How FDA Is Working to Accelerate Rare Disease Treatments

More than 7,000 rare diseases directly affect more than 30 million patients in the U.S. Although each rare disease, as defined by the Orphan Drug Act of 1983, affects fewer than 200,000 individuals in the U.S., or about one in 10, their effects can be devastating, and the path to diagnosis is often long. In some cases, it can take as many as five or more years to diagnose a rare disease, and the process can involve multiple specialists. This is because for each rare disease, the patient pool is small and symptoms can be confused with other conditions. Today, it is estimated that one in 13 of those with rare diseases remain undiagnosed, and most rare diseases, at present, have no approved U.S. Food and Drug Administration (FDA) treatment.¹

Efforts to advance treatment innovations for rare diseases, however, are producing exciting collaborations and discoveries. Led by the FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER), FDA works with external collaborators such as the National Organization for Rare Disorders and others to further understanding of not only the biology and etiology of rare diseases but therapeutics that may provide the greatest benefit. 

These efforts have led to more than 800 investigational new drug (IND) applications submitted to FDA for cell and gene therapy products. As recently as December 2023, two cell-based gene therapies, Casgevy and Lyfgenia, were approved to treat sickle cell disease in patients 12 years and older.¹

On the pharma side, CDER’s Accelerating Rare disease Cures (ARC) program, launched in May 2022, is managed by CDER’s Rare Disease Team and is a collaborative effort within CDER that brings together CBER, the Center for Devices and Radiological Health and other offices within FDA. ARC provides strategic overview of the center’s rare disease initiatives and activities, and by May 2023, had approved 22 new rare disease drugs. Combined, CBER and CDER have approved more than 550 unique drugs and biologics for over 1,100 rare diseases. Yet, even with these exciting numbers, the majority of rare diseases have no available treatments.² 

Regulatory Pathways for Rare Disease Products

FDA supports numerous initiatives in the quest to develop treatments for rare diseases. It works collaboratively with internal and external stakeholders to exchange scientific and regulatory information pertaining to disease states and the latest research. One example of this collaboration is CBER’s Office of Therapeutic Products (OTP) that works with investigational product sponsors to provide input on chemistry, manufacturing and controls, preclinical study design and clinical development. Another example is the Orphan Drug Grants Program, which helps to fund clinical investigators researching safe and effective orphan drug products used to treat rare diseases. Since the Orphan Drug Act was enacted in 1983, 40 percent of novel drug approvals are for treatments of rare diseases.²

From a review and approval perspective, product applications for rare diseases receive the same scrutiny as products used to treat other conditions. FDA will consider whether a drug is safe for its intended use and if the benefits to the population outweigh the risks. According to FDA, “Rare diseases are highly diverse, and the scientific considerations in specific diseases are unique and require case-by-case considerations for the particular development program at issue such as the natural history, the defined pathophysiology, the mechanism of action and other aspects of the disease or product. As such, no one program can be designed exactly like another. FDA is committed to helping sponsors create successful drug development programs that address the particular challenges posed by each disease and encourages sponsors to engage early with the agency to discuss their drug development program.”³

Post-market reviews are often lengthier for rare disease therapies, particularly for biologics. This lengthier surveillance is needed to evaluate any possible risks associated with gene and cellular therapy such as genetic mutations and immune reactions that may lead to rejection. One example of gene therapies with a lengthier post-approval monitoring requirement is those that use integrating viral vectors, which call for 15 years of patient monitoring.⁴

CBER reviews INDs and biologics license applications (BLA) using regulatory approval pathways of BLAs, premarket approvals, new drug applications and 510(k)s for medical devices. FDA may also award priority reviews to sponsors of rare pediatric disease product applications in cases in which sponsors had earlier product approvals in the same category. 

Patient Engagement to Inform Investigators 

Engaging patients, caregivers and other non-industry stakeholders helps FDA determine desirable treatment outcomes for specific conditions like rare diseases. As part of the 2016 21st Century Cures Act, the 2022 Food and Drug Omnibus Reform Act and the Prescription Drug User Fee Act (PDUFA) VI (in 2017) and VII (2022), FDA encourages communications through many public meetings through a number of forums. (A listing of upcoming meetings and transcripts of past meetings is found on FDA’s website.) These perspectives are captured and incorporated as FDA considers sponsor drug development and evaluation.

Patients Ask FDA is a web-based central entry point for patients and advocates to submit inquiries and meeting requests to enable FDA’s understanding of patient experiences and determine how patients define their own meaningful change outcomes so that treatments can be best balanced with risks. 

OTP hosts virtual educational sessions on regenerative medicine, called RegenMedEd, bringing together patients, caregivers, patient advocates, FDA staff, researchers and other experts to discuss regenerative medicine therapies, including gene and cell therapies, to explore opportunities for stakeholders to work together to advance research and development of promising products.

