The Flexibility Papers No. 3: Old Drugs, New Possibilities – Repurposing as Part of the Rare Disease Framework

In the first installment of The Flexibility Papers, we proposed a different starting point for rare disease drug development: rather than beginning with a conventional development program and asking what departures might be justified, FDA and sponsors should begin with the disease, the product, and the available evidence to identify a fit-for-purpose pathway. Our second installment considered how patient perspectives should meaningfully inform that process. This post takes up another part of the same question: What should development look like when the drug is not new, but its proposed use is?

Drug repurposing is a natural place to put fit-for-purpose development into practice. An approved drug being developed for a new rare disease indication may already have a substantial body of clinical and real-world experience. The task should be to determine what that evidence establishes, how it applies to the proposed use, and what questions remain unanswered. FDA’s Rare Disease Framework Initiative (which we first blogged about here) presents an opportunity to make that inquiry a predictable part of development and review, rather than an exception that each sponsor must negotiate anew.

The opportunity builds on work already underway. On August 5, 2026, FDA and the Reagan-Udall Foundation for the FDA convened a public meeting on drug repurposing. The Agency’s initiative focuses on approved drugs with no apparent commercial interest in adding a new use through a supplemental application which addresses an important public health need. But that focus should not inadvertently discourage commercially-sponsored repurposing. Clearer expectations for streamlined development could help create commercial interest where little exists today. HPM submitted a written comment as a follow-up to the August 5 meeting drawing on our experience counseling sponsors developing repurposed therapies for series and often rare diseases.

Start with What Is Known, Not Equipoise

The central question is not whether repurposed drugs should face a lower standard for approval. They should not. It is how the existing standards for safety and effectiveness can be met by appropriately leveraging evidence that already exists in a fit-for-purpose manner. Repurposed drugs often bring prior clinical trial data, real-world safety experience, published literature, and off-label experience with the proposed use, sometimes as standard of care. Mechanistic and pharmacologic information may help connect that evidence to the new indication. A fit-for-purpose approach should ask what each source contributes to the overall evidentiary package before determining what additional evidence generation is necessary, as we may not be at a place of clinical equipoise when starting a development program for a repurposed drug.

FDA highlighted concrete examples at the August 5 meeting, such as leucovorin in cerebral folate deficiency, where FDA described a substantial evidence determination based on a systematic review of published literature containing patient-level data, treated as an adequate and well-controlled investigation, with confirmatory support from the drug’s mechanism. FDA also described the use of real-world evidence as an external control arm and as confirmatory evidence for label expansions. These examples illustrate that leveraging existing evidence is not merely a theoretical possibility. The challenge is to explain when and how comparable approaches can be used in other programs.

Of course, an approved drug is not automatically safe or effective for every new use. A different population, dose, route of administration, formulation, or duration of treatment may leave important questions unresolved. Nor does widespread off-label use, by itself, establish effectiveness. We propose that FDA and sponsors explicitly identify where existing evidence is applicable, where a scientific bridge is needed, and what new evidence must be generated. Development should focus on addressing the more limited uncertainties for the proposed rare disease use, rather than starting from the expectation of a conventional development program (consistent with our recommendation in our first installment).

Placebo-Controlled Trials Face Heightened Feasibility Challenges

This is particularly important when off-label use has become standard of care. A placebo-controlled trial that requires patients to forgo that standard of care treatment creates a significant challenge to feasibility because patients and clinicians may be unwilling to participate.  Why would any patient with a serious, rare disease accept the possibility of being on a placebo when they can gain access to the same active ingredient off label?  Why would a clinician recommend participation in such a study when, as already discussed, there is not clinical equipoise, and their patients are coming to the clinic to access a treatment now?

FDA should not assume that withholding an established off-label therapy for any period of time is a feasible starting point just because a randomized, placebo-controlled study is “more interpretable” relative to other study designs. The framework should explicitly address how existing evidence and scientifically appropriate alternatives, such as baseline-controlled (patient-as-own-controlled) or externally-controlled designs, can resolve the remaining questions without requiring patients to forgo care that the clinical community regards as beneficial.  This is particularly true in diseases where there are objective assessments or where outcomes can be assessed by blinded adjudicators.

