A New Regulatory Process for Ultra-Rare Therapies - FDA Rare Disease Evidence Principles (RDEP) Process

Introduction

Approximately 300 million people globally live with a rare disease. Diseases such as cystic fibrosis, haemophilia, sickle-cell and amyotrophic lateral sclerosis (ALS) are all rare diseases. Much effort and focus are invested in developing new therapies and for some conditions there is widespread awareness and fund-raising. However, as many as 95% of rare diseases have no available therapies, only 5% of rare diseases have a licenced therapy in the U.S. Genetic origins account for approximately 72% of rare diseases and the majority of these first appear in childhood. It is estimated that there are over 6000 distinct rare diseases, each affecting fewer than 1 in 2000 people. Ultra-rare conditions affect even fewer individuals, while there is no single definition, an ultra-rare disease may affect less than 1 in 50,000 people and many affect less than 1 in a million individuals.

The Rare Disease Evidence Principles (RDEP)

The proportion of available medicinal products that treat rare conditions has increased over the decades and around half of all products authorised by the US Food and Drug Administration (FDA) over the last 5 years target rare diseases. While there is great progress for many living with a rare disease there are still significant challenges in advancing diagnosis, support, and treatment.

To provide additional support for sponsors of ultra-rare medicinal products, the FDA have proposed the Rare Disease Evidence Principles (RDEP) process. Its purpose is to provide greater speed and predictability in the review of therapies intended to treat rare diseases with very small patient populations, with significant unmet medical need, and that are driven by a known genetic defect. Products in scope for this process need to be treatments that are either correcting the gene responsible or are a replacement of an essential physiological protein that is otherwise deficient due to the gene defect. Products in scope can therefore come in any modality, small molecules, biologicals or cell and gene therapies. To enable consistency across the various FDA divisions that are typically involved in reviewing therapies across different therapeutic areas, and with differing modalities, this proposed process is jointly developed and implemented by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

To be eligible for the RDEP process, investigative therapies must target a very small, rare disease population or subpopulation (generally fewer than 1,000 patients in the United States equivalent to fewer than 1 in 340,000  people in the US) facing rapid deterioration in function leading to disability or death, for whom no adequate alternative therapies exist. The FDA state that the RDEP process will assure sponsors that drug licence reviews will encompass additional supportive data alongside single study data, which may include:

• Strong mechanistic or biomarker evidence
• Evidence from relevant non-clinical models
• Clinical pharmacodynamic data
• Case reports, expanded access data, or natural history studies

What are the challenges in ultra-rare disease?

In rare diseases the small population size and often urgent need for treatments has meant that products are regularly authorised based on a single pivotal study with some supportive evidence, rather than with multiple Phase 3 trials as is expected in more common diseases. This is recognised in both FDA and EMA regulatory guidance, as well as in other regions. In such guidance, developers are advised that results from a single study need to demonstrate significant clinical effectiveness and are encouraged to use a well-controlled study design.

The additional challenges in designing adequate trials in ultra-rare progressive genetic disorders are driven by an often heterogeneous disease presentation, variable and non-linear progression rates, wide population age range from infants to adults and the need for novel endpoint use. The inherent very small number of patients requires innovation to maximise all available data without burdensome study testing of already ill children and adults. Comparative trials may not be feasible or ethical in some cases. Single-arm trials require carefully considered supportive data to establish effectiveness. Clearly defining ‘confirmatory’ evidence with sponsors during development and before pivotal trial launch is a key RDEP process concept.

Recent examples in ultra-rare product development

Recent examples of FDA authorisation of treatments for rare genetic disorders based on a single-pivotal study have already included a variety of supportive data, for example;

Mechanistic evidence - Xenpozyme (olipudase alfa) for treating patients with acid sphingomyelinase deficiency (ASMD), a genetic condition, historically known as Niemann-Pick disease type A, A/B and B.

• placebo-controlled study (n=36) supported by the well-established aetiology of the disease, the mechanism of action of olipudase alfa, and pharmacodynamic biomarker data.

Ongoing study data - SEPHIENCE (sepiapterin) used to treat hyperphenylalaninaemia (HPA, excessive blood levels of phenylalanine) in adults and children with phenylketonuria (PKU).

• placebo-controlled study (n=98) supported by data from ongoing open-label study data.

External natural history data - KEBILIDI (eladocagene exuparvovec) for the treatment of adult and pediatric patients with aromatic L amino acid decarboxylase (AADC) deficiency.

• a single-arm study (n=13) supported by an external control natural history cohort.

