On May 14, PRIM&R hosted a webinar titled IRB Oversight and FDA Review of Studies that Include In-Vitro Diagnostics (IVDs), presented by Jonathan M. Green, MD, professor of medicine, pathology, and immunology, associate dean for human studies, and executive chair of the institutional review board (IRB) at Washington University School of Medicine in St. Louis, MO, and E. David Litwack, PhD, personalized medicine staff at the Office of In Vitro Diagnostics and Radiological Health at the US Food and Drug Administration (FDA).

At the conclusion of the webinar, Dr. Green and Dr. Litwack shared additional insight in response to questions from webinar attendees, and we’re pleased to share that with the readers of Ampersand.

1, At what point does an assay under development become an IVD? The intended use of the assay at this point is not to diagnose, treat, etc. since it’s still under development.

Jonathan M. Green (JMG) and David Litwack (DL): If the ultimate goal of the assay under development is to diagnose, cure, treat, mitigate, or prevent disease, then once any human specimens are being used, you must apply the investigational device exemption (IDE) regulation (21 CFR Part 812). It may be determined that studies of an assay are exempt from the IDE regulation, but that determination may only be appropriately made on a case-by-case basis.

2. For drug trials involving an IVD that have been reviewed by FDA as part of an investigational new drug (IND) review, is it reasonable to expect that FDA will advise whether they interpret there to be investigational IVDs?

JMG: One should not assume that because the trial has been reviewed by the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) in connection with an IND, that the IVD and/or IDE regulations have been fully considered. CDER or CBER may recognize that the study involves an investigational device, and consult the Center for Devices and Radiological Health (CDRH). However, this may not always be the case. The absence of any statement by CDER or CBER addressing the IVD and/or IDE regulations should not be interpreted to mean that an FDA determination has been made that the study does or does not involve an investigational IVD. The sponsor (who is the responsible party, and can be the principal investigator of a grant) and IRB should independently consider this issue, and ensure that the study complies with applicable laws and regulations, including the IVD and IDE regulations (21 CFR 809.10(c) and 21 CFR Part 812.

3. One of the examples of a regulated mobile device is a nonapproved heart monitor attachment for a mobile phone. Given your explanation of devices that are exempt from IDE regulations, would this example be considered exempt if it was not returning results to the patient or clinician but only to sponsor/manufacturer of the device?

JMG: Exemption is not based on whether the results are being provided to the sponsor or principal investigator. If the testing of a diagnostic device is non-invasive, does not require an invasive sampling procedure that presents significant risk, does not by design or intention introduce energy into a subject, is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure, and complies with the applicable labeling requirements, it would meet the exemption criteria in 21 CFR 812.2(c)(3). A heart monitor that detects ECG signals would not be an IVD, but it is a diagnostic device and would still have to meet the same criteria to qualify for this exemption. Note that exempt investigations remain subject to the clinical investigator disqualification provisions at 21 CFR 812.119.

4. The use of a confirmatory test in the investigational use of the IVD is one basis for exemption. Is this still true if the eventual intended use of the IVD will be to replace the confirmatory test?

JMG and DL: The use of a confirmatory test is one of the criteria used as a basis for exemption. Until the IVD itself is approved or cleared for the specific indication and use under investigation, in order to qualify as an exempt investigation under the IDE regulations, the investigational IVD that is being used as a diagnostic procedure must be confirmed by another, medically established product or procedure, in addition to meeting the other criteria for the exemption. This is true whether or not the IVD under investigation would, if eventually cleared or approved, replace the confirmatory test in medical practice.

5. You indicate the analysis should go as follows: (1) is the test an IVD, (2) if so, is it investigational, (3) if so, is it exempt, (4) if not, is it NSR or SR. In regards to #2, is this the same as asking if it is a clinical investigation? It was our understanding that in determining whether to apply FDA regulations to a study using an IVD, you ask whether the study meets the definition of a clinical investigation (use of a device evaluating safety or effectiveness OR data will be submitted to or held for inspection by the FDA). However, your analysis seems to focus more on whether the device is “investigational” in the second prong (e.g., whether is it cleared/approved and used according to indication). Can you elaborate?

JMG: In the review of any study, in order to determine if the FDA IDE regulations apply, you should determine whether the study meets the definition of a clinical investigation of a device. If it does, then the FDA IDE regulations apply. If not a clinical investigation, then the FDA IDE regulations do not apply. For example, at the bench science stage of development, in which there are no human subjects or samples yet involved, the study would not meet the definition of a clinical investigation. However, once human samples become involved, it meets the clinical investigation definition, even if these samples are just stored tissue, and if the study involves the use of a device that is not cleared, approved, or exempt (including a marketed device used outside of its cleared or approved intended use). At that stage, many IVD studies are exempt. In the typical case scenario that we see, the assay is being used to determine eligibility for a clinical trial, and this use is often a novel one. Thus, the IDE regulations clearly apply, and then we focus on applying the IDE regulations as we outlined during the webinar.

DL: Also, often times the focus of the trial is on an investigational drug or biological product rather than the investigational IVD. Nevertheless, investigations that determine the safety and effectiveness of the IVD—even if the sponsor doesn’t intend to further develop and market the tests—are still subject to the IDE regulation. This is often the scenario in drug trials that use investigational IVDs. The point of the trial is to gather data on the drug, but if, for instance, the IVD is used to select patients for the drug trial, the outcomes of the patients usually also give information on the safety and effectiveness of the IVD.

6. Can only IVD products be exempted under 812.2(c)(3)? If I have a non-IVD that (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 where the sponsor complies with applicable requirements in 809.10(c)(1) and (c)(2), can that non-IVD be exempt under 812.2(c)(3)?

DL: The exemption criteria apply to diagnostic devices, whether or not they are IVDs.

PRIM&R would like to thank Dr. Green and Dr. Litwack for sharing their expertise. Do you have an idea for a webinar? Consider contributing to our third annual Call for Webinar Proposals.

If you were unable to attend this webinar and are interested in purchasing the archive, you may do so here.