In response to the COVID-19 pandemic, large-scale research and pharmaceutical regulatory processes have proceeded at a dramatically increased pace with new and effective, evidence-based COVID-19 interventions rapidly making their way into the clinic. However, the swift generation of high-quality evidence and the efficient processing of regulatory authorisation have given rise to more specific and complex versions of well-known research ethics issues. In this paper, we identify three such issues by focusing on the authorisation of Molnupiravir, a novel antiviral medicine aimed (...) at reducing the ability of SARS-CoV-2 to multiply in the body, for clinical use by the National Health Service in England and the concomitant testing of Molnupiravir through the large-scale PANORAMIC randomised control trial. By analysing the ways in which the authorisation and clinical use of Molnupiravir complicate standard approaches to clinical equipoise, standard of care, and participant consent in the PANORAMIC randomised control trial we will explain some of ethical implications for clinical trials that aim to study the efficacy and safety of new COVID-19 and other therapeutics when conditional authorisation has already been granted and when such treatments have already been made available to patients by national health providers. (shrink)

Objective: To examine the current ethical review process of ethics committees in a non-pharmacological trial from the perspective of a clinical investigator.Design: Prospective collection of data at the Study Centre of the German Surgical Society on the duration, costs and administrative effort of the ERP of a randomised controlled multicentre surgical INSECT Trial between November 2003 and May 2005.Setting: Germany.Participants: 18 ethics committees, including the ethics committee handling the primary approval, responsible overall for 32 clinical sites throughout Germany. 8 (...) ethics committees were located at university medical schools and 10 at medical chambers. Duration was measured as days between submission and receipt of final approval, costs in euros and administrative effort by calculation of the product of the total number of different types of documents and the mean number of copies required .Results: The duration of the ERP ranged from 1 to 176 days. The median duration was 26 days at MSUs compared with 34 days at medical chambers. The total cost was €2947. 1 of 8 ethics committees at universities and 8 of 10 at medical chambers charged a median fee of €162 . The administrative effort for primary approval was 30. Four ethics committees required a higher administrative effort for secondary approval .Conclusion: The ERP for non-pharmacological multicentre trials in Germany needs improvement. The administrative process has to be standardised: the application forms and the number and content of the documents required should be identical or at least similar. The fees charged vary considerably and are obviously too high for committees located at medical chambers. However, the duration of the ERP was, with some exceptions, excellent. A centralised ethics committee in Germany for multicentre trials such as the INSECT Trial can simplify the ERP for clinical investigators in and outside the country. (shrink)

Objectives. The purpose of this study was to conduct the first randomized controlled trial (RCT) to evaluate the effectiveness of a second-generation mindfulness-based intervention (SG-MBI) for treating fibromyalgia syndrome (FMS). Compared to first generation mindfulness-based interventions, SG-MBIs are more acknowledging of the spiritual aspect of mindfulness. Design. A RCT employing intent-to-treat analysis. Methods. Adults with FMS received an 8-week SG-MBI known as meditation awareness training (MAT; n = 74) or an active control intervention known as cognitive behaviour theory for groups (...) (n = 74). Assessments were performed at pre-, post-, and 6-month follow-up phases. Results. Meditation awareness training participants demonstrated significant and sustained improvements over control group participants in FMS symptomatology, pain perception, sleep quality, psychological distress, non-attachment (to self, symptoms, and environment), and civic engagement. A mediation analysis found that (1) civic engagement partially mediated treatment effects for all outcome variables, (2) non-attachment partially mediated treatment effects for psychological distress and sleep quality, and (3) non-attachment almost fully mediated treatment effects for FMS symptomatology and pain perception. Average daily time spent in meditation was found to be a significant predictor of changes in all outcome variables. Conclusions. Meditation awareness training may be a suitable treatment for adults with FMS and appears to ameliorate FMS symptomatology and pain perception by reducing attachment to self. (shrink)

We simulate trial data to test speculative claims about research methods, such as the impact of publication bias.

