Elizabeth Mechcatie

A significant increase in cardiovascular events in patients with permanent atrial fibrillation who are taking dronedarone in the PALLAS trial has led the drug’s manufacturer to suspend the phase IIIb study.

Dronedarone (Multaq), a benzofuran derivative that is a an analogue of amiodarone, is approved in the United States and the European Union for a different population of patients with AF, not those with permanent AF, and "the benefit-risk of Multaq remains unchanged in its approved indication in nonpermanent AF," the company said in a press release issued on July 7.

The Food and Drug Administration approved dronedarone in 2009 for reducing the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors who are in sinus rhythm or who will be cardioverted. (In the EU, it is indicated for clinically stable adults with a history of nonpermanent AF or with current nonpermanent AF, to prevent the recurrence of AF or to lower the ventricular rate.)

PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) was discontinued for enrolled patients with permanent AF.

The international phase IIIb study compared dronedarone 400 mg twice daily (the approved dose) to placebo in about 3,000 patients with permanent AF, who were over age 65 and had comorbidities such as previous myocardial infarction, documented coronary artery disease, previous stroke, symptomatic heart failure, or diabetes. Patients with New York Heart Association class IV or unstable NYHA class III heart failure were excluded.

The company stopped the study in response to recommendations made by the study’s operations and data monitoring committees, after a significant increase in cardiovascular events was observed among those in the dronedarone arm, according to the statement.

In the statement, the study’s coprincipal investigator, Dr. Stuart Connolly, director of the cardiology division and professor of medicine at McMaster University, Hamilton, Ont., said that the committee members were "very disappointed to discover that the hypothesis that dronedarone would improve major outcomes for this high-risk patient population has been refuted."

Patients enrolled in PALLAS had permanent AF and were more likely to have advanced vascular disease than patients in whom the drug is currently indicated, who have intermittent AF and most often do not have advanced vascular disease, Dr. Connolly said in an interview.

"The results of PALLAS do not bear directly on the patients on dronedarone for the approved indication," he noted. "So it is reasonable to continue those patients on dronedarone, and I would expect that they will still benefit from it in terms of reduced cardiovascular hospitalization."

About 70% of the patients enrolled in PALLAS had had permanent AF for more than 2 years, and about 70% had NYHA class I-III heart failure at baseline, which the Sanofi statement listed as other differences between these patients and the patients enrolled in the ATHENA study that supported the currently approved indication. (In the ATHENA study, fewer than 30% of patients had NYHA class I-III heart failure and none had permanent AF, the statement said).

This is not the first indication that dronedarone may not be suitable for sicker patients. Its label already includes a black box warning that says the drug is contraindicated in patients with NYHA class IV heart failure or NYHA class II-III heart failure with a recent decompensation requiring hospitalization or referral to a heart failure clinic. This warning was based on the results of another dronedarone study that was stopped early – the ANDROMEDA study – which found that mortality was increased among such patients who were given dronedarone, when compared with placebo.

Dr. Connolly said he has received grant support and consulting and lecture fees from Sanofi.

A significant increase in cardiovascular events in patients with permanent atrial fibrillation who are taking dronedarone in the PALLAS trial has led the drug’s manufacturer to suspend the phase IIIb study.

Dronedarone (Multaq), a benzofuran derivative that is a an analogue of amiodarone, is approved in the United States and the European Union for a different population of patients with AF, not those with permanent AF, and "the benefit-risk of Multaq remains unchanged in its approved indication in nonpermanent AF," the company said in a press release issued on July 7.

The Food and Drug Administration approved dronedarone in 2009 for reducing the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors who are in sinus rhythm or who will be cardioverted. (In the EU, it is indicated for clinically stable adults with a history of nonpermanent AF or with current nonpermanent AF, to prevent the recurrence of AF or to lower the ventricular rate.)

PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) was discontinued for enrolled patients with permanent AF.

The international phase IIIb study compared dronedarone 400 mg twice daily (the approved dose) to placebo in about 3,000 patients with permanent AF, who were over age 65 and had comorbidities such as previous myocardial infarction, documented coronary artery disease, previous stroke, symptomatic heart failure, or diabetes. Patients with New York Heart Association class IV or unstable NYHA class III heart failure were excluded.

