1. Clinical equipoise & the RCT dilemma
Gopal Sreenivasan
Crown Professor of Ethics
Duke University

2. summary
problem: RCT permissible?
standard solution: equipoise
example

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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?

9. 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

10. 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

11. equipoise appearance of conflict depends on the inference
not known not to be effective
therefore, not effective
but perhaps this is a mistake

12. 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

13. 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

14. 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

15. solution RCT permissible when
there is clinical equipoise regarding the two arms at the beginning of the trial
trial is designed to make it reasonable to expect that successful results will disturb this equipoise

16. 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

17. 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

18. example
consider 2003 study of letrozole after tamoxifen for breast cancer
result announced in PE Goss et alia, NEJM (2003) 349:

19. 2003 example
news items concerned fact that the study was interrupted mid-course
preliminary analysis confirmed significant benefit from experimental intervention

20. 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

21. but
study was stopped
after 2.4 years
primary aim of the study was therefore not realised
to study 5 year effect

22. 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

23. uh oh?
stopping decision ‘undeniably diminishes the clinical usefulness of the data’
Bryant and Wolmark
accompanying NEJM editorial

24. thank you