9 February 2021
Chairs: Sandra Kweder (US Food and Drug Administration), Janet Nooney (Medicines and Healthcare Products Regulatory Agency), Agnès Saint-Raymond (European Medicines Agency)
1. Welcome and Introduction
Emer Cooke, EMA Executive Director and Chair of ICMRA, welcomed all participants. Emer Cooke emphasised the importance of discussing this topic in the current context of the COVID-19 pandemic: pregnant and lactating/breastfeeding women get infected and require treatment for COVID-19, but there are no data for most of these treatments and vaccines. Pregnant and breastfeeding women have not been included in clinical trials for COVID-19 vaccines, but we know many of them are, will or could be vaccinated. Pregnant women may have additional risk factors, and others will be vaccinated before knowing they are pregnant. This reality is cause to reflect and act not only for COVID-19 medicines and vaccines but also use the experience to agree a new global strategy to obtain systematic data in these populations.
In recent years several initiatives have been undertaken by regulators aiming at improving the situation but to have a real impact, international collaboration and a global convergent approach are key. A global effort also requires effective engagement with women and all stakeholders including sponsors, and health care professionals.
Emer Cooke concluded by emphasising the main objectives of this workshop:
- To take stock of available information and development strategies for COVID-19 vaccines and therapies in pregnant and breastfeeding women;
- To understand knowledge gaps/needs for COVID-19 vaccines and therapies in pregnant and breastfeeding women and how these can be overcome;
- To identify differences in requirements between regulators with the aim to work towards convergence;
- To identify opportunities for further international collaboration in this area;
- To explore how we can leverage the experience from COVID-19 vaccines in pregnant and breastfeeding women to move forward on a global strategy aiming at getting systematic information on these population groups.
2. Introduction to the Agenda
The three co-chairs explained how the workshop was structured.
3. COVID-19 in pregnancy and lactation: update on ongoing initiatives
Chairs: Janet Nooney (MHRA), Agnès Saint-Raymond (EMA)
Corinne de Vries (EMA) presented an update on the CONSIGN (Covid-19 infectiOn aNd medicineS In preGNancy- http://www.encepp.eu/encepp/viewResource.htm?id=39439) project and the international collaboration, to collect meaningful exposure data and study the impact of Covid-19 treatments on pregnant women and newborns.
The aim of CONSIGN is to guide evidence-based decision-making about COVID-19 vaccine indications, vaccination policies, and treatment options for pregnant women.
Objectives of CONSIGN:
- Assess use of medicines for COVID-19 treatment in pregnant women and compare with non-COVID-19/non-pregnant women of same age;
- Describe severity and clinical outcomes of COVID-19 in pregnant women compared to non-pregnant women of reproductive age;
- Assess and compare pregnancy and neonatal outcomes in different COVID-19 treatment groups of pregnant women;
- Establish collaborations with other global initiatives (ICMRA) and ensure sustainability.
CONSIGN works using other networks in pregnancy, namely ConcePTION, INOSS and COVI-PREG.
Recent activities within CONSIGN include EMA agreement on the protocol for the retrospective study in nine population-based electronic health and medical birth registers in eight EEA countries, as well as a description of EHR data sources in EU and a document outlining practical steps for international collaboration on meta-analyses. This has been shared with ICMRA, WHO and other organisations. Separate strands of work include near-real-time utilisation data from COVI-PREG and INOSS. Preliminary data from these were shared with the participants.
Participants were reminded the door is open for collaboration with any interested countries which have electronic health records and can participate in meta-analysis with CONSIGN, or which are not yet part of COVI-PREG or INOSS for meta-analyses on primary data.
Furthermore, ICMRA members were invited to participate in the ICMRA Technical Expert Working Group.
4. COVID-19 treatments in pregnancy and lactation
Chairs: Sandra Kweder (US FDA), Janet Nooney (MHRA)
Lynne Yao (US FDA) presented the situation regarding pregnant and lactating women based on clinical trials with available treatments for COVID-19 in the U.S. In summary, for remdesivir, pregnant women were not included in clinical trials. The product sponsor has committed to conduct a trial to evaluate pharmacokinetics and safety of remdesivir in pregnant women with COVID-19. Regarding treatments available through Emergency Use Authorisations, baricitinib excluded pregnant and lactating women (in ACTT-2) but allowed for their enrolment in ACTT-4; for bamlanivimab, pregnant but not lactating women were included; for casirivimab and imdevimab, pregnant women are included to obtain PK, safety, tolerability and immunogenicity data. Data from a published review on the inclusion of pregnant women in COVID-19 trials was also presented. Overall the vast majority of treatment trials actively excluded pregnant women and ongoing studies are predominantly pregnancy registry studies which follow women who receive the treatment in clinical practice.
