351. Research Risks

Updated July 1, 2021

Research Risk Defined

Federal regulations at 45 CFR 46.102 item (j), define minimal risk as "... the probability and magnitude of harm or discomfort anticipated in the 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." 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. Risks to participants should be reasonable in relation to potential benefits, if any, to participants, and the importance of the knowledge that may reasonably be expected to result. Risks to participants should be minimized by using procedures that are consistent with sound research design and do not unnecessarily expose participants to risk.

Determinations of greater than minimal risk are deduced from the definition for minimal risk.

Research risk can refer to:

1. The chances that individuals are willing to undertake for some desired goal; or
2. Conditions that make a situation dangerous per se.

The IRB must evaluate risk. The IRB should consider whether the anticipated benefit, either of new knowledge or of improved health for participants, justifies inviting any person to undertake the risks. The IRB should not approve research if risks are unreasonable in relation to anticipated benefits. IRB reviewers should be diligent to focus only on the risks associated with the protocol that are directly related to the research. Risks associated with the standard of care procedures that may provide the framework for the research should not factor into the risk classification. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research.

Effect of Risk Magnitude and Probability on Level of Risk

Once the risks associated with the research have been identified, the process of categorizing the risks as minimal or greater than minimal may begin. Two characteristics influence the nature of the risk: 1) the probability of harm; 2) the magnitude of harm. The magnitude of harm can be related to the severity, duration and reversibility of a potential harm. The IRB reviewer should consider both the likelihood and magnitude of harm and whether they are greater than those encountered in daily life or during routine physical or psychological examinations.

 In determining if research risk is minimal or greater than minimal, Principal Investigators (PIs) and the IRB must consider both the magnitude and probability of harm that may result from a risk. For example:

• Research that involves risk that is high in both magnitude and probability of harm likely constitutes greater than minimal risk.
• Research that involves risk that is neither high in magnitude nor probability of harm likely is minimal risk.

The degree of magnitude/probability, what the magnitude/probability may mean to participants, and type of risk bear consideration require more careful assessment. For example:

• Research that involves risk with a high magnitude and low probability of harm may be considered greater than minimal risk due to high magnitude or minimal risk due to low probability. Consider level of risk for research with a risk probability of 1 in 10,000 participants, when risk is blindness compared to when risk is severe stomach pain.
• Research that involves risk with a low in magnitude and high in probability of harm may be considered minimal risk due to the low magnitude or greater than minimal risk due to high probability. Consider level of risk for research with a probability that 1 in 10,000 compared to 1 in 5 participants will experience minor anxiety.

Regulatory Requirements for Research Risk

The federal regulations for IRB criteria for approval of research include two requirements related to research risk:

At §46.111 item (a)(1), the regulations specify risks must be minimized and that research should not unnecessarily expose participants to risk. Suggestions for minimizing risk include using:

• Sound research design and
• Procedures already being performed on participants for other purposes (when appropriate).

At §46.111 (a)(2), the regulations specify risks must be reasonable in relation to anticipated benefits to participants (if any) and to the importance of the knowledge that may be reasonably expected to result. In this regard, the regulations clarify that the IRB must consider:

• Only those risks and benefits that may result from the research and not risks/benefits that may result from care or treatment participants would receive if not participating in the research; and
• Possible long-range effects of applying the knowledge gained (e.g., effects of the research results on public policy).

Some of the basic and additional requirements for informed consent specify requirements for disclosure of risk to participants. The regulations at §46.116 require investigators to:

• Disclose reasonably foreseeable risks or discomforts to prospective participants before involving them in the research, under item (b)(2);
• For greater than minimal risk research, describe compensation or treatment when these will be available if injury occurs and whom to contact, or informing participants that no such compensation/treatment will be available, under item (b)(6); and
• When appropriate, state that a particular treatment or procedure may involve risks to the participant (or to the embryo or fetus, if the participant is or may become pregnant) which are currently unforeseeable, under item (c)(1).

The regulations also require additional safeguards for research involving vulnerable populations. For more information, see IRB policy for pregnant women/fetuses; prisoners; children; adults with impaired decision-making capacity; and persons who may be economically or educationally disadvantaged.

Identification and Assessment of Research Risk

In identifying risks, investigators and the IRB should consider only those risks that may be reasonably expected to occur as the result of the research. The IRB reviewer then assesses whether the risk to participants is reasonable in relation to the anticipated benefits to participants, if any, and the importance of the knowledge that may reasonably be expected to result. The IRB should not base risk determinations on risks associated with therapies or procedures participants would experience even if not participating in the research. However, participants should be informed of risks associated with procedures provided during or associated with the research, even if provided as standard-of-care.

To identify risks, it may be useful to consider categories of risks. The following is not meant to be definitive. It simply provides a framework for assessing risk.

(See IRB policy for risks related to participant privacy or data confidentiality.)

Harms from Research Design

• In designs involving random assignment, participants may not be assigned to the group that receives the more efficacious treatment.
• Participants assigned to the group receiving placebo may be at risk because their usual treatment may have been suspended during research participation, and they are not receiving an (albeit experimental) alternative).
• Participants in double-masked studies (i.e., neither participants nor researchers know group assignment) take the risk that information necessary for their care may not be readily available when needed.

