+-------------+-----------------------+-------------+-----------------+
| ########    |                       |             |                 |
|             |                       |             |                 |
| ########    |                       |             |                 |
|             |                       |             |                 |
| U.S. FOOD   |                       |             |                 |
| AND DRUG    |                       |             |                 |
| ADM         |                       |             |                 |
| INISTRATION |                       |             |                 |
|             |                       |             |                 |
| CENTER FOR  |                       |             |                 |
| DRUG        |                       |             |                 |
| EVALUATION  |                       |             |                 |
| AND         |                       |             |                 |
| RESEARCH    |                       |             |                 |
|             |                       |             |                 |
| **Division  |                       |             |                 |
| of          |                       |             |                 |
| Pulmonary   |                       |             |                 |
| and Allergy |                       |             |                 |
| Drug        |                       |             |                 |
| Products    |                       |             |                 |
| (HFD-570)   |                       |             |                 |
| B           |                       |             |                 |
| ackgrounder |                       |             |                 |
| for**       |                       |             |                 |
|             |                       |             |                 |
| **sNDA      |                       |             |                 |
| 21-077 --   |                       |             |                 |
| Advair      |                       |             |                 |
| Diskus      |                       |             |                 |
| 250/50,     |                       |             |                 |
| Advair      |                       |             |                 |
| Diskus      |                       |             |                 |
| 500/50**    |                       |             |                 |
+-------------+-----------------------+-------------+-----------------+
| **          | NDA 21-077/SE1-003    | **Category  | Corticoster     |
| Application |                       | of Drug:**  | oid/Long-Acting |
| #:**        |                       |             | ~2~-Agonist     |
+-------------+-----------------------+-------------+-----------------+
| *           | GlaxoSmithKline       | **Route of  | Oral Inhalation |
| *Sponsor:** |                       | Admini      |                 |
|             |                       | stration:** |                 |
+-------------+-----------------------+-------------+-----------------+
| **          | Advair Diskus 250/50  | **Medical   | Lydia I.        |
| Proprietary | and Advair Diskus     | Reviewer:** | G               |
| Name:**     | 500/50                |             | ilbert-McClain, |
|             |                       |             | MD, FCCP        |
+-------------+-----------------------+-------------+-----------------+
| **USAN/     | Fluticasone           | *           | May 4, 2001     |
| Established | propionate/salmeterol | *Submission |                 |
| Name:**     | xinafoate             | Date:**     |                 |
+-------------+-----------------------+-------------+-----------------+
| **\-\       |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\--** |                       |             |                 |
|             |                       |             |                 |
| **Lydia I.  |                       |             |                 |
| Gilbe       |                       |             |                 |
| rt-McClain, |                       |             |                 |
| MD, FCCP**  |                       |             |                 |
|             |                       |             |                 |
| **Medical   |                       |             |                 |
| Reviewer**  |                       |             |                 |
|             |                       |             |                 |
| **\-\-\-\-  |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\-\-\ |                       |             |                 |
| -\-\-\-\-\- |                       |             |                 |
| \-\-\-\--** |                       |             |                 |
|             |                       |             |                 |
| **Mary E.   |                       |             |                 |
| Purucker,   |                       |             |                 |
| MD, PhD**   |                       |             |                 |
|             |                       |             |                 |
| **Medical   |                       |             |                 |
| Team        |                       |             |                 |
| Leader**    |                       |             |                 |
+-------------+-----------------------+-------------+-----------------+

tABLE OF CONTENTS

EXECUTIVE SUMMARY [4](#executive-summary)

I. RECOMMENDATIONS [4](#i.-recommendations)

A. Recommendation on Approvability
[4](#a.-recommendation-on-approvability)

B. Recommendation on Phase 4 studies and Risk Management Steps
[4](#b.-recommendation-on-phase-4-studies-and-risk-management-steps)

II\. SUMMARY OF CLINICAL FINDINGS [4](#ii.-summary-of-clinical-findings)

A. Overview of clinical program [4](#a.-overview-of-clinical-program)

B. Efficacy [6](#b.-efficacy)

C. Safety [8](#c.-safety)

D. Dosing [9](#d.-dosing)

E. Special Population [9](#e.-special-population)

List of Abbreviations [11](#list-of-abbreviations)

CLINICAL REVIEW [12](#clinical-review)

I. INTRODUCTION AND BACKGROUND [12](#i.-introduction-and-background)

A. Drug Name, Indication, Dose, Regimens, Age Groups
[12](#a.-drug-name-indication-dose-regimens-age-groups)

B. State of Armamentarium for Indication
[12](#b.-state-of-armamentarium-for-indication)

C. Important Milestones in Product Development
[12](#c.-important-milestones-in-product-development)

D. Other Relevant Information [13](#d.-other-relevant-information)

**E. Important Issues with Pharmacologically Related Agents**
[13](#e.-important-issues-with-pharmacologically-related-agents)

II\. Chemistry, Pharmacology/Toxicology, Statistics
[13](#ii.-chemistry-pharmacologytoxicology-statistics)

III\. Human Pharmacokinetics and Pharmacodynamics
[14](#iii.-human-pharmacokinetics-and-pharmacodynamics)

IV\. Description of Clinical Data and Sources
[15](#iv.-description-of-clinical-data-and-sources)

A. Overall Data [15](#a.-overall-data)

B. Table of Clinical Studies [15](#b.-table-of-clinical-studies)

C. Postmarketing Experience [17](#c.-postmarketing-experience)

D. Literature Review [17](#d.-literature-review)

V. CLINICAL REVIEW METHODS [18](#v.-clinical-review-methods)

A. Conduct of the Review [18](#a.-conduct-of-the-review)

B. Overview of Materials Consulted in the Review
[18](#b.-overview-of-materials-consulted-in-the-review)

C. Overview of Methods used to Evaluate Data Quality and integrity
[18](#c.-overview-of-methods-used-to-evaluate-data-quality-and-integrity)

D. Ethical Conduct of Trials [18](#d.-ethical-conduct-of-trials)

E. Evaluation of Financial Disclosure
[19](#e.-evaluation-of-financial-disclosure)

VI\. INTEGRATED REVIEW OF EFFICACY
[19](#vi.-integrated-review-of-efficacy)

A. Conclusions [19](#a.-conclusions)

B. General Approach to the Review of the Efficacy of the Drug
[21](#b.-general-approach-to-the-review-of-the-efficacy-of-the-drug)

C. DETAILED REVIEW OF CLINICAL TRIALS
[21](#c.-detailed-review-of-clinical-trials)

VII\. INTEGRATED REVIEW OF SAFETY
[53](#vii.-integrated-review-of-safety)

A. CONCLUSIONS [53](#conclusions)

B. PATIENT EXPOSURE AND DEMOGRAPHICS
[56](#b.-patient-exposure-and-demographics)

C. METHODS AND SPECIFIC FINDINGS OF SAFETY REVIEW
[57](#c.-methods-and-specific-findings-of-safety-review)

VIII\. Dosing, Regimen, and Administration Issues
[71](#viii.-dosing-regimen-and-administration-issues)

IX\. Use in Special Populations [71](#ix.-use-in-special-populations)

A. Gender Effects [71](#a.-gender-effects)

B. Age, Race/Ethnicity effects on Safety or Efficacy
[71](#b.-age-raceethnicity-effects-on-safety-or-efficacy)

C. Pediatric Program [72](#c.-pediatric-program)

D. Other Populations i.e. Pregnancy, Renal, or Hepatic Compromise
[72](#d.-other-populations-i.e.-pregnancy-renal-or-hepatic-compromise)

X. Conclusions and Recommendations
[72](#x.-conclusions-and-recommendations)

A. Conclusions [72](#a.-conclusions-1)

B. Recommendations [73](#b.-recommendations)

XI\. Appendix [74](#xi.-appendix)

Chronic Bronchitis Symptoms Questionnaire (CBSQ)
[75](#chronic-bronchitis-symptoms-questionnaire-cbsq)

Baseline/Transition Dyspnea Index
[77](#baselinetransition-dyspnea-index)

The Chronic Respiratory Disease Questionnaire
[81](#the-chronic-respiratory-disease-questionnaire)

Modified Medical Research Council Dyspnea Scale
[83](#modified-medical-research-council-dyspnea-scale)

#  

# 

# EXECUTIVE SUMMARY

## I. RECOMMENDATIONS

## A. Recommendation on Approvability

Withheld pending Pulmonary and Allergy Drug Products Advisory Committee
\[PADAC\] meeting January 17, 2002.

## B. Recommendation on Phase 4 studies and Risk Management Steps

Recommendations on phase 4 studies and risk management steps would be
addressed after the Pulmonary and Allergy Drug Products Advisory
Committee meeting. The sponsor has an ongoing 3-year international study
to evaluate the effect of Advair Diskus 500/50 mcg bid and fluticasone
propionate 500 mcg bid via Diskus on survival in COPD patients. The
sponsor is evaluating bone mineral density and ophthalmologic effects of
inhaled corticosteroids over the 3-year period. This study should
provide critical safety information about the long-term use of inhaled
corticosteroids in COPD patients. Recommendations such as ophthalmologic
examinations, monitoring of bone density \[by DEXA\], and concomitant
use of calcium supplements and/or other therapies to reduce bone loss
would depend on the final approval decision.

## II. SUMMARY OF CLINICAL FINDINGS

## A. Overview of clinical program

The clinical development program for the indication for COPD for Advair®
Diskus was done concurrently with the development program for the Diskus
formulations of fluticasone \[Flovent®\] and salmeterol \[Serevent®\].
Three clinical trials of similar design conducted in a similar manner
have been submitted as supplements to three separate NDAs; NDA
21-077(Advair Diskus), NDA 20-833 (Flovent Diskus) and NDA 20-692
(Serevent Diskus). The patient population was similar in all three
studies. With this clinical program the sponsor is seeking approval of
all three products for the long-term maintenance treatment of COPD. Two
of the clinical studies \[SFCA3006 and SFCA3007\] were conducted with
Advair Diskus 500/50 and Advair Diskus 250/50 respectively and one study
\[FLTA3025\] was conducted with Flovent® Diskus 500 and Flovent® Diskus
250. The focus of this review will be on the clinical studies with
Advair Diskus with references to study FLTA3025 as appropriate.

Advair Diskus is the combination product comprised of the two drug
substances- salmeterol xinafoate and fluticasone propionate \[FP\] in a
dry powder formulation in the Diskus device. The two active moieties
produce different pharmacological actions in the airway. Salmeterol
xinafoate is a long-acting beta~2~-receptor agonist that produces
bronchodilation, while fluticasone propionate is a high potency
corticosteroid with anti-inflammatory properties, as would be expected
of this class of drugs. Salmeterol Inhalation Aerosol (Serevent® MDI)
was approved in 1998 for the treatment of bronchospasm associated with
COPD but neither fluticasone propionate or any other corticosteroid has
been approved for the treatment of COPD.

Given that Advair Diskus is a combination product, the clinical studies
with Advair® Diskus were designed to fulfill the regulatory requirements
set forth in the Code of Federal Regulations 21 CFR 300.50 regarding
fixed combinations of prescription drugs. Specifically, to establish
that each component makes a contribution to the claimed effects of the
combination and the dosage of each component is such that the
combination is safe and effective for the population requiring such
concurrent therapy. Therefore, the primary objective of these studies
was to assess the efficacy and safety of Advair Diskus 250/50 and Advair
Diskus 500/50, compared to its individual components and placebo.

In selecting the Advair dose for these trials, the sponsor relied on
previous clinical experience from other non-U.S. clinical trials with
fluticasone propionate. Previous clinical studies in patients with COPD
using fluticasone propionate 500 mcg bid have been reported to show some
benefit.[^1] The approved dose of salmeterol xinafoate is 50 mcg bid.
Therefore the sponsor elected to study Advair Diskus 500/50 mcg bid and
250/50 mcg bid. The lowest strength Advair Diskus 100/50 mcg was not
evaluated in this clinical program.

The two pivotal studies with Advair Diskus were conducted in male and
female subjects 40 years of age and older. Subjects were current or
former smokers with a FEV~1~ between 40% - 42% of predicted normal, a
ratio of FEV~1~ to force vital capacity (FEV~1~/FVC) of 47% -51% as well
as a history of chronic bronchitis. Subjects were stratified by
reversibility \[reversible vs. non-reversible\] based on their response
to bronchodilators as defined by the ATS \[see pg. 25\]. Study SFCA3006
was done with Advair Diskus 500/50 and study SFCA3007 was done with
Advair Diskus 250/50. These studies had 4 arms; Advair Diskus 500/50 or
250/50, Flovent ® Diskus 500 or 250, Serevent® Diskus 50, and placebo.
The contribution of fluticasone and salmeterol in the combination were
each assessed using a different primary endpoint. Change from Baseline
in pre-dose FEV~1~ was the primary endpoint used to evaluate the
contribution of fluticasone in the combination by comparing Advair
Diskus vs. salmeterol. Change from Baseline in 2-hr post dose FEV~1~ was
the primary endpoint used to evaluate the contribution of salmeterol in
the combination by comparing Advair Diskus vs. fluticasone. The asthma
trials with Advair Diskus were similarly designed except that FEV~1~ AUC
over 12 hours was used to assess the salmeterol effect and not 2-hr
post-dose FEV~1~. At the end of phase 2 meeting for the COPD program,
\[April 21, 1998\] the Division agreed that it was acceptable to use the
2-hr post dose FEV~1~ but that the sponsor should collect serial FEV~1~
measurements in at least one study to confirm the 12-hour duration of
action and the durability of that action over time. Therefore, the
sponsor collected serial FEV~1~ measurements over 12 hours on Treatment
Day 1 and at Week 12 in a subset of patients at 30 sites in study
SFCA3006.

A total of 1,414 patients were enrolled in these two pivotal trials. Of
these, 347 patients were exposed to Advair Diskus, 356 to Flovent®
Diskus, 341 to Serevent ® Diskus and 370 to placebo. Of the subjects
exposed to Advair Diskus, 169 received Advair Diskus 500/50 mcg bid and
178 received Advair Diskus 250/50 mcg bid. The mean duration of exposure
was 141.3 days for Advair Diskus 500/50 mcg bid and138.6 days for Advair
Diskus 250/50 mcg bid.

## B. Efficacy

Advair Diskus 500/50 and Advair Diskus 250/50 both met the efficacy
criteria for combination drug products as stated in the Code of Federal
Regulations. However the efficacy of Advair Diskus was not demonstrated
for any of the supportive secondary endpoints relevant to the COPD
indication. There was no treatment difference in COPD-related quality of
life, the frequency or severity of COPD exacerbations, or in the chronic
bronchitis symptom questionnaire. This finding seriously questions the
overall clinical significance of the FEV~1~ improvements seen in these
trials to the COPD population.

For the primary endpoints both, Advair Diskus 500/50 and 250/50 were
superior to placebo. In study SFCA3006 with Advair Diskus 500/50 mcg bid
the fluticasone effect in the combination was represented by a
model-adjusted mean difference of 67 mL \[p0.012\] and the salmeterol
effect was represented by a model-adjusted mean difference of 129 mL
\[p0.024\]. Similarly, in study SFCA3007 with Advair Diskus 250/50, the
fluticasone effect was demonstrated by a model-adjusted mean difference
of 69 mL \[p=0.012\] and the salmeterol effect had an adjusted mean
difference of 124 mL \[p\<0.001\].

The results seen for the primary efficacy endpoints were not affected by
smoking status.

In study SFCA3006 the effect size \[Advair vs. placebo\] for Advair for
the reversible group for the mean change from Baseline in mean morning
pre-dose FEV~1~ was 192 mL compared to 124 mL for the non-reversible
population. Therefore, the reversible population had an effect size that
was \[numerically\] 1.5 times that of the non-reversible population. In
study SFCA3007, the effect size for the reversible population was
\[numerically\] more than twice \[211 mL\] the effect size of the
non-reversible population \[97 mL\] for the mean change from Baseline in
mean morning pre-dose FEV~1~. For the mean change from Baseline in
post-dose FEV~1~ the effect size of the reversible population was
\[numerically\] 1.5 times that of the non-reversible population in both
studies.

Of the multiple secondary endpoints evaluated, the ones of clinical
relevance to the COPD population were COPD exacerbations, a revised
Chronic Bronchitis Symptom Questionnaire \[CBSQ\], COPD-related quality
of life as assessed by the Chronic Respiratory Disease Questionnaire
(CRDQ) and the assessment of dyspnea. The sponsor used the Baseline
Dyspnea Index/Transitional Dyspnea Index \[BDI/TDI\] to assess dyspnea.
Except for the assessment of dyspnea, Advair Diskus did not demonstrate
a treatment advantage over its individual components or placebo. In The
BDI/TDI Advair Diskus 500/50 had a clinically meaningful improvement
compared to placebo and salmeterol at Endpoint, but not compared with
fluticasone. In study SFCA3007, the incidence of COPD exacerbations of
any severity, and moderate/severe exacerbations were similar in the
Advair 250/50 and placebo groups. Of the number of discontinuations, the
percentage of withdrawals due to COPD exacerbations was greater in the
Advair 250/50 group compared to the placebo group \[Advair 250/50 28%
vs. placebo 24%\]. In study SFCA3006 subjects in the salmeterol
treatment group had the lowest incidence of exacerbations \[SAL 63 (39%)
vs. Advair 68 (41%)\] and the lowest number of withdrawals \[SAL 9 (20%)
vs. Advair 14 (27%)\] due to COPD exacerbations. The incidence of COPD
exacerbations of any severity was similar in the Advair 500/50 group and
the placebo group. However, of the number of withdrawals, the percentage
due to COPD exacerbations was higher in the Advair 500/50 \[27%\] group
compared to the placebo group \[23%\]. Although Advair had a clinically
meaningful change at Endpoint in the CBSQ and the CRDQ, no treatment
difference was demonstrated when compared with its individual components
or placebo.

Other secondary endpoints evaluated were AM peak flow, Ventolin use and
nighttime awakenings requiring Ventolin use. As expected, the AM peak
flow results were concordant with the FEV~1~ findings. The results were
similar in both studies. In study SFCA3006, the mean change in AM PEF at
Endpoint was 31.9 L/min for Advair Diskus 500/50 compared with 12.9
L/min for Flovent ® Diskus 500 and 16.8 L/min for Serevent ® Diskus. In
study SFCA3007, the improvement in AM PEF was 30.6 L/min for Advair
250/50 compared with 11.3 L/min for Flovent ® Diskus 250, and 14.7 L/min
for Serevent ® Diskus. Although there were improvements in Ventolin use
and nighttime awakenings, these changes were very small and difficult to
put in a clinical perspective. Also, these secondary endpoints and in
particular, nighttime awakenings are of more clinical relevance in an
asthmatic population.

Although Advair Diskus 500/50 and Advair Diskus 250/50 met the efficacy
criteria for combination drug products as set forth in the Code of
Federal Regulations, the data do not appear to be robustly supportive of
an indication for the long-term maintenance treatment of COPD.
Additionally, Advair Diskus 500/50 does not appear to offer a treatment
advantage over Advair Diskus 250/50. This finding is noteworthy in dose
selection considerations given the risks associated with long-term
corticosteroid use.

## C. Safety

The safety profile of beta~2~-agonists and corticosteroids is fairly
well understood and characterized in the asthma population. However,
although salmeterol has been approved for use in patients with COPD,
neither fluticasone propionate nor any other corticosteroid has been
approved for use in this patient population in the U.S. Although three
large multicenter studies conducted outside of the U.S. provide some
safety assessment of the use of inhaled corticosteroids for 6 months in
this population the long term safety effects of inhaled corticosteroids
in COPD patients is still not fully known.

Safety in the pivotal studies was assessed by monitoring AEs, routine
clinical laboratory tests, Cosyntropin stimulation testing \[selected
sites\], ECGs, 24-hour Holter monitoring \[selected sites\], vital signs
and oropharyngeal examinations. This reviewer incorporated relevant
safety information from study FLTA3025 in the safety review.

Adverse events more frequent in the active treatment groups than placebo
and occurring 3% included upper respiratory tract infection \[URTI\],
headache, throat irritation, viral respiratory infection,
sinusitis/sinus infection, candidiasis mouth/throat, muscle cramps and
spasms, muscle pain, hoarseness/dysphonia, upper respiratory
inflammation, and nasal congestion and blockage. Adverse events seen
more commonly in subjects receiving fluticasone either alone or in
combination with salmeterol included candidiasis mouth/throat,
hoarseness/dysphonia, throat irritation, sinusitis, viral respiratory
infections, and muscle cramps and spasms. A similar adverse event
profile was noted in the Flovent ® study FLTA 3025. A higher frequency
of pneumonia was noted in subjects receiving FP than for placebo \[FP
250 (1%), FP 500 (2%), Advair 500/50 (1%), placebo (\<1%)\].

There were 4 deaths in placebo-treated patients in these studies. There
were no deaths in any of the active treatment arms in any of the pivotal
studies.

There were no clinically meaningful changes in vital signs during the
study. Cardiovascular findings were similar among treatment groups and
did not suggest that subjects on salmeterol alone or in combination were
at increased risk of arrhythmias or cardiac-related adverse events. A
drug effect on QTc intervals assessed by Bazetts' and Fridericia's
correction formulae was not observed.

Cosyntropin (ACTH) stimulation testing results were not suggestive of
clinically significant adrenal suppression. There was some decrease in
post-stimulation serum cortisol levels compared to Treatment Day one
levels, but these differences were not clinically significant but tended
to suggest \[as expected\] that with higher doses of inhaled
corticosteroids there is some systemic exposure. In study FLTA3025,
measurements of serum cortisol AUC at treatment Week 4 showed a dose
dependent decrease in serum cortisol in subjects treated with Flovent
compared to placebo. Mean cortisol AUC~12~ was 21% lower than placebo
for FP 500 and 10% lower than placebo for FP 250.

Specific monitoring of bone mineral density or for ophthalmologic
effects were not done in this clinical program. Fractures and
ocular-related events were rare in all three studies. There were 13
reports of fractures in the Advair studies one of which was a fractured
femur in a 68-year-old female who sustained a fall. There were 10
reports of fractures in study FLTA3025. Five (5) were in the placebo
group, 3 were in the FP 500 group, and 2 were in the FP 250 treatment
group. Two reports of ocular pressure disorders occurred in the Advair
500/50 treatment group and 3 reports of cataracts occurred in the FP 500
group, 2 in study SFCA3006 and one in study FLTA3025. These pivotal
studies were not of sufficient duration and power to detect differences
between treatment groups for these uncommon events.

The sponsor is conducting a 3-year study with Advair 500/50, FP 500,
salmeterol 50 and placebo bid via Diskus in COPD patients \[SCO30003\]
to evaluate the effect of FP and Advair on survival in COPD. Bone
density will be evaluated over three years in a subpopulation of 600
patients. The study will assess fractures and ocular events in the
entire study population of 5000 patients. The results of this study will
be critical in assessing the long-term risk/benefit analysis for Advair
in the COPD population.

## D. Dosing

Advair Diskus comes in three strengths 100/50, 250/50, and 500/50. The
approval of the latter two strengths is being sought for COPD. In the
nomenclature the FP dose is written first followed by the salmeterol
dose. Advair Diskus is formulated for oral inhalation only. The proposed
dosing regimen is one inhalation twice a day.

## E. Special Population

Formal pharmacokinetic studies using Advair Diskus were not conducted to
examine gender differences or in special populations, such as elderly
patients specifically, or patients with hepatic, or renal impairment.

Pediatric subjects were not included in this clinical development
program. COPD as defined by the ATS is not a disease of the pediatric
age group. GlaxoSmithKline has asked for a waiver from the pediatric
study requirements with Advair Diskus for COPD. The Division stated at
the pre-sNDA meeting held December 1, 2000 that a waiver would most
likely be granted at the time of NDA approval.

# List of Abbreviations

AE Adverse Event

ALT Alanine aminotransferase

AM Morning

CRDQ Chronic respiratory disease questionnaire

ATS American Thoracic Society

BID/bid/BD Twice daily

BDI/TDI Baseline dyspnea index/transitional dyspnea index

CBSQ Chronic bronchitis symptom questionnaire

CRF Case report form

DPI Dry powder inhaler

DSI Division of Scientific Investigations

FEV~1~ Forced expiratory flow rate in one second

FP Fluticasone propionate

GI Gastrointestinal

ICS Inhaled corticosteroid

ITT Intent to treat

IRB Institutional Review Board

ISS Integrated summary of safety

ISE Integrated summary of efficacy

L Liter

L-hours liter-hours

LLN Lower limit of normal range

Mcg microgram

MDI Metered Dose Inhaler

Mins Minutes

PEF/PEFR Peak expiratory Flow \[Peak expiratory flow rate\]

PFT Pulmonary function test

PD Pharmacodynamic

PK Pharmacokinetic

PM Evening

PRN/prn As needed

PVC Premature ventricular contraction

SAE/SE Serious adverse event/Serious event

SAL Salmeterol

ULN Upper limit of normal

# CLINICAL REVIEW

## I. INTRODUCTION AND BACKGROUND

## A. Drug Name, Indication, Dose, Regimens, Age Groups

Advair Diskus 500/50 (fluticasone propionate 500 mcg and salmeterol 50
mcg), and Advair 250/50 (fluticasone propionate 250 mcg and salmeterol
50) are combination products of two previously approved drugs -
fluticasone propionate and salmeterol xinafoate. The proposed indication
is for the long-term maintenance treatment of COPD (including emphysema
and chronic bronchitis). The proposed dose is one oral inhalation bid.

## B. State of Armamentarium for Indication

The drugs currently approved for use in COPD are only for the relief of
dyspnea associated with the disease. These drugs include short acting
and long acting ~2~-agonists such as albuterol, salmeterol, and most
recently \[September 2001\] formoterol. The long and short acting
theophylline preparations and the anticholinergic drug ipratropium
bromide alone, and in combination with albuterol sulphate \[Combivent®\]
are also approved medications for the relief of bronchospasm associated
with COPD. The only therapy to date that has been shown to improve
survival in COPD is long term oxygen therapy in hypoxemic patients[^2].
Oral and inhaled corticosteroids are used off label for this disease
however; the benefit of corticosteroids in the long-term maintenance
treatment of COPD in contrast to their value in asthma is unclear. The
benefit of a short course of systemic corticosteroids in COPD patients
hospitalized with acute exacerbations has been reported in the
literature.[^3]

## C. Important Milestones in Product Development

The sponsor consulted with the Division of Pulmonary and Allergy Drug
Products at an end of phase 2 meeting held April 21, 1998 to discuss the
design of the pivotal trials. The Division informed the sponsor that the
proposed clinical trials were acceptable for Advair Diskus provided that
the combination policy requirements were met. Additionally, concerns
about the long-term use of the individual products (FP and salmeterol)
for COPD also needed to be satisfied. Specifically, the Division raised
concerns about the potential systemic effect of FP over time in elderly
patients and how to link the safety databases from the FP asthma NDA to
an older more fragile COPD population. In the case of salmeterol, the
Division commented that the data from Serevent Diskus asthma trials
suggest that dose-response and dose-delivery are somewhat different from
the Diskus compared to the MDI and therefore the dose response of
salmeterol in the COPD population with the Diskus device should be
characterized.

The Division accepted the sponsor's primary efficacy endpoint - 2-hr
post-dose FEV~1~ to assess the salmeterol effect in the combination
product. However the Division asked the sponsor to confirm the 12-hour
duration of action of salmeterol and the durability of that action over
time in at least one study. A meeting was held August 4, 2000 to discuss
electronic submissions and a pre-NDA meeting was held December 1, 2000
to discuss submission of the sNDAs. The sponsor initially intended to
submit a single sNDA containing all of the clinical data for all three
products \[Advair, salmeterol, and fluticasone propionate\] but this was
not acceptable to the Agency and the sponsor was asked to submit all of
the clinical data to three separate NDAs.

At the pre-NDA meeting the Division informed the sponsor of the concern
about the benefit/risk of administering a corticosteroid on a regular
basis to the COPD population and that the discussion of the use of
Flovent Diskus and Advair Diskus will likely be undertaken with an
Advisory Committee. The sponsor requested a priority review designation
at the pre-NDA meeting. The Division indicated that the preliminary data
did not warrant a priority review however, the decision would be made at
the time the sNDA is submitted. This sNDA was submitted in electronic
format on May 4, 2001 and the sNDA for Flovent Diskus and Serevent
Diskus were submitted on May 25, 2001. In a Telecon held Friday
September 28, 2001, the Division informed the sponsor that the
discussion of the use of Advair and Flovent Diskus in the COPD
population will be taken to the Pulmonary and Allergy Advisory Committee
meeting to be held January 17^th^, 2002.

## D. Other Relevant Information

See "Postmarketing Experience" section on page 15.

