Silver Spring, MD—The FDA doesn’t often remove a boxed warning on a prescription product, but, late last year, the agency did just that for combination therapies containing an inhaled corticosteroid (ICS) and long-acting beta-agonists (LABAs) in patients with asthma.

A Perspective article in the New England Journal of Medicine offers some background on the decision. The authors from the FDA’s Office of New Drugs and the Office of Translational Sciences, Center for Drug Evaluation and Research, point out that the risks were uncertain and that some healthcare professionals had recommended conducting large clinical trials to gather important safety information on these products.

The report recounts how, in December 2017, the FDA removed the boxed warning on combination products containing an inhaled corticosteroid and a LABA “on the basis of results from recently completed large safety trials that the agency required manufacturers to conduct. Removal of a boxed warning isn’t common, but we at the FDA believe that the data generated from the mandated trials support this regulatory action. The findings also improve the knowledge base for clinicians who treat patients with asthma.”

After trials suggested LABAs were associated with serious adverse outcomes, including asthma-related hospitalization, intubation, and death, the box warning was initially required in 2003. Yet, the authors note, two key investigations—the Salmeterol Nationwide Surveillance Study and the Salmeterol Multicenter Asthma Research Trial—occurred when patients taking LABAs were less likely to have concurrent use of inhaled corticosteroids, as was the case later.

“It was therefore unknown whether use of an inhaled corticosteroid in combination with a LABA—now considered the standard of care—would mitigate the risk of serious asthma outcomes,” the Perspective article state. “Consequently, the FDA required the boxed warning for LABAs and combination products.”

The safety trials, required by the FDA, documented meaningful decreases in asthma exacerbations among patients treated with combination products versus those treated with inhaled corticosteroids alone, according to the report. “On the basis of this strong and consistent evidence, we opted to remove the boxed warning right away, without convening an FDA advisory-committee meeting,” the FDA authors write.

They emphasize that the removal of the boxed warning doesn’t mean no safety concerns exist, explaining, “Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone.”

The article notes a few of those unanswered questions:
• The trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, but none of them showed a decrease in asthma-related hospitalizations. 
• Patients with life-threatening asthma were excluded because of safety and ethical concerns, so it is unknow whether results are generalizable to them.
• While the pediatric trial met the primary safety objective, the noninferiority margin was, for reasons of trial feasibility, larger than desired.
Yet, the authors said the trials were both reassuring and beneficial, suggesting additional benefits associated with combination therapy.

“Our conclusion based on the data generated from these trials is that there is not a significant increase in the risk of serious asthma-related events associated with combination therapy as compared with inhaled corticosteroids alone,” study authors conclude, writing that the evidence was “decisive.”

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