It takes a lot for the FDA to remove a boxed warning on a product, but the data generated by these four manufacturer-led trials of long-acting beta agonists and inhaled corticosteroid combination therapy warrant the regulatory reversal, Sally Seymour, MD, and her colleagues wrote in an accompanying editorial.
“Each completed trial met the prespecified objective and demonstrated noninferiority of combination products to inhaled corticosteroids alone with respect to the composite endpoint of asthma-related death, intubation, or hospitalization.
The majority of events were asthma-related hospitalizations; there were five intubations and deaths overall,” Dr. Seymour and her colleagues wrote.
All of the studies met their primary safety objective, and faced with this – and the consistency of the results among the studies – the path was clear.
“In addition, the observed reduction in asthma exacerbations that required systemic corticosteroids demonstrates a benefit associated with combination products. 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.”
There will always be areas of uncertainty, however.
“Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. 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. Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations. People with life-threatening asthma were excluded because of safety and ethical concerns, so we don’t know whether the results can be generalized to these patients.”
Nevertheless, the evidence in favor of combination therapy was clear and compelling enough to convince a national regulatory agency to change a stance on safety.
Dr. Seymour is the acting director of the FDA’s Division of Pulmonary, Allergy, & Rheumatology Products.
