FDA Briefing Document. Endocrinologic and Metabolic Drugs Advisory Committee Meeting. January 12, :00 AM to 5:00 PM

Transcription

1 FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting January 12, :00 AM to 5:00 PM The committee will discuss the safety and efficacy of new drug application (NDA) , proposed trade name NOCDURNA (established name: desmopressin), orally disintegrating sublingual tablets submitted by Ferring Pharmaceuticals, Inc. The proposed indication is treatment of nocturia due to nocturnal polyuria in adults who awaken two or more times each night to void. 1

2 The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought NDA Nocdurna (desmopressin) ODST to this Advisory Committee in order to gain the Committee s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2

3 Table of Contents Division Director Memorandum 4 Page Draft Points to Consider 9 Clinical-Statistical Summary 10 Clinical Summary Appendix 76 Reference List 83 Study Endpoints Consult Review 84 Division of Bone, Reproductive and Urologic Products Consult Review 96 Division of Psychiatry Products Consult Review 105 3

4 Division Director Memorandum Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolism and Endocrinology Products Date: December 15 th, 2014 From: To: Subject: Jean-Marc Guettier, MD Director, Division of Metabolism and Endocrinology Products (DMEP) Chair, Members and Invited Guests of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) Overview of the January 12, 2015 EMDAC meeting On January 12, 2015, the Endocrinologic and Metabolic Drugs Advisory Committee will discuss the safety and efficacy of new drug application (NDA) for NOCDURNA (desmopressin). The proposed indication is treatment of nocturia due to nocturnal polyuria in adults who awaken two or more times each night to void. Background Desmopressin is a synthetic analog of the neurohypophyseal nonapeptide hormone arginine vasopressin (AVP). Compared to arginine vasopressin, desmospressin has a longer duration of action, greater anti-diuretic properties and lower blood pressure raising effects. In the US, desmopressin is approved to treat central diabetes insipidus, hemophilia A, type 1 von Willebrand s disease, nocturnal enuresis in children and as a diagnostic test to measure renal concentrating abilities. Desmopressin reduces urinary volume through reabsorption of free water. Nocturia Clinically meaningful nocturia has been defined based on expert opinion as waking-up 2 or more times per night to void where each voiding episode is preceded and followed by sleep. The applicant relied on this criterion to select patients for participation in their pivotal trials. Risk factors for nocturia identified from cross-sectional and case-control data include advanced age, obesity, hypertension, snoring, diuretic use, anti-depressant use, diabetes, benign prostatic hypertrophy, prostate cancer and congestive heart failure. Prevalence of nocturia increases with age and as defined above is highly prevalent in older age groups. 4

5 Figure: Prevalence of Nocturia By Age and Sex (Tikkinen et al. 2006) 1 Observational and cross-sectional questionnaire-based studies have suggested a possible association between nocturia and abnormal sleep onset and maintenance, depression, decreased quality of life, and in patients older than 75 years old, falls and fracture. Nocturia can result from disorders that cause frequent, low volume, nighttime voids (e.g., overactive bladder, bladder obstruction) or frequent, high volume, nighttime voids [e.g., nocturnal polyuria, global polyuria (diabetes insipidus or mellitus)] or a combination of both. Patients with sleep disorders (e.g., obstructive sleep apnea, restless leg syndrome, and periodic limb movements) also complain of nocturia. Whether these patients wake-up because of a true need to urinate or as a result of an unrecognized sleep disturbance (an apneic episode or a limb movement) which they falsely attribute to the need to urinate has been raised by some studies. Nocturnal polyuria Nocturnal polyuria is a subset of nocturia characterized by excessive volume of urine produced at night. The diagnosis is age-dependent as has been defined as a nocturnal urine volume that exceeds 20% of the total 24-hour volume in adults younger than 35 years and 33% of the total 24-hour volume in adults older than 65 years respectively 2. It has been attributed to abnormalities in the diurnal variation of AVP secretion, to abnormalities in the diuresis of solutes (e.g., urea, sodium, potassium) and to nighttime mobilization of edematous fluid in conditions such as congestive heart failure, nephrotic syndrome, or venous insufficiency. Therapeutic Approach There are currently no FDA approved products for the treatment of nocturia or nocturnal polyuria. Desmopressin, at doses approved for other indications, is sometimes used off-label to treat patients with nocturia who have not responded to lifestyle/behavioral and therapeutic 1 Tikkinen et al. J Urol Feb; 175(2): van Kerrebroeck et al. Neurourol Urodyn. 2002; 21(2):

6 interventions that address the more immediate cause(s) of nocturia. Desmopressin is marketed in Europe and Canada for the treatment of nocturia in adults under the age of 65 years. Hyponatremia Acute and chronic dilutional hyponatremia are recognized risks associated with the use of desmopressin. Acute, severe, hyponatremia can cause neurologic dysfunction due to cerebral edema and result in loss of consciousness, seizure, coma, respiratory arrest and death. Recent observational, cross sectional and experimental studies suggest a possible association between mild chronic hyponatremia and neurocognitive impairment, gait disturbances and predisposition to falls, osteoporosis and fractures in elderly. Advanced age, female gender, medications (e.g., thiazide and loop diuretics, NSAIDs, anti-depressants), and specific disease states (e.g., renal impairment, congestive heart failure, nephrotic syndrome) predispose to hyponatremia. Regulatory History The NOCDURNA application (NDA ) was not approved in two previous cycles of review because the risks were deemed to outweigh the demonstrated benefits of the therapy for the proposed indication. It is important to note that the proposed indication for the first two cycles of reviews was different than the currently proposed indication. In the first two cycles of review, the applicant had proposed to indicate NOCDURNA for the treatment of adults with nocturia regardless of age or cause(s). For this resubmission the applicant proposes to indicate NOCDURNA for the treatment of nocturia due to nocturnal polyuria in all adult patients who awaken at least twice per night to void. First Review Cycle The pivotal study in the first cycle of review (Trial-CS029) was a 28 day study comparing the effect of four doses of NOCDURNA (10, 25, 50 and 100 mcg) to placebo. The primary objective of the trial was to demonstrate that participants randomized to NOCDURNA would have a significant reduction in the mean number of nocturnal voids and would be more likely to experience a 33% reduction in the number of nocturnal voids. Use of a two component coprimary endpoint was recommended to ensure that significant differences based on mean changes were not driven by the response of a few outliers. Only the 100 mcg dose group demonstrated a statistically significant effect over placebo at Day 28. In this dose group, the placebo adjusted mean (95% CI) reduction from baseline in the number of voids per night was (-0.85, -0.38) void per night and the odds of experiencing a 33% reduction from baseline in the number of nocturnal voids was greater on NOCDURNA than placebo [Odds ratio (95% CI); 2.9 (1.8, 4.7)]. Hyponatremia, including severe hyponatremia, was identified as a risk associated with the use of NOCDURNA in this trial. More people on active therapy withdrew due to hyponatremia and a clear dose-response relationship between incident cases of hyponatremia and NOCDURNA dose was observed. Furthermore, questions were raised with regard to the generalizability of the safety findings because specific patient populations with certain medical conditions common to patients with nocturia and known to predispose patients to hyponatremia were specifically 6

7 excluded from pivotal trial participation (e.g., renal impairment, use of loop diuretic, congestive heart failure). Post hoc analyses suggested a differential effect by gender and the possibility that lower, gender specific, dosing could yield a more favorable benefit risk profile. In the Complete Response Letter the applicant was instructed to conduct an additional trial. The Division also voiced a concern regarding interpretability of the clinical meaningfulness of the small effect size absent a demonstrated effect on a patient reported or clinical outcome. The applicant was advised to develop an instrument to capture the patient-perceived benefit of using NOCDURNA as a treatment for nocturia. Second Review Cycle The applicant conducted two new 3-month, placebo-controlled studies to address the deficiencies in the Complete Response Letter. Trial-CS40 evaluated the 25 mcg dose of Nocdurna in women and Trial-CS41 evaluated a 50 and 75 mcg dose of NOCDURNA in men. Both studies employed similar designs and relied on the same two co-primary efficacy endpoints as Trial-CS029. In women, NOCDURNA 25 mcg (Trial-CS40) resulted in a placebo-adjusted mean (95% CI) reduction from baseline in the number of voids per night of (-0.44, -0.04) void per night and increased odds of experiencing a 33% reduction from baseline in the number of nocturnal voids [Odds ratio (95% CI); 1.8 (1.2, 2.8)]. In men, NOCDURNA 75 mcg and 50 mcg (Trial-CS41) resulted in a placebo-adjusted mean (95% CI) reduction from baseline in the number of voids per night of (-0.60, -0.20) and (- 0.57, -0.17) void per night respectively and increased odds of experiencing a 33% reduction from baseline in the number of nocturnal voids [Odds ratio (95% CI); 2.0 (1.4, 3.0) and 2.0 (1.3, 3.0 for the 75 and 50 mcg dose respectively]. The Division again had difficulties interpreting the clinical meaningfulness of the small reported mean reduction in nocturnal voids (~ 1.7 voids per week in women and 2.8 voids per week in men). Although a patient reported instrument [e.g., Nocturia Quality of Life questionnaire (NQoL)] was used in the pivotal trial to measure the impact of nocturia and its treatment on the patient s quality of life, results derived from this instrument were not compelling because the instrument lacked validity 3, relied on a long recall period (i.e., average symptoms over twoweeks) and analyses were post-hoc, exploratory, unadjusted for multiplicity and results lacked consistence across time points. Hyponatremia for both sexes and at all doses was again noted as the most important risk associated with the use of NOCDURNA and questions regarding the generalizability of the trial derived hyponatremia risk estimates to the care setting for whom this drug were raised. 3 The instrument was noted to lack content validity because it failed to include all the dimensions of the impact of nocturia on a patient s quality of life and included dimensions not related to the concept the instrument was intended to measure. For example, the NQoL instrument was noted to lack an assessment of the psychological/emotional impact of nocturia, to include measurements of general concepts which could be impacted by non-nocturia related aspects of life (e.g., economic well-being), to include items not related to assessing the impact of nocturia treatment (e.g., worried about lack of available therapy). 7

8 Again, the magnitude of the demonstrated treatment effect was not deemed sufficient to justify the risk of hyponatremia and the application received a second Complete Response. The Division requested the sponsor carry out another trial with the objective of establishing the clinical meaningfulness of the demonstrated effect size using a patient reported instrument the applicant had been developing with input from the Study Endpoints Development team at FDA. Dispute and Proposed Path Forward The applicant appealed the Division s decision through a formal dispute resolution request (FDRR) and asked that the application be approved on the grounds that they had successfully demonstrated safety and efficacy of NOCDURNA 25 and 50 mcg. The appeal was denied. As a proposed path forward the applicant was asked to re-submit the application with additional data to support the robustness of the efficacy findings along with any data they viewed as relevant to informing the clinical importance of the demonstrated effect size (e.g., sleep data) and the Division was asked to convene an Advisory Committee for the purpose of presenting the totality of evidence to subject matter experts and publically discussing the issues raised in the first two cycles of reviews and more broadly, the benefit risk of NOCDURNA for the proposed indication. The Division has reviewed the additional information submitted by the applicant and these reviews are included in this background documents. The clinical and statistical review teams provide a detailed account of the history, efficacy and safety data in the Clinical Summary Document. FDA subject matter experts in urology from the Division of Bone, Reproductive and Urologic Products provide a perspective on the disease, the population evaluated in clinical trials, the effect size and the risks associated with NOCDURNA use in the document entitled Division of Bone, Reproductive and Urologic Products Consult Review. The Study Endpoints Development team provides a review of the validity of the patient reported outcomes instruments used in clinical trials in the document entitled, Study Endpoints Consult Review. Finally, FDA subject matter experts in sleep disorders have reviewed the argument made by the applicant that the increased time to first awakening (~40-50 minutes longer on NOCDURNA) may meaningfully impact a patient s quality of life in the document entitled Division of Psychiatry Products Consult Review. 8

9 Nocdurna: Draft Points to Consider Comment on whether the applicant has identified and adequately evaluated a population appropriate for the proposed indication. Explain your answers. Discuss the clinical impact expected from the observed placebo-adjusted effect size at NOCDURNA doses of 25 µg in women and 50 µg in men and comment on whether you believe this effect size represents a meaningful clinical benefit to patients with nocturia. In your answer, point to specific findings in the application that substantiate your position. In light of the overlap between the population at risk for hyponatremia and the population at risk for nocturia, discuss your level of concern with regard to the risk of acute and chronic hyponatremia in clinical practice. Discuss whether the CS-40 and CS-41 trials can reliably inform the risk in the general community. Discuss whether this risk can be adequately mitigated through proper patient selection, additional initial serum sodium monitoring and communications to patients and prescribers through labeling. Provide your reasons and offer additional suggestions if appropriate. In light of the available efficacy and safety findings in the application, comment on whether you believe the benefit of NOCDURNA outweigh the risks and support approval of this indication at the proposed doses for the proposed population. Explain your answer and recommend additional studies if you believe they are needed. Provide specific recommendations on ways to identify the patient population who may be a candidate for this drug in practice or in additional trials. 9

10 CLINICAL-STATISTICAL SUMMARY New Drug Application (NDA) Nocdurna (desmopressin) Orally Disintegrating Sublingual Tablet William Lubas, MD, PhD Dragos Roman, MD Jean-Marc Guettier, MD Division of Metabolism and Endocrinology Products (DMEP) Anna Kettermann, Dipl. Math, MA Mark Rothmann, PhD Division of Biometrics 2 12 January

11 Table of Tables Table 1 Pharmacodynamics of Desmopressin ODST in Children with PNE Table 2 Efficacy Results in the NOCT 2A, 3A and 4 Studies Table 3 Hyponatremia Reported as an Adverse Reaction in the Dose Titration Phase of Studies, NOCT 2A, 3A and 4 by Dose Table 4 Hyponatremia Reported as a Low Lab Value in the Dose Titration Phase of Studies, NOCT 2A, 3A and 4 by Dose Table 5 Change from Baseline to Final Visit (Day 28) in Mean Number of Nocturnal Voids (ITT, First part of co-primary endpoint) Table 6 Proportion of Subjects with >33% Reduction from Baseline in Mean Number of Nocturnal Voids (ITT, Second part of co-primary endpoint) Table 7 Change from Baseline to Final Visit (Day 28) in Mean Number of Nocturnal Voids with respect to gender (ITT, First part of co-primary endpoint) Table 8 Proportion of Subjects with >33% Reduction from Baseline in Mean Number of Nocturnal Voids with respect to gender (ITT, Second part of co-primary endpoint) Table 9 Mean (SD) Change from Baseline to Day 28 in NQoL (ITT Population) Table 10 Categorical Analysis of Hyponatremia (Lowest Serum Sodium) by Dose Trial CS Table 11 Minimum Serum Sodium by Gender in CS Table 12 Mean Baseline Void Parameters Table 13 Subject Disposition Table 14 First Co-primary Endpoint-Change from Baseline in Mean Number of Nocturnal Voids Averaged over a 3-Month period Studies CS40 and CS Table 15 Second Co-Primary Endpoint-Odds Ratio of Patients with >33% Response from Baseline Averaged over a 3-Month Period Studies CS40 and CS Table 16 Proportion of 33% Responders by Visit (CS40 and CS41) Table 17 Average Responder Analysis over 3 Months Table 18 Change from Baseline in Mean Time (minutes) to First Nighttime Void at Month 3 (CS40 and CS 41) Table 19 NQoL Domain Scores CS Table 20 N-QoL Domain Scores CS Table 21 Common Adverse Reactions Occurring at >2% of Subjects in Any Treatment Group in CS29, CS31, CS40 and CS Table 22 Categorical Analysis of Minimum Serum Sodium Values (Safety Analysis Set) CS40 (women) Table 23 Women with Serum Sodium < 130mmoL/L in CS Table 24 Categorical Analysis of Minimum Serum Sodium Values (Safety Analysis Set) in Part 1 of CS41 (men) Table 25 Men with Serum Sodium < 125mmoL/L in Part I of study CS Table 26 Categorical Analysis of Minimum Serum Sodium Values (Safety Analysis Set) in Study CS41 Part II Table 27 Men with Serum Sodium < 125mmoL/L in Part II of study CS Table 28 First Co-primary Endpoint of Mean Change from Baseline in Nocturnal Voids in Subjects With and Without Nocturnal Polyuria in CS40 (Females) and CS41 (Males)

