In Vitro Diagnostics (IVDs) are reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, to cure, mitigate, treat, or prevent disease. Such products are intended for use in the collection, preparation, and/or examination of specimens taken from the human body.
IVDs that are being tested for possible future marketing are devices, and may also be biological products. They are test articles under Food and Drug Administration (FDA) regulations and are subject to FDA regulations governing investigational devices (IDE regulations). When IVDs are used in research involving human subjects (or human samples), FDA’s regulations for the protection of human subjects (informed consent and IRB review) generally also apply.
Please note: FDA regulations differ from the Department for Health and Human Services (DHHS/OHRP) regulations in that the use of existing specimens, even if they are de-identified (see IRB Review below), are not exempt from IRB review.
IDE Exempt Studies
Studies may be exempt from FDA’s IDE regulations when the research meets all of the following criteria:
- The sponsor has labeled the device properly;
- The testing is non-invasive;
- The testing does not require an invasive sampling procedure that presents significant risk;
- The testing does not by design or intention introduce energy into a participant; and
- The testing is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically-established diagnostic product or procedure.
A document stating the research meets these criteria is also required at the time of study submission.
IRB Review
Unlike DHHS regulations, FDA regulations do not provide for exemption from IRB review when research involves existing specimens and the investigator records information without identifiers or linking codes (21 CFR 56.104). That means 45 CFR 46.104(b)(4) does not apply to FDA regulated studies. Nor do FDA regulations define “human subjects” with reference to the identifiability of the subject or of the subject’s private information (i.e., the donors of specimens/samples remain “human subjects” even when the specimens/samples are de-identified; 21 CFR 812.3(p)). Current FDA guidance indicates that IRB review is required for any IVD study involving human specimens/samples, even when the research involves no identifiers and the biological materials cannot be linked to any identifying information.
Informed Consent
With a few narrow exceptions (emergency and some DOD research), FDA regulations do not permit waiver of consent, even when studies are minimal risk and would meet criteria for waiver of consent under DHHS regulations. Under FDA regulations, informed consent is required for IVD studies involving samples that are identifiable (i.e., are labeled with identifiers or accompanied by the patient’s identifiable clinical information), as well as for studies in which the samples are not identifiable but are coded or linked to identifiable information.
FDA guidance, however, indicates that under some circumstances, when samples taken from excess clinical or research specimens cannot be identified (e.g., all linking codes and identifiers have been removed, or the investigator has no access to the code keys or identifying information), the agency will exercise “enforcement discretion” and permit the IRB to approve the study without requiring informed consent of the sample sources.
To be eligible for approval without a requirement for informed consent, FDA indicates that IVD research must meet the following criteria:
- The research must be conducted under an IRB-approved protocol;
- The research must meet criteria for an IDE exemption (see above);
- The research must use specimens left over from clinical care, specimen repositories, or other research (i.e., the specimens may not be collected specifically for the proposed research, and no additional specimen may be collected for the purpose of research);
- Individuals caring for the patients are different from and do not share information about the patient with those conducting the investigation;
- The specimens are provided for research without identifiers (codes are permissible only if neither the investigator nor anyone associated with the study has access to the code key or can identify the person who was the source of the specimen);
- Any clinical information supplied with the specimen must not be individually identifiable;
- No test results from the research may be reported to any subject or that subject’s health care provider; and
- The supplier of the specimens must have established policies and procedures to prevent the release of identifying information.
FDA recommends that the IRB review the policies and procedures that are in place to determine (1) that identifiers will not be released to investigators, and (2) whether there is the potential for test results to be necessary for clinical patient management (e.g., FDA suggests that if the research involves a public health threat such as anthrax or COVID-19, it may be necessary to report positive results; therefore informed consent might be required).
References
Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable: http://www.fda.gov/RegulatoryInformation/Guidances/ucm078384.htm
21 CFR 56.104)
45 CFR 46.104(b)(4)
21 CFR 56.102
21 CFR 812.3(p)