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Task force on research specific to pregnant and lactating women
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Task Force on Research Specific to Pregnant and Lactating Women John J. Byrne MD , Alexander M. Saucedo MD , Catherine Y. Spong MD PII: DOI: Reference:
S0146-0005(20)30007-0 https://doi.org/10.1016/j.semperi.2020.151226 YSPER 151226
To appear in:
Seminars in Perinatology
Please cite this article as: John J. Byrne MD , Alexander M. Saucedo MD , Catherine Y. Spong MD , Task Force on Research Specific to Pregnant and Lactating Women, Seminars in Perinatology (2020), doi: https://doi.org/10.1016/j.semperi.2020.151226
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Task Force on Research Specific to Pregnant and Lactating Women John J. Byrne MD Alexander M. Saucedo MD Catherine Y. Spong MD University of Texas Southwestern Medical Center Grant support: none Mailing Address University of Texas Southwestern Medical Center Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology 5323 Harry Hines Blvd H6:106 Dallas Texas 75390 phone: 214 648 3113 email: [email protected] Conflict of Interest: Dr. Spong was the chair of the Task Force on Research Specific to Pregnant and Lactating Women from its inception until 7/1/2018.
Abstract (100-150 words) The Task Force on Research Specific to Pregnant Women and Lactating Women was established by the 21st Century Cures Act and charged with providing advice and guidance to the Secretary of Health and Human Services on activities related to identifying and addressing gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women, including the development of, collaboration on, and coordination of such activities. The Task Force developed 15 recommendations based on information gleaned during four meetings and a public comment period. These recommendation include concrete actionable items to facilitate information and data for providers and the public.
In 2017, the 21st Century Cures Act included the establishment of a Task Force on Research Specific to Pregnant Women and Lactating Women. This task force was charged with providing advice and guidance to the Secretary of Health and Human Services (HHS) on activities related to identifying and addressing gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women, including the development of, collaboration on, and coordination of such activities. The Task Force built on a history of prior work in this area. Although not all inclusive (Figure 1), a major initial work in this area was the publication in 1985 of the HHS report of the Public Health Service Task Force on Women’s Health Issues (1). This report focused more broadly on women’s issues and included “requirements of postmarket surveillance” and that “adequate numbers of women be included in clinical trials of drugs that will be used by women, and of all new drugs that are to be recommended for use by women.“ This work was continued through the next decade by the Institute of Medicine and the National Institutes of Health (NIH) Revitalization Act emphasizing the importance of including women in clinical studies. The Institute of Medicine’s report, published in 1994 (2), reviewed the importance of including pregnant women in research, as noted in the executive summary (p 17) “It is critical to note that the committee is not advocating active recruitment of pregnant women into each and every clinical study. Rather, it is urging that the prevailing presumption regarding the participation of pregnant women in clinical trials and other intervention studies be shifted from one of exclusion to one of inclusion. The committee believes that a strengthened informed consent process can address specific concerns regarding the inclusion of pregnant women in clinical studies.”
The first major federal or professional initiatives focused on pregnant or lactating women was twenty years later in 2004 with the Food and Drug Administration (FDA) draft guidance for industry on clinical lactation studies. At that same time, the FDA wrote the guidance and the NICHD funded the Obstetric-Fetal Pharmacology Research Unit, which will be later known as the Obstetric-Fetal Pharmacology Research Centers, to improve the safety of therapeutic agents using in pregnancy and lactation. Over the last fifteen years, a flurry of activity – at least as compared to the prior century – has erupted from Federal agencues, professional societies and independent collaborative efforts, such as the Second Wave Initiative, focusing on the importance of research and data for pregnant women. In many of these efforts, recommendations were made. The Task Force’s recommendations acknowledge, and build upon this work. A group of interested societies and organizations came together in the fall of 2013 and generated the concept of what ultimately became the Task Force. This group formed a coalition, The Coalition to Advance Maternal Therapeutics (Figure 2), identifying specific guiding principles: (a) Quality care and treatment for women and their infants, (b) Current, evidencebased information about safety and efficacy of drugs, (c) appropriate research must be conducted, (d) government must prioritize clinical research on drugs’ effect through pregnancy and lactation. A stakeholder meeting was held with Federal agencies in June of 2014 to discuss the current state of research, and to identify areas for improvement. Specifically, they reviewed the need for evaluation of therapeutics in pregnancy and breastfeeding, deliberated on the role of agencies and organizations, and discussed how best to promote awareness and education.
Information from the coalition and other meetings/reports culminated in a congressional briefing on November 15, 2016 and ultimately in inclusion in the 21st Centery Cures Act. Section 2041 of the 21st Century Cures Act outlines the requirements for the Task Force (Figure 3). The authority was delegated from HHS to the National Institutes of Health Director on January 19, 2017. The Charter was established on March 13, 2017, the federal members were designated in May 2017 and non-federal members were approved in February 2018. The law outlined the requirements and timing of the report. Four open meetings were held between August 2017 and May 2018 covering each aspect of the report. To encourage active and open participation and input, all meetings were videocast and time was allotted in each meeting for presentations from the public. In addition, a request for information was solicited to further facilitate public input. The report was developed in real time between each of the meetings and vetted during each meeting. The final meeting, in May, was dedicated to the recommendations that were developed and approved in the open meeting. The report was submitted to Congress and the HHS Secretary in September 2018, as required by law. The report is available online (3). Fifteen recommendations were developed by the Task Force (3). The implementation of these recommendations require in some cases, broad social change, and in others, specific direct policy or procedural changes which could have dramatic impact. Omnipresent in the discussions and recommendations was the critical need to alter cultural assumptions that have limited the inclusion of pregnant/lactating women in research, thereby limiting the evidence and data of therapies in pregnant and lactating women. Although these recommendations were developed over the course of the four meetings, the historical recommendations were not
discussed until the final meeting to afford the opportunity to develop novel ideas as well as – in some cases - to further emphasize that some concepts are salient and would surface regardless.
Many recommendations involved increased funding, support, and new initiatives:
Increase the quantity, quality, and timeliness of research on safety and efficacy of therapeutic products used by pregnant women and lactating women
Expand the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology and therapeutics
Create a public awareness campaign to engage the public and health care providers in research on pregnant women and lactating women
Develop and implement evidence-based communication strategies with health care providers on information relevant to research on pregnant women and lactating women
Develop programs to drive discovery and development of therapeutics and new therapeutic products for conditions specific to pregnant women and lactating women
Develop separate programs to study therapeutic products used off-patent in pregnant women and lactating women using the National Institute of Health (NIH) Best Pharmaceuticals for Children Act (BPCA) as a model.
Others recommendations urged for adjustment and or expansion of existing programs, data, initiatives:
Leverage established and support new infrastructures/collaborations to perform research in pregnant women and lactating women.
Utilize and improve existing resources for data to inform the evidence and provide a foundation for research on pregnant women and lactating women
Optimize registries for pregnancy and lactation
There are a number of longstanding networks, registries, and medical data sources that could be leveraged to obtain needed data. In other cases, new initiatives would be needed as there is not current infrastsructure or the infrastructure in place is inadequate for the need.
Some of the recommendations were very concrete and could be accomplished with policy changes:
Remove regulatory barriers to research in pregnant women
As further described in the text this could include a modification of 45CFR46 subpart B, specifically changing 46.204(e) in subpart B to maternal consent alone. It was noted that there is recognized autonomy of a pregnant woman; that coupled with the evolution of family structure and for a child only one parental signature is required for research to benefit the child. This alteration would then allow alignment with the parental consent for pediatrics. In addition, adding in to 36.046 the option of “Minor increase over minimal risk” for pregnancy, as is the case with children in subpart D further would remove regulatory barriers for research in pregnant women.
Include and integrate pregnant women and lactating women in the clinical research agenda
The implementation of the Common Rule, a federal policy on the protection of human subjects, has already started this process by removing pregnant women as an example of a vulnerable population. Other opportunities include aligning or harmonizing the Food and Drug Administration language to also remove pregnant women as a vulnerable population. Furthermore the development of guidance to facilitate the conduct of research by the Department of Health and Human Services is an opportunity to further integrate inclusion.
Other recommendations require new policies or programs:
Reduce liability to facilitate an evidence base for new therapeutic products that may be used by women who are or may become pregnant and by lactating women
Implement a proactive approach to protocol development and study design to include pregnant women and lactating women in clinical research
These opportunities would provide an incentive for industry and others to work in this space and increase the ability to include these populations in research studies.
The final two recommendations were more administrative regarding continuation of the Task Force and oversight to monitor implementation of the recommendations.
The Department of Health and Human Services Secretary should consider exercising the authority provided in law to extend the PRGLAC Task Force when its charter expires in March 2019
Establish an Advisory Committee to monitor and report on implementation of recommendations, updating regulations, and guidance, as applicable, regarding the inclusion of pregnant women and lactating women in clinical research
Importantly, as part of the analysis, a literature review of overall therapies for specific conditions identified numerous gaps in information. Although over 90% of women take medications in pregnancy and 70% are prescribed medications in pregnancy – impacting 5.4 million women in the United States; three million women breastfeed and 500,000 women annually have difficulty making milk, the information available for counseling is extremely limited. As an example, approximately 8.5% of women have asthma and roughly half of these experience an asthma attack in the year prior to pregnancy. A literature review over a ten year period (2006-2017) identified only four randomized controlled trials in pregnancy, and no studies of pharmacokinetics or pharmacodynamics (PK/PD). In lactation, the situation is more dire, with no randomized trials, PK/PD studies and only 3 basic studies (3). Conditions specific to pregnancy are similar; as one example, nausea and vomiting of pregnancy or hyperemesis gravidarum, occurs in 3% of pregnancies and is a pregnancy specific condition, yet there are only 22 randomized control trials, five of which were on herbal or other “natural” therapies. Low milk supply is one of the most comonly cited reasons for early cessation or stopping exclusivity of breastfeeding, there were only 48 articles over the ten year period with eight trials, of which four studied herbal or alternative therapies. The state of obstetrics, specifically regarding the signifcant paucity of available data on medication in pregnancy and lactation, is eerily analogous to the state of pediatrics before the
implementation of the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA). The BPCA/PREA have improved the infrastructure and funding mechanisms to conduct studies/clinical trials in the pediatric population, improved the number of pediatric pharmacologists/researchers and have created a legal requirement to include children in drug studies. Conversely, the field of obstetrics has a limited number of researchers, limited basic science knowledge, and limited involvement of pregnant and lactating women in research. Although the research infrastructure for pregnancy and lactation has been developed by the NICHD , which established the Obstetric-Fetal Pharmacology Research Centers (OPRC) and Maternal-Fetal Medicine Unit (MFMU) Network, few individual large grants have been issued for research in this field. There currently stands a significant gap in knowledge in drug dosing, drug teratogenicity, and drug distribution/metabolism/excretion in pregnant and lacting women. Lastly, unlike the pediatric population, there is no requirement for the inclusion of pregnant or lactating women in drug studies. In summary, there is limited evidence or data on therapies specific to pregnant and lactating women. The PRGLAC Task Force was developed as a result of the 21st Century Cures Act and provided an overview of the topic, identifying 15 recommendations for the Health and Human Services Secretary and Congress. A renewal of the task force (4) will provide advice and guidance to the HHS Secretary on the implementation of the recommendations. These opportunities build on a long and rich history of the importance of including pregnant and lactating women in research. As highlighted in recent commentaries, there are many opportunities to obtain needed data to optimize care for pregnant and lactating women (5,6). Many women use medications in pregnancy and lactation and the ability to obtain information
on therapies already in use will help to guide care. Research in pregnant women should be prioritized as the scientific need is large and research in this population is underrepresented. Given that pregnancy sets the blueprint for life-long health, investment during pregnancy has the opportunity to improve global health.
References 1. Institute of Medicine. Women’s health. Report of the public health service task force on women’s health issues. Public Health Rep 1985;100:73-106 2. IOM Study: Women and Health Research Ethical and Legal Issues of Including Women in Clinical Studies, Volume 1 (1994) file:///C:/Users/S179308/Downloads/2304.pdf (accessed March 15, 2019) 3. Task force on research specific to pregnant women and lactating women: report to Secretary, Health and Human Services, Congress. Washington, DC: National Institute of Child Health and Human Development (2018) (https://www.nichd.nih.gov/sites/default/files/2018-09/PRGLAC_Report.pdf (accessed March 23, 2019) 4. https://www.nichd.nih.gov/newsroom/news/032519-PRGLAC (accessed April 7, 2019) 5. Byrne JJ and Spong CY. “Is It Safe?” — The Many Unanswered Questions about Medications and Breast-Feeding. N Engl J Med 2019; 380:1296-1297 DOI: 10.1056/NEJMp1817420 6. Eke AC, Dooley KE, Sheffield JS. Pharmacologic Research in Pregnant Women — Time to Get It Right. N Engl J Med 2019; 380:1293-1295 DOI: 10.1056/NEJMp1815325
1985: HHS Report of PHS Task Force on Women’s Health Issues 1991: Institute of Medicine meeting: Women and Health Research 1992: IOM Committee on Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies (Pub 1994) 1993: NIH Revitalization Act: Inclusion of women in clinical studies 1994: FDA Office of Women’s Health Conference: Regulated Products and Pregnant Women 2000: FDA/NICHD Conference: Clinical Pharmacology during Pregnancy; Addressing Clinical Needs through Science 2004: FDA draft Guidance for industry: Pharmacokinetics in Pregnancy – Study Design, Data Analysis, and Impact on Dosing and Labeling 2005: FDA draft Guidance for Industry: Clinical Lactation Study 2005: First NICHD Obstetrical Pharmacology Research Units funded 2007: ACOG Committee Opinion: Research Involving Women 2009: The Second Wave Initiative: Toward Responsible Inclusion of pregnant women in research 2010: NIH ORWH workshop: Enrolling Pregnant Women: Issues in Clinical Research 2011-2013 NIAID meetings regarding study design of clinical trials of vaccines in pregnant women 2012: National Vaccine Advisory Committee established Maternal Immunization working group (Pub 2017) 2013: The Coalition to Advance Maternal Therapeutics formed 2015: ACOG Committee Opinion: Ethical considerations of including women as research subjects 2015: NICHD/SMFM/ACOG/AAP workshop: Medications in Pregnancy and Lactation 2016: FDA meeting Evaluation of the Safety of Drugs and Biological Products used During Lactation 2016: Am. Society for Clinical Pharmacology and Therapeutics Inclusion of pregnant and breastfeeding women in research 2017: Cures Act establishing Task Force on Research Specific to Pregnant Women and Lactating Women 2017-2018: PRGLAC meetings 2018: FDA Risk Communication Advisory Committee meeting Requirements for Pregnancy and Lactation Labeling Figure 1: Historical recommendations for women, pregnancy women, and/or lactating women.
Figure 2. Members of the Coalition to Advance Maternal Therapeutics
Figure 3. Required components of the Task Force Report
Task Force on Research Specific to Pregnant and Lactating Women John J. Byrne MD , Alexander M. Saucedo MD , Catherine Y. Spong MD PII: DOI: Reference:
S0146-0005(20)30007-0 https://doi.org/10.1016/j.semperi.2020.151226 YSPER 151226
To appear in:
Seminars in Perinatology
Please cite this article as: John J. Byrne MD , Alexander M. Saucedo MD , Catherine Y. Spong MD , Task Force on Research Specific to Pregnant and Lactating Women, Seminars in Perinatology (2020), doi: https://doi.org/10.1016/j.semperi.2020.151226
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Task Force on Research Specific to Pregnant and Lactating Women John J. Byrne MD Alexander M. Saucedo MD Catherine Y. Spong MD University of Texas Southwestern Medical Center Grant support: none Mailing Address University of Texas Southwestern Medical Center Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology 5323 Harry Hines Blvd H6:106 Dallas Texas 75390 phone: 214 648 3113 email: [email protected] Conflict of Interest: Dr. Spong was the chair of the Task Force on Research Specific to Pregnant and Lactating Women from its inception until 7/1/2018.
Abstract (100-150 words) The Task Force on Research Specific to Pregnant Women and Lactating Women was established by the 21st Century Cures Act and charged with providing advice and guidance to the Secretary of Health and Human Services on activities related to identifying and addressing gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women, including the development of, collaboration on, and coordination of such activities. The Task Force developed 15 recommendations based on information gleaned during four meetings and a public comment period. These recommendation include concrete actionable items to facilitate information and data for providers and the public.
