Understanding the Research Rules Involving Pregnant Women and Fetuses
March 2015 Issue
By Kathryn Jones, BA,
As you may recall, the CRTIMES recently did a Feature Article on one of the vulnerable populations specifically mentioned in the federal regulations: children. This month we will focus on another class of vulnerable subjects: pregnant women and fetuses.
The IRB adheres to the Department of Health and Human Services’ Code of Federal Regulations 45 CFR 46 for the Protection of Human Subjects; and is overseen by the Office of Human Research Protections (OHRP). For FDA applicable studies, the IRB also applies the Food and Drug Administration’s Protection of Human Subjects Regulations 21 CFR 50. Both sets of regulations have subparts for vulnerable subjects. The FDA has regulations for the vulnerable population of children. The OHRP regulations have three subparts for vulnerable populations: pregnant women, prisoners, and children. For the purposes of this article, we will be focusing on Subpart B: Pregnant Women under the OHRP regulations, as the FDA regulations do not have a specific subpart for pregnant women. When pregnant women, human fetuses, or neonates are going to be included in the research, the IRB must make pregnancy findings.
You may be wondering why pregnant women are considered to be a vulnerable population. Why would pregnant women be excluded from a study? Historically, women were excluded from clinical research studies as recently as the 1990s due to the fear that participating in clinical trials would expose fetuses to drugs that could cause birth defects. In addition, both researchers and pharmaceutical companies were concerned about being held liable for harm to the fetus. For example, in the 1950s, a drug called Thalidomide was marketed in Europe for the treatment of morning sickness in early pregnancy. The use of this drug in pregnant women led to major birth defects in fetuses that were exposed to the drug. This experience led to the exclusion of women in research. Due to this exclusion, there was a severe lack of knowledge in how both drugs and medical devices would affect women. This became a growing issue in the research community due to the lack of data surrounding women.Changes began in 1990, when NIH created the Office of Research on Women’s Health to promote women’s health research as its primary focus. In 1993, Congress passed legislation that required clinical trials funded by the NIH to include women as a study population. In that same year, the FDA also removed a ban that excluded women of childbearing potential from early Phase 1 and some Phase II clinical trials. In addition, the FDA also released a “Guideline for the Study and Evaluation of Gender Differences in Clinical Evaluation of Drugs” to provide guidance to pharmaceutical companies on how data on women included in drug trials should be evaluated. In the next year, the FDA created the Office of Women’s Health. All of these changes led to the inclusion of women in clinical research.
Researchers planning a study must determine whether pregnant women will participate in the research. This includes both specifically targeting pregnant women and not excluding them from the study. If the research enrolls a single pregnant woman, then the IRB must review that research involving pregnant women based on specific criteria.
Review of research involving pregnant women, human fetuses, or neonates must include the following:
§Where scientifically appropriate, there are preclinical studies (including animal studies or non-pregnant women studies) to provide risk assessment data for pregnant women and fetuses
§Prospect of benefit
When considering excluding pregnant women from a study, investigators should consider the Belmont principle of “Respect for Persons”:
Investigators should respect the autonomy of pregnant women to make informed decisions about whether they participate in research. In including pregnant women, the following two points should be considered: (1) the potential benefits of therapy, and (2) the potential risks associated with the lack of treatment. However, the regulations regarding the inclusion of pregnant women and fetuses still need to be adhered to.
Although it may seem difficult to include pregnant women in research, there are a number of clinical research studies that reiterate how important it is to include pregnant women and fetuses in research due to the results of the studies of either stopping commonly accepted clinical practices, or resulting in new preventive therapies or treatments. These outcomes only highlight the strong impetus to include pregnant women in research, while protecting both the pregnant woman and fetus.
For example, in a study conducted by the Maternal Fetal Medicine Units (MFMU) Network, it was found that antibiotic treatment for pregnant women with asymptomatic bacterial vaginosis was actually associated with increased risk of preterm delivery. In another study conducted by MFMU, it has been found that weekly injections of progesterone helped prevent recurrent preterm birth and improved neonatal outcomes for pregnancies at risk.
If you are going to exclude pregnant women from your study, there should be a clear rationale for the exclusion criteria. If pregnant women are excluded from the research due to potential risks to the woman or fetus, then there must be a plan in place for ensuring that women of childbearing potential do not become pregnant throughout the duration of the study. Depending on the study, there can be a single pregnancy test at the beginning of the study; while in other studies, there may need to be multiple pregnancy tests. In addition to the possibility of multiple pregnancy tests, some studies may require language about contraception in the informed consent.
Pregnancy testing can be done in two different ways: by urine or blood samples. Blood tests are the more accurate of the two, and indicate at an earlier time that a person is pregnant. The IRB requires that either clinical personnel or study staff perform pregnancy testing, rather than accepting the results of a self-reported test from a subject. If pregnancy testing will be done, then this must be clearly delineated in both the protocol and the consent, and the process must be explained (i.e., how often it will be done, who will do it, etc.). It is important that there is a plan in place to protect the confidentiality of the test results.
For some studies that involve risk to pregnant women or fetuses, women of childbearing potential may be required to use an approved form of contraception to be able to participate in the study.
The IRB has sample template contraception language that can be inserted into the consent:
In the state of Massachusetts, a minor is defined as a person under 18 years old. If minors will be enrolled in the research, the investigator needs to explain to both the child and the parent about pregnancy testing, how the results will be reported, and contraception. Unless parental consent is waived by the IRB, both the parent‘s consent and minor’s assent are required for pregnancy testing for minors. If the minor is pregnant, then the investigator must have a plan for referring the minor subject to appropriate follow-up care, and there must be confidentiality protections in place. In Massachusetts, there are no specific laws regarding emancipated minors. OHRP defines an emancipated minor as: “A legal status conferred upon persons who have not yet attained the age of legal competency as defined by state law, but who are entitled to treatment as if they had by virtue of assuming adult responsibilities, such as self-support, marriage or procreation.” If the minor makes her own healthcare decisions, the IRB will waive parental consent, and the minor will consent for participation in the research. However, if the parent(s) of a minor still make the healthcare decisions for the child, then the parent needs to consent for the child’s participation in the research.
As in all consents, the investigator must inform subjects of any reasonably foreseeable risks or discomforts to the subject. In this instance, it is the responsibility of the investigator to inform the pregnant woman of the risks to both her and the fetus. In addition, the investigator must clearly delineate the risks for the pregnant woman and to the fetus. If pregnant women are being excluded, it should be noted in the consent that women of childbearing potential should avoid becoming pregnant and, if appropriate, the contraception language should be included in the consent. If pregnant women will be included in the research, then any monitoring or additional protections should be explained in the consent.
Pregnancy findings can also be a consideration in studies with male participants who will be taking certain drugs, devices, or biologics. Why would this be a consideration? The drug or device that the male participant would be taking for the research could harm a pregnant woman or the fetus. Depending on the study, male participants may be told in the consent that they must use a form of contraception or abstain from having sex with women. They may also be told that they must avoid donating sperm for a specific amount of time. This should all be clearly explained in both the consent and the protocol.
Beginning in the 1990s, there was a greater emphasis on including pregnant women as a population in research. There should always be a rationale if you are seeking to exclude pregnant women from your study, as it is important that effective treatments are developed for pregnant women. However, the risks and benefits of including this vulnerable population should be weighed; and it needs to be determined if the additional protections proposed are adequate to protect the pregnant woman and fetus.
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