FDA quietly kicks off process that could inform future rare disease regulatory reforms


Jun. 21, 2023

Reforms buried within the FY2023 omnibus spending bill require the development of a new report looking at the regulatory processes of the U.S. and E.U. as they relate to the development of drugs for rare diseases, and to offer recommendations on how to improve those processes in the U.S. Today, the FDA unveiled a contract notice that explains the process for how it will develop that report, obtain public input, and deliver the report’s final recommendations.

Background: legislative efforts to bolster rare disease drug development

  • Defining a “rare disease:”In the U.S., a disease or condition is defined as rare by the Orphan Drug Act (ODA) if it affects fewer than 200,000 people. Because these diseases affect so few people, it can be difficult to characterize and track disease progression – and develop drugs for treatment.
  • In the U.S., incentives for rare disease-focused drug development were first enacted in 1983 under the Orphan Drug Act,including market exclusivities (7 years of marketing exclusivity), waivers from certain user fees, and tax credits for certain development activities (currently worth 25% of development costs).
  • Meanwhile, in the EU rare diseases are defined using a different set of criteria.Regulation (EC) No 141/2000(the Orphan Regulation) provides the legal framework for orphan drug designations and incentives.The Orphan Regulation entered into force in January, 2000, outlining requirements for orphan designation and incentives, and establishing the EMA Committee for Orphan Medicinal Products (COMP). CommissionRegulation (EC) No 847/2000set the rules, defining an orphan drug as one “that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10 thousand persons in the Community when the application is made.”

Recently, U.S. legislators have asked the FDA to study the way that rare disease drugs are regulated in the U.S. and E.U.

  • Title III of the Consolidated Appropriations Act of 2023—known as the Food and Drug Omnibus Reform Act (FDORA)—included several directives related to rare diseases.In particular,Sec. 3202calls forseveral activitiesfocused on improving the treatment of rare diseases and conditions.[Click here to read our analysis of the FDORA legislation.]
  • Specifically, Section 3203(c) calls for a “study on European Union safety and efficacy reviews of drugs for rare diseases and conditions.”The law calls on the FDA to “enter into a contract with the National Academies of Sciences, Engineering, and Medicines to conduct a study on the processes for evaluating the safety and efficacy of drugs for rare diseases or conditions in the United States and the European Union.”
  • Per the FDORA, the contracted NASEM study is to study several processes in particular,such as the “flexibilities, authorities, or mechanisms available to regulators,” which supplemental data may be made available (such as open-label extension studies and expanded access programs), and collaborative regulatory efforts related to rare disease products and policies.
  • Notably, the legislation also calls for the report to formulate “recommendations for how Congress can support collaborative efforts” between U.S. and E.U. regulators.

FDA has now released additional details on the process and timeline for the National Academies study.

  • The contract’s period of performance is 16 months, from July 1, 2023, to October 31, 2024,according to a Statement of Work (SOW) accompanying FDA’snotice of intent to Sole Source to NASEM, first noticed by AgencyIQ.
  • While the legislative charge was broad, the SOW provides some limited hints into focal points of the study.In addition to landscape analysis regarding the “flexibilities, authorities, or mechanisms available” to the two regulatory bodies, the study will set out to evaluate how the agencies consider and use “supplemental data submitted during review processes.” This includes “data associated with open label extension studies and expanded access programs specific to rare diseases or conditions.” The study will also assess the current state of “collaborative efforts” between the United States and EU regulators. This includes sharing policy development and scientific information, as well as product development programs.That language is, as noted above, taken directly from the legislation.
  • In terms of logistics, the document lays out a timeline and list of deliverables for NASEM.According to its own policies, NASEM will solicit nominations, assemble, and appoint a committee of 12-15 subject matter experts to contribute to the study. The committee will convene at least five times, with at least two meetings providing an opportunity for public comment. Interestingly, the document specifies that at least three meetings will be held in a hybrid format, with in-person attendees meeting at the NASEM facilities in Washington, DC. The final two meetings will be reserved for closed session drafting and review of the report and recommendations.
  • The draft report is due within 14 months after contract award, and the final report is due on or before October 31, 2024. In addition to a draft and final report, NASEM is responsible for providing FDA with documentation of meetings and quarterly progress reports. The report itself is set to provide “recommendations as it relates to improving treatments for rare diseases.”
  • What’s next?The first NASEM committee meeting, which should take place within 4-6 months, is required to allocate time for “a public session for the sponsor to deliver the charge to the committee.”


