CENTER FOR DRUG EVALUATION AND
RESEARCH

APPLICATION NUMBER:

2056250rig15000

SUMMARY REVIEW

 

SUMMARY REVIEW OF REGULATORY ACTION
Date:

August 20, 2014

From:

Badrul A. Chowdhury, MD, PhD
Director, Division of Pulmonary, Allergy, and Rheumatology
Products, CDER, FDA

Subject:
NDA Number:
Applicant Name:
Date of Submission:
PDUFA Goal Date:
Proprietary Name:
Established Name:
Dosage form:

Division Director Summary Review
20-5625
GlaxoSmithKline
October 22, 2013
August 22, 2014
Arnuity Ellipta
Fluticasone furoate
Inhalation Powder (inhaler contains foil blister strip with 30
blisters containing powder for oral inhalation)
Strength:
Fluticasone furoate 100 mcg or 200 mcg per blister
Proposed Indications: Asthma
Action:
Approval
1. Introduction
GlaxoSmithKline (GSK) submitted this 505(b)(1) new drug application for use of
Arnuity Ellipta (fluticasone furoate 100 mcg or 200 mcg inhalation powder) for
maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and
older. The proposed dose is one inhalation (fluticasone furoate 100 mcg or 200 mcg)
once daily, with the starting dose based on prior asthma therapy and disease severity.
Fluticasone furoate, a corticosteroid, in the same Ellipta device is marketed as Breo
Ellipta (NDA 20-4275, approved in May 2013) for use in patients with COPD. The
application is based on clinical efficacy and safety studies. This summary review will
provide an overview of the application, with a focus on the clinical efficacy and safety
studies.

2. Background
There are several drug classes available for use in patients with persistent asthma. These
include inhaled corticosteroids (ICSs), inhaled long-acting beta-adrenergic agents
(LABAs), leukotriene modifying drugs, methylxanthines, and omalizumab. ICSs are
considered to be the most effective long-term therapy for persistent asthma, and are
commonly used as the first drug when a maintenance therapy is necessary. There are
several ICS containing products in the market in the United States, such as Asmanex
(mometasone furoate), Alvesco (ciclesonide), Flovent (fluticasone propionate), Pulmicort
(budesonide), and Qvar (beclomethasone dipropionae). When an adequate dose of ICS
has not provided asthma control, a second drug, such as a LABA is often added,
preferably for a limited time period with the intent of discontinuing the LABA once
asthma control is achieved and maintained. Since some patients with persistent asthma

Reference ID: 3613374

 2

use both an ICS and a LABA, these two drugs have been put together in the same
formulation and in the same device and marketed as inhaled combination products.
There are four such combination products in the market in the United States. These are
Advair Diskus and Advair HFA Inhalation Aerosol (both are a combination of fluticasone
propionate and salmeterol xinafoate), Symbicort (a combination of budesonide and
formoterol fumarate), and Dulera (a combination of mometasone furoate and formoterol
fumarate). Arnuity Ellipta will provide another choice of single entity ICS for use in
patients with asthma.
Fluticasone furoate is not a new molecular entity as fluticasone furoate is marketed as one
of the active components in Breo Ellipta, and as a nasal formulation for the treatment of
allergic rhinitis. Fluticasone propionate, another ester of fluticasone and propionic acid,
is marketed for a variety of indications, including allergic rhinitis and asthma as a single
ingredient product, and as a combination product (Advair) with salmeterol, a LABA, for
asthma and COPD. Corticosteroids have a variety of serious adverse effects that are well
known. Although ICSs do not usually have the typical serious systemic effects
associated with corticosteroids because systemic absorption from the inhaled route is
limited, ICSs can have serious local adverse reactions in the lung in COPD patients. For
example, Advair (fluticasone propionate plus salmeterol) is known to increase the risk of
pneumonia in patients with COPD, particularly at high doses. Such a risk of pneumonia
has not been seen in patients with asthma. Also, ICS at high doses have systemic effects,
such as changes in bone mineralization in COPD patients, and an effect on linear growth
in young growing patients with asthma. Identifying the appropriate dosing frequency of
ICSs is also important because the same nominal dose given once daily can have
substantially less efficacy compared to twice daily dosing, as was seen with fluticasone
propionate and ciclesonide in patients with asthma. 1, 2 Therefore, it is important to select
an appropriate dose and dosing frequency for any ICS.
Regulatory interaction between the Agency and GSK:
The Division and GSK had typical milestone meetings for Arnuity Ellipta for asthma, as
well as meetings for the development of combination products where fluticasone furoate
was one of the components of the combination product, such as Breo Ellipta for COPD.
The following timeline highlights some major discussion points that occurred during
clinical development of these products that are relevant for Arnuity Ellipta for asthma.
• End-of-Phase-2 meeting for Breo Ellipta asthma program, March 31, 2009: The
Division stated the need for confirmation of the dosing interval prior to initiating
confirmatory studies.
• Second End-of-Phase 2 meeting for Breo Ellipta asthma program, June 30, 2010:
The Division requested that relevant information from the asthma program, such as

