Towards an appropriate framework to facilitate responsible inclusion of pregnant women in drug development programs

• Published in: Current controlled trials in cardiovascular medicine Vol. 19; no. 1; p. 123
• Main Authors: Roes, Kit C B, van der Zande, Indira S E, van Smeden, Maarten, van der Graaf, Rieke
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.02.2018; BioMed Central; BMC
• Subjects: Adaptive design; Autoimmune diseases; Clinical trials; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Design; Drug Development; Drug dosages; Drug use; Female; Fetus - drug effects; Fetuses; Health aspects; Humans; Hypertension; Medical ethics; Methodology; Obstetrics; Pharmaceutical research; Pregnancy; Pregnant women; Research Design; Research ethics; Risk factors; Adaptive design; Research ethics; Research design; Methodology; Drug development; Pregnant women
• ISSN: 1745-6215; 1745-6215
• DOI: 10.1186/s13063-018-2495-9

Evidence-based treatment for pregnant women will ultimately require research conducted in the population of pregnant women. Currently, few scholars have addressed the issue of responsible inclusion of pregnant women in drug research. Because of additional risks associated with including pregnant women in drug research and the altered ways in which drugs are processed by the pregnant body, pregnant women cannot be treated as an ordinary subgroup in the various phases of drug development. Instead, responsible inclusion of pregnant women requires careful design and planning of research for pregnant women specifically. Knowledge about these aspects is virtually nonexistent. In this article, we present a practical framework for the responsible inclusion of pregnant women in drug development. We suggest that the framework consists of using a question-based approach with five key questions in combination with three prerequisites which should be addressed when considering inclusion of pregnant women in drug research. The five questions are: A. Can we consider the drug safe (enough) for first exposure in pregnant women and fetuses? B. In which dose range (potentially depending on gestational age) can the drug be considered to remain safe in pregnant women? C. At what dose (regimen, within the range considered safe) can we expect efficacy in pregnant women? D. Can efficacy be confirmed at the target dose, either similar to the initial population or different? E. Can clinical safety be confirmed at a sufficiently acceptable level at the target dose for pregnant women and fetuses, so as to conclude a positive benefit-risk ratio? Combining questions and prerequisites leads to a scheme for appropriate timing of responsible inclusion of pregnant women in drug research. Accordingly, we explore several research design options for including pregnant women in drug trials that are feasible within the framework. Ultimately, the framework may lead to (i) earlier inclusion of pregnant women in drug development, (ii) ensuring that key prerequisites, such as proper dosing, are addressed before more substantial numbers of pregnant women are included in trials, and (iii) optimal use of safety and efficacy data from the initial (nonpregnant) population throughout the drug development process.