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[Published by the Office for Protection
from Research Risks (now the Office of Human Research Protections), 1993] Institutional
Review Board Guidebook * CHAPTER V I* |
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A. Fetuses and Human In Vitro Fertilization B. Women D. Cognitively
Impaired Persons E. Prisoners F. Traumatized
and Comatose Patients I.
Minorities J. Students, Employees, and Normal
Volunteers
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 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.”] 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. 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. 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]. 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
Federal, state, and local laws
governing research involving human fetuses or fetal material 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.”
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. [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. 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.
Applicable regulations of the
Department of Agriculture, the Army, and the Air Force 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). 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]. 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]. 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. 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. 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.
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 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. 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. 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. 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. 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. 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. INTRODUCTION The primary issue surrounding the
participation of prisoners in research has always been whether prisoners have
a real choice regarding their participation in research, or whether their
situation prohibits the exercise of free choice. A secondary issue is whether
confidentiality of participation and of data can be adequately maintained in
the prison. The circumstances common in
prisons create environments in which the offer to participate in research is
necessarily coercive or creates a undue influence in favor of participation.
To the extent that living conditions in prison are bad and the provision of
health care is minimal or even nonexistent, the lack of control allowed
prisoners and the desire to obtain the advantages offered to those who agree
to participate may preclude their ability to weigh fairly the risks and
benefits involved in participation. For example, the investigator may propose
to move the research participants to special units where they are given
medical care and where the living conditions are better than those provided
to the general prison population. Another coercive situation would be where
prisoners must earn money to purchase the means by which to maintain their
health and personal hygiene, and one way to earn that money is by
participating in research. Other rewards for participation, such as offering parole
or a reduction in sentence, would constitute an undue inducement. Even the
opportunity to leave the prison cell and interact with people from outside
the prison may act as an undue inducement to participate in research. Nancy Dubler (1982) has described
the prison setting as “inherently coercive.” She describes prisons as brutal
and dangerous, “woefully overcrowded, understaffed, underprogrammed and
ill-supported by any coherent philosophy of reform, or even punishment” [p.
10]. She provides the following quote from a report in a prison inmate
magazine: Louisiana pays its prisoners from two to five cents an hour for their
labors, an amount grossly inadequate to meet their needs. To augment that
income, many inmates sell their “plasma” twice weekly to the privately-owned
plasma company located in the Main Prison, getting $9.50 each time. The
process involves the plasma firm drawing a pint of blood from the inmate,
extracting the plasma, then returning the “red blood” back to the inmate.
Whenever the bag containing the donor’s blood accidentally bursts, preventing
the return of the blood into the inmate, the firm’s policy is to suspend the
inmate from the plasma program for six weeks to allow sufficient time for his
blood cells to build back up. Such a suspension entails a total loss of $114
income for the inmate, money he would have earned during that six-week
period. But, as it turns out, the bursting of the blood bags of some donors
weren’t (sic) always caused by accidents. According to information from inmates
and security personnel, a number of inmate-employees of the plasma firm were
threatening to deliberately bust the bags of homosexuals and inmates in
protective custody units if the inmate-victim did not agree to “belong” to
them. It was reported that such threats were also utilized to extort sex from
them. According to an informed source, some of the inmate-victims
complained to the Warden’s office, providing names of those allegedly
involved in the homosexual extortion scheme. And, in a move that caught the
entire Main Prison by surprise, the Warden’s Office ordered the immediate
transfer of nine inmate plasma workers out of the Main Prison to outcamps,
all those believed to be involved. “I’ve been in this business for a long
time, and I thought I knew all the prison games,” the source told The
Angolite, shaking his head, “but this is a new one on me...’starving them
out,’ they called it.” In addition to problems of
coercion and undue inducement, the involvement of prisoners in research
raises questions of burden and benefit. Prisoners should neither bear an
unfair share of the burden of participating in research, nor should they be
excluded from its benefits, to the extent that voluntary participation is
possible. Prisoners’ rights to self-determination (autonomy)
should not be circumscribed more than required by applicable regulations (see
below). IRBs should refrain from assuming, without cause, that prospective
prisoner-subjects will lack the ability to make autonomous decisions about
participation in research. To the extent that prisoner-subjects are found
able to voluntarily consent to participation, and to the extent allowable
under applicable regulations, prisoners should be allowed the opportunity to
participate in potentially beneficial research. Another question is whether
prisoner-subjects can ethically be paid for participation, and if so, how
much. In nonprison settings, paying subjects to participate in research is
considered ethically acceptable, so long as it is commensurate with the discomfort
and/or inconvenience involved. Paying prisoners the same amount that would be
paid to nonprisoners may, however, be seen as unduly influential in a setting
where inmates can earn only a small fraction of that amount for any other
“work” activity. On the other hand, paying prisoners a fraction of what would
be paid to nonprisoners can be seen as exploitative. One suggestion that has
been offered is to require that investigators pay prisoners at the same rate
as they would pay nonprisoners, but that individuals would receive an amount
comparable to that paid for other prison tasks. The difference would be paid
into a general prison fund, to be used, for instance, to subsidize the wages
paid to all prisoners, or to be used for educational or recreational purposes
(to be determined by the prison population, not the administrators).
