Pulmonary Health Hub

SAN DIEGO – Caval angulation and filter tilt complicate removal of inferior vena cava filters, results from a large single-center study demonstrated.

"The use of retrievable IVC filters has increased significantly over the past 10 years," Jennifer Stevens said at the annual meeting of the American Venous Forum. "However, these filters have become permanent in many cases, with retrieval rates ranging anywhere from 15% to 59%. In one multicenter study, the retrieval rate was only 21%."

In an effort to examine patient characteristics and anatomic predictors associated with nonretrieval of IVC filters, Ms. Stevens, a fourth-year medical student at the University of Pittsburgh, and her associates reviewed all retrievable IVC filters that were placed in 404 patients at the university’s medical center between 2004 and 2009. Caval angulation at the lowest renal vein was categorized as straight, less than 30 degrees, 30-60 degrees, and greater than 60 degrees. Filter tilt was classified as none, less than 45 degrees, and 45-90 degrees. Filter thrombus was classified as less than one-third or greater than one-third.

Ms. Stevens reported that the majority of filters (65%) were placed in trauma patients, with prophylactic indications for insertion (57%). More than one-third of patients (41%) were between the ages of 26 and 50 years, and 61% were male.

Of the 404 filters placed, 166 (41%) were not retrieved. "These patients were more likely to be middle-aged males with a therapeutic indication for insertion," she said.

The most common reasons for nonretrieval were physician oversight (38%) and patient noncompliance (20%). Other reasons included significant thrombus that precluded removal (5%), a medical decision to leave the filter permanently placed (11%), and mechanical inability to remove the filter (12%).

The majority of the 24 cases of attempted but failed retrieval were in female trauma patients aged 51-75 years with a history of prior deep vein thrombosis requiring prophylactic filter insertion. "All of these retrievals had more than one separate attempt made before retrieval was aborted," Ms. Stevens said.

Dwell time was higher in patients who had failed retrieval (mean of 67 days vs. 30 days in patients whose filters were successfully retrieved), and 29% were still on warfarin. "Of note, 71% of these patients were categorized with a less than 30-degree angulation at the level of the renal vein," she said.

Ms. Stevens also presented findings from a subset of 39 cases of difficult filter retrievals that required adjunctive maneuvers, most commonly an extra snare (55%). More than half of these cases (62%) involved the Tulip filter.

Of all filters placed, 82 (20%) had apposition of the hook into the caval wall. Of those filters, 9 (11%) were difficult to retrieve.

Predictors of failed or difficult retrieval included any filter tilt or angulation at the renal veins (odds ratio 3.99) and longer dwell time (OR 1.02). Caval penetration by a filter strut was not a significant predictor of failed or difficult retrieval.

"From an anatomic standpoint, caval angulation and filter tilt complicate IVC filter retrieval," Ms. Stevens concluded. "Consideration should be given to deploying in a straight segment of the IVC even if not flush with the renal veins in order to optimize retrieval. Dwell time adversely affects retrieval success, and the overall retrieval rate continues to be moderate, suggesting physician prompts and patient follow-up reminders as possible future targets for improvement."

The study’s principal investigator was Dr. Rabih A. Chaer, a vascular surgeon at the university.

Ms. Stevens and Dr. Chaer had no relevant financial disclosures.

SAN DIEGO – Caval angulation and filter tilt complicate removal of inferior vena cava filters, results from a large single-center study demonstrated.

"The use of retrievable IVC filters has increased significantly over the past 10 years," Jennifer Stevens said at the annual meeting of the American Venous Forum. "However, these filters have become permanent in many cases, with retrieval rates ranging anywhere from 15% to 59%. In one multicenter study, the retrieval rate was only 21%."

In an effort to examine patient characteristics and anatomic predictors associated with nonretrieval of IVC filters, Ms. Stevens, a fourth-year medical student at the University of Pittsburgh, and her associates reviewed all retrievable IVC filters that were placed in 404 patients at the university’s medical center between 2004 and 2009. Caval angulation at the lowest renal vein was categorized as straight, less than 30 degrees, 30-60 degrees, and greater than 60 degrees. Filter tilt was classified as none, less than 45 degrees, and 45-90 degrees. Filter thrombus was classified as less than one-third or greater than one-third.

Ms. Stevens reported that the majority of filters (65%) were placed in trauma patients, with prophylactic indications for insertion (57%). More than one-third of patients (41%) were between the ages of 26 and 50 years, and 61% were male.

Of the 404 filters placed, 166 (41%) were not retrieved. "These patients were more likely to be middle-aged males with a therapeutic indication for insertion," she said.

The most common reasons for nonretrieval were physician oversight (38%) and patient noncompliance (20%). Other reasons included significant thrombus that precluded removal (5%), a medical decision to leave the filter permanently placed (11%), and mechanical inability to remove the filter (12%).

The majority of the 24 cases of attempted but failed retrieval were in female trauma patients aged 51-75 years with a history of prior deep vein thrombosis requiring prophylactic filter insertion. "All of these retrievals had more than one separate attempt made before retrieval was aborted," Ms. Stevens said.

Dwell time was higher in patients who had failed retrieval (mean of 67 days vs. 30 days in patients whose filters were successfully retrieved), and 29% were still on warfarin. "Of note, 71% of these patients were categorized with a less than 30-degree angulation at the level of the renal vein," she said.

Ms. Stevens also presented findings from a subset of 39 cases of difficult filter retrievals that required adjunctive maneuvers, most commonly an extra snare (55%). More than half of these cases (62%) involved the Tulip filter.

Of all filters placed, 82 (20%) had apposition of the hook into the caval wall. Of those filters, 9 (11%) were difficult to retrieve.

Predictors of failed or difficult retrieval included any filter tilt or angulation at the renal veins (odds ratio 3.99) and longer dwell time (OR 1.02). Caval penetration by a filter strut was not a significant predictor of failed or difficult retrieval.

