Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.  
  
 **History/Background and/or General Information**

The two common types of diabetes are type 1 and type 2. Type 1 diabetes, known
as insulin-dependent diabetes, is a chronic condition in which the pancreas
produces little or no insulin. Insulin is a hormone needed to allow sugar
(glucose) to enter cells to produce energy. Type 2 diabetes is the most common
form of diabetes, in which your body doesn't use insulin properly.  
  
According to the American Diabetes Association, 34.2 million Americans have
diabetes. Of the 34.2 million Americans, 14.3 million are seniors aged 65 and
older.1  
  
The complications of diabetes mellitus are far less common and less severe in
people who have well-controlled blood sugar levels.1 Acute complications
include hypoglycemia, hyperglycemia, diabetic coma, and nonketotic
hyperosmolar coma. Chronic hyperglycemia, resulting from poorly controlled
diabetes, may result in serious and life-threatening damage, including
dysfunction and failure of the eyes, kidneys, nervous system and
cardiovascular system.  
  
As of March 1, 2020, there is only one Food and Drug Administration (FDA)
approved implantable therapeutic continuous glucose monitoring system (I-CGM).
The Eversense E3 Continuous Glucose Monitoring (CGM) System was approved by
the FDA in June 2018, with expanded indications in June 2019.2 Please refer to
the FDA approval information located at <https://www.fda.gov/medical-
devices/eversense-e3-continuous-glucose-monitoring-system-p160048s016>. This
implantable CGM is a prescription device that provides real-time glucose
monitoring for patients with diabetes. The system consists of an implantable
fluorescence-based sensor, a smart transmitter, and a mobile application for
displaying glucose values, trends and alerts on the patient's compatible
mobile device. It is designed to replace fingerstick blood glucose testing for
diabetes treatment decisions as indicated in the FDA 2019 approval. The system
is intended to provide real-time glucose readings, provide glucose trend
information, and provide alerts for the detection and prediction of episodes
of low blood glucose (hypoglycemia) and high blood glucose (hyperglycemia).
The FDA requires the specific training or experience practitioners need in
order to use the device and insofar as the sale and distribution of the device
are restricted to practitioners who are enrolled in, undergoing, or have
completed the specific training identified in the labeling.2  
  
 **Covered Indications  
  
** I-CGMs are class III medical devices that require premarket approval by the
FDA. In order to be considered medically reasonable and necessary, the FDA
approved indication must include use as a therapeutic/non-adjunctive and non-
therapeutic/adjunctive CGM.3 The FDA recently approved expanding the
indications of an implantable CGM product to replace fingerstick blood glucose
measurements for diabetes treatment decisions.  
  
Therapeutic/non-adjunctive and non-therapeutic/adjunctive I-CGMs are
considered medically reasonable and necessary by Medicare when all of the
following coverage criteria (1-5) are met:

  1. The beneficiary has diabetes mellitus (Refer to the related Billing and Coding Article [A58110] for applicable diagnoses); **and** ,
  2. The beneficiary is insulin-treated with multiple (three or more) daily administrations of insulin or a Medicare-covered continuous subcutaneous insulin infusion (CSII) pump; **and** ,
  3. The beneficiary's insulin treatment regimen requires frequent adjustment by the beneficiary on the basis of blood glucose monitor (BGM) or CGM testing results; **and** ,
  4. Within six (6) months prior to ordering the I-CGM, the treating practitioner has an in-person visit with the beneficiary to evaluate their diabetes control and determined that criteria (1-3) above are met; **and** ,
  5. Routine recommended follow-up care is expected.

  
**Limitations  
  
** I-CGM devices will not be considered medically reasonable and necessary for
the following:

  1. Individuals that do not require insulin therapy.
  2. Short-term I-CGM (72 hours to 1 week) for diagnostic use.

**Exception:** for those beneficiaries who have previously met the coverage
criteria for a non-implantable therapeutic/non-adjunctive and non-
therapeutic/adjunctive continuous glucose monitor through the Medicare DME
benefit and subsequently choose to switch to the implantable device, they may
do so with a provider order. However, all other coverage criteria above must
be fulfilled in order for Medicare payment.  
  
 **Notice:** Services performed for any given diagnosis must meet all of the
indications and limitations stated in this LCD, the general requirements for
medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.

**Introduction  
  
** This evidence review focuses on evidence for FDA approved implantable
therapeutic continuous glucose monitors and whether this evidence is adequate
to draw conclusions about health outcomes for the Medicare population. Health
outcomes of interest include mortality, patient morbidity as a result of
diabetes, harm from treatments, and patient quality of life and function.
Additionally, proven intermediate outcomes in the causal pathway of health
outcomes are of interest. The current clinical evidence based on trial data
for I-CGMs includes one pivotal European trial, two pivotal U.S. clinical
trials under one investigational device exemption (IDE), two post-market
registry studies, and guideline and consensus statements.  
  
