Local INR Calibration: Still a Dream

Local INR Calibration: Still a Dream
Mar 18, 2010 3:28pm

From Julie Tange, Developmental Technologist at  Mayo Medical Laboratories:

Hi George, our lab recently brought up calibration of the INR/ISI again. I know this was a hot topic a couple of years ago and CLSI came up with a document providing guidelines. I had heard at that time that a couple of companies were developing calibrator sets to be sold commercially. However, it seems that the subject has fallen into the background and I haven’t seen any product being sold to promote INR/ISI calibration. Yes, Beckman has their verification and calibration set, but that is only for their instruments. What should I use for a “non-paired” reagent-instrument set? Thanks! Julie
Hi, Julie nice to “hear” from you. I am sorry to tell you that Beckman-Coulter, Inc has the only FDA-cleared local INR calibration kit on the market, and that, as you said, it is only cleared for use with their instruments and reagents. This is a source of frustration for coagulation laboratories everywhere, especially as local calibration is routine in Europe.

It is true that CLSI has a guideline, H54-A: Procedures for Validation of INR and Local Calibration of PT/INR Systems; Approved Guideline, chaired by Dorothy Adcock-Funk, MD. Here is the CLSI summary description:

This document describes the use of certified plasmas to enhance performance of the prothrombin time (PT )/International Normalized Ratio (INR ) system test; reviews limitations of the INR systems that may occur when a manufacturer-determined ISI is used without local verification or calibration; and provides a rationale for performing local ISI verification with recommendations as to when PT calibration may be indicated.

Two companies (that I know of) have brought kits with acceptable technical parameters to the FDA and all have failed to clear. It seems that for now, we have to continue to rely solely on manufacturers’ ISI. Geo.

2 Comments

From Julie Tange, Developmental Technologist at  Mayo Medical Laboratories:

Hi George, our lab recently brought up calibration of the INR/ISI again. I know this was a hot topic a couple of years ago and CLSI came up with a document providing guidelines. I had heard at that time that a couple of companies were developing calibrator sets to be sold commercially. However, it seems that the subject has fallen into the background and I haven’t seen any product being sold to promote INR/ISI calibration. Yes, Beckman has their verification and calibration set, but that is only for their instruments. What should I use for a “non-paired” reagent-instrument set? Thanks! Julie
Hi, Julie nice to “hear” from you. I am sorry to tell you that Beckman-Coulter, Inc has the only FDA-cleared local INR calibration kit on the market, and that, as you said, it is only cleared for use with their instruments and reagents. This is a source of frustration for coagulation laboratories everywhere, especially as local calibration is routine in Europe.

It is true that CLSI has a guideline, H54-A: Procedures for Validation of INR and Local Calibration of PT/INR Systems; Approved Guideline, chaired by Dorothy Adcock-Funk, MD. Here is the CLSI summary description:

This document describes the use of certified plasmas to enhance performance of the prothrombin time (PT )/International Normalized Ratio (INR ) system test; reviews limitations of the INR systems that may occur when a manufacturer-determined ISI is used without local verification or calibration; and provides a rationale for performing local ISI verification with recommendations as to when PT calibration may be indicated.

Two companies (that I know of) have brought kits with acceptable technical parameters to the FDA and all have failed to clear. It seems that for now, we have to continue to rely solely on manufacturers’ ISI. Geo.

By Steveduff
Mar 22, 2010 4:54am
George & Julie: Precision BioLogic had the great pleasure of working with Dr. Dorothy Adcock and Marilyn Johnston in a multi-center exercise to assess the efficacy of a frozen plasma-based local ISI calibration system. We abandoned commercialization due to regulatory obstacles (perhaps we should re-visit? I'd be interested in hearing from FF visitors on this) Results were published, and the abstract follows:

Thromb Haemost. 2002 Jan;87(1):74-9.

Evaluation of frozen plasma calibrants for enhanced standardization of the international normalized ratio (INR): a multi-center study.
Adcock DM, Johnston M.

Local ISI calibration has been proposed to improve INR accuracy and inter-laboratory precision. We evaluated the affect of local PT calibration on INR precision and accuracy using six levels of frozen plasma calibrants prepared and pooled from normal donors and patients stabilized on sodium warfarin (coumarin) based oral anticoagulant therapy (OAT). Reference prothrombin time (PT) and INR values were assigned to these calibrants in accordance with World Health Organization (WHO) procedure using rTF 95 international reference preparation (IRP) of thromboplastin (human recombinant). These calibrants, along with five similarly characterized individual OAT patient plasmas, were distributed to 127 laboratories in a multi-center study. Calibrant plasmas were evaluated and INR's subsequently determined on the 5 OAT test samples using: 1) the ISI and MNPT in place before the study (the local system), 2) the locally calibrated ISI value (local system with ISI calibration) and 3) a PT-INR calibration curve. Precision of INR results improved across the study group using the local system with ISI calibration and the PT-INR calibration curve methods, while accuracy of INR results improved using the PT-INR calibration curve approach only and not the local ISI calibration. The authors conclude that frozen plasma calibrants can be used locally to enhance precision and accuracy of PT results as reported in INR. These calibrants are effective over a range of reagents and instrument combinations. Furthermore, the PT-INR calibration curve appears to be the superior method for local calibration.
By Coag Research Dave McGlasson
Apr 12, 2010 7:45am
I also have to throw in my two cents on local calibration of PT/INR. I published the following paper in 2002 in Clin Lab Sci. 15:91-95. We also used the Precision-Biologic frozen calibrator system. See the following abstract:

The purpose of this study was to compare different reagent/instrument systems for determining prothrombin times (PT) and International Normalized Ratios (INR) on the mechanical STA automated coagulation analyzer (Diagnostica-Stago, Inc.) and two photo-optic coagulation analyzers, the BCS (Dade-Behring) and CA-540 (Sysmex). The following thromboplastins were used in this study: Neoplastine CI+ (CI+) (Diagnostica-Stago, Inc), Thromboplastin C+ (TC+), Thromborel S (TRS), and Innovin (I) (Dade-Behring). A mean normal geometric PT (MNPT) was determined for each reagent/instrument combination using 25 normal individuals. Manufacturer instrument specific ISI values were not available for the STA with TC+, TRS and I. The CA540 had no ISI value for CI+. The BCS system had no manufacturer assigned ISI values for TC+ and I. Generic photo-optic and mechanical ISI manufacturer values were used for these two systems. A local on-site calibration to determine our own International Sensitivity Index (ISI) values for each thromboplastin was performed using a protocol with a frozen ISI calibration plasma set from Precision BioLogic (Dartmouth, NS, Canada). After the local ISI results had been determined we ran 95 patient samples on each reagent/instrument system using the manufacturer ISI and the local calibrated ISI to determine the INR result. The patient samples included 5 subjects with a presence of a lupus anticoagulant, 30 heparinized subjects and 60 coumadin patients. The differences between manufacturer versus local calibrated ISI ranged from 0.9% to 18.9% for normal sample INRs and from 0.8% to 16.4% for patient sample INRs. The number (or proportion) of patient specimens with clinically significantly different INR values (>10.0% difference) ranged from zero for several reagent combinations to more than half (>50%) of those tested for several other combinations. Our results indicated that by locally calibrating ISI values, each laboratory may eliminate variability and guesswork between different reagent/instrument systems for ISI values when performing PT/INR assays. It was interesting when Siemens started to perform their FDA clearance work for their calibrators they were told to use the Precision-Biologic frozen calibrator system as their predicate device.

When Siemens informed the FDA that they had turned down the Precision BioLogic method the FDA was a little "red in the face."

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