1

Purucker ME, Rosebraugh CJ, Zhou F, Meyer RJ. Inhaled fluticasone propionate by diskus in the
treatment of asthma: A comparison of the efficacy of the same nominal dose given either once twice a day.
Chest 2003; 124:1584-93.
2
Chowdhury BA. Ciclesonide inhalation aerosol for persistent asthma. J Allergy Clin Immunol 2006;
117:1194-6. And, Alvesco (ciclesonide) Inhalation Aerosol, Package Insert, Product Label, Section 14.

Reference ID: 3613374

 dose selection data for the ?uticasone furoate and vilanterol monocomponents be
included in the COPD NDA.

meeting for Breo Ellipta for asthma, October 12, 2011: The Division
requested that an application for asthma be submitted concrurently with the OPD
application, given the novelty of both the ?uticasone furoate and vilanterol
components. GSK stated that the recommendation would be taken rmder advisement.
GSK noted that the strength of the bronchodilator ef?cacy data in asthma for Breo
Ellipta over vilanterol has provided mixed results. 3

meeting for Arnuity Ellipta for asthma, February 11, 2013: The Division
agreed with submission of the 100 me and 200 doses for registration, and noted
that evidence to support the 50 dose was weak.

3. Chemistry, Manufacturing, and Controls
The product Arnuity Ellipta (?uticasone fru'oate 100 and 200 mc inhalation
powder) includes a novel dry powder inhaler device, the Ellipta inhaler, which contains a
foil blister strip with 30 blisters. Each blister contains micronized ?uticasone fru'oate
(100 me or 200 mcg) and lactose monohydrate. The lactose monohydrate may contain
trace amounts of milk proteins. The proposed commercial presentation of Arnuity Ellipta
has 30 blisters each of ?uticasone furoate, which will be a one-month supply with a once
daily dosing regimen. The device has a dose cormter. The steps needed to use the
product are simple and similar to some other dry powder inhaler devices. To deliver a
dose, the patient will open the cover of the device. This action makes the powder from
one blister containing ?uticasone furoate ready for inhalation at the air?ow path inside
the device. The patient will then inhale through the mouthpiece of the device. If a
patient opens and closes the cover of the device without inhaling, the formulation powder
will be held inside the device and will no longer be available to be inhaled. The Arnuity
Ellipta device has been tested for usability, reliability, and ruggedness through in Vitro
testing, hrunan factor studies, and testing of devices used in the clinical program.

Arnuity Ellipta is packaged within a moisture-protecting foil tray with a desiccant packet.
GSK submitted adequate stability data to support an expiry of 30 months for the product
stored at room temperature inside the protective foil tray. Arnuity Ellipta should be
discarded after all doses are used or 6 weeks after removal from the protective package,
whichever comes fn?st.

The diug substances are manufactured at a GSK facility in mm, and diug
product, including the Arnuity Ellipta device is assembled at a GSK facility in 
The device components are fabricated by in MN All

manufactru?ing and testing facilities associated with this drug product have acceptable
establishment evaluation status. All DMFs associated with this application were also
formd to be acceptable.

 

3 GSK January 9. 2012 [press release]. Retrieved from 
news/pressreleases/ZO12/20 l2-pressrelease-840722.htm on February 7. 2013.