I will open the first part of this paper by trying to elucidate the frequentist foundations of RCTs. I will then present a number of methodological objections against the viability of these inferential principles in the conduct of actual clinical trials. In the following section, I will explore the main ethical issues in frequentist trials, namely those related to randomisation and the use of stopping rules. In the final section of the first part, I will analyse why RCTs (...) were accepted for regulatory purposes. I contend that their main virtue, from a regulatory viewpoint, is their impartiality, which is grounded in randomisation and fixed rules for the interpretation of the experiment. Thus the question will be whether Bayesian trials can match or exceed the achievements of frequentist RCTs in all these respects. In the second part of the paper, I will first present a quick glimpse of the introduction of Bayesianism in the field of medical experiments, followed by a summary presentation of the basic tenets of a Bayesian trial. The point here is to show that there is no such thing as “a” Bayesian trial. Bayesianism can ground many different approaches to medical experiments and we should assess their respective virtues separately. Thus I present two actual trials, planned with different goals in mind, and assess their respective epistemic, ethical and regulatory merits. In a tentative conclusion, I contend that, given the constraints imposed by our current regulatory framework, impartiality should preside over the design of clinical trials, even at the expense of many of their inferential and ethical virtues. (shrink)

There are two competing views regarding the role of mechanistic knowledge in inferences about the effectiveness of interventions. One view holds that inferences about the effectiveness of interventions should be based only on data from population-level studies (often statistical evidence from randomised trials). The other view holds that such inferences must be based in part on mechanistic evidence. The competing views are local principles of inference, the plausibility of which can be assessed by a more general normative principle (...) of inference. Bayesianism tells us to base inferences on both the ‘likelihood’ and the ‘prior’. The likelihood represents statistical evidence. One influence on the prior probability of a hypothesis like ‘d causes x’ is mechanistic knowledge of how d causes x. Thus, reasoning about such inferences by appealing to both statistical and mechanistic evidence is vindicated by our best general theory of inference. The primary contribution of this paper is to assess the merits and weaknesses of the arguments on both sides of the debate, using the Bayesian framework. This analysis lends support to those who argue that we should base our causal inferences about interventions in part on mechanistic evidence. (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)

According to manipulationist accounts of causal explanation, to explain an event is to show how it could be changed by intervening on its cause. The relevant change must be a ‘serious possibility’ claims Woodward 2003, distinct from mere logical or physical possibility—approximating something I call ‘scientific possibility’. This idea creates significant difficulties: background knowledge is necessary for judgments of possibility. Yet the primary vehicles of explanation in manipulationism are ‘invariant’ generalisations, and these are not well adapted to encoding such knowledge, (...) especially in the social sciences, as some of it is non-causal. Ceteris paribus (CP) laws or generalisations labour under no such difficulty. A survey of research methods such as case and comparative studies, randomised control trials, ethnography, and structural equation modeling, suggests that it would be more difficult and in some instances impossible to try to represent the output of each method in invariant generalisations; and that this is because in each method causal and non-causal background knowledge mesh in a way that cannot easily be accounted for in manipulationist terms. Ceteris paribus-generalisations being superior in this regard, a theory of explanation based on the latter is a better fit for social science. (shrink)

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: -/- The main aim of this review will be to assess the effects of changing practitioner empathy or patient expectations for all conditions. The main objective is to conduct a systematic review of randomised trials where the intervention involves manipulating either (a) practitioner empathy or (b) patient expectations, or (c) both.

ABSTRACT: Abstract Most modern knowledge is not science. The physical sciences have successfully validated theories to infer they can be used universally to predict in previously unexperienced circumstances. According to the conventional conception of science such inferences are falsified by a single irregular outcome. And verification is by the scientific method which requires strict regularity of outcome and establishes cause and effect. -/- Medicine, medical research and many “soft” sciences are concerned with individual people in complex heterogeneous populations. These populations (...) cannot be tested to demonstrate strict regularity of outcome in every individual. Neither randomised controlled trials nor observational studies in medicine are science in the conventional conception. Establishing and using medical and other “soft science” theories cannot be scientific. It requires conceptually different means: requiring expert judgement applying all available evidence in the relevant available factual matrix. -/- The practice of medicine is observational. Prediction of outcomes for the individual requires professional expertise applying available medical knowledge and evidence. Expertise in any profession can only be acquired through experience. Prior cases are the fundament of knowledge and expertise in medicine. Case histories, studies and series can provide knowledge of extremely high reliability applicable to establishing reliable general theories and falsifying others. Their collation, study and analysis should be a priority in medicine. Their devaluation as evidence, the failure to apply their lessons, the devaluation of expert professional judgement and the attempt to emulate the scientific method are all historic errors in the theory and practice of modern medicine. (shrink)

