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P111: Confirmatory Evidence of Effectiveness Used to Support Non-Oncologic Rare Disease Novel Drug Marketing Application Approvals

Poster Presenter

Bridget Nugent

Science Policy Analyst
FDA
United States

Objectives

To understand how confirmatory evidence (CE) of effectiveness is used to support rare disease drug approval, we categorized CE in approved new molecular entity (NME) new drug applications (NDAs) and original biologics license applications (BLAs) in the Center for Drug Evaluation and Research (CDER).

Method

CE information for non-oncologic NMEs approved in CDER from 2020-2023 was manually extracted from FDA review documents by at least two researchers and categorized based on the FDA’s 2023 draft CE guidance. FDA review divisions were consulted as needed for data verification.

Results

For an NME to be approved for marketing under an NDA or BLA, data must demonstrate that the product is both safe and effective. FDA requires that substantial evidence of effectiveness (SEE) is demonstrated for the approval of marketing applications. In cases where it may not be possible to conduct multiple adequate and well-controlled (AWC) trials, CE may also be considered to assess effectiveness in addition to one AWC trial. In September 2023, FDA issued a draft guidance on Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence. Categories of CE in this analysis were based on those described in this draft guidance, including: clinical evidence from a related indication, mechanistic or pharmacodynamic evidence, evidence from a relevant animal model, evidence from other members of the same pharmacologic class, natural history evidence, and evidence from expanded access use of an investigational drug. Utilizing FDA’s internal Data Analysis Search Host (DASH) database, we compiled information from 103 rare disease marketing applications for therapeutic NMEs approved by FDA’s Center for Drug Evaluation and Research (CDER) between January 1, 2020 through December 31, 2023. To focus our analysis on non-oncologic rare disease approvals, we excluded 43 products approved by CDER’s Office of Oncologic Disease. Only 13% (8/60) of non-oncologic rare disease NME approvals utilized 2 or more AWC trials to meet FDA’s statutory requirement for SEE. By comparison, 71% (49/69) of non-oncologic NMEs approved during the same time period for common diseases utilized 2 or more AWC trials to demonstrate SEE. The most commonly used category of CE supporting rare disease marketing applications with 1 AWC was mechanistic or pharmacodynamic evidence. Notably, many approvals utilized multiple CE types to demonstrate SEE.

Conclusion

There are 7,000 to 10,000 rare diseases (defined as impacting < 200,000 people in the US) affecting 30 million people nationwide. From 2020-2023, almost half of all non-oncologic NME approvals were for rare diseases. However, rare disease drug development often remains challenging due to limited understanding of disease biology, disease heterogeneity, and small patient populations, among other factors. The findings of this study show that 1 AWC trial plus CE is the most commonly used approach to demonstrate effectiveness of non-oncologic rare disease drug products. The type and quantity of CE needed in a development program is impacted by the features and results of the AWC trial that the CE is intended to substantiate. Mechanistic or pharmacodynamic evidence is frequently used as CE in recent non-oncologic rare disease NME approvals. This finding highlights the importance of strong basic and translational research to bolster clinical research programs for rare diseases. These results build a foundation for future regulatory research that can contribute to better transparency, understanding, and communication of CE used in rare disease drug development. In addition, insight from this analysis may facilitate FDA’s review of CE data in rare disease drug development programs.