Most phase III clinical trials today are explanatory. Because explanatory, or efficacy, trials test hypotheses under “ideal” conditions, they are not well suited to providing guidance on decisions made in most clinical care contexts. Pragmatic trials, which test hypotheses under “usual” conditions, are often better suited to this task. Yet, pragmatic, or effectiveness, trials are infrequently carried out. This mismatch between the design of clinical trials and the needs of health care professionals is frustrating for everyone involved, and explains some (...) of the challenges inherent in attempts to enhance knowledge translation and encourage evidence-based practice. The situation is more than simply frustrating, however; it is potentially unethical. Clinical trials must be socially valuable in order to (1) warrant the risks they impose on human research subjects and (2) fairly and efficiently assess new clinical interventions. Most bioethicists would agree that trials that have no social value, for instance, because their results do not have the potential to advance clinical care, should not be performed. What is less widely appreciated is that given limited research resources, trials that are more socially valuable should be preferred to trials that are less socially valuable when all else is equal. With respect to clinical trial design, I argue that while explanatory trials often have some social value, many have less social value than their pragmatic counterparts. On the basis of this general ethical assessment, I provide a preliminary defense of the position that clinical researchers should aim to conduct pragmatic trials, that is, that researchers face a burden of justification related to any idealizing elements added to trial designs. (shrink)

Philosophers of science have insisted that evidence of underlying mechanisms is required to support claims about the effects of medical interventions. Yet evidence about mechanisms does not feature on dominant evidence-based medicine “hierarchies.” After arguing that only inferences from mechanisms (“mechanistic reasoning”)—not mechanisms themselves—count as evidence, I argue for a middle ground. Mechanistic reasoning is not required to establish causation when we have high-quality controlled studies; moreover, mechanistic reasoning is more problematic than has been assumed. Yet where the problems can (...) be overcome, mechanistic reasoning can and should be used as evidence. (shrink)

Robin Nunn has argued that we should stop using the terms ‘placebo’ and ‘placebo effect’. I argue in support of Nunn’s position by considering the logic of why we perform placebo comparisons. Like all comparisons, placebo comparison is just a case of comparing one thing with another, but it is a mistake, I argue, to think of placebo comparison as a case where something is compared to ‘a placebo’. Rather, placebo comparison should be understood as a situation which sets-up the (...) treatment and control groups in a particular way; not as a case involving objects or procedures called ‘placebos’ employed in order to control for ‘placebo effects’. (shrink)

The explanatory/pragmatic-trial distinction enjoys a burgeoning philosophical and medical literature and a significant contingent of support among philosophers and healthcare stakeholders as an important way to assess the design and results of randomized controlled trials. A major motivation has been the need to provide relevant, generalizable data to drive healthcare decisions. While talk of pragmatic and explanatory trials could be seen as convenient shorthand, the distinction can also be seen as harboring deeper issues related to inferential strategies used to evaluate (...) causal claims regarding medical treatments. A comprehensive, critical analysis of the distinction and underlying epistemological framework upon which the distinction is based, particularly with respect to treatment effectiveness, has yet to be forthcoming. I provide this, analyzing the distinction’s relationship to generalizability and cognate distinctions between ideal conditions and real-world practice, internal and external validity, and efficacy and effectiveness. I also analyze recent philosophical work that relies on the explanatory/pragmatic-trial distinction and that advocates for more pragmatic trials. I conclude that as an organizing principle for trial-design decisions and trial evaluation, the explanatory/pragmatic-trial distinction is conceptually problematic and not as useful as its proponents seem to think. Since some pragmatic-trial features can be inimical to establishing treatment effectiveness, pragmatic-trial features should not be conflated with pragmatic trials’ avowed goals. If the distinction is to be useful, it and some associated concepts, including generalizability, should be reformulated, lest they continue to underlie a medical epistemology that could contribute to methodologically flawed and potentially unethical advice for the design and interpretation of trials. (shrink)

Philosophical Investigations, Volume 45, Issue 4, Page 414-429, October 2022.