In 2017, the 21st Century Cures Act included the establishment of a Task Force on Research Specific to Pregnant Women and Lactating Women. This task force was charged with providing advice and guidance to the Secretary of Health and Human Services (HHS) on activities related to identifying and addressing gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women, including the development of, collaboration on, and coordination of such activities. The Task Force built on a history of prior work in this area. Although not all inclusive (Figure 1), a major initial work in this area was the publication in 1985 of the HHS report of the Public Health Service Task Force on Women’s Health Issues (1). This report focused more broadly on women’s issues and included “requirements of postmarket surveillance” and that “adequate numbers of women be included in clinical trials of drugs that will be used by women, and of all new drugs that are to be recommended for use by women.“ This work was continued through the next decade by the Institute of Medicine and the National Institutes of Health (NIH) Revitalization Act emphasizing the importance of including women in clinical studies. The Institute of Medicine’s report, published in 1994 (2), reviewed the importance of including pregnant women in research, as noted in the executive summary (p 17) “It is critical to note that the committee is not advocating active recruitment of pregnant women into each and every clinical study. Rather, it is urging that the prevailing presumption regarding the participation of pregnant women in clinical trials and other intervention studies be shifted from one of exclusion to one of inclusion. The committee believes that a strengthened informed consent process can address specific concerns regarding the inclusion of pregnant women in clinical studies.”
The first major federal or professional initiatives focused on pregnant or lactating women was twenty years later in 2004 with the Food and Drug Administration (FDA) draft guidance for industry on clinical lactation studies. At that same time, the FDA wrote the guidance and the NICHD funded the Obstetric-Fetal Pharmacology Research Unit, which will be later known as the Obstetric-Fetal Pharmacology Research Centers, to improve the safety of therapeutic agents using in pregnancy and lactation. Over the last fifteen years, a flurry of activity – at least as compared to the prior century – has erupted from Federal agencues, professional societies and independent collaborative efforts, such as the Second Wave Initiative, focusing on the importance of research and data for pregnant women. In many of these efforts, recommendations were made. The Task Force’s recommendations acknowledge, and build upon this work. A group of interested societies and organizations came together in the fall of 2013 and generated the concept of what ultimately became the Task Force. This group formed a coalition, The Coalition to Advance Maternal Therapeutics (Figure 2), identifying specific guiding principles: (a) Quality care and treatment for women and their infants, (b) Current, evidencebased information about safety and efficacy of drugs, (c) appropriate research must be conducted, (d) government must prioritize clinical research on drugs’ effect through pregnancy and lactation. A stakeholder meeting was held with Federal agencies in June of 2014 to discuss the current state of research, and to identify areas for improvement. Specifically, they reviewed the need for evaluation of therapeutics in pregnancy and breastfeeding, deliberated on the role of agencies and organizations, and discussed how best to promote awareness and education.
Information from the coalition and other meetings/reports culminated in a congressional briefing on November 15, 2016 and ultimately in inclusion in the 21st Centery Cures Act. Section 2041 of the 21st Century Cures Act outlines the requirements for the Task Force (Figure 3). The authority was delegated from HHS to the National Institutes of Health Director on January 19, 2017. The Charter was established on March 13, 2017, the federal members were designated in May 2017 and non-federal members were approved in February 2018. The law outlined the requirements and timing of the report. Four open meetings were held between August 2017 and May 2018 covering each aspect of the report. To encourage active and open participation and input, all meetings were videocast and time was allotted in each meeting for presentations from the public. In addition, a request for information was solicited to further facilitate public input. The report was developed in real time between each of the meetings and vetted during each meeting. The final meeting, in May, was dedicated to the recommendations that were developed and approved in the open meeting. The report was submitted to Congress and the HHS Secretary in September 2018, as required by law. The report is available online (3). Fifteen recommendations were developed by the Task Force (3). The implementation of these recommendations require in some cases, broad social change, and in others, specific direct policy or procedural changes which could have dramatic impact. Omnipresent in the discussions and recommendations was the critical need to alter cultural assumptions that have limited the inclusion of pregnant/lactating women in research, thereby limiting the evidence and data of therapies in pregnant and lactating women. Although these recommendations were developed over the course of the four meetings, the historical recommendations were not
discussed until the final meeting to afford the opportunity to develop novel ideas as well as – in some cases - to further emphasize that some concepts are salient and would surface regardless.
Many recommendations involved increased funding, support, and new initiatives:
Increase the quantity, quality, and timeliness of research on safety and efficacy of therapeutic products used by pregnant women and lactating women
Expand the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology and therapeutics
Create a public awareness campaign to engage the public and health care providers in research on pregnant women and lactating women
Develop and implement evidence-based communication strategies with health care providers on information relevant to research on pregnant women and lactating women
Develop programs to drive discovery and development of therapeutics and new therapeutic products for conditions specific to pregnant women and lactating women
Develop separate programs to study therapeutic products used off-patent in pregnant women and lactating women using the National Institute of Health (NIH) Best Pharmaceuticals for Children Act (BPCA) as a model.
