Background: Decision-makers have implemented a variety of value assessment frameworks (VAFs) for orphan drugs in European jurisdictions, which has contributed to variations in access for rare disease patients. This review provides an overview of the strengths and limitations of VAFs for the reimbursement of orphan drugs in Europe, and may serve as a guide for decision-makers.Methods: A narrative literature review was conducted using the databases Pubmed, Scopus and Web of Science. Only publications in English were included. Publications known to the authors were added, as well as conference or research papers, or information published on the website of reimbursement and health technology assessment (HTA) agencies. Additionally, publications were included through snowballing or focused searches.Results: Although a VAF that applies a standard economic evaluation treats both orphan drugs and non-orphan drugs equally, its focus on cost-effectiveness discards the impact of disease rarity on data uncertainty, which influences an accurate estimation of an orphan drug’s health benefit in terms of quality-adjusted life-years (QALYs). A VAF that weighs QALYs or applies a variable incremental cost-effectiveness (ICER) threshold, allows the inclusion of value factors beyond the QALY, although their methodologies are flawed. Multi-criteria decision analysis (MCDA) incorporates a flexible set of value factors and involves multiple stakeholders’ perspectives. Nevertheless, its successful implementation relies on decision-makers’ openness toward transparency and a pragmatic approach, while allowing the flexibility for continuous improvement.Conclusion: The frameworks listed above each have multiple strengths and weaknesses. We advocate that decision-makers apply the concept of accountability for reasonableness (A4R) to justify their choice for a specific VAF for orphan drugs and to strive for maximum transparency concerning the decision-making process. Also, in order to manage uncertainty and feasibility of funding, decision-makers may consider using managed-entry agreements rather than implementing a separate VAF for orphan drugs.

Background: Nusinersen is an orphan drug intended for the treatment of spinal muscular atrophy (SMA), a severe genetic neuromuscular disorder. Considering the very high costs of orphan drugs and the expected market entry of cell and gene therapies, there is increased interest in the use of health technology assessment (HTA) for orphan drugs. This study explores the role of the economic evaluation and budget impact analysis on the reimbursement of nusinersen.Methods: Appraisal reports for nusinersen were retrieved from reimbursement and HTA agencies in Belgium, Canada, France, England and Wales, Germany, Italy, Ireland, Scotland, Sweden, the Netherlands, and the United States. Detailed information was extracted on the economic evaluation, the budget impact, the overall reimbursement decision, and the managed entry agreement (MEA). Costs were adjusted for inflation and currency.Results: Overall, the reports included limited data on budget impact, excluding information on the sources of data for cost and patient estimates. Only three jurisdictions reported on total budget impact, estimated between 30 and 40 million euros per year. For early-onset SMA, the incremental cost-effectiveness threshold (ICER) ranged from €464,891 to €6,399,097 per quality-adjusted life year (QALY) gained for nusinersen versus standard of care. For later-onset SMA, the ICER varied from €493,756 to €10,611,936 per QALY. Although none of the jurisdictions found nusinersen to be cost-effective, reimbursement was granted in each jurisdiction. Remarkably, only four reports included arguments in favor of reimbursement. However, the majority of the jurisdictions set up an MEA, which may have promoted a positive reimbursement decision.Conclusion: There is a need for more transparency on the appraisal process and conditions included in the MEA. Additionally, by considering all relevant criteria explicitly during the appraisal process, decision-makers are in a better position to justify their allocation of funds among the rising number of orphan drugs that are coming to the market in the near future.

