Teva Women’s Health, Inc.progesterone vaginal ring

NDA 201110 COMPLETE RESPONSE

Teva Women’s Health, Inc. Attention: Jennifer Norman, R.Ph. Director, Regulatory Affairs

425 Privet Road

Horsham, PA 19044

Dear Ms. Norman:

Please refer to your New Drug Application (NDA) dated and received on April 30, 2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for progesterone vaginal ring.

We acknowledge receipt of your amendments dated May 7 and 20, August 13 and 19, September 13, October 5, November 10 and 30, December 9 and 17, 2010, and January 31, 2011.

We also acknowledge receipt of your amendment dated February 18, 2011, 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

1. During the prior approval inspection (PAI) of your facility, foreign particulate contaminations were found in all five site transfer batches manufactured at the future commercial site. Conduct a thorough investigation to identify the root cause. Propose corrective measures and demonstrate that the root cause has been corrected by producing three production batches which show no particulates.

2. The progesterone vaginal ring contains | ff) % w/w concentration of progesterone dispersed evenly within the ring. The particle size distribution of progesterone is considered to be critical for the consistent release of progesterone. Amend your application to include a test for particle size distribution with acceptance criteria in the specification for the drug substance.

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3. The drug product specification is incomplete. Revise the “Description” of the drug product specification by adding “Free of particulates by visual inspection” and revise the

“Microbiological Examination” of the drug product specification to include “The absence of om »,

4. Analytical methods for the drug product are inadequate. To address this deficiency:

¢ Validate the accuracy of the HPLC test method for detection of impurity/degradation products in the drug substance.

¢ Validate the repeatability and intermediate precision of the drug product impurity test using samples spiked with the four known impurities at quantitation levels (QL).

e Revise the acceptance criteria of the relative standard deviation (RSD) MO) for establishing the system suitability of the HPLC method.

CLINICAL

You have not provided sufficient evidence of efficacy for the progesterone vaginal ring in the subgroup of women 35-42 years of age. This subgroup represents approximately 50% of the infertile women for whom your drug is intended for use as part of an Assisted Reproductive Technology (ART) treatment program. In general, the subgroup of infertile women 35-42 years of age has diminished ovarian reserve relative to women under the age of 35. You have not demonstrated that information obtained from the subgroup of women less than 35 years of age can be extrapolated to women in the older subgroup.

To address this concern, we continue to recommend that you conduct, prior to approval of your product, a randomized, active-controlled clinical trial to evaluate the efficacy of your product in women 35-42 years of age. The trial should be adequately powered to demonstrate sufficient retention of efficacy in the progesterone vaginal ring arm when compared to the active comparator. Details of the trial should be agreed upon with the Agency prior to the conduct of the study.

It is also possible that appropriate labeling, which would include a statement on limitation of use, and a postmarketing commitment to conduct the clinical trial described above would be sufficient to support approval of the progesterone vaginal ring for use in women less than

35 years of age.

LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate. If you revise labeling, your response must include updated content of labeling [21 CFR 314.50(1)(1)()] in structured product labeling (SPL) format as described at

http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. FACILITY INSPECTIONS

During recent inspections of the Northvale, NJ, testing facility and the Cincinnati, OH, manufacturing facility, our field investigator(s) conveyed deficiencies to the representatives of

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the facilities. Satisfactory resolution of these deficiencies is required before this application may be approved.

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 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:

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

¢ Present tabulations of the new safety data combined with the original NDA data.

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

¢ 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 NDA 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.

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In addition to the above deficiencies, the following issues should be addressed in your response to this letter:

PRODUCT QUALITY 1.

MICROBIOLOGY

1. The method validation studies for total yeast and mold count included an incubation temperature of 3 C, while the proposed test method has an incubation temperature of C. This appears to be an error based on information found later in the method validation package. The error occurs in section 5.2.1(i) and the correct temperature is listed in section 5.3. Revise ARD_RPT-5064 version 2.0 accordingly.

2. Submit the results from microbial enumeration studies on the stability and site transfer batches using the revised test methods.

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. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss what steps you need to take before the application may be approved. If you wish to have

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such a meeting, submit your meeting request as described in the FDA’s “Guidance for Industry - Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

CM153222.pdf.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, call Karl Stiller, Regulatory Project Manager, at (301) 796-1993. Sincerely, {See appended electronic signature page} Scott Monroe, M.D. Director Division of 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.

SCOTT E MONROE 02/28/2011

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