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)

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)

Ethically permissible clinical trials must not expose subjects to risks that are unreasonable in relation to anticipated benefits. In the research ethics literature, this moral requirement is typically understood in one of two different ways: as requiring the existence of a state of clinical equipoise, meaning a state of honest, professional disagreement among the community of experts about the preferred treatment; or as requiring an equilibrium between individual and collective ethics. It has been maintained that this second (...) interpretation makes it mandatory to minimize the number of patients receiving the treatment that will eventually be shown to be inferior by the trial. This requirement has led to the development of adaptive trials, i.e., trials in which treatment allocation is determined by data accumulated during interim analysis. Many statisticians argue that in some circumstances—typically with potentially high benefits, as in the much discussed ECMO trial—adaptive design is the only ethically permissible experimental design. Nevertheless, some proponents of clinical equipoise argue that adaptive trials are neither ethically required nor permissible. More specifically, they argue that clinical trials using adaptive designs fail to meet the moral requirement of clinical equipoise, since these trials presuppose an epistemic state that is incompatible with a physician’s duty of care to her subjects. This paper emphasizes that the debate is to a large extent resting on an epistemological confusion. Specifically, I argue that this response conflates two different conceptions of statistical evidence, and that recognizing this distinction elucidates an epistemological framework in which adaptive trials are both consistent with and recommended by the moral requirement of clinical equipoise. (shrink)

Outcome-adaptive randomization has been proposed as a corrective to certain ethical difficulties inherent in the traditional randomized clinical trial using fixed-ratio randomization. In particular, it has been suggested that OAR redresses the balance between individual and collective ethics in favour of the former. In this paper, I examine issues of welfare and autonomy arising in relation to OAR. A central issue in discussions of welfare in OAR is equipoise, and the moral status of OAR is crucially influenced by (...) the way in which this concept is construed. If OAR is based on a model of equipoise that demands strict indifference between competing interventions throughout the trial, such equipoise is disturbed by accruing data favouring one treatment over another; OAR seeks to redress this by weighting randomization to the seemingly superior treatment. However, this is a partial response, as patients continue to be allocated to the inferior therapy. Moreover, it rests upon considerations of aggregate harms and benefits, and does not therefore uphold individual ethics. Issues of fairness also arise, as early and late enrollees are randomized on a different basis. Fixed-ratio randomization represents a fuller and more consistent response to a loss of equipoise, as so construed. With regard to consent, the complexity of OAR poses challenges to adequate disclosure and comprehension. Additionally, OAR does not offer a remedy to the therapeutic misconception—participants’ tendency to attribute treatment allocation in an RCT to individual clinical judgments, rather than to scientific considerations—and, if anything, accentuates rather than alleviates this misconception. In relation to these issues, OAR fails to offer ethical advantages over fixed-ratio randomization. More broadly, the ethical basis of OAR can be seen to lie more in collective than in individual ethics, and overall it fares worse in this territory than fixed-ratio randomization. (shrink)

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical (...) class='Hi'>trials are conducted. Policy-makers are swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs. (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)

The article explores the challenges of ensuring voluntary and informed consent which is obtained from potential research subjects in the north‐eastern part of Romania. This study is one of the first empirical papers of this nature in Romania. The study used a quantitative survey design using the adapted Quality of Informed Consent (QuIC) questionnaire. The target population consisted of 100 adult persons who voluntarily enrolled in clinical trials. The informed consent form must contain details regarding the potential risks (...) and benefits, the aim of the clinical trial, study design, confidentiality, insurance and contact details in case of additional questions. Our study confirmed that although all required information was included in the ICF, few clinical trial participants truly understood it. We also found that the most important predictive factor for a good subjective and objective understanding of the clinical trial was the level of education. Our study suggests that researchers should consider putting more effort in order to help clinical trials participants achieve a better understanding of the informed consent. In this way they will ensure that participants’ decision‐making is meaningful and that their interests are protected. (shrink)

This article describes our efforts to screen and enrol clinical trial participants conscientiously in the COVID-19 pandemic setting. We present the standard screening and enrolment process prior to, and our process of adapting to, the pandemic. Our goal was to develop a way to screen and enrol people for clinical trials that was both equitable and effective. In addition, we outline the steps our research department took to ensure that ethical, clinical and logistical factors were considered (...) when matching a patient to a clinical trial. (shrink)