Alternatively, the difference could be paid into an escrow account, to be
distributed to the prisoner upon release or to be paid to the prisoner’s
family [Levine (1986), pp. 282-83; Veatch (1987), p. 60]. Finally, confidentiality is
extremely difficult to maintain in an environment such as prisons in which
there is no privacy. In prisons, people do not move about freely; the
movements of prisoners are carefully tracked. When inmates are moved around (e.g.,
to go to a research appointment), everyone will know about it. Prison
records, including medical records, are accessible to persons who in other
settings would not have access to such personal information. Consider the
inmate participating in HIV-related research. How will the sensitive nature
of the research be kept secret? Before an IRB approves any research in
prisons, the investigator must be able to ensure that the necessary
confidentiality can and will be maintained so that the participants are not
subjected to any risk from participation. To protect prisoners from the
exploitative conditions presented by these situations, DHHS issued
regulations governing research with prisoners, limiting it to studies with an
independent and valid reason for involving this particular population (e.g.,
studies of the effects of incarceration). These limitations were imposed in
response to, but are more restrictive than, the recommendations of the
National Commission. Writing about research on HIV infection and AIDS in
prisons, Dubler and Sidel (1989) summarize the goals of protection of
prisoners involved in research. They state that, “Inmates as a group need to
be protected from research designs that can acquire the data through
other routes and may present risks to inmates as a class. They need to be provided
with access to clinical trials of new and innovative therapies that
present the possibility of direct benefit to the subjects. They must be
presented with the opportunity for informed choice when appropriate, despite
recognition that the systematic deprivations and inherent coerciveness of the
institutions...compromise the consent process” [p. 204]. DHHS regulations have special
requirements regarding the membership of an IRB that reviews research
involving prisoners [45 CFR 46.304].
At least one member of the IRB must be a prisoner or a prisoner
representative with the appropriate background and experience to serve in
that capacity. A majority of IRB members (exclusive of prison members), must
have no other association, apart from IRB membership, with the prison(s)
involved. Only certain kinds of research
conducted or supported by DHHS may involve prisoners as subjects: (1) studies
(involving no more than minimal risk or inconvenience) of the possible
causes, effects, and processes of incarceration and criminal behavior; (2)
studies (involving no more than minimal risk or inconvenience) of prisons as
institutional structures or of prisoners as incarcerated persons; (3)
research on particular conditions affecting prisoners as a class (providing
the Secretary, HHS, has consulted with appropriate experts and published [his
or her] intent to support such research in the Federal Register);
and (4) research involving a therapy likely to benefit the prisoner subject
(and if the therapeutic research also involves nontherapeutic
research with a control group, the Secretary, HHS,
must also consult with appropriate experts and publish [his or her] intent to
support the research in the Federal Register). Much of the permissible research
is behavioral. Biomedical research concerning, for example, the effects of
limited exercise or prison diets on the overall physical condition of inmates
may also be permitted, providing the research procedures present no more than
minimal risk. IRBs should be alert to the possible risk of
retaliation by other inmates or prison guards posed by a prisoner’s
participation in a study of such topics as HIV infection or AIDS, rape, drug
use, or violent behavior within the institution. The IRB has additional
responsibilities when reviewing research involving prisoners [45 CFR 46.305]. It must determine
whether any advantages the prisoners may obtain through participation in the
research are of sufficient magnitude to impair the inmates’ ability to choose
to participate, given the institutional context of limited choice (advantage
as compared to the general living conditions, medical care, quality of food,
amenities, and opportunity for earnings in the prison) [45 CFR 46.305(a)(2)]. The IRB must
also decide if the risks involved in the research are commensurate with risks
that would be accepted by nonprisoner volunteers [45 CFR 305(a)(3)]. It must ensure
that the procedures for selecting subjects are fair and immune from arbitrary
intervention by prison authorities or prisoners [45 CFR 305(a)(4) ]. There must be
adequate assurances that parole boards will not take a prisoner’s
participation in research into account when making parole decisions, and each
prisoner must be clearly informed in advance that participation will have not
effect on his or her parole [45 CFR
46.305(a)(6)]. The research institution must thereafter certify to the
Secretary, HHS, that these special responsibilities have been fulfilled [45 CFR 46.305(c)]. An understanding of the definition
of minimal risk provided in 45 CFR
46 Subpart C is critical. The risks to which prisoners may be exposed by
participating in the research is not compared with the risks “normally
encountered...by prisoners,” but rather with risks “normally
encountered in the daily lives, or in the routine medical, dental or
psychological examination of healthy persons,” i.e.,
nonprisoners. Dubler and Sidel (1989) have argued that in assessing risk,
IRBs: 1. Ought not to use the risks that face prisoners in the prison
setting as the standard for acceptable risk; IRB members should be aware of any
state law governing research with prisoners. More than half the states have
legislation or regulations restricting research with prisoners; prisoners
incarcerated in non-federal penal institutions in states with no specific law
regarding prison research will lack the protection provided by such
restrictions; IRBs reviewing protocols that propose to involve subjects in
such institutions should therefore, recognize the special protective role
they play. IRBs in such situations would be well advised to study the
recommendations of the National Commission for the Protection of Human
Subjects on research with prisoners. These recommendations describe a series
of considerations that balance the risks of research with the conditions of
incarceration. Regulations promulgated by the FDA
[21 CFR 50 Subpart C]
have been stayed until further notice. IRBs should check the status of the
FDA regulations when reviewing research to which FDA regulations would apply. The Federal Bureau of Prisons
places special restrictions on research that takes place within the Bureau of
Prisons. Those regulations are published at 28 CFR Part 512. The restrictions
apply to any research involving inmates in the custody of the Attorney
General, and assigned to the Bureau of Prisons, regardless of the institution
in which the inmate is incarcerated (e.g., even if the inmate is
resident in a state institution). Primarily, research within the Federal
Bureau of Prisons is limited to research involving no more than minimal risk,
and, where applicable, must be consistent with the Bureau of Prisons’ policy
on medical experimentation and pharmaceutical testing [28 CFR 512.12].
