Challenges in Designing Clinical Trials to Test New Drugs in the Pregnant Woman and Fetus

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Key points

  • The development of new drugs to treat maternal and fetal conditions can be improved using approaches that are succeeding in other marginalized therapeutic areas.

  • Improved information about the risks and benefits of interventions during pregnancy is needed to facilitate study design and review by ethics boards, regulators, funders, and potential participants of studies.

  • It is important to ensure that the design and conduct of in vitro, ex vivo, and clinical studies are compatible with the needs of

Challenges

Profound changes in maternal physiology fundamentally alter pharmacokinetics (PK) and pharmacodynamics, often in an unpredictable fashion. There are 3 discrete and intimately dependent units comprising the mother, the fetus, and the placenta. The placenta, once thought to be a passive filter between the maternal and fetal compartments, is in fact a highly complex organ rich in transporters. The human placenta remains relatively understudied, particularly in early healthy pregnancy. Comparative

Funding

Globally, the allocation of resources to the development of new drugs is controversial, and pharmaceutical companies currently have many reasons to avoid investing in pregnancy research.24, 41 As noted in the legal section of this review, disadvantage risks are highly visible (legal liability, and so forth) and compare unfavorably to any potential financial benefits. Information about the burden of disease is available but needs to be presented more effectively to decision-makers in companies,

Ethics

The ethics of research involving pregnant women may seem straightforward. For example, a 1994 report by the US Institute of Medicine recommended that “pregnant women be presumed to be eligible for participation in clinical studies.”45 International ethical guidance also promotes appropriate research that recruits pregnant women (CIOMS 2016; https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf). On the other hand, a systematic review of ethical issues that arise during

Fetus and neonate

The central, and unique, problem for research in pregnancy is the need to account for the interests of 2 (or more) participants: the mother and her offspring. The balance between maternal and fetal interests is difficult to consider, both emotionally and cognitively, unless you have experienced it as a parent or a caregiver. However, families and clinicians do this regularly in clinical practice. Many people approach the situation with a natural inclination to avoid harm to a fetus. However, in

Solutions

Activities in single programs and for the community are summarized and compared in Fig. 1. These activities cannot be done in isolation. A systems approach is needed to address “all the layers of the onion,” which is illustrated in Fig. 2.

Summary

This review has addressed the challenges that arise when testing new and existing drugs that could be used during pregnancy. The authors have emphasized a multileveled approach needed to overcome these challenges.

Individual drug development programs need to gather a body of scientific and clinical information with drug development in mind. Drug development benefits from the structure provided by regulatory pathways, even if a regulatory filing is not an objective of a programme of research.

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