Democratic alternation in power involves uncontrolled policy experiments. One party is elected on one policy platform that it then implements. Things may go well or badly. When another party is elected in its place, it implements a different policy. In imposing policies on the whole community, parties in effect conduct non-randomized trials without control groups. In this paper, we endorse the general idea of policy experimentation but we also argue that it can be done better by deploying in policymaking (...) randomized controlled trials. We focus primarily on the democratic benefits of using randomized trials in policymaking and on how they can enhance the democratic legitimacy of policy. We argue that randomized trials resonate well with three key democratic principles: non-arbitrariness, revisability and public justification. Randomized trials’ contribution to non-arbitrariness and revisability is not unique; other types of evidence can advance these democratic principles as well. But through their peculiar democratic scrutability, randomized trials are well-equipped to contribute to the public justifiability of policy. (shrink)

It is sometimes thought that randomized study group allocation is uniquely proficient at producing comparison groups that are evenly balanced for all confounding causes. Philosophers have argued that in real randomized controlled trials this balance assumption typically fails. But is the balance assumption an important ideal? I run a thought experiment, the CONFOUND study, to answer this question. I then suggest a new account of causal inference in ideal and real comparative group studies that helps clarify the roles of (...) confounding variables and randomization. 1Confounders and Causes2The Balance Assumption3The CONFOUND Study 3.1CONFOUND 13.2CONFOUND 24Disjunction C and the Ideal Study 4.1The ultimate ‘other cause’: C4.2The ideal comparative group study4.3Required conditions for causal inference5Confounders as Causes, Confounders as Correlates6Summary. (shrink)

"Cluster randomized trials," in which groups of patients are randomly assigned to different therapeutic interventions, provide a powerful way of evaluating drugs. CRTs have not been widely used, in good part because of concerns about whether patients must give informed consent to participate in them. A better understanding of how CRTs fit into clinical practice resolves the concerns.

Owing to unique features of their design, cluster randomized trials complicate the interpretation of standard ethics guidelines. The recently published Ottawa statement on the ethical design and conduct of cluster randomized trials provides researchers and research ethics committees with detailed guidance on the design, conduct and review of cluster trials. The Ottawa statement sets out 15 recommendations, including guidance on the justification of study design, the need for research ethics committee review, the identification of research participants, obtaining (...) informed consent, the role of gatekeepers in protecting cluster interests, the assessment of benefits and harms, and the protection of vulnerable participants. (shrink)

Owing to unique features of their design, cluster randomized trials complicate the interpretation of standard ethics guidelines. The recently published Ottawa statement on the ethical design and conduct of cluster randomized trials provides researchers and research ethics committees with detailed guidance on the design, conduct, and review of cluster trials. The Ottawa statement sets out 15 recommendations, including guidance on the justification of study design, the need for research ethics committee review, the identification of research participants, obtaining (...) informed consent, the role of gatekeepers in protecting cluster interests, the assessment of benefits and harms, and the protection of vulnerable participants. (shrink)

This thesis addresses the tension in pragmatic cluster-randomized trials between their social value and the requirement to respect the autonomy of research participants. Pragmatic trials are designed to evaluate the effectiveness of treatments in real-world settings to inform clinical decision-making and promote cost-efficient care. These trials are often embedded into clinical settings and ideally include all patients who would receive the treatments under investigation as a part of routine care. Trialists increasingly adopt cluster-randomized designs—in which intact groups, (...) such as hospitals or clinics, are allocated randomly to study interventions—to simplify the inclusion of all patients. But including all-comers conflicts with the requirement to obtain written informed consent from research participants. Since informed consent is central to respecting patient autonomy, the question arises: how can the ends of autonomy and pragmatism be served simultaneously? Some philosophers argue that patients have an obligation to participate in clinical research and that this may negate consent requirements. I argue that while there may be grounds for a prima facie obligation for patients to participate in clinical research, no compelling argument has demonstrated that the obligation is enforceable. Others assert that broad application of a waiver of consent will facilitate the conduct of pragmatic cluster-randomized trials. I demonstrate that this proposal sharply conflicts with the historical origins of the waiver. I articulate a novel moral foundation for the use of a waiver of consent and show that when trials evaluate treatments delivered directly to patients, the autonomy interests at stake for participants are too substantial to permit its use. My solution draws a distinction between consent requirements in existing policy and consent as an autonomous authorization. As many pragmatic cluster-randomized trials are conducted in primary care settings with no research staff, I argue that patient autonomy can be promoted and protected using clinical-style consent, in which health providers seek verbal informed consent from patients and document it in the electronic health record. This approach has been associated with high rates of recruitment and, thus, may satisfy both requirements for social value and respect for autonomy. (shrink)