Research proposals are reviewed by the Director, Bureau of Prisons, following
review by the local institution and regional administrative units [28 CFR
512.14]. The policy on medical experimentation and pharmaceutical testing
generally prohibits biomedical research and drug testing on its inmates,
although individual prisoners in need of medical treatment and who qualify
for experimental therapy may participate in DHHS-approved clinical trials
“when recommended by the responsible physician and approved by the [Federal
Bureau of Prisons’] Medical Director” [Federal Bureau of Prisons, Health Services
Manual, Program Statement 6000.3, para. 6823]. For more information
concerning biomedical research involving prisoners under the jurisdiction of
the Federal Bureau of Prisons, contact: Ms. Harriet Lebowitz POINTS TO CONSIDER
Federal Bureau of Prisons, Health
Services Manual, Program Statement 6000.3 F. TRAUMATIZED AND COMATOSE PATIENTS INTRODUCTION Research involving emergency
patients is further complicated because there are a variety of state laws
concerning informed consent for emergency treatment that might be applied to
research on therapy for emergency patients. DHHS regulations (and the Federal
Policy) permit the waiver of informed consent requirements only in the case
of research that presents no more than minimal risk [45 CFR 46.116]. FDA regulations, on the
other hand, permit exception from the informed consent requirement for
patients confronted by a life-threatening situation where there is no
alternative method of approved or generally recognized therapy that provides
an equal or greater likelihood of saving the subject’s life [21 CFR 50.23]. Some legal
scholars have suggested that experimental emergency treatment might be given
to a patient who cannot give informed consent if, in the opinion of the
physician, it is the most promising treatment available. DHHS regulations say
only that “nothing in these regulations is intended to limit the authority of
a physician to provide emergency medical care, to the extent the physician is
permitted to do so under applicable Federal, State, or local law” [45 CFR 46.116(f)]. See also Guidebook Chapter 3, Section B,
“Informed Consent,” which discusses the circumstances under which the
DHHS requirements for consent may be altered or waived, and Chapter 2, Section B,
“Food and Drug Administration Regulations and Policies,” which addresses
the distinction between DHHS and FDA regulations on waiver of IRB review,
waiver of informed consent, and emergency use of a test article. The IRB should ensure that the
risks are minimized, the confidence in the anticipated benefits is
justifiable, and the risks are reasonable in relation to the anticipated
benefits. According to DHHS regulations (and the Federal Policy), IRBs may
waive the informed consent requirements when the risks are no more than
minimal, the research could not reasonably be carried out without waiving the
requirement of informed consent, and such a waiver would not adversely affect
the subject’s rights or welfare [45 CFR
46.116(d); Federal Policy §___.116(d)].
Subjects or their legally authorized representative should be provided with
pertinent information when, and if, it becomes possible and appropriate. DHHS
regulations and the Federal Policy preclude research presenting more than
minimal risk without the subject’s legally valid consent unless it is
possible to obtain the permission of the patient’s legally authorized
representative. The mental state of family members in the emergency situation
may, however, preclude good decision making. Further, it is often not
possible to locate family members in time to make the decisions necessary in
emergency care. IRBs and investigators should also note the distinction
between “next-of-kin” and “legally authorized representative.” Although
“consent” by next-of-kin is traditionally accepted by physicians treating
incompetent or comatose patients, family members do not have clear legal
authority to give such consent except in a few states having statutes or case
law on the subject. FDA regulations permit exception
from the informed consent requirements when both the investigator and a
physician not otherwise involved in the research certify in writing that: (1)
the subject is confronted by a life-threatening situation necessitating the
use of the test article; (2) informed consent cannot be obtained from the
subject because of an inability to communicate with, or obtain legally
effective consent from the subject; (3) there is not sufficient time to
obtain consent from the subject’s legally authorized representative;
and (4) there is no alternative method of approved or generally recognized
therapy that provides an equal or greater likelihood of saving the life of
the subject available [21 CFR
50.23]. Documentation of such circumstances must be submitted to an IRB
within five working days. In contrast, under the DHHS
regulations, if prior informed consent is not possible, and the IRB has not
waived the informed consent requirements (e.g., if the research
involves greater than minimal risk), the patient should be excluded from the
study and provided with standard care. In cases in which the requirement for
emergency care is foreseeable and subjects can be identified in advance (e.g.,
a study to be performed after elective major surgery), informed consent might
be obtained well before the surgery. IRBs and investigators should note
that where a patient requires emergency care, DHHS regulations requiring
prior IRB review remain in effect. While the regulations do not “limit the
authority of a physician to provide emergency medical care” [45 CFR 46.116(f)], they also do not
permit research activities to begin as part of emergency medical care unless
the research has received prior IRB review and approval [45 CFR 46.103(b); “Emergency Medical
Care,” OPRR Reports (May 15, 1991)]. While such patients may receive
emergency medical care, the patient may not be considered to be a research
subject. “Such emergency care may not be claimed as research, nor may the
outcome of such care be included in any report of a research activity” [OPRR
Reports (May 15, 1991)]. In contrast, FDA regulations do
allow for the emergency use of a test article, without prior IRB review and
approval, so long as the emergency use is reported to the IRB within five
working days of its occurrence. Any subsequent use of the test article is
subject to IRB review [21 CFR
50.23; 21 CFR 56.104(c)].
