Guidance

Evaluating Risks to Participants

IRBMED
Jul 12, 2023 2:30 pm
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In human research studies, the IRBs are responsible for evaluating the risks, weighing the probability of each risk coming to pass, and assessing the magnitude of harm that may result. It must then judge whether the anticipated benefit – e.g., improved health for the research participants (direct) or new knowledge that benefits society (indirect) – justifies inviting any person to undertake the risks.

An IRB cannot approve research in which the risks are judged unreasonable in relation to the anticipated benefits.

The risks associated with a specific research procedure are dependent on many factors, such as the research context (e.g., collecting public versus private information), its scope and scale (e.g., a single punch biopsy ≤2mm performed on the forearm versus multiple punch biopsies >2mm on the face), and the participant population (e.g., healthy young adults versus children with cognitive impairment).

  • Risk Classifications

    Definitions of minimal risk

    Minimal risk: 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. (See 45 CFR 46.102(j) and 21 CFR 56.102(i)).

    Specific to child participants: Minimal risk are those risks encountered during daily life by normal, average, healthy children living in safe environments or during the performance of routine physical or psychological examinations or tests. See SACHRP Recommendations and Research A-Z Children in Research guidance.

    Specific to prisoner participants: Minimal risk is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons. See 45 CFR 46.303(d) and Research A-Z Prisoners in Research guidance.

    Research that must comply with Department of Defense (DoD) special requirements: Minimal risk does not include the inherent occupational risks that certain subjects face in their everyday life, such as those:
    (1) Encountered by Service members, law enforcement, or first responders while on duty.
    (2) Resulting from or associated with high-risk behaviors or pursuits.
    (3) Experienced by individuals whose medical conditions involve frequent tests or constant pain.

    See DoD Instruction 3216.02 and HRPP Guidance “Additional Requirements for Investigators.”

    University of Michigan Risk Classifications

    No more than minimal risk applies to research that meets the definition of minimal risk.

    Minor increase over minimal risk applies to research activities that would be more harmful than those encountered in daily life but psychological, informational, and/or physical harm(s) do not rise to the level of moderate risk.  For research involving adult participants with cognitive impairment/diminished decision-making capacity (HRPP Operations Manual Part 7.II.D) or for children (45 CFR 46.406; 21 CFR 50.53), greater than minimal risk research with no prospect of direct benefit to participants can be approvable if the risks do not exceed minor increase over minimal, and the research must present a reasonable opportunity to further understanding, prevention, or alleviation of a serious problem affecting the health or welfare of the participant population.

    Moderate risk applies to research activities that do not rise to the severity of high risk, yet are incrementally greater than minimal -- e.g., the research could cause temporary or moderate psychological, informational, and/or physical harm(s).

    High risk applies to research activities that present severe/serious, long-lasting, or permanent potential harm(s).

    Clarification regarding FDA-regulated Investigational Devices

    Classifying an Investigational Device ‘Significant Risk’ or ‘Non-Significant Risk’ according to FDA regulations at 21 CFR 812.2(m) is a separate determination from whether the overall study poses minimal or greater than minimal risk to participants per 45 CFR 46.102(j)/21 CFR 56.102(i). These two kinds of risk determination may not always coincide in the context of a given research study.

  • Types of risks to research participants

    There are many types of risks to which research participants may be exposed.  The U-M IRBs generally consider three broad categories of risks: psychological (including invasion of privacy), informational (confidentiality, social, legal, employability-related), and physical.

    Psychological

    Participation in research may result in undesired changes in thought processes and/or emotions (e.g., anxiety, depression, confusion, stress, guilt, and loss of self-esteem). These changes may be momentary, temporary, or permanent; they may also occur as a single episode or be recurrent.  Some research has the potential for causing serious psychological harm.  In the research context, invasion of privacy usually involves either covert observation or researchers participating in situations/behavior that participants consider private.

    Informational (including privacy, legal, financial, and social harm)

    Confidentiality relates to safeguarding research data and information that has been given voluntarily by one person to another. Some social and behavioral research may yield information about participants that could be stigmatizing (e.g., social harm) or put them at risk of legal or financial repercussions. Genetic research may uncover information about a participant’s family or lineage that was previously unknown or may cause personal or interpersonal conflict (e.g., paternity concerns).  Release of confidential research information can also result in psychological harm to individuals (e.g. embarrassment, guilt, stress).

    Physical

    Research includes medical procedures that may result in pain, discomfort, or loss of physical functioning. Research may dictate the course of a participant’s clinical care and may use unproven drugs or experimental procedures that could result in serious injury.  Adverse outcomes can range from momentary and minimally discomforting to severe and permanently disabling.

