Decree 35/2005 (VIII. 26.) of the Minister of Health on the clinical trial of investigational medicinal products to be used on humans and on the application of the Good Clinical Practice Based on the authorisation granted in subsection o) of Section (2), § 247 of Act CLIV of 1997 on Health Care (hereinafter referred to as “Health Care Act”) and in subsection d) of Section (2) § 24 of Act XXV of 1998 on Pharmaceuticals for Human Use (hereinafter referred to as “Drug Law”) and in compliance with the provisions of the Oviedo Convention of the European Council on the protection of the human rights and dignity of human beings in respect of the application of biology and medical science announced in Act VI of 2002 as well as of the Additional Protocol on the Prohibition of Cloning Human Beings I hereby order the followings: § 1 The provisions of this Decree are applicable to medical research conducted with investigational products intended for human use (Section 157 of the Health Care Act; hereinafter referred to as “clinical trial”). Non-interventional trials are not considered as clinical trials in case: a) the medicine is not prescribed for the purpose of the trial, and b)the product is prescribed in the usual manner in accordance with the terms of the marketing authorisation; and c) the assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and d) no additional diagnostic or monitoring procedure is used on the patient beyond the usual clinical practice, and e) only epidemiological methods will be used for the analysis of the collected data. § 2 (1) In term of this Decree: a) clinical trial: any investigation in human subjects carried out in either one site or multiple sites intended to aa) discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), ab) and/or to identify any adverse reactions to one or more investigational medicinal product(s) ac) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the objective of ascertaining its (their) safety and/or efficacy and/or risk- benefit ratio not including non-interventional trials; b) multi-centre clinical trial: clinical trials conducted in line with the same protocol at more than one investigational sites by more than one investigator, where investigational sites may be situated within the European Economic Area (hereinafter referred to as the EEA), or, pursuant to an international treaty concluded with the European Community or the EEA, in a state with a legal status identical to that of EEA states (hereinafter referred to as a state party to the EEA- treaty) and in third countries; c) investigational medicinal product: a pharmaceutical form of an active substance or placebo being tested or used as a reference (comparator) in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form; d)sponsor: a natural or legal entity, a company without a legal personality which takes responsibility for the initiation, management and/or financing of a clinical trial. The investigator and the sponsor may be the same entity; e) investigator: a person qualified as a physician or a dentist who is responsible for the conduction of the clinical trial at the investigational site; f) principal investigator: the leader responsible for the team if a trial is conducted by a team of individuals at the investigational site; g) investigator’s brochure: a compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the investigational product or products enabling the physician or the trial supervisor to objectively assess the risk-benefit ratio of the clinical trial. The sponsor must update the brochure at least once a year; 1 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com h) protocol: a document that describes the objective(s), design, methodology, statistical considerations and organisation of a trial, also specifying the inclusion and exclusion criteria for trial subjects as well as monitoring and publication principles, including, successive versions of the protocol and protocol amendments; i) subject: an individual who participates in a clinical trial as either a recipient of the investigational medicinal product or a control; j) informed consent: the consent of an individual with capacity invited to participate in the trial obtained in accordance with Section 159 (1) e) of the Health Care Act, or with Section 159 (4) d) of the Health Care Act in case of persons with limited or no capacity to act; k) recruitment: public announcement by the health care provider conducting the clinical trial as authorised by the Országos Gyógyszerészeti Intézet (National Institute of Pharmacy, hereinafter referred to as “NIP”) for the inclusion of volunteers into a specific clinical trial as subjects in addition to the patients treated by the health care provider; l) adverse event: any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with the treatment applied; m) adverse reaction: all untoward and unintended responses to an investigational medicinal product related to any dose administered; n) serious adverse reaction or serious adverse event: any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect; o) unexpected adverse reaction: an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. investigator's brochure for an unauthorised investigational product or summary of product characteristics for an authorised product); p) equivalence study: the comparative analysis of the bioequivalence, pharmacodynamic or therapeutic equivalence of the investigational