Leading opinion Fallibility: a new perspective on the ethics of clinical trial enrollment Michel C. F. Shamy1*, Frank W. Stahnisch2,3, and Michael D. Hill3,4 The ethical principle of ‘equipoise’, introduced in 1974, represents the most widely influential justification for the enrollment of patients into randomized clinical trials. However, definitions of equipoise vary, and its terms are not universally accepted. In this paper, we suggest a new way of approaching the ethics of clinical trial enrollment, which we call fallibility. The principle of fallibility argues that all physician opinions are sufficiently uncertain to warrant investigation, and that the ethical justification for any trial becomes a question of its epistemic validity, by which we mean the strength of its hypotheses and methods. The principle of fallibility can be translated into practice through the virtues of humility, skepticism and caring. While we cite recent examples from stroke medicine to demonstrate the limitations of equipoise, we propose that fallibility may offer a more general means of addressing the controversies that arise surrounding randomized controlled trials in many disciplines of medicine. Key words: clinical trials, equipoise, ethics, fallibilism, history, stroke
Introduction How should clinicians decide whether it is ethically justifiable to enroll their patients into randomized clinical trials (RCTs)? This question has become increasingly important as the principles of Evidence-Based Medicine (EBM) have positioned the RCT at the centre of contemporary medical knowledge (1). One of the fundamental ethical dilemmas produced by RCTs – and the one that will be considered here – is the concern that some patients will be randomized to receive an intervention that is ineffective, or at least less effective, than the intervention against which it is compared in a trial context. Physicians, nurses and students may experience significant ethical angst around randomization when they believe a priori that one intervention will be less successful. As a consequence, they may become reluctant to enroll patients into trials, which delays trial completion and can bias trial results (2). Unresolved ethical dilemmas therefore can impair the Correspondence: Michel C. F. Shamy*, The Ottawa Hospital – Civic Campus, 1053 Carling Avenue, Room C2182a, Ottawa, Ontario, Canada K1Y 1T8. E-mail: [email protected] 1 Department of Medicine (Neurology), University of Ottawa, Ottawa, ON, Canada 2 Department of History, University of Calgary, Calgary, AB, Canada 3 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada 4 Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada Received: 3 September 2014; Accepted: 10 September 2014 Conflict of interest: None declared. Financial disclosures: The writing of this manuscript was not supported by any specific funding agency or grant. DOI: 10.1111/ijs.12376
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conduct and reliability of clinical trials, threatening the ability of modern medicine to acquire knowledge and apply it to the care of patients. Traditionally, ethical concerns surrounding clinical trial randomization have been allayed by appeals to the principle of equipoise, which is generally understood to refer to the presence of uncertainty or disagreement within a medical community (3). However, equipoise is not universally accepted (4–6). Moreover, recent experiences in clinical trial design and enrollment – prominently but not exclusively in the field of stroke medicine – have raised doubts about the ability of equipoise to address 21st century concerns (7–10). Therefore, in this paper, we introduce a novel approach to the ethics of clinical trial enrollment, which we call fallibility. While equipoise justifies clinical trials on the basis of a restrictive and cumbersome definition of uncertainty, fallibility argues that all physician opinions are sufficiently uncertain to warrant investigation. As a consequence, the ethical justification for any given trial becomes a question of its epistemic validity, meaning the strength of its central hypothesis and methods. While this might appear obvious, the ethics of clinical trial enrollment has never been explicitly defined in relation to the epistemic validity of the trial itself. From the perspective of the individual clinician enrolling patients, a fallibilistic approach to clinical trial ethics is operationalized through a set of virtues: humility, skepticism, and caring. Fallibility begins from the recognition that many questions of ethics (e.g. ‘What should we do?’) are related to questions of epistemology (e.g. ‘What do we know?’) (11–13) Epistemology is the branch of philosophy that is concerned with questions of knowledge, belief and uncertainty. Moreover, fallibility applies lessons from the history of medicine by acknowledging that clinicians’ decisions are best understood within a particular historical and scientific context that determines how they conceptualize patients’ symptoms, understand disease mechanisms, and select among treatments (14). As a consequence, belief in the efficacy of a treatment needs to be qualified: a treatment is believed to be effective here and now, based on our current knowledge and values (15). However, beliefs about efficacy can and do change over time.