Reluctance to endorse mask wearing to slow transmission of SARS-Cov-2 has been rationalized by the failure of randomized control trials (RCTs) to provide supportive evidence. In contrast, a mechanism-based approach suggests that mask wearing should be expected to reduce transmission: so that contrary evidence from RCTs likely reflects the need to focus policy attention on addressing interacting or mediating factors that offset the basic positive effect. The differing conclusions that result from these two approaches reflect the limitations of RCT-based (...) approaches that are compounded in scenarios, such as pandemics, where urgent decisions are required with limited evidence. (shrink)

Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of.

The temptation to use prospective observational studies (POS) instead of conducting difficult trials (RCTs) has always existed, but with the advent of powerful computers and large databases, it can become almost irresistible. We examine the potential consequences, were this to occur, by comparing two hypothetical studies of a new treatment: one RCT, and one POS. The POS inevitably submits more patients to inferior research methodology. In RCTs, patients are clearly informed of the research context, and 1:1 randomized allocation between (...) experimental and validated treatment balances risks for each patient. In POS, for each patient, the risks of receiving inferior treatment are impossible to estimate. The research context and the uncertainty are down-played, and patients and clinicians are at risk of becoming passive research subjects in studies performed from an outsider’s view, which potentially has extraneous objectives, and is conducted without their explicit, autonomous, and voluntary involvement and consent. (shrink)

: Recent controversial decisions to terminate several large clinical trials have called attention to the need for developing a sound ethical framework to determine when trials should be stopped in light of emerging efficacy data. Currently, the fundamental rationale for stopping trials early is based on the principle that equipoise has been disturbed. We present an analysis of the ethical and practical problems with the "equipoise disturbed" position and describe an alternative ethical framework based on the principle (...) of nonexploitation. This framework acknowledges the need for balancing the dual ethical obligations of clinical research, the protection of human subjects and the generation of new medical knowledge. Based on this framework, we put forward a proposal to make early stopping guidelines more stringent under specified conditions. The temporary withholding of apparent benefits in certain circumstances is justified by achieving a fair contract with the research participants, one that protects them from undue harm and exploitation while reducing the many uncertainties surrounding new investigational treatments that arise when trials are stopped prematurely. (shrink)

Although the use of the cluster randomized trial (CRT) design to evaluate vaccines, public health interventions or health systems is increasing, the ethical issues posed by the design are not adequately addressed, especially in low- and middle-income country settings (LMICs). To help reveal ethical challenges, qualitative interviews were conducted with key stakeholders experienced in designing and conducting two selected CRTs in Malawi. The 18 interviewed stakeholders included investigators, clinicians, nurses, data management personnel and community workers who were invited to share (...) their experiences related to implementation of CRTs. Data analysis revealed five major themes with ethical implications: (1) The moral obligation for health care providers to participate in health research and its compensation; (2) Suboptimal care services compromising the integrity of CRT; (3) Ensuring scientific validity and withholding care service; (4) Obtaining valid consent and permission for waiver of consent; and (5) Inadequate risk assessment for trial participation. Understanding key ethical issues posed by CRTs in Malawi could improve ethical review and research oversight of this particular study design. (shrink)

Volume 19, Issue 10, October 2019, Page 110-111.

BackgroundCognitive impairments are a core feature in schizophrenia and are linked to poor social functioning. Numerous studies have shown that cognitive remediation can enhance cognitive and functional abilities in patients with this pathology. The underlying mechanism of these behavioral improvements seems to be related to structural and functional changes in the brain. However, studies on neural correlates of such enhancement remain scarce.ObjectivesWe explored the neural correlates of cognitive enhancement following cognitive remediation interventions in schizophrenia and the differential effect between cognitive (...) training and other therapeutic interventions or patients’ usual care.MethodWe searched MEDLINE, PsycInfo, and ScienceDirect databases for studies on cognitive remediation therapy in schizophrenia that used neuroimaging techniques and a randomized design. Search terms included randomized controlled trial, cognitive remediation, cognitive training, rehabilitation, magnetic resonance imaging, po... (shrink)

Volume 19, Issue 10, October 2019, Page 101-103.

