FDA Revisits Old Issues for COPD Drug Indacaterol at Panel Review

The Food and Drug Administration’s longstanding concerns about the appropriate dose of Arcapta Neohaler (indacaterol maleate) for chronic obstructive pulmonary disease have not subsided despite additional studies conducted by the company. The agency will ask its Pulmonary-Allergy Drugs Advisory Committee to weigh the issue of multiple doses and dosing frequency at a March 8 meeting.

Although the advisory committee is being asked to discuss the safety and efficacy data for drug maker Novartis’ two proposed doses – 75 mcg and 150 mcg – of its long-acting beta agonist (LABA), background briefing documents released on March 4 make clear that the FDA’s preference lies with the 75-mcg dose. Reviewers believe that the higher dose provides little added benefit and raises safety concerns inherent with other LABAs.

Novartis seeks an indication for long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. In the United States, all currently marketed LABAs are dosed twice daily and marketed in only one dosage form, so Novartis is seeking to break new ground.

A once-daily dosing schedule would be somewhat novel. The only once-daily bronchodilator approved for COPD is the long-acting muscarinic antagonist Spiriva (tiotropium). In review documents, however, FDA staff question whether more frequent, or even less frequent, dosing is warranted.

The committee also will be asked to weigh a quality-of-life claim for the 150-mcg dose in the form of improved health status measured by the St. George’s Respiratory Questionnaire (SGRQ). Though the FDA seems skeptical that such a claim is supported, if granted it would make indacaterol the first bronchodilator to carry a quality-of-life claim based on the SGRQ.

More Questions Despite More Studies

That the agency is bringing dosing concerns to its advisory committee is not surprising given that they were the focus of an FDA "complete response" letter. However, Novartis’ response to the agency’s regulatory concerns clearly has not put them to rest.

Novartis’ original NDA, submitted in December 2008, sought approval for indacaterol inhalation powder at doses of 150 mcg and 300 mcg. These are the same doses subsequently approved in Europe, where the product is known as Onbrez Breezhaler.

The company is not seeking an asthma indication, although some of the clinical studies were conducted in asthma patients.

In an October 2009 "complete response" letter, the agency concluded that the doses proposed for marketing were high and unsupported by the NDA’s efficacy and safety data.

The FDA asked the company to explore efficacy and establish safety of lower doses and various dosing frequencies, to provide data showing a meaningful advantage of a higher dose compared with a lower dose, and to demonstrate that a higher dose is not associated with an unacceptable safety disadvantage.

Novartis submitted its response in October 2010 with results from six studies encompassing more than 2,000 patients. The new data included two dose-ranging studies, one dose regimen study, and three pivotal COPD trials.

With the resubmission, Novartis lowered the proposed doses to 75 mcg and 150 mcg. It asserted that the 150 mcg dose provides an efficacy advantage in patients with more severe bronchial obstruction based upon pharmacodynamic modeling analysis and the SGRQ data.

The SGRQ comprises 16 questions that assess disease symptoms, disturbances to patients’ daily physical activity, and the impact of disease on the patient. The instrument is frequently used as a quality of life assessment in clinical trials, according to Novartis’ briefing document.

New Regulatory and Scientific Paradigms

In a memo to the advisory committee, Dr. Badrul Chowdhury, director of the FDA’s division of pulmonary, allergy, and rheumatology products, said that the efficacy issues for discussion relate to the appropriate dose and the request for a health status claim based upon the SGRQ data. "In the U.S., no bronchodilators are approved in more than one dose, and none have claims for improvement in SGRQ. Thus, the indacaterol application represents some new regulatory and scientific paradigms," he wrote.

Safety concerns are linked to the appropriate dose because LABAs, particularly at high doses, have been associated with severe asthma exacerbations and asthma-related deaths in patients who use the drugs to treat asthma. "Although such a risk or worsening of disease has not been shown in patients with COPD, it is nevertheless important to select the appropriate and safe dose for a bronchodilator," Dr. Chowdhury stated.

The dose-ranging study data submitted in response to the FDA’s "complete response" letter show no clear separation in effect size, as measured by trough forced expiratory volume in 1 second (FEV1), compared with placebo, for the 37.5-mcg, 75-mcg, and 150-mcg doses. "These FEV1-based data do lend support for the 75 mcg-dose, but do not show clear efficacy advantage of the 150-mcg dose over the 75-mcg dose."

Dr. Chowdhury noted that there are no 12-week studies that include both the 75-mcg and 150-mcg doses in the same study.

