The current strategy of searching for an effective treatment for COVID-19 relies mainly on repurposing existing therapies developed to target other diseases. Conflicting results have emerged in regard to the efficacy of several tested compounds but later results were negative. The number of conducted and ongoing trials and the urgent need for a treatment pose the risk that false-positive results will be incorrectly interpreted as evidence for treatments’ efficacy and a ground for drug approval. Our purpose is twofold. First, we (...) show that the number of drug-repurposing trials can explain the false-positive results. Second, we assess the evidence for treatments’ efficacy from the perspective of evidential pluralism and argue that considering mechanistic evidence is particularly needed in cases when the evidence from clinical trials is conflicting or of low quality. Our analysis is an application of the program of Evidence Based Medicine Plus to the drug repurposing trials for COVID. Our study shows that if decision-makers applied EBM+, authorizing the use of ineffective treatments would be less likely. We analyze the example of trials assessing the efficacy of hydroxychloroquine as a treatment for COVID-19 and mechanistic evidence in favor of and against its therapeutic power to draw a lesson for decision-makers and drug agencies on how excessive hypothesis testing can lead to spurious findings and how studying negative mechanistic evidence can be helpful in discriminating genuine from spurious results. (shrink)

Experimental design is one aspect of a scientific method. A well-designed, properly conducted experiment aims to control variables in order to isolate and manipulate causal effects and thereby maximize internal validity, support causal inferences, and guarantee reliable results. Traditionally employed in the natural sciences, experimental design has become an important part of research in the social and behavioral sciences. Experimental methods are also endorsed as the most reliable guides to policy effectiveness. Through a discussion of some of the central concepts (...) associated with experimental design, including controlled variation and randomization, this chapter will provide a summary of key ethical issues that tend to arise in experimental contexts. In addition, by exploring assumptions about the nature of causation and by analyzing features of causal relationships, systems, and inferences in social contexts, this chapter will summarize the ways in which experimental design can undermine the integrity of not only social and behavioral research but policies implemented on the basis of such research. (shrink)

Gegenstand dieses Beitrags ist eine Auseinandersetzung mit der Wissenschaftlichkeit der Medizin. Den Leitfaden der Analyse bildet dabei ein jüngerer Ansatz in der analytischen Wissenschaftstheorie, wonach Systematizität als zentrales Kriterium von Wissenschaft anzusehen ist (Hoyningen-Huene 2013). Ich werde im Detail zeigen, dass die Medizin dieses mehrdimensionale Kriterium insgesamt erfüllt, dass aus der Wissenschaftlichkeit der Medizin aber gleichwohl normative Konsequenzen folgen, die beispielsweise zur Abgrenzung von der Homöopathie und einer kritischen Bewertung des biopsychosozialen Modells führen. Zudem resultieren der Anwendungscharakter der Medizin und (...) die zentrale Bedeutung des Arzt-Patienten-Verhältnisses nicht in einer Schwächung des Anspruchs der Medizin als Wissenschaft. (shrink)

Cancer research is experiencing ‘paradigm instability’, since there are two rival theories of carcinogenesis which confront themselves, namely the somatic mutation theory and the tissue organization field theory. Despite this theoretical uncertainty, a huge quantity of data is available thanks to the improvement of genome sequencing techniques. Some authors think that the development of new statistical tools will be able to overcome the lack of a shared theoretical perspective on cancer by amalgamating as many data as possible. We think instead (...) that a deeper understanding of cancer can be achieved by means of more theoretical work, rather than by merely accumulating more data. To support our thesis, we introduce the analytic view of theory development, which rests on the concept of plausibility, and make clear in what sense plausibility and probability are distinct concepts. Then, the concept of plausibility is used to point out the ineliminable role played by the epistemic subject in the development of statistical tools and in the process of theory assessment. We then move to address a central issue in cancer research, namely the relevance of computational tools developed by bioinformaticists to detect driver mutations in the debate between the two main rival theories of carcinogenesis. Finally, we briefly extend our considerations on the role that plausibility plays in evidence amalgamation from cancer research to the more general issue of the divergences between frequentists and Bayesians in the philosophy of medicine and statistics. We argue that taking into account plausibility-based considerations can lead to clarify some epistemological shortcomings that afflict both these perspectives. (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)

