Suggestions for
Further Reading
INTRODUCTION
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.]
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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
- The decision to terminate a pregnancy and procedures of abortion should 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 and compensation associated with
the procurement of fetal tissue should be prohibited, except payment for
reasonable expenses occasioned by the actual retrieval, storage, preparation,
and transportation of the tissues.
Informed Consent
- Potential recipients of such tissues, as well as research and health care
participants, should be properly informed about the source of the tissues in
question.
- The decision and consent to abort must precede discussion of the possible
use of the fetal tissue 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 decision to donate fetal
remains is sufficient for the use of tissue, unless the father objects (except
in cases of incest or rape).
- Consent should be obtained in compliance with state law and with the
Uniform Anatomical Gift Act.
Prohibiting Directed 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 provided by a family member, friend, or acquaintance should be
prohibited.
Abiding by State and Local Laws
- Researchers in states with statutes appearing to ban fetal tissue
transplants should seek clarification of the law.
Ethical Review of Research
- Customary review procedures should apply to research involving
transplantation of tissue from induced abortions.
Determining When Progress to Clinical Studies is Justified
- Sufficient evidence from animal experimentation is needed to justify
proceeding to human clinical trials. Acceptable preliminary data must be
presented to an appropriate Institutional Review Board, NIH Initial Review
Group, and National Advisory Council before Public Health Service funds would
be available.
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:
- Paternity is uncertain. In such cases it is not necessary for the IRB or
the research investigator to attempt to establish paternity.
- The father's whereabouts cannot be readily ascertained.
- The father does not acknowledge that he is the father of the fetus.
- The father has assumed no responsibility for the pregnancy and has
manifested no interest in or has denied responsibility for the well-being of
the fetus. [Note: It may be sufficient for an investigator to obtain a
statement to this effect from the mother. No further assessment of the facts
is required].
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
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B. WOMEN
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.
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Page
C. CHILDREN AND
MINORS
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.
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Page
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.
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