Ethical Issues in Phase I Oncology Trials

1. Ethical Issues in Phase I Oncology Trials Sandra L. Alfano, Pharm.D., CIP Chair, Human Investigation Committee-I and III

2. Objectives • Understand the ethical foundations of human subjects research • Review the data derived from meta-analyses regarding response rates and toxicity from Phase I Oncology trials • Discuss special considerations in doing research with oncology patients, especially Phase I trials

3. Ethical Foundations of Human Subjects Research • Nuremberg Code (1949) • Declaration of Helsinki (1964, updated 2008) • Belmont Report (1979)

4. National Research Act • Enacted in 1974 • Established National Commission for Protection of Human Subjects of Biomedical and Behavioral Research • Belmont Report • Report of National Commission for the Protection of Human Subjects of Research • Established the IRB system for regulating research

5. INSTITUTIONAL REVIEW BOARD • Responsible for protecting the rights and welfare of human subjects participating in research studies • Ensure research is conducted in accordance with accepted ethical standards

6. What governs/drives the IRB? • Ethical Principles • Federal Law • Federal Agencies and Their Regulations, Directives, Policies, and Guidance (FDA, DHHS, OHRP) • Yale University Assurance to DHHS (FWA) • Connecticut (State) Law & Regulations • Good Clinical Practice (GCP) (ICH) • University and HIC Policy

7. Belmont Report Ethical Principles • Respect for Persons • Beneficence • Justice • Contains the ethical principles upon which the U.S. Federal regulations for protection of human subjects are based

8. Respect for Persons • Individuals should be treated as an autonomous agent • Those with diminished autonomy should be protected • Voluntary participation

9. Respect for persons • Subjects have the right to choose what will or will not happen to them (Autonomy) • Entails the concepts of informed consent and voluntariness • Those with diminished autonomy should be protected • Concept of vulnerable subjects • Vulnerability of a given population or person sometimes changes

10. Beneficence • Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being • Two general rules • Do not harm • Maximize possible benefits/minimize possible harms • Are the risks presented justified?

11. Beneficence • Initial analysis as part of approval of the proposed protocol • Ongoing monitoring of risks and benefits throughout the study (via data and safety monitoring plan)

12. Justice • The Belmont Report tells us, “An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly…” • Ethical Obligation: fair sharing of burdens and benefits • Requirement: Equitable selection of research subjects; fairness in inclusion and exclusion criteria

13. Justice • Does the research involve individuals who are unlikely to benefit from the results of the research? • Who is likely to benefit? What connection do they have to the research subjects?

14. Approval considerations • Risk:Benefit ratio reasonable? • Selection of subjects equitable? • Appropriate informed consent • Data collected adequately monitored • Adequate provisions to protect privacy and maintain confidentiality of data • Risks are minimized? • Additional safeguards for those who need it (children, prisoners, etc.)

15. How are the principles applied? • Careful review of the protocol • Inclusion/Exclusion Criteria • DSMP and Stopping Rules • Risks/Benefits • Consent Process • In Case of Injury Section

16. How are the principles applied? • Careful review of the consent form • Purpose • Research Procedures • Risks • Anticipated Benefits • Alternative Treatments • Voluntariness

17. Terminology and Regulatory Definitions • Phase I: Studies done in normal healthy volunteers or patients with disease, primarily to determine toxicity (safety). • Phase II: Controlled clinical trials designed to demonstrate efficacy and relative safety. Normally, these are performed on closely monitored patients of limited number. • Phase III: Expanded trials, performed after effectiveness has basically been established at least to a certain degree. Intended to gather additional evidence of effectiveness for specific indications, and more precise definition of drug-related adverse effects. • Phase IV: Post marketing studies.

18. Phase I Clinical Trials • Translate laboratory research into the clinic arena • Major objective is to characterize the agent’s toxicity profile • Determine a dose and schedule appropriate for Phase II testing • Traditional Phase I studies use healthy volunteers • Phase I Oncology trials use patients with cancer who have exhausted standard therapy

19. Types of Phase I Oncology trials • First in man translational trials • Traditional chemotherapeutic agents • Newer targeted agents • Combinations of agents (some with FDA approval)

20. Phase I Oncology trials • Early work in the development of new agents • Designed to characterize toxicity • Little to no benefit to participants • Unknown risks, often felt to therefore be potentially high risk • Older data estimates response rate about 1.5-5% and death rate 0.5%

21. Are Phase I Oncology trials inherently unethical? • Relatively low clinical benefit • Small but definite risk of death • Serious but unquantified adverse effects • Substantial time commitment from patients (at end of life) • Informed consent given under the cloud of the therapeutic misconception

22. Therapeutic Misconception • Misconception that participating in research is the same as receiving individualized treatment from a physician • Research subjects fail to appreciate that the aim of research is to obtain scientific knowledge, and that any benefit that accrues is a by-product of the research

23. Ethical Issue: Concerns over Informed Consent • The question is, if a cancer patient really knew/understood what phase I trials are all about, how could anyone really agree to participate in a Phase I Oncology trial? • Concerns with deficient disclosure, exaggeration of benefits, and minimization of risks • Little empirical data on these issues • Beware of the therapeutic misconception

