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Significant Risk and Nonsignificant Risk Medical Device Studies |
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(FDA Information Sheets October 1, 1995; This replaces Bluebook Memorandum IDE Memorandum D86-1 (July 25, 1986) with the same title)
The Investigational Device Exemption (IDE) regulations (21 CFR Part 812) describe two types of device studies, "significant risk" (SR) and "nonsignificant risk" (NSR). An SR device study is defined [21 CFR 812.3(m)] as a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is an implant; or (2) is used in supporting or sustaining human life; or (3) is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents impairment of human health; or (4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. An NSR device investigation is one that does not meet the definition for a significant risk study. NSR device studies, however, should not be confused with the concept of "minimal risk," a term utilized in the Institutional Review Board (IRB) regulations (21 CFR Part 56) to identify certain studies that may be approved through an "expedited review" procedure. For both SR and NSR device studies, IRB approval prior to conducting clinical trials and continuing review by the IRB are required. In addition, informed consent must be obtained for either type of study (21 CFR Part 50).
Distinguishing Between SR and NSR Device Studies
The effect of the SR/NSR decision is very important to research sponsors and investigators. SR device studies are governed by the IDE regulations (21 CFR Part 812). NSR device studies have fewer regulatory controls than SR studies and are governed by the abbreviated requirements [21 CFR 812.2(b)]. The major differences are in the approval process and in the record keeping and reporting requirements. The SR/NSR decision is also important to FDA because the IRB serves, in a sense, as the FDA's surrogate with respect to review and approval of NSR studies. FDA is usually not apprised of the existence of approved NSR studies because sponsors and IRBs are not required to report NSR device study approvals to FDA.
If an investigator or a sponsor proposes the initiation of a claimed NSR investigation to an IRB, and if the IRB agrees that the device study is NSR and approves the study, the investigation may begin at that institution immediately, without submission of an IDE application to FDA. If an IRB believes that a device study is SR, the investigation may not begin until both the IRB and FDA approve the investigation. To help in the determination of the risk status of the device, IRBs should review information such as reports of prior investigations conducted with the device, the proposed investigational plan, a description of subject selection criteria, and monitoring procedures. The sponsor should provide the IRB with a risk assessment and the rationale used in making its risk determination [21 CFR 812.150(b)(10)].
SR/NSR Studies and the IRB
The NSR/SR Decision
The assessment of whether or not a device study presents a NSR is initially made by the sponsor. If the sponsor considers that a study is NSR, the sponsor provides the reviewing IRB an explanation of its determination and any other information that may assist the IRB in evaluating the risk of the study. The IRB may ask the sponsor for information such as a description of the device, reports of prior investigations with the device, the proposed investigational plan, a description of patient selection criteria and monitoring procedures, as well as any other information that the IRB deems necessary to make its decision. The IRB should ask the sponsor whether other IRBs have reviewed the proposed study and what determination was made. The sponsor should inform the IRB of the FDA's assessment of the device's risk if such an assessment has been made. The IRB may also consult with FDA for its opinion.
The IRB may agree or disagree with the sponsor's initial NSR assessment.
If the IRB agrees with the sponsor's initial NSR assessment and
approves the study, the study may begin without submission of
an IDE application to FDA. If the IRB disagrees, the sponsor
must notify FDA that a SR determination has been made. The study
can be conducted at that institution as a SR investigation following
FDA approval of an IDE application.
The risk determination should be based on the proposed use of a device in an investigation, and not on the device alone. In deciding if a study poses a SR, an IRB must consider the nature of the harm that may result from use of the device. Studies where the potential harm to subjects could be lifethreatening, could result in permanent impairment of a body function or permanent damage to body structure, or could necessitate medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to body structure should be considered SR. Also, if the subject must undergo a procedure as part of the investigational study, e.g., a surgical procedure, the IRB must consider the potential harm that could be caused by the procedure in addition to the potential harm caused by the device. Two examples follow:
FDA has the ultimate decision in determining if a device study
is SR or NSR. If the FDA does not agree with an IRB's decision
that a device study presents an NSR, an IDE application must
be submitted to FDA. On the other hand, if a sponsor files an
IDE with FDA because it is presumed to be an SR study, but FDA
classifies the device study as NSR, the FDA will return the IDE
application to the sponsor and the study would be presented to
IRBs as an NSR investigation.
IRB and Sponsor Responsibilities Following SR/NSR Determination
If IRB decides the study is Significant Risk:
If the IRB decides the study is Nonsignificant Risk:
The Decision to Approve or Disapprove
Once the SR/NSR decision has been reached, the IRB should consider whether the study should be approved or not. The criteria for deciding if SR and NSR studies should be approved are the same as for any other FDA regulated study (21 CFR 56.111). The IRB should assure that risks to subjects are minimized and are reasonable in relation to anticipated benefits and knowledge to be gained, subject selection is equitable, informed consent materials and procedures are adequate, and provisions for monitoring the study and protecting the privacy of subjects are acceptable. To assure that the risks to the subject are reasonable in relation to the anticipated benefits, the risks and benefits of the investigation should be compared to the risks and benefits of alternative devices or procedures. This differs from the judgment about whether a study poses a SR or NSR which is based solely upon the seriousness of the harm that may result from the use of the device. Minutes of IRB meetings must document the rationale for SR/NSR and subsequent approval or disapproval decisions for the clinical investigation.
FDA considers studies of all significant risk devices to present more than minimal risk; thus, full IRB review for all studies involving significant risk devices is necessary. Generally, IRB review at a convened meeting is also required when reviewing NSR studies. Some NSR studies, however, may qualify as minimal risk [21 CFR 56.102(i)] and the IRB may choose to review those studies under its expedited review procedures (21 CFR 56.110).
Examples of NSR/SR Devices
The following examples are provided to assist sponsors and IRBs in making SR/NSR determinations. The list includes many commonly used medical devices. Inclusion of a device in the NSR category should not be viewed as a conclusive determination, because the proposed use of a device in a study is the ultimate determinant of the potential risk to subjects. It is unlikely that a device included in the SR category could be deemed NSR due to the inherent risks associated with most such devices.
NONSIGNIFICANT RISK DEVICES
SIGNIFICANT RISK DEVICES
GENERAL MEDICAL USE
ANESTHESIOLOGY
CARDIOVASCULAR
DENTAL
EAR, NOSE AND THROAT
GASTROENTEROLOGY AND UROLOGY
GENERAL AND PLASTIC SURGERY
GENERAL HOSPITAL
NEUROLOGICAL
OBSTETRICS AND GYNECOLOGY
OPHTHALMICS
ORTHOPEDICS AND RESTORATIVE
RADIOLOGY
Your comments and suggestions for additional examples are welcome and should be sent to:
Program Operation Staffs (HFZ403)
Office of Device Evaluation
Center for Devices and Radiological Health
Food and Drug Administration
9200 Corporate Blvd.
Rockville, MD 20850
Updated March 26, 1997
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