  • Evaluating acceptability of risks

    If the reviewing IRB determines that the risk/benefit assessment is not appropriately favorable, investigators will be asked to revise the study’s methods to reduce these risks. For each study, risk must be minimized: decreased to the lowest level consistent with the study aims and objectives.

    Moderate or high risk of physical harm is sometimes unavoidable in clinical trials; and is indeed common in oncology trials. High physical risk research procedures can have outcomes as severe as death, permanent dysfunction or harm to an organ or part of the body, or serious infection, harmful immune system response, or tumor development.

    On the other hand, risks of psychological harm can often be decreased by appropriate screening for vulnerabilities, by a comprehensive informed consent process to ensure participants are making fully informed decisions, and sometimes by disclosure of additional information after research participation. Negative feelings induced by research interactions and interventions (e.g. impacts of feelings of sadness, tearfulness, preoccupation, or anger) are often milder and more transient for participants who are prepared for them.

    Actual informational harms are usually the result of inappropriate disclosure of research information: the risks are decreased by robust confidentiality protections and data security practices. See HRPP Data Security Guidelines and ITS Safe Computing website, and note that multiple University policies govern proper use of data.

    Research involving moderate or high risk of psychological or informational harm is not approvable by the U-M IRBs unless (1) the probability of the risk is sufficiently small, and (2) the potential for direct benefit to the individual participant is sufficiently large.

  • SPECIAL CASE – Risks of methods to induce or measure pain

    The following guidance is for studies designed to induce pain (most commonly using pressure, temperature, or electrical impulses) for the purpose of generating research data. Understanding of the causes and mechanisms of pain responses can be valuable to the improvement pain management, especially in combination with monitoring of the brain’s responses (e.g. functional MRI). Used here, the term pain threshold means the minimum point at which the research stimulus (e.g., heat) is perceived by the research participant as pain.

    IRB Assessment of Risk Level

    • The IRB considers stimulation up to a participant’s pain threshold to pose no more than minimal risk provided that the method(s) of stimulation are not invasive. Noninvasive procedures do not involve tools that break the skin or physically enter the body.
    • Exceeding an individual participant’s pain threshold (e.g., continuing to increase the stimulus after the participant has indicated pain) or continuing stimulation at the pain threshold level poses greater than minimal risk.
    • Invasive stimulation methods (e.g., intramuscular electrical stimulation using a needle electrode, or infusion of hypertonic saline) pose greater than minimal risk.
    • The experimental design or stimulus method may increase the risk to greater than minimal even if the actual stimulation administered is neither painful nor invasive as part of the experimental manipulation (e.g., in a study involving deception or concealment, subjects are told they will receive painful or anxiety provoking stimulation, but in actuality the stimulation is below the participant’s pain threshold and uses a noninvasive method that would not be anxiety provoking were it not for the deception or concealment).
    • Stimulus using a novel method may be determined to be greater than minimal risk.
       

    General Principles When Conducting Experimental Pain Research

    • There are individual differences in pain perception among research participants.
    • The stimulation levels for certain types of stimuli that produce pain are not well known. 
    • To assess pain threshold, generally it is considered no more than minimal risk to apply a gradually increasing stimulation if the stimulus is
      • terminated when the participant reports feeling pain; and
      • not invasive.  
    • If the researcher is not using a gradually increasing method of stimulation and wishes to designate the study as no more than minimal risk, the research application should include data supporting that the level of stimulation does not exceed or otherwise persist at the participant’s pain threshold.
    • To the extent the research design permits,
      • prepare participants for study procedures and possible effects to reduce anxiety and the risk of drop-out (this could include a description of study procedures, administering “sample” stimulations to the participant, and assuring the participant they can withdraw at any time if they wish to do so);
      • provide participants with the opportunity to terminate stimulations (this could include automated methods, verbal cues, or physical methods, such as removing their arm from a thermal Peltier);
      • assure participants they should not ‘push their limits’ (as applicable to the research objectives); and 
      • debrief participants after the study to obtain their opinions about the experience (Was it manageable or difficult; and if so, why?) as this information can inform changes to the study design.
Tags: U-M resource
Units: Institutional Review Boards (IRBMED)
Topic: Application Types Clinical Trial eResearch Regulatory Management (eRRM) Regulations & Policies (Federal, State & Local) Subject Populations
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Edited By: [email protected]
Last Updated: July 12, 2023 2:30 PM

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