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)

Novel immune therapies are increasingly based on the molecular differentiation of disease patterns. The related clinical studies are thus more often characterized by the so-called adaptive study designs (umbrella or basket studies including platform studies), which are continuously adjusted based on novel results. This paper analyses new study designs beyond the often-postulated need for regulation in order to identify ethical problems based on typical structural features and to—whenever possible—suggest solutions. To do so, it addresses the following topics: the relationship between (...) social and scientific values of a study as well as aspects of the scientific validity of new forms of evidence; the inclusion of study subjects under the condition of relative uncertainty; specific challenges in the process of ethical approval, and ethical and practical challenges in the process of informing patients and receiving informed consent. Additionally, the topic of a potential risk–benefit assessment of such therapies is addressed. (shrink)

A key role in inference is played by randomization, which has been extensively used in clinical trials designs. Randomization is primarily intended to prevent the source of bias in treatment allocation by producing comparable groups. In the frequentist framework of inference, randomization allows also for the use of probability theory to express the likelihood of chance as a source for the difference of end outcome. In the Bayesian framework, its role is more nuanced. The Bayesian analysis of clinical trials can (...) afford a valid rationale for selective controls, pointing out a more limited role for randomization than it is generally accorded. This paper is aimed to offer a view of randomization from the perspective of both frequentist and Bayesian statistics and discussing the role of randomization also in theoretical decision models. (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)

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 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)

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)

Outcome-adaptive randomization (OAR) has been proposed as a corrective to certain ethical difficulties inherent in the traditional randomized clinical trial (RCT) 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)