National Medical Policy

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1 National Medical Policy Subject: Policy Number: Continuous Glucose Monitoring Devices NMP333 Effective Date*: January 2007 Updated: June 2017 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State's Medicaid manual(s), publication(s), citations(s) and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link X National Coverage Determination (NCD) Durable Medical Equipment Reference List (280.1): National Coverage Manual Citation Local Coverage Determination (LCD)* Closed Loop Glucose Monitoring System (NCD 40.3) Article (Local)* X Other Medicare Learning Network Matters. Number: SE0738 Revised August 28, An Overview of Medicare Covered Diabetes Supplies and Services: Education/Medicare-Learning-Network- MLN/MLNMattersArticles/downloads/SE0738.pdf None Use Health Net Policy 1

2 Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Health Net, Inc. considers FDA approved Continuous Glucose Monitoring Systems (CGMS), medically necessary for the monitoring of unstable diabetes for any of the following: Short Term (Up to three days only): Short term use of CGMS can be beneficial in patients with diabetes to detect nocturnal hypoglycemia, the dawn phenomenon, and postprandial hyperglycemia and to assist in the management of hypoglycemic unawareness and when significant changes are made to their diabetes regimen (such as instituting new insulin or to pump therapy) as follows: Type 1 diabetics and Type II diabetics who require insulin who meets all of the following: 1. CGMS is requested by an endocrinologist; and 2. Patient has completed a comprehensive diabetic education program; and 3. Patient has a documented frequency of glucose self-testing an average of at least 4 times per day; and 4. Patient has been compliant with the regime recommended by a board certified endocrinologist, and 5. Insulin injections are required 3 or more times per day; and 6. Patient self-adjusts insulin dose based on self-testing results, and meets one or more of the following: a. Glycosylated hemoglobin (Hgb A1C) values 7 or greater, or b. Inadequate glycemic control despite compliance with frequent self and including fasting hyperglycemia (greater than 150 mg/dl) or recurring episodes of severe hypoglycemia (less than 50 mg/dl), or. c. Type I or Type II diabetic woman who is newly pregnant or a woman who has developed gestational diabetes that requires insulin therapy Long Term Use Health Net considers long-term use of CGMS in the treatment of type 1 diabetes and type II diabetes who require insulin medically necessary only for those who meet the criteria for short term use AND any of the following: Persistent, recurrent unexplained severe hypoglycemic events (commonly associated with brittle diabetes, extreme insulin sensitivity and/or very low insulin requirements), or 2

3 Hypoglycemia unawareness in a diabetic taking insulin, episodes of ketoacidosis, or Hospitalizations for uncontrolled glucose levels, or Frequent nocturnal hypoglycemia despite appropriate modifications in insulin therapy and compliance with frequent self-monitoring of blood glucose (i.e., at least four times daily). Note: Long term use of CGMS without an insulin infusion pumps is not common indication. Combined Continuous Subcutaneous Insulin Infusion and Blood Glucose Monitoring Systems Combined Continuous Subcutaneous Insulin Infusion and Blood Glucose Monitoring Systems are be considered medically necessary ONLY if patient meets conditions noted above for Long Term Use Health Net inc., considers use of an FDA-approved artificial pancreas device system (APDS) with a low glucose suspend feature (low glucose suspend system (LGS)/threshold suspend device system (i.e. MiniMed 530G/MiniMed 530G with Enlite) medically necessary in patients, age 16 and older with type 1 diabetes who meet the criteria noted above for long term use. Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or non-covered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes Diabetes mellitus, without mention of complication, Type II or unspecified type, not stated as uncontrolled, diabetes with unspecified complication, type I (juvenile type), uncontrolled Diabetes mellitus complicating pregnancy ICD-10 Codes (general codes related to diabetes) E09.00-E09.9 Drug or chemical induced diabetes mellitus E E10.65 Type 1 diabetes mellitus with complications E E11.69 Type 2 diabetes mellitus with complications O O Pre-existing diabetes mellitus in pregnancy, childbirth, and the puerperium (1 st, 2 nd and/or 3 rd trimester) O Unspecified pre-existing diabetes mellitus in pregnancy O24.33 O Gestational diabetes mellitus O Other pre-existing diabetes mellitus O