 **Internal Technology Assessment  
  
** Pubmed was searched for clinical studies that included "implantable
continuous glucose monitor" or "Eversense" (the only FDA approved implantable
CGM as of March 1, 2020). Literature was reviewed for inclusion if it met
these criteria, and all abstracts were reviewed. Studies must be published in
English language and specific to the human population. Only devices approved
by the FDA as of March 1, 2020 were included in this review.  
  
 **Pivotal clinical studies U.S.  
  
** Christiansen M, et al., reported on two studies conducted under IDE
#G150165, the PRECISE II and PRECISION studies. Data from both studies are
included in the FDA summary of safety and effectiveness data (SSED). PRECISE
II was a non-randomized, blinded, prospective single-arm study at 8 U.S. sites
evaluating 90 patients with type 1 and type 2 diabetes in 2016.(6) The I-CGM
glucose values and all glucose-related alerts were blinded to patients and
investigators. Management decisions were based on self-monitored blood
glucose. Of the initial 90 patients, 82 completed the 90 day visit with data.
The primary endpoint was the Mean Absolute Relative Difference (MARD) between
paired Eversense and Yellow Springs Instrument (YSI) reference measurements
through 90 days for reference glucose values from 40 to 400 mg/dL.(6) The
prospective, unblinded, multicenter PRECISION study evaluated 35 patients,
with enrollment starting in July 2017 and subject completion in February
2018.(7) Study outcome measurement was similar to PRECISE II. In PRECISION,
the glucose calculation algorithm was updated. Inclusion and exclusion
criteria, follow-up schedules, and accountability of patients are included in
the respective articles. The demographics of both trials are listed in Table 8
of the 2018 SSED.(13p15) The mean age of PRECISE II was 45 years (SD:16 years,
minimum age: 18, maximum age: 77) and 52 years (SD: 16 years, minimum age: 18,
maximum age: 75) for PRECISION. Table 9 of the SSED has diabetic history, with
PRECISE II having 28.6% type II patients and PRECISION having 32.2% type II
patients.(13p17) Types of insulin therapies for PRECISE II included: 14.3%
none, 31.4% multiple daily injections, 54.3% continuous insulin infusion pump;
PRECISION: 22.2% none, 26.7% multiple daily injections, 47.8% continuous
insulin infusion pump. Safety endpoints for both studies are in Table 10 in
the SSED and Table 11 reports the adverse events related or possibly related
to the device or procedure, with most related to dermatological issues.(13p18)
There were no infections in either study. Effectiveness results are tabulated
in Tables 13 - 26 of the SSED.(13p20-35) In PRECISE II, the overall reported
MARD value against reference glucose values was 8.8% (95% CI: 8.1 - 9.3%),
which was lower than the performance goal of 20%. The system identified 93% of
hypoglycemic events and 96% of hyperglycemic events per YSI. In PRECISION, the
MARD value against reference was 9.6% (95% CI 8.9 - 10.4). Precision
measurement results that compare data from two separate sensors from the same
subject are available for both studies (Tables 27 and 28) as is alert
performance (Tables 29 - 36).(13p36-39)  
  
 **Pivotal Clinical Studies Outside the U.S.  
  
** The Eversense implantable CGM study by Kropff J, et al., studied 71
patients in a 180-day prospective trial at seven clinical sites in Europe
November 2014 to November 2015. Baseline patient characteristics are reported
in Table 1 and include 66 type 1 and 5 type 2 patients with diabetes.(7p65)
Average age was 41.7 years (SD 12.6 years). The sensor accuracy compared to
venous plasma glucose samples using YSI 2300 STAT PLUS glucose and lactate
analyzer (YSI, Yellow Springs, OH) over the range of 2.2 - 22 mmol/L or 40 -
400 mg/dL is reported in Table 2.(7p66) The MARD compared to reference venous
glucose values (>4.2mmol/L) was 11.1% (95% CI 10.5, 11.7).(7) Table 3 reports
the accuracy of the sensor for glycemic ranges and for rates of change.(7p66)
In particular, in the range of <75 mg/dL, the MARD was 21.7%, SD 21.5 and 95%
CI 20.4, 23.0.(7) No device related serious adverse events occurred. Two cases
of incision site infection were reported; one received antibiotic treatment.
The authors note, "Results from the questionnaire data indicated high
participant acceptance of the system but did not register improved perceived
generic quality of life, as assessed per SF-36 questionnaire."(7p66)  
  