Evidence based-policy (EBP) is a popular research paradigm in the applied social sciences and within government agencies. Informally, EBP represents an explicit commitment to applying scientific methods to public affairs, in contrast to ideologically-driven or merely intuitive “common-sense” approaches to public policy. More specifically, the EBP paradigm places great weight on the results of experimental research designs, especially randomised controlled trials (RCTs), and systematic literature reviews that place evidential weight on experimental results. One hope is that such research (...) designs and approaches to analysing the scientific literature are sufficiently robust that they can settle what really ‘works’ in public policy. Can EBP succeed in displacing reliance on domain-specific expertise? On our account, this is seldom, if ever, the case. The key reason for this is that underlying this approach is generally an appeal to argument by induction, which always requires further assumptions to underwrite its validity, and if not induction, some other argument form that also requires assumptions that are very often not validated for the case at hand. (shrink)

Methadone maintenance therapy is a cost-effective, evidence-based treatment for heroin dependence. In the USA, a majority of heroin-dependent offenders are forced to detox from methadone when incarcerated. Recent research published in The Lancet has demonstrated the negative health and economic outcomes associated with such policies. Methadone Continuation Versus Forced Withdrawal on Incarceration in a Combined US Prison and Jail: A Randomised, Open Label Trial. The Lancet, 386, 350–359). This novel evidence raises questions as to the justification for current policies (...) of forced detox in American prisons. Opponents of methadone provision in prisons might offer arguments from retributivism, resource allocation and curative effectiveness to justify their position. This article contends that these arguments do not stand up to ethical scrutiny. In light of this, we hold that American policymakers should reform criminal justice policies to allow the initiation and continuation of methadone treatment in correctional settings. This would be consistent with both international recommendations and the example set by a number of other Western countries. (shrink)

As a way to make medical decisions, Evidence-Based Medicine (EBM) has failed. EBM's failure arises from not being founded on real-world decision-making. EBM aspires to a scientific standard for the best way to treat a disease and determine its cause, but it fails to recognise that the scientific method is inapplicable to medical and other real-world decision-making. EBM also wrongly assumes that evidence can be marshaled and applied according to an hierarchy that is determined in an argument by authority to (...) the method by which it has been obtained. If EBM had valid theoretical, practical or empirical foundations, there would be no hierarchy of evidence. In all real-world decision-making, evidence stands or falls on its inherent reliability. This has to be and can only be assessed on a case-by-case basis applying understanding and wisdom against the background of all available facts—the "factual matrix." EBM's failure is structural and was inevitable from its inception. EBM confuses the inherent reliability and probative value of evidence with the means by which it is obtained. -/- EBM is therefore an ad hoc construct and is not a valid basis for medical decision-making. This is further demonstrated by its exclusion of relevant scientific and probative real-world decision-making evidence and processes. It draws upon a narrow evidence base that is itself inherently unreliable. It fails to take adequate account of the nature of causation, the full range of evidence relevant to its determination, and differing approaches to determining cause and effect in real-world decision-making. EBM also makes a muddled attempt to emulate the scientific method and it does not acknowledge the role of experience, understanding and wisdom in making medical decisions. (shrink)

This dissertation is an investigation into how scientific values may influence the kinds of theories which are investigated, and in turn which theories become ‘mainstream’. I have focussed on psychedelic therapy as a family of theories, and I identified three main reasons as to why psychedelic therapy is somewhat incompatible with the current psychiatric paradigm: (1) the inability to conduct double-blind trials, (2) The inability to isolate one explanatory variable, and (3) The mystical and spiritual dimensions of the mechanisms (...) of action of psychedelic drugs. Because double-blind randomised controlled trials, isolating one explanatory variable, and neurobiological- style explanations of mechanisms of action are seen as an integral part of good psychiatric research, this means that psychedelic therapy is inherently disadvantaged as a research avenue in the current paradigm. These three things also arguably embody scientific values proposed by Kuhn (1977), such as accuracy, simplicity, and consistency. Helen Longino (1995) argues that Kuhn’s values do not simply increase the likelihood of a theory being true, but in some instances serve to perpetuate discriminatory ideologies. She proposes her own list of values as a route to a more equitable science, and by extension, a more equitable society. Interestingly, psychedelic therapy as a theory embodies many, if not all of the values proposed by Longino. This led me to my conclusion that if the psychiatric paradigm were more feminist according to Longino’s criteria, then psychedelic therapy would be considered a “better” theory. It would therefore be easier to conduct research in this area, and psychedelic therapy would have a better chance at becoming a mainstream treatment. (shrink)

The paper Post-Trial Acces To Treatment (PTA) offers an insight into current corporate policies and corporate best practices relating to the provision of PTA in low and middle income countries based on company sources. In these countries there is a greater appeal for pharmaceutical companies to take responsibility for providing PTA. However, the practice of providing PTA is the exception rather than the rule.

