There are three types of studies described in the regulations at 21 CFR Part 812: significant risk (SR) device studies, non-significant risk (NSR) device studies, and exempt studies. A brief description of these types of studies follows. Please refer to the FDA Information Sheet Guidance “Significant Risk and Nonsignificant Risk Medical Device Studies” for more detailed information about SR and NSR device studies, the importance of the IRB’s review, the regulatory requirements for these studies, and examples of devices in each category.
A. Significant Risk Device Studies
A significant risk device means an investigational device that:
• 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 a use in 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; or
• Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. (21 CFR 812.3(m))
Sponsors of investigational SR device studies are required to get an approved IDE from FDA before starting their study. 21 CFR 812.20 (FDA gives each IDE a number - for example #GXX0000, where XX denotes the year of the submission). Sponsors and clinical investigators of these studies must comply with the regulations at 21 CFR Part 812, "Investigational Device Exemptions."
If FDA disapproves an IDE, FDA’s letter will describe the reasons for the disapproval. If the sponsor submits an IDE amendment satisfactorily addressing the issues in FDA’s letter, the agency sends an IDE approval letter to the sponsor. In accordance with the regulations at Part 812, the study may not start until both FDA and the IRB have given their approval.
Note: A conditional approval letter from FDA allows the study to begin if the study is approved by the IRB, but requires the sponsor to provide additional clarifying information in order to obtain full approval for the study.
IRBs do not have to make the SR or NSR determination if FDA has already made the risk determination. Most often, clinical investigators submit SR device investigations for IRB review after the study has already received IDE approval from FDA. IRBs may ensure that SR device investigations have an FDA-approved IDE by asking the clinical investigator to request from the sponsor a copy of FDA’s IDE approval letter.
An IRB may be asked to review an SR device study before the sponsor receives FDA approval of an IDE submission. Under this circumstance, IRBs should be aware that because it is possible that FDA may not approve the IDE or may request significant changes to the research protocol, the IRB may need to re-evaluate the study after FDA reviews the application. If an IRB approves the significant risk device study before FDA approves the IDE, there may be more of a risk that clinical investigators will mistakenly enroll subjects before the study should be started (i.e, before FDA approves the IDE.)
B. Non-Significant Risk Device Studies
An NSR device is an investigational device that does not meet the definition of a significant risk device. If an IRB finds that an investigational medical device study poses a NSR, the sponsor does not need to submit an IDE to FDA before starting the study. If the IRB determines that the proposed study is an NSR study, the IRB may proceed to review the study under 21 CFR 56.109 and 21 CFR 56.111. FDA considers an NSR device study to have an approved IDE after IRB approval and when sponsors meet the abbreviated requirements at 21 CFR 812.2(b). Consequently, in most cases, FDA is not aware of non-significant risk device studies.
As stated above, if FDA has already made the risk determination, the IRB does not need to duplicate this effort. If, however, FDA has not made the risk determination or the IRB disagrees with the NSR determination made by a sponsor, then the IRB must notify the investigator and, where appropriate, the sponsor, that the study involves a significant risk device (21 CFR 812.66). If a sponsor or an IRB needs help in making the SR/NSR determination, it may ask for a written determination from FDA.
The IRB should consider the following in determining whether a device study poses a SR or NSR:
• the sponsor’s description of why the study is not SR • whether the proposed NSR research study meets the definition of “significant risk” (see above)
• the proposed use of the device as well as any protocol related procedures and tests, not just the device (test article) alone. (This process is different from the IRB review process found at 21 CFR 56.111(a)(2)).)
• additional information from the sponsor, if needed.
C. Exempt Studies
In accordance with 21 CFR 812.2(b), sponsors and investigators of certain studies are exempt from the requirements of 21 CFR Part 812, with the exception of §812.119 (disqualification of a clinical investigator). Examples of exempt studies are consumer preference testing, testing of a device modification, or testing of two or more devices in commercial distribution if the testing does not collect safety or effectiveness data, or put subjects at risk.
Studies of an already cleared medical device in which the device is used or investigated in accordance with the indications in the cleared labeling are exempt from Part 812. Note: Studies of a cleared device for a new use must comply with the human subject protection (informed consent and additional safeguards for children in research), IRB, and IDE regulations. Similarly, studies of a PMA approved device are exempt from the IDE requirements if the device is being studied for the indications in the approved labeling.
In addition, diagnostic device studies (e.g., in vitro diagnostic studies) are exempt from the requirements of 21 CFR Part 812 under certain circumstances. The study is exempt as long as the sponsor complies with the requirements at 21 CFR 809.10(c) for labeling, and if the testing: (i) is noninvasive; (ii) does not require an invasive sampling procedure that presents significant risk; (iii) does not by design or intention introduce energy into a subject; and (iv) is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure. 21 CFR 812.2(c)(3).