12 Table 29 Second Co-primary Endpoint 33% Responder Status in Subjects With and Without Nocturnal Polyuria in CS40 (Females) and CS41 (Males) Table 30 Second Co-primary Endpoint Odds Ratio of 33% Responder Status in the Total Population in CS40 (Females) and CS41 (Males) Table 31 Mean Change from Baseline (During 3 Months of Treatment) in Mean Nocturnal Voids in Subjects With and Without OAB/BPH in CS40 (Females) and CS41 (Males) (First Co-primary Endpoint) Table 32 33% Responder Status Study CS40 (Females) in Subjects with and without OAB (Second Co-Primary Endpoint) Table 33 33% Responder Status Study CS41 (Males) in Subjects with and without OAB/BPH (Second Co-Primary Endpoint) Table 34 Mean Change from Baseline in Daytime Voiding Frequency in Patients in CS40 (Females) and CS41 (Males) Table 35 Mean Change from Baseline in Daytime Voiding Frequency in OAB/BPH Patients in CS40 (Females) and CS41 (Males) Table 36 Mean Change from Baseline in Daytime Voiding Volume (ml) Patients in CS40 (Females) and CS41 (Males) Table 37 Mean Change from Baseline in Daytime Voiding Volume (ml) OAB/BPH Patients in CS40 (Females) and CS41 (Males)

13 Table of Figures Figure 1 Pharmacodynamics of Nocdurna in Adult Subjects with Nocturia (urine Osmolality >200 mosm/kg) Mean (SE) (urine osmolality >200 mosm/kg) Figure 2 Study Design of the NOCT studies Figure 3 Study Design for CS29 Part 1 & II and CS Figure 4 Monthly Change from Baseline in Mean Number of Nighttime Voids (ITT, First part of co-primary endpoint) Figure 5 Monthly Proportion of Subject with > 33% Reduction from Baseline in Mean Number of Nighttime Voids (ITT, Second part of co-primary endpoint) Figure 6 Mean Decrease in Nocturnal Urine Volume by Dose and Gender in Study CS Figure 7 Serum Sodium Levels in CS29 (without excluding any patients using the monitoring scheme) Figure 8 Serum Sodium Levels in SC29 (excluding subjects identified by monitoring on Day 4 and Day 28) Figure 9 CS40 Trial Design (Women) Figure 10 CS41 Trial Design (Men) Figure 11 Change in Mean Number of Voids Based on Missing 3 month Data CS Figure 12 Change in Mean Number of Voids Based on Missing 3 month Data CS Figure 13 Adjusted Change from Baseline during 3 Months of Treatment in Mean Number of Nocturnal Voids (Trials CS40 and CS41) Figure 14 Forest Plot on Mean Difference in the Change from Baseline in Mean Number of Nocturnal Voids (first co-primary endpoint) in Study CS40 for Women Treated with 25mcg Nocdurna and Placebo Figure 15 Forest Plot Mean Differences in the Change from Baseline in Mean Number of Nocturnal Voids (first co-primary endpoint) in Study CS41 for Men Treated with 50mcg Nocdurna and Placebo Figure 16 Proportion of 33% Responders by Visit (CS40 and CS41) Figure 17 % Response at Responder Thresholds in Females Figure 18 % Response at Responder Thresholds in Males Figure IMPACT- Study Trial Design Figure 20 Plot of Minimum Post-Dose Serum Sodium in CS Figure 21 Serum Sodium Levels in Pt Figure 22 Serum Sodium Levels in Pt Figure 23 Plot of Minimum Post-Dose Serum Sodium Levels in Part I of Study CS41 (men) Figure 24 Plot of Minimum Post-Dose Serum Sodium Levels in Part II of Study CS41 (men)

14 Executive Summary Ferring s initial trials for the nocturia indication were conducted with the tablet formulation at doses of 0.1, 0.2 and 0.4mg in studies NOCT-2A (men only), NOCT-3A (women only), and NOCT-4 (men and women) and the corresponding open-label extension studies NOCT-2B and NOCT-3B. These doses were chosen as they were found to be safe and effective in the treatment of primary nocturnal enuresis (PNE) in children and young adults. These studies had an open label run-in period to better select for responders and measured a 50% responder rate relative to baseline as the primary endpoint during the three week double-blind treatment phase. While these studies showed modest efficacy compared to placebo few of the patients were completely dry even though >80% of subjects were titrated to doses of 0.2mg or higher. In addition, a much higher rate of hyponatremia was observed at these doses than had been seen previously in younger patients treated for PNE. Ferring then designed trial CS29 to study lower doses of desmopressin using a new orally disintegrating sublingual tablet (ODST) formulation which had greater bioavailability than the original tablets. This study comprised Ferring s first official submission for the nocturia indication. Nocturia was defined as an average of 2 nocturnal voids per night as determined by a 3-day voiding diary. The study was designed as a double-blind, placebocontrolled study, without a run-in period, comparing doses of 10, 25, 50 or 100mcg of ODST (corresponding to 0.017mg, 0.042mg and 0.083mg and 0.17mg of the original tablet) at a predefined time point of Day 28. Study CS29 used a new primary endpoint consisting of two co-primary components (1) a mean reduction in the number of nighttime voids and (2) the proportion of subjects who showed at least a 33% reduction in the mean number of nocturnal voids. The statistical analysis plan required that Ferring test both co-primary endpoints independently at a p-value 0.05 and win on both endpoints. Nocturnal voids were recorded in a diary on 3 consecutive 24 hour periods at baseline and during the first four weeks of the study (e.g. Days 8, 15, 22 and 28). Statistical significance was seen only with the 100mcg dose on the prespecified time point, Day 28, which was also associated with a high incidence of hyponatremia. However, post-hoc analyses of different subgroups at different time points in this trial suggested differential efficacy by gender at lower doses which may have a more acceptable safety profile. Therefore the Compete Response (CR) letter issued to Ferring recommended a new placebo controlled clinical trial with a minimum duration of 3 months to confirm durability of efficacy and safety at lower gender specific doses. In response to the first CR the Ferring designed Study CS40 in women treated with the 25mcg dose and CS41 in men treated with both 50 and 75mcg doses compared to placebo. These studies used the same two co-primary endpoints as had been used in CS29 but the endpoints were measured using an longitudinal analysis, i.e. a repeated measures ANCOVA comparing change from baseline to Week 1, Month 1, Month 2 and Month 3, adjusted for age (< 65, 65), visit and baseline nocturnal voids. The longitudinal analysis was chosen because data from CS29 showed that there was a fair amount of variability at each individual time point (e.g. Day 28) and so it was felt that the average response over a longer treatment period might be more representative of the clinical benefit. This study 14

15 also prospectively tested a serum sodium monitoring scheme developed by Ferring, after a post hoc analysis of the CS29 data, to aid in identifying subjects at risk of hyponatremia so they could be discontinued from treatment prior to developing severe hyponatremia and any corresponding sequelae. During this time the sponsor was in discussion with the Study Endpoints and Labeling Division (SEALD) team about the development of a new patient reported outcome (PRO) questionnaire to assist in the evaluation of clinical benefit. However, as the new Nocturia Impact (NI) questionnaire was not ready at the time studies CS40 and CS41 were initiated the sponsor chose to use the Nocturia Quality of Life (NQoL) questionnaire from the literature instead. The NQoL questionnaire had been previously used in CS29 where it had given inconsistent results and was deemed inadequate by the SEALD team because of problems with content validity. Ferring was able to demonstrate statistical significance with both primary endpoints at the 25mcg dose in women (CS40) and the 50mcg dose in men (CS41); the doses Ferring is proposing for treatment. However, the Agency concluded the treatment effect size relative to placebo in the currently studied patient population with nocturia, e.g. a mean difference in the change from baseline of voids/night in women and voids/night in men, was modest and of unclear benefit. Hyponatremia was still observed in these trials but the sponsor s monitoring scheme was able to identify subjects before they went on to develop severe hyponatremia < 125mmoL/L. While monitoring significantly decreased the incidence of hyponatremia seen at the originally proposed dose of 100mcg and no serious adverse reactions were seen in these clinical trials due to hyponatremia there was still a persistent risk for hyponatremia and the Agency was concerned that the risk might become more apparent and more serious if the drug was used in a larger and more diverse population with additional comorbidities and risk factors with less controlled conditions than are present in clinical trials. Therefore, the Agency felt the risk/benefit assessment was still not in favor of treatment for this indication and issued the second CR letter asking the sponsor to conduct a new trial demonstrating a clinical meaningful impact of Nocdurna on reducing the frequency of nocturnal voids with the intention that the now validated NI diary might be able to provide such information. At the End of Review (EOR) and Formal Dispute Resolution Request (FDRR) meetings that followed the sponsor stressed that they had considered the 33% responder rate coprimary as a measurement of clinical benefit. They also provided additional data on higher thresholds for efficacy but only the 50% responder rate gave p-values of < 0.05 in both men and women. They highlighted that they considered the increase in sleep quality which they expected from the increase in time to first void as representative of clinical benefit. They believed the selective analysis of the NQoL data was evidence of some clinical benefit as well. The Agency responded the while studies CS40 and CS41 had been initiated under a special protocol assessment agreement which suggests the studies were adequate to meet scientific and regulatory requirements that did not mean that achievement of statistical significance in these trials would equate to approval since 15

16 approval is contingent upon review of the demonstrated effect size and the risks identified. Taking into account all of the data in support of clinical benefit, which was modest at best, relative to the risk of hyponatremia the risk/benefit calculus was still not in favor of approval of this indication. The Agency, however, was open to a clear discussion and airing of the relevant issues at an Advisory Committee (AC) meeting to get additional advice from experts in the field. In response to the AC submission Ferring is proposing even more stringent sodium monitoring including Week 1 (days 4 to 8) and Month 1 in all subjects 65 years of age and older and all subjects taking concomitant medication associated with the risk of hyponatremia. Patients with serum sodium levels that fall below the lower limit of normal would be discontinued from treatment. Initial packaging would be limited to 8 tablets to support compliance with serum sodium measurements during the first week of treatment for those patients at risk of hyponatremia. A medication guide would be dispensed and an education program would be implemented to help with identifying appropriate patients, maximizing lifestyle changes, and describing the risk of hyponatremia and details behind the sodium monitoring scheme. Ferring is also proposing to perform a post-approval claims-based study to follow the risk of severe hyponatremia and to expedite reporting of all cases of hyponatremia associated with the current indication. While some of these changes may be helpful in minimizing the risk of hyponatremia and thereby improve the risk/benefit calculus the Agency is still seeking clarity on the clinical benefit from the proposed indication. Introduction Product Description, Mechanism of action and Proposed Indication (Nocturia) Desmopressin has been approved in several presentations (subcutaneous injection, nasal spray, and oral tablets) for several indications: treatment of patients with diabetes insipidus who have a deficiency of endogenous vasopressin measurement of the kidney s ability to concentrate urine [i.e. renal concentration capacity testing (RCCT)] for patients with suspected renal disease treatment of children and young adults with primary nocturnal enuresis (PNE) to prevent bleeding in patients with hemophilia A or type I von Willebrand s Disease While there are currently no approved drugs for the treatment of nocturia in the US, desmopressin tablets which are available at 0.1mg and 0.2mg have been used off label to treat this indication. It is our concern given the current data that such use may be putting patients at an unacceptable risk for hyponatremia. Ferring has developed new lower dose orally disintegrating sublingual tablets (ODST) containing desmopressin which can be taken sublingually and dissolve immediately without the need for water. In this application Ferring is seeking to use ODST doses of 25mcg in women and 50mcg in men for the treatment of adults with nocturia due to 16

17 nocturnal polyuria who awaken two or more times each night to void prior to returning to sleep. Note these dosing recommendations, which were developed to lower the risk of hyponatremia in the elderly population, are much lower than is currently available off label as the 0.1mg and 0.2mg desmopressin tablets, because of different bioavailability, correspond to ODST doses of 60mcg and 120mcg, respectively. Nocturia: Pathophysiology and Available Therapies Nocturia refers to a condition prevalent particularly in the elderly in which individuals regularly need to wake up from sleep to void multiple times at night. It is associated with decrease in quality of sleep followed by daytime fatigue and sleepiness and a 2-fold increase in risk of falls, with subsequent risk of fractures. While there are many different etiologies for nocturia as described in the DRUBP Meeting Summary the sponsor in this application is seeking to treat adult subjects with nocturnal polyuria which has not responded to behavior and lifestyle modifications. Regulatory History of Nocdurna 1) End-of-Phase 2 meeting March 2007 a. Ferring sought a mean reduction in nighttime voids as the primary endpoint. DMEDP was concerned over the clinical benefit of a mean reduction in nighttime voids, as it did not guarantee that any patients had a large enough reduction in voids to result in a clinically relevant benefit and asked for a responder analysis as a co-primary endpoint. There was discussion over whether a 33% or a 50% responder threshold would be considered clinically beneficial as the literature was without clear guidance on the issue. Ferring insisted on the 33% threshold and the DMEDP agreed essentially designating this as a review issue stating in the meeting minutes assuming the results of the proposed Phase 3 trial are robust enough to show a clinically relevant response in a substantial proportion of the study population these data would support the short term efficacy of this product. b. A PRO was discussed but FDA was concerned that it would require a validated, reproducible instrument which showed consistency across clinical trials before it could be included in labeling. c. Sleep was discussed as an endpoint but there was no agreement on what constituted a clinically relevant benefit. 2) Initial submission June a. Study CS29 a double-blind, placebo-controlled study of both men and women with 10, 25, 50 and 100mcg of Nocdurna was performed to support short term efficacy along with an open label extension CS31 to support durability of the effect b. CS29 data showed that both greater efficacy and a higher risk of hyponatremia occurred at lower doses in women. c. Statistically significant efficacy was observed only at the highest dose of 100mcg in the combined male and female population which was 17