 **Post-Market Registry Studies  
  
** A study by Sanchez P et al. included deidentified data from the first 205
patients to reach a 90-day wear period in the Eversense Data Management System
(DMS).(8) This data was analyzed for mean sensor glucose (SG), median
interquartile range, coefficient of variation, glucose measurement index, and
percent and time across glucose ranges for various time periods. Data was
collected from August 1, 2018 to May 11, 2019. Patients were identified as
either type 1 (129), type 2 (18), or unreported (58). Only limited demographic
data was obtained. SG data and "patient-entered inputs such as meals,
exercise, and insulin are automatically uploaded" into the DMS through
smartphone connection. Results are listed in Table 1.(8p3) The MARD compared
to home blood glucose meters was 11.2% (SD 11.3%).(8) Patients chose to have
the sensor reinserted 78.5% of the time after the completion of the first
sensor wear.(8) The transmitter wear time median was 83.6%. No serious adverse
events were reported with 2% of patients reporting mild infection at the
insertion site (3 treated with oral antibiotics), 1.5% reporting hypoglycemia
that was self-treated, and 2% reporting failure to remove the sensor on first
attempt. The authors state, "In conclusion, the 90-day implanted Eversense
I-CGM system appears to be a valuable and safe tool for management of diabetes
with patients reinserting and using the device the majority of the time."(8p4)  
  
Deiss D et al., reports on the post-market clinical follow-up (PMCF) registry
in 534 centers in Europe and South Africa from June 2016 to August 2018.(9)
The initial device approval in Europe occurred in May 2016 for the 90-day
sensor and September 2017 for the 180-day sensor. All patients with implanted
sensors were enrolled prospectively, a total of 3,023 patients.(9) Patient
inclusion/exclusion criteria were consistent with the device label. A total of
969 patients had used the system for at least 6 months and 173 patients had
used the system for a minimum of 1 year. Adverse events were defined as, "any
untoward medical occurrence, unintended disease or injury, or untoward
clinical signs (including abnormal laboratory findings) in patients, users, or
other persons, whether or not related to the medical device.(9) A serious
adverse event (SAE) was defined as an AE that led to death, led to serious
deterioration in the health of the patient requiring medical assistance
including emergency medical services and/or hospitalization, or led to fetal
distress, fetal death, or a congenital abnormality or birth defect." AEs were
recorded at each visit and also between visits by patient report. Events were
adjudicated by a medical monitor. The primary safety endpoint was the rate of
SAEs through 4 sensor cycles. No SAEs were reported. The discontinuation rate
was 11% (337 patients), with the most common reason listed as unknown and next
most common listed as lack of medical reimbursement. Sensor location site
infection was reported at a rate of 0.96% and inability to remove the sensor
upon first attempt at 0.76%.(9) Sensor life was 91% for 90-day sensors and 75%
for 180-day sensors. The authors conclude, "The PMCF registry provides real-
world evidence that the Eversense I-CGM system is safe over multiple cycles of
use."(9p2)  
  
 **Evidence-Based Guidelines  
  
** According to information from 2019 Chamberlain JJ et al., the American
Diabetes Association (ADA) added this section on diabetes technology to the
Standards of Medical Care in Diabetes. The Professional Practice Committee of
the ADA who developed this guideline is comprised of an expert committee whose
appointment is based on excellence in research or clinical care. For these
recommendations, members systematically search the literature. The
recommendations are rated as A, B, C, or E.(10) Those with an A rating are
based on large, well-designed clinical trials or high-quality meta-analyses.
Recommendations with a B rating are based on well-conducted cohort studies,
while uncontrolled studies are given a C rating. An E rating is assigned when
there is no evidence from clinical trials, clinical trials might be
impractical, or evidence is conflicting. "The ADA funds development of the
standards from its general revenues, with no industry involvement or
support."(10)  
  
Recommendations for self-monitoring of blood glucose, continuous glucose
monitors, and automated insulin delivery are included in this document.
Several of the recommendations are listed below:  
  
 **Continuous Glucose Monitors  
  
** "Sensor-augmented pump therapy can be considered for children, adolescents,
and adults to improve glycemic control without increasing overall or severe
hypoglycemia. Benefits correlate with ongoing consistent use of the device.
(Grade A recommendation)"(10p74)  
  
 **Real-Time Continuous Glucose Monitor Use in Adults  
  
** "When used properly, real-time CGM in conjunction with intensive insulin
regimens is a useful tool to lower HbA1C levels in adults with type 1 diabetes
who are not meeting glycemic targets. (Grade A recommendation)."(10p76)  
  
"Real-time CGM may be a useful tool in those with hypoglycemia unawareness or
frequent hypoglycemic episodes. (Grade B recommendation)."  
  