The FDA’s regulations on emergency use of test articles is discussed in
greater detail in Guidebook Chapter
2, Section B, “Food and Drug Administration Regulations and Policies.”
Applicable state law concerning consent
to experimental emergency medical treatment for persons incapable of
consenting. Note that consent to medical treatment may differ from consent to
research. INTRODUCTION With the appearance of HIV,
concerns have emerged about circumstances under which persons with serious
and life-threatening conditions may have access to research drugs through
expanded access programs. The FDA’s Parallel Track program and Treatment IND
regulations seek to address these concerns. [For a discussion of these two
expanded availability mechanisms, see Guidebook Chapter 2, Section B, “Food
and Drug Administration Regulations and Policies.”] IRBs have a role both
in considering circumstances in which terminally ill persons are
appropriately excluded from research because they are a vulnerable group, and
in providing persons who have no therapeutic alternatives the opportunity to
receive the possible benefits of experimental interventions. [See
also Guidebook Chapter 5,
Section F, “AIDS/HIV-Related Research;” 21 CFR 312.34; and Federal
Register 57:13250-13259 (April 15, 1992).] DEFINITIONS The risk of coercion and undue
influence may be caused by a variety of factors. In addition to the fact that
severe illness often affects a person’s competence, terminally ill patients
may be vulnerable to coercion or undue influence because of a real or
perceived belief that participation is necessary to receive continuing care
from health professionals or because the receipt of any treatment is
perceived as preferable to receiving no treatment. Although terminally ill
patients should be protected from an understandable tendency to enroll in
research under false hopes, IRBs should not take too protective an attitude
toward competent patients simply because they are terminally ill. Some
terminally ill patients may find participation in research a satisfying way
of imparting some good to others out of their own misfortune. It is important to distinguish
between risks that may be justified by anticipated benefits for the research
subjects and risks associated with procedures performed purely for research
purposes. A particularly difficult issue relating to research involving
terminally ill patients arises in connection with the conduct of Phase 1 drug
trials in which the drugs involved are known to be particularly toxic (e.g.,
a new form of cancer chemotherapy). In some of these studies, any benefit to
the subject is, at best, highly unlikely. Despite the “therapeutic intent” of
the investigators to benefit the subject, subjects may in fact experience a
decline in health status, no improvements in terms of quality of life, or
lengthened life for only a short time. It is extremely important that
prospective subjects be clearly informed of the nature and likelihood of the
risks and benefits associated with this kind of research. The challenge to
the investigator and the IRB is to provide patients with an accurate
description of the potential benefits without engendering false hope. [See
Ackerman (1990).] The HIV epidemic has heightened
awareness of mechanisms for including in research persons who have serious
and life-threatening illness. Increasingly, individuals and advocacy groups
have emphasized the need for opportunities for terminally ill persons to
exercise their right of autonomy: to weigh themselves the risks and benefits
of participating in research on drugs, even where relatively little is known
about the safety or effectiveness of the drugs. Many desperately ill
individuals would like to take investigational drugs that may not be
available except through limited, well-controlled clinical trials because
they are in the very early stages of development. Although the HIV epidemic has
created a demand for expanded access to investigational drugs, the issue is
not new. In the 1970s, a number of physicians, generally at academic centers,
had access to investigational drugs through protocols outside the controlled
clinical trial prior to drug approval. This mechanism allowed these
physicians to provide investigational drugs to persons without satisfactory
alternative therapies, even though they were not part of a controlled trial
and the drug was not yet approved. The drugs in these protocols were usually
also under active development in controlled trials. A similar mechanism was
developed to provide investigational drugs to persons with cancer. The FDA
and the National Cancer Institute (NCI) developed a special category of drugs
called “Group C.” Group C drugs may be provided by oncologists to appropriate
cancer patients through protocols outside the controlled clinical trial prior
to the drug approval. In 1987, the FDA initiated a regulation establishing
the treatment investigational new drug application (Treatment IND), and in
1992, instituted a policy providing for a “parallel track” mechanism [21 CFR 312.34; Federal Register
57:13250-13259 (April 15, 1992)]. Under a Treatment IND protocol, eligible
patients have access to investigational new drugs intended to treat serious
or life-threatening diseases; Parallel Track protocols enable persons with
AIDS or HIV-related diseases who cannot participate in clinical trials to
have access to investigational drugs. [See Guidebook Chapter 2, Section B, “Food
and Drug Administration Regulations and Policies,” for a discussion of
expanded access mechanisms.] IRBs must also consider including
other information the patient might find relevant to making an informed
decision to participate. For example, subjects should be told whether or not
participation in the study is a condition for treatment at the institution;
any costs to the patient of the research should be stated explicitly. IRBs
should consider whether any payment might constitute an undue enticement,
particularly if the subject population is economically disadvantaged.
