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1 Response to Vagus Nerve Stimulation (VNS) Therapy Treatment-Resistant Depression (TRD) Indication Not Approvable Letter from the United States Food and Drug Administration (FDA), Dated August 11, 2004 Prepared By: Richard L. Rudolph, MD, Vice President, Clinical and Medical Affairs and Chief Medical Officer, Cyberonics, Inc. The following response addresses each of the safety and effectiveness issues the FDA identified in the August 11, 2004 not approvable letter sent in response to Cyberonics Premarket Approval Application Supplement (PMA-S) seeking a TRD indication for the VNS Therapy System (P970003/S50). Each issue is repeated below in italicized type followed by Cyberonics response. Each response shows where in the PMA-S or subsequent submissions the supporting documentation for the response can be located. SAFETY There are safety concerns associated with the use of your device, including known risks related to implantation or stimulation, including serious adverse events such as asystole/bradycardia and vocal cord paralysis. The safety risks associated with VNS Therapy, including asystole/bradycardia and vocal cord paralysis, are modest, well-characterized, and adequately described in the FDA-approved product labeling for the VNS Therapy System. The safety data collected during the TRD indication clinical studies are consistent with the information in the approved labeling (ie, the TRD safety data do not alter the established safety profile of VNS Therapy in any significant way). The overall VNS Therapy safety database now derives from approximately 30,000 Page 1 of 18 Volume 01 Page 1

2 treated patients and over 56,000 patient-years of experience. Such a large database provides a highly reliable safety profile for VNS Therapy. The risk of asystole/bradycardia is rare (occurring in about 1 to 2 patients per 1000 implants) and is generally associated with performing the initial lead test during the implant procedure in the operating room (page of the October 2003 PMA-S submission). Cardiac events reported post-operatively have been generally associated with the patient s pre-existing pre-implant condition. The approved labeling for VNS Therapy provides appropriate instructions and precautions to take should this event occur in the operating room. Vocal cord paralysis is an uncommon event occurring at a frequency of about one in 100 surgeries (5 of 454 subjects in epilepsy studies and 3 of 342 subjects in depression studies; pages and of the October 2003 PMA-S submission; the rates reported during commercial epilepsy use are lower--less than 0.5% [page ]). In most cases this condition is only temporary and resolves with time. Since vocal cord paralysis is typically unilateral, over time the contralateral vocal cord will generally compensate for the paralyzed vocal cord. During its formal presentation, Cyberonics presented these two specific known risks of VNS Therapy (asystole/bradycardia and vocal cord paralysis) to the June 15, 2004 Neurological Devices Panel. The FDA safety reviewer did not express any concerns about these risks during his panel presentation. The panel members did not express any concern regarding either of these two risks or the safety profile of VNS Therapy in general. To the contrary, panel members indicated that adequate safety had been demonstrated for Page 2 of 18 Volume 01 Page 2

3 VNS Therapy (June 15, 2004 Neurological Devices Panel Transcript, pages 358 to 363). In addition to known safety concerns, worsening depression was reported as a serious adverse event during the long-term D02 study. Without comparison to a control population, we are unable to determine whether your device places patients at increased risk for this event. The statement is misleading and incorrect. Cyberonics evaluated reports of worsening depression among subjects receiving VNS Therapy by comparing the frequency of those reports to the frequency of such events among subjects from multiple control populations. These analyses demonstrated that episodes of worsening depression among subjects receiving VNS Therapy are not due to VNS Therapy. Rather, such episodes are most likely due to the subjects underlying depressive illness. The most important analysis examining the relationship of VNS Therapy to episodes of worsening depression was a comparison of the incidence of worsening depression among subjects receiving active VNS Therapy or sham stimulation during the acute phase of the D- 02 study. In this randomized controlled comparison, the incidence of worsening depression was slightly greater in the control group (6% [7/116]) than it was in the active VNS Therapy group (4% [5/119]); one of the episodes in the active VNS Therapy group actually occurred prior to the initiation of stimulation, so the true incidence during acute VNS Therapy was only 3%, half that in the control group (October 27, 2003 PMA-S, p ; March 17, 2003 Deficiency Letter Response, pp ). Second, the availability of information on hospitalizations for psychiatric illness (a reasonable proxy for serious adverse events of worsening depression) in the D-04 subjects permitted a comparison of occurrences of worsening depression between the D-02 and D-04 subjects during 12 months of observation. Calculated on a per patient-year basis, the rates of Page 3 of 18 Volume 01 Page 3

