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Brentuximab vedotin approved in Japan
Credit: Linda Bartlett
The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) for the treatment of patients with relapsed or refractory, CD30+ Hodgkin lymphoma (HL) or anaplastic large-cell lymphoma (ALCL).
The approval was based on a phase 1/2 trial in Japanese patients with relapsed or refractory, CD30+ HL or systemic ALCL, as well as data from two phase 2 trials—one of 102 HL patients and one of 58 patients with ALCL.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
The conjugate employs a linker system designed to be stable in the bloodstream but release monomethyl auristatin E upon internalization into CD30-expressing tumor cells.
Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in August 2011 and gained conditional approval from Health Canada in February 2013 for the following indications:
- To treat HL patients who had failed autologous stem cell transplant (auto-SCT) or were not eligible for auto-SCT and had failed at least 2 prior multi-agent chemotherapy regimens
- To treat patients with systemic ALCL after they failed at least 1 multi-agent chemotherapy regimen.
The drug received conditional marketing authorization by the European Commission in October 2012 to treat:
- Adult patients with relapsed or refractory, systemic ALCL
- Adults with relapsed or refractory, CD30-positive HL who had undergone auto-SCT or received 2 prior therapies when auto-SCT or multi-agent chemotherapy were not appropriate.
The FDA has granted brentuximab vedotin orphan designation to treat mycosis fungoides. And trials have suggested the drug is active in diffuse large B-cell lymphoma, as well as leukemias and multiple myeloma.
However, brentuximab vedotin also made the FDA watch list due to adverse events associated with the drug’s use. The FDA added a boxed warning to the drug’s label in January 2012, after 3 cases of progressive multifocal leukoencephalopathy were reported in patients receiving brentuximab vedotin. 
Credit: Linda Bartlett
The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) for the treatment of patients with relapsed or refractory, CD30+ Hodgkin lymphoma (HL) or anaplastic large-cell lymphoma (ALCL).
The approval was based on a phase 1/2 trial in Japanese patients with relapsed or refractory, CD30+ HL or systemic ALCL, as well as data from two phase 2 trials—one of 102 HL patients and one of 58 patients with ALCL.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
The conjugate employs a linker system designed to be stable in the bloodstream but release monomethyl auristatin E upon internalization into CD30-expressing tumor cells.
Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in August 2011 and gained conditional approval from Health Canada in February 2013 for the following indications:
- To treat HL patients who had failed autologous stem cell transplant (auto-SCT) or were not eligible for auto-SCT and had failed at least 2 prior multi-agent chemotherapy regimens
- To treat patients with systemic ALCL after they failed at least 1 multi-agent chemotherapy regimen.
The drug received conditional marketing authorization by the European Commission in October 2012 to treat:
- Adult patients with relapsed or refractory, systemic ALCL
- Adults with relapsed or refractory, CD30-positive HL who had undergone auto-SCT or received 2 prior therapies when auto-SCT or multi-agent chemotherapy were not appropriate.
The FDA has granted brentuximab vedotin orphan designation to treat mycosis fungoides. And trials have suggested the drug is active in diffuse large B-cell lymphoma, as well as leukemias and multiple myeloma.
However, brentuximab vedotin also made the FDA watch list due to adverse events associated with the drug’s use. The FDA added a boxed warning to the drug’s label in January 2012, after 3 cases of progressive multifocal leukoencephalopathy were reported in patients receiving brentuximab vedotin.
Credit: Linda Bartlett
The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) for the treatment of patients with relapsed or refractory, CD30+ Hodgkin lymphoma (HL) or anaplastic large-cell lymphoma (ALCL).
The approval was based on a phase 1/2 trial in Japanese patients with relapsed or refractory, CD30+ HL or systemic ALCL, as well as data from two phase 2 trials—one of 102 HL patients and one of 58 patients with ALCL.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
The conjugate employs a linker system designed to be stable in the bloodstream but release monomethyl auristatin E upon internalization into CD30-expressing tumor cells.
Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in August 2011 and gained conditional approval from Health Canada in February 2013 for the following indications:
- To treat HL patients who had failed autologous stem cell transplant (auto-SCT) or were not eligible for auto-SCT and had failed at least 2 prior multi-agent chemotherapy regimens
- To treat patients with systemic ALCL after they failed at least 1 multi-agent chemotherapy regimen.
The drug received conditional marketing authorization by the European Commission in October 2012 to treat:
- Adult patients with relapsed or refractory, systemic ALCL
- Adults with relapsed or refractory, CD30-positive HL who had undergone auto-SCT or received 2 prior therapies when auto-SCT or multi-agent chemotherapy were not appropriate.
The FDA has granted brentuximab vedotin orphan designation to treat mycosis fungoides. And trials have suggested the drug is active in diffuse large B-cell lymphoma, as well as leukemias and multiple myeloma.
However, brentuximab vedotin also made the FDA watch list due to adverse events associated with the drug’s use. The FDA added a boxed warning to the drug’s label in January 2012, after 3 cases of progressive multifocal leukoencephalopathy were reported in patients receiving brentuximab vedotin.
FDA doesn’t hold drug trials to same standards
Credit: FDA
A new study suggests the US Food and Drug Administration (FDA) does not hold drug trials to the same set of standards.
The research revealed substantial differences in trials used to support drugs approved between 2005 and 2012.
Some drugs were approved based on results from multiple studies, while other approvals were based on data from a single trial.
Furthermore, trials varied greatly with regard to size, length of study period, type of comparator, and metrics of efficacy.
These results appear in the current issue of JAMA.
“Based on our analysis, some drugs are approved on the basis of large, high-quality clinical trials, while others are approved based on results of smaller trials,” said senior study author Joseph Ross, MD, of the Yale School of Medicine in New Haven, Connecticut.
“There was a lack of uniformity in the level of evidence the FDA used. We also found that only 40% of drug approvals involved a clinical trial that compared a new drug to existing treatment offerings. This is an important step for determining whether the new drug is a better option than existing, older drugs.”
Dr Ross and his colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions by characterizing key features of efficacy trials, such as size, duration, and endpoints.
The researchers used publicly available FDA documents to identify 188 drugs approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials.
The team identified trials for 201 of the indications. Four drugs (including 1 used for 2 different indications) were approved without a pivotal efficacy trial.
So among the 201 indications, the median number of trials reviewed per indication was 2 (interquartile range [IQR], 1-2.5). Seventy-four indications (36.8%) were approved on the basis of a single trial, 77 (38.3%) on data from 2 trials, and 50 (24.9%) on data from 3 or more trials.
