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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

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What are Laboratory Developed tests? Do we use them in Coagulation? What is their significance for your laboratory? And what is the FDA saying?

Okay, think of the old days, you could use whatever you wanted, any mix of reagents, for factor assays, platelet aggregations, and remember Euglobulin Clot Lysis? So, the question is, did these tests provide safe and effective care, or did we do harm? I would rather believe we wanted to provide the most reliable, robust and reproducible testing possible.

What is an LDT? LDTs are in vitro diagnostic products (IVDs) that are intended for clinical use and are designed, manufactured, and used within a single clinical laboratory which meets certain laboratory requirements. Specifically, such laboratoriesy must be certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and meet the regulatory requirements under CLIA to perform high complexity testing.⁽¹⁾

The FDA in the past has not exercised any discretion over most LDT, however the risks with most modern LDTs have become much greater thant those of a decade ago. With the evolution of molecular diagnostics, mass spec and viscoelastic testing, samples are being tested on a diverse and larger group of patients. Previously, testing may have been lower risk, and used only for a specialized need for a local patient population.⁽¹⁾

What is the FDA saying?

In September of 2023 the FDA announced a proposed rule to ensure the safety and effectiveness of these tests. It stated that even when the manufacturer of an LDT is a laboratory (as opposed to a manufacturer) the FDA is proposing a policy under which it intends to provide greater oversight of LDTs.⁽²⁾ Over the years there has been a series of case studies that involve inaccurate, unsafe, ineffective, or poor quality LDT’s that have caused patient harm.⁽²⁾

When a manufacturer submits a test to the FDA it is supported by clinical trial data, bench testing results, as well as product manufacturing and design characteristics. The FDA reviews the data relevant to analytical validity, clinical validity and safety. Thus LDT,s that are supported by sound science would remain on the market, but those who cannot meet those criteria would be withdrawn from the market.⁽²⁾

Most recently The FDA has released the Verifying Accurate Leading-edge IVCT Development Act (VALID). It was hoped that this could provide some type of guardrails on LDTs, but it was not passed by Congress. The FDA released its own proposed regulations based on a statute from 1976 which would allow them to oversee LDT without congressional action and without updates laws that address testing issues laboratories face today.⁽³⁾ This rule does not allow things like a technical certification which instead of having a FDA review could be used when the technology has already been approved by the submitted laboratory or to down classify tests that have a lower risk based on mitigating factors such as being monitored by proficiency testing or evidence in peer reviewed literature. The discussion now is how the rule could be changed to better support laboratories and allow for continued high quality innovation, and high-quality testing. It is important not to stifle innovation and provide patients with test results that are not commercially available. However, an LDT may be able to fill that gap.⁽³⁾

Why Do Laboratories Perform LDTs?

Laboratories develop LDTs, to meet unmet analytical or clinical needs using tests that are not FDA cleared or commercially available, or that are is not compatible with instruments owned by the laboratory or doesn't meet the performance goals desired for clinical care in a particular setting. Most clinical laboratories adhere to manufacturer FDA cleared testing and try to choose companies that offer the widest range of testing, and it may not be possible to put an LDT on certain analyzers. Most laboratories that use LDT's are larger academic centers and reference laboratories.⁽⁴⁾

One of the issues with LDT’s is how to charge for them, since they require a CPT code (Current Procedural Terminology). These codes are for medical procedures and laboratory tests, are defined by the American Medical Association (AMA), LDTs and IVD tests must have designated CPT codes in order for laboratories to bill and receive payment for performing the tests and to report the results for patient care. These codes are also used along with ICD-10 codes, which identify diagnosed medical conditions and indicate why particular tests are necessary. An existing CPT code may exist related to the LDT’s technology however, if there is no applicable CPT code, it may be launched with a miscellaneous code, and the laboratory can apply to the AMA for a new code.⁽⁵⁾ The requirements include that the test must improve patient outcomes (such as better treatment, shorter length of stay) and be published in a peer reviewed journal. This process may take up to two years.