18 associated with too high of a risk of severe hyponatremia to recommend approval. d. FDA recommended in their April 2010 action letter that Ferring repeat studies using lower gender specific dosing. FDA found the NQoL questionaire to be inadequate and recommended the sponsor focus on developing their own PRO instrument. 3) Post CR interactionsa. Studies CS40 (women, 25mcg vs. placebo) and CS41 (men, 50 and 75mcg vs. placebo) were developed in collaboration with the Agency and approved as SPAs. b. Ferring developed a serum sodium monitoring scheme using the data from CS29 to identify subjects at risk of severe hyponatremia so they could be identified and discontinued from treatment before they develop significant sequelae. c. Ferring began to develop and validate their own Nocturia Impact (NI) diary to measure the clinical impact of nocturia. 4) Second submission July a. Studies CS40 and CS41 were performed and used to support the utility of the sponsor s serum sodium monitoring scheme. b. Statistically significant efficacy at the proposed doses of 25mcg dose in women and the 50mcg dose in men was seen but it was noted that most of the observed effect could be also seen in the placebo group. The small to modest placebo subtracted decrease in the number of nighttime voids brought into question the clinically meaningful significance of the drug effect. c. Hyponatremia was still seen at these lower doses but the monitoring scheme was able to identify all subjects in the clinical trial who went on to develop severe hyponatremia (e.g. < 125mmoL/L). d. FDA recommended in their January 2013 action letter that Ferring conduct another study to demonstrate the clinical meaningful impact of the small to modest placebo-subtracted decrease in the number of nighttime voids given that there still was a risk for hyponatremia. 5) End-of-Review Meeting May a. FDA recommended that the sponsor repeat another clinical trial using their newly developed NI diary to demonstrate a clinically meaningful benefit. b. The sponsor insisted that had additional information from the literature about sleep quality to support clinical benefit. 6) Formal Dispute Resolution Request December a. The Agency acknowledged that studies CS40 and CS41 were performed under SPAs, but clarified that this meant that these studies met certain scientific and regulatory requirements but not that achievement of a statistically significant endpoint guaranteed approval. The Agency reemphasized that approval depended on the level of clinical benefit relative to the risk of hyponatremia. b. The Agency acknowledged that while the placebo-subtracted benefit seen with OAB drugs was similar to what was seen with Nocdurna that the 18

19 Agency considered prevention of daytime urgency/incontinence as a clinical benefit in and of itself. c. In their January 2014 response the Agency recommended that Ferring submit any additional information that could support clinical benefit and that all of the information be evaluated by a panel of experts during an open advisory committee (AC) meeting. 7) This submission and reason for AC January 2015 a. Ferring revised their indication to include only subjects with nocturnal polyuria who have failed life style changes. b. Ferring added additional conditions to their serum sodium monitoring scheme: to include all subjects 65 years of age or older and all subjects on medication associated with hyponatremia irrespective of age, and increased the serum sodium cut off for the discontinuation of medication to include any subject with a measurement below the lower limit of normal. c. Ferring proposed new initial packaging limited to 8 tablets to support compliance with serum sodium measurements during the first week of treatment for those patients at risk of hyponatremia. d. Ferring has proposed a new medication guide and an education program to help with identifying appropriate patients, maximizing lifestyle changes, and describing the risk of hyponatremia and details behind the sodium monitoring scheme. e. Ferring proposed to perform a post-approval claims-based study to follow the risk of severe hyponatremia and to expedite reporting of all cases of hyponatremia associated with the current indication. Pharmacokinetics/Pharmacodynamics of Nocdurna Japanese trial CS36 4, was the first PD trial, in the target nocturia patient population, exploring low doses of Nocdurna. Water-loaded Japanese nocturia patients, years of age were given single doses of Nocdurna of 10, 25, 50 and 100mcg. The antidiuretic effect was seen at minutes after administration of Nocdurna, reached a maximum effect (defined as time when the urine osmolality is >200 mosm/kg in water-loaded subjects) after minutes and had an average duration of antidiuretic action of 3-5 hours. 4 Yamaguchi O, Nishizawa O, Juul KV, Nørgaard JP. Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial. BJU Int Mar; 111(3):

20 Figure 1 Pharmacodynamics of Nocdurna in Adult Subjects with Nocturia (urine Osmolality >200 mosm/kg) Mean (SE) (urine osmolality >200 mosm/kg) 1 In children with identified primary nocturnal enuresis (PNE) dosages, providing a duration of action corresponding to a typical length of night-time sleep were established in a double-blind, placebo-controlled trial, CS The duration of action of desmopressin was established for three different urinary osmolality thresholds (125, 200 and 400 mosm/kg). A dose range ( mcg ODST corresponding to mcg tablet) demonstrated a duration of antidiuretic action of 7-11 hours, supporting the higher 100mcg and 400mcg doses of the tablet formulation used for the PNE indication. Table 1 Pharmacodynamics of Desmopressin ODST in Children with PNE 5 Vande Walle JG, Bogaert GA, Mattsson S, Schurmans T, Hoebeke P, Deboe V, Norgaard JP; Desmopressin Oral Lyophilisate PD/PK Study Group. A new fast-melting oral formulation of desmopressin: a pharmacodynamic study in children with primary nocturnal enuresis. BJU Int Mar;97(3):

21 In summary, Nocdurna doses of 25mcg (females) and 50mcg (males) have a mean duration of antidiuretic effect in the range of 3-5 hours in adults with nocturia compared to a duration 7-11 hours for the higher doses ( µg tablet) in children with PNE. The Nocdurna Clinical Program Tabular Listing of Studies Covered in Clinical Program 21

22 22

23 23

24 1. NOCT Studies The sponsor s initial trials for the nocturia indication were conducted with the tablet formulation at doses of 0.1, 0.2 and 0.4mg in studies NOCT-2A (men only), NOCT-3A (women only), and NOCT-4 (men and women) and the corresponding open-label extension studies NOCT-2B and NOCT-3B. These doses were chosen as they were found to be safe and effective in the treatment of PNE in children and young adults. Figure 2 Study Design of the NOCT studies These trials were designed to identify subjects with 2 average night time voids over a 7 night screening period, who responded to treatment with 0.1 to 0.4mg of desmopressin tablets, i.e. experienced a > 20% decrease in diuresis, during an initial open-label dose 24

25 titration phase and after a 7 day washout phase had a return to > 78% of their baseline number of night time voids. During the dose titration phase patients were instructed not to drink more than sufficient to satisfy their thirst from one hour before bedtime until eight hours after drug intake. They were also instructed to avoid drinking tea, coffee, Coca-Cola, alcohol or other liquids with a diuretic effect at night. Between 4 and 7% of screened subjects were withdrawn because they did not show at least a 20% decrease in diuresis during the open-label titration phase and another 7 to 15% of subjects were withdrawn because they did not return to > 78% of their baseline number of night time voids after the open-label titration phase. Very few of the patients, i.e. 2 to 4%, were completely dry that is had a 100% reduction in the number of night time voids so the optimal dose for the randomized double-blind placebo controlled phase of the study was based on the investigator s assessment. Of note, > 80% of subjects were placed on a dose of 0.2mg or higher during the double-blind phase of the study. The primary endpoint was the 50% responder rate relative to baseline. Instead of looking at an average response from each treatment, the endpoint sought to identify a subgroup with what might be considered a substantial change in the number of night time voids from baseline. In these clinical trials 33 to 46% of subjects in the desmopressin group had a 50% or greater decrease in the number of night time voids relative to baseline compared to a rate in the placebo group of 3 to 11%, which were all statistically significant. Table 2 Efficacy Results in the NOCT 2A, 3A and 4 Studies Source Noct-4 Clinical Study Report Synopsis 25

26 In these original studies at higher doses of desmopressin (0.1 to 0.4 mg tablets equivalent to 60 to 240mcg of ODST) the total desmopressin response of to voids was 2 to 3 times higher than the placebo response of to voids. The placebo subtracted desmopressin response was in the range of to voids which is significantly higher than the difference of to voids seen at lower doses in the final pivotal trials CS40 and CS41 which will be described later in this review. The time to awakening for the first nighttime void went from a baseline of approximately 150min (2.5hr) to 247 to 272min (4.1 to 4.5hr) on desmopressin compared to 175 to 196min (2.9 to 3.3hr) on placebo corresponding to a placebo subtracted increase of 67 to 94min (1.1 to 1.6hr). Of note, the placebo subtracted difference in time to first nighttime void will also be decreased at 39 to 49min (0.65 to 0.8hrs) in the final pivotal trials CS41 and CS40 to be described later in this review. As the prevalence of nocturia is known to increase with age it is not surprising that in these studies which enrolled subjects with 2 nighttime voids that the median age was around 65 years. However, in these studies it was also noted that there was an unusually higher risk of hyponatremia in the elderly population during the dose titration phase compared to what was seen in the younger patients treated for PNE. Table 3 Hyponatremia Reported as an Adverse Reaction in the Dose Titration Phase of Studies, NOCT 2A, 3A and 4 by Dose Table 4 Hyponatremia Reported as a Low Lab Value in the Dose Titration Phase of Studies, NOCT 2A, 3A and 4 by Dose A total of 13 patients (2%) in these studies had severe hyponatremia with serum sodium levels reported below 125mmol/L in these 3-week trials. 2. First NDA Submission 26

27 Ferring submitted a New Drug Aplication (NDA) on 29 June It included a single pivotal clinical trial (Trial CS29) and an open-label extension (Trial CS31). Pivotal Trial CS29 and Open-Label Extension CS31 In response to the NOCT data the sponsor decided to study efficacy at lower doses of desmopressin using a newly formulated ODST. Study CS29, Parts 1 & 2, and its openlabel extension, study CS31, were designed as the pivotal trials for the treatment of adult nocturia. Study CS29 consisted of two parts. Part 1, was a randomized, double-blind, placebo-controlled, parallel-group, multi-center 28 day efficacy trial with subjects randomized to one of 4 doses of desmopressin ODST (10, 25, 50, or 100mcg) or placebo. Part 2 was a 6 month double-blind extension in which patients on active therapy during Part 1 continued on the same therapy while subjects initially assigned to the placebo group were re-randomized to one of the 4 active treatment groups. The purpose of Phase 1 was to compare efficacy across several potential doses to placebo, while the objective of Part II was to collect additional blinded longer term efficacy and safety data. Study CS31, was initially a blinded continuation of CS29 Part 2, until the original study database was locked and data analyzed. Once the original data was analyzed patients who had originally been assigned to sub therapeutic doses of desmopressin ODST (e.g. 10mcg) during CS29 were randomly assigned to one of the doses with clear efficacy relative to placebo (e.g. 25, 50, or 100mcg). The schema for trials CS29 and CS31 is reproduced below. Of note, this study did not have a run-in period to select for responders but instead enrolled all subjects who met the inclusion/exclusion criteria, which is more analogous to how the drug would be used in a real use setting, and should provide more generalizable data. Figure 3 Study Design for CS29 Part 1 & II and CS31 27

28 Patient Population Men and women over 18 years of age with adult onset nocturia Median age of 64 years and 55% male Inclusion Criteria Adults with an average of 2 nocturnal voids per night as determined by a 3-day voiding diary measured over 3 consecutive 24-hour periods at baseline Exclusion Criteria Adults with the medical conditions that put them at a higher safety risk, had other treatable conditions responsible for their nocturia or had conditions that could confound the final analysis were excluded: renal insufficiency, hyponatremia, diabetes insipidus, clinical suspicion of urinary retention and/or post void residual volume >150 ml, current or past urologic malignancy, clinical evidence of current genitourinary tract pathology or neurogenic detrusor activity. Males with a clinical suspicion of bladder outlet obstruction and/or urine flow <5 ml/s or surgical treatment for bladder outlet obstruction/benign prostatic hyperplasia performed within the past 6 months Patients with lower urinary tract symptoms (LUTS) that required other treatments such as alpha-blockers, 5-alpha-reductase inhibitors, antispasmodics, anticholinergic or antimuscarinic therapy for overactive bladder were permitted in the study as long as they had been on stable therapy for 3 months prior to the screening date. Primary Endpoint Ferring proposed initially to compare mean changes in nocturnal voids as the primary endpoint. The Agency was concerned that a mean decrease in the number of night time voids, would not be adequate to define efficacy because the clinical significance for such a change was not clear, as it would not guarantee that individual subjects were getting a substantial enough reduction in the number of nighttime voids to draw clinical benefit from the therapy. Therefore the Agency recommended that Ferring use a co-primary endpoint that included both the mean change in nocdurnal voids and a responder component. Because it was unclear from the literature what % reduction of voids defines a clinical benefit it was decided to use a 33% reduction, (e.g. a reduction from 3 to 2 nighttime voids) as an estimate of a reasonable benefit, but Ferring also performed analyses looking at higher threshold reductions of 50 and 75%. The primary endpoint, consisted of two co-primary components (1) a mean reduction in the number of nighttime voids and (2) the proportion of subjects who show at least a 33% reduction in the mean number of nocturnal voids. The statistical analysis plan required that Ferring test both co-primary endpoints independently at a p-value 0.05 and win on 28

29 both endpoints. Nocturnal voids were recorded in a diary on 3 consecutive 24 hour periods at baseline and during the first four weeks of the study (e.g. Days 8, 15, 22 and 28); however efficacy was formally assessed only on prespecified Day 28. Secondary endpoints which were chosen were changes in the initial period of undisturbed sleep, total sleep time, a number of Quality Of Life questionnaires measuring Patient Reported Outcomes (PROs), and durability of effect in the open label extension CS031. Nocturnal urinary volume was also measured at baseline and Day 28. Efficacy Results For all patients (men and women) Nocdurna was statistically significant at the 100mcg dose with respect to both co-primary endpoints at the prespecified time point (Day 28). For the rest of this review the mean number of nocturnal voids will be referred to as the first co-primary and the 33% responder rate will be referred to as the second co-primary. Table 5 Change from Baseline to Final Visit (Day 28) in Mean Number of Nocturnal Voids (ITT, First part of co-primary endpoint) 29

30 Table 6 Proportion of Subjects with >33% Reduction from Baseline in Mean Number of Nocturnal Voids (ITT, Second part of co-primary endpoint) Given the uncertainty of what represents a clinically meaningful response, Ferring also analyzed responders using the stricter definitions of 50% and 75% reduction in nocturnal voids. Similar to the results seen at the 33% responder rate, the 50 and 75% responder rates for the 100mcg dose gave values of < and , respectively. Long Term Efficacy (CS31) No formal testing was planned by Ferring on the data from the long term extension Study CS31 as there was no placebo group for comparison after the first month of therapy. The continued dose response out to month 7 supports continued efficacy but the trend for increasing efficacy in both coprimary endpoints from month 1 to month 7 has to be taken in the context of the large patient drop out (>50%) during this part of the study which likely led to a selection of patients with greater efficacy. Figure 4 Monthly Change from Baseline in Mean Number of Nighttime Voids (ITT, First part of co-primary endpoint) 30

31 Figure 5 Monthly Proportion of Subject with > 33% Reduction from Baseline in Mean Number of Nighttime Voids (ITT, Second part of co-primary endpoint) Gender Differences in Efficacy A post hoc analysis of the efficacy data collected in study CS29 showed somewhat unexpectedly that women had greater efficacy at lower doses than men (see Tables 7 & 8). 31

32 Table 7 Change from Baseline to Final Visit (Day 28) in Mean Number of Nocturnal Voids with respect to gender (ITT, First part of co-primary endpoint) 32

33 Table 8 Proportion of Subjects with >33% Reduction from Baseline in Mean Number of Nocturnal Voids with respect to gender (ITT, Second part of coprimary endpoint) In the post hoc analysis of female subjects, Ferring calculated p-values < 0.05 for both parts of the co-primary endpoint, respectively at the prespecified time point of Day 28 for doses of 25 (p=0.02, p=0.02), 50 (p=0.009, p=0.04) and 100mcg (p<0.0001, p<0.0001). In the post hoc analysis of male subjects, Ferring calculated p-values < 0.05 for both parts of the co-primary endpoint, respectively at the prespecified time point of Day 28 only at the highest dose of 100mcg (p<0.048, p<0.0001). There was evidence of limited efficacy at the 50mcg dose on the other study Days 8, 15 and 22 but these were not prespecified time points. A closer look at the data suggests that part of the inability to show efficacy relative to placebo at the lower doses may be due to an increase in efficacy in the placebo group with the length of time subjects spent in the trial (see Tables 5, 6, 7 and 8). It seems reasonable that prolonged monitoring during the trial, requiring subjects to fill out voiding diaries and to measure urine output might affect subject behavior in ways that could limit nighttime fluid intake and subsequent urine production. That said, a similar increase in efficacy with time was less obvious in the 10mcg group which had little efficacy and was essentially a placebo as well. Therefore, individual variability and response to lifestyle changes during the trial itself impact on the final interpretation of the efficacy data. The difference in mean voids observed in CS29 at the highest dose of 100mcg on Day 28 was voids for all patients, voids for men and voids for women. This is somewhat lower than was seen in the NOCT studies (e.g to voids) in which higher doses were studied. Of note, this trend for a lower difference 33

34 in efficacy with respect to placebo, observed in trial CS29, will continue to be seen in the later studies which used even lower doses of Nocdurna (see Table 14). The clear difference in efficacy with respect to gender was also apparent when urine volume on Day 28 was compared to baseline in study CS29. In this study maximal decreases in night time urine volume were seen with doses of 25mcg in women and with doses of 50mcg in men. Figure 6 Mean Decrease in Nocturnal Urine Volume by Dose and Gender in Study CS29 Source Sponsor s Figure 3. Modelling Report/Desmopressin Sensitivity in Females vs. Males. The gender difference in efficacy had not been previously noted in studies in the primary nocturnal enuresis (PNE) population. Part of the reason for this is that higher doses in the range of 0.1 to 0.6 mg of the tablet formulation were studied in order to control urine output during the entire nighttime period (e.g. 8 to 10 hours) to prevent bed wetting. It is possible that the lower doses of < 0.1mg which would limit urine production for only 4 to 6 hours may be of some benefit in the adult nocturia population even if they don t completely keep patients from going to the bathroom throughout the night. Secondary Endpoints in Study CS29 Duration of Sleep Period Prior to First Nighttime Void As seen previously in the original NOCT studies, treatment with desmopressin in CS29 resulted in an increase in the time to first nighttime void, but a less pronounced benefit was seen with lower doses evaluated in Study CS29. The increases in initial sleep period showed a dose response with mean increases of 83, 85, and 107 minutes (or 1.4, 1.4 and 34

35 1.8 hr) in the 25mcg, 50mcg, and 100mcg groups, respectively, which corresponded to placebo subtracted differences of 44, 46, and 68 min (or 0.73, 0.77 and 1.1 hr). Recall the placebo subtracted increase in time in the NOCT studies at higher desmopressin doses ranged from 67 to 94min (or 1.1 to 1.6 hr). Whether an increase in time to first awakening represents a true clinical benefit cannot be confirmed from the currently available information as discussed in more detail in the DPP consult included in this briefing packet. Despite the increase in duration of sleep prior to the first nighttime void it needs to be noted that there was no observed change in total sleep time in CS29 associated with treatment of desmopressin relative to placebo. An improvement in total sleep time may have been easier to perceive as a clinical benefit, but again diary information is subjective. To obtain objective data for quantifying sleep parameters in a future study it would be necessary to include polysomnography. Patient Reported Outcomes The sponsor used the Nocturia Quality of Life (N-QoL) questionnaire to assess the impact of nocturia on the quality of life in the subjects enrolled in CS29. The N-QoL is a publically available self-administered Patient Reported Outcome (PRO) score aimed at assessing the impact of nocturia on quality of life 6. It was initially developed from study questionnaires given to men at urology clinics in the United Kingdom, and more recently has been shown to be applicable to women as well 7. The N-QoL is divided into two sections: a Sleep/Energy Domain (6 questions), a Bother/Concern domain (6 questions), and a Global Quality of Life question which is scored separately. The test asks subjects to respond to questions about how they felt over the past two weeks. This raises some concerns about the ability of the patients to remember accurately the impact of the events of concern. Subjects were asked to score 12 items on a 0 to 4 scale and the global question on a scale ranging from very good to very poor. Higher scores for the items in the test represented improved quality of life. Summary scores are computed by transforming the raw score onto a standardized scale of 0 to 100. So a subject who had perfect scores of 4 on all 12 items (i.e. no problem with sleep/energy or bother/concern) would have a raw score of 48 but a standardized score of 100. Although, some improvements in scores were seen in some domains more than in others and generally with higher doses, there were no statistically significant changes at any given dose relative to placebo. 6 Abraham L, Hareendran A, Mills IW, Martin ML, Abrams P, Drake MJ, MacDonagh RP, Noble JG. Development and validation of a quality-of-life measure for men with nocturia. Urology Mar;63(3): Mock LL, Parmelee PA, Kutner N, Scott J, Johnson TM 2nd. Content validation of symptom-specific nocturia quality-of-life instrument developed in men: issues expressed by women, as well as men. Urology Oct;72(4): Epub 2008 Aug 5. 35

36 Table 9 Mean (SD) Change from Baseline to Day 28 in NQoL (ITT Population) Sleep/Energy Domain Score 1) Difficult to concentrate the next day 2) Feel generally low in energy the next day 3) Require me to nap during the day 4) Less productive the next day 5) Participates less in activities I enjoy 6) Difficult to get enough sleep at night Bother/Concern Domain Score 1) Careful about when or how much I drink 2) Disturbing others by getting up at night to urinate 3) Preoccupied by about getting up at night to urinate 4) Worried it will get worse in the future 5) Worried there is no effective treatment 6) How bothersome is it getting up at night Placebo 10mcg 25mcg 50mcg 100mcg (19.30) 0.53 (1.09) 0.65 (1.14) 0.42 (1.05) 0.55 (1.08) 0.68 (1.02) 0.78 (1.07) (19.73) 0.35 (1.18) 0.44 (1.14) 0.51 (1.13) 0.55 (1.21) 0.50 (1.15) (23.54) 0.37 (1.17) 0.53 (1.18) 0.42 (1.13) 0.51 (1.09) 0.45 (1.13) 0.68 (1.28) (23.42) 0.47 (1.39) 0.41 (1.20) 0.53 (1.25) 0.69 (1.38) 0.63 (1.26) 14.6 (18.71) 0.62 (1.06) 0.57 (0.96) 0.49 (0.91) 0.59 (0.97) 0.54 (1.18) 0.68 (1.11) (21.29) 0.32 (1.30) 0.52 (1.27) 0.54 (1.25) 0.74 (1.08) 0.7 (1.25) (20.92) 0.61 (1.07) 0.65 (1.09) 0.4 (1.06) 0.62 (1.06) 0.57 (1.14) 0.8 (1.27) (25.46) 0.45 (1.36) 0.53 (1.20) 0.59 (1.29) 0.62 (1.37) (1.45) (21.09) 0.49 (1.09) 0.72 (1.11) 0.61 (1.00) 0.62 (1.09) 0.63 (1.17) 0.84 (1.20) (23.29) 0.51 (1.45) 0.57 (1.27) 0.75 (1.14) 0.68 (1.30) 0.68 (1.31) (1.02) (1.16) (1.31) (1.29) Average Overall Domain Score (17.50) (21.35) (18.07) (21.63) Global Quality of Life Term (0.71) (0.65) (0.94) (0.81) Scores in red were greater numerically than placebo, but none of the differences were statistically significant. Source Sponsor s Table The Domain scores that were higher than placebo are highlighted see text below (1.35) 17.3 (20.50) 0.35 (0.77) The Average Overall Domain Score averages the result of the Sleep/Energy Domain and Bother/Concern Domain Scores, while the Global Quality of Term is graded separately. Higher scores indicating better quality of life were seen for the Average Overall Domain Score and Global Quality of Life Term with doses of 25, 50 and 100mcg compared to placebo (see highlights in table above). These results were primarily due to improvements in the Bother/Concern domain which were seen at all doses, and smaller improvements in the Sleep/Energy domain which was seen primarily at the highest dose of 100mcg (see highlights in table above). The standard deviations for these observations were fairly large suggesting that there is a large individual variability in responses. The standard deviations in the measurements were much larger than the differences in the 36

37 mean scores seen in patients on Nocdurna compared to placebo. Note the specific increase of about one point which was seen in the Sleep/Energy Domain at the 100mcg dose compared to placebo ( =1.11) as part of the standardized score could have resulted if half of the subjects at the 100mcg dose had a one grade higher response to only one of the six possible Sleep/Energy Domain questions compared to the responses seen in the placebo group. It is not clear if such a small difference has any clinical significance. During the review of this submission the Study Endpoints and Labeling Division (SEALD) was consulted by the review division and determined that the content validity of the NQoL questionnaire had not been adequately established according to the 2009 PRO guidelines 8. This guidance describes how the FDA reviews and evaluates existing or newly created patient-reported outcome instruments for the purpose of labeling claims, but not for purposes other than labeling. The SEALD opinion described in more detail in another section of this briefing packet determined that this PRO did not adequately address the psychological/emotional impacts of nocturia and thereby could not be used to support a health related claim. Most of the items in the Bother/Concern domain were considered not useful as they did not measure the effectiveness of treatment, and the general quality of life question was considered too general as it could include nonhealthrelated aspects of life. In response to criticism received from the FDA following the NDA review regarding the Nocturia Quality of Life, Ferring initiated a dialogue with the FDA to develop and validate a new PRO, the Nocturia Impact (NI) Diary. This will be discussed in further detail in a subsequent section under the efficacy results for studies CS40 and CS41 later on in this briefing packet. Safety in CS29/CS31 The safety profile of desmopressin is generally well characterized, since desmopressin containing drug products having been approved and marketed since It is currently approved for several indications including treatment of central diabetes insipidus (CDI), prevention of night time bed wetting in children and young adults with primary nocturnal enuresis (PNE), measurement of the kidney s ability to concentrate urine during Renal Concentration Capacity Testing (RCCT), and treatment of bleeding episodes in patients with type I von Willebrand s disease and hemophilia A. Many adverse events associated with desmopressin can be anticipated based on the known mechanism of action and physiological responses to arginine vasopressin (i.e. water retention with subsequent hyponatremia). Adverse reactions seen in the CS29/CS31 safety population and at a rate greater than placebo include in order of frequency of occurrence: dry mouth, headache, URI, UTI, hyponatremia, nausea, nasopharyngitis, dizziness and blood sodium decreased. Of these the higher than previously reported rates for the adverse reactions of hyponatremia and blood sodium decreased resulted in the most concerning safety signal. Of note, whether the adverse reaction was coded as blood sodium decreased versus 8 Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 37

38 hyponatremia was up to the discretion of the treating physician. While no cases of hyponatremia or blood sodium decrease were considered serious adverse events (SAEs 9 ), nine pts (1.0%) were discontinued from the study due to blood sodium decreased in the Nocdurna treatment group compared to one patient in the placebo group (0.6%). Sixteen pts (1.9%) were discontinued from the study due to hyponatremia in the Nocdurna treatment group compared to no such patients in the placebo group (0%). As seen in Table 10, below, there was a clear dose response for hyponatremia across the dose range 10 to 100mcg/day. Table 10 Categorical Analysis of Hyponatremia (Lowest Serum Sodium) by Dose Trial CS29 Source Table ISS CS029 and CS031 Sponsor s ISS While the upper limit of normal for serum sodium in most labs is 135mmoL/L, for the sake of this review we will refer to hyponatremia as serum sodium < 130 mmol/l and severe hyponatremia as serum sodium < 125moL/L. Hyponatremia is a well described adverse reaction associated with the use of all desmopressin formulations and small decreases in serum sodium typically occur without significant sequelae. In the literature 10 chronic hyponatremia has been associated with metabolic bone loss, osteoporosis and fractures and even short term hyponatremia can affect attention testing and gait stability making subjects at increased risk for falls. That said much of the literature data on mild hyponatremia is confounded by other effects from medications that predispose to hyponatremia and by complex comorbid medical conditions seen in these elderly 9 SAEs-A serious adverse event is an AE that results in any of the following outcomes: death, is lifethreatening, results in persistent or significant incapacity with substantial disruption of ability to conduct normal life functions, results in hospitalization or prolongation of existing hospitalization, or results in a congenital anomaly/birth defect. 10 Cowen LE, Hodak SP, Verbalis JG Age-associated abnormalities of water homeostasis.. Endocrinol Metab Clin North Am Jun;42(2):

39 patients. Severe hyponatremia (serum sodium < 125 mmol/l) or a marked rapid drop in serum sodium from baseline, on the other hand are clear medical emergencies as they can directly lead to cerebral edema and hyponatremic seizures. Elderly patients are more susceptible to the development of hyponatremia because of a decrease in renal function which makes it harder for them to limit sodium excretion and because of the increased frequency of comorbid conditions that may secondarily interfere with sodium homeostasis in the elderly population. Under normal circumstance the elderly can maintain fluid homeostasis, but their ability to respond to external stresses is limited. Conditions that can predispose to the development of hyponatremia include volume depletion (due to vomiting, diarrhea, severe burns, blood loss), medications (e.g. diuretics, selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, antiepileptic drugs, chemotherapy agents), CHF, cirrhosis, renal failure, malignancies, pulmonary disorders (e.g. pneumonia, TB, acute respiratory failure), endocrine disorders (e.g. hypothyroidism, glucocorticoid deficiency) and SIADH (due to head trauma, neurosurgery, CNS infections) 11. In fact, hyponatremia is the most common electrolyte abnormality seen in the general hospital population with an incidence of about 1% in the US 12. Because of the concern for the risk of the development of hyponatremia, all patients were required to have baseline serum sodium levels 135 mmol/l in order to be included in study CS29. Despite this, a total of 57 (6.6%) subjects developed serum sodium <130 mmol/l on various doses of Nocdurna compared to only one such patient (0.6%) in the placebo group. The rate of hyponatremia increased with increasing dose of drug with severe hyponatremia, being seen primarily at doses of 50mcg and 100mcg. All cases of severe hyponatremia occurred in patients older than 65 years (male or female). Women typically had higher rates of hyponatremia at similar doses compared to men (see Table 11). Table 11 Minimum Serum Sodium by Gender in CS29 Source CS29 ISS Table Palmer BF, Gates JR, Lader M. Causes and management of hyponatremia. Ann Pharmacother Nov;37(11): Review 12 Al-Salman J, Kemp D, Randall D. Hyponatremia West J Med May;176(3):

40 In their post hoc analyses of these data, the sponsor determined that hyponatremia tended to occur early during treatment, primarily on Day 4 or Day 8. Figure 7 identifies serum sodium levels for individual subjects that fell outside of the mean. Figure 7 Serum Sodium Levels in CS29 (without excluding any patients using the monitoring scheme) Source Fig. 18 CS29 Clinical Trial Report. Note an individual spot could represent more than one patient. Without monitoring during treatment 11 patients (1.3%) had serum sodium levels <125mmoL/L and 46 patients (5.3%) had serum sodium levels values between 125 and 130 mmol/l. If Ferring had incorporated a monitoring plan to exclude all patients 50 years of age and older with serum sodium < 135mmoL/L at Day 4 and Day 28 visits all subjects with serum sodium < 125 mmol/l would have been identified and removed as shown in Figure 8. An analysis of the 7 patients (0.9%) who would have not been identified by these monitoring criteria and yet developed sodium values between 125 and 130 mmol/l during the study, showed that all had serum sodium levels > 130mmoL/L, by the next evaluation, even though only one of these patients had their Nocdurna dose discontinued. On the basis of this analysis, Ferring concluded that the risk of progression to severe hyponatremia in these borderline patients appeared to be low. 40

