Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. (...) We first propose a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs. (shrink)

Decentralized clinical trials (DCTs) have the potential to advance the conduct of clinical trials, but raise several ethical issues, including obtaining valid informed consent. The debate on the ethical issues resulting from digitalization is predominantly focused on direct risks relating to for example data protection, safety, and data quality. We submit however, that a broader view on ethical aspects of DCTs is needed to touch upon the new challenges that come with the DCT practice. Digitalization has (...) impacts that go beyond its direct purposes, by shaping behaviors, experiences, social relations, and values. We examine four elements of the informed consent procedure that are affected by DCTs, while taking these soft impacts of technologies into account: (i) informing participants and testing understanding, (ii) freedoms in relation to responsibilities and burdens, (iii) trust in participant-researcher relations, and (iv) impacts on the concept of privacy. Our analysis reveals that a broad view is key for optimal conduct of DCTs. In addition, it provides insight into the ethical impacts of DCTs on informed consent. Technologies such as DCTs potentially have profound impacts which are not immediately addressed by the existing regulatory frameworks, but nonetheless important to recognize. These findings can guide future practices of DCTs to foster the important values of clinical research in this novel approach for conducting clinical trials. (shrink)

Regulators rely on clinical trials for drug approval and labeling decisions. Health systems and clinicians rely on the evidence from trials to determine treatment, and patients rely on it to decide which courses of care to undertake. Many of these stakeholders presume that the careful review of individual studies is enough to address the ethical and scientific questions that arise in clinical trials. In what follows, however, we demonstrate that explicit consideration of trial portfolios—series of (...) trials that are interrelated by a common set of objectives—is crucial. the ethical acceptability and evidentiary probity of individual trials can change depending on the characteristics of the portfolios in which they are embedded. Second, how trial portfolios are composed, how well they are coordinated, and how efficiently they use information determines the balance of risks and benefits they present as well as their different prospects for generating socially valuable information; these three factors also raise distinct questions of justice. (shrink)

Relatively little has been written about the ethics of conducting early phase clinical trials involving subjects from the developing world. Below, I analyze ethical issues surrounding one of gene transfer’s most widely praised studies conducted to date: in this study, Italian investigators recruited two subjects from the developing world who were ineligible for standard of care because of economic considerations. Though the study seems to have rendered a cure in these two subjects, it does not appear to (...) have complied with various international guidelines that require that clinical trials conducted in the developing world be responsive to their populations’ health needs. Nevertheless, policies devised to address large scale, late stage trials, such as the AZT short‐course placebo trials, map somewhat awkwardly to early phase studies. I argue that interest in conducting translational research in the developing world, particularly in the context of hemophilia trials, should motivate more rigorous ethical thinking around clinical trials involving economically disadvantaged populations. (shrink)

ABSTRACTRelatively little has been written about the ethics of conducting early phase clinical trials involving subjects from the developing world. Below, I analyze ethical issues surrounding one of gene transfer’s most widely praised studies conducted to date: in this study, Italian investigators recruited two subjects from the developing world who were ineligible for standard of care because of economic considerations. Though the study seems to have rendered a cure in these two subjects, it does not appear to (...) have complied with various international guidelines that require that clinical trials conducted in the developing world be responsive to their populations’ health needs. Nevertheless, policies devised to address large scale, late stage trials, such as the AZT short‐course placebo trials, map somewhat awkwardly to early phase studies. I argue that interest in conducting translational research in the developing world, particularly in the context of hemophilia trials, should motivate more rigorous ethical thinking around clinical trials involving economically disadvantaged populations. (shrink)

Armed with expanded federal funding for human embryonic stem cell research and new methods for deriving pluripotent stem cells, stem cell researchers in the U.S. are poised to proceed with unprecedented speed toward the development of new clinical therapies. Staring into the new dawn of regenerative medicine, many observers may assume that the only responsible route to the clinic, both scientifically and ethically, is through FDA-approved clinical trials processes. Conventional wisdom dictates that, like pharmaceutical drugs and the (...) use of biological therapeutics, stem cell-based therapies will have to pass through a series of controlled studies — initially to assess safety and toxicity, then efficacy and comparative efficacy — before they can be justifiably administered to patients outside a clinical trials context. (shrink)

Ethical reasons are presented for requiring 1) that a proposal for a clinical trial should be accompanied by a thorough review of all previous trials that have examined the same and closely related questions, and 2) that a trial should be approved by a research ethics committee only if the investigator undertakes to register it in an appropriate register of clinical trials as soon as one exists.

