van-der-graaf

Dr Rieke van der Graaf
Prof dr Hans van Delden
Julius Center, Dpt Medical Humanities
UMC Utrecht, Netherlands
WMA Satellite Meeting during the 11th World Congress of
Bioethics, 26 June 2012
On the necessity of embedding clinical equipoise
in the Declaration of Helsinki
Outline
• Equipoise paradox
• What is equipoise?
• Perceived problems
• Answers
• Moral status
• Why embed equipoise?
• Conclusions
Equipoise paradox
• Many regard it as a fundamental ethical concept of
human subjects research
• Ethicists are criticial & not embedded in guidelines
Claim presentation:
• Time to focus on merits > weaknesses of the concept
• Sufficient reason to incorporate the concept in main
ethical guidelines
Outline
• Equipoise paradox
• What is equipoise?
• Perceived problems
• Answers
• Moral status
• Why embed equipoise?
• Conclusions
What is clinical equipoise?
Freedman 1987
genuine uncertainty in the expert medical community
about the preferred treatment
3 elements definition
1. Expert medical community
2. Preferred treatment
3. Genuine uncertainty
1. Expert medical community
• Uncertainty not in the mind of a single investigator,
but in broader community of clinical experts
2. Preferred treatment
Standard drug (S)
2. Preferred treatment
Standard drug (S) Experimental drug (E)
2. If S is superior to E…
Standard drug (S)
…participants have to be
provided with S
“Must be offered best
treatment known”
(Freedman)
3. Genuine uncertainty
• Equipoise not only grounded in therapeutic
obligation, but also in scientific duties
– Epistemic reasons to conduct a controlled trial
– Focus trials on solving questions that may
influence clinical decisions > theoretical questions
Outline
• Equipoise paradox
• What is equipoise?
• Perceived problems
• Answers
• Moral status
• Why embed equipoise?
• Conclusions
Perceived problems
• Expert community:
– Who are the members?
– How many?
– Patient should be in equipoise
• Preferred treatment
– May rule out many placebo-controlled trials
– Impossible to always offer best proven care
– Patients may still be harmed
• Genuine uncertainty
– What does it mean?
– When is it disturbed?
Equipoise controversy
• “Rehabilitate the concept” (PB Miller/Weijer 2003)
• “Not yet time to give up on equipoise” (Ashcroft 2004)
• “Equipoise is fundamentally flawed” (F Miller/Joffe
2011)
• “Equipoise is bankrupt, pull the plug” (Gifford 2007)
• “Equipoise is a muddy concept, beyond rehabilitation”
(Menikoff 2003)
Proposals of opponents: alternatives
• Alternative conceptions that can justify why we allow
compromises to individual interests patients
• Problems of alternatives:
– Conceive equipoise as overarching justification of
human subjects research
– opponents of the concept ‘resolve the ethical
problems of equipoise by abandoning the need for
equipoise’ (Freedman 1987)
Outline
• Equipoise paradox
• What is equipoise?
• Perceived problems
• Answers
• Moral status
• Why embed equipoise?
• Conclusions
1. Expert medical community
• Distinguish between
– those who are uncertain (virtual community of
experts)
– those who have to determine whether experts are
uncertain
• IRB, researchers, sponsors (also experts!)
• Physicians and patients may have own treatment
preferences ≠ clinical equipoise
2. Preferred treatment
• Extensive debate whether clinicians have therapeutic
duties as researchers
• Even proponents of the concept: unnecessary to
always offer the “best possible care”
• Focus on what cannot reasonably be withheld > what
should be provided
3. Genuine uncertainty: semantics
• Semantics of equipoise creates confusion over the
concept
• Alex London (2007):
– Distinguish between ‘agnosticism’ (don’t know)
and ‘conflict’
3. Genuine uncertainty: don’t know
•Safe?
•Effective?
•Efficacious?
