Vulnerable Subjects - Pregnant Women
Research involving pregnant women, fetuses and human in vitro fertilization are subject to special federal regulations that guide IRB deliberations on such studies.
Research studies involving pregnant women or fetuses can be approved by the IRB if the following requirements of federal regulations are satisfied:
- Preclinical studies have been conducted, including studies on pregnant animals; clinical studies, that include nonpregnant women and provide data for assessing potential risks to pregnant women and fetuses
- Risk to fetus is caused solely by interventions or procedures that hold prospect of direct benefit for the woman or the fetus or,
- If no benefit, risk to the fetus is not greater than minimal and the research develops important biomedical knowledge not obtainable by any other means.
- Any risk is the least possible for achieving the objectives of the research.
- Individuals engaged in the research will have no part in: 1) any decisions as to the timing, method, or procedures used to terminate a pregnancy, and 2) determining the viability of the fetus at the termination of the pregnancy; and
- No inducements, monetary or otherwise, will be offered to terminate the pregnancy.
Fetus means the product of conception from implantation until delivery.
Neonate means a newborn.
Pregnancy encompasses the period of time from implantation until delivery. A woman shall be assumed to be pregnant if she exhibits any of the pertinent presumptive signs of pregnancy, such as missed menses, until the results of a pregnancy test are negative or until delivery.
Viable, as it pertains to the neonate, means being able, after delivery, to survive (given the benefit of available medical therapy) to the point of independently maintaining heartbeat and respiration. If a neonate is viable then it may be included in research only to the extent permitted and in accordance with the requirements for research involving children.
Active Recruitment of Women
In order to assure that adequate numbers of women are included, researchers are encouraged to actively recruit women into clinical drug trials. For specific outreach methodologies, researchers should refer to the NIH Outreach Notebook of the Inclusion of Women and Minorities in Biomedical and behavioral Research (1994).
Women of Child-Bearing Potential
Historically, in order to avert harm to a developing fetus in an unsuspected pregnancy, physicians and the lay community expressed concerns regarding the participation of women of child-bearing potential in research. As a result, Federal agencies developed special guidelines for the protection of the developing fetus that excluded women of child-bearing potential from participation in some research. In 1977, for example, the FDA published a guideline that excluded most women of child-bearing potential from early phase drug trials. An exception was made for studies involving women with serious and life-threatening diseases.
Since then, questions raised by grass roots, professional consumer, and governmental groups regarding the adequacy and fairness in the distribution of the risks and benefits of research resulted in changes to the regulations for the involvement of women in research. At the same time, improved pregnancy tests and methods of contraception became available.
In 1988, the FDA issued guidelines that called for safety and efficacy profiles for women, elderly, and diverse racial groups as part of new drug applications (NDA). Then in 1993, following a broad public discussion about participation of women in clinical drug trials, the FDA issued a new guideline that eliminated restrictions on women of childbearing potential in all phases of drug trials.
The guideline detailed procedures for minimizing the risks of pregnancy in women participants, such as contraceptive counseling, pregnancy tests, timing of short term studies in relation to the menstrual cycle, and the process of informed consent. Though the FDA emphasized the importance of risk/benefit determinations for subjects entering various phases of clinical drug trials, they underscored that initial determinations regarding whether risks to a fetus were adequately addressed were best left to subjects, physicians, local IRB's, and study sponsors. The new guideline also called for gender analysis with special attention to factors affecting the role of the menstrual cycle, and exogenous hormone therapy in relation to the drug, as well as the influence of the drug on oral contraceptives.
The Department of Health and Human Services has also carefully examined the issue of participation of women of child bearing potential in research. Since the primary aim of clinical trials is to provide scientific evidence leading to a change in health policy or a standard of care, it is imperative to determine if the intervention or therapy being studied affects men and women differently. As stated in its guidelines, NIH Outreach Notebook of the Inclusion of Women and Minorities in Biomedical and Behavioral Research (1994), the NIH has concluded that the inclusion of women in research is sufficiently important that the only justifiable reason to exclude non-pregnant women of child-bearing potential from research is compelling evidence that the proposed research would be inappropriate with respect to the health of the subject or to the purpose of the research.
The policy statement referenced above pertains primarily to the inclusion of women as subjects in clinical trials, i.e., medical research testing new treatments. However, the inclusion of women in behavioral research is also important and should be accomplished unless there is a compelling rationale which establishes that inclusion is inappropriate with respect to the health of the subject or the purpose of the research.
Significant portions of the text below are presented verbatim as published in the Code of Federal regulations and the Federal Register.
