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Institutional Review Board
Guidebook
* CHAPTER VI *
SPECIAL CLASSES OF SUBJECTS
The federal regulations require that IRBs give special consideration to protecting the welfare of particularly vulnerable subjects, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons [Federal Policy §___.111]. For research to which the DHHS regulations are applicable, the DHHS regulations set forth specific provisions on research involving fetuses, pregnant women, and human in vitro fertilization [45 CFR 46 Subpart B]; prisoners [45 CFR 46 Subpart C]; and children [45 CFR 46 Subpart D]. In general, these special regulations allow IRBs to approve research that is of minimal risk or that will benefit the subjects directly. Investigations involving these subjects that present significantly greater than minimal risk without direct benefit to them must be reviewed and approved by the Secretary of Health and Human Services, in consultation with appropriate experts.
Special Note Regarding Applicability of DHHS Regulations. Institutions with DHHS-approved Assurances on file must abide by the provisions of 45 CFR 46 Subparts A-D. Some of the other departments and agencies have incorporated all provisions of 45 CFR 46 into their policies and procedures as well. The exemptions at 45 CFR 46.101(b), however, do not apply to research involving prisoners, fetuses, pregnant women, or human in vitro fertilization (i.e., research to which Subparts B and C apply). Also, the exemption at 45 CFR 46.101(b)(2), for research involving survey or interview procedures, or observation of public behavior, does not apply to research involving children (i.e., research to which Subpart D applies), except for research involving observations of public behavior when the investigator(s) do not participate in the activities being observed. [See Federal Policy §___.101, footnote 1.]
A. FETUSES AND HUMAN IN VITRO FERTILIZATION
INTRODUCTION
Research involving the human fetus raises special concerns for IRB reviewers. The fetus has a unique and inextricable relationship to the mother. It cannot consent to be a research subject. These circumstances have aroused lengthy public debate on the ethics of fetal research, and led to special federal regulations that guide IRB deliberations about fetal research [45 CFR 46 Subpart B]. The fetus may also be an indirect subject of research when women who may be pregnant participate. Research involving pregnant women is also regulated by 45 CFR 46 Subpart B. [See Guidebook Chapter 6, Section B, "Women."]
DEFINITIONS
Dead Fetus: An expelled or delivered fetus that exhibits no heartbeat, spontaneous respiratory activity, spontaneous movement of voluntary muscles, or pulsation of the umbilical cord (if still attached) [45 CFR 46.203(f)]. Generally, some organs, tissues, and cells (referred to collectively as fetal tissue) remain alive for varying periods of time after the total organism is dead.
Fetal Material: The placenta, amniotic fluid, fetal membranes, and the umbilical cord.
Fetus: The product of conception from the time of implantation until delivery. If the delivered or expelled fetus is viable, it is designated an infant [45 CFR 46.203(c)]. (Hereafter, the term "fetus" will refer to a living fetus unless otherwise specified.) The term "fetus" generally refers to later phases of development; the term "embryo" is usually used for earlier phases of development.
Human In Vitro Fertilization: Any fertilization involving human sperm and ova that occurs outside the human body.
Minimal Risk: A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests [Federal Policy §___.102(i)]. For example, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than the risk of doing so as part of routine physical examination.
Nonviable Fetus: 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 nonviable at a gestational age less than 20 weeks and weight less than 500 grams [Federal Register 40 (August 8, 1975): 33552], a specific determination as to viability must be made by a physician in each instance.
Pregnancy: The period from confirmation of implantation of a fertilized egg within the uterus until the fetus has entirely left the uterus (i.e., has been delivered). Implantation is confirmed through a presumptive sign of pregnancy such as missed menses or a positive pregnancy test [45 CFR 46.203(b)]. This "confirmation" may be in error, but, for research purposes, investigators would presume that a living fetus was present until evidence to the contrary was clear. Although fertilization occurs a week or more before implantation, the current inability to detect the fertilization event or the presence of a newly fertilized egg makes a definition of pregnancy based on implantation necessary.
Viable Infant: When referring to a delivered or expelled fetus, the term "viable infant" means likely to survive to the point of sustaining life independently, given the benefit of available medical therapy. This judgment is made by a physician. In accordance with DHHS regulations, the Secretary, HHS, may publish guidelines to assist in the determination of viability. Such guidelines were published in 1975, and specify an estimated gestational age of 20 weeks or more and a body weight of 500 grams or more as indices of fetal viability [Federal Register 40 (August 8, 1975): 33552]. These indices depend on the state of present technology and may be revised periodically.
OVERVIEW
In the early 1970s, considerable national concern was expressed about the ethics of fetal research and about reports of ethically questionable procedures involving human fetuses. Partly in response to these concerns, Congress established the National Commission for the Protection of Human Subjects in 1974, required that it study the subject of fetal research and make recommendations concerning such research to the Department of Health, Education and Welfare (the precursor of DHHS), and imposed a moratorium on federally funded fetal research until regulations based upon the Commission's recommendations were in place. Subsequent DHHS regulations on this subject implemented fully the recommendations of the National Commission. Congress may, from time to time, impose further limitations on research involving the human fetus; similarly, a number of states have laws affecting such research.
Although the Commission did not define the "personhood" of the fetus, it recognized the genetic heritage and vulnerability of the fetus, and affirmed that it should be treated respectfully and with dignity, regardless of its life prospects. The Commission also affirmed the legitimacy and importance of fetal research for improving the health of fetuses both in the present and the future. Risks to the fetus from any research procedure must not be more than minimal (e.g., from ultrasound or changes in maternal diet). If the risks exceed the level considered minimal, they must be justified by anticipated benefit for the health of the mother or the particular fetus.
The concept of minimal risk is evaluative rather than objective; considerable room for interpretation exists. In an effort to impart some objectivity, regulations concerning competent adult subjects define minimal risk in terms of those risks encountered in everyday life or in routine physical or psychological examinations [Federal Policy §___.102(i)]. Determinations of minimal risk to a fetus, however, can challenge an IRB. If risk to the fetus is deemed to be more than minimal and without anticipated medical benefit to the mother or the fetus, special provisions apply.
IRB CONSIDERATIONS
In addition to the general requirements for review of research by the IRB, prior research with animal subjects, and, if feasible, research with nonpregnant persons should form the basis of the risk/benefit assessment for fetal research. The proposed research should seek information not obtainable in any other way. If abortion is involved, the investigators may have no part in either the decision to abort or decisions about the timing or the method to be used; no change in the abortion procedure that would present more than minimal risk to the fetus or its mother can be introduced for research purposes. No monetary or other inducements (e.g., free care) may be offered to a woman to induce her to terminate her pregnancy for research purposes.
Ethics Advisory Board. The DHHS regulations mandate the establishment of a national Ethics Advisory Board whose responsibility is to render advice to the Secretary on various issues. Applications involving human in vitro fertilization must be reviewed by the Ethics Advisory Board before they can be funded [45 CFR 46.204]. Similarly, requests for modification or waiver of the regulatory requirements (e.g., research involving greater than minimal risk where therapeutic benefit to the fetus is lacking) must be approved by the Board. If the Board approves the request, the Secretary may authorize support of the research if the knowledge to be gained can be obtained in no other way and is important enough to justify the risk involved [45 CFR 46.211].
The Board's charter, however, expired in 1980 and has not been renewed as of this writing. Applications for federally-sponsored research involving human in vitro fertilization and embryo transfer may therefore not be funded until a Board is reestablished. Research protocols that require a waiver or modification of the regulatory requirements are similarly restricted. The Guidebook will provide updated information on the status of an Ethics Advisory Board as information becomes available.
Research Directed Toward the Fetus In Utero. Research in which the welfare of a fetus in utero must be considered may involve the fetus either directly or indirectly. The research may be directed toward the pregnant woman (in which case the fetus is indirectly involved), the fetus (in which case it is directly involved) or both. Where it is directed toward both the pregnant woman and the fetus in utero, the regulations pertaining to both subjects apply [45 CFR 46.207 (activities directed toward pregnant women as subjects) and 45 CFR 46.208 (activities directed toward fetuses in utero as subjects)]. Research directed toward the pregnant woman is discussed in Guidebook Chapter 6, Section B, "Women."