Most trials were randomized (89.3%) and double-blinded (79.5%). The median duration of a trial was 14.0 weeks (IQR, 6.0-26.0 weeks), and 113 trials (25.2%) lasted 6 months or longer.
The median number of total subjects enrolled in a trial was 446 (IQR, 205-678), and the median number of patients in the intervention arm of a study was 271 (IQR, 133-426).
More than half of trials (55.1%) used a placebo for comparison, 31.9% used an active comparator (such as another drug), and 12.9% had no comparator.
The primary endpoint was a surrogate outcome in 48.9% of trials, a clinical outcome for 29%, and a clinical scale for 22.1%.
These results suggest the quality of clinical trial evidence the FDA uses to make approval decisions varies widely across indications, the researchers said.
Study author Nicholas S. Downing, a student at the Yale School of Medicine, noted that survey data suggest patients expect drugs approved by the FDA to be both safe and effective.
“Based on our study of the data, we can’t be certain that this expectation is necessarily justified,” he said, “given the quantity and quality of the variability we saw in the drug approval process.”
Credit: FDA
A new study suggests the US Food and Drug Administration (FDA) does not hold drug trials to the same set of standards.
The research revealed substantial differences in trials used to support drugs approved between 2005 and 2012.
Some drugs were approved based on results from multiple studies, while other approvals were based on data from a single trial.
Furthermore, trials varied greatly with regard to size, length of study period, type of comparator, and metrics of efficacy.
These results appear in the current issue of JAMA.
“Based on our analysis, some drugs are approved on the basis of large, high-quality clinical trials, while others are approved based on results of smaller trials,” said senior study author Joseph Ross, MD, of the Yale School of Medicine in New Haven, Connecticut.
“There was a lack of uniformity in the level of evidence the FDA used. We also found that only 40% of drug approvals involved a clinical trial that compared a new drug to existing treatment offerings. This is an important step for determining whether the new drug is a better option than existing, older drugs.”
Dr Ross and his colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions by characterizing key features of efficacy trials, such as size, duration, and endpoints.
The researchers used publicly available FDA documents to identify 188 drugs approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials.
The team identified trials for 201 of the indications. Four drugs (including 1 used for 2 different indications) were approved without a pivotal efficacy trial.
So among the 201 indications, the median number of trials reviewed per indication was 2 (interquartile range [IQR], 1-2.5). Seventy-four indications (36.8%) were approved on the basis of a single trial, 77 (38.3%) on data from 2 trials, and 50 (24.9%) on data from 3 or more trials.
Most trials were randomized (89.3%) and double-blinded (79.5%). The median duration of a trial was 14.0 weeks (IQR, 6.0-26.0 weeks), and 113 trials (25.2%) lasted 6 months or longer.
The median number of total subjects enrolled in a trial was 446 (IQR, 205-678), and the median number of patients in the intervention arm of a study was 271 (IQR, 133-426).
More than half of trials (55.1%) used a placebo for comparison, 31.9% used an active comparator (such as another drug), and 12.9% had no comparator.
The primary endpoint was a surrogate outcome in 48.9% of trials, a clinical outcome for 29%, and a clinical scale for 22.1%.
These results suggest the quality of clinical trial evidence the FDA uses to make approval decisions varies widely across indications, the researchers said.
Study author Nicholas S. Downing, a student at the Yale School of Medicine, noted that survey data suggest patients expect drugs approved by the FDA to be both safe and effective.
“Based on our study of the data, we can’t be certain that this expectation is necessarily justified,” he said, “given the quantity and quality of the variability we saw in the drug approval process.”
Credit: FDA
A new study suggests the US Food and Drug Administration (FDA) does not hold drug trials to the same set of standards.
The research revealed substantial differences in trials used to support drugs approved between 2005 and 2012.
Some drugs were approved based on results from multiple studies, while other approvals were based on data from a single trial.
Furthermore, trials varied greatly with regard to size, length of study period, type of comparator, and metrics of efficacy.
These results appear in the current issue of JAMA.
“Based on our analysis, some drugs are approved on the basis of large, high-quality clinical trials, while others are approved based on results of smaller trials,” said senior study author Joseph Ross, MD, of the Yale School of Medicine in New Haven, Connecticut.
“There was a lack of uniformity in the level of evidence the FDA used. We also found that only 40% of drug approvals involved a clinical trial that compared a new drug to existing treatment offerings. This is an important step for determining whether the new drug is a better option than existing, older drugs.”
Dr Ross and his colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions by characterizing key features of efficacy trials, such as size, duration, and endpoints.
The researchers used publicly available FDA documents to identify 188 drugs approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials.
The team identified trials for 201 of the indications. Four drugs (including 1 used for 2 different indications) were approved without a pivotal efficacy trial.
So among the 201 indications, the median number of trials reviewed per indication was 2 (interquartile range [IQR], 1-2.5). Seventy-four indications (36.8%) were approved on the basis of a single trial, 77 (38.3%) on data from 2 trials, and 50 (24.9%) on data from 3 or more trials.
Most trials were randomized (89.3%) and double-blinded (79.5%). The median duration of a trial was 14.0 weeks (IQR, 6.0-26.0 weeks), and 113 trials (25.2%) lasted 6 months or longer.
The median number of total subjects enrolled in a trial was 446 (IQR, 205-678), and the median number of patients in the intervention arm of a study was 271 (IQR, 133-426).
More than half of trials (55.1%) used a placebo for comparison, 31.9% used an active comparator (such as another drug), and 12.9% had no comparator.
The primary endpoint was a surrogate outcome in 48.9% of trials, a clinical outcome for 29%, and a clinical scale for 22.1%.
These results suggest the quality of clinical trial evidence the FDA uses to make approval decisions varies widely across indications, the researchers said.
Study author Nicholas S. Downing, a student at the Yale School of Medicine, noted that survey data suggest patients expect drugs approved by the FDA to be both safe and effective.
“Based on our study of the data, we can’t be certain that this expectation is necessarily justified,” he said, “given the quantity and quality of the variability we saw in the drug approval process.”
Ponatinib back on the market
Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.
Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.
The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).
Safety concerns prompt action
Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.
Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.
The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.
Now, ponatinib is indicated for the treatment of:
- Adults with T315I-positive CML (chronic, accelerated, or blast phase)
- Adults with T315I-positive Ph+ ALL
- Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
- Adults with Ph+ ALL who cannot receive another TKI.
The starting dose of ponatinib remains 45 mg daily.
IND program
On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.
The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.
Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.
Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.
Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.
Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.
The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).
Safety concerns prompt action
Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.
Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.
The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.
Now, ponatinib is indicated for the treatment of:
- Adults with T315I-positive CML (chronic, accelerated, or blast phase)
- Adults with T315I-positive Ph+ ALL
- Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
- Adults with Ph+ ALL who cannot receive another TKI.