This paper discusses exceptional circumstances under which patients outside of clinical trials are likely to receive innovative stem cell-based interventions. These circumstances involve: (1) stem cell interventions not initially amenable to a clinical trials approach; (2) expanded access to investigational stem cell products (“compassionate use”); and (3) off-label uses of FDA approved stem cell products. This paper proposes a new approach to regulating these exceptional cases.

The relationship between the ethical standards for the governance of clinical trials and market forces can be complex and problematic. This article uses India as a case study to explore this nexus. From the mid-2000s, India became a popular destination for foreign-sponsored clinical trials. The Indian government had sought to both attract clinical trials and ensure these would be run in line with internationally accepted ethical norms. Reports of controversial medical research, however, triggered debate (...) about the robustness and suitability of India's regulatory system. In response to civil society pressure and interventions by the Supreme Court, the Indian government proposed additional measures aimed at strengthening protections for clinical trial participants. Whilst the reforms can be seen as a victory for human rights activists, they have also been criticised as being overly burdensome for sponsors. Indeed, their announcement prompted an exodus of clinical trials from India. Fearful of losing business to ‘rival’ countries, the Indian government is revisiting some of its proposals. The Indian example suggests that research ethics frameworks and national policies for economic development are increasingly intertwined. Host countries are in theory free to improve the lot of research participants, but doing so may make them appear less attractive to foreign sponsors, who can simply shift their activities to more industry-friendly jurisdictions. Although these economic pressures are unlikely to lead to a regulatory ‘race to the bottom’, they may limit host countries' ability to enact socially desirable reforms. (shrink)

Clinical trials are a central mechanism in the production of medical knowledge. They are the gold standard by which such knowledge is evaluated. They are widespread both in the United States and internationally; a National Institute of Health database reports over 106,000 active industry and government-sponsored trials (National Institutes of Health n.d.). They are an engine of the economy. The work of trials is complex; multiple people with diverse interests working across multiple settings simultaneously participate in (...) them, and they are underwritten by multiple organizational structures and diverse funding mechanisms. In the past several years, concern about the ethics of clinical trials has spiked dramatically .. (shrink)

The quest for effective medicines is very old. In modern times two important tools have been developed to evaluate efficacy of drugs: superiority and non-inferiority types of clinical trials. The former tests the null hypothesis of μ (the difference between a tested drug and comparator) ≤ 0 against μ > 0; the latter tests the null hypothesis of μ ≤ - Δ against, μ > - Δ, where Δ is the clinical difference from the comparator. In a (...) superiority trial, a new drug is tested against a placebo; in a non-inferiority trial, a new drug is tested against active treatment. In this paper, arguments are presented to show that a superiority trial against a placebo is scientifically sound but ethically unacceptable, whereas a non-inferiority trial against active treatment is ethically sound but scientifically not reliable. Switching from a superiority type of trial with placebo to a non-inferiority trial with an active-control — following the latest revision of Declaration of Helsinki — is in practice switching from the violation of the uncertainty principle to uncertainty of results. Given human and financial resources, it appears an academic question as to which is more unethical: to violate patients’ rights or to produce results without scientific value. All presented considerations lead to the conclusion that the use of a superiority trial of design with an active control instead of placebo will satisfy scientific needs, expectation of patients, and the ancient quest for effective medicines. In the era of Good (Clinical, Laboratory, Manufacture) Practice, the attention of those performing clinical trials is focused on the procedure, not always on its essence. However even the excellent performance of a trial which is not worth doing is fruitless. (shrink)

