Regulatory Science: Addressing Uncertainties in Medicines Development, Evaluation and Use

One key area of increased focus and importance in the Regulatory Science Strategy for 2025 published by the European Medicines Agency is the improved transparency of treatment decision-making at macro and micro (patient) levels, including the communication and management of uncertainties. Uncertainty can be defined as "lacking complete knowledge or understanding of a given situation". Uncertainties can be attributed to lacking clinical or patient data and result in uncertainties on behalf of decision-makers who need to make decisions based on these data. In the context of regulatory decision-making, uncertainty may translate into difficulties in evaluating the quality, safety, efficacy, and overall benefit-risk balance of a medicinal product for a given patient population. Uncertainties in drug development prior to the approval and reimbursement of medicines will also result in uncertainties in Health Technology Assessment, payer, patient, and healthcare provider decision-making. Stakeholders in drug development and evaluation (commercial and non-commercial developers, regulators, clinicians, academics, HTA) are keen to know how they could better manage and communicate uncertainties in their various decision-making contexts so as to improve their decision-making processes and allow for increased transparency towards the public, and especially patients.

This topic is dedicated to research aiming to address the complex question of how to manage and communicate uncertainties in medicines development, evaluation, and use. Currently, there is no structured approach for defining, categorizing, managing, and communicating uncertainties at various decision-making levels in drug development, evaluation, and use. Such decisions include the identification of unmet needs, the allocation of resources in drug development, the selection of clinical trial endpoints and outcomes, the selection of patient-reported outcome measures, regulatory evaluation, and the assessment of benefits and risks, health technology assessment, reimbursement, and clinical treatment decision-making. In the context of drug regulation, uncertainty management and communication tools (such as templates, guidance, checklists) are missing for assessors and developers. Topics where uncertainties revolve around include the type of (long-term) treatment effects, the appropriateness of clinical trial endpoints, the size of treatment effects and their relevance, patient-reported outcomes, etc. These represent policy and research foci receiving much attention from regulators, drug developers, scientists, clinicians, and patients, where evidence-based insights and solutions surrounding these would be highly welcomed.

Topics of interest are related to the (optimized) conceptualization, definition, categorization, management, and communication of uncertainties in healthcare decision-making spanning across the treatment lifecycle. We would like contributors to address uncertainties and evidence gaps in the clinical trial and real-world context, as well as in regulatory evaluation, market access, health technology assessment, and treatment use (including by patients and clinicians). Authors can also focus on how uncertainties and mitigation strategies are discussed and approached at the policy-making level. Authors are invited to address strategies for addressing communication and evidence gaps, such as real-world evidence. Strategies for improved transparency of uncertainties are also highly welcomed, including at the regulatory-HTA interface (parallel scientific advice) and at the patient-physician level via patient decision aids. Of interest are uncertainties regarding unmet (medical) needs, (long-term) treatment effects, appropriateness of endpoints, treatment strategies, and ways to address these. Different types of articles are welcomed, including umbrella or systematic reviews, original research (e.g., qualitative research, quantitative (survey) research), and perspective articles.

Keywords: clinical trials, regulatory evaluation, market access, health technology assessment, policy-making, treatment use, real world evidence, uncertainities, evidence gap

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.