4 CPT Codes Ambulatory continuous glucose monitoring of interstitial tissue fluid via a subcutaneous sensor for up to 72 hours; sensor placement, hook-up, calibration of monitor, patient training, removal of sensor, and printout of recording Ambulatory continuous glucose monitoring of interstitial tissue fluid by means of a subcutaneous sensor for a minimum of 72 hours; interpretation and report HCPCS Codes A4253 Blood glucose test or reagent strips for home blood glucose monitor, per 50 strips A4255 Platforms for home blood glucose monitor, 50 per box A4256 Normal, low and high calibrator solution/chips A4258 Spring-powered device for lancet, each A4259 Lancets, per box of 100 A9276 Sensor; invasive (e.g., subcutaneous), disposable, for use with interstitial continuous glucose monitoring system A9277 Transmitter, ext.w glucose monitor A9278 Monitor, ext, for glucose monitor E0607 Home blood glucose monitor E2100 Blood glucose monitor with integrated voice synthesizer E2101 Blood glucose monitor with integrated lancing/blood sample S1030 Continuous non-invasive glucose monitoring device, purchase S1031 Continuous non-invasive glucose monitoring device, rental, including sensor, sensor placement, and download to monitor S1034 Artificial pancreas device system (e.g., low glucose suspend [LGS] feature) including continuous glucose monitor, blood glucose device, insulin pump and computer algorithm that communicates with all of the devices S1035 Sensor; invasive (e.g., subcutaneous), disposable, for use with artificial pancreas device system S1036 Transmitter; external, for use with artificial pancreas device system S1037 Receiver (monitor); external, for use with artificial pancreas device system Scientific Rationale- Update June 2016 Per the FDA, three main categories of Artificial Pancreas Device Systems (APDSs) are under investigation (ie., Threshold Suspend Device System, Control-to-Range (CTR) System and Control -to-target (CTT) System.) Threshold Suspend Device System The goal of a threshold suspend device system is to help reduce the severity or reverse a dangerous drop in blood glucose level (hypoglycemia) by temporarily suspending insulin delivery when the glucose level falls to or approaches a low glucose threshold. These are sometimes referred to as low glucose suspend systems. This kind of system serves as a potential back-up when a patient is unable to respond to a hypoglycemic event. Patients using this system will still need to be active partners in managing their blood glucose levels by periodically checking their blood glucose levels and by giving themselves insulin or eating. Control-to-Range (CTR) System 4

5 A CTR system reduces the likelihood of a hypoglycemic event or a hyperglycemic event (when blood glucose is dangerously high) by adjusting insulin dosing only if a person s glucose level approaches the low or high glucose thresholds. Patients using this system will still need to check blood glucose levels and give themselves insulin to maintain control of glucose levels. Control -to-target (CTT) System A CTT system sets target glucose levels and tries to achieve these levels at all times. This system is fully automated and requires no interaction from the user (except for calibration of the continuous glucose monitoring system). CTR and CTT System Subtypes are dependent upon the drug or drugs being delivered and how each drug affects glucose levels. Three subtypes are being investigated: insulin-only, bi-hormonal and hybrid. There are no CTR or CTT devices FDA approved at this time. The MiniMed 530G with Enlite is the first artificial pancreas device system with Threshold Suspend approved by the FDA in September 2013 under its critical path initiative to accelerate the development and availability of a safe and effective artificial pancreas. The MiniMed 530G System is intended for continuous delivery of basal insulin (at user selectable rates) and administration of insulin boluses (in user selectable amounts) for the management of diabetes mellitus in persons, sixteen years of age and older, requiring insulin as well as for the continuous monitoring and trending of glucose levels in the fluid under the skin. The MiniMed 530G System can be programmed to automatically suspend delivery of insulin when the sensor glucose value falls below a predefined threshold value. The MiniMed 530G system includes the three parts required of an artificial pancreas system threshold suspend: An insulin pump Integrated continuous glucose monitoring (including Medtronic s Enlite sensor) Advanced algorithms to enable Threshold Suspend automation, a feature that automatically stops the delivery of insulin if sensor glucose levels reach a preset threshold and if the patient is unable to respond to the Threshold Suspend alarm. The Threshold Suspend feature shuts off insulin delivery when sensor glucose levels reach or go below a threshold, which can be set from 60 to 90 mg/dl, and if the patient is unable to respond to the Threshold Suspend alarm. Upon reaching the threshold value, the MiniMed 530G system will sound an alarm and all insulin delivery is stopped. The patient should take a fingerstick measurement and adjust treatment accordingly. If the person is sleeping, unconscious or otherwise unable to react to the alarm, the system will continue to suspend all insulin delivery for up to two hours. Per Medtronic, the Enlite sensor delivers better comfort and reliable CGM accuracy. In addition to the 31 percent improvement in overall accuracy, the Enlite sensor detects up to 93 percent of hypoglycemia episodes when predictive and threshold alerts are on. The Enlite sensor is also 69 percent smaller than the previous Medtronic sensor, to deliver improved comfort in using continuous glucose monitoring. Per the FDA approval, the MiniMed 530G System is not intended to be used directly for making therapy adjustments, but rather to provide an indication of when a finger stick may be required. All therapy adjustments should be based on measurements obtained using a home glucose monitor and not on values provided by the MiniMed 530G System. The MiniMed 530G System is not intended to be used directly for preventing or treating 5