•No balance in this
situation
E
3. Genuine uncertainty: conflict
•Both E and S standard
drugs for given condition
•Some experts favor E,
others favor S
E
S
3. Genuine uncertainty: conflict
• In the case of a conflict
experts are seldom
“equally poised”
3. Genuine uncertainty: conflict
• More experts favor E>S
• Researchers/IRBs
determine whether
experts are in equipoise
ES
3. Genuine uncertainty: conflict
• Irrelevant how many
• Strength of the
evidence matters
ES
Equipoise vs balance of trial arms
ES S E
Disturbance trial arms ≠ disturbance
equipoise
ES S E
Disturbance trial arms ≠ disturbance
equipoise
ES S E
3. Genuine uncertainty: disturbance
• Freedman: trial must be
designed to disturb
clinical equipoise
• Unrealistic: often many
RCTs, meta-analyses
ES
Outline
• Equipoise paradox
• What is equipoise?
• Perceived problems
• Answers
• Moral status
• Why embed equipoise?
• Conclusions
What does clinical equipoise require?
• Expert medical community should be in a state of
genuine agnosticism or conflict about the net
preferred medically established procedure for the
condition under study
• Those who consider initiating or continuing an RCT
1. Is there sufficient disagreement, or absence of
agreement among experts? (scientific component)
2. Can standard of care reasonably be withheld all-
things-considered (“therapeutic” component)
Moral status of equipoise
• Fundamental > foundational concept of research
ethics
• Prima facie obligation
• Deduced from scientific validity/social value and
favorable risk-benefit
– Adds substance to these norms
• Not a specific rule that determines comparator
• Threshold requirement
If equipoise cannot be met…
• …trial not necessarily unethical, but
• Burden of proof on researchers/IRBs to explicate
– Why it is necessary to conduct RCT (and not
observational study e.g.)
– Whether the control group can reasonably be
withheld the standard of care
Outline
• Equipoise paradox
• What is equipoise?
• Perceived problems
• Answers
• Moral status?
• Why embed
equipoise?
• Conclusions
§32 Declaration of Helsinki
• “The benefits, risks, burdens and effectiveness of a
new intervention must be tested against those of the
best current proven intervention”
• Applied rule focusing on testing of new interventions
and on precise comparator
• Needs further grounding: why provide best proven
care and when is it allowed to conduct controlled
studies?
Conclusions
• Weaknesses ≠ equipoise is flawed
• If we give up on equipoise we may lose a
requirement that explicitly asks for:
– scientific justifications of controlled trials
– taking professional standards into account when
considering these trials
• In order to protect the merits of equipoise and hence
the interests of patient-subjects clinical equipoise
should be incorporated in the Declaration
Some references
• Pictures: Istockphoto
• Ashcroft R. Equipoise, knowledge and ethics in clinical research in clinical research and
practice. Bioethics 1999;13:314-326.
• Freedman B. Equipoise and the ethics of clinical research. NEJM 1987;317(3):141-145.
• Gifford F. Pulling the plug on clinical equipoise: a critique of Miller and Weijer. Kennedy Inst
Ethics J 2007;17:203-226.
• London AJ. Clinical equipoise foundational requirement or fundamental error? In Steinbock
B, et al (ed.). Te Oxford Handbook of bioethics. Oxford University Press, Oxford 2007a, pp.
571-596.
• Menikoff J. Equipoise: beyond rehabilitation? Kennedy Inst Ethics J 2003;13(4):347-351.
• Miller GF, Joffe S. Equipoise and the randomized clinical trial dilemma. NEJM
2011;364:476-480.
• Van der Graaf R, Van Delden JJM. Equipoise should be amended, not abandoned. Clinical
Trials 2011;8:408-416.
• Van der Graaf R, Van Delden JJM. On what we will lose in giving up on equipoise: a reply to
Miller. Clinical Trials, forthcoming.
• Weijer C, Miller PB. When are research risks reasonable in relation to anticipated benefits.
Nat Med 2004;10(6): 570-573.