Removal of FDA Warning on Asthma Inhalants Follows Manufacturers' Research

William Busse, MD

The rationale for removing a boxed safety warning about long-acting beta-agonist (LABA) bronchodilators from inhalants combining LABA with a corticosteroid was described in recent commentary by the US Food and Drug Administration (FDA), in accompanying independent analysis of research from a collaboration of inhalant manufacturers.

The warning was issued in 2003 in response to asthma-related hospitalizations, intubations and deaths linked to LABA use. As the incidents were likely to have occurred without concurrent inhaled corticosteroid, the FDA mandated in 2011 that the 4 manufacturers marketing inhaled LABA plus corticosteroid combination products for asthma in the US conduct prospective, randomized, controlled trials comparing the safety of their product with that of inhaled glucocorticoid alone.

With concurrence of the FDA, the manufacturers harmonized their trial methods and established an independent joint oversight committee to provide a final combined analysis of 4 trials conducted in adolescents and adults.

Lead author of the report from the joint oversight committee was William Busse, MD, professor of Allergy & Immunology in the Department of Medicine, University of Wisconsin School of Medicine and Public Health.

"As members of the joint oversight committee, we performed a combined analysis of the four trials comparing an inhaled glucocorticoid plus a LABA (combination therapy) with an inhaled glucocorticoid," Busse and committee members wrote. "The primary outcome was a composite of asthma-related intubation or death. Post hoc secondary outcomes included serious asthma-related events and asthma exacerbations."

The oversight committee assessed data from 4 trials conducted with over 36,000 adolescent and adult patients through intent-to-treat analysis, although one trial was discontinued when the manufacturer withdrew its product from market. The FDA analyzed data from the 3 completed trials, as well as from a separate trial which had been conducted in children.

Busse and colleagues report that there was no higher risk of the most severe asthma-related outcomes (endotracheal intubation or death) among patients who used LABA plus corticosteroid combination inhalant products than those receiving an inhaled glucocortioid alone.

In the post hoc secondary analysis of serious asthma-related events, there was also no significant differences between the groups. Further, they calculated a 17% lower relative risk of asthma exacerbations with the combination products than with glucocorticoid alone.

The FDA decision in December 2017 to remove the boxed warning was described by evaluation staff in accompanying commentary with lead author Sally Seymour, MD, acting division director, of the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products, Center for Drug Evaluation & Research.

Seymour and colleagues found similar safety and efficacy results in their analysis of the 3 completed trials, noting that that each individual trial had met the primary safety objective and that the results were consistent between trials.

"On the basis of this strong and consistent evidence," Seymour and colleagues wrote, "we opted to remove the boxed warning right away, without convening an FDA advisory-committee meeting."

The study, "Combined Analysis of Asthma Safety Trials of Long-Acting β2-Agonists," and the FDA commentary on removing the boxed warning were both published in The New England Journal of Medicine last week.