Kate Sahan

Background: Because confirmatory clinical trials are costly, large-scale endeavors, the choice of their design carries significant weight. While the current methodological landscape offers tools to address residual pre-trial uncertainty through prespecified adaptations to design elements, design choices remain frequently constrained by prevailing orthodoxies. Methods: We examine how unacknowledged design uncertainties (e.g., sample size calculations based on incorrect effect size or variance estimates) impact the statistical, ethical, and resource-stewardship goals of confirmatory trials. We contrast how fixed and adaptive design strategies handle these uncertainties, detailing the operational safeguards, firewalls, and trade-offs (e.g., complexity, operational bias) required to preserve trial integrity. Results: Strict adherence to default templates prevents stakeholders from matching the design strategy to the specific complexities of the research question. We observe that the gold standard status of fixed designs often obscures their limitations in handling design uncertainties. A rigid adherence to these conventions can ethically hinder a trial’s ability to deliver conclusive results. Conversely, while adaptive designs can offer tools to efficiently reduce uncertainty, we acknowledge that adaptive elements are not without cost; their implementation requires rigorous safeguards to manage specific risks to trial integrity and potential operational biases. Conclusion: To better align clinical research with its ethical and scientific mandates, we issue two calls to action. First, trial designers, including statisticians, must clearly articulate how target and design uncertainties impact ethical obligations, promoting an open-minded evaluation of both fixed and adaptive methods. Second, stakeholders must foreground ethical considerations during design selection, requiring explicit justification for the use—or non-use—of adaptive elements. The ethical path forward is not to default to the old or blindly adopt the new, but to explicitly justify the chosen design based on its responsiveness to the specific uncertainties of the trial. We posit that trial design must transition from a habit-based process to one where pre-trial uncertainties are openly discussed and addressed.

The increasing integration of genomic medicine into routine medical care brings to light issues of complexity and uncertainty in the interpretation of genetic variation. We describe a fictional case study based on our experiences in the haematological malignancy setting to illustrate the complexities in using genomic testing to evaluate the suitability of relatives to act as stem cell donors. In particular, we demonstrate the ethical issues arising following the identification of a germline variant of uncertain significance (VUS) in a gene associated with inherited cancer susceptibility in a potential recipient. We discuss the factors that need to be considered, such as how this might influence donor selection, the potential for donor-derived leukaemia and the issues of offering testing to other family members. Popular discourse suggests genomics can offer clarity and transformation in healthcare. This case highlights the ethically complex nature of decision-making in genetic medicine due to the familial aspects of genomic information, the uncertain nature of many genomic results and how changes in the use of genomic information in clinical practice can call for urgent decision-making. This highlights the need for increased interdisciplinary working which takes into account the factors driving decisions for each specialty and recommends access to independent ethics support for members of the multidisciplinary team.

Comprehensive collections of cancer data, including genomic data, are needed to improve cancer risk prediction and treatments. A recent government review, Better, Broader, Safer: Using health data for research and analysis, has argued for high-quality Patient and Public Involvement and Engagement (PPIE) for ethical data use. In this paper we determine a role and justification for PPIE to govern uses of genomic data in fields like cancer. First, we analyse two public attitudes studies about the role of PPIE in genomics governance. Second, we characterise two ethically-significant features of the context of governing genomic data: 1) data aggregation leading to novel group formation, and 2) the hybrid territory of genomic cancer data uses. Thirdly, we bring together these aspects to describe a fully determined role for PPIE within an approach to governing cancer genomic data, which is tailored to major areas of ethical consideration. Our account is a novel interpretation of what PPIE is for in governance, how it may foster public support and how its success in so doing depends on it being tailored to context.

The Exception from Informed Consent (EFIC) permits patient enrolment into therapeutic emergency research where obtaining informed consent is challenging. Yet this fails to resolve a core ethical conflict in the research and has generated controversy. This is because existing justification and practice has relied on applying EFIC per study—a wholesale permission to enroll irrespective of circumstance—instead of per patient. Our novel justification for enrolment centers on applying EFIC per patient, which empowers the enrolling clinician to judge whether to enroll patients with an Exception. This contrasts with the idea that clinician judgment is surplus to the judgements already made by institutions in deciding the research may proceed. Instead, we show that enrolling clinician’s judgment is ethically significant and should not be overlooked: attending to this strengthens the research ethically and reduces controversy. There should be a bigger role for the clinician in the research enrolment space.