Equipoise and endovascular stroke trials The term ‘equipoise’ was introduced by American legal scholar Charles Fried in 1974 and was defined in reference to an individual physician’s uncertainty about the interventions being studied in a clinical trial (16). Fried argued that physicians would only be justified to enroll their patients into trials if they were undecided (i.e. did not have a preference) about the relative merits of the treatments under investigation. A physician who held the opinion that one treatment was superior to the other © 2014 World Stroke Organization
M. C. F. Shamy et al. would lack equipoise, and would be ethically prohibited from enrolling patients into that trial. Fried’s conception of equipoise therefore rests on the assumption that medical opinions about the relative efficacy of treatments should be considered stable and reliable arbiters of clinical trial enrollment. By medical opinion, we mean a clinician’s beliefs about diagnosis, prognosis and treatment in relation to a particular clinical scenario. As explored by recent scholarship in psychology, sociology and history, medical opinion arises from a complex interplay of knowledge and experience, acquired within a particular historical and cultural context (17–19). Medical opinion reflects influences that are conscious and unconscious, explicit and tacit, rational and empirical. Fried’s concept of equipoise remains popular, and has been used in the design of important clinical trials, most notably IST-3 (20). However, experiences surrounding the conduct of three recently-published RCTs in acute stroke therapy have led us to question the reliability of Fried’s equipoise. IMS-III, MR-RESCUE and SYNTHESIS sought to compare widely-used but as yet unproven endovascular therapies (mechanical thrombectomy and intra-arterial thrombolysis) to standard intravenous thrombolysis in acute ischemic stroke. Because many stroke physicians believe that endovascular therapies are the ‘intuitive solution,’ (21) they felt that they did not meet Fried’s criteria for equipoise and refused to enroll their patients into these trials (2). Despite the firmly held beliefs that led many physicians to withhold their patients from these trials, each trial failed to show the expected superiority of endovascular therapy (22–24). This scenario exemplifies three problems with Fried’s conception of equipoise. First, Fried’s equipoise requires that physicians enrolling patients into trials lack opinions of preference about one of the treatments being compared in a trial. However, physicians almost always have opinions about the value of a set of therapies in reference to a particular patient. Arguably, physicians would only lack preferences when they have no experience with the treatments in question, when absolutely no relevant data are available, or when the expected treatment effects and potential harms are both very small. Second, physicians’ opinions about the relative benefits of treatment or trial enrollment for a given patient are necessarily imprecise (25,26), reliant as they are upon general likelihoods rather than specific predictions .When a given clinical decision point is encountered infrequently, as is the case with acute stroke thrombolysis in most hospitals, this effect is magnified. Third, physician opinions are vulnerable to a number of influences that can render them unreliable (19). For example, a recent case gone very well or very badly may drive a physician’s opinion strongly in one direction (27). Moreover, there is a common tendency to be swayed by immediately appreciable effects – such as seeing an artery recanalize under angiography – despite the fact that these surrogate outcomes may not guarantee clinicallyrelevant benefits (28). Furthermore, local practice is frequently determined by those in positions of authority because medicine is socialized in a strongly hierarchical way (29). And when remuneration comes from performing procedures, physicians’ opin© 2014 World Stroke Organization
Leading opinion ions may also be influenced (consciously or unconsciously) by financial motives. As a consequence of these social, psychological, technological and economic factors, medical opinion may diverge from the existing evidence in the academic literature (18,30). This is the case in acute stroke therapy, where opinions about the benefit of endovascular therapy are held very strongly despite limited supporting data from clinical trials (31–34).
Clinical equipoise, opinion and consensus Recognizing the limitations of Fried’s concept of equipoise, McGill University bioethicist Benjamin Freedman proposed a widely-influential revision in 1987. Freedman argued that the ethical justification for clinical trial enrollment should depend upon ‘clinical equipoise,’ which he defined as the existence of ‘honest, professional disagreement’ within the medical community (3). Freedman allowed, and expected, that clinicians would have varying opinions about the efficacy of interventions under investigation. In fact, he argued that the ethical justification for clinical trials depended upon the existence of a multiplicity of opinions within the medical community prior to the conduct of a trial. Moreover, he specified that a trial would only be ethical if it led to the development of a new consensus where disagreement had previously existed. While Freedman’s conception of ‘clinical equipoise’ remains the standard of clinical trial ethics, his publications leave many important questions unanswered. For example, how is the diversity of opinion in the medical community to be determined, and how much disagreement is required to justify a clinical trial (35)? Most importantly, how is the relevant community to be defined with regards to the existence of ‘clinical equipoise’ around a specific question? With the development of highly specialized communities within medicine, increasing levels of expertise may be required to justify offering an opinion on any given issue (36). Importantly, Freedman’s ‘clinical equipoise’ faces deeper epistemic challenges surrounding its conceptions of opinion, uncertainty and consensus. Freedman assumes that the opinions of physicians taken in aggregate will be more reliable than the opinions of individual physicians. However, the limitations of medical opinion – particularly its susceptibility to personal and financial influences – will just as obviously apply to the multiplicity of opinions held within a community. Historical examples suggest how a widespread sense of certainty or uncertainty may arise within a community, independent of available knowledge. Freedman also assumes that the multiplicity of opinions that create ‘clinical equipoise’ exist because of a lack of medical knowledge, and that more knowledge will therefore produce consensus. This characterization of medicine’s epistemic landscape now appears to be inaccurate: for example, physicians are slow to adopt new practices, even in relation to widely publicized and highly rigorous clinical trials (2). Most disagreements over how to manage patients are not purely the product of differences in medical knowledge. Rather, disagreements usually reflect differences in the totality of knowledge, experiences and assumptions that clinicians use to evaluate individual clinical scenarios. These evaluations are what philosophers call ‘projectibility judgments,’ Vol 10, January 2014, 2–6
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Leading opinion in that they refer to decisions about whether a particular hypothesis is plausible (or ‘projectible’) on the basis of previously accepted research and experiences (37). Disagreements that depend upon projectibility judgments cannot be resolved by only one trial, regardless of how rigorously it may be performed (38). However, that is exactly the requirement mandated by Freedman’s concept of ‘clinical equipoise.’
