EU Clinical Trials Regulation 536/2014

Transcription

1 EU Clinical Trials Regulation 536/2014 How to comply with Article 9: the persons validating and assessing the application do not have conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators involved and of persons financing the clinical trial Helsinki, Finland Tom Southerington Research Lawyer, ethics committee member Hospital District of Southwest Finland

2 Background (Public) decision making should be objective, impartial, free from undue external influence A person taking part in decision making is challengeable (esteellinen, jäävi, jävig), if his/her relationship to (1) the matter at hand or (2) the parties involved is such that his/her objectivity may be endangered It is not required that the relationship actually, concretely influences the decision, just that in objective view the possibility exists Rules on challengeability / conflicts of interest seek to (1) ensure objectivity of decision making and also to (2) promote trust in the decision making system The way things are is not the only consideration, but also the way things look like If a challengeable person partook in decision making, the decision can be contested

3 Examples of challengeability / conflicts of interest - The official/member him/herself or relative is a party to the matter - The member is representing a party in the matter - The member can expect specific advantage or disadvantage depending on the decision - The member is employed by a party to the matter - The member is a board member or otherwise has a position of power in the organisation who is a party - Other specific reasons to question the members impartiality

4 EU Clinical Trials Regulation 536/2014 Role of ethics committees Q: What role will Ethics Committees have under the new Regulation? A: Ethics committees will be involved in the assessment of clinical trials application. However, as with the current situation, their responsibilities and detailed composition will be determined independently by each EU country. In this way the different traditions in the various Member States are respected. - Q&A: New rules for clinical trials conducted in the EU;

5 EU Clinical Trials Regulation 536/2014 Ethical review in the application process Article 4 Prior authorisation A clinical trial shall be subject to scientific and ethical review and shall be authorised in accordance with this Regulation. The ethical review shall be performed by an ethics committee in accordance with the law of the Member State concerned. The review by the ethics committee may encompass aspects addressed in Part I of the assessment report for the authorisation of a clinical trial as referred to in Article 6 and in Part II of that assessment report as referred to in Article 7 as appropriate for each Member State concerned. Member States shall ensure that the timelines and procedures for the review by the ethics committees are compatible with the timelines and procedures set out in this Regulation for the assessment of the application for authorisation of a clinical trial. Article 8 Decision on the clinical trial 4. A Member State concerned shall refuse to authorise a clinical trial if it disagrees with the conclusion of the reporting Member State as regards Part I of the assessment report on any of the grounds referred to in the second subparagraph of paragraph 2, or if it finds, on duly justified grounds, that the aspects addressed in Part II of the assessment report are not complied with, or where an ethics committee has issued a negative opinion which in accordance with the law of the Member State concerned is valid for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal.

6 EU Clinical Trials Regulation 536/2014 Preamble (18) It should be left to the Member State concerned to determine the appropriate body or bodies to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of ethics committees within the timelines for the authorisation of that clinical trial as set out in this Regulation. Such decisions are a matter of internal organisation for each Member State. When determining the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular patients or patients' organisations. They should also ensure that the necessary expertise is available. In accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons who collectively have the necessary qualifications and experience. The persons assessing the application should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free from any other undue influence.

7 EU Clinical Trials Regulation 536/2014 Definitions (11) Ethics committee means an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organisations; (Was: an independent body in a Member State, consisting of healthcare professionals and nonmedical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent - Directive 2001/20/EC)

8 EU Clinical Trials Regulation 536/2014 Article 9 Persons assessing the application 1. Member States shall ensure that the persons validating and assessing the application do not have conflicts of interest, are independent of the sponsor, of the clinical trial site and the investigators involved and of persons financing the clinical trial, as well as free of any other undue influence. In order to guarantee independence and transparency, the Member States shall ensure that persons admitting and assessing the application as regards the aspects addressed in Parts I and II of the assessment report have no financial or personal interests which could affect their impartiality. These persons shall make an annual declaration of their financial interests. 2. Member States shall ensure that the assessment is done jointly by a reasonable number of persons who collectively have the necessary qualifications and experience. 3. At least one layperson shall participate in the assessment. NOTE: Article 9 is not addressed to ethics committees, but applies to everyone participating in the assessment of applications

9 Clinical Trials Regulation Compared with ICH GCP and US FDA Requirements EU Regulation persons assessing applications ICH GCP Independent Ethics Committees FDA Institutional Review Boards (CFR - Code of Federal Regulations Title 21: Food and Drugs, Section 56) Persons do not have conflicts of interest, are independent of: sponsor clinical trial site investigators involved and persons financing the clinical trial, as well as free of any other undue influence No financial or personal interests which could affect impartiality At least one member who is independent of the institution/trial site recommended Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC At least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB Reasonable number of persons who collectively have the necessary qualifications and experience Reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics At least five members recommended At least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution At least one layperson participates in the assessment It is recommended that the IRB/IEC should include at least one member whose primary area of interest is in a nonscientific area Each IRB shall include at least one member whose primary concerns are in the scientific area and at least one member whose primary concerns are in nonscientific areas