The company stopped the study in response to recommendations made by the study’s operations and data monitoring committees, after a significant increase in cardiovascular events was observed among those in the dronedarone arm, according to the statement.

In the statement, the study’s coprincipal investigator, Dr. Stuart Connolly, director of the cardiology division and professor of medicine at McMaster University, Hamilton, Ont., said that the committee members were "very disappointed to discover that the hypothesis that dronedarone would improve major outcomes for this high-risk patient population has been refuted."

Patients enrolled in PALLAS had permanent AF and were more likely to have advanced vascular disease than patients in whom the drug is currently indicated, who have intermittent AF and most often do not have advanced vascular disease, Dr. Connolly said in an interview.

"The results of PALLAS do not bear directly on the patients on dronedarone for the approved indication," he noted. "So it is reasonable to continue those patients on dronedarone, and I would expect that they will still benefit from it in terms of reduced cardiovascular hospitalization."

About 70% of the patients enrolled in PALLAS had had permanent AF for more than 2 years, and about 70% had NYHA class I-III heart failure at baseline, which the Sanofi statement listed as other differences between these patients and the patients enrolled in the ATHENA study that supported the currently approved indication. (In the ATHENA study, fewer than 30% of patients had NYHA class I-III heart failure and none had permanent AF, the statement said).

This is not the first indication that dronedarone may not be suitable for sicker patients. Its label already includes a black box warning that says the drug is contraindicated in patients with NYHA class IV heart failure or NYHA class II-III heart failure with a recent decompensation requiring hospitalization or referral to a heart failure clinic. This warning was based on the results of another dronedarone study that was stopped early – the ANDROMEDA study – which found that mortality was increased among such patients who were given dronedarone, when compared with placebo.

Dr. Connolly said he has received grant support and consulting and lecture fees from Sanofi.

A significant increase in cardiovascular events in patients with permanent atrial fibrillation who are taking dronedarone in the PALLAS trial has led the drug’s manufacturer to suspend the phase IIIb study.

Dronedarone (Multaq), a benzofuran derivative that is a an analogue of amiodarone, is approved in the United States and the European Union for a different population of patients with AF, not those with permanent AF, and "the benefit-risk of Multaq remains unchanged in its approved indication in nonpermanent AF," the company said in a press release issued on July 7.

The Food and Drug Administration approved dronedarone in 2009 for reducing the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors who are in sinus rhythm or who will be cardioverted. (In the EU, it is indicated for clinically stable adults with a history of nonpermanent AF or with current nonpermanent AF, to prevent the recurrence of AF or to lower the ventricular rate.)

PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) was discontinued for enrolled patients with permanent AF.

The international phase IIIb study compared dronedarone 400 mg twice daily (the approved dose) to placebo in about 3,000 patients with permanent AF, who were over age 65 and had comorbidities such as previous myocardial infarction, documented coronary artery disease, previous stroke, symptomatic heart failure, or diabetes. Patients with New York Heart Association class IV or unstable NYHA class III heart failure were excluded.

The company stopped the study in response to recommendations made by the study’s operations and data monitoring committees, after a significant increase in cardiovascular events was observed among those in the dronedarone arm, according to the statement.

In the statement, the study’s coprincipal investigator, Dr. Stuart Connolly, director of the cardiology division and professor of medicine at McMaster University, Hamilton, Ont., said that the committee members were "very disappointed to discover that the hypothesis that dronedarone would improve major outcomes for this high-risk patient population has been refuted."

Patients enrolled in PALLAS had permanent AF and were more likely to have advanced vascular disease than patients in whom the drug is currently indicated, who have intermittent AF and most often do not have advanced vascular disease, Dr. Connolly said in an interview.

"The results of PALLAS do not bear directly on the patients on dronedarone for the approved indication," he noted. "So it is reasonable to continue those patients on dronedarone, and I would expect that they will still benefit from it in terms of reduced cardiovascular hospitalization."

About 70% of the patients enrolled in PALLAS had had permanent AF for more than 2 years, and about 70% had NYHA class I-III heart failure at baseline, which the Sanofi statement listed as other differences between these patients and the patients enrolled in the ATHENA study that supported the currently approved indication. (In the ATHENA study, fewer than 30% of patients had NYHA class I-III heart failure and none had permanent AF, the statement said).