What kind of patients may be recruited to early clinical trials of xenotransplantation? This is discussed under the assumption that the risk of viral infection to the public is non-negligible. Furthermore, the conditions imposed by the Helsinki declaration are analysed. The conclusion is that only patients at risk of dying and with no alternative treatment available should be recruited to xenotransplantation trials in the early phase. For some of the less dangerous cell or islet cell xenotransplantation other (...) categories might be recruited. The risk of cell and islet cell xenotransplantation should, however, be weighted against the development of other technologies.In order to safeguard the public, the opt-out clause in the Helsinki declaration should not be fully applied. Legally binding rules on obligatory monitoring and restrictions should be imposed—before clinical trials start. Journal of Medical Ethics. (shrink)

The outsourcing of clinical trials to Latin America by the transnational innovative pharmaceutical industry began about twenty years ago. Using archival information and field work in Argentina, Brazil, Costa Rica, Mexico and Peru, the authors discuss the regulatory contexts and the ethical dimensions of human experimentation in the region. More than 80% of all clinical trials in the region take place in these countries, and the European Medicines Agency has defined them as priority countries in Latin (...) America. The authors raise questions about the quality of data obtained from the trials and the violation of human rights during their implementation. Their findings are presented in this volume, the first in-depth analysis of clinical trials in the region.. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged (...) conventional thinking about therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged (...) conventional thinking about therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

Mood disorders, including major depressive disorder and bipolar disorder, are highly prevalent, frequently disabling, and sometimes deadly. Additional research and more effective medications are desperately needed, but clinical trials research in mood disorders is fraught with ethical issues. Although many authors have discussed these issues, most do so from a theoretical viewpoint. This manuscript uses available empirical data to inform a discussion of the primary ethical issues raised in mood disorders research. These include issues of consent and decision-making (...) capacity, including patients’ motivations for participating in research. We also address drug withdrawals, placebo controls, and the overall safety of research. Finally, we examine the extant literature for studies discussing potential indirect benefits of clinical trials research to participants. Taken together, the evidence suggests that clinical trials research incorporating drug withdrawals and placebo controls can be conducted safely and ethically, even in patients with severe or treatment-resistant mood disorders. In fact, given the dearth of effective treatment options for this population, it is our opinion that a moral imperative exists to extend the offer of research participation to severely ill or treatment-resistant groups. (shrink)

Any healthcare systems during a pandemic undergo tremendous pressure in pursuit of effective treatment to treat and limit the spread of the disease and its implications. Conducting clinical trials to find the potential therapy is the only way to battle the current coronavirus disease-2019 pandemic. The majority of the countries have joined the cause and are carrying out clinical studies in various capacities. As a result, the ethical committees have encountered a sudden inflow of a large number (...) of trial proposals that have placed them under pressure. Although ethical committees play a vital role in protecting patient safety and preserving research integrity, they need to make sure the efficiency and integrity of review are preserved and the standards of review are not relaxed. Thus, the participants’ dignity is well guarded while keeping a close check on their safety. (shrink)

Despite prevalent concerns about the ethical conduct of clinical trials, little is known about the day-to-day work of trials and the ethical challenges arising in them. This paper reports on a study designed to fill this gap and demonstrates a need to refine the oversight system for trials to reflect an understanding of this day-to-day work. It also illuminates ethical challenges that cannot be addressed by the oversight system and so necessitate a rethinking of the (...) class='Hi'>ethics of clinical trials. (shrink)

Our aims are to set forth a multiprinciple system for selecting among clinical trials competing for limited space in an immunotherapy production facility that supplies products under investigation by scientific investigators; defend this system by appealing to justice principles; and illustrate our proposal by showing how it might be implemented. Our overarching aim is to assist manufacturers of immunotherapeutic products and other potentially breakthrough experimental therapies with the ethical task of prioritizing requests from scientific investigators when production capacity (...) is limited. (shrink)

