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Institutional Review
Board * CHAPTER III
* Suggestions for
Further Reading
A. RISK/BENEFIT
ANALYSIS INTRODUCTION Risks to research subjects posed by participation in research should be
justified by the anticipated benefits to the subjects or society. This
requirement is clearly stated in all codes of research ethics, and is central to
the federal regulations. One of the major responsibilities of the IRB,
therefore, is to assess the risks and benefits of proposed research. DEFINITIONS Benefit: A valued or desired outcome; an advantage. 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. The definition of minimal risk for research involving prisoners differs
somewhat from that given for noninstitutionalized adults. [See 45 CFR
303(d) and Guidebook Chapter 6, Section E, "Prisoners."] Risk: The probability of harm or injury (physical,
psychological, social, or economic) occurring as a result of participation in
a research study. Both the probability and magnitude of possible harm may vary
from minimal to significant. Federal regulations define only "minimal
risk." OVERVIEW There are two sources of confusion in the assessment of risks and benefits.
One arises from the language employed in the discussion: "Risk" is a word
expressing probabilities; "benefits" is a word expressing a fact or state of
affairs. It is more accurate to speak as if both were in the realm of
probability: i.e., risks and expected or anticipated benefits. Another
confusion may arise because "risks" can refer to two quite different things: (1)
those chances that specific individuals are willing to undertake for some
desired goal; or (2) the conditions that make a situation dangerous per
se. The IRB is responsible for evaluating risk only in the second sense. It
must then judge whether the anticipated benefit, either of new knowledge or of
improved health for the research subjects, justifies inviting any person to
undertake the risks. The IRB should disapprove research in which the risks are
judged unreasonable in relation to the anticipated benefits. [See also
Guidebook Chapter 5, Section A, "Overview: Social Policy Experimentation."] IRB CONSIDERATIONS The IRB's assessment of risks and anticipated benefits involves a series of
steps. The IRB must: (1) identify the risks associated with the research, as
distinguished from the risks of therapies the subjects would receive even if not
participating in research; (2) determine that the risks will be minimized to the
extent possible [see Guidebook Chapter 3, Section A, "Risk/Benefit
Analysis," and Chapter 3, Section E, "Monitoring and Observation"]; (3) identify
the probable benefits to be derived from the research; (4) determine that the
risks are reasonable in relation to be benefits to subjects, if any, and the
importance of the knowledge to be gained; (5) assure that potential subjects
will be provided with an accurate and fair description of the risks or
discomforts and the anticipated benefits [see Guidebook Chapter 3,
Section B, "Informed Consent"]; and (6) determine intervals of periodic review,
and, where appropriate, determine that adequate provisions are in place for
monitoring the data collected [see Guidebook Chapter 3, Section E,
"Monitoring and Observation," and Chapter 3, Section H, "Continuing Review"]. In
addition, IRBs should determine the adequacy of the provisions to protect the
privacy of subjects and to maintain the
confidentiality of the data [see Guidebook Chapter 3,
Section D, "Privacy and Confidentiality"], and, where the subjects are likely to
be members of a vulnerable population (e.g., mentally disabled),
determine that appropriate additional safeguards are in place to protect the
rights and welfare of these subjects. [See Guidebook Chapter 6,
"Special Classes of Subjects."] Research to which DHHS regulations apply that
involves fetuses or pregnant women, prisoners, or children is governed by
special provisions [45 CFR 46 Subpart B, 45 CFR 46 Subpart C, and 45 CFR 46
Subpart D, respectively]. [See also, Guidebook Chapter 6,
"Special Classes of Subjects."] Identification and Assessment of Risks. In the process of
determining what constitutes a risk, only those risks that may result from the
research, as distinguished from those associated with therapies
subjects would undergo even if not participating in research, should be
considered. For example, if the research is designed to measure the behavioral
results of physical interventions performed for therapeutic reasons
(e.g., effects on memory of brain surgery performed for the relief of
epilepsy), then only the risks presented by the memory tests should be
considered when the IRB performs its risk/benefit analysis. It is possible for
the risks of the research to be minimal even when the therapeutic procedure
presents more than minimal risk. IRBs should recognize, however, that
distinguishing therapeutic from research activities can sometimes require very
fine line drawing. Before eliminating an activity from consideration in its
risk/benefit analysis, the IRB should be certain that the activity truly
constitutes therapy and not research. It is important to recognize that the potential risks faced by research
subjects may be posed by design features employed to assure valid results as
well as by the particular interventions or maneuvers that may be performed in
the course of the research. Subjects participating in a study whose research
design involves random assignment to treatment groups face the
chance that they may not receive the treatment that turns out to be more
efficacious. Subjects participating in a double-masked study
take the risk that the information necessary for individual treatment might not
be available to the proper persons when needed. In behavioral, social, and some
biomedical research, the methods for gathering information may pose the added
risk of invasion of privacy and possible violations of
confidentiality. Many risks of research are the risks inherent
in the methodologies of gathering and analyzing data, although the more obvious
risks may be those posed by particular interventions and procedures performed
during the course of research. A final potential risk to subjects is the possible long-range effect of
applying the knowledge gained through research. For example, information gained
about associative memory may enable advertising companies to develop new
techniques for encouraging arguably harmful consumer behaviors; associations
between race or gender and intelligence may have profound effects on public
policy. The regulations specifically provide, however, that IRBs should not
consider such effects "as among those research risks that fall within the
purview of its responsibility" [Federal Policy §___.111]. The risks to which research subjects may be exposed have been classified as
physical, psychological, social, and economic [Levine (1986), p. 42]. Physical Harms. Medical research often involves exposure
to minor pain, discomfort, or injury from invasive medical procedures, or harm
from possible side effects of drugs. All of these should be considered "risks"
for purposes of IRB review. Some of the adverse effects that result from
medical procedures or drugs can be permanent, but most are transient.
Procedures commonly used in medical research usually result in no more than
minor discomfort (e.g., temporary dizziness, the pain associated with
venipuncture). Some medical research is designed only to measure more
carefully the effects of therapeutic or diagnostic procedures applied in the
course of caring for an illness. Such research may not entail any significant
risks beyond those presented by medically indicated interventions. On the
other hand, research designed to evaluate new drugs or procedures may present
more than minimal risk, and, on occasion, can cause serious or disabling
injuries. Psychological Harms. Participation in research may result
in undesired changes in thought processes and emotion (e.g., episodes
of depression, confusion, or hallucination resulting from drugs, feelings of
stress, guilt, and loss of self-esteem). These changes may be either
transitory, recurrent, or permanent. Most psychological risks are minimal or
transitory, but IRBs should be aware that some research has the potential for
causing serious psychological harm. Stress and feelings of guilt or embarrassment may arise simply from
thinking or talking about one's own behavior or attitudes on sensitive topics
such as drug use, sexual preferences, selfishness, and violence. These
feelings may be aroused when the subject is being interviewed or filling out a
questionnaire. Stress may also be induced when the researchers manipulate the
subjects' environment - as when "emergencies" or fake "assaults" are staged to
observe how passersby respond. More frequently, however, IRBs will confront
the possibility of psychological harm when reviewing behavioral research that
involves an element of deception, particularly if the deception includes false
feedback to the subjects about their own performance. Some examples from the
American Psychological Association's guidebook, Ethical Principles in the
Conduct of Research with Human Subjects (1973), illustrate the kinds of
research - and the types of psychological risks - IRBs may
encounter: A social psychologist attached a psycho-galvanometer to subjects (male
college students). The participants were told that the needle would be
deflected if they were aroused, and that if the needle deflected when they
viewed photographs of nude males, it would indicate latent homosexuality.
Then false feedback was given so that the subjects were led to believe
incorrectly that they were latent homosexuals. After the experiment, the
ruse was explained. Students in a school of education were told by the experimenter that
questionnaires revealed that they were unsuited for the teaching profession,
although this was untrue. The expectation was that students with such
evaluations would do poorly in their course work because these negative
appraisals would lower their self-esteem. Many of the students were upset
with the "results" of the questionnaire and considered abandoning the
teaching profession. The work which seems to me to raise ethical questions of the most serious
type occurred in a military setting. It involved taking untrained soldiers,
disorienting them, placing them in an isolated situation, giving them false
instructions, and leading them, as individuals, to believe that they had
caused artillery to fire on their own troops and that heavy casualties had
occurred. The subjects ran, cried, and behaved in what they could only
consider an unsoldierly way, and no amount of debriefing could remove the
knowledge that they had done so. Invasion of privacy is a risk of a somewhat different character. In the
research context, it usually involves either covert observation or
"participant" observation of behavior that the subjects consider private.
[See Guidebook Chapter 3, Section D, "Privacy and Confidentiality."]
The IRB must make two determinations: (1) is the invasion of privacy involved
acceptable in light of the subjects' reasonable expectations of privacy in the
situation under study; and (2) is the research question of sufficient
importance to justify the intrusion? The IRB should also consider whether the
research design could be modified so that the study can be conducted without
invading the privacy of the subjects. Breach of confidentiality is sometimes confused with invasion of privacy,
but it is really a different problem. Invasion of privacy concerns access to a
person's body or behavior without consent; confidentiality of data concerns
safeguarding information that has been given voluntarily by one person to
another. [See Guidebook Chapter 3, Section D, "Privacy and
Confidentiality."] Some research requires the use of a subject's hospital, school, or
employment records. Access to such records for legitimate research purposes is
generally acceptable, as long as the researcher protects the confidentiality
of that information. The IRB must be aware, however, that a breach of
confidentiality may result in psychological harm to individuals (in the form
of embarrassment, guilt, stress, and so forth) or in social harm (see
below). Social and Economic Harms. Some invasions of privacy and
breaches of confidentiality may result in embarrassment within one's business
or social group, loss of employment, or criminal prosecution. Areas of
particular sensitivity are information regarding alcohol or drug abuse, mental
illness, illegal activities, and sexual behavior. Some social and behavioral
research may yield information about individuals that could "label" or
"stigmatize" the subjects. (e.g., as actual or potential delinquents
or schizophrenics). Confidentiality safeguards must be strong in these
instances. The fact that a person has participated in HIV-related drug trials
or has been hospitalized for treatment of mental illness could adversely
affect present or future employment, eligibility for insurance, political
campaigns, and standing in the community. A researcher's plans to contact such
individuals for follow-up studies should be reviewed with care. Participation in research may result in additional actual costs to
individuals. Any anticipated costs to research participants should be
described to prospective subjects during the consent process. Minimal Risk vs. Greater Than Minimal Risk. Once the risks
have been identified, the IRB must assess whether the research presents greater
than minimal risk. The regulations allow IRBs to provide expedited
review of proposals if certain conditions exist (the research must
present no more than minimal risk, and the involvement of human subjects must
fall into one or more categories approved by DHHS) [Federal Policy §___.110].
Alternatively, when the proposed research presents no more than minimal risk,
waiver or modification of consent requirements may be available (if certain
other conditions are met) [Federal Policy §___.116(d); note, however: FDA does
not provide for waiver of consent requirements]. In research presenting more than minimal risk, potential subjects must be
informed of the availability of medical treatment and compensation in the case
of research-related injury, including who will pay for the treatment and the
availability of other financial compensation [Federal Policy
§___.116(a)(6); 21 CFR 50.25(a)(6)]. Although institutions are not required to
provide care or payment for research injuries, many have procedures for reducing
the cost of research-related injuries by providing hospitalization and necessary
medical care, at least in emergency situations. A few institutions have formal
insurance programs to cover lost income, as well as the direct costs of
hospitalization and medical care. Minimal Risk and Especially Vulnerable Populations. DHHS
regulations on research involving fetuses and pregnant women [45 CFR 46 Subpart
B], research involving prisoners [45 CFR 46 Subpart C], and research involving
children [45 CFR 46 Subpart D] strictly limit research presenting more than
minimal risk. The National Commission for the Protection of Human
Subjects recommended special limitations on research presenting more
than minimal risk to persons institutionalized as mentally disabled. For such
subjects, the Commission recommended that minimal risk be defined in terms of
the risks normally encountered in the daily lives or the routine medical and
psychological examination of healthy subjects. IRBs should therefore determine
whether the proposed subject population would be more sensitive or vulnerable to
the risks posed by the research as a result of their general condition or
disabilities. If so, the procedures would constitute more than minimal risk for
those subjects. These concerns are equally applicable to other subjects. Taking a blood
sample or pulling a tooth may represent significant risk to a hemophiliac;
outdoor exercises might be dangerous to persons with asthma if the air is
polluted or saturated with allergens; modest changes in diet might be dangerous
to diabetics; and over-the-counter drugs, normally taken for minor ailments,
might pose more than minimal risk to pregnant women. Deciding whether or not
research procedures will present more than minimal risk to the proposed subject
population is a matter requiring careful consideration and case-by-case review.