This is not the first indication that dronedarone may not be suitable for sicker patients. Its label already includes a black box warning that says the drug is contraindicated in patients with NYHA class IV heart failure or NYHA class II-III heart failure with a recent decompensation requiring hospitalization or referral to a heart failure clinic. This warning was based on the results of another dronedarone study that was stopped early – the ANDROMEDA study – which found that mortality was increased among such patients who were given dronedarone, when compared with placebo.

Dr. Connolly said he has received grant support and consulting and lecture fees from Sanofi.

The Boostrix vaccine has been approved for use in people aged 65 years and older to prevent tetanus, diphtheria, and pertussis, the Food and Drug Administration announced on July 8.

This is the first vaccine approved for preventing all three diseases in this age group, according to the FDA statement announcing the approval. Until this approval, the other vaccines approved people aged 65 years and older prevented tetanus and diphtheria only.

Boostrix (combined diphtheria, tetanus, acellular pertussis [adsorbed] vaccine), which is administered as a single-dose booster injection, was initially approved in 2005 for use in adolescents aged 10 through 18 years, followed by approval for use in adults aged 18 through 64 years in 2008.

The latest approval was based on a study of about 1,300 people aged 65 years and older, which determined that antibody levels to pertussis among the adults "were comparable to the levels in infants who received a closely related vaccine that was shown to prevent pertussis," the statement said. In addition, antibody responses to the tetanus and diphtheria components were comparable to the levels achieved with a licensed tetanus and diphtheria vaccine.

The most common adverse reactions reported by the older adults after receiving Boostrix were headache, fatigue, and pain at the injection site were among common adverse reactions.

Boostrix, manufactured by GlaxoSmithKline Biologicals, is a booster and is not intended for use for primary vaccination.

The Boostrix vaccine has been approved for use in people aged 65 years and older to prevent tetanus, diphtheria, and pertussis, the Food and Drug Administration announced on July 8.

This is the first vaccine approved for preventing all three diseases in this age group, according to the FDA statement announcing the approval. Until this approval, the other vaccines approved people aged 65 years and older prevented tetanus and diphtheria only.

Boostrix (combined diphtheria, tetanus, acellular pertussis [adsorbed] vaccine), which is administered as a single-dose booster injection, was initially approved in 2005 for use in adolescents aged 10 through 18 years, followed by approval for use in adults aged 18 through 64 years in 2008.

The latest approval was based on a study of about 1,300 people aged 65 years and older, which determined that antibody levels to pertussis among the adults "were comparable to the levels in infants who received a closely related vaccine that was shown to prevent pertussis," the statement said. In addition, antibody responses to the tetanus and diphtheria components were comparable to the levels achieved with a licensed tetanus and diphtheria vaccine.

The most common adverse reactions reported by the older adults after receiving Boostrix were headache, fatigue, and pain at the injection site were among common adverse reactions.

Boostrix, manufactured by GlaxoSmithKline Biologicals, is a booster and is not intended for use for primary vaccination.

The Boostrix vaccine has been approved for use in people aged 65 years and older to prevent tetanus, diphtheria, and pertussis, the Food and Drug Administration announced on July 8.

This is the first vaccine approved for preventing all three diseases in this age group, according to the FDA statement announcing the approval. Until this approval, the other vaccines approved people aged 65 years and older prevented tetanus and diphtheria only.

Boostrix (combined diphtheria, tetanus, acellular pertussis [adsorbed] vaccine), which is administered as a single-dose booster injection, was initially approved in 2005 for use in adolescents aged 10 through 18 years, followed by approval for use in adults aged 18 through 64 years in 2008.

The latest approval was based on a study of about 1,300 people aged 65 years and older, which determined that antibody levels to pertussis among the adults "were comparable to the levels in infants who received a closely related vaccine that was shown to prevent pertussis," the statement said. In addition, antibody responses to the tetanus and diphtheria components were comparable to the levels achieved with a licensed tetanus and diphtheria vaccine.

The most common adverse reactions reported by the older adults after receiving Boostrix were headache, fatigue, and pain at the injection site were among common adverse reactions.

