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)

Despite the increasing recognition that heuristics may be involved in myriad scientific activities, much about how to use them prudently remains obscure. As typically defined, heuristics are efficient rules or procedures for converting complex problems into simpler ones. But this increased efficiency and problem-solving power comes at the cost of a systematic bias. As Wimsatt showed, biased modelling heuristics can conceal errors, leading to poor decisions or inaccurate models. This liability to produce errors presents a fundamental challenge to the philosophical (...) value of heuristic analyses. Heuristics may be powerful and efficient procedures, but their practical value for science and epistemology is significantly mitigated if we do not have a principled methodology for knowing how to use them wisely. In this essay, I extend Wimsatt’s analyses to argue that this challenge for a heuristic methodology can be met by appealing to second-order, or meta-, heuristics—that is, practical guidelines that prescribe the appropriate conditions for a first-order heuristic’s use. 1 Introduction2 Background3 Heuristics and Meta-heuristics4 A Hierarchical Model and Three Applications4.1 Decision making in emergency medicine4.2 Mathematical explanation in physics4.3 Resilience in ecological management5 Conclusion. (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)

The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of clinical equipoise have put forward alleged counter-examples to this restriction—describing instances of ethical placebo-controlled trials that apparently violate clinical equipoise. In this essay, we respond to these examples and show that clinical equipoise is not as restrictive of placebos as these authors assume. We argue that a subtler appreciation for clinical equipoise—in particular the distinction between (...) de facto and de jure interpretations of the concept—allows the concept to explain when and why a placebo control may be necessary to answer a question of clinical importance. (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)

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)