Sarah Heynemann

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.

Conduct of clinical research involving single patient subjects has a relatively long history. The notion of ‘N-of-1 trials’ first emerged in the 1980s, introducing a method for evaluating the impact of alternately exposing individuals ‘on’ and ‘off’ a particular treatment. In the years since, interest in conventional, randomised, ‘N-of-1 trials’ has fluctuated, though recent advancements in data science, remote monitoring technologies and, more broadly, the ‘personalised’ medicine era has seen renewed engagement with the methodology. Amongst patient cohorts with cancer conduct of such trials has, for the most part, been uncommon, given the methodology is best suited to study of chronic, stable conditions. In recent years however, there has been growing attention within oncology research communities to the idea of ‘N-of-1 trials’. In part, this has been driven by the need to accommodate increasingly granular levels of molecular heterogeneity in cancer research. However, use of the label ‘N-of-1 trial’ has been applied to a variety of research endeavours involving single participants, with varying resemblance to conventional definitions of an ‘N-of-1 trial’. In this paper we review recent cases in which the term ‘N-of-1 trial’ has been operationalised in relation to clinical research amongst adult cancer populations. We then consider both the epistemic and ethical implications of individual-patient research endeavours in oncology. We conclude by noting the phenomenon represents a new frontier for those engaged in ethical oversight, as well as other stake-holders in cancer clinical research, including clinicians, researchers and health-care consumers.

The term ‘N-of-1 trial’ has traditionally referred to a specific, well-defined, clinical trial methodology, involving evaluation of an intervention (or interventions) in a single individual, with alternating periods ‘on’ and ‘off’ an intervention. Given methodological constraints, such trials are best suited to the study of chronic, stable conditions, and so have had a limited role in progressive conditions like cancer. According to evidence-based medicine hierarchies, conventional, randomised, N-of-1 trials are considered ‘type 1’ evidence. In recent years, however, the term ‘N-of-1 trial’ has appeared with growing frequency within the academic cancer literature but with reference to a heterogeneous range of research activities (which diverge in various ways from the conventional N-of-1 trial design). In this qualitative study, 72 semi-structured interviews were conducted with key stakeholders across the cancer clinical trials landscape to explore perspectives regarding the notion of ‘N-of-1 trials’ in oncology. This included various types of ‘trial professionals’ (trialists, statisticians, ethicists and ethics review board members, industry, regulatory and reimbursement body representatives), as well as ‘consumer representatives’. Findings of this study highlight that two broad categories of issues are particularly salient to stakeholders in relation to single participant focused research: (1) issues to do with opportunity to participate, and (2) issues to do with consent and risk management. We draw attention to implications for those engaged in the review of various forms of single participant focused research, and how these differ from considerations pertinent to more traditional clinical research. In particular, we caution against any ‘one size fits all’ approach to assessment of ‘acceptable’ risk during ethical review of such activities. Finally, we consider whether novel forms of oversight may be required, including a possible role for ethics review boards to engage directly with individuals considering participation in such studies.