Ferring Pharmaceuticals Inc.Nocdurna (desmopressin) Orally Disintegrating Sublingual Tablets, 25 meg and 50 mcg

NDA 022517

Food and Drug Administration Silver Spring MD 20993

COMPLETE RESPONSE

Ferring Pharmaceuticals Inc. Attention: Laura Cooper Director, Regulatory Affairs 4 Gatehall Drive, 3" Floor Parsippany, NJ 07054

Dear Ms. Cooper:

Please refer to your New Drug Application (NDA) dated June 19, 2009, received June 22, 2009, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Nocdurna (desmopressin) Orally Disintegrating Sublingual Tablets, 25 meg and 50 mcg..

We acknowledge receipt of your amendments dated August 17 and 25, September 18 and 30, October 20, November 3, and December 22, 2009, and May 7 and August 17, 2010, and May 24 and October 14, 2011, and July 30 and 31, October 12 and 16, 2012, and January 9, 2013.

The July 30, 2012, submission constituted a complete response to our action letter dated April 22, 2010.

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.

CLINICAL/STATISTICAL

The treatment effect size of Nocdurna relative to placebo in the currently studied patient population with nocturia is modest and of unclear benefit.

In Study CS40, Nocdurna 25 meg in women was nominally significant versus placebo (p<0.05) for the co-primary endpoints of change from baseline in the average number of nocturnal voids over 3 months and 33% responder status over 3 months. The results for the continuous endpoint of change from baseline in average number of nocturnal voids was non-robust, as evidenced by non-significant results from sensitivity analyses based on per protocol population and “as treated” population. In Study CS41, Nocdurna 50 mcg and 75 mcg in men were each statistically significant versus placebo for the same co-primary endpoints and supported by sensitivity analyses. However, in both studies the placebo-subtracted difference yielded modest treatment effects of -0.22 voids/night in CS40 and -0.37 and -0.40 voids/night in CS41. The treatment effect was modest relative to within-group changes from baseline. The substantial change from baseline was likely due to the contribution of behavior and lifestyle modification that consisted of instructing patients to limit their fluid intake at bedtime and avoid drinks that may have a

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diuretic effect (caffeine, tea, etc). Because both treatment groups received similar instructions on behavior and lifestyle modification, the efficacy of Nocdurna is properly measured by the treatment difference with placebo. It is inappropriate to ignore the placebo response and assign clinical benefit based solely on a change from baseline in the Nocdurna treatment groups.

Although the newly proposed dosing regimen for men and women was associated with a lower incidence of hyponatremia than your originally proposed dose of 100 mcg, Nocdurna-treated patients still experienced a higher rate of low serum sodium levels than patients treated with placebo. In CS40, three women receiving Nocdurna 25 mcg versus none on placebo had serum sodium levels between 126 and 129 mmol/L. In CS41, severe hyponatremia (serum sodium < 125 mmol/L) was seen in two men receiving Nocdurna 50 meg and four men receiving Nocdurna 75 mcg versus none on placebo. No serious adverse events were reported as a result of these laboratory abnormalities but this is not unexpected given the closer monitoring in a clinical trial prompting treatment discontinuation.

Given the modest treatment effect and a persistent risk for hyponatremia, we remind you that in our April 22, 2010, Complete Response letter, we referenced the importance of an acceptable health-related quality of life tool to provide supportive evidence for the clinical benefit of treating nocturia. A positive patient-reported outcome is particularly important to offset a safety concern such as dilutional hyponatremia.

Your resubmission included patient-reported outcome measures based on the Nocturia Quality of Life (NQoL) questionnaire, the Work Productivity and Activity Index (WPAID), and a recently developed Nocturnal Impact Diary. We have previously communicated with you that the NQoL and WPAI were not acceptable measures in support of labeling. Regardless, the results on these two measures were not consistent. Although the Nocturnal Impact Diary appears to be an acceptable measure, its evaluation in Study 000034 did not yield evidence of efficacy due to the insufficient study sample size.

In order to address this deficiency you will need to conduct a trial demonstrating a clinically meaningful impact of Nocdurna on reducing the frequency of nocturnal voids. The patient population and evidence for clinical benefit can be discussed at an End-of-Review meeting.

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)(i)] in structured product labeling (SPL) format as described at

http://www. fda.gov/ForIndustry/DataS tandards/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.

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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. 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

clini

ical 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

upd:

lated 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. 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 Jennifer Johnson, Regulatory Health 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 IT Center for Drug Evaluation and Research

Reference ID: 3252296

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 01/30/2013

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