Over the past 4 decades since the Orphan Drug Act was passed in 1983, there have been tremendous advances in research, innovation, and regulatory policies that have spurred development of new treatments for rare diseases, but less than 5% of rare diseases have approved treatments on the market.¹ More must be done to meet the needs of people living with rare diseases. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) play a critical role in ensuring that drugs to treat rare diseases and conditions are safe and effective.

In addition, regulatory agencies help spur the scientific and technological innovation needed to advance drug development. A new report² from the National Academies of Sciences, Engineering, and Medicine (National Academies) asserts that (1) enhancing strategic engagement of the FDA with people living with a rare disease, their caregivers, and patient representatives throughout the full continuum of the drug development process; (2) supporting advancements in regulatory science; and (3) transparent reporting would improve the processes for evaluating the safety and efficacy of drugs for the patients who desperately need them.

An analysis of data on the number of new drug approvals by the FDA and the EMA, which was commissioned by the writing committee of the report,² found that the 2 agencies often reach the same regulatory decisions when it comes to the approval of drugs to treat rare diseases and conditions. The FDA and the EMA have regulatory flexibilities and mechanisms available to expedite the review and approval of drug products for rare diseases and generally align on the required evidence-based approaches. However, sponsors must navigate a range of complex challenges when designing and conducting studies for regulatory submission. There remains a lack of understanding and uncertainty on when and how regulatory agencies consider the use of new innovations or sources of data to inform regulatory decision-making.

Earlier this year, while the National Academies was engaged in its study, the FDA established the Rare Disease Innovation Hub³ (the Hub) to (1) directly engage sponsors, researchers, patient groups, and other interested parties; (2) advance regulatory science; and (3) enhance collaboration. If sufficient resources are provided, the Hub presents an opportunity for the agency to take the lead on implementing a few of the National Academies committee’s recommendations.²

Strategic engagement of the FDA with key stakeholders, particularly people with lived experience, is of critical importance throughout the drug review and approval process. Incorporating the perspectives and insights of people living with rare diseases and those caring for someone with a rare disease facilitates regulatory decision-making that is centered around the needs of patients. The National Academies committee recommended that the FDA take the steps necessary to fully implement paragraph 1137 of the Food and Drug Administration Safety and Innovation Act,⁴ which directs the Secretary of the Department of Health and Human Services to systematically incorporate the viewpoints of patients with rare diseases throughout the regulatory process.⁵

The Hub could serve as a place for the agency to explore more structured approaches to (1) engage people with lived experience in open public hearing sessions of FDA advisory committee meetings; (2) more actively recruit and support the participation of people from underrepresented and underresourced patient groups throughout review processes; and (3) develop in-person and hybrid education and training programs to assist patient groups in creating and maintaining tools (eg, patient registry, natural history data, translational tools) that can contribute to research and development for rare disease therapies.

The committee recognized that sponsors developing therapies to treat rare diseases and conditions are faced with myriad challenges when it comes to designing and conducting studies for regulatory review. Many rare disease companies are small- and medium-sized enterprises and would benefit from additional engagement from the FDA. Given the FDA’s extensive in-house expertise, the Hub, in collaboration with the National Institutes of Health, has the opportunity to work with the EMA, nongovernmental organizations, patient groups, and biopharmaceutical sponsors to implement a sponsor, investigator, and patient group navigation service to support the development of drugs to treat rare diseases and conditions. Proposed actions include (1) advising on the range of available regulatory pathways and flexibilities and (2) providing clarity on how to comply with regulatory policies, apply guidance, and meet requirements in rare disease drug development.

One of the most significant barriers to regulatory approval of therapies for rare diseases and conditions is the limited number of patients available to participate in clinical trials. Novel methods for study design and analysis of relevant data on drug safety and efficacy can make it possible to generate evidence for regulatory decision-making based on limited data. The Hub has an opportunity to facilitate the sharing of information on state-of-the-art regulatory science (including the use of biomarkers, the use of surrogate outcomes, and effective applications of alternative and confirmatory data) for informing regulatory decision-making for rare disease drug products.

Due to the complex nature of rare disease drug development, early collaboration and information exchange between the FDA and the EMA is critical. Such collaboration could lead to greater coordination on study design and alignment on data requirements, helping to reduce duplication of clinical testing and streamline the regulatory process for sponsors submitting marketing authorization applications to both agencies. The committee recommended that the FDA take steps to make relevant information on marketing authorization submissions, review milestones, approval and negative review decisions, and the use of regulatory flexibilities for rare disease drug products publicly available and easily accessible.

The committee recognized that implementing transparency mechanisms in ways that parallel what the EMA already does will not be easy and would likely require legal assessment and perhaps congressional intervention. At the same time, such measures would enable researchers and sponsors to better innovate and bring much-needed medications to the patients who so desperately need them. As a starting point, the Hub could help incubate approaches for enabling such information sharing in the future.

In addition, the Hub could serve as a focal point for the agency to ensure that ongoing programs relevant for rare disease drug development (eg, the Support for Clinical Trials Advancing Rare Disease Therapeutics pilot program⁶ and the Collaboration on Gene Therapies Global Pilot⁷) are assessed and the lessons learned are publicly shared.

Rare diseases and conditions affect up to 30 million people in the US and more than 300 million people across the globe. Meeting the urgent needs of these populations requires sufficient resources and priority setting so that regulatory agencies have the capacity to support innovative methods and enhance critical partnerships. It is important to recognize that the recommendations in this report² seek to (1) address one important element of a broader system of research and innovation and (2) facilitate the development of safe and effective drugs for rare diseases and conditions. The new FDA Hub is an important and innovative part of the regulatory ecosystem for rare disease drug development. Additional efforts are needed to understand the underlying biology and progression of disease, to validate biomarkers and clinical outcomes assessments, and to assess other approaches to meet the needs of people living with rare diseases and conditions.

Corresponding Author: Carolyn K. Shore, PhD, National Academies of Sciences, Engineering, and Medicine, 500 Fifth St NW, Washington, DC 20003 (cshore@nas.edu).

Published Online: October 2, 2024. doi:10.1001/jama.2024.20358

Conflict of Interest Disclosures: Dr Shore reported receiving funding from the US Food and Drug Administration and directing the National Academies Forum on Drug Discovery, Development, and Translation. No other disclosures were reported.

Disclaimer: The authors are solely responsible for the content of this article, which does not necessarily represent the views of the National Academies of Sciences, Engineering, and Medicine.

Additional Contributions: We acknowledge the contributions of the members of the consensus writing committee of the National Academies of Sciences, Engineering, and Medicine report,² and the considerable support of the National Academies staff.

Additional Information: Dr Shore and Ms Worku served as co-directors and Dr Kahn served as the chair of the National Academies of Sciences, Engineering, and Medicine consensus report.²