"From an anatomic standpoint, caval angulation and filter tilt complicate IVC filter retrieval," Ms. Stevens concluded. "Consideration should be given to deploying in a straight segment of the IVC even if not flush with the renal veins in order to optimize retrieval. Dwell time adversely affects retrieval success, and the overall retrieval rate continues to be moderate, suggesting physician prompts and patient follow-up reminders as possible future targets for improvement."

The study’s principal investigator was Dr. Rabih A. Chaer, a vascular surgeon at the university.

Ms. Stevens and Dr. Chaer had no relevant financial disclosures.

SAN DIEGO – Caval angulation and filter tilt complicate removal of inferior vena cava filters, results from a large single-center study demonstrated.

"The use of retrievable IVC filters has increased significantly over the past 10 years," Jennifer Stevens said at the annual meeting of the American Venous Forum. "However, these filters have become permanent in many cases, with retrieval rates ranging anywhere from 15% to 59%. In one multicenter study, the retrieval rate was only 21%."

In an effort to examine patient characteristics and anatomic predictors associated with nonretrieval of IVC filters, Ms. Stevens, a fourth-year medical student at the University of Pittsburgh, and her associates reviewed all retrievable IVC filters that were placed in 404 patients at the university’s medical center between 2004 and 2009. Caval angulation at the lowest renal vein was categorized as straight, less than 30 degrees, 30-60 degrees, and greater than 60 degrees. Filter tilt was classified as none, less than 45 degrees, and 45-90 degrees. Filter thrombus was classified as less than one-third or greater than one-third.

Ms. Stevens reported that the majority of filters (65%) were placed in trauma patients, with prophylactic indications for insertion (57%). More than one-third of patients (41%) were between the ages of 26 and 50 years, and 61% were male.

Of the 404 filters placed, 166 (41%) were not retrieved. "These patients were more likely to be middle-aged males with a therapeutic indication for insertion," she said.

The most common reasons for nonretrieval were physician oversight (38%) and patient noncompliance (20%). Other reasons included significant thrombus that precluded removal (5%), a medical decision to leave the filter permanently placed (11%), and mechanical inability to remove the filter (12%).

The majority of the 24 cases of attempted but failed retrieval were in female trauma patients aged 51-75 years with a history of prior deep vein thrombosis requiring prophylactic filter insertion. "All of these retrievals had more than one separate attempt made before retrieval was aborted," Ms. Stevens said.

Dwell time was higher in patients who had failed retrieval (mean of 67 days vs. 30 days in patients whose filters were successfully retrieved), and 29% were still on warfarin. "Of note, 71% of these patients were categorized with a less than 30-degree angulation at the level of the renal vein," she said.

Ms. Stevens also presented findings from a subset of 39 cases of difficult filter retrievals that required adjunctive maneuvers, most commonly an extra snare (55%). More than half of these cases (62%) involved the Tulip filter.

Of all filters placed, 82 (20%) had apposition of the hook into the caval wall. Of those filters, 9 (11%) were difficult to retrieve.

Predictors of failed or difficult retrieval included any filter tilt or angulation at the renal veins (odds ratio 3.99) and longer dwell time (OR 1.02). Caval penetration by a filter strut was not a significant predictor of failed or difficult retrieval.

"From an anatomic standpoint, caval angulation and filter tilt complicate IVC filter retrieval," Ms. Stevens concluded. "Consideration should be given to deploying in a straight segment of the IVC even if not flush with the renal veins in order to optimize retrieval. Dwell time adversely affects retrieval success, and the overall retrieval rate continues to be moderate, suggesting physician prompts and patient follow-up reminders as possible future targets for improvement."

The study’s principal investigator was Dr. Rabih A. Chaer, a vascular surgeon at the university.

Ms. Stevens and Dr. Chaer had no relevant financial disclosures.

SAN DIEGO – Caval angulation and filter tilt complicate removal of inferior vena cava filters, results from a large single-center study demonstrated.

"The use of retrievable IVC filters has increased significantly over the past 10 years," Jennifer Stevens said at the annual meeting of the American Venous Forum. "However, these filters have become permanent in many cases, with retrieval rates ranging anywhere from 15% to 59%. In one multicenter study, the retrieval rate was only 21%."

In an effort to examine patient characteristics and anatomic predictors associated with nonretrieval of IVC filters, Ms. Stevens, a fourth-year medical student at the University of Pittsburgh, and her associates reviewed all retrievable IVC filters that were placed in 404 patients at the university’s medical center between 2004 and 2009. Caval angulation at the lowest renal vein was categorized as straight, less than 30 degrees, 30-60 degrees, and greater than 60 degrees. Filter tilt was classified as none, less than 45 degrees, and 45-90 degrees. Filter thrombus was classified as less than one-third or greater than one-third.

Ms. Stevens reported that the majority of filters (65%) were placed in trauma patients, with prophylactic indications for insertion (57%). More than one-third of patients (41%) were between the ages of 26 and 50 years, and 61% were male.

Of the 404 filters placed, 166 (41%) were not retrieved. "These patients were more likely to be middle-aged males with a therapeutic indication for insertion," she said.

The most common reasons for nonretrieval were physician oversight (38%) and patient noncompliance (20%). Other reasons included significant thrombus that precluded removal (5%), a medical decision to leave the filter permanently placed (11%), and mechanical inability to remove the filter (12%).

The majority of the 24 cases of attempted but failed retrieval were in female trauma patients aged 51-75 years with a history of prior deep vein thrombosis requiring prophylactic filter insertion. "All of these retrievals had more than one separate attempt made before retrieval was aborted," Ms. Stevens said.

Dwell time was higher in patients who had failed retrieval (mean of 67 days vs. 30 days in patients whose filters were successfully retrieved), and 29% were still on warfarin. "Of note, 71% of these patients were categorized with a less than 30-degree angulation at the level of the renal vein," she said.

Ms. Stevens also presented findings from a subset of 39 cases of difficult filter retrievals that required adjunctive maneuvers, most commonly an extra snare (55%). More than half of these cases (62%) involved the Tulip filter.

