FDA'S REVIEW OF CLIA QUALITY CONTROL LABELING SUBMISSIONS TO BEGIN IN MID-JUNE AT EARLIEST UNDER DRAFT GUIDANCE; THREE-SITE TESTING REQUIRED FOR VALIDATION

FDA will begin reviewing in vitro diagnostic quality control labeling for compliance with requirements of the Clinical Laboratory Improvement Amendments of 1988 in mid-June at the earliest, according to a timetable outlined in an FDA guidance released on Jan. 12. The draft guidance describes criteria for FDA clearance of IVD QC instructions. FDA says that it will accept comments on the draft until March 15; the agency will begin accepting the 510(k)s, premarket approval applications, PMA supplements and product license applications for CLIA review 90 days after the guidance is finalized. Given a very quick turnaround between the end of the comment period and the publication of a final guidance, FDA could begin accepting premarket submissions in mid-June. However, it is more likely that FDA will take at least several weeks to review comments, resulting in a later start for the review of the premarket submissions. FDA initially had planned to begin reviewing the submissions Sept. 1, 1992 (the effective date of CLIA), but the program has been delayed pending completion of the guidance. Final CLIA regulations published in February 1992 mandate that when requested by a manufacturer, FDA must review IVD quality control labeling to determine if it can be used as an alternative to many of the quality control requirements outlined in the CLIA regs. Once the instructions are cleared by FDA, laboratories can follow the product's quality control labeling instead of following the applicable CLIA requirements. Although IVD manufacturers are not mandated by law to get their quality control labeling cleared by FDA, market forces are likely to prompt many manufacturers of currently available IVDs to request the CLIA review, resulting in a large influx of IVD submissions to FDA. CLIA quality control requirements are being phased in over a two-year period and go into full effect on Sept. 1, 1994. In light of the delay in the publication of the guidance, FDA will have little more than a year at most to review an expected 3,000-9,000 CLIA-related submissions. After Sept. 1, 1994, test labeling that has not been cleared by FDA cannot serve as a substitute for the CLIA quality control requirements. FDA notes that its ability to handle the increased workload "will depend on the actual number and timing of submissions received," and that applications will be evaluated under the "first in, first reviewed" policy. The agency "emphasizes that if manufacturers prepare quality submissions using this and other available guidance, FDA's ability to review applications expeditiously will be greatly enhanced." The agency's capacity to review the additional 510(k)s also will depend on the extent and timing of staffing increases at the clinical laboratory devices division of FDA's Center for Devices and Radiological Health, which will be handling most of the applications. The agency has announced plans to hire up to 50 additional IVD staffers ("The Gray Sheet" Nov. 23, p. 3), but this initiative has been put on hold. As expected, FDA's guidance proposes that in order to gain CLIA clearance, firms should conduct on-site testing to validate quality control instructions. The testing should involve "at least three laboratories," FDA says. The field studies are intended to "demonstrate that QC instructions are valid when QC is performed by testing personnel with the minimum qualifications permitted" under CLIA regulations [emphasis FDA's]. On-site studies would be required for new IVDs and tests for which the manufacturer is requesting a change in its CLIA "complexity" categorization. Manufacturers of previously cleared IVDs would be allowed to "submit photocopies of actual laboratory QC records and summarize the results generated by the laboratory" in lieu of on-site testing. In addition, these manufacturers could supply "supporting peer-reviewed literature references that provide data or information to show the validity of the QC instructions for the device." Manufacturers of marketed IVDs would miss out on the exemption from on-site testing if a number of incremental changes, resulting in a significant modification to the device, have been made since FDA clearance. For these devices, firms also would be required to "identify any modifications to the device in a 510(k) or PMA supplement submitted for CLIA QC validation assessment along with an explanation of these changes." Review of the new submissions will bring the device "up-to-date," FDA explains, adding that "failure to include such information may delay review of a submission." In addition to describing on-site study requirements, the draft document provides manufacturers with guidance on how a number of other CLIA quality control requirements, such as establishment and verification of performance specifications and calibration and control procedures, can be addressed in product labeling. FDA stresses that "QC validation requires more than a showing that QC instructions meet certain applicable requirements" of CLIA. "Manufacturers must demonstrate that their QC instructions are valid for the intended use(s) and complexity level of their device" [emphasis FDA's]. The guidance document includes a checklist of requirements for use by manufacturers and FDA reviewers. The reviewers will use the list "as guidance for an initial review when determining whether a submission is sufficiently complete for an in-depth review," FDA explains. FDA also announces in the draft document that it intends to implement a more stringent review of quality control instructions for all new IVDs regardless of whether a manufacturer requests a CLIA review. Review of IVD submissions will "include a more in-depth QC review" even in cases where "no CLIA review was requested" by the manufacturer, the guidance says. "The submission of deficient QC validation data or the submission of QC validation data that is inconsistent with performance claims may result in the device being found to be 'not substantially equivalent' in the case of a 510(k) or 'not approved' in the case of a PMA," FDA adds. FDA also has responsibility for assigning CLIA complexity categories to new IVDs, 510(k) exempt products and pre-1976 IVDs. The agency also will be considering requests for recategorization. The agency says it will inform manufacturers of categorizations and complexity scores "through routine action correspondence" on the submission. Under CLIA regs, IVDs are placed in one of three regulatory categories. The classification is determined by calculation of a score based on seven criteria, such as ease of use. FDA's plan to report the complexity score fulfills a request by manufacturers that were concerned that it will be difficult to appeal a categorization decision without knowing the test score.