ABSTRACT Many recent articles argue that participants who seroconvert during HIV prevention trials deserve treatment when they develop AIDS, and there is a general consensus that the participants in HIV/aids treatment trials should have continuing post‐trial access. As a result, the primary concern of many ethicists and activists has shifted from justifying an obligation to treat trial participants, to working out mechanisms through which treatment could be provided. In this paper I argue that this shift frequently conceals an (...) important assumption: that if there is an obligation to supply treatment, then any party who could provide it may be prevailed upon to discharge the obligation. This assumption is false. The reasons why trial participants should get ART affect who has the duty to provide it. We should not burden governments with the obligations of sponsors, nor researchers with the obligations of the international community. And we should not deprive a group of treatment because their need is less salient than that of research participants. Insisting otherwise may lead to people being wrongfully deprived of access to antiretrovirals. (shrink)

The general aim of this article is to give a critical interpretation of post-trial obligations towards individual research participants in the Declaration of Helsinki 2013. Transitioning research participants to the appropriate health care when a research study ends is a global problem. The publication of a new version of the Declaration of Helsinki is a great opportunity to discuss it. In my view, the Declaration of Helsinki 2013 identifies at least two clearly different types of post-trial obligations, specifically, access to (...) care after research and access to information after research. The agents entitled to receive post-trial access are the individual participants in research studies. The Declaration identifies the sponsors, researchers and host country governments as the main agents responsible for complying with the post-trial obligations mentioned above. To justify this interpretation of post-trial obligations, I first introduce a classification of post-trial obligations and illustrate its application with examples from post-trial ethics literature. I then make a brief reconstruction of the formulations of post-trial obligations of the Declaration of Helsinki from 2000 to 2008 to correlate the changes with some of the most salient ethical arguments. Finally I advance a critical interpretation of the latest formulation of post-trial obligations. I defend the view that paragraph 34 of ‘Post-trial provisions’ is an improved formulation by comparison with earlier versions, especially for identifying responsible agents and abandoning ambiguous ‘fair benefit’ language. However, I criticize the disappearance of ‘access to other appropriate care’ present in the Declaration since 2004 and the narrow scope given to obligations of access to information after research. (shrink)

In this paper, Isuggest that placebo effects, as we know them today, should be understood as experimental phenomena, low-level regularities whose causal structure is grasped through particular experimental designs with little theoretical guidance. Focusing on placebo interventions with needles for pain reduction -one of the few placebo regularities that seems to arise in meta-analytical studies- I discuss the extent to which it is possible to decompose the different factors at play through more fine-grained randomized clinical trials. My sceptical argument (...) is twofold. On the one hand, I argue that experiments alone are not enough to standardize interventions, and that it is necessary to include theories. On the other hand, I argue that the social interactions that seem to be part of placebo effects are difficult, if not impossible, to blind. Therefore, the measurement biases arising from the participants’ reactivity to the experimental setup cannot be controlled for. Further decomposition of placebo effects requires a theoretical account of the existing experimental regularities that may guide further tests. (shrink)

The usage of Randomised Evaluations(REs) in social inquiry has been recent and responses to them have been wide ranging.RE seek to make predictions on the impact of an intervention, when it is attempted in a new situation. REs work by first determining the impact of the intervention. Subsequently, for the new situation it is expected that the impact would be similar. -/- The problem of induction poses one of the most serious challenges to the epistemological status of RE claims (...) as the value of REs themselve stem from their predictive validity. If the problem of induction is not solved or evaded then belief in projections based on REs is undermined. -/- In this paper, I argue that the unique methodology of REs used in Social Sciences allows itself to evade the problem the successfully, warranting belief that future interventions would have similar impact. (shrink)

