A background assumption of this paper is that the repertoire of inference schemes available to humanity is not fixed, but subject to change as new schemes are invented or refined and as old ones are obsolesced or abandoned. This is particularly visible in areas like health and environmental sciences, where enormous societal investment has been made in finding ways to reach more dependable conclusions. Computational modeling of argumentation, at least for the discourse in expert fields, will require the possibility of (...) modeling change in a stock of schemes that may be applied to generate conclusions from data. We examine Randomized Clinical Trial, an inference scheme established within medical science in the mid-20th Century, and show that its successful defense by means of practical reasoning allowed for its black-boxing as an inference scheme that generates (and warrants belief in) conclusions about the effects of medical treatments. Modeling the use of a scheme is well-understood; here we focus on modeling how the scheme comes to be established so that it is available for use. (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 article presents the advantages and limitations of adaptive clinical trials for assessing the effectiveness of medical interventions and specifies the conditions that contributed to their development and implementation in clinical practice. I advance two arguments by discussing different cases of adaptive trials. The normative argument is that responsible adaptation should be taken seriously as a new way of doing clinical research insofar as a valid justification, sufficient understanding, and adequate operational conditions are provided. The (...) second argument is historical. The development of adaptive trials can be related to lessons learned from research in cases of urgency and to the decades-long efforts to end the productivity crisis of pharmaceutical research, which led to the emergence of translational, personalized, and, recently, precision medicine movements. (shrink)

The volume of clinical research is increasing exponentially—far beyond our ability to process and absorb the results. Given this situation, it may be beneficial to consider reducing the flow at its source. In what follows, I will motivate and critically evaluate the following proposal: researchers should conduct fewer clinical trials. More specifically, I c onsider whether researchers should be permitted to conduct only clinical research of very high quality and, in turn, whether research ethics committees should (...) prohibit all other, lower-quality research, even when it might appear to meet some minimal ethical standard. Following a close analysis of the social-value requirement of ethical clinical research, I argue that this proposal is defensible. The problem identified in this paper has two parts, quantity and quality, and some clarification is needed about the latter because “quality” is a highly contested term in the medical literature. When some scholars advocate for high-quality trials, they mean large-scale, simple, explanatory randomized controlled trials. Others, including myself, have defended a different characterization of high-quality research that tends more toward pragmatic trial design and the use of methods other than RCTs. Pragmatic trials aim to provide evidence that directly supports clinical decision-making in “usual” care settings. Unlike explanatory trials, which aim to abstract away from particular settings and patients, in the hopes of creating ideal conditions for the success of an intervention, pragmatic trials deliberately pursue knowledge of high applicability, through the use of representative subjects, clinically important questions, flexible treatment protocols, patient-oriented outcome measures, and so on. I see applicability as a marker of high-quality research. The context in which research is meant to be applied should be the context in which new interventions are evaluated. (shrink)

Over the past several decades, we devoted much energy to generating, reviewing and summarizing evidence. We have given far less attention to the issue of how to thoughtfully apply the evidence once we have it. That’s fine if all we care about is that our clinical decisions are evidence-based, but not so good if we also want them to be well-reasoned. Let us not forget that evidence based medicine (EBM) grew out of an interest in making medicine ‘rational’, with (...) the idea that rational clinical evaluations should be evidence-based. I agree with the uncontroversial statement that the best decision is supported, at least in part, by the best available evidence. Rationality, however, is constituted by reasoning, not evidence. Complete arguments are necessary for rational evaluations, arguments that begin with general evidence and end in a conclusion about a particular patient. In order to traverse these inferential gaps, medicine must address the issue of how to establish, as an intermediate premise, what the evidence has to say about the efficacy of an intervention for particular patients in a particular practice setting. (shrink)

t Intentional sampling methods are non-randomized procedures that select a group of individuals for a sample with the purpose of meeting specific prescribed criteria. In this paper we extend previous works related to intentional sampling, and address the problem of sequential allocation for clinical trials with few patients. Roughly speaking, patients are enrolled sequentially, according to the order in which they start the treatment at the clinic or hospital. The allocation problem consists in assigning each new patient (...) to one, and only one, of the alternative treatment arms. The main requisite is that the profiles in the alternative arms remain similar with respect to some relevant patients’ attributes (age, gender, disease, symptom severity and others). We perform numerical experiments based on a real case study and discuss how to conveniently set up perturbation parameters, in order to yield a suitable balance between optimality – the similarity among the relative frequencies of patients in the several categories for both arms, and decoupling – the absence of a tendency to allocate each pair of patients consistently to the same arm. (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)