### **E. Important Issues with Pharmacologically Related Agents**

N/A

## II. Chemistry, Pharmacology/Toxicology, Statistics

Advair Diskus is a combination of fluticasone propionate and salmeterol
xinafoate in a Diskus device. Fluticasone propionate is a potent
fluorinated glucocorticoid having the chemical name S-fluoromethyl
6-methyl-3-oxo-17-propionyloxyandrosta-1, 4-diene-17-carbothioate.
Fluticasone propionate is a white to off-white powder with a molecular
formula of C~24~H~31~F~3~O~5S~ and molecular weight of 500.6. Salmeterol
is a long-acting beta~2~ adrenergic agonist. The xinafoate salt of
salmeterol is used in the combination product and has the chemical name
4-hydroxy-^1^-\[((6-(4-phenylbutoxy)
hexyl)-amino)methyl\]-1,3-benzenedimethanol, 1-hydroxy-2-napthoate. It
is a white to off-white powder with a molecular formula of
C~25~H~37~NO~4~C~11~H~8~O~3~. The Diskus is a breath-actuated powder
delivery system containing 60 doses of the combination product. Each
dose of Advair is hermetically sealed in an individual double-foil
blister strip. Each blister on the double-foil strip within the device
contains 100, 250, or 500 mcg of microfine fluticasone propionate powder
and 72.5 mcg of microfine salmeterol xinafoate salt powder, equivalent
to 50 mcg of salmeterol base, in 12.5 mg of formulation containing
lactose. The device is equipped with a dose counter. After a blister
containing medication is opened by activating the device, the medication
is dispersed into the airstream created by the patient inhaling through
the mouthpiece.

Three strengths of Advair Diskus are currently marketed in and outside
of the U.S. for the long-term maintenance treatment of asthma. They are:

-   Advair Diskus 100/50 mcg

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-   Advair Diskus 250/50 mcg

-   Advair Diskus 500/50 mcg

The sponsor is seeking approval of the 2 higher strengths for the
long-term maintenance treatment of COPD. The proposed dosage is one
inhalation twice daily. Under standardized *in vitro* test conditions,
Advair Diskus 250/50 and 500/50 delivers 233 and 465 mcg of fluticasone
respectively and 45 mcg of salmeterol base per blister when tested at a
flow rate of 60 L/min for 2 seconds. In 9 adult patients with
obstructive lung disease and severely compromised lung function \[FEV~1~
20% -30% predicted\] mean peak inspiratory flow through a Diskus device
was 80.0 L/min \[range 46.1 to 115.3 L/min\].

Pharmacology/toxicology data were not submitted to this sNDA.

Dr. Ted Guo Biostatistician conducted a detailed statistical review of
the sNDA.

## III. Human Pharmacokinetics and Pharmacodynamics

Dr Sandra Suarez conducted the biopharmacology review of the sNDA. The
same biopharm studies were submitted to all three sNDAs. The sponsor did
not conduct clinical pharmacology studies with Advair Diskus during this
development program. The sponsor submitted the results of a previous
five-way crossover study \[SAS1005\] in 15 healthy subjects with Advair
HFA, Advair Diskus, FP, and salmeterol. In that study, the systemic
exposure from Advair HFA and Advair Diskus were similar. Systemic
exposure for salmeterol was lower from Advair Diskus compared with
Advair HFA. A dose proportionality study \[FLTA 1003\] was conducted
with FP to examine the comparability of FP pharmacokinetics and
pharmacodynamics following administration of 1000 mcg of fluticasone
propionate via the 50, 100, 250, and 500 mcg Diskus formulation.
Additionally, the sponsor conducted a randomized two-period cross-over
trial in COPD and healthy subjects with inhaled FP 500 mcg bid for 7
days followed by a single inhaled dose of FP 1000 mcg and placebo
infusion, or inhaled BDP 1000 mcg bid from a metered dose inhaler for 7
days followed by inhaled placebo and FP 1000 mcg infusion. \[Study
fms40243\]. The sponsor also evaluated systemic exposure of FP in a
subset of patients in the clinical study FLTA3025. This study showed a
dose-related reduction in serum cortisol levels. From Dr. Saurez's
review, dose proportionality of the 500 mcg strength of FP was not
demonstrated in study FLTA1003. This finding will influence the decision
on the approvability of FP 500 mcg BID administered via Flovent Diskus
250 as 2 inhalations bid however, for the combination product Advair
500/50 this finding is not as crucial

## IV. Description of Clinical Data and Sources

## A. Overall Data

The data used in this review were obtained from the sNDA 21-077/SE1-03
submission. Three pivotal trials were submitted: SFCA3006, SFCA3007, and
FLTA3025. All three studies are randomized, double blind
placebo-controlled multicenter trials conducted in a similar manner. All
three trials were submitted to 3 separate supplemental NDAs as was
required by the Agency. For the purpose of the Advair Diskus, the
clinical program must fulfill the combination policy requirements for
approval. To this end, this review will focus on studies

SFCA3006 and SFCA3007 with evaluation of the following assessments:

-   Advair Diskus 250/50 and 500/50 compared with salmeterol 50 to
    evaluate the contribution of FP to the combination product

-   Advair Diskus 250/50 and 500/50 compared with FP Diskus 250 and 500
    respectively to evaluate the contribution of salmeterol in the
    combination.

-   Advair Diskus 250/50 and 500/50 versus placebo to evaluate the
    overall safety and efficacy profile of the combination product.

Dr. Charles Lee reviewed the supplemental application for Flovent Diskus
\[sNDA 20-833/SE1-04\]. Relevant safety and efficacy findings from study
FLTA3025 will be referenced from his review. In addition to safety
assessments in the efficacy trials, the sponsor has submitted an
extensive safety database that includes data from the European 3-year
study in patients with COPD with Flovent 500 mcg bid \[ISOLDE\], 2
completed studies with FP in asthmatic patients, and the 120-safety day
update submitted August 31, 2001. This reviewer reviewed the 120-day
safety update and Dr. Charles Lee reviewed the safety information from
the FP studies. Relevant safety information from Dr. Lee's review is
referenced.

## B. Table of Clinical Studies

TABLE 1. PIVOTAL CLINICAL STUDIES

+-------+----+-------------------+----------+------------+------+------+
| Study | Lo | Study Objective   | Tr       | Primary    | N    | N    |
| \#    | ca |                   | eatments | Endpoints  | Ra   | C    |
|       | ti |                   | Arms/    |            | ndom | ompl |
|       | on |                   | BID      |            | ized | eted |
|       |    |                   | Dosage   |            |      |      |
|       |    |                   | (mcg)    |            |      |      |
+-------+----+-------------------+----------+------------+------+------+
| SFC   | US | Demonstrate       | Advair   | Change     | 691  | 440  |
| A3006 |    | efficacy of the   | Diskus   | from       |      |      |
|       |    | combination       | 500/50   | Baseline   |      |      |
|       |    | product over the  | SAL      | in 2-hr    |      |      |
|       |    | individual        | Diskus   | post-dose  |      |      |
|       |    | components and    | 50       | FEV~1~     |      |      |
|       |    | placebo           |          | \[to       |      |      |
|       |    |                   | FP       | assess the |      |      |
|       |    |                   | Diskus   | salmeterol |      |      |
|       |    |                   | 500      | effect in  |      |      |
|       |    |                   |          | Advair\]   |      |      |
|       |    |                   | Placebo  |            |      |      |
|       |    |                   | Diskus   | Change     |      |      |
|       |    |                   |          | from       |      |      |
|       |    |                   |          | baseline   |      |      |
|       |    |                   |          | in AM      |      |      |
|       |    |                   |          | pre-dose   |      |      |
|       |    |                   |          | FEV~1~     |      |      |
|       |    |                   |          | \[to       |      |      |
|       |    |                   |          | assess the |      |      |
|       |    |                   |          | FP effect  |      |      |
|       |    |                   |          | in         |      |      |
|       |    |                   |          | Advair\]   |      |      |
+-------+----+-------------------+----------+------------+------+------+
| SFC   | US | Demonstrate       | Advair   | Change     | 723  | 505  |
| A3007 |    | efficacy of the   | Diskus   | from       |      |      |
|       |    | combination       | 250/50   | Baseline   |      |      |
|       |    | product over the  | SAL      | in 2-hr    |      |      |
|       |    | individual        | Diskus   | post-dose  |      |      |
|       |    | components and    | 50       | FEV~1~     |      |      |
|       |    | placebo           |          | \[to       |      |      |
|       |    |                   | FP       | assess the |      |      |
|       |    |                   | Diskus   | salmeterol |      |      |
|       |    |                   | 250      | effect in  |      |      |
|       |    |                   |          | Advair\]   |      |      |
|       |    |                   | Placebo  |            |      |      |
|       |    |                   | Diskus   | Change     |      |      |
|       |    |                   |          | from       |      |      |
|       |    |                   |          | baseline   |      |      |
|       |    |                   |          | in AM      |      |      |
|       |    |                   |          | pre-dose   |      |      |
|       |    |                   |          | FEV~1~     |      |      |
|       |    |                   |          | \[to       |      |      |
|       |    |                   |          | assess the |      |      |
|       |    |                   |          | FP effect  |      |      |
|       |    |                   |          | in         |      |      |
|       |    |                   |          | Advair\]   |      |      |
+-------+----+-------------------+----------+------------+------+------+
| FLT   | US | Demonstrate       | FP       | Change     | 640  | 414  |
| A3025 |    | efficacy of       | Diskus   | from       |      |      |
|       |    | Flovent Diskus    | 500 , FP | baseline   |      |      |
|       |    | over placebo      | Diskus   | in         |      |      |
|       |    |                   | 250,     | pre-dose   |      |      |
|       |    |                   | placebo  | FEV~1~     |      |      |
+-------+----+-------------------+----------+------------+------+------+

## C. Postmarketing Experience

The fluticasone propionate /salmeterol combination product has not
received approval for COPD in any country. Fluticasone propionate has
obtained approval for COPD in several developing countries in the West
Indies, Africa, and South America, and in Pakistan, the Philippines,
Romania, Slovakia, Turkey, and Yugoslavia. Salmeterol has been approved
for use in patients with COPD in the U.S., Albania, Bulgaria, China,
Greece, Hong Kong, Korea, Malaysia, Moldova, Pakistan, Philippines,
Singapore, and Taiwan. Deaths reported in cases where salmeterol, FP, or
Advair were stated as used for COPD were reported in the 120-day safety
update in the "Post-Marketing Experience" Section. Three deaths in
patients taking Advair and one death in a patient taking FP were
reported. None of the deaths appear to be drug-related. Three of the
deaths were from cardiac causes and one was due to malignancy. Serious
adverse events that were reported in the post-marketing observational
studies either appear to be unrelated to Advair or in some cases
causality was unable to be established.

## D. Literature Review

The sponsor submitted an extensive review in support of the use of
corticosteroids in COPD, and the benefits of this combination therapy in
COPD. For the purposes of the sNDA review the following articles were
reviewed in detail. Other references are cited in footnotes as
appropriate throughout the review.

(I) Long term treatment with inhaled budesonide in persons with mild
    chronic obstructive pulmonary disease that continue smoking.
    *Romain A. Pauwels et.al for the European Respiratory Society Study
    on Chronic Obstructive Pulmonary Disease \[EUROSCOP\]. NEJM
    1999;340:1948-53*

(II) Randomised, double-blind, placebo controlled study of fluticasone
     propionate in patients with moderate to severe chronic obstructive
     pulmonary diseases: the ISOLDE trial. PS Burge et.al on behalf of
     the ISOLDE study investigators. *BMJ Vol 320; 1297-1303*

(III) Multicentre randomised placebo-controlled trial of inhaled
      fluticasone propionate in patients with chronic obstructive
      pulmonary disease. Pier Luigi Paggiaro et.al. On behalf of the
      international COPD study group. *Lancet Vol 351;773-779*

(IV) Antibiotic therapy in exacerbations of chronic obstructive
     pulmonary disease. *Ann Intern Med. 1987; 106:196-204*

(V) Standards for the diagnosis and care of patients with chronic
    obstructive pulmonary diseases. *Am J Respir Crit care Med. 1995;
    Vol 152 pp s77-s120*

(VI) Global Initiative for chronic obstructive lung disease \[GOLD\].
     Executive summary based on April 1998 meeting. *National Institutes
     of Health/National Heart, Lung and Blood Institute.*

# V. CLINICAL REVIEW METHODS

## A. Conduct of the Review

The two trials SFCA3006, and SFCA3007 and the 120-day safety update were
reviewed in detail. Safety results of study FLTA3025 were referenced
from Dr. Charles Lee's review. The two trials were reviewed separately
and discussed with the Medical Team Leader.

## B. Overview of Materials Consulted in the Review

The sNDA was submitted in electronic format and these materials were
used to conduct the review. The sNDA contained the safety and efficacy
findings of the three controlled clinical studies SFCA3006, SFCA3007,
and FLTA3025 and an ISS and ISE. During the review cycle, 4 additional
submissions from the sponsor in response to FDA questions related to the
sNDAs and the 120-day safety update were reviewed. Safety information
from the asthma studies with Flovent® submitted to the sNDA was
referenced from Dr. Charles Lee's review. The Medical officer Review of
NDA 21-077 for Advair Diskus for the indication for the long term
maintenance treatment of asthma was consulted.

## C. Overview of Methods used to Evaluate Data Quality and integrity

An audit by the Division of Scientific Investigations (DSI) was
conducted at 2 U.S. study sites and checked the sponsor's data and
analyses. One site from study SFCA3007 and one site from study FLTA3025
were audited. Dr. Charles Lee requested this audit as part of his review
of sNDA20-833/SE1-04. Therefore, this reviewer did not request
additional sites for auditing. The sites chosen were site #15557 UCLA -
Principal Investigator Donald P. Tashkin, and site \# 13564 Scripps
Clinical/Research Foundation - Principal Investigator Darlene Joan
Elias. Each of these two sites enrolled the largest number of patients
in both studies. The findings of the DSI audit did not preclude the use
of these data in the assessment of approvability. \[*See Dr. Charles
Lee's review for details of DSI inspection\]*

## D. Ethical Conduct of Trials

The studies were conducted in accordance with "Good Clinical Practice"
(GCP) guidelines and all applicable regulations including the
Declaration of Helsinki \[June 1964\] as modified by the 48^th^ World
Medical Association, Republic of South Africa, October 1996. All study
sites were registered with the FDA. The decision to participate in the
study was entirely voluntary. The subject or the subject's legally
authorized representative signed and dated the informed consent form
before the subject could participate in the study.

## E. Evaluation of Financial Disclosure

GlaxoSmithKline states in an organization-wide policy statement that
"Glaxo does not compensate clinical investigators in such a way as the
total amounts could vary with the outcome of the study". With regard to
"significant payments of other sorts" from the sponsor, the \$25,000
threshold for "payments of other sorts" was exceeded in the case of one
investigator participating in clinical trial SFCA3006 -- \[ \]. Of the
691 subjects in the study there were \[ \] (\<1%) subjects enrolled at
this investigator's site. Because the number of subjects was so small
GSK did not conduct an analysis to explore the effect of this
Investigator on the results of study SFCA3006. This reviewer concurs
that such a small number of subjects should not have the potential to
bias the outcome and/or conclusions of the study. GSK determined that no
investigator participating in the Advair studies had a proprietary
interest in Advair Diskus. Additionally, no investigators in the Advair
studies had a significant equity interest \[\> \$50,000\]. In summary,
the contribution of the one study center cited in study SFCA3006 in the
financial disclosure statement should not have had an impact on the
overall outcome or conclusions of the clinical program.

# VI. INTEGRATED REVIEW OF EFFICACY

## A. Conclusions

Advair Diskus 500/50 and Advair Diskus 250/50 were statistically
superior to placebo. For the primary efficacy endpoint "mean change from
Baseline in pre-dose FEV~1~" both Advair 500/50 and Advair Diskus 250/50
had a statistically significant treatment effect when compared with
salmeterol establishing the contribution of fluticasone in the
combination product. The model-adjusted treatment effect was 67 mL
\[p0.012\] for Advair Diskus 500/50, and 69 mL \[p=0.012\] for Advair
Diskus 250/50.

For the primary efficacy endpoint "mean change from Baseline in 2-hr
post-dose FEV~1~ the model adjusted treatment effect of Advair Diskus
compared to FP was 129 mL \[p\<0.001\] for Advair Diskus 500/50, and 124
mL \[p\<0.001\] for Advair Diskus 250/50. The comparison of Advair vs.
FP establishes the contribution of salmeterol in the combination
product.

In both studies subjects on Advair in the reversible population had a
numerically greater treatment effect than subjects in the non-reversible
population. Inferential analyses were not conducted for these subgroup
analyses.

Improvements in AM peak flow (PEF) measurements at Endpoint in patients
treated with Advair Diskus were numerically superior to patients treated
with SAL, FP, or placebo in both studies and are supportive of the
FEV~1~ results. This is not an unexpected finding as PEF measurements
also assess lung function and would be expected to be similar to FEV~1~
measurements. Nighttime awakenings and Ventolin^®^ use were evaluated as
secondary endpoints as well; however, numerical improvements were
generally very small and are difficult to assess from a clinical
standpoint. Also, nighttime awakenings requiring Ventolin use are of
more clinical relevance in an asthmatic population.

COPD-related quality of life was assessed with the Chronic Respiratory
Disease Questionnaire \[CRDQ\]. Although Advair Diskus 500/50 and 250/50
each had a clinically meaningful change \[\>10\] in the Overall score, a
clinically meaningful difference was not achieved between placebo or any
of the individual components. In the Chronic Respiratory Disease
Questionnaire, a clinically meaningful difference was not seen at
Endpoint between Advair Diskus and any of its individual components or
placebo.

The frequency of COPD exacerbations and withdrawals due to COPD
exacerbations were lowest in the salmeterol treatment group and similar
for the Advair Diskus and placebo groups in study SFCA3006. Of the
number of withdrawals, the percentage due to COPD exacerbations in
SFCA3006 was 20% in the salmeterol group compared with 23% in the
placebo group and 27% in the Advair 500/50 group. In study SFCA3007 of
the number of withdrawals due to COPD exacerbations 30% was in the
salmeterol group, 28% in the Advair 250/50 group, and 24% in the placebo
groups. The time to onset of COPD exacerbations and the number of severe
exacerbations were similar across treatment groups in SFCA3006. In
SFCA3007 the percentage of subjects with severe COPD exacerbations was
highest in the FP 250 group \[38%\] followed by the placebo and Advair
Diskus 250/50 groups \[34%\] and lowest in the salmeterol group \[31%\].

The Baseline Dyspnea Index/Transitional Dyspnea Index \[BDI/TDI\] was
used to evaluate dyspnea. At Endpoint there was a clinically meaningful
improvement in dyspnea in the Advair 500/50-treatment group compared
with placebo and salmeterol in study SFCA3006 but not with Advair Diskus
250/50 in study SFCA3007.

In summary Advair Diskus 500/50 and Advair Diskus 250/50 both met the
efficacy criteria for combination drug products as stated in the Code of
Federal Regulations. However except for dyspnea as evaluated with the
BDI/TDI with the 500/50 mcg dose, the efficacy of Advair Diskus was not
demonstrated for any of the secondary endpoints relevant to the COPD
indication. The patient population studied was not representative of the
COPD population at large in that \> 50% of the subjects showed
significant reversibility and the study was limited to only patients
with confirmed chronic bronchitis. The failure of Advair to demonstrate
a treatment effect in the secondary endpoints of relevance to COPD
\[i.e. exacerbations, CRDQ, CBSQ\] calls into question the clinical
significance of the FEV~1~ findings. Taken together, These data do not
appear to be robustly supportive of efficacy in the COPD population.

## B. General Approach to the Review of the Efficacy of the Drug

Described in section IV "Description of Clinical Data Sources" and
section V "Clinical Review Methods".

## C. DETAILED REVIEW OF CLINICAL TRIALS 

The three trials for the COPD indication are:

**SFCA3006.** "A Randomized, Double-Blind, Placebo-Controlled Trial
Evaluating the Safety and Efficacy of the Diskus Formulations of
Salmeterol 50 mcg bid and Fluticasone Propionate 500 mcg BID
Individually and in Combination as Compared to Placebo in COPD Subjects.
"

**SFCA 3007** "A Randomized, Double-Blind, Placebo-Controlled Trial
Evaluating the Safety and Efficacy of the Diskus Formulations of
Salmeterol 50 mcg bid and Fluticasone Propionate 250 mcg BID
Individually and in Combination as Compared to Placebo in COPD Subjects.
"

FLTA3025: "A Randomized, Double-Blind, Placebo-Controlled, Trial
Evaluating the Safety And Efficacy Of Fluticasone Propionate 500 mcg
BID, and 250 mcg BID Compared with Placebo in COPD Subjects".

For the purpose of the indication for Advair Diskus for the treatment of
COPD, studies SFCA3006 and SFCA3007 were reviewed in detail. The
comparison of the Advair Diskus 500/50 and Advair Diskus 250/50 with SAL
50 to evaluate the contribution of FP to the combination product, and
with FP 500 and 250 to evaluate the contribution of SAL 50 in the
combination product are critical to satisfy the regulatory requirements
for combination drug products. The Comparison of Advair Diskus to
placebo is helpful in determining the overall efficacy and safety of the
combination product. As previously stated study FLTA3025 will not be
reviewed in this document.

**TRIAL DESIGN of STUDIES SFCA3006 AND SFCA 3007**

##### OBJECTIVES

1.  To compare the efficacy of salmeterol 50 mcg bid, FP 500 mcg or FP
    250 mcg bid, Advair 500/50 mcg or Advair 250/50 mcg bid, and placebo
    when administered via the Diskus over a 24-week treatment period for
    the treatment of COPD subjects.

2.  To compare the safety of salmeterol 50 mcg bid, FP 500 mcg or 250
    mcg bid, Advair 500/50 mcg or 250/50 mcg bid, and placebo when
    administered via the Diskus over a 24-week treatment period for the
    treatment of COPD subjects.

3.  To compare the quality of life in COPD subjects receiving salmeterol
    bid, FP 500 mcg or FP 250 mcg bid, Advair 500/50 mcg or 250/50 mcg
    bid or placebo when administered via the Diskus over a 24-week
    treatment period.

These trials were randomized, double blind, placebo-controlled, parallel
group studies of 24 weeks duration. The studies had 2 phases. The first
phase was a 2-week run-in period where patients who met the entrance
criteria were placed on placebo via Diskus device one puff BID. During
the two-week run-in period, concurrent inhaled or oral sympathomimetic
or anticholinergic bronchodilator and corticosteroid therapies were
discontinued. Subjects on theophylline were permitted to continue it if
the dose had been stable for at least one month. During the run-in
period and throughout the study, subjects were allowed to take Ventolin
^®^ MDI, or nebules as needed. The 2-week run-in period was used to
establish a baseline for AM peak flow, supplemental Ventolin use,
nighttime awakenings requiring Ventolin use, and compliance. At
randomization subjects were randomized to one of the following
treatments via Diskus for a 24-week treatment period:

**SFCA3006**

-   Advair 500/50 mcg BID

-   SAL 50mcg BID

-   FP 500 mcg BID

-   Placebo BID

SFCA3007

-   Advair 250/50 mcg BID

-   SAL 50 mcg BID

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-   FP 250 mcg BID

-   Placebo BID

Patients were followed every week for the first 4 weeks, every 2 weeks
through Treatment Week 8, and then at 4-week intervals for the remainder
of the treatment period. Subjects who developed an exacerbation of COPD
after randomization were treated with antibiotic therapy as an
outpatient for up to two exacerbations but were withdrawn from the study
if a third exacerbation occurred, or if they required hospitalization to
treat an exacerbation.

*Reviewer Comment: The sponsor did not define COPD exacerbation per se
but defined the severity of an exacerbation based on the treatment the
subject received. \[See pg.26\]*

[PATIENT POPULATION]{.underline}

The inclusion and exclusion criteria were similar for both studies. The
differences are outlined in Table 2.

[Inclusion Criteria]{.underline}

Subjects had to be male and female patients diagnosed with COPD (ATS
definition)[^4] age 40 years or older and had to meet ALL of the
following inclusion criteria to be eligible for inclusion in the study:

-   Female subjects had to be of non-child-bearing potential or if of
    childbearing potential must have a negative serum pregnancy test and
    must use an approved contraceptive, undergo female sterilization, or
    their male partner must have undergone sterilization.

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-   Subjects had to have a current or prior history of 20 pack-years of
    cigarette smoking. Subjects who were ex-smokers must have
    discontinued smoking for at least 6 months prior to Screening.

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-   Subjects must have a history of cough productive of sputum on most
    days for at least 3 months of the year for at least 2 years, that
    was not attributable to another disease process.

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-   Subjects had to have a baseline FEV~1~ of \< 65% predicted normal
    but \> 0.70 L OR FEV~1~ 0.70 L AND \>40% but still \< 65% of
    predicted normal value \[according to Crapo et al.\][^5] AND
    FEV~1~/FVC ratio of 70%.

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-   Subjects also had to achieve a score of 2 on the Modified Medical
    Research Council Dyspnea Scale \[MMRCD\] (see Appendix on pg. 83) at
    screening

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-   Subjects had to have a score of 4 \[out of possible 16\] on the
    Chronic Bronchitis Symptoms Questionnaire \[CBSQ\] (see Appendix on
    pg. 75 for CBSQ) at Treatment Day 1 to qualify for the study.

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-   Subjects could be on inhaled corticosteroids not exceeding the doses
    outlined in Table 2, below.

[Exclusion Criteria]{.underline}

In addition to the usual exclusion criteria in clinical trials, subjects
were excluded for any of the following criteria:

-   A diagnosis of asthma as defined by the ATS[^6]

-   Alpha-1-antitripsin deficiency

-   Lung cancer, bronchiectasis, sarcoidosis, tuberculosis, lung
    fibrosis

-   A lobectomy within 1 year of the Screening visit

-   Current smokers who decided to quit smoking at the Screening Visit

-   Subjects with specific causes of airflow obstruction such as
    localized disease of the upper airways, bronchiectasis, and cystic
    fibrosis

-   Patients who required CPAP or BIPAP for COPD or sleep apnea

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-   Patients who had significant concurrent diseases that placed them at
    risk or interfered with clinical evaluations or influenced their
    participation in the study

-   Patients who required supplemental oxygen with the exception of
    those who live at high altitudes (i.e. above 3000 feet) and did not
    require oxygen for more than 12 hours per day and the maximum rate
    during the 12-hour period was not more than 2 liters/minute, or did
    not require more than 2 L/min of oxygen for more than 2 hours per
    day for exertion.

-   Patients with a history of drug or alcohol abuse

-   Patients with chest x-ray abnormalities not believed to be due to
    COPD

-   Patients with a clinically significant abnormal 12-lead ECG during
    the run-in period.

-   Patients who required beta-blockers digitalis, ketoconazole or
    fluconazole, phenothiazines, tricyclic antidepressants, MAO
    inhibitors, or immunosuppressive agents including cyclosporine,
    methotrexate and gold.

-   Patients with glaucoma requiring treatment with non-selective beta
    blockers

-   History of symptomatic or clinically significant pathological
    fractures

-   Subjects with a moderate or severe exacerbation during the Run-in
    period.

TABLE 2. Prior ICS Use - Differences for Study SFCA 3006 and SFCA3007

+------------------------------+----------------------+---------------+
|                              | **SFCA3006**         | **SFCA3007**  |
+------------------------------+----------------------+---------------+
| Prior ICS dosage (mcg/day)   |                      |               |
+------------------------------+----------------------+---------------+
| Beclomethasone dipropionate  | 1008 mcg/day (12/24  | 378-840       |
|                              | puffs)               |               |
| (Beclovent®, Vanceril®)      |                      |               |
+------------------------------+----------------------+---------------+
| Triamcinolone acetonide      | 1600 mcg/day (16     | 900-1600      |
| (Azmacort®)                  | puffs)               |               |
+------------------------------+----------------------+---------------+
| Flunisolide (Aerobid®)       | 2000mcg/day (8       | 1250-2000     |
|                              | puffs)               |               |
+------------------------------+----------------------+---------------+
| Fluticasone propionate MDI   | 880 mcg/day          | 440-660       |
| (Flovent®)                   |                      |               |
+------------------------------+----------------------+---------------+
| Fluticasone propionate DPI   | 1000 mcg/day         | 400-600       |
| (Flovent Rotadisk®)          |                      |               |
+------------------------------+----------------------+---------------+
| Budesonide (Pulmicort®       | 1600 mcg/day (8      | 800-1200      |
| Turbuhaler)                  | puffs)               |               |
+------------------------------+----------------------+---------------+

[STUDY PROCEDURE]{.underline}

To ensure an even distribution of reversible and non-reversible subjects
in each treatment group, assignment to study drug the sponsor stratified
according to the subjects' response to reversibility testing with
Ventolin at screening. Reversibility was defined as per the ATS criteria
for reversibility stated below.

**Reversible:** Subjects that demonstrated a bronchodilator response
(post albuterol) of 200 mL AND 12% improvement in FEV~1~ over Baseline.

**Non reversible:** Subjects that demonstrated a bronchodilator response
(post albuterol) of \<200 mL or \< 12% improvement in FEV~1~ over
Baseline.

Note: Bronchodilator response = percent improvement over Baseline,
calculated as follows:

*(post-bronchodilator FEV~1~ - pre-bronchodilator
FEV~1~)/pre-bronchodiator FEV~1~ X 100*

In the data analysis, the sponsor also defined a **poorly reversible
population** that they have indicated as applicable to the rest of the
world (ROW). The **poorly reversible population** was defined as
subjects that demonstrated an increase in **percent predicted** FEV~1~
of \< 10% after 4 puffs of albuterol inhalation aerosol at Screening.

