New approach methods on the bench side to accelerate clinical trials during pregnancy

ABSTRACT

Introduction

Pregnant women are therapeutic orphans as they are excluded from clinical drug development and therapeutic trials. We identify limitations in conducting clinical trials and propose two ‘New Approach Methods’(NAMs) to overcome them.

Areas covered

NAMs have proven invaluable tools in basic and clinical research to understand human health and disease better, elucidate mechanisms, and study the efficacy and toxicity of therapeutics that have not been possible through animal-based methodologies. The lack of humanized experimental models of FMi and drugs that can safely and effectively cross FMi to reduce the risk of adverse pregnancy has hindered progress in the field of reproductive pharmacology. This report discusses two technological advancements in perinatal research and medicine to accelerate clinical trials during pregnancy. (1) We have developed a humanized microphysiologic system, an Organ-on-a-chip (OOC) platform, to study FMi and their utility in pharmacological studies, and (2) use of extracellular vesicles (EVs) as drug delivery vehicles that are immunologically inert and can cross the fetomaternal barriers.

Expert opinion

We provide an overview of NAMs that can accelerate preclinical trials and develop drugs to cross the feto-maternal barriers to reduce the risk of adverse pregnancy outcomes like preterm birth.

KEYWORDS:

• Exosomes
• organ on chip
• perinatal medicine
• reproductive pharmacology
• preterm birth

Article highlights

• Adverse pregnancy outcomes are common, as pregnant women are excluded from clinical trials to determine the pharmacologic impact of drugs during pregnancy. The lack of reliable in vitro and in vivo models to conduct preclinical trials of drugs also contributes to the exclusion of pregnant women in clinical trials.

• New Approach Methods (NAMs) are required to determine drug pharmacologic impacts during pregnancy and accelerate clinical trials.

• This review introduces multiple microphysiologic systems (organs on a chip; OOC) of the feto-maternal interfaces to conduct preclinical trials during pregnancy. OOCs with cells derived from human pregnancy replicate intrauterine organs, and microchannels connecting different cell types of an organ maintain intercellular interactions as seen in utero.

• This review introduces extracellular vesicles (EVs; exosomes of 30-200 nm) as drugs or drug carriers that can cross the feto-maternal barrier system to study drugs’ effect on feto-maternal tissues. EVs are nonimmunogenic and can be engineered to contain specific drugs as a cargo.

• Successful adaptation of new approach methods to conduct preclinical trials will reduce the use of animal models that are not reliable.

• Humanized microphysiologic systems of reproductive tissues, specifically feto-maternal interface organs, are cheaper, faster, and easier to get valuable pharmacologic parameters that can accelerate clinical trials during pregnancy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This review is supported by R01HD100729, P42ES027704 (R Menon), R01HD113193 (A Kammala), and R01HD110400 (L Richardson) funds from NIH/NICHD.