Agile Therapeutics, Inc.levonorgestrel/ethinyl estradiol 120/30 mceg/day transdermal contraceptive delivery system

NDA 204017 COMPLETE RESPONSE

Agile Therapeutics, Inc.

Attention: Mark B. Carroll

Vice President, Regulatory Affairs and Quality Assurance 101 Poor Farm Road, 3rd Floor

Princeton, NJ 08540

Dear Mr. Carroll:

Please refer to your New Drug Application (NDA) dated April 12, 2012, received April 13, 2012, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for levonorgestrel/ethinyl estradiol 120/30 mceg/day transdermal contraceptive delivery system.

We acknowledge receipt of your amendment dated June 26, 2017, which constituted a complete response to our February 13, 2013, action letter.

We also acknowledge receipt of your amendment dated December 1, 2017, which was not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this letter.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

PRODUCT QUALITY

Drug Product Adhesion of your transdermal system to skin is critical for the safe and effective use of the drug

product. We relayed our concerns with the adhesion performance of your product in the February 13, 2013, Complete Response Letter. Significant adhesion problems remain based on quality issues discussed in this section and findings from your most recent clinical study, ATI- CL23 discussed in the CLINICAL section below.

As noted in our information request dated November 7, 2017, the goal of quality adhesion testing

is to assure that future batches of drug product are comparable to batches that have adequate in vivo adhesion. Based on our review of the manufacturing process and in-process controls, we

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determined that the in-process adhesion data for the clinical and commercial-scale intermediates were not comparable, and that there was a high frequency of invalid results.

In addition, the proposed finished product specification lacks a validated test and appropriate acceptance criteria for Part Tack. The current adhesion test, TP074, is highly variable, subjective, and results in uninterpretable data with non-comparable profiles between batches.

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

1. You have not demonstrated that the in-process adhesion and tack tests are suitable for ensuring the quality and the in vivo adhesion of the commercial-scale product.

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. The current in vitro adhesion test does not ensure adequate in vivo adhesion properties requisite for the safe and efficacious use of the drug product.

Facility Inspections

3. During a recent inspection of the Corium International Inc. (FEI 3003693015) manufacturing facility for this NDA, our field investigator observed objectionable conditions at the facility and conveyed that information to the representative of the facility at the close of the inspection.

CLINICAL

In your clinical trial (ATI-CL23),11.3% of patches result in less than 75% of adherence during the 7-day wear cycle and over half of subjects reported at least one complete patch detachment during the study. In this context, your Pearl Index was higher than expected for a combined hormonal contraceptive product, rates of subject discontinuation were above 50% and unscheduled bleeding (cycle control) on treatment was over 40%. It is unclear whether these findings were a result of inadequate adhesion of your product, application site tolerability issues, unscheduled bleeding or other issues.

Regarding efficacy, we identified twelve additional on-treatment pregnancies in Study ATI- CL23, 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. We are concerned about the implications of these findings for real-world use, and the extent to which the significant withdrawal and drop-out rates may have impacted the reliability of the results.

The serious risks with your product, including thromboembolic events, appear to be similar to those seen with other combined hormonal contraceptives.

In summary, based on the adhesion problems seen in your clinical trial and described in the product quality section, you have not demonstrated that your drug product has the in vivo adhesion properties requisite for its safe and effective use. The extent to which these adhesion issues affected efficacy, unscheduled bleeding and high subject discontinuation rates is unclear.

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Given that the main advantage of your combined hormonal contraceptive product would be a more convenient dosing schedule, we are unable to conclude that the reduced efficacy outweighs the risks and uncertainties described above.

Recommendations to Address the Deficiencies:

Drug Product

1. Assess whether the unacceptable in vivo adhesion properties observed in your clinical trial are the result of the current design and formulation of the drug product, or are due to some other factor(s).

2. Develop and validate in-process tests for tack and adhesion. Justify the acceptable ranges using results obtained during the manufacture of drug product batches with acceptable in vivo adhesion properties.

3. Develop and validate tests for part tack and adhesion for release and stability on the finished

drug product. Justify the acceptable ranges using results obtained from finished drug product batches with acceptable in vivo adhesion properties.

Facility Inspections

4. Satisfactory resolution of the objectionable conditions observed at the manufacturing facility (FEI 3003693015) for this NDA is required.

5. Assess whether the unacceptable in vivo adhesion properties are the result of the current design and formulation of the drug product, or are due to some other factor(s) and how this may contribute to efficacy, cycle control and safety of your product. Address the implications of the delays in applying the patch seen in your trial and the high withdrawal and dropout rates. 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.

PREA REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.

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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-of- Phase-2 (EOP2) meeting. In the absence of an EOP2 meeting, refer to the draft guidance below. The iPSP must contain an outline of the pediatric study or studies that you plan to conduct (including, to the extent practicable study objectives and design, age groups, relevant endpoints, and statistical approach); any request for a deferral, partial waiver, or waiver, if applicable, along with any supporting documentation, and any previously negotiated pediatric plans with other regulatory authorities. The iPSP should be submitted in PDF and Word format. Failure to include an Agreed iPSP with a marketing application could result in a refuse to file action.

For additional guidance on the timing, content, and submission of the iPSP, including an iPSP Template, please refer to the draft guidance for industry, Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at: http://www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM360507.pdf. In addition, you may contact the Division of Pediatric and Maternal Health at 301-796-2200 or email Pedsdrugs@fda.hhs.gov. For further guidance on pediatric product development, please refer to:

http://www. fda.gov/Drugs/DevelopmentA pprovalProcess/DevelopmentResources/ucm049867.htm.

PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) — a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the prescribing information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

PROPRIETARY NAME

Please refer to correspondence dated, September 11, 2017 which addresses the proposed proprietary name, Twirla (levonorgestrel/ethiny! estradiol) transdermal delivery System, 120/30 meg/day. This name was found acceptable pending approval of the application in the current review cycle. Resubmit the proposed proprietary name when you respond to the application deficiencies.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and

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clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

1. Describe in detail any significant changes or findings in the safety profile.

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

5. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

7. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

8. Provide English translations of current approved foreign labeling not previously submitted. OTHER Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in which to resubmit the application. A resubmission must fully address all the deficiencies listed in this letter and should be clearly

marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a

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complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” March 2015 at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 43743 L.pdf.

If you have any questions, call Charlene Williamson, Regulatory Project Manager, at (301) 796- 1025.

Sincerely,

{See appended electronic signature page}

Audrey Gassman, M.D.

Deputy Director

Division of Bone, Reproductive and Urologic Products

Office of Drug Evaluation III Center for Drug Evaluation and Research

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

AUDREY L GASSMAN 12/21/2017

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