At What Level of Collective Equipoise Does a Randomized Clinical Trial Become Ethical for the Members of Institutional Review Board/Ethical Committees?

2013·1.1 MB·English

by  Mhaskar, Rahul

156 At What Level of Collective Equipoise Does a Randomized Clinical Trial Become Ethical for the Members of Institutional Review Board/Ethical Committees?
ACTA INFORM MED. 2013 Sep; 21(3): 156-159 doi: 10.5455/aim.2013.21.156-159
Received: 05 May 2013 • Accepted: 20 June 2013
conflict of interest: none declared
© AVICENA 2013
At What Level of Collective Equipoise Does a
Randomized Clinical Trial Become Ethical for the
Members of Institutional Review Board/Ethical
Committees?
Rahul Mhaskar1,2, Barry B. Bercu2,3, Benjamin Djulbegovic1,2,4
Clinical Translational Science Institute, Center for Evidence-based Medicine and Health Outcomes Research,
Tampa, FLorida, USA1
Department of Internal Medicine, Division of Evidence-based Medicine and Health Outcomes Research University
of South Florida, Tampa, FLorida, USA2
Department of Pediatrics, Morsani College of Medicine, University of South Florida, Florida, USA3
H. Lee Moffitt Cancer Center & Research Institute, Departments of Hematology and Health Outcomes and Behavior,
Tampa, FLorida, USA4
Corresponding author: Prof. Benjamin Djulbegovic, PhD. University of South Florida & Moffitt Cancer Center. Mailing Address: USF Health Clinical Research.
12901 Bruce B. Downs Boulevard, MDC02, FL 33612. Phone # [phone]. Fax # [phone]. E-mail: [email protected]
Original paper as hard copy (paper based) and included Half of IRB members would approve the study
ABSTRACT six hypothetical scenarios outlining clinical when the median distribution of equipoise
Background: The conduct of a randomized trials targeted at measuring the collective among experts was 70% for treatment for
controlled trial (RCT) is deemed ethical only equipoise. We defined the collective equipoise leukemia in dogs and 85% for leukemia in
if we are in state of “equipoise” as to which as the situation when survey participants were rats (and 25% of IRB members would ap-
treatment would be most beneficial for the equally split (50:50) in their decision regard- prove such a study even if 100% of experts
patients. Individual equipoise applies to an ing whether a proposed clinical trial would be favors one treatment over another). None of
individual clinician or a member of ethical, ethical to conduct. The opinion of 100 experts the demographic features of respondents af-
institutional review board (IRB), whilst col- in the field expressed as proportion of experts fected collective equipoise. Conclusions: This
lective equipoise refers to the profession as favoring treatment A vs. B in each of the five is the first study assessing collective equipoise
a whole. It is argued that physicians are not scenarios was made available to the partici- among ethical committee/IRB members.
bound by the equipoise but their actions are pants. Results: The response rate of our survey Our study findings show that IRB members
directed by the confines of the expert opin- was 33% (71/218). Fifty percent of the IRB perceived that conduct of a trial enrolling
ion. Experts can agree or disagree in various members would approve an RCT addressing humans is unethical when the equipoise level
proportions on the merit of a given treatment. the efficacy of two drugs for the management is beyond 80% (80:20 distribution of uncer-
Hence, the collective equipoise will be often of headache even if 80% of experts favor one tainty). IRB members require a higher level
incomplete. In turn, the opinions of content treatment over another (median: 80%; third of equipoise when it comes to testing a new
expert in the field of the proposed trial influ- quartile: 80%). Similarly, half of participating drug in humans than in animals. A relatively
ence the IRB members’ decision regarding IRB members would approve the study when high level of equipoise is needed for IRB
trial approval. Methods: We conducted a the median distribution of equipoise among members to be comfortable to approve trials
survey of IRB members at University of South experts was 70% (70 in favor of treatment A involving life-threatening situations, children
Florida and the IRB members attending the vs. 30 in favor of treatment B) for treatment and elderly patients.
bioethics conference organized in Clearwater, of leukemia, 60% for treatment of geriatric Key words: randomized controlled trial, ethics,
Florida, USA. The survey was made available patients and 70% for treatment of newborns. Ethical committees.
1. INTRODUCTION
participants enrolled in the trials (1). to research in humans (4-6). That is,
There are three key approaches to The duty oriented–Kantian approach research should be conducted with
conducting scientific research in hu- refers to conduct of only research a goal to resolve existing uncertain-
mans: goal oriented, duty oriented which in the best interest of patients ties e.g. to compare the efficacy of
and the right-based approaches. The (2, 3). The right-based approach re- antibiotics use vs. watchful waiting
goal oriented approach also termed fers to conduct of only research to for the management of upper respira-
as utilitarian approach ensures scien- which patients have provided their tory tract infections among children.
tifically robust results which promise informed consent. The uncertainty If there are no uncertainties, there
maximum benefit to the greatest or equipoise principle is a common would be no need for clinical re-
number of future participants and factor among these three approaches search to inform decision-making (7).