Patients should be provided with relevant information well in advance of
making a decision about participation, and consultation with others such as
family members, close friends, clergy, or medical consultants should be
encouraged. IRBs may also find it advisable to
require that the clinical investigator be someone other than the patient’s
physician, that emergency services be readily available, or that there be
frequent monitoring of the progress of the research. Factors to consider in
making such decision include: anticipated toxicity of the therapeutic
interventions; extent to which subjects are likely to be debilitated by
either their illness or their therapy; the remaining life expectancy of the
subjects; and whether participation in the research would require a change in
residence (e.g., from home or hospice to a hospital or research
institution).
Federal Register
57:13250-13259 (April 15, 1992) [FDA: Parallel Track policy] INTRODUCTION There is no age at which
prospective subjects should become ineligible to participate in research.
Most older people are neither cognitively impaired nor live in institutional
settings. Nevertheless, investigators may avoid elderly subjects because of
difficulties in recruiting them to participate. Older persons tend to avoid
research that interrupts their daily routine, is uncomfortable or
inconvenient, or is not designed to provide direct benefits to them [Levine
(1986), p. 85; Sachs and Cassel (1990), p. 236; Cassel (1985), p. 46]. Also,
conducting research with older patients may be more difficult and more
costly. Elderly persons may have hearing or vision problems and may therefore
require more time to have the study explained to them. They also drop out of
studies at a higher rate than do younger subjects, so that investigators may
need to recruit more subjects initially to account for this possibility. Despite these difficulties, the
inclusion of older persons in the research enterprise is important. IRBs
should ensure that where they are excluded or treated specially, older
subjects are in need of protection and are not the object of disdain,
stereotyping, or paternalism. Together, researchers and the IRB should enable
older persons to share in the benefits and burdens of research. IRBs should treat cognitive
impairment in elderly subjects as they would cognitive impairment in any
prospective subject. [See Guidebook Chapter 6, Section
D, “Cognitively Impaired.”] The subject population should comprise
cognitively impaired persons only under the following circumstances: when
competent subjects are not appropriate for the study; if the study is related
to a problem unique to persons with that disability; and if the study
involves minimal risk [Annas and Glantz (1986), p. 1157]. The use of age as the criterion of
ability to consent and therefore participate in research is not valid.
Studies have shown that education, health status, and inadequate communication
about the research rather than age contribute to lack of comprehension and
recall [Sachs and Cassel (1990), pp. 235-36]. While it is recognized that
memory may be a problem for some elderly subjects (thus putting into question
their ability to provide continuing consent), the question for the IRB is
whether, despite some impairment to competence, subjects can make reasonable
choices. It has been suggested that in order to screen subjects for
sufficient comprehension and recall, a two-part consent process be used,
where the second part involves a test of the subject’s comprehension and
recall of the information presented in the first part. Repeated tests have
been found to improve recall. Prospective subjects who do not remember the
important facts about participation in the research after repeated testing
should not be included in the study [Levine (1986), p. 85; Sachs and Cassel
(1990), pp. 235-236]. In the past, persons in nursing
homes or other institutions have been selected as subjects because of their
easy accessibility. It is now recognized, however, that conditions in
institutional settings increase the chances for coercion and undue influence
because of the lack of freedom inherent in such situations. Research in these
settings should therefore be avoided, unless the involvement of the
institutional population is necessary to the conduct of the research (e.g.,
the disease or condition is endemic to the institutional setting, persons who
suffer from the disease or condition reside primarily in institutions, or the
study focuses on the institutional setting itself). [See Guidebook
Chapter 6, Section D, “Cognitively Impaired” for a
discussion of the problems of research involving institutionalized subjects.]
Annas and Glantz (1986) suggest that “a nursing home council, composed
primarily of residents, should review and approve any protocol before the
research can be conducted at their facility. Research that may seem trivial
to us in terms of risk, discomfort, disorientation, or dehumanizing effects
may not seem so trivial to this vulnerable and often frightened population”
[p. 1157]. POINTS TO CONSIDER
State and local laws regarding
research involving institutionalized individuals INTRODUCTION
The inclusion of minorities in
research is important, both to ensure that they receive an equal share of the
benefits of research and to ensure that they do not bear a disproportionate
burden. Most diseases affect all population groups, minority and nonminority
alike. For generalizability purposes, investigators must include the widest
possible range of population groups. Sometimes, however, minorities are subject
to a differential risk. Some research, for example, relates to conditions
that specifically affect various minority groups (e.g., sickle cell
anemia or Tay Sachs disease), so that involvement of the relevant minority
groups is imperative. Other research focuses on characteristics of diseases
or effectiveness of therapies in particular populations (e.g., HIV
transmission, treatment for hypertension), and may also concern conditions or
disorders that disproportionately affect certain racial or ethnic groups.
