DEXCOM G4® PLATINUM (PEDIATRIC) CONTINUOUS GLUCOSE MONITORING SYSTEM

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION | Device Generic Name: | Continuous Glucose Monitoring System | | --- | --- | | Device Trade Name: | Dexcom G4 PLATINUM (Pediatric) Continuous Glucose Monitoring System | | Device Procode: | MDS | | Applicant's Name and Address: | Dexcom Inc. 6340 Sequence Drive San Diego, CA 92121 | | Date(s) of Panel Recommendation: | None | | Premarket Approval Application (PMA) Number: | P120005/S002 | | Date of FDA Notice of Approval: | February 3, 2014 | | Expedited: | not applicable | The original PMA (P120005) was approved on October 5, 2012 and is indicated for detecting trends and tracking patterns in persons (age 18 and older) with diabetes. The SSED to support the indication is available on the CDRH website and is incorporated by reference here. The current supplement was submitted to expand the indication for pediatric patients (ages 2 to 17 years) and to add an alternate sensor insertion site on the upper buttocks for the pediatric population. ## II. INDICATIONS FOR USE The Dexcom G4 PLATINUM (Pediatric) Continuous Glucose Monitoring System is a glucose monitoring device indicated for detecting trends and tracking patterns in persons ages 2 to 17 with diabetes. The system is intended for single patient use and requires a prescription. The Dexcom G4 PLATINUM (Pediatric) System is indicated for use as an adjunctive device to complement, not replace, information obtained from standard home glucose monitoring devices. The Dexcom G4 PLATINUM (Pediatric) System aids in the detection of episodes of hyperglycemia and hypoglycemia, facilitating both acute and long-term therapy adjustments, which may minimize these excursions. Interpretation of the Dexcom G4 PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 1 {1} PLATINUM (Pediatric) System results should be based on the trends and patterns seen with several sequential readings over time. ### III. CONTRAINDICATIONS - Remove the Dexcom G4 PLATINUM sensor, transmitter, and receiver before Magnetic Resonance Imaging (MRI), Computed Tomography (CT) scan, or diathermy treatment. The Dexcom G4 PLATINUM (Pediatric) System has not been tested during MRI or CT scans or with diathermy treatment. The magnetic fields and heat could damage the device so that it might not display sensor glucose readings or provide alerts, and you might miss a low or high blood glucose value. - Taking medications with acetaminophen (such as Tylenol) while wearing the sensor may falsely raise your sensor glucose readings. The level of inaccuracy depends on the amount of acetaminophen active in your body and may be different for each person. ### IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Dexcom G4 PLATINUM (Pediatric) Continuous Glucose Monitoring labeling. ### V. DEVICE DESCRIPTION The current supplement is for the addition of a pediatric indications for use (ages 2 to 17 years) to the previously approved Dexcom G4 PLATINUM Continuous Glucose Monitoring System and to add an alternate insertion site on the upper buttocks for the pediatric population. The Dexcom G4 Platinum (Pediatric) Continuous Glucose Monitoring System (“The Pediatric System”) consists of the following components: the Dexcom G4 Platinum (Pediatric) Receiver, Dexcom G4 Platinum Transmitter, Dexcom G4 Platinum Sensor. No modifications were made to the sensor or transmitter components in this supplement. The receiver was modified to include warnings, as push notifications (that require user acknowledgement to continue use), relevant to the performance in the pediatric clinical study versus the adult study (See Section X.D.2 below for details on the study data and warnings). The pediatric receiver is differentiated from the previously approved adult receiver by using a new name (Dexcom G4 Platinum (Pediatric) Receiver). See the SSED for P120005 for a detailed device description. ### VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the control of diabetes. Control of diabetes can be achieved through a combination of methods and behaviors. Self-behaviors include healthy eating, taking medications, as appropriate, and being active. Methods of PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 2 {2} controlling glucose levels (glycemic control) have been shown to reduce severe diabetes-related complications. Methods of monitoring glycemic control include periodic measurement of Hemoglobin A1c (HbA1c), which reflects average blood glucose levels over a three month period. Self-monitoring of blood glucose using glucose meters and test strips provides quantitative measurements of fingerstick blood glucose at a single point in time for patients and their healthcare providers to monitor the effectiveness of glycemic control and make more immediate treatment modifications. Each alternative method for monitoring glycemic control has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY The Dexcom G4 PLATINUM (Pediatric) Continuous Glucose Monitoring System has not been marketed in the United States or any foreign country. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g. complications) associated with the use of the device. The following are possible effects of inserting a Sensor and wearing the adhesive patch: redness at the sensor insertion site, skin irritation (erythema/edema), local infection, inflammation, pain or discomfort, bleeding at the glucose Sensor insertion site, bruising, itching, scarring or skin discoloration, hematoma, tape irritation, Sensor or needle fracture during insertion, wear or removal. The risk related to either an inaccurate sensor value which should be outside of the patient's target range, missed alerts, false alerts, false negative hypoglycemia and hyperglycemic readings and false positive hypoglycemia and hyperglycemia is the risk of the device not alerting the user that additional blood glucose testing with a meter should be performed. Patients may also rely on the CGM to alert them to low glucose levels, which is of particular concern with the use of this device in pediatrics due to the poor low alert performance. Inaccurate calculation of the rate of change of glucose by the CGM could prevent a patient from performing additional blood glucose tests or taking measures to stop a trend of increasing or decreasing glucose levels which could lead to serious hypoglycemia or hyperglycemia if no action is taken to stop these glucose trends. There is a risk that patients that are relying on CGM values won't perform fingerstick testing as often as they would without the CGM. For the specific adverse events that occurred in the clinical studies, please see Section X below and the SSED for the original PMA (P120005). PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 3 {3} ## **IX. SUMMARY OF PRECLINICAL STUDIES** No new preclinical studies were submitted or required for the approval of the expanded indication proposed in this PMA Supplement. Please see the original P120005 SSED for details. ## **X. SUMMARY OF PRIMARY CLINICAL STUDIES** The applicant performed a pivotal clinical study to establish a reasonable assurance of safety and effectiveness of the Dexcom G4 Platinum (Pediatric) System in participants ages 2 to 17 years old for detecting trends and tracking patterns when used as an adjunct to blood glucose testing in subjects with diabetes mellitus. Data from this clinical study were the basis for the PMA supplement approval decision. A summary of the clinical study is presented below. ### **A. Study Design** Subjects were screened starting July 27, 2012 and the final subject's participation ended on December 17, 2012. A total of 176 patients were enrolled at 6 U.S. investigational sites. The purpose of the pivotal study was to evaluate the safety and effectiveness of the G4 Platinum (Pediatric) System when used as an adjunct to blood glucose testing over a 7-day period in subjects 2 to 17 years-old with diabetes mellitus. The study was an open-label, non-randomized, single-arm, multi-center, pivotal study. All 176 enrolled subjects participated in one G4 PLATINUM System sensor session for one 7-day wear period (168 hours) and wore two sensors simultaneously in either the abdomen, upper buttocks or one in each site. One of each of the paired systems was blinded (CGM values, trends, alerts/alarms not provided or displayed) and the other was unblinded during home use. Subjects manually entered fingerstick measurement values for calibration into both Receivers and were instructed to enter the same calibration values to both Receivers at the same time (one immediately after the other). The blinded CGM system was only used to evaluate device precision; the unblinded CGM system was considered the primary CGM system for device performance in comparison to the laboratory reference, Yellow Springs Instrument 2300 STAT Plus Glucose Analyzer. For the duration of this study, subjects were instructed to use CGM System information as an adjunct to (and not as a replacement for) standard self-monitoring blood glucose guidance of diabetes self-management. Three hundred sixty (360) Sensors were inserted, 8 (2%) of which were replacements. Three hundred fifty five (355) Receivers were used with three (3) replacements needed. Three hundred fifty-two (352) Transmitters were used with no replacements needed. The mechanical integrity of each sensor was assessed after removal. There were no reports of broken sensor wires. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 4 {4} ### In-Clinic Portion of the Study – The primary objective was to characterize the G4 Platinum (Pediatric) System performance in comparison to laboratory reference measurements on venous blood samples and against and self-monitoring blood glucose (SMBG) fingerstick measurements. There was no separate control group. The study evaluated the System performance with the abdomen and upper buttocks used as sensor insertion sites. The performance of the System was determined across the 7 days of sensor wear time. The study population comprised children and adolescents (ages 2 to 17) with diabetes mellitus. The study population was categorized in two age groups: Pre-school age (2 to 5 years) and school age (6 to 17 years). All subjects participated in one in-clinic session on day 1, 4 or 7 of sensor wear. For the subjects between ages 6-17 the in-clinic session was for up to six hours in duration. These subjects had venous blood draws (every 15 +/- 5 min) to allow for the comparison of the System to the reference method. These subjects also provided at least 2 fingerstick samples per hour (and as indicated for diabetes management or clinical safety purposes) for measures against SMBG. The in-clinic secession for subjects between 2 and 5 years of age lasted up to 4 hours, during which they were asked to only take at least two fingersticks per hour for comparison against SMBG measurements. The device performance for subjects 6-17 was primarily evaluated in terms of point and rate accuracy of the System in comparison to reference glucose measurements. The evaluation involved the assessment of many analyses of the data generated during the study (see Tables 3 to 15; Section X.D.2). Subjects' glucose levels were not intentionally manipulated during this study, so there are fewer data samples in the low and high glucose ranges than in the adult clinical study (P120005; age 18 and older). The study also characterized the CGM performance in comparison to SMBG measurements taken for all participants (2-17 years) using the LifeScan OneTouch Verio IQ blood glucose monitoring system. ### Home Portion of the Study – The remainder of the study, time between the in-clinic sessions, took place at home. During home use, the subjects used the blood glucose meter and test strips provided to take a minimum of 7 fingersticks per day for calibration, and to collect accuracy information against SMBG (the LifeScan OneTouch Verio IQ blood glucose monitoring system). Subjects were advised to conduct daily activities as normal during the use of the System. The subjects returned to the clinic at the end of the 7 day wear period to remove the sensor, and the sensor insertion sites were examined by the study staff. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 5 {5} 1. Clinical Inclusion and Exclusion Criteria Enrollment in the study was limited to patients who met the following inclusion criteria: a. Age 2 to 17 years b. Diagnosis of diabetes mellitus c. Would participate in one 7-day Sensor wear period d. Would wear 2 systems simultaneously (in either the abdomen, upper buttocks, or a combination of both sites) e. Would insert sensors on their own or have parent/guardian insert sensors f. Would not inject insulin or wear an insulin pump insertion set within 3 inches from the sensor sites during sensor wear g. Would only use the blood glucose meter provided for all blood glucose measurements performed during sensor wear h. Subjects ages 2-5, would participate in one in-clinic session of up to 4 hours in duration, during which at least 2 fingerstick measurements per hour (and as indicated for diabetes management or clinical safety purposes) were taken i. For subjects ages 6-17, would participate in one in-clinic session of up to 6 hours in duration, during which at least 2 fingerstick measurements per hour (and as indicated for diabetes management or clinical safety purposes) were taken j. For subjects ages 6-17, would have an intravenous catheter inserted for 4 blood draws per hour up to 6 hours during the in-clinic session and not to exceed 3 ml/kg k. Would take a minimum of 7 fingerstick measurements per day during home use (required fingerstick measurements for calibration purposes, additional for confirmatory/comparative purposes) with the blood glucose meter provided l. Would refrain from the use of acetaminophen during the Sensor wear period and for at least 24-hours prior to Sensor insertion m. Subject or guardian was able to speak, read, and write English Patients were not permitted to enroll in the study if they met any of the following exclusion criteria: a. Had extensive skin changes/diseases that precluded wearing the required number of devices on normal skin (e.g., extensive psoriasis, recent burns or severe sunburn, extensive eczema, extensive scarring, extensive tattoos, dermatitis herpetiformis) at the wear sites b. Had a known allergy to medical-grade adhesives c. Were pregnant as demonstrated by a positive pregnancy test within 72 hours of sensor insertion d. Had a hematocrit value that is outside the range of the blood glucose monitoring system used in the study e. Were participating in another investigational study protocol (if a subject had recently completed participation in another drug study, the subject must have completed that study at least 30 days prior to being enrolled in this study) PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 6 {6} f. Had a planned MRI scan, CT scan, or diathermy scheduled during the week of the study g. Had any condition that, in the opinion of the Investigator, would interfere with their participation in the trial (e.g., marked visual impairment) or pose an excessive risk to study staff (e.g., known history of hepatitis B or C, or HIV) # 2. Follow-up Schedule At the end of the study 7 day wear period (168 hours), subjects and guardians returned to the clinic to remove the systems by themselves. Upon removal, all the Sensor insertion sites were examined and evaluated by the study staff. Sensors were visually inspected at the study site for gross mechanical failure and the observations were documented. All used and unused Systems (including sensor, transmitter, and receiver) were returned by study staff to Dexcom. All used sensors underwent formal inspection under magnification. Study staff documented any Adverse Device Effects throughout the study to evaluate safety issues related to system use during the study. No long-term follow up was included in this study protocol. # 3. Clinical Endpoints The study characterized the performance of the system (6-17 year olds) in comparison with the laboratory reference venous sample measurements and assessed the system-reference matched pairs obtain in the in-clinic sessions. The study also characterized the CGM performance in comparison to SMBG measurements taken for all participants (2-17 years) and evaluated the CGM performance at an alternate insertion site (upper buttocks). Safety data of the System were also collected and characterized by the incidence and severity of Adverse Device Effects, Serious Adverse Device Events, and Unanticipated Adverse Device Effects experienced by study subjects. # B. Accountability of PMA Cohort All 176 subjects enrolled into the study participated in the in-clinic and the home portions of the study. Subjects ages 6-17 years contributed CGM-reference matched pairs to the efficacy data during the in-clinic portion of the study. All participants (2-17 years) contributed at least two fingerstick measurements per hour for comparison against SMBG measurements taken for using the LifeScan OneTouch Verio IQ blood glucose monitoring system during the in-clinic portion of the study. # C. Study Population Demographics and Baseline Parameters The demographics of the study population are typical for a continuous glucose monitoring system study performed in the US. See the following tables (Tables 1 and 2) for a description of the demographics and baseline characteristics of the study population. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 7 {7} **Table 1. Subject Demographics** | Category | Number of Subjects Enrolled (N=176) | | --- | --- | | Gender, N (%) | | | Male | 100 (57%) | | Female | 76 (43%) | | Age (years) | | | Mean | 11.5 | | SD | 4.2 | | Range | 2.3 – 17.9 | | Subjects < 6 | 29 (16%) | | Race | | | White | 165 (94%) | | Asian | 1 (1%) | | Black, African American, or of African Heritage | 2 (1%) | | Other | 8 (5%) | | Ethnicity | | | Hispanic or Latino | 21 (12%) | **Table 2. Subject Baseline Parameters** | Type of Diabetes at Diagnosis | | | --- | --- | | Type I | 175 (99%) | | Type II | 1 (1%) | | Diabetes Duration (years) | | | Mean | 4.8 | | SD | 3.7 | | Range | 0 - 16 | | Body Mass Index (kg/m^{2}) | | | Mean | 20.1 | | SD | 4.5 | | Range | 11.5 to 37.3 | | Baseline A1c (%) | | | Mean | 8.2 | | SD | 1.4 | | Range | 5.6-13.4 | #### **D. Safety and Effectiveness Results** ##### **1. Safety Results** PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 8 {8} The analysis of safety was based on all subjects enrolled for whom at least one sensor was inserted for the purposes of the study. The study enrolled 176 subjects for whom a total of 360 sensors were used (subjects wore two sensors concurrently). The safety data of the Pediatric System were assessed by evaluation of the incidence of all Adverse Device Effects (ADEs), Serious Adverse Device Events (SADEs), and Unanticipated Adverse Device Effects (UADEs) experienced by study subjects. Adverse events (AEs) were listed in terms of severity and relationship to device. Sensor insertion site and adhesive area were examined for erythema, edema and infection. The local skin reactions from the insertion site or the adhesive were evaluated quantitatively using Draize classifications. Adverse effects are described below. ***Adverse effects that occurred in the PMA clinical study:*** A total of 21 AEs were reported during the study affecting 14 subjects (8%). There were no UADEs or SAEs reported. No infections occurred at either insertion or adhesive areas. Seventeen (17) AEs were classified by the Investigators as mild or of moderate intensity and probably related to the device (ADEs). Sixteen (16) of these occurred in 9 subjects, and were related to the skin irritation (erythema/edema), defined as Draize score 2 and above. One (1) AE was reported due to pain/discomfort, deemed excessive per protocol, because the pain/discomfort continued during the wear period when the subject sat or laid down (buttocks location). Four (4) AEs were categorized as “Other”, and were device, disease or study related: - One (1) subject had redness at the sensor insertion site - One (1) subject had mild edema/erythema and a small skin cut at the location of the sensor pod. - One (1) disease related AE pertained to symptomatic hyperglycemia that was treated by the parent with insulin. - One (1) study-related AE involved a brief period of syncope during IV insertion attempts during the clinic session. The subject was provided juice and required no additional intervention from study staff. These events were classified as mild in severity, and skin irritation events either resolved by end of the subject’s study participation or were deemed on-going but stable at the termination visit. The very slight skin irritations, such as erythema and edema, occurred in low frequency and were consistent with the rates observed in previous clinical studies of the CGM system. No infection, bruising or bleeding occurred at the sensor needle insertion area or the adhesive area. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 9 {9} All adverse events were resolved or stable at study termination. Per protocol, the mechanical integrity of each Sensor was independently assessed after removal of the Sensor from the subcutaneous adipose tissue. There were no reports of broken Sensor wires. # 2. Effectiveness Results The primary effectiveness measurements for this study were based on the performance evaluation of the Dexcom G4 Platinum (Pediatric) System compared to the blood glucose values measured by the reference method (reference) during in-clinic sessions. Key effectiveness outcomes are presented in the tables below (Tables 3 to 15). The pediatric data is presented in tables 3A, 4A, 5A, 6A, 7A and C, 8A and C, and 9-15 and the adult data is provided for comparison in Tables 3B, 4B, 5B, 6B, 7B and 8B. # Agreement of Pediatric CGM System Results with Reference Readings: Agreement between the Pediatric CGM System and blood glucose values is characterized using paired CGM and reference values. The CGM and reference results were compared by pairing the reference blood glucose value to a CGM glucose reading that occurred immediately after the reference measurement was collected. The agreement of the Pediatric CGM System readings to blood glucose values was assessed by calculating the percentage of CGM readings that were within 15%, 20%, 30%, 40% and greater than 40% of the reference values. The total number of data pairs considered in this analysis was 9152. A total of 9555 Sensor-reference matched pairs were collected in this study; however, the final analysis included CGM readings that were within the measuring range of the System (40-400 mg/dL) (See also Tables 4A and 4B below). Eighty-two percent (82%) of the System readings fall within ±20 mg/dL (1.1 mmol/L) of the reference blood glucose values (< 80 mg/dL or 4.4 mmol/L) and within ±20% of the reference blood glucose values (≥ 80 mg/dL or 4.4 mmol/L). For readings less than or equal to 80 mg/dL (4.4 mmol/L) glucose the absolute difference in mg/dL (mmol/L) between the two glucose results was calculated. For values greater than 80 mg/dL (4.4 mmol/L) the absolute percent difference (%) from the reference values was calculated. The percentages of total readings within 15mg/dL (0.8 mmol/L) or 15%, 20 mg/dL (1.1 mmol/L) or 20%, 30 mg/dL (1.7 mmol/L) or 30%, 40 mg/dL (2.2 mmol/L) or 40% or greater than 40 mg/dL (2.2 mmol/L) or 40% were then calculated. Table 3-A is categorized within CGM glucose concentrations (first column) and outlines how often a reading on the CGM matched the reference blood glucose reading for pediatric ages 6-17 years old. Table 3-B similarly describes the data from the adult study (P120005) for comparison. Table 3-A. System Agreement to Reference (Ref) within CGM Glucose Ranges (Pediatric Study) PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 10 {10} | CGM Glucose Range mg/dL (mmol/L) | Number of paired CGM-Ref | Percent within 15/15% Ref | Percent within 20/20% Ref | Percent within 30/30% Ref | Percent within 40/40% Ref | Percent Greater than 40/40% Ref | | --- | --- | --- | --- | --- | --- | --- | | Overall | 2922 | 55% | 68% | 85% | 93% | 7% | | 40-60 (2.2-3.3) | 19 | 63% | 74% | 79% | 79% | 21% | | 61-80 (3.4-4.4) | 76 | 61% | 82% | 92% | 96% | 4% | | 81-180 (4.5-10.0) | 1155 | 56% | 69% | 84% | 94% | 6% | | 181-300 (10.1-16.7) | 1380 | 55% | 68% | 85% | 93% | 7% | | 301-350 (16.7-19.4) | 206 | 48% | 62% | 80% | 89% | 11% | | 351-400 (19.4-22.2) | 86 | 48% | 61% | 79% | 88% | 12% | Note: CGM readings are within 40-400 mg/dL (2.2-22.2 mmol/L). **Table 3-B. System Agreement to Reference (Ref) within CGM Glucose Ranges (Adult Study)** | CGM Glucose Range mg/dL (mmol/L) | Number of paired CGM-Ref | Percent within 15/15% Ref | Percent within 20/20% Ref | Percent within 30/30% Ref | Percent within 40/40% Ref | Percent Greater than 40/40% Ref | | --- | --- | --- | --- | --- | --- | --- | | Overall | 9152 | 71% | 82% | 92% | 97% | 3% | | 40-60 (2.2-3.3) | 512 | 67% | 78% | 88% | 94% | 6% | | 61-80 (3.4-4.4) | 781 | 73% | 85% | 94% | 98% | 2% | | 81-180 (4.5-10.0) | 3853 | 67% | 78% | 91% | 97% | 3% | | 181-300 (10.1-16.7) | 2784 | 72% | 84% | 93% | 96% | 4% | | 301-350 (16.7-19.4) | 775 | 82% | 91% | 97% | 98% | 2% | | 351-400 (19.4-22.2) | 447 | 74% | 84% | 91% | 95% | 5% | Note: CGM readings are within 40-400 mg/dL (2.2-22.2 mmol/L). # ***Agreement of CGM to Reference When CGM Reads “Low” or “High”:*** PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 11 {11} The System reports glucose concentrations between 40 and 400 mg/dL (2.2-22.2 mmol/L). When the G4 Pediatric System determines the glucose level is below 40 mg/dL (2.2 mmol/L), the Receiver displays “LOW” in Status Box. When the G4 Pediatric System determines that the glucose level is above 400 mg/dL (22.2 mmol/L), the Receiver displays “HIGH” in the Status Box. Because the System does not display glucose values below 40 mg/dL (2.2 mmol/L) or above 400 mg/dL (22.2 mmol/L), the comparisons to the actual blood glucose concentrations (as determined by the reference analyzer) when CGM is classified as “LOW” or “HIGH” are included separately in the following tables. Table 4-A summarizes the data from pediatric subjects ages 6-17 years and table 4-B similarly describes the data from the adult study (P120005) for comparison. The tables include the percentages of when reference values were less than certain glucose levels (for ‘LOW’), and when reference values were greater than certain glucose levels (for ‘HIGH’). **Table 4A. Number and Percentage of Reference (Ref) values when CGM readings are ‘LOW’ or ‘HIGH’ (Pediatric Study).