Christina Schmid

System Accuracy Evaluation of 43 Blood Glucose Monitoring Systems for Self-Monitoring of Blood Glucose according to DIN EN ISO 15197

Background: The accuracy of systems for self-monitoring of blood glucose is important, as reliable measurement results are a prerequisite for therapeutic decisions. Methods: This system accuracy evaluation study was performed according to DIN EN ISO 15197:2003 for 43 Conformité Européenne (CE)-labeled blood glucose (BG) monitoring systems. Measurement results of each system were compared with results of the designated comparison method (manufacturers measurement procedure): glucose oxidase method (YSI 2300 glucose analyzer) or hexokinase method (Hitachi 917/ cobas 501). Results: Complete assessment according to the International Organization for Standardization (ISO) standard was performed for 34 out of 43 systems, and 27 (79.4%) meet the requirements of the standard, i.e., ≥95% of their results showed at least the minimum acceptable accuracy. For 9 of the 43 systems, complete accuracy assessment was not performed due to an oxygen sensitivity (manufacturers labeling). The bias (according to Bland and Altman) of all 43 evaluated systems ranged from −14.1% to +12.4%. Conclusions: From the 34 systems completely assessed, 7 systems did not fulfill the minimal accuracy requirements of the ISO standard. The CE mark apparently does not guarantee that all BG systems provide accuracy according to the standard. Because inaccurate systems bear the risk of false therapeutic decisions, regular and standardized evaluation of BG meters and test strips should be requested in order to ensure adherence to quality standards.

Lot-to-Lot Variability of Test Strips and Accuracy Assessment of Systems for Self-Monitoring of Blood Glucose according to ISO 15197

Background: Accurate and reliable blood glucose (BG) measurements require that different test strip lots of the same BG monitoring system provide comparable measurement results. Only a small number of studies addressing this question have been published. Methods: In this study, four test strip lots for each of five different BG systems [Accu-Chek® Aviva (system A), FreeStyle Lite® (system B), GlucoCheck XL (system C), Pura™/mylife™ Pura (system D), and OneTouch® Verio ™ Pro (system E)] were evaluated with procedures according to DIN EN ISO 15197:2003. The BG system measurement results were compared with the manufacturers measurement procedure (glucose oxidase or hexokinase method). Relative bias according to Bland and Altman and system accuracy according to ISO 15197 were analyzed. A BG system consists of the BG meter itself and the test strips. Results: The maximum lot-to-lot difference between any two of the four evaluated test strip lots per BG system was 1.0% for system E, 2.1% for system A, 3.1% for system C, 6.9% for system B, and 13.0% for system D. Only two systems (systems A and B) fulfill the criteria of DIN EN ISO 15197:2003 with each test strip lot. Conclusions: Considerable lot-to-lot variability between test strip lots of the same BG system was found. These variations add to other sources of inaccuracy with the specific BG system. Manufacturers should regularly and effectively check the accuracy of their BG meters and test strips even between different test strip lots to minimize risk of false treatment decisions.

Evaluation of the Performance of a Novel System for Continuous Glucose Monitoring

Background: The performance of a continuous glucose monitoring (CGM) system in the early stage of development was assessed in an inpatient setting that simulates daily life conditions of people with diabetes. Performance was evaluated at low glycemic, euglycemic, and high glycemic ranges as well as during phases with rapid glucose excursions. Methods: Each of the 30 participants with type 1 diabetes (15 female, age 47 ± 12 years, hemoglobin A1c 7.7% ± 1.3%) wore two sensors of the prototype system in parallel for 7 days. Capillary blood samples were measured at least 16 times per day (at least 15 times per daytime and at least once per night). On two subsequent study days, glucose excursions were induced. For performance evaluation, the mean absolute relative difference (MARD) between CGM readings and paired capillary blood glucose readings and precision absolute relative difference (PARD), i.e., differences between paired CGM readings were calculated. Results: Overall aggregated MARD was 9.2% and overall aggregated PARD was 7.5%. During induced glucose excursions, MARD was 10.9% and PARD was 7.8%. Lowest MARD (8.5%) and lowest PARD (6.4%) were observed in the high glycemic range (euglycemic range, MARD 9.1% and PARD 7.4%; low glycemic range, MARD 12.3% and PARD 12.4%). Conclusions: The performance of this prototype CGM system was, particularly in the hypoglycemic range and during phases with rapid glucose fluctuations, better than performance data reported for other commercially available systems. In addition, performance of this prototype sensor was noticeably constant over the whole study period. This prototype system is not yet approved, and performance of this CGM system needs to be further assessed in clinical studies.

