Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD)

Mental Health America (MHA) thanks the Centers for Medicare and Medicaid Services (CMS) for reconsidering the National Coverage Determination (NCD) for Vagus Nerve Stimulation (VNS) for Treatment-Resistant Depression (TRD).

MHA – founded in 1909 – is the nation's leading community-based nonprofit dedicated to addressing the needs of those living with mental illness and to promoting the overall mental health of all Americans. Our work is driven by our commitment to promote mental health as a critical part of overall wellness, including prevention services for all, early identification and intervention for those at risk, integrated care, services, and supports for those who need it, with recovery as the goal.

MHA appreciates CMS’s effort to ensure that beneficiaries have access to mental health therapies that would truly be effective for them. MHA also has concern about the effect that this type of intermediate coverage determination could have on innovation in mental health therapeutics. For therapies that have: approval from the Food and Drug Administration (FDA), positive indications of effectiveness from the published literature and other available evidence, and no salient safety concern, MHA recommends that CMS take a more pragmatic study design approach patterned off of how the Center for Medicare and Medicaid Innovation (CMMI) evaluates the effectiveness of care delivery innovations in Medicare.

CMMI runs pragmatic trials to determine whether some change in coverage improves outcomes and/or reduced costs. These pragmatic trials can avoid burden and complexity for both the entity proposing the innovation and for the beneficiaries in the study, especially when formal randomized control trials (RCT) have already been conducted. In a CMMI evaluation, those in the treatment arms get access to the therapy as though it was covered by Medicare, and those in the control arms get Medicare as usual. The intervention is then evaluated using CMS’s existing clinical, claims, and administrative data collection capacities. By employing more pragmatic designs that better leverage existing capabilities and methodologies – appropriately modified for the specific coverage issue under consideration, including efforts to control for confounders or changes to outcomes instruments used – CMS could accelerate the translation of evidence to action and foster future innovations in behavioral health.

In such a pragmatic trial in the present instance, MHA recommends that CMS simulate how VNS would likely be used in the field. CMS should offer appropriate Medicare coverage for VNS, and include beneficiary diagnoses and treatment histories for which VNS has indicated effectiveness and for which VNS would likely be used if ultimately covered by CMS. Also, consistent with developing best practices in quality measurement for depression, the study should examine response to treatment in addition to full depression remission.

MHA appreciates CMS’s thoughtful consideration of MHA’s recommendations, and the careful balancing of ensuring Medicare beneficiaries have access to effective mental health therapies while promoting innovation in the therapies available. MHA looks forward to continuing to work with CMS on ensuring that patients have access to effective care that meets their needs.

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December 19, 2018

Tamara Syrek Jensen, Esq.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
The Centers for Medicare and Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: LivaNova Comments on Proposed Decision Memo for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD) (CAG-00313R2)

Dear Ms. Syrek Jensen,

On behalf of this underserved and vulnerable population of patients with treatment-resistant depression (TRD), the physicians who provide care for them and LivaNova PLC, we want to thank you and your staff at the Centers for Medicare & Medicaid Services (CMS) for reconsidering Medicare coverage of Vagus Nerve Stimulation (VNS) Therapy®. We appreciate the effort and thought that has gone into the entire process, beginning with the 2016 Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) meeting, the Agency for Healthcare Research and Quality (AHRQ) Technology Assessment (TA) and culminating in the Proposed Decision Memo. We further appreciate that CMS has included a provision for triggering a prospective, longitudinal study upon achieving a successful interim primary endpoint, which takes into account continuity of care for existing implanted patients and allows for an expanded patient population to have access upon establishing benefit via the interim primary endpoint.

As cited throughout the Proposed Decision Memo ("memo") and supporting data, TRD is a deadly illness. An estimated 15% die by suicide, and recent evidence from the Centers for Disease Control and Prevention (CDC) shows rates of suicide have increased by 24% over the past decade¹. Further, the patient population proposed in the memo face limited treatment options and have a vanishingly low (~1-4%) remission rate². This stands in stark contrast to patients with major depressive disorder (MOD) who are not as severely and chronically depressed as patients with TRD, who have multiple treatments available and experience a 30% remission rate. These facts inform our comments.

Like CMS, LivaNova wishes to ensure that any trial conducted in accordance with the agency's Coverage with Evidence Development (CED) policy enrolls and can be successfully executed in a manner that optimizes patient benefit while minimizing any risks. Specifically, any coverage policy should ensure the following principles are met:

• Patients for whom the therapy will benefit are encouraged to enroll in the CED study because:
  • They can receive an effective therapy in a reasonable timeframe;
  • Any concerns regarding making a co-pay for a control are addressed in an ethical and effective manner; and
  • They are assured continuity of care after the trial ends-a significant issue for patients who enrolled in the earlier clinical studies cited by the memo.
• Clear interim success criteria are defined that, if met, allow additional patients to benefit from the therapy without undue administrative delay; and
• There is a clear success criterion that, if met, ensures that CED can be exited and converted to coverage in a straightforward and timely fashion without any gap in coverage for this vulnerable population.

The following are key comments on the memo intended to ensure that the CED meets the principles outlined above. Appendix 1 includes supporting details and additional comments on the Proposed Decision Memo.

• We suggest eliminating the terms "primary outcome" and "secondary outcome," in favor of the standard CED language that the "clinical research study must address at least one of the following questions," followed by a listing of the key questions. The usage of the terms "primary" and "secondary" outcomes is ambiguous and confusing given the similarity to the concept of a primary endpoint. Further, none of the other 23 posted CED policies use the terms "primary outcome" or "secondary outcome" when describing the key questions to be addressed by a study under CED. Each of the 23 CED policies contain language such as "A clinical study must address one or more aspects of the following questions ... " and then lists those key questions. The sponsor then must design the study to meet this requirement. The CED Policy for VNS Therapy for TRD should follow this same precedent to avoid confusion and ensure that there is a clear success criterion.


• The CED policy should follow the 2011³ and 2018⁴ AHRQ recommendations and require that a study address one or more of the following key questions: changes in depressive severity, response rate, and remission rate. The 2016 MEDCAC panel⁵ had high confidence that "Improvement or decline in depression as measured by depression scales" is a valid and meaningful to Medicare beneficiaries. As stated by the 2011 and 2018 AHRQ work, this implies measuring the following on a publicly available, validated depression scale: changes to depressive severity, response rate and remission rate. If, despite our comment above, CMS continues to use the primary outcomes/secondary outcomes language, changes in depressive severity, response rate and remission rate should all be primary outcomes.

  Time to event (e.g ., response and remission) and durability of response and remission are rarely studied in clinical trials of depression but are important to patients. However, both outcomes are secondary to establishing that a therapy results in depressive symptom improvement. Hence, if the primary outcomes/secondary outcomes language is retained, these should be secondary outcomes. Specific comments on these definitions are included in Appendix 1.

  In summary, following AHRQ⁶ recommendations, we recommend the following framework for key research questions (aka, primary and secondary outcomes) that identifies the minimal set of information. This reduces the burden on clinicians and patients in a manner that encourages study participation.

  Scale completer	Measurement Scale Type	Changes in Depressive Severity	Response and Remission			Other Outcomes	Other Patient Reported Outcomes
  			Rate	Time to Event	Durability
  Medical personnel (clinician or central rater)	Depressive Symptoms Rating Scale (e.g., HAMD-24, MADRS, IDS-C)	Primary	Primary	Secondary	Secondary	Secondary (Suicidal Behavior*)
  	General Psychiatric Status (e.g., CGl-1)					Secondary
  Patient	Depressive Symptoms Rating Scale (e.g., IDS-SR, QIDS-SR PHQ-9)	Primary	Primary	Secondary	Secondary
  	Disability/Functioning (e.g., WHODAS, WPAI}						Secondary
  	Health-care resource utilization (from HER)						Secondary
  	Quality of Life (e.g., Q-LES-Q)						Primary
  Both	Adverse Event and Harm data, including all-cause mortality and death from suicide					Primary (Harms)

  *Scales focused on suicidality may be considered.


• Clinical response, defined as a 50% reduction in depressive symptoms, an appropriate measure of benefit, should be acceptable as a primary endpoint and for the interim success criteria to trigger allowing 1) existing patients in the placebo-control arm to have their devices activated and 2) additional patients to benefit from the therapy through enrollment in a prospective, longitudinal study. Remission is an important patient benefit and forms an integral part of the outcome measures that should be collected. However, it rarely occurs (1-4%)⁷ in the population of patients with TRD who have failed to respond to four or more prior treatments. When patients do achieve remission, it is often after 4-5 years of treatment⁸, far too long to ethically maintain patients on a placebo control. This 4-5 year period is also much too long to expect a blind to be maintained. Clinical response is a more realistic goal for these patients, is the standard outcome for trials for this population (TRD), and will result in providing an earlier signal allowing patients an opportunity to achieve a benefit. Further, studies have shown that patients who have failed to respond to four or more treatments achieve meaningful quality of life improvements with clinical response⁹. In Appendix 1, we describe how an interim analysis can be constructed to trigger the prospective longitudinal study for continued access and allowing additional patients to benefit.
• Medicare beneficiaries with bipolar disorder are an underrepresented subpopulation in clinical studies and, if receiving at least one mood stabilizing medication, should be covered by the CED policy, consistent with CMS CED guidance¹⁰. As noted in Section II of the Proposed Decision Memo, bipolar depression is difficult to treat (more than 30% fail to remit) and is characterized by frequent relapses. Further, when combined with MOD, bipolar disorder is the second leading cause of disability in the Medicare population. Patients with treatmentresistant bipolar disorder were included in all trials of VNS Therapy referenced in the Proposed Decision Memo and are part of its Food and Drug Administration (FDA)-approved indications. Failure to include this patient population would be at odds with Proposed Decision Memo item (I) from the CED guidance that directs study protocols to ensure "traditionally underrepresented groups" such as patients with bipolar depression be addressed, retained and reported on by the CED study. Appendix 1 contains additional comments regarding the Patient Criteria.

  Additionally and critically, the evidence supports that patients with bipolar depression are twice the risk of suicide. Lack of available successful treatments for bipolar TRD places this population at very high risk going forward, as the likelihood of CMS coverage for BPAD occurring in the near future, if not included in this CED, is very low.

• CMS' Final Decision Memo should describe covered trials in a manner that they can successfully enroll and is feasible to execute. We recommend changing the description of the trial throughout the Final Decision Memo to "randomized, blinded, controlled trial." Randomized controlled trials should strive to achieve a double-blind, as well as meeting other important methodological criteria that assure study integrity, by instituting the proper controls in the protocoL However, a known side effect of stimulating the vagus nerve is activation of nearby musculature. Given that the common side effects, which dissipate with time, must be disclosed as part of informed consent required by part (f) of the CED guidance¹¹, there is no assurance that patient blind can be maintained-even under sham or low levels of stimulation. Aaronson12 noted that over the course of the 22 week blinded period, 73% of patients at a low, but effective stimulation level, were able to guess their treatment group. Further, it is known that VNS Therapy may elicit a response even at low doses, confounding estimates of the treatment effect. Thus, describing the study as "double-blind" and placebo-controlled may make it infeasible to successfully design, enroll and execute a study. We agree, however, with CMS that the appropriate control for the study is a sham control, that is an implanted VNS device that is not turned on. This will help enrollment by ensuring that all patients have access to having the device turned on at the conclusion of the blinded treatment period.