41 Figure 8 Serum Sodium Levels in SC29 (excluding subjects identified by monitoring on Day 4 and Day 28) Source Fig. 19 CS29 Clinical Trial Report. Note an individual spot could represent more than one patient At the end of the full review of this NDA FDA issued a Complete Response (CR) for this application. The CR letter dated 22 April 2010 stated the following deficiencies and requirements to address such deficiencies that Ferring needed to address before Nocdurna could be approved: The placebo-controlled portion of your pivotal trial, FE CS029 [CS29 in this briefing document], demonstrated efficacy on two co-primary endpoints with only Nocdurna 100 mcg daily doses for 28 days, as determined by the prespecified 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. 41

42 In response to the CR letter the sponsor proposed and subsequently conducted two separate pivotal studies: CS40 in women treated with the 25mcg dose and CS41 in men treated with either 50 or 75mcg doses. The protocols for these two studies were designed under Special Protocol Agreements (SPA)s issued in Nov Ferring submitted a Complete Response on 30 July 2012 consisting primarily of the results of clinical trials CS40 and CS41, which will be summarized next. Second NDA Submission/Pivotal Clinical Trials CS40 and CS41 The pivotal studies CS40 (women) and CS41 (men) were similar in design and duration except that women were only randomized to a single desmopressin dose (25mcg) or placebo, while men were randomized to two possible desmopressin doses (50 and 75mcg) or placebo. The schema for these two clinical trials is presented below. While trial CS40 employed a standard parallel group design, trial CS41 included, in addition to the placebo-controlled parallel group design phase, an extension phase during which a 100mcg dose was evaluated. The purpose of this extension was to see if there was any benefit in titrating men who had safely been exposed to lower doses to a higher dose. Figure 9 CS40 Trial Design (Women) 42

43 Figure 10 CS41 Trial Design (Men) Both studies were stratified by age < 65 and 65 y/o (mean age 60 yrs, 13% 75yrs). The inclusion criteria identified an adult patient population with frequent nighttime voids: Inclusion Criteria (for a complete list of the inclusion criteria see the appendix) 2 nighttime voids per each night as determined by a 3-day voiding diary (most patients had a mean of 2 to <3 nighttime voids (48-60%) or 3 to <4 nocturnal voids (27-34%) at baseline); this is in contrast to Study CS29 in which subjects had to have an average of 2 nighttime voids over the 3 day screening period (i.e., as long as the total number of nighttime voids was 6 over 3 days, patients could have < 2 voids on individual nights). Similar to CS29 lifestyle changes were initiated during the screening period so patients had to continue to have 2 nighttime voids per night despite lifestyle changes before they received study medication. 43

44 Table 12 Mean Baseline Void Parameters Nocturnal Polyuria Index (NPI) is defined as the % of nocturnal urine volume divided by the 24 hour urine volume and has been used as a definition criterion for nocturnal polyuria. At baseline 89% of women and 87% of men had a NPI 33%. Urine volume produced during night >33% of total 24-hr urine volume is one of the proposed definitions for nocturnal polyuria 13. In both CS40 and CS41, subjects with potentially treatable medical causes of nocturnal polyuria and/or those with severe daytime lower urinary tract voiding dysfunction were excluded from the trials. Patients with concurrent non-severe daytime lower urinary tract voiding dysfunctions who were treated with stable doses of an antimuscarinic for overactive bladder (OAB) disease or alpha-blockers for benign prostatic hypertrophy (BPH) (mixed causes of nocturia) were eligible for the trial. In CS40 39 of 261 (15%) female subjects enrolled had OAB. In CS of 385 (31%) male enrolled subjects had OAB/BPH. All patients with OAB and BPH had to have stable disease (see exclusion criteria, below). 13 Appell RA, Sand PK. Neurourol Urodyn. 2008;27(1):34-9. Nocturia: etiology, diagnosis, and treatment. 44

45 The exclusion criteria excluded subjects with the medical conditions that put them at a higher safety risk, had other treatable conditions responsible for their nocturia or had conditions that could confound the final analysis: Exclusion Criteria (for a complete list of the inclusion criteria see the appendix) Renal insufficiency (egfr < 50mL/min, excluded 86/381=23% CS40, 159/618=26% CS41) Diabetes insipidus Uncontrolled diabetes Cardiac failure Uncontrolled hepatic or biliary disease Psychogenic or habitual polydipsia SIADH Hyponatremia Urological malignancy Sleep apnea Loop diuretics Neurogenic detrusor activity GU tract pathology (OAB with <8 voids/day and < 1episode of urgency /day were acceptable) Note- this criteria not in earlier study CS29 was added to exclude subjects with severe daytime voiding dysfunction. Bladder outlet obstruction in males (urine flow < 5mL/min) Urinary retention post void residual > 150mL (women, excluded 1/381=0.3% CS40); > 250mL (men, excluded 5/618=0.8% CS41) Concomitant medications The following medications were permitted, provided that the subject had been on a stable dose for the 3 months prior to the screening date (i.e., treatment was not initiated or discontinued and there was no change in dose during this period). In discussions between Ferring and FDA it was agreed to try to include in the study patients on stable regimens of concomitant medications in order to get an assessment for the possible risk of hyponatremia in a controlled study setting before the drug becomes available for general use. Antimuscarinic therapy for overactive bladder: tolterodine, fesoterodine, oxybutynin, darifenacin, hyoscyamine, trospium, solifenacin Sedative/hypnotic medications for sleep disorders Selective serotonin reuptake inhibitors (SSRIs): citalopram, duloxetine, venlafaxine, escitalopram, paroxetine, fluoxetine, sertraline. If SSRI therapy was initiated during the trial, additional serum sodium monitoring was performed approximately 3 and 7 days after treatment initiation. Chronic use of non-steroidal anti-inflammatory agents (NSAIDs). If chronic NSAID therapy was initiated during the trial, additional serum sodium monitoring was performed approximately 3 and 7 days after treatment initiation. Chlorpropamide 45

46 Carbamazepine Amiodarone Loop diuretics (furosemide, torsemide, ethacrynic acid) were prohibited. Other classes of diuretics (thiazides, triamterene, chlorthalidone, amiloride, indapamide) were permitted, either as monotherapy or combination therapy. Subjects using a diuretic were encouraged to take it in the morning, if medically feasible. In order to prevent hyponatremia all trial patients were given prespecified instruction on fluid restriction and lifestyle changes at the start of the screening period: The fluid intake was to be limited to a minimum in the evening (1 hour before until 8 hours after administration of study drug). Subjects were to empty their bladder before going to sleep at bedtime. Evening intake of liquids with diuretic effect, such as coffee, tea, caffeinated soft drinks, and alcoholic beverages, was discouraged. Treatment was to be interrupted during acute intercurrent illnesses that could be associated with fluid and/or electrolyte imbalance (such as systemic infections, fever, gastroenteritis) until the subject fully recovered. The treatment could have been restarted at the discretion of the Investigator once the condition of the subject was stabilized. To reemphasize, subjects who were eventually randomized into the trial must have continued to have 2 nightime voids despite lifestyle changes at the time they first received study medication. The study design was similar to CS29 in that it purposely did not have a run-in period to identify responders and non-responders, as had been used in the original NOCT studies, in order to more closely mimic how the drug would be used in general practice. Therefore, it is possible that the study results might have been different in a study population enriched for responders vs. non-responders. In contrast to Study CS29, CS40 and CS41 excluded subjects with severe daytime voiding dysfunction. This change was intended to better delineate a true nocturia population, as symptoms of daytime voiding dysfunction are primarily associated with overactive bladder and potentially a higher placebo effect. Voiding diary measurements were completed at baseline and prior to study visits on Day 8 (Week 1), Day 29±3 (Month 1), Day 57±7 (Month 2) and Day 85±7 (Month 3). The N- QoL questionnaire was completed at baseline and prior to study visits Day 29±3 (Month 1), and Day 85±7 (Month 3). For a more detailed summary of the study procedures see the appendix. Subject Disposition- CS40 (women) Most patients 233 (87%) completed the 3-month study with only 35 (13%) discontinuing prematurely. A similar number of subjects withdrew from the placebo 17 (13%) and 25mcg 18 (13%) treatment arms. The most common reason for withdrawal was protocol 46

47 violation which occurred in a similar number of subjects in the placebo 8 (6%) and 25mcg 7 (5%) treatment arms. CS41 (men) Most patients 327 (83%) completed the 3-month Part I of the study with only 68 (17%) discontinuing prematurely. Slightly more subjects withdrew desmopressin treatment arms 50mcg 23 (19%) and 75mcg 26 (20%) compared to the placebo arm 19 (13%). This was due to a slightly higher rate of withdrawal by subject 8 (7%) and 9 (7%) vs. 6 (4%) and protocol violation 6 (5%) and 6 (5%) vs. 3 (2%) (see Table 13). However, these minor differences probably did not impact on the integrity of the data as 98% of all subjects had at least one efficacy assessment after dosing initiation and all randomized subjects were included in the ITT analysis dataset. Table 13 Subject Disposition Source Table 3 ISE Of the 327 men who completed Part I of CS41 and entered into Part II, 315 (96%) completed Part II of the trial and only 12 (4%) discontinued prematurely. Primary Endpoint Both CS40 and CS41 had the same coprimary endpoints as used previously in CS29: 1) change from baseline in mean number of nocturnal voids 2) proportion of subjects with > 33% reduction in the mean number of nocturnal voids The statistical analysis plan required that Ferring test both coprimary endpoints independently at a p-value 0.05 and win on both endpoints. Nocturnal voids were recorded in a diary on 3 consecutive 24 hour periods at baseline, Week 1, Month 1, Month 2 and Month 3. In contrast to CS29 where the endpoint was measured on Study Day 28, in CS40 and CS41 the endpoints were measured using an longitudinal analysis, i.e. a repeated measures ANCOVA comparing change from baseline to Week 1, Month 1, Month 2 and Month 3, adjusted for age (< 65, 65), visit and baseline nocturnal voids. This was done because data from CS29 showed that there was a fair amount of variability at each 47

48 individual time point and so it was felt that the average response over a longer treatment period might be more representative of the clinical benefit. The Nocturia Impact (NI) diary had not been validated at the time this trial was initiated so Ferring used the N-QoL, the same questionnaire used in clinical trial CS29. A preliminary trial testing the utility of the NI diary, 34 IMPACT study was performed on 52 patients that had completed CS40 and CS41 and will be described later in this briefing packet. However, as 34 IMPACT was not adequately powered to evaluate efficacy based on drug assignment. In study CS40 both coprimary endpoints were statistically significant for the 25mcg dose over the 3 month study period (1 st coprimary p=0.028 and 2 nd coprimary p=0.0061). Among randomized subjects 17.9% (17.5% and 18.3% randomized to desmopressin and placebo respectively) did not have data on the number of voids at the 3-months visit. Among those subjects who did have data on the number of voids at 3 months 18 had data on the number of voids at one month. Figure 11 Change in Mean Number of Voids Based on Missing 3 month Data CS40 Change in number of voids Study CS40 Desmopressin 25 mcg Placebo Change in number of voids Baseline Day 4 Week 1 Month 1 Month 2 Month 3 Baseline Day 4 Week 1 Month 1 Month 2 Month 3 Study Visit Missing 3 month data All data at 3 month A graphical comparison between subjects who had and those who did not have data at 3- months visit is presented above. The graph consists of two panels where data for the treatment arm is plotted on the left side and data for the placebo arm is presented on the right. The values on y-axis indicate a mean change in number of voids per night; the values on x-axis indicate the visit. For both graphs, solid line represents subjects who provided data on the number of voids at 3-months visit; dashed line represents subjects 48

49 who did not have data at month 3. For each group, the change in number of voids was higher among subjects who did not drop out from the study prematurely than those subjects who had data at 3-months visit. Specifically, at month one of the study, subjects on the desmopressin arm who did not have a measurement for voids at month 3 had a mean reduction of 1.26 (sd 0.71) voids per night while subjects on the desmopressin arm who had a measurement for voids at month 3 had a mean reduction of 1.49 (sd 1.03) voids per night. So, among those subjects with a month 1 measurement for voids on the desmopressin arm, subjects who did not have a month 3 measurement for voids had a smaller mean reduction at month 1 (by 0.23 voids per night) than those subjects who had a month 3 measurement for voids. At month one of the study, subjects on the placebo arm who did not have a measurement for voids at month 3 had a mean reduction of 0.87 (sd 1.29) voids per night while subjects on the placebo arm who had a measurement for voids at month 3 had a mean reduction of 1.30 (sd 1.09) voids per night. So, among those subjects with a month 1 measurement for voids on the placebo arm, subjects who did not have a month 3 measurement for voids had a smaller mean reduction at month 1 (by 0.43 voids per night) than those subjects who had a month 3 measurement for voids. The missing data does not seem to have created any bias favoring desmopressin. In study CS41 both coprimary endpoints were statistically significant for the 50 and 75mcg doses over the 3 month study period (50mcg-1 st coprimary p= and 2 nd coprimary p=0.0009; 75mcg-1 st coprimary p< and 2 nd coprimary p=0.0004). Among randomized subjects 15.4% (16.3%, 17.3% and 12.6% randomized to desmopressin 50 mcg, desmopressin 75mcg and placebo, respectively) did not have data on number of voids at 3-months visit. Among those subjects who did have data on the number of voids at 3 months 20 (5 in desmopressin 50 mcg arm, 7 in desmopressin 75 mcg arm, and 8 in placebo arm) had data on the number of voids at one month. 49

50 Figure 12 Change in Mean Number of Voids Based on Missing 3 month Data CS41 Change in number of voids Study CS41 Desmopressin 50 mcg Desmopressin 75 mcg Change in number of voids Placebo Baseline Day 4 Week 1 Month 1 Month 2 Month 3 Baseline Day 4 Week 1 Month 1 Month 2 Month 3 Study Visit All data at 3 month Missing 3 month data Similar to before a graphical comparison between subjects who had and those who did not have data at 3-months visit is presented above. At month one of the study, subjects on the desmopressin 50 mcg arm who did not have a measurement for voids at month 3 had a mean reduction of 1.37 (sd 0.94) voids per night while subjects on the desmopressin 50 mcg arm who had a measurement for voids at month 3 had a mean reduction of 1.30 (sd 1.02) voids per night. So, among those subjects with a month 1 measurement for voids on the desmopressin 50 mcg arm, subjects who did not have a month 3 measurement for voids had a larger mean reduction at month 1 (by 0.07 voids per night) than those subjects who had a month 3 measurement for voids. At month one of the study, subjects on the desmopressin 75 mcg arm who did not have a measurement for voids at month 3 had a mean reduction of 1.56 (sd 0.82) voids per night while subjects on the desmopressin 75 mcg arm who had a measurement for voids at month 3 had a mean reduction of 1.38 (sd 1.03) voids per night. So, among those subjects with a month 1 measurement for voids on the desmopressin 75 mcg arm, subjects who did not have a month 3 measurement for voids had a larger mean reduction at month 1 (by 0.18 voids per night) than those subjects who had a month 3 measurement for voids. At month one of the study, subjects on the placebo arm who did not have a measurement for voids at month 3 had a mean reduction of 0.62 (sd 0.92) voids per night while subjects on the placebo arm who had a measurement for voids at month 3 had a mean reduction of 0.96 (sd 1.05) voids per night. So, among those subjects with a month 1 measurement for voids on the placebo arm, subjects who did not have a month 3 measurement for voids had a smaller mean reduction at month 1 (by 0.34 voids per night) 50

51 than those subjects who had a month 3 measurement for voids. The missing data does not seem to have created any bias favoring either desmopressin arm. Table 14 First Co-primary Endpoint-Change from Baseline in Mean Number of Nocturnal Voids Averaged over a 3-Month period Studies CS40 and CS41 Source table 10 ISE Table 15 Second Co-Primary Endpoint-Odds Ratio of Patients with >33% Response from Baseline Averaged over a 3-Month Period Studies CS40 and CS41 Source Table 13 ISE Fig. 13 shows that in both men and women there appears to be an increase in efficacy over the course of the first month of therapy for the first co-primary endpoint (number of voids) which is more or less maintained for the duration of the 3 month study and that there is no difference in efficacy between the 50 and 75mcg doses in men. It also demonstrates a large reduction in the number of voids in the placebo arm which contrasts with the small difference between the desmopressin and placebo effects noted in Table 14:,-0.22 voids associated with the 25mcg dose in Study CS40 and to voids associated with the 50mcg and 75mcg doses, respectively in Study CS41. 51

52 Figure 13 Adjusted Change from Baseline during 3 Months of Treatment in Mean Number of Nocturnal Voids (Trials CS40 and CS41) Source Fig. 4 ISE 52

53 A Forest Plot was constructed by the FDA to look at the mean number of nocturnal voids, the first co-primary endpoint, by subgroups including age (< 65 vs. 65yrs), race, BMI and baseline number of nocturnal voids. Figure 14 Forest Plot on Mean Difference in the Change from Baseline in Mean Number of Nocturnal Voids (first co-primary endpoint) in Study CS40 for Women Treated with 25mcg Nocdurna and Placebo In women treated with 25mcg of Nocdurna in clinical study CS40 (see Fig. 14) the point estimates are clearly on the side of efficacy for desmopressin in all treatment subgroups ranging from to

54 Figure 15 Forest Plot Mean Differences in the Change from Baseline in Mean Number of Nocturnal Voids (first co-primary endpoint) in Study CS41 for Men Treated with 50mcg Nocdurna and Placebo In men treated with 50mcg of Nocdurna in study CS41 (see Fig. 15) the point estimates for the treatment difference between 50 mcg desmopressin and placebo are clearly on the side of efficacy for 50 mcg desmopressin in all treatment subgroups ranging from to (for non-caucasian men). Of note, with respect to baseline nighttime voids both men and women with 3 nighttime voids had a point estimate representing only slightly greater efficacy than subjects with < 3 nighttime voids. 54

55 A closer look at the second co-primary endpoint (see Tables 16 and Fig. 16) gives similar results to those seen with the first co-primary endpoint namely a large effect in the placebo group and only a moderate difference in efficacy with desmopressin compared to placebo. Table 16 Proportion of 33% Responders by Visit (CS40 and CS41) Source Table 24 ISE (Part II data refers to patients treated with 100mcg of desmopressin who had been treated with 75mcg, 50mcg desmopressin or placebo, respectively during Part I, which is why the percentages are so much higher than in Part I) Figure 16 Proportion of 33% Responders by Visit (CS40 and CS41) CS40 (females) CS41 (males) 33% responders µg Placebo 33% responders µg 50 µg placebo baseline week 1 Month 1 Month 2 Month 3 baseline week 1 Month 1 Month 2 Month 3 Visit Visit Source Data from Table is plotted. The second co-primary endpoint also shows that in both men and women there is an increase in efficacy over the course of the first month of therapy which is maintained more or less for the duration of the 3 month study, and that there is no difference in efficacy between the 50 and 75mcg doses in men. It also illustrates the large effect in the placebo arm (40 to 72%, in men and women respectively) and the small difference in efficacy between desmopressin and placebo at individual time points, which ranged between 8% and 21%. Given the small difference in efficacy compared to placebo the question arises as to whether the observed effect constitutes a clinically relevant benefit. One way to identify a clear clinical benefit would be to show a complete reduction in the number of nighttime voids, but data from the original NOCT trials showed that only a very small percentage of 55

56 subjects were completely dry even with higher doses of up to 400mcg of desmopressin tablets. While complete reduction in the number of nighttime voids may not be possible for most subjects it is still informative to look at higher responder rates with higher thresholds than the 33% cut off in a post hoc analysis. Therefore, Ferring performed such an analysis looking at the higher responder thresholds of 50%, 66%, 75% and 100%. As might have been expected the percent of subjects at each visit that met a specific threshold decreased as the threshold used to define the responder was increased. Over the 3 months of treatment with desmopressin only the 33% and 50% responder thresholds had p-values <0.05 with respect to placebo in both men (50mcg) and women (25mcg), see Table 17. At higher thresholds more subjects continued to respond in the desmopressin treatment groups compared to placebo in both men and women but the p- values were <0.05 only in men (CS41). Figure 17 % Response at Responder Thresholds in Females Source Table 3.1 Appendix F SDN 30 7/31/14 56

57 Figure 18 % Response at Responder Thresholds in Males Source Table 3.2 Appendix F SDN 30 7/31/14 57

58 Table 17 Average Responder Analysis over 3 Months Highlighted p-values are < Subgroup Analyses of the Primary Endpoint Nocturnal Polyuria Although studies CS40 and CS41 did not require evidence of nocturnal polyuria as an inclusion criteria as shown in Table 12, 89% of women in CS40 and 87% of men in CS41 had a NPI 33% at baseline consistent with the definition of nocturnal polyuria. Efficacy for both coprimary endpoints was similar for the nocturnal polyuria subgroup as seen in the total population, which is not surprising given that almost 90% of both study populations had nocturnal polyuria (see appendix). The results for the first co-primary endpoint (placebo subtracted change in mean number of nocturnal voids) in the total population was CS40 females (25mcg) voids, and CS41 males (50mcg) voids compared to CS40 females (25mcg) voids and CS41 males (50mcg) voids in the nocturnal polyuria subjects (see appendix). The results for the second co-primary endpoint (measured as an odd ratio of the 33% responder status compared to placebo) in the total population was CS40 females (25mcg) 1.85, and CS41 males (50mcg) 1.98 compared to CS40 females (25mcg) 2.13 and CS41 58

59 males (50mcg) 2.00 in the nocturnal polyuria subjects, all approximately two-fold higher in the Nocdurna treatment groups. See the appendix Tables 28 to 30 for the detailed analyses. P-values were all less than 0.05 but again as this was not a prespecified analysis and did not included a multiplicity correction it is not possible to comment on the statistical significance of these findings. OAB/BPH Overall only 39 females (15%) in CS40 and 120 males (31%) in CS41 were enrolled with non-severe lower urinary tract voiding dysfunctions including OAB and BPH. Efficacy for the first co-primary endpoints was similar for the OAB/BPH subgroups as seen in the total population. The results for the first co-primary endpoint (placebo subtracted change in mean number of nocturnal voids) in CS40 females (25mcg) without OAB voids, and CS41 males (50mcg) without OAB/BPH voids compared to CS40 females (25mcg) with OAB voids and CS41 males (50mcg) with OAB/BPH voids. P- values were less than in men with and without OAB/BPH and in women without OAB. Odds ratios for the second co-primary endpoint, 33% responders, in CS40 females (25mcg) without OAB 1.86, and CS41 males (50mcg) without OAB/BPH 1.93 were similar to CS40 females (25mcg) with OAB 1.85 and CS41 males (50mcg) with OAB/BPH P-values were less than only in men and women without OAB/BPH (see appendix). Given that subjects with OAB/BPH might not gain a clinical benefit from a decrease in nighttime voids if it resulted in an increase in daytime symptoms due to an increase in urine volume during the day. Ferring compared voiding frequency and daytime urine volume in all subjects on Nocdurna compared to placebo and specifically in the subset with OAB/BPH. While there was no difference in daytime voiding frequency in either men or women in the general population if they were treated with Nocdurna or placebo, in the OAB/BPH population men on Nocdurna had a placebo subtracted increase in 0.79 voids during the day (see Table 33 in the appendix). While there was no difference in daytime urine volume in either men or women in the general population if they were treated with Nocdurna or placebo, in the OAB/BPH population both men and women with OAB/BPH had an approximately 100mL increase in urine volume during the day (see Table 35 in the appendix). Apparently the increase in urine volume was more of an issue in male subjects who also demonstrated an increase in voiding frequency in Table 33 and most likely had BPH than in women with OAB. There was no increase in the incidence of adverse reactions associated with OAB/BPH symptoms during the trial in OAB/BPH subjects but the study was not designed prospectively to look at such symptoms so it is not clear if they may have been adequately assessed. 59

60 Duration of Sleep Period Prior to First Nighttime Void (CS40 and CS 41) Given the concern over the small difference in efficacy between desmopressin and placebo groups in studies CS40 and CS41 the sponsor argued that the mean time to first nocturnal void, one of the secondary endpoints, could be used as evidence of clinically relevant benefit. In study CS40 in women, the mean time to first nocturnal void at baseline was around 145 min (2.4 hrs); with desmopressin there was an increase of 155 min (2.6 hrs), which was 49 minutes (0.8hrs) longer in the desmopressin group compared to the placebo group (p=0.0034). In study CS41 in men the mean time to first nocturnal void at baseline was around 146 min (2.4 hrs); with desmopressin 50mcg there was an increase of 112 min (1.9 hrs), which was 39 minutes (0.65hrs) longer in the desmopressin group compared to the placebo group (p=0.0064). Therefore with desmopressin treatment the time to first awakening in these trials more than doubles from about 2.4 hrs to 5.0 hrs in women and almost doubles from 2.4 hrs to 4.3 hrs in men. But again most of the treatment effect relative to a placebo was less than one hour. Of note even though both p-values were <0.05 they cannot be considered statistically significant as Ferring failed to show significance at earlier secondary endpoints which were part of the hierarchical testing procedure. Table 18 Change from Baseline in Mean Time (minutes) to First Nighttime Void at Month 3 (CS40 and CS 41) Source Table 18 ISE The Division of Psychiatry Products (DPP) review of this endpoint is addressed in more detail in the Sleep Summary in this briefing packet, but briefly they concluded that diary data was inadequate to confirm any change in the total amount of Slow Wave Sleep (SWS) which is the assumption that Ferring is making to support clinical relevance in time to first nighttime awakening. DPP recommended the use of polysomnography in any future clinical trials if Ferring wishes to continue to seek such a claim. 60

61 Patient Reported Outcomes (CS40 and CS 41) Similar to CS29 the sponsor used the N-QoL questionnaire to try to assess the impact of nocturia on the quality of life in subjects in CS40 and CS41. However as seen in CS29 the results were again inconsistent questioning the utility of this PRO as a measure of clinical benefit. According to the statistical analysis plan the N-QoL questionnaire was an exploratory endpoint and not part of any hierachical testing analysis to control for type 1 error. Diary measurements were performed at baseline, Month 1 and Month 3. In CS40, among randomized subjects, 248 of 268 (93%) provided data for analysis at Month 1 and 221 of 268 (82%) provided data for analysis at Month 3. The number of subjects who participated in those questionnaires was the same across all domains. Improvements favoring the 25mcg dose of desmopressin in women, were observed at Month 3 for Total Score (p=0.023) and both NQoL domain scores (Sleep/Energy, p=0.047 and Bother/Concern, p=0.025), however similar results were not seen at Month 1: Total Score (p=0.659), Sleep/Energy domain (p=0.818) and Bother/Concern domain (p=0.566), questioning the value of the Month 3 measurements and the utility of this PRO as a measure of clinical benefit. Table 19 NQoL Domain Scores CS40 In CS41, among randomized subjects, 366 of 395 (93%) provided data for analysis at Month 1 and 337 of 395 (85%) provided data for analysis at Month 3. The number of 61

62 subjects who participated in those questionnaires was the same across all domains. Ferring calculated p-values 0.05, favoring the Total Score for desmopressin 50mcg at 3 months (p=0.039) but not for desmopressin 75mcg (p=0.121). This observation is inconsistent with other efficacy observations that showed the effects of the 50 and 75 mcg doses being virtually the same. In contrast, both doses showed improvements in Total Score at Month 1 (50mcg, p=0.015 and 75mcg, p=0.035). The p-value for the Sleep/Energy domain was <0.05 for both doses at both Month 1 and Month 3 while the p- value for the Bother/Concern domain was >0.05 for either dose at either Month 1 or Month 3. Even though some of the select categories gave calculated p-values < 0.05, most of the calculated values were only slightly below 0.05, and the analyses did not take into account multiplicity and control for type 1 error. So in summary it is not possible to draw any clear conclusions in both men and women from these data. Table 20 N-QoL Domain Scores CS41 62

63 Nocturia Impact (NI) Diary Given the inconsistent results with the N-QoL PRO and the problems with the content validity of the N-QoL (see the SEALD review in the briefing packet) the Division had advised Ferring to develop a new PRO that, once validated, could be used to study the burden of nocturia in adult patients. In collaboration with the SEALD team the applicant developed the Nocturia Impact (NI) Diary which asks 10 specific questions related to nocturia followed by an overall impact question. There is some overlap between the N- QoL and the NI instruments. For instance, NI retains 7 of 12 specific questions and the final overall impact question included in the N-QoL questionnaire. However, the wording of these questions is changed and 4 new questions are added as the result of preliminary testing of a larger instrument containing 14 items. Ferring tested this PRO in a separate study, Study 00034, which was a 1 month, randomized, placebo-controlled, double-blind trial with 26 women and 26 men who had just completed the CS40 and CS41 studies. A washout period of >30 days was used to decrease the risk of any carryover effect. Subjects who received active treatment during CS40 or CS41 were to have been responders (defined as a reduction from baseline in nocturnal voids at the Month 1 visit of 33%) during the original CS40 or CS41 studies and subjects who received placebo during these 2 studies were to have been non-responders (defined as a reduction from baseline in nocturnal voids at the Month 1 visit of <33%) during the original CS40 and CS41 studies. This subject selection was performed to try to ensure inclusion of the most differentiated subjects, thereby increasing the likelihood of detecting a difference as the study was otherwise not adequately powered for the proposed endpoints. Subjects were re-randomized in study so subjects previously on placebo in CS40 or CS41 could have received drug and visa versa. Women were dosed with 25mcg or placebo. Men were dosed with 75mcg or placebo. Recall both 50mcg and 75mcg Nocdurna showed similar efficacy in men (see Figs. 13 and 15) but Ferring is currently seeking approval for only the 50 µg dose. Figure IMPACT- Study Trial Design 63

64 Efficacy, measured as the NI score, was determined by comparing results from two 3-day baseline diaries obtained during the screening period to one 3-day diary obtained at one month at the end of treatment. Given the small number of patients in this study the sponsor was not able to show efficacy with respect to the pre-specified co-primary endpoints in either men or woman and could not correlate the improvement in NI score to treatment with desmopressin. Instead, the sponsor presented a post hoc analysis comparing the difference in mean change in NI total score from Baseline to the Month 1 visit for responders versus nonresponders, where a responder was defined as subject who experienced a reduction from Baseline in nocturnal voids at the Month 1 visit of 33%, but could have been treated with either Nocdurna or placebo during the one month study. Similarly a non-responder had a less than 33% reduction in the number of nighttime voids at Month 1 compared to Baseline, but could have been treated with either Nocdurna or placebo during the one month study. While these results were positive and suggest the NI Diary can distinguish responders from non-responders and may eventually be useful in studying the burden of nocturia in this study population, the results from Study do not support a clinical benefit for the treatment with Nocdurna compared to placebo. Safety (CS40 and CS41) Given the hyponatremia seen in the early NOCT studies and study CS29, studies CS40 and CS41 were designed with lower desmopressin doses: men (50mcg) and women (25mcg) and frequent sodium monitoring to assess whether a monitoring scheme developed as part of a post hoc analysis in CS29 could be shown to prospectively identify subjects at risk of hyponatremia before they developed severe hyponatremia (serum sodium < 125 mmol/l) or a rapid drop in serum sodium from baseline as these can lead to cerebral edema and seizures. Because of the concern for the risk of the development of hyponatremia, all patients were required to have baseline serum sodium levels 135 mmol/l in order to be enrolled in the Phase 3 studies. In studies CS40 and CS41 6/649=0.9% and 11/1013=1.0% respectively, were screening failures due to baseline hyponatremia. Consistent with this exclusion criterion the sponsor is currently recommending baseline serum sodium screening for all subjects and starting therapy with Nocdurna only in patients with normal serum sodium levels at baseline. Because of the concern that patients with renal impairment might be at greater risk for hyponatremia patients, all patients in the clinical trials were also screened for signs of potential renal impairment based on serum creatinine values above the normal range and egfr < 50mL/min. A higher percentage of subjects were screening failures because of possible renal impairment i.e. 86/649=13% (CS40) and 159/1013=16% (CS41) than due to baseline hyponatremia. Ferring is currently recommending a contraindication to use in subjects with moderate to severe renal impairment but is not recommending baseline serum creatinine screening to check for renal impairment. 64