Most phase III clinical trials today are explanatory. Because explanatory, or efficacy, trials test hypotheses under “ideal” conditions, they are not well suited to providing guidance on decisions made in most clinical care contexts. Pragmatic trials, which test hypotheses under “usual” conditions, are often better suited to this task. Yet, pragmatic, or effectiveness, trials are infrequently carried out. This mismatch between the design of clinical trials and the needs of health care professionals (...) is frustrating for everyone involved, and explains some of the challenges inherent in attempts to enhance knowledge translation and encourage evidence-based practice. The situation is more than simply frustrating, however; it is potentially unethical. Clinical trials must be socially valuable in order to (1) warrant the risks they impose on human research subjects and (2) fairly and efficiently assess new clinical interventions. Most bioethicists would agree that trials that have no social value, for instance, because their results do not have the potential to advance clinical care, should not be performed. What is less widely appreciated is that given limited research resources, trials that are more socially valuable should be preferred to trials that are less socially valuable when all else is equal. With respect to clinical trial design, I argue that while explanatory trials often have some social value, many have less social value than their pragmatic counterparts. On the basis of this general ethical assessment, I provide a preliminary defense of the position that clinical researchers should aim to conduct pragmatic trials, that is, that researchers face a burden of justification related to any idealizing elements added to trial designs. (shrink)

This article examines issues relating to ethics decision‐making in clinical trials. The overriding concern is to ensure that the well being and the interests of human subjects are adequately safeguarded. In this respect, this article will embark on a critical analysis of theICH‐GCP Guideline. The purpose of such an undertaking is to highlight areas of concern and the shortcomings of the existingICH‐GCP Guideline. Particular emphasis is made on how ethics committees perform their duties and responsibilities in (...) line with the principles outlined in theICH‐GCP Guideline. This article will draw attention to the need for a new approach to addressing the weaknesses of theICH‐GCP Guideline in its present form. (shrink)

This article examines issues relating to ethics decision-making in clinical trials. The overriding concern is to ensure that the well being and the interests of human subjects are adequately safeguarded. In this respect, this article will embark on a critical analysis of the ICH-GCP Guideline. The purpose of such an undertaking is to highlight areas of concern and the shortcomings of the existing ICH-GCP Guideline. Particular emphasis is made on how ethics committees perform their duties and (...) responsibilities in line with the principles outlined in the ICH-GCP Guideline. This article will draw attention to the need for a new approach to addressing the weaknesses of the ICH-GCP Guideline in its present form. (shrink)

Advances in medicine are closely linked to clinical research, but certain study procedures may be in conflict with the fundamental principles of ethics and codes of conduct in medicine. Following an analysis of two studies involving treatments for acute myocardial infarction (AMI), the admissibility of continuing a study was questioned after the initial results for two types of treatment showed that one was significantly better than the other. Also considered doubtful was the information provided to patients with the (...) object of obtaining their informed consent. (shrink)

Until a few years ago, the prevailing view was that children should not be participants in clinical research trials because children were incapable of consenting to such nontherapeutic interventions and are particularly vulnerable to abuse. That view has undergone a significant shift in the last few years, particularly in the context of trials to test the safety and effectiveness of drugs. A number of events facilitated this change, including the widespread off-label distribution of drugs to children and (...) developments in the AIDS epidemic. These social forces have shifted the core ethical question from whether children should be research subjects to when children should be research subjects.The presumption in favor of including children as research subjects for drug trials has manifested itself primarily through two different reforms: a 1997 federal statute and a set of regulations promulgated by the Food and Drug Administration that recently became effective. Together they reflect the view that children deserve the same access to safe and effective therapies as adults. (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)

