# Presentation: 659131

## Pulmonary and Allergy Drugs Advisory Committee Meeting

Gaithersburg, Maryland January 17, 2002Lydia I. Gilbert-McClain, MD, FCCPMedical Reviewer, DPADP

**Gaithersburg, Maryland**** January 17, 2002****Lydia I. Gilbert-McClain, MD, FCCP****Medical Reviewer, DPADP**

**ADVAIR****TM**** DISKUS****(R)****(Fluticasone propionate/salmeterol inhalation powder)**

## CLINICAL ISSUES

**Clinical relevance of the Efficacy data**
**Application of data from these ADVAIR trials to the general COPD population**
**Adequacy of the Safety data**

## COMBINATION DRUG PRODUCT

**                                 **

**Not approved for use in COPD**

**Approved 1998 - Relief of bronchospasm associated with COPD**

**ADVAIR DISKUS**

**Fluticasone propionate**

**Salmeterol xinafoate**

## DEVELOPMENT PROGRAM

## OBJECTIVES

**1.**** ****Efficacy of ADVAIR 250/50 bid  and ADVAIR 500/50 bid**
**2. Safety of ADVAIR 250/50 bid and ADVAIR 500/50 bid**
**3.The “ quality of life” in COPD subjects receiving ADVAIR 250/50 bid  and ADVAIR 500/50 bid**

## FIXED COMBINATION DRUGS POLICY

**21 CFR 300.50 -Two or more drugs may be combined in a single dosage form when:**
**Each component makes a contribution to the claimed effects**
**The combination is safe and effective**
**SFCA3006, SFCA3007 adequately designed to fulfill the efficacy requirements of the policy**

## ENTRY CRITERIA

**Diagnosis of COPD [ATS definition]**
**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**
**Baseline FEV****1**** of < 65% predicted but > 0.70 L OR**
**FEV****1**** ******** 0.70 L AND > 40% < 65% predicted**
**AND FEV****1****/FVC ratio ******** 70%**

## PATIENT POPULATION ENROLLED

**Mean FEV****1**** across studies was 40% - 42% predicted  **
**Mean FEV****1****/FVC ratio across studies was 47% - 51%**
**Percentage of subjects  across studies with 12% improvement in FEV****1**** AND >200 ml absolute change  was 54% - 55%**

## PATIENT POPULATION ENROLLED

**All subjects had a history  of chronic bronchitis**
**Mean baseline symptom score  on Chronic Bronchitis Symptom Questionnaire ranged 6.9 - 7.5 [maximum possible score = 16]**
**Dyspnea score ******** 2 [scale 0 - 4]**

## Percentage of Discontinuations

## PRIMARY EFFICACY ENDPOINTS

**Pre-dose FEV****1 **** **
**Evaluate the contribution of FP in the combination**
**ADVAIR vs. Salmeterol**
**2-hr post-dose FEV****1**
**Evaluate the contribution of salmeterol in the combination**
**ADVAIR vs. FP**

## EFFICACY: Pre-dose FEV1

## EFFICACY: 2-hr Post-Dose FEV1

## EFFICACY: ADVAIR vs. Placebo (Reversible and Non-reversible populations)Pre-Dose FEV1

## EFFICACY: ADVAIR vs. Placebo(Reversible and Non-reversible populations)2- hour post- dose FEV1

## PATIENT-REPORTED OUTCOMES

**Evaluation of patient-related outcomes may be helpful in assessing the clinical relevance of FEV****1**** changes**
**Chronic Respiratory Disease Questionnaire [CRDQ] used in both studies**
**Sponsor-defined Minimal Clinically Important change  [MCIC] in Overall Score ********10**

## Chronic Respiratory Disease QuestionnaireOverall Score: Treatment Difference in Change From Baseline At Endpoint

## CRDQ: Dyspnea Domain Treatment Difference in Change from Baseline at Endpoint

## COPD EXACERBATIONS

**Severity of exacerbations**
**Time to first exacerbation**
**Time to first moderate/severe exacerbation**
**Number of withdrawals due to COPD   ****	****exacerbations**

## Percentage of Subjects with COPD Exacerbations

## Percentage of Subjects with Moderate/Severe Exacerbations

## Percentage of Withdrawals Due to COPD Exacerbations

## Chronic Bronchitis Symptoms Questionnaire [CBSQ]

**Cough frequency and severity**
**Chest discomfort**
**Sputum production**
**Sponsor-defined MCIC ********1.4**

## CBSQ GAS: Treatment Difference in Change from Baseline at Endpoint

## Transitional Dyspnea Index (TDI): Treatment Difference at Endpoint

## SAFETY

**Incidence of Cardiovascular events similar across treatment groups**
**No clinically significant change in heart rate**
**No drug-related QTc changes**
**Holter monitoring -  One case of heart block with ADVAIR 500/50**

## ADVERSE EVENTS

**Higher percentage of subjects in ADVAIR groups reported adverse events compared to placebo**
**ADVAIR 250/50****	****	****70%**
**Placebo****	****	****	****64%**
**ADVAIR 500/50****	****	****78%**
**Placebo****	****	****	****69%**

## ADVERSE EVENTS

## ADVERSE EVENTS

## OTHER ADVERSE EVENTS

**Fractures rarely reported**
**No cataracts reported**
**Two reports of ocular pressures disorders in the ADVAIR 500/50 group and one in the placebo group **
**Elevated blood glucose [ > 175 mg/dl]  similar in ADVAIR and placebo groups**** **

## SAFETY: Evaluation of HPA Axis Effects

**Mean AM cortisol levels comparable in ADVAIR and placebo groups on Treatment Day 1 and Endpoint**
**No adrenal insufficiency observed with  ACTH [Cosyntropin] stimulation testing**
**ACTH stimulation insensitive test for less than complete adrenal insufficiency**

## SUMMARY -  EFFICACY

**ADVAIR 250/50 and ADVAIR 500/50 meet efficacy criteria for combination drugs in the primary endpoints**
**Similar  efficacy for ADVAIR 250/50 and ADVAIR 500/50**
**Numerically, effect size in “Reversible” subjects  > effect size of “Non-reversible” subjects**

## SUMMARY - EFFICACY

**No clear treatment  advantage with ADVAIR for **
**COPD-related “quality of life”**
**COPD Symptoms **
**COPD exacerbations**
**Improvement in dyspnea**

## SUMMARY - SAFETY

**Higher incidence of candidiasis, viral respiratory infections and hoarseness/dysphonia with ADVAIR**
**No adrenal insufficiency observed with ACTH [Cosyntropin] stimulation testing**
**Studies not designed to evaluate bone mineral density**  **or ocular effects****	****	****	****	****	****	****	****	****	**