Ethics Committees/IRBs Today: Challenges for Efficiency and Quality

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1 Marjorie A. Speers, Ph.D. President and CEO Ethics Committees/IRBs Today: Challenges for Efficiency and Quality Copyright 2013 AAHRPP All rights reserved

2 Goal Clinical Research Globally Access to patients for Phase III trials Emerging markets Brazil, Russia, India, China, Mexico, and Thailand Data used to supporting marketing applications in U.S. and Europe Make medicines available in all countries Bioequivalence studies required

3 Emerging Markets (perhaps all markets) Challenges to conducting clinical trials Legal structure Disease burden Poverty and illiteracy Insufficiently trained workforce Huge costs associated with start-up of trials Non-compliance of investigators and ECs Coercion or undue influence on research subjects

4 Research Issues Related to Ethics Commonly Accepted Ethics Principles Respect for Person diminished capacity illiteracy Recruiting methods and consent process Access to investigational products and health care Decision-making capacity in the presence of lifethreatening disease

5 Commonly Accepted Ethics Principles Beneficence Do no harm Maximize potential benefits Risk and potential benefit analysis Minimize risks Trial termination rules Privacy interests and confidentiality of data Qualifications of investigator and research staff Sample size sufficient number of subjects

6 Commonly Accepted Ethics Principles Justice Burdens and benefits of research should be equally shared by the population Study design Inclusion and exclusion criteria Willingness to participate in trial Access to medicines after trials end Use of placebo groups in trials

7 Ethical Principles Become Law Brazil Resolution CNS 466/2012 on guidelines and rules for research involving human participants Resolution 251/97 on complementary rules for research with new pharmaceutical products, medicines, vaccines and diagnostic tests, and Resolution 304/2000 on complementary rules for research involving indigenous people Other countries Adopted a form of ICH-GCP (E6) Follow ICH-GCP (E6) Ministry of Health laws or guidance

8 Issue Brazil China India Mexico US ICH-GCP Criteria for Approval Has 28 criteria Has 53 criteria Has 12 principles Has 14 criteria Has 9 criteria Has 4 principles Continuing review required Not required Required at least annually Optional Not required Required at least annually Required at least annually Consent disclosures Has 9 required disclosures Has 7 required disclosures Has 16 required disclosures Has 11 required disclosures Has 8 required and 6 additional disclosures Has 20 required disclosures Protections for vulnerable individuals No specific terms No specific terms Specific terms for pregnant or nursing women, children, and other groups Specific terms for children, disabled, pregnant women, and subordinate groups FDA specific terms for children No specific terms

9 Current Controversies India Complaints concerning lack of consent Allegations of death associated with research Passage of strict laws include compensation for research-related injury determined by EC Six clinical trials have been approved in 2013 compared to nearly 500 in 2010 NIH pulled 40 clinical trials, sponsors moving to other countries

10 Current Controversies China GSK - misrepresentation of data in a neurology trial and corrupt sales practices in 2011 United States SUPPORT trial trial designed to study the safety and efficacy of oxygen levels given to neonates. Using oxygen levels within the range that is considered standard care, babies were randomized to either a high or low does. Critics raise what is research when standard care is studied and that consent document was not sufficient.

11 Expectations of Ethics Committees Participants and the public Sponsors Investigators

12 Expectations of Participants and the Public Trust the investigator to put their safety and well-being above all else. Have systems are in place to monitor their well-being. Answer their questions, and address any concerns they might have. Explain the research, including its potential benefits and risks, and obtain your permission in writing. Guard against conflict of interest. Protect their privacy.

13 ICH-GCP (E6) Sponsor Responsibilities Confirmation of Review by IRB/IEC The sponsor should obtain from the investigator/institution: (a) The name and address of the investigator's/institution s IRB/IEC. (b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations. (c) Documented IRB/IEC approval/favorable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested If the IRB/IEC conditions its approval/favorable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval/favorable opinion was given by the IRB/IEC The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/re-evaluations with favorable opinion, and of any withdrawals or suspensions of approval/favorable opinion.