In a typical comparative clinical trial the randomization scheme is fixed at the beginning of the study, and maintained throughout the course of the trial. A number of researchers have championed a randomized trial design referred to as ‘outcome-adaptive randomization.’ In this type of trial, the likelihood of a patient being enrolled to a particular arm of the study increases or decreases as preliminary information becomes available suggesting that treatment may be superior or inferior. While the design merits (...) of outcome-adaptive trials have been debated, little attention has been paid to significant ethical concerns that arise in the conduct of such studies. These include loss of equipoise, lack of processes for adequate informed consent, and inequalities inherent in the research design which could lead to perceptions of injustice that may have negative implications for patients and the research enterprise. This article examines the ethical difficulties inherent in outcome-adaptive trials. (shrink)

Background We report a randomised controlled clinical trial of neurofeedback therapy intervention for ADHD/ADD in adults. We focus on internal mechanics of neurofeedback learning, to elucidate the primary role of cortical self-regulation in neurofeedback. We report initial results; more extensive analysis will follow. Methods Trial has two phases: intervention and follow-up. The intervention consisted of neurofeedback treatment, including intake and outtake measurements, using a waiting-list control group. Treatment involved $\sim$40 hour-long sessions 2-5 times per week. Training involved either theta/beta (...) or sensorimotor-rhythm regimes, adapted by adding a novel 'inverse-training' condition to promote self-regulation. Follow-up (ongoing) will consist of self-report and executive function tests. Setting Intake and outtake measurements were conducted at University of Helsinki. Treatment was administered at partner clinic Mental Capital Care, Helsinki. Randomisation We randomly allocated half the sample then adaptively allocated the remainder to minimise baseline differences in prognostic variables. Blinding Waiting-list control design meant trial was not blinded. Participants 54 adult Finnish participants (mean age 36 years; 29 females) were recruited after screening by psychiatric review. 44 had ADHD diagnoses, 10 had ADD. Measurements Symptoms were assessed by computerised attention test (T.O.V.A.) and self-report scales, at intake and outtake. Performance during neurofeedback trials was recorded. Results Participants were recruited and completed intake measurements during summer 2012, before assignment to treatment and control, September 2012. Outtake measurements ran April-August 2013. After dropouts, 23 treatment and 21 waiting-list participants remained for analysis. Initial analysis showed that, compared to waiting-list control, neurofeedback promoted improvement of self-reported ADHD symptoms, but did not show transfer of learning to T.O.V.A. Comprehensive analysis will be reported elsewhere. Trial Registration "Computer Enabled Neuroplasticity Treatment (CENT)", ISRCTN13915109. Partly funded by Finnish science agency TEKES, project #440078. (shrink)

To address the burden of maternal morbidity and mortality in low‐ and middle‐income countries (LMICs), research with pregnant women in these settings is increasingly common. Pregnant women in LMIC‐context may experience vulnerability related to giving consent to participate in a clinical trial. To recognize possible layers of vulnerability this study aims to identify factors that influence the decision process towards clinical trial participation of pregnant women in an urban middle‐income setting. This qualitative research used participant observation, in‐depth interviews, (...) and focus group discussion with medical staff and pregnant women eligible for trial participation, at a regional hospital in Accra, Ghana. Besides lack of familiarity with modern scientific concepts, specific factors influencing the decision‐making process were identified. These include a wide power difference between health provider and patient, and a different perception of risk through externalization of responsibility of risk management within a religious context as well as a context shaped by authority. Also, therapeutic misconception was observed. The combination of these factors ensued women to rely on the opinion of the medical professional, rather than being guided by their own motivation to participation. Although being a (pregnant) woman per se should not render the label of being vulnerable, this study shows there are factors that influence the decision process of pregnant woman towards trial participation in a LMIC context that can result in vulnerability. The identification of context‐specific factors that can create vulnerability facilitates adaptation of the design and conduct of research in a culturally competent manner. (shrink)

