# Presentation: 804603

## 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

## Salmeterol

- Regulatory History
- Post-marketing Studies
- Serevent Nationwide Surveillance Study (SNS)
- Salmeterol Multicenter Asthma  Research Trial (SMART)
- Post-marketing Spontaneous Reports
- Product Label
- Summary

- PADAC Meeting

- July 13, 2005

## Salmeterol	

**Regulatory History**
- Post-marketing Studies
- Serevent Nationwide Surveillance Study (SNS)
- Salmeterol Multicenter Asthma  Research Trial (SMART)
- Post-marketing Spontaneous Reports
- Product Label
- Summary

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## 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 considered
- Advisory committee February 1993
- Approved February 1994 for asthma

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- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## Salmeterol	

- Regulatory History
**Post-marketing Studies**
**Serevent Nationwide Surveillance Study (SNS)**
**Salmeterol Multicenter Asthma  Research Trial (SMART)**
- Post-marketing Spontaneous Reports
- Product Label
- Summary

- PADAC Meeting

- July 13, 2005

## 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*

- PADAC Meeting

- July 13, 2005

## Serevent Nationwide Surveillance Study (SNS) - Results

*BMJ 1993; 306:1034-7*

- PADAC Meeting

- July 13, 2005

## Salmeterol	

- Regulatory History
**Post-marketing Studies**
**Serevent Nationwide Surveillance Study (SNS)**
**Salmeterol Multicenter Asthma  Research Trial (SMART)**
- Post-marketing Spontaneous Reports
- Product Label
- Summary

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## 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 enrolled
- Stopping Criteria
- RR of 1.4 for primary endpoint, alpha = .01
- RR of 3 for asthma related deaths, alpha =.01

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## SMART Results

- Results from early termination of study
- Did not meet pre-specified stopping criteria
- Did not meet non-inferiority objective
- Suggested a difference in some endpoints
- Based upon 28 week treatment period
- Inclusion of NDI search data
- Life table analyses

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## SMART Results - Disposition

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## SMART Results - Demographics

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## SMART Results – Primary EP

- *Intubation and mechanical ventilation

- PADAC Meeting

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## SMART Results – Key Secondary EP

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- July 13, 2005

## 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 ICS
- 38% African Americans used ICS

- PADAC Meeting

- July 13, 2005

## SMART Results  - ICS Use

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## SMART Results  - ICS Use

- PADAC Meeting

- July 13, 2005

## 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 one
- RR 4.37 for asthma related deaths
- CI excludes one
- RR 2.16 for respiratory related deaths
- CI excludes one

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## Salmeterol	

- Regulatory History
- Post-marketing Studies
- Serevent Nationwide Surveillance Study (SNS)
- Salmeterol Multicenter Asthma  Research Trial (SMART)
**Post-marketing Spontaneous Reports **
- Product Label
- Summary

- PADAC Meeting

- July 13, 2005

## Post-Marketing Reports

- Adverse Events Reporting System
- May 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

- PADAC Meeting

- July 13, 2005

## Salmeterol	

- Regulatory History
- Post-marketing Studies
- Serevent Nationwide Surveillance Study (SNS)
- Salmeterol Multicenter Asthma  Research Trial (SMART)
- Post-marketing Spontaneous Reports
**Product Label **
- Summary

- PADAC Meeting

- July 13, 2005

## Current Label

- Clinical Trials: SMART
- Results for primary and key secondary endpoints

- PADAC Meeting

- July 13, 2005

## Salmeterol	

- Regulatory History
- Post-marketing Studies
- Serevent Nationwide Surveillance Study (SNS)
- Salmeterol Multicenter Asthma  Research Trial (SMART)
- Post-marketing Spontaneous Reports
- Product Label
**Summary**

- PADAC Meeting

- July 13, 2005

## 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

- PADAC Meeting

- July 13, 2005

## Questions for Committee	

- 1.  The product labels of salmeterol containing products have been modified to include warnings related to the SMART study.
- 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?
- Based on the currently available information, do you agree that salmeterol should continue to be marketed in the United States?

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## 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?

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## 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

- PADAC Meeting

- July 13, 2005