August 14, 2012

Ethical Issues in Phase I Oncology Trials

Sandra L. Alfano, Pharm.D., CIPChair, Human Investigation Committee-I and III

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

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Ethical Foundations of Human Subjects Research

• Nuremberg Code (1949)• Declaration of Helsinki (1964, updated

2008)• Belmont Report (1979)

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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

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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

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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

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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

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Respect for Persons

• Individuals should be treated as an autonomous agent

• Those with diminished autonomy should be protected

• Voluntary participation

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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

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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?

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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)

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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

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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?

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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.)

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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

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How are the principles applied?

• Careful review of the consent form– Purpose– Research Procedures– Risks– Anticipated Benefits– Alternative Treatments– Voluntariness

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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.

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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

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Types of Phase I Oncology trials

• First in man translational trials• Traditional chemotherapeutic agents• Newer targeted agents• Combinations of agents (some with FDA

approval)

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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%

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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

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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

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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

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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

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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

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

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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

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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

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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

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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?

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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

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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

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Risks

• Death due to agent being tested (fatal toxicity)

• Grade 4 serious adverse events• Substantial time commitment (at end of

life)

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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

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

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

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

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

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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

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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

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