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U.S. Department of Health and Human Services

Post-Approval Studies (PAS)

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The FDA has the authority to require sponsors to perform a post-approval study (or studies) at the time of approval of a premarket approval (PMA), humanitarian device exemption (HDE), or product development protocol (PDP) application. Post-approval studies can provide patients, health care professionals, the device industry, the FDA and other stakeholders information on the continued safety and effectiveness (or continued probable benefit, in the case of an HDE) of approved medical devices. This database allows you to search Post-Approval Study information by applicant or device information.

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BIFS (Large PAS)

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Study Status Revised/Replaced Study
Application Number P020056 / PAS001
Date Current Protocol Accepted 08/03/2015
Study Name BIFS (Large PAS)
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
Detailed Study Protocol Parameters
Study Design Description 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 (SLR) 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 Natrelle® Silicone Gel 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 39,390 subjects having silicone gel-filled breast implants and 15,240 subjects with saline-filled implants. Natrelle® met enrollment goals, but the study was limited by low follow-up rates. The Large PAS requirement was re-designed (listed as Revised/Replaced on PAS webpage) with: a smaller cohort study, a Re-Operation data collection Phase (Re-Op Phase), and a case-control studies requirement. The smaller cohort study and the Re-Op Phase are ongoing and the description of study objectives/designs can be found in the PAS webpage under OSB Lead-Natrelle and 410 Combined Cohort 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 SLR was conducted. The SLR 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).

Study Population Description The study population is as per device indication. 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.
Sample Size The study will enroll 54,630 female subjects who elect to receive unilateral or bilateral breast implant, including: - 39,390 subjects who receive silicone gel-filled breast implant, 15,240 subjects who receive saline-filled breast implants (control subjects).
Data Collection 1. The long-term safety profile of silicone breast implants, especially as it relates to connective tissue diseases (CTD), neurological diseases, cancer (brain, lung, breast, and cervical/vulvar), and suicide and their associated signs and symptoms. 2. The impact of silicone breast implants on reproductive health (e.g., live vs. non-live births) and offspring health (i.e., congenital and neonatal anomalies and diseases of offspring conceived post-implant, including autoimmune diseases, cancer, and neurological diseases) 3. The impact of silicone breast implants on detection of breast cancer with mammography 4. Complications associated with silicone breast implants 5. The effect of silicone breast implants on overall feeling of satisfaction with life and with the decision to have implant surgery
Follow-up Visits and Length of Follow-up There are 4 follow up clinic visits at 1 wk post surgery, 1 year, 4 years and 10 years. Additionally, there is a patient questionnaire that is assessed annually.
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).


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.


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

BIFS (Large PAS) Schedule

Report Schedule
Date Due
FDA Receipt
Applicant's Reporting Status
Large PAS 3 month report 02/16/2007 03/09/2007 Overdue/Received
Large PAS 6 month report 05/18/2007 05/16/2007 On Time
Large PAS 9 month report 08/17/2007 08/16/2007 On Time
Large PAS 1 year report 11/17/2007 11/13/2007 On Time
Large PAS 15 month report 02/16/2008 02/12/2008 On Time
Large PAS 18 month report 05/17/2008 05/08/2008 On Time
Large PAS 21 month report 08/16/2008 08/13/2008 On Time
Protocol Deviations report 10/24/2008 10/24/2008 On Time
Large PAS 2 year report 11/16/2008 11/12/2008 On Time
Large PAS 27 month report 02/15/2009 02/13/2009 On Time
Large PAS 30 month report 05/17/2009 05/15/2009 On Time
Large PAS 33 month report 08/16/2009 08/14/2009 On Time
Large PAS 3 year report 11/16/2009 11/10/2009 On Time
Large PAS 39 month report 02/15/2010 02/12/2010 On Time
Large PAS 42 month report 05/17/2010 05/13/2010 On Time
Large PAS 45 month report 08/16/2010 08/11/2010 On Time
Large PAS 4 year report 11/16/2010 11/12/2010 On Time
Large PAS 51 month report 02/15/2011 02/11/2011 On Time
Large PAS 54 month report 05/17/2011 05/12/2011 On Time
Large PAS 57 month report 08/16/2011 08/15/2011 On Time
Large PAS 5 year report 11/16/2011 11/17/2011 Overdue/Received
Large PAS 63 month report 02/15/2012 02/10/2012 On Time
Large PAS 66 month report 05/16/2012 05/14/2012 On Time
Large PAS 69 month report 08/15/2012 08/09/2012 On Time
Large PAS 6 year report 11/19/2012 11/27/2012 On Time
Large PAS 7 year report 11/15/2013 11/14/2013 On Time
Large PAS 8 year report 11/15/2014 11/06/2014 On Time
Large PAS 9 year report-final 11/15/2015 11/13/2015 On Time

Contact Us

Julie Unger
Project Manager, Post-Approval Studies Program
Food and Drug Administration
10903 New Hampshire Ave
WO66-4206v Silver Spring, MD

Phone: (301) 796-6134
Fax: (301) 847-8140

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