Introducing fallibility That the ethics of clinical trial enrollment should somehow depend upon epistemic circumstances, and especially on the presence of uncertainty, is deeply appealing. Unfortunately, the definitions of uncertainty popularized by both Fried and Freedman are hard to evaluate and harder to achieve. We therefore propose a more general principle in the form of fallibility, which holds that medical knowledge is always uncertain. Whereas Freedman defines uncertainty in relation to the diversity of opinion within the medical community, fallibility holds that uncertainty is, has been, and always will be present, regardless of the state of agreement or disagreement within the medical community. All medical knowledge is incomplete, imperfect, and vulnerable to cultural and historical influences. As a consequence, any current practice is potentially eligible for investigation. While uncertainty is a necessary precondition for clinical trial enrollment, it is not a sufficient justification. Fallibility specifies that a clinical trial must be justified on the basis of its epistemic validity, meaning the strength of its central hypotheses and methodologies. For individual clinicians, the operationalization of fallibility consists of following three virtues: humility, skepticism, and caring. The principle of fallibility is related to the philosophical notion of fallibilism, which holds that ‘any of our opinions or beliefs about the outside world may turn out to be false.’ (39) Fallibilism has appeared in the writings of many scholars, and it is strongly associated with the influential 20th century philosopher of science Karl Popper. Canadian philosopher and physician Ross Upshur has previously proposed that fallibilism is the optimal epistemic approach to medical evidence, but our extension of fallibility as an ethical principle is novel (7). A fallibilistic approach to clinical research is strongly supported by studies in the history of medicine, which demonstrate how physicians of past eras have been convinced of the certainty of their opinions, only to see theories and practices evolve (40). Prominent examples of therapies that were widely accepted and then subsequently rejected include bloodletting for pneumonia, frontal lobotomy for depression, and external to internal carotid artery (EC-IC) bypass as a stroke preventative measure. The case of carotid endarterectomy provides another illustrative example. In the early 1980s, consensus within the medical community held that endarterectomy was a ‘well-established therapeutic approach’ for stroke prevention despite limited clinical trial data and mixed patient outcomes (41). Performing a clinical trial of endarterectomy vs. medical management was considered by many experts to be unethical. However, a series of large, well-designed trials completed in the late 1980s and early 1990s led to a new understanding of the utility of endarterectomy:
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M. C. F. Shamy et al. while it could be very effective in some patients (those with recent clinical events due to high grade stenoses), the vast majority of patients who had been routinely undergoing endarterectomy for decades were unlikely to have benefited (42). While practice gradually changed, consensus still remains elusive as further attempts to identify those patients most likely to benefit from surgery have led to new questions and new trials in the management of carotid stenosis (43). While fallibility recognizes that any particular practice is potentially subject to investigation, it does not require that RCTs be considered the only useful way of acquiring knowledge (6). RCTs tell us about the general efficacy of treatments for a population of patients, but can never guarantee the best treatment for any given patient. Moreover, the expectation that an RCT will be available to inform every clinical scenario is unrealistic in face of the variation produced by physicians, patients and environments. Finally, the privileged position assigned to RCT data is relatively new in the history of medicine and may eventually be supplanted by different opinions about medical evidence (44). Most importantly, fallibility does not guarantee that all clinical trials are ethical. Under equipoise, the ethical justification for a given trial depends upon the existence of uncertainty, either individually or collectively; under fallibility, uncertainty always exists. Therefore, the ethical justification for a trial depends upon its epistemic validity, meaning the strength of its central hypothesis and methodology, interpreted in light of prior knowledge and experience. While medical opinion can never be excised from medical practice, fallibility pushes clinicians to justify their opinions, to question their practices, and to consider whether the treatments under investigation in a clinical trial might not be beneficial to their patients. For example, fallibility would justify a trial of a new anticoagulant vs. warfarin if a strong argument could be made for the potential efficacy of that new agent on the basis of physiologic principles, laboratory research, and early phase trials. In contrast, a trial of orange juice vs. warfarin would likely be poorly supported by such evidence, and would be deemed unethical on these grounds. Even so sacrosanct a treatment as appendectomy could, theoretically, be subject to a clinical trial if a strong enough argument could be made that not all appendectomies may be necessary. The state of opinion within the medical community – at the level of individuals or of groups – would not be directly relevant to the ethical justification of any such trial.
