Regulatory Considerations for the Mother, Fetus and Neonate in Fetal Pharmacology Modeling.

Dionna J Green,Varsha Bhatt-Mehta,Donna Snyder,Gilbert J Burckart,Kyunghun Park

doi:10.3389/fped.2021.698611

Abstract

The regulatory framework for considering the fetal effects of new drugs is limited. This is partially due to the fact that pediatric regulations (21 CFR subpart D) do not apply to the fetus, and only US Health and Human Service (HHS) regulations apply to the fetus. The HHS regulation 45 CFR Part 46 Subpart B limits research approvable by an institutional review board to research where the risk to the fetus is minimal unless the research holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 CFR 46.204). Research that does not meet these requirements, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of pregnant women, fetuses, or neonates, may be permitted by the Secretary of the HHS after expert panel consultation and opportunity for public review and comment (45 CFR 46.407). If the product is regulated by the US Food and Drug Administration (FDA), FDA may get involved in the review process. The FDA does however have a Reviewer Guidance on Evaluating the Risks of Drug Exposure in Human Pregnancies from 2005 and this guidance does discuss the intensity of drug exposure. Estimation of that exposure using physiologically based pharmacokinetic (PBPK) modeling has been suggested by some investigators. Given that drug exposure during pregnancy will impact the fetus, a number of new guidances in the last 2 years also address inclusion of pregnant women in clinical drug trials. Therefore, the drug-specific information on fetal pharmacology will increase dramatically in the next decade due to interest in drugs administered in pregnancy and with the assistance of model-informed drug development.

Highlights

In his 1966 treatise on perinatal pharmacology, Sumner Yaffe stated that “The administration of a drug to a pregnant woman presents a unique problem to the physician; must he consider maternal pharmacologic mechanisms, but he must be aware of the fetus as a potential recipient of the drug” [1]
Ethical considerations and Food and Drug Administration (FDA) guidances have established the need to include pregnant women in drug development studies when appropriate, and these studies will allow an assessment of the drug therapy in fetuses using modeling
physiologically based pharmacokinetic (PBPK) modeling for the prediction of fetal drug concentrations is being explored in preliminary studies, and this approach is expected to mature quickly

Summary

Introduction

In his 1966 treatise on perinatal pharmacology, Sumner Yaffe stated that “The administration of a drug to a pregnant woman presents a unique problem to the physician; must he consider maternal pharmacologic mechanisms, but he must be aware of the fetus as a potential recipient of the drug” [1]. This dilemma is still a problem today; how can we assess the effects of a drug administered to the mother on the fetus?

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