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SILVER SPRING, MD. – A Food and Drug Administration advisory panel, citing numerous problems with cangrelor’s clinical trial program, has recommended against approval of the short-acting intravenous antiplatelet drug.
In a 7-2 vote, the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval of cangrelor for the proposed indication, "the reduction of death, MI, stent thrombosis, and ischemic-driven revascularization (IDR) in patients who have not been recently treated with a thienopyridine and who are undergoing PCI." The panel unanimously voted against approval for a second indication for cangrelor, for patients with stents who are at an increased risk for thrombotic events, such as stent thrombosis, when oral P2Y12 therapy is interrupted for surgery.
Cangrelor is a platelet P2Y12 inhibitor administered intravenously; with a half-life of 3-6 minutes, platelet function returns to normal within 1 hour of stopping the infusion of cangrelor, according to the manufacturer, the Medicines Company. The oral P2Y12 inhibitor clopidogrel has a more delayed action, with activity that lasts for days after is stopped.
The PCI indication is based on the results of the multinational CHAMPION PHOENIX study that compared cangrelor to clopidogrel in more than 11,000 patients undergoing PCI. The primary endpoint – a composite of death, MI, IDR, and stent thrombosis (ST) within 48 hours post-PCI – was 4.7% among those in the cangrelor arm, compared with 5.9 % in the clopidogrel arm, a significant difference that represented a 22% reduced risk (N. Engl. J. Med. 2013;368:1303-13). A 300-mg or 600-mg dose of clopidogrel was administered at the start of PCI or after PCI.
There was an increase in bleeding events overall among those on cangrelor (15.6% vs. 11%), but there were no significant differences in GUSTO severe or moderate bleeding events, no significant increase in TIMI major bleeding, and no significant differences in transfusions or fatal bleeding events between the two treatment arms.
The PHOENIX study was conducted after two large studies of patients with stable angina, unstable angina/non–ST-segment elevation MI, CHAMPION PCI (a study comparing cangrelor to clopidogrel during PCI in 8,667 patients) and CHAMPION PLATFORM (a study of 5,301 patients comparing cangrelor to placebo during PCI), were negative and were terminated early. The endpoint for those studies was a composite of death, MI, and IDR at 48 hours. Based on analyses of these studies, the primary endpoint was modified to include ST and an MI component that was based on the Universal Definition of MI. So, the biggest difference between the success of PHOENIX and the failure of the earlier PCI and PLATFORM studies was that the researchers used a different approach to define and track the MIs that patients developed during the studies and that served as primary end points.
Several panelists said they could not ignore the two negative studies and questioned whether PHOENIX could be considered the pivotal trial.
"In the background of two failed trials, and with all of the issues in almost every aspect of this trial, starting from design, oversight, DSMB [Data and Safety Management Board], how they counted efficacy, how they counted safety, it just left me with more uncertainty that I couldn’t defend the risk-benefit" profile, Dr. Stuart Rich, professor of medicine at University of Chicago.
Also voting no, Dr. James DeLemos, professor of medicine at the University of Texas Southwestern Medical Center at Dallas,said that the drug’s features were "intuitively appealing," and acknowledged the challenges in studying a drug that is administered for a short period of time, in a situation with low clinical endpoints. "But when I look at the data in aggregate," including the previous two studies, he added, "I’m just unconvinced that the risk-benefit is clearly favorable for clinically relevant endpoints ... [and] I am bothered that the math does not add up to a clear risk-benefit [profile] for this potent therapy in this situation."
One of the two panelists voting in favor of approval, the panel chair, Dr. Philip Sager, chair of the scientific programs committee at the cardiac safety research consortium, San Francisco, said while he agreed there were issues with the clinical trial, the endpoint was clinically significant, and the different analyses of the data "reassured me that the trial really did show a reduction in the primary endpoint" and that there was a net benefit.
The FDA review produced mixed opinions on whether the drug should be approved for the PCI indication. In briefing documents, filed before the meeting, the two clinical reviewers wrote that they were in favor of approval for the PCI indication. But Dr. Thomas A. Marciniak, clinical team leader in the FDA’s division of cardiovascular and renal products, recommended against approval for the PCI indication, citing multiple flaws in the CHAMPION PHOENIX study design, including the imbalance of clopidogrel dosing and what he considered were the inappropriate delays in clopidogrel administration, in the CHAMPION studies, including PHOENIX.
