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.

Guidelines for tuberculosis screening and preventive treatment among pregnant and breastfeeding women living with HIV in PEPFAR-supported countries

“…3HP is currently not recommended during pregnancy by the CDC owing to limited data on rifapentine pharmacokinetics, dosing, and safety during pregnancy [ 25 , 30 , 36 ]. More data is needed on the rifamycin agents as well as new agents being studied for TPT in nonpregnant adults [ 37 ]. Despite this, both Zimbabwe and Uganda recommend 3HP in addition to isoniazid-based regimens in pregnant WLHIV, and both Thailand and Eswatini recommend 3HP in breastfeeding WLHIV.…”

Accelerating investigation of new HIV drugs in pregnancy: advancing the research agenda from theory to action

“…Similar to most recent approaches for paediatric clinical development, new HIV treatment agents that are demonstrated to be efficacious in non-pregnant adults, defined by viral load suppression, do not need to be studied for efficacy in pregnancy as long as PK is comparable and appropriate dosing is established [18]. In addition, if adequate drug exposures are achieved in pregnancy, efficacy for prevention of vertical transmission does not need to be studied directly and can be inferred.…”

Pharmacokinetic Research in Pregnancy: Ethical Low‐Hanging Fruit?

“…Earlier conduct of such studies is critical to timely generation of pregnancyspecific data. 15 In addition, federal research regulations have specific risk thresholds for research in pregnancy that create challenges for early-phase research. Subpart B of the Code of Federal Regulations requires that research in pregnancy either hold the prospect of direct benefit (to the woman, fetus, or both), which is controversial in some earlier-phase studies; or entail no more than minimal risk to the fetus.…”

“…For instance, developmental and reproductive toxicology studies are required before pregnant individuals may enroll in prelicensure research but are expensive and prone to delays. Earlier conduct of such studies is critical to timely generation of pregnancy‐specific data 15 . In addition, federal research regulations have specific risk thresholds for research in pregnancy that create challenges for early‐phase research.…”