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When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand\u2010alone protocols, platform trials, single arm studies, sample size and the effect that follow\u2010up time during gestation has on analysis interpretations; and observational studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Pregnancy PK should be studied during drug development, after dosing in non\u2010pregnant persons is established (unless non\u2010clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand\u2010alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand\u2010alone pregnancy trial protocols can include pre\u2010specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost\u2010prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high\u2010priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jia2.25917","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T07:35:02Z","timestamp":1658216102000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Clinical and population\u2010based study design considerations to accelerate the investigation of new antiretrovirals during pregnancy"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4116-404X","authenticated-orcid":false,"given":"Sean S.","family":"Brummel","sequence":"first","affiliation":[{"name":"Department of Biostatistics Center for Biostatistics in AIDS Research  Boston Massachusetts USA"},{"name":"Harvard T.H. 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Chan School of Public Heath  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen C.","family":"Caniglia","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0389-9934","authenticated-orcid":false,"given":"Angela","family":"Colbers","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Radboud Institute for Health Sciences Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1435-8455","authenticated-orcid":false,"given":"Benjamin H.","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brookie M.","family":"Best","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences  San Diego California USA"},{"name":"Pediatrics Department \u2013 Rady Children's Hospital San Diego University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam El","family":"Gaaloul","sequence":"additional","affiliation":[{"name":"Product Development Medicines for Malaria Venture  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Hillier","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Gynecology and Reproductive Sciences University of Pittsburgh and the Magee\u2010Womens Research Institute  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzague","family":"Jourdain","sequence":"additional","affiliation":[{"name":"MIVEGEC University Montpellier  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saye H.","family":"Khoo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2818-9808","authenticated-orcid":false,"given":"Lynne M.","family":"Mofenson","sequence":"additional","affiliation":[{"name":"Research Department Elizabeth Glaser Pediatric AIDS Foundation  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Landon","family":"Myer","sequence":"additional","affiliation":[{"name":"Division of Epidemiology &amp; Biostatistics School of Public Health &amp; Family Medicine University of Cape Town  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Nachman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The State University of New York (SUNY)  Stony Brook New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3566-1688","authenticated-orcid":false,"given":"Lynda","family":"Stranix\u2010Chibanda","sequence":"additional","affiliation":[{"name":"Child and Adolescent Health Unit Faculty of Medicine and Health Sciences, University of Zimbabwe  Harare Zimbabwe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1100-9647","authenticated-orcid":false,"given":"Polly","family":"Clayden","sequence":"additional","affiliation":[{"name":"HIV i\u2010Base  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Memory","family":"Sachikonye","sequence":"additional","affiliation":[{"name":"HIV i\u2010Base  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahin","family":"Lockman","sequence":"additional","affiliation":[{"name":"Harvard T.H. 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