the Regulations
p.(None): referred to therein. Likewise, this Regulation should not affect national law prohibiting or restricting the
p.(None): use of any specific type of human or animal cells, or the sale, supply or use of medicinal products used as
p.(None): abortifacients. In addition, this Regulation should not affect national law prohibiting or restricting the
p.(None): sale, supply or use of medicinal products containing narcotic substances within the meaning of the
p.(None): relevant international conventions in force such as the Single Convention on Narcotic Drugs of 1961 of the
p.(None): United Nations. Member States should communicate those national provisions to the Commission.
p.(None):
p.(None):
p.(None): (75) Directive 2001/20/EC provides that no gene therapy trials may be carried out which result in
p.(None): modifications to the subject's germ line genetic identity. It is appropriate to maintain that provision.
p.(None):
p.(None): (1) Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011 laying down the
p.(None): rules and general principles concerning mechanisms for control by Member States of the Commission's exercise
p.(None): of implementing powers (OJ L 55, 28.2.2011, p. 13).
p.(None):
p.(None): L 158/10 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (76) Directive 95/46/EC of the European Parliament and of the Council (1) applies to the processing
p.(None): of personal data carried out in the Member States within the framework of this Regulation, under the
p.(None): supervision of the Member States competent authorities, in particular the public independent authorities
p.(None): designated by the Member States and Regulation (EC) No 45/2001 of the European Parliament and of the
p.(None): Council (2) applies to the processing of personal data carried out by the Commission and the Agency within the
p.(None): framework of this Regulation, under the supervision of the European Data Protection Supervisor. Those
...
p.(None): regarding the aspects referred to in paragraph 1 only within the period referred to in the first subparagraph.
p.(None):
p.(None): 3. For the purpose of obtaining and reviewing the additional information referred to in the second
p.(None): subparagraph of paragraph 2 from the sponsor in accordance with the second and third subparagraph, the Member State
p.(None): concerned may extend the period referred to in the first subparagraph of paragraph 2 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from the receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the Member State
p.(None): concerned in accordance with the second subparagraph, the application shall be deemed to have lapsed in
p.(None): that Member State concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 8
p.(None):
p.(None): Decision on the clinical trial
p.(None):
p.(None): 1. Each Member State concerned shall notify the sponsor through the EU portal as to whether the
p.(None): clinical trial is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of one single decision within five days from the reporting date or from the last day
p.(None): of the assessment referred to in Article 7, whichever is later.
p.(None):
p.(None): An authorisation of a clinical trial subject to conditions is restricted to conditions which by their
p.(None): nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the
p.(None): conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions,
p.(None): that conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the
p.(None): reporting Member State as regards Part I of the assessment report only on the following grounds:
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 5 or 8 of Article 6.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/19
p.(None):
p.(None): Where a Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
...
p.(None): only be withdrawn with respect to all Member States concerned. The reasons for the withdrawal shall be
p.(None): communicated through the EU portal.
p.(None):
p.(None):
p.(None): Article 13
p.(None):
p.(None): Resubmission
p.(None):
p.(None): This Chapter is without prejudice to the possibility for the sponsor to resubmit, following the refusal to grant an
p.(None): author isation or the withdrawal of an application, an application for authorisation to any intended
p.(None): Member State concerned. That application shall be deemed to be a new application for authorisation of another
p.(None): clinical trial.
p.(None):
p.(None):
p.(None): Article 14
p.(None):
p.(None): Subsequent addition of a Member State concerned
p.(None):
p.(None): 1. Where the sponsor wishes to extend an authorised clinical trial to another Member State (‘additional Member
p.(None): State concerned’), the sponsor shall submit an application dossier to that Member State through the EU portal.
p.(None):
p.(None): The application dossier may be submitted only after the notification date of the initial authorisation decision.
p.(None):
p.(None): 2. The reporting Member State for the application dossier referred to in paragraph 1 shall be the
p.(None): reporting Member State for the initial authorisation procedure.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/21
p.(None):
p.(None): 3. The additional Member State concerned shall notify the sponsor through the EU portal, within 52
p.(None): days from the date of submission of the application dossier referred to in paragraph 1, by way of one single
p.(None): decision as to whether the clinical trial is authorised, whether it is authorised subject to conditions, or whether
p.(None): the authorisation is refused.
p.(None):
p.(None): An authorisation of a clinical trial subject to conditions is restricted to conditions which by their
p.(None): nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 4. Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the
p.(None): conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions,
p.(None): that conclusion shall be deemed to be the conclusion of the additional Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, an additional Member State concerned may disagree with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None):
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under paragraph 5 or 6.
p.(None):
p.(None): Where an additional Member State concerned disagrees with the conclusion on the basis of the second
p.(None): subparagraph, it shall communicate its disagreement, together with a detailed justification, through the EU portal,
p.(None): to the Commission, to all Member States, and to the sponsor.
p.(None):
...
p.(None): Member State which shall not exceed 12 days from receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member States concerned shall jointly review any additional
p.(None): information provided by the sponsor together with the original application and shall share any considerations relevant
p.(None): to the applica tion. The coordinated review shall be performed within a maximum of 12 days from receipt
p.(None): of the additional informa tion and the further consolidation shall be performed within a maximum of seven days from
p.(None): the end of the coordinated review. When finalising the assessment report, the reporting Member State shall
p.(None): take due account of the considerations of the other Member States concerned and shall record how all such
p.(None): considerations have been dealt with.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period determined by the reporting
p.(None): Member State in accordance with the third subparagraph, the application shall be deemed to have lapsed
p.(None): in all Member States concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 19
p.(None):
p.(None): Decision on the substantial modification of an aspect covered by Part I of the assessment report
p.(None):
p.(None): 1. Each Member State concerned shall notify the sponsor through the EU portal as to whether the substantial
p.(None): modifi cation is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within five days from the reporting date.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/25
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State is that the substantial modification is acceptable or
p.(None): acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the
p.(None): conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with that conclusion of the
p.(None): reporting Member State only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None):
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
p.(None): the Commission, to all Member States and to the sponsor.
p.(None):
...
p.(None): State shall notify the sponsor as to whether or not the application complies with the requirements set
p.(None): out in points (a) and (b) of paragraph 1.
p.(None):
p.(None): L 158/26 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Where the Member State concerned has not notified the sponsor within the period referred to in the
p.(None): second sub paragraph, the substantial modification shall be deemed to concern an aspect covered by Part II of the
p.(None): assessment report and the application dossier shall be deemed to be complete.
p.(None):
p.(None): Where the sponsor has not provided comments nor completed the application dossier within the period
p.(None): referred to in the first subparagraph, the application shall be deemed to have lapsed in the Member State concerned.
p.(None):
p.(None): 4. For the purpose of this Article, the date on which the sponsor is notified in accordance with
p.(None): paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the
p.(None): validation date shall be the last day of the respective periods referred to in paragraphs 1 and 3.
p.(None):
p.(None): 5. The Member State concerned shall assess the application and shall submit to the sponsor, through
p.(None): the EU portal, Part II of the assessment report, including its conclusion, and the decision as to
p.(None): whether the substantial modification is authorised, whether it is authorised subject to conditions, or whether
p.(None): authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within 38 days from the validation date.
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 6. During the period referred to in the second subparagraph of paragraph 5, the Member State
p.(None): concerned may request, with justified reasons, additional information from the sponsor regarding the
p.(None): substantial modification as far as its territory is concerned.
p.(None):
p.(None): For the purpose of obtaining and reviewing this additional information from the sponsor, the Member
p.(None): State concerned may extend the period referred to in the second subparagraph of paragraph 5 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the Member State
p.(None): concerned in accordance with the third subparagraph, the application shall be deemed to have lapsed in that Member
p.(None): State.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None): 7. A Member State concerned shall refuse to authorise a substantial modification if it finds, on duly justified
...
p.(None): reasons, ad ditional information from the sponsor regarding this substantial modification as far as its territory is
p.(None): concerned.
p.(None):
p.(None): 3. For the purpose of obtaining and reviewing the additional information referred to in paragraph 2
p.(None): from the sponsor in accordance with the third and fourth subparagraph, the Member State concerned may
p.(None): extend the period referred to paragraph 1 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from the receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide the requested additional information within the period set by the
p.(None): Member State concerned in accordance with the second subparagraph, the application shall be deemed to have
p.(None): lapsed in that Member State.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 23
p.(None):
p.(None): Decision on the substantial modification of aspects covered by Parts I and II of the assessment report
p.(None):
p.(None): 1. Each Member State concerned shall notify the sponsor through the EU portal as to whether the substantial
p.(None): modifi cation is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within five days from the reporting date or
p.(None): from the last day of the assessment period referred to in Article 22, whichever is later.
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State is that the substantial modification of
p.(None): aspects covered by Part I of the assessment report is acceptable or acceptable subject to compliance with specific
p.(None): conditions, that conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the
p.(None): reporting Member State only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards suject safety and data reliability and robustness submitted under paragraph
p.(None): 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion regarding the substantial modification of
p.(None): aspects covered by Part I of the assessment report on the basis of the second subparagraph, it shall
p.(None): communicate its disagree ment, together with a detailed justification through the EU portal to the
...
p.(None): any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening.
p.(None): Where necessary to ensure timely reporting, the sponsor may, in accordance with section 2.4 of Annex
p.(None): III, submit an initial incomplete report followed up by a complete report.
p.(None):
p.(None): L 158/38 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Where a sponsor, due to a lack of resources, does not have the possibility to report to the
p.(None): database referred to in Article 40(1) and the sponsor has the agreement of the Member State concerned,
p.(None): it may report to the Member State where the suspected unexpected serious adverse reaction occurred. That
p.(None): Member State shall report the suspected unex pected serious adverse reaction in accordance with paragraph 1 of
p.(None): this Article.
p.(None):
p.(None):
p.(None): Article 43
p.(None):
p.(None): Annual reporting by the sponsor to the Agency
p.(None):
p.(None): 1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually
p.(None): through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational
p.(None): medicinal product used in a clinical trial for which it is the sponsor.
p.(None):
p.(None): 2. In the case of a clinical trial involving the use of more than one investigational medicinal
p.(None): product, the sponsor may, if provided for in the protocol, submit a single safety report on all
p.(None): investigational medicinal products used in that clinical trial.
p.(None):
p.(None): 3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymised data.
p.(None):
p.(None): 4. The obligation referred to in paragraph 1 starts with the first authorisation of a clinical
p.(None): trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor
p.(None): with the investigational medicinal product.
p.(None):
p.(None):
p.(None): Article 44
p.(None):
p.(None): Assessment by Member States
p.(None):
p.(None): 1. The Agency shall, by electronic means, forward to the Member States concerned the information
p.(None): reported in accordance with Article 42 and 43.
p.(None):
p.(None): 2. Member States shall cooperate in assessing the information reported in accordance with Articles
p.(None): 42and 43. The Commission may, by means of implementing acts, set up and modify the rules on such
p.(None): cooperation. Those imple menting acts shall be adopted in accordance with the examination procedure referred to in
p.(None): Article 88(2).
p.(None):
p.(None): 3. The responsible ethics committee shall be involved in the assessment of the information referred to in
p.(None): paragraphs 1 and 2, if it has been provided for in the law of the Member State concerned.
p.(None):
p.(None):
p.(None): Article 45
p.(None):
p.(None): Technical aspects
p.(None):
p.(None): Technical aspects for safety reporting in accordance with Articles 41 to 44 are contained in Annex III.
p.(None): Where necessary in order to improve the level of protection of subjects, the Commission shall be
...
p.(None): (a) whether Member States correctly supervise compliance with this Regulation;
p.(None): (b) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that
p.(None): point 8 of the Introduction and general principles contained in Annex I to Directive 2001/83/EC is complied with;
p.(None): (c) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that
p.(None): Article 25(5) of this Regulation is complied with.
p.(None): 2. The Union controls referred to in point (a) of paragraph 1 shall be organised in cooperation
p.(None): with the Member States concerned.
p.(None):
p.(None): The Commission shall prepare in cooperation with the Member States a programme for the Union controls
p.(None): referred to in points (b) and (c) of paragraph 1.
p.(None):
p.(None): The Commission shall report on the findings of each Union control carried out. Those reports shall, if
p.(None): appropriate, contain recommendations. The Commission shall submit those reports through the EU portal.
p.(None):
p.(None):
p.(None): CHAPTER XIV
p.(None):
p.(None): IT INFRASTRUCTURE
p.(None):
p.(None): Article 80
p.(None):
p.(None): EU portal
p.(None):
p.(None): The Agency shall, in collaboration with the Member States and the Commission, set up and maintain a
p.(None): portal at Union level as a single entry point for the submission of data and information relating to
p.(None): clinical trials in accordance with this Regulation. The EU portal shall be technically advanced and user-friendly
p.(None): so as to avoid unnecessary work.
p.(None):
p.(None): L 158/48 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Data and information submitted through the EU portal shall be stored in the EU database.
p.(None):
p.(None):
p.(None): Article 81
p.(None):
p.(None): EU database
p.(None):
p.(None): 1. The Agency shall, in collaboration with the Member States and the Commission, set up and
p.(None): maintain a EU data base at Union level. The Agency shall be considered to be the controller of the EU
p.(None): database and shall be responsible for avoiding unnecessary duplication between the EU database and the EudraCT and
p.(None): Eudravigilance databases.
p.(None):
p.(None): The EU database shall contain the data and information submitted in accordance with this Regulation.
p.(None):
p.(None): The EU database shall identify each clinical trial by a unique EU trial number. The sponsor shall
p.(None): refer to this EU trial number in any subsequent submission relating or referring to that clinical trial.
p.(None):
p.(None): 2. The EU database shall be established to enable cooperation between the competent authorities of
p.(None): the Member States concerned to the extent that it is necessary for the application of this Regulation and to search
p.(None): for specific clinical trials. It shall also facilitate the communication between sponsors and Member States
...
p.(None): the Official Journal of the European Union or at a later date specified therein. It shall not affect the validity
p.(None): of any delegated acts already in force.
p.(None):
p.(None): 4. As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the European Parliament
p.(None): and to the Council.
p.(None):
p.(None): 5. A delegated act adopted pursuant to Articles 27, 39, 45, 63(1) and 70 shall enter into force
p.(None): only if no objection has been expressed either by the European Parliament or the Council within a
p.(None): period of two months from notification of that act to the European Parliament and the Council or if,
p.(None): before the expiry of that period, the European Parliament and the Council have both informed the
p.(None): Commission that they will not object. That period shall be extended by two months at the initiative of the
p.(None): European Parliament or the Council.
p.(None):
p.(None):
p.(None): CHAPTER XVIII
p.(None):
p.(None): MISCELLANEOUS PROVISIONS
p.(None):
p.(None): Article 90
p.(None):
p.(None): Specific requirements for special groups of medicinal products
p.(None):
p.(None): This Regulation shall not affect the application of national law prohibiting or restricting the use of
p.(None): any specific type of human or animal cells, or the sale, supply or use of medicinal products containing,
p.(None): consisting of or derived from those cells, or of medicinal products used as abortifacients or of medicinal
p.(None): products containing narcotic substances within the meaning of the relevant international conventions in force such
p.(None): as the Single Convention on Narcotic Drugs of 1961 of the United Nations. The Member States shall communicate that
p.(None): national law to the Commission.
p.(None):
p.(None): No gene therapy clinical trials may be carried out which result in modifications to the subject's germ
p.(None): line genetic iden tity.
p.(None):
p.(None):
p.(None): Article 91
p.(None):
p.(None): Relation with other Union legislation
p.(None):
p.(None): This Regulation shall be without prejudice to Council Directive 97/43/Euratom (1), Council Directive
p.(None): 96/29/Euratom (2), Directive 2001/18/EC of the European Parliament and of the Council (3), Directive
p.(None): 2004/23/EC of the European Parlia ment and of the Council (4), Directive 2002/98/EC of the
p.(None): European Parliament and of the Council (5), Directive 2010/53/EC of the European Parliament and of
p.(None): the Council (6), and Directive 2009/41/EC of the European Parliament and of the Council. (7)
p.(None):
p.(None): (1) Council Directive 97/43/Euratom of 30 June 1997 on health protection of individuals against the dangers of
p.(None): ionizing radiation in rela tion to medical exposure, and repealing Directive 84/466/Euratom (OJ L 180, 9.7.1997, p.
p.(None): 22).
p.(None): (2) Council Directive 96/29/Euratom of 13 May 1996 laying down basic safety standards for the protection of the health
p.(None): of workers and the
p.(None): general public against the dangers arising from ionizing radiation (OJ L 159, 29.6.1996, p. 1).
p.(None): (3) Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into
...
p.(None): trade names in a number of authorised medicinal products, the protocol may define the treatment in terms
p.(None): of the active substance or Anatomical Therapeutic Chemical (ATC) code (level 3-5) only and not specify
p.(None): the trade name of each product.
p.(None):
p.(None): L 158/58 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 19. With regard to the notification of adverse events, the protocol shall identify the categories of:
p.(None):
p.(None): (a) adverse events or laboratory anomalies that are critical to safety evaluations and must be reported
p.(None): by the investigator to the sponsor, and
p.(None):
p.(None): (b) serious adverse events which do not require immediate reporting by the investigator to the sponsor.
p.(None):
p.(None): 20. The protocol shall describe the procedures for:
p.(None):
p.(None): (a) eliciting and recording adverse events by the investigator, and the reporting of relevant adverse
p.(None): events by the investigator to the sponsor;
p.(None):
p.(None): (b) reporting by the investigator to the sponsor of those serious adverse events which have been
p.(None): identified in the protocol as not requiring immediate reporting;
p.(None):
p.(None): (c) reporting of suspected unexpected serious adverse reactions by the sponsor to the Eudravigilance database; and
p.(None):
p.(None): (d) follow-up of subjects after adverse reactions including the type and duration of follow-up.
p.(None):
p.(None): 21. In case the sponsor intends to submit a single safety report on all investigational medicinal
p.(None): products used in the clinical trial in accordance with Article 43(2), the protocol shall indicate the reasons
p.(None): thereof.
p.(None):
p.(None): 22. Issues regarding labelling and the unblinding of investigational medicinal products shall be addressed
p.(None): in the protocol, where necessary.
p.(None):
p.(None): 23. The protocol shall be accompanied by the Charter of the Data Safety Monitoring Committee, if applicable.
p.(None):
p.(None): 24. The protocol shall be accompanied by a synopsis of the protocol.
p.(None):
p.(None):
p.(None): E. INVESTIGATOR'S BROCHURE (IB)
p.(None):
p.(None): 25. An IB, which has been prepared in accordance with the state of scientific knowledge and
p.(None): international guidance, shall be submitted.
p.(None):
p.(None): 26. The purpose of the IB is to provide the investigators and others involved in the clinical trial
p.(None): with information to facilitate their understanding of the rationale for, and their compliance with, key
p.(None): features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety
p.(None): monitoring procedures.
p.(None):
p.(None): 27. The information in the IB shall be presented in a concise, simple, objective, balanced and
p.(None): non-promotional form that enables a clinician or investigator to understand it and make an unbiased
p.(None): risk-benefit assessment of the appropriateness of the proposed clinical trial. It shall be prepared from
p.(None): all available information and evidence that supports the rationale for the proposed clinical trial and the safe use
...
p.(None):
p.(None): O. PROOF OF INSURANCE COVER OR INDEMNIFICATION (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 68. Proof of insurance, a guarantee, or a similar arrangement shall be submitted, if applicable.
p.(None):
p.(None): P. FINANCIAL AND OTHER ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 69. A brief description of the financing of the clinical trial.
p.(None):
p.(None): 70. Information on financial transactions and compensation paid to subjects and investigator/site for
p.(None): participating in the clinical trial shall be submitted.
p.(None):
p.(None): 71. Description of any other agreement between the sponsor and the site shall be submitted.
p.(None):
p.(None): Q. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 72. Proof of payment shall be submitted, if applicable.
p.(None):
p.(None): R. PROOF THAT DATA WILL BE PROCESSED IN COMPLIANCE WITH UNION LAW ON DATA PROTECTION
p.(None):
p.(None): 73. A statement by the sponsor or his or her representative that data will be collected and processed in accordance
p.(None): with Directive 95/46/EEC shall be provided.
p.(None):
p.(None): L 158/64 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX II
p.(None):
p.(None): APPLICATION DOSSIER FOR SUBSTANTIAL MODIFICATION
p.(None):
p.(None): A. INTRODUCTION AND GENERAL PRINCIPLES
p.(None): 1. Where a substantial modification concerns more than one clinical trial of the same sponsor and the same investi
p.(None): gational medicinal product, the sponsor may make a single request for authorisation of the substantial
p.(None): modifica tion. The cover letter shall contain a list of all clinical trials to which the application
p.(None): for substantial modification relates, with the EU trial numbers and respective modification code numbers of each of
p.(None): those clinical trials.
p.(None):
p.(None): 2. The application shall be signed by the sponsor or a representative of the sponsor. This signature
p.(None): shall confirm that the sponsor is satisfied that:
p.(None): (a) the information provided is complete;
p.(None): (b) the attached documents contain an accurate account of the information available; and
p.(None): (c) the clinical trial will be conducted in accordance with the amended documentation.
p.(None):
p.(None): B. COVER LETTER
p.(None): 3. A cover letter with the following information:
p.(None): (a) in its subject line, the EU trial number with the title of the clinical trial and the substantial
p.(None): modification code number which allows unique identification of the substantial modification, and which
p.(None): shall be used con sistently throughout the application dossier;
p.(None): (b) identification of the applicant;
p.(None): (c) identification of the substantial modification (the sponsor's substantial modification code number and
p.(None): date), whereby the modification may refer to several changes in the protocol or scientific supporting documents;
p.(None): (d) a highlighted indication of any special issues relating to the modification and an indication as to
p.(None): where the relevant information or text is located in the original application dossier;
p.(None): (e) identification of any information not contained in the modification application form that might
...
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p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
p.(None): both the unauthorised investigational medicinal product and the comparator or placebo;
p.(None):
p.(None): (c) pharmaceutical form, route of administration, quantity of dosage units;
p.(None):
p.(None): (d) the batch or code number identifying the contents and packaging operation;
p.(None):
p.(None): (e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None):
p.(None): (f) the subject identification number and/or the treatment number and, where relevant, the visit number;
p.(None):
p.(None): (g) the name of the investigator (if not included in (a) or (e));
p.(None):
p.(None): (h) directions for use (reference may be made to a leaflet or other explanatory document intended for
p.(None): the subject or person administering the product);
p.(None):
p.(None): (i) 'For clinical trial use only' or similar wording;
p.(None):
p.(None): (j) the storage conditions;
p.(None):
p.(None): (k) period of use (expiry date or re-test date as applicable), in month and year format and in a
p.(None): manner that avoids any ambiguity; and
p.(None):
p.(None): (l) 'Keep out of reach of children', except when the product is for use in trials where the product is not taken
p.(None): home by subjects.
p.(None):
p.(None): 2. Symbols or pictograms may be included to clarify certain information mentioned above. Additional
p.(None): informa tion, warnings or handling instructions may be displayed.
p.(None):
p.(None): 3. The address and telephone number of the main contact shall not be required to appear on the label if subjects have
p.(None): been given a leaflet or card which provides these details and have been instructed to keep this in
p.(None): their possession at all times.
p.(None):
p.(None):
p.(None): A.2. Limited labelling of immediate packaging
p.(None):
p.(None): A.2.1. Immediate and outer packaging provided together
p.(None):
p.(None): 4. When the product is provided to the subject or the person administering the medicinal product in
p.(None): an immediate packaging and outer packaging intended to remain together, and the outer packaging carries
p.(None): the particulars listed in section A.1., the following particulars shall appear on the immediate packaging
p.(None): (or any sealed dosing device that contains the immediate package):
p.(None):
p.(None): (a) name of the main contact;
p.(None):
p.(None): (b) pharmaceutical form, route of administration (may be excluded for oral solid dose forms), quantity
p.(None): of dosage units and, in the case of clinical trials which do not involve the blinding of the label,
p.(None): the name/ identifier and strength/potency;
p.(None):
p.(None): (c) batch and/or code number identifying the contents and packaging operation;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/73
p.(None):
...
Social / Soldier
Searching for indicator military:
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p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
p.(None): pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior
p.(None): to the intervention. This Regulation should therefore set clear rules whereby such patients may be enrolled in the
...
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
p.(None): clinical trial may be obtained, and information on the clinical trial may be given, after the decision to
p.(None): include the subject in the clinical trial, provided that this decision is taken at the time of the first
p.(None): intervention on the subject, in accordance with the protocol for that clinical trial" and that all of the
p.(None): following conditions are fulfilled:
p.(None):
p.(None): (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious
p.(None): medical condition, the subject is unable to provide prior informed consent and to receive prior information on the
p.(None): clinical trial;
p.(None):
p.(None): (b) there are scientific grounds to expect that participation of the subject in the clinical trial will
p.(None): have the potential to produce a direct clinically relevant benefit for the subject resulting in a
...
Social / Trade Union Membership
Searching for indicator union:
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p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/1
p.(None):
p.(None):
p.(None): I
p.(None):
p.(None): (Legislative acts)
p.(None):
p.(None):
p.(None):
p.(None): REGULATIONS
p.(None):
p.(None): REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
p.(None): of 16 April 2014
p.(None): on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC
p.(None): (Text with EEA relevance)
p.(None):
p.(None): THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,
p.(None):
p.(None): Having regard to the Treaty on the Functioning of the European Union, and in particular Articles 114
p.(None): and 168(4)(c) thereof,
p.(None):
p.(None): Having regard to the proposal from the European Commission,
p.(None):
p.(None): After transmission of the draft legislative act to the national parliaments,
p.(None):
p.(None): Having regard to the opinion of the European Economic and Social Committee (1), After consulting the Committee of the
p.(None): Regions,
p.(None): Acting in accordance with the ordinary legislative procedure (2), Whereas:
p.(None): (1) In a clinical trial the rights, safety, dignity and well-being of subjects should be protected
p.(None): and the data generated should be reliable and robust. The interests of the subjects should always take priority
p.(None): over all other interests.
p.(None):
p.(None): (2) In order to allow for independent control as to whether these principles are adhered to, a
p.(None): clinical trial should be subject to prior authorisation.
p.(None):
p.(None): (3) The existing definition of a clinical trial as contained in Directive 2001/20/EC of the European
p.(None): Parliament and of the Council (3) should be clarified. For that purpose, the concept of clinical trial should be more
p.(None): precisely defined by introducing the broader concept of ‘clinical study’ of which the clinical trial is a
p.(None): category. That category should be defined on the basis of specific criteria. This approach takes due
p.(None): account of international guidelines, and is in line with the Union law governing medicinal products,
p.(None): which builds on the dichotomy of ‘clinical trial’ and ‘non-interventional study’.
p.(None):
p.(None): (4) Directive 2001/20/EC aims to simplify and harmonise the administrative provisions governing
p.(None): clinical trials in the Union. However, experience shows that a harmonised approach to the regulation of
p.(None): clinical trials has only been partly achieved. This makes it in particular difficult to perform a given
p.(None): clinical trial in several Member
p.(None):
p.(None): (1) OJ C 44, 15.2.2013, p. 99.
p.(None): (2) Position of the European Parliament of 3 April 2014 (not yet published in the Official Journal) and decision of
p.(None): the Council of 14 April 2014.
p.(None): (3) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the
p.(None): laws, regulations and
p.(None): administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct
p.(None): of clinical trials on medicinal products for human use (OJ L 121, 1.5.2001, p. 34).
p.(None):
p.(None): L 158/2 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): States. Scientific development, however, suggests that future clinical trials will target more specific patient popula
p.(None): tions, such as subgroups identified through genomic information. In order to include a sufficient number
p.(None): of patients for such clinical trials it may be necessary to involve many, or all, Member States. The
p.(None): new procedures for the authorisation of clinical trials should stimulate the inclusion of as many Member States as
p.(None): possible. There fore, in order to simplify the procedures for the submission of an application dossier
p.(None): for the authorisation of a clinical trial, the multiple submission of largely identical information should
p.(None): be avoided and replaced by the submission of one application dossier to all the Member States concerned
p.(None): through a single submission portal. Given that clinical trials carried out in a single Member State are equally
p.(None): important to European clinical research, the application dossier for such clinical trials should also be submitted
p.(None): through that single portal.
p.(None):
p.(None):
p.(None): (5) As regards Directive 2001/20/EC, experience also indicates that the legal form of a Regulation
p.(None): would present advantages for sponsors and investigators, for example in the context of clinical trials
p.(None): taking place in more than one Member State, since they will be able to rely on its provisions
p.(None): directly, but also in the context of safety reporting and labelling of investigational medicinal products.
p.(None): Divergences of approach among different Member States will be therefore kept to a minimum.
p.(None):
p.(None):
p.(None): (6) The Member States concerned should cooperate in assessing a request for authorisation of a clinical trial.
p.(None): This co operation should not include aspects of an intrinsically national nature, such as informed consent.
p.(None):
p.(None):
p.(None): (7) In order to avoid administrative delays for starting a clinical trial, the procedure to be used should be
p.(None): flexible and efficient, without compromising patient safety or public health.
p.(None):
p.(None):
p.(None): (8) The timelines for assessing an application dossier for clinical trials should be sufficient to
p.(None): assess the file while, at the same time, ensuring quick access to new, innovative treatments and
p.(None): ensuring that the Union remains an attractive place for conducting clinical trials. Against this
p.(None): background, Directive 2001/20/EC introduced the concept of tacit authorisation. This concept should be
p.(None): maintained in order to ensure that timelines are adhered to. In the event of a public health crisis, Member
p.(None): States should have the possibility to assess and authorise a clin ical trial application swiftly. No minimal timelines
p.(None): for approval should therefore be established.
p.(None):
p.(None):
p.(None): (9) Clinical trials for the development of orphan medicinal products as defined in Regulation (EC)
p.(None): No 141/2000 of the European Parliament and of the Council (1) and of medicinal products addressed to
p.(None): subjects affected by severe, debilitating and often life-threatening diseases affecting no more than one person
p.(None): in 50 000 in the Union (ultra-rare diseases) should be fostered.
p.(None):
p.(None):
p.(None): (10) Member States should efficiently assess all clinical trials applications within the given
p.(None): timelines. A rapid yet in- depth assessment is of particular importance for clinical trials concerning
p.(None): medical conditions which are severely debilitating and/or life threatening and for which therapeutic options are
p.(None): limited or non-existent, as in the case of rare and ultra-rare diseases.
p.(None):
p.(None):
p.(None): (11) The risk to subject safety in a clinical trial mainly stems from two sources: the
p.(None): investigational medicinal product and the intervention. Many clinical trials, however, pose only a minimal additional
p.(None): risk to subject safety compared to normal clinical practice. This is particularly the case where the investigational
p.(None): medicinal product is covered by a marketing authorisation, that is the quality, safety and efficacy has
p.(None): already been assessed in the course of the marketing authorisation procedure" or, if that product is not used
p.(None): in accordance with the terms of the marketing authorisation, that use is evidence- based and supported by
p.(None): published scientific evidence on the safety and effi cacy of that product, and the intervention poses
p.(None): only very limited additional risk to the subject compared to normal clinical practice. Those low-intervention
p.(None): clinical trials are often of crucial importance for assessing stand ard treatments and diagnoses, thereby
p.(None): optimising the use of medicinal products and thus contributing to a high level of public health. Those
p.(None): clinical trials should be subject to less stringent rules, as regards monitoring, require ments for the contents of
p.(None): the master file and traceability of investigational medicinal products. In order to ensure subject safety they
p.(None): should however be subject to the same application procedure as any other clinical trial. The published
p.(None): scientific evidence supporting the safety and efficacy of an investigational medicinal product not used in
p.(None): accordance with the terms of the marketing authorisation could include high quality data published in
p.(None): scien tific journal articles, as well as national, regional or institutional treatment protocols, health
p.(None): technology assess ment reports or other appropriate evidence.
p.(None):
p.(None): (1) Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan
p.(None): medicinal products (OJ L 18, 22.1.2000, p. 1).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/3
p.(None):
p.(None): (12) The Recommendation of the Organisation for Economic Cooperation and Development (OECD) Council on
p.(None): the Governance of Clinical Trials of 10 December 2012 introduced different risk categories for clinical
p.(None): trials. Those categories are compatible with the categories of clinical trials defined in this Regulation as the OECD
p.(None): Categories A and B(1) correspond to the definition of a low-intervention clinical trial as set out in
p.(None): this Regulation, and the OECD Categories B(2) and C correspond to the definition of a clinical trial as set out in
p.(None): this Regulation.
p.(None):
p.(None):
p.(None): (13) The assessment of the application for a clinical trial should address in particular the
p.(None): anticipated therapeutic and public health benefits (relevance) and the risk and inconvenience for the
p.(None): subject. In respect of the relevance, various aspects should be taken into account, including whether the
p.(None): clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment of
p.(None): medicinal products and the authorisation of their placing on the market and whether surrogate end-points, when
p.(None): they are used, are justified.
p.(None):
p.(None):
p.(None): (14) Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent
p.(None): the popula tion groups, for example gender and age groups, that are likely to use the medicinal product
p.(None): investigated in the clinical trial.
...
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
p.(None): trials involving subjects in emer gency situations, minors, incapacitated subjects, pregnant and breastfeeding
p.(None): women and, where appropriate, other identified specific population groups, such as elderly people or people suffering
p.(None): from rare and ultra rare diseases.
p.(None):
p.(None):
p.(None): (20) In practice, sponsors do not always have all the information needed for submitting a complete
p.(None): application for authorisation of a clinical trial in all of the Member States where a clinical trial is
p.(None): eventually going to be conducted. It should be possible for sponsors to submit an application solely on the
p.(None): basis of documents assessed jointly by those Member States where the clinical trial might be conducted.
p.(None):
p.(None):
p.(None): (21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure
p.(None): the reli able functioning of the assessment procedure, however, an application for authorisation of a
p.(None): clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the
p.(None): sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an
p.(None): application.
p.(None):
p.(None): L 158/4 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (22) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest in
p.(None): extending the clinical trial to an additional Member States after the initial authorisation of the clinical trial. An
p.(None): authorisation mechanism should be provided to allow for such extension, while avoiding the re-assessment
p.(None): of the application by all the Member States concerned which were involved in the initial authorisation of the
p.(None): clinical trial.
p.(None):
p.(None):
p.(None): (23) Clinical trials are usually subject to many modifications after they have been authorised. Those
p.(None): modifications may relate to the conduct, the design, the methodology, the investigational or auxiliary
p.(None): medicinal product, or the investigator or clinical trial site involved. Where those modifications have a
p.(None): substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data
p.(None): generated in the clinical trial, they should be subject to an authorisation procedure similar to the initial
p.(None): authorisation procedure.
p.(None):
p.(None):
p.(None): (24) The content of the application dossier for authorisation of a clinical trial should be
p.(None): harmonised in order to ensure that all Member States have the same information available and to simplify
p.(None): the application process for clinical trials.
p.(None):
p.(None):
p.(None): (25) In order to increase transparency in the area of clinical trials, data from a clinical trial
p.(None): should only be submitted in support of a clinical trial application if that clinical trial has been
p.(None): recorded in a publicly accessible and free of charge database which is a primary or partner registry
p.(None): of, or a data provider to, the international clinical trials registry platform of the World Health
p.(None): Organization (WHO ICTRP). Data providers to the WHO ICTRP create and manage clinical trial records in a manner
p.(None): that is consistent with the WHO registry criteria. Specific provision should be made for data from clinical
p.(None): trials started before the date of application of this Regulation.
p.(None):
p.(None):
p.(None): (26) It should be left to Member States to establish the language requirements for the application
p.(None): dossier. To ensure that the assessment of the application for authorisation of a clinical trial functions
p.(None): smoothly, Member States should consider accepting a commonly understood language in the medical field as
p.(None): the language for the docu mentation not destined for the subject.
p.(None):
p.(None):
p.(None): (27) Human dignity and the right to the integrity of the person are recognised in the Charter of
p.(None): Fundamental Rights of the European Union (the ‘Charter’). In particular, the Charter requires that any
p.(None): intervention in the field of biology and medicine cannot be performed without free and informed consent of the
p.(None): person concerned. Directive 2001/20/EC contains an extensive set of rules for the protection of subjects.
p.(None): These rules should be upheld. Regarding the rules concerning the determination of the legally
p.(None): designated representatives of incapacitated persons and minors, those rules diverge in Member States. It
p.(None): should therefore be left to Member States to deter mine the legally designated representatives of
p.(None): incapacitated persons and minors. Incapacitated subjects, minors, pregnant women and breastfeeding women require
p.(None): specific protection measures.
p.(None):
p.(None):
p.(None): (28) An appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner should be
p.(None): respon sible for all medical care provided to the subject, including the medical care provided by other medical staff.
p.(None):
p.(None):
p.(None): (29) It is appropriate that universities and other research institutions, under certain circumstances
...
p.(None): withdraw that consent at any time. It is also necessary that research projects based on such data be
p.(None): made subject to reviews that are appropriate for research on human data, for example on ethical aspects,
p.(None): before being conducted.
p.(None):
p.(None):
p.(None): (30) In accordance with international guidelines, the informed consent of a subject should be in
p.(None): writing. When the subject is unable to write, it may be recorded through appropriate alternative means,
p.(None): for instance through audio or video recorders. Prior to obtaining informed consent, the potential subject
p.(None): should receive information in a prior interview in a language which is easily understood by him or her. The
p.(None): subject should have the opportunity to ask questions at any moment. Adequate time should be provided for
p.(None): the subject to consider his or her deci sion. In view of the fact that in certain Member States the only person
p.(None): qualified under national law to perform an interview with a potential subject is a medical doctor while in
p.(None): other Member States this is done by other profes sionals, it is appropriate to provide that the prior
p.(None): interview with a potential subject should be performed by a member of the investigating team qualified
p.(None): for this task under the national law of the Member State where the recruitment takes place.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/5
p.(None):
p.(None): (31) In order to certify that informed consent is given freely, the investigator should take into
p.(None): account all relevant circumstances which might influence the decision of a potential subject to participate in a
p.(None): clinical trial, in particu lar whether the potential subject belongs to an economically or socially
p.(None): disadvantaged group or is in a situation of institutional or hierarchical dependency that could inappropriately
p.(None): influence her or his decision to participate.
p.(None):
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
...
p.(None):
p.(None):
p.(None): (37) In order to allow patients to assess possibilities to participate in a clinical trial, and to allow for
p.(None): effective supervi sion of a clinical trial by the Member State concerned, the start of the clinical trial, the end
p.(None): of the recruitment of subjects for the clinical trial and the end of the clinical trial should be
p.(None): notified. In accordance with international standards, the results of the clinical trial should be reported within
p.(None): one year from the end of the clinical trial.
p.(None):
p.(None):
p.(None): (38) The date of the first act of recruitment of a potential subject is the date on which the first act of
p.(None): the recruitment strategy described in the protocol was performed, e. g. the date of a contact with a
p.(None): potential subject or the date of the publication of an advertisement for a particular clinical trial.
p.(None):
p.(None):
p.(None): (39) The sponsor should submit a summary of the results of the clinical trial together with a
p.(None): summary that is under standable to a layperson, and the clinical study report, where applicable, within the defined
p.(None): timelines. Where it is not possible to submit the summary of the results within the defined timelines for
p.(None): scientific reasons, for example when the clinical trial is still ongoing in third countries and data from
p.(None): that part of the trial are not available, which makes a statistical analysis not relevant, the sponsor
p.(None): should justify this in the protocol and specify when the results are going to be submitted.
p.(None):
p.(None): L 158/6 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (40) In order for the sponsor to assess all potentially relevant safety information, the investigator
p.(None): should, as a rule, report to him all serious adverse events.
p.(None):
p.(None):
p.(None): (41) The sponsor should assess the information received from the investigator, and report safety
p.(None): information on serious adverse events which are suspected unexpected serious adverse reactions to the
p.(None): European Medicines Agency (‘the Agency’).
p.(None):
p.(None):
p.(None): (42) The Agency should forward that information to the Member States for them to assess it.
p.(None):
p.(None):
p.(None): (43) The members of the International Conference on Harmonisation of Technical Requirements for
p.(None): Registration of Pharmaceuticals for Human Use (ICH) have agreed on a detailed set of guidelines on good clinical
p.(None): practice which is an internationally accepted standard for designing, conducting, recording and reporting clinical
p.(None): trials, consistent with principles that have their origin in the World Medical Association's Declaration of Helsinki.
p.(None): When designing, conducting, recording and reporting clinical trials, detailed questions may arise as to the
p.(None): appropriate quality standard. In such a case, the ICH guidelines on good clinical practice should be
p.(None): taken appropriately into account for the application of the rules set out in this Regulation, provided that there
p.(None): is no other specific guidance issued by the Commission and that those guidelines are compatible with this Regulation.
p.(None):
p.(None):
p.(None): (44) The conduct of a clinical trial should be adequately monitored by the sponsor in order to
...
p.(None): and reactions, all unex pected events that might materially influence the benefit-risk assessment of the
p.(None): medicinal product or that would lead to changes in the administration of a medicinal product or in
p.(None): overall conduct of a clinical trial are notified to the Member States concerned. Examples of such
p.(None): unexpected events include an increase in the rate of occur rence of expected serious adverse reactions
p.(None): which may be clinically important, a significant hazard to the patient population, such as lack of efficacy
p.(None): of a medicinal product, or a major safety finding from a newly completed animal study (such as
p.(None): carcinogenicity).
p.(None):
p.(None):
p.(None): (49) Where unexpected events require an urgent modification of a clinical trial, it should be
p.(None): possible for the sponsor and the investigator to take urgent safety measures without awaiting prior authorisation.
p.(None): If such measures consti tute a temporary halt of the clinical trial, the sponsor should apply for a substantial
p.(None): modification before restarting the clinical trial.
p.(None):
p.(None):
p.(None): (50) In order to ensure compliance of the conduct of a clinical trial with the protocol, and in
p.(None): order for investigators to be informed about the investigational medicinal products they administer, the sponsor
p.(None): should supply the inves tigators with an investigator's brochure.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/7
p.(None):
p.(None): (51) The information generated in a clinical trial should be recorded, handled and stored adequately
p.(None): for the purpose of ensuring subject rights and safety, the robustness and reliability of the data generated in the
p.(None): clinical trial, accu rate reporting and interpretation, effective monitoring by the sponsor and effective inspection
p.(None): by Member States.
p.(None):
p.(None):
p.(None): (52) In order to be able to demonstrate compliance with the protocol and with this Regulation, a
p.(None): clinical trial master file, containing relevant documentation to allow effective supervision (monitoring by
p.(None): the sponsor and inspection by Member States), should be kept by the sponsor and by the investigator. The
p.(None): clinical trial master file should be archived appropriately to allow for supervision after the clinical trial has
p.(None): ended.
p.(None):
p.(None):
p.(None): (53) Where there are problems with respect to the availability of authorised auxiliary medicinal products,
p.(None): unauthorised auxiliary medicinal products may be used in a clinical trial in justified cases. The price of the
p.(None): authorised auxiliary medicinal product should not be considered as having an effect on the availability of such
p.(None): medicinal products.
p.(None):
p.(None):
p.(None): (54) Medicinal products intended for research and development trials fall outside the scope of
p.(None): Directive 2001/83/EC of the European Parliament and of the Council (1). Such medicinal products include
p.(None): medicinal products used in the context of a clinical trial. They should be covered by specific rules
p.(None): taking account of their peculiarities. In establishing these rules, a distinction should be made between
p.(None): investigational medicinal products (the tested product and its reference products, including placebos) and
p.(None): auxiliary medicinal products (medicinal products used in the context of a clinical trial but not as
p.(None): investigational medicinal products), such as medicinal products used for background treatment, challenge
p.(None): agents, rescue medication, or used to assess end-points in a clinical trial. Auxiliary medicinal products
p.(None): should not include concomitant medications, that is medications unrelated to the clinical trial and not
p.(None): relevant for the design of the clinical trial.
p.(None):
p.(None):
p.(None): (55) In order to ensure subject safety and the reliability and robustness of data generated in a
p.(None): clinical trial, and in order to allow for the distribution of investigational and auxiliary medicinal
p.(None): products to clinical trial sites throughout the Union, rules on the manufacturing and import of both
p.(None): investigational and auxiliary medicinal products should be established. As is already the case for
p.(None): Directive 2001/20/EC, those rules should reflect the existing rules of good manufacturing practices for
p.(None): products covered by Directive 2001/83/EC. In some specific cases, it should be possible to allow
p.(None): deviations from those rules in order to facilitate the conduct of a clinical trial. Therefore, the
p.(None): applicable rules should allow for some flexibility, provided that subject safety, as well as relia bility and
p.(None): robustness of the data generated in the clinical trial are not compromised.
p.(None):
p.(None):
p.(None): (56) The requirement to hold an authorisation for manufacture or import of investigational medicinal products
p.(None): should not apply to the preparation of investigational radiopharmaceuticals from radionuclide generators,
p.(None): kits or radio nuclide precursors in accordance with the manufacturer's instructions for use in hospitals,
p.(None): health centres or clinics taking part in the same clinical trial in the same Member State.
p.(None):
p.(None):
p.(None): (57) Investigational and auxiliary medicinal products should be appropriately labelled in order to ensure subject
p.(None): safety and the reliability and robustness of data generated in clinical trials, and in order to allow
p.(None): for the distribution of those products to clinical trial sites throughout the Union. The rules for
p.(None): labelling should be adapted to the risks to subject safety and the reliability and robustness of data generated
p.(None): in clinical trials. Where the investigational or auxiliary medicinal product have already been placed on the
p.(None): market as an authorised medicinal product in accordance with Directive 2001/83/EC and Regulation (EC) No 726/2004
p.(None): of the European Parliament and of the Council (2), as a general rule no additional labelling should be
p.(None): required for clinical trials that do not involve the blinding of the label. Moreover, there are specific
p.(None): products, such as radiopharmaceuticals used as diagnostic inves tigational medicinal product, where the general rules
p.(None): on labelling are inappropriate in view of the very controlled setting of the use of radiopharmaceuticals in clinical
p.(None): trials.
p.(None):
p.(None):
p.(None): (58) In order to ensure clear responsibilities, the concept of a ‘sponsor’ of a clinical trial, in
p.(None): line with international guidelines, was introduced by Directive 2001/20/EC. This concept should be upheld.