CDER’s Rare Disease Team has also launched the Learning and Education to Advance and Empower Rare Disease Drug Developers, LEADER 3D, Initiative. Under LEADER 3D, input from stakeholders who design and conduct rare disease drug development programs is obtained and used to identify knowledge gaps related to regulatory considerations for rare disease drug development.

Information on efforts in rare disease research can be found on the ARC website and in the ARC program quarterly newsletter. This aggregated listing of resources is easily searchable with links to FDA guidances for rare disease drug development (searchable by topic area) and upcoming and recent events relevant to rare disease topics (e.g., workshops and webinars), including the recently added recording of panel 4 of FDA’s Rare Disease Day that took place on March 1, 2024.⁵

Additionally, Patient Listening Sessions are small, informal, nonregulatory, nonpublic meetings between patients and FDA that focus on patient experiences, perspectives and needs related to their health or a disease. These are particularly helpful in the case of understanding rare diseases, in which both patients’ experiences and priorities are less understood. These sessions have informed FDA meetings with medical product developers (though FDA is clear that the sessions are not about specific medical products) and, along with other supporting information, have provided therapeutic context for medical product reviews.

In one such example, in an October 2018 Patient Listening Session, CBER learned of specific thoughts and concerns of patients with hemophilia regarding participating in gene therapy clinical trials. Their input helped to shape the agenda for the “Product Development in Hemophilia” public workshop.³

Challenges in Rare Disease Product Development

By some estimates, the orphan drug market is growing at 11 percent annually, compared to a six percent growth in the non-orphan drug market.⁶ Yet, when it comes to drug design for rare disease therapeutics, establishing endpoints can be challenging. With phenotypic and genotypic diversity of these diseases, they can be difficult to accurately diagnose, and finding investigators who are able to commit resources to drug development is also challenging. 

Rare disease advocacy groups play a role in advancing the development of therapies for rare diseases through research support and coordination in patient-focused drug development and Patient Listening Sessions, and they may also collaborate with sponsors to help with clinical trial recruitment. In fact, FDA finds that many patient advocacy groups for rare diseases are adept at developing contacts and relationships with researchers whose research may be an eventual inroad toward a needed therapy. That being said, FDA also acknowledges that not all rare diseases have well-established advocacy groups, particularly those affecting very small numbers of individuals. Therefore, FDA strives to engage with all rare disease advocacy groups in a variety of ways.³

Rare disease drug developers may benefit from additional programs that have the potential to contribute to regulatory knowledge, practice or methodology for clinical studies to benefit rare disease drug development programs. Examples of these programs include:

Complex Innovative Trial Design Paired Meeting Program: This program is designed to facilitate the use of complex innovative design approaches with an emphasis in late-stage drug development. It promotes innovation by allowing FDA to publicly discuss the trial designs accepted by the paired meeting program, including trial designs for medical products that have not yet been approved by FDA. The application of these innovative methodologies in clinical studies for small populations is of particular interest for rare diseases.

Rare Disease Endpoint Advancement Pilot Program: This program is a joint CBER and CDER pilot program with PDUFA VII commitment mandated under the Food and Drug Omnibus Reform Act of 2022 that supports novel endpoint efficacy development for drugs and biologics that treat rare diseases by providing a mechanism for sponsors whose proposals are admitted to the pilot to collaborate with FDA throughout the efficacy endpoint development process.

Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program: This program gives a limited number of sponsors the opportunity for more frequent communication with FDA regarding clinical development issues. 

On a global scale, FDA is also supporting work toward a global regulatory convergence and ultimately global harmonization of regulations for products to treat rare diseases. Although still in the planning stages, the Collaboration on the Gene Therapies Global Pilot (CoGenT Global) would be a collaboration with international partners, global regulators and the World Health Organization in which a concurrent collaborative application review could potentially be established.³ 

Helping Patients Identify Clinical Trials

Patient participation in clinical research helps to inform and prioritize development of new therapies, including determining desired treatment outcomes and acceptable risks. Prior to COVID-19, the small patient pool of those with rare diseases made clinical trials challenging, particularly with the geographic spread of potential study participants. The pandemic, however, further and severely limited patients’ ability to access study centers. 

Although FDA does not itself conduct trials, it’s webpage Clinical Trials: What Patients Need to Know includes a searchable database of available trials by medical condition or intervention. It also includes patient-centric information on informed consent, diversity in clinical trial participation and the differences between clinical research and medical treatments.⁷ Providers can help patients identify potentially appropriate studies through this webpage, as well as through engagement with patient advocacy organizations.

Looking ahead, technological innovations such as wearables that allow for remote data collection may enable participation from a geographically diverse population. That data could be used to complement assessments of a drug’s positive or negative effect. Transportation assistance services to study sites might also be an important factor in patient recruitment, particularly for those who live a greater distance away.