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Are More Trials Really the Answer? Putting BehavioralEquipoise in CheckJoshua Crites aa Cleveland Clinic , BioethicsPublished online: 18 Feb 2011.

To cite this article: Joshua Crites (2011) Are More Trials Really the Answer? Putting Behavioral Equipoise in Check, TheAmerican Journal of Bioethics, 11:2, 16-17

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The American Journal of Bioethics

Ubel, P. A., and R. Silbergleit. 2011. Behavioral equipoise: A wayto resolve ethical stalemates in clinical research. American Journal ofBioethics 11(2): 1–8.

U.S. Preventive Services Task Force. 2009. Screening for breast can-cer: U.S. Preventive Services Task Force recommendation state-ment. Annals of Internal Medicine 151(10): 716–725.

Are More Trials Really the Answer?Putting Behavioral Equipoise in Check

Joshua Crites, Cleveland Clinic, Bioethics

In their article, Drs. Ubel and Silbergleit (2011) present “be-havioral equipoise” as a supplement to the notion of clinicalequipoise (CE) as it pertains to the justification for conduct-ing randomized controlled clinical trials (RCTs). As is wellknown, the notion of CE justifies the conduct of RCTs onlyto the extent that there is genuine uncertainty within theexpert medical community and that the trial is designed insuch a way to resolve this uncertainty (Freedman 1987, 144).The problem with this traditional view according to Ubeland Silbergleit is that some clinicians remain reluctant toadopt certain treatments even though others believe CE tohave been disturbed. In these cases there is little space tojustify the conduct of an additional trial that might serve toresolve “ethical stalemates” among clinicians who remainunconvinced by scientific evidence produced by the initialRCT.

To address these stalemates, Ubel and Silbergleit sug-gest the idea of behavioral equipoise (BE)—a state of uncer-tainty that is not based on the lack of empirical data, but in-stead on various behavioral factors that prevent widespreadadoption of the treatment modality in question. By the crite-rion of CE alone, additional RCTs are not ethically justifiedif uncertainty has been disturbed. But as Ubel and Silber-gleit are careful to point out, “A clinical trial can be justifiedeven in the presence of valid scientific evidence that onetreatment approach is superior to another, if (1) the beliefsand behaviors of relevant clinicians are resistant to this in-formation and (2) the trial is designed to address the causesof these beliefs and behaviors” (1). The argument for ad-ditional trials justified by BE is grounded in the idea thatclinicians are reluctant to adopt treatments for a varietyof reasons—some of which extend beyond a simple lackof empirical data that support the efficacy of a particulartherapy. CE can (and does) justify RCTs aimed at remov-ing uncertainty that is the result of a lack in empirical data,but once that trial has been conducted and enough expertsagree that CE has been disturbed, there are few scientificoptions aimed at addressing remaining stalemates in clini-cal practice. BE is therefore proposed as a means by whichadditional RCTs can be ethically justified in order to resolve

Address correspondence to Joshua Crites, Cleveland Clinic, Bioethics, 9500 Euclid Ave/JJ60, Cleveland, OH 44195, USA. E-mail:critesj@ccf.org

clinicians’ more subjective reasons for not adopting a par-ticular therapy.

The authors’ proposal has clear merit as far as under-standing the phenomenon of ethical stalemates in adopt-ing “proven” treatments and the need to rectify them inthe interest of maximizing the implementation of therapieswhich RCTs have demonstrated to be of superior therapeu-tic benefit. My concern is not that the authors have failedto provide an illustration of a key difficulty within clinicalresearch that requires focused attention. In fact, I think thatthe notion of BE should be examined further as it pertainsto the initial design of RCTs and subsequent alteration ofclinical practice. In what follows, I focus on two issues thatI take to be problematic with the use of BE to justify addi-tional RCTs. Both of these issues are highlighted in Ubel andSilbergleit’s response to the potential concern about patientharm but have farther reaching implications to the conceptof BE more generally. I then conclude with a few brief com-ments about resolving ethical stalemates without recourseto additional RCTs.

BEHAVIORAL EQUIPOISE, HARM, AND THE PURPOSE

OF CLINICAL RESEARCH

Ubel and Silbergleit instructively point out that there arereasons behind not adopting particular treatments that ex-tend beyond the simple absence of sound scientific datawhich demonstrate the superiority of those treatments.Clinical trials would be well served if researchers took thesemore subjective behavioral factors into account during thedesign stages of their research. However, and especiallywhen a trial is a placebo-controlled design, conducting ad-ditional trials to remove stalemates is ethically problematicif conflated with the intent to deliver a treatment to moreindividuals than are receiving the treatment in the clinic.Ubel and Silbergleit state:

Consider that, right now, thousands of patients already expe-rience strokes without receiving t-PA because their emergencyphysicians are not sufficiently convinced that the treatmentworks. A new RCT of t-PA would at least give patients a 50%

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Behavioral Equipoise: Resolving Ethical Stalemates

chance of receiving the drug. And if the trial further establishedthat t-PA was good for such patients, and thereby changed clin-ical practice, wouldn’t that matter in judging the moral accept-ability of such a trial? (1)

While I take it that the last question just quoted is intendedto be (mostly) rhetorical, the answer to this question—andin fact the priority of this question over whether more indi-viduals will receive t-PA through additional RCTs—is all-important. It does matter in judging the moral acceptabilityof a trial whether it will further establish the superiorityof a particular treatment. It also matters whether this trialwill subsequently change clinical practice. But this is allthat matters, given the commonly accepted understandingof clinical research as distinct from clinical practice, whereany benefit that befalls current participants is secondary tothe primary purpose of producing or enhancing generaliz-able knowledge aimed at benefiting future patients.

As stated here, it appears that the primary purpose ofan additional t-PA study would be to increase the frequencyof treating stroke with t-PA in the context of that trial. Evenif it can be argued that an additional RCT is ethically jus-tifiable, the basis of that justification lies in the attempt toremove uncertainty—not because more individuals will re-ceive treatment on trial than in the clinic. Unless Ubel andSilbergleit are prepared to give an argument for why weshould go against conventional understanding of the pur-pose of clinical research, and even if we can say that BE jus-tifies further trials, we must be careful to view those trialsas a means to produce additional evidence that will changeclinical practice, not as an opportunity to provide treatmentto study participants.

IS BE REALLY DISTINCT FROM CE?

Of course, the question remains of whether BE can in factjustify additional RCTs. If, after the “successful” conductof an initial RCT, relevant individuals remain unconvincedof the superiority of some particular treatment, it does notnecessarily matter whether the reason is behavioral or dueto a lack of convincing evidence. As Paul Miller and CharlesWeijer (2003) have pointed out, “Only when evidence hasaccumulated sufficiently in favor of one treatment such that‘no open-minded clinician informed of the results’ would fa-vor the alternative has CE been disturbed (Freedman, 144).The point is not that trials must be continued until the re-sults reach some arbitrary point of statistical significance.Rather, it is that they must be continued until the evidence gath-ered is sufficient to resolve significant disagreement within theexpert clinical community” (100, emphasis added). In the ex-ample of t-PA Ubel and Silbergleit provide, the expert clini-cal community consists not just of the advocates of t-PA but

also of the dissenters. Because there are still relevant groupsfor whom it is uncertain that t-PA is superior, CE remainsundisturbed. The reluctance of the dissenters to adopt t-PAis not necessarily linked to subjective behavioral factors butto a genuine lack of evidence that t-PA is superior in theemergency setting. As such, it is CE that justifies additionaltrials—trials that would address dissenting concerns by fo-cusing in this case on the effects of t-PA in the emergencysetting.

CONCLUSION

For the reasons just stated, BE (or CE, for that matter) cer-tainly cannot justify additional RCTs as a means for de-livering treatments to a maximum number of individuals.Furthermore, it appears as though BE does not do any morejustificatory work than CE with respect to ongoing uncer-tainty within relevant clinical communities. If further trialsare genuinely warranted, it is because the initial trial failedto produce enough convincing data to the relevant com-munity of experts. In other words, BE essentially collapsesinto CE. In those cases where no further trials are justifiedand yet a portion of clinicians remains reluctant to adopt aparticular treatment, perhaps something akin to postmar-keting phase 4 trials would be more appropriate to addressany remaining uncertainty. This would solve the problem ofthe limitations of nonscientific advocacy campaigns whilealso avoiding the difficulty of ethically justifying additionalRCTs.

Certainly, this last suggestion requires fine-tuning andis not meant as a panacea for the concerns raised here aboutUbel and Silbergleit’s article. Moreover, there is much aboutBE to be extolled. One of the most obvious benefits is theindication that RCTs need to be better designed initiallyto address certain behavioral factors involved in clinicalpractice. As we continue to struggle with these problems,behavioral equipoise stands to serve us well as an integralpart of moving forward with our understanding of clinicalresearch generally and of the reasons behind reluctance toadopt treatments that have been shown to be of superiortherapeutic benefit more specifically. �

REFERENCES

Freedman, B. 1987. Equipoise and the ethics of clinical research.New England Journal of Medicine 317(3): 141–145.

Miller, P. B., and C. Weijer. 2003. Rehabilitating equipoise. KennedyInstitute of Ethics Journal 13(2): 93–118.

Ubel, P. A., and R. Silbergleit. 2011. Behavioral equipoise: A wayto resolve ethical stalemates in clinical research. American Journal ofBioethics 11(2): 1–8.

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