VNS Therapy has been extensively studied in patients with TRD in 5 long-term, multi-center trials of over 1,000 patients. In addition to these TRD clinical trials, its safety profile has been extensively studied since 1988 in the 14 long-term, multi-center trials of over 6,500 patients that are documented in the literature. Details on the safety of the device is fully characterized in the FDA-approved, VNS Therapy System Physician's Manual. Additionally, VNS Therapy has been implanted in over 100,000 patients with drug-resistant epilepsy world-wide and over 3,000 patients in the US with TRD and thus has a wellestablished safety profile.

We want to thank you and your staff for the proposed change in coverage for patients that have been previously implanted with a VNS device for TRD. These changes allow replacement due to end of battery life or other issues and will greatly improve access to and continuity of care for these patients, avoiding gaps and inconsistencies in treatment that often occur while determining if a replacement will be covered. Thank you for your consideration of our comments on the Proposed Decision Memo and for continuing to work with us to give Medicare beneficiaries struggling with TRD access to VNS.

Sincerely,

/s/
Carla Monacelli
Vice President, Government Affairs and Market Access

/s/
Bryan D. Olin, Ph.D.
Senior Vice President, Clinical, Quality and Regulatory

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1 Curtin SC, Warner M, Hedegaard H. Increase in suicide in the United States, 1999-2014. NCHS data brief, no 241 . Hyattsville, MD: National Center for Health Statistics. 2016.
2 Dunner DL, Rush AJ, Russell JM, Burke M, et. al. Prospective, Long-Term, Multi-Center Study of the Naturalistic Outcomes of Patients with Treatment-Resistant Depression. J Clin Psychiatry, 2006;67:688-695.
3 Gaynes BN, Lux L, Lloyd S, Hansen RA, Gartlehner G, Thieda P, Brode S, Swinson Evans T, Jonas D, Crotty K, Viswanathan M, Lohr KN. Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults. Comparative Effectiveness Review No. 33. (Prepared by RT! International-University of North Carolina (RTI-UNC) Evidence based Practice Center under Contract No. 290-02-00161.) AHRQ Publication No. 11-EHC056-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. www.effectivehealthcare.ahrq.gov/reports/ fina l.cfm.
4 Registry of Patient Registries HHSA290201400004C, Library of Common Data Definitions: Depression Task 2.3.2 January 15, 2018, https://effectivehealthcare.ahrq .qov/sites/default/files/pdf/wh ite-paper-draft-definition-depression.pdf.
5 MEDCAC Meeting 4/27/2016 - Treatment Resistant Depression, Scoresheet, https://www.cms.gov/medicare-coveraqedatabase/ details/medcac-meetinq-details.aspx?MEDCACld=71
6 Registry of Patient Registries 2018, Appendix A, op. cit.
7 Dunner et. al. 2006, op. cit.
8 Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, Reimherr FW, Schwartz TL, and Zajecka JM. A 5~Year Observational Study of Patients With Treatment~Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality. American Journal of Psychiatry 2017; 174(7):640~648.
9 Conway CR, Kumar A, Xiong W, et al. Chronic vagus nerve stimulation significantly improves quality of life in treatmentwreslstant major depression. J Clin Psychiatry. 2018;79:18m12178.
10 CMS, Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development, https:f/www.cms.gov/medicarecoverage-database/details/medicare-coveraqe-document-details.aspx?MCDld=27.
11 CMS Coverage with Evidence Development Guidance op. cit.
12 Aaronson ST, Carpenter LL, Conway CR, et al: Vagus nerve stimulation therapy randomized to different amounts of electrical
charge for treatment-resistant depression: acute and chronic effects. Brain Stimulation 201 3;6:631-640.

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I am commenting on the Proposed Decision Memo for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD) (CAG-003113R2). I have considerable clinical and research experience with both VNS and TRD. I am a Professor in the Departments of Psychiatry and Radiology, Columbia University, and the Chief Emeritus of the Department of Biological Psychiatry, New York State Psychiatric Institute. I directed one of the four sites in the first trial of VNS in TRD (Rush et al., 2000), and conducted the first examinations of the neurocognitive effects of the intervention in this population (Sackeim, H. A. et al., 2001b) and predictors of outcome (Sackeim, H. A. et al., 2001d). I participated in the design and analysis of the sham-controlled trial of VNS in TRD (George et al., 2005; Rush, A. J. et al., 2005; Rush, A. J. et al., 2005b), and I identified the clinical signal that VNS showed remarkable durability of benefit in those who showed acute clinical response (Sackeim et al., 2007). This observation was since been confirmed in large sample, naturalistic follow-up and comparison to treatment-as-usual (TAU) (Aaronson et al., 2017). The evidence regarding durability of benefit was fundamental in impacting on the positive vote of the FDA Neurological Device Panel, and I participated in the discussions with FDA staff that led to approval of VNS for the TRD indication.

In addition to this background specifically relevant to study of the benefits and risks of VNS, I have broader experience in the evaluation and treatment of TRD. I am the author of the original Antidepressant Treatment History Form (ATHF), likely the most commonly used instrument world-wide to assess the adequacy of antidepressant treatments and to identify and quantify various degrees of TRD (Sackeim, 2001). I have led a workgroup that has recently revised this instrument, and produced the Antidepressant Treatment History Form—Short Form (ATHF-SF) (Sackeim et al., submitted). For 30 years, I led the clinical and research programs at Columbia University on electroconvulsive therapy (ECT), and this work has transformed the administration of this treatment, which is largely reserved for TRD (Sackeim, 2017). I have also participated in the key trials of transcranial magnetic stimulation (rTMS) that led to FDA approval of this modality for TRD (O'Reardon et al., 2007) and then its wide spread clinical adoption (George et al., 2010). I served as the Science Advisor and helped design and carryout the STAR*D trial (Fava et al., 2003; Rush et al., 2004), the largest prospective study of the efficacy of antidepressant treatments in major depressive disorder (MDD) (Rush et al., 2006). Thus, my comments are informed by a long history of clinical and research work with TRD using ECT, TMS, VNS, and pharmacotherapy.

I want to applaud CMS for taking positive action regarding VNS. Having a treatment like VNS approved by the FDA is a hollow achievement unless accompanied by health care insurance coverage or other reimbursement. The earlier decisions by CMS not to offer coverage for VNS in TRD has led to a universal lack of coverage by private insurers. Given the costs of the device and the associated surgery and programming, this has meant that over the last decade use of VNS in TRD has been mainly restricted to patients who could themselves pay the costs. This situation is particularly unfortunate since a sizable segment of those potentially helped by VNS for TRD are disabled by their mood disorder and without the requisite financial resources.

The reason VNS landed in this circumstance was due to the absence of class I evidence (i.e., sham-controlled) of efficacy. Prior to starting the VNS trials, Cyberonics, Inc. asked the TRD research community what would be the threshold for arguing that VNS had clinically significant antidepressant effects. The “experts” reached consensus that a 30% response rate (i.e., at least 50% symptom reduction) after a year of treatment would be the minimal threshold for considering VNS a useful intervention for this indication. Indeed, the two first trials did observe improvement rates consistent with this goal (Rush et al., 2000; Rush, A. J. et al., 2005a). However, in the second study, the period of sham, blinded treatment was only 10 weeks, and there was no statistical difference in the primary outcome at this time point. Nonetheless, for two main reasons experts, like myself, were enthusiastic about VNS’ therapeutic potential. First, the samples treated with VNS were among the most ill and treatment resistant patients ever studied in MDD. For example, in the original study the patients at Columbia averaged over 20 medication trials in the current episode. All of them had not benefited from ECT, with most courses administered under my direction. These were patients essentially without any other treatment option, and a significant number (albeit a minority) showed clinical improvement following chronic treatment with VNS (Rush et al., 2000; Rush, A. J. et al., 2005b). The second reason was more compelling. Of those who showed significant clinical benefit (i.e., response), between 60-80% maintained the benefit over a period of 1-2 years (Nahas et al., 2005; Sackeim et al., 2007).

TRD is associated with increased morbidity and mortality (Banankhah et al., 2015; Reutfors et al., 2018; Souery et al., 2007), increased medical and psychiatric health care costs (Amos et al., 2018; Kubitz et al., 2013; Lepine et al., 2012; Mahlich et al., 2018; Olfson et al., 2018; Russell et al., 2004), and markedly reduced quality of life (Johnston et al., 2018; Mrazek et al., 2014). However, TRD, if anything, is also associated with poor durability of benefit. STAR*D demonstrated that with each failed level of antidepressant treatment, the likelihood of remitting at the next level decreases, and if remission is obtained, the likelihood of relapse (during the subsequent year) increases (Rush, 2007; Rush et al., 2006). It was the research at Columbia that demonstrated that degree of antidepressant treatment resistance is a potent predictor of relapse in patients who remit following ECT (Prudic et al., 2013; Sackeim, H. A. et al., 2001; Sackeim et al., 1990; Sackeim et al., 1993; Sackeim, H. A. et al., 2000; Sackeim et al., 2008). Indeed, the most recent meta-analysis of the ECT literature concluded that the relapse/recurrence rate is approximately 50% in the year following ECT-induced remission (Jelovac et al., 2013). In other words, patients with TRD are expected to benefit less from antidepressant treatments, and, in particular, to relatively quickly lose whatever benefit they do achieve. In contrast, the most recent 5-year follow-up study of VNS in TRD, fully supported the observations of strong durability, with long-term benefit and durability far superior in those treated with VNS compared to TAU (Aaronson et al., 2017).

Thus, the extant data with VNS in TRD indicate a significant number may benefit, at least in terms of the classification of response, and that a high percentage will maintain the benefit once achieved. However, in the absence of Class I evidence regarding the “acute” effect, CMS and third-party payers have not supported coverage for this intervention in TRD. The decision by CMS to propose Coverage with Evidence Development (CED) for VNS in TRD is a positive step as long as the CMS-approved study is well designed and definitive.

As detailed in the Proposed Decision Memo, many of the stipulations for such a study are sound, including the requirement that patients be in episode at least 2 years or have at least 4 prior MDEs, that they have not benefited from at least 4 antidepressant treatments given at adequate dose and duration, and must not have benefited from a psychotherapy trial in any MDE. However, there are specific study recommendations in the Proposed Decision Memo that I think are problematic and could impede progress.

First, the primary outcomes all pertain remission, and use an unusual remission measure at that. In much of my own research the primary outcomes have also been remission. This includes the many of the ECT studies conducted at Columbia ((Sackeim et al., 1993; Sackeim, H. A. et al., 2000; Sackeim et al., 2008)), multi-site ECT studies I have chaired (Sackeim et al., 2009; Sackeim, H. A. et al., 2001a; Sackeim et al., 1993; Sackeim, H. A. et al., 2000; Sackeim et al., 2008), and studies of the acute effects of rTMS (George et al., 2010; O'Reardon et al., 2007). Indeed, I have repeatedly shown in ECT samples that response and remission rates are almost identical, and that a larger response than remission rate often indicates insufficient treatment (premature termination) with ECT (Prudic et al., 2004). This is simply not the case with VNS. Because VNS is a surgical intervention, and involves bothersome side effects such as voice alteration, patients typically consider VNS only after having failed to benefit from multiple, standard antidepressant treatments, including pharmacotherapy, psychotherapy, and other brain stimulation interventions. The patients who have participated to date in the VNS studies had levels of chronicity and treatment resistance that exceed any prior research in mood disorders, including all ECT trials. In my view, it is unrealistic to expect that substantial numbers of such patients will achieve remission, as opposed to response. For example, in the open, pilot study of VNS (n=59), the overall response and remission rates were 30.5% and 15.3%, respectively. However, the remission rate was > 30% among patients who had failed 2-3 adequate antidepressant trials prior to VNS (n=21), >10% among those who had failed 4-5 adequate trials (n=17), 0% among those who failed 6-7 adequate trials (n=8), and 0% among those who failed >7 adequate trials (by ATHF criteria). Given these data and the proposed inclusion criterion of at least 4 failed adequate trials, it should be expected that the expected remission rate with VNS after 1 year of treatment is around 5-10%. This rate is so low that an adequately powered study to detect a difference with sham (after 12 months) would require hundreds more patients than might have been anticipated, at considerable cost to CMS and the taxpayer.