An IRB may approve research directed toward the fetus in utero if: (1) the purpose of the research is to meet the health needs of the fetus and is conducted in a way that will minimize risk (e.g., a new technique for fetal transfusion for Rh incompatibility); or (2) the research poses no more than minimal risk to the fetus (e.g., minor changes in maternal diet or use of ultrasonography) and the purpose of the activity is the development of important biomedical knowledge that is unobtainable by other means [45 CFR 46.208]. Many possibilities for intrauterine treatment of fetuses are presently being explored. The initial efforts in this field will inevitably be innovative and experimental. When proposals for research on fetal therapy come before an IRB, the risks should be justified by a reasonable possibility of benefitting the fetus (e.g., increased chance of survival or avoidance of severe disability).
Research Involving the Fetus Ex Utero. If an ex utero fetus is judged viable (i.e., likely to survive to the point of sustaining life independently, given the benefit of available medical therapy), it is then called an infant. At this point, an IRB must be guided by regulations and policies dealing with children. [See 45 CFR 46 Subpart D.] A fetus is judged nonviable if it cannot possibly survive to the point of sustaining life independently, even with the support of available medical therapy, and will therefore die. Research involving a nonviable fetus that would either artificially maintain vital functions or hasten their failure is forbidden. Ethical considerations call upon investigators to maintain the dignity of this dying human subject and to avoid unseemly intrusions in the process of dying for research purposes [45 CFR 46.209].
Research With Dead Fetuses, Fetal Material, and the Placenta. Research activities involving the dead fetus, macerated fetal material, or cells, tissue, or organs excised from a dead fetus are governed by state laws and regulations [45 CFR 46.210]. The National Commission recommended that, in addition to conforming to such laws, research involving dead fetuses be compatible with commonly held views about respect for the dead.
Fetal Tissue Transplantation Research. Research involving the use of human fetal tissue obtained from induced abortions into patients suffering from such disorders as Parkinson Disease and juvenile diabetes has been the subject of considerable debate in the biomedical community. A moratorium on federally-funded research involving the therapeutic transplantation into humans of fetal tissue obtained from induced abortions, which was imposed by the Assistant Secretary for Health in 1988, was lifted on January 22, 1993, by presidential memorandum [Federal Register 58:7457 (February 5, 1993)]. A panel convened by NIH to deliberate on the concerns that gave rise to the moratorium issued recommendations regarding the ethical use of fetal tissue from induced abortions in therapeutic transplantation research [U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health (1988b)]. The panel's report was approved by NIH in December 1988. NIH has issued interim guidelines for the support and conduct of therapeutic human fetal tissue transplantation research [NIH Guide for Grants and Contracts 22 (No. 11, March 19, 1993)]. The interim guidelines, which closely follow the panel's recommendations, provide as follows:
Separating Abortion from Research
Prohibiting Payments and Other Inducements
Informed Consent
Prohibiting Directed Donations
Abiding by State and Local Laws
Ethical Review of Research
Determining When Progress to Clinical Studies is Justified
Resources discussing the ethical issues involved in the use of human fetal tissue for transplantation are provided in the "Suggestions for Further Reading" section at the end of this chapter. Restrictions on the use of fetal material for research purposes is an evolving area of the law. In addition to any federal requirements concerning the use of fetal tissue in research, many states have adopted legislation governing the use of fetal tissue, including use for transplantation purposes. IRBs should be aware of and adhere to any legal requirements relevant to their review of protocols that include the use of fetal tissue.
Research in Anticipation of Abortion. There are conflicting views about whether research in anticipation of abortion is permissible. Some people believe such research exploits already difficult (some consider the situation morally unacceptable) circumstances; others feel that the opportunity to test drugs or procedures on fetuses whose mothers have already made a decision to abort poses little real risk to those fetuses, while the research may save other fetuses from considerable risk. For example, some drugs produce birth defects if taken during pregnancy because they pass through the placenta to the fetus, and tests performed on animals - even primates - are not always a reliable indicator of what will happen in humans. To evaluate this effect accurately, experimental drugs must be tested in women to see whether they cross the placenta. It has been suggested that such tests pose less risk to a fetus-to-be-aborted than to a fetus going to term, because there is not time for the harm (e.g., birth defect) to materialize prior to abortion. There are, however, two ethical problems in this situation. First, the woman may change her mind about having the abortion after taking the experimental drug. Second, regardless of life prospects, the fetus is an unconsenting subject.
The National Commission for the Protection of Human Subjects wrestled with this problem and concluded that there is no difference between the moral status of a fetus destined for abortion and that of a fetus to be carried to term. Therefore, only those research procedures that would be acceptable for a fetus going to term may be performed in anticipation of abortion. If the IRB determines that the risk is acceptable for fetuses that will be carried to term, it is acceptable to select only fetuses-to-be-aborted as subjects. By limiting the risk to what is acceptable for the fetus to be carried to term, the right of the mother to change her mind about abortion is protected; by selecting only those fetuses destined for abortion as subjects, risk to fetuses carried to term is minimized. In practical terms, research procedures that take place at the same time and during the same process as the abortion itself most fully meet these conditions (e.g., a fetoscopic procedure initiated after administering drugs to initiate abortion).
Consent for Research Involving Fetuses. In all research in which human fetuses are the subjects of research, the consent of the mother on behalf of the fetus is required. As a general rule, the consent of the father on behalf of the fetus is also required before a fetus may be enrolled in research. Exceptions to the requirement that the father provide consent are permitted if: (1) the father's identity or whereabouts cannot reasonably be ascertained; (2) the father is not reasonably available; or (3) the pregnancy resulted from rape [45 CFR 46.107(b) and 45 CFR 46.208(b)].
The drafters of the regulations reasoned that the father's consent should be obtained in cases where the father is known and reasonably available for several reasons: (1) as co-progenitor, the father has an interest second only to that of the mother in the well-being of the fetus; (2) the father will be held legally responsible for the health needs of the child, and since these health needs may be affected by participation in research, the father ought to have a voice in determining to what risks the fetus should be exposed; and (3) involvement of a fetus in research in cases where the parents are not in agreement concerning participation is likely to disrupt the family unit as a whole, an additional risk for the fetus.
The IRB should provide guidance to investigators to assist in determining when a father is "reasonably available." Some examples of situations in which a father is customarily judged not to be "reasonably available" will assist the IRB in providing direction to investigators:
Investigators should document their reasons for deciding that a father was not "reasonably available" and should feel free to consult with the IRB in cases where applicability of the requirement for paternal consent is not clear.
In all studies, IRBs should ensure that the information provided to the parent(s) clearly distinguishes procedures performed for research purposes from procedures performed as a part of the standard care of medicine. Risks to the mother should be, so far as possible, distinguished from risks to the fetus; the limits of knowledge about the extent of those risks should be clearly presented.
Waiver of Specific Requirements by the Secretary. The Secretary, HHS, may modify or waive specific conditions or requirements of the regulations governing fetal research on the advice of a national Ethics Advisory Board and after an opportunity for public comment [45 CFR 46.211]. The primary considerations are whether the risks to the subject are so outweighed by the sum of the benefit to the subject and the importance of the knowledge to be gained as to warrant the modification or waiver, and whether the benefits of the research can be gained only if the modification or waiver is granted. [See discussion of the Ethics Advisory Board, above.]
The only waiver granted to date was in 1979 for research designed to assess the risk of fetoscopy as a method of prenatal diagnosis of genetic disorders. (It involved inserting a hollow tube into the uterus and extracting a small blood sample from the fetus for examination and testing.) Subjects were to be women who had already decided to undergo an abortion. Since the risk of the procedure was undetermined, it could not be said to be minimal; moreover, no medical benefit to the women or their fetuses was contemplated. Thus, the Department could not support the research without a waiver by the Secretary; that, in turn, required review and approval of the Ethics Advisory Board. The Board's report on this matter, with its conclusion that the research was ethically acceptable, was published in the Federal Register for public comment [Federal Register 44 (August 14, 1979): 47732]. The Secretary subsequently granted the waiver and provided support for the research.
