Based upon the needs of the population it serves, there may be instances when laboratories consider the option to modify an FDA-cleared or approved test system. Both the FDA and CLIA allow clinical laboratories to modify their FDA-approved tests, and even to develop their own tests, known as laboratory-developed tests (LDTs), as long as they follow CLIA requirements to validate the performance characteristics of their modified or in-house developed tests[i].
Whenever considering the modification of a test procedure, it is important to be aware that the modified use of a test system defaults the test to the high complexity testing category under CLIA regulations; and as a result, the testing site must meet all applicable CLIA requirements for high complexity testing. These requirements include establishing performance specifications that validate the non-standard laboratory developed methods (LDTs), and that the modified standard methods are fit for the intended use, as well as having personnel qualified to perform high complexity testing.
What does “test system modification” mean?
Test system modification means producing results via test systems not yet approved by the FDA, as well as applying these test results in a way other than that described in the intended use, precautions, limitations, or other sections of the manufacturer’s instructions aka “off-label use”.
Examples of the modification of existing FDA Approved test systems:
· Using instruments / kits for testing that have not received approval from the FDA for use in the United States, even if widely used in other countries.
· Using reagent / instrument combinations that do not have FDA approval. This might mean using reagents from manufacturers different from those of the instrument, and which are not listed by either the instrument or reagent manufacturer as approved for use by either.
· Deviating from manufacturers’ directions for performing the tests.
· “Off-label use”: utilizing the test results in a manner not yet approved by the FDA
Laboratory Developed Tests (LDTs)[ii]
In the past, laboratory developed tests have also been referred to as “in-house” tests. These assays have been developed, evaluated and validated by the laboratory itself. Often, a laboratory will choose to develop and use an LDT because a commercial test is not available to meet their needs. LDTs generally have not been subjected to FDA oversight because these diagnostic tests are only used within home laboratory, never sold to other laboratories or hospitals. Historically, LDTs comprised a relatively small volume of tests that were relatively simple, intended for use in diagnosing rare diseases or to meet the needs of a local patient population.
LDT’s are important to the continued development of personalized medicine, so it is important that in vitro diagnostics are accurate so that patients and health care providers do not seek unnecessary treatments, delay needed treatments, or become exposed to inappropriate therapies[iii].
Even one modified test system will change your laboratory to a testing facility that must meet all applicable CLIA requirements for high-complexity testing
If your laboratory is CLIA waived, and you modify a waived test system: the modified test system must now meet all applicable CLIA requirements for high complexity testing. These include added requirements for proficiency testing (PT), the establishment of performance specifications, quality control (QC), the institution of quality assessment (QA), adherence to specified personnel qualifications, and undergoing biennial onsite inspections. Laboratories with a CLIA Certificate of Waiver (COW) that are using modified test systems will need to upgrade to a CLIA Certificate of Compliance (COC) or a CLIA Certificate of Accreditation (COA), if they continue to use modified test systems.
If your laboratory is a moderate complexity CLIA facility, and you modify a moderate complexity test system, this test system also defaults to the high complexity testing category and will require the modified test system to meet all applicable CLIA requirements for high complexity testing, including the establishment of performance specifications, and adherence to high complexity personnel qualifications. No change required in compliance or accreditation certificates.
Key Considerations for High Complexity Testing:
1. The Establishment of Performance Specifications[iv]
A key requirement of the CLIA regulations for all laboratories that modify an FDA-cleared or approved test system is to establish performance specifications for that test system (i.e., accuracy, precision, analytical sensitivity, analytical specificity including interfering substances, reportable range of test results, reportable range and reference range, as well as any other performance characteristic required for test performance).
The FDA requires that modified or lab developed tests provide target values for test results and provide evidence for the expected ranges as well as information on test limitations and other factors that could generate false results.
The validation results include a statement as to whether the method is fit for the intended use. The needs of the customer define the intended use of the method. If all the data quality objectives are met as indicated by the data collected, the method is considered as validated.
2. Personnel Requirements
The personnel standards for high-complexity laboratories are appropriately more stringent than the requirements for moderate-complexity facilities. There are five positions that must be fulfilled in high-complexity labs:
A. Director;
B. Technical supervisor;
C. General supervisor;
D. Clinical consultant, and
E. Testing personnel.
Note: State and local jurisdictions vary in how they regulate laboratory testing. Some have requirements governing testing, personnel licensure, or phlebotomy. The person overseeing testing should ensure that all state and local requirements are met. When state, local, and federal requirements are not the same, follow the strictest requirement that applies to your site.
Validation standards set by accreditation organizations may also meet or exceed those set by CLIA, including standards regarding evaluation of lab-developed tests. Participating laboratories must meet these standards and criteria as well.
This may mean a significant commitment in resources to fulfill these requirements if the laboratory is not a high complex facility already.
Detailed CLIA personnel requirements for high complexity testing can be found at https://www.mass.gov/eohhs/docs/dph/clinical-lab/clia-lab-qualifications.pdf
The Decision: do you continue using your modified or laboratory developed test procedure or not?
This requires you to perform a cost / benefit analysis, taking into consideration the following:
If the modification of your test procedure changes the complexity of your laboratory from waived or moderate complexity to high complexity, along with all the attendant CLIA requirements for high complexity testing, including additional types of personnel, higher levels of personnel qualifications, more stringent performance specifications, additional quality procedures, and even a new a CLIA classification for the laboratory.
If you are already a high complexity laboratory, consider the cost of establishing additional performance specifications, and the need for added personnel who are qualified to perform high complexity tests.
[i] HHS: Laboratory developed tests do not require FDA approval or authorization. American Hospital Assn. Aug 21, 2020. https://www.aha.org/news/headline/2020-08-21-hhs-laboratory-developed-tests-do-not-require-fda-approval-or#:~:text=In%20an%20effort%20to%20reduce%20regulatory%20burden%2C%20the,of%20Health%20and%20Human%20Services%20announced%20this%20week.
[ii] MLO. Laboratory Developed Tests: what may be coming. October 19, 2012. https://www.mlo-online.com/laboratory-developed-tests-what-may-be-coming.php
[iii] US Food & Drug Administration. Laboratory Developed Tests 2021 https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/Downloads/LDT-and-CLIA_FAQs.pdf
[iv] COLA Laboratory Accreditation Manual. FDA Approved Methods Modified by the Lab, Non-FDA Approved Methods, and Test Methods Developed by the Laboratory In-House (P.90) March 2018. COLA Laboratory Accreditation Manual (8).pdf