Simplera™ System

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION | Device Generic Name: | Sensor, glucose, invasive, non-adjunctive | | --- | --- | | Device Trade Name: | Simplera system | | Device Procode: | PQF | | Applicant's Name and Address: | Medtronic MiniMed, Inc. 18000 Devonshire Street Northridge, CA 91325 | | Date(s) of Panel Recommendation: | None | | Premarket Approval Application (PMA) Number: | P160007/S047 | | Date of FDA Notice of Approval: | July 24, 2024 | The original PMA for the Guardian Connect System (P160007) was approved on March 8, 2018 and is indicated for continuous or periodic monitoring of glucose levels in the interstitial fluid under the skin, in patients (14 to 75 years of age) with diabetes mellitus. Glucose values from the Guardian Connect System are not intended to be used directly for making therapy adjustments. The SSED to support the indication is available on the CDRH website and is incorporated by reference here. The current Panel Track supplement was submitted to introduce the Simplera system, which has an all-in-one design and removes the need for calibration and can be used non-adjunctively in users 18 years and older unless otherwise indicated. ## II. INDICATIONS FOR USE The Simplera system is a real-time continuous glucose monitoring (CGM) system indicated for the management of diabetes in persons ages 18 years and older. The Simplera system does not require calibration and is designed to replace fingerstick blood glucose (BG) testing for diabetes treatment decisions, unless otherwise indicated. Interpretation of the Simplera system results should be based on the glucose trends and several sequential sensor readings over time. ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 1 of 29 {1} ### III. CONTRAINDICATIONS The Simplera system has no known contraindications. ### IV. WARNINGS AND PRECAUTIONS The full list of warnings and precautions can be found in the Simplera system labeling. The following are some, but not all, of warnings and precautions applicable to this device: The Simplera system should not be used in people: - Who are unwilling or unable to perform blood glucose tests as required - Who are unwilling or unable to maintain contact with their healthcare professional. - Whose vision and hearing do not allow recognition of the alerts sent by the app. Do not use Simplera system readings to make treatment decisions during the first 12 hours of wearing a sensor. Use a blood glucose meter reading to make treatment decisions when you see the “Check BG” icon during the first 12 hours of wearing a sensor. Taking medications that contain acetaminophen or paracetamol, including but not limited to cold medicines and fever reducers, can falsely raise sensor glucose readings. The level of inaccuracy depends on the amount of acetaminophen active in the body and can differ for each person. Falsely elevated sensor readings can result in over-administration of insulin, which can cause hypoglycemia. Always consult a healthcare professional before using sensor glucose values to make treatment decisions if a medication that contains acetaminophen or paracetamol is taken while wearing the sensor. Do not use continuous glucose monitoring if hydroxyurea, also known as hydroxycarbamide, is taken. Hydroxyurea is used to treat certain diseases, such as cancer and sickle cell anemia. Hydroxyurea use results in higher sensor glucose readings compared to blood glucose readings. Taking hydroxyurea while using continuous glucose monitoring can result in substantially higher sensor glucose readings in reports than actual blood glucose readings. Do not expose the Simplera sensor to Magnetic Resonance Imaging (MRI) equipment, diathermy devices, or other devices that generate strong magnetic fields (for example, CT scan, or other types of radiation). Exposure to strong magnetic fields can cause the sensor to malfunction, result in serious injury, or be unsafe. ### V. DEVICE DESCRIPTION The Simplera system is a continuous glucose monitoring (CGM) system. This system is intended to continuously monitor glucose levels in patients with diabetes mellitus, using an glucose sensor in combination with a mobile medical app for discrete display, without the need for fingersticks or calibrations. Patients should use a BG meter reading to make treatment decisions when the “Check BG” icon is displayed during the first 12 hours of PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 2 of 29 {2} wearing a sensor, if no sensor data is available, or if they are unsure that sensor glucose (SG) values are correct. The Simplera system consists of the Simplera sensor and the Simplera app, which work together to provide the user with real-time glucose values and alerts that assist with diabetes management decisions. The Simplera app includes apps for Apple® iOS, Apple Watch®, and Android products. ### **Simplera Sensor (MMT-5100J)** The sensor is a sterile, all-in-one glucose sensing device, intended as a single-patient, single-use component of a personal CGM system for the management of diabetes in persons 18 years of age and older. The sensor is intended for patient use for up to 6 days with an additional 24-hour grace period. It is intended to communicate with a compatible display device (i.e., the Simplera app) via Bluetooth® Low Energy (BLE) to provide glucose information for diabetes management. The sensor calculates user glucose concentrations based on collected signals from the interstitial fluid and transmits glucose and device data to the receiving device. It is intended to replace fingerstick BG readings for treatment decisions unless otherwise indicated. ### **Simplera App (iOS: MMT-8400; Android: MMT-8401)** The Simplera app (a mobile software application) is a component of the Simplera system. The Simplera app is not intended to be used on its own and is designed to be used with the Simplera sensor. The Simplera app is a software application that allows continuous glucose monitoring and includes features that support diabetes management, but it does not provide any direct therapy. It runs on a compatible iOS or Android mobile device and displays the data it receives wirelessly from the Simplera sensor. Information displayed on the app includes continuous glucose sensor values, glucose trend information, alert settings, and alerts that can help patients achieve and maintain euglycemia. From the mobile app, the sensor glucose data can be sent to cloud services systems, such as CareLink Personal (MMT-7333). When interfacing with the cloud services system, the app needs to have reliable cellular or Wi-Fi coverage, although the app can still be used as a stand-alone CGM device when no internet or cellular connection is available. ### **Key Features of the Simplera System** The functionality of the system is accomplished through interactions of the Simplera sensor and Simplera app. The key features for functionality of the system using the Simplera app are summarized below: - Support for the Simplera sensor i.e., pairing, unpairing, and displaying data received from the sensor - interactive graphical user interface - start-up wizard with animations and clips - status of the body-worn system devices and any operating faults detected - Ability to enter and delete events (eating, dosing, exercising, etc.) - Interface to manually enter BG value from a BG meter for optional calibration - Configuration and notification of sensor glucose alerts PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 3 of 29 {3} - Sensor data sharing to cloud services systems such as CareLink Personal (MMT-7333) and CareLink Connect (Android: MMT-6111, iOS: MMT-6112) - Storage of historical data - Support for Apple Watch # Optional Software The following optional software are compatible with the Simplera system: - MiniMed CareLink Personal (MMT-7333) - CareLink Connect (Android: MMT-6111, iOS: MMT-6112) This medical device product has functions subject to FDA premarket review as well as functions that are not subject to FDA premarket review. For this application, if the product has functions that are not subject to FDA premarket review, FDA assessed those functions only to the extent that they either could adversely impact the safety and effectiveness of the functions subject to FDA premarket review or they are included as a labeled positive impact that was considered in the assessment of the functions subject to FDA premarket review. # 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 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. Continuous glucose monitors can be used for detecting glycemic control trends and patterns. Automated insulin delivery devices can be used to automatically adjust insulin delivery from an insulin pump based on glucose data generated from a continuous glucose monitor. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with their healthcare provider to select the method that best meets their needs, expectations, and lifestyle. # VII. MARKETING HISTORY The Simplera system has not been marketed in the United States. The Simplera system is currently marketed in Europe and has not been withdrawn from marketing for any reason related to its safety or effectiveness. The Simplera system is an iteration of the Guardian Connect System without the required fingerstick sensor calibrations, although users may choose to enter optional fingerstick blood glucose values for calibration. The Guardian PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 4 of 29 {4} Connect System was approved for marketing in the United States on March 8, 2018 (P160007). The optional software (i.e., CareLink Personal) used with the Simplera system is the same as that currently used with the Guardian Connect System (P160007). This device has not been withdrawn from commercial distribution for any reason related to either safety or effectiveness. ### **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 Simplera System. Potential adverse effects related to sensor use include: - • Skin irritation or other reactions - • Bruising - • Discomfort - • Redness - • Bleeding - • Pain - • Rash - • Infection - • Raised bump - • Appearance of a small “freckle-like” dot where the sensor was inserted - • Allergic reaction - • Fainting secondary to anxiety or fear of needle insertion - • Soreness or tenderness - • Swelling at insertion site - • Sensor fracture, breakage, or damage - • Minimal blood splatter associated with sensor needle removal - • Residual redness associated with adhesive, tapes, or both - • Scarring There are potential adverse effects associated with making diabetes treatment decision when glucose values and rates of change provided by the device are inaccurate, as follows: The risks of making treatment decisions based on falsely high readings include inappropriate or excessive administration of insulin. These inappropriate treatments could increase the risk of hypoglycemia or prolong existing hypoglycemia which can result in seizures, loss of consciousness, and rarely, death. The risks of making treatment decisions based on falsely low readings include inappropriate administration of carbohydrates. These inappropriate treatments could increase the risk of hyperglycemia or prolong existing hyperglycemia, increasing ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 5 of 29 {5} exposure to long-term microvascular complications of diabetes (eye, kidney, nerve and heart disease) and acute diabetic ketoacidosis (DKA) which can result in weakness, seizures, and death. The risks of making treatment decisions based on inaccurate calculation of the rate of change of glucose could increase the risk of serious hypoglycemia or hyperglycemia if treatment is influenced by the inaccurate rate of change. Inaccurate calculation of the rate of change of glucose could also prevent a patient from taking measures to prevent a sustained increase or decrease in glucose levels, which could lead to serious hypoglycemia or hyperglycemia. The device also provides glucose alerts; these alerts may cause a user to take action to prevent potential future glycemic events. Potential adverse events may therefore also result from inaccuracies that cause a failure to trigger alerts or cause false alerts. This may cause users to take an inappropriate action, or incorrectly take no action, and result in increased risk or prolongation of hyperglycemia or hypoglycemia. There are potential risks associated with making acute and long-term therapy adjustments when glucose values and rates of change provided by the device are inaccurate. The risks of making therapy adjustments based on inaccurate device information include inappropriate adjustment of diabetes medication regimens. This could increase the risk of hypoglycemia and corresponding risk of seizures, loss of consciousness, and rarely, death; it may also increase the risk of hyperglycemia, increasing exposure to long-term microvascular complications of diabetes (eye, kidney, nerve and heart disease) and risk of DKA which can cause weakness, seizures, and death. There may be an additional risk that the display, or alerts related to the CGM device may not be able to override other applications or functions (phone, camera, messages) within the mobile device. This risk could potentially result in missed alerts, or temporary loss of access to the display. Missed alerts, or inability to access the display could result in missed opportunities to detect or prevent hypoglycemia or hyperglycemia and are discussed above. Human factors studies conducted assessed the safety of the user interface of the mobile app (sole display) for this device, and the ability for users to receive and understand alerts and notifications via the transmitter vibration feature. The human factors studies sufficiently assessed the potential for user error associated with comprehension of the impact of mobile device and app settings on notifications and Bluetooth communications, as well as use of the audio override feature. Software malfunction or failure to follow instructions of the Simplera app can lead to hypoglycemia, hyperglycemia, diabetic ketoacidosis, or possibly death. Keep the Simplera sensor out of the reach of children. The sensor and transmitter contain small parts and may pose a choking hazard that can result in serious injury or death. For the specific adverse events that occurred in the clinical study, please see Section X below. ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 6 of 29 {6} ## IX. SUMMARY OF NON-CLINICAL STUDIES ### A. Laboratory Studies Pre-clinical testing was performed on the Simplera Sensor (MMT-5100J). These pre-clinical studies included environmental, mechanical, and functional testing. The testing is summarized in Table 1. **Table 1:** Simplera Functional, Mechanical, and Environmental Tests | Test Name | Test Parameter | Acceptance Criteria | Pass/Fail | | --- | --- | --- | --- | | Chemical Exposure | Demonstrate the ability of the transmitter to withstand exposure to chemicals used in the cleaning procedure | No cracks, crazing, dissolving, or discoloration of the transmitter surface | Pass | | Drop Test per EN 60601-1 | Demonstrate safe operation after three repeated 1-meter drops onto 50 mm thick hardwood | Each unit must pass visual inspection, accuracy test, RF test, and leak test | Pass | | Random Vibration Test per EN 60601-1-11 | Demonstrate reliable operation after exposure to 10-100 Hz @ (1 m/s2)2/Hz, 100-200 Hz @ -3dB/octave, and 200-2000 Hz @ 0.5 (m/s2)2/Hz for 30 minutes in each axis | Each unit must pass visual inspection, accuracy test, and RF test | Pass | | Mechanical Shock per IEC 60601-1-11 | Demonstrate reliable operation after exposure to 150 m/s2 (15g) acceleration, with three shocks per axis in each direction ($\pm$X, Y, Z) for a total of 18 shocks | Each unit must pass visual inspection, accuracy test, and RF test | Pass | | Environmental storage conditions | Withstand 2 to 30°C, up to 95% relative humidity | Each unit must pass visual inspection, accuracy test, and RF test | Pass | | Temperature Shock Test | Demonstrate reliable performance after cycling from 0 to 45 °C with 