*Reviewer's Comment: When reversibility is defined as a function of
percent-predicted FEV~1~ some patients defined as Reversible by ATS
criteria could be defined as "Poorly Reversible" leading to potential
misunderstanding of the degree of individual patient responsiveness to
bronchodilators (see examples in the table below). Because this
definition of reversibility is seldom used in this country, details of
this population will not be discussed in this review.*

Table3. Reversibility Results for selected subjects Expressed as per ATS
criteria and as Percent Predicted \[Data from Listing 7.1 SFCA3006.pdf\]

+-------+----------+------+-------+----------+------------+----------+
| Su    | \%       | FE   | F     | \%       | Rev        | Rever    |
| bject | P        | V~1~ | EV~1~ | P        | ersibility | sibility |
| \#    | redicted | \[P  | \[P   | redicted |            | \[Change |
|       | FEV~1~   | re\] | ost\] | FEV~1~   | \[% change | in %     |
|       |          |      |       |          | in FEV~1~  | pre      |
|       | \[Pre\]  |      |       | \[Post\] | and        | dicted\] |
|       |          |      |       |          |            |          |
|       |          |      |       |          | Absolute   |          |
|       |          |      |       |          | mL\]       |          |
+-------+----------+------+-------+----------+------------+----------+
| 9029  | 20.1     | 0.71 | 1.01  | 28.61    | 42.3% ,    | 8.5%     |
|       |          |      |       |          | 300mL      |          |
+-------+----------+------+-------+----------+------------+----------+
| 9254  | 39.8     | 1.44 | 1.74  | 48.1     | 20.8% ,    | 8.3%     |
|       |          |      |       |          | 300 mL     |          |
+-------+----------+------+-------+----------+------------+----------+
| 9532  | 61.6     | 2.04 | 2.30  | 69.4     | 12.7%,     | 7.8%     |
|       |          |      |       |          | 260mL      |          |
+-------+----------+------+-------+----------+------------+----------+
| 9729  | 38.2     | 1.48 | 1.78  | 46.0     | 20.3%,     | 7.7%     |
|       |          |      |       |          | 300mL      |          |
+-------+----------+------+-------+----------+------------+----------+

[Withdrawal Criteria]{.underline}

Subjects were discontinued from the study if any of the following
occurred:

-   Three exacerbations requiring treatment with antibiotics

-   An exacerbation which required treatment with corticosteroids

-   Hospitalized for an exacerbation

-   An AE which led to study withdrawal

-   Not benefiting from treatment \[lack of efficacy/treatment failure\]

-   Used corticosteroids or other prohibited medication for another
    indication

-   Initiated use of CPAP device

-   Withdrew consent

-   Former smoker who started smoking during the study and smoked at
    least 7 consecutive days

-   Current smoker who stopped smoking during the study for \> 4 weeks

-   Inability to attend scheduled clinic visits.

[Exacerbations of COPD]{.underline}

The investigator assessed the severity of COPD exacerbations at each
clinic visit. Each COPD exacerbations was categorized according to one
of the following three levels of severity:

Mild: Defined as use of relief bronchodilator of more than 12 puffs \[or
more than 4 nebules\] per day for 2 consecutive days, but without the
need for any other additional medication \[this information collected
from subject diary records\]

Moderate: defined as requiring, per investigator judgement, either oral
antibiotics and/or corticosteroids.

Severe: Defined as requiring, per investigator judgement, inpatient
admission for treatment of an exacerbation of COPD. Subjects who
developed a severe exacerbation were discontinued from the study.

[STATISTICAL AND ANALYTICAL PLAN]{.underline}

[EFFICACY]{.underline}

[Primary Efficacy Endpoints]{.underline}

The mean change from Baseline at Endpoint in the Pre-dose FEV~1~ and 2
hr-post-dose FEV~1~ were the primary efficacy analyses. The pre-dose
FEV~1~ was the primary endpoint used to evaluate the effect of FP in the
combination product, while the 2 hr-post-dose FEV~1~ was the endpoint
used to evaluate the effect of SAL in the combination product. The
comparison was made between Advair Diskus \[500/50 and 250/50\] and SAL
50 to evaluate the effect of FP. The comparison was made between Advair
Diskus 500/50 and FP 500 in study SFCA3006 and between Advair Diskus
250/50 and FP 250 in study SFCA3007 to evaluate the effect of SAL.

Baseline FEV~1~ was the pre-dose FEV~1~ at Treatment Day 1.The endpoint
value for FEV~1~ measurements was the last on-treatment measurement
recorded excluding data from discontinuation visits for each subject.

[Sample size and power calculations]{.underline}

The standard deviation of the change from pre-dose Treatment Day 1
Baseline in pre-dose FEV~1~ at each treatment visit was assumed to be
0.28 L. Using a two sample t-test with an of 0.05 a sample size of 175
patients per treatment arm would provide 91% power to detect a
difference of 0.1 L for any pairwise treatment comparisons. A total of
692 subjects in 65 centers were randomized to study SFCA3006 and 723
subjects in 76 centers were randomized to study SFCA3007. The sponsor
indicated that the standard deviation of change from Baseline at
Endpoint in pre-dose FEV~1~ ranged from 220 mL to 239 mL for the ITT
population for study SFCA3006 and ranged from 204 mL to 277 mL for study
SFCA3007. For post-dose FEV~1~ the standard deviation of change from
Baseline at Endpoint ranged from 134 mL to 212 mL for the ITT population
for study SFCA3006 and ranged from 211 mL to 313 mL for study SFCA3007.
Therefore, the studies were adequately powered to show a 100 mL
difference for both pre-dose and post-dose FEV~1~ for the ITT
population.

[Secondary Efficacy Endpoints]{.underline}

The sponsor evaluated multiple secondary endpoints. Of these, the
secondary endpoints most relevant to COPD are:

-   Chronic Bronchitis symptom Questionnaire \[revised\]

-   Transition Dyspnea Index

-   COPD exacerbations

[Chronic Bronchitis Symptom Questionnaire \[CBSQ\]]{.underline}

The CBSQ combined selected questions from the Petty Subject Evaluation
Questionnaire and the Revised Global Petty Questionnaire for Ease of
Cough and Sputum Clearance[^7]. The CBSQ evaluated the COPD symptoms of
cough frequency and severity, chest discomfort, and sputum production on
a scale of 0-4 where a rating of 0 reflected no symptoms (see Appendix
On pg. 75). Subjects had to have a score of 4 out of possible 16 at
Treatment Day 1 to qualify for the study. The test was given at every
study visit as well as the discontinuation visit where possible.
Individual scores were added to provide a Global Assessment Score (GAS).
The minimal clinically important change (MCIC) for the CBSQ was
determined to be a change from baseline of 1.4 in the CBSQ GAS. The MCIC
was determined by matching changes from Baseline in the CBSQ GAS with a
separate measure of change in chronic bronchitis symptoms called the
Global Rate of Change \[GRC\]. The GRC was a 2-part question asked by
the investigator independent of the CBSQ of all available patients at
the Week 8, 16, and Discontinuation visit. Patients were first
classified as to whether their chronic bronchitis had improved, stayed
the same or deteriorated by asking the following question: "Since the
beginning of this study, has there been any change in your symptoms of
chronic bronchitis, that is, your cough, OR sputum production, OR chest
discomfort? If the patient indicated that there had been no change, a
score of 0 was given. If the patient indicated that there had been an
improvement or deterioration, the change was scored on the scale
outlined below: The investigator recorded a single number between --7
and 7.

  -------------- --------------------------------------------------------
  -7:            A very great deal worse

  -6:            A great deal worse

  -5:            A good deal worse

  -4:            Moderately worse

  -3:            Somewhat worse

  -2:            A little worse

  -1:            Almost the same, hardly any better at all

  0:             No change

  1:             Almost the same, hardly any better at all

  2:             A little better

  3:             Somewhat better

  4:             Moderately better

  5:             A good deal better

  6:             A great deal better

  7:             A very great deal better
  -------------- --------------------------------------------------------

Baseline/Transition Dyspnea Index (BDI/TDI)

The BDI/TDI scale was developed to provide a clinical measurement of
dyspnea. The Baseline (BDI) scale was given on Treatment Day 1 and rated
the Baseline severity of dyspnea on a scale of 0 --4 where 0 was most
severe. The BDI total score was the sum of the individual category
scores. The maximum possible BDI score was 12. The TDI measured the
change from Baseline using a --3 to +3 scale where negative numbers
indicated deterioration and 0 indicated no change. The TDI total score
could range from --9 to +9. \[see Appendix on pg. 77\].

Health Outcomes

COPD related quality of life was evaluated using the Chronic Respiratory
Disease Questionnaire \[CRDQ\]. The CRDQ contains 20 questions each
scored 0-7 in four domains: dyspnea, fatigue, emotional function, and
mastery \[see Appendix on pg.81\]. The domains can be grouped as
physical summary \[dyspnea and fatigue\] and emotional summary
\[emotional function and mastery\]. The primary quality of life endpoint
is the overall score \[sum of all 20 questions\] and this score can
range from 0-140. Higher CRDQ scores indicate better COPD-related
qualify of life. The CRDQ was administered at Baseline (Treatment Day
1), and at Treatment Weeks 2, 4, 8, 24, and at the Premature
Discontinuation Visit as appropriate. A mean score improvement of 0.5
points per item was considered to be clinically meaningful based on
published literature[^8]. Therefore, for this study, an improvement of
at least 10 in the Overall score was considered an overall improvement
in COPD-specific quality of life. For treatment group comparisons, a
difference of at least 10 in the Overall score in the mean change from
Baseline at Endpoint between treatment groups was considered clinically
meaningful. A reduced ITT population was used for the analysis of the
CDRQ data. Subjects were excluded from the analyses based on their
scores as follows:

1.  overall Baseline score greater than 130

2.  dyspnea score greater than 32

3.  fatigue score greater than 26

4.  emotional function score greater than 45

5.  mastery score greater than 26

Subjects with physical summary score greater than 58 and emotional
summary score greater than 71 were excluded from the analysis of their
corresponding domains. The Overall score was the primary measure for all
analyses.

SAFETY

Safety assessments include adverse event reporting, clinical chemistry
and hematology, ECG, and Holter monitoring \[at selected sites\], vital
signs, oropharyngeal examinations, and Cosyntropin \[ACTH\] stimulation
testing at selected sites.

**EFFICACY RESULTS**

RESULTS STUDY SFCA3006

**[Patient Disposition]{.underline}**

A total of 1,352 patients were screened, and 691patients were
randomized. Of the 1,352 subjects screened, 661 failed screening. The
most common reason for screening failure was not meeting the entrance
criteria of disease severity \[i.e. an FEV~1~/FVC of 70% and Baseline
FEV~1~ of 65% predicted but \>0.70L\].

Because of data integrity concerns the sponsor excluded all subjects (n
= \[ \]) enrolled with Investigator #\[ \] from the efficacy analyses.
The \[ \] subjects included \[ \] each in the placebo, Advair 500/50,
and SAL treatment groups and \[ \] in the FP 500 group. Therefore data
from 674 patients were analyzed for efficacy and the ITT population for
the efficacy analyses refers to these 674 patients. For the safety
analyses all 691 randomized patients were included.

Of the 674 subjects analyzed in the ITT population, 165 were in the
Advair Diskus 500/50 group, 160 in the salmeterol group, 168 were in the
Flovent Diskus 500 group, and 181 were in the placebo group. Two hundred
and thirty-four (234) of the 674 subjects withdrew from the study prior
to completion and 440 (65%) completed the study.

> **Table -4. Patient Disposition ITT Population SFCA 3006**

+-----------------+---------+---------+--------+-----------+---------+
|                 | **Pl    | **SAL   | **FP   | Advair    | **      |
|                 | acebo** | 50**    | 500**  | Diskus    | Total** |
|                 |         |         |        | 500/50    |         |
|                 | **      | **      | **n    |           | **N     |
|                 | n=181** | n=160** | =168** | **n       | =674**  |
|                 |         |         |        | =165**    |         |
+-----------------+---------+---------+--------+-----------+---------+
|                 |         |         |        |           |         |
+-----------------+---------+---------+--------+-----------+---------+
| **\# (%)        | 112     | 115     | 100    | 113 (68%) | 440     |
| Complete**      | (62%)   | (72%)   | (60%)  |           | (65%)   |
+-----------------+---------+---------+--------+-----------+---------+
| **\# (%)        | 69(38%) | 45      | 68     | 52 (32%)  | 234     |
| Withdrawn**     |         | (28%)   | (40%)  |           | (       |
|                 |         |         |        |           | 35%)^a^ |
+-----------------+---------+---------+--------+-----------+---------+
| **Reason for    |         |         |        |           |         |
| Withdrawal**    |         |         |        |           |         |
+-----------------+---------+---------+--------+-----------+---------+
| **Lack of       | 11 (6%) | 7 (4%)  | 3 (2%) | 3 (2%)    | 24 (4%) |
| Efficacy^b^**   |         |         |        |           |         |
+-----------------+---------+---------+--------+-----------+---------+
| **Adverse       | 17 (9%) | 11 (7%) | 21     | 11 (7%)   | 60      |
| Event**         |         |         | (      |           | (9%)^c^ |
|                 |         |         | 12.5%) |           |         |
+-----------------+---------+---------+--------+-----------+---------+
| **Protocol      | 8 (4%)  | 10 (6%) | 14     | 8 (5%)    | 40 (6%) |
| violation**     |         |         | (8%)   |           |         |
+-----------------+---------+---------+--------+-----------+---------+
| **Consent       | 11 (6%) | 4       | 5 (3%) | 10 (7%)   | 30      |
| withdrawn**     |         | (2.5%)  |        |           | (4.5%)  |
+-----------------+---------+---------+--------+-----------+---------+
| **Lost to       | 2 (1%)  | 1       | 3 (2%) | 1 (\<1%)  | 7 (1%)  |
| follow up**     |         | (\<1%)  |        |           |         |
+-----------------+---------+---------+--------+-----------+---------+
| **COPD          | 16 (9%) | 9 (6%)  | 17     | 14 (8.4%) | 56 (8%) |
| ex              |         |         | (10%)  |           |         |
| acerbation^d^** |         |         |        |           |         |
+-----------------+---------+---------+--------+-----------+---------+
| **\*Other**     | 4 (2%)  | 3 (2%)  | 5 (3%) | 5 (3.5%)  | 17      |
|                 |         |         |        |           | (2.5%)  |
+-----------------+---------+---------+--------+-----------+---------+
| \*Other:        |         |         |        |           |         |
| include         |         |         |        |           |         |
| noncompliance,  |         |         |        |           |         |
| subject         |         |         |        |           |         |
| relocation, or  |         |         |        |           |         |
| treatment       |         |         |        |           |         |
| needed for      |         |         |        |           |         |
| concurrent      |         |         |        |           |         |
| disease         |         |         |        |           |         |
|                 |         |         |        |           |         |
| ^a^ Deaths = 3  |         |         |        |           |         |
| bring the total |         |         |        |           |         |
| number of       |         |         |        |           |         |
| withdrawals to  |         |         |        |           |         |
| 247             |         |         |        |           |         |
|                 |         |         |        |           |         |
| ^b^ The sponsor |         |         |        |           |         |
| did not provide |         |         |        |           |         |
| a definition    |         |         |        |           |         |
| for "lack of    |         |         |        |           |         |
| efficacy"       |         |         |        |           |         |
|                 |         |         |        |           |         |
| ^c^From data    |         |         |        |           |         |
| listings a      |         |         |        |           |         |
| total of 59     |         |         |        |           |         |
| subjects        |         |         |        |           |         |
| withdrew due to |         |         |        |           |         |
| AE \[not        |         |         |        |           |         |
| counting the 3  |         |         |        |           |         |
| deaths\]        |         |         |        |           |         |
|                 |         |         |        |           |         |
| ^d^ COPD        |         |         |        |           |         |
| exacerbations   |         |         |        |           |         |
| are also        |         |         |        |           |         |
| included in     |         |         |        |           |         |
| "Adverse        |         |         |        |           |         |
| Events"         |         |         |        |           |         |
+-----------------+---------+---------+--------+-----------+---------+

The percentage of withdrawals due to COPD exacerbations was lowest
\[6%\] in the SAL group compared to the other groups \[placebo 9%, FP
10%, Advair 8%\].

Medication Compliance

Compliance was assessed from the reading on the dose counter on the
Diskus device. Median compliance ranged from 95% to 96% across treatment
groups. In 502 (75%) subjects the compliance rate was assessed as 90%
and 61 (\~10%) had compliance rates assessed as \< 80%.

Demographics

Four hundred and forty-five (66%) of the ITT patients were male. The
percentage of males was similar across treatment groups and ranged from
61% to 75%. Ninety-three percent (93%) of patients were Caucasian, 5
percent were Black, and the remainder were Asian or of other races.
Patients' ages ranged from 40 to 90 years. There were 324 \[48%\]
current smokers and 350 \[52%\] former smokers. The placebo group had a
higher percentage of current smokers \[54%\] compared to the other
treatment groups \[46%\]. The median number of pack-years smoked was
similar among treatment groups and ranged from 52.5 to 60.0 pack-years.
Former smokers tended to be older (42 --90 yrs) than current smokers
(40-81 yrs) and had a higher incidence of inhaled corticosteroids
\[ICS\] use (27-40%) than current smokers (10-23%). The majority of
subjects \[75%\] were not taking ICS prior to screening and the majority
\[76%\] reported having emphysema. The demographic characteristics for
the reversible and the non-reversible population were similar to that of
the overall ITT population. A total of 361 patients were stratified as
reversible, and 313 were non-reversible \[per ATS criteria\].

Table 5 - Characteristics of the Intent-to Treat population SFCA3006

+-------------+------------+------------+------------+----------------+
|             | *          | **SAL 50** | **FP 500** | **Advair       |
|             | *Placebo** |            |            | Diskus**       |
|             |            | **N= 160** | **N= 168** |                |
|             | **N =      |            |            | **N =165**     |
|             | 181**      |            |            |                |
+-------------+------------+------------+------------+----------------+
| Age (yrs)   | 64.0       | 63.5       | 64.42      | 61.9           |
|             |            |            |            |                |
| Mean        | 44-90      | 40-84      | 42-82      | 40-86          |
|             |            |            |            |                |
| Range       |            |            |            |                |
+-------------+------------+------------+------------+----------------+
| Gender      | 136 (75%)  | 103 (64%)  | 103 (61%)  | 103 (62%)      |
|             |            |            |            |                |
| Male        | 45 (25%)   | 57 (36%)   | 65 (39%)   | 62 (38%)       |
|             |            |            |            |                |
| Female      |            |            |            |                |
+-------------+------------+------------+------------+----------------+
| Race        | 166 (92%)  | 152 (95%)  | 156 (93%)  | 156 (95%)      |
|             |            |            |            |                |
| Caucasian   | 11 (6%)    | 6 (4%)     | 8 (5%)     | 7 (4%)         |
|             |            |            |            |                |
| Black       | 4 (2%)     | 2 (1%)     | 4 (2%)     | 2 (1%)         |
|             |            |            |            |                |
| Asian/Other |            |            |            |                |
+-------------+------------+------------+------------+----------------+
| Median      | 6.00       | 6.00       | 5.00       | 5.00           |
| Duration of |            |            |            |                |
| COPD (yr.)  |            |            |            |                |
+-------------+------------+------------+------------+----------------+
| Inhaled     | 148 (82%)  | 111 (69%)  | 126 (75%)  | 119 (72%)      |
| steroids at |            |            |            |                |
| screening   | 33 (18%)   | 49 (31%)   | 42 (25%)   | 46 (28%)       |
|             |            |            |            |                |
| No          |            |            |            |                |
|             |            |            |            |                |
| Yes         |            |            |            |                |
+-------------+------------+------------+------------+----------------+
| Former      | 84 (46%)   | 86 (54%)   | 91 (54%)   | 89 (54%)       |
| Smoker      |            |            |            |                |
|             | 97 (54%)   | 74 (46%)   | 77 (46%)   | 76 (46%)       |
| Current     |            |            |            |                |
| Smoker      |            |            |            |                |
+-------------+------------+------------+------------+----------------+
| Emphysema   | 142 (78%)  | 125 (78%)  | 125 (74%)  | 123 (75%)      |
|             |            |            |            |                |
| Yes         | 39 (22%)   | 35 (22%)   | 43 (26%)   | 46 (25%)       |
|             |            |            |            |                |
| No          |            |            |            |                |
+-------------+------------+------------+------------+----------------+
| MMRC        | 129 (71%)  | 90 (56%)   | 112 (67%)  | 108 (65%)      |
| Dyspnea     |            |            |            |                |
| Score       | 47 (26%)   | 62 (39%)   | 51 (30%)   | 55 (33%)       |
|             |            |            |            |                |
| 2           | 5 (3%)     | 8 (5%)     | 5 (3%)     | 2 (1%)         |
|             |            |            |            |                |
| 3           |            |            |            |                |
|             |            |            |            |                |
| 4           |            |            |            |                |
+-------------+------------+------------+------------+----------------+
|             |            |            |            |                |
+-------------+------------+------------+------------+----------------+

The screening spirometry results were consistent with airflow
obstruction with FEV~1~% predicted ranging from 40.25% to 41.48% across
treatment groups. The FEV~1~/FVC x100 ratio ranged from 47.64% to
49.41%. The FEV~1~ % predicted and the FEV~1~/FVC ratio were similar for
the reversible and the non-reversible population. The table below
summarizes the screening spirometry results for the overall ITT
population and the reversible and non-reversible population. The
bronchodilator response ranged from 19.23% to 21.18% across treatment
groups. The reversible subjects had a bronchodilator response ranging
from 28.05% to 31.56%, while the non-reversible population had a
bronchodilator response ranging from 8.04% to 10.28%. Screening
spirometry and bronchodilator response data were similar between the
former smokers and current smokers. Table 6 summarizes the spirometry
and bronchodilator response results.

Table 6 - Spirometry and Bronchodilator Response Results SFCA 3006

  ----------------- ------------------ -------------- -------------- --------------
                    **Placebo**        **SAL 50**     **FP 500**     **Advair
                                                                     500/50**

                    **ITT Population**                               

  Randomized n      181                160            168            165

  Mean FEV~1~       1282               1192           1174           1254
  \[mL\]                                                             

  FEV~1~ %          41.48              40.25          41.40          40.85
  predicted                                                          

  FEV~1~/FVC x 100  49.02              48.58          47.64          49.41

  Bronchodilator    19.33              21.18          19.23          20.58
  response \[%\]                                                     

                    **Reversible                                     
                    Population**                                     

  Randomized n      101                82             90             88

  Mean FEV~1~       1322               1250           1228           1366
  \[mL\]                                                             

  FEV~1~ %          40.85              39.12          40.82          41.25
  predicted                                                          

  FEV~1~/FVC x 100  48.91              48.32          47.74          50.20

  Bronchodilator    28.05              31.55          28.56          31.56
  response \[%\]                                                     

                    **Non-Reversible                                 
                    Population**                                     

  Randomized n      80                 78             78             77

  Mean FEV~1~       1230               1132           1114           1129
  \[mL\]                                                             

  FEV~1~ %          42.29              41.44          42.09          40.40
  predicted                                                          

  FEV~1~/FVC x 100  49.17              48.45          47.52          48.51

  Bronchodilator    8.33               10.28          8.46           8.04
  response \[%\]                                                     
  ----------------- ------------------ -------------- -------------- --------------

*Reviewer's Comments:*

*There are a number of concerns regarding the patient population
enrolled in this study and hence whether it is appropriate to generalize
the results of this trial to the COPD population as a whole. The
proportion of patients enrolled in the study with reversibility (54%) is
much higher than the approximately 30% reported in the population of
COPD patients at large*[^9]*. Secondly, all patients had to have a
diagnosis of chronic bronchitis to be enrolled in the study. While
chronic bronchitis and emphysema can occur together, the study entry
criteria specifically eliminated those COPD patients with relatively
"pure" emphysema. The diagnosis of emphysema was captured by patient
self-reporting without pre-defined objective criteria.*

EFFICACY RESULTS SFCA3006

Primary Efficacy Results

[Change from baseline in mean morning pre-dose FEV~1~ at
endpoint]{.underline}

This analysis evaluated the effects of FP 500 in the combination
product. The comparison was between Advair 500/50 and salmeterol 50. The
mean changes are displayed in the table below. Endpoint refers to the
last post-Baseline assessment (excluding the Discontinuation visit), the
post-Baseline N's stated were used for the mean change calculation.

**Table 7 Mean Change \[mL\] from Baseline in Pre-Dose FEV~1~** SFCA3006

  ------------------------- ------------------ --------- ----------- --------------
                            **Placebo**        **SAL**   **FP 500**  **Advair
                                                                     500/50**

                            **ITT Population**                       

  Baseline n                181                159       166         163

  Mean FEV~1~               1282               1192      1174        1254

  Endpoint n                171                158       161         157

  Mean FEV~1~ \[mL\]        1292               1303      1298        1410

  Mean Change               -4                 107^a^    109^a^      156^abc^

                            **Reversible                             
                            Population**                             

  Baseline n                101                81        88          86

  Mean FEV~1~               1322               1250      1228        1366

  Endpoint n                97                 81        86          84

  Mean FEV~1~ \[mL\]        1334               1382      1367        1545

  Mean Change               -1                 132       123         191

                            **Non-reversible                         
                            Population**                             

  Baseline n                80                 78        78          77

  Mean FEV~1~               1230               1132      1114        1129

  Endpoint n                74                 77        75          73

  Mean FEV~1~ \[mL\]        1238               1220      1219        1256

  Mean Change               -8                 80        93          116
  ------------------------- ------------------ --------- ----------- --------------

a p0.028 vs. placebo

b p0.016 vs. SAL

c p0.038 vs. FP500

For the ITT population, mean improvement in pre-dose FEV~1~ at Endpoint
was 156 mL (14.5% change) for Advair Diskus 500/50, and 107 mL (10.0%
change) for SAL 50 representing a mean difference of 49 ml \[p0.028\].
The model- adjusted mean difference was 67 mL \[p0.012\].

The mean treatment difference between Advair 500/50 and placebo for the
reversible and non-reversible population was 192 mL and 124 mL
respectively. Numerically, this is equivalent to a treatment effect size
for the reversible population that is 1.5 times the effect size for the
non-reversible population. Because the study was designed and powered
based on the ITT population inferential testing for these two subgroups
was not performed.

Table 8 summarizes the actual change from Baseline in Pre-Dose FEV~1~
across multiple timepoints for each treatment group. Over the 24 weeks
of treatment, mean changes from Baseline in AM pre-dose FEV~1~ ranged
from 159 mL to 192 mL for the Advair Diskus 500/50 group, 110 mL to 134
mL for the SAL 50 group, 69 mL to 131 mL for the FP 500 group and 18 mL
to 28 mL for the placebo group.

