ADVAIRTM DISKUS(R) (Fluticasone propionate/salmeterol inhalation by HC120730065145

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									         ADVAIRTM DISKUS(R)
 (Fluticasone propionate/salmeterol
          inhalation powder)


    Pulmonary and Allergy Drugs Advisory
            Committee Meeting

                   Gaithersburg, Maryland
                      January 17, 2002

         Lydia I. Gilbert-McClain, MD, FCCP
             Medical Reviewer, DPADP


Pulmonary and Allergy Drugs Advisory Committee
January 17, 2002
                         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




    Pulmonary and Allergy Drugs Advisory Committee
                                                     2
    January 17, 2002
        COMBINATION DRUG PRODUCT

                             ADVAIR DISKUS




Fluticasone propionate                          Salmeterol xinafoate

Not approved for use in COPD                        Approved 1998 - Relief of
                                                    bronchospasm associated
                                                    with COPD



   Pulmonary and Allergy Drugs Advisory Committee
                                                                                3
   January 17, 2002
            DEVELOPMENT PROGRAM

                     SFCA3006                     SFCA3007

*Treatment Advair 500/50                          Advair 250/50
   Arms
           FP 500                                 FP 250

                     Salmeterol 50                Salmeterol 50

                     Placebo                      Placebo

                    *One inhalation twice daily
                    FP = fluticasone propionate
 Pulmonary and Allergy Drugs Advisory Committee
                                                                  4
 January 17, 2002
                            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
  Pulmonary and Allergy Drugs Advisory Committee
                                                   5
  January 17, 2002
    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

    Pulmonary and Allergy Drugs Advisory Committee
                                                      6
    January 17, 2002
                          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 FEV1 of < 65% predicted but > 0.70 L OR

• FEV1  0.70 L AND > 40% < 65% predicted

• AND FEV1/FVC ratio  70%
     Pulmonary and Allergy Drugs Advisory Committee
                                                      7
     January 17, 2002
   PATIENT POPULATION ENROLLED
• Mean FEV1 across studies was 40% -
  42% predicted


• Mean FEV1/FVC ratio across studies
  was 47% - 51%


• Percentage of subjects across studies
  with 12% improvement in FEV1 AND
  >200 ml absolute change was 54% -
  55%
 Pulmonary and Allergy Drugs Advisory Committee
                                                  8
 January 17, 2002
        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]


    Pulmonary and Allergy Drugs Advisory Committee
                                                     9
    January 17, 2002
                           Percentage of Discontinuations
                     100
% Discontinuations

                     80




                     60                                       Advair
                                                              Placebo
                                                              Salmeterol
                     40
                                                              FP

                     20




                      0


                            ADVAIR 250/50     ADVAIR 500/50


         Pulmonary and Allergy Drugs Advisory Committee
                                                                           10
         January 17, 2002
       PRIMARY EFFICACY ENDPOINTS

• Pre-dose FEV1
 Evaluate the contribution of FP in the
  combination
 ADVAIR vs. Salmeterol

 2-hr post-dose FEV1
 Evaluate the contribution of salmeterol in
  the combination
 ADVAIR vs. FP


   Pulmonary and Allergy Drugs Advisory Committee
                                                    11
   January 17, 2002
                    EFFICACY: Pre-dose FEV1



                                 ADVAIR 250/50 ADVAIR 500/50
Mean FEV1 at
baseline: Advair                         1.207 L   1.254 L

Mean FEV1 at
baseline: SAL                            1.205 L   1.192 L

Advair - SAL at
Endpoint                                 0.069 L   0.067 L

 Pulmonary and Allergy Drugs Advisory Committee
                                                             12
 January 17, 2002
       EFFICACY: 2-hr Post-Dose FEV1


                                ADVAIR 250/50 ADVAIR 500/50
Mean FEV1 at
baseline: Advair                        1.207 L   1.254 L

Mean FEV1 at
baseline: FP                            1.236 L   1.174 L


Advair - FP at                          0.124 L   0.129 L
Endpoint

 Pulmonary and Allergy Drugs Advisory Committee
                                                            13
 January 17, 2002
     EFFICACY: ADVAIR vs. Placebo
(Reversible and Non-reversible populations)
              Pre-Dose FEV1

             Overall ITT            Reversible      Non-Reversible
             population             population      population
ADVAIR               0.164 L              0.211 L      0. 107 L
250/50
ADVAIR               0.160 L              0.192 L      0.124 L
500/50



  Pulmonary and Allergy Drugs Advisory Committee
                                                                  14
  January 17, 2002
     EFFICACY: ADVAIR vs. Placebo
(Reversible and Non-reversible populations)
          2- hour post- dose FEV1

                Overall ITT            Reversible      Non-reversible
                population             population      population
ADVAIR               0.223 L                 0.282 L      0.150 L
250/50
ADVAIR               0.233 L                 0.290 L      0.167 L
500/50


  Pulmonary and Allergy Drugs Advisory Committee
                                                                    15
  January 17, 2002
         PATIENT-REPORTED OUTCOMES


• Evaluation of patient-related outcomes may be
  helpful in assessing the clinical relevance of
  FEV1 changes