Background: COVID-19 has taken many lives worldwide and due to this, millions of persons are in grief. When the grief process lasts longer than 6 months, the person is in risk of developing Complicated Grief Disorder. The CGD is related to serious health consequences. To reduce the probability of developing CGD a preventive intervention could be applied. In developing countries like Mexico, the psychological services are scarce, self-applied interventions could provide support to solve this problem and reduce the health impact (...) even after the pandemic has already finished.Aims: To design and implement a self-applied intervention composed of 12 modules focused on the decrease of the risk of developing CGD, and increasing the life quality, and as a secondary objective to reduce the symptomatology of anxiety, depression, and increase of sleep quality. The Intervention Duelo COVID follows the principles of User Experience and is designed according to the needs and desires of a sample of the objective participants, to increase the adherence to the self-applied intervention, considered one of the main weaknesses of online interventions.Methods: A Randomized Controlled Trial will be conducted from the 22nd of December of 2020 to the first of June 2021. The participants will be assigned to an intervention with elements of Cognitive Behavioral Therapy, Acceptance and Commitment Therapy, Mindfulness and Positive Psychology. The control group will be a wait-list condition, that will receive the intervention 1.5–2 months after the pre-measurement were taken. The Power Size Calculation conducted through G*Power indicated the need for a total of 42 participants, which will be divided by 21 participants in each group. The platform will be delivered through responsive design assuring with this that the intervention will adapt to the screen size of cellphones, tablets, and computers.Ethics and Dissemination: The study counts with the approval of the Research Ethics Committee of the Autonomous University of Ciudad Juárez, México, and it is registered in Clinical Trials. The article is sent and registered in clinical trials before the recruitment started. The results will be reported in future conferences, scientific publications, and media. (shrink)

ABSTRACT The aim of this study is to determine how stakeholder engagement can be adapted for the conduct of COVID‐19‐related clinical trials in sub‐Saharan Africa. Nine essential stakeholder engagement practices were reviewed: formative research; stakeholder engagement plan; communications and issues management plan; protocol development; informed consent process; standard of prevention for vaccine research and standard of care for treatment research; policies on trial‐related physical, psychological, financial, and/or social harms; trial accrual, follow‐up, exit trial closure and results dissemination; and (...) post‐trial access to trial products or procedures. The norms, values, and practices of collectivist societies in Sub‐Saharan Africa and the low research literacy pose challenges to the conduct of clinical trials. Civil‐society organizations, members of community advisory boards and ethics committees, young persons, COVID‐19 survivors, researchers, government, and the private sector are assets for the implementation and translation of COVID‐19 related clinical trials. Adapting ethics guidelines to the socio‐cultural context of the region can facilitate achieving the aim of stakeholder engagement. (shrink)

While the HVTN 505 trial showed no overall efficacy of the tested vaccine to prevent HIV infection over placebo, markers measuring immune response to vaccination were strongly correlated with infection. This finding generated the hypothesis that some marker-defined vaccinated subgroups were partially protected whereas others had their risk increased. This hypothesis can be assessed using the principal stratification framework (Frangakis and Rubin, 2002) for studying treatment effect modification by an intermediate response variable, using methods in the sub-field of principal surrogate (...) (PS) analysis that studies multiple principal strata. Unfortunately, available methods for PS analysis require an augmented study design not available in HVTN 505, and make untestable structural risk assumptions, motivating a need for more robust PS methods. Fortunately, another sub-field of principal stratification, survivor average causal effect (SACE) analysis (Rubin, 2006) – which studies effects in a single principal stratum – provides many methods not requiring an augmented design and making fewer assumptions. We show how, for a binary intermediate response variable, methods developed for SACE analysis can be adapted to PS analysis, providing new and more robust PS methods. Application to HVTN 505 supports that the vaccine partially protected individuals with vaccine-induced T-cells expressing certain combinations of functions. (shrink)

Many drugs used in paediatric medicine are off-label. There is a rising call for the use of adaptive clinical trial designs in responding to the need for safe and effective drugs given their potential to offer efficiency and cost-effective benefits compared with traditional clinical trials. ADs have a strong appeal in paediatric clinical trials given the small number of available participants, limited understanding of age-related variability and the desire to limit exposure to futile or (...) unsafe interventions. Although the ethical value of adaptive trials has increasingly come under scrutiny, there is a paucity of literature on the ethical dilemmas that may be associated with paediatric adaptive designs. This paper highlights some of these ethical concerns around safety, scientific/social value and caregiver/guardian comprehension of the trial design. Against this background, the paper develops a non-static conceptual lens for understanding PADs. It shows that ADs are epistemically open and reduce some of the knowledge-associated uncertainties inherent in clinical trials as well as fast-track the time to draw conclusions about the value of evaluated drugs/treatments. On this note, the authors argue that PADs are ethically justifiable given they have multiple layers of safety, exposing enrolled children to lesser potential risks, create social/scientific value generally and for paediatric populations in particular, specifically foster the flourishing of paediatric populations and can significantly improve paediatric trial efficiency when properly designed and implemented. However, because PADs are relatively new and their regulatory, ethical and logistical characteristics are yet to be clarified in some jurisdictions, the cooperation of various public and private stakeholders is required to ensure that the interests of children, their caregivers and parents/guardians are best served while exposing paediatric research subjects to the most minimal of risks when they are enrolled in paediatric trials that use ADs. Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable. (shrink)

