Three million people in the UK live with a rare disease, yet drug development for these conditions is plagued by inconsistent trial methods that often fail to capture what patients actually experience. The core problem is twofold. First, small patient populations make it hard to detect whether a treatment works. Second, standard questionnaires (patient-reported outcome measures) rarely exist for rare diseases, so trial results miss crucial patient experiences. Qualitative interviews could fill that gap, and Bayesian statistical methods could reduce the number of patients needed by incorporating existing knowledge. But no standard guidance exists for using these approaches together, and both are vulnerable to optimism bias—patients and clinicians hoping a treatment works may skew their responses. This project will produce two practical guidance papers: one on using qualitative methods to assess efficacy in rare disease trials, and another on eliciting prior beliefs for Bayesian trial designs. The guidance will then be tested on a real rare disease trial. If successful, it will give trial designers a consistent, patient-focused toolkit. The result could be more approved treatments for rare diseases, trials that need fewer patients, and outcomes that genuinely reflect what matters to patients—not just what a questionnaire can measure.
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Background Rare diseases are conditions that affect fewer than 1 in 2000 people. However, although each condition is rare, there are over 7000 of them which means that there are 3 million people in the UK currently living with one and 1 in 17 are affected by one at some point in their lifetime. Drug development for rare diseases is a challenge. Small patient populations limit the power to detect clinically meaningful effects and there is a lack of disease-specific patient-reported outcome measures (PROMs) which means inferences are not reflective of the experiences of rare diseases. There is insufficient guidance on how to resolve these issues so new treatments for rare diseases are investigated inconsistently, contributing to ineffective healthcare - or none at all. Pai et al.1 identified that further research is needed including the use of qualitative research to complement trial data. Qualitative research can embed experiences that cannot be captured by PROMs in efficacy assessments and Bayesian methods can incorporate existing knowledge to reduce sample size. However, qualitative approaches can be sensitive to optimism biases, where patients or clinicians may have hope that the treatment will work, which will influence how they respond in their qualitative interviews about the treatment effect or in prior elicitation exercises. There are inconsistent recommendations about methods to account for bias in both prior elicitation, e.g. weighting prior densities2,3 and qualitative assessments of efficacy. Without guidance, patients are suffering a lack of approved treatments and suboptimal trial designs with a lack of patient-focus. Methods The project has three work packages: identifying current practice, developing guidance, and applying the guidance to a trial. The first work package will identify current practice of qualitative methods for rare disease trials using scoping reviews and interviews. The reviews will cover methods papers, guidance documents and trials outputs relating to qualitative efficacy assessment and prior elicitation in Bayesian designs. Qualitative interviews with stakeholders will also identify current practices. The second work package will develop guidance for qualitative efficacy assessment and prior elicitation in rare disease trials. Based on work package one, appropriate methods will be selected in consultation with all collaborators. Through a Consensus Development Panel I will engage a diverse group of experts and stakeholders, to reach agreement on best practice, which will be developed into two guidance papers - on qualitative methods for efficacy in rare disease trials, and qualitative methods for elicitation in Bayesian trial designs. The guidance will be non disease-specific. The third work package will apply the guidance to a current rare disease trial to refine the methods and illustrate their use. Impact and dissemination Dissemination will include a dissemination event, journal publications and conference presentations. Findings from this project will improve the design and analysis of rare disease trials by increasing consistency of methods and ensuring treatments are accurately investigated with lower sample size requirements. It will impact patients by capturing their experiences that cannot be measured by quantitative outcomes. This will ultimately lead to more approved treatments and better outcomes.
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