Ulrike Kamecke

ISO 15197: 2013 Evaluation of a Blood Glucose Monitoring System’s Measurement Accuracy:

Requirements for blood glucose monitoring systems (BGMS) for self-testing are regulated, for example, in the international standard ISO 15197:2013 (harmonized in the European Union as EN ISO 15197:2015). Regarding measuring accuracy of a BGMS, ISO 15197:2013 specifies the following criteria: (1) compared to a traceable laboratory method at least 95% of BGMS results have to be within ±15 mg/dl at glucose concentrations <100 mg/dl and within ±15% at ≥100 mg/dl; (2) in a consensus error grid analysis at least 99% of results have to be within zones A and B. This study was an ISO 15197:2013 accuracy evaluation at the Institut für Diabetes-Technologie Forschungsund Entwicklungsgesellschaft mbH an der Universität Ulm (accredited by the Deutsche Akkreditierungsstelle GmbH (DAkkS) as testing laboratory according to DIN EN ISO/ IEC 17025:2005 and 98/79/EC in terms of test procedures according to DIN EN ISO 15197) in compliance with all applicable regulatory requirements. The BGMS GlucoDr. autoTM AGM-4000 (All Medicus, Co, Ltd, Anyang-si, Republic of Korea) was tested. According to a statement of the manufacturer, this system is marketed in the UK as Glucozen.autoTM AGM-4000 (GlucoZen Ltd, Dudley, UK). Meters and three different lots of test strips were provided by the manufacturer. A YSI 2300 STAT Plus glucose analyzer (YSI Inc, Yellow Springs, OH, USA) that is traceable according to ISO 17511 was used for comparison measurements; trueness and precision were verified throughout the study. The BGMS was used according to its labeling and daily control measurements were performed. Each of the three test strip lots was tested in duplicate in 100 subjects; glucose concentrations of the capillary blood samples were distributed as specified in ISO 15197:2013. The accuracy criteria described above were applied to the BGMS and the relative bias was calculated. Over the whole glucose concentration range, the BGMS had 98.5% (Lot 1), 97% (Lot 2) and 96% (Lot 3) of results within the limits stipulated by ISO 15197:2013 (Figure 1). Percentages of results within the limits were 98.3%, 95%, and 98.3%, respectively, for glucose concentrations <100 mg/dl and 98.6%, 97.9%, and 95%, respectively, for glucose concentrations ≥100 mg/dl. All results of the three test strip lots were within zones A and B of the consensus error grid. The relative bias was 2.7% (Lot 1) and 2.6% (Lot 2 and Lot 3). In this study, the system showed more than the minimally required 95% of results within the ISO 15197 system accuracy limits and did not show obvious variations between the evaluated test strip lots. 727550 DSTXXX10.1177/1932296817727550Journal of Diabetes Science and TechnologyJendrike et al letter2017

The Clinical Research Tool: A High-Performance Microdialysis-Based System for Reliably Measuring Interstitial Fluid Glucose Concentration

Background: A novel microdialysis-based continuous glucose monitoring system, the so-called Clinical Research Tool (CRT), is presented. The CRT was designed exclusively for investigational use to offer high analytical accuracy and reliability. The CRT was built to avoid signal artifacts due to catheter clogging, flow obstruction by air bubbles, and flow variation caused by inconstant pumping. For differentiation between physiological events and system artifacts, the sensor current, counter electrode and polarization voltage, battery voltage, sensor temperature, and flow rate are recorded at a rate of 1 Hz. Method: In vitro characterization with buffered glucose solutions (cglucose = 0 − 26 × 10−3 mol liter−1) over 120 h yielded a mean absolute relative error (MARE) of 2.9 ± 0.9% and a recorded mean flow rate of 330 ± 48 nl/min with periodic flow rate variation amounting to 24 ± 7%. The first 120 h in vivo testing was conducted with five type 1 diabetes subjects wearing two systems each. A mean flow rate of 350 ± 59 nl/min and a periodic variation of 22 ± 6% were recorded. Results: Utilizing 3 blood glucose measurements per day and a physical lag time of 1980 s, retrospective calibration of the 10 in vivo experiments yielded a MARE value of 12.4 ± 5.7. Clarke error grid analysis resulted in 81.0%, 16.6%, 0.8%, 1.6%, and 0% in regions A, B, C, D, and E, respectively. Conclusion: The CRT demonstrates exceptional reliability of system operation and very good measurement performance. The ability to differentiate between artifacts and physiological effects suggests the use of the CRT as a reference tool in clinical investigations.

