Transcript Clinical equipoise and RCT design

Clinical equipoise and RCT
design
Charles Weijer, MD, PhD
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?
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 trial…A 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?”
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…”
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.
Clinical equipoise
• Freedman (1987): “[t]he 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.”
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
MD’s duty when “[t]here exists…an honest
professional disagreement among expert
clinicians about the preferred treatment.”
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
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
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
Who will be tested?
Who will be tested?
Who will be tested?
• Explanatory RCT: narrow study pop’n
• Freedman (1987): :This approach purchases scientific manageability at
the expense of an inability to apply the results to the ‘messy’
conditions of clinical practice…Overly [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
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
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).
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.”
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)
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...
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
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”
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
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”
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.”
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
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.
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.