Of all filters placed, 82 (20%) had apposition of the hook into the caval wall. Of those filters, 9 (11%) were difficult to retrieve.

Predictors of failed or difficult retrieval included any filter tilt or angulation at the renal veins (odds ratio 3.99) and longer dwell time (OR 1.02). Caval penetration by a filter strut was not a significant predictor of failed or difficult retrieval.

"From an anatomic standpoint, caval angulation and filter tilt complicate IVC filter retrieval," Ms. Stevens concluded. "Consideration should be given to deploying in a straight segment of the IVC even if not flush with the renal veins in order to optimize retrieval. Dwell time adversely affects retrieval success, and the overall retrieval rate continues to be moderate, suggesting physician prompts and patient follow-up reminders as possible future targets for improvement."

The study’s principal investigator was Dr. Rabih A. Chaer, a vascular surgeon at the university.

Ms. Stevens and Dr. Chaer had no relevant financial disclosures.

SAN DIEGO – Caval angulation and filter tilt complicate removal of inferior vena cava filters, results from a large single-center study demonstrated.

"The use of retrievable IVC filters has increased significantly over the past 10 years," Jennifer Stevens said at the annual meeting of the American Venous Forum. "However, these filters have become permanent in many cases, with retrieval rates ranging anywhere from 15% to 59%. In one multicenter study, the retrieval rate was only 21%."

In an effort to examine patient characteristics and anatomic predictors associated with nonretrieval of IVC filters, Ms. Stevens, a fourth-year medical student at the University of Pittsburgh, and her associates reviewed all retrievable IVC filters that were placed in 404 patients at the university’s medical center between 2004 and 2009. Caval angulation at the lowest renal vein was categorized as straight, less than 30 degrees, 30-60 degrees, and greater than 60 degrees. Filter tilt was classified as none, less than 45 degrees, and 45-90 degrees. Filter thrombus was classified as less than one-third or greater than one-third.

Ms. Stevens reported that the majority of filters (65%) were placed in trauma patients, with prophylactic indications for insertion (57%). More than one-third of patients (41%) were between the ages of 26 and 50 years, and 61% were male.

Of the 404 filters placed, 166 (41%) were not retrieved. "These patients were more likely to be middle-aged males with a therapeutic indication for insertion," she said.

The most common reasons for nonretrieval were physician oversight (38%) and patient noncompliance (20%). Other reasons included significant thrombus that precluded removal (5%), a medical decision to leave the filter permanently placed (11%), and mechanical inability to remove the filter (12%).

The majority of the 24 cases of attempted but failed retrieval were in female trauma patients aged 51-75 years with a history of prior deep vein thrombosis requiring prophylactic filter insertion. "All of these retrievals had more than one separate attempt made before retrieval was aborted," Ms. Stevens said.

Dwell time was higher in patients who had failed retrieval (mean of 67 days vs. 30 days in patients whose filters were successfully retrieved), and 29% were still on warfarin. "Of note, 71% of these patients were categorized with a less than 30-degree angulation at the level of the renal vein," she said.

Ms. Stevens also presented findings from a subset of 39 cases of difficult filter retrievals that required adjunctive maneuvers, most commonly an extra snare (55%). More than half of these cases (62%) involved the Tulip filter.

Of all filters placed, 82 (20%) had apposition of the hook into the caval wall. Of those filters, 9 (11%) were difficult to retrieve.

Predictors of failed or difficult retrieval included any filter tilt or angulation at the renal veins (odds ratio 3.99) and longer dwell time (OR 1.02). Caval penetration by a filter strut was not a significant predictor of failed or difficult retrieval.

"From an anatomic standpoint, caval angulation and filter tilt complicate IVC filter retrieval," Ms. Stevens concluded. "Consideration should be given to deploying in a straight segment of the IVC even if not flush with the renal veins in order to optimize retrieval. Dwell time adversely affects retrieval success, and the overall retrieval rate continues to be moderate, suggesting physician prompts and patient follow-up reminders as possible future targets for improvement."

The study’s principal investigator was Dr. Rabih A. Chaer, a vascular surgeon at the university.

Ms. Stevens and Dr. Chaer had no relevant financial disclosures.

SAN DIEGO – Caval angulation and filter tilt complicate removal of inferior vena cava filters, results from a large single-center study demonstrated.

"The use of retrievable IVC filters has increased significantly over the past 10 years," Jennifer Stevens said at the annual meeting of the American Venous Forum. "However, these filters have become permanent in many cases, with retrieval rates ranging anywhere from 15% to 59%. In one multicenter study, the retrieval rate was only 21%."

In an effort to examine patient characteristics and anatomic predictors associated with nonretrieval of IVC filters, Ms. Stevens, a fourth-year medical student at the University of Pittsburgh, and her associates reviewed all retrievable IVC filters that were placed in 404 patients at the university’s medical center between 2004 and 2009. Caval angulation at the lowest renal vein was categorized as straight, less than 30 degrees, 30-60 degrees, and greater than 60 degrees. Filter tilt was classified as none, less than 45 degrees, and 45-90 degrees. Filter thrombus was classified as less than one-third or greater than one-third.

Ms. Stevens reported that the majority of filters (65%) were placed in trauma patients, with prophylactic indications for insertion (57%). More than one-third of patients (41%) were between the ages of 26 and 50 years, and 61% were male.

Of the 404 filters placed, 166 (41%) were not retrieved. "These patients were more likely to be middle-aged males with a therapeutic indication for insertion," she said.

The most common reasons for nonretrieval were physician oversight (38%) and patient noncompliance (20%). Other reasons included significant thrombus that precluded removal (5%), a medical decision to leave the filter permanently placed (11%), and mechanical inability to remove the filter (12%).

The majority of the 24 cases of attempted but failed retrieval were in female trauma patients aged 51-75 years with a history of prior deep vein thrombosis requiring prophylactic filter insertion. "All of these retrievals had more than one separate attempt made before retrieval was aborted," Ms. Stevens said.

