Sue Sutter

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s accelerated approval process would operate as a lower approval standard if Genentech were allowed to maintain the metastatic breast cancer claim for Avastin, the Center for Drug Evaluation and Research states in a written summary of arguments to be presented at a June 28-29 hearing on the indication.

Current evidence does not justify allowing Avastin (bevacizumab) to retain an indication for combination use with paclitaxel in first-line metastatic breast cancer (MBC); doing so while Genentech designs and conducts additional confirmatory studies would jeopardize the integrity of the accelerated approval process, CDER says.

CDER also dispatches with Genentech’s argument that it should be allowed to demonstrate that the choice of chemotherapy partner is integral to Avastin’s benefit in MBC. Rather, the regulator asserts there is no proven scientific basis for Genentech’s view that Avastin’s effect is predicated upon substantive differences between paclitaxel and other chemotherapy agents.

The drug center stands by its view that as part of Avastin’s accelerated approval Genentech was required to confirm the magnitude of benefit seen in the E2100 pivotal trial, which the company has failed to do.

Making the Case

The document, released on May 16, summarizes the arguments CDER will make to presiding officer Dr. Karen Midthun and the Oncologic Drugs Advisory Committee at the June hearing.

In its written summary of arguments, Genentech said it does not plan to focus on the AVADO and RIBBON1 studies – which were intended to serve as confirmatory studies for Avastin’s accelerated approval in MBC. Rather, it will argue that accelerated approval should be maintained pending a confirmatory study of Avastin in combination with paclitaxel that also uses a biomarker to identify those patients most likely to benefit.

CDER’s filing makes clear the regulator’s focus will be both on the specific issues relating to the existing Avastin data as well as the bigger policy issue of accelerated approval standards.

CDER observes it took the "unprecedented step" of granting accelerated approval based solely on an interim analysis of progression-free survival in the E2100 trial, which studied Avastin in combination with paclitaxel. "This was the first approval of a nonhormonal agent in which evidence of a treatment effect on PFS [progression free survival] alone was viewed not as a surrogate end point, but rather as a clinical benefit because of the magnitude of improvement in PFS," CDER says.

Data from the E2100 trial showed a 5.5-month improvement in median PFS, and CDER granted accelerated approval because "in its best scientific judgment at that time, the magnitude of PFS in the single trial suggested that Avastin held promise for patients with MBC."

Two confirmatory trials studied Avastin in combination with chemotherapeutics other than paclitaxel. Avastin’s chemotherapy partner in AVADO was docetaxel, while RIBBON1 looked at Avastin in combination with taxanes, anthracyclines, or capecitabine. These studies showed statistically significant improvements in PFS ranging from less than one month to less than three months, well shy of the 5.5-month benefit seen with paclitaxel in E2100.

The "small effect" seen in the confirmatory trials was not enough to verify Avastin’s clinical benefit, CDER asserts.

"In order for the accelerated approval system to serve its purpose and not operate as a lower approval standard, CDER must be able to withdraw approvals when it determines, based upon careful consideration of the data, that the confirmatory trials have failed to verify clinical benefit," CDER says.

Accelerated Approval Encompasses "Accelerated Withdrawal"

"Accelerated withdrawal" is an integral part of the accelerated approval process, CDER maintains.

"Once postapproval trials fail to demonstrate the expected clinical benefit, the accelerated approval rubric does not contemplate – as Genentech argues – that the agency should ‘maintain’ approval while an applicant designs and conducts more trials with the hope of eventually verifying clinical benefit," CDER says. "If CDER were forced to allow products to stay on the market when the risk-benefit analysis shows that the product is not safe and effective for its intended use, the accelerated approval program would be significantly undermined."

The agency takes issue with Genentech’s assertion that the indication should be maintained as long as the data for Avastin in combination with paclitaxel continue to be reasonably likely to predict clinical benefit.

The "reasonably likely" language in the accelerated approval regulations refers to the relationship between a surrogate end point and clinical benefit, CDER explains. "In the case of Avastin’s MBC approval, there was no surrogate end point – CDER believed that 5.5 months of PFS could be deemed a clinical benefit, subject to confirmatory trials."

Genentech does not explain how it would enroll patients in a new, blinded, controlled trial of Avastin in combination with paclitaxel if this remains a labeled use, CDER says. Furthermore, such a study would likely take many years to complete.

"Rather than serving as a basis to ‘maintain’ approval, which is not part of the accelerated approval program, the new research proposed by Genentech, if completed favorably, could be used to support a new sBLA [Supplemental Biologics License Application] requesting an MBC indication."

