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.
Julie Unger
Project Manager, Post-Approval Studies Program
Food and Drug Administration
10903 New Hampshire Ave
WO66-4206v
Silver Spring, MD
20993-0002
Prospective, multi-center, historically controlled study to confirm that the post-procedure incidence of amenorrhea observed with
GYNECARE THERMACHOICE III (TC-III) Uterine Balloon Therapy System is comparable to that in the original THERMACHOICE I (TC-I) UBT System at 24 and 36 month post-procedure.
Study Population Description
381 subjects with the length of follow-up up to 36-month post-ablation procedure. Among the 381
subjects, 131 subjects were from TC-I study, and 250 subjects from TC-III study who will continue to be followed up to 36 months post-procedure.
Sample Size
The study statistical hypotheses, for the rate of amenorrhea, at 24 and 36-month post-procedure are:
A
power analysis estimated the sample size to be 121 subjects in each group to achieve 80% power to detect differences at 0.13 (this number was selected based on findings in the TC-I study).
Data Collection
In addition to clinical visit at week 2, month 6 and 12 post-procedure, patients were
contacted by telephone and/or by mail at 24 and 36 months following their ablation procedures to document long term response. If a patient reported any problems during the telephone contact that warranted further evaluation, a visit was scheduled to evaluate and treat the problem. The following information was obtained: menstrual bleeding and
pain patterns, incidence of pregnancy, contraception status, and incidence of any
adverse events and/or complications. Information was also be obtained related to incidence of
intervening gynecologic surgery such as hysterectomy or repeat ablations for continued or recurrent menorrhagia, and incidence of neoplasia or malignancy of the uterus. A quality-of-life questionnaire was completed at each clinical visit (week 2, month 6 and 12) and at 24 and 36 month post-procedure follow-up.
Followup Visits and Length of Followup
Clinical visits were scheduled at week 2, month 6 and 12 months post-procedure. Telephone and/or
mail interviews were done at 24 and 36 months following ablation procedure.
Final Study Results
Actual Number of Patients Enrolled
250
Actual Number of Sites Enrolled
13
Patient Followup Rate
72.4%
Final Safety Findings
The incidence of subjects with at least one adverse event was comparable in NPPC and
PPC groups. A number of 56 subjects (45.2%) in NPPC experienced a total of 98 adverse events and a number of 57 subjects (45.2%) in PPC group experienced a total of 104 adverse events.
The incidence of subjects with severe adverse events was 12.1% (15 subjects) in NPPC group and 10.3% (13 subjects) in PPC group. The incidence of subjects with adverse events related to study device was 3.2% (4 subjects) in NPPC group and 5.6% (7 subjects) in PPC group. The incidence of subjects with adverse events related to study procedure was 6.5% (8 subjects) in NPPC group and 8.7% (11 subjects) in PPC group. Furthermore, there was no unanticipated adverse event reported in this study. The incidence of subjects with adverse events that needed action was 44.4% (55 subjects) in NPPC group and 42.1% (53 subjects) in PPC group.
The rate of adverse events was comparable between curettage and no curettage groups. The loss to follow-up was 11.6% overall, however long term-data is only available for 72.4%., making assessment of safety difficult
Final Effectiveness Findings
Analysis #1 (Missing data imputed as failures) ¨C Primary Effectiveness Analysis
The success rate at 36-months
was greater in TCIII group (26.8%, 67 of 250 subjects) compared to TCI group (13.0%, 17 of 131 subjects). The difference in amenorrhea rates between TCIII group and TCI group was statistically significant, based on a one-sided Chi-Square test (p=0.001). The one-sided 95% confidence interval (CI) for the difference (TCIII minus TCI) in proportion of amenorrhea rates between two groups was (7.1%, 100%). Therefore, the sponsor concluded that the difference in true success rates between TCIII and TCI groups was at least 7.1% with 95% confidence.
The one-sided 95% confidence interval for the success rate in TCIII group was (22.2% - 100%), while the one-sided 95% confidence interval for the success rate in TCI group was (8.4% - 100%).
The observed amenorrhea rates in TCIII and TCI groups, the associated one-sided 95% confidence intervals for these success rates, as well as the p-value and confidence interval for the comparison of the amenorrhea rates recorded in TCIII and TCI groups, are presented in Text Table 7 below
Study Strengths and Weaknesses
Strengths include hypothesis driven sample size that was achieved for the duration of the study
allowing greater than 80% power to detect differences, however the follow-up rate was 72.4%, decreasing the ability to accurately measure the rate and type of adverse events. Since treatment failures did not include those who had additional procedures, the ability to fully assess safety was minimized.
Recommendations for Labeling Changes
Ethicon is required to submit revised labeling to include these long-term results as per their
approval order. For the primary effectiveness endpoint, they should report the results using an ITT analysis where all treatment failures (including repeat EA/ hysterectomy) and loss to follow-up are counted as failures. Secondary endpoints may be reported using an evaluable analysis. Data tables should be revised to reflect the 24 and 36 month results including the revisions that were made in response to this deficiency
