Ferring Pharmaceuticals Inc.Nocdurna (desmopressin) Orally Disintegrating Tablets, 25 mcg and 100 mcg

Dear Mr. Kim:

Please refer to your June 19, 2009, New Drug Application (NDA), received June 22, 2009, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Nocdurna (desmopressin) Orally Disintegrating Tablets, 25 mcg and 100 mcg.

We acknowledge receipt of your amendments dated August 17, 25, September 18, 30, October 20, November 3, and December 22, 2009, and January 14, March 11, April 15, and 19, 2010.

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

CLINICAL/STATISTICAL

1. The placebo-controlled portion of your pivotal trial, FE992026 CS029, demonstrated efficacy on two co-primary endpoints with only Nocdurna 100 meg daily doses for 28 days, as determined by the pre-specified sequential testing procedure for controlling type 1 error across the 4 doses. However, this dose was also associated with a high incidence of hyponatremia, a known side-effect of desmopressin that may have a serious clinical consequence outweighing any perceived benefit of reducing frequency of nocturnal voids. Post-hoc analyses of different subgroups at different time points in this trial suggest differential efficacy by gender at lower doses which may have a more acceptable safety profile. However, these additional analyses were not controlled at the overall 5% level of significance and cannot serve as sufficient evidence of efficacy for a different proposed dosing regimen.

In order to address this deficiency, you must conduct a clinical trial to confirm that a lower dosing regimen is a safe and effective treatment of adult nocturia. This trial should be a placebo-controlled trial with a minimum duration of 3 months to evaluate a longer period of durability and safety relative to placebo.

NDA 22-517 Page 2

CLINICAL PHARMACOLOGY

2. The pharmacokinetic information of the to-be-marketed formulation including the bioequivalence study (CS019) was derived using an analytical method that was not properly validated. In order to address this deficiency, you should:

e Reanalyze the bioequivalence study (CS019) pharmacokinetic samples with a validated analytical method and submit the data to the Agency for review, or

¢ Collect the pharmacokinetic samples in future clinical trials and make every effort to improve and properly validate the bioanalytical method to analyze study samples at the proposed dose strength(s).

NONCLINICAL

3. The nonclinical data you have provided qualify impurities new to this formulation and assess local toxicity. There are no nonclinical data provided to bridge to any listed desmopressin product. This bridge was supposed to be provided by the clinical bioequivalence study which utilized an analytic method that was not properly validated. In the absence of adequate clinical bridging information a comparative toxicology study of one month duration comparing your product to the listed drug product is needed.

LABELING

4. 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)(i)] in structured product labeling (SPL) format as described at http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

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.

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

6. 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.

NDA 22-517

Page 3

7.

10.

11.

12.

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

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.

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.

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.

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

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

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

CLINICAL COMMENTS NOT RELATED TO APPROVABILITY

Your clinical development program did not provide any direct evidence that reduced frequency of nocturnal voids is associated with a clinical benefit. References to increased risk of fractures in patients with nocturia are examples of an association and no conclusion can be made that treating nocturia will reduce the incidence of fractures. Similarly, you were not able to determine if reduced frequency in nocturnal voids would provide a meaningful benefit in the individual’s health-related quality of life. Although improved health-related quality of life does not form the basis for approval of this product, demonstration of such an improvement utilizing a tool that is acceptable to the Agency’s Study Endpoints and Labeling Development (SEALD) team will provide supportive evidence for treating nocturia.

You proposed a monitoring scheme to mitigate the risk of hyponatremia with the use of Nocdurna through the measurement of serum sodium on Days 4 and 28 of treatment based on an argument that decreased sodium occurs shortly after the initiation of therapy. This monitoring scheme was not tested in your clinical development program. However, it was noted that several patients in your program presented with hyponatremia, some severe, beyond Day 28. Any risk mitigation strategy for hyponatremia will need to be evaluated in your clinical development program for consideration in labeling.

NDA 22-517 Page 4

3. You should collect the pharmacokinetic samples in future clinical trials for obtaining exposure-response relationship. You should make every effort to improve and properly validate the bioanalytical method to analyze study samples at the proposed dose strength(s).

Within one year after the date of this letter, you are required to resubmit or take one of the other actions available under 21 CFR 314.110. If you do not take one of these actions, we will consider your lack of response a request to withdraw the application under 21 CFR 314.65. 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 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 Jennifer Johnson, Regulatory Project Manager, at (301) 796-2194.

Sincerely, {See appended electronic signature page}

Mary H. Parks, M.D.

Director

Division of Metabolism and Endocrinology Products Office of Drug Evaluation II

Center for Drug Evaluation and Research

Application Submission

Type/Number Type/Number Submitter Name Product Name NDA-22517 ORIG-1 FERRING NOCDURNA PHARMACEUTICA LS INC

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

MARY H PARKS 04/22/2010