1. Blood Glucose Meter 2010Working Group Report By The Working Group on Medical Measurements The Seventeenth Forum Meeting October 14-16, 2010

2. 2 Overview  Diabetes  Blood glucose monitoring instrument  Medical Regulatory Control  ISO 15197  Accuracy  What could metrology do more ？

3. 3 Diabetes Mellitus Abnormal concentrations of glucose in the blood caused by a relative or absolute deficiency in insulin secretion or by insulin resistance Leading to heart attack, blindness, poor circulation, gangrene, kidney disfunction or death No cure. Monitoring blood glucose is required

4. 4 The 10 leading causes of death by broad income group (2004) Source ： WHO Note: Countries are grouped based on their 2004 gross national income by the World Bank.

5. 5 Leading cause of death ranking tables in Chinese Taipei (2001~2008) No.20082007200620052004200320022001 1Cancer 2Heart disease Cerebrovascular disease Heart disease Cerebrovascular disease 3 Heart disease Cerebrovascular disease Heart disease 4PneumoniaDiabetes Accident injury 5Diabetes Accident injury Diabetes 6AccidentPneumonia Chronic liver disease and cirrhosis 7 Chronic lower respiratory tract diseases Chronic liver disease and cirrhosis Pneumonia Nephritis, renal syndrome and renal lesions 8 Chronic liver disease and cirrhosis Nephritis, renal syndrome and renal lesions Pneumonia 9Suicide 10 Nephritis, renal syndrome and renal lesions Hypertensive disease Department of Health, Executive Yuan, Taiwan

6. 6 The Number and Percentage of Diabetes Patients International Diabetes Institute 2003-2007 Diabetes percentage of people in the world 2003-2007 Number of Global Diabetes Global Diabetes patients, from 194 million in 2003 increased to 246 million people in 2007, estimated in 2025 to 380 million people; The percentage of people, from 5.1% growth in 2003 to 7.3% in 2025. The Americas’, Europe’s and Japan’s diabetes need the glucose monitoring up to 70 % in the global demand. 2008-2011 Market survey and investment advisory report of blood glucose meter in China

7. 7 Blood Glucose Analyzer Introduction –Multifunction biochemistry test –Plasma Sample –Displayed, printed and stored in memory –Mainly Used by Health Facility Features –Excellent Precision and Accuracy –Simple, safe operation, autocalibration and autosampling

8. 8 Blood Glucose Meter Introduction Mainly for layperson to monitor and take action to control the concentration or glucose present in the blood A relatively small drop of blood is placed on a disposable test strip which interfaces with a digital meter. Inaccuracy 2 times larger than blood glucose analyzer Features –Palm of the hand — battery powered –Volume of blood sample —μL –Test time — 3 to 60 sec

9. 9 Global market demand for blood-glucose meter US$ mn Diagnostics & Imaging Week Global blood glucose monitoring device, with 13% growth rate increase in 2009. It will reach 9.73 billion U.S. dollars in market size in 2009. Global blood glucose monitoring device, with 13% growth rate increase in 2009. It will reach 9.73 billion U.S. dollars in market size in 2009. The major manufacturers, including Roche Diagnostics (Roche), Johnson & Johnson (Johnson & Johnson), Bayer Diagnostics (Bayer), Abbott Laboratories (Abbott). They were combined market share of 86%. The major manufacturers, including Roche Diagnostics (Roche), Johnson & Johnson (Johnson & Johnson), Bayer Diagnostics (Bayer), Abbott Laboratories (Abbott). They were combined market share of 86%. 2003~2009 Blood glucose monitoring market in the world 2006 Major glucose monitoring vendor market share 2008-2011 Market survey and investment advisory report of blood glucose meter in China

10. 10 FDA Classification of Medical Device General Controls General Controls and Special Controls(510K) General Controls, Special Controls and Premarket Approval(PMA) GMP (parts of medical devices not needed to inspect) Class I Class II Inspection and registration GMP Inspection and registration Class III GMP Inspection and registration + Clinical trail reference Medical Regulatory Control in Chinese Taipei/USA

11. 11 Evaluate the accuracy of blood-glucose meter Journal of Biomedical & Laboratory Sciences, 2008 Deviation of the percentage of assessments Error Grid analysis Accu-Check Advantage versus EasyPlus mini/ Bionime Estimated Blood Measured Blood 42 Rightest TM GM300. A is the district for the measured values with the reference blood glucose values of "20% of the error. B is the district for the error of ≧ 20. NCCLS proposed deviation should below 20%, ADA's recommendation is 5%, ISO standard for the accuracy is 10% of the deviation. Reproducibility analysis of glucose meter

12. 12 ISO 15197 (Metrological Requirement) ISO 15197 (2003) ： In vitro diagnostic test systems - Requirements for blood-glucose monitoring systems for self-testing in managing diabetes mellitus. 1Scope Measure glucose level in capillary blood sample self-testing by laypersons for management of diabetes mellitus 4 Design and development 4.3 Traceability 7Analytical performance evaluation 7.2 Precision evaluation 7.3 System accuracy evaluation 7.4 Minimum acceptable system accuracy

13. 13 4.3 Traceability chain(informative)

14. 14 7.2 Accuracy evaluation 7.2.2 repeatability evaluation –Number of instruments: 10 –Test in 10 times/instrument –Sample: Vein blood –Average, Standard deviation, Coefficient of variation 7.2.3 intermediate precision evaluation (precision between reproducibility and repeatability) –Number of instruments: 10 –Test in 10 days/instrument –Average, Standard deviation, Coefficient of variation –Same method, test items and location –Operator, equipment, calibration, environment and time differ Interval Glucose concentration mmol/L (mg/dL) 11.7 to 2.8 (30 to 50) 22.9 to 6.1 (51 to 110) 36.2 to 8.3 (111 to 150) 48.4 to 13.9 (151 to 250) 514.0 to 22.2 (251 to 400) Interval Glucose concentration mmol/L(mg/dL) 11.7 to 2.8 (30 to 50) 25.3 to 8.0 (96 to 144) 315.5 to 23.3 (280 to 420)

15. 15 7.3 System accuracy evaluation Sample: 100 capillary blood Temperature: (23 ± 5) ℃ Number of instruments: 2 Standard deviation, Regression curve Percentage of samples % Glucose concentration mmol/L (mg/dL) 5< 2.8 (< 50) 152.8 to 4.3 (50 to 80) 204.4 to 6.7 (80 to 120) 306.7 to 11.1 (120 to 200) 1511.2 to 16.6 (201 to 300) 1016.7 to 22.2 (301 to 400) 5> 22.2 (> 400) 95% of the result When the blood glucose results below 75 mg / dL, the error should be less than 15 mg / dL When the blood glucose results above 75 mg / dL (inclusive), the error should be less than 20%

16. 16 Factors affecting accuracy  Interferences High levels of certain substances (such as vitamin C) in blood affects the test result values such as using GDH-PQQ test strips to cause false high glucose result  Hematocrit (the amount of red blood cells in the blood). a high hematocrit, test low for blood glucose  Traceability of meter  Environmental effects (Ambient temperature, Humidity and altitude)  Size and quality of blood sample

17. 17 European directive on In-Vitro Diagnostic Medical Devices (IVDD 98/79/EC), The traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order. Blood glucose meter test by NIST SRM 965a glucose in human serum material done by CMS, ITRI in 2008 Investigate the Accuracy of Blood Glucose Meter SR M 965 a NIST SRM 965a concentration: Level 1 is 34.56 mg/dL ， Level 2 is 78.5 mg/dL Level 3 is 122.1 mg/dL ， Level 4 is 292.6 mg/dL NIST SRM 965a concentration: Level 1 is 34.56 mg/dL ， Level 2 is 78.5 mg/dL Level 3 is 122.1 mg/dL ， Level 4 is 292.6 mg/dL FY2008 Investigate 11commercially available blood glucose meters, the result shows that the maximum error value is 80% in 11 pieces of glucose meters 。 test

18. 18 Adverse Events  Glucose meters have one of the highest number of device adverse events reported per year(generally under-reported) in USA  100 deaths associated with glucose meters reported between 1992-2009 in USA 13 deaths caused by non-glucose interference 11 deaths caused by False High result 6 deaths caused by Low result FDA Perspective - Public Health Notification: Potentially Fatal Errors with GDH-PQQ Glucose Monitoring Technology by Courtney C. Harper, Ph.D(USA )

19. 19 What could metrology do more ？  More samples are tested min. 360 samples 1  More sites used min. at 3 sites 1  Tested over time min. 2 weeks 1  Revising accuracy standard 1 >95% (or >and = of individual glucose results >95% (or >and = ) ？ of individual glucose results +12 (or + mg/dL from the reference glucose +12 (or + 15) ？ mg/dL from the reference glucose values when values when the blood glucose results below and +15% when over 75 mg / dL  …… 1 1 CLIA Waiver Studies:: Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices Jan. 30, 2008 Tighter Performance Criteria (test method and MPE)

20. 20 Modify Traceability Chain A Database of High Order Reference Materials and Reference Measurement Procedures by R.i. Weilgosz, BIPM (JCTLM Meeting 2008)

21. 21 Establish Commutable Calibrator and Reference Procedure IVD manufacturers (100) Agents Medical laboratories (20,000) SI units Medical laboratories in hospitals (Medical center: 18, Regional hospital: 41, District hospital: 456) Development of CRM Build verification techniques Provide verification method Assistance of building quality system Development of verification and traceability techniques Clinical medicine (blood glucose, cholesterol, creatinine, urea, uric acid, hormones, etc.) National Standards Laboratory (Primary standard) In-house RM Traceability Authentication People

22. 2011 Plan The Working Group on Medical Measurements The Seventeenth Forum Meeting October 14-16, 2010

23. 23 IVD Medical Device Control based on Metrological Perspective Purpose metrology’s role in IVD Device Control Key points of Report 1. Medical Device Administrative Control System for IVD Device (controlled both by Health Authority and Metrology Authority or either one) and the International Standards 2. Metrological requirements of IVD Medical Device 3. Metrological Infrastructure for IVD Medical Device to assist incumbent authority and industry 4. The role of Metrology Authority to complement with Health Authority