5-minute ramp time and 2-hour dwell time at each plateau | Each unit must pass accuracy test and RF test | Pass | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 7 of 29 {7} | Test Name | Test Parameter | Acceptance Criteria | Pass/Fail | | --- | --- | --- | --- | | Operating Environmental Conditions | Demonstrate the ability to operate with temperature of 2-40 °C, 15-95% relative humidity, 700-1060 hPa | Each unit must pass visual inspection, accuracy test, and RF test | Pass | | Fluid ingress per IPX8 (International Protection) per IEC 60529 | Demonstrate reliable operation of the transmitter after submerged to a depth of 8ft for 30 minutes | Each unit must pass visual inspection, accuracy test, and RF test. | Pass | | Protection against solid foreign objects per IP4X (International Protection) per IEC 60529 | Demonstrate that the full diameter of 1.0mm spherical probe cannot pass through any opening of the transmitter | The full diameter of a 1.0mm spherical probe cannot pass through any opening of the transmitter. | Pass | All protocols, test reports, and acceptance criteria have been reviewed and found to be acceptable. All devices met all pre-defined acceptance criteria during testing. The Simplera system was also subjected to Electromagnetic Compatibility (EMC) testing to confirm that the devices will function properly in the presence of electromagnetic signals that may be encountered in the intended use environment. The testing is summarized in Table 2. **Table 2:** Simplera System Functional and Environmental Tests | Test Name | Test Parameter | Acceptance Criteria | Pass/Fail | | --- | --- | --- | --- | | EMC/EMI Testing per EN 60601-1-2:2020 | Demonstrate ability of the system to operate in environments with EMI which meet the standard of EN 60601-1-2:2020 | No unrecoverable observations and no latent effects resulting from exposure | Pass | | Wireless Coexistence | Demonstrate ability of system to operate in the presence of other wireless devices operating in the 2.4 GHz band | No observations at the applied levels and no latent effects resulting from exposure | Pass | | FCC | Demonstrate compliance with FCC regulation | Emitted levels must be per FCC CFR 47 Part 15.247. | Pass | | Security and logistical systems | Demonstrate that the system operates reliably when exposed to various security and logistical system devices | No observations at the applied levels and no latent effects resulting from exposure | Pass | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 8 of 29 {8} All protocols, test reports, and acceptance criteria have been reviewed and found to be acceptable. All devices met all pre-defined acceptance criteria during testing. ### Shelf Life The Simplera sensor has a shelf-life of 1 year, when stored in the primary packaging at 2-30°C, humidity up to 95% RH according to the requirements of ISO 11607: Packaging for Terminally Sterilized Medical Devices, ASTM D 4169: Standard Practice for Performance Testing of Shipping Containers and Systems, and ASTM F 1929: Standard Test Method for Detecting Leaks in Porous Medical Packaging by Dye Penetration. ### Packaging/Ship Testing Medtronic packages all devices to meet the requirements for shipping as defined in ASTM D4169, Standard Practice for Performance Testing of Shipping Containers and Systems. This enables packages to withstand typical events associated with distribution without defects or loss of sterility as applicable. The ability of the package to protect the products throughout handling, distribution, and the storage environment was successfully evaluated and documented. ### Software Software verification and validation were carried out in accordance with the FDA Guidance: Content of Premarket Submissions for Device Software Functions (June 14, 2023) for an “enhanced” level of documentation. Software development activities included establishing detailed software requirements, linking requirements with associated verification tests, software code reviews, unit testing, system level testing and defect tracking and dispositioning to ensure the software conforms to patient needs and intended uses. Software validation was successfully completed for the Simplera sensor and the Simplera application. ### B. Animal Studies No animal studies were used to support the safety and effectiveness of the Simplera system. ### C. Additional Studies ### Biocompatibility Biocompatibility testing for the components of the Simplera Sensor (sensor flex, sensor subassembly) was performed in accordance with the recommendations of ISO 10993-1, Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing. The results of these tests are listed in Table 3. Table 3: Simplera System Biocompatibility Test Summary | Test | Testing Summary | | --- | --- | | Cytotoxicity | Pass – Non-cytotoxic | | Irritation | Pass – Non-irritating | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 9 of 29 {9} | Test | Testing Summary | | --- | --- | | Pyrogenicity | Pass – Non-pyrogenic | | Sensitization | Pass – Non-sensitizing | | Systemic Toxicity (Acute) | Pass – Non-toxic | | Repeated (Sub-Acute) Toxicity | Pass – Non-toxic | | Genotoxicity | Pass – Non-genotoxic | | Implantation (12 weeks) | Pass | ### *Sterility* The method employed for the sterilization of the Simplera Sensor is ethylene oxide (EtO). The sterilization process used to sterilize the sensor was validated according to EN ISO 11135:2014, *Sterilization of health-care products – Ethylene oxide – Requirements for the development, validation, and routine control of a sterilization process for medical devices*. All sterilized components met the standards of EN ISO 11135 to assure a sterility assurance level (SAL) of 10$^{-6}$. ### *Human Factors* Human Factors usability validation studies were conducted in accordance with IEC 62366, *Medical Devices – Application of Usability Engineering to Medical Devices* and the FDA Guidance: “*Applying Human Factors and Usability Engineering to Medical Device: Guidance for Industry and Food and Drug Administration Staff*” (February 3, 2016). Medtronic conducted a usability validation study to provide evidence that the Simplera system could be used safely and effectively. There were 19 total participants 18 years of age and older in the study with a mix of CGM naïve and CGM experienced participants. 16 participants were responsible for their own therapy while an additional 3 Adult Caregiver dyads were included. All the critical tasks of the Simplera system for the intended population were evaluated. All use errors, close calls and use difficulties observed during completion of critical tasks were analyzed, and the root causes and impacts were assessed. For any use errors and close calls, a residual risk analysis was performed to determine whether design changes would further reduce the risks and to assess the residual risks related to the benefits to the patient. There were no new patterns of use errors that indicate further design mitigations were required. For this reason, the Simplera system can be used safely and effectively by users 18 years of age and older with diabetes for the intended use and use environments. ## **X. SUMMARY OF PRIMARY CLINICAL STUDY(IES)** The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the Simplera system for the management of diabetes in the US under IDE #G200156. Data from this clinical study were the basis for the PMA approval decision for use of the Simplera system in persons ages 18 years and older for up to 6 PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 10 of 29 {10} days with an additional 24-hours grace period. A summary of the clinical study is presented below. ### **A. Study Design** The CIP330 study was a multi-center, randomly assigned, prospective design without controls. Subjects were randomly assigned to frequent sample testing (FST) day and FST time. Subjects wore the devices up to a 7-day training period, followed by a 7-day study period. Investigational center staff ensured 176-188 hours of sensor wear (sensors could be removed at that time or after that time to ensure that