[See also Guidebook Chapter 6, "Special Classes of Subjects."] Determination That Risks Are Minimized. Risks, even when
unavoidable, can be reduced or managed. Precautions, safeguards, and
alternatives can be incorporated into the research activity to reduce the
probability of harm or limit its severity or duration. IRBs are responsible for
assuring that risks are minimized to the extent possible. In reviewing any protocol, IRBs should obtain complete information regarding
experimental design and the scientific rationale (including the results of
previous animal and human studies) underlying the proposed research, and the
statistical basis for the structure of the investigation. IRBs should analyze
the beneficial and harmful effects anticipated in the research, as well as the
effects of any treatments that might be administered in ordinary practice, and
those associated with receiving no treatment at all. In addition, they should
consider whether potentially harmful effects can be adequately detected,
prevented, or treated. The risks and complications of any underlying disease
that may be present must also be assessed. IRBs should determine whether the investigators are competent in the area
being studied, and whether they serve dual roles (e.g., treating
physician, teacher, or employer in addition to researcher) that might complicate
their interactions with subjects. For example, an investigator's eagerness for a
subject to continue in a research project (to obtain as much data as possible)
may conflict with the responsibility, as a treating physician, to discontinue a
therapy that is not helpful or that results in significant adverse effects
without countervailing benefit. Likewise, teachers or supervisors who conduct
research could (wittingly or unwittingly) coerce student- or employee-subjects
into participating. Thus any potential conflicts of interest must be identified
and resolved before IRB approval is granted. Another way for IRBs to meet this responsibility is to assess whether the
research design will yield useful data. When the sample size is too small to
yield valid conclusions or an hypothesis is imprecisely formulated, subjects may
be exposed to risk without sufficient justification. While good research design
may not itself reduce or eradicate risks to subjects, poor or faulty research
design means that the risks are not likely to be reasonable in relation to the
benefits. To help assess the research design, some IRBs include a
biostatistician as a member; others consult with statisticians when the need
arises. Not all procedures designed to increase the statistical validity of a
study may be justified. Procedures, even those included for purposes of good
research design, that add disproportionate risks to subjects may be
unacceptable. [See Guidebook Chapter 4, "Considerations of Research
Design."] A useful method of minimizing risk is to assure that adequate safeguards are
incorporated into the research design. Frequent monitoring, the presence of
trained personnel who can respond to emergencies, or coding of data to protect
confidentiality are examples. It may be necessary to exclude individuals or
classes of subjects (e.g., pregnant women, diabetics, people with high
blood pressure) whose vulnerability to a drug or procedure may increase with the
risks to them. In certain types of clinical trials, special provisions need to
be made for monitoring the data as they accumulate to assure the safety of
patients, or to assure that no group or subgroup in a trial is compromised by a
less effective treatment. Data monitoring should also be used to ensure that the
trial does not continue after reliable results have been obtained. In
large-scale drug trials, this often requires establishing a specialized
data and safety monitoring board or committee to review the
incoming data at stated intervals. [See Guidebook Chapter 3, Section E,
"Monitoring and Observation," Chapter 4, "Considerations of Research Design,"
and Chapter 5, Section B, "Drug Trials."] A subject's symptoms or condition may worsen during the course of a study,
and medical problems caused by an adverse reaction to experimental therapy or an
unrelated illness may arise. If the study design is such that the investigators
do not know which treatment individual subjects are receiving, there should be a
mechanism permitting someone else to break the code so that appropriate
treatment can be provided to a subject experiencing such difficulty. In a
medical emergency, individuals in single- or
double-masked studies may require treatment by physicians
unfamiliar with the research. In such cases, providing the subject with a card
or bracelet identifying someone who can provide the necessary information is a
wise precaution. The investigator can often obtain research data from the procedures performed
for diagnosis or treatment of a patient's condition, thus avoiding unnecessary
risks to the subjects. Research should always be designed to avoid exposing
participants to unnecessary risks, particularly if invasive or risky procedures
(e.g., spinal tap, cardiac catheterization) are involved. In behavioral research involving deception or incomplete disclosure,
especially if the research may induce psychological stress, guilt, or
embarrassment, it is often suggested that subjects be
"debriefed" after their participation. Debriefing gives the
investigator an opportunity to explain any deception involved and to help the
subjects deal with any distress occasioned by the research. In rare instances,
such debriefing may not be helpful C it may even be harmful. Some subjects may
not benefit from being told that the research found them to be willing to
inflict serious harm to others, have homosexual tendencies, or possess a
borderline personality. Again, the IRB must be sensitive to possible harms, and
use good judgment, evaluating the potential risks on a case-by-case basis.
[See Guidebook Chapter 3, Section B, "Informed Consent."] Assessment of Anticipated Benefits. The benefits of research
fall into two major categories: benefits to subjects and benefits to society.
Frequently, the research subjects are undergoing treatment, diagnosis, or
examination for an illness or abnormal condition. This kind of research often
involves evaluation of a procedure that may benefit the subjects by ameliorating
their conditions or providing a better understanding of their disorders.
Patients and healthy individuals may also agree to participate in research that
is either not related to any illnesses they might have or that is related to
their conditions but not designed to provide any diagnostic or
therapeutic benefit. Such research is designed principally to
increase our understanding and store of knowledge about human physiology and
behavior. Research that has no immediate therapeutic intent may, nonetheless,
benefit society as a whole. These benefits take the form of increased knowledge,
improved safety, technological advances, and better health. The IRB should
assure that the anticipated benefits to research subjects and the knowledge
researchers expect to gain are clearly identified. Direct payments or other forms of remuneration offered to
potential subjects as an incentive or reward for participation should not be
considered a "benefit" to be gained from research. [See Guidebook
Chapter 3, Section G, "Incentives for Participation."] Although participation in
research may be a personally rewarding activity or a humanitarian contribution,
these subjective benefits should not enter into the IRB's analysis of benefits
and risks. Determination That the Risks Are Reasonable in Relation to
Anticipated Benefits. Evaluation of the risk/benefit ratio is the major
ethical judgment that IRBs must make in reviewing research proposals. The
risk/benefit assessment is not a technical one valid under all circumstances;
rather, it is a judgment that often depends upon prevailing community standards
and subjective determinations of risk and benefit. Consequently, different IRBs
may arrive at different assessments of a particular risk/benefit ratio. Determining whether the risks are reasonable in relation to the benefits
depends on a number of factors, and each case must be reviewed individually. An
IRB's decision depends not only on currently available information about the
risks and benefits of the interventions involved in the research, but also on
the degree of confidence about this knowledge. Although information drawn from
animal research may be highly suggestive of the risks and benefits to be
expected for humans, it is not conclusive (because human responses may differ
from those of animals). Similarly, absence of data concerning risks does not
necessarily mean that no risks exist. An IRB's assessment of risks and benefits must also take into account the
proposed subjects of the research (e.g., children, pregnant women,
terminally ill). [See Guidebook Chapter 3, Section C, "Selection of
Subjects."] In addition, IRBs should be sensitive to the different feelings
individuals may have about risks and benefits. Some subjects may view surgery
(and thus avoiding chronic illness or prolonged medication) as a benefit while
others would consider it a significant risk (and instead view chronic medication
as a benefit because they can avoid the need for surgery). An elderly person
might consider hair loss or a small scar an insignificant risk, whereas a
teenager could well be concerned about it. IRB members should remember that
their appraisals of risks and benefits are also subjective. Finally,
risk/benefit assessments will depend on whether the research: (1) involves the
use of interventions that have the intent and reasonable probability of
providing benefit for the individual subjects; or (2) only involves procedures
performed for research purposes. In research involving an intervention expected to provide direct benefit to
the subjects, a certain amount of risk is justifiable. In studies designed to
evaluate therapies for life-threatening illness, risk of serious adverse effects
may be acceptable. However, in any trial of a new or not-yet-validated
treatment, the ratio of benefits to risks should be similar to those presented
by any available alternative therapy. In research where no direct benefits to the subject are anticipated, the IRB
must evaluate whether the risks presented by procedures performed solely to
obtain generalizable knowledge are ethically acceptable. There should be a limit
to the risks society (through the government and research institutions) asks
individuals to accept for the benefit of others, but IRBs should not be
overprotective. While the IRB must consider the importance of the knowledge that
may result from the research, the IRB's appreciation of that importance may, at
times, be limited. If only minimal risks are involved IRBs do not need to
protect competent adult subjects from participating in research considered
unlikely to yield any benefit. Disclosure of Risks and Benefits. See Guidebook
Chapter 3, Section B, "Informed Consent." Continuing Review and Monitoring of Data. The Federal Policy
requires that IRBs continue to reevaluate research projects at intervals
appropriate to the degree of risk but not less than once a year [Federal Policy
§___.108(e)]. Periodic review of the research activity is necessary to determine
whether the risk/benefit ratio has shifted, whether there are unanticipated
findings involving risks to subjects, and whether any new information regarding
the risks and benefits should be provided to subjects. It is important to note
that the risk/benefit ratio may change over time. At the time of initial review,
the IRB should determine whether an independent data and safety
monitoring board or committee is required, and should also set a date
for reevaluating the research project. The issue of continuing review by the IRB
is addressed more fully in Guidebook Chapter 3, Section H, "Continuing
Review." During the course of a study, unexpected side effects may occur or knowledge
resulting from another research project may become available. The IRB may then
need to reassess the balance of risks to benefits. In light of the reassessment,
the IRB may require that the research be modified or halted altogether.
Alternatively, special precautions or criteria for inclusion may be relaxed.
Between IRB reviews, it is largely the researchers' responsibility to keep the
IRB informed of significant findings that affect the risk/benefit ratio. In
larger studies or clinical trials, a data and safety monitoring committee may be
responsible for keeping the IRB up-to-date. Even isolated incidents of
unanticipated adverse reactions must be reported to the IRB. The IRB must then
decide whether the research should be modified. In addition, a report from one
research activity may sometimes be relevant to the evaluation of another. Federal policy also requires that investigators inform subjects of any
important new information that might affect their willingness to continue
participating in the research [Federal Policy §___. 116]. [See
Guidebook Chapter 3, Section B, "Informed Consent."] POINTS TO CONSIDER 1. Are both risks and anticipated benefits accurately identified, evaluated,
and described? 2. Are the risks greater than minimal risk? Has the IRB taken into account
any special vulnerabilities among prospective subjects that might be relevant to
evaluating the risk of participation? 3. If the research involves the evaluation of a therapeutic procedure, have
the risks and benefits of the research interventions been evaluated separately
from those of the therapeutic interventions? 4. Has due care been used to minimize risks and maximize the likelihood of
benefits? 5. Are there adequate provisions for a continuing reassessment of the balance
between risks and benefits? Should there be a data and safety monitoring
committee? B. INFORMED CONSENT INTRODUCTION Informed consent is one of the primary ethical requirements underpinning
research with human subjects; it reflects the basic principle of respect
for persons. It is too often forgotten that informed consent is an
ongoing process, not a piece of paper or a discrete moment in time. Informed
consent assures that prospective human subjects will understand the nature of
the research and can knowledgeably and voluntarily decide
whether or not to participate. This assurance protects all parties C both the
subject, whose autonomy is respected, and the investigator, who
otherwise faces legal hazards. The "proxy consent" of someone other than the
subject is not the same as the subject's own consent, although it may be an
acceptable substitute when a subject is unable to give informed consent.