The subsequent research with VNS has not altered this projection. In the sham-controlled study, there was a 15% response rate with active VNS and a 10% response rate with sham at the end of the sham-controlled period (10-weeks post-recovery phase) (Rush, A. J. et al., 2005). After 12 months of intervention, the response and remission rates were 27.2% and 15.8%, respectively (George et al., 2005; Rush, A. J. et al., 2005b). While a remission rate of 15.8% is substantial, 56.8% of the sample had 2-3 unsuccessful ATHF treatments in the current episode. In the patients to be recruited for the study outlined by CMS (minimum 4 unsuccessful adequate treatments), the remission rate after a year of active VNS is likely to be between 5-10%. Of note, George et al. (2005) compared the 12-month outcomes with VNS to a TAU TRD group and reported only a 6.7% 12-month remission rate. In other words, it may be possible to conduct a trial with remission as the primary outcome, but the sample size could be prohibitive given the infrequency of the primary outcome. In the recent 5-year observational study of patients treated with VNS vs. TAU, Aaronson et al. (2017) found that the median time to first response was 12 months for VNS and 48 months for TAU. The comparable values for remission were 49 months and 65 months, respectively.

I suggest switching from remission to response as the primary outcome not just as a matter of practicality. In this population, obtaining response is clinically important, and at times, life-saving. The VNS samples are characterized by severe symptom severity, chronicity, and marked treatment resistance. These are all factors that portend poor outcome with antidepressant treatment. Obtaining a minimum reduction of 50% in depressive symptoms can have meaningful impact on patients’ lives, their extent of impairment and disability, and their rates of suicide attempt and completed suicide. For example, we demonstrated in the first open pilot study and extension that VNS reported superior health-related quality of life (HRQOL) than those who had not achieved response (Sackeim, H. A. et al., 2001c). This same effect has since been repeatedly observed (Conway et al., 2018; George et al., 2005).

The most serious reservation about the use of response as a primary outcome pertains to the belief that the extent of residual symptomatology predicts early relapse. Since the seminal work by Kupfer and Prien, it has been thought that durability of benefit is relatively poor unless nearly complete symptom resolution is achieved (i.e., remission) Prien (Prien and Kupfer, 1986; Prien et al., 1984). However, these findings derive principally from pharmacological studies, and not from interventions that are stimulating the brain on a continuous 24/7 basis. I published extensive data on the durability of benefit in VNS patients who had achieved 50-59%, 60-79%, or 80-100% improvement in HRSD24 scores either 3 months or 12 months after starting VNS. Despite the clinical features of the samples (chronicity, severity and treatment resistance), all the subgroups showed strong durability of benefit with a follow-up period of either 1 or 2 years. The relapse/recurrence rate was substantially below what would be expected in an ECT sample, for example. Of particular note, while the group that achieved the least short-term symptomatic improvement (50-59%) tended to have the highest rate of relapse, this was a small effect, and even this group showed strong durability. In short, my expectation is that real VNS will produce a substantially higher response rate than sham VNS (at a 12-month time point, e.g., 30% vs. 15%), and furthermore, that patients who continue to receive active VNS will show strong durability of benefit regardless of whether they achieved acute response or remission. Since the Proposed Decision Memo includes a substantial follow-up period, this hypothesis can be rigorously tested.

My second concern regarding the Proposed Decision Memo concerns the inclusion/exclusion criteria, and specifically, the exclusion of bipolar patients and patients with atypical depression (overlapping subgroups). It is common in studies of TRD to include both bipolar and unipolar MDE. For example, all the serial ECT RCTs conducted at Columbia University included both unipolar and bipolar patients, as has been the case at other ECT research groups around the world. Partly, this is because bipolar depression is especially difficult to treat, with serious concerns about the value of traditional antidepressant medications in this condition (Geddes and Miklowitz, 2013; Goodwin et al., 2016; Malhi et al., 2015; Pacchiarotti et al., 2013). . Furthermore, research with ECT has consistently reported that bipolar depressed patients respond/remit at the same rates as unipolar patients, but that bipolar patients require about 1.5 fewer treatments (i.e., a difference in speed of benefit, but not in likelihood) (Daly et al., 2001; Sackeim and Prudic, 2005; Sienaert et al., 2009). The work on VNS in TRD likewise included both bipolar and unipolar patients, and found no signal of a difference in efficacy (and rates of induction of mania were low).

The efficacy of VNS in bipolar depression will be a critical issue if the proposed study is positive and leads to a change in CMS coverage of VNS in TRD. In my mind, it would be a mistake to exclude bipolar patients and to miss critical information. My preference would be to have as the primary outcome measure, the endpoint response rate for the real and sham group computed across patients with either bipolar (I or II) and unipolar depression. I would separately power the study for a sufficient sample of unipolar patients to test the critical hypothesis in a secondary analysis restricted to the unipolar subgroup. In this way, one can protect the analysis of unipolar patients by ensuring sufficient sample size for a pure mandatory analysis while preserving the capacity to collect important data on bipolar depression that contributes to the overall primary analysis. I would exclude rapid cycling patients from such a study, as we have always done in our ECT research. Their frequent change in clinical state introduces noise in efficacy/effectiveness trials, and presents significant clinical management problems.

I agree with the Proposed Decision Memo that patients with a history of psychosis should be excluded, including schizophrenia, schizoaffective disorder, and psychotic depression. I do not see the rationale for excluding patients with atypical depression symptoms (over eating, over sleeping, rejection sensitivity, mood reactivity, etc.). There are no data that indicate that such patients are especially at risk due to treatment with VNS or that they are especially likely not to respond. The distinction between typical and atypical depression largely stemmed from the work of Donald Klein’s group at Columbia where it was shown that typical and atypical patients differ in likelihood of benefit from treatment with MAOIs and TCAs (Liebowitz et al., 1988; Quitkin et al., 1988). Both groups responded to both types of medication, the difference in benefit was relative. Poorer response in atypical depression has not been established for other classes of medication (e.g., SSRIs, SNRIs, etc.), or for any brain stimulation intervention. Indeed, Husain et al. (2008) reported that patients with atypical depression were more likely to remit with ECT than those with typical depression. There is considerable overlap between atypical and bipolar depression. I think it would be wise to document the subtype in diagnostic work-up and examine whether it has prognostic implications in secondary analyses. If this approach is taken, the symptom scale used for classifying the primary outcome should include assessment of reversed vegetative features (e.g., HRSD28).

Thank you for this opportunity to comment on the Proposed Decision Memo for VNS for TRD. With the caveats I have detailed, I believe a study like the sham-controlled RCT outlined in the memo can be extremely valuable and I applaud this effort.