the devices were not removed pre-maturely). In the event when early sensor removal occurred during the training period, the subjects were able to continue their participation in the study period based on the discretion of the principal investigator (PI). During this pivotal study, sensor data were collected in a blinded approach, where the Simplera sensor was used as a recorder for the purpose of data collection. There was no real time data communication during the study. During Yellow Springs Instruments (YSI™)/Self-Monitoring of Blood Glucose (SMBG) frequent sample testing (FST), venous blood glucose concentrations or SMBG (subjects 2–6 years only) were measured periodically. These values were compared to sensor glucose values (SGVs) to determine sensor accuracy. At the end of the study, raw sensor data collected by the Simplera system were processed through the final Athena Plus algorithm, using the zero-calibration scheme for analysis through the study endpoints. A total of 243 previously-diagnosed type 1 or type 2 diabetes subjects were enrolled for a total of 230 subjects including 118 adult subjects (18–80 years of age) and 112 pediatric subjects (2-17 years of age) to complete the study. The first subject was enrolled on July 15, 2020. The final subject visit was completed on November 16, 2020. There were 13 investigational sites. Although the study enrolled users as young as 2 years old, the study conclusions only support the safety and effectiveness of the Simplera sensor utilizing the Athena Plus algorithm in patients 18-80 years of age. Therefore, the data reported in this SSED will only be from study participants 18-80 years of age. #### **1. Clinical Inclusion and Exclusion Criteria** Enrollment in the CIP330 study was limited to patients who met the following inclusion criteria: 1. Individual is 2-80 years of age at time of enrollment. 2. Subject has a clinical diagnosis of type 1 or type 2 diabetes: a) If subject is 14-80 years of age, subject has a clinical diagnosis of type 1 or type 2 diabetes for a minimum of 6 months duration as determined via medical record/ source documentation by an individual qualified to make a medical diagnosis. PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 11 of 29 {11} b) If subject is 2-13 years of age, subject has a clinical diagnosis of type 1 or type 2 diabetes as determined via medical record/ source documentation by an individual qualified to make a medical diagnosis. 3. If subject is participating in a YSI-FST, subject has adequate venous access as assessed by investigator or appropriate staff. 4. Subjects participating in the high and low glucose challenges must have an insulin carbohydrates ratio(s) and insulin sensitivity factor(s). Subjects without ratios may participate under observation only. Patients were not permitted to enroll in the CIP330 study if they met any of the following exclusion criteria: 1. Subject will not tolerate tape adhesive in the area of sensor placement as assessed by a qualified individual. 2. Subject has any unresolved adverse skin condition in the area of sensor or device placement (e.g., psoriasis, rash, Staphylococcus infection). 3. Subject is actively participating in an investigational study (e.g., drug or device) wherein he/she has received treatment from an investigational study (drug or device) in the last 2 weeks prior to Visit 1. (Please note participation in an observational study is acceptable.) 4. Subject is female of child-bearing potential and has a pregnancy screening test that is positive. 5. Subject is a sexually active female of childbearing potential and is not using a form of contraception deemed reliable by the investigator. 6. Subject is female and plans to become pregnant during the course of the study. 7. Subject has had a hypoglycemic seizure within the past 6 months prior to enrollment. 8. Subject has had hypoglycemia resulting in loss of consciousness within the past 6 months prior to enrollment. 9. Subject has had an episode of diabetic ketoacidosis (DKA) within the past 6 months prior to enrollment. 10. Subject has a history of a seizure disorder. 11. Subject has central nervous system or cardiac disorder resulting in syncope. 12. Subject has a history of myocardial infarction, unstable angina, coronary artery bypass surgery, coronary artery stenting, transient ischemic attack (TIA), cerebrovascular accident (CVA), angina, congestive heart failure, ventricular rhythm disturbances, or thromboembolic disease 13. If subject is 7-80 years of age, subject has a hematocrit (Hct) more than 10% below the lower limit of normal reference range (please note that patients may use prior blood draw from routine care as long as the blood draw is within 6 months of screening and report of lab included with subject source documents). 14. Subject has a history of adrenal insufficiency. 15. Subject is a member of the research staff involved with the study. PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 12 of 29 {12} ## 2. Follow-up Schedule Subjects 14–80 years of age were scheduled to make 12 visits to the clinical study site, including the Enrollment/Screening visit (visit 1) and Study and device training (visit 2). Whereas, subjects 2-13 years of age were scheduled to make 8 visits to the clinical study site, including the Enrollment/Screening visit (visit 1) and Study and device training (visit 2). Subjects wore the devices up to a 7-day Training Period, followed by a 7-day Study Period. In the event that early sensor removal occurred during the Training Period, the subject could continue to the Study Period based on PI discretion. During the study period, subjects (14–80 years of age) underwent 4 days of YSI FSTs, each FST was approximately 8 hours during the in-clinic visit. Whereas, subjects (ages 7-13 years of age) underwent 2 days of YSI FST, each approximately 6 hours during the in-clinic visit. During the YSI FST, venous blood samples were drawn every 5-15 minutes and analyzed using the YSI. Study subjects 2-6 years of age underwent 2 days of SMBG FSTs, each were approximately 4 hours during the in-clinic visit. The frequency of blood draws with SMBG was every 5–30 minutes. ## 3. Clinical Endpoints With regards to safety, a descriptive analysis was used to characterize adverse events: - Skin assessment at sensor insertion sites - All adverse events With regards to effectiveness, the primary endpoint of the Accuracy Study was as follows: - For accuracy with the Athena Plus algorithm, the Simplera Sensor values were compared to YSI plasma glucose values during YSI FSTs. A within 20% mean agreement rate (±20 mg/dL when SG less than (<) 80 mg/dL), between Simplera sensor values and YSI plasma glucose values during YSI FST days was evaluated against the null Hypothesis (mean agreement rate ≤75%). With regard to success/failure criteria, the study pass/fail criteria was based on statistical hypothesis of the primary endpoints. The study would be considered a success if the evaluation criteria meets the predefined threshold. The secondary endpoints were evaluated in a fixed sequence of testing for adjustment of multiplicity. The results were compared to the Special Controls for sensor accuracy (SG limit of 50-400 mg/dL [2.8-22.2 mmol/L]) outlined in 21 CFR 862.1355 for integrated continuous glucose monitor (iCGM), although the Simplera system is not an iCGM. PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 13 of 29 {13} ## **B. Accountability of PMA Cohort** A total of 123 subjects 18-80 years of age were enrolled in the study, of which 2 were screen failures. A total of 121 subjects entered the Training Period, with 120 subjects completing the Training Period. A total of 119 subjects entered the Study Period, with 118 subjects completing the 7-day Study Period. A total of 3 subjects were withdrawn during the course of the study. ## **C. Study Population Demographics and Baseline Parameters** The demographics of the study population are typical for a study performed in the US. The Simplera sensor pivotal study had a total enrollment of 121 Type 1 and