0A4F4F9BD490A749D5437F821CF06DF1
Reflection Paper on Ethical and GCP Aspects of Clinical Trials of Medicinal Products for Human Use Conducted Outside of the EU/EEA and Submitted in Marketing Authorization Applications to the EU Regulatory Authorities (2012)
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-paper-ethical-good-clinical-practice-aspects-clinical-trials-medicinal-products-human-use/european-economic-area-submitted-marketing-autho_en.pdf
http://leaux.net/URLS/ConvertAPI Text Files/9908F623FF00D6D784F0D79D79321DD4.en.txt
Examining the file media/Synopses/9908F623FF00D6D784F0D79D79321DD4.html:
This file was generated: 2020-07-15 06:41:40
| 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 / Criminal Convictions
Searching for indicator prisoners:
(return to top)
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
...
Political / nomad
Searching for indicator nomads:
(return to top)
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
...
Political / political affiliation
Searching for indicator party:
(return to top)
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 2/42
p.000039:
p.000039: 1. Glossary
p.000039: AR: Assessment Report
p.000039:
p.000039: COE: Council of Europe
p.000039:
p.000039: CHMP: Committee for Medicinal Products for Human Use
p.000039:
p.000039: CMD: Coordination Group for Mutual Recognition and Decentralised Procedures COMP:
p.000039: Committee for Orphan Medicinal Products
p.000039: CTFG: Clinical Trial Facilitation Group
p.000039:
p.000039: DCP: Decentralised Procedure
p.000039:
p.000039: EEA: European Economic Area
p.000039:
p.000039: EMA: European Medicines Agency
p.000039:
p.000039: EPAR: European Public Assessment Report
p.000039:
p.000039: GCP: Good Clinical Practice
p.000039:
p.000039: GCP IWG: GCP Inspectors Working Group
p.000039:
p.000039: HCP-WG: Working Group with Healthcare Professionals’ Organisations ICH:
p.000039: International Conference on Harmonization
p.000039: IMP: Investigational Medicinal Product
p.000039:
p.000039: MAA: Marketing Authorisation Application
p.000039:
p.000039: MRP: Mutual Recognition Procedure
p.000039:
p.000039: MSs: Member States
p.000039:
p.000039: NGOs: Non-governmental organisations
p.000039:
p.000039: PCWP: Working Party with Patients’ and Consumers’ Organizations
p.000039:
p.000039: PDCO: Paediatric Committee
p.000039:
p.000039: SAG: Scientific Advisory Group
p.000039:
p.000039: WHO: World Health Organization
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 3/42
p.000039:
p.000039: 2. Introduction
p.000039: A marketing authorisation for a medicinal product for human use in Europe can be granted either via
p.000039: the centralised procedure, through the decentralised procedure, mutual recognition or at national level.
p.000039:
p.000039: The EMA is responsible for the evaluation of applications for European marketing authorisation for medicinal products,
p.000039: through the centralised procedure.The decentralized procedure is to be used in order to obtain marketing authorization
p.000039: in more than one Member State where the medicinal product in question has not yet received a marketing authorization in
p.000039: any Member State at the time of application. The mutual recognition procedure is to be used in order to obtain
p.000039: marketing authorization in additional Member States where the medicinal product in question has received a marketing
p.000039: authorization in any other Member State at the time of application.
p.000039: The scope of this Reflection Paper is to clarify the practical application of requirements for clinical trials
...
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 5/42
p.000039:
p.000039: In December 2008 the EMA published a strategy paper “Acceptance of clinical trials conducted in third countries for
p.000039: evaluation in Marketing Authorisation Applications”
p.000039: (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000072.js p&jsenabled=true)
p.000039: outlining four areas for action. These are:
p.000039: 1. Clarify the practical application of ethical standards for clinical trials, in the context of European Medicines
p.000039: Agency activities.
p.000039: 2. Determine the practical steps undertaken during the provision of guidance and advice in the drug development
p.000039: phase.
p.000039: 3. Determine the practical steps to be undertaken during the Marketing Authorisation phase
p.000039:
p.000039: 4. International cooperation in the regulation of clinical trials, their review and inspection and capacity building
p.000039: in this area.
p.000039: In 2009 the EMA established a Working Group on clinical trials on medicinal products for human use conducted outside
p.000039: EU/EEA.
p.000039: The Working Group, includes representatives of Committee for Medicinal Products for Human Use (CHMP), of the Paediatric
p.000039: Committee (PDCO), of the Committee for Orphan Medicinal Products (COMP), of the Clinical Trial Facilitation Group
p.000039: (CTFG), of the GCP Inspector Working group (GCP-IWG),
p.000039: Of the Working Group with Healthcare Professionals’ Organisations (HCP-WG), of the
p.000039:
p.000039: Working Party with Patients’ and Consumers’ Organisations (PCWP), of the Coordination Group for Mutual Recognition and
p.000039: Decentralized Procedures - Human (CMDh), of EMA and of the European Commission Pharmaceutical Unit
p.000039: This working Group has been asked to develop practical proposals for tasks and procedures or guidance to address the
p.000039: four action areas set out above. The present document reflects the results of the activities of this Working Group.
p.000039:
p.000039: 3. International cooperation in the regulation of clinical trials, their review and inspection and capacity building
p.000039: in this area
p.000039: International cooperation has been clearly identified as a key foundation in developing a robust international
p.000039: framework for the conduct of clinical trials. As more and more clinical trials on medicinal products marketed in the EU
p.000039: are performed in countries outside of the EU, enhanced international cooperation is seen as essential to ensure that,
p.000039: as far as possible, there is a common international approach to the oversight of clinical trials. In addition the
p.000039: clinical trials are conducted, increasingly in countries, where the ethics and regulatory systems are not fully
p.000039: developed and with which EU regulators have limited formal contacts or experience in the domain of clinical trials.
p.000039: Building contact with, and between, the National Regulatory Authorities and Ethics Committees in these countries, their
p.000039: regional networks and associations, and the establishment of an international network of clinical trial regulators
p.000039: should therefore be a fundamental objective.
...
Searching for indicator political:
(return to top)
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
...
Political / vulnerable
Searching for indicator vulnerable:
(return to top)
p.002011: 3. International cooperation in the regulation of clinical trials, their review and inspection and capacity building in
p.002011: this area 6
p.002011: 3.1. Identification of priorities
p.000007: 7
p.000007: 3.2. Identification of opportunities and partners 9
p.000007: 3.2.1. Identification of other initiatives
p.000009: 9
p.000009: 3.2.2. Categories of initiatives and actions 9
p.000009: 3.2.3. Establishment of contact with key initiatives 10
p.000009: 3.3. Action plan
p.000010: 10
p.000010: 3.3.1. Core activities
p.000010: 10
p.000010: 3.3.2. Short Term activities:
p.000011: 11
p.000011: 3.3.3. Long Term activities:
p.000012: 12
p.000012: 3.4. Resource considerations 13
p.000012: 3.5. Example of initiatives
p.000013: 13
p.000013: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000013: use in the context of the activities of the European Regulatory Authorities
p.000014: 14
p.000014: 4.1. Ethics committee and national regulatory authority oversight 16
p.000014: 4.2. Information/Consent procedure 18
p.000014: 4.3. Confidentiality
p.000021: 21
p.000021: 4.4. Fair compensation
p.000022: 22
p.000022: 4.5. Vulnerable populations
p.000024: 24
p.000024: 4.6. Placebo and active comparator 26
p.000024: 4.7. Access to treatment post trial 28
p.000024: 4.8. Applicability of data to EEA population 29
p.000024: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000024: phase 29
p.000024: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000031: 31
p.000031: 5.2. Issues related to feasibility of clinical trials 31
p.000031: 5.3. General measures to assure data quality when conducting trials outside the EU 32
p.000031: 5.4. Considerations for designing clinical trials 33
p.000031: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000034: 34
p.000034: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000034: 34
p.000034: 6.2. Inspections: Triggers for inspection to be identified by assessor 36
p.000034: 6.3. Actions available in response to non compliance 37
p.000034: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039: 39
...
p.000039: regulators from less well developed National Regulatory Authorities, to develop their expertise in the review of MAAs.
p.000039: Ethics Committees:
p.000039:
p.000039: • FERCAP initiative, http://www.fercap-sidcer.org/aboutus.php
p.000039:
p.000039: • Assessment of / assistance in implementing Ethics Committes
p.000039:
p.000039: • Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
p.000039: • Evaluation of clinical trials.
p.000039:
p.000039: • Investigation of systems for accreditation
p.000039:
p.000039: • Information exchange
p.000039:
p.000039: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000039: use in the context of the activities of the European Regulatory Authorities
p.000039: For the purpose of research, three ethical principles should be adhered to:
p.000039:
p.000039: a) respect for persons,
p.000039:
p.000039: b) beneficence/non-maleficence and
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 14/42
p.000039:
p.000039: c) justice, where respect for persons includes the respect for autonomy and the protection of dependent and vulnerable
p.000039: persons, beneficence/non- maleficence is defined as the ethical obligation to maximize benefits and to avoid or
p.000039: minimize harms, and justice is a fair distribution of the burdens and benefits of research1.
p.000039: “The rights safety and wellbeing of the trials subjects are the most important consideration and should prevail over
p.000039: the interests of science and society”. 2
p.000039: Clinical trials conducted in countries outside of the EU/EEA and used in MAAs in the EEA or in applications for a
p.000039: Scientific Opinion under article 58 of the Regulation (EC) No. 726/2004, must be conducted on the basis of principles
p.000039: equivalent to the ethical principles and principles of good clinical practice applied to clinical trials in the EEA3.
p.000039: Ethical principles have been established mainly by intergovernmental organisations such as the Council of Europe or
p.000039: WHO, or by professional bodies such as the World Medical Association, as well as in national or regional legislation or
p.000039: guidance. The latter often refer directly or indirectly to the internationally established principles.
p.000039: Ethical principles governing the conduct of clinical trials are set out in the Charter of Fundamental Rights of the
p.000039: European Union (2000)i the Council of Europe’s Convention on Human Rights and Biomedicine (1997)ii and its Additional
p.000039: Protocol on Biomedical Research (2005)iii, the Universal Declaration of Human Rights (1948)iv, the Convention for the
p.000039: protection of Human Rights and fundamental Freedoms (1950)v, the United Nations’ Convention on the Rights of the Child
...
p.000039: independent examination of its scientific merit, including assessment of the importance of the aim of research, and
p.000039: multidisciplinary review of its ethical acceptability,4 In many countries an application also has to be made to a
p.000039: Regulatory Authority, before a clinical trial may commence.
p.000039: It is an important element of international cooperation that Regulatory Authorities support compliance with local
p.000039: requirements in each country as well as reinforcing international ethical and good clinical practice standards.
p.000039: All the information which is necessary for the ethical assessment of the research project should be given in written
p.000039: form to the Ethics Committee. 5 The Ethics Committee, in preparing its opinion should consider amongst others the
p.000039: points set out in art. 3, 4, 5 and 6 of the Directive 2001/20/EC, the Appendix to the additional protocol on biomedical
p.000039: research (COE- Information to be given to the Ethics Committee), and chapters 2 and 3 of ICH E 6 and WHO (CIOMS)
p.000039: guidelines 2. The Ethics Committees hould be satisfied that no undue influence, including that of a financial nature
p.000039: (or limiting or increasing access to medical care), will be exerted on persons, to participate in research. In this
p.000039: respect, particular attention must be given to vulnerable or dependent persons.6 EU legislation gives particular
p.000039: attention to protection of paediatric subjects7.
p.000039: The Ethics Committee shall give clearly stated reasons for its positive or negative conclusions. 8
p.000039: The declaration of Helsinki states that “No change to the protocol may be made without consideration and approval by
p.000039: the ethics committee”.9 EU Directive 2001/20/EC specifies that this should apply to substantial amendments.10 Research
p.000039: projects should be re-examined if this is justified in the light of scientific developments or events arising in the
p.000039: course of the research. 11
p.000039: “The ethics committee must have the right to monitor ongoing studies”12 “and to report to institutional or governmental
p.000039: authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that
p.000039: they have approved or in the conduct of the studies”.13
p.000039: If the clinical trial is planned to be conducted in a country with limited Regulatory Authority or Ethics Committees
p.000039: framework and limited oversight of the clinical trial, the sponsor should put in place alternative solutions in order
p.000039: to ensure an adequate review of the clinical trial protocol. A possible option could be to consider complementing the
p.000039: ethics Committees review in that country by submitting the study protocol for ethical and scientific review to an
...
p.000039: There should be assurance that the review is independent and that there is no conflict of interest that might affect
p.000039: the judgment of members of the Ethics Committee in relation to any aspect of the research. A declaration of possible
p.000039: conflict of interest should be provided by any of the Ethics Committee members.15Any members with a special or
p.000039: particular, direct or indirect, interest in a proposal should not take part in its assessment if that interest could
p.000039: subvert the member’s objective judgment. Ethics Committees have to be pluralist and representative of all stakeholders,
p.000039: multidisciplinary and independent.16.Ethics Committee should be so composed as to be able to provide complete and
p.000039: adequate review of the research proposals submitted to them. Membership should include physicians, scientists and other
p.000039: professionals such as nurses, lawyers, ethicists, clergy as well as lay persons including patients’ representatives,
p.000039: qualified to represent the cultural and moral values of the community and to ensure that the rights of the research
p.000039: subjects will be respected. When illiterate persons form the focus of a study they should also be considered for
p.000039: consultation in the Ethics Committee decision process. Ethics Committees should include appropriate expertise
p.000039: paediatric and/or mental health disorders or other vulnerable populations or take advice in clinical, ethical and
p.000039: psychosocial problems in these fields when reviewing protocols involving these populations. The Ethics Committee in the
p.000039: country where the trial is to be conducted should have, as either members or consultants, persons with understanding of
p.000039: the community's customs and traditions.” Such persons should be able, for example, to indicate suitable members of the
p.000039: community to serve as intermediaries between investigators and subjects and to advise on whether material benefits or
p.000039: inducements may be
p.000039:
p.000039: 14 Art. 12 of Directive 2001/20/EC
p.000039: 15 WHO (CIOMS) Guideline 2.
p.000039: 16 Art.19 International Declaration on Bioethics (UNESCO); ICH E6 paragraphs 1.27 and 3
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 17/42
p.000039:
p.000039: regarded as appropriate in the light of a community's gift-exchange and other customs and traditions”.17
p.000039: Expertise used should be documented and recorded by the Ethics Committee. Paediatric expertise requirements, as
p.000039: described in paragraph 8 of European Ethical considerations for clinical trials on medicinal products conducted with
p.000039: the paediatric population, should be complied with 18
p.000039:
p.000039:
p.000039: Regulatory action/ action plan
p.000039:
p.000039: 1. Failure to submit a protocol to an independent EC is a serious violation of ethical standards. EU Regulatory
...
p.000039: representatives of the group or community concerned may be sought. In no case should a collective community agreement
p.000039: or the consent of a community leader or other authority substitute for an individual’s informed consent”29 . “In some
p.000039: cultural contexts an investigator may enter a community to conduct or approach prospective subjects for their
p.000039: individual consent only after obtaining permission from a community leader, a council of elders, or another designated
p.000039: authority.
p.000039: Such customs must be respected. In no case, however, may the permission of a community leader or other authority
p.000039: substitute for individual informed consent” 30
p.000039: The consent process and the information provided should take into account the needs of persons who are unfamiliar with
p.000039: medical concepts and technology31. All documentation (information and consent/assent) must be written in a lay-friendly
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
...
p.000039: “unrecognised congenital defects are generally excluded”.55
p.000039: Regulatory action/action plan
p.000039:
p.000039: 48 Art. 31 of Additional Protocol on Biomedical research (COE) 2005 49 WHO (CIOMS) Guideline 19
p.000039: 50 Paragraph 5.8 of ICH-E6
p.000039: 51 Paragraph 4.8.10 of ICH-E6
p.000039: 52 Art 11 juncto appendix of Additional Protocol on Biomedical research (COE) 2005; Paragraph 3.1.2 of ICH-E6. 53 Art.
p.000039: 6.3 (h) and (i) of Directive 2001/20/EC
p.000039: 54 Art. 6.3 of Directive 2001/20/EC
p.000039: 55 Paragraph 22 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 23/42
p.000039:
p.000039: 1. Failure to provide fair compensation by insurance or indemnity is a serious violation of ethical standards. The
p.000039: applicant for a MAA should provide EU Competent Authorities with a summary of the provisions made to provide for the
p.000039: fair compensation of subjects for trial related injury. This information can form part of the clinical study report
p.000039: section on ethical considerations and informed consent.
p.000039: 2. EMA and EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
p.000039: insurance, indemnity or compensation for research related injury and where applicable to seek additional assurance that
p.000039: trial subjects’ interest have been protected.
p.000039:
p.000039: 4.5. Vulnerable populations
p.000039:
p.000039: In the context of this paper, one of the main concerns is the vulnerability of person due to poverty, lack of adequate
p.000039: health care systems or lack of access to medicines,
p.000039: The definition of vulnerability is based on existing ethical guidelines. Nevertheless vulnerability has to be
p.000039: considered in terms of a condition, or situation affecting persons and making people vulnerable in particular situation
p.000039: rather than considering a specific population as vulnerable (people that are part of a specific population considered
p.000039: vulnerable may or may not be vulnerable).
p.000039: The key concern is to avoid that vulnerable persons or group are exploited for the benefit of EU patients. At the same
p.000039: time the benefit to the patient of taking part in the study and the ethics of potentially turning them away simply
p.000039: because they fit one of the vulnerable categories needs to be considered. Special care should be paid to the
p.000039: benefit/risk balance and to minimizing risk and burden when clinical trials are conducted in vulnerable populations56
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
p.000039: not pregnant, or on persons who are not deprived of liberty, whether the person undergoing research has been informed
p.000039: of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a
p.000039: state to receive the information, whether the necessary authorisation has been given specifically and in writing by the
p.000039: legal representative, and the person (or pregnant woman) concerned does not object.
p.000039: Exceptionally and under the protective conditions prescribed by law, where the research may not have the potential to
p.000039: produce results of direct benefit to the health of the person concerned, such research may be authorised, if it can
p.000039: contribute to the benefit of the group concerned whilst fulfilling the other conditions described above. “Measures of
p.000039: such benefit would include the importance of knowledge gained, severity of the issue to be addressed, commonality of
p.000039: the issue, likelihood of obtaining results from proposed research, and usefulness of benefits obtained”.66
p.000039:
p.000039:
p.000039:
p.000039: 62 Recital 3 of Directive 2001/20/EC
p.000039: 63 Recital 4 and art. 1 of Regulation EC/1901/2006 and art. 4 of Directive 2001/20/EC.
p.000039: 64 Belmont Report: ethical principles and guidelines for the protection of human subjects of research, Section D 3. 65
p.000039: Art. 17 of Declaration of Helsinki (2008).
p.000039: 66 Paragraph 12 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 25/42
p.000039:
p.000039: The need for special protection of the vulnerable population rights and welfare should be reviewed and applied, where
p.000039: relevant. Vulnerable subjects should not be recruited into a trial where this was not explicitly foreseen in the trial
p.000039: protocol or other information provided to and approved by the Ethics Committe. Any special consent procedures or other
p.000039: precautions required should have been explicitly described to the Ethics Committe and approved by them.
p.000039: The decision to include vulnerable subjects in a trial should be fully justified by the sponsor. “Medical research
p.000039: involving a disadvantaged or vulnerable population or community is only justified if the research is responsive to the
p.000039: health needs and priorities of this population or community and if there is a reasonable likelihood that this
p.000039: population or community stands to benefit from the results of the research”67.
p.000039:
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. The inclusion of vulnerable subjects in a clinical trial without the approval of the Ethics Committe and without
p.000039: implementation of the appropriate consent processes is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in such an unethical manner, when submitted in support of a
p.000039: MAA in accordance with Directive 2001/83 EC and Regulation No (EC) 726/2004.
p.000039: 2. The applicant for a MAA should provide drug regulatory authorities with an adequate and appropriate justification
p.000039: for inviting vulnerable individuals or groups to serve as research subjects and the description of the specific
p.000039: measures and means implemented to protect their rights and welfare, should be included in the protocol and in the
p.000039: clinical study report (in accordance to ICH E3) and should made public in the Public Assessment Report
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: the inclusion of vulnerable populations and where applicable to seek additional assurance that the inclusion of such
p.000039: populations was justified and their rights and welfare protected.
p.000039:
p.000039: 4.6. Placebo and active comparator
p.000039:
p.000039: The capacity of a trial to produce reliable results is a pre-requisite for the ethical justification of that trial.
p.000039: “Research shall neither delay nor deprive trial participants of medically necessary preventive, diagnostic or
p.000039: therapeutic procedures”.68 A clinical trial cannot be justified ethically unless it is capable of producing
p.000039: scientifically reliable results. “In some circumstances it may be acceptable to use an alternative comparator, such as
p.000039: placebo or "no treatment”,69 whilst taking into account that “the rights, safety and wellbeing of the trials subjects
p.000039: are the most important considerations and should prevail over the interests of science and society”.70
p.000039: The rationale for the use of placebo in a number of therapeutic areas is not always widely understood. Where such
p.000039: designs are deemed necessary and ethical, failure to follow them can have negative consequences. Either it will lead to
p.000039: such products not being authorised in the absence of adequate evidence of efficacy or if they were to be authorised
p.000039: with a suboptimal trial design this could give rise to the approval of less effective or ultimately ineffective
p.000039: (placebo equivalent) medicines. EU regulators
p.000039:
p.000039:
...
p.000039: may relate to the use of placebo or duration of use of placebo, poorly optimised background therapy, use of
p.000039: inappropriate comparator, inappropriate investigations, lack of consent etc.. This aspect is addressed below.
p.000039: Review procedures
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 34/42
p.000039:
p.000039: • At the time of the application, information should be provided on where each clinical trial was performed and on
p.000039: how relevant ethical requirements were met.
p.000039: • As part of the review of the MAA, assessors should consider whether or not there are major ethical concerns
p.000039: relating to the studies that have been included in the dossier to support the MAA. Assessors should confirm in the
p.000039: Assessment Report that they have not identified any major ethical issues in their assessment of the studies, that the
p.000039: studies have been approved by the relevant Ethics Committe and by the National Regulatory Authority, that the sponsor
p.000039: has provided the statement that the studies have been conducted as set out in Annex 1 of Directive 2001/83, and that
p.000039: they have not identified any major concerns regarding the conduct of the study. Particular attention should be paid
p.000039: where vulnerable patients are included within the trial population, and/or trials are conducted in low to middle income
p.000039: countries, and/or where no EEA Ethics Committee has reviewed and approved the study/studies for trials performed
p.000039: outside the EU.
p.000039: • In considering the design of studies, assessors should consider international guidelines for biomedical research
p.000039: involving human subjects where it is recommended that research is responsive to the health needs and priorities of the
p.000039: population or community in which it is carried out and any intervention or product developed or knowledge generated
p.000039: will be made reasonably available for the benefit of that population or community. Applicants are encouraged to provide
p.000039: such information, in so far as it is possible. Whilst it will not always be possible for assessors to conclude
p.000039: definitively, questions or concerns in relation to this area may be included in the List of Questions to the applicant
p.000039: The EU assessment report should reflect:
p.000039:
p.000039: 1. That it has been determined that all clinical trials were conducted in accordance with the principles of good
p.000039: clinical practice and the above mentioned ethical requirements ,
p.000039: 2. Any ethical concerns that have been raised,
p.000039:
p.000039: 3. How these ethical concerns have been addressed and whether they had an impact on the assessment of the quality,
p.000039: safety and efficacy of the product,
p.000039: 4. Whether the CHMP has sought additional ethical advice, if felt necessary
p.000039:
p.000039: 5. A summary of the reasons for and outcome of any GCP inspections requested (these may be routine or triggered)
p.000039: summarised,
p.000039: 6. Discussion of applicability of data to the EU/EEA population
p.000039:
...
p.000039: Inclusion in the guidance of the items listed below, and the consistent application of this, will substantially improve
p.000039: the content of assessment reports and hence the Public Assessment Report in respect of ethical and GCP compliance.
p.000039: The CHMP or RMS assessment report and the Public Assessment Reports should address the following aspects:
p.000039: • The steps taken to evaluate and provide assurance regarding the ethical conduct of the trials should be
p.000039: described as should any significant deficiencies and how they have been addressed.
p.000039: • The standard GCP review should be summarised in an annex to the CHMP or RMS Assessment Report and to the Public
p.000039: Assessment Report, It should list, for each clinical trial submitted the protocol identification and title, start and
p.000039: end date, identification of the sponsor, of the countries where each trial was conducted and the numbers of subjects
p.000039: recruited in each country. The nature of the patient population should also be described (age and gender and any
p.000039: particular considerations of vulnerability). The standards to which the trials were conducted should be identified.
p.000039: This summary should be based on information to be supplied, electronically, by the applicant.
p.000039: • During the course of the assessment, any relevant ethical issue such as access to treatment post trial, use of
p.000039: placebo or treatment interruptions, choice of active comparators, treatment of vulnerable populations should be
p.000039: highlighted as part of the assessment of the individual trial.,
p.000039: • The justifications for the study designs, choice of comparators and selection of study populations, should be
p.000039: provided with particular emphasis on those studies that involve increased ethical sensitivity due to their design,
p.000039: indication, patient population or location of conduct. The applicability of the trial to the EEA population should be
p.000039: discussed where relevant.
p.000039: • A comment that “no ethical issues were identified” may be sufficient where applicable.
p.000039:
p.000039: • If available, information on Patients’ involvement in study design should be communicated,
p.000039:
p.000039: • When a GCP inspection is performed, the reason(s) for inspection should be described. The outcome and
p.000039: consequences on the assessment of a MAA should be further elaborated. Relevant information from the inspection report
p.000039: may be made publicly accessible.
p.000039: • When GCP/ethical concerns have been raised, the assessment report should present the issue, describe any
p.000039: external expertise sought and the advice received, and discuss the ethical aspects and their consequences on the
p.000039: assessment of the quality, safety and efficacy of the product.
p.000039: • The actions taken should be reflected in the Public Assessment Reports.
p.000039:
p.000039: Regulatory action/action plan
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 40/42
p.000039:
...
Searching for indicator vulnerability:
(return to top)
p.000039: The declaration of Helsinki states that “No change to the protocol may be made without consideration and approval by
p.000039: the ethics committee”.9 EU Directive 2001/20/EC specifies that this should apply to substantial amendments.10 Research
p.000039: projects should be re-examined if this is justified in the light of scientific developments or events arising in the
p.000039: course of the research. 11
p.000039: “The ethics committee must have the right to monitor ongoing studies”12 “and to report to institutional or governmental
p.000039: authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that
p.000039: they have approved or in the conduct of the studies”.13
p.000039: If the clinical trial is planned to be conducted in a country with limited Regulatory Authority or Ethics Committees
p.000039: framework and limited oversight of the clinical trial, the sponsor should put in place alternative solutions in order
p.000039: to ensure an adequate review of the clinical trial protocol. A possible option could be to consider complementing the
p.000039: ethics Committees review in that country by submitting the study protocol for ethical and scientific review to an
p.000039: Ethics Committee (s) that operates within an established regulatory framework with ethical standards equivalent to
p.000039: those applying in the EU (based in an EU or non EU Country). This would be particularly relevant where the study design
p.000039: (e.g. choice of comparator) or the vulnerability of the proposed patient population might give rise to additional
p.000039:
p.000039: 4 Art. 6 (2) and Art. 9 (2) of Directive 2001/20/EC, Art.9 and 10 Additional Protocol on biomedical research (COE),
p.000039: Paragraph 15 of Declaration of Helsinki, WHO (CIOMS) guidelines 2.
p.000039: 5 Art. 11 of Additional Protocol on biomedical research (COE). 6 Art.12 of Additional Protocol on biomedical research
p.000039: (COE).
p.000039: 7 Paragraph 8.2 of EU Ethical Considerations for clinical trials on medicinal products conducted with the paediatric
p.000039: population
p.000039: 8 Art. 6 (5) of Directive 2001/20/EC; Art.9 Additional Protocol on biomedical research (COE) Explanatory report
p.000039: paragraph 42.
p.000039: 9 Paragraph 15 of Declaration of Helsinki 10 Art. 10 (a) of Directive 2001/20/EC
p.000039: 11 Art. 24 of Additional Protocol on biomedical research (COE) 12 Paragraph 15 of Declaration of Helsinki
p.000039: 13 WHO (CIOMS) guideline 2
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 16/42
p.000039:
p.000039: concerns. In this case the deliberations and conclusions of that committee(s) should be made available to the local
p.000039: Ethics Committee and regulatory authority, making clear to what extent the committee has considered the location and
p.000039: circumstances in which the trial is to be conducted. Such an approach does not substitute for the need to apply to, and
...
p.000039: Expertise used should be documented and recorded by the Ethics Committee. Paediatric expertise requirements, as
p.000039: described in paragraph 8 of European Ethical considerations for clinical trials on medicinal products conducted with
p.000039: the paediatric population, should be complied with 18
p.000039:
p.000039:
p.000039: Regulatory action/ action plan
p.000039:
p.000039: 1. Failure to submit a protocol to an independent EC is a serious violation of ethical standards. EU Regulatory
p.000039: Authorities should disregard data obtained in a such unethical manner, when submitted in support of a MAA in accordance
p.000039: with Directive 2001/83 EC or Regulation EC 726/2004.
p.000039: 2. Requirements for submission to the national regulatory authority of each country in which the trial is conducted
p.000039: and to the Ethics Committee (s) in those countries must be complied with, and evidence of both submissions and
p.000039: approvals provided. The applicant for a MAA should provide EU Regulatory Authorities with a summary of Ethics
p.000039: Committee, and National Regulatory Authority approvals of each clinical trial supporting the MAA. This information
p.000039: should form part of the clinical study report in accordance with ICH E3.
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern (e.g.
p.000039: arising from their design, the local regulatory framework within which they are conducted, the vulnerability of the
p.000039: study subjects) and where applicable seek additional assurance that the trials have been ethically conducted.
p.000039: 4. Where clear serious concerns are identified the EU Regulatory Authorities should communicate these concerns to the
p.000039: National Regulatory Authority of the Country (ies) concerned.
p.000039: 5. The Sponsor ensuring that the clinical trial is reviewed by an appropriate EC should consider the opportunity to
p.000039: submit the clinical trial also to an Ethics Committee (either in an EU or non EU Country) that operates within an
p.000039: established regulatory framework with ethical standards equivalent to those applying in the EU. Evidence of the
p.000039: mechanisms put in place should be provided.
p.000039:
p.000039: 4.2. Information/Consent procedure
p.000039:
p.000039: Scientific research as well as any preventive, diagnostic or therapeutic medical intervention involving human subjects
p.000039: is only to be carried out with the prior, free, express, specific, documented and informed consent of the person
p.000039: concerned, based on adequate and comprehensible information 19 provided both in writing (or optionally pictorially for
p.000039: illiterate individuals) and orally. Furthermore, consent should, be given, and may be withdrawn, by the person
p.000039: concerned at any time and for any reason without disadvantage or prejudice. 20 “Informed consent is documented by means
p.000039: of a written,
p.000039:
p.000039: 17 WHO (CIOMS) Guideline 3.
...
p.000039: and significant variations of those processes in the clinical trials supporting the MAA and include sample information
p.000039: sheets on consent forms. This information should form part of the clinical study report in accordance with ICH E3.
p.000039:
p.000039:
p.000039: 29 Art. 6 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005) 30 WHO (CIOMS) Guideline 4
p.000039: 31 WHO (CIOMS) Guideline 4
p.000039: 32 WHO(CIOMS) Guideline 4
p.000039: 33 WHO (CIOMS) Guideline 4
p.000039: 34 Paragraph 6.3 of Ethical considerations for clinical trials on medicinal products conducted with the pediatric
p.000039: population 35 Art. 12 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005)
p.000039: 36 WHO (CIOMS) Guideline 6
p.000039: 37 WHO (CIOMS) Guideline 4 and 6
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 20/42
p.000039:
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: the consent process (e.g. arising from the patient population included and their capacity to provide informed consent,
p.000039: the regulatory framework within which they are conducted, the vulnerability of the study subjects) and where applicable
p.000039: seek additional assurance that consent was properly obtained.
p.000039: 4. Additional good practice guidelines on the communication of the information to the potential participants in
p.000039: research may be required to better describe some research situations and should be developed, with input from patients’
p.000039: organisations and community groups as well as other experts in ethics and clinical trials.
p.000039:
p.000039: 4.3. Confidentiality
p.000039:
p.000039: Any information of a personal nature collected during a clinical trial shall be considered as confidential and treated
p.000039: according to the rules relating to the protection of individuals with regard to the processing of personal data38.
p.000039: Process refers to any operation or set of operations performed upon personal data, including collecting, using,
p.000039: accessing, making available, disclosing, transferring, retaining or destroying personal identifiable Information.
p.000039: “To the greatest extent possible, such information should not be used or disclosed for purposes other than those for
p.000039: which it was collected or consented to, consistent with international law, in particular international human rights
p.000039: law”.39
p.000039: Any participant in research shall be entitled to know any information collected on his/her health. Such information or
p.000039: other personal information collected for a research project will be accessible to him/her in conformity with the
p.000039: applicable laws on the protection of individuals with regard to processing of personal data40.
...
p.000039: 50 Paragraph 5.8 of ICH-E6
p.000039: 51 Paragraph 4.8.10 of ICH-E6
p.000039: 52 Art 11 juncto appendix of Additional Protocol on Biomedical research (COE) 2005; Paragraph 3.1.2 of ICH-E6. 53 Art.
p.000039: 6.3 (h) and (i) of Directive 2001/20/EC
p.000039: 54 Art. 6.3 of Directive 2001/20/EC
p.000039: 55 Paragraph 22 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 23/42
p.000039:
p.000039: 1. Failure to provide fair compensation by insurance or indemnity is a serious violation of ethical standards. The
p.000039: applicant for a MAA should provide EU Competent Authorities with a summary of the provisions made to provide for the
p.000039: fair compensation of subjects for trial related injury. This information can form part of the clinical study report
p.000039: section on ethical considerations and informed consent.
p.000039: 2. EMA and EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
p.000039: insurance, indemnity or compensation for research related injury and where applicable to seek additional assurance that
p.000039: trial subjects’ interest have been protected.
p.000039:
p.000039: 4.5. Vulnerable populations
p.000039:
p.000039: In the context of this paper, one of the main concerns is the vulnerability of person due to poverty, lack of adequate
p.000039: health care systems or lack of access to medicines,
p.000039: The definition of vulnerability is based on existing ethical guidelines. Nevertheless vulnerability has to be
p.000039: considered in terms of a condition, or situation affecting persons and making people vulnerable in particular situation
p.000039: rather than considering a specific population as vulnerable (people that are part of a specific population considered
p.000039: vulnerable may or may not be vulnerable).
p.000039: The key concern is to avoid that vulnerable persons or group are exploited for the benefit of EU patients. At the same
p.000039: time the benefit to the patient of taking part in the study and the ethics of potentially turning them away simply
p.000039: because they fit one of the vulnerable categories needs to be considered. Special care should be paid to the
p.000039: benefit/risk balance and to minimizing risk and burden when clinical trials are conducted in vulnerable populations56
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
...
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
...
p.000039: authorisation procedures. The application of GCP and ethical requirements and steps taken to confirm this, or any
p.000039: related issues should be reflected in the Public Assessment Reports.
p.000039: For example, guidance to assessors outlines the nature of clinical trial information that should be included in the
p.000039: assessment report at Day 80 and in the CHMP assessment report/EPAR. (see Guidance Document – Day 80 Clinical
p.000039: Assessment Report http://www.ema.europa.eu/pdfs/human/chmptemplates/CHMP-D80-AR-
p.000039: Guidance/D80AR_Clinical_Guidance_rev10_09.pdf ).
p.000039: Inclusion in the guidance of the items listed below, and the consistent application of this, will substantially improve
p.000039: the content of assessment reports and hence the Public Assessment Report in respect of ethical and GCP compliance.
p.000039: The CHMP or RMS assessment report and the Public Assessment Reports should address the following aspects:
p.000039: • The steps taken to evaluate and provide assurance regarding the ethical conduct of the trials should be
p.000039: described as should any significant deficiencies and how they have been addressed.
p.000039: • The standard GCP review should be summarised in an annex to the CHMP or RMS Assessment Report and to the Public
p.000039: Assessment Report, It should list, for each clinical trial submitted the protocol identification and title, start and
p.000039: end date, identification of the sponsor, of the countries where each trial was conducted and the numbers of subjects
p.000039: recruited in each country. The nature of the patient population should also be described (age and gender and any
p.000039: particular considerations of vulnerability). The standards to which the trials were conducted should be identified.
p.000039: This summary should be based on information to be supplied, electronically, by the applicant.
p.000039: • During the course of the assessment, any relevant ethical issue such as access to treatment post trial, use of
p.000039: placebo or treatment interruptions, choice of active comparators, treatment of vulnerable populations should be
p.000039: highlighted as part of the assessment of the individual trial.,
p.000039: • The justifications for the study designs, choice of comparators and selection of study populations, should be
p.000039: provided with particular emphasis on those studies that involve increased ethical sensitivity due to their design,
p.000039: indication, patient population or location of conduct. The applicability of the trial to the EEA population should be
p.000039: discussed where relevant.
p.000039: • A comment that “no ethical issues were identified” may be sufficient where applicable.
p.000039:
p.000039: • If available, information on Patients’ involvement in study design should be communicated,
p.000039:
p.000039: • When a GCP inspection is performed, the reason(s) for inspection should be described. The outcome and
p.000039: consequences on the assessment of a MAA should be further elaborated. Relevant information from the inspection report
p.000039: may be made publicly accessible.
p.000039: • When GCP/ethical concerns have been raised, the assessment report should present the issue, describe any
p.000039: external expertise sought and the advice received, and discuss the ethical aspects and their consequences on the
...