medicinal product with another medicine (based on pharmacokinetic results); q) r) SUSAR: Suspected Unexpected Serious Adverse Reaction; s) Phase I study: the investigation of the tolerability, safety, pharmacokinetics, pharmacodynamic effects of an investigational medicinal product in healthy volunteers or special patient populations. Phase I studies can also be conducted to establish the therapeutic dose range; t) Phase II study: a study of the investigational medicinal product for an indication selected on the basis of its pharmacological effect to establish its efficacy, the relationship between dose and effect, the optimal therapeutic dose as well as safety and tolerability. u) Phase III study: a randomized, controlled, comparative study involving a larger patient population to demonstrate the efficacy, safety and tolerability of the investigational medicinal product; v) Phase IV study: a study to further investigate the risk-benefit ratio, the safety and tolerability of the investigational medicinal product with a marketing authorization when used according to the summary of product characteristics. (2) With regard to matters not regulated in Section (1), for the purposes of this Decree, the definitions of terms in the Health Care Act, the Drug Law, the act on the approval procedure for medical research in humans, the clinical trial of investigational medicinal products for human use and clinical trial of medical devices intended for human use, the act on the marketing of medicines for human use, and the act on the personal and material conditions of the production of medicines for human use will be taken into account. (3) With regard to investigational medicinal products, the provisions of the legislation on the qualification criteria for the quality assurance pharmacist will also be applied mutatis mutandis. 3. § (1) Each clinical trial, including bioavailability and bioequivalence studies, must be planned, conducted and reported in line with the principles of Good Clinical Practice (hereinafter referred to as “GCP”) and the Helsinki Declaration on the ethical principles of medical research. The text of the GCP as amended will be published by the NIP in Hungarian language. An announcement regarding the publication and its place be made by the NIP in the Health Care Journal (Egészségügyi Közlöny). (2) At all times, clinical trials must be planned and conducted in accordance with the professional standards, in particular the detailed guides published by the European Commission on clinical trials as amended, which will be published by the NIP in Hungarian 2 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com translation. (3) A set of methodology guidelines on significant professional and ethical issues, in particular the definition of and distinction between clinical study phases and the use of placebo in clinical trials will be published by NIP and the Ethics Committee for Clinical Pharmacology of the Medical Research Council (hereinafter referred to as ETT-KFEB), an independent ethics committee as defined in a separate law. An announcement regarding the publication of the guidelines and its place will be placed by the NIP and ETT-KFEB in the Official Gazette (Hivatalos Értesítõ) published as a supplement of the Hungarian Official Journal. (4) This decree will be applied in line with Regulation (EC) No 1901/2006/EC of the European Parliament and of the Council on medicinal products for paediatric use amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive2001/83/EC and Regulation (EC) No 726/2004 as well as EC/1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Protection of trial subjects § 4 The rights, safety and welfare of the subject have a priority over the interests of the science and society, therefore the exposure of the subjects to risks must be limited to the minimum extent. §5(1) Clinical trials may be conducted, and investigational medicinal products may be used on humans only in the possession of the NIP's authorisation. Clinical trials may be conducted only according to terms specified in the NIP's approval resolution, and to the requirements given in the approved protocol. Terms specified in the approval resolution of the clinical trial, and the requirements given in the authorized protocol, as well as requirements relating to the commencement and control of clinical trials are qualified as occupational rules. (2) Mentally competent persons may be involved in clinical trials only if terms specified in Sections (1) to (3) of § 159 of the Health Care Act and requirements given in this regulation are met. (3) The clinical trial may not replace studies and medical treatments necessary on the basis of the state of the subject. (4) In the event the use of placebo is planned, the research documentation attached to the application for official authorisation must contain a case-specific justification of the necessity for the use of a control group in the trial. The use of placebo may not pose substantial additional risks to the subject or the threat of irreversible health injury. Placebo may only be used for the shortest time required, the subject’s condition must be continuously monitored throughout the trial, and in case of any symptoms indicating substantial deterioration in the subject’s condition, the subject must immediately receive the best available scientifically accepted therapy. (5) The clinical trial must be planned and conducted