System accuracy evaluation of FORA Test N Go Blood Glucose Monitoring System versus YSI 2300 STAT Plus glucose analyzer following ISO 15197:2013

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1 System Accuracy Evaluation of Project number: Fora System accuracy evaluation of Blood Glucose Monitoring System versus YSI 2300 STAT Plus glucose analyzer following ISO 15197:2013 Date: 13 th October th October /21

2 System Accuracy Evaluation of Table of contents Abstract... 3 Responsible Parties & Signatures Introduction Material and Methods Recruitment of test subjects Blood glucose monitoring system (BGMS) Reference standard Preparation of test samples Test of blood glucose Statistics Results Ratio of test subjects Test results Accuracy results following ISO 15197:2013 (E) Accuracy results following ISO 15197: Statistical analysis Absolute differences between and YSI 2300 STAT PLUS Conclusion and Discussion References Appendix /21

3 System Accuracy Evaluation of Abstract Objective: The goal of the study was to assess the accuracy and reliability of Fora blood glucose monitoring system (BGMS) in the clinical studies according to the international standard ISO 15197: 2013(E) criteria and more stringent guidelines. Methods: The study sample was collected from 108 subjects comprised 53 patients with types 1 diabetes and 36 patients with types 2 diabetes, and 19 people with type unknown. The capillary blood specimens was collected via fingertip stick from participants at AMCR Institute (700 West El Norte Parkway, Suite 201, Escondido, CA 92026) and tested on three different lots of test strips. Results: The Fora BGMS met the requirements of ISO 15197:2013 from all three lots of test strips tested. Reagent system lot Within ± 5 mg/dl & ± 5 % (Within ± 0.28 mmol/l & ± 5 %) Within ± 10 mg/dl & ± 10 % (Within ± 0.56 mmol/l & ± 10 %) Within ± 15 mg/dl & ± 15 % (Within ± 0.83 mmol/l & ± 15 %) TD14D228-C0E 144 / 200 (72.0 %) 192 / 200 (96.0 %) 197 / 200 (98.5 %) TD14D828-C0E 142 / 200 (71.0 %) 195 / 200 (97.5 %) 197 / 200 (98.5 %) TD14D928-C0E 139 / 200 (69.5 %) 192 / 200 (96.0 %) 198 / 200 (99.0 %) This BGMS is also compliant with the requirements of DIN EN ISO 15197:2003 with all 3 reagent system lot(s). Reagent system lot Within ± 5 mg/dl & ± 5 % (Within ± 0.28 mmol/l & ± 5 %) Within ± 10 mg/dl & ± 10 % (Within ± 0.56 mmol/l & ± 10 %) Within ± 10 mg/dl & ± 15 % (Within ± 0.56 mmol/l & ± 15 %) Within ± 15 mg/dl & ± 20 % (Within ± 0.83 mmol/l & ± 20 %) TD14D228-C0E 117 / 200 (58.5 %) 178 / 200 (89.0 %) 196 / 200 (98.0 %) 199 / 200 (99.5 %) TD14D828-C0E 107 / 200 (53.5 %) 169 / 200 (84.5 %) 197 / 200 (98.5 %) 199 / 200 (99.5 %) TD14D928-C0E 112 / 200 (56.0 %) 171 / 200 (85.5 %) 194 / 200 (97.0 %) 200 / 200 (100 %) Conclusion: The study suggest that the Fora blood glucose monitoring system not only met the current accuracy standard (ISO15197:2003), but also met with the minimum acceptable accuracy standard published in the newer 2013 guideline (ISO15197:2013) when compared the test results with a laboratory reference. 3/21