Additional Restrictions on Fetal Research. Congress imposes additional restrictions on fetal research from time to time; IRBs should therefore consult with OPRR if they are unsure of the current status of such research.
Research Involving Human In Vitro Fertilization. DHHS regulations require all research involving human in vitro fertilization or embryo transfer to be reviewed by a national Ethics Advisory Board before it can be funded by the Department [45 CFR 46.204(d)]. The lapse in the Board has precluded federal funding of human in vitro fertilization research. The American College of Obstetricians and Gynecologists (ACOG) and the American Fertility Society (AFS) have recently established a National Advisory Board on Ethics in Reproduction, which plans to establish guidelines for research in this area. IRBs reviewing privately funded in vitro fertilization research might consider consulting with the new ACOG/AFS advisory board.
Levine (1986) provides an overview of the issues presented by in vitro fertilization, as well as resources for further reading. He notes that while the Ethics Advisory Board found research on in vitro fertilization ethically acceptable and set forth criteria for conducting such research [see Report (June 18, 1979)], the Board did not foresee many of the issues that have since been identified. One issue of importance to IRBs is what Levine calls "the problem of 'spare' embryos" [pp. 315-319]. IRBs should assure that investigators have clearly addressed what will happen to embryos that are not used in the particular embryo transfer procedure for which they were created (e.g., "they [will] be used for research purposes, they [will] be implanted in the uterus of another woman, or they [will] be destroyed"); investigators should ensure that participants are informed of and consent, in writing, to the resolution of this question. Investigators should also clarify to participants the ownership of the embryos that are not used in the procedure (e.g., that they "belong" to the laboratory and may not be removed by the parents, or that they "belong" to the biological mother). Levine describes how these questions were reviewed by the IRB at the Yale University School of Medicine [pp. 317-319].
POINTS TO CONSIDER
1. Is animal research an appropriate prerequisite? Has it been completed? Where appropriate and feasible, has research with nonpregnant women been completed?
2. If there is any risk to a fetus, is the information sought judged to be important? Could it be obtained by any other means?
3. Is risk to the fetus minimal?
4. In research with a nonviable fetus ex utero, is any intervention proposed that would shorten or prolong the natural course of dying?
5. Are the investigators involved in any decisions about an abortion process (e.g., timing or method) that is related to the research?
6. Is abortion encouraged for research purposes (e.g., are free care or services offered)?
7. Do any applicable federal, state, or local laws restrict such research?
8. From whom must consent be obtained?
APPLICABLE LAWS AND REGULATIONS
45 CFR 46 Subpart B [DHHS: Additional protections pertaining to research, development, and related activities involving fetuses, pregnant women, and in vitro fertilization] Federal Register 58:7457 (February 5, 1993) [Fetal tissue transplantation research] NIH Guide for Grants and Contracts 22 (No. 11, March 19, 1993) [NIH interim guidelines for the support and conduct of therapeutic human fetal tissue transplantation research]
Federal, state, and local laws governing research involving human fetuses or fetal material
INTRODUCTION
Special regulatory requirements govern the participation of pregnant women in research [45 CFR 46 Subpart B]. Research involving women who are or may become pregnant receives special attention from IRBs because of women's additional health concerns during pregnancy and because of the need to avoid unnecessary risk to the fetus. Further, in the case of a pregnant woman, IRBs must determine when the informed consent of the father to the research is required. Special attention is justified because of the involvement of a third party (the fetus) who may be affected but cannot give consent and because of the need to prevent harm or injury to future members of society. Procedural protections beyond the basic requirements for protecting human subjects are prescribed in DHHS regulations for research involving pregnant women [45 CFR 46 Subpart B]. No specific DHHS regulations are directed toward research involving lactating women.
The inclusion of women in research studies is discussed in this Section and in Guidebook
Chapter 3, Section C, "Selection of Subjects."
DEFINITIONS
Lactation: The period of time during which a woman is providing her breast milk to an
infant or child.
Minimal Risk: A risk is minimal where the probability and magnitude of harm or
discomfort anticipated in the proposed research are not greater, in and of themselves, than
those ordinarily encountered in daily life or during the performance of routine physical or
psychological examinations or tests [Federal Policy §___.102(i)]. For example, the risk of
drawing a small amount of blood from a healthy individual for research purposes is no
greater than the risk of doing so as part of routine physical examination.
Pregnancy: The period from confirmation of implantation of a fertilized egg within the
uterus until the fetus has entirely left the uterus (i.e., has been delivered). Implantation is
confirmed through a presumptive sign of pregnancy such as missed menses or a positive
pregnancy test [45 CFR 46.203(b)]. This "confirmation" may be in error, but, for research
purposes, investigators would presume that a living fetus was present until evidence to the
contrary was clear. Although fertilization occurs a week or more before implantation, the
current inability to detect the fertilization event or the presence of a newly fertilized egg
makes a definition of pregnancy based on implantation necessary.
IRB CONSIDERATIONS
Pregnant women may be involved in several categories of research. IRB duties differ in
each category, but the primary objectives are assessing: (1) whether the research is directed
toward the mother's health or toward the fetus; and (2) the risks to the woman and to the
fetus or infant. Subsequent actions depend on those assessments. Research directed toward
the fetus is discussed in Guidebook Chapter 6, Section A, "Fetuses and Human In Vitro
Fertilization." For research activities directed toward pregnant women as subjects, the
federal regulations provide that no pregnant woman may be involved as a subject unless
either: (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 [45 CFR 46.207].
Inclusion of Women in Study Populations. NIH policy requires the inclusion of women
and minorities in research study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder, or condition under study. Specifically, the NIH
policy states:
Applications for grants and cooperative agreements that involve human subjects are required to include minorities and both genders in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy applies to all research involving human subjects and human materials, and applies to males and females of all ages. If one gender and/or minorities are excluded or are inadequately represented in this research, particularly in proposed population-based studies, a clear compelling rationale for exclusion or inadequate representation should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study.
Assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH...recognize[s] that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., American Indians or Alaskan Natives, Asians or Pacific Islanders, Blacks, Hispanics). Provide the rationale for studies on single minority population groups.
Applications for support of research involving human subjects must employ a study design with gender and/or minority representation (by age distribution, risk factors, incidence/prevalence, etc.) appropriate to the scientific objectives of the research. It is not an automatic requirement for the study design to provide statistical power to answer the questions posed for men and women and racial/ethnic groups separately; however, whenever there are scientific reasons to anticipate differences between men and women, and racial/ethnic groups, with regard to the hypothesis under investigation, applicants should include an evaluation of these gender and minority group differences in the proposed study. If adequate inclusion of one gender and/or minorities is impossible or inappropriate with respect to the purpose of the research because of the health of the subjects, or other reasons, or if in the only study population available, there is a disproportionate representation of one gender or minority/majority group, the rationale for the study population must be well explained and justified [PHS Grant Application form 398, pp. 21-22].
[See also publication and interpretation of the NIH policy in the NIH Guide for Grants and Contracts 20 (No. 32, August 23, 1991): 1-3.]
In addition, principal investigators of funded grants and cooperative agreements falling under the scope of the policy must report annually on the number of subjects planned and enrolled to date by ethnic origin and gender [Application for Continuation of a Public Health Service Grant, form 2590, pp. 7-9 and Form Page 7].
This information should also be available for IRB review, both for its initial review and for its annual review for continuation of projects. The role of the IRB in assuming responsibility for reviewing the adequacy of representation of women and minorities in studies has been controversial. IRBs around the country have deliberated the relevance of the inclusion of women and minorities in studies to their consideration of whether the welfare and safety of subjects are adequately protected. Their responses cross the entire spectrum of possibilities, from considering the question irrelevant to regarding it as one of utmost importance. Discussion is continuing at many levels in the federal government in an effort to develop IRB guidance policies. NIH expects to provide further guidance concerning the policy, which will be published in the NIH Guide for Grants and Contracts during 1993.