Monitoring of clinical trials is important to ensure adherence to protocol, to safeguard the rights of research participants and to achieve compliance with principles of good clinical practice. Recent regulatory changes in India require Ethics Committees to keep an oversight of ongoing clinical trials including on-site monitoring. In this article, we share the experience of on-site monitoring of clinical trials by the Ethics Committee of a tertiary care, academic and research centre (...) in India. We found a large number of shortcomings in the areas of informed consent, adverse events, insurance and reimbursement, which would not have been detected by off-site document review. Interestingly, many shortcomings were also not detected by on-site monitoring arranged by clinical trial sponsors. We therefore conclude that on-site monitoring of ongoing clinical trials is a highly important activity for Indian Ethics Committees. (shrink)

Xenotransplant patient selection recommendations restrict clinical trial participation to seriously ill patients for whom alternative therapies are unavailable or who will likely die while waiting for an allotransplant. Despite a scholarly consensus that this is advisable, we propose to examine this restriction. We offer three lines of criticism: (1) The risk–benefit calculation may well be unfavorable for seriously ill patients and society; (2) the guidelines conflict with criteria for equitable patient selection; and (3) the selection of seriously ill patients (...) may compromise informed consent. We conclude by highlighting how the current guidance reveals a tension between the societal values of justice and beneficence. (shrink)

Garland, Morain, and Sugarman (2023) can be congratulated for their comprehensive and sharp analysis of physicians’ ethical duties with respect to pragmatic clinical trials (PCTs). PCTs embed resea...

Randomized and double-blind clinical trials are widely regarded as the most reliable way of studying the effects of medical interventions. According to received wisdom, if a new drug or treatment is to be accepted in clinical practice, its safety and efficacy must first be demonstrated in such trials. For ethical and scientific reasons, it is generally considered necessary to monitor a trial in various ways as it proceeds and to analyze data as they accumulate. Monitoring and (...) interim analyses are often conducted by a so-called data monitoring committee (DMC), a group of experts independent of both sponsors and investigators. On the basis of DMC recommendations, sponsors sometimes decide to discontinue trials .. (shrink)

Ex-vivo tissue engineering is an emerging medical technology. Its aim is to regenerate tissues and organs and to restore them to full physiological activity. Some clinical trials with human tissue engineered products have been conducted and others will follow. These trials not only have to confirm the therapeutic value of the HTEP, they also have to provide insight in its regenerative activity, its safety and long-term effects. The development of these trials is aggravated by the complexity (...) of the tissue engineering process and product. This paper investigates how this complexity influences the ethical conduct of clinical trials with HTEPs. We focus on the value and validity of the trial, the risk-benefit ratio and the protection of the trial participant. We argue that trials with HTEPs need a robust methodology. The risk-benefit ratio of a new HTEP must be determined and compared with available efficacious therapies. This requires the identification and minimisation of risks associated with tissue engineering. Finally a process as complex as tissue engineering presents serious challenges for the informed consent process, and for the protection of the trial participant during and after the trial. (shrink)

As a consequence of the COVID-19 pandemic, the number of decentralized clinical trials, trials conducted in whole or in part at locations other than traditional clinical trial sites, significantly increased. While these trials have the potential advantage of access, participant centricity, convenience, lower costs, and efficiency, they also raise a number of important ethical and practical concerns. Here we focus on a number of those concerns, including participant safety, privacy and confidentiality, remote consent, digital access (...) and proficiency, and trial oversight. Awareness of these ethical complexities will help foster the development of processes and cooperative solutions to promote safe, ethical trials going forward, optimized to decrease burden and increase access for all participants. (shrink)

Healthy Volunteers (HVs) who participate in clinical trials are a vulnerable group that deserves specific protection. We assessed the number and types of studies that involve HVs around the world and outline the methodological barriers to their analysis. We found that tens of thousands of HVs are involved every year in clinical trials in a large variety of countries and that the overwhelming majority of studies are not “first-in-human” but pharmacokinetic studies. The two cornerstones for both (...) ethical and safe participation of HVs in clinical trials are properly obtained informed consent, and a minimization of exposure to risk, in particular by avoiding concealed participation in multiple trials. To minimize the risk of exploitation of HVs and their exposure to risk, we propose ways to ensure genuine informed consent, and advocate setting up national Healthy Volunteer volunteer registries as established in France and the U.K. (shrink)

