Table 1.
Key principles and proposed outcomes for the study of new antiretrovirals (ARVs) in pregnancy
| If the agent is efficacious in non‐pregnant adults (viral load suppression) and adequate drug exposures are achieved in pregnancy, then efficacy can be assumed in pregnancy without additional trials. | |||
| If the agent is efficacious in non‐pregnant adults (viral load suppression) and adequate drug exposures are achieved in pregnancy, then efficacy for prevention of vertical transmission can be inferred. | |||
| All new agents must to be studied in pregnant people for pharmacokinetics/optimal dosing and short‐term safety. | |||
| Dedicated pregnancy safety studies assessing pregnancy, birth and infant outcomes should be conducted for all new ARVs with expected broad use in pregnant women and women who may become pregnant. | |||
| There is no expectation to have meaningful clinical information about teratogenicity risk before registration; large numbers of observations with exposure at conception/early pregnancy are needed to identify the increased risk of rare events and will only come through post‐marketing surveillance/registries/phase 4 studies. | |||
| Once pharmacokinetic/dosing and short‐term safety in pregnancy are determined to be adequate, there should be no restrictions to access during pregnancy once the ARV is licensed. |
| Clinical outcome | Criteria for robust evaluation in pregnancy | Timing of results availability | Comment |
|---|---|---|---|
| Treatment efficacy (viral load suppression) | Not required for any ARV | N/A | Efficacy extrapolated from adult trials |
| Vertical prevention efficacy | Not required for any ARV | N/A | Inferred based on virologic efficacy |
| Pharmacokinetic/dosing | Require for ALL new ARVs | Included with application for licensing | Exception: if clear non‐clinical or early clinical signal of reprotoxicity precludes use in pregnancy |
| Short‐term safety | Require for ALL new ARVs | Included with application for licensing | Exception: if clear non‐clinical or early clinical signal of reprotoxicity precludes use in pregnancy |
| Composite of: foetal loss (SAB/stillbirth), preterm birth, foetal growth restriction (SGA) and neonatal mortality | Dedicated pregnancy study should be prioritized for ALL new ARVs expected to have high use in women who are or could become pregnant | Study underway at the time of licensing but completed after licensing | Lack of these outcome evaluations should NOT be used to limit the access to ARVs based on pregnancy or pregnancy potential. WHO is leading real‐time processes to regularly assess the priority products for which accelerated development is needed. a Comparative studies with composite outcome likely necessary as described in Brummel et al. b |
| Teratogenicity | Direct, robust clinical evaluation not routine/feasible | Post‐licensure (surveillance and pharmacovigilance) | Preclinical or early clinical signal of reprotoxicity would generally preclude clinical study or use in pregnancy. |
| Medical disorders of pregnancy (hypertension and gestational diabetes mellitus) | Robust evaluation only if specific concern/signal | Post‐licensure | Collect outcomes in all studies in pregnancy recognizing limited power (small numbers) for robust evaluation. Specific studies may be warranted. |
| Postnatal growth, development, organ toxicity, neurodevelopment and non‐structural adverse foetal effects | Robust evaluation only if specific concern/signal | Post‐licensure | Comparative studies likely necessary as described in Brummel et al. b |
Abbreviations: SAB, spontaneous abortion; SGA, small for gestational age.
a
World Health Organization. Antiretroviral drug optimization. CADO Reports. WHO; 2022. Available from: https://www.who.int/groups/antiretroviral‐drug‐optimization.
b
Brummel et al. [9].