I. EXECUTIVE SUMMARY The MRCT Center Post-trial Responsibilities: Continued Access to an Investigational Medicine Framework outlines a case-based, principled, stakeholder approach to evaluate and guide ethical responsibilities to provide continued access to an investigational medicine at the conclusion of a patient’s participation in a clinical trial. The Post-trial Responsibilities (PTR) Framework includes this Guidance Document as well as the accompanying Toolkit. A 41-member international multi-stakeholder Workgroup convened by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard (...) University (MRCT Center) developed this Guidance and Toolkit. Project Motivation A number of international organizations have discussed the responsibilities stakeholders have to provide continued access to investigational medicines. The World Medical Association, for example, addressed post-trial access to medicines in Paragraph 34 of the Declaration of Helsinki (WMA, 2013): “In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.” This paragraph and other international guidance documents converge on several consensus points: • Post-trial access (hereafter referred to as “continued access” in this Framework [for terminology clarification – see definitions]) is the responsibility of sponsors, researchers, and host country governments; • The plan for continued access should be determined before the trial begins, and before any individual gives their informed consent; • The protocol should delineate continued access plans; and • The plan should be transparent to potential participants and explained during the informed consent process. -/- However, there is no guidance on how to fulfill these responsibilities (i.e., linking specific responsibilities with specific stakeholders, conditions, and duration). To fill this gap, the MRCT Center convened a working group in September of 2014 to develop a framework to guide stakeholders with identified responsibilities. This resultant Framework sets forth applicable principles, approaches, recommendations and ethical rationales for PTR regarding continued access to investigational medicines for research participants. (shrink)

The current study is a pilot trial to examine the effects of a nonelective, classroom-based, teacher-implemented, mindfulness meditation intervention on standard clinical measures of mental health and affect in middle school children. A total of 101 healthy sixth-grade students (55 boys, 46 girls) were randomized to either an Asian history course with daily mindfulness meditation practice (intervention group) or an African history course with a matched experiential activity (active control group). Self-reported measures included the Youth Self Report (YSR), a modified (...) Spielberger State-Trait Anxiety Inventory, and the Cognitive and Affective Mindfulness Measure –Revised. Both groups decreased significantly on clinical syndrome subscales and affect but did not differ in the extent of their improvements. Meditators were significantly less likely to develop suicidal ideation or thoughts of self-harm than controls. These results suggest that mindfulness training may yield both unique and non-specific benefits that are shared by other novel activities. (shrink)

This paper is part of a project that is based on the notion of a dialectical system, introduced by Magari as a way of capturing trial and error mathematics. In Amidei et al. (2016, Rev. Symb. Logic, 9, 1–26) and Amidei et al. (2016, Rev. Symb. Logic, 9, 299–324), we investigated the expressive and computational power of dialectical systems, and we compared them to a new class of systems, that of quasi-dialectical systems, that enrich Magari’s systems with a natural mechanism (...) of revision. In the present paper we consider a third class of systems, that of p-dialectical systems, that naturally combine features coming from the two other cases. We prove several results about p-dialectical systems and the sets that they represent. Then we focus on the completions of first-order theories. In doing so, we consider systems with connectives, i.e. systems that encode the rules of classical logic. We show that any consistent system with connectives represents the completion of a given theory. We prove that dialectical and q-dialectical systems coincide with respect to the completions that they can represent. Yet, p-dialectical systems are more powerful; we exhibit a p-dialectical system representing a completion of Peano Arithmetic that is neither dialectical nor q-dialectical. (shrink)

When discussing the safety of research subjects, including their exploitation and vulnerability as well as failures in clinical research, recent commentators have focused mostly on countries with low or middle-income economies. High-income countries are seen as relatively safe and well-regulated. This article presents irregularities in clinical trials in an EU member state, Poland, which were revealed by the Supreme Audit Office of Poland (the NIK). Despite adopting many European Union regulations, including European Commission directives concerning Good Clinical Practice, these (...) irregularities occurred. Causes as well as potential solutions to make clinical trials more ethical and safer are discussed. (shrink)

Exploratory experiments are widely characterized as experiments that do not test hypotheses. Experiments that do test hypotheses are characterized as confirmatory experiments. Philosophers have pointed out that research programmes can be both confirmatory and exploratory. However, these definitions preclude single experiments being characterized as both exploratory and confirmatory; how can an experiment test and not test a hypothesis? Given the intuition that some experiments are exploratory, some are confirmatory, and some are both, a recharacterization of the relationship between exploratory and (...) confirmatory experimentation is needed. I discuss ‘phase IV’ trials to show what this recharacterization could look like. Phase IV trials can be exploratory and confirmatory insofar as they concurrently test hypotheses and explore for unforeseen phenomena. Even if it is uncontroversial that a single experiment can have multiple aims, the recharacterization of the relationship between exploratory and confirmatory experimentation is still required for these aims to be held together coherently. I offer an alternative characterization of the relationship between exploratory and confirmatory experimentation where the former remains a distinct kind of experimentation but is not characterized as non-hypothesis-testing. (shrink)

