The increasing emphasis on rare diseases brings with it both hope and challenges. With over 7,000 rare diseases detected globally, affecting millions of people, the need for novel treatments is crucial.(1) Yet, developing and determining the value of these interventions has some unique challenges. Conventional frameworks for evidence generation, typically developed for common conditions, may not align with the realities of small patient populations, heterogeneous disease progression, and lack of natural history data as in case of rare diseases. This makes it crucial to move beyond traditional methods and develop fit-for-purpose evidence packages that can successfully elucidate the value of rare diseases interventions.(1-3)
One of the main concerns in rare disease research is the lack of patients, which hinders the feasibility of large randomized controlled trials (RCTs). Typical endpoints may also be difficult to apply due to high variability of disease manifestations that may not be effectively described by standard outcome measures. To address this, evidence packages for rare diseases must integrate diverse sources of information, right from clinical trial data to real-world evidence (RWE), natural history studies, and patient-reported outcomes (PROs). Such an integrated methodology enables stakeholders, including regulators, health technology assessment (HTA) bodies, and payers, to obtain an all-inclusive understanding of the value of an intervention.(2-4)
Customizing the evidence package to the decision context is an equally important factor. For regulatory approvals, although the emphasis is on demonstrating safety and efficacy with the best available study designs; they are often supported by surrogate endpoints. However, for payers and HTA agencies, the focus is often on the long-term efficacy, cost-effectiveness, and the larger impact on patients and caregivers. This warrants cautious alignment of clinical data with economic models, quality-of-life (QoL) metrics, and studies on disease burden. By designing the evidence to meet the specific expectations of all the involved stakeholders, developers can more effectively generate the evidence required for regulatory submissions.(2-4)
Another key factor in formulating fit-for-purpose evidence packages is the collaboration among stakeholders. Rare disease populations often play a central role in defining important endpoints, assisting with data collection, and allowing for the outcomes being evaluated to correctly depict important benefits to patients and caregivers. Collaborations across industry, academia, and patient groups can also enable the development of disease registries and natural history databases that act as crucial drivers of evidence generation. Optimizing advanced analytics, digital health tools, and novel study designs, such as basket trials or adaptive designs further enhances these evidence packages, offering the necessary flexibility in rare disease settings.(2-4)
Finally, the goal is to secure market access for rare disease treatments while ensuring that patients receive well-timed and fair access to novel therapies that can transform their lives. By moving beyond unyielding, one-size-fits-all frameworks and emphasizing fit-for-purpose evidence generation, stakeholders can better encapsulate the multidimensional value of interventions for rare disease. This transformation in evidence strategy is instrumental in bridging the gap between scientific innovation and real-world patient benefit.
Become A Certified HEOR Professional – Enrol yourself here!
References
- Liu J, Barrett JS, Leonardi ET, et al. Natural History and Real-World Data in Rare Diseases: Applications, Limitations, and Future Perspectives. J Clin Pharmacol. 2022; 62 Suppl 2(Suppl 2):S38-S55.
- National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Processes to Evaluate the Safety and Efficacy of Drugs for Rare Diseases or Conditions in the United States and the European Union; Shore CK, Worku TL, Smith CW, et al., editors. Regulatory Processes for Rare Disease Drugs in the United States and European Union: Flexibilities and Collaborative Opportunities. Washington (DC): National Academies Press (US); 2024 Oct 30. 4, Alternative and Confirmatory Data. Available from: https://www.ncbi.nlm.nih.gov/books/NBK609394/
- Pai M, Yeung CHT, Akl EA, et al. Strategies for eliciting and synthesizing evidence for guidelines in rare diseases. BMC Med Res Methodol. 2019 Mar 28;19(1):67.
- ISPOR. Workshop: Development of Evidence Packages for Regulatory and Reimbursement Submissions in Rare Diseases: Real‐World Examples. 2015. (Accessed online on 28th August 2025). Available at: https://www.ispor.org/docs/default-source/presentations/597.pdf?sfvrsn=b428af52_1