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

Abstract

Introduction To 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. Discussion The 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. Conclusions A 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).

The HIV drug optimization agenda: promoting standards for earlier investigation and approvals of antiretroviral drugs for use in adolescents living with HIV

“…Therefore, enrolment of adolescent girls also depends on the country policy that dictates the age when adolescent girls can use contraceptives. Especially in resourcelimited settings key issues pertaining to the use of contraceptives in adolescent girls such as cultural norms, religious beliefs, community perspectives and stigma (for HIV and contraceptive use), might pose major enrolment concerns and could be addressed during the trial planning phase [31]. Raising community awareness and education is also crucial [32].…”

Pooled Prevalence of Adverse Pregnancy and Neonatal Outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results From a Systematic Review and Meta-Analyses to Inform Trials of Novel HIV Prevention Interventions During Pregnancy

“…Clearly, there is an ethical and public health imperative to include pregnant and breastfeeding women in clinical research (28). This need certainly extends to purposefully establishing the safety and efficacy of new HIV treatment and prevention methods in pregnant individuals with or at risk for HIV (5,29). This can be illustrated by the 2019 finding from the Tsepamo study in Botswana that periconceptual dolutegravir use by women living with HIV may increase neural tube defects (30,31).…”

Ethical issues in therapeutic use and research in pregnant and breastfeeding women

“…The HIV research community has led the way in many aspects of pharmacological research in pregnant and breastfeeding women, from trial design, advocating for the earlier and routine inclusion of pregnant or potentially pregnant women in such studies, 12 providing guiding principles for the design and analysis of high quality pharmacokinetic studies 13,14 and providing an ethical framework on which to underpin this. 15 A 2016 systematic review of all pharmacokinetic studies in pregnancy identified 198 studies exploring 121 different medications.…”

“…Only a decade later, when registry data had accumulated and the studies were eventually done in pregnant women, did it become clear that there was a species difference in the observed toxicity; no embryotoxicity was observed among pregnant humans. 12,24 The potential benefits of research participation include later access to the fruits of a particular research endeavour: a safe, tolerable and effective drug. Systematic exclusion from research is unjust partly because it results in systematic exclusion from these benefits.…”

“…Accepting this as a potential risk from the outset, a clinical trial enables evaluation in a controlled context: women who become pregnant in the context of a study should be allowed to continue on the trial and on study drug, with all evaluations and appropriate monitoring of both the foetus and the mother-otherwise nothing will be learned to benefit others who follow. 12,13 As discussed by Fairlie and colleagues, rather than immediate withdrawal from a clinical trial, follow-up for safety endpoints should be standard irrespective of whether the participant remains on the investigational drug or is switched to standard of care. If she is in the second or third trimester, she could be invited for pharmacokinetic analysis to provide data on the drug disposition in pregnancy.…”