6 hypoglycemia but to suspend insulin delivery when the user is unable to respond to the Threshold Suspend alarm to take measures to prevent or treat hypoglycemia himself. As a condition of approval, Medtronic will conduct a post-approval study including children ages two and older. American Diabetes Association The American Diabetes Association s 2015 Standards in Diabetes include the following recommendation under the section on recommended therapy for type 1 diabetes: For patients with frequent nocturnal hypoglycemia and/or hypoglycemia unawareness, a sensor-augmented low glucose threshold suspend pump may be considered. The ADA noted a large randomized trial in type 1 diabetic patients with nocturnal hypoglycemia reported that sensor-augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values (Bergenstal et al, study noted in scientific rationale below- Nov 2013) The American Association of Clinical Endocrinologists/American College of Endocrinology The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) clinical practice guidelines for developing a diabetes mellitus comprehensive care plan (2015) make the following recommendation: Candidates for continuous subcutaneous insulin infusion (CSII) include patients with type 1 diabetes (T1D) and patients with type 2 diabetes (T2D) who are insulin dependent (Grade A; (BEL 1*). CSII should only be used in patients who are motivated and Knowledgeable in DM selfcare, including insulin adjustment. To ensure patient safety, prescribing physicians must have expertise in CSII therapy, and CSII users must be thoroughly educated and periodically reevaluated. Sensor-augmented CSII, including those with a thresholdsuspend function, should be considered for patients who are at risk of hypoglycemia (Grade A; BEL 1). *Best evidence levels (BEL) level 1= strong evidence (i.e., Meta-analysis of randomized controlled trials (MRCT), Randomized controlled trials (RCT) A recommendation= strong recommendation Agrawal et al (2015) reported the automatic Threshold Suspend (TS) feature of the MiniMed 530G system (Medtronic MiniMed, Inc., Northridge, CA), when enabled, suspends insulin delivery for up to 2h when the sensor glucose (SG) value reaches a preset threshold. SG data from 20,973 patients who enabled the TS feature at their discretion and uploaded pump and sensor data to CareLink (Medtronic MiniMed, Inc.) from October 15, 2013 to July 21, 2014 were analyzed. Comparisons between 758,382 patient-days wherein the TS feature was enabled at any time and 166,791 patient-days in which it was not enabled were made. Further comparisons were made between data collected during daytime (8:00 a.m. to 10:00 p.m.) and nighttime (10:00 p.m. to 8:00 a.m.) hours. Data from subsets of patients who enabled the TS feature all of the time (n=14,673) versus those who never enabled the TS feature (n=2,249) were also compared. Recovery from hypoglycemia during and after 2-h pump suspension events was also assessed. The TS feature was enabled on 82% of patient-days. Patient-days in which the TS feature was enabled, compared with patient-days in which it was not, had 69% fewer SG values 50mg/dL (0.64% vs. 2.09%, 6

7 respectively; P<0.001). The reduction in hypoglycemia seen on TS-enabled days was more pronounced during nighttime than during daytime hours. SG data from full-time users of the TS feature reflected a 62% reduction in values 50mg/dL and a 5.6% reduction in values 300mg/dL compared with data from nonusers (P<0.001 for each). The median SG value at the start of 2-h suspensions was 60 (interquartile range [IQR], 57-66) mg/dl, immediately after was 87 (IQR, ) mg/dl, and 4h later was 164 (IQR, ) mg/dl. The authors concluded the TS feature, when enabled consistently, reduced hypoglycemic exposure, and for those who had it enabled 100% of the time, hyperglycemia was also reduced. Scientific Rationale Update June 2015 New et al (2015) investigated the best glucose monitoring strategy for maintaining euglycaemia by comparing self-monitoring of blood glucose with continuous glucose monitoring, with or without an alarm function. A 100-day, randomized controlled study was conducted at four European centers, enrolling 160 patients with Type 1 or Type 2 diabetes, on multiple daily insulin injections or continuous subcutaneous insulin infusion. Participants were randomized to continuous glucose monitoring without alarms (n = 48), continuous glucose monitoring with alarms (n = 49) or self-monitoring of blood glucose (n = 48). Time spent outside the glucose target during days was 9.9 h/day for the continuous glucose monitoring without alarms group, 9.7 h/day for the continuous glucose monitoring with alarms group and 10.6 h/day for the self-monitoring of blood glucose group (P = 0.18 and 0.08 compared with continuous glucose monitoring without and with alarms, respectively).the continuous glucose monitoring with alarms group spent less time in hypoglycemia compared with the self-monitoring of blood glucose group (1.0 h/day and 1.6 h/day, respectively; 95% CI -1.2 to -0.1; P = 0.030). Among those treated with continuous subcutaneous insulin infusion, time spent outside the glucose target was significantly different when comparing continuous glucose monitoring without alarms and self-monitoring of blood glucose (-1.9 h/day; 95% CI -3.8 to 0.0; P = ) and when comparing continuous glucose monitoring with alarms and self-monitoring of blood glucose (-2.4 h/day; 95% CI -4.1 to -0.5; P = ). There was no difference in HbA1c reduction from baseline in the three groups; however, the proportion of participants with a reduction of 6 mmol/mol ( 0.5%) was higher in the continuous glucose monitoring without alarms (27%) and continuous glucose monitoring with alarms groups (25%) than in the self-monitoring of blood glucose group (10.6%). The authors concluded the study shows that the use of continuous glucose monitoring reduces time spent outside glucose targets compared with self-monitoring of blood glucose, especially among users of insulin pumps. Kovatchev et al (2015) estimated the effect size of hypoglycemia risk reduction on closedloop control (CLC) versus open-loop (OL) sensor-augmented insulin pump therapy in supervised outpatient setting. Twenty patients with type 1 diabetes initiated the study at the Universities of Virginia, Padova, and Montpellier and Sansum Diabetes Research Institute; 18 completed the entire protocol. Each patient participated in two 40-h outpatient sessions, CLC versus OL, in randomized order. Sensor (Dexcom G4) and insulin pump (Tandem t:slim) were connected to Diabetes Assistant (DiAs)-a smartphone artificial pancreas platform. The patient operated the system through the DiAs user interface during both CLC and OL; study personnel supervised on site and monitored DiAs remotely. There were no dietary restrictions; 45-min walks in town and restaurant dinners were included in both CLC and OL; alcohol was permitted. The primary outcome-reduction in risk for hypoglycemia as measured by the low blood glucose (BG) index (LGBI)-resulted in an effect size of 0.64, P = 0.003, with a twofold reduction of hypoglycemia requiring carbohydrate treatment: 1.2 vs. 2.4 episodes/session on CLC versus OL (P = 0.02). This was accompanied by a slight decrease in percentage of time in the target range of mmol/l (66.1 vs. 70.7%) and increase in mean BG (8.9 vs. 8.4 mmol/l; P = 0.04) on CLC 7