** | Reference mg/dL (mmol/L) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | CGM Readings | CGM-Ref pairs | <55 (3.1) | <60 (3.3) | <70 (3.9) | <80 (4.4) | >80 (4.4) | Total | | ‘LOW’ | n | 0 | 0 | 0 | 0 | 13 | 13 | | | % | 0% | 0% | 0% | 0% | 100% | | | Reference mg/dL (mmol/L) | | | | | | | | | CGM Readings | CGM-Ref pairs | >340 (18.9) | >320 (17.8) | >280 (15.6) | >240 (13.3) | <240 (13.3) | Total | | ‘HIGH’ | n | 38 | 51 | 68 | 69 | 1 | 70 | | | % | 54% | 73% | 97% | 99% | 1% | | Note: In the pediatric clinical study, the subject’s glucose levels were not intentionally manipulated during this study, so there are fewer data samples in the low and high glucose ranges than in the adult clinical study. **Table 4B. Number and Percentage of Reference (Ref) values when CGM readings are ‘LOW’ or ‘HIGH’ (Adult Study).** | Reference mg/dL (mmol/L) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | CGM Readings | CGM-Ref pairs | <55 (3.1) | <60 (3.3) | <70 (3.9) | <80 (4.4) | >80 (4.4) | Total | | ‘LOW’ | n | 64 | 82 | 122 | 142 | 13 | 155 | | | % | 41% | 53% | 79% | 92% | 8% | | | Reference mg/dL (mmol/L) | | | | | | | | | CGM Readings | CGM-Ref pairs | >340 (18.9) | >320 (17.8) | >280 (15.6) | >240 (13.3) | <240 (13.3) | Total | | ‘HIGH’ | n | 189 | 220 | 238 | 246 | 2 | 248 | | | % | 76% | 89% | 96% | 99% | 1% | | PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 12 {12} The results above in Table 4A demonstrate that the pediatric study had poorer performance at low values (40 mg/dL) as compared with the adult study (P120005). Table 4A shows that, per the reference reading, the subject had a blood glucose value >80 mg/dL 100% of the time (13 total instances) the CGM displayed “LOW” (i.e., <40 mg/dL). For comparison, the adult subjects had blood glucose values >80 mg/dL only 8% of the time when the CGM read “LOW” (Table 4B). The pediatric and adult study demonstrated similar performance in detecting “HIGH” glucose values (>400 mg/dL). ### Concurrence of System and Laboratory Reference Values: The percentage of concurring CGM readings and reference values were included in Table 5-A (pediatric study from ages 6-17 year olds) and 5-B (adult study conducted in P120005). The tables are categorized by each CGM glucose range (first column) and describe, for each range of CGM glucose readings, what percentage of paired reference values were in the same glucose range (shaded) or in glucose ranges above and below the paired CGM readings. Table 5-A. Concurrence of CGM System Readings and Reference (Ref) values (Pediatric Study). PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 13 {13} | CGM mg/dL (mmol/L) | Number of Paired CGM-Ref | Percent of matched pairs in each Ref glucose range for each Sensor glucose range Ref mg/dL (mmol/L) | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | <40 (<2.2) | 40-60 (2.2- 3.3) | 61- 80 (3.4- 4.4) | 81- 120 (4.4- 6.7) | 121- 160 (6.7- 8.9) | 161- 200 (8.9- 11.1) | 201- 250 (11.1- 13.9) | 251- 300 (13.9- 16.7) | 301- 350 (16.7- 19.4) | 351- 400 (19.4- 22.2) | >400 (>22.2) | | <40 (<2.2) | 13 | 0% | 0% | 0% | 54% | 31% | 15% | 0% | 0% | 0% | 0% | 0% | | 40- 60 (2.2- 3.3) | 19 | 0% | 21% | 58% | 16% | 5% | 0% | 0% | 0% | 0% | 0% | 0% | | 61- 80 (3.4- 4.4) | 76 | 0% | 21% | 45% | 30% | 4% | 0% | 0% | 0% | 0% | 0% | 0% | | 81- 120 (4.4- 6.7) | 338 | 0% | 1% | 20% | 66% | 12% | 1% | 0% | 0% | 0% | 0% | 0% | | 121- 160 (6.7- 8.9) | 511 | 0% | 0% | 1% | 36% | 54% | 7% | 1% | 0% | 0% | 0% | 0% | | 161- 200 (8.9- 11.1) | 596 | 0% | 0% | 0% | 4% | 40% | 48% | 6% | 1% | 0% | 0% | 0% | | 201- 250 (11.1- 13.9) | 658 | 0% | 0% | 0% | 1% | 9% | 44% | 41% | 5% | 0% | 0% | 0% | | 251- 300 (13.9- 16.7) | 432 | 0% | 0% | 0% | 0% | 2% | 7% | 50% | 36% | 3% | 0% | 2% | | 301- 350 (16.7- 19.4) | 206 | 0% | 0% | 0% | 0% | 0% | 2% | 18% | 59% | 21% | 0% | 0% | | 351- 400 (19.4- 22.2) | 86 | 0% | 0% | 0% | 0% | 0% | 0% | 3% | 28% | 50% | 16% | 2% | | >400 (>22.2) | 70 | 0% | 0% | 0% | 0% | 0% | 0% | 1% | 14% | 41% | 36% | 7% | Table 5-B. Concurrence of CGM System Readings and Reference (Ref) values (Adult Study). PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 14 {14} | CGM mg/dL (mmol/L) | Number of Paired CGM-Ref | Percent of matched pairs in each Ref glucose range for each Sensor glucose range Ref mg/dL (mmol/L) | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | <40 (<2.2) | 40-60 (2.2-3.3) | 61-80 (3.4-4.4) | 81-120 (4.4-6.7) | 121-160 (6.7-8.9) | 161-200 (8.9-11.1) | 201-250 (11.1-13.9) | 251-300 (13.9-16.7) | 301-350 (16.7-19.4) | 351-400 (19.4-22.2) | >400 (>22.2) | | <40 (<2.2) | 155 | 6% | 48% | 37% | 7% | 1% | 0% | 0% | 0% | 0% | 0% | 0% | | 40- 60 (2.2- 3.3) | 512 | 4% | 49% | 36% | 11% | 1% | 0% | 0% | 0% | 0% | 0% | 0% | | 61- 80 (3.4- 4.4) | 781 | 0% | 22% | 51% | 24% | 1% | 0% | 0% | 0% | 0% | 0% | 0% | | 81- 120 (4.4- 6.7) | 1706 | 0% | 2% | 17% | 66% | 13% | 1% | 0% | 0% | 0% | 0% | 0% | | 121- 160 (6.7- 8.9) | 1492 | 0% | 0% | 1% | 25% | 60% | 13% | 2% | 0% | 0% | 0% | 0% | | 161- 200 (8.9- 11.1) | 1240 | 0% | 0% | 0% | 2% | 28% | 53% | 16% | 2% | 0% | 0% | 0% | | 201- 250 (11.1- 13.9) | 1181 | 0% | 0% | 0% | 0% | 3% | 21% | 51% | 21% | 3% | 1% | 0% | | 251- 300 (13.9- 16.7) | 1018 | 0% | 0% | 0% | 0% | 0% | 4% | 19% | 49% | 24% | 3% | 0% | | 301- 350 (16.7- 19.4) | 775 | 0% | 0% | 0% | 0% | 0% | 0% | 3% | 28% | 51% | 16% | 1% | | 351- 400 (19.4- 22.2) | 447 | 0% | 0% | 0% | 0% | 0% | 0% | 3% | 10% | 43% | 38% | 7% | | >400 (>22.2) | 248 | 0% | 0% | 0% | 0% | 0% | 0% | 1% | 6% | 21% | 57% | 15% | ### *Evaluation of Accuracy:* Accuracy between matched pairs was also estimated for participants ages 6 to 17 years by calculating the percent difference between the System reading and the reference value. The System and reference values were compared by pairing the System reading that fell immediately after the reference value was collected. The mean percent difference is the average of all positive and negative percent differences between the two devices and demonstrates whether the System reads higher or lower on average than the reference at each glucose range. Another estimate used to evaluate the accuracy of the System is the absolute percent difference. The absolute percent difference provides the percent difference or 'distance' between the System and reference values, but does not PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 15 {15} demonstrate whether the System is reading, on average, higher or lower than the reference standard. The mean absolute percent difference is the average “distance” (regardless if positive or negative) between System readings and reference values. These accuracy measures in differences are based on 2922 paired glucose results and summarized in the following tables (Tables 6-A and Table 6-B) represent the system difference within CGM glucose ranges from the pediatric and adults studies, respectively. Table 6-A. System Difference to Reference (Ref) within CGM Glucose Ranges (Pediatric Study). | CGM Glucose Ranges mg/dL (mmol/L) | # of Paired System -Ref | Mean Percent Difference (%) | Median Percent Difference (%) | Mean Absolute Percent Difference (%) | Median Absolute Percent Difference (%) | | --- | --- | --- | --- | --- | --- | | Overall | 2922 | 13.5 | 11.6 | 17.4 | 13.5 | | 40-60 (2.2-3.3) | 19 | -18.1 (-1.0) | -9.1 (-0.5) | 19.2 (1.1) | 9.1 (0.5) | | 61-80 (3.4-4.4) | 76 | -3.7 (-0.2) | -2.3 (-0.1) | 13.4 (0.7) | 10.6 (0.6) | | 81-180 (4.5-10.0) | 1155 | 11.9 | 9.7 | 17.0 | 13.0 | | 181-300 (10.1-16.7) | 1380 | 14.8 | 12.4 | 17.4 | 13.3 | | 301-350 (16.7-19.4) | 206 | 19.2 | 15.9 | 19.4 | 15.9 | | 351-400 (19.4-22.2) | 86 | 18.5 | 15.5 | 19.1 | 15.5 | * For CGM≤ 80 mg/dL (4.4 mmol/L), the differences in mg/dL (mmol/L) are included instead of percent differences (%). Note: CGM readings are within 40 to 400 mg/dL (2.2-22.2 mmol/L), inclusive. Table 6-B. System Difference to Reference (Ref) within CGM Glucose Ranges (Adult Study). PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 16 {16} | CGM Glucose Ranges mg/dL (mmol/L) | # of Paired System -Ref | Mean Percent Difference (%) | Median Percent Difference (%) | Mean Absolute Percent Difference (%) | Median Absolute Percent Difference (%) | | --- | --- | --- | --- | --- | --- | | Overall | 9152 | 2.9 | 1.7 | 13.3 | 9.8 | | 40-60 (2.2-3.3) | 512 | -10.0 (-0.6) | -8.2 (-5.2) | 13.5 (0.8) | 9.7 (0.5) | | 61-80 (3.4-4.4) | 781 | -2.4 (-0.1) | -0.4 (0.0) | 11.4 (0.6) | 8.6 (0.5) | | 81-180 (4.5-10.0) | 3853 | 4.8 | 3.0 | 13.8 | 9.8 | | 181-300 (10.1-16.7) | 2784 | 2.1 | 0.0 | 11.9 | 9.2 | | 301-350 (16.7-19.4) | 775 | 3.8 | 2.8 | 9.8 | 7.9 | | 351-400 (19.4-22.2) | 447 | 10.4 | 7.7 | 12.8 | 9.1 | * For CGM ≤ 80 mg/dL (4.4 mmol/L), the differences in mg/dL (mmol/L) are included instead of percent differences (%). Note: CGM readings are within 40 to 400 mg/dL (2.2-22.2 mmol/L), inclusive. **Low and High Glucose Alerts:** The System has programmable High and Low Glucose Alerts that can be changed by the user and a non-changeable Low Glucose Alarm set at 55 mg/dL. The labeling instructs the user to consult with their doctor to determine what alert settings would be best for them. To assess the ability of the System to detect high and low glucose levels the CGM results were compared to reference results at low and high blood glucose levels and it was determined if the alert may have sounded. The System and reference readings were compared by pairing the CGM System reading that occurred immediately after the reference reading was collected. There were 9555 paired System and reference results evaluated. **Low Glucose Alert:** Estimates of how well the adjustable Low Glucose Alert performed are presented below in Tables 7-A through 7-C followed by the definitions of the terms used in the tables. Table 7-A represents the alert evaluation within 15 minutes of the reference reading for the pediatric study. It is a sub-set of the pediatric population – subjects age 6 to 17 years who had reference measurements every 15 minutes. Table 7-B represents the alert evaluation within 15 minutes of the reference reading for the adult study. Table 7C represents the alert evaluation within 30 minutes of an SMBG reading for 2 to 5 year old subjects in the pediatric study. #### Hypoglycemia Alert Rate: PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 17 {17} The Alert Rate shows how often the alert was right or wrong. The True Alert Rate is the % of time the device alarmed when the blood glucose level was at or above the alert setting within 15 or 30 minutes before or after the device alarmed. The False Alert Rate is the % of time the device alarmed when the blood glucose level was below the alert setting within 15 or 30 minutes before or after the device alarmed. # Hypoglycemia Detection Rate: The Detection Rate shows how often the device recognized and alerted that there was an episode of hypoglycemia or how often it missed such an event. The Hypoglycemia Detection Rate is the % of time the blood glucose level was at or above the alert setting and the device alarmed within 15 or 30 minutes before or after the blood glucose was at or above the alert settings. The Hypoglycemia Missed Detection Rate is the % of time the blood glucose was at or above the alert setting, but the device did not alarm within 15 or 30 minutes before or after the blood glucose was at or above the alert setting. **Table 7-A. Hypoglycemic Alert and Detection Rate Evaluation Compared to Reference (Pediatric Study, Ages 6-17).** | Alert Level mg/dL (mmol/L) | True Alert Rate | False Alert Rate | Hypoglycemia Detection Rate | Hypoglycemia Missed Detection Rate | | --- | --- | --- | --- | --- | | 55 (3.1) | 0% | 100% | 0% | 100% | | 60 (3.3) | 11% | 89% | 25% | 75% | | 70 (3.9) | 47% | 53% | 50% | 50% | | 80 (4.4) | 55% | 45% | 55% | 45% | | 90 (5.0) | 69% | 31% | 62% | 38% | | 100 (5.6) | 75% | 25% | 62% | 38% | **Table 7-B. Hypoglycemic Alert and Detection Rate Evaluation Compared to Reference (Adult Study).** | Alert Level mg/dL (mmol/L) | True Alert Rate | False Alert Rate | Hypoglycemia Detection Rate | Hypoglycemia Missed Detection Rate | | --- | --- | --- | --- | --- | | 55 (3.1) | 50% | 50% | 71% | 29% | | 60 (3.3) | 64% | 36% | 75% | 25% | | 70 (3.9) | 79% | 21% | 83% | 17% | | 80 (4.4) | 87% | 13% | 86% | 14% | | 90 (5.0) | 90% | 10% | 89% | 11% | PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 18 {18} **Table 7-C. Hypoglycemic Alert and Detection Rate Evaluation Compared to SMBG (Pediatric Study, Ages 2-5).** | Alert Level mg/dL (mmol/L) | True Alert Rate | False Alert Rate | Hypoglycemia Detection Rate | Hypoglycemia Missed Detection Rate | | --- | --- | --- | --- | --- | | 55 (3.1) | 3% | 97% | 57% | 43% | | 60 (3.3) | 11% | 89% | 62% | 38% | | 70 (3.9) | 29% | 71% | 77% | 23% | | 80 (4.4) | 35% | 65% | 85% | 15% | | 90 (5.0) | 51% | 49% | 89% | 11% | | 100 (5.6) | 64% | 36% | 91% | 38% | The above analysis demonstrates poor Low Glucose Alert performance in 6-17 year olds in the pediatric study (Table 7A). When the Low Glucose Alert was set to 55 mg/dL the alert never sounded (i.e., the CGM detected 0% of glucose excursions below 55 mg/dL). The alert only sounded 11% and 47% of the time when the alerts were set at 60 mg/dL and 70 mg/dL, respectively. In comparison, when the alert was set at 55 mg/dL in the adult study (Table 7B) the alert sounded 50% of the time and 64% and 79% when set at 60 mg/dL and 70 mg/dL, respectively. The study showed similar poor performance in the 2-5 year old participants using SMBG as a reference (Table 7C) with the 55 mg/dL alarm sounding only 3% of the time. *High Glucose Alert:* Estimates of how well the adjustable High Glucose Alert performed are presented in the tables (Table 8A-8C) followed by the definitions of the terms used in the tables. Table 8-A represents the alert evaluation within 15 minutes of the reference reading for a sub-set of the pediatric population in the pediatric study (subjects age 6 to 17 years) who had reference measurements every 15 minutes. Table 8-B represents the alert evaluation within 15 minutes of the reference reading for the adult study. Table 8-C represents the alert evaluation within 30 minutes of an SMBG reading for 2 to 5 year old subjects in the pediatric study. # Hyperglycemia Alert Rate: The Alert Rate shows how often the alert was right or wrong. The True Alert Rate is the % of time the device alarmed when the blood glucose level was at or above the alert setting within 15 or 30 minutes before or after the device alarmed. The False Alert Rate is the % of time the device alarmed when the blood glucose level was below the alert setting within 15 or 30 minutes before or after the device alarmed. # Hyperglycemia Detection Rate: The Detection Rate shows how often the device recognized and alerted that there was an episode of hyperglycemia or how often it missed such an event. The Hyperglycemia Detection Rate is the % of time the blood glucose level was at or PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 19 {19} above the alert setting and the device alarmed within 15 or 30 minutes before or after the blood glucose was at or above the alert settings. The Hyperglycemia Missed Detection Rate is the % of time the blood glucose was at or above the alert setting, but the device did not alarm within 15 or 30 minutes before or after the blood glucose was at or above the alert setting. **Table 8A. Hyperglycemic Alert and Detection Rate Evaluation Compared to Reference (Pediatric Study, Ages 6-17).** | Alert Setting mg/dL (mmol/L) | True Alert Rate | False Alert Rate | Hyperglycemia Detection Rate | Hyperglycemia Missed Detection Rate | | --- | --- | --- | --- | --- | | 120 (6.7) | 91% | 9% | 98% | 2% | | 140 (7.8) | 87% | 13% | 99% | 1% | | 180 (10.0) | 75% | 25% | 99% | 1% | | 200 (11.1) | 71% | 29% | 98% | 2% | | 220 (12.2) | 67% | 33% | 97% | 3% | | 240 (13.3) | 62% | 38% | 96% | 4% | | 300 (16.7) | 43% | 57% | 93% | 7% | **Table 8B. Hyperglycemic Alert and Detection Rate Evaluation Compared to Reference (Adult Study).** | Alert Setting mg/dL (mmol/L) | True Alert Rate | False Alert Rate | Hyperglycemia Detection Rate | Hyperglycemia Missed Detection Rate | | --- | --- | --- | --- | --- | | 120 (6.7) | 95% | 5% | 98% | 2% | | 140 (7.8) | 94% | 6% | 97% | 3% | | 180 (10.0) | 92% | 8% | 97% | 3% | | 200 (11.1) | 92% | 29% | 98% | 3% | | 220 (12.2) | 91% | 9% | 95% | 5% | | 240 (13.3) | 91% | 9% | 94% | 6% | | 300 (16.7) | 82% | 18% | 86% | 14% | **Table 8C. Hyperglycemic Alert and Detection Rate Evaluation Compared to Reference (Pediatric Study, Ages 2-5).