Performance Evaluation of a Continuous Glucose Monitoring System under Conditions Similar to Daily Life

Background: This study aimed at evaluating and comparing the performance of a new generation of continuous glucose monitoring (CGM) system versus other CGM systems, under daily lifelike conditions. Methods: A total of 10 subjects (7 female) were enrolled in this study. Each subject wore two Dexcom G4™ CGM systems in parallel for the sensor lifetime specified by the manufacturer (7 days) to allow assessment of sensor-to-sensor precision. Capillary blood glucose (BG) measurements were performed at least once per hour during daytime and once at night. Glucose excursions were induced on two occasions. Performance was assessed by calculating the mean absolute relative difference (MARD) between CGM readings and paired capillary BG readings and precision absolute relative difference (PARD), i.e., differences between paired CGM readings. Results: Overall aggregate MARD was 11.0% (n = 2392). Aggregate MARD for BG >70 mg/dl was 13.7%; for BG between 70 and 180 mg/dl, MARD was 11.4%; and for BG >180 mg/dl, MARD was 8.5%. Aggregate PARD was 7.3%, improving from 11.6% on day 1 to 5.2% on day 7. Conclusions: The Dexcom G4 CGM system showed good overall MARD compared with results reported for other commercially available CGM systems. In the hypoglycemic range, where CGM performance is often reported to be low, the Dexcom G4 CGM system achieved better MARD than that reported for other CGM systems in the hypoglycemic range. In the hyperglycemic range, the MARD was comparable to that reported for other CGM systems, whereas during induced glucose excursions, the MARD was similar or slightly worse than that reported for other CGM systems. Overall PARD was 7.3%, improving markedly with sensor life time.

System Accuracy Evaluation of Four Systems for Self-Monitoring of Blood Glucose Following ISO 15197 Using a Glucose Oxidase and a Hexokinase-Based Comparison Method

Background: The standard ISO (International Organization for Standardization) 15197 is widely accepted for the accuracy evaluation of systems for self-monitoring of blood glucose (SMBG). Accuracy evaluation was performed for 4 SMBG systems (Accu-Chek® Aviva, Contour®XT, GlucoCheck XL, GlucoMen® LX PLUS) with 3 test strip lots each. To investigate a possible impact of the comparison method on system accuracy data, 2 different established methods were used. Methods: The evaluation was performed in a standardized manner following test procedures described in ISO 15197:2003 (section 7.3). System accuracy was assessed by applying ISO 15197:2003 and in addition ISO 15197:2013 criteria (section 6.3.3). For each system, comparison measurements were performed with a glucose oxidase (YSI 2300 STAT Plus™ glucose analyzer) and a hexokinase (cobas® c111) method. Results: All 4 systems fulfilled the accuracy requirements of ISO 15197:2003 with the tested lots. More stringent accuracy criteria of ISO 15197:2013 were fulfilled by 3 systems (Accu-Chek Aviva, ContourXT, GlucoMen LX PLUS) when compared to the manufacturer’s comparison method and by 2 systems (Accu-Chek Aviva, ContourXT) when compared to the alternative comparison method. All systems showed lot-to-lot variability to a certain degree; 2 systems (Accu-Chek Aviva, ContourXT), however, showed only minimal differences in relative bias between the 3 evaluated lots. Conclusions: In this study, all 4 systems complied with the evaluated test strip lots with accuracy criteria of ISO 15197:2003. Applying ISO 15197:2013 accuracy limits, differences in the accuracy of the tested systems were observed, also demonstrating that the applied comparison method/system and the lot-to-lot variability can have a decisive influence on accuracy data obtained for a SMBG system.

