Food and Drug Administration Division of Pulmonary and Allergy Drug Products Pulmonary-Allergy Drugs...
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Food and Drug Administration Division of Pulmonary and Allergy Drug Products Pulmonary-Allergy Drugs Advisory Committee Meeting July 13, 2005 Safety of Long-acting Beta-agonist Bronchodilators Salmeterol Sally M. Seymour, M.D. Medical Officer Division of Pulmonary and Allergy Drug Products
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Transcript of Food and Drug Administration Division of Pulmonary and Allergy Drug Products Pulmonary-Allergy Drugs...
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Pulmonary-Allergy Drugs Advisory Committee Meeting
July 13, 2005
Safety of Long-acting Beta-agonist Bronchodilators
Salmeterol
Sally M. Seymour, M.D.
Medical Officer
Division of Pulmonary and Allergy Drug Products
July 13, 2005
PADAC Meeting
2
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Regulatory History Post-marketing Studies
Serevent Nationwide Surveillance Study (SNS)Salmeterol Multicenter Asthma Research Trial
(SMART) Post-marketing Spontaneous Reports Product Label Summary
July 13, 2005
PADAC Meeting
3
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Regulatory History Post-marketing Studies
Serevent Nationwide Surveillance Study (SNS)Salmeterol Multicenter Asthma Research Trial
(SMART) Post-marketing Spontaneous Reports Product Label Summary
July 13, 2005
PADAC Meeting
4
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Regulatory History Serevent Inhalation Aerosol
Approved February 1994 for asthma Maintenance treatment of asthma & prevention of
bronchospasm in patients with reversible obstructive airways disease
Discontinued by Sponsor as part of CFC phase out Serevent Diskus
Approved September 1997 Advair Diskus
Fluticasone propionate & salmeterol xinafoate Approved August 2000
July 13, 2005
PADAC Meeting
5
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Regulatory History Salmeterol Inhalation Aerosol NDA
Two Phase 3 twelve-week clinical trials (n=556) Improvement in FEV1 Improvement in AM PEFR Improvement in mean % days and mean % nights with
no asthma symptoms Less rescue medication use
SNS results consideredAdvisory committee February 1993Approved February 1994 for asthma
July 13, 2005
PADAC Meeting
6
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Regulatory History
Reports of life-threatening respiratory events and fatalities within first 6 months after approval
Label revised January 1995 – new WARNINGS Serious acute respiratory events, including fatalities
have been reported with salmeterol Salmeterol not for acute symptoms Salmeterol not a substitute for inhaled corticosteroids Salmeterol should not be initiated in worsening or
acutely deteriorating asthma Patients should have a short acting beta agonist for
acute symptoms
July 13, 2005
PADAC Meeting
7
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Regulatory History
Physician and patient education program Sponsor committed to safety study
Salmeterol Multicenter Asthma Research Trial (SMART)
Safety study in 30K patients with asthma SMART initiated July 1996
Amended June 1999 to increase population from 30K to 60K
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Regulatory History SMART
Planned Interim analysis in 2002 26K enrolled
DSMB analysis Point estimates suggested excess risk with salmeterol
in total population African Americans may be at particular risk
DSMB recommendations Optimal to continue study if timely recruitment feasible If timely recruitment not feasible, terminate study and
disseminate findings within 3-6 months
July 13, 2005
PADAC Meeting
9
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Regulatory History Sponsor terminated SMART in January 2003 Dear Healthcare Professional Letter January 2003 Label revised August 2003 based upon preliminary
SMART data Boxed Warning Information regarding SMART in Clinical Trials Section
Full SMART data submitted August 2003 NDI search performed and adjudication pending
SMART study report submitted February 2004 Included adjudicated NDI data
Label revised September 2004
July 13, 2005
PADAC Meeting
10
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Regulatory History Post-marketing Studies
Serevent Nationwide Surveillance Study (SNS)
Salmeterol Multicenter Asthma Research Trial (SMART)
Post-marketing Spontaneous Reports Product Label Summary
July 13, 2005
PADAC Meeting
11
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Serevent Nationwide Surveillance Study (SNS)
Randomized, double-blind, active-controlled (salbutamol), parallel group, 16-week trial in UK
N=25,180 (2:1 randomization) Salmeterol 50mcg BID vs. salbutamol 200mcg
QID Clinic visits after 4, 8, and 16 weeks Outcome measures
Serious adverse events Reasons for withdrawals
BMJ 1993; 306:1034-7
July 13, 2005
PADAC Meeting
12
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Serevent Nationwide Surveillance Study (SNS) - Results
BMJ 1993; 306:1034-7
July 13, 2005
PADAC Meeting
13
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Regulatory History Post-marketing Studies
Serevent Nationwide Surveillance Study (SNS)
Salmeterol Multicenter Asthma Research Trial (SMART)
Post-marketing Spontaneous Reports Product Label Summary
July 13, 2005
PADAC Meeting
14
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Multicenter Asthma Research Trial(SMART) Protocol
Multi-center, randomized, double-blind, placebo-controlled, parallel group study
Treatment period: 28 weeks Sample Size: 30,000 (increased to 60,000 in 1999)
Age 12 yrs Clinical diagnosis of asthma Currently taking asthma medications, but no LABA
Treatment groups: Salmeterol MDI 50mcg BID Placebo BID
One clinic visit then phone calls Q 4wks
July 13, 2005
PADAC Meeting
15
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Protocol Primary Endpoint: Combined respiratory-related
deaths and respiratory-related life-threatening experiences (intubation & mechanical ventilation)