** | Alert Setting mg/dL (mmol/L) | True Alert Rate | False Alert Rate | Hyperglycemia Detection Rate | Hyperglycemia Missed Detection Rate | | --- | --- | --- | --- | --- | | 120 (6.7) | 92% | 8% | 98% | 2% | | 140 (7.8) | 90% | 10% | 98% | 2% | | 180 (10.0) | 87% | 13% | 96% | 4% | | 200 (11.1) | 85% | 15% | 96% | 4% | | 220 (12.2) | 81% | 19% | 95% | 5% | PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 20 {20} | Alert Setting mg/dL (mmol/L) | True Alert Rate | False Alert Rate | Hyperglycemia Detection Rate | Hyperglycemia Missed Detection Rate | | --- | --- | --- | --- | --- | | 240 (13.3) | 80% | 20% | 95% | 5% | | 300 (16.7) | 71% | 29% | 90% | 10% | The above analysis demonstrates the High Glucose Alert performance in the pediatric study (Table 8A and 8C) in comparison with the adult study (Table 8B). When the High Glucose Alert was set to 300 mg/dL the alert sounded only 43% of the time in the pediatric study (6-17 years) and 71% of the time with 2-5 year old data using SMBG values as the reference. In the Adult study, the alert sounded 82% of the time when glucose values were greater than 300 mg/dL. #### ***Calibration Stability:*** The System must be calibrated every 12 hours. To demonstrate performance of the System over a 12-hour calibration period, Sensors in the pediatric study were evaluated to verify that performance remains consistent over the 12-hour calibration period. Systems from all pediatric participants (2-17 year olds) were evaluated in 2-hour increments after calibration and performance was estimated at each 2-hour interval and stratified by glucose concentrations by calculating the percentage of System readings within 15 mg/dL (0.9 mmol/L) or 15%, 20 mg/dL (1.1 mmol/L) or 20%, 30 mg/dL (1.7 mmol/L) or 30%, 40 mg/dL (2.2 mmol/L) or 40% and greater than 40 mg/dL (2.2 mmol/L) or 40% of the reference values in Table 9. **Table 9. Percentage of System Readings within Reference (Ref) Values with Data Stratified in 2-hour Increments after Calibration.** | Time from Calibration | Number of Paired System-Ref | Percent within 15/15% | Percent within 20/20% | Percent within 30/30% | Percent within 40/40% | Percent greater Than 40/40% | | --- | --- | --- | --- | --- | --- | --- | | 0-2 hours | 648 | 65% | 75% | 87% | 93% | 7% | | 2-4 hours | 649 | 51% | 67% | 86% | 93% | 7% | | 4-6 hours | 630 | 51% | 61% | 80% | 90% | 10% | | 6-8 hours | 409 | 52% | 68% | 85% | 95% | 5% | | 8-10 hours | 296 | 53% | 69% | 84% | 93% | 7% | | 10-12 hours | 253 | 58% | 74% | 89% | 95% | 5% | | 12-14 hours | 37 | 32% | 38% | 65% | 78% | 22% | Note: CGM readings are within 40 to 400 mg/dL (2.2-22.2 mmol/L), inclusive. #### ***Sensor Life and Sensor Stability:*** *Sensor Life:* Sensors can be worn for up to 7 days (168 hours). To estimate how reliably a sensor will work over 7 days, 351 sensors were evaluated during the pediatric study to determine how many days/hours of readings each sensor provided. Eighty-five percent (85%) of the sensors lasted until day 7 (145-168 hours). PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 21 {21} *Sensor Stability:* To assess the stability of sensor performance over the 7 day time period, the sensors in the pediatric study (from all participants; 2-17 years old) were evaluated across the 7-day wear period by comparing CGM performance to reference (Table 10) or to SMBG readings (Table 11). In Table 10 performance was estimated by calculating the percentage of System readings within 15 mg/dL (0.9 mmol/L) or 15%, 20 mg/dL (1.1 mmol/L) or 20%, 30 mg/dL (1.7 mmol/L) or 30%, 40 mg/dL (2.2 mmol/L) or 40% and greater than 40 mg/dL (2.2 mmol/L) or 40% of the reference values at the beginning (Day 1), middle (Day 4) and end (Day 7) of the System lifecycle. The average and median of the absolute percent differences are included in the table below (Table 10). **Table 10. System Sensor Stability Relative to Reference (Ref) (Accuracy over Time, Pediatric Study).** | Day of Wear | Number of Paired System-Ref | Mean Absolute Percent Differences (%) | Median Absolute Percent Differences (%) | Percent within 15/15% Ref | Percent within 20/20% Ref | Percent within 30/30% Ref | Percent within 40/40% Ref | Percent greater than 40/40% Ref | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Day 1 | 1016 | 21.2% | 15.8% | 48% | 61% | 78% | 85% | 15% | | Day 4 | 810 | 16.0% | 13.9% | 52% | 66% | 87% | 97% | 3% | | Day 7 | 1096 | 15.1% | 11.3% | 63% | 76% | 89% | 96% | 4% | Note: CGM readings are within 40 to 400 mg/dL (2.2-22.2 mmol/L), inclusive In Table 11 the performance was estimated by calculating the percentage of system readings from all pediatric participants (2-17 year olds) within various percentages of the SMBG values at each day of the sensor wear period. The average and median of the absolute percent differences are included in the table. **Table 11. System Sensor Stability Relative to SMBG (Accuracy over Time, Pediatric Study).** | Day of Wear | Number of Paired System-SMBG | Mean Absolute Percent Differences (%) | Median Absolute Percent Differences (%) | Percent within 15/15% SMBG | Percent within 20/20% SMBG | Percent within 30/30% SMBG | Percent within 40/40% SMBG | Percent greater than 40/40% SMBG | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Day 1 | 3216 | 18.8% | 14.2% | 53% | 65% | 81% | 90% | 10% | | Day 2 | 2148 | 16.2% | 12.4% | 60% | 74% | 87% | 94% | 6% | | Day 3 | 1977 | 15.2% | 11.0% | 63% | 76% | 89% | 95% | 5% | | Day 4 | 2830 | 14.0% | 10.9% | 66% | 79% | 91% | 96% | 4% | | Day 5 | 1768 | 15.4% | 10.7% | 67% | 78% | 90% | 95% | 5% | | Day 6 | 1704 | 14.3% | 9.8% | 68% | 79% | 90% | 96% | 4% | | Day 7 | 2675 | 12.4% | 9.2% | 72% | 83% | 94% | 97% | 3% | Note: CGM readings are within 40 to 400 mg/dL (2.2-22.2 mmol/L), inclusive PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 22 {22} # ***Sensor insertion site location (abdomen vs. upper buttock):*** To assess the buttock as an additional insertion site the system performance was assessed when the sensor was inserted in either of the sites for all pediatric participants (age 2-17 years). The overall CGM-reference percent agreement for the % of CGM measurements within %20/20 of reference for the two sites were comparable at 67.8% for abdomen and 68.4% for the upper buttocks. The overall CGM performance at the two insertion sites in reference to SMBG was comparable at 78% for abdomen, and 74% for the upper buttock. The results demonstrate that the CGM performs similarly in the abdomen and buttocks insertion locations for pediatric subjects. # ***Precision of the System Reading:*** All subjects wore two Systems (one blinded) simultaneously with sensor in either the abdomen, upper buttocks or one in each site during the study to assess the sensor precision of two Systems worn on the same patient at the same time for all participants (ages 2-17 years). Imprecision was evaluated using Paired Absolute Relative Difference (PARD) and Percent Coefficient of Variation (PCV) between two concurrently worn sensors. The overall mean PARD of the System during the study was 10% with a coefficient of variation (PCV) of 7% which demonstrates acceptable agreement. The analysis demonstrated similar precision whether the two sensor were both worn on the abdomen (6% PCV; 9% PARD), both on the buttocks (7% PCV; 10% PARD), or one on the abdomen and the other on the buttocks (7.5% PCV; 11% PARD). # ***Number of Readings Provided:*** The System is capable of providing a reading up to every 5 minutes (up to 288 readings per day). For a variety of reasons (e.g., sensor failure), the System may not display a glucose reading and readings are “skipped.” The number of actual Sensor values provided to subjects during the pediatric study over the entire 7-day period and the corresponding percentage is summarized below in Table 12 for all participating ages (2-17 years). Adjusted within each system wear-day, the System provided an average of 95% of all expected glucose readings as seen in Table 13. **Table 12. Number of Readings Provided by Each Sensor over 7-Days (Pediatric Study).** | % of Total Possible Readings Provided | Total Readings Provided (Min-Max) | % of Systems Providing that Number of Readings | | --- | --- | --- | | 0-25% | 103-427 | 2.6% | | 26-50% | 569-954 | 2.6% | | 51-75% | 1006-1484 | 8.5% | | 76-100% | 1518-1992 | 86.2% | PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 23 {23} **Table 13. System Readings within Wear Days (Pediatric Study).** | | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | Day 7 | All Days (N=108) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Mean | 97% | 96% | 96% | 95% | 94% | 94% | 92% | 95% | | Median | 99% | 99% | 99% | 99% | 99% | 99% | 98% | 99% | | STD | 6% | 10% | 9% | 12% | 14% | 14% | 17% | 12% | # ***Agreement and Accuracy Relative to SMBG:*** During the study, agreement between the System and blood glucose values was also characterized using paired System and self-monitoring blood glucose (SMBG) meters results (see Tables 14 and 15 below). The System and SMBG values from all pediatric ages (2-17 years) were compared by pairing the comparative SMBG value to a System glucose reading that occurred immediately after the SMBG was collected. These results characterize the performance patients expect during real-time use of the system in their daily diabetes management when comparing the system readings to their home blood glucose meter results. Both Tables (tables 14 and 15) are categorized within CGM glucose ranges (first column). CGM readings within the measuring range of the device (40-400 mg/dL glucose) are included in this analysis. **Table 14. System Agreement to SMBG within CGM Glucose Ranges (Pediatric Study).