Health / Cognitive Impairment
Searching for indicator impairment:
(return to top)
p.000039: provide EU Regulatory Authorities with a summary of the steps taken to protect confidentiality and the consent obtained
p.000039: to enable the use of and access to the subjects’ data.
p.000039:
p.000039: 4.4. Fair compensation
p.000039:
p.000039: Article 3.2 (f) of Directive 2001/20/EC requires that provision is made for insurance or indemnity.
p.000039:
p.000039:
p.000039:
p.000039: 44 Art. 10 of Convention on Human Rights and Biomedicine of the Council of Europe (COE); Art. 27 of Additional Protocol
p.000039: on Biomedical research (COE), 2005
p.000039: 45 WHO (CIOMS) Guideline 18
p.000039: 46 Paragraph 4.8.10 of ICH E6
p.000039: 47 Paragraph 18 of Ethical considerations for clinical trials on medicinal products conducted with pediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 22/42
p.000039:
p.000039: Art 31 of the Additional Protocol on Biomedical research of Council of Europe states that “The person who has suffered
p.000039: damage as a result of participation in research shall be entitled to fair compensation
p.000039: 48 according to the conditions and procedures prescribed by law"
p.000039: The WHO-CIOMS Guideline 19 recommends that research subjects who suffer injury as a result of their participation
p.000039: should be entitled to free medical treatment for such injury and to such financial or other assistance as would
p.000039: compensate them equitably for any resultant impairment, disability or handicap.
p.000039: In the case of death as a result of their participation, their dependants are entitled to compensation.
p.000039:
p.000039: “Subjects must not be asked to waive the right to compensation or required to show negligence or lack of a reasonable
p.000039: degree of skill on the part of the investigator in order to claim free medical treatment or compensation. The informed
p.000039: consent process or form should contain no words that would absolve an investigator [or sponsor] from responsibility in
p.000039: the case of accidental injury, or that would imply that subjects would waive their right to seek compensation for
p.000039: impairment, disability or handicap.
p.000039: Prospective subjects should be informed that they will not need to take legal action to secure the free medical
p.000039: treatment or compensation for injury to which they may be entitled. They should also be told what medical service or
p.000039: organisation or individual will provide the medical treatment and what organisation will be responsible for providing
p.000039: compensation”. 49
p.000039: Before the research begins, the sponsor, whether a pharmaceutical company or other organisation or institution, should
p.000039: agree to provide compensation for any injury for which subjects are entitled to compensation, or come to an agreement
p.000039: with the investigator concerning the circumstances in which the investigator must rely on his or her own insurance
p.000039: coverage (for example, for negligence or failure of the investigator to follow the protocol, or where government
p.000039: insurance coverage is limited to negligence). In certain circumstances it may be advisable to follow both courses.
p.000039: “Sponsors should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution
p.000039: against claims arising from the trial, except for claims that arise from malpractice and/or negligence”.50
p.000039: “Both the informed consent discussion and the written informed consent form and any other written information to be
p.000039: provided to subjects involved in research should include explanations of the compensation and/or treatment available to
p.000039: the subject in the event of trial-related injury”.51
...
Health / Drug Usage
Searching for indicator drug:
(return to top)
p.000009: 3.3. Action plan
p.000010: 10
p.000010: 3.3.1. Core activities
p.000010: 10
p.000010: 3.3.2. Short Term activities:
p.000011: 11
p.000011: 3.3.3. Long Term activities:
p.000012: 12
p.000012: 3.4. Resource considerations 13
p.000012: 3.5. Example of initiatives
p.000013: 13
p.000013: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000013: use in the context of the activities of the European Regulatory Authorities
p.000014: 14
p.000014: 4.1. Ethics committee and national regulatory authority oversight 16
p.000014: 4.2. Information/Consent procedure 18
p.000014: 4.3. Confidentiality
p.000021: 21
p.000021: 4.4. Fair compensation
p.000022: 22
p.000022: 4.5. Vulnerable populations
p.000024: 24
p.000024: 4.6. Placebo and active comparator 26
p.000024: 4.7. Access to treatment post trial 28
p.000024: 4.8. Applicability of data to EEA population 29
p.000024: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000024: phase 29
p.000024: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000031: 31
p.000031: 5.2. Issues related to feasibility of clinical trials 31
p.000031: 5.3. General measures to assure data quality when conducting trials outside the EU 32
p.000031: 5.4. Considerations for designing clinical trials 33
p.000031: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000034: 34
p.000034: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000034: 34
p.000034: 6.2. Inspections: Triggers for inspection to be identified by assessor 36
p.000034: 6.3. Actions available in response to non compliance 37
p.000034: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039: 39
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 2/42
p.000039:
p.000039: 1. Glossary
p.000039: AR: Assessment Report
p.000039:
p.000039: COE: Council of Europe
p.000039:
p.000039: CHMP: Committee for Medicinal Products for Human Use
p.000039:
p.000039: CMD: Coordination Group for Mutual Recognition and Decentralised Procedures COMP:
p.000039: Committee for Orphan Medicinal Products
p.000039: CTFG: Clinical Trial Facilitation Group
p.000039:
p.000039: DCP: Decentralised Procedure
p.000039:
...
p.000039: be addressed before and during the conduct of the clinical trials and not only by assessment and inspection at the time
p.000039: of MA evaluation, by which point the trials have been completed, in some cases several years earlier.
p.000039: Actions to meet this objective therefore need to encompass EMA processes having an impact on clinical trials commencing
p.000039: prior to early phase clinical development. These processes include development of guidelines, Scientific Advice, Orphan
p.000039: Product Designation and Paediatric Investigation Plans and continue through to the finalisation of the CHMP opinion on
p.000039: the MAA/Scientific Opinion/Article 58 application evaluation, and post-authorisation activities and inspections.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 5/42
p.000039:
p.000039: In December 2008 the EMA published a strategy paper “Acceptance of clinical trials conducted in third countries for
p.000039: evaluation in Marketing Authorisation Applications”
p.000039: (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000072.js p&jsenabled=true)
p.000039: outlining four areas for action. These are:
p.000039: 1. Clarify the practical application of ethical standards for clinical trials, in the context of European Medicines
p.000039: Agency activities.
p.000039: 2. Determine the practical steps undertaken during the provision of guidance and advice in the drug development
p.000039: phase.
p.000039: 3. Determine the practical steps to be undertaken during the Marketing Authorisation phase
p.000039:
p.000039: 4. International cooperation in the regulation of clinical trials, their review and inspection and capacity building
p.000039: in this area.
p.000039: In 2009 the EMA established a Working Group on clinical trials on medicinal products for human use conducted outside
p.000039: EU/EEA.
p.000039: The Working Group, includes representatives of Committee for Medicinal Products for Human Use (CHMP), of the Paediatric
p.000039: Committee (PDCO), of the Committee for Orphan Medicinal Products (COMP), of the Clinical Trial Facilitation Group
p.000039: (CTFG), of the GCP Inspector Working group (GCP-IWG),
p.000039: Of the Working Group with Healthcare Professionals’ Organisations (HCP-WG), of the
p.000039:
p.000039: Working Party with Patients’ and Consumers’ Organisations (PCWP), of the Coordination Group for Mutual Recognition and
p.000039: Decentralized Procedures - Human (CMDh), of EMA and of the European Commission Pharmaceutical Unit
p.000039: This working Group has been asked to develop practical proposals for tasks and procedures or guidance to address the
p.000039: four action areas set out above. The present document reflects the results of the activities of this Working Group.
p.000039:
p.000039: 3. International cooperation in the regulation of clinical trials, their review and inspection and capacity building
p.000039: in this area
p.000039: International cooperation has been clearly identified as a key foundation in developing a robust international
...
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
p.000039: dignity, human rights and fundamental freedoms or to limit their scope. 35
p.000039: “Sponsors and investigators have a duty to refrain from unjustified deception, undue influence, or intimidations” 36and
p.000039: “to renew the informed consent of each subject if there are significant changes in the conditions or procedures of the
p.000039: research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate” 37
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. Failure to obtain informed consent (and/or assent where applicable) is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in a such unethical manner, when submitted in support of a MAA
p.000039: in accordance with Directive 2001/83 EC or Regulation EC 726/2004.
p.000039: 2. The applicant for a MAA should provide EU drug regulatory authorities with a summary of the consent processes used
p.000039: and significant variations of those processes in the clinical trials supporting the MAA and include sample information
p.000039: sheets on consent forms. This information should form part of the clinical study report in accordance with ICH E3.
p.000039:
p.000039:
p.000039: 29 Art. 6 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005) 30 WHO (CIOMS) Guideline 4
p.000039: 31 WHO (CIOMS) Guideline 4
p.000039: 32 WHO(CIOMS) Guideline 4
p.000039: 33 WHO (CIOMS) Guideline 4
p.000039: 34 Paragraph 6.3 of Ethical considerations for clinical trials on medicinal products conducted with the pediatric
p.000039: population 35 Art. 12 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005)
p.000039: 36 WHO (CIOMS) Guideline 6
p.000039: 37 WHO (CIOMS) Guideline 4 and 6
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 20/42
p.000039:
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: the consent process (e.g. arising from the patient population included and their capacity to provide informed consent,
p.000039: the regulatory framework within which they are conducted, the vulnerability of the study subjects) and where applicable
...
p.000039: protocol or other information provided to and approved by the Ethics Committe. Any special consent procedures or other
p.000039: precautions required should have been explicitly described to the Ethics Committe and approved by them.
p.000039: The decision to include vulnerable subjects in a trial should be fully justified by the sponsor. “Medical research
p.000039: involving a disadvantaged or vulnerable population or community is only justified if the research is responsive to the
p.000039: health needs and priorities of this population or community and if there is a reasonable likelihood that this
p.000039: population or community stands to benefit from the results of the research”67.
p.000039:
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. The inclusion of vulnerable subjects in a clinical trial without the approval of the Ethics Committe and without
p.000039: implementation of the appropriate consent processes is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in such an unethical manner, when submitted in support of a
p.000039: MAA in accordance with Directive 2001/83 EC and Regulation No (EC) 726/2004.
p.000039: 2. The applicant for a MAA should provide drug regulatory authorities with an adequate and appropriate justification
p.000039: for inviting vulnerable individuals or groups to serve as research subjects and the description of the specific
p.000039: measures and means implemented to protect their rights and welfare, should be included in the protocol and in the
p.000039: clinical study report (in accordance to ICH E3) and should made public in the Public Assessment Report
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: the inclusion of vulnerable populations and where applicable to seek additional assurance that the inclusion of such
p.000039: populations was justified and their rights and welfare protected.
p.000039:
p.000039: 4.6. Placebo and active comparator
p.000039:
p.000039: The capacity of a trial to produce reliable results is a pre-requisite for the ethical justification of that trial.
p.000039: “Research shall neither delay nor deprive trial participants of medically necessary preventive, diagnostic or
p.000039: therapeutic procedures”.68 A clinical trial cannot be justified ethically unless it is capable of producing
p.000039: scientifically reliable results. “In some circumstances it may be acceptable to use an alternative comparator, such as
p.000039: placebo or "no treatment”,69 whilst taking into account that “the rights, safety and wellbeing of the trials subjects
...
p.000039: national or regional health care system. The applicant should describe the provisions made for post trial access to
p.000039: treatment and medical care for study participants depending on their localization and the treatment and medical care
p.000039: otherwise available. This information can form part of the clinical study report section on ethical considerations in
p.000039: accordance with ICH E3.
p.000039: 2. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: access to treatment post trial and where applicable to seek additional assurance that the solution was appropriate and
p.000039: ethically acceptable.
p.000039: 3. EU Regulatory Authorities will summarize this information in the Public Assessment report.
p.000039:
p.000039: 4.8. Applicability of data to EEA population
p.000039:
p.000039: There are several issues relating to the applicability of trials conducted outside EU/EEA to European populations.
p.000039: These involve factors both intrinsic and extrinsic to the study population and EEA population. 78
p.000039: These are discussed in the “Reflection Paper on the extrapolation of results from clinical studies conducted outside
p.000039: the EU to the EU population” xxi 79 (Doc. Ref. EMEA/CHMP/EWP/692702/2008) and the ICH 1998 E5(R1) Ethnic Factors in the
p.000039: Acceptability of Foreign Clinical Data
p.000039: (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E5_R1/Step4/E5_R1
p.000039: Guideline.pdf). 80 xxii
p.000039:
p.000039: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000039: phase
p.000039: The EMA has a role in stimulating innovation and research in the pharmaceutical sector. The Agency gives scientific
p.000039: advice and protocol assistance to companies for the development of new medicinal products and draws up scientific
p.000039: guidelines aimed at helping applicants in the development of medicinal products. The tasks and responsibilities of the
p.000039: Agency under the Paediatric Regulation
p.000039:
p.000039: 77 WHO (CIOMS) Guideline 21
p.000039: 78 ICH 1998 E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
p.000039: 79 Reflection paper on the extrapolation of results from clinical studies conducted outside the EU to the EU population
p.000039: EMEA/CHMP/EWP/692702/2008
p.000039: 80 ICH 1998 E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 29/42
p.000039:
p.000039: include the provision of objective scientific decisions on the development plan for medicines for use in children.
p.000039: European pharmaceutical legislation (and that in other regions of the world also) requires clinical trials to be
p.000039: performed prior to the granting of a marketing authorisation. The analytical, pharmaco- toxicological and clinical
p.000039: requirements in respect of testing of medicinal products are set out in the Annex 1 of Directive 2001/83/EC. Additional
...
p.000039:
p.000039: • Availability of qualified investigators willing and available to conduct the trials,
p.000039:
p.000039: • Preparation for MAA, in those other countries,
p.000039:
p.000039: • Lower costs in some countries,
p.000039:
p.000039: • More rapid approval of trials,
p.000039:
p.000039: • Willingness of patients to participate in trials due to the trial facilitating access to higher standard of care
p.000039: and / or medication(s) not otherwise available to them,
p.000039: • Small number of relevant patients existing in Europe,
p.000039:
p.000039: • Availability of patients who are naïve to treatment,
p.000039:
p.000039: • Difficulty in recruiting patients due to differences in standard of care across developed countries.
p.000039:
p.000039: These issues or other circumstances influencing the location of clinical trials outside the EEA should be clearly
p.000039: identified. The applicant should provide the rationale for the location of such clinical trials and detail its plan for
p.000039: addressing ethical and operational issues related to its proposed development plan.
p.000039: Agency working groups should take into consideration the circumstances driving the location of trials when considering
p.000039: requests for advice, establishing requirements for the conduct of trials or developing guidelines and should:
p.000039: • highlight these circumstances and their related risks
p.000039:
p.000039: • try to minimise the risk by recommending some corrective actions or other alternatives for the drug development
p.000039: plan or clinical trials proposals
p.000039: • make the applicant aware of those potential issues before the trial is conducted whenever possible, or before
p.000039: the MA application
p.000039: • clearly identify the potential impact on the ethical aspects of trials and the quality of clinical data to be
p.000039: generated.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 30/42
p.000039:
p.000039: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000039:
p.000039: When addressing the targeted indication(s) and its applicability to the European population, both the applicant and EMA
p.000039: parties/ committees should specifically consider the following issues that could influence the decision to conduct
p.000039: trials outside the EU:
p.000039: • Condition(s) less frequent in the EU/EEA than in other non-EEA countries
p.000039:
p.000039: • Small number of affected subjects worldwide due to the rarity of the condition (e.g. rare diseases)
p.000039:
p.000039: • Applicability of the targeted drug claim in the European population when the disease is predominant mainly
p.000039: outside Europe (e.g. tropical diseases)
p.000039: • Different therapeutic needs in the European population
p.000039:
p.000039: • Clinical data to be generated may be of little relevance to the European population (e.g. notable difference in
p.000039: disease management).
p.000039: When applicable according to the procedure applied for, the applicant should consider the relevance of its clinical
p.000039: program, in relation to:
p.000039: • Applicability of the proposed indication and the therapeutic needs of the European population
p.000039:
p.000039: • Prevalence of the condition in non-EEA countries and in EEA countries.
p.000039:
p.000039: The consequences of drug development with clinical trials conducted outside the EEA (completely or partially) should be
p.000039: considered with regards to:
p.000039: • Limitations of data extrapolation from non-EU patients to the EEA
p.000039:
p.000039: • Impact of the geographic source of patients on the efficacy and safety results and their extrapolation the
p.000039: European population in the context of disease management (e.g. national characteristics of disease management and
p.000039: patient care)
p.000039: • Validity of the selected comparators (active or placebo) for enabling assessment of the Risk/Benefit balance of
p.000039: the product for the European population
p.000039: • Pre-specified subgroup analyses based on ethnicity and/or regions of the world
p.000039:
p.000039: • Evaluation of the level of adherence to standard background treatment regimes for a specific disease
p.000039: • Take into consideration possible differences in genetic profiles which could influence the drug response.
p.000039: Where a scientific advice, guidance or assessment relates to an application for a scientific opinion in the context of
p.000039: article 58 of Regulation No (EC) 726/2004 the considerations should relate to the population for which the medicinal
p.000039: product is to be used, rather than the EU population.
p.000039:
p.000039: 5.2. Issues related to feasibility of clinical trials
p.000039:
p.000039: The applicant should provide any available information on its development plan:
p.000039:
p.000039: • Details on the planned locations of the trials planned in the EEA and outside
p.000039:
p.000039: • Criteria for the selection of the non-EEA countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 31/42
p.000039:
p.000039: As such information may be limited or unavailable in the early phases of drug development, the applicant could provide
p.000039: a commitment to comply with general regulatory/GCP and ethical principles. Applicants are encouraged to seek follow-up
p.000039: advice when the drug development plan become clearer and clinical trials outside of the EU/EEA are foreseen
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
p.000039: to allow consideration of the possible consequences on the future MAA and results interpretation. This feasibility
p.000039: assessment should include as a minimum:
p.000039: • Recruitment plan for patients in the EEA and outside
p.000039:
p.000039: • Selection criteria and numbers of centres per country or regions outside the EEA
p.000039:
p.000039: • Duration of trial recruitment and expected impact of comparability of results over time in case of very long
p.000039: recruitment (e.g. duration of recruitment longer than 3 years for rare disease).
p.000039:
p.000039: 5.3. General measures to assure data quality when conducting trials outside the EU
p.000039:
p.000039: Issues that may have an impact on the quality of data to be generated should be clearly identified and resolved when
p.000039: possible:
p.000039: • Duration of the study
p.000039:
p.000039: • Complexity of the trial design, e.g.: requirement for blinding / shipments of samples (e.g. tissues)/ specific
p.000039: or high level of technology platforms required (e.g. MRI)/ frequency of biological/radiological monitoring/capability
p.000039: for storing clinical trials materials
p.000039: • Restricted access to specific tests and laboratory with possible impact on final data quality (e.g. testing of
p.000039: HIV resistance)
p.000039: • Access to active comparators/ placebo/ age-appropriate formulation at the national level or when provided by the
p.000039: applicant
p.000039: • Differences in Patients-Reported Outcomes
p.000039:
p.000039: • Limitations for long term follow up of patients after treatment (active comparator and study drug)
p.000039: discontinuation
p.000039: • Anticipated quality of data monitoring and training of investigators
p.000039:
p.000039: Specific measures to be taken into consideration in order to assure the quality of results should include:
p.000039: • Identification of limitations in extrapolating data from non-EU patients to the EEA populations, such as
p.000039: different ethnicities, underlying specific conditions
p.000039: • Different local epidemiology of infectious pathogens and / or disease pathology
p.000039:
p.000039: • Appropriateness of study design in accordance with the European guidelines and the most up to date scientific
p.000039: recommendations and ethical requirements
p.000039: • Choice of claim for superiority versus non inferiority in relation to a proper identification of therapeutic
p.000039: needs and respective recruitment capacity in the EEA and outside
p.000039: • Identification of standards of care for the targeted disease among countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 32/42
p.000039:
p.000039: • Drug and study acceptability by the patients in the targeted countries and by the national ECs
p.000039:
p.000039: • Research responsive to the health needs and priorities of the population or community in which it is carried
p.000039: out.
p.000039:
p.000039: 5.4. Considerations for designing clinical trials:
p.000039:
p.000039: The applicant should pay particular attention when designing trials outside the EEA in order to avoid generating data
p.000039: not relevant for the intended purpose:
p.000039: • Study design:
p.000039:
p.000039: - Risk of futility when efficacy assessment based on an inaccurate statistical hypothesis (e.g. inappropriate
p.000039: claim of superiority due to an underestimation of disease outcome in the countries outside the EEA )
p.000039: - Choice and access to active comparators and availability of other therapeutics required for best disease
p.000039: management in the selected countries
p.000039: - Level of overall standard of care in the targeted countries
p.000039:
p.000039: - Stopping rules in case of lack of efficacy or safety issue
p.000039:
p.000039: - Existence and responsibilities of the independent Data and Safety Monitoring Board and/ or Data Monitoring Board
p.000039: - Availability of a local accredited laboratory in the Country where the study is performed to provide testing of
p.000039: samples.
p.000039: • Analysis of factors potentially impacting on the ability to extrapolate the clinical trial results to the EU
p.000039: population, such as:
p.000039: - Sources of data variability
p.000039:
p.000039: disease outcome and management
p.000039:
p.000039: parameters impacting the drug effect variability standards of patients management care
p.000039: specific measures for assessment of treatment adherence in some specific cases
p.000039:
p.000039: - Validation of outcome measure, to be used in the non-EEA population (e.g. Quality Of Life scoring)
p.000039: - Implementation and interpretation of biomarkers and surrogate end-points
p.000039:
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. Clinical trials are conducted not only for submission to the EEA but also to many other regulators worldwide. In
p.000039: order to minimise risk of non-approvability of the application due to the choice of study populations not applicable to
p.000039: the EU/ EEA population or trial designs not acceptable in the EEA sponsors should seek EU scientific advice prior to
p.000039: the conduct of those trials.
p.000039: 2. EMA Committees and working Parties evaluating requests for Scientific Advice, Orphan designation, and Paediatric
p.000039: Investigation Plans and National Regulatory Authorities when applicable should systematically consider the issues
p.000039: raised in this reflection paper and apply the proposals during their assessments and recommendations/opinions provided
p.000039: to the applicants.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 33/42
p.000039:
p.000039: 3. Applicants should clearly explain why data from the patient populations selected are applicable to the EEA
p.000039: population unless the product is intended to be used outside the EEA.
p.000039:
...
Searching for indicator influence:
(return to top)
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 29/42
p.000039:
p.000039: include the provision of objective scientific decisions on the development plan for medicines for use in children.
p.000039: European pharmaceutical legislation (and that in other regions of the world also) requires clinical trials to be
p.000039: performed prior to the granting of a marketing authorisation. The analytical, pharmaco- toxicological and clinical
p.000039: requirements in respect of testing of medicinal products are set out in the Annex 1 of Directive 2001/83/EC. Additional
p.000039: requirements and incentives apply to encourage the conduct of clinical trials for the development of medicines for the
p.000039: treatment of children and for the treatment of patients with rare diseases. These requirements may increase the number
p.000039: and scope of clinical trials being conducted, not all of which can or need to be carried out in Europe. Clinical trials
p.000039: conducted in the EEA should comply with applicable laws and regulations. In addition, applicants intending to submit in
p.000039: the EEA are advised to consult with EEA regulators about the design and ethical conduct of clinical trials prior to
p.000039: their commencement when it is planned to conduct those trials in countries outside EU/EEA. EEA regulators should ensure
p.000039: that every opportunity is taken prior to the commencement of clinical trials to influence their design and ensure their
p.000039: ethical conduct.
p.000039: Several operational or technical considerations lead to the conduct of clinical trials in a widening range of
p.000039: countries:
p.000039: • Availability of patients willing to participate in clinical trials, and with the relevant disease profile,
p.000039:
p.000039: • Availability of qualified investigators willing and available to conduct the trials,
p.000039:
p.000039: • Preparation for MAA, in those other countries,
p.000039:
p.000039: • Lower costs in some countries,
p.000039:
p.000039: • More rapid approval of trials,
p.000039:
p.000039: • Willingness of patients to participate in trials due to the trial facilitating access to higher standard of care
p.000039: and / or medication(s) not otherwise available to them,
p.000039: • Small number of relevant patients existing in Europe,
p.000039:
p.000039: • Availability of patients who are naïve to treatment,
p.000039:
p.000039: • Difficulty in recruiting patients due to differences in standard of care across developed countries.
p.000039:
p.000039: These issues or other circumstances influencing the location of clinical trials outside the EEA should be clearly
p.000039: identified. The applicant should provide the rationale for the location of such clinical trials and detail its plan for
p.000039: addressing ethical and operational issues related to its proposed development plan.
p.000039: Agency working groups should take into consideration the circumstances driving the location of trials when considering
p.000039: requests for advice, establishing requirements for the conduct of trials or developing guidelines and should:
p.000039: • highlight these circumstances and their related risks
p.000039:
p.000039: • try to minimise the risk by recommending some corrective actions or other alternatives for the drug development
p.000039: plan or clinical trials proposals
p.000039: • make the applicant aware of those potential issues before the trial is conducted whenever possible, or before
p.000039: the MA application
p.000039: • clearly identify the potential impact on the ethical aspects of trials and the quality of clinical data to be
p.000039: generated.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 30/42
p.000039:
p.000039: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000039:
p.000039: When addressing the targeted indication(s) and its applicability to the European population, both the applicant and EMA
p.000039: parties/ committees should specifically consider the following issues that could influence the decision to conduct
p.000039: trials outside the EU:
p.000039: • Condition(s) less frequent in the EU/EEA than in other non-EEA countries
p.000039:
p.000039: • Small number of affected subjects worldwide due to the rarity of the condition (e.g. rare diseases)
p.000039:
p.000039: • Applicability of the targeted drug claim in the European population when the disease is predominant mainly
p.000039: outside Europe (e.g. tropical diseases)
p.000039: • Different therapeutic needs in the European population
p.000039:
p.000039: • Clinical data to be generated may be of little relevance to the European population (e.g. notable difference in
p.000039: disease management).
p.000039: When applicable according to the procedure applied for, the applicant should consider the relevance of its clinical
p.000039: program, in relation to:
p.000039: • Applicability of the proposed indication and the therapeutic needs of the European population
p.000039:
p.000039: • Prevalence of the condition in non-EEA countries and in EEA countries.
p.000039:
p.000039: The consequences of drug development with clinical trials conducted outside the EEA (completely or partially) should be
p.000039: considered with regards to:
p.000039: • Limitations of data extrapolation from non-EU patients to the EEA
p.000039:
p.000039: • Impact of the geographic source of patients on the efficacy and safety results and their extrapolation the
p.000039: European population in the context of disease management (e.g. national characteristics of disease management and
p.000039: patient care)
p.000039: • Validity of the selected comparators (active or placebo) for enabling assessment of the Risk/Benefit balance of
p.000039: the product for the European population
p.000039: • Pre-specified subgroup analyses based on ethnicity and/or regions of the world
p.000039:
p.000039: • Evaluation of the level of adherence to standard background treatment regimes for a specific disease
p.000039: • Take into consideration possible differences in genetic profiles which could influence the drug response.
p.000039: Where a scientific advice, guidance or assessment relates to an application for a scientific opinion in the context of
p.000039: article 58 of Regulation No (EC) 726/2004 the considerations should relate to the population for which the medicinal
p.000039: product is to be used, rather than the EU population.
p.000039:
p.000039: 5.2. Issues related to feasibility of clinical trials
p.000039:
p.000039: The applicant should provide any available information on its development plan:
p.000039:
p.000039: • Details on the planned locations of the trials planned in the EEA and outside
p.000039:
p.000039: • Criteria for the selection of the non-EEA countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 31/42
p.000039:
p.000039: As such information may be limited or unavailable in the early phases of drug development, the applicant could provide
p.000039: a commitment to comply with general regulatory/GCP and ethical principles. Applicants are encouraged to seek follow-up
p.000039: advice when the drug development plan become clearer and clinical trials outside of the EU/EEA are foreseen
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
...
Health / HIV/AIDS
Searching for indicator HIV:
(return to top)
p.000039: a commitment to comply with general regulatory/GCP and ethical principles. Applicants are encouraged to seek follow-up
p.000039: advice when the drug development plan become clearer and clinical trials outside of the EU/EEA are foreseen
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
p.000039: to allow consideration of the possible consequences on the future MAA and results interpretation. This feasibility
p.000039: assessment should include as a minimum:
p.000039: • Recruitment plan for patients in the EEA and outside
p.000039:
p.000039: • Selection criteria and numbers of centres per country or regions outside the EEA
p.000039:
p.000039: • Duration of trial recruitment and expected impact of comparability of results over time in case of very long
p.000039: recruitment (e.g. duration of recruitment longer than 3 years for rare disease).
p.000039:
p.000039: 5.3. General measures to assure data quality when conducting trials outside the EU
p.000039:
p.000039: Issues that may have an impact on the quality of data to be generated should be clearly identified and resolved when
p.000039: possible:
p.000039: • Duration of the study
p.000039:
p.000039: • Complexity of the trial design, e.g.: requirement for blinding / shipments of samples (e.g. tissues)/ specific
p.000039: or high level of technology platforms required (e.g. MRI)/ frequency of biological/radiological monitoring/capability
p.000039: for storing clinical trials materials
p.000039: • Restricted access to specific tests and laboratory with possible impact on final data quality (e.g. testing of
p.000039: HIV resistance)
p.000039: • Access to active comparators/ placebo/ age-appropriate formulation at the national level or when provided by the
p.000039: applicant
p.000039: • Differences in Patients-Reported Outcomes
p.000039:
p.000039: • Limitations for long term follow up of patients after treatment (active comparator and study drug)
p.000039: discontinuation
p.000039: • Anticipated quality of data monitoring and training of investigators
p.000039:
p.000039: Specific measures to be taken into consideration in order to assure the quality of results should include:
p.000039: • Identification of limitations in extrapolating data from non-EU patients to the EEA populations, such as
p.000039: different ethnicities, underlying specific conditions
p.000039: • Different local epidemiology of infectious pathogens and / or disease pathology
p.000039:
p.000039: • Appropriateness of study design in accordance with the European guidelines and the most up to date scientific
p.000039: recommendations and ethical requirements
p.000039: • Choice of claim for superiority versus non inferiority in relation to a proper identification of therapeutic
p.000039: needs and respective recruitment capacity in the EEA and outside
p.000039: • Identification of standards of care for the targeted disease among countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
...
Health / Mentally Disabled
Searching for indicator disability:
(return to top)
p.000039: EMA/121340/2011
p.000039: Page 18/42
p.000039:
p.000039: signed and dated informed consent form”.21 The trial participant should be given a copy of his/her consent once it is
p.000039: signed. Refusal to give consent or withdrawal of consent to participation in research shall not lead to any form of
p.000039: liability (particularly of a financial nature) and/or to any form of discrimination against the person concerned, in
p.000039: particular regarding the right to medical care 22. The same level of care and information should be maintained during
p.000039: treatment or investigations.
p.000039: The informed consent of each subject shall be renewed if there are significant changes in the conditions or procedures
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
...
p.000039: to enable the use of and access to the subjects’ data.
p.000039:
p.000039: 4.4. Fair compensation
p.000039:
p.000039: Article 3.2 (f) of Directive 2001/20/EC requires that provision is made for insurance or indemnity.
p.000039:
p.000039:
p.000039:
p.000039: 44 Art. 10 of Convention on Human Rights and Biomedicine of the Council of Europe (COE); Art. 27 of Additional Protocol
p.000039: on Biomedical research (COE), 2005
p.000039: 45 WHO (CIOMS) Guideline 18
p.000039: 46 Paragraph 4.8.10 of ICH E6
p.000039: 47 Paragraph 18 of Ethical considerations for clinical trials on medicinal products conducted with pediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 22/42
p.000039:
p.000039: Art 31 of the Additional Protocol on Biomedical research of Council of Europe states that “The person who has suffered
p.000039: damage as a result of participation in research shall be entitled to fair compensation
p.000039: 48 according to the conditions and procedures prescribed by law"
p.000039: The WHO-CIOMS Guideline 19 recommends that research subjects who suffer injury as a result of their participation
p.000039: should be entitled to free medical treatment for such injury and to such financial or other assistance as would
p.000039: compensate them equitably for any resultant impairment, disability or handicap.
p.000039: In the case of death as a result of their participation, their dependants are entitled to compensation.
p.000039:
p.000039: “Subjects must not be asked to waive the right to compensation or required to show negligence or lack of a reasonable
p.000039: degree of skill on the part of the investigator in order to claim free medical treatment or compensation. The informed
p.000039: consent process or form should contain no words that would absolve an investigator [or sponsor] from responsibility in
p.000039: the case of accidental injury, or that would imply that subjects would waive their right to seek compensation for
p.000039: impairment, disability or handicap.
p.000039: Prospective subjects should be informed that they will not need to take legal action to secure the free medical
p.000039: treatment or compensation for injury to which they may be entitled. They should also be told what medical service or
p.000039: organisation or individual will provide the medical treatment and what organisation will be responsible for providing
p.000039: compensation”. 49
p.000039: Before the research begins, the sponsor, whether a pharmaceutical company or other organisation or institution, should
p.000039: agree to provide compensation for any injury for which subjects are entitled to compensation, or come to an agreement
p.000039: with the investigator concerning the circumstances in which the investigator must rely on his or her own insurance
p.000039: coverage (for example, for negligence or failure of the investigator to follow the protocol, or where government
p.000039: insurance coverage is limited to negligence). In certain circumstances it may be advisable to follow both courses.
p.000039: “Sponsors should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution
p.000039: against claims arising from the trial, except for claims that arise from malpractice and/or negligence”.50
p.000039: “Both the informed consent discussion and the written informed consent form and any other written information to be
p.000039: provided to subjects involved in research should include explanations of the compensation and/or treatment available to
p.000039: the subject in the event of trial-related injury”.51
p.000039: Information shall be provided to the EC and where required to the National Regulatory Authority, on details of any
...
Health / Mentally Incapacitated
Searching for indicator incapable:
(return to top)
p.000039: considered in terms of a condition, or situation affecting persons and making people vulnerable in particular situation
p.000039: rather than considering a specific population as vulnerable (people that are part of a specific population considered
p.000039: vulnerable may or may not be vulnerable).
p.000039: The key concern is to avoid that vulnerable persons or group are exploited for the benefit of EU patients. At the same
p.000039: time the benefit to the patient of taking part in the study and the ethics of potentially turning them away simply
p.000039: because they fit one of the vulnerable categories needs to be considered. Special care should be paid to the
p.000039: benefit/risk balance and to minimizing risk and burden when clinical trials are conducted in vulnerable populations56
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
...
Health / Physically Disabled
Searching for indicator illness:
(return to top)
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
p.000039: not pregnant, or on persons who are not deprived of liberty, whether the person undergoing research has been informed
p.000039: of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a
p.000039: state to receive the information, whether the necessary authorisation has been given specifically and in writing by the
p.000039: legal representative, and the person (or pregnant woman) concerned does not object.
p.000039: Exceptionally and under the protective conditions prescribed by law, where the research may not have the potential to
...
Health / Physically Ill
Searching for indicator sick:
(return to top)
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
...
Health / Pregnant
Searching for indicator pregnant:
(return to top)
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
p.000039: not pregnant, or on persons who are not deprived of liberty, whether the person undergoing research has been informed
p.000039: of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a
p.000039: state to receive the information, whether the necessary authorisation has been given specifically and in writing by the
p.000039: legal representative, and the person (or pregnant woman) concerned does not object.
p.000039: Exceptionally and under the protective conditions prescribed by law, where the research may not have the potential to
p.000039: produce results of direct benefit to the health of the person concerned, such research may be authorised, if it can
p.000039: contribute to the benefit of the group concerned whilst fulfilling the other conditions described above. “Measures of
p.000039: such benefit would include the importance of knowledge gained, severity of the issue to be addressed, commonality of
p.000039: the issue, likelihood of obtaining results from proposed research, and usefulness of benefits obtained”.66
p.000039:
p.000039:
p.000039:
p.000039: 62 Recital 3 of Directive 2001/20/EC
p.000039: 63 Recital 4 and art. 1 of Regulation EC/1901/2006 and art. 4 of Directive 2001/20/EC.
p.000039: 64 Belmont Report: ethical principles and guidelines for the protection of human subjects of research, Section D 3. 65
p.000039: Art. 17 of Declaration of Helsinki (2008).
p.000039: 66 Paragraph 12 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 25/42
p.000039:
p.000039: The need for special protection of the vulnerable population rights and welfare should be reviewed and applied, where
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.000007: 7
p.000007: 3.2. Identification of opportunities and partners 9
p.000007: 3.2.1. Identification of other initiatives
p.000009: 9
p.000009: 3.2.2. Categories of initiatives and actions 9
p.000009: 3.2.3. Establishment of contact with key initiatives 10
p.000009: 3.3. Action plan
p.000010: 10
p.000010: 3.3.1. Core activities
p.000010: 10
p.000010: 3.3.2. Short Term activities:
p.000011: 11
p.000011: 3.3.3. Long Term activities:
p.000012: 12
p.000012: 3.4. Resource considerations 13
p.000012: 3.5. Example of initiatives
p.000013: 13
p.000013: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000013: use in the context of the activities of the European Regulatory Authorities
p.000014: 14
p.000014: 4.1. Ethics committee and national regulatory authority oversight 16
p.000014: 4.2. Information/Consent procedure 18
p.000014: 4.3. Confidentiality
p.000021: 21
p.000021: 4.4. Fair compensation
p.000022: 22
p.000022: 4.5. Vulnerable populations
p.000024: 24
p.000024: 4.6. Placebo and active comparator 26
p.000024: 4.7. Access to treatment post trial 28
p.000024: 4.8. Applicability of data to EEA population 29
p.000024: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000024: phase 29
p.000024: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000031: 31
p.000031: 5.2. Issues related to feasibility of clinical trials 31
p.000031: 5.3. General measures to assure data quality when conducting trials outside the EU 32
p.000031: 5.4. Considerations for designing clinical trials 33
p.000031: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000034: 34
p.000034: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000034: 34
p.000034: 6.2. Inspections: Triggers for inspection to be identified by assessor 36
p.000034: 6.3. Actions available in response to non compliance 37
p.000034: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039: 39
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 2/42
p.000039:
p.000039: 1. Glossary
...
p.000039:
p.000039: Research may only be undertaken if the research project has been approved by an EC (or other body authorised to review
p.000039: clinical research on human beings) with appropriate jurisdiction for the investigator sites and trial concerned, after
p.000039: independent examination of its scientific merit, including assessment of the importance of the aim of research, and
p.000039: multidisciplinary review of its ethical acceptability,4 In many countries an application also has to be made to a
p.000039: Regulatory Authority, before a clinical trial may commence.
p.000039: It is an important element of international cooperation that Regulatory Authorities support compliance with local
p.000039: requirements in each country as well as reinforcing international ethical and good clinical practice standards.
p.000039: All the information which is necessary for the ethical assessment of the research project should be given in written
p.000039: form to the Ethics Committee. 5 The Ethics Committee, in preparing its opinion should consider amongst others the
p.000039: points set out in art. 3, 4, 5 and 6 of the Directive 2001/20/EC, the Appendix to the additional protocol on biomedical
p.000039: research (COE- Information to be given to the Ethics Committee), and chapters 2 and 3 of ICH E 6 and WHO (CIOMS)
p.000039: guidelines 2. The Ethics Committees hould be satisfied that no undue influence, including that of a financial nature
p.000039: (or limiting or increasing access to medical care), will be exerted on persons, to participate in research. In this
p.000039: respect, particular attention must be given to vulnerable or dependent persons.6 EU legislation gives particular
p.000039: attention to protection of paediatric subjects7.
p.000039: The Ethics Committee shall give clearly stated reasons for its positive or negative conclusions. 8
p.000039: The declaration of Helsinki states that “No change to the protocol may be made without consideration and approval by
p.000039: the ethics committee”.9 EU Directive 2001/20/EC specifies that this should apply to substantial amendments.10 Research
p.000039: projects should be re-examined if this is justified in the light of scientific developments or events arising in the
p.000039: course of the research. 11
p.000039: “The ethics committee must have the right to monitor ongoing studies”12 “and to report to institutional or governmental
p.000039: authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that
p.000039: they have approved or in the conduct of the studies”.13
p.000039: If the clinical trial is planned to be conducted in a country with limited Regulatory Authority or Ethics Committees
p.000039: framework and limited oversight of the clinical trial, the sponsor should put in place alternative solutions in order
p.000039: to ensure an adequate review of the clinical trial protocol. A possible option could be to consider complementing the
...
p.000039: Human Genetic Data; art 8 Charter of fundamental rights of the European Union
p.000039: 40 Art. 26 of Additional Protocol on Biomedical research (COE), 2005
p.000039: 41 Art. 6 of Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on
p.000039: the free movement of such data
p.000039: 42 WHO (CIOMS) Guideline 18
p.000039: 43 Art 27 of additional Protocol on Biomedical research (COE), 2005
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 21/42
p.000039:
p.000039: participant” [including the minor and/or his/her legal representative] ”not to receive such information”, in accordance
p.000039: with national law.44“During the process of obtaining informed consent the investigator should inform the prospective
p.000039: subjects about the precautions that will be taken to protect confidentiality”.45
p.000039: The written information and informed consent form to be provided to subjects should include explanations:
p.000039: a) of the extent to which the monitor(s), the auditor(s), the Ethics Committe and the regulatory authority(ies) will be
p.000039: granted direct access to the subject's original medical records for verification of clinical trial procedures and/or
p.000039: data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000039: regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable
p.000039: representative is authorising such access.
p.000039: b) “that records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws
p.000039: and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’
p.000039: identity will remain confidential”.46
p.000039: Biological sample retention, planned analysis and the need for consent to such use (and reuse) should be in accordance
p.000039: with what is described in the protocol. Samples cannot be used for purposes different of the ones described in the
p.000039: protocol without a new written informed consent
p.000039: The trial documents should be archived for a duration that takes into consideration the potential need for long-term
p.000039: review, particularly for trials performed in children (long-term safety).
p.000039: Where personal information is collected, stored, accessed, used, or disposed of, a researcher should ensure that the
p.000039: privacy, confidentiality and cultural sensitivities of the subject and/or the collectivity are respected, most of all
p.000039: when children are involved47.
