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