Compliance with the provisions in this policy may be monitored and addressed
through post payment data analysis and subsequent medical review audits.

#### Covered Indications

I-CGMs are class III medical devices that require premarket approval by the
FDA. In order to be considered reasonable and necessary, the FDA approved
indication must include use as a therapeutic CGM.1 The FDA recently approved
expanding the indications of an implantable CGM product to replace fingerstick
blood glucose measurements for diabetes treatment decisions.

Therapeutic I-CGMs are considered reasonable and necessary by Medicare when
all of the following coverage criteria (1-4) are met:

  1. The beneficiary has diabetes mellitus (Refer to the ICD-10 code list in the LCD-related Policy Article for applicable diagnoses); and,
  2. The beneficiary's treating practitioner has concluded that the beneficiary (or beneficiary's caregiver) has sufficient training using the I-CGM prescribed as evidenced by providing a prescription; and,
  3. The I-CGM is prescribed in accordance with its FDA indications for use; and,
  4. The beneficiary for whom a CGM is being prescribed, to improve glycemic control, meets at least one of the criteria below: 
    1. The beneficiary is insulin-treated; or,
    2. The beneficiary has a history of problematic hypoglycemia with documentation of at least one of the following: 
      1. Recurrent (more than one) level 2 hypoglycemic events (glucose <54mg/dL (3.0mmol/L)) that persist despite multiple (more than one) attempts to adjust medication(s) and/or modify the diabetes treatment plan; or,
      2. A history of one level 3 hypoglycemic event (glucose <54mg/dL (3.0mmol/L)) characterized by altered mental and/or physical state requiring third-party assistance for treatment of hypoglycemia.

#### CGM Continued Coverage

Every six (6) months following the initial prescription of the CGM, the
treating practitioner conducts an in-person or Medicare-approved telehealth
visit with the beneficiary to document adherence to their CGM regimen and
diabetes treatment plan.

#### Limitations

I-CGM devices will not be considered reasonable and necessary for short-term
(72 hours to 1 week) diagnostic use.

**Exception:** For those beneficiaries who have previously met the coverage
criteria for a non-implantable therapeutic 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.

#### **Background**

Diabetes mellitus is a chronic metabolic disease involving an underproduction
or resistance to insulin, resulting in elevated blood glucose levels. The two
most common types of diabetes are type 1 (T1DM) and type 2 (T2DM).2 T1DM
comprises approximately 5-10% of diabetes cases and describes an etiology in
which an autoimmune response damages the insulin-producing beta cells of the
pancreas, resulting in insufficient insulin production. Conversely, T2DM is
characterized by insulin resistance.2,3 In T2DM, an individual's insulin
production fails to offset the deficit that is created by the resistance.2
T2DM constitutes an estimated 90%-95% of diabetes cases.3

Approximately 11.3% of Americans have diagnosed diabetes, and an additional
3.4% of Americans are estimated to have undiagnosed diabetes. The prevalence
of diabetes is known to increase with age. In Medicare aged populations in the
United States ( 65 years of age), 22.4% of the population has diagnosed
diabetes, with an additional 4.7% estimated to have undiagnosed diabetes.4
Economic evaluations have estimated that diabetes annually accounts for $237
billion in direct US medical expenditure, and an additional $90 billion in
lost productivity.5

Acute complications of diabetes include hypoglycemia, hyperglycemia, diabetic
coma, and 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. The complications of diabetes mellitus are far less
common and less severe in people who have well-controlled blood sugar
levels.2,

To prevent and/or delay the development of both short- and long-term
complications of diabetes, the American Diabetes Association recommends
person-centered care aimed at timely treatment decisions following evidence-
based guidelines. Person-centered care goals include minimizing the
progression of hyperglycemia with more intensive approaches for individuals at
higher risk which include those with higher glucose levels (e.g., fasting
blood glucose 110-125 mg/dL, 2-hour post-challenge glucose 173-199 mg/dL, A1C
_>_ 6.0%).6.

