Inclusion of pregnant women in antiretroviral drug research: what is needed to move forwards?

Elaine J. Abrams,Polly Clayden,Catriona Waitt,Lee Fairlie,Matthew Chersich,Saye Khoo,Celicia Serenata,Willem Francois Venter,Michelle Moorhouse,Shahin Lockman,Helen Rees,Marta Boffito,Amandine Cournil

doi:10.1002/jia2.25372

Abstract

IntroductionTo adequately ascertain drug safety and efficacy, drug trials need to include participants from all groups likely to receive the medication following approval. Pregnant women, however, are mostly excluded from trials, and women participating are often required to use highly effective contraception and taken off study product (even off study) if they conceive. There is little commercial incentive for including pregnant women in clinical trials, even when preclinical animal and human pharmacokinetic and safety data appear reassuring. With this conservative approach, large numbers of pregnant women are exposed to drug postlicensing with little known about drug safety and efficacy, and little done to systematically monitor outcomes of pregnancy exposure.DiscussionThe article focuses on antiretrovirals for treating and preventing HIV, and presents potential approaches which could extend to other therapeutic areas, to obtaining adequate and timely data to inform use of these drugs in this population. Most importantly the pregnancy risk profile of investigational agents can be systematically stratified from low to high risk, based on guidelines from regulatory bodies. This stratification can determine the progress through preclinical work with animals and non‐pregnant women to opportunistic studies among women who become pregnant on a clinical trial or within routine clinical treatment. Stratification can include pregnant women in clinical trials, concurrent with Phase II/III trials in non‐pregnant adults, and ultimately to postmarketing surveillance for outcomes in pregnant women and their infants. Each step can be enabled by clear criteria from international and local regulatory bodies on progression through study phases, standardized protocols for collecting relevant data, collaborative data sharing, pregnancy outcomes surveillance systems supported by committed funding for these endeavours.ConclusionsA formalized step‐wise approach to including pregnant women in antiretroviral drug research should become the new norm. Systematic implementation of this approach would yield more timely and higher quality pregnancy dosing, safety and efficacy data. Through more vigorous action, regulatory bodies could responsibly overcome reluctance to include pregnant women in drug trials. Funders, researchers and programme implementers need to be galvanized to progressively include pregnant women in research – the use of newer, more effective drugs in women is at stake (349).

Highlights

To adequately ascertain drug safety and efficacy, drug trials need to include participants from all groups likely to receive the medication following approval
Informed consent must be obtained by the pregnant woman in all cases; where direct benefit is solely for the fetus, informed consent from the father is recommended, apart from circumstances where this is not possible or desirable [14]
Research is recommended if there is a compelling social benefit for research and if alternative means of accessing termination of pregnancy (TOP) is possible

Summary

| INTRODUCTION

Antiretroviral (ARV) drug use in pregnancy has evolved from single and two-drug regimens for prevention of vertical infection, to three-drug regimens for all pregnant and breastfeeding women, to protect their own health in addition to preventing vertical (and horizontal) transmission [1,2,3]. Guidance from the WHO, US FDA, European Medicines Agency and local regulatory agencies about the type and amount of safety data required before ARVs can be used in clinical trials involving pregnant women or women of childbearing potential (WOCP), is lacking, and would go a step further in stratifying risk and including pregnant women in different phases of studies These bodies could provide considerations on legal and litigation aspects of including pregnant women in research. Draft guidance from the Food and Drug Administration (FDA) in 2018 highlighted several important reasons for including pregnant women in research, including the need for safe and effective drugs in pregnancy; the need for adequate safety, efficacy and dosing data; and; the possibility of access to benefits for the mother and fetus that are not available outside the research setting [14]. The Task Force suggested a number of ways that data can be obtained from pregnancy including: pharmacokinetic or pharmacodynamic studies in pregnant women, expanded access to surveillance mechanisms such as registries, post-marketing surveillance, post trial data; strengthen evidence base on the impact of common disease on pregnant women, and increasing the number of controlled trials evaluating the risks of using drugs during pregnancy [18]

| DISCUSSION

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