Across the various studies for indacaterol, the accumulated SGRQ data showed statistical significance over placebo for all active treatments, aside from tiotropium, including the full range of indacaterol doses. In an analysis of pooled data from the COPD trials, Dr. Chowdhury pointed out that there was no statistically significant difference among the indacaterol doses in terms of the percentage of patients for whom an improvement in SGRQ score was considered clinically important. "Considering the evidence collectively, a labeling claim based on the improvement in SGRQ scores for the dose of 150 mcg seems to be questionable," he concluded.

Safety Concerns in Both Asthma and COPD

The earlier asthma studies raised safety concerns because there were two deaths in the indacaterol group in one study, and both patients were receiving concomitant inhaled corticosteroids, Dr. Chowdhury noted. Furthermore, serious adverse events related to asthma exacerbation or respiratory events appeared to be more common in indacaterol-treated patients.

A safety addendum to the clinical review written by Dr. Banu Karimi-Shah, a medical officer with the FDA’s division of pulmonary, allergy, and rheumatology products, discussed a blinded, adjudicated analysis comparing indacaterol-treated patients with controls with regard to respiratory-related death, hospitalization and intubation. The analysis was conducted by Novartis at the FDA’s request to establish whether there was a safety disadvantage with the 150-mcg dose.

Focusing on data from the COPD population, Dr. Karimi-Shah wrote: "Although the magnitude of the signal is not large, there does appear to be a numerical trend of increasing incidence of acute respiratory-related events, particularly those that were adjudicated as having been COPD-related, as the dose of indacaterol rises from 75 mcg to 300 mcg.

The Food and Drug Administration’s longstanding concerns about the appropriate dose of Arcapta Neohaler (indacaterol maleate) for chronic obstructive pulmonary disease have not subsided despite additional studies conducted by the company. The agency will ask its Pulmonary-Allergy Drugs Advisory Committee to weigh the issue of multiple doses and dosing frequency at a March 8 meeting.

Although the advisory committee is being asked to discuss the safety and efficacy data for drug maker Novartis’ two proposed doses – 75 mcg and 150 mcg – of its long-acting beta agonist (LABA), background briefing documents released on March 4 make clear that the FDA’s preference lies with the 75-mcg dose. Reviewers believe that the higher dose provides little added benefit and raises safety concerns inherent with other LABAs.

Novartis seeks an indication for long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. In the United States, all currently marketed LABAs are dosed twice daily and marketed in only one dosage form, so Novartis is seeking to break new ground.

A once-daily dosing schedule would be somewhat novel. The only once-daily bronchodilator approved for COPD is the long-acting muscarinic antagonist Spiriva (tiotropium). In review documents, however, FDA staff question whether more frequent, or even less frequent, dosing is warranted.

The committee also will be asked to weigh a quality-of-life claim for the 150-mcg dose in the form of improved health status measured by the St. George’s Respiratory Questionnaire (SGRQ). Though the FDA seems skeptical that such a claim is supported, if granted it would make indacaterol the first bronchodilator to carry a quality-of-life claim based on the SGRQ.

More Questions Despite More Studies

That the agency is bringing dosing concerns to its advisory committee is not surprising given that they were the focus of an FDA "complete response" letter. However, Novartis’ response to the agency’s regulatory concerns clearly has not put them to rest.

Novartis’ original NDA, submitted in December 2008, sought approval for indacaterol inhalation powder at doses of 150 mcg and 300 mcg. These are the same doses subsequently approved in Europe, where the product is known as Onbrez Breezhaler.

The company is not seeking an asthma indication, although some of the clinical studies were conducted in asthma patients.

In an October 2009 "complete response" letter, the agency concluded that the doses proposed for marketing were high and unsupported by the NDA’s efficacy and safety data.

The FDA asked the company to explore efficacy and establish safety of lower doses and various dosing frequencies, to provide data showing a meaningful advantage of a higher dose compared with a lower dose, and to demonstrate that a higher dose is not associated with an unacceptable safety disadvantage.

Novartis submitted its response in October 2010 with results from six studies encompassing more than 2,000 patients. The new data included two dose-ranging studies, one dose regimen study, and three pivotal COPD trials.

With the resubmission, Novartis lowered the proposed doses to 75 mcg and 150 mcg. It asserted that the 150 mcg dose provides an efficacy advantage in patients with more severe bronchial obstruction based upon pharmacodynamic modeling analysis and the SGRQ data.

The SGRQ comprises 16 questions that assess disease symptoms, disturbances to patients’ daily physical activity, and the impact of disease on the patient. The instrument is frequently used as a quality of life assessment in clinical trials, according to Novartis’ briefing document.