[See Guidebook Chapter 6, "Special Classes of Subjects."] Federal
Policy consent requirements are provided in §§___.116 and ___.117; FDA consent
requirements are provided in 21 CFR 50.20-27 and 21 CFR 56.109. OVERVIEW The Nuremberg Code, developed by the International Military
Tribunal that tried Nazi physicians for the "experiments" they performed on
unconsenting inmates of concentration camps, was the first widely recognized
document to deal explicitly with the issue of informed consent and
experimentation on human subjects. The first principle of the code states: The voluntary consent of the human subject is absolutely essential. This
means that the person involved should have legal capacity to give consent;
should be so situated as to be able to exercise free power of choice without
the intervention of any element of force, fraud, deceit, duress,
over-reaching, or other ulterior form of constraint or coercion; and should
have sufficient knowledge and comprehension of the elements of the subject
matter involved as to enable him to make an understanding and enlightened
decision. This latter element requires that before the acceptance of an
affirmative decision by the experimental subject there should be made known to
him the nature, duration and purpose of the experiment; the method and means
by which it is to be conducted; all inconveniences and hazards reasonably to
be expected; and the effects upon his health or person which may possibly come
from his participation in the experiment. All subsequent codes and regulations, insofar as they pertain to competent,
adult subjects, follow these principles closely. Although the elements of informed consent (i.e., full disclosure,
adequate comprehension, voluntary choice) are easy to enumerate, recent
empirical studies suggest they are not so easy to achieve. Even the best
intentions do not ensure against failures of communication C information may be
poorly conveyed or subjects may forget (if indeed they ever understood) that
they are involved in a research project. Enhancing the likelihood that informed
consent will take place is a challenge to which IRBs should respond with
imagination and good judgment. When the proposed research will involve
vulnerable subjects or the research design involves incomplete disclosure or
deception, the challenges to the IRB are even greater. Certain populations
(e.g., children or mentally retarded individuals) may not be able to
understand the required information, whereas other populations (e.g., prisoners
or institutionalized individuals) are so situated that the voluntariness of
their consent may be in doubt. Hospitalized patients, particularly those who are
seriously ill or undergoing emergency treatment, may also need special
protection. Problems raised by the involvement of some vulnerable populations
are discussed in other sections of this Guidebook. [See Chapter 6,
"Special Classes of Subjects."] IRB CONSIDERATIONS The issues discussed in this section are general IRB considerations regarding
informed consent, and they apply generally to the review of research that
involves human subjects. Problems surrounding the use of deception or incomplete
disclosure are discussed near the end of this section under the headings
"Exceptions," "Deception and Incomplete Disclosure," and "Placebos,
Randomization, and Double-Masked Clinical Trials." The Regulations. The federal regulations require that
certain information must be provided to each subject [Federal Policy
§___.116(a)]: (1) A statement that the study involves research, an explanation of the
purposes of the research and the expected duration of the subject's
participation, a description of the procedures to be followed, and
identification of any procedures which are experimental; (2) A description of any reasonably foreseeable risks or discomforts to the
subject; (3) A description of any benefits to the subject or to others which may
reasonably be expected from the research; (4) A disclosure of appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the subject; (5) A statement describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained; (6) For research involving more than minimal risk, an explanation as to
whether any compensation and an explanation as to whether any medical
treatments are available if injury occurs and, if so, what they consist of, or
where further information may be obtained; (7) An explanation of whom to contact for answers to pertinent questions
about the research and research subjects' rights, and whom to contact in the
event of a research-related injury to the subject; and (8) A statement that participation is voluntary, refusal to participate
will involve no penalty or loss of benefits to which the subject is otherwise
entitled, and the subject may discontinue participation at any time without
penalty or loss of benefits to which the subject is otherwise
entitled. The regulations further provide that the following additional information be
provided to subjects, where appropriate [Federal Policy §___.116(b)]: (1) 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; (2) Anticipated circumstances under which the subject's participation may
be terminated by the investigator without regard to the subject's consent; (3) Any additional costs to the subject that may result from participation
in the research; (4) The consequences of a subject's decision to withdraw from the research
and procedures for orderly termination of participation by the subject; (5) A statement that significant new findings developed during the course
of the research which may relate to the subject's willingness to continue
participation will be provided to the subject; and (6) the approximate number of subjects involved in the
study. Investigators may seek consent only under circumstances that provide the
prospective subject or his or her representative sufficient opportunity to
consider whether or not to participate, and that minimize the possibility of
coercion or undue influence. Furthermore, the information must be written in
language that is understandable to the subject or representative. The consent
process may not involve the use of exculpatory language through which the
subject or representative is made to waive or appear to waive any of the
subject's legal rights, or releases or appears to release the investigator,
sponsor, institution, or agents from liability for negligence [Federal Policy
§___.116]. Adequacy of the Content. One of the IRB's most important
activities is evaluating the information to be provided to potential subjects in
light of the risks and benefits of the proposed research procedures. Each IRB
member brings a different perspective to this review. Certain expert members may
be able to correct the technical information or identify omissions in the
consent documents provided by the investigators. Other members may add their
reactions to the way information is provided or question the adequacy of the
information. Whether or not the information is deemed "adequate" depends partly
on the impression being conveyed (e.g., whether it is clear that a
procedure is to be done for research purposes). In making a judgment concerning what information should be disclosed in the
informed consent process, the IRB should attempt to view the matter from the
subject's perspective by asking what facts the subjects might want to know
before deciding whether or not to participate in the research. Information could
be deemed "material" if it might influence the decision of any reasonable
person. For example, the risk of death from cardiac catheterization might be
statistically small, and, therefore, seem unimportant to an investigator, but
the risk may loom large for people invited to undergo the procedure for the
benefit of others. Research in sensitive areas such as child abuse, illegal
activities such as drug or alcohol abuse, or reportable communicable diseases
such as HIV, also may pose risks to subjects about which they should be
informed. Where the potential for the need to report such information to
authorities exists, subjects should be so informed before agreeing to
participate in the study. Depending on the circumstances, potential subjects may
also feel it is "material" to be informed about additional costs that might
arise during the course of the research, the identity of the research sponsor,
any circumstances that would make it difficult or dangerous to withdraw from the
research, or the amount or kind of inconvenience involved. Expression. IRBs must ensure that information will be
presented to prospective subjects in language they can understand. How well
subjects understand that information will vary according to the population from
which subjects will be drawn. For example, if all the subjects will be
registered nurses, they will probably understand most medical terms, but if the
population consists of college students, an intermediate level of understanding
can be anticipated. If English is not the subject population's primary language,
the explanations and the forms should be translated into the subjects' native
language. The medical terms and complex sentences in oral presentations and consent
forms often need to be presented in simpler terms C even for the educated
layperson. If the prospective subjects include children, persons whose primary
language is not English, or populations with the average of a sixth grade
education, the IRB should take special care to ensure that both oral
presentations and consent forms are comprehensible to all subjects. In these
cases, ordinary language should replace technical terms (e.g., upper
extremities are better referred to as arms, hematoma as a bruise, venipuncture
as taking blood from your arm with a needle, and so forth). Some IRBs find that their lay members are particularly helpful in suggesting
necessary modifications. Others ask members of the proposed subject population
(e.g., children, clinic patients) to review consent forms and indicate
what parts they do not understand. In addition, the informed consent may not contain any exculpatory
language: Subjects may not be asked to waive (or appear to waive) any
of their legal rights, nor may they be asked to release the investigator,
sponsor, or institution (or its agents) from liability for negligence. Process. It is essential that IRB members think of informed
consent not as a form that must be signed, but as an educational process that
takes place between the investigator and the prospective subject. No one can
guarantee that another person has understood the information presented; one can
only inform prospective subjects as clearly as possible. No one can guarantee
that another's choice is voluntary; one can only attempt to remove obvious
impediments to free choice by being alert to coercive aspects of the consent
procedure. In cases where there is reason for special concern about pressure
(e.g., when patients are invited to participate in research conducted
by their physician, or when students, military personnel, employees, etc., are
asked to participate in research conducted by their supervisors), the IRB may
require some form of monitoring (such as the presence of an impartial observer).
If the research presents significant risk, or if subjects are likely to have
difficulty understanding the information to be provided, the IRB may suggest
that investigators employ devices such as audiovisual aids, tests of the
information presented, or consent advisors. Because obtaining informed consent is an educational process, the IRB should
do what it can to enhance the prospective subject's comprehension of the
information presented. It should consider the nature of the proposed subject
population, the type of information to be conveyed, and the circumstances under
which the consent process will take place (e.g., manner, timing, place,
personnel involved). After answering these questions, the IRB may want to
suggest changes in the timing or location of an investigator's first contact
with potential subjects, or changes in how others will contact subjects during
or following the study. For example, some investigators may plan to release
their data to a "data broker" who will in turn make the data available to other
researchers. IRBs should review the appropriateness of making the data available
in this way, and should ensure that subjects will be informed about who will
have access to the data and who might contact them. Sometimes the information to be imparted to prospective subjects is so
complex or possibly disturbing that it may require some time for it to be
absorbed and appreciated. In these circumstances, the IRB might suggest that the
investigator either present the information and discuss the issues with
prospective subjects on more than one occasion, or that a period of time elapse
between imparting the information and requesting a signature on the consent
form. During this waiting period, prospective subjects might be encouraged to
discuss their possible participation with family members, close friends, or
trusted advisors. Other approaches to communicating complex information include
the use of audio-visual materials and brochures. Documentation. In most cases the federal regulations require
that informed consent be documented [Federal Policy §___.117; FDA regulations 21
CFR 50.27], but they also provide for some important exceptions. Documentation
usually involves the use of a written consent form containing all the
information to be disclosed and signed by the subject or the subject's legal
representative. It should be reiterated, however, that these documents are not
substitutes for discussion. The person who signed the consent form must be given
a copy as a reference and reminder of the information conveyed. A "short form"
may sometimes be used [Federal Policy §___.117(b)(2); FDA regulations 21 CFR
50.27(b)(2)]. The use of a short form means that the information is presented
without benefit of a written version of the consent document. Before a short
form can be used, the IRB must first review and approve a written summary of
what will be presented. Each oral presentation must be witnessed by a third
person, who must sign both the consent form and a copy of the written summary of
the presentation. A copy of the summary must be provided to those who sign the
consent form so that they have the information available for future reference
[Federal Policy §___.117(b)(2)]. The IRB may waive the regulatory requirement for written documentation of
consent in cases where: (1) the principal risks are those associated with a
breach of confidentiality concerning the subject's
participation in the research (e.g., studies on sensitive topics such
as drug abuse or sexual deviance); and (2) the consent document is the only
record linking the subject with the research [Federal Policy §___.117(c)(1)].
Written documentation of consent may also be waived when the research presents
no more than minimal risk and involves procedures that do not
require written consent when they are performed outside of a research setting
[Federal Policy §___.117(c)(2); FDA regulations on IRB review, 21 CFR
56.109(c)]. [See Guidebook Chapter 3, Section A, "Risk/Benefit
Analysis."] At institutions that require IRB review of all research involving human
subjects (including research exempt from the federal regulations), the IRB may
decide to waive consent documentation requirements for research that would be
exempt from the federal regulations (e.g., most survey
and observational research). IRBs taking such an approach should be careful,
however, to make sure that the subjects will be provided adequate information
about the research. The IRB may decide that, in some cases, subjects should be
provided written copies of the information conveyed despite the fact that they
are not asked to sign a consent form. Exceptions. Federal regulations on informed consent specify
the information that must be disclosed to prospective subjects [Federal Policy
§___.116; FDA regulations on consent, 21 CFR 50.25]. The regulations do permit
modifications in the consent procedure, and, under certain circumstances,
informed consent may be waived entirely if the research meets certain conditions
[Federal Policy §___.116(c)-(d)]. Such modifications and waivers are not allowed
under FDA regulations. [But see 21 CFR 50.23, which sets out
conditions under which the obtaining of informed consent for use of a test
article can be deemed infeasible]. Situations in which modification or waiver of
consent may be indicated call for careful consideration by the IRB. Decisions to
waive informed consent or documentation of informed consent should be clearly
documented in the IRB's minutes. [See also Guidebook Chapter 6, Section
F, "Traumatized and Comatose Patients."] The IRB may approve a waiver of some or all of the consent requirements
provided that: (1) the research involves no more than minimal
risk to subjects [see Guidebook Chapter 3, Section A,
"Risk/Benefit Analysis"]; (2) the waiver or alteration will not adversely affect
the rights and welfare of the subjects; (3) the research could not practicably
be carried out without the waiver or alteration; and (4) whenever appropriate,
the subjects will be provided with additional pertinent information after they
have participated in the study [Federal Policy §__.116(d)]. Most commentators
suggest that the IRB also determine whether the knowledge being sought is
important enough to justify whatever invasion of privacy may be required either
to obtain information about unconsenting (or unaware) subjects or to involve
them in research under false pretenses. [See Guidebook Chapter 3,
Section D, "Privacy and Confidentiality."] Under the Federal Policy (but not FDA regulations), if the research is
designed to evaluate or demonstrate possible changes in (or alternatives to)
provision of benefits or services provided for under federal, state, or local
programs, an IRB may approve alteration or waiver of the consent requirements
[Federal Policy §___.116(c)]. If the research could not practicably be carried
out without the waiver or alteration of the consent requirements, the IRB may
approve such a waiver. Both the National Commission for the Protection
of Human Subjects and the President's Commission for the Study of Ethical
Problems in Medicine and Biomedical and Behavioral Research recommended
that such waivers be granted only if subjects will not be denied benefits or
services to which they are otherwise legally entitled. Record Reviews. Sometimes, especially in epidemiological
studies, scientists need to review thousands of records to identify appropriate
subjects for their study. (Consent is not an issue for record reviews of
deceased individuals because federal regulations apply only to research
involving living human subjects [Federal Policy §___.102(f)].) It is often
difficult, if not impossible, to obtain the permission of everyone whose records
are contained in the files. For this preliminary part of the research, IRBs will
generally waive the consent requirement if: (1) they are satisfied that the
information contained in the files is not particularly sensitive; (2) the
investigator has devised procedures to protect the confidentiality of the
information to be collected; and (3) the study could not practicably be carried
out if consent were required. Some university hospitals notify all incoming
patients that their records may be reviewed for research purposes; others
provide an opportunity to consent (or refuse to consent) to such use. Contacting potential subjects to obtain further information is a more
sensitive phase of the research. IRBs should consider how the investigator
proposes to make the initial contact with potential subjects (e.g.,
through employer, physician, institution having custody of the records, or
directly by the investigator) and what information will be conveyed at that
time. [See Guidebook Chapter 3, Section D, "Privacy and
Confidentiality," and Chapter 4, Section E, "Epidemiologic Studies."] In making decisions regarding record reviews and plans for contacting
individuals thus identified, IRBs should consider the importance of the
research, the extent to which privacy will be invaded, the sensitivity of the
information to which the investigators will have access, plans for further
contact of the subjects, and the feasibility of obtaining consent from all
prospective subjects. For further discussion of records research, including consent issues,
see Guidebook Chapter 4, Section E, "Epidemiologic Studies." Observation in which Subject's Identity will be Recorded.