• Lack of resources necessary to protect research participants. Such resources include staffing and personnel, in terms of availability, number, expertise, and experience; psychological, social, or medical services, including counseling or social support services that may be required because of research participation; psychological, social, or medical monitoring, ancillary care, equipment needed to protect participants, and resources for participant communication, such as language translation services.

Harms from Lack of Resources Necessary to Protect Research Participants

• Such resources include staffing and personnel, in terms of availability, number, expertise, and experience; psychological, social, or medical services, including counseling or social support services that may be required because of research participation; psychological, social, or medical monitoring, ancillary care, equipment needed to protect participants, and resources for participant communication, such as language translation services.

Physical Harms

More common to medical or biological research than to social, behavioral, or educational research, physical harms include exposure to

• Pain, discomfort, or injury from invasive medical procedures or device research;
• Dizziness or fainting; or
• Harm from side effects of drugs or devices.

Physical discomforts associated with prolonged fasting for a research procedure must also be considered.

When assessing physical harms, the IRB must determine if the research risks are greater than those associated with medically indicated interventions. Research designed to evaluate new drugs or procedures may present more than minimal risk and may include unforeseen risks to participants or fetuses in pregnant women, or mutagenic effects.

Psychological Harms

Psychological harms may result from undesirable changes in thoughts and emotions (e.g., depression, confusion, anxiety, guilt, or loss of self-esteem). These changes may be transitory, recurrent, or permanent. The duration affects the magnitude of harm.

Stress and feelings of guilt or embarrassment may arise from thinking or talking about one's own behavior or attitudes on sensitive topics such as drug use, sexual preferences, selfishness, and violence. Researchers may manipulate participants' environments to induce stress.

IRBs must also consider the possibility of psychological harm when behavioral research involves deception, particularly if the deception includes false feedback to participants about their own performance. When incomplete disclosure or deception is used, debriefing participants after their participation may minimize risk of psychological harm.

Social and Economic Harms

Some research may result in embarrassment within one's business or social group, loss of employment, or criminal prosecution. Research may yield information that could "label" or "stigmatize" participants. Areas of sensitivity include research involving alcohol and drug abuse, mental illness, illegal activities, and sexual behavior.

Researchers and the IRB must be acutely aware of negative repercussions that may result from breaches of privacy or confidentiality related to participation in a specific research study. Plans for follow-up contact in such studies requires special precautions to minimize unauthorized disclosure.

Minimizing Risks

As noted previously, federal regulations require that risks are minimized (i.e., reduced or managed).

Investigators and the IRB must determine that, to the degree possible, precautions, safeguards, and alternatives have been incorporated into the research activity to:

• Limit the severity or duration of harms (i.e., magnitude of harm) and
• Reduce the likelihood harms will occur (i.e., probability of harm).

Risks may be minimized by ensuring PIs possess the requisite competence in the area being studied and have the resources necessary to safely conduct the research.

To evaluate whether other, less risky methods might yield the desirable results, IRBs assess information about the scientific rationale and experimental design underlying the proposed research and the statistical basis for the investigation.

IRBs compare effects of the experimental treatment or of receiving no treatment at all to effects of treatments that might be administered in ordinary practice.

IRBs consider whether harmful effects can be adequately detected, prevented, or treated; and whether the risks and complications of underlying diseases may be unnecessarily exacerbated by the research.

IRBs must evaluate whether the research design will yield useful data. When the sample size is too small to yield valid conclusions or a hypothesis is imprecisely formulated, participants may be exposed to risk without sufficient justification.

Investigators must be cognizant of potential conflicts that may result from serving dual roles. For example, an investigator's eagerness for a participant to continue in a research project to amass more data may conflict with her/his/their responsibility as the treating physician to discontinue a therapy that is not helpful or may be harmful. (See IRB policy for inherently influential recruitment situations for more information and examples about conflicting researcher roles.)

Risk is minimized by incorporating adequate safeguards into research design wherever possible. Safeguards may include:

• Obtaining data from procedures performed for diagnosis or treatment instead of performing separate tests/procedures for the research;
• Excluding individuals or population groups when a specific characteristic may make participants more vulnerable to risks of a drug or procedure;
• Routinely monitoring data for patterns or problems, or to ensure a trial doesn't continue after reliable results have been obtained;
• Ensuring trained personnel are present to respond to emergencies;
• Including a mechanism to inform participants or others about an individual's involvement and treatment in a study involving single or double-blinding (e.g., giving participants a card or bracelet identifying someone who is available to break the code when necessary); and
• Coding data to protect confidentiality.
• An explanation as to whether any medical treatments are available if injury occurs. If medical treatments are available if injury occurs, what they consist of, or where further information may be obtained.
• An explanation of the consequences of a participant’s decision to withdraw from the research.
• A statement that the treatment or procedure may involve risks to the participant which are currently unforeseeable.