Discussion centers on issues of justice, beneficence, appropriate levels of inclusion, generalizability of study results, and liability of sponsors. The exclusion of women from studies raises considerations of justice because exclusion deprives women from the possibility of directly benefitting from participation (e.g., receiving a potentially beneficial medical therapy).
Exclusion or inappropriate representation further raises issues of generalizability: If women are excluded or are not appropriately represented, the data generated by the study may not be generalizable beyond the male study population; women as a class will therefore not benefit. In considering the inclusion of women in the study, IRBs should note the limitations on generalizability that may result from study size or other factors. The ability to evaluate gender differences may depend on sample sizes that the investigator cannot reasonably attain.
Women of child-bearing potential may be excluded from studies not only because of concern for the welfare of the fetus, but also because of possible legal liability of sponsors and investigators for harm caused by investigational agents or other research activities. Consideration of the liability issue requires balancing the protection of women and potential fetuses against the benefits that would result from their inclusion (i.e., direct benefits and the generalizability of data).
Until a consensus is reached on this question, IRBs should continue to consider representation of women in study protocols in their deliberations on the adequacy of protections of the safety and welfare of subjects.
In 1977 the FDA issued guidelines limiting the involvement of women of childbearing potential in Phase 1 and early Phase 2 clinical drug trials, with which IRBs should be familiar. [See General Considerations for the Clinical Evaluation of Drugs (1977) and Guidelines for the Format and Content of the Clinical and Statistical Sections of New Drug Applications (1988).] The FDA is reevaluating its policy on the exclusion of women of childbearing potential from such clinical studies [U.S. General Accounting Office (1992)], and has indicated that it will revise the 1977 guidelines to permit and encourage the inclusion of women of childbearing potential in research.
Studies in Which Pregnancy is Coincidental to Subject Selection. Any study in which
women of childbearing potential are possible subjects may inadvertently include pregnant
women. DHHS regulations require that, when appropriate, subjects be provided a
"statement that the particular treatment or procedure may involve risks to the subject (or to
the embryo or fetus, if the subject is or may become pregnant) which are currently
unforeseeable" as part of the informed consent process [Federal Policy §___.116(b)(1)].
IRBs must judge whether the mother's participation would pose any risk to the fetus or
nursing infant. In some studies, IRBs may need to ensure that nonpregnant subjects are
advised to avoid pregnancy or nursing for a time during or following the research.
Furthermore, where appropriate, subjects should be advised to notify the investigator
immediately should they become pregnant. In some instances there may be potential risk
sufficient to justify requiring that pregnant women either be specifically excluded from the
research or studied separately.
Studies Directed Primarily Toward the Mother's Health. Many women enter pregnancy
with health problems or develop new ones during pregnancy. Some problems are affected
positively or negatively by pregnancy; others are unaffected. A considerable amount of
research is conducted on health problems that occur during pregnancy (e.g., arthritis,
hypertension, diabetes); despite standard therapy, deterioration of maternal health may also
necessitate experimental treatment. In research undertaken to meet the health problems of a
pregnant woman, her needs generally take precedence over those of the fetus [45 CFR
46.207], except, perhaps, where the health benefit to the woman is minimal and risk to the
fetus is high. If, for example, an experimental drug were considered necessary to improve a
pregnant woman's condition, her consent alone would be sufficient to authorize its
administration - even though it might have unknown or greater than minimal risk for the
fetus. In reviewing such studies IRBs must attempt to ensure that the risk to the fetus is
minimized, consistent with achieving the research objective.
Studies Directed Toward Pregnancy. Numerous studies are conducted that address the
normal and abnormal processes of pregnancy, labor, and delivery. Some (e.g., studying the
physiological mechanisms maintaining pregnancy or initiating labor) are not directed to the
health of either the mother or fetus. Others (e.g., studying the effects of strict control of
maternal diabetes on pregnancy outcome) involve research on improving maternal health
and research on the fetus, thus requiring review for both sets of considerations. [See
Guidebook Chapter 6, Section A, "Fetuses and Human In Vitro Fertilization."] The
requirements for IRB approval will sometimes conflict, depending on how the research is
categorized (e.g., whether or not it is directed toward improving maternal health determines
the degree of fetal risk permitted and paternal consent requirements). In such instances, the
IRB will have to determine which circumstances prevail and which requirements apply.
The primary requirement for approval in this category is an IRB determination that the risk
to the fetus is "minimal." The broad definition of minimal risk places great responsibility
for good judgment on IRB members. The definition suggests that if the estimated risk to the
fetus is no more than that from established procedures routinely used in an uncomplicated
pregnancy or in a pregnancy with complications comparable to those being studied, the risk
is considered minimal. Ultrasound exams, maternal exercise comparable to job- or
recreation-related levels, amniocentesis, and delivery in a sitting position might be
considered minimally risky in most pregnancies. If the IRB cannot conclude that fetal risk is
minimal, it may conditionally approve the research, subject to review and approval by the
Secretary, HHS [45 CFR 46.211]. As with fetal research, the Secretary may modify or
waive specific conditions or requirements of the regulations governing fetal research on the
advice of a national Ethics Advisory Board and after an opportunity for public comment [45
CFR 46.211]. The primary consideration is whether the risks to the subjects are so
outweighed by the sum of the benefit to the subjects and the importance of the knowledge to
be gained as to warrant the modification or waiver. A further consideration is whether the
benefits of the research can be gained without the modification or waiver.
Consent. Once the research is approved under the IRB's minimal risk standard, the IRB
must make a judgment regarding the consent. DHHS regulations require both the woman's
and the father's consent for research in this category unless: (1) the purpose of the research
is to meet the health needs of the mother; (2) the father's identity or whereabouts cannot
reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted
from rape. Issues of consent are discussed in Chapter 6, Section A, "Fetuses and Human In
Vitro Fertilization."
Lactating Women. Although there are no specific regulations for research involving
lactating women, IRB review should include a focus on safety for the nursing infant (the
mother's own child or one to whom she provides her milk). IRBs should require that
investigators provide assurance that taking breast milk samples, maternal dietary
modifications, drugs given to the mother, or other research manipulations will not unduly
threaten the supply or nutritional content of colostrum or milk for nursing infants.
Studies to Develop or Evaluate Methods of Enhancing Conception or Contraception.
These studies are closely related to research involving pregnant women and raise some of
the same concerns. There are no special regulations for this category of research, but
special IRB attention is needed. IRBs should ensure that there is an adequate explanation of
the risks, benefits, reversibility, and alternatives; that backup protection against unintended
pregnancy is provided when appropriate; and that the possibility of failure (and options
available for dealing with unintended pregnancies) are satisfactorily described.
Research on Abortion Techniques. DHHS regulations do not deal directly with research
on abortion techniques. In reviewing such research, risks to the woman would be a primary
consideration. IRBs should keep in mind, however, that if a fetus survived the abortion and
was viable, the infant might be severely damaged. IRBs must be aware of local
requirements and the most current federal laws and policies before proceeding to review
the proposed research.
Exemption from Review. Note that the exemptions from IRB review provided for in 45
CFR 46.101(b) [Federal Policy §___.101(b)] do not apply to research involving pregnant
women [Federal Register 56 (June 18, 1991): 28013, note 1].
POINTS TO CONSIDER
1. For all studies, is there reason to exclude pregnant or lactating women? If so, how strict
should the screening measures be?
2. For all studies involving pregnant women, have appropriate studies on animals and
nonpregnant humans been conducted? Is any special monitoring of the informed consent
process needed?
3. For studies directed toward maternal health, is the risk to the fetus the least possible
consistent with the research objectives? Will the mother be adequately informed of the
potential risk to the fetus and of alternative treatments and their risks and benefits?
