Section XVI:

FDA - Regulated Products

WPP #: XVI-1

Title 1:

Review of Devices (SR vs. NSR Determination and Actions)

Effective Date:

08-12-14

Revision History:

06-20-00; 06-07-04; 06-21-06; 02-05-07

Policy Statement

Research studies intending to evaluate safety and/or effectiveness of an investigational device must be conducted in compliance with 21 CFR 812. The IRB is responsible for verifying that studies involving investigational devices have a valid Investigational Device Exemption (IDE) issued by the FDA, qualify for an IDE exemption, or qualify for an abbreviated IDE. When an IDE is required, the IRB must make a Significant Risk/Non-Significant Risk determination regarding the device, unless this determination has already been made by the FDA.

Definitions

  1. Medical Device: A medical device is defined, in part, as any health care product that does not achieve its primary intended purposes by chemical action or by being metabolized. Medical devices include, among other things, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis (IVD) of disease and other medical conditions such as pregnancy.
  2. Investigational Device: An investigational device is a medical device that is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device, including new devices as well as certain modifications or new intended uses of legally marketed devices.
  3. Investigational Device Exemption: An IDE permits a device, that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations, to collect safety and effectiveness data.
  4. Non-invasive Device or Procedure: A device is considered non-invasive if it does not 1) penetrate the skin or mucous membranes of the body, the ocular cavity or urethra; or 2) enter the ear beyond the external auditory canal, the nose beyond the nares, the mouthy beyond the pharynx, the anal canal beyond the rectum, or the vagina beyond the cervical os. Simple venipuncture is considered non-invasive. The use of surplus body samples of body fluids or tissues that are left over from the samples taken for non-investigational purposes is also considered non-invasive.
  5. Significant Risk: A 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 intended as 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.
  6. Non-Significant Risk: A 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 by the convened IRB prior to conducting clinical trials and continuing review by the IRB are required.

Procedures and Guidance

In addition to complying with requirements of 21 CFR 50 and 56, all studies designed to test the safety or effectiveness of an investigational device must be conducted according to 21 CFR 812, Investigational Device Exemptions. When conducting a study designed to test safety or efficacy of an investigational device, one of the following conditions must apply:

  1. The investigational device qualifies for one of the exemption categories identified in 21 CFR 812.2(c);
  2. The study meets the abbreviated IDE requirements identified in 21 CFR 812(b); or
  3. The study is conducted under a valid IDE issued by the FDA;

The study sponsor is responsible for determining whether an investigational device requires an IDE issued by the FDA before a study may proceed. Further details pertaining to each of these options are outlined below.

  1. Investigations Exempted from the IDE Requirements

    21 CFR 812 provides exemptions from the IDE requirements; meaning 21 CFR 812 and the IDE requirements are not applicable when the device meets one of the criteria below. The study sponsor is responsible for determining when an investigational device meets the exemption criteria.

    1. A device, other than a transitional device, in commercial distribution immediately before May 28, 1976, when used or investigated in accordance with the indications in labeling in effect at that time.
    2. A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under subpart E of part 807 in determining substantial equivalence.
    3. A diagnostic device, if the sponsor complies with applicable requirements of 809.10(c) and if the testing is:
      1. Is noninvasive,
      2. Does not require an invasive sampling procedure that presents significant risk,
      3. Does not by design or intention introduce energy into a subject, and
      4. Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.
    4. A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two of more devices in commercial distribution, if the testing is not for the purpose of determining safety and effectiveness and does not put subjects at risk.
    5. A device intended solely for veterinary use.
    6. A device shipped solely for research on or with laboratory animals and labeled in accordance with 812.5(c).
    7. A custom device as defined in 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.
  2. Abbreviated IDE Requirements (Non-Significant Risk Devices)

    The FDA considers an investigational device to have an approved application for an IDE when a device is a non-significant risk device that is not banned and the sponsor:

    • Labels the device in accordance with 812.5;
    • Obtains IRB approval of the investigation after presenting the reviewing IRB with a brief explanation of why the device is not a significant risk device, and maintains such approval;
    • Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator’s care, informed consent under 21 CFR 50 and documents it, unless documentation is waived by an IRB under 56.109(c).
    • Complies with the requirements of 21 CFR 812.46 with respect to monitoring investigations;
    • Maintains the records required under 21 CFR 812.140(b) (4) and (5) and makes the reports required under 21 CFR 812.150(b)(1) through (3) and (5) through (10);
    • Ensures that participating investigators maintain the records required by 21 CFR 812.140(a)(3)(i) and make the reports required under 21 CFR 812.159(a)(1),(2),(5), and (7); and
    • Complies with the prohibitions in 812.7 against promotion and other practices.

    If the IRB agrees that the device is a non-significant risk, non-banned device, the study may proceed following IRB approval. The IRB’s responsibilities for making the significant risk/non-significant risk determination are outlined below.