Diabetes treatment relies on diet, exercise, lifestyle modifications, and in
many, medications in order to keep their blood sugar under a stable and
controlled level. Close glucose monitoring either multiple times a day or
continuously may be warranted in those diabetics that are having difficulty
maintaining that level.2,7

Continuous glucose monitoring (CGM) devices measure glucose via interstitial
fluid instead of blood. CGM systems traditionally rely on a multi-part system
that often involves: 1.) a sensor that is inserted into subcutaneous tissue;
2.) A receiver/mobile application consisting of a display and interface; 3.) a
transmitter component that is attached to the sensor and worn externally.7,8
The sensors for these subcutaneous CGM systems need to be removed and replaced
every 6- to 14-days depending upon the system.7

Despite the number of benefits that subcutaneous CGM offer in the diabetes
mellitus (DM) management paradigm, some CGM studies have reported relatively
high attrition rates that patients attributed to discomfort, contact
dermatitis, issues changing the sensors, and physical interference with
activities of daily living.9 The rationale for implantable continuous glucose
monitoring (I-CGM) seeks to circumvent these negative patient experiences.
Unlike with subcutaneous CGM, I-CGM involves a sensor that is surgically
implanted for longer spans of time between replacement, allowing for skin
barrier closure, and less frequent manipulation.

The primary aim of this summary of evidence is to determine if I-CGM performs
with equivalent clinical validity, efficacy, safety, and patient perceived
benefit when compared with subcutaneous CGM devices. The secondary aim of this
summary of evidence is to evaluate the expected magnitude of benefit across
the aforementioned outcomes resulting from the inclusion of I-CGM into the
diabetes management paradigm.

At the time of this review, the Eversense E3 is the only device that has
received clearance for use by the United States Food and Drug Administration
(FDA). However, it is this Medicare Administrative Contractor's expectation
that additional devices are in the development and/or FDA approval process and
soon may be publicly available. Hence this policy is to reflect coverage
criteria and accompanying evidentiary review and analysis on I-CGM devices in
an agnostic manner without endorsement of any specific product.

### Food and Drug Administration (FDA) Approvals

Eversense Continuous Glucose Monitoring System:
<https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160048A.pdf>

### Literature Analysis

#### Clinical Validity

The accuracy of CGM devices is most commonly assessed by evaluating mean
absolute relative difference (MARD). The MARD value represents the average
percent difference between glucose readings that are concurrently obtained at
multiple timepoints via an index test (I-CGM in this instance) and via an
established reference standard test. MARD is then reported as a percentage,
with lower values signifying a higher degree of test accuracy.10 For
reference, one narrative review reported that the majority of CGM systems
achieve an average MARD of between 9% to 14%, and that a MARD of < 10% had
been discussed as a threshold for a CGM system that is accurate enough to
inform insulin dosage decisions.11 Thirteen of the studies (14 publications)
identified by the literature search evaluated the accuracy of I-CGM with
MARD.12-25

Four of these 13 studies performed comparative analyses analyzing the accuracy
of I-CGM compared with subcutaneous CGM systems.13,14,18,20

Fokkert and colleagues conducted a multi-test diagnostic cohort study among 23
athletes with T1DM. All 23 participants utilized an Eversense device, Free
Style Libre (FSL) Flash Glucose Monitoring (FGM) system (subcutaneous CGM),
and Free Style Libre Precision NeoPro strips (diagnostic standard). During
normal activity among this sample of patients, Eversense performed with a MARD
of 13%  6%, and the FSL FGM system had a MARD of 12%  5%; differences in
these MARD values were not statistically quantified.18

One study conducted a three-way MARD analysis, comparing the accuracy of
Eversense, the FSL Pro system (subcutaneous CGM), and the Dexcom G5 system
(DG5) in a head-to-head fashion, with the StatStrip Xpress meter serving as
the diagnostic standard. In this trial, 23 adults with T1DM utilized all 4
glucose monitoring devices over a 6-week timespan. Over the course of this
trial, the authors reported that the MARD of Eversense was 14.8%  14.8%; FSL
Pro performed with a MARD of 16.3%  15.4%, and the MARD of Libre Pro was
18.0%  17.9%. Jafri et al., then performed a pairwise comparison between
these three MARD values, and determined that in this study, DG5 was
significantly more accurate (P=0.004) than FSL Pro, and Eversense was
significantly more accurate than both DG5 (P=0.008) and FSL Pro (P<0.000).20

