The FDA has expanded the regulatory toolkit during President Donald Trump’s second term, adding new mechanisms for rare diseases while putting the Biden-era platform technology designation into action.
Across 16 months of leadership turnover, the FDA has created mechanisms that promise accelerated routes to market for eligible investigational therapies. The pathways remain undefined, however, in ways that leave experts with questions about their impact.
Last year, the agency introduced the plausible mechanism pathway and rare disease evidence principles (RDEP). The initiatives, both of which target rare diseases, join a list of mechanisms the FDA began introducing more than 30 years ago to accelerate drug development and regulatory review for some drug candidates.
“Sponsors should think of these [newer] pathways as potentially complementary, but should also be mindful that they are not substitutes or alternatives,” Eva Temkin, partner at Arnold & Porter, told BioSpace in an email.
Temkin, who advises biopharma companies on drug development, approval and marketing, used the plausible mechanism pathway to describe how the new initiatives differ from established programs. The plausible mechanism pathway is a “very narrow construct under which specific types of evidence may be considered sufficient under a specified set of circumstances,” she said.
Temkin contrasted the narrow focus of the plausible mechanism pathway with the FDA’s traditional “expedited programs,” including the Fast Track and Breakthrough Therapy designations and priority review. The older initiatives “address more programmatic considerations,” such as the frequency of agency interactions and review timelines for promising new drugs in broader areas of unmet medical need, Temkin said.
Indeed, during a recent FDA workshop held to discuss implementation of the plausible mechanism guidelines, Gene Therapy CMC Branch Chief Anna Kwilas clarified that the program is a framework for achieving approval of applicable products, rather than a new approval pathway.
While such high-level differences between the old and new initiatives are clear, questions about the details and implications of the latest mechanisms remain unanswered. The plausible mechanism pathway’s effect on postmarketing obligations and conduct is among the open legal and regulatory questions posed by FDA’s draft guidance, Temkin said. Other uncertainties relate to the pathway’s commercial impact.
“There are questions about regulatory exclusivities and other incentives for drugs approved using the kinds of data described in the framework guidance—and what the impacts will be on the competitive landscape for those products,” Temkin said.
With Temkin advising sponsors to use all relevant frameworks and designations concurrently, BioSpace has provided a guide to understanding each mechanism and how it may apply to rare disease programs to maximize the benefits.
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What FDA programs are available to rare disease drug developers?
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Marty Makary and Vinay Prasad—the former FDA commissioner and Center for Biologics Evaluation and Research director, respectively—introduced the plausible mechanism pathway in an article published in The New England Journal of Medicine in November. Citing the case of Baby KJ, who last year was treated with a single-use CRISPR therapy, Prasad and Makary outlined the need for a regulatory pathway for products that address diseases that affect too few patients to be evaluated in randomized trials.
Under the pathway, such products could come to market based on evidence that they engage their biological targets and on signs of clinical improvement. At the time, William Blair analysts said the pathway could accelerate development of some genetic therapies but cautioned that additional clarity was needed.
In February, the FDA provided more information in draft guidance on the mechanism. The framework applies to individualized therapies that target the “specific pathophysiologic abnormality serving as the root cause of a disease,” the agency clarified. Genome editing and RNA-based treatments are the focus of the draft.
However, the draft provided little new information, Harpreet Singh, chief medical officer at Precision for Medicine and a former division director of Oncology at the FDA, told BioSpace in February. Public feedback on the draft confirmed the biopharma industry still has questions, with the trade group PhRMA calling for clarifications and examples in multiple areas in its response to FDA.
FDA introduced the rare disease evidence principles (RDEP) in September 2025 to support faster, more predictable reviews of therapies for ultrarare diseases. The principles apply specifically to diseases that affect fewer than 1,000 patients in the U.S., cause significant unmet medical need and are driven by known genetic defects. Sponsors can apply to the FDA any time before starting a pivotal trial.
Under the program, the agency and sponsor work with patients and experts to define the evidence needed for approval. The interactions position companies to include additional supportive data in submissions for approval, which require one adequate and well-controlled study and “robust” confirmatory evidence such as biomarker findings and nonclinical results.
