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


Everyone likes to open and play with new things, to learn how they work and what you can make them do- however, when you learn that your laboratory is getting a new coagulation analyzer most reactions are a little different. Emotions can run from excitement to dread. Where does one start?

Most laboratorians have lived through several generation of analyzers- I remember tilt tubes- try validating that. There are lots of checklists, guidance documents and procedures from the manufacturer to assist in this monumental task. Even before you get the analyzer it is important to understand its footprint, what are the electrical requirements, does it pass security requirement of your IT department? Let's not forget temperature requirements and where will with put the analyzer is it freestanding giant or does it need a table?

Of course everyone knows we need to perform method correlation to your old analyzer (old analyzer is truth), correlation between your new coagulation analyzers, reference interval, precision, accuracy, quality control ranges, therapeutic ranges; sensitivity of reagents, linearity, calibration, calibration verification, verification of analyzer and computer set-up; evaluation of reports; verification of implementation readiness of laboratory staff and clinicians; writing new procedures (1), and also do not forget the laboratory on line manual. Wait, what about setting up the middleware, if the analyzer is on a line and hooked up to a centrifuge will you be getting platelet poor plasma? Setting up the QC on the analyzer? Then, who crunches the data, are you validating or verifying your reference intervals? Who decides if the results are acceptable and who needs to do the final signoff? And after all of that... You need to move out your old analyzer and put this new one in its place, that means you need to ensure it is working the same so, wait for it, yep you need to conduct some type of validation. Make sure you have outstanding validation records because when you get inspected, they will for sure look at this entire process. I am pretty sure that most people that work in the coagulation laboratory know all of this- and know they need to comply with national, federal and state regulations and using guidelines provided by CLSI, CLIA, CAP, ISLH and ICSH. So that is not the focus of this blog, this will look at what is less obvious when bringing up a new coagulation analyzer in particular in the special coagulation laboratory.

 

THEN and NOW:

Special coagulation laboratories were notorious for using any reagents on any analyzer in any combination. That is, not the manufacturer's FDA approved reagent/ instrument combination. For example, a factor assay might include reagent from Siemens, on a STAGO analyzer with deficient plasma from George King using a standard from Precision Biologics. Try to troubleshoot that! When you have a problem who do you contact? Instrument manufacturer? Reagent manufacturer? Now as opposed to then there is the added issue of it being a test that has been modified which meets the qualifications of a laboratory developed test (LDT).

What is an LDT? They can be non-FDA cleared or approved tests that are developed and validated by the laboratory offering the assay. Tests that include a combination of reagents and/or kits prepared by the laboratory, labeled as Analyte Specific Reagents (ASR), Research Use Only (RUO), or Investigational Use Only (IUO). They can also be modified FDA-approved tests where there has been a change in intended use. For example, a change in the specimen type; the type of analysis (e.g., qualitative vs. quantitative); the purpose of the assay (e.g., screening, diagnosis, prognosis, monitoring, and /or confirmation); or the target population(s). While the laboratory is using all FDA approved reagents for this factor assay, the combination has not been approved, so it is a modification or an LDT. (2)

 

Why do we use an LDT?

Why would a laboratory do this? The laboratory needs to determine what assay best suits the needs of their laboratory. For example, let's say you are a hemophilia center, you need an aPTT reagent that has a good sensitivity to both FVIII and FIX, well what if your manufacturer's reagent is insensitive to those factors, you may choose to use another manufacturers reagent to achieve better sensitivity. What about using fresh frozen plasma versus lyophilized plasma which is offered by the manufacturer? Maybe there is too much variation in the reconstitution of the deficient plasma, or you need a fast turn around time for your factor assays and you can't wait for a 30 minute reconstitution, therefore you may provide better care using a frozen deficient plasma. What about a different standard? Maybe the manufacturer standard has a much shorter measuring range, and you can extend it using another product. Does that answer your question? It is much easier to bring up a test that has been cleared by the FDA since most of the sensitivity and specificity, interference and stability testing are performed by the manufacturer. (3)

Challenges with LDTs can include the standardization or harmonization with other testing platforms and the increased validation and QA requirements.(3) Based on state regulatory requirements, these tests may have to be approved by the DOH including a risk assessment that determines if a clinician acts on the test result and it is incorrect, are there other tests that can provide supporting information that can help to minimize the patients' risk. There also may be issues when submitting proficiency testing results and not having a peer group for comparison.

Another reason to modify an FDA cleared kit is if they fail to meet clinical needs, in particular when the analytical measuring range needs to be extended.(3) If you look at a Protein C assay, many of the standards only go to 100% and the normal range exceeds that limit. If the manufacturers kit is not cleared for dilutions or measuring above the AMR, the laboratory will modify the test, either by adding a dilution on the analyzer, or changing the standard, both which require additional validation. The dilution has to be validated by comparing manual dilutions and precision studies also should be performed to make sure that there aren't dilution errors. The same applies if you need to lower the limit of detection and possibly detect samples below the standard curve. If you need to add a lower point to the curve, it needs to be validated.

 

FDA Cleared Test from one manufacturer put on another analyzer

Now what? This may have been a test that was provided by your previous reagent/instrument combination, but your new analyzer doesn't have a kit for this particular test, what can you do? First, you need to determine if there is an application for the test on the new analyzer, or you will have to figure that one out. The manufacturer of the analyzer may be able to help with settings, but after that the ball is in your court. You need to conduct a very through validation of this test. All of the normal validation must be performed, as well as a stability study of their reagent on the new analyzer as well as carry-over studies. In New York State, or in any state that provides testing to New York State as a reference laboratory, they need to submit the test to the New York State DOH which includes a risk assessment, literature support in addition to appropriate validation studies. You need to make sure that the reagent performs the same on this analyzer as the instrument/reagent combination that had FDA approval. There should be sufficient method correlation samples to be able to evaluate how the test compares to truth.

 

CONCLUSION:

Besides the obvious studies that need to be performed when validating an analyzer, there are also situations when the validation is not so obvious. It may require more extensive validation and quality assurance. The most important aspect is to ensure that the test will provide the best information to the clinicians to diagnosis and treat their patients. Now that should be very obvious!



REFERENCES:

  1. Validation of Hemostasis Assays, Analyzers, and Reagents https://oncohemakey.com/validation-of-hemostasis-assays-analyzers-and-reagents/
  2. Ryan, MP., Oversight of Clinical Laboratories in New York State, Division of Laboratory Quality Certification Wadsworth Center New York State Department of Health, March 2018, https://www.health.ny.gov/commissioner/grand_rounds/tick_borne_diseases/docs/ryan.pdf
  3. Snozek, C., FDA-Cleared versus Laboratory-Developed Tests: Why Start from Scratch When Kits Are Available? The Journal of Applied Laboratory Medicine, Volume 2, Issue 1, 1 July 2017, Pages 130–131.