in a way which minimises any possible injury, pain, fear or anxiety of the subject. During planning and control of the clinical trial all foreseeable risks relating to the age and health state of the subject must be taken into consideration. (6) The health state of the subject must be carefully controlled and documented before the commencement of the clinical trial, continuously during the clinical trial, and after the trial. (7) If the clinical trial involves the inclusion of persons of reproductive age, during the planning and approval of the clinical trial and the provision of information to subjects, particular attention must be paid to the impact of trial participation on the subject’s reproductive ability and pre-existing or subsequent pregnancy, as well as the health of the embryo or the foetus. (8)Act LXIII of 1992 on the protection of personal data and on the disclosure of data of public interest, and Act XLVII of 1997 on the handling and protection of health care data and of the relating personal data, as well as regulations relating to data handling covered by separate legal rules must be followed during the clinical trials. (9) With the exception of healthy volunteers, primarily patients receiving medical care from the health care provider conducting the clinical trial must be enrolled in clinical trials. 3 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com (10) The health care provider conducting the clinical trial may only recruit subjects with capacity to act through an announcement published in the printed press or on its own web site, as well as the website of professional and patient organisations or the sponsor. Such an announcement may not be published for advertising purposes, and may not specify the name and manufacturer of the investigational medicinal product, or the name of the entity authorised to market it. The recruitment announcement published must refer to the existence of the official authorisation. (11) Subjects may receive a compensation for their loss of income and actual and confirmed costs incurred in connection with their participation in the clinical trial, in particular travelling costs. No other remuneration or fee may be payable to subjects with the exception of non- therapeutic pharmacokinetic or interaction, Phase I or bio equivalence studies. (12)Investigational medicinal products and any tools used for their administration must be made available by the sponsor free. Subject information, informed consent to the clinical trial § 6 (1) The principal investigator or the investigator informs the mentally competent person to be involved in the clinical trial orally and in writing in Hungarian - or in the mother tongue of the person or in any other language designated by the person as known to him/her - in a way interpretable even for the laic on the contents of Sections (3) and (4) of § 159 of the Health Care Act. (2)Person giving information must take a special care to establish if the person to be involved in the study is mentally competent or not. Establishments made in relation to it are recorded by the person giving information in the research and health documentation. (3)The information and the informed consent must be recorded on a separate sheet in writing. One original of the informed consent and of the written information must be retained in the research documentation, and one original must be handed over to the subject. (4)The written information must contain, in particular, the followings: a) identification data of the clinical trial; b) reference to the research nature of the clinical trial, the purpose of the clinical trial, its expected duration, the number of persons to be involved, the process of the clinical trial, the nature and frequency of the proposed interventions c) all other accepted treatment options available to the subject, information regarding the possibility that the clinical trial may interrupt the treatment already in progress, and the potential consequences of suspension of the treatment already in progress for the subject; d) detailed description of the possible and expected consequences, risks and discomforts, as well as reference if adverse events may occur during the clinical trial which are unforeseeable; e) a description of reasonably expected benefits, or in the event participation in the clinical trial involves no benefit for the subject, communication of this fact; f) information on treatment, compensation and indemnification to be offered in case of occurrence of damages arising out of the clinical trial [Section (1) § 21 of the Health Care Act], and on the method of their use, as well as the name and availability of person and organisation in Hungary whom or which the subject may contact in case of occurrence of the damage; g) compensation of the subject for costs if any; h) notification of the fact that the consent is voluntary and uninfluenced, and may be revoked at any time either verbally or in writing without justification and any disadvantages to the subject; i) rules relating to the handling of the data of the subject and to their accessibility; j) detailed information on the essence of the application of the placebo if a placebo is used, and on the likelihood of the subject's getting into the placebo group; k) brief description of the effects of the investigational medicinal product; l) the future healthcare of the subject after completion of the trial, if