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
• open-label access to drug at 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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Question
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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)
• added written protocol, independent review
• Belmont Report (1979)
• added justice, fair subject selection

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Key U.S. Regulatory Documents

• 45 Code of Federal Regulations 46 (45 CFR 46)
• Common Rule
• Subpart D Pediatric regulations
• 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

• Dual allegiance
• to study/community
• to patient/subject
• 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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Question
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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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Question
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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, amendments
• 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 as ongoing process, not one-time event

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Components Of Valid Consent

• Voluntariness
• Undermined by coercion, not by incentives,
  life-threatening disease
• Capacity
• Disclosure
• Undermined by deception, manipulation
• 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
• discussion in primary 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

1. Structured, planned approach
2. Clarify how participation in the study differs
   from standard care
3. Be honest about uncertainty
4. 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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Writing a Great Consent Form

• Use a template to structure your form
• Start w/ We are inviting you to take part 
• Avoid unqualified use of treatment to describe
  study interventions 
• Use a user-friendly, conversational style
• Format the consent form in a way that facilitates
  easy reading
• (See http//www.cancer.gov/clinicaltrials/understa
  nding/simplification-of-informed-consent-docs/page
  2)

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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

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,
  scientific openness
• Bias in research
• design
• conduct
• analysis
• reporting
• Increased risks to human subjects

Bekelman JE, JAMA 289454, 2003
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Question
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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
• Will participants be worse off inside than
  outside the study?
• Can alternate design provide valid answer?
• Does design minimize risk maximize be-nefit,
  consistent w/ 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)