Original paper / aCTa inFOrM MeD. 2013 Sep; 21(3): 156-159
At What Level of Collective Equipoise Does a Randomized Clinical Trial Become Ethical for the Members of Institutional Review Board/Ethical Committees? 157
Randomized controlled trials research in humans including IRB of trial by participants for the six sce-
(RCTs) are considered as the gold members’ decision regarding trial narios. We assessed the difference be-
standard for informing treatment de- approval. Hence, it is worthwhile tween the collective equipoise esti-
cisions as RCTs are based on a deduc- to investigate under which circum- mates of non-MD IRB members and
tive method. That is, if the assump- stances IRB members will be equally IRB members who were physicians
tions of the test are met, a positive split (50:50) in their decision to ap- by employing the Mann-Whitney test
result obtained via a RCT implies the prove a proposed RCT as a function (14). We conducted simple logistic re-
appropriate causal conclusion. Hence of the proportion of experts favoring gression to determine the impact of
the majority of researchers and par- one treatment over another? Accord- demographic variables on the collec-
ticipating patients accept RCTs as ingly, we conducted a survey of IRB tive equipoise.
a tool to resolve existing uncertain- members to assess the degree of col-
3. RESULTS
ties (8) (9). However, the conduct of lective equipoise necessary for a spe-
a RCT is deemed ethical only if we cific type of trial to be deemed eth- The response rate of our survey
are uncertain that is in state of “equi- ical and hence approved by IRB. was 33% (71/218). Sixty seven percent
poise” as to which treatment would (146/218) of the participants were fe-
2. METHODS
be most beneficial for the patients. If males and 33% (72/218) were males.
we are truly in equipoise, a clinical Data collection: We conducted a Fifty eight percent (126/218) were ac-
trial, and particularly a RCT, serves survey of IRB members at Univer- tive members of the IRB at the time of
the patients’ interest best, since he or sity of South Florida and the IRB the survey. Fourteen percent (31/218)
she does not lose out prospectively members attending the bioethics were physicians (holding a MD de-
on the benefits for participation as conference organized in Clearwater, gree). The median age of participants
the treatment, that is being tested, Florida, USA. This paper represents was 48 years (range: 24-75 years). On
has equal chances to be as beneficial a full description of the previously average the participants served for 3
as harmful (6). reported analysis in the abstract years on IRB (median: 3 years, range:
Any new study is designed based form only (12). The survey was dis- 0.5-12 years).
on the existing knowledge of the tributed to 218 IRB members. The Fifty percent of the IRB members
treatments being tested. Existing in- survey was made available as hard would approve an RCT addressing
formation can range from simply not copy (paper based) and included six the efficacy of two drugs for the man-
knowing to having different degrees hypothetical scenarios outlining agement of headache even if 80% of
of uncertainties including a state of clinical trials targeted at measuring experts favor one treatment over an-
equipoise when we are equally po- the collective equipoise. We defined other (median: 80%; third quartile:
sitioned in our beliefs between the the collective equipoise as the situa- 80%) (Table).
benefits and harms of a certain treat- tion when survey participants were Even if 70% (median: 70%; third
ment or the choice between two or equally split (50:50) in their deci- quartile: 80%) of experts favor one
more competing treatments (6, 10). sion regarding whether a proposed treatment over another 50% of IRB
The state of equipoise can be held by clinical trial would be ethical to con- members would approve an RCT ad-
researchers, patients and members duct. In each of the five scenarios dressing the efficacy of two drugs for
of the community at large including the choice of the treatment was de- the management of leukemia. That is,
the research regulatory officials such termined by chance alone (flip of a 25% of IRB members would accept
as members of the institutional re- coin). The opinion of 100 experts in enrollment into a trial addressing
view board (IRB) who approve the the field expressed as proportion of safety and efficacy of two treatments
trials. experts favoring treatment A vs. B in for the management of leukemia
Individual equipoise applies to an each of the five scenarios was made even if 80% of the experts favor one
individual clinician or IRB member, available to the participants. IRB treatment over another (Table).