  • The key question for companies interested in rare disease regulatory policy: What changes might this lead Congress and regulators to make?Congress’ intent seems clear: This report is to form the basis of recommendations for future legislative changes, and especially with respect to collaborative efforts. In addition, the public-focused meeting format could form an opportunity for rare disease-focused companies, patients and stakeholder groups to offer their own opinions regarding opportunities to borrow beneficial policies from European regulators. AsAgencyIQ has previously noted, one potential policy difference that legislators could seek to borrow is the E.U.’s definition of “rare,” which is a set percentage, rather than a specific number of patients, which prevents rare diseases from becoming more rare as the population increases.
  • However, the report comes at an especially strange time for E.U. regulatory policy, making NASEM’s job more complicated.While most legislators who voted in favor for this legislation were likely unaware, the European Union is in the process of a dramatic overhaul of its Orphan Drug Regulation by way of a proposed revision of its Pharmaceutical Legislation.As AgencyIQ explained earlier this month, many of those proposed reforms would profoundly affect the way that orphan products are developed and brought to the market – much to the dismay of the pharmaceutical industry. That the European Commission is in the midst of planning to move away from its existing regulations and toward a new system could blunt the impact of NASEM’s report – or at the very least, complicate its efforts to draw simple conclusions.
  • Given the timeline for the report, however, any changes are likely to be years away.The report isn’t due for publication until October 2024, and it’s likely any recommendations made in the report would require further regulatory and legislative action, which would likely require significant additional time and effort to implement.
  • But if we had to guess, international regulatory harmonization will be a topic of interest for NASEM.For example, top FDA executives have previously heralded international convergence and harmonization as the solution to gene therapy development for diseases with small populations. Last month at acell and gene therapy conferencefireside chat, FDA Center for Biologics Evaluation and Research (CBER) director Peter Marks rearticulated this vision [See AgencyIQ’s analyses ofFebruary Rare Disease Day Eventand anApril Alliance for a Stronger FDA eventfor more on this topic.] Marks explained that he feels the greatest opportunity to benefit the development of therapies for rare diseases lies in alignment between regulatory authorities on submission requirements for these applications, to enable standardized review packages and concurrent submission and review of product applications.
  • The NASEM notice also comes as FDA is working elsewhere to advance rare disease policy.Earlier this month, FDA partnered with the Duke-Margolis Center for Health Policy to host a meeting on the Rare Disease Endpoint Advancement (RDEA) pilot program, which was required under the latest Prescription Drug User Fee Act (PDUFA) program reauthorization (and then again under FDORA, redundantly).Launching on July 1, the program will select proposals and allow for additional “sponsor-driven” communication with FDA regarding endpoints. That said, since the RDEA pilot program is not intended to lead to qualification of an endpoint or result in a regulatory decision, discussions between FDA and sponsors during the RDEA pilot program arenot bindinganddo notguaranteethat a novel efficacy endpoint will be accepted. [Read full AgencyIQ analysis of the workshop here.].

Featuring previous research by Laura DiAngelo and Rachel Coe.
To contact the author of this item, please email Amanda Conti (aconti@agencyiq.com).
To contact the editor of this item, please email Alexander Gaffney (agaffney@agencyiq.com)

Key Documents and Dates

Get an insider’s view on regulatory movements.

Sign up for AgencyIQ’s newsletters to receive exclusive regulatory updates and analysis impacting the life sciences or chemical industry.

Copy link
Powered by Social Snap