4. For studies of pregnancy, labor, or delivery, is the risk to the fetus "minimal?" Is the
father's consent required?
5. For studies of lactating women, is the supply and content of breast milk adequately
protected?
6. For studies of conception or contraception, are the risks, benefits, reversibility, and
alternatives adequately explained? In contraceptive studies, is there adequate explanation of
possible failure and of the options available for dealing with unintended pregnancies?
7. Will women be appropriately represented in the study? Does the study need to be
designed to allow evaluation of gender differences?
APPLICABLE LAWS AND REGULATIONS
Federal policy for the protection of human subjects 21 CFR 50.25(b)(1) [FDA: Informed consent] 45 CFR 46, Subpart B [DHHS: Additional protections pertaining to research, development, and related activities involving fetuses, pregnant women, and in vitro fertilization]
Applicable regulations of the Department of Agriculture, the Army, and the Air Force
Federal laws that may limit research involving the living human fetus
State and local laws governing research involving human fetuses
NIH policy concerning inclusion of women and minorities in study populations. NIH Guide
for Grants and Contracts 20 (No. 32, August 23, 1991): 1-3. The policy also appears in
the application packet for PHS Grants, form PHS 398, pp. 21-22, and in NIH Requests for
Proposals (RFPs).
Application for Continuation of a Public Health Service Grant, form 2590, pp. 7-9 and
Form Page 7.
U.S. Department of Health and Human Services. Public Health Service. Food and Drug
Administration. General Considerations for the Clinical Evaluation of Drugs.
Washington, D.C.: U.S. Government Printing Office, 1977. (Under revision.)
U.S. Department of Health and Human Services. Public Health Service. Food and Drug
Administration. Guidelines for the Format and Content of the Clinical and Statistical
Sections of New Drug Applications. Washington, D.C.: U.S. Government Printing Office,
1988.
INTRODUCTION
The ethical mandate of IRBs is to protect the rights and welfare of human research subjects.
IRBs are obligated to ensure that research studies do not endanger the safety or well-being
of human subjects or undermine public confidence in the conduct of research. The special
vulnerability of children makes consideration of involving them as research subjects
particularly important. To safeguard their interests and to protect them from harm, special
ethical and regulatory considerations are in place for reviewing research involving
children. Title 45 CFR Part 46, Subpart D provides for "Additional Protections for
Children Involved as Subjects of Research." Research that is contrary to the rights and
welfare of child-subjects is prohibited. A good summary of the ethical considerations
surrounding research involving children can be found in Levine (1989).
DEFINITIONS
Assent: A child's affirmative agreement to participate in research. Mere failure to object
should not be construed as assent [45 CFR 46.402(b)].
Benefit: A valued or desired outcome; an advantage.
Children: Persons who have not attained the legal age for consent to treatment or
procedures involved in the research, as determined under the applicable law of the
jurisdiction in which the research will be conducted [45 CFR 46.402(a)].
Emancipated Minor: 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. (See also: Mature Minor.)
Guardian: An individual who is authorized under applicable state or local law to give
permission on behalf of a child to general medical care [45 CFR 46.402(3)].
Mature Minor: Someone who has not reached adulthood (as defined by state law) but who
may be treated as an adult for certain purposes (e.g., consenting to medical care). Note that
a mature minor is not necessarily an emancipated minor. (See also: Emancipated Minor.)
Minimal Risk: A risk is minimal where the probability and magnitude of harm or
discomfort anticipated in the proposed research are not greater, in and of themselves, than
those ordinarily encountered in daily life or during the performance of routine physical or
psychological examinations or tests [Federal Policy §___.102(i)]. For example, the risk of
drawing a small amount of blood from a healthy individual for research purposes is no
greater than the risk of doing so as part of routine physical examination.
Permission: The agreement of parent(s) or guardian to the participation of their child or
ward in research [45 CFR 46.402(c)].
Risk: The probability of harm or injury (physical, psychological, social, or economic)
occurring as a result of participation in a research study. Both the probability and magnitude
of possible harm may vary from minimal to significant. Federal regulations define only
"minimal risk." (See also: Minimal Risk.)
IRB CONSIDERATIONS
Analysis of Probable Risks, Possible Benefits, and Associated Discomforts. IRBs
reviewing research involving children as subjects must consider the benefits, risks, and
discomforts inherent in the proposed research and assess their justification in light of the
expected benefits to the child-subject or to society as a whole. In calculating the degree of
risk and benefit, the IRB should weigh the circumstances of the subjects under study, the
magnitude of risks that may accrue from the research procedures, and the potential benefits
the research may provide to the subjects or class of subjects.
The federal regulations require IRBs to classify research involving children into one of four categories and to document their discussions of the risks and benefits of the research study. The four categories of research involving children that may be approved by IRBs, based on degree of risk and benefit to individual subjects, are as follows:
1. Research not involving greater than minimal risk [45 CFR 46.404].
2. Research involving greater than minimal risk, but presenting the prospect of direct benefit to an individual subject. Research in this category is approvable provided: (a) the risk is justified by the anticipated benefit to the subject; and (b) the relationship of risk to benefit is at least as favorable as any available alternative approach [45 CFR 46.405].
3. Research involving greater than minimal risk with no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition. Research in this category is approvable provided: (a) the risk represents a minor increase over minimal risk; (b) the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational settings; and (c) the intervention or procedure is likely to yield generalizable knowledge about the subject's disorder or condition that is of vital importance for the understanding or amelioration of the subject's disorder or condition [45 CFR 46.406].
4. Research that is not otherwise approvable, but which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. Research that is not approvable under 45 CFR 46.404, 46.405, or 46.406 may be conducted or funded by DHHS provided that the IRB, and the Secretary, after consultation with a panel of experts, finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a significant problem affecting the health and welfare of children. The panel of experts must also find that the research will be conducted in accordance with sound ethical principles [45 CFR 46.407].
In all cases, the IRB must determine that adequate provisions have been made for soliciting
the assent of children and the permission of their parents or guardians [45 CFR 46.408].
Assessing Probable Risks. Central to IRBs' consideration of research involving children is
the determination of what constitutes minimal risk. Procedures that usually present no more
than minimal risk to a healthy child include: urinalyses, obtaining small blood samples,
EEGs, allergy scratch tests, minor changes in diet or daily routine, and/or the use of
standard psychological or educational tests. The assessment of the probability and
magnitude of the risk, however, may be different in sick children and may vary depending
on the diseases or conditions the subjects may have. For example, obtaining blood samples
from a hemophiliac child may present more than minimal risk to the child. On the other
hand, IRBs may consider that children suffering from chronic illnesses who are accustomed
to invasive procedures are placed at minimal risk by involvement in similar research
procedures, in contrast to children who have not had such experiences. The IRB must also
consider the extent to which research procedures would be a burden to any child, regardless
of whether the child is accustomed to the proposed procedures.
Procedures that exceed the limits of minimal risk may be difficult to define in the abstract,
but should not be too difficult to identify on a case-by-case basis. Riskier procedures might
include biopsy of internal organs, spinal taps, or the use of drugs whose risks to children
have not yet been established. Behavioral interventions likely to cause psychological stress
may also exceed minimal risk.
Assessing Possible Benefits. In assessing the possible benefits of research intervention,
the IRB should consider the variability in health statuses among potential subjects. For
example, a potential subject might be a normal, healthy child, or a child who has been
exposed to a disease or a toxin (e.g., meningococcus or lead) where it is known that a
percentage of the children exposed will actually experience untoward consequences. A
child may also be in an early state of disease, e.g., an HIV-infected child, or may actually
suffer from disease or other significant medical condition. Thus the IRB must take into
account the current health status of a child and the likelihood of progression to a worsened
state without research intervention.
