Bioethics and translational research

1. Bioethics and translational research Benjamin S. Wilfond MD Seattle Children’s Hospital Treuman Katz Center for Pediatric Bioethics Center for Clinical and Translational Research University of Washington Division of Bioethics, Department of Pediatrics Center for Genomics and Health Equity, Department of Bioethics and Humanities Regulatory Support and Bioethics Core, Institute of Translational Health Sciences

2. What Makes Clinical Research Ethical? • Informed consent • Compliance with the 10 commandments • IRB review • Informed consent and IRB review • Compliance with Nuremberg, Helsinki, and Belmont • Compliance with 45 CFR 46 • All of the above? From Ezekiel Emanuel

3. Translational CycleCenter for Genomics and Healthcare EqualityUniversity of Washington Development Discovery Assessment & Priority Setting Outcomes Delivery

4. Case • BY is a 46 year old post-menopausal mentally disabled woman with DCIS. • Caregivers from her “home” with power of attorney for health care decisions, bring her to the clinic for enrollment in STAR trial, randomized trial of tamoxifen vs. raloxifene for the prevention of breast cancer in high risk women. • She fulfills all entry criteria but cannot consent.

5. The Question • The physician who saw BY wants the IRB to reconsider the subject selection criteria for the STAR trial • The IRB debates the question: • Is it ethical to enroll a mentally incompetent patient in a Phase III randomized chemo-prevention trial?

6. Wide Array of Ethical Guidelines • 1947 Nuremberg Code • 1964 Declaration of Helsinki • 1979 Belmont Report • 1982 CIOMS • 1991 Common Rule • “born in scandal”; not systematic; often incomplete; sometimes contradictory

7. Promote scientific knowledge Benefit to patient and family Clinical Care Research Goals are constrained by ethical obligations Joffe and Miller. Hastings Center Report 2008

8. Why Do We Need Ethical Guidelines? • Clinical research develops generalizable knowledge that improves health or increases understanding • People who participate in clinical research are a means to securing that generalizable knowledge • As a means, these people can be exploited, that is be used as a means for the benefits of others • Ethical benchmarks for clinical research are meant to minimize the possibility of exploitation

9. 8 Ethical Benchmarks • Collaborative Partnership • Social Value • Scientific Validity • Fair Subject Selection • Favorable Risk-Benefit Ratio • Independent Review • Informed Consent • Respect for Human Subjects Emanuel et al. (2000) JAMA; (2004) J Infect Dis

10. Collaborative Partnership • Clinical research should involve the community in which it occurs • This requires: • Community participation in planning, conducting and overseeing research, and integrating research results into the health system. • Avoidance of supplanting existing health care services and the sharing rewards with the community.

11. Collaborative Partnership • Mechanisms to achieve collaborative partnerships include: • Community based participatory research • Community advisory boards • Patient advocates on scientific advisory boards and IRBS • Advocates for funding of research

12. Social Value • Clinical research should lead to improvements in health or advancement in generalizable knowledge • Must consider how the research will affect: • Participants in the research • Community in which research is conducted • World

13. Valueless research • non-generalizable studies • “Me too” studies • Non-disseminated research

14. Scientific Validity • Research should produce reliable and valid data that can be interpreted • Research must be conducted in a methodologically rigorous manner that is practically feasible

15. Invalid research • Studies with biased endpoints, instruments or statistical tests • Studies that cannot enroll sufficient subjects • Underpowered studies

16. Fair Subject Selection • The scientific objectives of the study—not vulnerability or privilege—should guide inclusion criteria and targeted populations • Lowering risk and enhancing generalizability can then be considered

17. Fair Subject Selection • Convenient groups should not be selected. • Groups should not be excluded without scientific reasons. • Higher risk is a reason to exclude certain groups. • Should not select rich, politically powerful or otherwise well connected people for “promising research” studies.

18. Favorable Risk-Benefit Ratio • Risks to participants should be balanced by the benefit to individual participants, and when appropriate, the benefit to society. • The approach • Risks identified, assessed and minimized. • Potential benefits to individuals enhanced. • If potential benefits to individual outweigh risks to the individual, then proceed. • If risks outweigh the benefits to the individual then evaluate risks against the benefits to the society. • Consider risks to the community

19. Risks • Potential risks to consider include: • Physical —death, disability, infection • Psychological —depression and anxiety • Social —discrimination • Economic —job loss • Community risks to others not directly involved in the research • Evaluate the: • Likelihood of harm • Magnitude of harm • Identify mechanisms to minimize risks: • Additional diagnostic tests • Hospitalizations • Confidentiality protections

20. Benefits to the individual • Consider physical, psychological, social, and economic benefits to the individual • Consider only benefits from research interventions not benefit from added health services or payment that are not necessary to the research goals • Benefits related to payment or other services may be justified and even obligatory, but are independent of the benefit/risk calculation • Respect • Beneficence • Justice

21. Independent Review • Because investigators have multiple legitimate interests, they have potential conflicts of interest • Independent review of the research minimizes these conflicts • Independent review also assures society it will not benefit from abuse of subjects

22. Informed Consent • Informed consent ensures individuals decide whether they enroll in research and whether research fits with their own values, interests, and goals. • For those who cannot consent—such as children and mentally impaired—must be sure research fits with their interests.

