August 14, 2012

Ethical Issues in Phase I Oncology TrialsEthical Issues in Phase I Oncology Trials

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

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

August 14, 2012

ObjectivesObjectives

• 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

August 14, 2012

Ethical Foundations of Human Subjects ResearchEthical 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)

August 14, 2012

National Research ActNational 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

August 14, 2012

INSTITUTIONAL REVIEW BOARDINSTITUTIONAL 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

August 14, 2012

What governs/drives the IRB?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

August 14, 2012

Belmont Report Ethical PrinciplesBelmont 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

August 14, 2012

Respect for PersonsRespect 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

August 14, 2012

Respect for personsRespect 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

August 14, 2012

BeneficenceBeneficence

• 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?

August 14, 2012

BeneficenceBeneficence

• 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)

August 14, 2012

JusticeJustice

• 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

August 14, 2012

JusticeJustice

• 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?

August 14, 2012

Approval considerationsApproval 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.)

August 14, 2012

How are the principles applied?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

August 14, 2012

How are the principles applied?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

August 14, 2012

Terminology and Regulatory DefinitionsTerminology 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.

August 14, 2012

Phase I Clinical TrialsPhase 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

August 14, 2012

Types of Phase I Oncology trialsTypes 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)

August 14, 2012

Phase I Oncology trialsPhase 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%

August 14, 2012

Are Phase I Oncology trials inherently unethical?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

August 14, 2012

Therapeutic MisconceptionTherapeutic 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

August 14, 2012

Ethical Issue: Concerns over Informed ConsentEthical 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

August 14, 2012

Consent issuesConsent 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

August 14, 2012

Consent issuesConsent 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

August 14, 2012

Consent Issues: InformationConsent 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

August 14, 2012

Consent Issues: ComprehensionConsent 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

August 14, 2012

Consent Issues: VoluntarinessConsent 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

August 14, 2012

Consent issuesConsent 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

August 14, 2012

Ethical Issue: Concerns over Risk/Benefit analysisEthical 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?

August 14, 2012

Trends in Risks and Benefits in Phase I Oncology trialsTrends 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

August 14, 2012

Risks and Benefits of Phase I Oncology Trials, 1991-2002Risks 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

August 14, 2012

RisksRisks

• 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)

August 14, 2012

Types of BenefitsTypes 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

August 14, 2012

4 areas of decision-making process in Phase I oncology trials4 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

August 14, 2012

ResultsResults

• 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

August 14, 2012

Results cont’dResults 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

August 14, 2012

Rationality and decision-makingRationality 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

August 14, 2012

Options to eliminate misconceptionsOptions 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

August 14, 2012

ConclusionsConclusions

• 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

August 14, 2012

ReferencesReferences

• 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