FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting January ...

108 Pages·2015·6.53 MB·English

FDA Briefing Document

Endocrinologic and Metabolic Drugs
Advisory Committee Meeting

January 12, 2015
8:00 AM to 5:00 PM

The committee will discuss the safety and efficacy of new drug application (NDA)
022517, 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
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 22-517 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
Table of Contents

Page

Division Director Memorandum 4

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
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 15th, 2014

From: Jean-Marc Guettier, MD
Director, Division of Metabolism and Endocrinology Products (DMEP)

To: Chair, Members and Invited Guests of the Endocrinologic and Metabolic
Drugs Advisory Committee (EMDAC)

Subject: 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) 022517 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
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 respectively2. 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. 2006 Feb; 175(2):596-600.
2 van Kerrebroeck et al. Neurourol Urodyn. 2002; 21(2):179-83.
5
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 022517) 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 co-
primary 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 -0.61 (-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
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 -0.24 (-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 -0.40 (-0.60, -0.20) and -0.37 (-
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 validity3, relied on a long recall period (i.e., average symptoms over two-
weeks) 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
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
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
CLINICAL-STATISTICAL SUMMARY

New Drug Application (NDA) 22-517

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 2015

10