Current treatments for chronic pain have limited benefit. We describe a resilience intervention for individuals with chronic pain which is based on a model of viewing chronic pain as dysregulated homeostasis and which seeks to restore homeostatic self-regulation using strategies exemplified by survivors of extreme environments. The intervention is expected to have broad effects on well-being and positive emotional health, to improve cognitive functions, and to reduce pain symptoms thus helping to transform the suffering of pain into self-growth. A total (...) of 88 Veterans completed the pre-assessment and were randomly assigned to either the treatment intervention or control. Fifty-eight Veterans completed pre- and post-testing. The intervention covered resilience strengths organized into four modules: engagement, social relatedness, transformation of pain and building a good life. A broad set of standardized, well validated measures were used to assess three domains of functioning: health and well-being, symptoms, and cognitive functions. Two-way Analysis of Variance was used to detect group and time differences. Broadly, results indicated significant intervention and time effects across multiple domains: Pain decreased in present severity [F = 5.02, p < 0.05, η2p = 0.08], total pain over six domains [F = 14.52, p < 0.01, η2p = 0.21], and pain interference [F = 6.82, p < 0.05, η2p = 0.11]; Affect improved in pain-related negative affect [F = 7.44, p < 0.01, η2p = 0.12], fear [F = 7.70, p < 0.01, η2p = 0.12], and distress [F = 10.87, p < 0.01, η2p = 0.16]; Well-being increased in pain mobility [F = 5.45, p < 0.05, η2p = 0.09], vitality [F = 4.54, p < 0.05, η2p = 0.07], and emotional well-being [F = 5.53, p < 0.05, η2p = 0.09] Mental health symptoms and the cognitive functioning domain did not reveal significant effects. This resilience intervention based on homeostatic self-regulation and survival strategies of survivors of extreme external environments may provide additional sociopsychobiological tools for treating individuals with chronic pain that may extend beyond treating pain symptoms to improving emotional well-being and self-growth.Clinical Trial Registration: Registered with ClinicalTrials.gov. (shrink)

Key messages The research environment has changed since clinical equipoise was first proposed 30 years ago New trial designs—such as umbrella and basket trials, adaptive platform trials, and cluster randomised trials—raise new ethical challenges for evaluating the state of scientific uncertainty and communicating about risks with patients and participants Clinical equipoise needs to evolve We propose the design of specific guidelines to provide ethics committees and trialists with instructions for how to evaluate equipoise in (...) the context of new designs and biomarkers and how to optimise communication with participants. (shrink)

To give substance to the rhetoric of ‘learning health systems’, a variety of novel trial designs are being explored to more seamlessly integrate research with medical practice, reduce study duration and reduce the number of participants allocated to ineffective interventions. Many of these designs rely on response adaptive randomisation. However, critics charge that RAR is unethical on the grounds that it violates the principle of equipoise. In this paper, I reconstruct critiques of RAR as holding that it is inconsistent (...) with five important ethical principles. I then argue that these criticisms rest on a faulty view of equipoise encouraged by the idea that a RAR study models the beliefs of a single rational agent about the relative merits of the interventions being studied. I outline a view in which RAR models an idealised health system in which diverse communities of fully informed experts shrink or grow as their constituent members update their expert opinions in light of reliable medical evidence. I show how a proper understanding of clinical equipoise can reconcile this conception of RAR with these five ethical principles. This analysis removes an in-principle objection to RAR and sheds important light on the relationship between clinical equipoise and transient diversity in the scientific community. (shrink)

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)

