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The approval of the oral anticoagulant rivaroxaban for patients with acute coronary syndrome has been delayed for a second time by the Food and Drug Administration, according to the manufacturer, Janssen Pharmaceuticals.
In a March 4 statement, the company announced that the FDA has issued a second Complete Response Letter regarding the application for approval of rivaroxaban, a factor Xa inhibitor marketed as Xarelto, for reducing the risk of cardiovascular events in people with acute coronary syndrome (ACS). The statement says that in response to the FDA’s first Complete Response Letter, issued in June 2012, the company had submitted some of the missing data from the ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) trial. The data were on 843 (63%) of the people enrolled in the study whose vital status was unknown, which, when included, did not affect the mortality benefit observed in the study, according to the statement.
The phase III ATLAS ACS 2 TIMI 51 results were submitted as part of the application filed in December 2011 for approval of rivaroxaban for reducing the risk of thrombotic cardiovascular events "in patients with ACS [ST-elevation myocardial infarction (STEMI), non–ST-elevation myocardial infarction (NSTEMI), or unstable angina] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine," at a 2.5-mg twice-daily dose.
But at a meeting in May 2012, an FDA advisory panel voted 6 to 4, with 1 abstention, against approval of this indication, with those voting no citing a large amount of missing data and safety concerns among the reasons for their votes.
The company statement does not specify the FDA’s reasons for not approving the ACS indication. The FDA issues Complete Response Letters for a drug when there are outstanding issues that need to be resolved before approval, but does not announce when Complete Response Letters are issued. Like the last time, Janssen said that the company is evaluating the FDA’s letter and will continue to work with the FDA to respond to the agency’s questions.
In an interview, Dr. Sanjay Kaul, one of the FDA panelists who voted against approval at the May 2012 panel meeting, said that the company did "a commendable job" of obtaining vital status information in over 60% of those missing this information. However, data are missing in 3.2%, which "is still much higher than that reported in contemporary ACS trials such as TRITON, PLATO, APPRAISE II, or TRACER," he added.
Moreover, although concerns about the missing data dominated the panel deliberations, "it was not the only issue with potential relevance to the approvability of the expanded indication for rivaroxaban," said Dr. Kaul, a professor at the University of California, Los Angeles. Those issues included the lack of a dose response with the 2.5-mg, but not the 5-mg dose, yielding benefit; and "divergent effects" of the two doses on ischemic endpoints (reduction of CV mortality, but not MI, with 2.5 mg and reduction of MI, but not CV mortality, with the 5-mg dose).
Others issues raised at the meeting were the lack of external evidence supporting the role of dual antiplatelet regimen plus novel anticoagulant therapy and the lack of a statistically persuasive treatment benefit, as defined by a robust P value below .001, to allow approval on the basis of one trial, he said.
He said that while he could not speculate as to why the Complete Response Letter was issued, he would not be surprised "if any one or all of these issues played a major role in the FDA’s decision."
Dr. Kaul, who is also attending cardiologist at Cedars-Sinai Medical Center, Los Angeles, disclosed that he owns stock in Johnson & Johnson, of which Janssen is a subsidiary.
First approved in July 2011 for prophylaxis of deep vein thrombosis or pulmonary embolism in patients undergoing hip or knee replacement surgery, rivaroxaban is now approved for six indications, including the treatment of DVT or PE and for reducing the recurrence of DVT and PE after initial treatment.
The approval of the oral anticoagulant rivaroxaban for patients with acute coronary syndrome has been delayed for a second time by the Food and Drug Administration, according to the manufacturer, Janssen Pharmaceuticals.
In a March 4 statement, the company announced that the FDA has issued a second Complete Response Letter regarding the application for approval of rivaroxaban, a factor Xa inhibitor marketed as Xarelto, for reducing the risk of cardiovascular events in people with acute coronary syndrome (ACS). The statement says that in response to the FDA’s first Complete Response Letter, issued in June 2012, the company had submitted some of the missing data from the ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) trial. The data were on 843 (63%) of the people enrolled in the study whose vital status was unknown, which, when included, did not affect the mortality benefit observed in the study, according to the statement.
The phase III ATLAS ACS 2 TIMI 51 results were submitted as part of the application filed in December 2011 for approval of rivaroxaban for reducing the risk of thrombotic cardiovascular events "in patients with ACS [ST-elevation myocardial infarction (STEMI), non–ST-elevation myocardial infarction (NSTEMI), or unstable angina] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine," at a 2.5-mg twice-daily dose.
But at a meeting in May 2012, an FDA advisory panel voted 6 to 4, with 1 abstention, against approval of this indication, with those voting no citing a large amount of missing data and safety concerns among the reasons for their votes.
The company statement does not specify the FDA’s reasons for not approving the ACS indication. The FDA issues Complete Response Letters for a drug when there are outstanding issues that need to be resolved before approval, but does not announce when Complete Response Letters are issued. Like the last time, Janssen said that the company is evaluating the FDA’s letter and will continue to work with the FDA to respond to the agency’s questions.
