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Clinical and population-based study design considerations to accelerate the investigation of new antiretrovirals during pregnancy.
Brummel, Sean S; Stringer, Jeff; Mills, Ed; Tierney, Camlin; Caniglia, Ellen C; Colbers, Angela; Chi, Benjamin H; Best, Brookie M; Gaaloul, Myriam El; Hillier, Sharon; Jourdain, Gonzague; Khoo, Saye H; Mofenson, Lynne M; Myer, Landon; Nachman, Sharon; Stranix-Chibanda, Lynda; Clayden, Polly; Sachikonye, Memory; Lockman, Shahin.
Afiliación
  • Brummel SS; Department of Biostatistics, Center for Biostatistics in AIDS Research, Boston, Massachusetts, USA.
  • Stringer J; Harvard T.H. Chan School of Public Heath, Boston, Massachusetts, USA.
  • Mills E; School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Tierney C; MTEK Sciences, Vancouver, British Columbia, Canada.
  • Caniglia EC; MTEK Sciences, Kigali, Rwanda.
  • Colbers A; Department of Biostatistics, Center for Biostatistics in AIDS Research, Boston, Massachusetts, USA.
  • Chi BH; Harvard T.H. Chan School of Public Heath, Boston, Massachusetts, USA.
  • Best BM; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Gaaloul ME; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Hillier S; Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • Jourdain G; Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, California, USA.
  • Khoo SH; Pediatrics Department - Rady Children's Hospital San Diego, University of California San Diego, La Jolla, California, USA.
  • Mofenson LM; Product Development, Medicines for Malaria Venture, Geneva, Switzerland.
  • Myer L; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh and the Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
  • Nachman S; MIVEGEC University Montpellier, Montpellier, France.
  • Stranix-Chibanda L; Department of Pharmacology, University of Liverpool, Liverpool, UK.
  • Clayden P; Research Department, Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA.
  • Sachikonye M; Division of Epidemiology & Biostatistics, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa.
  • Lockman S; Department of Pediatrics, The State University of New York (SUNY), Stony Brook, New York, USA.
J Int AIDS Soc ; 25 Suppl 2: e25917, 2022 07.
Article en En | MEDLINE | ID: mdl-35851758
INTRODUCTION: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. 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-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies. DISCUSSION: Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical 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-alone 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-alone pregnancy trial protocols can include pre-specified 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-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias. CONCLUSIONS: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Complicaciones Infecciosas del Embarazo / Infecciones por VIH / Antirretrovirales Tipo de estudio: Clinical_trials / Guideline / Observational_studies Límite: Female / Humans / Pregnancy Idioma: En Revista: J Int AIDS Soc Asunto de la revista: SINDROME DA IMUNODEFICIENCIA ADQUIRIDA (AIDS) Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Complicaciones Infecciosas del Embarazo / Infecciones por VIH / Antirretrovirales Tipo de estudio: Clinical_trials / Guideline / Observational_studies Límite: Female / Humans / Pregnancy Idioma: En Revista: J Int AIDS Soc Asunto de la revista: SINDROME DA IMUNODEFICIENCIA ADQUIRIDA (AIDS) Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos