A framework for evidence of the safety of medicines in pregnancy and breastfeeding
Dear Editor
In 2019, ConcePTION, an Innovative Medicines Initiative-funded (1) research consortium embarked on a series of studies aimed at establishing an international network and framework to improve the evaluation of the safety of medicines in pregnancy and breastfeeding. We represent 88 public and private organisations dedicated to this 5-year programme.
Pregnant and breastfeeding women are almost invariably excluded from controlled clinical trials; postmarketing safety monitoring focuses on reporting harms. A recent editorial by Laura Riley (2) raised the need not only to include pregnant women in clinical trials, but also to invest in public health surveillance systems for monitoring exposures to medicines during pregnancy, and capturing maternofetal outcomes after marketing of the medicines. It is a global imperative to involve large numbers of women in research projects focusing on maternal health. The ConcePTION project aims to address the gaps that have been identified.
ConcePTION has been running for just over two-and-a-half years. The project aims to establish a framework to support the implementation of a system that will enable the generation of robust scientific evidence in a rapid timeframe. Our work commenced in Europe, but it is our ambition to propose standards for global adoption to address the paucity of evidence. ConcePTION unites various existing networks, and includes more than fifty organizations. Researchers are working collaboratively as a network to collate data based on a common data model optimized for pregnancy pharmacovigilance, which will support expert evaluation and thereby enable the generation of knowledge. Our objective is to ensure that this network is sustainable in the long-term. The overall goal is to characterise, rapidly and efficiently, harms and risks associated with the use of medicines in pregnant and breastfeeding women. Our work is focused on optimising safety data collection, facilitating analyses of these data, and augmenting the interpretation of potential safety signals gathered concerning pregnant and breastfeeding women.
We recognise that women rely on advice from healthcare professionals, labelling applied to pharmaceutical products, information from the regulatory authorities, online resources, and family and friends (3). Each of these sources should draw on scientific evidence. However, for pregnancy and breastfeeding cohorts, that evidence is largely lacking, incomplete, conflicting, or may simply be inaccessible to the people seeking information. In particular, systematic follow-up to assess potential longer-term effects is generally lacking. For example, the labels of medicinal products at the time of first marketing usually state that there is a lack of evidence regarding use during pregnancy and breastfeeding (4), while any new evidence that might be generated is incorporated into labels only several decades later (mean = 27 years) (5). Our conclusion is that there is not only a dearth of new medicines, trusted and unbiased evidence concerning the safety of authorised medicines is absent, even after decades of use. The main reason for this is that we fail to monitor the postmarketing safety of medicines in a systematic manner. Regulatory reporting systems focus on only on adverse outcomes and disregard reports with a positive outcome. This imbalance hampers an objective assessment of the safety of the newly marketed medicines.
The requirement for change spans the lifecycle of medicines, from preclinical safety (where the animal models require significant improvement due to the lack of translation to the clinical setting), through clinical studies (due to protocol exclusions), through to the postmarketing environment (where evidence generation often takes decades). It is also vital that once the required scientific and medical evidence has been generated, the evidence is collected, collated, and disseminated from a trusted central source.
We should include the use of medicines by breastfeeding women. Short- and long-term benefits of breastfeeding to both mothers and infants have been well documented. However, robust clinical lactation studies are rare and existing data cannot be translated with confidence into evidence-based clinical practice. In order to provide evidence for medicine transfer to breastmilk, we need to test milk from mothers receiving treatment during the post-partum period. The biobank developed within IMI ConcePTION will enable analyses to be conducted and reported according to defined standards and protocols (6).
The complex and disconnected universe of postmarketing safety data requires a multi-faceted approach to provide a satisfactory solution. We propose the collection of a standard set of data fields (core data elements), designed to facilitate medical assessment by providing the essential evidence. The fields are a logical extension of the current harmonised data standards for individual case safety reports (ICSRs) used to exchange adverse event drug reports worldwide (7), with the additional content required to support analyses of pregnancy and lactation-related data. We have also assessed existing medical coding systems, covering adverse events, indications, medicinal products, as well as units and measures, in order to provide a sound basis for evaluation of normalised data. It is recognised that the Brighton Collaboration provides an excellent range of case definitions related to both COVID-19 (8) and pregnancy outcomes, but even here further work is required to provide an internationally agreed set of terms and a retrieval strategy for reports of neurodevelopmental delay, for example.
