LETTER
Zafirlukast in Asthma
Peter K. Honig, MD;
Raymond Anthracite, MD; and
John K. Jenkins, MD
1 January 1998 | Volume 128 Issue 1 | Page 70
TO THE EDITOR:
Suissa and colleagues' article [1] illustrates potential limitations of peer review in evaluating manuscripts submitted for publication. It also reinforces the importance of a priori designation of the primary end points and statistical methods to be used in the conduct and analysis of randomized, controlled clinical trials.
Zafirlukast was approved by the U.S. Food and Drug Administration (FDA) on 26 September 1996 for prophylaxis and long-term treatment of asthma [2]. This approval was based, in part, on the results of the large, prospective, placebo-controlled trial (study 0029) [3] that is referenced in Suissa and colleagues' article and within which the authors' investigation was conducted as a nested study. Study 0029 was designed with explicit predefined primary and secondary end points and was analyzed with prespecified statistical rules and procedures.
As Suissa and colleagues stated, their study was conducted as a subprotocol to this larger study. Although Suissa and colleagues' study used standardized data collection forms, the protocol submitted to the FDA was regarded by Zeneca Pharmaceuticals as "exploratory" and as such contained no prespecified primary end point or explicit statistical methods for analyzing the results. These are critical elements for reducing bias in the conduct, analysis, and reporting of clinical trials and raise the issue of the limitations of peer review in assessing clinical trial reports [4]. For example, Suissa and colleagues describe selected analyses as "significant" on the basis of inferential statistical tests that are inappropriate tools to apply to retrospectively defined comparisons. Without having the study protocol to review, peer reviewers and editors do not know whether manuscripts submitted for publication report planned comparisons of prospectively defined end points or the results of exploratory data analyses. We believe that the results of the study should be considered as hypothesis-generating and that confirmation in additional prospective, well-controlled trials is needed.
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Author and Article Information
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U.S. Food and Drug Administration; Rockville, MD 20857
1. Suissa S, Dennis R, Ernst P, Sheehy O, Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1997; 126:177-83.
2. Zafirlukast product label. Wilmington, DE: Zeneca Pharmaceuticals.
3. ICI Pharma. A multicenter double blind placebo controlled trial of Accolate in mild to moderate asthmatic patients needing chronic treatment. Trial number 9188IL/0029. Canada, 1992.
4. Sackett DL. Bias in analytic research. J Chronic Dis. 1979; 32:51-63.
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