p.(None):
p.(None):
p.(None): (59) In practice, there may be loose, informal networks of researchers or research institutions which
p.(None): jointly conduct a clinical trial. Those networks should be able to be co-sponsors of a clinical trial.
p.(None): In order not to weaken the
p.(None):
p.(None): (1) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code
p.(None): relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67).
p.(None): (2) Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community
p.(None): procedures for
p.(None): the authorisation and supervision of medicinal products for human and veterinary use and establishing a European
p.(None): Medicines Agency (OJ L 136, 30.4.2004, p. 1.)
p.(None):
p.(None): L 158/8 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): concept of responsibility in a clinical trial, where a clinical trial has several sponsors, they should all be subject
p.(None): to the obligations of a sponsor under this Regulation. However, the co-sponsors should be able to split
p.(None): up the responsibilities of the sponsor by contractual agreement.
p.(None):
p.(None):
p.(None): (60) In order to ensure that enforcement action may be taken by Member States and that legal
p.(None): proceedings may be brought in appropriate cases, it is appropriate to provide that sponsors that are not
p.(None): established in the Union should be represented by a legal representative in the Union. However in view of the
p.(None): divergent approaches of the Member States as regards civil and criminal liability, it is appropriate to leave to each
p.(None): Member State concerned, as regards its territory, the choice as to whether or not to require such a legal
p.(None): representative, provided that at least a contact person is established in the Union.
p.(None):
p.(None):
p.(None): (61) Where, in the course of a clinical trial, damage caused to the subject leads to the civil or
p.(None): criminal liability of the investigator or the sponsor, the conditions for liability in such cases, including issues
p.(None): of causality and the level of damages and sanctions, should remain governed by national law.
p.(None):
p.(None):
p.(None): (62) In clinical trials compensation should be ensured for damages successfully claimed in accordance with the
p.(None): applic able laws. Therefore Member States should ensure that systems for compensation for damages
p.(None): suffered by a subject are in place which are appropriate to the nature and the extent of the risk.
p.(None):
p.(None):
p.(None): (63) The Member State concerned should be given the power to revoke the authorisation of a clinical
p.(None): trial, suspend a clinical trial or require the sponsor to modify a clinical trial.
p.(None):
p.(None):
p.(None): (64) In order to ensure compliance with this Regulation, Member States should be able to conduct
p.(None): inspections and should have adequate inspection capacities.
p.(None):
p.(None):
p.(None): (65) The Commission should be able to control whether Member States correctly supervise compliance
p.(None): with this Regulation. Moreover, the Commission should be able to control whether regulatory systems of
p.(None): third countries ensure compliance with the specific provisions of this Regulation and Directive 2001/83/EC
p.(None): concerning clinical trials conducted in third countries.
p.(None):
p.(None):
...
p.(None): linking together the summary, the layperson's summary, the protocol and the clinical study report of one clinical
p.(None): trial, as well as linking to data from other clin ical trials which used the same investigational medicinal product.
p.(None): All clinical trials should be registered in the EU database prior to being started. As a rule, the start
p.(None): and end dates of the recruitment of subjects should also be published in the EU database. No personal data of
p.(None): data subjects participating in a clinical trial should be recorded in the EU database. The information in the
p.(None): EU database should be public, unless specific reasons require that a piece of information should not be
p.(None): published, in order to protect the right of the individual to private life and the right to the protection
p.(None): of personal data, recognised by Articles 7 and 8 of the Charter. Publicly available infor mation contained in the
p.(None): EU database should contribute to protecting public health and fostering the innovation capacity of European
p.(None): medical research, while recognising the legitimate economic interests of sponsors.
p.(None):
p.(None):
p.(None): (68) For the purposes of this Regulation, in general the data included in a clinical study report
p.(None): should not be consid ered commercially confidential once a marketing authorisation has been granted, the
p.(None): procedure for granting
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/9
p.(None):
p.(None): themarketing authorisation has been completed, the application for marketing authorisation has been withdrawn. In
p.(None): addition, the main characteristics of a clinical trial, the conclusion on Part I of the assessment
p.(None): report for the authorisation of a clinical trial, the decision on the authorisation of a clinical trial, the
p.(None): substantial modification of a clinical trial, and the clinical trial results including reasons for temporary halt and
p.(None): early termination, in general, should not be considered confidential.
p.(None):
p.(None):
p.(None): (69) Within a Member State, there may be several bodies involved in the authorisation of clinical
p.(None): trials. In order to allow for effective and efficient cooperation between Member States, each Member
p.(None): State should designate one contact point.
p.(None):
p.(None):
p.(None): (70) The authorisation procedure set out in this Regulation is largely controlled by Member States.
p.(None): Nevertheless, the Commission and the Agency should support the good functioning of that procedure, in
p.(None): accordance with this Regulation.
p.(None):
p.(None):
p.(None): (71) In order to carry out the activities provided for in this Regulation, Member States should be allowed
p.(None): to levy fees. However, Member States should not require multiple payments to different bodies involved in
p.(None): the assessment, in a given Member State, of an application for authorisation of a clinical trial.
p.(None):
p.(None):
p.(None): (72) In order to ensure uniform conditions for the implementation of this Regulation, implementing
p.(None): powers should be conferred on the Commission in respect of the establishment and modification of rules
p.(None): on cooperation between the Member States when assessing the information provided by the sponsor on the
p.(None): Eudravigilance data base and the specification of detailed arrangements for inspection procedures. Those
p.(None): powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the
p.(None): Council (1).
p.(None):
p.(None):
p.(None): (73) In order to supplement or amend certain non-essential elements of this Regulation, the power to
p.(None): adopt acts in accordance with Article 290 of the Treaty on the Functioning of the European Union (TFEU) should be
p.(None): delegated to the Commission in respect of: the amendment of Annexes I, II, IV and V to this Regulation
p.(None): in order to adapt them to technical progress or to take account of international regulatory developments
p.(None): in which the Union or the Member States are involved, in the field of clinical trials; the amendment of Annex III
p.(None): in order to improve the information on the safety of medicinal products, to adapt technical requirements to
p.(None): technical progress or to take account of international regulatory developments in the field of safety
p.(None): requirements in clinical trials endorsed by bodies in which the Union or the Member States participate;
p.(None): the specification of the principles and guidelines of good manufacturing practice and the detailed
p.(None): arrangements for inspection for ensuring the quality of investiga tional medicinal products; the amendment
p.(None): of Annex VI in order to ensure subject safety and the reliability and robustness of data generated in
p.(None): a clinical trial or to take account of technical progress. It is of particular impor tance that the
p.(None): Commission carry out appropriate consultations during its preparatory work, including at expert level. The
p.(None): Commission, when preparing and drawing-up delegated acts, should ensure a simultaneous, timely and appropriate
p.(None): transmission of relevant documents to the European Parliament and to the Council.
p.(None):
p.(None):
p.(None): (74) Directive 2001/83/EC provides that that Directive does not affect the application of national
p.(None): legislation prohi biting or restricting the sale, supply or use of medicinal products as abortifacients. Directive
p.(None): 2001/83/EC provides that national legislation prohibiting or restricting the use of any specific type of
p.(None): human or animal cells is not, in principle, affected by either that Directive or any of the Regulations
p.(None): referred to therein. Likewise, this Regulation should not affect national law prohibiting or restricting the
p.(None): use of any specific type of human or animal cells, or the sale, supply or use of medicinal products used as
p.(None): abortifacients. In addition, this Regulation should not affect national law prohibiting or restricting the
p.(None): sale, supply or use of medicinal products containing narcotic substances within the meaning of the
p.(None): relevant international conventions in force such as the Single Convention on Narcotic Drugs of 1961 of the
p.(None): United Nations. Member States should communicate those national provisions to the Commission.
p.(None):
p.(None):
p.(None): (75) Directive 2001/20/EC provides that no gene therapy trials may be carried out which result in
p.(None): modifications to the subject's germ line genetic identity. It is appropriate to maintain that provision.
p.(None):
p.(None): (1) Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011 laying down the
p.(None): rules and general principles concerning mechanisms for control by Member States of the Commission's exercise
p.(None): of implementing powers (OJ L 55, 28.2.2011, p. 13).
p.(None):
p.(None): L 158/10 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (76) Directive 95/46/EC of the European Parliament and of the Council (1) applies to the processing
p.(None): of personal data carried out in the Member States within the framework of this Regulation, under the
p.(None): supervision of the Member States competent authorities, in particular the public independent authorities
p.(None): designated by the Member States and Regulation (EC) No 45/2001 of the European Parliament and of the
p.(None): Council (2) applies to the processing of personal data carried out by the Commission and the Agency within the
p.(None): framework of this Regulation, under the supervision of the European Data Protection Supervisor. Those
p.(None): instruments strengthen personal data protection rights, encompassing the right to access, rectification and
p.(None): withdrawal, as well as specify the situations when restriction on those rights may be imposed. With a view to
p.(None): respecting those rights, while safeguarding the robust ness and reliability of data from clinical trials used
p.(None): for scientific purposes and the safety of subjects participating in clinical trials, it is appropriate to
p.(None): provide that, without prejudice to Directive 95/46/EC, the withdrawal of informed consent should not affect
p.(None): the results of activities already carried out, such as the storage and use of data obtained on the basis of informed
p.(None): consent before withdrawal.
p.(None):
p.(None):
p.(None): (77) Subjects should not have to pay for investigational medicinal products, auxiliary medicinal
p.(None): products, medical devices used for their administration and procedures specifically required by the
p.(None): protocol, unless the law of the Member State concerned provides otherwise.
p.(None):
p.(None):
p.(None): (78) The authorisation procedure set out in this Regulation should apply as soon as possible, in order for
p.(None): sponsors to reap the benefits of a streamlined authorisation procedure. However, in view of the importance
p.(None): of the extensive IT functionalities required for the authorisation procedure, it is appropriate to provide that
p.(None): this Regulation should only become applicable once it has been verified that the EU portal and the EU database are
p.(None): fully functional.
p.(None):
p.(None):
p.(None): (79) Directive 2001/20/EC should be repealed to ensure that only one set of rules applies to the
p.(None): conduct of clinical trials in the Union. In order to facilitate the transition to the rules set out in
p.(None): this Regulation, sponsors should be allowed to start and conduct a clinical trial in accordance with Directive
p.(None): 2001/20/EC during a transitional period.
p.(None):
p.(None):
p.(None): (80) This Regulation is in line with the major international guidance documents on clinical trials,
p.(None): such as the 2008 version of the World Medical Association's Declaration of Helsinki and good clinical
p.(None): practice, which has its origins in the Declaration of Helsinki.
p.(None):
p.(None):
p.(None): (81) As regards Directive 2001/20/EC, experience also shows that a large proportion of clinical
p.(None): trials are conducted by non-commercial sponsors. Non-commercial sponsors frequently rely on funding which
p.(None): comes partly or entirely from public funds or charities. In order to maximise the valuable contribution
p.(None): of such non-commercial sponsors and to further stimulate their research but without compromising the quality of
p.(None): clinical trials, measures should be taken by Member States to encourage clinical trials conducted by those sponsors.
p.(None):
p.(None):
p.(None): (82) This Regulation is based on the double legal basis of Articles 114 and 168(4)(c) TFEU. It
p.(None): aims at achieving an internal market as regards clinical trials and medicinal products for human use,
p.(None): taking as a base a high level of protection of health. At the same time, this Regulation sets high
p.(None): standards of quality and safety for medicinal products in order to meet common safety concerns as regards
p.(None): these products. Both objectives are being pursued simultaneously. These two objectives are inseparably
p.(None): linked and one is not secondary to another. Regarding Article 114 TFEU, this Regulation harmonises the
p.(None): rules for the conduct of clinical trials in the Union, therefore ensuring the functioning of the internal
p.(None): market in view of the conduct of a clinical trial in several Member States, the acceptability throughout the Union
p.(None): of data generated in a clinical trial and submitted in the application for the authorisation of another
p.(None): clinical trial or of the placing on the market of a medicinal product, and the free movement of
p.(None): medicinal products used in the context of a clinical trial. Regarding Article 168(4)(c) TFEU, this
p.(None): Regulation sets high standards of quality and safety for medicinal products by ensuring that data
p.(None): generated in clinical trials are reliable and robust, thus ensuring that treatments and medicines which
p.(None): are intended to be an improvement of a treatment of patients build on reliable and robust data.
p.(None): Moreover, this Regulation sets high standards of quality and safety of medicinal products used in the
p.(None): context of a clinical trial, thus ensuring the safety of subjects in a clinical trial.
p.(None):
p.(None): (1) Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of
p.(None): individuals with regard to the processing of personal data and on the free movement of such data (OJ L 281, 23.11.1995,
p.(None): p. 31).
p.(None): (2) Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of
p.(None): individuals with
p.(None): regard to the processing of personal data by the Community institutions and bodies and on the free movement of such
p.(None): data (OJ L 8, 12.1.2001, p. 1).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/11
p.(None):
p.(None): (83) This Regulation respects the fundamental rights and observes the principles recognised in
p.(None): particular by the Charter and notably human dignity, the integrity of the person, the rights of the
p.(None): child, respect for private and family life, the protection of personal data and the freedom of art and science.
p.(None): This Regulation should be applied by the Member States in accordance with those rights and principles.
p.(None):
p.(None): (84) The European Data Protection Supervisor has given an opinion (1) pursuant to Article 28(2) of
p.(None): Regulation (EC) No 45/2001.
p.(None):
p.(None): (85) Since the objective of this Regulation, namely to ensure that, throughout the Union, clinical trial data are
p.(None): reliable and robust while ensuring respect for the rights, safety, dignity and well-being of subjects,
p.(None): cannot be sufficiently achieved by the Member States but can rather, by reason of its scale, be better achieved at
p.(None): Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of
p.(None): the Treaty on Euro pean Union. In accordance with the principle of proportionality, as set out in that
p.(None): Article, this Regulation does not go beyond what is necessary in order to achieve that objective,
p.(None):
p.(None): HAVE ADOPTED THIS REGULATION:
p.(None):
p.(None): CHAPTER I
p.(None):
p.(None): GENERAL PROVISIONS
p.(None):
p.(None): Article 1
p.(None):
p.(None): Scope This Regulation applies to all clinical trials conducted in the Union. It does not apply to non-interventional
p.(None): studies.
p.(None):
p.(None): Article 2
p.(None):
p.(None): Definitions
p.(None):
p.(None): 1. For the purposes of this Regulation, the definitions of ‘medicinal product’, ‘radiopharmaceutical’,
p.(None): ‘adverse reaction’, ‘serious adverse reaction’, ‘immediate packaging’ and ‘outer packaging’ set out in points (2),
p.(None): (6), (11), (12), (23) and (24), respectively, of Article 1 of Directive 2001/83/EC apply.
p.(None):
p.(None): 2. For the purposes of this Regulation, the following definitions also apply:
p.(None): (1) ‘Clinical study’ means any investigation in relation to humans intended:
p.(None):
p.(None): (a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal
p.(None): products;
p.(None): (b) to identify any adverse reactions to one or more medicinal products; or
p.(None): (c) to study the absorption, distribution, metabolism and excretion of one or more medicinal products; with the
p.(None): objective of ascertaining the safety and/or efficacy of those medicinal products;
p.(None): (2) ‘Clinical trial’ means a clinical study which fulfils any of the following conditions:
p.(None): (a) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall
p.(None): within normal clinical practice of the Member State concerned;
p.(None):
p.(None): (b) the decision to prescribe the investigational medicinal products is taken together with the decision
p.(None): to include the subject in the clinical study; or
p.(None): (c) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.
p.(None):
p.(None): (1) OJ C 253, 3.9.2013, p. 10.
p.(None):
p.(None): L 158/12 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (3) ‘Low-intervention clinical trial’ means a clinical trial which fulfils all of the following conditions:
p.(None):
p.(None): (a) the investigational medicinal products, excluding placebos, are authorised;
p.(None):
p.(None): (b) according to the protocol of the clinical trial,
p.(None):
p.(None): (i) the investigational medicinal products are used in accordance with the terms of the marketing
p.(None): authorisa tion; or
p.(None):
p.(None): (ii) the use of the investigational medicinal products is evidence-based and supported by published
p.(None): scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member
p.(None): States concerned; and
p.(None):
p.(None): (c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or
p.(None): burden to the safety of the subjects compared to normal clinical practice in any Member State concerned;
p.(None):
p.(None): (4) ‘Non-interventional study’ means a clinical study other than a clinical trial;
p.(None):
p.(None): (5) ‘Investigational medicinal product’ means a medicinal product which is being tested or used
p.(None): as a reference, including as a placebo, in a clinical trial;
p.(None):
p.(None): (6) ‘Normal clinical practice’ means the treatment regime typically followed to treat, prevent, or diagnose a
p.(None): disease or a disorder;
p.(None):
p.(None): (7) ‘Advanced therapy investigational medicinal product’ means an investigational medicinal product which
p.(None): is an advanced therapy medicinal product as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007 of
...
p.(None): irrespective of changes to the labelling of the medicinal product, which is used as an auxiliary medicinal product;
p.(None):
p.(None): (11) ‘Ethics committee’ means an independent body established in a Member State in accordance with the
p.(None): law of that Member State and empowered to give opinions for the purposes of this Regulation, taking
p.(None): into account the views of laypersons, in particular patients or patients' organisations;
p.(None):
p.(None): (12) ‘Member State concerned’ means the Member State where an application for authorisation of a clinical trial or
p.(None): of a substantial modification has been submitted under Chapters II or III of this Regulation respectively;
p.(None):
p.(None): (13) ‘Substantial modification’ means any change to any aspect of the clinical trial which is made after
p.(None): notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to have a substantial
p.(None): impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the
p.(None): clinical trial;
p.(None):
p.(None): (14) ‘Sponsor’ means an individual, company, institution or organisation which takes responsibility for the
p.(None): initiation, for the management and for setting up the financing of the clinical trial;
p.(None):
p.(None): (1) Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
p.(None): medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/13
p.(None):
p.(None): (15) ‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical trial site;
p.(None):
p.(None): (16) ‘Principal investigator’ means an investigator who is the responsible leader of a team of
p.(None): investigators who conduct a clinical trial at a clinical trial site;
p.(None):
p.(None): (17) ‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
p.(None): investigational medicinal product or as a control;
p.(None):
p.(None): (18) ‘Minor’ means a subject who is, according to the law of the Member State concerned, under the age of legal
p.(None): compe tence to give informed consent;
p.(None):
p.(None): (19) ‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal competence to give
p.(None): informed consent, incapable of giving informed consent according to the law of the Member State concerned;
p.(None):
p.(None): (20) ‘Legally designated representative’ means a natural or legal person, authority or body which,
p.(None): according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject
p.(None): who is an incapaci tated subject or a minor;
...
p.(None): protocol;
p.(None):
p.(None): (27) ‘Early termination of a clinical trial’ means the premature end of a clinical trial due to any reason before the
p.(None): condi tions specified in the protocol are complied with;
p.(None):
p.(None): (28) ‘Temporary halt of a clinical trial’ means an interruption not provided in the protocol of the
p.(None): conduct of a clinical trial by the sponsor with the intention of the sponsor to resume it;
p.(None):
p.(None): (29) ‘Suspension of a clinical trial’ means interruption of the conduct of a clinical trial by a Member State;
p.(None):
p.(None): (30) ‘Good clinical practice’ means a set of detailed ethical and scientific quality requirements for designing,
p.(None): conducting, performing, monitoring, auditing, recording, analysing and reporting clinical trials ensuring
p.(None): that the rights, safety and well-being of subjects are protected, and that the data generated in the clinical trial
p.(None): are reliable and robust;
p.(None):
p.(None): (31) ‘Inspection’ means the act by a competent authority of conducting an official review of documents,
p.(None): facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority
p.(None): to be related to the clinical trial and that may be located at the clinical trial site, at the sponsor's and/or
p.(None): contract research organisation's facilities, or at other establishments which the competent authority sees fit to
p.(None): inspect;
p.(None):
p.(None): L 158/14 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (32) ‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal product is
p.(None): administered and which does not necessarily have a causal relationship with this treatment;
p.(None): (33) ‘Serious adverse event’ means any untoward medical occurrence that at any dose requires inpatient
p.(None): hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability
p.(None): or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death;
p.(None): (34) ‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature, severity or outcome of which
p.(None): is not consistent with the reference safety information;
p.(None): (35) ‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
p.(None): format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
p.(None): accompanying an application for marketing authorisation.
p.(None): 3. For the purposes of this Regulation, a subject who falls under the definition of both ‘minor’
p.(None): and ‘incapacitated subject’ shall be deemed to be an incapacitated subject.
p.(None):
p.(None):
p.(None): Article 3
p.(None):
p.(None): General principle
p.(None):
p.(None): A clinical trial may be conducted only if:
p.(None): (a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and
...
p.(None): State concerned. The review by the ethics committee may encompass aspects addressed in Part I of the
p.(None): assessment report for the authorisation of a clinical trial as referred to in Article 6 and in Part II
p.(None): of that assessment report as referred to in Article 7 as appropriate for each Member State concerned.
p.(None):
p.(None): Member States shall ensure that the timelines and procedures for the review by the ethics committees
p.(None): are compatible with the timelines and procedures set out in this Regulation for the assessment of the
p.(None): application for authorisation of a clinical trial.
p.(None):
p.(None):
p.(None): Article 5
p.(None):
p.(None): Submission of an application
p.(None):
p.(None): 1. In order to obtain an authorisation, the sponsor shall submit an application dossier to the intended Member
p.(None): States concerned through the portal referred to in Article 80 (the ‘EU portal’).
p.(None):
p.(None): The sponsor shall propose one of the Member States concerned as reporting Member State.
p.(None):
p.(None): If a Member State concerned other than the proposed reporting Member State is willing to be the
p.(None): reporting Member State or where the proposed reporting Member State does not wish to be the reporting Member State,
p.(None): this shall be noti fied through the EU portal to all Member States concerned not later than three days
p.(None): after the application dossier is submitted.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/15
p.(None):
p.(None): If only one Member State concerned is willing to be the reporting Member State or if the clinical trial involves only
p.(None): one Member State, that Member State shall be the reporting Member State.
p.(None):
p.(None):
p.(None): If there is no Member State concerned willing to be the reporting Member State or if there is more
p.(None): than one Member State concerned willing to be the reporting Member State, the reporting Member State
p.(None): shall be selected by agreement among the Member States concerned taking into account the recommendations referred
p.(None): to in point (c) of Article 85(2).
p.(None):
p.(None):
p.(None): If there is no agreement among the Member States concerned, the proposed reporting Member State shall
p.(None): be the reporting Member State.
p.(None):
p.(None):
p.(None): The reporting Member State shall notify the sponsor and the other Member States concerned that it is
p.(None): the reporting Member State, through the EU portal, within six days from the submission of the application dossier.
p.(None):
p.(None):
p.(None): 2. The sponsor shall, when applying for a low-intervention clinical trial, where the investigational
p.(None): medicinal product is not used in accordance with the terms of the marketing authorisation but the use
p.(None): of that product is evidence-based and supported by published scientific evidence on the safety and
p.(None): efficacy of that product, propose one of the Member States concerned where the use is evidence-based, as
p.(None): reporting Member State.
p.(None):
p.(None):
p.(None): 3. Within 10 days from the submission of the application dossier, the reporting Member State shall validate the
...
p.(None): Member States concerned, finds that the application dossier is not complete, or that the clinical trial applied for
p.(None): does not fall within the scope of this Regulation, it shall inform the sponsor thereof through the EU portal and
p.(None): shall set a maximum of 10 days for the sponsor to comment on the application or to complete the application dossier
p.(None): through the EU portal.
p.(None):
p.(None):
p.(None): Within five days from receipt of the comments or the completed application dossier, the reporting Member
p.(None): State shall notify the sponsor as to whether or not the application complies with the requirements set
p.(None): out in points (a) and (b) of the first subparagraph of paragraph 3.
p.(None):
p.(None):
p.(None): Where the reporting Member State has not notified the sponsor within the period referred to in the
p.(None): second sub paragraph, the clinical trial applied for shall be deemed to fall within the scope of this
p.(None): Regulation and the application dossier shall be considered complete.
p.(None):
p.(None):
p.(None): Where the sponsor has not provided comments or completed the application dossier within the period referred to in the
p.(None): first subparagraph, the application shall be deemed to have lapsed in all Member States concerned.
p.(None):
p.(None):
p.(None): 6. For the purposes of this Chapter, the date on which the sponsor is notified in accordance with
p.(None): paragraph 3 or 5 shall be the validation date of the application. Where the sponsor is not notified, the
p.(None): validation date shall be the last day of the respective periods referred to in paragraphs 3 and 5.
p.(None):
p.(None): L 158/16 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 6
p.(None):
p.(None): Assessment report — Aspects covered by Part I
p.(None):
p.(None): 1. The reporting Member State shall assess the application with regard to the following aspects:
p.(None):
p.(None): (a) Whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor;
p.(None):
p.(None): (b) Compliance with Chapter V with respect to the following:
p.(None):
p.(None): (i) The anticipated therapeutic and public health benefits taking account of all of the following:
p.(None):
p.(None): — the characteristics of and knowledge about the investigational medicinal products;
p.(None):
p.(None): — the relevance of the clinical trial, including whether the groups of subjects participating in the
p.(None): clinical trial represent the population to be treated, or if not, the explanation and justification
p.(None): provided in accordance with point (y) of paragraph 17 of Annex I to this Regulation; the current state
p.(None): of scientific knowledge; whether the clinical trial has been recommended or imposed by regulatory authorities in
p.(None): charge of the assess ment and authorisation of the placing on the market of medicinal products; and,
p.(None): where applicable, any opinion formulated by the Paediatric Committee on a paediatric investigation plan in
p.(None): accordance with Regu lation (EC) No 1901/2006 of the European Parliament and of the Council (1);
p.(None):
p.(None): — the reliability and robustness of the data generated in the clinical trial, taking account
p.(None): of statistical approaches, design of the clinical trial and methodology, including sample size
p.(None): and randomisation, comparator and endpoints;
...
p.(None):
p.(None): (d) Compliance with the labelling requirements set out in Chapter X;
p.(None):
p.(None): (e) The completeness and adequateness of the investigator's brochure.
p.(None):
p.(None): 2. The reporting Member State shall draw up an assessment report. The assessment of the aspects referred to in
p.(None): para graph 1 shall constitute Part I of the assessment report.
p.(None):
p.(None): 3. The assessment report shall contain one of the following conclusions concerning the aspects addressed in Part
p.(None): I of the assessment report:
p.(None):
p.(None): (a) the conduct of the clinical trial is acceptable in view of the requirements set out in this Regulation;
p.(None):
p.(None): (b) the conduct of the clinical trial is acceptable in view of the requirements set out in this
p.(None): Regulation, but subject to compliance with specific conditions which shall be specifically listed in that
p.(None): conclusion; or
p.(None):
p.(None): (c) the conduct of the clinical trial is not acceptable in view of the requirements set out in this Regulation.
p.(None):
p.(None): 4. The reporting Member State shall submit, through the EU portal, the final Part I of the
p.(None): assessment report, including its conclusion, to the sponsor and to the other Member States concerned
p.(None): within 45 days from the validation date.
p.(None):
p.(None): (1) Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal
p.(None): products for paedia tric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and
p.(None): Regulation (EC) No 726/2004 (OJ L 378, 27.11.2006, p. 1).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/17
p.(None):
p.(None): 5. For clinical trials involving more than one Member State, the assessment process shall include three phases:
p.(None): (a) an initial assessment phase performed by the reporting Member State within 26 days from the validation date;
p.(None): (b) a coordinated review phase performed within 12 days from the end of the initial assessment phase
p.(None): involving all Member States concerned;
p.(None): (c) a consolidation phase performed by the reporting Member State within seven days from the end of
p.(None): coordinated review phase.
p.(None): During the initial assessment phase, the reporting Member State shall develop a draft Part I of the assessment report
p.(None): and circulate it to all other Member States concerned.
p.(None):
p.(None): During the coordinated review phase, all Member States concerned shall jointly review the application
p.(None): based on the draft Part I of the assessment report and shall share any considerations relevant to the application.
p.(None):
p.(None): During the consolidation phase, the reporting Member State shall take due account of the considerations
p.(None): of the other Member States concerned when finalising Part I of the assessment report and shall record
p.(None): how all such considerations have been dealt with. The reporting Member State shall submit the final Part
p.(None): I of the assessment report to the sponsor and all other Member States concerned within the period referred to
p.(None): in paragraph 4.
p.(None):
p.(None): 6. For the purposes of this Chapter, the date on which the final Part I of the assessment report
p.(None): is submitted by the reporting Member State to the sponsor and to the other Member States concerned shall be the
p.(None): reporting date.
p.(None):
...
p.(None): information provided by the sponsor together with the original application and shall share any considerations relevant
p.(None): to the applica tion. The coordinated review shall be performed within a maximum of 12 days of the receipt of the
p.(None): additional informa tion and the further consolidation shall be performed within a maximum of seven days
p.(None): of the end of coordinated review. When finalising Part I of the assessment report, the reporting Member
p.(None): State shall take due account of the considerations of the Member States concerned and shall record how all such
p.(None): considerations have been dealt with.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the reporting Member
p.(None): State in accordance with the third subparagraph, the application shall be deemed to have lapsed in all Member States
p.(None): concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 7
p.(None):
p.(None): Assessment report — Aspects covered by Part II
p.(None):
p.(None): 1. Each Member State concerned shall assess, for its own territory, the application with respect to
p.(None): the following aspects:
p.(None): (a) compliance with the requirements for informed consent as set out in Chapter V;
p.(None): (b) compliance of the arrangements for rewarding or compensating subjects with the requirements set out in Chapter
p.(None): V and investigators;
p.(None):
p.(None): L 158/18 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (c) compliance of the arrangements for recruitment of subjects with the requirements set out in Chapter V;
p.(None): (d) compliance with Directive 95/46/EC;
p.(None): (e) compliance with Article 49;
p.(None): (f) compliance with Article 50;
p.(None): (g) compliance with Article 76;
p.(None): (h) compliance with the applicable rules for the collection, storage and future use of biological samples of the
p.(None): subject. The assessment of the aspects referred to in the first subparagraph shall constitute Part II of the assessment
p.(None): report.
p.(None): 2. Each Member State concerned shall complete its assessment within 45 days from the validation
p.(None): date and submit, through the EU portal, Part II of the assessment report, including its conclusion, to the sponsor.
p.(None):
p.(None): Each Member State concerned may request, with justified reasons, additional information from the sponsor
p.(None): regarding the aspects referred to in paragraph 1 only within the period referred to in the first subparagraph.
p.(None):
p.(None): 3. For the purpose of obtaining and reviewing the additional information referred to in the second
p.(None): subparagraph of paragraph 2 from the sponsor in accordance with the second and third subparagraph, the Member State
p.(None): concerned may extend the period referred to in the first subparagraph of paragraph 2 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from the receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
...
p.(None): clinical trial is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of one single decision within five days from the reporting date or from the last day
p.(None): of the assessment referred to in Article 7, whichever is later.
p.(None):
p.(None): An authorisation of a clinical trial subject to conditions is restricted to conditions which by their
p.(None): nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the
p.(None): conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions,
p.(None): that conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the
p.(None): reporting Member State as regards Part I of the assessment report only on the following grounds:
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 5 or 8 of Article 6.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/19
p.(None):
p.(None): Where a Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
p.(None): the Commission, to all Member States, and to the sponsor.
p.(None):
p.(None): 3. Where, regarding the aspects covered by Part I of the assessment report, the clinical trial is acceptable or
p.(None): acceptable subject to compliance with specific conditions, the Member State concerned shall include in its
p.(None): decision its conclusion on Part II of the assessment report.
p.(None):
p.(None): 4. A Member State concerned shall refuse to authorise a clinical trial if it disagrees with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report on any of the
p.(None): grounds referred to in the second sub paragraph of paragraph 2, or if it finds, on duly justified grounds, that
p.(None): the aspects addressed in Part II of the assessment report are not complied with, or where an ethics committee has
p.(None): issued a negative opinion which in accordance with the law of the Member State concerned is valid for that entire
p.(None): Member State. That Member State shall provide for an appeal procedure in respect of such refusal.
p.(None):
p.(None): 5. Where the conclusion of the reporting Member State as regards Part I of the assessment report
p.(None): is that the clinical trial is not acceptable, that conclusion shall be deemed to be the conclusion of all Member
p.(None): States concerned.
p.(None):
...
p.(None):
p.(None): Persons assessing the application
p.(None):
p.(None): 1. Member States shall ensure that the persons validating and assessing the application do not have
p.(None): conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators
p.(None): involved and of persons financing the clinical trial, as well as free of any other undue influence.
p.(None):
p.(None): In order to guarantee independence and transparency, the Member States shall ensure that persons
p.(None): admitting and asses sing the application as regards the aspects addressed in Parts I and II of the
p.(None): assessment report have no financial or personal interests which could affect their impartiality. These persons
p.(None): shall make an annual declaration of their financial interests.
p.(None):
p.(None): 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who
p.(None): collectively have the necessary qualifications and experience.
p.(None):
p.(None): 3. At least one layperson shall participate in the assessment.
p.(None):
p.(None):
p.(None): Article 10
p.(None):
p.(None): Specific considerations for vulnerable populations
p.(None):
p.(None): 1. Where the subjects are minors, specific consideration shall be given to the assessment of the
p.(None): application for authorisation of a clinical trial on the basis of paediatric expertise or after taking
p.(None): advice on clinical, ethical and psycho social problems in the field of paediatrics.
p.(None):
p.(None): L 158/20 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the
p.(None): applica tion for authorisation of a clinical trial on the basis of expertise in the relevant disease
p.(None): and the patient population concerned or after taking advice on clinical, ethical and psychosocial
p.(None): questions in the field of the relevant disease and the patient population concerned.
p.(None):
p.(None): 3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the
p.(None): assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant
p.(None): condition and the population represented by the subject concerned.
p.(None):
p.(None): 4. If according to the protocol a clinical trial provides for the participation of specific groups
p.(None): or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of
p.(None): the application for authorisation of that clinical trial on the basis of expertise in the population represented by
p.(None): the subjects concerned.
p.(None):
p.(None): 5. In any application for authorisation of a clinical trial referred to in Article 35, specific consideration
p.(None): shall be given to the circumstances of the conduct of the clinical trial.
p.(None):
p.(None):
p.(None): Article 11
p.(None):
p.(None): Submission and assessment of applications limited to aspects covered by Part I or Part II of the
p.(None): assessment report
...
p.(None): application on the aspects covered by Part I of the assessment report shall be deemed to have lapsed.
p.(None):
p.(None):
p.(None): Article 12
p.(None):
p.(None): Withdrawal
p.(None):
p.(None): The sponsor may withdraw the application at any time until the reporting date. In such a case, the application may
p.(None): only be withdrawn with respect to all Member States concerned. The reasons for the withdrawal shall be
p.(None): communicated through the EU portal.
p.(None):
p.(None):
p.(None): Article 13
p.(None):
p.(None): Resubmission
p.(None):
p.(None): This Chapter is without prejudice to the possibility for the sponsor to resubmit, following the refusal to grant an
p.(None): author isation or the withdrawal of an application, an application for authorisation to any intended
p.(None): Member State concerned. That application shall be deemed to be a new application for authorisation of another
p.(None): clinical trial.
p.(None):
p.(None):
p.(None): Article 14
p.(None):
p.(None): Subsequent addition of a Member State concerned
p.(None):
p.(None): 1. Where the sponsor wishes to extend an authorised clinical trial to another Member State (‘additional Member
p.(None): State concerned’), the sponsor shall submit an application dossier to that Member State through the EU portal.
p.(None):
p.(None): The application dossier may be submitted only after the notification date of the initial authorisation decision.
p.(None):
p.(None): 2. The reporting Member State for the application dossier referred to in paragraph 1 shall be the
p.(None): reporting Member State for the initial authorisation procedure.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/21
p.(None):
p.(None): 3. The additional Member State concerned shall notify the sponsor through the EU portal, within 52
p.(None): days from the date of submission of the application dossier referred to in paragraph 1, by way of one single
p.(None): decision as to whether the clinical trial is authorised, whether it is authorised subject to conditions, or whether
p.(None): the authorisation is refused.
p.(None):
p.(None): An authorisation of a clinical trial subject to conditions is restricted to conditions which by their
p.(None): nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 4. Where the conclusion of the reporting Member State as regards Part I of the assessment report is that the
p.(None): conduct of the clinical trial is acceptable or acceptable subject to compliance with specific conditions,
p.(None): that conclusion shall be deemed to be the conclusion of the additional Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, an additional Member State concerned may disagree with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None):
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under paragraph 5 or 6.
p.(None):
...
p.(None): with the original application and shall share any considerations relevant to the application. The
p.(None): coordinated review shall be performed within a maximum of 12 days from the receipt of the additional
p.(None): information and the further consolidation shall be performed within a maximum of seven days from the end
p.(None): of the coordinated review. The reporting Member State shall take due account of the considerations of
p.(None): the Member States concerned and shall record how all such considerations have been dealt with.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the reporting Member
p.(None): State in accordance with the third subparagraph, the application shall be deemed to have lapsed in the
p.(None): additional Member State concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None): 7. The additional Member State concerned shall assess, for its territory, the aspects addressed in
p.(None): Part II of the assess ment report within the period referred to in paragraph 3 and submit, through
p.(None): the EU portal, Part II of the assessment report, including its conclusion, to the sponsor. Within that
p.(None): period it may request, with justified reasons, additional information from the sponsor regarding aspects
p.(None): addressed in Part II of the assessment report as far as its territory is concerned.
p.(None):
p.(None): L 158/22 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 8. For the purpose of obtaining and reviewing the additional information referred to in paragraph 7
p.(None): from the sponsor in accordance with the second and third subparagraphs, the additional Member State concerned may
p.(None): extend the period referred to in paragraph 7 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the additional
p.(None): Member State concerned which shall not exceed 12 days from receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the additional Member
p.(None): State concerned in accordance with the second subparagraph, the application shall be deemed to have lapsed in the
p.(None): additional Member State concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None): 9. Where, regarding the aspects covered by Part I of the assessment report, the conduct of the
p.(None): clinical trial is accept able or acceptable subject to compliance with specific conditions, the
p.(None): additional Member State concerned shall include in its decision its conclusion on Part II of the assessment
p.(None): report.
p.(None):
p.(None): 10. The additional Member State concerned shall refuse to authorise the clinical trial if it
p.(None): disagrees with the conclu sion of the reporting Member State as regards Part I of the assessment
...
p.(None): period, the conclusion on Part I of the assessment report shall be deemed to be the decision of that additional
p.(None): Member State concerned on the application for authorisation of the clinical trial.
p.(None):
p.(None): 12. A sponsor shall not submit an application dossier in accordance with this Article where a
p.(None): procedure set out in Chapter III is pending as regards that clinical trial.
p.(None):
p.(None):
p.(None): CHAPTER III
p.(None):
p.(None): AUTHORISATION PROCEDURE FOR A SUBSTANTIAL MODIFICATION OF A CLINICAL TRIAL
p.(None):
p.(None): Article 15
p.(None):
p.(None): General principles
p.(None):
p.(None): A substantial modification, including the addition of a clinical trial site or the change of a
p.(None): principal investigator in the clinical trial site, may only be implemented if it has been approved in
p.(None): accordance with the procedure set out in this Chapter.
p.(None):
p.(None):
p.(None): Article 16
p.(None):
p.(None): Submission of application
p.(None):
p.(None): In order to obtain an authorisation, the sponsor shall submit an application dossier to the Member
p.(None): States concerned through the EU portal.
p.(None):
p.(None):
p.(None): Article 17
p.(None):
p.(None): Validation of an application for the authorisation of a substantial modification of an aspect covered by Part I of the
p.(None): assessment report
p.(None):
p.(None): 1. The reporting Member State for the authorisation of a substantial modification shall be the
p.(None): reporting Member State for the initial authorisation procedure.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/23
p.(None):
p.(None): Member States concerned may communicate to the reporting Member State any considerations relevant to the validation of
p.(None): the application of a substantial modification within five days from the submission of the application dossier.
p.(None):
p.(None): 2. Within six days from the submission of the application dossier, the reporting Member State shall validate the
p.(None): appli cation taking into account considerations expressed by the other Member States concerned and notify
p.(None): the sponsor through the EU portal as to whether:
p.(None):
p.(None): (a) the substantial modification concerns an aspect covered by Part I of the assessment report; and
p.(None):
p.(None): (b) the application dossier is complete in accordance with Annex II.
p.(None):
p.(None): 3. Where the reporting Member State has not notified the sponsor within the period referred to in
p.(None): paragraph 2, the substantial modification applied for shall be deemed to concern an aspect covered by Part I of the
p.(None): assessment report and the application dossier shall be deemed to be complete.
p.(None):
p.(None): 4. Where the reporting Member State, taking into account considerations expressed by the other
p.(None): Member States concerned, finds that the application does not concern an aspect covered by Part I of the
p.(None): assessment report or that the application dossier is not complete, it shall inform the sponsor thereof
p.(None): through the EU portal and shall set a maximum of 10 days for the sponsor to comment on the
p.(None): application or to complete the application dossier through the EU portal.
p.(None):
p.(None): Within five days from receipt of the comments or the completed application dossier, the reporting Member
...
p.(None): and 4.
p.(None):
p.(None):
p.(None): Article 18
p.(None):
p.(None): Assessment of a substantial modification of an aspect covered by Part I of the assessment report
p.(None):
p.(None): 1. The reporting Member State shall assess the application with regard to an aspect covered by
p.(None): Part I of the assess ment report, including whether the clinical trial will remain a low-intervention clinical
p.(None): trial after its substantial modifica tion, and draw up an assessment report.
p.(None):
p.(None): 2. The assessment report shall contain one of the following conclusions concerning the aspects addressed in Part
p.(None): I of the assessment report:
p.(None):
p.(None): (a) the substantial modification is acceptable in view of the requirements set out in this Regulation;
p.(None):
p.(None): (b) the substantial modification is acceptable in view of the requirements set out in this Regulation,
p.(None): but subject to compliance with specific conditions which shall be specifically listed in that conclusion; or
p.(None):
p.(None): (c) the substantial modification is not acceptable in view of the requirements set out in this Regulation.
p.(None):
p.(None): 3. The reporting Member State shall submit, through the EU portal, the final assessment report
p.(None): including its conclu sion, to the sponsor and to the other Member States concerned within 38 days from the
p.(None): validation date.
p.(None):
p.(None): For the purposes of this Article and Articles 19 and 23, the reporting date shall be the date on
p.(None): which the final assess ment report is submitted to the sponsor and to the other Member States concerned.
p.(None):
p.(None): L 158/24 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 4. For clinical trials involving more than one Member State the assessment process of substantial
p.(None): modification shall include three phases:
p.(None):
p.(None): (a) an initial assessment phase performed by the reporting Member State within 19 days from the validation date;
p.(None):
p.(None): (b) a coordinated review phase performed within 12 days from the end of the initial assessment phase
p.(None): involving all Member States concerned; and
p.(None):
p.(None): (c) a consolidation phase performed by the reporting Member State within seven days from the end of
p.(None): coordinated review phase.
p.(None):
p.(None): During the initial assessment phase, the reporting Member State shall develop a draft assessment report
p.(None): and circulate it to all Member States concerned.
p.(None):
p.(None): During the coordinated review phase, all Member States concerned shall jointly review the application
p.(None): based on the draft assessment report and shall share any considerations relevant to the application.
p.(None):
p.(None): During the consolidation phase, the reporting Member State shall take due account of the considerations
p.(None): of the other Member States concerned when finalising the assessment report and shall record how all such
p.(None): considerations have been dealt with. The reporting Member State shall submit the final assessment report
p.(None): to the sponsor and all other Member States concerned by the reporting date.
p.(None):
p.(None): 5. The reporting Member State may extend the period referred to in paragraph 3 by a further 50
p.(None): days for clinical trials involving an advanced therapy investigational medicinal product or a medicinal
...
p.(None): information provided by the sponsor together with the original application and shall share any considerations relevant
p.(None): to the applica tion. The coordinated review shall be performed within a maximum of 12 days from receipt
p.(None): of the additional informa tion and the further consolidation shall be performed within a maximum of seven days from
p.(None): the end of the coordinated review. When finalising the assessment report, the reporting Member State shall
p.(None): take due account of the considerations of the other Member States concerned and shall record how all such
p.(None): considerations have been dealt with.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period determined by the reporting
p.(None): Member State in accordance with the third subparagraph, the application shall be deemed to have lapsed
p.(None): in all Member States concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None):
p.(None): Article 19
p.(None):
p.(None): Decision on the substantial modification of an aspect covered by Part I of the assessment report
p.(None):
p.(None): 1. Each Member State concerned shall notify the sponsor through the EU portal as to whether the substantial
p.(None): modifi cation is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within five days from the reporting date.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/25
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State is that the substantial modification is acceptable or
p.(None): acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the
p.(None): conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with that conclusion of the
p.(None): reporting Member State only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None):
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
p.(None): the Commission, to all Member States and to the sponsor.
p.(None):
p.(None): A Member State concerned shall refuse to authorise a substantial modification if it disagrees with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report on any of the
...
p.(None): Validation, assessment and decision regarding a substantial modification of an aspect covered by Part II of the
p.(None): assessment report
p.(None):
p.(None): 1. Within six days from the submission of the application dossier, the Member State concerned shall
p.(None): notify the sponsor through the EU portal of the following:
p.(None):
p.(None): (a) whether the substantial modification concerns an aspect covered by Part II of the assessment report; and
p.(None):
p.(None): (b) whether the application dossier is complete in accordance with Annex II.
p.(None):
p.(None): 2. Where the Member State concerned has not notified the sponsor within the period referred to in paragraph
p.(None): 1, the substantial modification applied for shall be deemed to concern an aspect covered by Part II of
p.(None): the assessment report and the application dossier shall be deemed to be complete.
p.(None):
p.(None): 3. Where the Member State concerned finds that the substantial modification does not concern an aspect
p.(None): covered by Part II of the assessment report or that the application dossier is not complete, it shall
p.(None): inform the sponsor thereof through the EU portal and shall set a maximum of 10 days for the sponsor
p.(None): to comment on the application or to complete the application dossier through the EU portal.
p.(None):
p.(None): Within five days from receipt of the comments or the completed application dossier, the reporting Member
p.(None): State shall notify the sponsor as to whether or not the application complies with the requirements set
p.(None): out in points (a) and (b) of paragraph 1.
p.(None):
p.(None): L 158/26 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Where the Member State concerned has not notified the sponsor within the period referred to in the
p.(None): second sub paragraph, the substantial modification shall be deemed to concern an aspect covered by Part II of the
p.(None): assessment report and the application dossier shall be deemed to be complete.
p.(None):
p.(None): Where the sponsor has not provided comments nor completed the application dossier within the period
p.(None): referred to in the first subparagraph, the application shall be deemed to have lapsed in the Member State concerned.
p.(None):
p.(None): 4. For the purpose of this Article, the date on which the sponsor is notified in accordance with
p.(None): paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the
p.(None): validation date shall be the last day of the respective periods referred to in paragraphs 1 and 3.
p.(None):
p.(None): 5. The Member State concerned shall assess the application and shall submit to the sponsor, through
p.(None): the EU portal, Part II of the assessment report, including its conclusion, and the decision as to
p.(None): whether the substantial modification is authorised, whether it is authorised subject to conditions, or whether
p.(None): authorisation is refused.
p.(None):
p.(None): Notification shall be done by way of a single decision within 38 days from the validation date.
p.(None):
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
...
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None): 7. A Member State concerned shall refuse to authorise a substantial modification if it finds, on duly justified
p.(None): grounds, that the aspects covered by Part II of the assessment report are not complied with or where
p.(None): an ethics committee has issued a negative opinion which, in accordance with the law of that Member
p.(None): State concerned, is valid for that entire Member State. That Member State shall provide for an appeal procedure
p.(None): in respect of such refusal.
p.(None):
p.(None): 8. Where the Member State concerned has not notified the sponsor of its decision within the periods set out in
p.(None): para graphs 5 and 6, the substantial modification shall be deemed to be authorised in that Member State.
p.(None):
p.(None):
p.(None): Article 21
p.(None):
p.(None): Substantial modification of aspects covered by Parts I and II of the assessment report
p.(None):
p.(None): 1. Where a substantial modification relates to aspects covered by Parts I and II of the assessment
p.(None): report, the applica tion for authorisation of that substantial modification shall be validated in accordance with
p.(None): Article 17.
p.(None):
p.(None): 2. The aspects covered by Part I of the assessment report shall be assessed in accordance with
p.(None): Article 18 and the aspects covered by Part II of the assessment report shall be assessed in accordance with Article
p.(None): 22.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/27
p.(None):
p.(None): Article 22
p.(None):
p.(None): Assessment of a substantial modification of aspects covered by Parts I and II of the assessment report
p.(None): — Assessment of the aspects covered by Part II of the assessment report
p.(None):
p.(None): 1. Each Member State concerned shall assess, for its own territory, the aspects of the substantial
p.(None): modification which are covered by Part II of the assessment report and submit, through the EU portal, that
p.(None): report, including its conclusion, to the sponsor within 38 days from the validation date.
p.(None):
p.(None): 2. During the period referred to in paragraph 1, the Member State concerned may request, with justified
p.(None): reasons, ad ditional information from the sponsor regarding this substantial modification as far as its territory is
p.(None): concerned.
p.(None):
p.(None): 3. For the purpose of obtaining and reviewing the additional information referred to in paragraph 2
p.(None): from the sponsor in accordance with the third and fourth subparagraph, the Member State concerned may
p.(None): extend the period referred to paragraph 1 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from the receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide the requested additional information within the period set by the
...
p.(None): An authorisation of a substantial modification subject to conditions is restricted to conditions which by
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State is that the substantial modification of
p.(None): aspects covered by Part I of the assessment report is acceptable or acceptable subject to compliance with specific
p.(None): conditions, that conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with the conclusion of the
p.(None): reporting Member State only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards suject safety and data reliability and robustness submitted under paragraph
p.(None): 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion regarding the substantial modification of
p.(None): aspects covered by Part I of the assessment report on the basis of the second subparagraph, it shall
p.(None): communicate its disagree ment, together with a detailed justification through the EU portal to the
p.(None): Commission, to all Member States, and to the sponsor.
p.(None):
p.(None): L 158/28 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Where, regarding the substantial modification of aspects covered by Part I of the assessment report, the
p.(None): substantial modification is acceptable or acceptable subject to compliance with specific conditions, the
p.(None): Member State concerned shall include in its decision its conclusion on the substantial modification of aspects
p.(None): covered by Part II of the assessment report.
p.(None):
p.(None): 4. A Member State concerned shall refuse to authorise a substantial modification if it disagrees with the
p.(None): conclusion of the reporting Member State as regards the substantial modification of aspects covered by Part I of the
p.(None): assessment report on any of the grounds referred to in second subparagraph of paragraph 2, or if it
p.(None): finds, on duly justified grounds, that the aspects covered by Part II of the assessment report are not
p.(None): complied with, or where an ethics committee has issued a negative opinion which in accordance with the
p.(None): law of the Member State concerned, is valid for that entire Member State. That Member State concerned shall
p.(None): provide for an appeal procedure in respect of such refusal.
p.(None):
p.(None): 5. Where the conclusion of the reporting Member State as regards the substantial modification of aspects
p.(None): covered by Part I of the assessment report is that the substantial modification is not acceptable, that
p.(None): conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): 6. Where the Member State concerned has not notified the sponsor of its decision within the
...
p.(None):
p.(None): Data submitted in the application dossier
p.(None):
p.(None): 1. The application dossier for the authorisation of a clinical trial shall contain all required
p.(None): documentation and infor mation necessary for the validation and assessment referred to in Chapter II and relating
p.(None): to:
p.(None): (a) the conduct of the clinical trial, including the scientific context and arrangements taken,
p.(None): (b) the sponsor, investigators, potential subjects, subjects, and clinical trial sites;
p.(None):
p.(None): (c) the investigational medicinal products and, where necessary, the auxiliary medicinal products, in
p.(None): particular their properties, labelling, manufacturing and control;
p.(None):
p.(None): (d) measures to protect subjects;
p.(None):
p.(None): (e) justification as to why the clinical trial is a low-intervention clinical trial, in cases where
p.(None): this is claimed by the sponsor.
p.(None): The list of required documentation and information is set out in Annex I.
p.(None):
p.(None): 2. The application dossier for the authorisation of a substantial modification shall contain all required
p.(None): documentation and information necessary for the validation and assessment referred to in Chapter III:
p.(None):
p.(None): (a) a reference to the clinical trial or clinical trials which are substantially modified using the EU trial number
p.(None): referred to in the third subparagraph of Article 81(1) (the ‘EU trial number’);
p.(None):
p.(None): (b) a clear description of the substantial modification, in particular, the nature of and the reasons for substantial
p.(None): modifi cation;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/29
p.(None):
p.(None): (c) a presentation of data and additional information in support of the substantial modification, where necessary;
p.(None): (d) a clear description of the consequences of the substantial modification as regards the rights and safety of
p.(None): the subject and the reliability and robustness of the data generated in the clinical trial.
p.(None): The list of required documentation and information is set out in Annex II.
p.(None):
p.(None): 3. Non-clinical information submitted in an application dossier shall be based on data derived from studies
p.(None): complying with Union law on the principles of good laboratory practice, as applicable at the time of performance of
p.(None): those studies.
p.(None):
p.(None): 4. Where reference is made in the application dossier to data generated in a clinical trial, that
p.(None): clinical trial shall have been conducted in accordance with this Regulation or, if conducted prior to the date
p.(None): referred to in the second paragraph of Article 99, in accordance with Directive 2001/20/EC.
p.(None):
p.(None): 5. Where the clinical trial referred to in paragraph 4 has been conducted outside the Union, it
p.(None): shall have been conducted in accordance with principles equivalent to those of this Regulation as regards
p.(None): the rights and safety of the subject and the reliability and robustness of the data generated in the clinical
p.(None): trial.
p.(None):
p.(None): 6. Data from a clinical trial started as from the date referred to in the second paragraph of
p.(None): Article 99 shall only be submitted in an application dossier if that clinical trial has been registered
p.(None): prior to its start in a public register which is a primary or partner registry of, or a data provider to, the
p.(None): WHO ICTRP.
p.(None):
p.(None): Data from a clinical trial started before the date referred to in the second paragraph of Article 99 shall only be
p.(None): submitted in an application dossier if that clinical trial is registered in a public register which is a primary or
p.(None): partner registry of, or a data provider to, the WHO ICTRP or if the results of that clinical trial have
p.(None): been published in an independent peer- reviewed scientific publication.
p.(None):
p.(None): 7. Data submitted in an application dossier which do not comply with paragraphs 3 to 6 shall not
p.(None): be considered in the assessment of an application for authorisation of a clinical trial or of a substantial
p.(None): modification.
p.(None):
p.(None):
p.(None): Article 26
p.(None):
p.(None): Language requirements
p.(None):
p.(None): The language of the application dossier, or parts thereof, shall be determined by the Member State concerned.
p.(None):
p.(None): Member States, in applying the first paragraph, shall consider accepting, for the documentation not
p.(None): addressed to the subject, a commonly understood language in the medical field.
p.(None):
p.(None):
p.(None): Article 27
p.(None):
p.(None): Update by way of delegated acts
p.(None):
p.(None): The Commission shall be empowered to adopt delegated acts in accordance with Article 85 in respect of
p.(None): amending Annexes I and II in order to adapt them to technical progress or to take account of
p.(None): international regulatory develop ments in which the Union or the Member States are involved, in the field of
p.(None): clinical trials.
p.(None):
p.(None):
p.(None): CHAPTER V
p.(None):
p.(None): PROTECTION OF SUBJECTS AND INFORMED CONSENT
p.(None):
p.(None): Article 28
p.(None):
p.(None): General rules
p.(None):
p.(None): 1. A clinical trial may be conducted only where all of the following conditions are met:
p.(None): (a) the anticipated benefits to the subjects or to public health justify the foreseeable risks and
p.(None): inconveniences and compliance with this condition is constantly monitored;
p.(None): (b) the subjects, or where a subject is not able to give informed consent, his or her legally
p.(None): designated representative, have been informed in accordance with Article 29(2) to (6);
p.(None):
p.(None): L 158/30 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (c) the subjects, or where a subject is not able to give informed consent, his or her legally
p.(None): designated representative, have given informed consent in accordance with Article 29(1), (7) and (8);
p.(None):
p.(None): (d) the rights of the subjects to physical and mental integrity, to privacy and to the protection of
p.(None): the data concerning them in accordance with Directive 95/46/EC are safeguarded;
p.(None):
p.(None): (e) the clinical trial has been designed to involve as little pain, discomfort, fear and any other foreseeable risk
p.(None): as possible for the subjects and both the risk threshold and the degree of distress are specifically
p.(None): defined in the protocol and constantly monitored;
p.(None): (f) the medical care provided to the subjects is the responsibility of an appropriately qualified medical
p.(None): doctor or, where appropriate, a qualified dental practitioner;
p.(None):
p.(None): (g) the subject or, where the subject is not able to give informed consent, his or her legally designated
p.(None): representative has been provided with the contact details of an entity where further information can be received in
p.(None): case of need;
p.(None): (h) no undue influence, including that of a financial nature, is exerted on subjects to participate in the clinical
p.(None): trial.
...
p.(None): time shall be given for the subject or his or her legally designated representative to consider his or her decision to
p.(None): participate in the clinical trial.
p.(None):
p.(None): 2. Information given to the subject or, where the subject is not able to give informed consent, his or her
p.(None): legally desig nated representative for the purposes of obtaining his or her informed consent shall:
p.(None): (a) enable the subject or his or her legally designated representative to understand:
p.(None): (i) the nature, objectives, benefits, implications, risks and inconveniences of the clinical trial;
p.(None): (ii) the subject's rights and guarantees regarding his or her protection, in particular his or her
p.(None): right to refuse to participate and the right to withdraw from the clinical trial at any time without
p.(None): any resulting detriment and without having to provide any justification;
p.(None):
p.(None): (iii) the conditions under which the clinical trial is to be conducted, including the expected duration of
p.(None): the subject's participation in the clinical trial; and
p.(None):
p.(None): (iv) the possible treatment alternatives, including the follow-up measures if the participation of the
p.(None): subject in the clinical trial is discontinued;
p.(None): (b) be kept comprehensive, concise, clear, relevant, and understandable to a layperson;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/31
p.(None):
p.(None): (c) be provided in a prior interview with a member of the investigating team who is appropriately
p.(None): qualified according to the law of the Member State concerned;
p.(None):
p.(None): (d) include information about the applicable damage compensation system referred to in Article 76(1); and
p.(None):
p.(None): (e) include the EU trial number and information about the availability of the clinical trial results
p.(None): in accordance with paragraph 6.
p.(None):
p.(None): 3. The information referred to in paragraph 2 shall be prepared in writing and be available to
p.(None): the subject or, where the subject is not able to give informed consent, his or her legally designated
p.(None): representative.
p.(None):
p.(None): 4. In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the
p.(None): information needs of specific patient populations and of individual subjects, as well as to the methods used to give
p.(None): the information.
p.(None):
p.(None): 5. In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood
p.(None): the infor mation.
p.(None):
p.(None): 6. The subject shall be informed that the summary of the results of the clinical trial and a
p.(None): summary presented in terms understandable to a layperson will be made available in the EU database,
p.(None): referred to in Article 81 (the ‘EU data base’), pursuant to Article 37(4), irrespective of the outcome
p.(None): of the clinical trial, and, to the extent possible, when the summaries become available.
p.(None):
...
p.(None):
p.(None): 2. For clinical trials that fulfil the conditions set out in paragraph 3, informed consent shall be
p.(None): deemed to have been obtained if:
p.(None):
p.(None): (a) the information required under points (a), (b), (d) and (e) of Article 29(2) is given, in
p.(None): accordance with what is laid down in the protocol, prior to the inclusion of the subject in the
p.(None): clinical trial, and this information makes clear, in particular, that the subject can refuse to
p.(None): participate in, or withdraw at any time from, the clinical trial without any resulting detriment; and
p.(None):
p.(None): (b) the potential subject, after being informed, does not object to participating in the clinical trial.
p.(None):
p.(None): 3. Informed consent may be obtained by the simplified means set out in paragraph 2, if all the
p.(None): following conditions are fulfilled:
p.(None):
p.(None): (a) the simplified means for obtaining informed consent do not contradict national law in the Member State concerned;
p.(None):
p.(None): (b) the methodology of the clinical trial requires that groups of subjects rather than individual
p.(None): subjects are allocated to receive different investigational medicinal products in a clinical trial;
p.(None):
p.(None): (c) the clinical trial is a low-intervention clinical trial and the investigational medicinal products
p.(None): are used in accordance with the terms of the marketing authorisation;
p.(None):
p.(None): L 158/32 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (d) there are no interventions other than the standard treatment of the subjects concerned;
p.(None):
p.(None): (e) the protocol justifies the reasons for obtaining informed consent with simplified means and
p.(None): describes the scope of information provided to the subjects, as well as the ways of providing information.
p.(None):
p.(None): 4. The investigator shall document all refusals and withdrawals and shall ensure that no data for
p.(None): the clinical trial are collected from subjects that refuse to participate in or have withdrawn from the clinical
p.(None): trial.
p.(None):
p.(None):
p.(None): Article 31
p.(None):
p.(None): Clinical trials on incapacitated subjects
p.(None):
p.(None): 1. In the case of incapacitated subjects who have not given, or have not refused to give, informed consent
p.(None): before the onset of their incapacity, a clinical trial may be conducted only where, in addition to the conditions set
p.(None): out in Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the incapacitated subjects have received the information referred to in Article 29(2) in a way that is adequate in
p.(None): view of their capacity to understand it;
p.(None):
...
p.(None): concerned in com parison with the standard treatment of the incapacitated subject's condition.
p.(None):
p.(None): 2. Point (g)(ii) of paragraph 1 shall be without prejudice to more stringent national rules
p.(None): prohibiting the conduct of those clinical trials on incapacitated subjects, where there are no scientific
p.(None): grounds to expect that participation in the clinical trial will produce a direct benefit to the subject
p.(None): outweighing the risks and burdens involved.
p.(None):
p.(None): 3. The subject shall as far as possible take part in the informed consent procedure.
p.(None):
p.(None):
p.(None): Article 32
p.(None):
p.(None): Clinical trials on minors
p.(None):
p.(None): 1. A clinical trial on minors may be conducted only where, in addition to the conditions set out in
p.(None): Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the minors have received the information referred to in Article 29(2) in a way adapted to their
p.(None): age and mental maturity and from investigators or members of the investigating team who are trained or
p.(None): experienced in working with children;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/33
p.(None):
p.(None): (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information
p.(None): referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is
p.(None): respected by the investi gator;
p.(None): (d) no incentives or financial inducements are given to the subject or his or her legally designated
p.(None): representative except for compensation for expenses and loss of earnings directly related to the participation in the
p.(None): clinical trial;
p.(None): (e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in
p.(None): minors or the clin ical trial is essential with respect to minors to validate data obtained in
p.(None): clinical trials on persons able to give informed consent or by other research methods;
p.(None): (f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is
p.(None): of such a nature that it can only be carried out on minors;
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
p.(None): (ii) some benefit for the population represented by the minor concerned and such a clinical trial will
...
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
p.(None): clinical trial may be obtained, and information on the clinical trial may be given, after the decision to
p.(None): include the subject in the clinical trial, provided that this decision is taken at the time of the first
p.(None): intervention on the subject, in accordance with the protocol for that clinical trial" and that all of the
p.(None): following conditions are fulfilled:
p.(None):
p.(None): (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious
p.(None): medical condition, the subject is unable to provide prior informed consent and to receive prior information on the
p.(None): clinical trial;
p.(None):
p.(None): (b) there are scientific grounds to expect that participation of the subject in the clinical trial will
p.(None): have the potential to produce a direct clinically relevant benefit for the subject resulting in a
p.(None): measurable health-related improvement alle viating the suffering and/or improving the health of the subject, or in
p.(None): the diagnosis of its condition;
p.(None):
p.(None): (c) it is not possible within the therapeutic window to supply all prior information to and obtain
...
p.(None): information referred to in Article 29(2) shall be given as soon as possible to the the subject or his
p.(None): or her legally designated representative, whichever is sooner.
p.(None):
p.(None): For the purposes of point (b), where informed consent has been obtained from the legally designated
p.(None): representative, informed consent to continue the participation in the clinical trial shall be obtained
p.(None): from the subject as soon as he or she is capable of giving informed consent.
p.(None):
p.(None): 3. If the subject or, where applicable, his or her legally designated representative does not give
p.(None): consent, he or she shall be informed of the right to object to the use of data obtained from the clinical trial.
p.(None):
p.(None):
p.(None): CHAPTER VI
p.(None):
p.(None): START, END, TEMPORARY HALT, AND EARLY TERMINATION OF A CLINICAL TRIAL
p.(None):
p.(None): Article 36
p.(None):
p.(None): Notification of the start of a clinical trial and of the end of the recruitment of subjects
p.(None):
p.(None): 1. The sponsor shall notify each Member State concerned of the start of a clinical trial in
p.(None): relation to that Member State through the EU portal.
p.(None):
p.(None): That notification shall be made within 15 days from the start of the clinical trial in relation to that Member State.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/35
p.(None):
p.(None): 2. The sponsor shall notify each Member State concerned of the first visit of the first subject
p.(None): in relation to that Member State through the EU portal.
p.(None):
p.(None): That notification shall be made within 15 days from the first visit of the first subject in relation to that Member
p.(None): State.
p.(None):
p.(None): 3. The sponsor shall notify each Member State concerned of the end of the recruitment of subjects for a
p.(None): clinical trial in that Member State through the EU portal.
p.(None):
p.(None): That notification shall be made within 15 days from the end of the recruitment of subjects. In case of re-start of
p.(None): recruit ment, paragraph 1 shall apply.
p.(None):
p.(None):
p.(None): Article 37
p.(None):
p.(None): End of a clinical trial, temporary halt and early termination of a clinical trial and submission of the results
p.(None):
p.(None): 1. The sponsor shall notify each Member State concerned of the end of a clinical trial in
p.(None): relation to that Member State through the EU portal.
p.(None):
p.(None): That notification shall be made within 15 days from the end of the clinical trial in relation to that Member State.
p.(None):
p.(None): 2. The sponsor shall notify each Member State concerned of the end of a clinical trial in all Member States
p.(None): concerned through the EU portal.
p.(None):
p.(None): That notification shall be made within 15 days from the end of the clinical trial in the last Member State concerned.
p.(None):
p.(None): 3. The sponsor shall notify each Member State concerned of the end of a clinical trial in all Member States
p.(None): concerned and in all third countries in which the clinical trial has been conducted through the EU portal.
p.(None):
...
p.(None):
p.(None): However, where, for scientific reasons detailed in the protocol, it is not possible to submit a summary
p.(None): of the results within one year, the summary of results shall be submitted as soon as it is available.
p.(None): In this case, the protocol shall specify when the results are going to be submitted, together with a
p.(None): justification.
p.(None):
p.(None): In addition to the summary of the results, where the clinical trial was intended to be used for
p.(None): obtaining a marketing authorisation for the investigational medicinal product, the applicant for marketing
p.(None): authorisation shall submit to the EU database the clinical study report within 30 days after the day the
p.(None): marketing authorisation has been granted, the proce dure for granting the marketing authorisation has been
p.(None): completed, or the applicant for marketing authorisation has withdrawn the application.
p.(None):
p.(None): For cases where the sponsor decides to share raw data on a voluntary basis, the Commission shall produce guidelines for
p.(None): the formatting and sharing of those data.
p.(None):
p.(None): 5. The sponsor shall notify each Member State concerned of a temporary halt of a clinical trial
p.(None): in all Member States concerned for reasons not affecting the benefit-risk balance through the EU portal.
p.(None):
p.(None): That notification shall be made within 15 days from the temporary halt of the clinical trial in all
p.(None): Member States concerned and shall include the reasons for such action.
p.(None):
p.(None): L 158/36 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 6. When a temporarily halted clinical trial referred to in paragraph 5 is resumed the sponsor
p.(None): shall notify each Member State concerned through the EU portal.
p.(None):
p.(None): That notification shall be made within 15 days from the restart of the temporarily halted clinical
p.(None): trial in all Member States concerned.
p.(None):
p.(None): 7. If a temporarily halted clinical trial is not resumed within two years, the expiry date of this
p.(None): period or the date of the decision of the sponsor not to resume the clinical trial, whichever is
p.(None): earlier, shall be deemed to be the date of the end of the clinical trial. In the case of early
p.(None): termination of the clinical trial, the date of the early termination shall be deemed to be the date of the
p.(None): end of the clinical trial.
p.(None):
p.(None): In the case of early termination of the clinical trial for reasons not affecting the benefit-risk
p.(None): balance, the sponsor shall notify each Member State concerned through the EU portal of the reasons for
p.(None): such action and, when appropriate, follow-up measures for the subjects.
p.(None):
p.(None): 8. Without prejudice to paragraph 4, where the clinical trial protocol provides for an intermediate
p.(None): data analysis date prior to the end of the clinical trial, and the respective results of the clinical
p.(None): trial are available, a summary of those results shall be submitted to the EU database within one year of the
p.(None): intermediate data analysis date.
p.(None):
p.(None):
p.(None): Article 38
p.(None):
p.(None): Temporary halt or early termination by the sponsor for reasons of subject safety
p.(None):
p.(None): 1. For the purposes of this Regulation, the temporary halt or early termination of a clinical
p.(None): trial for reasons of a change of the benefit-risk balance shall be notified to the Member States concerned through
p.(None): the EU portal.
p.(None):
p.(None): That notification shall be made without undue delay but not later than in 15 days of the date of the
p.(None): temporary halt or early termination. It shall include the reasons for such action and specify follow-up measures.
p.(None):
p.(None): 2. The restart of the clinical trial following a temporary halt as referred to in paragraph 1
p.(None): shall be deemed to be a substantial modification subject to the authorisation procedure laid down in Chapter III.
p.(None):
p.(None):
p.(None): Article 39
p.(None):
p.(None): Update of the contents of the summary of results and summary for laypersons
p.(None):
p.(None): The Commission shall be empowered to adopt delegated acts in accordance with Article 89 in order to
p.(None): amend Annexes IV and V, in order to adapt them to technical progress or to take account of
p.(None): international regulatory develop ments, in which the Union or the Member States are involved, in the field of
p.(None): clinical trials.
p.(None):
p.(None):
p.(None): CHAPTER VII
p.(None):
p.(None): SAFETY REPORTING IN THE CONTEXT OF A CLINICAL TRIAL
p.(None):
p.(None): Article 40
p.(None):
p.(None): Electronic database for safety reporting
p.(None):
p.(None): 1. The European Medicines Agency established by Regulation (EC) No 726/2004 (the ‘Agency’) shall set up and main
p.(None): tain an electronic database for the reporting provided for in Articles 42 and 43. That database shall be
p.(None): a module of the database referred to in Article 24 of Regulation (EC) No 726/2004 (the ‘Eudravigilance database’).
p.(None):
p.(None): 2. The Agency shall, in collaboration with Member States, develop a standard web-based structured
p.(None): form for the reporting by sponsors to the database referred to in paragraph 1 of suspected unexpected serious adverse
p.(None): reactions.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/37
p.(None):
p.(None): Article 41
p.(None):
p.(None): Reporting of adverse events and serious adverse events by the investigator to the sponsor
p.(None):
p.(None): 1. The investigator shall record and document adverse events or laboratory abnormalities identified in the
p.(None): protocol as critical to the safety evaluation and report them to the sponsor in accordance with the
p.(None): reporting requirements and within the periods specified in the protocol.
p.(None):
p.(None): 2. The investigator shall record and document all adverse events, unless the protocol provides differently. The
p.(None): investi gator shall report to the sponsor all serious adverse events occurring to subjects treated by
p.(None): him or her in the clinical trial, unless the protocol provides differently.
p.(None):
p.(None): The investigator shall report serious adverse events to the sponsor without undue delay but not later
p.(None): than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events,
p.(None): the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send
p.(None): a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an
p.(None): impact on the benefit-risk balance of the clinical trial.
p.(None):
p.(None): 3. The sponsor shall keep detailed records of all adverse events reported to it by the investigator.
p.(None):
p.(None): 4. If the investigator becomes aware of a serious adverse event with a suspected causal
p.(None): relationship to the investiga tional medicinal product that occurs after the end of the clinical trial in a
p.(None): subject treated by him or her, the investigator shall, without undue delay, report the serious adverse event to the
p.(None): sponsor.
p.(None):
p.(None):
p.(None): Article 42
p.(None):
p.(None): Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency
p.(None):
p.(None): 1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without
p.(None): delay to the database referred to in Article 40(1) all relevant information about the following suspected
p.(None): unexpected serious adverse reactions.:
p.(None): (a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in
p.(None): that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred
p.(None): at a clinical trial site in the Union or in a third country;
p.(None): (b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of
p.(None): pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical
p.(None): trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:
p.(None): (i) by that sponsor, or
p.(None): (ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical
p.(None): trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the
p.(None): sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product
p.(None): or information to a future potential marketing authorisation holder on safety matters shall not be
p.(None): considered a joint development; and
p.(None): (c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in
p.(None): any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after
p.(None): the end of the clin ical trial.
p.(None): 2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency
p.(None): shall take account of the seriousness of the reaction and shall be as follows:
p.(None): (a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and
p.(None): in any event not later than seven days after the sponsor became aware of the reaction;
p.(None): (b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not
p.(None): later than 15 days after the sponsor became aware of the reaction;
p.(None): (c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or
p.(None): non- life threatening but which turns out to be fatal or life-threatening, as soon as possible and in
p.(None): any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening.
p.(None): Where necessary to ensure timely reporting, the sponsor may, in accordance with section 2.4 of Annex
p.(None): III, submit an initial incomplete report followed up by a complete report.
p.(None):
p.(None): L 158/38 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Where a sponsor, due to a lack of resources, does not have the possibility to report to the
p.(None): database referred to in Article 40(1) and the sponsor has the agreement of the Member State concerned,
p.(None): it may report to the Member State where the suspected unexpected serious adverse reaction occurred. That
p.(None): Member State shall report the suspected unex pected serious adverse reaction in accordance with paragraph 1 of
p.(None): this Article.
p.(None):
p.(None):
p.(None): Article 43
p.(None):
p.(None): Annual reporting by the sponsor to the Agency
p.(None):
p.(None): 1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually
p.(None): through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational
p.(None): medicinal product used in a clinical trial for which it is the sponsor.
p.(None):
p.(None): 2. In the case of a clinical trial involving the use of more than one investigational medicinal
p.(None): product, the sponsor may, if provided for in the protocol, submit a single safety report on all
p.(None): investigational medicinal products used in that clinical trial.
p.(None):
p.(None): 3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymised data.
p.(None):
p.(None): 4. The obligation referred to in paragraph 1 starts with the first authorisation of a clinical
p.(None): trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor
p.(None): with the investigational medicinal product.
p.(None):
p.(None):
p.(None): Article 44
p.(None):
p.(None): Assessment by Member States
p.(None):
p.(None): 1. The Agency shall, by electronic means, forward to the Member States concerned the information
p.(None): reported in accordance with Article 42 and 43.
p.(None):
p.(None): 2. Member States shall cooperate in assessing the information reported in accordance with Articles
p.(None): 42and 43. The Commission may, by means of implementing acts, set up and modify the rules on such
p.(None): cooperation. Those imple menting acts shall be adopted in accordance with the examination procedure referred to in
p.(None): Article 88(2).
p.(None):
p.(None): 3. The responsible ethics committee shall be involved in the assessment of the information referred to in
p.(None): paragraphs 1 and 2, if it has been provided for in the law of the Member State concerned.
p.(None):
p.(None):
p.(None): Article 45
p.(None):
p.(None): Technical aspects
p.(None):
p.(None): Technical aspects for safety reporting in accordance with Articles 41 to 44 are contained in Annex III.
p.(None): Where necessary in order to improve the level of protection of subjects, the Commission shall be
p.(None): empowered to adopt delegated acts in accordance with Article 89 in order to amend Annex III for any of the
p.(None): following purposes:
p.(None): (a) improving the information on the safety of medicinal products;
p.(None): (b) adapting technical requirements to technical progress;
p.(None): (c) taking account of international regulatory developments in the field of safety requirements in clinical trials,
p.(None): endorsed by bodies in which the Union or the Member States participate.
p.(None):
p.(None):
p.(None): Article 46
p.(None):
p.(None): Reporting with regard to auxiliary medicinal products
p.(None):
p.(None): Safety reporting with regard to auxiliary medicinal products shall be made in accordance with Chapter 3
p.(None): of Title IX of Directive 2001/83/EC.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/39
p.(None):
p.(None): CHAPTER VIII
p.(None):
p.(None): CONDUCT OF A CLINICAL TRIAL, SUPERVISION BY THE SPONSOR, TRAINING AND EXPERIENCE, AUXILIARY MEDI CINAL PRODUCTS
p.(None):
p.(None): Article 47
p.(None):
p.(None): Compliance with the protocol and good clinical practice
p.(None):
p.(None): The sponsor of a clinical trial and the investigator shall ensure that the clinical trial is conducted in accordance
p.(None): with the protocol and with the principles of good clinical practice.
p.(None):
p.(None): Without prejudice to any other provision of Union law or Commission guidelines, the sponsor and the
p.(None): investigator, when drawing up the protocol and when applying this Regulation and the protocol, shall also
p.(None): take appropriate account of the quality standards and the ICH guidelines on good clinical practice.
p.(None):
p.(None): The Commission shall make publicly available the detailed ICH guidelines on good clinical practice
p.(None): referred to in the second paragraph.
p.(None):
p.(None):
p.(None): Article 48
p.(None):
p.(None): Monitoring
p.(None):
p.(None): In order to verify that the rights, safety and well-being of subjects are protected, that the reported
p.(None): data are reliable and robust, and that the conduct of the clinical trial is in compliance with the
p.(None): requirements of this Regulation, the sponsor shall adequately monitor the conduct of a clinical trial. The
p.(None): extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment
p.(None): that takes into consideration all characteristics of the clinical trial, including the following
p.(None): characteristics:
p.(None): (a) whether the clinical trial is a low-intervention clinical trial;
p.(None): (b) the objective and methodology of the clinical trial; and
p.(None): (c) the degree of deviation of the intervention from normal clinical practice.
p.(None):
p.(None): Article 49
p.(None):
p.(None): Suitability of individuals involved in conducting the clinical trial
p.(None):
p.(None): The investigator shall be a medical doctor as defined in national law, or a person following a profession
p.(None): which is recog nised in the Member State concerned as qualifying for an investigator because of the
p.(None): necessary scientific knowledge and experience in patient care.
p.(None):
p.(None): Other individuals involved in conducting a clinical trial shall be suitably qualified by education,
p.(None): training and experience to perform their tasks.
p.(None):
p.(None):
p.(None): Article 50
p.(None):
p.(None): Suitability of clinical trial sites
p.(None):
p.(None): The facilities where the clinical trial is to be conducted shall be suitable for the conduct of the clinical trial in
p.(None): compliance with the requirements of this Regulation.
p.(None):
p.(None):
p.(None): Article 51
p.(None):
p.(None): Traceability, storage, return and destruction of investigational medicinal products
p.(None):
p.(None): 1. Investigational medicinal products shall be traceable. They shall be stored, returned and/or destroyed as
p.(None): appropriate and proportionate to ensure the safety of the subject and the reliability and robustness of the data
p.(None): generated in the clin ical trial, in particular, taking into account whether the investigational medicinal product is
p.(None): an authorised investigational medicinal product, and whether the clinical trial is a low-intervention clinical trial.
p.(None):
p.(None): L 158/40 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): The first subparagraph shall also apply to unauthorised auxiliary medicinal products.
p.(None):
p.(None): 2. The relevant information regarding the traceability, storage, return and destruction of medicinal
p.(None): products referred to in paragraph 1 shall be contained in the application dossier.
p.(None):
p.(None):
p.(None): Article 52
p.(None):
p.(None): Reporting of serious breaches
p.(None):
p.(None): 1. The sponsor shall notify the Member States concerned about a serious breach of this Regulation
p.(None): or of the version of the protocol applicable at the time of the breach through the EU portal without undue delay
p.(None): but not later than seven days of becoming aware of that breach.
p.(None):
p.(None): 2. For the purposes of this Article, a ‘serious breach’ means a breach likely to affect to a
p.(None): significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the
p.(None): clinical trial.
p.(None):
p.(None):
p.(None): Article 53
p.(None):
p.(None): Other reporting obligations relevant for subject safety
p.(None):
p.(None): 1. The sponsor shall notify the Member States concerned through the EU portal of all unexpected events which
p.(None): affect the benefit-risk balance of the clinical trial, but are not suspected unexpected serious adverse
p.(None): reactions as referred to in Article 42. That notification shall be made without undue delay but no
p.(None): later than 15 days from the date the sponsor became aware of this event.
p.(None):
p.(None): 2. The sponsor shall submit to the Member States concerned, through the EU portal, all inspection
p.(None): reports of third country authorities concerning the clinical trial. When requested by a Member State concerned, the
p.(None): sponsor shall submit a translation of the report or of its summary in an official language of the Union indicated in
p.(None): the request.
p.(None):
p.(None):
p.(None): Article 54
p.(None):
p.(None): Urgent safety measures
p.(None):
p.(None): 1. Where an unexpected event is likely to seriously affect the benefit-risk balance, the sponsor
p.(None): and the investigator shall take appropriate urgent safety measures to protect the subjects.
p.(None):
p.(None): 2. The sponsor shall notify the Member States concerned, through the EU portal, of the event and
p.(None): the measures taken.
p.(None):
p.(None): That notification shall be made without undue delay but no later than seven days from the date the measures have been
p.(None): taken.
p.(None):
p.(None): 3. This Article is without prejudice to Chapters III and VII.
p.(None):
p.(None):
p.(None): Article 55
p.(None):
p.(None): Investigator's brochure
p.(None):
p.(None): 1. The sponsor shall provide the investigator with the investigator's brochure.
p.(None):
p.(None): 2. The investigator's brochure shall be updated where new and relevant safety information becomes
p.(None): available, and shall be reviewed by the sponsor at least once per year.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/41
p.(None):
p.(None): Article 56
p.(None):
p.(None): Recording, processing, handling and storage of information
p.(None):
p.(None): 1. All clinical trial information shall be recorded, processed, handled, and stored by the sponsor
p.(None): or investigator, as applicable, in such a way that it can be accurately reported, interpreted and
p.(None): verified while the confidentiality of records and the personal data of the subjects remain protected in
p.(None): accordance with the applicable law on personal data protec tion.
p.(None):
p.(None): 2. Appropriate technical and organisational measures shall be implemented to protect information and
p.(None): personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction
p.(None): or accidental loss, in particular where the processing involves the transmission over a network.
p.(None):
p.(None):
p.(None): Article 57
p.(None):
p.(None): Clinical trial master file
p.(None):
p.(None): The sponsor and the investigator shall keep a clinical trial master file. The clinical trial master
p.(None): file shall at all times contain the essential documents relating to that clinical trial which allow
p.(None): verification of the conduct of a clinical trial and the quality of the data generated, taking into
p.(None): account all characteristics of the clinical trial, including in particular whether the clinical trial is
p.(None): a low-intervention clinical trial. It shall be readily available, and directly accessible upon request, to
p.(None): the Member States.
p.(None):
p.(None): The clinical trial master file kept by the investigator and that kept by the sponsor may have a different
p.(None): content if this is justified by the different nature of the responsibilities of the investigator and the sponsor.
p.(None):
p.(None):
p.(None): Article 58
p.(None):
p.(None): Archiving of the clinical trial master file
p.(None):
p.(None): Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the
p.(None): content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the
p.(None): medical files of subjects shall be archived in accordance with national law.
p.(None):
p.(None): The content of the clinical trial master file shall be archived in a way that ensures that it is
p.(None): readily available and acces sible, upon request, to the competent authorities.
p.(None):
p.(None): Any transfer of ownership of the content of the clinical trial master file shall be documented. The
p.(None): new owner shall assume the responsibilities set out in this Article.
p.(None):
p.(None): The sponsor shall appoint individuals within its organisation to be responsible for archives. Access to
p.(None): archives shall be restricted to those individuals.
p.(None):
p.(None): The media used to archive the content of the clinical trial master file shall be such that the
p.(None): content remains complete and legible throughout the period referred to in the first paragraph.
p.(None):
p.(None): Any alteration to the content of the clinical trial master file shall be traceable.
p.(None):
p.(None):
p.(None): Article 59
p.(None):
p.(None): Auxiliary medicinal products
p.(None):
p.(None): 1. Only authorised auxiliary medicinal products may be used in a clinical trial.
p.(None):
p.(None): 2. Paragraph 1 shall not apply where no authorised auxiliary medicinal product is available in the
p.(None): Union or where the sponsor cannot reasonably be expected to use an authorised auxiliary medicinal product. A
p.(None): justification to this effect shall be included in the protocol.
p.(None):
p.(None): L 158/42 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Member States shall ensure that unauthorised auxiliary medicinal products may enter their
p.(None): territories for the purpose of their use in a clinical trial in accordance with paragraph 2.
p.(None):
p.(None):
p.(None): CHAPTER IX
p.(None):
p.(None): MANUFACTURING AND IMPORT OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): Article 60
p.(None):
p.(None): Scope of this Chapter
p.(None):
p.(None): This Chapter shall apply to the manufacture and import of investigational medicinal products and
p.(None): auxiliary medicinal products.
p.(None):
p.(None):
p.(None): Article 61
p.(None):
p.(None): Authorisation of manufacturing and import
p.(None):
p.(None): 1. The manufacturing and import of investigational medicinal products in the Union shall be subject
p.(None): to the holding of an authorisation.
p.(None):
p.(None): 2. In order to obtain the authorisation referred to in paragraph 1, the applicant shall meet the
p.(None): following require ments:
p.(None):
p.(None): (a) it shall have at its disposal, for manufacture or import, suitable and sufficient premises,
p.(None): technical equipment and control facilities complying with the requirements set out in this Regulation;
p.(None):
p.(None): (b) it shall have permanently and continuously at its disposal the services of at least one qualified person who
p.(None): fulfils the conditions of qualification set out in Article 49(2) and (3) of Directive 2001/83/EC (‘qualified person’).
p.(None):
p.(None): 3. The applicant shall specify, in the application for authorisation, the types and pharmaceutical forms of
p.(None): the investi gational medicinal product manufactured or imported, the manufacturing or import operations,
p.(None): the manufacturing process where relevant, the site where the investigational medicinal products are to be
p.(None): manufactured or the site in the Union to which they are to be imported, and detailed information concerning the
p.(None): qualified person.
p.(None):
p.(None): 4. Articles 42 to 45, and point (e) of Article 46 of Directive 2001/83/EC shall apply mutatis mutandis to the
p.(None): authorisa tion referred to in paragraph 1.
p.(None):
p.(None): 5. Paragraph 1 shall not apply to any of the following processes:
p.(None):
p.(None): (a) re-labelling or re-packaging, where those processes are carried out in hospitals, health centres or clinics,
p.(None): by pharma cists or other persons legally authorised in the Member State concerned to carry out such processes, and if
p.(None): the inves tigational medicinal products are intended to be used exclusively in hospitals, health centres or
p.(None): clinics taking part in the same clinical trial in the same Member State;
p.(None):
p.(None): (b) preparation of radiopharmaceuticals used as diagnostic investigational medicinal products where this
p.(None): process is carried out in hospitals, health centres or clinics, by pharmacists or other persons legally
p.(None): authorised in the Member State concerned to carry out such process, and if the investigational medicinal
p.(None): products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same
p.(None): clinical trial in the same Member State;
p.(None):
p.(None): (c) the preparation of medicinal products referred to in points (1) and (2) of Article 3 of Directive
p.(None): 2001/83/EC for use as investigational medicinal products, where this process is carried out in hospitals,
p.(None): health centres or clinics legally authorised in the Member State concerned to carry out such process
p.(None): and if the investigational medicinal products are intended to be used exclusively in hospitals, health
p.(None): centres or clinics taking part in the same clinical trial in the same Member State.
p.(None):
p.(None): 6. Member States shall make the processes set out in paragraph 5 subject to appropriate and
p.(None): proportionate require ments to ensure subject safety and reliability and robustness of the data generated in
p.(None): the clinical trial. They shall subject the processes to regular inspections.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/43
p.(None):
p.(None): Article 62
p.(None):
p.(None): Responsibilities of the qualified person
p.(None):
p.(None): 1. The qualified person shall ensure that each batch of investigational medicinal products
p.(None): manufactured in or imported into the Union complies with the requirements set out in Article 63 and
p.(None): shall certify that those requirements are fulfilled.
p.(None):
p.(None): 2. The certification referred to in paragraph 1 shall be made available by the sponsor at the
p.(None): request of the Member State concerned.
p.(None):
p.(None): Article 63
p.(None):
p.(None): Manufacturing and import
p.(None):
p.(None): 1. Investigational medicinal products shall be manufactured by applying manufacturing practice which
p.(None): ensures the quality of such medicinal products in order to safeguard the safety of the subject and the
p.(None): reliability and robustness of clinical data generated in the clinical trial (‘good manufacturing practice’). The
p.(None): Commission shall be empowered to adopt delegated acts in accordance with Article 89 in order to specify the
p.(None): principles and guidelines of good manufacturing practice and the detailed arrangements for inspection for
p.(None): ensuring the quality of investigational medicinal products, taking account of subject safety or data reliability
p.(None): and robustness, technical progress and global regulatory developments in which the Union or the Member States are
p.(None): involved.
p.(None):
p.(None): In addition, the Commission shall also adopt and publish detailed guidelines in line with those principles of good
p.(None): manu facturing practice and revise them when necessary in order to take account of technical and scientific progress.
p.(None):
p.(None): 2. Paragraph 1 shall not apply to the processes referred to in Article 61(5).
p.(None):
p.(None): 3. Investigational medicinal products imported into the Union shall be manufactured by applying quality standards
p.(None): at least equivalent to those laid down pursuant to paragraph 1.
p.(None):
p.(None): 4. The Member States shall ensure compliance with the requirements of this Article by means of inspections.
p.(None):
p.(None): Article 64
p.(None):
p.(None): Modification of authorised investigational medicinal products
p.(None):
p.(None): Articles 61, 62 and 63 shall apply to authorised investigational medicinal products only as regards any
p.(None): modification of such products not covered by a marketing authorisation.
p.(None):
p.(None): Article 65
p.(None):
p.(None): Manufacturing of auxiliary medicinal products
p.(None):
p.(None): Where the auxiliary medicinal product is not authorised, or where an authorised auxiliary medicinal product is
p.(None): modified while such modification is not covered by a marketing authorisation, it shall be manufactured
p.(None): according to the good manufacturing practice referred to in Article 63(1) orto at least an equivalent
p.(None): standard, in order to ensure appropriate quality.
p.(None):
p.(None): CHAPTER X
p.(None):
p.(None): LABELLING
p.(None):
p.(None): Article 66
p.(None):
p.(None): Unauthorised investigational and unauthorised auxiliary medicinal products
p.(None):
p.(None): 1. The following information shall appear on the outer packaging and on the immediate packaging of
p.(None): unauthorised investigational medicinal products and unauthorised auxiliary medicinal products:
p.(None): (a) information to identify contact persons or persons involved in the clinical trial;
p.(None): (b) information to identify the clinical trial;
p.(None):
p.(None): L 158/44 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (c) information to identify the medicinal product;
p.(None):
p.(None): (d) information related to the use of the medicinal product.
p.(None):
p.(None): 2. The information which is to appear on the outer packaging and immediate packaging shall ensure
p.(None): subject safety and reliability and robustness of the data generated in the clinical trial, while taking account of
p.(None): the design of the clinical trial, whether the products are investigational or auxiliary medicinal product,
p.(None): and whether they are products with par ticular characteristics.
p.(None):
p.(None): The information which is to appear on the outer packaging and immediate packaging shall be clearly legible.
p.(None):
p.(None): A list of information which is to appear on the outer packaging and immediate packaging is set out in Annex VI.
p.(None):
p.(None):
p.(None): Article 67
p.(None):
p.(None): Authorised investigational and authorised auxiliary medicinal products
p.(None):
p.(None): 1. Authorised investigational medicinal products and authorised auxiliary medicinal products shall be labelled:
p.(None):
p.(None): (a) in accordance with Article 66(1); or
p.(None):
p.(None): (b) in accordance with Title V of Directive 2001/83/EC.
