Ethical Dilemmas in Clinical Research: Resolving Clinical Uncertainty

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Ethical Dilemmas in Clinical Research Resolving
Clinical Uncertainty

• M. Sara Rosenthal, Ph.D.
• Director, Program for Bioethics and Patients
  Rights
• Co-Chair, Hospital Ethics Committee
• www.ukhealthcare.uky.edu/bioethics

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Ethical Principles of the Belmont Report (1979)

• Respect for Persons Disclosure, informed
  consent, confidentiality
• Beneficence Risks of research do not outweigh
  potential benefits
• Justice Burdens and benefits of research be
  evenly distributed among populations

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What Leads to Belmont?

• Post WWII
• 1947 The Nuremberg Code -- in response to Nazi
  medical research atrocities conducted. Largely
  ignored by U.S. scientists. The first sentence
  The voluntary consent of the human subject is
  absolutely essential makes it clear that it is
  NEVER okay to experiment on children.
• 1930-1970 Tuskegee Syphilis Study (400 Black
  males w/syphilis followed and not treated
  routine spinal taps masked as treatment.)
• 1951 The U.S. Department of Defence (DOD) adopts
  a formal set of rules based on Nuremberg Code.
  Called the Pentagon policy, created by the Armed
  Forces Medical Policy Council (AFMPC). Not taken
  seriously within the military its existence was
  uncovered in 1994, by the Advisory Committee.

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Research Ethics in the 1960s

• 1960s Willowbrook (fed live hep A virus to
  mentally diasabled patients) Jewish Chronic
  Disease Hospital cancer cell study (injected live
  cancer cells into subjects).
• 1964 The Declaration of Helsinki (World Medical
  Association)
• 1966 Henry Beechers article in NEJM New
  Guidelines by the PHS, and the creation of
  International Review Boards (IRBs)

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Research Ethics in the Watergate Era

• 1972 Three U.S. court informed consent
  landmarks
• Canterbury v. Spence
• Cobbs v. Grant
• Wilkinson V. Vesy
• From Canterbury The patients right of
  self-decision can be effectively exercised only
  if the patient possesses enough information to
  enable an intelligent choice. The patient should
  make his own determination on treatment. Informed
  consent is a basic social policy...

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Research Ethics in the Ford Era

• 1974 Regulations created by the Dept. of Health,
  Edu.,and Welfare (DHEW), which later became the
  Dept. of Health Human Services (DHHS).
• 1975 National Commission for the Protection of
  Human Subjects of Biomedial and Behavioral
  Research (made up of NIH PHS and HHS) is set up.

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Research Ethics in the Carter Era

• 1979 National Commission publishes The Belmont
  Report, famous for its 3 basic ethical
  principles Respect for Persons (NOT
  autonomy) beneficence ( which means do not
  harm maximize possible benefits minimize
  possible harm) and Justice (fairness in
  distribution).

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4 Core Ethical Principles

• Respect for Persons Informed consent
  confidentiality
• Beneficence Improve wellbeing while doing no
  harm (weighing risks versus benefits of research)
• Non-Malificence Dont inflict harm and dont
  refuse aid (are trials beginning in
  equipoise/uncertainty?)
• Justice Fairly distribute the burdens and
  benefits of research

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What Is Informed Consent?

• Disclosure
• Capacity and CompetencyUnderstand and
  appreciate
• Voluntariness

• Elderly or Minors
• Neurologically impaired
• Dementia
• Depression
• Anxiety
• Language and literacy
• Coercion

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Nonmalificence

• A duty not to harm or inflict evil on a
  patient/participant Pharmacovigilance
• A duty to intervene to prevent imminent harm to
  patient or at-risk third party. Example A duty
  to discontinue a trial?