14 Is Obtaining a Letter that the EC or IRB Approved the Clinical Trial Sufficient? What does a letter of EC or IRB approval for the trial tell the sponsor? The EC or IRB approved the trial The period of approval, usually with an expiration date Requirement to report certain types of events to the EC or IRB (usually)

15 What s Missing from the Approval Letter? Does the EC or IRB follow ICH-GCP and applicable laws and regulations Is the EC or IRB composed consistent with legal and GCP requirements Does the EC or IRB have procedures to conduct initial and continuing review, and review of modifications to previously approved research

16 Why Should Sponsors Care? Those who select research sites do not qualify sites based compliance and quality of the EC or IRB Do not know applicable laws and regulations Do not know the composition of the EC or IRB Do not know the operating procedures of the EC or IRB

17 Common Misunderstanding about ECs or IRBs Competent EC or IRB Members and Staff Knowledge SOPs Some EC or IRB members and staff do not know the laws and regulations they must follow or the requirements in ICH-GCP Training programs for EC or IRB members and staff are rare or limited

18 Initial and Continuing review Initial review Lack criteria for reviewing and approving research GCP does not specify criteria for approval of clinical trials Criteria for approval of research contained in US FDA regulations or Brazil law are used to a greater or lesser extent Continuing review Not conducted

19 What Can Sponsors Do? Trial design Most issues relating to ethics should be handled in the design of the clinical trial Trial design Identification and minimization of risks Procedures to protect privacy interests of subjects Procedures to maintain the confidentiality of identifiable data Sample size Access, if any, to medicine after trial ends

20 More Design issues Enrollment criteria Inclusion/exclusion criteria Illiteracy Poverty Ability to comply with protocol requirements Consent process and documentation Process versus document Recruitment methods

21 Expectations of Investigators Ethics committees will: Conduct a fair and transparent review of the research protocol Be competent and knowledgeable to conduct the review Be clear in their expectations of investigators in submitting protocols Be clear in describing the terms for approval of protocols Be timely Work with, not against, investigators Be accountable for their actions

22 Challenges that Ethics Committees Face Lack of institutional leadership Limited resources Lack of educational opportunities Lack of accountability In Brazil, model of national and local ethics committees

23 Focus of Human Research Protection Organization IRB or EC Researchers and Research staff } Human Research Protection Program Protecting research participants is a shared responsibility

24 Human Research Protection Program Investigators and Research Staff Quality Improvement Education Programs Organizational Plan Conflict of Interest Separation of Business Interests from EC Participant Outreach IRB or EC Contracts and Grants

25 Elements of a Quality Management System Management Commitment Continuous Improvement Culture Customer Service & Satisfaction Quality Management System Elements QMS Administration Measurement & Analysis Competence, Awareness, & Training Documentation System

26 Focus on Quality Improvement Efficiency and Quality EC or IRB Review and Turnaround Times Documentation in minutes Use of approval criteria Consent disclosures

27 IRB Staff Performance Defined targets for completion of each process by EC or IRB staff; examples: 5-day target for pre-review correspondence 3-day target for post-meeting correspondence 4-day target for review of post-meeting PI response Monthly reports on percentage of studies completed within target review times for each EC or IRB staff process 27

28 Surveys Annual researcher satisfaction online survey on HRPP Survey with research participants on their experiences with research participation 28

29 Post-approval Monitoring Monitor compliance of investigators, the EC or IRB and its administrative office Routine, for-cause, and high-risk study audits Site start-up visits for sponsor-investigators Privacy/data security focused audits Process and track subject inquiries and complaints Process and track allegations of noncompliance 29

30 Overall IRB Review Times

31 IRB Review Times Academic Institutions

32 IRB Review Times - Hospitals

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36 Partnership between EC and Investigator Roles and responsibilities should be clear Obligation of the EC to share policies and procedures and make the ethics review process transparent for investigators Both parties must know and understand Brazil s law for protecting human research subjects

37 Local ECs Set high standards for performance Met and exceed national law Develop a customer-friendly model of operation Develop local expertise and competence Ensure institutional support

38 Accreditation What it is External validation that the research site, including the ethics committee, is meeting high standards of performance Why it is important Preserve public trust Address government concerns Standard for doing business

39 Three Domains Domain 1: Organization Domain 2: IRB or EC Domain 3: Researcher and Research Staff

40 Domain I: Organization Standard I-1: The Organization has a systematic and comprehensive Human Research Protection Program that affords protections for all research participants. Individuals within the Organization are knowledgeable about and follow the policies and procedures of the Human Research Protection Program. Define research activities and which rules apply Have a recognized organizational official Independence of IRB or EC Define ethical standards of the organization Have education activities Review process of scientific validity of research

41 Domain I: Organization Standard I-2: The Organization ensures that the Human Research Protection Program has resources sufficient to protect the rights and welfare of research participants for the research activities that the Organization conducts or oversees. Standard I-3: The Organization s transnational research activities are consistent with the ethical principles set forth in its Human Research Protection Program and meet equivalent levels of participant protection as research conducted in the Organization s principal location while complying with local laws and taking into account cultural context.