Humility, skepticism and caring As we propose it, the bioethical principle of fallibility can be operationalized by individual clinicians by following three virtues: humility, skepticism, and caring. Virtues refer to qualities that are valued, desired and attainable, and that can apply to the everyday activities of individuals. Humility, a virtue advocated by Sir William Osler, refers to an ‘unpretentious openness’ about one’s own limitations (45). Faced with the results of trials that contradict one’s own opinions, a humble physician would consider the possibility that her own opinions may be wrong. In © 2014 World Stroke Organization
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M. C. F. Shamy et al. contrast, equipoise as defined by Fried does not allow for this possibility, as a clinician’s opinion (regardless of its justification) is used as the final arbiter of decisions about clinical trial enrollment. Physicians can become entrenched in their opinions and conclude that trials whose results oppose their own views must have been flawed. When humble clinicians consider that they cannot predict outcomes for all patients, the distinction between the experimental nature of clinical trials and the experimental nature of every day practice fades away. The second virtue of fallibility is skepticism, or the willingness to question the therapeutic and technological approaches of our time. The history of medicine tells of thousands of interventions that were celebrated at one time and that were eventually proven to be of limited use, or were even completely debunked (15). Many of our current treatments will likely be subject to similar re-evaluation in the coming years and decades. Skepticism involves recognizing the contingent and often arbitrary nature of medical practices, as a step towards considering why we do things the way we do, and how we might do them better. The third virtue of fallibility is the duty to care. Acknowledging the principle of fallibility means recognizing that even those treatments that we consider to be ‘standard of care’ will ultimately be modified or even rejected, and that it is the desire of clinicians to do what is best for their patients that is universal. The duty to care does not demand that there will be only one acceptable treatment strategy for a given clinical scenario. Fallibility therefore differs from clinical equipoise, which envisions the development of consensus-based ‘best practices’ from clinical trial data. Fallibility’s celebration of the duty to care condemns clinical trials that involve the withholding of treatment or the exposure of patients to harm when such practices cannot be supported by a strong epistemic foundation. For example, the famous Tuskegee experiments, in which African Americans with syphilis were denied treatment even when penicillin was available, would not be justifiable from a fallibilistic perspective. The exploitation or deception of patients to secure enrollment into trials for academic or financial purposes would also be unethical from a fallibilistic perspective, in that such behavior could not possibly be of benefit to patients, even in light of the fundamental uncertainty of medical practice.
Conclusion How should physicians approach the ethical challenges produced by the enrollment of patients into RCTs? Recent experiences in stroke medicine have highlighted the limitations of the popular principle of equipoise as a means of guiding clinicians’ decisionmaking. In this paper, we have proposed a new concept called fallibility, which we believe better addresses contemporary clinicians’ concerns surrounding the ethics of clinical trial enrollment. Supported by argumentation from history and philosophy, fallibility contends that medical knowledge is necessarily incomplete, and that any intervention may be subject to improvement. Therefore, there is always sufficient uncertainty to justify a clinical trial; in fact, every day practice involves constant experimentation. As a consequence, the ethical justification for a clinical trial must © 2014 World Stroke Organization
depend upon the trial’s epistemic validity, by which we mean the strength of the trial’s central hypothesis and methods, evaluated in light of prior knowledge and experience. If a reasonable argument can be made in favor of enrolling patients into a trial, clinicians should be humble about their own opinions, skeptical of contemporary practices, and should act in such a fashion that reflects the universal duty to care for patients. The principle of fallibility implies that the desire to do what is best for our patients is separable from the belief that we will always know what that best treatment entails.
References 1 Sackett DL. Evidence-based medicine. Semin Perinatol 1997; 21:3–5. 2 Chimowitz MI. Endovascular treatment for acute ischemic stroke – still unproven. N Engl J Med 2013; 368:952–5. 3 Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317:141–5. 4 Sackett DL. Equipoise: a term whose time (if it ever came) has surely gone. CMAJ 2000; 163:835–6. 5 Chiong W. The real problem with equipoise. Am J Bioeth 2006; 6:34– 47. 6 Miller FG, Joffe S. Equipoise and the dilemma of randomized clinical trials. N Engl J Med 2011; 364:476–80. 7 Goyal M, Shamy M, Menon BK et al. Endovascular stroke trials: why we must enroll all eligible patients. Stroke 2013; 44:3591–5. 8 Chard JA, Lilford RJ. The use of equipoise in clinical trials. Soc Sci Med 1998; 47:891–8. 9 Garcia J, Elbourne D, Snowdon C. Equipoise: a case study of the view of clinicians involved in two neonatal trials. Clin Trials 2004; 1:170–8. 10 Deng C, Hanna K, Bril V et al. Challenges of clinical trial design when there is a lack of clinical equipoise: use of a response-conditional crossover design. J Neurol 2012; 259:348–52. 11 Daston L, Galison P. Objectivity. New York, Zone Books, 2010:51. 12 Howick J. The Philosophy of Evidence-Based Medicine. Chichester, Wiley-Blackwell, 2011:24. 13 Upshur REG. A call to integrate ethics and evidence-based medicine. Virtual Mentor 2013; 15:86–9. 14 Rosenberg CE, Golden J. Framing Disease: Studies in Cultural History. New Brunswick, NJ, Rutgers University Press, 1992:xiii. 15 Pressman JD. Last Resort: Psychosurgery and the Limits of Medicine. Cambridge, Cambridge University Press, 1998:15. 