The starting dose of ponatinib remains 45 mg daily.
IND program
On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.
The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.
Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.
Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.
Less than 3 months after it was pulled from the market due to safety concerns, ponatinib (Iclusig) is once again commercially available in the US.
Ariad Pharmaceuticals, Inc., has begun shipping the drug to Biologics, Inc., its exclusive specialty pharmacy. And the pharmacy has started filling prescriptions and distributing ponatinib to patients in need.
The drug is approved by the US Food and Drug Administration (FDA) to treat chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).
Safety concerns prompt action
Last October, the latest results of the phase 2 PACE trial revealed that ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.
Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. But in December, the agency decided the drug could return to the market if new safety measures were implemented.
The FDA approved revised prescribing information and a communications Risk Evaluation and Mitigation Strategy for ponatinib. The prescribing information includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.
Now, ponatinib is indicated for the treatment of:
- Adults with T315I-positive CML (chronic, accelerated, or blast phase)
- Adults with T315I-positive Ph+ ALL
- Adults with CML (chronic, accelerated, or blast phase) who cannot receive another TKI
- Adults with Ph+ ALL who cannot receive another TKI.
The starting dose of ponatinib remains 45 mg daily.
IND program
On November 1, 2013, there were approximately 640 patients receiving ponatinib through commercial channels in the US. Since then, the drug was only made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis.
The FDA has approved more than 370 INDs since early November, and more than 300 patients have received ponatinib at no cost through this process.
Ariad expects most of these patients, many of whom received a 3-month supply of ponatinib, to transition from the IND program to commercial therapy by the end of the first quarter of 2014. The IND program is now closed to new patients with Ph+ leukemias.
Ponatinib is currently priced in the US at approximately $125,000 per year. For more information on the drug, visit www.iclusig.com.
Committee votes against rivaroxaban for ACS
Credit: Mass. General Hospital
A US Food and Drug Administration (FDA) advisory committee has voted against expanding the indication for the anticoagulant rivaroxaban (Xarelto).
The drug’s developers are seeking approval for rivaroxaban to be used in combination with standard antiplatelet therapy to reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The proposed dose is 2.5 mg twice daily for 90 days.
But the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted—nearly unanimously (with 1 abstention)—against this approval.
And the FDA will take this recommendation into account when deciding whether or not to expand rivaroxaban’s indication. This will be the FDA’s third time reviewing the drug for the aforementioned indication.
Rivaroxaban is currently FDA-approved to reduce the risk of stroke and thrombosis in patients with non-valvular atrial fibrillation, treat patients with venous thromboembolism (VTE), reduce the risk of recurrent VTE, and reduce the risk of VTE in patients who have undergone knee replacement surgery or hip replacement surgery.
Headed for a third rejection?
The advisory committee’s recommendation was based on a review of data from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in January 2012.
The study showed that rivaroxaban, given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients. But it also increased the risk of major bleeding and intracranial hemorrhage.
Based on these results, rivaroxaban’s developers—Janssen Research & Development, LLC, and Bayer HealthCare—filed for FDA approval of rivaroxaban to treat patients with ACS.
In June 2012, the FDA rejected the application, a month after an advisory committee voted against the approval. The committee had expressed concerns about the risks of bleeding associated with rivaroxaban, as well as reservations about missing data from the ATLAS ACS 2 TIMI 51 trial.
Though Janssen and Bayer went on to submit the missing data, the FDA rejected the drug again in March 2013. However, the FDA suggested the companies apply for approval using rivaroxaban for a limited time after ACS development, as the drug might be safer and more effective when given this way.
So the companies submitted an application for rivaroxaban given within the first 90 days of ACS diagnosis.
The advisory committee voted against this use of the drug, however, saying it seems the benefits of this treatment still do not outweigh the risks for this patient population.
A representative from Janssen said the company still believes rivaroxaban can be useful for patients with ACS, and Janssen and Bayer will work with the FDA to address the issues the committee raised.
For more details and data on rivaroxaban, see the briefing information compiled for the advisory committee’s meeting.
Credit: Mass. General Hospital
A US Food and Drug Administration (FDA) advisory committee has voted against expanding the indication for the anticoagulant rivaroxaban (Xarelto).
The drug’s developers are seeking approval for rivaroxaban to be used in combination with standard antiplatelet therapy to reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The proposed dose is 2.5 mg twice daily for 90 days.
But the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted—nearly unanimously (with 1 abstention)—against this approval.
And the FDA will take this recommendation into account when deciding whether or not to expand rivaroxaban’s indication. This will be the FDA’s third time reviewing the drug for the aforementioned indication.
Rivaroxaban is currently FDA-approved to reduce the risk of stroke and thrombosis in patients with non-valvular atrial fibrillation, treat patients with venous thromboembolism (VTE), reduce the risk of recurrent VTE, and reduce the risk of VTE in patients who have undergone knee replacement surgery or hip replacement surgery.
Headed for a third rejection?
The advisory committee’s recommendation was based on a review of data from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in January 2012.
The study showed that rivaroxaban, given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients. But it also increased the risk of major bleeding and intracranial hemorrhage.
Based on these results, rivaroxaban’s developers—Janssen Research & Development, LLC, and Bayer HealthCare—filed for FDA approval of rivaroxaban to treat patients with ACS.
In June 2012, the FDA rejected the application, a month after an advisory committee voted against the approval. The committee had expressed concerns about the risks of bleeding associated with rivaroxaban, as well as reservations about missing data from the ATLAS ACS 2 TIMI 51 trial.
Though Janssen and Bayer went on to submit the missing data, the FDA rejected the drug again in March 2013. However, the FDA suggested the companies apply for approval using rivaroxaban for a limited time after ACS development, as the drug might be safer and more effective when given this way.
So the companies submitted an application for rivaroxaban given within the first 90 days of ACS diagnosis.
The advisory committee voted against this use of the drug, however, saying it seems the benefits of this treatment still do not outweigh the risks for this patient population.
A representative from Janssen said the company still believes rivaroxaban can be useful for patients with ACS, and Janssen and Bayer will work with the FDA to address the issues the committee raised.
For more details and data on rivaroxaban, see the briefing information compiled for the advisory committee’s meeting.
Credit: Mass. General Hospital
A US Food and Drug Administration (FDA) advisory committee has voted against expanding the indication for the anticoagulant rivaroxaban (Xarelto).
The drug’s developers are seeking approval for rivaroxaban to be used in combination with standard antiplatelet therapy to reduce the risk of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The proposed dose is 2.5 mg twice daily for 90 days.