Phase 1 Trials. The issue of Phase 1 drug studies deserves special consideration. The
usual approach to designing drug studies involving children as subjects is for appropriate
studies to be conducted first in animals, adults, and older children before young children are
involved as research subjects. There are some studies, however, in which data may not be
entirely generalizable from older populations, and in which the existence of life-threatening
conditions for children are important considerations in the IRB's risk/benefit analysis. The
requirement for previous testing in adults or older children may thus not be appropriate.
Furthermore, some diseases specific to children may require that children be involved
without data from older groups (e.g., there is no adult model that mimics the state of
HIV-infected newborns; Wilms' tumor and various cancers such as neuroblastoma affect
infants who do not survive into older childhood.) In some cases "tandem" studies in older
populations and children may be justifiable. For example, some Phase 1 studies in children
might be based on only pharmacologic safety and toxicity data (completed Phase 1 and
ongoing Phase 2) but without complete effectiveness data from trials in adults and older
children. If the IRB approves a Phase 1 drug trial, the consent document must specify what
is known about the probability that, and the degree to which, an intervention will be of
possible benefit based on all of these data.
Consent Procedures. When children or minors are involved in research, the regulations
require the assent of the child or minor and the permission of the parent(s), in place of the
consent of the subjects.
Given that children have not reached their full intellectual and emotional capacities and are legally unable to give valid consent, involving children in research requires the permission of their parents or legally authorized representatives. The IRB must determine whether the permission of both parents is necessary, and the conditions under which one parent may be considered "not reasonably available" [45 CFR 46.408]. (Examples of circumstances in which parental permission may be inappropriate are discussed below.) In addition, the regulations require that the IRB determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent [45 CFR 46.408(a)].
The regulations provide that an IRB may find that the permission of one parent is sufficient for research to be conducted under 45 CFR 46.404 (minimal risk research) or 45 CFR 46.405 (research involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects) [45 CFR 46.408(b)]. Where research is covered by 45 CFR 46.406 and 45 CFR 46.407, and permission is to be obtained from parents, both parents must give their permission, unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child [45 CFR 46.408(b)].
While children may be legally incapable of giving informed consent, they nevertheless may possess the ability to assent to or dissent from participation. Out of respect for children as developing persons, children should be asked whether or not they wish to participate in the research, particularly if the research: (1) does not involve interventions likely to be of benefit to the subjects; and (2) the children can comprehend and appreciate what it means to be a volunteer for the benefit of others. The IRB must determine for each protocol - depending on such factors as the nature of the research and the age, status, and condition of the proposed subjects - whether all or some of the children are capable of assenting to participation. Where appropriate, IRBs may choose to review on a case-by-case basis whether assent should be sought from given individual subjects. The federal regulations do not require that assent be sought from children starting at a specific age, but that their assent should be sought when, in the judgment of the IRB, the children are capable of providing their assent. IRBs are to take into account the ages, maturity, and psychological state of the children involved [45 CFR 46.408(a)].
When the research offers the child the possibility of a direct benefit that is important to the health or well-being of the child and is available only in the context of the research, the IRB may determine that the assent of the child is not necessary [45 CFR 46.408(a)]. Additionally, in such circumstances a child's dissent, which should normally be respected, may be overruled by the child's parents, at the IRB's discretion. When research involves the provision of experimental therapies for life-threatening diseases such as cancer, however, IRBs should be sensitive to the fact that parents may wish to try anything, even when the likelihood of success is marginal and the probability of extreme discomfort is high. Should the child not wish to undertake such experimental therapy, difficult decisions may have to be made. In general, if the child is a mature adolescent and death is imminent, the child's wishes should be respected.
When the IRB determines that the assent of the child is required, it must also determine that the provisions for obtaining and documenting assent are adequate [45 CFR 46.408(e)]. The child should be given an explanation of the proposed research procedures in a language that is appropriate to the child's age, experience, maturity, and condition. This explanation should include a discussion of any discomforts and inconveniences the child may experience if he or she agrees to participate.
For some research activities, IRBs may require that either an IRB member or an advocate for the child be present during the assent and permission procedures to verify the child's understanding and to support the child's preferences. The IRB may also require that the parent(s) or a close family member be present during the research, especially if a young child will be exposed to significant discomfort or inconvenience, or if the child will be required to spend time in an unfamiliar place.
The requirement for parental permission may be inappropriate in some cases. Examples include research involving older adolescents who, under applicable law, may consent on their own behalf for selected treatments (e.g., treatment for venereal disease, drug abuse, or emotional disorders). In other research (e.g., research on child abuse or neglect), there may be serious doubt as to whether the parents' interests adequately reflect the child's interests. In these cases, IRBs should devise alternative procedures for protecting the rights and interests of the children asked to participate, including, perhaps, the court appointment of special guardians.
Parental permission may sometimes be insufficient to protect the child's interests. In cases involving transplants (e.g., of bone marrow or a kidney) between minor siblings, the parents' concern for the afflicted child may interfere with their consideration of the best interests of the healthy donor. Therefore, IRBs may want to consider asking for court review of the parents' decision. [See also Guidebook Chapter 5, Section G, "Transplants."]
The IRB should consult legal counsel about the applicability of any state laws affecting
consent for the proposed research. The IRB should be aware of the age of majority in the
state as well as laws or court decisions that might limit the right of parents to consent on
behalf of their children in certain circumstances. Age and conditions of emancipation will
differ from state to state. In some states the age at which a child can give consent to medical
care differs depending on the medical condition involved (e.g., venereal diseases). The
federal regulations require that all research activities must comply not only with the
regulations but also with the law of the state in which they are performed.
Exemption From Review. The exemption at 45 CFR 46.101(b)(2), for research involving
survey or interview procedures or observation of public behavior, does not apply to
research with children covered by Subpart D, except for research involving observations of
public behavior when the investigator(s) do not participate in the activities being observed.
The remaining exemptions in 45 CFR 46.101(b)(2) apply to research involving children.
Wards of the State. The special protections for children set forth in Subpart D include
additional limitations on some research involving children who are wards of the state or
any other agency, institution, or entity. Where the research involves greater than minimal
risk to the subjects with no prospect of direct benefit to individual subjects (45 CFR
46.406), or requires HHS Secretarial approval (45 CFR 46.407), the research must either
be related to their status as wards, or else be conducted in schools, camps, hospitals,
institutions, or similar settings in which the majority of children involved as subjects are not
wards [45 CFR 46.409]. The IRB must require, for each child who is a ward, appointment
of an advocate in addition to any other individual acting on behalf of the child as a guardian
or in loco parentis.
IRBs should be particularly concerned with the involvement of HIV-infected children who are in foster care, but who are also not wards. Many of these children are from racial or ethnic minorities. IRBs need to give special attention to groups of children such as these who, while they need special protections, should not be denied the opportunity to participate in research that may potentially be of benefit to them.
Finally, whenever institutionalized children might be involved in research, care should be
taken to ensure that they are not included as participants simply because of their availability
to the investigator.
POINTS TO CONSIDER
1. Does the research have an identifiable prospect of direct benefit to the individual child
participant? Can that benefit be achieved through alternative means?
2. Does the research have an identifiable prospect of risk to the individual child
participant? What safeguards are proposed to minimize these risks? When procedures
involving greater than minimal risk to children are anticipated, are convincing scientific and
ethical justifications given?
3. Is the inclusion of normal volunteers justified?
4. Do studies involving placebo controls place the child at greater risk by withholding from
selected subjects potentially therapeutic research drugs or interventions?
5. When possible, have appropriate studies been conducted on animals and adults first?
Will older children be enrolled before younger ones?
6. What is the age of majority in the state? Can a child consent to medical care for certain
conditions, and, if so, at what age? What legal limits are there on the right of parents to
consent on behalf of their children?
7. Is permission of both parents necessary? Under what conditions may one of the parents
be considered "not reasonably available?"
8. Will efforts be made to ensure that parents' permission to involve their children in
research studies is free from coercion, exploitation, and/or unrealistic promises?
