By Rebecca Mayo, J.D.
A Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver application for manufacturers of in vitro diagnostic devices may be obtained for tests that are simple laboratory examinations and procedures that have an insignificant risk of an erroneous result. The FDA has issued a new draft guidance to outline recommended approaches for establishing the safety and effectiveness or substantial equivalence of a candidate test in the hands of trained operators and demonstrating the test is simple to perform and has an insignificant risk of erroneous results in the hands of untrained operators in CLIA-waived settings (Notice, 83 FR 61391, November 29, 2018).
Study design options. The guidance discusses four study design options to provide a variety of study design options that can be used to demonstrate that a candidate tests meets the CLIA statutory criteria for waiver. The first option is a comparison study in which the results of the candidate test in the hands of untrained operators are compared to the results of the candidate test in the hands of trained operators. The FDA believes this will be the appropriate option for the majority of candidate tests since premarket performance studies generally include data sets establishing the accuracy of a candidate test in the hands of the trained operators. The second is a comparison study which compares the performance of the candidate test between untrained and train operators instead of comparing performance between "new" and "old" systems.
The third is an alternative to comparison studies in which flex and human factors engineering studies may provide sufficient assurance that the change in user populations and environment of use between non-waived and waived settings will not adversely impact the results provided by the candidate test. These three options are appropriate when sufficient valid scientific evidence can be derived from the combination of the prior performance studies and the new studies to demonstrate that a candidate test meets the CLIA statutory criteria for waiver. The final option is a comparison study in which the results of the candidate test in the hands of untrained operators are directly compared to the results of an appropriate comparative method in the hands of trained operators. This is useful for Dual Submission where a 510(k) and CLIA waiver are being sought concurrently.
Study design considerations. Applicants should evaluate test performance in setting designed to replicate the actual CLIA-waived settings, patients/samples, and test operators. The study should be conducted at a minimum of three sites that are in different demographic and geographic locations. The study should include 1-3 untrained operators at each site and at least 9 untrained operators across all sites. Trained operators should meet the qualifications to perform moderate complexity testing and have previous training in performing the candidate test or the comparative method. Untrained operators should only be provided with the Quick Reference Instruction sheet with no additional instructions, no opportunity to ask other participants.
Specimens should be obtained from subjects who meet inclusion and exclusion criteria corresponding to the intended use population of the test. Samples should be collected from consecutive patients over one month. Each sample should be split in to two parts to allow testing by an untrained operator on one part and testing by a trained operator on the other. If the sample cannot be split, then a second sample from the same patient should be collected within a suitable time interval.
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