IVD Technology
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Originally Published May 2000
REGULATIONS & STANDARDS
FDA takes over CLIA complexity determinations
Joseph L. Hackett
For the past nine years, in accord with the requirements of the Clinical Laboratory Improvement Amendments of 1988 (CLIA), the Centers for Disease Control and Prevention (CDC) has been categorizing IVD test systems into one of three categories based on their complexity (high complexity, moderate complexity, or waived). To date, CDC has categorized approximately 26,000 test systems.
This complexity assignment is of central importance to the CLIA program because it determines which laboratories may purchase and use a particular test. Laboratories certified under the CLIA inspection program to perform high-complexity tests (that is, laboratories that satisfy the maximum personnel, quality control, and proficiency testing requirements) may perform all types of tests. Laboratories certified to perform moderate-complexity tests can use only moderate-complexity and waived tests. Laboratories with a certificate of waiver are exempt from routine inspection and direct regulatory oversight, but are restricted to the use of waived tests only.
CDC's development of the review programs for complexity assignments has generally been regarded as excellent, but having premarket reviews performed by both FDA and CDC has produced redundancy and, in some cases, administrative confusion. In an attempt to streamline the product review process, the Department of Health and Human Services began to consider reassigning the complexity categorization activities from CDC to FDA.
In February 1999, representatives from CDC, FDA, and the Health Care Financing Administration (HCFA) signed a memorandum of agreement to formalize this transfer. The agreement outlined a blueprint for reassignment of the complexity determination program from CDC to FDA and also provided the resources to support it. The intent of the three agencies was to transfer administrative responsibility for the program without compromising the procedures or processes previously developed by CDC.
Transfer Team Formed
In preparation for FDA to take on the task of determining CLIA complexity status, the agency formed a CLIA complexity transfer team consisting of several members from each review branch. Beginning in July, members of the team visited CDC for CLIA training and began working with CDC complexity reviewers on product submissions. As part of the transfer, CDC provided FDA with all of its records, including the CLIA complexity database in electronic format, copies of relevant Federal Register notices, and other related documents.
The CLIA complexity team developed a comprehensive educational and quality control program to support transfer of the complexity review system to FDA. In addition, FDA databases are currently being modified to allow incorporation of CLIA complexity elements into the central FDA system. The agency is now developing both administrative and scientific guidances to help manufacturers obtain more timely complexity decisions. The management objective is to merge the complexity review process as much as possible into the ongoing FDA review process. This will allow "one-stop shopping" for the manufacturer and maintain administrative consistency in the work processes.
The transfer provides a mechanism and opportunity for FDA to make complexity determination a component of its ongoing routine review work, to be completed concurrently with its premarketing review. FDA expects this simultaneous review process to be more timely than the previous procedure—CDC had been performing the complexity determinations only after FDA had completed its review.
In August 1999, FDA issued a letter to manufacturers of IVD devices notifying them of the transfer in responsibilities. In December 1999, HCFA, CDC, and FDA jointly published a notice of the transfer in the Federal Register.1
The transition from CDC to FDA for CLIA complexity determinations is now official and complete. FDA will continue to work cooperatively with CDC to ensure that consistency with past review practices is maintained.
CLIA complexity reviews are now performed by the Division of Clinical Laboratory Devices (DCLD), which is in the Office of Device Evaluation at FDA's Center for Devices and Radiological Health. DCLD will take the administrative lead for all CLIA complexity determinations, including those used to classify products approved by FDA's Center for Biological Evaluation and Research (CBER).
Criteria
As CDC did, FDA will make determinations of high or moderate complexity according to the following seven criteria described in the CLIA regulation:2
- Level of knowledge (high, moderate, or low) required to perform the test.
- The level of training and experience required to perform the test.
- Reagents and materials preparation.
- Characteristics of the operational steps.
- Calibration, quality control, and proficiency testing materials.
- Test system troubleshooting and proficiency testing materials.
- Interpretation and judgment.
Tests seeking to attain waived status undergo a more complex pattern of oversight than high or moderate complexity tests because the CLIA statute requires such laboratory examinations to be simple and highly accurate, with an insignificant risk of erroneous results. There are three routes for obtaining waived designation. The first is based on the CLIA statute, which provides a list of IVD tests that can be automatically considered waived complexity because of their design simplicity and history of use.3 Such tests include the following:
- Dipstick or tablet reagent urinalysis (nonautomated) for bilirubin, glucose, hemoglobin, ketones, leukocytes, nitrite, acidity, specific gravity, urobilinogen, and protein.
- Fecal occult blood.
- Ovulation tests (visual color comparison tests for luteinizing hormone).
- Urine pregnancy tests (visual color comparison tests).
- Erythrocyte sedimentation rate (nonautomated).
- Hemoglobin (copper sulfate method).
- Hemoglobin by single-analyte instruments giving direct measurement and readout.
- Blood glucose monitoring devices cleared by FDA for home use.
- Spun microhematocrits.
The final route to waived complexity is by formal review. The criteria applied to this review process were outlined in a proposed regulation published in the Federal Register.4 To attain waived complexity by this route, a test must satisfy the following requirements:
- Be simple and foolproof in design.
- Require no sample manipulation or analytical interpretation.
- Be able to resist environmental conditions.
- Have highly accurate and precise performance characteristics in the hands of nonprofessional users.
- Have user friendly (seventh-grade reading level) instructions for use.
Conclusion
To help companies understand the requirements for a CLIA waiver, FDA plans to publish a checklist explaining the elements outlined in the Federal Register notice. The agency will also formally review protocols for clinical studies to ensure that they will generate the data required for a device to attain waived status.
FDA has established a CLIA home page with links to the CDC and the HCFA home pages. Continuing CDC's practice, FDA complexity determinations will be made available on this site. For more information about the CLIA complexity determination transfer, Clara Sliva can be reached by e-mail at clia@cdrh.fda.gov, by phone at 301/827-0496, and by fax at 301/827-1401.
References
1. Federal Register, 64 FR:73561, December 30, 1999.
2. Code of Federal Regulations, 42 CFR 493.17.
3. 42 CFR 493.15(c).
4. Federal Register, 60 FR:47534, September 13, 1995.
Joseph L. Hackett is associate director of FDA's Division of Clinical Laboratory Devices and a member of the IVD Technology editorial advisory board.
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