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. EU Regulatory Authorities should disregard reports which fail to properly protect the confidentiality of the trial
p.000039: subjects, when submitted in support of a MAA in accordance with Directive 2001/83 EC or Regulation No (EC) 726/2004.
p.000039: These reports should be returned to the applicant and the breaches of confidentiality rectified (including removal of
p.000039: confidential information from their database) prior to eventual resubmission.
p.000039: 2. EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
p.000039: confidentiality (e.g. arising from the use of genetic information or bio banked samples) and where applicable seek
p.000039: additional assurance that confidentiality has been properly maintained. When requested, the applicant for a MAA should
p.000039: provide EU Regulatory Authorities with a summary of the steps taken to protect confidentiality and the consent obtained
p.000039: to enable the use of and access to the subjects’ data.
p.000039:
p.000039: 4.4. Fair compensation
p.000039:
p.000039: Article 3.2 (f) of Directive 2001/20/EC requires that provision is made for insurance or indemnity.
p.000039:
p.000039:
p.000039:
p.000039: 44 Art. 10 of Convention on Human Rights and Biomedicine of the Council of Europe (COE); Art. 27 of Additional Protocol
p.000039: on Biomedical research (COE), 2005
p.000039: 45 WHO (CIOMS) Guideline 18
p.000039: 46 Paragraph 4.8.10 of ICH E6
p.000039: 47 Paragraph 18 of Ethical considerations for clinical trials on medicinal products conducted with pediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 22/42
p.000039:
p.000039: Art 31 of the Additional Protocol on Biomedical research of Council of Europe states that “The person who has suffered
p.000039: damage as a result of participation in research shall be entitled to fair compensation
p.000039: 48 according to the conditions and procedures prescribed by law"
p.000039: The WHO-CIOMS Guideline 19 recommends that research subjects who suffer injury as a result of their participation
p.000039: should be entitled to free medical treatment for such injury and to such financial or other assistance as would
p.000039: compensate them equitably for any resultant impairment, disability or handicap.
p.000039: In the case of death as a result of their participation, their dependants are entitled to compensation.
p.000039:
p.000039: “Subjects must not be asked to waive the right to compensation or required to show negligence or lack of a reasonable
...
p.000039: 6.3 (h) and (i) of Directive 2001/20/EC
p.000039: 54 Art. 6.3 of Directive 2001/20/EC
p.000039: 55 Paragraph 22 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 23/42
p.000039:
p.000039: 1. Failure to provide fair compensation by insurance or indemnity is a serious violation of ethical standards. The
p.000039: applicant for a MAA should provide EU Competent Authorities with a summary of the provisions made to provide for the
p.000039: fair compensation of subjects for trial related injury. This information can form part of the clinical study report
p.000039: section on ethical considerations and informed consent.
p.000039: 2. EMA and EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
p.000039: insurance, indemnity or compensation for research related injury and where applicable to seek additional assurance that
p.000039: trial subjects’ interest have been protected.
p.000039:
p.000039: 4.5. Vulnerable populations
p.000039:
p.000039: In the context of this paper, one of the main concerns is the vulnerability of person due to poverty, lack of adequate
p.000039: health care systems or lack of access to medicines,
p.000039: The definition of vulnerability is based on existing ethical guidelines. Nevertheless vulnerability has to be
p.000039: considered in terms of a condition, or situation affecting persons and making people vulnerable in particular situation
p.000039: rather than considering a specific population as vulnerable (people that are part of a specific population considered
p.000039: vulnerable may or may not be vulnerable).
p.000039: The key concern is to avoid that vulnerable persons or group are exploited for the benefit of EU patients. At the same
p.000039: time the benefit to the patient of taking part in the study and the ethics of potentially turning them away simply
p.000039: because they fit one of the vulnerable categories needs to be considered. Special care should be paid to the
p.000039: benefit/risk balance and to minimizing risk and burden when clinical trials are conducted in vulnerable populations56
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
...
p.000039: The use of placebo is permissible in accordance with principles foreseen in the Directive 2001/20/EC, Directive
p.000039: 2005/28/EC, the WHO (CIOMS) Guidelines 8 and 11, paragraph 32 of the Declaration of Helsinki (2008), article 23 of the
p.000039: Additional Protocol on Biomedical Research of the Council of Europe(2005), paragraph 2.1; 2.2; 2.3 and 2.12 of the Note
p.000039: for Guidance on Good Clinical Practice (CPMP/ICH/135/95), paragraphs 9.2.1 and 9.2.3 of the guideline on ethical
p.000039: considerations for clinical trials on medicinal products conducted with the paediatric population (2008) and ICH E10
p.000039: (Choice of Control Group). The CPMP position statement on the use of placebo in clinical trials (28 June 2001
p.000039: EMEA/17424/01) should also be taken into account.71
p.000039: Studies carried out in countries outside EU/EEA should meet the same ethical principles and standards applied to
p.000039: studies performed in the EEA. Derogation from these principles should not be accepted in particular in the context of
p.000039: the European marketing authorisation procedure.
p.000039: EU Regulatory Authorities should neither require nor accept study designs, involving placebo or other comparator, which
p.000039: would not be ethically acceptable in the EEA.
p.000039: “Economic [or logistical] reason for the unavailability of an established effective intervention cannot justify a
p.000039: placebo-controlled study in a country of limited resources when it would be unethical to conduct a study with the same
p.000039: design in a population with general access to the effective intervention outside the study”. 72
p.000039: Lack of access of patients in communities within, or outside of, the EEA, to the EEA-licensed (or equivalent)
p.000039: comparator cannot be a justification to withhold this treatment option to those patients when participating in a trial
p.000039: regardless of the reasons for the lack of access (e.g. no reimbursement, no national marketing authorisation).
p.000039: Regardless of the location of the trial, all patients participating in these trials should receive the same or a
p.000039: similar standard of care and comparable treatment options as trial participants within the EEA.
p.000039: EU Regulatory Authorities should verify that the study has been reviewed by the Ethics Committees and that they have
p.000039: determined: whether the use of placebo or other comparator is ethically acceptable in the context of that trial;
p.000039: whether the safety and rights of the subjects have been fully protected and whether prospective subjects would be fully
p.000039: informed about the use of placebo and/or other comparators and available alternative treatments and gave their informed
p.000039: consent (or informed refusal), in accordance with above cited ethical principles. 73
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. Sponsors should describe in detail in the protocol and in the clinical study report the justification for the use
p.000039: of placebo and/or choice of active comparator in accordance with the ethical principles referred to above. This
p.000039: information can form part of the clinical study report in accordance with ICH3 and protocol in accordance with ICH E6.
p.000039: 2. EU Regulatory Authorities will identify those studies that may give rise to special ethical concern regarding the
p.000039: use of placebo or other comparators and where applicable seek additional assurance that the design was appropriate and
p.000039: ethically acceptable.
p.000039:
p.000039:
p.000039:
p.000039: 71 http://www.ema.europa.eu/pdfs/human/press/pos/1742401en.pdf
p.000039: 72 WHO (CIOMS) Guideline 11
p.000039: 73 WHO (CIOMS) Guideline 11
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 27/42
p.000039:
p.000039: 3. Where it is determined that a study design was not acceptable in accordance with the aforementioned criteria, it
p.000039: should not be accepted in support of a MAA in accordance with Directive 2001/83 EC and Regulation No (EC) 726/2004.
p.000039: 4. If a sponsor has particular concern about a particular trial design, it is strongly advised to seek scientific
p.000039: advice with Regulators on study design before carrying out the trials
p.000039:
p.000039: 4.7. Access to treatment post trial
p.000039:
p.000039: Patients’ access to innovative medicinal products varies widely. Differences in patients’ access mostly reflect
p.000039: differences in the economic situation and social and health care systems of the country or region both inside the EEA
p.000039: and countries outside EU/EEA.
p.000039: Whether the medicinal product is likely to be available in the community or country where the research study is
p.000039: conducted should be considered by the sponsor, Ethics Committees and National Regulatory Authorities. New medicinal
p.000039: products should be intended for marketing in the countries or regions where the clinical trials are conducted. For the
p.000039: individual patient who participated in a clinical trial continued access to the product that has been identified as
p.000039: beneficial is crucial. It is recognized; however, that post trial access of patients to treatment or medical care
p.000039: provided by sponsor or investigator cannot substitute for shortcomings of national or regional health care systems.
p.000039: Paragraph 14 of the Declaration of Helsinki requires that the protocol should describe arrangements for post-study
p.000039: access by study subjects to interventions identified as beneficial in the study or access to other appropriate care or
p.000039: benefits 74
p.000039: WHO demands that before consenting, subjects must be “informed, whether, when and how any products or interventions
p.000039: proven by the research to be safe and effective will be made available to them after they have completed their
p.000039: participation in the research and whether they will be expected to pay for them”.75
p.000039: Paragraph 33 of the Declaration of Helsinki requires: “At the conclusion of the study, patients entered into the study
p.000039: are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example,
p.000039: access to interventions identified as beneficial in the study or to other appropriate care or benefits”.76
p.000039: For the time between end of the trial and the availability of the licensed product on the market, the continuation of
p.000039: treatment by the sponsor needs to be considered, e.g. in the context of compassionate use. The cessation of a
p.000039: beneficial possibly life-saving or -prolonging treatment at or after marketing of the product due to economic reasons,
p.000039: e.g. low personal income of the patients and/or no reimbursement is problematic. Ethical Committees, national
p.000039: regulatory authorities and patients participating in a clinical trial need to be fully informed prior to any decision
p.000039: on their part whether and under what conditions study participants will have access to a treatment that has been shown
p.000039: to be safe and effective for them during the trial taking into account the specific situation in their country or
p.000039: region.
p.000039: Depending on national or regional healthcare systems, participation in a trial may also offer access to significantly
p.000039: better medical care than would otherwise be available. The cessation of the standard of care available during the
p.000039: trial, once a trial is over, has been widely criticized. Ethics committees, national regulatory authorities and
p.000039: patients participating in a clinical trial need to be fully informed
p.000039:
p.000039: 74 Para.33 of Declaration of Helsinki (2008) 75 WHO (CIOMS) Guideline 5
p.000039: 76 Para.33 of Declaration of Helsinki (2008)
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 28/42
p.000039:
p.000039: prior to any decision on what post trial medical care or other relevant benefits will be provided by the investigator
p.000039: or sponsor.77
p.000039: Transparency on matters of post trial access to treatment and medical care is paramount for clinical trials submitted
p.000039: to EMA in support of European MAA. The Applicant should describe the situation of trial participants with regard to
p.000039: post trial access to treatment and medical care with respect to the local situation where the trial is conducted. The
p.000039: Applicant should describe what provisions were made for post trial access to treatment and medical care and what
p.000039: information was given to the patients prior to their consent. This information will be summarised in the European
p.000039: Public Assessment Report (EPAR).
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. The applicant for a MAA should provide EU Regulatory Authorities with a description of the situation of trial
p.000039: participants with regard to post trial access to treatment and medical care depending on their localization and the
p.000039: national or regional health care system. The applicant should describe the provisions made for post trial access to
p.000039: treatment and medical care for study participants depending on their localization and the treatment and medical care
p.000039: otherwise available. This information can form part of the clinical study report section on ethical considerations in
p.000039: accordance with ICH E3.
p.000039: 2. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: access to treatment post trial and where applicable to seek additional assurance that the solution was appropriate and
p.000039: ethically acceptable.
p.000039: 3. EU Regulatory Authorities will summarize this information in the Public Assessment report.
p.000039:
p.000039: 4.8. Applicability of data to EEA population
p.000039:
p.000039: There are several issues relating to the applicability of trials conducted outside EU/EEA to European populations.
p.000039: These involve factors both intrinsic and extrinsic to the study population and EEA population. 78
p.000039: These are discussed in the “Reflection Paper on the extrapolation of results from clinical studies conducted outside
p.000039: the EU to the EU population” xxi 79 (Doc. Ref. EMEA/CHMP/EWP/692702/2008) and the ICH 1998 E5(R1) Ethnic Factors in the
p.000039: Acceptability of Foreign Clinical Data
p.000039: (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E5_R1/Step4/E5_R1
p.000039: Guideline.pdf). 80 xxii
p.000039:
p.000039: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000039: phase
p.000039: The EMA has a role in stimulating innovation and research in the pharmaceutical sector. The Agency gives scientific
p.000039: advice and protocol assistance to companies for the development of new medicinal products and draws up scientific
p.000039: guidelines aimed at helping applicants in the development of medicinal products. The tasks and responsibilities of the
p.000039: Agency under the Paediatric Regulation
p.000039:
p.000039: 77 WHO (CIOMS) Guideline 21
p.000039: 78 ICH 1998 E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
...
p.000039: requirements in respect of testing of medicinal products are set out in the Annex 1 of Directive 2001/83/EC. Additional
p.000039: requirements and incentives apply to encourage the conduct of clinical trials for the development of medicines for the
p.000039: treatment of children and for the treatment of patients with rare diseases. These requirements may increase the number
p.000039: and scope of clinical trials being conducted, not all of which can or need to be carried out in Europe. Clinical trials
p.000039: conducted in the EEA should comply with applicable laws and regulations. In addition, applicants intending to submit in
p.000039: the EEA are advised to consult with EEA regulators about the design and ethical conduct of clinical trials prior to
p.000039: their commencement when it is planned to conduct those trials in countries outside EU/EEA. EEA regulators should ensure
p.000039: that every opportunity is taken prior to the commencement of clinical trials to influence their design and ensure their
p.000039: ethical conduct.
p.000039: Several operational or technical considerations lead to the conduct of clinical trials in a widening range of
p.000039: countries:
p.000039: • Availability of patients willing to participate in clinical trials, and with the relevant disease profile,
p.000039:
p.000039: • Availability of qualified investigators willing and available to conduct the trials,
p.000039:
p.000039: • Preparation for MAA, in those other countries,
p.000039:
p.000039: • Lower costs in some countries,
p.000039:
p.000039: • More rapid approval of trials,
p.000039:
p.000039: • Willingness of patients to participate in trials due to the trial facilitating access to higher standard of care
p.000039: and / or medication(s) not otherwise available to them,
p.000039: • Small number of relevant patients existing in Europe,
p.000039:
p.000039: • Availability of patients who are naïve to treatment,
p.000039:
p.000039: • Difficulty in recruiting patients due to differences in standard of care across developed countries.
p.000039:
p.000039: These issues or other circumstances influencing the location of clinical trials outside the EEA should be clearly
p.000039: identified. The applicant should provide the rationale for the location of such clinical trials and detail its plan for
p.000039: addressing ethical and operational issues related to its proposed development plan.
p.000039: Agency working groups should take into consideration the circumstances driving the location of trials when considering
p.000039: requests for advice, establishing requirements for the conduct of trials or developing guidelines and should:
p.000039: • highlight these circumstances and their related risks
p.000039:
p.000039: • try to minimise the risk by recommending some corrective actions or other alternatives for the drug development
p.000039: plan or clinical trials proposals
p.000039: • make the applicant aware of those potential issues before the trial is conducted whenever possible, or before
p.000039: the MA application
p.000039: • clearly identify the potential impact on the ethical aspects of trials and the quality of clinical data to be
p.000039: generated.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
...
p.000039: a commitment to comply with general regulatory/GCP and ethical principles. Applicants are encouraged to seek follow-up
p.000039: advice when the drug development plan become clearer and clinical trials outside of the EU/EEA are foreseen
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
p.000039: to allow consideration of the possible consequences on the future MAA and results interpretation. This feasibility
p.000039: assessment should include as a minimum:
p.000039: • Recruitment plan for patients in the EEA and outside
p.000039:
p.000039: • Selection criteria and numbers of centres per country or regions outside the EEA
p.000039:
p.000039: • Duration of trial recruitment and expected impact of comparability of results over time in case of very long
p.000039: recruitment (e.g. duration of recruitment longer than 3 years for rare disease).
p.000039:
p.000039: 5.3. General measures to assure data quality when conducting trials outside the EU
p.000039:
p.000039: Issues that may have an impact on the quality of data to be generated should be clearly identified and resolved when
p.000039: possible:
p.000039: • Duration of the study
p.000039:
p.000039: • Complexity of the trial design, e.g.: requirement for blinding / shipments of samples (e.g. tissues)/ specific
p.000039: or high level of technology platforms required (e.g. MRI)/ frequency of biological/radiological monitoring/capability
p.000039: for storing clinical trials materials
p.000039: • Restricted access to specific tests and laboratory with possible impact on final data quality (e.g. testing of
p.000039: HIV resistance)
p.000039: • Access to active comparators/ placebo/ age-appropriate formulation at the national level or when provided by the
p.000039: applicant
p.000039: • Differences in Patients-Reported Outcomes
p.000039:
p.000039: • Limitations for long term follow up of patients after treatment (active comparator and study drug)
p.000039: discontinuation
p.000039: • Anticipated quality of data monitoring and training of investigators
p.000039:
p.000039: Specific measures to be taken into consideration in order to assure the quality of results should include:
p.000039: • Identification of limitations in extrapolating data from non-EU patients to the EEA populations, such as
p.000039: different ethnicities, underlying specific conditions
p.000039: • Different local epidemiology of infectious pathogens and / or disease pathology
p.000039:
p.000039: • Appropriateness of study design in accordance with the European guidelines and the most up to date scientific
p.000039: recommendations and ethical requirements
p.000039: • Choice of claim for superiority versus non inferiority in relation to a proper identification of therapeutic
p.000039: needs and respective recruitment capacity in the EEA and outside
p.000039: • Identification of standards of care for the targeted disease among countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 32/42
p.000039:
p.000039: • Drug and study acceptability by the patients in the targeted countries and by the national ECs
p.000039:
p.000039: • Research responsive to the health needs and priorities of the population or community in which it is carried
p.000039: out.
p.000039:
p.000039: 5.4. Considerations for designing clinical trials:
p.000039:
p.000039: The applicant should pay particular attention when designing trials outside the EEA in order to avoid generating data
p.000039: not relevant for the intended purpose:
p.000039: • Study design:
p.000039:
p.000039: - Risk of futility when efficacy assessment based on an inaccurate statistical hypothesis (e.g. inappropriate
p.000039: claim of superiority due to an underestimation of disease outcome in the countries outside the EEA )
p.000039: - Choice and access to active comparators and availability of other therapeutics required for best disease
p.000039: management in the selected countries
p.000039: - Level of overall standard of care in the targeted countries
p.000039:
p.000039: - Stopping rules in case of lack of efficacy or safety issue
p.000039:
p.000039: - Existence and responsibilities of the independent Data and Safety Monitoring Board and/ or Data Monitoring Board
p.000039: - Availability of a local accredited laboratory in the Country where the study is performed to provide testing of
p.000039: samples.
p.000039: • Analysis of factors potentially impacting on the ability to extrapolate the clinical trial results to the EU
p.000039: population, such as:
p.000039: - Sources of data variability
p.000039:
p.000039: disease outcome and management
p.000039:
p.000039: parameters impacting the drug effect variability standards of patients management care
p.000039: specific measures for assessment of treatment adherence in some specific cases
p.000039:
p.000039: - Validation of outcome measure, to be used in the non-EEA population (e.g. Quality Of Life scoring)
p.000039: - Implementation and interpretation of biomarkers and surrogate end-points
p.000039:
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. Clinical trials are conducted not only for submission to the EEA but also to many other regulators worldwide. In
p.000039: order to minimise risk of non-approvability of the application due to the choice of study populations not applicable to
p.000039: the EU/ EEA population or trial designs not acceptable in the EEA sponsors should seek EU scientific advice prior to
p.000039: the conduct of those trials.
...
p.000039: assessment report at Day 80 and in the CHMP assessment report/EPAR. (see Guidance Document – Day 80 Clinical
p.000039: Assessment Report http://www.ema.europa.eu/pdfs/human/chmptemplates/CHMP-D80-AR-
p.000039: Guidance/D80AR_Clinical_Guidance_rev10_09.pdf ).
p.000039: Inclusion in the guidance of the items listed below, and the consistent application of this, will substantially improve
p.000039: the content of assessment reports and hence the Public Assessment Report in respect of ethical and GCP compliance.
p.000039: The CHMP or RMS assessment report and the Public Assessment Reports should address the following aspects:
p.000039: • The steps taken to evaluate and provide assurance regarding the ethical conduct of the trials should be
p.000039: described as should any significant deficiencies and how they have been addressed.
p.000039: • The standard GCP review should be summarised in an annex to the CHMP or RMS Assessment Report and to the Public
p.000039: Assessment Report, It should list, for each clinical trial submitted the protocol identification and title, start and
p.000039: end date, identification of the sponsor, of the countries where each trial was conducted and the numbers of subjects
p.000039: recruited in each country. The nature of the patient population should also be described (age and gender and any
p.000039: particular considerations of vulnerability). The standards to which the trials were conducted should be identified.
p.000039: This summary should be based on information to be supplied, electronically, by the applicant.
p.000039: • During the course of the assessment, any relevant ethical issue such as access to treatment post trial, use of
p.000039: placebo or treatment interruptions, choice of active comparators, treatment of vulnerable populations should be
p.000039: highlighted as part of the assessment of the individual trial.,
p.000039: • The justifications for the study designs, choice of comparators and selection of study populations, should be
p.000039: provided with particular emphasis on those studies that involve increased ethical sensitivity due to their design,
p.000039: indication, patient population or location of conduct. The applicability of the trial to the EEA population should be
p.000039: discussed where relevant.
p.000039: • A comment that “no ethical issues were identified” may be sufficient where applicable.
p.000039:
p.000039: • If available, information on Patients’ involvement in study design should be communicated,
p.000039:
p.000039: • When a GCP inspection is performed, the reason(s) for inspection should be described. The outcome and
p.000039: consequences on the assessment of a MAA should be further elaborated. Relevant information from the inspection report
p.000039: may be made publicly accessible.
p.000039: • When GCP/ethical concerns have been raised, the assessment report should present the issue, describe any
p.000039: external expertise sought and the advice received, and discuss the ethical aspects and their consequences on the
p.000039: assessment of the quality, safety and efficacy of the product.
p.000039: • The actions taken should be reflected in the Public Assessment Reports.
p.000039:
p.000039: Regulatory action/action plan
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
...
Social / Age
Searching for indicator age:
(return to top)
p.000039: treatment or investigations.
p.000039: The informed consent of each subject shall be renewed if there are significant changes in the conditions or procedures
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
p.000039: to the child and the child’s response should be documented. “Strong and definitive objections from the child should be
p.000039: respected”. 27
p.000039: “If a subject is unable to read or if a legally acceptable representative is unable to read an impartial witness should
p.000039: be present during the entire informed consent discussion. After the written informed consent form and any other written
p.000039: information to be provided, is read and explained to the subject or the subject’s legally acceptable representative,
...
p.000039: EMA/121340/2011
p.000039: Page 19/42
p.000039:
p.000039: “In appropriate cases of research carried out on a group of persons or a community, additional agreement of the legal
p.000039: representatives of the group or community concerned may be sought. In no case should a collective community agreement
p.000039: or the consent of a community leader or other authority substitute for an individual’s informed consent”29 . “In some
p.000039: cultural contexts an investigator may enter a community to conduct or approach prospective subjects for their
p.000039: individual consent only after obtaining permission from a community leader, a council of elders, or another designated
p.000039: authority.
p.000039: Such customs must be respected. In no case, however, may the permission of a community leader or other authority
p.000039: substitute for individual informed consent” 30
p.000039: The consent process and the information provided should take into account the needs of persons who are unfamiliar with
p.000039: medical concepts and technology31. All documentation (information and consent/assent) must be written in a lay-friendly
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
...
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
...
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
p.000039: to allow consideration of the possible consequences on the future MAA and results interpretation. This feasibility
p.000039: assessment should include as a minimum:
p.000039: • Recruitment plan for patients in the EEA and outside
p.000039:
p.000039: • Selection criteria and numbers of centres per country or regions outside the EEA
p.000039:
p.000039: • Duration of trial recruitment and expected impact of comparability of results over time in case of very long
p.000039: recruitment (e.g. duration of recruitment longer than 3 years for rare disease).
p.000039:
p.000039: 5.3. General measures to assure data quality when conducting trials outside the EU
p.000039:
p.000039: Issues that may have an impact on the quality of data to be generated should be clearly identified and resolved when
p.000039: possible:
p.000039: • Duration of the study
p.000039:
p.000039: • Complexity of the trial design, e.g.: requirement for blinding / shipments of samples (e.g. tissues)/ specific
p.000039: or high level of technology platforms required (e.g. MRI)/ frequency of biological/radiological monitoring/capability
p.000039: for storing clinical trials materials
p.000039: • Restricted access to specific tests and laboratory with possible impact on final data quality (e.g. testing of
p.000039: HIV resistance)
p.000039: • Access to active comparators/ placebo/ age-appropriate formulation at the national level or when provided by the
p.000039: applicant
p.000039: • Differences in Patients-Reported Outcomes
p.000039:
p.000039: • Limitations for long term follow up of patients after treatment (active comparator and study drug)
p.000039: discontinuation
p.000039: • Anticipated quality of data monitoring and training of investigators
p.000039:
p.000039: Specific measures to be taken into consideration in order to assure the quality of results should include:
p.000039: • Identification of limitations in extrapolating data from non-EU patients to the EEA populations, such as
p.000039: different ethnicities, underlying specific conditions
p.000039: • Different local epidemiology of infectious pathogens and / or disease pathology
p.000039:
p.000039: • Appropriateness of study design in accordance with the European guidelines and the most up to date scientific
p.000039: recommendations and ethical requirements
p.000039: • Choice of claim for superiority versus non inferiority in relation to a proper identification of therapeutic
p.000039: needs and respective recruitment capacity in the EEA and outside
p.000039: • Identification of standards of care for the targeted disease among countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 32/42
p.000039:
p.000039: • Drug and study acceptability by the patients in the targeted countries and by the national ECs
p.000039:
...
p.000039: EMA/121340/2011
p.000039: Page 39/42
p.000039:
p.000039: The CHMP or RMS assessment reports are obtained from the assessments at the different phases of the marketing
p.000039: authorisation procedures. The application of GCP and ethical requirements and steps taken to confirm this, or any
p.000039: related issues should be reflected in the Public Assessment Reports.
p.000039: For example, guidance to assessors outlines the nature of clinical trial information that should be included in the
p.000039: assessment report at Day 80 and in the CHMP assessment report/EPAR. (see Guidance Document – Day 80 Clinical
p.000039: Assessment Report http://www.ema.europa.eu/pdfs/human/chmptemplates/CHMP-D80-AR-
p.000039: Guidance/D80AR_Clinical_Guidance_rev10_09.pdf ).
p.000039: Inclusion in the guidance of the items listed below, and the consistent application of this, will substantially improve
p.000039: the content of assessment reports and hence the Public Assessment Report in respect of ethical and GCP compliance.
p.000039: The CHMP or RMS assessment report and the Public Assessment Reports should address the following aspects:
p.000039: • The steps taken to evaluate and provide assurance regarding the ethical conduct of the trials should be
p.000039: described as should any significant deficiencies and how they have been addressed.
p.000039: • The standard GCP review should be summarised in an annex to the CHMP or RMS Assessment Report and to the Public
p.000039: Assessment Report, It should list, for each clinical trial submitted the protocol identification and title, start and
p.000039: end date, identification of the sponsor, of the countries where each trial was conducted and the numbers of subjects
p.000039: recruited in each country. The nature of the patient population should also be described (age and gender and any
p.000039: particular considerations of vulnerability). The standards to which the trials were conducted should be identified.
p.000039: This summary should be based on information to be supplied, electronically, by the applicant.
p.000039: • During the course of the assessment, any relevant ethical issue such as access to treatment post trial, use of
p.000039: placebo or treatment interruptions, choice of active comparators, treatment of vulnerable populations should be
p.000039: highlighted as part of the assessment of the individual trial.,
p.000039: • The justifications for the study designs, choice of comparators and selection of study populations, should be
p.000039: provided with particular emphasis on those studies that involve increased ethical sensitivity due to their design,
p.000039: indication, patient population or location of conduct. The applicability of the trial to the EEA population should be
p.000039: discussed where relevant.
p.000039: • A comment that “no ethical issues were identified” may be sufficient where applicable.
p.000039:
p.000039: • If available, information on Patients’ involvement in study design should be communicated,
p.000039:
p.000039: • When a GCP inspection is performed, the reason(s) for inspection should be described. The outcome and
p.000039: consequences on the assessment of a MAA should be further elaborated. Relevant information from the inspection report
p.000039: may be made publicly accessible.
p.000039: • When GCP/ethical concerns have been raised, the assessment report should present the issue, describe any
...
Social / Child
Searching for indicator child:
(return to top)
p.000039: persons, beneficence/non- maleficence is defined as the ethical obligation to maximize benefits and to avoid or
p.000039: minimize harms, and justice is a fair distribution of the burdens and benefits of research1.
p.000039: “The rights safety and wellbeing of the trials subjects are the most important consideration and should prevail over
p.000039: the interests of science and society”. 2
p.000039: Clinical trials conducted in countries outside of the EU/EEA and used in MAAs in the EEA or in applications for a
p.000039: Scientific Opinion under article 58 of the Regulation (EC) No. 726/2004, must be conducted on the basis of principles
p.000039: equivalent to the ethical principles and principles of good clinical practice applied to clinical trials in the EEA3.
p.000039: Ethical principles have been established mainly by intergovernmental organisations such as the Council of Europe or
p.000039: WHO, or by professional bodies such as the World Medical Association, as well as in national or regional legislation or
p.000039: guidance. The latter often refer directly or indirectly to the internationally established principles.
p.000039: Ethical principles governing the conduct of clinical trials are set out in the Charter of Fundamental Rights of the
p.000039: European Union (2000)i the Council of Europe’s Convention on Human Rights and Biomedicine (1997)ii and its Additional
p.000039: Protocol on Biomedical Research (2005)iii, the Universal Declaration of Human Rights (1948)iv, the Convention for the
p.000039: protection of Human Rights and fundamental Freedoms (1950)v, the United Nations’ Convention on the Rights of the Child
p.000039: (1989)vi, the Universal Declaration on Bioethics and Human Rights (UNESCO, 2005)vii, the Universal Declaration on the
p.000039: Human Genome and Human Rights (UNESCO, 1997)viii, the International Declaration on Human Genetic Data (UNESCO, 2003)ix,
p.000039: the CIOMS-WHO International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva 2002)x, the
p.000039: Declaration of Helsinki of the World Medical Association (2008)xi, Opinion 17 of the European Group on Ethics (2003)xii
p.000039: and the EU Ethical considerations for clinical trials on medicinal products conducted with the paediatric population
p.000039: (2008)xiii. Practical steps to implement ethical requirements are set out in the CPMP/ICH/135/95 guideline on Good
p.000039: Clinical Practice (1995) (ICH E6)xiv and ICH E11 Note for guidance on clinical investigation of medicinal products in
p.000039: the paediatric population (2001)xv.
p.000039: The European pharmaceutical legislation sets out the ethical requirements for the conduct of clinical trials in
p.000039: Directive 2001/20/ECxvi, Directive 2005/28/ECxvii and Directive 2001/83/ECxviii. Provisions of the European Paediatric
p.000039: Regulation 1901/06/EC are equally taken into considerationxix.
p.000039: Provisions for the protection of personal data are laid down in Directive 1995/46/ECxx,
p.000039: The extent to which these various documents pertinent to clinical trials (both legal and ethical instruments) are taken
p.000039: into account in national or regional legislation within or outside EU is variable. They overlap in many areas, but some
p.000039: given greater precision on certain points whilst on others there are differences in approach. The aim of the present
...
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
p.000039: to the child and the child’s response should be documented. “Strong and definitive objections from the child should be
p.000039: respected”. 27
p.000039: “If a subject is unable to read or if a legally acceptable representative is unable to read an impartial witness should
p.000039: be present during the entire informed consent discussion. After the written informed consent form and any other written
p.000039: information to be provided, is read and explained to the subject or the subject’s legally acceptable representative,
p.000039: and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s
p.000039: participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the
p.000039: witness should sign and personally date the consent form. By signing the consent form, the witness attests that the
p.000039: information in the consent form and any other written information was accurately explained to, and apparently
p.000039: understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely
p.000039: given by the subject or the subject’s legally acceptable representative”28.
p.000039: Mechanisms should be put in place to ensure that the trial subject is aware that they are participating in research.
p.000039:
p.000039:
p.000039: 21 Art. 2 (j) of Directive 2001/20/EC; Paragraph 1.28 of ICH E6, 1995
p.000039: 22 Art. 14 section 2 of the Additional Protocol on Biomedical Research to the Convention on Human Rights and
p.000039: Biomedicine and section 80 of its Explanatory report
...
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 41/42
p.000039:
p.000039: 3. References
p.000039:
p.000039: i Charter of Fundamental Rights of the European Union (2000) http://www.europarl.europa.eu/charter/default_en.htm
p.000039: ii Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of
p.000039: Biology and Medicine: Convention on Human Rights and Biomedicine. European Treaty Series – No 164. Oviedo, 4 IV 1997
p.000039: http://conventions.coe.int/treaty/en/treaties/html/164.htm
p.000039: iii Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research (Strasbourg
p.000039: 2005) http://conventions.coe.int/treaty/en/treaties/html/195.htm
p.000039: iv Universal Declaration of Human Rights of 1948, http://www.un.org/en/documents/udhr/ v Convention for the protection
p.000039: of Human Rights and fundamental Freedoms (COE, 1950) ,
p.000039: http://www.echr.coe.int/nr/rdonlyres/d5cc24a7-dc13-4318-b457-5c9014916d7a/0/englishanglais.pdf
p.000039: vi United Nations High Commissioner for Human Rights: Convention on the Rights of the Child (20/11/1989).
p.000039: http://www.ohchr.org/english/law/pdf/crc.pdf
p.000039: vii UNESCO. Universal Declaration on Bioethics and Human Rights (2005)
p.000039: http://portal.unesco.org/en/ev.php-RL_ID=31058&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: viii Universal Declaration on the Human Genome and Human Rights (UNESCO, 1997) http://portal.unesco.org/en/ev.php-
p.000039: URL_ID=13177&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: ix International Declaration on Human Genetic Data (UNESCO, 2003) http://portal.unesco.org/en/ev.php-
p.000039: URL_ID=17720&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: x CIOMS-WHO International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva 2002) ,
p.000039: http://www.cioms.ch/frame_guidelines_nov_2002.htm
p.000039: xi World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human
p.000039: Subjects.
p.000039: Revision 2008 http://www.wma.net/en/30publications/10policies/b3/index.html
p.000039: xii Opinion n.17 of the European Group on Ethics in Science and New Technologies to the European Commission : “Ethical
p.000039: aspects of clinical research in developing countries” http://ec.europa.eu/european_group_ethics/docs/avis17_en.pdf
p.000039: xiii EU Ethical considerations for clinical trials on medicinal products conducted with the paediatric population
p.000039: (2008) http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/ethical_considerations.pdf
p.000039: xiv ICH E6 Guideline on Good Clinical Practice (1995), http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf xv Clinical
p.000039: investigation of medicinal products in the paediatric population. ICH E11.
...
Searching for indicator children:
(return to top)
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 18/42
p.000039:
p.000039: signed and dated informed consent form”.21 The trial participant should be given a copy of his/her consent once it is
p.000039: signed. Refusal to give consent or withdrawal of consent to participation in research shall not lead to any form of
p.000039: liability (particularly of a financial nature) and/or to any form of discrimination against the person concerned, in
p.000039: particular regarding the right to medical care 22. The same level of care and information should be maintained during
p.000039: treatment or investigations.
p.000039: The informed consent of each subject shall be renewed if there are significant changes in the conditions or procedures
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
...
p.000039: a) of the extent to which the monitor(s), the auditor(s), the Ethics Committe and the regulatory authority(ies) will be
p.000039: granted direct access to the subject's original medical records for verification of clinical trial procedures and/or
p.000039: data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000039: regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable
p.000039: representative is authorising such access.
p.000039: b) “that records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws
p.000039: and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’
p.000039: identity will remain confidential”.46
p.000039: Biological sample retention, planned analysis and the need for consent to such use (and reuse) should be in accordance
p.000039: with what is described in the protocol. Samples cannot be used for purposes different of the ones described in the
p.000039: protocol without a new written informed consent
p.000039: The trial documents should be archived for a duration that takes into consideration the potential need for long-term
p.000039: review, particularly for trials performed in children (long-term safety).
p.000039: Where personal information is collected, stored, accessed, used, or disposed of, a researcher should ensure that the
p.000039: privacy, confidentiality and cultural sensitivities of the subject and/or the collectivity are respected, most of all
p.000039: when children are involved47.
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. EU Regulatory Authorities should disregard reports which fail to properly protect the confidentiality of the trial
p.000039: subjects, when submitted in support of a MAA in accordance with Directive 2001/83 EC or Regulation No (EC) 726/2004.
p.000039: These reports should be returned to the applicant and the breaches of confidentiality rectified (including removal of
p.000039: confidential information from their database) prior to eventual resubmission.
p.000039: 2. EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
p.000039: confidentiality (e.g. arising from the use of genetic information or bio banked samples) and where applicable seek
p.000039: additional assurance that confidentiality has been properly maintained. When requested, the applicant for a MAA should
p.000039: provide EU Regulatory Authorities with a summary of the steps taken to protect confidentiality and the consent obtained
p.000039: to enable the use of and access to the subjects’ data.
p.000039:
p.000039: 4.4. Fair compensation
p.000039:
p.000039: Article 3.2 (f) of Directive 2001/20/EC requires that provision is made for insurance or indemnity.
p.000039:
p.000039:
p.000039:
p.000039: 44 Art. 10 of Convention on Human Rights and Biomedicine of the Council of Europe (COE); Art. 27 of Additional Protocol
p.000039: on Biomedical research (COE), 2005
p.000039: 45 WHO (CIOMS) Guideline 18
p.000039: 46 Paragraph 4.8.10 of ICH E6
p.000039: 47 Paragraph 18 of Ethical considerations for clinical trials on medicinal products conducted with pediatric
p.000039: population.
p.000039:
...
p.000039: insurance coverage is limited to negligence). In certain circumstances it may be advisable to follow both courses.
p.000039: “Sponsors should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution
p.000039: against claims arising from the trial, except for claims that arise from malpractice and/or negligence”.50
p.000039: “Both the informed consent discussion and the written informed consent form and any other written information to be
p.000039: provided to subjects involved in research should include explanations of the compensation and/or treatment available to
p.000039: the subject in the event of trial-related injury”.51
p.000039: Information shall be provided to the EC and where required to the National Regulatory Authority, on details of any
p.000039: insurance, indemnity or compensation to cover damage arising in the context of the research project52 (in particular
p.000039: “provision for indemnity or compensation in the event of injury or death attributable to a clinical trial, and any
p.000039: insurance or indemnity to cover the liability of the investigator and sponsor”). 53
p.000039: In preparing its opinion, the Ethics Committe (and where required the National Regulatory Authority) should consider
p.000039: these provisions54 and should pay careful attention to waivers of liability in the insurance contract, in particular
p.000039: with respect generally to long term effects and on development for children included in research. However,
p.000039: “unrecognised congenital defects are generally excluded”.55
p.000039: Regulatory action/action plan
p.000039:
p.000039: 48 Art. 31 of Additional Protocol on Biomedical research (COE) 2005 49 WHO (CIOMS) Guideline 19
p.000039: 50 Paragraph 5.8 of ICH-E6
p.000039: 51 Paragraph 4.8.10 of ICH-E6
p.000039: 52 Art 11 juncto appendix of Additional Protocol on Biomedical research (COE) 2005; Paragraph 3.1.2 of ICH-E6. 53 Art.
p.000039: 6.3 (h) and (i) of Directive 2001/20/EC
p.000039: 54 Art. 6.3 of Directive 2001/20/EC
p.000039: 55 Paragraph 22 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 23/42
p.000039:
p.000039: 1. Failure to provide fair compensation by insurance or indemnity is a serious violation of ethical standards. The
p.000039: applicant for a MAA should provide EU Competent Authorities with a summary of the provisions made to provide for the
p.000039: fair compensation of subjects for trial related injury. This information can form part of the clinical study report
p.000039: section on ethical considerations and informed consent.
p.000039: 2. EMA and EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
p.000039: insurance, indemnity or compensation for research related injury and where applicable to seek additional assurance that
p.000039: trial subjects’ interest have been protected.
p.000039:
p.000039: 4.5. Vulnerable populations
...
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
...
p.000039: Acceptability of Foreign Clinical Data
p.000039: (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E5_R1/Step4/E5_R1
p.000039: Guideline.pdf). 80 xxii
p.000039:
p.000039: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000039: phase
p.000039: The EMA has a role in stimulating innovation and research in the pharmaceutical sector. The Agency gives scientific
p.000039: advice and protocol assistance to companies for the development of new medicinal products and draws up scientific
p.000039: guidelines aimed at helping applicants in the development of medicinal products. The tasks and responsibilities of the
p.000039: Agency under the Paediatric Regulation
p.000039:
p.000039: 77 WHO (CIOMS) Guideline 21
p.000039: 78 ICH 1998 E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
p.000039: 79 Reflection paper on the extrapolation of results from clinical studies conducted outside the EU to the EU population
p.000039: EMEA/CHMP/EWP/692702/2008
p.000039: 80 ICH 1998 E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 29/42
p.000039:
p.000039: include the provision of objective scientific decisions on the development plan for medicines for use in children.
p.000039: European pharmaceutical legislation (and that in other regions of the world also) requires clinical trials to be
p.000039: performed prior to the granting of a marketing authorisation. The analytical, pharmaco- toxicological and clinical
p.000039: requirements in respect of testing of medicinal products are set out in the Annex 1 of Directive 2001/83/EC. Additional
p.000039: requirements and incentives apply to encourage the conduct of clinical trials for the development of medicines for the
p.000039: treatment of children and for the treatment of patients with rare diseases. These requirements may increase the number
p.000039: and scope of clinical trials being conducted, not all of which can or need to be carried out in Europe. Clinical trials
p.000039: conducted in the EEA should comply with applicable laws and regulations. In addition, applicants intending to submit in
p.000039: the EEA are advised to consult with EEA regulators about the design and ethical conduct of clinical trials prior to
p.000039: their commencement when it is planned to conduct those trials in countries outside EU/EEA. EEA regulators should ensure
p.000039: that every opportunity is taken prior to the commencement of clinical trials to influence their design and ensure their
p.000039: ethical conduct.
p.000039: Several operational or technical considerations lead to the conduct of clinical trials in a widening range of
p.000039: countries:
p.000039: • Availability of patients willing to participate in clinical trials, and with the relevant disease profile,
p.000039:
p.000039: • Availability of qualified investigators willing and available to conduct the trials,
p.000039:
p.000039: • Preparation for MAA, in those other countries,
p.000039:
p.000039: • Lower costs in some countries,
p.000039:
p.000039: • More rapid approval of trials,
p.000039:
p.000039: • Willingness of patients to participate in trials due to the trial facilitating access to higher standard of care
p.000039: and / or medication(s) not otherwise available to them,
p.000039: • Small number of relevant patients existing in Europe,
p.000039:
p.000039: • Availability of patients who are naïve to treatment,
p.000039:
p.000039: • Difficulty in recruiting patients due to differences in standard of care across developed countries.
...
Social / Elderly
Searching for indicator elderly:
(return to top)
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
...
Social / Ethnicity
Searching for indicator ethnic:
(return to top)
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
p.000039: dignity, human rights and fundamental freedoms or to limit their scope. 35
p.000039: “Sponsors and investigators have a duty to refrain from unjustified deception, undue influence, or intimidations” 36and
p.000039: “to renew the informed consent of each subject if there are significant changes in the conditions or procedures of the
p.000039: research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate” 37
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. Failure to obtain informed consent (and/or assent where applicable) is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in a such unethical manner, when submitted in support of a MAA
p.000039: in accordance with Directive 2001/83 EC or Regulation EC 726/2004.
p.000039: 2. The applicant for a MAA should provide EU drug regulatory authorities with a summary of the consent processes used
p.000039: and significant variations of those processes in the clinical trials supporting the MAA and include sample information
...
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
...
p.000039: Public Assessment Report (EPAR).
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. The applicant for a MAA should provide EU Regulatory Authorities with a description of the situation of trial
p.000039: participants with regard to post trial access to treatment and medical care depending on their localization and the
p.000039: national or regional health care system. The applicant should describe the provisions made for post trial access to
p.000039: treatment and medical care for study participants depending on their localization and the treatment and medical care
p.000039: otherwise available. This information can form part of the clinical study report section on ethical considerations in
p.000039: accordance with ICH E3.
p.000039: 2. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: access to treatment post trial and where applicable to seek additional assurance that the solution was appropriate and
p.000039: ethically acceptable.
p.000039: 3. EU Regulatory Authorities will summarize this information in the Public Assessment report.
p.000039:
p.000039: 4.8. Applicability of data to EEA population
p.000039:
p.000039: There are several issues relating to the applicability of trials conducted outside EU/EEA to European populations.
p.000039: These involve factors both intrinsic and extrinsic to the study population and EEA population. 78
p.000039: These are discussed in the “Reflection Paper on the extrapolation of results from clinical studies conducted outside
p.000039: the EU to the EU population” xxi 79 (Doc. Ref. EMEA/CHMP/EWP/692702/2008) and the ICH 1998 E5(R1) Ethnic Factors in the
p.000039: Acceptability of Foreign Clinical Data
p.000039: (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E5_R1/Step4/E5_R1
p.000039: Guideline.pdf). 80 xxii
p.000039:
p.000039: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000039: phase
p.000039: The EMA has a role in stimulating innovation and research in the pharmaceutical sector. The Agency gives scientific
p.000039: advice and protocol assistance to companies for the development of new medicinal products and draws up scientific
p.000039: guidelines aimed at helping applicants in the development of medicinal products. The tasks and responsibilities of the
p.000039: Agency under the Paediatric Regulation
p.000039:
p.000039: 77 WHO (CIOMS) Guideline 21
p.000039: 78 ICH 1998 E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
p.000039: 79 Reflection paper on the extrapolation of results from clinical studies conducted outside the EU to the EU population
p.000039: EMEA/CHMP/EWP/692702/2008
p.000039: 80 ICH 1998 E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 29/42
p.000039:
p.000039: include the provision of objective scientific decisions on the development plan for medicines for use in children.
p.000039: European pharmaceutical legislation (and that in other regions of the world also) requires clinical trials to be
p.000039: performed prior to the granting of a marketing authorisation. The analytical, pharmaco- toxicological and clinical
p.000039: requirements in respect of testing of medicinal products are set out in the Annex 1 of Directive 2001/83/EC. Additional
p.000039: requirements and incentives apply to encourage the conduct of clinical trials for the development of medicines for the
p.000039: treatment of children and for the treatment of patients with rare diseases. These requirements may increase the number
p.000039: and scope of clinical trials being conducted, not all of which can or need to be carried out in Europe. Clinical trials
p.000039: conducted in the EEA should comply with applicable laws and regulations. In addition, applicants intending to submit in
p.000039: the EEA are advised to consult with EEA regulators about the design and ethical conduct of clinical trials prior to
p.000039: their commencement when it is planned to conduct those trials in countries outside EU/EEA. EEA regulators should ensure
p.000039: that every opportunity is taken prior to the commencement of clinical trials to influence their design and ensure their
...
p.000039: practice in the conduct of clinical trials on medicinal products for human use
p.000039: http://eudravigilance.emea.europa.eu/human/docs/directives/Dir2001-20_en.pdf
p.000039: xvii DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as
p.000039: regards investigational medicinal products for human use, as well as the requirements for authorisation of the
p.000039: manufacturing or importation of such products
p.000039: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:091:0013:0019:en:PDF
p.000039: xviii DIRECTIVE 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code
p.000039: relating to medicinal products for human use
p.000039: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2001L0083:20070126:EN:PDF xix REGULATION (EC) No
p.000039: 1901/2006 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
p.000039: of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive
p.000039: 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004
p.000039: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:378:0001:0019:EN:PDF
p.000039: xx Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals
p.000039: with regard to the processing of personal data and on the free movement of such data
p.000039: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31995L0046:EN:HTML
p.000039: xxi Reflection Paper on the extrapolation of results from clinical studies conducted outside the EU to the EU
p.000039: population” (Doc. Ref. EMEA/CHMP/EWP/692702/2008)
p.000039: xxii ICH 1998 E5(R1) Ethnic Factors in the Acceptability of Foreign Clinical Data
p.000039: (http://www.ich.org/LOB/media/MEDIA481.pdf)
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
...
Searching for indicator ethnicity:
(return to top)
p.000039:
p.000039: • Applicability of the targeted drug claim in the European population when the disease is predominant mainly
p.000039: outside Europe (e.g. tropical diseases)
p.000039: • Different therapeutic needs in the European population
p.000039:
p.000039: • Clinical data to be generated may be of little relevance to the European population (e.g. notable difference in
p.000039: disease management).
p.000039: When applicable according to the procedure applied for, the applicant should consider the relevance of its clinical
p.000039: program, in relation to:
p.000039: • Applicability of the proposed indication and the therapeutic needs of the European population
p.000039:
p.000039: • Prevalence of the condition in non-EEA countries and in EEA countries.
p.000039:
p.000039: The consequences of drug development with clinical trials conducted outside the EEA (completely or partially) should be
p.000039: considered with regards to:
p.000039: • Limitations of data extrapolation from non-EU patients to the EEA
p.000039:
p.000039: • Impact of the geographic source of patients on the efficacy and safety results and their extrapolation the
p.000039: European population in the context of disease management (e.g. national characteristics of disease management and
p.000039: patient care)
p.000039: • Validity of the selected comparators (active or placebo) for enabling assessment of the Risk/Benefit balance of
p.000039: the product for the European population
p.000039: • Pre-specified subgroup analyses based on ethnicity and/or regions of the world
p.000039:
p.000039: • Evaluation of the level of adherence to standard background treatment regimes for a specific disease
p.000039: • Take into consideration possible differences in genetic profiles which could influence the drug response.
p.000039: Where a scientific advice, guidance or assessment relates to an application for a scientific opinion in the context of
p.000039: article 58 of Regulation No (EC) 726/2004 the considerations should relate to the population for which the medicinal
p.000039: product is to be used, rather than the EU population.
p.000039:
p.000039: 5.2. Issues related to feasibility of clinical trials
p.000039:
p.000039: The applicant should provide any available information on its development plan:
p.000039:
p.000039: • Details on the planned locations of the trials planned in the EEA and outside
p.000039:
p.000039: • Criteria for the selection of the non-EEA countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 31/42
p.000039:
p.000039: As such information may be limited or unavailable in the early phases of drug development, the applicant could provide
p.000039: a commitment to comply with general regulatory/GCP and ethical principles. Applicants are encouraged to seek follow-up
p.000039: advice when the drug development plan become clearer and clinical trials outside of the EU/EEA are foreseen
...
Social / Homeless Persons
Searching for indicator homeless:
(return to top)
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
...
Social / Incarcerated
Searching for indicator liberty:
(return to top)
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
p.000039: not pregnant, or on persons who are not deprived of liberty, whether the person undergoing research has been informed
p.000039: of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a
p.000039: state to receive the information, whether the necessary authorisation has been given specifically and in writing by the
p.000039: legal representative, and the person (or pregnant woman) concerned does not object.
p.000039: Exceptionally and under the protective conditions prescribed by law, where the research may not have the potential to
p.000039: produce results of direct benefit to the health of the person concerned, such research may be authorised, if it can
p.000039: contribute to the benefit of the group concerned whilst fulfilling the other conditions described above. “Measures of
p.000039: such benefit would include the importance of knowledge gained, severity of the issue to be addressed, commonality of
p.000039: the issue, likelihood of obtaining results from proposed research, and usefulness of benefits obtained”.66
p.000039:
p.000039:
p.000039:
p.000039: 62 Recital 3 of Directive 2001/20/EC
p.000039: 63 Recital 4 and art. 1 of Regulation EC/1901/2006 and art. 4 of Directive 2001/20/EC.
p.000039: 64 Belmont Report: ethical principles and guidelines for the protection of human subjects of research, Section D 3. 65
p.000039: Art. 17 of Declaration of Helsinki (2008).
p.000039: 66 Paragraph 12 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
...
Searching for indicator restricted:
(return to top)
p.000039: Page 31/42
p.000039:
p.000039: As such information may be limited or unavailable in the early phases of drug development, the applicant could provide
p.000039: a commitment to comply with general regulatory/GCP and ethical principles. Applicants are encouraged to seek follow-up
p.000039: advice when the drug development plan become clearer and clinical trials outside of the EU/EEA are foreseen
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
p.000039: to allow consideration of the possible consequences on the future MAA and results interpretation. This feasibility
p.000039: assessment should include as a minimum:
p.000039: • Recruitment plan for patients in the EEA and outside
p.000039:
p.000039: • Selection criteria and numbers of centres per country or regions outside the EEA
p.000039:
p.000039: • Duration of trial recruitment and expected impact of comparability of results over time in case of very long
p.000039: recruitment (e.g. duration of recruitment longer than 3 years for rare disease).
p.000039:
p.000039: 5.3. General measures to assure data quality when conducting trials outside the EU
p.000039:
p.000039: Issues that may have an impact on the quality of data to be generated should be clearly identified and resolved when
p.000039: possible:
p.000039: • Duration of the study
p.000039:
p.000039: • Complexity of the trial design, e.g.: requirement for blinding / shipments of samples (e.g. tissues)/ specific
p.000039: or high level of technology platforms required (e.g. MRI)/ frequency of biological/radiological monitoring/capability
p.000039: for storing clinical trials materials
p.000039: • Restricted access to specific tests and laboratory with possible impact on final data quality (e.g. testing of
p.000039: HIV resistance)
p.000039: • Access to active comparators/ placebo/ age-appropriate formulation at the national level or when provided by the
p.000039: applicant
p.000039: • Differences in Patients-Reported Outcomes
p.000039:
p.000039: • Limitations for long term follow up of patients after treatment (active comparator and study drug)
p.000039: discontinuation
p.000039: • Anticipated quality of data monitoring and training of investigators
p.000039:
p.000039: Specific measures to be taken into consideration in order to assure the quality of results should include:
p.000039: • Identification of limitations in extrapolating data from non-EU patients to the EEA populations, such as
p.000039: different ethnicities, underlying specific conditions
p.000039: • Different local epidemiology of infectious pathogens and / or disease pathology
p.000039:
p.000039: • Appropriateness of study design in accordance with the European guidelines and the most up to date scientific
p.000039: recommendations and ethical requirements
p.000039: • Choice of claim for superiority versus non inferiority in relation to a proper identification of therapeutic
p.000039: needs and respective recruitment capacity in the EEA and outside
p.000039: • Identification of standards of care for the targeted disease among countries
p.000039:
p.000039:
...
Social / Institutionalized
Searching for indicator institutionalized:
(return to top)
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
...
Social / Linguistic Proficiency
Searching for indicator language:
(return to top)
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 19/42
p.000039:
p.000039: “In appropriate cases of research carried out on a group of persons or a community, additional agreement of the legal
p.000039: representatives of the group or community concerned may be sought. In no case should a collective community agreement
p.000039: or the consent of a community leader or other authority substitute for an individual’s informed consent”29 . “In some
p.000039: cultural contexts an investigator may enter a community to conduct or approach prospective subjects for their
p.000039: individual consent only after obtaining permission from a community leader, a council of elders, or another designated
p.000039: authority.
p.000039: Such customs must be respected. In no case, however, may the permission of a community leader or other authority
p.000039: substitute for individual informed consent” 30
p.000039: The consent process and the information provided should take into account the needs of persons who are unfamiliar with
p.000039: medical concepts and technology31. All documentation (information and consent/assent) must be written in a lay-friendly
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
p.000039: dignity, human rights and fundamental freedoms or to limit their scope. 35
p.000039: “Sponsors and investigators have a duty to refrain from unjustified deception, undue influence, or intimidations” 36and
p.000039: “to renew the informed consent of each subject if there are significant changes in the conditions or procedures of the
p.000039: research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate” 37
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. Failure to obtain informed consent (and/or assent where applicable) is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in a such unethical manner, when submitted in support of a MAA
p.000039: in accordance with Directive 2001/83 EC or Regulation EC 726/2004.
p.000039: 2. The applicant for a MAA should provide EU drug regulatory authorities with a summary of the consent processes used
...
Searching for indicator linguistic:
(return to top)
p.000039: The consent process and the information provided should take into account the needs of persons who are unfamiliar with
p.000039: medical concepts and technology31. All documentation (information and consent/assent) must be written in a lay-friendly
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
p.000039: dignity, human rights and fundamental freedoms or to limit their scope. 35
p.000039: “Sponsors and investigators have a duty to refrain from unjustified deception, undue influence, or intimidations” 36and
p.000039: “to renew the informed consent of each subject if there are significant changes in the conditions or procedures of the
p.000039: research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate” 37
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. Failure to obtain informed consent (and/or assent where applicable) is a serious violation of ethical standards.
...
Social / Literacy
Searching for indicator illiterate:
(return to top)
p.000039: proposals. When there are objective grounds for considering that the conditions in the request for this authorisation
p.000039: are no longer met, or there is information raising doubts about the safety or scientific validity of the clinical
p.000039: trial, it should be possible to suspend or prohibit the trial notifying the sponsor thereof. 14
p.000039: There should be assurance that the review is independent and that there is no conflict of interest that might affect
p.000039: the judgment of members of the Ethics Committee in relation to any aspect of the research. A declaration of possible
p.000039: conflict of interest should be provided by any of the Ethics Committee members.15Any members with a special or
p.000039: particular, direct or indirect, interest in a proposal should not take part in its assessment if that interest could
p.000039: subvert the member’s objective judgment. Ethics Committees have to be pluralist and representative of all stakeholders,
p.000039: multidisciplinary and independent.16.Ethics Committee should be so composed as to be able to provide complete and
p.000039: adequate review of the research proposals submitted to them. Membership should include physicians, scientists and other
p.000039: professionals such as nurses, lawyers, ethicists, clergy as well as lay persons including patients’ representatives,
p.000039: qualified to represent the cultural and moral values of the community and to ensure that the rights of the research
p.000039: subjects will be respected. When illiterate persons form the focus of a study they should also be considered for
p.000039: consultation in the Ethics Committee decision process. Ethics Committees should include appropriate expertise
p.000039: paediatric and/or mental health disorders or other vulnerable populations or take advice in clinical, ethical and
p.000039: psychosocial problems in these fields when reviewing protocols involving these populations. The Ethics Committee in the
p.000039: country where the trial is to be conducted should have, as either members or consultants, persons with understanding of
p.000039: the community's customs and traditions.” Such persons should be able, for example, to indicate suitable members of the
p.000039: community to serve as intermediaries between investigators and subjects and to advise on whether material benefits or
p.000039: inducements may be
p.000039:
p.000039: 14 Art. 12 of Directive 2001/20/EC
p.000039: 15 WHO (CIOMS) Guideline 2.
p.000039: 16 Art.19 International Declaration on Bioethics (UNESCO); ICH E6 paragraphs 1.27 and 3
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 17/42
p.000039:
p.000039: regarded as appropriate in the light of a community's gift-exchange and other customs and traditions”.17
p.000039: Expertise used should be documented and recorded by the Ethics Committee. Paediatric expertise requirements, as
...
p.000039: should form part of the clinical study report in accordance with ICH E3.
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern (e.g.
p.000039: arising from their design, the local regulatory framework within which they are conducted, the vulnerability of the
p.000039: study subjects) and where applicable seek additional assurance that the trials have been ethically conducted.
p.000039: 4. Where clear serious concerns are identified the EU Regulatory Authorities should communicate these concerns to the
p.000039: National Regulatory Authority of the Country (ies) concerned.
p.000039: 5. The Sponsor ensuring that the clinical trial is reviewed by an appropriate EC should consider the opportunity to
p.000039: submit the clinical trial also to an Ethics Committee (either in an EU or non EU Country) that operates within an
p.000039: established regulatory framework with ethical standards equivalent to those applying in the EU. Evidence of the
p.000039: mechanisms put in place should be provided.
p.000039:
p.000039: 4.2. Information/Consent procedure
p.000039:
p.000039: Scientific research as well as any preventive, diagnostic or therapeutic medical intervention involving human subjects
p.000039: is only to be carried out with the prior, free, express, specific, documented and informed consent of the person
p.000039: concerned, based on adequate and comprehensible information 19 provided both in writing (or optionally pictorially for
p.000039: illiterate individuals) and orally. Furthermore, consent should, be given, and may be withdrawn, by the person
p.000039: concerned at any time and for any reason without disadvantage or prejudice. 20 “Informed consent is documented by means
p.000039: of a written,
p.000039:
p.000039: 17 WHO (CIOMS) Guideline 3.
p.000039: 18 Art. 4 of Directive 2001/20/EC and Paragraph 8 of EU Ethical Considerations for clinical trials on medicinal
p.000039: products conducted with the paediatric population
p.000039: 19 Art.2 (j), art. 3.2 (b) and art. 4-5 of Directive 2001/20/EC; Art. 5-6, 16 (iv) (v)-17 of Convention on Human Rights
p.000039: and Biomedicine of the Council of Europe (COE); Art. 13-16 of Additional protocol on Biomedical research (COE), 2005;
p.000039: Art. 5 and 9 of Universal declaration on Human genome and Human Rights; Art. 8-9 of International Declaration on Human
p.000039: Genetic Data (2003); Paragraphs 22,24,26,27,28 and 29 of Declaration of Helsinki (2008); Art. 3 (2) of Charter of
p.000039: Fundamental Rights of the European Union (2000); Art. 5 of Universal Declaration on Bioethics and Human Rights (UNESCO
p.000039: , 2005); Paragraph 1.28 and 2.9 of ICH E6
p.000039: 20 Art. 3.2 (e) of Directive 2001/20/EC; Art. 6 of Universal Declaration on Bioethics and Human Rights (Unesco,2005);
p.000039: Art. 14 Additional Protocol on Biomedical research (COE), 2005
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 18/42
p.000039:
...
p.000039: or the consent of a community leader or other authority substitute for an individual’s informed consent”29 . “In some
p.000039: cultural contexts an investigator may enter a community to conduct or approach prospective subjects for their
p.000039: individual consent only after obtaining permission from a community leader, a council of elders, or another designated
p.000039: authority.
p.000039: Such customs must be respected. In no case, however, may the permission of a community leader or other authority
p.000039: substitute for individual informed consent” 30
p.000039: The consent process and the information provided should take into account the needs of persons who are unfamiliar with
p.000039: medical concepts and technology31. All documentation (information and consent/assent) must be written in a lay-friendly
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
...
Social / Marital Status
Searching for indicator single:
(return to top)
p.000039:
p.000039: 5. A summary of the reasons for and outcome of any GCP inspections requested (these may be routine or triggered)
p.000039: summarised,
p.000039: 6. Discussion of applicability of data to the EU/EEA population
p.000039:
p.000039: Actions to take if there are concerns over the ethics of studies
p.000039:
p.000039: 1. Where the assessor is concerned that a study may not have been conducted ethically, the assessors should first
p.000039: seek further clarification from the applicant who should be given the opportunity to justify their position.
p.000039: 2. The CHMP should develop appropriate links with experts in ethics in relation to clinical trials who could advise
p.000039: on such issues, as appropriate. It is proposed that CHMP should establish a pool of experts to advise, when requested,
p.000039: on the ethical aspects of clinical trials. A structure similar to a SAG might be envisaged. It is essential that if
p.000039: actions were to follow CHMP’s assessment of a study as ‘not conducted in accordance to the appropriate ethical
p.000039: requirements’, the assessment and any conclusions should be robust.
p.000039: Consequences of a study being considered unethical
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 35/42
p.000039:
p.000039: 1. If, (after taking appropriate advice), the CHMP concludes that a study has not been carried out in accordance with
p.000039: the appropriate ethical requirements, the CHMP must conclude upon additional steps. No single solution will be
p.000039: applicable to all situations, as issues are likely to be complex.
p.000039: 2. Therefore the European Medicines Agency /CHMP must have a number of possible tools at its disposal. These may
p.000039: include the following:
p.000039: 2.1. Assessment of the application excluding data from the studies or part of the studies deemed unethical.
p.000039: Additional analyses may be required. This could result in an application that is not approvable.
p.000039: 2.2. Publishing the circumstances and details of studies which were found not to have been conducted in accordance
p.000039: with ethical requirements.
p.000039: 2.3. A graded system of potential actions. Such a system should be developed (see 6.3).
p.000039:
p.000039: 3. Regulatory authorities should have some degree of discretion over how, when and if to take action, taking into
p.000039: account the circumstances of the trial, and the nature and severity of the issues that have been identified, as well as
p.000039: the medical need for the product.
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. The European Medicines Agency should establish a pool of experts to advise the CHMP in its assessment of the
p.000039: ethical aspects of clinical trials submitted within the MAA, and define their membership, required expertise, mandate
p.000039: and procedures, and the process by which the CHMP, EMA or other Agencies’ scientific committee, may consult them. Such
p.000039: consultation would only be required where ethical concerns had been identified and could be on general matters of
p.000039: principle involved in establishing requirements and guidance, or specific cases involving particular trials and
p.000039: products.
p.000039: 2. EU Regulatory Authorities should develop a system and adequate guidance for review of MAA dossiers, to facilitate
...
Social / Racial Minority
Searching for indicator minority:
(return to top)
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
...
Searching for indicator racial:
(return to top)
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
...
Social / Religion
Searching for indicator religion:
(return to top)
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
p.000039: dignity, human rights and fundamental freedoms or to limit their scope. 35
p.000039: “Sponsors and investigators have a duty to refrain from unjustified deception, undue influence, or intimidations” 36and
p.000039: “to renew the informed consent of each subject if there are significant changes in the conditions or procedures of the
p.000039: research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate” 37
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. Failure to obtain informed consent (and/or assent where applicable) is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in a such unethical manner, when submitted in support of a MAA
p.000039: in accordance with Directive 2001/83 EC or Regulation EC 726/2004.
p.000039: 2. The applicant for a MAA should provide EU drug regulatory authorities with a summary of the consent processes used
p.000039: and significant variations of those processes in the clinical trials supporting the MAA and include sample information
...
Social / Soldier
Searching for indicator armed forces:
(return to top)
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
...
Social / Trade Union Membership
Searching for indicator union:
(return to top)
p.002011: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.002011:
p.002011:
p.002011:
p.002011:
p.002011: Released for Consultation
p.002011: 26 May 2010
p.002011:
p.002011: End of consultation 30
p.002011: September 2010
p.002011:
p.002011: Agreed and Endorsement by CMD 14 June
p.002011: 2011
p.002011:
p.002011:
p.002011: Agreed by EMA Working Group on Clinical Trials conducted outside of the EU/EEA
p.002011: 05 July 2011
p.002011:
p.002011: Endorsement by CHMP 19
p.002011: October 2011
p.002011:
p.002011: Endorsement by EMA Management Board 15 December 2011
p.002011:
p.002011: Endorsement by Heads of Medicines Agencies 24 February 2012
p.002011:
p.002011: Date coming into effect
p.002011: 1 May 2012
p.002011:
p.002011:
p.002011: Keywords
p.002011: Clinical trials, GCP, Marketing Authorisation Applications, EMA, EU, Ethics, conducted outside of the EU
p.002011:
p.002011:
p.002011:
p.002011:
p.002011:
p.002011:
p.002011:
p.002011:
p.002011:
p.002011: 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom
p.002011: Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416
p.002011: E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the
p.002011: European Union
p.002011:
p.002011: © European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
p.002011:
p.002011: Table of contents
p.002011: 1. Glossary 3
p.002011: 2. Introduction 4
p.002011: 3. International cooperation in the regulation of clinical trials, their review and inspection and capacity building in
p.002011: this area 6
p.002011: 3.1. Identification of priorities
p.000007: 7
p.000007: 3.2. Identification of opportunities and partners 9
p.000007: 3.2.1. Identification of other initiatives
p.000009: 9
p.000009: 3.2.2. Categories of initiatives and actions 9
p.000009: 3.2.3. Establishment of contact with key initiatives 10
p.000009: 3.3. Action plan
p.000010: 10
p.000010: 3.3.1. Core activities
p.000010: 10
p.000010: 3.3.2. Short Term activities:
p.000011: 11
p.000011: 3.3.3. Long Term activities:
p.000012: 12
p.000012: 3.4. Resource considerations 13
p.000012: 3.5. Example of initiatives
p.000013: 13
p.000013: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000013: use in the context of the activities of the European Regulatory Authorities
p.000014: 14
...
p.000039: EMA/121340/2011
p.000039: Page 3/42
p.000039:
p.000039: 2. Introduction
p.000039: A marketing authorisation for a medicinal product for human use in Europe can be granted either via
p.000039: the centralised procedure, through the decentralised procedure, mutual recognition or at national level.
p.000039:
p.000039: The EMA is responsible for the evaluation of applications for European marketing authorisation for medicinal products,
p.000039: through the centralised procedure.The decentralized procedure is to be used in order to obtain marketing authorization
p.000039: in more than one Member State where the medicinal product in question has not yet received a marketing authorization in
p.000039: any Member State at the time of application. The mutual recognition procedure is to be used in order to obtain
p.000039: marketing authorization in additional Member States where the medicinal product in question has received a marketing
p.000039: authorization in any other Member State at the time of application.
p.000039: The scope of this Reflection Paper is to clarify the practical application of requirements for clinical trials
p.000039: conducted outside of the EU/EEA and submitted in Marketing Authorisation Applications to the EMA (through the
p.000039: centralised procedure) or to National competent Authorities (through decentralised, mutual recognition, or national
p.000039: procedures) . The Paper set up practical steps to be undertaken during the provision of guidance and advice in the
p.000039: medicine development phase and during the evaluation of Marketing Authorisation Applications.
p.000039: In the context of this document the term “countries outside EU/EEA” means any countries that are not Member States
p.000039: (MSs) of the European Union (EU)/European Economic Area (EEA).
p.000039: The final scope of the document is to strengthen the process (mainly in its earlier phases) to assure, at the time of
p.000039: MAA assessment, that clinical trials conducted in countries outside EU/EEA have been conducted in accordance with the
p.000039: principle of Good Clinical Practice (GCP) and equivalent ethical standards as those applied/requested in the EU.
p.000039: Details for regulatory action/action plan to be implemented and/or to be translated in future guidance are described
p.000039: below. The Reflection Paper is a starting point in the context of a more extensive programme focussed on the
p.000039: acceptance, of clinical trials conducted in countries outside EU/EEA and submitted to the European Regulatory
p.000039: Authorities in MAAs. During the development of this paper a number of issues were identified which are not addressed in
p.000039: the present EU legislation. These have been communicated to the EU Commission for their consideration in the context of
p.000039: the future revision of the clinical trials legislation.
p.000039: The scope of the Reflection Paper is endorsed by the Heads of Medicines Agencies and by the Coordination Group for
p.000039: Mutual Recognition and Decentralised Procedures (CMD-h) with regard to the Mutual Recognition Procedure (MRP) and
p.000039: Decentralised Procedure (DCP).
p.000039: The best approach for achieving these objectives is to ensure that a robust framework exists for the oversight and
p.000039: conduct of clinical trials, no matter where in the world the clinical investigators’ sites are located and patients
p.000039: recruited. An international network of Supervisory Bodies (Regulators and Ethics Committees) from all countries
p.000039: involved, working together to share best practices, experiences and information and working to standards agreed and
...
