Overcoming Communication Challenges for the Approval of New Therapies for Rare Diseases

“When you hear hoofbeats, don’t expect to see a zebra.” Medical students learn this phrase to encourage them to start a differential diagnosis with the most common conditions; however, to diagnose a rare disease, they need to be able to recognize the uncommon, unique, and unexpected—sometimes, the hoofbeats really are zebras.

The rare disease community has embraced the zebra as a symbol because they are uncommon and unexpected in everyday life, and each is unique with a one-of-a-kind pattern of stripes. Although each condition may be rare individually, collectively, these “medical zebras” have a prevalence of more than 350 million people worldwide [1], and more than 30 million in the United States.

Scientific advancements in fields like gene and cell therapies, precision medicine, and AI-driven diagnostics—along with efforts by global regulatory agencies to encourage and facilitate clinical development and regulatory innovation—have accelerated medical advances for rare diseases. Even with these efforts, the path to approval is rarely straightforward. According to the NIH, an estimated 7000 rare diseases have a known molecular cause, but only about 500 have an FDA-approved treatment. This contributes to the huge unmet need, leaving 93% of rare diseases with no approved therapy in the United States [1,2].

Several factors can make clinical development challenging for rare disease indications, including small patient populations, limited understanding of the etiology and potential therapeutic targets, and, often, a lack of regulatory precedent. Sponsors must forge a new path through unknown territory, leading to complex regulatory interactions and barriers to approval. ??

In this issue of BOLDAPPROVED, we show how a strong regulatory communication strategy can help overcome challenges faced by sponsors of rare disease therapies as they navigate the journey to approval.

1)????? Educating your audience about the rare disease indication

In addition to communicating their clinical efficacy and safety data, rare disease drug developers must put additional effort into educating their audience about the disease.

The Orphan Drug Act, passed in 1983, defines a rare disease as a disease or condition that affects fewer than 200,000 people in the US. Rare diseases are considered “orphaned” when there are inadequate therapies available, and a lack of resources and knowledge to fuel the development of new therapies. There may be very few clinicians with the appropriate expertise to understand, diagnose, and treat the orphaned disease. The medical community and health authorities may lack basic disease awareness outside of those few experts.

For the value of the drug to be recognized, sponsors need to educate regulatory audiences on the rare disease pathophysiology, clinical manifestations, diagnostic criteria, the inadequacy of the current standard of care, and the resulting high unmet need for new treatments. Sponsors should recruit and leverage clinical experts in rare disease indications who can speak from their own experiences about the challenges they face in diagnosis and treatment. The sponsor’s scientists can link these clinical experiences to the preclinical and translational research underpinning the therapy.

Often the greatest challenge is to help audiences understand what constitutes a clinically meaningful treatment benefit to patients. ?Beyond the clinical and scientific voices, sponsors must convey the voice of the patient and caregivers, to further establish the burden of disease, the burden of care, and the medical need.

2)????? Communicating the rationale for novel primary endpoints for approval

Sponsors of first-in-indication and/or first-in-class therapies for rare diseases typically lack a well-established regulatory pathway to approval. In these cases, the burden of establishing the bar for regulatory approval falls primarily on the sponsor, who must communicate the rationale for why the endpoints were selected, how they were validated, and how they can support an evaluation of clinically meaningful efficacy. In addition, the timing and frequency of assessments and the statistical methods to combine those assessments and determine statistical significance must be validated.

Endpoints for rare disease clinical trials are often tailored specifically to that disease and may require the development of novel clinical outcomes measures and diagnostics. For example, a clinical study for a rare disease characterized by progressive dysfunction over time may include an endpoint that is a composite measure of cognitive function and ability to perform activities of daily living, to establish a clinically meaningful benefit.

FDA published a Final Guidance to industry in December 2023, “Rare Diseases: Considerations for the Development of Drugs and Biological Products,” which provides non-binding recommendations for sponsors of rare disease therapies in selecting endpoints. When communicating with regulators or external advisors, sponsors should refer to the guidance directly and demonstrate how their rationale for novel endpoints has followed it. Using the language directly from the guidance will make them more likely to agree with the approach.

3)????? Leveraging accelerated and expedited approval pathways

The accelerated approval pathway holds great promise for expediting the availability of rare disease therapies to patients with urgent unmet medical needs.

The FDA may grant accelerated approval based on the demonstration of an effect on a surrogate endpoint which is “reasonably likely to predict a clinical benefit.” This allows the drug to be accessed by patients, while the sponsor continues to gather data to confirm clinical benefit. Accelerated approval has been highly successful in oncology, even for rare cancers; however, the pathway has been underutilized for non-oncology rare diseases.

Rare disease therapies are more likely to require novel surrogate endpoints that may only apply to a single indication; such endpoints must be validated on a case-by-case basis. Justification of a novel surrogate endpoint is challenging due to inevitable gaps in the data, the subjective nature of whether a measure is “reasonably likely” to predict clinical benefit, and potential disagreements with FDA reviewers.? Sponsors should request a Type C meeting with FDA as early as possible in development to discuss any novel surrogate endpoint proposed to support accelerated approval (FDA guidance for Type C meetings regarding new surrogate endpoints). Sponsors can also refer to the FDA table of surrogate endpoints to review what endpoints have been used to support both traditional and accelerated approval pathways and inform their preparations.

Sponsors may consider requesting RMAT (Regenerative Medicine Advanced Therapy) designation, which was created by FDA to support the advancement of cell therapies, therapeutic tissue engineering products, and human cell and tissue products for the treatment of serious or life-threatening diseases. This designation provides comprehensive benefits intended to expedite development and review, including enhanced communication opportunities, accelerated approval support, and intensive guidance beginning as early as Phase 1.