Type 2 diabetic subjects 18-80 years of age. Table 4 provides a high-level summary of the population demographics for subjects 18-80 years of age. **Table 4: CIP330 Study Population Demographics** | Characteristic | Subjects 18–80 years of age Number of Subjects =121^{a} | | --- | --- | | n | 121 | | Mean (SD) | 45.7 (18.5) | | Median | 47.0 | | Min, max | 18.0, 80.0 | | **Gender N (%)** | | | Female | 61 (50.4%) | | Male | 60 (49.6%) | | **Race N (%)** | | | Asian | 4 (3.3%) | | Black or African American | 9 (7.4%) | | Native Hawaiian / Other Pacific Islander | 1 (0.8%) | | White | 103 (85.1%) | | Other race | 3 (2.5%) | | American Indian or Alaska Native | 1 (0.8%) | | Asian, White | None | | **Ethnicity N (%)** | | | Hispanic or Latino | 20 (16.5%) | | Not Hispanic or Latino | 98 (81.0%) | | Unknown | 3 (2.5%) | | **Diabetes Type (%)** | | | Type 1 insulin requiring | 73 (60.3%) | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 14 of 29 {14} | Characteristic | Subjects 18–80 years of age Number of Subjects =121^{a} | | --- | --- | | Type 2 insulin requiring | 26 (21.5%) | | Type 2 non-insulin requiring | 22 (18.2%) | | **Diabetes History (Years)** | | | n | 121 | | Mean (SD) | 19.1 (13.0) | | Median | 15.5 | | Min, max | 0.6, 57.7 | | **Height (cm)** | | | n | 121 | | Mean (SD) | 170.8 (9.9) | | Median | 169.0 | | Min, max | 144.8, 190.5 | | **Weight (kg)** | | | n | 121 | | Mean (SD) | 88.0 (20.3) | | Median | 85.1 | | Min, max | 44.4, 146.7 | | **Body Mass Index (BMI) (kg/m2)** | | | n | 121 | | Mean (SD) | 30.2 (6.7) | | Median | 28.8 | | Min, max | 16.5, 51.5 | | **Baseline A1C (%)^{b}** | | | n | 120 | | Mean (SD) | 7.3 (1.3) | | Median | 7.1 | | Min, max | 5.2, 11.9 | | **Total Daily Dose (TDD)^{c} of Insulin (Units)** | | | n | 99 | | Mean (SD) | 54 (30.5) | | Median | 46 | | Min, max | 9, 180 | | **CGM Experience** | | | CGM experienced | 99 (81.8%) | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 15 of 29 {15} | Characteristic | Subjects 18–80 years of age Number of Subjects =121^{a} | | --- | --- | | CGM naïve | 22 (18.2%) | | **Pump Experience** | | | Pump experienced | 47 (38.8%) | | Pump naïve | 74 (61.2%) | a. Excludes 2 subjects who were screen failures. b. One subject had A1C(greater than 15.0% and was excluded from the A1C analysis c. Only subjects requiring insulin were included in the TDD analysis #### **D. Safety and Effectiveness Results** ##### **1. Safety Results** The safety was assessed by evaluation of the incidence of all serious Adverse Events, Adverse Device Effects (ADEs), Serious Adverse Device Events (SADEs), and Unanticipated Adverse Device Effects (UADEs) experienced by study subjects in addition to the skin assessments. ##### *Adverse Events* A total of 1 procedure-related adverse event and 1 serious adverse event was reported from all investigational sites for 18–80 year-old study subjects enrolled in the study. There was 1 serious adverse event of bilateral hydronephrosis, which was not device or procedure related. ##### *Skin Assessments* The majority of skin observations were related to observations at the insertion site, including red and pink dots, raised areas around insertion, raised bump, and a drop of blood at the insertion site. The severity of these observations was predominately mild. One occurrence of bruising at the insertion/application area was characterized as moderate ≥ 6cm . ##### **Adverse effects that occurred in the PMA clinical study:** There were no reports of unanticipated adverse device effects after 7 days of use. There were no reports of device-related or procedure-related serious adverse events after 7 days of use. There were no reports of severe hypoglycemia, severe hyperglycemia, or diabetic ketoacidosis. ##### **2. Effectiveness Results** Data collected during the study was post-processed after the study using the Athena Plus algorithm to convert the raw sensor information to sensor glucose values. For the accuracy information presented in the following section, PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 16 of 29 {16} laboratory-based comparator method (CM) using the YSI 2300 Analyzer was used. For values less than 70 mg/dL, the absolute difference in mg/dL between the two glucose results was calculated. For values greater than or equal to 70 mg/dL, the absolute difference (%) relative to comparator method values was calculated. **Table 5:** CGM System Agreement to CM within CGM Glucose Ranges, N=116 | CGM Glucose Range (mg/dL) | Number of Subjects | Number of paired CGM and CM | Percent within 15 mg/dL | Percent within 20 mg/dL | Percent within 40 mg/dL | Percent within 15% | Percent within 20% | Percent within 40% | Bias mg/dL | MARD (%) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | <54 | 29 | 164 | 84.1 | 90.9 | 98.2 | - | - | - | -7.8 | 14.6 | | 54-69 | 72 | 1,609 | 90.1 | 94.7 | 98.2 | - | - | - | -2.3 | 10.6 | | 70-180 | 116 | 9,655 | - | - | - | 74.3 | 85.7 | 98.6 | -1.6 | 11.0 | | 181-250 | 101 | 2,593 | - | - | - | 85.6 | 94.8 | 99.6 | -8.5 | 8.6 | | >250 | 79 | 1,384 | - | - | - | 89.8 | 96.7 | 100.0 | -14.1 | 7.4 | **Table 6:** CGM System Agreement to CM within CM Glucose Ranges, N=116 | CM Range (mg/dL) | Number of paired CGM-CM | Percent within 15 mg/dL | Percent within 20 mg/dL | Percent within 40 mg/dL | Percent within 15% | Percent within 20% | Percent within 40% | Mean bias (mg/dL) | MARD (%) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | <54 | 235 | 72.8 | 83.4 | 100.0 | --- | --- | --- | 10.6 | 22.7 | | 54-69 | 2030 | 84.8 | 93.4 | 99.8 | --- | --- | --- | 4.9 | 12.7 | | 70-180 | 8818 | --- | --- | --- | 77.7 | 88.5 | 99.0 | -1.0 | 10.1 | | 181-250 | 2625 | --- | --- | --- | 84.5 | 94.6 | 99.7 | -10.0 | 8.6 | | >250 | 1697 | --- | --- | --- | 84.4 | 94.3 | 99.4 | -23.1 | 8.8 | The following table shows the rate of concurrence between the Simplera system and a laboratory comparator method (CM). The tables are organized by CGM system glucose ranges, and they tabulate the percent of paired CM measurements that were in the identical range (shaded diagonal), as well as those CM PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 17 of 29 {17} measurements that were in glucose ranges above and below the paired CGM readings. **Table 7:** Overall Concurrence of CM Values and CGM Readings (N=116) | CGM Reference Glucose Ranges (mg/dL) | Percent of Matched Pairs-in Each CM Glucose Range for Each CGM Glucose Range | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | CM (mg/dL) | | | | | | | | | | | | | | Number of Paired CGM-CM (n) | <50 | ≥50-60 | >60-80 | >80-120 | >120 - 160 | >160 - 200 | >200 - 250 | >250 - 300 | >300 - 350 | >350 - 400 | >400 | | <50 | 207 | 15.0 | 42.5 | 37.7 | 4.3 | 0.5 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | >=50-60 | 684 | 5.8 | 43.4 | 47.1 | 2.3 | 1.3 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | >60-80 | 2285 | 1.9 | 15.6 | 68.5 | 12.6 | 1.3 | 0.1 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | >80-120 | 3693 | 0.1 | 0.9 | 12.6 | 68.8 | 16.9 | 0.5 | 0.1 | 0.1 | 0.0 | 0.0 | 0.0 | | >120-160 | 3532 | 0.0 | 0.0 | 0.1 | 17.6 | 66.3 | 15.3 | 0.6 | 0.1 | 0.0 | 0.0 | 0.0 | | >160-200 | 2149 | 0.0 | 0.0 | 0.0 | 0.3 | 15.0 | 59.7 | 24.2 | 0.7 | 0.1 | 0.0 | 0.0 | | >200-250 | 1678 | 0.0 | 0.0 | 0.0 | 0.0 | 0.7 | 12.5 | 63.6 | 21.8 | 1.1 | 0.2 | 0.0 | | >250-300 | 879 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.1 | 11.1 | 53.8 | 31.6 | 3.0 | 0.3 | | >300-350 | 404 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.2 | 7.4 | 66.3 | 25.5 | 0.5 | | >350-400 | 101 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 13.9 | 78.2 | 7.9 | | >400 | 14 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 71.4 | 28.6 | The Simplera reports glucose values between 50 and 400 mg/dL. When Simplera determines the sensor reading is below 50 mg/dL, it displays “Below 50 mg/dL” on the mobile app. When Simplera determines the glucose level is above 400 mg/dL, it displays “Above 400 mg/dL” on the mobile app. Because the System does not display glucose values below 50 mg/dL or above 400 mg/dL, the comparisons