p.(None):
p.(None): 2. Notwithstanding point (b) of paragraph 1, where the specific circumstances, provided for in the protocol, of a
p.(None): clin ical trial so require in order to ensure the safety of the subject or the reliability and
p.(None): robustness of data generated in a clinical trial, additional particulars relating to the identification of the
p.(None): clinical trial and of the contact person shall appear on the outer packaging and the immediate packaging of authorised
p.(None): investigational medicinal products. A list of these ad ditional particulars appearing on the outer packaging and
p.(None): immediate packaging is set out in section C of Annex VI.
p.(None):
p.(None):
p.(None): Article 68
p.(None):
p.(None): Radiopharmaceuticals used as investigational medicinal products or as auxiliary medicinal products for a
p.(None): medical diagnosis
p.(None):
p.(None): Articles 66 and 67 shall not apply to radiopharmaceuticals used as diagnostic investigational medicinal
p.(None): products or as diagnostic auxiliary medicinal products.
p.(None):
p.(None): The products referred to in the first paragraph shall be labelled appropriately in order to ensure the safety of the
p.(None): subject and the reliability and robustness of data generated in the clinical trial.
p.(None):
p.(None):
p.(None): Article 69
p.(None):
p.(None): Language
p.(None):
p.(None): The language of the information on the label shall be determined by the Member State concerned. The
p.(None): medicinal product may be labelled in several languages.
p.(None):
p.(None):
p.(None): Article 70
p.(None):
p.(None): Delegated act
p.(None):
p.(None): The Commission shall be empowered to adopt delegated acts in accordance with Article 89 in respect of
p.(None): amending Annex VI in order to ensure subject safety and the reliability and robustness of data generated
p.(None): in a clinical trial or to take account of technical progress.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/45
p.(None):
p.(None): CHAPTER XI
p.(None):
p.(None): SPONSOR AND INVESTIGATOR
p.(None):
p.(None): Article 71
p.(None):
p.(None): Sponsor
p.(None):
p.(None): A clinical trial may have one or several sponsors.
p.(None):
p.(None): Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution
p.(None): or an organisation. Such delegation shall be without prejudice to the responsibility of the sponsor, in
p.(None): particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical
p.(None): trial.
p.(None):
p.(None): The investigator and the sponsor may be the same person.
p.(None):
p.(None):
p.(None): Article 72
p.(None):
p.(None): Co-sponsorship
p.(None):
p.(None): 1. Without prejudice to Article 74, where a clinical trial has more than one sponsor, all sponsors
p.(None): shall have the responsibilities of a sponsor set out in this Regulation, unless the sponsors decide otherwise in a
p.(None): written contract setting out their respective responsibilities. Where the contract does not specify to which sponsor a
p.(None): given responsibility is attrib uted, that responsibility shall lie with all sponsors.
p.(None):
p.(None): 2. By way of derogation from paragraph 1, the sponsors shall be jointly responsible for establishing:
p.(None): (a) a sponsor responsible for compliance with the obligations of a sponsor in the authorisation
p.(None): procedures set out in Chapters II and III;
p.(None): (b) a sponsor responsible for being a contact point for receiving all questions from subjects,
p.(None): investigators or any Member State concerned regarding the clinical trial and providing answers to them;
p.(None): (c) a sponsor responsible for implementing the measures taken in accordance with Article 77.
p.(None):
p.(None): Article 73
p.(None):
p.(None): Principal investigator
p.(None):
p.(None): A principal investigator shall ensure compliance of a clinical trial at a clinical trial site with the
p.(None): requirements of this Regulation.
p.(None):
p.(None): The principal investigator shall assign tasks among the members of the team of investigators in a way
p.(None): which is not compromising the safety of subjects and the reliability and robustness of the data
p.(None): generated in the clinical trial at that clinical trial site.
p.(None):
p.(None):
p.(None): Article 74
p.(None):
p.(None): Legal representative of the sponsor in the Union
p.(None):
p.(None): 1. Where the sponsor of a clinical trial is not established in the Union, that sponsor shall
p.(None): ensure that a natural or legal person is established in the Union as its legal representative. Such
p.(None): legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant
p.(None): to this Regulation, and shall be the addressee for all communications with the sponsor provided for in
p.(None): this Regulation. Any communication to that legal representative shall be deemed to be a communication to the
p.(None): sponsor.
p.(None):
p.(None): 2. Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their
p.(None): terri tory, or on their territory and the territory of a third country, provided that they ensure that
p.(None): the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall
p.(None): be the addressee for all communications with the sponsor provided for in this Regulation.
p.(None):
p.(None): L 158/46 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. As regards clinical trials to be conducted in more than one Member State, all those Member States may choose
p.(None): not to apply paragraph 1 provided that they ensure that the sponsor establishes at least a contact
p.(None): person in the Union in respect of that clinical trial who shall be the addressee for all communications
p.(None): with the sponsor provided for in this Regulation.
p.(None):
p.(None):
p.(None): Article 75
p.(None):
p.(None): Liability
p.(None):
p.(None): This Chapter shall not affect the civil and criminal liability of the sponsor, investigator, or persons to whom the
p.(None): sponsor has delegated tasks.
p.(None):
p.(None):
p.(None): CHAPTER XII
p.(None):
p.(None): DAMAGE COMPENSATION
p.(None):
p.(None): Article 76
p.(None):
p.(None): Damage compensation
p.(None):
p.(None): 1. Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from
p.(None): par ticipation in a clinical trial conducted on their territory are in place in the form of insurance,
p.(None): a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the
p.(None): nature and the extent of the risk.
p.(None):
p.(None): 2. The sponsor and the investigator shall make use of the system referred to in paragraph 1 in
p.(None): the form appropriate for the Member State concerned where the clinical trial is conducted.
p.(None):
p.(None): 3. Member States shall not require any additional use of the system referred to in paragraph 1
p.(None): from the sponsor for low-intervention clinical trials, if any possible damage that could be suffered by
p.(None): a subject resulting from the use of the investigational medicinal product in accordance with the protocol
p.(None): of that specific clinical trial on the territory of that Member State is covered by the applicable
p.(None): compensation system already in place.
p.(None):
p.(None):
p.(None): CHAPTER XIII
p.(None):
p.(None): SUPERVISION BY MEMBER STATES, UNION INSPECTIONS AND CONTROLS
p.(None):
p.(None): Article 77
p.(None):
p.(None): Corrective measures to be taken by Member States
p.(None):
p.(None): 1. Where a Member State concerned has justified grounds for considering that the requirements set out in this
p.(None): Regu lation are no longer met, it may take the following measures on its territory:
p.(None): (a) revoke the authorisation of a clinical trial;
p.(None): (b) suspend a clinical trial;
p.(None): (c) require the sponsor to modify any aspect of the clinical trial.
p.(None): 2. Before the Member State concerned takes any of the measures referred to in paragraph 1 it
p.(None): shall, except where immediate action is required, ask the sponsor and/or the investigator for their
p.(None): opinion. That opinion shall be delivered within seven days.
p.(None):
p.(None): 3. The Member State concerned shall immediately after taking a measure referred to in paragraph 1
p.(None): inform all Member States concerned through the EU portal.
p.(None):
p.(None): 4. Each Member State concerned may consult the other Member States concerned before taking any of
p.(None): the measures referred to in paragraph 1.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/47
p.(None):
p.(None): Article 78
p.(None):
p.(None): Member State inspections
p.(None):
p.(None): 1. Member States shall appoint inspectors to perform inspections in order to supervise compliance
p.(None): with this Regu lation. They shall ensure that those inspectors are adequately qualified and trained.
p.(None):
p.(None): 2. Inspections shall be conducted under the responsibility of the Member State where the inspection takes place.
p.(None):
p.(None): 3. Where a Member State concerned intends to carry out an inspection on its territory or in a
p.(None): third country with regard to one or several clinical trials which are conducted in more than one Member State
p.(None): concerned, it shall notify its intention to the other Member States concerned, the Commission and the
p.(None): Agency, through the EU portal, and shall inform them of its findings after the inspection.
p.(None):
p.(None): 4. Inspections fees, if any, may be waived for non-commercial sponsors.
p.(None):
p.(None): 5. In order to efficiently use the resources available and to avoid duplications, the Agency shall
p.(None): coordinate the co operation between Member States concerned on inspections conducted in Member States, in third
p.(None): countries, and inspec tions conducted in the framework of an application for a marketing authorisation under
p.(None): Regulation (EC) No 726/2004.
p.(None):
p.(None): 6. Following an inspection, the Member State under whose responsibility the inspection has been
p.(None): conducted shall draw up an inspection report. That Member State shall make the inspection report
p.(None): available to the inspected entity and the sponsor of the relevant clinical trial and shall submit the inspection
p.(None): report through the EU portal.
p.(None):
p.(None): 7. The Commission shall specify, by means of implementing acts, the detailed arrangements for the
p.(None): inspection pro cedures including the qualification and training requirements for inspectors. Those
p.(None): implementing acts shall be adopted in accordance with the examination procedure referred to in Article 88(2).
p.(None):
p.(None):
p.(None): Article 79
p.(None):
p.(None): Union controls
p.(None):
p.(None): 1. The Commission may conduct controls in order to verify:
p.(None): (a) whether Member States correctly supervise compliance with this Regulation;
p.(None): (b) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that
p.(None): point 8 of the Introduction and general principles contained in Annex I to Directive 2001/83/EC is complied with;
p.(None): (c) whether the regulatory system applicable to clinical trials conducted outside the Union ensures that
p.(None): Article 25(5) of this Regulation is complied with.
p.(None): 2. The Union controls referred to in point (a) of paragraph 1 shall be organised in cooperation
p.(None): with the Member States concerned.
p.(None):
p.(None): The Commission shall prepare in cooperation with the Member States a programme for the Union controls
p.(None): referred to in points (b) and (c) of paragraph 1.
p.(None):
p.(None): The Commission shall report on the findings of each Union control carried out. Those reports shall, if
p.(None): appropriate, contain recommendations. The Commission shall submit those reports through the EU portal.
p.(None):
p.(None):
p.(None): CHAPTER XIV
p.(None):
p.(None): IT INFRASTRUCTURE
p.(None):
p.(None): Article 80
p.(None):
p.(None): EU portal
p.(None):
p.(None): The Agency shall, in collaboration with the Member States and the Commission, set up and maintain a
p.(None): portal at Union level as a single entry point for the submission of data and information relating to
p.(None): clinical trials in accordance with this Regulation. The EU portal shall be technically advanced and user-friendly
p.(None): so as to avoid unnecessary work.
p.(None):
p.(None): L 158/48 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Data and information submitted through the EU portal shall be stored in the EU database.
p.(None):
p.(None):
p.(None): Article 81
p.(None):
p.(None): EU database
p.(None):
p.(None): 1. The Agency shall, in collaboration with the Member States and the Commission, set up and
p.(None): maintain a EU data base at Union level. The Agency shall be considered to be the controller of the EU
p.(None): database and shall be responsible for avoiding unnecessary duplication between the EU database and the EudraCT and
p.(None): Eudravigilance databases.
p.(None):
p.(None): The EU database shall contain the data and information submitted in accordance with this Regulation.
p.(None):
p.(None): The EU database shall identify each clinical trial by a unique EU trial number. The sponsor shall
p.(None): refer to this EU trial number in any subsequent submission relating or referring to that clinical trial.
p.(None):
p.(None): 2. The EU database shall be established to enable cooperation between the competent authorities of
p.(None): the Member States concerned to the extent that it is necessary for the application of this Regulation and to search
p.(None): for specific clinical trials. It shall also facilitate the communication between sponsors and Member States
p.(None): concerned and enable sponsors to refer to previous submissions of an application for authorisation of a
p.(None): clinical trial or a substantial modification. It shall also enable citizens of the Union to have access
p.(None): to clinical information about medicinal products. To this end all data held in the EU database shall be
p.(None): in an easily searchable format, all related data shall be grouped together by way of the EU trial
p.(None): number, and hyperlinks shall be provided to link together related data and documents held on the EU
p.(None): database and other databases managed by the Agency.
p.(None):
p.(None): 3. The EU database shall support the recording and submission to the Medicinal Product Dictionary, contained in
p.(None): the Eudravigilance database, of all the data on medicinal products without a marketing authorisation in
p.(None): the Union and substances not authorised as part of a medicinal product in the Union, that are necessary
p.(None): for the maintenance of that dictionary. To this effect and also with the purpose of enabling the
p.(None): sponsor to cross-refer to prior applications, an EU medicinal product number shall be issued for every
p.(None): medicinal product without a marketing authorisation and an EU active substances code shall be issued for
p.(None): each new active substance not previously authorised as part of a medicinal product in the Union. This shall
p.(None): be done before or during the application for authorisation of the first clinical trial with that product or active
p.(None): substance submitted in accordance with this Regulation. Those numbers shall be mentioned in all subsequent applications
p.(None): for clinical trials and for substantial modifications.
p.(None):
p.(None): The data submitted, in accordance with the first subparagraph, describing medicinal products and
p.(None): substances shall comply with Union and international standards for the identification of medicinal products and
p.(None): active substances. When an investigational medicinal product which already has a marketing authorisation
p.(None): in the Union and/or an active substance which is part of a medicinal product with a marketing
p.(None): authorisation in the Union, is to be used in a clinical trial, the relevant product and active substance
p.(None): numbers shall be referred to in the application for that clinical trial.
p.(None):
p.(None): 4. The EU database shall be publicly accessible unless, for all or part of the data and
p.(None): information contained therein, confidentiality is justified on any of the following grounds:
p.(None):
p.(None): (a) protecting personal data in accordance with Regulation (EC) No 45/2001;
p.(None):
p.(None): (b) protecting commercially confidential information, in particular through taking into account the
p.(None): status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in
p.(None): disclosure;
p.(None):
p.(None): (c) protecting confidential communication between Member States in relation to the preparation of the
p.(None): assessment report;
p.(None):
p.(None): (d) ensuring effective supervision of the conduct of a clinical trial by Member States.
p.(None):
p.(None): 5. Without prejudice to paragraph 4, unless there is an overriding public interest in disclosure,
p.(None): data contained in the application dossier shall not be publicly accessible before the decision on the clinical trial
p.(None): has been made.
p.(None):
p.(None): 6. The EU database shall contain personal data only insofar as this is necessary for the purposes of paragraph
p.(None): 2.
p.(None):
p.(None): 7. No personal data of subjects shall be publicly accessible.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/49
p.(None):
p.(None): 8. The user interface of the EU database shall be available in all official languages of the Union.
p.(None):
p.(None): 9. The sponsor shall permanently update in the EU database information on any changes to the
p.(None): clinical trials which are not substantial modifications but are relevant for the supervision of
p.(None): the clinical trial by the Member States concerned.
p.(None):
p.(None): 10. The Agency, the Commission and Member States shall ensure that the data subject may effectively exercise
p.(None): his or her rights to information, to access, to rectify and to object in accordance with Regulation (EC)
p.(None): No 45/2001 and national data protection legislation implementing Directive 95/46/EC, respectively. They
p.(None): shall ensure that the data subject may effectively exercise the right of access to data relating to him
p.(None): or her, and the right to have inaccurate or incomplete data corrected or erased. Within their
p.(None): respective responsibilities, the Agency, the Commission and Member States shall ensure that inaccurate and
p.(None): unlawfully processed data are deleted, in accordance with the applicable law. Corrections and deletions shall
p.(None): be carried out as soon as possible, but no later than 60 days of a request being made by a data subject.
p.(None):
p.(None):
p.(None): Article 82
p.(None):
p.(None): Functionality of the EU portal and the EU database
p.(None):
p.(None): 1. The Agency shall, in collaboration with the Member States and the Commission, draw up the
p.(None): functional specifica tions for the EU portal and the EU database, together with the time frame for their
p.(None): implementation.
p.(None):
p.(None): 2. The Management Board of the Agency shall, on the basis of an independent audit report, inform
p.(None): the Commission when it has verified that the EU portal and the EU database have achieved full
p.(None): functionality and the systems meet the functional specifications drawn up pursuant to paragraph 1.
p.(None):
p.(None): 3. The Commission shall, when it is satisfied that the conditions referred to in paragraph 2 have
p.(None): been fulfilled, publish a notice to that effect in the Official Journal of the European Union.
p.(None):
p.(None):
p.(None): CHAPTER XV
p.(None):
p.(None): COOPERATION BETWEEN MEMBER STATES
p.(None):
p.(None): Article 83
p.(None):
p.(None): National contact points
p.(None):
p.(None): 1. Each Member State shall designate one national contact point in order to facilitate the
p.(None): functioning of the proced ures set out in Chapters II and III.
p.(None):
p.(None): 2. Each Member State shall communicate the contact point referred to in paragraph 1 to the
p.(None): Commission. The Commission shall publish a list of the national contact points.
p.(None):
p.(None):
p.(None): Article 84
p.(None):
p.(None): Support by the Agency and the Commission
p.(None):
p.(None): The Agency shall support the functioning of the cooperation of the Member States in the framework of
p.(None): the authorisa tion procedures set out in Chapters II and III of this Regulation by maintaining and
p.(None): updating the EU portal and the EU database in accordance with the experience acquired during the implementation
p.(None): of this Regulation.
p.(None):
p.(None): The Commission shall support the functioning of the cooperation of the Member States referred to in Article 44(2).
p.(None):
p.(None):
p.(None): Article 85
p.(None):
p.(None): Clinical Trials Coordination and Advisory Group
p.(None):
p.(None): 1. A Clinical Trials Coordination and Advisory Group (CTAG), composed of the national contact points referred to
p.(None): in Article 83 is hereby established.
p.(None):
p.(None): L 158/50 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. The CTAG shall have the following tasks:
p.(None): (a) to support the exchange of information between the Member States and the Commission on the experience acquired
p.(None): with regard to the implementation of this Regulation;
p.(None): (b) to assist the Commission in providing the support referred to in the second paragraph of Article 84;
p.(None): (c) to prepare recommendations on criteria regarding the selection of a reporting Member State.
p.(None): 3. The CTAG shall be chaired by a representative of the Commission.
p.(None):
p.(None): 4. The CTAG shall meet at regular intervals and whenever the situation requires, on a request from
p.(None): the Commission or a Member State. Any item of the agenda of the meeting shall be placed at the
p.(None): request of the Commission or a Member State.
p.(None):
p.(None): 5. The secretariat shall be provided by the Commission.
p.(None):
p.(None): 6. The CTAG shall draw up its rules of procedure. The rules of procedure shall be made public.
p.(None):
p.(None):
p.(None): CHAPTER XVI
p.(None):
p.(None): FEES
p.(None):
p.(None): Article 86
p.(None):
p.(None): General principle
p.(None):
p.(None): This Regulation shall be without prejudice to the possibility for Member States to levy a fee for the
p.(None): activities set out in this Regulation, provided that the level of the fee is set in a transparent
p.(None): manner and on the basis of cost recovery prin ciples. Member States may establish reduced fees for
p.(None): non-commercial clinical trials.
p.(None):
p.(None):
p.(None): Article 87
p.(None):
p.(None): One payment per activity per Member State
p.(None):
p.(None): A Member State shall not require, for an assessment as referred to in Chapters II and III, multiple
p.(None): payments to different bodies involved in this assessment.
p.(None):
p.(None):
p.(None): CHAPTER XVII
p.(None):
p.(None): IMPLEMENTING ACTS AND DELEGATED ACTS
p.(None):
p.(None): Article 88
p.(None):
p.(None): Committee procedure
p.(None):
p.(None): 1. The Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use established by
p.(None): Directive 2001/83/EC. That committee shall be a committee within the meaning of Regulation (EU) No 182/2011.
p.(None):
p.(None): 2. Where reference is made to this paragraph, Article 5 of Regulation (EU) No 182/2011 shall apply.
p.(None):
p.(None): Where the committee delivers no opinion, the Commission shall not adopt the draft implementing act and the third sub
p.(None): paragraph of Article 5(4) of Regulation (EU) No 182/2011 shall apply.
p.(None):
p.(None):
p.(None): Article 89
p.(None):
p.(None): Exercise of the delegation
p.(None):
p.(None): 1. The power to adopt delegated acts is conferred on the Commission subject to the conditions laid
p.(None): down in this Article.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/51
p.(None):
p.(None): 2. The power to adopt delegated acts referred to in Articles 27, 39, 45, 63(1) and 70 shall be
p.(None): conferred on the Commission for a period of five years from the date referred to in the second paragraph of Article
p.(None): 99. The Commission shall draw up a report in respect of the delegated powers not later than six months
p.(None): before the end of the five year period. The delegation of powers shall be tacitly extended for periods
p.(None): of an identical duration, unless the European Parliament or the Council opposes such extension not later than
p.(None): three months before the end of each period.
p.(None):
p.(None): 3. The delegation of power referred to in Articles 27, 39, 45, 63(1) and 70 may be revoked at any time by the
p.(None): Euro pean Parliament or by the Council. A decision of revocation shall put an end to the delegation of the power
p.(None): specified in that decision. It shall take effect the day following the publication of the decision in
p.(None): the Official Journal of the European Union or at a later date specified therein. It shall not affect the validity
p.(None): of any delegated acts already in force.
p.(None):
p.(None): 4. As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the European Parliament
p.(None): and to the Council.
p.(None):
p.(None): 5. A delegated act adopted pursuant to Articles 27, 39, 45, 63(1) and 70 shall enter into force
p.(None): only if no objection has been expressed either by the European Parliament or the Council within a
p.(None): period of two months from notification of that act to the European Parliament and the Council or if,
p.(None): before the expiry of that period, the European Parliament and the Council have both informed the
p.(None): Commission that they will not object. That period shall be extended by two months at the initiative of the
p.(None): European Parliament or the Council.
p.(None):
p.(None):
p.(None): CHAPTER XVIII
p.(None):
p.(None): MISCELLANEOUS PROVISIONS
p.(None):
p.(None): Article 90
p.(None):
p.(None): Specific requirements for special groups of medicinal products
p.(None):
p.(None): This Regulation shall not affect the application of national law prohibiting or restricting the use of
p.(None): any specific type of human or animal cells, or the sale, supply or use of medicinal products containing,
p.(None): consisting of or derived from those cells, or of medicinal products used as abortifacients or of medicinal
p.(None): products containing narcotic substances within the meaning of the relevant international conventions in force such
p.(None): as the Single Convention on Narcotic Drugs of 1961 of the United Nations. The Member States shall communicate that
p.(None): national law to the Commission.
p.(None):
p.(None): No gene therapy clinical trials may be carried out which result in modifications to the subject's germ
p.(None): line genetic iden tity.
p.(None):
p.(None):
p.(None): Article 91
p.(None):
p.(None): Relation with other Union legislation
p.(None):
p.(None): This Regulation shall be without prejudice to Council Directive 97/43/Euratom (1), Council Directive
p.(None): 96/29/Euratom (2), Directive 2001/18/EC of the European Parliament and of the Council (3), Directive
p.(None): 2004/23/EC of the European Parlia ment and of the Council (4), Directive 2002/98/EC of the
p.(None): European Parliament and of the Council (5), Directive 2010/53/EC of the European Parliament and of
p.(None): the Council (6), and Directive 2009/41/EC of the European Parliament and of the Council. (7)
p.(None):
p.(None): (1) Council Directive 97/43/Euratom of 30 June 1997 on health protection of individuals against the dangers of
p.(None): ionizing radiation in rela tion to medical exposure, and repealing Directive 84/466/Euratom (OJ L 180, 9.7.1997, p.
p.(None): 22).
p.(None): (2) Council Directive 96/29/Euratom of 13 May 1996 laying down basic safety standards for the protection of the health
p.(None): of workers and the
p.(None): general public against the dangers arising from ionizing radiation (OJ L 159, 29.6.1996, p. 1).
p.(None): (3) Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into
p.(None): the environment of genetically modified organisms and repealing Council Directive 90/220/EEC (OJ L 106, 17.4.2001, p.
p.(None): 1).
p.(None): (4) Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of
p.(None): quality and safety for the
p.(None): donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells (OJ L
p.(None): 102, 7.4.2004, p. 48).
p.(None): (5) Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality
p.(None): and safety for the collection, testing, processing, storage and distribution of human blood and blood components and
p.(None): amending Directive 2001/83/EC (OJ L 33, 8.2.2003, p. 30).
p.(None): (6) Directive 2010/53/EU of the European Parliament and of the Council of 7 July 2010 on standards of quality and
p.(None): safety of human organs
p.(None): intended for transplantation (OJ L 207, 6.8.2010, p. 14).
p.(None): (7) Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of
p.(None): genetically modified micro- organisms (OJ L 125, 21.5.2009, p. 75).
p.(None):
p.(None): L 158/52 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 92
p.(None):
p.(None): Investigational medicinal products, other products and procedures, free of charge for the subject
p.(None): Without prejudice to the Member States' competence for the definition of their health policy and for
p.(None): the organisation and delivery of health services and medical care, the costs for investigational medicinal
p.(None): products, auxiliary medicinal products, medical devices used for their administration and procedures
p.(None): specifically required by the protocol shall not be borne by the subject, unless the law of the Member State
p.(None): concerned provides otherwise.
p.(None):
p.(None): Article 93
p.(None): Data protection
p.(None): 1. Member States shall apply Directive 95/46/EC to the processing of personal data carried out in the
p.(None): Member States pursuant to this Regulation.
p.(None):
p.(None): 2. Regulation (EC) No 45/2001 shall apply to the processing of personal data carried out by the Commission and
p.(None): the Agency pursuant to this Regulation.
p.(None):
p.(None): Article 94
p.(None): Penalties
p.(None): 1. Member States shall lay down rules on penalties applicable to infringements of this Regulation
p.(None): and shall take all measures necessary to ensure that they are implemented. The penalties provided for shall be
p.(None): effective, proportionate and dissuasive.
p.(None): 2. The rules referred to in paragraph 1 shall address, inter alia, the following:
p.(None): (a) non-compliance with the provisions laid down in this Regulation on submission of information intended to be made
p.(None): publicly available to the EU database;
p.(None): (b) non-compliance with the provisions laid down in this Regulation on subject safety.
p.(None):
p.(None): Article 95
p.(None): Civil and criminal liability
p.(None):
p.(None): This Regulation is without prejudice to national and Union law on the civil and criminal liability of
p.(None): a sponsor or an investigator.
p.(None):
p.(None): CHAPTER XIX
p.(None):
p.(None): FINAL PROVISIONS
p.(None):
p.(None): Article 96
p.(None):
p.(None): Repeal
p.(None): 1. Directive 2001/20/EC is repealed as from the date referred to in the second paragraph of Article 99.
p.(None):
p.(None): 2. References to Directive 2001/20/EC shall be construed as references to this Regulation and shall be read in
p.(None): accord ance with the correlation table laid down in Annex VII.
p.(None):
p.(None): Article 97
p.(None): Review
p.(None): Five years after the date referred to in the second paragraph of Article 99, and every five years
p.(None): thereafter, the Commis sion shall present a report to the European Parliament and to the Council on
p.(None): the application of this Regulation. That report shall include an assessment of the impact that the
p.(None): Regulation has had on scientific and technological progress, comprehensive information on the different
p.(None): types of clinical trials authorised pursuant to this Regulation, and the measures required in order to
p.(None): maintain the competitiveness of European clinical research. The Commission shall, if appropriate, present a
p.(None): legislative proposal based on that report in order to update the provisions set out in this Regu
p.(None): lation.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/53
p.(None):
p.(None): Article 98
p.(None):
p.(None): Transitional provision
p.(None):
p.(None): 1. By way of derogation from Article 96(1) of this Regulation, where the request for authorisation
p.(None): of a clinical trial has been submitted before the date referred to in the second paragraph of Article 99 of this
p.(None): Regulation pursuant to Dir ective 2001/20/EC, that clinical trial shall continue to be governed by that Directive
p.(None): until three years from that date.
p.(None):
p.(None): 2. By way of derogation from Article 96(1) of this Regulation, where the request for authorisation of a clinical
p.(None): trial is submitted between six months after the date of publication of the notice referred to in Article
p.(None): 82(3) of this Regulation and 18 months after the date of publication of that notice, or, if the
p.(None): publication of that notice occurs earlier than 28 November 2015, where that request is submitted between
p.(None): 28 May 2016 and 28 May 2017, that clinical trial may be started in accordance with Articles 6, 7 and 9 of
p.(None): Directive 2001/20/EC. That clinical trial shall continue to be governed by that Directive until 42 months after
p.(None): the date of publication of the notice referred to in Article 82(3) of this Regu lation, or, if that
p.(None): publication occurs earlier than 28 November 2015, until 28 May 2019.
p.(None):
p.(None): Article 99
p.(None):
p.(None): Entry into force
p.(None):
p.(None): This Regulation shall enter into force on the twentieth day following that of its publication in the
p.(None): Official Journal of the European Union.
p.(None):
p.(None): It shall apply as from six months after the publication of the notice referred to in Article 82(3),
p.(None): but in any event no earlier than 28 May 2016.
p.(None):
p.(None):
p.(None):
p.(None): This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Strasbourg, 16
p.(None): April 2014.
p.(None):
p.(None): For the European Parliament The President
p.(None): M. SCHULZ
p.(None): For the Council The President
p.(None): D. KOURKOULAS
p.(None):
p.(None): L 158/54 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX I
p.(None):
p.(None): APPLICATION DOSSIER FOR THE INITIAL APPLICATION
p.(None):
p.(None): A. INTRODUCTION AND GENERAL PRINCIPLES
p.(None):
p.(None): 1. The sponsor shall, where appropriate, refer to any previous applications. If these applications
p.(None): have been submitted by another sponsor, the written agreement from that sponsor shall be submitted.
p.(None):
p.(None): 2. Where a clinical trial has more than one sponsor, detailed information of the responsibilities of
p.(None): each of the sponsors shall be submitted in the application dossier.
p.(None):
p.(None): 3. The application shall be signed by the sponsor or a representative of the sponsor. This signature confirms
p.(None): that the sponsor is satisfied that:
p.(None):
p.(None): (a) the information provided is complete;
p.(None):
p.(None): (b) the attached documents contain an accurate account of the information available;
p.(None):
p.(None): (c) the clinical trial is to be conducted in accordance with the protocol; and
p.(None):
p.(None): (d) the clinical trial is to be conducted in accordance with this Regulation.
p.(None):
p.(None): 4. The application dossier for an application limited to Part I of the assessment report referred to
p.(None): in Article 11 shall be limited to sections B to J and Q of this Annex.
p.(None):
p.(None): 5. Without prejudice to Article 26, the application dossier for an application limited to Part II of
p.(None): the assessment report referred to in Article 11 and the application dossier for an application referred to in
p.(None): Article 14 shall be limited to sections K to R of this Annex.
p.(None):
p.(None):
p.(None): B. COVER LETTER
p.(None):
...
p.(None):
p.(None): (b) whether the clinical trial involves the first administration of a new active substance to humans;
p.(None):
p.(None): (c) whether scientific advice relating to the clinical trial or the investigational medicinal product
p.(None): has been given by the Agency, a Member State or a third country;
p.(None):
p.(None): (d) whether the clinical trial is part or is intended to be part of a Paediatric Investigation Plan (PIP) as
p.(None): referred to in Title II, Chapter 3, of Regulation (EC) No 1901/2006 (if the Agency has already issued a
p.(None): decision on the PIP, the cover letter contains the link to the decision of the Agency on its website);
p.(None):
p.(None): (e) whether investigational medicinal products or auxiliary medicinal products are a narcotic,
p.(None): psychotropic or radiopharmaceutical;
p.(None):
p.(None): (f) whether the investigational medicinal products consist of or contain a genetically-modified organism
p.(None): or organisms;
p.(None):
p.(None): (g) whether the sponsor has obtained an orphan designation for the investigational medicinal product for
p.(None): an orphan condition;
p.(None):
p.(None): (h) a comprehensive list, including the regulatory status, of all investigational medicinal products and
p.(None): a list of all auxiliary medicinal products; and
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/55
p.(None):
p.(None): (i) a list of medical devices which are to be investigated in the clinical trial but which are not part of the
p.(None): inves tigational medicinal product or products, together with a statement as to whether the medical
p.(None): devices are CE-marked for the intended use.
p.(None): 8. The cover letter shall indicate where the information listed in paragraph 7 is contained in the
p.(None): application dossier.
p.(None):
p.(None): 9. The cover letter shall indicate if the clinical trial is considered by the sponsor to be a
p.(None): low-intervention clinical trial and shall contain a detailed justification thereof.
p.(None):
p.(None): 10. The cover letter shall indicate if the methodology of the clinical trial requires that groups of
p.(None): subjects rather than individual subjects are allocated to receive different investigational medicinal
p.(None): products in a clinical trial, and as a consequence whether informed consent will be obtained by simplified means.
p.(None):
p.(None): 11. The cover letter shall indicate the location in the application dossier of the information necessary for
p.(None): assessing whether an adverse reaction is a suspected unexpected serious adverse reaction, that is the
p.(None): reference safety information.
p.(None):
p.(None): 12. In the case of a resubmission, the cover letter shall specify the EU trial number for the
p.(None): previous clinical trial application, highlight the changes as compared to the previous submission and, if
p.(None): applicable, specify how any unresolved issues in the first submission have been addressed.
p.(None):
p.(None):
p.(None): C. EU APPLICATION FORM
p.(None):
...
p.(None): (c) the sponsor's protocol code number specific for all versions of it (if relevant);
p.(None): (d) the date and number of the version, to be updated when it is amended;
p.(None): (e) a short title or name assigned to the protocol; and
p.(None): (f) the name and address of the sponsor, as well as the name and function of the representative or representa
p.(None): tives of the sponsor authorised to sign the protocol or any substantial modification to the protocol.
p.(None): 16. The protocol shall, when possible, be written in an easily accessible and searchable format, rather than scanned
p.(None): images.
p.(None):
p.(None): 17. The protocol shall at least include:
p.(None): (a) a statement that the clinical trial is to be conducted in compliance with the protocol, with this Regulation
p.(None): and with the principles of good clinical practice;
p.(None): (b) a comprehensive list of all investigational medicinal products and of all auxiliary medicinal products;
p.(None): (c) a summary of findings from non-clinical studies that potentially have clinical significance and from other
p.(None): clinical trials that are relevant to the clinical trial;
p.(None): (d) a summary of the known and potential risks and benefits including an evaluation of the anticipated bene fits
p.(None): and risks to allow assessment in accordance with Article 6; for subjects in a clinical trial in an
p.(None): emer gency situation, the scientific grounds for expecting that the participation of the subjects has the potential to
p.(None): produce a direct clinically relevant benefit shall be documented;
p.(None): (e) where patients were involved in the design of the clinical trial, a description of their involvement;
p.(None):
p.(None): L 158/56 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (f) a description of, and justification for, the dosage, the dosage regime, the route and mode of
p.(None): administra tion, and the treatment period for all investigational medicinal products and auxiliary medicinal products;
p.(None):
p.(None): (g) a statement of whether the investigational medicinal products and auxiliary medicinal products
p.(None): used in the clinical trial are authorised; if authorised, whether they are to be used in the clinical
p.(None): trial in accord ance with the terms of their marketing authorisations, and, if not authorised, a justification for
p.(None): the use of non-authorised auxiliary medicinal products in the clinical trial;
p.(None):
p.(None): (h) a description of the groups and subgroups of the subjects participating in the clinical trial,
p.(None): including, where relevant, groups of subjects with specific needs, for example. age, gender, participation
p.(None): of healthy volunteers, subjects with rare and ultra rare diseases;
p.(None):
p.(None): (i) references to literature and data that are relevant to the clinical trial, and that provide background for
p.(None): the clinical trial;
p.(None):
p.(None): (j) a discussion of the relevance of the clinical trial in order to allow assessment in accordance with Article
p.(None): 6;
p.(None):
p.(None): (k) a description of the type of clinical trial to be conducted and a discussion of the trial design
p.(None): (including a schematic diagram of trial design, procedures and stages, if relevant);
p.(None):
...
p.(None):
p.(None): (q) arrangements for the maintenance of clinical trial treatment randomisation codes and procedures
p.(None): for breaking codes, if relevant;
p.(None):
p.(None): (r) a description of procedures for the identification of data to be recorded directly on the Case
p.(None): Report Forms considered as source data;
p.(None):
p.(None): (s) a description of the arrangements to comply with the applicable rules for the collection,
p.(None): storage and future use of biological samples from clinical trial subjects, where applicable, unless
p.(None): contained in a sepa rate document;
p.(None):
p.(None): (t) a description of the arrangements for tracing, storing, destroying and returning the
p.(None): investigational medi cinal product and unauthorised auxiliary medicinal product in accordance with Article 51;
p.(None):
p.(None): (u) a description of the statistical methods to be employed, including, if relevant:
p.(None):
p.(None): — timing of any planned interim analysis and the number of subjects planned to be enrolled;
p.(None):
p.(None): — reasons for choice of sample size;
p.(None):
p.(None): — calculations of the power of the clinical trial and clinical relevance;
p.(None):
p.(None): — the level of significance to be used;
p.(None):
p.(None): — criteria for the termination of the clinical trial;
p.(None):
p.(None): — procedures for accounting for missing, unused, and spurious data and for reporting any deviation from
p.(None): the original statistical plan; and
p.(None):
p.(None): — the selection of subjects to be included in the analyses;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/57
p.(None):
p.(None): (v) a description of the subject inclusion and exclusion criteria, including criteria for withdrawing
p.(None): individual subjects from treatment or from the clinical trial;
p.(None):
p.(None): (w) a description of procedures relating to the withdrawal of subjects from treatment or from the
p.(None): clinical trial including procedures for the collection of data regarding withdrawn subjects, procedures for replace
p.(None): ment of subjects and the follow-up of subjects that have withdrawn from treatment or from the clinical
p.(None): trial;
p.(None):
p.(None): (x) a justification for including subjects who are incapable of giving informed consent or other special popu
p.(None): lations, such as minors;
p.(None):
p.(None): (y) a justification for the gender and age allocation of subjects and, if a specific gender or age
p.(None): group is excluded from or underrepresented in the clinical trials, an explanation of the reasons and
p.(None): justification for these exclusion criteria;
p.(None):
p.(None): (z) a detailed description of the recruitment and informed consent procedure, especially when subjects
p.(None): are incapable of giving informed consent;
p.(None):
...
p.(None):
p.(None): (ag) a description of ethical considerations relating to the clinical trial if those have not been
p.(None): described else where;
p.(None):
p.(None): (ah) a statement from the sponsor (either in the protocol or in a separate document) confirming that
p.(None): the investigators and institutions involved in the clinical trial are to permit clinical trial-related
p.(None): monitoring, audits and regulatory inspections, including provision of direct access to source data and documents;
p.(None):
p.(None): (ai) a description of the publication policy;
p.(None):
p.(None): (aj) duly substantiated reasons for the submission of the summary of the results of the clinical
p.(None): trials after more than one year;
p.(None):
p.(None): (ak) a description of the arrangements to comply with the applicable rules on the protection of personal data; in
p.(None): particular organisational and technical arrangements that will be implemented to avoid unauthorised access,
p.(None): disclosure, dissemination, alteration or loss of information and personal data processed;
p.(None):
p.(None): (al) a description of measures that will be implemented to ensure confidentiality of records and personal data of
p.(None): subjects;
p.(None):
p.(None): (am) a description of measures that will be implemented in case of data security breach in order to
p.(None): mitigate the possible adverse effects.
p.(None):
p.(None): 18. If a clinical trial is conducted with an active substance available in the Union under different
p.(None): trade names in a number of authorised medicinal products, the protocol may define the treatment in terms
p.(None): of the active substance or Anatomical Therapeutic Chemical (ATC) code (level 3-5) only and not specify
p.(None): the trade name of each product.
p.(None):
p.(None): L 158/58 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 19. With regard to the notification of adverse events, the protocol shall identify the categories of:
p.(None):
p.(None): (a) adverse events or laboratory anomalies that are critical to safety evaluations and must be reported
p.(None): by the investigator to the sponsor, and
p.(None):
p.(None): (b) serious adverse events which do not require immediate reporting by the investigator to the sponsor.
p.(None):
p.(None): 20. The protocol shall describe the procedures for:
p.(None):
p.(None): (a) eliciting and recording adverse events by the investigator, and the reporting of relevant adverse
p.(None): events by the investigator to the sponsor;
p.(None):
p.(None): (b) reporting by the investigator to the sponsor of those serious adverse events which have been
p.(None): identified in the protocol as not requiring immediate reporting;
p.(None):
p.(None): (c) reporting of suspected unexpected serious adverse reactions by the sponsor to the Eudravigilance database; and
p.(None):
p.(None): (d) follow-up of subjects after adverse reactions including the type and duration of follow-up.
p.(None):
p.(None): 21. In case the sponsor intends to submit a single safety report on all investigational medicinal
p.(None): products used in the clinical trial in accordance with Article 43(2), the protocol shall indicate the reasons
p.(None): thereof.
p.(None):
p.(None): 22. Issues regarding labelling and the unblinding of investigational medicinal products shall be addressed
p.(None): in the protocol, where necessary.
p.(None):
p.(None): 23. The protocol shall be accompanied by the Charter of the Data Safety Monitoring Committee, if applicable.
p.(None):
p.(None): 24. The protocol shall be accompanied by a synopsis of the protocol.
...
p.(None): all available information and evidence that supports the rationale for the proposed clinical trial and the safe use
p.(None): of the investigational medi cinal product in the clinical trial and be presented in the form of summaries.
p.(None):
p.(None): 28. If the investigational medicinal product is authorised, and is used in accordance with the terms
p.(None): of the marketing authorisation, the approved summary of product characteristics (SmPC) shall be the IB. If the
p.(None): condi tions of use in the clinical trial differ from those authorised, the SmPC shall be supplemented with a summary
p.(None): of relevant non-clinical and clinical data that support the use of the investigational medicinal product
p.(None): in the clinical trial. Where the investigational medicinal product is identified in the protocol only by
p.(None): its active substance, the sponsor shall select one SmPC as equivalent to the IB for all medicinal
p.(None): products that contain that active substance and are used at any clinical trial site.
p.(None):
p.(None): 29. For a multinational clinical trial where the medicinal product to be used in each Member State
p.(None): concerned is authorised at national level, and the SmPC varies among Member States concerned, the sponsor
p.(None): shall choose one SmPC for the whole clinical trial. This SmPC shall be the one best suited to ensure patient safety.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/59
p.(None):
p.(None): 30. If the IB is not an SmPC, it shall contain a clearly identifiable section called the ‘Reference
p.(None): Safety Information’ (RSI). In accordance with paragraphs 10 and 11 of Annex III, the RSI shall contain product
p.(None): information on the investigational medicinal product and on how to determine what adverse reactions are to
p.(None): be considered as expected adverse reactions, and on the frequency and nature of those adverse reactions.
p.(None):
p.(None):
p.(None): F. DOCUMENTATION RELATING TO COMPLIANCE WITH GOOD MANUFACTURING PRACTICE (GMP) FOR THE INVESTIGA
p.(None): TIONAL MEDICINAL PRODUCT
p.(None):
p.(None): 31. As regards documentation relating to GMP compliance, the following shall apply.
p.(None):
p.(None): 32. No documentation needs to be submitted where the investigational medicinal product is authorised and is
p.(None): not modified, whether or not it is manufactured in the Union.
p.(None):
p.(None): 33. If the investigational medicinal product is not authorised, and does not have a marketing authorisation
p.(None): from a third country that is party to the International Conference on Harmonisation of Technical
p.(None): Requirements for Registration of Pharmaceuticals for Human Use (ICH), and is not manufactured in the
p.(None): Union, the following documentation shall be submitted:
p.(None): (a) a copy of the authorisation referred to in Article 61; and
p.(None):
p.(None): (b) certification by the qualified person in the Union that the manufacturing complies with GMP at
p.(None): least equivalent to the GMP in the Union, unless there are specific arrangements provided for in mutual recogni tion
p.(None): agreements between the Union and third countries.
p.(None): 34. In all other cases, a copy of the authorisation referred to in Article 61 shall be submitted.
p.(None):
p.(None): 35. For processes related to investigational medicinal products set out in Article 61(5), which are not subject to an
p.(None): authorisation in accordance with Article 61, documentation to demonstrate compliance with the requirements referred
p.(None): to in Article 61(6) shall be submitted.
p.(None):
p.(None):
p.(None): G. INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER (IMPD)
p.(None):
p.(None): 36. The IMPD shall give information on the quality of any investigational medicinal product, the manufacture
p.(None): and control of the investigational medicinal product, and data from non-clinical studies and from its clinical use.
p.(None):
p.(None): 1.1. Data relating to the investigational medicinal product
p.(None):
p.(None): Introduction
p.(None):
p.(None): 37. Regarding data, the IMPD may be replaced by other documentation which may be submitted alone or
p.(None): with a simplified IMPD. The details of this ‘simplified IMPD’ are set out in section 1.2 ‘Simplified IMPD by
p.(None): referring to other documentation’.
p.(None):
p.(None): 38. Each section of the IMPD shall be prefaced with a detailed table of contents and a glossary of terms.
p.(None):
p.(None): 39. The information in the IMPD shall be concise. The IMPD must not be unnecessarily voluminous. It is preferable to
p.(None): present data in tabular form accompanied by a brief narrative highlighting the main salient points.
p.(None):
p.(None):
p.(None): Quality data
p.(None):
p.(None): 40. Quality data shall be submitted in a logical structure such as that of Module 3 of the ICH
p.(None): Common Technical Document format.
p.(None):
p.(None):
p.(None): Non-clinical pharmacology and toxicology data
p.(None):
p.(None): 41. The IMPD shall also contain summaries of non-clinical pharmacology and toxicology data for any
p.(None): investiga tional medicinal product used in the clinical trial in accordance with international guidance.
p.(None): It shall contain a reference list of studies conducted and appropriate literature references. Wherever
p.(None): appropriate, it is preferable to present data in tabular form accompanied by a brief narrative
p.(None): highlighting the main salient points. The summaries of the studies conducted shall allow an assessment of
p.(None): the adequacy of the study and whether the study has been conducted according to an acceptable protocol.
p.(None):
p.(None): L 158/60 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 42. Non-clinical pharmacology and toxicology data shall be submitted in a logical structure, such as
p.(None): that of Module 4 of the ICH Common Technical Document format.
p.(None):
p.(None): 43. The IMPD shall provide a critical analysis of the data, including justification for omissions of
p.(None): data, and an assessment of the safety of the product in the context of the proposed clinical trial
p.(None): rather than a mere factual summary of the studies conducted.
p.(None):
p.(None): 44. The IMPD shall contain a statement of the good laboratory practice status or equivalent standards,
p.(None): as referred to in Article 25(3).
p.(None):
p.(None): 45. The test material used in toxicity studies shall be representative of that of the clinical trial use in terms of
p.(None): quali tative and quantitative impurity profiles. The preparation of the test material shall be subject
p.(None): to the controls necessary to ensure this and thus support the validity of the study.
p.(None):
p.(None):
p.(None): Data from previous clinical trials and human experience
p.(None):
p.(None): 46. Data from previous clinical trials and human experience shall be submitted in a logical structure,
p.(None): such as that of Module 5 of the ICH Common Technical Document format.
p.(None):
p.(None): 47. This section shall provide summaries of all available data from previous clinical trials and human
p.(None): experience with the investigational medicinal products.
p.(None):
p.(None): It shall also contain a statement of the compliance with good clinical practice of those previous
p.(None): clinical trials, as well as a reference to the public entry referred to in Article 25(6).
p.(None):
p.(None):
...
p.(None): further monitoring of effects and safety in the clinical trials shall also be discussed.
p.(None):
p.(None):
p.(None): 1.2. Simplified IMPD by referring to other documentation
p.(None):
p.(None): 50. The applicant may refer to other documentation submitted alone or with a simplified IMPD.
p.(None):
p.(None): Possibility of referring to the IB
p.(None):
p.(None): 51. The applicant may either provide a stand-alone IMPD or cross-refer to the IB for the reference
p.(None): safety informa tion and the summaries of pre-clinical and clinical parts of the IMPD. In the latter case, the
p.(None): summaries of pre- clinical information and clinical information shall include data, preferably in tables,
p.(None): providing sufficient detail to allow assessors to reach a decision on the potential toxicity of the investigational
p.(None): medicinal product and the safety of its use in the proposed clinical trial. If there is some special
p.(None): aspect of the pre-clinical data or clinical data that requires a detailed expert explanation or discussion beyond
p.(None): what would usually be included in the IB, the pre-clinical and clinical information shall be submitted as part of the
p.(None): IMPD.
p.(None):
p.(None):
p.(None): Possibility of referring to the SmPC
p.(None):
p.(None): 52. The applicant may submit the version of the SmPC valid at the time of application, as the IMPD if the
p.(None): investi gational medicinal product is authorised. The exact requirements are detailed in Table 1. Where
p.(None): new data are provided, it should be clearly identified.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/61
p.(None):
p.(None): Table 1: Content of the simplified IMPD
p.(None):
p.(None):
p.(None): Types of previous assessment
p.(None): The investigational medicinal product is authorised or has a marketing authorisation in an ICH country and is
p.(None): used in the clinical trial:
p.(None): — within the conditions of the SmPC
p.(None): — outside the conditions of the SmPC
p.(None): — after modification (for example blinding)
p.(None): Another pharmaceutical form or strength of the inves tigational medicinal product is authorised or
p.(None): has a marketing authorisation in an ICH country and the investigational medicinal product is
p.(None): supplied by the marketing authorisation holder
p.(None): The investigational medicinal product is not authorised and has no marketing authorisation in an ICH
p.(None): country but the active substance is contained in an authorised medicinal product, and
p.(None): — is supplied by the same manufacturer
p.(None): — is supplied by another manufacturer
p.(None): The investigational medicinal product was subject to a previous clinical trial application and authorised
p.(None): in the Member State concerned and has not been modified, and
p.(None): Quality data
p.(None):
p.(None):
p.(None):
p.(None): SmPC SmPC P+A
p.(None): SmPC+P+A
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): SmPC+P+A SmPC+S+P+A
p.(None): Non-clinical data
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): If appropriate SmPC
p.(None): Yes
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): Yes Yes
p.(None): Clinical data
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): If appropriate SmPC
p.(None): Yes
...
p.(None): Reconstitution and Diluents)
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): 53. If the investigational medicinal product is defined in the protocol in terms of active substance or
p.(None): ATC code (see above, paragraph 18), the applicant may replace the IMPD by one representative SmPC for
p.(None): each active substance/active substance pertaining to that ATC group. Alternatively, the applicant may
p.(None): provide a collated document containing information equivalent to that in the representative SmPCs for each active
p.(None): substance that could be used as an investigational medicinal product in the clinical trial.
