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)

Randomization is an integral part of well-designed statistical trials, and is also a required procedure in legal systems. Implementation of honest, unbiased, understandable, secure, traceable, auditable and collusion resistant randomization procedures is a mater of great legal, social and political importance. Given the juridical and social importance of randomization, it is important to develop procedures in full compliance with the following desiderata: (a) Statistical soundness and computational efficiency; (b) Procedural, cryptographical and computational security; (c) Complete auditability and traceability; (d) (...) Any attempt by participating parties or coalitions to spuriously influence the procedure should be either unsuccessful or be detected; (e) Open-source programming; (f) Multiple hardware platform and operating system implementation; (g) User friendliness and transparency; (h) Flexibility and adaptability for the needs and requirements of multiple application areas (like, for example, clinical trials, selection of jury or judges in legal proceedings, and draft lotteries). This paper presents a simple and easy to implement randomization protocol that assures, in a formal mathematical setting, full compliance to the aforementioned desiderata for randomization procedures. (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 (...) class='Hi'>Clinical Practice, these irregularities occurred. Causes as well as potential solutions to make clinical trials more ethical and safer are discussed. (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)

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)

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)

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)

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)

The desideratum of semantic interoperability has been intensively discussed in medical informatics circles in recent years. Originally, experts assumed that this issue could be sufficiently addressed by insisting simply on the application of shared clinical terminologies or clinical information models. However, the use of the term ‘ontology’ has been steadily increasing more recently. We discuss criteria for distinguishing clinical ontologies from clinical terminologies and information models. Then, we briefly present the role clinical ontologies play in (...) two multicentric research projects. Finally, we discuss the interactions between these different kinds of knowledge representation artifacts and the stakeholders involved in developing interoperational real-world clinical applications. We provide ontology engineering examples from two EU-funded projects. (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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

A novel advantage of the use of machine learning (ML) systems in medicine is their potential to continue learning from new data after implementation in clinical practice. To date, considerations of the ethical questions raised by the design and use of adaptive machine learning systems in medicine have, for the most part, been confined to discussion of the so-called “update problem,” which concerns how regulators should approach systems whose performance and parameters continue to change even after they have (...) received regulatory approval. In this paper, we draw attention to a prior ethical question: whether the continuous learning that will occur in such systems after their initial deployment should be classified, and regulated, as medical research? We argue that there is a strong prima facie case that the use of continuous learning in medical ML systems should be categorized, and regulated, as research and that individuals whose treatment involves such systems should be treated as research subjects. (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.

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)

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 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)

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)

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)

Adaptation and stress are two main concepts useful for better understanding the phases of illness and health-related human behavior. The two faces of adaptation, adaptation as a process and adaptation as a product, have raised the question of how long the adaptation process will take in cancer trajectories. The care setting transition from clinical-based into home-based cancer care has stressed the role of family caregivers (FCG) in cancer management. This study examines how types of demanded healthcare information affect the (...) FCG’s role in catalyzing the adaptation of female cancer patients. The mindsponge theory was used in conceptual development and results interpretation. Bayesian Mindsponge Framework (BMF) analytics was used for statistical analysis on a dataset of 48 spouses (husbands) and 12 other family members in five congested communities of Surabaya, Indonesia. Results showed that among the six types of demanded healthcare information, FCGs with a higher tendency to demand cancer-specific information are more likely to need support in catalyzing the adaptation of female cancer patients. Meanwhile, FCGs with a higher demand for information on alternative therapies are less likely to need support in catalyzing cancer adaptation. Other types of healthcare information have ambiguous effects on the need for support in cancer adaptation assistance. This study reveals that the demanded cancer-specific information, e.g., cancer’s prognosis or likely outcome, must be prioritized to assist FCG’s role in catalyzing adaptation among female cancer patients. Cancer prognosis and outcomes reflect the future of cancer care results. (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)

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.

