Abstract
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:Can we consider the drug safe (enough) for first exposure in pregnant women and fetuses?In which dose range (potentially depending on gestational age) can the drug be considered to remain safe in pregnant women?At what dose (regimen, within the range considered safe) can we expect efficacy in pregnant women?Can efficacy be confirmed at the target dose, either similar to the initial population or different?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.
Highlights
Over the past decades, bioethicists, pharmacologists, regulators, and researchers have called attention to the inclusion of pregnant women in clinical research in order to improve the evidence base underlying maternal and fetal health [1,2,3,4,5]
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 population throughout the drug development process
We challenge the current underrepresentation and we support the idea that including a smaller group of pregnant women in a wellcontrolled setting is preferable to exposing the whole population of pregnant women to unknown risks
Summary
Bioethicists, pharmacologists, regulators, and researchers have called attention to the inclusion of pregnant women in clinical research in order to improve the evidence base underlying maternal and fetal health [1,2,3,4,5]. The United States Food and Drug Administration (FDA) recently replaced its traditional pregnancy categories for drug use in pregnant women by the Pregnancy and Lactation Labeling Rule (PLLR, Final Rule), which is expected to provide further incentives for the development and conduction of clinical research in pregnant women [12]. Despite these attempts to respond to the call for inclusion, the underrepresentation and exclusion of pregnant women from clinical research remains common practice [5, 13]. There are various reasons for the continuing status quo, such as a fear of harming the fetus, numerous liability concerns, and the question whether pregnant women would be willing to participate even if they were found to be eligible [14,15,16]
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