References

Aaronson, S.T., Sears, P., Ruvuna, F., Bunker, M., Conway, C.R., Dougherty, D.D., Reimherr, F.W., Schwartz, T.L., Zajecka, J.M., 2017. A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality. Am. J. Psychiatry 174(7), 640-648.
Conway, C.R., Kumar, A., Xiong, W., Bunker, M., Aaronson, S.T., Rush, A.J., 2018. Chronic Vagus Nerve Stimulation Significantly Improves Quality of Life in Treatment-Resistant Major Depression. J. Clin. Psychiatry 79(5).
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Fava, M., Rush, A.J., Trivedi, M.H., Nierenberg, A.A., Thase, M.E., Sackeim, H.A., Quitkin, F.M., Wisniewski, S., Lavori, P.W., Rosenbaum, J.F., Kupfer, D.J., 2003. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr. Clin. North Am. 26(2), 457-494, x.
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Prudic, J., Haskett, R.F., McCall, W.V., Isenberg, K., Cooper, T., Rosenquist, P.B., Mulsant, B.H., Sackeim, H.A., 2013. Pharmacological strategies in the prevention of relapse after electroconvulsive therapy. J. ECT 29(1), 3-12.
Prudic, J., Olfson, M., Marcus, S.C., Fuller, R.B., Sackeim, H.A., 2004. Effectiveness of electroconvulsive therapy in community settings. Biol. Psychiatry 55(3), 301-312.
Quitkin, F.M., Stewart, J.W., McGrath, P.J., Liebowitz, M.R., Harrison, W.M., Tricamo, E., Klein, D.F., Rabkin, J.G., Markowitz, J.S., Wager, S.G., 1988. Phenelzine versus imipramine in the treatment of probable atypical depression: defining syndrome boundaries of selective MAOI responders. Am. J. Psychiatry 145(3), 306-311.
Rush, A.J., 2007. STAR*D: what have we learned? Am. J. Psychiatry 164(2), 201-204.
Rush, A.J., Fava, M., Wisniewski, S.R., Lavori, P.W., Trivedi, M.H., Sackeim, H.A., Thase, M.E., Nierenberg, A.A., Quitkin, F.M., Kashner, T.M., Kupfer, D.J., Rosenbaum, J.F., Alpert, J., Stewart, J.W., McGrath, P.J., Biggs, M.M., Shores-Wilson, K., Lebowitz, B.D., Ritz, L., Niederehe, G., Group, S.D.I., 2004. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control. Clin. Trials 25(1), 119-142.
Rush, A.J., George, M.S., Sackeim, H.A., Marangell, L.B., Husain, M.M., Giller, C., Nahas, Z., Haines, S., Simpson, R.K.J., Goodman, R., 2005. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol. Psychiatry 47(4), 276-286.
Rush, A.J., Marangell, L.B., Sackeim, H.A., George, M.S., Brannan, S.K., Davis, S.M., Howland, R., Kling, M.A., Rittberg, B.R., Burke, W.J., Rapaport, M.H., Zajecka, J., Nierenberg, A.A., Husain, M.M., Ginsberg, D., Cooke, R.G., 2005a. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol. Psychiatry 58(5), 347-354.
Rush, A.J., Sackeim, H.A., Marangell, L.B., George, M.S., Brannan, S.K., Davis, S.M., Lavori, P., Howland, R., Kling, M.A., Rittberg, B., Carpenter, L., Ninan, P., Moreno, F., Schwartz, T., Conway, C., Burke, M., Barry, J.J., 2005b. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol. Psychiatry 58(5), 355-363.
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D., Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D., McGrath, P.J., Rosenbaum, J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava, M., 2006. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry 163(11), 1905-1917.
Sackeim, H.A., 2001. The definition and meaning of treatment-resistant depression. J. Clin. Psychiatry 62 Suppl 16, 10-17.
Sackeim, H.A., 2017. Modern Electroconvulsive Therapy: Vastly Improved yet Greatly Underused. JAMA psychiatry 74(8), 779-780.
Sackeim, H.A., Aaronson, S.T., Bunker, M., Conway, C.R., Demitrack., M.A., Geroge, M.S., Prudic, J., Thase, M.E., Rush, A.J., submitted. The assessment of ressitance to antiderpessant treatmen: Rationale for the Antidepressant Treatment History Form - Short Form (ATHF-SF). Jounral of Psychiatric Research.
Sackeim, H.A., Brannan, S.K., Rush, A.J., George, M.S., Marangell, L.B., Allen, J., 2007. Durability of antidepressant response to vagus nerve stimulation (VNS). Int J Neuropsychopharmacol 10(6), 817-826.
Sackeim, H.A., Dillingham, E.M., Prudic, J., Cooper, T., McCall, W.V., Rosenquist, P., Isenberg, K., Garcia, K., Mulsant, B.H., Haskett, R.F., 2009. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch. Gen. Psychiatry 66(7), 729-737.
Sackeim, H.A., Haskett, R.F., Mulsant, B.H., Thase, M.E., Mann, J.J., Pettinati, H.M., Greenberg, R.M., Crowe, R.R., Cooper, T.B., Prudic, J., 2001a. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA 285(10), 1299-1307.
Sackeim, H.A., Haskett, R.F., Mulsant, B.H., Thase, M.E., Mann, J.J., Pettinati, H.M., Greenberg, R.M., Crowe, R.R., Cooper, T.B., Prudic, J., 2001. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA 285(10), 1299-1307.
Sackeim, H.A., Keilp, J.G., Rush, A.J., George, M.S., Marangell, L.B., Dormer, J.S., Burt, T., Lisanby, S.H., Husain, M., Cullum, C.M., Oliver, N., Zboyan, H., 2001b. The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression. Neuropsychiatry. Neuropsychol. Behav. Neurol. 14(1), 53-62.
Sackeim, H.A., Prudic, J., 2005. Length of the ECT course in bipolar and unipolar depression. J. ECT 21(3), 195-197.
Sackeim, H.A., Prudic, J., Devanand, D.P., Decina, P., Kerr, B., Malitz, S., 1990. The impact of medication resistance and continuation pharmacotherapy on relapse following response to electroconvulsive therapy in major depression. J. Clin. Psychopharmacol. 10(2), 96-104.
Sackeim, H.A., Prudic, J., Devanand, D.P., Kiersky, J.E., Fitzsimons, L., Moody, B.J., McElhiney, M.C., Coleman, E.A., Settembrino, J.M., 1993. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N. Engl. J. Med. 328(12), 839-846.
Sackeim, H.A., Prudic, J., Devanand, D.P., Nobler, M.S., Lisanby, S.H., Peyser, S., Fitzsimons, L., Moody, B.J., Clark, J., 2000. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch. Gen. Psychiatry 57(5), 425-434.
Sackeim, H.A., Prudic, J., Devanand, D.P., Nobler, M.S., Lisanby, S.H., Peyser, S., Fitzsimons, L., Moody, B.J., Clark, J., 2000. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch. Gen. Psychiatry 57(5), 425-434.
Sackeim, H.A., Prudic, J., Nobler, M.S., Fitzsimons, L., Lisanby, S.H., Payne, N., Berman, R.M., Brakemeier, E.L., Perera, T., Devanand, D.P., 2008. Effects of pulse width and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. Brain stimulation 1(2), 71-83.
Sackeim, H.A., Rush, A.J., George, M.S., Marangell, L.B., Husain, M.M., Nahas, Z., Johnson, C.R., Seidman, S., Giller, C., Haines, S., Simpson, R.K., Jr., Goodman, R.R., 2001c. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 25(5), 713-728.
Sackeim, H.A., Rush, A.J., George, M.S., Marangell, L.B., Husain, M.M., Nahas, Z., Johnson, C.R., Seidman, S., Giller, C., Haines, S., Simpson, R.K., Jr., Goodman, R.R., 2001d. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 25(5), 713-728.
Sienaert, P., Vansteelandt, K., Demyttenaere, K., Peuskens, J., 2009. Ultra-brief pulse ECT in bipolar and unipolar depressive disorder: differences in speed of response. Bipolar Disord 11(4), 418-424.

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Thank you for the opportunity to provide comments on the Centers for Medicare and Medicaid Services (CMS) proposed national coverage determination of Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD).

AHIP is the national trade association whose members provide coverage for health care and related services to millions of Americans every day. Through these offerings, we improve and protect the health and financial security of consumers, families, businesses, communities and the nation. We are committed to market-based solutions and public-private partnerships that improve affordability, value, access, and well-being for consumers.

CMS proposes to cover FDA-approved VNS devices for 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. CMS delineates several criteria that must be used to identify patients demonstrating TRD. Additionally, CMS will review studies to determine if they meet 13 criteria and, if so, CMS will post the study on its CED website. 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.

In 2006, CMS received a complete, formal request to reconsider the NCD to include coverage of VNS for TRD for patients who had either (1) been previously treated with or refused electroconvulsive therapy (ECT) for the treatment of depression, or (2) had been previously hospitalized for depression. The specific indication requested for VNS coverage was for the adjunctive long-term treatment of chronic or recurrent depression in patients over the age of 18 who were experiencing a major depressive episode and had not had an adequate response to four or more adequate depression treatments. On May 4, 2007, CMS determined that there was sufficient evidence to conclude that VNS was not reasonable and necessary for TRD and it has remained non-covered since then.

In May 2018, CMS received a formal request to reconsider the NCD to remove non-coverage of VNS therapy for TRD. The scope of this review is limited to surgically implanted VNS only for the treatment of TRD.

We are concerned that CMS is proposing Medicare coverage for an intervention that has not yet proved to be a safe or effective treatment for TRD. The available evidence on these devices in insufficient to determine the effects of VNS on health outcomes related to TRD. Specifically:

The medical literature is incomplete and does not show that VNS is reasonable and necessary for treatment of TRD. The literature also does not adequately address the associated risk, which is necessary to ensure practitioners and patients are making fully informed decisions.

Therefore, we recommend that CMS should seek more information to determine safety and efficacy prior to determining it is appropriate to provide coverage for VNS to Medicare beneficiaries.

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The National Alliance on Mental Illness (NAMI) is pleased to submit the following comments on the proposed CMS Decision Memorandum on coverage under Medicare for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD). As the nation’s largest organization representing people living with serious mental illness and their families, NAMI commends CMS for moving forward to expand coverage for treatment.

Depression carries an enormous public health burden for our nation and is one of the most substantial contributors to disability. About 1/3 of people living with depression fail to achieve symptom relief after trying numerous antidepressant medications prescribed for them – often over a period of years. These individuals living with TRD can often experience an unremitting chronic episode of depression and prolonged suffering with significant negative health outcomes, greater risk of suicide attempts, and higher health care utilization and costs than their remitted counterparts.

Individuals living with TRD that fail to achieve remission and symptom relief have few available options. This is particularly the case for individuals that have been experiencing TRD for years. These individuals are in desperate need of access to all antidepressant treatment options that are approved by the FDA. NAMI is therefore very pleased that CMS is taking steps towards expanding its coverage of FDA approved VNS Therapy.

It is particularly noteworthy that CMS is addressing patient continuity of care by proposing to cover VNS device replacement if it is required due to the end of battery life, or any other device-related malfunction. This marks an improvement in coverage expansion as it will provide much needed consistency in coverage across the Medicare Administrative Contractors (MACs). A NAMI member in Minnesota had a lifelong struggle with major depression until 2009, when he had a VNS implanted in his chest. When the battery was due to be replaced, he struggled to fund the cost. This proposed policy change would have helped him continue to have access to effective treatment for his depression. We feel confident that the proposed change will help additional beneficiaries in a similar situation.

NAMI is encouraged that CMS is also proposing to cover, in prospective longitudinal studies, individuals with TRD that have been implanted with FDA approved VNS devices that have completed enrollment in a CMS approved study. It is important to close this gap in treatment among study participants. NAMI would recommend that this coverage be expanded in the final draft to include new patient access if the study has demonstrated positive findings. This would be very helpful as it generally takes an extended period of time for coverage policies to be updated. Simply put, new patients should be able to benefit from VNS to treat severe symptoms.

NAMI would further note that the proposed CED excludes patients who have been diagnosed with bipolar disorder. This is concerning to NAMI as people living with bipolar disorder are at an even higher suicide risk than people with depression. A number of studies (Aronson, 2017) have demonstrated the positive impact of VNS in mitigating symptoms such as suicidal ideation in individuals living with bipolar disorder. Including people living with bipolar in the proposed CED study would help provide answers on ways in which VNS can be helpful to individuals with treatment refractory bipolar disorder.

Thank you for this opportunity to comment on this important Coverage Determination Memorandum.

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Dennis J Kutzer, MD
Service Chief, Crisis Admissions Unit
Sheppard Pratt Health System
6501 N. Charles Street
Baltimore, MD 21204
410-938-5435
djkutzer@sheppardpratt.org

I am a front line psychiatrist with over 35 years of experience. I have focused my clinical care for individuals with difficult to treat Major Depressive Disorder, Bipolar Disorder Type I and II and Schizophrenia. I am currently following six patients all with Bipolar Disorder who were part of a research study with Scott Aaronson ,MD.

Patient 1 is a 41yo F. whose VNS was implanted in 2006 as part of a stud. The pt had 8 admissions prior to the VNS after implantation no hospitalizations . She has been able to graduate nursing school, is now working and hopes to be off disability in 6 months.

Patient 2 ia a 44yo F. with Bipolar I depressed with psychosis. She was implanted in 2006. Prior to this she had 20+ admissions. She needed an implant replacement in 2017. Since her re-implant she has had 3 hospitalizations.

Patient 3is a 66yo M with Bipolar I disorder depressed. He was also implanted in 2006 and needed a replacement in 2015. Prior to VNS had had 12 hospitalizations and 6 suicide attempts. Since 2006 ,no suicide attempts and no hospitalizations.

Patient 4 is a 50yo Bipolar I depressed with 9 hospitalizations before the 2006 implant and none since.

Pt 5 is a 59yo F with Bipolar I depressed. This pt was enrolled in the study but was assigned to the sham group. She made a serious suicide attempt. I took over her care and started her implant. Prior to the implant she had been hospitalized 6 times and sicne the unit was turend on had on brief hopsitlaization for lithium neurotoxicity.

Pt. 6 is a 70yo Bipolar I depressed who missed the deadline to enroll in the study. Fortunately a relative offered to pay for the device. Prior to implantation 15 admissions since the implant no hospitalizations. She is very active with her church and family.

CMS wants to do another double blind study after one was completed before the FDA gave approval to use VNS in TRD. The new study would exclude Bipolar Disorder patients leaving out a substantial number of people suffering with these illnesses. The group of 6 patients that I discussed above would have been excluded in the first study.

CMS also want to require that a successful trial if complete remission as a successful outcome. Depression, be it Unipolar or Bipolar are chronic illnesses that require ongoing treatment. In my 6 patients, I have only one who could be considered to be a complete remission. However the other 5 have not needed hospital stays and have an improved quality of life since the VNS implants.