9. Are mechanisms in place to ensure that children are involved as research subjects in
ways that do not undermine their dignity as young persons? Are provisions made that show
respect for the developing rights of children, such as: (a) obtaining their assent, and, where
appropriate, honoring their dissent; and (b) protecting their need for privacy and the
confidentiality of information regarding them?
10. Are there special problems that call for the presence of a monitor or advocate during
consent procedures?
11. Are special needs of adolescents such as counseling and confidentiality accounted for in
the research design?
12. Are there any special problems such as confidentiality and reporting that might arise in
sensitive research about child abuse or sexual practices of teenagers?
13. If conditions present in children have implications for other family members' health
statuses, are appropriate mechanisms proposed for dealing with the larger family unit (e.g.,
genetic risks or HIV infection)?
14. Should parents be required to be present during the conduct of the research? (Are
proposed subjects to be very young? Are the procedures involved painful? Must subjects
stay overnight in the hospital when they otherwise would not have to?)
APPLICABLE LAWS AND REGULATIONS
| 45 CFR 46 Subpart D | [DHHS: Additional protections for children involved as subjects in research] |
The IRB should consult legal counsel about any applicable state laws affecting research involving children as subjects, including laws affecting consent procedures.
D. COGNITIVELY IMPAIRED PERSONS
INTRODUCTION
The predominant ethical concern in research involving individuals with psychiatric,
cognitive, or developmental disorders, or who are substance abusers is that their disorders
may compromise their capacity to understand the information presented and their ability to
make a reasoned decision about participation. Many individuals with disabilities affecting
their reasoning powers may be residents of institutions responsible for their total care and
treatment. The impact of institutionalization may further compromise their ability to exercise
free choice (voluntariness). (These concerns apply both to voluntary patients and those
committed involuntarily.) The eagerness for release may induce an institutionalized person,
especially one who is involuntarily confined, to participate in research out of a desire to
appear "rational" and "cooperative" to those who will make decisions about his or her
release.
It is important to protect the privacy of all subjects and the confidentiality of information
gathered in research exploring emotionally sensitive topics. Many patients do not want even
the fact of their institutionalization divulged.
DEFINITIONS
Cognitively Impaired: Having either a psychiatric disorder (e.g., psychosis, neurosis,
personality or behavior disorders), an organic impairment (e.g., dementia) or a
developmental disorder (e.g., mental retardation) that affects cognitive or emotional
functions to the extent that capacity for judgment and reasoning is significantly diminished.
Others, including persons under the influence of or dependent on drugs or alcohol, those
suffering from degenerative diseases affecting the brain, terminally ill patients, and persons
with severely disabling physical handicaps, may also be compromised in their ability to
make decisions in their best interests.
Competence: Technically, a legal term, used to denote capacity to act on one's own behalf;
the ability to understand information presented, to appreciate the consequences of acting (or
not acting) on that information, and to make a choice. (See also: Incompetence,
Incapacity.)
Competence may fluctuate as a function of the natural course of a mental illness, response to
treatment, effects of medication, general physical health, and other factors. Therefore,
mental status should be re-evaluated periodically. As a designation of legal status,
competence or incompetence pertains to an adjudication in court proceedings that a person's
abilities are so diminished that his or her decisions or actions (e.g., writing a will) should
have no legal effect. Such adjudications are often determined by inability to manage
business or monetary affairs and do not necessarily reflect a person's ability to function in
other situations.
Incapacity: Refers to a person's mental status and means inability to understand information
presented, to appreciate the consequences of acting (or not acting) on that information, and
to make a choice. Often used as a synonym for incompetence.
Incompetence: Technically, a legal term meaning inability to manage one's own affairs.
Often used as a synonym for incapacity.
Institution: A residential facility that provides food, shelter, and professional services
(including treatment, skilled nursing, intermediate or long-term care, and custodial or
residential care). Examples include general, mental, or chronic disease hospitals; inpatient
community mental health centers; halfway houses and nursing homes; alcohol and drug
addiction treatment centers; homes for the aged or dependent, residential schools for the
mentally or physically handicapped; and homes for dependent and neglected children.
IRB CONSIDERATIONS
IRBs that regularly review research involving vulnerable subjects (such as the mentally
disabled) are required by DHHS and FDA regulations to consider including among their
members one or more individuals who are knowledgeable about and experienced in
working with those subjects [45 CFR 46.107; 21 CFR 56.107]. In addition, the IRB must be
sure that additional safeguards are in place to protect the rights and welfare of these
subjects [45 CFR 46.111(b); 21 CFR 56.111(b)]. Unlike research involving children,
prisoners and fetuses, however, no additional DHHS regulations specifically govern
research involving persons who are cognitively impaired.
The recommendations of the National Commission for the Protection of Human Subjects
resemble the recommendations made with respect to children. [See Guidebook Chapter 6,
Section C, "Children and Minors."] More recently, Annas and Glantz (1986) have argued
that research should involve cognitively impaired subjects only where: (1) they comprise
the only appropriate subject population; (2) the research question focuses on an issue
unique to subjects in this population; and (3) the research involves no more than minimal
risk. Levenson and Hamric (1989) argue that research involving greater than minimal risk
may be acceptable where the purpose of the research is therapeutic with respect to
individual subjects and where the risk is commensurate with the degree of expected benefit.
Selection of Subjects. It is now generally accepted that research involving persons whose
autonomy is compromised by disability or restraints on their personal freedom should bear
some direct relationship to their condition or circumstances. Persons who are
institutionalized, particularly if disabled, should not be chosen for studies that bear no
relation to their situation just because it would be convenient for the researcher. An
institutional setting can be advantageous to the conduct of research - the population is easily
accessible, close supervision to prevent extraneous influences is possible, and medical
monitoring and emergency services are available. Some not uncommon characteristics of
the institutional setting, however, create circumstances that may compromise the voluntary
nature of participation in research. For example, institutionalized individuals may have
become emotionally dependent on their caretakers and may acquiesce too readily to
requests for their "cooperation." Persons who are totally dependent on an institution may be
vulnerable to perceived or actual pressures to conform to institutional wishes for fear of
being denied services or privileges. If medical care, staff attention, or living conditions are
inadequate, an invitation to move into a special unit or research ward may be appealing.
Finally, with little or no opportunity to make decisions regarding their daily living, the
ability of institutionalized subjects to make choices may be further diminished.
Nevertheless, IRBs should not make assumptions as to the effect of an institutional setting
on voluntariness or competence. People do not automatically become incapable of
competent and voluntary consent the moment they enter a mental institution. On the other
hand, institutionalized individuals (particularly retarded persons) have been used as
convenient research subjects in drug tests totally unrelated to their disorders or
institutionalization. This exploitation of the vulnerable and the "voiceless" led the National
Commission to recommend that, even in research on mental disabilities, subjects should be
recruited from among noninstitutionalized populations whenever possible.
Degree of Risk. No clear consensus exists on the acceptable degree of risk when mentally
compromised persons are involved in the research. One position holds that research that
presents more than minimal risk should involve mentally compromised persons only if they
will derive a direct and significant benefit from participation. The National Commission
recommended that a minor increase over minimal risk may be permitted in research
involving those institutionalized as mentally disabled, but only where the research is
designed to evaluate an intervention of foreseeable benefit to their care. For research that
does not involve beneficial interventions and that presents more than minimal risk, the
National Commission recommended that the anticipated knowledge sought should be of
vital importance for understanding or eventually alleviating the subject's disorder or
condition. Finally, the National Commission recommended that there be additional ethical
review at the national level for research projects the IRB believes should be supported -
because the knowledge to be gained may be of major significance to the prevention,
diagnosis, or treatment of mental disorders - but that would not otherwise be approved at
the local level. The American College of Physicians has similarly recommended the
creation of a national board to review research that involves more than minimal risk and
that carries no direct benefit for the subjects [1989, p. 846]. Since the mechanism of a
national board is not currently available, IRBs reviewing such research should consider
obtaining assistance from expert consultants.