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5 System Accuracy Evaluation of 1. Introduction Diabetes is a chronic illness that requires continuing medical care and ongoing patient self-management education and support to prevent acute complications and to reduce the risk of long-term complications. It is predicted that the total number of people with diabetes will rise from 171 million in 2000 to 366 million in Clinical evidence has clearly indicated that improved metabolic control leads to a significant reduction in microvascular complications associated with diabetes. Self-monitoring blood glucose system (SMBG) has become an important and efficacy tool in the daily blood glucose management for people with diabetes. Optimal utilization of SMBG can lead to improvements in glycemic control by providing patients with immediate feedback on the impact of food, exercise, or medication on their blood sugar. Therefore, simple-to-use and accurate performance will be the conditions needed in a good glucose meter. The Fora Blood Glucose monitoring system for this study provides a faster and more effective way of blood glucose measurement. Furthermore, these glucose meters employ good technology which can eliminate miscoding errors that could lead to inaccurate results. Features of self-monitoring blood glucose system (SMBG) include ease-of-use, capillary action, electrodes with carbon, and biosensor technology. This study was to evaluate the system accuracy following ISO 15197: protocol and if possible, the newly published ISO 19197: guideline. EN ISO 15197:2003 is an international standard published by International Standard Origination (ISO) specifying requirements for in vitro glucose monitoring systems on self-testing in managing diabetes mellitus. The minimum acceptable accuracy for results produced by a glucose monitoring system shall be as follows: Ninety-five percent (95 %) of the individual glucose results shall fall within ± 15 mg/dl (± 0.83 mmol/l) of the results of the reference measurement at glucose concentrations < 75 mg/dl (< 4.2 mmol/l) and within ± 20 % at glucose concentrations 75 mg/dl ( 4.2 mmol/l). In 2013, ISO has published a newer standard ISO 15197:2013 (E) which tightens the accuracy acceptance criteria. The minimum acceptable accuracy for results produced by a glucose monitoring system has been changed to the followings: Ninety-five percent (95 %) of the individual glucose results shall fall within ± 15 mg/dl (± 0.83 mmol/l) of the results of the reference measurement at glucose concentrations < 100 mg/dl (< 5.55 mmol/l) and within ± 15 % at glucose concentrations 100 mg/dl ( 5.55 mmol/l). Comparison between 2 ISO standards: EN ISO 15197: 2003 ISO 15197: 2013 (E) Maximum deviation from glucose reference value At glucose levels < 75 mg/dl (< 4.2 mmol/l) At glucose levels 75 mg/dl ( 4.2 mmol/l) ± 15mg/dl (0.83 mmol/l) ± 20% At glucose levels < 100 mg/dl (< 5.5 mmol/l) At glucose levels 100 mg/dl ( 4.2 mmol/l) ± 15mg/dl (0.83 mmol/l) ± 15% 5/21

6 System Accuracy Evaluation of The Clarke error grid (CEG) analysis 4 was part of ISO guideline to quantify the clinical accuracy of blood glucose readings generated by meters as compared to a reference value. According to ISO guideline, the error grids subdivided into five zones. Values in zones A and B represent accurate or acceptable glucose results which have no effect on clinical action. If values fall into in zone C, it may prompt unnecessary corrections that could impact on clinical outcome. Values in zone D could lead to significant medical risk for patients and values in zone E could have dangerous consequence resulted from an inappropriate treatment. To help the treatment for type I diabetes patients, ISO guideline requires 99% of individual glucose measured values shall fall within zones A and B of the CEG. The objective for this study was to access the accuracy of Fora based on ISO protocol and if possible, the new ISO 2013 guideline. 2. Material and Methods 2.1 Recruitment of test subjects: Test subjects were recruited to AMCR Institute based on the inclusion and exclusion criteria set from the study protocol. Inclusion: Male or female subjects with diabetes type 1 or 2 or healthy subjects, potentially including the employees of the sponsor. Minimum age of 18 years. Exclusion: Pregnancy or lactation period Severe acute disease Severe chronic disease with potential risk during the trial Discrepancy between 2 YSI references. According to BS EN ISO 15197: 2013(E), results from the reference method were evaluated to verify sample stability. If the values between first and last reference differ by >4% at glucose 100mg/dl ( 5.55mmol/l) or >4mg/dl (>0.22mmol/l) at glucose <100mg/dl (<5.55mmol/l), indicating glucose instability in the sample, the results for that sample had to be rejected. 2.2 Blood glucose monitoring system (BGMS) Fora glucose monitoring systems are market-ready glucose meters with FDA approval # K Each comes with complete packaging, manual and quick user guide. Twelve meters were used in this study. They were divided into 2 stations with six at each station. Meter: Serial number Station A01-A A07-A12 2 6/21

7 System Accuracy Evaluation of Key features of Fora monitoring system: Blood sample: Capillary and venous blood Sample volume: 0.5 l Measuring range: mg/dl ( mmol/l) Analysis time: 5 seconds Operating temperature: Operating humidity: < 85% R.H. Hematocrit range: % Measurement technology: Glucose dehydrogenase (GDH-FAD) Calibration: Plasma The evaluation was performed with 3 lots of test strips. Reagent system: Blood glucose test strip: Lot Lot number Expiry 1 TD14D228-C0E TD14D828-C0E TD14D928-C0E Control solutions were used to verify the performance and function of the meters each morning during the study. Control solution Lot number Expiry Control Solution Level 2 WA13B Target range Lot 1: 138~186 Lot 2: 139~187 Lot 3: 137~ Reference standard The reference used in this study was a Yellow Springs 2300 (YSI 2300) manufactured by YSI incorporated (Yellow Springs, OH) which detected glucose concentration based on a glucose oxidase method The readings of the YSI analyzer was validated by running the analyzer with the National Institute of Standards and Technology (NIST) secondary reference material SRM 965a which consists of four levels of standard glucose concentrations. Glucose reference was determined as the average of at least duplicated measurements from the YSI. 7/21

8 System Accuracy Evaluation of 2.4 Preparation of Samples Capillary blood samples were collected based on the ISO 15197:2013 guideline to have certain percentage of subject samples in the following concentration categories: Concentration category Percentage of samples [%] Glucose concentration [mg/dl (mmol/l)] Number of test subjects based on ( 2.77) > (> ) > (> ) > (> ) > (> ) > (> ) > 400 (> 22.20) 5 Samples were assigned to the respective glucose concentration category depending on the mean from the YSI measurements. If the total number of test subjects on each concentration category was filled, no additional samples would be added. According to the ISO guideline, the following samples were adjusted by either natural decayed at 37ºC or spiked with additional glucose to fall into specific concentration categories. Concentration category Sample no. 1 85, 96, 97, , 86, 95, 99, 100, 101, 102, 103, 105, 106, , 93, Test of Blood Glucose Sample capillary blood was obtained by a finger stick using a 25G safety lancet. The blood sample was immediately collected onto a Lithium-Heparin Microvette (~ 200 μl) The capillary blood was then placed on a parafilm and tested on Fora blood glucose monitoring systems (6 devices per station with test strip lot 1, 2, and 3). The remaining blood in the lithium-heparin microvette was then immediately placed on a centrifuge to separate plasma. The glucose concentration of the plasma was then determined by the YSI 2300 using one electrode. The measurement was repeated once and the true glucose concentration of the subject glucose was determined by the average of the YSI values. 8/21

9 System Accuracy Evaluation of 2.6 Statistical analysis In this study, the following statistical analyses were performed: Bias analysis according to Bland and Altman 5. Regression analysis according to Passing and Bablok Results 3.1 Test subjects Total of 108 test subjects were enrolled in the study. Among them, 8 test subjects were excluded for the following reasons. Reagent system lot total test subjects Number of subjects rejected Based on ISO 15197: 2013 (E) criteria The change between first (before the measurement procedure) and second (after the measurement procedure) comparison measurement result is > 4 % at glucose concentrations > 100 mg/dl or > 4 mg/dl at glucose concentrations 100 mg/dl (acceptance criterion for sample stability) The concentration category was already filled Additional exclusion criteria based on Fora protocol HCT is high than 50% or below 35% /21

10 System Accuracy Evaluation of The detail test log Reagent system lot Number of included samples Glucose concentration range (YSI 2300 STAT Plus TM glucose analyzer) minimum maximum Hematocrit range [%] Age [years] Type 1 / Type 2 / NA 53 / 36 / / 36 / / 36 / 19 Gender [male / female / unknown] 48 / 50 / / 50 / / 50 / 10 Temperature [ ] (during the test) Humidity [%] (during the test) Test results Accuracy results following ISO 15197:2013 (E) Summary: Glucose concentration range: 37 mg/dl (2.06 mmol/l) to mg/dl (26.4 mmol/l) Test strip lot 1: Lot: TD14D228-C0E Within ± 15 mg/dl & ± 15 % (Within ± 0.83 mmol/l & ± 15 %) 198 / 200 (99.0 %) Test strip lot 2: Lot: TD14D828-C0E Within ± 15 mg/dl & ± 15 % (Within ± 0.83 mmol/l & ± 15 %) 199 / 200 (99.5 %) 10/21

11 System Accuracy Evaluation of Test strip lot 3: Lot: TD14D928-C0E Within ± 15 mg/dl & ± 15 % (Within ± 0.83 mmol/l & ± 15 %) 194 / 200 (97.0 %) All three lots: Within Consensus Error Grid zones A and B 600 / 600 (100 %) Conclusion: The Fora BGMS met the requirements of new ISO standard (ISO 15197:2013). Detail results: System accuracy results for glucose concentrations < 100 mg/dl (5.55 mmol/l) Reagent system lot Within ± 5 mg/dl (Within ± 0.28 mmol/l) Within ± 10 mg/dl (Within ± 0.56 mmol/l) Within ± 15 mg/dl (Within ± 0.83 mmol/l) TD14D228-C0E 47 / 64 (73.4 %) 61 / 64 (95.3 %) 64 / 64 (100 %) TD14D828-C0E 50 / 64 (78.1 %) 61 / 64 (95.3 %) 63 / 64 (98.4 %) TD14D928-C0E 49 / 64 (76.6 %) 64 / 64 (100 %) 64 / 64 (100 %) System accuracy results for glucose concentrations 100 mg/dl (5.55 mmol/l) Reagent system lot Within ± 5 % Within ± 10 % Within ± 15 % TD14D228-C0E 72 / 136 (52.9 %) 118 / 136 (86.8 %) 134 / 136 (98.5 %) TD14D828-C0E 59 / 136 (43.4 %) 109 / 136 (80.2 %) 136 / 136 (100 %) TD14D928-C0E 64 / 136 (47.1 %) 108 / 136 (79.4 %) 130 / 136 (95.6 %) System accuracy results for glucose concentrations between 37 mg/dl (2.06 mmol/l) and mg/dl (26.4 mmol/l) Reagent system lot Within ± 5 mg/dl & ± 5 % (Within ± 0.28 mmol/l & ± 5 %) Within ± 10 mg/dl & ± 10 % (Within ± 0.56 mmol/l & ± 10 %) Within ± 15 mg/dl & ± 15 % (Within ± 0.83 mmol/l & ± 15 %) TD14D228-C0E 144 / 200 (72.0 %) 192 / 200 (96.0 %) 197 / 200 (98.5 %) TD14D828-C0E 142 / 200 (71.0 %) 195 / 200 (97.5 %) 197 / 200 (98.5 %) TD14D928-C0E 139 / 200 (69.5 %) 192 / 200 (96.0 %) 194 / 200 (97.0 %) 11/21

12 System Accuracy Evaluation of Accuracy results following ISO 15197:2003 Summary: Glucose concentration range: 37 mg/dl (2.06 mmol/l) to mg/dl (26.4 mmol/l) Test strip lot 1: Lot: TD14D228-C0E Within ± 15 mg/dl & ± 20 % (Within ± 0.83 mmol/l & ± 20 %) 199 / 200 (99.5 %) Test strip lot 2: Lot: TD14D828-C0E Within ± 15 mg/dl & ± 20 % (Within ± 0.83 mmol/l & ± 20 %) 199 / 200 (99.5 %) Test strip lot 3: Lot: TD14D928-C0E Within ± 15 mg/dl & ± 20 % (Within ± 0.83 mmol/l & ± 20 %) 200 / 200 (100.0 %) All three lots: Within Consensus Error Grid zones A and B 600 / 600 (100 %) Conclusion: Fora BGMS also is in compliance with the requirements of DIN EN ISO 15197:2003 for all 3 reagent system lot(s). 12/21

13 System Accuracy Evaluation of Detail results: System accuracy results for glucose concentrations < 75 mg/dl (4.2 mmol/l) Reagent system lot Within ± 5 mg/dl (Within ± 0.28 mmol/l) Within ± 10 mg/dl (Within ± 0.56 mmol/l) Within ± 15 mg/dl (Within ± 0.83 mmol/l) TD14D228-C0E 29 / 38 (76.3 %) 36 / 38 (94.7 %) 38 / 38 (100 %) TD14D828-C0E 32 / 38 (84.2 %) 35 / 38 (92.1 %) 37 / 38 (97.4 %) TD14D928-C0E 31 / 38 (81.6 %) 38 / 38 (100 %) 38 / 38 (100 %) System accuracy results for glucose concentrations 75 mg/dl (4.2 mmol/l) Reagent system lot Within ± 5 % Within ± 10 % Within ± 15 % Within ± 20 % TD14D228-C0E 88 / 162 (54.3 %) 142 / 162 (87.7 %) 160 / 162 (98.8 %) 161 / 162 (99.4 %) TD14D828-C0E 75 / 162 (46.3 %) 134 / 162 (82.7 %) 162 / 162 (100 %) 162 / 162 (100 %) TD14D928-C0E 81 / 162 (50.0 %) 133 / 162 (82.1 %) 156 / 162 (96.3 %) 162 / 162 (100 %) System accuracy results for glucose concentrations between 37 mg/dl (2.06 mmol/l) and mg/dl (26.4 mmol/l) Reagent system lot Within ± 5 mg/dl & ± 5 % (Within ± 0.28 mmol/l & ± 5 %) Within ± 10 mg/dl & ± 10 % (Within ± 0.56 mmol/l & ± 10 %) Within ± 10 mg/dl & ± 15 % (Within ± 0.56 mmol/l & ± 15 %) Within ± 15 mg/dl & ± 20 % (Within ± 0.83 mmol/l & ± 20 %) TD14D228-C0E 88 / 162 (54.3 %) 142 / 162 (87.7 %) 160 / 162 (98.8 %) 161 / 162 (99.4 %) TD14D828-C0E 75 / 162 (46.3 %) 134 / 162 (82.7 %) 162 / 162 (100 %) 162 / 162 (100 %) TD14D928-C0E 81 / 162 (50.0 %) 133 / 162 (82.1 %) 156 / 162 (96.3 %) 162 / 162 (100 %) 13/21

14 System Accuracy Evaluation of Consensus Error Grid for with three reagent system lots Region Number Percent A % B % C % D % E /21

15 System Accuracy Evaluation of Statistical Analysis Summary of bias analysis (Bland and Altman) n=200 Reagent system lot 1: TD14I615-CDC Reagent system lot 2: TD14I815-CDC Reagent system lot 3: TD14I915-CDC Bias 95% Limits of agreement Bias [%] 95% Limits of agreement [%] to to to to to to /21

16 Summary of regression analysis (Passing and Bablok) Fora System Accuracy Evaluation of n=200 Regression Reagent system lot 1: TD14D228-C0E Reagent system lot 2: TD14 D828-C0E Reagent system lot 3: TD14 D928-C0E Y= X Y= X Y= X 16/21

17 System Accuracy Evaluation of Blood Glucose Monitoring System Absolute differences between and YSI 2300 STAT PLUS 17/21

18 System Accuracy Evaluation of 4. Conclusion and discussion: This study showed that the Fora blood glucose monitoring system not only met the current accuracy standard (ISO15197:2003), but also exceeded the minimum acceptable accuracy standard published in the newer 2013 guideline (ISO15197:2013) when compared the test results with a laboratory reference. In addition, 99% of the data points fall within Zone A & B of Consensus Error Grid, which means that when user obtained a value using Fora monitor, it should not result in a clinical decision that could be deemed inappropriate. There are several glucose monitoring systems out in the market. Since FDA is in preparation of tightening the accuracy standard to ± 15% by adopting the new ISO15197:2013 standard. Based on the results, it will be reasonable assumption that Fora met the new ISO standard, and therefore would be a reasonable selection for users if they like to use meter with a higher accuracy. Reference a International Diabetes Federation, the global burden. b. In vitro diagnostic test systems - Requirements for blood-glucose monitoring systems for self-testing in managing diabetes mellitus. EN ISO 15197:2003. c. In vitro diagnostic test systems - Requirements for blood-glucose monitoring systems for self-testing in managing diabetes mellitus. ISO 15197:2013. d. Parkes JL, Slatin SL, Pardo S, Ginsberg BH: A new consensus error grid to evaluate the clinical significance of inaccuracies in the measurement of blood glucose. Diabetes Care 2000; 23: e. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: f. Passing H, Bablok. A new biometrical procedure for testing the equality of measurements from two different analytical methods. Application of linear regression procedures for method comparison studies in clinical chemistry, Part I. J Clin Chem Clin Biochem 1983; 21: /21