Much has been published about the ethical issues encountered by clinicians in genetics/genomics, but those experienced by clinical laboratory scientists are less well described. Clinical laboratory scientists now frequently face navigating ethical problems in their work, but how they should be best supported to do this is underexplored. This lack of attention is also reflected in the ethics tools available to clinical laboratory scientists such as guidance and deliberative ethics forums, developed primarily to manage issues arising within the clinic. We explore what ethical issues are being experienced by clinical scientists, how they think such issues could be best analysed and managed, and whether their practice might be enhanced by more situated approaches to ethics deliberation and practice such as ethical preparedness. From thematic analysis of cases presented by clinical scientists at a specially convened meeting of the UK Genethics Forum, we derived three main ethical themes: (1) the redistribution of labour and responsibilities resulting from the practice of genomic medicine; (2) the interpretation and certainty of results and (3) the proposal that better standardisation and consistency of ethical approaches (for example, more guidelines and policy) could resolve some of the challenges arising. We argue that although standardisation is important for promoting shared understandings of good (including ethical) practice, supplementary approaches to enhance and sustain ethical preparedness will be important to help clinical scientists and others in the recently expanded genetic/genomic medicine environment foster quality ethical thinking.

Between 2013 and 2017, targeted malaria elimination (TME), a package of interventions that includes mass drug administration (MDA)–was piloted in communities with reservoirs of asymptomatic P. falciparum across the Greater Mekong sub-Region (GMS). Coverage in target communities is a key determinant of the effectiveness of MDA. Drawing on mixed methods research conducted alongside TME pilot studies, this article examines the impact of the community engagement, local social context and study design on MDA coverage. Qualitative and quantitative data were collected using questionnaire-based surveys, semi-structured and in-depth interviews, focus group discussions, informal conversations, and observations of study activities. Over 1500 respondents were interviewed in Myanmar, Vietnam, Cambodia and Laos. Interview topics included attitudes to malaria and experiences of MDA. Overall coverage of mass anti-malarial administration was high, particularly participation in at least a single round (85%). Familiarity with and concern about malaria prompted participation in MDA; as did awareness of MDA and familiarity with the aim of eliminating malaria. Fear of adverse events and blood draws discouraged people. Hence, community engagement activities sought to address these concerns but their impact was mediated by the trust relationships that study staff could engender in communities. In contexts of weak healthcare infrastructure and (cash) poverty, communities valued the study’s ancillary care and the financial compensation. However, coverage did not necessarily decrease in the absence of cash compensation. Community dynamics, affected by politics, village conformity, and household decision-making also affected coverage. The experimental nature of TME presented particular challenges to achieving high coverage. Nonetheless, the findings reflect those from studies of MDA under implementation conditions and offer useful guidance for potential regional roll-out of MDA: it is key to understand target communities and provide appropriate information in tailored ways, using community engagement that engenders trust.

The spread of artemisinin-resistance in Plasmodium falciparum is a threat to current global malaria control initiatives. Targeted malaria treatment (TMT), which combines mass anti-malarial administration with conventional malaria prevention and control measures, has been proposed as a strategy to tackle this problem. The effectiveness of TMT depends on high levels of population coverage and is influenced by accompanying community engagement activities and the local social context. The article explores how these factors influenced attitudes and behaviours towards TMT in Kayin (Karen) State, Myanmar. Semi-structured interviews were conducted with villagers from study villages (N = 31) and TMT project staff (N = 14) between March and July 2015. Community engagement consisted of a range of activities to communicate the local malaria situation (including anti-malarial drug resistance and asymptomatic malaria), the aims of the TMT project, and its potential benefits. Community engagement was seen by staff as integral to the TMT project as a whole and not a sub-set of activities. Attitudes towards TMT (including towards community engagement) showed that developing trusting relationships helped foster participation. After initial wariness, staff received hospitality and acceptance among villagers. Offering healthcare alongside TMT proved mutually beneficial for the study and villagers. A handful of more socially-mobile and wealthy community members were reluctant to participate. The challenges of community engagement included time constraints and the isolation of the community with its limited infrastructure and a history of conflict. Community engagement had to be responsive to the local community even though staff faced time constraints. Understanding the social context of engagement helped TMT to foster respectful and trusting relationships. The complex relationship between the local context and community engagement complicated evaluation of the community strategy. Nonetheless, the project did record high levels of population coverage.