- Email: [email protected]
Maternal immunization: US FDA regulatory considerations
Vaccine 21 (2003) 3487–3491
Maternal immunization: US FDA regulatory considerations Marion F. Gruber Center for Biologics Evaluation and Research (CBER), US FDA, Woodmont Office Complex 1 Rockville Pike, Rockville, MD 20852, USA Received 8 December 2002; accepted 25 March 2003
Abstract Vaccination of pregnant women provides important health benefits to both, mother and infant, and has been an important disease prevention strategy in these two groups. While most vaccines currently licensed in the US are not indicated for use during pregnancy, depending on the vaccine, vaccination programs do frequently include pregnant women. In addition, recent emphasis has been placed on maternal immunization strategies to protect young infants from severe infections. Currently, unless the vaccine is specifically indicated four maternal immunization, no data are collected regarding the vaccine’s safety in pregnant women prior to licensure. However, more females of childbearing age participate in clinical trials and a broad range of novel vaccine products are in development indicated for adolescents and adults. Thus, there is increasing concern for the unintentional exposure of an embryo/fetus before information is available regarding the potential risk versus benefit of the vaccine. Since pregnant women are usually excluded from participation in clinical trials, conclusions regarding developmental risk at the time of licensure are frequently based solely on data derived from developmental toxicity studies in animal models. This paper will review regulatory, preclinical and clinical issues as they pertain to development programs for vaccines intended for vaccination during pregnancy. Published by Elsevier Science Ltd. Keywords: Maternal immunization; Vaccine; Developmental toxicity; Pregnancy; Prenatal immunization; Regulatory consideration
1. Past and current situation Vaccination of pregnant women provides important benefits to both mother and infant and represents an important disease prevention strategy in these two groups. For example, maternal immunization with tetanus toxoid vaccines during the third trimester of pregnancy has been very successful in preventing neonatal and puerperal tetanus in developing countries [1]. Polio vaccine was given routinely to pregnant women in the US in the late 1950s and early 1960s [2]. While most vaccines currently licensed in the US are not indicated for use during pregnancy, depending on the vaccine, vaccination programs do frequently include pregnant women. For example, pregnant women at risk for serious consequences from pneumococcal disease and influenza are recommended to receive the pneumococcal polysaccharide and inactivated influenza vaccines in their second and third trimester of pregnancy. In addition, there are a number of vaccines including hepatitis A and B or meningococcal vaccines recommended for immunization of pregnant women for endemic or epidemic exposure [3]. The general approach taken by the Advisory Committee for ImmuE-mail address: [email protected] (M.F. Gruber). 0264-410X/03/$ – see front matter. Published by Elsevier Science Ltd. doi:10.1016/S0264-410X(03)00357-8
nization Practices (ACIP) is that the benefit of vaccination among pregnant women usually outweighs the risk for potential adverse effects in the mother or developing offspring when (a) the risk for disease exposure is high, (b) infection poses a special risk to mother and fetus, and (c) the vaccine is unlikely to cause harm. Live virus vaccines are generally contraindicated for pregnant women because of the potential risk of transmission of the vaccine virus to the fetus. The need to reduce perinatal infant morbidity and mortality particularly against pathogens that are life-threatening during the neonatal period, such as group B Streptococcus (GBS), and Streptococcus pneumoniae, and the widespread emergence of antibiotic resistant strains underscores the importance for alternative vaccination approaches in this area. Thus, emphasis has been placed on maternal immunization strategies to protect young infants from severe infectious disease through passive antibody transfer from mother to fetus. In addition, vaccination during the third trimester of pregnancy maximizes maternal antibody production and potentially could extend protective immunity during early infancy. Sustained levels of protective antibody could be achieved during the first few months of life when many vaccines are poorly immunogenic in infants. Other possible benefits of maternal immunization include reduced maternal
3488
M.F. Gruber / Vaccine 21 (2003) 3487–3491
colonization (GBS, herpes simplex virus (HSV), vertical disease transmission (HIV)) and IgA antibody transmission in breast milk [4]. Maternal immunization strategies may also offer an alternative for illnesses that are not preventable by current approaches (respiratory syncytial virus (RSV), otitis media) [5]. Vaccines to prevent neonatal group B streptococcal disease by administration during pregnancy have recently been identified as high priority new vaccines [6]. Maternal immunization trials have been and are currently conducted in the US, including trials using pneumococcal conjugate vaccine, GBS conjugate vaccine, and vaccines against respiratory syncytial virus [7]. In addition, a number of controlled clinical trials have recently been conducted using Haemophilus influenzae type B and pneumococcal polysaccharide vaccines. The objective of these studies was to demonstrate the induction of an immune response in the mother and transfer of maternal antibody to the fetus. Some of these studies assessed the occurrence of common local and systemic adverse events experienced by the mother (e.g. injection site reactions and fever) as well as outcomes such as gestational age, birth weight, and mortality and morbidity of infants. Based on the outcomes assessed, data suggested that the vaccine antigens studied were well tolerated and immunogenic in pregnant women [8–11].