Launched in June 2025 as one of former Commissioner Marty Makary’s chief initiatives, the FDA Commissioner’s National Priority Voucher (CNPV) pilot program intends to shorten the review time for products that are aligned with certain U.S. national priorities from 10–12 months to 1–2 months. These include addressing a health crisis in the U.S., delivering more innovative cures, addressing an unmet public health need and increasing domestic drug manufacturing as a national security issue.
To date, the FDA has approved seven products under the CNPV program. Despite Makary’s departure earlier this month, the program will live on, according to the Department of Health and Human Services (HHS). There will be “no change to the name or direction of the CNPV program at this time,” an HHS spokesperson told Fierce Biotech on May 26.
In draft guidance released in 2024, the FDA fleshed out the platform technology designation created by Congress the previous year through the Consolidated Appropriations Act. The FDA designation is open to well-understood and reproducible technologies that can be used by multiple products to drive significant efficiencies in drug development or manufacturing.
After receiving the status, companies can reuse previously submitted information about the designated platform technology to support new filings to the FDA. However, sponsors “are unlikely to see great utility in the program until the second or third submission based on the platform technology,” Temkin said.
The agency awarded the first such designation to Sarepta Therapeutics in June 2025 for its viral vector rAAVrh74, used in the company’s gene therapies. Weeks later, the FDA revoked the designation, citing three patient deaths linked to the platform. In October, the second platform technology designation went to Krystal Biotech for its non-replicating HSV-1 viral vector.
FDA created the accelerated approval pathway in 1992 in response to the AIDS epidemic. Codified by Congress in 2012, the pathway supports earlier approval for drugs that address serious unmet medical needs based on surrogate or intermediate clinical endpoints. Review time under this pathway is around six months compared to the standard 10 months. If products are approved, companies must run confirmatory trials to show that the surrogate or intermediate outcome leads to real clinical benefit.
Also implemented in 1992, FDA Priority Review designation entitles companies to a speedier review as the agency’s goal is to take action on an application within six months and allocates resources accordingly. Unlike the accelerated approval pathway, however, this mechanism does not allow companies to leverage alternative endpoints.
Priority review is intended for investigational products the FDA deems would provide significant safety or efficacy improvements in the diagnosis or prevention of serious conditions when compared to standard applications.
In 1997, Congress directed the FDA to create a fast track program as part of the adoption of the Food and Drug Administration Modernization Act. Drug candidates that treat or prevent conditions with no current therapies meet the criteria, as do molecules with possible advantages over existing treatments. Sponsors benefit from more frequent engagement with FDA and may be eligible for accelerated approval.
Established by Congress in 2012 as part of the Food and Drug Administration Safety and Innovation Act, Breakthrough Therapy designation builds on the older Fast Track mechanism. Sponsors receive all the Fast Track designation features, plus intensive FDA guidance on an efficient drug development program and organizational commitment involving senior managers. Breakthrough status is available to sponsors with preliminary clinical evidence showing that a molecule may provide a substantial improvement over available therapies on a clinically significant endpoint.
Enacted in 2016 through the 21st Century Cures Act, the Regenerative Medicine Advanced Therapy designation supports expedited development and review of cell, gene and tissue products. Developers of such products can secure the designation after generating preliminary clinical evidence that they address a serious or life-threatening condition.
Another key FDA pathway for rare disease developers is Orphan drug designation. Intended for drugs or biological products that prevent, diagnose or treat a rare disease or condition, this mechanism offers several advantages, including tax credits for qualified clinical trials and a potential seven years of market exclusivity after approval. Orphan drug designation was implemented in 1983 with the enactment of the Orphan Drug Act.
First enacted in 2012, the FDA’s rare pediatric disease priority review voucher (PRV) program aims to incentivize drug development for these diseases by attaching a voucher to approvals granted under the designation. Companies can use the PRV to expedite the drug review timeline for another product—down to around six months from the usual 12 months—or they can sell the voucher to gain much-needed revenue in a space that doesn’t fit the traditional pharmaceutical revenue model. Prior to submitting a marketing application, drug sponsors hoping to leverage this pathway should request rare pediatric disease designation.
The PRV program, which most recently lapsed at the end of 2024, was reauthorized in February in a spending bill signed by President Donald Trump. The program will sunset after Sept. 30, 2029, unless it is reauthorized again.
