Clinical Equipoise - Canadian Association of Emergency Physicians

Clinical Equipoise: “Do
Do We
Really Need Another Study?”
Study?
CAEP 2012
John M Tallon MD MSc FRCPC
VP Medical Programs, Emergency and Health Services Commission Province of British
Services Commission, Province of British Columbia
No Disclosures, No Conflicts of Interest
Research and R
h d
Emergency Medicine
g y
"an undertaking intended to extend knowledge through a
disciplined inquiry or systematic investigation."
Objectives:
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Define (and explore) Define
(and explore) “clinical
clinical equipoise
equipoise”
Elaborate on why clinical equipoise is important
Controversies of clinical equipoise
Demonstrate relevance (to EM) of clinical equipoise with examples
equipoise with examples
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Key Words, Documents and Concepts y
p
in Medical Ethics and Research
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TCPStatement
Fiduciaryy
Beneficence
Common Rule
Common Rule
Belmont Report
Nuremberg Code
Nazi Experiments
p
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Helsinki Declaration
Epistemology
p
gy
Agnosticism
Clinical Equipoise
Clinical Equipoise
National Research Act
Tuskegee Syphilis Study
Willowbrook Hepatitis p
Experiments
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Clinical Equipoise: Origins
Clinical Equipoise: Origins
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1974: C Fried
– Original elucidation of concept
– A neo‐Kantian ethical justification for doctrine of equipoise (therapeutic mandate/optimal care)
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1987: B Freedman
– Nails it: see final definition...
Nails it: see final definition
Fried C: Medical Experimentation: Personal Integrity and Social Policy, New York;
Elsevier Publishing: 1974
Elsevier Publishing: 1974
Freedman, B. (1987) 'Equipoise and the ethics of clinical research'.
The New England Journal of Medicine, 317, (3):141‐145.
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“Equipoise and the ethics of clinical q p
research”
“The ethics of clinical research requires equipoise‐‐a state of genuine uncertainty on the part of the clinical
state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial Should the investigator
merits of each arm in a trial. Should the investigator discover that one treatment is of superior therapeutic merit he or she is ethically obliged to offer that
merit, he or she is ethically obliged to offer that treatment.”
Freedman B. N Engl J Med. 1987 Jul 16;317(3):141‐5
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“Equipoise
Equipoise and the ethics of clinical and the ethics of clinical
research” “I suggest an alternative concept of equipoise, which would be based on present or imminent controversy in the clinical community over the preferred treatment. According to this concept of "clinical equipoise," the requirement is satisfied if there is genuine uncertainty within the expert medical community‐‐not necessarily on the part of the individual investigator‐‐about the preferred treatment.”
Freedman B. N Engl J Med. 1987 Jul 16;317(3):141‐5. 8
Clinical equipoise
Clinical equipoise
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“...means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial..”
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“Once a certain threshold of evidence is passed, there is no longer genuine uncertainty d th
i
l
i
t i t
about the most beneficial treatment...”
Miller and Joffe NEJM 2011
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Is Clinical Equipoise Important?
Is Clinical Equipoise Important?
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Yes!
Used and taught in TCPS!
Used and taught in TCPS!
Used every day by REBs!
Used by all clinical researchers!
d b ll l
l
h !
Used to predicate decisions on study design p
y
g
and legitimacy!
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TRI‐COUNCIL POLICY STATEMENT
2010
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“The existence of a genuine uncertainty on the part of the relevant expert community about what therapy or therapies are most effective g
for a given condition”
For this reason, clinical equipoise may be considered as a starting point for the design
considered as a starting point for the design and review of clinical trials
http://www.pre.ethics.gc.ca/pdf/eng/tcps2/TCPS_2_FINAL_Web.pdf
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Parachutes and Equipoise
Parachutes and Equipoise
“Parachute
Parachute use to prevent death and major trauma use to prevent death and major trauma
related to gravitational challenge: systematic review of randomised controlled trials”
review of randomised controlled trials”
Smith GC, Pell JP. Parachute use to prevent death ...randomised controlled trials.
BMJ. 2003 Dec 20;327(7429):1459‐61.
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OBJECTIVES: p
p
g
j
g
To determine whether parachutes are effective in preventing major trauma related to gravitational challenge.
DESIGN: Systematic review of randomised controlled trials.
DATA SOURCES
DATA SOURCES: Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists.
STUDY SELECTION: Studies showing the effects of using a parachute during free fall.
MAIN OUTCOME MEASURE: Death or major trauma, defined as an injury severity score > 15.