to the actual blood glucose levels (as determined by the comparator method) when the CGM value is classified as “Below 50 mg/dL” or “Above 400 mg/dL” is evaluated separately, and the cumulative percentages when laboratory comparator values were less than certain glucose levels (for “Below 50 mg/dL”), and when laboratory comparator values were greater than certain glucose levels (for “Above 400 mg/dL”) are presented in the table below. PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 18 of 29 {18} **Table 8:** Number and Percentage of CGM Readings ‘Below 50 mg/dL’ (LOW) and ‘Above 400 mg/dL’ (HIGH) Compared to CM | CGM Reading | CGM-CM Pairs | Comparator (mg/dL) | | | | | Total | | --- | --- | --- | --- | --- | --- | --- | --- | | | | <55 | <60 | <70 | <80 | ≥80 | | | **Below 50 mg/dL** | Cumulative, n | 67 | 119 | 169 | 197 | 10 | 207 | | | Cumulative % | 32% | 57% | 82% | 95% | 5% | -- | | CGM Reading | CGM-CM Pairs | >340 | >320 | >280 | >240 | ≤240 | Total | | **Above 400 mg/dL** | Cumulative, n | 14 | 14 | 14 | 14 | 0 | 14 | | | Cumulative % | 100% | 100% | 100% | 100% | 0% | -- | The following table shows the consistency of sensor clinical performance during the sensor wear period by comparing the CM values to their paired sensor points collected on each day of sensor wear in the CIP330 study. **Table 9:** Sensor Stability Relative to CM (Accuracy Over Time) | Sensor Wear Period | Number of Subjects | Number of Paired CGM-YSI | Percent of SG within 20/20% CM (%)^{a} | Mean Absolute Relative Difference (%) | | --- | --- | --- | --- | --- | | Day 1 | 77 | 2305 | 81.3 | 13.7 | | Day 2 | 72 | 2072 | 92.9 | 10.1 | | Day 3 | 77 | 2398 | 91.4 | 9.9 | | Day 4 | 111 | 3909 | 92.4 | 9.5 | | Day 5 | 61 | 1900 | 94.2 | 9.0 | | Day 6 | 53 | 1567 | 92.9 | 9.0 | | Day 7 | 44 | 1254 | 90.3 | 10.2 | | Overall | 116 | 15405 | 90.7 | 10.2 | $^{a}$For 20% agreement, ±20mg/dL used when CM <70 mg/dL. The following table provides data to present sensor accuracy at detecting specific glucose rates of change. These concurrence tables provide the percent of matched CM pairs to CGM values over specific glucose rates of change as observed during the CIP330 study. The top right and bottom left corners of the table represent the PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 19 of 29 {19} areas where there is the most incongruence between the CGM rate of change and the CM rate of change. Table 10: Concurrence of CGM and Comparator Method (CM) Rate of Change Stratified by Different CGM Rate Ranges | CGM Rate Ranges (mg/dL/min) | Percent of Matched Pairs in Each CM Rate Range for Each CGM Rate Range | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | CM Rate of Change (mg/dL/min) | | | | | | | | | | Number of Subjects | Number of Paired CGM-YSI | <-2 | [-2, -1) | [-1, 0) | [0, 1] | 1, 2] | >2 | | <-2 | 64 | 201 | 58.2% (117/201) | 33.8% (68/201) | 6.5% (13/201) | 1.5% (3/201) | 0.0% (0/201) | 0.0% (0/201) | | [-2, -1) | 101 | 838 | 7.9% (66/838) | 48.8% (409/838) | 40.9% (343/838) | 2.3% (19/838) | 0.0% (0/838) | 0.1% (1/838) | | [-1, 0) | 116 | 7350 | 0.2% (18/7350) | 4.1% (301/7350) | 75.9% (5581/7350) | 19.1% (1407/7350) | 0.5% (35/7350) | 0.1% (8/7350) | | [0, 1] | 116 | 5484 | 0.1% (3/5484) | 0.6% (33/5484) | 22.9% (1257/5484) | 68.5% (3757/5484) | 7.6% (416/5484) | 0.3% (18/5484) | | (1, 2] | 113 | 1156 | 0.0% (0/1156) | 0.1% (1/1156) | 2.5% (29/1156) | 31.5% (364/1156) | 56.5% (653/1156) | 9.4% (109/1156) | | >2 | 77 | 350 | 0.0% (0/350) | 0.0% (0/350) | 0.6% (2/350) | 4.6% (16/350) | 36.0% (126/350) | 58.9% (206/350) | ### Precision Analysis Precision of the sensor was evaluated by comparing the results from two separate sensors worn on the same subject at the same time. The following table provides the summary of a precision analysis. Table 11: System Precision Statistics, Subjects 18 years and Older | Number of Paired Points | Paired Absolute Relative Difference (PARD |SD|) | Precision Coefficient of Variance (PCV) | | --- | --- | --- | --- | --- | | 36459 | 8.8 (8.8) | 6.2 | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 20 of 29 {20} ### *Alert Performance* The Simplera system includes threshold alerts and predictive alerts. A threshold alert is issued if measured glucose is below or above the user-defined low or high alert set point. A predictive alert is issued if measured glucose is predicted to go below or above the user-defined low or high alert set point within a set period of time (up to 60 minutes ahead). Alert performance was evaluated to obtain ‘true alert’ and ‘false alert’ rates, and ‘correct detection’ and ‘missed detection’ rates. The descriptions and tables below describe the alert rate performance of the device within the CIP330 study. - • The correct detection rate is the rate that the device alerted when it should have alerted. For example, the blood glucose was below the hypoglycemic threshold, or above the hyperglycemic threshold, and the device sounded an alert (within +/- 15 or 30 minutes for the threshold alerts, and within 15 or 30 minutes following predictive alerts). - • The Missed Event Detection Rate is the rate at which the device did not alert when it should have (within +/- 15 or 30 minutes for the threshold alerts, and within 15 or 30 minutes following predictive alerts). For example, the blood glucose was below the hypoglycemic threshold, or above the hyperglycemic threshold, and the device did not sound a threshold or predictive alert. This is the complement of the confirmed event detection rate. - • The true alert rate is the rate at which the blood glucose value confirmed that the continuous glucose monitor alert was triggered correctly. For example: - ○ True Threshold Hypoglycemic alert rate alerted when the continuous glucose monitor read that the user was below the low threshold and the user's blood glucose was actually below that low threshold (within +/- 15 or 30 minutes of the alert) - ○ True Threshold Hyperglycemic alert rate alerted when the continuous glucose monitor read that the user was above the high threshold and the user's blood glucose was actually above that high threshold (within +/- 15 or 30 minutes of the alert) - ○ True Predictive Hypoglycemic alert rate alerted when the continuous glucose monitor predicted that the user would reach below the low threshold and the user's blood glucose was actually below that low threshold within 15 or 30 minutes following the alert - ○ True Predictive Hyperglycemic alert rate alerted when the continuous glucose monitor predicted that the user would reach above the high threshold and the user's blood glucose was actually above that high threshold within 15 or 30 minutes following the alert. - • The false alert rate is the rate at which the blood glucose value did not confirm that the CGM alert was triggered correctly. It is the complement of the true alert rate. For example: - ○ False Threshold Hypoglycemic alert rate the alarm alerted when the continuous glucose monitor read that the user was below the low ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 21 of 29 {21} threshold but the users blood glucose was actually above that low threshold (within ± 15 or 30 minutes of the alert) ○ False Threshold Hyperglycemic alert rate the alarm alerted when the continuous glucose monitor read that the user was above the high threshold but the user's blood glucose was actually below that high threshold (within ± 15 or 30 minutes of the alert) ○ False Predictive Hypoglycemic alert rate the alarm alerted when the continuous glucose monitor predicted that the user would be below the low threshold but the user's blood glucose was actually above that low threshold within 15 or 30 minutes following the alert. ○ False Predictive Hyperglycemic alert rate the alarm alerted when the continuous glucose monitor predicted that the user would be above the high threshold but the user's blood glucose was actually below the high threshold within 15 or 30 minutes following the alert. Table 12: Glucose True Alert Performance, Athena Plus Zero Calibration | mg/dL | Threshold Only | | Predictive Only | | Threshold and Predictive | | | --- | --- | --- | --- | --- | --- | --- | | | ±30 min | ±15 min | ±30 min | ±15 min | ±30 min | ±15 min | | 63 | 73.7% | 72.9% | 40.2% | 36.0% | 48.6% | 45.2% | | 65 | 75.4% | 75.4% | 43.4% | 39.6% | 52.0% | 49.2% | | 70 | 81.0% | 80.4% | 42.5% | 41.0% | 53.3% | 52.0% | | 80 | 79.4% | 78.0% | 44.9% | 41.8% | 55.4% | 52.8% | | 90 | 75.9% | 75.9% | 49.2% | 46.1% | 58.5% | 56.4% | | 180 | 88.5% | 88.3% | 63.0% | 60.5% | 72.5% | 70.8% | | 220 | 89.8% | 89.1% | 60.8% | 58.5% | 71.2% | 69.5% | | 250 | 90.1% | 89.5% | 57.7% | 55.2% | 68.5% | 66.7% | | 300 | 95.7% | 95.7% | 62.0% | 57.2% | 72.5% | 69.2% | Table 13: Glucose False Alert Performance, Athena Plus Zero Calibration | mg/dL | Threshold Only | | Predictive Only | | Threshold and Predictive | | | --- | --- | --- | --- | --- | --- | --- | | | ±30 min | ±15 min | ±30 min | ±15 min | ±30 min | ±15 min | | 63 | 26.3% | 27.1% | 59.8% | 64.0% | 51.4% | 54.8% | | 65 | 24.6% | 24.6% | 56.6% | 60.4% | 48.0% | 50.8% | | 70 | 19.0% | 19.6% | 57.5% | 59.0% | 46.7% | 48.0% | | 80 | 20.6% | 22.0% | 55.1% | 58.2% | 44.6% | 47.2% | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 22 of 29 {22} | mg/dL | Threshold Only | | Predictive Only | | Threshold and Predictive | | | --- | --- | --- | --- | --- | --- | --- | | | ±30 min | ±15 min | ±30 min | ±15 min | ±30 min | ±15 min | | 90 | 24.1% | 24.1% | 50.8% | 53.9% | 41.5% | 43.6% | | 180 | 11.5% | 11.8% | 37.0% | 39.5% | 27.5% | 29.2% | | 220 | 10.2% | 10.9% | 39.2% | 41.5% | 28.8% | 30.5% | | 250 | 9.9% | 10.5% | 42.3% | 44.8% | 31.5% | 33.3% | | 300 | 4.3% | 4.3% | 38.0% | 42.8% | 27.5% | 30.8% | **Table 14:** Glucose Correct Detection Alert Performance, Athena Plus Zero Calibration | mg/dL | Threshold Only | | Predictive Only | | Threshold and Predictive | | | --- | --- | --- | --- | --- | --- | --- | | | ±30 min | ±15 min | ±30 min | ±15 min | ±30 min | ±15 min | | 63 | 65.9% | 65.9% | 94.1% | 90.4% | 94.1% | 91.1% | | 65 | 72.0% | 70.6% | 95.8% | 93.0% | 95.8% | 93.7% | | 70 | 82.2% | 82.2% | 94.7% | 92.1% | 94.7% | 92.8% | | 80 | 86.8% | 84.9% | 96.2% | 93.4% | 96.2% | 93.9% | | 90 | 84.9% | 84.6% | 94.4% | 90.2% | 94.4% | 91.9% | | 180 | 90.2% | 88.3% | 98.4% | 95.1% | 98.6% | 95.8% | | 220 | 85.9% | 85.6% | 95.8% | 93.3% | 96.1% | 94.0% | | 250 | 80.3% | 80.3% | 93.6% | 90.6% | 93.6% | 91.6% | | 300 | 74.6% | 73.7% | 94.9% | 89.0% | 94.9% | 89.8% | **Table 15:** Glucose Missed Detection Alert Performance, Athena Plus Zero Calibration | mg/dL | Threshold Only | | Predictive Only | | Threshold and Predictive | | | --- | --- | --- | --- | --- | --- | --- | | | ±30 min | ±15 min | ±30 min | ±15 min | ±30 min | ±15 min | | 63 | 34.1% | 34.1% | 5.9% | 9.6% | 5.9% | 8.9% | | 65 | 28.0% | 29.4% | 4.2% | 7.0% | 4.2% | 6.3% | | 70 | 17.8% | 17.8% | 5.3% | 7.9% | 5.3% | 7.2% | | 80 | 13.2% | 15.1% | 3.8% | 6.6% | 3.8% | 6.1% | | 90 | 15.1% | 15.4% | 5.6% | 9.8% | 5.6% | 8.1% | | 180 | 9.8% | 11.7% | 1.6% | 4.9% | 1.4% | 4.2% | PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 23 of 29 {23} | mg/dL | Threshold Only | | Predictive Only | | Threshold and Predictive | | | --- | --- | --- | --- | --- | --- | --- | | | ±30 min | ±15 min | ±30 min | ±15 min | ±30 min | ±15 min | | 220 | 14.1% | 14.4% | 4.2% | 6.7% | 3.9% | 6.0% | | 250 | 19.7% | 19.7% | 6.4% | 9.4% | 6.4% | 8.4% | | 300 | 25.4% | 26.3% | 5.1% | 11.0% | 5.1% | 10.2% | ### *Sensor Life* Among the 128 sensors evaluated, 11 sensors (8.6%) were censored from the survival analysis due to various reasons not related to the to-be-marketed device (e.g., subject dropped out of the study, subject accidentally removed sensors at the incorrect time, and software anomalies that are only applicable to the investigational device but resolved for the commercial device). 75.2% of the sensors lasted through the end of the entire six-day wear period, and 66.7% lasted through the end of the six-day wear period with the 24-hour grace period. #### 3. Subgroup Analyses No analyses were performed for specific subgroups. #### 4. Pediatric Extrapolation In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population. ### **XI. 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 13 principal 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. ### **XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION** In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Clinical Chemistry and Toxicology Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel. PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 24 of 29 {24} # XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES ## A. Effectiveness Conclusions The effectiveness of the Simplera sensor was based on the performance evaluation of the sensor compared to the blood glucose values measured during in-clinic sessions spanning the wear period of the sensor (6 days plus optional 24-hour grace period). The performance data presented above (Tables 5 to 15) established the sensor performance across the claimed measuring range (50 to 400 mg/dL glucose), and the precision, with zero calibrations throughout the 6-day wear period for the Simplera sensor. The performance data presented above also established the performance of the alarms and alerts of the Simplera sensor. The results of the clinical studies performed to support this submission establish a reasonable assurance of effectiveness that the Simplera system can be used as intended in the intended use population with zero calibration. ## B. Safety Conclusions The risks of the device are based on the adverse events observed in the clinical study described in Section X above, and the potential adverse effects of the device on health as described in Section VIII above. In the CIP330 pivotal study, there were no device-related or procedure-related serious adverse events, or unanticipated adverse device effects after 7 days of use. In addition, the skin assessments at the insertion site were carried out, and the majority of skin observations were related to the observations at the insertion site, including red and pink dots, raised areas or bumps around the insertion site and a drop of blood at the insertion site. The severity of these observations was predominately mild. ## C. Benefit-Risk Determination The probable benefits and risks of the device are based primarily on data collected in the clinical and analytical studies to support approval of the Simplera system as described above. Potential adverse effects of the device on health are described in Section VIII above and also summarized below. A summary of the benefits and risks of this device is presented below. ### Summary of Benefits: This device is intended to replace self-monitoring of blood glucose testing for diabetes treatment decisions. The adjustable threshold and predictive glucose alerts are intended to warn users to take action to treat or prevent a hypoglycemic or hyperglycemic event. ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 25 of 29 {25} Further, CGM measurements, which are performed every 5 minutes via an indwelling sensor, do not require repeated fingersticks with a lancet for each measurement as is required for each individual blood glucose measurement with a traditional blood 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. This device presents an additional probable benefit of convenience compared to the previous version of the device (Guardian Connect System) from the same manufacturer, in that the device does not require calibration with fingerstick blood glucose measurements, and can also be used non-adjunctively, unless otherwise indicated, to make diabetes treatment decisions without performing confirmatory fingerstick blood glucose measurements. This results in a reduction in pain and inconvenience relative to systems that require these measurements. Furthermore, real time knowledge of whether blood glucose is increasing or decreasing adds information unavailable by traditional discrete monitoring. 