Behavioral scientists sometimes need to observe the behavior of people who
either are not aware that they are being observed or who are unaware that their
behavior is being recorded for research purposes. Because subjects might behave
differently if they knew they were being observed, researchers may request that
the consent requirements be waived (if subjects must be unaware of their
involvement, they will not have the opportunity to consent or refuse to
participate in the research). Videotaping of the responses of passersby to
staged emergencies (e.g., heart attacks or criminal assaults),
observing the interaction between patients and staff in mental hospitals, and
studying homosexual activities in public rest rooms are three examples of this
kind of study. In the first case, the subjects have no knowledge of (and, therefore, have
not consented to) the presence of an observer or recording equipment. When the
behavior observed may be embarrassing, or when the staged conditions are
stressful, this kind of study poses ethical problems for the investigator and
the IRB. In the second example, although the patients and staff of the mental
hospital may be aware that someone is observing their behavior, they may not be
aware of why they are being observed. In the study, "On Being Sane in Insane
Places," social scientists disguised themselves as mental patients and made
important observations of the behavior patterns of both patients and staff in
mental hospitals. This kind of research presents ethical problems, because the
subjects might not consent to the pseudo-patient's presence if they were aware
of the real purpose. In the "Tea Room Trade" study, a social scientist adopted the role of "watch
queen" (i.e., lookout) for homosexuals engaged in sexual acts in public
rest rooms. Although his subjects obviously knew of his presence, they did not
know (at least until after publication of his results) that they were being
studied. The unwitting subjects also did not know that the investigator recorded
their license plate numbers and searched motor vehicle registration files for
their names and addresses. A year later, he disguised his appearance and
interviewed these subjects, purportedly for a different kind of study, thus
obtaining information about their family and social life. Commentators have
suggested that the subjects would neither have consented to the researcher's
presence in the rest room nor responded to his later survey questionnaire had
they known his real purpose. The "Tea Room Trade" study raises many of the same ethical questions as the
other two examples, but the problems are compounded because the investigator
identified the subjects, and, through further deception, obtained possibly
private information about their family and social life. (Identifying the
subjects placed them at risk of serious legal, social, and economic harm since
the behavior being studied was illegal.) The last two studies illustrate another sensitive problem IRBs must consider
when reviewing research involving covert observation. Although consent
requirements can be waived if the IRB determines that the knowledge to be gained
is important, this decision can easily be influenced by the extent to which IRB
members approve of either the subject matter or what they expect may be the
findings of the research. IRB members should guard against the inclination to
approve or disapprove research based upon their personal feelings about the
possible outcome of a research proposal. Drawing the line between judgments
about the social or scientific value of a particular study and personal
attitudes towards the subject matter of that study is admittedly difficult. IRB
members should try to distinguish between qualms they may have about the subject
matter (e.g., homosexuality or drug abuse) and qualms they may have
about the research methods (e.g., covert observation, staged events,
and so forth). Deception and Incomplete Disclosure. Sometimes, particularly
in behavioral research, investigators plan to withhold information about the
real purpose of the research or even to give subjects false information about
some aspect of the research. This means that the subject's consent may not be
fully informed. For example, to discover whether certain kinds of background
music are more distracting than others in a learning situation, an investigator
might recruit subjects and explain that certain aspects of learning and memory
are being studied. If the research is to be conducted, some of the consent
requirements must be waived. Subjects would be told that they would be required
to learn sets of words and then be tested on how well they remember those words,
but they would be deceived about the purpose of the research and certain
elements of the study design. A contrasting example, much discussed in the literature, is the Milgram study
of obedience. Subjects of this study were told that, as part of a learning
study, they were to give electric shocks each time a "student" made an error in
learning. Although they consented to participate in a study of learning, they
were unwittingly involved in a study of their own obedience and willingness to
inflict pain. Subjects were told about the true nature and purpose of the
research after they had participated. This research has been criticized for the
emotional stress it caused and the "inflicted insight" provided to the subjects
about their own behavior (neither of which they had consented to). Although
Milgram's follow-up studies indicated that few if any subjects reported that
they had misgivings about participating in the research, many commentators argue
that such deception is wrong per se. [See Guidebook Chapter 3,
Section D, "Privacy and Confidentiality."] IRBs reviewing research involving incomplete disclosure or outright deception
must apply common sense and sensitivity to the problem. They must first decide
whether the information to be withheld would influence the decision of
prospective subjects about participating in the research. In the case of the
research about the effects of background music on learning and memory, this
determination would be relatively easy. IRB members might well disagree among
themselves, however, about the Milgram study. (Scholars and commentators have
disagreed about it for years.) According to the regulations, research should not
be permitted at all if the risk to subjects is more than minimal and the
subjects are not being informed of things they would consider material to a
decision to participate. In deciding whether to waive or alter consent requirements, IRBs must
consider the risks to which subjects will be exposed. To receive a waiver of
consent requirements, the study must present no more than minimal risk. Further,
the waiver must not adversely affect the rights and welfare of subjects, and
must be essential to the ability to carry out the research. A final condition for waiving some or all of the elements of informed consent
is that, whenever appropriate, subjects will be given additional pertinent
information after they have participated in such a study. The IRB must decide if
subjects should be debriefed either after participating in
research unwittingly or after knowingly participating in research that involved
some form of deception. It is clear that debriefing is appropriate when it
contributes to the subject's welfare (i.e., when it corrects painful or
stressful misperceptions, or when it reduces pain, stress, or anxiety concerning
the subject's performance). There is greater uncertainty over whether it is
appropriate to debrief subjects when such a debriefing could itself produce
pain, stress, or anxiety (i.e., IRBs must be concerned with cases where
debriefing subjects might harm them but failure to debrief subjects would wrong
them). Further descriptions of risks encountered in research involving deception are
included in the discussion of psychological harms in the Guidebook Chapter 3,
Section A, "Risk/Benefit Analysis." Placebos, Randomization, and Double-Masked Clinical Trials.
Involving subjects in clinical trials where they may receive a
placebo instead of the experimental therapy or where they may
not be told which of several treatments they will receive could be said to
entail an element of deception. Most commentators now believe that if subjects
are told they may receive a placebo, and if the design of the clinical trial is
explained to them, no deception is involved. When the particular therapy a subject receives will be assigned on a
scientifically random basis, this selection process must be
explained to prospective subjects in language they can understand. Merely
telling them that the assignment to treatment will be done randomly,
mathematically, or by lottery may not be sufficient. Instead, more of an
explanation should be given. In a two-arm trial, for example, subjects should be
told that there is a 50 percent chance of receiving one of two treatments
thought to be beneficial for patients with their particular kind of disease;
that one is the standard treatment and the other is the experimental treatment;
that the experimental treatment is thought to be at least as good as the
standard treatment; and that their physician will not be the person who decides
which treatment they receive. If the study involves the use of placebos,
subjects should be told the chances of receiving the various possible
treatments, including the chance of receiving a placebo. It is important that prospective subjects understand that a
double-masked design means that neither they, their physicians,
nor the investigators treating and evaluating them will know which treatment
they have received. If it is important to the research design that neither the
investigators nor the subjects know about developing trends in the data, the
fact that such developments will not affect their assignment during the course
of the study should be communicated to prospective subjects prior to enrollment.
[See Guidebook Chapter 4, "Considerations of Research Design."] Subjects should understand that although they may withdraw from the study at
any time, they will not be given any information about which treatment(s) seem
to be better or worse until the study is completed. The significance of
developing trends in the data has played an important role in placebo trials
involving experimental AIDS drugs. When sufficient data showed the drug AZT to
be effective in slowing the progress of the disease, the status of subjects
receiving the placebos was revealed, and they were offered the drug. Continued
provision of placebos once the experimental drug was shown to be effective was
considered unethical. IRBs should consider the relevance of developing trends in
the data to continued consent. In double-masked clinical trials, there should be a mechanism for someone
other than the investigator to break the code to discover which treatment a
particular subject has been given in case the subject experiences a worsening of
his or her condition or an adverse effect that requires medical intervention.
This procedural safeguard should also be explained to prospective subjects. Consent as a Continuing Process. Consent is not a single
event; rather, it is a process. Since subjects always retain the right to
withdraw from a research project, their continuing consent is important. IRBs
should be aware that subjects often seem to forget they are involved in research
or have difficulty distinguishing research interventions from diagnostic and
therapeutic interventions. When a research proposal is first approved, the IRB
should determine whether consent should be renegotiated as a formal matter
during the course of the research. If renegotiation is required, the frequency
and/or events that will trigger this process should be decided upon and made
clear to the investigators. Federal policy also requires that investigators inform subjects of any
important new information that might affect their willingness to continue
participating in the research [Federal Policy §___. 116]. For instance, a
totally independent study might find an unanticipated adverse effect
(e.g., birth defects or carcinogenicity) in a drug or substance being
used in research. IRBs should determine whether any new findings or reports of
adverse effects (in the present study or other studies) should be communicated
to subjects. The IRB should also receive copies of any such information conveyed
to the subjects. When the proposed subjects are seriously ill, or, for some other reason,
might not be able to make decisions about continuing in the research
(e.g., children or cognitively impaired individuals), the IRB may
suggest that family members be closely involved with the research to evaluate
its impact on the subject and to request that the subject be withdrawn from the
study if conditions warrant. POINTS TO CONSIDER l. Do the investigators plan to involve a particularly vulnerable subject
population? 2. Do the proposed explanations of the research provide an accurate
assessment of its risks and anticipated benefits? Is the possibility (or
improbability) of direct benefit to the subjects fairly and clearly
described? 3. Is the language and presentation of the information to be conveyed
appropriate to the subject population? (Consider the level of complexity and the
need for translation into a language other than English.) 4. Are the timing of and setting for the explanation of the research
conducive to good decision making? Can anything more be done to enhance the
prospective subjects' comprehension of the information and their ability to make
a choice? 5. Who will be explaining the research to potential subjects? Should someone
in addition to or other than the investigator be present? 6. Should subjects be reeducated and their consent required periodically? 7. Should the IRB monitor incoming data to determine whether new information
should be conveyed to participating subjects? How often should this occur? Who
is responsible for bringing new information to the attention of the IRB between
scheduled reviews? 8. If a waiver of some or all of the consent requirements is requested, does
the importance of the research justify such a waiver? Is more than minimal risk
involved? Can the research design be modified to eliminate the need for
deception or incomplete disclosure? Will subjects be given more information
after completing their participation? Would the information to be withheld be
something prospective subjects might reasonably want to know in making their
decision about participation? APPLICABLE LAWS AND REGULATIONS Local laws: Federal requirements for informed consent do not necessarily meet
all the requirements of local laws. Therefore, IRBs should be aware of any state
and local requirements regarding informed consent. C. SELECTION OF
SUBJECTS INTRODUCTION Defining the appropriate group of subjects for a research project involves a
variety of factors - requirements of scientific design, susceptibility to risk,
likelihood of benefit, practicability, and considerations of fairness. IRBs are
required to make a specific determination that the selection of subjects is
equitable [Federal Policy §___.111(a)(3)]. OVERVIEW The requirement for an equitable selection of subjects helps ensure that the
burdens and benefits of research will be fairly distributed. When the
National Commission for the Protection of Human Subjects
recommended that IRBs be required to make this determination, they noted that
questions of equity have only recently been associated with scientific research.
In the 19th and early 20th centuries, the burdens of research fell largely upon
poor patients in hospital wards, while the benefits flowed primarily to private
patients. This inequity was starkly revealed in the Tuskegee syphilis study, in
which disadvantaged blacks in the rural south were recruited for studies of the
untreated course of a disease that was by no means confined to that population.
Such unjustified overutilization of certain segments of the population led the
National Commission to recommend that selection of research subjects be
scrutinized to determine "whether some classes (e.g., welfare patients,
racial and ethnic minorities, or persons confined to institutions) are being
systematically selected simply because of their easy availability, their
compromised position or their manipulability, rather than for reasons directly
related to the problem being studied." Easy availability, compromised position, and susceptibility to manipulation
often overlap. For example, psychology students are readily available for
psychological research, medical students are readily available for medical
research, prisoners, patients in mental institutions, and military personnel are
readily available for a variety of research activities, and employees of drug
manufacturing companies are readily available for pharmaceutical research.