42 Domain I: Organization Standard I-4: The Organization responds to the concerns of research participants. Mechanism for research participants to discuss problems, concerns, and questions; obtain information; and offer input Activities to enhance understanding of research among research participants Involvement of community members in research design and implementation

43 Domain I: Organization Standard I-5: The Organization measures and improves, when necessary, compliance with organizational policies and procedures and applicable laws, regulations, codes, and guidance. The Organization also measures and improves, when necessary, the quality, effectiveness, and efficiency of the Human Research Protection Program. Collect objective data to assess: compliance quality, efficiency, effectiveness Mechanism for researchers and staff to bring forth concerns or suggestions Identification, management, and reporting (as required) of noncompliance

44 Domain I: Organization Standard I-6: The Organization has and follows written policies and procedures to ensure that research is conducted so that financial conflicts of interest are identified, managed, and minimized or eliminated. Organizational conflict of interest Individual conflict of interest

45 Domain I: Organization Standard I-7: The Organization has and follows written policies and procedures to ensure that the use of any investigational or unlicensed test article complies with all applicable legal and regulatory requirements. Test articles have appropriate regulatory approval or exemptions Handling of test articles conforms to legal and regulatory requirements Follow legal and regulatory requirements governing emergency use of test articles

46 Domain I: Organization Standard I-8: The Organization works with public, industry, and private Sponsors to apply the requirements of the Human Research Protection Program to all participants. Written agreements with sponsors address: Provision of medical care for research participants with a research-related injury Findings from site monitoring that affect the safety of participants or influence the conduct of the study are reported to the Organization Findings from data and safety monitoring are reported to the Organization Role of the investigator in the publication or disclosure of results If participant safety could be affected by study results after the study has ended, agreement with Investigator or Organization about how the Sponsor will notify the site about the results in order to consider informing participants

47 Domain II: IRB or EC Standard II-1: The structure and composition of the IRB or EC are appropriate to the amount and nature of the research reviewed and in accordance with requirements of applicable laws, regulations, codes, and guidance. Appropriate expertise and representation on IRB or EC Qualified chair, members, and staff Separation of business interests from ethics review function Conflict of interest of IRB or EC members Appropriate expertise of IRB or EC members to review each protocol

48 Domain II: IRB or EC Standard II-2: The IRB or EC evaluates each research protocol or plan to ensure the protection of participants. Use of exemptions, if applicable Procedures to conduct meetings Procedures to conduct initial and continuing reviews and reviews of modifications by the convened IRB or EC Procedures to conduct initial and continuing reviews and reviews of modification using an expedited procedure Procedures to address unanticipated problems involving risks to participants or others Procedures for suspending or terminating IRB or EC approval of research Procedures for managing multi-site research, if applicable

49 Domain II: IRB or EC Standard II-3: The IRB or EC approves each research protocol or plan according to criteria based on applicable laws, regulations, codes, and guidance. Analysis of risks and potential benefits Adequate data and safety monitoring plans Equitable selection of participants (including advertisements, recruitment methods and payment arrangements) Provisions to protect privacy interests of research participants Provisions to maintain confidentiality of identifiable data Adequate consent process Documentation of the consent process Waivers or alterations of the consent process or waivers of requirement to document the consent process

50 Domain II: IRB or EC Standard II-4: The IRB or EC provides additional protections for individuals who are vulnerable to coercion or undue influence and participate in research. Additional safeguards not related to consent process Assessment of capacity to consent and consent process Planned emergency research

51 Domain II: IRB or EC Standard II-5: The IRB or EC maintains documentation of its activities. Follow legal and regulatory requirements, sponsor s requirements, and organizational policies and procedures Complete set of material relevant to the review of the protocol Documentation of IRB or EC discussions and decisions

52 Domain III: Researchers and Research Staff Standard III-1: In addition to following applicable laws and regulations, Researchers and Research Staff adhere to ethical principles and standards appropriate for their discipline. In designing and conducting research studies, Researchers and Research Staff have the protection of the rights and welfare of research participants as a primary concern. Know what activities are research Identify and disclose financial interests Use sound study designs Have necessary resources to conduct research Recruit participants in a fair and equitable manner Use appropriate consent processes and document consent Address participants concerns, complaints, or requests for information

53 Domain III: Researchers and Research Staff Standard III-2: Researchers and Research Staff meet requirements for conducting research with participants and comply with all applicable laws, regulations, codes, and guidance; the Organization s policies and procedures for protecting research participants; and the IRB s or EC s determinations. Qualified by training and experience Maintain oversight over each research study and staff Follow requirements of the protocol and requirements of the organization and of the IRB or EC Follow reporting requirements

54 Summary Ethics committees must function in a complex and demanding environment Ethics committees are expected to be effective and efficient Ethics committees must be accountable and demonstrate their accountability Ethics committees should be part of the solution not part of the problem in clinical research