16 Fried C. Medical Experimentation: Personal Integrity and Social Policy. Amsterdam, North-Holland Publishing, 1974:51. 17 Higgs J, Jones MA, Loftus S, Christensen N (eds). Clinical Reasoning in the Health Professions. Amsterdam, Elsevier, 2008:89–100. 18 Starr P. The Social Transformation of American Medicine. New York, Basic Books, 1982:136. 19 Fleck L. The Genesis and Development of a Scientific Fact. Chicago, IL, University of Chicago Press, 1979:98. 20 The IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomized controlled trial. Lancet 2012; 379:2352–63. 21 Almekhlafi MA, Hill MD. Combined intravenous and intra-arterial approach in acute stroke treatment. Expert Opin Pharmacother 2007; 8:1837–49. 22 Broderick JP, Palesh YY, Demchuk AM et al. Endovascular therapy after intravenous tPA versus tPA alone for stroke. N Engl J Med 2013; 368:893–903. 23 Ciccone A, Valvassori L, Nichelatti M et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368:904–13. 24 Kidwell CS, Jahan R, Gornbein J et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368:914–23. Vol 10, January 2014, 2–6
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Leading opinion 25 Groopman J. How Doctors Think. Boston, Houghton Mifflin Harcourt, 2007:3. 26 Croskerry P. Achieving quality in clinical decision making: cognitive strategies and detection of bias. Acad Emerg Med 2002; 9:1184–204. 27 Ioannidis JPA. Why most published research findings are false. PLoS Med 2005; 2:e124. 28 Tversky A, Kahnemann A. Judgment under uncertainty: heuristics and biases. Science 1974; 185:1124–31. 29 Montgomery K. How Doctors Think: Clinical Judgment and the Practice of Medicine. Oxford, Oxford University Press, 2005:141. 30 Hampton JR. Evidence-based medicine, opinion-based medicine, and real-world medicine. Perspect Biol Med 2002; 45:549–68. 31 Furlan A, Higashida R, Wechsler L et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II Study: a Randomized Controlled Trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282:2003–11. 32 Smith WS, Sung G, Saver J et al. Mechanical thrombectomy for acute ischemic stroke: final results of the MultiMERCI trial. Stroke 2008; 39:1205–12. 33 Penumbra Pivotal Stroke Trial Investigators. Penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke 2009; 40:2761–8. 34 Saver JL, Jahan R, Levy EI et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomized, parallel-group, non-inferiority trial. Lancet 2012; 380:1241–9.
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M. C. F. Shamy et al. 35 Cherry MJ. What are our moral duties? Critical reflections on clinical equipoise and publication ethics, clinical choices, and moral theory. J Med Philos 2013; 38:581–9. 36 Weisz G. Divide and Conquer: a Comparative History of Medical Specialization. Oxford, Oxford University Press, 2006:xvi. 37 Goodman N. Fact, Fiction, and Forecast, 4th edn. Cambridge, Harvard University Press, 1983:84. 38 Fedyk M, Shamy MCF. Projectibility, disagreement and consensus: a challenge to clinical equipoise. Theor Appl Ethics 2014; In press. 39 Upshur REG. Seven characteristics of medical evidence. J Eval Clin Pract 2000; 6:93–7. 40 Vogel MJ, Rosenberg CE (eds). The Therapeutic Revolution: Essays in the Social History of American Medicine. Philadelphia, University of Pennsylvania Press, 1979:4. 41 Allen GS, Preziosi TJ. Carotid endarterectomy: a prospective study of its efficacy and safety. Medicine 1981; 160:298–309. 42 Easton JD, Wilterdink JL. Carotid endarterectomy: trials and tribulations. Ann Neurol 1994; 35:5–17. 43 Paraskevas KI, Mikhalidis DP, Liapis CD, Veith FJ. Critique of the Carotid Revascularization versus Stenting Trial (CREST): flaws in CREST and Its Interpretation. Eur J Vasc Endovasc Surg 2013; 45:539– 45. 44 Guyatt GH. Evidence-based medicine. ACP J Club 1991; 114:A-16. 45 Coulehan J. A gentle and humane temper: humility in medicine. Perspect Biol Med 2011; 54:206–16.
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Introduction How should clinicians decide whether it is ethically justifiable to enroll their patients into randomized clinical trials (RCTs)? This question has become increasingly important as the principles of Evidence-Based Medicine (EBM) have positioned the RCT at the centre of contemporary medical knowledge (1). One of the fundamental ethical dilemmas produced by RCTs – and the one that will be considered here – is the concern that some patients will be randomized to receive an intervention that is ineffective, or at least less effective, than the intervention against which it is compared in a trial context. Physicians, nurses and students may experience significant ethical angst around randomization when they believe a priori that one intervention will be less successful. As a consequence, they may become reluctant to enroll patients into trials, which delays trial completion and can bias trial results (2). Unresolved ethical dilemmas therefore can impair the Correspondence: Michel C. F. Shamy*, The Ottawa Hospital – Civic Campus, 1053 Carling Avenue, Room C2182a, Ottawa, Ontario, Canada K1Y 1T8. E-mail: [email protected] 1 Department of Medicine (Neurology), University of Ottawa, Ottawa, ON, Canada 2 Department of History, University of Calgary, Calgary, AB, Canada 3 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada 4 Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada Received: 3 September 2014; Accepted: 10 September 2014 Conflict of interest: None declared. Financial disclosures: The writing of this manuscript was not supported by any specific funding agency or grant. DOI: 10.1111/ijs.12376