Pregnant Women as Human Research Subjects
Drug research using pregnant women as subjects is governed by the federal regulations. In accordance Federal Regulations, "no pregnant woman may be involved as a subject in a human clinical research project unless:
(1) the purpose of the activity is to meet the health needs of the mother and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or
(2) the risk to the fetus is minimal. "
Research involving pregnant women is permitted only if the mother and the father are legally competent and both have given their consent after having been fully informed regarding the possible impact on the fetus, except that the father's consent need not be secured if
(1) the purpose of the activity is to meet the health needs of the mother;
(2) his identity or whereabouts cannot be reasonably ascertained;
(3) he is not reasonably available; or
(4) the pregnancy resulted from rape.
Women of Child-Bearing Potential as Human Research Subjects
Non-pregnant women should not be excluded from any phase of research unless the science of the project or the health of the subject will be compromised. Regarding clinical drug research, Phase I, II and III trials should have the proportion of women in the study which at least reflects the proportion of women in the population that will receive the drug when it is marketed, and should enroll numbers adequate to detect clinically significant sex differences in drug metabolism and response.
Risk to Fertility
It is expected that both male and female subjects will be informed about potential risks to their fertility including the development of any abnormalities or abnormalities in function of reproductive organs as a consequence of the proposed study intervention. "Where abnormalities of reproductive organs or their function (spermatogenesis or ovulation) have been observed in experimental animals as a consequence of the proposed study intervention, the decision to include subjects of reproductive age in a clinical study should be based on a careful risk/benefit evaluation, taking into account the nature of the abnormalities, the dosage needed to induce them, the consistency of the findings in different species, the severity of the illness being treated, the potential importance of the drug, the availability of alternative treatment, and the duration of therapy.
"Where subjects of reproductive potential are included in studies of drugs showing reproductive toxicity in animals, the clinical studies should include appropriate monitoring and/or laboratory studies to allow detection of these effects. Long-term follow-up will usually be needed to evaluate the effects of such drugs in humans.
Risk to Fetus and/or Infant
- General Guidelines: "Appropriate precautions should be taken in research studies to guard against inadvertent exposure of fetuses to potentially toxic agents and to inform subjects and subjects of potential risk and the need for precautions. In all cases, the informed consent document and investigator's drug information brochure should include all available information regarding the potential risk of fetal toxicity. If animal reproductive toxicity studies are complete, the results should be presented, with some explanation of their significance in humans. If these studies have not been completed, other pertinent information should be provided, such as general assessment of fetal toxicity in drugs with related structures or pharmacological effects. If no relevant information is available, the informed consent should explicitly note the potential for fetal risk. "In general, it is expected that reproductive toxicity studies will be completed before there is large-scale exposure of women of child-bearing potential, i.e., usually by the end of Phase II and before any expanded access program is implemented.
- Minimizing the Possibility of Fetal Exposure: "Pregnancy testing may be used to detect unsuspected pregnancy prior to initiation of study treatment. Timing of the start of the study to coincide with or immediately following the onset of menses is also an adequate indication that the subject is not pregnant. The investigator should ascertain that the subjects will responsibly employ a reliable method of contraception or abstinence for the duration of the drug or treatment exposure, which may exceed the length of the study. If requested, the investigator should be able to refer the subject to a knowledgeable counselor or physician for contraception advice."
- Inclusion of Women in Early Clinical Trials (Phase I and Early Phase II): "In some cases, there may be a basis for requiring [inclusion] of women in early studies. When the disease under study is serious and affects women, and especially when a promising drug for the disease is being developed and made available rapidly under FDA's accelerated approval or real access procedures, a case can be made for requiring that women [be allowed to] participate in clinical studies at an early stage. When such a drug becomes available under expanded access mechanisms (for example, treatment INDS or parallel track) or is marketed rapidly under subpart E procedures because an effect of survival or irreversible morbidity has been shown in the earliest controlled trials, it is medically important that a representative sample of the entire population likely to receive the drug has been studied, including representatives of both genders. Under these circumstances, clinical protocols should not place unwarranted restrictions of participation of women.
- Risk to Infant of Nursing Mother: The potential for harm from exposure to a drug with unknown risks exists for nursing infants, as well as fetuses. Therefore, this policy applies to breast feeding female subjects who are potential subjects in a drug trial in the same manner in which it applies to gestating women.
Research Involving Human In Vitro Fertilization
The Federal regulations require that all investigators proposing research involving human in vitro fertilization with or without embryo transfer must submit a full protocol to the IRB for review. In order to obtain Federal funding for the research, the project must receive review by a national Ethics Advisory Board. The IRB may consult with the American College of Obstetricians and Gynecologists (ACOG) and/or the American Fertility Society (AFS) when reviewing protocols involving human in vitro fertilization.
The greatest problem regarding in vitro fertilization for the IRB involves the use of "spare" embryos. Consent forms for all in vitro fertilization procedures should address what will happen to embryos that are not used in the particular embryo transfer procedure for which they were created (e.g., will they be used for research purposes, will they be implanted in other women, will they be destroyed, etc.)
Research Directed Toward the Fetus In Utero
Three circumstances may affect in utero research. In the first, the study is directed toward pregnant women, in which the fetus is indirectly involved in the research. In the second, the study is directed toward the fetus, that is, the fetus is the research subject. Finally, there are situations where both the pregnant woman and the fetus are the subjects of the research.
The IRB may only approve in utero research when one of the following two criteria are met in addition to all other applicable institutional, Federal, State and local requirements.
The purpose of the research is to meet the health needs of the fetus and is conducted in a way that will minimize risk (for example a new technique for fetal transfusion for Rh incompatibility); or
The research poses no more than minimal risk to the fetus and the purpose of the activity is the development of important biomedical knowledge that is unobtainable by other means.
Research Involving the Fetus Ex Utero
The Federal regulations indicate that an ex utero (delivered) fetus is viable if, in the judgment of the physician, it is likely to survive to the point of sustaining life independently, given the benefit of available medical therapy. If the expelled or delivered fetus is viable, the regulations for research involving children will apply.
A non-viable fetus is defined by the Federal regulation as "an expelled or delivered fetus which, although it is living, cannot possibly survive to the point of sustaining life independently, even with the support of available medical therapy. Although it may be presumed that an expelled or delivered fetus is non-viable at a gestational age less than 20 weeks and weight less than 500 grams, a specific determination as to viability must be made by a physician in each instance." Research involving a non-viable fetus that would either artificially maintain vital functions or hasten their failure is forbidden by Federal regulations. Ethical considerations require respect for the dignity of the dying human subject and an avoidance of unseemly intrusions into the process of dying for research purposes.
Research with Dead Fetuses, Fetal Material, and the Placenta
Investigators are required to conduct research involving human fetuses, fetal material, and the placenta according to the following regulatory requirements:
Separating Abortion from Research
The decision to terminate a pregnancy and procedures of abortion must be kept independent from the retrieval and use of fetal tissue.
The timing and method of abortion should not be influenced by the potential uses of fetal tissue for transplantation or medical research.
Prohibiting Payments and Other Inducements
Payments and other forms of remuneration with the procurement of fetal tissue are prohibited, except payment for reasonable expenses occasioned by the actual retrieval, storage, preparation, and transportation of the tissue.
- Potential recipients of fetal tissue, as well as research and health care participants should be informed about the source of the tissues in question. This information should be provided to prospective subjects in the informed consent form.
- The decision and consent to terminate pregnancy must precede discussion of the possible use of the fetal tissue in research and any request for such consent that might be required for that use.
- Fetal tissue from induced abortions should not be used in medical research without the prior consent of the pregnant woman. Her consent to donate fetal remains is sufficient for the use of fetal tissue.
- Consent should be obtained in compliance with Federal and State law.
Prohibiting Direct Donations
- The pregnant woman should be prohibited from designating the transplant recipient of the fetal tissue.
- Anonymity between donor and recipient should be maintained, so that the donor does not know who will receive the tissue, and the identity of the donor is concealed from the recipient and transplant team.
- Experimental transplants performed with fetal tissue from induced abortions by a family member, friend, or acquaintance should be prohibited.
Compliance with State and Local Laws
Research utilizing fetal tissue should comply with all applicable state laws and local ordinances. Currently, Virginia statutes are silent concerning research utilizing fetal tissue. Investigators are reminded that state law periodically changes, and does vary from state to state. Investigators conducting research outside of Virginia should be familiar with the applicable requirements of the state or country where the research is to take place- should we add a section on viable /non-viable embryos? What about embryonic stem cells??.
Research in Anticipation of Abortion
After lengthy review, the National Commission determined that there is no difference between the moral status of a fetus destined for abortion and that of a fetus which is expected to be carried to term. Therefore, only those research procedures that are acceptable for a fetus going to term may be performed in anticipation of abortion, to preserve the mother's right to change her mind about ending the pregnancy.
Consent Signature Requirements
The mother's consent is required when the research holds:
- the prospect of direct benefit to the pregnant woman , or
- the prospect of a direct benefit both to the pregnant woman and the fetus , or
- no prospect of benefit for the woman nor the fetus but risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means;
Consent from the mother *and* father is required (unless the father is absent, incompetent, unknown or the pregnancy resulted from rape/incest) when the research holds out the prospect of direct benefit solely to the fetus.
Consent Decision Chart for Pregnant Women and Fetuses
Direct benefit to mother only
Direct benefit to mother and fetus
Direct benefit to fetus only
No direct benefit or societal benefits only
Risk is more than minimal
Mother and father's consent
NOT APPROVABLE BY IRB
Risk is no more than minimal
Mother and father's consent