Partial Pressure of Oxygen in Capillary Blood Samples from the Fingertip

Many people with diabetes routinely measure their blood glucose (BG) on capillary blood samples from the fingertip. Beside other interfering factors, the blood samples’ partial pressure of oxygen (pO2) can affect BG measurements, particularly in systems based on glucose oxidase (GOx) enzyme reactions on test strips.1,2 Indeed, many of the available home-use systems for self-monitoring of blood glucose (SMBG) utilize the GOx enzyme reaction, which is prone to oxygen interference; however, in the literature, poor information is available concerning physiological pO2 values and possible variations in capillary blood from the fingertip in people with diabetes. In this investigation, the pO2 of capillary blood samples obtained from fingertips was determined in 110 subjects (55 female, 31 with type 1 diabetes mellitus, 69 with type 2 diabetes mellitus, 10 without diabetes; mean age 61 years, from 19 to 78 years); most of them were expected to perform SMBG regularly. The subjects had no acute serious diseases. They participate regularly in SMBG system evaluation studies at the Institute for Diabetes-Technology GmbH at Ulm University, Ulm, Germany. The study protocol was approved by the Ulm University Ethics Committee. Capillary blood samples were obtained by skin puncture, and the pO2 was analyzed on a blood gas analyzer (OPTI™ CCA-TS Analysator, OPTI Medical System Inc., Roswell, GA). Maintenance, handling, and quality control of the blood gas analyzer were performed according to the manufacturer’s labeling. Regular internal and external quality control measurements were performed, as required by German national guidelines. Sample collection and pO2 measurements were performed by trained clinical personnel. The 110 subjects showed a mean pO2 of 71.1 mmHg (standard deviation ± 6.9 mmHg), ranging from 49 to 86 mmHg. Female and male subjects showed similar mean pO2 values (72.5 and 69.8 mmHg, respectively). Ninety-four subjects (~85%) showed pO2 values between >60 and ≤80 mmHg, 6 subjects (~5%) showed pO2 values ≤60 mmHg, and 10 subjects (~9%) showed pO2 values >80 mmHg (Figure 1). Lowest pO2 values (53 and 49 mmHg) were found in two subjects with stable chronic respiratory disease. Figure 1. Relative number of subjects with pO2 values within the respective category. Our results indicate that a broad range of capillary pO2 values occur among a population of healthy people and people with diabetes without acute serious diseases. In a previous study using venous blood samples adjusted to different pO2 levels, we observed remarkable measurement deviations with some GOx systems. Particularly at pO2 ≤45 mmHg, we found considerably overestimated measurements.2 Decreased pO2 values can occur in patients with respiratory diseases, such as chronic obstructive pulmonary disease,3 which is described as being associated with type 2 diabetes.4 At high altitudes or also during long-distance flights, up to ~40% decreased pO2 is reported for arterial blood samples;5 a similar behavior can also be expected for capillary blood samples from the fingertip. In conditions with decreased pO2 values in capillary blood, measurements with oxygen-sensitive systems could be affected, and hypoglycemic events might not be detected adequately. Further investigations should be performed focusing on pO2 variations in capillary blood from fingertips in people with diabetes and the possible impact on glucose measurement results obtained with oxygen-sensitive systems.

Analytical Performance Requirements for Systems for Self-Monitoring of Blood Glucose With Focus on System Accuracy: Relevant Differences Among ISO 15197:2003, ISO 15197:2013, and Current FDA Recommendations.

In the European Union (EU), the ISO (International Organization for Standardization) 15197 standard is applicable for the evaluation of systems for self-monitoring of blood glucose (SMBG) before the market approval. In 2013, a revised version of this standard was published. Relevant revisions in the analytical performance requirements are the inclusion of the evaluation of influence quantities, for example, hematocrit, and some changes in the testing procedures for measurement precision and system accuracy evaluation, for example, number of test strip lots. Regarding system accuracy evaluation, the most important change is the inclusion of more stringent accuracy criteria. In 2014, the Food and Drug Administration (FDA) in the United States published their own guidance document for the premarket evaluation of SMBG systems with even more stringent system accuracy criteria than stipulated by ISO 15197:2013. The establishment of strict accuracy criteria applicable for the premarket evaluation is a possible approach to further improve the measurement quality of SMBG systems. However, the system accuracy testing procedure is quite complex, and some critical aspects, for example, systematic measurement difference between the reference measurement procedure and a higher-order procedure, may potentially limit the apparent accuracy of a given system. Therefore, the implementation of a harmonized reference measurement procedure for which traceability to standards of higher order is verified through an unbroken, documented chain of calibrations is desirable. In addition, the establishment of regular and standardized post-marketing evaluations of distributed test strip lots should be considered as an approach toward an improved measurement quality of available SMBG systems.

System accuracy evaluation of systems for point-of-care testing of blood glucose: a comparison of a patient-use system with six professional-use systems.

