Clinical equipoise and RCT design

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Clinical equipoise and RCT design

• Charles Weijer, MD, PhD

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The question

• Upon what ethical grounds may the physician
  offer RCT enrollment to a patient?
• at least two answers to this question
• uncertainty principle
• clinical equipoise
• which is the preferred moral basis of the RCT?

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Physician-patient relationship

• Fiduciary relationship
• when the physician becomes an investigator other
  ends come into play
• Hellman and Hellman (1991) Consider first the
  initial formulation of a trialA new agent that
  promises more effectiveness is the subject of
  study. The control group must be given either an
  unsatisfactory treatment or a placebo. Even
  though the therapeutic value of the new agent is
  unproved, if physicians think it has promise, are
  they acting in the best interests of their
  patients in allowing them to be randomly assigned
  to the control group?

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The uncertainty principle

• Peto et al. (1976) Physicians who are convinced
  that one treatment is better than another for a
  particular patient of theirs cannot ethically
  choose at random which treatment to give they
  must do what they think best for the particular
  patient. For this reason, physicians who feel
  they already know the answer cannot enter their
  patients into a trial. If they think, whether for
  a wise or silly reason, that they know the answer
  before the trial starts, they should not enter
  any patients

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Problems

• Can a physician ever be said to have erred?
• So long as she maintains she was uncertain she
  cannot be said to have made an enrollment error
  -- a problem
• Peto (1998) qualification of uncertainty with
  substantially and reasonably
• As the moral locus is the individual clinician,
  we are left with the same problem.

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Clinical equipoise

• Freedman (1987) the ethics of medical
  practice grants no ethical or normative meaning
  to a treatment preference, however powerful, that
  is based on a hunch or anything less than
  evidence publicly presented and convincing to the
  clinical community. Persons are licensed as
  physicians after they demonstrate the acquisition
  of this professionally validated knowledge, not
  after they reveal a superior capacity for
  guessing.

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Clinical equipoise

• Physician norms are not individual but derive
  from the community of practitioners
• treatments within a RCT may be consistent with
  the standard of care owed the patient
• Offering RCT enrollment is consistent with MDs
  duty when there existsan honest professional
  disagreement among expert clinicians about the
  preferred treatment.

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The preferred moral basis

• Equipoise arises
• evidence accrues as to the benefit of a new drug
• split in practice in the clinical community
• Freedman (1987) A state of clinical equipoise
  is consistent with a decided treatment preference
  on the part of the investigators. They must
  simply recognize that their less favored
  treatment is preferred by colleagues whom they
  consider to be responsible and competent.
• clinical equipoise is the preferred moral basis
  for the RCT

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Clinical equipoise -- part II

• Freedman (1987) the trial must be designed in
  such a way as to make it reasonable to expect
  that, if it is successfully completed, clinical
  equipoise will be disturbed. In other words, the
  results of a successful trial should be
  convincing enough to resolve the dispute among
  clinicians.
• ethical preconditions of clinical research are
  framed as an issue in medical epistemology
• what constitutes good treatment is defined by
  practice accepted by the community of expert
  clinicians

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New area for moral inquiry

• Ethicists have labored long at the fringes of
  science (informed consent limiting scope)
• clinical equipoise implies that aspects of RCT
  design are matters of ethical concern
• Who will be tested? What will be tested? How many
  will be tested? When will the study be complete?
• ethicists must now engage scientists in a
  dialogue as to the nature of good science

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Who will be tested?
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Who will be tested?
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Who will be tested?

• Explanatory RCT narrow study popn
• Freedman (1987) This approach purchases
  scientific manageability at the expense of an
  inability to apply the results to the messy
  conditions of clinical practiceOverly
  explanatory trials, designed to resolve some
  theoretical question, fail to satisfy the second
  requirement of clinical research, since the
  special conditions of the trial will render it
  useless for influencing clinical decisions even
  if it is successfully completed.
• clinical equipoise requires that research
  subjects be representative of those in the target
  clinical population

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What will be tested?

• Rothman (1994) The continuing unethical use of
  placebo controls.
• Regarded by FDA as the gold standard
• clinical equipoise requires honest, professional
  disagreement as to the preferred treatment
• 1st generation treatments placebo control
• 2nd generation treatments active control

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What will be tested?