The objective of this research programme is to contribute to the establishment of the emerging science of Formal Ontology in Information Systems via a collaborative project involving researchers from a range of disciplines including philosophy, logic, computer science, linguistics, and the medical sciences. The re­searchers will work together on the construction of a unified formal ontology, which means: a general framework for the construction of ontological theories in specific domains. The framework will be constructed using the axiomatic-deductive method of modern (...) formal ontology. It will be tested via a series of applications relating to on-going work in Leipzig on medical taxonomies and data dictionaries in the context of clinical trials. This will lead to the production of a domain-specific ontology which is designed to serve as a basis for applications in the medical field. (shrink)

ABSTRACT“Evidence-based” methods, which most prominently include randomized controlled trials, have gained increasing purchase as the “gold standard” for assessing the effect of public policies. But the enthusiasm for evidence-based research overlooks questions about the reliability and applicability of experimental findings to diverse real-world settings. Perhaps surprisingly, a qualitative study of British educators suggests that they are aware of these limitations and therefore take evidence-based findings with a much larger grain of salt than do policy makers. Their experience suggests that (...) the real world is more heterogeneous than the world imagined by evidence-based policy enthusiasts. (shrink)

* Special Issue on the Philosophical Dimensions of the Trial* This summarises and discusses the contributions.

The transferability problem—whether the results of an experiment will transfer to a treatment population—affects not only Randomized Controlled Trials but any type of study. The problem for any given type of study can also, potentially, be addressed to some degree through many different types of study. The transferability problem for a given RCT can be investigated further through another RCT, but the variables to use in the further experiment must be discovered. This suggests we could do better on the (...) epistemological problem of transferability by promoting, in the repeated process of formulating public health guidelines, feedback loops of information from the implementation setting back to researchers who are defining new studies. (shrink)

Our goal in this paper is to articulate a precise concept of at least a certain kind of disease-mongering, showing how pharmaceutical marketing can commercially exploit certain diseases when their best definition is given through the success of a treatment in a clinical trial. We distinguish two types of disease-mongering according to the way they exploit the definition of the trial population for marketing purposes. We argue that behind these two forms of disease-mongering there are two well-known problems in the (...) statistical methodology of clinical trials (the reference class problem and the distinction between statistical and clinical significance). Overcoming them is far from simple. (shrink)

How, if at all, should race figure in criminal trials with a jury? How far should attorneys be allowed or encouraged to probe the racial sensitivities of jurors and what does this mean for the appropriate way to present cases which involve racial profiling and, therefore, are likely to pit the words and actions of a white policeman against those of a young black man?

Patient-funded trials are gaining traction as a means of accelerating clinical translation. However, such trials sidestep mechanisms that promote rigor, relevance, efficiency, and fairness. We recommend that funding bodies or research institutions establish mechanisms for merit review of patient-funded trials, and we offer some basic criteria for evaluating PFT protocols.

Jury science is fraught with difficulty. Since legal and institutional hurdles render it all but impossible to study live criminal jury deliberation, researchers make use of various indirect methods to evaluate jury performance. But each of these methods are open to methodological criticism and, strikingly, some of the highest-profile jury research programmes in recent years have reached opposing conclusions. Uncertainty about jury performance is an obstacle for legal reform—ongoing debates about the ‘justice gap’ for complainants of sexual offences has rendered (...) these problems stark. This paper proposes a way to advance the debate. (shrink)

Introduction and Discussion of a Special Issue in philosophy of law "Philosophical Dimensions of the Trial" -/- .

Background If trials of therapeutic interventions are to serve society's interests, they must be of high methodological quality and must satisfy moral commitments to human subjects. The authors set out to develop a clinical - trials compendium in which standards for the ethical treatment of human subjects are integrated with standards for research methods. Methods The authors rank-ordered the world's nations and chose the 31 with >700 active trials as of 24 July 2008. Governmental and other authoritative (...) entities of the 31 countries were searched, and 1004 English-language documents containing ethical and/or methodological standards for clinical trials were identified. The authors extracted standards from 144 of those: 50 designated as ‘core’, 39 addressing trials of invasive procedures and a 5% sample of the remainder. As the integrating framework for the standards we developed a coherent taxonomy encompassing all elements of a trial's stages. Findings Review of the 144 documents yielded nearly 15 000 discrete standards. After duplicates were removed, 5903 substantive standards remained, distributed in the taxonomy as follows: initiation, 1401 standards, 8 divisions; design, 1869 standards, 16 divisions; conduct, 1473 standards, 8 divisions; analysing and reporting results, 997 standards, four divisions; and post-trial standards, 168 standards, 5 divisions. Conclusions The overwhelming number of source documents and standards uncovered in this study was not anticipated beforehand and confirms the extraordinary complexity of the clinical trials enterprise. This taxonomy of multinational ethical and methodological standards may help trialists and overseers improve the quality of clinical trials, particularly given the globalisation of clinical research. (shrink)

Some placebo-controlled trials can continue ethically after a candidate vaccine is found to be safe and efficacious.

