Improving the safety of fetal therapy trials and studies

Anna David, MD, PhD
Co-Chair, Fetal Therapy SIG

Conducting clinical trials in pregnancy raises many challenges, primarily due to safety concerns for the mother and her fetus. This is particularly the case when testing new fetal therapies. There have been a number of initiatives to improve the safety of pregnancy trials. The Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) has identified and addressed gaps in knowledge and research on safe and effective therapies for pregnant/lactating women and the fetus¹. The US Food and Drug Administration (FDA) has also issued draft guidance entitled ‘Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials’², to facilitate discussion across stakeholder groups to promote maternal and fetal health and inform therapeutic decisions during pregnancy. The importance of fetal analgesia and anaesthesia for interventions is highlighted by the recently updated Society for Maternal Fetal Medicine guidelines for fetal surgery³.

To assess therapeutic safety, we can monitor important signals about the wellbeing of the mother and fetus, using Adverse Events or AEs. But historically there has been a lack of a comprehensive AE framework in pregnancy trials, with only a handful of AEs available. This has severely limited the understanding of risks in conducting clinical trials in pregnant women. Researchers have now launched a standard terminology for safety monitoring for pregnant women and their fetuses during development or assessment of fetal therapy studies. The terminology, called MFAET: Maternal Fetal Adverse Event Terminology will transform the safety of innovation in fetal therapies, ultimately improving their outcomes⁴.

Adverse Events or AEs are defined as “any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this product.” To assess the safety of a drug or intervention, researchers record any AEs which occur during clinical trials. AEs have standard definitions to ensure good communication between clinical trial staff. And to get the most detailed safety data, these AEs are usually graded from 1 to 5. Standard criteria exist for defining and grading hundreds of AEs outside pregnancy. The Common Terminology Criteria for Adverse Events (CTCAE) is the most commonly used grading system, listing hundreds of AEs. But until recently there was no system to define or grade maternal or fetal AEs.

MFAET is a new comprehensive terminology to help MFM healthcare practitioners to develop innovative fetal therapies. A video describing the development of MFAET is available here. First an international multidisciplinary group filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on CTCAE generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives.

Fetal AEs are defined as being diagnosable in utero, for example with USS/MR imaging, CTG/fetal heart rate monitoring and they must have potential to cause a detrimental effect to the fetus. AEs that only manifest after birth were considered to be neonatal AEs, even if they had originated in utero. Neonatal Adverse Events can be graded using the International Neonatal Consortium (INC) Neonatal AE Severity Scale (NAESS)⁵.

Some fetal AEs relate to specific organs or systems, eg abnormalities of the gastrointestinal, renal, brain or musculoskeletal systems detected by imaging. Other fetal AEs are disorders of fetal movement, cardiac dysfunction (Table), poor fetal growth and abnormal fetal fluid collection (Table). Other defined and graded AEs include fetal heart rate abnormalities eg bradycardia and tachyarrhythmia, fetal neoplasm and general fetal structural abnormalities. Definitions were also developed specifically for AEs related to fetal interventions eg fetal intraoperative injury, fetal procedural hemorrhage.

The current version 1.1 of MFAET is completely integrated with the corresponding terms in MedDRA. The terminology has been shared and reviewed with regulatory authorities (MHRA, FDA, EMA). Resources including a spreadsheet of MedDRA numerical codes and instructions for use, are available here.

The terminology can also be used not only for clinical trials, but to evaluate safety and outcomes of observational studies eg case control or cohort. Using MFAET will transform the conduct of clinical trials of fetal therapies, making them much safer for pregnant women and their babies.

References:

1. NICHD. Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) [Internet]. Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2018. Available from: https://www.nichd.nih.gov/sites/default/files/2018-09/PRGLAC_Report.pdf
2. U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials Guidance for Industry [Internet]. 2018. Available from: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
3. Norton ME, Cassidy A, Ralston SJ, Chatterjee D, Farmer D, Beasley AD, et al. Society for Maternal-Fetal Medicine (SMFM) Consult Series #59: The use of analgesia and anesthesia for maternal-fetal procedures. Am J Obstet Gynecol [Internet]. 2021; Available from: http://dx.doi.org/10.1016/j.ajog.2021.08.031
4. Spencer RN, Hecher K, Norman G, Marsal K, Deprest J, Flake A, et al. Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology. Prenat Diagn [Internet]. 2022 Jan 12;42(1):15–26. Available from: https://onlinelibrary.wiley.com/doi/10.1002/pd.6047
5. Salaets T, Turner MA, Short M, Ward RM, Hokuto I, Ariagno RL, et al. Development of a neonatal adverse event severity scale through a Delphi consensus approach. Arch Dis Child [Internet]. 2019 Dec;104(12):1167–73. Available from: http://adc.bmj.com/lookup/doi/10.1136/archdischild-2019-317399