The FDA’s Pulmonary-Allergy Drugs Advisory Committee on Tuesday will consider whether a novel two-drug combination inhaler for asthma should be the first FDA-approved product containing an inhaled corticosteroid (budesonide) and a short-acting beta2-adrenergic agonist (albuterol sulfate).
Also novel is the proposed indication of preventing severe exacerbations, and the use of an inhaled corticosteroid-containing product as a reliever medication rather than a controller medication, according to the FDA’s briefing document.
FDA reviewers are particularly interested in panel members’ views on whether positive adult efficacy data from a pivotal trial should be extrapolated to patients age 18 and under due to “uncertainties” concerning the combination’s effectiveness in the study’s pediatric population.
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.”
The rationale for BDA is that short-acting beta2-adrenergic agonists like albuterol are effective in providing rapid symptom relief, while the addition of the corticosteroid can treat inflammation and thus prevent or reduce the severity of exacerbations.
The product’s developer Avillion is proposing a high-dose version (90 μg of albuterol with 80 μg of budesonide) for patients 12 years and up, and a low-dose version (90 μg of albuterol with 40 μg of budesonide) for children 4 years and older, but under 12 years of age.
The primary source of efficacy and safety data is the MANDALA trial, an event-driven, randomized, double-blind, parallel group, active comparator-controlled trial, which evaluated the efficacy and safety of BDA versus albuterol alone. The 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 versions, or two actuations of 90 μg albuterol. Most patients (97%) were 12 years or older.
This included 83 patients 4 years and older, but under 12 years of age, randomized to low-dose BDA or albuterol; 100 pediatric patients age 12 or older randomized to low-dose BDA, high-dose BDA, or albuterol; and 2,940 adults randomized to low-dose BDA, high-dose BDA, or albuterol.
Results from the trial 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, “efficacy in the two pediatric subgroups … is uncertain because the upper confidence limits for the hazard ratios exceed 1,” FDA staff wrote. Among kids ages 4 years to under 12, for example, even the point estimate for the hazard ratio exceeded 1 (HR 1.09, 95% CI 0.46-2.56).
“We hypothesize the wide confidence intervals and high degree of uncertainty may be a function of small sample sizes,” noted agency staff.
FDA reviewers also observed that safety data were consistent with the known risk profiles of budesonide and albuterol, and that there were no significant differences between age cohorts or evidence of increased risk from as-needed inhaled corticosteroid use in pediatric patients.
Advisory committee members will consider whether efficacy and safety data support a favorable benefit/risk assessment for BDA use in the adult age group, as well as the two pediatric age groups, and if not, what additional data are needed.
Moreover, with the small number of pediatric patients in the MANDALA trial, FDA staff noted that pediatric extrapolation “will be an important consideration for this program.”
“Pediatric extrapolation can extend what is known about the adult population (e.g., efficacy) to pediatric subjects based upon an assessment of the relevant similarities of disease and response to therapy between the two populations,” they wrote. “Given the novelty of this product, we request [advisory committee] discussion on the role of this product in pediatrics and whether extrapolation is appropriate to establish the benefit of BDA in pediatric patients or if additional data are needed.”