women by public health policy makers or interested medical groups. Potential risks involved in prenatal immunization programs include adverse effects caused by constituents of the vaccine products (e.g. adjuvants, preservatives, stabilizers), and inherent biological activity of the antigens, as well as potential adverse effects caused by the immune response induced by the vaccine. While the relative exposure to the vaccine antigen may be very short, the induced maternal immune response is likely to persist and there is concern that it may affect the development of the fetus as well as its developing immune system leading to potential congenital and/or functional abnormalities [12–14]. Moreover, immune modulation in the mother caused by vaccination during pregnancy could theoretically have an adverse influence on pregnancy outcome [15]. In addition, there is a broad range of vaccines currently in clinical trials including live attenuated vector vaccines, recombinant DNA vaccines, vaccine antigens conjugated to carrier proteins, and combination vaccines. These are often formulated with novel adjuvants, excipients, stabilizers and preservatives and may be administered by new routes of administration. For some of these products there is little preclinical or clinical experience. Many of these are indicated for adolescents and adults including females of reproductive age underscoring the need for a more systematic approach to developmental toxicity assessments.
2. Risks associated with maternal immunization and immunization of women of reproductive age
3. Regulatory considerations: preclinical issues
There is to date no documented evidence of reproductive toxic effects in humans caused by the use of currently approved vaccines. However, when assessing the preclinical and clinical safety of a preventive vaccine, regulatory considerations take into account not only previous experiences but also theoretical concerns. Thus, the regulatory approach does not presume a product is safe until it has been directly tested using appropriate preclinical test methods and well-designed, adequately powered clinical trials. Currently, unless the vaccine is specifically indicated for maternal immunization, no data are collected regarding the vaccine’s safety in pregnant women during the pre-licensure phase. However, as more women of child-bearing potential participate in clinical trials and as more preventive vaccines are being developed for adolescents and adults, there is increasing concern for the unintentional exposure of an embryo/fetus before information is available regarding the potential risk versus benefit of the vaccine. In addition, use of licensed vaccines in females of childbearing potential will likely result in the inadvertent exposure of pregnant women and fetuses. Considering that more than half of pregnancies are unintended, it is unlikely that vaccine exposure would be avoided in these pregnancies prior to their clinical recognition. Moreover, following approval, vaccines which do not have specific regulatory approval for use during pregnancy may be recommended for use in pregnant
Until recently, few or no licensed vaccines have been tested for reproductive/developmental toxicity in animals prior to their use in humans. However, there is concern that there is no data to address developmental risk in pregnant women or women of reproductive age at the time of licensure. Thus, developmental toxicity studies in animal models offer one approach to identify potential developmental hazards. This approach appears to be justified as: (a) the target population for vaccines often includes women in their reproductive years who may become pregnant during the time frame of vaccination, (b) clinicians are confronted with situations where immunization of pregnant women may be appropriate, e.g. when pregnant women are thought to be at higher risk from complications of a vaccine preventable disease (e.g. influenza), and (c) vaccine labeling must have a statement about use during pregnancy (21 CFR 201.57 (f)(6)). Consequently, the FDA has developed policy for reproductive toxicity studies for vaccines indicated for maternal immunization and/or immunization of women of childbearing age, and has published a draft guidance document for industry entitled “Considerations for Reproductive Toxicity Studies for Preventive Vaccines for Infectious Disease Indications” [16]. The draft document provides some technical guidance regarding developmental toxicity studies for preventive vaccines. The approach to developmental toxicity studies for preventive vaccines was the subject of
M.F. Gruber / Vaccine 21 (2003) 3487–3491
a workshop co-sponsored by the CBER, the FDA Office of Womens Health (OWH) and the Society of Toxicology (SOT), on 2 and 3 December 2002 [17]. Discussions focused on the technical aspects, experimental design and animal models for developmental toxicity studies for preventive vaccines, as well as the type of information that should be derived from such studies to assure it will be relevant and useful for the assessment of human risk. The draft guidance document will be revised according to recommendations made by experts and workshop participants. 4. Regulatory considerations: clinical issues 4.1. Clinical trials Clinical evaluations of the safety, immunogenicity and efficacy of vaccines indicated for maternal immunization should follow the standards in 21 CFR 312. Further guidance regarding general issues that need to be considered can be found in a publication by Goldenthal et al. [18]. Immunization of pregnant women presents unique issues, since it is important to not only address safety and efficacy in the pregnant women, but also in the offspring. Thus, any recommendation to use a vaccine in pregnant women will require data from large-scale safety studies to ensure that increased rates of pregnancy and labor complications are not detected. It should be noted that it may not be possible to rule out all possible adverse events pre-licensure. However, adverse events that one might be concerned about in the mother include miscarriage, premature labor, uterine bleeding, pre-eclampsia/eclampsia, chorioamnionitis/other infections and other complications of pregnancy. In offspring, adverse events of interest may include neonatal death, prematurity, low birth weight, neonatal infections/sepsis, as well as neonatal complications that might be assessed by admissions to the Neonatal Intensive Care Unit. Additional events of interest that may occur include congenital malformations and functional defects (e.g. hearing impairment/learning disabilities). It should be noted that the choice of a particular safety endpoint which will determine the size of the clinical trial will depend on the product and the disease the product is intended to prevent. Some special issues that should be considered in designing clinical trials for a vaccine indicated for maternal immunization will be reviewed below. It is recommended that review of safety reports by a data safety monitoring board (DSMB) for occurrence of adverse events occur early in the clinical trial following immunization of an initial cohort of pregnant subjects. Maternal health records for prenatal visits should be evaluated by study personnel, in order to detect pregnancy or labor complications (e.g. hypertension, pre-eclampsia, intrauterine growth retardation, oligohydramnios, spontaneous abortion, preterm labor etc.). Systemic reactions specific to pregnancy should be solicited in order to assess a possible relationship to vaccine (e.g.