Others recommendations urged for adjustment and or expansion of existing programs, data, initiatives:
Leverage established and support new infrastructures/collaborations to perform research in pregnant women and lactating women.
Utilize and improve existing resources for data to inform the evidence and provide a foundation for research on pregnant women and lactating women
Optimize registries for pregnancy and lactation
There are a number of longstanding networks, registries, and medical data sources that could be leveraged to obtain needed data. In other cases, new initiatives would be needed as there is not current infrastsructure or the infrastructure in place is inadequate for the need.
Some of the recommendations were very concrete and could be accomplished with policy changes:
Remove regulatory barriers to research in pregnant women
As further described in the text this could include a modification of 45CFR46 subpart B, specifically changing 46.204(e) in subpart B to maternal consent alone. It was noted that there is recognized autonomy of a pregnant woman; that coupled with the evolution of family structure and for a child only one parental signature is required for research to benefit the child. This alteration would then allow alignment with the parental consent for pediatrics. In addition, adding in to 36.046 the option of “Minor increase over minimal risk” for pregnancy, as is the case with children in subpart D further would remove regulatory barriers for research in pregnant women.
Include and integrate pregnant women and lactating women in the clinical research agenda
The implementation of the Common Rule, a federal policy on the protection of human subjects, has already started this process by removing pregnant women as an example of a vulnerable population. Other opportunities include aligning or harmonizing the Food and Drug Administration language to also remove pregnant women as a vulnerable population. Furthermore the development of guidance to facilitate the conduct of research by the Department of Health and Human Services is an opportunity to further integrate inclusion.
Other recommendations require new policies or programs:
Reduce liability to facilitate an evidence base for new therapeutic products that may be used by women who are or may become pregnant and by lactating women
Implement a proactive approach to protocol development and study design to include pregnant women and lactating women in clinical research
These opportunities would provide an incentive for industry and others to work in this space and increase the ability to include these populations in research studies.
The final two recommendations were more administrative regarding continuation of the Task Force and oversight to monitor implementation of the recommendations.
The Department of Health and Human Services Secretary should consider exercising the authority provided in law to extend the PRGLAC Task Force when its charter expires in March 2019
Establish an Advisory Committee to monitor and report on implementation of recommendations, updating regulations, and guidance, as applicable, regarding the inclusion of pregnant women and lactating women in clinical research
Importantly, as part of the analysis, a literature review of overall therapies for specific conditions identified numerous gaps in information. Although over 90% of women take medications in pregnancy and 70% are prescribed medications in pregnancy – impacting 5.4 million women in the United States; three million women breastfeed and 500,000 women annually have difficulty making milk, the information available for counseling is extremely limited. As an example, approximately 8.5% of women have asthma and roughly half of these experience an asthma attack in the year prior to pregnancy. A literature review over a ten year period (2006-2017) identified only four randomized controlled trials in pregnancy, and no studies of pharmacokinetics or pharmacodynamics (PK/PD). In lactation, the situation is more dire, with no randomized trials, PK/PD studies and only 3 basic studies (3). Conditions specific to pregnancy are similar; as one example, nausea and vomiting of pregnancy or hyperemesis gravidarum, occurs in 3% of pregnancies and is a pregnancy specific condition, yet there are only 22 randomized control trials, five of which were on herbal or other “natural” therapies. Low milk supply is one of the most comonly cited reasons for early cessation or stopping exclusivity of breastfeeding, there were only 48 articles over the ten year period with eight trials, of which four studied herbal or alternative therapies. The state of obstetrics, specifically regarding the signifcant paucity of available data on medication in pregnancy and lactation, is eerily analogous to the state of pediatrics before the
implementation of the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA). The BPCA/PREA have improved the infrastructure and funding mechanisms to conduct studies/clinical trials in the pediatric population, improved the number of pediatric pharmacologists/researchers and have created a legal requirement to include children in drug studies. Conversely, the field of obstetrics has a limited number of researchers, limited basic science knowledge, and limited involvement of pregnant and lactating women in research. Although the research infrastructure for pregnancy and lactation has been developed by the NICHD , which established the Obstetric-Fetal Pharmacology Research Centers (OPRC) and Maternal-Fetal Medicine Unit (MFMU) Network, few individual large grants have been issued for research in this field. There currently stands a significant gap in knowledge in drug dosing, drug teratogenicity, and drug distribution/metabolism/excretion in pregnant and lacting women. Lastly, unlike the pediatric population, there is no requirement for the inclusion of pregnant or lactating women in drug studies. In summary, there is limited evidence or data on therapies specific to pregnant and lactating women. The PRGLAC Task Force was developed as a result of the 21st Century Cures Act and provided an overview of the topic, identifying 15 recommendations for the Health and Human Services Secretary and Congress. A renewal of the task force (4) will provide advice and guidance to the HHS Secretary on the implementation of the recommendations. These opportunities build on a long and rich history of the importance of including pregnant and lactating women in research. As highlighted in recent commentaries, there are many opportunities to obtain needed data to optimize care for pregnant and lactating women (5,6). Many women use medications in pregnancy and lactation and the ability to obtain information
on therapies already in use will help to guide care. Research in pregnant women should be prioritized as the scientific need is large and research in this population is underrepresented. Given that pregnancy sets the blueprint for life-long health, investment during pregnancy has the opportunity to improve global health.