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conduct and reliability of clinical trials, threatening the ability of modern medicine to acquire knowledge and apply it to the care of patients. Traditionally, ethical concerns surrounding clinical trial randomization have been allayed by appeals to the principle of equipoise, which is generally understood to refer to the presence of uncertainty or disagreement within a medical community (3). However, equipoise is not universally accepted (4–6). Moreover, recent experiences in clinical trial design and enrollment – prominently but not exclusively in the field of stroke medicine – have raised doubts about the ability of equipoise to address 21st century concerns (7–10). Therefore, in this paper, we introduce a novel approach to the ethics of clinical trial enrollment, which we call fallibility. While equipoise justifies clinical trials on the basis of a restrictive and cumbersome definition of uncertainty, fallibility argues that all physician opinions are sufficiently uncertain to warrant investigation. As a consequence, the ethical justification for any given trial becomes a question of its epistemic validity, meaning the strength of its central hypothesis and methods. While this might appear obvious, the ethics of clinical trial enrollment has never been explicitly defined in relation to the epistemic validity of the trial itself. From the perspective of the individual clinician enrolling patients, a fallibilistic approach to clinical trial ethics is operationalized through a set of virtues: humility, skepticism, and caring. Fallibility begins from the recognition that many questions of ethics (e.g. ‘What should we do?’) are related to questions of epistemology (e.g. ‘What do we know?’) (11–13) Epistemology is the branch of philosophy that is concerned with questions of knowledge, belief and uncertainty. Moreover, fallibility applies lessons from the history of medicine by acknowledging that clinicians’ decisions are best understood within a particular historical and scientific context that determines how they conceptualize patients’ symptoms, understand disease mechanisms, and select among treatments (14). As a consequence, belief in the efficacy of a treatment needs to be qualified: a treatment is believed to be effective here and now, based on our current knowledge and values (15). However, beliefs about efficacy can and do change over time.
Equipoise and endovascular stroke trials The term ‘equipoise’ was introduced by American legal scholar Charles Fried in 1974 and was defined in reference to an individual physician’s uncertainty about the interventions being studied in a clinical trial (16). Fried argued that physicians would only be justified to enroll their patients into trials if they were undecided (i.e. did not have a preference) about the relative merits of the treatments under investigation. A physician who held the opinion that one treatment was superior to the other © 2014 World Stroke Organization
M. C. F. Shamy et al. would lack equipoise, and would be ethically prohibited from enrolling patients into that trial. Fried’s conception of equipoise therefore rests on the assumption that medical opinions about the relative efficacy of treatments should be considered stable and reliable arbiters of clinical trial enrollment. By medical opinion, we mean a clinician’s beliefs about diagnosis, prognosis and treatment in relation to a particular clinical scenario. As explored by recent scholarship in psychology, sociology and history, medical opinion arises from a complex interplay of knowledge and experience, acquired within a particular historical and cultural context (17–19). Medical opinion reflects influences that are conscious and unconscious, explicit and tacit, rational and empirical. Fried’s concept of equipoise remains popular, and has been used in the design of important clinical trials, most notably IST-3 (20). However, experiences surrounding the conduct of three recently-published RCTs in acute stroke therapy have led us to question the reliability of Fried’s equipoise. IMS-III, MR-RESCUE and SYNTHESIS sought to compare widely-used but as yet unproven endovascular therapies (mechanical thrombectomy and intra-arterial thrombolysis) to standard intravenous thrombolysis in acute ischemic stroke. Because many stroke physicians believe that endovascular therapies are the ‘intuitive solution,’ (21) they felt that they did not meet Fried’s criteria for equipoise and refused to enroll their patients into these trials (2). Despite the firmly held beliefs that led many physicians to withhold their patients from these trials, each trial failed to show the expected superiority of endovascular therapy (22–24). This scenario exemplifies three problems with Fried’s conception of equipoise. First, Fried’s equipoise requires that physicians enrolling patients into trials lack opinions of preference about one of the treatments being compared in a trial. However, physicians almost always have opinions about the value of a set of therapies in reference to a particular patient. Arguably, physicians would only lack preferences when they have no experience with the treatments in question, when absolutely no relevant data are available, or when the expected treatment effects and potential harms are both very small. Second, physicians’ opinions about the relative benefits of treatment or trial enrollment for a given patient are necessarily imprecise (25,26), reliant as they are upon general likelihoods rather than specific predictions .When a given clinical decision point is encountered infrequently, as is the case with acute stroke thrombolysis in most hospitals, this effect is magnified. Third, physician opinions are vulnerable to a number of influences that can render them unreliable (19). For example, a recent case gone very well or very badly may drive a physician’s opinion strongly in one direction (27). Moreover, there is a common tendency to be swayed by immediately appreciable effects – such as seeing an artery recanalize under angiography – despite the fact that these surrogate outcomes may not guarantee clinicallyrelevant benefits (28). Furthermore, local practice is frequently determined by those in positions of authority because medicine is socialized in a strongly hierarchical way (29). And when remuneration comes from performing procedures, physicians’ opin© 2014 World Stroke Organization
Leading opinion ions may also be influenced (consciously or unconsciously) by financial motives. As a consequence of these social, psychological, technological and economic factors, medical opinion may diverge from the existing evidence in the academic literature (18,30). This is the case in acute stroke therapy, where opinions about the benefit of endovascular therapy are held very strongly despite limited supporting data from clinical trials (31–34).
