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| General |
| Study Status |
Redesigned/Replaced Study |
Application Number /
Requirement Number |
P030053 / PAS001 |
| Date Original Protocol Accepted |
11/17/2006
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| Date Current Protocol Accepted |
10/01/2014
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| Study Name |
Large PAS
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| Device Name |
MEMORYGEL SILICONE GEL -FILLED BREAST IMPLANTS
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| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
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| Data Source |
New Data Collection
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| Comparison Group |
Concurrent & Historical Control
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| Analysis Type |
Analytical
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| Study Population |
Adolescent: 13-18 yrs,
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
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| 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).
The Large PAS for the MemoryGel® Silicone Breast Implant was an observational prospective cohort study (10 years of follow-up), originally designed to address very rare adverse events with the target enrollment goal of 41,900 MemoryGel® and 1,000 saline patients. Mentor® met patient enrollment goals, but the study was limited by low follow-up rates. The Large PAS was re-designed (listed as Revised/Replaced on the PAS webpage) with: a re-operation data collection phase (Re-op Phase), a smaller cohort study, and a case-control studies requirement. The smaller cohort study and Re-Op Phase are ongoing and the description of study objectives and designs can be found in the PAS webpage under OSB Lead-MemoryGel and Shape Glow Study and OSB Lead-Re-Op Phase. The case-control study requirements originally were designed to study the following endpoints: rare connective tissue diseases, rare neurological diseases, brain cancer, cervical/vulvar cancer and lymphoma. The PAS case-control study requirements were put-on hold while the systematic literature review was conducted. The systematic literature review demonstrated insufficient evidence of association between silicone gel-filled breast implants and lymphoma, brain cancer, cervical cancer, rare connective tissue diseases (CTDs), or rare neurological events. Therefore, the PAS case-control studies were terminated because using case-control studies to evaluate these rare adverse events among patients with silicone breast implants would not provide additional value.
The FDA continues to monitor these rare adverse events using other postmarket surveillance tools and real-world data (e.g. NBIR, PROFILE, MDRs)
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| Study Population |
Study Population consists of women who receive MemoryGel and saline breast implants for augmentation, revision-augmentation, reconstruction and revision-reconstruction . This device is indicated for breast augmentation for women at least 22 years old and for breast reconstruction for women of any age. Breast Augmentation includes primary breast augmentation to increase the breast size, as well as revision surgery to correct or improve the results of a primary breast augmentation surgery. Breast reconstruction includes primary reconstruction to replace breast tissue that has been removed due to cancer or trauma or that has failed to develop properly due to a severe breast abnormality. Breast reconstruction also includes revision surgery to correct or improve the results of a primary breast reconstruction surgery.
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| Sample Size |
41,900 MemoryGel and 1,000 saline patients
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| Key Study Endpoints |
Baseline data will be collected from the study subjects using patient self-administered questionnaire during the visit for preoperative evaluation. For MemoryGel patients, information on local complications including reasons for re-operation with or without removal of breast implants and reasons for removal, results of MRI evaluations, and results of rheumatologic or neurological evaluations will be collected during scheduled follow-up and on an interim/unscheduled basis, as needed.
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| Follow-up Visits and Length of Follow-up |
3 surgeon visits (1, 4-6 and 9-10 years post-implantation) and 10 annual follow-up questionnaire completed by participants during 10 years of study
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| Interim or Final Data Summary |
| Interim Results |
A total of 42,928 female patients (41,911 MemoryGel, 1,017 saline) were enrolled. Through May 1, 2010, the Year 1 follow-up rate of surgeon visit for MemoryGel participants was 22.8%; the Year 1, 2, 3 follow-up rates of patient questionnaire were 21.4%, 24.3%, 23.0% for MemoryGel and 5.9%, 7.3% , 16.7% for saline participants respectively. The follow-up rates were too low to provide meaningful safety information at this time.
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| Actual Number of Patients Enrolled |
A total of 41,452 MemoryGel participants were enrolled in the study.
Enrollment by indication was: 26,173 primary augmentation participants, 8382 revision-augmentation participants, 5023 primary reconstruction participants, 1761 revision-reconstruction participants, and 113 participants with missing indication information.
