Advancing Novel Treatments for Rare Diseases: FDA Unveils and Previews New Efforts to Assess Therapies for Very Small Patient Populations

Since taking the reins as FDA Commissioner, Dr. Martin Makary has repeatedly expressed an interest in new regulatory pathways, or new options for evidence generation, that would enable more flexible FDA review of investigational therapies, especially for rare and ultra-rare diseases.

For instance, during his confirmation hearing, Dr. Makary described a vision in which FDA could “customize the regulatory process” for the underlying medical condition. ¹ During an early press interview as Commissioner, Dr. Makary previewed a potential new regulatory pathway for rare disease drugs based on a “plausible mechanism” of action.² In an article outlining FDA’s policy priorities, Dr. Makary highlighted the promise of “big data” to facilitate more efficient and effective postmarket surveillance in situations where the conduct of randomized trials prior to FDA approval of a drug may not be feasible.³

Last week, more details regarding this vision came into focus with FDA’s announcement of two new initiatives:

• The Rare Disease Evidence Principles initiative to help facilitate approval of drugs to treat certain rare conditions; and
• A forthcoming “plausible mechanism” pathway for individualized therapies.

Both efforts are designed to address the challenges inherent in developing substantial evidence of effectiveness for drug or biologic treatments for diseases that affect small populations of patients.

Rare Disease Evidence Principles (RDEP)

FDA intends to implement a new program, administered jointly by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), to enable RDEP participants to receive “clearer guidance on the types of evidence that can be used to demonstrate substantial evidence of effectiveness.”⁴ It appears that, for selected products, this program will supplement FDA’s general recommendations that were previously provided in the draft guidance, Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence.⁵

Specifically, through the RDEP program, it appears that FDA will work collaboratively with sponsors to design an evidence generation plan that includes a combination of one adequate and well-controlled study (which may be a single arm trial) and “robust data that provides strong confirmatory evidence of the drug’s treatment effect,” such as:

• Evidence of the drug’s treatment effect on the direct pathophysiology of the disease;
• Evidence from a relevant non-clinical model;
• Therapeutically relevant clinical pharmacodynamic data;
• Other clinical data including case reports and expanded access data; or
• Other confirmatory evidence developed through the appropriate selection of external controls or natural history studies.⁶

FDA reviewers will conduct an initial meeting with a sponsor to discuss and help develop the plan for evidence generation. This dialogue may continue at “critical points of determining relevant evidence” or otherwise at “significant milestones in the drug development and/or application process.”⁷Although FDA states that “concurrence on study design and qualifying confirmatory evidence would not necessarily indicate that the Agency expects to determine that a drug is approvable,”⁸ the enhanced communication seems designed to provide the sponsor with a better (and perhaps more certain) understanding of FDA’s goalposts for success.

Sponsors should be aware, however, that FDA has narrowly scoped the eligibility criteria for the RDEP initiative. The Agency will consider requests to participate from sponsors of therapies meeting the following conditions:

• The therapy will treat a disease related to a known genetic defect and is specific to the correction of that defect (e., either correcting the gene or replacing an essential physiological protein that is otherwise deficient due to the gene defect);
• The genetic defect is the major driver of the pathophysiology of the disease;
• The disease affects a very small population or subpopulation of patients in the United States (g., generally less than 1,000 patients);
• The clinical course of the disease is progressive deterioration in function leading to rapid and/or significant disability or death in a relatively short period of time;
• There are no adequate alternative therapies that alter the course of the disease; and
• A pivotal trial of the therapy has not yet been launched.⁹

FDA has outlined high-level details regarding how sponsors may submit a request to participate in the RDEP program. In sum, eligible sponsors are directed to submit a formal meeting request in connection with the applicable investigational new drug (IND) file.¹⁰ The meeting request should be “appropriate for the sponsor’s stage in the drug development process” and should include “reasonable evidence” that the eligibility criteria are met and that the safety and efficacy of the drug can be demonstrated by one adequate and well-controlled study plus confirmatory evidence. FDA’s decision to accept a drug for review under the RDEP program will be made by the CDER or CBER drug review teams in consultation with the Rare Disease Policy and Portfolio Council—a group of senior leaders from the Centers that was established as part of FDA’s Rare Disease Innovation Hub Strategic Agenda to facilitate cross-Center dialogue and consistent decision-making.¹¹

“Plausible Mechanism” Pathway Preview

Also last week, CBER Center Director Dr. Vinay Prasad outlined his thinking around FDA review and approval of novel therapies, including previewing an upcoming, long-awaited announcement of a “plausible mechanism” regulatory pathway for certain products.

In opening remarks made during a workshop on rare disease drug development, Dr. Prasad explained that he was “firmly committed” to the principle of regulatory flexibility for FDA review of treatments for rare, serious conditions.¹² FDA, he said, would make new therapies available “at the first sign of clinical promise,” rather than, for example, waiting for data on overall survival.

In that vein, Dr. Prasad previewed FDA’s upcoming announcement of the plausible mechanism pathway. This will, he said, be a roadmap to marketing authorization for “bespoke” therapies, which he described as “completely individualized” such that “[person A] gets one treatment and [person B] gets the next treatment and [person C] gets a different treatment.” Further details on the roadmap will be provided in an article that Drs. Makary and Prasad are expected to submit “soon” to The New England Journal of Medicine for publication.