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 11/42
p.000039:
p.000039: - information on relevant activities underway by other regulatory authorities or international
p.000039: organisations/initiatives/partnerships.
p.000039: • Establishing, sharing and maintaining a list of relevant contact points for the organisations, authorities and
p.000039: initiatives (international, regional, national etc.) involved in these areas including the priority countries
p.000039: • Establishing links – formal and informal – with other projects and initiatives in relation to the priority
p.000039: countries:
p.000039: - Inventory of all organisations and initiatives (international, regional and national e.g. WHO mediated groups,
p.000039: ASEAN, African initiatives such as West African Health Organization (WAHO) and the Economic Community of West African
p.000039: States (ECOWAS etc.) and training and other capacity building initiatives already implemented and ongoing by these
p.000039: organisations.
p.000039: - Inventory of the models of initiatives implemented and their real efficacy
p.000039:
p.000039: - Information on relevant activities underway by other regulatory authorities and international partners.
p.000039:
p.000039: 3.3.3. Long Term activities:
p.000039:
p.000039: The establishment of a “Service” or “Centre” that could enable sharing - through continuous links with the
p.000039: international organisations, the European Union MSs and institutions and those of countries outside EU/EEA, as well as
p.000039: NGOs (non-governmental organisations) - the following (and other) information for each country where a relevant number
p.000039: of clinical trials are conducted:
p.000039: 1. the laws and regulations governing this field;
p.000039:
p.000039: 2. Information on National Regulatory Authorities, Ethics Committees and GCP Inspectorates;
p.000039:
p.000039: 3. Information on GCP inspections and their outcome
p.000039:
p.000039: 4. Models of initiatives implemented and information on obstacles encountered and their real efficacy.
p.000039:
p.000039: This could provide a useful support for implementing interventions that can be more targeted to the real needs, more
p.000039: selective, complementary and avoiding duplication. The interventions should be defined on the basis of the results of
p.000039: experiences already carried out with success, to contribute to the process of ensuring that research on medicinal
p.000039: products respects GCP and ethical requirements in accordance with the international human rights law.
p.000039: In this way, such a “Service” would allow the participating partner countries and international organisations to be up
p.000039: to date on the latest developments in the field could be particularly useful in the following contexts:
p.000039: 1. when EMA and National Regulatory Agencies need to verify compliance to the principles of GCP for a certain
p.000039: clinical trial;
p.000039: 2. when EMA and other international, regional and national organisations or NGOs want to support a country through
p.000039: capacity building initiatives, such as training programmes for investigators or for members of Ethics Committees or GCP
...
p.000039: EMA/121340/2011
p.000039: Page 14/42
p.000039:
p.000039: c) justice, where respect for persons includes the respect for autonomy and the protection of dependent and vulnerable
p.000039: persons, beneficence/non- maleficence is defined as the ethical obligation to maximize benefits and to avoid or
p.000039: minimize harms, and justice is a fair distribution of the burdens and benefits of research1.
p.000039: “The rights safety and wellbeing of the trials subjects are the most important consideration and should prevail over
p.000039: the interests of science and society”. 2
p.000039: Clinical trials conducted in countries outside of the EU/EEA and used in MAAs in the EEA or in applications for a
p.000039: Scientific Opinion under article 58 of the Regulation (EC) No. 726/2004, must be conducted on the basis of principles
p.000039: equivalent to the ethical principles and principles of good clinical practice applied to clinical trials in the EEA3.
p.000039: Ethical principles have been established mainly by intergovernmental organisations such as the Council of Europe or
p.000039: WHO, or by professional bodies such as the World Medical Association, as well as in national or regional legislation or
p.000039: guidance. The latter often refer directly or indirectly to the internationally established principles.
p.000039: Ethical principles governing the conduct of clinical trials are set out in the Charter of Fundamental Rights of the
p.000039: European Union (2000)i the Council of Europe’s Convention on Human Rights and Biomedicine (1997)ii and its Additional
p.000039: Protocol on Biomedical Research (2005)iii, the Universal Declaration of Human Rights (1948)iv, the Convention for the
p.000039: protection of Human Rights and fundamental Freedoms (1950)v, the United Nations’ Convention on the Rights of the Child
p.000039: (1989)vi, the Universal Declaration on Bioethics and Human Rights (UNESCO, 2005)vii, the Universal Declaration on the
p.000039: Human Genome and Human Rights (UNESCO, 1997)viii, the International Declaration on Human Genetic Data (UNESCO, 2003)ix,
p.000039: the CIOMS-WHO International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva 2002)x, the
p.000039: Declaration of Helsinki of the World Medical Association (2008)xi, Opinion 17 of the European Group on Ethics (2003)xii
p.000039: and the EU Ethical considerations for clinical trials on medicinal products conducted with the paediatric population
p.000039: (2008)xiii. Practical steps to implement ethical requirements are set out in the CPMP/ICH/135/95 guideline on Good
p.000039: Clinical Practice (1995) (ICH E6)xiv and ICH E11 Note for guidance on clinical investigation of medicinal products in
p.000039: the paediatric population (2001)xv.
p.000039: The European pharmaceutical legislation sets out the ethical requirements for the conduct of clinical trials in
p.000039: Directive 2001/20/ECxvi, Directive 2005/28/ECxvii and Directive 2001/83/ECxviii. Provisions of the European Paediatric
p.000039: Regulation 1901/06/EC are equally taken into considerationxix.
...
p.000039: mechanisms put in place should be provided.
p.000039:
p.000039: 4.2. Information/Consent procedure
p.000039:
p.000039: Scientific research as well as any preventive, diagnostic or therapeutic medical intervention involving human subjects
p.000039: is only to be carried out with the prior, free, express, specific, documented and informed consent of the person
p.000039: concerned, based on adequate and comprehensible information 19 provided both in writing (or optionally pictorially for
p.000039: illiterate individuals) and orally. Furthermore, consent should, be given, and may be withdrawn, by the person
p.000039: concerned at any time and for any reason without disadvantage or prejudice. 20 “Informed consent is documented by means
p.000039: of a written,
p.000039:
p.000039: 17 WHO (CIOMS) Guideline 3.
p.000039: 18 Art. 4 of Directive 2001/20/EC and Paragraph 8 of EU Ethical Considerations for clinical trials on medicinal
p.000039: products conducted with the paediatric population
p.000039: 19 Art.2 (j), art. 3.2 (b) and art. 4-5 of Directive 2001/20/EC; Art. 5-6, 16 (iv) (v)-17 of Convention on Human Rights
p.000039: and Biomedicine of the Council of Europe (COE); Art. 13-16 of Additional protocol on Biomedical research (COE), 2005;
p.000039: Art. 5 and 9 of Universal declaration on Human genome and Human Rights; Art. 8-9 of International Declaration on Human
p.000039: Genetic Data (2003); Paragraphs 22,24,26,27,28 and 29 of Declaration of Helsinki (2008); Art. 3 (2) of Charter of
p.000039: Fundamental Rights of the European Union (2000); Art. 5 of Universal Declaration on Bioethics and Human Rights (UNESCO
p.000039: , 2005); Paragraph 1.28 and 2.9 of ICH E6
p.000039: 20 Art. 3.2 (e) of Directive 2001/20/EC; Art. 6 of Universal Declaration on Bioethics and Human Rights (Unesco,2005);
p.000039: Art. 14 Additional Protocol on Biomedical research (COE), 2005
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 18/42
p.000039:
p.000039: signed and dated informed consent form”.21 The trial participant should be given a copy of his/her consent once it is
p.000039: signed. Refusal to give consent or withdrawal of consent to participation in research shall not lead to any form of
p.000039: liability (particularly of a financial nature) and/or to any form of discrimination against the person concerned, in
p.000039: particular regarding the right to medical care 22. The same level of care and information should be maintained during
p.000039: treatment or investigations.
p.000039: The informed consent of each subject shall be renewed if there are significant changes in the conditions or procedures
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
...
p.000039: adequate protection without the subject’s consent.
p.000039: “An investigator who proposes to perform genetic tests of known clinical or predictive value on biological samples that
p.000039: can be linked to an identifiable individual must obtain the informed consent of the individual or, when indicated, the
p.000039: permission of a legally authorised representative. Conversely, before performing a genetic test that is of known
p.000039: predictive value or gives reliable information about a known heritable condition, and individual consent or permission
p.000039: has not been obtained, investigators must see that biological samples are fully anonymized and unlinked; this ensures
p.000039: that no information about specific individuals can be derived from such research or passed back to them”. 42
p.000039: If research gives rise to information of clinical significance to the current or future health or quality of life of
p.000039: research participants, this information shall be available if they want to receive it. That shall be done within a
p.000039: framework of health care or specific counselling43,“In communication of such information, due care must be taken in
p.000039: order to protect confidentiality and to respect any wish of a
p.000039:
p.000039: 38 Art. 3.2(c) of Directive 2001/20/EC
p.000039: 39 Art. 9 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005); art. 14 International Declaration of
p.000039: Human Genetic Data; art 8 Charter of fundamental rights of the European Union
p.000039: 40 Art. 26 of Additional Protocol on Biomedical research (COE), 2005
p.000039: 41 Art. 6 of Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on
p.000039: the free movement of such data
p.000039: 42 WHO (CIOMS) Guideline 18
p.000039: 43 Art 27 of additional Protocol on Biomedical research (COE), 2005
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 21/42
p.000039:
p.000039: participant” [including the minor and/or his/her legal representative] ”not to receive such information”, in accordance
p.000039: with national law.44“During the process of obtaining informed consent the investigator should inform the prospective
p.000039: subjects about the precautions that will be taken to protect confidentiality”.45
p.000039: The written information and informed consent form to be provided to subjects should include explanations:
p.000039: a) of the extent to which the monitor(s), the auditor(s), the Ethics Committe and the regulatory authority(ies) will be
p.000039: granted direct access to the subject's original medical records for verification of clinical trial procedures and/or
...
p.000039: Investigation Plans and National Regulatory Authorities when applicable should systematically consider the issues
p.000039: raised in this reflection paper and apply the proposals during their assessments and recommendations/opinions provided
p.000039: to the applicants.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 33/42
p.000039:
p.000039: 3. Applicants should clearly explain why data from the patient populations selected are applicable to the EEA
p.000039: population unless the product is intended to be used outside the EEA.
p.000039:
p.000039: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000039: Submission, validation, assessment and inspection of the clinical trials contained in the Marketing Authorisation
p.000039: Application
p.000039: Recital 16 of Regulation (EC) No 726/2004 states that, with respect to clinical trials conducted outside the Community
p.000039: on medicinal products destined to be authorised within the Community, at the time of the evaluation of the application
p.000039: for authorisation, it should be verified that these trials were conducted in accordance with the principles of good
p.000039: clinical practice and the ethical requirements equivalent to the provisions of the said Directive.
p.000039: Article 6(1) of the same regulation requires that “the application include a statement to the effect that clinical
p.000039: trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC.”
p.000039: Article 56 (4) of the same regulation foresees that “the Committee for Medicinal Products for Human Use may, if they
p.000039: consider it appropriate, seek guidance on important questions of a general scientific or ethical nature.”
p.000039: As a consequence, the Marketing Authorisation evaluation should ensure that these GCP principles have been applied to
p.000039: all clinical trials submitted in the dossier, and, that ethical guidance is sought if required.
p.000039: Furthermore, an application for Marketing Authorisation for medicinal products for any population shall be regarded as
p.000039: valid only if requirements of the Article 7 of the European Paediatric Regulation are met.
p.000039:
p.000039: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000039:
p.000039: Background
p.000039:
p.000039: Three scenarios are considered:
p.000039:
p.000039: • The first relates to acceptability of foreign data for the EU, from a scientific viewpoint. This is already
p.000039: adequately covered elsewhere (see section 4.8).
p.000039: • The second relates to concern over the conduct of the study, and data reliability – this should trigger requests
p.000039: for clarification from the applicant, and also discussion with inspectors as to whether a GCP inspection may be
p.000039: appropriate or required (see 6.2).
p.000039: • The third relates to concern over the design of studies in relation to acceptability in Europe. Such concerns
p.000039: may relate to the use of placebo or duration of use of placebo, poorly optimised background therapy, use of
...
p.000039: Suspension/Urgent safety restriction/revocation of the Marketing Authorisation are considered where the non-compliance
p.000039: is identified after the MA has been granted in accordance with the legislation, guidance and rules applicable.
p.000039: Penalties
p.000039:
p.000039: The possibility of applying specific penalties should be considered and the mechanism for application of those
p.000039: penalties identified.
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EU Regulatory Authorities should develop a clear and detailed system for regulatory actions in case of non
p.000039: compliance with ethical and GCP requirements.
p.000039: 2. Where clear serious concerns are identify the EU Regulatory Authority should communicate these concerns to the
p.000039: National Regulatory Authority of the Country(ies) concerned.
p.000039:
p.000039: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039:
p.000039: The European Medicines Agency publishes on its website (www.ema.europa.eu) a full scientific assessment report called a
p.000039: European Public Assessment Report (EPAR) for every medicine granted a central marketing authorisation by the European
p.000039: Commission. Similarly, Public Assessment Reports are published on National Agencies’ websites or the Heads of Medicines
p.000039: Agencies website (www.hma.eu ) for medicines nationally authorised through the decentralised or mutual recognition
p.000039: procedures.
p.000039: Regulation (EC) No 726/2004 requires that competent authorities verify that clinical trials, in particular when carried
p.000039: out outside the European Union, were conducted in accordance with the principles of good clinical practice and the
p.000039: ethical requirements equivalent to Directive 2001/20/EC.
p.000039: The outcome of the process improvement for review of MAA dossiers and identification of studies of potential ethical or
p.000039: GCP concern proposed in the above section 5.1 should be made publicly accessible. Transparency on Regulatory
p.000039: Authorities’ GCP review during Marketing Authorisation procedures is necessary because of public and patients’ right
p.000039: to information about medicines and their development, including regarding good clinical practice in the conduct of
p.000039: clinical trials which is an important factor in patients’ willingness to participate in trials and their trust in
p.000039: medicines.
p.000039: The Public Assessment Report summarises the quality, safety and efficacy data evaluated and the outcome of that
p.000039: evaluation during the marketing authorisation processes in order to ensure that consistent and appropriate information
p.000039: is provided to the public on the clinical trials included in the MAA. Public Assessment Report are produced to standard
p.000039: formats and their content based on the CHMP Assessment Report (AR) or Reference Member State (RMS) AR after deletion of
p.000039: commercially confidential information.
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 39/42
p.000039:
p.000039: The CHMP or RMS assessment reports are obtained from the assessments at the different phases of the marketing
...
p.000039: Page 40/42
p.000039:
p.000039: 1. The CHMP or RMS assessment report and the Public Assessment Reports should describe clearly the clinical trials
p.000039: included in the Marketing Application dossier, listing the trials and details concerning their conduct. The applicant
p.000039: should provide tabular listings of this information to facilitate this process.
p.000039: 2. The CHMP or RMS assessment report and Public Assessment Reports should describe the assessment of the ethical
p.000039: issues and GCP compliance of the trials in the MAA, steps (including inspection) taken to confirm this and expert
p.000039: advice sought. They should confirm that the trials are considered to have fulfilled requirements, or, if that is not
p.000039: the case should describe the circumstances and details of studies which have been found not conducted in accordance
p.000039: with ethical requirements and GCP, and the actions taken as a consequence
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 41/42
p.000039:
p.000039: 3. References
p.000039:
p.000039: i Charter of Fundamental Rights of the European Union (2000) http://www.europarl.europa.eu/charter/default_en.htm
p.000039: ii Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of
p.000039: Biology and Medicine: Convention on Human Rights and Biomedicine. European Treaty Series – No 164. Oviedo, 4 IV 1997
p.000039: http://conventions.coe.int/treaty/en/treaties/html/164.htm
p.000039: iii Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research (Strasbourg
p.000039: 2005) http://conventions.coe.int/treaty/en/treaties/html/195.htm
p.000039: iv Universal Declaration of Human Rights of 1948, http://www.un.org/en/documents/udhr/ v Convention for the protection
p.000039: of Human Rights and fundamental Freedoms (COE, 1950) ,
p.000039: http://www.echr.coe.int/nr/rdonlyres/d5cc24a7-dc13-4318-b457-5c9014916d7a/0/englishanglais.pdf
p.000039: vi United Nations High Commissioner for Human Rights: Convention on the Rights of the Child (20/11/1989).
p.000039: http://www.ohchr.org/english/law/pdf/crc.pdf
p.000039: vii UNESCO. Universal Declaration on Bioethics and Human Rights (2005)
p.000039: http://portal.unesco.org/en/ev.php-RL_ID=31058&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: viii Universal Declaration on the Human Genome and Human Rights (UNESCO, 1997) http://portal.unesco.org/en/ev.php-
p.000039: URL_ID=13177&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: ix International Declaration on Human Genetic Data (UNESCO, 2003) http://portal.unesco.org/en/ev.php-
p.000039: URL_ID=17720&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: x CIOMS-WHO International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva 2002) ,
p.000039: http://www.cioms.ch/frame_guidelines_nov_2002.htm
...
Social / Unemployment
Searching for indicator unemployed:
(return to top)
p.000039: benefit/risk balance and to minimizing risk and burden when clinical trials are conducted in vulnerable populations56
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
...
Social / Women
Searching for indicator women:
(return to top)
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 24/42
p.000039:
p.000039: “Children represent a vulnerable population with developmental, physiological and psychological differences from
p.000039: adults, which make age- and development- related research important for their benefit”.62 Clinical research on children
p.000039: should be carried out under conditions affording the best possible protection for these subjects, without subjecting
p.000039: paediatric population to unnecessary trials.63
p.000039: Women
p.000039: Women are not per se a vulnerable group. However, in some societies women are not accorded full rights, either in law
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
p.000039: not pregnant, or on persons who are not deprived of liberty, whether the person undergoing research has been informed
p.000039: of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a
p.000039: state to receive the information, whether the necessary authorisation has been given specifically and in writing by the
p.000039: legal representative, and the person (or pregnant woman) concerned does not object.
p.000039: Exceptionally and under the protective conditions prescribed by law, where the research may not have the potential to
p.000039: produce results of direct benefit to the health of the person concerned, such research may be authorised, if it can
p.000039: contribute to the benefit of the group concerned whilst fulfilling the other conditions described above. “Measures of
p.000039: such benefit would include the importance of knowledge gained, severity of the issue to be addressed, commonality of
p.000039: the issue, likelihood of obtaining results from proposed research, and usefulness of benefits obtained”.66
p.000039:
p.000039:
p.000039:
p.000039: 62 Recital 3 of Directive 2001/20/EC
p.000039: 63 Recital 4 and art. 1 of Regulation EC/1901/2006 and art. 4 of Directive 2001/20/EC.
p.000039: 64 Belmont Report: ethical principles and guidelines for the protection of human subjects of research, Section D 3. 65
p.000039: Art. 17 of Declaration of Helsinki (2008).
p.000039: 66 Paragraph 12 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population
p.000039:
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
p.000039: to the child and the child’s response should be documented. “Strong and definitive objections from the child should be
p.000039: respected”. 27
p.000039: “If a subject is unable to read or if a legally acceptable representative is unable to read an impartial witness should
p.000039: be present during the entire informed consent discussion. After the written informed consent form and any other written
p.000039: information to be provided, is read and explained to the subject or the subject’s legally acceptable representative,
p.000039: and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s
p.000039: participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the
p.000039: witness should sign and personally date the consent form. By signing the consent form, the witness attests that the
p.000039: information in the consent form and any other written information was accurately explained to, and apparently
p.000039: understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely
...
p.000039: has not been obtained, investigators must see that biological samples are fully anonymized and unlinked; this ensures
p.000039: that no information about specific individuals can be derived from such research or passed back to them”. 42
p.000039: If research gives rise to information of clinical significance to the current or future health or quality of life of
p.000039: research participants, this information shall be available if they want to receive it. That shall be done within a
p.000039: framework of health care or specific counselling43,“In communication of such information, due care must be taken in
p.000039: order to protect confidentiality and to respect any wish of a
p.000039:
p.000039: 38 Art. 3.2(c) of Directive 2001/20/EC
p.000039: 39 Art. 9 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005); art. 14 International Declaration of
p.000039: Human Genetic Data; art 8 Charter of fundamental rights of the European Union
p.000039: 40 Art. 26 of Additional Protocol on Biomedical research (COE), 2005
p.000039: 41 Art. 6 of Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on
p.000039: the free movement of such data
p.000039: 42 WHO (CIOMS) Guideline 18
p.000039: 43 Art 27 of additional Protocol on Biomedical research (COE), 2005
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 21/42
p.000039:
p.000039: participant” [including the minor and/or his/her legal representative] ”not to receive such information”, in accordance
p.000039: with national law.44“During the process of obtaining informed consent the investigator should inform the prospective
p.000039: subjects about the precautions that will be taken to protect confidentiality”.45
p.000039: The written information and informed consent form to be provided to subjects should include explanations:
p.000039: a) of the extent to which the monitor(s), the auditor(s), the Ethics Committe and the regulatory authority(ies) will be
p.000039: granted direct access to the subject's original medical records for verification of clinical trial procedures and/or
p.000039: data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000039: regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable
p.000039: representative is authorising such access.
p.000039: b) “that records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws
p.000039: and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’
p.000039: identity will remain confidential”.46
p.000039: Biological sample retention, planned analysis and the need for consent to such use (and reuse) should be in accordance
...
Social / education
Searching for indicator education:
(return to top)
p.000039: complementary to the other numerous initiatives being carried out by international, European, regional and national
p.000039: organisations in this field.
p.000039: Existing initiatives have not always been implemented with a clear picture of what has been done already, what the
p.000039: results have been and what is being done in the same geographical area, in the same field of study etc.. As a
p.000039: consequence, there may be little knowledge of:
p.000039: • neglected areas of intervention;
p.000039:
p.000039: • the necessity for complementary interventions that can be more effective;
p.000039:
p.000039: • previous initiatives with favourable or unfavourable results;
p.000039:
p.000039: • the risk of duplication of initiatives.
p.000039:
p.000039: The group is aware of different initiatives at different levels carried out by different organisations. These
p.000039: initiatives can be categorised as follows:
p.000039:
p.000039: 3.2.2. Categories of initiatives and actions
p.000039:
p.000039: • Assessment of National supervisory bodies (Regulatory Authorities and Ethics Committees)
p.000039:
p.000039: • Strengthening National Supervisory bodies
p.000039:
p.000039: - national regulatory authority
p.000039:
p.000039: - ethics committee
p.000039:
p.000039: - other authorities
p.000039:
p.000039: Examples of initiatives are provided in section 3.5.
p.000039:
p.000039: • Strengthening the initiative of other Organizations
p.000039:
p.000039: - University education
p.000039:
p.000039: - Civil society organization
p.000039:
p.000039: - Investigator networks
p.000039:
p.000039: - Health care Systems
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 9/42
p.000039:
p.000039: 3.2.3. Establishment of contact with key initiatives
p.000039:
p.000039: Relevant contact points for these different initiatives and countries of interest should be identified and good
p.000039: communication established in order to obtain:
p.000039: • updated knowledge of the situation in each of the priority countries
p.000039:
p.000039: • an evaluation on what has already been done to date;
p.000039:
p.000039: • reciprocal knowledge of what is being done in this field;
p.000039:
p.000039: • a continuous update on what is going to be done.
p.000039:
p.000039: This will facilitate the identification of partnerships for joint, common or coordinated activities.
p.000039:
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EMA will identify other initiatives that are being carried out in the area of clinical trials supervision, mapping
p.000039: of regulatory systems in place and capacity building.
p.000039: 2. EMA will identify contact points with the other initiatives in order to identify partnerships for joint, common or
p.000039: coordinated activities.
p.000039: 3. EMA will ensure that the mapping is established in cooperation with other partners
p.000039:
p.000039: 3.3. Action plan
p.000039:
p.000039: Three major directions are identified:
p.000039:
...
p.000039: time the benefit to the patient of taking part in the study and the ethics of potentially turning them away simply
p.000039: because they fit one of the vulnerable categories needs to be considered. Special care should be paid to the
p.000039: benefit/risk balance and to minimizing risk and burden when clinical trials are conducted in vulnerable populations56
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
...
p.000039: part of EU Regulators
p.000039: 4. The study was conducted mainly/solely outside EEA
p.000039:
p.000039: 5. Concern about the stability of IMP in a non-temperate climate
p.000039:
p.000039: In case of concerns identified during the review of an application for Marketing Authorisation, questions should be
p.000039: addressed to the sponsor. The concern will also be discussed between assessors and inspectors, and an inspection may be
p.000039: initiated whenever required. Inspections may also be requested as part of a programme of routine inspections.
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. The criteria used as the basis for both routine and triggered GCP inspections and the process for identifying
p.000039: triggers for GCP inspections should be further developed and systematised.
p.000039: 2. Frameworks for contact with National Regulatory Authorities, to gain/share information on the GCP compliance and
p.000039: local inspection, in the countries where clinical trials take place as well to conduct joint inspection should be
p.000039: developed.
p.000039:
p.000039: 6.3. Actions available in response to non compliance
p.000039:
p.000039: This reflection paper seeks to reinforce the regulatory framework for the conduct of ethical, scientifically valid
p.000039: clinical trials, and the protection of trial subjects. Ideally such measures would ensure that significant
p.000039: non-compliance would not occur. The processes available to address situations where requirements have not been
p.000039: followed, should strive to further refine and reinforce the framework for the conduct of trials and the understanding
p.000039: of requirements by all involved. The range of actions available should also include activities that involve
p.000039: communication, education and refinement as the preferred course. In some circumstances this will not be possible, or
p.000039: appropriate, not least because by the time of the MAA, the clinical trials in question are generally completed and
p.000039: little can be done to remedy deficiencies in the conduct of those particular trials.
p.000039: Trial subjects and their communities also need to be assured that their rights and welfare will be supported and
p.000039: reinforced by regulators, both locally, and internationally as the entire process of development of medicines relies on
p.000039: the willingness of individuals to participate in clinical trials.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 37/42
p.000039:
p.000039: Particular emphasis should be given to trials conducted in countries outside EU/EEA. The role and authority of the
p.000039: Ethics Committees and National Regulatory Authorities in the countries where the trials are conducted should be
p.000039: supported. When non compliance with GCP regulatory obligations and ethical concerns are detected, action should include
p.000039: communication with the National Regulatory Authority concerned. This action should be proportionate to the consequences
p.000039: of the observed violation on the rights and welfare of the trial subjects and of the deficiencies on the data
p.000039: integrity.
p.000039: There is the need to define and to make public the consequences of non compliance with GCP and above mentioned ethical
p.000039: concerns in designing, conducting, recording and reporting of the clinical trials included in the MAA.
p.000039: Non compliance which significantly affects the rights, safety or well being of the subjects or the quality and
p.000039: integrity of the data reported is not acceptable, and will result in rejection of data and/or other regulatory actions.
p.000039: Regulatory options should include the following:
p.000039:
p.000039: Information and possible action by regulators of countries outside EU/EEA
p.000039:
p.000039: Information on non-compliance should be made available to the Regulatory Authority in the country in which the trial
p.000039: non-compliance has been identified and to other regulators in the international network, (subject to appropriate
p.000039: confidentiality arrangements if applicable).
p.000039: Request for additional information or action by the sponsor
p.000039:
p.000039: The sponsor may be asked to supply additional information or explanation, conduct further analyses or data
p.000039: collection/review, or to commission further monitoring or independent audits of a wider range of sites.
p.000039: Inspection or re-inspection
p.000039:
p.000039: (Further) sites involved in the same trial/and or further trials and/or sponsor site/Marketing Authorisation Holders
p.000039: may be inspected to determine the extent of non-compliance.
p.000039: Rejection of data/exclusion of trial/negative opinion
p.000039:
p.000039: Data obtained from clinical site(s) or from a trial found to be seriously non compliant with GCP and/or ethical
p.000039: requirements should be excluded from use in support of the MAA.
p.000039: Education and Facilitation
p.000039:
p.000039: Applicants and/or Marketing Authorisation Holders may be informed of non-compliance and advised on how this can be
p.000039: remedied for future trials, and in some cases action may be possible for the trial in question.
p.000039: Warning
p.000039:
p.000039: The EMA may issue a formal warning reminding Applicants and/or Marketing Authorisation Holders of their GCP obligations
p.000039: relating to the conduct of clinical trials in accordance with above mentioned ethical and GCP requirements
p.000039: Transparency regarding clinical trial conduct and compliance including non-compliant Marketing Authorisations
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 38/42
p.000039:
p.000039: The EPAR should describe any serious non-compliance encountered and discuss the steps taken as a consequence. This
p.000039: should be done whether the CHMP opinion is positive or negative or the application is withdrawn prior to the opinion.
p.000039: Suspension of the Marketing Authorisation/Urgent Safety restriction /Revocation of the Marketing Authorisation
p.000039: Suspension/Urgent safety restriction/revocation of the Marketing Authorisation are considered where the non-compliance
p.000039: is identified after the MA has been granted in accordance with the legislation, guidance and rules applicable.
p.000039: Penalties
p.000039:
p.000039: The possibility of applying specific penalties should be considered and the mechanism for application of those
p.000039: penalties identified.
...
Social / gender
Searching for indicator gender:
(return to top)
p.000039: Page 39/42
p.000039:
p.000039: The CHMP or RMS assessment reports are obtained from the assessments at the different phases of the marketing
p.000039: authorisation procedures. The application of GCP and ethical requirements and steps taken to confirm this, or any
p.000039: related issues should be reflected in the Public Assessment Reports.
p.000039: For example, guidance to assessors outlines the nature of clinical trial information that should be included in the
p.000039: assessment report at Day 80 and in the CHMP assessment report/EPAR. (see Guidance Document – Day 80 Clinical
p.000039: Assessment Report http://www.ema.europa.eu/pdfs/human/chmptemplates/CHMP-D80-AR-
p.000039: Guidance/D80AR_Clinical_Guidance_rev10_09.pdf ).
p.000039: Inclusion in the guidance of the items listed below, and the consistent application of this, will substantially improve
p.000039: the content of assessment reports and hence the Public Assessment Report in respect of ethical and GCP compliance.
p.000039: The CHMP or RMS assessment report and the Public Assessment Reports should address the following aspects:
p.000039: • The steps taken to evaluate and provide assurance regarding the ethical conduct of the trials should be
p.000039: described as should any significant deficiencies and how they have been addressed.
p.000039: • The standard GCP review should be summarised in an annex to the CHMP or RMS Assessment Report and to the Public
p.000039: Assessment Report, It should list, for each clinical trial submitted the protocol identification and title, start and
p.000039: end date, identification of the sponsor, of the countries where each trial was conducted and the numbers of subjects
p.000039: recruited in each country. The nature of the patient population should also be described (age and gender and any
p.000039: particular considerations of vulnerability). The standards to which the trials were conducted should be identified.
p.000039: This summary should be based on information to be supplied, electronically, by the applicant.
p.000039: • During the course of the assessment, any relevant ethical issue such as access to treatment post trial, use of
p.000039: placebo or treatment interruptions, choice of active comparators, treatment of vulnerable populations should be
p.000039: highlighted as part of the assessment of the individual trial.,
p.000039: • The justifications for the study designs, choice of comparators and selection of study populations, should be
p.000039: provided with particular emphasis on those studies that involve increased ethical sensitivity due to their design,
p.000039: indication, patient population or location of conduct. The applicability of the trial to the EEA population should be
p.000039: discussed where relevant.
p.000039: • A comment that “no ethical issues were identified” may be sufficient where applicable.
p.000039:
p.000039: • If available, information on Patients’ involvement in study design should be communicated,
p.000039:
p.000039: • When a GCP inspection is performed, the reason(s) for inspection should be described. The outcome and
p.000039: consequences on the assessment of a MAA should be further elaborated. Relevant information from the inspection report
p.000039: may be made publicly accessible.
p.000039: • When GCP/ethical concerns have been raised, the assessment report should present the issue, describe any
...
Social / orphan
Searching for indicator orphan:
(return to top)
p.000024: phase 29
p.000024: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000031: 31
p.000031: 5.2. Issues related to feasibility of clinical trials 31
p.000031: 5.3. General measures to assure data quality when conducting trials outside the EU 32
p.000031: 5.4. Considerations for designing clinical trials 33
p.000031: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000034: 34
p.000034: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000034: 34
p.000034: 6.2. Inspections: Triggers for inspection to be identified by assessor 36
p.000034: 6.3. Actions available in response to non compliance 37
p.000034: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039: 39
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 2/42
p.000039:
p.000039: 1. Glossary
p.000039: AR: Assessment Report
p.000039:
p.000039: COE: Council of Europe
p.000039:
p.000039: CHMP: Committee for Medicinal Products for Human Use
p.000039:
p.000039: CMD: Coordination Group for Mutual Recognition and Decentralised Procedures COMP:
p.000039: Committee for Orphan Medicinal Products
p.000039: CTFG: Clinical Trial Facilitation Group
p.000039:
p.000039: DCP: Decentralised Procedure
p.000039:
p.000039: EEA: European Economic Area
p.000039:
p.000039: EMA: European Medicines Agency
p.000039:
p.000039: EPAR: European Public Assessment Report
p.000039:
p.000039: GCP: Good Clinical Practice
p.000039:
p.000039: GCP IWG: GCP Inspectors Working Group
p.000039:
p.000039: HCP-WG: Working Group with Healthcare Professionals’ Organisations ICH:
p.000039: International Conference on Harmonization
p.000039: IMP: Investigational Medicinal Product
p.000039:
p.000039: MAA: Marketing Authorisation Application
p.000039:
p.000039: MRP: Mutual Recognition Procedure
p.000039:
p.000039: MSs: Member States
p.000039:
p.000039: NGOs: Non-governmental organisations
p.000039:
p.000039: PCWP: Working Party with Patients’ and Consumers’ Organizations
p.000039:
p.000039: PDCO: Paediatric Committee
p.000039:
p.000039: SAG: Scientific Advisory Group
p.000039:
p.000039: WHO: World Health Organization
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
...
p.000039: of clinical trials on medicinal products for human use. To be taken into account during the assessment of an
p.000039: application, clinical trials, conducted outside the European Community, which relate to medicinal products intended to
p.000039: be used in the European Community, shall be designed, implemented and reported on what good clinical practice and
p.000039: ethical principles are concerned, on the basis of principles, which are equivalent to the provisions of Directive
p.000039: 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the
p.000039: Declaration of Helsinki.”
p.000039: The EMA Work Programme for 2008 (http://www.ema.europa.eu/pdfs/general/direct/emeawp/
p.000039: EMEA_Work_Programme_2008_full.pdf) set out a number of objectives relating to the acceptance, in MAAs submitted to the
p.000039: EMA, of clinical trials conducted in countries outside the EEA on medicinal products for human use. All clinical trials
p.000039: from phase I to phase IV (including BE/BA studies) are required to meet internationally agreed ethical and data quality
p.000039: standards or their equivalent. These objectives need to be built into the process of clinical development. They need to
p.000039: be addressed before and during the conduct of the clinical trials and not only by assessment and inspection at the time
p.000039: of MA evaluation, by which point the trials have been completed, in some cases several years earlier.
p.000039: Actions to meet this objective therefore need to encompass EMA processes having an impact on clinical trials commencing
p.000039: prior to early phase clinical development. These processes include development of guidelines, Scientific Advice, Orphan
p.000039: Product Designation and Paediatric Investigation Plans and continue through to the finalisation of the CHMP opinion on
p.000039: the MAA/Scientific Opinion/Article 58 application evaluation, and post-authorisation activities and inspections.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 5/42
p.000039:
p.000039: In December 2008 the EMA published a strategy paper “Acceptance of clinical trials conducted in third countries for
p.000039: evaluation in Marketing Authorisation Applications”
p.000039: (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000072.js p&jsenabled=true)
p.000039: outlining four areas for action. These are:
p.000039: 1. Clarify the practical application of ethical standards for clinical trials, in the context of European Medicines
p.000039: Agency activities.
p.000039: 2. Determine the practical steps undertaken during the provision of guidance and advice in the drug development
p.000039: phase.
p.000039: 3. Determine the practical steps to be undertaken during the Marketing Authorisation phase
p.000039:
p.000039: 4. International cooperation in the regulation of clinical trials, their review and inspection and capacity building
p.000039: in this area.
p.000039: In 2009 the EMA established a Working Group on clinical trials on medicinal products for human use conducted outside
p.000039: EU/EEA.
p.000039: The Working Group, includes representatives of Committee for Medicinal Products for Human Use (CHMP), of the Paediatric
p.000039: Committee (PDCO), of the Committee for Orphan Medicinal Products (COMP), of the Clinical Trial Facilitation Group
p.000039: (CTFG), of the GCP Inspector Working group (GCP-IWG),
p.000039: Of the Working Group with Healthcare Professionals’ Organisations (HCP-WG), of the
p.000039:
p.000039: Working Party with Patients’ and Consumers’ Organisations (PCWP), of the Coordination Group for Mutual Recognition and
p.000039: Decentralized Procedures - Human (CMDh), of EMA and of the European Commission Pharmaceutical Unit
p.000039: This working Group has been asked to develop practical proposals for tasks and procedures or guidance to address the
p.000039: four action areas set out above. The present document reflects the results of the activities of this Working Group.
p.000039:
p.000039: 3. International cooperation in the regulation of clinical trials, their review and inspection and capacity building
p.000039: in this area
p.000039: International cooperation has been clearly identified as a key foundation in developing a robust international
p.000039: framework for the conduct of clinical trials. As more and more clinical trials on medicinal products marketed in the EU
p.000039: are performed in countries outside of the EU, enhanced international cooperation is seen as essential to ensure that,
p.000039: as far as possible, there is a common international approach to the oversight of clinical trials. In addition the
p.000039: clinical trials are conducted, increasingly in countries, where the ethics and regulatory systems are not fully
p.000039: developed and with which EU regulators have limited formal contacts or experience in the domain of clinical trials.
...
p.000039: management in the selected countries
p.000039: - Level of overall standard of care in the targeted countries
p.000039:
p.000039: - Stopping rules in case of lack of efficacy or safety issue
p.000039:
p.000039: - Existence and responsibilities of the independent Data and Safety Monitoring Board and/ or Data Monitoring Board
p.000039: - Availability of a local accredited laboratory in the Country where the study is performed to provide testing of
p.000039: samples.
p.000039: • Analysis of factors potentially impacting on the ability to extrapolate the clinical trial results to the EU
p.000039: population, such as:
p.000039: - Sources of data variability
p.000039:
p.000039: disease outcome and management
p.000039:
p.000039: parameters impacting the drug effect variability standards of patients management care
p.000039: specific measures for assessment of treatment adherence in some specific cases
p.000039:
p.000039: - Validation of outcome measure, to be used in the non-EEA population (e.g. Quality Of Life scoring)
p.000039: - Implementation and interpretation of biomarkers and surrogate end-points
p.000039:
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. Clinical trials are conducted not only for submission to the EEA but also to many other regulators worldwide. In
p.000039: order to minimise risk of non-approvability of the application due to the choice of study populations not applicable to
p.000039: the EU/ EEA population or trial designs not acceptable in the EEA sponsors should seek EU scientific advice prior to
p.000039: the conduct of those trials.
p.000039: 2. EMA Committees and working Parties evaluating requests for Scientific Advice, Orphan designation, and Paediatric
p.000039: Investigation Plans and National Regulatory Authorities when applicable should systematically consider the issues
p.000039: raised in this reflection paper and apply the proposals during their assessments and recommendations/opinions provided
p.000039: to the applicants.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 33/42
p.000039:
p.000039: 3. Applicants should clearly explain why data from the patient populations selected are applicable to the EEA
p.000039: population unless the product is intended to be used outside the EEA.
p.000039:
p.000039: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000039: Submission, validation, assessment and inspection of the clinical trials contained in the Marketing Authorisation
p.000039: Application
p.000039: Recital 16 of Regulation (EC) No 726/2004 states that, with respect to clinical trials conducted outside the Community
p.000039: on medicinal products destined to be authorised within the Community, at the time of the evaluation of the application
p.000039: for authorisation, it should be verified that these trials were conducted in accordance with the principles of good
p.000039: clinical practice and the ethical requirements equivalent to the provisions of the said Directive.
p.000039: Article 6(1) of the same regulation requires that “the application include a statement to the effect that clinical
p.000039: trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC.”
...
