In January 2005, the oversight responsibility of the Post-Approval Studies Program was transferred to the Division of Epidemiology (DEPI) of the Office of Surveillance and Biometrics (OSB)/Center for Devices and Radiological Health (CDRH).
The CDRH Post-Approval Studies Program encompasses design, tracking, oversight, and review responsibilities for studies mandated as a condition of approval of a premarket approval (PMA) application, protocol development product (PDP) application, or humanitarian device exemption (HDE) application. The program helps ensure that well-designed post-approval studies (PAS) are conducted effectively and efficiently and in the least burdensome manner.
CDRH has established an automated, internal tracking system that efficiently identifies the reporting status of active PAS studies ordered since January 1, 2005 based on study timelines incorporated in study protocols and agreed upon by the CDRH and applicants. This system represents CDRH's effort to ensure that all PAS commitments are fulfilled in a timely manner.
In addition, CDRH launched this publicly available webpage to keep all stakeholders informed of the progress of each PAS. The webpage displays general information regarding each PAS, as well as the overall study status (based on protocol-driven timelines and the adequacy of the data) and the applicant's reporting status for each submission due.
Transit. Adolescent B (as adults) : 18-21 yrs,
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.
500 TRD patients treated with adjunctive VNS Therapy and a minimum of 300 TRD patients
who are not treated with VNS Therapy.
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 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.
(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.
Followup Visits and Length of Followup
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.
Final Study Results
Actual Number of Patients Enrolled
841 (494 VNS & 301 TAU)
Actual Number of Sites Enrolled
Patient Followup Rate
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 Effectiveness 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 and Weaknesses
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
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