RESULTS: RESULTS
We were unable to identify any randomised controlled trials of parachute intervention.
CONCLUSIONS: y
p
,
p
As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the i d d
ti i t d i d bl bli d
d i d l b
t ll d
t i l f th
parachute.
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CONCLISION: Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only
interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and
evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.
Smith GC, Pell JP. Parachute use to prevent death ...randomised controlled trials.
BMJ. 2003 Dec 20;327(7429):1459‐61.
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The Parachute Paradigm:
The Parachute Paradigm: •
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Are RCTs evil?
Are RCTs ethical?
Are RCTs ethical?
Are RCTs with placebo ethical?
In a RCT/study of 2000 patients does / d f
d
equipoise disappear at patient enrollment #1500...#1700?
Is violation of equipoise always “unethical”?
s o at o o equ po se a ays u et ca ?
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Issues with Clinical Research:
Issues with Clinical Research:
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How can a clinician offer their patient optimal How
can a clinician offer their patient optimal
medical care (the therapeutic obligation) at the same time that their treatment (the h
i
h h i
(h
scientific obligation) is selected by chance in the context of an RCT???
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Problems with Clinical Equipoise:
Problems with Clinical Equipoise:
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Imprecision in definition
Imprecision
in definition
Reliance on expert opinion
Efficacy determination limitations based upon surrogate outcomes
surrogate outcomes
High cost of new treatments and lack of population health focus
population health focus
Interim analysis study terminations
Challenges of geography and resources
Joffe S and Miller F, 2012, 2011
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NY Times Article: Show me the Equipoise? NOT! •
“New Drugs Stir Debate on Rules of Clinical Trials”
– Metastatic melanoma drug, PLX4032 versus usual chemotherapy
– Results of phase 2 testing and observational data show dramatic improvement with PLX4032 (versus usual care)
– FDA demands RCT; patients and oncologists disagree!
(NOTE: final RCT just published late 2011 showed positive results)
NYTimes, Harmon A. Sept 18, 2010 A1
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TRI‐COUNCIL POLICY STATEMENT
2010: Placebo Controlled Trials
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Article 11.2 (a) A new therapy or intervention should generally be tested against an established effective therapy
The use of an active treatment comparator in a
The use of an active treatment comparator in a clinical trial of a new therapy is generally the appropriate trial design when an established
appropriate trial design when an established effective therapy exists for the population and clinical indication under study
li i l i di ti
d t d
http://www.pre.ethics.gc.ca/pdf/eng/tcps2/TCPS_2_FINAL_Web.pdf
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Solutions to Equipoise Issues:
Solutions to Equipoise Issues:
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Component Analysis in ethics assessment Component
Analysis in ethics assessment
process:
“ h
“When are research risks reasonable in relation h k
bl
l
to benefits?”
Therapeutic risk versus non‐therapeutic risk
Therapeutic risk: Still use Clinical Equipoise
Therapeutic risk: Still use Clinical Equipoise
Consistent with competent care?
Risks reasonable?
Weijer and Miller, Nature Medicine, 2004
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Bayesian Concepts:
Bayesian Concepts:
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Shifting beyond 50%
Utilizing LRs in clinical practise
Credibility intervals (CrI) versus confidence
Credibility intervals (CrI) versus confidence intervals (CI)
C
Concept of Marginal Informativeness
t fM i lI f
ti
Ethical advantages in interim analysis
Greenland S. Bayesian perspectives for epidemiological research, I:
foundations and basic methods. Int J Epidemiol. 2006;35:765‐775.
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Clinical Example:
Clinical Example:
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Disease: Appendicitis
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Intervention: Surgery versus antibiotics/RCT.
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Does this proposed RCT possess the p p
p
appropriate elements of clinical equipoise?
Hansson J et al. Antibiotics as First‐line Therapy for Acute Appendicitis: Evidence for a Change in Clinical Practice. World J Surg. 2012 May 9.
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What is the Role of Observational Studies?
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Set the stage for RCTs
I f
Inform the equipoise argument
h
i i
Serve as a means of avoiding an RCT?
Inform expert opinion
Inform public policy (tobacco and cancer)
Inform public policy (tobacco and cancer)
Contribute to the marginal Informativeness of any research question...
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Do Observational Studies Fail to Provide “the Truth”?
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Anti‐arrhythmic studies
HTS saline in trauma
HTS saline in trauma
HTS in major head injury
HRT and ischemic cardiac disease
Arthroscopic surgery for knee OA
Arthroscopic surgery for knee OA
ALS for trauma?