** | CGM Glucose Ranges mg/dL (mmol/L) | Number of Paired System-SMBG | Percent within 15/15% SMBG | Percent within 20/20% SMBG | Percent within 30/30% SMBG | Percent within 40/40% SMBG | Percent greater than 40/40% SMBG | | --- | --- | --- | --- | --- | --- | --- | | Overall | 16318 | 64% | 76% | 89% | 95% | 5% | | 40-60 (2.2-3.3) | 487 | 44% | 55% | 68% | 81% | 19% | | 61-80 (3.4-4.4) | 1340 | 59% | 70% | 85% | 93% | 7% | | 81-180 (4.5-10.0) | 7084 | 62% | 74% | 90% | 95% | 5% | | 181-300 (10.1-16.7) | 5627 | 69% | 80% | 90% | 95% | 5% | | 301-350 (16.7-19.4) | 1176 | 65% | 77% | 90% | 96% | 4% | | 351-400 (19.4-22.2) | 604 | 58% | 72% | 86% | 94% | 6% | Note: CGM readings are within 40 to 400 mg/dL (2.2-22.2 mmol/L), inclusive. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 24 {24} For the analysis presented in Table 15, the Mean and Median Percent Difference and the Mean and Median Absolute Percent Difference were calculated to further illustrate the comparison between CGM readings and SMBG results **Table 15. System Difference to SMBG within CGM Glucose Ranges (Pediatric Study).** | CGM Glucose Ranges mg/dL (mmol/L) | Number of Paired System-SMBG | Mean Percent Difference (%) | Median Percent Difference (%) | Mean Absolute Percent Difference (%) | Median Absolute Percent Difference (%) | | --- | --- | --- | --- | --- | --- | | Overall | 16318 | 2.2 | 0.9 | 15.3 | 11.0 | | *40-60 (2.2-3.3) | 487 | -22.1 (-1.2) | -17.0 (-0.9) | 23.9 (1.3) | 18.0 (1.0) | | *61-80 (3.4-4.4) | 1340 | -11.8 (-0.7) | -8.0 (-0.4) | 17.0 (0.9) | 11.0 (0.6) | | 81-180 (4.5-10.0) | 7084 | 1.1 | -1.0 | 15.4 | 11.4 | | 181-300 (10.1-16.7) | 5627 | 5.7 | 3.4 | 13.5 | 9.5 | | 301-350 (16.7-19.4) | 1176 | 9.6 | 7.2 | 14.2 | 10.4 | | 351-400 (19.4-22.2) | 604 | 12.7 | 10.2 | 16.1 | 11.9 | * For CGM ≤ 80 mg/dL (4.4 mmol/L), the differences in mg/dL (mmol/L) are included instead of percent differences (%). Note: CGM readings are within 40 to 400 mg/dL (2.2-22.2 mmol/L). The pivotal clinical study described above demonstrates that the G4 Platinum (Pediatric) System performance in pediatric subjects was not as accurate as the performance of the same device in adults. In addition, the performance of the hypoglycemic detection alert in the pediatric study was poor relative to that seen in the adult study, particularly at blood glucose concentrations below 70 milligrams per deciliter of blood. Despite these limitations, the study did demonstrate that the device is effective for tracking and trending to determine patterns in glucose levels, and for alerting patients when glucose values are approaching potentially dangerously high (hyperglycemic) and/or dangerously low (hypoglycemic) levels. To communicate the reduced accuracy in pediatric patients to users, two warnings are included in the labeling, and are displayed on the receiver screen when a new sensor session is started or the alert thresholds are changed: - In a pediatric clinical study, larger differences were observed between this CGM device and actual blood glucose values compared to those differences observed in the adult clinical study. Use your blood glucose meter for treatment decisions. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 25 {25} - In a pediatric clinical study, a significant number of low glucose events were not detected by CGM. Do not rely solely on CGM alerts to detect low glucose. ### 3. Subgroup Analyses The pediatric System performance was evaluated within study population subgroups, such as age (2-5, 6-12, 13-17 years), sensor insertion location (abdomen, upper buttocks), gender, diabetes type, baseline HbA1C, baseline body mass index (BMI), type of diabetes treatment. Although not powered for analysis of subpopulations, no significant differences in performance were noted based on the analysis of these subgroups. ### E. Financial Disclosure The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 6 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data. ## XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Clinical Chemistry and Clinical Toxicology Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA did not raise new issues of safety and effectiveness that had not been previously addressed for similar devices and substantially duplicates information previously reviewed by this panel. ## XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES ### A. Effectiveness Conclusions The results of the pivotal clinical study performed in this submission establish a reasonable assurance of safety and effectiveness for the Dexcom G4 Platinum (Pediatric) System for detecting trends and tracking patterns when used as intended, as an adjunct to blood glucose testing in subjects with diabetes mellitus. The primary effectiveness measurements for this study were based on the performance evaluation of the Dexcom G4 Platinum (Pediatric) System compared to the blood glucose values measured by reference during in-clinic sessions (6-17 year old subjects) that were PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 26 {26} obtained over the 7 day wear period of the sensor. The effectiveness of the system was also compared SMBG measurements (2-17 year olds). The performance data presented above (Tables 3A, 4A, 5A, 6A, 7A and C, 8A and C, 9 to 15) support the effectiveness conclusions and established the accuracy across the claimed measuring range (40 to 400 mg/dL glucose), precision, abdomen and upper buttock sensor insertion sites, the claimed calibration frequency (calibrate every 12 hours), the 7 day wear period for the sensor, the alarms and alerts, and the number of readings displayed in the 7 day wear period. As demonstrated in the performance evaluation above, the pediatric clinical study demonstrated that the CGM performance in pediatric subjects was not as accurate (Tables 3A, 4A, and 5A) as the performance of the same device in adults (Tables 3B, 4B, and 5B). In addition, the performance hypoglycemic detection alert in the pediatric study was poor (Table 7A and C, 8A and C) in comparison to that seen in the adult study (Table 7B and 8B), particularly at blood glucose concentrations <70 mg/dL. However, despite the reduced accuracy in this patient population in the low glucose range, the CGM provides valuable tracking and trending information to children and their parents as well as high glucose alerts. The beneficial information gained from this device, in addition to the strong warnings in the labeling and receiver display explaining the differences in performance in pediatrics versus adults, outweighs the risk of missed low glucose alerts. Therefore, the clinical study data demonstrate that the G4 PLATINUM (Pediatric) CGM System was sufficiently effective in the intended use population for this intended use. ## **B. Safety Conclusions** The risks of the device are based on nonclinical laboratory data (provided in the original PMA; P120005) as well as on data collected in a clinical study conducted to support PMA approval as described above. The following events are possible adverse device effects of inserting a sensor into your skin: local infection, inflammation, pain or discomfort, bleeding at the glucose sensor insertion site, bruising, itching, scarring or skin discoloration, hematoma, tape irritation, sensor or needle fracture during insertion, wear or removal. During the clinical studies the following device-related non-serious events were reported: Twenty one (21) AEs were reported, affecting 14 subjects. One (1) AE was due to pain/discomfort during wear. Sixteen (16) AEs were related to skin irritation (erythema/edema). Four (4) AEs were categorized as 'Other', disease or study related. No infections occurred at either insertion or adhesive areas. All AEs were considered 'mild or moderate' in intensity and 'probably related' to the device. AEs were transient, and resolved by the end of the subject's participation in the study or deemed on-going, but stable at study termination. Per protocol, the mechanical integrity of each sensor was independently assessed after removal of the sensor from PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 27 {27} the subcutaneous adipose tissue. There were no reports of broken sensor wires, nor any sensor wire detachments from the sensor housing units. No SAEs or UADEs were reported in the clinical studies. However, there are risks related to either an inaccurate sensor value outside of the patient’s