|
|
| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P020056 / PAS002 |
| Date Original Protocol Accepted |
11/17/2006
|
| Date Current Protocol Accepted |
11/17/2006
|
| Study Name |
Core
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
|
| Data Source |
New Data Collection
|
| Comparison Group |
No Control
|
| Analysis Type |
Analytical
|
| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
715 patients including 455 primary augmentation, 147 revision-augmentation, 98 primary-reconstruction and 15 revision-reconstruction patients.
|
| Actual Number of Sites Enrolled |
23
|
| Patient Follow-up Rate |
The follow-up rates for each cohort varied, but the overall rate was above 65% at Year 10. The follow-up rate was highest in the revision-reconstruction group and lowest in the revision-augmentation group. Specifically, the follow-up rate at Year 10 by cohorts were as follows; 66.8% in the augmentation cohort 63.8% in the revision-augmentation, 75.4% in the reconstruction and 80.0% in the revision-reconstruction cohort.
|
| Final Safety Findings |
The most commonly reported complications for all cohorts include capsular contracture, breast pain, swelling, symmetry, wrinkling and implant malposition. The overall implant rupture rates by patient were 9.5% in the augmentation, 6.3% revision-augmentation, 27.2% in the reconstruction, and 6.7% in the revision-reconstruction cohort. The rate of any reoperation by 10 years post-implant was highest in the reconstruction cohort (71.5%), followed by revision cohorts (46.7% in the revision-reconstruction and 46.0% in the revision-augmentation cohorts), and lowest in the augmentation cohort (36.1%). The most frequently reported reason for reoperation varied with the indication. The most common primary reasons for reoperation were asymmetry, capsular contracture, device rupture, implant malposition, need for biopsy, patient request for style/size change and ptosis. Specifically for the revision-reconstruction patients, nipple complications were reported as the most common reason for reoperation. The incidence of breast implant removal by 10 years post-implant was highest in the reconstruction cohort (53.8%), followed by in the revision-augmentation cohort (32.4%), in the augmentation cohort (18.6%) and in the revision-reconstruction cohort (13.3%). The most common reasons for replacement/removal vary depending on the indication group. The most common reasons for implant replacement and removals are as follow: Asymmetry, capsular contracture, device rupture, implant malposition and patient request for style/size change.
|
| Final Effect Findings |
Majority of the patients and physicians were satisfied with the surgical outcome. In the augmentation cohort, the patient and physician satisfaction was 93% and 94%, respectively, 84% and 83% in the augmentation revision cohort, 84% and 86% in the reconstruction cohort, 72% and 80% in the revision-reconstruction cohort
|
| Study Strengths & Weaknesses |
One of the study strength is that the study is a prospective, multicenter study that provides long term data up to 10 years on the safety and effectiveness of the device. The weaknesses of the study were the lack of a comparison group and lack of statistical power to detect rare events due to the small sample size
|
| Recommendations for Labeling Changes |
The labeling will be updated based on the safety and effectiveness results reported in the final PAS report.
|
| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P020056 / PAS003 |
| Date Original Protocol Accepted |
11/17/2006
|
| Date Current Protocol Accepted |
11/17/2006
|
| Study Name |
Focus Group
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Other Study Design
|
| Data Source |
New Data Collection
|
| Comparison Group |
No Control
|
| Analysis Type |
Descriptive
|
| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
There were 29 augmentation participants and 23 reconstruction participants.
|
| Actual Number of Sites Enrolled |
N/A
|
| Patient Follow-up Rate |
N/A, There was no follow-up of focus group participants.
|
| Final Safety Findings |
N/A, There are no safety findings.
|
| Study Strengths & Weaknesses |
The strength of the study was that the focus groups included augmentation and reconstruction patients. The weakness of the study was that the participants many not be representative of all breast implant patients.
|
| Recommendations for Labeling Changes |
Changes were made to the Patient Planner based on the recommendatin of the focus groups. These changes included changing the order of text in the planner and making the planner available on-line.
|
| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P020056 / PAS004 |
| Date Original Protocol Accepted |
11/17/2006
|
| Date Current Protocol Accepted |
11/17/2006
|
| Study Name |
Adjunct
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
|
| Data Source |
New Data Collection
|
| Comparison Group |
No Control
|
| Analysis Type |
Descriptive
|
| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
A total of 84, 329 patients were enrolled in the study; 45,055 in the reconstruction cohort and
39,274 in the revision cohort
|
| Actual Number of Sites Enrolled |
2,696 sites
|
| Patient Follow-up Rate |
Reconstruction cohort: 54.3% at Year 1, 29.8% at Year 3, 17.8% at Year 5
Revision cohort: 47.9% at Year 1, 26.1% at Year 3, 15.7% at Year 5
|
| Final Safety Findings |
The most commonly observed complications in the reconstruction and revision cohorts were capsular contracture, asymmetry, implant palpability/visibility, implant malposition and wrinkling. The cumulative 5-year risk rate for these complications in reconstruction and revision were as follows, respectively; capsular contracture (15.0%, 21.5%), asymmetry (11.1%, 10.6%),
implant palpability/visibility (7.1%, 11.5%), implant malposition (6.5%, 7.1%) and wrinkling (5.6%,
8.9%).
The rate of any reoperation at 5 years post-implantation was 34.4% in the reconstruction cohort and 30.1% in the revision cohort.
The most common reasons by cohort for reoperation were: capsular contracture (30.9%), cosmetic (30.9%), infection (5.1%) in the reconstruction cohort capsular contracture (44.3%), cosmetic (33.6%), and infection (4.8%) in the revision cohort.
The incidence of implant removal with replacement at 5 years post-implantation was 18.6% in the reconstruction cohort and in the revision cohort. The incidence of implant removal without replacement at 5 years post-implantation was 5.1% in the reconstruction cohort and 4.3% in the revision cohort.
The Kaplan-Meier cumulative rupture rates at 5 years were 1.3% in the reconstruction cohort and 1.5% in the revision cohort.
|
| Final Effect Findings |
For the reconstruction cohort, on a 1 (definitely dissatisfied) to 5 (definitely satisfied) scale, the average satisfaction level for patients and physicians was 4.3-4.4 at each follow-up timepoint. For the revision cohort, the average satisfaction level for patients and physicians was 4.4-4.5 at each follow-up timepoint.
|
| Study Strengths & Weaknesses |
A large number of patients were enrolled in the adjunct study. However, the study was originally designed to address the public health needs of reconstruction and revision patients before
device approval and to gather safety data regarding short-term post-implant complications under a limited clinical protocol without follow-up goals. The follow-up rates of the reconstruction cohort at 1, 3 and 5 years were 54.3%, 29.8%, 17.8%, respectively. The follow-up rates were slightly lower in the revision cohort, i.e., 47.9% at Year 1, 26.1% at Year 3, 15.7% at Year 5. The poor patient compliance provides limited meaningful interpretation of the available safety
results.
|
| Recommendations for Labeling Changes |
No. The Adjunct Study was designed to address the public health needs of reconstruction and revision patients before device approval. The follow-up rates of the reconstruction cohort and revision cohort were low for the duration of the study. Therefore, there is lack of valuable safety data from the study due to poor patient compliance.
|
| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P020056 / PAS006 |
| Date Original Protocol Accepted |
10/17/2006
|
| Date Current Protocol Accepted |
10/17/2006
|
| Study Name |
Informed Decision Process
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Cross-Sectional Study
|
| Data Source |
New Data Collection
|
| Comparison Group |
No Control
|
| Analysis Type |
Descriptive
|
| Interim or Final Data Summary |
| Interim Results |
There is no interim device safety Information from this study
|
| Actual Number of Patients Enrolled |
The Informed Decision Process consisted of yearly surveys. Each year a different sample was selected for the survey. These are the results for 2011 annual report.
84 surveys were returned. Per the condition of approval, the sponsor did administer the survey to a random selection of 50 physicians.
|
| Actual Number of Sites Enrolled |
N/A
|
| Patient Follow-up Rate |
N/A
|
| Final Safety Findings |
N/A
|
| Final Effect Findings |
The majority (85.7%) of all respondents are satisfied with the Patient Planner, with 55.9% rating it Very Good and 29.8% rating it Good.
|
| Study Strengths & Weaknesses |
The sample of physicians was chosen randomly, which is a strength of the study.
However, the observational, cross-sectional design of the study does not allow for any hypothesis testing. The results are descriptional only.
|
| Recommendations for Labeling Changes |
Allergan is not currently proposing labeling changes based upon the survey results.
|
| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P020056 / PAS007 |
| Date Original Protocol Accepted |
01/16/2015
|
| Date Current Protocol Accepted |
01/16/2015
|
| Study Name |
Re-Op Phase
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
|
| Data Source |
New Data Collection
|
| Comparison Group |
Concurrent Control
|
| Analysis Type |
Descriptive
|
| Detailed Study Protocol Parameters |
| Study Objectives |
On August 30th -31st, 2011, the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee (link) met to discuss updates on the postmarket experience of silicone gel-filled breast implants and to make recommendations on issues related to the monitoring of silicone gel-filled breast implants. The Advisory Panel recommended more efficient approaches to assessing the performance of silicone gel-filled breast implants than continuing new enrollment in the large prospective studies. Their recommendations included conducting a systematic literature review and re-designing the Large Post-Approval Studies (PAS) to have more efficient methodologies to assess rare outcomes. In response, FDA entered a collaboration with the American Society of Plastic Surgeons (ASPS), the Plastic Surgeons Foundation (PSF), breast implant manufacturers and patient advocate groups, to establish the National Breast Implant Registry (NBIR) and the PROFILE Registry (established to collect data on potential cases of breast-implant anaplastic large cell lymphoma (BI-ALCL)). Tufts University was tasked with conducting a systematic literature review to look at rare endpoints (listed below) and silicone gel-filled breast implants. Details on the literature review methodology and findings can be found here (Balk EM, et al., Long-Term Health Outcomes in Women With Silicone Gel Breast Implants: A Systematic Review. Ann Intern Med. 2016. 2;164(3):164-75).
This Re-Op Phase Study requirement was designed as part of the re-design of the LARGE PAS for the Natrelle® Silicone Gel Breast Implant. In this Re-Op Phase, data will be collected when subjects with Natrelle® silicone breast implants have secondary surgical procedures/re-operations. This requirement will serve as a bridge between the Large PAS and NBIR.
|
| Study Population |
The NBIR arm consists of subjects implanted with round responsive devices or saline devices who were originally enrolled in the BIFS study but were not selected to remain in the smaller 10-year follow-up cohort study (BIFS arm).
|
| Sample Size |
37,390 subjects with Natrelle silicone gel-filled breast implants and 14,995 subjects with saline-filled breast implants.
|
| Key Study Endpoints |
Implant removal and reoperation rates; Reasons for reoperation.
|
| Follow-up Visits and Length of Follow-up |
The follow-up data will be collected when the participant requires a secondary procedure/reoperation.
|
| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
50,584 subjects
|
| Actual Number of Sites Enrolled |
953 sites
|
| Patient Follow-up Rate |
n/a (no active follow up); follow up for 10 years total
|
| Final Safety Findings |
There were a total of 190 reoperations reported in the NBIR arm of the BIFS-001 Study. In the Silicone cohort, reoperations were reported for 180 subjects (0.5%). In the Saline cohort, reoperations were reported for 10 subjects (<0.1%).
|
| Final Effect Findings |
Not assessed
|
| Study Strengths & Weaknesses |
Data was passively collected, as there was no active follow up in the study. Patients were only followed up if they required a reoperation. This was only recorded in the study if the patient followed up with the original surgeon and that information was submitted.
- By the end of the study, there were only 318 sites that were active (653 sites were inactive). Approximately 20,000 patients were considered “completed due to site closure.” If the site was closed or inactive, even if a patient received a reoperation, it would not have been reported.
- The reported reoperation rates in this study do not seem to be consistent with other previous studies. Given the passively collected data, this suggests that there is missing data, which is a significant limitation to this study.
|
| Recommendations for Labeling Changes |
The significant limitations of the study design given the fact that this was passive surveillance should be mentioned as a caveat of the study data. Interpretation of this study data is limited given the amount of missing data.
|
| General |
| Study Status |
Ongoing |
Application Number /
Requirement Number |
P020056 / PAS008 |
| Date Original Protocol Accepted |
08/03/2015
|
| Date Current Protocol Accepted |
08/25/2016
|
| Study Name |
Natrelle and 410 Combined Cohort
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
|
| Data Source |
New Data Collection
|
| Comparison Group |
Concurrent & Historical Control
|
| Analysis Type |
Analytical
|
| Detailed Study Protocol Parameters |
| Study Objectives |
On August 30th -31st, 2011, the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee (link) met to discuss updates on the postmarket experience of silicone gel-filled breast implants and to make recommendations on issues related to the monitoring of silicone gel-filled breast implants. The Advisory Panel recommended more efficient approaches to assessing the performance of silicone gel-filled breast implants than continuing new enrollment in the large prospective studies. Their recommendations included conducting a systematic literature review and re-designing the Large Post-Approval Studies (PAS) to have more efficient methodologies to assess rare outcomes. In response, FDA entered a collaboration with the American Society of Plastic Surgeons (ASPS), the Plastic Surgeons Foundation (PSF), breast implant manufacturers and patient advocate groups, to establish the National Breast Implant Registry (NBIR) and the PROFILE Registry (established to collect data on potential cases of breast-implant anaplastic large cell lymphoma (BI-ALCL)). Tufts University was tasked with conducting a systematic literature review to look at rare endpoints (listed below) and silicone gel-filled breast implants. Details on the literature review methodology and findings can be found here (Balk EM, et al., Long-Term Health Outcomes in Women With Silicone Gel Breast Implants: A Systematic Review. Ann Intern Med. 2016. 2;164(3):164-75).
This Combined Cohort study was designed as part of the re-design of the LARGE PAS. This is a smaller cohort study to primarily address safety outcomes (i.e., including local complications, less rare connective tissue diseases, rheumatologic and neurologic signs and symptoms, breast cancer, lung cancer and suicide), reproduction and pregnancy outcomes, lactation problems, effects on mammography, effects on patient satisfaction with breasts and psychosocial well-being, and silicone subject compliance with magnetic resonance imaging (MRI) recommendations. This re-structured PAS, once completed as designed, would satisfy the post-approval requirements for both the Natrelle® (P020056) and Natrelle® 410 (P040046) silicone breast implants. The Round Responsive and Style 410 implants will be compared with saline implants or national norms.
In addition, information gained from the NBIR will help strengthen the general understanding of implantation rates and certain risks associated with breast implants.
|
| Study Population |
Subjects who have received Allergan silicone gel-filled breast implants or saline implants will be eligible to participate in the study.
INCLUSION:
Subjects must meet all of the following inclusion criteria at the time of surgery:
1) Female, age 18 years or older (age 22 or older for breast augmentation subjects)
2) Exhibit fluency and literacy in English or Spanish
EXCLUSION:
Subjects who meet any of the following criteria are not eligible for enrollment in the study:
1) Are transgender
2) If a saline implant subject, have a current or past unilateral or bilateral silicone gel-filled breast implant
3) Investigator decision that subject is not a suitable candidate for a long-term observational study
CONTINUATION (BIFS ARM ONLY):
Subjects are eligible to continue in the BIFS arm if they meet all of the following criteria:
1) Have complete baseline and years 1, 2, 3, and 4 follow-up questionnaires available (including the Satisfaction with Breasts and Psychosocial Well-Being modules of the BREAST-Q). Saline reconstruction and revision reconstruction do not need to have complete BREAST-Q questionnaires at baseline.
2) Meet all enrollment criteria, specifically the minimum age requirements for silicone implants (18 or older for reconstruction subjects and 22 or older for augmentation subjects), and were free of all target diseases at baseline
3) Are enrolled at a site that is selected in the cluster sampling to continue in the BIFS arm under Amendment
5.
|
| Sample Size |
2,000 subjects with Allergan Round Responsive silicone gel filled breast implants and 245 subjects with saline implants selected from the Breast Implant Follow-up Study (BIFS) cohorts, and 530 newly enrolled Style 410 highly cohesive silicone breast implants.
The BIFS continuation arm will be targeted to include 20 saline revision augmentation, 11 saline reconstruction, and 11 saline revision-reconstruction subjects. If the cluster sampling results in insufficient subjects from these groups, additional subjects (who would otherwise not qualify for the BIFS arm) will be selected from continuing sites at random to meet the targets.
|
| Key Study Endpoints |
Adverse events (including local complications, less rare connective tissue diseases, rheumatologic and neurologic signs and symptoms, breast cancer, lung cancer and suicide), reproduction and pregnancy outcomes, lactation problem, effects on mammography, effects on satisfaction with breasts and psychosocial well쳌]being, and silicone subject compliance with MRI recommendations.
|
| Follow-up Visits and Length of Follow-up |
10 years
Subject questionnaire will be collected annually. Office visits at Year 1, 4 and 10 for participants enrolled in the device group.
|
| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
BIFS-ARM:
2,000 Round Responsive subjects
257 Control subjects
410-ARM:
472 Style 410 subjects
|
| Actual Number of Sites Enrolled |
BIFS-ARM – 74 sites; 410-ARM – 27 sites
|
| Patient Follow-up Rate |
BIFS-ARM:
The 9 year follow up rates are:
72.0% - Round Responsive cohort
75.1% - Saline cohort
410-ARM:
The 4 year follow-up rate is:
100% - Style 410 cohort
|
| General |
| Study Status |
Other |
Application Number /
Requirement Number |
P020056 / PAS005 |
| Date Original Protocol Accepted |
11/17/2006
|
| Date Current Protocol Accepted |
11/17/2006
|
| Study Name |
Device failure Study
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Bench/Lab Study
|
| Data Source |
New Data Collection
|
| Comparison Group |
No Control
|
| Analysis Type |
Descriptive
|
| General |
| Study Status |
Redesigned/Replaced Study |
Application Number /
Requirement Number |
P020056 / PAS001 |
| Date Original Protocol Accepted |
11/17/2006
|
| Date Current Protocol Accepted |
08/03/2015
|
| Study Name |
BIFS (Large PAS)
|
| Device Name |
NATRELLE SILICONE-FILLED BREAST IMPLANTS
|
| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
|
| Data Source |
New Data Collection
|
| Comparison Group |
Concurrent & Historical Control
|
| Analysis Type |
Analytical
|
| Study Population |
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
|
| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
* NOTE: The PAS001 (BIFS Large PAS) were revised and replaced with two ongoing PASs, i.e. PAS007 (Re-Op Phase, i.e. the NBIR arm selected for Re-Op study), and PAS008 (Natrelle and 410 combined cohort).
