This is the first post in an ongoing blog series about TransCelerate’s efforts to help biopharma R&D organizations navigate global regulations and improve safety for medications prescribed to pregnant and breastfeeding individuals. Future topics in this series will include tips on cultural shifts within an organization, patient experience in clinical trials, and future TransCelerate projects, among others.
In 2019, 4.2 million babies were born in the European Union and 3.75 million in the United States. Drug utilization studies estimate that between 44% and 99% of pregnant women will take medication during pregnancy, yet very few are approved for specific use during pregnancy and breastfeeding (one new chemical entity in the last thirty years).
It’s an under-researched patient population and is of utmost importance. The thalidomide crisis in the 1960s is a perfect example. Pregnant women that took the medication had catastrophic side effects for their fetuses.
We are still feeling the reverberation of that decision today. It’s been 60 years, and pregnant women are still rarely allowed to be enrolled in clinical trials. For medicines to be developed specifically for pregnant or breastfeeding women, it’s the industry’s responsibility to design safeguards and rules for this research. It’s not just an issue for pregnant women either. There isn’t enough research on patient safety when breastfeeding or how medicines can affect neurodevelopmental delay in infants.
As a relatively new field, researchers in industry or academia can have difficulty understanding the global landscape of existing and evolving regulations and guidance on monitoring the safety of medicines taken during pregnancy and breastfeeding.
TransCelerate established its Interpretation of Pharmacovigilance Guidances and Regulations Initiative in 2017 to help the clinical research ecosystem navigate global regulations concerning different topics. Last year, the team decided to address these regulations concerning the safety of medicines in pregnancy and breastfeeding.
The Current State of Affairs
This is an issue that’s near and dear to our hearts. Between the two of us, we have family members and friends that need to be on medication for chronic illnesses, some of whom are planning a family. Prior to becoming a PV expert, I [Amalia] worked as a community pharmacist. I vividly remember situations where I was asked to dispense medication to pregnant women, and we didn’t have the risk information for the medicines. Currently, only a few medicines are developed specifically for use during pregnancy. In the last 40 years, only atosiban was developed and approved for use during pregnancy, while only five others are licensed for use in the U.K.
Medicines are prescribed at the attending physician’s discretion; more and more patients and parents want to be involved in the prescribing decision. It is not easy to weigh the benefits and risks when two lives are involved! Combined with the lack of information on product labels, it’s difficult to answer questions posed by patients, causing pharmacists to direct patients back to their doctors.
If patients don’t feel like their doctors or pharmacists feel confident that the medication is safe for use when pregnant, what do they do? My MSc Research conducted under Dr. David Lewis` supervision [Amalia] shows it is not a clear decision. Many women didn’t know which sources they could trust. Often there were discrepancies between the sources, or the information was so scientific that it was difficult to understand for anyone that doesn’t work in the field. Or a common misconception the public has is that certain medicines are safe to take in the third trimester, but that might not necessarily be true. A fetus’ brain and central nervous system are developing rapidly in the third trimester. The cerebrum begins to develop grooves and ridges and separates into the left brain and right brain. The cerebellum is the fastest-growing part of the brain in the third trimester. Some medications—like sodium valproate—can be associated with significant risks if used in the third trimester.
Thankfully, there has been progress within the biopharma R&D industry to better investigate and regulate the drug safety of this patient population over the past 15 years.
In 2012, the International Coalition of Medicines Regulatory Authorities (ICMRA) was formed. ICMRA is a coalition of approximately 40 global Health Authorities that aims to provide a global architecture to support information sharing, crisis response, and address regulatory science issues.
Additionally, the European Union, the United Kingdom, and the U.S. have foundational literature on this topic. Some countries have more legislation in the clinical setting, while others have more in post-marketing. There are discrepancies, but these three regions are more active in producing legislation and recommendations concerning pregnancy and breastfeeding.
Where are the areas of improvement?
At TransCelerate, we decided we were in the best position to compile and analyze global regulations and create a landscape assessment. Using a phased approach, the team analyzed the current regulatory ecosystem (and relevant initiatives) in focused territories, covering drug safety regulations and guidances addressing pregnancy and breastfeeding from early clinical development to post-marketing settings.
We also wanted to evaluate further if the global legislation is harmonized. To start, the team distributed a survey to TransCelerate Member Companies to identify the top pain points in this area. Three topics stood out:
- Discrepancies in regulations. The top burden reported by our members was the number of discrepancies in guidance between countries, making it difficult to operate global studies. For example, different countries’ requirements range from not allowing pregnant women to enroll in COVID-19 studies to encouraging a sponsor to conduct a study on pregnant women if the benefit/risk assessment is positive and there is a need to develop a medication during pregnancy.