Chemotherapy Partner Hypothesis Does Not Hold Water

Genentech has hypothesized that chemotherapy partners that provide for prolonged combined exposure with Avastin may result in the strongest treatment effect. Yet this hypothesis has not been substantiated by either clinical or nonclinical evidence, CDER says.

"To support this argument, CDER expects that there should be some proven scientific basis for substantial differences, such as evidence of drug interactions or synergistic/overlapping toxicity between Avastin and other chemotherapy drugs. There is none," CDER says. Evidence submitted to date, such as population pharmacokinetic analyses, suggest no unique interactions between Avastin and any of the chemotherapy agents administered in the trials.

"In the absence of a scientifically supported basis for chemotherapy-specific interactions the more likely explanation for the failure of the clinical trials to verify the results of the E2100 trial is that the magnitude of the PFS treatment effect observed in E2100 is an outlier."

Genentech’s argument on the importance of chemotherapy partner used also runs contrary to its prior position, CDER says, noting that the company initially sought broad approval of Avastin in combination with all taxane-based chemotherapies based solely on the E2100 data.

No One Is Moving Goal Posts at CDER

CDER further disputes Genentech’s argument that it has changed its approval standards for MBC treatments. The regulator consistently maintained in conversations with Genentech that the adequacy of PFS as an approval end point would depend upon the overall dataset and the magnitude of benefit, it says.

"CDER has not in any way sought to ‘move the goal posts,’ " the filing states. "CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable."

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

The Food and Drug Administration’s accelerated approval process would operate as a lower approval standard if Genentech were allowed to maintain the metastatic breast cancer claim for Avastin, the Center for Drug Evaluation and Research states in a written summary of arguments to be presented at a June 28-29 hearing on the indication.

Current evidence does not justify allowing Avastin (bevacizumab) to retain an indication for combination use with paclitaxel in first-line metastatic breast cancer (MBC); doing so while Genentech designs and conducts additional confirmatory studies would jeopardize the integrity of the accelerated approval process, CDER says.

CDER also dispatches with Genentech’s argument that it should be allowed to demonstrate that the choice of chemotherapy partner is integral to Avastin’s benefit in MBC. Rather, the regulator asserts there is no proven scientific basis for Genentech’s view that Avastin’s effect is predicated upon substantive differences between paclitaxel and other chemotherapy agents.

The drug center stands by its view that as part of Avastin’s accelerated approval Genentech was required to confirm the magnitude of benefit seen in the E2100 pivotal trial, which the company has failed to do.

Making the Case

The document, released on May 16, summarizes the arguments CDER will make to presiding officer Dr. Karen Midthun and the Oncologic Drugs Advisory Committee at the June hearing.

In its written summary of arguments, Genentech said it does not plan to focus on the AVADO and RIBBON1 studies – which were intended to serve as confirmatory studies for Avastin’s accelerated approval in MBC. Rather, it will argue that accelerated approval should be maintained pending a confirmatory study of Avastin in combination with paclitaxel that also uses a biomarker to identify those patients most likely to benefit.

CDER’s filing makes clear the regulator’s focus will be both on the specific issues relating to the existing Avastin data as well as the bigger policy issue of accelerated approval standards.

CDER observes it took the "unprecedented step" of granting accelerated approval based solely on an interim analysis of progression-free survival in the E2100 trial, which studied Avastin in combination with paclitaxel. "This was the first approval of a nonhormonal agent in which evidence of a treatment effect on PFS [progression free survival] alone was viewed not as a surrogate end point, but rather as a clinical benefit because of the magnitude of improvement in PFS," CDER says.

Data from the E2100 trial showed a 5.5-month improvement in median PFS, and CDER granted accelerated approval because "in its best scientific judgment at that time, the magnitude of PFS in the single trial suggested that Avastin held promise for patients with MBC."

Two confirmatory trials studied Avastin in combination with chemotherapeutics other than paclitaxel. Avastin’s chemotherapy partner in AVADO was docetaxel, while RIBBON1 looked at Avastin in combination with taxanes, anthracyclines, or capecitabine. These studies showed statistically significant improvements in PFS ranging from less than one month to less than three months, well shy of the 5.5-month benefit seen with paclitaxel in E2100.

The "small effect" seen in the confirmatory trials was not enough to verify Avastin’s clinical benefit, CDER asserts.

"In order for the accelerated approval system to serve its purpose and not operate as a lower approval standard, CDER must be able to withdraw approvals when it determines, based upon careful consideration of the data, that the confirmatory trials have failed to verify clinical benefit," CDER says.