while collective equipoise refers members were requested to answer Even if 60% (median: 60%; third
to the profession as a whole (10). the question: “under which circum- quartile: 70%) of experts favor one
Freedman et al argued that physi- stances of the experts’ agreement/ treatment over another 50% of the
cians are not bound by the equi- disagreement would you approve a IRB members would approve an RCT
poise but their actions are directed randomized trial for each of the sce- addressing the safety and efficacy of
by the confines of the expert opinion narios listed above?” The survey was two antibiotics in the treatment of
(11). Experts can agree or disagree modeled after the one described by pneumonia among elderly patients.
in various proportions on the merit who assessed collective equipoise in That is, 25% of the IRB members
of a given proposal, and in their be- lay people (13). We collected data on would accept enrollment into trial
liefs, say if treatment A is superior to demographics including years of ser- assessing safety and efficacy of antibi-
treatment B. Hence, the collective vice with IRB from the participants. otics for the treatment of pneumonia
equipoise will be often incomplete. Our study was approved by Univer- among elderly patients even if 70% of
In turn, the opinions of content ex- sity of South Florida IRB. the experts favor one treatment over
pert in the field (e.g. oncologists) of Data analysis: We conducted de- another (Table).
the proposed trial influence the in- scriptive analysis including median Even if 70% (median: 70%; third
dividuals involved in the conduct of and interquartile range of approval quartile: 75%) of experts favor one
aCTa inFOrM MeD. 2013 Sep; 21(3): 156-159 / Original paper
158 At What Level of Collective Equipoise Does a Randomized Clinical Trial Become Ethical for the Members of Institutional Review Board/Ethical Committees?
level is beyond 80% (80:20 distribu-
Scenario Median (%) Third quartile (%)
tion of uncertainty). That is, when
Analgesic A vs. B for the management of headache 80 80
Treatment A vs. B for the management of leukemia 70 80 80% or more experts prefer treat-
Antibiotic A vs. B for the prevention of post–surgical pneumonia in geriatric ment “A” over the competing treat-
60 70
patients ment, then half of the IRB members
Antibiotic A vs. B for the prevention of post–surgical pneumonia in would prefer that the treatment “A”
70 75
newborns
may be used in practice instead of
Treatment A vs. B that is developed for humans for the management of
70 90 evaluating its safety and efficacy via
leukemia and now being tested in dogs with leukemia
clinical trials. Our findings are in line
Treatment A vs. B that is developed for humans for the management of
leukemia and now being tested in rats with leukemia 85 100 with previous research conducted by
Johnson et al. enrolling a convenient
Table 1. Results of trial testing safety and efficacy of two drugs in our sample
sample of 105 lay individuals and 8
treatment over another 50% of the had an impact on the collective equi- medical students (15)
IRB members would approve an RCT poise. Individuals enrolled in the study
addressing the safety and efficacy of by Johnson et al perceived that con-
4. DISCUSSION
two antibiotics in the treatment of duct of a trial enrolling humans in
pneumonia among newborns recov- This is the first survey assessing col- unethical when the equipoise level
ering from surgery. That is, 25% of lective equipoise among ethical com- is beyond 70% (70:20 distribution of
the IRB members would accept en- mittee/IRB members. Findings of our uncertainty) (15)
rollment into trial testing safety and survey indicate that IRB members re- Interestingly, under the assump-
efficacy of the treatment of pneu- quire a higher level of equipoise (i.e. tions that experimental treatment is
monia among new born babies re- more uncertainty) when it comes to >80% successful most rational deci-
covering from surgery even if 75% of testing a new drug in humans than sion for patients themselves is to trust
the experts favor one treatment over in animals. The trial enrolling hu- researchers (and by extension IRB
another (Table). mans most likely to be tolerated is members), despite the possibility that
Even if 70% (median: 70%; third the comparison of analgesics for the the researchers or IRB members may
quartile: 90%) of experts favor one treatment of headache. IRB members decide to approve the study based on
treatment over another 50% of the responded with a significant varia- the factors other than patients’ ben-
IRB members would approve an RCT tion in their acceptance ranging from efits: the likelihood of obtaining suc-
addressing the safety and efficacy of 50% to 100%. A relatively high level cessful treatment appears to justify
two drugs in dogs. That is, 25% of of equipoise is needed for IRB mem- putting oneself in a vulnerable posi-
the IRB members would accept en- bers to be comfortable to approve a tion (16).
rollment into trial testing safety and trial involving life-threatening situa-
REFERENCES
efficacy in dogs even if 90% of the tions, such as trial addressing efficacy
experts favor one treatment over an- and harms of two competing inter- 1. Resnik DB. Paternalism and Utili-
other. Even if 85% (median: 85%; ventions for leukemia. Our survey tarianism in Research with Human
third quartile: 100%) of experts favor results show that the highest level Participants. Health care analysis :
one treatment over another 50% of of equipoise is required when new HCA: journal of health philosophy
the IRB members would approve an drugs are tested in older populations and policy. 2012. Epub 2012/10/19.
