UAMS Human Research Advisory Committee
Drugs and Devices
July 31, 2002
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 CFR812.3(m) ; 45 CFR).] 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 (HRAC) regulations (21CF56) to identify certain studies that may be approved through an "expedited review" procedure. For both SR and NSR device studies, HRAC approval prior to conducting clinical trials and continuing review by the HRAC are required. In addition, informed consent must be obtained for either type of study (21 CFR 50; 45 CFR).).
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 (21CFR812; 45 CFR).). NSR device studies have fewer regulatory controls than SR studies and are governed by the abbreviated requirements [21 CFR812.2(b); 45 CFR).]. 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 HRAC 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 HRACs 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 HRAC, and if the HRAC 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 HRAC believes that a device study is SR, the investigation may not begin until both the HRAC and FDA approve the investigation. To help in the determination of the risk status of the device, HRACs 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 HRAC with a risk assessment and the rationale used in making its risk determination [21 CFR812.150(b)(10); 45 CFR).].
SR/NSR Studies and the HRAC
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 HRAC an explanation of its determination and any other information that may assist the HRAC in evaluating the risk of the study. The HRAC 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 HRAC deems necessary to make its decision. The HRAC should ask the sponsor whether other HRACs have reviewed the proposed study and what determination was made. The sponsor should inform the HRAC of the FDA's assessment of the device's risk if such an assessment has been made. The HRAC may also consult with FDA for its opinion.
The HRAC may agree or disagree
with the sponsor's initial NSR assessment. If the HRAC 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 HRAC 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
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 HRAC must consider the nature of the harm that may result from use of the device. Studies where the potential harm to subjects could be life threatening, 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 HRAC must consider the potential harm that could be caused by the procedure in addition to the potential harm caused by the device.
FDA has the ultimate decision in determining if a device study is SR or NSR. If the FDA does not agree with an HRAC'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 HRACs as an NSR investigation.
If HRAC decides the study is Significant Risk:
a. Notify sponsor and investigator of SR decision
b. After IDE obtained by sponsor, proceed to review study applying requisite criteria (21 CFR 56.111)
a. Submit IDE to FDA or, if electing not to proceed with study, notify FDA (CDRH Program Operations Staff 3015941190) of the SR determination;
b. Study may not begin until FDA approves IDE and HRAC approves the study.
c. Sponsor and investigator(s) must comply with IDE regulations (21 CFR Part 812), as well as informed consent and HRAC regulations (21 CFR Parts 50 and 56).
If the HRAC decides the study is Non-significant Risk:
The Decision to Approve or Disapprove
Once the SR/NSR decision has been reached, the HRAC 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 CFR56.111; 45 CFR).). The HRAC 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 HRAC meetings must document the rationale for SR/NSR and subsequent approval or disapproval decisions for the clinical investigation.
studies of all significant risk devices to present more than minimal risk; thus,
full HRAC review for all studies involving significant risk devices is
necessary. Generally, HRAC review at a convened meeting is also required when
reviewing NSR studies. Some NSR studies, however, may qualify as minimal risk
[21 CFR56.102(i); 45
CFR).] and the HRAC may choose to
review those studies under its expedited review procedures (21
Examples of NSR/SR Devices: The following examples are provided to assist sponsors and HRACs 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. Refer to this website for a current list: http://www.fda.gov/oc/ohrt/HRACs/devices.html#nonsig
GENERAL MEDICAL USE
urologic with antiinfective coatings ||General
Hospital longterm percutaneous, implanted, subcutaneous and
cerebrovascular, occlusion balloon
transluminal coronary angioplasty, intraaortic balloon with
GASTROENTEROLOGY AND UROLOGY
GENERAL AND PLASTIC SURGERY
OBSTETRICS AND GYNECOLOGY
(for men) made from new materials (e.g., polyurethane) ||Contraceptive
In Vitro Diagnostics (IVDs) ||Diaphragms
Electrosurgical Instruments for Tubal Coagulation ||New
Devices for Occlusion of the Vas Deferens
Occlusion Devices (Bands or Clips) |
ORTHOPEDICS AND RESTORATIVE