Cluster randomised trials are an increasingly important methodological tool in health research but they present challenges to the informed consent requirement. In the relatively limited literature on the ethics of cluster research there is not much clarity about the reasons for which seeking informed consent in cluster randomised trials may be morally challenging. In this paper, I distinguish between the cases where informed consent in cluster trials may be problematic due to the distinct features of (...) ‘population-based’ interventions, which have not been adequately discussed in the research ethics literature, and the cases where informed consent may be problematic for reasons that investigators also encounter in other research designs. I claim that informed consent requirements in cluster trials should be adjusted to the level of risk involved, arguing for a more comprehensive notion of research risk than that currently found in the research ethics guidelines, and the amount of freedom to be sacrificed in relation to a particular research aim. I conclude that these two factors are the most important to consider when assessing whether a cluster study should proceed when informed consent is infeasible or difficult to obtain. (shrink)

What kinds of evidence reliably support predictions of effectiveness for health and social care interventions? There is increasing reliance, not only for health care policy and practice but also for more general social and economic policy deliberation, on evidence that comes from studies whose basic logic is that of JS Mill's method of difference. These include randomized controlled trials, case–control studies, cohort studies, and some uses of causal Bayes nets and counterfactual-licensing models like ones commonly developed in econometrics. The (...) topic of this paper is the 'external validity' of causal conclusions from these kinds of studies. We shall argue two claims. Claim, negative: external validity is the wrong idea; claim, positive: 'capacities' are almost always the right idea, if there is a right idea to be had. If we are right about these claims, it makes big problems for policy decisions. Many advice guides for grading policy predictions give top grades to a proposed policy if it has two good Mill's-method-of difference studies that support it. But if capacities are to serve as the conduit for support from a method-of-difference study to an effectiveness prediction, much more evidence, and much different in kind, is required. We will illustrate the complexities involved with the case of multisystemic therapy, an internationally adopted intervention to try to diminish antisocial behaviour in young people. (shrink)

The central dilemma concerning randomized clinical trials (RCTs) arises out of some simple facts about causal methodology (RCTs are the best way to generate the reliable causal knowledge necessary for optimally-informed action) and a prima facie plausible principle concerning how physicians should treat their patients (always do what it is most reasonable to believe will be best for the patient). A number of arguments related to this in the literature are considered. Attempts to avoid the dilemma fail. Appeals to (...) informed consent and mechanisms for minimizing the resulting harm are important for policy, but informed consent is problematic and mechanisms for minimization of harm do not address the dilemma. Appeals to some sort of contract model of justification are promising and illuminating. Keywords: randomized clinical trials, ethics CiteULike Connotea Del.icio.us What's this? (shrink)

This paper discusses the issue of overriding the right of individual consent to participation in cluster randomised trials (CRTs). We focus on CRTs testing the efficacy of non-pharmaceutical interventions. As an example, we consider school closures during the COVID-19 pandemic. In Norway, a CRT was promoted as necessary for providing the best evidence to inform pandemic management policy. However, the proposal was rejected by the Norwegian Research Ethics Committee since it would violate the requirement for individual informed consent. (...) This sparked debate about whether ethics stand in the way of evidence-based health policy, since the Norwegian Research Ethics law’s strict requirements for individual consent make it practically impossible to carry out CRTs of public health interventions. We argue that, in the case of the school closure trial, the suggested CRT would not have eliminated an epistemic gap and thus would not have justified the violation of consent rights. First, we focus on the methodological challenges to estimating quantifiable effects of school closures in the specific case of an airborne infectious disease. Second, in line with Evidential Pluralism, we highlight the value of alternative lines of evidence for informing school closure policy in a pandemic. In general, we propose that a trial requiring the waiver of participants’ consent rights must be highly likely to eliminate an epistemic gap. We elaborate on the practical aspects of this criterion and discuss the potential advantages of adding it to the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. (shrink)