References 1. Institute of Medicine. Women’s health. Report of the public health service task force on women’s health issues. Public Health Rep 1985;100:73-106 2. IOM Study: Women and Health Research Ethical and Legal Issues of Including Women in Clinical Studies, Volume 1 (1994) file:///C:/Users/S179308/Downloads/2304.pdf (accessed March 15, 2019) 3. Task force on research specific to pregnant women and lactating women: report to Secretary, Health and Human Services, Congress. Washington, DC: National Institute of Child Health and Human Development (2018) (https://www.nichd.nih.gov/sites/default/files/2018-09/PRGLAC_Report.pdf (accessed March 23, 2019) 4. https://www.nichd.nih.gov/newsroom/news/032519-PRGLAC (accessed April 7, 2019) 5. Byrne JJ and Spong CY. “Is It Safe?” — The Many Unanswered Questions about Medications and Breast-Feeding. N Engl J Med 2019; 380:1296-1297 DOI: 10.1056/NEJMp1817420 6. Eke AC, Dooley KE, Sheffield JS. Pharmacologic Research in Pregnant Women — Time to Get It Right. N Engl J Med 2019; 380:1293-1295 DOI: 10.1056/NEJMp1815325
1985: HHS Report of PHS Task Force on Women’s Health Issues 1991: Institute of Medicine meeting: Women and Health Research 1992: IOM Committee on Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies (Pub 1994) 1993: NIH Revitalization Act: Inclusion of women in clinical studies 1994: FDA Office of Women’s Health Conference: Regulated Products and Pregnant Women 2000: FDA/NICHD Conference: Clinical Pharmacology during Pregnancy; Addressing Clinical Needs through Science 2004: FDA draft Guidance for industry: Pharmacokinetics in Pregnancy – Study Design, Data Analysis, and Impact on Dosing and Labeling 2005: FDA draft Guidance for Industry: Clinical Lactation Study 2005: First NICHD Obstetrical Pharmacology Research Units funded 2007: ACOG Committee Opinion: Research Involving Women 2009: The Second Wave Initiative: Toward Responsible Inclusion of pregnant women in research 2010: NIH ORWH workshop: Enrolling Pregnant Women: Issues in Clinical Research 2011-2013 NIAID meetings regarding study design of clinical trials of vaccines in pregnant women 2012: National Vaccine Advisory Committee established Maternal Immunization working group (Pub 2017) 2013: The Coalition to Advance Maternal Therapeutics formed 2015: ACOG Committee Opinion: Ethical considerations of including women as research subjects 2015: NICHD/SMFM/ACOG/AAP workshop: Medications in Pregnancy and Lactation 2016: FDA meeting Evaluation of the Safety of Drugs and Biological Products used During Lactation 2016: Am. Society for Clinical Pharmacology and Therapeutics Inclusion of pregnant and breastfeeding women in research 2017: Cures Act establishing Task Force on Research Specific to Pregnant Women and Lactating Women 2017-2018: PRGLAC meetings 2018: FDA Risk Communication Advisory Committee meeting Requirements for Pregnancy and Lactation Labeling Figure 1: Historical recommendations for women, pregnancy women, and/or lactating women.
Figure 2. Members of the Coalition to Advance Maternal Therapeutics
Figure 3. Required components of the Task Force Report