Resident University of California, San Francisco, School of Medicine San Francisco, California, United States
Background: The turn of the 21st century came with a series of legislative efforts to address the unavoidable off-label use of drugs in pediatric populations. These policies oscillated between serial, sometime simultaneous, incentivized versus mandated approaches to increase pediatric labeling of drugs and the number of pediatric clinical trials. Objective: Here, I investigate the historical evolution of these two approaches and how they have shaped the current state and future needs to advance equity in pediatric drug trials. Design/Methods: First, I compare the voluntary approach of the Food and Drug Administration Modernization Act (FDAMA) of 1997 to the mandated approach of the proposed Pediatric Rule of 1997, including the lawsuit leading to the latter’s invalidation. Next, I compare the outcomes in pediatric drug labeling between the Best Pharmaceuticals for Children Act (BPCA) of 2003 and the Pediatric Research Equity Act (PREA) of 2003. Finally, I discuss the performance of mandated pediatric clinical trials following PREA and current legislation. Results: Initial policies in the 20th century were focused on increasing the labeling of pediatric indications for drugs. The FDAMA of 1997 from Congress, later reauthorized as the BPCA of 2003, financially incentivized the voluntary inclusion of pediatric patients in trials. The FDA, on the other hand, proposed the Pediatric Rule in 1997 which would have mandated up-front data for assessing safety and efficacy in pediatric patients and pediatric-specific dosing regimens for all new drug applications. However, this was invalidated in federal court in 2002 following a lawsuit citing an overstep in authority. Instead, the PREA of 2003 allowed for mandatory pediatric assessment for new indications, labeling or formulations of drugs approved for adult diseases. As of March 2024, BPCA alone has led to 221 pediatric labeling changes versus the 709 labeling changes from the PREA alone. Though these data would suggest that a more regulated legislative approach is more effective, a 2019 study by Hwang et al found that only ~34% (75 of 222) of drugs that required pediatric post-market clinical trials under PREA had been completed in a ~7-year period.
Conclusion(s): Federal policies at the end of the 20th century aimed to accelerate equity in drug safety and efficacy for pediatric diseases. More recent legislation has moved towards more mandatory, regulated policies that have increased pediatric drug labeling but may require more oversight to ensure compliance of mandatory pediatric clinical trials to address the issues of pediatric off-label drug use.
