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  1. Warning Letters

WARNING LETTER

Allergan MARCS-CMS 607690 —


Delivery Method:
VIA UNITED PARCEL SERVICE
Product:
Medical Devices

Recipient:
Recipient Name
Brent Saunders
Recipient Title
Chief Executive Officer and President
Allergan

2525 Dupont Drive
Irvine, CA 92612
United States

Issuing Office:
Center for Devices and Radiological Health

United States


WARNING LETTER

 

Brent Saunders
Chief Executive Officer and President
c/o
Ms. Kelly Carty
Executive Director, Regulatory Affairs
Allergan
2525 Dupont Drive
Irvine, California 92612


Dear Mr. Saunders:

The Food and Drug Administration (FDA) approved your devices, NATRELLE Silicone-Filled Breast Implants (“Round Responsive implants”), under Premarket Approval (PMA) Application, P020056, and NATRELLE 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants (“Style 410 implants”), under PMA P040046, on November 17, 2006, and February 20, 2013, respectively. In addition to periodic reporting requirements, FDA ordered your firm to conduct certain post-approval studies in accordance with 21 C.F.R. § 814.82(a), to provide information on the long-term device performance, and to evaluate device performance under general conditions of use. For your reference, the Approval Orders are attached, which detail the post-approval study (PAS) requirements that were imposed as conditions of approval for your devices.

Under 21 C.F.R. § 814.82(a)(2) and (9), FDA may impose PAS requirements as a condition of device approval when necessary to provide reasonable assurance, or the continued reasonable assurance, of the safety and effectiveness of the device under the conditions of use prescribed, recommended, or suggested in the labeling of the device. Specifically, FDA may require as a condition to approval the continuing evaluation by the applicant on the safety, effectiveness, and reliability of the device, including the number of patients to be evaluated, as well as other requirements FDA determines are necessary to provide continued reasonable assurance of the safety and effectiveness of the device.

As discussed in detail below, your firm has failed to comply with the PAS requirements established under 21 C.F.R. § 814.82(a) for your devices.

Round Responsive Implants:

The “Large Postapproval Study” requirements, detailed in item 2 of the Round Responsive implant PMA Approval Order dated November 17, 2006, are listed below. Specifically, you have failed to comply with requirements 1, 3, and 5.


1.Conduct a 10-year large postapproval study to evaluate certain safety endpoints pursuant to the protocol dated October 16, 2006. Under the redesigned study (described below): Conduct a 10-year study to compare Round Responsive implants with Saline implants or national norms with regard to long-term safety; reproduction, pregnancy outcomes, and lactation; effects of mammography; effects of satisfaction with breasts and psychosocial well-being, and silicone subject compliance with magnetic resonance imaging (MRI) recommendations.

2.Enroll 39,390 Allergan silicone gel implant patients (Round Responsive implants) and 19,605 saline-filled breast implant patients as the control group. Under the redesigned study (described below): Enroll at least 2,000 subjects with Round Responsive implants and 245 subjects with saline implants.

3.Collect data on the following safety endpoints: long-term local complications, connective tissue diseases (CTDs), CTD signs and symptoms, neurological disease, neurological signs and symptoms, offspring issues, reproductive issues, lactation issues, cancer, suicide, mammography issues, and MRI compliance and rupture results.

4.Collect data via annual subject questionnaires, either completed via the web, mail, or telephone.

5.Collect local complication data from physician evaluations at 1, 4, and 10 years.

On August 30-31, 2011, FDA convened the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee to discuss the post-market experience of certain approved silicone gel-filled breast implants, including challenges with both subject enrollment and follow-up in large PASs involving silicone gel-filled breast implants. Together with other recommendations, the Panel advised a redesign of these PASs to use more efficient methodologies (e.g., smaller cohorts) to assess long-term outcomes.

Your redesigned study (P020056/S023/A008 and P040046/S012/A003), “NATRELLE and 410 Combined Cohort,” was approved by FDA on August 3, 2015. When completed, this redesigned study would satisfy certain post-approval requirements for both the Round Responsive implants and Style 410 implants. Specifically, the redesigned study modified the “Large Postapproval Study” described above and the “Natrelle 410 Breast Implant US Post-Approval Study” described below and evaluates both the Round Responsive implants and Style 410 implants under one study.