But the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted—nearly unanimously (with 1 abstention)—against this approval.
And the FDA will take this recommendation into account when deciding whether or not to expand rivaroxaban’s indication. This will be the FDA’s third time reviewing the drug for the aforementioned indication.
Rivaroxaban is currently FDA-approved to reduce the risk of stroke and thrombosis in patients with non-valvular atrial fibrillation, treat patients with venous thromboembolism (VTE), reduce the risk of recurrent VTE, and reduce the risk of VTE in patients who have undergone knee replacement surgery or hip replacement surgery.
Headed for a third rejection?
The advisory committee’s recommendation was based on a review of data from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in January 2012.
The study showed that rivaroxaban, given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients. But it also increased the risk of major bleeding and intracranial hemorrhage.
Based on these results, rivaroxaban’s developers—Janssen Research & Development, LLC, and Bayer HealthCare—filed for FDA approval of rivaroxaban to treat patients with ACS.
In June 2012, the FDA rejected the application, a month after an advisory committee voted against the approval. The committee had expressed concerns about the risks of bleeding associated with rivaroxaban, as well as reservations about missing data from the ATLAS ACS 2 TIMI 51 trial.
Though Janssen and Bayer went on to submit the missing data, the FDA rejected the drug again in March 2013. However, the FDA suggested the companies apply for approval using rivaroxaban for a limited time after ACS development, as the drug might be safer and more effective when given this way.
So the companies submitted an application for rivaroxaban given within the first 90 days of ACS diagnosis.
The advisory committee voted against this use of the drug, however, saying it seems the benefits of this treatment still do not outweigh the risks for this patient population.
A representative from Janssen said the company still believes rivaroxaban can be useful for patients with ACS, and Janssen and Bayer will work with the FDA to address the issues the committee raised.
For more details and data on rivaroxaban, see the briefing information compiled for the advisory committee’s meeting.
FDA committee votes in favor of vorapaxar
Credit: Andre E.X. Brown
An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.
The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.
The FDA will take this opinion into account when deciding whether or not to approve the drug.
The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.
In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.
The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).
The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.
Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).
However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.
And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.
These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.
The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.
The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.
Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.
For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.
Credit: Andre E.X. Brown
An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.
The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.
The FDA will take this opinion into account when deciding whether or not to approve the drug.
The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.
In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.
The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).
The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.
Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).
However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.
And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.
These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.
The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.
The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.
Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.
For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.
Credit: Andre E.X. Brown
An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.
The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.
The FDA will take this opinion into account when deciding whether or not to approve the drug.
The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.
In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.
The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).
The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.
Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).
However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.
And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.
These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.
The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.
The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.
Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.
For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.
Survey quantifies impact of drug shortages
Credit: Rhoda Baer
Drug shortages remain a serious problem for patient safety, according to a small survey of US pharmacy directors.
Of the nearly 200 directors, 49% said patients received suboptimal treatment as a result of drug shortages.
Fifty-five percent of respondents reported medication errors resulting from shortages. And 45% reported adverse events due to drug shortages, including a small number of disabling events and deaths.
These results appear in the Journal of Managed Care Pharmacy.
“Drug shortages are the first thing I think about when I get up in the morning, and it is the last thing on my mind when I go to bed at night,” said study author Gary Fennessy, of Northwestern Memorial HealthCare in Chicago, Illinois.
“This is not a problem that is going to go away on its own. Healthcare leaders must not lose sight of it as a major contributor to patient harm or consider its adverse effects inevitable.”
With this in mind, Fennessy and his colleagues sent an electronic survey on drug shortages to 1516 directors of pharmacy.
The survey asked respondents to include information on patient demographics, patient complaints, adverse events, medication errors, patient outcomes, and institutional costs related to drug shortages.
Only 193 pharmacy directors responded. The majority were from acute care institutions serving less than 100 patients. The locations were divided evenly among suburban, urban, and rural institutions.
The medications most commonly reported to be in short supply were analgesics/anesthetics (n=176, 92%), anti-emetics (n=171, 89%), and electrolytes/total parenteral nutrition (n=162, 84%).
Respondents said drug shortages contributed to a variety of issues, including medication errors (such as giving the wrong dose, the wrong drug, or the wrong frequency).
Fifty-three percent of respondents reported 1 to 10 medication errors resulting from drug shortages. And 2% reported more than 30 medication errors.
Eighty-five percent of respondents said patients had to use alternative medications due to drug shortages, 71% said patients’ experienced delays in treatment, and 49% said patients received suboptimal treatment.
Thirty-three percent of respondents said drug shortages resulted in an increased stay in the hospital, 16% said drug shortages caused treatment failure, and 12% said shortages caused hospital readmission.
Forty-one percent of respondents reported 1 to 5 possible or probable adverse events related to drug shortages, and 3% reported more than 15 adverse events.
One percent of respondents reported 1 to 5 patient deaths resulting from drug shortages, 2% reported a disabling adverse event in 1 to 5 patients, and 19% reported adverse events requiring intervention in 1 to 5 patients.
Fifty respondents provided numbers on their estimated costs resulting from drug shortages. And 73% of these individuals calculated costs greater than $100,000.
Thirty-eight percent of respondents said their organization had received at least 1 patient complaint related to drug shortages. And of those respondents reporting the actual number of patient complaints, 18% reported more than 10 complaints.
“This survey is the first that we are aware of to describe the effects that drug shortages have on patient complaints,” said study author Despina Kotis, PharmD, also of Northwestern Memorial HealthCare.
“It clearly shows that patients are aware these shortages are happening, and they are upset that their care is being adversely affected by them.”
Credit: Rhoda Baer
Drug shortages remain a serious problem for patient safety, according to a small survey of US pharmacy directors.
Of the nearly 200 directors, 49% said patients received suboptimal treatment as a result of drug shortages.
Fifty-five percent of respondents reported medication errors resulting from shortages. And 45% reported adverse events due to drug shortages, including a small number of disabling events and deaths.
These results appear in the Journal of Managed Care Pharmacy.
“Drug shortages are the first thing I think about when I get up in the morning, and it is the last thing on my mind when I go to bed at night,” said study author Gary Fennessy, of Northwestern Memorial HealthCare in Chicago, Illinois.
“This is not a problem that is going to go away on its own. Healthcare leaders must not lose sight of it as a major contributor to patient harm or consider its adverse effects inevitable.”
With this in mind, Fennessy and his colleagues sent an electronic survey on drug shortages to 1516 directors of pharmacy.
The survey asked respondents to include information on patient demographics, patient complaints, adverse events, medication errors, patient outcomes, and institutional costs related to drug shortages.
