Neonatal drug development addressed in FDA final guidance

The US Food and Drug Administration (FDA) issued final guidance this week to assist sponsors in developing clinical pharmacology studies for neonatal populations. The guidance is meant to address gaps in neonatal labeling and encourage the development of therapies that are “unique to neonates.”

The guidance is tailored to sponsors developing these studies for investigational new drug applications (INDs), new drug applications (NDAs), biologics license applications (BLAs) and supplements to those applications.

The guidance revises a draft version issued in August 2019. Changes include adding immunogenicity as a factor to consider when designing these studies, providing additional information on total volume to be administered for parenteral formulations, and clarification on using microsampling methodology.

“Given that most drugs used in neonatal intensive care units (NICUs) are used off-label, it is important that drug information be obtained in neonates to address gaps in neonatal labeling,” states the guidance.”

The guidance builds on legislative efforts to boost incentives for pediatric drug studies under the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA), which were made permanent under Title V of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA).

At the request of Pfizer, the guidance adds a new section on immunogenicity testing. “We suggest that agency consider adding a section of immunogenicity for biologics, including a discussion that immune system and its response may vary over the state of development, particularly for preterm neonates.”

The guidance states that “immunogenicity to certain products (e.g., therapeutic proteins, peptides, oligonucleotides) can negatively impact the PK, PD, safety, and/or efficacy of the drug. The immune response in the neonatal period can differ from that of adults or older children; furthermore, how these differences affect the immunogenicity risk is not fully understood. Therefore, the immunogenicity of a drug should be assessed in neonatal trials regardless of the knowledge gained in adults and older children.”

The final version also provides additional information on total volume to be administered for parenteral formulations. “Consideration should be given to the total volume for parenteral formulations to be administered, as the total intake volume may be limited and should also take into account the volume already received through parenteral nutrition and other standard-of-care drugs,” said the guidance.

It further states that formulations should be developed to permit accurate dosing, and “studies of drugs in neonates should account for and capture information on potential interactions with tubing used for both parenteral and enteral administration and any potential interactions with co-administered fluids (including parenteral nutrition), enteral nutrition, and other therapeutic products.”

The final version also revises the section on bioanalytical methods by adding details on using microsampling methodology.

The final version has revised that portion to read: “Standardized sample collection, and validated methods can reduce the number of limitations associated with the biomatrix. Before use in a neonatal pharmacokinetic assessment, the sponsors should account for any bias in concentration measurements of the microsampling methodology compared to those from a traditional sampling approach (e.g., plasma concentrations) that might have been used during the drug development in adults.”

Final guidance

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Neonatal drug development addressed in FDA final guidance

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