Boscari and colleagues performed two separate trials comparing the MARD of
Eversense with that of DG5. In the first trial, 11 adults with T1DM and HbA1c
> 10% at baseline were enrolled, and Yellow Spring Instruments (YSI) STAT plus
2300 was used as the reference standard. Over the 1-week follow-up, the median
absolute relative difference of I-CGM (11.4% [IQR: 5.04% to 18.54%]) was
statistically significantly less accurate (signed-rank test _P_ <0.05)
compared with that of Dexcom G5 (DG5) (7.91% (IQR: 4.14% to 14.30%).13The
second trial was designed as a crossover RCT study, in which 16 adults with
T1DM and HbA1c < 10% underwent 12 weeks of DG5 and 12 weeks of Eversense, with
self-monitoring of blood glucose (SMBG) serving as the reference test. Among
this sample of 16 participants, the MARD of Eversense (12.27%  11.55%) was
significantly more accurate ( _P <_0.001) when compared with the MARD of DG5
(13.14%  14.76%).14

Nine single-test diagnostic accuracy studies were also identified; these
publications assessed the MARD of I-CGM compared against a diagnostic
reference standard (YSI 2300 STAT Plus, SMBG, or venous blood laboratory
measurements). Among these 9 studies, the average MARD of I-CGM ranged between
8.8% to 12.3%.15-17,19,21-25

#### Clinical Efficacy

Glycated hemoglobin (HbA1c) is a key measure used to evaluate diabetes risk
and morbidity.2 Although the American Diabetes Association recognizes that
individual HbA1c normal ranges may vary, they recognize 7% as the standard
threshold which most adult diabetics try to stay below.26 None of the 16
studies included in the literature review performed a comparative analysis of
HbA1c change between I-CGM and subcutaneous CGM. However, 6 noncomparative
studies meeting inclusion did assess HbA1c among patients using Eversense,
including 3 that performed a pretest-posttest analysis. Among those 3 before-
and-after trials, all 3 determined that mean HbA1c levels statistically
significantly decreased between baseline (mean: 7.4% - 7.6%) and final study
follow-up (mean: 6.9% - 7.19%).16,21,27 No statistical analyses were performed
in the other 3 studies evaluating HbA1c, but all 3 noted a trend of HbA1c
reduction following management with I-CGM.14,19,28

Time in Range (TIR) is an often-utilized surrogate outcome, used to evaluate
the efficacy of diabetes management. TIR measures the percentage of time that
CGM readings fall within the target blood glucose range (commonly defined as
between 70 - 180 mg/dL).10,29 One study was identified that directly compared
TIR between patients using I-CGM systems and those utilizing subcutaneous CGM
systems.14 Boscari et al., 2022 conducted a crossover RCT trial in which
patients underwent 12 weeks of management with Eversense I-CGM, and 12 weeks
of management with the Dexcom G5 (DG5) system. Results of this study showed
that on average, 71.14%  12.29% of the I-CGM group readings were in the
target range, which was statistically significantly favored ( _P_ <0.028) when
compared with the 66.99%  11.8% mean TIR exhibited by the DG5 group. Four
additional studies also evaluated TIR, but only among patients managing DM
with I-CGM.23,24,27,28 One of these 4 studies performed a pretest-posttest
statistical analysis among 100 adults with T1DM. Irace et al., found that
diabetes management with Eversense was associated with a significant
improvement of TIR compared with baseline.27 For 3 of the 4 noncomparative
trials evaluating mean TIR during management with Eversense, the mean TIR was
between 62.3% - 69% 23,24,27; the forth study had multiple different cohorts
based upon patient characteristics and could not be pooled.28