required; m) n) the name of the insurance company stated in the liability insurance prescribed by Section (5) § 3 of Act XCV of 2005 on drugs to be used on humans and on the modification of other laws regulating the drug market. (5) (6)The subject's informed consent must contain at least the followings: a)identification data of the clinical trial; b)designation of the health service provider where the clinical trial will be conducted; 4 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com c)name, position, designation of the scope of the leader of the clinical trial and of the person giving information; d) identifiers of the subject (name, date and place of birth), and, in case of subjects with limited or no capacity to act, also the identifiers of the person authorized to give consent as defined in Section 16 § of the Health Care Act (hereinafter referred to as “the person authorized to give consent”); e) declaration by the subject, or, in the case of subjects with limited or no capacity to act, the person authorized to give consent, that his/her consent to participation in the clinical trial was given after receiving information according to Paragraph (1), voluntarily and freely, in awareness that it may be revoked any time, either verbally or in writing, without justification; f) date of the signature of the informed consent form; g) the signature of the principal investigator or of the person giving information; h) signature of the person consenting the patient. (7)The person giving the information and the subject - as well as the person entitled to make a declaration in case of an incapacitated subject - sign also the written information given in Section (4). (8)In case of a verbal informed consent, two witnesses are required to confirm with their signatures that the subject received the information as defined in Paragraph (4), was advised of the content of the informed consent as defined in Paragraph (6), and consented to it verbally. (9) If any new substantial information becomes available in connection with the clinical trial that would affect the contents of the written information, an amendment of the authorisation must be initiated in accordance with the provisions of Section 18. The subject must be informed again in conformity with the amended written information, and his or her consent must be requested for the continuation of the clinical trial. 6/A. § (1) If a sample is collected during the clinical trial for human genetic testing, the subject must be informed separately about the procedure. Information must also cover the subject’s right to refuse to give a sample, in which case the genetic data of the subject may not be used even anonymously. Refusal to give a sample will not constitute an obstacle to the subject’s participation in the rest of the clinical trial. Information on and consent to the sampling will be included in a separate document. (2) Before collection of a sample for human genetic testing, as part of a genetic consultation, the subject must be advised of a) the purpose and quantitative and qualitative details of the sampling, b) the risks and benefits of the testing and lack of testing, c) the potential consequences of the findings for the subject and his or her family, d) the manner and duration of the storage of the genetic sample and data and the various options regarding the identification of the genetic samples and data stored in different forms, e) if not specified otherwise in a statement by the subject, the potential transfer of the genetic sample into an archived collection, f) the subject’s right to learn about the genetic data generated during the human genetics testing, g) the option to decide about depositing the sample in a biobank and about the manner of deposition, including (ga) storage with personal identification information, (gb) storage with data encryption, (gc) storage with pseudonymised data, meaning the code that replaces personal identification information will be known only to the subject, (gd) storage with anonymised data, meaning all personal identification information of the subject has been made unsuitable for identification. (3) The subject must be informed of the option to include the sample deposited in the biobank for further investigations. In this case, the subject must make a statement regarding whether he or she consents to the use of the sample for diagnostic purposes, research purposes or both, that is for diagnostic and research purposes, depending on the primary purpose of the sampling. 6/B. § (1) If a sample is collected during the trial for human genetic testing, a separate informed consent will be prepared. (2) The subject’s informed consent will include the following as a minimum: a) identifiers of the clinical trial; b) name of the health care provider where the clinical trial is to be conducted; c) name, position and funcion of the principal investigator and/or the person providing the information; d) identifiers of the subject (name, date and place of birth), and, in case of subjects with limited or no capacity to act, also the identifiers of the person authorized to give consent as 5 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com defined in Section 16 of the Health Care Act (hereinafter referred to as “person authorized to give consent”); e) declaration by the subject, or, in the case of subjects with limited or no capacity to act, the person authorized to give consent, that