Coronavirus disease 2019 is a fast-developing viral pandemic spreading across the globe. Due to lack of availability of proven medicines against COVID-19, physicians have resorted to treatments through large trials of investigational drugs with poor evidence or those used for similar diseases. Large trials randomize 100–500+ patients at multiple hospitals in different countries to either receive these drugs or standard treatment. In order to expedite the process, some regulatory agencies had also given permission to use drugs approved for (...) other diseases, despite a lack of evidence of efficacy in COVID-19. In this review, we highlight the potential ethical issues that should be addressed during the use of investigational drugs with little prior evidence as a treatment options during a pandemic. We discuss the impact of design of randomized clinical trials using LOTUS trial as an example and that of off-label use of drugs like chloroquine/hydroxychloroquine on the safety of patients during COVID-19. We conclude that the adaptive randomized clinical trial designs offer a flexible and efficient approach, enabling patients to quickly switch to successful treatments, while minimizing the number of patients on standard of care. Randomized clinical trial design should consider blinding of investigators and only representative patients who can provide consent should be included. We also conclude the emergency approvals of drugs should be carefully issued and off-label use should be restricted in pandemics. Streamlined regulatory guidelines for emergency drug use in a pandemic can also help in providing benefit and minimizing harm to patients in the future. (shrink)

ObjectivesMany older adults with visual impairment also have significant hearing loss. The aim was to investigate the effectiveness of a newly developed Dual Sensory Loss protocol on communication and wellbeing of older persons with DSL and their communication partners in the Netherlands and Belgium.MethodsParticipants and their communication partners were randomized in the “DSL-protocol” intervention group or a waiting-list control group. The intervention took 3 to 5 weeks. Occupational therapists focused on optimal use of hearing aids, home-environment modifications and effective communication (...) strategies. The primary outcome was the Communication Strategies domain of the Communication Profile for the Hearing Impaired. Secondary outcomes measured in participants were the Low Vision Quality Of Life Adjustment subscale, the Center for Epidemiological Studies - Depression Scale, De Jong Gierveld Loneliness Scale and the Fatigue Assessment Scale. The Hearing Handicap and Disability Inventory - Reaction of Others subscale and the Care-related Quality of Life - 7 Dimensions was measured in communication partners. Measurements were taken at baseline and 3-month follow-up. Linear mixed models were used to analyze effects between groups over time for every outcome measure.ResultsIntention-to-treat analyses showed a significant effect of the DSL-protocol on the use of verbal strategies in favor of the control group, however, this effect was non-significant after adjustment for confounding. Effect sizes of other outcomes varied between −0.23 [−0.57, 0.12] and 0.30 [−0.05, 0.64]. The LMM showed a significant effect on the HHDI-Reaction of others scale in favor of communication partners in the treatment group, however, the effect did not remain significant at a 0.01 significance level and the effect size was very small and non-significant 0.12, 95% CI [−0.27 to 0.51]. Adjusted analyses did not reveal treatment effects.ConclusionThe DSL-protocol did not clearly contribute to the enhancement of communication and wellbeing in DSL-patients. Possible reasons for the lack of effects are OTs not being comfortable giving advice on communication and psychosocial issues or the short-term treatment and follow-up period. Further study is warranted to find out how the protocol may be adapted or whether it is necessary to involve mental healthcare professionals.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NTR2843. (shrink)

Clinical trials play a crucial role in generating evidence about healthcare interventions and improving outcomes for current and future patients. For individual trial participants, however, there are inevitably trade‐offs involved in clinical trial participation, given that trials have traditionally been designed to benefit future patient populations rather than to offer personalised care. Failure to understand the distinction between research and clinical care and the likelihood of benefit from participation in clinical trials has been (...) termed the ‘therapeutic misconception’. The evolution of the clinical trials landscape, including greater integration of clinical trials into healthcare and development of novel trial methodologies, may reinforce the significance of the therapeutic misconception and other forms of misunderstanding while at the same time (paradoxically) challenging its salience. Using cancer clinical trials as an exemplar, we describe how methodological changes in early‐ and late‐phase clinical trial designs, as well as changes in the design and delivery of healthcare, impact upon the therapeutic misconception. We suggest that this provides an impetus to re‐examine the ethics of clinical research, particularly in relation to trial access, participant selection, communication and consent, and role delineation. (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 Platform Adaptive trial of Novel antiviRals for eArly treatMent of COVID-19 In the Community 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)

