UAMS Human Research
Risk Benefit Analysis
July 31, 2002
Subject: Risk/Benefit Analysis
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
HRAC, therefore, is to assess the risks and benefits of proposed research.
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 [38CFR16.102(i)].
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
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 HRAC 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 HRAC should disapprove research in which the risks are judged unreasonable in relation to the anticipated benefits.
The HRAC's assessment of risks and anticipated benefits involves a series of steps. The HRAC must:
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
the probable benefits to be derived from the research
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 and
6. Determine intervals of periodic review, and, where appropriate, determine that adequate provisions are in place for monitoring the data collected
In addition, HRACs should determine the adequacy of the provisions to protect the privacy of subjects and to maintain the confidentiality of the data 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 HRAC policy 17.1-17.9).
Identification and Assessment of
In the process of determining what constitutes a risk, only those risks that may
result from the research, as distinguished from those associated with
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 HRAC 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.
HRACs 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 HRAC 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 HRACs should not consider such effects "as among those research
risks that fall within the purview of its responsibility" (38
Classification of Risk. The risks to which research subjects may
be exposed have been classified as physical, psychological, social, and economic
[Levine (1986), p. 42].
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 HRAC 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.
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 HRACs should be aware that some research has the potential for
causing serious psychological harm.
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
Minimal Risk and Especially Vulnerable Populations. DHHS regulations on research involving fetuses and pregnant women [45 CFR46(b)], research involving prisoners [45CFR46(c)], and research involving children [45 CFR 46(d)] strictly limit research presenting more than minimal risk. For more information about "Special Populations", see HRAC policy 17.1-17.13.
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.
HRACs are responsible for assuring that risks are minimized to the extent
In reviewing any protocol, HRACs 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. HRACs 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
HRACs should determine whether the
investigators are qualified 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 HRAC
approval is granted.
Another way for HRACs 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.
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.
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 HRAC should assure that the anticipated benefits to research
subjects and the knowledge researchers expect to gain are clearly
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. Although participation in research may be a personally rewarding activity or a humanitarian contribution, these subjective benefits should not enter into the HRAC's analysis of benefits and risks.