**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 patients 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-with-Evidence-
Development/index.html>).

  1. 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.
  2. The rationale for the study is well supported by available scientific and medical evidence.
  3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
  4. 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.
  5. The study is sponsored by an organization or individual capable of completing it successfully.
  6. 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.
  7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
  8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
  9. 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.
  10. 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).
  11. 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 studys 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).
  12. 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.
  13. 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
investigators 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.)