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Defining “Minimal Risk” in Clinical Research

Often investigators refer to a clinical study as “minimal risk” while pointing to the side effects as being minor or acceptable for the given condition, and/or that the procedures in the study are common in medicine and rarely have severe complications.  While this may be valid and common terminology for clinical patient management, for regulatory purposes this would not satisfy the very specific definition of minimal risk as provided by the FDA.

Despite common parlance, “minimal risk” has a definition in the regulations. The FDA defines “minimal risk” broadly for us in 21 CFR 50.3(k):

            “Minimal risk means that 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.”

This means that the risks of the research are those that a healthy person could expect to encounter at routine clinical visits. 

Examples of procedures that are generally considered to meet the minimal risk threshold include:

  • Blood sampling from a vein or indwelling line (in children, the blood volume must be less than a limit based on total blood volume)
  • MRI without contrast and without sedation
  •  “Surface” (external only) imaging, without the use of contrast agents
  • Placement of a peripheral venous line for less than 24 hours

Examples of procedures that are not considered to be minimal risk include:

  • Administration of virtually any investigative drug or biologic, even if the product is approved for the indication being studied or for other indications and is known to have a generally mild safety profile and adverse events are rare. 
  • A clinical investigation of a device that involves invasive sampling
  • MRI with contrast and/or sedation 

In the IRB review process, the assessment of whether a submission is categorized as “minimal risk” in accordance with the regulatory definition is important because it impacts how the research may be reviewed. Any research that is more than minimal risk or that is minimal risk but does not fall into the expedited categories defined by the federal regulations, must be reviewed by the convened IRB.

However, minimal risk research that does fall into one or more of the expedited categories may be reviewed through a different pathway. The IRB regulations permit, but do not require, an IRB to review certain categories of research through an expedited procedure if the research involves no more than minimal risk and falls into at least one of the expedited categories defined by the federal regulations. The “expedited review pathway” involves review of the research by the IRB chairperson (or by one or more experienced reviewers designated by the chairperson) from among members of the IRB in accordance with the requirements set forth in 45 CFR 46.110.   These reviews often take less time because the review does not need to be conducted at a scheduled IRB meeting. The expedited reviewer can make the decisions to approve or to conditionally approve a submission, but if they have questions that cannot be resolved to get to one of these outcomes, the submission must be escalated to the full board for review at a convened meeting.