There are multiple ongoing post-marketing studies concerning COVID-19 immunisation and pregnancy, including COVI-PREG (9), CONSIGN (10), and V-Safe (11). These studies have their merits, and they will produce valuable evidence concerning COVID-19, immunisation, and pregnancy outcomes. We should consider the increased power of these programmes if they were to collect, collate, and analyse data in a standardised manner. Increasing the statistical power would maximise the value of the research, and increase the level of confidence in the evidence generated.
In conclusion, we support the call from Allyah Abbas-Hanif and her colleagues on the need to change the clinical trials landscape initially where there is a compelling clinical need by implementing strategies in support of the inclusion of pregnant women and neonates. We wish expand by calling for further support and investment in public and private health surveillance systems optimized for monitoring pregnancy and breastfeeding in the postmarketing setting. The collaborative effort required should span the development of medicines throughout the lifecycle, and requires cooperation between all stakeholders.
Yours sincerely
Dr David J Lewis, Qualified Person for Pharmacovigilance, Novartis Pharma GmbH, Wehr, Germany
Senior Visiting Research Fellow, School of Life and Medical Sciences, University of Hertfordshire, England
Dr Laura Yates, University of KwaZulu-Natal, South Africa
Professor Eugene van Puijenbroek, Pharmacovigilance Centre Lareb, The Netherlands
References
1. IMI ConcePTION. Project Factsheet. https://www.imi.europa.eu/projects-results/project-factsheets/conception (Accessed Oct 20, 2021).
2. Riley L. (Editorial) mRNA Covid-19 vaccines in pregnant women. N Engl J Med 2021; 384 (24): 2342-3. doi: https://doi.org10.1056/NEJMe2107070.
3. Alexe, A. Is my treatment harming my baby? A critical appraisal of a patient`s journey through purportedly transparent pregnancy safety data. Master Thesis 2021, Eu2P Master Programme, University of Bordeaux, France.
4. Ramoz, L.L. and N.M. Patel-Shori, Recent changes in pregnancy and lactation labeling: retirement of risk categories. Pharmacotherapy, 2014; 34 (4): 389-95.
5. Adam, M.P., J.E. Polifka, and J.M. Friedman, Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet, 2011; 157C(3): 175-82.
6. IMI ConcePTION. The European Breast Milk Collection. https://www.imi-conception.eu/biobank/ (Accessed Oct 17, 2021).
7. European Medicines Agency. ICH guideline E2B (R3) on electronic transmission of individual case safety reports (ICSRs) - data elements and message specification - implementation guide. EMA/CHMP/ICH/287/1995. 28 July 2013. https://www.ema.europa.eu/en/documents/scientific-guideline/internationa.... (Accessed Oct 17, 2021).
8. Brighton Collaboration. Safety Platform for Emergency vACcines (SPEAC). https://brightoncollaboration.us/covid-19/. (Accessed Oct 17, 2021).
9. COVI-PREG registry for pregnant women exposed to SARS-CoV-2 (COVID-19, CONSIGN study), EUPAS39226. http://www.encepp.eu/encepp/viewResource.htm?id=40543. (Accessed Oct 17, 2021).
10. CONSIGN description of international collaboration in the area of medicines use and effects in COVID-19 affected pregnancies (CONSIGN-International) EUPAS40317. http://www.encepp.eu/encepp/viewResource.htm?id=42594. (Accessed Oct 17, 2021).
11. V-safe COVID-19 vaccine pregnancy registry. Atlanta: Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafepregnancy... on 03 May 2021. (Accessed Oct 17, 2021).
Competing interests:
The ConcePTION project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821520. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.
David Lewis and Amalia Alexe work for a pharmaceutical company (Novartis).
