What Makes Oncology Clinical Research Ethical

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What Makes OncologyClinical Research Ethical?

• Steven Joffe, MD, MPH
• Assistant Professor of Pediatrics

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Objectives

• Understand the ethical tensions in the
  investigator-subject relationship
• Learn a systematic approach to evaluating the
  ethics of oncology trials
• Understand how to improve the consent process for
  cancer clinical research
• Consider the challenges raised by con-flicts of
  interest in oncology research

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Case

• Patients with imatinib-refractory GIST
• Offered participation in RCT of sunitinib vs.
  placebo
• Trial includes open-label access to drug at time
  of progression
• two prestigious medical centers, MD Anderson U
  of Michiganrefused to join in

Mishra R. Placebos break taboo in cancer drug
tests. Boston Globe, A1, July 4, 2004
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Case (Contd)

• When patients have an advanced cancer the
  cancer is growing, there isnt any way the
  placebo can be helpful (to the patient). To
  argue that a placebo trial is in societys
  interests has nothing to do with helping these
  patients.
• Assoc. Director, U of Michigan Cancer Center
  (quoted in R. Mishra, Boston Globe, July 4, 2004)

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History Of Research Ethics

• Landmark events
• Nazi experiments
• Willowbrook hepatitis studies (1956-72)
• Jewish Chronic Disease Hospital studies (1963)
• Henry Beechers NEJM article (1966)
• Tuskegee Syphilis Study (1932-72)
• AIDS clinical trials (late 1980s)

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Codes Of Research Ethics

• Nuremberg Code (1947)
• informed consent, societal value, unacceptable
  levels of risk
• Declaration of Helsinki (orig. 1964)
• written protocol, independent review
• Belmont Report (1979)
• justice, fair subject selection

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Key Regulatory Documents

• 45 Code of Federal Regulations 46 (45 CFR 46)
• Common Rule
• 21 CFR 50 56 (FDA regulations)
• Privacy Rule under HIPAA (2003)

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Definition of Clinical Research

• research class of activities designed to
  develop or contribute to generalizable knowledge
• practice interventions designed solely to
  enhance the well being of an individual patient
  or client

Belmont Report, 1979
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The Clinician-Investigator

• Clinician-investigator has dual allegiance
• to study/community
• to patient/subject
• This creates a (legitimate) conflict of interest
• Important to be aware of this tension
• Miller et al. JAMA 2801449

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Example Of Conflict

• NSABP trials--1994
• PI at St. Luc Hospital in Montreal falsified
  procedure dates and hormone-receptor status so
  that breast cancer patients would appear to meet
  eligibility criteria for a clinical trial

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PI Response

• My sole concern at all times was the health of
  my patients. I firmly believed that a patient
  who was able to enter into an NSABP trial
  received the best therapy and follow-up
  treatment. For me, it was difficult to tell a
  woman with breast cancer that she was ineligible
  to receive the best available treatment because
  she did not meet 1 criteria out of 22

Poisson R. N Engl J Med3301460
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Criteria for Ethical Research

• Social value
• Scientific validity
• Fair subject selection
• Reasonable balance of risks benefits
• Independent review
• Informed consent
• Respect for enrolled subjects

Emanuel et al. JAMA 283 2701
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Social Value

• Study must ask an important question
• valuable for improving health and/or for basic
  scientific knowledge
• research is unethical if question is trivial, has
  already been answered, etc.

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Scientific Validity

• Even if question is important, study is unethical
  if methods arent likely to answer it
• not feasible
• poor measures
• inadequate sample size
• poor statistical analysis
• biased reporting (or non-reporting)

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Fair Subject Selection

• Historically, risky or non-beneficial research
  has disproportionately enrolled vulnerable
  populations
• ethnic minorities
• mentally incapacitated, institutionalized
• Conversely, exclusion of certain groups from
  research disenfranchises them from benefits of
  the knowledge gained

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Risk/Benefit Balance

• Benefits of a clinical trial must justify the
  risks
• sometimes, the risk/benefit ratio for the
  participant is clearly unfavorable
• e.g., research-related biopsies

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Risk/Benefit Balance

• Benefits of a clinical trial must justify the
  risks
• sometimes, the risk/benefit ratio for the
  participant is clearly unfavorable
• e.g., research-related biopsies

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Risk/Benefit Balance

• To approve a study, the IRB must find that
• risks to subjects are reasonable in relation to
  anticipated benefits, if any, to subjects, and
  the importance of the knowledge that may
  reasonably be expected to result

