What Makes Oncology Clinical Research Ethical

1. What Makes OncologyClinical Research Ethical? Steven Joffe, MD, MPH Assistant Professor of Pediatrics

2. 2 Objectives Understand the ethical tensions in the investigator-subject relationship Learn a systematic approach to evaluating the ethics of oncology trials Understand how to improve the consent process for cancer clinical research Consider the challenges raised by con-flicts of interest in oncology research

3. 3 Case Patients with imatinib-refractory GIST Offered participation in RCT of sunitinib vs. placebo open-label access to drug at progression �two prestigious medical centers, MD Anderson�& U of Michigan�refused to join in�

4. 4 Case (Cont�d) �When patients have an advanced cancer & the cancer is growing, there isn�t any way the placebo can be helpful [to the patient]. To argue that a placebo trial is in society�s interests has nothing to do with helping these patients.� Assoc. Director, U of Michigan Cancer Center (quoted in R. Mishra, Boston Globe, July 4, 2004)

5. 5 Question

6. 6 History Of Research Ethics Landmark events Nazi experiments Willowbrook hepatitis studies (1956-72) Jewish Chronic Disease Hospital studies (1963) Henry Beecher�s NEJM article (1966) Tuskegee Syphilis Study (1932-72) AIDS clinical trials (late 1980�s)

7. 7 Codes Of Research Ethics Nuremberg Code (1947) informed consent, societal value, unacceptable levels of risk Declaration of Helsinki (orig. 1964) added written protocol, independent review Belmont Report (1979) added justice, fair subject selection

8. 8 Key U.S. Regulatory Documents 45 Code of Federal Regulations 46 (45 CFR 46) �Common Rule� Subpart D: Pediatric regulations 21 CFR 50 & 56 (FDA regulations) Privacy Rule under HIPAA (2003)

9. 9 Definition of Clinical Research research: �class of activities designed to develop or contribute to generalizable knowledge� practice: �interventions designed solely to enhance the well being of an individual patient or client�

10. 10 The Clinician-Investigator Dual allegiance to study/community to patient/subject Creates a (legitimate) conflict of interest Important to be aware of this tension Miller et al. JAMA 280:1449

11. 11 Example Of Conflict NSABP trials--1994 PI at St. Luc Hospital in Montreal falsified procedure dates and hormone-receptor status so that breast cancer patients would appear to meet eligibility criteria for a clinical trial

12. 12 PI Response �My sole concern at all times was the health of my patients. I firmly believed that a patient who was able to enter into an NSABP trial received the best therapy and follow-up treatment. For me, it was difficult to tell a woman with breast cancer that she was ineligible to receive the best available treatment because she did not meet 1 criteria out of 22��

13. 13 Question

14. 14 Criteria for Ethical Research Social value Scientific validity Fair subject selection Reasonable balance of risks & benefits Independent review Informed consent Respect for enrolled subjects

15. 15 Social Value Study must ask an important question valuable for improving health and/or for basic scientific knowledge research is unethical if question is trivial, has already been answered, etc.

16. 16 Scientific Validity Even if question is important, study is unethical if methods aren�t likely to answer it not feasible poor measures inadequate sample size poor statistical analysis biased reporting (or non-reporting)

17. 17 Fair Subject Selection Historically, risky or non-beneficial research has disproportionately enrolled vulnerable populations ethnic minorities mentally incapacitated, institutionalized Conversely, exclusion of certain groups from research disenfranchises them from benefits of the knowledge gained Cancer pts often labelled as vulnerable�but not strictly trueCancer pts often labelled as vulnerable�but not strictly true

18. 18 Risk/Benefit Balance Benefits of a clinical trial must justify the risks sometimes, the risk/benefit ratio for the participant is clearly unfavorable e.g., research-related biopsies

19. 19 Risk/Benefit Balance Benefits of a clinical trial must justify the risks sometimes, the risk/benefit ratio for the participant is clearly unfavorable e.g., research-related biopsies

20. 20 Question

21. 21 Risk/Benefit Balance To approve a study, the IRB must find that �risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result�

22. 22 Independent Review Institutional Review Boards (IRBs) independent review is mandated by federal regulation for most research with human subjects IRBs review studies at inception science, risk/benefit ratio, informed consent IRBs also monitor studies as they proceed continuing reviews, amendments adverse events, unanticipated problems

23. 23 Informed Consent Ensure respect for individuals� values & preferences in decisions about their medical care & research participation respect for patient/subject autonomy View as ongoing process, not one-time event

24. 24 Components Of Valid Consent Voluntariness Undermined by coercion, not by incentives, life-threatening disease Capacity Disclosure Undermined by deception, manipulation Understanding Decision Voluntariness: not obviously compromised by financial incentives, disease. Disease not �coercive� in moral sense.Voluntariness: not obviously compromised by financial incentives, disease. Disease not �coercive� in moral sense.

25. 25 Basic Elements of Research Consent nature of research, purpose, duration, procedures, what is experimental risks benefits to self & others alternatives implications for confidentiality research-related injury & compensation whom to contact consent is voluntary; freedom to withdraw 45 CFR 46

26. 26 The Therapeutic Misconception �the belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data for the purpose of contributing to scientific knowledge�. It is not a misconception to believe that participants probably will receive good clinical care during research. But it is a misconception to believe that the purpose of clinical trials is to administer treatment rather than to conduct research� Distinguish from therapeutic misestimationDistinguish from therapeutic misestimation

27. 27 Factors Associated WithImproved Understanding Patient-subject discussion in primary language higher education/SES younger age (geriatric patients at risk)

28. 28 Factors Associated WithImproved Understanding Consent process reading consent form carefully receiving template-based consent form having a 3rd party present at discussion having time to review consent form more detailed information (to a point) more readable forms intensive educational process

29. 29 Strategy For Soliciting Informed Consent Structured, planned approach Clarify how participation in the study differs from standard care Be honest about uncertainty Discuss how participation in trials serves a critical public good

30. 30 Example of a Structured Approach

31. Writing a Great Consent Form Use a template to structure your form Start w/ �We are inviting you to take part��� Avoid unqualified use of �treatment� to describe study interventions� Use a user-friendly, conversational style Format the consent form in a way that facilitates easy reading (See http://www.cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-docs/page2) 31

32. 32 Respect For Subjects Share new information Avoid conflicts of interest Maintain confidentiality Show gratitude for subjects� contributions Inform subjects of results

33. 33 A Few Words About Conflicts of Interest Definition: a COI occurs when �a professional judgment concerning a primary interest�tends to be unduly influenced by a secondary interest��

34. 34 Interests In Research Primary Valid, valuable science Including dissemination of research results Respect for & welfare of subjects Secondary Non-financial Promotions Publications Prestige Financial Research funding Income

35. 35 Potential ConsequencesOf Conflicts Of Interest Decreased communication of research findings, scientific openness Bias in research design conduct analysis reporting Increased risks to human subjects

36. 36 Question

37. 37 Guidelines Re: Conflict of Interest Avoid where possible Minimize or manage Disclose In industry-sponsored research, ensure contractual rights to data access, publication, etc.

38. 38 Summary Ethical guidance is needed to prevent exploitation of subjects in research 7 principles offer systematic approach to determining whether a study is ethical Balancing of principles when applied to particular trials can be complex Clarity about conflicts of interest can help investigators navigate this difficult issue

39. 39 Reflections On Case Purpose of study is to validate efficacy of sunitinib for imatinib-refractory GIST Not to �be helpful to the patient� Critical questions: Will participants be worse off inside than outside the study? Can alternate design provide valid answer? Does design minimize risk & maximize be-nefit, consistent w/ obtaining valid results?

40. Appendix

41. 41 Important Elements of Informed Consent Statement that the study involves research Statement that participation is voluntary Visual protocol schema Description of foreseeable risks Description of any benefits Disclosure of appropriate alternatives Explanation of whether compensation for injury is available Statement describing the degree to which identifiable records will be kept confidential Name of person to contact for answers to questions

42. 42 Additional Elements of Informed Consent May include information about Risks to the participant that are unanticipated Circumstances when participation may be terminated by the investigator Additional costs to the participant Consequences of the decision to withdraw Significant new finding and whether and/or when they will be shared with participants Approximate number of individuals in the study