In looking at data for using VNS in epilepsy from 1997., VNS reduced medically refractory epilepsy by an average of 45%, with a 36% reduction in seizures at 3 – 12months with a 51% reduction greater than 1 year. I suppose that for epilepsy to be in full remission that it should be close to 100 %. Why such a discrepancy between its use in epilepsy and depression. I’m sure the 51% whose epilepsy responded to VNS did have an improvement in their quality of life. Likewise, the VNS in depression result in improved quality of life. I have always respected the FDA in how intensely they research the issues before them in making a decision. It seems that to repeat studies that already were done is wasteful and redundant..

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December 19, 2018

Tamara Syrek Jensen, Esq.
Director, Coverage and Analysis Group
Office of Clinical Standards and Quality
Centers for Medicare and Medicaid Services
7500 Security Blvd. Baltimore, MD 21244

Subject:    CMS Proposed Decision Memo for Vagus Nerve Stimulation (VNS) for Treatment-Resistant Depression (TRD) (CAG-00313R2)

Dear Ms. Jensen:

The American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS) and American Society for Stereotactic and Functional Neurosurgery (ASSFN), appreciate the opportunity to comment on the above referenced draft coverage decision memo regarding Medicare coverage for vagus nerve stimulation (VNS) for treatment-resistant depression (TRD), released on November 19, 2018.

As we mentioned in our comments submitted on June 29, 2018, when CMS announced their intention to review their non-coverage decision for VNS for TRD, we support coverage for this procedure.  Despite decades of research, patients with TRD continue to have very limited options.  We are pleased to see that CMS will be permitting some Medicare patients to have access to this important treatment option for their TRD.  However, we question the decision to restrict Medicare coverage to patients enrolled in a clinical trial.  We feel the current literature submitted as part of the initial request for review is robust and shows clear evidence of efficacy and cost-benefit for VNS for TRD.  Medicare patients who meet the established criteria for this treatment should, therefore, have unfettered access to this life-changing and life-saving therapy.  As part of the FDA approval process in 2005 and since that time, a strong body of evidence has been developed for VNS for TRD.  With suicide continuing to be among the top ten causes of death in the United States, we urge CMS to make this potentially life-saving procedure available to appropriately selected patients without undue burden on the patient or the treating surgeon.

Rather than requiring a prospective randomized controlled trial that will duplicate pivotal studies that have already shown VNS for TRD to be safe and effective, we would urge the agency to consider less onerous options for further evidence development, such as participation in clinical registries.  Gathering real world experience outside of the study setting would be more useful than restricting coverage to study populations.  Given the current state of the evidence, withholding this effective treatment from appropriately selected patients that we know are good candidates for the procedure and likely to benefit is unethical.  Patients with TRD by definition have tried and failed other treatment options and are at high risk for suicide.  Furthermore, although the draft decision memo proposes coverage for patients in a clinical trial, the patient would be subject to a co-payment, even if they were placed in the implanted but untreated control group.  In addition to the ethical considerations of sham surgery, there is the practical issue of difficulty in replicating the experience of having the device turned on for the patients in the control group.  For all of the reasons stated, we urge the agency to finalize a national coverage policy with fewer restrictions and a greater consideration of the clear efficacy and safety of VNS for TRD.

Thank you for considering our recommendations.  Please contact us if you have any questions or need additional information.

Sincerely,

Shelly D. Timmons, MD, PhD, President
American Association of Neurological Surgeons

Ganesh Rao, MD, President
Congress of Neurological Surgeons

Robert E. Gross, MD, PhD, President
American Society for Stereotactic and Functional Neurosurgery

Staff Contact:
Catherine Jeakle Hill
Senior Manager, Regulatory Affairs
AANS/CNS Washington Office
25 Massachusetts Avenue, NW, Suite 610
Washington, DC  20001
Phone:  202-446-2026
Fax:  202-628-5264
E-mail:  chill@neurosurgery.org

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I am sending this comment after careful review of the CMS comments regarding Vagus Nerve Stimulation (VNS) for Medicare coverage of VNS for the FDA approved indication of treatment resistant depression (TRD). I appreciated the broad range of reviewers who apparently consolidated their comments in the review. However, as a psychiatrist for over 30 years doing both clinical research as well as managing the challenges of TRD daily, I cannot help but state that the comments are not consistent with a group of experts who have been assigned to review the data and the comments that resulted in the review. As "experts" assigned to this task, I remain perplexed at the comments and recommendations set by a committee with this responsibility. TRD is a leading cause of PREVENTABLE death worldwide, and has become the number one cause of worldwide disability. If data demonstrated the strength of evidence supported the long-term efficacy and functional improvement as shown by VNS in TRD for other malignant and potentially fatal illness ( e.g. non-treatable cancer, Hep-C ) I assume the decision would be compelling enough to support the treatment. I have over 80 patients ( estimating that 20% would not be alive today, 70% of those who did not die as a result of their MDD contributing to their morbidity and mortality - including less medication/hospitalizations/and return to pre-morbid occupational/social function) which 3/4 over the last decade have a return of their life compared to others who I treat aggressively with TRD ( I have data to show 80% relapse or suffer recurrence) with SUSTAINED EFFICACY and data supports this as you know. The studies clearly replicate that RESPONSE often evolves into REMISSION and recovery with VNS; unlike treatment as usual. I realize my limited time/space to make additional comments, however, I ask that you look at this data and realize that even if 1/3 of TRD patients benefit - each are a life, and there are NO OTHER TREATMENTS that show this same impact for TRD! Looking at the group reviewing this data, I am perplexed at what is missing? please go back and think about this as a malignant cancer (which nothing has been close to the numbers of human life's are impacted compared to TRD - and I am not insensitive to those who suffer from these other illnesses with high morbidity and mortality). TRD is not like an infection, expecting immediate REMISSION is not common, but over time is more than possible with treatments that have empirical evidence that over time, these individuals have life's that have been transformed ( percent higher than anything else to date). I am grateful for your comments, and please hear that many of these individuals would have continued to be on multiple medications, not functional, and other related morbidity and mortality issues that I can say with confidence - would not have been possible if not for VNS. I add that this is especially true for bipolar depression - which you are all aware has a mortality of 25% just by suicide not to mention the impact on other comorbid illness that impacts the human individual and society. As a professional, I would be ashamed for my profession if this committte fails to recognize the impact supported by data for both unipolar and bipolar TRD, and certain that you know data suggests 75% of unipolar MDD is actually bipolar TRD. If support of VNS for either form of TRD is ignored or denied by reasons unclear to myself and my patients, I ask that you understand the negative impact and reflection that Medicare will have by setting the treatment of the number one cause of worldwide disability BACKWARDS and pray that none of those making this decision will have to face the consequences in themselves or loved ones who may suffer from TRD and the recurrent nature resulting in significant morbidity and mortality on ALL impacted. Thank you for your attention, and I am grateful for your open mind and hearts to understand the data and this UNMET need in our society which can no longer ignore as though it was a psychological or modifiable illness without novel treatments such as VNS. Let us welcome a new beginning rather than move backwards in naïve decisions.

John Zajecka, MD Professor of Psychiatry, Rush University .

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Dear Dr. Susan Miller, Lead Medical Officer & David Dolan, MBA, Lead Analyst,

I am delighted to see that CMS is reconsidering its stand on Vagal Nerve Stimulation. I am the Medical Director of the Division of Neuropsychiatry at Dent Neurologic Institute in Buffalo, New York. This is America’s largest freestanding neurosciences institute. We have significant experience with treatment resistant depression and offer a wide variety of treatments. I currently have approximately 3 dozen patient’s benefiting from VNS.

The current data available, such as the D 23 VNS for 3 times a day registry study with close to 800 patients, is already conclusive regarding the efficacy and benefits of VNS. That being said, I have substantive comments regarding potential changes to the proposed study. The exclusion of patients suffering from bipolar depression would be a great disservice to these individuals, their families, and are already overburdened healthcare system in general. I have experience with the great benefit derived by my patient’s with bipolar disorder. Additionally, in discussions with national thought leaders they echo my concerns.

Care must be taken to assess this particular group of patients and the data related to them accurately. In other words, they are the most difficult to treat patient’s. As the name would imply, they are indeed treatment resistant. Therefore, we cannot look at their outcomes as if they were the “worried well.” In fact, according to the Star D Trial, lack of response to 2 Antidepressants makes a likelihood of remission with the next Antidepressant only 13.7%. I fear that unrealistic expectations could doom an otherwise effective treatment for thousands of suffering Americans.

Respectfully,

Horacio A Capote M.D.

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Dr. Susan Miller, Lead Medical Officer
David Dolan, MBA, Lead Analyst.

Dear Dr. Miller and Mr. Dolan,

I appreciate this opportunity to provide comments about the proposed expansion of coverage for VNS to treat TRD. I am a clinical researcher with more than 2 decades of experience conducting TRD device-based clinical trials such as the one CMS is calling for with CED criteria, including several large multi-site VNS trials sponsored by Cyberonics. Additionally, I am a practicing psychiatrist, and I have personally been involved in the initiation or management of VNS therapy for approximately 50 TRD patients, many of which were participants in research trials.

I have advocated for CMS coverage of VNS therapy for TRD, and I believe the existing published evidence base suggests efficacy and safety of the treatment for a meaningful portion of appropriately selected TRD candidates. I also generally support a CMS plan for coverage with the development of additional evidence. However, I note there are several flaws with the proposed study design which render it incompatible with CES criterion 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."

A methodologically appropriate study design for a trial of VNS therapy in the TRD population would not establish "remission" as the primary outcome to measure of efficacy. Rather, categorical "response" (defined by at least 50% decrease in depressive symptoms on a chosen measure) would be the outcome standard for trials of this type with a TRD population. The majority of TRD patients who will seek VNS and enroll in such a trial are fully disabled and have been symptomatic for decades despite many trials of psychotropic medication and psychotherapy. Many have comorbid medical disorders and/or historical or environmental variables which contribute to the overall severity and chronicity of their brain disease. The expected frequency of threshold remission with this patient sample, regardless of the type of investigational treatment, is too low to make it an appropriate primary outcome for the trial.

A methodologically appropriate study design for a trial of VNS therapy for TRD would not exclude depressed individual with Bipolar I or Bipolar II forms of illness. The body of available evidence describing the efficacy of VNS, upon which the FDA approval was based, included individuals with both unipolar and bipolar forms of depression. There remains a paucity of available treatments for people with bipolar depression, and I can think of no good reason to advocate for one less option should VNS be proven effective for them.

A methodologically appropriate study design for a trial of VNS therapy for TRD would not exclude depressed individual with "atypical" neurovegetative features. Depression is a phenotypically heterogeneous disorder, and there exists no evidence to suggest that one particular pattern of neurovegetative symptoms or features is more or less linked to the efficacy of VNS therapy for TRD.

I urge you to seek direct consultative input from investigators who have experience designing and conducting VNS and other neurotherapeutic device-based trials for TRD patients as you move forward with refining your CES study design.

Sincerely Yours,
Linda L. Carpenter, MD
Chief, Butler Hospital Mood Disorders Program
Professor, Brown Department of Psychiatry and Human Behavior

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I am very interested in the approval in the near future of vagal nerve stimulation for the treatment of Treatment resistant depression. This is a population that is very vulnerable in terms of suffering, and become a very significant burden to family and to society because of difficulty managing day-to-day life. Rates of family failure and unemployment are quite high. The cost of treatment for patients with treatment resistant depression is very significant both on an outpatient and inpatient basis. This is a population with very frequent and repetitive inpatient hospitalizations. Suicide attempts and suicide success is very high in this population. The suffering on a personal, family, and society basis is tremendous.