Exclusion or inappropriate representation of these groups, by design or
inadvertence, would be unjust. Further, to the extent that participation in
research offers direct benefits to the subjects (in HIV research, for
example, the receipt of a promising new drug), underrepresentation of
minorities denies them, in a systematic way, the opportunity to benefit. A
glaring example of abuse of minority populations’ bearing the burden of
research can be found in the Tuskegee study, in which a group of African-American
men suffering from syphilis were left untreated, despite the availability of
penicillin, in order to study the natural course of the disease. The manner in which subjects are
selected bears directly on the problem of inclusion of minorities. The choice
of a geographic area for recruitment may affect the representation of racial
and ethnic groups in study populations. Also, to the extent that minorities
are reliant on public rather than private health care systems, recruitment of
subjects from private physicians will tend to exclude minorities and
recruitment from public health clinics will tend to overinclude them. In
fact, recruiting subjects from any health care system assumes that
appropriate subjects have access to and exercise their ability to access a
health care system, which may contribute to the homogeneity of the study
population. Some writers have suggested that investigators change recruitment
strategies so that they recruit subjects through community-based institutions
such as churches and neighborhood organizations, rather than solely through
health care institutions. In many studies, several institutions collaborate,
thereby enrolling subjects from different geographic locations. Such
collaborations may also provide a mechanism for ensuring appropriate
representation of women and minorities in the study population. One justification that is offered
for research with homogeneous populations is that it is a more simple, less
costly way to conduct clinical trials. The more diverse the study population,
the larger the subject pool must be (to achieve statistical significance when
controlling for differences in race, gender, and ethnicity) and the more
variables must be accounted for in analyzing the data. Nonetheless, when
homogeneous populations are used, study results are then limited in their
applicability to the precise population involved in the study, and may, in
fact, hide inaccuracies. Research designs that include
diverse study populations are, therefore, highly desirable. IRBs should
require investigators to justify protocols that call for homogeneous study
populations. They should also be aware of the implications of various
recruiting strategies, and be prepared to suggest alternative recruitment
methods so as to ensure an appropriately diverse or focused subject
population. In doing so, the IRB should also be aware of the special needs of
prospective subjects, such as the provision of child care or transportation. In addition to ensuring adequate
appropriate representation of minorities in study populations (and guarding
against inappropriate overburdening of minorities), IRBs must ensure that any
special vulnerabilities of subjects are accounted for and handled
appropriately. To the extent that prospective minority study populations are
also economically or educationally disadvantaged, IRBs should safeguard their
rights and welfare by making sure that any possible coercion or undue
influence is eliminated (e.g., compensation that is not commensurate
with the risk, discomfort, or inconvenience involved, or recruiting in
institutional settings where voluntary participation might be compromised). IRBs should also safeguard the
consent process (and, indeed, the entire research relationship) to ensure
open and free communication between the researcher and the prospective
subject. Consent documents must be written in language easily understandable
to subjects; the possibility of illiteracy should be accounted for, as should
the need for communicating in foreign languages. The informed consent
documents should be available in English and other languages as appropriate
to the subject population(s). Foreign language consent documents should be
developed using quality control procedures such as translation from English
to the other language and then back to English, to ensure that the
information is correctly conveyed. The role of cultural norms of subjects
should also be addressed [Federal Policy ___.111(b)].
The involvement of representatives from the target population(s) may also be
pertinent to IRB review. IRBs should keep in mind that the
goal here is to ensure that minorities share fairly the benefits and burdens
of the research enterprise. In offering protection, however, IRBs should
avoid paternalism and stereotyping. POINTS TO CONSIDER
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 Public Health Service Grants, form PHS 398, pp.