Flash Glucose Monitoring: Differences Between Intermittently Scanned and Continuously Stored Data:

The flash glucose monitoring system FreeStyle Libre (Abbott Diabetes Care Ltd., Witney, UK) measures interstitial glucose concentrations and continuously stores measurement values every 15 minutes. To obtain a current glucose reading, users have to scan the sensor with the reader. In a clinical trial, 5% of the scanned data showed relative differences of more than ±10% compared with continuously stored data points (median −0.5%). Such differences might impact results of studies using this system. It should be indicated whether scanned or continuously stored data were used for analyses. Health care professionals might have to differentiate between data reports from clinical software and the scanned data their patients are provided with. Additional information on these differences and their potential impact on therapeutic decisions would be helpful.

Occlusion Detection Time in Insulin Pumps at Two Different Basal Rates

Background: The detection of insulin infusion set (IIS) occlusions is an important feature of insulin pumps with regard to patient safety. However, there are no requirements for a time limit until an alarm has to be triggered after an occlusion occurred. The standard IEC 60601-2-24 is applicable for insulin pumps and describes test settings and procedures to determine occlusion detection time (ODT). Methods: In this study, ODT of six different insulin pump models with different IIS (in total 10 different insulin pump systems) was tested for two basal rates (1.0 U/h and 0.1 U/h). Results: Differences were seen between the tested pump systems. At a basal rate of 1.0 U/h all insulin pump systems showed an acceptable ODT of less than 5 hours. However, at a basal rate of 0.1 U/h, as often used in children, the median ODT ranged from approximately 4 hours to more than 40 hours. With the lower basal rate, median ODT was longer than 6-8 hours for 9 of the 10 systems. Conclusions: Insulin pump users should not blindly rely on occlusion alarms but perform regular glucose monitoring and manufacturers should develop mechanisms that allow an earlier detection at low basal rates.

Establishing Methods to Determine Clinically Relevant Bolus and Basal Rate Delivery Accuracy of Insulin Pumps

Background: Adequate testing of delivery accuracy of insulin pumps is under discussion. Especially for patch pumps, test settings are challenging. In addition, evaluation and presentation of accuracy results in a way that is reasonable and useful for clinicians, not only for technicians, is important. Methods: Test setups based on IEC 60601-2-24 were used and, in addition, different setups for patch pumps were compared to identify an adequate alternative for pumps without external infusion set. These setups are applicable for both bolus and basal rate accuracy testing. In addition, evaluation procedures considering clinical relevance were compiled. Results: A setup for patch pumps that provides reliable results could be realized. Evaluation of basal rate accuracy data should also consider the actual clinical use of insulin pumps and thus, deviating from IEC 60601-2-24, compose the whole measurement period without excluding the first 24 hours. In addition to the presentation using trumpet curves, accuracy of 1-hour windows should be evaluated and displayed. Conclusions: This article proposes an approach on how to test, evaluate, and present bolus and basal rate accuracy of insulin pumps from a clinical perspective.

Reporting Insulin Pump Accuracy: Trumpet Curves According to IEC 60601-2-24 and Beyond

Accuracy of insulin pump basal rate delivery, if tested according to the standard IEC 60601-2-24 for infusion pumps, shall be presented as a trumpet curve. This way of graphical presentation is common; however, it is often misunderstood and misinterpreted by people. It is often assumed that a trumpet curve shows the error rate as a function of time, thus implying an increasing accuracy in the course of time. On the contrary, the horizontal axis of a trumpet curve shows increasingly long observation windows. In addition, trumpet curves display only extreme values, that is, those windows with minimal and maximal deviation, which might not be representative for the total deviation. This commentary provides information regarding the calculations and the interpretation of trumpet curves and proposes alternative approaches.