The redesigned study established new enrollment numbers for the Round Responsive implant, Saline implant, and Style 410 implant arms. 2775 subjects were to be enrolled across a minimum of (b)(4) sites: 2,000 subjects with Round Responsive implants, 245 subjects with Saline implants, and 530 subjects with Style 410 implants. The redesigned study includes approximately 2,000 Round Responsive implant and 245 Saline implant subjects from the originally enrolled >40,000 subjects in the “Large Postapproval Study,” while requiring new enrollment of 530 subjects with Style 410 implants. At the time of their enrollment in the redesigned study, the subjects from the Round Responsive implant and Saline implant arms were selected using cluster sampling and had completed all baseline and years 1, 2, 3, and 4 follow-up questionnaires.

Under the redesigned study, subjects were to be followed for a total of 10 years after implantation of the devices. “Follow-up” under the redesigned study refers to the number of subjects who provide health information at baseline and annual questionnaire data for each of 10 years, and the Round Responsive implant and Style 410 implant subjects who complete a physical exam conducted by an investigator at years 1, 4, and 10 (each, an “office visit”). Based on the redesigned study’s design, your firm’s target follow-up rate is (b)(4) at the end of year 10.

The redesigned study was designed with a 10 year subject cumulative drop-out rate of (b)(4) Based on this cumulative drop-out rate, your firm determined that the following minimum numbers of subjects are important to adequately evaluate a meaningful difference in outcome information: (b)(4) subjects in the Round Responsive implant arm, (b)(4) subjects in the Saline implant arm, and (b)(4) subjects in the Style 410 implant arm.

On August 2, 2016, FDA received your firm’s submission, P020056/R072 (Bundled with P040046/R020). Although FDA issued a decision letter on October 6, 2016, to your firm indicating the study status on FDA’s website would remain as “progress adequate,” the letter included an advisory related to office visit follow-up rates. Your 2016 report revealed that the office visit follow-up rates for the Round Responsive implant arm were (b)(4) of 2,000) and (b)(4)) for years 1 and 4, respectively, even though the year 4 follow-up window was extended to 2-7 years post implantation (i.e., subjects would be counted as having completed the year 4 office visit follow-up provided that they were seen any time between 2 years (+1 day) to 7 years). Because the study was ongoing, and there were still many subjects who had not reached or exceeded their year 4 office visit follow-up window, these follow-up rates were considered acceptable at that time. The decision letter reminded your firm that it is important to keep reasonably high (>80%) office visit follow-up rates to ensure unbiased implementation of the study and to obtain meaningful results. Your firm was asked to consider strategies to ensure/improve office visit follow-up rates, and several strategies were recommended by FDA.

On August 2, 2017, FDA received your firm’s submission, P020056/R077 (Bundled with P040046/R024). Although FDA issued a decision letter on November 08, 2017, to your firm indicating the study status on FDA’s website would remain as “progress adequate,” the letter included a deficiency related to office visit follow-up rates. Specifically, compliance with the years 1 and 4 office visits were (b)(4) of 2,000) and (b)(4), respectively, for the Round Responsive implant arm. Given that the year 4 office visit follow-up window had been extended as described above, it was unclear why the study had made little progress in collecting more subjects’ office visit data. Although your firm incorporated some recommended strategies to improve office visit compliance, including biannual telephone outreach to subjects and biannual calls to sites, the office visit follow-up rates remained low. To ensure the redesigned study was implemented and monitored in a timely manner, your firm was asked to provide additional information, such as obstacles you encountered, strategies that you took, and strategies that you planned to take to improve office visit compliance. This additional information was supplied in P020056/R077/A001 (Bundled with P040046/R024/A001), and the proposed strategies were deemed acceptable by FDA on February 1, 2018. However, as described below, the proposed strategies for improving office visit follow-up rates were ineffective.

On August 3, 2018, FDA received your firm’s submission P020056/(b)(4) (Bundled with P040046/(b)(4)), which was later amended. A decision letter was issued on October 30, 2018, with multiple deficiencies, including a request for a (b)(4) to facilitate interpretation of office visit follow-up data. On November 29, 2018, FDA received your firm’s response to the deficiency letter in P020056/(b)(4) (Bundled with P040046(b)(4)). In response, FDA issued several interactive deficiencies, including deficiencies related to the (b)(4). Your firm provided responses to all of the interactively issued deficiencies by February 10, 2019. FDA issued a decision letter to your firm, dated May 14, 2020, indicating that the study status on FDA’s website would be changed to “progress inadequate” due, in part, to the low office visit follow-up rate of the Round Responsive implant arm. Deficiencies issued in response to P020056/(b)(4) and P040046/(b)(4) and subsequent correspondence are described in more detail in FDA’s decision letter referenced in the next paragraph.