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): 1.3. IMPD in cases of placebo
p.(None):
p.(None):
p.(None):
p.(None): 54. If the investigational medicinal product is a placebo, the information requirements shall be limited
p.(None): to quality data. No additional documentation is required if the placebo has the same composition as the tested
p.(None): investiga tional medicinal product (with the exception of the active substance), is manufactured by the
p.(None): same manufac turer, and is not sterile.
p.(None):
p.(None): L 158/62 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): H. AUXILIARY MEDICINAL PRODUCT DOSSIER
p.(None):
p.(None): 55. Without prejudice to Article 65, the documentation requirements set out in sections F and G shall
p.(None): also apply to auxiliary medicinal products. However, where the auxiliary medicinal product is authorised
p.(None): in the Member State concerned, no additional information is required.
p.(None):
p.(None):
p.(None): I. SCIENTIFIC ADVICE AND PAEDIATRIC INVESTIGATION PLAN (PIP)
p.(None):
p.(None): 56. If available, a copy of the summary of scientific advice of the Agency, or of any Member State or third country,
p.(None): with regard to the clinical trial shall be submitted.
p.(None):
p.(None): 57. If the clinical trial is part of an agreed PIP, a copy of the Agency's decision on the agreement
p.(None): on the PIP, and the opinion of the Paediatric Committee, unless these documents are fully accessible
p.(None): via the internet shall be submitted. In the latter case, a link to this documentation in the cover letter is
p.(None): sufficient (see section B).
p.(None):
p.(None):
p.(None): J. CONTENT OF THE LABELLING OF THE INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): 58. A description of the content of the labelling of the investigational medicinal product in accordance
p.(None): with Annex VI shall be provided.
p.(None):
p.(None):
p.(None): K. RECRUITMENT ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 59. Unless described in the protocol, a separate document shall describe in detail the procedures for
p.(None): inclusion of subjects and shall provide a clear indication of what the first act of recruitment is.
p.(None):
...
p.(None): on the reason for using an impartial witness, on the selection of the impartial witness and on the
p.(None): procedure for obtaining informed consent shall be provided;
p.(None):
p.(None): (c) in the case of clinical trials in emergency situations as referred to in Article 35, the procedure for obtaining
p.(None): the informed consent of the subject or the legally designated representative to continue the clinical
p.(None): trial shall be described;
p.(None):
p.(None): (d) in the case of clinical trials in emergency situations as referred to in Article 35, the description of the
p.(None): pro cedures followed to identify the urgency of the situation and to document it;
p.(None):
p.(None): (e) in the case of clinical trials where their methodology requires that groups of subjects rather than individual
p.(None): subjects are allocated to receive different investigational medicinal products, as referred to in Article
p.(None): 30, and where, as a consequence, simplified means for obtaining informed consent will be used, the simplified
p.(None): means shall be described.
p.(None):
p.(None): 63. In the cases set out in paragraph 62, the information given to the subject and to his or her
p.(None): legally designated representative shall be submitted.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/63
p.(None):
p.(None): M. SUITABILITY OF THE INVESTIGATOR (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 64. A list of the planned clinical trial sites, the name and position of the principal investigators
p.(None): and the planned number of subjects at the sites shall be submitted.
p.(None):
p.(None): 65. Description of the qualification of the investigators in a current curriculum vitae and other relevant
p.(None): documents shall be submitted. Any previous training in the principles of good clinical practice or
p.(None): experience obtained from work with clinical trials and patient care shall be described.
p.(None):
p.(None): 66. Any conditions, such as economic interests and institutional affiliations, that might influence the
p.(None): impartiality of the investigators shall be presented.
p.(None):
p.(None): N. SUITABILITY OF THE FACILITIES (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 67. A duly justified written statement on the suitability of the clinical trial sites adapted to the
p.(None): nature and use of the investigational medicinal product and including a description of the suitability of
p.(None): facilities, equipment, human resources and description of expertise, issued by the head of the
p.(None): clinic/institution at the clinical trial site or by some other responsible person, according to the
p.(None): system in the Member State concerned, shall be submitted.
p.(None):
p.(None): O. PROOF OF INSURANCE COVER OR INDEMNIFICATION (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 68. Proof of insurance, a guarantee, or a similar arrangement shall be submitted, if applicable.
p.(None):
p.(None): P. FINANCIAL AND OTHER ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 69. A brief description of the financing of the clinical trial.
p.(None):
p.(None): 70. Information on financial transactions and compensation paid to subjects and investigator/site for
p.(None): participating in the clinical trial shall be submitted.
p.(None):
p.(None): 71. Description of any other agreement between the sponsor and the site shall be submitted.
p.(None):
p.(None): Q. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 72. Proof of payment shall be submitted, if applicable.
p.(None):
p.(None): R. PROOF THAT DATA WILL BE PROCESSED IN COMPLIANCE WITH UNION LAW ON DATA PROTECTION
p.(None):
p.(None): 73. A statement by the sponsor or his or her representative that data will be collected and processed in accordance
p.(None): with Directive 95/46/EEC shall be provided.
p.(None):
p.(None): L 158/64 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX II
p.(None):
p.(None): APPLICATION DOSSIER FOR SUBSTANTIAL MODIFICATION
p.(None):
p.(None): A. INTRODUCTION AND GENERAL PRINCIPLES
p.(None): 1. Where a substantial modification concerns more than one clinical trial of the same sponsor and the same investi
p.(None): gational medicinal product, the sponsor may make a single request for authorisation of the substantial
p.(None): modifica tion. The cover letter shall contain a list of all clinical trials to which the application
p.(None): for substantial modification relates, with the EU trial numbers and respective modification code numbers of each of
p.(None): those clinical trials.
p.(None):
p.(None): 2. The application shall be signed by the sponsor or a representative of the sponsor. This signature
p.(None): shall confirm that the sponsor is satisfied that:
p.(None): (a) the information provided is complete;
p.(None): (b) the attached documents contain an accurate account of the information available; and
p.(None): (c) the clinical trial will be conducted in accordance with the amended documentation.
p.(None):
p.(None): B. COVER LETTER
p.(None): 3. A cover letter with the following information:
p.(None): (a) in its subject line, the EU trial number with the title of the clinical trial and the substantial
p.(None): modification code number which allows unique identification of the substantial modification, and which
p.(None): shall be used con sistently throughout the application dossier;
p.(None): (b) identification of the applicant;
p.(None): (c) identification of the substantial modification (the sponsor's substantial modification code number and
...
p.(None): where the relevant information or text is located in the original application dossier;
p.(None): (e) identification of any information not contained in the modification application form that might
p.(None): impact on the risk to subjects; and
p.(None): (f) where applicable, a list of all clinical trials which are substantially modified, with EU trial numbers and
p.(None): respec tive modification code numbers.
p.(None):
p.(None): C. MODIFICATION APPLICATION FORM
p.(None): 4. The modification application form, duly completed.
p.(None):
p.(None): D. DESCRIPTION OF THE MODIFICATION
p.(None): 5. The modification shall be presented and described as follows:
p.(None): (a) an extract from the documents to be amended showing previous and new wording in track changes, as
p.(None): well as an extract showing only the new wording, and a explanation of the changes; and
p.(None): (b) notwithstanding point (a), if the changes are so widespread or far-reaching that they justify an
p.(None): entirely new version of the document, a new version of the entire document (in such cases, an
p.(None): additional table lists the amendments to the documents, whereby identical changes can be grouped).
p.(None): 6. The new version of the document shall be identified by the date and an updated version number.
p.(None):
p.(None): E. SUPPORTING INFORMATION
p.(None): 7. Where applicable, additional supporting information shall at least include:
p.(None): (a) summaries of data;
p.(None): (b) an updated overall risk/benefit assessment;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/65
p.(None):
p.(None): (c) possible consequences for subjects already included in the clinical trial;
p.(None):
p.(None): (d) possible consequences for the evaluation of the results;
p.(None):
p.(None): (e) documents which relate to any changes to the information provided to subjects or their legally
p.(None): designated representatives, the informed consent procedure, informed consent forms, information sheets, or
p.(None): to letters of invitation; and
p.(None):
p.(None): (f) a justification for the changes sought in the application for a substantial modification.
p.(None):
p.(None): F. UPDATE OF EU APPLICATION FORM
p.(None):
p.(None): 8. If a substantial modification involves changes to entries on the EU application form referred to in
p.(None): Annex I, a revised version of that form shall be submitted. The fields affected by the substantial
p.(None): modification shall be high lighted in the revised form.
p.(None):
p.(None): G. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 9. Proof of payment shall be submitted, if applicable.
p.(None):
p.(None): L 158/66 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX III
p.(None):
p.(None): SAFETY REPORTING
p.(None):
p.(None): 1. REPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR TO THE SPONSOR
p.(None): 1. The investigator does not need to actively monitor subjects for adverse events once the clinical trial
p.(None): has ended with regard to the subjects treated by him, unless otherwise provided for in the protocol.
p.(None):
p.(None): 2. REPORTING OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) BY THE SPONSOR TO THE AGENCY
p.(None): IN ACCORDANCE WITH ARTICLE 42
p.(None): 2.1. Adverse Events and Causality
p.(None): 2. Medication errors, pregnancies and uses outside what is foreseen in the protocol, including misuse
p.(None): and abuse of the product, shall be subject to the same obligation to report as adverse reactions.
p.(None):
p.(None): 3. In determining whether an adverse event is an adverse reaction, consideration shall be given to
p.(None): whether there is a reasonable possibility of establishing a causal relationship between the event and the
p.(None): investigational medi cinal product based on an analysis of available evidence.
p.(None):
p.(None): 4. In the absence of information on causality provided by the reporting investigator, the sponsor shall consult the
p.(None): reporting investigator and encourage him to express an opinion on this issue. The causality assessment
p.(None): given by the investigator shall not be downgraded by the sponsor. If the sponsor disagrees with the
p.(None): investigator's causality assessment, the opinion of both the investigator and the sponsor shall be provided with the
...
p.(None): antici pated pharmacological properties of a medicinal product or events related to the subject's disease.
p.(None):
p.(None): 7. The RSI shall be contained in the SmPC or the IB. The covering letter shall refer to the
p.(None): location of the RSI in the application dossier. If the investigational medicinal product is
p.(None): authorised in several Member States concerned with different SmPCs, the sponsor shall select the most
p.(None): appropriate SmPC, with reference to subject safety, as the RSI.
p.(None):
p.(None): 8. The RSI may change during the conduct of a clinical trial. For the purpose of reporting SUSARs the version of
p.(None): the RSI at the moment of occurrence of the SUSAR shall apply. Thus, a change of the RSI impacts on
p.(None): the number of adverse reactions to be reported as SUSARs. Regarding the applicable RSI for the purpose
p.(None): of the annual safety report, see section 3 of this Annex.
p.(None):
p.(None): 9. If information on expectedness has been provided by the reporting investigator, this shall be taken into consid
p.(None): eration by the sponsor.
p.(None):
p.(None): 2.3. Information for the reporting of SUSARs
p.(None): 10. The information shall at least include:
p.(None): (a) a valid EU trial number;
p.(None): (b) a sponsor study number;
p.(None): (c) an identifiable coded subject;
p.(None): (d) an identifiable reporter;
p.(None): (e) a SUSAR;
p.(None): (f) a suspect investigational medicinal product (including active substance name-code);
p.(None): (g) a causality assessment.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/67
p.(None):
p.(None): 11. In addition, in order to properly process the report electronically, the following administrative
p.(None): information shall be provided:
p.(None): (a) the sender's (case) safety report unique identifier;
p.(None): (b) the receive date of the initial information from the primary source;
p.(None): (c) the receipt date of the most recent information;
p.(None): (d) the worldwide unique case identification number;
p.(None): (e) the sender identifier.
p.(None):
p.(None): 2.4. Follow-up reports of SUSARs
p.(None): 12. If the initial report of a SUSAR referred to in point (a) of Article 42(2) (fatal or
p.(None): life-threatening) is incomplete, for example if the sponsor has not provided all the information within
p.(None): seven days, the sponsor shall submit a completed report based on the initial information within an additional
p.(None): eight days.
p.(None):
p.(None): 13. The clock for initial reporting (day 0 = Di 0) starts as soon as the information containing the
p.(None): minimum reporting criteria has been received by the sponsor.
p.(None):
p.(None): 14. If significant new information on an already reported case is received by the sponsor, the clock
p.(None): starts again at day zero, that is the date of receipt of the new information. This information shall
p.(None): be reported as a follow-up report within 15 days.
p.(None):
p.(None): 15. If the initial report of a SUSAR referred to in Article 42(2)(c) (initially considered to be
p.(None): non-fatal or non-life- threatening but which turns out to be fatal or life-threatening) is incomplete, a
p.(None): follow-up report shall be made as soon as possible, but within a maximum of seven days of first knowledge of the
...
p.(None): sponsor. The blind shall be maintained for other persons responsible for the ongoing conduct of the
p.(None): clinical trial (such as the management, monitors, investigators) and those persons responsible for data
p.(None): analysis and interpretation of results at the conclusion of the clinical trial, such as biometrics personnel.
p.(None):
p.(None): 20. Unblinded information shall be accessible only to persons who need to be involved in the safety
p.(None): reporting to the Agency, to Data Safety Monitoring Boards ('DSMB'), or to persons performing ongoing
p.(None): safety evaluations during the clinical trial.
p.(None):
p.(None): 21. However, for clinial trials carried out in high morbidity or high mortality disease, where efficacy
p.(None): end-points could also be SUSARs or when mortality or another 'serious' outcome, that may potentially be
p.(None): reported as a SUSAR, is the efficacy end-point in a clinical trial, the integrity of the clinical trial may be
p.(None): compromised if the blind is systematically broken. Under these and similar circumstances, the sponsor
p.(None): shall highlight in the protocol which serious events are to be treated as disease-related and are not
p.(None): subject to systematic unblinding and expedited reporting.
p.(None):
p.(None): 22. If following unblinding, an event turns out to be a SUSAR the reporting rules for SUSARs set out in Article 42 and
p.(None): in Section 2 of this Annex shall apply.
p.(None):
p.(None): 3. ANNUAL SAFETY REPORTING BY THE SPONSOR
p.(None): 23. The report shall contain, in an appendix, the RSI in effect at the start of the reporting period.
p.(None):
p.(None): L 158/68 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 24. The RSI in effect at the start of the reporting period shall serve as RSI during the reporting period.
p.(None):
p.(None): 25. If there are significant changes to the RSI during the reporting period they shall be listed in
p.(None): the annual safety report. Moreover, in this case the revised RSI shall be submitted as an appendix to
p.(None): the report, in addition to the RSI in effect at the start of the reporting period. Despite the change to the RSI,
p.(None): the RSI in effect at the start of the reporting period serves as RSI during the reporting period.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/69
p.(None):
p.(None): ANNEX IV
p.(None):
p.(None): CONTENT OF THE SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL
p.(None):
p.(None): The summary of the results of the clinical trial shall contain information on the following elements:
p.(None):
p.(None):
p.(None): A. CLINICAL TRIAL INFORMATION:
p.(None):
p.(None): 1. Clinical trial identification (including title of the trial and protocol number);
p.(None):
p.(None): 2. Identifiers (including EU trial number, other identifiers);
p.(None):
p.(None): 3. Sponsor details (including scientific and public contact points);.
p.(None):
p.(None): 4. Paediatric regulatory details (including information whether the clinical trial is a part of a
p.(None): Paediatric Investigation Plan);
p.(None):
p.(None): 5. Result analysis stage (including information about intermediate data analysis date, interim or final
p.(None): analysis stage, date of global end of the clinical trial). For clinical trials replicating studies on
p.(None): already authorised investigational medicinal products and used in accordance with the terms of the
p.(None): marketing authorisation, the summary of the results should also indicate identified concerns in the overall
p.(None): results of the clinical trial relating to relevant aspects of the efficacy of the related medicinal product;
p.(None):
p.(None): 6. General information about the clinical trial (including information about main objectives of the
p.(None): trial, trial design, scientific background and explanation of rationale for the trial; date of the start
p.(None): of the trial, measures of protec tion of subjects taken, background therapy; and statistical methods used);
p.(None):
p.(None): 7. Population of subjects (including information with actual number of subjects included in the clinical
p.(None): trial in the Member State concerned, in the Union and in third countries; age group breakdown, gender breakdown).
p.(None):
p.(None): B. SUBJECT DISPOSITION:
p.(None):
p.(None): 1. Recruitment (including information on the number of subjects screened, recruited and withdrawn;
p.(None): inclusion and exclusion criteria; randomisation and blinding details; investigational medicinal products used);
p.(None):
p.(None): 2. Pre-assignment Period;
p.(None):
p.(None): 3. Post Assignment Periods.
p.(None):
p.(None): C. BASELINE CHARACTERISTICS:
p.(None):
p.(None): 1. Baseline Characteristics (Required) Age;
p.(None):
p.(None): 2. Baseline Characteristics (Required) Gender;
p.(None):
p.(None): 3. Baseline Characteristics (Optional) Study Specific Characteristic.
p.(None):
p.(None): D. END POINTS:
p.(None):
p.(None): 1. End point definitions (*)
p.(None):
p.(None): 2. End Point #1 Statistical Analyses
p.(None): 3. End Point #2 Statistical Analyses
p.(None): (*) Information shall be provided for as many end points as defined in the protocol.
p.(None):
p.(None): L 158/70 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): E. ADVERSE EVENTS:
p.(None):
p.(None): 1. Adverse events information;
p.(None):
p.(None): 2. Adverse event reporting group;
p.(None):
p.(None): 3. Serious adverse event;
p.(None):
p.(None): 4. Non-serious adverse event.
p.(None):
p.(None): F. ADDITIONAL INFORMATION:
p.(None):
p.(None): 1. Global Substantial Modifications;
p.(None):
p.(None): 2. Global Interruptions and re-starts;
p.(None):
p.(None): 3. Limitations, addressing sources of potential bias and imprecisions and Caveats;
p.(None):
p.(None): 4. A declaration by the submitting party on the accuracy of the submitted information.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/71
p.(None):
p.(None): ANNEX V
p.(None):
p.(None): CONTENT OF THE SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL FOR LAYPERSONS
p.(None):
p.(None): The summary of the results of the clinical trial for laypersons shall contain information on the following elements:
p.(None): 1. Clinical trial identification (including title of the trial, protocol number, EU trial number and other
p.(None): identifiers);
p.(None): 2. Name and contact details of the sponsor;
p.(None): 3. General information about the clinical trial (including where and when the trial was conducted, the main
p.(None): objectives of the trial and an explanation of the reasons for conducting it);
p.(None): 4. Population of subjects (including information on the number of subjects included in the trial in
p.(None): the Member State concerned, in the Union and in third countries; age group breakdown and gender
p.(None): breakdown; inclusion and exclu sion criteria);
p.(None): 5. Investigational medicinal products used;
p.(None): 6. Description of adverse reactions and their frequency;
p.(None): 7. Overall results of the clinical trial;
p.(None): 8. Comments on the outcome of the clinical trial;
p.(None): 9. Indication if follow up clinical trials are foreseen;
p.(None): 10. Indication where additional information could be found.
p.(None):
p.(None): L 158/72 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX VI
p.(None):
p.(None): LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): A. UNAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): A.1. General rules
p.(None):
p.(None): 1. The following particulars shall appear on the immediate and the outer packaging:
p.(None):
p.(None): (a) name, address and telephone number of the main contact for information on the product, clinical
p.(None): trial and emergency unblinding; this may be the sponsor, contract research organisation or investigator (for the
p.(None): purpose of this Annex this is referred to as the 'main contact');
p.(None):
p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
p.(None): both the unauthorised investigational medicinal product and the comparator or placebo;
p.(None):
p.(None): (c) pharmaceutical form, route of administration, quantity of dosage units;
p.(None):
p.(None): (d) the batch or code number identifying the contents and packaging operation;
p.(None):
p.(None): (e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None):
p.(None): (f) the subject identification number and/or the treatment number and, where relevant, the visit number;
p.(None):
...
p.(None): home by subjects.
p.(None):
p.(None): 2. Symbols or pictograms may be included to clarify certain information mentioned above. Additional
p.(None): informa tion, warnings or handling instructions may be displayed.
p.(None):
p.(None): 3. The address and telephone number of the main contact shall not be required to appear on the label if subjects have
p.(None): been given a leaflet or card which provides these details and have been instructed to keep this in
p.(None): their possession at all times.
p.(None):
p.(None):
p.(None): A.2. Limited labelling of immediate packaging
p.(None):
p.(None): A.2.1. Immediate and outer packaging provided together
p.(None):
p.(None): 4. When the product is provided to the subject or the person administering the medicinal product in
p.(None): an immediate packaging and outer packaging intended to remain together, and the outer packaging carries
p.(None): the particulars listed in section A.1., the following particulars shall appear on the immediate packaging
p.(None): (or any sealed dosing device that contains the immediate package):
p.(None):
p.(None): (a) name of the main contact;
p.(None):
p.(None): (b) pharmaceutical form, route of administration (may be excluded for oral solid dose forms), quantity
p.(None): of dosage units and, in the case of clinical trials which do not involve the blinding of the label,
p.(None): the name/ identifier and strength/potency;
p.(None):
p.(None): (c) batch and/or code number identifying the contents and packaging operation;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/73
p.(None):
p.(None): (d) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None): (e) the subject identification number and/or the treatment number and, where relevant, the visit number; and
p.(None): (f) period of use (expiry date or re-test date as applicable), in month and year format and in a
p.(None): manner that avoids any ambiguity.
p.(None):
p.(None): A.2.2. Small immediate packaging
p.(None): 5. If the immediate packaging takes the form of blister packs or small units such as ampoules on
p.(None): which the particulars required in section A.1. cannot be displayed, the outer packaging provided shall
p.(None): bear a label with those particulars. The immediate packaging shall contain the following:
p.(None): (a) name of the main contact;
p.(None): (b) route of administration (may be excluded for oral solid dose forms) and, in the case of clinical trials which do
p.(None): not involve the blinding of the label, the name/identifier and strength/potency;
p.(None): (c) batch or code number identifying the contents and packaging operation;
p.(None): (d) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None): (e) the subject identification number/treatment number and, where relevant, the visit number; and
p.(None): (f) period of use (expiry date or re-test date as applicable), in month and year format and in a
p.(None): manner that avoids any ambiguity.
p.(None):
p.(None): B. UNAUTHORISED AUXILIARY MEDICINAL PRODUCTS
p.(None): 6. The following particulars shall appear on the immediate and the outer packaging:
p.(None): (a) name of the main contact;
...
p.(None): (d) batch or code number identifying the contents and packaging operation;
p.(None): (e) clinical trial reference code allowing identification of the clinical trial site, investigator and subject;
p.(None): (f) directions for use (reference may be made to a leaflet or other explanatory document intended for
p.(None): the subject or person administering the product);
p.(None): (g) 'For clinical trial use only' or similar wording;
p.(None): (h) the storage conditions; and
p.(None): (i) period of use (expiry date or retest date as applicable).
p.(None):
p.(None): C. ADDITIONAL LABELLING FOR AUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None): 7. In accordance with Article 67(2), the following particulars shall appear on the immediate and the outer packa
p.(None): ging:
p.(None): (a) name of the main contact;
p.(None): (b) clinical trial reference code allowing identification of the clinical trial site, investigator,
p.(None): sponsor and subject;
p.(None): (c) 'For clinical trial use only' or similar wording.
p.(None):
p.(None): D. REPLACING OF INFORMATION
p.(None): 8. The particulars listed in sections A, B and C, other than those particulars listed in paragraph 9,
p.(None): may be omitted from the label of a product and made available by other means, for example by use of a
p.(None): centralised electronic randomisation system, use of a centralised information system, provided that the
p.(None): safety of the subject and the reliability and robustness of data are not compromised. This shall be justified in the
p.(None): protocol.
p.(None):
p.(None): L 158/74 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 9. The particulars referred to in the following points shall not be omitted from the label of a product:
p.(None):
p.(None): (a) paragraph 1, points (b), (c), (d), (f), (j) and (k);
p.(None):
p.(None): (b) paragraph 4, points (b), (c), (e), and (f);
p.(None):
p.(None): (c) paragraph 5, points (b), (c), (e), and (f);
p.(None):
p.(None): (d) paragraph 6, points (b), (d), (e), (h), and (i).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/75
p.(None):
p.(None): ANNEX VII
p.(None):
p.(None): CORRELATION TABLE
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): Article 1(1)
p.(None): Article 1(2)
p.(None): Directive 2001/20/EC
p.(None): This Regulation
p.(None):
p.(None): Article 1 and Article 2(1) and (2) points (1), (2) and (4)
p.(None): Article 2(2) point (30)
p.(None):
p.(None): Article 1(3), first subparagraph Article 1(3), second subparagraph Article 1(4)
p.(None): Article 2
p.(None): Article 3(1)
p.(None): Article 3(2)
p.(None): Article 3(3)
p.(None): Article 3(4)
p.(None): Article 4
p.(None): Article 5
p.(None): Article 6
p.(None): Article 7
p.(None): Article 8
p.(None): Article 9 Article 10(a) Article 10(b) Article 10(c) Article 11
p.(None): Article 12
p.(None): Article 13(1)
p.(None): Article 13(2)
p.(None): Article 13(3), first subparagraph Article 13(3), second subparagraph Article 13(3), third subparagraph Article 13(4)
p.(None): Article 13(5)
p.(None): Article 14
p.(None): Article 15(1)
p.(None): Article 15(2)
p.(None): —
p.(None): Article 47, third subparagraph Article 47, second subparagraph Article 2
p.(None): —
p.(None): Articles 4, 28, 29 and 76 Article 28(1)(f)
p.(None): Article 28(1)(g)
p.(None): Articles 10(1), 28, 29 and 32
p.(None): Articles 10(2), 28, 29 and 31
p.(None): Articles 4 to 14
p.(None): Articles 4 to 14
p.(None): —
p.(None): Articles 4 to 14
p.(None): Articles 15 to 24
p.(None): Article 54
p.(None): Articles 37 and 38
p.(None): Article 81
p.(None): Article 77
p.(None): Article 61(1) to (4)
p.(None): Article 61(2)
p.(None): Articles 62(1) and 63(1) and (3)
p.(None): Article 63(1)
p.(None): —
p.(None): Article 62
p.(None): —
p.(None): Articles 66 to 70
p.(None): Article 78(1), (2) and (5)
p.(None): Article 78(6)
p.(None):
p.(None): L 158/76 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): Article 15(3)
p.(None): Article 15(4)
p.(None): Directive 2001/20/EC
p.(None): This Regulation
p.(None):
p.(None): —
p.(None): —
p.(None):
p.(None): Article 15(5)
p.(None): Article 16
p.(None): Article 17(1)(a) to (c) Article 17(1)(d) Article 17(2)
p.(None): Article 17(3)(a) Article 17(3)(b) Article 18
p.(None): Article 19, first paragraph, first sentence Article 19, first paragraph, second sentence Article 19, second paragraph
p.(None): Article 19, third paragraph Article 20
p.(None): Article 21
p.(None): Article 22
p.(None): Article 23
p.(None): Article 24
p.(None): Articles 57, 58 and 78(7)
p.(None): Article 41
p.(None): Article 42
p.(None): —
p.(None): Article 43
p.(None): —
p.(None): Article 44(1)
p.(None): —
p.(None): Article 75
p.(None): Article 74
p.(None): Article 92
p.(None): —
p.(None): —
p.(None): Article 88
p.(None): —
p.(None): —
...
Social / Victim of Abuse
Searching for indicator abuse:
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p.(None): to letters of invitation; and
p.(None):
p.(None): (f) a justification for the changes sought in the application for a substantial modification.
p.(None):
p.(None): F. UPDATE OF EU APPLICATION FORM
p.(None):
p.(None): 8. If a substantial modification involves changes to entries on the EU application form referred to in
p.(None): Annex I, a revised version of that form shall be submitted. The fields affected by the substantial
p.(None): modification shall be high lighted in the revised form.
p.(None):
p.(None): G. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 9. Proof of payment shall be submitted, if applicable.
p.(None):
p.(None): L 158/66 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX III
p.(None):
p.(None): SAFETY REPORTING
p.(None):
p.(None): 1. REPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR TO THE SPONSOR
p.(None): 1. The investigator does not need to actively monitor subjects for adverse events once the clinical trial
p.(None): has ended with regard to the subjects treated by him, unless otherwise provided for in the protocol.
p.(None):
p.(None): 2. REPORTING OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) BY THE SPONSOR TO THE AGENCY
p.(None): IN ACCORDANCE WITH ARTICLE 42
p.(None): 2.1. Adverse Events and Causality
p.(None): 2. Medication errors, pregnancies and uses outside what is foreseen in the protocol, including misuse
p.(None): and abuse of the product, shall be subject to the same obligation to report as adverse reactions.
p.(None):
p.(None): 3. In determining whether an adverse event is an adverse reaction, consideration shall be given to
p.(None): whether there is a reasonable possibility of establishing a causal relationship between the event and the
p.(None): investigational medi cinal product based on an analysis of available evidence.
p.(None):
p.(None): 4. In the absence of information on causality provided by the reporting investigator, the sponsor shall consult the
p.(None): reporting investigator and encourage him to express an opinion on this issue. The causality assessment
p.(None): given by the investigator shall not be downgraded by the sponsor. If the sponsor disagrees with the
p.(None): investigator's causality assessment, the opinion of both the investigator and the sponsor shall be provided with the
p.(None): report.
p.(None):
p.(None): 2.2. Expectedness, unexpectedness and the RSI
p.(None): 5. In determining whether an adverse event is unexpected, consideration shall be given to whether the event adds
p.(None): significant information on the specificity, increase of occurrence, or severity of a known, already
p.(None): documented serious adverse reaction.
p.(None):
p.(None): 6. The expectedness of an adverse reaction shall be set out by the sponsor in the RSI. Expectedness shall be deter
p.(None): mined on the basis of events previously observed with the active substance and not on the basis of the
p.(None): antici pated pharmacological properties of a medicinal product or events related to the subject's disease.
p.(None):
...
Social / Women
Searching for indicator women:
(return to top)
p.(None):
p.(None): (18) It should be left to the Member State concerned to determine the appropriate body or bodies
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
p.(None): ethics committees within the timelines for the authorisation of that clinical trial as set out in this
p.(None): Regulation. Such decisions are a matter of internal organisation for each Member State. When determining
p.(None): the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular
p.(None): patients or patients' organisations. They should also ensure that the necessary expertise is available. In
p.(None): accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons
p.(None): who collectively have the necessary qualifi cations and experience. The persons assessing the application
p.(None): should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free
p.(None): from any other undue influence.
p.(None):
p.(None):
p.(None): (19) The assessment of applications for the authorisation of clinical trials should be conducted on
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
p.(None): trials involving subjects in emer gency situations, minors, incapacitated subjects, pregnant and breastfeeding
p.(None): women and, where appropriate, other identified specific population groups, such as elderly people or people suffering
p.(None): from rare and ultra rare diseases.
p.(None):
p.(None):
p.(None): (20) In practice, sponsors do not always have all the information needed for submitting a complete
p.(None): application for authorisation of a clinical trial in all of the Member States where a clinical trial is
p.(None): eventually going to be conducted. It should be possible for sponsors to submit an application solely on the
p.(None): basis of documents assessed jointly by those Member States where the clinical trial might be conducted.
p.(None):
p.(None):
p.(None): (21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure
p.(None): the reli able functioning of the assessment procedure, however, an application for authorisation of a
p.(None): clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the
p.(None): sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an
p.(None): application.
p.(None):
p.(None): L 158/4 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (22) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest in
p.(None): extending the clinical trial to an additional Member States after the initial authorisation of the clinical trial. An
p.(None): authorisation mechanism should be provided to allow for such extension, while avoiding the re-assessment
...
p.(None): dossier. To ensure that the assessment of the application for authorisation of a clinical trial functions
p.(None): smoothly, Member States should consider accepting a commonly understood language in the medical field as
p.(None): the language for the docu mentation not destined for the subject.
p.(None):
p.(None):
p.(None): (27) Human dignity and the right to the integrity of the person are recognised in the Charter of
p.(None): Fundamental Rights of the European Union (the ‘Charter’). In particular, the Charter requires that any
p.(None): intervention in the field of biology and medicine cannot be performed without free and informed consent of the
p.(None): person concerned. Directive 2001/20/EC contains an extensive set of rules for the protection of subjects.
p.(None): These rules should be upheld. Regarding the rules concerning the determination of the legally
p.(None): designated representatives of incapacitated persons and minors, those rules diverge in Member States. It
p.(None): should therefore be left to Member States to deter mine the legally designated representatives of
p.(None): incapacitated persons and minors. Incapacitated subjects, minors, pregnant women and breastfeeding women require
p.(None): specific protection measures.
p.(None):
p.(None):
p.(None): (28) An appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner should be
p.(None): respon sible for all medical care provided to the subject, including the medical care provided by other medical staff.
p.(None):
p.(None):
p.(None): (29) It is appropriate that universities and other research institutions, under certain circumstances
p.(None): that are in accord ance with the applicable law on data protection, be able to collect data from
p.(None): clinical trials to be used for future scientific research, for example for medical, natural or social
p.(None): sciences research purposes. In order to collect data for such purposes it is necessary that the subject
p.(None): gives consent to use his or her data outside the protocol of the clinical trial and has the right to
p.(None): withdraw that consent at any time. It is also necessary that research projects based on such data be
p.(None): made subject to reviews that are appropriate for research on human data, for example on ethical aspects,
p.(None): before being conducted.
p.(None):
p.(None):
p.(None): (30) In accordance with international guidelines, the informed consent of a subject should be in
p.(None): writing. When the subject is unable to write, it may be recorded through appropriate alternative means,
...
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
...
p.(None): shall make an annual declaration of their financial interests.
p.(None):
p.(None): 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who
p.(None): collectively have the necessary qualifications and experience.
p.(None):
p.(None): 3. At least one layperson shall participate in the assessment.
p.(None):
p.(None):
p.(None): Article 10
p.(None):
p.(None): Specific considerations for vulnerable populations
p.(None):
p.(None): 1. Where the subjects are minors, specific consideration shall be given to the assessment of the
p.(None): application for authorisation of a clinical trial on the basis of paediatric expertise or after taking
p.(None): advice on clinical, ethical and psycho social problems in the field of paediatrics.
p.(None):
p.(None): L 158/20 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the
p.(None): applica tion for authorisation of a clinical trial on the basis of expertise in the relevant disease
p.(None): and the patient population concerned or after taking advice on clinical, ethical and psychosocial
p.(None): questions in the field of the relevant disease and the patient population concerned.
p.(None):
p.(None): 3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the
p.(None): assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant
p.(None): condition and the population represented by the subject concerned.
p.(None):
p.(None): 4. If according to the protocol a clinical trial provides for the participation of specific groups
p.(None): or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of
p.(None): the application for authorisation of that clinical trial on the basis of expertise in the population represented by
p.(None): the subjects concerned.
p.(None):
p.(None): 5. In any application for authorisation of a clinical trial referred to in Article 35, specific consideration
p.(None): shall be given to the circumstances of the conduct of the clinical trial.
p.(None):
p.(None):
p.(None): Article 11
p.(None):
p.(None): Submission and assessment of applications limited to aspects covered by Part I or Part II of the
p.(None): assessment report
p.(None):
p.(None): Where the sponsor so requests, the application for authorisation of a clinical trial, its assessment and
p.(None): the conclusion shall be limited to the aspects covered by Part I of the assessment report.
p.(None):
p.(None): After the notification of the conclusion on the aspects covered by Part I of the assessment report,
p.(None): the sponsor may within two years apply for an authorisation limited to aspects covered by Part II of the
p.(None): assessment report. In that appli cation the sponsor shall declare that he is not aware of any new substantial
p.(None): scientific information that would change the validity of any item submitted in the application on the aspects
...
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
p.(None): (ii) some benefit for the population represented by the minor concerned and such a clinical trial will
p.(None): pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with
p.(None): the standard treatment of the minor's condition.
p.(None): 2. The minor shall take part in the informed consent procedure in a way adapted to his or her
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
p.(None): clinical trial may be obtained, and information on the clinical trial may be given, after the decision to
p.(None): include the subject in the clinical trial, provided that this decision is taken at the time of the first
p.(None): intervention on the subject, in accordance with the protocol for that clinical trial" and that all of the
...
p.(None): that the sponsor is satisfied that:
p.(None):
p.(None): (a) the information provided is complete;
p.(None):
p.(None): (b) the attached documents contain an accurate account of the information available;
p.(None):
p.(None): (c) the clinical trial is to be conducted in accordance with the protocol; and
p.(None):
p.(None): (d) the clinical trial is to be conducted in accordance with this Regulation.
p.(None):
p.(None): 4. The application dossier for an application limited to Part I of the assessment report referred to
p.(None): in Article 11 shall be limited to sections B to J and Q of this Annex.
p.(None):
p.(None): 5. Without prejudice to Article 26, the application dossier for an application limited to Part II of
p.(None): the assessment report referred to in Article 11 and the application dossier for an application referred to in
p.(None): Article 14 shall be limited to sections K to R of this Annex.
p.(None):
p.(None):
p.(None): B. COVER LETTER
p.(None):
p.(None): 6. The cover letter shall specify the EU trial number and the universal trial number and shall draw
p.(None): attention to any features which are particular to the clinical trial.
p.(None):
p.(None): 7. However, in the cover letter it is not necessary to reproduce information already contained in
p.(None): the EU applica tion form, with the following exceptions:
p.(None):
p.(None): (a) specific features of the clinical trial population, such as subjects not able to give informed consent,
p.(None): minors and pregnant or breastfeeding women;
p.(None):
p.(None): (b) whether the clinical trial involves the first administration of a new active substance to humans;
p.(None):
p.(None): (c) whether scientific advice relating to the clinical trial or the investigational medicinal product
p.(None): has been given by the Agency, a Member State or a third country;
p.(None):
p.(None): (d) whether the clinical trial is part or is intended to be part of a Paediatric Investigation Plan (PIP) as
p.(None): referred to in Title II, Chapter 3, of Regulation (EC) No 1901/2006 (if the Agency has already issued a
p.(None): decision on the PIP, the cover letter contains the link to the decision of the Agency on its website);
p.(None):
p.(None): (e) whether investigational medicinal products or auxiliary medicinal products are a narcotic,
p.(None): psychotropic or radiopharmaceutical;
p.(None):
p.(None): (f) whether the investigational medicinal products consist of or contain a genetically-modified organism
p.(None): or organisms;
p.(None):
p.(None): (g) whether the sponsor has obtained an orphan designation for the investigational medicinal product for
p.(None): an orphan condition;
p.(None):
p.(None): (h) a comprehensive list, including the regulatory status, of all investigational medicinal products and
p.(None): a list of all auxiliary medicinal products; and
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/55
p.(None):
p.(None): (i) a list of medical devices which are to be investigated in the clinical trial but which are not part of the
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.(None): the subject to consider his or her deci sion. In view of the fact that in certain Member States the only person
p.(None): qualified under national law to perform an interview with a potential subject is a medical doctor while in
p.(None): other Member States this is done by other profes sionals, it is appropriate to provide that the prior
p.(None): interview with a potential subject should be performed by a member of the investigating team qualified
p.(None): for this task under the national law of the Member State where the recruitment takes place.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/5
p.(None):
p.(None): (31) In order to certify that informed consent is given freely, the investigator should take into
p.(None): account all relevant circumstances which might influence the decision of a potential subject to participate in a
p.(None): clinical trial, in particu lar whether the potential subject belongs to an economically or socially
p.(None): disadvantaged group or is in a situation of institutional or hierarchical dependency that could inappropriately
p.(None): influence her or his decision to participate.
p.(None):
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
...
p.(None): of a substantial modification has been submitted under Chapters II or III of this Regulation respectively;
p.(None):
p.(None): (13) ‘Substantial modification’ means any change to any aspect of the clinical trial which is made after
p.(None): notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to have a substantial
p.(None): impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the
p.(None): clinical trial;
p.(None):
p.(None): (14) ‘Sponsor’ means an individual, company, institution or organisation which takes responsibility for the
p.(None): initiation, for the management and for setting up the financing of the clinical trial;
p.(None):
p.(None): (1) Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
p.(None): medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/13
p.(None):
p.(None): (15) ‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical trial site;
p.(None):
p.(None): (16) ‘Principal investigator’ means an investigator who is the responsible leader of a team of
p.(None): investigators who conduct a clinical trial at a clinical trial site;
p.(None):
p.(None): (17) ‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
p.(None): investigational medicinal product or as a control;
p.(None):
p.(None): (18) ‘Minor’ means a subject who is, according to the law of the Member State concerned, under the age of legal
p.(None): compe tence to give informed consent;
p.(None):
p.(None): (19) ‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal competence to give
p.(None): informed consent, incapable of giving informed consent according to the law of the Member State concerned;
p.(None):
p.(None): (20) ‘Legally designated representative’ means a natural or legal person, authority or body which,
p.(None): according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject
p.(None): who is an incapaci tated subject or a minor;
p.(None):
p.(None): (21) ‘Informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in
p.(None): a par ticular clinical trial, after having been informed of all aspects of the clinical trial that are
p.(None): relevant to the subject's decision to participate or, in case of minors and of incapacitated subjects, an
p.(None): authorisation or agreement from their legally designated representative to include them in the clinical trial;
p.(None):
p.(None): (22) ‘Protocol’ means a document that describes the objectives, design, methodology, statistical
p.(None): considerations and or ganisation of a clinical trial. The term ‘protocol’ encompasses successive versions
p.(None): of the protocol and protocol modifications;
p.(None):
p.(None): (23) ‘Investigator's brochure’ means a compilation of the clinical and non-clinical data on the
p.(None): investigational medicinal product or products which are relevant to the study of the product or products in humans;
p.(None):
p.(None): (24) ‘Manufacturing’ means total and partial manufacture, as well as the various processes of dividing up, packaging
p.(None): and labelling (including blinding);
p.(None):
p.(None): (25) ‘Start of a clinical trial’ means the first act of recruitment of a potential subject for a
p.(None): specific clinical trial, unless defined differently in the protocol;
p.(None):
p.(None): (26) ‘End of a clinical trial’ means the last visit of the last subject, or at a later point in time as defined in the
p.(None): protocol;
p.(None):
p.(None): (27) ‘Early termination of a clinical trial’ means the premature end of a clinical trial due to any reason before the
...
p.(None): to be related to the clinical trial and that may be located at the clinical trial site, at the sponsor's and/or
p.(None): contract research organisation's facilities, or at other establishments which the competent authority sees fit to
p.(None): inspect;
p.(None):
p.(None): L 158/14 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (32) ‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal product is
p.(None): administered and which does not necessarily have a causal relationship with this treatment;
p.(None): (33) ‘Serious adverse event’ means any untoward medical occurrence that at any dose requires inpatient
p.(None): hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability
p.(None): or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death;
p.(None): (34) ‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature, severity or outcome of which
p.(None): is not consistent with the reference safety information;
p.(None): (35) ‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
p.(None): format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
p.(None): accompanying an application for marketing authorisation.
p.(None): 3. For the purposes of this Regulation, a subject who falls under the definition of both ‘minor’
p.(None): and ‘incapacitated subject’ shall be deemed to be an incapacitated subject.
p.(None):
p.(None):
p.(None): Article 3
p.(None):
p.(None): General principle
p.(None):
p.(None): A clinical trial may be conducted only if:
p.(None): (a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and
p.(None): (b) it is designed to generate reliable and robust data.
p.(None):
p.(None):
p.(None): CHAPTER II
p.(None):
p.(None): AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL
p.(None):
p.(None): Article 4
p.(None):
p.(None): Prior authorisation
p.(None):
p.(None): A clinical trial shall be subject to scientific and ethical review and shall be authorised in accordance with this
p.(None): Regulation.
p.(None):
p.(None): The ethical review shall be performed by an ethics committee in accordance with the law of the Member
p.(None): State concerned. The review by the ethics committee may encompass aspects addressed in Part I of the
p.(None): assessment report for the authorisation of a clinical trial as referred to in Article 6 and in Part II
p.(None): of that assessment report as referred to in Article 7 as appropriate for each Member State concerned.
p.(None):
p.(None): Member States shall ensure that the timelines and procedures for the review by the ethics committees
p.(None): are compatible with the timelines and procedures set out in this Regulation for the assessment of the
p.(None): application for authorisation of a clinical trial.
p.(None):
p.(None):
p.(None): Article 5
...
p.(None): the subject or, where the subject is not able to give informed consent, his or her legally designated
p.(None): representative.
p.(None):
p.(None): 4. In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the
p.(None): information needs of specific patient populations and of individual subjects, as well as to the methods used to give
p.(None): the information.
p.(None):
p.(None): 5. In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood
p.(None): the infor mation.
p.(None):
p.(None): 6. The subject shall be informed that the summary of the results of the clinical trial and a
p.(None): summary presented in terms understandable to a layperson will be made available in the EU database,
p.(None): referred to in Article 81 (the ‘EU data base’), pursuant to Article 37(4), irrespective of the outcome
p.(None): of the clinical trial, and, to the extent possible, when the summaries become available.
p.(None):
p.(None): 7. This Regulation is without prejudice to national law requiring that both the signature of the
p.(None): incapacitated person and the signature of his or her legally designated representative may be required on the informed
p.(None): consent form.
p.(None):
p.(None): 8. This Regulation is without prejudice to national law requiring that, in addition to the informed
p.(None): consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing
p.(None): the information given to him or her, shall also assent in order to participate in a clinical trial.
p.(None):
p.(None):
p.(None): Article 30
p.(None):
p.(None): Informed consent in cluster trials
p.(None):
p.(None): 1. Where a clinical trial is to be conducted exclusively in one Member State, that Member State
p.(None): may, without preju dice to Article 35, and by way of derogation from points (b), (c), and (g) of
p.(None): Article 28(1), Article 29(1), point (c) of Article 29(2), Article 29(3), (4) and (5), points (a), (b) and (c) of
p.(None): Article 31(1) and points (a), (b) and (c) of Article 32(1), allow the investigator to obtain informed consent by
p.(None): the simplified means set out in paragraph 2 of this Article, provided that all of the conditions set out in
p.(None): paragraph 3 of this Article are fulfilled.
p.(None):
p.(None): 2. For clinical trials that fulfil the conditions set out in paragraph 3, informed consent shall be
p.(None): deemed to have been obtained if:
p.(None):
p.(None): (a) the information required under points (a), (b), (d) and (e) of Article 29(2) is given, in
p.(None): accordance with what is laid down in the protocol, prior to the inclusion of the subject in the
p.(None): clinical trial, and this information makes clear, in particular, that the subject can refuse to
p.(None): participate in, or withdraw at any time from, the clinical trial without any resulting detriment; and
p.(None):
...
p.(None):
p.(None): 2. Point (g)(ii) of paragraph 1 shall be without prejudice to more stringent national rules
p.(None): prohibiting the conduct of those clinical trials on incapacitated subjects, where there are no scientific
p.(None): grounds to expect that participation in the clinical trial will produce a direct benefit to the subject
p.(None): outweighing the risks and burdens involved.
p.(None):
p.(None): 3. The subject shall as far as possible take part in the informed consent procedure.
p.(None):
p.(None):
p.(None): Article 32
p.(None):
p.(None): Clinical trials on minors
p.(None):
p.(None): 1. A clinical trial on minors may be conducted only where, in addition to the conditions set out in
p.(None): Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the minors have received the information referred to in Article 29(2) in a way adapted to their
p.(None): age and mental maturity and from investigators or members of the investigating team who are trained or
p.(None): experienced in working with children;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/33
p.(None):
p.(None): (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information
p.(None): referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is
p.(None): respected by the investi gator;
p.(None): (d) no incentives or financial inducements are given to the subject or his or her legally designated
p.(None): representative except for compensation for expenses and loss of earnings directly related to the participation in the
p.(None): clinical trial;
p.(None): (e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in
p.(None): minors or the clin ical trial is essential with respect to minors to validate data obtained in
p.(None): clinical trials on persons able to give informed consent or by other research methods;
p.(None): (f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is
p.(None): of such a nature that it can only be carried out on minors;
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
p.(None): (ii) some benefit for the population represented by the minor concerned and such a clinical trial will
p.(None): pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with
p.(None): the standard treatment of the minor's condition.
p.(None): 2. The minor shall take part in the informed consent procedure in a way adapted to his or her
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
...
p.(None): shall be submitted, including any printed materials, and audio or visual recordings. The procedures proposed for
p.(None): hand ling responses to the advertisement shall be outlined. This includes copies of communications used
p.(None): to invite subjects to participate in the clinical trial and arrangements for information or advice to the respondents
p.(None): found not to be suitable for inclusion in the clinical trial.
p.(None):
p.(None):
p.(None): L. SUBJECT INFORMATION, INFORMED CONSENT FORM AND INFORMED CONSENT PROCEDURE (INFORMATION PER
p.(None): MEMBER STATE CONCERNED)
p.(None):
p.(None): 61. All information given to the subjects (or, where applicable, to their legally designated
p.(None): representatives) before their decision to participate or abstain from participation shall be submitted together with
p.(None): the form for written informed consent, or other alternative means according to Article 29(1) for recording informed
p.(None): consent.
p.(None):
p.(None): 62. A description of procedures relating to informed consent for all subjects, and in particular:
p.(None):
p.(None): (a) in clinical trials with minors or incapacitated subjects, the procedures to obtain informed consent from the
p.(None): legally designated representatives, and the involvement of the minor or incapacitated subject shall be
p.(None): described;
p.(None):
p.(None): (b) if a procedure with consent witnessed by an impartial witness is to be used, relevant information
p.(None): on the reason for using an impartial witness, on the selection of the impartial witness and on the
p.(None): procedure for obtaining informed consent shall be provided;
p.(None):
p.(None): (c) in the case of clinical trials in emergency situations as referred to in Article 35, the procedure for obtaining
p.(None): the informed consent of the subject or the legally designated representative to continue the clinical
p.(None): trial shall be described;
p.(None):
p.(None): (d) in the case of clinical trials in emergency situations as referred to in Article 35, the description of the
p.(None): pro cedures followed to identify the urgency of the situation and to document it;
p.(None):
p.(None): (e) in the case of clinical trials where their methodology requires that groups of subjects rather than individual
p.(None): subjects are allocated to receive different investigational medicinal products, as referred to in Article
p.(None): 30, and where, as a consequence, simplified means for obtaining informed consent will be used, the simplified
p.(None): means shall be described.
p.(None):
p.(None): 63. In the cases set out in paragraph 62, the information given to the subject and to his or her
...
Social / education
Searching for indicator education:
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p.(None): take appropriate account of the quality standards and the ICH guidelines on good clinical practice.
p.(None):
p.(None): The Commission shall make publicly available the detailed ICH guidelines on good clinical practice
p.(None): referred to in the second paragraph.
p.(None):
p.(None):
p.(None): Article 48
p.(None):
p.(None): Monitoring
p.(None):
p.(None): In order to verify that the rights, safety and well-being of subjects are protected, that the reported
p.(None): data are reliable and robust, and that the conduct of the clinical trial is in compliance with the
p.(None): requirements of this Regulation, the sponsor shall adequately monitor the conduct of a clinical trial. The
p.(None): extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment
p.(None): that takes into consideration all characteristics of the clinical trial, including the following
p.(None): characteristics:
p.(None): (a) whether the clinical trial is a low-intervention clinical trial;
p.(None): (b) the objective and methodology of the clinical trial; and
p.(None): (c) the degree of deviation of the intervention from normal clinical practice.
p.(None):
p.(None): Article 49
p.(None):
p.(None): Suitability of individuals involved in conducting the clinical trial
p.(None):
p.(None): The investigator shall be a medical doctor as defined in national law, or a person following a profession
p.(None): which is recog nised in the Member State concerned as qualifying for an investigator because of the
p.(None): necessary scientific knowledge and experience in patient care.
p.(None):
p.(None): Other individuals involved in conducting a clinical trial shall be suitably qualified by education,
p.(None): training and experience to perform their tasks.
p.(None):
p.(None):
p.(None): Article 50
p.(None):
p.(None): Suitability of clinical trial sites
p.(None):
p.(None): The facilities where the clinical trial is to be conducted shall be suitable for the conduct of the clinical trial in
p.(None): compliance with the requirements of this Regulation.
p.(None):
p.(None):
p.(None): Article 51
p.(None):
p.(None): Traceability, storage, return and destruction of investigational medicinal products
p.(None):
p.(None): 1. Investigational medicinal products shall be traceable. They shall be stored, returned and/or destroyed as
p.(None): appropriate and proportionate to ensure the safety of the subject and the reliability and robustness of the data
p.(None): generated in the clin ical trial, in particular, taking into account whether the investigational medicinal product is
p.(None): an authorised investigational medicinal product, and whether the clinical trial is a low-intervention clinical trial.
p.(None):
p.(None): L 158/40 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): The first subparagraph shall also apply to unauthorised auxiliary medicinal products.
p.(None):
p.(None): 2. The relevant information regarding the traceability, storage, return and destruction of medicinal
p.(None): products referred to in paragraph 1 shall be contained in the application dossier.
p.(None):
p.(None):
p.(None): Article 52
p.(None):
p.(None): Reporting of serious breaches
p.(None):
p.(None): 1. The sponsor shall notify the Member States concerned about a serious breach of this Regulation
p.(None): or of the version of the protocol applicable at the time of the breach through the EU portal without undue delay
...
Social / embryo
Searching for indicator embryo:
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p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
...
p.(None): 2. The minor shall take part in the informed consent procedure in a way adapted to his or her
p.(None): age and mental maturity.
p.(None):
p.(None): 3. If during a clinical trial the minor reaches the age of legal competence to give informed
p.(None): consent as defined in the law of the Member State concerned, his or her express informed consent shall
p.(None): be obtained before that subject can continue to participate in the clinical trial.
p.(None):
p.(None):
p.(None): Article 33
p.(None):
p.(None): Clinical trials on pregnant or breastfeeding women
p.(None):
p.(None): A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out
p.(None): in Article 28, the following conditions are met:
p.(None): (a) the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman
p.(None): concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; or
p.(None): (b) if such clinical trial has no direct benefit for the pregnant or breastfeeding woman concerned, or her embryo,
p.(None): foetus or child after birth, it can be conducted only if:
p.(None): (i) a clinical trial of comparable effectiveness cannot be carried out on women who are not pregnant
p.(None): or breast feeding;
p.(None): (ii) the clinical trial contributes to the attainment of results capable of benefitting pregnant or breastfeeding
p.(None): women or other women in relation to reproduction or other embryos, foetuses or children; and
p.(None): (iii) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the pregnant or
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
...
Social / gender
Searching for indicator gender:
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p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/3
p.(None):
p.(None): (12) The Recommendation of the Organisation for Economic Cooperation and Development (OECD) Council on
p.(None): the Governance of Clinical Trials of 10 December 2012 introduced different risk categories for clinical
p.(None): trials. Those categories are compatible with the categories of clinical trials defined in this Regulation as the OECD
p.(None): Categories A and B(1) correspond to the definition of a low-intervention clinical trial as set out in
p.(None): this Regulation, and the OECD Categories B(2) and C correspond to the definition of a clinical trial as set out in
p.(None): this Regulation.
p.(None):
p.(None):
p.(None): (13) The assessment of the application for a clinical trial should address in particular the
p.(None): anticipated therapeutic and public health benefits (relevance) and the risk and inconvenience for the
p.(None): subject. In respect of the relevance, various aspects should be taken into account, including whether the
p.(None): clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment of
p.(None): medicinal products and the authorisation of their placing on the market and whether surrogate end-points, when
p.(None): they are used, are justified.
p.(None):
p.(None):
p.(None): (14) Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent
p.(None): the popula tion groups, for example gender and age groups, that are likely to use the medicinal product
p.(None): investigated in the clinical trial.
p.(None):
p.(None):
p.(None): (15) In order to improve treatments available for vulnerable groups such as frail or older people,
p.(None): people suffering from multiple chronic conditions, and people affected by mental health disorders,
p.(None): medicinal products which are likely to be of significant clinical value should be fully and appropriately
p.(None): studied for their effects in these specific groups, including as regards requirements related to their
p.(None): specific characteristics and the protection of the health and well-being of subjects belonging to these groups.
p.(None):
p.(None):
p.(None): (16) The authorisation procedure should provide for the possibility to extend the timelines for the assessment
p.(None): in order to allow the sponsor to address questions or comments raised during the assessment of the
p.(None): application dossier. Moreover, it should be ensured that, within the extension period, there is always
p.(None): sufficient time for assessing the additional information submitted.
p.(None):
p.(None):
p.(None): (17) The authorisation to conduct a clinical trial should address all aspects of subject protection
p.(None): and data reliability and robustness. That authorisation should therefore be contained in a single
p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
...
p.(None): clinical trials that are relevant to the clinical trial;
p.(None): (d) a summary of the known and potential risks and benefits including an evaluation of the anticipated bene fits
p.(None): and risks to allow assessment in accordance with Article 6; for subjects in a clinical trial in an
p.(None): emer gency situation, the scientific grounds for expecting that the participation of the subjects has the potential to
p.(None): produce a direct clinically relevant benefit shall be documented;
p.(None): (e) where patients were involved in the design of the clinical trial, a description of their involvement;
p.(None):
p.(None): L 158/56 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (f) a description of, and justification for, the dosage, the dosage regime, the route and mode of
p.(None): administra tion, and the treatment period for all investigational medicinal products and auxiliary medicinal products;
p.(None):
p.(None): (g) a statement of whether the investigational medicinal products and auxiliary medicinal products
p.(None): used in the clinical trial are authorised; if authorised, whether they are to be used in the clinical
p.(None): trial in accord ance with the terms of their marketing authorisations, and, if not authorised, a justification for
p.(None): the use of non-authorised auxiliary medicinal products in the clinical trial;
p.(None):
p.(None): (h) a description of the groups and subgroups of the subjects participating in the clinical trial,
p.(None): including, where relevant, groups of subjects with specific needs, for example. age, gender, participation
p.(None): of healthy volunteers, subjects with rare and ultra rare diseases;
p.(None):
p.(None): (i) references to literature and data that are relevant to the clinical trial, and that provide background for
p.(None): the clinical trial;
p.(None):
p.(None): (j) a discussion of the relevance of the clinical trial in order to allow assessment in accordance with Article
p.(None): 6;
p.(None):
p.(None): (k) a description of the type of clinical trial to be conducted and a discussion of the trial design
p.(None): (including a schematic diagram of trial design, procedures and stages, if relevant);
p.(None):
p.(None): (l) a specification of the primary end-points and the secondary end-points, if any, to be measured during the
p.(None): clinical trial;
p.(None):
p.(None): (m) a description of the measures taken to minimise bias, including, if applicable,
p.(None): randomisation and blinding;
p.(None):
p.(None): (n) a description of the expected duration of subject participation and a description of the sequence and dur
p.(None): ation of all clinical trial periods, including follow-up, if relevant;
p.(None):
p.(None): (o) a clear and unambiguous definition of the end of the clinical trial in question and, if it is not the
p.(None): date of the last visit of the last subject, a specification of the estimated end date and a justification thereof;
p.(None):
p.(None): (p) a description of the criteria for discontinuing parts of the clinical trial or the entire clinical trial;
p.(None):
p.(None): (q) arrangements for the maintenance of clinical trial treatment randomisation codes and procedures
p.(None): for breaking codes, if relevant;
p.(None):
...
p.(None):
p.(None): — timing of any planned interim analysis and the number of subjects planned to be enrolled;
p.(None):
p.(None): — reasons for choice of sample size;
p.(None):
p.(None): — calculations of the power of the clinical trial and clinical relevance;
p.(None):
p.(None): — the level of significance to be used;
p.(None):
p.(None): — criteria for the termination of the clinical trial;
p.(None):
p.(None): — procedures for accounting for missing, unused, and spurious data and for reporting any deviation from
p.(None): the original statistical plan; and
p.(None):
p.(None): — the selection of subjects to be included in the analyses;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/57
p.(None):
p.(None): (v) a description of the subject inclusion and exclusion criteria, including criteria for withdrawing
p.(None): individual subjects from treatment or from the clinical trial;
p.(None):
p.(None): (w) a description of procedures relating to the withdrawal of subjects from treatment or from the
p.(None): clinical trial including procedures for the collection of data regarding withdrawn subjects, procedures for replace
p.(None): ment of subjects and the follow-up of subjects that have withdrawn from treatment or from the clinical
p.(None): trial;
p.(None):
p.(None): (x) a justification for including subjects who are incapable of giving informed consent or other special popu
p.(None): lations, such as minors;
p.(None):
p.(None): (y) a justification for the gender and age allocation of subjects and, if a specific gender or age
p.(None): group is excluded from or underrepresented in the clinical trials, an explanation of the reasons and
p.(None): justification for these exclusion criteria;
p.(None):
p.(None): (z) a detailed description of the recruitment and informed consent procedure, especially when subjects
p.(None): are incapable of giving informed consent;
p.(None):
p.(None): (aa) a description of the treatments, including medicinal products, which are permitted or not
p.(None): permitted, before or during the clinical trial;
p.(None):
p.(None): (ab) a description of the accountability procedures for the supply and administration of medicinal products to
p.(None): subjects including the maintenance of blinding, if applicable;
p.(None):
p.(None): (ac) a description of procedures for monitoring subject compliance, if applicable; (ad) a description of
p.(None): arrangements for monitoring the conduct of the clinical trial;
p.(None): (ae) a description of the arrangements for taking care of the subjects after their participation in
p.(None): the clinical trial has ended, where such additional care is necessary because of the subjects'
p.(None): participation in the clin ical trial and where it differs from that normally expected for the medical condition in
p.(None): question;
p.(None):
p.(None): (af) a specification of the efficacy and safety parameters as well as the methods and timing for
p.(None): assessing, recording, and analysing these parameters;
p.(None):
p.(None): (ag) a description of ethical considerations relating to the clinical trial if those have not been
...
p.(None): A. CLINICAL TRIAL INFORMATION:
p.(None):
p.(None): 1. Clinical trial identification (including title of the trial and protocol number);
p.(None):
p.(None): 2. Identifiers (including EU trial number, other identifiers);
p.(None):
p.(None): 3. Sponsor details (including scientific and public contact points);.
p.(None):
p.(None): 4. Paediatric regulatory details (including information whether the clinical trial is a part of a
p.(None): Paediatric Investigation Plan);
p.(None):
p.(None): 5. Result analysis stage (including information about intermediate data analysis date, interim or final
p.(None): analysis stage, date of global end of the clinical trial). For clinical trials replicating studies on
p.(None): already authorised investigational medicinal products and used in accordance with the terms of the
p.(None): marketing authorisation, the summary of the results should also indicate identified concerns in the overall
p.(None): results of the clinical trial relating to relevant aspects of the efficacy of the related medicinal product;
p.(None):
p.(None): 6. General information about the clinical trial (including information about main objectives of the
p.(None): trial, trial design, scientific background and explanation of rationale for the trial; date of the start
p.(None): of the trial, measures of protec tion of subjects taken, background therapy; and statistical methods used);
p.(None):
p.(None): 7. Population of subjects (including information with actual number of subjects included in the clinical
p.(None): trial in the Member State concerned, in the Union and in third countries; age group breakdown, gender breakdown).
p.(None):
p.(None): B. SUBJECT DISPOSITION:
p.(None):
p.(None): 1. Recruitment (including information on the number of subjects screened, recruited and withdrawn;
p.(None): inclusion and exclusion criteria; randomisation and blinding details; investigational medicinal products used);
p.(None):
p.(None): 2. Pre-assignment Period;
p.(None):
p.(None): 3. Post Assignment Periods.
p.(None):
p.(None): C. BASELINE CHARACTERISTICS:
p.(None):
p.(None): 1. Baseline Characteristics (Required) Age;
p.(None):
p.(None): 2. Baseline Characteristics (Required) Gender;
p.(None):
p.(None): 3. Baseline Characteristics (Optional) Study Specific Characteristic.
p.(None):
p.(None): D. END POINTS:
p.(None):
p.(None): 1. End point definitions (*)
p.(None):
p.(None): 2. End Point #1 Statistical Analyses
p.(None): 3. End Point #2 Statistical Analyses
p.(None): (*) Information shall be provided for as many end points as defined in the protocol.
p.(None):
p.(None): L 158/70 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): E. ADVERSE EVENTS:
p.(None):
p.(None): 1. Adverse events information;
p.(None):
p.(None): 2. Adverse event reporting group;
p.(None):
p.(None): 3. Serious adverse event;
p.(None):
p.(None): 4. Non-serious adverse event.
p.(None):
p.(None): F. ADDITIONAL INFORMATION:
p.(None):
p.(None): 1. Global Substantial Modifications;
p.(None):
p.(None): 2. Global Interruptions and re-starts;
p.(None):
p.(None): 3. Limitations, addressing sources of potential bias and imprecisions and Caveats;
p.(None):
p.(None): 4. A declaration by the submitting party on the accuracy of the submitted information.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/71
p.(None):
p.(None): ANNEX V
p.(None):
p.(None): CONTENT OF THE SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL FOR LAYPERSONS
p.(None):
p.(None): The summary of the results of the clinical trial for laypersons shall contain information on the following elements:
p.(None): 1. Clinical trial identification (including title of the trial, protocol number, EU trial number and other
p.(None): identifiers);
p.(None): 2. Name and contact details of the sponsor;
p.(None): 3. General information about the clinical trial (including where and when the trial was conducted, the main
p.(None): objectives of the trial and an explanation of the reasons for conducting it);
p.(None): 4. Population of subjects (including information on the number of subjects included in the trial in
p.(None): the Member State concerned, in the Union and in third countries; age group breakdown and gender
p.(None): breakdown; inclusion and exclu sion criteria);
p.(None): 5. Investigational medicinal products used;
p.(None): 6. Description of adverse reactions and their frequency;
p.(None): 7. Overall results of the clinical trial;
p.(None): 8. Comments on the outcome of the clinical trial;
p.(None): 9. Indication if follow up clinical trials are foreseen;
p.(None): 10. Indication where additional information could be found.
p.(None):
p.(None): L 158/72 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX VI
p.(None):
p.(None): LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): A. UNAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): A.1. General rules
p.(None):
p.(None): 1. The following particulars shall appear on the immediate and the outer packaging:
p.(None):
p.(None): (a) name, address and telephone number of the main contact for information on the product, clinical
p.(None): trial and emergency unblinding; this may be the sponsor, contract research organisation or investigator (for the
p.(None): purpose of this Annex this is referred to as the 'main contact');
p.(None):
p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
...
Social / orphan
Searching for indicator orphan:
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p.(None): directly, but also in the context of safety reporting and labelling of investigational medicinal products.
p.(None): Divergences of approach among different Member States will be therefore kept to a minimum.
p.(None):
p.(None):
p.(None): (6) The Member States concerned should cooperate in assessing a request for authorisation of a clinical trial.
p.(None): This co operation should not include aspects of an intrinsically national nature, such as informed consent.
p.(None):
p.(None):
p.(None): (7) In order to avoid administrative delays for starting a clinical trial, the procedure to be used should be
p.(None): flexible and efficient, without compromising patient safety or public health.
p.(None):
p.(None):
p.(None): (8) The timelines for assessing an application dossier for clinical trials should be sufficient to
p.(None): assess the file while, at the same time, ensuring quick access to new, innovative treatments and
p.(None): ensuring that the Union remains an attractive place for conducting clinical trials. Against this
p.(None): background, Directive 2001/20/EC introduced the concept of tacit authorisation. This concept should be
p.(None): maintained in order to ensure that timelines are adhered to. In the event of a public health crisis, Member
p.(None): States should have the possibility to assess and authorise a clin ical trial application swiftly. No minimal timelines
p.(None): for approval should therefore be established.
p.(None):
p.(None):
p.(None): (9) Clinical trials for the development of orphan medicinal products as defined in Regulation (EC)
p.(None): No 141/2000 of the European Parliament and of the Council (1) and of medicinal products addressed to
p.(None): subjects affected by severe, debilitating and often life-threatening diseases affecting no more than one person
p.(None): in 50 000 in the Union (ultra-rare diseases) should be fostered.
p.(None):
p.(None):
p.(None): (10) Member States should efficiently assess all clinical trials applications within the given
p.(None): timelines. A rapid yet in- depth assessment is of particular importance for clinical trials concerning
p.(None): medical conditions which are severely debilitating and/or life threatening and for which therapeutic options are
p.(None): limited or non-existent, as in the case of rare and ultra-rare diseases.
p.(None):
p.(None):
p.(None): (11) The risk to subject safety in a clinical trial mainly stems from two sources: the
p.(None): investigational medicinal product and the intervention. Many clinical trials, however, pose only a minimal additional
p.(None): risk to subject safety compared to normal clinical practice. This is particularly the case where the investigational
p.(None): medicinal product is covered by a marketing authorisation, that is the quality, safety and efficacy has
p.(None): already been assessed in the course of the marketing authorisation procedure" or, if that product is not used
p.(None): in accordance with the terms of the marketing authorisation, that use is evidence- based and supported by
p.(None): published scientific evidence on the safety and effi cacy of that product, and the intervention poses
p.(None): only very limited additional risk to the subject compared to normal clinical practice. Those low-intervention
p.(None): clinical trials are often of crucial importance for assessing stand ard treatments and diagnoses, thereby
p.(None): optimising the use of medicinal products and thus contributing to a high level of public health. Those
p.(None): clinical trials should be subject to less stringent rules, as regards monitoring, require ments for the contents of
p.(None): the master file and traceability of investigational medicinal products. In order to ensure subject safety they
p.(None): should however be subject to the same application procedure as any other clinical trial. The published
p.(None): scientific evidence supporting the safety and efficacy of an investigational medicinal product not used in
p.(None): accordance with the terms of the marketing authorisation could include high quality data published in
p.(None): scien tific journal articles, as well as national, regional or institutional treatment protocols, health
p.(None): technology assess ment reports or other appropriate evidence.
p.(None):
p.(None): (1) Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan
p.(None): medicinal products (OJ L 18, 22.1.2000, p. 1).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/3
p.(None):
p.(None): (12) The Recommendation of the Organisation for Economic Cooperation and Development (OECD) Council on
p.(None): the Governance of Clinical Trials of 10 December 2012 introduced different risk categories for clinical
p.(None): trials. Those categories are compatible with the categories of clinical trials defined in this Regulation as the OECD
p.(None): Categories A and B(1) correspond to the definition of a low-intervention clinical trial as set out in
p.(None): this Regulation, and the OECD Categories B(2) and C correspond to the definition of a clinical trial as set out in
p.(None): this Regulation.
p.(None):
p.(None):
p.(None): (13) The assessment of the application for a clinical trial should address in particular the
p.(None): anticipated therapeutic and public health benefits (relevance) and the risk and inconvenience for the
p.(None): subject. In respect of the relevance, various aspects should be taken into account, including whether the
p.(None): clinical trial has been recommended or imposed by regulatory authorities in charge of the assessment of
p.(None): medicinal products and the authorisation of their placing on the market and whether surrogate end-points, when
p.(None): they are used, are justified.
p.(None):
p.(None):
p.(None): (14) Unless otherwise justified in the protocol, the subjects participating in a clinical trial should represent
...
p.(None):
p.(None): 7. However, in the cover letter it is not necessary to reproduce information already contained in
p.(None): the EU applica tion form, with the following exceptions:
p.(None):
p.(None): (a) specific features of the clinical trial population, such as subjects not able to give informed consent,
p.(None): minors and pregnant or breastfeeding women;
p.(None):
p.(None): (b) whether the clinical trial involves the first administration of a new active substance to humans;
p.(None):
p.(None): (c) whether scientific advice relating to the clinical trial or the investigational medicinal product
p.(None): has been given by the Agency, a Member State or a third country;
p.(None):
p.(None): (d) whether the clinical trial is part or is intended to be part of a Paediatric Investigation Plan (PIP) as
p.(None): referred to in Title II, Chapter 3, of Regulation (EC) No 1901/2006 (if the Agency has already issued a
p.(None): decision on the PIP, the cover letter contains the link to the decision of the Agency on its website);
p.(None):
p.(None): (e) whether investigational medicinal products or auxiliary medicinal products are a narcotic,
p.(None): psychotropic or radiopharmaceutical;
p.(None):
p.(None): (f) whether the investigational medicinal products consist of or contain a genetically-modified organism
p.(None): or organisms;
p.(None):
p.(None): (g) whether the sponsor has obtained an orphan designation for the investigational medicinal product for
p.(None): an orphan condition;
p.(None):
p.(None): (h) a comprehensive list, including the regulatory status, of all investigational medicinal products and
p.(None): a list of all auxiliary medicinal products; and
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/55
p.(None):
p.(None): (i) a list of medical devices which are to be investigated in the clinical trial but which are not part of the
p.(None): inves tigational medicinal product or products, together with a statement as to whether the medical
p.(None): devices are CE-marked for the intended use.
p.(None): 8. The cover letter shall indicate where the information listed in paragraph 7 is contained in the
p.(None): application dossier.
p.(None):
p.(None): 9. The cover letter shall indicate if the clinical trial is considered by the sponsor to be a
p.(None): low-intervention clinical trial and shall contain a detailed justification thereof.
p.(None):
p.(None): 10. The cover letter shall indicate if the methodology of the clinical trial requires that groups of
p.(None): subjects rather than individual subjects are allocated to receive different investigational medicinal
p.(None): products in a clinical trial, and as a consequence whether informed consent will be obtained by simplified means.
p.(None):
p.(None): 11. The cover letter shall indicate the location in the application dossier of the information necessary for
p.(None): assessing whether an adverse reaction is a suspected unexpected serious adverse reaction, that is the
p.(None): reference safety information.
p.(None):
...
Social / parents
Searching for indicator parent:
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p.(None):
p.(None): 4. If the investigator becomes aware of a serious adverse event with a suspected causal
p.(None): relationship to the investiga tional medicinal product that occurs after the end of the clinical trial in a
p.(None): subject treated by him or her, the investigator shall, without undue delay, report the serious adverse event to the
p.(None): sponsor.
p.(None):
p.(None):
p.(None): Article 42
p.(None):
p.(None): Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency
p.(None):
p.(None): 1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without
p.(None): delay to the database referred to in Article 40(1) all relevant information about the following suspected
p.(None): unexpected serious adverse reactions.:
p.(None): (a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in
p.(None): that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred
p.(None): at a clinical trial site in the Union or in a third country;
p.(None): (b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of
p.(None): pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical
p.(None): trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:
p.(None): (i) by that sponsor, or
p.(None): (ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical
p.(None): trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the
p.(None): sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product
p.(None): or information to a future potential marketing authorisation holder on safety matters shall not be
p.(None): considered a joint development; and
p.(None): (c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in
p.(None): any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after
p.(None): the end of the clin ical trial.
p.(None): 2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency
p.(None): shall take account of the seriousness of the reaction and shall be as follows:
p.(None): (a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and
p.(None): in any event not later than seven days after the sponsor became aware of the reaction;
p.(None): (b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not
p.(None): later than 15 days after the sponsor became aware of the reaction;
p.(None): (c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or
p.(None): non- life threatening but which turns out to be fatal or life-threatening, as soon as possible and in
p.(None): any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening.
p.(None): Where necessary to ensure timely reporting, the sponsor may, in accordance with section 2.4 of Annex
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
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p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/1
p.(None):
p.(None):
p.(None): I
p.(None):
p.(None): (Legislative acts)
p.(None):
p.(None):
p.(None):
p.(None): REGULATIONS
p.(None):
p.(None): REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
p.(None): of 16 April 2014
p.(None): on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC
p.(None): (Text with EEA relevance)
p.(None):
p.(None): THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,
p.(None):
p.(None): Having regard to the Treaty on the Functioning of the European Union, and in particular Articles 114
p.(None): and 168(4)(c) thereof,
p.(None):
p.(None): Having regard to the proposal from the European Commission,
p.(None):
p.(None): After transmission of the draft legislative act to the national parliaments,
p.(None):
p.(None): Having regard to the opinion of the European Economic and Social Committee (1), After consulting the Committee of the
p.(None): Regions,
p.(None): Acting in accordance with the ordinary legislative procedure (2), Whereas:
p.(None): (1) In a clinical trial the rights, safety, dignity and well-being of subjects should be protected
p.(None): and the data generated should be reliable and robust. The interests of the subjects should always take priority
p.(None): over all other interests.
p.(None):
p.(None): (2) In order to allow for independent control as to whether these principles are adhered to, a
p.(None): clinical trial should be subject to prior authorisation.
p.(None):
p.(None): (3) The existing definition of a clinical trial as contained in Directive 2001/20/EC of the European
p.(None): Parliament and of the Council (3) should be clarified. For that purpose, the concept of clinical trial should be more
p.(None): precisely defined by introducing the broader concept of ‘clinical study’ of which the clinical trial is a
p.(None): category. That category should be defined on the basis of specific criteria. This approach takes due
p.(None): account of international guidelines, and is in line with the Union law governing medicinal products,
p.(None): which builds on the dichotomy of ‘clinical trial’ and ‘non-interventional study’.
p.(None):
p.(None): (4) Directive 2001/20/EC aims to simplify and harmonise the administrative provisions governing
p.(None): clinical trials in the Union. However, experience shows that a harmonised approach to the regulation of
p.(None): clinical trials has only been partly achieved. This makes it in particular difficult to perform a given
...
p.(None): qualified under national law to perform an interview with a potential subject is a medical doctor while in
p.(None): other Member States this is done by other profes sionals, it is appropriate to provide that the prior
p.(None): interview with a potential subject should be performed by a member of the investigating team qualified
p.(None): for this task under the national law of the Member State where the recruitment takes place.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/5
p.(None):
p.(None): (31) In order to certify that informed consent is given freely, the investigator should take into
p.(None): account all relevant circumstances which might influence the decision of a potential subject to participate in a
p.(None): clinical trial, in particu lar whether the potential subject belongs to an economically or socially
p.(None): disadvantaged group or is in a situation of institutional or hierarchical dependency that could inappropriately
p.(None): influence her or his decision to participate.
p.(None):
p.(None):
p.(None): (32) This Regulation should be without prejudice to national law requiring that, in addition to the
p.(None): informed consent given by the legally designated representative, a minor who is capable of forming an
p.(None): opinion and assessing the information given to him or her, should himself or herself assent in order to participate
p.(None): in a clinical trial.
p.(None):
p.(None):
p.(None): (33) It is appropriate to allow that informed consent be obtained by simplified means for certain
p.(None): clinical trials where the methodology of the trial requires that groups of subjects rather than
p.(None): individual subjects are allocated to receive different investigational medicinal products. In those clinical
p.(None): trials the investigational medicinal products are used in accordance with the marketing authorisations, and the
p.(None): individual subject receives a standard treatment regardless of whether he or she accepts or refuses to participate in
p.(None): the clinical trial, or withdraws from it, so that the only consequence of non-participation is that data
p.(None): relating to him or her are not used for the clinical trial. Such clinical trials, which serve to
p.(None): compare established treatments, should always be conducted within a single Member State.
p.(None):
p.(None):
p.(None): (34) Specific provisions should be defined for the protection of pregnant and breastfeeding women
p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
...
p.(None): context of a clinical trial, thus ensuring the safety of subjects in a clinical trial.
p.(None):
p.(None): (1) Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of
p.(None): individuals with regard to the processing of personal data and on the free movement of such data (OJ L 281, 23.11.1995,
p.(None): p. 31).
p.(None): (2) Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of
p.(None): individuals with
p.(None): regard to the processing of personal data by the Community institutions and bodies and on the free movement of such
p.(None): data (OJ L 8, 12.1.2001, p. 1).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/11
p.(None):
p.(None): (83) This Regulation respects the fundamental rights and observes the principles recognised in
p.(None): particular by the Charter and notably human dignity, the integrity of the person, the rights of the
p.(None): child, respect for private and family life, the protection of personal data and the freedom of art and science.
p.(None): This Regulation should be applied by the Member States in accordance with those rights and principles.
p.(None):
p.(None): (84) The European Data Protection Supervisor has given an opinion (1) pursuant to Article 28(2) of
p.(None): Regulation (EC) No 45/2001.
p.(None):
p.(None): (85) Since the objective of this Regulation, namely to ensure that, throughout the Union, clinical trial data are
p.(None): reliable and robust while ensuring respect for the rights, safety, dignity and well-being of subjects,
p.(None): cannot be sufficiently achieved by the Member States but can rather, by reason of its scale, be better achieved at
p.(None): Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of
p.(None): the Treaty on Euro pean Union. In accordance with the principle of proportionality, as set out in that
p.(None): Article, this Regulation does not go beyond what is necessary in order to achieve that objective,
p.(None):
p.(None): HAVE ADOPTED THIS REGULATION:
p.(None):
p.(None): CHAPTER I
p.(None):
p.(None): GENERAL PROVISIONS
p.(None):
p.(None): Article 1
p.(None):
p.(None): Scope This Regulation applies to all clinical trials conducted in the Union. It does not apply to non-interventional
p.(None): studies.
p.(None):
p.(None): Article 2
p.(None):
p.(None): Definitions
p.(None):
p.(None): 1. For the purposes of this Regulation, the definitions of ‘medicinal product’, ‘radiopharmaceutical’,
p.(None): ‘adverse reaction’, ‘serious adverse reaction’, ‘immediate packaging’ and ‘outer packaging’ set out in points (2),
p.(None): (6), (11), (12), (23) and (24), respectively, of Article 1 of Directive 2001/83/EC apply.
p.(None):
...
p.(None):
p.(None): 6. For the purposes of this Chapter, the date on which the sponsor is notified in accordance with
p.(None): paragraph 3 or 5 shall be the validation date of the application. Where the sponsor is not notified, the
p.(None): validation date shall be the last day of the respective periods referred to in paragraphs 3 and 5.
p.(None):
p.(None): L 158/16 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 6
p.(None):
p.(None): Assessment report — Aspects covered by Part I
p.(None):
p.(None): 1. The reporting Member State shall assess the application with regard to the following aspects:
p.(None):
p.(None): (a) Whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor;
p.(None):
p.(None): (b) Compliance with Chapter V with respect to the following:
p.(None):
p.(None): (i) The anticipated therapeutic and public health benefits taking account of all of the following:
p.(None):
p.(None): — the characteristics of and knowledge about the investigational medicinal products;
p.(None):
p.(None): — the relevance of the clinical trial, including whether the groups of subjects participating in the
p.(None): clinical trial represent the population to be treated, or if not, the explanation and justification
p.(None): provided in accordance with point (y) of paragraph 17 of Annex I to this Regulation; the current state
p.(None): of scientific knowledge; whether the clinical trial has been recommended or imposed by regulatory authorities in
p.(None): charge of the assess ment and authorisation of the placing on the market of medicinal products; and,
p.(None): where applicable, any opinion formulated by the Paediatric Committee on a paediatric investigation plan in
p.(None): accordance with Regu lation (EC) No 1901/2006 of the European Parliament and of the Council (1);
p.(None):
p.(None): — the reliability and robustness of the data generated in the clinical trial, taking account
p.(None): of statistical approaches, design of the clinical trial and methodology, including sample size
p.(None): and randomisation, comparator and endpoints;
p.(None):
p.(None): (ii) The risks and inconveniences for the subject, taking account of all of the following:
p.(None):
p.(None): — the characteristics of and knowledge about the investigational medicinal products and the auxiliary medicinal
p.(None): products;
p.(None):
p.(None): — the characteristics of the intervention compared to normal clinical practice;
p.(None):
p.(None): — the safety measures, including provisions for risk minimisation measures, monitoring, safety reporting,
p.(None): and the safety plan;
p.(None):
p.(None): — the risk to subject health posed by the medical condition for which the investigational medicinal
p.(None): product is being investigated;
p.(None):
p.(None): (c) Compliance with the requirements concerning the manufacturing and import of investigational medicinal
p.(None): products and auxiliary medicinal products set out in Chapter IX;
p.(None):
p.(None): (d) Compliance with the labelling requirements set out in Chapter X;
p.(None):
p.(None): (e) The completeness and adequateness of the investigator's brochure.
p.(None):
p.(None): 2. The reporting Member State shall draw up an assessment report. The assessment of the aspects referred to in
...
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 5 or 8 of Article 6.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/19
p.(None):
p.(None): Where a Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
p.(None): the Commission, to all Member States, and to the sponsor.
p.(None):
p.(None): 3. Where, regarding the aspects covered by Part I of the assessment report, the clinical trial is acceptable or
p.(None): acceptable subject to compliance with specific conditions, the Member State concerned shall include in its
p.(None): decision its conclusion on Part II of the assessment report.
p.(None):
p.(None): 4. A Member State concerned shall refuse to authorise a clinical trial if it disagrees with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report on any of the
p.(None): grounds referred to in the second sub paragraph of paragraph 2, or if it finds, on duly justified grounds, that
p.(None): the aspects addressed in Part II of the assessment report are not complied with, or where an ethics committee has
p.(None): issued a negative opinion which in accordance with the law of the Member State concerned is valid for that entire
p.(None): Member State. That Member State shall provide for an appeal procedure in respect of such refusal.
p.(None):
p.(None): 5. Where the conclusion of the reporting Member State as regards Part I of the assessment report
p.(None): is that the clinical trial is not acceptable, that conclusion shall be deemed to be the conclusion of all Member
p.(None): States concerned.
p.(None):
p.(None): 6. Where the Member State concerned has not notified the sponsor of its decision within the relevant periods
p.(None): referred to in paragraph 1, the conclusion on Part I of the assessment report shall be deemed to be the
p.(None): decision of the Member State concerned on the application for authorisation of the clinical trial.
p.(None):
p.(None): 7. The Member States concerned shall not request additional information regarding the aspects addressed
p.(None): in Part I of the assessment report from the sponsor after the reporting date.
p.(None):
p.(None): 8. For the purposes of this Chapter, the notification date shall be the date on which the
p.(None): decision referred to in para graph 1 is notified to the sponsor. Where the sponsor has not been notified in
p.(None): accordance with paragraph 1, the notifi cation date shall be deemed to be the last day of the period provided for in
p.(None): paragraph 1.
p.(None):
p.(None): 9. If no subject has been included in the clinical trial in a Member State concerned within two years from the
p.(None): notifica tion date of the authorisation, the authorisation shall expire in that Member State concerned
p.(None): unless an extension, on request of the sponsor, has been approved following the procedure set out in Chapter III.
p.(None):
p.(None):
p.(None): Article 9
...
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the additional
p.(None): Member State concerned which shall not exceed 12 days from receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the additional Member
p.(None): State concerned in accordance with the second subparagraph, the application shall be deemed to have lapsed in the
p.(None): additional Member State concerned.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None): 9. Where, regarding the aspects covered by Part I of the assessment report, the conduct of the
p.(None): clinical trial is accept able or acceptable subject to compliance with specific conditions, the
p.(None): additional Member State concerned shall include in its decision its conclusion on Part II of the assessment
p.(None): report.
p.(None):
p.(None): 10. The additional Member State concerned shall refuse to authorise the clinical trial if it
p.(None): disagrees with the conclu sion of the reporting Member State as regards Part I of the assessment
p.(None): report on any of the grounds referred to in second subparagraph of paragraph 4, or if it finds, on duly
p.(None): justified grounds, that the aspects addressed in Part II of the assessment report are not complied with, or where
p.(None): an ethics committee has issued a negative opinion which, in accord ance with the law of the additional Member
p.(None): State concerned, is valid for that entire additional Member State. That addi tional Member State concerned shall
p.(None): provide for an appeal procedure in respect of such refusal.
p.(None):
p.(None): 11. Where the additional Member State concerned has not notified the sponsor of its decision within
p.(None): the period referred to in paragraph 3, or in case that period has been extended in accordance with paragraph 6 or 8
p.(None): where that ad ditional Member State concerned has not notified the sponsor of its decision within the extended
p.(None): period, the conclusion on Part I of the assessment report shall be deemed to be the decision of that additional
p.(None): Member State concerned on the application for authorisation of the clinical trial.
p.(None):
p.(None): 12. A sponsor shall not submit an application dossier in accordance with this Article where a
p.(None): procedure set out in Chapter III is pending as regards that clinical trial.
p.(None):
p.(None):
p.(None): CHAPTER III
p.(None):
p.(None): AUTHORISATION PROCEDURE FOR A SUBSTANTIAL MODIFICATION OF A CLINICAL TRIAL
p.(None):
p.(None): Article 15
p.(None):
p.(None): General principles
p.(None):
p.(None): A substantial modification, including the addition of a clinical trial site or the change of a
p.(None): principal investigator in the clinical trial site, may only be implemented if it has been approved in
p.(None): accordance with the procedure set out in this Chapter.
p.(None):
p.(None):
p.(None): Article 16
p.(None):
p.(None): Submission of application
p.(None):
p.(None): In order to obtain an authorisation, the sponsor shall submit an application dossier to the Member
p.(None): States concerned through the EU portal.
p.(None):
...
