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An FDA advisory panel on Tuesday gave near unanimous backing to a novel two-drug combination inhaler for use in adults with asthma, while rejecting the product for younger children.

By a 16-1 margin, the FDA's Pulmonary-Allergy Drugs Advisory Committee voted that the benefits of the combination inhaler outweigh the risks in adults with asthma. If ultimately approved by the agency, the combination would be the first approved product containing an inhaled corticosteroid (budesonide) and a short-acting beta₂-adrenergic agonist (albuterol sulfate).

However, the group of outside experts said the data do not support the combination inhaler for children ages 4 years to under 12 (by a vote of 16-1), and were split on adolescents ages 12 years and up, with a majority (9-8) saying there was not a favorable risk-benefit profile for this population.

In explaining their yes votes for the adult population, panel members referred to the efficacy and safety results from the pivotal MANDALA trial, which tested the combination versus an inhaler containing albuterol alone.

"The consensus, by a large majority, was favorable, mainly because in this older age group there was a robust efficacy signal, and there were minimal safety concerns," said committee chair David Au, MD, of the University of Washington in Seattle, summing up the panel's views.

But, while the proposed indication for the combination of budesonide and albuterol (BDA) is "for the as-needed treatment or prevention of bronchoconstriction, and for the prevention of exacerbations in patients with asthma 4 years of age and older," panel members had questions about the the combination's efficacy in the younger age groups.

Committee members were mostly concerned that the vast majority of patients in MANDALA were adults, and that data from the trial would need to be extrapolated to the adolescent and pediatric patients in order for the FDA to make a determination on the benefit and risks of BDA in those populations.

"You can't extrapolate from the adult data to this small subgroup" of younger children, said Sally Hunsberger, PhD, a mathematical statistician at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, explaining her vote against the product in the group of kids ages 4 years to under 12. "I think we need efficacy data. You need long-term safety data, and we need to learn more about how this would be used in this population."

"There are too many uncertainties related to the efficacy," said Michelle Cloutier, MD, of the University of Connecticut School of Medicine in Farmington. "It is unclear how to use this combination in young children, especially in asthma of different severity, as well as in different indications, including exercise-induced asthma."

The MANDALA trial included 3,132 patients with moderate-to-severe asthma randomized 1:1:1 to three regimens: two actuations each of the 90/80 μg or 90/40 μg BDA combination inhalers, or two actuations of 90 μg albuterol. Most patients (97%) were 12 years or older. The youngest group of children received only the lower-dose product.

Results depicted in a forest plot analysis showed a significant delay in time to first acute exacerbation in both BDA groups overall compared with the albuterol group:

• Low-dose BDA: HR 0.84 (95% CI 0.70-0.99)
• High-dose BDA: HR 0.74 (95% CI 0.62-0.88)

Similarly, results for the large adult subgroup also supported the treatment's efficacy. However, among the small subgroup of 83 kids ages 4 years to under 12, there was no evidence of efficacy with the lower-dose BDA inhaler (HR 1.09, 95% CI 0.46-2.56).

Panel Splits on Adolescents

Efficacy data for the product in the 100 adolescent patients (age 12 years to under 18) were mixed, with neither the low-dose or high-dose BDA inhalers showing a significant benefit over the albuterol control arm.

The products's developers, Avillion and AstraZeneca, are proposing a high-dose version of BDA for patients 12 years and up. During the meeting, ED Piper, MBBS, of AstraZeneca, explained that the efficacy results from MANDALA actually appear to favor the low-dose BDA over the high-dose regimen for adolescents, but said the results were likely due to "chance" (forest plot data shown):

• Low-dose BDA: HR 0.57 (95% CI 0.17-1.95)
• High-dose BDA: HR 1.44 (95% CI 0.54-3.87)

"It seems implausible that the lower BDA dose would outperform in adolescents given the clear dose-response in the overall MANDALA population across all endpoints," said Piper. "We also noted the patterns of use were similar for both BDA doses for adolescents."

However, this seemed to cause some uncertainty among panel members regarding both the efficacy of the combination and the correct dose to be used.

"The risk are known, and mostly manageable," said Edward Kim, MD, of the University of North Carolina School of Medicine in Chapel Hill. "However, the benefits to me were unclear. Even were we to assume the benefits were there from extrapolation, the correct dose, I think, is also unclear. I would need a larger sample size with more clear efficacy."

Panel members who voted yes said they were reassured by the combination's safety profile, although some said their yes votes were "soft."

"I voted yes due to the reassuring short-term safety data that was presented, with no major safety signals identified," said Bridgette Jones, MD, of the University of Missouri-Kansas City School of Medicine.

"Although there are varying phenotypes in both children and adults, I do think full extrapolation is appropriate in this age group and that you would expect similar outcomes for a variable risk-benefit assessment as with adults," said Jones. "I do think there is a need for more long-term safety data to determine overall exposure long-term."

Jones was also the only panel member to vote yes on the risk-benefit question for the younger pediatric patients. "I think there are kids in the 4- to 12-year age group that would likely benefit from this medication and our job is to make that educated guess," she said. "The art of medicine occurs in the doctor's office where we determine which children may benefit from the use of certain medications."

While the FDA is not required to follow the advice of its advisory committees, it usually does.

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