Unlocking the Benefits of FDA’s Orphan Drug Designation

Securing an orphan drug designation is no small feat, in part because the number of patients affected cannot exceed 200,000 in the United States, despite population growth over 40 years.

Capone

The FDA’s Orphan Drug Designation (ODD) program provides incentives to sponsor organizations for the development of innovative treatments for rare diseases. Since its adoption in 1983, the Orphan Drug Act has helped countless individuals living with these conditions gain access to life-enhancing and life-saving therapies. The ODD program affords a variety of benefits to those who successfully apply; these benefits are aimed at incentivizing and streamlining the development of new drugs and biologics to manage orphan diseases. However, obtaining an ODD is not without its challenges.¹

What Is the FDA ODD?
ODD provides incentives such as tax credits, marketing exclusivity, fee waivers, and the opportunity to apply for grants to support clinical trials. It also gives sponsors access to specialized regulatory assistance from the FDA’s Office of Orphan Products Development (OOPD). This support can expedite the development process by providing guidance on how best to design clinical trials that meet regulatory approval requirements for drugs and biologics intended to manage a rare disease or condition.

The ODD itself is granted following FDA review of an application including evidence demonstrating potential efficacy of the drug through data obtained from nonclinical studies and/or clinical trials.

To qualify for an ODD, a drug or biologic must be intended to manage a rare disease, defined as a disease or condition affecting fewer than 200,000 individuals in the United States. Once an ODD has been granted, sponsors may be eligible for certain benefits such as tax credits for clinical trial or qualified clinical testing costs, a waiver of the Prescription Drug User Fee Act application fee when a marketing application is submitted, and the potential to receive 7 years of marketing exclusivity upon product approval.

How to Apply for ODD
The process of applying for an ODD is straightforward, although it requires detailed information about the drug or biologic being developed. Applicants must provide documentation establishing the product’s potential to manage a rare disease or condition. The application must include details on the proposed use of the product and other pertinent information, such as details surrounding the disease or condition; sufficient scientific rationale to show the drug or biologic demonstrates promise to manage, diagnose, or prevent the disease or condition; and a sufficient population estimate to show the disease or condition meets the definition of a rare disease.

Once submitted, applications are reviewed by the OOPD, which determines whether all criteria for ODD approval have been met.² Applications are reviewed by the OOPD within 90 days of receipt.

Common Challenges With Gaining ODD Status
Although the process of applying for ODD status is straightforward, there are issues creating challenges for sponsors.

Proving rare disease status. Demonstrating the disease or condition meets the definition of a rare disease requires proving its prevalence in fewer than 200,000 individuals in the United States. Current epidemiological studies aren’t always available to cite, in which case companies may have to justify their estimates based on existing data and projections about the incidence of new cases, life expectancy, etc. Although perhaps frustrating, companies may not cite recent FDA designations granted to other products for the same indication, because the FDA requires every application to include an independent prevalence analysis.

Providing appropriate evidence. This may be especially difficult for some indications. Although clinical evidence is preferred, companies can use nonclinical evidence to satisfy this requirement. The FDA prefers to see a positive effect of the drug in an appropriate animal model of the disease; however, valid animal models for some rare diseases do not exist, making demonstration of potential benefit challenging prior to availability of clinical data.

Outside of obtaining the ODD, there are also challenges in doing the required studies for approval. By the very nature of rare diseases, there are not large numbers of patients available to enroll in clinical trials. If there are several drug development programs underway targeting the same indication, competition for patients can create a significant hurdle. The same approval standard applies to orphan drugs and nonorphan drugs (ie, demonstration of substantial evidence of effectiveness with an acceptable safety profile). Although the FDA does work with sponsors regarding acceptable drug development programs for orphan drugs, the ability to enroll appropriate numbers of patients in clinical trials within a reasonable time frame can be a challenge.

The Bottom Line
US regulations have maintained a prevalence of fewer than 200,000 individuals as the definition of a rare disease³ since the Orphan Drug Act was signed into law approximately 40 years ago. However, during that time, our nation’s population has grown by more than 100 million individuals, meaning some diseases that met the statutory definition of rare in 1983 may no longer qualify today.⁴ The European Union has addressed this issue by basing its definition of a rare disease on prevalence per 10,000 population. A change to this approach in the United States could increase the number of diseases, and thus treatments, eligible for ODD. In the meantime, US companies need to work within the status quo and remain steadfast in their goal of bringing life-enhancing and life-saving drugs and biologics to market for those living with rare diseases. 

Author Information
Rachel Capone, MSHS, is a regulatory affairs manager at Syner-G BioPharma Group.

References
1. Designating an orphan product: drugs and biological products. FDA. Updated July 8, 2022. Accessed August 21, 2023. https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products
2. Frequently asked questions. Center for Drug Evaluation and Research NextGen Portal. Accessed August 21, 2023. https://cdernextgenportal.fda.gov/CDER_FAQ_Page
3. Wainstock D, Katz A. Advancing rare disease policy in Latin America: a call to action. Lancet Reg Health Am. 2023;18:100434. doi:10.1016/j.lana.2023.100434
4. Historical population change (1910-2020). US Census Bureau. April 26, 2021. Accessed August 21, 2023. https://www.census.gov/data/tables/time-series/dec/popchange-data-text.html