55,279
The evaluable subjects by indications are summarized in table below:
Subjects by Indication 39,069 Silicone 14,487 Saline
augmentation 28,365 (72.6%) 13,379 (92.4%)
revision augmentation 5,662(14.5%) 896 (6.2%)
reconstruction 4,386(11.2%) 171 (1.2%)
revision reconstruction 656(1.7%) 41 (0.3%)
|
| Actual Number of Sites Enrolled |
873
|
| Patient Follow-up Rate |
The follow-up rates from year 1 to 8 are 70.2%, 74.8%, 74.4%, 69.4%, 60.5%, 55.1%, 50.8%, and 63.2% for Silicone cohort, and 46.1%, 53.8%, 60.9%, 58.6%, 52.9%, 46.0%, 42.0%, and 50.0% for Saline cohort, respectively. . Follow-up rate is calculated as [actual observed subjects/(yearly cohort - completed study without data in visit window)].
|
| Final Safety Findings |
Deaths
There were 367 deaths (311 silicone and 56 saline) reported, which represents 0.7% of the analyzed population with a calculated event rate of 25 per 10,000 subject years. The most common cause of death was breast cancer (0.2%). Less than 0.1% of subjects in each cohort committed suicide. None of the deaths were related to the implant.
Very rare adverse events
All collected data (including any data on events occurring through Year 7) encompassing a total of > 157,000 observed subject years. For augmentation, reconstruction, and revision-augmentation cohorts, no event rate was twice as high in silicone subjects compared to national norms. Higher standard incidence ratios (SIRs) were observed in the revision-reconstruction cohort for scleroderma, Sjogren’s syndrome, and dermatomyositis/polymyositis.
Rare target adverse events
All collected data (including any data on events occurring through Year 7) encompassing a total of > 157,000 observed silicone subject years and > 14,000 observed saline subject years. No adverse event demonstrated an increased risk (adjusted risk ratios) associated with the NATRELLE Silicone-filled Breast Implants compared to saline breast implants since all the 90% confidence interval included 1.0.
Local complications
The Year 5 Kaplan Meier rates for local complications as well as rates of reoperation and implant removal with and without replacement are compared with Allergan’s Core study. In the Augmentation, Reconstruction, and Revision-Augmentation cohorts, no rate was higher in the BIFS study compared to the Core Study. Higher local complication rates were observed in the Revision-Reconstruction cohort that had smaller sample sizes (699 in BIFS study and 15 in Core study). The Kaplan-Meier estimated cumulative incidence rates at 5 years for less frequent, but severe complications were infection (0.3%-1.9%), rupture (1.4%-2.6%), removal without replacement (1.1%-2.4%). Rheumatologic Signs & Symptoms
There was no clear pattern to reports of rheumatologic signs and symptoms, although there were ~500 possible events in silicone vs less than 5 events occur in saline, and some symptoms occurred more frequently in the silicone cohort compared to the saline cohort, even after an age-adjusted analysis.
|
| Final Effect Findings |
A total of 12,758 (32.6%) Silicone subjects and 1,393 (9.6%) saline subjects completed the year 4 questionnaire. On the 100-point BREAST-Q scale, median satisfaction with breasts was 33.3 for both the Silicone and Saline cohorts at baseline and improved to 94.4 in both cohorts at year 1. At year 4, the median satisfaction with breasts decreased slightly to 88.9 for both cohorts.
The medians of psychosocial well-being scores were 66.7 for Silicone and 58.3 for Saline at baseline and improved to 97.2 for each cohort at year 1. At year 4, psychosocial well-being scores were 91.7 for Silicone and 88.9 for saline.
|
| Study Strengths & Weaknesses |
Strength:
This is a large cohort study.
Weakness:
The follow-up rates are low (~40-60% from years 5-8) and the percentages of censoring/missing data are high (94% saline and 54% Silicone at year 1). Missing data and/or loss to follow-up introduce study bias and limit the interpretation of the study results.
|
| Recommendations for Labeling Changes |
Due to very low follow-up rates after 5 years post-implant, labeling changes are not recommended
|