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 2. Where the conclusion of the reporting Member State is that the substantial modification is acceptable or
p.(None): acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the
p.(None): conclusion of the Member State concerned.
p.(None):
p.(None): Notwithstanding the first subparagraph, a Member State concerned may disagree with that conclusion of the
p.(None): reporting Member State only on the following grounds:
p.(None):
p.(None): (a) when it considers that participation in the clinical trial would lead to a subject receiving an
p.(None): inferior treatment than in normal clinical practice in the Member State concerned;
p.(None):
p.(None): (b) infringement of its national law as referred to in Article 90;
p.(None):
p.(None): (c) considerations as regards subject safety and data reliability and robustness submitted under
p.(None): paragraph 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion on the basis of the second subparagraph,
p.(None): it shall communicate its disagreement, together with a detailed justification, through the EU portal, to
p.(None): the Commission, to all Member States and to the sponsor.
p.(None):
p.(None): A Member State concerned shall refuse to authorise a substantial modification if it disagrees with the
p.(None): conclusion of the reporting Member State as regards Part I of the assessment report on any of the
p.(None): grounds referred to in the second sub paragraph, or where an ethics committee has issued a negative
p.(None): opinion which, in accordance with the law of that Member State concerned, is valid for that entire Member
p.(None): State. That Member State shall provide for an appeal procedure in respect of such refusal.
p.(None):
p.(None): 3. Where the conclusion of the reporting Member State, as regards the substantial modification of aspects
p.(None): covered by Part I of the assessment report, is that the substantial modification is not acceptable, that conclusion
p.(None): shall be deemed to be the conclusion of all Member States concerned.
p.(None):
p.(None): 4. Where the Member State concerned has not notified the sponsor of its decision within the period
p.(None): referred to in paragraph 1, the conclusion of the assessment report shall be deemed to be the decision of the
p.(None): Member State concerned on the application for authorisation of the substantial modification.
p.(None):
p.(None):
p.(None): Article 20
p.(None):
p.(None): Validation, assessment and decision regarding a substantial modification of an aspect covered by Part II of the
p.(None): assessment report
p.(None):
p.(None): 1. Within six days from the submission of the application dossier, the Member State concerned shall
p.(None): notify the sponsor through the EU portal of the following:
p.(None):
p.(None): (a) whether the substantial modification concerns an aspect covered by Part II of the assessment report; and
p.(None):
p.(None): (b) whether the application dossier is complete in accordance with Annex II.
p.(None):
p.(None): 2. Where the Member State concerned has not notified the sponsor within the period referred to in paragraph
p.(None): 1, the substantial modification applied for shall be deemed to concern an aspect covered by Part II of
p.(None): the assessment report and the application dossier shall be deemed to be complete.
p.(None):
...
p.(None): their nature cannot be fulfilled at the time of that authorisation.
p.(None):
p.(None): 6. During the period referred to in the second subparagraph of paragraph 5, the Member State
p.(None): concerned may request, with justified reasons, additional information from the sponsor regarding the
p.(None): substantial modification as far as its territory is concerned.
p.(None):
p.(None): For the purpose of obtaining and reviewing this additional information from the sponsor, the Member
p.(None): State concerned may extend the period referred to in the second subparagraph of paragraph 5 by a maximum of 31 days.
p.(None):
p.(None): The sponsor shall submit the requested additional information within the period set by the Member State
p.(None): concerned which shall not exceed 12 days from receipt of the request.
p.(None):
p.(None): Upon receipt of the additional information, the Member State concerned shall complete its
p.(None): assessment within a maximum of 19 days.
p.(None):
p.(None): Where the sponsor does not provide additional information within the period set by the Member State
p.(None): concerned in accordance with the third subparagraph, the application shall be deemed to have lapsed in that Member
p.(None): State.
p.(None):
p.(None): The request for additional information and the additional information shall be submitted through the EU portal.
p.(None):
p.(None): 7. A Member State concerned shall refuse to authorise a substantial modification if it finds, on duly justified
p.(None): grounds, that the aspects covered by Part II of the assessment report are not complied with or where
p.(None): an ethics committee has issued a negative opinion which, in accordance with the law of that Member
p.(None): State concerned, is valid for that entire Member State. That Member State shall provide for an appeal procedure
p.(None): in respect of such refusal.
p.(None):
p.(None): 8. Where the Member State concerned has not notified the sponsor of its decision within the periods set out in
p.(None): para graphs 5 and 6, the substantial modification shall be deemed to be authorised in that Member State.
p.(None):
p.(None):
p.(None): Article 21
p.(None):
p.(None): Substantial modification of aspects covered by Parts I and II of the assessment report
p.(None):
p.(None): 1. Where a substantial modification relates to aspects covered by Parts I and II of the assessment
p.(None): report, the applica tion for authorisation of that substantial modification shall be validated in accordance with
p.(None): Article 17.
p.(None):
p.(None): 2. The aspects covered by Part I of the assessment report shall be assessed in accordance with
p.(None): Article 18 and the aspects covered by Part II of the assessment report shall be assessed in accordance with Article
p.(None): 22.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/27
p.(None):
p.(None): Article 22
p.(None):
p.(None): Assessment of a substantial modification of aspects covered by Parts I and II of the assessment report
p.(None): — Assessment of the aspects covered by Part II of the assessment report
p.(None):
p.(None): 1. Each Member State concerned shall assess, for its own territory, the aspects of the substantial
p.(None): modification which are covered by Part II of the assessment report and submit, through the EU portal, that
...
p.(None): 4 or 6 of Article 18.
p.(None):
p.(None): Where the Member State concerned disagrees with the conclusion regarding the substantial modification of
p.(None): aspects covered by Part I of the assessment report on the basis of the second subparagraph, it shall
p.(None): communicate its disagree ment, together with a detailed justification through the EU portal to the
p.(None): Commission, to all Member States, and to the sponsor.
p.(None):
p.(None): L 158/28 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Where, regarding the substantial modification of aspects covered by Part I of the assessment report, the
p.(None): substantial modification is acceptable or acceptable subject to compliance with specific conditions, the
p.(None): Member State concerned shall include in its decision its conclusion on the substantial modification of aspects
p.(None): covered by Part II of the assessment report.
p.(None):
p.(None): 4. A Member State concerned shall refuse to authorise a substantial modification if it disagrees with the
p.(None): conclusion of the reporting Member State as regards the substantial modification of aspects covered by Part I of the
p.(None): assessment report on any of the grounds referred to in second subparagraph of paragraph 2, or if it
p.(None): finds, on duly justified grounds, that the aspects covered by Part II of the assessment report are not
p.(None): complied with, or where an ethics committee has issued a negative opinion which in accordance with the
p.(None): law of the Member State concerned, is valid for that entire Member State. That Member State concerned shall
p.(None): provide for an appeal procedure in respect of such refusal.
p.(None):
p.(None): 5. Where the conclusion of the reporting Member State as regards the substantial modification of aspects
p.(None): covered by Part I of the assessment report is that the substantial modification is not acceptable, that
p.(None): conclusion shall be deemed to be the conclusion of the Member State concerned.
p.(None):
p.(None): 6. Where the Member State concerned has not notified the sponsor of its decision within the
p.(None): periods referred to in paragraph 1, the conclusion on the substantial modification of aspects covered by
p.(None): Part I of the assessment report shall be deemed to be the decision of the Member State concerned on
p.(None): the application for authorisation of the substantial modification.
p.(None):
p.(None):
p.(None): Article 24
p.(None):
p.(None): Persons assessing the application for a substantial modification
p.(None):
p.(None): Article 9 applies to assessments made under this Chapter.
p.(None):
p.(None):
p.(None): CHAPTER IV
p.(None):
p.(None): APPLICATION DOSSIER
p.(None):
p.(None): Article 25
p.(None):
p.(None): Data submitted in the application dossier
p.(None):
p.(None): 1. The application dossier for the authorisation of a clinical trial shall contain all required
p.(None): documentation and infor mation necessary for the validation and assessment referred to in Chapter II and relating
p.(None): to:
p.(None): (a) the conduct of the clinical trial, including the scientific context and arrangements taken,
...
p.(None): representative.
p.(None):
p.(None): 4. In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the
p.(None): information needs of specific patient populations and of individual subjects, as well as to the methods used to give
p.(None): the information.
p.(None):
p.(None): 5. In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood
p.(None): the infor mation.
p.(None):
p.(None): 6. The subject shall be informed that the summary of the results of the clinical trial and a
p.(None): summary presented in terms understandable to a layperson will be made available in the EU database,
p.(None): referred to in Article 81 (the ‘EU data base’), pursuant to Article 37(4), irrespective of the outcome
p.(None): of the clinical trial, and, to the extent possible, when the summaries become available.
p.(None):
p.(None): 7. This Regulation is without prejudice to national law requiring that both the signature of the
p.(None): incapacitated person and the signature of his or her legally designated representative may be required on the informed
p.(None): consent form.
p.(None):
p.(None): 8. This Regulation is without prejudice to national law requiring that, in addition to the informed
p.(None): consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing
p.(None): the information given to him or her, shall also assent in order to participate in a clinical trial.
p.(None):
p.(None):
p.(None): Article 30
p.(None):
p.(None): Informed consent in cluster trials
p.(None):
p.(None): 1. Where a clinical trial is to be conducted exclusively in one Member State, that Member State
p.(None): may, without preju dice to Article 35, and by way of derogation from points (b), (c), and (g) of
p.(None): Article 28(1), Article 29(1), point (c) of Article 29(2), Article 29(3), (4) and (5), points (a), (b) and (c) of
p.(None): Article 31(1) and points (a), (b) and (c) of Article 32(1), allow the investigator to obtain informed consent by
p.(None): the simplified means set out in paragraph 2 of this Article, provided that all of the conditions set out in
p.(None): paragraph 3 of this Article are fulfilled.
p.(None):
p.(None): 2. For clinical trials that fulfil the conditions set out in paragraph 3, informed consent shall be
p.(None): deemed to have been obtained if:
p.(None):
p.(None): (a) the information required under points (a), (b), (d) and (e) of Article 29(2) is given, in
p.(None): accordance with what is laid down in the protocol, prior to the inclusion of the subject in the
p.(None): clinical trial, and this information makes clear, in particular, that the subject can refuse to
p.(None): participate in, or withdraw at any time from, the clinical trial without any resulting detriment; and
p.(None):
p.(None): (b) the potential subject, after being informed, does not object to participating in the clinical trial.
p.(None):
...
p.(None): describes the scope of information provided to the subjects, as well as the ways of providing information.
p.(None):
p.(None): 4. The investigator shall document all refusals and withdrawals and shall ensure that no data for
p.(None): the clinical trial are collected from subjects that refuse to participate in or have withdrawn from the clinical
p.(None): trial.
p.(None):
p.(None):
p.(None): Article 31
p.(None):
p.(None): Clinical trials on incapacitated subjects
p.(None):
p.(None): 1. In the case of incapacitated subjects who have not given, or have not refused to give, informed consent
p.(None): before the onset of their incapacity, a clinical trial may be conducted only where, in addition to the conditions set
p.(None): out in Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the incapacitated subjects have received the information referred to in Article 29(2) in a way that is adequate in
p.(None): view of their capacity to understand it;
p.(None):
p.(None): (c) the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing
p.(None): the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial
p.(None): at any time, is respected by the investigator;
p.(None):
p.(None): (d) no incentives or financial inducements are given to the subjects or their legally designated representatives,
p.(None): except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial;
p.(None):
p.(None): (e) the clinical trial is essential with respect to incapacitated subjects and data of comparable validity cannot be
p.(None): obtained in clinical trials on persons able to give informed consent, or by other research methods;
p.(None):
p.(None): (f) the clinical trial relates directly to a medical condition from which the subject suffers;
p.(None):
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None):
p.(None): (i) a direct benefit to the incapacitated subject outweighing the risks and burdens involved; or
p.(None):
p.(None): (ii) some benefit for the population represented by the incapacitated subject concerned when the clinical trial
p.(None): relates directly to the life-threatening or debilitating medical condition from which the subject suffers and such
p.(None): trial will pose only minimal risk to, and will impose minimal burden on, the incapacitated subject
...
p.(None):
p.(None): 2. Point (g)(ii) of paragraph 1 shall be without prejudice to more stringent national rules
p.(None): prohibiting the conduct of those clinical trials on incapacitated subjects, where there are no scientific
p.(None): grounds to expect that participation in the clinical trial will produce a direct benefit to the subject
p.(None): outweighing the risks and burdens involved.
p.(None):
p.(None): 3. The subject shall as far as possible take part in the informed consent procedure.
p.(None):
p.(None):
p.(None): Article 32
p.(None):
p.(None): Clinical trials on minors
p.(None):
p.(None): 1. A clinical trial on minors may be conducted only where, in addition to the conditions set out in
p.(None): Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the minors have received the information referred to in Article 29(2) in a way adapted to their
p.(None): age and mental maturity and from investigators or members of the investigating team who are trained or
p.(None): experienced in working with children;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/33
p.(None):
p.(None): (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information
p.(None): referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is
p.(None): respected by the investi gator;
p.(None): (d) no incentives or financial inducements are given to the subject or his or her legally designated
p.(None): representative except for compensation for expenses and loss of earnings directly related to the participation in the
p.(None): clinical trial;
p.(None): (e) the clinical trial is intended to investigate treatments for a medical condition that only occurs in
p.(None): minors or the clin ical trial is essential with respect to minors to validate data obtained in
p.(None): clinical trials on persons able to give informed consent or by other research methods;
p.(None): (f) the clinical trial either relates directly to a medical condition from which the minor concerned suffers or is
p.(None): of such a nature that it can only be carried out on minors;
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None): (i) a direct benefit for the minor concerned outweighing the risks and burdens involved; or
p.(None): (ii) some benefit for the population represented by the minor concerned and such a clinical trial will
p.(None): pose only minimal risk to, and will impose minimal burden on, the minor concerned in comparison with
...
p.(None): nature and the extent of the risk.
p.(None):
p.(None): 2. The sponsor and the investigator shall make use of the system referred to in paragraph 1 in
p.(None): the form appropriate for the Member State concerned where the clinical trial is conducted.
p.(None):
p.(None): 3. Member States shall not require any additional use of the system referred to in paragraph 1
p.(None): from the sponsor for low-intervention clinical trials, if any possible damage that could be suffered by
p.(None): a subject resulting from the use of the investigational medicinal product in accordance with the protocol
p.(None): of that specific clinical trial on the territory of that Member State is covered by the applicable
p.(None): compensation system already in place.
p.(None):
p.(None):
p.(None): CHAPTER XIII
p.(None):
p.(None): SUPERVISION BY MEMBER STATES, UNION INSPECTIONS AND CONTROLS
p.(None):
p.(None): Article 77
p.(None):
p.(None): Corrective measures to be taken by Member States
p.(None):
p.(None): 1. Where a Member State concerned has justified grounds for considering that the requirements set out in this
p.(None): Regu lation are no longer met, it may take the following measures on its territory:
p.(None): (a) revoke the authorisation of a clinical trial;
p.(None): (b) suspend a clinical trial;
p.(None): (c) require the sponsor to modify any aspect of the clinical trial.
p.(None): 2. Before the Member State concerned takes any of the measures referred to in paragraph 1 it
p.(None): shall, except where immediate action is required, ask the sponsor and/or the investigator for their
p.(None): opinion. That opinion shall be delivered within seven days.
p.(None):
p.(None): 3. The Member State concerned shall immediately after taking a measure referred to in paragraph 1
p.(None): inform all Member States concerned through the EU portal.
p.(None):
p.(None): 4. Each Member State concerned may consult the other Member States concerned before taking any of
p.(None): the measures referred to in paragraph 1.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/47
p.(None):
p.(None): Article 78
p.(None):
p.(None): Member State inspections
p.(None):
p.(None): 1. Member States shall appoint inspectors to perform inspections in order to supervise compliance
p.(None): with this Regu lation. They shall ensure that those inspectors are adequately qualified and trained.
p.(None):
p.(None): 2. Inspections shall be conducted under the responsibility of the Member State where the inspection takes place.
p.(None):
p.(None): 3. Where a Member State concerned intends to carry out an inspection on its territory or in a
p.(None): third country with regard to one or several clinical trials which are conducted in more than one Member State
p.(None): concerned, it shall notify its intention to the other Member States concerned, the Commission and the
p.(None): Agency, through the EU portal, and shall inform them of its findings after the inspection.
p.(None):
p.(None): 4. Inspections fees, if any, may be waived for non-commercial sponsors.
p.(None):
p.(None): 5. In order to efficiently use the resources available and to avoid duplications, the Agency shall
p.(None): coordinate the co operation between Member States concerned on inspections conducted in Member States, in third
...
p.(None): request of the Commission or a Member State.
p.(None):
p.(None): 5. The secretariat shall be provided by the Commission.
p.(None):
p.(None): 6. The CTAG shall draw up its rules of procedure. The rules of procedure shall be made public.
p.(None):
p.(None):
p.(None): CHAPTER XVI
p.(None):
p.(None): FEES
p.(None):
p.(None): Article 86
p.(None):
p.(None): General principle
p.(None):
p.(None): This Regulation shall be without prejudice to the possibility for Member States to levy a fee for the
p.(None): activities set out in this Regulation, provided that the level of the fee is set in a transparent
p.(None): manner and on the basis of cost recovery prin ciples. Member States may establish reduced fees for
p.(None): non-commercial clinical trials.
p.(None):
p.(None):
p.(None): Article 87
p.(None):
p.(None): One payment per activity per Member State
p.(None):
p.(None): A Member State shall not require, for an assessment as referred to in Chapters II and III, multiple
p.(None): payments to different bodies involved in this assessment.
p.(None):
p.(None):
p.(None): CHAPTER XVII
p.(None):
p.(None): IMPLEMENTING ACTS AND DELEGATED ACTS
p.(None):
p.(None): Article 88
p.(None):
p.(None): Committee procedure
p.(None):
p.(None): 1. The Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use established by
p.(None): Directive 2001/83/EC. That committee shall be a committee within the meaning of Regulation (EU) No 182/2011.
p.(None):
p.(None): 2. Where reference is made to this paragraph, Article 5 of Regulation (EU) No 182/2011 shall apply.
p.(None):
p.(None): Where the committee delivers no opinion, the Commission shall not adopt the draft implementing act and the third sub
p.(None): paragraph of Article 5(4) of Regulation (EU) No 182/2011 shall apply.
p.(None):
p.(None):
p.(None): Article 89
p.(None):
p.(None): Exercise of the delegation
p.(None):
p.(None): 1. The power to adopt delegated acts is conferred on the Commission subject to the conditions laid
p.(None): down in this Article.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/51
p.(None):
p.(None): 2. The power to adopt delegated acts referred to in Articles 27, 39, 45, 63(1) and 70 shall be
p.(None): conferred on the Commission for a period of five years from the date referred to in the second paragraph of Article
p.(None): 99. The Commission shall draw up a report in respect of the delegated powers not later than six months
p.(None): before the end of the five year period. The delegation of powers shall be tacitly extended for periods
p.(None): of an identical duration, unless the European Parliament or the Council opposes such extension not later than
p.(None): three months before the end of each period.
p.(None):
p.(None): 3. The delegation of power referred to in Articles 27, 39, 45, 63(1) and 70 may be revoked at any time by the
p.(None): Euro pean Parliament or by the Council. A decision of revocation shall put an end to the delegation of the power
p.(None): specified in that decision. It shall take effect the day following the publication of the decision in
p.(None): the Official Journal of the European Union or at a later date specified therein. It shall not affect the validity
p.(None): of any delegated acts already in force.
...
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): 1.3. IMPD in cases of placebo
p.(None):
p.(None):
p.(None):
p.(None): 54. If the investigational medicinal product is a placebo, the information requirements shall be limited
p.(None): to quality data. No additional documentation is required if the placebo has the same composition as the tested
p.(None): investiga tional medicinal product (with the exception of the active substance), is manufactured by the
p.(None): same manufac turer, and is not sterile.
p.(None):
p.(None): L 158/62 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): H. AUXILIARY MEDICINAL PRODUCT DOSSIER
p.(None):
p.(None): 55. Without prejudice to Article 65, the documentation requirements set out in sections F and G shall
p.(None): also apply to auxiliary medicinal products. However, where the auxiliary medicinal product is authorised
p.(None): in the Member State concerned, no additional information is required.
p.(None):
p.(None):
p.(None): I. SCIENTIFIC ADVICE AND PAEDIATRIC INVESTIGATION PLAN (PIP)
p.(None):
p.(None): 56. If available, a copy of the summary of scientific advice of the Agency, or of any Member State or third country,
p.(None): with regard to the clinical trial shall be submitted.
p.(None):
p.(None): 57. If the clinical trial is part of an agreed PIP, a copy of the Agency's decision on the agreement
p.(None): on the PIP, and the opinion of the Paediatric Committee, unless these documents are fully accessible
p.(None): via the internet shall be submitted. In the latter case, a link to this documentation in the cover letter is
p.(None): sufficient (see section B).
p.(None):
p.(None):
p.(None): J. CONTENT OF THE LABELLING OF THE INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): 58. A description of the content of the labelling of the investigational medicinal product in accordance
p.(None): with Annex VI shall be provided.
p.(None):
p.(None):
p.(None): K. RECRUITMENT ARRANGEMENTS (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 59. Unless described in the protocol, a separate document shall describe in detail the procedures for
p.(None): inclusion of subjects and shall provide a clear indication of what the first act of recruitment is.
p.(None):
p.(None): 60. Where the recruitment of subjects is done through advertisement, copies of the advertising material
p.(None): shall be submitted, including any printed materials, and audio or visual recordings. The procedures proposed for
p.(None): hand ling responses to the advertisement shall be outlined. This includes copies of communications used
p.(None): to invite subjects to participate in the clinical trial and arrangements for information or advice to the respondents
p.(None): found not to be suitable for inclusion in the clinical trial.
p.(None):
p.(None):
p.(None): L. SUBJECT INFORMATION, INFORMED CONSENT FORM AND INFORMED CONSENT PROCEDURE (INFORMATION PER
p.(None): MEMBER STATE CONCERNED)
p.(None):
p.(None): 61. All information given to the subjects (or, where applicable, to their legally designated
...
p.(None):
p.(None): G. PROOF OF PAYMENT OF FEE (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 9. Proof of payment shall be submitted, if applicable.
p.(None):
p.(None): L 158/66 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX III
p.(None):
p.(None): SAFETY REPORTING
p.(None):
p.(None): 1. REPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR TO THE SPONSOR
p.(None): 1. The investigator does not need to actively monitor subjects for adverse events once the clinical trial
p.(None): has ended with regard to the subjects treated by him, unless otherwise provided for in the protocol.
p.(None):
p.(None): 2. REPORTING OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) BY THE SPONSOR TO THE AGENCY
p.(None): IN ACCORDANCE WITH ARTICLE 42
p.(None): 2.1. Adverse Events and Causality
p.(None): 2. Medication errors, pregnancies and uses outside what is foreseen in the protocol, including misuse
p.(None): and abuse of the product, shall be subject to the same obligation to report as adverse reactions.
p.(None):
p.(None): 3. In determining whether an adverse event is an adverse reaction, consideration shall be given to
p.(None): whether there is a reasonable possibility of establishing a causal relationship between the event and the
p.(None): investigational medi cinal product based on an analysis of available evidence.
p.(None):
p.(None): 4. In the absence of information on causality provided by the reporting investigator, the sponsor shall consult the
p.(None): reporting investigator and encourage him to express an opinion on this issue. The causality assessment
p.(None): given by the investigator shall not be downgraded by the sponsor. If the sponsor disagrees with the
p.(None): investigator's causality assessment, the opinion of both the investigator and the sponsor shall be provided with the
p.(None): report.
p.(None):
p.(None): 2.2. Expectedness, unexpectedness and the RSI
p.(None): 5. In determining whether an adverse event is unexpected, consideration shall be given to whether the event adds
p.(None): significant information on the specificity, increase of occurrence, or severity of a known, already
p.(None): documented serious adverse reaction.
p.(None):
p.(None): 6. The expectedness of an adverse reaction shall be set out by the sponsor in the RSI. Expectedness shall be deter
p.(None): mined on the basis of events previously observed with the active substance and not on the basis of the
p.(None): antici pated pharmacological properties of a medicinal product or events related to the subject's disease.
p.(None):
p.(None): 7. The RSI shall be contained in the SmPC or the IB. The covering letter shall refer to the
p.(None): location of the RSI in the application dossier. If the investigational medicinal product is
p.(None): authorised in several Member States concerned with different SmPCs, the sponsor shall select the most
p.(None): appropriate SmPC, with reference to subject safety, as the RSI.
p.(None):
p.(None): 8. The RSI may change during the conduct of a clinical trial. For the purpose of reporting SUSARs the version of
p.(None): the RSI at the moment of occurrence of the SUSAR shall apply. Thus, a change of the RSI impacts on
p.(None): the number of adverse reactions to be reported as SUSARs. Regarding the applicable RSI for the purpose
p.(None): of the annual safety report, see section 3 of this Annex.
p.(None):
...
General/Other / Incapacitated
Searching for indicator incapacitated:
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p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
p.(None): (18) It should be left to the Member State concerned to determine the appropriate body or bodies
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
p.(None): ethics committees within the timelines for the authorisation of that clinical trial as set out in this
p.(None): Regulation. Such decisions are a matter of internal organisation for each Member State. When determining
p.(None): the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular
p.(None): patients or patients' organisations. They should also ensure that the necessary expertise is available. In
p.(None): accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons
p.(None): who collectively have the necessary qualifi cations and experience. The persons assessing the application
p.(None): should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free
p.(None): from any other undue influence.
p.(None):
p.(None):
p.(None): (19) The assessment of applications for the authorisation of clinical trials should be conducted on
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
p.(None): trials involving subjects in emer gency situations, minors, incapacitated subjects, pregnant and breastfeeding
p.(None): women and, where appropriate, other identified specific population groups, such as elderly people or people suffering
p.(None): from rare and ultra rare diseases.
p.(None):
p.(None):
p.(None): (20) In practice, sponsors do not always have all the information needed for submitting a complete
p.(None): application for authorisation of a clinical trial in all of the Member States where a clinical trial is
p.(None): eventually going to be conducted. It should be possible for sponsors to submit an application solely on the
p.(None): basis of documents assessed jointly by those Member States where the clinical trial might be conducted.
p.(None):
p.(None):
p.(None): (21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure
p.(None): the reli able functioning of the assessment procedure, however, an application for authorisation of a
p.(None): clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the
p.(None): sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an
p.(None): application.
p.(None):
p.(None): L 158/4 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (22) In practice, in order to reach recruitment targets or for other reasons, sponsors may have an interest in
...
p.(None): Organization (WHO ICTRP). Data providers to the WHO ICTRP create and manage clinical trial records in a manner
p.(None): that is consistent with the WHO registry criteria. Specific provision should be made for data from clinical
p.(None): trials started before the date of application of this Regulation.
p.(None):
p.(None):
p.(None): (26) It should be left to Member States to establish the language requirements for the application
p.(None): dossier. To ensure that the assessment of the application for authorisation of a clinical trial functions
p.(None): smoothly, Member States should consider accepting a commonly understood language in the medical field as
p.(None): the language for the docu mentation not destined for the subject.
p.(None):
p.(None):
p.(None): (27) Human dignity and the right to the integrity of the person are recognised in the Charter of
p.(None): Fundamental Rights of the European Union (the ‘Charter’). In particular, the Charter requires that any
p.(None): intervention in the field of biology and medicine cannot be performed without free and informed consent of the
p.(None): person concerned. Directive 2001/20/EC contains an extensive set of rules for the protection of subjects.
p.(None): These rules should be upheld. Regarding the rules concerning the determination of the legally
p.(None): designated representatives of incapacitated persons and minors, those rules diverge in Member States. It
p.(None): should therefore be left to Member States to deter mine the legally designated representatives of
p.(None): incapacitated persons and minors. Incapacitated subjects, minors, pregnant women and breastfeeding women require
p.(None): specific protection measures.
p.(None):
p.(None):
p.(None): (28) An appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner should be
p.(None): respon sible for all medical care provided to the subject, including the medical care provided by other medical staff.
p.(None):
p.(None):
p.(None): (29) It is appropriate that universities and other research institutions, under certain circumstances
p.(None): that are in accord ance with the applicable law on data protection, be able to collect data from
p.(None): clinical trials to be used for future scientific research, for example for medical, natural or social
p.(None): sciences research purposes. In order to collect data for such purposes it is necessary that the subject
p.(None): gives consent to use his or her data outside the protocol of the clinical trial and has the right to
p.(None): withdraw that consent at any time. It is also necessary that research projects based on such data be
p.(None): made subject to reviews that are appropriate for research on human data, for example on ethical aspects,
p.(None): before being conducted.
p.(None):
p.(None):
...
p.(None): notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to have a substantial
p.(None): impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the
p.(None): clinical trial;
p.(None):
p.(None): (14) ‘Sponsor’ means an individual, company, institution or organisation which takes responsibility for the
p.(None): initiation, for the management and for setting up the financing of the clinical trial;
p.(None):
p.(None): (1) Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy
p.(None): medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/13
p.(None):
p.(None): (15) ‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical trial site;
p.(None):
p.(None): (16) ‘Principal investigator’ means an investigator who is the responsible leader of a team of
p.(None): investigators who conduct a clinical trial at a clinical trial site;
p.(None):
p.(None): (17) ‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
p.(None): investigational medicinal product or as a control;
p.(None):
p.(None): (18) ‘Minor’ means a subject who is, according to the law of the Member State concerned, under the age of legal
p.(None): compe tence to give informed consent;
p.(None):
p.(None): (19) ‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal competence to give
p.(None): informed consent, incapable of giving informed consent according to the law of the Member State concerned;
p.(None):
p.(None): (20) ‘Legally designated representative’ means a natural or legal person, authority or body which,
p.(None): according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject
p.(None): who is an incapaci tated subject or a minor;
p.(None):
p.(None): (21) ‘Informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in
p.(None): a par ticular clinical trial, after having been informed of all aspects of the clinical trial that are
p.(None): relevant to the subject's decision to participate or, in case of minors and of incapacitated subjects, an
p.(None): authorisation or agreement from their legally designated representative to include them in the clinical trial;
p.(None):
p.(None): (22) ‘Protocol’ means a document that describes the objectives, design, methodology, statistical
p.(None): considerations and or ganisation of a clinical trial. The term ‘protocol’ encompasses successive versions
p.(None): of the protocol and protocol modifications;
p.(None):
p.(None): (23) ‘Investigator's brochure’ means a compilation of the clinical and non-clinical data on the
p.(None): investigational medicinal product or products which are relevant to the study of the product or products in humans;
p.(None):
p.(None): (24) ‘Manufacturing’ means total and partial manufacture, as well as the various processes of dividing up, packaging
p.(None): and labelling (including blinding);
p.(None):
p.(None): (25) ‘Start of a clinical trial’ means the first act of recruitment of a potential subject for a
p.(None): specific clinical trial, unless defined differently in the protocol;
p.(None):
p.(None): (26) ‘End of a clinical trial’ means the last visit of the last subject, or at a later point in time as defined in the
p.(None): protocol;
p.(None):
p.(None): (27) ‘Early termination of a clinical trial’ means the premature end of a clinical trial due to any reason before the
p.(None): condi tions specified in the protocol are complied with;
p.(None):
p.(None): (28) ‘Temporary halt of a clinical trial’ means an interruption not provided in the protocol of the
p.(None): conduct of a clinical trial by the sponsor with the intention of the sponsor to resume it;
p.(None):
p.(None): (29) ‘Suspension of a clinical trial’ means interruption of the conduct of a clinical trial by a Member State;
p.(None):
...
p.(None): contract research organisation's facilities, or at other establishments which the competent authority sees fit to
p.(None): inspect;
p.(None):
p.(None): L 158/14 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (32) ‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal product is
p.(None): administered and which does not necessarily have a causal relationship with this treatment;
p.(None): (33) ‘Serious adverse event’ means any untoward medical occurrence that at any dose requires inpatient
p.(None): hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability
p.(None): or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death;
p.(None): (34) ‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature, severity or outcome of which
p.(None): is not consistent with the reference safety information;
p.(None): (35) ‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
p.(None): format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
p.(None): accompanying an application for marketing authorisation.
p.(None): 3. For the purposes of this Regulation, a subject who falls under the definition of both ‘minor’
p.(None): and ‘incapacitated subject’ shall be deemed to be an incapacitated subject.
p.(None):
p.(None):
p.(None): Article 3
p.(None):
p.(None): General principle
p.(None):
p.(None): A clinical trial may be conducted only if:
p.(None): (a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and
p.(None): (b) it is designed to generate reliable and robust data.
p.(None):
p.(None):
p.(None): CHAPTER II
p.(None):
p.(None): AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL
p.(None):
p.(None): Article 4
p.(None):
p.(None): Prior authorisation
p.(None):
p.(None): A clinical trial shall be subject to scientific and ethical review and shall be authorised in accordance with this
p.(None): Regulation.
p.(None):
p.(None): The ethical review shall be performed by an ethics committee in accordance with the law of the Member
p.(None): State concerned. The review by the ethics committee may encompass aspects addressed in Part I of the
p.(None): assessment report for the authorisation of a clinical trial as referred to in Article 6 and in Part II
p.(None): of that assessment report as referred to in Article 7 as appropriate for each Member State concerned.
p.(None):
p.(None): Member States shall ensure that the timelines and procedures for the review by the ethics committees
p.(None): are compatible with the timelines and procedures set out in this Regulation for the assessment of the
p.(None): application for authorisation of a clinical trial.
p.(None):
p.(None):
p.(None): Article 5
p.(None):
p.(None): Submission of an application
p.(None):
p.(None): 1. In order to obtain an authorisation, the sponsor shall submit an application dossier to the intended Member
...
p.(None): conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators
p.(None): involved and of persons financing the clinical trial, as well as free of any other undue influence.
p.(None):
p.(None): In order to guarantee independence and transparency, the Member States shall ensure that persons
p.(None): admitting and asses sing the application as regards the aspects addressed in Parts I and II of the
p.(None): assessment report have no financial or personal interests which could affect their impartiality. These persons
p.(None): shall make an annual declaration of their financial interests.
p.(None):
p.(None): 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who
p.(None): collectively have the necessary qualifications and experience.
p.(None):
p.(None): 3. At least one layperson shall participate in the assessment.
p.(None):
p.(None):
p.(None): Article 10
p.(None):
p.(None): Specific considerations for vulnerable populations
p.(None):
p.(None): 1. Where the subjects are minors, specific consideration shall be given to the assessment of the
p.(None): application for authorisation of a clinical trial on the basis of paediatric expertise or after taking
p.(None): advice on clinical, ethical and psycho social problems in the field of paediatrics.
p.(None):
p.(None): L 158/20 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the
p.(None): applica tion for authorisation of a clinical trial on the basis of expertise in the relevant disease
p.(None): and the patient population concerned or after taking advice on clinical, ethical and psychosocial
p.(None): questions in the field of the relevant disease and the patient population concerned.
p.(None):
p.(None): 3. Where the subjects are pregnant or breastfeeding women, specific consideration shall be given to the
p.(None): assessment of the application for authorisation of a clinical trial on the basis of expertise in the relevant
p.(None): condition and the population represented by the subject concerned.
p.(None):
p.(None): 4. If according to the protocol a clinical trial provides for the participation of specific groups
p.(None): or subgroups of subjects, where appropriate, specific consideration shall be given to the assessment of
p.(None): the application for authorisation of that clinical trial on the basis of expertise in the population represented by
p.(None): the subjects concerned.
p.(None):
p.(None): 5. In any application for authorisation of a clinical trial referred to in Article 35, specific consideration
p.(None): shall be given to the circumstances of the conduct of the clinical trial.
p.(None):
p.(None):
p.(None): Article 11
p.(None):
p.(None): Submission and assessment of applications limited to aspects covered by Part I or Part II of the
p.(None): assessment report
p.(None):
p.(None): Where the sponsor so requests, the application for authorisation of a clinical trial, its assessment and
...
p.(None): qualified according to the law of the Member State concerned;
p.(None):
p.(None): (d) include information about the applicable damage compensation system referred to in Article 76(1); and
p.(None):
p.(None): (e) include the EU trial number and information about the availability of the clinical trial results
p.(None): in accordance with paragraph 6.
p.(None):
p.(None): 3. The information referred to in paragraph 2 shall be prepared in writing and be available to
p.(None): the subject or, where the subject is not able to give informed consent, his or her legally designated
p.(None): representative.
p.(None):
p.(None): 4. In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the
p.(None): information needs of specific patient populations and of individual subjects, as well as to the methods used to give
p.(None): the information.
p.(None):
p.(None): 5. In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood
p.(None): the infor mation.
p.(None):
p.(None): 6. The subject shall be informed that the summary of the results of the clinical trial and a
p.(None): summary presented in terms understandable to a layperson will be made available in the EU database,
p.(None): referred to in Article 81 (the ‘EU data base’), pursuant to Article 37(4), irrespective of the outcome
p.(None): of the clinical trial, and, to the extent possible, when the summaries become available.
p.(None):
p.(None): 7. This Regulation is without prejudice to national law requiring that both the signature of the
p.(None): incapacitated person and the signature of his or her legally designated representative may be required on the informed
p.(None): consent form.
p.(None):
p.(None): 8. This Regulation is without prejudice to national law requiring that, in addition to the informed
p.(None): consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing
p.(None): the information given to him or her, shall also assent in order to participate in a clinical trial.
p.(None):
p.(None):
p.(None): Article 30
p.(None):
p.(None): Informed consent in cluster trials
p.(None):
p.(None): 1. Where a clinical trial is to be conducted exclusively in one Member State, that Member State
p.(None): may, without preju dice to Article 35, and by way of derogation from points (b), (c), and (g) of
p.(None): Article 28(1), Article 29(1), point (c) of Article 29(2), Article 29(3), (4) and (5), points (a), (b) and (c) of
p.(None): Article 31(1) and points (a), (b) and (c) of Article 32(1), allow the investigator to obtain informed consent by
p.(None): the simplified means set out in paragraph 2 of this Article, provided that all of the conditions set out in
p.(None): paragraph 3 of this Article are fulfilled.
p.(None):
p.(None): 2. For clinical trials that fulfil the conditions set out in paragraph 3, informed consent shall be
p.(None): deemed to have been obtained if:
p.(None):
...
p.(None):
p.(None): 3. Informed consent may be obtained by the simplified means set out in paragraph 2, if all the
p.(None): following conditions are fulfilled:
p.(None):
p.(None): (a) the simplified means for obtaining informed consent do not contradict national law in the Member State concerned;
p.(None):
p.(None): (b) the methodology of the clinical trial requires that groups of subjects rather than individual
p.(None): subjects are allocated to receive different investigational medicinal products in a clinical trial;
p.(None):
p.(None): (c) the clinical trial is a low-intervention clinical trial and the investigational medicinal products
p.(None): are used in accordance with the terms of the marketing authorisation;
p.(None):
p.(None): L 158/32 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (d) there are no interventions other than the standard treatment of the subjects concerned;
p.(None):
p.(None): (e) the protocol justifies the reasons for obtaining informed consent with simplified means and
p.(None): describes the scope of information provided to the subjects, as well as the ways of providing information.
p.(None):
p.(None): 4. The investigator shall document all refusals and withdrawals and shall ensure that no data for
p.(None): the clinical trial are collected from subjects that refuse to participate in or have withdrawn from the clinical
p.(None): trial.
p.(None):
p.(None):
p.(None): Article 31
p.(None):
p.(None): Clinical trials on incapacitated subjects
p.(None):
p.(None): 1. In the case of incapacitated subjects who have not given, or have not refused to give, informed consent
p.(None): before the onset of their incapacity, a clinical trial may be conducted only where, in addition to the conditions set
p.(None): out in Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the incapacitated subjects have received the information referred to in Article 29(2) in a way that is adequate in
p.(None): view of their capacity to understand it;
p.(None):
p.(None): (c) the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing
p.(None): the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial
p.(None): at any time, is respected by the investigator;
p.(None):
p.(None): (d) no incentives or financial inducements are given to the subjects or their legally designated representatives,
p.(None): except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial;
p.(None):
p.(None): (e) the clinical trial is essential with respect to incapacitated subjects and data of comparable validity cannot be
p.(None): obtained in clinical trials on persons able to give informed consent, or by other research methods;
p.(None):
p.(None): (f) the clinical trial relates directly to a medical condition from which the subject suffers;
p.(None):
p.(None): (g) there are scientific grounds for expecting that participation in the clinical trial will produce:
p.(None):
p.(None): (i) a direct benefit to the incapacitated subject outweighing the risks and burdens involved; or
p.(None):
p.(None): (ii) some benefit for the population represented by the incapacitated subject concerned when the clinical trial
p.(None): relates directly to the life-threatening or debilitating medical condition from which the subject suffers and such
p.(None): trial will pose only minimal risk to, and will impose minimal burden on, the incapacitated subject
p.(None): concerned in com parison with the standard treatment of the incapacitated subject's condition.
p.(None):
p.(None): 2. Point (g)(ii) of paragraph 1 shall be without prejudice to more stringent national rules
p.(None): prohibiting the conduct of those clinical trials on incapacitated subjects, where there are no scientific
p.(None): grounds to expect that participation in the clinical trial will produce a direct benefit to the subject
p.(None): outweighing the risks and burdens involved.
p.(None):
p.(None): 3. The subject shall as far as possible take part in the informed consent procedure.
p.(None):
p.(None):
p.(None): Article 32
p.(None):
p.(None): Clinical trials on minors
p.(None):
p.(None): 1. A clinical trial on minors may be conducted only where, in addition to the conditions set out in
p.(None): Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the minors have received the information referred to in Article 29(2) in a way adapted to their
p.(None): age and mental maturity and from investigators or members of the investigating team who are trained or
p.(None): experienced in working with children;
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/33
p.(None):
p.(None): (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information
p.(None): referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial at any time, is
p.(None): respected by the investi gator;
...
p.(None): the diagnosis of its condition;
p.(None):
p.(None): (c) it is not possible within the therapeutic window to supply all prior information to and obtain
p.(None): prior informed consent from his or her legally designated representative;
p.(None):
p.(None): (d) the investigator certifies that he or she is not aware of any objections to participate in the
p.(None): clinical trial previously expressed by the subject;
p.(None):
p.(None): (e) the clinical trial relates directly to the subject's medical condition because of which it is not possible within
p.(None): the thera peutic window to obtain prior informed consent from the subject or from his or her legally designated
p.(None): representative and to supply prior information, and the clinical trial is of such a nature that it may
p.(None): be conducted exclusively in emergency situations;
p.(None):
p.(None): (f) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in
p.(None): comparison with the standard treatment of the subject's condition.
p.(None):
p.(None): 2. Following an intervention pursuant to paragraph 1, informed consent in accordance with Article 29
p.(None): shall be sought to continue the participation of the subject in the clinical trial, and information on
p.(None): the clinical trial shall be given, in accordance with the following requirements:
p.(None):
p.(None): (a) regarding incapacitated subjects and minors, the informed consent shall be sought by the
p.(None): investigator from his or her legally designated representative without undue delay and the information
p.(None): referred to in Article 29(2) shall be given as soon as possible to the subject and to his or her legally
p.(None): designated representative;
p.(None):
p.(None): (b) regarding other subjects, the informed consent shall be sought by the investigator without undue
p.(None): delay from the subject or his or her legally designated representative, whichever is sooner and the
p.(None): information referred to in Article 29(2) shall be given as soon as possible to the the subject or his
p.(None): or her legally designated representative, whichever is sooner.
p.(None):
p.(None): For the purposes of point (b), where informed consent has been obtained from the legally designated
p.(None): representative, informed consent to continue the participation in the clinical trial shall be obtained
p.(None): from the subject as soon as he or she is capable of giving informed consent.
p.(None):
p.(None): 3. If the subject or, where applicable, his or her legally designated representative does not give
p.(None): consent, he or she shall be informed of the right to object to the use of data obtained from the clinical trial.
p.(None):
p.(None):
p.(None): CHAPTER VI
p.(None):
p.(None): START, END, TEMPORARY HALT, AND EARLY TERMINATION OF A CLINICAL TRIAL
p.(None):
...
p.(None): quali tative and quantitative impurity profiles. The preparation of the test material shall be subject
p.(None): to the controls necessary to ensure this and thus support the validity of the study.
p.(None):
p.(None):
p.(None): Data from previous clinical trials and human experience
p.(None):
p.(None): 46. Data from previous clinical trials and human experience shall be submitted in a logical structure,
p.(None): such as that of Module 5 of the ICH Common Technical Document format.
p.(None):
p.(None): 47. This section shall provide summaries of all available data from previous clinical trials and human
p.(None): experience with the investigational medicinal products.
p.(None):
p.(None): It shall also contain a statement of the compliance with good clinical practice of those previous
p.(None): clinical trials, as well as a reference to the public entry referred to in Article 25(6).
p.(None):
p.(None):
p.(None): Overall risk and benefit assessment
p.(None):
p.(None): 48. This section shall provide a brief integrated summary that critically analyses the non-clinical and
p.(None): clinical data in relation to the potential risks and benefits of the investigational medicinal product in
p.(None): the proposed clinical trial unless this information is already provided in the protocol. In the latter case, it
p.(None): shall cross-refer to the rele vant section in the protocol. The text shall identify any studies that were
p.(None): terminated prematurely and discuss the reasons. Any evaluation of foreseeable risks and anticipated benefits for
p.(None): studies on minors or incapacitated adults shall take account of the specific provisions set out in this Regulation.
p.(None):
p.(None): 49. Where appropriate, safety margins shall be discussed in terms of relative systemic exposure to the
p.(None): investiga tional medicinal product, preferably based on ‘area under the curve’ (AUC) data, or peak
p.(None): concentration (Cmax) data, whichever is considered more relevant, rather than in terms of applied dose. The clinical
p.(None): relevance of any findings in the non-clinical and clinical studies along with any recommendations for
p.(None): further monitoring of effects and safety in the clinical trials shall also be discussed.
p.(None):
p.(None):
p.(None): 1.2. Simplified IMPD by referring to other documentation
p.(None):
p.(None): 50. The applicant may refer to other documentation submitted alone or with a simplified IMPD.
p.(None):
p.(None): Possibility of referring to the IB
p.(None):
p.(None): 51. The applicant may either provide a stand-alone IMPD or cross-refer to the IB for the reference
p.(None): safety informa tion and the summaries of pre-clinical and clinical parts of the IMPD. In the latter case, the
p.(None): summaries of pre- clinical information and clinical information shall include data, preferably in tables,
p.(None): providing sufficient detail to allow assessors to reach a decision on the potential toxicity of the investigational
p.(None): medicinal product and the safety of its use in the proposed clinical trial. If there is some special
p.(None): aspect of the pre-clinical data or clinical data that requires a detailed expert explanation or discussion beyond
p.(None): what would usually be included in the IB, the pre-clinical and clinical information shall be submitted as part of the
p.(None): IMPD.
p.(None):
p.(None):
...
p.(None): 59. Unless described in the protocol, a separate document shall describe in detail the procedures for
p.(None): inclusion of subjects and shall provide a clear indication of what the first act of recruitment is.
p.(None):
p.(None): 60. Where the recruitment of subjects is done through advertisement, copies of the advertising material
p.(None): shall be submitted, including any printed materials, and audio or visual recordings. The procedures proposed for
p.(None): hand ling responses to the advertisement shall be outlined. This includes copies of communications used
p.(None): to invite subjects to participate in the clinical trial and arrangements for information or advice to the respondents
p.(None): found not to be suitable for inclusion in the clinical trial.
p.(None):
p.(None):
p.(None): L. SUBJECT INFORMATION, INFORMED CONSENT FORM AND INFORMED CONSENT PROCEDURE (INFORMATION PER
p.(None): MEMBER STATE CONCERNED)
p.(None):
p.(None): 61. All information given to the subjects (or, where applicable, to their legally designated
p.(None): representatives) before their decision to participate or abstain from participation shall be submitted together with
p.(None): the form for written informed consent, or other alternative means according to Article 29(1) for recording informed
p.(None): consent.
p.(None):
p.(None): 62. A description of procedures relating to informed consent for all subjects, and in particular:
p.(None):
p.(None): (a) in clinical trials with minors or incapacitated subjects, the procedures to obtain informed consent from the
p.(None): legally designated representatives, and the involvement of the minor or incapacitated subject shall be
p.(None): described;
p.(None):
p.(None): (b) if a procedure with consent witnessed by an impartial witness is to be used, relevant information
p.(None): on the reason for using an impartial witness, on the selection of the impartial witness and on the
p.(None): procedure for obtaining informed consent shall be provided;
p.(None):
p.(None): (c) in the case of clinical trials in emergency situations as referred to in Article 35, the procedure for obtaining
p.(None): the informed consent of the subject or the legally designated representative to continue the clinical
p.(None): trial shall be described;
p.(None):
p.(None): (d) in the case of clinical trials in emergency situations as referred to in Article 35, the description of the
p.(None): pro cedures followed to identify the urgency of the situation and to document it;
p.(None):
p.(None): (e) in the case of clinical trials where their methodology requires that groups of subjects rather than individual
p.(None): subjects are allocated to receive different investigational medicinal products, as referred to in Article
p.(None): 30, and where, as a consequence, simplified means for obtaining informed consent will be used, the simplified
p.(None): means shall be described.
p.(None):
p.(None): 63. In the cases set out in paragraph 62, the information given to the subject and to his or her
p.(None): legally designated representative shall be submitted.
p.(None):
p.(None): 27.5.2014 EN
...