Family members can provide crucial support to individuals participating in clinical trials. In research on the “newest frontier” of Deep Brain Stimulation (DBS)—the use of DBS for psychiatric conditions—family member support is frequently listed as a criterion for trial enrollment. Despite the significance of family members, qualitative ethics research on DBS for psychiatric conditions has focused almost exclusively on the perspectives and experiences of DBS recipients. This qualitative study is one of the first to include both DBS recipients and (...) their family members as interview participants. Using dyadic thematic analysis—an approach that takes both the individuals and the relationship as units of analyses—this study analyzes the complex ways in which family relationships can affect DBS trial participation, and how DBS trial participation in turn influences family relationships. Based on these findings, we propose ways to improve study designs to better take family relationships into account, and better support family members in taking on the complex, essential roles that they play in DBS trials for psychiatric conditions. (shrink)

The principle of clinical equipoise has been variously characterized by ethicists and clinicians as fundamentally flawed, a myth, and even a moral balm. Yet, the principle continues to be treated as the de facto gold standard for conducting randomized control trials in an ethical manner. Why do we hold on to clinical equipoise, despite its shortcomings being widely known and well-advertised? This paper reviews the most important arguments criticizing clinical equipoise as well as what the most prominent proposed alternatives (...) are. In the process, it evaluates the justification for continuing to use clinical equipoise as the gold standard for randomized control trials. (shrink)

The trial took place at Bristol Crown Court, England, United Kingdom for the murder of Joanna Yeates, and Dr Vincent Tabak was the Defendant. The author attended at court for this trial and this paper notes many of the obvious and unsatisfactory legal and procedural points in this trial. Dr Vincent Tabak was convicted of the murder at this trial. Of course the jury were not to know the finer points of law as the lower court judge did not advise (...) the jury of any such points before they adjourned to make their decision. All but one concluded that Dr Tabak was guilty as charged, although even the charge was vague and all-encompassing as he was charged with ‘murder between Friday 17 December 2010 and Sunday 19 December 2010’. Defence counsel, very eminent barrister-at-law, appeared to be cowed by the other side and let them walk all over this case procedurally. For example, prosecution counsel handed him 1200 pages of evidence on the first day of the trial, as if to FULFIL disclosure obligations. E was stunned and asked the court for time off. But this was never again discussed. -/- The lower court judge appeared as if he had already decided on the case. When Defence Counsel asked him if he had before him a copy of a certain document, he flippantly say he had it but had left it on his desk in his room. When Defence Counsel, of international renown, was ready to present his opening speech and cross-examination of his client, Dr Vincent Tabak, this lower court judge dismissed the jury to their lunch break knowing that counsel was going to speak. Court had to be adjourned and the members of the jury quickly assembles by the court porters as they were leaving the court, which must have hampered their interest in what counsel’s statement said. A photograph of a dead body by a roadside, allegedly, Miss Yeates, was shown by projector slide a dozen irrelevant times during the trial period, thus embedding that photograph in the jury’s mind. The computer evidence leaves much to be desired and could, some suggested, easily have been concocted by the prosecution team, abusing the law of metadata evidence. Te lady who presented it did not give the court her qualifications and her expertise if any- and much more that beggars belief and loses trust in the British Criminal Justice System, such as it is, following ‘form over substance’. -/- . (shrink)

The oft-told story of Leibniz’s doctrine of the best world, or optimism, is that it enjoyed a great deal of popularity in the eighteenth century until the massive earthquake that struck Lisbon on 1 November 1755 destroyed its support. Despite its long history, this story is nothing more than a commentators’ fiction that has become accepted wisdom not through sheer weight of evidence but through sheer frequency of repetition. In this paper we shall examine the reception of Leibniz’s doctrine of (...) the best world in the eighteenth century in order to get a clearer understanding of what its fate really was. As we shall see, while Leibniz’s doctrine did win a good number of adherents in the 1720s and 1730s, especially in Germany, support for it had largely dried up by the mid-1740s; moreover, while opponents of Leibniz’s doctrine were few and far between in the 1710s and 1720s, they became increasing vocal in the 1730s and afterwards, between them producing an array of objections that served to make Leibnizian optimism both philosophically and theologically toxic years before the Lisbon earthquake struck. (shrink)

