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FDA QS Implementation for CoDx Lab-Developed Tests
Introduction
FDA’s guidance document for in vitro companion diagnostic devices (IVD CoDx) states that, ideally, an IVD CoDx is approved at the same time as the corresponding therapeutic product (i.e., a drug or biologic). Since safety and efficacy of the therapeutic product are dependent on device performance, use of an FDA-cleared or -approved IVD CoDx is stipulated in the therapeutic product labeling. Thus, any entity, including a laboratory, that develops an IVD CoDx in partnership with a pharmaceutical company is expected to obtain FDA clearance or approval for the IVD CoDx.Myriad Genetic Laboratories, Inc. (Myriad) recently received premarket approval (PMA) for the BRACAnalysis CDx™ test as an IVD CoDx. Myriad initially designed and developed BRACAnalysis as a laboratory developed test (LDT) for determination of a patient’s risk of hereditary breast and ovarian cancer. The BRACAnalysis CDx™ test is approved to analyze germline BRCA1 and BRCA2 gene mutations to determine patient eligibility for the ovarian cancer drug Lynparza™ (olaparib).
A PMA sponsor must submit manufacturing and Quality System regulation (QS reg) documentation to FDA and, in most cases, a preapproval inspection of the manufacturing site is required. The FDA QS reg, 21 CFR 820, was designed to apply to a wide variety of medical devices in both small and large firms. FDA follows a standard process for reviewing QS reg information in a PMA submission. As an LDT, there are certain aspects of the BRACAnalysis CDx™ test that challenge the traditional implementation of the QS reg. FDA worked closely with the laboratory to assist them in developing an FDA-compliant quality system. The purpose of this article is to highlight some key challenges and potential solutions to implementing an FDA-compliant quality system for an LDT, using BRACAnalysis CDx™ as a case study.
Results
Device Description. In the case of an LDT, the laboratory is both the “manufacturer” and the “user” of the device. Thus, boundaries of the device may not be obvious within the context of laboratory operations. The “device description” for the BRACAnalysis™ CDx companion diagnostic does not encompass the entire laboratory process. In accordance with the definition of an IVD, Myriad determined that the BRACAnalysis CDx™ “device” includes critical reagents, instruments, and software used to run the test, in addition to the written procedure for running the test. This approach allowed Myriad to distinguish their role as “manufacturer” from “user” within their clinical laboratory.Design Control. A key requirement of design control is determination of design inputs (21 CFR 820.30(c)). Design inputs require upfront identification of customer and user expectations, which in principle is similar to how some labs implement the “Customer Focus” aspect of their quality system . Myriad built an FDA-compliant design control program by leveraging design principles inherent in its existing CLIA-based quality system. To meet design validation (21 CFR 820.30(g)) requirements for the BRACAnalysis CDx™, Myriad and their pharma partner performed a clinical study to demonstrate the test’s ability to select patients for the drug.
Final Acceptance. Final acceptance activities (21 CFR 820.80(d)) are designed to describe the final quality control of a finished device prior to its release for distribution. Since laboratories do not usually “release” the LDT as a discrete product, it may be unclear how the QS reg for final acceptance applies to LDTs. FDA and Myriad determined that final acceptance applied primarily to the BRACAnalysis CDx™ reagents that are formulated by Myriad for internal use.
Complaint Handling. CLIA requires that laboratories have procedures for handling complaints related to laboratory operations (e.g., unlabeled specimens, patient confidentiality, laboratory qualification, etc.). According to FDA’s QS reg for complaint handling, 21 CFR 820.198, an IVD manufacturer should investigate complaints about a test from its customers (e.g., clinical laboratory customers). For BRACAnalysis CDx™, Myriad developed a triage system to determine whether a particular complaint was related to laboratory operations or was to be handled under 21 CFR 820.198 (e.g., a complaint potentially relating to test design or manufacturing).
Conclusions
The BRACAnalysis CDx™ case example demonstrates that clinical laboratories can develop an FDA-compliant quality system. The flexibility of the QS reg allows the laboratory to take a number of approaches to meet its requirements. In general, laboratories can leverage their existing quality activities to implement an FDA-compliant system. Definition and description of the device is critical in determining how the QS reg should be implemented for a particular LDT. Laboratories are encouraged to collaborate with FDA through the Pre-Submission Program to define and describe the laboratory’s processes to meet certain aspects of the QS reg.References available upon request.
This article originally appeared in the February 2016 Global Forum.