On February 26, 2020, the U.S. Food and Drug Administration (FDA) released a guidance document for Dual 510(k) and CLIA waiver application studies to assist device manufacturers when utilizing this particular clearance/waiver pathway. The FDA suggests this pathway is the easiest and fastest approach for manufacturers to simultaneously obtain a CLIA waiver and 510(k) clearance for new In Vitro Diagnostic (IVD) tests. In addition, the FDA believes this pathway will serve patients and providers by adding efficiencies to the process of bringing simple and precise IVD tests to CLIA-waived settings.
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The Clinical Laboratory Improvement Amendments (CLIA) of 1988 refer to federal regulatory standards that provide supervision of all clinical laboratories and the established set of standards to be observed by facilities performing testing and procedures for non-research purposes. All clinical laboratories in the United States involved in the testing of human specimens—such as blood, tissue, and other body fluids for the purpose of diagnosis, prognosis, treatment, health assessment or prevention of a medical condition or disease—are required to comply with the CLIA standards.
It is mandatory for U.S. clinical laboratories to acquire the certificates for the performance of complex diagnostic tests, or obtain a waiver from CLIA requirements to perform simple tests that have “an insignificant risk of an erroneous result.” The CLIA ‘Certificate of Waiver’ is a mechanism whereby a clinician can perform and bill for simple tests in an office setting so long as the tests are granted waived status under CLIA. These tests do not require laboratory skills and pose no reasonable risk of harm, even if the test is performed incorrectly. If an IVD is not identified as a waived test, a manufacturer can submit an application for waiver to the FDA.
Studies for Dual 510(k) and CLIA Waiver by Application
The dual submission program is designed to provide simultaneous review of both applications for 510(k) premarket notification and CLIA Waiver by application with the purpose of reducing time spent on the authorization processes. This guidance, in addition to the Medical Device User Fee Amendments of 2012 (MDUFA III), allows for a single submission filing for both types of applications. It will be important for manufacturers to capitalize on the dual submission pathway to optimize business efficiencies. As of March 2020, there are a total of 193,474 laboratory sites and 79,686 physician office laboratories that can perform CLIA-waived testing in the United States.2
The guidance document published by the FDA in February 2020 aids medical device manufacturers in the development of study designs for dual submission and outlines the criteria used to determine whether this framework can be applied. For example, a dual submission is especially appropriate for a device that is simple, possesses fail-safe/failure alert mechanisms, provides a series of pre-analytical steps, and are subject to premarket notification requirements.
A key takeaway from this guidance is the suggestion that while 510(k) IVD studies are often performed by trained operators, such as test operators or moderate complexity laboratory personnel, it is important to design a dual pathway study to replicate settings, samples and test operators to demonstrate CLIA Waiver criteria. These studies should be conducted in waived settings using the typical intended user who has limited training—or no training/hands-on experience—in conducting laboratory testing.
Most importantly, the FDA provides guidance for designing a single set of comparison and reproducibility studies with the data generated supporting both 510(k) clearance and CLIA Waiver requirements. Device manufacturers are encouraged to inform the FDA of its plans to leverage a dual submission pathway with a Pre-Submission notification. FDA further recommends that the Pre-Submission process includes planned study designs for comparison and reproducibility studies developed by the device manufacturer to suit the requirements applicable to both 510(k) premarket notification and CLIA Waiver applications.
Typically, a dual submission should include all content required for the application of 510(k) clearance and CLIA Waiver by application as though these submissions were separate and sequential. Potentially, contents related to comparison and reproducibility studies could overlap, thus, one set of comparison and reproducibility studies may be used for the application of 510(k) clearance and CLIA Waiver.
The FDA recommends the following elements to be included in a dual 510(k)/CLIA Waiver submission:
- The description of the device and demonstration that it’s simple to use.
- Risk analysis results, such as the list of identified potential sources of error from the device as would be derived from risk management as outlined in ISO 14971 “Medical devices – Application of risk management to medical devices.”
- A description of the measures taken to mitigate the risk of errors and verification confirming the ability of failure alerts, fail-safe mechanisms and other control measures as effective in reducing the risk of errors.
- Detailed results of the flex studies showing insensitivity of the test system to usage variations.
- Results of the analytical studies, including design details.
- Results of the design and comparison studies that confirm the device has an insignificant risk of errors.
- The description of the design and results of reproducibility studies executed by untrained operators.
- The description of the clinical performance study including predicate comparison as needed for 510(k) or dual submission for some devices.
- All information regarding labeling of the device and the instructions for use in accordance with a simple device.
Further information on general study design consideration for CLIA Waiver studies are provided in Section V of the FDA’s guidance here: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-dual-510k-and-clia-waiver-application-studies.1
How Can NAMSA Help?
NAMSA is the industry leader in driving successful regulatory outcomes. Our teams of regulatory, statistical, quality, preclinical, and clinical research Associates have many years of experience working for, and with, the FDA. Not only do we understand how to obtain the most meaningful feedback possible throughout the Pre-Submission process, but we also possess unmatched experience on how to utilize this data to accelerate regulatory submissions and ultimately, product approvals.
Clinical Research Services: https://namsa.com/services/clinical-research/
Regulatory & Quality Services: https://namsa.com/services/regulatory-and-quality-consulting/
IVD Services: https://namsa.com/services/ivd/
Uchenna Ifediora possesses 10 years of clinical monitoring experience and currently serves as NAMSA’s Senior Clinical Research Associate. She has vast experience in Companion Diagnostics (CDx) supporting IVD clinical studies in the U.S., UK, Singapore and China. She is an experienced CRA in providing leadership and direction to clinical site management team members from study start through close-out. Uchenna holds a Master of Science Degree in Environmental Protection and Management from the University of Edinburgh, United Kingdom.