Dwell time was higher in patients who had failed retrieval (mean of 67 days vs. 30 days in patients whose filters were successfully retrieved), and 29% were still on warfarin. "Of note, 71% of these patients were categorized with a less than 30-degree angulation at the level of the renal vein," she said.

Ms. Stevens also presented findings from a subset of 39 cases of difficult filter retrievals that required adjunctive maneuvers, most commonly an extra snare (55%). More than half of these cases (62%) involved the Tulip filter.

Of all filters placed, 82 (20%) had apposition of the hook into the caval wall. Of those filters, 9 (11%) were difficult to retrieve.

Predictors of failed or difficult retrieval included any filter tilt or angulation at the renal veins (odds ratio 3.99) and longer dwell time (OR 1.02). Caval penetration by a filter strut was not a significant predictor of failed or difficult retrieval.

"From an anatomic standpoint, caval angulation and filter tilt complicate IVC filter retrieval," Ms. Stevens concluded. "Consideration should be given to deploying in a straight segment of the IVC even if not flush with the renal veins in order to optimize retrieval. Dwell time adversely affects retrieval success, and the overall retrieval rate continues to be moderate, suggesting physician prompts and patient follow-up reminders as possible future targets for improvement."

The study’s principal investigator was Dr. Rabih A. Chaer, a vascular surgeon at the university.

Ms. Stevens and Dr. Chaer had no relevant financial disclosures.

Smokers with interstitial lung abnormalities on high-resolution CT show both reduced total lung capacity and a lesser amount of emphysema, compared with those who didn’t have interstitial lung abnormalities, according to a report in the March 10 issue of the New England Journal of Medicine.

In addition, the magnitude of these two reductions is greatest among smokers who also have chronic obstructive pulmonary disease (COPD), said Dr. George R. Washko of the pulmonary and critical care division at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his associates.

"Our findings are consistent with, and add weight to, previous studies showing that cigarette smoking is associated with both spirometric restriction and areas of high attenuation on HRCT. Since emphysema and interstitial lung abnormalities have opposing effects on lung volume, our findings suggest that HRCT may provide important diagnostic information in smokers whose total lung capacity is unexpectedly ‘normal,’ " they noted.

"We speculate that this could be clinically important to physicians who may think that a patient who does not have symptoms or characteristic abnormalities on lung function tests is disease free, when in fact the patient could be affected by two of the consequences of smoking – emphysema and interstitial lung abnormalities," Dr. Washko and his colleagues said.

The investigators examined the relationship among radiographic interstitial lung abnormalities, total lung capacity, and emphysema in a cohort of 2,416 smokers who had been recruited for an ongoing study of COPD being conducted at 21 clinical centers.

The cohort included white (75%) and black (25%) subjects aged 45-80 years who reported a history of at least 10 pack-years of smoking. Slightly more than half of the subjects were men, 44% were still actively smoking, and 41% met criteria for COPD.

The overall prevalence of interstitial lung abnormalities affecting more than 5% of any lung zone on HRCT was 8%. Another 36% of the subjects showed "indeterminate" findings, and 56% showed no interstitial lung abnormalities.

The lung abnormalities included nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, and traction bronchiectasis.

Interstitial lung abnormalities were associated with both a decrease in total lung capacity and a lesser amount of emphysema. In addition, there was an inverse relationship between these abnormalities and the severity of COPD, the researchers said (N. Engl. J. Med. 2011;364:897-906).

Further follow-up is needed "to determine whether these radiographic abnormalities, and the associated reductions in lung volumes, are transient or stable, or whether they will progress to clinically significant disease," Dr. Washko and his associates said.

In an editorial accompanying the report, Dr. Talmadge E. King Jr. said that the "long-term implications of this and similar studies using HRCT scans in asymptomatic subjects are unknown. There is the concern that such scans may be overinterpreted, leading to a high rate of unnecessary diagnoses and perhaps unwarranted treatment" (N. Engl. J. Med. 2011;364:968-70). In this study, more than one-third of the HRCT scans were deemed "indeterminate" for the presence of interstitial lung abnormalities, which "probably reflects the fact that the boundary between HRCT images of the lungs in health and disease is blurred," noted Dr. King of the department of medicine at the University of California, San Francisco.

However, he thought it was noteworthy that Dr. Washko and his colleagues found that interstitial lung abnormalities were associated with less radiographic emphysema. "It is interesting to speculate that the pathobiology of smoking can lead to two distinct patterns of injury – emphysema (with destruction of the lung) or interstitial lung disease (with macrophage accumulation and fibrosis).

"Conversely ... the relative lack of emphysema could be simply a reflection of the fact that interstitial lung abnormalities mask emphysema or that more severe emphysema limits the extent of interstitial lung abnormalities," Dr. King said.

This study was supported by the National Institutes of Health and the Parker B. Francis Foundation. Dr. Washko reported ties to MedImmune, and his associates reported ties to Siemens, Actelion, Gilead, InterMune, Novartis, Perceptive Imaging, GE Medical Systems, GlaxoSmithKline, AstraZeneca, Toshiba Medical, and AZE. Dr. King reported ties to Actelion, InterMune, ImmuneWorks, Philips Respironics, CV Therapeutics, and Genzyme.

Smokers with interstitial lung abnormalities on high-resolution CT show both reduced total lung capacity and a lesser amount of emphysema, compared with those who didn’t have interstitial lung abnormalities, according to a report in the March 10 issue of the New England Journal of Medicine.

In addition, the magnitude of these two reductions is greatest among smokers who also have chronic obstructive pulmonary disease (COPD), said Dr. George R. Washko of the pulmonary and critical care division at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his associates.

"Our findings are consistent with, and add weight to, previous studies showing that cigarette smoking is associated with both spirometric restriction and areas of high attenuation on HRCT. Since emphysema and interstitial lung abnormalities have opposing effects on lung volume, our findings suggest that HRCT may provide important diagnostic information in smokers whose total lung capacity is unexpectedly ‘normal,’ " they noted.