**Table 8 - Summary of Pre-Dose FEV~1~ \[mL\] Across Multiple Timepoints
SFCA3006 \[Data Table 7.3 SFCA3006.pdf\] (All timepoints not shown)**

+-------------+-----+--------+---+--------+---+-------+---+--------+
|             | P   |        | * |        | * |       | * |        |
|             | lac |        | * |        | * |       | * |        |
|             | ebo |        | S |        | F |       | A |        |
|             |     |        | A |        | P |       | d |        |
|             |     |        | L |        | 5 |       | v |        |
|             |     |        | 5 |        | 0 |       | a |        |
|             |     |        | 0 |        | 0 |       | i |        |
|             |     |        | * |        | * |       | r |        |
|             |     |        | * |        | * |       | D |        |
|             |     |        |   |        |   |       | i |        |
|             |     |        |   |        |   |       | s |        |
|             |     |        |   |        |   |       | k |        |
|             |     |        |   |        |   |       | u |        |
|             |     |        |   |        |   |       | s |        |
|             |     |        |   |        |   |       | 5 |        |
|             |     |        |   |        |   |       | 0 |        |
|             |     |        |   |        |   |       | 0 |        |
|             |     |        |   |        |   |       | / |        |
|             |     |        |   |        |   |       | 5 |        |
|             |     |        |   |        |   |       | 0 |        |
|             |     |        |   |        |   |       | * |        |
|             |     |        |   |        |   |       | * |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+
|             | n   | Change | n | Change | n | C     | n | Change |
|             |     | (mL)   |   | (mL)   |   | hange |   | (mL)   |
|             |     | \[SE\] |   | \[SE\] |   | (mL)  |   | \[SE\] |
|             |     |        |   |        |   | \     |   |        |
|             |     |        |   |        |   | [SE\] |   |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+
| Week 1      | 168 | -7     | 1 | 127    | 1 | 76    | 1 | 173    |
|             |     | \[12\] | 5 | \[14\] | 6 | \     | 5 | \[19\] |
|             |     |        | 5 |        | 0 | [14\] | 6 |        |
|             |     | **     |   | **1    |   |       |   | **1    |
|             |     | 0.3%** |   | 1.8%** |   | **8   |   | 6.7%** |
|             |     |        |   |        |   | .2%** |   |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+
| Week 4      | 147 | -4     | 1 | 130    | 1 | 78    | 1 | 178    |
|             |     | \[15\] | 4 | \[15\] | 4 | \     | 4 | \[19\] |
|             |     |        | 1 |        | 8 | [15\] | 7 |        |
|             |     | **     |   | **1    |   |       |   | **1    |
|             |     | 1.2%** |   | 2.0%** |   | **7   |   | 6.8%** |
|             |     |        |   |        |   | .8%** |   |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+
| Week 6      | 141 | 15     | 1 | 114    | 1 | 96    | 1 | 192    |
|             |     | \[17\] | 3 | \[17\] | 4 | \     | 4 | \[22\] |
|             |     |        | 8 |        | 1 | [18\] | 2 |        |
|             |     | **     |   | **1    |   |       |   | **1    |
|             |     | 2.9%** |   | 0.9%** |   | **9   |   | 7.5%** |
|             |     |        |   |        |   | .4%** |   |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+
| Week 12     | 127 | -12    | 1 | 110    | 1 | 81\   | 1 | 186    |
|             |     | \[19\] | 3 | \[20\] | 2 | [21\] | 3 | \[20\] |
|             |     |        | 1 |        | 1 |       | 2 |        |
|             |     | **     |   | **1    |   | **8   |   | **1    |
|             |     | 0.7%** |   | 0.7%** |   | .2%** |   | 7.1%** |
+-------------+-----+--------+---+--------+---+-------+---+--------+
| Week 16     | 119 | 19     | 1 | 115    | 1 | 103   | 1 | 159    |
|             |     | \[19\] | 2 | \[19\] | 0 | \     | 2 | \[22\] |
|             |     |        | 3 |        | 6 | [23\] | 5 |        |
|             |     | **     |   | **1    |   |       |   | **1    |
|             |     | 3.0%** |   | 0.9%** |   | **9   |   | 4.4%** |
|             |     |        |   |        |   | .4%** |   |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+
| Week 20     | 113 | 7      | 1 | 121    | 1 | 122   | 1 | 163    |
|             |     | \[21\] | 2 | \[20\] | 0 | \     | 1 | \[23\] |
|             |     |        | 0 |        | 3 | [25\] | 7 |        |
|             |     | **     |   | **1    |   |       |   | **1    |
|             |     | 2.5%** |   | 1.0%** |   | **11  |   | 5.2%** |
|             |     |        |   |        |   | .6%** |   |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+
| Week 24     | 112 | -18    | 1 | 116    | 9 | 131   | 1 | 180    |
|             |     | \[22\] | 1 | \[21\] | 9 | \     | 1 | \[24\] |
|             |     |        | 4 |        |   | [26\] | 3 |        |
|             |     | **     |   | **1    |   |       |   | **1    |
|             |     | 0.3%** |   | 0.7%** |   | **11  |   | 6.5%** |
|             |     |        |   |        |   | .9%** |   |        |
+-------------+-----+--------+---+--------+---+-------+---+--------+

Advair Diskus 500/50 had numerically greater improvements in Pre-dose
FEV~1~ at all timepoints throughout the study compared to its individual
components and placebo, although Endpoint was selected *a priori* to
assess the contribution of fluticasone to the combination.

[Mean Change From Baseline at Endpoint in 2-hr Post-Dose
FEV~1~]{.underline}

This variable was analyzed as the primary measure of efficacy to
evaluate the effect of salmeterol in the combination product. The
comparison of interest is Advair Diskus 500/50 vs. FP 500.

**Table 9 - Mean Change (mL) from Baseline in 2-Hour Post-Dose FEV~1~
ITT Population SFCA 3006**

+----------------+-----------+-----------+-------------+-------------+
|                | **        | **SAL     | **FP 500**  | **Advair    |
|                | Placebo** | 50**      |             | Diskus      |
|                |           |           | **N=168**   | 500/50**    |
|                | **N=      | **N=160** |             |             |
|                | 181**     |           |             | **N=165**   |
+----------------+-----------+-----------+-------------+-------------+
| Baseline N     | 181       | 159       | 166         | 163         |
+----------------+-----------+-----------+-------------+-------------+
| Baseline mean  | 1282      | 1192      | 1174        | 1254        |
| FEV~1~ \[mL\]  | \[491\]   | \[441\]   | \[445\]     | \[546\]     |
| (SD)           |           |           |             |             |
+----------------+-----------+-----------+-------------+-------------+
| Endpoint n     | 171       | 158       | 160         | 156         |
+----------------+-----------+-----------+-------------+-------------+
| Mean 2-hour    | 1324      | 1429      | 1327        | 1515        |
| Post-Dose      | \[504\]   | \[532\]   | \[501\]     | \[616\]     |
| FEV~1~ at      |           |           |             |             |
| Endpoint       |           |           |             |             |
| \[mL\] (SD)    |           |           |             |             |
+----------------+-----------+-----------+-------------+-------------+
| Mean change    | 28        | 233^a^    | 138^a,b^    | 261^a,c^    |
| from Baseline  | \[231\]   | \[283\]   | \[231\]     | \[261\]     |
| in morning     |           |           |             |             |
| 2-hour         | 3.7%      | 21.6%     | 13.1%       | 24.2%       |
| post-dose      |           |           |             |             |
| FEV~1~ \[mL\]  |           |           |             |             |
| \[SD\]         |           |           |             |             |
|                |           |           |             |             |
| Percent change |           |           |             |             |
+----------------+-----------+-----------+-------------+-------------+

a p0.024 vs. placebo

b p0.043 vs. SAL 50

c p0.001 vs. FP 500

The p-values are based on comparisons of estimated (model adjusted)
means rather than the actual mean changes shown in the table.

There was a greater increase in the 2-hr post-dose FEV~1~ at Endpoint in
the Advair 500/50 treatment group (261 mL) compared with the FP 500
treatment group (138 mL). The mean treatment difference is 123 mL \[p
0.024\]

The model-adjusted mean treatment difference was 129 mL. The mean
treatment difference between Advair 500/50 and placebo for the
reversible and the non-reversible population was 290 mL and 167 mL
respectively. Numerically, these results demonstrate an effect size for
the reversible population that was 1.5 times the treatment effect for
the non-reversible population. No inferential statistics on the subgroup
analyses were performed.

**Table 10 - Mean Change from Baseline in Post-Dose FEV~1~** Reversible
and Non-Reversible Population SFCA3006

+-----------+------+-----+------+--------+------+-----+-----+------+
|           | #    |     |      |        | **   |     |     |      |
|           | #### |     |      |        | Non- |     |     |      |
|           | # Re |     |      |        | Reve |     |     |      |
|           | vers |     |      |        | rsib |     |     |      |
|           | ible |     |      |        | le** |     |     |      |
+-----------+------+-----+------+--------+------+-----+-----+------+
|           | Pla  | SAL | FP   | Advair | Pla  | SAL | FP  | Ad   |
|           | cebo | 50  | 500  | Diskus | cebo | 50  | 500 | vair |
|           |      |     |      | 500/50 |      |     |     | Di   |
|           | N    | N   | N=90 |        | N=80 | N   | N   | skus |
|           | =101 | =82 |      | N=88   |      | =78 | =78 |      |
|           |      |     |      |        |      |     |     | 500  |
|           |      |     |      |        |      |     |     | /50- |
|           |      |     |      |        |      |     |     |      |
|           |      |     |      |        |      |     |     | N=77 |
+-----------+------+-----+------+--------+------+-----+-----+------+
| Baseline  | 101  | 81  | 88   | 86     | 80   | 78  | 78  | 77   |
| n         |      |     |      |        |      |     |     |      |
+-----------+------+-----+------+--------+------+-----+-----+------+
| Mean (mL) | 1322 | 1   | 1228 | 1366   | 1230 | 1   | 114 | 1129 |
|           |      | 250 |      |        |      | 132 |     |      |
+-----------+------+-----+------+--------+------+-----+-----+------+
| Endpoint  | 97   | 81  | 86   | 84     | 74   | 77  | 75  | 73   |
| n         |      |     |      |        |      |     |     |      |
+-----------+------+-----+------+--------+------+-----+-----+------+
| Mean (mL) | 1363 | 1   | 1405 | 1672   | 1274 | 1   | 1   | 1335 |
|           |      | 538 |      |        |      | 315 | 237 |      |
+-----------+------+-----+------+--------+------+-----+-----+------+
| Mean      | 29   | 287 | 161  | 319    | 28   | 175 | 111 | 195  |
| change    |      |     |      |        |      |     |     |      |
| (mL)      |      |     |      |        |      |     |     |      |
+-----------+------+-----+------+--------+------+-----+-----+------+

Onset of Effect and Duration of Effect

Onset, offset, and duration of effect were defined based on the serial
FEV~1~ measurements collected on Treatment Day 1, and at Treatment Week
12. Onset of effect was defined as the time point within 4 hours
post-dose at which the increase of FEV~1~ achieved 100 mL or greater
above Day 1 Baseline. The duration of effect was defined as the
difference between time of onset to time of offset of effect. The time
to offset was defined as the time point post dose at which a given
subject's FEV~1~ dropped below the 100 mL improvement threshold for two
consecutive timepoints. Most patients in the Advair Diskus and
salmeterol groups \[ 87%\] achieved 100 mL improvement in FEV~1~ over
Baseline within 4 hours on Treatment Day 1 and Treatment Week 12
compared to 61.1% and 67.7% of subjects in the FP 500 group and 49.5%
and 61.5% of subjects in the placebo group on Treatment Day 1, and
Treatment Week 12 respectively.

*Reviewer's comment. In previous COPD studies with salmeterol MDI an
improvement of 12% in FEV~1~ was used to define onset of effect and not
an absolute increase of 100 ml as is being used here. The onset of
effect of Advair is driven by the salmeterol component. The Baseline
mean FEV~1~ for the SAL 50 group was 1192 ml and for Advair 500/50 was
1254. Therefore, an increase of 100 ml would be equivalent to an
improvement of about 8%. The sponsor should reanalyze the data using a
12% improvement to evaluate onset and duration of effect as was done for
other COPD studies with salmeterol.*

*Reviewer Comment:*

*The sponsor explained that since 12% of the mean Baseline FEV~1~ for
all treatment groups was less than 200 mL the greater of a mean 12%
increase and a mean increase of 200 mL is 200 mL for every treatment
group. From data submitted via Facsimile on December 12, 2001, the
sponsor showed that at 0.5 hrs, 38% of subjects in the Advair group
reached or exceeded the threshold of at least 12% and at least 200 mL
above the subject's pre-dose value on Treatment Day 1. The mean time to
reach an increase of at least 12% and at least 200 mL above the
subject's pre-dose value on Treatment Day 1 was 2.01 hrs for the Advair
group, 1.74 hrs for the salmeterol group and 3.96 hours for the placebo
group. The percentage of subjects reaching that threshold was 74% in the
Advair group, 67% in the salmeterol group and 26% in the placebo group.*

Secondary Efficacy Measures SFCA3006

Diary Data

AM PEF

Patients in the placebo group had a higher mean AM PEFR \[measured
pre-dosing\] at Baseline compared to subjects in the active treatment
groups. There were greater improvements in AM PEF in the Advair group
overall and throughout the study compared with the placebo, SAL 50, and
FP 500 groups. The mean change from baseline in AM PEF was 31.9 L/min
for Advair Diskus 500/50, 16.8 L/min for SAL 50, and 12.9 L/min for FP
500 \[see table below\].

> Table 11 - AM PEF Results SFCA3006

+-----------------------+-------------+---------+--------+------------+
|                       | #####       | **SAL   | **FP   | **Advair   |
|                       | **Placebo** | 50**    | 500**  | Diskus     |
|                       |             |         |        | 500/50**   |
+-----------------------+-------------+---------+--------+------------+
| Baseline n            | 181         | 158     | 167    | 162        |
+-----------------------+-------------+---------+--------+------------+
| \*Baseline Mean       | 269.5       | 252.1   | 243.7  | 254.0      |
| (L/min)               |             |         |        |            |
+-----------------------+-------------+---------+--------+------------+
| Month 3 n             | 141         | 135     | 138    | 138        |
+-----------------------+-------------+---------+--------+------------+
| Mean (L/min)          | 276.2       | 272.7   | 263.7  | 287.2      |
+-----------------------+-------------+---------+--------+------------+
| Month 6 n             | 116         | 123     | 102    | 118        |
+-----------------------+-------------+---------+--------+------------+
| Mean L/min            | 283.5       | 281.4   | 273.4  | 286.1      |
+-----------------------+-------------+---------+--------+------------+
| \*\*Overall           | 179         | 157     | 166    | 162        |
|                       |             |         |        |            |
| N                     | 267.1       | 268.7   | 256.6  | 284.7      |
|                       |             |         |        |            |
| Mean (L/min)          | -2.7        | 16.8    | 12.9   | 31.9       |
|                       |             |         |        |            |
| Mean Change           |             |         |        |            |
+-----------------------+-------------+---------+--------+------------+

*[\*]{.underline}Baseline for AM PEFR is the average of the values
between Screening and Day 1.*

*\*\*Overall = the entire treatment period.*

[Ventolin® Use]{.underline}

The total symptomatic Ventolin use at baseline was similar across
treatment groups and ranged from 4.2 puffs/24 hrs in the Advair Diskus
500/50 group to 4.9 /24 hrs in the placebo group. Over the course of the
study, subjects in all the active treatment groups had slight decreases
in Ventolin® use compared with placebo. The overall changes were small
with Ventolin use in the Advair group decreasing by 1.2 puffs/24 hours
and by 0.9 puffs/24 hrs and 0.4 puffs/24 hrs in the SAL 50 and FP 500
groups respectively.

[Nighttime Awakenings /Night Requiring Ventolin]{.underline}

At Baseline there were very few nighttime awakenings across treatment
groups. The mean number of nighttime awakenings ranged from 0.22 to 0.27
equivalent to one nighttime awakening every 4.5 to 3.7 nights. All the
active treatment groups had a reduction in nighttime awakenings
requiring Ventolin use however, the overall changes were very small. For
example, in the Advair Diskus 500/50 group the number of nighttime
awakenings decreased from 0.22/night at baseline to 0.19/night
equivalent to a change from one awakening every 4.5 nights to one
awakening every 5.2 nights. In the SAL 50 group, there was a decrease
from 0.26 awakenings/night at Baseline to 0.17 awakenings/night overall,
equivalent to a decrease from one awakening every 3.8 nights to one
awakening every 5.8 nights.

[Chronic Bronchitis Questionnaire \[CBSQ GAS\]]{.underline}

*Please refer to the "Statistical and analytical" section for
description of the CBSQ GAS*. There was a mean minimal clinically
important change of \>1.4 from Baseline in the CBSQ GAS for all
treatment groups including placebo. The difference between placebo and
Advair Diskus or its individual components did not constitute a
clinically meaningful difference.

**Table 12 - Summary of Mean Change from Baseline in CBSQ GAS**

ITT Population SFCA3006

+------------------+----------+-----------+-----------+----------------+
| **Time Point**   | **P      | **SAL     | **FP      | **Advair       |
|                  | lacebo** | 50**      | 500**     | Diskus**       |
|                  |          |           |           |                |
|                  | **n =    | **N=160** | **N=168** | **N=165**      |
|                  | 181**    |           |           |                |
+------------------+----------+-----------+-----------+----------------+
| Treatment Day 1  | 180      | 159       | 167       | 164            |
| (Baseline)       |          |           |           |                |
|                  | 7.3      | 7.4       | 7.0       | 6.9            |
| n                |          |           |           |                |
|                  |          |           |           |                |
| mean             |          |           |           |                |
+------------------+----------+-----------+-----------+----------------+
| Week 12          | 127      | 131       | 120       | 132            |
|                  |          |           |           |                |
| n                | 5.7      | 5.6       | 5.0       | 4.8            |
|                  |          |           |           |                |
| mean             | 1.3      | 1.8       | 2.0       | 2.1            |
|                  |          |           |           |                |
| mean change      |          |           |           |                |
+------------------+----------+-----------+-----------+----------------+
| Week 24          | 112      | 120       | 100       | 112            |
|                  |          |           |           |                |
| n                | 5.4      | 5.0       | 5.2       | 4.8            |
|                  |          |           |           |                |
| mean             | 1.6      | 2.0       | 1.9       | 2.1            |
|                  |          |           |           |                |
| mean change      |          |           |           |                |
+------------------+----------+-----------+-----------+----------------+
| Endpoint         | 172      | 158       | 161       | 157            |
|                  |          |           |           |                |
| n                | 5.7      | 5.6       | 5.5       | 5.1            |
|                  |          |           |           |                |
| mean             | 1.5      | 1.9       | 1.6       | 1.8            |
|                  |          |           |           |                |
| mean change      |          |           |           |                |
+------------------+----------+-----------+-----------+----------------+

[Baseline Dyspnea Index/Transitional Dyspnea Index
\[BDI/TDI]{.underline}

At Baseline \[Treatment Day 1\] the BDI scores ranged from 5.8 to 6.2.
This corresponds to a moderate level of dyspnea at Baseline. At Endpoint
the mean TDI score for the Advair Diskus 500/50 group was numerically
greater than the mean TDI score for the SAL 50, FP 500, and placebo
groups. Advair Diskus 500/50 had a clinically meaningful difference
\[\>1\] compared to placebo and salmeterol but not FP. The summary of
the BDI/TDI Dyspnea Index score is shown in the table below.

Table 13 - Summary of BDI/TDI Total Score ITT Population SFCA3006

+-------------+-------------+-------------+-------------+-------------+
| **Time      | **Placebo** | **SAL 50**  | **FP 500**  | **Advair    |
| point**     |             |             |             | Diskus      |
|             | **N=181**   | **N=160**   | **N=168**   | 500/50**    |
|             |             |             |             |             |
|             |             |             |             | **N=165**   |
+-------------+-------------+-------------+-------------+-------------+
| Day1 (BDI)  | 179         | 154         | 164         | 160         |
|             |             |             |             |             |
| N           | 5.8         | 5.9         | 6.0         | 6.2         |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 12     | 127         | 131         | 120         | 132         |
| (TDI)       |             |             |             |             |
|             | 0.6         | 1.3         | 1.4         | 2.0         |
| N           |             |             |             |             |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 24     | 112         | 116         | 100         | 113         |
| (TDI)       |             |             |             |             |
|             | 0.6         | 1.6         | 1.9         | 2.7         |
| N           |             |             |             |             |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Endpoint    | 172         | 158         | 161         | 157         |
| (TDI)       |             |             |             |             |
|             | 0.4         | 0.9         | 1.3         | 2.1         |
| N           |             |             |             |             |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

[Exacerbations of COPD]{.underline}

Four secondary endpoints related to COPD exacerbations were evaluated.
They were:

-   Severity of exacerbation

-   Time to first exacerbation

-   Time to first moderate or severe exacerbation

-   Number of withdrawals due to COPD exacerbation

Of note is that the sponsor did not state in the protocol how a COPD
exacerbation would be defined. However, the sponsor defined the severity
of COPD exacerbations predicated on the use of self-administered rescue
Ventolin, and Investigator use of antibiotics, corticosteroids or
hospitalization. \[see page 26\]

*Reviewer comment: Most published definitions of COPD exacerbations
encompass some combination of three clinical findings: worsening
dyspnea, increase in sputum purulence, and increase in sputum volume. A
severity scale for acute exacerbations developed by Anthonisen and
colleagues is based on these findings as well as others.*[^10]

The incidence and frequency of exacerbations as defined by the sponsor
was similar across the treatment groups but was lowest in the SAL group.
A total of 79 (44%) subjects in the placebo group, 63 (39%) in the SAL
50 group, 77 (46%) in the FP 500 group and 68 (41%) in the Advair Diskus
group had at least one COPD exacerbation. There was no difference in the
time to the onset of a COPD exacerbation among treatment groups and no
difference in the number of moderate/severe exacerbations among
treatment groups.

> Table 14 - Incidence of COPD exacerbations. ITT Population SFCA3006

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 2%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 10%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4"><strong>COPD Exacerbation of Any Severity</strong></td>
<td></td>
<td colspan="4"><strong>Moderate/severe COPD Exacerbation</strong></td>
</tr>
<tr class="even">
<td>No of Exac. N (%)</td>
<td><p>Placebo</p>
<p>N=181</p></td>
<td><p>SAL</p>
<p>N=160</p></td>
<td><p>FP</p>
<p>N=168</p></td>
<td><p>Advair</p>
<p>N=165</p></td>
<td></td>
<td><p>Placebo</p>
<p>N=181</p></td>
<td><p>SAL</p>
<p>N=160</p></td>
<td><p>FP</p>
<p>168</p></td>
<td><p>Advair</p>
<p>N=165</p></td>
</tr>
<tr class="odd">
<td>None</td>
<td>102 (56%)</td>
<td>97 (61%)</td>
<td>91(54%)</td>
<td>97 (59%)</td>
<td></td>
<td>118 (65%)</td>
<td>100 (63%)</td>
<td>101 (60%)</td>
<td>104 (63%)</td>
</tr>
<tr class="even">
<td>1</td>
<td>50 (28%)</td>
<td>45 (28%)</td>
<td>52 (31%)</td>
<td>47 (28%)</td>
<td></td>
<td><p>48</p>
<p>(27%)</p></td>
<td><p>46</p>
<p>(29%)</p></td>
<td>54 (32%)</td>
<td><p>45</p>
<p>(27%)</p></td>
</tr>
<tr class="odd">
<td>2</td>
<td>13 (7%)</td>
<td>11 (7%)</td>
<td>16 (10%)</td>
<td>12 (7%)</td>
<td></td>
<td>12 (7%)</td>
<td>12 (8%)</td>
<td>11 (7%)</td>
<td>13 (8%)</td>
</tr>
<tr class="even">
<td>3</td>
<td>2 (1%)</td>
<td>3 (2%)</td>
<td>1 (&lt;1)</td>
<td>4 (2%)</td>
<td></td>
<td>2 (1%)</td>
<td>2 (1%)</td>
<td>2 (1%)</td>
<td>1 (&lt;1%)</td>
</tr>
<tr class="odd">
<td>4</td>
<td>14 (8%)</td>
<td>4 (3%)</td>
<td>8 (5%)</td>
<td>5 (3%)</td>
<td></td>
<td>1 (&lt;1)</td>
<td>0</td>
<td>0</td>
<td>2 (1%)</td>
</tr>
</tbody>
</table>

Subgroup analysis in Current smokers and Former smokers

Summary statistics showed that the combination group had similar results
for the primary efficacy endpoints regardless of smoking status. For the
primary endpoint mean change in pre-dose FEV~1~ at Endpoint, the mean
treatment difference between Advair and SAL was 47 mL in former smokers
compared with 52 mL in current smokers. For the primary endpoint change
in 2-hr post-dose FEV~1~ at Endpoint the mean treatment difference
between Advair and FP was117 mL in former smokers and 132 mL in current
smokers. These results are displayed in the table below.

**Table 15 - Summary of Results Displayed by Smoking Status**

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 1%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="6"><strong>Former Smokers</strong></td>
<td colspan="5"><strong>Current Smokers</strong></td>
</tr>
<tr class="even">
<td><strong>Efficacy Variable</strong></td>
<td><p><strong>Placebo</strong></p>
<p><strong>N=84</strong></p></td>
<td colspan="2"><p><strong>SAL 50</strong></p>
<p><strong>N=86</strong></p></td>
<td><p><strong>FP 500</strong></p>
<p><strong>N=91</strong></p></td>
<td colspan="2"><p><strong>Advair 500/50</strong></p>
<p><strong>N=81</strong></p></td>
<td colspan="2"><p><strong>Placebo</strong></p>
<p><strong>N=97</strong></p></td>
<td><p><strong>SAL 50</strong></p>
<p><strong>N=74</strong></p></td>
<td><p><strong>FP 500</strong></p>
<p><strong>N=77</strong></p></td>
<td><p><strong>Advair 500/50</strong></p>
<p><strong>N=76</strong></p></td>
</tr>
<tr class="odd">
<td colspan="12"><strong>Pre-Dose FEV<sub>1</sub> (mL) Change from
Baseline</strong></td>
</tr>
<tr class="even">
<td>Mean change at Endpoint</td>
<td>16</td>
<td>132</td>
<td colspan="2">139</td>
<td>179</td>
<td colspan="2">- 21</td>
<td colspan="2">78</td>
<td>73</td>
<td>130</td>
</tr>
<tr class="odd">
<td colspan="12"><strong>Post-Dose FEV<sub>1</sub> (mL) Change from
Baseline</strong></td>
</tr>
<tr class="even">
<td>Mean Change at Endpoint</td>
<td>45</td>
<td>243</td>
<td colspan="2">140</td>
<td>257</td>
<td colspan="2">15</td>
<td colspan="2">221</td>
<td>134</td>
<td>266</td>
</tr>
<tr class="odd">
<td colspan="12"><strong>Transition Dyspnea Index (TDI)</strong></td>
</tr>
<tr class="even">
<td>Mean at Endpoint</td>
<td>-0.1</td>
<td>1.0</td>
<td colspan="2">1.3</td>
<td>1.9</td>
<td colspan="2">0.7</td>
<td colspan="2">0.9</td>
<td>1.3</td>
<td>2.2</td>
</tr>
</tbody>
</table>

HEALTH OUTCOMES RESULTS

COPD-related Quality of Life assessed by the CRDQ

*See discussion of secondary endpoints in "Statistical and Analytical"
section for description. One of the objectives of the pivotal studies
was to compare the quality of life in COPD subjects receiving Advair,
its individual components, or placebo for 24-weeks.*

Results

A total of 663 of the 674 subjects \[excluding Investigator 1403\] in
the ITT population were included in the reduced ITT population for the
CRDQ analyses. The results of the Overall score at Endpoint and at other
timepoints are summarized in the table below.

Table 16. Mean Change from Baseline in Overall CRDQ Score at Endpoint
and other Timepoints. Reduced ITT Population Study SFCA3006 \[data from
Table 8.1 SFCA3006.pdf\]

  -------------- -------------- -------------- -------------- --------------
  Timepoint      Placebo        SAL 50         FP 500         Advair 500/50

  Day 1          N=177          N=157          N=166          N=163

  Mean \[SD\]    86.2 \[17.1\]  87.6 \[17.5\]  88.5 \[17.4\]  87.1 \[18.3\]

  Endpoint       N=175          N=155          N=163          N=161

  Mean\[SD\]     91.3 \[24\]    95.8\[22\]     93.5 \[21.2\]  97.1 \[22\]

  Mean change    5              8              4.8            10
  from Baseline                                               

  Week 2         N=154          N=150          N=157          N=153

  Mean change    3.3            6              5.8            8.5
  from Baseline                                               

  Week 4         N=149          N=138          N=147          N=144

  Mean change    7.8            8.5            6.1            11.6
  from Baseline                                               

  Week 8         N=140          N=132          N=138          N=135

  Mean change    8.9            9              9.4            14.3
  from Baseline                                               

  Week 24        N=102          N=107          N=95           N=100

  Mean change    8.9            11.5           10.1           13.1
  from Baseline                                               
  -------------- -------------- -------------- -------------- --------------

At Endpoint, subjects in the Advair Diskus 500/50 treatment group had a
mean change from Baseline of 10 in Overall score. This improvement meets
the predefined minimal change of 10 to be considered as an overall
improvement in COPD-specific quality of life. However, there was no
clinically meaningful difference in improvement between Advair and any
treatment group at Endpoint nor at any other timepoint. When Overall
scores were analyzed by smoking status, a clinically meaningful
improvement at Endpoint was seen in former smokers in the Advair Diskus
500/50 group but not in the current smokers in the Advair Diskus 500/50
treatment group. A clinically important improvement in the Overall score
was seen at all timepoints except at Week 2 for the Advair Diskus 500/50
group. However, there was no clinically important difference between
treatment groups at any timepoint. \[*See Table 17 below\]*

Table 17 - Summary of CRDQ Overall Score Results from Baseline at
Endpoint and other Timepoints by Smoking Status \[data from tables 8.29
--8.85 SFCA3006.pdf\]

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 3%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4">Current Smokers</td>
<td></td>
<td colspan="4">Former Smokers</td>
</tr>
<tr class="even">
<td>Timepoint</td>
<td><p>Placebo</p>
<p>N=97</p></td>
<td><p>SAL</p>
<p>N=74</p></td>
<td><p>FP 500</p>
<p>N=77</p></td>
<td><p>Advair 500/50</p>
<p>N=76</p></td>
<td></td>
<td><p>Placebo</p>
<p>N=84</p></td>
<td><p>SAL 50</p>
<p>N=86</p></td>
<td><p>FP 500</p>
<p>N=91</p></td>
<td><p>Advair 500/50</p>
<p>N=89</p></td>
</tr>
<tr class="odd">
<td>Endpoint</td>
<td>N=94</td>
<td>N=73</td>
<td>N=74</td>
<td>N=74</td>
<td></td>
<td>N=81</td>
<td>N=82</td>
<td>N=89</td>
<td>N=87</td>
</tr>
<tr class="even">
<td>Mean change</td>
<td>6.6</td>
<td>7.4</td>
<td>6.3</td>
<td>8.5</td>
<td></td>
<td>3.1</td>
<td>8.5</td>
<td>3.5</td>
<td>11.2</td>
</tr>
<tr class="odd">
<td>Week 2</td>
<td>N=89</td>
<td>N=69</td>
<td>N=71</td>
<td>N=71</td>
<td></td>
<td>N=65</td>
<td>N=81</td>
<td>N=86</td>
<td>N=82</td>
</tr>
<tr class="even">
<td>Mean change</td>
<td>4.4</td>
<td>4.8</td>
<td>7.2</td>
<td>7.7</td>
<td></td>
<td>1.8</td>
<td>7.1</td>
<td>4.6</td>
<td>9.1</td>
</tr>
<tr class="odd">
<td>Week 4</td>
<td>N=84</td>
<td>N=65</td>
<td>N=67</td>
<td>N=66</td>
<td></td>
<td>N=65</td>
<td>N=73</td>
<td>N=80</td>
<td>N=78</td>
</tr>
<tr class="even">
<td>Mean change</td>
<td>9</td>
<td>6.6</td>
<td>6.5</td>
<td>10</td>
<td></td>
<td>6.2</td>
<td>10.2</td>
<td>5.7</td>
<td>13</td>
</tr>
<tr class="odd">
<td>Week 8</td>
<td>N=78</td>
<td>N=62</td>
<td>N=62</td>
<td>N=63</td>
<td></td>
<td>N=62</td>
<td>N=70</td>
<td>N=76</td>
<td>N=72</td>
</tr>
<tr class="even">
<td>Mean change</td>
<td>9.8</td>
<td>6.9</td>
<td>10.8</td>
<td>12.8</td>
<td></td>
<td>7.7</td>
<td>10.8</td>
<td>8.1</td>
<td>15.6</td>
</tr>
<tr class="odd">
<td>Week 24</td>
<td>N=53</td>
<td>N=47</td>
<td>N=39</td>
<td>N=46</td>
<td></td>
<td>N=49</td>
<td>N=60</td>
<td>N=56</td>
<td>N=54</td>
</tr>
<tr class="even">
<td>Mean change</td>
<td>10.1</td>
<td>12.3</td>
<td>11.7</td>
<td>11.4</td>
<td></td>
<td>7.6</td>
<td>10.9</td>
<td>9</td>
<td>14.5</td>
</tr>
</tbody>
</table>

For the individual domains a difference in the mean change from Baseline
at Endpoint among treatment groups was considered clinically meaningful
if the difference between groups was statistically significant and met
the 0.5 point improvement per item criterion. Using the 0.5 point
improvement per item criterion, an improvement in the domains and the
summary score was determined by the number of items in the domain x 0.5
points. Therefore, a clinically meaningful improvement in a domain would
be as follows:

  ----------------------------------- -----------------------------------
  Dyspnea domain                      2.5 point improvement

  Emotional function domain           3.5 point improvement

  Fatigue domain                      2.0 point improvement

  Mastery domain                      2.0 point improvement
  ----------------------------------- -----------------------------------

Subjects in the Advair Diskus 500/50 group achieved clinically important
improvements at Endpoint in the Dyspnea and Fatigue domains only
whereas, subjects in the SAL 50 group achieved a clinically important
improvement at Endpoint in the Dyspnea domain only. None of the other
treatment groups achieved clinically important improvements at Endpoint
in any of the domains. However, in across treatment comparisons, Advair
Diskus 500/50 did not have a clinically important improvement in any
domain at Endpoint or at any other timepoint.

