Mentor Worldwide LLC & Acclarent MARCS-CMS 573520 — March 18, 2019

WARNING LETTER

• Product: Medical Devices ; Premarket Approval (PMA)

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• Recipient: Alex Gorsky; Chairman, Board of Directors and Chief Executive Officer; Mentor Worldwide LLC & Acclarent; 33 Technology Drive; Irvine, CA 92618; United States

• Issuing Office: Center for Devices and Radiological Health; 10903 New Hampshire Avenue; Silver Spring, MD 20993-0002; United States

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WARNING LETTER

VIA UNITED PARCEL SERVICE

March 18, 2019

Alex Gorsky
Chairman, Board of Directors and
Chief Executive Officer
c/o Manchi Cheung
Director, Regulatory Affairs, Mentor Worldwide LLC & Acclarent
33 Technology Drive
Irvine, CA 92618

Dear Mr. Gorsky:

The Food and Drug Administration (FDA) approved your device, MemoryShape, under Premarket Approval (PMA) Application, P060028, on June 14, 2013. In addition to the periodic reporting requirements, FDA ordered your firm to conduct a post-approval study (PAS) 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 order is attached, which details the PAS requirements that were imposed as a condition of approval for your device.

Under 21 C.F.R. § 814.82(a)(2) and (9), FDA may impose post-approval study 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 postapproval study requirements established under 21 C.F.R. § 814.82(a) for your device. The MemoryShape Post-Approval Study requirements, detailed in item 3 of the PMA Approval Order dated June 14, 2013, are shown below. Specifically, you have failed to comply with requirements 1 and 2 shown below.

1. Evaluate the long-term clinical performance of MemoryShape Breast Implants under general conditions of use in the postmarket environment.
2. Enroll 2,518 women receiving MemoryShape Breast Implants and 300 women undergoing other aesthetic surgery as the comparison group.
3. Follow the study subjects annually for 10 years.
4. Collect data on the following safety endpoints: connective tissue diseases (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 study participants' responses to questions addressing their perceived quality of life and satisfaction with their breast implants.
6. Collect data from physician evaluations at 1, 5, and 10 years
7. Conduct device explant analyses for all devices retrieved from women enrolled in the study.

On September 16, 2015, FDA received your firm’s revised study protocol (P060028/S013) to modify the MemoryShape PAS and include both MemoryShape and MemoryGel (approved under P030053) devices in one study. The revised protocol submission was approved on February 12, 2016, and the study is being tracked as the “MemoryGel and Shape Glow Study”.

Based on the approved revised study protocol, your firm is required to conduct a 10-year post-approval observational study to include a total of 2,518 women undergoing breast augmentation, breast reconstruction, or revision surgery with MemoryShape or MemoryGel Breast Implants, with a minimum of 750 subjects enrolled in each device family, at up to 100 sites. The study includes a concurrent control group of 300 women who are undergoing an aesthetic surgery other than breast implant surgery. Annual follow-up percentage targets for years one through five are (b)(4)%, (b)(4)%, (b)(4)%, (b)(4)%, and (b)(4)% respectively. A subset of the breast implant patients was to be included in effectiveness questionnaires using the BREAST-Q to evaluate quality of life and satisfaction with breast implants.

On February 3, 2017, FDA received your firm’s submission, P060028/R019 (Bundled with P030053/R069). Although the FDA issued a decision letter on April 4, 2017, to your firm indicating the study status on FDA’s website would remain as “progress adequate” (study met milestones at the time), the letter included advisories related to strategies on how to improve enrollment. At the time of the report, the study met enrollment milestones, but the FDA noted that if the enrollment rate observed at that time did not improve, it would not facilitate reaching the target enrollment of (b)(4) subjects by (b)(4). There were also advisories to improve future reports by providing more detailed information regarding complications and excluded subjects.