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| Actual Number of Sites Enrolled |
2,342
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| Patient Follow-up Rate |
At year 7, the overall follow-up rate was 20.1%.
Follow-up rate by indication was: 19.2% primary augmentation group, 17.6% revision-augmentation group, 27.9% primary reconstruction group, 22.7% revision-reconstruction group, and 22% missing indication group.
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| Final Safety Findings |
Participant Reported Complications and Reoperations
For MemoryGel participants in the primary augmentation cohort, the cumulative incidence rate at 7 years of participant reported key local complications/reoperations was estimated to be 35.9% for any complication or reoperation, 3.3% for breast infection, 19.6% for breast pain related to implants, 8.7% for capsular contracture Baker Grade II, 7.2% for capsular contracture Baker Grades III/IV, 0.7% for MRI confirmed rupture, 8.2% for suspected rupture, 6.2% for implant removal, and 11.7% for reoperation.
For MemoryGel participants in the revision-augmentation cohort, the cumulative incidence rate at 7 years of participant reported key local complications/reoperations was estimated to be 50.8% for any complication or reoperation, 4.0% for breast infection, 25.0% for breast pain related to implants, 20.2% for capsular contracture Baker Grade II, 18.0% for capsular contracture Baker Grades III/IV, 2.8% for MRI confirmed rupture, 14.2% for suspected rupture, 12.5% for implant removal, and 18.9% for reoperation.
For MemoryGel participants in the primary reconstruction cohort, the cumulative incidence rate at 7 years of participant reported key local complications/reoperations was estimated to be 53.4% for any complication or reoperation, 6.3% for breast infection, 29.6% for breast pain related to implants, 12.3% for capsular contracture Baker Grade II, 12.7% for capsular contracture Baker Grades III/IV, 2.2% for MRI confirmed rupture, 12.5% for suspected rupture, 15.9% for implant removal, and 24.7% for reoperation.
For MemoryGel participants in the revision-reconstruction cohort, the cumulative incidence rate at 7 years of participant reported key local complications/reoperations was estimated to be 58.5% for any complication or reoperation, 5.9% for breast infection, 27.8% for breast pain related to implants, 16.1% for capsular contracture Baker Grade II, 18.3% for capsular contracture Baker Grades III/IV, 2.6% for MRI confirmed rupture, 15.6% for suspected rupture, 17.4% for implant removal, and 26.6% for reoperation.
Reasons for Reoperation
Among MemoryGel participants the Kaplan-Meier estimated cumulative incidences through seven years following implantation of participant reported reoperation are 11.7% for primary augmentation participants, 18.9% for revision-augmentation participants, 24.7% for primary reconstruction participants, and 26.6% for revision-reconstruction participants.
Among primary augmentation participants, the two most frequent reasons for reoperation (at the procedure level) were capsular contracture Baker Grades II/III/IV (26.8% of procedures) and patient requested size change (21.0%).
Among revision-augmentation participants, the two most frequent reasons for reoperation were capsular contracture Baker Grades II/III/IV and patient requested size change (31.1% and 19.9% of procedures, respectively).
Among primary reconstruction participants, the two most frequent reasons for reoperation were asymmetry (22.1%) and capsular contracture Baker Grades II/III/IV (20.0%).
Among revision-reconstruction participants, the two most frequent reasons for reoperation were asymmetry and capsular contracture Baker Grades II/III/IV (24.4% and 21.4%, respectively).
Reasons for Explantation
In the two augmentation cohorts, the most frequent reason for explantation during the seven years after implantation was patient requested size change (58.9% and 44.8% of procedures among participants in the primary augmentation and revision-augmentation cohorts, respectively). In the two reconstruction cohorts, the most frequent reason for explantation was asymmetry (26.4% and 31.2% of procedures among participants in the primary reconstruction and revision-reconstruction cohorts, respectively).
Due to word limits, the safety results are continued in the effectiveness section below.
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| Final Effect Findings |
There were no study objectives related to effectiveness. The information that follows is a continuation of safety findings.