Abstract Background: Point-of-care testing (POCT) of blood glucose (BG) is performed by medical personnel in clinical settings as well as by patients themselves for self-monitoring of blood glucose (SMBG) at home. We investigated if a system mainly intended for SMBG by people with diabetes, but also suitable for BG measurements by medical personnel, can achieve measurement accuracy on capillary blood samples comparable with professional-use POCT systems. Methods: System accuracy was evaluated under standardised conditions, following the ISO standard 15197:2003. For each system (one SMBG system with three test strip lots and six professional-use systems), measurement results from capillary blood samples of 100 subjects were compared with a standardised laboratory glucose oxidase method (YSI 2300 glucose analyser). Results: The seven evaluated systems showed 99.5% or 100% of the measurement results within the required system accuracy limits of ISO 15197:2003 (±0.83 mmol/L at BG concentrations <4.2 mmol/L and ±20% at BG concentrations ≥4.2 mmol/L). Applying the more stringent requirements of the revision ISO 15197:2013, the systems showed between 99% and 100% of the measurement results within the accuracy limits (±0.83 mmol/L at BG concentrations <5.55 mmol/L and ±15% at BG concentrations ≥5.55 mmol/L) and between 82% and 98% when even more restrictive limits were applied (±0.56 mmol/L and ±10%, respectively). Conclusions: Data from this study, which focused on system accuracy, suggest that SMBG systems can achieve system accuracy that is comparable with professional-use systems when measurements are performed on capillary blood samples by trained personnel in a standardised and controlled setting.

System Accuracy of Blood Glucose Monitoring Systems: Impact of Use by Patients and Ambient Conditions

For self-monitoring of blood glucose by people with diabetes, the reliability of the measured blood glucose values is a prerequisite in order to ensure correct therapeutic decisions. Requirements for system accuracy are defined by the International Organization for Standardization (ISO) in the standard EN ISO 15197:2003. However, even a system with high analytical quality is not a guarantee for accurate and reliable measurement results. Under routine life conditions, blood glucose measurement results are affected by several factors. First, the act of performing measurements as well as the handling of the system may entail numerous possible error sources, such as traces of glucose-containing products on the fingertips, the use of deteriorated test strips, or the incorrect storage of test strips. Second, ambient and sampling conditions such as high altitude, partial pressure of oxygen, ambient temperature, and the use of alternate test sites can have an influence on measurement results. Therefore, the user-friendliness of a system and the quality of the manufacturers labeling to reduce the risk of handling errors are also important aspects in ensuring reliable and accurate measurement results. In addition, the analytical performance of systems should be less prone to user errors and ambient conditions. Finally, people with diabetes must be aware of the information and instructions in the manufacturers labeling and must be able to measure and interpret blood glucose results correctly.

Impact of Partial Pressure of Oxygen in Blood Samples on the Performance of Systems for Self-Monitoring of Blood Glucose

BACKGROUND The partial pressure of oxygen (pO2) in blood samples can affect glucose measurements with oxygen-sensitive systems. In this study, we assessed the influence of different pO2 levels on blood glucose (BG) measurements with five glucose oxidase (GOD) systems and one glucose dehydrogenase (GDH) system. All selected GOD systems were indicated by the manufacturers to be sensitive to increased oxygen content of the blood sample. MATERIALS AND METHODS Venous blood samples of 16 subjects (eight women, eight men; mean age, 52 years; three with type 1 diabetes, four with type 2 diabetes, and nine without diabetes) were collected. Aliquots of each sample were adjusted to the following pO2 values: ≤45 mm Hg, approximately 70 mm Hg, and ≥150 mm Hg. For each system, five consecutive measurements on each sample were performed using the same test strip lot. Relative differences between the mean BG value at a pO2 level of approximately 70 mm Hg, which was considered to be similar to pO2 values in capillary blood samples, and the mean BG value at pO2 levels ≤45 mm Hg and ≥150 mm Hg were calculated. RESULTS The GOD systems showed mean relative differences between 11.8% and 44.5% at pO2 values ≤45 mm Hg and between -14.6% and -21.2% at pO2 values ≥150 mm Hg. For the GDH system, the mean relative differences were -0.3% and -0.2% at pO2 values ≤45 mm Hg and ≥150 mm Hg, respectively. CONCLUSIONS The magnitude of the pO2 impact on BG measurements seems to vary among the tested oxygen-sensitive GOD systems. The pO2 range in which oxygen-sensitive systems operate well should be provided in the product information.