his/her consent to participation in genetic testing for pharmacology purpose was given after accepting or declining the provision of information as specified in Section 6/A, voluntarily and freely, in awareness that it may be revoked any time, either verbally or in writing, without justification; f) consent to the collection of sample in the quantity and quality specified in the information and to the use of the data of the subject, g) the statement on the storage of samples, with the option to deposit the sample provided by him or her in a biobank in the required manner, including storage in accordance with Section 6/A (2) g). h) the statement of the subject regarding the inclusion of the sample deposited in the biobank for further investigations; in this case, the subject must make a statement regarding whether he or she consents to the use of the sample for diagnostic purposes, research purposes or both, that is for diagnostic and research purposes, depending on the primary purpose of the sampling, i) disclosure of the results even in the event the subject has no access to them, j) consent to or rejection of the possibility of being contacted in the future k) date of signature on the informed consent; l) signatures of the principal investigator or the person providing the information; m) signature of the person giving the informed consent. Clinical trials made on persons of minor age § 7 Clinical trial may be conducted on persons of minor age, even if the contents of Section (4) § 159 and of § 4 to § 6 of Health Care Act are adequately followed, if all the following terms are met: a) the research in question is indispensable for the validation of data acquired with clinical trials made on mentally competent persons or with other research methods; b) the research is directly related to the clinical aspect from which the person of minor age suffers, or is of a nature which may be conducted only on persons of minor age; c) the informed consent given by the person entitled to make a declaration contains the presumable will of the person of minor age capable of having an opinion and evaluating the situation, and this declaration may be withdrawn at any time without causing any disadvantage to the person of minor age; d) the investigator having an experience in connection with persons of minor age adequately informed the person of minor age on the investigation, its adverse and beneficial effects in a way understandable to him/her - depending on his/her intellectual level; e) the explicit wish of a minor who is capable of forming an opinion and assessing this information to refuse participation or to be withdrawn from the clinical trial at any time is taken into consideration by the investigator or the principal investigator; f except for the compensation as per Section 5 § (11), no incentives, financial inducements, benefits or fees may be given to a minor subject; g) the relevant scientific guides of the European Medicines Agency established by the European Parliament's and the Council's Regulation 726/2004/EC on the specification of community procedures relating to the licensing and supervision of drugs destined for human or veterinary treatment purposes, and on the establishment of the European Medicines Agency (hereinafter: EMEA) are observed; h) the clinical trial was planned and is conducted with the minimisation of pain, anxiety, fear and of any other risk foreseeable in connection with the disease and with the state of advancement of the person of minor age; i) the trial is conducted in a way in which both the risk threshold and the extent of pain are individually specified, and are continuously monitored; j) the ECCP OF MRC supports the protocol from special-ethical aspects in the possession of the expert opinion of a paediatrician. Clinical trials on adults with no capacity to act § 8 Persons, who definitely refused to take part in such trials previously when they were mentally competent, may not be involved in any clinical trials. Persons, who refused to accept the given trial previously when they were mentally competent, may not be involved in the given 6 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com clinical trial either. § 9 With the exception of emergency research as defined in Section 160 of the Health Care Act, even if the provisions of Section 159 (4), Sections 4 through 6 and Section 8 of the Health Care Act are applied, clinical trials may only be conducted on majors placed under guardianship excluding or limiting their capacity if all of the following conditions are met: a) the informed consent of person authorized to give consent must represent the presumed will of a subject and it may be revoked at any time without detriment to the subject; b) the subject was informed of the trial, of its beneficial and adverse effects in a comprehensible manner; c) the investigator and the principal investigator fully takes it into consideration, if the subject capable of having an opinion and evaluating the situation definitely refuses to take part in the clinical trial or wants to withdraw from the trial at any time: d) except for the compensation as per Section 5 (11), no incentives, financial inducements, benefits or fees may be given to a subject; e) the research in question is essential to validate data obtained in clinical trials on persons with capacity to act or by other research methods and relates directly to a life-threatening or debilitating