Ethical Principles in Clinical Research

1. Ethical Principles in Clinical Research Christine Grady Department of Clinical Bioethics National Institutes of Health

2. Moral problem in clinical research • The purpose of clinical research is generation of knowledge about human health and illness • Benefit to participants, although it often occurs, is not the purpose of research • People are the means to developing useful knowledge; and are thus at risk of exploitation

3. Ethics of Clinical Research • Ethical requirements in clinical research aim to: • minimize the possibility of exploitation; • ensure that subjects’ rights and welfare are respected while contributing to the generation of knowledge.

4. Codes and Guidelines • Nuremberg Code(1949) • Declaration Of Helsinki(1964, 75, 83, 89, 96 2000) • The Belmont Report(1979) • CIOMS/WHO International Ethical Guidelines For Biomedical Research Involving Human Subjects(1993, 2002) • ICH/GCP-International Conference on Harmonization- Good Clinical Practice(1996)

5. THE BELMONT REPORTNational Commission for the Protection of Human Subjects of Biomedical and Behavioral Research • Difference between clinical research and clinical practice

6. THE BELMONT REPORT • Ethical principles underlying the conduct of research: • Respect for persons • Beneficence • Justice

7. U.S. Regulations and Guidelines • The Common Rule (US 45CFR.46) • NIH policy and guidelines • FDA regulations (US 21CFR50 and 56) • NIH assurance (FWA)

8. 45CFR.46 Protection of Human Subjects • Composition and function of a local institutional review board (IRB) • Criteria for IRB approval of proposals • Requirements regarding informed consent

9. 45CFR 46 • Subpart B- Fetuses, pregnant women, and human in vitro fertilization • Subpart C- Prisoners as subjects • Subpart D- Children

10. FDA REGULATIONS • 21CFR.50 Protection of Human Subjects (informed consent) • New Subpart D on research with children • 21CFR.56 IRB composition and function

11. Ethical framework: existing guidance • Much guidance developed in response to specific historical events • Divergent recommendations • Certain issues incompletely addressed in codes and regulations • Need for a systematic, coherent, universally applicable framework

12. Ethical framework: 7 principles • Valuable scientific question • Valid scientific methodology • Fair subject selection • Favorable risk-benefit evaluation • Independent review • Informed consent • Respect for enrolled subjects Emanuel E, Wendler D, Grady C. What makes clinical research ethical? Journal of the American Medical Association 2000; 283(20):2701-11

13. Essential Elements of Ethical Research Valuable Scientific Question Limited Resources and Avoidance of Exploitation A socially, clinically, or scientifically useful research question that will generate useful new knowledge about human health

14. Essential Elements of Ethical Research Valid Scientific Methodology Limited Resources and Avoidance of Exploitation Study design, methodology, statistical power, and feasible strategy that will yield valid, reliable, generalizable, and interpretable data.

15. Essential Elements of Ethical Research Fair Subject Selection Justice Selection of subjects for reasons of science, related to the purpose of the study, not because they are readily available, vulnerable, or otherwise easily exploited, or are favored.

16. Selection of subjects • Consistent with scientific goals: • Select subjects to minimize risks and maximize benefits • Do not exclude groups or individuals without a good reason of science or susceptibility to risk, harm, or burden • Consider distribution of burdens and benefits of research

17. Research as risk or benefit? Research as ‘risk’ Subjects need protection Research as ‘benefit’ Subjects need access

18. Essential Elements of Ethical Research Balance of Risks and Benefits Non-maleficence and Beneficence • Minimize risks to subjects • Maximize benefits to individual subjects and to society • Benefits should be proportional to or outweigh risks.

19. Risks in research • Defining risks • Probability and magnitude • Types of risk • Uncertainty • Minimizing risks • Limiting risk

20. Benefits in research • Defining benefits • Direct versus secondary benefits • Maximizing benefits • Balancing risks and benefits

21. Benefits and Risks in Research [I]nterests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects’ rights have been protected. The Belmont Report

22. Essential Elements of Ethical Research Independent Review Minimize conflict of interest Public Accountability Independent review of clinical research ensures the public that investigator biases have not distorted the approach, that ethical requirements have been fulfilled, and that subjects will not be exploited.

23. Criteria for IRB Review(45CFR.46.111 and 21CFR56.111) • Risks … are minimized. • Risks are justified by anticipated benefits, if any, to the subjects or the importance of the knowledge to be gained • Subjects will be selected and treated fairly • Informed consent is adequate

24. Essential Elements of Ethical Research Informed Consent Respect for Persons Voluntary agreement to participate, based on understanding the objectives, risks, benefits, and alternatives of the research.

25. Informed Consent • The voluntary consent of the human subject is absolutely essential. Nuremberg Code • For all biomedical research involving human subjects, the investigator must obtain the informed consent of the prospective subject…or authorized representative. CIOMS guidelines

26. Informed Consent • To the degree subjects are capable, they should be given the opportunity to choose what shall or shall not happen to them. • Consent process: information, comprehension, and voluntariness. The Belmont Report

27. Informed consent • Capacity to consent • Protection of those with limited capacity • Disclosure of information • Assessing understanding • Voluntary decision making. Avoiding coercion and ‘undue’ influence • Authorization

28. Essential Elements of Ethical Research Respect for Enrolled Subjects Beneficence and Respect for Persons • Right to withdraw. • Confidentiality of subject data. • Informing subjects. • Monitoring subject welfare.

29. Respect for enrolled subjects • During the course of the experiment the human subject should be at liberty to bring the experiment to an end… Nuremberg Code • …Every precaution should be taken to respect the privacy of the subject ,the confidentiality of the subject’s information, and to minimize the impact of the study on … physical and mental integrity and on the personality of the subject. Helsinki 2000

30. Ethical framework: 7 principles • Valuable scientific question • Valid scientific methodology • Fair subject selection • Favorable risk-benefit evaluation • Independent review • Informed consent • Respect for enrolled subjects

31. Balancing principles • Example: Randomized Controlled Trials • a rigorous design <-> maximizing benefits/minimizing harms • Equipoise • Randomization

32. Choice of control • “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.” (Helsinki 2000) • Balance the need to answer the valuable question in a scientifically rigorous way, with consideration of risks and benefits.

33. Clinical Equipoise • “Genuine uncertainty within the scientific community...” about the comparative merits of intervention ‘A’ and ‘B’ (Freedman, 1987)

34. Randomization • Random assignment • No individualization • No preferences • Do participants understand random assignment?

35. Links to more information • http://www.wma.net • http://www.cioms.ch • http://ohrp.osophs.dhhs.gov • http://ohsr.od.nih.gov/ • http://www/fda.gov • http://cme.nci.nih.gov/