"We speculate that this could be clinically important to physicians who may think that a patient who does not have symptoms or characteristic abnormalities on lung function tests is disease free, when in fact the patient could be affected by two of the consequences of smoking – emphysema and interstitial lung abnormalities," Dr. Washko and his colleagues said.

The investigators examined the relationship among radiographic interstitial lung abnormalities, total lung capacity, and emphysema in a cohort of 2,416 smokers who had been recruited for an ongoing study of COPD being conducted at 21 clinical centers.

The cohort included white (75%) and black (25%) subjects aged 45-80 years who reported a history of at least 10 pack-years of smoking. Slightly more than half of the subjects were men, 44% were still actively smoking, and 41% met criteria for COPD.

The overall prevalence of interstitial lung abnormalities affecting more than 5% of any lung zone on HRCT was 8%. Another 36% of the subjects showed "indeterminate" findings, and 56% showed no interstitial lung abnormalities.

The lung abnormalities included nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, and traction bronchiectasis.

Interstitial lung abnormalities were associated with both a decrease in total lung capacity and a lesser amount of emphysema. In addition, there was an inverse relationship between these abnormalities and the severity of COPD, the researchers said (N. Engl. J. Med. 2011;364:897-906).

Further follow-up is needed "to determine whether these radiographic abnormalities, and the associated reductions in lung volumes, are transient or stable, or whether they will progress to clinically significant disease," Dr. Washko and his associates said.

In an editorial accompanying the report, Dr. Talmadge E. King Jr. said that the "long-term implications of this and similar studies using HRCT scans in asymptomatic subjects are unknown. There is the concern that such scans may be overinterpreted, leading to a high rate of unnecessary diagnoses and perhaps unwarranted treatment" (N. Engl. J. Med. 2011;364:968-70). In this study, more than one-third of the HRCT scans were deemed "indeterminate" for the presence of interstitial lung abnormalities, which "probably reflects the fact that the boundary between HRCT images of the lungs in health and disease is blurred," noted Dr. King of the department of medicine at the University of California, San Francisco.

However, he thought it was noteworthy that Dr. Washko and his colleagues found that interstitial lung abnormalities were associated with less radiographic emphysema. "It is interesting to speculate that the pathobiology of smoking can lead to two distinct patterns of injury – emphysema (with destruction of the lung) or interstitial lung disease (with macrophage accumulation and fibrosis).

"Conversely ... the relative lack of emphysema could be simply a reflection of the fact that interstitial lung abnormalities mask emphysema or that more severe emphysema limits the extent of interstitial lung abnormalities," Dr. King said.

This study was supported by the National Institutes of Health and the Parker B. Francis Foundation. Dr. Washko reported ties to MedImmune, and his associates reported ties to Siemens, Actelion, Gilead, InterMune, Novartis, Perceptive Imaging, GE Medical Systems, GlaxoSmithKline, AstraZeneca, Toshiba Medical, and AZE. Dr. King reported ties to Actelion, InterMune, ImmuneWorks, Philips Respironics, CV Therapeutics, and Genzyme.

Smokers with interstitial lung abnormalities on high-resolution CT show both reduced total lung capacity and a lesser amount of emphysema, compared with those who didn’t have interstitial lung abnormalities, according to a report in the March 10 issue of the New England Journal of Medicine.

In addition, the magnitude of these two reductions is greatest among smokers who also have chronic obstructive pulmonary disease (COPD), said Dr. George R. Washko of the pulmonary and critical care division at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his associates.

"Our findings are consistent with, and add weight to, previous studies showing that cigarette smoking is associated with both spirometric restriction and areas of high attenuation on HRCT. Since emphysema and interstitial lung abnormalities have opposing effects on lung volume, our findings suggest that HRCT may provide important diagnostic information in smokers whose total lung capacity is unexpectedly ‘normal,’ " they noted.

"We speculate that this could be clinically important to physicians who may think that a patient who does not have symptoms or characteristic abnormalities on lung function tests is disease free, when in fact the patient could be affected by two of the consequences of smoking – emphysema and interstitial lung abnormalities," Dr. Washko and his colleagues said.

The investigators examined the relationship among radiographic interstitial lung abnormalities, total lung capacity, and emphysema in a cohort of 2,416 smokers who had been recruited for an ongoing study of COPD being conducted at 21 clinical centers.

The cohort included white (75%) and black (25%) subjects aged 45-80 years who reported a history of at least 10 pack-years of smoking. Slightly more than half of the subjects were men, 44% were still actively smoking, and 41% met criteria for COPD.

The overall prevalence of interstitial lung abnormalities affecting more than 5% of any lung zone on HRCT was 8%. Another 36% of the subjects showed "indeterminate" findings, and 56% showed no interstitial lung abnormalities.

The lung abnormalities included nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, and traction bronchiectasis.

Interstitial lung abnormalities were associated with both a decrease in total lung capacity and a lesser amount of emphysema. In addition, there was an inverse relationship between these abnormalities and the severity of COPD, the researchers said (N. Engl. J. Med. 2011;364:897-906).

Further follow-up is needed "to determine whether these radiographic abnormalities, and the associated reductions in lung volumes, are transient or stable, or whether they will progress to clinically significant disease," Dr. Washko and his associates said.

In an editorial accompanying the report, Dr. Talmadge E. King Jr. said that the "long-term implications of this and similar studies using HRCT scans in asymptomatic subjects are unknown. There is the concern that such scans may be overinterpreted, leading to a high rate of unnecessary diagnoses and perhaps unwarranted treatment" (N. Engl. J. Med. 2011;364:968-70). In this study, more than one-third of the HRCT scans were deemed "indeterminate" for the presence of interstitial lung abnormalities, which "probably reflects the fact that the boundary between HRCT images of the lungs in health and disease is blurred," noted Dr. King of the department of medicine at the University of California, San Francisco.