Accelerated Approval Encompasses "Accelerated Withdrawal"

"Accelerated withdrawal" is an integral part of the accelerated approval process, CDER maintains.

"Once postapproval trials fail to demonstrate the expected clinical benefit, the accelerated approval rubric does not contemplate – as Genentech argues – that the agency should ‘maintain’ approval while an applicant designs and conducts more trials with the hope of eventually verifying clinical benefit," CDER says. "If CDER were forced to allow products to stay on the market when the risk-benefit analysis shows that the product is not safe and effective for its intended use, the accelerated approval program would be significantly undermined."

The agency takes issue with Genentech’s assertion that the indication should be maintained as long as the data for Avastin in combination with paclitaxel continue to be reasonably likely to predict clinical benefit.

The "reasonably likely" language in the accelerated approval regulations refers to the relationship between a surrogate end point and clinical benefit, CDER explains. "In the case of Avastin’s MBC approval, there was no surrogate end point – CDER believed that 5.5 months of PFS could be deemed a clinical benefit, subject to confirmatory trials."

Genentech does not explain how it would enroll patients in a new, blinded, controlled trial of Avastin in combination with paclitaxel if this remains a labeled use, CDER says. Furthermore, such a study would likely take many years to complete.

"Rather than serving as a basis to ‘maintain’ approval, which is not part of the accelerated approval program, the new research proposed by Genentech, if completed favorably, could be used to support a new sBLA [Supplemental Biologics License Application] requesting an MBC indication."

Chemotherapy Partner Hypothesis Does Not Hold Water

Genentech has hypothesized that chemotherapy partners that provide for prolonged combined exposure with Avastin may result in the strongest treatment effect. Yet this hypothesis has not been substantiated by either clinical or nonclinical evidence, CDER says.

"To support this argument, CDER expects that there should be some proven scientific basis for substantial differences, such as evidence of drug interactions or synergistic/overlapping toxicity between Avastin and other chemotherapy drugs. There is none," CDER says. Evidence submitted to date, such as population pharmacokinetic analyses, suggest no unique interactions between Avastin and any of the chemotherapy agents administered in the trials.

"In the absence of a scientifically supported basis for chemotherapy-specific interactions the more likely explanation for the failure of the clinical trials to verify the results of the E2100 trial is that the magnitude of the PFS treatment effect observed in E2100 is an outlier."

Genentech’s argument on the importance of chemotherapy partner used also runs contrary to its prior position, CDER says, noting that the company initially sought broad approval of Avastin in combination with all taxane-based chemotherapies based solely on the E2100 data.

No One Is Moving Goal Posts at CDER

CDER further disputes Genentech’s argument that it has changed its approval standards for MBC treatments. The regulator consistently maintained in conversations with Genentech that the adequacy of PFS as an approval end point would depend upon the overall dataset and the magnitude of benefit, it says.

"CDER has not in any way sought to ‘move the goal posts,’ " the filing states. "CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable."

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

The Food and Drug Administration’s accelerated approval process would operate as a lower approval standard if Genentech were allowed to maintain the metastatic breast cancer claim for Avastin, the Center for Drug Evaluation and Research states in a written summary of arguments to be presented at a June 28-29 hearing on the indication.

Current evidence does not justify allowing Avastin (bevacizumab) to retain an indication for combination use with paclitaxel in first-line metastatic breast cancer (MBC); doing so while Genentech designs and conducts additional confirmatory studies would jeopardize the integrity of the accelerated approval process, CDER says.

CDER also dispatches with Genentech’s argument that it should be allowed to demonstrate that the choice of chemotherapy partner is integral to Avastin’s benefit in MBC. Rather, the regulator asserts there is no proven scientific basis for Genentech’s view that Avastin’s effect is predicated upon substantive differences between paclitaxel and other chemotherapy agents.

The drug center stands by its view that as part of Avastin’s accelerated approval Genentech was required to confirm the magnitude of benefit seen in the E2100 pivotal trial, which the company has failed to do.

Making the Case

The document, released on May 16, summarizes the arguments CDER will make to presiding officer Dr. Karen Midthun and the Oncologic Drugs Advisory Committee at the June hearing.

In its written summary of arguments, Genentech said it does not plan to focus on the AVADO and RIBBON1 studies – which were intended to serve as confirmatory studies for Avastin’s accelerated approval in MBC. Rather, it will argue that accelerated approval should be maintained pending a confirmatory study of Avastin in combination with paclitaxel that also uses a biomarker to identify those patients most likely to benefit.

