Do you claim analytical performance studies in accordance with GLP in your FDA submissions for IVDs? Has FDA inquired into the nature of GLP compliance during your application review?
Good Laboratory Practice (GLP) regulations (21 CFR Part 58) were set forth by FDA in 1978 in response to public concerns that several important studies supporting the safety of FDA-regulated products were seriously flawed due to poor research practices and laboratory misconduct. The GLP regulations apply to nonclinical laboratory studies supporting research or marketing applications for FDA-regulated products. They promote the minimum basic requirements for study conduct, personnel, facilities, equipment, written protocols, operating procedures, study reports, and a system of quality assurance oversight.
The regulation defines “nonclinical laboratory study” as an in vivo or in vitro experiment in which a test article is studied prospectively in a test system under laboratory conditions to determine its safety and states that the term does not include studies utilizing human subjects (21 CFR 58.3(d)).
FDA has issued two follow-up Q&A documents, the first in 1981 with updates in 1999 and 2007 (“Good Laboratory Practices Questions and Answers”) and the second in August 2013 (“The Applicability of Good Laboratory Practice in Premarket Device Submissions: Questions & Answers”). The latter provides additional clarification with respect to medical devices.
Included in the 2013 Q&A draft guidance is a question about applicability to in vitro diagnostic devices (IVDs). FDA’s response is that “Studies intended to evaluate the performance of IVD devices to determine their safety typically utilize human subjects or specimens derived from human subjects and are therefore not subject to the GLP regulation.”
Consequently, are all validation studies in support of the safety of IVDs outside the scope of GLP? What about analytical performance studies? In fact, in another 2013 FDA guidance document (“Design Considerations for Pivotal Clinical Investigations”), the agency refers to non-clinical studies as “e.g., bench, animal or measurement studies and, for in vitro diagnostic devices, analytical validation studies”.
Even in the 2013 Q&A draft guidance, statements that “GLPs apply to the chemical procedures used to characterize the test article, to determine the stability of the test article and its mixtures, and to determine the homogeneity and concentration of test article mixtures” and “Likewise, the GLPs apply to the chemical procedures used to analyze specimens (e.g. clinical chemistry, urinalysis)” conflict somewhat with the proclamation that GLP is not applicable to IVDs.
Isn’t it important that IVD analytical performance assessments for measurement bias, precision, limits of quantitation and detection, linearity, interferences, carry-over, and reagent/sample stability be conduced in a laboratory compliant with applicable sections of the GLP regulations?
Granted, a large part of the GLP rules pertain to animal care and animal care/supply facilities, however, the majority of the promulgated requirements definitely apply to IVD analytical performance characteristics validations generally conducted in the manufacturer’s in-house laboratory. These performance studies often use contrived spiked samples or pooled human samples not individually identifiable. They need an approved written Protocol with clear objectives and methods, a Study Director, written SOPs, and QA oversight; adequate personnel, training, resources, facilities, equipment, specimen/data storage, and record retention; adherence to reagent labeling for handling and expiration dating; avoidance of contamination; and study reporting. All of these parameters are GLP requirements.
Of paramount importance are safety and effective performance of the FDA-regulated product. It is easy to indicate “N/A” to the animal requirements, so why not require conduct of IVD non-clinical studies in compliance with GLP for that additional credible layer of assurance?