Mark Sheehan

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.

This discussion builds on the significant advances in patient and public involvement (PPI) in health technology assessment (HTA) over the past two decades. It draws on key concepts that are raised in the early chapters in this Part with a view to refining our understanding of these concepts so that the development of thinking in this arena can continue to evolve. The discussion is framed around four key concepts: decision-making, the functional difference between patient and public involvement, representation, and epistemic injustice. Firstly, the discussion distinguishes between the HTA process and the final decision-making step, advocating for patient involvement in evidence gathering but public involvement in decision-making to ensure fairness. Secondly, it examines the concept of representation, differentiating between descriptive and political representation, and emphasises the importance of clear roles for PPI contributors. Thirdly, the issue of epistemic injustice is addressed, focusing on testimonial and hermeneutic injustices that patients may face. By examining the contrary, epistemic justice, the discussion argues for the proper treatment of patient knowledge and the provision of appropriate forums for expression. Overall, the discussion suggests that refining these distinctions will enhance the rationale and practice of PPI in HTA, leading to more nuanced practice and just healthcare provision.

Introduction: Governments create policies to address societal needs and then assess their effectiveness through policy metrics. The UK Rare Diseases Framework and its England Rare Diseases Action Plans aim to improve the lives of people with lived experience of rare diseases and their carers. Reaching these goals requires more effective engagement with those least likely to interact with NHS services. This paper outlines a protocol to identify relevant high-level policy metrics while engaging underserved and underrepresented groups. Methods and Analysis: A long list of candidate metrics for the 36 Actions linked to the four Priority Areas of the Framework was compiled from government logic models. The list was discussed in three workshops, and irrelevant, ambiguous, or time-irrelevant metrics were removed. Additional metrics were identified through an evidence review and expert opinion. In the first round of a two-round eDelphi study, shortlisted metrics will be grouped into the four Priority Areas: Faster Diagnosis, Increased Healthcare Professional Awareness, Better Care Coordination, and Improved Access to Specialist Care, Treatment, and drugs. An eDelphi panel of 50 people living with rare disease or their carers, as well as 50 professional stakeholders, will rate each metric on a 1-9 scale. The sample size allows for 20% attrition. Consensus for inclusion or exclusion will be based on 70% agreement (7-9 for ‘very valuable’, 1-3 for ‘not valuable’), with fewer than 15% rating the metric at the opposite end of the scale. Metrics will be included or excluded if consensus is reached in both groups; otherwise, they will remain under consideration in Round 2. In Round 1, eDelphi participants may propose additional metrics, which will be included in Round 2. After two rounds, a final set of policy metrics will be selected. Any discrepancies in Round 2 ratings will be explored through further research. Ethics and Dissemination: The Coventry University Group Research Ethics Committee has approved the study (P183377). The results will be disseminated to people with lived experience of rare disease and professional stakeholders through conferences, events, and newsletters and submitted to a peer-reviewed journal. If adopted, the identified metrics will inform decision-making on rare disease policies in England and beyond. Registration Details: ISRCTN41639707 ARTICLE SUMMARY: Strengths and limitations of this study: The study’s strength lies in its equal representation of individuals with lived experience of rare diseases and professional stakeholders, ensuring contextually relevant and widely accepted policy metrics. Efforts are made to include underserved groups, ensuring the meaningful representation of underrepresented sub-populations. The findings will primarily apply to the England Rare Diseases Action Plans, limiting their generalisability to other countries or healthcare systems. The heterogeneity of the study population may pose challenges in reaching consensus, potentially impacting the robustness of the agreed-policy metrics. Despite targeted recruitment efforts, challenges in including underserved groups may result in a less representative sample, affecting the study’s generalisability.

Recent literature has drawn attention to the complex relationship between health care and the environmental crisis. Healthcare systems are significant contributors to climate change and environmental degradation, and the environmental crisis is making our health worse and thus putting more pressure on healthcare systems; our health and the environment are intricately linked. In light of this relationship, we might think that there are no trade‐offs between health and the environment; that healthcare decision‐makers have special responsibilities to the environment; and that environmental values should be included in healthcare resource‐allocation decisions. However, we argue that these claims are mistaken. The environmental crisis involves a wider range of considerations than just health. There is a plurality of reasons to act on the environment; we might do so to protect the natural world, to prevent catastrophes in other parts of the world, or to avert climate war and displacement. Trading‐off between health care and environmental sustainability is thus unavoidable and requires sensitivity to all these reasons. Healthcare decision‐makers are not well placed to be sensitive to these reasons, nor do they have the democratic authority to make such value judgements. Therefore, decisions about environmental sustainability interventions should be made at a ‘higher level’ of resource allocation. Importantly, hospitals have environmental duties but not environmental responsibilities; their job is to provide the best healthcare possible within the constraints given to them, not to choose between health care and other goods.

Healthcare delivery and access, both in the United States and globally, were negatively affected during the entirety of the COVID-19 pandemic. This was particularly true during the first year when countries grappled with high rates of illness and implemented non-pharmaceutical interventions such as stay-at-home orders. Among children with special healthcare needs, research from the United Kingdom (U.K.) has shown that the pandemic response uniquely impacted various aspects of their care, including decreased access to care, delays in diagnosis, and poorer chronic disease control. In response to these findings, and to begin to comprehend whether the concerning findings from the nationalized system of healthcare in the U.K. extend to the highly dissimilar United States (U.S.) healthcare context, we reviewed the literature on alterations in access to and delivery of care during the early stages of the COVID-19 pandemic for children with special healthcare needs in the U.S. We then utilize these findings to consider the ethical and policy considerations of alterations in healthcare provision during pandemics and crisis events in the U.K. and U.S. and make recommendations regarding how the needs of CSHCN should be considered during future responses.

There are good practical reasons to use electronic consent (e-consent) in randomised trials, especially when conducting large-scale clinical trials to answer population-level health research questions. However, determining ethical reasons for e-consent is not so clear and depends on a proper understanding of what e-consent means when used in clinical trials and its ethical significance. Here we focus on four features of ethical significance which give rise to a range of ethical considerations relating to e-consent and merit further focused ethics research.

In recent years, the case has been made for special attention to be paid to a branch of research in the field of bioethics called ‘translational bioethics’. In this paper, we start by considering some of the assumptions that those advancing translational approaches to bioethics make about bioethics and compare them to the reality of bioethics as an academic field. We move on to explain how those who make this case, implicitly or explicitly, for translational bioethics go awry because of how they understand the ‘gap’ between bioethical inquiry and practical settings that requires bridging. We consider three interpretations of this ‘translation gap’ in bioethics: (i) the gap between theory and practice, (ii) the gap between the force of normative claims and practical contextual realities and (iii) the gap between relevance or applicability to practice and actual application or implementation in practice. In each case, we show how a proper understanding of the nature of the academic field of bioethics undermines how these gaps have been formulated, and how any need for talk of ‘translational bioethics’ is removed.