Background: Countries are struggling to provide affordable access to medicines while supporting the market entry of innovative, expensive products. This Perspective aims to discuss challenges and avenues for balancing health care system objectives of access, affordability and innovation related to medicines in Belgium (and in other countries).Methods: This Perspective focuses on the R&D, regulatory approval and market access phases, with particular attention to oncology medicines, precision medicines, orphan medicines, advanced therapies, repurposed medicines, generics and biosimilars. The authors conducted a narrative review of the peer-reviewed literature, of the grey literature (such as policy documents and reports of consultancy agencies), and of their own research.Results: Health care stakeholders need to consider various initiatives for balancing innovation with access to medicines, which relate to clinical and non-clinical outcomes (e.g. supporting the conduct of pragmatic clinical trials, treatment optimisation and patient preference studies, optimising the use of real-world evidence in market access decision making), value assessment (e.g. increasing the transparency of the reimbursement system and criteria, tailoring the design of managed entry agreements to specific types of uncertainty), affordability (e.g. harnessing the role of generics and biosimilars in encouraging price competition, maximising opportunities for personalising and repurposing medicines) and access mechanisms (e.g. promoting collaboration and early dialogue between stakeholders including patients). Conclusion:Although there is no silver bullet that can balance valuable innovation with affordable access to medicines, (Belgian) policy and decision makers should continue to explore initiatives that exploit the potential of both the on-patent and off-patent pharmaceutical markets.

Introduction: The expansion of orphan drug treatment at increasing prices, together with uncertainties regarding their (cost-)effectiveness raises difficulties for decision-makers to assess these drugs for reimbursement. The present qualitative study aims to gain better insight into current value assessment and appraisal frameworks for orphan drugs, and provides guidance for improvement.Methods: 22 European experts from 19 different countries were included in a qualitative survey, followed by in-depth semi-structured interviews. These experts were academics, members of reimbursement agencies or health authorities, or members of regulatory or health/social insurance institutions. Adopting a Grounded Theory approach, transcripts were analysed according to the QUAGOL method, supported by the qualitative data analysis software Nvivo.Results: Although participants indicated several good practices (e.g., the involvement of patients and the presence of structure and consistency), several barriers (e.g., the lack of transparency) lead to questions regarding the efficiency of the overall reimbursement process. In addition, the study identified a number of “contextual” determinants (e.g., bias, perverse effects of the orphan drug legislation, and an inadequate consideration of the opportunity cost), which may undermine the legitimacy of orphan drug reimbursement decisions.Conclusion: The present study provides guidance for decision-makers to improve the efficiency of orphan drug reimbursement. In particular, decision-makers can generate quick wins by limiting the impact of contextual determinants rather than improving the methods included in the HTA. When implemented into a framework that promotes “Accountability for Reasonableness” (A4R), this allows decision-makers to improve the legitimacy of reimbursement decisions concerning future orphan drugs.

IntroductionThe very high costs of orphan drugs, together with the uncertainties regarding their (cost-)effectiveness raise questions regarding the efficiency and legitimacy of their health technology assessment (HTA) and appraisal process. The aim of the present, qualitative study was to investigate how experts on the reimbursement of these treatments perceive the HTA and appraisal process in their country. Moreover, it aimed to provide specific conditions and practical recommendations for their improvement.MethodsTwenty-two European experts from 19 different countries were included in a qualitative survey and semi-structured interviews. Transcripts were analyzed using the qualitative data analysis software Nvivo. A grounded theory approach was adopted to develop a set of well-defined concepts from the cyclic analysis of the empirical data.ResultsFirst, analysis of the expert interviews yielded five good practices for an efficient HTA and appraisal of orphan drugs: a high level of transparency, patient involvement, a clear decision-making structure with room for flexibility, mechanisms to minimize bias and an explicit consideration of the opportunity cost. Meanwhile, participants highlighted several barriers to the overall process, such as a lack of trust between the different stakeholders and imbalances in negotiation power. In addition, the results allowed to identify a number of ‘contextual’ determinants that may undermine the legitimacy of the final decision, such as bias and the perverse effects of the orphan drug legislation. Drawing from the experts’ experiences, a toolkit was developed that includes an extensive number of specific recommendations (and conditions) for decision-makers to improve the legitimacy and efficiency of their HTA and appraisal of orphan drugs.ConclusionsOverall, the results showed that decision-makers should focus on limiting the impact of the contextual determinants rather than improving the methods included in the HTA. This will contribute to further legitimize reimbursement choices for orphan drugs towards the wider public.