However, he thought it was noteworthy that Dr. Washko and his colleagues found that interstitial lung abnormalities were associated with less radiographic emphysema. "It is interesting to speculate that the pathobiology of smoking can lead to two distinct patterns of injury – emphysema (with destruction of the lung) or interstitial lung disease (with macrophage accumulation and fibrosis).

"Conversely ... the relative lack of emphysema could be simply a reflection of the fact that interstitial lung abnormalities mask emphysema or that more severe emphysema limits the extent of interstitial lung abnormalities," Dr. King said.

This study was supported by the National Institutes of Health and the Parker B. Francis Foundation. Dr. Washko reported ties to MedImmune, and his associates reported ties to Siemens, Actelion, Gilead, InterMune, Novartis, Perceptive Imaging, GE Medical Systems, GlaxoSmithKline, AstraZeneca, Toshiba Medical, and AZE. Dr. King reported ties to Actelion, InterMune, ImmuneWorks, Philips Respironics, CV Therapeutics, and Genzyme.

Smokers with interstitial lung abnormalities on high-resolution CT show both reduced total lung capacity and a lesser amount of emphysema, compared with those who didn’t have interstitial lung abnormalities, according to a report in the March 10 issue of the New England Journal of Medicine.

In addition, the magnitude of these two reductions is greatest among smokers who also have chronic obstructive pulmonary disease (COPD), said Dr. George R. Washko of the pulmonary and critical care division at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his associates.

"Our findings are consistent with, and add weight to, previous studies showing that cigarette smoking is associated with both spirometric restriction and areas of high attenuation on HRCT. Since emphysema and interstitial lung abnormalities have opposing effects on lung volume, our findings suggest that HRCT may provide important diagnostic information in smokers whose total lung capacity is unexpectedly ‘normal,’ " they noted.

"We speculate that this could be clinically important to physicians who may think that a patient who does not have symptoms or characteristic abnormalities on lung function tests is disease free, when in fact the patient could be affected by two of the consequences of smoking – emphysema and interstitial lung abnormalities," Dr. Washko and his colleagues said.

The investigators examined the relationship among radiographic interstitial lung abnormalities, total lung capacity, and emphysema in a cohort of 2,416 smokers who had been recruited for an ongoing study of COPD being conducted at 21 clinical centers.

The cohort included white (75%) and black (25%) subjects aged 45-80 years who reported a history of at least 10 pack-years of smoking. Slightly more than half of the subjects were men, 44% were still actively smoking, and 41% met criteria for COPD.

The overall prevalence of interstitial lung abnormalities affecting more than 5% of any lung zone on HRCT was 8%. Another 36% of the subjects showed "indeterminate" findings, and 56% showed no interstitial lung abnormalities.

The lung abnormalities included nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, and traction bronchiectasis.

Interstitial lung abnormalities were associated with both a decrease in total lung capacity and a lesser amount of emphysema. In addition, there was an inverse relationship between these abnormalities and the severity of COPD, the researchers said (N. Engl. J. Med. 2011;364:897-906).

Further follow-up is needed "to determine whether these radiographic abnormalities, and the associated reductions in lung volumes, are transient or stable, or whether they will progress to clinically significant disease," Dr. Washko and his associates said.

In an editorial accompanying the report, Dr. Talmadge E. King Jr. said that the "long-term implications of this and similar studies using HRCT scans in asymptomatic subjects are unknown. There is the concern that such scans may be overinterpreted, leading to a high rate of unnecessary diagnoses and perhaps unwarranted treatment" (N. Engl. J. Med. 2011;364:968-70). In this study, more than one-third of the HRCT scans were deemed "indeterminate" for the presence of interstitial lung abnormalities, which "probably reflects the fact that the boundary between HRCT images of the lungs in health and disease is blurred," noted Dr. King of the department of medicine at the University of California, San Francisco.

However, he thought it was noteworthy that Dr. Washko and his colleagues found that interstitial lung abnormalities were associated with less radiographic emphysema. "It is interesting to speculate that the pathobiology of smoking can lead to two distinct patterns of injury – emphysema (with destruction of the lung) or interstitial lung disease (with macrophage accumulation and fibrosis).

"Conversely ... the relative lack of emphysema could be simply a reflection of the fact that interstitial lung abnormalities mask emphysema or that more severe emphysema limits the extent of interstitial lung abnormalities," Dr. King said.

This study was supported by the National Institutes of Health and the Parker B. Francis Foundation. Dr. Washko reported ties to MedImmune, and his associates reported ties to Siemens, Actelion, Gilead, InterMune, Novartis, Perceptive Imaging, GE Medical Systems, GlaxoSmithKline, AstraZeneca, Toshiba Medical, and AZE. Dr. King reported ties to Actelion, InterMune, ImmuneWorks, Philips Respironics, CV Therapeutics, and Genzyme.

Smokers with interstitial lung abnormalities on high-resolution CT show both reduced total lung capacity and a lesser amount of emphysema, compared with those who didn’t have interstitial lung abnormalities, according to a report in the March 10 issue of the New England Journal of Medicine.

In addition, the magnitude of these two reductions is greatest among smokers who also have chronic obstructive pulmonary disease (COPD), said Dr. George R. Washko of the pulmonary and critical care division at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his associates.

"Our findings are consistent with, and add weight to, previous studies showing that cigarette smoking is associated with both spirometric restriction and areas of high attenuation on HRCT. Since emphysema and interstitial lung abnormalities have opposing effects on lung volume, our findings suggest that HRCT may provide important diagnostic information in smokers whose total lung capacity is unexpectedly ‘normal,’ " they noted.

"We speculate that this could be clinically important to physicians who may think that a patient who does not have symptoms or characteristic abnormalities on lung function tests is disease free, when in fact the patient could be affected by two of the consequences of smoking – emphysema and interstitial lung abnormalities," Dr. Washko and his colleagues said.

The investigators examined the relationship among radiographic interstitial lung abnormalities, total lung capacity, and emphysema in a cohort of 2,416 smokers who had been recruited for an ongoing study of COPD being conducted at 21 clinical centers.