3489
uterine cramps, contractions, changes in fetal movement, vaginal bleeding or discharge). Assessments of hematologic parameters, blood chemistries and urinalyses at baseline and periodically post-vaccination should be considered to assess for unexpected toxicities. Local and systemic reactions that are moderate or severe should be clinically evaluated. The consent form should clearly state clinical experience with the vaccine, i.e. whether or not the vaccine has been tested in pregnant women, and if so, the number of pregnant women vaccinated and the descriptions and frequencies of any adverse experience observed. A clear understanding of this point is essential to the informed consent. For certain vaccines, there may be concerns that immunization of pregnant females may interfere with the ability of the offspring to mount an active immune response to either the same or a related vaccine antigen. Such concerns may also need to be addressed on a case-by-case basis in clinical immunogenicity studies in infants born to mothers who have been immunized with the vaccine. In addition, the infant should be followed for at least 6–12 months following birth to monitor for normal infant growth and development. 4.2. Pregnancy registries The CBER draft guidance “Considerations for Reproductive Toxicity Studies for Preventive Vaccines for Infectious Disease Indications” also includes recommendations for the establishment of pregnancy registries for the purpose of monitoring any adverse events experienced by vaccinated pregnant women, as well as tracking any developmental toxicities displayed by infants post licensure. Pregnancy registries are encouraged for products indicated for maternal immunization and for products likely to be used in women of reproductive age. The establishment of a pregnancy registry may encourage health care providers to prospectively report exposures in pregnancy, which will result in better post-marketing data. FDA (CDER) has published a guidance for industry document entitled “Establishing Pregnancy Registries” intended to provide sponsors with advice on how to establish pregnancy exposure registries to monitor the outcomes of pregnancies for women who have been exposed to specific medical products, including biological products and vaccines [19]. The FDA Office of Women’s Health has also worked to encourage the creation of and participation in pregnancy registries by creating a website that provides information about pregnancy registries for medicinal products used by pregnant women. The ultimate goal of pregnancy exposure registries is to provide clinically relevant human data that can be used in a product’s labeling to provide medical care providers with useful information for treating or counseling patients who are pregnant or anticipating pregnancy. 4.3. Pregnancy labeling initiative Under current FDA regulations (21 CFR 201.57(f)(6)), unless a drug is not adsorbed systematically and is not known
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to have a potential for indirect harm to a fetus, the label of a licensed drug or biological product must include a subsection which provides relevant preclinical and clinical narrative information regarding teratogenic effects and effects on reproduction and pregnancy, as well as postnatal development. The regulations also require that each product must be classified under one of five pregnancy categories (A–D or X) on the basis of risk of reproductive and developmental adverse effects or, for certain categories, on the basis of such risk weighed against potential benefit. The regulation also specifies the language that is to follow the category designation. However, clinicians who treat pregnant women have expressed concerns that the information contained in the pregnancy labeling subsection is not sufficient to enable the clinician to make an informed decision about use of a drug or biological product in pregnant women and women of childbearing potential. In addition, information on how to respond to inadvertent fetal exposure is lacking. For example, a wide range of products and potential clinical situations are lumped into five categories and thus, erroneously suggest that drugs or biological products within a category present similar risk. In addition, there is, in general, a lack of data from human clinical studies in the pregnancy category section of the label. The FDA is proposing to amend its regulations concerning the format and content of the pregnancy, labor and delivery, and nursing mothers subsections of the labeling for human prescription drugs and biological products [20]. This rule would eliminate the current pregnancy categories and would include information on labor and delivery in the pregnancy subsection. The proposal would require labeling to include a summary assessment of the risks of using a product during pregnancy and lactation and broader discussion of the data, animal and human, that underlie the evaluation of risks associated with a product. The intent is to separate information about risk from information about benefit using a standardized descriptive text with built-in flexibility. The label would also include clinical information to help health care professionals advise women about the use of drugs and biological products during pregnancy and lactation and would also address inadvertent exposure. 4.4. 45CFR Part 46 protection of human research subjects The basic regulations for conducting research in human subjects for federally funded research are contained in 45 CFR 46, subpart (A) covering protection for all human subjects. Subpart (B) pertains to research involving fetuses, pregnant women and human in vitro fertilization. These regulations promote a policy for including pregnant women in clinical research provided the following conditions are met: pregnant women or fetuses can be involved in research when (a) scientifically appropriate preclinical and clinical studies on non-pregnant women have been conducted, (b) procedures will directly benefit the woman, or both the woman
and the fetus, or, if there is no prospect of benefit for the woman nor the fetus, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge. If the research is designed to meet the health needs of the mother and the risk to the fetus is minimal then the woman’s consent alone is sufficient. Also, if the research is designed to meet the health needs of the mother, the mother and the fetus, or provide important biomedical knowledge, the consent of the woman is sufficient for her to participate in the study. However, the regulations under subpart (B) were recently changed to indicate that, if the research holds out the prospect of direct benefit solely to the fetus, the consent of both the pregnant woman and the father will need to be obtained under informed consent provisions of subpart (A) of 45 CFR 46 before the woman can participate in the trial. However, there are exceptions to the requirement for paternal consent, such as when the pregnancy is the result of rape, or if the father is unavailable, incompetent, or temporarily incapacitated (45 CFR 46. 204 “research involving pregnant women or fetuses”) [21]. In summary, maternal immunization holds promises to prevent infectious diseases during a period of increased vulnerability in infants. As more potential candidate vaccines for use during pregnancy become available, increased attention is being given to screen these products for developmental hazards in animals before their use in humans. It is important to not only address the safety and efficacy in pregnant women, but also in their offspring. Any recommendation to use a vaccine in pregnant women will require data from large-scale safety studies. The trend in pregnancy labeling is to provide clinically useful information to both the patient and the practitioner when making a decision about using drugs during pregnancy. References [1] Miller JK. The prevention of neonatal tetanus by maternal immunization, Environ Child Health 1972;159–167. [2] Heinonen OP, Shapiro S, Monson RR. Immunization during pregnancy against poliomyelitis and influenza: relation to childhood malignancy. Int. J. Epidemiol. 1973;2:229–35. [3] Recommended adult immunization schedule-United States, 2002–2003, MMWR October 11, 2002;51(40):904–8. [4] Munoz FM, Englund JA. Vaccines in pregnancy. Infect Dis Clin North Am 2001;15:253–71. [5] Englund JA, Glezen WP. Passive immunization for the prevention of otitis media. Vaccine 2001;19:S116–21. [6] Analysis and Action Plan for the National Vaccine Advisory Committee-Institute of Medicine Report, Vaccines for the 21st Century, June 2001. [7] Glezen P. Maternal vaccines, primary Care: clinics in office practice, vol. 28. 2001;791–806. [8] Englund J, Glezen P, Turner C, Harvey J, Thompson C, Siber G. Transplacental antibody transfer following maternal immunization with polysaccharide and conjugate Haemophilus influenzae type b vaccines. J Inf Dis 1995;171:99–105. [9] O’Dempsey TJD, McArdle T, Ceesay SJ, et al. Immunization with a pneumococcal capsular polysaccharide vaccine during pregnancy. Vaccine 1996;14:963–70.
M.F. Gruber / Vaccine 21 (2003) 3487–3491 [10] Baker CJ, Rench MA, Edwards MS, Carpenter RJ, Hays BM, Kasper D. Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus. N Engl J Med 1988;319:1180– 5. [11] Mulholland K, Suara RO, Siber G, et al. Maternal immunization with Haemophilus influenzae type b polysaccharide-Tetanus protein conjugate vaccine in the Gambia. JAMA 1996;275:1182– 8. [12] Verdier F, Barrow B, Bruge J. Reproductive toxicity testing of vaccines. Toxicology 2003;185:213–9. [13] Holladay SD, Sharova L, Smith BJ, et al. Nonspecific stimulation of the maternal immune system. I. Effects on teratogen-induced fetal malformations. Teratology 2000;62:413–9. [14] Sharova L, Sura P, Smith BJ, et al. Nonspecific stimulation of the maternal immune system. II. Effects on the gene expression of the fetus. Teratology 2000;62:420–8.
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[15] Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478–82. [16] Guidance for industry: considerations for reproductive toxicity studies for preventive vaccines for infectious disease indications: FR vol. 65, September 8; 2000. [17] Non-clinical safety evaluation of preventive vaccines. SOT CCT workshop, 2–3 December 2002, http://www.toxicology.org/ memberservices/meetings/cct-vaccines.html. [18] Goldenthal KL, McVittie LD. The clinical evaluation of preventive vaccines for infectious diseases indications. In: Biologics development: A regulatory Overview (Parexel). 2nd ed. 1997;123–39 (Chapter 7). [19] Guidance for Industry: Establishing Pregnancy Exposure Registries, August 2002, www.fda.gov/cder/guidance/index.htm. [20] Federal Register, vol. 62, no. 147, 41061–41063. [21] Federal Register, vol. 66, no. 219, 56775–56780.