The upcoming Regulation No 536/2014 on clinical trials on medicinal products for human use, which will replace the current Clinical Trial Directive at the end of 2021, has triggered a significant reform of research ethics committee systems in Europe. Changes related to ethics review of clinical trials in the EU were considered to be essential to create a more favourable environment to conduct clinical trials in the EU. The concern is, however, (...) that the role of the research ethics committees will weaken in at least some of the Member States because the new Regulation allows narrowing down the scope of ethics review as compared with the currently valid Clinical Trial Directive. Although the new Regulation may lead to faster approval procedures for clinical trials, which is especially relevant in the context of pandemics, high-quality ethics reviews integrating methodological aspects of a clinical trial should nevertheless be ensured. To maintain high research ethics standards as well as to foster measures to mitigate potential negative consequences of the reform, it is therefore of vital importance to start debating and sharing the reflections about the potential consequences of these transformations and trends as soon as possible. (shrink)

Drug repurposing is a strategy of identifying new potential uses for already existing drugs. Many researchers adopted this method to identify treatment or prevention during the COVID-19 pandemic. However, despite the considerable number of repurposed drugs that were evaluated, only some of them were labeled for new indications. In this article, we present the case of amantadine, a drug commonly used in neurology that attracted new attention during the COVID-19 outbreak. This example illustrates some of the ethical challenges associated with (...) the launch of clinical trials to evaluate already approved drugs. In our discussion, we follow the ethics framework for prioritization of COVID-19 clinical trials proposed by Michelle N Meyer and colleagues (2021). We focus on four criteria: social value, scientific validity, feasibility, and consolidation/collaboration. We claim that launching amantadine trials was ethically justified. Although the scientific value was anticipated to be low, unusually, the social value was expected to be high. This was because of significant social interest in the drug. In our view, this strongly supports the need for evidence to justify why the drug should not be prescribed or privately accessed by interested parties. Otherwise, a lack of evidence-based argument could enhance its uncontrolled use. With this paper, we join the discussion on the lessons learned from the pandemic. Our findings will help to improve future efforts to decide on the launch of clinical trials on approved drugs when dealing with the widespread off-label use of the drug. (shrink)

As the_number of clinical trials continues to grow, there is an increasing need for education and training in the field. The clinical research climate is less forgiving of errors and oversights and therefore requires more knowledge of regulations and requirements. This brand new edition details new laws and regulations in protecting children participating in clinical trials and how a new focus on privacy of individual health information in the United States has changed how medical records (...) are handled. Includes a manual for investigators, research nurses and study coordinators with minimal experience or who are new to clinical research An easy-to-read and open text design using ‘sidebars’ of examples and information boxes related to the main text Includes a list of Frequently Asked Questions and Glossary Duke Clinical Research Institute is the world’s largest academic clinical research organisation and is well known and respected within the clinical research community. (shrink)

Research and clinical trial development for rare diseases pose unique bioethical challenges. Much of the literature on rare diseases focuses on patient advocacy and drug development to manage or cu...

In an adaptive clinical trial , key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts’ views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate (...) the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. (shrink)

It was the spring of 2020 when the email came to our inboxes—a memo from our Institutional Review Board informing us that we were approved to begin conducting our pragmatic clinical trial with a wa...