Boostrix, manufactured by GlaxoSmithKline Biologicals, is a booster and is not intended for use for primary vaccination.

The Boostrix vaccine has been approved for use in people aged 65 years and older to prevent tetanus, diphtheria, and pertussis, the Food and Drug Administration announced on July 8.

This is the first vaccine approved for preventing all three diseases in this age group, according to the FDA statement announcing the approval. Until this approval, the other vaccines approved people aged 65 years and older prevented tetanus and diphtheria only.

Boostrix (combined diphtheria, tetanus, acellular pertussis [adsorbed] vaccine), which is administered as a single-dose booster injection, was initially approved in 2005 for use in adolescents aged 10 through 18 years, followed by approval for use in adults aged 18 through 64 years in 2008.

The latest approval was based on a study of about 1,300 people aged 65 years and older, which determined that antibody levels to pertussis among the adults "were comparable to the levels in infants who received a closely related vaccine that was shown to prevent pertussis," the statement said. In addition, antibody responses to the tetanus and diphtheria components were comparable to the levels achieved with a licensed tetanus and diphtheria vaccine.

The most common adverse reactions reported by the older adults after receiving Boostrix were headache, fatigue, and pain at the injection site were among common adverse reactions.

Boostrix, manufactured by GlaxoSmithKline Biologicals, is a booster and is not intended for use for primary vaccination.

The Boostrix vaccine has been approved for use in people aged 65 years and older to prevent tetanus, diphtheria, and pertussis, the Food and Drug Administration announced on July 8.

This is the first vaccine approved for preventing all three diseases in this age group, according to the FDA statement announcing the approval. Until this approval, the other vaccines approved people aged 65 years and older prevented tetanus and diphtheria only.

Boostrix (combined diphtheria, tetanus, acellular pertussis [adsorbed] vaccine), which is administered as a single-dose booster injection, was initially approved in 2005 for use in adolescents aged 10 through 18 years, followed by approval for use in adults aged 18 through 64 years in 2008.

The latest approval was based on a study of about 1,300 people aged 65 years and older, which determined that antibody levels to pertussis among the adults "were comparable to the levels in infants who received a closely related vaccine that was shown to prevent pertussis," the statement said. In addition, antibody responses to the tetanus and diphtheria components were comparable to the levels achieved with a licensed tetanus and diphtheria vaccine.

The most common adverse reactions reported by the older adults after receiving Boostrix were headache, fatigue, and pain at the injection site were among common adverse reactions.

Boostrix, manufactured by GlaxoSmithKline Biologicals, is a booster and is not intended for use for primary vaccination.

The Boostrix vaccine has been approved for use in people aged 65 years and older to prevent tetanus, diphtheria, and pertussis, the Food and Drug Administration announced on July 8.

This is the first vaccine approved for preventing all three diseases in this age group, according to the FDA statement announcing the approval. Until this approval, the other vaccines approved people aged 65 years and older prevented tetanus and diphtheria only.

Boostrix (combined diphtheria, tetanus, acellular pertussis [adsorbed] vaccine), which is administered as a single-dose booster injection, was initially approved in 2005 for use in adolescents aged 10 through 18 years, followed by approval for use in adults aged 18 through 64 years in 2008.

The latest approval was based on a study of about 1,300 people aged 65 years and older, which determined that antibody levels to pertussis among the adults "were comparable to the levels in infants who received a closely related vaccine that was shown to prevent pertussis," the statement said. In addition, antibody responses to the tetanus and diphtheria components were comparable to the levels achieved with a licensed tetanus and diphtheria vaccine.

The most common adverse reactions reported by the older adults after receiving Boostrix were headache, fatigue, and pain at the injection site were among common adverse reactions.

Boostrix, manufactured by GlaxoSmithKline Biologicals, is a booster and is not intended for use for primary vaccination.

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.

The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.

Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."

Based on dialysis status, the new recommendations are as follows:

• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.

The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.

• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."

Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.

ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.

The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.

He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.

The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.

Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.

Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.

The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.

ADELPHI, MD. – A Food and Drug Administration advisory panel on June 21 voted 11-1 that the data on canakinumab did not support its approval as a treatment for gouty arthritis attacks, in patients who have not responded adequately to nonsteroidal anti-inflammatory drugs or colchicine.