4 worsening depression among the D-02 and D-04 subjects were essentially the same: and respectively (March 17, 2003, Deficiency Letter Response, p 12). In the pre-implant phase of the D-02 study (after informed consent was signed but prior to implantation) there were two events of suicide attempts and three events of worsening of depression (October 27, 2003 PMA-S, p ). In the D-02 long-term study, (data through October 10, 2002) there were 62 events of worsening depression in 31 subjects; about half of the subjects (15 subjects) had a single episode of this event, and the other subjects had multiple events of worsening depression (October 27, 2003 PMA-S, p ; January 31, day meeting submission, pp. 9-10). The large number of serious depression-related events during the relatively short pre-implant phase of the D-02 study, as well as the tendency for some study subjects to have multiple recurrent events of worsening depression, are indicative of a very severely ill depressed population. These findings are also more consistent with a conclusion that the subjects underlying depressive illness, not VNS Therapy, is the cause of the episodes of worsening depression observed in the VNS Therapy study subjects. Reports of worsening depression among the D-02 subjects generally declined over 24 months of observation, a pattern that suggests increasing effectiveness of VNS Therapy over time. (Note that this analysis incorporates 24-month data included in this PMA-S Amendment and was not available at the time of the PMA-S submission in October 2003.) Additionally, the percentages of subjects who had baseline scores of 0 or 1 on the depressed mood item of the Hamilton Rating Scale for Depression and who showed an increase in that score (indicative of an increase in depressed mood) to 3 or 4 at the 12-month observation were compared for the D-02 group, the combined D-01, D-02, D-03 population, and the D-04 group. The rates of worsening of mood thus defined were essentially the same for the three groups: 24% (5/21), 26% (6/23), and 25% (1/4) respectively (March 17, 2004 Deficiency Letter Response, Table 2.7, p. 23). Page 4 of 18 Volume 01 Page 4

5 Thus the systematically collected safety data described above show that the rate of worsening depression is no greater among subjects receiving adjunctive VNS therapy than it is among subjects receiving placebo (sham VNS), and it is similar to the rate among subjects receiving antidepressant drugs without VNS therapy. EFFECTIVENESS A chief limitation of the long-term pivotal D02 clinical study, observational control D04 study comparative analysis was that the data were not derived from a randomized subject data set, but rather a comparison of outcomes from an investigational device study and observational control study. While it is true that the long-term D-02/D-04 comparison utilized a non-randomized observational control, it is also true that many of the subsequent potential limitations identified by the FDA do not necessarily follow or are simply incorrect. The results from the D-02 and D-04 studies provide strong evidence that adjunctive VNS Therapy is associated with greater improvement in depression in patients with TRD than is standard-of-care treatment (no VNS); none of the possible limitations of the data set, when thoroughly explored, appear to have a reasonable chance of accounting for the differential outcomes observed between these studies, particularly when considering the treatment-resistant nature of the study populations. Additionally when one understands the natural history of depressed patients as treatment-resistant as those included in the D-01 and D-02 studies, one cannot reasonably attribute the durability of the 3- and 12-month outcomes in the D-01 and D-02 subjects followed for up to 24 months to anything other than the effectiveness of VNS Therapy. Page 5 of 18 Volume 01 Page 5