8 versus OL. The authors concluded CLC running on a smartphone (DiAs) in outpatient conditions reduced hypoglycemia and hypoglycemia treatments when compared with sensor-augmented pump therapy. This was accompanied by marginal increase in average glycemia resulting from a possible overemphasis on hypoglycemia safety. Maahs et al (2014) conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels. Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which 1 CGM glucose values 60 mg/dl occurred. Overnight hypoglycemia with at least one CGM value 60 mg/dl occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI ]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dl during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dl following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dl following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm. The authors concluded use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis. Gehlaut et al (2015) reported hypoglycemia is often the limiting factor for intensive glucose control in diabetes management, however its actual prevalence in type 2 diabetes (T2DM) is not well documented. A total of 108 patients with T2DM wore a continuous glucose monitoring system (CGMS) for 5 days. Rates and patterns of hypoglycemia and glycemic variability (GV) were calculated. Patient and medication factors were correlated with rates, timing, and severity of hypoglycemia. Of the patients, 49.1% had at least 1 hypoglycemic episode (mean 1.74 episodes/patient/ 5 days of CGMS) and 75% of those patients experienced at least 1 asymptomatic hypoglycemic episode. There was no significant difference in the frequency of daytime versus nocturnal hypoglycemia. Hypoglycemia was more frequent in individuals on insulin (alone or in combination) (P =.02) and those on oral hypoglycemic agents (P <.001) compared to noninsulin secretagogues. CGMS analysis resulted in treatment modifications in 64% of the patients. T2DM patients on insulin exhibited higher glycemic variability (GV) scores (2.3 ± 0.6) as compared to those on oral medications (1.8 ± 0.7, P =.017). The authors concluded CGMS can provide rich data that show glucose excursions in diabetes patients throughout the day. Consequently, unwarranted onset of hypo- and hyperglycemic events can be detected, intervened, and prevented by using CGMS. Hypoglycemia was frequently unrecognized by the patients in this study (75%), which increases their potential risk of significant adverse events. Incorporation of CGMS into the routine management of T2DM would increase the detection and self-awareness of hypoglycemia resulting in safer and potentially better overall control. Nakamura and Balo (2015) sought to evaluate the accuracy and efficacy of Dexcom G4 Platinum CGM System. Seventy-two subjects enrolled at 4 US centers; 61% were male; 83% had T1DM and17% had T2DM. Subjects wore at least 1 system for up to 7 days. Subjects participated in a total of 36 hours in the clinic to contribute YSI reference glucose measurements with venous blood draws every 15 minutes on study Day 1, Day 4, and Day 7. The overall mean absolute relative difference (ARD) versus YSI was 13% with a median of 10%. Precision ARD was 9% ± 4% between 2 sensors with a 7% coefficient of variation. The mean ARD versus SMBG was 14% with a median of 11%. One hundred two (94%) sensors lasted 7 days and the systems displayed 97% of their expected glucose readings in 8

