Ethical Issues in Phase I
Oncology Trials
Sandra L. Alfano, Pharm.D., CIP
Chair, Human Investigation
Committee-I and III
August 14, 2012
Objectives
• Understand the ethical foundations of
human subjects research
• Review the data derived from metaanalyses 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
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
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 wellbeing
• Two general rules
– Do not harm
– Maximize possible
benefits/minimize possible harms
• Are the risks presented justified?
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)
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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
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?
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.)
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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 drugrelated adverse effects.
• Phase IV: Post marketing studies.
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
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)
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%
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
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
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
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
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
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
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
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
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
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?
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
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
August 14, 2012
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
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
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
August 14, 2012
References
• Glannon, W: J Med Ethics 2006;32:2525
• Agrawal M and Emanuel, EJ: JAMA 2003;
290:1075-1082
• Roberts et al: JAMA 2004;292:21302140
• Horstmann et al: NEJM 2005;352:895904
• Agrawal M et al: J Clin Onc 2006;
24:4479-4484
August 14, 2012