Beginner’s Guide to IRB Review of IVD Research

In vitro diagnostic (IVD) devices are tests used on human biospecimens (e.g., blood or tumor tissue) to diagnose diseases or other conditions, monitor a person’s health, or help manage a current condition. Although IVDs themselves do not treat, prevent, or cure diseases, the data they output can be an important part of disease management.

IVDs are used in almost all clinical research. They can be essential for selecting appropriate participants, identifying potential adverse reactions, and studying how a drug affects the human body. However, the testing itself often occurs in laboratories or some other healthcare setting away from research participants.

Additionally, while the Food and Drug Administration (FDA) regulates all IVDs as medical devices, the agency has generally not enforced device regulations for certain IVDs designed, manufactured, and used within a single CLIA-certified laboratory. IVDs meeting this definition are known as laboratory developed tests (LDTs).

For these reasons, it can be difficult for researchers and institutional review board (IRB) members alike to determine when an IVD is investigational and, if it is, which regulations apply.

Whether you’re new to IVD research or could use a refresher, this high-level overview will help you navigate IRB review requirements for IVDs.

What is a “Human Subject” in the Context of IVD Research?

Under FDA’s medical device regulations, a subject (also called a “participant”) is “a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control.” This means if your research uses an investigational device on human biospecimens, your project involves human subjects and requires IRB oversight (more on that below).

You may never interact with the people from whom the samples were collected. You might not even obtain identifiable information about the donors. None of that matters: If your IVD study uses human samples, you’re doing human subjects research.

When Does Research Involve an Investigational IVD?

When an IVD is the object of study, it is investigational, regardless of the device’s approval status or intended use in the study.

The IVD may be the primary focus of the clinical trial, or it may be evaluated in a minor, exploratory objective. solely focusing on investigational IVDs (also known as IVD clinical trials) are easy to identify for two reasons:

• They are clearly collecting data about the device’s safety, effectiveness, validity, or performance.
• The developer/manufacturer of the IVDs are typically the entity that submits the study.

It may be more challenging to recognize a second type of investigational IVDs: using an IVD to guide therapeutic management of participants in a clinical investigation, when the IVD is not already approved for this purpose. This includes both unapproved IVDs and marketed IVDs used off-label.

When such an IVD is essential for the safe and effective use of a corresponding therapeutic product, it is known as an IVD companion diagnostic device.

An IVD is “guiding therapeutic management” when it is used for any of the following activities:

• Assessing a potential participant’s eligibility, such as confirming the presence of a particular cancer mutation
• Assigning participants to a treatment arm; this includes stratifying participants based on IVD results
• Determining dose level for a particular participant or group of participants
• Monitoring participants for side effects, such as increased lab values
• Predicting which participants are most likely to experience serious adverse event

Often used in drug clinical trials, these investigational IVDs are not the primary research focus, and the device developer or manufacturer is rarely involved in the study. Therefore, it is imperative sponsors identify these investigational IVDs for the IRB.

What IRB Regulations Apply to Research Involving Investigational IVDs?

As with all FDA-regulated human subjects research, your study must comply with the requirements for IRB review (21 CFR 56) and informed consent (21 CFR 50).

Additionally, studies involving an investigational IVD may also be subject to the investigational device exemption (IDE) requirements (21 CFR 812). The applicability of the IDE regulations depends on the level of risk the IVD use presents to study subjects and will fall into one of three categories:

• Exempt from the IDE requirements
• Nonsignificant risk (NSR): must comply with abbreviated IDE requirements, and the IRB must concur with the sponsor’s NSR assessment
• Significant risk (SR): must comply with full IDE requirements, including approval by both the FDA and IRB prior to study initiation

If your study involves an investigational IVD, you’ll need to determine which category best fits your research. The FDA is the final arbiter if the study sponsor and IRB disagree. Note: If your IVD meets the definition of an LDT, it falls under FDA enforcement discretion. For such tests, neither the FDA nor many IRBs enforce compliance with the medical device regulations. Thus, an LDT may not need an SR/NR determination, but risks of sampling procedures and invalid results should be disclosed in the informed consent form (ICF).

What Information Does the IRB Need When Reviewing Investigational IVDs?

To ensure an efficient and compliant IRB review, researchers should provide the following information:

• In the IRB submission form, identify any investigational IVD(s) used in your study, specify its regulatory status, and indicate whether you think its use is IDE exempt, NSR, or SR.
• Describe the investigational IVD(s) and how each will be used in the clinical trial.
• Provide the device’s user manual or instructions for use (IFU). Early in an IVD’s development, a formal IFU may not be available; in such cases, the protocol or other supporting documentation should provide sufficient information for the IRB to make a robust device and risk determination.
• Describe the risks of IVD use (including risks associated with sampling procedures and impacts of false positives/negatives) in the ICF.
• If the device or its use changes during the clinical trial, submit a modification to the IRB; the regulatory status may need reassessment.

As always, respond promptly to IRB requests for additional information, which may include a request for the FDA’s formal device risk assessment.

Collaboration to Simplify IVD Research Oversight

IVDs occupy a unique position in the array of regulatory controls and guidance that may confound novices in this realm. By working collaboratively with the IRB and FDA, sponsors and researchers can gain the expertise to turn a potentially process into a clear and straightforward pathway to study approval.

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