9 average. The time spent in low CGM readings during nighttime hours decreased from the first night use to the 6th night (P <.001) with a small difference in average CGM glucose from 147 ± 40 mg/dl to 166 ± 62 mg/dl. There were no serious adverse events or infectious complications reported. The authors concluded the study showed the Dexcom G4 Platinum CGM System is one of the most accurate CGMs. The significant reduction in nocturnal time spent in a hypoglycemic state observed during this study suggests that a longer term study of CGM use, especially nocturnal use, could be beneficial for patients with hypoglycemia unawareness. Scientific Rationale Update June 2014 Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and relative impairment in insulin secretion. Initial therapy for Type 2 begins with diet, weight reduction, and exercise and oral medications such as metformin. Oral agents become less effective as beta cell function declines and it may be necessary to add additional oral agents or an injectable agent, including insulin, or to switch to insulin. There is no consensus on which option is most effective but insulin is the recommended second-line medication for patients with elevated A1C or with symptoms of hyperglycemia despite medication titration. The American Diabetes Association (2104) states that the use of CGM may be useful as a supplemental tool to self-monitoring in diabetics taking insulin who experience hypoglycemia unawareness and/or frequent hypoglycemic episodes. In a multicenter study, Zick et al (2007) demonstrated that episodes of hypoglycemia (glucose values < 60 mg/dl) were underreported with self-monitoring blood glucose (SMBG) in patients with type 2 DM receiving multiple daily injections. Blinded CGM was conducted over a 72-h period at pretreatment and 8 weeks later at post-treatment. The analysis of this multicenter study of 367 patients showed 56.9% experienced hypoglycemia as documented by CGM, but only 26.4% reported hypoglycemia by SMBG. The A1C did decrease over the course of the study. Garg et al (2006) demonstrated that insulin-requiring patients with type 1 (n = 75) and type 2 (n = 16) DM reduced hyperglycemia without increasing hypoglycemia. In this prospective, randomized, controlled trial patients wore the CGM device for 3 days, and this was repeated three consecutive times. During the first period patients did not have access to the data; however, during the second and third periods, patients had real-time information. The use of real-time data improved glycemic excursions with 21% less time as hypoglycemic (glucose values < 55mg/dL), 23% less time as hyperglycemic ( 240mg/dL), and 26% more time in target (81 140mg/dL) range (P < for each comparison). Gandhi et al. (2011) conducted a systematic review and meta-analysis to assess the efficacy of CGM in improving glycemic control and reducing hypoglycemia compared to selfmonitored blood glucose (SMBG) in patients with type 1 (T1DM) and type 2 (T2DM) diabetic mellitus. Nineteen randomized controlled trials (n=1801) met inclusion criteria. Three RCTs included patients with Type 2 diabetes. One RCT included patients with either type of diabetes. There was a mixture of patients with Type 2 diabetes who did and did not require insulin. The baseline HbA1C was typically greater than 7.0%. Compared to SMBG, metaanalysis showed that CGM was associated with a significant reduction in mean HbA1c in adult type 1 and type 2 diabetics, but no significant effect was noted in children and adolescents. The authors stated that the current body of literature had several limitations including the following: overall, device studies were structured to demonstrate a maximal difference in the outcome and often provided more education, visits, support, feedback and access to patients resulting in co-intervention effect and bias that exaggerated the treatment effect; heterogeneity of the documentation of hypoglycemia and hyperglycemia; 9

10 changing technology; small number of randomized controlled trials using currently available devices; adult populations tended to be fairly young; and the number of T2DM patients was low. Scientific Rationale Update November 2013 Effective treatment modalities, including insulin analogues and continuous glucose monitors (CGMs) are available for diabetics but a substantial proportion of patients with diabetes cannot achieve adequate glycemic control. Compounding this difficulty is the trade-off between improved glycemic control and an increased risk for hypoglycemia (low blood glucose levels), which can cause seizure, coma and death. The artificial pancreas or closed loop system that can mimic normal pancreatic beta cell function thereby restoring normal metabolic homeostasis without causing hypoglycemia is being evaluated as a significant therapeutic option for the treatment of diabetes. To accelerate availability of a closed-loop system, the FDA has identified the artificial pancreas as one of its critical path initiatives and has formed the Interagency Artificial Pancreas Working Group. The FDA is helping advance the development of an artificial pancreas device system by prioritizing the review of research protocol studies, providing clear guidelines to industry, setting performance and safety standards, fostering discussions between government and private researchers, sponsoring public forums, and finding ways to shorten study and review time. The FDA s release of Final Guidance for Industry and the Food and Drug Administration Staff: The Content of Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications for Artificial Pancreas Device Systems is intended to provide clarity for manufacturers, investigators and reviewers in the development of this important technology and allows manufacturers and researchers to be innovative and flexible in how they develop studies. It also promotes greater communication between the FDA and manufacturers and researchers, which will support the rapid, safe and effective development of an APDS. There are three types of artificial pancreases. It should be noted that patients using any of these systems still need to monitor their blood glucose concentration, set appropriate basal rates for their insulin pump, and give pre-meal bolus insulin to maintain control of their glucose levels Threshold suspend automatic system that suspends or reduces insulin delivery temporarily when the sensor value reaches or approaches (reactive or predictive, respectively) a predetermined lower threshold of measured interstitial glucose. Control-to-Target (CTT) system that sets target glucose levels and tries to automatically maintain these levels at all times. Control-to-Range (CTR) system automatic system that adjusts insulin dosing only if a person's glucose levels reach or approach predetermined higher and lower thresholds CTR and CTT System Subtypes are dependent upon the drug or drugs being delivered and how each drug affects glucose concentrations. Subtypes may include insulin only or a bihormonal control system that includes both insulin and glucagon that are automatically released depending on the blood glucose level. In September 2013, the FDA approved the MiniMed 530G System under a new FDA category, called "OZO: Artificial Pancreas Device System, OZO indicating it is a threshold sensor type device. The device is worn externally and consists of an insulin pump with a continuous glucose monitor (CGM) that can be programmed to automatically suspend the delivery of insulin for two hours when the sensor glucose value detects that interstitial 10

