CMS Pub. 100-03, ch. 1, § 160.18

A. General

Vagus Nerve Stimulation (VNS) is a pulse generator, similar to a pacemaker, that is

surgically implanted under the skin of the left chest and an electrical lead (wire) is

connected from the generator to the left vagus nerve. Electrical signals are sent from the

battery-powered generator to the vagus nerve via the lead. These signals are in turn sent

to the brain. The Food and Drug Administration (FDA) approved VNS for treatment of

refractory epilepsy in 1997 and for resistant depression in 2005.

B. Nationally Covered Indications

Effective for services performed on or after July 1, 1999, VNS is reasonable and

necessary for patients with medically refractory partial onset seizures for whom surgery

is not recommended or for whom surgery has failed.

Effective for services performed on or after February 15, 2019, the Centers for Medicare

& Medicaid Services (CMS) will cover FDA-approved VNS devices for treatment

resistant depression (TRD) through Coverage with Evidence Development (CED) when

offered in a CMS-approved, double-blind, randomized, placebo-controlled trial with a

follow-up duration of at least one year with the possibility of extending the study to a

prospective longitudinal study when the CMS-approved, double-blind, randomized

placebo-controlled trial has completed enrollment, and there are positive interim findings.

Each study must be approved by CMS and as a fully-described, written part of its

protocol, must address whether VNS improves health outcomes for TRD patients

compared to a control group, by answering all of the following research questions

below. The details of the prospective longitudinal study must be described in the original

protocol for the double-blind, randomized, placebo-controlled trial. Response is defined

as a ≥ 50% improvement in depressive symptoms from baseline, as measured by a

guideline recommended depression scale assessment tool. Remission is defined as being

below the threshold on a guideline recommended depression scale assessment tool. The

following research questions must be addressed in a separate analysis for patients with

bipolar and unipolar disease.

Research Questions:

• What is the rate of response (defined as person months of response/total months

of study participation)?

• What is the rate of remission (defined as person months of response/total months

of study participation)?

• What is the time from treatment until response scores are first achieved?

• What is the time from treatment until remission scores are first achieved?

• What are the population distributions of the maximum months of response, both

consecutive and overall, separately?

• What are the population distributions of the maximum months of remission, both

consecutive and overall, separately?

• What are the patient variables associated with successful treatment of TRD with

VNS?

• What are the observed harms?

• What are the changes in disability, quality of life, general psychiatric status, and

suicidality?

Patient Criteria:

The following criteria must be used to identify patients demonstrating TRD:

• The patient must be in a major depressive disorder (MDD) episode for ≥ two years or

have had at least four episodes of MDD, including the current episode. In order to

confirm the patient has MDD, accepted diagnostic criteria from the most current

edition of the Diagnostic and Statistical Manual for Mental Disorder (DSM) and a

structured clinical assessment are to be used.

• The patient’s depressive illness meets a minimum criterion of four prior failed

treatments of adequate dose and duration as measured by a tool designed for this

purpose.

• The patient is experiencing a major depressive episode (MDE) as measured by a

guideline recommended depression scale assessment tool on two visits, within a 45-day span prior to implantation of the VNS device.

Patients must maintain a stable medication regimen for at least four weeks before device

implantation.

If patients with bipolar disorder are included, the condition must be carefully characterized.

Patients must not have:

• Current or lifetime history of psychotic features in any MDE;

• Current or lifetime history of schizophrenia or schizoaffective disorder;

• Current or lifetime history of any other psychotic disorder;

• Current or lifetime history of rapid cycling bipolar disorder;

• Current secondary diagnosis of delirium, dementia, amnesia, or other cognitive disorder;

• Current suicidal intent; or,

• Treatment with another investigational device or investigational drugs.

Individuals who receive placebo VNS will be offered active VNS at the end of the trial.

In addition, CMS will review studies to determine if they meet the 13 criteria listed below.