24. Consent issues • Patients hope for stabilization, improvement or even cure. Either are not given accurate information, or fail to understand the information they are provided • Most patients have deficient understanding of the objectives of Phase I research • Being vulnerable subjects, thinking may be clouded, and some say unable to make their own decisions

25. Consent issues • Informed consent is not only a document. • It is a process: a dialogue between the researcher and the subject. Information exchange needs to take place before, during, and sometimes after the study. • Involves information, comprehension, and voluntariness

26. Consent Issues: Information • Purpose of the research • Research procedures/expectations explained • Known (and unknown) risks explained with possible ramifications • Economic considerations (impact on individual) • Benefits stated reasonably in relation to phase of protocol • Alternatives noted to inform decision

27. Consent Issues: Comprehension • The manner and context in which information is conveyed are as important as the information itself • Organized presentation of the material • Providing sufficient time to ask questions and to consider participation • Investigator getting consent must assure comprehension • Decision-making capacity must be assessed

28. Consent Issues: Voluntariness • Begin with an invitation to participate • Free of coercion (overt threat of harm) • Free of undue influence (offer or promise of excessive or improper reward) • Participant is free to decline or to withdraw at any time without repercussions

29. Consent issues Be sure that: • Informed consent process is not misleading. • Benefit is not overstated • Risk/Benefit ratio is carefully considered • These factors are especially important in Phase I oncology trials

30. Ethical Issue: Concerns over Risk/Benefit analysis • Is there risk? Yes, but hopefully minimized. Also, with newer agents, and better supportive care, risk levels may be less than historically reported • Is there benefit? Maybe, but minimal due to study design • What standard is used to calculate? • Who gets to decide?

31. Trends in Risks and Benefits in Phase I Oncology trials • ASCO data from 1991-2002 • 243 objective responses among 6474 patients (3.8% response rate) • 137 deaths from any cause, 35 of which were classified as fatal toxicity (0.54%) • 670 non-fatal serious grade 3 or 4 toxic events (overall serious toxicity rate of 10.3%) Roberts et al: JAMA 2004;292:2130-2140

32. Risks and Benefits of Phase I Oncology Trials, 1991-2002 • 10.6% response rate (7.5% partial, 3.1% complete), while 34.1% had stable disease or less-than-partial response (NOTE: better response than previously reported) • 58/11935 deaths (0.49%) at least possibly related, but 18 definitely related and 7 probably related (0.21% fatal toxicity) • 14.3% had grade 4 toxic effects in a subset of studies, but overall, 5251 grade 4 toxic effects were reported in 11935 participants (no rate reported) • Horstmann et al: NEJM 2005;352:895-904

33. Risks • Death due to agent being tested (fatal toxicity) • Grade 4 serious adverse events • Substantial time commitment (at end of life)

34. Types of Benefits • Direct benefit: direct physiologic effect from the intervention • Collateral (indirect) benefit: “inclusional’ benefit from participating in the research • Aspirational benefit: benefit to society and future patients from results of the study • Response rates only measure direct benefit Glannon J Med Ethics 2006:32:252-5

35. 4 areas of decision-making process in Phase I oncology trials • How subjects perceive their options and alternatives • What pressures they feel • How they understand the purpose and risks • How they assess benefits Agrawal: JCO 2006; 24:4479-4484

36. Results • 163 interviewed • Well aware of alternatives but largely did not consider them • Did not feel a lot of pressure to participate from researchers or family, but 75% felt pressure because their cancer was growing • Purpose to kill cancer cells was most important Agrawal: JCO 2006; 24:4479-4484

37. Results cont’d • Even 10% chance of death would not dissuade participation • “Therapeutic optimists”: hoped to benefit although they recognized others would not • “This is not the picture of inexperienced, uninformed, and vulnerable phase I oncology patients commonly portrayed.” Agrawal: JCO 2006; 24:4479-4484

38. Rationality and decision-making • Therapeutic Misconception: A belief in a direct benefit without much, if any, consideration of risk Versus • Rational therapeutic optimism: weighing low probable benefit against risk when one is facing death

39. Options to eliminate misconceptions • Be explicit in consent that study is not designed to benefit the subject • Pay subjects for participating in Phase I trials, to send the message that they are participating for the sake of science and should be compensated for it

40. Conclusions • Not all Phase I oncology trials are alike in design or response rates • Ethical concerns include realistic estimates of risks and benefits, and the need for truly informed consent • Arguments are made that autonomous individuals should be allowed to make their own decisions • Vulnerability and capacity to consent must be considered

41. References • Glannon, W: J Med Ethics 2006;32:252-5 • Agrawal M and Emanuel, EJ: JAMA 2003; 290:1075-1082 • Roberts et al: JAMA 2004;292:2130-2140 • Horstmann et al: NEJM 2005;352:895-904 • Agrawal M et al: J Clin Onc 2006; 24:4479-4484