Only 193 pharmacy directors responded. The majority were from acute care institutions serving less than 100 patients. The locations were divided evenly among suburban, urban, and rural institutions.
The medications most commonly reported to be in short supply were analgesics/anesthetics (n=176, 92%), anti-emetics (n=171, 89%), and electrolytes/total parenteral nutrition (n=162, 84%).
Respondents said drug shortages contributed to a variety of issues, including medication errors (such as giving the wrong dose, the wrong drug, or the wrong frequency).
Fifty-three percent of respondents reported 1 to 10 medication errors resulting from drug shortages. And 2% reported more than 30 medication errors.
Eighty-five percent of respondents said patients had to use alternative medications due to drug shortages, 71% said patients’ experienced delays in treatment, and 49% said patients received suboptimal treatment.
Thirty-three percent of respondents said drug shortages resulted in an increased stay in the hospital, 16% said drug shortages caused treatment failure, and 12% said shortages caused hospital readmission.
Forty-one percent of respondents reported 1 to 5 possible or probable adverse events related to drug shortages, and 3% reported more than 15 adverse events.
One percent of respondents reported 1 to 5 patient deaths resulting from drug shortages, 2% reported a disabling adverse event in 1 to 5 patients, and 19% reported adverse events requiring intervention in 1 to 5 patients.
Fifty respondents provided numbers on their estimated costs resulting from drug shortages. And 73% of these individuals calculated costs greater than $100,000.
Thirty-eight percent of respondents said their organization had received at least 1 patient complaint related to drug shortages. And of those respondents reporting the actual number of patient complaints, 18% reported more than 10 complaints.
“This survey is the first that we are aware of to describe the effects that drug shortages have on patient complaints,” said study author Despina Kotis, PharmD, also of Northwestern Memorial HealthCare.
“It clearly shows that patients are aware these shortages are happening, and they are upset that their care is being adversely affected by them.”
Credit: Rhoda Baer
Drug shortages remain a serious problem for patient safety, according to a small survey of US pharmacy directors.
Of the nearly 200 directors, 49% said patients received suboptimal treatment as a result of drug shortages.
Fifty-five percent of respondents reported medication errors resulting from shortages. And 45% reported adverse events due to drug shortages, including a small number of disabling events and deaths.
These results appear in the Journal of Managed Care Pharmacy.
“Drug shortages are the first thing I think about when I get up in the morning, and it is the last thing on my mind when I go to bed at night,” said study author Gary Fennessy, of Northwestern Memorial HealthCare in Chicago, Illinois.
“This is not a problem that is going to go away on its own. Healthcare leaders must not lose sight of it as a major contributor to patient harm or consider its adverse effects inevitable.”
With this in mind, Fennessy and his colleagues sent an electronic survey on drug shortages to 1516 directors of pharmacy.
The survey asked respondents to include information on patient demographics, patient complaints, adverse events, medication errors, patient outcomes, and institutional costs related to drug shortages.
Only 193 pharmacy directors responded. The majority were from acute care institutions serving less than 100 patients. The locations were divided evenly among suburban, urban, and rural institutions.
The medications most commonly reported to be in short supply were analgesics/anesthetics (n=176, 92%), anti-emetics (n=171, 89%), and electrolytes/total parenteral nutrition (n=162, 84%).
Respondents said drug shortages contributed to a variety of issues, including medication errors (such as giving the wrong dose, the wrong drug, or the wrong frequency).
Fifty-three percent of respondents reported 1 to 10 medication errors resulting from drug shortages. And 2% reported more than 30 medication errors.
Eighty-five percent of respondents said patients had to use alternative medications due to drug shortages, 71% said patients’ experienced delays in treatment, and 49% said patients received suboptimal treatment.
Thirty-three percent of respondents said drug shortages resulted in an increased stay in the hospital, 16% said drug shortages caused treatment failure, and 12% said shortages caused hospital readmission.
Forty-one percent of respondents reported 1 to 5 possible or probable adverse events related to drug shortages, and 3% reported more than 15 adverse events.
One percent of respondents reported 1 to 5 patient deaths resulting from drug shortages, 2% reported a disabling adverse event in 1 to 5 patients, and 19% reported adverse events requiring intervention in 1 to 5 patients.
Fifty respondents provided numbers on their estimated costs resulting from drug shortages. And 73% of these individuals calculated costs greater than $100,000.
Thirty-eight percent of respondents said their organization had received at least 1 patient complaint related to drug shortages. And of those respondents reporting the actual number of patient complaints, 18% reported more than 10 complaints.
“This survey is the first that we are aware of to describe the effects that drug shortages have on patient complaints,” said study author Despina Kotis, PharmD, also of Northwestern Memorial HealthCare.
“It clearly shows that patients are aware these shortages are happening, and they are upset that their care is being adversely affected by them.”
Out-of-pocket costs hinder adherence to imatinib
Credit: CDC
When their share of prescription costs becomes too high, many patients with chronic myeloid leukemia (CML) will skip doses of imatinib or stop taking the drug entirely, new research suggests.
In a study of about 1500 patients, the median co-payment for an imatinib prescription was about $30 per fill, but the range was $0 to $4792.
Patients with higher co-payments were 70% more likely than their peers to stop taking imatinib and 42% more likely to skip doses of the drug.
Stacie B. Dusetzina, PhD, of the University of North Carolina at Chapel Hill, and her colleagues conducted this research and described the results in the Journal of Clinical Oncology.
Co-payment requirements vary
The researchers analyzed health plan claims from privately insured adults (ages 18 to 64) from 2002 to 2011. The data included 1541 CML patients beginning treatment with imatinib.
For the whole study period, the mean co-payment was $108 for a 30-day supply of imatinib. Patients in the lowest 25th percentile paid a mean of $17, and patients in the upper 75th percentile paid a mean of $53.
As expected, monthly co-payments increased over time. They averaged $55 in 2002 and $145 in 2011, with 6.4% of patients paying more than $500 a month.
Dr Dusetzina noted that the data only included patients on employer-based insurance plans, and most individuals had low out-of-pocket costs.
“We studied people who are part of large employer groups, so their insurance is probably more generous than someone who is buying insurance on a private market that does not have a lot of negotiating power,” she said.
Costs correlate with adherence
In the first 180 days of treatment, 30% of patients with higher co-payments were non-adherent to imatinib treatment, compared to 21% of patients with lower co-payments. Non-adherence was defined as having less than 80% of days with imatinib available.
Seventeen percent of patients with higher co-payments discontinued taking imatinib, compared to 10% of patients with lower co-payments. Discontinuation was defined as having a gap of more than 60 days after the exhaustion of imatinib therapy.
These data did not include patients who could not begin taking imatinib due to costs. Therefore, Dr Dusetzina said this study likely underestimates the effects of drug costs on treatment adherence.
