Introduction: Uncertainty influences the amount of risk in decision making, and is typically related to clinical benefit, value for money, affordability, and/or adoption/diffusion of the technology (e.g., drug, device, procedure, etc.). Although evidence-based review processes within each stage of the technology lifecycle have been implemented to minimize uncertainty, high-quality information addressing that related to orphan and ultra-orphan drugs is often unavailable. The role that patients, as experts in their disease, may play in providing such information has yet to be fully explored.

Objective: The objective of this systematic review was to identify existing and proposed opportunities for patients with rare diseases and their families to provide input aimed at reducing decision uncertainties throughout the lifecycle of an orphan or ultra-orphan drug.

Methods: A comprehensive review of published and gray literature describing roles for patients and families in activities related to orphan and ultra-orphan drugs was conducted. In addition, the websites of regulatory and centralized reimbursement decision-making bodies in the top 22 OECD (Organisation for Economic Cooperation and Development) countries by gross domestic product (GDP) were scanned to identify current opportunities for patients with rare diseases in both stages. The websites of umbrella patient organizations for rare diseases in these countries were also scanned. These roles were then mapped onto a matrix to determine the stage in the technology lifecycle and types of uncertainties they directly or indirectly addressed.

Results: Across the 22 countries, nine roles for patients within regulatory related processes were identified, with at least one in each country. These roles were not specific to patients with rare diseases. Similarly, six different opportunities for patient input in centralized drug review processes were identified, all of which applied to patients, in general, rather than just those with rare diseases. 'Real-world' examples of patient involvement explicitly related to rare diseases centered around 11 different themes. Seven fell within the research and development or clinical trial stages of a drug's lifecycle. Of the remaining four, three were associated with education and advocacy. All of the proposed roles identified focused on greater involvement in (1) the design and conduct of clinical trials, or (2) the 'valuation' of evidence during reimbursement decision making. When mapped onto the matrix of decision uncertainties, almost all of the existing and proposed roles addressed 'clinical benefit'. Roles for patients in reducing 'value for money', affordability, or adoption/diffusion uncertainties were mainly indirect, and a result of patient involvement in activities aimed at generating information on clinical benefit, which is then used to inform discussions around these uncertainties.

Conclusions: While patient involvement in activities that directly address uncertainties in clinical benefit may not be 'rare', opportunities for reducing those related to 'value for money', affordability, and adoption/diffusion remain scarce.