6 As a result, our ability to make meaningful conclusions from the data you provided was affected by the following limitations: Failure of the randomized controlled pivotal D02 acute study to reach its primary efficacy endpoint. While it is true that the acute D-02 study did not show statistical significance in the primary analysis, it is also true that the acute study did show a statistically significant separation on a key secondary analysis (found to be persuasive by the Panel s Clinical Reviewer; June 15, 2004 Neurological Devices Panel Transcript, p. 431) and several additional secondary analyses. Furthermore, there was numerical superiority favoring VNS Therapy in all the analyses. Of course, this is not likely to occur by chance alone. Thus, although the results of the acute D-02 study cannot by themselves prove the effectiveness of adjunctive VNS Therapy, they do provide significant supportive evidence of its long-term effectiveness. In the analyses of the acute phase D-02 study results, the Inventory of Depressive Symptomatology Self Report (IDS-SR) response rates showed a statistically significant advantage for VNS Therapy over sham-control: 17% response vs. 7% response (p=0.032) using the last observation carried forward (LOCF) method. Additionally, a repeated measures linear regression analysis of IDS-SR scores showed a trend advantage for VNS Therapy at 12-weeks (p=0.053) (October 27, 2003 PMA-S, p ). There was a statistically significant difference in the average IDS-SR scores between the treatment and sham-control groups at 5 weeks (p=0.035) and 8 weeks (p=0.010). These observed treatment differences reflect the accumulated treatment differences at each of those time points (overall difference p = 0.08) (October 27, 2003 PMA-S, p ). Additionally, although not discussed in the PMA-S summary report but provided in the analysis tables, the IDS-SR percent change from the recovery period for the treatment group showed a statistically significant change (p=0.017) while the control group did not (0.173) Page 6 of 18 Volume 01 Page 6

7 (October 27, 2003 PMA-S, p ), and the HRSD repeated measures linear regression analysis showed similar differences in the average scores between treatment and shamcontrol at 5-weeks (p=0.052) and 8-weeks (p=0.051) as seen with the IDS-SR (October 27, 2003 PMA-S, p ). Potential bias of a non-randomized data set in the long-term D02, D04 comparative analysis that could reasonably affect the clinical outcomes reported in your study. A non-randomized data set has more potential for producing imbalances between study groups in baseline characteristics (covariates) than does a randomized data set. The D-02 and D-04 subjects, however, appear to be essentially identical as regards observed prognostically important covariates. The use of a propensity adjustment strategy, a wellaccepted approach to address potential imbalances in baseline covariates in observational data sets, was incorporated into the primary efficacy analysis and further demonstrated that differences in measured baseline covariates did not account for the superior outcome in the subjects who received adjunctive VNS Therapy. Of the 18 baseline patient and disease characteristics for which data were collected (these included most, if not all, known prognostic factors for response to antidepressant therapy), only three characteristics were shown to be statistically significantly different between the D-02 and D-04 evaluable populations used for the efficacy analyses. One of these, ethnic origin, is extremely unlikely to constitute a clinically meaningful difference as Caucasians constituted at least 90% of both the D-02 and D-04 groups. The other two statistically significant differences were the percentages of subjects who had electroconvulsive therapy (higher in the D-02 group), either lifetime or in the current depressive episode prior to study enrollment, and the distribution of the number of lifetime episodes of depression (the D-04 group had a higher percentage of subjects with Page 7 of 18 Volume 01 Page 7

8 more than 10 lifetime episodes). These differences probably offset each other as regards their contribution, if any, to the level of treatment resistance of the subjects (October 27, 2003 PMA-S, pp ). Importantly, the sole predictor of response to VNS therapy in the D-01 feasibility study (and an important predictor of relapse in electroconvulsive therapy studies), the number of failed adequate antidepressant treatments in the current depressive episode, was represented equally in the D-02 and D-04 groups: each group had a mean of 3.5 adequate failed antidepressant treatments in the current episode prior to enrollment (October 27, 2003 PMA-S, p ). The propensity score calculated from the measured baseline covariates did not contribute to the statistical significance observed in the primary effectiveness analysis, as demonstrated by a non-significant p value of for the effect of the propensity score (October 27, 2003 PMA-S, pp ). Of further note, the FDA statistician acknowledged that the use of the propensity adjustment strategy was both acceptable and performed well to address the potential bias of baseline covariate imbalance between the D-02 and D-04 groups. Potential bias of unmeasured patient variables in the long-term D02, D04 comparative analysis that could reasonably affect the clinical outcomes reported in your study. Unmeasured patient variables (covariates) can be a source of potential bias in both non-randomized and randomized trial designs. In the specific case of the D-02/D-04 comparative analysis, there are several reasons why it is highly unlikely that unmeasured covariates affected the differential outcomes. It is a reasonable assumption that the D-02 and D-04 groups did not differ significantly on unmeasured covariates because the measured baseline covariates included most (if not all) Page 8 of 18 Volume 01 Page 8

9 known prognostic factors, with few exceptions the differences between the D-02 and D-04 subjects in the measured covariates were negligible (suggesting the same would be the case for unmeasured covariates), and the D-02 and D-04 groups were both quite large (205 and 124 subjects respectively), providing a high degree of assurance that any unobserved covariates would likely be equally distributed between the D-02 and D-04 groups, or would be so rare as to be of no consequence in their impact on the statistical significance of the results. The patient and disease covariates that were not recorded at baseline, such as family predisposition for affective disorder, have not been demonstrated to be significant predictors of treatment response in studies of antidepressant therapy. Several types of sensitivity analyses demonstrated that the statistical significance of the D- 02/D-04 difference observed in the primary effectiveness analysis was not sensitive to the introduction of a hypothetical or potential unmeasured covariate. To have had an appreciable effect, an unmeasured covariate would need to be have been markedly unbalanced between the two groups (unlikely since the groups were relatively large and since they matched up well in almost every other respect), would have had to occur in a large percentage of subjects (or else there would not have been a sufficient pull to make a difference in the outcome measures), and would have had to lack correlation with each of the 18 variables that were assessed and found not to affect outcome (highly unlikely). Given the extremely low likelihood of meeting these three conditions, it is virtually impossible that any relevant covariate that was not already measured would have had a significant impact on outcome differences between the two studies. Additionally when actual unbalanced variables were added to the primary effectiveness repeated measures model as a test of sensitivity, the p- value did not change (new data included in this PMA-S Amendment). Page 9 of 18 Volume 01 Page 9

10 Potential bias of unmasked ratings in the long-term D02, D04 comparative analysis that could reasonably affect the clinical outcomes reported in your study. Potential bias of research centers having more interest in the treatment study (the pivotal D02 study) rather than the naturalistic, observational control study (the D04 control study) that could reasonably affect the clinical outcomes reported in your study. Potential bias of patient expectation of participating in an investigational study for a new therapy versus the expectation of participating in an observational, control study that could reasonably affect the clinical outcomes reported in your study. The potential biases from unmasked ratings, research centers having more interest in the D-02 study than in the D-04 study, and patient expectations being different depending on which study the patient enrolled in can be summarized as a concern that there was a systematic bias favoring D-02 over D-04. Though theoretically possible, there is no evidence in the data to support this notion, no reason to believe that the outcome differences induced by such potential biases would grow stronger over time, and no basis in the published literature to expect that the improvements from depression that occurred in the highly treatment-resistant D-01 and D-02 subjects would be sustained (as was observed). Such potential biases are thought to contribute to the so-called placebo response (non-specific response), which is addressed below. Additionally, the D-05 study results and the published literature on electroconvulsive therapy (ECT) provide a further basis to conclude that the potential biases cited above are not operative in the D-02/D-04 comparison. Study D-05 was a videotaped assessment to determine the interrater reliability of the D-02 raters. This study involved sending videotapes of the HRSD rating interviews to a third party rater (Columbia University) for evaluation. The third party rater was blinded as to the treatment assignment and length of study participation of the videotaped depressed subjects. Thus even though the site rater would have known that a D-02 subject was receiving VNS Page 10 of 18 Volume 01 Page 10

11 Therapy during the long-term D-02 study, the third party rater, being blinded to length of study participation of the videotaped subject, would not. Since there was a very high correlation (correlation coefficient of 0.94) between the third party rater and the site raters as to the HRSD scores (March 17, 2004 Deficiency Letter Response, p. 26), one can reasonably discount the possibility of bias from unmasked ratings. In ECT recipients (who by nature are often treatment-resistant, but generally less so than were the D-02 subjects), patient expectations do not bias treatment outcome. This is demonstrated by the finding that patients receiving low dose unilateral ECT have much lower response rates than do patients receiving high dose unilateral ECT, even though the difference in the dose of therapy is imperceptible to the patients (Sackeim HA, Prudic J, Devanand DP, et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med. 1993; 328:839-46). Inability to distinguish the improvement attributable to VNS therapy from the improvement attributable to a placebo response in the long-term D02, D04 comparative analysis. Quite to the contrary of the statement above, a comparison of the long-term D-02 study outcomes with the long-term D-04 study outcomes--plus a comparison of the acute phase D-02 outcomes in subjects receiving active or sham VNS and the durability of the improvements observed in the highly treatment-resistant D-01 and D-02 subjects over 12 to 24 months--provide compelling evidence to attribute the D-02 and D-01 subjects improvement to VNS Therapy and to distinguish that improvement from a placebo response. Such a conclusion becomes even more apparent when one considers the nature of placebo response and the naturalistic history of the course of illness in patients with TRD. The long-term improvements observed in the D-02 subjects were consistently statistically significantly superior to the long-term improvements observed in the D-04 subjects (October Page 11 of 18 Volume 01 Page 11

12 27, 2003 PMA-S, pp ). This is a remarkable finding because meta-analyses of antidepressant drug trials that compare two active treatments show negligible differences between the treatments (U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. Depression in Primary Care: Volume 2. Treatment of Major Depression. Clinical Practice Guideline Number ). In the D-02 acute study, there was a consistent numerical trend favoring greater improvement in subjects treated with active VNS Therapy than in subjects treated with sham VNS (placebo); the difference reached statistical significance on several secondary outcomes (October 27, 2003 PMA-S, pp ). Approximately 60% to 70% of the D-01 and D and 12-month responders continued to maintain their response at the 12- and 24-month follow-up observations. This high rate of sustained response in patients with TRD is without precedent in the published literature (see following bullets) and by itself constitutes strong evidence that the improvements observed in the D-01 and D-02 subjects are not attributable to a placebo response (new data included in this PMA-S Amendment). Even in non-treatment-resistant depressed patients, placebo response is well established to be a phenomenon that occurs early in the course of treatment, but does not persist as have the responses observed in the VNS Therapy-treated subjects (Quitkin FM, Rabkin JD, Markowitz JM, et al. Use of pattern analysis to identify true drug response. A Replication. Arch Gen Psychiatry. 1987; 44: ). In TRD, placebo response is inherently much lower (approximately 10%) than it is in nontreatment-resistant depression (Thase ME, Rush AJ. Treatment-Resistant Depression. Psychopharmacology: The Fourth Generation of Progress, edited by Floyd E. Bloom and David J. Kupfer. 1995; ). By contrast, 12-month response rates during adjunctive VNS Therapy in the D-02 study ranged from 22% to 37% (depending on which rating scale was used) (October 27, 2003 PMA-S, pp ). Page 12 of 18 Volume 01 Page 12

13 Although there is a dearth of published literature reporting long-term response and sustained response rates in patients receiving active treatment for TRD, the ECT literature provides a useful benchmark because many patients who receive ECT are treatment-resistant. This literature shows that patients who respond to ECT but have a prior history of resistance to antidepressant medication (even those with a history of a lesser level of resistance than the D- 02 and D-01 subjects) are unlikely to sustain their response when given antidepressant drugs and/or ECT as maintenance treatment. Less than a third of medication-resistant depressed patients maintain their response, despite continued active treatment, during the 12 months following a response to ECT (Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry. 2000; 57: ). By contrast, approximately two thirds of adjunctive VNS Therapy responders maintain their response during 12 to 24 months of continued VNS Therapy. Inability to distinguish the improvement attributable to VNS therapy from the improvement attributable to concomitant antidepressant treatments in the long-term D02, D04 comparative analysis. Quite to the contrary of the statement above, the results of multiple analyses of concomitant antidepressant treatment use by the D-02 and D-04 subjects allow a reliable conclusion that the superior long-term outcomes observed in the D-02 subjects are attributable to VNS Therapy and not to more intensive exposure to concomitant antidepressant therapy than that experienced by the D-04 subjects. Concomitant antidepressant drug use was higher in D-02 subjects who were non-responders and D-04 subjects overall than it was in the D-02 subjects who achieved a response. During the 12 months of observation, 77% of the D-02 non-responders and 81% of all D-04 subjects Page 13 of 18 Volume 01 Page 13