On August 1, 2019, FDA received your firm’s submission, P020056/(b)(4) (Bundled with P040046/(b)(4),) and deficiencies identified during the review of P020056/(b)(4) (Bundled with P040046/(b)(4)) were further evaluated at this time. FDA issued a decision letter dated May 14, 2020, to your firm to provide detailed descriptions of deficiencies and indicate that the study status on FDA’s website would be changed to “progress inadequate.” According to your firm’s submission, the office visit follow-up rate for the Round Responsive implant arm was (b)(4) at year 4 (with the extended follow-up window), which is similar to your 2018 report (b)(4) and is significantly decreased from (b)(4) 2,000) at year 1. Thus, (b)(4) of 2,000 originally enrolled) in the Round Responsive implant arm may not have been evaluated by an investigator after year 1. The low office visit follow-up rate at year 4—which is already less than the target follow-up rate of (b)(4) at the end of year 10—prevents the meaningful evaluation of outcome information, and, based on the late stage in the study period, and your study will fail to meet the target follow-up rate of (b)(4) at year 10.

Additionally, the number of Institutional Review Board (IRB)-approved sites participating in the Round Responsive implant arm decreased from (b)(4). The closure of these (b)(4) sites has the potential to result in the loss of (b)(4) subjects, or over (b)(4) of the total Round Responsive implant arm. The closure of the IRB-approved sites will likely further affect your firm’s ability to reach the (b)(4) target follow-up rate for the year 10 office visit and also calls into question whether your firm will maintain the target number of subjects in the Round Responsive implant arm at the end of the study. You previously stated that you are exploring alternatives for the final year 10 office visit. However, more than (b)(4) of subjects in the group (b)(4) have already reached the end of the year 10 office visit follow-up window (10.5 years), and the remaining (b)(4) subjects are already within the year 10 office visit follow-up window (7 years (+1 day) to 10.5 years). If the current protocol is changed significantly to facilitate completion of the year 10 office visit, the 10-year data collected from these subjects may not be poolable. We recommend that you consider alternative strategies to fulfill your post-approval requirements with FDA in the event changes to your protocol render the data un-poolable.

Your firm failed to collect local complication data, including safety endpoint data, during the year 4 physician evaluation at a follow-up rate necessary to meet the target follow-up rate of (b)(4) at year 10. This failure prevents adequate evaluation of the safety, effectiveness, and reliability of the device at this late stage in the study period (year 9) and will prevent such an evaluation at the end of the study (year 10). You are thereby in violation of the requirements established as a condition to your device’s approval under 21 C.F.R. § 814.82(a)(2) and (9). Failure to promptly correct this failure may result in withdrawal of your PMA under 21 C.F.R. § 814.82(c).

Style 410 Implants:

The “Natrelle 410 Breast Implant US Post-Approval Study” requirements, detailed in item 3 of the Style 410 implant PMA Approval Order dated February 20, 2013, are listed below. Specifically, you have failed to comply with requirements 1 and 2, which we also note may impact your compliance with requirements 4, 5, and 6.

1.       Evaluate the long-term clinical performance of Natrelle 410 Breast implants under general conditions of use in the postmarket environment.

2.       Enroll (b)(4) women receiving NATRELLE 410 Breast Implants and (b)(4) women receiving NATRELLE Saline implants as the comparison group. Under the redesigned study (described above): Enroll 530 subjects with Style 410 implants and 245 subjects with Saline implants.

3.       Follow subjects annually for 10 years.

4.       Collect data on the following safety endpoints: CTDs, rheumatologic and neurologic signs and symptoms, cancer (lung and breast, including the potential of breast implant interference with mammography and delay of breast cancer detection), suicide/attempted suicide, local complications (including infection, rupture; including rupture rate following mammography), reoperation and implant removal, reproductive complications in women who attempt to have children, lactation complications, and congenital deformities.

5.       Collect effectiveness data from subjects’ responses to questions addressing their satisfaction with the breast implants and psychosocial well-being via annual patient questionnaires.

6.       Collect data from physician evaluations at 1, 5, and 10 years. Under the redesigned study (described above): Collect data from investigator evaluations during office visits at years 1, 4, and 10.