Definitive Results via RCT
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Clinical Research Example
Clinical Research Example
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EMS ETI for major head injury
12+ observational studies showing 12
observational studies showing “harm”
harm
One small RCT showing “good outcomes”
You, as REB, as asked to consider a larger RCT
g
Does clinical equipoise exist?
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Are RCTs Always Needed? Example
Are RCTs Always Needed? Example
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Tacrolimus (FK 506) story
Pittsburgh group “knew”
Pittsburgh group knew that FK 506 worked
that FK 506 worked
FDA mandated that RCTs begin....
Pittsburgh refused to join the RCT and b h f d
h
d
randomize patients to placebo
Same issue held for sulfonamides in the 1930’s a d 0s
and 40’s
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What Can EMS ALS do for Trauma or Cardiac Arrest Patients?
C di A
t P ti t ?
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ALS Versus BLS
ALS Versus BLS
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Interventions – ALS
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Interventions – BLS
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Intubation
IV drugs
Training
RSI?
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BMV
IV (fluids)
Training
Other meds?
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Advanced life support versus basic life support in pp
pp
the pre‐hospital setting: a meta‐analysis.
Summary‐ Results
• 18 articles of 1081 reviewed were included
18 articles of 1081 reviewed were included
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9 trauma studies (16,857 patients)
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OR for survival in ALS treated 0 892 (95% CI 0 775 1 026)
OR for survival in ALS treated 0.892 (95% CI 0.775, 1.026)
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9 cardiac
9
cardiac arrest studies (7659 patients)
studies (7659 patients)
OR for survival in ALS treated: 1.468 (95% CI 1.257, 1.715)
OR for survival if physician ALS: 2 047 (95% CI 1 593 2 631)
OR for survival if physician‐ALS: 2.047 (95% CI 1.593, 2.631)
Bakalos G, et al. Resuscitation. 2011 Sep;82(9):1130‐7. 29
Advanced life support versus basic life support in Advanced
life support versus basic life support in
the pre‐hospital setting: a meta‐analysis.
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Summary‐ Discussion
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ALS care does not improve survival in trauma
ALS
care does not improve survival in trauma vs. vs
BLS [p=0.005]
ALS
ALS care improves survival in CA, more so with i
i l i CA
ith
physician‐ALS
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Bakalos G, et al. Resuscitation. 2011 Sep;82(9):1130‐7. 30
You are the REB
You are the REB
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Will you grant “ethics approval” for ALS versus BLS RCT study?
BLS RCT study?
Does equipoise exist?
What is your impression of the literature?
Of the therapeutic mandate?
Of the therapeutic mandate?
Of the current standard of care?
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ROC: Resuscitation Outcomes Consortium
https://roc.uwctc.org/tiki/tiki‐index.php
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ROC: Amiodarone, lidocaine or placebo for out‐of‐hospital cardiac arrest due to ventricular fibrillation or tachycardia (ALPS)
ventricular fibrillation or tachycardia (ALPS)
The goal of ALPS is to determine if survival to h
l f
d
f
l
hospital discharge is improved with early (and if necessary) repeated therapeutic administration of a new Captisol‐Enabled formulation of IV amiodarone (PM101) compared to no antiarrhythmic
y
drug (placebo) or lidocaine
g (p
)
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ROC: Amiodarone, lidocaine or placebo for out‐of‐hospital cardiac arrest due to ventricular fibrillation or tachycardia (ALPS)
ventricular fibrillation or tachycardia (ALPS)
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“No
No pharmacologic agent has ever been pharmacologic agent has ever been
demonstrated to improve survival to hospital discharge after cardiac arrest It is not known
discharge after cardiac arrest. It is not known whether these drugs may cause more harm than good ”
than good.
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You are the REB? Ethics approval?
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Conclusions:
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“Clinical
Clinical Equipoise
Equipoise” concept here to stay
concept here to stay
Integral component of current Canadian REBs
Component analysis of research (therapeutic versus non therapeutic paradigms) assists the p
p
g )
ethical assessment.
Controversy continues around specific issues
Controversy continues around specific issues of equipoise ie expert opinion, geography etc
K
Know your REB approach!
REB
h!
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““Wisdom is knowing what to do d
k
h
d
next skill is knowing how to do
next, skill is knowing how to do it and virtue is doing it”
it, and virtue is doing it
David Starr Jordan
Special Thanks to Departments of p
p
Emergency Medicine, Dalhousie University and UBC and Dr. KS Joseph, UBC
d UBC d D KS J
h UBC
[email protected]
john tallon@gov bc ca
[email protected]
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