Gilbert J. Burckart

Pediatric developmental safety assessment presents distinct challenges in drug development. Children undergo dynamic changes in organ systems and drug disposition pathways during development, and drug‐related effects may be delayed or manifested differently than in adults. Pharmacovigilance data, primarily from adults, is not always predictive of the response in children. Historically, juvenile animal studies have been used for nonclinical pediatric drug safety assessments exclusively, but the reduction in animal testing is a goal of public health agencies. To address this concern, the Office of Clinical Pharmacology at the U.S. FDA and the Triangle CERSI (Center of Excellence in Regulatory Science and Innovation) convened a workshop entitled: “Pediatric Developmental Safety Assessment and New Approach Methodologies (NAMs),” attended by experts from regulatory agencies, academia, and industry. Discussions focused on three overarching topics: (i) Secondary Pharmacology Screening Tools for Assessing Pediatric Developmental Safety; (ii) Non‐clinical Tools for Pediatric Developmental Safety Assessment; and (iii) Computational and Data‐Driven Tools for Pediatric Developmental Safety. These topics were examined within the framework of the S11 Nonclinical Safety Testing In Support of Development of Pediatric Pharmaceuticals and E11A Pediatric Extrapolation guidances, which promote structured, question‐based pediatric extrapolation in drug development and authorization. The workshop concluded that NAMs hold considerable promise to advance the assessment of pediatric drug developmental safety.

Drug safety in pediatric patients has always been a concern. Major tragedies with drugs in pediatric patients created an environment of caution, but the experience with pediatric legislation and drug development over the past 20 years has eased the cautionary approach to pediatric drug safety. The advent of new methods of safety testing, driven by the movement away from animal use in research, provides new opportunities to screen for and prevent adverse developmental effects of drugs on pediatric patients. One approach that can be explored for use in pediatric developmental safety testing is secondary pharmacology, or screening for off‐target drug effects. Secondary pharmacology, which is an established screening mechanism described in ICH S7A, could provide the opportunity to answer important off‐target questions. Examples of 12 specific secondary pharmacology targets related to adverse effects on pediatric development are provided. Clinical pharmacology plays a critical role in the interpretation of secondary pharmacology through quantitative studies necessary to validate positive findings and through the final assessment of the risk:benefit associated with these findings. In conclusion, secondary pharmacology screening has the potential to reduce animal testing while addressing two critical objectives: screening drugs for off‐target effects and providing information on off‐target effects relevant to pediatric developmental safety.

Background and Objectives Lagging pediatric safety and effectiveness data increase the risks to children associated with off-label drug use. The objective of this study was to delineate the frequency of, and reasons behind, delays in the completion of mandated pediatric postmarketing requirement (PMR) studies. Methods Publicly accessible and internal US Food and Drug Administration (FDA) data were aggregated to characterize pediatric PMRs issued from 2012 to 2024, including relevant dates, durations, and deferral extension (DE) requests. Sponsor size, and clinical trial enrollment status were also examined. Results There were 1160 pediatric PMRs identified, 459 of which were associated with 1176 DE requests. Despite a significant decline in the annual number of PMRs issued (slope [95% confidence interval]: − 3.64 [− 6.50, − 0.79] year⁻¹, p = 0.02), an increase in the annual number of DE requests (5.24 [2.16, 8.31] year⁻¹, p < 0.01) was observed. Declines in negotiated timelines for PMR completion and durations of time granted per request were also seen. Issues related to clinical trial conduct predominated DE rationale in every year and accounted for 48% of all requests. One in 10 delayed trials failed to initiate enrollment before the PMR due date and 1 in 5 cited problems with clinical trial conduct before enrollment began. Smaller companies (< 500 employees) exhibited higher DE request rates, lower PMR success rates, and accounted for an increasing proportion of PMRs over the review period (from 17% in 2012 to 72% in 2024). Conclusions Year-on-year increases in DE requests reinforce ongoing challenges to timely and successful pediatric trial completion. Difficulties with clinical trial conduct appear to be the primary driver for these delays although the underlying root causes have yet to be elucidated. Regulators, sponsors, and stakeholder partners should work cooperatively to remediate delayed pediatric drug development timelines and reduce the duration of off-label drug use in children.

Challenges to medication administration arise in children when pediatric-friendly (PF) formulations are lacking. This study examines the extent to which PF formulations were developed for use in pediatric trials of drugs awarded 6-months of patent extension under a written request (WR). Publicly accessible and proprietary data were aggregated to characterize the formulations used in studies submitted to the U.S. FDA in support of pediatric labeling for WRs issued through September 2025. From 1998-2025, exclusivity was awarded to 321 unique sponsor:drug pairs satisfying the requirements of a WR. A majority, (235/321), received a new or updated pediatric indication and nearly all (310/321) resulted in pediatric labeling. Drugs intended for oral administration (n = 213) were supported by 304 studies. The majority (173/304) exclusively studied adult solid dosage forms (SDF), a minority (129/304) used at least one PF dosage form, and 2 accomplished labeling without the conduct of clinical trials. SDF were exclusively used in 26.3%, 44.9%, 85.1%, and 94.1% of studies in children < 2 yr, 2-5 yr, 6-12 yr and > 12 yr, respectively. Of trials employing an oral PF formulation, 85% were associated with a marketed PF product at labeling. Marketed oral PF formulations were also associated with 8% of cases where studies relied exclusively on a s SDF. Nearly all non-enteral drug studies were supported by existing commercial formulations with only investigational inhalation formulations making their way to market. Legislative provisions enacted to incentivize pediatric drug development incompletely extend to pediatric reformulation efforts despite the associated financial gains.

In February of 2024, the Product Quality Research Institute held a virtual workshop entitled “Model-Informed Drug Development (MIDD) Approaches in Pediatric Formulation Development.” The workshop covered a range of topics related to pediatric formulation development and testing, including dissolution testing and applications to modeling drug absorption in developing pediatric patients. Workshop speakers reviewed the progress that has been made to advance our understanding of ontogeny related processes that drive interactions with product formulations and inform pediatric product development. They discussed recently constructed pediatric biorelevant models that provide more realistic information about drug dissolution in pediatric patients and their use in physiologically based models to produce data for regulatory submissions. Despite the progress, opportunities remain to expand the fund of knowledge on pediatric absorptive processes that will support the development of pediatric-friendly drug formulations. Graphical Abstract