Keep Commercial and Non-Commercial Repurposing in View

The workshop’s focus on drugs without a commercially interested sponsor should not suggest that leveraging existing evidence is appropriate only when commercial development is absent, or that industry-sponsored programs should face a higher regulatory bar. Commercial development is often what converts fragmented off-label or compounded use into a consistently manufactured, FDA-approved therapy supported by product-specific labeling, pharmacovigilance, and reliable patient access. For rare disease programs, we believe the framework should apply the same scientific principles for evaluating existing evidence, whether the effort originates with a company, an academic investigator, or a patient organization. The scientific value of evidence should not depend on who brings it forward.

The MODERN Labeling Act incorporates, rather than lowers, FDA’s approval standards for the labeling updates it authorizes. The policy implication is straightforward: if FDA is developing a framework for determining how existing evidence can satisfy those standards when commercial interest is absent, that work should also help sponsors understand how to develop repurposed therapies. A rare disease framework should use the repurposing initiative to facilitate commercial participation, not inadvertently make the absence of a sponsor the condition for a streamlined approach.

From Individual Examples to a Dependable Pathway

FDA’s Rare Disease Framework presents an opportunity to turn these lessons into a dependable pathway for repurposing. We see four concrete approaches that could make the evaluation of existing evidence more predictable and help patients, researchers, and sponsors pursue promising new uses:

First, establish an evidentiary roadmap that begins with existing knowledge. FDA should explain how published literature, real-world evidence, natural history information, prior FDA findings, and pharmacologic bridging can contribute to the safety and effectiveness assessment for a new rare disease use. The roadmap should address when existing evidence may be sufficient without a new efficacy study, when non-traditional designs or statistical approaches can resolve remaining questions, and what limitations would require additional evidence. It should also address appropriate alternatives, where established off-label use makes a placebo-controlled trial infeasible or raises concerns about clinical equipoise. We propose a structured assessment of what is known and what is missing, not a presumption that every program needs the same studies.

Second, define submission and review mechanisms so early engagement yields an actionable development plan. FDA should clarify the submission vehicle, including 505(b)(2) applications and labeling supplements, opportunities to expedite review, and early-engagement options, so sponsors know how and to whom to bring a repurposing program. Under the Rare Disease Framework, we propose that those discussions also produce a documented understanding of the evidence FDA considers relevant, the bridging needed to support reliance on it, and the remaining development questions. Where expectations later change, FDA should explain the scientific basis. A roadmap is useful only if sponsors and reviewers can rely on it throughout development.

Third, explicitly leverage regulatory programs to encourage commercially sponsored repurposing. Generic entry and patent expiration can erode incentives to invest in developing new uses of approved drugs. FDA should articulate how existing information on repurposed drugs can meet the criteria for Breakthrough Therapy Designation and consider new administrative programs, similar to the START Pilot, that could reduce the burden and speed the timing of obtaining FDA feedback. For rare disease drug repurposing, clearer expectations for using existing evidence and more efficient access to review staff could help make development more feasible.

Fourth, connect patient input to the repurposing evidence assessment. As we proposed in our second installment, patient perspectives should inform meaningful treatment benefits, feasible trial designs, and the assessment of uncertainty. For repurposing programs, we propose that early discussions and regulatory decisions also consider patients’ experience with existing off-label use and patients’ willingness to accept uncertainty, which should be elicited rather than assumed. That information should help inform a fit-for-purpose plan for resolving the questions that remain.

Across these recommendations, FDA should translate the approach into guidance, reviewer training, and shared review practices, with examples explaining both when reliance on existing evidence was appropriate and when it was not, and how that information informs the design of a fit-for-purpose development program. That would help turn the lessons of individual repurposing programs into the consistent, predictable approach envisioned by the Rare Disease Framework.

The Rare Disease Framework Initiative should treat repurposing as a concrete opportunity to make fit-for-purpose development the norm. Valuable new uses that lack commercial interest deserve attention, but FDA should also make it easier to identify feasible development pathways for sponsors.  Doing so will attract more sponsor-led development, where the added predictability of appropriately streamlined development will lead to investment in the untapped potential of repurposing.