RCT addressing the safety and effi- and children who are considered to 2. Kelly MP, Moore TA. The judgement
cacy of two drugs in rats. That is, 25% be potentially vulnerable to viola- process in evidence-based medi-
of the IRB members would accept en- tion of free consent to participate cine and health technology assess-
rollment into trial testing safety and in a trial. Institutional review board ment. Social theory & health: STH.
efficacy of two drugs in rats even if members participating in our survey 2012;10(1):1-19. Epub 2012/12/12.
100% of the experts favor one treat- preferred experiments on rats com- 3. Rothhaar M. Human dignity and
ment over another (Table). pared with dogs and dogs compared human rights in bioethics: the Kan-
Fifty percent (93/187) of non-MD with humans with requirement of in- tian approach. Medicine, health
IRB members would approve an RCT creasing degree of equipoise, respec- care, and philosophy. 2010; 13(3): 251-
assessing the efficacy of two drugs for tively. The degree of collective equi- 257. Epub 2010/04/23.
the management of headache if 75% poise was not influenced by demo- 4. Alderson P. Equipoise as a means
(median: 75%; third quartile: 90%) of graphic factors. However, IRB mem- of managing uncertainty: person-
experts favor one treatment over an- bers without a MD degree required al, communal and proxy. Journal of
other while 50% (15/31) of MD IRB statistically significantly higher level medical ethics. 1996; 22(3): 135-139.
members would accept enrollment of equipoise to approve the conduct Epub 1996/06/01.
into trial even if 80% (median: 80%; of a trial compared to IRB members 5. Anderson JA. Contextualizing clin-
third quartile: 80%) of the experts with an MD degree. ical research: the epistemological
favor one treatment over another (P In summary, our study findings role of clinical equipoise. Theoret-
value= 0.01). show that IRB members perceived ical medicine and bioethics. 2009;
None of the demographic features that conduct of a trial enrolling hu- 30(4): 269-288. Epub 2009/05/01.
of the participating IRB members mans is unethical when the equipoise 6. Djulbegovic B. Uncertainty and
Original paper / aCTa inFOrM MeD. 2013 Sep; 21(3): 156-159
At What Level of Collective Equipoise Does a Randomized Clinical Trial Become Ethical for the Members of Institutional Review Board/Ethical Committees? 159
equipoise: at interplay between epis- sponding to uncertainties in clinical J Med Ethics. 1991; 17: 30-34.
temology, decision making and eth- research. J Med Philosophy. 2007; 14. Hart A. Mann-Whitney test is not
ics. The American journal of the 32: 79-98. just a test of medians: differences in
medical sciences. 2011; 342(4): 282- 11. Freedman B. Equipoise and the eth- spread can be important. BMJ. 2001;
289. Epub 2011/08/06. ics of clinical research. The New 323(7309): 391-393. Epub 2001/08/18.
7. Djulbegovic B, Hozo I, S. G. Uncer- England journal of medicine. 1987; 15. Johnson N, Lilford RJ, Brazier W.
tainty in clinical Medicine. In: Dov 317(3): 141-145. Epub 1987/07/16. At what level of collective equipoise
M, Gabbay, Woods J, Editors. Ency- 12. Djulbegovic B, Bercu BB, Editors. does a clinical trial become ethical?
clopedia of Medical Philosophy. San At what level of collective equipoise Journal of medical ethics. 1991; 17(1):
Dieago, North Holland, 2011. does a clinical trial become ethical 30-34. Epub 1991/03/01.
8. Cartwright N. Are RCTs the Gold for the IRB members? . University of 16. Djulbegovic B, Hozo I. When is it
Standard? BioSocieties. 2007; 2(01): South Florida Third National Sym- rational to participate in a clinical
11-20. posium - Bioethical Considerations trial? A game theory approach in-
9. Cartwright N. A philosopher’s view in Human Subject Research, 2002 corporating trust, regret and guilt.
of the long road from RCTs to effec- March 8-10; Clearwater, FL, USA. BMC medical research methodolo-
tiveness. The Lancet. 2011; 377(9775): 13. Johnson N, Lilford JR, Brazier W. gy. 2012; 12: 85. Epub 2012/06/26.
1400-1401. At what level of collective equipoise
10. Djulbegovic B. Articulating and re- does a clinical trial become ethical?
aCTa inFOrM MeD. 2013 Sep; 21(3): 156-159 / Original paper