Proponents of evidence-based medicine have argued convincingly for applying this scientific method to medicine. However, the current methodological framework of the EBM movement has recently been called into question, especially in epidemiology and the philosophy of science. The debate has focused on whether the methodology of randomized controlled trials provides the best evidence available. This paper attempts to shift the focus of the debate by arguing that clinical reasoning involves a patchwork of evidential approaches and that the emphasis on evidence (...) hierarchies of methodology fails to lend credence to the common practice of corroboration in medicine. I argue that the strength of evidence lies in the evidence itself, and not the methodology used to obtain that evidence. Ultimately, when it comes to evaluating the effectiveness of medical interventions, it is the evidence obtained from the methodology rather than the methodology that should establish the strength of the evidence. (shrink)

Evidence-based medicine (EBM) makes use of explicit procedures for grading evidence for causal claims. Normally, these procedures categorise evidence of correlation produced by statistical trials as better evidence for a causal claim than evidence of mechanisms produced by other methods. We argue, in contrast, that evidence of mechanisms needs to be viewed as complementary to, rather than inferior to, evidence of correlation. In this paper we first set out the case for treating evidence of mechanisms alongside evidence of correlation in (...) explicit protocols for evaluating evidence. Next we provide case studies which exemplify the ways in which evidence of mechanisms complements evidence of correlation in practice. Finally, we put forward some general considerations as to how the two sorts of evidence can be more closely integrated by EBM. (shrink)

The issue of how to incorporate the individual's first‐hand experience of illness into broader medical understanding is a major question in medical theory and practice. In a philosophical context, phenomenology, with its emphasis on the subject's perception of phenomena as the basis for knowledge and its questioning of naturalism, seems an obvious candidate for addressing these issues. This is a review of current phenomenological approaches to medicine, looking at what has motivated this philosophical approach, the main problems it faces and (...) suggesting how it might become a useful philosophical tool within medicine, with its own individual, but interrelated, contribution to make to current medical debates. After the general background, there is a brief summary of phenomenological ideas and their current usage in a medical context. Next is a critique of four key claims within current phenomenological medical works, concerning both the role phenomenology plays and the supposedly clear divide between phenomenology and other approaches. There are significant problems within these claims, largely because they overlook the complexity of the questions they consider. Finally, there is some more in‐depth examination of phenomenology itself and the true complexity of phenomenological debate concerning subjectivity. The aim is to show that it will be both more productive and truer to phenomenology itself, if we use phenomenology as a philosophical method for explicating and gaining deeper understanding of complex and fundamental problems, which are central to medicine, rather than as providing simple, but flawed solutions. (shrink)

Proponents of evidence-based medicine and some philosophers of science seem to agree that knowledge of mechanisms can help solve the problem of applying results of controlled studies to target populations (‘the problem of extrapolation’). We describe the problem of extrapolation, characterize mechanisms, and outline how mechanistic knowledge might be used to solve the problem. Our main thesis is that there are four often overlooked problems with using mechanistic knowledge to solve the problem of extrapolation. First, our understanding of mechanisms is (...) often (and arguably, likely to remain) incomplete. Secondly, knowledge of mechanisms is not always applicable outside the tightly controlled laboratory conditions in which it is gained. Thirdly, mechanisms can behave paradoxically. Fourthly, as Daniel Steel points out, using mechanistic knowledge faces the problem of the ‘extrapolator’s circle’. At the same time, when the problems with mechanistic knowledge have been addressed, such knowledge can and should be used to mitigate (nothing can entirely solve) the problem of extrapolation. (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 philosophy of medicine is an area that has experienced significant growth and change in the last decade or so. While usually thought to be distinct from bioethics, the philosophy of medicine addresses a wide range of questions having to do with epistemology, metaphysics, and values. In this survey, I use the concept of the reference class to draw connections between a number of questions of longstanding and of more recent concern in the philosophy of medicine. By focusing on the (...) way in which the reference class plays a role in questions and approaches that sometimes seem to be at odds with one another, I hope to illustrate the ways in which these oppositions are less complete than they might at first appear, and to show how the connections between different problems are being redrawn. (shrink)