• Freedman (1990) lists five conditions in which a
  placebo control may be used
• there is no standard treatment
• standard treatment is no better than placebo
• standard treatment is placebo
• the net therapeutic advantage of standard
  treatment has been called into question by new
  evidence or
• effective treatment exists but is not available
  due to cost or short supply (additional caveats
  apply).

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What will be tested?

• Informed consent and risk-benefit ratio are
  separate requirements of U.S. regulations
• Levine (1985) placebo in other contexts would be
  a non-therapeutic risk
• IRB must ensure risks are minimized (i) by
  using procedures which are consistent with sound
  research design and which do not unnecessarily
  expose subjects to risk.

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What will be tested?

• 1. the incentives are wrong
• 2. no agreed upon test for statistical
  significance
• 3. historical control assumption
• 4. assay sensitivity
• each of these propositions has been challenged
  (Freedman, 1996 Weijer 1999)

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How many will be tested?

• Protocol section examined least by IRBs
• too large subjects will be exposed
  unnecessarily to risk
• too small unlikely to answer question
• deeper questions...

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How many will be tested?

• Scrutinize components of sample size too
• type I error probability of rejecting the null
  hypothesis when in fact Ho is true
• equipoise would have us examine the choice
  relative to the circumstances
• less conservative may be appropriate for RCT of
  novel treatments for rare disease

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How many will be tested?

• Type II error probability of failing to reject
  Ho when in fact Ha is true power 1- prob (type
  II error) typically less conservative
• repeatedly shown that negative RCTs are often
  under-powered violates equipoise
• a robust RCT (power 90 or 95) would be likely
  to disturb equipoise even if the RCT result was
  negative

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When will the study be complete?

• RCTs with mortality or serious morbidity as an
  outcome should have a DSMB
• researcher, clinician, biostatistician, ethicist,
  community
• RCT may be stopped early if needed

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When will the study be complete?

• DSMBs employ statistical stopping guides
• prevent inflation of overall type I error
• more stringent boundaries are set early in RCT
• Other crucial questions
• How skeptical are clinicians? What is the quality
  of the data? How much data is in the pipeline?
  Do other published result shed light on the
  question?
• Pocock (1993) inevitable sacrifice of
  individual ethics for collective ethics

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When will the study be complete?

• Clinical equipoise implies that treatments in RCT
  are consistent with standard of care individual
  ethics are not compromised
• the RCT ought to be stopped when moral conditions
  for its initiation no longer obtain
• RCT ought to continue until sufficient evidence
  has been gathered to resolve the dispute among
  clinicians.

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Conclusion

• Clinical equipoise is the preferred moral basis
  of the RCT
• Important implications for RCT design
• new moral terrain
• new relationship between scientists and ethicists

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Further reading

• Freedman B. Equipoise and the ethics of clinical
  research. New England Journal of Medicine 1987
  317 141-145.
• Freedman B, Shapiro S. Ethics and statistics in
  clinical research towards a more comprehensive
  examination. Journal of Statistical Planning and
  Inference 1994 42 223-240.
• Fuks A, Weijer C, Freedman B, et al.. A study in
  contrasts eligibility criteria in a twenty-year
  sample of NSABP and POG clinical trials. Journal
  of Clinical Epidemiology 1998 51 69-79.
• Shapiro S, Weijer C, Freedman B. Reporting who
  was studied in clinical trials -- Is there static
  on the line? Journal of Clinical Epidemiology,
  forthcoming.
• Weijer C, Crouch RA. Why should we include women
  and minorities in randomized controlled trials?
  Journal of Clinical Ethics 1999 10 100-106.

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Further reading

• Freedman B. Placebo-controlled trials and the
  logic of clinical purpose. IRB A Review of Human
  Subjects Research 1990 12(6) 1-6.
• Freedman B, Weijer C, Glass KC. Placebo orthodoxy
  in clinical research I empirical and
  methodological myths. Journal of Law, Medicine
  and Ethics 1996 24 243-251.
• Freedman B, Glass KC, Weijer C. Placebo
  orthodoxy in clinical research II ethical,
  legal, and regulatory myths. Journal of Law,
  Medicine and Ethics 1996 24 252-259.
• Weijer C. Placebo-controlled trials in
  schizophrenia Are they ethical? Are they
  necessary? Schizophrenia Research 1999 35
  211-218.
• Weijer C. Thinking clearly about research risk
  implications of the work of Benjamin Freedman.
  IRB A Review of Human Subjects Research 1999
  21(6) 1-5.