Unlike its friendly cousin the placebo effect, the nocebo effect has been almost ignored. Epistemic and ethical confusions related to its existence have gone all but unnoticed. Contrary to what is often asserted, adverse events following from taking placebo interventions are not necessarily nocebo effects; they could have arisen due to natural history. Meanwhile, ethical informed consent has centred almost exclusively on the need to inform patients about intervention risks with patients to preserve their autonomy. Researchers have failed to consider (...) the harm caused by the way in which the information is conveyed. In this paper, I argue that the magnitude of nocebo effects must be measured using control groups consisting of untreated patients. And, because the nocebo effect can produce harm, the principle of non-maleficence must be taken into account alongside autonomy when obtaining informed consent and communicating intervention risks with patients. There are no data in this work. (shrink)

Unlike its friendly cousin the placebo effect, the nocebo effect (the effect of expecting a negative outcome) has been almost ignored. Epistemic and ethical confusions related to its existence have gone all but unnoticed. Contrary to what is often asserted, adverse events following from taking placebo interventions are not necessarily nocebo effects; they could have arisen due to natural history. Meanwhile, ethical informed consent (in clinical trials and clinical practice) has centred almost exclusively on the need to inform patients about (...) intervention risks with patients to preserve their autonomy. Researchers have failed to consider the harm caused by the way in which the information is conveyed. In this paper, I argue that the magnitude of nocebo effects must be measured using control groups consisting of untreated patients. And, because the nocebo effect can produce harm, the principle of non-maleficence must be taken into account alongside autonomy when obtaining (ethical) informed consent and communicating intervention risks with patients. (shrink)

What makes a high-quality biomarker experiment? The success of personalized medicine hinges on the answer to this question. Unfortunately, as many commentators have now emphasized, the quality of most biomarker experiments to date has been quite low. Although the technical side of this problem has received considerable attention, the philosophical issues remain largely unexplored. In this paper, I argue that understanding what constitutes a high-quality biomarker experiment requires some fundamental shifts in how we think about the epistemology, ontology, and methodology (...) of clinical translation. (shrink)

The revised Declaration of Helsinki allows placebo-controlled trials to be used even when there is an established therapy, provided there are adequate ‘methodological’ reasons for doing so. This seems to violate the principle of beneficence: where there is an established therapy, physicians treating patients with a placebo are withholding a known effective therapy. Because of this problem, we hypothesised that clinical researchers may be unwilling to risk violating the principle of beneficence and employ placebo-controlled trials in cases where there is (...) an established therapy. In this paper, we began to investigate this hypothesis. After summarising the arguments for and against using placebo controls in clinical practice, we exploredthe extent to which placebo-controlled trials are used in cases where there is an established therapy. To do this, we conducted as systematic search for all placebo-controlled trials published in 2015 in the five highest impact general medical journals. We identified 70 placebo-controlled trials. Of these, 66 were for indications where there was no established effective therapy. Only four used a placebo control in spite of there being an available effective therapy. The infrequent use of placebo controlled trials where established therapy exists highlights a seeming discrepancy between what the Declaration of Helsinki allows and what clinical investigators believe to be ethically acceptable. The evidence presented in this paper suggests that the Declaration of Helsinki be reconsidered, and perhaps revised, in light of actual practice. (shrink)

In the first half of this dissertation, I develop a heuristic methodology for analyzing scientific solutions to the problem of underdetermination. Heuristics are rough-and-ready procedures used by scientists to construct models, design experiments, interpret evidence, etc. But as powerful as they are, heuristics are also error-prone. Therefore, I argue that they key to prudently using a heuristic is the articulation of meta-heuristics---guidelines to the kinds of problems for which a heuristic is well- or ill-suited. Given that heuristics will introduce certain (...) errors into our scientific investigations, I emphasize the importance of a particular category of meta-heuristics involving the search for robust evidence. Robustness is understood to be the epistemic virtue bestowed by agreement amongst multiple modes of determination. The more modes we have at our disposal, and the more these confirm the same result, the more confident can we be that a result is not a mere artifact of some heuristic simplification. Through an analysis of case-studies in the philosophy of biology and clinical trials, I develop a principled method for modeling and evaluating heuristics and robustness claims in a qualitative problem space. The second half of the dissertation deploys the heuristic methodology to address ethical and epistemological issues in the science of clinical trials. To that end, I develop a network model for the problem space of clinical research, capable of representing the various kinds of experiments, epistemic relationships, and ethical justifications intrinsic to the domain. I then apply this model to ongoing research with the antibacterial agent, moxifloxacin, for the treatment of tuberculosis, tracking its development from initially successful and promising in vitro and animal studies to its disappointing and discordant performance across five human efficacy trials. Given this failure to find a robust result with moxifloxacin across animal and human studies, what should researchers now do? While my final analysis of this case does not definitively answer that question, I demonstrate how my methodology, unlike a statistical meta-analysis, helps to clarify the directions for further research. (shrink)