21-22, and in NIH Requests for Proposals (RFPs). J. STUDENTS, EMPLOYEES, AND
NORMAL VOLUNTEERS INTRODUCTION The principle of respect
for persons requires that research participants are, where capable
of doing so, allowed to act autonomously and to express their right of
self-determination. These principles are effectuated through the process of
informed consent, which involves providing subjects with all relevant
information about the study, including the risks and benefits involved, in
clear and simple language, and ensuring that the information is understood
and appreciated. Furthermore, the agreement to participate must be voluntary;
the consent negotiations must be free from elements of coercion or undue
inducement to participate. In research involving normal volunteers,
particularly where the research involves more than minimal risk,
IRBs must ensure that any monetary payments to subjects are not so great as
to constitute an undue inducement. This issue may be particularly difficult
for IRBs to deal with. Since subjects who volunteer to participate in such
studies are usually compensated for their time and discomfort, IRBs should
seriously scrutinize the payment schedules to ensure that any compensation
offered is commensurate with the time, discomfort, and risk involved. Even
so, where a research procedure involves serious discomfort and/or the real,
though slight, possibility of serious harm (e.g., studies that
involve the insertion and positioning of catheters in veins or the heart),
one can easily imagine that the motivation of persons who volunteer to
participate may be monetary. IRBs should pay particular attention to the
proposed study population and whether it may comprise persons who are likely
to be vulnerable to coercion or undue influence, such as persons who are
educationally or economically disadvantaged. The federal regulations require
that IRBs employ special safeguards under such circumstances [Federal Policy §___.111(b); 45 CFR 46.111(b)]. One area where normal volunteers
are employed in research is in Phase 1 drug trials. The justification for the
involvement of normal, healthy subjects is the need for volunteers whose
experience with the trial materials is more easily analyzed because of the
existence of fewer confounding factors. While Phase 1 trials are the first
use of experimental drugs and devices in humans, preliminary studies
involving animals provide investigators with data indicating a high likelihood
of safe use in humans. Studies have indicated that the risk of injury from
participating in Phase 1 studies is small, about the same as the risk of
being injured while working as an office secretary [Levine (1982)]. The
likelihood of risk, including the availability of animal data, should be
scrutinized by IRBs. Normal volunteers, like students
and employees, should be recruited through general announcements or
advertisements, rather than through individual solicitations. Personal
solicitations increase the likelihood that participation will be the result
of undue influence, either because of the relationship between the recruiter
and the prospective subject, or methods of communication employed by the
recruiter that may act to persuade prospective subjects to participate, thus
compromising the voluntariness of the agreement to participate. Investigators and IRBs should
carefully consider what will happen if and when a normal volunteer should
become sick or be injured during the research. As with any research involving
human subjects, such issues should be clearly spelled out in the informed
consent document, and should be reviewed carefully with the prospective
subject. For example, subjects should be told: whether any medical treatments
will be made available should injury occur and, if so, what they consist of;
whom to contact should a research-related injury occur; and that they may
discontinue participation at any time without penalty or loss of benefits to
which they would otherwise be entitled [Federal Policy §___.116(a)(6-8); 45 CFR 46.116(a)(6-8)]. In addition,
where appropriate subjects should be told whether they will be dropped from
the study in the event of injury or illness, and whether they will be
required to pay for treatment of research-related injuries or illness
[Federal Policy §___.116(b)(2-3); 45 CFR 46(b)(2-3)]. Where illness in
healthy volunteers does occur, particularly during a drug study,
investigation by an independent physician may be warranted. [See Fazackerley,
Randall, and Pleuvry (1987).] The issues raised by the
involvement of healthy subjects in genetic research is discussed in Guidebook
Chapter 5, Section H,
“Human Genetic Research.” Students. Universities, and the association of
investigators with them, provide investigators with a ready pool of research
subjects: students. Many IRBs have faced the question of whether and in what
way students may participate in research. Two questions that have been posed
are whether students - medical students, in particular - should be allowed to
participate in biomedical research (and whether special protections should be
adopted to restrict their participation), and whether participation in
research can appropriately be included as a course component for course
credit. The latter practice is commonly employed in psychology departments. The problem with student
participation in research conducted at the university is the possibility that
their agreement to participate will not be freely given. Students may
volunteer to participate out of a belief that doing so will place them in
good favor with faculty (e.g., that participating will result in
receiving better grades, recommendations, employment, or the like), or that
failure to participate will negatively affect their relationship with the
investigator or faculty generally (i.e., by seeming “uncooperative,”
not part of the scientific community). Prohibiting all student participation
in research, however, may be an over protective reaction. An alternative way
to protect against coercion is to require that faculty-investigators advertise
for subjects generally (e.g., through notices posted in the school
or department) rather than recruit individual students directly. As with any
research involving a potentially vulnerable subject population, IRBs should
pay special attention to the potential for coercion or undue influence and
consider ways in which the possibility of exploitation can be reduced or
eliminated. Whether medical students in
particular require special protections has been hotly debated. Some
universities have either prohibited their participation or severely
restricted it to, for instance, research involving minimal risk and minimal
interruption of time. Strong arguments have been made against such
protections, including claims that as future physicians (and possibly researchers)
they may be obliged to participate. Angoff has argued that protecting medical
students to a greater degree than protecting other normal volunteers smacks
of elitism. Angoff (1985) states, “One may wonder why it is acceptable to ask
the masses to accept risk in the name of science but not the very people
whose futures are linked to the successful perpetuation of biomedical
research” [p. 10]. Nolan (1979), Levine (1984), Angoff (1985), and others
have argued that medical students are in a particularly good position to
participate in some biomedical research because of their ability to
comprehend the procedures involved in studies and evaluate the risks
involved, which may not be possible to achieve with other normal volunteers.