As a principal investigator in an earlier vagal nerve stimulation clinical trial for treatment resistant depression, I witnessed a remarkable response in remission rates in a population that suffered from extremely severe depression. Additionally, I have continued to regulate many of these patients because of the lack of other providers who know how to do this. I have seen persistence of remission in many of my patients over the past 10 years since the trial was completed.

I most recently was able to see the impact of vagal nerve stimulation on treatment resistant depression. A college professor who was totally disabled by severe depression was implanted in a clinical trial about 10 years ago. She achieved remission of her depression and maintained this remission over the past 10 years. Recently, the battery died and it took about three months prior to being able to arrange for reimplantation of a new vagal nerve stimulator generator. Within a week of the battery failing, this patient’s level of depression regressed to the premorbid state. This persisted until reimplantation, and within two weeks after activating the new device, the mood return to its level of remission that was maintained during the first 10 years after implantation. In fact, the subject commented that she had some doubts about the remission being related to the VNS device, but is certainly now fully convinced that the remission was secondary to the device.

I think that Vagal nerve stimulation is a very important option for appropriately chosen treatment resistant depression patients. 10 years ago, some of the fear of high use of vagal nerve stimulation is now mitigated somewhat by the availability of transcranial magnetic stimulation. In that this is a non-invasive procedure, in the algorithm of treatment, transcranial magnetic stimulation will probably be used prior to her recommendation of a vagal nerve stimulation.

Nevertheless, the availability of vagal nerve stimulation is crucial for patients who suffer from this type of depression. This availability will reduce patient suffering, reduce psychiatric hospitalizations and use of psychiatric services, and will reduce suicide attempts and suicide completions. In doing so, there will be a significant societal savings in terms of costs as well as in terms of helping this depressed population resume productivity.

I hope that this procedure will soon be approved for appropriately selected patients who should have the opportunity for this type of intervention.

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I am the medical director of the Brain Stimulation Service at the Medical University of South Carolina. Our division includes a variety of brain stimulation methods for treatment resistant psychiatric disorders. We employ electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS, and deep brain stimulation (DBS). We were one of the first centers to have VNS implanted for treatment resistant depression (TRD). Dr. Mark George, the division director, follows many of these patients as needed. Most are doing well so long as their devices are working. I have encountered about 10 patients, all were patients that had decompensated AFTER the internal pulse generator had expired. We could get them re-implanted and back into recovery. I found the durability of VNS fascinating in this cohort of patients. We do not have anything else, including ECT and TMS, that can capture durability like that. We would be very interested in participating in further work to get a life saving treatment available to more people that meet stringent criteria for VNS. Prior registry data mentioned in prior CMS comments suggest that patients with TRD who received adjunctive VNS demonstrated demonstrably higher response and remission rates compared to patients with TRD who received treatment as usual. I also find it interesting that if this were a cancer treatment that had similar results, it would have already been covered. I suggest do what other science is needed but to not delay treatment based on possible psychiatric stigma.

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As a practicing clinician for 28 years who had a number of patients in the initial clinical trials, I can attest to the benefits of this treatment in patients who have failed all other options - patients who I had nothing left to offer. Given the positive clinical data, including long-term data, the mortality rate of Major Depression, and FDA approval for VNS for TRD, I am unable to understand why this life-saving treatment was not covered prior. As you are aware, your lack of coverage led to denial of coverage by the insurance industry, making this treatment unavailable to those who desperately need it. If you require yet another study, you will continue to severely limit the number of patients who can access this treatment, and give cover to the entire insurance industry to continue to deny coverage. Patients are dying; the data are strong, and this treatment should be covered.

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December 18, 2018

Via Electronic Submission

Re: Public Comments in Response to the Reconsideration of National Coverage Determination (NCD) 160.18 for Vagus Nerve Stimulation (VNS) for Treatment of Resistant Depression (TRD)

Dear Dr. Susan Miller and Mr. David Dolan,

On behalf of the Medical Device Manufacturers Association (MDMA), a national trade association representing hundreds of innovative companies in the field of medical technology, I am pleased to submit MDMA’s comments in response to the proposed decision memo for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD).

MDMA provides educational and advocacy assistance to innovative and entrepreneurial medical technology companies, and it is out mission to ensure that patients have timely access to safe and effective medical products. Our members, the majority of which are small to mid-sized, research driven medical device companies, have a strong record of delivering innovative therapies to treat chronic diseases and life-threatening conditions while lowering the cost of care. We are very pleased CMS is reconsidering the coverage of VNS Therapy for treatment resistant depression, but we do not believe the proposed changes go far enough to provide coverage for Medicare beneficiaries who continue to suffer from chronic and recurrent depression that is refractory to treatment as usual.

VNS Therapy was approved by the FDA in July 2005 for the adjunctive treatment of chronic or recurrent depression. Since that time, researchers have devoted considerable resources and effort to improve and expand the clinical evidence. A total of 17 clinical trials evaluate the safety and efficacy of VNS Therapy in patients with TRD.

The studies include:

• Two RCTs of VNS Therapy in TRD;
• Two prospective, non-randomized comparative studies (VNS Therapy vs. TAU);
• Two retrospective comparative studies (TRD vs. TAU);
• Ten single arm observational studies;
• One TAU only single arm study.

Seven of these clinical trials have been conducted by LivaNova to demonstrate the safety and efficacy of VNS Therapy in TRD. All studies provide clear evidence that patients treated with VNS Therapy have improvement in their TRD with time. Importantly there was no measure assessed in the SLR where TAU was superior to VNS+TAU. Two of these studies, (Aaronson et al, 2013 and 2017) were two of the largest and longest duration studies of a treatment for TRD. These studies demonstrated the safety, tolerability, efficacy and durability of the use of VNS in TRD when compared to treatment as usual over a 5-year follow-up.

VNS Therapy is the only treatment that has demonstrated positive results over a five year period in TRD. Despite this, CMS is seeking confirmation of these results in a double-blinded RCT. Multiple, overlapping, and duplicative studies unnecessarily impose additional burdensome requirements on all with little or no new information at the end to show for the effort. Requiring a double blind, sham controlled study after a medical device is already deemed safe and effective by the FDA exposes patients needlessly to ineffective placebo control. If the CMS thinks more study is needed, it would appear more would be gained by studying VNS Therapy via a registry rather than an RCT. A registry study would provide the opportunity to evaluate the clinical outcomes of VNS Therapy in real world settings.

It is important that any framework for CED have the key factors necessary to ensure the study can successfully enroll, is not burdensome to patients and clinicians, and provides information to inform a coverage decision. While we believe the totality of the evidence is strong enough for CMS to not require an RCT, we want to weigh in on concerns we have about the proposed CED as it is currently written.

All patients in the study will undergo a surgical procedure and under Medicare guidelines will be required to pay a substantial co-insurance. Despite this, patients relegated to the placebo control group will continue treatments as usual (TAU); treatment that has already been demonstrated to have very little short term and virtually no long-term improvement in their health status. This could make it very difficult to enroll patients in the study, if at all.

The current FDA indication statement for VNS Therapy does not differentiate between unipolar and bipolar depression. That CMS would exclude patients in a diagnostic category that is not excluded in the FDA indications for use for this device is disconcerting, especially because studies have shown patients with bipolar disorder are at a higher risk of suicide than unipolar depressed patients. VNS Therapy has been shown to have a specific lower all-cause mortality rate and anti-suicidal effect (Aaronson et al, 2017). Therefore, it is our belief patients with bipolar disorder should be provided access to VNS Therapy under CED or in any future coverage determination. Patients with atypical depression also fall under the FDA indication statement and were included in the D-21 and D-23 studies. These patients should also be provided access to VNS Therapy as well.

Thank you for the opportunity to comment and provide our perspective. We appreciate CMS’ effort in reviewing the evidence and developing this process to provide access for the under-served TRD population. We respectfully request consideration be given to addressing our concerns in the final decision memo so that patients who have few treatment options will have improved access to this treatment option.

Sincerely,
Mark B. Leahey
President & CEO, MDMA

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December 17, 2018

Ms. Seema Verma
Administrator
Centers for Medicare & Medicaid Services

Re: Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD)

I am writing on behalf of the Depression and Bipolar Support Alliance (DBSA) the leading peer-led organization for people with the lived experience of a mood disorder: depression or bipolar disorder. These serious, all-too-often life-threatening conditions combine to affect more than 21 million Americans adults, cost an estimated $23 billion in lost work productivity and are a contributing factor for 90 percent of the nation's deaths by suicide.

Unlike any other organization of its kind, DBSA is created for and led by individuals who themselves have a mood disorder diagnosis. This first-person lived experience informs everything that we do. DBSA's vision is wellness for people with mood disorders. Every person deserves the opportunity not just to survive, but to thrive, and to do that, we need to ensure true wellness as the end-goal for mental health treatment. Further, we believe that an open and collaborative approach to treatment that accounts for the whole person-where she or he is right now-is what allows people to achieve what they personally define as wellness.

While, the priority for treatment is ensuring that a person living with depression (whether unipolar or along the bipolar spectrum) is provided a pathway out of crisis and onto stability, all too often, this baseline stability is also the end goal established for successful long-term care. In a 2018 DBSA distributed Supporting Wellness survey nearly one third of the 6,400 respondents reported having 10 or more discrete periods of severe depression; 36% indicate that its impact is persistent. When responding, participants did not make a distinction between a diagnosis of unipolar depression or bipolar depression, but rather the symptoms they experience.

Urgency and need for greater access
In the 60 years that have passed since the first antidepressant medication was approved by FDA, there have been significant advances in the scientific understanding of depression. Yet, treatment options that support individual definitions of wellness remain elusive for many. Innovation has been incremental. People electing such treatment are consequently frustrated by and losing hope of a medical product solution. It is with this patient-centric view that DBSA strongly supports access to all FDA approved treatment options for people living with depression regardless of its natural history.

For many Americans financial burdens are one of the biggest barriers to access. That is why DBSA strongly supports the Centers for Medicare & Medicaid Services CMS Proposed Decision Memo for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD) (CAG-00313R2).

When considering the memo it is imperative to recognize that no one medical product intervention typically provides the entire range of symptom relief for depression. These interventions have differing risk/benefit tolerances for each individual and the considerations around the risks and benefits can often be different. When seeking a medical product intervention, patients weigh the risks and benefits of that intervention against symptom relief, functional considerations and well-being outcomes. Added to the decision-making process is the fact that an intervention may not be consistent in both its symptom relief and side-effects among the patient population. This often results in a frustrating trial-and-error period for both prescribers, who want to help their patients, and the patient, who is looking for improvement. Further complicating the treatment analysis is the reality that the prescriber may approach the challenge from the clinical perspective—symptom relief—while the patient, on the other hand, may be seeking well-being outcomes.

Additionally, the idea of wellness cannot be embraced without considering the whole health of the individual. The comorbidities associated with depression are not insignificant. The prevalence of depression among individuals living with heart disease, diabetes, polycystic ovary syndrome, CPOD, movement disorders, and Alzheimer’s—to name a few—is well known. And, the effect depression can have on the positive outcomes of comorbid conditions is significant. Choosing between effective treatment for a comorbidity and mental health is counter-productive: individuals living with mental health conditions on average die 25 years sooner, as a result of co-occurring conditions that can be exacerbated by and/or exacerbate depression. The cost of settling for reduced symptoms for many can be a matter of life and death.