23. Four Elements • Competence/capacity of the subject • Disclosure of information to the subject • Understanding or comprehension by the subject • Voluntariness of the decision

24. Federal Regulations for Disclosure • Purpose and duration of participation • Risks • Alternatives • Benefits • Confidentiality of records • Compensation for injuries • Person to contact for answers to questions • Voluntariness and right to withdraw

25. Respect for Human Subjects • The ethical requirements of research do not end with a signed consent document. Also include: • Protecting confidentiality • Permitting withdrawal • Providing new information • Monitoring welfare • Informing participants what was learned from the research • Providing “fair benefits” for participation in research

26. 8 Ethical Requirements • Collaborative Partnership • Social Value • Scientific Validity • Fair Subject Selection • Favorable Risk-Benefit Ratio • Independent Review • Informed Consent • Respect for Human Subjects Emanuel et al. (2004) J Infect Dis

27. Required • All 8 benchmarks are necessary and essential to make clinical research ethical. • Independent review and informed consent are procedural benchmarks to ensure certain values are achieved. • Other procedures may achieve these values. In some circumstances, independent review and informed consent can be waived.

28. Universal • All 8 ethical benchmarks are universal. They do not apply only to the US or Europe. They apply to clinical research everywhere. • The 8 ethical benchmarks must be adapted to the local health, economic, cultural and technological circumstances. For instance, disease risk effects risk-benefit evaluation.

29. Benchmarks may Conflict • What is fair in subject selection may increase risks • What enhances scientific validity may increase risks • What is necessary to respect enrolled subjects or obtain informed consent may compromise scientific validity

30. Resolving Conflicts • No simple formula for resolving conflicts. • Adjust design to meet the requirements. This is sometimes termed “balancing”, “weighing” or “specifying” the principles. • The important point is to be clear about what is being done and give reasons why. • Different approaches may equally ethical.

31. Expertise • The expertise necessary to implement these benchmarks includes: • Educated and trained investigators • IRBs with investigators, statisticians, ethicists, and community representatives.

32. Back to Our Question(s) • Is it ethical to enroll a mentally incompetent patient in a Phase III randomized chemo-prevention trial? • Is it ethical to enroll BY in a randomized trial to determine which of two hormonal therapies is better at preventing cancer with the fewest side effects?

33. Emphasize Informed Consent • BY cannot consent • There are many eligible participants for the STAR trial • BY is not necessary to the trial • Enroll patients who can consent

34. Emphasize Risk-Benefit & Social Value • Informed consent is not an absolute requirement. • The risk-benefit ratio is positive • BY is at least as well off in the trial as in clinical care and will be contributing to scientific knowledge • As long as mentally disabled patients are not being unfairly targeted, enroll BY

35. Emphasize Fair Subject Selection • To deny BY access to the STAR trail would be unjust. • She meets eligibility criteria and has a similar risk-benefit ratio to other potential participants. • The only reason for excluding her is unrelated to science but related to mental condition.

36. What is our mission? Protect participants and communities Promote scientific knowledge Trustworthy research practices

37. ITHS Bioethics Consultations (www.iths.org) • Providing a forum for discussion and analysis of ethical issues in clinical and translational research • For researchers, research staff and trainees, IRBs, research participants and their families, and communities • Advisory to requestor • Supplemental to IRB or DMC oversight • Conducted via phone, email or in person • Written report can be provided

38. Research Bioethics Consult Questions • Community engagement: • How can I establish sustainable relationships with communities? • How should I negotiate disagreements with community stakeholders? • How should I share the research data with the community? • Study Development: • Should I provide incentives for participation? • What if informed consent isn't practical for my study? • When is a placebo-control ethically appropriate? • Study Implementation: • What should I do if a participant doesn't have the capacity for consent? • Can I withdraw a participant against his/her wishes? • What must I do if my participants need medical care or other help? • Study Analysis: • Should I tell participants about their research findings? • What if a participant requests their data be withdrawn? • Who should be an author on the publication of my study?

39. Thanks to… • Members of the ITHS Bioethics Team of the Regulatory Support and Bioethics Core: Kelly Edwards, Malia Fullerton, Maureen Kelley, and Ben Wilfond • Department of Bioethics, National Institutes of Health Clinical Center (from whom we adopted some slides from the “ethical and regulatory aspects of clinical research course”) • Slides, webcast, and podcasts at • http://www.bioethics.nih.gov/hsrc/index.shtml