The reviewers did not support approval for the bridge-to-surgery indication because of the lack of clinical data from the pharmacodynamic trial – the BRIDGE study – which compared cangrelor with placebo in 210 patients with ACS or who were treated with a coronary stent and were at increased risk of thrombotic events after discontinuing an oral platelet inhibitor before coronary artery bypass graft surgery. Levels of platelet inhibition associated with a low risk of thrombotic events such as stent thrombosis were maintained in 99% of those treated with cangrelor, vs. 19% of those on placebo, a statistically significant difference (JAMA 2012;307:265-74).
While panelists said the drug could be effective for this indication, they said that a clinical study was needed to determine the drug’s risk-benefit profile in this setting and that the degree of unmet need for this use was not clear.
In a statement issued by the Medicines Company after the panel meeting, Dr. Clive A. Meanwell, the chairman and chief executive officer, said "we continue to believe in the safety and efficacy of cangrelor and look forward to working with the Agency as it completes its review." The deadline for the FDA decision is April 30.
Cangrelor has not been approved in any country to date.
The FDA usually follows the recommendations of its advisory panels. Advisory panel members have been cleared of potential conflicts related to the meeting topic. Occasionally, a panelist is given a waiver, but no waivers were given at this meeting.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel, citing numerous problems with cangrelor’s clinical trial program, has recommended against approval of the short-acting intravenous antiplatelet drug.
In a 7-2 vote, the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval of cangrelor for the proposed indication, "the reduction of death, MI, stent thrombosis, and ischemic-driven revascularization (IDR) in patients who have not been recently treated with a thienopyridine and who are undergoing PCI." The panel unanimously voted against approval for a second indication for cangrelor, for patients with stents who are at an increased risk for thrombotic events, such as stent thrombosis, when oral P2Y12 therapy is interrupted for surgery.
Cangrelor is a platelet P2Y12 inhibitor administered intravenously; with a half-life of 3-6 minutes, platelet function returns to normal within 1 hour of stopping the infusion of cangrelor, according to the manufacturer, the Medicines Company. The oral P2Y12 inhibitor clopidogrel has a more delayed action, with activity that lasts for days after is stopped.
The PCI indication is based on the results of the multinational CHAMPION PHOENIX study that compared cangrelor to clopidogrel in more than 11,000 patients undergoing PCI. The primary endpoint – a composite of death, MI, IDR, and stent thrombosis (ST) within 48 hours post-PCI – was 4.7% among those in the cangrelor arm, compared with 5.9 % in the clopidogrel arm, a significant difference that represented a 22% reduced risk (N. Engl. J. Med. 2013;368:1303-13). A 300-mg or 600-mg dose of clopidogrel was administered at the start of PCI or after PCI.
There was an increase in bleeding events overall among those on cangrelor (15.6% vs. 11%), but there were no significant differences in GUSTO severe or moderate bleeding events, no significant increase in TIMI major bleeding, and no significant differences in transfusions or fatal bleeding events between the two treatment arms.
The PHOENIX study was conducted after two large studies of patients with stable angina, unstable angina/non–ST-segment elevation MI, CHAMPION PCI (a study comparing cangrelor to clopidogrel during PCI in 8,667 patients) and CHAMPION PLATFORM (a study of 5,301 patients comparing cangrelor to placebo during PCI), were negative and were terminated early. The endpoint for those studies was a composite of death, MI, and IDR at 48 hours. Based on analyses of these studies, the primary endpoint was modified to include ST and an MI component that was based on the Universal Definition of MI. So, the biggest difference between the success of PHOENIX and the failure of the earlier PCI and PLATFORM studies was that the researchers used a different approach to define and track the MIs that patients developed during the studies and that served as primary end points.
Several panelists said they could not ignore the two negative studies and questioned whether PHOENIX could be considered the pivotal trial.
"In the background of two failed trials, and with all of the issues in almost every aspect of this trial, starting from design, oversight, DSMB [Data and Safety Management Board], how they counted efficacy, how they counted safety, it just left me with more uncertainty that I couldn’t defend the risk-benefit" profile, Dr. Stuart Rich, professor of medicine at University of Chicago.