Types of Additional Procedures
Among MemoryGel participants having reoperations during the seven years after implantaton, the most frequent type of procedure in each cohort and overall was implant removal with or without replacement with any device (48.9% of procedures overall). Also frequent in each of the cohorts were capsulectomy (12.3% of procedures overall), pocket adjustment (8.2% of procedures overall), and open capsulotomy (7.5% of procedures overall).
Connective Tissue Disease and Fibromyalgia
Among all MemoryGel participants, there were a total of 349 new cases of rheumatoid arthritis (incidence rate per 10,000 person-years of 32.2), 46 new cases of scleroderma (incidence rate = 4.2), 66 new cases of SLE (incidence rate = 6.0), 62 new cases of Sjögren?s disease (incidence rate = 5.7), 204 new cases of other CTDs (incidence rate = 18.8), and 307 new cases of fibromyalgia (incidence rate = 28.4).
Cancer
Overall, 532 MemoryGel participants without a history of cancer at baseline experienced newly diagnosed cases of cancer. There were 116 participants with newly diagnosed cases of breast cancer, 5 with lung cancer, 3 with brain cancer, and 408 with other types of cancer, including 65 with melanoma. The incidence rates (per 10,000 person-years) were 63.8, 13.9, 0.6, 0.4, and 48.9 for all types of cancer, breast cancer, lung cancer, brain cancer, and other cancers, respectively. The incidence rate (per 10,000 person-years) was 7.8 for melanoma.
Neurological Disease
There were a total of 394 new cases of neurological disease among MemoryGel participants. There were 47 new cases of multiple sclerosis, 17 of myositis, and 332 of other types of neurological diseases. The incidence rates (per 10,000 person-years) were 35.8, 4.3, 1.5, and 30.7 for all types of neurological diseases, multiple sclerosis, myositis, and other neurological diseases, respectively. The most
common ?other neurological diseases? included epilepsy, headache, peripheral neuropathy, stroke, trigeminal neuralgia, and tumor.
Rheumatological and Neurological Signs and Symptoms
Overall, the estimates of mean post-baseline prevalence for MemoryGel participants were highest for persistent non-traumatic joint pain (estimate = 12.9%) and persistent sleep disorders at night (estimate = 25.8%).
Reproduction and Offspring
Overall, a total of 3133 post-operative pregnancies have been reported among MemoryGel participants. Among them, there were a total of 501 miscarriages or stillbirths (16.0%), with 416 miscarriages (13.3%) and 85 stillbirths (2.7%). Overall, a total of 1710 offspring have been reported among MemoryGel participants. Among these, there were 234 premature births (13.7%), 155 low birth weight babies (9.1%), and 194 babies that required neonatal intensive care (11.3%). There were no reported births of children with cleft lip, neural tube defect, or pyloric stenosis. There was one reported birth of cleft palate and one of esophageal deformity. There were 25 reported births (1.5% of births) with other birth defects or congenital malformations.
Suicide
There have been a total of 173 known deaths among the MemoryGel participants. There have been 5 known suicides among these 173 deaths.
Anaplastic Large Cell Lymphoma
There has been one confirmed case of Anaplastic Large Cell Lymphoma (ALCL) in a Large PAS participant.
MRI Compliance and Rupture
At years 1, 2, 3, 4, 5, 6, and 7, only 3.4%, 4.7%, 5.2%, 5.5%, 4.9%, 4.5%, and 4.4%, respectively, of MemoryGel participants reported having had an MRI since completing their last questionnaire. Overall, of the 2051 MemoryGel participants with an MRI, there were 132 participants (6.4%) with rupture.
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| Study Strengths & Weaknesses |
Overall, there are a total of 255,541 person-years of follow-up among MemoryGel participants. However, results are difficult to interpret due to the very low follow-up rate. Loss to follow-up can introduce study bias and limits the interpretation of the study results, as those that remain in the study may not be comparable to those that were lost. FDA and the sponsor have agreed to replace the original LARGE study requirement with a new study design to fulfill the condition of approval.
It should also be noted that not all reported cases of CTD or neurological diseases were confirmed as board-certified diagnosed cases. Therefore, the current cases reported in this study (self-reported by participants as diagnosed by a board-certified specialist, rheumatologist or neurologist) may not represent the actual rate.
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| Recommendations for Labeling Changes |
Due to very low follow-up rate, labeling changes are not recommended.
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