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Coagulation Corner


Saturday, February 4, 2017

Coagulation and Laboratory
Developed Tests

Written By Donna Castellone, MS, MT (ASCP) SH | LinkedIn

Laboratory Developed Test (LDTs) are tests that laboratories develop according to their own procedures. Many of these are known as "in house tests: and have no manufacturer kit. Why are these so important? Well there are many tests that are performed that if they had to go through FDA approval, there return on investment for a company would not be beneficial. Getting a submission through the FDA is very labor intensive and expensive. Also, a new test doesn't have a predicate that it can be compared to, this further complicates the submission. When you think about it all tests were LDT's and created for an unmet need. However, there are also modifications to tests. These include:

  • 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 (this may include running a body fluid, when it is only approved for serum).

The regulatory framework for these tests have been covered by CLIA 88, however the FDA has expressed an interest in regulating LDTs as medical devices. This would impact things like drug detection by mass spec, or DNA sequencing assays or newborn screening.

What about coagulation assays? In house tests are Bethesda assays, or Euglobulin Clot Lysis, Factor XIII, Platelet aggregation- lumi aggregation- Multimer assays for von Willebrand disease-to mention a few. What about the assays that are modified, such as using different deficient plasma for factor assays other than the manufacturer cleared on the analyzer? What if you change the buffer? What about running a different manufacturer's kit on your analyzer? Now the plot thickens.

The FDA published a draft guideline in 2014, which has not been finalized. On January 13, 2017 they released a discussion paper on LDT's stating that they would not issue a final guideline until there could be more public discussion.
Discussion Paper on Laboratory Developed Tests (LDTs) January 13, 2017

I don't think that the FDA realized the amount of tests that would be involved and the review process as well as the impact on patient care. If you are a hemophilia center, and it was decided that Bethesda testing- which is a high complexity test, had to stop testing until it was reviewed would have serious impact on the detection of formation of inhibitors in these patients. The basis of their review is risk based. At present, the oversite for these tests come from CLIA, or are enforced by the state. New York State has strict validation procedures for LDT's and how they can be implemented and used in the laboratory.

Let's look at this from the FDA perspective- they have a responsibility to the public to ensure that tests are valid and provide reliable information to provide clinicians with information to help diagnose and treat disorders. The public, without understanding a laboratory validation procedure may see LDTs as unreliable analysis.

The discordance comes from consumer groups, IVD companies, pharma, insurance companies supporting the LDT oversight versus the laboratory community including hospital laboratories, academic centers, laboratory professional societies all express opposition to the FDA oversight approach. The basis of the concern includes slowing innovation, increased cost and decreased patient access.

Tests would be placed in categories of low, moderate and high risk: low risk; Little potential for injury, adjunctive tests identifying one of many characteristics of a tissue or cell with little clinical impact; moderate risk- potential non-serious injury, relatively easy to detect false result-tests where multiple findings used to direct Rx; disease monitoring tests and high risk: Serious injury if incorrect, difficult to detect false result-companion diagnostics, cancer diagnosis, serious communicable diseases.

The discussion paper proposes a complementary approach supported by CLIA, CMS, FDA and members of the laboratory community. These discussions have been going on for a long time- since 2010 and still is complicated trying to balance opinions and outcomes as to what is best for patient care.

I think there has to be a balance, many tests, are well established, with supporting data on patient outcomes despite the fact that there are no manufacturer's kits. Results for the mentioned coagulation tests provide clinicians will tools that are used in the management of patients with coagulation disorders. The introduction of the direct oral anticoagulants are an example of laboratories struggling with how to provide information to clinicians on the detection of these drugs. The FDA allowed these drugs to be introduced without anyway for the laboratory to monitor, or detect them. One of the important things to remember is that when clinical trials are conducted on drugs, it is important for patients to conform to set parameters and not have comorbidities that may mask the impact of that drug. While in the real world, patients are more complicated, and really do require monitoring, in particular when there were no reversal agents.

I have been in the laboratory for 40 years, I have done manual tilt tubes, bleeding times, platelet retraction, I have done C14 serotonin release assays for HIT when that was the only option. There were gels that were performed for von Willebrand detection and Protein C. All of these LDT's lead to the development of assays that have been FDA approved. Of course we know more, we have more resources, and for sure we have a ton more regulations, some are very good, others take so much time away from testing, that laboratories get frustrated and make the decision to drop the test or send it out, which may not be in the best interest of the patient.

I am hoping that all of the agencies will remember that most labs conduct due diligence when implementing tests to ensure that outcomes reflect the patents clinician picture. I am also glad that they are there for the handful that don't!





 




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