“If you went to the pharmacy to obtain your prescription, and they said it was $5000, and you walked away because you couldn’t afford to pay, you’re not in the data,” she said. “We could only study individuals who filled at least one prescription.”
Dr Dusetzina also said these findings have implications beyond imatinib and CML. Many new treatments for rare conditions can cost insurers and patients more than $100,000 year.
“Our results are particularly relevant for specialty pharmaceutical products—those that cost over $10,000 a month,” she said.
“However, the lessons learned likely relate to any pharmaceutical product that has high out-of-pocket costs. It is important that we identify strategies to make effective but expensive medications more affordable to patients.”
Credit: CDC
When their share of prescription costs becomes too high, many patients with chronic myeloid leukemia (CML) will skip doses of imatinib or stop taking the drug entirely, new research suggests.
In a study of about 1500 patients, the median co-payment for an imatinib prescription was about $30 per fill, but the range was $0 to $4792.
Patients with higher co-payments were 70% more likely than their peers to stop taking imatinib and 42% more likely to skip doses of the drug.
Stacie B. Dusetzina, PhD, of the University of North Carolina at Chapel Hill, and her colleagues conducted this research and described the results in the Journal of Clinical Oncology.
Co-payment requirements vary
The researchers analyzed health plan claims from privately insured adults (ages 18 to 64) from 2002 to 2011. The data included 1541 CML patients beginning treatment with imatinib.
For the whole study period, the mean co-payment was $108 for a 30-day supply of imatinib. Patients in the lowest 25th percentile paid a mean of $17, and patients in the upper 75th percentile paid a mean of $53.
As expected, monthly co-payments increased over time. They averaged $55 in 2002 and $145 in 2011, with 6.4% of patients paying more than $500 a month.
Dr Dusetzina noted that the data only included patients on employer-based insurance plans, and most individuals had low out-of-pocket costs.
“We studied people who are part of large employer groups, so their insurance is probably more generous than someone who is buying insurance on a private market that does not have a lot of negotiating power,” she said.
Costs correlate with adherence
In the first 180 days of treatment, 30% of patients with higher co-payments were non-adherent to imatinib treatment, compared to 21% of patients with lower co-payments. Non-adherence was defined as having less than 80% of days with imatinib available.
Seventeen percent of patients with higher co-payments discontinued taking imatinib, compared to 10% of patients with lower co-payments. Discontinuation was defined as having a gap of more than 60 days after the exhaustion of imatinib therapy.
These data did not include patients who could not begin taking imatinib due to costs. Therefore, Dr Dusetzina said this study likely underestimates the effects of drug costs on treatment adherence.
“If you went to the pharmacy to obtain your prescription, and they said it was $5000, and you walked away because you couldn’t afford to pay, you’re not in the data,” she said. “We could only study individuals who filled at least one prescription.”
Dr Dusetzina also said these findings have implications beyond imatinib and CML. Many new treatments for rare conditions can cost insurers and patients more than $100,000 year.
“Our results are particularly relevant for specialty pharmaceutical products—those that cost over $10,000 a month,” she said.
“However, the lessons learned likely relate to any pharmaceutical product that has high out-of-pocket costs. It is important that we identify strategies to make effective but expensive medications more affordable to patients.”
Credit: CDC
When their share of prescription costs becomes too high, many patients with chronic myeloid leukemia (CML) will skip doses of imatinib or stop taking the drug entirely, new research suggests.
In a study of about 1500 patients, the median co-payment for an imatinib prescription was about $30 per fill, but the range was $0 to $4792.
Patients with higher co-payments were 70% more likely than their peers to stop taking imatinib and 42% more likely to skip doses of the drug.
Stacie B. Dusetzina, PhD, of the University of North Carolina at Chapel Hill, and her colleagues conducted this research and described the results in the Journal of Clinical Oncology.
Co-payment requirements vary
The researchers analyzed health plan claims from privately insured adults (ages 18 to 64) from 2002 to 2011. The data included 1541 CML patients beginning treatment with imatinib.
For the whole study period, the mean co-payment was $108 for a 30-day supply of imatinib. Patients in the lowest 25th percentile paid a mean of $17, and patients in the upper 75th percentile paid a mean of $53.
As expected, monthly co-payments increased over time. They averaged $55 in 2002 and $145 in 2011, with 6.4% of patients paying more than $500 a month.
Dr Dusetzina noted that the data only included patients on employer-based insurance plans, and most individuals had low out-of-pocket costs.
“We studied people who are part of large employer groups, so their insurance is probably more generous than someone who is buying insurance on a private market that does not have a lot of negotiating power,” she said.
Costs correlate with adherence
In the first 180 days of treatment, 30% of patients with higher co-payments were non-adherent to imatinib treatment, compared to 21% of patients with lower co-payments. Non-adherence was defined as having less than 80% of days with imatinib available.
Seventeen percent of patients with higher co-payments discontinued taking imatinib, compared to 10% of patients with lower co-payments. Discontinuation was defined as having a gap of more than 60 days after the exhaustion of imatinib therapy.
These data did not include patients who could not begin taking imatinib due to costs. Therefore, Dr Dusetzina said this study likely underestimates the effects of drug costs on treatment adherence.
“If you went to the pharmacy to obtain your prescription, and they said it was $5000, and you walked away because you couldn’t afford to pay, you’re not in the data,” she said. “We could only study individuals who filled at least one prescription.”
Dr Dusetzina also said these findings have implications beyond imatinib and CML. Many new treatments for rare conditions can cost insurers and patients more than $100,000 year.
“Our results are particularly relevant for specialty pharmaceutical products—those that cost over $10,000 a month,” she said.
“However, the lessons learned likely relate to any pharmaceutical product that has high out-of-pocket costs. It is important that we identify strategies to make effective but expensive medications more affordable to patients.”
NICE recommends pixantrone for NHL
Credit: Bill Branson
Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).
In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.
But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.
NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.
The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.
“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”
Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.
Clinical effectiveness
NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.
However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.
The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.
At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).
The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).
Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.
Cost-effectiveness
The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.
The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.
According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.
The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.
Marketing authorization
Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.
The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.
Credit: Bill Branson
Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).
In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.
But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.
NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.
The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.
“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”
Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.
Clinical effectiveness
NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.
However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.
The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.
At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).
The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).
Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.
Cost-effectiveness
The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.
The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.
According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.
The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.
Marketing authorization
Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.
The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.
Credit: Bill Branson
Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).
In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.
But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.
NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.
The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.
“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”
Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.
Clinical effectiveness
NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.
However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.
The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.
At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).
The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).
Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.
