Approaches to accelerating the study of new antiretrovirals in pregnancy

Abstract

Introduction: Women who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available.

Discussion: The World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year-long workshop on "Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women." Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre- and post-licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non-pregnant adults, provided that drug levels in pregnancy are similar. However, short-term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre-clinical studies is essential for pregnancy short-term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post-marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two-drug regimens, long-acting ARVs and ARVs administered through novel delivery systems.

Conclusions: Implementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women.

Keywords: ARV; antiretrovirals; clinical trials; pregnancy; pregnancy outcomes; registrational trials.

Figure 1

Framework and approaches to expedite the timeline for the study of new antiretrovirals drugs in pregnancy. (1) Involve women of childbearing potential living with HIV from the identification of research questions through the study design, recruitment, conduct and dissemination of results. (2) Perform non‐clinical developmental and reproductive toxicology studies (DART) earlier during drug development for all new HIV agents. Fertility and early embryonic development (FEED) and embryo‐foetal development (EFD) studies should be completed during or no later than the end of the phase 2 registrational trials. (3) Pre‐ and postnatal development (PPND) studies should be completed during early phase 3 or no later than the end of phase 3 registrational trial. (4) Women who become pregnant in registrational trials should be given the option to make an informed choice to stay on study drug once early non‐clinical FEED and EFD studies are completed, with no negative signals and dosing is established in non‐pregnant people. (5) Enrol pregnant women in specific studies to determine pharmacokinetic (PK) and preliminary safety as soon as late non‐clinical PPND studies are completed with no negative signals for all new HIV agents. (6) Investigate adverse maternal, pregnancy and birth outcomes through dedicated pregnancy safety studies for all new priority HIV agents identified through CADO as soon as dosing is confirmed. (7) Expand systematic and rigorous active safety surveillance studies to enable systematic and rapid detection of adverse birth outcomes and rare events, such as birth defects associated with exposure to antiretrovirals during pregnancy.