Accuracy of five systems for self-monitoring of blood glucose in the hands of adult lay-users and professionals applying ISO 15197: 2013 accuracy criteria and potential insulin dosing errors

Abstract Objective: In this study, accuracy in the hands of intended users was evaluated for five self-monitoring of blood glucose (SMBG) systems based on ISO 15197:2013, and possibly related insulin dosing errors were calculated. In addition, accuracy was assessed in the hands of study personnel. Methods: For each system (Accu-Chek1 Aviva Connect [A], Contour2 Next One [B], FreeStyle Freedom Lite3 [C], GlucoMen4 areo [D] and OneTouch Verio5 [E]) one test strip lot was evaluated as required by ISO 15197:2013, clause 8. Number and percentage of SMBG measurements within ±15 mg/dl and ±15% of the comparison measurements at glucose concentrations <100 mg/dl and ≥100 mg/dl, respectively, were calculated. In addition, data is presented in surveillance error grids, and insulin dosing errors were modeled. The study was registered at ClinicalTrials.gov (NCT03033849). Results: Four systems (A, B, C, D) fulfilled the tested reagent system lot ISO 15197:2013 accuracy criteria with the tested reagent system lot with at least 95% (lay-users) and 99.5% (study personnel) of results within the defined limits. Measurements with all five systems were within the clinically acceptable zones of the consensus error grid and the surveillance error grid. Median modeled insulin dosing errors were between -0.8 and +0.6 units for measurements performed by lay-users and between -0.7 and +0.8 units for study personnel. Frequent lay-user errors were not checking the test strips’ expiry date, applying blood incorrectly and handling the device incorrectly. Conclusion: In this study, the systems showed slight differences in the number of results within ISO 15197:2013 accuracy limits. Inaccurate SMBG measurements can result in insulin dosing errors and adversely affect glycemic control. Trial registration: ClinicalTrials.gov identifier: NCT03033849.

Accuracy Assessment of an Improved Version of an Established Blood Glucose Monitoring System for Self-Testing Following ISO 15197:2013

The international standard ISO 15197 describes system requirements for blood glucose monitoring systems (BGMS). The implementation of a new version of this standard in 2013, which was harmonized in the EU as EN ISO 15197:2015, aimed to further improve the quality of available systems by, for example, setting stricter accuracy criteria. This study was conducted to assess conformity of a new version of the Accu-Chek® Active (Roche Diabetes Care GmbH, Mannheim, Germany) to system accuracy requirements of ISO 15197:2013. The improved BGMS does not require coding with a lotspecific code chip anymore which will eliminate a possible source of improper use of codechips. The BGMS comprises the meter and test strips and is labeled for self-testing by people with diabetes as well as for use by health care professionals. The study was conducted at the Institut für DiabetesTechnologie Forschungsund Entwicklungsgesellschaft mbH an der Universität Ulm, Ulm, Germany in July 2016 and was performed in compliance with the Good Clinical Practice guidelines and regulatory requirements were fulfilled. Meters, test strips and control solution were provided by Roche Diabetes Care GmbH. Systems were set and maintained according to the manufacturer’s instructions and daily control measurements were performed. Based on procedures of ISO 15197:2013, capillary blood samples from the fingertips of at least 100 different subjects with a defined distribution of blood glucose (BG) concentrations were measured with 3 different lots of the test strips of the BGMS and a hexokinase-based comparison method (Cobas Integra® 400 plus; Roche Instrument Center, Rotkreuz, CH). Comparison measurements were performed at the study site; the method is ISO 17511 traceable according to the manufacturer. Data were analyzed at the study site. Differences between results of the BGMS and the comparison measurements were calculated and the number of values within the system accuracy limits of ISO 15197:2013 was determined. In addition, the relative bias was calculated according to Bland and Altman. At BG concentrations <100 mg/dl (52 values), 100% (Lots 1, 2, and 3) of BGMS results fell within ±15 mg/dl of the comparison values. At BG concentrations ≥100 mg/dl (148 values), 98% (Lot 1), 99.3% (Lot 2), and 100% (Lot 3) of BGMS results were within ±15%. For all BG concentrations (28 mg/dl-451 mg/dl), 98.5% (Lot 1), 99.5% (Lot 2), and 100% (Lot 3) were within the respective limits. Furthermore, 100% of the results were in consensus error grid zone A (see Figure 1). The relative bias was -5.4% (Lot 1), -2.3% (Lot 2), and -1.6% (Lot 3). This study confirmed that the BGMS had at the introduction on the market a high level of accuracy and fulfilled with three manufacturer-provided lots the system accuracy requirements of ISO 15197:2013. 688304 DSTXXX10.1177/1932296816688304Journal of Diabetes Science and TechnologyKamecke et al letter2017