Social / parents
Searching for indicator parent:
(return to top)
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
p.000039: to the child and the child’s response should be documented. “Strong and definitive objections from the child should be
p.000039: respected”. 27
p.000039: “If a subject is unable to read or if a legally acceptable representative is unable to read an impartial witness should
p.000039: be present during the entire informed consent discussion. After the written informed consent form and any other written
p.000039: information to be provided, is read and explained to the subject or the subject’s legally acceptable representative,
p.000039: and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s
p.000039: participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the
p.000039: witness should sign and personally date the consent form. By signing the consent form, the witness attests that the
...
Searching for indicator parents:
(return to top)
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
p.000039: to the child and the child’s response should be documented. “Strong and definitive objections from the child should be
p.000039: respected”. 27
p.000039: “If a subject is unable to read or if a legally acceptable representative is unable to read an impartial witness should
p.000039: be present during the entire informed consent discussion. After the written informed consent form and any other written
p.000039: information to be provided, is read and explained to the subject or the subject’s legally acceptable representative,
p.000039: and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s
p.000039: participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.000039: application, clinical trials, conducted outside the European Community, which relate to medicinal products intended to
p.000039: be used in the European Community, shall be designed, implemented and reported on what good clinical practice and
p.000039: ethical principles are concerned, on the basis of principles, which are equivalent to the provisions of Directive
p.000039: 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the
p.000039: Declaration of Helsinki.”
p.000039: The EMA Work Programme for 2008 (http://www.ema.europa.eu/pdfs/general/direct/emeawp/
p.000039: EMEA_Work_Programme_2008_full.pdf) set out a number of objectives relating to the acceptance, in MAAs submitted to the
p.000039: EMA, of clinical trials conducted in countries outside the EEA on medicinal products for human use. All clinical trials
p.000039: from phase I to phase IV (including BE/BA studies) are required to meet internationally agreed ethical and data quality
p.000039: standards or their equivalent. These objectives need to be built into the process of clinical development. They need to
p.000039: be addressed before and during the conduct of the clinical trials and not only by assessment and inspection at the time
p.000039: of MA evaluation, by which point the trials have been completed, in some cases several years earlier.
p.000039: Actions to meet this objective therefore need to encompass EMA processes having an impact on clinical trials commencing
p.000039: prior to early phase clinical development. These processes include development of guidelines, Scientific Advice, Orphan
p.000039: Product Designation and Paediatric Investigation Plans and continue through to the finalisation of the CHMP opinion on
p.000039: the MAA/Scientific Opinion/Article 58 application evaluation, and post-authorisation activities and inspections.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 5/42
p.000039:
p.000039: In December 2008 the EMA published a strategy paper “Acceptance of clinical trials conducted in third countries for
p.000039: evaluation in Marketing Authorisation Applications”
p.000039: (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000072.js p&jsenabled=true)
p.000039: outlining four areas for action. These are:
p.000039: 1. Clarify the practical application of ethical standards for clinical trials, in the context of European Medicines
p.000039: Agency activities.
p.000039: 2. Determine the practical steps undertaken during the provision of guidance and advice in the drug development
p.000039: phase.
p.000039: 3. Determine the practical steps to be undertaken during the Marketing Authorisation phase
p.000039:
p.000039: 4. International cooperation in the regulation of clinical trials, their review and inspection and capacity building
p.000039: in this area.
p.000039: In 2009 the EMA established a Working Group on clinical trials on medicinal products for human use conducted outside
p.000039: EU/EEA.
p.000039: The Working Group, includes representatives of Committee for Medicinal Products for Human Use (CHMP), of the Paediatric
p.000039: Committee (PDCO), of the Committee for Orphan Medicinal Products (COMP), of the Clinical Trial Facilitation Group
...
p.000039:
p.000039: • Investigation of systems for accreditation
p.000039:
p.000039: • Information exchange
p.000039:
p.000039: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000039: use in the context of the activities of the European Regulatory Authorities
p.000039: For the purpose of research, three ethical principles should be adhered to:
p.000039:
p.000039: a) respect for persons,
p.000039:
p.000039: b) beneficence/non-maleficence and
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 14/42
p.000039:
p.000039: c) justice, where respect for persons includes the respect for autonomy and the protection of dependent and vulnerable
p.000039: persons, beneficence/non- maleficence is defined as the ethical obligation to maximize benefits and to avoid or
p.000039: minimize harms, and justice is a fair distribution of the burdens and benefits of research1.
p.000039: “The rights safety and wellbeing of the trials subjects are the most important consideration and should prevail over
p.000039: the interests of science and society”. 2
p.000039: Clinical trials conducted in countries outside of the EU/EEA and used in MAAs in the EEA or in applications for a
p.000039: Scientific Opinion under article 58 of the Regulation (EC) No. 726/2004, must be conducted on the basis of principles
p.000039: equivalent to the ethical principles and principles of good clinical practice applied to clinical trials in the EEA3.
p.000039: Ethical principles have been established mainly by intergovernmental organisations such as the Council of Europe or
p.000039: WHO, or by professional bodies such as the World Medical Association, as well as in national or regional legislation or
p.000039: guidance. The latter often refer directly or indirectly to the internationally established principles.
p.000039: Ethical principles governing the conduct of clinical trials are set out in the Charter of Fundamental Rights of the
p.000039: European Union (2000)i the Council of Europe’s Convention on Human Rights and Biomedicine (1997)ii and its Additional
p.000039: Protocol on Biomedical Research (2005)iii, the Universal Declaration of Human Rights (1948)iv, the Convention for the
p.000039: protection of Human Rights and fundamental Freedoms (1950)v, the United Nations’ Convention on the Rights of the Child
p.000039: (1989)vi, the Universal Declaration on Bioethics and Human Rights (UNESCO, 2005)vii, the Universal Declaration on the
p.000039: Human Genome and Human Rights (UNESCO, 1997)viii, the International Declaration on Human Genetic Data (UNESCO, 2003)ix,
p.000039: the CIOMS-WHO International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva 2002)x, the
p.000039: Declaration of Helsinki of the World Medical Association (2008)xi, Opinion 17 of the European Group on Ethics (2003)xii
p.000039: and the EU Ethical considerations for clinical trials on medicinal products conducted with the paediatric population
p.000039: (2008)xiii. Practical steps to implement ethical requirements are set out in the CPMP/ICH/135/95 guideline on Good
p.000039: Clinical Practice (1995) (ICH E6)xiv and ICH E11 Note for guidance on clinical investigation of medicinal products in
p.000039: the paediatric population (2001)xv.
p.000039: The European pharmaceutical legislation sets out the ethical requirements for the conduct of clinical trials in
p.000039: Directive 2001/20/ECxvi, Directive 2005/28/ECxvii and Directive 2001/83/ECxviii. Provisions of the European Paediatric
p.000039: Regulation 1901/06/EC are equally taken into considerationxix.
p.000039: Provisions for the protection of personal data are laid down in Directive 1995/46/ECxx,
p.000039: The extent to which these various documents pertinent to clinical trials (both legal and ethical instruments) are taken
p.000039: into account in national or regional legislation within or outside EU is variable. They overlap in many areas, but some
p.000039: given greater precision on certain points whilst on others there are differences in approach. The aim of the present
p.000039: document is not to establish a new, additional, set of principles but rather to describe how the regulatory processes
p.000039: of the EMA and EU National Competent Authorities can take these into account in a practical way.
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: 1 WHO (CIOMS) Guidelines 2
p.000039: 2 Paragraph 2.3 of ICH-E6
p.000039: 3 Paragraph 8 of the Preamble of Annex 1 to Directive 2001/83/EC
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 15/42
p.000039:
p.000039: 4.1. Ethics committee and national regulatory authority oversight
p.000039:
p.000039: Research may only be undertaken if the research project has been approved by an EC (or other body authorised to review
p.000039: clinical research on human beings) with appropriate jurisdiction for the investigator sites and trial concerned, after
p.000039: independent examination of its scientific merit, including assessment of the importance of the aim of research, and
p.000039: multidisciplinary review of its ethical acceptability,4 In many countries an application also has to be made to a
p.000039: Regulatory Authority, before a clinical trial may commence.
p.000039: It is an important element of international cooperation that Regulatory Authorities support compliance with local
p.000039: requirements in each country as well as reinforcing international ethical and good clinical practice standards.
p.000039: All the information which is necessary for the ethical assessment of the research project should be given in written
p.000039: form to the Ethics Committee. 5 The Ethics Committee, in preparing its opinion should consider amongst others the
p.000039: points set out in art. 3, 4, 5 and 6 of the Directive 2001/20/EC, the Appendix to the additional protocol on biomedical
p.000039: research (COE- Information to be given to the Ethics Committee), and chapters 2 and 3 of ICH E 6 and WHO (CIOMS)
p.000039: guidelines 2. The Ethics Committees hould be satisfied that no undue influence, including that of a financial nature
p.000039: (or limiting or increasing access to medical care), will be exerted on persons, to participate in research. In this
p.000039: respect, particular attention must be given to vulnerable or dependent persons.6 EU legislation gives particular
p.000039: attention to protection of paediatric subjects7.
p.000039: The Ethics Committee shall give clearly stated reasons for its positive or negative conclusions. 8
p.000039: The declaration of Helsinki states that “No change to the protocol may be made without consideration and approval by
p.000039: the ethics committee”.9 EU Directive 2001/20/EC specifies that this should apply to substantial amendments.10 Research
p.000039: projects should be re-examined if this is justified in the light of scientific developments or events arising in the
p.000039: course of the research. 11
p.000039: “The ethics committee must have the right to monitor ongoing studies”12 “and to report to institutional or governmental
...
p.000039: compensation”. 49
p.000039: Before the research begins, the sponsor, whether a pharmaceutical company or other organisation or institution, should
p.000039: agree to provide compensation for any injury for which subjects are entitled to compensation, or come to an agreement
p.000039: with the investigator concerning the circumstances in which the investigator must rely on his or her own insurance
p.000039: coverage (for example, for negligence or failure of the investigator to follow the protocol, or where government
p.000039: insurance coverage is limited to negligence). In certain circumstances it may be advisable to follow both courses.
p.000039: “Sponsors should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution
p.000039: against claims arising from the trial, except for claims that arise from malpractice and/or negligence”.50
p.000039: “Both the informed consent discussion and the written informed consent form and any other written information to be
p.000039: provided to subjects involved in research should include explanations of the compensation and/or treatment available to
p.000039: the subject in the event of trial-related injury”.51
p.000039: Information shall be provided to the EC and where required to the National Regulatory Authority, on details of any
p.000039: insurance, indemnity or compensation to cover damage arising in the context of the research project52 (in particular
p.000039: “provision for indemnity or compensation in the event of injury or death attributable to a clinical trial, and any
p.000039: insurance or indemnity to cover the liability of the investigator and sponsor”). 53
p.000039: In preparing its opinion, the Ethics Committe (and where required the National Regulatory Authority) should consider
p.000039: these provisions54 and should pay careful attention to waivers of liability in the insurance contract, in particular
p.000039: with respect generally to long term effects and on development for children included in research. However,
p.000039: “unrecognised congenital defects are generally excluded”.55
p.000039: Regulatory action/action plan
p.000039:
p.000039: 48 Art. 31 of Additional Protocol on Biomedical research (COE) 2005 49 WHO (CIOMS) Guideline 19
p.000039: 50 Paragraph 5.8 of ICH-E6
p.000039: 51 Paragraph 4.8.10 of ICH-E6
p.000039: 52 Art 11 juncto appendix of Additional Protocol on Biomedical research (COE) 2005; Paragraph 3.1.2 of ICH-E6. 53 Art.
p.000039: 6.3 (h) and (i) of Directive 2001/20/EC
p.000039: 54 Art. 6.3 of Directive 2001/20/EC
p.000039: 55 Paragraph 22 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 23/42
p.000039:
p.000039: 1. Failure to provide fair compensation by insurance or indemnity is a serious violation of ethical standards. The
p.000039: applicant for a MAA should provide EU Competent Authorities with a summary of the provisions made to provide for the
p.000039: fair compensation of subjects for trial related injury. This information can form part of the clinical study report
...
p.000039: When applicable according to the procedure applied for, the applicant should consider the relevance of its clinical
p.000039: program, in relation to:
p.000039: • Applicability of the proposed indication and the therapeutic needs of the European population
p.000039:
p.000039: • Prevalence of the condition in non-EEA countries and in EEA countries.
p.000039:
p.000039: The consequences of drug development with clinical trials conducted outside the EEA (completely or partially) should be
p.000039: considered with regards to:
p.000039: • Limitations of data extrapolation from non-EU patients to the EEA
p.000039:
p.000039: • Impact of the geographic source of patients on the efficacy and safety results and their extrapolation the
p.000039: European population in the context of disease management (e.g. national characteristics of disease management and
p.000039: patient care)
p.000039: • Validity of the selected comparators (active or placebo) for enabling assessment of the Risk/Benefit balance of
p.000039: the product for the European population
p.000039: • Pre-specified subgroup analyses based on ethnicity and/or regions of the world
p.000039:
p.000039: • Evaluation of the level of adherence to standard background treatment regimes for a specific disease
p.000039: • Take into consideration possible differences in genetic profiles which could influence the drug response.
p.000039: Where a scientific advice, guidance or assessment relates to an application for a scientific opinion in the context of
p.000039: article 58 of Regulation No (EC) 726/2004 the considerations should relate to the population for which the medicinal
p.000039: product is to be used, rather than the EU population.
p.000039:
p.000039: 5.2. Issues related to feasibility of clinical trials
p.000039:
p.000039: The applicant should provide any available information on its development plan:
p.000039:
p.000039: • Details on the planned locations of the trials planned in the EEA and outside
p.000039:
p.000039: • Criteria for the selection of the non-EEA countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 31/42
p.000039:
p.000039: As such information may be limited or unavailable in the early phases of drug development, the applicant could provide
p.000039: a commitment to comply with general regulatory/GCP and ethical principles. Applicants are encouraged to seek follow-up
p.000039: advice when the drug development plan become clearer and clinical trials outside of the EU/EEA are foreseen
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
p.000039: to allow consideration of the possible consequences on the future MAA and results interpretation. This feasibility
p.000039: assessment should include as a minimum:
p.000039: • Recruitment plan for patients in the EEA and outside
p.000039:
p.000039: • Selection criteria and numbers of centres per country or regions outside the EEA
p.000039:
...
p.000039: of the observed violation on the rights and welfare of the trial subjects and of the deficiencies on the data
p.000039: integrity.
p.000039: There is the need to define and to make public the consequences of non compliance with GCP and above mentioned ethical
p.000039: concerns in designing, conducting, recording and reporting of the clinical trials included in the MAA.
p.000039: Non compliance which significantly affects the rights, safety or well being of the subjects or the quality and
p.000039: integrity of the data reported is not acceptable, and will result in rejection of data and/or other regulatory actions.
p.000039: Regulatory options should include the following:
p.000039:
p.000039: Information and possible action by regulators of countries outside EU/EEA
p.000039:
p.000039: Information on non-compliance should be made available to the Regulatory Authority in the country in which the trial
p.000039: non-compliance has been identified and to other regulators in the international network, (subject to appropriate
p.000039: confidentiality arrangements if applicable).
p.000039: Request for additional information or action by the sponsor
p.000039:
p.000039: The sponsor may be asked to supply additional information or explanation, conduct further analyses or data
p.000039: collection/review, or to commission further monitoring or independent audits of a wider range of sites.
p.000039: Inspection or re-inspection
p.000039:
p.000039: (Further) sites involved in the same trial/and or further trials and/or sponsor site/Marketing Authorisation Holders
p.000039: may be inspected to determine the extent of non-compliance.
p.000039: Rejection of data/exclusion of trial/negative opinion
p.000039:
p.000039: Data obtained from clinical site(s) or from a trial found to be seriously non compliant with GCP and/or ethical
p.000039: requirements should be excluded from use in support of the MAA.
p.000039: Education and Facilitation
p.000039:
p.000039: Applicants and/or Marketing Authorisation Holders may be informed of non-compliance and advised on how this can be
p.000039: remedied for future trials, and in some cases action may be possible for the trial in question.
p.000039: Warning
p.000039:
p.000039: The EMA may issue a formal warning reminding Applicants and/or Marketing Authorisation Holders of their GCP obligations
p.000039: relating to the conduct of clinical trials in accordance with above mentioned ethical and GCP requirements
p.000039: Transparency regarding clinical trial conduct and compliance including non-compliant Marketing Authorisations
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 38/42
p.000039:
p.000039: The EPAR should describe any serious non-compliance encountered and discuss the steps taken as a consequence. This
p.000039: should be done whether the CHMP opinion is positive or negative or the application is withdrawn prior to the opinion.
p.000039: Suspension of the Marketing Authorisation/Urgent Safety restriction /Revocation of the Marketing Authorisation
p.000039: Suspension/Urgent safety restriction/revocation of the Marketing Authorisation are considered where the non-compliance
p.000039: is identified after the MA has been granted in accordance with the legislation, guidance and rules applicable.
p.000039: Penalties
p.000039:
p.000039: The possibility of applying specific penalties should be considered and the mechanism for application of those
p.000039: penalties identified.
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EU Regulatory Authorities should develop a clear and detailed system for regulatory actions in case of non
p.000039: compliance with ethical and GCP requirements.
p.000039: 2. Where clear serious concerns are identify the EU Regulatory Authority should communicate these concerns to the
p.000039: National Regulatory Authority of the Country(ies) concerned.
p.000039:
p.000039: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039:
p.000039: The European Medicines Agency publishes on its website (www.ema.europa.eu) a full scientific assessment report called a
p.000039: European Public Assessment Report (EPAR) for every medicine granted a central marketing authorisation by the European
p.000039: Commission. Similarly, Public Assessment Reports are published on National Agencies’ websites or the Heads of Medicines
p.000039: Agencies website (www.hma.eu ) for medicines nationally authorised through the decentralised or mutual recognition
p.000039: procedures.
p.000039: Regulation (EC) No 726/2004 requires that competent authorities verify that clinical trials, in particular when carried
...
p.000039: http://conventions.coe.int/treaty/en/treaties/html/164.htm
p.000039: iii Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research (Strasbourg
p.000039: 2005) http://conventions.coe.int/treaty/en/treaties/html/195.htm
p.000039: iv Universal Declaration of Human Rights of 1948, http://www.un.org/en/documents/udhr/ v Convention for the protection
p.000039: of Human Rights and fundamental Freedoms (COE, 1950) ,
p.000039: http://www.echr.coe.int/nr/rdonlyres/d5cc24a7-dc13-4318-b457-5c9014916d7a/0/englishanglais.pdf
p.000039: vi United Nations High Commissioner for Human Rights: Convention on the Rights of the Child (20/11/1989).
p.000039: http://www.ohchr.org/english/law/pdf/crc.pdf
p.000039: vii UNESCO. Universal Declaration on Bioethics and Human Rights (2005)
p.000039: http://portal.unesco.org/en/ev.php-RL_ID=31058&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: viii Universal Declaration on the Human Genome and Human Rights (UNESCO, 1997) http://portal.unesco.org/en/ev.php-
p.000039: URL_ID=13177&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: ix International Declaration on Human Genetic Data (UNESCO, 2003) http://portal.unesco.org/en/ev.php-
p.000039: URL_ID=17720&URL_DO=DO_TOPIC&URL_SECTION=201.html
p.000039: x CIOMS-WHO International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva 2002) ,
p.000039: http://www.cioms.ch/frame_guidelines_nov_2002.htm
p.000039: xi World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human
p.000039: Subjects.
p.000039: Revision 2008 http://www.wma.net/en/30publications/10policies/b3/index.html
p.000039: xii Opinion n.17 of the European Group on Ethics in Science and New Technologies to the European Commission : “Ethical
p.000039: aspects of clinical research in developing countries” http://ec.europa.eu/european_group_ethics/docs/avis17_en.pdf
p.000039: xiii EU Ethical considerations for clinical trials on medicinal products conducted with the paediatric population
p.000039: (2008) http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/ethical_considerations.pdf
p.000039: xiv ICH E6 Guideline on Good Clinical Practice (1995), http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf xv Clinical
p.000039: investigation of medicinal products in the paediatric population. ICH E11.
p.000039: CPMP/ICH/2711/99. http://www.emea.europa.eu/pdfs/human/ich/271199EN.pdf
p.000039: xvi DIRECTIVE 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the
p.000039: laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical
p.000039: practice in the conduct of clinical trials on medicinal products for human use
p.000039: http://eudravigilance.emea.europa.eu/human/docs/directives/Dir2001-20_en.pdf
p.000039: xvii DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as
p.000039: regards investigational medicinal products for human use, as well as the requirements for authorisation of the
p.000039: manufacturing or importation of such products
p.000039: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:091:0013:0019:en:PDF
p.000039: xviii DIRECTIVE 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code
p.000039: relating to medicinal products for human use
...
Economic / Economic/Poverty
Searching for indicator poverty:
(return to top)
p.000039: 50 Paragraph 5.8 of ICH-E6
p.000039: 51 Paragraph 4.8.10 of ICH-E6
p.000039: 52 Art 11 juncto appendix of Additional Protocol on Biomedical research (COE) 2005; Paragraph 3.1.2 of ICH-E6. 53 Art.
p.000039: 6.3 (h) and (i) of Directive 2001/20/EC
p.000039: 54 Art. 6.3 of Directive 2001/20/EC
p.000039: 55 Paragraph 22 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 23/42
p.000039:
p.000039: 1. Failure to provide fair compensation by insurance or indemnity is a serious violation of ethical standards. The
p.000039: applicant for a MAA should provide EU Competent Authorities with a summary of the provisions made to provide for the
p.000039: fair compensation of subjects for trial related injury. This information can form part of the clinical study report
p.000039: section on ethical considerations and informed consent.
p.000039: 2. EMA and EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
p.000039: insurance, indemnity or compensation for research related injury and where applicable to seek additional assurance that
p.000039: trial subjects’ interest have been protected.
p.000039:
p.000039: 4.5. Vulnerable populations
p.000039:
p.000039: In the context of this paper, one of the main concerns is the vulnerability of person due to poverty, lack of adequate
p.000039: health care systems or lack of access to medicines,
p.000039: The definition of vulnerability is based on existing ethical guidelines. Nevertheless vulnerability has to be
p.000039: considered in terms of a condition, or situation affecting persons and making people vulnerable in particular situation
p.000039: rather than considering a specific population as vulnerable (people that are part of a specific population considered
p.000039: vulnerable may or may not be vulnerable).
p.000039: The key concern is to avoid that vulnerable persons or group are exploited for the benefit of EU patients. At the same
p.000039: time the benefit to the patient of taking part in the study and the ethics of potentially turning them away simply
p.000039: because they fit one of the vulnerable categories needs to be considered. Special care should be paid to the
p.000039: benefit/risk balance and to minimizing risk and burden when clinical trials are conducted in vulnerable populations56
p.000039: rThe health needs of the Country should be reflected.
...
General/Other / Dependent
Searching for indicator dependent:
(return to top)
p.000039: • EMA works, in cooperation with the European Commission DG Development and with WHO on a project to help
p.000039: regulators from less well developed National Regulatory Authorities, to develop their expertise in the review of MAAs.
p.000039: Ethics Committees:
p.000039:
p.000039: • FERCAP initiative, http://www.fercap-sidcer.org/aboutus.php
p.000039:
p.000039: • Assessment of / assistance in implementing Ethics Committes
p.000039:
p.000039: • Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
p.000039: • Evaluation of clinical trials.
p.000039:
p.000039: • Investigation of systems for accreditation
p.000039:
p.000039: • Information exchange
p.000039:
p.000039: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000039: use in the context of the activities of the European Regulatory Authorities
p.000039: For the purpose of research, three ethical principles should be adhered to:
p.000039:
p.000039: a) respect for persons,
p.000039:
p.000039: b) beneficence/non-maleficence and
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 14/42
p.000039:
p.000039: c) justice, where respect for persons includes the respect for autonomy and the protection of dependent and vulnerable
p.000039: persons, beneficence/non- maleficence is defined as the ethical obligation to maximize benefits and to avoid or
p.000039: minimize harms, and justice is a fair distribution of the burdens and benefits of research1.
p.000039: “The rights safety and wellbeing of the trials subjects are the most important consideration and should prevail over
p.000039: the interests of science and society”. 2
p.000039: Clinical trials conducted in countries outside of the EU/EEA and used in MAAs in the EEA or in applications for a
p.000039: Scientific Opinion under article 58 of the Regulation (EC) No. 726/2004, must be conducted on the basis of principles
p.000039: equivalent to the ethical principles and principles of good clinical practice applied to clinical trials in the EEA3.
p.000039: Ethical principles have been established mainly by intergovernmental organisations such as the Council of Europe or
p.000039: WHO, or by professional bodies such as the World Medical Association, as well as in national or regional legislation or
p.000039: guidance. The latter often refer directly or indirectly to the internationally established principles.
p.000039: Ethical principles governing the conduct of clinical trials are set out in the Charter of Fundamental Rights of the
p.000039: European Union (2000)i the Council of Europe’s Convention on Human Rights and Biomedicine (1997)ii and its Additional
p.000039: Protocol on Biomedical Research (2005)iii, the Universal Declaration of Human Rights (1948)iv, the Convention for the
...
p.000039: multidisciplinary review of its ethical acceptability,4 In many countries an application also has to be made to a
p.000039: Regulatory Authority, before a clinical trial may commence.
p.000039: It is an important element of international cooperation that Regulatory Authorities support compliance with local
p.000039: requirements in each country as well as reinforcing international ethical and good clinical practice standards.
p.000039: All the information which is necessary for the ethical assessment of the research project should be given in written
p.000039: form to the Ethics Committee. 5 The Ethics Committee, in preparing its opinion should consider amongst others the
p.000039: points set out in art. 3, 4, 5 and 6 of the Directive 2001/20/EC, the Appendix to the additional protocol on biomedical
p.000039: research (COE- Information to be given to the Ethics Committee), and chapters 2 and 3 of ICH E 6 and WHO (CIOMS)
p.000039: guidelines 2. The Ethics Committees hould be satisfied that no undue influence, including that of a financial nature
p.000039: (or limiting or increasing access to medical care), will be exerted on persons, to participate in research. In this
p.000039: respect, particular attention must be given to vulnerable or dependent persons.6 EU legislation gives particular
p.000039: attention to protection of paediatric subjects7.
p.000039: The Ethics Committee shall give clearly stated reasons for its positive or negative conclusions. 8
p.000039: The declaration of Helsinki states that “No change to the protocol may be made without consideration and approval by
p.000039: the ethics committee”.9 EU Directive 2001/20/EC specifies that this should apply to substantial amendments.10 Research
p.000039: projects should be re-examined if this is justified in the light of scientific developments or events arising in the
p.000039: course of the research. 11
p.000039: “The ethics committee must have the right to monitor ongoing studies”12 “and to report to institutional or governmental
p.000039: authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that
p.000039: they have approved or in the conduct of the studies”.13
p.000039: If the clinical trial is planned to be conducted in a country with limited Regulatory Authority or Ethics Committees
p.000039: framework and limited oversight of the clinical trial, the sponsor should put in place alternative solutions in order
p.000039: to ensure an adequate review of the clinical trial protocol. A possible option could be to consider complementing the
p.000039: ethics Committees review in that country by submitting the study protocol for ethical and scientific review to an
...
p.000039: or in practice. Therefore, in some cases women may be regarded as being in a position of vulnerability in the sense
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
p.000039: not pregnant, or on persons who are not deprived of liberty, whether the person undergoing research has been informed
p.000039: of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a
...
General/Other / Impaired Autonomy
Searching for indicator autonomy:
(return to top)
p.000039: • Protocol assistance/Scientific Advice
p.000039:
p.000039: • Assessment of clinical trials and clinical data
p.000039:
p.000039: • EMA works, in cooperation with the European Commission DG Development and with WHO on a project to help
p.000039: regulators from less well developed National Regulatory Authorities, to develop their expertise in the review of MAAs.
p.000039: Ethics Committees:
p.000039:
p.000039: • FERCAP initiative, http://www.fercap-sidcer.org/aboutus.php
p.000039:
p.000039: • Assessment of / assistance in implementing Ethics Committes
p.000039:
p.000039: • Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
p.000039: • Evaluation of clinical trials.
p.000039:
p.000039: • Investigation of systems for accreditation
p.000039:
p.000039: • Information exchange
p.000039:
p.000039: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000039: use in the context of the activities of the European Regulatory Authorities
p.000039: For the purpose of research, three ethical principles should be adhered to:
p.000039:
p.000039: a) respect for persons,
p.000039:
p.000039: b) beneficence/non-maleficence and
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 14/42
p.000039:
p.000039: c) justice, where respect for persons includes the respect for autonomy and the protection of dependent and vulnerable
p.000039: persons, beneficence/non- maleficence is defined as the ethical obligation to maximize benefits and to avoid or
p.000039: minimize harms, and justice is a fair distribution of the burdens and benefits of research1.
p.000039: “The rights safety and wellbeing of the trials subjects are the most important consideration and should prevail over
p.000039: the interests of science and society”. 2
p.000039: Clinical trials conducted in countries outside of the EU/EEA and used in MAAs in the EEA or in applications for a
p.000039: Scientific Opinion under article 58 of the Regulation (EC) No. 726/2004, must be conducted on the basis of principles
p.000039: equivalent to the ethical principles and principles of good clinical practice applied to clinical trials in the EEA3.
p.000039: Ethical principles have been established mainly by intergovernmental organisations such as the Council of Europe or
p.000039: WHO, or by professional bodies such as the World Medical Association, as well as in national or regional legislation or
p.000039: guidance. The latter often refer directly or indirectly to the internationally established principles.
p.000039: Ethical principles governing the conduct of clinical trials are set out in the Charter of Fundamental Rights of the
p.000039: European Union (2000)i the Council of Europe’s Convention on Human Rights and Biomedicine (1997)ii and its Additional
p.000039: Protocol on Biomedical Research (2005)iii, the Universal Declaration of Human Rights (1948)iv, the Convention for the
...
p.000039: 20 Art. 3.2 (e) of Directive 2001/20/EC; Art. 6 of Universal Declaration on Bioethics and Human Rights (Unesco,2005);
p.000039: Art. 14 Additional Protocol on Biomedical research (COE), 2005
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 18/42
p.000039:
p.000039: signed and dated informed consent form”.21 The trial participant should be given a copy of his/her consent once it is
p.000039: signed. Refusal to give consent or withdrawal of consent to participation in research shall not lead to any form of
p.000039: liability (particularly of a financial nature) and/or to any form of discrimination against the person concerned, in
p.000039: particular regarding the right to medical care 22. The same level of care and information should be maintained during
p.000039: treatment or investigations.
p.000039: The informed consent of each subject shall be renewed if there are significant changes in the conditions or procedures
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
...
General/Other / Manipulable
Searching for indicator manipulate:
(return to top)
p.000039: that they may have a limited capacity to protect their own interests.
p.000039: In locations where the social, political or economic position of women could be deemed as questionable (whether in law
p.000039: or in practice), this should be considered in the trial protocol and, where appropriate, special provisions for the
p.000039: protection of their rights and welfare should be applied, for example concerning informed consent.
p.000039:
p.000039: Restrictions in research on vulnerable subjects
p.000039:
p.000039: Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may
p.000039: continually be sought as research subjects, owing to their ready availability in settings where research is conducted,
p.000039: or the conditions they suffer from (e.g. renal insufficiency). “Given their dependent status and their frequently
p.000039: compromised capacity for free consent, they should be protected against the danger of being involved in research solely
p.000039: for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic
p.000039: condition”.64
p.000039: “Medical research involving a disadvantaged or vulnerable population or community is only justified if the research is
p.000039: responsive to the health needs and priorities of this population or community and if there is a reasonable likelihood
p.000039: that this population or community stands to benefit from the results of the research”.65
p.000039: Research should be undertaken in vulnerable population only when particular conditions are met e.g. whether the results
p.000039: of the research have the potential to produce real and direct benefit to the trial subject, whether research of
p.000039: comparable effectiveness cannot be carried out on individuals capable of giving consent or for example on women who are
p.000039: not pregnant, or on persons who are not deprived of liberty, whether the person undergoing research has been informed
p.000039: of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a
p.000039: state to receive the information, whether the necessary authorisation has been given specifically and in writing by the
p.000039: legal representative, and the person (or pregnant woman) concerned does not object.
p.000039: Exceptionally and under the protective conditions prescribed by law, where the research may not have the potential to
...
General/Other / Public Emergency
Searching for indicator emergency:
(return to top)
p.000039: signed. Refusal to give consent or withdrawal of consent to participation in research shall not lead to any form of
p.000039: liability (particularly of a financial nature) and/or to any form of discrimination against the person concerned, in
p.000039: particular regarding the right to medical care 22. The same level of care and information should be maintained during
p.000039: treatment or investigations.
p.000039: The informed consent of each subject shall be renewed if there are significant changes in the conditions or procedures
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
...
p.000039: rThe health needs of the Country should be reflected.
p.000039: “Vulnerability” is defined as susceptibility of being wounded. Vulnerability is applied both to individuals and to
p.000039: populations. “Vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own
p.000039: interests”,57 that means “individuals whose willingness to volunteer in a clinical trial may be unduly influenced by
p.000039: the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from
p.000039: senior members of a hierarchy in case of refusal to participate”58 “More formally, vulnerable persons may have
p.000039: insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own
p.000039: interests” 59
p.000039: Example of vulnerable subjects are patients with incurable diseases, or that have serious, potentially disabling or
p.000039: life-threatening diseases, 60 persons in nursing homes, unemployed or impoverished persons, patients in emergency
p.000039: situations, homeless persons, nomads, refugees, prisoners, members of a group with a hierarchical structure, members of
p.000039: the armed forces 61,minors and those incapable of giving consent. Other groups or classes may also be considered
p.000039: vulnerable (e.g. elderly persons, people receiving welfare benefits or social assistance some ethnic and racial
p.000039: minority groups and individuals who are politically powerless) This list is not exhaustive and many other categories
p.000039: not mentioned in this text but that fall in the definition of vulnerable population could be included.
p.000039: Children
p.000039:
p.000039:
p.000039:
p.000039: 56 Art 15, 18 and 20 of the Additional Protocol on Biomedical Research of the Council of Europe 57 WHO (CIOMS)
p.000039: Guideline 13
p.000039: 58 Paragraph 1.61 of ICH-E6,
p.000039: 59 WHO (CIOMS) Guideline 13
p.000039: 60 WHO (CIOMS) Guideline 13
p.000039: 61 Paragraph 1.61 of ICH-E6,
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
...
General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.002011:
p.002011: © European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
p.002011:
p.002011: Table of contents
p.002011: 1. Glossary 3
p.002011: 2. Introduction 4
p.002011: 3. International cooperation in the regulation of clinical trials, their review and inspection and capacity building in
p.002011: this area 6
p.002011: 3.1. Identification of priorities
p.000007: 7
p.000007: 3.2. Identification of opportunities and partners 9
p.000007: 3.2.1. Identification of other initiatives
p.000009: 9
p.000009: 3.2.2. Categories of initiatives and actions 9
p.000009: 3.2.3. Establishment of contact with key initiatives 10
p.000009: 3.3. Action plan
p.000010: 10
p.000010: 3.3.1. Core activities
p.000010: 10
p.000010: 3.3.2. Short Term activities:
p.000011: 11
p.000011: 3.3.3. Long Term activities:
p.000012: 12
p.000012: 3.4. Resource considerations 13
p.000012: 3.5. Example of initiatives
p.000013: 13
p.000013: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000013: use in the context of the activities of the European Regulatory Authorities
p.000014: 14
p.000014: 4.1. Ethics committee and national regulatory authority oversight 16
p.000014: 4.2. Information/Consent procedure 18
p.000014: 4.3. Confidentiality
p.000021: 21
p.000021: 4.4. Fair compensation
p.000022: 22
p.000022: 4.5. Vulnerable populations
p.000024: 24
p.000024: 4.6. Placebo and active comparator 26
p.000024: 4.7. Access to treatment post trial 28
p.000024: 4.8. Applicability of data to EEA population 29
p.000024: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000024: phase 29
p.000024: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000031: 31
p.000031: 5.2. Issues related to feasibility of clinical trials 31
p.000031: 5.3. General measures to assure data quality when conducting trials outside the EU 32
p.000031: 5.4. Considerations for designing clinical trials 33
p.000031: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000034: 34
p.000034: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000034: 34
...
p.000039: are performed in countries outside of the EU, enhanced international cooperation is seen as essential to ensure that,
p.000039: as far as possible, there is a common international approach to the oversight of clinical trials. In addition the
p.000039: clinical trials are conducted, increasingly in countries, where the ethics and regulatory systems are not fully
p.000039: developed and with which EU regulators have limited formal contacts or experience in the domain of clinical trials.
p.000039: Building contact with, and between, the National Regulatory Authorities and Ethics Committees in these countries, their
p.000039: regional networks and associations, and the establishment of an international network of clinical trial regulators
p.000039: should therefore be a fundamental objective.
p.000039: The ultimate objective is to have a system for regulators of clinical trials i) with harmonized approach for clinical
p.000039: trial oversight, ii) with strengthened efficiency of the controls by exchange of information and implementation of
p.000039: synergies between countries. In this system, the following local instruments should be in place, wherever clinical
p.000039: trials are performed:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 6/42
p.000039:
p.000039: 1. Regulations that permit trials of medicinal products only if the trial is authorised by the national regulatory
p.000039: authority and/or by the concerned Ethic Committee(s) in that country and that take actions against violations;
p.000039: 2. Ethics Committees that are truly independent, professionally sound and adequately resourced;
p.000039:
p.000039: 3. Clinical Trial information made public, by implementation of registers;
p.000039:
p.000039: 4. Systems of follow-up of clinical trials by the National Regulatory Authority and concerned Ethics Committe (s),
p.000039: with authority to suspend and or stop clinical trials when needed;
p.000039: 5. Systems of control of clinical trials before, during and after their conduct, through the use of GCP Inspection by
p.000039: the National Regulatory Authority;
p.000039: 6. Regulations that permit the marketing of medicinal products only if authorised and that take actions against non
p.000039: compliance;
p.000039: 7. Regulations that allow the possibility of refusal by National Regulatory Agencies of the marketing authorisation
p.000039: of medicinal products when safety and efficacy have not been shown through trials conducted in accordance with GCP and
p.000039: ethical requirements.
p.000039: These instruments should be publicly available and transparent.
p.000039:
p.000039: The scope of this section is to specifically reflect on how to enhance international cooperation in the regulation of
p.000039: clinical trials performed including countries outside the EEA. Such an approach will promote confidence among Ethics
p.000039: Committees and Regulatory Authorities, avoid unnecessary duplication and multiplication of on site inspections, and
p.000039: allow exchange of valuable information. This approach should be implemented in a consistent and explicit way. It is
p.000039: recognised that achieving this objective is a long-term goal; nonetheless in order to reach that goal it is necessary
p.000039: to identify and take steps, in a phased manner, towards its achievement. In order to set priorities and identify the
p.000039: possible steps to be taken in achieving the objective described, a number of concerns and opportunities have been
p.000039: considered.
p.000039:
p.000039: 3.1. Identification of priorities
p.000039:
p.000039: It is recognised that with limited resources, there is a need to prioritise particular activities and/or interaction
p.000039: with particular regions/countries. A first step is to identify the countries where important or growing numbers of
p.000039: clinical trials are performed, followed by communication with the National Regulatory Authorities / international
...
p.000039: Authorities and secondly on a review of the regulatory systems in place for the supervision of clinical trials in those
p.000039: countries, including countries where Bioequivalence trials are conducted.
p.000039:
p.000039: 3.2. Identification of opportunities and partners
p.000039:
p.000039: 3.2.1. Identification of other initiatives
p.000039:
p.000039: In order to look for synergies and avoid duplication of effort, any work performed by the EMA Working Groups should be
p.000039: complementary to the other numerous initiatives being carried out by international, European, regional and national
p.000039: organisations in this field.
p.000039: Existing initiatives have not always been implemented with a clear picture of what has been done already, what the
p.000039: results have been and what is being done in the same geographical area, in the same field of study etc.. As a
p.000039: consequence, there may be little knowledge of:
p.000039: • neglected areas of intervention;
p.000039:
p.000039: • the necessity for complementary interventions that can be more effective;
p.000039:
p.000039: • previous initiatives with favourable or unfavourable results;
p.000039:
p.000039: • the risk of duplication of initiatives.
p.000039:
p.000039: The group is aware of different initiatives at different levels carried out by different organisations. These
p.000039: initiatives can be categorised as follows:
p.000039:
p.000039: 3.2.2. Categories of initiatives and actions
p.000039:
p.000039: • Assessment of National supervisory bodies (Regulatory Authorities and Ethics Committees)
p.000039:
p.000039: • Strengthening National Supervisory bodies
p.000039:
p.000039: - national regulatory authority
p.000039:
p.000039: - ethics committee
p.000039:
p.000039: - other authorities
p.000039:
p.000039: Examples of initiatives are provided in section 3.5.
p.000039:
p.000039: • Strengthening the initiative of other Organizations
p.000039:
p.000039: - University education
p.000039:
p.000039: - Civil society organization
p.000039:
p.000039: - Investigator networks
p.000039:
p.000039: - Health care Systems
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 9/42
p.000039:
p.000039: 3.2.3. Establishment of contact with key initiatives
p.000039:
p.000039: Relevant contact points for these different initiatives and countries of interest should be identified and good
p.000039: communication established in order to obtain:
p.000039: • updated knowledge of the situation in each of the priority countries
p.000039:
p.000039: • an evaluation on what has already been done to date;
p.000039:
p.000039: • reciprocal knowledge of what is being done in this field;
p.000039:
p.000039: • a continuous update on what is going to be done.
p.000039:
p.000039: This will facilitate the identification of partnerships for joint, common or coordinated activities.
p.000039:
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EMA will identify other initiatives that are being carried out in the area of clinical trials supervision, mapping
p.000039: of regulatory systems in place and capacity building.