Subjects selected from these populations are also compromised to the extent that
their jobs, promotions, grades, etc., are dependent upon those who might be
recruiting them for research. This circumstance makes them susceptible to
manipulation. Prisoners and patients in mental institutions are confined
under the strict control of people whom they must please and to whom they must
appear cooperative and rational if they are to earn their release. These
potential subjects may believe, probably as a result of their dependent
situation, that agreeing to participate in research will be viewed positively by
their wardens, psychiatrists, or social workers. They are also readily available
in large numbers, and, therefore, have historically been involved as subjects of
drug research that is totally unrelated to the basis of their confinement.
Mental patients and prisoners have accepted the risks of research in
disproportionate numbers, while the benefits of the research in which they
participated went to all segments of the population. This situation led the
National Commission to suggest that investigators be required to justify any
proposed involvement of hospital patients, other institutionalized persons,
disproportionate numbers of racial or ethnic minorities, or persons at the lower
end of the socioeconomic scale. Patients may also be susceptible to real or imaginary pressure to
participate. If an investigator also serves as a patient's primary physician, he
or she may feel obliged to participate in the research out of a desire to
please, gratitude, or fear that failure to do so will result in hostility or
abandonment. Patients who are dependent upon a particular facility for their
care (e.g., Veterans Hospitals, Indian Health Service Hospitals, or
community health clinics) may feel that they will be treated less well or with
less favor if they refuse to participate in research. With these caveats in mind, investigators and IRBs must be careful not to
overprotect vulnerable populations so that they are excluded from
participating in research in which they wish to participate, particularly where
the research involves therapies for conditions with no available treatments
(such as HIV). So too, patients with serious or poorly understood disorders may
want to participate frequently in research designed to provide a better
understanding of their condition. The fact that the subject may be either a
patient of the principal investigator or a patient in the clinic or hospital
where the investigator conducts the research should not preclude them from the
opportunity to choose to participate as often as they wish. [See
Guidebook Chapter 6, "Special Classes of Subjects."] Just as the inclusion of disproportionate numbers of racial or ethnic
minorities in research studies might overburden these groups without affording
them the benefits that will result from the research, so will
underrepresentation of these groups in study populations ensure that they will
not benefit from the research. The National Institutes of Health (NIH) requires
that its research grantees include minorities and women in study populations "so
that the research findings can be of benefit to all persons at risk of the
disease, disorder, or condition under study." If a proposed project includes a
study population in which women and minorities are not appropriately
represented, the investigator must provide "a clear compelling rationale for
their exclusion or inadequate representation" [Application for PHS Grants, form
PHS 398, pp. 21-22, and NIH Requests for Proposals (RFPs)]. See
Guidebook Chapter 6, Section B, "Women," and Chapter 6, Section I, "Minorities,"
for further discussion of this issue. IRB CONSIDERATIONS The National Commission recommended that, as a matter of
social justice, there should be an order of preference in the selection of
classes of subjects: adults before children, competent individuals before
incompetent individuals, and noninstitutionalized persons before
institutionalized persons. In addition, the Commission believed that those who
are already burdened (e.g., by disabilities or institutionalization)
should not be asked to accept the burdens of research unless other appropriate
subjects cannot be found (i.e., if the research concerns their
particular disability or circumstance). IRBs should consider the extent to which
a proposed subject population is already burdened by poverty, illness, poor
education, or chronic disabilities in deciding whether they are a suitable
subject population. When determining whether the burdens of research are being distributed
equitably, it is appropriate for an IRB to consider more than the risks
associated with the research procedures. It may be appropriate to consider such
things as inconvenience (i.e., the time required, travel involved,
restrictions on diet, or other activities), discomfort, and embarrassment as
burdens of participating in research. To encourage a broad cross-section of research subjects, IRBs might consider
the manner in which subjects will be recruited. Will notices appear only on the
bulletin boards of the psychology department or the medical school? Will
investigators personally recruit subjects only in community health clinics? If a
new treatment is available only in the research context, and it is a scarce
resource (in that only a small proportion of those who could benefit from the
therapy can be accepted as research subjects), the IRB should try to devise
procedures to ensure that subjects from a variety of locations and circumstances
have an equal chance of being selected. This becomes particularly important when
the intervention is a life-saving procedure (e.g., organ transplant or
germ-free environment). IRBs should consider means for reducing the pressures on certain classes of
subjects to participate in research. Patients should be reassured during the
consent process that no benefits to which they are otherwise entitled, and no
care or concern on the part of the health care providers, will be jeopardized by
a decision not to participate in research. In cases where the principal
investigator is the potential subject's physician, the IRB might find it
preferable for someone other than the physician-investigator to discuss
participation with the potential subject or to solicit the patient's consent. In
other cases, the possibility of pressure may be reduced by consulting beforehand
with representatives of the proposed subject group. Some IRBs have guidelines that prohibit professors from soliciting their
students as subjects and supervisors from including their employees in research.
A scientist's proposal to involve students, technicians, and junior members of
the laboratory in his or research should be examined with care. The line between
protecting the vulnerable and being unduly paternalistic is
difficult to draw. This is one of the IRB's recurrent challenges. But avoiding
the use of a group of subjects repeatedly on the grounds of mere convenience
must not prevent free and competent adults from volunteering to
be subjects of research as often as they wish. Those who accept the risks or burdens of being research subjects should be
the ones who share in its benefits whenever possible. One group of subjects
should not be asked always to bear the risks of research for the benefit of
others. Those who have participated as research subjects should have the first
opportunity to receive a therapy that the research has demonstrated to be safe
and effective (e.g., subjects of clinical trials who were either in a
control group or recipients of a therapy that proved not to be superior should
be offered the treatment that the trial demonstrated to be preferable). The
study design should provide for the adequate representation of women and
minorities in the study population so that the findings will be meaningful for
those groups and they can, therefore, share in the benefits of the research.
Adequate representation of women and minorities is particularly important in
studies of diseases, disorders, and conditions that disproportionately affect
them. Note that risk/benefit assessments are relevant to subject selection
[see, e.g., Guidebook Chapter 5, Section B, "Women"]. POINTS TO CONSIDER l. Will the burdens of participating in the research fall on those most
likely to benefit from the research? 2. Will the solicitation of subjects avoid placing a disproportionate share
of the burdens of research on any single group? 3. Does the nature of the research require or justify using the proposed
subject population? 4. Are there any groups of people who might be more susceptible to the risks
presented by the study and who therefore ought to be excluded from the research?
Are the procedures for identifying such individuals adequate? 5. To the extent that benefits to the subjects are anticipated, are they
distributed fairly? Do other groups of potential subjects have a greater need to
receive any of the anticipated benefits? 6. To the extent that participation in the study is burdensome, are these
burdens distributed fairly? Is the proposed subject population already so
burdened that it would be unfair to ask them to accept an extra burden? 7. Will any special physiological, psychological, or social characteristics
of the subject group pose special risks for them? 8. Would it be possible to conduct the study with other, less vulnerable
subjects? What additional expense or inconvenience would that entail? Does the
convenience of the researcher or possible improvement in the quality of the
research justify the involvement of subjects who may either be susceptible to
pressure or who are already burdened? 9. Has the selection process overprotected potential subjects who
are considered vulnerable (e.g., children, cognitively impaired,
economically or educationally disadvantaged persons, patients of researchers,
seriously ill persons) so that they are denied opportunities to participate in
research? 10. If the subjects are susceptible to pressures, are there mechanisms that
might be used to reduce the pressures or minimize their impact? APPLICABLE LAWS AND REGULATIONS NIH policy concerning inclusion of women and minorities in study populations.
NIH Guide for Grants and Contracts 20 (No. 32, August 23, 1991): 1-3.
The policy also appears in the application packet for PHS Grants, form PHS 398,
pp. 21-22, and in NIH Requests for Proposals (RFPs). D. PRIVACY AND CONFIDENTIALITY INTRODUCTION The possibility that research may invade the privacy of individuals or result
in a breach of confidentiality sometimes arises in biomedical and behavioral
research. Under certain circumstances, an invasion of privacy or breach of
confidentiality may even present a risk of serious harm to subjects
(e.g., as when the researcher obtains information about subjects that
would, if disclosed by the researcher, jeopardize their jobs or lead to their
prosecution for criminal behavior). Under less dramatic circumstances, an
invasion of privacy or breach of confidentiality can be a moral wrong, or, at
least in theory, provide cause for legal action against a researcher or
institution. Privacy can be defined in terms of having control over the extent, timing,
and circumstances of sharing oneself (physically, behaviorally, or
intellectually) with others. Confidentiality pertains to the treatment of
information that an individual has disclosed in a relationship of trust and with
the expectation that it will not be divulged to others in ways that are
inconsistent with the understanding of the original disclosure without
permission. Privacy and Research. In the context of research, concerns about
privacy pertain primarily to the methods used to obtain information about
subjects. Objections to the nature of information being sought in research are
sometimes couched in the language of privacy (i.e., that it would be an
invasion of a subject's privacy even to inquire about certain matters of a
personal nature). IRBs are often reluctant to accept these arguments, which tend
to preclude research on such topics. In any event, the issue of whether there
may be harm in asking certain questions is less a matter of privacy than one of
risks versus benefits, and is, therefore, not discussed in this Section. Researchers ordinarily use information that subjects have disclosed or
provided voluntarily for research purposes (i.e., with their informed
consent). Under these circumstances, there is little reason for concern about
privacy, other than to assure that appropriate confidentiality of research data
is maintained. Where privacy issues do arise is in regard to information
obtained for research purposes without the consent of subjects. Although serious
privacy questions arise with relatively few protocols reviewed by IRBs, the
questions that do arise can involve difficult and subjective judgments about
matters of propriety. Concerns about the privacy interests of research subjects may arise in
several different contexts. Privacy Issues in the Use of Personally Identifiable Records. Identifying
suitable subjects often presents no ethical problems. Physicians studying a
particular disease may be able to identify subjects from among their own
patients, and the sociologist interested in studying people who have recently
been married can identify their subjects through public records. Privacy
concerns may arise when potential subjects cannot be identified from public
records or from sources to which the researcher's work provides access. To identify suitable subjects, researchers must sometimes approach
institutions (e.g., hospitals or schools) seeking information generally
regarded as confidential (e.g., the identity of patients treated for a
particular condition or students meeting a particular criterion). In some
circumstances, the researcher needs information that would make it possible to
contact suitable subjects to obtain further data. In other circumstances, no
contact with subjects is contemplated because the information to be obtained
from the records is sufficient (or will be combined with data from other
sources). In these cases, personal identifiers may not need to be recorded by
the researchers, or, if recorded, can be destroyed at some stage of the
research. All of these factors are relevant to IRB assessments of privacy and
confidentiality issues in research. When patients give information about themselves to a doctor or hospital for
the purpose of facilitating diagnosis or treatment of disease, they do so in a
relationship of trust. They generally expect that the information will be shared
only as necessary for their health care or reimbursement by their insurance
company or other third party payer; patients would not expect information that
identifies them to be passed on in casual conversations at cocktail parties or
made available to journalists or to university students writing papers. Nor do
they necessarily intend that the information will be shared with even their
closest family members. Health care providers should respect the patient's
trust. They should not betray the confidence placed in them. (The same may be
said of educators with regard to students, and of employers with regard to
employees.) Yet such confidences are not absolute; patient records are commonly
used for a variety of purposes other than the care of a particular patient C for
the management of the organization through quality assurance programs and for
utilization review. To say that an organization has an obligation to keep
certain patient information confidential does not resolve the question of what
uses are appropriate for those records. Clearly, some important research cannot be conducted unless an investigator
gains access to many records (sometimes thousands). In epidemiological studies,
scientists may seek to determine, for example, whether certain industrial or
environmental contaminants are associated with an increase in birth defects or
deaths from cancer. In their search they might wish to review thousands of
hospital or employment records to identify infants born with a defect, patients
suffering from a particular form of cancer, or workers exposed to a particular
substance. Without access to such records, an investigator cannot identify
potential subjects or match the relevant records. [See Guidebook
Chapter 4, Section E, "Epidemiologic Studies."] It is not possible to specify precisely when an institution should honor a
researcher's request to examine records or when an IRB should approve this
potential invasion of privacy. In 1977, the Privacy Protection Study Commission
concluded that medical records can legitimately be used for biomedical or
epidemiological research without the individual's explicit authorization,
provided that the medical care provider maintaining the record: The National Commission endorsed this recommendation, and concluded
that in studies of documents, records, or pathological specimens where the
subjects are identified, informed consent may be waived if the IRB determines
that the subject's interests are adequately protected and the importance of the
research justifies the invasion of privacy. Unless otherwise required by the
head of the department or agency funding or conducting the research, federal
regulations (except those promulgated by the FDA) exempt from review all
research involving the collection or study of existing data, documents, records,
pathological specimens, or diagnostic specimens from IRB review if the sources
are publicly available or if the information is recorded by the investigator in
a manner that does not allow subjects to be identified, either directly or
through identifiers that are linked to them [Federal Policy §___.101(b)(4)].