clinical condition from which the incapacitated adult concerned suffers; f) the clinical trial has been designed and will be conducted to minimise pain, anxiety, fear and any other foreseeable risk in relation to the current condition and developmental stage of the subject; g) the trial is conducted in a way in which both the risk threshold and the extent of pain are individually specified, and are continuously monitored; h) the ETT-KFEB supports the protocol from special-ethical aspects in the possession of an expert opinion given in accordance with the disease in question and with the patient group concerned; i) it is reasonably expected that the application of the investigational medicinal product has beneficial effects in excess of the adverse effects for the patient, or does not constitute a risk at all. § 10 Persons enlisted in § 9 may not be involved in clinical trials as healthy volunteers. § 11 If a subject becomes mentally competent as a result of a judicial decision or of the change of his/her state during the clinical trial, he/she must be informed of the clinical trial as soon as possible, and his/her acceptance of its continuation must be acquired with the observance of the contents of § 6. Otherwise the clinical trial may not be continued on the persons involved. Prerequisites of applying for an official authorisation § 12 (1) If another natural or legal entity, or a company without a legal personality is assigned by the sponsor to discharge some or all of its responsibilities related to the trial, the sponsor remains liable for compliance with the provisions of this Decree and with the provisions of a separate law on clinical trials. If the sponsor is not established in one of the states which are party to the EEA-treaty, then its legal representative must be established in a state which is party to the EEA-agreement. (2) – (5) (6) The contract between the health service provider and the sponsor relating to the clinical trial of the investigational medicinal product may be signed also before the licensing procedure; however its validity is subject to the official licensing of the clinical trial. (7) Phase I clinical trials may only be conducted at investigational sites qualified by NIP as clinical pharmacological sites. The qualification process must be conducted upon the request of the head of the health care provider. In the course of the qualification process, NIP will conduct an on-site inspection. The qualification process must be repeated every three years. Official authorisation of the clinical trial § 13 (1) (2) Use of an investigational medicinal product on humans may be authorised if the personal terms of the principal investigator and the material terms of the investigational site(s) comply with terms specified in Annex 2 to this decree. (3) – (4) 7 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com § 14 (1) Sponsor notifies the head of the health care provider conducting the clinical trial and the principal investigator about NIP’s decision regarding the approval, and prior to the commencement of the trial submits NIP’s decision and the protocol synopsis in Hungarian to the competent institutional ethics committee (hereinafter referred to as IKEB). If the health care provider is not a health care institution, the IKEB of the institution with the area for emergency healthcare provision where the registered seat of the health care provider conducting the trial is located will have competence. (2) With respect to clinical trials, IKEB responsibilities include the protection of the subjects’ rights and safety. IKEB may not issue a professional-ethical opinion in connection with clinical trials. (3) Along with NIP’s decision, the professional-ethical specialized authority statement will also be sent to the sponsor. 15. § Procedure of the ETT-KFEB § 16 (1) The composition of the ETT-KFEB is subject to Section (6) § 159 of the Health Care Act. (2) The sponsor may ask the ETT-KFEB for an opinion in relation to the clinical trials in any special-ethical issue to which the ETT-KFEB replies within sixty days. § 17 (1) – (7) (8)The ETT-KFEB retains the master file of the trial, and documents relating to the archiving, to the qualification of the investigators, and to the control procedures for three years following the completion of the trial. § 18 § 18/A Inspection of clinical trials § 19 (1) A person having a pharmacist's or physician's diploma or an equivalent diploma and certification of a GCP course organised by a university, not older than five years, may be the controller of the NIP. The NIP has a registry of the controllers. Before the commencement of the control the controller presents his/her certificate issued by the NIP and authorising him/her to perform the inspection. (2) – (4) (5) During an approved clinical trial, the subjects and the person authorized to give consent, the investigators, ETT-KFEB, the head of the health care provider conducting the trial, and IKEB may file complaints with NIP if they believe that the clinical trial is conducted contrary to the specifications of the authorisation or the protocol. During an approved clinical trial, IKEB may communicate its remarks to the principal investigator and the head of the health care provider, and forward them to ETT-KFEB, which may initiate an inspection at NIP in justified cases. (6) – (7) (8) The inspector as defined in Paragraph (1) must make a written statement