Ferring Pharmaceuticals Inc.: progesterone

Following a pre-license inspection of ecerceconicreaccirt listed in this application, conveyed deficiencies fo the representative of the facility.

The facility should provide satisfactory responses to these deficiencies to the FDA office indicated on the FDA Form 483 prior to your complete response to your application.

Your complete response should include the date(s) of the facility's response to the FDA Form 483. The assessment of application approvability and the resolution of inspection deficiencies would be evaluated upon receipt of the complete response and may include re-inspection of the facility.

We reserve further comment on the proposed labeling until the application is otherwise adequate.

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.

1. Your to-be-marketed combination drug-device product, progesterone vaginal ring, contacts the skin and mucosal surface for a permanent contact duration (cumulative single, multiple or repeated long-term use or contact exceeds 30 days), and you provided insufficient biocompatibility information to support this contact duration.

To meet the biocompatibility requirements and adequately evaluate and support safety of the to-be-marketed progesterone vaginal ring product, satisfactorily address the following testing paradigm:

= For products that are inherently cytotoxic or products that demonstrate cytotoxicity, perform additional testing using several dilutions of the extracts derived from the final, finished, to-be-marketed combination progesterone vaginal ring product to determine the level at which cytotoxicity no longer occurs.

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.

We also stated in the February 28, 2011, Complete Response letter that a possible alternative approach would be appropriate labeling, which would include a statement on limitation of use along with a post-marketing commitment to conduct the clinical trial described above.

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

The July 31, 2014, submission constituted a complete response to our January 30, 2013, action letter.

To address this deficiency you will need to conduct a trial to demonstrate that Nocdurna provides a meaningful clinical benefit that is associated with the reduction in number of nocturnal voids in adults with nocturia due to nocturnal polyuria.

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 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.

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.

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.

We have previously communicated with you that the NQoL and WPAI were not acceptable measures in support of labeling.

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.

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.

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.

This bridge was supposed to be provided by the clinical bioequivalence study which utilized an analytic method that was not properly validated.

Your clinical development program did not provide any direct evidence that reduced frequency of nocturnal voids is associated with a clinical benefit.

Agency's Study Endpoints and Labeling Development (SEALD) team will provide supportive evidence for treating nocturia.

3. You should collect the pharmacokinetic samples in future clinical trials for obtaining exposure-response relationship.