Table 18 Summary of Mean Change from Baseline at Endpoint in CRDQ
Domains

+-----------------+---------+-------------+-------------+-------------+
|                 | Placebo | SAL 50      | FP 500      | Advair      |
|                 |         |             |             | Diskus      |
|                 | N=81    | N=160       | N=168       | 500/50      |
|                 |         |             |             |             |
|                 |         |             |             | N=165       |
+-----------------+---------+-------------+-------------+-------------+
| Dyspnea domain  |         |             |             |             |
|                 |         |             |             |             |
| \[clinically    |         |             |             |             |
| important       |         |             |             |             |
| change 2.5 \]   |         |             |             |             |
+-----------------+---------+-------------+-------------+-------------+
| Day 1 mean      | 17.4    | 17.9        | 18.2        | 18          |
+-----------------+---------+-------------+-------------+-------------+
| Endpoint mean   | 19.5    | 20.8        | 20.7        | 22.1        |
+-----------------+---------+-------------+-------------+-------------+
| Mean Change     | 2.1     | 2.9         | 2.4         | 4.2         |
+-----------------+---------+-------------+-------------+-------------+
| Fatigue domain  |         |             |             |             |
| \[\[clinically  |         |             |             |             |
| important       |         |             |             |             |
| change 2.0 \]   |         |             |             |             |
+-----------------+---------+-------------+-------------+-------------+
| Day 1 mean      | 15.1    | 15.5        | 15.6        | 15.5        |
+-----------------+---------+-------------+-------------+-------------+
| Endpoint mean   | 15.7    | 17.3        | 16.6        | 17.5        |
+-----------------+---------+-------------+-------------+-------------+
| Mean change     | 0.5     | 1.8         | 0.9         | 2           |
+-----------------+---------+-------------+-------------+-------------+
| Emotional       |         |             |             |             |
| function        |         |             |             |             |
| \[clinically    |         |             |             |             |
| important       |         |             |             |             |
| change 3.5 \]   |         |             |             |             |
+-----------------+---------+-------------+-------------+-------------+
| Day 1 mean      | 33.4    | 33.1        | 33.3        | 32.7        |
+-----------------+---------+-------------+-------------+-------------+
| Endpoint mean   | 35      | 35.8        | 34.4        | 35.2        |
+-----------------+---------+-------------+-------------+-------------+
| Mean change     | 1.4     | 2.6         | 0.9         | 2.5         |
+-----------------+---------+-------------+-------------+-------------+
| Mastery domain  |         |             |             |             |
| \[clinically    |         |             |             |             |
| important       |         |             |             |             |
| change 2.0 \]   |         |             |             |             |
+-----------------+---------+-------------+-------------+-------------+
| Day 1 mean      | 19.6    | 19.6        | 20.2        | 19.6        |
+-----------------+---------+-------------+-------------+-------------+
| Endpoint        | 20.7    | 21          | 20.8        | 21.3        |
+-----------------+---------+-------------+-------------+-------------+
| Mean change     | 1.1     | 1.3         | 0.6         | 1.8         |
+-----------------+---------+-------------+-------------+-------------+

RESULTS STUDY SFCA3007

**[Patient Disposition]{.underline}**

A total of 1,489 patients were screened, and 723 patients were
randomized and 766 failed screening. The most common reason for
screening failure \[516 subjects (67%)\] was not meeting the entrance
criteria of an FEV~1~/FVC of 70% and Baseline FEV~1~, of 65% predicted
but \>0.70 L. Of the 723 subjects randomized 178 were in the Advair
Diskus 250/50 group, 177 in the salmeterol group, 183 were in the
fluticasone Diskus 250 group, and 185 were in the placebo group. Two
hundred and eighteen subjects \[30%\] withdrew from the study prior to
completion and 505 (70%) completed the study.

**Table 19 - Patient Disposition ITT Population SFCA 3007 \[*Data source
SFCA3007.pdf pg. 81*\]**

+-----------------+---------+---------+--------+------------+--------+
|                 | **      | **SAL   | **FP   | **Advair   | **T    |
|                 | Placebo | 50**    | 250**  | Diskus     | otal** |
|                 | n       |         |        | 250/50**   |        |
|                 | =-185** | **      | **n    |            | **N    |
|                 |         | n=177** | =183** | **n =178** | =723** |
+-----------------+---------+---------+--------+------------+--------+
| \# (%) Complete | 126     | 121     | 133    | 125 (70%)  | 505    |
|                 | (68%)   | (68%)   | (73%)  |            | (70%)  |
+-----------------+---------+---------+--------+------------+--------+
| \# (%)          | 59(32%) | 56      | 50     | 53 (30%)   | 218    |
| Withdrawn       |         | (32%)   | (27%)  |            | (30%)a |
+-----------------+---------+---------+--------+------------+--------+
| Reason for      |         |         |        |            |        |
| Withdrawal      |         |         |        |            |        |
+-----------------+---------+---------+--------+------------+--------+
| Lack of         | 14      | 8       | 6 (3%) | 3 (2%)     | 31     |
| Efficacy        | (7.5%)  | (4.5%)  |        |            | (4%)   |
+-----------------+---------+---------+--------+------------+--------+
| ^a^Adverse      | 7 (4%)  | 6 (3%)  | 9 (5%) | 9 (5%)     | 31     |
| Event           |         |         |        |            | (      |
|                 |         |         |        |            | 4%)^b^ |
+-----------------+---------+---------+--------+------------+--------+
| Protocol        | 9 (5%)  | 8       | 9 (5%) | 7 (4%)     | 33     |
| violation       |         | (4.5%)  |        |            | (4.5%) |
+-----------------+---------+---------+--------+------------+--------+
| Consent         | 11 (6%) | 9       | 5 (3%) | 10 (5%)    | 35     |
| withdrawn       |         | (4.5%)  |        |            | (5%)   |
+-----------------+---------+---------+--------+------------+--------+
| Lost to follow  | 0       | 3 (2%)  | 4 (2%) | 6 (3%)     | 13     |
| up              |         |         |        |            | (2%)   |
+-----------------+---------+---------+--------+------------+--------+
| COPD            | 14      | 17      | 13     | 15 (8.4%)  | 59     |
| exacerbation    | (7.5%)  | (9.6%)  | (7%)   |            | (8%)   |
+-----------------+---------+---------+--------+------------+--------+
| **\***Other     | 4 (2%)  | 5 (3%)  | 4 (2%) | 3 (2%)     | 17 (2  |
|                 |         |         |        |            | %)     |
+-----------------+---------+---------+--------+------------+--------+
| \*Other:        |         |         |        |            |        |
| include         |         |         |        |            |        |
| noncompliance,  |         |         |        |            |        |
| subject         |         |         |        |            |        |
| relocation,     |         |         |        |            |        |
| site closure,   |         |         |        |            |        |
| and surgery     |         |         |        |            |        |
|                 |         |         |        |            |        |
| *a The number   |         |         |        |            |        |
| of subjects     |         |         |        |            |        |
| withdrawing due |         |         |        |            |        |
| to AE is 37 per |         |         |        |            |        |
| data listing    |         |         |        |            |        |
| 9.4 pg. 5770    |         |         |        |            |        |
| --5785          |         |         |        |            |        |
| SFCA3007.pdf.   |         |         |        |            |        |
| This number of  |         |         |        |            |        |
| withdrawals     |         |         |        |            |        |
| includes 7 COPD |         |         |        |            |        |
| exacerbations.  |         |         |        |            |        |
| Excluding the   |         |         |        |            |        |
| COPD            |         |         |        |            |        |
| exacerbations   |         |         |        |            |        |
| listed in       |         |         |        |            |        |
| listing 9.4 the |         |         |        |            |        |
| number of       |         |         |        |            |        |
| withdrawals due |         |         |        |            |        |
| to AE is 30 and |         |         |        |            |        |
| not 31 as       |         |         |        |            |        |
| stated in the   |         |         |        |            |        |
| table. Other    |         |         |        |            |        |
| difficulties in |         |         |        |            |        |
| interpreting    |         |         |        |            |        |
| these data      |         |         |        |            |        |
| include the     |         |         |        |            |        |
| lack of a       |         |         |        |            |        |
| definition of   |         |         |        |            |        |
| "lack of        |         |         |        |            |        |
| efficacy", and  |         |         |        |            |        |
| the failure to  |         |         |        |            |        |
| explain when a  |         |         |        |            |        |
| COPD            |         |         |        |            |        |
| exacerbation is |         |         |        |            |        |
| counted as AE   |         |         |        |            |        |
| and when it is  |         |         |        |            |        |
| not. In the     |         |         |        |            |        |
| in-text table   |         |         |        |            |        |
| on page 81 from |         |         |        |            |        |
| which the data  |         |         |        |            |        |
| in this table   |         |         |        |            |        |
| are obtained,   |         |         |        |            |        |
| withdrawals due |         |         |        |            |        |
| to AE, and due  |         |         |        |            |        |
| to COPD are     |         |         |        |            |        |
| counted         |         |         |        |            |        |
| separately.     |         |         |        |            |        |
| However, in the |         |         |        |            |        |
| listing         |         |         |        |            |        |
| "withdrawals    |         |         |        |            |        |
| due to AEs"     |         |         |        |            |        |
| \[listing 9.4\] |         |         |        |            |        |
| 7 COPD events   |         |         |        |            |        |
| are included.*  |         |         |        |            |        |
+-----------------+---------+---------+--------+------------+--------+

The number of withdrawals due to COPD exacerbations were similar across
treatment groups but was slightly higher in the Advair Diskus 250/50 and
SAL 50 groups compared to placebo.

Medication Compliance

Compliance was assessed based on the dose counter on the Diskus device.
The median compliance was 96% in each treatment groups. A total of 560
(77%) of subjects had a compliance rate of 90%. Fourteen percent (99) of
subjects had compliance rates of 80% to \<90%, and 54(\~9%) had
compliance rates of \< 80%.

Demographics

Overall, 63 % \[457\] of the ITT patients were male. The percentage
across treatment groups ranged from 58% to 68%. Ninety-three percent of
patients \[675\] were Caucasian, 4% were Black, and the remainder were
Asian or of other races. Patient ages ranged from 40 to 87 years. There
were 342 \[47%\] current smokers and 381 \[53%\] former smokers. The
majority of subjects \[541, 75%\] were not taking inhaled
corticosteroids prior to screening. The majority of subjects \[483;
67%\] reported having emphysema. A slightly higher percentage of
patients in the Advair Diskus 250/50 treatment group were former smokers
(57%) compared to the other treatment groups (range 49% -53%). The
median number of pack-years smoked was similar among treatment groups
and ranged from 53 to 60 pack-years. A total of 398 patients were
stratified as reversible, and 324 were non-reversible. The demographic
characteristics for the reversible and the non-reversible population
were generally similar to that of the overall ITT population.

Table 20 - Characteristics of the Intent-to Treat population \[SFCA
3007\]

+------------+-----------+-----------+--------------+-----------------+
|            | **        | **SAL     | **FP 250**   | **Advair Diskus |
|            | Placebo** | 50**      |              | 250/50**        |
|            |           |           | **N= 183**   |                 |
|            | **N =     | **N=      |              | **N =178**      |
|            | 185**     | 177^a^**  |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| Age (yrs)  | 64.8      | 64.2      | 63.3         | 63.4            |
|            |           |           |              |                 |
| Mean       | 40-81     | 42-87     | 40-84        | 40-87           |
|            |           |           |              |                 |
| Range      |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| Gender     | 126 (68%) | 102 (58%) | 121 (66%)    | 108 (59%)       |
|            |           |           |              |                 |
| Male       | 59 (32%)  | 75 (42%)  | 62 (34%)     | 70 (41%)        |
|            |           |           |              |                 |
| Female     |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| Race       | 173 (94%) | 165 (93%) | 167 (91%)    | 170 (95%)       |
|            |           |           |              |                 |
| Caucasian  | 6 (3%)    | 7 (4%)    | 9 (5%)       | 5 (3%)          |
|            |           |           |              |                 |
| Black      | 6 (3%)    | 5 (3%)    | 7 (4%)       | 3 (2%)          |
|            |           |           |              |                 |
| A          |           |           |              |                 |
| sian/Other |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| Median     | 6.00      | 6.00      | 6.00         | 6.00            |
| Duration   |           |           |              |                 |
| of COPD    |           |           |              |                 |
| (yrs)      |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| Emphysema  | 126       | 142       | 132 \[72\]   | 137 \[77\]      |
|            | \[68\]    | \[80\]    |              |                 |
| Yes        |           |           | 51 \[28\]    | 41 \[23\]       |
|            | 59 \[32\] | 35 \[20\] |              |                 |
| No         |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| Inhaled    | 130 (70%) | 142 (80%) | 132 (74%)    | 137 (77%)       |
| steroids   |           |           |              |                 |
| at         | 55 (30%)  | 35 (20%)  | 51 (26%)     | 41 (23%)        |
| screening  |           |           |              |                 |
|            |           |           |              |                 |
| No         |           |           |              |                 |
|            |           |           |              |                 |
| Yes        |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| Former     | 98 (53%)  | 87 (49%)  | 95 (52%)     | 101 (57%)       |
| Smoker     |           |           |              |                 |
|            | 87 (47%)  | 90 (51%)  | 88 (48%)     | 77 (43%)        |
| Current    |           |           |              |                 |
| Smoker     |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| \*MMRC     | 118 (64%) | 120 (68%) | 116 (63%)    | 109 (61%)       |
| Dyspnea    |           |           |              |                 |
| Score      | 58 (31%)  | 49 (28%)  | 63 (34%)     | 63 (35%)        |
|            |           |           |              |                 |
| 2          | 9 (5%)    | 8 (4%)    | 2 (3%)       | 6 (4%)          |
|            |           |           |              |                 |
| 3          |           |           |              |                 |
|            |           |           |              |                 |
| 4          |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+
| ^a^ Total  |           |           |              |                 |
| number in  |           |           |              |                 |
| SAL 50     |           |           |              |                 |
| group 176  |           |           |              |                 |
| \[79       |           |           |              |                 |
| non-r      |           |           |              |                 |
| eversible, |           |           |              |                 |
| 97         |           |           |              |                 |
| re         |           |           |              |                 |
| versible\] |           |           |              |                 |
| per        |           |           |              |                 |
| sponsor's  |           |           |              |                 |
| submission |           |           |              |                 |
| 10/17/2001 |           |           |              |                 |
| *res       |           |           |              |                 |
| ponse.pdf* |           |           |              |                 |
| pg. 13     |           |           |              |                 |
| making     |           |           |              |                 |
| total      |           |           |              |                 |
| subjects   |           |           |              |                 |
| in ITT     |           |           |              |                 |
| population |           |           |              |                 |
| 722 and    |           |           |              |                 |
| not 723    |           |           |              |                 |
|            |           |           |              |                 |
| \*Two      |           |           |              |                 |
| subjects   |           |           |              |                 |
| in the FP  |           |           |              |                 |
| 250 group  |           |           |              |                 |
| had        |           |           |              |                 |
| missing    |           |           |              |                 |
| data       |           |           |              |                 |
+------------+-----------+-----------+--------------+-----------------+

The screening spirometry results for the ITT population were consistent
with moderate airflow obstruction with FEV~1~% predicted ranging from
41.37% to 42.05% across treatment groups. The FEV~1~/FVC x100 ratio
ranged from 49. 48% to 51.29%. The spirometry results for the reversible
and the non-reversible population were also consistent with moderate
airflow obstruction with FEV~1~ % predicted ranging from 40.37% to 42.67
% for the reversible population and 41.19% and 42% for the
non-reversible population. The bronchodilator response for the ITT
population ranged from 19.53% to 21.31% across treatment groups. The
reversible subjects had a bronchodilator response ranging from 29.88% to
30.87%, while the non-reversible population had a bronchodilator
response ranging from 7.93% -8.58%. The table below summarizes the
screening spirometry and bronchodilator response results for the ITT,
reversible and non-reversible populations.

> Table 21 - Screening Spirometry and Bronchodilator Response SFCA3007

  ----------------------- ---------------- ----------- -------------- ------------
                          Placebo          SAL         FP 250         Advair
                                                                      250/50

                          ITT Population                              

  Randomized n            185              177         183            178

  Mean FEV~1~ \[mL\]      1289             1245        1313           1252

  FEV~1~ % predicted      42.05            41.94       41.96          41.37

  FEV~1~/FVC x100         49.63            50.83       51.29          49.48

  Bronchodilator response 20.24            21.31       19.53          20.14
  \[%}                                                                

                          Reversible                                  
                          Population                                  

  Randomized n            102              97          100            99

  Mean FEV~1~ \[mL\]      1313             1235        1359           1286

  FEV~1~ % predicted      42.67            40.37       42.59          40.87

  FEV~1~/FVC x100         51.01            50.81       52.16          49.56

  Bronchodilator response 29.72            30.87       28.93          29.88
  \[%}                                                                

                          Non-reversible                              
                          Population                                  

  Randomized n            83               79          83             79

  Mean FEV~1~ \[mL\]      1259             1245        1256           1208

  FEV~1~ % predicted      41.29            43.64       41.19          42.00

  FEV~1~/FVC x100         47.94            50.69       50.19          49.37

  Bronchodilator response 8.58             9.56        8.19           7.93
  \[%}                                                                
  ----------------------- ---------------- ----------- -------------- ------------

EFFICACY RESULTS SFCA3007

**[Primary Efficacy Results]{.underline}**

[Change from baseline in mean morning pre-dose FEV~1~ at
endpoint]{.underline}

This endpoint evaluates the effect of FP 250 in the combination product.
The comparison of interest is between Advair 250/50 and salmeterol 50.
The mean changes are displayed in the table below. Endpoint refers to
the last post-Baseline assessment (excluding the Discontinuation Visit),
the post-Baseline Ns stated were used for the mean change calculation.

Table 22 - Mean Change \[mL\] from Baseline in Pre-Dose FEV~1~ SFCA3007

  -------------- ---------------- -------------- -------------- --------------
                 Placebo          SAL            FP 250         Advair 250/50

                 ITT Population                                 

  Baseline n     185              177            183            178

  Mean FEV~1~    1232             1205           1236           1207
  \[mL\]                                                        

  Endpoint n     172              168            175            171

  Mean FEV~1~    1240             1303           1351           1375
  \[mL\]                                                        

  Mean change    1                91^a^          109^a^         165^ab^

                 Reversible                                     
                 Population                                     

  Baseline n     102              97             100            99

  Mean FEV~1~    1327             1237           1350           1284
  \[mL\]                                                        

  Endpoint n     93               93             96             96

  Mean FEV1      1325             1389           1500           1476
  \[mL\]                                                        

  Mean change    -15              141            138            196

                 Non-reversible                                 
                 Population                                     

  Baseline n     83               79             83             79

  Mean FEV~1~    1116             1151           1098           1111
  \[mL\]                                                        

  Endpoint n     79               74             79             75

  Mean FEV~1~    1141             1176           1170           1245
  \[mL\]                                                        

  Mean change    19               26             74             116
  -------------- ---------------- -------------- -------------- --------------

a p0.005 vs. placebo

b p=0.012 vs. SAL 50

For the ITT population, mean improvement in AM pre-dose FEV~1~ at
Endpoint in the Advair Diskus 250/50 group was 165 mL compared with 91mL
in the SAL 50 group \[p = 0.012\]. The model-adjusted mean difference
was, 69 mL\[p=0.012\].

For the primary endpoint "mean change from Baseline in pre-dose FEV~1~",
the mean treatment difference between Advair 250/50 and placebo was 211
mL for the reversible population and 97 mL for the non-reversible
population. Numerically, this is equivalent to a treatment difference in
the reversible population that was twice the treatment effect seen in
the non-reversible population. Inferential statistics were not done on
these subgroups.

Over the 24 weeks of treatment, mean changes from Baseline in AM
pre-dose FEV~1~ ranged from 153 mL to 189 mL \[15.8% to 19.2%\] for the
Advair Diskus 250/50 group, 102 mL to 129 mL \[9.2% to 12.8%\] for the
SAL 50 group, 83 mL to 118 mL \[7.3% to 11.3%\] for the FP 250 group and
3 mL to 49 mL \[0.5% to 5.6%\] for the placebo group. Similar to study
SFCA3006, Advair Diskus 250/50 had numerically greater improvements in
AM Pre-dose FEV~1~ at all timepoints throughout the study compared to
its individual components and placebo.

Mean Change from Baseline in 2-hour Post-Dose FEV~1~

The comparison of interest is Advair 250/50 vs. FP 250. There was a
statistically significant greater increase in the 2-hr post-dose FEV~1~
at Endpoint in the Advair 250/50 treatment group \[281 mL, 27.0%\]
compared with FP 250 \[147 mL, 13.8%\], placebo \[58 mL, 5.9%\], and SAL
50 \[200 mL, 19.0%\] p0.007.The results are displayed in the table
below.

Table 23 - Mean change \[mL\] from Baseline in 2-hour Post-Dose FEV~1~
ITT Population- Study SFCA3007 \[Data from Tables 7.4-7.5 SFCA3007.pdf\]

+-------------+-------------+-------------+--------+------------------+
|             | Placebo     | SAL 50      | FP 250 | Advair Diskus    |
|             |             |             |        | 250/50           |
|             | N=185       | N=177       | N=183  |                  |
|             |             |             |        | N=178            |
+-------------+-------------+-------------+--------+------------------+
| Baseline n  | 185         | 177         | 166    | 163              |
+-------------+-------------+-------------+--------+------------------+
| Mean FEV~1~ | 1232        | 1205        | 1236   | 1207             |
| \[mL\]      |             |             |        |                  |
+-------------+-------------+-------------+--------+------------------+
| Endpoint n  | 172         | 168         | 175    | 171              |
+-------------+-------------+-------------+--------+------------------+
| Mean 2-hour | 1298        | 1413        | 1389   | 1490             |
| post-dose   |             |             |        |                  |
| FEV~1~ at   |             |             |        |                  |
| Endpoint    |             |             |        |                  |
| \[mL\]      |             |             |        |                  |
+-------------+-------------+-------------+--------+------------------+
| Mean change | 58          | 200         | 147    | 281              |
| from        |             |             |        |                  |
| Baseline in | .           |             |        |                  |
| morning     |             |             |        |                  |
| 2-hour      |             |             |        |                  |
| post-dose   |             |             |        |                  |
| FEV~1~      |             |             |        |                  |
| \[mL\]      |             |             |        |                  |
+-------------+-------------+-------------+--------+------------------+

The mean change in post-dose FEV~1~ for the Advair 250/50 group compared
with placebo was numerically greater \[282 mL\] in the reversible
population compared with the non-reversible population \[150 mL\]. Again
no inferential analyses were conducted in these subgroups.

Table 24 - Summary of mean Change \[mL\] in Post-Dose FEV~1~

  ---------- ------------ ------ ------ --------- -- ---------------- ------ ------ --------
             Reversible                              Non-Reversible                 

             Placebo      SAL 50 FP 250 Advair       Placebo          SAL 50 FP 250 Advair
                                        250/50                                      250/50

  Baseline n 102          97     100    99           83               79     83     79

  Mean       1327         1237   1350   1284         1116             1151   1098   1111
  \[mL\]                                                                            

  Endpoint n 93           93     96     96           79               74     79     75

  Mean       1386         1510   1541   1608         1194             1270   1203   1340

  Mean       46           262    179    328          71               119    107    221
  change                                                                            
  \[mL\]                                                                            
  ---------- ------------ ------ ------ --------- -- ---------------- ------ ------ --------

SECONDARY EFFICACY MEASURES

Diary Data

AM PEF

There were numerically greater improvements in AM PEF in the Advair
Diskus 250/50 group throughout the study compared to all other treatment
groups. The mean change from Baseline in AM PEF at Endpoint was 30.6
L/min for the Advair Diskus 250/50 group compared with 0.8 L/min for the
placebo group, 11.3 L/min for the SAL 50 group and 14.7L/min for the FP
250 group. The AM PEF results are summarized in Table 25.

Table 25 - AM PEF Results SFCA3007

+-------------+-------------+-------------+-------------+-------------+
| Time Point  | Placebo     | SAL 50      | FP 250      | Advair      |
|             |             |             |             | Diskus      |
|             |             |             |             | 250/50      |
+-------------+-------------+-------------+-------------+-------------+
| Baseline    | 184         | 176         | 182         | 175         |
|             |             |             |             |             |
| N           | 220.3       | 210.3       | 220.0       | 206.1       |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Month 3     | 149         | 146         | 154         | 152         |
|             |             |             |             |             |
| N           | 225.2       | 228.9       | 231.5       | 240.2       |
|             |             |             |             |             |
| Mean        | 2.1         | 15.8        | 12.2        | 34.7        |
|             |             |             |             |             |
| Mean change |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Month 6     | 128         | 124         | 136         | 130         |
|             |             |             |             |             |
| N           | 230.0       | 235.9       | 242.6       | 246.4       |
|             |             |             |             |             |
| Mean        | 6.9         | 17.0        | 17.9        | 38.6        |
|             |             |             |             |             |
| Mean change |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Overall     | 183         | 174         | 177         | 173         |
|             |             |             |             |             |
| N           | 220.2       | 225.3       | 230.7       | 236.3       |
|             |             |             |             |             |
| Mean        | 0.8         | 14.7        | 11.3        | 30.6        |
|             |             |             |             |             |
| Mean change |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

Ventolin Use

The mean number of puffs of Ventolin used per day was similar across
treatment groups and ranged from 5.1 to 4.8 puffs. Over the course of
the study, mean changes from Baseline in daily Ventolin use were very
small and ranged from --1.1 puffs to --0.9 puffs for the Advair Diskus
250/50 group to --0.1 puffs to 0.1 puffs for the placebo group.

Nighttime Awakenings/Night Requiring Ventolin

At Baseline there were very few awakenings at night requiring Ventolin
use. The mean number of nighttime awakenings ranged from 0.20 to 0.24
awakenings/night equivalent to one nighttime awakening every 5 to 4.2
nights. The overall changes in mean number of nighttime awakenings were
--0.12 for Advair Diskus 250/50, -0.03, -0.06, and 0.02 for FP 250, SAL,
and placebo respectively. These changes correspond to one nighttime
awakening requiring Ventolin use every 8, 5, 7, or 4 nights for the
Advair Diskus 250/50, FP 250, SAL 50 and placebo group respectively.