Maternal immunization: US FDA regulatory considerations Marion F. Gruber Center for Biologics Evaluation and Research (CBER), US FDA, Woodmont Office Complex 1 Rockville Pike, Rockville, MD 20852, USA Received 8 December 2002; accepted 25 March 2003
Abstract Vaccination of pregnant women provides important health benefits to both, mother and infant, and has been an important disease prevention strategy in these two groups. While most vaccines currently licensed in the US are not indicated for use during pregnancy, depending on the vaccine, vaccination programs do frequently include pregnant women. In addition, recent emphasis has been placed on maternal immunization strategies to protect young infants from severe infections. Currently, unless the vaccine is specifically indicated four maternal immunization, no data are collected regarding the vaccine’s safety in pregnant women prior to licensure. However, more females of childbearing age participate in clinical trials and a broad range of novel vaccine products are in development indicated for adolescents and adults. Thus, there is increasing concern for the unintentional exposure of an embryo/fetus before information is available regarding the potential risk versus benefit of the vaccine. Since pregnant women are usually excluded from participation in clinical trials, conclusions regarding developmental risk at the time of licensure are frequently based solely on data derived from developmental toxicity studies in animal models. This paper will review regulatory, preclinical and clinical issues as they pertain to development programs for vaccines intended for vaccination during pregnancy. Published by Elsevier Science Ltd. Keywords: Maternal immunization; Vaccine; Developmental toxicity; Pregnancy; Prenatal immunization; Regulatory consideration
1. Past and current situation Vaccination of pregnant women provides important benefits to both mother and infant and represents an important disease prevention strategy in these two groups. For example, maternal immunization with tetanus toxoid vaccines during the third trimester of pregnancy has been very successful in preventing neonatal and puerperal tetanus in developing countries [1]. Polio vaccine was given routinely to pregnant women in the US in the late 1950s and early 1960s [2]. While most vaccines currently licensed in the US are not indicated for use during pregnancy, depending on the vaccine, vaccination programs do frequently include pregnant women. For example, pregnant women at risk for serious consequences from pneumococcal disease and influenza are recommended to receive the pneumococcal polysaccharide and inactivated influenza vaccines in their second and third trimester of pregnancy. In addition, there are a number of vaccines including hepatitis A and B or meningococcal vaccines recommended for immunization of pregnant women for endemic or epidemic exposure [3]. The general approach taken by the Advisory Committee for ImmuE-mail address: [email protected] (M.F. Gruber). 0264-410X/03/$ – see front matter. Published by Elsevier Science Ltd. doi:10.1016/S0264-410X(03)00357-8
nization Practices (ACIP) is that the benefit of vaccination among pregnant women usually outweighs the risk for potential adverse effects in the mother or developing offspring when (a) the risk for disease exposure is high, (b) infection poses a special risk to mother and fetus, and (c) the vaccine is unlikely to cause harm. Live virus vaccines are generally contraindicated for pregnant women because of the potential risk of transmission of the vaccine virus to the fetus. The need to reduce perinatal infant morbidity and mortality particularly against pathogens that are life-threatening during the neonatal period, such as group B Streptococcus (GBS), and Streptococcus pneumoniae, and the widespread emergence of antibiotic resistant strains underscores the importance for alternative vaccination approaches in this area. Thus, emphasis has been placed on maternal immunization strategies to protect young infants from severe infectious disease through passive antibody transfer from mother to fetus. In addition, vaccination during the third trimester of pregnancy maximizes maternal antibody production and potentially could extend protective immunity during early infancy. Sustained levels of protective antibody could be achieved during the first few months of life when many vaccines are poorly immunogenic in infants. Other possible benefits of maternal immunization include reduced maternal
3488
M.F. Gruber / Vaccine 21 (2003) 3487–3491
colonization (GBS, herpes simplex virus (HSV), vertical disease transmission (HIV)) and IgA antibody transmission in breast milk [4]. Maternal immunization strategies may also offer an alternative for illnesses that are not preventable by current approaches (respiratory syncytial virus (RSV), otitis media) [5]. Vaccines to prevent neonatal group B streptococcal disease by administration during pregnancy have recently been identified as high priority new vaccines [6]. Maternal immunization trials have been and are currently conducted in the US, including trials using pneumococcal conjugate vaccine, GBS conjugate vaccine, and vaccines against respiratory syncytial virus [7]. In addition, a number of controlled clinical trials have recently been conducted using Haemophilus influenzae type B and pneumococcal polysaccharide vaccines. The objective of these studies was to demonstrate the induction of an immune response in the mother and transfer of maternal antibody to the fetus. Some of these studies assessed the occurrence of common local and systemic adverse events experienced by the mother (e.g. injection site reactions and fever) as well as outcomes such as gestational age, birth weight, and mortality and morbidity of infants. Based on the outcomes assessed, data suggested that the vaccine antigens studied were well tolerated and immunogenic in pregnant women [8–11].
