Reconciling sprinkle administration information in approved NDA labeling with sprinkle bioequivalence study recommendations in FDA product-specific guidances for generic drug development

Abstract

Objectives: Certain patient populations (e.g., children and the elderly) may not be able to swallow solid oral dosage forms. In the absence of availability of a dosage form that is appropriate for these patient groups, liquids and/ or soft foods as described in the Food and Drug Administration (FDA)-approved product labeling can be used as a suitable vehicle(s) for oral administration of the specific drug product. The approved labeling of some new drug application (NDA) products contains information for sprinkle administration on liquids or soft foods. Since abbreviated new drug application (ANDA) products must demonstrate bioequivalence (BE) to the reference listed drug (RLD) products, and since the generic drug labeling is the same as RLD, generic applicants are recommended to conduct in vivo BE sprinkle study using one of the soft foods mentioned in RLD labeling. The current FDA guidance specifically recommends that generic applicants conduct a sprinkle BE study if the labeling of a modified-release (MR) RLD product states that the product can be administered sprinkled on soft foods. For ANDAs, such recommendations for in vivo BE sprinkle studies for MR products are routinely communicated in the respective product-specific guidance (PSG) published by FDA and readily available for prospective ANDA applicants. FDA guidance does not recommend sprinkle BE study for an immediate-release (IR) product since the formulation differences between IR generic and RLD products are not expected to impact administration with food vehicle. Materials and Methods: FDALabel and PSG databases were searched for current NDAs with sprinkle labeling and individual PSGs with recommendations for an in vivo sprinkle BE study, respectively. Results from FDALabel were narrowed to NDAs for oral solid dosage forms with approved labeling for sprinkle administration on food vehicles. Only MR NDAs with sprinkle labeling were included in the final analysis as recommended by FDA for inclusion of in vivo sprinkle BE study recommendations in PSGs for generic products. We searched the FDA external PSG database for availability of respective PSGs containing in vivo sprinkle study recommendations for those MR products with approved NDA labeling for sprinkle administration. Results: Of the 57 NDAs with FDA-approved drug products that are labeled to include sprinkle administration, 45 NDAs were MR (tablet, capsule, and granule) products. Forty-two (93%) of the 45 MR products have PSGs with in vivo sprinkle BE study recommendations. Standardized data extraction sheets created by Microsoft Excel 2019 for data extraction were utilized. Conclusion: FDA has a sprinkle-study PSG for almost all currently approved MR NDAs. The results of our study show that in vivo BE study recommendations in PSGs closely match information in the approved drug labeling. Applicants who plan to develop MR generic products should visit the FDA public web page for the availability of the product-specific BE recommendations for the proposed products.