Decisions concerning the inclusion or exclusion of vulnerable subjects in studies of innovative or nonvalidated interventions, therapy, or diagnostic procedures that hold out the promise of directly benefiting the vulnerable subject are based on an individual risk/benefit assessment. For studies whose interventions or procedures do not hold out the promise of direct benefit to the vulnerable subject, the level of risk to which the subject may be exposed is restricted, and higher levels of approval beyond the IRB are required as the subject is exposed to a higher level of risk. Generally, studies which include one or more vulnerable populations should attempt to reduce the anticipated risk to minimal risk whenever the interventions or procedures do not hold out promise of direct benefit to the vulnerable subject. The definition and a discussion of minimal risk can be found in Module 3. “Minimal-risk” studies are generally approvable by an IRB. In some cases the IRB will approve studies where the risk to the subject is no more than a minor increase over minimal risk (when the interventions or procedures do not hold out promise of direct benefit to the vulnerable subject). In these cases, the intervention or procedure must be consistent in type and risk level with those experienced by the vulnerable subject in their daily lives, and generalizable knowledge about the subject’s disorder or condition is likely to result from their participation. Studies that will expose vulnerable subjects to more than a minor increase over minimal risk will be approved by the IRB only when there is a strong possibility that the research will produce profound generalizable knowledge for a condition affecting the health and welfare of the vulnerable population being studied. For studies funded by the DHHS, the IRB may refer the protocol to the DHHS Secretary, who may convene a panel of experts and request public comments on the proposed research before making a decision. A similar panel may be convened for FDA-sponsored research.