21 October 2021
David J Lewis
Qualified Person for Pharmacovigilance
Dr Laura Yates, University of KwaZulu-Natal, South Africa; Professor Eugene van Puijenbroek, Pharmacovigilance Centre Lareb, The Netherlands; Amalia Alexe, MSc Pharm, Novartis Pharma AG, Basel, Switzerland
Rapid Response:
A framework for evidence of the safety of medicines in pregnancy and breastfeeding
Dear Editor
In 2019, ConcePTION, an Innovative Medicines Initiative-funded (1) research consortium embarked on a series of studies aimed at establishing an international network and framework to improve the evaluation of the safety of medicines in pregnancy and breastfeeding. We represent 88 public and private organisations dedicated to this 5-year programme.
Pregnant and breastfeeding women are almost invariably excluded from controlled clinical trials; postmarketing safety monitoring focuses on reporting harms. A recent editorial by Laura Riley (2) raised the need not only to include pregnant women in clinical trials, but also to invest in public health surveillance systems for monitoring exposures to medicines during pregnancy, and capturing maternofetal outcomes after marketing of the medicines. It is a global imperative to involve large numbers of women in research projects focusing on maternal health. The ConcePTION project aims to address the gaps that have been identified.
ConcePTION has been running for just over two-and-a-half years. The project aims to establish a framework to support the implementation of a system that will enable the generation of robust scientific evidence in a rapid timeframe. Our work commenced in Europe, but it is our ambition to propose standards for global adoption to address the paucity of evidence. ConcePTION unites various existing networks, and includes more than fifty organizations. Researchers are working collaboratively as a network to collate data based on a common data model optimized for pregnancy pharmacovigilance, which will support expert evaluation and thereby enable the generation of knowledge. Our objective is to ensure that this network is sustainable in the long-term. The overall goal is to characterise, rapidly and efficiently, harms and risks associated with the use of medicines in pregnant and breastfeeding women. Our work is focused on optimising safety data collection, facilitating analyses of these data, and augmenting the interpretation of potential safety signals gathered concerning pregnant and breastfeeding women.
We recognise that women rely on advice from healthcare professionals, labelling applied to pharmaceutical products, information from the regulatory authorities, online resources, and family and friends (3). Each of these sources should draw on scientific evidence. However, for pregnancy and breastfeeding cohorts, that evidence is largely lacking, incomplete, conflicting, or may simply be inaccessible to the people seeking information. In particular, systematic follow-up to assess potential longer-term effects is generally lacking. For example, the labels of medicinal products at the time of first marketing usually state that there is a lack of evidence regarding use during pregnancy and breastfeeding (4), while any new evidence that might be generated is incorporated into labels only several decades later (mean = 27 years) (5). Our conclusion is that there is not only a dearth of new medicines, trusted and unbiased evidence concerning the safety of authorised medicines is absent, even after decades of use. The main reason for this is that we fail to monitor the postmarketing safety of medicines in a systematic manner. Regulatory reporting systems focus on only on adverse outcomes and disregard reports with a positive outcome. This imbalance hampers an objective assessment of the safety of the newly marketed medicines.
The requirement for change spans the lifecycle of medicines, from preclinical safety (where the animal models require significant improvement due to the lack of translation to the clinical setting), through clinical studies (due to protocol exclusions), through to the postmarketing environment (where evidence generation often takes decades). It is also vital that once the required scientific and medical evidence has been generated, the evidence is collected, collated, and disseminated from a trusted central source.
We should include the use of medicines by breastfeeding women. Short- and long-term benefits of breastfeeding to both mothers and infants have been well documented. However, robust clinical lactation studies are rare and existing data cannot be translated with confidence into evidence-based clinical practice. In order to provide evidence for medicine transfer to breastmilk, we need to test milk from mothers receiving treatment during the post-partum period. The biobank developed within IMI ConcePTION will enable analyses to be conducted and reported according to defined standards and protocols (6).
The complex and disconnected universe of postmarketing safety data requires a multi-faceted approach to provide a satisfactory solution. We propose the collection of a standard set of data fields (core data elements), designed to facilitate medical assessment by providing the essential evidence. The fields are a logical extension of the current harmonised data standards for individual case safety reports (ICSRs) used to exchange adverse event drug reports worldwide (7), with the additional content required to support analyses of pregnancy and lactation-related data. We have also assessed existing medical coding systems, covering adverse events, indications, medicinal products, as well as units and measures, in order to provide a sound basis for evaluation of normalised data. It is recognised that the Brighton Collaboration provides an excellent range of case definitions related to both COVID-19 (8) and pregnancy outcomes, but even here further work is required to provide an internationally agreed set of terms and a retrieval strategy for reports of neurodevelopmental delay, for example.