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)

Introduction: Clinical practice guidelines (CPGs) are an important source of justification for clinical decisions in modern evidence-based practice. Yet, we have given little attention to how they argue their evidence. In particular, how do CPGs argue for treatment with long-term medications that are increasingly prescribed to older patients? Approach and rationale: I selected six disease-specific guidelines recommending treatment with five of the medication classes most commonly prescribed for seniors in Ontario, Canada. I considered the stated aims of these (...) CPGs and the techniques employed towards those aims. Finally, I reconstructed and logically analysed the arguments supporting recommendations for pharmacotherapy. Analysis: The primary function of CPGs is rhetorical, or persuasive, and their means of persuasion include both a display of their credibility and their argumentation. Arguments supporting pharmacotherapy recommendations for the target population follow a common inductive pattern: statistical generalization from randomized controlled trial (RCT) and meta-analysis evidence. Two of the CPGs also argue their treatment recommendations for older patients in this style, while three fail to justify pharmacotherapy specifically for the older population. Discussion: The arguments analysed lack the auxiliary assumptions that would warrant making a generalization about the clinical effectiveness of medications for the older population. Guidelines reason using simple induction, while ignoring important inferential gaps. Future guidelines should aspire to be well-reasoned rather than simply evidence-based; argue from a plurality of evidence; be wary of hasty inductions; appropriately limit the scope of their recommendations; and avoid making law-like, prescriptive generalizations. (shrink)

The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, (...) more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling. (shrink)

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)

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)

Medical scientists employ ‘quality assessment tools’ (QATs) to measure the quality of evidence from clinical studies, especially randomized controlled trials (RCTs). These tools are designed to take into account various methodological details of clinical studies, including randomization, blinding, and other features of studies deemed relevant to minimizing bias and error. There are now dozens available. The various QATs on offer differ widely from each other, and second-order empirical studies show that QATs have low inter-rater reliability and (...) low inter-tool reliability. This is an instance of a more general problem I call the underdetermination of evidential significance. Disagreements about the strength of a particular piece of evidence can be due to different—but in principle equally good—weightings of the fine-grained methodological features which constitute QATs. (shrink)

Social scientists and research ethicists have begun, somewhat belatedly, to confront and address the ethical challenges raised by public policy experiments. In doing so however, they have not fully availed themselves of the large and sophisticated literature on the ethics of clinical research which has developed over the past 40 years. While clinical and public policy research are different, I argue that the clinical research ethics literature yields valuable insights for discussions of the ethics of policy experiments. (...) Focusing on seven ethical issues which have received a good deal of attention in public and scholarly discussions of the ethics of policy experiments, I make use of the history of reflection on the ethics of clinical research to provide guidance to researchers planning and conducting policy experiments. (shrink)

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

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

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 (...) class='Hi'>Clinical Practice, these irregularities occurred. Causes as well as potential solutions to make clinical trials more ethical and safer are discussed. (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)

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)

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)

Driven by the use cases of PubChemRDF and SCAIView, we have developed a first community-based clinical trial ontology (CTO) by following the OBO Foundry principles. CTO uses the Basic Formal Ontology (BFO) as the top level ontology and reuses many terms from existing ontologies. CTO has also defined many clinical trial-specific terms. The general CTO design pattern is based on the PICO framework together with two applications. First, the PubChemRDF use case demonstrates how a drug Gleevec is linked (...) to multiple clinical trials investigating Gleevec’s related chemical compounds. Second, the SCAIView text mining engine shows how the use of CTO terms in its search algorithm can identify publications referring to COVID-19-related clinical trials. Future opportunities and challenges are discussed. (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)