The cohort included white (75%) and black (25%) subjects aged 45-80 years who reported a history of at least 10 pack-years of smoking. Slightly more than half of the subjects were men, 44% were still actively smoking, and 41% met criteria for COPD.

The overall prevalence of interstitial lung abnormalities affecting more than 5% of any lung zone on HRCT was 8%. Another 36% of the subjects showed "indeterminate" findings, and 56% showed no interstitial lung abnormalities.

The lung abnormalities included nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, and traction bronchiectasis.

Interstitial lung abnormalities were associated with both a decrease in total lung capacity and a lesser amount of emphysema. In addition, there was an inverse relationship between these abnormalities and the severity of COPD, the researchers said (N. Engl. J. Med. 2011;364:897-906).

Further follow-up is needed "to determine whether these radiographic abnormalities, and the associated reductions in lung volumes, are transient or stable, or whether they will progress to clinically significant disease," Dr. Washko and his associates said.

In an editorial accompanying the report, Dr. Talmadge E. King Jr. said that the "long-term implications of this and similar studies using HRCT scans in asymptomatic subjects are unknown. There is the concern that such scans may be overinterpreted, leading to a high rate of unnecessary diagnoses and perhaps unwarranted treatment" (N. Engl. J. Med. 2011;364:968-70). In this study, more than one-third of the HRCT scans were deemed "indeterminate" for the presence of interstitial lung abnormalities, which "probably reflects the fact that the boundary between HRCT images of the lungs in health and disease is blurred," noted Dr. King of the department of medicine at the University of California, San Francisco.

However, he thought it was noteworthy that Dr. Washko and his colleagues found that interstitial lung abnormalities were associated with less radiographic emphysema. "It is interesting to speculate that the pathobiology of smoking can lead to two distinct patterns of injury – emphysema (with destruction of the lung) or interstitial lung disease (with macrophage accumulation and fibrosis).

"Conversely ... the relative lack of emphysema could be simply a reflection of the fact that interstitial lung abnormalities mask emphysema or that more severe emphysema limits the extent of interstitial lung abnormalities," Dr. King said.

This study was supported by the National Institutes of Health and the Parker B. Francis Foundation. Dr. Washko reported ties to MedImmune, and his associates reported ties to Siemens, Actelion, Gilead, InterMune, Novartis, Perceptive Imaging, GE Medical Systems, GlaxoSmithKline, AstraZeneca, Toshiba Medical, and AZE. Dr. King reported ties to Actelion, InterMune, ImmuneWorks, Philips Respironics, CV Therapeutics, and Genzyme.

Smokers with interstitial lung abnormalities on high-resolution CT show both reduced total lung capacity and a lesser amount of emphysema, compared with those who didn’t have interstitial lung abnormalities, according to a report in the March 10 issue of the New England Journal of Medicine.

In addition, the magnitude of these two reductions is greatest among smokers who also have chronic obstructive pulmonary disease (COPD), said Dr. George R. Washko of the pulmonary and critical care division at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his associates.

"Our findings are consistent with, and add weight to, previous studies showing that cigarette smoking is associated with both spirometric restriction and areas of high attenuation on HRCT. Since emphysema and interstitial lung abnormalities have opposing effects on lung volume, our findings suggest that HRCT may provide important diagnostic information in smokers whose total lung capacity is unexpectedly ‘normal,’ " they noted.

"We speculate that this could be clinically important to physicians who may think that a patient who does not have symptoms or characteristic abnormalities on lung function tests is disease free, when in fact the patient could be affected by two of the consequences of smoking – emphysema and interstitial lung abnormalities," Dr. Washko and his colleagues said.

The investigators examined the relationship among radiographic interstitial lung abnormalities, total lung capacity, and emphysema in a cohort of 2,416 smokers who had been recruited for an ongoing study of COPD being conducted at 21 clinical centers.

The cohort included white (75%) and black (25%) subjects aged 45-80 years who reported a history of at least 10 pack-years of smoking. Slightly more than half of the subjects were men, 44% were still actively smoking, and 41% met criteria for COPD.

The overall prevalence of interstitial lung abnormalities affecting more than 5% of any lung zone on HRCT was 8%. Another 36% of the subjects showed "indeterminate" findings, and 56% showed no interstitial lung abnormalities.

The lung abnormalities included nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, and traction bronchiectasis.

Interstitial lung abnormalities were associated with both a decrease in total lung capacity and a lesser amount of emphysema. In addition, there was an inverse relationship between these abnormalities and the severity of COPD, the researchers said (N. Engl. J. Med. 2011;364:897-906).

Further follow-up is needed "to determine whether these radiographic abnormalities, and the associated reductions in lung volumes, are transient or stable, or whether they will progress to clinically significant disease," Dr. Washko and his associates said.

In an editorial accompanying the report, Dr. Talmadge E. King Jr. said that the "long-term implications of this and similar studies using HRCT scans in asymptomatic subjects are unknown. There is the concern that such scans may be overinterpreted, leading to a high rate of unnecessary diagnoses and perhaps unwarranted treatment" (N. Engl. J. Med. 2011;364:968-70). In this study, more than one-third of the HRCT scans were deemed "indeterminate" for the presence of interstitial lung abnormalities, which "probably reflects the fact that the boundary between HRCT images of the lungs in health and disease is blurred," noted Dr. King of the department of medicine at the University of California, San Francisco.

However, he thought it was noteworthy that Dr. Washko and his colleagues found that interstitial lung abnormalities were associated with less radiographic emphysema. "It is interesting to speculate that the pathobiology of smoking can lead to two distinct patterns of injury – emphysema (with destruction of the lung) or interstitial lung disease (with macrophage accumulation and fibrosis).

"Conversely ... the relative lack of emphysema could be simply a reflection of the fact that interstitial lung abnormalities mask emphysema or that more severe emphysema limits the extent of interstitial lung abnormalities," Dr. King said.