Introduction: Clinical policies control several aspects of clinical practice, including individual treatment and care, resource management and healthcare professionals’ etiquette. This article presents Clinical Policy Ethics Assessment Tool, an ethical assessment tool for clinical policies that could be used not only by clinical ethics committees but also by policy committees or other relevant groups. Aim: The aim of this study was to find or create a tool to identify ethical issues and/or confirm ethical validity in (...) nursing practice policies, protocols and guidelines. Methodology: The development of Clinical Policy Ethics Assessment Tool involved first a literature review, followed by modification of the Research Protocol Ethics Assessment Tool, which was created to identify research protocols’ ethical issues, and finally, a trial of Clinical Policy Ethics Assessment Tool to ensure its reliability and validity. Ethical consideration: The policies analysed trialling Clinical Policy Ethics Assessment Tool were in the public domain and did not contain any confidential information. Despite that, Clinical Policy Ethics Assessment Tool also had the approval of a research ethics committee. Results: Research Protocol Ethics Assessment Tool was chosen as the template for a Clinical Policy Ethics Assessment Tool, to which several modifications were added to adapt it to work within a nursing practice context. Clinical Policy Ethics Assessment Tool was tested twice, which resulted in a general test–retest reliability coefficient = 0.86, r = 0.84, α1 = 0.817, α2 = 0.824 and interclass correlation coefficient = 0.874. Discussion: Contemporary nursing practice in a developed country is often ruled by clinical policies. The use of Clinical Policy Ethics Assessment Tool could confirm the ethical validity of those clinical practice policies, impacting on nurses’ education, values and quality of care. Conclusion: Clinical Policy Ethics Assessment Tool has the potential to detect ethical issues and facilitate the correction and improvement of clinical policies and guidelines in a structured way. This is especially so as it has shown reliability in detecting issues in clinical policies involving human participants and in encouraging policymakers to consider common ethical dilemmas in nursing practice. (shrink)

This study examined the quality of children's assent to a clinical trial. In subjects younger than 9 years of age, understanding of most aspects of the study was found to be poor to non-existent. Understanding of procedures was poor in almost all subjects. In addition, voluntariness may have been compromised in many subjects by their belief that failure to complete the study would displease others. If the fact that a child's assent has been obtained is used to justify the (...) exposure of that child to the potential harm of a non-therapeutic blood sample, the assent must be meaningful. In the nutrition study observed here, the quality of the assent of children younger than 9 years of age was very poor. The assent therefore did not provide a valid justification for requesting a blood sample from these children. This study indicates that most children younger than 9 years of age cannot be expected to consent or assent to clinical research in a meaningful way. The current age of 7 years for initiating assent (in addition to parental consent) is possibly not appropriate and should be reconsidered. (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)

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)

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)

Informed consent represents a specific protocol for obtaining consent from a fully informed human subject to take part in clinical research. Still, informed consent is not only required for clinical trials but it also represents a critical precondition before enrolment in standard everyday medical procedures. Relevant fundamental criteria for obtaining informed consent must be followed, and that is that patient must have the decisional capacity to reach autonomous decision. The patient must be adequately informed and not coerced. (...) Evaluating decisional capacity is crucial to providing the required level of care. The decision of which decisional capacity tool to use can be challenging because of various dissimilarities among the instruments. In this paper, four widely documented instruments have been evaluated, namely, the MacArthur Competence Assessment Tool for Treatment (MacCAT-T), the Hopkins Competency Assessment Test (HCAT), the Structured Interview for Competency/Incompetency Assessment Testing, Ranking Inventory (SICIATRI), and the Capacity Assessment Tool (CAT). Some of them include a fully structured interview; semi-structured forms characterise others. Most of them are adaptable for different scenarios, and yet, some are tailored for specific treatment decisions. Some evaluate all four components of decisional capacity, while others do not. Although a broad range of capacity assessment tools is available, it has been shown that they notably improve the accuracy of capacity evaluations. Given that many pathological conditions could result in impaired decisional capacity, physicians must be able to correctly and consistently assess the capacity for which education and previous experience are pivotal. (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)

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)

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)

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)

BackgroundHIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care (SoC) for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate SoC in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania.MethodsA mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and (...) modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee (CAC) with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders' Advisory Group (SAG), which includes two CAC representatives.ResultsKey recommendations from participatory community workshops, CAC and SAG meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative.ConclusionParticipatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting.Trial registrationCurrent Controlled Trials ISRCTN64716212. (shrink)

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)

