# Presentation: 821163

## FDA PresentationAdvair Diskus 500/50  

**Carol Bosken, MD, ScM, MPH**
**Medical Officer**
**Division of Pulmonary and Allergy Products**
**Feng Zhou, MS**
**Statistical Reviewer**
**Division of Biometrics II**

## Outline

- History of development program
- Dr. Carol Bosken
- Introduction to Efficacy results
- Dr. Carol Bosken
- Efficacy results
- Ms. Feng Zhou
- Safety results and summary
- Dr. Carol Bosken

## Outline

- History of development program
- Dr. Carol Bosken
- Introduction to efficacy results
- Dr. Carol Bosken
- Efficacy results
- Ms. Feng Zhou
- Safety  results and summary
- Dr. Carol Bosken

## Original Approval of Advair Diskus for COPD 

- Advair Diskus 250/50 was approved for the maintenance treatment of  airflow obstruction in  patients with COPD  associated with chronic bronchitis in November 2003
- Original development program designed to demonstrate contribution of each component of Advair (Fluticasone propionate [FP] and salmeterol [SAL]) to the efficacy of Advair in improving lung function

## Original Approval of Advair Diskus for COPD 

- Advair was superior to each of the relevant individual components for pre and post-dose FEV1 endpoints but the improvement with the 500/50 mcg dose was not superior to the improvement  seen with Advair 250/50
- No additional  benefit with other efficacy measures such as patient-reported outcomes, and exacerbation rates for either dose
- Patients enrolled in the study must have had a history of chronic bronchitis by the standard clinical definition

## Original Approval of Advair Diskus for COPD

- The approval is limited
- 250/50 mcg BID only
- Recommended only for patient with COPD associated with chronic bronchitis
- Phase IV commitment
- 1-year study to assess the effects of Advair 250/50 mcg BID on the incidence of COPD exacerbations
- 2-year study to assess the effects of Advair 250/50 mcg BID on bone mineral density

## Protocol Design  (Study SCO30003)

- 3-year treatment period
- Efficacy outcome
- Primary – all-cause mortality
- Key secondary outcomes
- COPD-related mortality
- Long term oxygen therapy
- Other endpoints
- Moderate and severe COPD exacerbations
- Patient reported outcome measures
- Pulmonary function (FEV1)

## Protocol Design (Study SCO30003)

- Treatments
- Advair (SFC) 500/50 mcg BID
- Fluticasone propionate (FP) 500 mcg BID
- Salmeterol (SAL) 50 mcg BID
- Sample size
-  3800 to give an 80% power to detect a 5.0% difference between Advair and placebo

## Agency Review(Study SCO30003)                            

- With mortality as the primary efficacy outcome, one study could be sufficient IF
- The results are statistically robust
- Safety findings do not alter the risk/benefit unfavorably
- International enrollment acceptable BUT
- trends in the US population would have to support efficacy
- No objection to one dose of Advair

## Trial Conduct (Study SCO30003) 

- Amendments
- Moderate and severe COPD exacerbations were made the key secondary efficacy outcome
- Increase in sample size to 6040
- Pre-NDA discussions with Agency
- Two studies would be required to support the decrease in exacerbations claim.

## NDA Submission

-  Proposed Indications
- Increase survival
- Decrease exacerbation rate
- Decrease airflow obstruction
- Population
- All patients with COPD
- Dose
- 500/50 mcg BID

## NDA Submission

- SCO30003 (Study 03))
- 3 years
-  Mortality and exacerbation rate
- SFCB3024 (Study 24)
- 1 yr study conducted entirely outside of the US
- Lung function and exacerbation rate
- No prior consultation with the Agency
- SFCA3006
- Submitted with original application COPD indication
- 6 months
- Used to support the treatment of airflow obstruction indication only

## Saint George’s Respiratory Questionnaire

|  Total Score | SAL | FP | SFC |
| --- | --- | --- | --- |
| Study SCO30003
    N 
    Difference from placebo  | 
980
-1.0 | 
1005
-2.0 | 
1002
-3.1 |
| Study SFCB3024
    N 
    Difference from placebo  | 
321
-1.0 | 
340
-0.6 | 
320
-2.0 |

## Outline

- History of development program
- Dr. Carol Bosken
- Introduction to efficacy results
- Dr. Carol Bosken
- Efficacy results
- Ms. Feng Zhou
- Safety results and summary
-  Dr. Carol Bosken

## Introduction to Efficacy Results

- Patient populations
- Efficacy endpoints

## Populations

|  
Characteristic | SCO30003
N=6112 | SFCB3024
N=1465 |
| --- | --- | --- |
| History of cough and sputum production | --- | + |
| History of previous exacerbation | --- | 1 mod/severe in 12 months prior to enrollment |
| FEV1, % predicted
     Inclusion criteria
     Baseline pre-BD FEV1 | 
< 60
40 | 
25-70
45 |

## Regional Variation in Demographic Variables (Study SCO30003)

|  
Region | 
N (%) | Age
( > 65 years) | 
Sex
(M) | BMI
(<18 kg/m2) | FEV1 % predicted
(mean) |
| --- | --- | --- | --- | --- | --- |
| USA | 1388 (23%) | 56% | 60% | 4% | 39 |
| Asia | 758 (12%) | 66% | 90% | 18% | 36 |
| E Europe | 1154 (19%) | 45% | 84% | 3% | 42 |
| W Europe | 1908 (31%) | 56% | 78% | 3% | 43 |
| Other | 904 (15%) | 60% | 72% | 6% | 39 |

## Regional Variation in Medical Practice (Study SCO30003)

- ICS taken by 64% of W Europeans in contrast to 45 to 49% of the other populations
- Oxygen saturation obtained in 90% of US patients in contrast to 48% of E European patients and 55 to 73% of the other populations

## Introduction to Efficacy Results

- Patient populations
- Efficacy endpoints

## Survival Endpoint       (Study SCO30003)

- An unequivocal endpoint with essentially complete follow-up
- Cause of death
- Prospectively defined
- Adjudicated by the CEC
- Analysis
- All cause mortality
- On treatment mortality
- COPD-related mortality

## Exacerbation Endpoint            (Study SCO30003)

- A COPD exacerbation was defined as moderate if treated with systemic corticosteroids and/or antibiotics and severe if hospitalization was required
- No required symptoms
- No time limits on duration of exacerbation or requirement for a specified period of time between exacerbations
- No limit on number of exacerbations

##  Exacerbation Endpoint (Study SCO30003)

- Duration highly variable
- Median 12 days
- Range 1 to 747 days
- 12% greater than 30 days
- Multiple short treatment courses within a single Moderate/severe COPD exacerbation
- Would not count as an exacerbation, no matter how severe, if not treated (i.e. end of life decision, patient did not get to hospital)
- Antibiotic and corticosteroid-treated exacerbations not identical

## Exacerbation Endpoint(Study SFCB3024)

- Exacerbation definition  with
- Guidelines for symptoms
- Must have 7 days between exacerbations
- Treat the exacerbation for 10 days

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