 **Professional Society Recommendations/Consensus Statements/Other Expert
Opinion  
  
** In 2016, the American Association of Clinical Endocrinologists and the
American College of Endocrinology convened a conference to review available
CGM data. They felt the evidence supported the use of CGM in patients with
type 1 diabetes and the benefits are likely to apply, whenever, intensive
insulin therapy is used, whether the patients has type 1 or type 2. Fonseca V
et al., reported findings from this conference, and felt that patients older
than 65 years with comorbidities and/or risk for severe hypoglycemia may have
significant benefits, though at that time, additional studies were needed.(11)
"The primary purpose of CGM is to identify glucose patterns, hypoglycemia, and
hyperglycemia." (11) The goal of management is to maximize time in the desired
glucose range. The authors concluded, "CGM improves glycemic control, reduces
hypoglycemia, and may reduce overall costs of diabetes management. Expanding
CGM coverage and utilization is likely to improve the health outcomes of
people with diabetes."  
  
The Advanced Technologies and Treatments for Diabetes Congress convened an
international panel of experts in CGM technologies to make recommendations on
the use on CGMs. Danne T et al., indicated the panel made recommendations on
these topics: limitations of HbA1c; use of glucose monitoring methodologies to
guide management and assess outcomes in different patient populations; minimum
requirements for CGM performance; definition and assessment of hypoglycemia in
clinical studies; assessment of glycemic variability; time in range; and
visualization, analysis, and documentation of key CGM metrics.(12)

In examination of this diabetes management technology, the findings of the
2019 ADA clinical guideline are noted: "Use of self-monitoring of blood
glucose (SMBG) or CGM is most important for insulin-treated patients because
it enables them to adjust therapy to minimize hypoglycemia and manage
hyperglycemia."10 Reduction of hypoglycemia and hyperglycemia are accepted
health outcomes in the management of diabetes. SMBG involves finger-sticks to
obtain capillary blood samples at a single point in time. With certain CGMs,
patients can receive real-time data, trending information, and alert
notification of hypoglycemia or hyperglycemia. Additionally, the need for
finger-sticks is reduced, thus reducing patient burden. CGMs measure
interstitial glucose, which correlates well with plasma (venous) glucose.10 In
February 2019, the FDA approved an implantable CGM system for the expanded
indication of replacement of finger-stick blood glucose testing for diabetes
treatment. (<https://www.fda.gov/medical-devices/eversense-e3-continuous-
glucose-monitoring-system-p160048s016>).  
  
CGMs can provide a significant amount of patient data, such as time in
hypoglycemia range, time in target range, and time in hyperglycemia range,
that allows patients to see how medications, meals, and exercise affect blood
glucose and if necessary help patients make behavioral changes. Alerts to
notify patients of hypoglycemia and hyperglycemia are available, which is
particularly helpful if patients have hypoglycemia unawareness. For optimal
management of glucose, accuracy of the device is important. Furthermore, CGMs
should be used consistently. "Real-time CGM should be used as close to daily
as possible for maximal benefit (Grade A recommendation)."10  
  
On February 28, 2022, Medicare expanded coverage of CGMs to include both
therapeutic/non-adjunctive and non-therapeutic/adjunctive CGMs for patients on
intensive insulin therapy meeting certain criteria. Adjunctive CGMs are not
covered. By analogy, if implantable CGMs are shown to produce similar results
to the current FDA approved non-implantable therapeutic/non-adjunctive and
non-therapeutic/adjunctive CGMs, then implantable CGMs will similarly improve
health outcomes for these Medicare patients with diabetes on insulin. The
available clinical studies for implantable CGMs include pivotal trials from
the U.S. and Europe, and post-market registry data. The available studies are
all sponsor supported however bias in the objective data has not been
previously noted. Data submitted to the FDA from the sponsor is additionally
available for review in the SSED. Both the pre-market and real-world post-
market data support patient benefit with MARD and other relevant data in the
acceptable range. In the U.S. pivotal trials, most patients had type 1
diabetes, though a little less than 1/3 had type II. Few patients appeared to
be in the Medicare aged population, but age does not influence the current CGM
coverage criteria. Thus, the results of the trials for this implantable device
should be applicable to the Medicare population. The risk of the device
appears minimal based on reported adverse events to date. The accuracy of the
device over various ranges, in particular lower glucose ranges where there are
also limitations with external sensor devices, has improved over time, as
demonstrated in the PRECISE II trial in comparison to the PRECISION trial.  
  
Objective criteria of this implantable device is similar to external sensor
therapeutic CGMs. Therefore, coverage of this device will be in line with
current CGM criteria.