Medical research makes intensive use of statistics in order to support its claims. In this paper we make explicit an epistemological tension between the conduct of clinical trials and their interpretation: statistical evidence is sometimes discarded on the basis of an underlined Bayesian reasoning. We suggest that acknowledging the potentiality of Bayesian statistics might contribute to clarify and improve comprehension of medical research. Nevertheless, despite Bayesianism may provide a better account for scientific inference with respect to the standard frequentist approach, (...) Bayesian statistics is rarely adopted in clinical research. The main reason lies in the supposed subjective elements characterizing this perspective. Hence, we discuss this objection presenting the so-called Reference analysis, a formal method which has been developed in the context of objective Bayesian statistics in order to define priors which have a minimal or null impact on posterior probabilities. Furthermore, according to this method only available data are relevant sources of information, so that it resists the most common criticisms against Bayesianism. (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)

Scientism is a philosophy which purports to define what the world ‘really is’. It adopts what the philosopher Thomas Nagel called ‘an epistemological criterion of reality’, defining what is real as that which can be discovered by certain quite specific methods of investigation. As a consequence all features of experience not revealed by those methods are deemed ‘subjective’ in a way that suggests they are either not real, or lie beyond the scope of meaningful rational inquiry. This devalues capacities that (...) (we argue) are in fact essential components of good reasoning and virtuous practice. Ultimately, the implications of scientism for statements of value undermine value-judgements essential for science itself to have a sound basis. Scientism has implications, therefore, for ontology, epistemology and also for which claims we can assert as objective truths about the world. Adopting scientism as a world view will have consequences for reasoning and decision-making in clinical and other contexts. We analyse the implications of this approach and conclude that we need to reject scientism if we are to avoid stifling virtuous practice and to develop richer conceptions of human reasoning. (shrink)

In the biomedical, behavioural and social sciences, the leading method used to estimate causal effects is commonly randomised controlled trials (RCTs) that are generally viewed as both the source and justification of the most valid evidence. In studying the foundation and theory behind RCTs, the existing literature analyses important single issues and biases in isolation that influence causal outcomes in trials (such as randomisation, statistical probabilities and placebos). The common account of biased causal inference is described in a general way (...) in terms of probabilistic imbalances between trial groups. This paper expands the common account of causal bias by distinguishing between the range of biases arising between trial groups but also within one of the groups or across the entire sample during trial design, implementation and analysis. This is done by providing concrete examples from highly influential RCT studies. In going beyond the existing RCT literature, the paper provides a broader, practice-based account of causal bias that specifies the between-group, within-group and across-group biases that affect the estimated causal results of trials – impacting both the effect size and statistical significance. Within this expanded framework, we can better identify the range of different types of biases we face in practice and address the central question about the overall validity of the RCT method and its causal claims. A study can face several smaller biases (related simultaneously to a smaller sample, smaller estimated effect, greater unblinding etc.) that generally add up to greater aggregate bias. Though difficult to measure precisely, it is important to assess and provide information in studies on how much different sources of bias, combined, can explain the estimated causal effect. The RCT method is thereby often the best we have to inform our policy decisions – and the evidence is strengthened when combined with multiple studies and other methods. Yet there is room for continually improving trials and identifying ways to reduce biases they face and to increase their overall validity. Implications are discussed. (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)

According to the Russo-Williamson Thesis, causal claims in the health sciences need to be supported by both difference-making and mechanistic evidence. In this article, we attempt to determine whether Evidence-based Medicine can be improved through the consideration of mechanistic evidence. We discuss the practical composition and function of each RWT evidence type and propose that exposure-outcome evidence provides associations that can be explained through a hypothesis of causation, while mechanistic evidence provides finer-grained associations and knowledge of entities that ultimately explains (...) a causal hypothesis. We suggest that mechanistic evidence holds untapped potential to add value to the assessment of evidence quality in EBM and propose initial recommendations for the integration of mechanistic and exposure-outcome evidence to improve EBM by robustly leveraging available evidence in support of good medical decisions. (shrink)