- Post-authorization safety studies. Global legislation varies to a large degree in reference to processing cases for post-authorization safety studies. For example, the requirements for the European Union differ so widely from U.S. requirements that sponsors need different study protocols for each.
- Lack of data and data standards. We are starting to see some data, especially as the industry is trying to do the right thing for this patient population. But the industry does not have a large data lake or pooled data source on pregnant and breastfeeding individuals to help find good answers to difficult problems.
How to navigate global pregnancy & breastfeeding regulations
But it’s not all doom and gloom. The industry has recognized the importance of this problem and is collaborating on solutions to today’s problems. The International Council of Harmonisation (ICH) E21 is a new working group dedicated to harmonization and creating a global standard. The National Institutes of Health (NIH) established a task force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) as part of the 21st Century Cures Act. The Innovative Medicines Initiative (IMI) funds the ConcePTION project to radically and rapidly reduce uncertainty about the effects of medication used during pregnancy and breastfeeding.
The industry also has robust preclinical safety testing to identify high-risk teratogens to eliminate any chemical structures or entities in medicine that have an indication of possible mutagenic or teratogenic effects.
TransCelerate has done its part by creating and releasing the “Regulatory Landscape Comparison by Regulation Topic” and the “Initiatives & Regulatory Landscape Assessment Output” tools. These two documents cover existing regulations and guidances from Europe, the U.S., Canada, Asia, and Africa. The exercise was an enormous undertaking, and it took the team a year and a half to compile all the details.
Based on the insights obtained from our research and Member Company feedback, we later published the paper “Points to Consider for Pregnancy throughout the Product Lifecycle (Based on the Regulatory Guidance across the Globe)” to help pharmaceutical companies better understand and comply with ambiguous or inconsistent regulatory requirements or guidance. Excitingly, ConcePTION is building upon TransCelerate’s tools in its efforts. This is a perfect example of why we are committed to working with TransCelerate. Having receptive audiences from other stakeholders that can use our information and expert insights allows for greater collaboration and faster progress toward the industry’s goals.
This suite of solutions helps companies meet Health Authorities’ expectations by more effectively and efficiently operationalizing the development of applicable processes and tools to monitor medication exposures and safety events in pregnant and breastfeeding women.
The future of pregnancy & breastfeeding safety considerations
Hopefully, these efforts will help and encourage sponsors to
r plan to enroll pregnant women where it is ethical and appropriate to do so. We expect that the industry will further study how COVID affected pregnancies. Three years ago, we were not even aware of the disease and had no way of fighting it. 324 days after the characterization of the virus, we had the first vaccine, and were aware of how Sars-CoV-2 had the propensity to mutate. Since then, there have been about 120,000 pregnancies studied.
We have seen that without vaccination, the virus is deadly in pregnancy with potentially serious consequences for both the mother and the fetus. Yet with the vaccine, it can prevent 15% of stillbirths related to the virus and improves outcomes and protects 90% of mothers leading to an improvement in neonatal health once the baby is born.
This is a perfect illustration of international collaboration. Looking at the data worldwide, the biopharma industry has made a massive difference in global health by working together to improve public health related to the most recent pandemic virus.
There is value in unity and working to improve health in each of our functions and accelerate scientific discoveries. TransCelerate’s work on this topic isn’t complete. In our research, we realized there are still plenty of opportunities for global associations and working groups to collaborate. The IGR-PV team is now trying to convene these groups to reduce duplication of efforts and share tools and learnings. TransCelerate will also release an expanded points to consider toolkit and a paper later in 2023.
Together, the TransCelerate Pregnancy & Breastfeeding team is trying to build a future where the industry is deliberately designing medications and clinical trials to test whether they are appropriate for use in pregnant women. Our hope is that through the work of TransCelerate and other organizations around the world, we will make a difference and find tomorrow’s new medicine that protects the health of both mother and child.
Amalia Alexe is Policy and Liaison Lead, within the QPPV/ PRRC Office of Novartis GmbH in Switzerland and Team Lead for TransCelerate’s Interpretation of Guidances and Regulations Pregnancy and Breastfeeding team. In her role at Novartis, she leads external projects for PV alongside partners from academia and the industry and is responsible to lead inspection and audit readiness activities within the QPPV PRRC Office.
Prof. David Lewis is the Head of the QPPV PRRC Office at Novartis Pharma GmbH in Germany as well as Visiting Professor at the School of Life and Medical Sciences, University of Hertfordshire.He is also the executive sponsor for TransCelerate’s Pregnancy & Breastfeeding team. He has worked in country affiliates and in a variety of global safety & risk management functions with both investigational & marketed products, as well as in roles involving systems and processes. Dr. Lewis is the author of over 30 papers on the safety of medicines as well as research papers on neuropharmacology.
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