  3. Investigational Device Exemption (IDE) Requirements (Significant Risk Devices)

    When an investigational device does not meet either an IDE exemption or an abbreviated IDE, a study may only be approved when the FDA has issued an Investigational Device Exemption. An IDE is considered approved 30 days after the FDA receives the application; the sponsor may receive earlier notification of approval. While the sponsor of a study is responsible for determining when an IDE is required, the IRB is responsible for verifying that an IDE number is valid for the proposed study.

    • When the IDE is held by a sponsor-investigator, at least one of the following may be used for IDE verification:
      • A study protocol, as submitted to the FDA, including an IDE number
      • Communication from the FDA with verification of the IDE
    • When the IDE is held by a sponsor, at least one of the following may be used for IDE verification:
      • A sponsor protocol specifying the IDE number
      • Communication from the sponsor verifying the IDE number
      • Communication from the FDA verifying the IDE number
  4. Distinguishing Between Significant Risk (SR) and Non-Significant Risk (NSR) Device Studies

    NSR device studies have fewer regulatory controls than SR studies and are governed by the abbreviated requirements [21 CFR 812.2(b)]. The SR/NSR decision is important to FDA because the IRB serves, in a sense, as the Agency'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 the 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 the 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, the VCU IRB may 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 principal investigator/sponsor should provide the IRB with a risk assessment and the rationale used in making its risk determination [21 CFR 812.150(b)(10)].

  5. Making the Significant Risk / Non-Significant Risk Decision
    1. Initial Assessment: The assessment of whether or not a device study presents a NSR is initially made by the sponsor. The sponsor may or may not be providing financial support for the research study. In some cases, the sponsor may be the manufacturer and/or the investigator. If the sponsor considers that a study is NSR, the sponsor provides the IRB with an explanation of its determination and any other information that may assist the IRB in evaluating the risk of the study.
    2. IRB Requests and Reviews Additional Information, As Needed: The IRB may utilize several types of information in determining risk including a description of the device, reports of prior investigations with the device, the proposed investigational plan, a description of patient selection criteria, and monitoring plan. The sponsor must inform the IRB of the FDA’s assessment of the device's risk if such an assessment has been made for the device or for a predicate device. If requested by the IRB, the sponsor should inform the IRB whether other IRBs have reviewed the proposed study and what determination was made. The IRB may also consult with FDA for its opinion.
    3. IRB Makes Its Own Assessment: The IRB must document Significant Risk/Nonsignificant Risk device determinations in the minutes and reference the rationale used by the IRB for the determination.

      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 with the sponsor’s NSR assessment, the sponsor should notify FDA that a SR determination has been made. The study can be conducted as a SR investigation following FDA approval of an IDE application. The sponsor, not the IRB is responsible for the IDE application process.

      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, the 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 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 IRB must consider the potential harm that could be caused by the procedure in addition to the potential harm caused by the device.

    4. Ultimate Authority: 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 a NSR, an IDE application must be submitted to FDA. The FDA becomes informed of the NSR determination indirectly by the sponsor(s), who must file "abbreviated IDE requirements" {21 CFR 812.2(b).}

      NOTES: The IRB is not bound by regulations to determine the need for an IDE or ‘abbreviated IDE”, but rather is limited to determinations of SR/NSR (on their own behalf) and reporting such determinations to the sponsor.

  6. IRB Responsibilities Following SR/NSR Determination:
    1. Significant Risk Determination: If the IRB decides the study is Significant Risk, the following responsibilities must be carried out by the VCU IRB:
      • The VCU IRB must document the determination of SR and the rationale.
      • The VCU IRB must notify the sponsor and investigator of the SR decision.
      • The VCU IRB can proceed to review the study applying the requisite criteria within 21 CFR 56.111.
    2. Non-Significant Risk Determination: If the IRB decides the study is Non-Significant Risk, the following responsibilities must be carried out by the VCU IRB:
      • VCU IRB minutes must document determination of NSR and the rationale.
      • IRB proceeds to review study applying requisite criteria [21 CFR 56.111].
  7. The VCU IRB Decision to Approve/Disapprove:

    Once the SR/NSR decision has been reached, the IRB will 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 will 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 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.

    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, full IRB review 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].

    When a study involves an investigational device, the IRB should evaluate the adequacy of the investigator's plans for control of the investigational device. The reviewer may require the use of the investigational drug pharmacy or central supply for control and monitoring of investigational devices (as appropriate) and may require specific post-approval monitoring or other stipulations.

References

Medical Devices
Significant Risk and Nonsignificant Risk Medical Device Studies
21 CFR Part 812. (§812.60, §812.62, §812.64 , §812.66)
VCU Office of Research Website: VCU Faculty-Held IND or IDE