Regulatory Evaluations of Companion Diagnostic Medical Devices in Clinical Trials: Experiences of an Independent IRB

Introduction

Companion diagnostic (CDx) medical devices, typically in vitro devices, play a pivotal role in precision medicine by providing critical information necessary for the safe and effective utilization of corresponding drugs or biological products. Additionally, companion diagnostics can include imaging devices. The term “critical” signifies the requirement of appropriate labeling of drugs or biological products to include the use of diagnostic devices.

CDx devices are employed in clinical trials for purposes including patient stratification, diagnosis, treatment decisions, prognosis, monitoring therapy response, and measuring resistance markers. These devices play a crucial role in the therapeutic decision-making process to develop precision medicine strategies. If the diagnostic test proves inaccurate, the subsequent treatment decision may not be optimal. Therefore, CDx devices used during clinical trials typically require a distinct regulatory determination by relevant authorities, such as an Institutional Review Board (IRB) or the Food and Drug Administration (FDA). During the review, the IRB must identify these CDx devices and make appropriate regulatory determinations. The IRB and the FDA can determine that a CDx device poses non-significant risk (NSR) or doesn’t meet those requirements, whereas only the FDA can confirm that a CDx device constitutes significant risk and requires an Investigational Device Exemption (IDE).

WCG CDx Clinical Trials Experience

To identify companion diagnostic medical devices utilized in clinical trials, a thorough review was conducted of all device clinical trials received by WCG from January 2023 to June 2023. Three primary sources were examined for determinations regarding companion diagnostic devices: 1. The device checklists, which outline the regulatory requirements as per 21 CFR 812; 2. Documentation of device risk status provided by the sponsor, including rationale for NSR and/or FDA letters; and 3. IRB board minutes language. The determinations made by either the IRB or the FDA regarding the CDx devices were further analyzed. Additionally, the device clinical trials were categorized based on their indications as either oncology-related or non-oncology-related.

From January to June 2023, WCG reviewed 652 clinical trials involving FDA-regulated devices. Of these, 47 (7.20 percent) used CDx devices. The IRB made 36 (76.6 percent) determinations with supporting sponsor rationale and received documentation of FDA risk determinations for 11 (23.4 percent) cases. Most (42, or 89.4 percent) CDx devices were used in oncology, with 15 (36 percent) being FoundationOne CDx devices. Five devices (10.6 percent) were used in non-oncology fields such as hematology, genetics, hepatology, and cardiovascular disease. The FDA made significant risk determinations for three (27 percent) devices in non-oncology fields. All oncology-related CDx devices were deemed to be NSR by the IRB or the FDA. The IRB played a key role in identifying and classifying most of the NSR CDx devices.

The data indicate that the majority of CDx devices were utilized for oncology indications, as reflected in the currently approved CDx devices by the FDA.¹ The use of CDx devices was intended to aid in participant identification and study enrollment. While the majority of CDx devices are used in oncology indications, their use in non-oncology indications is also advantageous. Most of the CDx devices met the FDA requirements for  NSR devices, as determined by the IRB and occasionally by the FDA. This analysis shows that our checklists, minutes, communication with sponsors regarding NSR rationale, and regulatory documentation (FDA letters, etc.) have ensured that the IRB consistently recognizes when a CDx device determination is necessary and documents it accordingly.

Recommendations and Best Practices

Based on our experience, we recommend the following as best practices for IRBs:

How to identify a CDx device in a protocol:

• Review inclusion/exclusion criteria, subject screening section, and study design to identify any investigational tests which measure the presence or absence of a specific biomarker such as protein expression, genetic amplification, deletion or mutation, or antibodies against infectious agents.
• Determine if the study requires the presence or absence of specific biomarkers for enrollment.
• Identify whether the presence or absence of specific biomarkers is required for treatment decisions to a specific group.

Adhere to the abbreviated IDE requirements as outlined in (§812.2(b)),² along with the supplementary criteria specified below,^3,4 which can assist the board in evaluating the risk of the device in the research:

1. Will use of the investigational test results lead to some trial subjects foregoing or delaying a treatment that is known to be effective?
2. Will use of the investigational test results expose trial subjects to safety risks (e.g., adverse events from the experimental therapy) that (in some “net” sense) exceed the risks encountered with control therapies or non-trial standard of care?
3. Is it likely, based on a priori information about the investigational therapy, that incorrect test results would degrade the safety or efficacy of participants’ treatment?
4. Does specimen acquisition, done for investigational testing and outside the standard of care, require an invasive sampling procedure that presents significant risk?

Our analysis indicates that our checklists, meeting minutes, communication with sponsors regarding confirmation for NSR rationale, and regulatory documentation (including FDA letters) have effectively ensured that the IRB consistently recognizes and documents when a CDx device determination is required.

Does your study involve companion diagnostic (CDx) devices? Ensure proper regulatory determinations and get the guidance you need with WCG’s IRB experts. Our team is here to help you navigate the complexities of CDx device classification, risk assessment, and compliance. Advance your study with confidence. Complete the form below to reach out with your questions or to discuss your study’s specific needs.

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References

1. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.
2. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-812.
3. https://cersi.umd.edu/sites/cersi.umd.edu/files/D1S09-Bijwaard-v1.pdf.
4. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/principles-codevelopment-in-vitro-companion-diagnostic-device-therapeutic-product.