Rare diseases are a public health priority. Over 6,000 rare diseases affect 3.5% to 5.9% of the worldwide population or ~300 million people (Nguengang Wakap et al 2020). In the United States (US), 25 to 30 million people are estimated to be living with a rare disease, including more than 500 rare cancers (National Organization for Rare Disorders [NORD] 2023).
Last year we marked the 40th anniversary of the US Food and Drug Administration (FDA) Orphan Drug Act. Yet over 90% of rare diseases lack an FDA-approved treatment (NORD 2023). In May 2022, the FDA Center for Drug Evaluation and Research (CDER) launched the Accelerating Rare disease Cures (ARC) Program, which aims to drive scientific and regulatory innovation and engagement to increase the development of effective and safe treatment options addressing the unmet needs of patients with rare diseases.
In October 2022, CDER announced a joint program with the Center for Biologics Evaluation and Research (CBER) on the Rare Disease Endpoint Advancement (RDEA) Pilot Program to support novel efficacy endpoint development and the timely approval of drugs and biological products that treat rare diseases, including pediatric rare diseases. The RDEA Pilot Program is designed for sponsors with an active pre-Investigational New Drug (IND) or IND application for a rare disease. To participate, a sponsor must submit a proposal to the RDEA program. FDA began accepting proposals on July 1, 2023, and the pilot program will run through June 30, 2027. FDA will review all proposals and select a maximum of 1 RDEA proposal and 1 alternate proposal per submission quarter in fiscal year 2024 through the third quarter of fiscal year 2027, with a maximum of 3 RDEA proposals per year.
On September 29, 2023, the FDA announced the launch of the Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program to help further accelerate the development of novel drug and biological products for rare diseases. The FDA began accepting applications to the START program between January 2 and March 1, 2024, and will select up to 3 participants for each center (CDER and CBER). The program is open to sponsors of orphan products currently in clinical trials under an active IND application.
For CBER-related products, eligible products must have an active IND and be a gene or cellular therapy intended to address an unmet medical need for a rare disease or serious condition, which is likely to lead to significant disability or death within the first decade of life. Selected sponsors will be able to obtain frequent advice and regular ad-hoc communication with FDA staff to address product-specific development issues, including, but not limited to, clinical study design, choice of the control group, and fine-tuning the choice of the patient population. Details on the program’s eligibility requirements were posted in the Federal Register Notice.
In addition, the FDA issued the final guidance for industry document “Rare Diseases: Considerations for the Development of Drugs and Biological Products” in December 2023.
Compared to a marketing application for a “common” disease, what are the similarities?
The short answer is there are more similarities than differences. Sponsors will still need to develop a drug and test it in the target population including discovery and nonclinical and clinical studies. Unmet medical need and benefit/risk will need to be established, and all the components of a marketing application (e.g., Common Technical Document) are required. At the time of the marketing application, there is no special documentation to include unless the sponsor intends to request priority review.
What are the differences?
FDA requires a sponsor to apply for orphan drug designation (ODD) to be eligible for incentives including tax credits for qualified clinical trials, exemption from user fees, and potential 7 years of market exclusivity after approval. To apply, there is a specific form/template that must include a justification that the disease or condition meets the orphan drug status (i.e., affecting fewer than 200,000 people in the US).
Importantly, the current prevalence of the disease in the US must be provided to support orphan disease status. Consequently, simply noting that a disease is rare because it is well known (e.g., Amyotrophic Lateral Sclerosis [ALS]), or that it is listed on a website associated with rare diseases is not sufficient. A sponsor must receive ODD from the FDA before submitting a marketing application to be eligible for incentives at the time of the filing of the marketing application.
Due to the rarity of the disease, most clinical development programs will consist of only 1 pivotal study including multiple study centers across multiple countries to enroll enough patients to adequately assess benefit/risk. The FDA recommends early meetings to gain alignment on study design and choice of endpoints. Furthermore, modeling and simulation methods may also be necessary to inform dosing and study design due to such small populations. Thus, sponsors should consider applying for the RDEA and/or START Pilot Programs to take advantage of these additional opportunities for increased engagement with the FDA as early as possible.
Of note, in the US, having ODD granted for an orphan drug/rare disease before submission of the marketing application does not guarantee other special/expedited programs such as priority review, fast track, and the Oncology Center of Excellence Real-Time Oncology Review (RTOR). These programs must be requested/applied for separately based on the program’s eligibility criteria (e.g., serious/life-threatening, unmet medical need, oncology drug) by the sponsor.
How can we help?
Developing drugs for rare diseases poses various clinical, regulatory, and commercial challenges. Certara has a variety of services including model-informed drug development, regulatory services, medical communications, and real-world evidence and consulting that can help you navigate the landscape. Check out this white paper for more information:
References
Nguengang Wakap S, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28:165–73.
National Organization for Rare Disorders (NORD). Rare Disease Facts & Statistics. Accessed 27 October 2023.