In a landmark move, in December 2023, the U.S. Food and Drug Administration (FDA) released a detailed guidance document titled “Rare Diseases: Considerations for the Development of Drugs and Biological Products.” The FDA guidance document is a significant stride towards addressing the complexities and challenges of developing rare disease treatments. This is a final version of a draft guidance issued in February 2019. The agency says it has decided “to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate standards of safety and effectiveness, for products that are being developed to treat severely debilitating or life-threatening (SDLT) rare diseases.” For these products, FDA adds, “clinical investigations can often proceed with modifications to the typical nonclinical development programs described in the guidance.”

Key Highlights of the FDA Guidance:

• Enhanced Patient and Caregiver Input: Recognizing the critical role of patient experiences, the guidance emphasizes the inclusion of patient and caregiver perspectives, particularly in understanding disease impact and treatment effectiveness. “Patient input can provide important information about patients’ experiences, perspectives, needs, and priorities that can be incorporated throughout the drug development process. This engagement can take many forms, such as providing solicited consultation on scientific issues (e.g., clinically meaningful treatment effects), working with industry sponsors as they design and conduct clinical investigations, and contributing to patient-focused drug development initiatives,” the agency wrote.
• Pediatric Considerations: Special attention is given to pediatric populations, acknowledging the distinct needs and challenges in developing treatments for children with rare diseases. FDA “strongly encourages” sponsors to study the drug in all relevant pediatric populations, from birth to age 17, and to develop pediatric formulations of drugs to allow for accurate dosing for the youngest patients. In cases where clinical studies include pediatric and adult participants, FDA advised sponsors to consider the relevance of endpoints to both groups and assess whether results could be combined in a single statistical analysis.
• External Controls and Prevalence Estimates: The guidance discusses the potential of using external controls in clinical investigations for rare diseases with unmet medical needs. However, due to inherent limitations like lack of blinding, such designs are advised for situations where the drug effect is unmistakably large or in diseases with a well-understood natural history.
• Disease Prevalence Estimation: Accurate disease prevalence estimation is crucial for determining adequate study enrollment. Prevalence estimates should encompass all phenotypic subtypes anticipated to respond to the investigational drugs.
• Flexibility in Clinical Trial Design: The FDA recognizes the unique challenges in rare disease drug development and suggests flexibility in trial design while maintaining the integrity and scientific validity of the studies.
• Safety and Effectiveness Standards: The document underscores the same evidence standards for establishing safety and effectiveness for both rare and common diseases.
• Natural History Considerations: Despite eliminating a section on natural history studies, the guidance acknowledges their importance in understanding disease progression and assisting in trial design.

Notably, the guidance reflects a significant shift towards more patient-focused, innovative approaches in drug development. This movement by the agency will hopefully spur continued innovation in rare disease drug development, hopefully benefiting mitochondrial patients in the future.