Investigators and IRB members have a responsibility to perform an assessment of the risks and potential benefits of a research protocol in accordance with the principle of beneficence, as defined in the Belmont Report, which states that risks must be minimized and the risks and benefits must be shown to be in a favorable ratio. As participants in research, subjects may be exposed to complex activities consisting of various procedures and interventions. These procedures and interventions may be administered to subjects for different reasons, either therapeutic or nontherapeutic. The first step in evaluating a protocol’s risk-benefit relationship is to classify the procedures and interventions, the research components, that present risks as either therapeutic or nontherapeutic. It is the intentof the intervention or procedure, therapeutic or nontherapeutic, that drives the moral analysis of these components. A therapeutic intervention or procedure is administered with the intent of providing direct benefit to the research subject. A nontherapeutic intervention or procedure is administered solely for scientific purposes. This distinction between research components prevents the justification of risky nontherapeutic procedures by the benefits that may flow from therapeutic procedures. Decisions regarding the appropriateness of interventions or procedures that are therapeutic are made exactly as they are in clinical practice (i.e., the associated risks are justified exclusively in terms of the degree of benefit that can be expected to accrue to the subject). Risks associated with nontherapeutic procedures or interventions must be justified by the importance of the generalizable knowledge that may be expected to result from the research study. Research risks are reasonable in relation to the anticipated benefits when the IRB determines that the moral standards for both therapeutic and nontherapeutic procedures are fulfilled. This ethical assessment of a protocol’s procedures and interventions is called a component analysis.
At first glance, a component analysis of a research protocol seems quite tedious and time-consuming. However, in practice it can typically be accomplished quite easily. The first step is to take a global look at the risks posed by the various therapeutic and nontherapeutic procedures and interventions in a protocol and determine if any exceed minimal risk. The definition of minimal risk and a description of how IRBs utilize the concept can be found at this link. If no procedures or interventions exceed minimal risk, a component analysis is not required and the protocol is deemed of minimal risk. Investigators are simply responsible for ensuring that all risks are minimized before submitting the protocol for review by the IRB. The IRB will review minimal-risk protocols according to its policies. If a protocol contains therapeutic or nontherapeutic components that exceed minimal risk, then a component analysis is required. The specific assessment conducted on each greater-than-minimal-risk component is dependent on whether it is a therapeutic or nontherapeutic component. The followinglink provides a social-behavioral and biomedical example of the distinction between therapeutic and nontherapeutic components of a protocol.
Assessing Nontherapeutic Procedures and Interventions
After distinguishing between therapeutic and nontherapeutic procedures and interventions and ensuring that all risks are minimized, all nontherapeutic procedures and interventions that present, or appear to present, more than minimal risk must undergo a component analysis to properly assess the risk-benefit relationship. A component analysis requires investigators to assess whether the risks expected to accrue to the subject from each nontherapeutic procedure or intervention are reasonable in relation to the anticipated benefits. The knowledge to be gained from that procedure (i.e., the scientific “value added” of this procedure) is the only likely benefit, although any indirect benefit that the subject derives directly and exclusively from the procedure may also be factored in. If the risks are found to be reasonable relative to these anticipated benefits, the nontherapeutic component is considered ethical. Healthy adult research subjects may assume significant risks, as long as these risks have been properly disclosed during the informed-consent process and are commensurate with the knowledge to be gained or the scientific value of the study and any other benefit derived from the research. The investigator’s risk-benefit assessment of the nontherapeutic procedure or intervention is then reviewed by the IRB. To assist in the deliberations, the IRB may draw upon the opinions of experts from relevant disciplines as well as representatives of the community. Once the IRB has concluded that the risks associated with specific nontherapeutic components of the protocol are justified by the potential value of the knowledge to be gained, the protocol can be approved. Because vulnerable subjects may have difficulty providing informed consent (understanding and protecting their own interests) or because their circumstances may subject them to intimidation and exploitation, the degree of risk associated with a nontherapeutic procedure or intervention to which a vulnerable subject may be exposed is limited to minimal or a minor increase over minimal (assuming other requirements for enrolling vulnerable subjects are met). Module 7contains additional information on vulnerable subjects.
Assessing Therapeutic Procedures and Interventions
Therapeutic procedures and interventions are those administered with the intent of directly benefiting the subject. Once a specific procedure or intervention in a protocol has been categorized as therapeutic, its justification is determined in exactly the same manner as in clinical practice (i.e., the risks associated with specific procedures or interventions are justified exclusively in terms of the degree of benefit that is expected to accrue to the subject). It is a subject-specific risk-benefit judgment. The only ceiling for the probability and magnitude of risk from therapeutic or beneficial procedures is that they are not to exceed those of the benefits that can reasonably be expected to accrue to the subject. An additional requirement is that therapeutic procedures and interventions offered the subject while participating in the protocol must be at least as advantageous to the subject as any available alternative procedures and interventions (unless the subject has considered and refused to accept a superior alternative). Two alternative procedures or interventions that are considered to be equally advantageous to the subject are considered to be in a state of clinical equipoise. A brief discussion of clinical equipoise is available at this link.
When evaluating a study with one or more therapeutic procedures or components, the IRB must take reasonable steps to be assured that the risks are reasonable relative to the benefits expected to accrue to the subject and that a state of clinical equipoise exists for each of the therapeutic procedures or components. This will involve a critical evaluation of the study’s justification and, in selected cases, a review of the medical literature or consultation with relevant experts. This assessment should take into account the efficacy of the treatment or procedure, side effects, ease of administration, and similar issues.
Note – The framework or model for analyzing the risk-benefit relationship in research protocols was formulated by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research during the late 1970s and culminated in the concept of component analysis. Some federal regulations were written before the National Commission had fully articulated the concept of component analysis (e.g., 45 CFR 46, Subparts B and C, which outline special protections for pregnant women, human fetuses, neonates and prisoners). The existence of regulations based on different models for analyzing the risk-benefit relationship has led to some confusion regarding the appropriate model investigators and IRB members should follow. The use of component analysis, as described above, will lead to ethical decisions.