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.  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.

It is important  however, to realize when considering modification of a test procedure,  that the modified use of a test system (“off-label use”)  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 non-standard laboratory developed methods (LDTs), and 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?

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.

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

(New) Laboratory Developed Tests (LDTs)[i]

In the past, laboratory developed tests have also been referred to as “in-house” tests. These are assays 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 tests that were relatively simple, intended for use in diagnosing rare diseases or to meet the 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 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. Or, an existing test may not apply to a particular subpopulation from which the lab has patients.

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 in compliance or accreditation certificates.

A special note about “Off-label Use” of waived tests[ii]:

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.

Key Considerations for High Complexity Testing:

  1. The Establishment of Performance Specifications[iii]

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, reference intervals and any other performance characteristic required for test performance).

  1. Accuracy and Precision

Statistical measurements of accuracy and precision reveal a lab test’s basic reliability. These terms, which describe sources of variability, are not interchangeable. A test method can be precise (reliable reproducibility) without being accurate (measuring what it is supposed to measure and its true value) or vice versa.

  1. Sensitivity and Specificity

The tests that a provider chooses in order to diagnose or monitor a medical condition are based on their inherent ability to distinguish whether you have the condition or do not have the condition. Depending on the symptoms and medical history, a provider will order tests to confirm a condition (tests with high sensitivity) or tests to rule out the condition (tests with high specificity).

Other attributes and data quality objectives include, but are not limited to[iv]:

  1. detection limit,
  2. limit of quantitation,
  3. linearity,
  4. reference range

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. 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:

  1. Director;
  2. Technical supervisor;
  3. General supervisor;
  4. Clinical consultant, and
  5. Testing personnel.

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 http://www.mass.gov/eohhs/docs/dph/clinical-lab/clia-lab-qualifications.pdf

The Decision

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:

If 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.

Originally Published in AAFP POL Insights

Resources:
[i] MLO. Laboratory Developed Tests: what may be coming. October 19, 2012.
http://www.mlo-online.com/laboratory-developed-tests-what-may-be-coming.php
[ii] Munley, E, Leading Age. CMS Clarifies Off-Label Use of Waived Blood Glucose Monitoring Systems in Healthcare Facilities. December 11, 2014.  https://www.leadingage.org/CMS_Clarifies_Off_Label_Waived_Blood_Glucose_Monitoring_Systems_in_Facilities.aspx
[iii] Lab Tests Online.  AACC. Laboratory Developed Tests(LDTs) April 14, 2011
https://labtestsonline.org/understanding/features/ldt
[iv] FDA. Science and Research.  Volume I – 5.4 Test Methods and Method Validation.. http://www.fda.gov/ScienceResearch/FieldScience/ucm171818.htm

About The Author

Irwin is Quality Advisor for COLA Resources, Inc (CRI®). where he provides a wide range of technical assistance to laboratories across the country. He previously held the position of Executive Director at Community Response, a community-based organization that provides HIV/AIDS support services in metropolitan Chicago. Prior to that position he was the Laboratory Manager of Crittenden Memorial Hospital, West Memphis, AR. He holds a Bachelor of Science degree from Brooklyn College, a Medical Technology degree from Good Samaritan School of Medical Technology, a Master of Science degree from Colorado State University, and a Master of Business Administration degree from the University of Memphis.