9 Things to Know About CDER’s Efforts on Rare Diseases

The Orphan Drug Act defines a rare disease as any disease or condition that affects less than 200,000 people in the U.S. There are approximately 25 to 30 million Americans living with a rare disease (about 1 in 10 people). Many rare conditions are life-threatening, and most do not have treatments. Accelerating the development of safe and effective drugs is CDER’s core mission, and CDER understands there are unique challenges in demonstrating the safety and effectiveness of drugs that treat rare diseases.

Here are some things to know about CDER’s efforts to accelerate the development of safe and effective drugs to treat rare diseases and conditions: 

1. Drug development for the approximately 10,000+ rare diseases and conditions can be complex for many reasons.
Rare disease drug development is uniquely challenging due to issues such as small and diverse patient populations that often restrict trial design options, natural history that is often not well understood, and a lack of drug development tools. As such, traditional and well-established clinical trial designs may not support rare disease clinical investigations. For these and many other reasons, many rare diseases have few or no treatments available for patients who suffer from them. 

2. In 2022, CDER launched the Accelerating Rare disease Cures (ARC) Program to help bridge the gap between the complexities of rare disease drug development and the pressing needs of patients.
CDER’s ARC Program strives to increase the number of treatments for rare diseases by promoting innovative scientific design, providing a deeper understanding of regulatory policies, and engaging with patients and their advocates, academic researchers, clinicians, and drug developers. The ARC Program is a CDER-wide program managed by CDER’s Rare Diseases Team (RDT) and is built on collaboration among CDER’s Office of the Center Director, Office of New Drugs, Office of Translational Sciences and Office of Communications. Critical to its mission, the ARC Program also brings together offices and centers across the agency, such as the Office of the Commissioner including the Office of Pediatric Therapeutics and the Office of Orphan Products Development, the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health, and the Oncology Center of Excellence. Since launching, the ARC Program has emerged as a conduit for empowering the rare disease community to harness their collective experiences and expertise to drive progress. 

3. CDER and CBER are collaborating to establish FDA’s Rare Disease Innovation Hub. 
FDA’s Rare Disease Innovation Hub will work across rare diseases but will especially focus on products intended for smaller populations or for diseases where the natural history is variable and not fully understood. It will leverage the activities of CDER’s ARC Program to enhance existing cross-center collaborations.

The Hub will have three primary functions:

• Serve as a single point of connection and engagement with the rare disease community, including patient and caregiver groups, trade organizations, and scientific/academic organizations, for matters that intersect CDER and CBER. The Hub will help the larger rare disease community navigate important intersections across FDA that affect patients with rare diseases, such as medical devices, including diagnostic tests, and combination products.
• Enhance intercenter collaboration to address common scientific, clinical and policy issues related to rare disease product development, including relevant cross-disciplinary approaches related to product review, and promote consistency across offices and centers.
• Advance regulatory science with dedicated workstreams for consideration of novel endpoints, biomarker development and assays, innovative trial design, real world evidence, and statistical methods.

4. There are four expedited review programs to help make drugs that fill unmet needs for serious conditions, of which many are rare, available as rapidly as possible. From 2015-2023, 88% of new drug and biologic approvals in CDER utilized at least one expedited program.

• Fast Track- Fast Track is a process designed to expedite the development and review of drugs intended to treat serious conditions and fill an unmet medical need. Benefits of having Fast Track designation may include more frequent meetings with FDA as well as the option for a “rolling review” (required parts of the marketing application come into FDA at different times).
• Breakthrough Therapy- Breakthrough Therapy designation is a process designed to expedite the development and review of drugs intended to treat a serious condition and for which preliminary clinical evidence may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). FDA provides intensive guidance on an effective drug development, organizational commitment involving senior managers, and the option for a “rolling review” under this program.
• Priority Review- A drug may qualify for priority review if the drug treats a serious condition and, if approved, would provide significant improvement in safety or effectiveness over available therapies. This designation allows for a shorter review timeline compared to standard review.
• Accelerated Approval- Accelerated approval allows earlier approval of drugs that treat serious conditions, provide meaningful advantage over available therapies, and demonstrate an effect on a surrogate endpoint (a measurement that is thought to predict clinical benefit, but is not itself a measure of clinical benefit). Sponsors must verify and confirm clinical benefit in post-approval clinical studies or confirmatory trials.