Searching for indicator incapacity:
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p.(None):
p.(None): (30) ‘Good clinical practice’ means a set of detailed ethical and scientific quality requirements for designing,
p.(None): conducting, performing, monitoring, auditing, recording, analysing and reporting clinical trials ensuring
p.(None): that the rights, safety and well-being of subjects are protected, and that the data generated in the clinical trial
p.(None): are reliable and robust;
p.(None):
p.(None): (31) ‘Inspection’ means the act by a competent authority of conducting an official review of documents,
p.(None): facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority
p.(None): to be related to the clinical trial and that may be located at the clinical trial site, at the sponsor's and/or
p.(None): contract research organisation's facilities, or at other establishments which the competent authority sees fit to
p.(None): inspect;
p.(None):
p.(None): L 158/14 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (32) ‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal product is
p.(None): administered and which does not necessarily have a causal relationship with this treatment;
p.(None): (33) ‘Serious adverse event’ means any untoward medical occurrence that at any dose requires inpatient
p.(None): hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability
p.(None): or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death;
p.(None): (34) ‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature, severity or outcome of which
p.(None): is not consistent with the reference safety information;
p.(None): (35) ‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
p.(None): format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
p.(None): accompanying an application for marketing authorisation.
p.(None): 3. For the purposes of this Regulation, a subject who falls under the definition of both ‘minor’
p.(None): and ‘incapacitated subject’ shall be deemed to be an incapacitated subject.
p.(None):
p.(None):
p.(None): Article 3
p.(None):
p.(None): General principle
p.(None):
p.(None): A clinical trial may be conducted only if:
p.(None): (a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests; and
p.(None): (b) it is designed to generate reliable and robust data.
p.(None):
p.(None):
p.(None): CHAPTER II
p.(None):
p.(None): AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL
p.(None):
p.(None): Article 4
p.(None):
p.(None): Prior authorisation
p.(None):
p.(None): A clinical trial shall be subject to scientific and ethical review and shall be authorised in accordance with this
p.(None): Regulation.
p.(None):
...
p.(None): subjects are allocated to receive different investigational medicinal products in a clinical trial;
p.(None):
p.(None): (c) the clinical trial is a low-intervention clinical trial and the investigational medicinal products
p.(None): are used in accordance with the terms of the marketing authorisation;
p.(None):
p.(None): L 158/32 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (d) there are no interventions other than the standard treatment of the subjects concerned;
p.(None):
p.(None): (e) the protocol justifies the reasons for obtaining informed consent with simplified means and
p.(None): describes the scope of information provided to the subjects, as well as the ways of providing information.
p.(None):
p.(None): 4. The investigator shall document all refusals and withdrawals and shall ensure that no data for
p.(None): the clinical trial are collected from subjects that refuse to participate in or have withdrawn from the clinical
p.(None): trial.
p.(None):
p.(None):
p.(None): Article 31
p.(None):
p.(None): Clinical trials on incapacitated subjects
p.(None):
p.(None): 1. In the case of incapacitated subjects who have not given, or have not refused to give, informed consent
p.(None): before the onset of their incapacity, a clinical trial may be conducted only where, in addition to the conditions set
p.(None): out in Article 28, all of the following conditions are met:
p.(None):
p.(None): (a) the informed consent of their legally designated representative has been obtained;
p.(None):
p.(None): (b) the incapacitated subjects have received the information referred to in Article 29(2) in a way that is adequate in
p.(None): view of their capacity to understand it;
p.(None):
p.(None): (c) the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing
p.(None): the information referred to in Article 29(2) to refuse participation in, or to withdraw from, the clinical trial
p.(None): at any time, is respected by the investigator;
p.(None):
p.(None): (d) no incentives or financial inducements are given to the subjects or their legally designated representatives,
p.(None): except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial;
p.(None):
p.(None): (e) the clinical trial is essential with respect to incapacitated subjects and data of comparable validity cannot be
p.(None): obtained in clinical trials on persons able to give informed consent, or by other research methods;
p.(None):
...
General/Other / Natural Hazards
Searching for indicator hazard:
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p.(None): it is appropriate to provide that there should be arrangements for traceability, storage, return and destruction of
p.(None): investigational medi cinal products, depending on the nature of the clinical trial. For the same reasons,
p.(None): there should also be such arrangements for unauthorised auxiliary medicinal products.
p.(None):
p.(None):
p.(None): (47) During a clinical trial, a sponsor may become aware of serious breaches of the rules for the conduct of
p.(None): that clin ical trial. This should be reported to the Member States concerned in order for action to be
p.(None): taken by those Member States, where necessary.
p.(None):
p.(None):
p.(None): (48) Apart from the reporting of suspected unexpected serious adverse reactions, there may be other events which
p.(None): are relevant in terms of benefit-risk balance and which should be reported in a timely manner to the
p.(None): Member States concerned. It is important for subject safety that, in addition to serious adverse events
p.(None): and reactions, all unex pected events that might materially influence the benefit-risk assessment of the
p.(None): medicinal product or that would lead to changes in the administration of a medicinal product or in
p.(None): overall conduct of a clinical trial are notified to the Member States concerned. Examples of such
p.(None): unexpected events include an increase in the rate of occur rence of expected serious adverse reactions
p.(None): which may be clinically important, a significant hazard to the patient population, such as lack of efficacy
p.(None): of a medicinal product, or a major safety finding from a newly completed animal study (such as
p.(None): carcinogenicity).
p.(None):
p.(None):
p.(None): (49) Where unexpected events require an urgent modification of a clinical trial, it should be
p.(None): possible for the sponsor and the investigator to take urgent safety measures without awaiting prior authorisation.
p.(None): If such measures consti tute a temporary halt of the clinical trial, the sponsor should apply for a substantial
p.(None): modification before restarting the clinical trial.
p.(None):
p.(None):
p.(None): (50) In order to ensure compliance of the conduct of a clinical trial with the protocol, and in
p.(None): order for investigators to be informed about the investigational medicinal products they administer, the sponsor
p.(None): should supply the inves tigators with an investigator's brochure.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/7
p.(None):
p.(None): (51) The information generated in a clinical trial should be recorded, handled and stored adequately
p.(None): for the purpose of ensuring subject rights and safety, the robustness and reliability of the data generated in the
p.(None): clinical trial, accu rate reporting and interpretation, effective monitoring by the sponsor and effective inspection
p.(None): by Member States.
p.(None):
p.(None):
p.(None): (52) In order to be able to demonstrate compliance with the protocol and with this Regulation, a
p.(None): clinical trial master file, containing relevant documentation to allow effective supervision (monitoring by
...
General/Other / Public Emergency
Searching for indicator emergency:
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p.(None): participating in clinical trials and in particular when the clinical trial does not have the potential
p.(None): to produce results of direct benefit to her or to her embryo, foetus or child after birth.
p.(None):
p.(None):
p.(None): (35) Persons performing mandatory military service, persons deprived of liberty, persons who, due to
p.(None): a judicial deci sion, cannot take part in clinical trials, and persons, who due to their age,
p.(None): disability or state of health are reliant on care and for that reason accommodated in residential care
p.(None): institutions, that is accommodations providing an uninterrupted assistance for persons who necessitate such
p.(None): assistance, are in a situation of subordination or factual dependency and therefore may require specific protective
p.(None): measures. Member States should be allowed to maintain such additional measures.
p.(None):
p.(None):
p.(None): (36) This Regulation should provide for clear rules concerning informed consent in emergency
p.(None): situations. Such situ ations relate to cases where for example a patient has suffered a sudden life-threatening
p.(None): medical condition due to multiple traumas, strokes or heart attacks, necessitating immediate medical intervention.
p.(None): For such cases, interven tion within an ongoing clinical trial, which has already been approved, may be
p.(None): pertinent. However, in certain emergency situations, it is not possible to obtain informed consent prior
p.(None): to the intervention. This Regulation should therefore set clear rules whereby such patients may be enrolled in the
p.(None): clinical trial under very strict condi tions. In addition, the said clinical trial should relate directly
p.(None): to the medical condition because of which it is not possible within the therapeutic window to obtain
p.(None): prior informed consent from the subject or from his or her legally designated representative. Any
p.(None): previously expressed objection by the patient should be respected, and informed consent from the subject
p.(None): or from his or her legally designated representative should be sought as soon as possible.
p.(None):
p.(None):
p.(None): (37) In order to allow patients to assess possibilities to participate in a clinical trial, and to allow for
p.(None): effective supervi sion of a clinical trial by the Member State concerned, the start of the clinical trial, the end
p.(None): of the recruitment of subjects for the clinical trial and the end of the clinical trial should be
p.(None): notified. In accordance with international standards, the results of the clinical trial should be reported within
p.(None): one year from the end of the clinical trial.
p.(None):
p.(None):
p.(None): (38) The date of the first act of recruitment of a potential subject is the date on which the first act of
p.(None): the recruitment strategy described in the protocol was performed, e. g. the date of a contact with a
...
p.(None): breastfeeding woman concerned, her embryo, foetus or child after birth;
p.(None): (c) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse
p.(None): impact on the health of the child; and
p.(None): (d) no incentives or financial inducements are given to the subject except for compensation for expenses
p.(None): and loss of earnings directly related to the participation in the clinical trial.
p.(None):
p.(None):
p.(None): Article 34
p.(None):
p.(None): Additional national measures
p.(None):
p.(None): Member States may maintain additional measures regarding persons performing mandatory military service,
p.(None): persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical
p.(None): trials, or persons in residential care institutions.
p.(None):
p.(None): L 158/34 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): Article 35
p.(None):
p.(None): Clinical trials in emergency situations
p.(None):
p.(None): 1. By way of derogation from points (b) and (c) of Article 28(1), from points (a) and (b) of
p.(None): Article 31(1) and from points (a) and (b) of Article 32(1), informed consent to participate in a
p.(None): clinical trial may be obtained, and information on the clinical trial may be given, after the decision to
p.(None): include the subject in the clinical trial, provided that this decision is taken at the time of the first
p.(None): intervention on the subject, in accordance with the protocol for that clinical trial" and that all of the
p.(None): following conditions are fulfilled:
p.(None):
p.(None): (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious
p.(None): medical condition, the subject is unable to provide prior informed consent and to receive prior information on the
p.(None): clinical trial;
p.(None):
p.(None): (b) there are scientific grounds to expect that participation of the subject in the clinical trial will
p.(None): have the potential to produce a direct clinically relevant benefit for the subject resulting in a
p.(None): measurable health-related improvement alle viating the suffering and/or improving the health of the subject, or in
p.(None): the diagnosis of its condition;
p.(None):
p.(None): (c) it is not possible within the therapeutic window to supply all prior information to and obtain
p.(None): prior informed consent from his or her legally designated representative;
p.(None):
p.(None): (d) the investigator certifies that he or she is not aware of any objections to participate in the
p.(None): clinical trial previously expressed by the subject;
p.(None):
p.(None): (e) the clinical trial relates directly to the subject's medical condition because of which it is not possible within
p.(None): the thera peutic window to obtain prior informed consent from the subject or from his or her legally designated
p.(None): representative and to supply prior information, and the clinical trial is of such a nature that it may
p.(None): be conducted exclusively in emergency situations;
p.(None):
p.(None): (f) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in
p.(None): comparison with the standard treatment of the subject's condition.
p.(None):
p.(None): 2. Following an intervention pursuant to paragraph 1, informed consent in accordance with Article 29
p.(None): shall be sought to continue the participation of the subject in the clinical trial, and information on
p.(None): the clinical trial shall be given, in accordance with the following requirements:
p.(None):
p.(None): (a) regarding incapacitated subjects and minors, the informed consent shall be sought by the
p.(None): investigator from his or her legally designated representative without undue delay and the information
p.(None): referred to in Article 29(2) shall be given as soon as possible to the subject and to his or her legally
p.(None): designated representative;
p.(None):
p.(None): (b) regarding other subjects, the informed consent shall be sought by the investigator without undue
p.(None): delay from the subject or his or her legally designated representative, whichever is sooner and the
p.(None): information referred to in Article 29(2) shall be given as soon as possible to the the subject or his
p.(None): or her legally designated representative, whichever is sooner.
p.(None):
p.(None): For the purposes of point (b), where informed consent has been obtained from the legally designated
...
p.(None): MEMBER STATE CONCERNED)
p.(None):
p.(None): 61. All information given to the subjects (or, where applicable, to their legally designated
p.(None): representatives) before their decision to participate or abstain from participation shall be submitted together with
p.(None): the form for written informed consent, or other alternative means according to Article 29(1) for recording informed
p.(None): consent.
p.(None):
p.(None): 62. A description of procedures relating to informed consent for all subjects, and in particular:
p.(None):
p.(None): (a) in clinical trials with minors or incapacitated subjects, the procedures to obtain informed consent from the
p.(None): legally designated representatives, and the involvement of the minor or incapacitated subject shall be
p.(None): described;
p.(None):
p.(None): (b) if a procedure with consent witnessed by an impartial witness is to be used, relevant information
p.(None): on the reason for using an impartial witness, on the selection of the impartial witness and on the
p.(None): procedure for obtaining informed consent shall be provided;
p.(None):
p.(None): (c) in the case of clinical trials in emergency situations as referred to in Article 35, the procedure for obtaining
p.(None): the informed consent of the subject or the legally designated representative to continue the clinical
p.(None): trial shall be described;
p.(None):
p.(None): (d) in the case of clinical trials in emergency situations as referred to in Article 35, the description of the
p.(None): pro cedures followed to identify the urgency of the situation and to document it;
p.(None):
p.(None): (e) in the case of clinical trials where their methodology requires that groups of subjects rather than individual
p.(None): subjects are allocated to receive different investigational medicinal products, as referred to in Article
p.(None): 30, and where, as a consequence, simplified means for obtaining informed consent will be used, the simplified
p.(None): means shall be described.
p.(None):
p.(None): 63. In the cases set out in paragraph 62, the information given to the subject and to his or her
p.(None): legally designated representative shall be submitted.
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/63
p.(None):
p.(None): M. SUITABILITY OF THE INVESTIGATOR (INFORMATION PER MEMBER STATE CONCERNED)
p.(None):
p.(None): 64. A list of the planned clinical trial sites, the name and position of the principal investigators
p.(None): and the planned number of subjects at the sites shall be submitted.
p.(None):
p.(None): 65. Description of the qualification of the investigators in a current curriculum vitae and other relevant
p.(None): documents shall be submitted. Any previous training in the principles of good clinical practice or
p.(None): experience obtained from work with clinical trials and patient care shall be described.
p.(None):
p.(None): 66. Any conditions, such as economic interests and institutional affiliations, that might influence the
...
p.(None): identifiers);
p.(None): 2. Name and contact details of the sponsor;
p.(None): 3. General information about the clinical trial (including where and when the trial was conducted, the main
p.(None): objectives of the trial and an explanation of the reasons for conducting it);
p.(None): 4. Population of subjects (including information on the number of subjects included in the trial in
p.(None): the Member State concerned, in the Union and in third countries; age group breakdown and gender
p.(None): breakdown; inclusion and exclu sion criteria);
p.(None): 5. Investigational medicinal products used;
p.(None): 6. Description of adverse reactions and their frequency;
p.(None): 7. Overall results of the clinical trial;
p.(None): 8. Comments on the outcome of the clinical trial;
p.(None): 9. Indication if follow up clinical trials are foreseen;
p.(None): 10. Indication where additional information could be found.
p.(None):
p.(None): L 158/72 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX VI
p.(None):
p.(None): LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): A. UNAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): A.1. General rules
p.(None):
p.(None): 1. The following particulars shall appear on the immediate and the outer packaging:
p.(None):
p.(None): (a) name, address and telephone number of the main contact for information on the product, clinical
p.(None): trial and emergency unblinding; this may be the sponsor, contract research organisation or investigator (for the
p.(None): purpose of this Annex this is referred to as the 'main contact');
p.(None):
p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
p.(None): both the unauthorised investigational medicinal product and the comparator or placebo;
p.(None):
p.(None): (c) pharmaceutical form, route of administration, quantity of dosage units;
p.(None):
p.(None): (d) the batch or code number identifying the contents and packaging operation;
p.(None):
p.(None): (e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None):
p.(None): (f) the subject identification number and/or the treatment number and, where relevant, the visit number;
p.(None):
p.(None): (g) the name of the investigator (if not included in (a) or (e));
p.(None):
p.(None): (h) directions for use (reference may be made to a leaflet or other explanatory document intended for
p.(None): the subject or person administering the product);
p.(None):
p.(None): (i) 'For clinical trial use only' or similar wording;
p.(None):
p.(None): (j) the storage conditions;
p.(None):
p.(None): (k) period of use (expiry date or re-test date as applicable), in month and year format and in a
p.(None): manner that avoids any ambiguity; and
p.(None):
...
General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.(None): medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121).
p.(None):
p.(None): 27.5.2014 EN
p.(None): Official Journal of the European Union
p.(None): L 158/13
p.(None):
p.(None): (15) ‘Investigator’ means an individual responsible for the conduct of a clinical trial at a clinical trial site;
p.(None):
p.(None): (16) ‘Principal investigator’ means an investigator who is the responsible leader of a team of
p.(None): investigators who conduct a clinical trial at a clinical trial site;
p.(None):
p.(None): (17) ‘Subject’ means an individual who participates in a clinical trial, either as recipient of an
p.(None): investigational medicinal product or as a control;
p.(None):
p.(None): (18) ‘Minor’ means a subject who is, according to the law of the Member State concerned, under the age of legal
p.(None): compe tence to give informed consent;
p.(None):
p.(None): (19) ‘Incapacitated subject’ means a subject who is, for reasons other than the age of legal competence to give
p.(None): informed consent, incapable of giving informed consent according to the law of the Member State concerned;
p.(None):
p.(None): (20) ‘Legally designated representative’ means a natural or legal person, authority or body which,
p.(None): according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject
p.(None): who is an incapaci tated subject or a minor;
p.(None):
p.(None): (21) ‘Informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in
p.(None): a par ticular clinical trial, after having been informed of all aspects of the clinical trial that are
p.(None): relevant to the subject's decision to participate or, in case of minors and of incapacitated subjects, an
p.(None): authorisation or agreement from their legally designated representative to include them in the clinical trial;
p.(None):
p.(None): (22) ‘Protocol’ means a document that describes the objectives, design, methodology, statistical
p.(None): considerations and or ganisation of a clinical trial. The term ‘protocol’ encompasses successive versions
p.(None): of the protocol and protocol modifications;
p.(None):
p.(None): (23) ‘Investigator's brochure’ means a compilation of the clinical and non-clinical data on the
p.(None): investigational medicinal product or products which are relevant to the study of the product or products in humans;
p.(None):
p.(None): (24) ‘Manufacturing’ means total and partial manufacture, as well as the various processes of dividing up, packaging
p.(None): and labelling (including blinding);
p.(None):
p.(None): (25) ‘Start of a clinical trial’ means the first act of recruitment of a potential subject for a
p.(None): specific clinical trial, unless defined differently in the protocol;
p.(None):
p.(None): (26) ‘End of a clinical trial’ means the last visit of the last subject, or at a later point in time as defined in the
p.(None): protocol;
p.(None):
p.(None): (27) ‘Early termination of a clinical trial’ means the premature end of a clinical trial due to any reason before the
p.(None): condi tions specified in the protocol are complied with;
p.(None):
p.(None): (28) ‘Temporary halt of a clinical trial’ means an interruption not provided in the protocol of the
p.(None): conduct of a clinical trial by the sponsor with the intention of the sponsor to resume it;
p.(None):
p.(None): (29) ‘Suspension of a clinical trial’ means interruption of the conduct of a clinical trial by a Member State;
p.(None):
p.(None): (30) ‘Good clinical practice’ means a set of detailed ethical and scientific quality requirements for designing,
p.(None): conducting, performing, monitoring, auditing, recording, analysing and reporting clinical trials ensuring
p.(None): that the rights, safety and well-being of subjects are protected, and that the data generated in the clinical trial
p.(None): are reliable and robust;
p.(None):
p.(None): (31) ‘Inspection’ means the act by a competent authority of conducting an official review of documents,
p.(None): facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority
p.(None): to be related to the clinical trial and that may be located at the clinical trial site, at the sponsor's and/or
p.(None): contract research organisation's facilities, or at other establishments which the competent authority sees fit to
p.(None): inspect;
p.(None):
p.(None): L 158/14 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (32) ‘Adverse event’ means any untoward medical occurrence in a subject to whom a medicinal product is
p.(None): administered and which does not necessarily have a causal relationship with this treatment;
p.(None): (33) ‘Serious adverse event’ means any untoward medical occurrence that at any dose requires inpatient
p.(None): hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability
p.(None): or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death;
p.(None): (34) ‘Unexpected serious adverse reaction’ means a serious adverse reaction, the nature, severity or outcome of which
p.(None): is not consistent with the reference safety information;
p.(None): (35) ‘Clinical study report’ means a report on the clinical trial presented in an easily searchable
p.(None): format, prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and
p.(None): accompanying an application for marketing authorisation.
p.(None): 3. For the purposes of this Regulation, a subject who falls under the definition of both ‘minor’
p.(None): and ‘incapacitated subject’ shall be deemed to be an incapacitated subject.
p.(None):
p.(None):
p.(None): Article 3
p.(None):
p.(None): General principle
p.(None):
...
General/Other / Undue Influence
Searching for indicator undue influence:
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p.(None): sufficient time for assessing the additional information submitted.
p.(None):
p.(None):
p.(None): (17) The authorisation to conduct a clinical trial should address all aspects of subject protection
p.(None): and data reliability and robustness. That authorisation should therefore be contained in a single
p.(None): administrative decision by the Member State concerned.
p.(None):
p.(None):
p.(None): (18) It should be left to the Member State concerned to determine the appropriate body or bodies
p.(None): to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of
p.(None): ethics committees within the timelines for the authorisation of that clinical trial as set out in this
p.(None): Regulation. Such decisions are a matter of internal organisation for each Member State. When determining
p.(None): the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular
p.(None): patients or patients' organisations. They should also ensure that the necessary expertise is available. In
p.(None): accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons
p.(None): who collectively have the necessary qualifi cations and experience. The persons assessing the application
p.(None): should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free
p.(None): from any other undue influence.
p.(None):
p.(None):
p.(None): (19) The assessment of applications for the authorisation of clinical trials should be conducted on
p.(None): the basis of appro priate expertise. Specific expertise should be considered when assessing clinical
p.(None): trials involving subjects in emer gency situations, minors, incapacitated subjects, pregnant and breastfeeding
p.(None): women and, where appropriate, other identified specific population groups, such as elderly people or people suffering
p.(None): from rare and ultra rare diseases.
p.(None):
p.(None):
p.(None): (20) In practice, sponsors do not always have all the information needed for submitting a complete
p.(None): application for authorisation of a clinical trial in all of the Member States where a clinical trial is
p.(None): eventually going to be conducted. It should be possible for sponsors to submit an application solely on the
p.(None): basis of documents assessed jointly by those Member States where the clinical trial might be conducted.
p.(None):
p.(None):
p.(None): (21) The sponsor should be allowed to withdraw the application for authorisation of a clinical trial. To ensure
p.(None): the reli able functioning of the assessment procedure, however, an application for authorisation of a
p.(None): clinical trial should be withdrawn only for the entire clinical trial. It should be possible for the
p.(None): sponsor to submit a new application for authorisation of a clinical trial following the withdrawal of an
p.(None): application.
p.(None):
...
p.(None):
p.(None): 6. Where the Member State concerned has not notified the sponsor of its decision within the relevant periods
p.(None): referred to in paragraph 1, the conclusion on Part I of the assessment report shall be deemed to be the
p.(None): decision of the Member State concerned on the application for authorisation of the clinical trial.
p.(None):
p.(None): 7. The Member States concerned shall not request additional information regarding the aspects addressed
p.(None): in Part I of the assessment report from the sponsor after the reporting date.
p.(None):
p.(None): 8. For the purposes of this Chapter, the notification date shall be the date on which the
p.(None): decision referred to in para graph 1 is notified to the sponsor. Where the sponsor has not been notified in
p.(None): accordance with paragraph 1, the notifi cation date shall be deemed to be the last day of the period provided for in
p.(None): paragraph 1.
p.(None):
p.(None): 9. If no subject has been included in the clinical trial in a Member State concerned within two years from the
p.(None): notifica tion date of the authorisation, the authorisation shall expire in that Member State concerned
p.(None): unless an extension, on request of the sponsor, has been approved following the procedure set out in Chapter III.
p.(None):
p.(None):
p.(None): Article 9
p.(None):
p.(None): Persons assessing the application
p.(None):
p.(None): 1. Member States shall ensure that the persons validating and assessing the application do not have
p.(None): conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators
p.(None): involved and of persons financing the clinical trial, as well as free of any other undue influence.
p.(None):
p.(None): In order to guarantee independence and transparency, the Member States shall ensure that persons
p.(None): admitting and asses sing the application as regards the aspects addressed in Parts I and II of the
p.(None): assessment report have no financial or personal interests which could affect their impartiality. These persons
p.(None): shall make an annual declaration of their financial interests.
p.(None):
p.(None): 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who
p.(None): collectively have the necessary qualifications and experience.
p.(None):
p.(None): 3. At least one layperson shall participate in the assessment.
p.(None):
p.(None):
p.(None): Article 10
p.(None):
p.(None): Specific considerations for vulnerable populations
p.(None):
p.(None): 1. Where the subjects are minors, specific consideration shall be given to the assessment of the
p.(None): application for authorisation of a clinical trial on the basis of paediatric expertise or after taking
p.(None): advice on clinical, ethical and psycho social problems in the field of paediatrics.
p.(None):
p.(None): L 158/20 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 2. Where the subjects are incapacitated subjects, specific consideration shall be given to the assessment of the
p.(None): applica tion for authorisation of a clinical trial on the basis of expertise in the relevant disease
p.(None): and the patient population concerned or after taking advice on clinical, ethical and psychosocial
...
p.(None):
p.(None): L 158/30 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (c) the subjects, or where a subject is not able to give informed consent, his or her legally
p.(None): designated representative, have given informed consent in accordance with Article 29(1), (7) and (8);
p.(None):
p.(None): (d) the rights of the subjects to physical and mental integrity, to privacy and to the protection of
p.(None): the data concerning them in accordance with Directive 95/46/EC are safeguarded;
p.(None):
p.(None): (e) the clinical trial has been designed to involve as little pain, discomfort, fear and any other foreseeable risk
p.(None): as possible for the subjects and both the risk threshold and the degree of distress are specifically
p.(None): defined in the protocol and constantly monitored;
p.(None): (f) the medical care provided to the subjects is the responsibility of an appropriately qualified medical
p.(None): doctor or, where appropriate, a qualified dental practitioner;
p.(None):
p.(None): (g) the subject or, where the subject is not able to give informed consent, his or her legally designated
p.(None): representative has been provided with the contact details of an entity where further information can be received in
p.(None): case of need;
p.(None): (h) no undue influence, including that of a financial nature, is exerted on subjects to participate in the clinical
p.(None): trial.
p.(None): 2. Without prejudice to Directive 95/46/EC, the sponsor may ask the subject or, where the subject is not able to
p.(None): give informed consent, his or her legally designated representative at the time when the subject or the
p.(None): legally designated representative gives his or her informed consent to participate in the clinical trial to consent to
p.(None): the use of his or her data outside the protocol of the clinical trial exclusively for scientific purposes.
p.(None): That consent may be withdrawn at any time by the subject or his or her legally designated representative.
p.(None):
p.(None): The scientific research making use of the data outside the protocol of the clinical trial shall be
p.(None): conducted in accordance with the applicable law on data protection.
p.(None):
p.(None): 3. Any subject, or, where the subject is not able to give informed consent, his or her legally designated
p.(None): representative, may, without any resulting detriment and without having to provide any justification, withdraw from
p.(None): the clinical trial at any time by revoking his or her informed consent. Without prejudice to Directive
p.(None): 95/46/EC, the withdrawal of the informed consent shall not affect the activities already carried out and
...
General/Other / participants in a control group
Searching for indicator placebo:
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p.(None): to include the subject in the clinical study; or
p.(None): (c) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.
p.(None):
p.(None): (1) OJ C 253, 3.9.2013, p. 10.
p.(None):
p.(None): L 158/12 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): (3) ‘Low-intervention clinical trial’ means a clinical trial which fulfils all of the following conditions:
p.(None):
p.(None): (a) the investigational medicinal products, excluding placebos, are authorised;
p.(None):
p.(None): (b) according to the protocol of the clinical trial,
p.(None):
p.(None): (i) the investigational medicinal products are used in accordance with the terms of the marketing
p.(None): authorisa tion; or
p.(None):
p.(None): (ii) the use of the investigational medicinal products is evidence-based and supported by published
p.(None): scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member
p.(None): States concerned; and
p.(None):
p.(None): (c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or
p.(None): burden to the safety of the subjects compared to normal clinical practice in any Member State concerned;
p.(None):
p.(None): (4) ‘Non-interventional study’ means a clinical study other than a clinical trial;
p.(None):
p.(None): (5) ‘Investigational medicinal product’ means a medicinal product which is being tested or used
p.(None): as a reference, including as a placebo, in a clinical trial;
p.(None):
p.(None): (6) ‘Normal clinical practice’ means the treatment regime typically followed to treat, prevent, or diagnose a
p.(None): disease or a disorder;
p.(None):
p.(None): (7) ‘Advanced therapy investigational medicinal product’ means an investigational medicinal product which
p.(None): is an advanced therapy medicinal product as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007 of
p.(None): the European Parliament and of the Council (1);
p.(None):
p.(None): (8) ‘Auxiliary medicinal product’ means a medicinal product used for the needs of a clinical trial
p.(None): as described in the protocol, but not as an investigational medicinal product;
p.(None):
p.(None): (9) ‘Authorised investigational medicinal product’ means a medicinal product authorised in accordance with
p.(None): Regulation (EC) No 726/2004 or in any Member State concerned in accordance with Directive 2001/83/EC,
p.(None): irrespective of changes to the labelling of the medicinal product, which is used as an investigational medicinal
p.(None): product;
p.(None):
p.(None): (10) ‘Authorised auxiliary medicinal product’ means a medicinal product authorised in accordance with
p.(None): Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC,
p.(None): irrespective of changes to the labelling of the medicinal product, which is used as an auxiliary medicinal product;
p.(None):
p.(None): (11) ‘Ethics committee’ means an independent body established in a Member State in accordance with the
p.(None): law of that Member State and empowered to give opinions for the purposes of this Regulation, taking
...
p.(None): in any event not later than seven days after the sponsor became aware of the reaction;
p.(None): (b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not
p.(None): later than 15 days after the sponsor became aware of the reaction;
p.(None): (c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or
p.(None): non- life threatening but which turns out to be fatal or life-threatening, as soon as possible and in
p.(None): any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening.
p.(None): Where necessary to ensure timely reporting, the sponsor may, in accordance with section 2.4 of Annex
p.(None): III, submit an initial incomplete report followed up by a complete report.
p.(None):
p.(None): L 158/38 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): 3. Where a sponsor, due to a lack of resources, does not have the possibility to report to the
p.(None): database referred to in Article 40(1) and the sponsor has the agreement of the Member State concerned,
p.(None): it may report to the Member State where the suspected unexpected serious adverse reaction occurred. That
p.(None): Member State shall report the suspected unex pected serious adverse reaction in accordance with paragraph 1 of
p.(None): this Article.
p.(None):
p.(None):
p.(None): Article 43
p.(None):
p.(None): Annual reporting by the sponsor to the Agency
p.(None):
p.(None): 1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually
p.(None): through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational
p.(None): medicinal product used in a clinical trial for which it is the sponsor.
p.(None):
p.(None): 2. In the case of a clinical trial involving the use of more than one investigational medicinal
p.(None): product, the sponsor may, if provided for in the protocol, submit a single safety report on all
p.(None): investigational medicinal products used in that clinical trial.
p.(None):
p.(None): 3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymised data.
p.(None):
p.(None): 4. The obligation referred to in paragraph 1 starts with the first authorisation of a clinical
p.(None): trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor
p.(None): with the investigational medicinal product.
p.(None):
p.(None):
p.(None): Article 44
p.(None):
p.(None): Assessment by Member States
p.(None):
p.(None): 1. The Agency shall, by electronic means, forward to the Member States concerned the information
p.(None): reported in accordance with Article 42 and 43.
p.(None):
p.(None): 2. Member States shall cooperate in assessing the information reported in accordance with Articles
p.(None): 42and 43. The Commission may, by means of implementing acts, set up and modify the rules on such
p.(None): cooperation. Those imple menting acts shall be adopted in accordance with the examination procedure referred to in
p.(None): Article 88(2).
p.(None):
...
p.(None):
p.(None):
p.(None): Yes Yes
p.(None):
p.(None): — no new data are available since last amendment to the clinical trial application,
p.(None): — new data are available since last amendment to the clinical trial application,
p.(None): — is used under different conditions
p.(None): Reference to previous submission
p.(None):
p.(None): New data New data New data
p.(None):
p.(None): If appropriate If appropriate If appropriate
p.(None):
p.(None): (S: Data relating to the active substance; P: Data relating to the investigational medicinal product; A: Additional
p.(None): information on Facilities and Equipment, Adventitious Agents Safety Evaluation, Novel Excipients, and Solvents for
p.(None): Reconstitution and Diluents)
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): 53. If the investigational medicinal product is defined in the protocol in terms of active substance or
p.(None): ATC code (see above, paragraph 18), the applicant may replace the IMPD by one representative SmPC for
p.(None): each active substance/active substance pertaining to that ATC group. Alternatively, the applicant may
p.(None): provide a collated document containing information equivalent to that in the representative SmPCs for each active
p.(None): substance that could be used as an investigational medicinal product in the clinical trial.
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None):
p.(None): 1.3. IMPD in cases of placebo
p.(None):
p.(None):
p.(None):
p.(None): 54. If the investigational medicinal product is a placebo, the information requirements shall be limited
p.(None): to quality data. No additional documentation is required if the placebo has the same composition as the tested
p.(None): investiga tional medicinal product (with the exception of the active substance), is manufactured by the
p.(None): same manufac turer, and is not sterile.
p.(None):
p.(None): L 158/62 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): H. AUXILIARY MEDICINAL PRODUCT DOSSIER
p.(None):
p.(None): 55. Without prejudice to Article 65, the documentation requirements set out in sections F and G shall
p.(None): also apply to auxiliary medicinal products. However, where the auxiliary medicinal product is authorised
p.(None): in the Member State concerned, no additional information is required.
p.(None):
p.(None):
p.(None): I. SCIENTIFIC ADVICE AND PAEDIATRIC INVESTIGATION PLAN (PIP)
p.(None):
p.(None): 56. If available, a copy of the summary of scientific advice of the Agency, or of any Member State or third country,
p.(None): with regard to the clinical trial shall be submitted.
p.(None):
p.(None): 57. If the clinical trial is part of an agreed PIP, a copy of the Agency's decision on the agreement
p.(None): on the PIP, and the opinion of the Paediatric Committee, unless these documents are fully accessible
p.(None): via the internet shall be submitted. In the latter case, a link to this documentation in the cover letter is
p.(None): sufficient (see section B).
p.(None):
p.(None):
p.(None): J. CONTENT OF THE LABELLING OF THE INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): 58. A description of the content of the labelling of the investigational medicinal product in accordance
...
p.(None): breakdown; inclusion and exclu sion criteria);
p.(None): 5. Investigational medicinal products used;
p.(None): 6. Description of adverse reactions and their frequency;
p.(None): 7. Overall results of the clinical trial;
p.(None): 8. Comments on the outcome of the clinical trial;
p.(None): 9. Indication if follow up clinical trials are foreseen;
p.(None): 10. Indication where additional information could be found.
p.(None):
p.(None): L 158/72 EN
p.(None): Official Journal of the European Union
p.(None): 27.5.2014
p.(None):
p.(None): ANNEX VI
p.(None):
p.(None): LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS
p.(None):
p.(None): A. UNAUTHORISED INVESTIGATIONAL MEDICINAL PRODUCTS
p.(None):
p.(None): A.1. General rules
p.(None):
p.(None): 1. The following particulars shall appear on the immediate and the outer packaging:
p.(None):
p.(None): (a) name, address and telephone number of the main contact for information on the product, clinical
p.(None): trial and emergency unblinding; this may be the sponsor, contract research organisation or investigator (for the
p.(None): purpose of this Annex this is referred to as the 'main contact');
p.(None):
p.(None): (b) the name of the substance and its strength or potency, and in the case of blind clinical trials the
p.(None): name of the substance is to appear with the name of the comparator or placebo on the packaging of
p.(None): both the unauthorised investigational medicinal product and the comparator or placebo;
p.(None):
p.(None): (c) pharmaceutical form, route of administration, quantity of dosage units;
p.(None):
p.(None): (d) the batch or code number identifying the contents and packaging operation;
p.(None):
p.(None): (e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not
p.(None): given elsewhere;
p.(None):
p.(None): (f) the subject identification number and/or the treatment number and, where relevant, the visit number;
p.(None):
p.(None): (g) the name of the investigator (if not included in (a) or (e));
p.(None):
p.(None): (h) directions for use (reference may be made to a leaflet or other explanatory document intended for
p.(None): the subject or person administering the product);
p.(None):
p.(None): (i) 'For clinical trial use only' or similar wording;
p.(None):
p.(None): (j) the storage conditions;
p.(None):
p.(None): (k) period of use (expiry date or re-test date as applicable), in month and year format and in a
p.(None): manner that avoids any ambiguity; and
p.(None):
p.(None): (l) 'Keep out of reach of children', except when the product is for use in trials where the product is not taken
p.(None): home by subjects.
p.(None):
p.(None): 2. Symbols or pictograms may be included to clarify certain information mentioned above. Additional
p.(None): informa tion, warnings or handling instructions may be displayed.
p.(None):
p.(None): 3. The address and telephone number of the main contact shall not be required to appear on the label if subjects have
p.(None): been given a leaflet or card which provides these details and have been instructed to keep this in
p.(None): their possession at all times.
p.(None):
p.(None):
...
Orphaned Trigger Words
p.(None): trial.
p.(None): 2. Without prejudice to Directive 95/46/EC, the sponsor may ask the subject or, where the subject is not able to
p.(None): give informed consent, his or her legally designated representative at the time when the subject or the
p.(None): legally designated representative gives his or her informed consent to participate in the clinical trial to consent to
p.(None): the use of his or her data outside the protocol of the clinical trial exclusively for scientific purposes.
p.(None): That consent may be withdrawn at any time by the subject or his or her legally designated representative.
p.(None):
p.(None): The scientific research making use of the data outside the protocol of the clinical trial shall be
p.(None): conducted in accordance with the applicable law on data protection.
p.(None):
p.(None): 3. Any subject, or, where the subject is not able to give informed consent, his or her legally designated
p.(None): representative, may, without any resulting detriment and without having to provide any justification, withdraw from
p.(None): the clinical trial at any time by revoking his or her informed consent. Without prejudice to Directive
p.(None): 95/46/EC, the withdrawal of the informed consent shall not affect the activities already carried out and
p.(None): the use of data obtained based on informed consent before its withdrawal.
p.(None):
p.(None):
p.(None): Article 29
p.(None):
p.(None): Informed consent
p.(None):
p.(None): 1. Informed consent shall be written, dated and signed by the person performing the interview referred to in
p.(None): point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed
p.(None): consent, his or her legally desig nated representative after having been duly informed in accordance
p.(None): with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate
p.(None): alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and
p.(None): date the informed consent document. The subject or, where the subject is not able to give informed
p.(None): consent, his or her legally designated representative shall be provided with a copy of the document (or
p.(None): the record) by which informed consent has been given. The informed consent shall be documented. Adequate
p.(None): time shall be given for the subject or his or her legally designated representative to consider his or her decision to
p.(None): participate in the clinical trial.
p.(None):
p.(None): 2. Information given to the subject or, where the subject is not able to give informed consent, his or her
p.(None): legally desig nated representative for the purposes of obtaining his or her informed consent shall:
p.(None): (a) enable the subject or his or her legally designated representative to understand:
p.(None): (i) the nature, objectives, benefits, implications, risks and inconveniences of the clinical trial;
p.(None): (ii) the subject's rights and guarantees regarding his or her protection, in particular his or her
p.(None): right to refuse to participate and the right to withdraw from the clinical trial at any time without
p.(None): any resulting detriment and without having to provide any justification;
p.(None):
p.(None): (iii) the conditions under which the clinical trial is to be conducted, including the expected duration of
p.(None): the subject's participation in the clinical trial; and
p.(None):
p.(None): (iv) the possible treatment alternatives, including the follow-up measures if the participation of the
p.(None): subject in the clinical trial is discontinued;
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| abuse | Victim of Abuse |
| access | Access to Social Goods |
| age | Age |
| authority | Relationship to Authority |
| breastfeeding | breastfeeding |
| child | Child |
| children | Child |
| criminal | criminal |
| dependency | Drug Dependence |
| disability | Mentally Disabled |
| education | education |
| elderly | Elderly |
| embryo | embryo |
| emergency | Public Emergency |
| family | Motherhood/Family |
| foetus | Fetus/Neonate |
| foetuses | Fetus/Neonate |
| gender | gender |
| hazard | Natural Hazards |
| healthy volunteers | Healthy People |
| home | Property Ownership |
| incapable | Mentally Incapacitated |
| incapacitated | Incapacitated |
| incapacity | Incapacitated |
| influence | Drug Usage |
| language | Linguistic Proficiency |
| liberty | Incarcerated |
| military | Soldier |
| minor | Youth/Minors |
| opinion | philosophical differences/differences of opinion |
| orphan | orphan |
| parent | parents |
| party | political affiliation |
| placebo | participants in a control group |
| pregnant | Pregnant |
| restricted | Incarcerated |
| single | Marital Status |
| substance | Drug Usage |
| undue influence | Undue Influence |
| union | Trade Union Membership |
| unlawful | Illegal Activity |
| vulnerable | vulnerable |
| women | Women |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| child | ['children'] |
| children | ['child'] |
| foetus | ['foetuses'] |
| foetuses | ['foetus'] |
| incapacitated | ['incapacity'] |
| incapacity | ['incapacitated'] |
| influence | ['substance'] |
| liberty | ['restricted'] |
| restricted | ['liberty'] |
| substance | ['influence'] |
Trigger Words
capacity
consent
ethics
protect
protection
risk
Applicable Type / Vulnerability / Indicator Overlay for this Input