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Pulmonary-Allergy Drugs Advisory Committee July 13, 2005

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Title: Pulmonary-Allergy Drugs Advisory Committee July 13, 2005


1
Pulmonary-Allergy Drugs Advisory CommitteeJuly
13, 2005
  • Safety of Long-acting Beta-agonist
    Bronchodilators
  • Formoterol
  • J.H. Gunkel, M.D.
  • Medical Officer
  • Division of Pulmonary and Allergy Drug Products

2
Order of Presentation
  • Product Information
  • Product Regulatory History
  • Overview of NDA with Relevant Phase 3 Study
    Results
  • Phase 4 Post-marketing Study
  • Post-marketing Spontaneous Reports
  • Summary and Conclusions

3
Product Information
  • Foradil Aerolizer (formoterol fumarate
    inhalation powder) Novartis Pharmaceuticals
    Corporation
  • Foradil is a capsule dosage form containing a dry
    powder for oral inhalation using the
    breath-actuated Aerolizer inhaler
  • Formoterol fumarate is a racemate of (R,R)- and
    (S,S)- enantiomers

4
Order of Presentation
  • Product Information
  • Product Regulatory History
  • Overview of NDA with Relevant Phase 3 Study
    Results
  • Phase 4 Post-marketing Study
  • Post-marketing Spontaneous Reports
  • Summary and Conclusions

5
Foradil Regulatory History
  • NDA for asthma submitted June, 1997
  • Foradil clinical program evaluated two doses
  • 12 mcg twice daily
  • 24 mcg twice daily
  • Results with 24 mcg BID dose indicated
  • Higher rate of serious asthma exacerbations than
    with 12 mcg BID
  • No evidence of efficacy advantage over 12 mcg BID

6
Foradil Regulatory History
  • Therefore, only Foradil 12 mcg BID dose approved
    for maintenance treatment of asthma in adults and
    children 5 years of age and older (February 2001)
  • Finding of ? asthma exacerbations with 24 mcg BID
    dose warranted additional investigation, but
    routine post-marketing surveillance might not be
    helpful when event of concern was also underlying
    disease

7
Foradil Regulatory History
  • Approval included Phase 4 commitment to conduct
    a large, simple, placebo-controlled postmarketing
    study to further evaluate the safety and efficacy
    of one or more dose levels of Foradil Aerolizer
    above that of the approved dosein comparison to
    the safety and efficacy of the approved dose.
  • Results of SMART not known when Foradil Phase 4
    study was designed

8
Order of Presentation
  • Product Information
  • Product Regulatory History
  • Overview of NDA with Relevant Phase 3 Study
    Results
  • Phase 4 Post-marketing Study
  • Post-marketing Spontaneous Reports
  • Summary and Conclusions

9
Foradil NDA
  • 3 asthma studies in the NDA were considered
    pivotal
  • Studies 040, 041 in adults, adolescents
  • Pediatric study (5-12 years) 049

10
Foradil NDA
  • Studies 040, 041 Adults and adolescents
  • Randomized, double-blind, placebo- and
    active-controlled
  • 12-week treatment
  • Asthmatics ? 12 yrs, FEV1 ? 40 predicted, 15
    reversibility
  • Treatments
  • Foradil 12 mcg BID
  • Foradil 24 mcg BID
  • Albuterol 180 mcg QID
  • Placebo

11
Foradil NDA
  • Study 049 Children
  • 1-year study
  • Asthmatics 5-12 yrs, FEV1 50-85 predicted, 15
    reversibility
  • Treatments
  • Foradil 12 mcg BID
  • Foradil 24 mcg BID
  • Placebo

12
Foradil NDA Efficacy
13
Foradil NDA Serious Asthma Exacerbations
Study Foradil 12 mcg BID Foradil 24 mcg BID Albuterol Placebo
040a 0/136 (0) 4/135 (3.0)c 2/134 (1.5) 0/136 (0)
041a 1/139 (0.7) 5/136 (3.7)d 0/138 (0) 2/141 (1.4)
049b 8/171 (4.7) 11/171 (6.4) N.A. 0/176 (0)
aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died aAdults and adolescents ? 12 yrs bChildren 5-12 yrs c1 patient required intubation d 2 patients had respiratory arrest, 1 died
14
Foradil NDA Summary
  • Foradil 24 mcg BID not approved because serious
    asthma exacerbations were more common than with
    12 mcg BID in all 3 pivotal studies
  • There was no efficacy advantage of Foradil 24 mcg
    BID
  • Serious asthma exacerbations were more common in
    children than adults at both doses
  • Phase 4 study commitment

15
Order of Presentation
  • Product Information
  • Product Regulatory History
  • Overview of NDA with Relevant Phase 3 Study
    Results
  • Phase 4 Post-marketing Study
  • Post-marketing Spontaneous Reports
  • Summary and Conclusions

16
Foradil Phase 4 Study
  • Randomized, parallel group, placebo-controlled.
    Run-in period followed by 16-week treatment
    period with 5 study visits
  • Patient population intended to be similar to
    Phase 3 studies to allow comparison of outcomes