This article brings a historical perspective to explain the recent dissemination of randomized controlled trials (RCTs) as the new “gold standard” method to assess international development projects. Although the buzz around RCT evaluations dates from the 2000s, we show that what we are witnessing now is a second wave of RCTs, while a first wave began in the 1960s and ended by the early 1980s. Drawing on content analysis of 123 RCTs, participant observation, and secondary sources, we compare the (...) two waves in terms of the participants in the network of expertise required to carry out field experiments and the characteristics of the projects evaluated. The comparison demonstrates that researchers in the second wave were better positioned to navigate the political difficulties caused by randomization. We explain the differences in the expertise network and in the type of projects as the result of concurrent transformations in the fields of development aid and the economics profession. We draw on Andrew Abbott’s concept of “hinges,” as well as on Bourdieu’s concept of “homology” between fields, to argue that the similar positions and parallel struggles conducted by two groups of actors in the two fields served as the basis for a cross-field alliance, in which RCTs could function as a “hinge” linking together the two fields. (shrink)

We raise a problem of applicability of RCTs to validate nuclear diagnostic imaging tests. In spite of the wide application of PET and other similar techniques that use radiopharmaceuticals for diagnostic purposes, RCT-based evidence on their validity is sparse. We claim that this is due to a general conceptual problem that we call Prevalence of Treatment, which arises in connection with designing RCTs for testing any diagnostic procedure in the present context of medical research, and is particularly apparent in this (...) case. We also identify three practical reasons why RCTs do not qualify as the best option for PET validation, which have to do with specific characteristics of nuclear diagnostic imaging, and of radiopharmaceuticals. The paper is meant to contribute both to the philosophical discussion on the EBM hierarchy of evidence, and on the specific debate on radiopharmaceuticals in nuclear medicine. (shrink)

This short review piece is from a textbook on Medical Ethics.

This article brings a historical perspective to explain the recent dissemination of randomized controlled trials (RCTs) as the new “gold standard” method to assess international development projects. Although the buzz around RCT evaluations dates from the 2000s, we show that what we are witnessing now is a second wave of RCTs, while a first wave began in the 1960s and ended by the early 1980s. Drawing on content analysis of 123 RCTs, participant observation, and secondary sources, we compare the (...) two waves in terms of the participants in the network of expertise required to carry out field experiments and the characteristics of the projects evaluated. The comparison demonstrates that researchers in the second wave were better positioned to navigate the political difficulties caused by randomization. We explain the differences in the expertise network and in the type of projects as the result of concurrent transformations in the fields of development aid and the economics profession. We draw on Andrew Abbott’s concept of “hinges,” as well as on Bourdieu’s concept of “homology” between fields, to argue that the similar positions and parallel struggles conducted by two groups of actors in the two fields served as the basis for a cross-field alliance, in which RCTs could function as a “hinge” linking together the two fields. (shrink)

Objective: Ethical guidelines are designed to ensure benefits, protection and respect of participants in clinical research. Clinical trials must now be registered on open-access databases and provide details on ethical considerations. This systematic survey aimed to determine the extent to which recently registered clinical trials report the use of standard of care and post-trial obligations in trial registries, and whether trial characteristics vary according to setting. Methods: We selected global randomized trials registered on http://www.clinicaltrials.gov and http://www.controlled-trials.com. (...) We searched for intervention trials of HIV/AIDS, malaria, and tuberculosis from 9 October 2004, the date of the most recent version of the Helsinki Declaration, to 10 April 2007. Results: We collected data from 312 trials. Fifty-eight percent (58%, 95% CI = 53 to 64) of trial protocols report informed consent. Fifty-eight percent (58%, 95% CI = 53 to 64) of trials report active controls. Almost no trials (1%, 95% CI = 0.5 to 3) mention post-trial provisions. Most trials measure surrogate outcomes. Twenty percent (20%, 95% CI = 16 to 25) of trials measure patient-important outcomes, such as death; and the odds that these outcomes are in a low income country are five times greater than for a developed country (odds ratio (OR) 5.03, 95% CI = 2.70 to 9.35, p = < 0.001). Pharmaceutical companies are involved in 28% (CI = 23 to 33) of trials and measure surrogate outcomes more often than nonpharmaceutical companies (OR 2.45, 95% CI = 1.18 to 5.09, p = 0.31). Conclusion: We found a large discrepancy in the quality of reporting and approaches used in trials in developing settings compared to wealthier settings. (shrink)

