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Correspondence |

Comments on the Salmeterol Multicenter Asthma Research Trial FREE TO VIEW

Sally M. Seymour, MD; Eugene J. Sullivan, MD, FCCP; Badrul A. Chowdhury, MD, PhD; Robert J. Meyer, MD; Ruthanna C. Davi, MS
Author and Funding Information

Affiliations: Food and Drug Administration, Silver Spring, MD,  National Jewish Research and Medical Center, Denver, CO,  GlaxoSmithKline, Research Triangle Park, NC

Correspondence to: Sally M. Seymour, MD, Food and Drug Administration, Silver Spring, MD; e-mail: sally.seymour@fda.hhs.gov



Chest. 2006;130(3):930-931. doi:10.1378/chest.130.3.930
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To the Editor:

The Salmeterol Multicenter Asthma Research Trial (SMART)1was initiated to further explore the signal for asthma-related death seen in the Serevent Nationwide Surveillance Study2in light of US postmarketing reports3 of asthma fatalities associated with salmeterol. SMART confirms the earlier findings that salmeterol use leads to an increased incidence of asthma-related death. We have two comments on the report by Nelson et al.1

The authors1 note that certain end points in SMART did not reach statistical significance. While true, in interpreting the meaning of this failure to reach statistical significance, the premature termination of the study has to be considered. For example, while there was no statistically significant difference between treatment groups for the primary end point (respiratory-related death or life-threatening experience: risk ratio, 1.40; 95% confidence interval, 0.9 to 2.1), if the study had continued as planned, it is likely that this comparison would have reached statistical significance.

It is also unclear why certain analyses were included in the report1; for instance, data are included from the 28-week treatment period combined with data spontaneously reported for a 6-month poststudy period (Table 6). The authors1 state that patients may have continued to take unused study medication after the study was completed. However, it is possible that placebo-treated patients could have initiated treatment with salmeterol following their participation in the study, which would obscure any treatment effect. Also, the authors included analyses based on an artificial division of the study into two “phases,” based on different recruitment strategies. Whether this post hoc, exploratory analysis was initiated based on a scientific hypothesis or data dredging is unclear. Nonetheless, in both phases, there were more asthma-related deaths in the salmeterol group. Interested readers may review the proceedings of the Food and Drug Administration advisory committee convened to discuss SMART and the public statements issued by the Food and Drug Administration.,34

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Dr. Nelson is a consultant, speaker, and recipient of research grants from GlaxoSmithKline, and was also a member of the Morbidity and Mortality Review Committee. Dr. Dorinsky is an employee of GlaxoSmithKline.

Nelson, HS, Weiss, ST, Bleecker, ER, et al (2006) The Salmeterol Multicenter Asthma Research Trial.Chest129,15-26. [CrossRef] [PubMed]
 
Cast, W, Fuller, R, Hall, J, et al Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.BMJ1993;306,1034-1037. [CrossRef] [PubMed]
 
US FDA Pulmonary-Allergy Drugs Advisory Committee Meeting, July 13, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005–4148T1.htm. Accessed March 27, 2006.
 
US FDA drug information. Serevent Diskus, Advair Diskus, and Foradil information. Available at: http://www.fda.gov/cder/drug/infopage/LABA/default.htm. Accessed March 27, 2006.
 
To the Editor:

The data collection and analysis of the Salmeterol Multicenter Asthma Research Trial were conducted with rigor, scientific integrity, and without known bias; our article was a transparent, peer-reviewed communication designed to inform health-care practitioners.

Dr. Seymour questions why data from the 28-week treatment period plus a 6-month follow-up period were included along with data from the 28-week treatment period. The protocol included a 6-month follow-up because patients received 6 months of therapy and underwent minimal procedures to retrieve unused medication. It is well-recognized that medication therapy compliance is poor; therefore, patients may have had study medication left and continued to take it beyond the 28-week period. Although it is possible that patients receiving placebo may have initiated salmeterol therapy after the study, the only planned analysis included the data from the 28-week treatment period plus the additional 6-month follow-up period, which were provided to an independent Data Safety Monitoring Board and subsequently to the US Food and Drug Administration (FDA). After study termination and the reporting on the interim analysis, further discussions with the US FDA led to an agreement to focus the analysis on the 28-week treatment period, although no substantial differences exist between the analysis of the 28-week treatment period and that of the 28-week treatment period plus the 6-month follow-up period.

Dr. Seymour further questions the data reported for the two distinct phases. These data were acknowledged in the article as being exploratory. It is well-recognized that study design and recruitment approaches can lead to confounding in studies. Switching from media-driven recruitment, yielding 13 asthma-related deaths in 15,342 patients (phase I), to investigator-driven recruitment, yielding 3 asthma-related deaths in 11,013 patients (phase II), suggests that the recruitment approach may have affected outcomes. Furthermore, the quality of care and the physician-patient relationship can affect outcomes and were likely different between the phases, providing the scientific basis for this analysis.

We agree that interested readers should review the breadth of the data and the proceedings of the US FDA advisory committee that was convened to discuss long-acting β-agonists.


Figures

Tables

References

Nelson, HS, Weiss, ST, Bleecker, ER, et al (2006) The Salmeterol Multicenter Asthma Research Trial.Chest129,15-26. [CrossRef] [PubMed]
 
Cast, W, Fuller, R, Hall, J, et al Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.BMJ1993;306,1034-1037. [CrossRef] [PubMed]
 
US FDA Pulmonary-Allergy Drugs Advisory Committee Meeting, July 13, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005–4148T1.htm. Accessed March 27, 2006.
 
US FDA drug information. Serevent Diskus, Advair Diskus, and Foradil information. Available at: http://www.fda.gov/cder/drug/infopage/LABA/default.htm. Accessed March 27, 2006.
 
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