The beliefs involved in the placebo effect are often assumed to be self-fulfilling, that is, the truth of these beliefs would merely require the patient to hold them. Such a view is commonly shared in epistemology. Many epistemologists focused, in fact, on the self-fulfilling nature of these beliefs, which have been investigated because they raise some important counterexamples to Nozick’s “tracking theory of knowledge.” We challenge the self-fulfilling nature of placebo-based beliefs in multi-agent contexts, analyzing their deep epistemological nature and (...) the role of higher-order beliefs involved in the placebo effect. (shrink)

Increasing philosophical attention is being directed to the rapidly growing discipline of evidence-based medicine. Philosophical discussions of EBM, however, remain narrowly focused on randomization, mechanisms, and the sociology of EBM. Other aspects of EBM have been all but ignored, including the nature of clinical reasoning and the question of whether it can be standardized; the application of EBM principles to the logic, value, and ethics of diagnosis and prognosis; evidence synthesis ; and the nature and ethics of placebo controls. Philosophical (...) analysis in each of these areas has the potential to enhance the discussion of EBM methodology and practice. (shrink)

Hierarchies of evidence are an important and influential tool for appraising evidence in medicine. In recent years, hierarchies have been formally adopted by organizations including the Cochrane Collaboration [1], NICE [2,3], the WHO [4], the US Preventive Services Task Force [5], and the Australian NHMRC [6,7]. The development of such hierarchies has been regarded as a central part of Evidence-Based Medicine, a movement within healthcare which prioritises the use of epidemiological evidence such as that provided by Randomised Controlled Trials. Philosophical (...) work on the methodology of medicine has so far mostly focused on claims about the superiority of RCTs, and hence has largely neglected the questions of what hierarchies are, what assumptions they require, and how they affect clinical practice. This thesis shows that there is great variation in the hierarchies defended and in the interpretations they are, and can be, given. The interpretative assumptions made in using hierarchies are crucial to the content and defensibility of the underlying philosophical commitments concerning evidence and medical practice. Once this variation is been identified, it becomes clear that the little philosophical work that has been done so far affects only some hierarchies, under some interpretations. Modest interpretations offered by La Caze [11], conditional hierarchies like GRADE [12-14], and heuristic approaches such as that defended by Howick et al. [15,16] all survive previous philosophical criticism. This thesis extends previous criticisms by arguing that modest interpretations are so weak as to be unhelpful for clinical practice; that GRADE and similar conditional models omit clinically relevant information, such as information about variation in treatments’ effects and the causes of different responses to therapy; and that heuristic approaches lack the necessary empirical support. The conclusion is that hierarchies in general embed untenable philosophical assumptions: principally that information about average treatment effects backed by high-quality evidence can justify strong recommendations, and that the impact of evidence from individual studies can and should be appraised in isolation. Hierarchies are a poor basis for the application of evidence in clinical practice. The Evidence-Based Medicine movement should move beyond them and explore alternative tools for appraising the overall evidence for therapeutic claims. (shrink)

Debates about the ethics and effects of placebos and whether ‘placebos’ in clinical trials of complex treatments such as acupuncture are adequate rage. Yet there is currently no widely accepted definition of the ‘placebo’. A definition of the placebo is likely to inform these controversies. Grünbaum’s characterization of placebos and placebo effects has been touted by some authors as the best attempt thus far, but has not won widespread acceptance largely because Grünbaum failed to specify what he means by a (...) therapeutic theory and because he does not stipulate a special role for expectation effects. Grünbaum claims that placebos are treatments whose ‘characteristic features’ do not have therapeutic effects on the target disorder. I show that with four modifications, Grünbaum’s definition provides a defensible account of placebos for the purpose of constructing placebo controls within clinical trials. The modifications I introduce are: adding a special role for expectations, insisting that placebo controls control for all and only the effects of the incidental treatment features, relativizing the definition of placebos to patients, and introducing harmful interventions and nocebos to the definitional scheme. I also provide guidance for classifying treatment features as characteristic or incidental. (shrink)

John Worrall and Nancy Cartwright have both argued that randomized controlled trials are “testing the wrong theory.” They claim that RCTs are designed to test inferences about the causal relationships in the study population, but this does not guarantee a justified inference about the causal relationships in the more diverse population in clinical practice. In this article I argue that the epistemology of theory testing in trials is more complicated than either Worrall’s or Cartwright’s accounts suggest. I illustrate this more (...) complex theoretical structure with case studies in medical theory testing from Alzheimer’s research and anticancer drugs in personalized medicine. (shrink)