If CMS determines that they meet these criteria, the study will be posted on CMS’ CED

website (https://www.cms.gov/Medicare/Coverage/Coverage-w ith-Evidence-Development/index.html).

a) The principal purpose of the study is to test whether the item or service meaningfully

improves health outcomes of affected beneficiaries who are represented by the

enrolled subjects.

b) The rationale for the study is well supported by available scientific and medical

evidence.

c) The study results are not anticipated to unjustifiably duplicate existing knowledge.

d) The study design is methodologically appropriate and the anticipated number of

enrolled subjects is sufficient to answer the research question(s) being asked in the

National Coverage Determination.

e) The study is sponsored by an organization or individual capable of completing it

successfully.

f) The research study is in compliance with all applicable Federal regulations

concerning the protection of human subjects found in the Code of Federal

Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug

Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In

addition, to further enhance the protection of human subjects in studies conducted

under CED, the study must provide and obtain meaningful informed consent from

patients regarding the risks associated with the study items and/or services, and the

use and eventual disposition of the collected data.

g) All aspects of the study are conducted according to appropriate standards of

scientific integrity.

h) The study has a written protocol that clearly demonstrates adherence to the standards

listed here as Medicare requirements.

i) The study is not designed to exclusively test toxicity or disease pathophysiology in

healthy individuals. Such studies may meet this requirement only if the disease or

condition being studied is life threatening as defined in 21 CFR §312.81(a) and the

patient has no other viable treatment options.

j) The clinical research studies and registries are registered on the

www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the

enrollment of the first study subject. Registries are also registered in the Agency for

Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).

k) The research study protocol specifies the method and timing of public release of all

prespecified outcomes to be measured including release of outcomes if outcomes are

negative or study is terminated early. The results must be made public within 12

months of the study’s primary completion date, which is the date the final subject

had final data collection for the primary endpoint, even if the trial does not achieve

its primary aim. The results must include number started/completed, summary results

for primary and secondary outcome measures, statistical analyses, and adverse

events. Final results must be reported in a publicly accessibly manner; either in a

peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible

registry dedicated to the dissemination of clinical trial information such as

ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for

studies with negative or incomplete results).

l) The study protocol must explicitly discuss beneficiary subpopulations affected by the

item or service under investigation, particularly traditionally underrepresented

groups in clinical studies, how the inclusion and exclusion criteria effect enrollment

of these populations, and a plan for the retention and reporting of said populations in

the trial. If the inclusion and exclusion criteria are expected to have a negative effect

on the recruitment or retention of underrepresented populations, the protocol must

discuss why these criteria are necessary.

m) The study protocol explicitly discusses how the results are or are not expected to be

generalizable to affected beneficiary subpopulations. Separate discussions in the

protocol may be necessary for populations eligible for Medicare due to age,

disability or Medicaid eligibility.

Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality

(AHRQ) supports clinical research studies that CMS determines meet the above-listed

standards and address the above-listed research questions.

The principal investigator must submit the complete study protocol, identify the relevant

CMS research questions that will be addressed and cite the location of the detailed

analysis plan for those questions in the protocol, plus provide a statement addressing how

the study satisfies each of the standards of scientific integrity (a. through m. listed above),

as well as the investigator’s contact information, to the address below. The information

will be reviewed, and approved studies will be identified on the CMS website.

Director, Coverage and Analysis Group

Centers for Medicare & Medicaid Services (CMS)

7500 Security Blvd., Mail Stop S3-02-01

Baltimore, MD 21244-1850

C. Nationally Non-Covered Indications

Effective for services performed on or after July 1, 1999, VNS is not reasonable and

necessary for all other types of seizure disorders which are medically refractory and for

whom surgery is not recommended or for whom surgery has failed.

VNS is non-covered for the treatment of TRD when furnished outside of a CMS-approved CED study.

All other indications of VNS for the treatment of depression are nationally non-covered.

D. Other

Patients implanted with a VNS device for TRD may receive a VNS device replacement if

it is required due to the end of battery life, or any other device-related malfunction.

(This NCD last reviewed February 2019.)