[See also Guidebook Chapter 1, Section A, "Jurisdiction of the
Institutional Review Board," and Chapter 4, Section A, "Considerations of
Research Design C Introduction."] In cases where researchers gain access to identified records without the
individual's explicit permission, methods for reducing the associated privacy
problems should be considered. For instance, an institution possessing records
on suitable subjects may be willing to contact them and ask their permission to
release their names to the researcher. Depending on the purpose of the research,
the possible biases that this approach would create may be unacceptable, but in
other studies it may prove feasible. Another approach is for institutions to
make known the uses to which its records may be put in advance, so that
individuals will be aware that their records may be used in research. Some
institutions provide an opportunity for people to consent (or withhold consent)
to use at the time of the initial creation of the record. Other institutions
have been reluctant to do this because of either logistical difficulties or
systematic biases that might be built into subsequent research. Still another
approach, which may be feasible on occasion, is for the researcher to become an
employee of, or consultant to, the institution and thereby gain proper access to
the records. Various other creative solutions may be negotiated among
researchers, institutions, and IRBs. No firm rule can be stated; this is one of
many areas in which IRBs must exercise common sense and sound judgment. Observational Studies. Of all the methods used to locate suitable
subjects and obtain data, covert observation and participant observation are
especially likely to raise concerns about privacy. Covert observation includes
the use of concealed devices to record information for later analysis
(e.g., tape recording conversations or videotaping personal
interactions) and concealment of the researcher (e.g., behind a one-way
mirror) as the behavior of subjects is observed and recorded. In participant
observation, the researcher assumes a role in the setting or group being
studied. When the purpose of these methods is to gain access to information not
ordinarily available to "outsiders," questions of privacy arise. (Similar issues
about obtaining information not intended to be disclosed can be raised about
many other forms of research that involve deception.) Several factors may be relevant to an IRB's evaluation of such privacy
questions. One is the extent to which the behavior in question is public. Covert
observation of public behavior (e.g., observing pedestrians on the
street) raises little if any concern about privacy; concealed observation of
people in their homes would be quite another matter. Some behavior that occurs
in public places may not really be public behavior C the individuals involved
have a reasonable expectation of privacy. Research involving covert recording of
conversations in public parks or filming of activities in public rest rooms
clearly raises invasion of privacy questions. Observational studies in
quasi-public places (e.g., hospital emergency rooms or state mental
hospital wards) may also raise such concerns. A question sometimes raised about the use of covert observation in research
is whether an ethical issue exists if the subjects never become aware of the
invasion of privacy. That is, if subjects are never aware that their behavior
has been observed or recorded for research purposes, they can hardly feel
embarrassed, guilty, or that their rights have been violated. On the other hand,
it can be argued that an invasion of privacy is wrong, whether or not the
subjects are ever aware of it. In some cases, subjects may inadvertently learn
of their involvement in the research, perhaps when the study is published, and
feel that they have been harmed. Most observational research, except that involving children and minors, is
exempt from federal regulations. For studies involving adults, current
regulations require IRB review only for the most risky observational
investigations C those in which two conditions exist: (1) the observations are
recorded in a manner that allows the subjects to be identified, directly or
through identifiers linked to them; and (2) the observations recorded, if they
became known outside the research, could reasonably place the subject either at
risk of criminal or civil liability or cause damage to the subject's financial
standing, employability, or reputation [Federal Policy §___.101(b)(2)]. Clearly,
in such studies one of the IRB's major concerns should be to determine if it is
necessary to record information in a way that entails such risk, and, if so,
whether the provisions for maintaining confidentiality of the data are adequate.
Observational research involving children and minors must be reviewed by the IRB
unless the research involves observations of public behavior when the
investigator(s) do not participate in the activities being observed; IRB review
is also required where the two conditions described above obtain (i.e.,
identifiers will be recorded and the observations could place the subjects at
risk). Confidentiality of Research Data. A major set of concerns about
confidentiality pertains to the methods used to ensure that information obtained
by researchers about their subjects is not improperly divulged. Perhaps because
the creation and handling of confidential records is routine in medical
institutions, discussions of confidentiality as a special ethical responsibility
of researchers have been more prominent in the social sciences than in the
biomedical sciences. Nevertheless, the need for confidentiality exists in
virtually all studies in which data are collected about identified subjects. It
is in the interest of researchers C and essential to the conduct of research on
sensitive topics C that researchers be able to offer subjects some assurance of
confidentiality. These assurances should be given honestly, which sometimes
requires the researcher and the IRB to make explicit provisions for preventing
breaches of confidentiality. In most research, assuring confidentiality is only a matter of following some
routine practices: substituting codes for identifiers, removing face sheets
(containing such items as names and addresses) from survey instruments
containing data, properly disposing of computer sheets and other papers,
limiting access to identified data, impressing on the research staff the
importance of confidentiality, and storing research records in locked cabinets.
Most researchers are familiar with the routine precautions that should be taken
to maintain the confidentiality of data. More elaborate procedures may be needed
in some studies, either to give subjects the confidence they need to participate
and answer questions honestly, or to enable researchers to offer strong,
truthful assurances of confidentiality. Such elaborate procedures may be
particularly necessary for studies in which data are collected on sensitive
matters such as sexual behavior or criminal activities. In studies where subjects are selected because of a sensitive, stigmatizing,
or illegal characteristic (e.g., persons who have sexually abused
children, sought treatment in a drug abuse program, or who have tested positive
for HIV), keeping the identity of participants confidential may be as or more
important than keeping the data obtained about the participants confidential. In
such instances, any written record linking subjects to the study can create a
threat to confidentiality. Having the subjects of these studies sign consent
forms may increase the risk of a breach of confidentiality, because the consent
form itself constitutes a record, complete with signature, that identifies
particular individuals of the group studied. The Federal Policy allows IRBs to
waive the requirement for the investigator to obtain a signed consent form where
it will be the only record linking subjects to the research, and where a breach
of confidentiality presents the principal risk of harm that might result from
the research [Federal Policy §___.117(c)]. FDA regulations allow IRBs to waive
the signed consent form requirement only when the research presents no more than
minimal risk and involves procedures that do not normally require consent when
performed outside the research context [21 CFR 56.109(c)]. If both FDA
regulations and the Federal Policy apply to a protocol, the IRB must meet the
requirements of both. In this instance, documentation of informed consent can be
waived only if the consent form is the sole record linking subjects to the
research, the research involves minimal risk, breach of confidentiality is the
principal risk of harm and the procedure involved in the research is one that
does not normally require consent when performed outside the research context.
(Note that the foregoing waiver provisions apply to documentation of informed
consent and not waiver of the requirement to obtain informed consent.) Where data are being collected about sensitive issues (such as illegal
behavior, alcohol or drug use, or sexual practices or preferences) protection of
confidentiality consists of more than preventing accidental disclosures. There
have been instances where the identities of subjects or research data about
particular subjects have been sought by law enforcement agencies, sometimes
under subpoena, and with the threat of incarceration of the uncooperative
researcher. Under federal law (and some state laws), researchers can obtain an
advance grant of confidentiality that will provide protection even against a
subpoena for research data [Public Health Service Act §301(d)]. Although
regulations implementing §301(d) are not in place as of this writing, the PHS
has issued an Interim Policy Statement [also called the "Interim Guidance" (May
22, 1989)] that sets forth PHS policy exercising the its authority to grant
certificates of confidentiality. Section 301(d) extends to "biomedical,
behavioral, clinical, or other research" an earlier authority (in '303 of the
Public Health Service Act) that was available only for "research on mental
health, including research on the use and effect of alcohol and other
psychoactive drugs." To take advantage of §301(d), the investigator must request a grant of
confidentiality from the appropriate official. Protection for research on mental
disorders or the use and effects of alcohol and other psychoactive drugs can be
obtained from the National Institute on Alcohol Abuse and Alcoholism (NIAAA),
the National Institute on Drug Abuse (NIDA), or the National Institute of Mental
Health (NIMH), which, in 1991, became components of NIH. Certificates of
confidentiality for biomedical, behavioral, clinical, or other research that
does not fall into these categories are issued by the Assistant Secretary for
Health. Protection is available for: (1) direct federal activities (i.e.,
intramural research); (2) federally-funded activities; and (3) research in the
United States that has no federal funding. Under the Interim Policy, protection
will be granted "sparingly," and only "when the research is of a sensitive
nature where the protection is judged necessary to achieve the research
objectives." The Policy defines "sensitive" research as involving the collection
of information falling into any of the following categories: Additional policy considerations apply to research that involves the
collection of data that relates to communicable diseases. The Assistant
Secretary for Health has, therefore, issued a further PHS policy on the granting
of certificates of confidentiality to projects that "intend routinely to
determine whether its subjects have communicable diseases and that are required
to report them under State law" [Memorandum, James O. Mason, "Certificates of
ConfidentialityC Disease Reporting," August 9, 1991]. Certificates will be
issued: (1) where the referring treating physicians assure the project that they
have complied with reporting requirements; or (2) where there is no referring
physician, the investigator has reached an agreement with the health department
about how he or she will cooperate with the department to help serve the
purposes of the reporting requirements (unless the investigator can show why
such cooperation is precluded); and (3) only where disclosures of identifiable
information about subjects comply with regulations on subject protection and are
explained clearly to subjects prior to their participation. For further information concerning PHS certificates of confidentiality under
'301(d) of the Public Health Service Act and the Interim Guidance,
contact: In addition to certificates of confidentiality available under §301(d), the
U.S. Attorney General is authorized to grant protection for research concerning
drug abuse under the Controlled Substance Act. For more information write to the
Drug Enforcement Administration, 14501 I St., N.W., Washington, D.C. 20537. For studies in which the data to be obtained concern illegal or stigmatizing
activities but which are not eligible for these statutory shields against
subpoena, careful attention should be given to a series of decisions related to
confidentiality: (1) whether the researcher will record subject identifiers at
all (including on consent forms); (2) if identifiers are to be collected,
whether they will be retained after the data are coded; (3) if identifiers are
not destroyed, how are they to be maintained; and (4) what subjects should be
told about these matters as part of the informed consent process. Some
researchers enlist a third party (sometimes in another country) to act as a
custodian of keys to coded identifiers or lists of participants. This approach
may provide some protection for the data, but may expose the researcher to legal
risks. Where such steps are contemplated, investigators should seek competent
legal advice regarding the advisability of such arrangements. Clearly, different types of studies entail different confidentiality
problems. A variety of methods for protecting confidentiality are available for
different situations, including situations in which there is a danger of
deductive identification of otherwise anonymous subjects on the basis of
separate elements of data (e.g., birthdate, occupation, and zip code).
A substantial and highly specialized literature has developed on methods for
safeguarding confidentiality. Among the available methods for assuring
confidentiality are statistical techniques and physical or computerized methods
for maintaining the security of stored data. The more sensitive the data being
collected, the more important it is for the researcher and the IRB to be
familiar with the state of the art in protecting confidentiality. IRB CONSIDERATIONS Privacy. In reviewing some protocols, an IRB may have to consider
whether an invasion of privacy is involved. No ready and clear criteria are
available for evaluating this question. IRBs must base decisions on their
members' sense of propriety and the particular circumstances of the study. Among
the relevant factors are: the private nature of the information sought, the
likelihood the subjects would regard the release of information as an invasion
of privacy, the importance of the research, and the availability of alternative
ways to do the study. Much research in which privacy concerns may be relevant will not necessarily
come to the attention of the IRB. Under federal regulations, IRBs need not even
review proposed research involving observation unless someone (e.g.,
the investigator or department head) determines that it falls in the category of
research that requires IRB review, as discussed above [Federal Policy
§--___.101(b)(2)]. Some institutions review all observational research, as a
matter of policy, to ensure that the IRB sees those few protocols for which
review is required. Although the Federal Policy exempts from IRB review most
research involving access to existing records, data, and surgical and diagnostic
specimens, some institutions require review of the protocols to assure that the
information is sought for a legitimate purpose and that research involving a
record of individually identifiable information receives regular IRB review. Investigators sometimes want access to existing records to identify people
suitable for inclusion in a study. If the subjects' names will be recorded by
the investigator for follow-up (either for further record reviews or for
personal contact), this research requires IRB review. In such instances, the IRB
must determine whether the consent of subjects should be sought (e.g.,
by the institution holding the records) before the researcher gains access to
the records. Factors to consider in deciding if consent must be sought include
the sensitivity of the information to be reviewed, the vulnerability of the
subject population, and the purpose for which the investigator wants access to
the information. The Buckley Amendment [the General Education Provisions Act (20
USC 1232)] requires parental consent for release of records or identifiable
information about children in public schools; instructional materials to be used
in connection with any research or experimental program must be open to
inspection by the parents or guardians of the children to be involved. Protection of Confidentiality. When information linked to individuals
will be recorded as part of the research design, IRBs should assure that
adequate precautions will be taken to safeguard the confidentiality of the
information. Sensitive information is sometimes obtained in the course of
behavioral research, research with the cognitively impaired, AIDS research, and
research dealing with drug and alcohol abuse. Various specialized security
methods have been developed to maintain the confidentiality of such information.
IRBs that review research in which confidentiality of data is important should
have at least one member (or consultant) familiar with the strengths and
weaknesses of the different mechanisms available, including the statutory
shields against subpoena that are available. IRBs should also be aware of the
regulatory provision for waiving documentation of consent when a signed consent
form would itself constitute a risk to the subjects [Federal Policy
§___.117(c)(1)]. Finally, IRBs should be aware that federal officials have the right to
inspect research records, including consent forms and individual medical
records, to ensure compliance with the rules and standards of their programs.
FDA rules require that information regarding this authority be included on the
consent forms for all research regulated by that agency; the Federal Policy,
which applies to DHHS, and FDA regulations require that subjects be informed of
the extent to which confidentiality of research records can be maintained
[Federal Policy §___.116(a)(5); 21 CFR 50.25(a)(5)]. Identifiable information
obtained by federal officials during such inspections is protected by the
provisions of the Privacy Act of 1974. POINTS TO CONSIDER 1. Does the research involve observation or intrusion in situations where the
subjects have a reasonable expectation of privacy? Would reasonable people be
offended by such an intrusion? Can the research be redesigned to avoid the
intrusion? 2. If privacy is to be invaded, does the importance of the research objective
justify the intrusion? What if anything, will the subject be told later? 3. If the investigators want to review existing records to select subjects
for further study, whose permission should be sought for access to those records
(the physician, the institution maintaining the records, the subjects)? How
should the subjects be approached (through their physician, the medical records
department, the institution)? 4. Will the investigator(s) be collecting sensitive information about
individuals? If so, have they made adequate provisions for protecting the
confidentiality of the data through coding, destruction of identifying
information, limiting access to the data, or whatever methods that may be
appropriate to the study? If the information obtained about subjects might
interest law enforcement or other government agencies to the extent that they
might demand personally identifiable information, can a grant of confidentiality
be sought from a federal or state agency to protect the research data and the
identity of the subjects from subpoena or other legal process? 5. Are the investigator's disclosures to subjects about confidentiality
adequate? Should documentation of consent be waived in order to protect
confidentiality? APPLICABLE LAWS AND REGULATIONS The Public Health Service Act [§301(d)] permits the Secretary, HHS, to
authorize persons conducting biomedical and behavioral research to protect the
privacy of subjects, even against subpoena. Persons so authorized may not be
compelled to testify in any federal, state, or local civil, criminal,
administrative, legislative, or other proceedings. Regulations that predate
§301(d) and that are used for guidance in implementing '301(d) for research
relating to mental health (including alcohol and drug abuse) are published at 42
CFR 2A. The "Interim Policy Statement" on protection of identity of research
subjects dated May 22, 1989, sets forth the policy of the PHS in accordance with
§301(d). The Controlled Substance Act (21 USC 872) permits the U.S. Attorney General
to authorize persons conducting educational or research programs concerning drug
abuse to withhold the names and other identifying characteristics of the
subjects of such research. This provision is implemented by FDA regulations
published at 21 CFR 1315.21. The Buckley Amendment to the General Education Provisions Act (20 USC 1232)
requires parental permission for access to records or identifiable information
of children in public schools. The Privacy Act of 1974 [5 USC 552(a)] prohibits federal agencies from
disclosing records maintained in a system of records to any person, with certain
exceptions, or other agency except upon a written request by, or with the prior
written consent of, the individual to whom the record pertains. The Freedom of Information Act (5 USC 552) exempts information such as
medical or personnel records the disclosure of which would constitute a clearly
unwarranted invasion of personal privacy from mandatory release by federal
agencies. E. MONITORING AND OBSERVATION INTRODUCTION One of the areas to be reviewed in proposed research is the researcher's plan
for collection, storage, and analysis of data. Monitoring of the research by the
researcher is important because preliminary data may signal the need to change
the research design, change the information presented to subjects, or even to
terminate the project before the scheduled end date. Both the timing and adequacy of the plan for analysis are important. If the
data are not analyzed until the project is terminated, the chance to make
mid-course corrections is lost. If the data are not properly analyzed, the
research itself is not valid, and proper conclusions may not result. DEFINITIONS Monitoring: The collection and analysis of data as the project
progresses to assure the appropriateness of the research, its design, and
subject protections. Review: The concurrent oversight of research on a periodic basis by an
IRB. In addition to the at least annual reviews mandated by the federal
regulations, reviews may, if deemed appropriate, also be conducted on a
continuous or periodic basis [Federal Policy §___.108(e)]. IRB CONSIDERATIONS For an IRB to approve proposed research, the protocol must, when appropriate,
include plans for monitoring the data collected to ensure the safety of subjects
[Federal Policy §___.111(a)(6)]. Investigators sometimes misinterpret this
requirement as calling for annual reports to the IRB so that the IRB can monitor
the project. In fact, however, §___.111 requires that, when appropriate,
researchers must provide the IRB with a description of their plans for analyzing
the data during the collection process. Concurrent collection and analysis
enables the researcher to identify flaws in the study design early in the
project. At this point, researchers are to reevaluate the risks to human
subjects to assure that they are no greater than initially predicted. Like other considerations, the level of monitoring in the research plan
should be related to the degree of risk posed by the research. Furthermore,
where the research will be performed at foreign sites, the IRB at the United
States institution may want to require different monitoring and/or more frequent
reporting than that required by the foreign institution. [See also
Guidebook Chapter 3, Section A, "Risk/Benefit Analysis," and Chapter 6, Section
K, "International Research."] IRBs should assure themselves that the progress of clinical trials will be
adequately monitored to determine if information generated from them (or other
related trials) should be passed on to the subjects, affect recruitment of
subjects, change the ratio of risks and benefits, or lead to modification or
discontinuation of the treatments being evaluated. Under normal circumstances,
it is neither necessary nor desirable for the IRB itself to undertake data
monitoring. Because investigators may have strong interests in continuing a
clinical trial, however (e.g., to obtain a higher level of statistical
significance to ensure publication of the results), it is important that other,
independent persons be responsible for monitoring trials and for decisions about
modification or discontinuation of trials. It is the IRB's responsibility to
ensure that these functions are carried out by an appropriate group. The review
group should be required to report its findings to the IRB on an appropriate
schedule. Many trials, especially multicentered or double-masked studies, have
independent data monitoring boards that fulfill this function. The primary
responsibility of these monitoring boards is to safeguard human subjects by
analyzing accumulating data relevant to risks and benefits on a regular basis.
Especially in long-term trials, where patient enrollment or follow-up occurs
over a long period of time, the boards review data periodically to assess
effectiveness and toxicity. They must decide if and when the data are
sufficiently favorable to one treatment that the study should be ended, which
sometimes occurs sooner than the investigators had planned. Similarly,
monitoring boards must decide whether adverse effects are serious enough to
warrant termination of the trial [Federal Policy §___.113]. [See also
Guidebook Chapter 3, Section E, "Monitoring and Observation."] IRBs may want to monitor not only the collection of data but also the
informed consent process. The IRB should not delegate the monitoring of the
informed consent process to others. Finally, the regulations also require periodic IRB reviews of research
[Federal Policy §___.109(e)]. Periodic IRB review is discussed in the Guidebook
in Chapter 3, Section H, "Continuing Review." POINTS TO CONSIDER l. How will the research data be recorded and maintained? APPLICABLE LAWS AND REGULATIONS Federal Policy §___.111(a)(6) [Criteria for IRB approval of research] F. ADDITIONAL SAFEGUARDS INTRODUCTION The protection of human subjects is the paramount consideration of the IRB.
Each project should be reviewed to determine whether some or all of the subjects
are likely to be vulnerable to coercion or undue influence to participate. These
vulnerabilities may be subtle but may limit the ability of certain subjects to
refuse to participate or to continue to participate in the research. The IRB
must assure that due consideration of this issue is addressed in the research
plan. Additional safeguards may need to be included in the study to protect the
rights and welfare of these subjects. IRB CONSIDERATIONS The federal regulations provide that additional safeguards to protect
subjects' rights and welfare must be included in any study where "some or all of
the subjects are likely to be vulnerable to coercion or undue influence"
[Federal Policy §___.111(b)]. Examples of such vulnerable subjects are children,
prisoners, pregnant women, mentally disabled persons, and persons who are
economically or educationally disadvantaged. Provision of additional safeguards
for three of these groups (children, prisoners, and pregnant women) is handled
differently by DHHS. The DHHS regulations provide distinct rules (which differ
from the Federal Policy) for research involving fetuses, pregnant women, and
human in vitro fertilization (45 CFR 46 Subpart B), prisoners (Subpart C), and
children (Subpart D). The consent process must be conducted only under circumstances that provide
the prospective subject sufficient opportunity to consider whether or not to
participate. Research conditions must also minimize the possibility of coercion
or undue influence to give consent. Persons with acute and/or severe physical or mental illness may be overly
compliant with requests to participate in research due to the effects of their
illness or due to the prospect of relief from suffering. Clinical studies must
be specially designed to assure that patients are able to consent freely.
Additional safeguards may include such requirements as the co-consent of
relatives, parents, or impartial observers. In acute illness, patients may need
to be treated before being entered into research protocols as subjects. This may
mean that subjects are sometimes lost to the research protocol. Occasionally, the institutional setting in which the consent is sought will
pose the possibility of coercion. Conducting research at institutions that
provide services to subjects may be perceived as implying that continued service
is dependent upon participation in the research. Students in the educational
setting may be concerned that refusal to participate will affect their grades.
These institutional pressures should be addressed in the research design. The
protocol must adequately preserve the right to refuse participation. The requirement to obtain informed consent should be seen as not only a legal
obligation, but also as a moral obligation. The research design must adequately
address how informed consent will be obtained and what information will be given
to prospective subjects. IRBs must look at the coercion issue in each proposal
and insist on experimental designs that protect against undue influence to
participate. See Guidebook Chapter 3, Section B for a fuller description of
informed consent requirements. POINTS TO CONSIDER 1. Are recruitment procedures designed to assure that informed consent is
freely given? APPLICABLE LAWS AND REGULATIONS
G. INCENTIVES FOR PARTICIPATION
INTRODUCTION
Each year, thousands of individuals are paid for participating in biomedical
and behavioral research funded either by federal departments and agencies or
private institutions. Although payments are usually monetary, both patients and
normal healthy volunteers may be offered other rewards in lieu of or in addition
to money. Free medical care, extra vacation time, and academic rewards (in the
form of a grade or a letter of recommendation) are examples of alternative
rewards. Regardless of the form of remuneration, the issues for IRBs remain the
same. IRBs must consider whether paid participants in research are recruited
fairly, informed adequately, and paid appropriately. Taking into consideration
the subjects' medical, employment, and educational status, and their financial,
emotional and community resources, the IRB must determine whether the rewards
offered for participation in research constitute undue inducement.