Key Secondary Endpoints: Asthma-related death Asthma-related deaths and life-threatening experiences All-cause SAEs All-cause death
July 13, 2005
PADAC Meeting
16
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Protocol Non-inferiority design - not designed to show
a difference between salmeterol and placebo Powered to rule out
40% increase in combined respiratory related deaths and life threatening experiences
3 times increase in asthma related deaths Planned interim analysis after ~half of
subjects enrolledStopping Criteria
RR of 1.4 for primary endpoint, alpha = .01 RR of 3 for asthma related deaths, alpha =.01
July 13, 2005
PADAC Meeting
17
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART – Interim Analysis
Interim analysis performed after 26K enrolled in 2002
DSMB reviewed data Potential treatment group difference African Americans may be at particular risk
DSMB recommended Continue study if recruitment feasible Terminate study if recruitment not feasible and
disseminate findings within 3-6 months SMART terminated January 2003
July 13, 2005
PADAC Meeting
18
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results Results from early termination of study
Did not meet pre-specified stopping criteriaDid not meet non-inferiority objectiveSuggested a difference in some endpoints
Based upon 28 week treatment period Inclusion of NDI search data Life table analyses
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results - Disposition
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results - Demographics
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results – Primary EP
*Intubation and mechanical ventilation
July 13, 2005
PADAC Meeting
22
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results – Key Secondary EP
July 13, 2005
PADAC Meeting
23
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results Inhaled Corticosteroid (ICS) Use
ICS analyses all post hoc ICS use recorded at baseline ICS not randomly assigned 47% total population used ICS
50% Caucasians used ICS38% African Americans used ICS
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results - ICS Use
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART Results - ICS Use
July 13, 2005
PADAC Meeting
26
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART - Conclusions SMART stopped early
Interim analysis and difficulty with recruitment Total population
RR 1.4 for primary outcome events -respiratory related deaths or life threatening experiences
CI did not exclude oneRR 4.37 for asthma related deaths
CI excludes oneRR 2.16 for respiratory related deaths
CI excludes one
July 13, 2005
PADAC Meeting
27
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
SMART - Conclusions Caucasian Subpopulation
No treatment group difference for primary endpoint Numeric increase in asthma related deaths and
respiratory related deaths in salmeterol group African American Subpopulation
Numeric increase in salmeterol group for primary endpoint events
Numeric increase in salmeterol group for Asthma related deaths Respiratory related deaths Combined asthma related deaths or life threatening
experiences (CI excludes 1)
No definitive conclusions regarding ICS use
July 13, 2005
PADAC Meeting
28
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Regulatory History Post-marketing Studies
Serevent Nationwide Surveillance Study (SNS)Salmeterol Multicenter Asthma Research Trial
(SMART) Post-marketing Spontaneous Reports Product Label Summary
July 13, 2005
PADAC Meeting
29
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Post-Marketing Reports
Adverse Events Reporting SystemMay 1994-February 2005
Reviewed by Office of Drug Safety 201 deaths reported in US with salmeterol
91 asthma-related deaths 10 possible asthma-related deaths
Difficult to draw conclusions
July 13, 2005
PADAC Meeting
30
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Regulatory History Post-marketing Studies
Serevent Nationwide Surveillance Study (SNS)Salmeterol Multicenter Asthma Research Trial
(SMART) Post-marketing Spontaneous Reports Product Label Summary
July 13, 2005
PADAC Meeting
31
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Current Label
Clinical Trials: SMART Results for primary and key secondary endpoints
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Salmeterol Regulatory History Post-marketing Studies
Serevent Nationwide Surveillance Study (SNS)Salmeterol Multicenter Asthma Research Trial
(SMART) Post-marketing Spontaneous Reports Product Label Summary
July 13, 2005
PADAC Meeting
33
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Summary Regulatory History SNS
Numerical increase in respiratory/asthma deaths in salmeterol group
Fewer withdrawals due to respiratory or asthma events
SMART Total population
Increase in asthma and respiratory related deaths African American Subpopulation
Increase primary events Increase combined asthma related deaths or life threatening
experiences Not designed to assess the effects ICS use on
outcomes Product label
July 13, 2005
PADAC Meeting
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Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Questions for Committee
1. The product labels of salmeterol containing products have been modified to include warnings related to the SMART study.
a. Based on currently available information, what further actions, if any, do you recommend that the Agency take to communicate or otherwise manage the risks of severe asthma exacerbations seen in the SMART study?
b. Based on the currently available information, do you agree that salmeterol should continue to be marketed in the United States?
July 13, 2005
PADAC Meeting
35
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
Questions for Committee
3. What further investigation, if any, do you recommend to be performed by GSK that can improve the understanding of the nature and magnitude of the risk of salmeterol?
July 13, 2005
PADAC Meeting
36
Food and Drug Administration
Division of Pulmonary and Allergy Drug Products
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