Janet Nooney (MHRA) summarised how regulators can ensure data are collected:
- Questioning rationale for exclusion and request company’s future plans for studying effects in pregnancy and breastfeeding;
- Requesting post-licensing studies, including clinical trials, cohort studies and registries;
- Improving transparency around inclusion or exclusion in trial registries and databases to facilitate easy identification of whether pregnant or breastfeeding women can participate.
The discussion highlighted that although we are no longer at an initial phase of the pandemic, regulators still don’t have the necessary pre-authorisation clinical data. The inclusion of pregnant and breastfeeding women in clinical trials should be the standard, based on a benefit/risk analysis of factors such as pre-clinical data, safety data from use in other populations, and not underestimating the risks of untreated disease for mother and infant.
The SARS CoV-2 virus does not spare women of reproductive age and pregnant women and their developing foetuses may be more severely affected by viral infections, even though to date the full extent of additional risk posed by pregnancy in COVID-19 is not established. The systematic exclusion of pregnant women from therapeutic trials results in complete lack of identification of efficacious and safe treatments to prevent adverse maternal, pregnancy, and birth outcomes. Systematic inclusion of pregnant women should be based on consideration of available data on risk and benefit and will require a profound change of mindset.
5. COVID-19 vaccines in pregnancy and lactation
Chairs: Sandra Kweder (US FDA), Agnès Saint-Raymond (EMA)
Corinne de Vries (EMA) presented an overview of pregnant women in clinical trials for the authorised COVID-19 vaccines in the EU (i.e. Pfizer/BioNTech, Moderna and Astra Zeneca). Pregnant women were excluded from the pre-authorisation clinical trials, although a few unexpected pregnancies were reported in the trials. EU Marketing Authorisation Holders have post-authorisation commitments (observational studies/registries, follow-up of vaccinees) to get data in pregnant women. Failing to include pregnant women in COVID-19 vaccines trials reflects that risks associated with viral infections in pregnancy and the experience with the use and benefits of other vaccines for pregnant women and infants, e.g. influenza vaccines, were not taken into account.
Jeff Roberts (US FDA) presented the Fact Sheets that address use in pregnancy for the vaccines under the US Emergency Use Authorisations (Pfizer/BioNTech and Moderna). Pregnant women are not specifically excluded from the indications, but the Sheets do state that, despite reproductive toxicology studies not suggesting any risk, data are insufficient to inform vaccine related risk in pregnancy. The Letter of Authorisation for the EUAs for both vaccines documents that the companies will collect observational data related to pregnancy exposures and outcomes. Meanwhile, public health authorities in the US advise that pregnant women may be vaccinated against the virus, and they note the discussion about benefit-risk considerations with a health care provider can be helpful. Given the limited currently available evidence, it is clear that more data adequate for labelling are urgently needed to inform benefit-risk decision-making by pregnant women and healthcare providers.
Christine Guillard (WHO) presented ongoing WHO activities regarding monitoring of safety of COVID-19 vaccines in pregnancy, including guidance on active and passive surveillance of vaccinated pregnant women, mapping of pregnancy registries in low- and middle-income countries, and development of a template to facilitate individual country safety monitoring.
ICMRA members were invited to share data or experience on pregnancy and breastfeeding with COVID-19 vaccines. Israel reported on the vaccination of pregnant women (independently of trimester) as well as vaccination of breastfeeding women. These women will be followed-up and data shared. Participants mentioned that at least in one country pregnant women are not eligible for vaccination. Other members were invited to share further information/data in writing.
