From the Journals

FDA reverses warning on LABA-containing asthma medications

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FDA: Compelling evidence demands quick action

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.



The combination a long-acting beta agonist (LABA) and an inhaled glucocorticoid decreases the risk of an asthma exacerbation by 17%, without increasing the risk of asthma-related intubation or death.

Illustration of lungs MattZ90/thinkstockphotos

An independent analysis of four large, drug company–sponsored trials supports the Food and Drug Administration’s recent decision to remove the black box warning on LABA/inhaled glucocorticoid products, wrote William W. Busse, MD, and his colleagues. The report was published in the New England Journal of Medicine.

“Our analysis confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials: by 21% in the GlaxoSmithKline trial [hazard ratio 0.79], by 16% in the AstraZeneca trial [HR. 0.84], and by 11% in the Merck trial [HR 0.89],” wrote Dr. Busse of the University of Wisconsin, Madison, and his coauthors.

The FDA based its December 2017 reversal on an initial review of the studies, which were reviewed by an independent committee and are now public. Dr. Busse led the expert analysis of the studies, which the FDA required after it put the black box warning on the combination products.

In 2010, the FDA advised that LABAs shouldn’t be used as first-line therapy for asthma and required a black box warning on all LABA-containing products. Despite an FDA-conducted meta-analysis that found no increase in serious asthma-related incidents, the agency said there wasn’t enough subgroup evidence to support the safety of LABAs when combined with an inhaled glucocorticoid.

“FDA stated that the small numbers of patients who were enrolled in these studies prevented a definitive conclusion regarding mitigation of serious asthma-related events with the addition of inhaled glucocorticoids,” the investigators stated.

The agency required the four companies marketing a LABA for asthma to conduct prospective randomized trials comparing the safety of LABA/inhaled glucocorticoid to inhaled glucocorticoid alone. The trials by AstraZeneca, GlaxoSmithKline, Merck, and Novartis were identical. Three had complete, 26-week data; Novartis submitted partial data, as it withdrew its product from the American market in 2015. The committee reviewed all of the studies, which comprised a total of 36,010 teens and adults (aged 12-91 years). The primary endpoint was a composite of asthma-related intubation or death; secondary endpoints were a composite of hospitalization, intubation, or death, and individual assessments of each of those events.

Among the four studies, there were three asthma-related intubations: two in the inhaled-glucocorticoid group and one in the combination-therapy group. There were also two asthma-related deaths, both in the combination group.

Serious asthma-related events occurred in 108 of the inhaled glucocorticoid group (0.60%) and in 119 of the combination-therapy group (0.66%), a nonsignificant difference.

However, the combination therapy did confer a significant 17% reduction in asthma exacerbations. Exacerbations occurred in 11.7% of the inhaled glucocorticoid group and in 9.8% of the combination therapy group (relative risk 0.83; P less than 0.001). All four trials showed a similarly decreased risk of exacerbation.

The committee looked at several subgroups, dividing the cohort by age, race/ethnicity/ obesity, and smoking history. The advantage associated with combination therapy remained significant in all these analyses.


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