about his or her interest in, and business and other relationship with the inspected parties. This statement must be taken into consideration when assigning the inspector to the inspection in question. (9) Upon request, the sponsor must provide NIP with sample from the required lot of the investigational medicinal product in an amount sufficient for quality testing within 1 working day. 20. § 8 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com Report on adverse events § 21 (1) The investigator shall immediately notifiy the sponsor and the IKEB of any serious adverse events, with the exception of those defined as not to be reported immediately in the protocol or the investigator’s brochure. Following immediate notification, the investigator provides the sponsor and IKEB with a detailed written report of the event. In the notification and the written report, the subject may only be identified by his or her unique code. (2)The investigator reports to the sponsor all adverse events and abnormal laboratory results regarded to be of particular importance in respect of the safety assessment of the trial in line with the specifications of and within the timeframe provided in the protocol. (3)In case of reported death of the subject the investigator provides all additionally required information to the sponsor and to the IKEB. (4)The sponsor shall keep regular records of each adverse event reported by the investigator. Upon request, this record will be made available to the countries party to the EEA-treaty and whose territory the clinical trials are conducted in. Report on serious adverse reactions § 22 (1) The sponsor ensures that all suspected serious unexpected adverse reactions that are fatal or life-threatening and all related relevant information are reported to the EMEA EudraVigilance database immediately but no later than seven days from obtaining knowledge of such. The sponsor ensures that all suspected serious unexpected adverse reactions occurring at Hungarian investigational sites that are fatal or life-threatening and all related relevant information are reported electronically to NIP, the ETT-KFEB and the competent authority of countries which are party to the EEA-treaty immediately but no later than seven days from obtaining knowledge of such. Within an additional eight days, the sponsor will also report all significant information obtained during the follow-up of the adverse event in question. (2) The sponsor ensures that all other suspected serious unexpected adverse reactions are reported to the EMEA EudraVigilance database immediately but no later than fifteen days from obtaining knowledge of such. The sponsor will report all other suspected serious unexpected adverse reactions occurring at Hungarian investigational sites electronically to NIP, the ETT- KFEB and the competent authority of countries which are party to the EEA-treaty immediately but no later than seven days from obtaining knowledge of such. (3) Periodically, but at least every six months, the sponsor shall provide NIP, ETT-KFEB and all other investigators participating in the clinical trial with a cumulative list in electronic format containing all SUSAR associated with a given investigational medicinal product. (4) Once a year, the sponsor provides NIP, the ETT-KFEB and the competent authority of countries which are party to the EEA-treaty with an electronic report containing all suspected serious adverse reactions occurring over this period and associated with the investigational medicinal product, as well as information on the subjects' safety. (5) NIP keeps a record of all SUSARs reported in connection with a given investigational medicinal product. In the case of non-commercial trials the NIP, and for all other trials the sponsor, will report all received SUSARs in connection with the investigational medicinal product to the EMEA immediately but no later than the deadline specified in Paragraphs (1) and (2). (6) In addition to the provisions in Sections 21 and this Section, the sponsor and the investigator must take all urgent safety measures to protect the subjects against any immediate threat after any new information or event jeopardising subject safety or concerning the continuation of the trial or the development of the investigational medicinal product become known to them. The sponsor shall immediately but no later than 24 hours notify NIP ETT-KFEB of such events and measures taken. Report on the completion of the trial § 23 (1) The sponsor notifies the NIP of the completion of the trial, of the number of patients involved, and of significant events on a data-sheet downloadable from the webpage of the EMEA within ninety days from the completion of the trial. The NIP informs the ETT-KFEB within eight days from the notification. 