Pragmatic clinical trials are a relatively new methodological approach to the execution of clinical research that can increase research efficiency and provide access to unique data. Some have suggested that the costs and delays associated with obtaining informed consent could make PCTs difficult or even impossible to execute. Alternative consent models have been proposed, some of which lower standards of disclosure, delay consent, or waive it altogether. We analyze the permissibility of changes to informed consent in the (...) context of Canadian research ethics policies, legislation, common law, professional codes of ethics, and professional standards of practice. We find that Canadian law and policy relating to informed consent clearly applies to any clinician who might be involved in a PCT. In addition, existing consent norms seem unable to accommodate alternative consent models for pragmatic research if such models would involve lowering the standard of disclosure. The strong emphasis on the primacy... (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)

Achieving a good clinical trial design increases the likelihood that a trial will take place as planned, including that data will be obtained from a sufficient number of participants, and the total number of participants will be the minimal required to gain the knowledge sought. A good trial design also increases the likelihood that the knowledge sought by the experiment will be forthcoming. Achieving such a design is more than good sense—it is ethically required in experiments when participants are (...) at risk of harm. This paper argues that doing a power analysis effectively contributes to ensuring that a trial design is good. The ethical importance of good trial design has long been recognized for trials in which there is risk of serious harm to participants. However, whether the quality of a trial design, when the risk to participants is only minimal, is an ethical issue is rarely discussed. This paper argues that even in cases when the risk is minimal, the quality of the trial design is an ethical issue, and that this is reflected in the emphasis the Belmont Report places on the importance of the benefit of knowledge gained by society. The paper also argues that good trial design is required for true informed consent. (shrink)

The author discusses the social influences that gave rise to the presumption in favor of children's participation in research and emphasizes the need for an ethical framework to guide decision-making in this context. Specifically, the author proposes a framework of child-centered bioethics that integrates the core bioethics principles of beneficence and autonomy with an assessment of children's needs and interests. Finally, the author articulates recommendations regarding mature minors and institutional review boards consistent with this framework in order to resolve the (...) difficult ethical issues posed by including children of all ages in clinical drug trials. (shrink)

Biomedical ethics requires that clinical trial participants be accurately informed of the potential risks associated with investigational medical products. We found that the vaccine manufacturer Merck made false statements to the trial participants about the safety of Gardasil in its Future II HPV vaccine trial in Denmark. The clinical study protocol specified that safety testing was one of the trial’s primary objectives, but the recruitment brochure given to trial participants stated this was not the case, as allegedly (...) the vaccine had already been proven safe in previous trials. The advertising material for the trial and the informed consent forms stated that the comparator was saline or an inactive substance, when, in fact, it contained Merck’s proprietary aluminum adjuvant which is highly immunogenic. Several trial participants experienced long-term disabling symptoms during the trial, also some randomized to the adjuvant “placebo” control group. In all cases, their serious adverse events were dismissed as unrelated to the study treatment by Merck’s clinical investigators. We demonstrate that Merck’s published statements about the safety of their proprietary aluminum adjuvant is contradicted by the research evidence. The use of adjuvants as “placebos” in vaccine clinical trials is unethical as it makes it difficult to discover serious vaccine harms. (shrink)

This systematic review identifies and critically evaluates instruments that have been developed to measure clinical trial informed consent comprehension in non-cognitively-impaired adults.Literature searches were carried out on Medline (Ovid), PsycInfo, CINHAL, ERIC, ScienceDirect, and Cochrane Library for English language articles published between January 1980 and September 2008. Instruments were excluded if they focused on consent onto paediatric trials, the construct under study was primarily capacity or competency, or the instrument was developed specifically for psychiatric or cognitively-impaired populations. Instruments (...) selected for review were evaluated against the following criteria: (1) method of item generation; (2) type and format of test items; (3) administration and interpretation of test results; and (4) psychometric properties.Three instruments met our defined inclusion criteria: the Deaconess Informed Consent Comprehension Test (DICCT), the Quality of Informed Consent (QuIC) questionnaire and the Brief Informed Consent Protocol (BICEP). Each instrument varied in terms of content measured. Significantly, these are the first standardized instruments developed to assess comprehension in non-cognitively-impaired adults. Yet, each instrument had its own set of limitations such as the lack of generalizability and the absence of details pertaining to how test results should be used to guide clinical decision-making.Standardized clinical trial informed consent comprehension assessments have been developed to identify gaps in research participants' understanding and ensure that respect for patient autonomy is satisfied. (shrink)