In an interview, Dr. Sanjay Kaul, one of the FDA panelists who voted against approval at the May 2012 panel meeting, said that the company did "a commendable job" of obtaining vital status information in over 60% of those missing this information. However, data are missing in 3.2%, which "is still much higher than that reported in contemporary ACS trials such as TRITON, PLATO, APPRAISE II, or TRACER," he added.
Moreover, although concerns about the missing data dominated the panel deliberations, "it was not the only issue with potential relevance to the approvability of the expanded indication for rivaroxaban," said Dr. Kaul, a professor at the University of California, Los Angeles. Those issues included the lack of a dose response with the 2.5-mg, but not the 5-mg dose, yielding benefit; and "divergent effects" of the two doses on ischemic endpoints (reduction of CV mortality, but not MI, with 2.5 mg and reduction of MI, but not CV mortality, with the 5-mg dose).
Others issues raised at the meeting were the lack of external evidence supporting the role of dual antiplatelet regimen plus novel anticoagulant therapy and the lack of a statistically persuasive treatment benefit, as defined by a robust P value below .001, to allow approval on the basis of one trial, he said.
He said that while he could not speculate as to why the Complete Response Letter was issued, he would not be surprised "if any one or all of these issues played a major role in the FDA’s decision."
Dr. Kaul, who is also attending cardiologist at Cedars-Sinai Medical Center, Los Angeles, disclosed that he owns stock in Johnson & Johnson, of which Janssen is a subsidiary.
First approved in July 2011 for prophylaxis of deep vein thrombosis or pulmonary embolism in patients undergoing hip or knee replacement surgery, rivaroxaban is now approved for six indications, including the treatment of DVT or PE and for reducing the recurrence of DVT and PE after initial treatment.
The approval of the oral anticoagulant rivaroxaban for patients with acute coronary syndrome has been delayed for a second time by the Food and Drug Administration, according to the manufacturer, Janssen Pharmaceuticals.
In a March 4 statement, the company announced that the FDA has issued a second Complete Response Letter regarding the application for approval of rivaroxaban, a factor Xa inhibitor marketed as Xarelto, for reducing the risk of cardiovascular events in people with acute coronary syndrome (ACS). The statement says that in response to the FDA’s first Complete Response Letter, issued in June 2012, the company had submitted some of the missing data from the ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) trial. The data were on 843 (63%) of the people enrolled in the study whose vital status was unknown, which, when included, did not affect the mortality benefit observed in the study, according to the statement.
The phase III ATLAS ACS 2 TIMI 51 results were submitted as part of the application filed in December 2011 for approval of rivaroxaban for reducing the risk of thrombotic cardiovascular events "in patients with ACS [ST-elevation myocardial infarction (STEMI), non–ST-elevation myocardial infarction (NSTEMI), or unstable angina] in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine," at a 2.5-mg twice-daily dose.
But at a meeting in May 2012, an FDA advisory panel voted 6 to 4, with 1 abstention, against approval of this indication, with those voting no citing a large amount of missing data and safety concerns among the reasons for their votes.
The company statement does not specify the FDA’s reasons for not approving the ACS indication. The FDA issues Complete Response Letters for a drug when there are outstanding issues that need to be resolved before approval, but does not announce when Complete Response Letters are issued. Like the last time, Janssen said that the company is evaluating the FDA’s letter and will continue to work with the FDA to respond to the agency’s questions.
In an interview, Dr. Sanjay Kaul, one of the FDA panelists who voted against approval at the May 2012 panel meeting, said that the company did "a commendable job" of obtaining vital status information in over 60% of those missing this information. However, data are missing in 3.2%, which "is still much higher than that reported in contemporary ACS trials such as TRITON, PLATO, APPRAISE II, or TRACER," he added.
Moreover, although concerns about the missing data dominated the panel deliberations, "it was not the only issue with potential relevance to the approvability of the expanded indication for rivaroxaban," said Dr. Kaul, a professor at the University of California, Los Angeles. Those issues included the lack of a dose response with the 2.5-mg, but not the 5-mg dose, yielding benefit; and "divergent effects" of the two doses on ischemic endpoints (reduction of CV mortality, but not MI, with 2.5 mg and reduction of MI, but not CV mortality, with the 5-mg dose).
Others issues raised at the meeting were the lack of external evidence supporting the role of dual antiplatelet regimen plus novel anticoagulant therapy and the lack of a statistically persuasive treatment benefit, as defined by a robust P value below .001, to allow approval on the basis of one trial, he said.
He said that while he could not speculate as to why the Complete Response Letter was issued, he would not be surprised "if any one or all of these issues played a major role in the FDA’s decision."
Dr. Kaul, who is also attending cardiologist at Cedars-Sinai Medical Center, Los Angeles, disclosed that he owns stock in Johnson & Johnson, of which Janssen is a subsidiary.
First approved in July 2011 for prophylaxis of deep vein thrombosis or pulmonary embolism in patients undergoing hip or knee replacement surgery, rivaroxaban is now approved for six indications, including the treatment of DVT or PE and for reducing the recurrence of DVT and PE after initial treatment.