Also voting no, Dr. James DeLemos, professor of medicine at the University of Texas Southwestern Medical Center at Dallas,said that the drug’s features were "intuitively appealing," and acknowledged the challenges in studying a drug that is administered for a short period of time, in a situation with low clinical endpoints. "But when I look at the data in aggregate," including the previous two studies, he added, "I’m just unconvinced that the risk-benefit is clearly favorable for clinically relevant endpoints ... [and] I am bothered that the math does not add up to a clear risk-benefit [profile] for this potent therapy in this situation."
One of the two panelists voting in favor of approval, the panel chair, Dr. Philip Sager, chair of the scientific programs committee at the cardiac safety research consortium, San Francisco, said while he agreed there were issues with the clinical trial, the endpoint was clinically significant, and the different analyses of the data "reassured me that the trial really did show a reduction in the primary endpoint" and that there was a net benefit.
The FDA review produced mixed opinions on whether the drug should be approved for the PCI indication. In briefing documents, filed before the meeting, the two clinical reviewers wrote that they were in favor of approval for the PCI indication. But Dr. Thomas A. Marciniak, clinical team leader in the FDA’s division of cardiovascular and renal products, recommended against approval for the PCI indication, citing multiple flaws in the CHAMPION PHOENIX study design, including the imbalance of clopidogrel dosing and what he considered were the inappropriate delays in clopidogrel administration, in the CHAMPION studies, including PHOENIX.
The reviewers did not support approval for the bridge-to-surgery indication because of the lack of clinical data from the pharmacodynamic trial – the BRIDGE study – which compared cangrelor with placebo in 210 patients with ACS or who were treated with a coronary stent and were at increased risk of thrombotic events after discontinuing an oral platelet inhibitor before coronary artery bypass graft surgery. Levels of platelet inhibition associated with a low risk of thrombotic events such as stent thrombosis were maintained in 99% of those treated with cangrelor, vs. 19% of those on placebo, a statistically significant difference (JAMA 2012;307:265-74).
While panelists said the drug could be effective for this indication, they said that a clinical study was needed to determine the drug’s risk-benefit profile in this setting and that the degree of unmet need for this use was not clear.
In a statement issued by the Medicines Company after the panel meeting, Dr. Clive A. Meanwell, the chairman and chief executive officer, said "we continue to believe in the safety and efficacy of cangrelor and look forward to working with the Agency as it completes its review." The deadline for the FDA decision is April 30.
Cangrelor has not been approved in any country to date.
The FDA usually follows the recommendations of its advisory panels. Advisory panel members have been cleared of potential conflicts related to the meeting topic. Occasionally, a panelist is given a waiver, but no waivers were given at this meeting.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel, citing numerous problems with cangrelor’s clinical trial program, has recommended against approval of the short-acting intravenous antiplatelet drug.
In a 7-2 vote, the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against approval of cangrelor for the proposed indication, "the reduction of death, MI, stent thrombosis, and ischemic-driven revascularization (IDR) in patients who have not been recently treated with a thienopyridine and who are undergoing PCI." The panel unanimously voted against approval for a second indication for cangrelor, for patients with stents who are at an increased risk for thrombotic events, such as stent thrombosis, when oral P2Y12 therapy is interrupted for surgery.
Cangrelor is a platelet P2Y12 inhibitor administered intravenously; with a half-life of 3-6 minutes, platelet function returns to normal within 1 hour of stopping the infusion of cangrelor, according to the manufacturer, the Medicines Company. The oral P2Y12 inhibitor clopidogrel has a more delayed action, with activity that lasts for days after is stopped.
The PCI indication is based on the results of the multinational CHAMPION PHOENIX study that compared cangrelor to clopidogrel in more than 11,000 patients undergoing PCI. The primary endpoint – a composite of death, MI, IDR, and stent thrombosis (ST) within 48 hours post-PCI – was 4.7% among those in the cangrelor arm, compared with 5.9 % in the clopidogrel arm, a significant difference that represented a 22% reduced risk (N. Engl. J. Med. 2013;368:1303-13). A 300-mg or 600-mg dose of clopidogrel was administered at the start of PCI or after PCI.
