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.
The Large post-approval study is a 10-year cohort study to address specific issues for which
the Core Study was not designed to fully answer, as well as to provide a long-term real-world assessment of study endpoints
Study Population Description
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.
41,900 MemoryGel and 1,000 saline patients
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.
Followup Visits and Length of Followup
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
Final Study Results
Actual Number of Patients Enrolled
A total of 41,452 MemoryGel participants were enrolled in the study.
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.
Final Effectiveness 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).
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.
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.
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.
Study Strengths and 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.
Recommendations for Labeling Changes
Due to very low follow-up rate, labeling changes are not recommended.