7.       Conduct device explant analyses for all devices retrieved from women enrolled in the study.

Under the redesigned study (described above) submitted in P020056/S023/A008 (P020056/PAS008, which is the same as P040046/PAS003), your firm is required to enroll 530 subjects with Style 410 implants. As described above, your firm anticipated that (b)(4) of subjects would drop-out at the end of the 10-year study; therefore, the minimum required number of subjects for the Style 410 implant arm is (b)(4). Enrollment of this number of subjects is important to adequately evaluate a meaningful difference in outcomes and was proposed by your firm in the redesigned study protocol, and FDA approved the protocol, in part, on the basis of the subject cumulative drop-out rate.

Under the redesigned study, your firm had 14 months to completely enroll the Style 410 implant arm. The study was initiated in November 2015 and should have been completely enrolled by January 2017.

On August 1, 2019, FDA received your firm’s submission, P020056/(b)(4) (Bundled with P040046/(b)(4)) and deficiencies identified during the review of P020056/(b)(4) (Bundled with P040046/(b)(4)) were further evaluated at this time. FDA issued a decision letter on May 14, 2020, to your firm indicating the study status on FDA’s website would be changed to “progress inadequate” due, in part, to inadequate enrollment into the Style 410 implant arm. This decision letter also provides descriptions of the deficiencies described herein as well as other deficiencies. At the time of your August 1, 2019, submission (30 months after the study should have been completely enrolled), your firm had only enrolled (b)(4) of the required 530 subjects in the Style 410 implant arm of the redesigned study. Due to the worldwide recall of BIOCELL textured implants on July 24, 2019, you reported that you stopped enrollment in the Style 410 implant arm.

In addition, we note that although the Style 410 implant arm is not fully enrolled, the interim year 1 office visit follow-up rates are below the (b)(4) target follow-up rate for year 10. In your firm’s 2018 submission P020056(b)(4) (Bundled with P040046(b)(4)), your firm reported an interim year 1 office visit follow-up rate of (b)(4) which increased to (b)(4) in your firm’s 2019 submission P020056/(b)(4) (Bundled with P040046/(b)(4)). When considered in light of your firm’s anticipated subject drop-out rate of (b)(4) per year, FDA does not anticipate that the Style 410 implant arm will reach the target (b)(4) office visit follow-up rate in year 10.

Your firm’s failure to enroll the required number of subjects in the Style 410 implant arm prevents adequate continuing evaluation of the safety, effectiveness, and reliability of the device and the continued reasonable assurance of the safety and effectiveness of your device, in violation of the requirements established as a condition to your device’s approval under 21 C.F.R. § 814.82(a)(2) and (9). FDA believes it is important for you to complete the redesigned study to develop a long-term safety profile for the device. We recommend that your firm consider alternative strategies, such as retrospective enrollment, to fulfill enrollment of the Style 410 implant arm. Failure to promptly correct this failure may result in withdrawal of your PMA under 21 C.F.R. § 814.82(c).

FDA also advises that failure to conduct any PAS in compliance with the IRB regulations in 21 C.F.R. Part 56 and the informed consent regulations in 21 C.F.R. Part 50 may be grounds for withdrawal of approval of a PMA.

You should take prompt action to correct the violations addressed in this letter.

Within 15 working days from the date of this letter, please provide a plan to address the issues described in this letter, or provide documentation showing that you have complied with your firm’s post-approval requirements and notify this office in writing of the specific steps you have taken to correct the noted violations and to ensure that these violations or similar violations do not occur again. Please include supporting documentation of the corrective actions you have taken. If your planned corrections will occur over time, please include a detailed timetable for implementation of those corrections.

Your response to this letter should be identified as a “Post-Approval Study Protocol PMA Supplement” and reference the CMS Case #607690, sent to:       

     U.S. Food and Drug Administration

     Center for Devices and Radiological Health

     PMA Document Mail Center - WO66-G609

     10903 New Hampshire Avenue

     Silver Spring, MD 20993-0002

If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. If you do not believe that you are in violation, please respond to FDA with your reasoning and any supporting information for our consideration.

Finally, you should understand that there are many FDA requirements pertaining to the manufacture and marketing of devices. This letter pertains only to certain of your firm’s PAS requirements, and does not necessarily address other obligations your firm has under the law.

If you have any questions about the content of this letter, please contact: Jennifer Stevenson at (301) 796-5615 or via e-mail at Jennifer.Stevenson@fda.hhs.gov.


Sincerely yours,

/S/

Binita S. Ashar, MD, MBA, F.A.C.S.
Director
OHT4: Office of Surgical and Infection Control Devices
Office of Product Evaluation and Quality
Center for Devices and Radiological Health

 

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