Modern health care relies extensively on the use of technologies for assessing and treating patients, so it is important to be certain that health care technologies perform their professed functions in an effective and safe manner. Philosophers of technology have developed methods to assign and evaluate the functions of technological products, the major elements of which are described in the ICE theory. This paper questions whether the standard of evidence advocated by the ICE theory is adequate for ascribing and assessing (...) technologies employed in health care. The paper proposes that the general problem with the standard of evidence embodied in the ICE theory is too permissive for assessing medical technologies, in that it does not take into account the relative benefit and harm of medical technologies in ensuring safe functional performance in patients. The paper illustrates how evidence-based medicine has demonstrated the value of clinical research methods, including observational studies, randomized and non-randomized clinical trials, and formal techniques, such as meta-analysis, to measure therapeutic effectiveness. I argue, therefore, that evidence from clinical research studies should take precedence over the testimonial evidence and other types of non-clinical evidence, in providing justification for health technologies. (shrink)

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)

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)

During the recent Ebola epidemic, some commentators and stakeholders argued that it would be unethical to carry out a study that withheld a potential treatment from affected individuals with such a serious, untreatable disease. As a result, the initial trials of experimental treatments did not have control arms, despite important scientific reasons for their inclusion. In this paper, we consider whether the duty to rescue entails that it would be unethical to withhold an experimental treatment from patient-participants with serious (...) diseases for which there are no effective treatments, even when doing so is scientifically necessary to test the effectiveness of the treatment. We argue that the duty to rescue will rarely apply. The context of medical research also throws new light on the content of the duty to rescue, since the interests of future patients—who stand to benefit from the fruits of medical research—are relevant to whether the duty applies. (shrink)

There has been a growing concern over establishing norms that ensure the ethically acceptable and scientifically sound conduct of clinical trials. Among the leading norms internationally are the World Medical Association's Declaration of Helsinki, guidelines by the Council for International Organizations of Medical Sciences, the International Conference on Harmonization's standards for industry, and the CONSORT group's reporting norms, in addition to the influential U.S. Federal Common Rule, Food and Drug Administration's body of regulations, and information sheets by the (...) Department of Health and Human Services. There are also many norms published at more local levels by official agencies and professional groups.Any account of international standards should cover both scientific and ethical norms at once – the two are conceptually intertwined. Recent sources recognize that “[s]cientifically unsound research on human subjects is unethical in that it exposes research subjects to risks without possible benefit.”. (shrink)

The effective altruism movement aims to save lives in the most cost-effective ways. In the future, technology will allow radical life extension, and anyone who survives until that time will gain potentially indefinite life extension. Fighting aging now increases the number of people who will survive until radical life extension becomes possible. We suggest a simple model, where radical life extension is achieved in 2100, the human population is 10 billion, and life expectancy is increased by simple geroprotectors like metformin (...) or nicotinamide mononucleotide by three more years on average, so an additional 750 million people survive until “immortality”. The cost of clinical trials to prove that metformin is a real geroprotector is $65 million. In this simplified case, the price of a life saved is around eight cents, 10 000 times cheaper than saving a life from malaria by providing bed nets. However, fighting aging should not be done in place of fighting existential risks, as they are complementary causes. (shrink)

Interventions aiming to slow, stop, or reverse the aging process are starting to enter clinical trials. Though this line of research is nascent, it has the potential to not only prevent prolonged human suffering, but also to extend human well-being. As this line of research develops, it is important to understand the ethical constraints of conducting such research. This paper discusses some of these constraints. In particular, it discusses the ethical difficulties of conducting this research in a way (...) that would produce reliable data regarding the effectiveness of an anti-aging intervention. Clinical trials of such interventions, I argue, will be faced with a dilemma between two confounding variables. Eliminating the variables requires introducing ethically problematic research practices. Thus, researchers must either perform research in ethically problematic ways, or forego the conduct of high-impact clinical research on anti-aging interventions. (shrink)