• Chronic Respiratory Disease Questionnaire
  [CRDQ] used in both studies

• Sponsor-defined Minimal Clinically Important
  change [MCIC] in Overall Score 10
     Pulmonary and Allergy Drugs Advisory Committee
                                                      16
     January 17, 2002
 Chronic Respiratory Disease Questionnaire
Overall Score: Treatment Difference in Change
          From Baseline At Endpoint

                       CRDQ [Overall Score]
                                      ADVAIR        ADVAIR
                                       250/50        500/50
 Advair - Placebo                         5             5
 Advair - SAL                            3.6            2
 Advair - FP                            -0.4           5.2
 MCIC  10


   Pulmonary and Allergy Drugs Advisory Committee
                                                              17
   January 17, 2002
          CRDQ: Dyspnea Domain
Treatment Difference in Change from Baseline
                 at Endpoint


                  MCIC =  2.5
                     ADVAIR                         ADVAIR
                      250/50                         500/50
 Advair - Placebo       1.2                           2.1
 Advair - SAL           0.9                           1.3
 Advair - FP            0.1                           1.8




   Pulmonary and Allergy Drugs Advisory Committee
                                                              18
   January 17, 2002
              COPD EXACERBATIONS


Severity of exacerbations

Time to first exacerbation

Time to first moderate/severe
exacerbation

Number of withdrawals due to COPD
    exacerbations

   Pulmonary and Allergy Drugs Advisory Committee
   January 17, 2002
                           Percentage of Subjects with COPD
                                    Exacerbations

                        100
% Subjects with Exac.



                         80




                         60                                                   Advair
                                                                              Placebo
                                                                              Salmeterol
                         40
                                                                              FP

                         20




                          0


                                 ADVAIR 250/50                ADVAIR 500/50

                        Pulmonary and Allergy Drugs Advisory Committee
                                                                                           20
                        January 17, 2002
Percentage of Subjects with Moderate/Severe
               Exacerbations
   % Subjects with Mod/Sev Exac.   100




                                   80




                                   60                                    Advair
                                                                         Placebo
                                   40
                                                                         Salmeterol
                                                                         FP

                                   20




                                    0


                                         ADVAIR 250/50   ADVAIR 500/50

     Pulmonary and Allergy Drugs Advisory Committee
                                                                                      21
     January 17, 2002
Percentage of Withdrawals Due to COPD
            Exacerbations
                 100




                 80
% Withdrawals




                 60                                                   Advair
                                                                      Placebo
                 40
                                                                      Salmeterol
                                                                      FP

                 20




                  0


                         ADVAIR 250/50                ADVAIR 500/50

                Pulmonary and Allergy Drugs Advisory Committee
                                                                                   22
                January 17, 2002
       Chronic Bronchitis Symptoms
          Questionnaire [CBSQ]


 Cough frequency and severity

 Chest discomfort

 Sputum production

 Sponsor-defined MCIC 1.4

    Pulmonary and Allergy Drugs Advisory Committee
                                                     23
    January 17, 2002
CBSQ GAS: Treatment Difference in Change
       from Baseline at Endpoint

             Treatment difference in CBSQ GAS
                         MCIC  1.4

                                 ADVAIR 250/50     ADVAIR 500/50

Advair - Placebo                             0.7        0.3

Advair - SAL                                 0.6       -0.1

Advair - FP                                 -0.1        0.2

  Pulmonary and Allergy Drugs Advisory Committee
                                                              24
  January 17, 2002
Transitional Dyspnea Index (TDI): Treatment
           Difference at Endpoint



                                 ADVAIR 250/50 ADVAIR 500/50

 Advair - Placebo                           0.7     1.7

 Advair - SAL                               0.1     1.2

 Advair - FP                                  0     0.8

 MCIC  1

   Pulmonary and Allergy Drugs Advisory Committee
                                                           25
   January 17, 2002
                                   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


    Pulmonary and Allergy Drugs Advisory Committee
                                                     26
    January 17, 2002
                        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%



    Pulmonary and Allergy Drugs Advisory Committee
                                                     27
    January 17, 2002
                    ADVERSE EVENTS
                       Advair                    Placebo
                       250/50

Candidiasis 10%                                  1%

Hoarsness/             5%                        0
dysphonia

Viral                  6%                        3%
respiratory
infections



Pulmonary and Allergy Drugs Advisory Committee
                                                           28
January 17, 2002
                    ADVERSE EVENTS
                                Advair            Placebo
                                500/50

Upper respiratory 17%                             10%
tract infection

Viral respiratory               8%                3%
infections

Candidiasis                     7%                1%

Hoarseness/                     3%                2%
dysphonia


 Pulmonary and Allergy Drugs Advisory Committee
                                                            29
 January 17, 2002
                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
    Pulmonary and Allergy Drugs Advisory Committee
                                                     30
    January 17, 2002
   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

    Pulmonary and Allergy Drugs Advisory Committee
                                                     31
    January 17, 2002
                 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

    Pulmonary and Allergy Drugs Advisory Committee
                                                     32
    January 17, 2002
                       SUMMARY - EFFICACY


• No clear treatment advantage with ADVAIR
  for
      COPD-related “quality of life”

      COPD Symptoms

      COPD exacerbations

      Improvement in dyspnea
    Pulmonary and Allergy Drugs Advisory Committee
                                                     33
    January 17, 2002
                    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


 Pulmonary and Allergy Drugs Advisory Committee
                                                  34
 January 17, 2002

								
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