Cost-effectiveness
The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.
The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.
According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.
The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.
Marketing authorization
Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.
The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.
FDA approves ibrutinib for previously treated MCL
The US Food and Drug Administration (FDA) has has granted accelerated approval for
ibrutinib (Imbruvica) to treat patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.
Ibrutinib works by inhibiting the function of Bruton’s tyrosine kinase, a molecule that plays an important role in the survival of malignant B cells.
The drug showed promising results in the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August.
The FDA granted ibrutinib breakthrough therapy designation because of these results and the life-threatening nature of MCL. Ibrutinib is the second drug with breakthrough therapy designation to receive FDA approval.
The FDA granted ibrutinib accelerated approval, rather than traditional approval, because the drug has not yet shown a clinical benefit. Accelerated approval of a drug is based
on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to
predict clinical benefit.
PCYC-1104 trial
The data published in NEJM included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.
The
overall response rate was 68%, with a complete response rate of 21% and
a partial response rate of 47%. With an estimated median follow-up of
15.3 months, the estimated median response duration was 17.5 months.
The
estimated progression-free survival was 13.9 months, and the overall
survival was not reached. The estimated rate of overall survival was 58%
at 18 months.
Common nonhematologic adverse events included
diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%),
dyspnea (27%), constipation (25%), upper respiratory tract infection
(23%), vomiting (23%), and decreased appetite (21%). The most common
grade 3, 4, or 5 infection was pneumonia (6%).
Grade 3 and 4
hematologic adverse events included neutropenia (16%), thrombocytopenia
(11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.
The “Warnings and Precautions” section of ibrutinib’s prescribing information notes that patients taking ibrutinib have experienced hemorrhage, fatal and non-fatal infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.
For the full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.
Ibrutinib is now commercially available. It is co-marketed by Pharmacyclics (based in Sunnyvale, California) and Janssen Biotech, Inc. (based in Raritan, New Jersey). 
The US Food and Drug Administration (FDA) has has granted accelerated approval for
ibrutinib (Imbruvica) to treat patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.
Ibrutinib works by inhibiting the function of Bruton’s tyrosine kinase, a molecule that plays an important role in the survival of malignant B cells.
The drug showed promising results in the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August.
The FDA granted ibrutinib breakthrough therapy designation because of these results and the life-threatening nature of MCL. Ibrutinib is the second drug with breakthrough therapy designation to receive FDA approval.
The FDA granted ibrutinib accelerated approval, rather than traditional approval, because the drug has not yet shown a clinical benefit. Accelerated approval of a drug is based
on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to
predict clinical benefit.
PCYC-1104 trial
The data published in NEJM included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.
The
overall response rate was 68%, with a complete response rate of 21% and
a partial response rate of 47%. With an estimated median follow-up of
15.3 months, the estimated median response duration was 17.5 months.
The
estimated progression-free survival was 13.9 months, and the overall
survival was not reached. The estimated rate of overall survival was 58%
at 18 months.
Common nonhematologic adverse events included
diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%),
dyspnea (27%), constipation (25%), upper respiratory tract infection
(23%), vomiting (23%), and decreased appetite (21%). The most common
grade 3, 4, or 5 infection was pneumonia (6%).
Grade 3 and 4
hematologic adverse events included neutropenia (16%), thrombocytopenia
(11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.
The “Warnings and Precautions” section of ibrutinib’s prescribing information notes that patients taking ibrutinib have experienced hemorrhage, fatal and non-fatal infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.
For the full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.
Ibrutinib is now commercially available. It is co-marketed by Pharmacyclics (based in Sunnyvale, California) and Janssen Biotech, Inc. (based in Raritan, New Jersey).
The US Food and Drug Administration (FDA) has has granted accelerated approval for
ibrutinib (Imbruvica) to treat patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.
Ibrutinib works by inhibiting the function of Bruton’s tyrosine kinase, a molecule that plays an important role in the survival of malignant B cells.
The drug showed promising results in the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August.
The FDA granted ibrutinib breakthrough therapy designation because of these results and the life-threatening nature of MCL. Ibrutinib is the second drug with breakthrough therapy designation to receive FDA approval.
The FDA granted ibrutinib accelerated approval, rather than traditional approval, because the drug has not yet shown a clinical benefit. Accelerated approval of a drug is based
on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to
predict clinical benefit.
PCYC-1104 trial
The data published in NEJM included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.
The
overall response rate was 68%, with a complete response rate of 21% and
a partial response rate of 47%. With an estimated median follow-up of
15.3 months, the estimated median response duration was 17.5 months.
The
estimated progression-free survival was 13.9 months, and the overall
survival was not reached. The estimated rate of overall survival was 58%
at 18 months.
Common nonhematologic adverse events included
diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%),
dyspnea (27%), constipation (25%), upper respiratory tract infection
(23%), vomiting (23%), and decreased appetite (21%). The most common
grade 3, 4, or 5 infection was pneumonia (6%).
Grade 3 and 4
hematologic adverse events included neutropenia (16%), thrombocytopenia
(11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.
The “Warnings and Precautions” section of ibrutinib’s prescribing information notes that patients taking ibrutinib have experienced hemorrhage, fatal and non-fatal infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.
For the full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.
Ibrutinib is now commercially available. It is co-marketed by Pharmacyclics (based in Sunnyvale, California) and Janssen Biotech, Inc. (based in Raritan, New Jersey).
Fraud, errors were behind delay of apixaban approval, report shows
Credit: Esther Dyson
Medication mistakes, reporting errors, and record changes are what led the US Food and Drug Administration (FDA) to delay approval of the anticoagulant apixaban (Eliquis), according to a report in Pharmaceutical Approvals Monthly.
The report reveals that a number of patients enrolled on the ARISTOTLE trial received the wrong medication or the wrong dose, some serious adverse events went unreported, and employees who worked at trial sites in China altered records to cover up noncompliance with “good clinical practice.”
Apixaban won FDA approval last December as prophylaxis for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. And that approval was based on results of the ARISTOTLE trial.
Prior to the approval, the FDA twice rejected a new drug application filed by apixaban’s developers, Pfizer and Bristol-Myers Squibb. But the agency’s reasons were not immediately made public.
Now, the Pharmaceutical Approvals Monthly report and FDA documents show that “data irregularities” were behind the decision.
In January 2012, Bristol-Myers Squibb notified the FDA of the cover-up attempt that occurred at (at least) 1 trial site in China. The company had learned that its senior manager at a site in Shanghai and an employee from a contract research organization had altered source records to conceal good clinical practice violations. (The employees were subsequently fired.)