65 In studies CS40 and CS41, serum sodium was monitored regularly throughout the trials: at screening, Days 4, 8, 29, 57 and 85. In men in study CS41 there were additional measurements on days 15 and 22 as well. The following safety measures were implemented in the trial: If serum sodium was 130mmoL/L, the subject was scheduled for a visit as soon as possible for further evaluation. If serum sodium at this visit was 125mmoL/L, the subject was withdrawn from the trial and treatment was stopped immediately. Note that Ferring s currently proposed monitoring scheme recommends stopping Nocdurna in patients whose sodium falls below 135mmoL/L so it is likely to result in fewer subjects developing severe hyponatremia (< 125mmoL/L) than would be observed in this clinical trial. Given that this was a closely monitored clinical trial it was felt that it was safe to continue subjects on desmopressin whose serum sodium drops into the intermediate range of 126 to 135mmoL/L to see if they would correct on their own or continue to drop to lower levels. Because of the study results the sponsor is currently recommending additional monitoring for (1) all subjects 65 years of age or (2) at risk of hyponatremia due to use of concomitant medications that may cause hyponatremia regardless of age. The monitoring will consist of measuring serum sodium once during the first week after starting treatment (i.e. between days 4 and 8) and a second time at one month. Nocdurna should be discontinued if serum sodium drops below 135mmoL/L so subjects are less likely to drop to the low serum sodium levels that were permitted in CS40 and CS41. The sponsor believes that this monitoring scheme should successfully identify subjects at risk of hyponatremia before they develop any serious adverse reactions due to progression to severe hyponatremia. Consistent with what was observed in previous studies with desmopressin, hyponatremia, which was captured in the trial under several terms such as hyponatremia and blood sodium increased, was the most concerning safety signals from the list of common adverse reactions and showed a clear dose response. The frequency of hyponatremia was <1% in the placebo group compared to 1% (10mcg), 2% (25mcg), 3% (50mcg), 4% (75mcg) and 6% (100mcg) with Nocdurna treatment. The frequency of blood sodium decreased was <1% in the placebo group compared to <1% (25mcg), 50mcg (2%), 75mcg (2%) and 100mcg (4%) with Nocdurna treatment. 65

66 Table 21 Common Adverse Reactions Occurring at >2% of Subjects in Any Treatment Group in CS29, CS31, CS40 and CS41 In CS40 three women had their lowest serum sodium levels between 126 and 129mmoL/L but all normalized their serum sodium on their own without need for intervention. No women had severe hyponatremia defined as serum sodium levels 125mmoL/L. 66

67 Table 22 Categorical Analysis of Minimum Serum Sodium Values (Safety Analysis Set) CS40 (women) Source Table 11-6 fe cs40-report-body Table 23 Women with Serum Sodium < 130mmoL/L in CS40 Source Table 11-7 fe cs40-report-body Figure 20 Plot of Minimum Post-Dose Serum Sodium in CS40 Source Fig fe cs40-report-body The observations made in Study CS40 are consistent with those from Study CS29 were 4 women had serum sodium levels between 126 and 129mmoL/L on the 25mcg dose, and none developed severe hyponatremia ( 125mmoL/L). In the placebo-controlled part of CS41, six men developed severe hyponatremia ( 125mmoL/L) at doses of 50mcg (n=2), and 75mcg (n=4), and all were discontinued from the trial. 67

68 Table 24 Categorical Analysis of Minimum Serum Sodium Values (Safety Analysis Set) in Part 1 of CS41 (men) Source Table fe cs41-report-body Table 25 Men with Serum Sodium < 125mmoL/L in Part I of study CS41 Source Table fe cs41-report-body Note Highlighted subjects who appear to be at risk of severe hyponatremia given the sponsor s proposed monitoring scheme will be described in more detail below. For clarification, while subject (see Table 25) treated with the 50mcg dose did not reach a serum sodium level <125mmoL/L until the two month visit he already had a serum sodium level of <135mmoL/L at the week one and one month visits and as such would have been identified by the sponsor s proposed monitoring scheme before he developed serum hyponatremia. Figure 21 Serum Sodium Levels in Pt

69 In addition subject (see Table 25), the other subject treated with desmopressin 50mcg who went on to have a serum sodium level of < 125mmoL/L was discontinued at the 7 day visit because of a complaint of dizziness. At the Day 4 visit this subject s serum sodium was already between 130 and 125mmoL/L and as such he would have been identified by the sponsor s proposed monitoring scheme. Therefore he should have been discontinued from further treatment in a real use situation even if he had not had symptoms of dizziness. Of note this was the only patient in the Safety Database that was discontinued for a distinct Adverse Reaction associated with a low serum sodium level. For the rest of the subjects hyponatremia was identified only as a result of the prespecified monitoring scheme. Figure 22 Serum Sodium Levels in Pt Source Fig fe cs41-report-body (red circles correspond to values after desmopressin was discontinued). Finally, for clarification while subject (see Table 25) would not have been required to have serum sodium monitoring on Days 4 and 28 because he was 64 and so under the recommended cut off age of 65 years for additional sodium monitoring, he was receiving the 75mcg dose which is higher than the dose the sponsor is currently recommending for approval. 69

70 Figure 23 Plot of Minimum Post-Dose Serum Sodium Levels in Part I of Study CS41 (men) Figure 23 displays the minimum serum sodium levels observed in CS41 in men treated with placebo, 50 and 75mcg of Nocdurna. In addition to subject (see Table 25) described previously, three other subjects in the blue oval (see Fig. 23) had serum sodium levels of 125 mmol/l or lower and were treated with the 75mcg dose which the sponsor is not recommending for approval. The two subjects, and , in the red oval with serum sodium levels of 125mmoL/L were treated with the 50mcg dose. They were 74 and 79 years of age and so would have been picked up by the sponsor s proposed monitoring scheme for all subjects 65 years of age and older. In Part II of CS41, all men were titrated up to the Nocdurna dose of 100mcg for an additional month of therapy. Two subjects developed post-baseline serum sodium levels 125 mmol/l and were discontinued from the study. One of these subjects (see Table 27) was 58 years of age and would not have been picked up by Ferring s proposed monitoring scheme; however, Ferring is not recommending treatment at the higher dose of 100mcg. 70

71 Table 26 Categorical Analysis of Minimum Serum Sodium Values (Safety Analysis Set) in Study CS41 Part II Source Table fe cs41-report-body Table 27 Men with Serum Sodium < 125mmoL/L in Part II of study CS41 Source Table fe cs41-report-body Figure 24 Plot of Minimum Post-Dose Serum Sodium Levels in Part II of Study CS41 (men) In the earlier studies CS29 and CS31 there were two cases of severe hyponatremia ( 125mmoL/L) in men at doses of 100mcg, two cases at 50mcg and one case at the 10mcg dose. The case on the 10mcg dose was a 78 year old male who developed a pulmonary infection on day 327 who did not have the medication discontinued during the intercurrent illness. The two cases at the 50mcg dose would have been picked up by the sponsor s proposed monitoring scheme. 71

72 Risk-Benefit Analysis Following review of the July 2012 submission of studies CS40 and CS41 the agency concluded that, relative to placebo, the treatment effect size associated with Nocdurna in the currently studied patient population with nocturia was modest and of unclear benefit. The 0.22 reduction of nocturnal voids relative to placebo observed in study CS40 in females amounts to an average reduction of 1 nocturnal void every 5 days. Similarly, the 0.4 placebo-subtracted reduction in voids seen in males in study CS41 is equivalent to reduction of 1 nocturnal void every 2-3 days. This analysis assumes all patients have a similar response and does not take into account that there may be subgroups of responders with greater than average efficacy. The Nocdurna clinical program did not provide convincing evidence of clinical benefit beyond the above mentioned reduction in nocturnal voids. The rationale behind developing a pharmacological intervention for the treatment of nocturia is that nocturia has been associated with deterioration in the quality of life and the increased risk of fractures, particularly in the elderly, a patient group for whom fractures (such as hip fractures) are associated with (1) an exceedingly high morbidity (need for orthopedic surgical procedures); (2), loss of independence (it has been estimated that a substantial percent of patients who sustained a hip fracture do not return to a normal ambulatory status and 50% are no longer ambulatory independent at 1 year), and (3) an increase in mortality 14,15 ). That said, hyponatremia, which has been seen in the Nocdurna development program, in and of itself has been implicated in the literature as contributing to metabolic bone loss, osteoporosis, changes in attention span and gait stability making subjects at increased risk for falls and fractures which may mitigate any potential benefit. Nocturnal voids served as a substitute for clinical benefit in the Nocdurna program. In the absence of a clear placebo-subtracted effect, the only evidence of additional benefit comes from improvement in sleep quality and improvements in quality of life. However, the effects of Nocdurna on these endpoints have been both small, inconsistent (see PRO results), or of unclear significance (e.g. increase in sleep duration prior to first nighttime void). In addition, although the risk of severe hyponatremia has been reduced considerably once the Nocdurna doses have been reduced in both males and females there is still a persistent 14 Nakagawa H, Niu K, Hozawa A, Ikeda Y, Kaiho Y, Ohmori-Matsuda K, Nakaya N, Kuriyama S, Ebihara S, Nagatomi R, Tsuji I, Arai Y. Impact of nocturia on bone fracture and mortality in older individuals: a Japanese longitudinal cohort study. J Urol Oct;184(4): Kupelian V, Fitzgerald MP, Kaplan SA, Norgaard JP, Chiu GR, Rosen RC. Association of nocturia and mortality: results from the Third National Health and Nutrition Examination Survey. J Urol Feb;185(2):

73 risk for hyponatremia which may become more apparent if the drug is used in a larger and more diverse population with additional comorbidities and risk factors under clinical practice conditions that differ considerably from the relatively controlled environment of a clinical trial. After all, men at the 75mcg dose and women at the 50mcg dose, doses only slightly higher than Ferring is currently proposing, developed severe hyponatremia (i.e. serum sodium 125moL/L) and some of them were younger than the 65 years of age which is the cut off age for which Ferring is proposing additional sodium monitoring. Therefore, FDA issued a second Complete Response letter on 30 January 2013 asking for additional information: 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 (EOR) meeting. At the EOR meeting 6 May 2013 FDA indicated that they agreed with the applicant that the two pivotal trials CS40 and CS41 had reached nominal statistical significance on the co-primary endpoints, but given the small to modest difference in efficacy compared to placebo we did not interpret this information by itself to be an adequate measure of clinical benefit because it was not supported by consistent, convincing and reproducible evidence from the PROs which had been used in these trials. The Division clarified that it sees the reduction of urinary volume and the extension in the period of undisturbed sleep as pharmacodynamic effects of desmopressin which, mechanistically reduces urine production, delays filling of the bladder and the subsequent need to void. We consider such endpoints as biomarkers of drug activity rather than clinical endpoints. Ferring emphasized the importance in the quality of sleep and the increase in time of undisturbed sleep prior to the first night time awakening represented specific clinical benefits, but the division argued that the PRO results were not consistent with a clear clinical benefit and that a validated PRO would be especially helpful. In the end, the Division recommended that the sponsor repeat another trial adequately powered to show efficacy using the newly developed NI diary to demonstrate the presumed clinical benefit associated with Nocdurna. Given the differences in interpretation of the data between the Division and Ferring, the applicant submitted a Formal Dispute Resolution Request (FDRR). The applicant argued that in their opinion they had successfully demonstrated safety and efficacy in studies CS40 and CS41 which had been agreed to under Special Protocol Assessments. They also claimed that the Division was acting inconsistent with the approach taken by the Division of Bone, Reproductive and Urologic Products in approving the lower urinary tract symptoms drugs for the treatment of overactive bladder (OAB) where similar modest levels of efficacy compared to placebo were used for approval. During the meeting the following items were discussed: Clinical efficacy and robustness of data in studies CS40 and CS41 The risk of hyponatremia in general and of severe hyponatremia in particular, and how it affects the risk versus benefit ratio for Nocdurna 73

74 Adequacy of safety monitoring The size of Nocdurna s treatment effect compared to placebo Health-related quality of life measures (HRQoL) and its importance in this application given the modest treatment effect on reducing the number of nighttime voids Clinical benefit associated with the observed changes in the length of undisturbed sleep Clinical benefit associated with the observed reduction in the number of nighttime voids Effect of behavior and lifestyle modifications on reduction in the number of nighttime voids Advantages of presenting the data at an Advisory Committee meeting The FDRR review acknowledged that SPA s assess whether protocols are adequate to meet scientific and regulatory requirements, but they do not indicate that the results of the study are adequate for this purpose. Indeed, approval for marketing of an application requires that the entire package is examined for adequacy to allow marketing. To achieve statistical significance on a primary endpoint in and of itself, does not equate to automatic approval. This would negate any consideration of possible safety findings that arise in determining if there is appropriate safety in view of the efficacy findings to allow marketing. Approval decisions are judgments that consider whether substantial evidence of efficacy has been demonstrated and whether the magnitude of the demonstrated effect size is clinically important and appropriate in relation to safety findings. In the case of the OAB drugs prevention of daytime urgency/incontinence was considered a clinical benefit in and of itself even if the benefit was only modest and there was no similar risk of hyponatremia due to treatment so these drugs require a different risk/benefit assessment. As Ferring did not agree with that the Division s recommendation for an additional study demonstrating the clinical meaningful impact of treatment on the frequency of nocturnal voids using the newly developed NI diary was necessary to confirm clinical benefit, it was recommended that Ferring instead submit any additional information, including their analysis that the increase in time to first void could represent a clinically relevant benefit, to support their application and that an Advisory Committee (AC) meeting be set up to permit the public review by experts of the magnitude of clinical efficacy and safety findings and possible mitigation strategies. In the current submission the applicant is focusing on the treatment of subjects with nocturnal polyuria who despite lifestyle changes and appropriate treatment of other medical causes of nocturia continue to have 2 or more nighttime voids. All patients should have serum sodium monitoring at baseline. Additional monitoring during the first week (days 4 to 8) and a repeat measure at the end of the first month is required for all subjects 65 years of age and older and for all subjects irrespective of age who are taking concomitant medication associated with the risk of hyponatremia. Patients with serum sodium levels that fall below the lower limit of normal should be discontinued from treatment. Initial packaging will be limited to 8 tablets to support compliance with serum sodium measurements during the first week of treatment for those 74

75 patients at risk of hyponatremia. A medication guide will be dispensed and an education program will be implemented to help with identifying appropriate patients, maximizing lifestyle changes, and describing the risk of hyponatremia and details behind the sodium monitoring scheme. Ferring is also proposing to perform a post-approval claims-based study to follow the risk of severe hyponatremia and to expedite reporting of all cases of hyponatremia associated with the current indication. 75