Discussion focussed on the need to change the mindset and including (instead of excluding) pregnant and breastfeeding women in clinical trials. For COVID-19 vaccines in earlier development, regulators should still encourage sponsors, where preclinical data or prior experience do not suggest risk to actively include these women in pre-authorisation clinical trials. Overall both regulators and sponsors need to refocus from collecting data in post-authorisation to active studies pre-authorisation. These same principles also apply more broadly beyond COVID-19, but this pandemic is providing a window to their urgency. Lessons learned from the study and use of other vaccines in pregnant and breastfeeding women as well as from other populations (e.g. paediatrics) can inform on how to do this well. Lack of follow-up when women become pregnant and withdraw or are withdrawn from clinical trials is also a missed opportunity to analyse the pregnancy outcomes, but the real key is proactive study in first place.
Moving forward, regulators must be more systematic in addressing the need for early planning and data collection for COVID-19 vaccines in pregnant and breastfeeding women. One way to address this is by requesting that developers propose a “Maternal Investigation Plan” to be submitted when discussing their development program with regulators in which they outline how and when they will study these populations.
Labelling of COVID-19 differs between countries; some allows for health care professionals to administer the vaccine on the basis of a benefit/risk decision. This flexibility was welcome; however, the key issue remains that the healthcare professionals lack the data to make such decision.
It was reiterated that a change in mindset for vaccines in pregnancy, as for treatments for COVID-19, will require increased engagement with all stakeholders (sponsors, ethics committees, health care professionals) and women themselves. In general, it is expected that pregnant women will be highly motivated to be part of such engagement, just as they are asking for access to the COVID-19 vaccines and have historically been motivated to participate in clinical trials for obstetric conditions.
Communication/agreement that ICMRA might consider recommendations for key messages to be used in public fora to highlight the need to include pregnant and breastfeeding women throughout the life cycle of a medicinal product is essential.
6. Conclusions / International Collaboration in this area
Chairs: Sandra Kweder (US FDA), Janet Nooney (MHRA), Agnès Saint-Raymond (EMA)
Development of treatments and vaccines for COVID-19 show once more that there is a scientific knowledge gap regarding medicines efficacy and safety in pregnancy and breastfeeding: most treatment and vaccine trials actively excluded pregnant women.
There is an absolute and pressing need to change the way we approach medicines in pregnancy and breastfeeding. Specifically, we need to shift from systematic exclusion to inclusion of pregnant and breastfeeding women in clinical trials to obtain the necessary data for these populations. Doing this with care and consideration for potential risk and benefits is possible. Other changes include follow-up data from women who withdraw from trials due to pregnancy. Lessons learned from use of other vaccines in pregnant and breastfeeding women as well as from development of medicines in other populations (e.g. paediatrics) can provide a roadmap for how to enable such trials.
Inclusion of pregnant and breastfeeding women should be proposed for COVID-19 treatment and vaccine future trials. ICMRA members within their countries/regions should promote discussion with sponsors on such inclusion.
A (global) “Maternal Investigation Plan” /package to be submitted by applicants on how they intend to study these populations should be established. ICMRA has a role e.g. by discussing criteria, Maternal Investigation Plans and expectations for the inclusion of these populations and on communication (e.g. ICMRA statement).
This change of approach will require international collaboration and harmonisation. It is proposed to develop an ICH Guideline on the topic.
Increased communication and transparency with global agreement on key messages should be promoted.
ICMRA members within their countries/regions should relay and promote transparency around inclusion of pregnant and breastfeeding women in clinical trials and ensure their experiences are already captured in registries and other observational studies.
A change of mindset requires increased engagement with (pregnant) women and all stakeholders: sponsors, ethics committees and Marketing Authorisation Holders. Regulators themselves should not only focus on requiring robust data collection post-authorisation, but where reproductive toxicity studies support doing so, rather request pre-authorisation data from clinical trials in pregnant and breastfeeding women.
7. Closing remarks and next steps
Chairs: Sandra Kweder (US FDA), Janet Nooney (MHRA), Agnès Saint-Raymond (EMA)
ICMRA members are invited to share in writing any national activity and data on pregnancy and breastfeeding for COVID-19 treatments and vaccines.
ICMRA will continue to support international collaboration as part of CONSIGN (through ICMRA Technical Experts Working Group on COVID-19 infection and medicines in pregnancy). ICMRA members are welcome to join the Technical Experts Working Group.
The co-Chairs closed the meeting by thanking the presenters, participants and ICMRA secretariat.
ICMRA secretariat will follow-up within the ICMRA Policy TCs and consider a follow-up workshop.