In a recent article for Clinical Leader, Mark A. Tobolowsky and Frank J. Sasinowski of Hyman, Phelps, & McNamara shed light on a major regulatory development that could reshape how therapies for ultra-rare diseases reach patients. 

That development is the Rare Disease Evidence Principles (RDEP) initiative, a new program designed to provide more flexibility in evaluating treatments for conditions that affect very small patient populations. Here, we explain the program’s goals, highlight some of its potential benefits, and explore what biopharma leaders can expect going forward.

What is RDEP?

For decades, drug development for rare and ultra-rare conditions has been burdened by barriers that are difficult to overcome. Recruiting participants, securing funding, and proving efficacy through large, placebo-controlled studies are challenging enough for rare disease programs, let alone conditions that affect fewer than a thousand people. In the past, some therapies have found a pathway to approval with smaller patient pools, but these cases were the exception, not the rule.

The FDA’s new RDEP initiative is meant to clarify and expand how flexibility can be applied in these situations. Under RDEP, certain drugs for ultra-rare genetic diseases may be approved based on one adequate and well-controlled study, which could be a single-arm trial, combined with strong supporting evidence. That supporting evidence might come from natural history studies, patient case reports, expanded access programs, or pharmacodynamic data. RDEP doesn’t change the FDA’s statutory approval standards, but it does formalize when and how confirmatory evidence can supplement trial results.

Why this matters:

The implications of RDEP extend far beyond easing regulatory hurdles. By recognizing biological plausibility and allowing for alternative forms of confirmatory data, the program provides rare disease sponsors with something that has often been missing: clarity. Sponsors pursuing treatments for ultra-rare conditions have often faced uncertainty about whether their trial design would be considered sufficient. RDEP provides a clearer roadmap, which in turn can reduce delays, streamline development, and attract investor confidence.

Consider the financial side. Developing a therapy for a disease that impacts only a handful of families worldwide is already a daunting fundraising challenge. Venture capital and other funding sources are more likely to back programs that operate under defined regulatory pathways. By laying out explicit criteria and processes, RDEP could help rare disease innovators secure the resources they need to move forward.

The initiative also underscores a change in how patient data and lived experience are valued. The FDA has emphasized that patient input, whether through listening sessions or other engagement, can be incorporated into RDEP reviews. This recognition of the patient voice signals progress toward a more inclusive drug development process, where real-world impact is considered alongside traditional endpoints.

Challenges ahead:

RDEP is a promising step, but it doesn’t eliminate the obstacles facing ultra-rare drug development. Sponsors must still generate compelling safety and efficacy data, and FDA reviewers retain discretion in determining whether a program qualifies. In addition, the agency has made clear that post-marketing studies may be required to further validate a drug’s benefits.

There’s also the matter of consistency. Historically, flexibility has been applied unevenly across FDA divisions. The creation of the Rare Disease Policy and Portfolio Council, which will help oversee RDEP decisions, should help keep things organized, but questions remain about how uniformly the program will be applied in practice.

For sponsors and their partners, the takeaway is that RDEP can open doors, but careful preparation and strategy are essential. Understanding eligibility criteria, identifying the right sources of supporting data, and maintaining transparent communication with regulators will be critical to making the most of this new pathway.

The bigger picture:

The FDA’s embrace of RDEP reflects a growing recognition that traditional trial models don’t always serve the needs of rare disease communities. For families living with progressive, life-limiting genetic conditions, every year without treatment is significant. By lowering barriers to approval while maintaining rigorous standards, the program has the potential to accelerate access to much-needed therapies and encourage innovation in areas of high unmet need.

At Harbor Clinical, we’ve seen firsthand the unique challenges that rare disease sponsors face. From study design and site selection to patient recruitment and regulatory navigation, the path is filled with hurdles.

Programs like RDEP are an encouraging sign that the regulatory landscape is evolving. But the challenges of rare disease drug development don’t go away. If your organization is pursuing therapies for rare or ultra-rare conditions, our team can help support your efforts.

To learn more, visit the services section of our website or call us at (781) 775-0342. As a niche CRO, we have the experience and flexibility to assist.