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4

4. Nonclinical Pharmacology and Toxicology
GSK submitted results from a full preclinical program to the Agency. The program
included studies in which animals were dosed with fluticasone furoate. The toxicity
profile of fluticasone furoate has been characterized previously for the nasal spray NDA
(Veramyst Nasal Spray NDA 22-051, approved on April 27, 2007). Briefly, fluticasone
furoate was non-genotoxic, non-carcinogenic, non-teratogenic, and had no effect on
fertility in animals. The fluticasone furoate label carries a Pregnancy Category C
designation because of the known effects of corticosteroids on embryofetal development.

5. Clinical Pharmacology and Biopharmaceutics
GSK submitted results from a comprehensive clinical pharmacology program that
included studies to assess protein binding and metabolism and the pharmacokinetics after
single and multiple inhaled doses of fluticasone furoate. The majority of studies were
conducted in healthy volunteers, but several studies were done specifically to assess
pharmacokinetics in patients and the effect of renal and hepatic impairment. Fluticasone
furoate has a low oral bioavailability and systemic exposure primarily due to absorption
of the inhaled portion. The estimated half-life for fluticasone furoate is 24 hours.
Fluticasone furoate is a substrate of CYP3A4 and P-gp. The inhibition potential is low
when administered by the inhaled route and no specific dose adjustments are
recommended when the product is administered with other drugs. No significant effects
due to age, or renal impairment on pharmacokinetic parameters were observed, so no
dose adjustment for age or renal function is recommended. Systemic exposure of
fluticasone furoate is higher in hepatic impairment patients. In addition, a decrease in
serum cortisol was noted in patients with moderate hepatic impairment. Therefore
caution should be used in patients with moderate or severe hepatic impairment. A study
to assess QTc effects did not indicate any clinically relevant prolongation of the QTc
interval at the therapeutic dose.

6. Clinical Microbiology
GSK proposed acceptable testing regimen involving the bulk drug product and the
product packaged in the blister packs.

7.

Clinical and Statistical – Efficacy
a. Overview of the clinical program
Some characteristics of the relevant clinical studies that form the basis of review and
regulatory decision-making for this application are shown in Table 1 and Table 2. Table
1 summarizes the main studies conducted to support dose selection and dosing frequency
for fluticasone furoate. Table 2 summarizes the main studies conducted in patients with
asthma. The design and conduct of these studies are briefly described below, followed by
efficacy findings and conclusions. Safety findings are discussed in Section 8. For
brevity, the studies are referenced later in this review by the last four digits of the study
number.

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 5

Table 1. Relevant dose selection studies for fluticasone furoate in patients with asthma
ID
Year*

Study Characteristics †
Treatment groups ‡
N§
Primary efficacy
variables ¶
- Patient age
- Patient characteristics
- Study design, objective
- Study duration
Fluticasone furoate -- Dose-ranging studies
- 12 to 78 yr
FF 200 mg QD PM
99
FEV1 trough at
109684
[2007- Asthma, medium dose ICS
FF 400 mcg QD PM
101
week 8
2008]
- Parallel arm, DB
FF 600 QD PM
107
- 8 weeks
FF 800 mcg QD PM
102
FP 500 mcg BID
110
Placebo
103
- 12 to 80 yr
FF 100 mcg QD PM
105
FEV1 trough at
109685
[2007- Asthma, low dose ICS
FF 200 mg QD PM
101
week 8
2008]
- Parallel arm, DB
FF 300 mcg QD PM
103
- 8 weeks
FF 400 mcg QD PM
99
FP 250 mcg BID
100
Placebo
107
- 12 to 78 yr
FF 25 mcg QD PM
97
FEV1 trough at
109687
[2007- Asthma, no ICS
FF 50 mcg QD PM
100
week 8
2008]
- Parallel arm, DB
FF 100 mcg QD PM
110
- 8 weeks
FF 200 mcg QD PM
95
FP 100 mcg BID
110
Placebo
94
Fluticasone furoate -- Dose-regimen study
- 12 to 76 yr
FF 200 mcg QD PM
140
FEV1 trough at the
112202
[2007- Asthma
FF 100 mcg BID
142
end of 28-day
2008]
- Cross over, DB
FP 200 mcg QD PM
42
treatment period
- 28 days
FP 100 mcg BID
43
Placebo
187
* Study ID shown (top to bottom) as GSK’s study number, and [year study started-completed]
† DB=double blind, DD=double dummy
‡ FF=fluticasone furoate in Arnuity device; FP=fluticasone propionate
§ Intent to treat
¶ Primary efficacy variables are shown.

Regions and
Countries

US, Canada,
Mexico, W Eur,
E Eur, S Africa,
Australia,
Thailand
(18% US)
US, Canada,
Mexico, W Eur,
E Eur, S Korea,
Philippines
(32% US)
US, Canada, S
Africa, Other
(36% US)

US

Table 2. Relevant clinical studies with Arnuity Ellipta (fluticasone furoate) in patients with asthma
ID
Year*

Study Characteristics †
Treatment groups ‡
N§
- Patient age
- Patient characteristics
- Study design, objective
- Study duration
Pivotal efficacy and safety studies supporting Arnuity Ellipta 100 mcg
- ≥ 12 yr, mean 41 yrs
FF 100 mcg QD
114
112059
Trial 1
FP 250 mcg BID
114
- On ICS, ± LABA
[2010Placebo
115
- Parallel arm, DB
2012]
- 24 weeks
106827
Trial 2
[20102011]

Reference ID: 3613374

- ≥ 12 yr, mean 40 yrs
- On ICS, ± LABA
- Parallel arm, DB
- 12 weeks

FF 100 mcg QD
FF/VI 100/25 mcg QD
Placebo

205
201
203

Primary efficacy
variable ¶

Regions and
Countries

1 : ΔFEV1 trough
baseline to week 24

US, Poland,
Romania,
Germany,
Belgium
(57% US)
US, Poland,
Romania,
Ukraine,
Germany, Japan
(32% US)

o

1 : ΔFEV1 trough
baseline to week 12
o
1 : ΔFEV1 0-24 hr
baseline to week 12
o

 6

ID
Year*

Study Characteristics †
Treatment groups ‡
N§
- Patient age
- Patient characteristics
- Study design, objective
- Study duration
Pivotal efficacy and safety studies supporting Arnuity Ellipta 200 mcg
- ≥ 12 yr mean 46 yrs
FF 100 mcg QD
119
114496
Trial 3
FF 200 mcg QD
119
- On ICS, no LABA
[2011- Parallel arm, DB
2012]
- 24 weeks
- ≥ 12 yr, mean 46 yrs
FF 200 mcg QD
194
106829
Trial 4
FF/VI 200/25 mcg QD 197
- On ICS, no LABA
[2010FP 500 mcg BID
195
- Parallel arm, DB
2011]
- 24 weeks
Supporting long-term safety studies
- ≥ 12 yr, mean 42 yrs
FF 100 mcg QD
1010
106837
[2010- Asthma
FF/VI 100/25 mcg QD 1009
2011]
- Parallel arm, DB
- 76 weeks

Primary efficacy
variable ¶

Regions and
Countries

1 : ΔFEV1 trough
baseline to week 24

US, Argentina,
Russia, Mexico,
France, Chile
(23% US)
US, E and W
Europe, Japan
(24% US)

o

1 : ΔFEV1 trough
baseline to week 24
o
1 : ΔFEV1 0-24 hr
baseline to week 24
o

US, E and W
Europe, Japan,
Philippines,
Mexico, S Amer
(18% US)
- ≥ 12 yr, mean 39 yrs
FF/VI 100/25 mcg QD 201
US, Germany,
106839
[2009- Asthma
FF/VI 200/25 mcg QD 202
Ukraine,
FP 500 BID
2011]
- Parallel arm, DB
100
Thailand
- 52 weeks
(38% US)
* Study ID shown (top to bottom) as GSK’s study number, as referenced in the proposed Breo Ellipta product label,
and [year study started-completed]
† DB=double blind, DD=double dummy
‡ FF=fluticasone furoate in Arnuity Ellipta; FP=fluticasone propionate; FF/VI = Breo Ellipta (fluticasone furoate and
vilanterol inhalation powder);
§ Intent to treat (ITT)
¶ Analyzed based on linear regression models (ANCOVA) adjusting for baseline FEV1, region, sex, and age. In the
analysis of trough FEV1, last observation carried forward was used to missing measurement in patients who withdrew
from the study. Analysis of post-dose 0-24 hr serial FEV1 was on weighted mean and restricted to patient who
completed the study with no imputation for missing data.

b. Design and conduct of the studies
Fluticasone furoate dose ranging (9684, 9685, 9787) and dose regimen (2202) studies:
These studies were conducted in patients with persistent asthma with varying severity
commensurate to the doses of fluticasone that were used in these studies: study 9684
enrolled patients who were symptomatic on moderate-dose ICS, study 9685 enrolled
patients who were symptomatic on low-dose ICS, study 9687 enrolled patients who were
symptomatic on SABA, and study 2202 enrolled patients with persistent asthma. Study
treatment arms and primary efficacy variable are shown in Table 1. The primary analysis
for studies 9684, 9685, and 9687 was linear trend in dose response in trough FEV1 at
week 8. The primary analysis of study 2202 was non-inferiority of fluticasone furoate
200 mg QD to fluticasone furoate 100 mg BID trough FEV1 at week 8. Safety
assessments included adverse event recording, vital signs, physical examination including
oropharyngeal examination, clinical laboratory and hematology measures, and 24-hour
urinary cortisol excretion.

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 7

Pivotal efficacy and safety studies (2059, 6827, 4496, 6829):
These studies were similar in design conducted in patients with persistent asthma with
varying severity commensurate to the dose of study drug, and for duration of study and
treatment arms (Table 2). Patients eligible for the studies were required to have a
diagnosis of asthma for at least 12 weeks, had been using an ICS at a stable dose for at
least 4 weeks, with or without a concomitant LABA treatment. Eligible patients entered
a 4-week run-in period to establish eligibility, assess compliance, and measure baseline
characteristics, followed by double-blind treatment period (Table 2). Concomitant
LABA was prohibited during run-in and double-blind periods. Patients withdrawing
from taking the study treatment were not followed up for efficacy or safety assessment.
Primary efficacy variables are shown in Table 2. Safety assessments included adverse
event recording, vital signs, physical examination, clinical laboratory and hematology
measures, and ECGs.
Supportive long-term safety studies (6837, 6839):
These studies were conducted in patients with persistent asthma. Study treatment arms
are shown in Table 1. Safety assessments included adverse event recording, vital signs,
physical examination, and clinical laboratory and hematology measures.
c. Efficacy findings and conclusions
The clinical program is adequate to support efficacy of Arnuity Ellipta 100 mcg and 200
mcg (fluticasone furoate 100 mcg and 200 mcg) in patients with asthma.
Fluticasone furoate dose ranging and dose regimen:
As discussed in section 2 above, selection of an appropriate dose and dosing regimen is
an important consideration for the development of ICSs. GSK conducted adequate
exploration of dose ranges in 3 studies and dose regimen in 1 study (Table 1).
In dose ranging studies, trough FEV1 responses showed efficacy of fluticasone furoate
100 mcg once daily near the maximal efficacy with fluticasone furoate 200 mcg once
daily (Figure 1). Efficacy was also demonstrated with fluticasone furoate 50 mcg once
daily, but the difference compared to placebo and compared to other doses was less.
With increasing doses of fluticasone furoate, the trough FEV1 response reached a plateau,
but also seemed to numerically decrease at the very high end of doses (Figure 1). Based
on these data, GSK selected the nominal dose of fluticasone furoate 100 and 200 mcg for
confirmatory studies. This was reasonable and acceptable to the Agency.
Results of the dose regimen study showed numerically similar changes in trough FEV1
from baseline compared to placebo for fluticasone furoate 200 mcg once daily and
fluticasone furoate 100 mcg twice daily, which supports a once-daily dosing regimen for
fluticasone furoate. The study had sensitivity to detect a difference between once- and
twice-daily ICS dosing, since a numerically superior improvement in FEV1 compared to
placebo was seen for the true twice-daily comparator, fluticasone propionate (Figure 2).

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 8

Figure 1. Adjusted treatment difference from placebo for change from baseline in trough FEV1 in
liters at week 8 from three dose ranging studies in asthma (FF=fluticasone furoate, FP=fluticasone
propionate).

Figure 2. Adjusted treatment difference from placebo for change from baseline in trough FEV1 in
liters at day 28 from dose regimen study in asthma (FF=fluticasone furoate, FP=fluticasone
propionate).

Reference ID: 3613374

 9

Fluticasone furoate pivotal efficacy:
The submitted data support efficacy of both Arnuity Ellipta 100 mcg and 200 mcg once
daily doses. The 100 mcg dose demonstrated statistically significant difference from
placebo in FEV1 based on primary efficacy measures in two studies (Table 3 and Table
4). Various secondary efficacy measures, such as symptom-free period, rescue
medication use, and ACT score, were also supportive. The 200 mcg dose showed
numerical trend of higher response compared to the 100 mcg dose for the primary
efficacy measure (Table 5), and also for various secondary efficacy measures. The
efficacy of fluticasone furoate 100 mcg once-daily and fluticasone propionate 250 mcg
twice-daily were numerically comparable (Table 3), and the efficacy of fluticasone
furoate 200 mcg once-daily and fluticasone propionate 500 mcg twice-daily were also
numerically comparable (Table 6).
Table 3. Primary efficacy variable results from Study 2059
Placebo
FF 100 mcg QD
N=115
N=114
Change from baseline in trough FEV1 in L to week 24, All Patients
Mean change
0.02
0.17
Difference [95% CI], p value
0.15 [0.04, 0.26], 0.01

FP 250 mcg BID
N=114
0.15
0.14 [0.03, 0.26], 0.01

Table 4. Primary efficacy variable results from Study 6827
Placebo
N=203
Change from baseline in trough FEV1 in L to week 12, All Patients
Lease squares mean change
0.22
Difference [95% CI], p value
Change from baseline in FEV1 0-24 hr in L to week 12, Completers
Mean change
0.25
Difference [95% CI], p value

FF 100 mcg QD
N=205
0.32
0.14 [0.05, 0.22], 0.002
0.38
0.19 [0.06, 0.31], 0.003

Table 5. Primary efficacy variable results from Study 4496
FF 100 mcg QD
N=108
Change from baseline in trough FEV1 in L to week 24 All Patients
Mean change
0.20
Difference [95% CI]

FF 200 mcg QD
N=111
0.29
0.08 [-0.04, 0.19]

Table 6. Primary efficacy variable results from Study 6829
FP 500 mcg BID
N=195
Change from baseline in trough FEV1 in L to week 24 All Patients
Lease squares mean change
0.17
Difference [95% CI]
Change from baseline in FEV1 0-24 hr in L to week 24, Completers
Mean change
0.26
Difference [95% CI]

Reference ID: 3613374

FP 200 mcg QD
N=195
0.22
0.02 [-0.07, 0.10]
0.33
0.07 [-0.07, 0.21]

 10

8.

Safety
a. Safety database
The safety assessment of Arnuity Ellipta is based on studies shown in Table 1 and Table
2. The safety database for Arnuity Ellipta was large and adequate.
b. Safety findings and conclusion
The submitted data support the safety of Arnuity Ellipta 100 mcg and 200 mcg
(fluticasone furoate 100 mcg and 200 mcg) in patients with asthma
GSK conducted a comprehensive safety analysis of the available data. Safety analysis
included evaluation of deaths, serious adverse events (SAEs 4), common adverse events
(AEs), and assessment of adverse events of interest related to HPA axis.
There were 2 deaths in the clinical program, both in patients receiving Arnuity Ellipta
100 mcg dose. One death was in a 65 year-old male patient from respiratory failure
secondary to lung cancer, and another death was in a 62 year-old patient with
concomitant diabetes who developed sepsis. SAEs were reported in 52 subjects across
treatment groups. The most frequent SAE was asthma exacerbations. The SAEs were
generally balanced across treatment groups and do not raise any specific concerns.
Common adverse events included headache, nasopharyngitis, upper respiratory tract
infection, bronchitis, oropharyngeal pain, and cough. There were no dose-dependent
increases in adverse events. There were no clinically meaningful changes in laboratory
parameters, or ECGs.
c. REMS/RiskMAP
GSK submitted a Risk Management Plan for Arnuity Ellipta, which consists of routine
pharmacovigilance practices. A REMS is not necessary for Arnuity Ellipta as inhaled
corticosteroids have a well-established safety profile and there were no unique safety
signals identified for Arnuity Ellipta that would require a REMS.

9. Advisory Committee Meeting
An Advisory Committee meeting was not held to discus this application as the safety and
efficacy for an ICS such as fluticasone furoate in asthma is well understood. There were
no unique findings in the Arnuity Ellipta program that would warrant a discussion at an
Advisory Committee meeting.

4

Serious Adverse Drug Experience is defined in 21 CFR 312.32 as any adverse drug experience occurring
at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience
(defined in the same regulation as any adverse drug experience that places the patient or subject, in the
view of the investigator, at immediate risk of death from the reaction as it occurred), inpatient
hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity,
or a congenital anomaly/birth defect.

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 11

10. Pediatric
GSK requested a deferral for studies in patients 5 to 11 years of age and a waiver for
patients below 5 years of age with the reasoning that effective treatments for asthma for
these ages are already available in the market and clinical in these patients are
impractical. There are four deferred studies in pediatric patients 5-11 years of age: 1) a
12-week dose ranging, efficacy and safety study; 2) a 2 week knemometry study; 3) a 6
week HPA axis study; and 4) a 52 week growth study. GSKs proposal was discussed at
PeRC meeting on September 25, 2013, before the application was submitted, and on
February 12, 2014, during review of this application, and PeRC found GSKs request
acceptable.

11. Other Relevant Regulatory Issues
a. DSI Audits
A DSI audit was not necessary and not conducted for this application. During review of
this application, the review team did not identify any irregularities that would raise
concerns regarding data integrity. All studies were conducted in accordance with
accepted ethical standards.
b. Financial Disclosure
The applicant submitted acceptable financial disclosure statements. Two investigators
had significant financial interest in GSK. The number of subjects enrolled at these
investigator sites was not large enough to alter the outcome of any study. Furthermore,
the multi-center nature of the studies makes it unlikely that financial interest could have
influenced or biased the results of these studies.
c. Others
There are no outstanding issues with consults received from OPDP, DMEPA, or from
other groups in CDER.
12. Labeling
a. Proprietary Name
GSK submitted Arnuity Ellipta as the proposed proprietary name, which was accepted by
DMEPA.
b. Physician Labeling
GSK submitted a label in the Physician Labeling Rule format. The label was reviewed
by various disciplines of this Division, the Division of Medical Policy Programs (DMPP),
DRISK, DMEPA, and by OPDP. Various changes to different sections of the label were
done to reflect the data accurately and to better communicate the findings to healthcare
providers. The Division and GSK have agreed on the final label language.
c. Carton and Immediate Container Labels
These were reviewed by various disciplines of this Division and DMEPA, and found to
be acceptable.

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 12

d. Patient Labeling and Medication Guide
Arnuity Ellipta will have a patient labeling. There will not be a Medication Guide for
Arnuity Ellipta.

13. Action and Risk Benefit Assessment
a. Regulatory Action
GSK has submitted adequate data to support approval of Arnuity Ellipta (fluticasone
furoate 100 mcg or 200 mcg inhalation powder) for maintenance treatment of asthma as
prophylactic therapy in patients 12 years of age and older. The regulatory action for this
application is Approval.
b. Risk-Benefit Assessment
The overall risk-benefit assessment supports approval of Arnuity Ellipta inhalation
powder at a dose of one inhalation (fluticasone furoate 100 mcg or 200 mcg) once daily
for treatment of asthma. The risks with the use of Arnuity Ellipta are typical of ICSs,
such as effects on adrenal axis. The safety findings from the clinical program did not
identify adrenal axis suppression and clinically significant findings related to effects on
adrenal axis. The safety findings were typical of other ICSs for the treatment of asthma.
The efficacy findings of the two doses were robust and consistent with expected efficacy
of ICSs in asthma. The benefit of Arnuity Ellipta in asthma outweighs the potential risk.
c. Post-marketing Risk Management Activities
None.
d. Post-marketing Study Commitments
None, other than PREA required pediatric studies.

Reference ID: 3613374

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electronically and this page is the manifestation of the electronic
signature.
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---------------------------------------------------BADRUL A CHOWDHURY
08/20/2014

Reference ID: 3613374