There was an increase in bleeding events overall among those on cangrelor (15.6% vs. 11%), but there were no significant differences in GUSTO severe or moderate bleeding events, no significant increase in TIMI major bleeding, and no significant differences in transfusions or fatal bleeding events between the two treatment arms.
The PHOENIX study was conducted after two large studies of patients with stable angina, unstable angina/non–ST-segment elevation MI, CHAMPION PCI (a study comparing cangrelor to clopidogrel during PCI in 8,667 patients) and CHAMPION PLATFORM (a study of 5,301 patients comparing cangrelor to placebo during PCI), were negative and were terminated early. The endpoint for those studies was a composite of death, MI, and IDR at 48 hours. Based on analyses of these studies, the primary endpoint was modified to include ST and an MI component that was based on the Universal Definition of MI. So, the biggest difference between the success of PHOENIX and the failure of the earlier PCI and PLATFORM studies was that the researchers used a different approach to define and track the MIs that patients developed during the studies and that served as primary end points.
Several panelists said they could not ignore the two negative studies and questioned whether PHOENIX could be considered the pivotal trial.
"In the background of two failed trials, and with all of the issues in almost every aspect of this trial, starting from design, oversight, DSMB [Data and Safety Management Board], how they counted efficacy, how they counted safety, it just left me with more uncertainty that I couldn’t defend the risk-benefit" profile, Dr. Stuart Rich, professor of medicine at University of Chicago.
Also voting no, Dr. James DeLemos, professor of medicine at the University of Texas Southwestern Medical Center at Dallas,said that the drug’s features were "intuitively appealing," and acknowledged the challenges in studying a drug that is administered for a short period of time, in a situation with low clinical endpoints. "But when I look at the data in aggregate," including the previous two studies, he added, "I’m just unconvinced that the risk-benefit is clearly favorable for clinically relevant endpoints ... [and] I am bothered that the math does not add up to a clear risk-benefit [profile] for this potent therapy in this situation."
One of the two panelists voting in favor of approval, the panel chair, Dr. Philip Sager, chair of the scientific programs committee at the cardiac safety research consortium, San Francisco, said while he agreed there were issues with the clinical trial, the endpoint was clinically significant, and the different analyses of the data "reassured me that the trial really did show a reduction in the primary endpoint" and that there was a net benefit.
The FDA review produced mixed opinions on whether the drug should be approved for the PCI indication. In briefing documents, filed before the meeting, the two clinical reviewers wrote that they were in favor of approval for the PCI indication. But Dr. Thomas A. Marciniak, clinical team leader in the FDA’s division of cardiovascular and renal products, recommended against approval for the PCI indication, citing multiple flaws in the CHAMPION PHOENIX study design, including the imbalance of clopidogrel dosing and what he considered were the inappropriate delays in clopidogrel administration, in the CHAMPION studies, including PHOENIX.
The reviewers did not support approval for the bridge-to-surgery indication because of the lack of clinical data from the pharmacodynamic trial – the BRIDGE study – which compared cangrelor with placebo in 210 patients with ACS or who were treated with a coronary stent and were at increased risk of thrombotic events after discontinuing an oral platelet inhibitor before coronary artery bypass graft surgery. Levels of platelet inhibition associated with a low risk of thrombotic events such as stent thrombosis were maintained in 99% of those treated with cangrelor, vs. 19% of those on placebo, a statistically significant difference (JAMA 2012;307:265-74).
While panelists said the drug could be effective for this indication, they said that a clinical study was needed to determine the drug’s risk-benefit profile in this setting and that the degree of unmet need for this use was not clear.
In a statement issued by the Medicines Company after the panel meeting, Dr. Clive A. Meanwell, the chairman and chief executive officer, said "we continue to believe in the safety and efficacy of cangrelor and look forward to working with the Agency as it completes its review." The deadline for the FDA decision is April 30.
Cangrelor has not been approved in any country to date.
The FDA usually follows the recommendations of its advisory panels. Advisory panel members have been cleared of potential conflicts related to the meeting topic. Occasionally, a panelist is given a waiver, but no waivers were given at this meeting.
AT AN FDA ADVISORY COMMITTEE MEETING