9 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com Retaining of trial documentation § 24 (1) The trial master file must contain all basic documents which make it possible to evaluate both the conduction of the clinical trial and the quality of the data. Documents must evidence if the investigators and the sponsor met the principles of GCP. The trial master file serves as a basis for inspections made by inspectors independent from the sponsor or by authorities. (2) The sponsor and the investigator must retain basic documents relating to the clinical trial, necessary for the post-control of the clinical trial at least for five years after the completion of the trial, and must archive them in a way which enables easy retrieval. The sponsor must designate persons who are responsible for the archiving at the sponsor, and access to the archives must be limited exclusively to persons authorised to have an access. (3) Any change in the processed data and in the ownership of the documentation of the trial must be documented. The new owner must undertake to observe regulations relating to data- handling and archiving in a written declaration. (4) Data-carriers used for archiving must provide for complete and legible documents. Miscellaneous and transitional provisions § 25 (1) This decree comes into force on 15lh September, 2005 - except for the contents of Section (2) -, and its regulations must be applied in procedures launched after its coming into effect. (2) The provisions in Section (9), subsection n) of Section (4) § 6, and subsection m) of Section (2) § 17 - with the deviation given in Section (4) - come into force on 1st November, 2005. (3) (4) (5) – (6) (7) The sponsor is required to pay an administrative service fee for the proceedings regulated in this Decree in the amount as defined in a separate law. The administrative service fee is exclusive of value added tax. No administrative service fee is charged for the approval procedure of non- commercial trials. (8) (9) (10) (11)The purpose of this Decree is to ensure compliance with the following Union acts: a) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use; b) Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products. (12) This decree defines the provision required for the implementation of Regulation (EC) No 1901/2006/EC of the European Parliament and of the Council on medicinal products for paediatric use amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive2001/83/EC and Regulation (EC) No 726/2004. (13) This decree defines the provision required for the implementation of EC/1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. 10 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com Annex 1 to Decree 35/2005 (VIII. 26.) of the Minister of Health Annex 2 to Decree 35/2005 (VIII. 26.) of the Minister of Health Personal and material terms of the completion of the clinical trials The following types of investigational sites may be distinguished in respect of their scopes: I. Clinical pharmacological investigational site for phase I trials II. Clinical investigational site for phase II trials III. Other clinical investigational site /. Clinical pharmacological investigational site for phase I trial A) Material terms: Clinical pharmacological investigational site at a university clinic or at a clinical ward, a unit provided with an intensive therapeutic division background within the institute - separated from the active care unit - for which laboratory tools and facilities necessary for phase I studies are available. As specified among the minimum requirements for central duty in a separate law, clinical pharmacology trial sites must be equipped with machinery, instruments and other devices, with the exception of the obstetric kit and a vehicle. The number of hospital beds for the clinical trial will be specified in the decision on the classification of the trial site. B) Personal terms: 1. The manager of the clinical pharmacological investigational site must have a) a specialist's qualification in any clinical field, b) a certification exam on clinical pharmacology, 2. The investigator must have a) a specialist's qualification in any clinical field, b) a certification exam on clinical pharmacology or a certification of a successful examination at a GCP course organised by a university, and not older than five years before the commencement of the clinical trial. 3. The principal investigator must have completed a certification exam on clinical pharmacology. //. Clinical investigational site for trial in phase II A) Material terms: In-patient ward or a special out-patient clinic at a university clinic or hospital, or other specialist's surgery which has an intensive therapeutic division background within the institute, as well as adequate diagnostic units the facilities and personnel, and which meets the personal and material minimum terms relating to the health institution and specified in a separate legal rule, and is provided with tools and facilities necessary for the conduction of the proposed trial. B) Personal terms: The principal investigator must have a specialist’s qualification in a clinical field corresponding with the intended use of the investigational medicinal product, with a certification exam on 11 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com clinical pharmacology, or a certificate confirming successful completion of a GCP training course organised by a university not more than five years ago. In case persons of minor age are also included in the trial, a paediatrician must be also involved as an investigator. ///. Clinical investigational site for other clinical trials 1. Other clinical trials may be conducted if material terms specified in article II. A) are met, as well as in a physician's or paediatrician's surgery. 2. The principal investigator must have a certificate confirming successful completion of a GCP training course organised by a university not more than five years ago. Annex 3 to Decree 35/2005 (VIII. 26.) of the Minister of Health 12 PDF Creator - PDF4Free v2.0 http://www.pdf4free.com