An Evolving Regulatory Environment for Rare and Orphan Diseases

A rare, or orphan, disease by definition affects a small percentage of the population — fewer than 200,000 people in the U.S. But the numbers add up, and taken together, rare diseases impact an estimated 30 million Americans. Orphan drugs have historically faced a number of barriers, such as limited research and development (R&D) investment due to an expected lack of profitability as well as challenges in clinical trial design and recruitment. Before 1983, only 38 orphan drugs had received U.S. Food and Drug Administration (FDA) approval. Since then, the FDA has significantly changed its approach to rare and orphan diseases.

The FDA Since 1983

The Orphan Drug Act of 1983 was instrumental in changing the number of orphan drugs approved in the U.S. The law established the Office of Orphan Products Development, providing financial incentives for pharmaceutical companies to develop orphan drugs and making it more viable to invest in orphan drug research and development. The impact was clear: Between 1983 and 2020, FDA approved 599 orphan drugs.

Since 1983, the FDA has continued to expand its attention to rare diseases and the drugs treating them. In 2016, the FDA granted 333 (57%) of the 582 orphan drug designation requests it received – nearly 10 times the number of designations the agency awarded in 1986.

The agency’s 2019 guidance, Rare Diseases: Common Issues in Drug Development, called attention to the need for natural history studies for rare diseases. The guidance provided the agency’s thinking on the design and implementation of such studies. It also broadened eligibility for orphan drug clinical trials conducted to demonstrate safety and effectiveness of orphan drugs. Today, nearly a third of all pipeline drugs are indicated for rare diseases, and the FDA continues to provide public support for awareness programs, such as 2022 Rare Disease Day.

FDA Expedited Programs

While the Office of Orphan Products Development is responsible for reviewing applications and assigning orphan designations, it is not involved in a drug’s approval. That is part of the responsibility of the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER). These centers, in conjunction with the FDA and U.S. Department for Health and Human Services (DHHS), prepared guidance on expedited programs for sponsors of orphan drug trials.

Because most rare diseases are indeed “serious or life-threatening disorders with unmet medical needs,” orphan drugs may be able to take advantage of at least one of the FDA’s four expedited programs:

• Fast-track designation: Helps get drugs treating serious and life-threatening conditions to market as quickly as possible
• Breakthrough therapy designation: Gives priority review to therapies offering substantial advantages (based on early clinical trials) over existing options for patients with severe or life-threatening diseases
• Priority review designation: Indicates the FDA’s goal of taking action on the application within six months
• Accelerated approval: Allows drugs for serious conditions filling an unmet medical need to be approved based on “a surrogate endpoint”

Other FDA Orphan Disease Focus Areas

The FDA and the life sciences industry recognized the impact of the Orphan Drug Act and the advances in medicine over the past few decades. In order to support the continued need for rare disease drug development, the FDA took action to ensure they could continue to drive progress in this area. In 2017, the agency launched its Orphan Drug Modernization Plan, designed to help enable a “more efficient, scientifically advanced, predictable and modern approach to the approval of safe and effective treatments for rare diseases.”

In addition, the FDA funded the Rare Disease Cures Accelerator, which set out to facilitate cooperation and standardization to enhance the clinical trial process for rare diseases. This initiative includes a data analytics platform, RDCA-DAP. The platform aims to use standardized data to “inform rare disease characterization, clinical trial design and other critical questions in rare disease drug development.” By pulling together existing data and making that data available, RDCA-PAP seeks “to accelerate the regulatory approval of new therapies.”

A Lasting Impact

Through its various initiatives and programs, the FDA shows a demonstrated, increased effort in supporting the development of rare and orphan drugs. This is especially important as we consider roughly 90% of rare diseases have no approved treatment and orphan drug development takes 18% longer than the average time required for new drugs, according to the Tufts Center for the Study of Drug Development.

However, it remains important to plan and seek expert advice as early in the development process as possible. Partnering with experts with FDA and orphan drug experience is key to successfully navigating the regulatory environment for rare and orphan diseases.

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