76 Clinical Summary Appendix Inclusion Criteria for CS40/CS41 1. Provided written informed consent prior to performance of any trial-related activity 2. Were female and 18 years of age (at the time of written consent) 3. Had at least 2 nocturnal voids every night in a consecutive 3-day period during the screening period (as determined by the diary dispensed at Visit 1 and collected at Visit 2). Exclusion Criteria for CS40/CS41 1. Evidence of severe daytime voiding dysfunction defined as: - Urge urinary incontinence (more than 1 episode/day in the 3-day diary period) - Urgency (more than 1 episode/day in the 3-day diary period) - Frequency (more than 8 daytime voids/day in the 3-day diary period) 2. Interstitial cystitis 3. Urinary retention or a post void residual volume in excess of 150 ml (female), 250 ml (male) as confirmed by bladder ultrasound performed after suspicion of urinary retention 4. Habitual or psychogenic polydipsia (fluid intake resulting in a urine production exceeding 40 ml/kg/24 hours) 5. Central or nephrogenic diabetes insipidus 6. Syndrome of inappropriate anti-diuretic hormone 7. Current or a history of urologic malignancies 8. Genitourinary tract pathology (e.g., infection or stone in the bladder and urethra causing symptoms) 9. Neurogenic detrusor activity (detrusor over activity) 10. Suspicion or evidence of cardiac failure 11. Uncontrolled hypertension 12. Uncontrolled diabetes mellitus 13. Hyponatremia: - Serum sodium level must have been within normal limits 14. Renal insufficiency: - Serum creatinine must have been within normal limits and estimated glomerular filtration rate (GFR) must have been 50 ml/min 15. Hepatic and/or biliary diseases: - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels must not have been more than twice the upper limit of normal range - Total bilirubin level must not have been >1.5 mg/dl 16. History of obstructive sleep apnea 17. Previous desmopressin treatment for nocturia 18. Treatment with another investigational product within 3 months prior to screening 19. Concomitant treatment with any prohibited medication 21. Known alcohol or substance abuse 22. Work or lifestyle that may have interfered with regular nighttime sleep (e.g., shift workers) 76

77 23. Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier that, in the judgment of the Investigator, would impair participation in the trial. Exclusion Criteria for CS40 only 24. Pregnancy, breastfeeding, or a plan to become pregnant during the period of the clinical trial. Subjects of reproductive age must have had documentation of a reliable method of contraception. All pre- and perimenopausal subjects were to have pregnancy tests performed. Amenorrhea >12 months duration, based on the reported date of the last menstrual period, was sufficient documentation of postmenopausal status, and postmenopausal subjects did not require a pregnancy test. Exclusion Criteria for CS41 only 24. Chronic prostatitis/chronic pelvic pain syndrome 25. Suspicion of BOO or urine flow <5 ml/sec as confirmed by uroflowmetry performed after suspicion of BOO 26. Surgical treatment, including transurethral resection, for BOO or BPH within the past 6 months Study Procedures for CD40 and CS41 The Screening Visit was to take place a maximum of 21 days prior to dosing on study Day 1. Inclusion and exclusion criteria and concomitant medication were verified and blood was drawn for hematology and clinical chemistry including serum sodium. Diaries were dispensed and subjects were trained in completing their diaries. Subjects were given a measuring cup for urine volume (in cc s) and a cup that could be used to measure fluid intake (in oz). Instructions for calculating fluid intake were provided in the diary. Fluid intake, urine volume, and observations of nocturia and sleep over a consecutive 3-day period were to be recorded immediately before treatment initiation. Subjects were instructed to empty their bladder before going to bed and to limit fluid intake to satisfy thirst only. The subjects were instructed to start recording the screening diary 3-7 days before study Day 1. On study Day 1 subjects were trained and instructed on completion of the N-QoL questionnaire and study medication was dispensed. Fluid intake, urine volume, and observations of nocturia and sleep were to be recorded for the day of randomization and 2 additional days immediately after treatment initiation. In CS40 during study Day 4; Day 8 (Week 1); Day 29±3 (Month 1); and Day 57±7 (Month 2) diaries dispensed at the prior visit were collected, blood samples were drawn for analysis of serum sodium, and subjects were interviewed about any changes in concomitant medication and any AEs since the last visit. New diaries were dispensed with instructions to record nocturia and sleep observations (each visit) over a consecutive 3-day period during the week prior to the next visit. Study medication was dispensed (Days 8, 29 and 57) and the N-QoL questionnaire was completed (Day 29). Nocturnal urine volume (Day 8) and 24-hour urine volume (Day 57) diaries were dispensed to be recorded over a consecutive 3-day period during the week prior to the next scheduled visit. The End of Trial Visit was performed at Day 85±7 (Month 3); N-QoL was 77

78 completed and blood samples were taken for hematology and clinical chemistry including serum sodium. In CS41, Part 1, there were an additional two visits for serum sodium measurements: Day 15±3 (Week 2), and Day 22±3 (Week 3). In CS41, Part 2, men were titrated up to the 100mcg dose and serum sodium measurements were performed weekly. In addition, voiding diaries were dispensed prior to the last visit and blood samples were also taken for hematology and clinical chemistry at the last visit. 78

79 Additional Efficacy Analyses Nocturnal Polyuria Table 28 First Co-primary Endpoint of Mean Change from Baseline in Nocturnal Voids in Subjects With and Without Nocturnal Polyuria in CS40 (Females) and CS41 (Males) These findings should be compared to data from the first co-primary endpoint for the total population (see Table 14). Table 29 Second Co-primary Endpoint 33% Responder Status in Subjects With and Without Nocturnal Polyuria in CS40 (Females) and CS41 (Males) This table needs to be compared to odds ratio data from the second co-primary for the total population presented below in Table 30. Table 30 Second Co-primary Endpoint Odds Ratio of 33% Responder Status in the Total Population in CS40 (Females) and CS41 (Males) 79

80 OAB/BPH population Table 31 Mean Change from Baseline (During 3 Months of Treatment) in Mean Nocturnal Voids in Subjects With and Without OAB/BPH in CS40 (Females) and CS41 (Males) (First Co-primary Endpoint) Source Response to Teleconference between FDA and Ferring 18 Feb 2014 Table 32 33% Responder Status Study CS40 (Females) in Subjects with and without OAB (Second Co-Primary Endpoint) Source Response to Teleconference between FDA and Ferring 18 Feb 2014 Appendix G 80

81 Table 33 33% Responder Status Study CS41 (Males) in Subjects with and without OAB/BPH (Second Co-Primary Endpoint) Source Response to Teleconference between FDA and Ferring 18 Feb 2014 Appendix G Table 34 Mean Change from Baseline in Daytime Voiding Frequency in Patients in CS40 (Females) and CS41 (Males) Source Response to Teleconference between FDA and Ferring 18 Feb 2014 Table 35 Mean Change from Baseline in Daytime Voiding Frequency in OAB/BPH Patients in CS40 (Females) and CS41 (Males) Source Response to Teleconference between FDA and Ferring 18 Feb

82 Table 36 Mean Change from Baseline in Daytime Voiding Volume (ml) Patients in CS40 (Females) and CS41 (Males) Source Response to Teleconference between FDA and Ferring 18 Feb 2014 Table 37 Mean Change from Baseline in Daytime Voiding Volume (ml) OAB/BPH Patients in CS40 (Females) and CS41 (Males) Source Response to Teleconference between FDA and Ferring 18 Feb

83 REFERENCE LIST Yamaguchi O, Nishizawa O, Juul KV, Nørgaard JP. Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial. BJU Int Mar; 111(3): Vande Walle JG, Bogaert GA, Mattsson S, Schurmans T, Hoebeke P, Deboe V, Norgaard JP; Desmopressin Oral Lyophilisate PD/PK Study Group. A new fast-melting oral formulation of desmopressin: a pharmacodynamic study in children with primary nocturnal enuresis. BJU Int Mar;97(3): Abraham L, Hareendran A, Mills IW, Martin ML, Abrams P, Drake MJ, MacDonagh RP, Noble JG. Development and validation of a quality-of-life measure for men with nocturia. Urology Mar;63(3): Mock LL, Parmelee PA, Kutner N, Scott J, Johnson TM 2nd. Content validation of symptom-specific nocturia quality-of-life instrument developed in men: issues expressed by women, as well as men. Urology Oct;72(4): Epub 2008 Aug 5. Cowen LE, Hodak SP, Verbalis JG Age-associated abnormalities of water homeostasis.. Endocrinol Metab Clin North Am Jun;42(2): Palmer BF, Gates JR, Lader M. Causes and management of hyponatremia. Ann Pharmacother Nov;37(11): Review Al-Salman J, Kemp D, Randall D. Hyponatremia West J Med May;176(3): Appell RA, Sand PK. Neurourol Urodyn. 2008;27(1):34-9. Nocturia: etiology, diagnosis, and treatment. Nakagawa H, Niu K, Hozawa A, Ikeda Y, Kaiho Y, Ohmori-Matsuda K, Nakaya N, Kuriyama S, Ebihara S, Nagatomi R, Tsuji I, Arai Y. Impact of nocturia on bone fracture and mortality in older individuals: a Japanese longitudinal cohort study. J Urol Oct;184(4): Kupelian V, Fitzgerald MP, Kaplan SA, Norgaard JP, Chiu GR, Rosen RC. Association of nocturia and mortality: results from the Third National Health and Nutrition Examination Survey. J Urol Feb;185(2):

84 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire STUDY ENDPOINTS TRACKING NUMBER IND/NDA/BLA NUMBER NDA LETTER DATE/SUBMISSION NUMBER SDN 30 PDUFA GOAL DATE January 31, 2015 DATE OF CONSULT REQUEST August 21, 2014 REVIEW DIVISION MEDICAL REVIEWER REVIEW DIVISION PM STUDY ENDPOINTS REVIEWER(S) ASSOCIATE DIRECTOR, STUDY ENDPOINTS (ACTING) Division of Metabolism and Endocrinology Products (DMEP) William Lubas, M.D., Ph.D. (Clinical TL: Dragos Roman, M.D.) Jennifer Johnson Sarrit Kovacs, Ph.D. Elektra Papadopoulos, M.D., M.P.H. REVIEW COMPLETION DATE December 9, 2014 ESTABLISHED NAME TRADE NAME APPLICANT CLINICAL OUTCOME ASSESSMENT TYPE ENDPOINT(S) CONCEPT(S) MEASURE(S) Desmopressin orally disintegrating sublingual tablets Nocdurna Ferring Pharmaceuticals, Inc. Patient-reported outcome Intensity of nocturia impacts Nocturia Impact (NI) Diary; Nocturia Quality-of-Life (NQoL) questionnaire INDICATION INTENDED POPULATION(S) Treatment of Nocturia Adult males or females ( 20 years of age) with at least 2 nocturnal voids every night in a consecutive 3-day period as documented in the diary during the screening period. 84

85 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire A. EXECUTIVE SUMMARY This Study Endpoints review is provided as a response to a request for consultation by the Division of Metabolism and Endocrinology Products (DMEP) regarding NDA The applicant (in dialogue with FDA) developed the Nocturia Impact (NI) Diary based on the existing instrument, Nocturia Quality-of-Life (NQoL) questionnaire, that was used in both phase 3 trials (CS40 and CS41). Several changes were made in the development of the NI Diary to address the limitations of the NQoL. These limitations include the relatively long recall period (2 weeks) of the NQoL, which is problematic for distinguishing treatment benefit in drug development trials where a patient s condition fluctuates, as can occur in patients with nocturia. A comparison of the NQoL and the NI diary is appended. The NI Diary was included in a one-month long phase 3b extension study (IMPACT Trial; CS000034) that enrolled a subgroup of adult patients with nocturia who had completed CS40 and CS41). CS was small (n=56) and exploratory in nature. Its primary objective was to assess the psychometric properties of the NI Diary. Given its exploratory nature, no conclusions of effectiveness can be made using the NI Diary in CS Hence, the NI Diary results cannot serve as a basis for labeling claims. The NQoL was used in Studies CS40 and CS41. However, the analyses conducted by the applicant with the NQoL were also post hoc and exploratory per discussion with the clinical reviewer, Dr. Lubas (December 5, 2015). The review concludes that the clinical trial evidence submitted by the applicant is inadequate to support labeling claims on the basis of the NI Diary or NQoL because of the exploratory nature of the data. Therefore, these clinical trial results do not meet standards for inclusion in labeling claims. However, the NI Diary was developed specifically for use in clinical trials and may be able to support labeling claims if it demonstrates a clinically meaningful and statistically significant treatment effect in adequate and well-controlled trials. 85

86 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire B. ABBREVIATED STUDY ENDPOINT REVIEW The NQoL and the NI Diary were reviewed in previous Study Endpoints reviews (James Stansbury/Laurie Burke). Both instruments were paper-based measures and were administered in English only. A history of the development of the NI Diary and its comparison with the NQoL are appended. Briefly, the NI Diary produces a single overall score. The majority of the items of the NI Diary measure sleep impacts of nocturia; therefore, the overall score produced by NI Diary instrument would most accurately be described as such. The NQoL produces two scores: (a) the Sleep/Energy score and (b) the Bother/Concern score. The NI Diary items reflect patient input and many of its items are derived from the NQoL. We note that a subset of the NI Diary s items may be less relevant to assess in a drug treatment trial (e.g., Do you worry that the nocturia will get worse in the future? ). There are also several inconsistencies among versions within the sponsor s submissions (in PRO Dossier, conceptual framework, item comparison table, and CS clinical trial protocol/crf). More specifically, there is different wording across versions for Item 8 (additional words tripping or ) and/or Item 11 (additional word overnight ). Despite these findings, there are no apparent concerns that are of the magnitude that would preclude inclusion in labeling of clinically meaningful and statistically robust clinical trial data derived using this instrument. The following information regarding the NI Diary and NQoL can be found in the appendices. Appendix A: NQoL Conceptual Framework Appendix B: NI Diary Conceptual Framework Appendix C: NI Diary Scoring Appendix D: Comparison of the Items in the NI Diary and NQoL Appendix E: Nocturia Quality-of-Life (NQoL) Appendix F: Nocturia Impact Diary (NI Diary) Appendix G: Development Process of the NI Diary 86

87 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire APPENDIX A - NQOL CONCEPTUAL FRAMEWORK Note: This conceptual framework was reproduced from a previous Study Endpoints review based on a submission from the applicant. 87

88 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire APPENDIX B - NI DIARY CONCEPTUAL FRAMEWORK Reviewer s comment: This figure was reproduced from the applicant s submission. However, in contrast to the figure, it is our understanding that the overall impact item (Item 12) is not included in the total NI Diary score. 88

89 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire APPENDIX C - NI DIARY SCORING From the applicant s PRO Dossier (page 128 of 574) 89

90 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire APPENDIX D - COMPARISON OF ITEMS IN NI DIARY AND NQOL Reviewer s comments: While this table was reproduced from the sponsor s submission, we noted that Item 11 does not share the same wording with the instrument appended. The version used for the table above included the additional word overnight in Item 11 as well as the additional words tripping or in Item 8. 90

91 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire APPENDIX E - NOCTURIA QUALITY-OF-LIFE (NQOL) 91

92 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire 92

93 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire APPENDIX F - NOCTURIA IMPACT (NI) DIARY 93

94 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire 94

95 Study Endpoints Review Sarrit Kovacs, Ph.D. NDA Nocdurna Nocturia Impact (NI) Diary and Nocturia Quality-of-Life (NQoL) questionnaire APPENDIX G - DEVELOPMENT PROCESS OF THE NI DIARY 95