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Chest

Volume 143, Issue 5, May 2013, Pages 1208-1213
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Commentary
US Food and Drug Administration-Mandated Trials of Long-Acting β-Agonists Safety in Asthma: Will We Know the Answer?

https://doi.org/10.1378/chest.12-2881Get rights and content

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.

Section snippets

The Trials

Four of the randomized trials, identically designed, each involve 11,700 adult and adolescent patients with asthma per study, for a total of 46,800 patients, while a smaller trial involves 6,200 children.9 Each trial compares the combination of a LABA with an ICS (LABA+ICS) vs monotherapy with the same ICS at the same dose. The primary end point is a composite of serious asthma outcomes, including asthma-related death, intubation, or hospitalization, observed over a 6-month follow-up. These

Effect of LABA Discontinuation at Randomization

The first methodologic issue relates to the patients already treated with a LABA+ICS combination and who are eligible to enter these trials. Upon randomization, these patients are allocated to either continuing LABA+ICS treatment, albeit possibly with another agent, depending on the study they have been recruited to, or discontinuing their LABA+ICS treatment and replacing it by a treatment of an ICS only, which can impact the outcome. A meta-analysis of five randomized controlled trials

Effect of the Primary Outcome Definition

The second methodologic issue arises from the primary outcome definition in these trials, namely, a composite end point that includes asthma-related death, intubation, or hospitalization occurring during the 6-month follow-up period. While the FDA recognizes that the results will be dominated by the hospitalization component of the outcome, it is useful to anticipate the effect of this dominance.9 We used data from a pooled analysis of formoterol trials and a meta-analysis that provided data on

Effect of Multiple Trials

The third issue arises from the inference involving four trials of the same question. The 90%–power calculation to rule out a relative risk of 2.0 for the composite outcome when, in truth, there is no increase in the risk, arrived at a sample size of 11,700 patients with asthma per study. Thus, for each study, the 90% power implies that there is only a 10% probability that the study will produce a false result with the upper bound of the CI larger than 2.0 (which will deem the drug as

Conclusion

We discussed three methodologic issues that will inherently affect the risk estimates produced by the FDA-mandated trials and their interpretation. First and foremost, in view of the effect of LABA discontinuation from patients already using these drugs at enrollment and existing data from meta-analyses, the relative risk for each study could be underestimated by a factor of at least 20%. While 20% does not, at first glance, appear to be a major reduction, it is noteworthy that the highest

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Suissa has participated in advisory boards and as speaker for all manufacturers of the long acting β-agonists under study, namely, AstraZeneca plc, GlaxoSmithKline plc, Merck & Co Inc, and Novartis AG; and is on the data monitoring committee of one of the trials on the safety of formoterol fumarate (Novartis AG). Dr Ariel has participated in clinical trials, advisory boards, and as

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