women by public health policy makers or interested medical groups. Potential risks involved in prenatal immunization programs include adverse effects caused by constituents of the vaccine products (e.g. adjuvants, preservatives, stabilizers), and inherent biological activity of the antigens, as well as potential adverse effects caused by the immune response induced by the vaccine. While the relative exposure to the vaccine antigen may be very short, the induced maternal immune response is likely to persist and there is concern that it may affect the development of the fetus as well as its developing immune system leading to potential congenital and/or functional abnormalities [12–14]. Moreover, immune modulation in the mother caused by vaccination during pregnancy could theoretically have an adverse influence on pregnancy outcome [15]. In addition, there is a broad range of vaccines currently in clinical trials including live attenuated vector vaccines, recombinant DNA vaccines, vaccine antigens conjugated to carrier proteins, and combination vaccines. These are often formulated with novel adjuvants, excipients, stabilizers and preservatives and may be administered by new routes of administration. For some of these products there is little preclinical or clinical experience. Many of these are indicated for adolescents and adults including females of reproductive age underscoring the need for a more systematic approach to developmental toxicity assessments.
2. Risks associated with maternal immunization and immunization of women of reproductive age
3. Regulatory considerations: preclinical issues
There is to date no documented evidence of reproductive toxic effects in humans caused by the use of currently approved vaccines. However, when assessing the preclinical and clinical safety of a preventive vaccine, regulatory considerations take into account not only previous experiences but also theoretical concerns. Thus, the regulatory approach does not presume a product is safe until it has been directly tested using appropriate preclinical test methods and well-designed, adequately powered clinical trials. Currently, unless the vaccine is specifically indicated for maternal immunization, no data are collected regarding the vaccine’s safety in pregnant women during the pre-licensure phase. However, as more women of child-bearing potential participate in clinical trials and as more preventive vaccines are being developed for adolescents and adults, there is increasing concern for the unintentional exposure of an embryo/fetus before information is available regarding the potential risk versus benefit of the vaccine. In addition, use of licensed vaccines in females of childbearing potential will likely result in the inadvertent exposure of pregnant women and fetuses. Considering that more than half of pregnancies are unintended, it is unlikely that vaccine exposure would be avoided in these pregnancies prior to their clinical recognition. Moreover, following approval, vaccines which do not have specific regulatory approval for use during pregnancy may be recommended for use in pregnant
Until recently, few or no licensed vaccines have been tested for reproductive/developmental toxicity in animals prior to their use in humans. However, there is concern that there is no data to address developmental risk in pregnant women or women of reproductive age at the time of licensure. Thus, developmental toxicity studies in animal models offer one approach to identify potential developmental hazards. This approach appears to be justified as: (a) the target population for vaccines often includes women in their reproductive years who may become pregnant during the time frame of vaccination, (b) clinicians are confronted with situations where immunization of pregnant women may be appropriate, e.g. when pregnant women are thought to be at higher risk from complications of a vaccine preventable disease (e.g. influenza), and (c) vaccine labeling must have a statement about use during pregnancy (21 CFR 201.57 (f)(6)). Consequently, the FDA has developed policy for reproductive toxicity studies for vaccines indicated for maternal immunization and/or immunization of women of childbearing age, and has published a draft guidance document for industry entitled “Considerations for Reproductive Toxicity Studies for Preventive Vaccines for Infectious Disease Indications” [16]. The draft document provides some technical guidance regarding developmental toxicity studies for preventive vaccines. The approach to developmental toxicity studies for preventive vaccines was the subject of
M.F. Gruber / Vaccine 21 (2003) 3487–3491
a workshop co-sponsored by the CBER, the FDA Office of Womens Health (OWH) and the Society of Toxicology (SOT), on 2 and 3 December 2002 [17]. Discussions focused on the technical aspects, experimental design and animal models for developmental toxicity studies for preventive vaccines, as well as the type of information that should be derived from such studies to assure it will be relevant and useful for the assessment of human risk. The draft guidance document will be revised according to recommendations made by experts and workshop participants. 4. Regulatory considerations: clinical issues 4.1. Clinical trials Clinical evaluations of the safety, immunogenicity and efficacy of vaccines indicated for maternal immunization should follow the standards in 21 CFR 312. Further guidance regarding general issues that need to be considered can be found in a publication by Goldenthal et al. [18]. Immunization of pregnant women presents unique issues, since it is important to not only address safety and efficacy in the pregnant women, but also in the offspring. Thus, any recommendation to use a vaccine in pregnant women will require data from large-scale safety studies to ensure that increased rates of pregnancy and labor complications are not detected. It should be noted that it may not be possible to rule out all possible adverse events pre-licensure. However, adverse events that one might be concerned about in the mother include miscarriage, premature labor, uterine bleeding, pre-eclampsia/eclampsia, chorioamnionitis/other infections and other complications of pregnancy. In offspring, adverse events of interest may include neonatal death, prematurity, low birth weight, neonatal infections/sepsis, as well as neonatal complications that might be assessed by admissions to the Neonatal Intensive Care Unit. Additional events of interest that may occur include congenital malformations and functional defects (e.g. hearing impairment/learning disabilities). It should be noted that the choice of a particular safety endpoint which will determine the size of the clinical trial will depend on the product and the disease the product is intended to prevent. Some special issues that should be considered in designing clinical trials for a vaccine indicated for maternal immunization will be reviewed below. It is recommended that review of safety reports by a data safety monitoring board (DSMB) for occurrence of adverse events occur early in the clinical trial following immunization of an initial cohort of pregnant subjects. Maternal health records for prenatal visits should be evaluated by study personnel, in order to detect pregnancy or labor complications (e.g. hypertension, pre-eclampsia, intrauterine growth retardation, oligohydramnios, spontaneous abortion, preterm labor etc.). Systemic reactions specific to pregnancy should be solicited in order to assess a possible relationship to vaccine (e.g.