Chronic Bronchitis Symptoms Questionnaire

The results for study SFCA3007 are shown in table 26. The results are
similar to the results seen in SFCA3006. All treatment groups
\[including placebo\] had a mean change at endpoint that met the MCIC.
However, the difference between placebo and Advair Diskus, or its
individual components did not constitute a clinically meaningful change.

Table 26 - Summary of Mean Change from Baseline in CBSQ GAS

ITT Population SFCA3007

+-------------------+-------------+-------------+----------+----------+
| Time Point        | Placebo     | SAL 50      | FP 250   | Advair   |
|                   |             |             |          | 250/50   |
+-------------------+-------------+-------------+----------+----------+
| Treatment Day 1   | 185         | 177         | 183      | 178      |
| (Baseline)        |             |             |          |          |
|                   | 7.5         | 7.0         | 7.4      | 7.3      |
| N                 |             |             |          |          |
|                   |             |             |          |          |
| Mean              |             |             |          |          |
+-------------------+-------------+-------------+----------+----------+
| Week 12           | 139         | 136         | 147      | 144      |
|                   |             |             |          |          |
| N                 | 6.0         | 5.4         | 5.2      | 5.0      |
|                   |             |             |          |          |
| Mean              | 1.4         | 1.6         | 2.2      | 2.3      |
|                   |             |             |          |          |
| Mean change       |             |             |          |          |
+-------------------+-------------+-------------+----------+----------+
| Week 24           | 126         | 121         | 133      | 125      |
|                   |             |             |          |          |
| N                 | 5.6         | 5.2         | 4.9      | 4.8      |
|                   |             |             |          |          |
| Mean              | 1.8         | 1.9         | 2.5      | 2.5      |
|                   |             |             |          |          |
| Mean change       |             |             |          |          |
+-------------------+-------------+-------------+----------+----------+
| Endpoint          | 172         | 169         | 175      | 172      |
|                   |             |             |          |          |
| N                 | 6.1         | 5.6         | 5.2      | 5.2      |
|                   |             |             |          |          |
| Mean              | 1.4         | 1.5         | 2.2      | 2.1      |
|                   |             |             |          |          |
| Mean change       |             |             |          |          |
+-------------------+-------------+-------------+----------+----------+

Baseline/Transition Dyspnea Index (BDI/TDI)

Baseline scores (Treatment day 1) ranged from 5.7 to 6.2 Mean TDI scores
were comparable for all three active treatment groups at Endpoint as
shown in Table 27.

Table 27 - Summary of BDI/TDI Total Score ITT Population SFCA3007

+-------------+-------------+-------------+-------------+-------------+
| Time Point  | Placebo     | SAL 50      | FP 250      | Advair      |
|             |             |             |             | Diskus      |
|             |             |             |             | 250/50      |
+-------------+-------------+-------------+-------------+-------------+
| Day 1 (BDI) | 183         | 176         | 179         | 174         |
|             |             |             |             |             |
| N           | 5.7         | 6.1         | 6.2         | 6.1         |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 12     | 139         | 136         | 147         | 144         |
|             |             |             |             |             |
| N           | 1.5         | 1.5         | 1.6         | 1.8         |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 24     | 126         | 121         | 132         | 125         |
| (TDI)       |             |             |             |             |
|             | 1.7         | 1.8         | 2.0         | 2.4         |
| N           |             |             |             |             |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Endpoint    | 172         | 169         | 175         | 172         |
| (TDI)       |             |             |             |             |
|             | 1.0         | 1.6         | 1.7         | 1.7         |
| N           |             |             |             |             |
|             |             |             |             |             |
| Mean        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

Exacerbations of COPD

The highest incidence of COPD exacerbations occurred in the FP 250 and
Advair 250/50 groups and lowest in the SAL group. Thirty-seven (37%)
percent of subjects in the SAL group, 39% in the placebo group, 40% in
the Advair 250/50 group and 43% in the FP 250 group experienced one or
more COPD exacerbations. The SAL group also had the lowest percentage of
moderate/severe exacerbations. Based on the sponsor's definition of
severity \[*see pg.25*\], 31% of subjects in the SAL group, 34% of
subjects in the placebo and Advair Diskus 250/50 groups, and 38% of
subjects in the FP 250 group had moderate/severe exacerbations. The time
to first COPD exacerbation and the number of withdrawals due to COPD
exacerbations were similar among treatment groups.

Subgroup Analysis by Smoking Status

For the primary endpoint change from Baseline in pre-dose FEV~1~ current
smokers had a numerically greater mean treatment effect \[107 ml\]
compared with former smokers \[31 m\] for the comparison Advair 250/50
vs. SAL. For the primary endpoint change from Baseline in 2-hr post-dose
FEV~1~, former smokers had a numerically similar effect \[138 ml\]
compared with current smokers \[124 ml\] for the comparison Advair
250/50 vs. FP 250. No inferential analyses for these subgroups were
done. The primary efficacy results by smoking status are displayed in
the table.

Table 28 - Summary of Efficacy Results Displayed by Smoking Status

+-------+-------+------+-------+-------+-------+-------+-------+-------+
|       | F     |      |       |       | Cu    |       |       |       |
|       | ormer |      |       |       | rrent |       |       |       |
|       | Sm    |      |       |       | Sm    |       |       |       |
|       | okers |      |       |       | okers |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+-------+
| Eff   | Pl    | SAL  | FP    | A     | Pl    | SAL   | FP250 | A     |
| icacy | acebo |      | 250   | dvair | acebo |       |       | dvair |
| Var   |       | N=90 |       | 2     |       | N=87  | N=95  | 2     |
| iable | N=87  |      | N=88  | 50/50 | N=98  |       |       | 50/50 |
|       |       |      |       |       |       |       |       |       |
|       |       |      |       | N=77  |       |       |       | N=101 |
+-------+-------+------+-------+-------+-------+-------+-------+-------+
| Pre   |       |      |       |       |       |       |       |       |
| -Dose |       |      |       |       |       |       |       |       |
| F     |       |      |       |       |       |       |       |       |
| EV~1~ |       |      |       |       |       |       |       |       |
| (mL)  |       |      |       |       |       |       |       |       |
| C     |       |      |       |       |       |       |       |       |
| hange |       |      |       |       |       |       |       |       |
| from  |       |      |       |       |       |       |       |       |
| Bas   |       |      |       |       |       |       |       |       |
| eline |       |      |       |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+-------+
| Mean  | 4     | 96   | 80    | 127   | -3    | 86    | 136   | 193   |
| c     |       |      |       |       |       |       |       |       |
| hange |       |      |       |       |       |       |       |       |
| at    |       |      |       |       |       |       |       |       |
| End   |       |      |       |       |       |       |       |       |
| point |       |      |       |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+-------+
| 2-Hr  |       |      |       |       |       |       |       |       |
| Post  |       |      |       |       |       |       |       |       |
| -Dose |       |      |       |       |       |       |       |       |
| F     |       |      |       |       |       |       |       |       |
| EV~1~ |       |      |       |       |       |       |       |       |
| (mL)  |       |      |       |       |       |       |       |       |
| C     |       |      |       |       |       |       |       |       |
| hange |       |      |       |       |       |       |       |       |
| from  |       |      |       |       |       |       |       |       |
| Bas   |       |      |       |       |       |       |       |       |
| eline |       |      |       |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+-------+
| Mean  | 52    | 222  | 115   | 253   | 64    | 177   | 176   | 301   |
| C     |       |      |       |       |       |       |       |       |
| hange |       |      |       |       |       |       |       |       |
| at    |       |      |       |       |       |       |       |       |
| End   |       |      |       |       |       |       |       |       |
| point |       |      |       |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+-------+
| Trans |       |      |       |       |       |       |       |       |
| ition |       |      |       |       |       |       |       |       |
| Dy    |       |      |       |       |       |       |       |       |
| spnea |       |      |       |       |       |       |       |       |
| Index |       |      |       |       |       |       |       |       |
| (TDI) |       |      |       |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+-------+
| Mean  | 1.1   | 1.7  | 1.6   | 1.6   | 0.9   | 1.5   | 1.8   | 1.8   |
| at    |       |      |       |       |       |       |       |       |
| End   |       |      |       |       |       |       |       |       |
| point |       |      |       |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+-------+

HEALTH OUTCOMES RESULTS

COPD-related quality of life was evaluated using the CRDQ in the same
manner as for study SFCA3006. The same criteria were used to define the
Reduced ITT Population. A total of 705 out of 723 randomized subjects
were included in the Reduced ITT Population. At Endpoint, subjects in
the Advair Diskus 250/50 and FP 250 treatment group had a mean change
from Baseline in the Overall CRDQ score of 10 thereby meeting the
predefined minimal change considered as an overall improvement in
COPD-related quality of life. There was no clinically meaningful
improvement between any treatment group neither at Endpoint or any other
timepoint. When Overall scores were analyzed by smoking status, a
clinically meaningful improvement at Endpoint was seen in current
smokers in the Advair Diskus 250/50 group and in former smokers in the
FP 250 group. The results of the Overall score are summarized in the
table below.

Table 29 - Mean Change from Baseline in Overall CRDQ Score at Endpoint
and other Timepoints SFCA3007 ITT population

<table>
<colgroup>
<col style="width: 18%" />
<col style="width: 10%" />
<col style="width: 1%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 1%" />
<col style="width: 8%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 1%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Timepoint</td>
<td colspan="3">Placebo</td>
<td colspan="3">SAL 50</td>
<td colspan="3">FP 250</td>
<td colspan="4">Advair Diskus 250/50</td>
</tr>
<tr class="even">
<td><p>Day1</p>
<p>N</p>
<p>Mean [SD]</p></td>
<td colspan="3"><p>180</p>
<p>84.8 [17.8]</p></td>
<td colspan="3"><p>173</p>
<p>86.3 [18]</p></td>
<td colspan="3"><p>177</p>
<p>85.5 [17.4]</p></td>
<td colspan="4"><p>175</p>
<p>84.1 [17.6]</p></td>
</tr>
<tr class="odd">
<td><p>Endpoint</p>
<p>N</p>
<p>Mean [SD]</p>
<p>Mean Change</p></td>
<td colspan="3"><p>177</p>
<p>89.6 [24.9]</p>
<p>5.0</p></td>
<td colspan="3"><p>170</p>
<p>93.0 [21.3]</p>
<p>6.4</p></td>
<td colspan="3"><p>170</p>
<p>96.4 [20.3]</p>
<p>10.4</p></td>
<td colspan="4"><p>169</p>
<p>93.9</p>
<p>10</p></td>
</tr>
<tr class="even">
<td><p>Week 2</p>
<p>N</p>
<p>Mean change from Baseline</p></td>
<td colspan="3"><p>161</p>
<p>3.8</p></td>
<td colspan="3"><p>158</p>
<p>6.2</p></td>
<td colspan="3"><p>161</p>
<p>5.2</p></td>
<td colspan="4"><p>162</p>
<p>7.5</p></td>
</tr>
<tr class="odd">
<td><p>Week 4</p>
<p>N</p>
<p>Mean change from Baseline</p></td>
<td colspan="3"><p>148</p>
<p>7.5</p></td>
<td colspan="3"><p>158</p>
<p>6.2</p></td>
<td colspan="3"><p>155</p>
<p>9.2</p></td>
<td colspan="4"><p>162</p>
<p>7.5</p></td>
</tr>
<tr class="even">
<td><p>Week 8</p>
<p>N</p>
<p>Mean change from Baseline</p></td>
<td colspan="3"><p>138</p>
<p>9.4</p></td>
<td colspan="3"><p>136</p>
<p>7.7</p></td>
<td colspan="3"><p>142</p>
<p>10.1</p></td>
<td colspan="4"><p>145</p>
<p>11.2</p></td>
</tr>
<tr class="odd">
<td><p>Week 24</p>
<p>N</p>
<p>Mean change from Baseline</p></td>
<td colspan="3"><p>116</p>
<p>9.4</p></td>
<td colspan="3"><p>113</p>
<p>10.3</p></td>
<td colspan="3"><p>122</p>
<p>13.6</p></td>
<td colspan="4"><p>119</p>
<p>13.3</p></td>
</tr>
<tr class="even">
<td></td>
<td colspan="6">Current Smokers</td>
<td colspan="7">Former Smokers</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><p>Placebo</p>
<p>N=83</p></td>
<td><p>SAL</p>
<p>N=87</p></td>
<td><p>FP 250</p>
<p>N=84</p></td>
<td colspan="2"><p>Advair 250/50</p>
<p>N=76</p></td>
<td colspan="2"><p>Placebo</p>
<p>N=98</p></td>
<td colspan="2"><p>SAL</p>
<p>N=86</p></td>
<td colspan="2"><p>FP 250</p>
<p>N=94</p></td>
<td><p>Advair 250/50</p>
<p>N=99</p></td>
</tr>
<tr class="even">
<td colspan="14">Mean Change in Overall CRDQ Score</td>
</tr>
<tr class="odd">
<td>Mean change at Endpoint</td>
<td>5.2</td>
<td colspan="2">6.6</td>
<td>9.5</td>
<td>11.2</td>
<td colspan="2">4.9</td>
<td colspan="2">6.3</td>
<td colspan="2">11.1</td>
<td colspan="2">9.1</td>
</tr>
</tbody>
</table>

Similar to the results in study SFCA3006, a clinically important
improvement in the Overall score was seen at all timepoints except at
Week 2 for the Advair Diskus 250/50 group. There was no clinically
important difference between treatment groups at any timepoint. In the
analysis of the individual Domains, all treatment groups \[including
placebo\] achieved A MCIC at Endpoint in the Dyspnea Domain. Advair
Diskus 250/50 also achieved a MCIC in the Fatigue Domain. Table 30
summarizes the changes at Endpoint in the individual domains.

Table 30 - Summary of Mean Change from Baseline at Endpoint in CRDQ
Domains

+-----------------------------------+-------+------+------+------------+
|                                   | Pl    | SAL  | FP   | Advair     |
|                                   | acebo | 50   | 250  | Diskus     |
|                                   |       |      |      | 250/50     |
+-----------------------------------+-------+------+------+------------+
| Dyspnea Domain \[MCIC 2.5\]       | 2.8   | 2.9  | 3.3  | 4.1        |
|                                   |       |      |      |            |
| Mean change                       |       |      |      |            |
+-----------------------------------+-------+------+------+------------+
| Fatigue Domain \[MCIC 2.0\]       | 1.5   | 0.9  | 1.7  | 2.5        |
|                                   |       |      |      |            |
| Mean Change                       |       |      |      |            |
+-----------------------------------+-------+------+------+------------+
| Emotional Function Domain \[MCIC  | 1.1   | 1.4  | 2.5  | 2.4        |
| 3.5\]                             |       |      |      |            |
|                                   |       |      |      |            |
| Mean Change                       |       |      |      |            |
+-----------------------------------+-------+------+------+------------+
| Mastery Domain                    | 1     | 0.9  | 1.8  | 1.9        |
|                                   |       |      |      |            |
| \[MCIC 2.0\] Mean Change          |       |      |      |            |
+-----------------------------------+-------+------+------+------------+

EFFICACY CONCLUSIONS

Summary

Advair Diskus 500/50 mcg and Advair Diskus 250/50 mcg both met the
established efficacy criteria for combination drug products as stated in
the Code of Federal Regulations. However except for dyspnea as evaluated
with the BDI/TDI with the 500/50 mcg dose, the efficacy of Advair Diskus
was not demonstrated for any of the secondary endpoints relevant to the
COPD indication. The patient population studied was not representative
of the COPD population at large in that \> 50% of the subjects showed
significant reversibility and the study was limited to only patients
with confirmed chronic bronchitis. The failure to demonstrate efficacy
with the secondary endpoints of relevance to COPD \[i.e. exacerbations,
CRDQ, CBSQ\] calls into question the clinical significance of the FEV~1~
findings. Taken together the efficacy data do not appear to support
broad-based efficacy conclusions in the proposed population. The
efficacy conclusions are outlined below in bulleted text.

Both Advair Diskus 500/50 mcg and Advair Diskus 250/50 mcg bid showed
statistically significant effect compared to placebo for each of the
primary endpoints "mean change from Baseline in pre-dose FEV~1~ and 2-hr
post-dose FEV~1~". Compared to their individual components FP 500 mcg
and 250 mcg and SAL 50 mcg, Advair Diskus 500/50 and Advair Diskus
250/50 had a statistically significant treatment effect. This finding
established from a regulatory standpoint the efficacy requirement for
Advair as a combination drug product in that both components contributed
to the effect of the combination.

-   When the primary efficacy endpoints were assessed by populations
    \[reversible vs. Non-reversible\], the reversible population had a
    treatment effect that was numerically greater \[63%\] than the
    treatment effect seen in the non-reversible population for both
    primary endpoints in both studies.

-   Advair Diskus 500/50 and 250/50 did not have a clinically meaningful
    change compared with placebo or any of its components in the chronic
    bronchitis questionnaire

-   Both studies failed in their quality of life objective. Compared to
    placebo or their individual components, neither Advair Diskus 500/50
    nor Advair Diskus 250/50 had a clinically meaningful change in
    COPD-related quality of life as assessed by the CRDQ.

-   In the assessment of dyspnea using the BDI/TDI, using a score of 1.0
    as clinically meaningful Advair 500/50 had a meaningful improvement
    in dyspnea compared with placebo and salmeterol, but Advair 250/50
    did not.

-   Treatment with Advair 500/50 and Advair 250/50 did not result in a
    significant decrease in the frequency or severity of COPD
    exacerbations nor the time to COPD exacerbations.

-   The percentage of withdrawals due to COPD exacerbations was similar
    for Advair Diskus and placebo in both studies.

-   Changes in nighttime awakenings requiring Ventolin use were
    numerically small and of questionable clinical value in assessing
    effect of therapy for the COPD population.

-   Inferential analyses in former smokers and current smokers were not
    conducted but the results seen for Advair Diskus in the overall ITT
    population did not appear to be affected by smoking status.

-   In study SFCA3006 74% of subjects on Advair 500/50 mcg bid achieved
    a 12% increase in FEV~1~ and at least 200 mL improvement above
    pre-dose FEV~1~ values on Treatment Day ~1~.

# VII. INTEGRATED REVIEW OF SAFETY

## CONCLUSIONS

The safety findings in the two pivotal studies SFCA3006, SFCA3007 were
similar. Safety findings in these two studies that were consistent with
corticosteroid effects were similar to findings in the Flovent study
FLTA3025.

The majority of the patients in the Advair studies were male Caucasians.
Minority races represented only 5% of the study population. Median age
was \~ 63 years and most patients had extensive smoking histories and
had a long-standing history of COPD. Exposure to study treatment was
adequate to assess safety over the 24-week active treatment period.

The frequency of adverse events was relatively high in the two studies.
A total of 1000 \[71%\] subjects from the two Advair studies reported at
least one adverse event. Subjects in the Advair and FP groups had the
highest incidence of adverse events \[75%\] compared to placebo 66%\] or
salmeterol. \[68%\] The incidence of AEs with Advair 250/50 was 70%
compared with 64% for placebo while in study SFCA3006 the incidence of
AEs with Advair 500/50 was 78% compared with 69% for placebo. There was
a high \[30% -36%\] dropout rate across all three studies\].

Adverse events occurring in Advair 500/50 and 250/50, FP 250, FP 500 or
salmeterol at a frequency 3% and more frequently than in placebo
included headache, upper respiratory tract infection, throat irritation,
upper respiratory inflammation, sinusitis/sinus infection, candidiasis,
hoarseness/dysphonia, musculoskeletal pain, muscle cramps and spasms and
viral infections.

Candidiasis of the mouth/throat, hoarseness/dysphonia, throat
irritation, and muscle cramps and spasms were highest in the in Advair
treatment groups compared to the other treatment arms in both studies.
Subjects treated with FP 250 and 500 in the two studies had higher
incidences of candidiasis, sinusitis, hoarseness/dysphonia, and viral
respiratory infections compared to placebo and salmeterol. Across
studies subjects treated with Advair or FP had higher incidences of
candidiasis, hoarseness/dysphonia and viral respiratory infections.
These AEs are listed in the current labeling for Flovent and Advair
Diskus.

Three deaths occurred in the placebo group during the study. Two were
related to malignancy and one was due to aspiration pneumonia following
surgery. There were no deaths in any active treatment group during the
study. A total of 74 \[5%\] patients \[including the 3 deaths
mentioned\] had a least one serious AE. None of the serious AEs appear
to be drug-related. Excluding deaths a total of 50 \[3.5%\] patients
withdrew from the study due to serious AEs.

There were some discrepancies in the number of subjects withdrawing from
the study due to adverse events in the sponsor's data tables and in-text
tables. However, the overall number of withdrawals due to AEs were
\[approximately 98(7%\]. None of the adverse events that led to
withdrawal appear to be drug-related. In general drug-related adverse
events were mainly limited to events that are known to be associated
with corticosteroid use \[i.e. candidiasis mouth/throat,
hoarseness/dysphonia, and throat irritation\].

The sponsor did not monitor bone mineral density in the Advair studies.
There were 13 reports of fractures. Six occurred in the Advair Diskus
groups, 2 in the FP 250/50 group, 4 in the placebo group, and one in the
salmeterol group. Case narratives were not provided for all the patients
who sustained fractures. One patient who received Advair 250/50
sustained a broken femur after a fall and two patients who received
Advair 500/50 were reported to have osteoporosis.

There were only 3 reports of cataracts and ocular pressure disorders
during the study. However, these adverse events were not specifically
monitored for during the studies.

The sponsor did an extensive cardiovascular evaluation with 12-lead ECGs
and 24-hour Holter monitoring. The cardiovascular-related adverse events
did not appear to be causally related to Advair and in. study SFCA3007,
the highest incidence of cardiovascular events was reported in the
placebo group, while in study SFCA3006 the incidence was similar across
treatment groups. An independent cardiologist evaluated QTc intervals.
There did not appear to be a relationship with QTc prolongation and
Advair in the two studies reviewed.

Relatively few reports of hyperglycemia were noted in the two studies.
However, the sponsor's threshold for hyperglycemia was \> 175 mg/dl.
With this liberal definition, a meaningful assessment of the effect of
Advair on blood glucose could not be made. Similarly, given the
sponsor's threshold for hypokalemia \[\<3.0\] it was difficult to assess
the effect \[if any\] of Advair on potassium levels. Changes in liver
function tests were generally similar among treatment groups.

The effect of Advair Diskus on HPA axis in COPD patients was evaluated
in a subset of patients in both Advair studies. The number of subjects
studied was relatively small. Neither of the studies had findings
suggestive of adrenal suppression, however Cosyntropin stimulation
testing is primarily intended for the diagnosis of adrenal insufficiency
rather than to detect or quantify the more subtle finding of HPA-axis
suppression. Therefore, these negative findings do not rule out the
occurrence of systemic corticosteroid effects due to inhaled fluticasone
in COPD patients, particularly with more long-term exposure.

In several supportive studies there has been substantial evidence of
systemic exposure. For example in an open-label 4-way crossover study
\[FLTA1003\] in which normal subjects received single doses of1000 mcg
of Flovent Diskus via four different dosage strengths, the mean 24-hour
urinary cortisol excretion was decreased by 42% to 62% compared to
baseline in all treatment groups. In pivotal study FLTA3025 serum
cortisol AUC~12~ measured at Week 4 was reduced in subjects in the FP
250 and FP 500 groups compared with subjects in the placebo group. A
dose response effect was noted with the FP 500 and FP 250 groups having
mean cortisol AUC~12~ values that were 21% and 10% lower than placebo
respectively.

In the ISOLDE trial \[FLIT78\][^11] 12 subjects \[3%\] in the FP 500 mcg
treatment group compared with 2 subjects \[\<1%\] in the placebo group
had decreased cortisol reported as an AE. Skin hemorrhage was reported
by 9 \[2%\] subjects in the FP group compared with 1 \[\<1%\] subject in
the placebo group. Reports of hyperglycemia were similar in the FP and
placebo group (6\[2%\] FP vs. 5 \[1%\] placebo). \[*Medical Officer Dr.
Charles Lee's sNDA20-833/SE1-04 review\]*

The sponsor evaluated the effects on bone mineral density in two
controlled long-term studies of FP \[FLTA3001 and FLTA3017\] in patients
with asthma. The lumbar spine was the only area in these studies that
underwent prospective quality assurance from the osteoporosis central
laboratory while results from the proximal femur; a more sensitive area
for corticosteroid effect did not. In these studies the lumbar spine
bone mineral density measurements did not show a difference between FP
and placebo. The patient population in these studies was younger and
probably less sensitive than older COPD patients to bone effects of
corticosteroids. \[*Medical Officer Dr. Charles Lee's
sNDA20-833/SE1-004\]*

The 120-safety update contained blinded data from ongoing controlled
clinical studies, non-US regional studies and clinical pharmacology
studies. An assessment of adverse events could not be made from these
blinded data.

## B. PATIENT EXPOSURE AND DEMOGRAPHICS

Of the 1,414 patients treated in the two Advair trials, 347 received
Advair Diskus, 356 received Flovent ® Diskus, 341 received salmeterol,
and 370 received placebo. Of the subjects receiving Advair, 169 received
Advair Diskus 500/50 mcg bid, and 178 patients received Advair 250/50
mcg bid. Of the subjects receiving Flovent® 173 received Flovent Diskus
500 mcg bid and 183 received Flovent ® Diskus 250 mcg bid. The mean
duration of exposure to active treatment was 137.8 days for Advair
Diskus 500/50, 141.3 days for Advair Diskus 250/50 bid, 126.5 days for
Flovent ® 500 mcg bid, 138.5 days for Flovent ® 250 mcg, and 138.6 for
salmeterol. The dropout rate was relatively high and ranged from 30% to
36%.

In both studies the majority of the subjects were male and made up 63%
of the study population. The minority races were underrepresented in
both studies and made up approximately 5% \[3.5% black, 1.5% Asian or
Other\] of the study population. Subjects had a mean age of
approximately 63 years with ages ranging from 40 to 90 years of age.
Most patients were long time smokers with a long-standing history of
COPD ranging from 1 to 51 years \[median duration 6 years\]. Patients
were heavy smokers with a 20 -- 220 pack-year smoking history \[median
range 53-60 pack-years\]. Objective criteria for diagnosing emphysema
were not defined in the trials but most patients \[63% -78%\] reported
having a diagnosis of COPD. All patients had to have chronic bronchitis
by definition to be in the trials. Approximately half of the patients
\[46% -54%\] were current smokers. The majority of subjects \[69% -82%\]
were not using inhaled corticosteroids at Screening. Most patients had a
MMRC dyspnea Score of 2 or 3 signifying dyspnea while walking on level
group or while walking on level ground for 100 yards or less.

## C. METHODS AND SPECIFIC FINDINGS OF SAFETY REVIEW

The safety findings for studies SFCA3006 and SFCA3007 were reviewed in
detail. The safety findings of study FLTA3025 was reviewed by Dr.
Charles Lee in his review of the supplemental NDA for Flovent ® Diskus
\[sNDA 20-833/SE1-04\]. Safety findings from his review that are related
to the use of corticosteroids are referenced in this review. The sponsor
provided additional safety information from several other studies. These
studies were four completed non-U.S. studies with Flovent® \[MDI
formulation\] 500 mcg bid in subjects with COPD, data from two long-term
asthma studies using Flovent ® \[MDI and Rotadisk\], adverse events and
HPA axis data from a completed clinical pharmacology study FLTA 1003,
and blinded data from two ongoing controlled clinical trials and 23
non-US regional trials. A 120-safety day update was submitted on August
31, 2001 that included blinded data from the ongoing controlled clinical
studies, pharmacology studies, and the non-U.S. regional studies. Dr.
Charles Lee did a review of the completed non-US studies with Flovent
and this Medical Officer reviewed the 120-day safety update. Safety
findings from the Flovent studies that are relevant to the use of
corticosteroid therapy will be referenced from Dr. Charles Lee's review.

*The safety findings of SFCA3006 are presented first followed by the
safety findings of SFCA3007, and the 120-safety update.*

SAFETY RESULTS SFCA3006

Extent of Exposure

A total of 100 (55%) patients were exposed to Advair Diskus for 24
weeks, 23 (14%) patients were exposed for 20 to \<24 weeks 9(5%)
patients were exposed for 16 to \<20 weeks and the remainder for \<16
weeks. The mean number of treatment days was 137.8 with a median range
of 2 to 191. A total of 97 (56%) patients were exposed to FP 500 for 24
weeks with a mean exposure of 126.5 days. Mean exposure to SAL 50 was
141.1 days with 109 (66%) subjects exposed to treatment for 24 weeks.
Exposure for 24 weeks in the placebo group was noted in 101 (55%)
patients.