New Regulatory and Scientific Paradigms

In a memo to the advisory committee, Dr. Badrul Chowdhury, director of the FDA’s division of pulmonary, allergy, and rheumatology products, said that the efficacy issues for discussion relate to the appropriate dose and the request for a health status claim based upon the SGRQ data. "In the U.S., no bronchodilators are approved in more than one dose, and none have claims for improvement in SGRQ. Thus, the indacaterol application represents some new regulatory and scientific paradigms," he wrote.

Safety concerns are linked to the appropriate dose because LABAs, particularly at high doses, have been associated with severe asthma exacerbations and asthma-related deaths in patients who use the drugs to treat asthma. "Although such a risk or worsening of disease has not been shown in patients with COPD, it is nevertheless important to select the appropriate and safe dose for a bronchodilator," Dr. Chowdhury stated.

The dose-ranging study data submitted in response to the FDA’s "complete response" letter show no clear separation in effect size, as measured by trough forced expiratory volume in 1 second (FEV1), compared with placebo, for the 37.5-mcg, 75-mcg, and 150-mcg doses. "These FEV1-based data do lend support for the 75 mcg-dose, but do not show clear efficacy advantage of the 150-mcg dose over the 75-mcg dose."

Dr. Chowdhury noted that there are no 12-week studies that include both the 75-mcg and 150-mcg doses in the same study.

Across the various studies for indacaterol, the accumulated SGRQ data showed statistical significance over placebo for all active treatments, aside from tiotropium, including the full range of indacaterol doses. In an analysis of pooled data from the COPD trials, Dr. Chowdhury pointed out that there was no statistically significant difference among the indacaterol doses in terms of the percentage of patients for whom an improvement in SGRQ score was considered clinically important. "Considering the evidence collectively, a labeling claim based on the improvement in SGRQ scores for the dose of 150 mcg seems to be questionable," he concluded.

Safety Concerns in Both Asthma and COPD

The earlier asthma studies raised safety concerns because there were two deaths in the indacaterol group in one study, and both patients were receiving concomitant inhaled corticosteroids, Dr. Chowdhury noted. Furthermore, serious adverse events related to asthma exacerbation or respiratory events appeared to be more common in indacaterol-treated patients.

A safety addendum to the clinical review written by Dr. Banu Karimi-Shah, a medical officer with the FDA’s division of pulmonary, allergy, and rheumatology products, discussed a blinded, adjudicated analysis comparing indacaterol-treated patients with controls with regard to respiratory-related death, hospitalization and intubation. The analysis was conducted by Novartis at the FDA’s request to establish whether there was a safety disadvantage with the 150-mcg dose.

Focusing on data from the COPD population, Dr. Karimi-Shah wrote: "Although the magnitude of the signal is not large, there does appear to be a numerical trend of increasing incidence of acute respiratory-related events, particularly those that were adjudicated as having been COPD-related, as the dose of indacaterol rises from 75 mcg to 300 mcg.

The Food and Drug Administration’s longstanding concerns about the appropriate dose of Arcapta Neohaler (indacaterol maleate) for chronic obstructive pulmonary disease have not subsided despite additional studies conducted by the company. The agency will ask its Pulmonary-Allergy Drugs Advisory Committee to weigh the issue of multiple doses and dosing frequency at a March 8 meeting.

Although the advisory committee is being asked to discuss the safety and efficacy data for drug maker Novartis’ two proposed doses – 75 mcg and 150 mcg – of its long-acting beta agonist (LABA), background briefing documents released on March 4 make clear that the FDA’s preference lies with the 75-mcg dose. Reviewers believe that the higher dose provides little added benefit and raises safety concerns inherent with other LABAs.

Novartis seeks an indication for long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. In the United States, all currently marketed LABAs are dosed twice daily and marketed in only one dosage form, so Novartis is seeking to break new ground.

A once-daily dosing schedule would be somewhat novel. The only once-daily bronchodilator approved for COPD is the long-acting muscarinic antagonist Spiriva (tiotropium). In review documents, however, FDA staff question whether more frequent, or even less frequent, dosing is warranted.

The committee also will be asked to weigh a quality-of-life claim for the 150-mcg dose in the form of improved health status measured by the St. George’s Respiratory Questionnaire (SGRQ). Though the FDA seems skeptical that such a claim is supported, if granted it would make indacaterol the first bronchodilator to carry a quality-of-life claim based on the SGRQ.