My dissertation argues that Plato composed the figure of Socrates as a three- dimensional literary character who experiences and confronts emotions in ways that other studies have overlooked. By adopting a dramatic, non-dogmatic mode of reading the dialogues and emphasizing the literary elements of the texts and their dramatic connections, this dissertation offers a new and compelling portrait of Socrates in the dialogues that relate his finals weeks of life: Theaetetus, Euthyphro, Apology, Crito, and Phaedo. This study in turn provides (...) new insights into the genre of Plato’s texts and demonstrates how he exploited the dramatic nature of the prose dialogue to capture social-historical realities surrounding the trial and execution of Socrates. By emphasizing emotional and interpersonal aspects of Plato’s texts, my dissertation shows that Plato’s dialogues are profitably read through a literary lens to recover their complex reconstruction of Socrates’ place and time in history. (shrink)

Moral anti-theodicists have posed a consequentialist argument against the theodical enterprise: that theodicies lead to harmful consequences in reality and that this should be sufficient reason to motivate abandoning the practise of theodicising altogether. In this paper, I examine variants of this argument and discuss several prominent responses from theodicists, including the separation thesis. I argue that while these responses are effective in resisting the global conclusion by the anti-theodicist, it still leaves the theodical enterprise vulnerable to a weaker version (...) of the consequentialist critique. In response, I develop an account of ‘theodicies-of-embrace-protest’ which is able to preserve the meaningful strides made in traditional theodicies while taking seriously the criticisms of the moral anti-theodicists. I suggest that sceptical theism fits this bill. (shrink)

Did the impartiality of clinical trials play any role in their acceptance as regulatory standards for the safety and efficacy of drugs? According to the standard account of early British trials in the 1930s and 1940s, their impartiality was just rhetorical: the public demanded fair tests and statistical devices such as randomization created an appearance of neutrality. In fact, the design of the experiment was difficult to understand and the British authorities took advantage of it to promote their (...) own particular interests. I claim that this account is based on a poorly defined concept of experimental fairness . I present an alternative approach in which a test would be impartial if it incorporates warrants of non-manipulability. With this concept, I reconstruct the history of British trials showing that they were indeed fair and this fairness played a role in their acceptance as regulatory yardsticks. (shrink)

Kafka’s The Trial describes how K slowly loses his familiar language. He does speak a language but his language becomes monologic towards others and the language of others becomes monologic towards K. There seems to be no other person who, in a private and professional life, can respond to K’s words and gestures in a manner which K can understand. The others embody their own meanings into K’s words. Such meanings only possess value within the discourses of self-styled legal experts (...) and officials who act in K’s name. The officials and experts assume that their own meanings are authoritative. K fails to gain access to their meanings. The question posed by Husserl’s phenomenology of language is ‘why?’ Conklin argues that K’s experiences seem not unlike Lyotard’s sense of a different or ‘untranslatable gap’. K remains on the fringe or outside what the experts take as an authoritative language. As a consequence, K’s experiential body slowly dies. This death paradoxically occurs at the same moments that the experts believe that they are addressing ‘K’s case’. Conklin explains the paradox by retrieving Husserl’s sense of a meaning-conferring act and the failure of K’s meaning-conferring acts from being fulfilled in the language of the legal experts. (shrink)

The world’s first COVID-19 human challenge trial using the D614G strain of SARS-CoV-2 is underway in the United Kingdom. The Wellcome Trust is funding challenge stock preparation of the Beta variant (B.1.351) for a follow-up human challenge trial, and researchers at Imperial College London are considering conducting that trial. However, little has been written thus far about the ethical justifiability of human challenge trials with SARS-CoV-2 variants of concern. While vaccine resistance as such does not increase risks for volunteers (...) in COVID-19 challenge trials, we explore two specific characteristics of some variants that may initially be thought to make such trials unethical and conclude that SARS-CoV-2 variant challenge trials can remain ethical. (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)

This paper discusses the so-called non-interference assumption (NIA) grounding causal inference in trials in both medicine and the social sciences. It states that for each participant in the experiment, the value of the potential outcome depends only upon whether she or he gets the treatment. Drawing on methodological discussion in clinical trials and laboratory experiments in economics, I defend the necessity of partial forms of blinding as a warrant of the NIA, to control the participants’ expectations and their (...) strategic interactions with the experimenter. (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 paper discusses the judgment of Judge William Overton in McLean vs. Arkansas Board of Education (1982), and the subsequent philosophical literature that discusses this judgment.