CHAPTER 14

14.0 General

If research appears to use a device for an indication for which it has not been cleared, the IRB staff will review FDA regulations to verify that the research meets the definition of a device investigation. Device studies must satisfy one of the following:

• Have an Investigational Device Exemption (IDE) approved by the FDA under 21 CFR 812.30.
• Be categorized as fitting abbreviated requirements under 21 CFR 812.2(b).
• Be deemed by the FDA as being exempt from the requirement to have an IDE under 21 CFR 812.2(c).

By reviewing the protocol, some form of communication from the sponsor or a letter from the FDA to the sponsor; the IRB primary reviewer will determine whether the study has a valid FDA-approved and issued IDE. The investigator’s brochure may not be used to verify the IDE.

If an IDE is not required, the primary reviewer will determine whether the study meets the requirements for an abbreviated IDE or exemption from the requirement for an IDE. A study requiring an IDE will not be approved until the IRB verifies a valid IDE is in place.

14.1 Abbreviated Requirements

The following categories of investigations are considered to have applications for IDEs, unless FDA has notified a sponsor under 21 CFR 812.20(a) that approval of an application is required:

An investigation of a device other than a significant risk device, if the device is not a banned device and the sponsor:

1. Labels the device in accordance with 21 CFR 812.5;
2. 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;
3. Ensures that each PI participating in an investigation of the device obtains from each subject under the PI’s care, informed consent under 21 CFR Part 50 and documents it, unless documentation is waived by an IRB under 56.109(c);
4. Complies with the requirements of 21 CFR 812.46 with respect to monitoring investigations;
5. Maintains the records required under 21 CFR 812.140(b)(4) & (5) and makes the reports required under 21 CFR 812.150(b) (1)-(3) and (5)-(10);
6. Ensures that participating PIs maintain the records required by 21 CFR 812.140(a)(3)(i) and make the reports required under 21 CFR 812.150(a)(1), (2), (5) & (7); and
7. Complies with the prohibitions in 21 CFR 812.7 against promotion and other practices.
8. An investigation of a device other than one subject to 21 CFR 812.2(e), if the investigation was begun on or before July 16, 1980 and to be completed, and is completed on or before January 19, 1981.

14.2 Applying for and/or Filing an IDE

Visit the FDA website for instructions for completing and submitting an IDE:

https://www.fda.gov/medical-devices/investigational-device-exemption-ide/ide-application

14.3 Exemptions

The regulations at 21 CFR 812.2 do not apply to investigations that fit one of the following categories:

• 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.
• A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976, that the 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 that the FDA reviewed under Subpart E of part 807 in determining substantial equivalence.
• A diagnostic device, if the sponsor complies with applicable requirements in 21 CFR 809.10(c) and if the testing is:
  1. non-invasive,
  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.
• A device undergoing consumer preference testing, testing of a modification or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk.
• A device intended solely for veterinary use.
• A device shipped solely for research on or with laboratory animals and labeled in accordance with 21 CFR 812.5(c).
• A custom device as defined in 21 CFR 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.

14.4 Significant and Non-Significant Risk Determination

The IRB will review research involving the investigational device at a full board meeting if a PI or sponsor claims a device is not a significant risk. The IRB will determine if the study using the device is significant risk, within the context of the overall study, by reviewing the criteria in 21 CFR 812.3(m).

A significant risk device means that the device:

• Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
• Is purported or represented to be for use supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject.
• Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject.
• Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

A non-significant risk device study is one that does not meet the definition for a significant risk device study.

If the IRB determines that the study using the device is not “significant risk,” it will document that and the rationale for the decision in the minutes. The IRB will notify the PI of its determination, and the study may begin without submission of an IDE application to the FDA.

If the IRB disagrees with the sponsor’s or PI’s assessment that a device study is “non-significant risk” and determines that the study using the device is “significant risk,” it will notify the PI, and where applicable, the sponsor (21 CFR 812.66) and document its determination in the IRB minutes.

The study will be tabled, the sponsor or PI must apply for an IDE, and the study may not begin until the FDA approves the IDE application and the IRB approves the study. Upon receipt of FDA approval, the sponsor or PI must provide the IRB with the FDA’s approval letter or conditional approval letter as part of the re-submission process.