Background: In response to the pandemic caused by COVID-19, World Health Organization (WHO), together with International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), developed research protocols facilitating global collaboration and accelerating the understanding of the disease, to identify the potential symptoms and persistent sequelae in infected individuals, which can be used in different areas of health, that is, in primary care, at a hospital or outpatient level, both public and private. Objective: To describe the International Severe Acute Respiratory and (...) Emerging Infection Consortium (ISARIC) protocol as a new global collaborative platform for global clinical trials targeting post-COVID-19 patients. Methods: The standardized forms were developed from the COVID-19 Clinical Characterization Protocol (PCC) by the ISARIC/WHO working group composed of specialist researchers with experience in clinical research in different areas of medicine and public health, especially outbreaks and infectious diseases. Conclusion: It is expected that the creation of a database composed of different populations from all over the world will help in the characterization of risk factors, in the best form of clinical intervention and in the best prevention strategies for physical, neurological and psychosocial sequelae in the medium and long term in post-COVID-19 patients. (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)

Current debates surrounding the virtues and shortcomings of randomization are symptomatic of a lack of appreciation of the fact that causation can be inferred by two distinct inference methods, each requiring its own, specific experimental design. There is a non-statistical type of inference associated with controlled experiments in basic biomedical research; and a statistical variety associated with randomized controlled trials in clinical research. I argue that the main difference between the two hinges on the satisfaction of the (...) comparability requirement, which is in turn dictated by the nature of the objects of study, namely homogeneous or heterogeneous populations of biological systems. Among other things, this entails that the objection according to which randomized experiments fail to provide better evidence for causation because randomization cannot guarantee comparability is mistaken. (shrink)

Heterogeneous treatment effects represent a major issue for medicine as they undermine reliable inference and clinical decision-making. To overcome the issue, the current vision of precision and personalized medicine acknowledges the need to control individual variability in response to treatment. In this paper, we argue that gene-treatment-environment interactions (G × T × E) undermine inferences about individual treatment effects from the results of both genomics-based methodologies—such as genome-wide association studies (GWAS) and genome-wide interaction studies (GWIS)—and randomized controlled (...) class='Hi'>trials (RCTs). Then, we argue that N-of-1 trials can be a solution to overcome difficulties in handling individual variability in treatment response. Although this type of trial has been suggested as a promising strategy to assess individual treatment effects, it nonetheless has limitations that limit its use in everyday clinical practice. We analyze the existing variability within the designs of N-of-1 trials in terms of a continuum where each design prioritizes epistemic and pragmatic considerations. We then support wider use of the designs located at the pragmatic end of the explanatory-pragmatic continuum. (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)

Introduction: Liposomal bupivacaine (LB) is a long-acting analgesic that, due to its liposomal formulation, purportedly extends its analgesic effect up to 72 hours. However, the clinical efficacy of LB appears mixed. This systematic review seeks to evaluate the effectiveness of liposomal bupivacaine in improving postoperative outcomes compared to ropivacaine (ROPI), another commonly used long-acting analgesic. -/- Materials and Methods: Prospective and randomized controlled trials (RCTs) evaluating the efficacy of LB compared to ROPI were selected for review. Primary (...) outcomes included hospital length of stay (LOS) and postoperative opioid consumption measured in oral morphine equivalents (OME). Secondary outcomes included analgesic cost. -/- Results: 14 studies met the review criteria. We found that LB and ROPI are equivalent in managing postoperative pain. 8 of the 14 trials reported equal efficacy between LB and ROPI as determined by OME post-procedure and 10 of the 14 trials reported similar LOS after surgery. These findings remained consistent across multiple surgical procedures and multiple drug administrative modalities. -/- Conclusion: Our systematic review found that LB was not superior to ROPI in reducing postoperative OME use and hospital LOS. The only consistent finding was the significantly increased cost of LB compared to that of ROPI. Therefore, the use of LB over ROPI cannot be justified. (shrink)

