Hong Kong Respiratory Medicine

Badrul A. Chowdhury, Sally M. Seymour, Theresa M. Michele, Anthony G. Durmowicz, Dongmei Liu,and Curtis J. Rosebraugh, N Engl J Med 2011; 365:2247-2249December 15, 2011

In July 2011, the Food and Drug Administration (FDA) approved Arcapta Neohaler (indacaterol maleate powder), a long-acting beta-agonist (LABA), at a dose of 75 μg once daily as a bronchodilator for patients with chronic obstructive pulmonary disease (COPD).1 Since the European Medicines Agency (EMA) had approved indacaterol at doses of 150 μg and 300 μg in 2009,2 one might question why the FDA selected a 75-μg dose.

Historically, LABAs have been developed first for patients with asthma and then the same dose has been applied to patients with COPD. Indacaterol's manufacturer, Novartis, took a different approach: it focused primarily on patients with COPD and proposed two different doses for marketing. Novartis submitted its new drug application (NDA) to the FDA in October 2009, proposing doses of 150 μg and 300 μg once daily. The NDA was not approved, because the data did not show a meaningful difference in efficacy between the proposed doses and a lower dose (75 μg), and there were safety concerns regarding the proposed doses.

In the original NDA, dose-ranging explorations were limited to an adaptive-design trial that included a 2-week dose-ranging phase with seven treatment groups (four indacaterol groups [75 μg to 600 μg], two active-comparator groups, and a placebo group) followed by a 26-week confirmatory phase. The primary efficacy end point was the forced expiratory volume in one second (FEV1) 24 hours after the administration of a dose; at this time the drug concentration should be at its lowest, the so-called “drug trough.” An independent data monitoring committee reviewed the 2-week interim data.3 The guidelines given to the committee for dose selection were that the dose had to result in a trough FEV1 both 0.12 liters higher than that achieved with placebo and higher than trough FEV1 levels achieved both with tiotropium and with formoterol, that it had to produce a greater area under the FEV1 curve 1 to 4 hours after a dose than that associated both with tiotropium and with formoterol, and that the lowest dose fulfilling the above two criteria and the next-highest dose were to be selected. On the basis of these criteria, 150 μg and 300 μg of indacaterol were chosen for the trial's confirmatory phase. According to the FDA's analyses of the data, all doses of indacaterol were more effective than placebo and had a similar effect size, which suggests that all doses were on a plateau of the dose–response curve.

Given the concern about LABAs' association with serious exacerbations of asthma and asthma-related deaths,4 review of the safety data for indacaterol in patients with asthma suggested that the proposed doses might be higher than necessary. As compared with control groups, groups of patients with asthma who were treated with indacaterol (300 μg or 600 μg) in addition to inhaled glucocorticoids had a small numerical increase in serious asthma exacerbations and respiratory-related deaths. These events are typically very rare in preapproval LABA studies.

Novartis's criteria were geared toward selection of an indacaterol dose that would provide greater efficacy than both of the active comparators formoterol and tiotropium; this requirement may have led to the selection of higher doses of indacaterol without consideration of their safety consequences. Therefore, further exploration of the efficacy and safety of lower doses was required, and the FDA requested dose exploration in patients with asthma, whose condition is more responsive to the bronchodilatory effects of beta-agonists and so more likely to show a clear separation of doses.

Novartis submitted a complete response to the FDA's concerns in December 2010, including data from new dose-ranging studies (with indacaterol doses of 18.75 to 150 μg) and confirmatory studies. In the dose-ranging studies for both asthma and COPD, the FEV1 profile showed that, after the first dose, there was some increase in efficacy with larger doses, with the results with the 75-μg and 150-μg doses separating from those achieved with lower doses; however, at week 2, the effects of different doses were harder to discriminate from one another, which suggests that the bronchodilator effect of indacaterol had reached a plateau (see graphsFigure 1Asthma and COPD Dose-Ranging Trials.). Given the variability of FEV1 response, the effect in some patients who receive a 37.5-μg dose may still lie on the upward slope of the bronchodilator-effect curve, whereas with the 75-μg dose, the effect in most patients will be on the plateau.

Novartis evaluated the 75-μg and 150-μg doses of indacaterol in separate confirmatory COPD trials, and at 12 weeks, both resulted in a 24-hour trough FEV1 that was significantly higher than that in the placebo group. Secondary efficacy variables that the FDA considered included the FEV1 at other time points, rescue-medication use, symptoms, and health-related quality of life, as measured on the St. George's Respiratory Questionnaire. Pooled results for health-related quality of life at week 12 demonstrated a statistical improvement over placebo with 75 μg of indacaterol, but higher doses did not further improve quality of life and the results had overlapping confidence intervals, so this analysis was not helpful in dose discrimination.

Since there were no confirmatory trials directly comparing the 75-μg and 150-μg doses, Novartis conducted model-based analyses to support their conclusion that the 150-μg dose provided additional benefit in patients with more severe bronchial obstruction. The FDA concluded that the model-based analyses were insufficient to support approval of a second, higher dose of indacaterol and could not replace comparison of the two proposed doses in a clinical trial. Other efficacy data did not provide convincing evidence of a clinically meaningful benefit of the 150-μg dose over the 75-μg dose.

Review of the overall safety database for indacaterol in patients with COPD did not show worrisome findings, particularly at the lower doses of 75 and 150 μg. At the FDA's request, a blinded, adjudicated analysis of controlled COPD trials was conducted by an external independent committee to determine the safety of indacaterol with respect to death, intubation, and hospitalization related to asthma, COPD, or pneumonia. The analysis included 23 trials and 11,755 patients with COPD. No safety signals were identified for the 75-μg and 150-μg doses of indacaterol.

The indacaterol clinical development program (see the Supplementary Appendix, available with the full text of this article at NEJM.org) posed many interesting challenges for the FDA and was discussed at a March 2011 meeting of the agency's Pulmonary-Allergy Drugs Advisory Committee.5 The major safety concern was linked to dose selection, because LABAs, particularly at high doses, may cause severe asthma exacerbations and deaths among patients with asthma. Patients with COPD do not appear to have a similar risk of worsening disease; however, the FDA emphasized dose selection and safety to ensure that the marketed dose would provide maximal benefit without posing unnecessary safety risks.

The safety database for indacaterol showed possible asthma exacerbations and respiratory-related deaths at the 300-μg dose in patients with asthma. In contrast, the 75-μg dose of indacaterol provided bronchodilation similar to that achieved with 150 μg. In addition, there was no confirmatory trial comparing the 75-μg and 150-μg doses head to head to demonstrate that the 150-μg dose provides additional benefit over the lower dose. Other data from the clinical development of indacaterol (e.g., comparisons with active controls or scores on the Mahler Transitional Dyspnea Index) may have been weighed differently by the EMA and influenced its decision to approve the 150-μg and 300-μg doses of indacaterol. But on the basis of the FDA's own analyses, the agency concluded that the overall risk–benefit assessment supports the use of 75 μg of Arcapta Neohaler once daily for long-term bronchodilator treatment in patients with COPD.

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