According to FDA documents, the cover-up included failure to report 4 potential adverse events, late reports on 3 other events, and the omission of 3 patient outcomes. In addition, there were errors in patient names and dates, some Chinese and English records didn’t match up, and some patient records disappeared before a site visit by FDA inspectors.
Only 35 patients enrolled in the ARISTOTLE trial were treated at the Shanghai site, but the employees who perpetrated the fraud had also worked at 24 of the 36 trial sites in China.
So the FDA performed analyses excluding data from the Shanghai site alone, from the 24 sites where the employees worked, and from all 36 sites in China. And they found that apixaban’s efficacy still held up.
However, there was still the issue of ARISTOTLE participants receiving the wrong medication or the wrong dose. According to Bristol-Myers Squibb, the trial’s double-blind design allowed for dispensing errors.
Initially, the company said this meant that 7.3% of patients who were set to receive apixaban and 1.2% of patients who were set to receive warfarin may have received the wrong drug or dose at some point during the study. However, after additional review, the company said those percentages were likely much lower.
Regardless of the actual percentages, the FDA said this information suggests a pattern of inadequate oversight. And an independent review by FDA medical team leader Thomas Marciniak appears to support that statement. In addition to the aforementioned errors, his review revealed records of doctor visits taking place after patients’ deaths.
In spite of the errors and the fraud, the FDA said it remained convinced of apixaban’s efficacy. So the agency decided to approve the drug and leave out any mention of the data irregularities on the drug’s label.
Credit: Esther Dyson
Medication mistakes, reporting errors, and record changes are what led the US Food and Drug Administration (FDA) to delay approval of the anticoagulant apixaban (Eliquis), according to a report in Pharmaceutical Approvals Monthly.
The report reveals that a number of patients enrolled on the ARISTOTLE trial received the wrong medication or the wrong dose, some serious adverse events went unreported, and employees who worked at trial sites in China altered records to cover up noncompliance with “good clinical practice.”
Apixaban won FDA approval last December as prophylaxis for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. And that approval was based on results of the ARISTOTLE trial.
Prior to the approval, the FDA twice rejected a new drug application filed by apixaban’s developers, Pfizer and Bristol-Myers Squibb. But the agency’s reasons were not immediately made public.
Now, the Pharmaceutical Approvals Monthly report and FDA documents show that “data irregularities” were behind the decision.
In January 2012, Bristol-Myers Squibb notified the FDA of the cover-up attempt that occurred at (at least) 1 trial site in China. The company had learned that its senior manager at a site in Shanghai and an employee from a contract research organization had altered source records to conceal good clinical practice violations. (The employees were subsequently fired.)
According to FDA documents, the cover-up included failure to report 4 potential adverse events, late reports on 3 other events, and the omission of 3 patient outcomes. In addition, there were errors in patient names and dates, some Chinese and English records didn’t match up, and some patient records disappeared before a site visit by FDA inspectors.
Only 35 patients enrolled in the ARISTOTLE trial were treated at the Shanghai site, but the employees who perpetrated the fraud had also worked at 24 of the 36 trial sites in China.
So the FDA performed analyses excluding data from the Shanghai site alone, from the 24 sites where the employees worked, and from all 36 sites in China. And they found that apixaban’s efficacy still held up.
However, there was still the issue of ARISTOTLE participants receiving the wrong medication or the wrong dose. According to Bristol-Myers Squibb, the trial’s double-blind design allowed for dispensing errors.
Initially, the company said this meant that 7.3% of patients who were set to receive apixaban and 1.2% of patients who were set to receive warfarin may have received the wrong drug or dose at some point during the study. However, after additional review, the company said those percentages were likely much lower.
Regardless of the actual percentages, the FDA said this information suggests a pattern of inadequate oversight. And an independent review by FDA medical team leader Thomas Marciniak appears to support that statement. In addition to the aforementioned errors, his review revealed records of doctor visits taking place after patients’ deaths.
In spite of the errors and the fraud, the FDA said it remained convinced of apixaban’s efficacy. So the agency decided to approve the drug and leave out any mention of the data irregularities on the drug’s label.
Credit: Esther Dyson
Medication mistakes, reporting errors, and record changes are what led the US Food and Drug Administration (FDA) to delay approval of the anticoagulant apixaban (Eliquis), according to a report in Pharmaceutical Approvals Monthly.
The report reveals that a number of patients enrolled on the ARISTOTLE trial received the wrong medication or the wrong dose, some serious adverse events went unreported, and employees who worked at trial sites in China altered records to cover up noncompliance with “good clinical practice.”
Apixaban won FDA approval last December as prophylaxis for stroke and systemic embolism in patients with nonvalvular atrial fibrillation. And that approval was based on results of the ARISTOTLE trial.
Prior to the approval, the FDA twice rejected a new drug application filed by apixaban’s developers, Pfizer and Bristol-Myers Squibb. But the agency’s reasons were not immediately made public.
Now, the Pharmaceutical Approvals Monthly report and FDA documents show that “data irregularities” were behind the decision.
In January 2012, Bristol-Myers Squibb notified the FDA of the cover-up attempt that occurred at (at least) 1 trial site in China. The company had learned that its senior manager at a site in Shanghai and an employee from a contract research organization had altered source records to conceal good clinical practice violations. (The employees were subsequently fired.)
According to FDA documents, the cover-up included failure to report 4 potential adverse events, late reports on 3 other events, and the omission of 3 patient outcomes. In addition, there were errors in patient names and dates, some Chinese and English records didn’t match up, and some patient records disappeared before a site visit by FDA inspectors.
Only 35 patients enrolled in the ARISTOTLE trial were treated at the Shanghai site, but the employees who perpetrated the fraud had also worked at 24 of the 36 trial sites in China.
So the FDA performed analyses excluding data from the Shanghai site alone, from the 24 sites where the employees worked, and from all 36 sites in China. And they found that apixaban’s efficacy still held up.
However, there was still the issue of ARISTOTLE participants receiving the wrong medication or the wrong dose. According to Bristol-Myers Squibb, the trial’s double-blind design allowed for dispensing errors.
Initially, the company said this meant that 7.3% of patients who were set to receive apixaban and 1.2% of patients who were set to receive warfarin may have received the wrong drug or dose at some point during the study. However, after additional review, the company said those percentages were likely much lower.
Regardless of the actual percentages, the FDA said this information suggests a pattern of inadequate oversight. And an independent review by FDA medical team leader Thomas Marciniak appears to support that statement. In addition to the aforementioned errors, his review revealed records of doctor visits taking place after patients’ deaths.
In spite of the errors and the fraud, the FDA said it remained convinced of apixaban’s efficacy. So the agency decided to approve the drug and leave out any mention of the data irregularities on the drug’s label.