Wednesday, May 22, 2019

by IRWIN Z. ROTHENBERG, MBA, MS, CLS(ASCP) 

There may be circumstances when laboratories consider the option to modify an FDA-cleared or approved test system. These may be due to the specific needs of the population served, or based on cost/benefit analyses of instrumentation and reagent use; or based on the logistics of in-house testing capabilities.  CLIA allows 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 the requirements to validate the performance characteristics of their modified or in-house developed tests.

However, it is important to realize when considering modification of a test procedure 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 that the LDTs and the modified standard methods are fit for the intended use and that the lab has personnel qualified to perform high complexity testing. Thus, decisions to modify test procedures or use must be made with full awareness of the consequences for the laboratory operation.

What does test system “modification” mean?

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.  

Modifications to existing FDA-approved test systems include:

1. 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.

1. 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.

1. Deviating from manufacturers’ directions for performing the tests.

1. “Off-label use”:  utilizing the test in a manner not yet approved by the FDA. 

A special note about “Off-label Use” of waived blood glucose monitoring systems:

Using a waived blood glucose monitoring system  (BGMS)  to test a patient whose hematocrit or oxygenation level is above or below the range indicated in the manufacturer’s instructions would be an example of an “off- label use” of this system.  Results of blood glucose testing in this situation may lead to clinical interventions that could cause patient harm.  If the patient’s hematocrit and oxygenation level are within the manufacturer’s stated limits, then performing a glucose test using the waived glucose monitoring system would not be considered off-label testing and the test system would still be considered waived.

(New) Laboratory Developed Tests (LDTs)

In the past, these have also been referred to as “in-house” tests. These are tests that 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 never sold to other laboratories or hospitals. Historically, LDTs comprised a relatively small volume of testing intended for use in diagnosing rare diseases or to meet the specific needs of a local patient population. 

There can be several reasons why a commercial test has not been developed for a particular analyte or disease of interest. For example, many LDTs are genetic tests developed for rare diseases. These are also diseases affecting only a small subset of the population, thus reducing the incentive for a manufacturer to develop a commercial version because the market for such a product would be small, without a potential decent return on investment. 

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, the establishment of Performance Specifications, Quality Control, Quality Assessment, and adherence to high complexity personnel qualifications. 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; this includes required biennial on-site inspections.     

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 in compliance or accreditation certificates would be needed.

High Complexity Testing requirements include:

1. The Establishment of Performance Specifications

A key requirement of the CLIA regulations for all laboratories that modify an FDA-cleared or approved test system is to establish (validate) performance specifications for that test system (i.e., accuracy, precision, analytical sensitivity, analytical specificity including interfering substances, reportable range of test results, reference intervals and 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.

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.

1. More Stringent 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 filled in high-complexity labs: 

A. Director; 

B. Technical supervisor; 

C. General supervisor; 

D. Clinical consultant, and 

E. Testing personnel.

A significant commitment in resources may be needed 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 http://www.mass.gov/eohhs/docs/dph/clinical-lab/clia-lab-qualifications.pdf

The decision: whether to 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:

Does the modification of your test procedure change the complexity of your laboratory from waived or moderate complexity to high complexity? Is it worth 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 control 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.

IRWIN Z. ROTHENBERG, MBA, MS, CLS(ASCP) 

Irwin Z. Rothenberg is a Technical Writer/Quality Advisor for COLA’s Educational subsidiary, COLA Resources, Inc. (CRI), a leader in online continuing education for physicians, laboratory personnel, and allied health professionals.  CRI offers continuing education through online courses, informational products in both electronic and hard copy form, webinars on cutting-edge technology and regulatory issues, and CRI on-site Symposia for Clinical Laboratories, providing live educational sessions and interactive workshops with leading industry organizations. For more information, visit their website at www.criedu.org or call 1-800-981-9883.