On August 10, 2017, FDA received your firm’s submission, P060028/R022 (Bundled with P030053/R071). Although the FDA issued a decision letter on November 27, 2017, to your firm indicating the study status on FDA’s website would remain as “progress adequate”, the letter included an advisory related to the enrollment strategy. Specifically, your firm proposed to (b)(4), which still would not allow reaching the target enrollment of (b)(4) subjects by (b)(4), per the approved protocol. FDA acknowledged your new efforts and advised you to continue following the newly proposed (b)(4) until the date of the next interim report, then re-evaluate your enrollment progress and if needed provide another newly estimated monthly site and subject enrollment plan that would ensure completion of the study enrollment by (b)(4), per approved study protocol.

On February 12, 2018, FDA received your firm’s submission, P060028/R023 (Bundled with P030053/R075). Your firm reported a total of 334 subjects enrolled (216 for MemoryGel, 40 for MemoryShape, and 51 for other aesthetic surgery as of January 2018). Although the FDA issued a decision letter on May 11, 2018, to your firm indicating study status on FDA’s website would remain as “progress adequate”, there were advisories regarding the quality and completeness of the data, how to improve that in future reports, and how to improve follow-up rates. Specifically, your firm was advised on the need to provide more detailed information regarding complications and excluded subjects (as previously advised in decision letters for P060028/R019, P030053/R069, and recognized in your interactive response email dated April 4, 2017). Your firm was also advised to make efforts to maximize rates of follow-up. The rate of follow-up in the report, based on the theoretical yield, was (b)(4), which is much lower than the target follow-up rate (b)(4). Furthermore, you had several data inconsistencies throughout the report. The most concerning ones were on the race/ethnicity data, “missing” operative characteristics, and overall patient accounting. Your firm addressed and acknowledged the data inconsistencies via interactive review on April 10, 2018. Your firm was advised to avoid data discrepancies as much as possible so that FDA can better assess your study results. Finally, revisions to the study timeline have not been approved. FDA tracks study progress by the approved timeline, which reflects completion of study enrollment by (b)(4).

On February 12, 2019, FDA received your submission P060028/R026 (bundled with P030053/R079) containing updates on your study enrollment and follow-up rates through December 13, 2018. Per the approved PAS protocol, your PAS enrollment was to be completed with a target of (b)(4) subjects by (b)(4). Your firm reports a total of 2,498 subjects have been enrolled (1,930 for MemoryGel, 102 for MemoryShape, and 319 for other aesthetic surgery).

Per the February 12, 2019, enrollment update, your firm has failed to enroll the required number of study subjects with the MemoryShape device; and therefore, you are failing to fulfill a condition of approval for P060028. Your firm was given the opportunity to implement measures to improve study enrollment. Although you have described the slow enrollment was due to the (b)(4) MemoryShape device; per data submitted in your interim reports, a total of (b)(4) MemoryShape devices have been implanted as of the end of 2018. In addition, only 78 sites have been enrolled; per the protocol, your firm had the option to enroll up to (b)(4) sites. These (b)(4) records do not support your rationale for slow enrollment of MemoryShape study subjects. We also note the following study deficiencies:

• As of December 13, 2018, only 102 subjects have been enrolled in the MemoryShape device group. Per the approved protocol, your firm was required to enroll (b)(4) MemoryShape subjects by (b)(4).
• The effectiveness cohort was to include the first ~500 breast implant patients who are enrolled in the study; overall there are 189 evaluable patients in the BREAST-Q cohort which is also below target.

Your firm failed to enroll the required number of PAS participants. This failure prevents adequate continuing evaluation of the safety, effectiveness, and reliability of the device. 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). Failure to promptly correct this failure may result in withdrawal of your PMA under 21 CFR 814.82(c).

FDA also advises that failure to conduct any post-approval studies in compliance with the institutional review board 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 the 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 requirement and notify this office in writing of the specific steps you have taken to correct the noted violation and to ensure that this violation 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# 573520, 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.

Finally, you should understand that there are many FDA requirements pertaining to the manufacture and marketing of devices. This letter pertains only to the issue of 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/

Ann M. Ferriter
Director, Division of Analysis and Program
Operations
Office of Compliance
Center for Devices and Radiological Health