This study was supported by the National Institutes of Health and the Parker B. Francis Foundation. Dr. Washko reported ties to MedImmune, and his associates reported ties to Siemens, Actelion, Gilead, InterMune, Novartis, Perceptive Imaging, GE Medical Systems, GlaxoSmithKline, AstraZeneca, Toshiba Medical, and AZE. Dr. King reported ties to Actelion, InterMune, ImmuneWorks, Philips Respironics, CV Therapeutics, and Genzyme.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on March 8 recommended that the inhaled bronchodilator indacaterol should be approved for patients with chronic obstructive pulmonary disease.

The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 13-4 that the data on the safety and efficacy of the 75-mcg dose of indacaterol, as a maintenance treatment, provided substantial evidence to support the drug’s approval at this dose, for the proposed indication: the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Indacaterol, a long-acting beta-2 adrenergic agonist (LABA) that is administered in a dry-powder inhaler, has a rapid onset of effect sustained over 24 hours, according to Novartis, which filed for approval of two once-daily doses: 75 mcg and 150 mcg. But in a 12-5 vote, the panel recommended against approval of the higher dose, largely because of the paucity of data directly comparing the two doses and, as the panel chair said, "No compelling difference" in efficacy that was evident between the two doses.

The 150-mcg once-daily dose and a higher dose (300 mcg once daily) of indacaterol were approved to treat COPD in the European Union in September 2009, where it is marketed as the Onbrez Breezhaler; the drug at those doses is now approved in more than 50 countries.

Initially, Novartis had applied for approval of these two doses in December 2008, but the FDA requested that the company study lower doses of the drug, after the agency review concluded that no clinically meaningful advantage had been shown for the 300-mcg dose over the 150-mcg dose and because of safety concerns. There were more cardiovascular and cerebrovascular adverse events among patients with COPD treated with indacaterol, when compared with those on placebo and the active compactor, formoterol; and in studies of indacaterol in patients with asthma, there were some deaths, possibly related to indacaterol. In addition, treatment with inhaled LABAs has been linked to severe asthma exacerbations and asthma-related deaths in patients with asthma.

At the meeting, Novartis presented the results of five phase III studies of the 75-mcg, 150-mcg, and 300-mcg doses, compared with placebo or active controls in approximately 4,000 patients with COPD. After 12 weeks, there were significant improvements in lung function associated with each dose, when compared with placebo. In the safety database of patients with COPD, the risk of serious cardiovascular events (including MI, stroke, or cardiac death) was not increased, and there was no increase in acute respiratory events associated with any dose of indacaterol studied, according to Novartis.

If both doses were approved, indacaterol would be the first bronchodilator in the United States to be approved at two doses for the treatment of COPD; only one dose of formoterol and salmeterol, which are also LABAs, are approved for COPD treatment

Pending approval, Novartis plans to market indacaterol in the United States as the Arcapta Neohaler.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict but not at this meeting.

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.

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.

The Food and Drug Administration on March 4 removed a warning pertaining to liver injury from the boxed warning on the ambrisentan label.

After a review of clinical trial data and postmarketing safety information, the FDA determined that ambrisentan (Letairis) presents only a small risk of liver injury and decided that monthly serum liver enzyme tests will no longer be required. The agency added that health care professionals should order liver enzyme tests if deemed clinically necessary. Ambrisentan is approved for the treatment of pulmonary arterial hypertension (PAH).

The boxed warning will continue to contain cautions about the use of ambrisentan during pregnancy. Preclinical studies showed that the drug can cause serious birth defects in animals. The drug will continue to be available only through a restricted distribution program called the Letairis Education and Access Program (LEAP).

In women of childbearing potential, the LEAP program requires evidence of a monthly pregnancy test before ambrisentan may be shipped.

Ambrisentan is an endothelin receptor antagonist. Endothelin is a naturally occurring substance that causes blood vessels to narrow, preventing normal blood flow in people with PAH. Ambrisentan has been shown to improve patients’ ability to exercise and to slow the progression of the disease.

The Food and Drug Administration on March 4 removed a warning pertaining to liver injury from the boxed warning on the ambrisentan label.

After a review of clinical trial data and postmarketing safety information, the FDA determined that ambrisentan (Letairis) presents only a small risk of liver injury and decided that monthly serum liver enzyme tests will no longer be required. The agency added that health care professionals should order liver enzyme tests if deemed clinically necessary. Ambrisentan is approved for the treatment of pulmonary arterial hypertension (PAH).

The boxed warning will continue to contain cautions about the use of ambrisentan during pregnancy. Preclinical studies showed that the drug can cause serious birth defects in animals. The drug will continue to be available only through a restricted distribution program called the Letairis Education and Access Program (LEAP).

In women of childbearing potential, the LEAP program requires evidence of a monthly pregnancy test before ambrisentan may be shipped.

Ambrisentan is an endothelin receptor antagonist. Endothelin is a naturally occurring substance that causes blood vessels to narrow, preventing normal blood flow in people with PAH. Ambrisentan has been shown to improve patients’ ability to exercise and to slow the progression of the disease.

The Food and Drug Administration on March 4 removed a warning pertaining to liver injury from the boxed warning on the ambrisentan label.

After a review of clinical trial data and postmarketing safety information, the FDA determined that ambrisentan (Letairis) presents only a small risk of liver injury and decided that monthly serum liver enzyme tests will no longer be required. The agency added that health care professionals should order liver enzyme tests if deemed clinically necessary. Ambrisentan is approved for the treatment of pulmonary arterial hypertension (PAH).

The boxed warning will continue to contain cautions about the use of ambrisentan during pregnancy. Preclinical studies showed that the drug can cause serious birth defects in animals. The drug will continue to be available only through a restricted distribution program called the Letairis Education and Access Program (LEAP).

In women of childbearing potential, the LEAP program requires evidence of a monthly pregnancy test before ambrisentan may be shipped.

Ambrisentan is an endothelin receptor antagonist. Endothelin is a naturally occurring substance that causes blood vessels to narrow, preventing normal blood flow in people with PAH. Ambrisentan has been shown to improve patients’ ability to exercise and to slow the progression of the disease.