The most recent (Fifth) revision of the Declaration of Helsinki, adopted in October 2000 by the World Medical Association (WMA), reinforces the longstanding prohibition against offering placebo instead of effective therapy. The WMA left no doubt that if a beneficial treatment for a condition has already been recognised, it is unethical to offer placebo in place of such treatment to anyone in a study of the same condition. We have previously drawn attention to the discrepancy between the spirit of the (...) Declaration and the common practice of using placebo controls in randomised trials even if effective treatment exists. Despite the mandates of the Declaration of Helsinki and concern from ethicists and scientists, the US Food and Drug Administration (FDA) continues to demand and defend placebo‐controlled evidence of efficacy and safety for the development of many new pharmaceuticals, even if effective therapy exists. We suggest that the FDA's arguments defending their practice are insufficient to justify medical research that violates the Declaration of Helsinki. (shrink)

Biomedical research and study design have recently been examined in detail by philosophers of science, who, like biomedical researchers, are concerned with the ability to accurately represent causal relationships through scientific study and apply these relationships to improve the health of individuals and populations. Epistemology—defined by the OED as "the theory of knowledge, especially with regard to its methods, validity, and scope, and the distinction between justified belief and opinion"—is fundamental to these concerns. In particular, philosophers of science and biomedical (...) researchers have discussed the epistemological value of randomized-controlled trials in regards to their individual components.... (shrink)

The epistemological principles underlying randomized, controlled trials and evidence-based medicine generally have not received the attention they require. Broadly speaking, they are the application of work done over several centuries in philosophy and scientific method. The epistemological base is sound, but it also implies internal limitations, having to do with decreasing generality, which particularly affect application to psychological problems. The principles also have nothing to say about values. The question of the 'objective validity' of scientific method is briefly discussed.

In his recent book, Keith Morrison argues that RCTs have garnered a privileged place in educational research, driving out other valuable approaches. Morrison acknowledges RCTs or similar designs ca...

This paper critically examines a particular strategy for resolving the central ethical dilemma associated with randomized clinical trials — the “community equipoise” strategy . The dilemma is that RCTs appear to violate a physician's duty to choose that therapy which there is most reason to believe is in the patient's best interest, randomizing patients even once evidence begins to favor one treatment. The community equipoise strategy involves the suggestion that our judgment that neither treatment is to be preferred is (...) to be assessed according to a community rather than an individual standard. Thus, though a physician may personally believe that there is some reason to prefer one treatment, patients can legitimately be randomized if there remains disagreement in the community of medical professionals. Rationales in favor of this conception include the following: medical knowledge is best understood as residing in the community, the judgments of others count as evidence, and so should change one's own opinion, subjects would not be better off outside the trial, and the point of any trial is the resolution of dispute in the medical community. I critically examine these rationales and argue that they are insufficient. Amongst the problems are tensions between various of these underlying rationales, and important ambiguities in just what the CE criterion is to amount to. Finally, I argue that even if use of CE was justified, it would not justify carrying out RCTs anywhere near long enough to discharge our duty to gain reliable knowledge on which to base safe and effective medical practice. Hence, we need some different justification for carrying out RCTs. (shrink)

Madole & Harden argue that just as the results of randomized controlled trials (RCTs) represent gains in causal knowledge and are useful, despite their limitations, so too are the findings of human behavior genetics. We argue that this analogy is misleading. Unlike RCTs, the results of human behavior genetics research cannot suggest efficacious interventions, nor point toward future research.

This paper critically examines a particular strategy for resolving the central ethical dilemma associated with randomized clinical trials (RCTs) — the “community equipoise” strategy (CE). The dilemma is that RCTs appear to violate a physician's duty to choose that therapy which there is most reason to believe is in the patient's best interest, randomizing patients even once evidence begins to favor one treatment. The community equipoise strategy involves the suggestion that our judgment that neither treatment is to be preferred (...) (that there obtains a state of “equipoise”) is to be assessed according to a community rather than an individual standard. Thus, though a physician may personally believe that there is some reason to prefer one treatment, patients can legitimately be randomized if there remains disagreement in the community of medical professionals. Rationales in favor of this conception include the following: (i) medical knowledge is best understood as residing in the community, (ii) the judgments of others count as evidence, and so should change one's own opinion, (iii) subjects would not be better off outside the trial, and (iv) the point of any trial is the resolution of dispute in the medical community. I critically examine these rationales and argue that they are insufficient. Amongst the problems are tensions between various of these underlying rationales, and important ambiguities in just what the CE criterion is to amount to. Finally, I argue that even if use of CE was justified, it would not justify carrying out RCTs anywhere near long enough to discharge our duty to gain reliable knowledge on which to base safe and effective medical practice. Hence, we need some different justification for carrying out RCTs. (shrink)