FDA panel supports approval of two-drug asthma inhaler for adults, split on adolescents

The FDA’s Pulmonary-Allergy Drug Advisory Committee voted 16-1 in favor of approving the fixed-dose combination of budesonide and albuterol sulfate metered dose inhaler for patients with asthma aged 18 years and older.

However, the panel was split, with an 8-9 vote, on whether the benefits of this treatment outweigh the risks for an adolescent patient population aged 12 to younger than 18 years, and they were largely unanimous in voting against its approval, with a 1-16 vote, for young children aged 4 to younger than 12 years.

Supporting data

The fixed-dose combination of budesonide and albuterol sulfate metered dose inhaler (Avillion, AstraZeneca), or BDA, has been submitted to FDA for review for the as-needed treatment or prevention of bronchoconstriction and to prevent asthma exacerbations among patients with asthma aged 4 years and older.

“It is important to highlight that although the mono-components of BDA, budesonide and albuterol, have both been FDA approved for many years, BDA would represent a novel product in several ways,” Elisabeth Boulos, MD, medical officer in the division of pulmonology, allergy and critical care at the FDA, said during a prerecorded FDA presentation. “First, the proposed indication ‘to prevent exacerbations’ would be new for a reliever treatment for asthma. Second, BDA would be the first fixed-dose combination product combining an inhaled corticosteroid and short-acting beta agonist, thus representing a new intended use for an inhaled corticosteroid in the treatment of asthma.”

FDA asked the panel to review the overall efficacy of BDA across age groups, but to also focus on the pediatric population regarding whether data from adults could be extrapolated to children and considering safety concerns associated with increased corticosteroid exposure, as BDA could be used alongside controller inhaled corticosteroids (ICS).

The panel reviewed data from the randomized, double-blind MANDALA trial, which included 3,132 patients with asthma — including 100 adolescents aged 12 years and older to younger than 18 years, and 83 children aged 4 years and older to younger than 12 years — who received BDA with doses of 160 µg budesonide with 180 µg albuterol, BDA with doses of 80 µg budesonide and 180 µg albuterol, or 180 µg albuterol sulfate alone.

Overall, the study met its primary endpoint, showing a significant delay in the time to first severe acute exacerbation in the overall population receiving BDA 160/180 (HR = 0.74; 95% CI, 0.62-0.88) or BDA 80/180 (HR = 0.84; 95% CI, 0.7-0.99).

When analyzed by age, the FDA called the results “uncertain” as the 95% confidence intervals crossed 1 for both doses in the 12-to-18 age group, and for the lower dose in the younger age group, as this population did not receive the higher dose.

Because of the smaller numbers of children in the trial, and the lack of significance seen in these groups, FDA asked the panel whether adult data could be extrapolated to support efficacy in the younger population. Data are appropriate to extrapolate if the disease is the same in adults and children, the response to treatment is the same, there is a high confidence in evidence and there are no significant knowledge gaps, according to the FDA.

Specifically, the FDA presented data from a post-hoc Bayesian analysis showing that, in order to reach statistical significance with a 95% confidence interval that does not cross 1, 96% of the total events would have to be borrowed from adults for each analysis of adolescents receiving high-dose BDA and young children receiving low-dose BDA.

A review of the safety data did not reveal new safety signals, with no significant differences between the age cohorts, according to data from the FDA. Researchers also noted that systemic ICS-related toxicities were infrequent and mostly mild to moderate in intensity, with no concerning patterns by age.

Voting rationale

For patients aged 18 years and older, the panel members largely voted in support of approval due to the robust efficacy signal and minimal safety concerns.

However, their split vote for the adolescent group reflected concerns about whether adult data could be confidently extrapolated to this group, uncertainty surrounding the appropriate dose, a request for further study in a larger group of patients and the potential for abuse of the inhaler in the treatment of exercise-induced asthma.

“I find myself in this incredible conundrum, with data that’s all over the place, in all likelihood because of small sample size,” James M. Tracy, DO, clinical professor of pediatrics at University of Nebraska College of Medicine, who ultimately voted in favor of approval for the adolescent group, said during the pre-vote discussion. “My general sense is that, if taken in their singular form, these are not two new drugs. We’re comparing populations when in reality, for most of who do this for a living, it’s individuals we take care of. There are an awful lot of adolescents who would very much benefit from a product like this. Just because the sample is not powered to sufficiently answer the question, I’m not sure it’s doing our patients a service by putting the kibosh on this.”

Heterogeneity in the data makes it too difficult to extrapolate results from adults to adolescents, Alex Kaizer, PhD, assistant professor in the department of biostatistics and informatics at University of Colorado-Anschutz Medical Campus, said after his “no” vote.

“What would help drive the extrapolation would be more data or more observations to further identify that the effect sizes align with the adult population as we would hypothesize and give us more confidence that potentially long-term safety outcomes could be followed,” he said.

Although voting in supporting of approval, Mary Cataletto, MD, clinical professor of pediatrics at New York University Grossman School of Medicine, said that an approval in this population would require targeted education.

“If they’re going to use BDA the way they use albuterol as premedication for exercise, there is a potential that they’re going to abuse it,” she said. “Even though I said yes, I think the exercise-induced asthma section needs to be very carefully crafted and followed.”

Some other panel members who voted yes said they did so based on the FDA’s precedent to generally extend approval in adults to this age group.

“Certainly there are differences in prevalence of different [asthma] phenotypes in adults vs. kids,” Bridgette L. Jones, MD, MSc, FAAAAI, FAAP, professor of pediatrics in the division of allergy, asthma, immunology and pediatric clinical pharmacology, toxicology and therapeutic innovation at Children’s Mercy Kansas City, who voted in support of approval for both adolescents and young children, said in the discussion ahead of the vote. “But overall if you look at asthma national guidelines, for the most part many of the treatments have consistently been very similar for children and adults. I don’t think we have any biological or scientific evidence that effective drug targets especially for ICS and short-acting beta agonists would be that dissimilar between children and adults.”

When it came to the younger children examined, in addition to the previously expressed concerns, the panel also discussed the need for long-term safety data, especially regarding the impact of treatment on growth and bone density, and how the treatment would be used in a real-world setting.

“I voted no, and I wish I didn’t have to, [as we heard throughout the day this was called] a ‘simple and elegant relief,’ ‘novel’ and ‘unique,’” Randi Redmond Oster, MBA, acting consumer representative on the panel and co-founder and president of Help Me Health. “What an opportunity if we could have approved this. But I want to make sure that the message is clear: small data slows down the process. Going forward I hope that this message is an opportunity for when the testing samples are coming in, to push back and say we need more, because we know where this is going to go at the end.”