DBSA applauds and appreciates this action by CMS that proposes changes to the vagus nerve stimulation (VNS) NCD (160.18) for VNS for treatment resistant depression (TRD) that would expand Medicare coverage. When considering this change, we respectfully request recognition that people living with depression experience symptoms—not clinical labels applied through clinical observation due to lack of biomarkers. This often leads to not only mis-diagnosis, but a change in diagnosis depending on the clinical observation at a particular moment in time. For the millions of Americans living with persistent depression symptoms as a result of a clinical diagnosis of unipolar depression or bipolar depression, the result is the same: lost opportunity to lead a self-defined thriving life. Let’s make sure all people experiencing depression have the same access to care and opportunity to lead self-defined lives of wellness.

Respectfully,

Michael Pollock
Chief Executive Officer
Depression and Bipolar Support Alliance

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I have been a practicing Psychiatrist for decades. As such, I recognize that Major Depression is a disease associated with significant morbidity and mortality despite the availability of a multitude of pharmacological, non-pharmacological and biological treatments. Even with all the advances that have been made in our therapeutic options, great challenges remain in achieving remission of disease for many patients with Major Depression. In this context of profound human suffering and less than optimal therapeutic outcomes in a disease like Major Depression which has such a high rate of prevalence, it is my fervent hope and considered clinical opinion that every therapeutic option should be made available to alleviate illness and suffering as soon as it has been determined to be safe, effective and well studied in diverse populations. I am hopeful that VNS can become a viable option for a select number of my patients. They deserve nothing less than our utmost efforts to ensure that they can avail themselves of all safe treatments so that they can return to a full, productive and improved quality of life.

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December 17, 2018

Tamara Syrek Jensen, JD
Centers for Medicare & Medicaid Services
Director, Coverage and Analysis Group
7500 Security Boulevard
Mail Stop S3-02-01
Baltimore, MD 21244-1850

Dear Ms. Jensen:

I am writing on behalf of the Association for Behavioral Health and Wellness (ABHW). ABHW is the national voice for payers that manage behavioral health insurance benefits. ABHW member companies provide coverage to approximately 200 million people in both the public and private sectors to treat mental health, substance use disorders, and other behaviors that impact health and wellness. We appreciate the opportunity to comment on the Proposed Decision Memo for Vagus Nerve Stimulation (VNS) for Treatment Resistant Depression (TRD) (CAG-00313R2).

ABHW is supportive of research to determine whether or not VNS is an appropriate treatment for TRD. We recognize the impact that TRD has on the health and well-being of individuals, on employment, and on health care spending. However, we believe this research should be done via a grant, perhaps from the National Institutes of Health (NIH), or by the companies seeking coverage for the VNS treatment they developed. We do not believe it is the role of the Centers for Medicare and Medicaid Services (CMS) to fund a clinical trial via the Medicare program and are unaware of this approach being considered a common practice. In fact, we believe moving forward with implementation of the proposed Decision Memo would set a dangerous precedent for Medicare, and other federal programs, funding services through investigational studies.

This proposal sets up a scenario where CMS is in essence diverting federal treatment dollars to fund research of a treatment that has limited evidence to date. We also don’t believe that CMS is in the best position to be evaluating clinical trials or making judgements on their results. Is there something that makes VNS so different that it can’t go through the normal clinical trial process with research dollars from usual funders instead of having the program funded by the Medicare program that typically pays for evidence based treatment?

Additionally, as we read the proposed Decision Memo it is setting up a scenario where the managed care organization (MCO) has to manage the investigational randomized trials. This is outside the normal scope of a payer. MCOs are not set up to adjudicate who should be approved for a clinical trial without Institutional Review Board (IRB) protections. Furthermore, there is not a lot of valid science available to make a decision regarding who gets enrolled in a VNS trial and the criteria in the proposed Decision Memo that must be used to identify patients demonstrating TRD is vague. For example, there is no definition of “adequate” dose and duration of treatment in the criteria that the patient must have “four prior failed treatments of adequate dose and duration.”

We urge CMS to encourage funding for VNS clinical trials through a source other than the Medicare program.

Thank you again for the opportunity to comment on the proposed Decision Memo. If you would like to discuss ABHW’s comments please call Pamela Greenberg, MPP, President and CEO, at (202) 449-7660.

Sincerely,

Pamela Greenberg, MPP
President and CEO

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Thanks for the opportunity to comment on the VNS for TRD proposed protocol.

I have served as PI of several protocols utilizing VNS for TRD and have overseen the treatment of dozens of individuals. Some of them I still provide treatment or consultation for. I have been impressed by three important observations:

1.- Individuals who have improved after treatment with VNS for TRD but did not approach or sustained remission, may have life changing benefit even when significant residual symptoms remain. In my opinion, since treatment of chronic, disabling, difficult to treat, and degenerative conditions in psychiatry and medicine are not required to reach remission, this represents a double standard for patients who suffer from TRD. We would not ask this of patients with epilepsy, pain, dementia, OCD, schizophrenia, or Parkinson's.

2.- The time required to observe the full effects of VNS for TRD is more than 2 months, especially if you are establishing a dose that may be well tolerated and robust enough to ensure you have the best chances of benefit in an abbreviated period of time. If you choose remission as an outcome for this duration, this will have a direct effect in the power of the proposed study to detect a signal of benefit which would increase the risk of a type II error.

3.- Individuals with bipolar disorder type I or type II diagnoses are often funded among those less likely to respond to standard treatments. Previous studies have included individuals with bipolar disorder and their benefit from VNS appears to be important also. Excluding these individuals appears unnecessary at this time, there is no evidence that they may behave differently in terms of complications or response rates.

As a treatment provider, long term member of patient advocacy groups, [PHI Redacted] I urge you to reconsider the study design to allow greater duration of treatment, consider response or other less stringent primary outcome category instead of remission, and include bipolar disorder patients,

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After many years working on the TRD registry trial, it is heartening to see some clear progress on making VNS available to patients with severe treatment resistant depression. I am however concerned about misperceptions of my paper in the American Journal of Psychiatry and how it is applied to the current recommendation for a randomized clinical trial. The cohort for the paper involves following patients over five years. Both the response and remission rates reported grow over time. While I would speculate in an RCT we would see separation of remission rates between an active and a sham VNS arm, I am not sure when that would take place. As my paper reported (and was cited in the proposed memo) the median time to remission in the registry for VNS patients was over four years vs. 12 months as a median time to response. It seems ethically questionable to subject severely depressed patients to sham treatment for perhaps a year or more to demonstrate adequate statistical separation by remission. The more usual bar of response seems more obtainable and more consistent with what we clinically view as a good outcome in chronic illness. Looking realistically at our potential subjects for a Medicare CED, we will use patients on Medicare due to disability for depression. How many depression disabled Medicare recipients ever go off disability (which would be remission)? The goal is improved quality of life not the absence of symptoms. When VNS is used for epilepsy is the goal remission from all seizures? No, nor should it be with depression.

Also the suggestion to not allow patients with atypical depression or bipolar depression is completely unfounded by my work and the work of many other investigators. We never excluded atypical depression and if anything I get better response rates for my bipolar depressed patients than my unipolar patients. In my article, I included the patient perspective from one of my bipolar depressed patients which highlights the excellent responses we can see in this population.

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Vagal Nerve stimulation
I am a practicing Board Certified Psychiatrist in Oregon. I have been practicing for 30 yrs. I had previously commented on why CMS should allow Medicare to cover V N S implantations, follow up, replacement of device for Treatment Resistant Depression. I would like CMS to reconsider the requirement of requiring an RCT study before considering VNS as a covered procedure for TRD.

I believe this requirement is going to place undue burden on those who experience TRD.

1. TRD is a leading cause of disability worldwide and in our country. Like most chronic diseases, TRD contributes to significant disease related burden, many end up experiencing other chronic medical co- morbidities and overall health outcome deteriorates and leads to high morbidity and mortality. TRD carries high risk for suicide and often have chronic suicidal ideas, thoughts and risk.

TRD is often the end result of delay in treatment and multiple failed treatment attempts with multiple medication trials. With limited access to ECT and general cultural barriers to using ECT in our country, I feel many patients end up quitting treatment all together or have repeated hospitalizations. Clinically many of my patients with TRD reach a point of severity where they have needed placement in state hospitals or long turn institutionalization in secure group homes, needing ongoing monitoring just to keep them safe.

TRD contributes to significant direct and Indirect costs. It cost roughly $35000 per person per month in Oregon’s state hospital and roughly $10,000 per person monthly in a secure group home. The indirect cost due to lost productivity and social impact is even higher

VNS is an FDA approved treatment modality for TRD. CMS asking for an additional RCT study and the study criteria required to prove its role before CMS would allow Medicare to approve is unethical and discriminatory. This is against the spirit of health care parity law, and is likely to deprive many patients with TRD when all else has failed. This is against the vision articulated by our President Trump when he signed into law the use of orphan drugs for terminal diseases! Yet CMS wants yet another RCT study even when FDA approved VNS for TRD. The end point; inclusion and exclusion criteria required by CMS will deprive many people suffering with TRD from the study and obtaining a much needed life saving Treatment. Many patients with TRD have chronic suicide risk, never reach remission and have significant disability. The suggested inclusion criteria ( absence of Bipolar depression, absence of suicide risk, needing remission, waiting one year as a Control group) in the sample will excludes many who would otherwise have been helped by VNS. Having to wait one year with ongoing TRD in the control arm without the risk of worsening is going to pose serious challenges. As many are likely to worsen, become suicidal and place their treating physician in an ethically conflicting situation of depriving TRD control group especially when it is FDA approved for TRD.

In Oregon study of such nature can only be undertaken in large university settings such as OHSU; Portland; Oregon. Most of our state is underserved, people live in Rural areas and have to travel large distances and our state has serious challenges to access care. This will pose undue burden in asking patients to travel to one city in our state to participate in an RCT study. I plead that CMS may in turn consider a Registry based study, pool large number of patients from all over the country so as to satisfy the efficacy, cost saved including direct and indirect costs, and other outcomes of VNS used forTRD. CMS may also consider studying the change in depression scores when VNS is used for patients for treatment resistant partial seizures where there is an indication and is currently approved.

I am particularly concerned about what happens to the patients who participate in the study and who will cover their care after the end of the study.

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I am a psychiatrist in private practice and on faculty at the Mayo Clinic School of Medicine in Arizona. I have treated numerous patients with TRD over the 26 years I have been in practice. I used VNS in 10 patients and would have treated more, except that Medicare withdrew funding, with private insurers following suit.

Of the 10 patients, who had failed nearly every treatment known, including ECT in some cases, 8 had a meaningful result and 5 achieved remission. Recently, a patient's VNS battery failed leading to relapse of his depression, including suicidal ideation. The battery was replaced, and the patient returned to remission in a short time.

VNS can take longer than other treatments to work. It is worth the wait, in my opinion, especially for patients who have little else to turn to after years of other failed treatments.

I would therefore urge CMS to approve the Proposed Decision Memo for VNS for TRD. It literally can save lives.

Thank you.

