Many pregnant people must face the fact that despite strides made in drug development, very few approved drugs have been explicitly studied in pregnant patients, and many pregnancy-related conditions lack approved therapies. Despite this fact, a multi-national study conducted in Europe, North and South America, and Australia found over 80% of their respondents reported using at least one medication (prescribed or over the counter) while pregnant. These data demonstrate that there is wide use of medications during pregnancy, but there remains a lack of evidence-based information regarding dosage, safety of the medication to the mother and fetus, and the effectiveness of drugs used off-label for pregnancy-related conditions.
Pregnant people are generally excluded from clinical trials because of ethical and medical concerns for the fetus and mother. While advocacy and policy efforts have sought to increase inclusion of pregnant people in clinical trials, there remains a long way to go to address the unmet needs of this population. In this blog article, we review the strategy of drug repurposing for use in pregnancy-related conditions and address its challenges.
Repurposing
In the face of limited drug development in this population, alternate strategies such as drug repurposing have emerged, which can save time and money compared to traditional drug development. Drug repurposing refers to “studying the drugs that are already approved to treat one disease or condition to determine if they are safe and effective for treating other diseases,” according to the National Center for Advancing Translational Sciences (NCATS). Traditional drug development is expensive and the process of developing, testing, gaining regulatory approval, and marketing a novel drug takes many years. Repurposed drugs, on the other hand, can often rely on previous research and information including preclinical studies, toxicology, and pharmacology.
Areas for Repurposing in Pregnancy
There are various situations in pregnancy where drug repurposing can play an important role. Repurposing is critical for conditions that only affect pregnant people and that are challenging to study, such as placental dysfunction, spontaneous preterm birth, placenta accreta, hyperemesis gravidarum, and obstetric hemorrhage. Another unmet area of medical need is where infections during pregnancy can be transmitted to the fetus. This is particularly challenging when available therapies for those infections, such as valganciclovir for cytomegalovirus (CMV) and pyrimethamine and sulfadiazine (in the first trimester) for toxoplasmosis and malaria, can cause birth defects. Drug repurposing is also useful when the standard treatment is contraindicated in pregnancy. Thalidomide, for example, is used in multiple myeloma and leprosy, but cannot be used in pregnancy due to the risk of severe birth defects.
Unfortunately, there are very few examples of repurposing in pregnancy. The lack of novel drug development focused on treating conditions that specifically affect pregnancy means that repurposing could be uniquely beneficial. By collecting information on medications taken during pregnancy, researchers can generate hypotheses about additional uses.
While drug repurposing offers many benefits, it also comes with challenges. If a drug has been approved for one population and a company would like it to be approved for a different population, they may still need to conduct additional studies to address specific safety or efficacy concerns, as well as dosing. Other challenges include patent issues and market exclusivity. When a drug is off-patent, it is challenging to attract money to perform trials with the drug.
Research Efforts
FDA and NCATS/NIH launched the CURE ID mobile app (available in the App Store for iPhone users and on the Play Store for Android users) and website to capture real-world data from clinicians for difficult-to-treat infectious diseases in 2019. Very recently, CURE ID also launched its patient portal where patients can submit their own treatment experiences. The patient portal is especially useful for collecting clinical information about indications and drugs used off-label from pregnant patients, since these patients are highly invested in their conditions and the impact their medications could have on their developing babies. CURE ID encourages pregnant patients to submit information about the drugs they are taking so that real-world data can be collected to evaluate the safety and effectiveness of drugs as well as to see if any signals can be identified through this mechanism of data collection.
CURE ID was later transformed into a public-private partnership, the CDRC, to engage relevant stakeholders in the process of translating initial efficacy signals into research questions to be studied in randomized controlled trials (RCTs) that may ultimately be used to support regulatory approvals.
Policy and Regulatory Efforts
Legislative and policy incentives to support repurposing have encouraged the development of treatments for other diseases and populations with high unmet medical need that could also be applied to the pregnant population.
The US, European, and UK regulatory agencies published an article in 2021 calling for stronger global partnerships among scientists, clinicians, and regulators to improve knowledge on medicines for pregnant people. One of their recommendations focuses on reducing the clinical and regulatory barriers that companies face when testing or developing a drug for pregnant people. The European Union (EU)’s Pediatric Investigational Plan and the US’s Pediatric Research Equity Act and Best Pharmaceuticals for Children Act could serve as models for developing incentives and requirements for testing medications in pregnant populations. Additionally, in 2022, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) approved a new efficacy guideline, providing a globally accepted framework to enable inclusion of pregnant and breast-feeding individuals in clinical trials.
Moreover, collaboration between clinicians and professional societies, patient advocacy groups, and pregnancy exposure registries offer an opportunity to collect data on the use of medications during pregnancy. FDA has also published guidance in recent years to promote the inclusion of pregnant people in clinical trials, as well as guidance on designing post-approval pregnancy safety studies.
Conclusion
Obstetric conditions impact the lives of many pregnant individuals and medication use during pregnancy is common. While there are perceived barriers to traditional drug development for pregnancy-related conditions, drug repurposing is a promising strategy to improve the development of new obstetric drugs.
Acknowledgements
We thank Heather Stone (FDA Office of Medical Policy), Dr. Leonard Sacks (FDA Office of Medical Policy), Dr. Lynne Yao (FDA Division of Pediatric and Maternal Health), and Dr. Kaveeta Vasisht (FDA Office of Women’s Health) for their helpful discussions and comments on this article.