Agile Therapeutics, Inc.: levonorgestrel/ethinyl estradiol

Therefore, we have identified the following drug product quality deficiencies:

2. The finished drug product specification is not adequate to ensure the quality, tack and adhesion of the drug product at release and on stability.

Regarding efficacy, we identified twelve additional on-treatment pregnancies in Study ATICL23, which resulted in a Pearl Index of 5.83 (95% CI 4.45-7.21), with a significant number of the FDA-adjudicated pregnancies occurring in women who had delays in applying patches.

If the unacceptable adhesion is due to the design and formulation of the drug product, we recommend that you design a new transdermal system and conduct another clinical trial with the new transdermal system in the US population.

Please be advised that under the Food and Drug Administration Safety and Innovation Act (FDASIA), you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End-ofPhase-2 (EOP2) meeting.

We acknowledge receipt of your June 24, 2013, submission to your new drug application (NDA) for Twirla (levonorgestrel and ethinyl estradiol) transdermal delivery system.

For the reasons explained below, we do not consider this submission to be a complete response to our February 13, 2013, action letter.

We will not start the review clock until we receive a complete response.

June 24, 2013, document without first soliciting feedback from FDA regarding your approach.

We strongly recommend that you request a meeting with us prior to another submission so that you can fully understand our concerns described in the Complete Response letter, including our concerns with your completed phase 3 studies and our rationale for the need for a new phase 3 trial.

You could consider including information from your June 24, 2013, submission as part of the meeting briefing package together with specific questions to FDA.

Twirla (levonorgestrel and ethinyl estradiol) transdermal system for the prevention of pregnancy in women who elect to use a transdermal system as a method of contraception.

The study should use your proposed to-be-marketed product after you have adequately addressed the product quality deficiencies (see below) that may have impacted the efficacy findings in your completed studies.

The current specification provided in the NDA does not contain a test for cold flow or shear as requested and discussed in our Information Request letters and your October 17, 2012, response.

October 17, 2012, the bounds of the acceptance criteria cannot be adequately justified based on statistical analyses.

© ethinyl estradiol (or equivalent presentation of language and units).

Additionally, the identifying label on the backing membrane of the drug product (each patch) must, at a minimum, include the name of the product and the strength.

This is consistent with FDA's current policy regarding the identifying label for all transdermal drug delivery systems.

An information request letter was sent to the DMF holder on March 14, 2012. These deficiencies must be adequately addressed before this application can be approved.

8. During the facility inspection, it was noted that different equipment was used for the manufacture of clinical trial supplies as compared to that proposed for the commercial product.

Inspection requests may be resubmitted upon receipt of your Complete Response submission.

10. If you intend to rely on safety or efficacy data from Study ATI-CL12, conduct an external audit of the data submitted in the final study report, and include the findings of the audit in your Complete Response Submission.

1. You provided an assessment of skin adhesion characteristics in the October 17, 2012, submission entitled "Summary of Reasons for Unscheduled Patch Change by Subject Selfment Safety Population" (Clinical/Statistical Report: Table 14.3.7_4.1).

NOV 30 2010 Rev 04 DCR # 10475) was not evaluated because the method stated to use the test weight specified in the specification, but there was no specification for shear.

Effective AUG 06 2010 Rev 05 DCR # 10317) (b) (4)

1. Adjust the in vitro drug release criterion at the 72 hour time point from No Less Than (NLT) |] % to NLT | }% for both ethinyl estradiol and levonorgestrel.

1. Address whether the product quality deficiencies described above may have impacted the findings in your clinical pharmacology studies.

If the product quality deficiencies can be adequately addressed, provide a revised analysis that corrects for/compensates for this potential carry-over effect.

8. Provide English translations of current approved foreign labeling not previously submitted.