More Questions Despite More Studies

That the agency is bringing dosing concerns to its advisory committee is not surprising given that they were the focus of an FDA "complete response" letter. However, Novartis’ response to the agency’s regulatory concerns clearly has not put them to rest.

Novartis’ original NDA, submitted in December 2008, sought approval for indacaterol inhalation powder at doses of 150 mcg and 300 mcg. These are the same doses subsequently approved in Europe, where the product is known as Onbrez Breezhaler.

The company is not seeking an asthma indication, although some of the clinical studies were conducted in asthma patients.

In an October 2009 "complete response" letter, the agency concluded that the doses proposed for marketing were high and unsupported by the NDA’s efficacy and safety data.

The FDA asked the company to explore efficacy and establish safety of lower doses and various dosing frequencies, to provide data showing a meaningful advantage of a higher dose compared with a lower dose, and to demonstrate that a higher dose is not associated with an unacceptable safety disadvantage.

Novartis submitted its response in October 2010 with results from six studies encompassing more than 2,000 patients. The new data included two dose-ranging studies, one dose regimen study, and three pivotal COPD trials.

With the resubmission, Novartis lowered the proposed doses to 75 mcg and 150 mcg. It asserted that the 150 mcg dose provides an efficacy advantage in patients with more severe bronchial obstruction based upon pharmacodynamic modeling analysis and the SGRQ data.

The SGRQ comprises 16 questions that assess disease symptoms, disturbances to patients’ daily physical activity, and the impact of disease on the patient. The instrument is frequently used as a quality of life assessment in clinical trials, according to Novartis’ briefing document.

New Regulatory and Scientific Paradigms

In a memo to the advisory committee, Dr. Badrul Chowdhury, director of the FDA’s division of pulmonary, allergy, and rheumatology products, said that the efficacy issues for discussion relate to the appropriate dose and the request for a health status claim based upon the SGRQ data. "In the U.S., no bronchodilators are approved in more than one dose, and none have claims for improvement in SGRQ. Thus, the indacaterol application represents some new regulatory and scientific paradigms," he wrote.

Safety concerns are linked to the appropriate dose because LABAs, particularly at high doses, have been associated with severe asthma exacerbations and asthma-related deaths in patients who use the drugs to treat asthma. "Although such a risk or worsening of disease has not been shown in patients with COPD, it is nevertheless important to select the appropriate and safe dose for a bronchodilator," Dr. Chowdhury stated.

The dose-ranging study data submitted in response to the FDA’s "complete response" letter show no clear separation in effect size, as measured by trough forced expiratory volume in 1 second (FEV1), compared with placebo, for the 37.5-mcg, 75-mcg, and 150-mcg doses. "These FEV1-based data do lend support for the 75 mcg-dose, but do not show clear efficacy advantage of the 150-mcg dose over the 75-mcg dose."

Dr. Chowdhury noted that there are no 12-week studies that include both the 75-mcg and 150-mcg doses in the same study.

Across the various studies for indacaterol, the accumulated SGRQ data showed statistical significance over placebo for all active treatments, aside from tiotropium, including the full range of indacaterol doses. In an analysis of pooled data from the COPD trials, Dr. Chowdhury pointed out that there was no statistically significant difference among the indacaterol doses in terms of the percentage of patients for whom an improvement in SGRQ score was considered clinically important. "Considering the evidence collectively, a labeling claim based on the improvement in SGRQ scores for the dose of 150 mcg seems to be questionable," he concluded.

Safety Concerns in Both Asthma and COPD

The earlier asthma studies raised safety concerns because there were two deaths in the indacaterol group in one study, and both patients were receiving concomitant inhaled corticosteroids, Dr. Chowdhury noted. Furthermore, serious adverse events related to asthma exacerbation or respiratory events appeared to be more common in indacaterol-treated patients.

A safety addendum to the clinical review written by Dr. Banu Karimi-Shah, a medical officer with the FDA’s division of pulmonary, allergy, and rheumatology products, discussed a blinded, adjudicated analysis comparing indacaterol-treated patients with controls with regard to respiratory-related death, hospitalization and intubation. The analysis was conducted by Novartis at the FDA’s request to establish whether there was a safety disadvantage with the 150-mcg dose.

Focusing on data from the COPD population, Dr. Karimi-Shah wrote: "Although the magnitude of the signal is not large, there does appear to be a numerical trend of increasing incidence of acute respiratory-related events, particularly those that were adjudicated as having been COPD-related, as the dose of indacaterol rises from 75 mcg to 300 mcg.