...
p.000039: clinical trials
p.000039: • Motivating sponsors and Marketing Authorisation applicants to ensure adequate levels of control before and
p.000039: during the conduct of their own clinical trials.
p.000039: The proposed action plan addresses them.
p.000039:
p.000039: 3.3.1. Core activities
p.000039:
p.000039: The core set of actions consists in ensuring planned and coordinated contribution of GCP inspectors, marketing
p.000039: authorisation assessors and experts in the following areas of intervention depending on the needs identified in
p.000039: conjunction with the priority countries and based on the information obtained on the existence of other initiatives
p.000039: carried out by other organisations:
p.000039: • Controls of clinical trials:
p.000039:
p.000039: - GCP inspection
p.000039:
p.000039: Increase the number of inspections in the priority countries and stakeholders of particular interest
p.000039: Encourage observed, joint inspections and complementary inspection programs with National Regulatory Authorities
p.000039: - Develop frameworks and priority topics for information exchange and follow up on inspections
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 10/42
p.000039:
p.000039: • Regulatory authorities (evaluation and inspection sectors):
p.000039:
p.000039: - Assistance with the establishment and operation of National Regulatory Authority systems for review and
p.000039: oversight of clinical trials, and evaluation of the processes established
p.000039: - Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
p.000039: - Scientific / technical support
p.000039:
p.000039: - Protocol assistance/Scientific Advice
p.000039:
p.000039: - Support for Assessment of clinical trials. Seek the contribution of the Clinical Trial Facilitation Group and
p.000039: specialists in pharmaceutical/non-clinical/clinical evaluation in specific fields
p.000039: - Explore and establish frameworks for different types of information exchange and networking for Regulatory
p.000039: Authorities.
p.000039: • Ethics committees (Ethics Committees):
p.000039:
p.000039: - Assistance with the establishment and operation of Ethics Committees, and evaluation of their processes
p.000039: - Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
p.000039: - National registries of Ethics Committees and documentation on their composition and activity should be
p.000039: established
p.000039: - Evaluation of clinical trials by Ethics Committees – the cooperation of EU Ethics Committees
p.000039: can be sought
p.000039:
p.000039: - Investigation of systems for accreditation or evaluation of Ethics Committees
p.000039:
...
p.000039: In this way, such a “Service” would allow the participating partner countries and international organisations to be up
p.000039: to date on the latest developments in the field could be particularly useful in the following contexts:
p.000039: 1. when EMA and National Regulatory Agencies need to verify compliance to the principles of GCP for a certain
p.000039: clinical trial;
p.000039: 2. when EMA and other international, regional and national organisations or NGOs want to support a country through
p.000039: capacity building initiatives, such as training programmes for investigators or for members of Ethics Committees or GCP
p.000039: inspectors;
p.000039: 3. when a scientific institution or a pharmaceutical company wants to conduct a clinical trial;
p.000039:
p.000039: 4. when a qualified institution wants to provide advice on the preparation of regulations or procedures in this
p.000039: field.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 12/42
p.000039:
p.000039: 3.4. Resource considerations
p.000039:
p.000039: It is recognised that additional resources will be needed to address these objectives, both short and long-term.
p.000039: Liaison and communication with the actors identified below will help to establish possible funding and collaboration
p.000039: opportunities:
p.000039: • EU Commission
p.000039:
p.000039: • European Medicines Agency
p.000039:
p.000039: • EU Member States
p.000039:
p.000039: • Non EU National Regulatory Authority partners interested or concerned by such initiatives
p.000039:
p.000039: • International and regional organisations:
p.000039:
p.000039: - Organisations responsible for funding projects
p.000039:
p.000039: - Organisations responsible for organizing the activities (without funding): to be categorized for areas of
p.000039: activity (e.g. training, legislation, GCP, etc.)
p.000039: - Organisations that fall under both categories
p.000039:
p.000039: In this context it is recognised that WHO and some National Regulatory Authorities in particular have a range of
p.000039: activities ongoing that are of particular relevance and interest.
p.000039:
p.000039:
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EMA and EU Regulatory Authorities will identify resource requirements and budget to support the contribution of
p.000039: the EU Regulators.
p.000039: 2. EMA and EU Regulatory Authorities will identify and work with other funding bodies in order to benefit from
p.000039: potential funds to support EMA or EU Member State experts contribution to capacity building exercises.
p.000039: 3. EMA and EU Regulatory Authorities will identify and work with other funding bodies in order to identify funds that
p.000039: may help delegates from concerned countries outside EU/EEA to participate and benefit from capacity building exercises.
p.000039:
p.000039: 3.5. Example of initiatives
p.000039:
p.000039: GCP Inspections:
p.000039: • Increase the number of inspections in priority countries and stakeholders of particular interest EU-CMDh
p.000039: Coordinated program between EU-MSs for inspecting bioequivalence trial facilities with
p.000039: high level of activity.
p.000039:
p.000039: • Encourage observed and joint inspections with local authorities
...
p.000039: the paediatric population (2001)xv.
p.000039: The European pharmaceutical legislation sets out the ethical requirements for the conduct of clinical trials in
p.000039: Directive 2001/20/ECxvi, Directive 2005/28/ECxvii and Directive 2001/83/ECxviii. Provisions of the European Paediatric
p.000039: Regulation 1901/06/EC are equally taken into considerationxix.
p.000039: Provisions for the protection of personal data are laid down in Directive 1995/46/ECxx,
p.000039: The extent to which these various documents pertinent to clinical trials (both legal and ethical instruments) are taken
p.000039: into account in national or regional legislation within or outside EU is variable. They overlap in many areas, but some
p.000039: given greater precision on certain points whilst on others there are differences in approach. The aim of the present
p.000039: document is not to establish a new, additional, set of principles but rather to describe how the regulatory processes
p.000039: of the EMA and EU National Competent Authorities can take these into account in a practical way.
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: 1 WHO (CIOMS) Guidelines 2
p.000039: 2 Paragraph 2.3 of ICH-E6
p.000039: 3 Paragraph 8 of the Preamble of Annex 1 to Directive 2001/83/EC
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 15/42
p.000039:
p.000039: 4.1. Ethics committee and national regulatory authority oversight
p.000039:
p.000039: Research may only be undertaken if the research project has been approved by an EC (or other body authorised to review
p.000039: clinical research on human beings) with appropriate jurisdiction for the investigator sites and trial concerned, after
p.000039: independent examination of its scientific merit, including assessment of the importance of the aim of research, and
p.000039: multidisciplinary review of its ethical acceptability,4 In many countries an application also has to be made to a
p.000039: Regulatory Authority, before a clinical trial may commence.
p.000039: It is an important element of international cooperation that Regulatory Authorities support compliance with local
p.000039: requirements in each country as well as reinforcing international ethical and good clinical practice standards.
p.000039: All the information which is necessary for the ethical assessment of the research project should be given in written
p.000039: form to the Ethics Committee. 5 The Ethics Committee, in preparing its opinion should consider amongst others the
p.000039: points set out in art. 3, 4, 5 and 6 of the Directive 2001/20/EC, the Appendix to the additional protocol on biomedical
p.000039: research (COE- Information to be given to the Ethics Committee), and chapters 2 and 3 of ICH E 6 and WHO (CIOMS)
p.000039: guidelines 2. The Ethics Committees hould be satisfied that no undue influence, including that of a financial nature
p.000039: (or limiting or increasing access to medical care), will be exerted on persons, to participate in research. In this
p.000039: respect, particular attention must be given to vulnerable or dependent persons.6 EU legislation gives particular
p.000039: attention to protection of paediatric subjects7.
p.000039: The Ethics Committee shall give clearly stated reasons for its positive or negative conclusions. 8
p.000039: The declaration of Helsinki states that “No change to the protocol may be made without consideration and approval by
p.000039: the ethics committee”.9 EU Directive 2001/20/EC specifies that this should apply to substantial amendments.10 Research
p.000039: projects should be re-examined if this is justified in the light of scientific developments or events arising in the
p.000039: course of the research. 11
p.000039: “The ethics committee must have the right to monitor ongoing studies”12 “and to report to institutional or governmental
p.000039: authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that
p.000039: they have approved or in the conduct of the studies”.13
p.000039: If the clinical trial is planned to be conducted in a country with limited Regulatory Authority or Ethics Committees
p.000039: framework and limited oversight of the clinical trial, the sponsor should put in place alternative solutions in order
p.000039: to ensure an adequate review of the clinical trial protocol. A possible option could be to consider complementing the
p.000039: ethics Committees review in that country by submitting the study protocol for ethical and scientific review to an
p.000039: Ethics Committee (s) that operates within an established regulatory framework with ethical standards equivalent to
p.000039: those applying in the EU (based in an EU or non EU Country). This would be particularly relevant where the study design
p.000039: (e.g. choice of comparator) or the vulnerability of the proposed patient population might give rise to additional
p.000039:
p.000039: 4 Art. 6 (2) and Art. 9 (2) of Directive 2001/20/EC, Art.9 and 10 Additional Protocol on biomedical research (COE),
p.000039: Paragraph 15 of Declaration of Helsinki, WHO (CIOMS) guidelines 2.
p.000039: 5 Art. 11 of Additional Protocol on biomedical research (COE). 6 Art.12 of Additional Protocol on biomedical research
p.000039: (COE).
p.000039: 7 Paragraph 8.2 of EU Ethical Considerations for clinical trials on medicinal products conducted with the paediatric
p.000039: population
p.000039: 8 Art. 6 (5) of Directive 2001/20/EC; Art.9 Additional Protocol on biomedical research (COE) Explanatory report
p.000039: paragraph 42.
p.000039: 9 Paragraph 15 of Declaration of Helsinki 10 Art. 10 (a) of Directive 2001/20/EC
p.000039: 11 Art. 24 of Additional Protocol on biomedical research (COE) 12 Paragraph 15 of Declaration of Helsinki
p.000039: 13 WHO (CIOMS) guideline 2
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 16/42
p.000039:
p.000039: concerns. In this case the deliberations and conclusions of that committee(s) should be made available to the local
p.000039: Ethics Committee and regulatory authority, making clear to what extent the committee has considered the location and
p.000039: circumstances in which the trial is to be conducted. Such an approach does not substitute for the need to apply to, and
p.000039: follow the requirements of, a local Ethics Committee or to submit to the regulatory authority of the country where the
p.000039: trial is to be conducted.
p.000039: It is the responsibility of the sponsor to ensure that an appropriate EC reviews the clinical trial
p.000039:
p.000039: A clinical trial should not take place in a country in the absence of a review by an Ethics Committees in that country.
p.000039: If such a committee does not exist it should be established as a pre-requisite before the trial take place.
p.000039: The local Ethics Committee (s) and the regulatory authority (where applicable) in the country where the trial is to be
p.000039: conducted should review the trial, ensuring that the proposed research is ethical, takes into account the local
p.000039: conditions and requirements, that the local sites are suitable and that circumstances and arrangements for the conduct
p.000039: of the research are appropriate for that country and the study population concerned.
p.000039: In multicentre studies, a central Ethics Committe could review the study from a scientific and ethical standpoint, and
p.000039: the local Ethics Committe could verify the practicability of the study in their communities, including the
p.000039: infrastructures, the state of training, and ethical considerations of local significance
p.000039: It should be clear that any Ethics Committee reviewing the trial should be able to withhold approval of the research
p.000039: proposals. When there are objective grounds for considering that the conditions in the request for this authorisation
p.000039: are no longer met, or there is information raising doubts about the safety or scientific validity of the clinical
p.000039: trial, it should be possible to suspend or prohibit the trial notifying the sponsor thereof. 14
p.000039: There should be assurance that the review is independent and that there is no conflict of interest that might affect
p.000039: the judgment of members of the Ethics Committee in relation to any aspect of the research. A declaration of possible
p.000039: conflict of interest should be provided by any of the Ethics Committee members.15Any members with a special or
...
p.000039: country where the trial is to be conducted should have, as either members or consultants, persons with understanding of
p.000039: the community's customs and traditions.” Such persons should be able, for example, to indicate suitable members of the
p.000039: community to serve as intermediaries between investigators and subjects and to advise on whether material benefits or
p.000039: inducements may be
p.000039:
p.000039: 14 Art. 12 of Directive 2001/20/EC
p.000039: 15 WHO (CIOMS) Guideline 2.
p.000039: 16 Art.19 International Declaration on Bioethics (UNESCO); ICH E6 paragraphs 1.27 and 3
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 17/42
p.000039:
p.000039: regarded as appropriate in the light of a community's gift-exchange and other customs and traditions”.17
p.000039: Expertise used should be documented and recorded by the Ethics Committee. Paediatric expertise requirements, as
p.000039: described in paragraph 8 of European Ethical considerations for clinical trials on medicinal products conducted with
p.000039: the paediatric population, should be complied with 18
p.000039:
p.000039:
p.000039: Regulatory action/ action plan
p.000039:
p.000039: 1. Failure to submit a protocol to an independent EC is a serious violation of ethical standards. EU Regulatory
p.000039: Authorities should disregard data obtained in a such unethical manner, when submitted in support of a MAA in accordance
p.000039: with Directive 2001/83 EC or Regulation EC 726/2004.
p.000039: 2. Requirements for submission to the national regulatory authority of each country in which the trial is conducted
p.000039: and to the Ethics Committee (s) in those countries must be complied with, and evidence of both submissions and
p.000039: approvals provided. The applicant for a MAA should provide EU Regulatory Authorities with a summary of Ethics
p.000039: Committee, and National Regulatory Authority approvals of each clinical trial supporting the MAA. This information
p.000039: should form part of the clinical study report in accordance with ICH E3.
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern (e.g.
p.000039: arising from their design, the local regulatory framework within which they are conducted, the vulnerability of the
p.000039: study subjects) and where applicable seek additional assurance that the trials have been ethically conducted.
p.000039: 4. Where clear serious concerns are identified the EU Regulatory Authorities should communicate these concerns to the
p.000039: National Regulatory Authority of the Country (ies) concerned.
p.000039: 5. The Sponsor ensuring that the clinical trial is reviewed by an appropriate EC should consider the opportunity to
p.000039: submit the clinical trial also to an Ethics Committee (either in an EU or non EU Country) that operates within an
p.000039: established regulatory framework with ethical standards equivalent to those applying in the EU. Evidence of the
p.000039: mechanisms put in place should be provided.
p.000039:
p.000039: 4.2. Information/Consent procedure
p.000039:
p.000039: Scientific research as well as any preventive, diagnostic or therapeutic medical intervention involving human subjects
p.000039: is only to be carried out with the prior, free, express, specific, documented and informed consent of the person
p.000039: concerned, based on adequate and comprehensible information 19 provided both in writing (or optionally pictorially for
p.000039: illiterate individuals) and orally. Furthermore, consent should, be given, and may be withdrawn, by the person
p.000039: concerned at any time and for any reason without disadvantage or prejudice. 20 “Informed consent is documented by means
p.000039: of a written,
p.000039:
p.000039: 17 WHO (CIOMS) Guideline 3.
p.000039: 18 Art. 4 of Directive 2001/20/EC and Paragraph 8 of EU Ethical Considerations for clinical trials on medicinal
p.000039: products conducted with the paediatric population
p.000039: 19 Art.2 (j), art. 3.2 (b) and art. 4-5 of Directive 2001/20/EC; Art. 5-6, 16 (iv) (v)-17 of Convention on Human Rights
...
p.000039: liability (particularly of a financial nature) and/or to any form of discrimination against the person concerned, in
p.000039: particular regarding the right to medical care 22. The same level of care and information should be maintained during
p.000039: treatment or investigations.
p.000039: The informed consent of each subject shall be renewed if there are significant changes in the conditions or procedures
p.000039: of the research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate. 23
p.000039: In particular studies alternative ways of documenting the informed consent may need to be established as described
p.000039: below. For persons who are not capable of exercising autonomy, special measures are to be taken to protect their rights
p.000039: and interests. Research on a person without the capacity to consent (children, adults with severe mental disability, 24
p.000039: or behavioural disorders25 and research in emergency situations may be undertaken only if the necessary authorisation
p.000039: has been given specifically and in writing by the legal representative or an authority, person or body provided for by
p.000039: law and having received adequate information, taking into account the person’s previously expressed wishes or
p.000039: objections.
p.000039: An adult not able to consent shall as far as possible take part in the information/authorisation procedure.26 In
p.000039: proportion to age and degree of maturity, the child should participate in the (informed) consent process together with
p.000039: the parents and provide assent. The process of informed consent should be conducted with enough time and at the same
p.000039: time as obtaining consent from the parent(s) or the legal representative, so that the informed consent reflects the
p.000039: presumed will of the minor or of the adults who do not have the capacity to consent. The information process provided
p.000039: to the child and the child’s response should be documented. “Strong and definitive objections from the child should be
p.000039: respected”. 27
p.000039: “If a subject is unable to read or if a legally acceptable representative is unable to read an impartial witness should
...
p.000039: given by the subject or the subject’s legally acceptable representative”28.
p.000039: Mechanisms should be put in place to ensure that the trial subject is aware that they are participating in research.
p.000039:
p.000039:
p.000039: 21 Art. 2 (j) of Directive 2001/20/EC; Paragraph 1.28 of ICH E6, 1995
p.000039: 22 Art. 14 section 2 of the Additional Protocol on Biomedical Research to the Convention on Human Rights and
p.000039: Biomedicine and section 80 of its Explanatory report
p.000039: 23 WHO(CIOMS) Guideline 6
p.000039: 24 Art. 3.2 (d), 4 and 5 of Directive 2001/20/EC; Art. 6 of Convention on Human Rights and Biomedicine of the Council
p.000039: of Europe (COE)
p.000039: 25 WHO (CIOMS) International guidelines n. 15
p.000039: 26 Art. 4 (a), (b) and (c) and art. 5 (a), (b) and (c) of Directive 2001/20/EC; Art. 14 and 15 of Additional protocol
p.000039: on Biomedical research (COE), 2005
p.000039: 27 Paragraphs 7- 7.2 of Ethical considerations for clinical trials on medicinal products conducted with the pediatric
p.000039: population.
p.000039: 28 Paragraph 4.8.9 of ICH E6
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 19/42
p.000039:
p.000039: “In appropriate cases of research carried out on a group of persons or a community, additional agreement of the legal
p.000039: representatives of the group or community concerned may be sought. In no case should a collective community agreement
p.000039: or the consent of a community leader or other authority substitute for an individual’s informed consent”29 . “In some
p.000039: cultural contexts an investigator may enter a community to conduct or approach prospective subjects for their
p.000039: individual consent only after obtaining permission from a community leader, a council of elders, or another designated
p.000039: authority.
p.000039: Such customs must be respected. In no case, however, may the permission of a community leader or other authority
p.000039: substitute for individual informed consent” 30
p.000039: The consent process and the information provided should take into account the needs of persons who are unfamiliar with
p.000039: medical concepts and technology31. All documentation (information and consent/assent) must be written in a lay-friendly
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
...
p.000039: 39 Art. 9 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005); art. 14 International Declaration of
p.000039: Human Genetic Data; art 8 Charter of fundamental rights of the European Union
p.000039: 40 Art. 26 of Additional Protocol on Biomedical research (COE), 2005
p.000039: 41 Art. 6 of Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on
p.000039: the free movement of such data
p.000039: 42 WHO (CIOMS) Guideline 18
p.000039: 43 Art 27 of additional Protocol on Biomedical research (COE), 2005
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 21/42
p.000039:
p.000039: participant” [including the minor and/or his/her legal representative] ”not to receive such information”, in accordance
p.000039: with national law.44“During the process of obtaining informed consent the investigator should inform the prospective
p.000039: subjects about the precautions that will be taken to protect confidentiality”.45
p.000039: The written information and informed consent form to be provided to subjects should include explanations:
p.000039: a) of the extent to which the monitor(s), the auditor(s), the Ethics Committe and the regulatory authority(ies) will be
p.000039: granted direct access to the subject's original medical records for verification of clinical trial procedures and/or
p.000039: data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000039: regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable
p.000039: representative is authorising such access.
p.000039: b) “that records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws
p.000039: and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’
p.000039: identity will remain confidential”.46
p.000039: Biological sample retention, planned analysis and the need for consent to such use (and reuse) should be in accordance
p.000039: with what is described in the protocol. Samples cannot be used for purposes different of the ones described in the
p.000039: protocol without a new written informed consent
p.000039: The trial documents should be archived for a duration that takes into consideration the potential need for long-term
p.000039: review, particularly for trials performed in children (long-term safety).
p.000039: Where personal information is collected, stored, accessed, used, or disposed of, a researcher should ensure that the
p.000039: privacy, confidentiality and cultural sensitivities of the subject and/or the collectivity are respected, most of all
...
p.000039: Prospective subjects should be informed that they will not need to take legal action to secure the free medical
p.000039: treatment or compensation for injury to which they may be entitled. They should also be told what medical service or
p.000039: organisation or individual will provide the medical treatment and what organisation will be responsible for providing
p.000039: compensation”. 49
p.000039: Before the research begins, the sponsor, whether a pharmaceutical company or other organisation or institution, should
p.000039: agree to provide compensation for any injury for which subjects are entitled to compensation, or come to an agreement
p.000039: with the investigator concerning the circumstances in which the investigator must rely on his or her own insurance
p.000039: coverage (for example, for negligence or failure of the investigator to follow the protocol, or where government
p.000039: insurance coverage is limited to negligence). In certain circumstances it may be advisable to follow both courses.
p.000039: “Sponsors should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution
p.000039: against claims arising from the trial, except for claims that arise from malpractice and/or negligence”.50
p.000039: “Both the informed consent discussion and the written informed consent form and any other written information to be
p.000039: provided to subjects involved in research should include explanations of the compensation and/or treatment available to
p.000039: the subject in the event of trial-related injury”.51
p.000039: Information shall be provided to the EC and where required to the National Regulatory Authority, on details of any
p.000039: insurance, indemnity or compensation to cover damage arising in the context of the research project52 (in particular
p.000039: “provision for indemnity or compensation in the event of injury or death attributable to a clinical trial, and any
p.000039: insurance or indemnity to cover the liability of the investigator and sponsor”). 53
p.000039: In preparing its opinion, the Ethics Committe (and where required the National Regulatory Authority) should consider
p.000039: these provisions54 and should pay careful attention to waivers of liability in the insurance contract, in particular
p.000039: with respect generally to long term effects and on development for children included in research. However,
p.000039: “unrecognised congenital defects are generally excluded”.55
p.000039: Regulatory action/action plan
p.000039:
p.000039: 48 Art. 31 of Additional Protocol on Biomedical research (COE) 2005 49 WHO (CIOMS) Guideline 19
p.000039: 50 Paragraph 5.8 of ICH-E6
p.000039: 51 Paragraph 4.8.10 of ICH-E6
p.000039: 52 Art 11 juncto appendix of Additional Protocol on Biomedical research (COE) 2005; Paragraph 3.1.2 of ICH-E6. 53 Art.
p.000039: 6.3 (h) and (i) of Directive 2001/20/EC
p.000039: 54 Art. 6.3 of Directive 2001/20/EC
p.000039: 55 Paragraph 22 of Ethical considerations for clinical trials on medicinal products conducted with paediatric
p.000039: population.
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 23/42
p.000039:
p.000039: 1. Failure to provide fair compensation by insurance or indemnity is a serious violation of ethical standards. The
p.000039: applicant for a MAA should provide EU Competent Authorities with a summary of the provisions made to provide for the
p.000039: fair compensation of subjects for trial related injury. This information can form part of the clinical study report
p.000039: section on ethical considerations and informed consent.
p.000039: 2. EMA and EU Regulatory Authorities should identify those studies that may give rise to special concern regarding
...
p.000039: for clarification from the applicant, and also discussion with inspectors as to whether a GCP inspection may be
p.000039: appropriate or required (see 6.2).
p.000039: • The third relates to concern over the design of studies in relation to acceptability in Europe. Such concerns
p.000039: may relate to the use of placebo or duration of use of placebo, poorly optimised background therapy, use of
p.000039: inappropriate comparator, inappropriate investigations, lack of consent etc.. This aspect is addressed below.
p.000039: Review procedures
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 34/42
p.000039:
p.000039: • At the time of the application, information should be provided on where each clinical trial was performed and on
p.000039: how relevant ethical requirements were met.
p.000039: • As part of the review of the MAA, assessors should consider whether or not there are major ethical concerns
p.000039: relating to the studies that have been included in the dossier to support the MAA. Assessors should confirm in the
p.000039: Assessment Report that they have not identified any major ethical issues in their assessment of the studies, that the
p.000039: studies have been approved by the relevant Ethics Committe and by the National Regulatory Authority, that the sponsor
p.000039: has provided the statement that the studies have been conducted as set out in Annex 1 of Directive 2001/83, and that
p.000039: they have not identified any major concerns regarding the conduct of the study. Particular attention should be paid
p.000039: where vulnerable patients are included within the trial population, and/or trials are conducted in low to middle income
p.000039: countries, and/or where no EEA Ethics Committee has reviewed and approved the study/studies for trials performed
p.000039: outside the EU.
p.000039: • In considering the design of studies, assessors should consider international guidelines for biomedical research
p.000039: involving human subjects where it is recommended that research is responsive to the health needs and priorities of the
p.000039: population or community in which it is carried out and any intervention or product developed or knowledge generated
p.000039: will be made reasonably available for the benefit of that population or community. Applicants are encouraged to provide
p.000039: such information, in so far as it is possible. Whilst it will not always be possible for assessors to conclude
p.000039: definitively, questions or concerns in relation to this area may be included in the List of Questions to the applicant
p.000039: The EU assessment report should reflect:
p.000039:
p.000039: 1. That it has been determined that all clinical trials were conducted in accordance with the principles of good
p.000039: clinical practice and the above mentioned ethical requirements ,
p.000039: 2. Any ethical concerns that have been raised,
p.000039:
p.000039: 3. How these ethical concerns have been addressed and whether they had an impact on the assessment of the quality,
p.000039: safety and efficacy of the product,
...
p.000039: This reflection paper seeks to reinforce the regulatory framework for the conduct of ethical, scientifically valid
p.000039: clinical trials, and the protection of trial subjects. Ideally such measures would ensure that significant
p.000039: non-compliance would not occur. The processes available to address situations where requirements have not been
p.000039: followed, should strive to further refine and reinforce the framework for the conduct of trials and the understanding
p.000039: of requirements by all involved. The range of actions available should also include activities that involve
p.000039: communication, education and refinement as the preferred course. In some circumstances this will not be possible, or
p.000039: appropriate, not least because by the time of the MAA, the clinical trials in question are generally completed and
p.000039: little can be done to remedy deficiencies in the conduct of those particular trials.
p.000039: Trial subjects and their communities also need to be assured that their rights and welfare will be supported and
p.000039: reinforced by regulators, both locally, and internationally as the entire process of development of medicines relies on
p.000039: the willingness of individuals to participate in clinical trials.
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 37/42
p.000039:
p.000039: Particular emphasis should be given to trials conducted in countries outside EU/EEA. The role and authority of the
p.000039: Ethics Committees and National Regulatory Authorities in the countries where the trials are conducted should be
p.000039: supported. When non compliance with GCP regulatory obligations and ethical concerns are detected, action should include
p.000039: communication with the National Regulatory Authority concerned. This action should be proportionate to the consequences
p.000039: of the observed violation on the rights and welfare of the trial subjects and of the deficiencies on the data
p.000039: integrity.
p.000039: There is the need to define and to make public the consequences of non compliance with GCP and above mentioned ethical
p.000039: concerns in designing, conducting, recording and reporting of the clinical trials included in the MAA.
p.000039: Non compliance which significantly affects the rights, safety or well being of the subjects or the quality and
p.000039: integrity of the data reported is not acceptable, and will result in rejection of data and/or other regulatory actions.
p.000039: Regulatory options should include the following:
p.000039:
p.000039: Information and possible action by regulators of countries outside EU/EEA
p.000039:
p.000039: Information on non-compliance should be made available to the Regulatory Authority in the country in which the trial
p.000039: non-compliance has been identified and to other regulators in the international network, (subject to appropriate
p.000039: confidentiality arrangements if applicable).
p.000039: Request for additional information or action by the sponsor
p.000039:
p.000039: The sponsor may be asked to supply additional information or explanation, conduct further analyses or data
p.000039: collection/review, or to commission further monitoring or independent audits of a wider range of sites.
p.000039: Inspection or re-inspection
p.000039:
p.000039: (Further) sites involved in the same trial/and or further trials and/or sponsor site/Marketing Authorisation Holders
p.000039: may be inspected to determine the extent of non-compliance.
p.000039: Rejection of data/exclusion of trial/negative opinion
p.000039:
p.000039: Data obtained from clinical site(s) or from a trial found to be seriously non compliant with GCP and/or ethical
p.000039: requirements should be excluded from use in support of the MAA.
p.000039: Education and Facilitation
p.000039:
p.000039: Applicants and/or Marketing Authorisation Holders may be informed of non-compliance and advised on how this can be
p.000039: remedied for future trials, and in some cases action may be possible for the trial in question.
p.000039: Warning
p.000039:
p.000039: The EMA may issue a formal warning reminding Applicants and/or Marketing Authorisation Holders of their GCP obligations
p.000039: relating to the conduct of clinical trials in accordance with above mentioned ethical and GCP requirements
p.000039: Transparency regarding clinical trial conduct and compliance including non-compliant Marketing Authorisations
p.000039:
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 38/42
p.000039:
p.000039: The EPAR should describe any serious non-compliance encountered and discuss the steps taken as a consequence. This
p.000039: should be done whether the CHMP opinion is positive or negative or the application is withdrawn prior to the opinion.
p.000039: Suspension of the Marketing Authorisation/Urgent Safety restriction /Revocation of the Marketing Authorisation
p.000039: Suspension/Urgent safety restriction/revocation of the Marketing Authorisation are considered where the non-compliance
p.000039: is identified after the MA has been granted in accordance with the legislation, guidance and rules applicable.
p.000039: Penalties
p.000039:
p.000039: The possibility of applying specific penalties should be considered and the mechanism for application of those
p.000039: penalties identified.
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EU Regulatory Authorities should develop a clear and detailed system for regulatory actions in case of non
p.000039: compliance with ethical and GCP requirements.
p.000039: 2. Where clear serious concerns are identify the EU Regulatory Authority should communicate these concerns to the
p.000039: National Regulatory Authority of the Country(ies) concerned.
p.000039:
p.000039: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039:
p.000039: The European Medicines Agency publishes on its website (www.ema.europa.eu) a full scientific assessment report called a
p.000039: European Public Assessment Report (EPAR) for every medicine granted a central marketing authorisation by the European
p.000039: Commission. Similarly, Public Assessment Reports are published on National Agencies’ websites or the Heads of Medicines
p.000039: Agencies website (www.hma.eu ) for medicines nationally authorised through the decentralised or mutual recognition
p.000039: procedures.
p.000039: Regulation (EC) No 726/2004 requires that competent authorities verify that clinical trials, in particular when carried
p.000039: out outside the European Union, were conducted in accordance with the principles of good clinical practice and the
p.000039: ethical requirements equivalent to Directive 2001/20/EC.
p.000039: The outcome of the process improvement for review of MAA dossiers and identification of studies of potential ethical or
p.000039: GCP concern proposed in the above section 5.1 should be made publicly accessible. Transparency on Regulatory
p.000039: Authorities’ GCP review during Marketing Authorisation procedures is necessary because of public and patients’ right
p.000039: to information about medicines and their development, including regarding good clinical practice in the conduct of
p.000039: clinical trials which is an important factor in patients’ willingness to participate in trials and their trust in
p.000039: medicines.
p.000039: The Public Assessment Report summarises the quality, safety and efficacy data evaluated and the outcome of that
...
General/Other / Undue Influence
Searching for indicator undue influence:
(return to top)
p.000039:
p.000039: Research may only be undertaken if the research project has been approved by an EC (or other body authorised to review
p.000039: clinical research on human beings) with appropriate jurisdiction for the investigator sites and trial concerned, after
p.000039: independent examination of its scientific merit, including assessment of the importance of the aim of research, and
p.000039: multidisciplinary review of its ethical acceptability,4 In many countries an application also has to be made to a
p.000039: Regulatory Authority, before a clinical trial may commence.
p.000039: It is an important element of international cooperation that Regulatory Authorities support compliance with local
p.000039: requirements in each country as well as reinforcing international ethical and good clinical practice standards.
p.000039: All the information which is necessary for the ethical assessment of the research project should be given in written
p.000039: form to the Ethics Committee. 5 The Ethics Committee, in preparing its opinion should consider amongst others the
p.000039: points set out in art. 3, 4, 5 and 6 of the Directive 2001/20/EC, the Appendix to the additional protocol on biomedical
p.000039: research (COE- Information to be given to the Ethics Committee), and chapters 2 and 3 of ICH E 6 and WHO (CIOMS)
p.000039: guidelines 2. The Ethics Committees hould be satisfied that no undue influence, including that of a financial nature
p.000039: (or limiting or increasing access to medical care), will be exerted on persons, to participate in research. In this
p.000039: respect, particular attention must be given to vulnerable or dependent persons.6 EU legislation gives particular
p.000039: attention to protection of paediatric subjects7.
p.000039: The Ethics Committee shall give clearly stated reasons for its positive or negative conclusions. 8
p.000039: The declaration of Helsinki states that “No change to the protocol may be made without consideration and approval by
p.000039: the ethics committee”.9 EU Directive 2001/20/EC specifies that this should apply to substantial amendments.10 Research
p.000039: projects should be re-examined if this is justified in the light of scientific developments or events arising in the
p.000039: course of the research. 11
p.000039: “The ethics committee must have the right to monitor ongoing studies”12 “and to report to institutional or governmental
p.000039: authorities any serious or continuing non-compliance with ethical standards as they are reflected in protocols that
p.000039: they have approved or in the conduct of the studies”.13
p.000039: If the clinical trial is planned to be conducted in a country with limited Regulatory Authority or Ethics Committees
...
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
p.000039: dignity, human rights and fundamental freedoms or to limit their scope. 35
p.000039: “Sponsors and investigators have a duty to refrain from unjustified deception, undue influence, or intimidations” 36and
p.000039: “to renew the informed consent of each subject if there are significant changes in the conditions or procedures of the
p.000039: research or if new information becomes available that could affect the willingness of subjects to continue to
p.000039: participate” 37
p.000039: Regulatory action/ action plan:
p.000039:
p.000039: 1. Failure to obtain informed consent (and/or assent where applicable) is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in a such unethical manner, when submitted in support of a MAA
p.000039: in accordance with Directive 2001/83 EC or Regulation EC 726/2004.
p.000039: 2. The applicant for a MAA should provide EU drug regulatory authorities with a summary of the consent processes used
p.000039: and significant variations of those processes in the clinical trials supporting the MAA and include sample information
p.000039: sheets on consent forms. This information should form part of the clinical study report in accordance with ICH E3.
p.000039:
p.000039:
p.000039: 29 Art. 6 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005) 30 WHO (CIOMS) Guideline 4
p.000039: 31 WHO (CIOMS) Guideline 4
p.000039: 32 WHO(CIOMS) Guideline 4
p.000039: 33 WHO (CIOMS) Guideline 4
p.000039: 34 Paragraph 6.3 of Ethical considerations for clinical trials on medicinal products conducted with the pediatric
p.000039: population 35 Art. 12 of Universal Declaration on Bioethics and Human Rights (UNESCO, 2005)
p.000039: 36 WHO (CIOMS) Guideline 6
p.000039: 37 WHO (CIOMS) Guideline 4 and 6
p.000039:
...