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 that they need to take action to treat asymptomatic hypoglycemia 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 hypoglycemia 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 benefit to users not possible with traditional blood glucose monitoring. #### Summary of Risks: The risks associated with the use of any CGM system are hypoglycemia or hyperglycemia related to use of inaccurate sensor glucose values to make treatment decisions and/or the system not alerting the user to hypoglycemic or hyperglycemic states due to inaccurate sensor glucose readings, or the sensor failing/malfunctioning/dislodging significantly earlier than the end of its intended wear period. ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 26 of 29 {26} The risks of making treatment decisions based on falsely high readings include inappropriate or excessive administration of insulin. These inappropriate treatments could increase the risk of hypoglycemia or prolong existing hypoglycemia which can result in seizures, loss of consciousness, and rarely, death. For the Simplera system, taking medications such as acetaminophen may result in significant falsely high CGM readings. The risks of making treatment decisions based on falsely low readings include inappropriate administration of carbohydrates. These inappropriate treatments could increase the risk of hyperglycemia or prolong existing hyperglycemia, increasing exposure to long-term microvascular complications of diabetes (eye, kidney, nerve, and heart disease) and acute diabetic ketoacidosis (DKA) which can result in weakness, seizures, and death. In the clinical study, a bias of -23.1 mg/dL was observed in the >250 mg/dL glucose range for the Simplera system in the intended use population of age 18 and older, which raised concern about risks introduced with use of this system non-adjunctively. However, the negative bias in the hyperglycemic glucose ranges is not expected to result in an increased risk of severe hypoglycemia given that the lower sensor glucose readings would lead to more conservative diabetes management decisions. While the large negative bias in the hyperglycemic glucose ranges may result in a user making multiple smaller glucose corrections to address hyperglycemia, if hyperglycemia is promptly addressed per routine glucose management, this would amount to an inconvenience rather than a safety risk and thus was weighed against the probable benefits of the device. Inaccurate calculation of the rate of change of glucose by the device could increase the risk of serious hypoglycemia or hyperglycemia if treatment is influenced by the inaccurate rate of change. Inaccurate calculation of the rate of change of glucose by the device could also prevent a patient from taking measures to prevent a sustained increase or decrease in glucose levels, which could lead to serious hypoglycemia or hyperglycemia. The risks of inappropriate treatment decisions due to inaccurate glucose values for a system intended for non-adjunctive use cannot be adequately mitigated by warnings in the system labeling to perform fingerstick glucose measurements if symptoms are not consistent with the glucose values displayed by the device alone. Such users may not have symptoms of hypoglycemia or persistent hyperglycemia until glucose levels are closer to a critical value, and thus proper alternative monitoring and treatment decisions may be delayed. The Day 1 performance of the Simplera sensor reported in the clinical study was considerably lower during the first 12 hours of wear as compared to the second 12 hours of wear. As such, there is a risk related to non-adjunctive use of the device during the first 12 hours of wear if patients make decisions on diabetes management based on inaccurate sensor readings alone without confirmation by blood glucose testing. As a mitigation, the adjunctive use period of the device was designated as 12 hours to ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 27 of 29 {27} minimize the risk of patient harm related to insulin over-dose or under-dose due to inaccurate CGM readings being used non-adjunctively. The risks of making therapy adjustments based on inaccurate glucose value and/or rate-of-change from the device include inappropriate adjustment of diabetes medication regimens. This could increase the risk of hypoglycemia and corresponding risk of seizures, loss of consciousness, and rarely, death; it may also increase the risk of hyperglycemia, increasing exposure to long-term microvascular complications of diabetes (eye, kidney, nerve and heart disease) and risk of acute diabetic ketoacidosis (DKA) which can cause weakness, seizures, and death. Further, when sensor glucose values are not available due to premature sensor failure, the user, who should have backup blood glucose monitoring supplies, may not have sufficient backup supplies or replacement CGM sensors expect that in sufficient quantity to replicate the level of monitoring expected from a CGM system, nor would there be the opportunity to continue predictive or threshold glucose alerts. The Simplera sensor survival under best-case circumstances is reported as 75.2% at 144 hours (6 days) and 66.7% at 165 hours. The sensor wear period of up to 6 days with a grace period of an additional 24 hours adequately support the use of the sensor non-adjunctively. The device also provides glucose alerts; these alerts help users to take action to prevent potential future glycemic events. Adverse events may therefore also result from inaccuracies that cause a failure to trigger alerts or cause false alerts. This may cause users to take an inappropriate action, or incorrectly take no action, and result in increased risk or prolongation of hyperglycemia or hypoglycemia. There is a minor risk of skin irritation, inflammation, or infection due to either the sensor needle or the adhesive. There is a risk of sensor breakage leaving a sensor fragment under the skin. This event was reported infrequently with previously approved sensors. No sensor breakage was documented in the clinical study reviewed. Reported sensor breakage rate with similar devices has been very low, however, and this study was not powered to assess the rate of breakage. There are risks relating to the use of the mobile application, the sole display for this device. Risks of the use of a mobile application as the sole device display include delayed or missed alerts due to loss of mobile application connectivity or operation, improper application setup, lack of comprehension of the audio override feature, and lack of comprehension of alert features that may result in an increased risk of hypoglycemia or hyperglycemia. There is no alternate display for this device. Human factors studies assessed the safety of the user interface of the mobile app (sole display) for this device. The level of information necessary to understand the safety aspects of the user interface, and how it supports the user and reduces the potential for use error was provided by the sponsor, and found to be adequate. Further, the human factors study sufficiently assessed the potential for user error associated with ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 28 of 29 {28} comprehension of the impact of phone and app settings on notifications and Bluetooth communications. # 1. Patient Perspective Patient perspectives considered during the review included patients’ preference for CGMs that can be used non-adjunctively and elimination of frequent self-insertion for calibration. In conclusion, given the available information above, the data support that for the proposed intended use of the Simplera system for diabetes management in people 18 years and older, 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. The benefits of using the Simplera system, as discussed above, outweigh the risks. # **XIV. CDRH DECISION** CDRH issued an approval order on July 24, 2024. The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820). # **XV. 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. # **XVI. REFERENCES** None. ---PMA P160007/S047: FDA Summary of Safety and Effectiveness Data 29 of 29