Members of the FDA’s Arthritis Advisory Committee considered canakinumab a promising treatment, and all but one panelist agreed that the 150-mg subcutaneous dose that was studied in two phase III trials was shown to be effective in treating an attack of gouty arthritis in this population.

But, in another vote, the panel unanimously agreed that the safety profile of canakinumab did not support approval for this indication, because of concerns that included the lack of long-term safety data including the potential long-term risk of infections and the lack of data on the effects of recurrent treatment. (Only 43 patients in the studies had received three or more injections and most had been treated only once.)

The need for more data in likely patient candidates who are less healthy than those in the trials, such as those with advanced renal disease, was another concern cited by the panel. Several panelists also expressed concern that unless use was restricted in some way, canakinumab might be used to treat a broader population than described in the proposed indication.

Canakinumab (Ilaris), a monoclonal antibody that neutralizes interleukin-1beta, was approved in June 2009 for the treatment of a rare disorder, cryopyrin-associated periodic syndromes (CAPS). The new indication proposed by the manufacturer, Novartis Pharmaceuticals, is for the treatment of gouty arthritis attacks in patients who cannot obtain an adequate response with NSAIDs or colchicine.

The company described canakinumab as the first targeted anti-inflammatory treatment for gout, which could be used to treat about 6% of the patients with gouty arthritis, an estimated 300,000 patients in the United States.

In the two phase III trials of approximately 450 patients, most of whom were male and white, (mean age was early 50s) with at least three gouty arthritis attacks a year, a single 150-mg injection of canakinumab, was compared with an intramuscular injection of triamcinolone (40 mg) in treating an acute attack.

Those treated with canakinumab had significantly greater reductions in pain intensity of the affected joint, as measured by changes in a visual pain scale (a primary end point) 72 hours after the injection, compared with those treated with triamcinolone. The risk of having another gouty arthritis flare over the 12 weeks after treatment – the other primary end point – was also significantly reduced among those treated with canakinumab, compared with those on triamcinolone.

The rates of adverse events, including serious adverse events, were higher among those treated with canakinumab, compared with those on triamcinolone and included infections (19% vs. 13%, respectively) and serious infections (2% vs. 0%, respectively). Treatment with canakinumab also was associated with an increase in serum triglycerides levels, declines in renal function, and elevations in serum uric acid, and hypertension. There were three cases of renal failure among gout patients treated with canakinumab, who had predisposing factors, according to the company.

Canakinumab is under review in the European Union for the same indication.

The FDA usually follows the recommendations of its advisory panels. Members of FDA advisory panels have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally they may be given a waiver, but not at this meeting.

ADELPHI, MD. – A Food and Drug Administration advisory panel on June 21 voted 11-1 that the data on canakinumab did not support its approval as a treatment for gouty arthritis attacks, in patients who have not responded adequately to nonsteroidal anti-inflammatory drugs or colchicine.

Members of the FDA’s Arthritis Advisory Committee considered canakinumab a promising treatment, and all but one panelist agreed that the 150-mg subcutaneous dose that was studied in two phase III trials was shown to be effective in treating an attack of gouty arthritis in this population.

But, in another vote, the panel unanimously agreed that the safety profile of canakinumab did not support approval for this indication, because of concerns that included the lack of long-term safety data including the potential long-term risk of infections and the lack of data on the effects of recurrent treatment. (Only 43 patients in the studies had received three or more injections and most had been treated only once.)

The need for more data in likely patient candidates who are less healthy than those in the trials, such as those with advanced renal disease, was another concern cited by the panel. Several panelists also expressed concern that unless use was restricted in some way, canakinumab might be used to treat a broader population than described in the proposed indication.

Canakinumab (Ilaris), a monoclonal antibody that neutralizes interleukin-1beta, was approved in June 2009 for the treatment of a rare disorder, cryopyrin-associated periodic syndromes (CAPS). The new indication proposed by the manufacturer, Novartis Pharmaceuticals, is for the treatment of gouty arthritis attacks in patients who cannot obtain an adequate response with NSAIDs or colchicine.

The company described canakinumab as the first targeted anti-inflammatory treatment for gout, which could be used to treat about 6% of the patients with gouty arthritis, an estimated 300,000 patients in the United States.

