Date of Award

January 2024

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Reshma Ramachandran

Abstract

Hypothesis: The Food and Drug Administration (FDA) Amendments Act of 2007 (FDAAA) had an effect on drug safety, as measured by number and timing of postmarket safety-related actions (PMAs) and drug incentivization, measured by the number of therapies entering and progressing through clinical trial stages.

Introduction: FDAAA expanded the FDA's authority in drug safety, including allowing the FDA to mandate postmarketing requirements (PMRs) and better surveil therapies in the postmarket period, and incentivization, through the Priority Review Voucher (PRV) program. This study evaluates FDAAA’s impact on the number and timing of PMAs and its effectiveness in stimulating drug development for PRV-eligible neglected tropical and rare pediatric diseases.

Methods: Public data from the FDA and clinical trial databases were analyzed. Therapeutics approved between 2001–2019 were categorized as pre- or post-FDAAA and classified according to drug and regulatory characteristics. Safety actions (e.g., boxed warnings, drug safety communications, withdrawals). PRV-related trends in clinical trial progression, voucher transactions, and associated therapeutic revenues were examined using Kaplan-Meier analysis and multivariate regression models.

Results: Among 560 novel therapeutics, 23.2% experienced PMAs during a median follow-up of 12.1 years. Post-FDAAA, the time to first PMA shortened significantly (2.1 vs. 4.6 years, p=0.0002). Therapies with FDAAA-mandated PMRs were significantly more likely to experience safety actions in multivariate analysis (p=0.02). Orphan-designated drugs were associated with reduced likelihood of a PMA, while accelerated approvals correlated with higher rates of PMAs. Voucher sale values remained stable (median $105M) and were mostly awarded to smaller pharmaceutical companies. The PRV program was associated with faster progression of rare pediatric disease therapies through clinical phases post-implementation but did not significantly change the percentage of therapies entering clinical trials for neglected tropical diseases.

Discussion: FDAAA improved the FDA's capacity to address postmarket safety risks earlier but did not alter overall PMA rates. The PRV program showed mixed success, accelerating rare pediatric drug development but less effectively stimulating neglected disease therapies. Future efforts should refine regulatory tools to enhance safety monitoring and incentivize equitable therapeutic development.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/14/2027

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