OVERVIEW
Federal regulations governing research with human subjects contain no
specific guidance for IRB review of payment practices. One of the primary
responsibilities of IRBs, however, is to ensure that a subject's decision to
participate in research will be truly voluntary, and that consent will be sought
"only under circumstances that provide the prospective subject...sufficient
opportunity to consider whether or not to participate and that minimize the
possibility of coercion or undue influence" [Federal Policy §___.116; 21 CFR
50.20]. Incentives for participation in research are discussed in the FDA's
Information Sheet, "Payment to Research Subjects" (February 1989). Clear cases of coercion (i.e., actual threats) are readily
identifiable; it is more difficult to recognize undue inducement. An offer one
could not refuse is essentially coercive (or "undue"). Undue inducements may be
troublesome because: (1) offers that are too attractive may blind prospective
subjects to the risks or impair their ability to exercise proper judgment; and
(2) they may prompt subjects to lie or conceal information that, if known, would
disqualify them from enrolling — or continuing — as participants in a research
project. IRB CONSIDERATIONS
IRBs must attempt to make sure that prospective subjects realize that their
participation is voluntary, and that choosing not to participate will not
adversely affect their relationship with the institution or its staff in any
way. To make this determination, IRBs should know who the subjects will be, what
incentives are being offered, and the conditions under which the offer will be
made. Some institutions have adopted policies regarding the recruitment and payment
of volunteers. In general, they attempt to minimize the possibility of coercion
or undue influence by requesting that subjects be recruited by open, written
invitation rather than by personal solicitation. Institutions try to ensure that
the consent document contains a detailed account of the terms of payment,
including a description of the conditions under which a subject would receive
partial or no payment (for example, what will happen if they withdraw part way
through the research). Determining the appropriateness of the incentive is another matter. For
research that requires subjects to undergo only minor inconvenience or
discomfort, a modest payment will usually be adequate. Reimbursement for travel,
babysitting, and so forth may also be provided. In more complex research
projects, IRBs tend to base their assessment on the prevailing payment practices
within their institution or general locale. Volunteers are often compensated for
their participation according to an established fee schedule, based upon the
complexity of the study, the type and number of procedures to be performed, the
time involved, and the anticipated discomfort or inconvenience. Standard
payments may be established for each tissue or fluid sample collected, depending
on the type of sample (blood, urine, or saliva) and the time (day or evening)
the sample is to be collected. Alternatively, subjects may be paid an hourly
rate or a fixed amount, depending on the duration of the study and whether the
study requires admission to research ward. Extra payments are usually provided
for a variety of additional inconveniences (e.g., the imposition of dietary
restrictions). Payments may vary according to a number of factors, and,
therefore, IRBs may need to become familiar with the accepted standards within
their community as well as the anticipated discomforts and inconveniences
involved in a particular study to judge appropriateness of payments. Some
institutions have a ceiling on the amount an individual may earn in any one
study or during a given length of time (e.g., per year, per semester). One of the most perplexing problems for IRBs is how to assess the
appropriateness of payment offers for experiments that involve the assumption of
risk or significant discomfort. On a practical level, it is probably impossible
for an IRB to determine what amount of money or type of reward would unduly
influence a particular individual to accept a given degree of risk. Although our
society generally accepts the premise that those assuming risk deserve reward,
the application of this rule in establishing payment for subjects in biomedical
and behavioral experiments is still being debated. The appropriateness of
proposed payments is a matter each institution must address in formulating its
policies. IRB members tend to approach the problem of assuming risk for pay from one of
two positions. One side argues that normal healthy volunteers are able to
exercise free choice, and that, since judging the acceptability of risk and
weighing the benefits is a personal matter, IRBs should refrain from imposing
their own views on potential subjects. On this view, IRB responsibility should
be confined to ensuring that consent is properly informed. Other IRB members
argue that the IRB should protect potential subjects from inducements that may
affect their ability to make an informed, voluntary choice. It should be noted
that, in this context, incentives need not be financial to cause problems. Free
health care for persons with limited resources and major medical problems may be
a significant inducement to participate in research (even if the research
activity is nontherapeutic). There is no consensus as to whether this kind of
inducement is unacceptable. In assessing this potential problem, IRBs might
consider whether only the destitute agree to volunteer or if people who can
obtain good medical care on their own agree to participate as well. IRBs may
need to monitor subject recruitment to make such determinations.
POINTS TO CONSIDER
1. Are all conditions in keeping with standards for voluntary and informed
consent?
2. Are the incentives offered reasonable, based upon the complexities and
inconveniences of the study and the particular subject population?
3. Are there special standards that the IRB ought to apply to the review of
research in which volunteers are asked to assume significant risk?
4. Should the IRB monitor subject recruitment to determine whether coercion
or undue influence is a problem?
APPLICABLE LAWS AND REGULATIONS
Federal Policy §___.109(e) [IRB review of research] 45 CFR 50.20 [FDA: General requirements for informed consent] H. CONTINUING REVIEW
INTRODUCTION
IRB CONSIDERATIONS
The responsibility for continued monitoring of approved research is as
important as the initial review and approval. It is only after research has
begun that the real risks can be evaluated and the preliminary results used to
compute the actual risk/benefit ratio; the IRB can then determine the
correctness of the initial judgment. Some IRBs have set up a complaint
procedure that allows subjects to indicate whether they believe that they were
treated unfairly or that they were placed at more risk than was agreed upon at
the beginning of the research. A report form available to all researchers and
staff may be helpful for informing the IRB of unforeseen problems or
accidents. The IRB may find that scheduled progress reports are an effective
means of monitoring some research. The risk/benefit ratio may change over time. Not only unexpected results
and effects of the research project itself, but new knowledge resulting from
other research may affect the balance. After reassessment, the IRB may require
that the research be modified or halted altogether. The IRB may need to impose
special precautions or relax special requirements it had previously imposed on
the research protocol. Federal policy requires that investigators inform subjects of any important
new information that might affect their willingness to continue participating
in the research [Federal Policy §___.116(b)(5)]. The IRB should make a
determination whether any new findings, new knowledge, or adverse effects
should be communicated to subjects. The IRB should receive copies of any such
information conveyed to subjects. Any necessary changes to the consent
document(s) must be reviewed and approved by the IRB. [See also
Guidebook Chapter 3, Section B, "Informed Consent."] The IRB has the authority to observe, or have a third party observe, the
consent process and the research itself [Federal Policy §___.109(e)]. The
researcher is obligated to keep the IRB informed of unexpected findings
involving risks and to report any occurrence of serious harm to subjects
[Federal Policy §___.103(b)(5)]. Reports of preliminary data analysis may be
helpful to the researcher and the IRB in monitoring the need to continue the
project. An open and cooperative effort between the researcher and the IRB
protects everyone concerned. IRBs have the authority to suspend or terminate approval of research that
is not being conducted in accordance with the IRB's requirements or that has
been associated with unexpected serious harm to subjects [Federal Policy
§___.113]. If the IRB decides to suspend or terminate its approval of a
research project, the IRB shall report its decision promptly to the
investigator(s), appropriate institutional officials, and the department or
agency head (or designated office, such as OPRR). The IRB's report must
include a statement of the reasons for the suspension or
termination. POINTS TO CONSIDER 1. Are the actual risks and benefits as anticipated? 2. Have any subjects been seriously harmed? 3. Has the IRB been informed of any unforeseen problems or accidents that may
have occurred? 4. Should the IRB request that the investigator(s) submit scheduled progress
reports? 5. Should the investigator(s) submit progress reports more often than
annually? 6. Since the last IRB review, have subjects been informed of any important
new information that might affect their willingness to continue participating in
the research? 7. Have any new findings, knowledge, or adverse effects come to light that
should be, but have not been, communicated to subjects? 8. Does the progress of the project together with the results of other new
research indicate that the IRB should either impose special precautions or relax
special requirements it had previously imposed? 9. Do the consent documents need to be revised? 10. Has due care been used to reduce risks and increase the likelihood of
benefit? 11. Are the procedures agreed upon at the beginning of the research still
being used? 12. Does the protocol adequately provide for continuing assessment of the
balance between risks and benefits? 13. Should IRB approval be continued, or should approval be suspended or
terminated? 14. When should the IRB next review the project (taking into account what has
been learned about the actual risk to subjects since the project first received
IRB approval)? APPLICABLE LAWS AND REGULATIONS
SUGGESTIONS FOR FURTHER READING
A. Risk/Benefit Analysis
B. Informed Consent
Return to Index Page
________________________
Guidebook
BASIC IRB REVIEW
Federal Policy for the protection of human subjects
Federal
Policy §___.116 [General requirements for informed consent]
Federal Policy
§___.117 [Documentation of informed consent]
21 CFR 50 [FDA: Informed
consent]
21 CFR 50.20 [FDA: General requirements for informed
consent]
21 CFR 50.23 [FDA: Exception from general requirement]
21 CFR
50.25 [FDA: Elements of informed consent]
21 CFR 50.27 [FDA: Documentation
of informed consent]
21 CFR 56 [FDA: IRB review and
approval]Federal Policy §___.111(a)(3) [Criteria for IRB approval of
research]
21 CFR 56.111(a)(3) [FDA: Criteria for IRB approval of
research]
(i)
determines that such use or disclosure does not violate any limitations under
which the record or information was collected;
(ii) ascertains that use
or disclosure in individually identifiable form is necessary to accomplish the
research or statistical purpose for which use or disclosure is to be
made;
(iii) determines that the importance of the research or statistical
purpose for which any use or disclosure is to be made is such as to warrant the
risk to the individual from additional exposure of the record or information
contained therein;
(iv) requires that adequate safeguards to protect the
record or information from unauthorized disclosure be established and maintained
by the user or recipient, including a program for removal or destruction of
identifiers; and
(v) obtains consent in writing before any further use or
redisclosure of the record or information in individually identifiable form is
permitted.
(a)
Information relating to sexual attitudes, preferences, or practices;
(b)
Information relating to the use of alcohol, drugs, or other addictive
products;
(c) Information pertaining to illegal conduct;
(d)
Information that if released could reasonably be damaging to an individual's
financial standing, employability, or reputation within the
community;
(e) Information that would normally be recorded in a patient's
medical record, and the disclosure of which could reasonably lead to social
stigmatization or discrimination;
(f) Information pertaining to an
individual's psychological well-being or mental health.
Information in
other categories, not listed here, might also be considered sensitive because of
specific cultural or other factors, and protection can be granted in such cases
upon appropriate justification and explanation.
Ms. Olga Boikess
National Institute of Mental
Health
17C-02 Parklawn Building
5600 Fishers Lane
Rockville, MD
20857
Tel: (301) 443-3877
Federal Policy §___.101(b)(2) [To what does this policy
apply?]
Federal Policy §___.101(b)(4) [To what does this policy
apply?]
Federal Policy §___.115(a)(5) [IRB records]
Federal Policy
§___.116(a)(5) [General requirements for informed consent]
Federal Policy
§___.117 [Documentation of informed consent]
21 CFR 50.25 [FDA: Elements of
informed consent]
21 CFR 50.27 [FDA: Documentation of informed
consent]
21 CFR 56.109(c) [FDA: IRB review of research]
2.
Considering the degree of risk, is the plan for monitoring the research adequate
in terms of timeliness and thoroughness?
3. If the principal investigator
is other than full-time on the project, is the oversight and monitoring time
sufficient?
4. Is there a mechanism for providing information to the IRB
in the event that unexpected results are discovered? (Unexpected results may
raise the possibility of unanticipated risks to subjects.)
5. Does the
institution have a data and safety monitoring board? If so, should it be asked
to monitor the project under review? If the institution does not have a data and
safety monitoring board, should the IRB request or recommend that one be
appointed, either by the institution or the sponsor, for this project?
There
are many other examples of possible sources of undue influence on subjects. It
may not be possible to remove all sources of influence, but the IRB must examine
each project to assure the elimination of coercion and minimization of other
influences.
2. What special safeguards are included to protect the
rights and welfare of subjects who are likely to be vulnerable to coercion or
undue influence (e.g., children, prisoners, pregnant women, persons with
physical or mental illness, and persons who are economically or educationally
disadvantaged)?
3. Does the nature of the disease or behavioral issue to
be studied permit free consent?
4. Are any incentives offered for
participation likely to unduly influence a prospective subject's decision to
participate?
5. Is there an adequate procedure for monitoring the consent
process, and should the IRB or its representative observe the process?
Federal Policy §___.111(b) [Criteria for IRB approval of
research]
Federal Policy §___.116 [General requirements for
consent]
Federal Policy §___.117 [Documentation of informed
consent]
45 CFR 46.111(b) [DHHS: Criteria for IRB approval of
research]
45 CFR 46 Subpart B [DHHS: Additional protections pertaining
to research, development, and related activities involving fetuses, pregnant
women, and human in vitro fertilization]
45 CFR 46 Subpart C [DHHS:
Additional protections pertaining to biomedical and behavioral research
involving prisoners as subjects]
45 CFR 46 Subpart D [DHHS: Additional
protections for children involved as subjects in research]
Federal Policy
§___.111 [Criteria for IRB approval of research]
Federal Policy §___.116
[General requirements for informed consent]
It would be a mistake to see the IRB approval process as a
one-time step in the life of a research project. IRB approval is a temporary
authority that may be withdrawn at any time if warranted by the conduct of the
research. The regulations authorize the IRB to establish procedures for the
concurrent monitoring of research activities [Federal Policy §___.109(e)].
DHHS and FDA rules require reevaluation of approved research at intervals that
are appropriate to the degree of risk [Federal Policy §___.109(e)]. Periodic
review of research activities is necessary to determine whether approval
should be continued or withdrawn. All research must be reviewed at least
annually.
The initial IRB review is based on the researcher's best
assessment about anticipated results, risk, and procedures. The IRB uses its
expertise to judge whether this estimate is reasonable and supportable. At the
time of its initial review, the IRB must determine how often it should
reevaluate the research project and set a date for its next review.
Federal Policy §___.103(b)(4)-(5) [Assuring compliance with this
policy — research conducted or supported by federal departments or
agencies]
Federal Policy §___.109(e) [IRB review of research]
Federal
Policy §___.110(b) [Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in approved
research]
Federal Policy §___.113 [Suspension or termination of IRB
approval]
Federal Policy §___.116(b)(5) [General requirements for informed
consent]
Federal Policy §___.117 [Documentation of informed
consent]
Chapter III: Basic IRB
Review