Adverse Events Incidence

A total of 515 (74%) subjects reported at least one adverse event. The
percentage of subjects that reported at least one AE was highest in the
FP 500 (80%) and Advair Diskus (78%) groups. As expected, candidiasis of
the mouth/throat was seen mostly in the FP 500 group (10%) and the
Advair Diskus 500/50 group (7%) compared to \<1% each for the Salmeterol
and placebo groups. Muscle cramps were reported most frequently in the
Advair Diskus 500/50 group (8%). The 10 most common events were
headaches, upper respiratory tract infections (URTI), musculoskeletal
pain, throat irritation, upper respiratory inflammation, viral
respiratory infections, candidiasis of the mouth/throat, cough, nasal
congestion/blockage, and muscle cramps and spasms. Five fractures were
reported during the treatment period. One in the placebo group, 1
patient in the SAL 50 group who fell of a ladder, and three patients in
the Advair Diskus group. The sponsor did not provide case narratives for
these cases except to mention that 2 of the cases \[#9688 and 10292\]
had a diagnosis of osteoporosis. Table 31 shows the adverse events more
frequent than placebo and occurring 3%.

Table 31 - Adverse Events more Frequent than Placebo and Occurring 3%
SFCA3006 \[data table 9.2 SFCA3006.pdf\]

+-----------------------+---------+-----------+---------+-------------+
| Adverse event         | Placebo | SAL 50    | FP 500  | Advair      |
|                       |         |           |         | 500/50      |
|                       | N=185   | N=164     | N=173   |             |
|                       |         |           |         | N=169       |
+-----------------------+---------+-----------+---------+-------------+
| Any adverse event     | 127     | 1         | 138     | 131 \[78%\] |
|                       | \[69%\] | 19\[73%\] | \[80%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Headaches             | 25      | 30\[18%\] | 35      | 30\[18%\]   |
|                       | \[14%\] |           | \[20%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Upper respiratory     | 18      | 20\[12%\] | 25      | 28 \[17%\]  |
| tract infection       | \[10%\] |           | \[14%\] |             |
| \[URTI\]              |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+
| Throat irritation     | 1       | 17        | 1       | 19\[11%\]   |
|                       | 4\[8%\] | \[10%\]   | 1\[6%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Musculoskeletal pain  | 23      | 21\[13%\] | 1       | 20\[12%\]   |
|                       | \[12%\] |           | 3\[8%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Viral respiratory     | 6\[3%\] | 12\[7%\]  | 17      | 14\[8%\]    |
| infections^a^         |         |           | \[10%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Candidiasis           | 1\[1%\] | 1\[1%\]   | 17      | 12\[7%\]    |
| mouth/throat          |         |           | \[10%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Upper respiratory     | 1       | 12\[7%\]  | 1       | 15\[9%\]    |
| inflammation^b^       | 2\[6%\] |           | 1\[6%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Nasal                 | 7\[4%\] | 10\[6%\]  | 1       | 7\[4%\]     |
| congestion/blockage   |         |           | 3\[8%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Muscle cramps &       | 4\[2%\] | 8\[5%\]   | 3\[2%\] | 13\[8%\]    |
| spasms                |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+
| Chest symptoms        | 6\[3%\] | 8\[5%\]   | 7\[4%\] | 6\[4%\]     |
+-----------------------+---------+-----------+---------+-------------+
| Sinusitis/sinus       | 4\[2%\] | 5\[3%\]   | 6\[3%\] | 7\[4%\]     |
| infection             |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+
| Hoarseness/dysphonia  | 4\[2%\] | 1\[\<1%\] | 9\[5%\] | 5\[3%\]     |
+-----------------------+---------+-----------+---------+-------------+
| Dizziness             | 5\[3%\] | 6\[4%\]   | 5\[3%\] | 5\[3%\]     |
+-----------------------+---------+-----------+---------+-------------+
| Muscle pain           | 1\      | 1\[\<1%\] | 5\[3%\] | 7\[4%\]     |
|                       | [\<1%\] |           |         |             |
+-----------------------+---------+-----------+---------+-------------+
| Pain \[non-site       | 6\[3%\] | 7\[4%\]   | 3\[2%\] | 5\[3%\]     |
| specific\]            |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+
| Hypertension\*        | 4\[2%\] | 7\[4%\]   | 5\[3%\] | 5\[3%\]     |
+-----------------------+---------+-----------+---------+-------------+
| Anxiety               | 2\[1%\] | 6\[4%\]   | 2\[1%\] | 5\[3%\]     |
+-----------------------+---------+-----------+---------+-------------+
| Chronic obstructive   | 2\[1%\] | 2\[1%\]   | 5       | 2\[1%\]     |
| airways disease       |         |           | \[3%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Lower respiratory     | 2\[1%\] | 6\[4%\]   | 2\[1%\] | 2\[1%\]     |
| signs & symptoms      |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+
| Sputum abnormalities  | 4\[2%\] | 2\[1%\]   | 1\      | 5\[3%\]     |
|                       |         |           | [\<1%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| \*One other patient   |         |           |         |             |
| was listed as having  |         |           |         |             |
| "high blood pressure" |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+
| a The preferred term  |         |           |         |             |
| for flu or flu        |         |           |         |             |
| symptoms              |         |           |         |             |
|                       |         |           |         |             |
| b Includes all AEs of |         |           |         |             |
| cold symptoms         |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+

Deaths and Serious Adverse Events

Three subjects in the placebo group died. One patient died of
adenocarcinoma of the small intestine. One patient died of recurrent
thyroid cancer and the other patient died due to aspiration pneumonia
two months following surgery for multiple colonic tumors.

Serious AEs

Thirty-nine subjects \[including the three subjects who died\]
experienced at least one SAE during the treatment period. Twelve (7%)
subjects were in the FP 500 treatment group and 9 (5%) subjects were in
the Advair 500/50 treatment group. The SAEs are summarized in the
following table. None of these SAEs appear to be drug-related.

Table 32. Serious Adverse Events SFCA3006

+--------------------------+------+--------+-------+---------+-------+
|                          | Pla  | SAL 50 | FP    | Advair  | T     |
|                          | cebo |        | 500   | 500/50  | otals |
|                          |      | N =164 |       |         |       |
|                          | N    |        | N=173 | N=169   | 691   |
|                          | =185 |        |       |         |       |
+--------------------------+------+--------+-------+---------+-------+
| Serious Adverse Event    | 11   | 7 (4%) | 12    | 9 (5%)  | 39    |
| \[SAE\] n (%)            | (6%) |        | (7%)  |         | (6%)  |
+--------------------------+------+--------+-------+---------+-------+
| Withdrawal due to SAE n  | 6    | 6      | 12    | 7 (4%)  | 31    |
| (%)                      | (3%) | (3.6%) | (7%)  |         | (     |
|                          |      |        |       |         | 4.5%) |
+--------------------------+------+--------+-------+---------+-------+
| SAE                      |      |        |       |         |       |
+--------------------------+------+--------+-------+---------+-------+
| COPD                     | 2    | 2^a^   | 5     | 2       | 11    |
| exacerbation/worsening   |      |        |       |         | (     |
| COPD                     |      |        |       |         | 1.6%) |
+--------------------------+------+--------+-------+---------+-------+
| Respiratory failure      | 0    | 0      | 1     | 0       | 1     |
+--------------------------+------+--------+-------+---------+-------+
| Chest pain/atypical      | 2    |        |       | 2       | 4     |
| chest pains              |      |        |       |         |       |
+--------------------------+------+--------+-------+---------+-------+
| Angina                   | 0    | 1      | 1     | 0       | 2     |
+--------------------------+------+--------+-------+---------+-------+
| Pneumonia                | 0    |        | 2^b^  | 2       | 4     |
+--------------------------+------+--------+-------+---------+-------+
| a Also reported atrial   |      |        |       |         |       |
| flutter                  |      |        |       |         |       |
|                          |      |        |       |         |       |
| b Also reported COPD     |      |        |       |         |       |
| exacerbation.            |      |        |       |         |       |
|                          |      |        |       |         |       |
| The other serious        |      |        |       |         |       |
| adverse events each      |      |        |       |         |       |
| reported once in one     |      |        |       |         |       |
| patient were             |      |        |       |         |       |
| pericarditis, ischemic   |      |        |       |         |       |
| cardiomyopathy, deep     |      |        |       |         |       |
| vein thrombosis,         |      |        |       |         |       |
| adenocarcinoma of the    |      |        |       |         |       |
| intestine, colon tumor,  |      |        |       |         |       |
| recurrent thyroid        |      |        |       |         |       |
| cancer, anxiety and      |      |        |       |         |       |
| withdrawal symptoms,     |      |        |       |         |       |
| spontaneous pneumthorax, |      |        |       |         |       |
| diverticulitis, codeine  |      |        |       |         |       |
| overdose, stroke,        |      |        |       |         |       |
| concussion and fractured |      |        |       |         |       |
| vertebrae, small bowel   |      |        |       |         |       |
| obstruction, tennis      |      |        |       |         |       |
| elbow, cellulitis,       |      |        |       |         |       |
| cholecystitis and        |      |        |       |         |       |
| diverticular disease     |      |        |       |         |       |
+--------------------------+------+--------+-------+---------+-------+

Adverse Events leading to withdrawal

*The Adverse events leading to study discontinuation were listed in
listing 9.6 pg. 6692. The total numbers listed in the in-text table on
page 181 SFCA3006.pdf are slightly different from the data listing.
Additionally, there are differences in the number of subjects
withdrawing due to an adverse event in the in-text table on page 93 SFCA
3006.pdf. The withdrawals due to AEs are discussed from the data
obtained from data listing 9.6 pg. 6692 SFCA 3006 and are discussed by
treatment group.*

A total of 61 subjects are listed as withdrawn from the study due to
AEs. This number includes 2 of the deaths previously discussed.

Placebo

A total of 18 subjects are listed as discontinuing due to an AE. These
include 7 of the SAEs discussed above including 2 of the 3 deaths. Two
cases of COPD exacerbation are listed. Events in two subjects might be
related to the formulation \[bad taste in mouth, hoarseness, dry mouth
(1 subject), nausea and vomiting (1 subject)\].

SAL 50

Nine (9) subjects in the SAL 50 group are listed as discontinuing due to
AEs. Five of these are listed as serious. It is unlikely that any of
these events are related to the study drug although the case of angina
occurring 5 weeks after starting study medication \[#9060\] in a 71 year
old male with a history of coronary artery disease could have been
aggravated by the use of salmeterol.

FP 500

Twenty-two (22) subjects are listed as discontinuing due to AEs. Of
these subjects 12 had SAEs. The SAEs include 5 cases of COPD
exacerbation, 3 cases of pneumonia, and 1 case of respiratory failure.
Also among the AEs leading to withdrawal are 2 cases of candidiasis of
the mouth/throat, 2 cases of hoarseness, and one case of cough.
Candidiasis of the mouth/throat and hoarseness are known
corticosteroid-related effects.

Advair Diskus 500/50

Twelve (12) subjects in the Advair Diskus 500/50 discontinued due to
AEs. Of these, 7 subjects had SAEs. The serious events include 2 cases
of pneumonia, 2 cases of chest pain/atypical chest pain, 1 case of
cholecystitis, and 2 cases of

COPD exacerbations.

Drug-related Events

*Reviewer Comment: The sponsor did not provide case narratives of the
adverse events considered by the Investigator to be drug-related
therefore it was difficult to assess causality for most of these events
except for events that are know to be associated with inhaled
corticosteroid or beta-agonist use.*

Candidiasis, throat irritation, and hoarseness/dysphonia occurred more
frequently in the FP 500 and Advair 500/50 treatment groups compared
with salmeterol and placebo. Seventeen (10 percent) of subjects in the
FP 500 treatment group and 11 (7%) of subjects in the Advair Diskus
500/50 treatment group reported candidiasis of the mouth/throat. There
were 4 cases of candidiasis at an unspecified site in the Advair Diskus
500/50 treatment group and 2 (1%) in the FP 500 group. When candidiasis
was reported together as candidiasis of the mouth/throat, candidiasis
unspecified, and unspecified oropharyngeal plaques a total of 19 cases
in the FP 500 group and 19 cases in the Advair Diskus group were
reported. Throat irritation was experience by 11 (7%) of subjects in the
Advair Diskus group, 2 (1%) of subjects in the FP 500 group, 5 (3%)
subjects in the placebo group and 4 (2%) subjects in the SAL 50 group.
Throat irritation could probably be formulation-related as well as drug
related. More subjects in the FP group (8 \[5%\]) reported
hoarseness/dysphonia compared to the other treatment groups (Advair
500/50 4 \[2%\], SAL 1 \[\<1%\], and placebo 4 \[2%). Other events
reported as drug-related by the Investigator that are possibly related
to the study drug are muscle cramps and spasms occurring in the SAL
group \[4 (2%)\] and the Advair Diskus group \[2 (1%)\]. Three cases of
cataracts and 3 cases of ocular pressure disorders were reported. Two
cases of cataracts were reported in the FP 500 group and 1 in the
placebo group and 2 cases of ocular pressure disorders were reported in
the Advair 500/50 group and 1 case in the placebo group. Although these
adverse events are known to associate with corticosteroid use, without
case narratives it is difficult to establish causality.

Cardiovascular Safety

Adverse Events

The incidence of cardiovascular events was similar across treatment
groups; 14 (8%) in the placebo group, 12 (7%) in the SAL 50 group, 13
(8%) in the FP 500 group and 14 (8%) in the Advair Diskus 500/50
treatment group. The most frequent cardiovascular events were
hypertension and palpitations. There were 21 reported AEs of
hypertension 4 (2%) in the placebo group, 7 (4%) in the SAL 50 group, 5
(3%) in the FP 500 group and 5 (3%) in the Advair Diskus 500/50 group.
There were 6 reports of palpitations, 3 (2%) in the placebo group,
1(\<1%) in the FP 500 group and 2 (1%) in the Advair Diskus 500/50
group. There were 2 (1%) cases each of tachycardia and tachyarrhythmias
in the SAL 50 group. All the other cardiovascular-related events each
occurred in \< 1% of patients across treatment groups.

ECGs

An abnormal and clinically significant ECG was defined *a priori* as a
12-lead tracing with any of the following:

-   Myocardial ischemia

-   Left or right ventricular hypertrophy

-   Clinically significant conduction abnormalities (e.g. LBBB, WPW)

-   Clinically significant arrhythmias (e.g. atrial fibrillation,
    ventricular tachycardia)

Four subjects in the placebo group, 2 in the SAL 50 group, 4 in the FP
500 group, and 3 in the Advair Diskus 500/50 treatment group had
abnormal clinically significant ECGs at screening or during the study.
One subject in the placebo, SAL 50, and Advair Diskus treatment groups
and 3 subjects in the FP group had clinically significant abnormal ECGs
at screening but were allowed to participate in the study. These
patients had no clinically significant changes in their ECG tracing when
their ECGs were repeated during the study. Three patients in the placebo
group with ECG abnormalities during the treatment period were withdrawn.
One patient was discontinued due to a myocardial infarction, another was
discontinued due to COPD exacerbation and had an episode of ventricular
tachycardia, and one patient had atrial enlargement on a repeat ECG
tracing \[*Data from CRFs*\]. One subject in the SAL group was
discontinued after Treatment Week 8 due to ischemic changes and left
atrial enlargement. One subject in the FP 500 group also experienced a
left atrial abnormality, and was discontinued due to pneumonia. One
subject in the Advair Diskus 500/50 treatment group was discontinued due
to atrial flutter and one subject who experienced nodal tachycardia was
discontinued due to pneumonia. Heart rate as measured by ECG was similar
across treatment groups and did not change significantly during the
course of the 24 weeks of treatment.

QTc Intervals

QTc intervals were calculated using Bazett's square root formula
\[QTcB\] and Fridericia's formula \[QTcF\]. The sponsor defined
prolonged QTc intervals as \> 440 msecs. The majority of subjects across
treatment groups had normal QTc intervals at screening and throughout
the study. Using Bazett's formula,

84% - 88% of subjects had QTc interval \<440 msecs and using
Fridericia's formula 94% -96% had QTc \< 440 msecs. Using Bazett's
formula 1% - 2% of patients across treatment groups at screening had QTc
intervals \>470 msec. No patient in the placebo group had a QTc interval
\> 470 msecs during the treatment period. Five (5) patients in the
Advair Diskus 500/50 group had QTc intervals \> 470 msecs during the
study. Four of these subjects had QTc intervals \>470 msecs at
screening. One subject with QTc interval of 440.0 msecs at screening had
a QTc interval of 471.4 msecs at week 24. The two subjects in the FP 500
group with QTc intervals \> 470 msecs during the study had QTc intervals
\> 440 msecs at screening. One of these subjects was later discontinued
from the study due to COPD exacerbation. Two (2) patients in the SAL 50
group had QTc intervals \> 470 msecs. Both of these subjects had QTc
intervals \> 440 msecs at screening. Using Fridericia's formula only 4
subjects in the Advair Diskus treatment group had QTc intervals \> 470
msecs. The QTc interval changes that occurred during the study were not
associated with QTc-related events and were not the reason for
discontinuation from the study in any subject.

Holter Monitoring

The sponsor conducted Holter monitoring over a 24-hour period at
screening and at Week 4 in a subset of patients. A total of 158 subjects
at screening and 130 patients at Treatment Week 4 had 24-hour Holter
monitoring. Most subjects ( 95%) in each treatment group had ECG data
from Holter monitoring within normal limits. Five subjects \[one subject
each in the placebo, SAL, and Advair group, and 2 subjects in the FP
group\] experienced significant changes from screening in Holter
monitoring. One subject in the FP group experienced atrial
flutter/atrial fibrillation, and one subject in the Advair Diskus group
experience heart block. There were three cases of ventricular
tachycardia one each in the placebo, SAL, and FP 500 group treatment
groups.

Vital Signs (pulse, blood pressure)

There were no significant changes in vital signs across treatment groups
during the study. At Baseline pulse and blood pressure were similar
across treatment groups.

Clinical Laboratory Results

Clinical laboratory tests were conducted at screening, Week 12, and Week
24. A threshold range for each laboratory measurement was defined by
factors greater than and less than the upper and lower limits of the
normal range for that measurement. The factors for calculating these
ranges were pre-specified.

Few subjects (2% in each treatment group) had hematology parameters that
were outside sponsor-defined threshold values. Of these subjects, 2 in
the Advair Diskus group had eosinophils values above the sponsor-defined
threshold \[\>20%\] and 3 had WBC counts above the sponsor-defined
threshold \[\>16x10^3^/uL\]. No patients in the Advair Diskus 500/50 or
FP 500 treatment groups had lymphocyte or monocyte counts outside of the
sponsor-defined threshold \[\>60% for lymphocytes and \> 15% for
monocytes\]. In clinical chemistry parameters, less than 1% of subjects
had values outside of the sponsor-defined threshold values for LFTs,
calcium, creatinine, phosphorous and potassium. A higher percentage of
subjects \[ 4%\] had values outside the sponsor-defined threshold value
for glucose. Seven (4%) subjects in the Advair Diskus 500/50 group, 6
(4%) subjects in the FP 500 group and 5 (3%) subjects in the placebo and
SAL groups had glucose levels greater than the threshold value. The
sponsor's pre-defined threshold for high and low values is significantly
different from what would prompt treatment and/or medical evaluation in
clinical practice \[see table 33 below\]. For example, with the
sponsor's threshold limits, patients with fasting glucose values of 120
mg/dL but 175 mg/dL would not be outside the threshold for high glucose.
However, a fasting glucose value of 120 mg/dL in the clinical setting
would prompt an evaluation for diabetes. Similarly a potassium of \<3.5
or \>5.5 meq/L would be addressed in clinical practice. However, the
sponsor's threshold for a low potassium is \<3.0 mEq/l.

*Table 33 - Sponsor-Defined Laboratory Threshold Values* \[Data from
Listing 9.7 pg. 6719-6721 SFCA 3006.pdf Lab. references ranges obtained
from SAS transport files\]\]

  ------------- -------- ----------------- ------------- ----------- ---------- -------------
  Analyte                Sponsor-defined                 Lab                    Range in
                         threshold values                reference              traditional
                                                         range                  units

                Units    Low               High          Low         High       

  ALT           U/L                        \>120                     \>35 U/L   

  AST           U/L                        \>120                     \>36 U/L   

  Alkaline      U/L                        \>300                     \>115 U/L  
  phosphatase                                                                   

  Bilirubin     mg/dl                      2             \<3 (mol/L) \>21       0.3 --1.0
                                                                     (mol/L)    mg/dL

  Calcium       mg/dl    \<8               \>12          \<2.1       \>2.57     9 --10.5
                                                         (nmol/L)    (nmol/L)   mg/dL

  Creatinine    mg/dl                      \>2           \<40        \>110      \<1.5 mg/dL
                                                         (mol/L)     (mol/L)    

  Glucose       mg/dl    \<55              \>175         \<3.9       6.7        70 --120
                                                         (mmol/L)    (mmol/L)   mg/dL

  WBC                    2.8 x10^3^/L      16x10^3^/uL                          

  Potassium     mEq/l    \<3.0             \>6.0         3.4         5.4        Same as mEq/L
                                                         (mmol/l)    (mmol/L)   

  Eosinophils   \%                         \>20                      6.8%       

  Lymphocytes   \%                         60            15.4%       48.5%      

  Monocytes     \%                         \>15          2.6%        10.1%      
  ------------- -------- ----------------- ------------- ----------- ---------- -------------

Cosyntropin Stimulation Testing

The effect of Advair Diskus 500/50 on HPA Axis was evaluated by morning
plasma cortisol concentration and short cosyntropin stimulation testing
at Treatment Day 1 and Endpoint at selected sites. Morning plasma
cortisol values of \< 4 mcg/dL, peak post stimulation cortisol of \<
14.5 mcg/dL, and change from baseline of \< 5.6 mcg/dL were considered
abnormal *a priori*. The threshold values in the Cosyntropin package
insert was 18.0 mcg/dL and 7 mcg/dL however the sponsor used lower
values because the sponsor used the HPLC assay and not the less specific
radioimmunoassay \[RIA\] upon which the values in the package insert
were based. The results are obtained from data table 9.10 and 9.11 on
pg. 1462 and 1463 SFCA3006.pdf.

Table 34 - ACTH Stimulation Testing Results SFCA3006

  -------------- ---------- ------- ------- ------- ------- ------- -------- -------
                 Placebo)           SAL 50          FP 500          Advair   
                                                    (               Diskus   
                                                                    500/50   

  Day 1 N        44                 38              39              39       

                 Pre        Post    Pre     Post    Pre     Post    Pre      Post

  Mean           12.75      24.19   12.37   24.12   13.09   24.01   13.66    24.71

  Endpoint N     35                 36              37              36       

  Mean           12.89      23.61   11.77   23.20   12.04   21.42   12.14    21.92
  -------------- ---------- ------- ------- ------- ------- ------- -------- -------

Normal pre-stimulation plasma cortisol \> 4 mcg/dL

Normal post-stimulation cortisol \> 14.5 mcg/dL

Endpoint: Week 24, or discontinuation

The mean basal and post-ACTH stimulation plasma cortisol levels were
comparable among treatment groups on Treatment Day 1 and at Endpoint.
The post-stimulation cortisols for the FP 500 and the Advair Diskus
500/50 treatment groups at Endpoint were slightly lower compared with
post-stimulation cortisols on Day 1. The overall results are not
suggestive of clinically significant adrenal suppression.

*Reviewer Comment: There are discrepancies in the subject numbers in
several of the data tables with the cortisol results. Most of these
discrepancies are small and is not expected to affect the overall
results. However, the sponsor has been asked to clarify these
discrepancies and submit corrected data tables.*

Six (6) subjects had abnormal ACTH stimulation testing results
\[pre-stimulation cortisol \< 4 mcg/dL and/or post-stimulation cortisol
\< 14.5 mcg/dl\] during the treatment period. One subject each was in
the placebo and SAL group, and 2 patients each were in the FP 500 and
Advair Diskus 500/50 group. \[*Data from Listing 9.12 pg. 9090 --9095
SFCA3006.pdf\]* The results for these patients are outlined below. The
results for subjects 11179 in the FP group and 11178 in the Advair group
seem odd. However, taken as is they support the fact that there is as
expected systemic exposure with FP doses of 500 mcg.

Table 35. Subjects with Abnormal ACTH stimulation results SFCA3006

+----------------------+-----------------------------------------------+
| Treatment Group      | Subject                                       |
+----------------------+-----------------------------------------------+
| Placebo              | Subject 8929                                  |
|                      |                                               |
|                      | At Discontinuation \[29 days\]                |
|                      |                                               |
|                      | Pre =14.61                                    |
|                      |                                               |
|                      | Post=13.20                                    |
+----------------------+-----------------------------------------------+
| SAL 50               | Subject 10797                                 |
|                      |                                               |
|                      | At discontinuation \[54 days\]                |
|                      |                                               |
|                      | Pre=12.61                                     |
|                      |                                               |
|                      | Post=14.01                                    |
+----------------------+-----------------------------------------------+
| FP 500               | Subject 10884 at discontinuation \[79 days\]  |
|                      |                                               |
|                      | Pre=0.50                                      |
|                      |                                               |
|                      | Post=8.80                                     |
|                      |                                               |
|                      | Subject 11179 at discontinuation \[18 days\]  |
|                      |                                               |
|                      | Pre=9.50                                      |
|                      |                                               |
|                      | Post=9.50                                     |
+----------------------+-----------------------------------------------+
| Advair Diskus 500/50 | Subject 11178 at week 24                      |
|                      |                                               |
|                      | Pre = 7.90                                    |
|                      |                                               |
|                      | Post =7.10                                    |
|                      |                                               |
|                      | Subject 11287 at discontinuation \[56 days\]  |
|                      |                                               |
|                      | Pre=4.70                                      |
|                      |                                               |
|                      | Post =13.61                                   |
+----------------------+-----------------------------------------------+

SAFETY RESULTS SFCA 3007

Extent of Exposure

Of the 178 patients who received Advair Diskus 250/50, 112 (63%) were
exposed to the drug for 24 weeks, 19 (11%) patients were exposed for 20
to \<24 weeks 10 (6%) patients were exposed for 16 to \<20 weeks and 37
patients were exposed for \<16 weeks. The mean number of treatment days
was 141.3 days with a median range of 1 to 186 days. A total of 116
(63%) patients were exposed to FP 250 for 24 weeks with a mean exposure
of 138.5 days. Mean exposure to SAL 50 was 136.1 days with 108 (61%) of
subjects exposed to treatment for 24 weeks. A total of 110 (59%)
patients in the placebo group were exposed for 24 weeks.

Adverse Events Incidence

A total of 485 (67%) subjects reported at least one adverse event. The
percentage of subjects reporting at least one AE was highest in the FP
250 and Advair Diskus 250/50 groups \[70% in each group\]. As expected,
candidiasis of the mouth/throat occurred more frequently in the Advair
Diskus 500/50 group (10%) and in the FP 250 group (6%). The 10 most
common \[3%\] events regardless of causality were headaches, upper
respiratory tract infections (URTI), candidiasis mouth/throat, diarrhea,
chest symptoms, and hoarseness/dysphonia. Eight (8) fractures were
reported during the treatment period. Three occurred each in the placebo
group, and Advair Diskus 250/50 treatment groups and 2 in the FP 250
group. Of the 3 subjects in the Advair/Diskus group who sustained
fractures one was a 58 year-old woman \[#16741\] who fractured her femur
due to a fall and withdrew from the study. Another subject \[#16636\]
sustained 3 broken ribs in a car accident and withdrew from the study.

The highest incidence of AEs occurred within the first month of
treatment in all treatment groups. Thirty-five percent of subjects in
the placebo group, 38% in the SAL 50 group 44% in the FP 250 group and
41% in the Advair 250/50 Diskus group reported at least one AE within
the first month of treatment. Table 36 list the most common \[3%\]
events that occurred during the treatment period.

Table 36 - Adverse Events more Frequent than Placebo and Occurring 3%
SFCA3007 \[data table 9.2 SFCA3007.pdf\]

+-----------------------+---------+-----------+---------+-------------+
| Adverse event         | Placebo | SAL 50    | FP 250  | Advair      |
|                       |         |           |         | 250/50      |
|                       | N=185   | N=177     | N=183   |             |
|                       |         |           |         | N=178       |
+-----------------------+---------+-----------+---------+-------------+
| Any adverse event     | 118     | 114       | 129     | 124 \[70%\] |
|                       | \[64%\] | \[64%\]   | \[70%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Headaches             | 22      | 17\[10%\] | 21      | 28\[16%\]   |
|                       | \[12%\] |           | \[11%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Candidiasis           | 2\[1%\] | 5\[3%\]   | 1       | 17\[10%\]   |
|                       |         |           | 1\[6%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Throat irritation     | 13      | 7 \[4%\]  | 10      | 15 \[8%\]   |
|                       | \[7%\]  |           | \[5%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Sinusitis             | 5       | 8 \[5%\]  | 14      | 6 \[3%\]    |
|                       | \[3%\]  |           | \[8%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Fever                 | 5       | 0         | 5       | 8 \[4%\]    |
|                       | \[3%\]  |           | \[3%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Hoarseness/dysphonia  | 0       | 1         | 5       | 9 \[5%\]    |
|                       |         | \[\<1%\]  | \[3%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Dizziness             | 3\[2%\] | 6\[3%\]   | 1       | 7 \[4%\]    |
|                       |         |           | \       |             |
|                       |         |           | [\<1%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Viral respiratory     | 6       | 5 \[3%\]  | 8       | 10 \[6%\]   |
| infections            | \[3%\]  |           | \[4%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Upper respiratory     | 6\[3%\] | 5 \[3%\]  | 7       | 4 \[2%\]    |
| inflammation          |         |           | \[4%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Muscle cramps &       | 2\[1%\] | 2 \[1%\]  | 5       | 6 \[3%\]    |
| spasms                |         |           | \[3%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Rhinorrhea/post nasal | 3\[2%\] | 5\[3%\]   | 2       | 3 \[2%\]    |
| drip                  |         |           | \[1%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Nasal                 | 4\[2%\] | 2\[1%\]   | 1       | 5 \[3%\]    |
| congestion/blockage   |         |           | \       |             |
|                       |         |           | [\<1%\] |             |
+-----------------------+---------+-----------+---------+-------------+
| Epistaxis             | 2\[1%\] | 3\[2%\]   | 5\[3%\] | 1\[\<1%\]   |
+-----------------------+---------+-----------+---------+-------------+
| Pain                  | 3\[2%\] | 2 \[1%\]  | 5       | 2 \[1%\]    |
|                       |         |           | \[3%\]  |             |
+-----------------------+---------+-----------+---------+-------------+
| Cough                 | 2       | 7 \[4%\]  | 1       | 2 \[1%\]    |
|                       | \[1%\]  |           | \       |             |
|                       |         |           | [\<1%\] |             |
+-----------------------+---------+-----------+---------+-------------+
|                       |         |           |         |             |
+-----------------------+---------+-----------+---------+-------------+

Deaths and Serious Adverse Events

There were no deaths during the study.