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Duty to Warn

• Legal precedents
• Tarasoff
• Pate v. Threlkel
• Pharmacovigilance A duty to warn of known
  risks
• Thalidomide
• DES
• Dalkon Shield
• Fen/Phen
• Vioxx

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Justice

• Distributing more fairly the burdens and benefits
  of research
• Treating all patients/participants equally

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Vulnerable Populations

• Less capacity to consent
• Less access to healthcare
• More gullible and trusting
• Not well-represented in clinical or market
  studies women, minorities, children

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When is it ethical to enroll a patient into an
RCT?

• When there is genuine uncertainty (Fried, 1974)
• Frieds Equipoise The INDIVIDUAL
  investigator/physician decides uncertainty
• The Uncertainty Principle (Peto, 1976 Br J
  Cancer) -- widely used outside U.S.

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Reframing of Fried and Peto (1987)

• Clinical Equipoise
• Uncertainty in the clinical COMMUNITY over
  whether Treatment A is better than Treatment B
• Investigator bias and hunches do not disturb
  clinical equipoise
• Clinical trial goal resolve dispute in clinical
  community

• Theoretical Equipoise
• Genuine uncertainty over whether Treatment A is
  better than Treatment B in Patient Population
• Easily disturbed by investigator bias or hunches
• balancing on a knifes edge
• Unethical to continue research once disturbed

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Clinical EquipoiseA Community Uncertainty

• Sets out a standard of social approval of
  research by IRBs
• Shifts moral locus from individual PI to members
  of the relevant, expert, clinical community

• Progress relies on consensus within medical and
  research communities
• Community of expert practitioners decide whether
  there is genuine uncertainty, expressed by
  honest, professional disagreement.

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The work of Benjamin Freedman (1951-1997)

• Freedman. Equipoise and The Ethics of Clinical
  Research. NEJM 1987317141-45.
• Completely reframed clinical trials and
  investigator responsibilities
• Landmark research ethics article, generating
  entire body of literature

• Freedmans Legacy
• Reframing issues related to consent valid
  versus ignorant consent
• Reframing Ramsey/ McCormack debate regarding NT
  research in children
• Coining clinical equipoise

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Clinical Trials Do We Start in Equipoise?

• An investigator has a hunch that Treatment A is
  superior to Treatment B but there is no evidence
  yet to support her hunch.

• Do all populations respond to a treatment in the
  same way?
• Pharmagogenetics
• International study sites

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International Research and Equipoise

• Example Placebo-controlled trial of short-course
  of AZT for women in Uganda (AIDS clinical trial
  group 076 protocol)
• Ugandan women are randomized to nothing or
  treatment we already know is effective and better
  

• M. Angell (NEJM, 1997) When effective treatment
  exists, a placebo may not be used
• Must use best KNOWN treatment for control group

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International Research and Equipoise

• Are treatment contexts similar?
• Equipoise may exist when we change the treatment
  population in significant ways (London, 2001)
• Are U.S. and Uganda the same treatment contexts?
• Is nothing the prevailing standard of care?

• Are there significant physiological differences
  that would change responses to AZT? (E.g. anemia)
• Malnourished women versus well-nourished women
• No access to healthcare at all versus wide access
  to healthcare

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Rural Populations and Equipoise

• Are treatment contexts similar?
• Equipoise may exist when we change the treatment
  population in significant ways (London, 2001)
• Is Eastern KY the same treatment context as NYC?

• Are there significant physiological differences
  that would change responses treatments in urban
  versus rural pops?

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Conclusions about Equipoise

• Equipoise is the moral underpinning of enrolling
  participants in clinical trials
• Moral locus of uncertainty should probably reside
  with relevant experts within the clinical
  community
• Individual uncertainty (FE or Peto) cannot be
  disturbed by biases, hunches, etc.
• Individual uncertainty must at the minimum rely
  on some evidentiary standard to be disturbed

• Moral distress over individual uncertainty can be
  created if clinical equipoise is not the standard
• New interpretations of FE, Peto and Freedman are
  still reframing equipoise (Weijer, London).