Angoff and others have also argued that it is acceptable to pay medical
students as one would any research participant. Requiring participation in
research for course credit (or extra credit) is also controversial, though
common in the social and behavioral sciences. The justification offered for
requiring student participation is educational benefit [Gamble (1982); Cohen
(1982)]. Clearly, however, participation of students is seen by
faculty-investigators as necessary to the conduct of their research. Grant
budgets often do not allow investigators to pay subjects; giving course
credit or extra credit is a means of obtaining sufficient participation
rates. Again, the issue for IRBs is whether such arrangements for selecting
subjects is fair and noncoercive. Participation in studies might be
mandatory or for extra credit. Students in beginning psychology courses, for
instance, might be required to serve as subjects for a given number of hours
of research or in a given number of research projects. Or they might be given
the option of participating for additional grade credit. Several mechanisms
have been suggested for diminishing or eliminating the coercive aspect of
student participation for course credit that IRBs might find useful. Gamble
(1982) describes a departmental guideline for research involving students
where extra credit is offered for participation. Students are to be given
other options for fulfilling the research component that were comparable in
terms of time, effort, and educational benefit: “for example, short papers,
special projects, book reports, and brief quizzes on additional readings” [p.
7]. He raises concerns about the comparability of such alternatives with
participating in research (e.g., that if they participate in
studies, all they have to do is show up and spend the time, but if they
choose to write a paper, it gets graded, and if they do extra readings, they
have to be tested on them), and concludes that paying student subjects as
researchers would any other subject is the only way to protect students’ freedom
of choice to participate. Cohen (1982) describes a similar policy that seems
to meet these concerns. To fulfill the research component, students can
either participate in five hours of research, write a brief research paper,
or attend faculty research colloquia. The paper is not graded, and students
who attend the colloquia have only to show up. If students do choose to
participate in studies, the policy seeks to increase the likelihood that
participation is freely chosen by requiring: that students be given several
studies to choose from and may not be required to volunteer for any
particular study; that the studies must not involve more than minimal risk;
that students can withdraw from the study at any time without losing the
extra credit [p. 11]. Another concern raised by the
involvement of students as subjects is confidentiality. As with research
involving human subjects generally, IRBs should be aware that research
involving the collection of data on sensitive subjects such as mental health,
sexual activity, or the use of illicit drugs or alcohol presents risks to
subjects of which they should be made aware and from which they should be
protected, to the greatest extent possible. The close environment of the
university amplifies this problem. Where students are likely to be
participating in research, IRBs should consider including a student member or
consulting with students where appropriate. Employees. The issues with respect to employees as
research subjects are essentially identical to those involving students as
research subjects: coercion or undue influence, and confidentiality. As
medical students have seemed ideal subjects by biomedical researchers,
employees of drug companies have been seen by investigators as ideal subjects
in some ways, because of their ability to comprehend the protocol and to
understand the importance of the research and compliance with the protocol.
Meyers (1979) provides a good summary of the structure of employee volunteer
research programs. As student participation raises questions of the ability
to exercise free choice because of the possibility that grades or other
important factors will be affected by decisions to participate, employee
research programs raise the possibility that the decision will affect
performance evaluations or job advancement. It may also be difficult to
maintain the confidentiality of personal medical information or research data
when the subjects are also employees, particularly when the employer is also
a medical institution [Meyers (1979)]. APPLICABLE
LAWS AND REGULATIONS
INTRODUCTION The procedure for approving
DHHS-supported research with a foreign component begins with the domestic
institution with which the U.S. investigator(s) are affiliated. If the U.S.
institution has an approved MPA on file with DHHS, the proposed research must
be reviewed and approved by the institution’s IRB before submission for
funding, as with any research involving human subjects. If DHHS funds the
research, each foreign institution should, upon request, submit an
appropriate Assurance to OPRR. Since, at the present time, no international
code prescribes exactly the same procedures for protecting human subjects as
do the U.S. regulations, OPRR reviews the actual procedures detailed by the
foreign institution as the primary basis for negotiating acceptable
Assurances. International codes will, however, be taken into consideration in
the negotiations. If the institution’s practices are not equivalent to the
U.S. regulations, OPRR can require that particular procedures be followed
before recommending approval of the substitution. If the U.S. institution holds an
MPA, but the research is funded by a non-DHHS source, DHHS is less involved
in review of the protocols for human subjects protections. Rather, as required
by 45 CFR 46.103, the MPA-holding
institution retains responsibility for protecting the rights and welfare of
all human subjects involved in research under the institution’s auspices. One difficult issue is determining
what constitutes “protections that are at least equivalent” to the federal
regulations. In the case of DHHS, this determination is made by OPRR. The
broad policy outlines of international standards, such as the Declaration of Helsinki or the Nuremberg Code, are a starting place,
but are not alone sufficient. Written descriptions of the specific procedural
implementation of such policies that have been adopted by the foreign
institution are required. Departments and agencies other
than DHHS follow different procedures for reviewing and approving research
with foreign components. IRBs should consult the particular department or
agency involved. [See list of persons to contact in Appendix 3.] APPLICABLE LAWS AND
REGULATIONS
SUGGESTIONS FOR FURTHER READING A. Fetuses and Human In Vitro
Fertilization
B. Women
C. Children and
Minors
D. Cognitively
Impaired Persons
E. Prisoners
F. Traumatized
and Comatose Patients
Previously titled “Emergency Use of a Test Article.”
G. Terminally
Ill Patients
H. Elderly/Aged
Persons
I. Minorities
J. Students,
Employees, and Normal Volunteers
K.
International Research
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