**_Patient Reported Outcome Metrics (PROMs)_**

Boscari et al., 2022 was the only publication that comparatively analyzed
patient reported outcome metrics (PROMs) between I-CGM and subcutaneous CGM.14
In this crossover trial, all 16 patients underwent 12 weeks of management with
the Eversense system, and 12 weeks with the DG5. Patient quality of life (QOL)
was measured with the validated 17-item Diabetes Distress Scale (DDS), which
asks respondents to evaluate each item with a 6-point Likert Scale ranging
from 1 (no problem) to 6 (serious problem). Eversense was statistically
significantly favored compared with DG5 for the total DDS score (I-CGM, 2.1 
1.1; DG5, 2.6  1.4; P=0.009) as well as for the emotional burden domain score
(I-CGM, 2.1  1.0; DG5, 2.7  1.4; P=0.01), regimen-related distress domain
score (I-CGM, 2.1  1.1; DG5, 2.7  1.3; P=0.007), and the interpersonal
distress score (I-CGM, 2.0  1.1; DG5, 2.6  1.2; P=0.003). Only the
physician-related distress domain score was not significantly different
(P=0.12) between DG5 and Eversense groups. Patient satisfaction with CGM
devices were measured with the Diabetes Treatment Satisfaction Questionnaire
(DTSQ), which is an 8-item survey that patients are to score between 0 (not
satisfied) and 6 (extremely satisfied). The average total DTSQ score provided
by respondents using Eversense (31.2  4.3) was not significantly different (
_P_ =0.96) when compared with the mean DTSQ respondent score for the Dexcom G5
system (31.3  3.9).14

Two noncomparative studies (3 publications) evaluated patient perceived change
in QOL following diabetes management with I-CGM.12,21,28 Among the 3
publications, QOL was assessed with the 36-Item Short Form Health Survey
(SF-36), 28-Item DDS, and the Audit of Diabetes Dependent Quality of Life
(ADDQoL) questionnaire. Only one of these two trials performed a before-and-
after statistical analysis, and the authors concluded that no significant
change in QOL was observed over time.28 Three noncomparative studies evaluated
patient satisfaction with varying PROMs.12,16,28 One trial found that 84% of
respondents would choose to be re-inserted with Eversense for implantation
cycle if given the opportunity.12 Christiansen and colleagues examined patient
satisfaction with the validated CGM Satisfaction Scale Questionnaire, which
asks patients to rate items on a Likert Scale ranging from 1 (lowest
satisfaction/largest hassle) through 5 (most satisfaction/least hassle).16
This study found that among the 35 respondents, the mean overall satisfaction
score with I-CGM was 3.9  0.6. Among the respondents, only 20% of I-CGM users
indicated that they would be unwilling to use I-CGM again after the study
concluded. A third study found that the median DTSQ score over 180 days
changed between a median of 0-2 points, which was not statistically
quantified.28

**_Safety_**

None of the 16 primary studies meeting inclusion for the evidentiary review
performed a comparative safety analysis between I-CGM and subcutaneous CGM.

However, 10 noncomparative studies assessed the safety profile of I-CGM. Six
of the 10 studies considered the incidence of serious adverse events (SAEs),
with all 6 reporting that no SAEs occurred.15,17,19,21,27,30 Additionally, two
studies stated that no adverse events occurred at all during study follow-
up.13,14 For the remaining 8 studies assessing, the heterogeneity of how
adverse events were grouped together and reported precluded the pooling of
event rates across studies. Generally, events were infrequent, and mostly
consisted of transient skin irritation at the patch site, site infection,
pain, and difficulty removing the sensor during first
attempt.15,16,19,21,23,27,28,30

**Professional Society Recommendations**

While the American Diabetes Association (ADA), American Association of
Clinical Endocrinology (AACE), Diabetes Canada Clinical Practice Guidelines,
and National Institute for Health and Care Excellence (NICE) all have
position/guideline recommendations supporting CGM, none of these specifically
discuss if and when I-CGM should be considered in the treatment
paradigm.6,31-33 The following position statements directly invoke I-CGM, but
only discuss optimal patient selection criteria:

