Title: Pulmonary-Allergy Drugs Advisory Committee July 13, 2005
1Pulmonary-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
2Order 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
3Product 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
4Order 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
5Foradil 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
6Foradil 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
7Foradil 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 -
8Order 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
9Foradil NDA
- 3 asthma studies in the NDA were considered
pivotal - Studies 040, 041 in adults, adolescents
- Pediatric study (5-12 years) 049
10Foradil 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
11Foradil 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
12Foradil NDA Efficacy
13Foradil 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
14Foradil 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
15Order 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
16Foradil 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
17Foradil 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
18Foradil 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)
19Foradil 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)
20Foradil 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)
21Foradil 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
22Foradil 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)
23Foradil Phase 4 Study ResultsAdverse Events
24Foradil Phase 4 Study Results Serious Adverse
Events
25Summary Serious Asthma Exacerbations in Foradil
Studies
26Order 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
27Post-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
28Order 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
29Summary 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
30Questions 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?
31Questions 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?
32Division 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