5. FDA continues to see an upward trajectory in the number and percentage of drugs approved to treat rare conditions or diseases.

"Novel" drugs are new drugs never before approved or marketed in the U.S. Certain drugs are classified as new molecular entities (NME) for purposes of FDA review.

More than half (28 of 55, or 51%) of CDER’s novel drug approvals in 2023 were approved to prevent, diagnose or treat a rare disease or condition. Examples include:

• The first treatment for Friedreich’s ataxia, an inherited, degenerative disease that damages the nervous system.
• The first treatment for activated phosphoinositide 3-kinase delta, a genetic disorder that impairs the immune system.

6. CDER recently established a new advisory committee to help FDA explore the complex issues related to genetic metabolic disease drug development.
In 2023, CDER announced the new Genetic Metabolic Diseases Advisory Committee (GeMDAC). Under the purview of CDER’s Division of Rare Diseases and Medical Genetics, genetic metabolic diseases are rare conditions that interfere with a person’s metabolism, that is the body’s ability to convert food into energy and remove waste and unhealthy substances. The GeMDAC will advise FDA on the safety and effectiveness of human drug and biological products under investigation or submitted for marketing approval for use in the treatment of genetic metabolic diseases. 

7. Under the ARC Program, CDER developed the Learning and Education to Advance and Empower Rare Disease Drug Developers (LEADER 3D) initiative to better understand the hurdles in bringing rare disease products to market.
As part of this initiative, RDT engaged with stakeholders who design and conduct rare disease clinical trials. The goal was to identify regulatory topics that could benefit from the development or expansion of educational materials and provide recommendations for continued educational efforts and outreach. From this engagement, which included focused interviews with the rare disease drug development community and a public docket, CDER released the LEADER 3D Public Report of External Stakeholder Analysis. 

Based on the LEADER 3D Public Report findings, RDT is now developing educational resources to address the challenges in bringing safe and effective drug and biological products to market for patients with rare diseases.

8. CDER partners with other FDA centers and offices on initiatives to help advance rare disease drug development, such as the Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program and the Rare Disease Endpoint Advancement (RDEA) Pilot Program.
CDER and CBER initiated the START Pilot Program with hopes that insights gained through this pilot will provide information on how best to facilitate more efficient development of potentially life-saving therapies for rare diseases, and will help sponsors generate high-quality, reliable data to support future new drug or biologics license applications. Selected participants will have access to frequent advice from FDA staff to address product-specific development issues, including clinical study design, choice of control group, and fine-tuning the choice of patient population. These increased interactions include addressing early development issues that may otherwise delay or prevent a promising novel product from progressing to the pivotal clinical trial stage and ensuring a clear understanding of the information and data needed to facilitate product development.

The RDEA Pilot Program is a joint CDER and CBER initiative that supports efficacy endpoint (or outcome) development and the timely approval of drugs and biological products that treat rare diseases, including rare diseases in children. The program is designed for drug developers with an active investigational new drug (IND) application or pre-IND stage for a rare disease. It is also intended for sponsors who do not yet have an active drug development program but have, or are starting, a natural history study where they intend to examine the proposed endpoint.

9. CDER partners with the Critical Path Institute (C-Path) under the ARC Program on several rare disease projects. These public-private partnerships connect various rare disease stakeholders such as advocacy groups, academics, drug developers, patients, and other partners, with the FDA to help identify solutions for challenges in rare disease drug development.

• The Lysosomal Diseases Consortium seeks to connect FDA, leading academic institutions, drug developers, patient groups, and non-government organizations to address unmet drug development needs for patients living with lysosomal diseases (inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies).
• The Critical Path for Rare Neurodegenerative Diseases aims to advance the understanding of neurodegenerative diseases, in addition to fostering the development of treatments for rare neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).

For more information about these projects and to find out how to get involved, please email cpld@c-path.org.

For more information about CDER’s rare disease work and the ARC Program, join the CDER Rare Disease News listserv.