3489
uterine cramps, contractions, changes in fetal movement, vaginal bleeding or discharge). Assessments of hematologic parameters, blood chemistries and urinalyses at baseline and periodically post-vaccination should be considered to assess for unexpected toxicities. Local and systemic reactions that are moderate or severe should be clinically evaluated. The consent form should clearly state clinical experience with the vaccine, i.e. whether or not the vaccine has been tested in pregnant women, and if so, the number of pregnant women vaccinated and the descriptions and frequencies of any adverse experience observed. A clear understanding of this point is essential to the informed consent. For certain vaccines, there may be concerns that immunization of pregnant females may interfere with the ability of the offspring to mount an active immune response to either the same or a related vaccine antigen. Such concerns may also need to be addressed on a case-by-case basis in clinical immunogenicity studies in infants born to mothers who have been immunized with the vaccine. In addition, the infant should be followed for at least 6–12 months following birth to monitor for normal infant growth and development. 4.2. Pregnancy registries The CBER draft guidance “Considerations for Reproductive Toxicity Studies for Preventive Vaccines for Infectious Disease Indications” also includes recommendations for the establishment of pregnancy registries for the purpose of monitoring any adverse events experienced by vaccinated pregnant women, as well as tracking any developmental toxicities displayed by infants post licensure. Pregnancy registries are encouraged for products indicated for maternal immunization and for products likely to be used in women of reproductive age. The establishment of a pregnancy registry may encourage health care providers to prospectively report exposures in pregnancy, which will result in better post-marketing data. FDA (CDER) has published a guidance for industry document entitled “Establishing Pregnancy Registries” intended to provide sponsors with advice on how to establish pregnancy exposure registries to monitor the outcomes of pregnancies for women who have been exposed to specific medical products, including biological products and vaccines [19]. The FDA Office of Women’s Health has also worked to encourage the creation of and participation in pregnancy registries by creating a website that provides information about pregnancy registries for medicinal products used by pregnant women. The ultimate goal of pregnancy exposure registries is to provide clinically relevant human data that can be used in a product’s labeling to provide medical care providers with useful information for treating or counseling patients who are pregnant or anticipating pregnancy. 4.3. Pregnancy labeling initiative Under current FDA regulations (21 CFR 201.57(f)(6)), unless a drug is not adsorbed systematically and is not known
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to have a potential for indirect harm to a fetus, the label of a licensed drug or biological product must include a subsection which provides relevant preclinical and clinical narrative information regarding teratogenic effects and effects on reproduction and pregnancy, as well as postnatal development. The regulations also require that each product must be classified under one of five pregnancy categories (A–D or X) on the basis of risk of reproductive and developmental adverse effects or, for certain categories, on the basis of such risk weighed against potential benefit. The regulation also specifies the language that is to follow the category designation. However, clinicians who treat pregnant women have expressed concerns that the information contained in the pregnancy labeling subsection is not sufficient to enable the clinician to make an informed decision about use of a drug or biological product in pregnant women and women of childbearing potential. In addition, information on how to respond to inadvertent fetal exposure is lacking. For example, a wide range of products and potential clinical situations are lumped into five categories and thus, erroneously suggest that drugs or biological products within a category present similar risk. In addition, there is, in general, a lack of data from human clinical studies in the pregnancy category section of the label. The FDA is proposing to amend its regulations concerning the format and content of the pregnancy, labor and delivery, and nursing mothers subsections of the labeling for human prescription drugs and biological products [20]. This rule would eliminate the current pregnancy categories and would include information on labor and delivery in the pregnancy subsection. The proposal would require labeling to include a summary assessment of the risks of using a product during pregnancy and lactation and broader discussion of the data, animal and human, that underlie the evaluation of risks associated with a product. The intent is to separate information about risk from information about benefit using a standardized descriptive text with built-in flexibility. The label would also include clinical information to help health care professionals advise women about the use of drugs and biological products during pregnancy and lactation and would also address inadvertent exposure. 4.4. 45CFR Part 46 protection of human research subjects The basic regulations for conducting research in human subjects for federally funded research are contained in 45 CFR 46, subpart (A) covering protection for all human subjects. Subpart (B) pertains to research involving fetuses, pregnant women and human in vitro fertilization. These regulations promote a policy for including pregnant women in clinical research provided the following conditions are met: pregnant women or fetuses can be involved in research when (a) scientifically appropriate preclinical and clinical studies on non-pregnant women have been conducted, (b) procedures will directly benefit the woman, or both the woman