What does it mean when you modify a FDA approved test, or develop your own LDT. CLIA allows laboratories to do this as long as they follow the requirements to validate the performance characteristics. However, this "off label" use now makes the test a high complexity test and the testing site must have the qualified personnel to conduct the testing. This includes if the laboratory is CLIA waived and modifies a test system. The testing site must meet the applicable CLIA requirements for high complexity testing including establishing performance specifications that validate the non standard LDT and that the modified standard methods are fit for the intended use population.⁽⁵⁾

What is considered a modification? This can relate to producing results on test systems not yet approved by the FDA or applying test results in ways other than described in the manufacturer's instructions and or intended use.⁽⁵⁾

Modication 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 ⁽⁵⁾

The International Council for Standardization in Hematology (ICSH) recommends:

• Wherever possible, medical laboratories should select procedures which have been validated for their intended use.
• If a test system has not received the relevant regulatory approval, it will require validation locally, which is defined as the provision of objective evidence through a defined process that a test system meets requirements for an intended use.⁽⁷⁾

Defining what constitutes sufficient degree of local modification to require new validation may not be straightforward and may be interpreted differently by different regulatory or accreditation bodies. Standard methods used outside their intended scope and validated methods which have been subsequently modified are also considered LDTs. This is particularly relevant for laboratories testing pediatric samples with test systems which have not received regulatory approval for use in paediatric samples. The use of a reagent/kit on another manufacturer's analyser, when that particular reagent/analyser combination does not have regulatory approval, is also considered an LDT by most regulatory authorities.⁽⁷⁾

Deviation from the manufacturer's IFU for a test system will require validation as a LDT.
How does this relate to coagulation testing:

1. Modification of an existing protocol: Example Modifying dilutions for factor assays, modifying calibration curves, modifying incubation periods, modifying the diluent.
2. Introducing a new reagent on an analyzer: using a different PT/aPTT reagent, using a different factor deficient plasma, using a different calibrator, modifying anti-Xa assays for DOACs, using different reagents for platelet aggregation.
3. Introducing a new methodology on a platform not supplied by the manufacturer: Chromogenic assays, Ecarin based assay, Protein S activity, DOAC testing kit FDA approved for a different analyzer.⁽⁷⁾
4. For viscoelastic testing LDTs require extra runs and validations. There are no FDA approved viscoelastic assays for OB-GYN, therefore it is an LDT. However, how do you prevent doctors from sending a test to the laboratory? You run the tests that are sent to the laboratory. It is the laboratory director who ensures the clinician understands the limitations of the results. Viscoelastic testing can be used to guide blood transfusions but not to diagnosis von Willebrand disease. It is important for clinicians to understand the limitation of testing and how LDT's can be used in patient care.(8)

CLIA regulations require 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).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 validated.⁽⁶⁾

It is important to be aware of state regulatory requirements. Any laboratory that conducts testing on patients from New York State must submit an LDT validation to the state in order to be able to use it. This includes all of the performance specifications as well as a risk assessment, supporting tests for diagnosis and peer-reviewed literature.

Conclusion:

Deciding to set up an LDT is a commitment. The laboratory must be able to comply with all of the validations required as well as ensuring the test is robust and results will reflect a patients' clinical condition. You can't just add or change reagents on an FDA approved test without demonstrating that it works and having the data that proves it performs correctly. Proceed with caution, and for all we know, it may become more difficult to bring these into the coagulation laboratory.

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References:

1. January 18, 2024: FDA and CMS Issue Joint Statement on LDTs: Americans Deserve Accurate and Reliable Diagnostic Tests, Wherever They Are Made. https://www.fda.gov/medical-devices/medical-devices-news-and-events/fda-and-cms-americans-deserve-accurate-and-reliable-diagnostic-tests-wherever-they-are-made
2. Medical Devices; Laboratory Developed Tests, A Proposed Rule by the Food and Drug Administration on 10/03/2023 https://www.federalregister.gov/documents/2023/10/03/2023-21662/medical-devices-laboratory-developed-tests
3. Karcher, D., Anticipating FDA regulations, CAP Today, January 2024
4. Genzen JR. Regulation of Laboratory-Developed Tests. Am J Clin Pathol. 2019 Jul 5;152(2):122-131. doi: 10.1093/ajcp/aqz096. PMID: 31242284; PMCID: PMC6610067.
5. Reimbursement for laboratory-developed and in vitro diagnostic tests, Arizona State University, https://assets.thermofisher.com/TFS-Assets/GSD/Reference-Materials/reimbursement-for-molecular-diagnostic-tests-paper.pdf
6. Gardiner C, Coleman R, de Maat MPM, et al. International Council for Standardization in Haematology (ICSH) laboratory guidance for the evaluation of haemostasis analyser-reagent test systems. Part 1: Instrument-specific issues and commonly used coagulation screening tests. Int J Lab Hematol. 2021; 43: 169–183.
7. Volod, O, Panelists on viscoelastic testing, CAP today, January 2024.



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