In closing, Dr. Prasad also emphasized that these regulatory flexibilities would not be used to simply rubber stamp approval for therapies supported by inadequate evidence of effectiveness. By way of example, he highlighted concerns with products in which the mechanism of action is not related to the disease process; where the evidence fails to show a consistent effect on endpoints (e.g., no consistent duration of progression-free-survival); where the evidence shows an effect on a small number of endpoints; or where the data indicate that risks outweigh benefits (e.g., by resulting in greater mortality). He noted that FDA would continue to “strike the balance” between speeding effective therapies to market and serving as a gatekeeper for ineffective products.

Observations and Next Steps

The challenges of rare disease drug development are familiar ground for FDA policymakers. The efforts of the Agency’s new leaders to build on past regulatory science efforts and strive for solutions that strike a balance between facilitating patient access to new treatments and upholding FDA’s gold-standard regulatory review, however, are promising.

As with other recently announced FDA efforts—such as the Commissioner’s National Priority Voucher (CNPV) program¹³ and the FDA PreCheck program¹⁴—the primary benefit of the RDEP process appears to lie in the enhanced opportunity for earlier and more frequent communication with FDA decision-makers. If implemented effectively, the RDEP initiative will reduce the time and cost of product development and improve the predictability of FDA’s review of applications for promising rare disease treatments.

Unlike earlier FDA programs that were established by Congress, negotiated through user fee agreements, or implemented via FDA regulation or guidance, the RDEP program (like the CNPV and PreCheck programs) appears to have been rolled out, at least initially, before key details were established. For instance, it is not yet clear what FDA will regard as “reasonable evidence” that eligibility criteria have been met and the safety and efficacy of the investigational drug can be demonstrated by one adequate and well-controlled study plus confirmatory evidence. The RDEP announcement does not indicate how many sponsors will be admitted to the program or how good manufacturing practice expectations might be accommodated. Further, it does not set forth a timeline for FDA’s review of sponsor requests to participate; although, given that sponsors are directed to indicate their interest through formal meeting requests, the Agency may intend to follow the timelines in FDA’s meeting guidance, Formal Meetings Between the FDA and Sponsors or Applicants.¹⁵

Hopefully, additional details are forthcoming. In the meantime, sponsors considering participation in the program may want to reach out to FDA—either on their own or through a third-party advisor—to request more information that could help inform their decision-making.

¹Nomination of Martin Makary to serve as Commissioner of Food and Drugs Before the S. Comm. on Health, Educ., Labor & Pensions, 119th Cong. (2025) (statement of Dr. Martin Makary, nominee, in response to questions), https://www.help.senate.gov/hearings/nomination-of-martin-makary-to-serve-as-commissioner-of-food-and-drugs.

²The Megyn Kelly Show, Ep. 1051, Interview with Dr. Marty Makary (Apr. 17, 2025), https://www.megynkelly.com/watch/ep-1051-fighting-the-swamp-and-conflicts-of-interest-and-finding-autism-cause-with-dr-marty-makary.

³Makary MA, Prasad V, Priorities for a New FDA, JAMA, 2025;334(7):565–566. doi:10.1001/jama.2025.10116.

⁴FDA Press Release, FDA Advances Rare Disease Drug Development with New Evidence Principles (Sep. 3, 2025), https://www.fda.gov/news-events/press-announcements/fda-advances-rare-disease-drug-development-new-evidence-principles.

⁵See FDA, Guidance for Industry, Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence (Sep. 2023), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical.

⁶See FDA, CDER/CBER Rare Disease Evidence Principles (RDEP) (updated Sep. 3, 2025), https://www.fda.gov/industry/fda-rare-disease-innovation-hub/cdercber-rare-disease-evidence-principles-rdep.

⁷Id.

⁸Id.

⁹See id.

¹⁰If there is no IND for the product, FDA will assign a pre-IND number so that a meeting can be scheduled. Id.

¹¹See id.; see also Rare Disease Innovation Hub Strategic Agenda 2025, file:///C:/Users/121080/Downloads/rare_disease_innovation_hub_strategic_agenda.pdf.

¹²FDA & Duke Margolis Institute for Health Policy, On the RISE: Controls in Rare Disease Clinical Trials for Small and Diminishing Populations (visited Sep. 9, 2025) (statement of Dr. Vinay Prasad), https://healthpolicy.duke.edu/events/rise-controls-rare-disease-clinical-trials-small-and-diminishing-populations.

¹³See FDA, Commissioner’s National Priority Voucher (CNPV) Pilot Program (updated July 22, 2025), https://www.fda.gov/industry/commissioners-national-priority-voucher-cnpv-pilot-program.

¹⁴See FDA, FDA Announces New FDA PreCheck Program to Boost U.S. Drug Manufacturing (updated Aug. 7, 2025), https://www.fda.gov/news-events/press-announcements/fda-announces-new-fda-precheck-program-boost-us-drug-manufacturing.

¹⁵See FDA, Formal Meetings Between the FDA and Sponsors or Applicants (Draft Guidance) (updated Sept. 22, 2023), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formal-meetings-between-fda-and-sponsors-or-applicants-pdufa-products.