10 Independence of what? Sponsor, investigator and persons financing are probably (?) clear, but what is a clinical trial site? Regulation does not define ICH GCP: the location(s) where trial-related activities are actually conducted Clinical trial agreements: varying styles, some name several locations (clinic, lab, pharmacy ), some name just the applicable clinic/unit or the hospital as a whole Clinical trial site does not necessarily equal the legal person employing the investigator, contracting for research etc; could be a hospital, clinic, unit etc. E.g. city hospitals are often not separate legal entities, still the city should not be a clinical trial site too big, too vague Hospital districts may encompass all hospitals in their area and be the only legal entity, HDs as a whole should not be clinical trial sites too big, too vague Often in discussions clinical trial site = the hospital, research centre, institution

11 Independence of the Site Unlike ICH GCP and FDA/CFR the Regulation requires that every person participating in assessment is independent of the clinical trial site It seems that under ICH and CFR persons from the trial site can participate in decisions concerning their own site, unless there are (other?) conflicts of interest It seems that under the Regulation persons from the same site can be EC members, but not necessarily able to take part in assessing applications concerning their own site The main challenge in comparison to current situation could be the requirement for independence of the clinical trial site Current organisation and interpretation at least in Finland is that colleagues from the same site are not considered challengeable just because they work on the site, unless there are other specific reasons / conflicts of interest making them challengeable A practical concern especially in multi-site studies in a small country could be that ensuring sufficient expertise might prove tricky if colleaques from the trial sites are automatically challengeable What is independence? independence of anything causing conflicting interests, of external factors influencing decisions, financial, contractual, emotional, etc. administrative independence official makes decisions at own discretion independently of employer or other authorities, has liability for acts in office (virkavastuu, tjänsteansvar), and no compromising affiliations/dependencies/factors

12 How to comply with Article 9? Member States shall ensure they must comply Is current administrative law sufficient or do we need new specific rules for ethics committees and other officials assessing clinical trials? Regulation leaves the organisation of the bodies involved in the assessment to the Member States and does not define concepts like independence or conflict of interest In order to guarantee independence and transparency, the Member States shall ensure that persons. have no financial or personal interests which could affect their impartiality Community legislation only where Member States cannot act effectively (subsidiarity, proportionality) Member States define the organisation of ECs as well as the criteria for independence, what kind of interests could affect impartiality etc. They need to consider the adequacy of their existing rules on administrative processess Ethics review or assessment as a whole probably does not require special treatment, presumably applicable legislation already exists Interpretation of current rules should be checked and guidance given if tweaks needed

13 How to comply with Article 9 In any case ethical committee(s) should be able to maintain capacity to act in the required timelines even when some members are absent or abstain because of conflicting interests Rules on quorum Enough members, also with overlapping expertise Recognise that having necessary qualifications and experience does not necessarily mean that every parkinsons trial has to be assessed by a neurologist, every cancer trial by an oncologist etc. Regulation does not prevent asking for outside expert opinions (timelines) Special attention to vulnerable populations (Article 10) Transparency of affiliations, declaration of financial interests

14 Thank You

15 Extras

16 Community subsidiarity Member States are sovereign states and EU competence in this area is based on subsidiarity and proportionality Subsidiarity: EU may intervene only if it is capable of acting more effectively than the Member States, and Proportionality: EU acts may not exceed what is necessary to achieve the objectives of the EU treaties (85) Since the objective of this Regulation, namely to ensure that, throughout the Union, clinical trial data are reliable and robust while ensuring respect for the rights, safety, dignity and well-being of subjects, cannot be sufficiently achieved by the Member States but can rather, by reason of its scale, be better achieved at Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Regulation does not go beyond what is necessary in order to achieve that objective

17 Declaration of Helsinki Research Ethics Committees 23. The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No amendment to the protocol may be made without consideration and approval by the committee. After the end of the study, the researchers must submit a final report to the committee containing a summary of the study s findings and conclusions.

18 TITLE 21--FOOD AND DRUGS PART INSTITUTIONAL REVIEW BOARDS Subpart B--Organization and Personnel CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER A--GENERALPART INSTITUTIONAL REVIEW BOARDS Subpart B--Organization and Personnel Sec IRB membership. (a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, cultural backgrounds, and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review the specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. * * * The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects. (b) Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the instituton's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender. No IRB may consist entirely of members of one profession. (c) Each IRB shall include at least one member whose primary concerns are in the scientific area and at least one member whose primary concerns are in nonscientific areas. (d) Each IRB shall include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution. (e) No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB. (f) An IRB may, in its discretion, invite individuals with competence in special areas to assist in the review of complex issues which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB. [46 FR 8975, Jan. 27, 1981, as amended at 56 FR 28028, June 18, 1991; 56 FR 29756, June 28, 1991; 78 FR 16401, Mar. 15, 2013]

19 ICH GPC 1.27 Independent Ethics Committee (IEC) An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving / providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.

20 ICH GPC 3.2 Composition, Functions and Operations The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include: (a) At least five members. (b) At least one member whose primary area of interest is in a nonscientific area. (c) At least one member who is independent of the institution/trial site. Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC An IRB/IEC may invite nonmembers with expertise in special areas for assistance.