11 glucose levels have fallen below a value set by the user (a predefined threshold). The MiniMed 530G continuously measures and displays glucose values, and also continuously administers basal insulin boluses in in user selected amount Bergenstal et al (2013) evaluated sensor-augmented insulin-pump therapy with and without the threshold-suspend feature in patients with nocturnal hypoglycemia. Two hundred and forty-seven (247) patients with type 1 diabetes and documented nocturnal hypoglycemia were randomly assigned to receive a sensor-augmented insulin-pump therapy with (121) or without (126) the Threshold Suspend feature for three months. The primary safety outcome was change in HbA1C, a measurement that shows an individual's average blood glucose control over a three month period. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemic events. AUC is a standard way to summarize two key parameters of hypoglycemic events - the magnitude and the duration. Reported results: The mean AUC for nocturnal hypoglycemic events was 37.5 percent lower in the Threshold Suspend group Nocturnal hypoglycemic events occurred 31.8% less frequently in the Threshold Suspend group than in the control group The mean AUC for combined daytime and nighttime hypoglycemic events was 31.4% lower in the threshold-suspend group than in the control group [5]. There was no change in HbA1C in either group. No serious adverse events occurred in the Threshold Suspend group. The percentages of nocturnal sensor glucose values of less than 50, 50 to less than 60 mg and 60 to less than 70 mg were significantly reduced in the thresholdsuspend group After 1438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6±40.7 Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis The authors concluded that over the over a 3-month period the use of sensor-augmented insulin pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing glycosolated hemoglobin values. They noted several limitations including that sensor glucose values were used for all analyses without validation by another reference method. Second, according to the definition used for hypoglycemic events that could be evaluated, runs of sensor glucose values of 65 mg per deciliter or less lasting less than 20 minutes and those with evidence of a pump interaction were not analyzed. Third, the generalizability of the study results may be limited because only hypoglycemia-prone patients were enrolled. Finally, the 3-month duration of the study may have been too short to show a benefit with respect to the quality of life. (This study was funded by Medtronic MiniMed; ASPIRE ClinicalTrials.gov number, NCT ) Scientific Rationale Update December 2012 The American Diabetic Association s (ADA s) 2012 clinical practice recommendations for the treatment and management of diabetes mellitus include the following recommendations for Continuous Glucose Monitoring (CGM): 11

12 Continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens can be a useful tool to lower A1c in selected adults (age 25 years) with type 1 diabetes. Although the evidence for A1c lowering is less strong in children, teens, and younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device. CGM may be a supplemental tool to SMBG in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes. ADA also listed the initiation of CGM as a treatment option for individuals when treatment goals are not met. As a treatment option for individuals when treatment goals are not met Szypowska et al. (2012) Real-time continuous glucose monitoring (RT-CGM) provides detailed information on glucose patterns and trends, thus allowing the patients to manage their diabetes more effectively. The aim of this study was to explore the potential beneficial effects of the use of RT-CGM on diabetes management compared with self blood glucose measurement (SBGM) in patients with type 1 diabetes mellitus (T1DM), by means of a systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, and the Cochrane Library were searched through by two independent investigators for RCTs concerning the use of RT-CGM in patients with T1DM. Only studies with a similar insulin regimen in the experimental and control groups were included in the analysis. Seven RCTs (n=948) met the inclusion criteria. Combined data from all studies showed better HbA1c reduction in subjects using RT-CGM compared with those using SBGM (mean difference (MD) -0.25; 95% confidence interval (95% CI): from to -0.17; P<0.001). Patients treated with insulin pump and RT-CGM had a lower HbA1c level compared with subjects managed with insulin pump and SBGM (four RCTs, n=497; MD -0.26; 95% CI: from to -0.10; P=0.002). The benefits of applying RT-CGM were not associated with an increasing rate of major hypoglycemic episodes. The use of RT-CGM for over 60-70% of time was associated with a significant lowering of HbA1c. RT-CGM is more beneficial than SBGM in reducing HbA1c in patients with type 1 diabetes. Further studies are needed to evaluate the efficacy of this system in the pediatric population, especially in very young children. Scientific Rationale Update March 2011 Battelino et al (2011) assessed the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes in a randomized, controlled, multicenter study. 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated HbA(1c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dl) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients. The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI ; P = 0.03). HbA (1c) at 26 weeks was lower in the continuous monitoring group than in the control group (difference -0.27%; 95% CI to -0.07; P = 0.008). Time spent in 70 to 180 mg/dl normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0). The investigators concluded continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA (1c) in children and adults with type 1 diabetes. 12

