1. August 14, 2012 Ethical Issues in Phase I Oncology Trials Sandra L. Alfano, Pharm.D., CIP Chair, Human Investigation Committee-I and III Sandra L. Alfano, Pharm.D., CIP Chair, Human Investigation Committee-I and III

2. August 14, 2012 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 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. August 14, 2012 Ethical Foundations of Human Subjects Research Nuremberg Code (1949) Declaration of Helsinki (1964, updated 2008) Belmont Report (1979) Nuremberg Code (1949) Declaration of Helsinki (1964, updated 2008) Belmont Report (1979)

4. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 Respect for Persons Beneficence Justice Contains the ethical principles upon which the U.S. Federal regulations for protection of human subjects are based

8. August 14, 2012 Respect for Persons Individuals should be treated as an autonomous agent Those with diminished autonomy should be protected Voluntary participation Individuals should be treated as an autonomous agent Those with diminished autonomy should be protected Voluntary participation

9. August 14, 2012 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 –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. August 14, 2012 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? 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. August 14, 2012 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) 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. August 14, 2012 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 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. August 14, 2012 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? 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. August 14, 2012 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.) –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. August 14, 2012 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 Careful review of the protocol –Inclusion/Exclusion Criteria –DSMP and Stopping Rules –Risks/Benefits –Consent Process –In Case of Injury Section

16. August 14, 2012 How are the principles applied? Careful review of the consent form –Purpose –Research Procedures –Risks –Anticipated Benefits –Alternative Treatments –Voluntariness Careful review of the consent form –Purpose –Research Procedures –Risks –Anticipated Benefits –Alternative Treatments –Voluntariness

17. August 14, 2012 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. 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. August 14, 2012 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 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. August 14, 2012 Types of Phase I Oncology trials First in man translational trials Traditional chemotherapeutic agents Newer targeted agents Combinations of agents (some with FDA approval) First in man translational trials Traditional chemotherapeutic agents Newer targeted agents Combinations of agents (some with FDA approval)

20. August 14, 2012 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% 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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? 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 Risks Death due to agent being tested (fatal toxicity) Grade 4 serious adverse events Substantial time commitment (at end of life) Death due to agent being tested (fatal toxicity) Grade 4 serious adverse events Substantial time commitment (at end of life)

34. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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. August 14, 2012 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 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