An alliance of established experts on critical care, Front Line COVID-19 Critical Care Alliance (FLCCC), has published two protocols for treatment of COVID-19. The first one, methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+), is intended for hospital and intensive care unit treatment of pulmonary phases of the disease. It is based on affordable, commonly available components: anti-inflammatory corticosteroids (methylprednisolone, "M"), high-dose vitamin C infusion (ascorbic acid, "A"), vitamin B1 (thiamine, "T"), anticoagulant heparin ("H"), antiparasitic agent ivermectin, and supplemental components ("+") (...) including melatonin, vitamin D, elemental zinc, and magnesium. -/- The MATH+ protocol has received scarce attention due to the World Health Organization (WHO) advising against the use of corticosteroids in the beginning of the pandemic. In addition, randomized controlled clinical trials were required as a condition for adoption of the protocol. As the hospital mortality rate of MATH+ treated patients was approximately a quarter of the rate of patients receiving a standard of care, the authors of the protocol considered performing such trials unethical. Other parties have later performed clinical trials with corticosteroids and anticoagulants, which has led to a more widespread adoption of these components. -/- In October 2020, ivermectin was upgraded from an optional component to an essential component of the protocol. According to the authors, ivermectin is considered the first agent effective for both prophylaxis (prevention) of COVID-19 and for treatment of all phases of COVID-19 including outpatient treatment of the early symptomatic phase. Therefore, at the end of October 2020, a separate ivermectin-based I-MASK+ protocol for prophylaxis and early outpatient treatment of COVID-19 was published. (shrink)

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)

Decision-making by a Data and Safety Monitoring Board (DSMB) regarding clinical trial conduct and termination is intricate and largely limited by cases and rules. Decision-making by legal jury is also intricate and largely constrained by cases and rules. In this paper, I argue by analogy that legal decision-making, which strives for a balance between competing demands of conservatism and innovation, supplies a good basis to the logic behind DSMB decision-making. Using the doctrine of precedents in legal reasoning as my (...) central analog will lead us to a decision-theoretic analogy for much more systematic documentation of decisions in clinical trials. My conclusion is twofold: every DSMB decision should articulate a clear general principle (a ratio decidendi) that gives reason for the decision; and all such decisions should be made public. I use Bartha’s (2010) theory of analogical arguments to both frame and assess my argument by analogy. (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 argue that charging people to participate in research is likely to undermine the fundamental ethical bases of clinical research, especially the principles of social value, scientific validity, and fair subject selection.

Background: The internationalization of clinical studies requires a shared understanding of the fundamental ethical values guiding clinical studies. It is important that these values are not only embraced at the legal level but also adopted by clinicians themselves during clinical studies. Objective: Our goal is to provide an insight on how clinicians in Germany and Poland perceive and identify the different ethical issues regarding informed consent in clinical studies. Methods: To gain an understanding of how clinicians (...) view clinical studies in the countries they work in, we carried out semi-structured problem-centered interviews per telephone in Poland (n = 6) and Germany (n = 6). Our interviewees concentrated on three main topics: an appraisal of the normative framework, challenges in the information process and the protection of all participants in clinical studies. Results: Clinicians generally supported the normative framework, even though they considered it quite complex. In the two study countries, a widely noted dilemma in the information process was whether to overburden participants with extensive information or risking leaving out important facts. Clinicians were ready to exclude larger population groups from participating in clinical studies when the information process could not be carried out with standard procedures or when their inclusion was ethically sensitive. Conclusion: Clinicians need to gain a better understanding of the consequences of excluding larger population groups form participating in clinical studies. They should seek assistance in improving the information process for the inclusion of underrepresented groups in clinical studies. (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 Belmont Report was written by a US Commission charged by the US Congress to advise on research supported by the US government. Its focus was understandably domestic. In the 40 years since its publication, clinical research has become increasingly international. Many clinical trials have sites in multiple countries, and many of the host countries are relatively impoverished. Such research raises some distinctive ethical issues. This paper outlines some of the key ethical challenges that have been raised (...) by clinical research conducted in low- and middle-income countries (LMICs) and sponsored by high-income country (HIC) institutions. It then considers whether the Belmont Report has the resources to address these problems and argues that it does not. The article closes by noting some parallels between this international research and domestic US research, which suggest that the US might benefit from the discussions abroad. (shrink)