14.5 PI Responsibilities

• Must not begin the study or obtain informed consent of any subject prior to IRB and FDA approval.
• Ensure that the clinical investigation is conducted according to the signed PI agreement for clinical investigations, the investigational plan, applicable regulations (21 CFR 812), and any conditions of approval imposed by the reviewing IRB or FDA.
• Supervise all testing of the device involving human subjects in accordance with 21 CFR 812.43(c)(4)(ii) and 812.110(b).
• Permit use of an investigational device only with subjects under the supervision of the PI and supply the investigational device only to persons authorized to receive it.
• Provide for control or take adequate precautions, including storage of the device in a securely locked area to which access is limited to prevent inappropriate use of the device in accordance with 21 CFR 812.100, and return any remaining supply of the device (or otherwise dispose of it as directed by the sponsor) upon completion or termination of the clinical investigation or the PI’s part of an investigation.
• Permit the FDA to inspect and copy any records pertaining to the investigation, including those which may identify subjects (21 CFR 812.145).
• Prepare and submit to the sponsor:
  • Progress reports,
  • Final report,
  • Financial disclosure reports,
  • Any other information requested by the FDA (21 CFR 812.110).

14.6 In Vitro Diagnostic Devices

In vitro diagnostic devices (IVDs) are products (reagents, instruments, and systems) intended for use in diagnosis of disease or other conditions, including a determination of the state of health, to cure, mitigate, treat, or prevent a disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body (21 CFR 809.3). IVDs are devices under the regulations and are therefore subject to FDA regulation. In many cases, the research usually involves the comparison of the IVD under investigation to the “gold standard” using data generated from samples analyzed on both instruments. The comparison data and subsequent statistical analysis are submitted to the FDA for consideration of clearance or approval for marketing.

Technically, within the FDA regulations there is no distinction between an IVD and a device that may be implanted regarding informed consent of subjects in the study. However, the samples used in IVD studies typically are laboratory samples that have already been analyzed for clinical and/or diagnostic reasons and obtaining informed consent to use the samples for IVD analyses would be cumbersome. In a recent guidance document, the FDA informed IRBs and others that it does not object to the use of “leftover specimens” in IVD studies without the consent of the specimen donors, providing that:

• The investigation meets the IDE exemption criteria at 21 CFR 812(c)(3).
• The study uses leftover specimens collected for routine clinical care or analysis and/or leftover specimens that were previously collected for research purposes.
• The specimens are not individually identifiable.
• The specimens may be accompanied by clinical information if the information does not make the specimen source identifiable to the PI or any other person associated with the investigation.
• The individuals caring for the patients are different from and do not share information about the patient with those conducting the study.
• The specimens are provided to the PI without identifiers, and the supplier has established procedures to prevent the release of personal information.
• The study has been reviewed and approved by an IRB.

The FDA has a guidance document entitled “In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions” which should be considered when proposing IVD studies:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/in-vitro-diagnostic-ivd-device-studies-frequently-asked-questions

Proposed research on IVDs may be reviewed using an expedited review process providing that the research meets all applicability criteria.

14.7 Principal Investigator Responsibilities in Storage and Use of Investigational Devices

Investigational devices must be stored in a locked room designated for research or in a locked cabinet within a room designated for research that is under the direct control of the PI and accessible only to the PI and their authorized and IRB-approved staff. If applicable, the storage area for investigational devices must be separated from storage areas for approved devices.

An investigational device or its packaging must be labeled with the following information:

• The name and place of business of the manufacturer, packer, or distributor.
• The quantity of contents, if appropriate; and
• The following statement: "CAUTION - Investigational device. Limited by Federal law to investigational use."

The label or other labeling must describe all relevant contraindications, hazards, adverse effects, interfering substances, or devices, warnings, and precautions.

An investigational device is to be used only on subjects under the PI's supervision or under the supervision of a Co-PI on the study. A PI will not supply an investigational device to any person not authorized to receive it. The PI is responsible for records of receipt, use, or disposition of a device that:

• Relate to the type and quantity of the device.
• The dates of its receipt.
• The batch number or code mark.
• The names of all persons who received, used, or disposed of each device; and
• Why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of.

Upon completion or termination of a clinical investigation or the PI's part in an investigation, or at the sponsor's request, the PI must return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs.