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U.S. Department of Health and Human Services

Post-Approval Studies (PAS)

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The FDA has the authority to require sponsors to perform a post-approval study (or studies) at the time of approval of a premarket approval (PMA), humanitarian device exemption (HDE), or product development protocol (PDP) application. Post-approval studies can provide patients, health care professionals, the device industry, the FDA and other stakeholders information on the continued safety and effectiveness (or continued probable benefit, in the case of an HDE) of approved medical devices. This database allows you to search Post-Approval Study information by applicant or device information.

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OSB Lead-Registry Study

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Study Status Completed
Application Number P970003 S050/ PAS001
Date Current Protocol Accepted 06/04/2015
Study Name OSB Lead-Registry Study
General Study Protocol Parameters
Study Design Prospective Cohort Study
Data Source Sponsor Registry
Comparison Group Concurrent Control
Analysis Type Analytical
Study Population Transit. Adolescent B (as adults) : 18-21 yrs, Adult: >21
Detailed Study Protocol Parameters
Study Design Description This is a 5-year, prospective, observational, multi-center

patient outcome registry to follow the clinical course and outcome of patients with treatment-resistant depression (TRD) who are currently in a major depressive episode (MDE) treated with and without VNS Therapy. The study is a new enrollment study.

Study Population Description The registry will enroll a minimum of 500 Treatment-Resistant Depression (TRD) patients treated with adjunctive VNS Therapy and a minimum of 300 TRD patients who are not treated with VNS Therapy.
Sample Size 500 TRD patients treated with adjunctive VNS Therapy and a minimum of 300 TRD patients who are not treated with VNS Therapy.

Data Collection Primary Endpoint

Response based on MADRS Assessment: Defined as ¡Ý 50% improvement from baseline in Montgomery Asberg Depression Rating Scale (MADRS) score at visit month assessment post-baseline across the 60 months of follow-up.

Secondary Endpoints

Secondary endpoints are separated into two groups: Group 1 includes clinically important prospectively defined endpoints that if found statistically significant (P < 0.05) will be submitted for consideration for label claim. Group 2 will include other supportive secondary endpoints.

Group 1: Secondary Endpoints for Label Claim:

(a) Response based on Clinical Global Impression (CGI): The Clinical Global Impressions is a clinicianrated scale used to assess the level of severity and improvement in depressive symptoms over time. For the analysis, a response is defined as achievement of CGI rating ¡°1¡± or ¡°2¡± (¡°Very much improved¡± or ¡°Much improved¡±) at visit month assessment post-baseline.

(b) Duration (or maintenance) of response based on MADRS: Defined as the difference between the first recorded date post-baseline that response is achieved (MADRS ¡Ý 50%) and the first date at which maintenance of the MADRS reduction decreases to 40% or less. Sackeim et al. (2007) suggested using a criterion of maintenance of response at follow-up visit months assessments post-response to

40% in order to avoid characterizing a minor decrease (e.g., from 51% to 49%) as a loss of benefit. Only a subpopulation that achieved response will be included in the summary.

(c) Remission based on MADRS: Defined as MADRS total score ¡Ü9 at visit month assessment postbaseline.

(d) Duration of remission based on MADRS: Defined as the recorded post-baseline date of first recurrence/relapse (¡Ý 20 MADRS score) minus the recorded date of first achieved remission (MADRS

score ¡Ü 9). Only a subpopulation that achieved remission will be included in the summary.

Group 2: Supportive Exploratory Secondary Endpoints:

(a) Response based on Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR)

(b) Remission based on SLICE-C Psychiatric Status Rating and QIDS-SR.

(c) Recurrence/Relapse

(d) Suicidality

(e) Predictors of suicide attempts and suicidal ideation

(f) Quality of Life, Health Outcomes and Depression


(g) Safety Endpoints: (i) Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER); and (ii) MDR reportable events on VNS treated patients.

Follow-up Visits and Length of Follow-up All of the patients are planned to be followed for 60 months after enrollment. Visits include a screening and a baseline visit, and follow up visits at 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after baseline.
Interim or Final Data Summary
Interim Safety Information The "Frequency, Intensity, and Burden of Side Effects Rating" (FIBSR) is a 3-item self-report scale that assesses frequency, intensity, and impairment of the side effects caused by antidepressant medications and is completed by the patient at each visit. A total of 581 patients answered the FIBSR at baseline. Of these, 320 were VNS patients and 261 non-VNS patients. Baseline percentages of patients exhibiting no side effects (frequency and intensity) or no impairment were higher in the non-VNS group. The percentages of patients with no side effects relative to frequency, intensity, and impairment were higher for the non-VNS patients excluding the 24 month time point where the percentage of the VNS group with no side effects related to frequency, intensity and impairment were higher than non-VNS group. An assessment of suicidality is completed at each visit by both the registry site and the central rater group and a determination made as to whether the patient has made a suicidal gesture or attempt since the last visit. Baseline captures the history of attempts or gestures prior to entering the study. This assessment captures the number of gestures or attempts, the intent of the gesture or attempt, and the medical threat of the gesture or attempt. A total of 572 patients had an assessment of suicidality at baseline. Of these, 313 patients were in the VNS group and 259 in the non-VNS group. The percentages of patients reporting a gesture or attempt as recorded by either the central rater group or the registry sites at the 3 24 month follow-up visits are summarized below. In the non-VNS group, gestures or attempts were relatively stable for visits 3 and 6 months, but exhibited a modest increase at 9, 12 and 18 month visits; the VNS group exhibited a downward trend over visits 3 12 months with an increase at the 18-month follow up interval and a decrease at the 24-month time point.
Actual Number of Patients Enrolled 841 (494 VNS & 301 TAU)
Actual Number of Sites Enrolled 61
Patient Follow-up Rate 40-50%
Final Safety Findings The percentage of patients experiencing a score of 5 or 6 (least favorable) on the frequency, intensity and burden subscales of the FIBSER, respectively, are similar in all groups and decrease over time for all groups.

Increased scores on items from MADRS, QIDS-SR and the Assessment of Suicidality may indicate risk for suicide. In looking at each of these items, suicide risks decreased over time in all treatment groups, but greater for patients treated with VNS Therapy with statistically significant separation for VNS Therapy over TAU treated patients across all three assessments at multiple time points.

A total of 308 MDR events for 166 patients were reported regarding VNS Therapy patients enrolled the study. None of the events reported would be classified as unanticipated adverse device effects.

Patients in the VNS Therapy group experienced a greater than 50% reduction in all-Cause Mortality and completed suicides as compared with patients in the TAU group. Eight patients in the TAU group and 7 patients in the VNS Therapy group died during the trial. Of these, 4 (57%) deaths were considered suicides, 2 in the TAU group and 2 in the VNS group.

Final Effect Findings A higher response rate based on MADRS was observed in the VNS treated group vs. TAU treated group (38.1% for the VNS D-23+D-21 group vs. 17.0% for the TAU; P<0.001). Also, a better response rate was seen in the VNS D-23 only group as compared to the TAU group (37.4% vs. 17.2%, respectively, P<0.001).

The overall trend regarding response, remission and recurrence are consistent across efficacy instruments and shows superiority of VNS Therapy treated group over the TAU group. Patients in the VNS Therapy group experienced statistically significant benefits compared to patients in the TAU group for 13 out of 15 clinical outcomes measured and 2 of the 4 quality of life or health outcomes measured. Sensitivity analyses conducted to assess the impact of missing data did not change the general study conclusions.

Study Strengths & Weaknesses Study Strengths:

First study to evaluate safety and effectiveness of adjunctive VNS Therapy in patients with treatment resistant depression

Prospective cohort study design is considered a design that can provide strong evidence in an observational study

Large sample size with long-term follow-up

Study Weaknesses:

Substantial losses to follow-up (40-50%), which differed among the dosing and non-dosing groups

Potential for residual confounding despite use of propensity scoring adjustment

Recommendations for Labeling Changes labeling changes are recommended

OSB Lead-Registry Study Schedule

Report Schedule
Date Due
FDA Receipt
Applicant's Reporting Status
6 month registry report 01/13/2006 01/12/2006 On Time
1 year Registry report 07/15/2006 07/12/2006 On Time
18 month registry report 01/13/2007 01/10/2007 On Time
2 year registry report 07/15/2007 07/11/2007 On Time
3 year registry report 08/01/2008 07/31/2008 On Time
42 month registry report 03/09/2009 02/27/2009 On Time
4 year registry report 08/07/2009 08/06/2009 On Time
54 month registry report 02/05/2010 01/29/2010 On Time
5 year registry report 08/06/2010 07/27/2010 On Time
6 year registry report 08/05/2011 08/05/2011 On Time
7 year (84 month) registry report 08/03/2012 08/03/2012 On Time
8 year registry report 08/03/2013 08/02/2013 On Time
9 year report 08/03/2014 08/04/2014 Overdue/Received
10 year report-final report 08/03/2015 07/31/2015 On Time

Contact Us

Julie Unger
Project Manager, Post-Approval Studies Program
Food and Drug Administration
10903 New Hampshire Ave
WO66-4206v Silver Spring, MD

Phone: (301) 796-6134
Fax: (301) 847-8140

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