Limiting Risks. IRBs must be sure that investigators have included a description of
appropriate psychological or medical screening criteria to prevent or reduce the chances of
adverse reactions to the therapeutic and research procedures. When appropriate, IRBs
might want to require that other health care providers be consulted to ensure that proposed
research procedures will not be detrimental to ongoing therapeutic regimens. Specific
diagnostic, symptomatic, and demographic criteria for subject recruitment should be
described in the research proposal.
Any plan to hospitalize subjects or extend hospitalization for research purposes should be
justified by the investigator. The effects of separation from supportive family or friends, of
disruption in schooling or employment, and the question of responsibility for bearing any
additional costs should be carefully considered by the IRB. Methods for assuring adequate
protections for the privacy of the subjects and the confidentiality of the information
gathered should also be described by the investigator. Individually identifiable information
that is "sensitive" should be safeguarded, and requests for the release of such information to
others, for research or auditing, should be allowed only when continued confidentiality is
guaranteed.
Problems of Consent and Competence. Consent to research involving cognitively
impaired subjects through any of the intramural programs of the National Institutes of Health
(e.g., the National Institute of Mental Health, the National Institute of Neurological and
Communicative Disorders and Stroke, the National Institute on Aging, and the National
Institute on Alcohol Abuse and Alcoholism) is guided by NIH policy on consent to research
with impaired human subjects. This policy sets out, in matrix form, conditions under which
cognitively impaired subjects may participate in research of varying risk.
As a general rule, all adults, regardless of their diagnosis or condition, should be presumed competent to consent unless there is evidence of serious mental disability that would impair reasoning or judgment. Even those who do have a diagnosed mental disorder may be perfectly able to understand the matter of being a research volunteer, and quite capable of consenting to or refusing participation. Mental disability alone should not disqualify a person from consenting to participate in research; rather, there should be specific evidence of individuals' incapacity to understand and to make a choice before they are deemed unable to consent.
Persons formally adjudged incompetent have a court-appointed guardian who must be consulted and consent on their behalf. Officials of the institution in which incompetent patients reside (even if they are the patient's legal guardians) are not generally considered appropriate, since their supervisory duties may give rise to conflicting interests and loyalties. Family members or others financially responsible for the patient may also be subject to conflicting interests because of financial pressures, emotional distancing, or other ambivalent feelings common in such circumstances. IRBs should bear this in mind when determining appropriate consent procedures for cognitively impaired subjects.
Some individuals may be incompetent and have no legal guardian. One such example would be mentally retarded adults whose parents "voluntarily" institutionalized them as children and have never subsequently gone through formal proceedings to determine incompetence and have a guardian appointed. Another example would be geriatric patients with progressive cognitive disorders (e.g., senile dementia of the Alzheimer type). Typically, a spouse or adult child of such patients consents to their medical care, but no one is a "legally authorized representative." The extent to which family members may legally consent to the involvement of such patients in research (especially if no benefit to the subjects is anticipated) is not clear. According to a position paper published by the American College of Physicians (1989), surrogates of cognitively impaired persons should not consent to research that holds out no expected benefit if such research presents more than minimal risk of harm or discomfort. As mentioned earlier, the ACP also, however, recommended the creation of a national board to review research that involves more than minimal risk and that carries no direct benefit for the subjects [1989, p. 846].
Because no generally accepted criteria for determining competence to consent to research (for persons whose mental status is uncertain or fluctuating) exist, the role of the IRB in assessing the criteria proposed by the investigator is of major importance. The selection of an appropriate representative to consent on behalf of those unable to consent for themselves must be accomplished without clear guidance from statutes, case law, or regulations. Within the boundaries of existing legal precedents, IRBs can be creative in helping investigators formulate appropriate procedures in these uncertain areas. IRBs should be sure, however, to seek legal advice to determine the applicability of state laws that might affect the participation of legally incompetent persons in research. [See also Levine (1986), pp. 270-76.]
IRBs should be cautious about recommending legal proceedings to establish guardianship for the purpose of obtaining consent for research participation. Despite a temptation to recommend this course of action to "be on the safe side," depriving individuals of their freedom should not be taken lightly. Many states give guardians and conservators authority to make nearly all important decisions on behalf of the individual they represent. (These decisions are conditioned by an anticipated benefit to the individual.) The National Commission recommended that guardianships established for purposes of authorizing participation in research be limited to the provision and continuance (or withdrawal) of permission regarding the subject's participation in the research. The National Commission also urged that, despite the fact that consent may be obtained from a legally authorized representative or guardian, the feelings and expressed wishes of an incompetent person should still be respected. IRBs should consider whether to require investigators to solicit prospective subjects' "assent" (i.e., the willing and, to the extent possible, knowledgeable participation of those unable to give legally valid consent). IRBs should also determine whether an incompetent person's refusal to participate in research should override consent given by a legal guardian. The National Commission recommended that such decisions be based on the amount of risk involved in the research and the likelihood that the subjects will derive health benefits from their participation. [See Report and Recommendations: Research Involving Those Institutionalized as Mentally Infirm, Recommendations 2, 3, and 4.] The National Commission also recommended that in the case of research involving more than minimal risk, the objection of an adult subject who is incapable of consenting should be binding, unless the individual's participation is specifically authorized by a court of law, the intervention is expected to provide a direct health benefit to the subject, and the intervention is available only in the context of the research. [See id., Recommendation 4.] Note, however, that where local law allows institutionalized persons the right to refuse therapy, objections to participation may not be overridden.
Procedures can sometimes be developed to enhance the possibility that subjects can consent
for themselves. Criteria for determining competence might vary according to the degree of
risk or discomfort presented by the research procedures and the extent to which therapeutic
gains can be anticipated. The setting in which consent is sought and the person seeking it
can also influence a potential subject's ability to comprehend or appreciate what is being
asked. An uncomfortable chair, a room that is either too noisy or lacking in privacy, or a
physician the patient dislikes may all create anxiety or resistance that would not exist if the
information were presented by another person, at another time, or in another place. The
National Commission recommended that, in certain cases, a consent auditor be appointed by
the IRB to determine whether proposed subjects consent, assent, or object to their
participation in research, especially if the research involves more than minimal risk and no
foreseeable direct benefit.
POINTS TO CONSIDER
1. Does the IRB need to include a member knowledgeable about and experienced with the
mentally disabled or cognitively impaired?
2. Does the research pertain to mental disabilities so that it is necessary to involve persons
who are mentally disabled as subjects?
3. If the investigator proposes to involve institutionalized individuals, has he or she
provided sufficient justification for using that population? Are noninstitutionalized subjects
appropriate for the research and reasonably available? Does the research pertain to aspects
of institutionalization?
4. Are adequate procedures proposed for evaluating the mental status of prospective
subjects to determine whether they are capable of consenting? Are these procedures
appropriate both to the subject population and the nature of the proposed research?
5. Is more than minimal risk involved? If so, is the risk justified by anticipated benefits to
the participating subjects and the importance of the knowledge that may reasonably be
expected to result?
6. Is it possible to identify persons authorized to give legally valid consent on behalf of any
individuals judged incapable of consenting on their own behalf? Should assent of the
prospective subjects also be required? If incapable of giving valid consent, can subjects'
objection to participation be overridden? Under what circumstances?
7. Should an advocate or consent auditor be appointed to ensure that the preferences of
potential subjects are elicited and respected? Should someone ensure the continuing
agreement of subjects to participate, as the research progresses?
8. Should the patient's physician or other health care provider be consulted before any
individual is invited to participate in the research? Is the research likely to interfere with
ongoing therapy or regimens? Is it possible that the request to participate itself might
provoke anxiety, stress, or other serious negative response?
APPLICABLE LAWS AND REGULATIONS
IRBs should be aware of any applicable law in their state, particularly those relating to
consent by family members on behalf of persons incapable of consenting on their own. Note
that consent to participation in research may differ from consent to medical treatment. In
addition, it should be noted that some federal agencies (including components of the
Department of Defense) prohibit the participation of mentally disabled persons in research
conducted under their auspices.