Control interventions (often called “sham,” “placebo,” or “attention controls”) are essential for studying the efficacy or mechanism of physical, psychological, and self-management interventions in clinical trials. This article presents core recommendations for designing, conducting, and reporting control interventions to establish a quality standard in nonpharmacological intervention research. A framework of additional considerations supports researchers’ decision making in this context. We also provide a reporting checklist for control interventions to enhance research transparency, usefulness, and rigour.

Introduction Current treatments for pain have limited benefits and worrying side effects. Some studies suggest that pain is reduced when clinicians deliver positive messages. However, the effects of positive messages are heterogeneous and have not been subject to meta-analysis. We aimed to estimate the efficacy of positive messages for pain reduction. -/- Methods We included randomized trials of the effects of positive messages in a subset of the studies included in a recent systematic review of context factors for (...) treating pain. Several electronic databases were searched. Reference lists of relevant studies were also searched. Two authors independently undertook study selection, data extraction, risk of bias assessment, and analyses. Our primary outcome measures were differences in patient- or observer-reported pain between groups who were given positive messages and those who were not. -/- Results Of the 16 randomized trials (1703 patients) that met the inclusion criteria, 12 trials had sufficient data for meta-analysis. The pooled standardized effect size was −0.31 (95% confidence interval [CI] −0.61 to −0.01, p = 0.04, I2 = 82%). The effect size remained positive but not statistically significant after we excluded studies considered to have a high risk of bias (standard effect size −0.17, 95% CI −0.54 to 0.19, P = 0.36, I2 = 84%). -/- Conclusion Care of patients with chronic or acute pain may be enhanced when clinicians deliver positive messages about possible clinical outcomes. However, we have identified several limitations of the present study that suggest caution when interpreting the results. We recommend further high-quality studies to confirm (or falsify) our result. -/- FUNDING -/- Alexander Mebius research has been funded through the ERC grant "Philosophy of Pharmacology: Safety, Statistical Standards, and Evidence Amalgamation" (GA: 639276). (shrink)

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)

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.

In the beginning of the COVID pandemic, researchers and bioethicists called for human challenge trials to hasten the development of a vaccine for COVID. However, the fact that we lacked a specific, highly effective treatment for COVID led many to argue that a COVID challenge trial would be unethical and we ought to pursue traditional phase III testing instead. These ethical objections to challenge trials may have slowed the progress of a COVID vaccine, so it is important to (...) evaluate their merit. One common way of doing so is to make an analogy to other social practices that are relevantly similar and which we currently sanction. We submit that non-directed live organ donation (NDLOD) is a promising analogy. After arguing that the risks to volunteers for each activity appear similar, we explore potential disanalogies that would undermine the comparison. We note that there are differences in both the kind and certainty of benefit secured by NDLOD compared to challenge trials. We conclude these differences are insufficient to make NDLOD permissible and challenge trials impermissible. Ultimately, if we think the risks associated with NDLOD are ethically permissible, then we should think the same of the risks associated with COVID challenge trials. (shrink)

Immunology researchers are beginning to explore the possibilities of reproducibility, reuse and secondary analyses of immunology data. Open-access datasets are being applied in the validation of the methods used in the original studies, leveraging studies for meta-analysis, or generating new hypotheses. To promote these goals, the ImmPort data repository was created for the broader research community to explore the wide spectrum of clinical and basic research data and associated findings. The ImmPort ecosystem consists of four components–Private Data, Shared Data, (...) Data Analysis, and Resources—for data archiving, dissemination, analyses, and reuse. To date, more than 300 studies have been made freely available through the ImmPort Shared Data portal , which allows research data to be repurposed to accelerate the translation of new insights into discoveries. (shrink)