Ectopic pregnancy is defined as the fertilized ovum implants in a location outside the endometrial cavity, remains to be an important cause of maternal morbidity and mortality worldwide and is a health problem with incidence ranges between 0.25% and 2% of all pregnancies. In our study, in Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of Obstetrics and Gynecology from 2011 to 2013, 96 cases with diagnosis of ectopic pregnancy managed by the adapted RCOG’s Guide were analyzed retrospectively. (...) The data were analyzed as follows: age, the history of operation, smoking, the presence of intrauterine device, blood groups, hemoglobin, platelets, values of B-hCG, the diagnostic interval, intra-abdominal free fluid and/or acute abdomen, the method of treatment and the success of treatment. (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)

Biomarkers are widely used not only as prognostic or diagnostic indicators, or as surrogate markers of disease in clinical trials, but also to formulate theories of pathogenesis. We identify two problems in the use of biomarkers in mechanistic studies. The first problem arises in the case of multifactorial diseases, where different combinations of multiple causes result in patient heterogeneity. The second problem arises when a pathogenic mediator is difficult to measure. This is the case of the oxidative stress (...) (OS) theory of disease, where the causal components are reactive oxygen species (ROS) that have very short half-lives. In this case, it is usual to measure the traces left by the reaction of ROS with biological molecules, rather than the ROS themselves. Borrowing from the philosophical theories of signs, we look at the different facets of biomarkers and discuss their different value and meaning in multifactorial diseases and system medicine to inform their use in patient stratification in personalized medicine. (shrink)

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)

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)

Objectives: Machine learning (ML) has the potential to facilitate “continual learning” in medicine, in which an ML system continues to evolve in response to exposure to new data over time, even after being deployed in a clinical setting. In this article, we provide a tutorial on the range of ethical issues raised by the use of such “adaptive” ML systems in medicine that have, thus far, been neglected in the literature. -/- Target audience: The target audiences for this (...) tutorial are the developers of ML AI systems, healthcare regulators, the broader medical informatics community, and practicing clinicians. -/- Scope: Discussions of adaptive ML systems to date have overlooked the distinction between 2 sorts of variance that such systems may exhibit—diachronic evolution (change over time) and synchronic variation (difference between cotemporaneous instantiations of the algorithm at different sites)—and underestimated the significance of the latter. We highlight the challenges that diachronic evolution and synchronic variation present for the quality of patient care, informed consent, and equity, and discuss the complex ethical trade-offs involved in the design of such systems. (shrink)

We argue that the universal recommendations against “off-label” pediatric use of approved COVID-19 issued by the FDA, CDC, and AAP are overbroad. Especially for higher-risk children, vaccination can be ethically justified even before FDA authorization or approval – and similar reasoning is relevant for even younger patients. Legal risks can also be managed, although the FDA, CDC, and Department of Health and Human Services (HHS) should move quickly to provide clarity.

The public health crisis is started with emergence of new coronavirus on 11 February 2020 which triggered as coronavirus disease-2019 (COVID-19) pandemics. The causative agent in COVID-19 is made up of positively wrapped single-stranded RNA viruses ~ 30 kb in size. The epidemiology, clinical features, pathophysiology, and mode of transmission have been documented well in many studies, with additional clinical trials are running for several antiviral agents. The spreading potential of COVID-19 is faster than its two previous (...) families, the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Apart from clinical manifestation, comorbid status is playing key role for prevalence of COVID-19 infection and mortalities. The comorbid effects associated with COVID-19 are diabetes, cardiovascular, digestive, hepatitis-B, cerebrovascular, hypertension, liver injury, coronary heart disease, cancer, rheumatoid arthritis, and neurological impairment. Antimalarial drugs (chloroquine and hydroxychloroquine), remdesivir, Tocilizumab, clopinavir/ritonavir, convalescent plasma therapy, spike protein-angiotensin-converting enzyme 2 (ACE2) inhibitors, human monoclonal antibodies, mRNA-1273, mesenchymal stem cells, Indian and Chinese traditional medicine, small molecules antioxidant, natural products and dietary supplements, high doses of vitamin-E, -C, -D, minerals, flavonoids,and IFN-beta are therapeutic intervention running to develop treatment against COVID-19. Although clinical usage of these therapeutic agents against COVID-19 is well documented, cytokine storms, absence of appropriate animal model have limited its therapeutic use. This review explores the clinical information currently available on COVID-19 on the mechanisms of infection, prevention, management, comorbid status, and current drug treatment options. (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)