Serious Adverse Events

Thirty-five subjects experienced at least one SAE during the treatment
period. Eleven (5%) subjects were in the FP 250 treatment group and 8
(4%) subjects were in the Advair 250/50 treatment group. The SAEs are
listed in the table below.

*Note: The sponsor's in-text table and text on page 159 reports a total
of 34 SAEs with 10 occurring in the FP 250 treatment group. The sponsor
acknowledged \[pg160\] that because of a recording error in the
medication stop date 2 SAEs experienced by subject #12438 in the FP
group should have been considered as SAEs during the treatment period.*

On review of the case narratives none of the SAEs appear to be
drug-related.

Table 37 - Serious Adverse Events SFCA 3007

+--------------------------+------+--------+-------+---------+---+------+
|                          | Pla  | SAL 50 | FP    | Advair  |   | To   |
|                          | cebo |        | 250   | 250/50  |   | tals |
|                          |      | N =177 |       |         |   |      |
|                          | N    |        | N=183 | N=178   |   | 723  |
|                          | =185 |        |       |         |   |      |
+--------------------------+------+--------+-------+---------+---+------+
| Serious Adverse Event    | 11   | 5 (3%) | \*11  | 8 (4%)  | 3 |      |
| \[SAE\] n (%)            | (6%) |        | (5%)  |         | 5 |      |
|                          |      |        |       |         | ( |      |
|                          |      |        |       |         | 5 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| Withdrawal due to SAE n  | 5    | 5      | 7     | 4 (4%)  | 2 |      |
| (%)                      | (3%) | (3.6%) | (7%)  |         | 1 |      |
|                          |      |        |       |         | ( |      |
|                          |      |        |       |         | 3 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| SAE                      |      |        |       |         |   |      |
+--------------------------+------+--------+-------+---------+---+------+
| Chronic obstructive      | 1    | 2 (1%) | 4     | 0       | 7 |      |
| airways disease          | (\   |        | (     |         | ( |      |
| (COAD)^a^                | <1%) |        | 2%)\* |         | \ |      |
|                          |      |        |       |         | < |      |
|                          |      |        |       |         | 1 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| Cholelithiasis           | 1    | 0      | 2     | 0       | 3 |      |
|                          | (\   |        | (1%)  |         | ( |      |
|                          | <1%) |        |       |         | \ |      |
|                          |      |        |       |         | < |      |
|                          |      |        |       |         | 1 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| Chest pain               | 2    | 0      | 0     | 1       | 3 |      |
|                          | (1%) |        |       | (\<1%)  | ( |      |
|                          |      |        |       |         | \ |      |
|                          |      |        |       |         | < |      |
|                          |      |        |       |         | 1 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| Pneumonia                | 0    | 1      | 1     | 0       | 2 |      |
|                          |      | (\<1%) | (     |         | ( |      |
|                          |      |        | \<1%) |         | \ |      |
|                          |      |        |       |         | < |      |
|                          |      |        |       |         | 1 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| Cholecystitis            | 0    | 0      | 1     | 1       | 4 |      |
|                          |      |        | (     | (\<1%)  | ( |      |
|                          |      |        | \<1%) |         | \ |      |
|                          |      |        |       |         | < |      |
|                          |      |        |       |         | 1 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| ^b^Fractures             | 1    | 0      | 0     | 1       | 2 |      |
|                          | (\   |        |       | (\      | ( |      |
|                          | <1%) |        |       | <1%)^b^ | \ |      |
|                          |      |        |       |         | < |      |
|                          |      |        |       |         | 1 |      |
|                          |      |        |       |         | % |      |
|                          |      |        |       |         | ) |      |
+--------------------------+------+--------+-------+---------+---+------+
| \*One subject experience |      |        |       |         |   |      |
| a COPD exacerbation and  |      |        |       |         |   |      |
| worsening sinusitis      |      |        |       |         |   |      |
| during the treatment     |      |        |       |         |   |      |
| period but was           |      |        |       |         |   |      |
| incorrectly recorded as  |      |        |       |         |   |      |
| occurring after          |      |        |       |         |   |      |
| discontinuing treatment. |      |        |       |         |   |      |
|                          |      |        |       |         |   |      |
| a The preferred term for |      |        |       |         |   |      |
| COPD                     |      |        |       |         |   |      |
|                          |      |        |       |         |   |      |
| b The patient in the     |      |        |       |         |   |      |
| Advair group was a       |      |        |       |         |   |      |
| 58-year old female who   |      |        |       |         |   |      |
| sustained a fractured    |      |        |       |         |   |      |
| femur after a fall while |      |        |       |         |   |      |
| attempting to climb into |      |        |       |         |   |      |
| her locked home. The     |      |        |       |         |   |      |
| patient in the placebo   |      |        |       |         |   |      |
| group had chest          |      |        |       |         |   |      |
| contusions and rib       |      |        |       |         |   |      |
| fractures following a    |      |        |       |         |   |      |
| motor vehicle accident.  |      |        |       |         |   |      |
|                          |      |        |       |         |   |      |
| The other serious        |      |        |       |         |   |      |
| adverse events each      |      |        |       |         |   |      |
| reported once in one     |      |        |       |         |   |      |
| patient were             |      |        |       |         |   |      |
| appendicitis, coronary   |      |        |       |         |   |      |
| artery disease,          |      |        |       |         |   |      |
| worsening depression,    |      |        |       |         |   |      |
| right breast cancer,     |      |        |       |         |   |      |
| epistaxis, and prostate  |      |        |       |         |   |      |
| cancer (placebo group),  |      |        |       |         |   |      |
| hemorrhagic cerebral     |      |        |       |         |   |      |
| infarction and possible  |      |        |       |         |   |      |
| TIA (SAL 50 group),      |      |        |       |         |   |      |
| splenic enlargement,     |      |        |       |         |   |      |
| myocardial infarction,   |      |        |       |         |   |      |
| suspected hypoglycemia,  |      |        |       |         |   |      |
| and acute pancreatitis   |      |        |       |         |   |      |
| (FP 250 group), basal    |      |        |       |         |   |      |
| cell carcinoma of the    |      |        |       |         |   |      |
| nose, streptococcal      |      |        |       |         |   |      |
| bacteremia/infection of  |      |        |       |         |   |      |
| the pharynx, myeloid     |      |        |       |         |   |      |
| leukemia, spontaneous    |      |        |       |         |   |      |
| pneumothorax, and        |      |        |       |         |   |      |
| cardiac arrhythmia       |      |        |       |         |   |      |
| (Advair Diskus 250/50).  |      |        |       |         |   |      |
+--------------------------+------+--------+-------+---------+---+------+

Adverse Events leading to withdrawal

*See page 42 Table 19 for discussion on the discrepancy with the number
of subjects with AEs leading to withdrawal. Also there is a discrepancy
in the number of subjects with withdrawal due to AEs in the text and
in-text table on page 160-161 and in Listing 9.4 pg. 5770-5785. The
number of subject withdrawals due to AEs is stated as 34 with 10
subjects in the FP group on pages 160-161.However, in the data listing
9.4 pg. 5778- 5782 the total number of subjects listed as withdrawing
due to AEs in the FP 250 group is 13. The AEs leading to withdrawals are
discussed based on data from listing 9.4 pg. 5770 --5785. Based on those
data the total number of subject withdrawals due to AEs is 37.*

Of the 37 subjects who withdrew due to AEs, 10 were in the placebo
group, 7 were in the SAL 50 group, 13 were in the FP 250 group and 9
were in the Advair Diskus 250/50 group. None of these events that led to
withdrawal appear to be drug related.

Drug-related Events

*The sponsor did not provide case narratives for the adverse events
considered by the Investigator to be drug-related therefore it was
difficult for this reviewer to assess causality for most of these
events. However, except for events such as candidiasis or
hoarseness/dysphonia that are know to be associated with inhaled
corticosteroid use, the other events described as drug-related by the
Investigator \[e.g. wounds and lacerations in a patient on SAL and
depression in a patient on placebo\] are unlikely by this reviewer's
assessment to be drug-related.*

Candidiasis, throat irritation, and hoarseness/dysphonia occurred more
frequently in the FP 250 and Advair 250/50 treatment groups compared
with salmeterol and placebo. Seventeen (10 percent) of subjects in the
Advair Diskus 200/50 group and 11 (6%) subjects in the FP 250 treatment
group reported candidiasis of the mouth/throat. There were 4 cases (2%)
of candidiasis at an unspecified site in the FP 250 group and 2 (1%) in
the Advair Diskus 250/50 treatment group. No cases of unspecified
oropharyngeal plaques were reported in the Advair or FP groups but 1
case was reported each in the placebo and SAL groups. Throat irritation
was experience by 15 (8%) subjects in the Advair Diskus 250/50 group, by
10 (5%) of subjects in the FP 250 group, by 7 (4%) subjects in the SAL
group and by 13 (7%) subjects in the placebo group. More subjects in the
Advair Diskus 250/50 group (9 \[5%\]) reported hoarseness/dysphonia
compared to the other treatment groups (FP 250 5 \[3%\] subjects, SAL
1\[\<1%\] subject. No cataracts or glaucoma were reported however the
sponsor did not specifically monitor patients for these adverse events.
Other events reported as drug-related by the Investigator that by this
reviewer's assessment are possibly related to the study drug are
hyperglycemia \[1\] and abnormal liver function tests \[1\] in the FP
250 group, and muscle cramps and spasms \[1\] in the SAL group. Two
cases of oral itching and irritation \[one each in the SAL and FP
group\] and one case of oral lesions \[Advair 250/50 group\] could
possibly be drug or formulation-related.

Cardiovascular Safety

Adverse Events

The incidence of cardiovascular events was highest in the placebo group
\[16 subjects (9%)\] followed by the SAL 50 group \[11 (6%)\] The FP 250
and Advair Diskus 250/50 groups had the lowest percentage \[4%\] of
cardiovascular events. The most frequent \[2%\] cardiovascular events
were hypertension and syncope. There were 5 (3%) reported AEs of
hypertension in the placebo and in the SAL 50 group, 4 \[2%\] in the
Advair Diskus 250/50 group and 2 \[1%\] in the FP 250 group. There were
2 reports of syncope (1%) in the SAL group and 3 (2%) reports in the
Advair Diskus 250/50 group. Each of the other cardiovascular-related
events occurred in \< 1% of patients across treatment groups.

ECGs

An abnormal and clinically significant ECG was defined *a priori* as
described in study SFCA3006 \[*See pg.60*\]

Most subjects had normal ECG tracings or had abnormal tracings that were
not clinically significant at screening. Only 3 subjects \[one each in
the placebo, SAL and FP 250 group\] had an abnormal ECG tracing that was
clinically significant at screening. No Subjects in the FP 250 or Advair
Diskus 250/50 groups had clinically significant changes from baseline in
their ECG tracings during the study. Two subjects were discontinued due
to clinically significant ECG changes. One subject was in the placebo
group and had left bundle branch block and QTc prolongation and one
subject was in the SAL group and had QTc prolongation. The QTc
prolongation in the patient in the SAL group did not exceed 470 msecs.

QTc Intervals

QTc intervals were calculated using Bazett's square root formula
\[QTcB\] and Fridericia's formula \[QTcF\]. The sponsor defined
prolonged QTc intervals as \> 440 msecs. The majority of subjects across
treatment groups had normal QTc intervals at screening and throughout
the study. Using Bazett's formula mean QTc ranged from 414.64 msecs to
417.56 msecs. Using Bazett's or Fridericia's formula only 5 patients at
screening had QTc intervals \>470 msecs. Two of these patients were in
the Advair Diskus 250/50 treatment group. The QTc intervals were not
significantly changed during the study. One subject in the placebo group
discontinued because of the onset of LBBB and QTc prolongation. The QTc
at screening in this subject was 407.9 msecs and at discontinuation was
475.3. The QTc findings overall were not suggestive of any drug-related
effects.

Vital Signs (pulse, blood pressure)

At Baseline pulse and blood pressure were similar across treatment
groups. There were no significant changes in vital signs across
treatment groups during the study.

Clinical Laboratory Results

Clinical laboratory tests \[fasting\] were performed on samples
collected at screening, Week 12 and Week 24. The sponsor defined a
threshold range for each laboratory measurement by factors greater than
and less than the upper and lower limits of the normal range for that
measurement *\[See Table 33 pg. 62\]*. The majority of subjects ( 91%)
had either no change in hematology parameters or a shift into the normal
range at Treatment Weeks 12 and 24. Few subjects \[2%\] in each
treatment group had hematology parameters that were outside
sponsor-defined threshold values. The majority of subjects \[87%\] had
either no change in clinical chemistry parameters or a shift into the
normal range at Weeks 12 and 24 and at the Discontinuation visit. The
most common shifts observed were shifts to "high" in glucose and ALT
values. Seventeen subjects had glucose values above the sponsor's
pre-defined threshold \[\>175 mg/dl\]. Three subjects were in the Advair
Diskus 250/50 group, 5 were in the FP 250 group, 6 were in the SAL group
and 3 were in the placebo group. Elevated glucose as an AE was reported
in 8 subjects two of whom were in the Advair Diskus 250/50 treatment
groups. As mentioned for study SFCA3006, the sponsor's threshold for
high glucose of \>175 mg/dl would have failed to capture high glucose
levels that generally would be addressed in clinical practice.

Cosyntropin Stimulation Testing

The effect of Advair Diskus 500/50 on HPA Axis was evaluated by morning
plasma cortisol concentration and short cosyntropin stimulation testing
at Treatment Day 1 and Endpoint at selected sites as was done in study
SFCA3006. The mean pre and post-stimulation cortisol results were
similar across treatment groups at Day 1 and Endpoint. Results are
depicted in table 38. \[Data obtained from data table 9.10 and 9.11 in
pg. 965 and 966 SFCA3007. A total of 4 subjects had post-stimulation
cortisols \< 14.5 mcg/dl at Endpoint. Two subjects were in the placebo
group, and 1 subject each was in the SAL and Advair 250/50 group \[Data
table 9.16 pg. 973\].

*Reviewer comment: There were minor discrepancies in the patient numbers
\[ 1 patient in some treatment groups\] in some of the tables with
cortisol results. The sponsor has been asked to clarify these
discrepancies but these are not expected to affect the overall results.*

Table 38 ACTH Stimulation Testing Results SFCA3007

  -------------- --------- ------- --------- ------- --------- ------- --------- -------
                 Placebo           SAL 50            FP 250            Advair    
                 (n=185)           (n=177)           (n=183)           Diskus    
                                                                       250/50    
                                                                       (n=178)   

                 Pre       Post    Pre       Post    Pre       Post    Pre       Post

  Day 1 N        54        53      51        53      50        50      44        45

  Mean           12.43     25.94   12.98     24.61   11.56     23.96   13.40     23.89

  Endpoint N     27        25      29        28      26        24      32        29

  Mean           11.13     23.23   12.24     23.57   10.55     22.14   12.38     23.19
  -------------- --------- ------- --------- ------- --------- ------- --------- -------

Normal pre-stimulation plasma cortisol \> 4 mcg/dl

Normal post-stimulation cortisol \> 14.5 mcg/dL

Endpoint: Week 24, or discontinuation

**[120-Safety Update]{.underline}**

The cut-off date for collection of all safety information in the
supplemental NDA was 30 September 2000. The 120-day safety update
includes all safety information reported during the period of 01 October
2000 to 31 May 2001. The safety update includes data from 4 clinical
pharmacology studies, 2 controlled clinical studies, 23-non U.S.
regional studies and selected safety information from a completed
long-term FP asthma study FLTA3001.

No clinically relevant adverse events were reported for the completed
clinical pharmacology studies. There were no completed clinical studies
within this reporting period that evaluated SAL, FP, or Advair in the
treatment of COPD. Therefore no analyses of AEs can be conducted for the
120-safety day report since treatment assignment remains blinded. Two
controlled clinical studies with Advair Diskus 500/50 mcg and its
individual components \[SAL 50 and FP 500 mcg\] are ongoing.
Twenty-three non-US regional studies including a total of 4 studies with
the combination product \[Advair\] in COPD subjects are ongoing. There
have been 16 deaths reported to date in the two controlled clinical
trials and 11 deaths in the 23 non-U.S. regional studies. The majority
of the deaths were due to cardiac causes \[cardiac arrest, myocardial
infarction, and chest pain\]

A 2 year study to assess the long term safety of FP Inhalation Aerosol
100 mcg bid and 500 mcg bid versus placebo bid in adult subjects with
moderate asthma \[Study FLTA3001\] was mentioned in the 120-safety
update but no data from that study were provided.

Eight SAEs \[including 4 deaths\] were reported in post-marketing
observational studies. Three of these deaths were due to cardiac causes
and one was due to metastatic cancer of the stomach. There have been 42
spontaneous reports of deaths from September 18, 1998 through May 05,
2000 from the New Zealand Regulatory Authority and New Zealand's
Intensive Medicine Monitoring Program. The patients had been on
salmeterol. A causality assessment has not been determined.

# VIII. Dosing, Regimen, and Administration Issues

Advair Diskus comes in three strengths 100/50 mcg, 250/50 mcg, and
500/50 mcg. The sponsor is seeking approval for the 250/50 and the
500/50mcg strengths only. The proposed dosing regimen is one inhalation
twice daily.

# IX. Use in Special Populations

## A. Gender Effects

A greater percentage (63%) of subjects participating in the efficacy
clinical studies was male. The incidence of candidiasis mouth/throat and
hoarseness/dysphonia was lower in males \[5% -6% with candidiasis and \<
1% -2% with hoarseness\] than females \[9% to 14% with candidiasis and
5% to 7% with hoarseness\]. The incidence by gender was comparable for
other adverse events. There were no gender-related differences in
effectiveness.

## B. Age, Race/Ethnicity effects on Safety or Efficacy

Subjects age in the clinical studies ranged from 40 to 90 years and the
majority of subjects were Caucasian. There was not a representative
number of patients in the other ethnic groups to allow for meaningful
statistical comparisons. Although there were some scattered differences
in the incidence of individual AEs, there did not appear to be any
age-related or ethic origin-related differences in efficacy or safety.

## C. Pediatric Program

In compliance with 21 CFR 314.55(c)(3) Glaxo has requested a waiver of
submission of an assessment of pediatric use with Advair ® Diskus in
subjects 0 to 16 years of age for COPD. The reason the sponsor gives for
the waiver request is that the disease being studied COPD as defined by
the ATS does not occur in this age group. The sponsor further states
that COPD occurs in patients who have usually been smoking for 20 or
more years and that symptoms commonly present in the 5^th^ decade of
life. Progressive airflow obstruction is also observed in patients with
COPD. The Clinical program for COPD studied only subjects aged 40 years
and older with a substantial smoking history.

Safety data and dosing recommendations are available for pediatric
subjects 12 years of age and older from asthma studies with Advair
Diskus. The sponsor currently has a pediatric program addressing safety
and dosing recommendations for Advair Diskus in asthmatic patients 4 to
11 years of age. Pediatric studies in subjects with asthma 6 months to 4
years of age are currently ongoing with both active components
\[salmeterol, FP\] of Advair.

The sponsor's request for a waiver for studies with Advair Diskus for
the indication of COPD in the pediatric population is appropriate.

## D. Other Populations i.e. Pregnancy, Renal, or Hepatic Compromise

Formal studies were not conducted in subjects with renal impairment or
hepatic compromise. Since FP is predominantly cleared by hepatic
metabolism impairment of liver function may lead to accumulation of FP
in plasma. Therefore, patients with hepatic disease should be closely
monitored. There are no adequate and well-controlled studies with Advair
Diskus in pregnant women. No pregnancies were reported during the
conduct of the Advair studies or the Flovent study FLTA3025. Because
subjects with COPD tend to be older pregnancy might be less of an issue
for the use of Advair Diskus for this indication than it is for the
asthma indication. Nevertheless, Advair Diskus should be used during
pregnancy only if the potential benefit justifies the potential risk to
the fetus.

# X. Conclusions and Recommendations

## A. Conclusions

-   Advair Diskus 500/50 and Advair Diskus 250/50 met the efficacy
    criteria for combination drug products as set forth in the Code of
    Federal regulations but approval for the treatment of COPD remains
    questionable.

-   The efficacy results for Advair Diskus 500/50 were similar to the
    efficacy results for Advair Diskus 250/50.

-   The improvement in lung function (FEV~1~) seen in the clinical
    trials was not accompanied by improvements in clinically relevant
    endpoints such as reduction in the frequency or severity of COPD
    exacerbations, or symptom scores,

-   Advair did not demonstrate a treatment advantage for COPD-related
    quality of life

-   There was a clinically meaningful change in the TDI at Endpoint with
    Advair 500/50 compared to placebo and salmeterol but not with FP.

-   The patient population studied did not represent the general COPD
    population as a whole. Over 50% of the patients had significant
    reversibility compared with up to 30% in the COPD population and all
    patients in these studies had chronic bronchitis. This brings into
    question the efficacy of this therapy in COPD patients whose
    clinical presentation is predominately emphysema without associated
    chronic bronchitis.

-   There was a relatively high incidence of oral candidiasis in the FP
    and Advair groups and respiratory infections tended to be higher in
    the FP and Advair groups compared to placebo and SAL.

-   The sponsor's threshold for laboratory values were very liberal
    making it difficult to evaluate the true incidence of hyperglycemia
    and hypokalemia in the pivotal studies.

-   Monitoring for decreased bone mineral density and ocular pressure
    disorders and cataracts was not done in these studies.

## B. Recommendations

A recommendation on approval is withheld pending the Advisory Committee
meeting January 17^th^ 2001.

# XI. Appendix

## Chronic Bronchitis Symptoms Questionnaire (CBSQ)

The CBSQ scale combined selected questions from the Petty subject
Evaluation Questionnaire

And the Revised Global Petty Questionnaire for Ease of Cough and Sputum
Clearance. The CBSQ evaluated the COPD symptoms of cough frequency and
severity, chest discomfort, and sputum production on a scale of 0-4,
where a rating of 0 reflect no symptoms. Subjects had to have a score of
4 out of a possible 16 at Treatment Day 1 to qualify for the study.

![](media/image1.png){width="5.9944444444444445in"
height="6.638888888888889in"}

## Baseline/Transition Dyspnea Index

The BDI scale administered on Treatment Day 1 rate the Baseline severity
of dyspnea on a graded scale from 0 to 4 where Grade 0 was most severe.
The scores depended on ratings for three different categories:
functional impairment, magnitude of task, and magnitude of effort as
shown below.

![](media/image3.png){width="5.5in" height="4.458333333333333in"}

![](media/image4.png){width="5.53125in" height="5.052083333333333in"}

![](media/image6.png){width="5.552083333333333in" height="5.1875in"}

The Transition (TDI) scale administered at each subsequent visit denoted
changes from Baseline in functional impairment, magnitude of task, and
magnitude of effort. The scale ranged form --3 to + 3 where negative
numbers indicated deterioration, 0 was no change, and positive numbers
indicated improvement as shown below.

![](media/image7.png){width="5.520833333333333in"
height="7.677083333333333in"}

## The Chronic Respiratory Disease Questionnaire

From " A measure of quality of life for clinical trials in chronic lung
disease". Gordon H Guyatt et.al. Thorax 1987; 42: 773-778

![](media/image8.png){width="3.6875in" height="5.65625in"}

![](media/image9.png){width="5.997222222222222in"
height="8.184722222222222in"}

## Modified Medical Research Council Dyspnea Scale

  ---------- ------------ -----------------------------------------------
  Grade      Degree       

  0          None         Not troubled with breathlessness except with
                          strenuous exercise

  1          Slight       Troubled by shortness of breath when hurrying
                          on the level or walking up a slight hill

  2          Moderate     Walks slower than people of the same age on the
                          level because of breathlessness or has to stop
                          for breath when walking at own pace on the
                          level

  3          Severe       Stops for breath after walking about 100 yards
                          or after a few minutes on the level

  4          Very severe  Too breathless to leave the house or breathless
                          when dressing or undressing
  ---------- ------------ -----------------------------------------------

[^1]: PS Burge et.al Randomized double blind placebo controlled study of
    fluticasone propionate in patients with moderate to severe chronic
    obstructive pulmonary disease: the ISOLDE trial. *BMJ vol 320 13 May
    2000; 1297-1303*

    Pier Luigi Paggiaro et.al. Multicentre randomized placebo-controlled
    trial of inhaled fluticasone propionate in patients with chronic
    obstructive pulmonary disease. The Lancet Vol 351 March 14, 1998;
    773-779

[^2]: Report of the Medical Research Council Working Party. 1981. Long
    term domiciliary oxygen therapy in chronic hypoxic cor pulmonale
    complicating chronic bronchitis and emphysema. *Lancet* **1**:
    681-685

    Nocturnal Oxygen Therapy Trial Group (NOTT) 1980. Continuous or
    nocturnal oxygen therapy in hypoxemic chronic obstructive lung
    disease. *Ann Intern. Med*. **93**: 391-398

[^3]: ^?^ Dennis E. Niewoehner et.al. For the Department of Veterans
    Affairs Cooperative Study Group. Effect of systemic glucocorticoids
    on exacerbations of chronic obstructive pulmonary disease. *NEJM*
    vol 340 no. **25** 1941-1947

[^4]: Chronic obstructive pulmonary disease (COPD) is defined as a
    disease state characterized by the presence of airflow obstruction
    due to chronic bronchitis or emphysema; the airflow obstruction is
    generally progressive, may be accompanied by airway hyperreactivity,
    and may be partially reversible. *Am J Respir Crit Care Med Vol 152.
    pp S77-S120, 1995*

[^5]: Crapo RO, Morris AH, Gardner RM. Reference spirometric values
    using techniques and equipment that meet ATS recommendations. *Am
    Rev Respir Dis 1981; 123: 659-64*

[^6]: Asthma is a clinical syndrome characterized by increased
    responsiveness of the tracheobronchial tree to a variety of stimuli.
    The major symptoms of asthma are paroxysms of dyspnea, wheezing and
    cough, which may vary from mild and almost undetectable to severe
    and unremitting (status asthmaticus). *Am J Respir Crit Care Med Vol
    152. pp S77-S120, 1995*

[^7]: Petty TL. The national mucolytic study: results of a randomized,
    double blind, placebo-controlled study of iodinated glycerol in
    chronic obstructive bronchitis. Chest 1990;97:75-83

    Rubin Bk, Ramirez O, Ohar JA. Iodinated glycerol has no effect on
    pulmonary function, symptom score, or sputum properties in patients
    with stable chronic bronchitis. Chest 1996;109348-52

[^8]: Jaeschke R, Singer J, Guyatt GH. Measurement of health status:
    ascertaining the minimal clinically important difference. Controlled
    Clinical Trials 1989;10:407-15

[^9]: Standards for the Diagnosis and Care of Patients with Chronic
    Obstructive Pulmonary Disease. *Am J Respir Crit Care Med Vol 152.
    Pp. S77-S120, 1995*

[^10]: Severity of COPD exacerbations: Type 1 (severe) -- Increased
    dyspnea, sputum volume, and sputum purulence (ii) Type 2 (moderate)
    -- Two of these three symptoms are present (iii) Type 3 (mild) --
    One of these three symptoms are present in addition to at least one
    of the following findings: upper respiratory infection within the
    past 5 days; fever without other cause; increased wheezing;
    increased cough; or increase in respiratory rate or heart rate by
    20% as compared with baseline. *Anthonisen et.al Antibiotic therapy
    in exacerbations of chronic obstructive pulmonary disease. Ann Int
    Med; 1987 **106**: 196-204*

[^11]: The ISOLDE \[Inhaled steroids in obstructive lung disease\] trial
    was a 3-year Non-U.S. multicenter, double blind, placebo-controlled,
    parallel group study of the efficacy and tolerability of long-term
    FP 500 mcg BID in COPD.