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Clinical equipoise& the RCT dilemma
Gopal Sreenivasan
Crown Professor of Ethics
Duke University
summary
i. problem: RCT permissible?
ii. standard solution: equipoise
iii. example
clinical trials• is it permissible to do medical
research with human beings?• isn’t medical research
basically just better, fancier clinical care?
– no, they are fundamentally different
research vs. clinical care
• they have fundamentally different aims
– medical research: to produce generalisable medical knowledge
– clinical care: to secure the best (health) interests of the patient
research vs. clinical care
• their different aims appear to be in conflict, i.e.
– aims of clinical research appear inconsistent with the best health interests of the individual
– moreover, this is inherent in the nature of medical research
apparent conflict
best seen as between investigator’s scientific duty
to produce valid general knowledge
investigator’s clinical duty to advance best health interests
of individual subject
apparent conflict
arises because RCT enrolment seems inconsistent with subject’s best health interests because of presumed inferiority
of unproven experimental arm which ‘half’ the subjects will get
how to resolve?
• which obligation should prevail in this conflict?
– isn’t it obviously the obligation of the person as physician?• are not the interests of the
individual sacrosanct?
how to resolve?
• should not the obligation of the person as physician prevail?
– if the conflict is inherent in the nature of medical research, this entails not doing any research
– but medical practice depends on (past) research
conundrum?
• indeed, the physician’s own obligation later
– to provide the best care to patients (in the future)
• depends on research now– conflict is between present and
future patients
equipoise• appearance of conflict
depends on the inference– not known not to be effective– therefore, not effective
• but perhaps this is a mistake
equipoise• ‘equipoise’ exists between two
treatments, A and B, when– there is ‘a state of genuine
uncertainty regarding the comparative merits’ of A and B• Benjamin Freedman
equipoise• if the investigator is in a state of
equipoise between the experimental arm and the control arm of an RCT
– then she does not violate her obligation as physician
– for she does not knowingly offer inferior treatment to the subject
clinical equipoise
requires existence of honest professional disagreement in expert community about which of trial’s two arms is clinically
superior [assuming that ] one ≈ standard of care
solution• RCT permissible when
i. there is clinical equipoise regarding the two arms at the beginning of the trial
ii. trial is designed to make it reasonable to expect that successful results will disturb this equipoise
solution• if investigator has a preference,
why does this not violate her obligation as physician?
– because the standards of professional responsibility are social in nature
• Freedman’s official answer
solution• but plausibility of this also
implicitly relies on fact that medical community has a high(er) standard of evidence
– indeed, a ‘gold’ standard: RCT!• that is why clinical equipoise is
robust: disturbed only by RCT
example• consider 2003 study of
letrozole after tamoxifen for breast cancer
– result announced in PE Goss et alia, NEJM (2003) 349: 1793-1802.
2003 example• news items concerned fact
that the study was interrupted mid-course
– preliminary analysis confirmed significant benefit from experimental intervention
yay!• to wit, a 43 percent reduction
in risk of a recurrence or of new contralateral breast cancer
• study was stopped and placebo group was allowed to cross-over
but• study was stopped
– after 2.4 years• primary aim of the study was
therefore not realised– to study 5 year effect
oh• therefore cannot document
– a ‘survival’ advantage• defined in terms of 5 years
– recommendation for 5 (or indeed > 2.4) year treatment• data do not support
uh oh?• stopping decision ‘undeniably
diminishes the clinical usefulness of the data’
– Bryant and Wolmark• accompanying NEJM editorial
thank you