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I am very pleased that CMS has decided to pursue a coverage with evidence randomized clinical trial for vagus nerve stimulation (VNS) in Treatment Refractory Depression (TRD).

I am a Professor of Psychiatry at Washington University Department of Psychiatry in St. Louis and have been working in the area of VNS for TRD for the past 17 years. I have been intimately involved in both the clinical trials assessing efficacy for this treatment, as well as the scientific studies attempting to elucidate how this treatment works in TRD. Our sites in St. Louis (Washington University and St. Louis University) have implanted over 85 TRD patients with VNS.

I have had the good fortune to be a front row observer of the benefits of this therapy: VNS is effective in bringing about sustained antidepressant effects in a large subset of patients with TRD. In fact, there is no other therapy that can match the sustained benefits in the TRD population.

Based on my extensive experience, the currently proposed randomized clinical trial draft for VNS for TRD put forward by CMS has several significant limitations.

1) The choice of Remission as a "primary outcome" is not reasonable in the TRD population. I would recommend selection of "response" (at least 50% reduction in depressive symptoms from baseline) as the primary outcome, with measurement of "remission" as a secondary outcome.

My recommendation stems from several lines of evidence:

First, VNS targets the "highly resistant" end of the TRD spectrum, i.e., those depressed patients who are the "sickest of the sick". The FDA requirements for VNS in TRD includes the patient having failed 4 adequate dose-duration antidepressant trials. Further, antidepressant treatment studies looking at this severe version of TRD demonstrate that "remission" (i.e., near eradication of all depressive symptoms), is an exceedingly rare event. For example, Dunner et al. (Dunner et al., 2006, J Clin Psych) demonstrated that only 3.6% of severe TRD patients (identical to those eligible for VNS) achieved remission after one year of "treatment as usual". Hence, selection of remission as a primary outcome for a VNS for TRD trial is not reasonable, as it is a too low frequency outcome.

Second, all VNS TRD clinical trials to date demonstrated that a considerably larger percentage of TRD patients achieved and sustained response than remission. This response, in most instances, is life-changing (for example dropping a Hamilton Depression Rating Scale score from 36 to 18). In fact, recent research by our group in St. Louis (Conway et al., 2018, J Clin Psych) demonstrates that TRD patients receiving VNS for TRD experience clinically meaningful improvements in quality of life even at reductions in depression scores that are less than classically defined response (i.e., less than 50%). Hence, on average, the majority of those receiving "response" to VNS for TRD are achieving a clinically meaningful improvement in quality of life, which, we believe, is a realistic and desirable endpoint.

Finally, having dedicated my life to the study of TRD and its treatments, I believe TRD is a chronic modifiable medical condition that can usually be improved, but that "cure" (remission) is not a realistic goal. In this sense, it is similar to other medical conditions (e.g., congestive heart failure, renal failure, severe diabetes) in which a cure is not realistic; however, marked improvements in function are achievable.

2) The exclusion of TRD patients with bipolar illness. I recommend patients with TRD occurring in bipolar I and bipolar II should be included in this proposed RCT.

There are several reasons that I believe patients with bipolar disorder should be included.

First, the FDA indication for VNS for TRD does include both unipolar and bipolar disorders. Further, all of the existing VNS therapy TRD clinical trials conducted to date (including all of those cited by the decision memo in Section VII) have included a significant number of bipolar patients (20-25%), and these studies all demonstrate bipolar TRD patients have equivalent response and remission rates.

Additionally, studies support that the risk of suicide in bipolar depression approaches twice that of unipolar depression (Jamieson KR. 2000; J Clin Psych). Excluding these patients places them, who otherwise have lost hope in achieving an antidepressant response, at higher risk of the ultimate bad outcome (completed suicide).

Finally, the Proposed Decision Memo under the final design recommendation letter "l" states that the treatment (VNS for TRD) design should include provisions to insure that "signficant subpopulations of Medicare beneficiaries, especially typically underrepresented groups of patients, have access to this treatment", I believe that the BPAD disorder population is such a subpopulation and failure to include these patients in this trial will lead to their being unable to access this treatment for years to come. Further, the Proposed Decision memo further states (under recommendation letter "m") that a goal of the design would be to allow generalization of the findings; including BPAD patients would allow this.

Once again, I greatly appreciate all the work CMS has done in reviewing VNS for TRD and choosing to move forward with a RCT, and I hope that CMS reconsiders the above two modifications to the protocol.

Charles R. Conway, MD
Professor of Psychiatry and Director,
Washington University Center for the
Advancement of Research in Resistant
Mood and Affective Disorders (CARRMA)
Washington University School of Medicine
St. Louis, MO 63110

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Thank you for moving forward with this CED for VNS. TRD is an enormous issue which contributes to morbidity, disability and more options are essential. I am a board certified psychiatrist and sleep specialist. I am also the chief medical officer for Brainsway, (a deep TMS manufacturer) and I conduct clinical trials. I have been a PI on nine clinical trials. There are several comments I would like to make regarding the design of the current study.

VNS naturally is self selecting treatment and should only be offered to patients who have had chronic or very recurrent AND refractory depression even if they had non sustained responses to other treatments

Specifically, VNS should only be offered to patients who have failed or had intolerable side effects from ECT. (No patient will consider VNS without first trying ECT)

Having received experimental treatment treatment should not preclude them as long as it is not within a month of VNS implantation.

Presently you are excluding some patients unnecessarily: Patients with bipolar depression, history of psychosis, or atypical features. You should not be rigid with a specific amount of time in depressed state and you should not exclude patients who are suicidal unless they have a high imminent intent, after all these patients have limited options.

Looking at the long term outcome data from the Dr. Aaronson's recent study, these patients should also have a chance to have greater time being well even if they are suicidal.

For outcome you are setting the bar too high with remission: the primary outcome should be # weeks in response status in active versus sham and the secondary outcome can be # of weeks where the patient has greater than 20hours of work/school/household work. Remission can really be exploratory. Most of these patients are disabled, so you should not aim too high.

I would be glad to discuss this issue further.

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I provided VNS treatment for treatment resistant major depression early on. I had three patients who received VNS. One had no response. One had a partial response. One--perhaps the most severe--had a complete remission and has been in remission for over a decade. She has had two replacement devices that she paid for herself. She has returned to a normal life after many years of being nearly bed-ridden. While the number is patients is small, the positive impact on one of three patients has been wonderful.

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I am a clinician and researcher in the field of TRD and I have been conducting studies and clinical trials in depression using medications and devices for over 10 years. I follow clinically a large number of patients with severe TRD and I provide expert consultation for colleagues and patients.

I have two comments in regard to the proposed approval of VNS.
First, I profoundly disagree with the use of "remission". The use of “remission” in a population of patients with severe chronic unremitting depression is absolutely inappropriate as main outcome. One would not expect studies in patients with severe chronic back pain or severe migraine to achieve complete remission, or patients with severe treatment-refractory epilepsy to be completely seizure-free to determine the efficacy of a treatment. Similarly, in other chronic psychiatric disorders, the threshold to determine improvement is 30%, as one would not expect patients with OCD to become free of obsessions or patients with psychosis to be in complete remission. The "response" definition used for depression clinical trials is " 50% or more improvement in a symptom scale" and it is a remnant of clinical trials in the ‘60s’ and ‘70s when acute depression was treated in inpatient settings with tricyclics. Remission of symptoms may be a reasonable outcome for young patients with episodic illness, but it is NOT reasonable for the patients who are the appropriate candidates for VNS.

Moreover, after years of being severely ill, there are often consequences at the level of functioning (like being on disability or in financial distress), social (divorce, loss of friendships, isolation) which are not reversed by improvement in symptoms, at least not within the timeframe of a clinical trial, and continue to affect self-esteem, expectations, sense of guilt regardless of symptom severity.

The other major issue I would like to comment on is the exclusion of patients with Bipolar depression from accessing VNS, as Bipolar depression represents a substantial proportion of the patients with TRD.

Bipolar depression is often chronic and more difficult to treat, and the number of medications that have shown effect in Bipolar depression is extremely limited, therefore VNS could make a substantial impact on the burden of disease for many patients.

There is no clear justification for excluding patients with Bipolar depression from the study. VNS has shown to be equally well tolerated, and the response rate appeared to be the same.

I personally follow many patients with Bipolar depression who were implanted over 10 years ago and are doing amazingly well. Patients with Bipolar depression should be required to be on a mood stabilizer and monitored for the onset of rapid cycling or hypomania symptoms, but other than that I would strongly recommend to include them in the study and to use stratified randomization.

Thank you for allowing the opportunity to provide comments.

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I work in the front line of clinical medicine. As soon as VNS was FDA approved, one of my patients with very severe treatment-resistant depression underwent adjunctive implantation. It took over 1 year to stop her suicidal ideation. Whereas I was seeing her weekly to every 2 weeks because of suicide risk, I have since been seeing her every 4 months. She is now about 17 years on VNS. At around 9 years, her battery ran out and over several months she relapsed. Upon getting a new device, she remitted after about 3-5 months. The patient is very thankful this treatment option was available. She had only brief responses to several ECT trials. Nothing maintained her fairly well.

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I appreciate that CMS will pay for a small amount of devices for a study but I suggest CMS take this one step further. The US Govt Agency FDA approved this device. CMS as a Govt Agency of the US should approve VNS for TRD whole scale. There is no other TRD treatment in the literature that can deliver a 1/6 remission rate that lasts 2+ years. If CMS can show another, better studied treatment exists, I would like to see it. Until that point I hope CMS actually increases coverage greater than what is being proposed in this letter. The last decade of essentially no VNS for TRD has been harmful and makes no sense vis a vis the two federal agencies being at odds with each other.

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I am director of the Division of Neurotherapeutics in the Department of Psychiatry at Massachusetts General Hospital and an Associate Professor of Psychiatry at Harvard Medical School. The Division of Neurotherapeutics encompasses all surgical and/or device-related treatments for psychiatric illness and includes electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), ablative limbic system procedures (e.g., anterior cingulotomy), and deep brain stimulation (DBS). WE have several dozen patients treated with VNS for treatment resistant depression (TRD) and I served as an investigator and co-author for the D23 VNS for TRD Registry study.

I am surprised that CMS did not provide full coverage for VNS for appropriate patients with TRD. The published D23 Registry study is, to my knowledge, the largest clinical trial for TRD ever published (n=795 patients) and the results were convincing. Patients with TRD who received adjunctive VNS demonstrated demonstrably higher response and remission rates compared to patients with TRD who received treatment as usual (TAU). While the clinical trial that CMS proposes will provide VNS therapy to some patients with TRD, I believe this limited access is unwarranted and unnecessary given the clear results of the D23 Registry study. Requiring an additional clinical trial feels like kicking the can down the road regarding a final decision regarding CMS coverage for all appropriate patients with TRD. I strongly recommend that CMS reconsider its determination and provide such coverage without the need for yet another clinical trial.

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I have had 8 treatment resistant patients get implanted with VNS and 7 of them improved, some tremendously. I had many other patients turned away by insurers who declined to approve this intervention on the basis that their interpretation of CMS's position was that it still was experimental. These folks were the sickest of the sick, having failed almost all available meds and ECT before being implanted. Their response was remarkable. As time passed and batteries died, benefit was lost as they had trouble getting approval for new batteries and depression returned. I therefore strongly urge CMS to clearly support this valuable and underutilized treatment option to aid our refractory patients.

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