14 either added a new antidepressant treatment or increased an existing antidepressant dose by an antidepressant resistance rating (ARR) level of one or more. By contrast, only 56% of the D-02 subjects who were responders to VNS therapy either added a new antidepressant treatment or increased an existing antidepressant dose by an ARR level of one or more (p < 0.01 for comparison with D-02 non-responders and p < for comparison with D-04 subjects) (October 27, 2003 PMA-S, pp ). Twice as many D-02 responders (44%) had no ARR changes or removed or decreased medications by at least one ARR level or were not taking medications as compared to nonresponders (23%) (October 27, 2003 PMA-S, p ). Additionally, those D-02 subjects who did not have a significant increase in their concomitant antidepressant treatment (ie, an increase in dose of an existing antidepressant treatment or the addition of a new antidepressant treatment) had a 51% response rate versus 23% for those who did have a significant increase in concomitant antidepressant treatment (new data included in this PMA-S Amendment). These findings strongly support the conclusion that the VNS therapy responders derived their benefit from VNS therapy (or an augmentation effect of VNS therapy), rather than from the concomitant antidepressant treatments. Analyses of treatment intensity and use of specific treatments (eg, ECT, olanzepine) did not show notable differences between the D-02 and D-04 groups (October 27, 2003 PMA-S, p ). Additionally, a series of sensitivity analyses on the primary outcome analysis (a repeated measures linear regression analysis comparing the IDS-SR scores of the D-02 subjects with those of the D-04 subjects) using various censoring methods to exclude any possibility of benefit from a concomitant treatment provide further support for the conclusion that the superior long-term outcomes observed in the D-02 subjects are attributable to VNS Therapy and not to more intensive exposure to concomitant antidepressant therapy than that Page 14 of 18 Volume 01 Page 14

15 experienced by the D-04 subjects. Several censoring methodologies were used. For each methodology, the result was the same: the D-02 subjects improved more than did the D-04 subjects. In the first methodology, only those D-02 subjects scores recorded prior to the addition of an antidepressant (drug or ECT) treatment or an increase in an existing treatment by an ARR level of one or more were used in the analysis; the D-04 subjects scores were not censored. The result of this analysis, like the uncensored comparison of D-02 scores with D- 04 scores, yielded a statistically significant difference favoring VNS Therapy (p < 0.001). In the second methodology, a D-02 subject s scores were censored as described above, but then the subject s last IDS-SR score before the concomitant antidepressant treatment change was used for subsequent assessment points (ie, a last-observation-carried-forward approach); D- 04 subjects only had their scores censored if the antidepressant treatment addition or increase occurred during the first 3 months of treatment (to more closely match the D-02 subjects who were not permitted to have such changes during the first 3 months of the study). Again the result of this analysis yielded a statistically significant difference favoring VNS Therapy (p < 0.001) (new data included in this PMA-S Amendment). Only the harshest censoring methodology, which employed an asymmetric last-observationcarried-forward type approach (ie, D-02 but not D-04 results were censored), did not reach statistical significance; even this analysis only barely missed statistical significance (p=0.052)--despite having the effect of truncating the benefit of VNS Therapy in the D-02 subjects to a mean of 7 of the 12 months of the study (October 27, 2003 PMA-S, pp ). The results of the various censored analyses provide very persuasive evidence that the superior D-02 outcomes are not attributable to more intensive exposure to concomitant antidepressant therapy in D-02 subjects than that experienced by the D-04 subjects because these analyses have the effect of removing all therapeutic contribution from adding or Page 15 of 18 Volume 01 Page 15

16 increasing concomitant antidepressant treatments. Thus one is left with VNS Therapy as the explanation for why the D-02 subjects improved more than did the D-04 subjects. In ECT studies, duration of current episode and medication resistance are predictors of ECT response and long-term relapse during continuation treatment. The strength of continuation antidepressant medication regimens has been reported to be unrelated to the risk of relapse. These observations provide additional rationale to conclude that in the highly resistant and chronically ill D-01 and D-02 subjects, VNS Therapy--not the concomitant medications--are responsible for the observed sustained improvements. Because of all of the issues identified above, we do not believe the submitted clinical data are sufficient to demonstrate safety and effectiveness of your device. You should therefore provide clinical data from a new, scientifically sound, randomized, controlled study, which addresses concomitant treatment use and includes adequate safety assessments in both the treatment and control group. As described in the responses above, the previously submitted data supplemented by the additional data and analyses submitted in this PMA-S amendment demonstrate the safety and effectiveness of VNS Therapy for the proposed TRD indication consistent with the standard described in 21 CFR and the least burdensome provisions of the FDA Modernization Act of Moreover, owing to the inherent limitations of studying an implantable device-based therapy such as the VNS Therapy System in a long-term randomized control trial for a disorder such as TRD, the incremental level of confidence that would likely be derived from the results of such a study is rather small. Accordingly, and considering the consequent delay in making VNS Therapy available to the TRD Page 16 of 18 Volume 01 Page 16

17 population, to require a new trial would be inconsistent with the least burdensome provisions of the FDA Modernization Act of The D-02 acute trial results strongly suggest that a 3-month randomized controlled treatment phase is inadequate to demonstrate a statistically significant difference between VNS Therapy and a sham control condition in subjects with TRD absent an extremely large (and therefore impractical) sample size. This is probably explained by the nature of these patients underlying depressive illness: the profound brain alterations associated with persistent and unresponsive depression require prolonged exposure to an effective therapy to fully respond. A randomized controlled trial utilizing a sham treatment for periods longer than 3 to 4 months would be ethically controversial at best and therefore probably infeasible at many investigational sites (Dr. John Rush; June 15, 2004 Neurological Devices Panel Transcript, p 206). A randomized controlled trial utilizing as an active control one, or even a choice of one of two, standard agents as monotherapy or as an add-on to existing stable antidepressant regimens is infeasible from a practical research perspective. The TRD subjects studied in the VNS Therapy TRD indication clinical development program have failed so many prior treatments that it would be virtually impossible to recruit over a reasonable time period an adequately sized study population who would be eligible to receive the control treatment. One design for a new trial that is feasible would be to replicate the D-02/D-04 comparison as a randomized control trial. Such a study, however, would be incapable of addressing five of the eight limitations cited by the FDA in the not approvable letter of August 11, 2004 to any greater extent than does the D-02/D-04 comparison submitted in the PMA-S. Additionally, conducting such a trial would delay availability of VNS Therapy for TRD population for at least 3 to 4 years. Page 17 of 18 Volume 01 Page 17

18 Specifically, a randomized controlled replication of the D-02/D-04 comparison would not fully address: 1) the failure of the D-02 acute study to reach statistical significance on its primary efficacy endpoint, 2) the potential bias of unmeasured patient variables (because imbalances in unmeasured variables are also possible in the setting of a randomized trial), 3) the potential bias of unmasked ratings (because the adverse effects of VNS, especially the occurrence of voice alteration in a substantial proportion of patients, preclude absolute blinding), 4) the inability to distinguish improvement attributable to VNS Therapy from improvement attributable to a placebo response, 5) the inability to distinguish the improvement attributable to VNS Therapy from improvement attributable to concomitant antidepressant treatments (because study subjects would still be allowed access to a large variety of concomitant antidepressant treatments making ascertainment that the frequency and intensity of that concomitant treatment was identical in both treatment groups no more certain than it is in the D-02/D-04 comparison submitted in the PMA-S.) Page 18 of 18 Volume 01 Page 18