CDER’s filing makes clear the regulator’s focus will be both on the specific issues relating to the existing Avastin data as well as the bigger policy issue of accelerated approval standards.

CDER observes it took the "unprecedented step" of granting accelerated approval based solely on an interim analysis of progression-free survival in the E2100 trial, which studied Avastin in combination with paclitaxel. "This was the first approval of a nonhormonal agent in which evidence of a treatment effect on PFS [progression free survival] alone was viewed not as a surrogate end point, but rather as a clinical benefit because of the magnitude of improvement in PFS," CDER says.

Data from the E2100 trial showed a 5.5-month improvement in median PFS, and CDER granted accelerated approval because "in its best scientific judgment at that time, the magnitude of PFS in the single trial suggested that Avastin held promise for patients with MBC."

Two confirmatory trials studied Avastin in combination with chemotherapeutics other than paclitaxel. Avastin’s chemotherapy partner in AVADO was docetaxel, while RIBBON1 looked at Avastin in combination with taxanes, anthracyclines, or capecitabine. These studies showed statistically significant improvements in PFS ranging from less than one month to less than three months, well shy of the 5.5-month benefit seen with paclitaxel in E2100.

The "small effect" seen in the confirmatory trials was not enough to verify Avastin’s clinical benefit, CDER asserts.

"In order for the accelerated approval system to serve its purpose and not operate as a lower approval standard, CDER must be able to withdraw approvals when it determines, based upon careful consideration of the data, that the confirmatory trials have failed to verify clinical benefit," CDER says.

Accelerated Approval Encompasses "Accelerated Withdrawal"

"Accelerated withdrawal" is an integral part of the accelerated approval process, CDER maintains.

"Once postapproval trials fail to demonstrate the expected clinical benefit, the accelerated approval rubric does not contemplate – as Genentech argues – that the agency should ‘maintain’ approval while an applicant designs and conducts more trials with the hope of eventually verifying clinical benefit," CDER says. "If CDER were forced to allow products to stay on the market when the risk-benefit analysis shows that the product is not safe and effective for its intended use, the accelerated approval program would be significantly undermined."

The agency takes issue with Genentech’s assertion that the indication should be maintained as long as the data for Avastin in combination with paclitaxel continue to be reasonably likely to predict clinical benefit.

The "reasonably likely" language in the accelerated approval regulations refers to the relationship between a surrogate end point and clinical benefit, CDER explains. "In the case of Avastin’s MBC approval, there was no surrogate end point – CDER believed that 5.5 months of PFS could be deemed a clinical benefit, subject to confirmatory trials."

Genentech does not explain how it would enroll patients in a new, blinded, controlled trial of Avastin in combination with paclitaxel if this remains a labeled use, CDER says. Furthermore, such a study would likely take many years to complete.

"Rather than serving as a basis to ‘maintain’ approval, which is not part of the accelerated approval program, the new research proposed by Genentech, if completed favorably, could be used to support a new sBLA [Supplemental Biologics License Application] requesting an MBC indication."

Chemotherapy Partner Hypothesis Does Not Hold Water

Genentech has hypothesized that chemotherapy partners that provide for prolonged combined exposure with Avastin may result in the strongest treatment effect. Yet this hypothesis has not been substantiated by either clinical or nonclinical evidence, CDER says.

"To support this argument, CDER expects that there should be some proven scientific basis for substantial differences, such as evidence of drug interactions or synergistic/overlapping toxicity between Avastin and other chemotherapy drugs. There is none," CDER says. Evidence submitted to date, such as population pharmacokinetic analyses, suggest no unique interactions between Avastin and any of the chemotherapy agents administered in the trials.

"In the absence of a scientifically supported basis for chemotherapy-specific interactions the more likely explanation for the failure of the clinical trials to verify the results of the E2100 trial is that the magnitude of the PFS treatment effect observed in E2100 is an outlier."

Genentech’s argument on the importance of chemotherapy partner used also runs contrary to its prior position, CDER says, noting that the company initially sought broad approval of Avastin in combination with all taxane-based chemotherapies based solely on the E2100 data.

No One Is Moving Goal Posts at CDER

CDER further disputes Genentech’s argument that it has changed its approval standards for MBC treatments. The regulator consistently maintained in conversations with Genentech that the adequacy of PFS as an approval end point would depend upon the overall dataset and the magnitude of benefit, it says.

"CDER has not in any way sought to ‘move the goal posts,’ " the filing states. "CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable."

This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.

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’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.