There are multiple ongoing post-marketing studies concerning COVID-19 immunisation and pregnancy, including COVI-PREG (9), CONSIGN (10), and V-Safe (11). These studies have their merits, and they will produce valuable evidence concerning COVID-19, immunisation, and pregnancy outcomes. We should consider the increased power of these programmes if they were to collect, collate, and analyse data in a standardised manner. Increasing the statistical power would maximise the value of the research, and increase the level of confidence in the evidence generated.
In conclusion, we support the call from Allyah Abbas-Hanif and her colleagues on the need to change the clinical trials landscape initially where there is a compelling clinical need by implementing strategies in support of the inclusion of pregnant women and neonates. We wish expand by calling for further support and investment in public and private health surveillance systems optimized for monitoring pregnancy and breastfeeding in the postmarketing setting. The collaborative effort required should span the development of medicines throughout the lifecycle, and requires cooperation between all stakeholders.
Yours sincerely
Dr David J Lewis, Qualified Person for Pharmacovigilance, Novartis Pharma GmbH, Wehr, Germany
Senior Visiting Research Fellow, School of Life and Medical Sciences, University of Hertfordshire, England
Dr Laura Yates, University of KwaZulu-Natal, South Africa
Professor Eugene van Puijenbroek, Pharmacovigilance Centre Lareb, The Netherlands
Amalia Alexe MSc Pharm, Novartis Pharma AG, Basel, Switzerland
References
1. IMI ConcePTION. Project Factsheet. https://www.imi.europa.eu/projects-results/project-factsheets/conception (Accessed Oct 20, 2021).
2. Riley L. (Editorial) mRNA Covid-19 vaccines in pregnant women. N Engl J Med 2021; 384 (24): 2342-3. doi: https://doi.org10.1056/NEJMe2107070.
3. Alexe, A. Is my treatment harming my baby? A critical appraisal of a patient`s journey through purportedly transparent pregnancy safety data. Master Thesis 2021, Eu2P Master Programme, University of Bordeaux, France.
4. Ramoz, L.L. and N.M. Patel-Shori, Recent changes in pregnancy and lactation labeling: retirement of risk categories. Pharmacotherapy, 2014; 34 (4): 389-95.
5. Adam, M.P., J.E. Polifka, and J.M. Friedman, Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet, 2011; 157C(3): 175-82.
6. IMI ConcePTION. The European Breast Milk Collection. https://www.imi-conception.eu/biobank/ (Accessed Oct 17, 2021).
7. European Medicines Agency. ICH guideline E2B (R3) on electronic transmission of individual case safety reports (ICSRs) - data elements and message specification - implementation guide. EMA/CHMP/ICH/287/1995. 28 July 2013. https://www.ema.europa.eu/en/documents/scientific-guideline/internationa.... (Accessed Oct 17, 2021).
8. Brighton Collaboration. Safety Platform for Emergency vACcines (SPEAC). https://brightoncollaboration.us/covid-19/. (Accessed Oct 17, 2021).
9. COVI-PREG registry for pregnant women exposed to SARS-CoV-2 (COVID-19, CONSIGN study), EUPAS39226. http://www.encepp.eu/encepp/viewResource.htm?id=40543. (Accessed Oct 17, 2021).
10. CONSIGN description of international collaboration in the area of medicines use and effects in COVID-19 affected pregnancies (CONSIGN-International) EUPAS40317. http://www.encepp.eu/encepp/viewResource.htm?id=42594. (Accessed Oct 17, 2021).
11. V-safe COVID-19 vaccine pregnancy registry. Atlanta: Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafepregnancy... on 03 May 2021. (Accessed Oct 17, 2021).
Competing interests: The ConcePTION project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821520. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. David Lewis and Amalia Alexe work for a pharmaceutical company (Novartis).