In the last decade alone, a growing body of preliminary evidence suggests that classic psychedelics (CPs) can rapidly and durably ameliorate symptoms and cognitive deficits associated with depression. However, the mechanisms by which CPs work in the brain are not well understood. Rodent translational research, in which experimental findings from rodents are translated to humans, is fundamental in achieving this goal. This chapter focuses on a representative subset of human and rodent studies investigating CPs for depression, including the various lines (...) of research that have been initiated to understand how they work. Our aim is to show that in addition to epistemic challenges that scientists face in translating findings from rodents to humans, there is also mismatch between experimental approaches used to investigate CPs in humans and rodents. We thus show current experimental practices are not conducive to mechanistic discovery. We end with a set of positive proposals to expedite the drive to translate CPs into effective treatments for depression. -/- Keywords: classic psychedelics, psychiatry, clinical trials, collaboration, extrapolation, major depressive disorder, open science, philosophy of science, rodent models, scientific practice, translation, validity . (shrink)

The current ethical and regulatory framework for research is often charged with burdening investigators and impeding socially valuable research. To address these concerns, a growing number of research ethicists argue that informed consent should be adapted to the risks of research participation. This would require less rigorous consent standards in low-risk research than in high-risk research. However, the current discussion is restricted to cases of research in which the risks of research participation are outweighed by the potential clinical benefits (...) for the individual research participant. Furthermore, current proposals do not address the worry that risk-adapted informed consent may result in enrolling participants into research without their autonomous authorization. In this paper, we show how the standard view of informed consent – consent as autonomous authorization – can be adapted to risk even when the research does not have a favourable risk-benefit profile for the participant. Our argument has two important implications: first, it implies that current and proposed consent standards are not adequately calibrated to risk and, second, that consent standards also need to be adapted to factors other than risk. (shrink)

Recent clinical trials show that psychedelics such as LSD and psilocybin can be given safely in controlled conditions, and can cause lasting psychological benefits with one or two administrations. Supervised psychedelic sessions can reduce symptoms of anxiety, depression, and addiction, and improve well-being in healthy volunteers, for months or even years. But these benefits seem to be mediated by "mystical" experiences of cosmic consciousness, which prompts a philosophical concern: do psychedelics cause psychological benefits by inducing false or implausible (...) beliefs about the metaphysical nature of reality? This book is the first scholarly monograph in English devoted to the philosophical analysis of psychedelic drugs. Its central focus is the apparent conflict between the growing use of psychedelics in psychiatry and the philosophical worldview of naturalism. Within the book, Letheby integrates empirical evidence and philosophical considerations in the service of a simple conclusion: this "Comforting Delusion Objection" to psychedelic therapy fails. While exotic metaphysical ideas do sometimes come up, they are not, on closer inspection, the central driver of change in psychedelic therapy. Psychedelics lead to lasting benefits by altering the sense of self, and changing how people relate to their own minds and lives-not by changing their beliefs about the ultimate nature of reality. The upshot is that a traditional conception of psychedelics as agents of insight and spirituality can be reconciled with naturalism (the philosophical position that the natural world is all there is). Controlled psychedelic use can lead to genuine forms of knowledge gain and spiritual growth-even if no Cosmic Consciousness or transcendent divine Reality exists. Philosophy of Psychedelics is an indispensable guide to the literature for researchers already engaged in the field of psychedelic psychiatry, and for researchers-especially philosophers-who want to become acquainted with this increasingly topical field. (shrink)

Objective: A deep understanding of the relationship between a scarce drug's dose and clinical response is necessary to appropriately distribute a supply-constrained drug along these lines. Summary of key data: The vast majority of drug development and repurposing during the COVID-19 pandemic – an event that has made clear the ever-present scarcity in healthcare systems –has been ignorant of scarcity and dose optimisation's ability to help address it. Conclusions: Future pandemic clinical trials systems should obtain dose optimisation (...) data, as these appear necessary to enable appropriate scarce resource allocation according to societal values. (shrink)