normal range or a false alert/alarm is the risk of performing an unnecessary additional blood glucose test to confirm the erroneous sensor reading. The risk of medical harm is, however, mitigated through labeling which emphasizes that patients should confirm all CGM readings prior to making treatment decisions. The risk related to either an inaccurate sensor value which should be outside of the patient’s target range, missed alerts, false alerts, false negative hypoglycemia and hyperglycemic readings and false positive hypoglycemia and hyperglycemia is the risk of the device not alerting the user that additional blood glucose testing with a meter should be performed. However, since patients who only use blood glucose meters to manage their diabetes without the aid of a CGM would also be unaware of the need to perform additional testing to detect an abnormal blood sugar (unless they were exhibiting symptoms of an abnormal blood glucose), the risk of inaccurate results related to the use of this device is no greater than the risk of managing diabetes with a meter alone unless patients omit a blood glucose test that they would have otherwise performed if they were not using the sensor or the sensor was not reading within their target glucose range. There is a risk that patients that are relying on CGM values won’t perform fingerstick testing as often as they would without the CGM. However, patients typically do not test frequently enough with a meter to calculate the rate of change, therefore, this risk is no greater than with traditional glucose monitoring with a meter alone. Patients may also rely on the CGM to alert them to low glucose levels, which is of particular concern with the use of this device in pediatrics due to the poor low alert performance. However, the labeling and receiver display warns that a significant number of low glucose events were not detected by the CGM in the pediatric study and warns not to rely solely on CGM alerts to detect low glucose. These warnings in the labeling help to mitigate the risk of poor alert performance. Inaccurate calculation of the rate of change of glucose by the CGM could prevent a patient from performing additional blood glucose tests or taking measures to stop a trend of increasing or decreasing glucose levels which could lead to serious hypoglycemia or hyperglycemia if no action is taken to stop these glucose trends. However as patients often do not test frequently enough with a meter to calculate the rate of change, this risk is not greater than with traditional glucose monitoring with a meter. Inaccurate estimation of the rate of change of glucose could also lead to unnecessary additional blood glucose tests or inappropriate measures to stop an incorrect trend of increasing or decreasing glucose level. However the risk of medical harm is limited to instances where the user relies on the rate of change calculated by the sensor without confirmation by a blood glucose meter. This risk is partially PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 28 {28} mitigated by the requirement for subjects to base treatment decisions on blood glucose levels. ### C. Benefit-Risk Conclusions The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above as well as the as well as the data collected in the original PMA (P120005). This submission is for an expansion of the intended use population from 18 and older in the original PMA (P120005) down to 2 years of age. This device is intended to supplement self monitoring of blood glucose to track and trend interstitial glucose levels as estimates of glucose excursions in the blood. The adjustable hypoglycemia and hyperglycemia alerts are intended to warn the patients that they need to test their blood sugar to see if they need to take action to treat or prevent a hypoglycemic or hyperglycemic event. Furthermore, CGM measurements, which are performed every 5 minutes for 7 days via an indwelling sensor, do not require repeated performance of fingersticks with a lancet for each measurement as is required for each individual blood glucose measurement with a traditional glucose meter. These functions are not feasible using traditional blood glucose monitoring as blood glucose meters only provide information about discrete, intermittent blood glucose levels and therefore are unable to provide information regarding patterns of glycemic excursions throughout the day and night when patients may be unable to test their blood glucose. The CGM includes a software package to aid in the evaluation of glucose trends over several days to detect patterns which may indicate a need to adjust therapy, but might be missed with infrequent, intermittent blood glucose monitoring. Furthermore, real time knowledge of whether blood glucose is increasing or decreasing adds information unavailable by traditional discrete monitoring in pediatric patients. This information regarding direction and rate of change can alert users that they need to take action to prevent hypoglycemia or hyperglycemia. The alert functions can notify users and/or their parents that they need to test their blood sugar to see if they need to take action to treat asymptomatic hypoglycaemia or hyperglycemia before their blood glucose concentration reaches a dangerous level. This is especially helpful for individuals with hypoglycemia unawareness (these individuals may develop severe hypoglycemia with loss of consciousness, seizures, or rarely death without the normal warning symptoms), or during the night when subjects may have prolonged hypoglycaemia that does not waken them which could proceed to severe hypoglycemia if not treated in time. Traditional blood glucose monitoring is not able to capture these potentially dangerous episodes of asymptomatic hypoglycemia. Therefore, this device provides significant benefit to users not possible with traditional glucose monitoring. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 29 {29} In addition, the risks of using the System to determine diabetes therapy are mitigated by labeling that states that this device should not be used to adjust therapy. The labeling warns patients that they should only adjust therapy based on blood glucose measurements. The labeling and the receiver displays the following warnings regarding use of this system in the pediatric population: - In a pediatric clinical study, larger differences were observed between this CGM device and actual blood glucose values compared to those differences observed in the adult clinical study. Use your blood glucose meter for treatment decision. - In a pediatric clinical study, a significant number of low glucose events were not detected by CGM. Do not rely solely on CGM alerts to detect low glucose. Despite the reduced accuracy in this patient population, particularly in the low glucose range, the CGM provides valuable tracking and trending information to children and their parents. If the expected performance of the device is understood, the beneficial information gained from this device outweighs the risk of missed low glucose alerts. Therefore, the strong warnings added to the labeling and receiver display explaining the differences in performance in pediatrics compared to adults and warning against relying solely on CGM alerts to detect low glucose help to mitigate the risks of poor performance. The labeling further advises patients that if their CGM reading does not correspond to their symptoms of high or low blood sugar, they should not rely on the CGM reading, but should perform a blood glucose measurement. Users are further advised that if there is a discrepancy between the CGM and the blood glucose result, the user should recalibrate the CGM to improve accuracy. In conclusion, given the available information above, the data support that for detecting trends and tracking patterns in glucose levels, the probable benefits outweigh the probable risks. # D. Overall Conclusions The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use when utilized in accordance with product labeling as an adjunct to information obtained from standard home glucose monitoring devices. The benefits of using the System, as discussed above, outweigh the risks. # XIII. CDRH DECISION CDRH issued an approval order on February 3, 2014. The final conditions of approval are described in the approval order. PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 30 {30} The applicant’s manufacturing facility was inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820). #### **XIV. APPROVAL SPECIFICATIONS** Directions for use: See device labeling. Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling. Post-approval Requirements and Restrictions: See approval order PMA P120005/S002: FDA Summary of Safety and Effectiveness Data Page 31