45 CFR 46.111(a)(2)
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Independent Review

• Institutional Review Boards (IRBs)
• independent review is mandated by federal
  regulation for most research with human subjects
• IRBs review studies at inception
• science, risk/benefit ratio, informed consent
• IRBs also monitor studies as they proceed
• continuing reviews at least annually
• reporting of adverse events, unanticipated
  problems

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Informed Consent

• Ensure respect for individuals values
  preferences in decisions about their medical care
  research participation
• respect for patient/subject autonomy
• View informed consent as ongoing process, not
  one-time event

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Components Of Valid Consent

• Voluntariness
• freedom from coercion
• Capacity
• Disclosure
• Understanding
• Decision

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Basic Elements of Research Consent

• nature of research, purpose, duration,
  procedures, what is experimental
• risks
• benefits to self others
• alternatives
• implications for confidentiality
• research-related injury compensation
• whom to contact
• consent is voluntary freedom to withdraw
• 45 CFR 46

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The Therapeutic Misconception

• the belief that the purpose of a clinical trial
  is to benefit the individual patient rather than
  to gather data for the purpose of contributing to
  scientific knowledge. It is not a misconception
  to believe that participants probably will
  receive good clinical care during research. But
  it is a misconception to believe that the purpose
  of clinical trials is to administer treatment
  rather than to conduct research

National Bioethics Advisory Commission Ethical
and Policy Issues in International Research 2001
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Factors Associated WithImproved Understanding

• Patient-subject
• English as first language
• higher education/SES
• younger age (geriatric patients at risk)

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Factors Associated WithImproved Understanding

• Consent process
• reading consent form carefully
• receiving template-based consent form
• having a 3rd party present at discussion
• having time to review consent form
• more detailed information (to a point)
• more readable forms
• intensive educational process

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Strategy For Soliciting Informed Consent

• Structured, planned approach
• Clarify how participation in the study differs
  from standard care
• Incremental differences
• Be honest about uncertainty
• Discuss how participation in trials serves a
  critical public good

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Example of a Structured Approach
Understand disease clinical status
Understand current treatment
Understand clinical trial
Pediatrics 119e849 (2007)
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Respect For Subjects

• Share new information
• Avoid conflicts of interest
• Maintain confidentiality
• Show gratitude for subjects contributions
• Inform subjects of results

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A Few Words About Conflicts of Interest

• Definition
• a COI occurs when a professional judgment
  concerning a primary interesttends to be unduly
  influenced by a secondary interest

Thompson D. NEJM 29573, 1993
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Interests In Research

• Primary
• Valid, valuable science
• Including dissemination of research results
• Respect for welfare of subjects

• Secondary
• Non-financial
• Promotions
• Publications
• Prestige
• Financial
• Research funding
• Income

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Potential ConsequencesOf Conflicts Of Interest

• Decreased communication of research findings
• Bias in research
• design
• conduct
• analysis
• reporting
• Increased risks to human subjects

Bekelman JE, JAMA 289454, 2003
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Guidelines Re Conflict of Interest

• Avoid where possible
• Minimize or manage
• Disclose
• In industry-sponsored research, ensure
  contractual rights to data access, publication,
  etc.

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Summary

• Ethical guidance is needed to prevent
  exploitation of subjects in research
• 7 principles offer systematic approach to
  determining whether a study is ethical
• Balancing of principles when applied to
  particular trials can be complex
• Clarity about conflicts of interest can help
  investigators navigate this difficult issue

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Reflections On Case

• Purpose of study is to validate efficacy of
  sunitinib for imatinib-refractory GIST
• Not to be helpful to the patient
• Critical questions
• Can alternate design provide valid answer?
• Does design best minimize risk maximize
  benefit, consistent with obtaining valid results?

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Appendix
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Important Elements of Informed Consent

• Statement that the study involves research
• Statement that participation is voluntary
• Visual protocol schema
• Description of foreseeable risks
• Description of any benefits
• Disclosure of appropriate alternatives
• Explanation of whether compensation for injury is
  available
• Statement describing the degree to which
  identifiable records will be kept confidential
• Name of person to contact for answers to
  questions

45CFR46.116(a)
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Additional Elements of Informed Consent

• May include information about
• Risks to the participant that are unanticipated
• Circumstances when participation may be
  terminated by the investigator
• Additional costs to the participant
• Consequences of the decision to withdraw
• Significant new finding and whether and/or when
  they will be shared with participants
• Approximate number of individuals in the study

45CFR46.116(b)