19 System Accuracy Evaluation of Blood Glucose Monitoring System Appendix Raw data with adjusted samples marked Subject- ID Diabetes type [1/2/NA] Sex [f/m] Age [years] Date Temperature [ ] Humidity [%] Haematocrit (meas.) [%] adjusted glucose category sampling time value2 sampling time Lot: TD14D228-C0E Lot: TD14D828-C0E Lot: TD14D928-C0E 1 NA m /10/ :11 07: m /10/ :09 08: m /10/ :28 08: f /10/ :45 08: NA m /10/ :05 09: NA f /10/ :28 09: NA m /10/ :00 10: NA f /10/ :11 10: NA f /10/ :34 10: NA m /10/ :54 10: NA m /10/ :12 11: NA m /10/ :06 13: m /10/ :29 13: f /10/ :51 13: m /10/ :39 14: m /10/ :53 14: f /10/ :32 15: NA /10/ :35 15: f /10/ :56 15: f /10/ :03 16: f /10/ :21 07: m /10/ :37 07: m /10/ :43 07: m /10/ :08 08: f /10/ :44 08: f /10/ :18 09: m /10/ :21 09: f /10/ :37 09: m /10/ :59 10: f /10/ :14 10: f /10/ :30 10: NA f /10/ :50 10: m /10/ :44 11: f /10/ :47 11: NA /10/ :20 13: m /10/ :39 13: f /10/ :45 13: f /10/ :07 14: f /10/ :41 14: f /10/ :07 15: /21

20 System Accuracy Evaluation of Blood Glucose Monitoring System Subject- ID Diabetes type [1/2/NA] Sex [f/m] Age [years] Date Temperature [ ] Humidity [%] Haematocrit (meas.) [%] adjusted glucose category sampling time value2 sampling time Lot: TD14D228-C0E Lot: TD14D828-C0E Lot: TD14D928-C0E 43 2 m /10/ :30 15: m /10/ :43 15: m /10/ :21 07: f /10/ :45 07: f /10/ :02 08: f /10/ :44 08: f /10/ :01 09: f /10/ :27 09: m /10/ :38 09: m /10/ :14 10: m /10/ :35 10: f /10/15 73, :08 11: m /10/ :34 11: m /10/ :58 13: f /10/ :13 13: m /10/ :37 13: m /10/ :01 14: m /10/ :36 14: m /10/ :52 14: f /10/ :09 15: NA /10/ :45 15: m /10/ :36 07: NA NA /10/ :53 07: m /10/ :11 08: m /10/ :33 08: f /10/ :56 08: f /10/ :11 09: NA /10/ :40 09: m /10/ :11 11: m /10/ :47 10: f /10/ :24 11: f /10/ :12 13: f /10/ :39 13: NA /10/ :09 14: NA /10/ :55 14: f /10/ :23 15: f /10/ :20 15: f /10/ :43 15: NA f /10/ :21 16: NA f /10/ :39 16: /21

21 System Accuracy Evaluation of Blood Glucose Monitoring System Subject- ID Diabetes type [1/2/NA] Sex [f/m] Age [years] Date Temperature [ ] Humidity [%] Haematocrit (meas.) [%] adjusted glucose category sampling time value2 sampling time Lot: TD14D228-C0E Lot: TD14D828-C0E Lot: TD14D928-C0E 86 1 m /10/ :03 07: f /10/ :03 08: f /10/ :51 09: m /10/ :07 09: m /10/ :14 10: f /10/ :57 09: NA /10/ :58 12: f /10/ :54 16: m /10/ :32 16: m /10/ :10 16: m /10/ :18 13: m /10/ :23 13: m /10/ :49 16: f /10/ :12 14: NA /10/ :23 15: NA /10/ :30 15: NA f /10/ :04 13: NA m /10/ :18 13: NA m /10/ :12 11: NA f /10/ :11 13: /21