In robustness analysis, hypotheses are supported to the extent that a result proves robust, and a result is robust to the extent that we detect it in diverse ways. But what precise sense of diversity is at work here? In this paper, I show that the formal explications of evidential diversity most often appealed to in work on robustness – which all draw in one way or another on probabilistic independence – fail to shed light on the notion of diversity (...) relevant to robustness analysis. I close by briefly outlining a promising alternative approach inspired by Horwich’s (1982) eliminative account of evidential diversity. (shrink)

What makes a high-quality biomarker experiment? The success of personalized medicine hinges on the answer to this question. In this paper, I argue that judgment about the quality of biomarker experiments is mediated by the problem of theoretical underdetermination. That is, the network of biological and pathophysiological theories motivating a biomarker experiment is sufficiently complicated that it often frustrates valid interpretation of the experimental results. Drawing on a case-study in biomarker diagnostic development from neurooncology, I argue that this problem of (...) underdetermination can be overcome with greater coordination across the biomarker research trajectory. I then sketch an account for how coordination across a research trajectory can be evaluated. I ultimate conclude that what makes a high-quality biomarker experiment must be judged by the epistemic contribution it makes to this coordinated research effort. (shrink)

This thesis examines philosophical controversies surrounding the evaluation of medical treatments, with a focus on the evidential roles of randomised trials and mechanisms in Evidence-Based Medicine. Current 'best practice' usually involves excluding non-randomised trial evidence from systematic reviews in cases where randomised trials are available for inclusion in the reviews. The first paper challenges this practice and evaluates whether adding of evidence from non-randomised trials might improve the quality and precision of some systematic reviews. The second paper compares the alleged (...) methodological benefits of randomised trials over observational studies for investigating treatment benefits. It suggests that claims about the superiority of well-conducted randomised controlled trials over well-conducted observational studies are justified, especially when results from the two methods are contradictory. The third paper argues that postulating the unpredictability paradox in systematic reviews when no detectable empirical differences can be found requires further justification. The fourth paper examines the problem of absence causation in the context of explaining causal mechanisms and argues that a recent solution is incomplete and requires further justification. Solving the problem by describing absences as causes of 'mechanism failure' fails to take into account the effects of absences that lead to vacillating levels of mechanism functionality. The fifth paper criticises literature that has emphasised functioning versus 'broken' or 'non-functioning' mechanisms emphasising that many diseases result from increased or decreased mechanism function, rather than complete loss of function. Mechanistic explanations must account for differences in the effectiveness of performed functions, yet current philosophical mechanistic explanations do not achieve this. The last paper argues that the standard of evidence embodied in the ICE theory of technological function is too permissive for evaluating whether the proposed functions of medical technologies have been adequately assessed and correctly ascribed. It argues that high-quality evidence from clinical studies is necessary to justify functional ascriptions to health care technologies. (shrink)

It has been almost 20 years since the field of bioethics was galvanized by a controversial series of multinational AZT trials employing placebo controls on pregnant HIV-positive women in the developing world even though a standard of care existed in the sponsor countries. The trove of ethical investigations that followed was thoughtful and challenging, yet an important and problematic methodological assumption was left unexplored. In this article, I revisit the famous “double standard of care” case study in order to offer (...) novel consideration of the placebo orthodoxy that underlies much of the ethical debate. This majority view found in medical research is that placebo-controlled trials are methodologically superior to comparative trials that use active controls. I challenge this orthodoxy and argue that lives were unnecessarily lost in these trials as a result. Furthermore, current HIV research on vaccines and microbicides is now poised to repeat the error of subscribing to the placebo orthodoxy. (shrink)

According to Howick (2009a), the three main reasons for believing that placebo-controlled trials (PCTs) are methodologically superior to active-controlled trials (ACTs)—sensitivity, absolute effect...

A resilient issue in research ethics is whether and when a placebo-controlled trial is justified if it deprives research subjects of a recognized treatment. The clinicians' moral duty to provide the best available care seems to require the use of ‘active’ controlled trials that use an established treatment as a control whenever such a therapy is available. In another regard, ACTs are supposedly methodologically inferior to PCTs. Hence, the moral duty of the clinical researcher to use the best methods will (...) favor PCTs. In this target article, I analyze the three reasons for believing that ACTs are inferior to PCTs namely: 1) ACTs lack ‘assay sensitivity’; 2) ACTs do not measure absolute effect size; and 3) ACTs require more participants; and I contend that none are acceptable. Consequently the tension between clinical and research ethics dissolves: the moral duty of the clinician to avoid PCTs is unopposed by methodological considerations. (shrink)