13 Garg et al (2011) compared use of CGM in subjects with type 1 diabetes on multiple daily injection (MDI) therapy versus continuous subcutaneous insulin infusion (CSII) therapy for 6 months. Sixty type 1 diabetic adults with similar baseline characteristics, using either MDI (n = 30) or CSII (n = 30) therapy, were enrolled in this 6-month prospective study. Subjects were instructed to wear the DexCom SevenPLUS continuous glucose monitor at all times throughout the study. All subjects were initially blinded from the CGM glucose data. After 4 weeks of blinded CGM use, the CGM was unblinded, making glucose data available to the patient. The CGM remained in the unblinded state for the remainder of the study (20 weeks). Clinic visits occurred every 4 weeks, at which time A1C values were collected and CGM data were downloaded. Mean baseline (± SD) A1C was 7.61 (± 0.76) and 7.63 (± 0.68) for CSII and MDI, respectively. Without any significant therapy change, A1C decrease at 12 weeks was similar in both groups. When compared with the blinded phase, unblinded use of CGM was associated with similar but significant reductions in glycemic control and variability parameters. In addition, both therapy groups had similar changes in mean glucose and glucose variability indexes at 3 and 6 months. Predefined per protocol analysis (sensor use at least 6 days/week) showed greater improvement in time spent in target range glycemia, mmol/l ( mg/dl), in the CSII group. The investigators concluded that CGM provides similar benefits in glucose control for patients using MDI or CSII therapy. The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group evaluated 436 children and adults with type 1 diabetes randomized to a treatment group that used CGM (N = 224), or a control group that used standard home blood glucose monitoring (N = 212) and completed 12 months of follow-up. After 6 months, the original control group initiated CGM while the treatment group continued use of CGM for 6 months. Baseline risk factors for severe hypoglycemia (SH) were evaluated over 12 months of follow-up using proportional hazards regression. CGM-derived indices of hypoglycemia were used to predict episodes of SH over a 24-h time horizon. The SH rate was 17.9 per 100 person-years, and a higher rate was associated with the occurrence of SH in the prior 6 months and female sex. SH frequency increased eightfold when 30% of CGM values were 70 mg/dl on the prior day (4.5 vs. 0.5%), but the positive predictive value (PPV) was low (<5%). Results were similar for hypoglycemic area under the curve and the low blood glucose index calculated by CGM. The authors concluded SH in the 6 months prior to the study was the strongest predictor of SH during the study. CGM-measured hypoglycemia over a 24-h span is highly associated with SH the following day but the PPV is low. Li et al (2010) evaluated the accuracy and safety of continuous glucose monitoring system (CGMS) in subjects with normal glucose tolerance (NGT), impaired glucose regulation (IGR) and newly-diagnosed type 2 diabetes mellitus (T2DM). A total of 162 subjects (53 NGT, 53 IGR and 56 newly diagnosed T2DM) at years old were recruited. Each subject received a continuous glucose monitoring (CGM) of CGMS SYSTEM GOLD(TM) (Medtronic Minimed, Northridge, CA) for 3 consecutive days and was instructed to self-calibrate the interstitial glucose levels with finger-stick blood glucose measurements (self-monitoring of blood glucose, SMBG) 7 times daily. Means of median absolute difference (median AD) and median absolute relative difference (median RAD) were calculated to assess the difference between CGM and SMBG values. The correlation between CGM and SMBG values were analyzed with the liner regression analysis. The data were analyzed by the ISO criteria for home glucose meters and Clarke error grid analysis. All participants showed a good tolerance to the insertion of CGMS sensor and wearing the device. The mean duration of CGMS recording was (75.6 ± 8.3) h. A total of 4324 glucose meter values were paired with glucose measurements from CGMS. Overall, a good relationship and no significant difference over a wide range (were found between CGM and SMBG values. The median AD was 0.5 ( ) mmol/l and the median RAD 7.55% (3.33% %) with 87.16% of 13