In this essay, we defend the design of the Salk polio vaccine trial and try to put some limits on the role schemata should play in designing clinical research studies. Our presentation is structured as a response to de Freitas and Pietrobon who identified the CONSORT statement as a schema that would have, had it existed at the time, ruled out the design of the Salk polio vaccine trial of 1954 in favor of a completely randomized controlled clinical trial. We (...) argue that large-scale public health interventions often require evidence beyond simple efficacy, the limit of what an RCT can provide, and that the design actually adopted for the Salk trial represented a reasonable—albeit imperfect—compromise. This is of more than historical interest in that many contemporary studies are of the scale and scope to require a more pragmatic, rather than explanatory, approach to study design. (shrink)

This article considers the prospects of inference to the best explanation as a method of confirming causal claims vis-à-vis the medical evidence of mechanisms. I show that IBE is actually descriptive of how scientists reason when choosing among hypotheses, that it is amenable to the balance/weight distinction, a pivotal pair of concepts in the philosophy of evidence, and that it can do justice to interesting features of the interplay between mechanistic and population level assessments.

Within public health, and increasingly other areas of social policy, there are widespread calls to increase or improve the use of evidence for policy-making. Often these calls rest on an assumption that increased evidence utilisation will be a more efficient or effective means of achieving social goals. Yet a clear elucidation of what can be considered “good evidence” for policy is rarely articulated. Many of the current discussions of best practise in the health policy sector derive from the evidence-based medicine (...) movement, embracing the “hierarchy of evidence” that places experimental trials as pre-eminent in terms of methodological quality. However, a number of problems arise if these hierarchies are used to rank or prioritise policy relevance. Challenges in applying evidence hierarchies to policy questions arise from the fact that the EBM hierarchies rank evidence of intervention effect on a specified and limited number of outcomes. Previous authors have noted that evidence forms at the top of... (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)

The present paper deals with the problem of evaluating empirical evidence for therapeutic decisions in medicine. The article discusses the views of Nancy Cartwright and John Worrall on the function that randomization plays in ascertaining causal relations with reference to the therapies applied. The main purpose of the paper is to present a general idea of alternative method of evaluating empirical evidence. The method builds on data analysis that makes use of rough set theory. The first attempts to apply the (...) method show that it is an interesting alternative to randomized controlled trials. (shrink)

The replication crisis has spawned discussions on the meaning of replication. In fact, in order to determine whether an experiment fails to replicate, it is necessary to establish what replication is. This is, however, a difficult task, as it is possible to attribute different meanings to it. This paper offers a solution to this problem of ambiguity by engineering a concept of replication that, if compared to other proposals, stands out for being not only broadly applicable but also sufficiently specific. (...) It features a minimal level of operationalism, which would otherwise limit its applicability, while it heavily relies on replication’s specific epistemic functions, which are inter-disciplinary. Another merit is its context sensitivity, which enables it to differentiate instances of replication from non-instances of replication in every scientific discipline according to the discipline’s own standards. (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)

The UK’s National Institute for Health and Care Excellence is responsible for conducting health technology assessment on behalf of the National Health Service. In seeking to justify its recommendations to the NHS about which technologies to fund, NICE claims to adopt two complementary ethical frameworks, one procedural—accountability for reasonableness —and one substantive—an ‘ethics of opportunity costs’ that rests primarily on the notion of allocative efficiency. This study is the first to empirically examine normative changes to NICE’s approach and to analyse (...) whether these enhance or diminish the fairness of its decision-making, as judged against these frameworks. It finds that increasing formalisation of NICE’s approach and a weakening of the burden of proof laid on technologies undergoing HTA have together undermined its commitment to EOC. This implies a loss of allocative efficiency and a shift in the balance of how the interests of different NHS users are served, in favour of those who benefit directly from NICE’s recommendations. These changes also weaken NICE’s commitment to AfR by diminishing the publicity of its decision-making and by encouraging the adoption of rationales that cannot easily be shown to meet the relevance condition. This signals a need for either substantial reform of NICE’s approach, or more accurate communication of the ethical reasoning on which it is based. The study also highlights the need for further empirical work to explore the impact of these policy changes on NICE’s practice of HTA and to better understand how and why they have come about. (shrink)