Clinical equipoise, opinion and consensus Recognizing the limitations of Fried’s concept of equipoise, McGill University bioethicist Benjamin Freedman proposed a widely-influential revision in 1987. Freedman argued that the ethical justification for clinical trial enrollment should depend upon ‘clinical equipoise,’ which he defined as the existence of ‘honest, professional disagreement’ within the medical community (3). Freedman allowed, and expected, that clinicians would have varying opinions about the efficacy of interventions under investigation. In fact, he argued that the ethical justification for clinical trials depended upon the existence of a multiplicity of opinions within the medical community prior to the conduct of a trial. Moreover, he specified that a trial would only be ethical if it led to the development of a new consensus where disagreement had previously existed. While Freedman’s conception of ‘clinical equipoise’ remains the standard of clinical trial ethics, his publications leave many important questions unanswered. For example, how is the diversity of opinion in the medical community to be determined, and how much disagreement is required to justify a clinical trial (35)? Most importantly, how is the relevant community to be defined with regards to the existence of ‘clinical equipoise’ around a specific question? With the development of highly specialized communities within medicine, increasing levels of expertise may be required to justify offering an opinion on any given issue (36). Importantly, Freedman’s ‘clinical equipoise’ faces deeper epistemic challenges surrounding its conceptions of opinion, uncertainty and consensus. Freedman assumes that the opinions of physicians taken in aggregate will be more reliable than the opinions of individual physicians. However, the limitations of medical opinion – particularly its susceptibility to personal and financial influences – will just as obviously apply to the multiplicity of opinions held within a community. Historical examples suggest how a widespread sense of certainty or uncertainty may arise within a community, independent of available knowledge. Freedman also assumes that the multiplicity of opinions that create ‘clinical equipoise’ exist because of a lack of medical knowledge, and that more knowledge will therefore produce consensus. This characterization of medicine’s epistemic landscape now appears to be inaccurate: for example, physicians are slow to adopt new practices, even in relation to widely publicized and highly rigorous clinical trials (2). Most disagreements over how to manage patients are not purely the product of differences in medical knowledge. Rather, disagreements usually reflect differences in the totality of knowledge, experiences and assumptions that clinicians use to evaluate individual clinical scenarios. These evaluations are what philosophers call ‘projectibility judgments,’ Vol 10, January 2014, 2–6
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Leading opinion in that they refer to decisions about whether a particular hypothesis is plausible (or ‘projectible’) on the basis of previously accepted research and experiences (37). Disagreements that depend upon projectibility judgments cannot be resolved by only one trial, regardless of how rigorously it may be performed (38). However, that is exactly the requirement mandated by Freedman’s concept of ‘clinical equipoise.’
Introducing fallibility That the ethics of clinical trial enrollment should somehow depend upon epistemic circumstances, and especially on the presence of uncertainty, is deeply appealing. Unfortunately, the definitions of uncertainty popularized by both Fried and Freedman are hard to evaluate and harder to achieve. We therefore propose a more general principle in the form of fallibility, which holds that medical knowledge is always uncertain. Whereas Freedman defines uncertainty in relation to the diversity of opinion within the medical community, fallibility holds that uncertainty is, has been, and always will be present, regardless of the state of agreement or disagreement within the medical community. All medical knowledge is incomplete, imperfect, and vulnerable to cultural and historical influences. As a consequence, any current practice is potentially eligible for investigation. While uncertainty is a necessary precondition for clinical trial enrollment, it is not a sufficient justification. Fallibility specifies that a clinical trial must be justified on the basis of its epistemic validity, meaning the strength of its central hypotheses and methodologies. For individual clinicians, the operationalization of fallibility consists of following three virtues: humility, skepticism, and caring. The principle of fallibility is related to the philosophical notion of fallibilism, which holds that ‘any of our opinions or beliefs about the outside world may turn out to be false.’ (39) Fallibilism has appeared in the writings of many scholars, and it is strongly associated with the influential 20th century philosopher of science Karl Popper. Canadian philosopher and physician Ross Upshur has previously proposed that fallibilism is the optimal epistemic approach to medical evidence, but our extension of fallibility as an ethical principle is novel (7). A fallibilistic approach to clinical research is strongly supported by studies in the history of medicine, which demonstrate how physicians of past eras have been convinced of the certainty of their opinions, only to see theories and practices evolve (40). Prominent examples of therapies that were widely accepted and then subsequently rejected include bloodletting for pneumonia, frontal lobotomy for depression, and external to internal carotid artery (EC-IC) bypass as a stroke preventative measure. The case of carotid endarterectomy provides another illustrative example. In the early 1980s, consensus within the medical community held that endarterectomy was a ‘well-established therapeutic approach’ for stroke prevention despite limited clinical trial data and mixed patient outcomes (41). Performing a clinical trial of endarterectomy vs. medical management was considered by many experts to be unethical. However, a series of large, well-designed trials completed in the late 1980s and early 1990s led to a new understanding of the utility of endarterectomy:
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M. C. F. Shamy et al. while it could be very effective in some patients (those with recent clinical events due to high grade stenoses), the vast majority of patients who had been routinely undergoing endarterectomy for decades were unlikely to have benefited (42). While practice gradually changed, consensus still remains elusive as further attempts to identify those patients most likely to benefit from surgery have led to new questions and new trials in the management of carotid stenosis (43). While fallibility recognizes that any particular practice is potentially subject to investigation, it does not require that RCTs be considered the only useful way of acquiring knowledge (6). RCTs tell us about the general efficacy of treatments for a population of patients, but can never guarantee the best treatment for any given patient. Moreover, the expectation that an RCT will be available to inform every clinical scenario is unrealistic in face of the variation produced by physicians, patients and environments. Finally, the privileged position assigned to RCT data is relatively new in the history of medicine and may eventually be supplanted by different opinions about medical evidence (44). Most importantly, fallibility does not guarantee that all clinical trials are ethical. Under equipoise, the ethical justification for a given trial depends upon the existence of uncertainty, either individually or collectively; under fallibility, uncertainty always exists. Therefore, the ethical justification for a trial depends upon its epistemic validity, meaning the strength of its central hypothesis and methodology, interpreted in light of prior knowledge and experience. While medical opinion can never be excised from medical practice, fallibility pushes clinicians to justify their opinions, to question their practices, and to consider whether the treatments under investigation in a clinical trial might not be beneficial to their patients. For example, fallibility would justify a trial of a new anticoagulant vs. warfarin if a strong argument could be made for the potential efficacy of that new agent on the basis of physiologic principles, laboratory research, and early phase trials. In contrast, a trial of orange juice vs. warfarin would likely be poorly supported by such evidence, and would be deemed unethical on these grounds. Even so sacrosanct a treatment as appendectomy could, theoretically, be subject to a clinical trial if a strong enough argument could be made that not all appendectomies may be necessary. The state of opinion within the medical community – at the level of individuals or of groups – would not be directly relevant to the ethical justification of any such trial.
Humility, skepticism and caring As we propose it, the bioethical principle of fallibility can be operationalized by individual clinicians by following three virtues: humility, skepticism, and caring. Virtues refer to qualities that are valued, desired and attainable, and that can apply to the everyday activities of individuals. Humility, a virtue advocated by Sir William Osler, refers to an ‘unpretentious openness’ about one’s own limitations (45). Faced with the results of trials that contradict one’s own opinions, a humble physician would consider the possibility that her own opinions may be wrong. In © 2014 World Stroke Organization
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M. C. F. Shamy et al. contrast, equipoise as defined by Fried does not allow for this possibility, as a clinician’s opinion (regardless of its justification) is used as the final arbiter of decisions about clinical trial enrollment. Physicians can become entrenched in their opinions and conclude that trials whose results oppose their own views must have been flawed. When humble clinicians consider that they cannot predict outcomes for all patients, the distinction between the experimental nature of clinical trials and the experimental nature of every day practice fades away. The second virtue of fallibility is skepticism, or the willingness to question the therapeutic and technological approaches of our time. The history of medicine tells of thousands of interventions that were celebrated at one time and that were eventually proven to be of limited use, or were even completely debunked (15). Many of our current treatments will likely be subject to similar re-evaluation in the coming years and decades. Skepticism involves recognizing the contingent and often arbitrary nature of medical practices, as a step towards considering why we do things the way we do, and how we might do them better. The third virtue of fallibility is the duty to care. Acknowledging the principle of fallibility means recognizing that even those treatments that we consider to be ‘standard of care’ will ultimately be modified or even rejected, and that it is the desire of clinicians to do what is best for their patients that is universal. The duty to care does not demand that there will be only one acceptable treatment strategy for a given clinical scenario. Fallibility therefore differs from clinical equipoise, which envisions the development of consensus-based ‘best practices’ from clinical trial data. Fallibility’s celebration of the duty to care condemns clinical trials that involve the withholding of treatment or the exposure of patients to harm when such practices cannot be supported by a strong epistemic foundation. For example, the famous Tuskegee experiments, in which African Americans with syphilis were denied treatment even when penicillin was available, would not be justifiable from a fallibilistic perspective. The exploitation or deception of patients to secure enrollment into trials for academic or financial purposes would also be unethical from a fallibilistic perspective, in that such behavior could not possibly be of benefit to patients, even in light of the fundamental uncertainty of medical practice.
Conclusion How should physicians approach the ethical challenges produced by the enrollment of patients into RCTs? Recent experiences in stroke medicine have highlighted the limitations of the popular principle of equipoise as a means of guiding clinicians’ decisionmaking. In this paper, we have proposed a new concept called fallibility, which we believe better addresses contemporary clinicians’ concerns surrounding the ethics of clinical trial enrollment. Supported by argumentation from history and philosophy, fallibility contends that medical knowledge is necessarily incomplete, and that any intervention may be subject to improvement. Therefore, there is always sufficient uncertainty to justify a clinical trial; in fact, every day practice involves constant experimentation. As a consequence, the ethical justification for a clinical trial must © 2014 World Stroke Organization
depend upon the trial’s epistemic validity, by which we mean the strength of the trial’s central hypothesis and methods, evaluated in light of prior knowledge and experience. If a reasonable argument can be made in favor of enrolling patients into a trial, clinicians should be humble about their own opinions, skeptical of contemporary practices, and should act in such a fashion that reflects the universal duty to care for patients. The principle of fallibility implies that the desire to do what is best for our patients is separable from the belief that we will always know what that best treatment entails.
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