General/Other / cultural difference
Searching for indicator culturally:
(return to top)
p.000039: cultural contexts an investigator may enter a community to conduct or approach prospective subjects for their
p.000039: individual consent only after obtaining permission from a community leader, a council of elders, or another designated
p.000039: authority.
p.000039: Such customs must be respected. In no case, however, may the permission of a community leader or other authority
p.000039: substitute for individual informed consent” 30
p.000039: The consent process and the information provided should take into account the needs of persons who are unfamiliar with
p.000039: medical concepts and technology31. All documentation (information and consent/assent) must be written in a lay-friendly
p.000039: language, using wording appropriate to age, psychological and intellectual maturity and must be designed to protect
p.000039: vulnerable and poorly educated subjects involved in research. Pictorial forms are also recommended for illiterate
p.000039: subjects.
p.000039: Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for
p.000039: adherence to the standard required in the informed consent process. “Also, they should describe and justify in the
p.000039: research protocol the procedure they plan to use in communicating information to subjects” 32 “For collaborative
p.000039: research in developing countries the research project should, if necessary, include the provision of resources to
p.000039: ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings”33.
p.000039: Where appropriate, a cultural mediator, familiar with medical terminology, independent from the sponsor and
p.000039: investigator, experienced in the language, social habits, culture, traditions, religion and particular ethnic
p.000039: differences should be available to provide help in the process of obtaining informed consent, but should not consent on
p.000039: behalf of the subject. 34 Nevertheless, cultural diversity and pluralism are not to be invoked to infringe upon human
p.000039: dignity, human rights and fundamental freedoms or to limit their scope. 35
...
General/Other / participants in a control group
Searching for indicator controlXgroup:
(return to top)
p.000039: (placebo equivalent) medicines. EU regulators
p.000039:
p.000039:
p.000039: 67 Para.17 of the Declaration of Helsinki (2008) and WHO (CIOMS) Guidance n. 10. 68 Article 23 of Additional protocol
p.000039: on biomedical research (COE), 2005
p.000039: 69 WHO (CIOMS) Guideline 11
p.000039: 70 Paragraph 2.3 of ICH-E6
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 26/42
p.000039:
p.000039: will ensure that the rationale for the use of study designs involving placebo or other comparators is clearly set out
p.000039: and communicated, in order to ensure that such trials could be conducted in the EU.
p.000039: The use of placebo is permissible in accordance with principles foreseen in the Directive 2001/20/EC, Directive
p.000039: 2005/28/EC, the WHO (CIOMS) Guidelines 8 and 11, paragraph 32 of the Declaration of Helsinki (2008), article 23 of the
p.000039: Additional Protocol on Biomedical Research of the Council of Europe(2005), paragraph 2.1; 2.2; 2.3 and 2.12 of the Note
p.000039: for Guidance on Good Clinical Practice (CPMP/ICH/135/95), paragraphs 9.2.1 and 9.2.3 of the guideline on ethical
p.000039: considerations for clinical trials on medicinal products conducted with the paediatric population (2008) and ICH E10
p.000039: (Choice of Control Group). The CPMP position statement on the use of placebo in clinical trials (28 June 2001
p.000039: EMEA/17424/01) should also be taken into account.71
p.000039: Studies carried out in countries outside EU/EEA should meet the same ethical principles and standards applied to
p.000039: studies performed in the EEA. Derogation from these principles should not be accepted in particular in the context of
p.000039: the European marketing authorisation procedure.
p.000039: EU Regulatory Authorities should neither require nor accept study designs, involving placebo or other comparator, which
p.000039: would not be ethically acceptable in the EEA.
p.000039: “Economic [or logistical] reason for the unavailability of an established effective intervention cannot justify a
p.000039: placebo-controlled study in a country of limited resources when it would be unethical to conduct a study with the same
p.000039: design in a population with general access to the effective intervention outside the study”. 72
p.000039: Lack of access of patients in communities within, or outside of, the EEA, to the EEA-licensed (or equivalent)
p.000039: comparator cannot be a justification to withhold this treatment option to those patients when participating in a trial
p.000039: regardless of the reasons for the lack of access (e.g. no reimbursement, no national marketing authorisation).
...
Searching for indicator placebo:
(return to top)
p.002011: this area 6
p.002011: 3.1. Identification of priorities
p.000007: 7
p.000007: 3.2. Identification of opportunities and partners 9
p.000007: 3.2.1. Identification of other initiatives
p.000009: 9
p.000009: 3.2.2. Categories of initiatives and actions 9
p.000009: 3.2.3. Establishment of contact with key initiatives 10
p.000009: 3.3. Action plan
p.000010: 10
p.000010: 3.3.1. Core activities
p.000010: 10
p.000010: 3.3.2. Short Term activities:
p.000011: 11
p.000011: 3.3.3. Long Term activities:
p.000012: 12
p.000012: 3.4. Resource considerations 13
p.000012: 3.5. Example of initiatives
p.000013: 13
p.000013: 4. Clarification of the practical application of ethical standards for clinical trials on medicinal products for human
p.000013: use in the context of the activities of the European Regulatory Authorities
p.000014: 14
p.000014: 4.1. Ethics committee and national regulatory authority oversight 16
p.000014: 4.2. Information/Consent procedure 18
p.000014: 4.3. Confidentiality
p.000021: 21
p.000021: 4.4. Fair compensation
p.000022: 22
p.000022: 4.5. Vulnerable populations
p.000024: 24
p.000024: 4.6. Placebo and active comparator 26
p.000024: 4.7. Access to treatment post trial 28
p.000024: 4.8. Applicability of data to EEA population 29
p.000024: 5. Determine the practical steps to be undertaken during the provision of guidance and advice in the drug development
p.000024: phase 29
p.000024: 5.1. Assessment of therapeutic needs in the EEA and relationships with its drug development plan
p.000031: 31
p.000031: 5.2. Issues related to feasibility of clinical trials 31
p.000031: 5.3. General measures to assure data quality when conducting trials outside the EU 32
p.000031: 5.4. Considerations for designing clinical trials 33
p.000031: 6. Determine the practical steps to be undertaken during the marketing authorisation phase
p.000034: 34
p.000034: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000034: 34
p.000034: 6.2. Inspections: Triggers for inspection to be identified by assessor 36
p.000034: 6.3. Actions available in response to non compliance 37
p.000034: 6.4. Transparency, including improvement of Public Assessment Report content and consistency
p.000039: 39
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
...
p.000039:
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. The inclusion of vulnerable subjects in a clinical trial without the approval of the Ethics Committe and without
p.000039: implementation of the appropriate consent processes is a serious violation of ethical standards.
p.000039: EU Regulatory Authorities should disregard data obtained in such an unethical manner, when submitted in support of a
p.000039: MAA in accordance with Directive 2001/83 EC and Regulation No (EC) 726/2004.
p.000039: 2. The applicant for a MAA should provide drug regulatory authorities with an adequate and appropriate justification
p.000039: for inviting vulnerable individuals or groups to serve as research subjects and the description of the specific
p.000039: measures and means implemented to protect their rights and welfare, should be included in the protocol and in the
p.000039: clinical study report (in accordance to ICH E3) and should made public in the Public Assessment Report
p.000039: 3. EU Regulatory Authorities should identify those studies that may give rise to special ethical concern regarding
p.000039: the inclusion of vulnerable populations and where applicable to seek additional assurance that the inclusion of such
p.000039: populations was justified and their rights and welfare protected.
p.000039:
p.000039: 4.6. Placebo and active comparator
p.000039:
p.000039: The capacity of a trial to produce reliable results is a pre-requisite for the ethical justification of that trial.
p.000039: “Research shall neither delay nor deprive trial participants of medically necessary preventive, diagnostic or
p.000039: therapeutic procedures”.68 A clinical trial cannot be justified ethically unless it is capable of producing
p.000039: scientifically reliable results. “In some circumstances it may be acceptable to use an alternative comparator, such as
p.000039: placebo or "no treatment”,69 whilst taking into account that “the rights, safety and wellbeing of the trials subjects
p.000039: are the most important considerations and should prevail over the interests of science and society”.70
p.000039: The rationale for the use of placebo in a number of therapeutic areas is not always widely understood. Where such
p.000039: designs are deemed necessary and ethical, failure to follow them can have negative consequences. Either it will lead to
p.000039: such products not being authorised in the absence of adequate evidence of efficacy or if they were to be authorised
p.000039: with a suboptimal trial design this could give rise to the approval of less effective or ultimately ineffective
p.000039: (placebo equivalent) medicines. EU regulators
p.000039:
p.000039:
p.000039: 67 Para.17 of the Declaration of Helsinki (2008) and WHO (CIOMS) Guidance n. 10. 68 Article 23 of Additional protocol
p.000039: on biomedical research (COE), 2005
p.000039: 69 WHO (CIOMS) Guideline 11
p.000039: 70 Paragraph 2.3 of ICH-E6
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 26/42
p.000039:
p.000039: will ensure that the rationale for the use of study designs involving placebo or other comparators is clearly set out
p.000039: and communicated, in order to ensure that such trials could be conducted in the EU.
p.000039: The use of placebo is permissible in accordance with principles foreseen in the Directive 2001/20/EC, Directive
p.000039: 2005/28/EC, the WHO (CIOMS) Guidelines 8 and 11, paragraph 32 of the Declaration of Helsinki (2008), article 23 of the
p.000039: Additional Protocol on Biomedical Research of the Council of Europe(2005), paragraph 2.1; 2.2; 2.3 and 2.12 of the Note
p.000039: for Guidance on Good Clinical Practice (CPMP/ICH/135/95), paragraphs 9.2.1 and 9.2.3 of the guideline on ethical
p.000039: considerations for clinical trials on medicinal products conducted with the paediatric population (2008) and ICH E10
p.000039: (Choice of Control Group). The CPMP position statement on the use of placebo in clinical trials (28 June 2001
p.000039: EMEA/17424/01) should also be taken into account.71
p.000039: Studies carried out in countries outside EU/EEA should meet the same ethical principles and standards applied to
p.000039: studies performed in the EEA. Derogation from these principles should not be accepted in particular in the context of
p.000039: the European marketing authorisation procedure.
p.000039: EU Regulatory Authorities should neither require nor accept study designs, involving placebo or other comparator, which
p.000039: would not be ethically acceptable in the EEA.
p.000039: “Economic [or logistical] reason for the unavailability of an established effective intervention cannot justify a
p.000039: placebo-controlled study in a country of limited resources when it would be unethical to conduct a study with the same
p.000039: design in a population with general access to the effective intervention outside the study”. 72
p.000039: Lack of access of patients in communities within, or outside of, the EEA, to the EEA-licensed (or equivalent)
p.000039: comparator cannot be a justification to withhold this treatment option to those patients when participating in a trial
p.000039: regardless of the reasons for the lack of access (e.g. no reimbursement, no national marketing authorisation).
p.000039: Regardless of the location of the trial, all patients participating in these trials should receive the same or a
p.000039: similar standard of care and comparable treatment options as trial participants within the EEA.
p.000039: EU Regulatory Authorities should verify that the study has been reviewed by the Ethics Committees and that they have
p.000039: determined: whether the use of placebo or other comparator is ethically acceptable in the context of that trial;
p.000039: whether the safety and rights of the subjects have been fully protected and whether prospective subjects would be fully
p.000039: informed about the use of placebo and/or other comparators and available alternative treatments and gave their informed
p.000039: consent (or informed refusal), in accordance with above cited ethical principles. 73
p.000039: Regulatory action/action plan:
p.000039:
p.000039: 1. Sponsors should describe in detail in the protocol and in the clinical study report the justification for the use
p.000039: of placebo and/or choice of active comparator in accordance with the ethical principles referred to above. This
p.000039: information can form part of the clinical study report in accordance with ICH3 and protocol in accordance with ICH E6.
p.000039: 2. EU Regulatory Authorities will identify those studies that may give rise to special ethical concern regarding the
p.000039: use of placebo or other comparators and where applicable seek additional assurance that the design was appropriate and
p.000039: ethically acceptable.
p.000039:
p.000039:
p.000039:
p.000039: 71 http://www.ema.europa.eu/pdfs/human/press/pos/1742401en.pdf
p.000039: 72 WHO (CIOMS) Guideline 11
p.000039: 73 WHO (CIOMS) Guideline 11
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 27/42
p.000039:
p.000039: 3. Where it is determined that a study design was not acceptable in accordance with the aforementioned criteria, it
p.000039: should not be accepted in support of a MAA in accordance with Directive 2001/83 EC and Regulation No (EC) 726/2004.
p.000039: 4. If a sponsor has particular concern about a particular trial design, it is strongly advised to seek scientific
p.000039: advice with Regulators on study design before carrying out the trials
p.000039:
p.000039: 4.7. Access to treatment post trial
p.000039:
p.000039: Patients’ access to innovative medicinal products varies widely. Differences in patients’ access mostly reflect
p.000039: differences in the economic situation and social and health care systems of the country or region both inside the EEA
p.000039: and countries outside EU/EEA.
p.000039: Whether the medicinal product is likely to be available in the community or country where the research study is
p.000039: conducted should be considered by the sponsor, Ethics Committees and National Regulatory Authorities. New medicinal
...
p.000039: trials outside the EU:
p.000039: • Condition(s) less frequent in the EU/EEA than in other non-EEA countries
p.000039:
p.000039: • Small number of affected subjects worldwide due to the rarity of the condition (e.g. rare diseases)
p.000039:
p.000039: • Applicability of the targeted drug claim in the European population when the disease is predominant mainly
p.000039: outside Europe (e.g. tropical diseases)
p.000039: • Different therapeutic needs in the European population
p.000039:
p.000039: • Clinical data to be generated may be of little relevance to the European population (e.g. notable difference in
p.000039: disease management).
p.000039: When applicable according to the procedure applied for, the applicant should consider the relevance of its clinical
p.000039: program, in relation to:
p.000039: • Applicability of the proposed indication and the therapeutic needs of the European population
p.000039:
p.000039: • Prevalence of the condition in non-EEA countries and in EEA countries.
p.000039:
p.000039: The consequences of drug development with clinical trials conducted outside the EEA (completely or partially) should be
p.000039: considered with regards to:
p.000039: • Limitations of data extrapolation from non-EU patients to the EEA
p.000039:
p.000039: • Impact of the geographic source of patients on the efficacy and safety results and their extrapolation the
p.000039: European population in the context of disease management (e.g. national characteristics of disease management and
p.000039: patient care)
p.000039: • Validity of the selected comparators (active or placebo) for enabling assessment of the Risk/Benefit balance of
p.000039: the product for the European population
p.000039: • Pre-specified subgroup analyses based on ethnicity and/or regions of the world
p.000039:
p.000039: • Evaluation of the level of adherence to standard background treatment regimes for a specific disease
p.000039: • Take into consideration possible differences in genetic profiles which could influence the drug response.
p.000039: Where a scientific advice, guidance or assessment relates to an application for a scientific opinion in the context of
p.000039: article 58 of Regulation No (EC) 726/2004 the considerations should relate to the population for which the medicinal
p.000039: product is to be used, rather than the EU population.
p.000039:
p.000039: 5.2. Issues related to feasibility of clinical trials
p.000039:
p.000039: The applicant should provide any available information on its development plan:
p.000039:
p.000039: • Details on the planned locations of the trials planned in the EEA and outside
p.000039:
p.000039: • Criteria for the selection of the non-EEA countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 31/42
p.000039:
p.000039: As such information may be limited or unavailable in the early phases of drug development, the applicant could provide
...
p.000039: A feasibility assessment for recruiting the targeted number of patients in a clinical trial should be provided in order
p.000039: to allow consideration of the possible consequences on the future MAA and results interpretation. This feasibility
p.000039: assessment should include as a minimum:
p.000039: • Recruitment plan for patients in the EEA and outside
p.000039:
p.000039: • Selection criteria and numbers of centres per country or regions outside the EEA
p.000039:
p.000039: • Duration of trial recruitment and expected impact of comparability of results over time in case of very long
p.000039: recruitment (e.g. duration of recruitment longer than 3 years for rare disease).
p.000039:
p.000039: 5.3. General measures to assure data quality when conducting trials outside the EU
p.000039:
p.000039: Issues that may have an impact on the quality of data to be generated should be clearly identified and resolved when
p.000039: possible:
p.000039: • Duration of the study
p.000039:
p.000039: • Complexity of the trial design, e.g.: requirement for blinding / shipments of samples (e.g. tissues)/ specific
p.000039: or high level of technology platforms required (e.g. MRI)/ frequency of biological/radiological monitoring/capability
p.000039: for storing clinical trials materials
p.000039: • Restricted access to specific tests and laboratory with possible impact on final data quality (e.g. testing of
p.000039: HIV resistance)
p.000039: • Access to active comparators/ placebo/ age-appropriate formulation at the national level or when provided by the
p.000039: applicant
p.000039: • Differences in Patients-Reported Outcomes
p.000039:
p.000039: • Limitations for long term follow up of patients after treatment (active comparator and study drug)
p.000039: discontinuation
p.000039: • Anticipated quality of data monitoring and training of investigators
p.000039:
p.000039: Specific measures to be taken into consideration in order to assure the quality of results should include:
p.000039: • Identification of limitations in extrapolating data from non-EU patients to the EEA populations, such as
p.000039: different ethnicities, underlying specific conditions
p.000039: • Different local epidemiology of infectious pathogens and / or disease pathology
p.000039:
p.000039: • Appropriateness of study design in accordance with the European guidelines and the most up to date scientific
p.000039: recommendations and ethical requirements
p.000039: • Choice of claim for superiority versus non inferiority in relation to a proper identification of therapeutic
p.000039: needs and respective recruitment capacity in the EEA and outside
p.000039: • Identification of standards of care for the targeted disease among countries
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 32/42
p.000039:
...
p.000039: Article 6(1) of the same regulation requires that “the application include a statement to the effect that clinical
p.000039: trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC.”
p.000039: Article 56 (4) of the same regulation foresees that “the Committee for Medicinal Products for Human Use may, if they
p.000039: consider it appropriate, seek guidance on important questions of a general scientific or ethical nature.”
p.000039: As a consequence, the Marketing Authorisation evaluation should ensure that these GCP principles have been applied to
p.000039: all clinical trials submitted in the dossier, and, that ethical guidance is sought if required.
p.000039: Furthermore, an application for Marketing Authorisation for medicinal products for any population shall be regarded as
p.000039: valid only if requirements of the Article 7 of the European Paediatric Regulation are met.
p.000039:
p.000039: 6.1. Points to consider during the assessment process: identify assessment issues and processes
p.000039:
p.000039: Background
p.000039:
p.000039: Three scenarios are considered:
p.000039:
p.000039: • The first relates to acceptability of foreign data for the EU, from a scientific viewpoint. This is already
p.000039: adequately covered elsewhere (see section 4.8).
p.000039: • The second relates to concern over the conduct of the study, and data reliability – this should trigger requests
p.000039: for clarification from the applicant, and also discussion with inspectors as to whether a GCP inspection may be
p.000039: appropriate or required (see 6.2).
p.000039: • The third relates to concern over the design of studies in relation to acceptability in Europe. Such concerns
p.000039: may relate to the use of placebo or duration of use of placebo, poorly optimised background therapy, use of
p.000039: inappropriate comparator, inappropriate investigations, lack of consent etc.. This aspect is addressed below.
p.000039: Review procedures
p.000039:
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 34/42
p.000039:
p.000039: • At the time of the application, information should be provided on where each clinical trial was performed and on
p.000039: how relevant ethical requirements were met.
p.000039: • As part of the review of the MAA, assessors should consider whether or not there are major ethical concerns
p.000039: relating to the studies that have been included in the dossier to support the MAA. Assessors should confirm in the
p.000039: Assessment Report that they have not identified any major ethical issues in their assessment of the studies, that the
p.000039: studies have been approved by the relevant Ethics Committe and by the National Regulatory Authority, that the sponsor
p.000039: has provided the statement that the studies have been conducted as set out in Annex 1 of Directive 2001/83, and that
p.000039: they have not identified any major concerns regarding the conduct of the study. Particular attention should be paid
p.000039: where vulnerable patients are included within the trial population, and/or trials are conducted in low to middle income
...
p.000039: Assessment Report http://www.ema.europa.eu/pdfs/human/chmptemplates/CHMP-D80-AR-
p.000039: Guidance/D80AR_Clinical_Guidance_rev10_09.pdf ).
p.000039: Inclusion in the guidance of the items listed below, and the consistent application of this, will substantially improve
p.000039: the content of assessment reports and hence the Public Assessment Report in respect of ethical and GCP compliance.
p.000039: The CHMP or RMS assessment report and the Public Assessment Reports should address the following aspects:
p.000039: • The steps taken to evaluate and provide assurance regarding the ethical conduct of the trials should be
p.000039: described as should any significant deficiencies and how they have been addressed.
p.000039: • The standard GCP review should be summarised in an annex to the CHMP or RMS Assessment Report and to the Public
p.000039: Assessment Report, It should list, for each clinical trial submitted the protocol identification and title, start and
p.000039: end date, identification of the sponsor, of the countries where each trial was conducted and the numbers of subjects
p.000039: recruited in each country. The nature of the patient population should also be described (age and gender and any
p.000039: particular considerations of vulnerability). The standards to which the trials were conducted should be identified.
p.000039: This summary should be based on information to be supplied, electronically, by the applicant.
p.000039: • During the course of the assessment, any relevant ethical issue such as access to treatment post trial, use of
p.000039: placebo or treatment interruptions, choice of active comparators, treatment of vulnerable populations should be
p.000039: highlighted as part of the assessment of the individual trial.,
p.000039: • The justifications for the study designs, choice of comparators and selection of study populations, should be
p.000039: provided with particular emphasis on those studies that involve increased ethical sensitivity due to their design,
p.000039: indication, patient population or location of conduct. The applicability of the trial to the EEA population should be
p.000039: discussed where relevant.
p.000039: • A comment that “no ethical issues were identified” may be sufficient where applicable.
p.000039:
p.000039: • If available, information on Patients’ involvement in study design should be communicated,
p.000039:
p.000039: • When a GCP inspection is performed, the reason(s) for inspection should be described. The outcome and
p.000039: consequences on the assessment of a MAA should be further elaborated. Relevant information from the inspection report
p.000039: may be made publicly accessible.
p.000039: • When GCP/ethical concerns have been raised, the assessment report should present the issue, describe any
p.000039: external expertise sought and the advice received, and discuss the ethical aspects and their consequences on the
p.000039: assessment of the quality, safety and efficacy of the product.
p.000039: • The actions taken should be reflected in the Public Assessment Reports.
p.000039:
p.000039: Regulatory action/action plan
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
...
Orphaned Trigger Words
p.000039: Details for regulatory action/action plan to be implemented and/or to be translated in future guidance are described
p.000039: below. The Reflection Paper is a starting point in the context of a more extensive programme focussed on the
p.000039: acceptance, of clinical trials conducted in countries outside EU/EEA and submitted to the European Regulatory
p.000039: Authorities in MAAs. During the development of this paper a number of issues were identified which are not addressed in
p.000039: the present EU legislation. These have been communicated to the EU Commission for their consideration in the context of
p.000039: the future revision of the clinical trials legislation.
p.000039: The scope of the Reflection Paper is endorsed by the Heads of Medicines Agencies and by the Coordination Group for
p.000039: Mutual Recognition and Decentralised Procedures (CMD-h) with regard to the Mutual Recognition Procedure (MRP) and
p.000039: Decentralised Procedure (DCP).
p.000039: The best approach for achieving these objectives is to ensure that a robust framework exists for the oversight and
p.000039: conduct of clinical trials, no matter where in the world the clinical investigators’ sites are located and patients
p.000039: recruited. An international network of Supervisory Bodies (Regulators and Ethics Committees) from all countries
p.000039: involved, working together to share best practices, experiences and information and working to standards agreed and
p.000039: recognized by all, can provide an effective platform for such a robust framework. The Reflection Paper highlights and
p.000039: emphasizes the need for cooperation between Supervisory Bodies involved in the supervision of clinical trials and the
p.000039: need to extend and link networks to support these activities in particular in countries where the ethics and
p.000039: regulatory systems/aspects are not fully developed/available. The EMA will seek to build and extend its relationship
p.000039: with regulators in all part of the world and with international organisations in order to work
p.000039:
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 4/42
p.000039:
p.000039: to achieve this. Examples of activities already implemented, ongoing or to be implemented, in this context, are
p.000039: provided.
p.000039: The revisions to the pharmaceutical legislation which came into place in 2005 increased emphasis on the ethical
p.000039: standards required of clinical trials conducted outside the European Economic Area (EEA) and included in MAAs submitted
p.000039: for Marketing Authorisation.
p.000039: It is acknowledged that the number of patients recruited in countries outside of the EEA is substantial
p.000039: (http://www.ema.europa.eu/Inspections/GCPgeneral.html). Some clinical trials are conducted across several regions,
p.000039: including Europe, whereas many others are conducted solely outside of the EEA.
p.000039: Regulation (EC) No EC/726/2004 states in recital 16:
p.000039:
p.000039: “There is also a need to provide for the ethical requirements of Directive 2001/20/EC of 4 April 2001 of the European
p.000039: Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member
p.000039: States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products
p.000039: for human use to apply to medicinal products authorised by the Community. In particular, with respect to clinical
...
p.000039: EMA/121340/2011
p.000039: Page 7/42
p.000039:
p.000039: • Australia/New Zealand: this area provides 1.5%, mainly from Australia (1.3%).
p.000039:
p.000039: • Central/South America (8.5 % in total): the major contributors is Brazil (2.5 %), followed by Argentina (2%),
p.000039: Mexico (1.3%), Costa Rica (0.5%) and Peru (0.5%).
p.000039: • Commonwealth of Independent States (3.8 in total): Russia (2.8%) and Ukraine (0.8%)
p.000039:
p.000039: • Eastern Europe-non EU (0.5 % in total) : Croatia (0.3%).
p.000039:
p.000039: • North America (34.54% of the total, mainly from USA (29.98%))
p.000039:
p.000039: • EU/EEA/EFTA (39.4% of the total)
p.000039:
p.000039: Therefore some of these countries and others where there is an increase in the number of clinical trials or patient
p.000039: participation in trials should be considered as a priority. In addition some countries contributed less in terms of
p.000039: absolute/total number but are prioritised for assistance in development of their Regulatory activities and expertise.
p.000039: Since the EMA information is limited to centrally authorised products, collecting equivalent information from MSs and
p.000039: other regulatory partners, including WHO, and non-EU regulatory agencies, and from sponsor associations (in particular
p.000039: on ongoing trends) should also be considered. EMA will ensure that a process is developed to bring together the
p.000039: different sources of information to make these available for the International Network.
p.000039: Type of Regulatory System in place
p.000039:
p.000039: Those countries that have a limited regulatory system or one that is still under development (small or very new
p.000039: National Regulatory Authorities with a limited legal framework for the oversight of clinical trials) should also be
p.000039: considered as a priority as part of a wider contribution to capacity building across the global regulatory network and
p.000039: to enable countries to develop effective systems for development of medicines addressing their own health priorities.
p.000039: It will be useful to obtain high level information from all countries from which clinical trials are submitted to the
p.000039: EU or via WHO in order to identify these countries.
p.000039: Countries where there is little information available and/or where information suggests that Ethics Committees may not
p.000039: be properly established should also be identified as priorities.
p.000039: In order to evaluate the level of priority in the context of the aforementioned criteria, it is proposed that a high
p.000039: level “mapping” of information should be established in cooperation between EMA, MS, regulatory authorities and
p.000039: international organizations in relation to:
p.000039: • the level of activity in the field of clinical trials, identifying subcategories of those clinical trials (e.g.
p.000039: Phase I including first in Human trials, Bioequivalence studies, phase II and III in specified therapeutic areas phase
p.000039: IV);
p.000039: • the established and functional regulatory framework for clinical trial authorisation (national regulatory
p.000039: authorities and Ethics Committees), GCP inspections.
p.000039: • the infrastructure for and levels of investigator support and training.
p.000039:
p.000039: This ‘mapping’ should identify the strengths and weaknesses of the national systems, should identify whether capacity
p.000039: building or related development activities are ongoing and should help to select areas for possible cooperation: the
p.000039: selection of the areas for cooperation (i.e. GCP inspections, strengthening of Regulatory Systems or Ethics Committees
p.000039: (strengthened cooperation, capacity building and/or focussed, joint, training) will depend on the needs identified in
p.000039: the countries included in the priority list and should be oriented to avoid duplication with other initiatives in the
p.000039: same area of intervention. The
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 8/42
p.000039:
p.000039: mapping should also identify the opportunities for cooperation with all countries including those where the systems are
p.000039: already developed, and authorities already exist and are functional (see section 3.2)
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EU Regulatory Authorities will prioritise the countries outside EU/EEA with which it will focus its interaction
p.000039: based firstly on the numbers of trial subjects recruited there as part of clinical trials submitted to EU Regulatory
p.000039: Authorities and secondly on a review of the regulatory systems in place for the supervision of clinical trials in those
p.000039: countries, including countries where Bioequivalence trials are conducted.
p.000039:
p.000039: 3.2. Identification of opportunities and partners
p.000039:
p.000039: 3.2.1. Identification of other initiatives
p.000039:
p.000039: In order to look for synergies and avoid duplication of effort, any work performed by the EMA Working Groups should be
p.000039: complementary to the other numerous initiatives being carried out by international, European, regional and national
p.000039: organisations in this field.
p.000039: Existing initiatives have not always been implemented with a clear picture of what has been done already, what the
...
p.000039: oversight of clinical trials, and evaluation of the processes established
p.000039: - Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
p.000039: - Scientific / technical support
p.000039:
p.000039: - Protocol assistance/Scientific Advice
p.000039:
p.000039: - Support for Assessment of clinical trials. Seek the contribution of the Clinical Trial Facilitation Group and
p.000039: specialists in pharmaceutical/non-clinical/clinical evaluation in specific fields
p.000039: - Explore and establish frameworks for different types of information exchange and networking for Regulatory
p.000039: Authorities.
p.000039: • Ethics committees (Ethics Committees):
p.000039:
p.000039: - Assistance with the establishment and operation of Ethics Committees, and evaluation of their processes
p.000039: - Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
p.000039: - National registries of Ethics Committees and documentation on their composition and activity should be
p.000039: established
p.000039: - Evaluation of clinical trials by Ethics Committees – the cooperation of EU Ethics Committees
p.000039: can be sought
p.000039:
p.000039: - Investigation of systems for accreditation or evaluation of Ethics Committees
p.000039:
p.000039: - Explore and establish frameworks for different types of information exchange and networking of Ethics Committees
p.000039: This core set of actions should be refined in accordance with the results and will contribute to the update of the
p.000039: short term and long term activities, described hereunder.
p.000039:
p.000039: 3.3.2. Short Term activities:
p.000039:
p.000039: In the following context, regional groups and associations of national regulatory authorities or ethics committee
p.000039: bodies will often facilitate activities and improve the efficiency and effectiveness of the activities involved.
p.000039: • Establishing and maintaining high level information on:
p.000039:
p.000039: - the established regulatory frameworks for clinical trial authorisation (National Regulatory Authorities and
p.000039: Ethics Committees), GCP inspections, and investigator support and training in priority countries in order to identify
p.000039: and prioritise the areas for increased cooperation; this action can be done by assessment of the available systems,
p.000039: partly as a collaborative work with other established initiatives.
p.000039: - the level of activity in the field of clinical trials (numbers, types and purpose [national market/’export’] of
p.000039: clinical trials), in order to identify the interest of the country. This action requires identification of other
p.000039: sources of information (e.g. registries of clinical trials, National Regulatory Authorities etc).
p.000039:
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 11/42
p.000039:
p.000039: - information on relevant activities underway by other regulatory authorities or international
p.000039: organisations/initiatives/partnerships.
p.000039: • Establishing, sharing and maintaining a list of relevant contact points for the organisations, authorities and
p.000039: initiatives (international, regional, national etc.) involved in these areas including the priority countries
p.000039: • Establishing links – formal and informal – with other projects and initiatives in relation to the priority
p.000039: countries:
p.000039: - Inventory of all organisations and initiatives (international, regional and national e.g. WHO mediated groups,
p.000039: ASEAN, African initiatives such as West African Health Organization (WAHO) and the Economic Community of West African
...
p.000039:
p.000039: • International and regional organisations:
p.000039:
p.000039: - Organisations responsible for funding projects
p.000039:
p.000039: - Organisations responsible for organizing the activities (without funding): to be categorized for areas of
p.000039: activity (e.g. training, legislation, GCP, etc.)
p.000039: - Organisations that fall under both categories
p.000039:
p.000039: In this context it is recognised that WHO and some National Regulatory Authorities in particular have a range of
p.000039: activities ongoing that are of particular relevance and interest.
p.000039:
p.000039:
p.000039: Regulatory action/action plan
p.000039:
p.000039: 1. EMA and EU Regulatory Authorities will identify resource requirements and budget to support the contribution of
p.000039: the EU Regulators.
p.000039: 2. EMA and EU Regulatory Authorities will identify and work with other funding bodies in order to benefit from
p.000039: potential funds to support EMA or EU Member State experts contribution to capacity building exercises.
p.000039: 3. EMA and EU Regulatory Authorities will identify and work with other funding bodies in order to identify funds that
p.000039: may help delegates from concerned countries outside EU/EEA to participate and benefit from capacity building exercises.
p.000039:
p.000039: 3.5. Example of initiatives
p.000039:
p.000039: GCP Inspections:
p.000039: • Increase the number of inspections in priority countries and stakeholders of particular interest EU-CMDh
p.000039: Coordinated program between EU-MSs for inspecting bioequivalence trial facilities with
p.000039: high level of activity.
p.000039:
p.000039: • Encourage observed and joint inspections with local authorities
p.000039:
p.000039: • Increase the capacity for inspection information sharing
p.000039:
p.000039: • The EMA and FDA lunched an initiative on GCP, with the following key objectives:
p.000039:
p.000039: 1. To conduct Periodic Information Exchanges on GCP-Related Information
p.000039:
p.000039: 2. To conduct collaborative GCP inspections
p.000039:
p.000039: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of
p.000039: the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities
p.000039: EMA/121340/2011
p.000039: Page 13/42
p.000039:
p.000039: 3. To share information on interpretation of GCP Harmonization of practice
p.000039: EMA, through its GCP IWG (Inspectors Working Group) organises every year a specific training for EU inspectors. Since
p.000039: 2007 it has included representation from WHO and non EU regulatory authorities (e.g. Australia, Bosnia and
p.000039: Herzegovina, Brazil, Canada, Costa Rica, China, Ghana, Kenya, Iceland, India, Indonesia, Israel, Jordan, Japan,
p.000039: Republic of Korea, Macedonia, Malawi, Montenegro, Mexico, Nigeria, Norway, Philippines, Russian Federation, Saudi
p.000039: Arabia, Singapore, Serbia, Singapore, South Africa, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United States,
p.000039: Zambia) in order to contribute to increased communication and sharing of best practices and expertise among regulatory
p.000039: authorities from within the EU and from countries outside EU/EEA in relation to GCP inspection activities.
p.000039: Regulatory authorities (evaluation and inspection sectors):
p.000039:
p.000039: • Assessment of / assistance in implementing National Regulatory Authorities WHO, Immunization standards,
p.000039: strengthening national regulatory authorities,
p.000039: • Training (courses, workshops, support in the preparation of guidelines/SOPs etc.)
p.000039:
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| HIV | HIV/AIDS |
| access | Access to Social Goods |
| age | Age |
| armed forces | Soldier |
| authority | Relationship to Authority |
| autonomy | Impaired Autonomy |
| child | Child |
| children | Child |
| controlXgroup | participants in a control group |
| culturally | cultural difference |
| dependent | Dependent |
| disability | Mentally Disabled |
| drug | Drug Usage |
| education | education |
| elderly | Elderly |
| emergency | Public Emergency |
| ethnic | Ethnicity |
| ethnicity | Ethnicity |
| gender | gender |
| homeless | Homeless Persons |
| illiterate | Literacy |
| illness | Physically Disabled |
| impairment | Cognitive Impairment |
| incapable | Mentally Incapacitated |
| influence | Drug Usage |
| institutionalized | Institutionalized |
| language | Linguistic Proficiency |
| liberty | Incarcerated |
| linguistic | Linguistic Proficiency |
| manipulate | Manipulable |
| minor | Youth/Minors |
| minority | Racial Minority |
| nomads | nomad |
| opinion | philosophical differences/differences of opinion |
| orphan | orphan |
| parent | parents |
| parents | parents |
| party | political affiliation |
| placebo | participants in a control group |
| political | political affiliation |
| poverty | Economic/Poverty |
| pregnant | Pregnant |
| prisoners | Criminal Convictions |
| racial | Racial Minority |
| religion | Religion |
| restricted | Incarcerated |
| sick | Physically Ill |
| single | Marital Status |
| undue influence | Undue Influence |
| unemployed | Unemployment |
| union | Trade Union Membership |
| vulnerability | vulnerable |
| vulnerable | vulnerable |
| women | Women |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| child | ['children'] |
| children | ['child'] |
| controlXgroup | ['placebo'] |
| drug | ['influence'] |
| ethnic | ['ethnicity'] |
| ethnicity | ['ethnic'] |
| influence | ['drug'] |
| language | ['linguistic'] |
| liberty | ['restricted'] |
| linguistic | ['language'] |
| minority | ['racial'] |
| parent | ['parents'] |
| parents | ['parent'] |
| party | ['political'] |
| placebo | ['controlXgroup'] |
| political | ['party'] |
| racial | ['minority'] |
| restricted | ['liberty'] |
| vulnerability | ['vulnerable'] |
| vulnerable | ['vulnerability'] |
Trigger Words
capacity
consent
cultural
developing
ethics
justice
protect
protection
risk
volunteer
welfare
Applicable Type / Vulnerability / Indicator Overlay for this Input