14 sensor values meeting the ISO home glucose meter criteria. The Clarke error grid analysis showed that 99.58% of the readings from CGMS fell into the clinical acceptable zones including 87.5% values in zone A (clinical exact) and 12.1% values in zone B (benign error). The investigators concluded both safe and well-tolerated, continuous glucose monitoring provides comparatively accurate blood glucose values to guide the diagnosis and treatment of diabetes. Scientific Rationale Update November 2009 Continuous glucose monitoring (CGM) devices represent a critical step toward achieving automated glucose measurement, offering people with diabetes a promising new tool for maintaining optimal glucose control. Through the use of enzymatic sensors, inserted subcutaneously in the abdomen or ex vivo by means of microdialysis fluid extraction, real-time minimally invasive continuous glucose monitoring (CGM) devices estimate blood glucose by measuring a patient s interstitial fluid (ISF) glucose concentration. Signals acquired from the interstitial space are subsequently calibrated with capillary blood glucose samples, a method that has raised certain questions regarding the effects of physiological time lags and of the duration of processing delays built into these devices. The time delay between a blood glucose reading and the value displayed by a continuous glucose monitor consists of the sum of the time lag between ISF and plasma glucose, in addition to the inherent electrochemical sensor delay due to the reaction process and any front-end signal-processing delays required to produce smooth traces. Filter responses for each algorithm are examined using in vitro hypoglycemic and hyperglycemic clamps, as well as with an analysis of fast glucose excursions from a typical meal response. Results demonstrate that the digital filters used by each algorithm do not cause adverse effects to fast physiologic glucose excursions, although nonphysiologic signal characteristics can produce greater delays. Scientific Rationale Update August 2008 The CGMS is not intended for day-to-day monitoring or long-term self-care and it is not a replacement for standard blood glucose monitoring, in the majority of diabetic patients. At this time, it is only intended for use to discover trends in glucose levels. The main advantage of continuous glucose monitoring is that it can help identify fluctuations and trends that would otherwise go unnoticed with standard HbA1c tests and intermittent finger stick measurements. For example, the device can capture dangerously low overnight blood glucose levels which often go undetected, reveal high blood sugar levels between meals, show early morning spikes in blood sugar, evaluate how diet and exercise affect blood sugars, or provide up to a 72-hour complete review of the effects of changes made to your therapy by your health care team. At this time, live-read glucose sensors have been used. These units provide frequent digital readouts of the patient's current interstitial glucose concentrations along with trend information. The precise role of these devices will certainly evolve as they become more accurate, available, and more randomized studies are completed to compare the CGMS to SMBT. (2007) American Diabetes Association (ADA) presented the Minimally Invasive Technology Role and Evaluation (MITRE) study during the 67th Scientific Session. The researchers evaluated the efficacy of 2 minimally invasive CGMS devices in a study of more than 400 patients with type 1 or type 2 diabetes treated with insulin. Of the patients, 102 were randomly assigned to the CGMS manufactured by Minimed, and 100 patients were assigned to the Biographer. The remaining patients were assigned to either a standard control group or an "attention" control group to control for the potential effect of increased contact with 14

15 healthcare professionals in patients receiving CGMS. All 4 patient groups demonstrated a decline in mean HbA1c, especially during the first few months of the study. By month 18, the percentage of patients who had a relative reduction of at least 12.5% was 15% in the Biographer group, 27% in the CGMS group, 24% in the standard control, and 27% in the attention control group. The relative decline in HbA1c from baseline ranged from 1% to 4.6%. None of these differences was significantly different from baseline or the results of the other groups. These results suggest that the use of the CGMS conferred a small benefit, but only in the short term. Future studies that are appropriately powered and designed are essential to understand the benefits of these CGMS devices or lack thereof. Hypoglycemia Unawareness and Episodes of Nocturnal Hypoglycemia A particular problem among insulin dependent diabetics is nocturnal hypoglycemia, which if uncontrolled can lead to irreparable cardiovascular or neurological damage. Nocturnal hypoglycemia is more common with long-acting insulins that have a distinct peak four to eight hours after injection (such as NPH insulin, 70/30 insulin or Mix 25 insulin) and is more likely when the evening dose of long-acting insulin is taken before the evening meal rather than at bedtime. The protective glucagon and epinephrine responses to hypoglycemia often become impaired in these patients, so that they are less likely to develop warning symptoms such as sweating and anxiety (called hypoglycemia unawareness). These effects are in part due to hypoglycemia itself, which transiently reduces both symptoms and counter-regulatory hormone responses. Severe hypoglycemia can be defined as an episode that is undetected by the patient or is detected so late that intervention by someone else is required to inject glucagon or to take the patient to the hospital to receive intravenous glucose. In a preliminary report from the Diabetes Control and Complications Trial, 817 patients with type 1 diabetes were followed for a mean of 21 months. There were 714 episodes of severe hypoglycemia in 216 of the patients. Over one-half of the episodes occurred at night, and over three-quarters in those receiving intensive insulin therapy. By far the best predictor of severe hypoglycemia was a previous episode of severe hypoglycemia. The risk was also increased in patients with high initial hemoglobin A1C (HbA1c) values that decreased quickly after intensive therapy was begun. An additional risk factor for the development of hypoglycemia is the administration of an angiotensin-converting enzyme (ACE) inhibitor. These drugs, which are often given to diabetics to slow the rate of progression of diabetic nephropathy, can increase insulin sensitivity and glucose disposal. This response is generally beneficial in that it tends to improve glycemic control slightly. Chetty et al. (2008) conducted a systematic review and meta-analysis of seven randomized controlled trials (n=335) that compared SMBG to CGM in type 1 diabetics. Five studies included pediatric populations. The primary outcome was the reduction in A1c. Compared to SMBG, CGM did not result in a significant reduction in A1c (p=0.055) or sensitivity analysis (p=0.775). The authors reported that there was some indication of decreased nocturnal hypoglycemia in the CGMS group. A significant reduction in the A1c was seen when the pediatric population was analyzed separately (p=0.036). (2007) American Association of Clinical Endocrinologists (AAEC) In their guidelines for the management of diabetes, the AAEC lists CGMS as a clinical consideration for type 1 diabetics with unstable glucose control and patients who cannot achieve an acceptable 15