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The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.
During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:
• continued marketing with no label changes;
• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;
• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or
• market withdrawal.
First Up: Assessing the Level of Risk
Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.
The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.
SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.
The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.
In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.
After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.
Study Population Was High-Risk
Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.
In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.
Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.
In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.
A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.
Assessing Risk by Subgroup
There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.
In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.
However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.
“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.
Three-Month Decision Point
Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.
Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.
The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.
Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.
Elsevier Global Medical News and “The Pink Sheet” are both owned by Elsevier.
The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.
During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:
• continued marketing with no label changes;
• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;
• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or
• market withdrawal.
First Up: Assessing the Level of Risk
Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.
The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.
SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.
The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.
In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.
After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.
Study Population Was High-Risk
Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.
In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.
Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.
In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.
A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.
Assessing Risk by Subgroup
There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.
In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.
However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.
“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.
Three-Month Decision Point
Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.
Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.
The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.
Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.
Elsevier Global Medical News and “The Pink Sheet” are both owned by Elsevier.
The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.
During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:
• continued marketing with no label changes;
• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;
• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or
• market withdrawal.
First Up: Assessing the Level of Risk
Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.
The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.
SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.
The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.
In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.
After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.
Study Population Was High-Risk
Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.
In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.
Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.
In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.
A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.
Assessing Risk by Subgroup
There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.
In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.
However, the agency analysis to be presented at the advisory committee meeting suggests the FDA now sees little difference in the risk among groups.
“Although the hazard ratio for MACE was 1.00 in the diabetes alone CV subgroup compared with 1.28 and 1.18 in the cardiovascular disease alone and cardiovascular plus diabetes subgroups, respectively, the logrank test interaction p-value was 0.56,” FDA clinical reviewer Dr. Monique Falconer notes. “Thus the treatment effect did not differ significantly among the three CV risk subgroups.” In its questions to the committee, the agency asks members to provide their interpretation of these subgroup analysis results for MACE in subjects without a history of CV disease.
Three-Month Decision Point
Another critical element to Abbott’s defense is its argument that SCOUT showed no increased CV risk among subjects who lost weight and had no increases in blood pressure or pulse. The study included some subjects with sustained increases in blood pressure and pulse, and subjects continued in SCOUT even if they did not demonstrate sufficient weight loss, defined as at least 5% during the first three months of treatment.
Current labeling states that blood pressure and pulse should be measured before starting therapy and monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Increasing the sibutramine dose or discontinuing therapy should be considered if a patient has not lost at least four pounds in the first four weeks of treatment, the labeling states.
The company proposes a boxed warning stating that therapy should be discontinued in patients with increases in blood pressure (at least 10 mm Hg) or pulse (at least 10 bpm) on two consecutive assessments during the first three months of treatment. The warning would advise discontinuing sibutramine when patients do not achieve at least 5% weight loss response at three months. The FDA is asking the committee whether the risk for MACE can be mitigated by these measures.
Abbott also proposes adding a communication plan to its REMS with monitoring and screening tools, but it does not seek to add any elements to assure safe use.
Elsevier Global Medical News and “The Pink Sheet” are both owned by Elsevier.