025: Pediatric Drug Development Programs for Locally Acting Drug-Device Combination Products

Statement of Purpose, Innovation or Hypothesis: Pediatric drug-device combination products pose a unique challenge to pediatric drug development. While regulatory guidelines require sponsors to consider age-appropriate formulations, there are currently no requirements for the development of age-appropriate delivery devices despite the need to ensure that an adequate amount of drug is delivered. In this study, pediatric drug development programs for locally acting drug-device combination products were systematically reviewed to gain a better understanding of the pediatric drug development of these products.
Description of Methods and Materials: FDA’s public pediatric labeling site was used to establish a database of locally acting drugs (LADs) with pediatric labeling approved by the FDA between 01/2002 to 12/2020. LADs were defined as those with minimal systemic absorption and whose mechanism of action occurred at the site of drug administration. A sub-analysis of LAD-device combination products was performed for this study from a previously conducted survey of LADs. Each pediatric labeling update for the selected drug-device combination products in the pediatric labeling database was captured as a submission. When the different indications and/or age groups had different dosing regimens within one labeling update, they were captured as separate submissions to aid with categorization. Information extracted for each drug included therapeutic indications, labeled pediatric and adult doses, studied pediatric doses, and other characteristics of the pediatric study programs such as the number and type of pediatric clinical studies and utilization of extrapolation of efficacy. Definitions for categorization of the labeled dose are provided in Table 1. When assessing the characteristics of the pediatric programs, submissions with pediatric approvals based on extrapolation of efficacy from adult findings, literature reviews or adult bioequivalence studies that did not have any pediatric clinical programs were excluded from these analyses.
Data and

Results: A total of 137 drug products approved for pediatrics between January 2002 and December 2020 that met the definition of LADs were identified, out of which, 31 were considered drug-device combination products. These included 61% inhalation (19/31), 26% nasal (8/31) and 13% vaginal and intrauterine devices (4/31). For these products, a total of 54 pediatric submissions were identified. The labeled pediatric dose was the same as adult dose (SAAD) in 54% (29/54) of submissions and the labeled pediatric dose for 81% (44/54) submissions was supported by independent PD/efficacy studies in pediatric patient. 73% of submissions had three or more pediatric clinical trials with some inhalation drug-device combination product submissions having up to eleven pediatric clinical trials per submission. Sixty-nine percent of submissions (34/49) studied more than one dose and/or dosing regimen in the pediatric studies. Extrapolation of efficacy approach was only utilized in 28% (15/54) of submissions. In comparison, the labeled pediatric dose for non-device LADs was SAAD in 74% (99/133) of submissions, and the labeled pediatric dose was supported by independent PD/efficacy studies in 57% (76/133) of submissions. Seventy-Five percent (82/110) of non-device LAD submissions studied only one dose and/or dosing regimen, 77% (85/110) of submissions had up to three pediatric clinical trials, and 45% (49/110) of submissions utilized extrapolation of efficacy.
Interpretation, Conclusion or Significance: This work showcases that pediatric programs for locally acting drug-device products are characterized by relatively large sized pediatric clinical programs, low utilization of extrapolation of efficacy and increased use of PD/efficacy studies to support the labeled pediatric dose.