**_American Diabetes Association (ADA)_** ** - **In the safety subheading of a
2022 clinical practice guideline published by the ADA Professional Practice
Committee, the authors state that contact dermatitis has been associated with
all CGM devices, often linked to isobornyl acrylate. In some patients who have
sensitivities to the tape used with subcutaneous CGM patches, the authors
comment that I-CGM may provide an alternative that could preclude dermatitis
events.34

**_European Association for the Study of Diabetes (EASD)_** **- **A consensus
report published jointly by the EASD and the ADA in 2021 states that I-CGM
could be a clinical alternative for patients who have sensitivities to the
adhesive that is required with subcutaneous CGM.35

**_American Association of Clinical Endocrinology (AACE)_** **- **In 2021, the
AACE issued a Grade C recommendation that clinicians should ensure patients
undergoing treatment with CGM do not ingest any substances that could
interfere with reliable interstitial glucose readings.32 In the evidence
section that informs this recommendation, Grunberger et al., cite other CGM
systems that are susceptible to inaccuracy when in the presence of
acetaminophen, ascorbic acid, xylose, bilirubin, or uric acid. Conversely,
this **** section reports that Eversense sensors are only vulnerable to
inaccuracy in the presence of mannitol or tetracycline, consistent with the
contraindications listed by the FDA packaging.36

**Other Expert Opinion**

Deiss et al., 2019 present a collection of consensus best practice
recommendations by a panel of international clinicians who were involved with
early Eversense clinical trials.37 Among the best practices, the following
considerations are mentioned in relation to optimal patient selection
criteria:

  * The authors note that the adhesive for Eversense does not contain isobornyl acrylate. Additionally, they also discuss how the daily changing of adhesive allows for regular skin care at the site. They conclude that both of these characteristics make I-CGM a viable alternative for patients with a history of skin reactions to adhesives.
  * Deiss et al., suggest that I-CGM is an ideal alternative to subcutaneous CGM for people who have an ongoing environmental risk to continued permanent breach of the skin, such as dust exposure.
  * Deiss and colleagues mention the need for mobile device compatibility with the app, as well as ability to navigate the app. They then comment that certain groups of patients may be unable to access or use this technology and would not be suitable candidates for I-CGM.



This updated evidentiary review is being conducted to evaluate whether the
published evidence base continues to support the equivalency of implantable
continuous glucose monitors (I-CGMs) and traditional subcutaneous continuous
glucose monitors (CGMs) in the management of adult diabetes mellitus (DM). The
evidence suggests that for adult patients managing DM, I-CGM performs with
little to no difference in diagnostic accuracy, patient-reported efficacy
outcomes, objective measures, and device/procedure-related adverse event rate
when compared to subcutaneous CGM. Furthermore, the evidence suggests that the
optimal patient selection criteria for I-CGM and for subcutaneous CGM are
largely overlapping. Although limited in quality, this evidence base is
sufficient to determine noninferiority/equivalency between I-CGM and
subcutaneous CGM.

Additionally, although no direct evidence was identified that assessed I-CGM
utilization among non-insulin treated (NIT) patients with diabetes complicated
by hypoglycemia, there is still adequate evidence in support of the apparent
equivalence with subcutaneous CGM systems among this population. Firstly,
among the approved indications for I-CGM, the U.S. Food and Drug
Administration (FDA) has cleared Eversense to "provide glucose trend
information", and to "provide alerts for the detection and prediction of
episodes of low blood glucose (hypoglycemia) and high blood glucose
(hyperglycemia)".38 Also, although outside of the scope of the main
evidentiary review, three publications were identified via bibliographic
cross-referencing that evaluated subcutaneous CGM benefit among this subgroup
of patients. One of these three trials concluded that among NIT patients with
DM complicated by hypoglycemia, subcutaneous CGM systems resulted in a
significantly greater reduction in HbA1c than SMBG.33 The other two studies
suggested CGM systems were able to detect hypoglycemic events among non-
insulin treated patients that were overwhelmingly undetectable by symptoms or
SMBG.39,40.