Commentary |

US Food and Drug Administration-Mandated Trials of Long-Acting β-Agonists Safety in AsthmaLong-acting β-Agonists Safety Trials in Asthma: Will We Know the Answer?

Samy Suissa, PhD; Amnon Ariel, MD, FCCP
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From the Center for Clinical Epidemiology (Dr Suissa), Lady Davis Institute–Jewish General Hospital, and the Departments of Epidemiology and Biostatistics and Medicine, McGill University, Montreal, QC, Canada; and Lung Unit (Dr Ariel), Emek Medical Center, Afula, Israel.

Correspondence to: Prof Samy Suissa, Centre for Clinical Epidemiology, Jewish General Hospital, 3755 Cote Ste-Catherine, Montreal, QC, H3T 1E2, Canada; e-mail: samy.suissa@mcgill.ca

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Chest. 2013;143(5):1208-1213. doi:10.1378/chest.12-2881
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For 2 decades, long-acting β-agonists (LABAs) have been associated with increased asthma-related death risks in several randomized trials, even when added to inhaled corticosteroids (ICSs). In reaction, the US Food and Drug Administration (FDA) recently mandated that the manufacturers of LABAs conduct five large, noninferiority, randomized trials of the LABA+ICS combination in 53,000 patients with asthma. Three methodologic issues in these trials could lead to masking of or falsely detecting elevated risks. First, the effect of LABA discontinuation among the many patients already using these drugs at enrollment can result in an underestimation of the relative risk by a factor of around 20%. This effect will bias downward the upper bound of the resulting CI away from the preset noninferiority margin of 2.0 for the relative risk, artificially making it more difficult to detect a risk increase. Second, the composite asthma outcome will be dominated by asthma hospitalization, possibly dwarfing an increased risk of asthma-related death, with differences as wide as seven deaths under the LABA+ICS combination vs one death under ICS alone remaining statistically uncertain. Finally, because of the multiple identical trials being requested from the different manufacturers of LABAs, even if each trial is powered at 90%, there is a 41% likelihood that at least one of the trials will not rule out a risk increase when, in truth, there is no risk increase. In view of these impediments, the FDA should preempt such complexities by establishing decision rules regarding the interpretation of the results from these momentous safety trials before their completion, expected in 2017.

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