4)????? Establishing rationale for non-traditional clinical trial design

Sponsors of therapies for rare diseases often seek approval on the basis of a single pivotal trial because there are not enough patients to support a second confirmatory trial, which FDA typically requires to demonstrate “substantial evidence of efficacy.” FDA has shown regulatory flexibility in these situations, particularly when a high unmet need exists.

An analysis by AGENCYIQ revealed that in 2024, 66% of new molecular entities approved by the FDA’s Center for Drug Evaluation and Research were approved based on one pivotal trial. Of these, approximately 70% had orphan disease designation and 20% received accelerated approval [4]. Although the approach has been successful most frequently in oncology indications, these additional communication opportunities can benefit sponsors who are developing therapies in diverse array of rare disease indications.

This regulatory latitude is often essential in the clinical trial design to support approval for rare disease therapies. Sponsors may employ non-traditional study designs such as n-of-1, early escape, or adaptive randomization. Furthermore, as placebo-controlled trials are often not feasible or ethical to conduct in rare disease indications, the use of a matched real-world control arm, or a natural history control may be necessary. FDA leadership has expressed their commitment to exercising regulatory flexibility to promote new rare disease approvals through the Accelerating Rare disease Cures (ARC) program, and pilot programs for cell and gene therapies like the Support for clinical Trials Advancing Rare disease Therapeutics (START) program.

5)????? Directly address issues and uncertainties in clinical data

Even the most meticulously designed clinical development program, with full alignment and support from FDA, can ultimately result in clinical data with significant issues and uncertainties.

Sponsors seeking approval for rare disease therapies are more likely to encounter challenges with their clinical data that increase the likelihood of complex regulatory communication challenges, including increasing the chances of an FDA Advisory Committee meeting (AdComm). For rare disease therapy sponsors, an AdComm may be the highest-impact and most public hurdle prior to an approval decision. Sponsors must directly address the Committee’s questions and concerns, while presenting their data in the strongest and most persuasive way possible.

All of the challenges described above are amplified at an AdComm because, unlike the ongoing interactions over years with FDA, the AdComm typically takes place in a single day. The sponsor must condense all of the relevant material into a single briefing document, a 60-90 minute presentation, and be prepared to address all the Committee’s questions in a limited timeframe, sometimes in as little as 20 minutes. The preparation for an AdComm should be underpinned by a strategically focused regulatory communication strategy to address the key issues.?

Conclusion

The chance to improve the lives of patients with rare diseases and their caregivers starts with regulatory approval. It is crucial to begin early and to have the right support. Our highly experienced team has helped many sponsors of rare disease therapies prepare for complex regulatory interactions. We begin with a compelling regulatory communication strategy that drives effective interactions with FDA, guides the writing of the submission, and often culminates in the preparation for an AdComm. We understand these unique challenges and are ready to help our clients overcome them.

About the Authors

Angela W. Corona, PhD, is a Senior Scientific Director with BOLDAPPROVALS where she supports teams approaching new drug or biologics approvals. With 10 years of broad medical and regulatory communications experience across a range of therapeutic areas, including neurology/neurodegenerative disease, oncology, and immunology, she has played a key role in preparing teams for AdComms, strategic submission messaging, and other complex regulatory communication challenges. Her PhD training was in neuroscience at The Ohio State University, and she performed post-doctoral research in Alzheimer’s disease at Case Western Reserve University.?

Steven C. Cohen is the Managing Director of BOLDAPPROVALS, the division of BOLDSCIENCE that prepares clients for AdComms, regulatory submissions for the approval of new therapeutics (NDAs/BLAs), FDA meetings, and label development. Steven has 34 years of leadership in communication consulting, strategy, and delivery coaching, including 119 AdComm preparations. He has supported numerous health authority interactions at key milestones and led submission messaging workshops. He has trained and coached over 1000 scientists, clinicians, and other leaders across disciplines. Steven earned a bachelor’s degree in French Literature from Wesleyan University. He studied medical science at NY Medical College and marketing, communication, and the Internet at Columbia University.

About BOLDAPPROVALS

BOLDAPPROVALS blends science, communication, and technology to support product approvals. We deliver comprehensive support for FDA Advisory Committee meetings (AdComms), submission messaging, labeling strategy, and health authority interactions.

Our proven methodology integrates in-house scientific expertise with communication consulting to develop compelling, data-driven arguments for persuasive presentations, responses to questions, and briefing materials.

Our highly experienced team has supported over 250 AdComm preparations and aligned teams on messages for regulatory submissions and interactions with health authorities. Our team can address the unique needs of your people, products, and circumstances. ??1,2

To learn more about how BOLDAPPROVALS can help your team identify and overcome issues, please visit boldapprovals.com, email [email protected], or call Steven Cohen at +1 (646) 930-0453.?

References:

1. Shourick J, et al. Orphanet J Rare Dis. 2021;16(1):139.

2. Kaufmann P, et al. Orphanet J Rare Dis. 2018;13(1):196.

3. Fermaglich L, Miller KL. Orphanet J Rare Dis. 2023;18(1):163.

4. Conti A. “Analysis: The majority of novel drugs approved by FDA rely on evidence from a single pivotal trial.” AGENCYIQ by POLITICO. February 7, 2025. https://www.agencyiq.com/blog/analysis-the-majority-of-novel-drugs-approved-by-fda-rely-on-evidence-from-a-single-pivotal-trial/