Resumen En este artículo propongo un análisis crítico de varias tendencias filosóficas contrarias al uso de la noción de verdad en el ámbito epistemológico, especialmente la de Rorty. En particular, sostengo que la verdad es un concepto clave para el estudio del conocimiento, especialmente el científico, en cuanto toma una forma concisa en los procedimientos experimentales de carácter probatorio-empírico. Gracias a este enfoque, busco socavar varias tesis de los enfoques de la ‘posverdad’ por medio del uso de un conjunto de (...) procedimientos científicos de obtención de evidencias en varios campos vinculados a la disciplina práctica de la medicina.In thispaper, I present a critical analysis of several philosophical tendencies that go against the use of the notion of truth in epistemology, especially Rorty’s one. Particularly, I claim that truth is a key conceptfor the study of knowledge, especially the scientific knowledge, as it takes a concise form through the experimentalprocedures for eliciting evidences. With the help of this analysis, I seek to undermine some ‘post-truth’ theses by means of analyying some scientific procedures to get evidences in severalfields related to the practical discipline of medicine. (shrink)

This chapter addresses the problem of ranking available drugs in guideline development to support clinicians in their work. Based on a pragmatic approach to the notion of evidence and a hierarchical view on different kinds of evidence this chapter introduces a decision aid, HiDAD, which draws on the multi criteria decision making literature. This decision aid implements the wide-spread intuition that there are different kinds of evidence with varying degrees of importance by relying on a strict ordinal ordering of kinds (...) of evidence. In order to construct a ranking every pair of drugs is first compared separately on all kinds of evidence. Next, these quantitative comparisons are then aggregated into an overall comparison between drugs based on all the available evidence in a way which avoids that evidence of less importance is trumped by evidence of the higher levels. Finally, these overall comparisons are used to determine the final ranking of drugs which then informs the process of guideline writing. Properties, modifications and applicability of the decision aid HiDAD are discussed and assessed. (shrink)

NAIRN S. Nursing Inquiry 2012; 19: 6–17 A critical realist approach to knowledge: implications for evidence‐based practice in and beyond nursingThis paper will identify some of the key conceptual tools of a critical realist approach to knowledge. I will then apply these principles to some of the competing epistemologies that are prevalent within nursing. There are broadly two approaches which are sometimes distinct from each other and sometimes inter‐related. On one side, there is the view that all healthcare interventions should (...) be judged on the principles of randomised controlled trials and the other is a preoccupation with language in which healthcare interventions are subjected to a discursive interrogation. These debates are configured through the idea of a hierarchy of knowledge that is accorded uncritical acceptance by some and virulent distaste by others. I will argue that the notion of hierarchy is problematic and is largely argued for in unproductive epistemological terms. What is required is a shift towards a theory that emphasises the contextual nature of the ways that knowledge is produced and disseminated. In other words, there is no single hierarchy of knowledge, but there are multiple hierarchies of knowledge. (shrink)

There are some philosophical questions that can be answered without attention to the social context in which evidence is produced and distributed.ing away from social context is an excellent way to ignore messy details and lay bare the underlying structure of the limits of inference. Idealization is entirely appropriate when one is essentially asking: In the best of all possible worlds, what am I entitled to infer? Yet, philosophers’ concerns often go beyond this domain. As an example I examine the (...) debate on mechanistic evidence and then reevaluate a canonical case study in this debate. I show that for the assessment of actual evidence, produced in a world that is far from ideal, omission of the social aspects of medical epistemology leads philosophers to draw the wrong lessons from cases they take as paradigmatic cases for their views. I close by arguing that social epistemology provides an avenue to incorporate these complications and provides the necessary framework to understand medical evidence. (shrink)