In the two phase III trials of approximately 450 patients, most of whom were male and white, (mean age was early 50s) with at least three gouty arthritis attacks a year, a single 150-mg injection of canakinumab, was compared with an intramuscular injection of triamcinolone (40 mg) in treating an acute attack.

Those treated with canakinumab had significantly greater reductions in pain intensity of the affected joint, as measured by changes in a visual pain scale (a primary end point) 72 hours after the injection, compared with those treated with triamcinolone. The risk of having another gouty arthritis flare over the 12 weeks after treatment – the other primary end point – was also significantly reduced among those treated with canakinumab, compared with those on triamcinolone.

The rates of adverse events, including serious adverse events, were higher among those treated with canakinumab, compared with those on triamcinolone and included infections (19% vs. 13%, respectively) and serious infections (2% vs. 0%, respectively). Treatment with canakinumab also was associated with an increase in serum triglycerides levels, declines in renal function, and elevations in serum uric acid, and hypertension. There were three cases of renal failure among gout patients treated with canakinumab, who had predisposing factors, according to the company.

Canakinumab is under review in the European Union for the same indication.

The FDA usually follows the recommendations of its advisory panels. Members of FDA advisory panels have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally they may be given a waiver, but not at this meeting.

ADELPHI, MD. – A Food and Drug Administration advisory panel on June 21 voted 11-1 that the data on canakinumab did not support its approval as a treatment for gouty arthritis attacks, in patients who have not responded adequately to nonsteroidal anti-inflammatory drugs or colchicine.

Members of the FDA’s Arthritis Advisory Committee considered canakinumab a promising treatment, and all but one panelist agreed that the 150-mg subcutaneous dose that was studied in two phase III trials was shown to be effective in treating an attack of gouty arthritis in this population.

But, in another vote, the panel unanimously agreed that the safety profile of canakinumab did not support approval for this indication, because of concerns that included the lack of long-term safety data including the potential long-term risk of infections and the lack of data on the effects of recurrent treatment. (Only 43 patients in the studies had received three or more injections and most had been treated only once.)

The need for more data in likely patient candidates who are less healthy than those in the trials, such as those with advanced renal disease, was another concern cited by the panel. Several panelists also expressed concern that unless use was restricted in some way, canakinumab might be used to treat a broader population than described in the proposed indication.

Canakinumab (Ilaris), a monoclonal antibody that neutralizes interleukin-1beta, was approved in June 2009 for the treatment of a rare disorder, cryopyrin-associated periodic syndromes (CAPS). The new indication proposed by the manufacturer, Novartis Pharmaceuticals, is for the treatment of gouty arthritis attacks in patients who cannot obtain an adequate response with NSAIDs or colchicine.

The company described canakinumab as the first targeted anti-inflammatory treatment for gout, which could be used to treat about 6% of the patients with gouty arthritis, an estimated 300,000 patients in the United States.

In the two phase III trials of approximately 450 patients, most of whom were male and white, (mean age was early 50s) with at least three gouty arthritis attacks a year, a single 150-mg injection of canakinumab, was compared with an intramuscular injection of triamcinolone (40 mg) in treating an acute attack.

Those treated with canakinumab had significantly greater reductions in pain intensity of the affected joint, as measured by changes in a visual pain scale (a primary end point) 72 hours after the injection, compared with those treated with triamcinolone. The risk of having another gouty arthritis flare over the 12 weeks after treatment – the other primary end point – was also significantly reduced among those treated with canakinumab, compared with those on triamcinolone.

The rates of adverse events, including serious adverse events, were higher among those treated with canakinumab, compared with those on triamcinolone and included infections (19% vs. 13%, respectively) and serious infections (2% vs. 0%, respectively). Treatment with canakinumab also was associated with an increase in serum triglycerides levels, declines in renal function, and elevations in serum uric acid, and hypertension. There were three cases of renal failure among gout patients treated with canakinumab, who had predisposing factors, according to the company.

Canakinumab is under review in the European Union for the same indication.

The FDA usually follows the recommendations of its advisory panels. Members of FDA advisory panels have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally they may be given a waiver, but not at this meeting.