The European framework surrounding clinical trials on medicinal products for human use is going to change as demonstrated by the large debate at European institutional level. One of the major challenges is to overcome the lack of harmonisation of clinical trial procedures among countries. This aspect is gaining more and more importance, considering the increasing number of multicentre and multinational studies. In this work, the actual European rules governing the Clinical Trial Application have been analysed throughout (...) the different steps including the registration of the trial in the European database; the preparation of documents to be submitted and their contents; the preparation of documents related to the information and consent process; the submission to competent bodies. Specific issues related to paediatric research and trials involving non EU/EEA countries have been addressed as well. Results reveal that the European legislation offers a well defined set of European rules covering different aspects of a Clinical Trial Application. However, these are not suitable to meet the challenges from multicentre and multinational clinical studies. A stronger set of rules, such as is available in a composite European Regulation has been adopted and is expected to harmonise practices and enable sponsors to carry out well conducted trials. But will the new regulation overcome the existing criticisms of Directive 2001/20/EC? (shrink)

It is not uncommon for multiple clinical trials at the same institution to recruit concurrently from the same patient population. When the relevant pool of patients is limited, as it often is, trials essentially compete for participants. There is evidence that such a competition is a predictor of low study accrual, with increased competition tied to increased recruitment shortfalls. But there is no consensus on what steps, if any, institutions should take to approach this issue. In this (...) article, we argue that an institutional policy that prioritises some trials for recruitment ahead of others is ethically permissible and indeed prima facie preferable to alternative means of addressing recruitment competition. We motivate this view by appeal to the ethical importance of minimising the number of studies that begin but do not complete, thereby exposing their participants to unnecessary risks and burdens in the process. We then argue that a policy of prioritisation can be fair to relevant stakeholders, including participants, investigators and funders. Finally, by way of encouraging and helping to frame future debate, we propose some questions that would need to be addressed when identifying substantive ethical criteria for prioritising between studies. (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.

Clinical trial results are often interpreted by inductive reasoning, in a trial design-limited manner, directed toward modifications of the current clinical practice. Deductive reasoning is an alternative in which results of relevant trials are combined in indisputable premises that lead to a conclusion easily testable in future trials.

This paper describes one possible origin point for fraudulent behavior within the American pharmaceutical industry. We argue that during the late nineteenth century therapeutic reformers sought to promote both laboratory science and increasingly systematized forms of clinical experiment as a new basis for therapeutic knowledge. This process was intertwined with a transformation in the ethical framework in which medical science took place, one in which monopoly status was replaced by clinical utility as the primary arbiter of pharmaceutical legitimacy. (...) This new framework fundamentally altered the set of epistemic virtues—a phrase we draw from the philosophical field of virtue epistemology—considered necessary to conduct reliable scientific inquiry regarding drugs. In doing so, it also made possible new forms of fraud in which newly emergent epistemic virtues were violated. To make this argument, we focus on the efforts of Francis E. Stewart and George S. Davis of Parke, Davis & Company. Therapeutic reformers within the pharmaceutical industry, such as Stewart and Davis, were an important part of the broader normative and epistemic transformation we describe in that they sought to promote laboratory science and systematized clinical trials toward the twin goals of improving pharmaceutical science and promoting their own commercial interests. Yet, as we suggest, Parke, Davis & Company also serves as an example of a company that violated the very norms that Stewart and Davis helped introduce. We thus seek to describe one possible origin point for the widespread fraudulent practices that now characterize the pharmaceutical industry. We also seek to describe an origin point for why we conceptualize such practices as fraudulent in the first place. (shrink)

Mounting evidence suggests that participation in clinical trials confers neither advantage nor disadvantage on those enrolled. Narrow focus on the question of a “trial effect,” however, distracts from a broader mechanism by which patients may benefit from ongoing clinical research. We hypothesize that the existence of clinical trials infrastructure—the organizational culture, systems, and expertise that develop as a product of sustained participation in cooperative clinical trials research—may function as a quality improvement lever, improving (...) the quality of care and outcomes of all patients within an institution or region independent of their individual participation in trials. We further contend that this “infrastructure effect” can yield particular benefits for patients in low- and middle-income countries. The hypothesis of an infrastructure effect as a quality improvement intervention, if correct, justifies enhanced research capacity in LMIC as a pillar of health system development. (shrink)

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)

Hastings Center Report, Volume 52, Issue 5, Page 42-43, September–October 2022.