IRB Review of In Vitro Diagnostic Devices in Precision Medicine Trials

Advances in molecular pathology have led to a paradigm shift in clinical trial design: instead of developing drugs that target a specific type of cancer, precision medicine trials investigate therapeutic products that target a specific genetic mutation. For example, in a basket study design, individuals with various types of cancer–but with the same genetic mutation–are eligible for enrollment into the same clinical trial. Even if a clinical trial targets only one type of cancer, enrollment is often limited to individuals who possess a particular “actionable mutation” that has been shown to respond to the investigational product. Thus, these precision medicine trials usually require genetic testing for the actionable mutation.

The regulatory status of the genetic test often raises several questions during IRB review, including whether the assay is an investigational device and, if so, whether it is exempt from FDA investigational device regulations or requires a significant risk/non-significant risk determination. 

Confusion can arise because, while confirmatory genetic testing is generally done in a Clinical Laboratory Improvement Amendment (CLIA)-certified central laboratory, the assay is usually not FDA-approved. Additionally, while some tests are developed as a companion diagnostic device to the study drug, the prototype clinical trial assay is often not intended to be marketed for clinical use (particularly in early-phase clinical trials).

In its review of the clinical trial assays used in precision medicine trial protocols, an IRB should weigh several considerations.

Clinical trial assays are in vitro diagnostic (IVD) devices and may also be laboratory developed tests (LDTs).

The FDA’s definition of a device encompasses both IVD devices and the subset of IVD devices known as LDTs.1 IVD devices include clinical trial assays that are composed of reagents and instruments used to examine human biospecimens in order to determine the presence of the required actionable mutation.2

LDTs are intended for clinical use and are designed, manufactured, and used within a single laboratory.3 Depending on how a clinical trial assay is designed and used within a precision medicine trial, the device may meet the FDA’s definition of an LDT.

CLIA status is separate from FDA status.

Although many precision medicine trials require that any laboratory testing be conducted in a CLIA-certified laboratory, and despite FDA recommendations for the use of analytically-validated tests, a laboratory’s CLIA certification is independent from the question of whether the clinical trial assay itself is subject to the FDA investigational device exemption (IDE) regulations. Thus, although the accuracy and reliability of the clinical trial assay may be relevant to an IRB’s consideration of study risk and benefit, the CLIA status of a laboratory should not affect the analysis of whether an assay is subject to the FDA IDE regulations.

Investigational IVD devices, including investigational LDTs, are subject to the FDA IDE regulations.

Clinical investigations of devices to determine safety or effectiveness are subject to the FDA’s IDE regulations, unless the research meets one of the specified exemption criteria.4 The FDA generally considers the use of IVD devices to be investigational when the IVD results will be used to decide how to how to enroll, assign, or manage subjects in a clinical trial of a therapeutic product, unless the use of the IVD device is already approved or cleared.5

This is true of all clinical investigations of IVD devices, regardless of whether the test is an LDT. Although the FDA currently exercises enforcement discretion and does not regulate LDTs, this enforcement discretion does not extend to clinical investigations of LDTs. Thus, a clinical trial assay (LDT or not) may be considered an investigational device if the assay is not FDA-approved or being used according to indication and if the test results are used to determine whether a clinical trial participant receives a therapeutic product.

Special considerations for IDE exemption or significant risk/non-significant risk determinations.

Many investigational IVD devices will meet the FDA’s diagnostic device exemption criteria and therefore will not be subject to IDE requirements.6 Important considerations for the use of clinical trial assays include whether testing requires a new research biopsy or whether testing can be done using archival tissue samples. Another significant factor is whether the clinical trial assay results will be confirmed by an FDA-approved test or medically accepted diagnostic practice prior to making decisions related to enrolling, assigning, or managing subjects.

If an investigational IVD device is not IDE-exempt, the IRB must determine whether its use within the clinical trial represents a significant risk or non-significant risk.7 The FDA assesses the risk presented by investigational IVD devices primarily by the potential consequences to the subject of an incorrect test result.8 For example, the use of a clinical trial assay to make enrollment decisions may pose serious risk to the health, safety, or welfare of subjects because an incorrect test result could lead to subjects foregoing or delaying a treatment that is known to be effective, or being exposed to higher safety risks than the control arm or standard of care.9 However, it is important to remember that the risk assessment of an investigational IVD device depends on the specifics of the protocol and includes considerations related to the way the test result will be used and the subject population that will be enrolled.

As the number of precision medicine trials continues to grow, the research community should stay apprised of FDA expectations related to IRB review of the IVDs used in these protocols. The agency has indicated that additional guidance will soon be released that further addresses the topic of investigational IVD devices used in clinical investigations of therapeutic products and will include information about determining investigational IVD risk.

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1 See 21 U.S.C. § 321(h) (2016).

2 See 21 C.F.R. § 809.3(a) (2016).

3 See FDA Draft Guidance, Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) (October 2014),

4 21 C.F.R. § 812.2(a) and (c) (2016).

5 See, e.g., FDA Guidance, In Vitro Companion Diagnostic Devices (August 2014), ; FDA Draft Guidance, Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product (July 2016),

6 See 21 C.F.R. §812.2(c)(3) (2016).

7 See 21 C.F.R. §812.2(b) (2016); 21 C.F.R. §812.3(m) (2016).

8 See Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product, supra note 5; FDA Guidance, In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions (June 2010),

9 Id.

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