17
Foradil Phase 4 Study Design
  • Patient Inclusion
  • Asthmatics ? 12 yrs
  • Using inhaled beta-agonist
  • FEV1 ? 40 predicted, 12 reversibility
  • Patient Exclusion
  • Hospitalization or ER visit within 1 month
  • Parenteral, oral steroids within 1 month
  • Combination LABA and steroid must be replaced by
    monotherapies
  • Changing medications or dosages within 3-4 weeks

18
Foradil Phase 4 Study Design
  • Study Treatments
  • Foradil 24 mcg BID
  • Foradil 12 mcg BID
  • Placebo BID
  • Foradil 12 mcg BID 2 on-demand doses/day
    (open-label)
  • Albuterol rescue 90 mcg up to 8 doses/day (4
    doses/day for open-label)

19
Foradil Phase 4 Study Results Patient Disposition
  • Study conducted February, 2002 - March, 2004, in
    194 U.S. centers
  • 3820 patients screened
  • 2085 patients treated
  • 1791 patients completed
  • 294 patients discontinued (adverse event gt
    withdrawn consent gt lost to follow-up gt protocol
    violation gt unsatisfactory therapeutic effect)

20
Foradil Phase 4 Study Amendments
  • Study protocol amended 3 times after enrollment
    began (February 2002)
  • April 2002 and March 2003 amendments modified
    the use of concomitant medications to be
    consistent with GINA guidelines more use of
    corticosteroids
  • April 2003 to accelerate enrollment (age, FEV1
    criteria, medication washouts)

21
Foradil Phase 4 Study Results Baseline
Foradil 12 mcg BID N527 Foradil 24 mcg BID N527 Placebo N514 Foradil Open-label N517 Phase 3 Studies N1095
Mean age (yr) 39.2 38.5 37.8 36.9 34.3
Male () Female 47.6 52.4 44.4 55.6 41.1 58.9 46.4 53.6 45.4 54.6
Caucasian African American Asian Other 81.6 11.2 1.9 5.3 78.0 14.2 2.1 7.2 78.2 11.9 2.7 7.2 77.6 14.1 2.1 6.2 86.5 6.7 0 6.8
Baseline FEV1 ( predicted) 68.2 68.5 69.0 69.5 64.3
FEV1 reversibility () 24.2 24.1 23.3 22.4 18.3
22
Foradil Phase 4 Study Results Baseline
Foradil 12 mcg BID N527 Foradil 24 mcg BID N527 Placebo N514 Foradil Open-label N517
Oral steroid courses N () None 1-2 gt2 438 (83.1) 79 (15.0) 10 (1.9) 432 (82.0) 76 (14.4) 17 (3.2) 432 (84.0) 77 (15.0) 5 (1.0) 430 (83.2) 77 (14.9) 8 (1.5)
ER Visits - N () None 1-2 gt2 493 (93.5) 29 (5.5) 5 (0.9) 487 (92.4) 31 (5.0) 7 (1.3) 480 (93.4) 33 (6.4) 1 (0.2) 481 (93.0) 28 (5.4) 6 (1.2)
Hospitalizations N () None 1-2 gt2 517 (98.1) 10 (1.9) 0 518 (98.3) 6 (1.2) 0 508 (98.8) 6 (1.2) 0 506 (97.9) 7 (1.4) 2 (0.4)
23
Foradil Phase 4 Study ResultsAdverse Events
24
Foradil Phase 4 Study Results Serious Adverse
Events
25
Summary Serious Asthma Exacerbations in Foradil
Studies
26
Order of Presentation
  • Product Information
  • Product Regulatory History
  • Overview of NDA with Relevant Phase 3 Study
    Results
  • Phase 4 Post-marketing Study
  • Post-marketing Spontaneous Reports
  • Summary and Conclusions

27
Post-marketing Spontaneous Reports
  • AERS contains 180 domestic reports for
    formoterol, as of June 14, 2005
  • 11 reports of bronchospasm and obstruction
  • Since June, 2001, 4 domestic deaths were reported
  • Of 4 domestic deaths, 2 were from myocardial
    infarction, 2 other causes not reported

28
Order of Presentation
  • Product Information
  • Product Regulatory History
  • Overview of NDA with Relevant Phase 3 Study
    Results
  • Phase 4 Post-marketing Study
  • Post-marketing Spontaneous Reports
  • Summary and Conclusions

29
Summary and Conclusions
  • In Phase 3 studies, serious asthma exacerbations
    occurred more frequently with Foradil 24 mcg BID
    than Foradil 12 mcg BID
  • Foradil 24 mcg BID not approved
  • Serious asthma exacerbations more frequent in
    children
  • Phase 4 study results inconclusive
  • Small N and no children

30
Questions To Committee
  • The label of the formoterol containing product
    does not include warnings comparable to the
    warnings that are present in the salmeterol
    containing products.
  • Based on the currently available information,
    should the label of formoterol containing
    products include warnings similar to those in the
    salmeterol label?
  • Based on the currently available information, do
    you agree that formoterol should continue to be
    marketed in the United States?

31
Questions To Committee
  • What further investigation, if any, do you
    recommend to be performed by Novartis that can
    improve the understanding of the nature and
    magnitude of the risk of formoterol?

32
Division of Pulmonary and Allergy Drug Products
Parklawn Building, Room 10B-45 5600 Fishers Lane,
HFD-570 Rockville, MD 20857
Phone 301-827-1050 Fax 301-827-1271
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