Other real-world evidence – Luxturna (voretigene neparvovec) used to treat adults and children with loss of vision due to inherited retinal dystrophy.

• a single open-label controlled study (n=31) supported by medical chart review.

In future, sponsors can use the RDEP process to discuss proposed supportive data with FDA prior to starting a single pivotal trial with the aim of confirming what will be acceptable during licence application review.

Development of treatments for ultra-rare disease are often led by small sponsors or academic institutions, so funding can be challenging. If setbacks are encountered with the FDA then development can stall, or stop altogether, leading to lengthy delays for patients. A defined pathway to authorisation is key to the success of development programs of therapies for ultra-rare diseases. Recent examples illustrate the impact of uncertainty to sponsors and potential delay in access for patients when it is unclear what is deemed acceptable at review. The FDA review of Stealth BioTherapeutics’ elamipretide in Barth syndrome, which affects around 150 people in the U.S  was complex. Since initial clinical trial data were presented in 2019 review has including 4 different FDA divisions, and, following a 16.5 month priority review, the FDA issued a notice that the application would not be approved via a complete response letter (CRL).

A resubmission, a positive vote at a Cardiovascular and Renal Drugs Advisory Committee meeting and a pathway forward under accelerated approval finally resulted in an eventual authorisation in July 2025. Similarly,  Saol Therapeutics application for the product SL1009 (sodium dichloroacetate) for the treatment of Pyruvate Dehydrogenase Complex Deficiency (PDCD), ended with a CRL in September 2025, despite data from two Phase 3 studies in a disease that affects less than 1,000 people in the U.S. Further data generation in this population could take several more years. In both cases patient advocacy groups highlight the frustration associated with lengthy reviews and perceived lack of flexibility on behalf of FDA.

The range in modalities used to treat rare genetic disorders can be seen from all the above examples.  Scientific innovation in advanced therapies as well as potential drug repurposing all bring hope for new treatments. The table below is a snapshot of the range of therapeutic approaches currently used to treat ultra-rare genetic diseases and the relative complexity of administering each type.

Therapeutic approaches to ultra-rare genetic disease.

When therapeutic approaches are so varied in an already challenging setting, the type of acceptable confirmatory evidence cannot be standardised, and processes to support sponsors in defining what could be acceptable for authorisation are essential for increasing access to potentially life-changing treatment.

Sponsor considerations in ultra-rare disease development

Existing regulatory support for sponsors designing pivotal trials is available through published guidance and scientific advice from regulatory bodies like FDA and EMA. In addition, both FDA and EMA have an established ‘orphan designation’ process that provide sponsors incentives to develop therapies in rare diseases. Available schemes to support development in serious hard to treat conditions include Fast-track and Break-through designations in the US and PRIME in the EU. These schemes can be used to garner enhanced interactions with regulators to plan adequate evidence generation for individual products, multiple designations can be held for an investigational drug.

Designations available during development of ultra-rare therapies for serious diseases.

While PRIME is not exclusive to rare disease, most PRIME designations are granted in rare disease settings. A total of 32 of the 33 products authorised under the PRIME scheme outside of infectious diseases are treatments for a rare or ultra-rare disease.

Leveraging the opportunities to interact with regulators to discuss the clinical trial design and the generation of confirmatory evidence can improve the chances of approval and increase speed of access to much-needed treatments, RDEP is another opportunity for sponsors for interaction with FDA developing therapies for ultra-rare genetic diseases.

How to apply for the Rare Disease Evidence Principles (RDEP) process

In the proposed process a sponsor can submit a request for review under the RDEP process to their IND prior to launching a pivotal trial along with a formal meeting request. The sponsor is expected to include evidence that the eligibility criteria are met and that one confirmatory trial will be sufficient to demonstrate safety and efficacy. Participation is decided by the relevant review centre in consultation with FDAs Research Rare Disease Policy and Portfolio Council (RRDPPC). Accepted applicants will have an initial meeting with the FDA review team, the data that will demonstrate safety and effectiveness will be discussed along with engagement with FDA at significant milestones in future development.

Summary

RDEP is the first process explicitly proposing support for developers of ultra-rare therapies for genetic conditions, including a pathway for single-arm studies as confirmatory data. Given the large number of genetic diseases, each impacting relatively few individuals, progress in supporting development of new therapies is important and welcome.

Contact Clinigen Life Cycle Service if you have any questions, or for strategic support of medicinal products in rare diseases Regulatory@clinigengroup.com