and the fetus, or, if there is no prospect of benefit for the woman nor the fetus, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge. If the research is designed to meet the health needs of the mother and the risk to the fetus is minimal then the woman’s consent alone is sufficient. Also, if the research is designed to meet the health needs of the mother, the mother and the fetus, or provide important biomedical knowledge, the consent of the woman is sufficient for her to participate in the study. However, the regulations under subpart (B) were recently changed to indicate that, if the research holds out the prospect of direct benefit solely to the fetus, the consent of both the pregnant woman and the father will need to be obtained under informed consent provisions of subpart (A) of 45 CFR 46 before the woman can participate in the trial. However, there are exceptions to the requirement for paternal consent, such as when the pregnancy is the result of rape, or if the father is unavailable, incompetent, or temporarily incapacitated (45 CFR 46. 204 “research involving pregnant women or fetuses”) [21]. In summary, maternal immunization holds promises to prevent infectious diseases during a period of increased vulnerability in infants. As more potential candidate vaccines for use during pregnancy become available, increased attention is being given to screen these products for developmental hazards in animals before their use in humans. It is important to not only address the safety and efficacy in pregnant women, but also in their offspring. Any recommendation to use a vaccine in pregnant women will require data from large-scale safety studies. The trend in pregnancy labeling is to provide clinically useful information to both the patient and the practitioner when making a decision about using drugs during pregnancy. References [1] Miller JK. The prevention of neonatal tetanus by maternal immunization, Environ Child Health 1972;159–167. [2] Heinonen OP, Shapiro S, Monson RR. Immunization during pregnancy against poliomyelitis and influenza: relation to childhood malignancy. Int. J. Epidemiol. 1973;2:229–35. [3] Recommended adult immunization schedule-United States, 2002–2003, MMWR October 11, 2002;51(40):904–8. [4] Munoz FM, Englund JA. Vaccines in pregnancy. Infect Dis Clin North Am 2001;15:253–71. [5] Englund JA, Glezen WP. Passive immunization for the prevention of otitis media. Vaccine 2001;19:S116–21. [6] Analysis and Action Plan for the National Vaccine Advisory Committee-Institute of Medicine Report, Vaccines for the 21st Century, June 2001. [7] Glezen P. Maternal vaccines, primary Care: clinics in office practice, vol. 28. 2001;791–806. [8] Englund J, Glezen P, Turner C, Harvey J, Thompson C, Siber G. Transplacental antibody transfer following maternal immunization with polysaccharide and conjugate Haemophilus influenzae type b vaccines. J Inf Dis 1995;171:99–105. [9] O’Dempsey TJD, McArdle T, Ceesay SJ, et al. Immunization with a pneumococcal capsular polysaccharide vaccine during pregnancy. Vaccine 1996;14:963–70.
M.F. Gruber / Vaccine 21 (2003) 3487–3491 [10] Baker CJ, Rench MA, Edwards MS, Carpenter RJ, Hays BM, Kasper D. Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus. N Engl J Med 1988;319:1180– 5. [11] Mulholland K, Suara RO, Siber G, et al. Maternal immunization with Haemophilus influenzae type b polysaccharide-Tetanus protein conjugate vaccine in the Gambia. JAMA 1996;275:1182– 8. [12] Verdier F, Barrow B, Bruge J. Reproductive toxicity testing of vaccines. Toxicology 2003;185:213–9. [13] Holladay SD, Sharova L, Smith BJ, et al. Nonspecific stimulation of the maternal immune system. I. Effects on teratogen-induced fetal malformations. Teratology 2000;62:413–9. [14] Sharova L, Sura P, Smith BJ, et al. Nonspecific stimulation of the maternal immune system. II. Effects on the gene expression of the fetus. Teratology 2000;62:420–8.
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[15] Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478–82. [16] Guidance for industry: considerations for reproductive toxicity studies for preventive vaccines for infectious disease indications: FR vol. 65, September 8; 2000. [17] Non-clinical safety evaluation of preventive vaccines. SOT CCT workshop, 2–3 December 2002, http://www.toxicology.org/ memberservices/meetings/cct-vaccines.html. [18] Goldenthal KL, McVittie LD. The clinical evaluation of preventive vaccines for infectious diseases indications. In: Biologics development: A regulatory Overview (Parexel). 2nd ed. 1997;123–39 (Chapter 7). [19] Guidance for Industry: Establishing Pregnancy Exposure Registries, August 2002, www.fda.gov/cder/guidance/index.htm. [20] Federal Register, vol. 62, no. 147, 41061–41063. [21] Federal Register, vol. 66, no. 219, 56775–56780.