Rivaroxaban's ACS Claim Faces Data Quality Hurdle

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee will be asked at a May 23 meeting whether the advantage seen with Johnson & Johnson/Bayer HealthCare AG’s Xarelto (rivaroxaban) in acute coronary syndromes is undermined by the extent of missing data in the pivotal trial.

In background briefing materials released May 21, the FDA said the pivotal ATLAS ACS 2-TIMI 51 trial had substantial missing data, including lack of vital status, because of the withdrawal of consent. In its draft questions for discussion, the FDA’s Division of Cardiovascular and Renal Drug Products seeks the committee’s views on how the missing data affected interpretation of the ATLAS efficacy results. In that study, rivaroxaban was associated with a statistically significant reduction in the risk of the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, though with significantly increased bleeding.

The review division appears interested in using rivaroxaban as the platform for a broader discussion on issues surrounding missing data in cardiovascular studies. According to the draft questions, the committee will be asked whether the agency should prespecify trial standards for data quality in the same way it prespecifies standards for demonstrating statistical significance.

The committee will be asked to vote on whether rivaroxaban should be approved in ACS and, if so, how it should be labeled.

Finally, the division plans to ask committee members the unusual question of whether, if the ACS claim is approved, they will use rivaroxaban for such patients in clinical practice.

Three Indications, Three Advisory Committees

Johnson & Johnson’s Janssen Pharmaceuticals division is seeking approval of the Factor Xa inhibitor to reduce the risk of thrombotic CV events in patients with acute ACS – defined as ST elevation myocardial infarction (STEMI), non-STEMI, or unstable angina – in combination with aspirin alone or aspirin plus clopidogrel or ticlopidine. The proposed dose is 2.5 mg twice daily.

The supplemental new drug application is undergoing a priority review, with a June 29 Prescription Drug User Fee Act (PDUFA) date. If approved, the ACS indication would be the third for rivaroxaban. The drug gained its initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery. In November, it added a claim for stroke risk reduction in patients with atrial fibrillation.

The ACS claim marks the third advisory committee meeting for rivaroxaban; the cardiorenal panel previously recommended approval for the deep vein thrombosis prophylaxis and atrial fibrillation indications.

ACS Claim Rests on the Shoulders of ATLAS

The proposed indication is based on the phase III, 15,526-patient ATLAS trial, the results of which were published in the New England Journal of Medicine in November (2011;366:9-19 [doi:10.1056/NEJMoa1112277]).

The trial randomized ACS patients to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo; patients were stratified based upon whether they received concomitant aspirin alone (stratum 1) or aspirin with a thienopyridine (stratum 2). In her April 30 clinical review, medical officer Karen Hicks said stratum 2 was the most clinically relevant stratum for U.S. ACS patients.

Dr. Hicks said she recommended approval of rivaroxaban in ACS, finding efficacy to have been demonstrated under numerous different analyses.

"In all strata, including subjects treated with aspirin (stratum 1) and subjects treated with aspirin plus a thienopyridine (stratum 2), on-treatment plus 30 days (sponsor’s modified intent to treat) and intent to treat analyses ... demonstrated that rivaroxaban (combined, 2.5 mg twice daily, and 5 mg twice daily) significantly reduced the occurrence of the composite primary end point of cardiovascular death, myocardial infarction or stroke, compared with placebo, in ACS subjects stabilized 1-7 days post index event," Dr. Hicks said. "Numerous sensitivity analyses confirmed these results."

These efficacy results were statistically significant, regardless of whether data from three Indian clinical trial sites were included or excluded. The sponsors proposed to exclude the sites because of Good Clinical Practice violations.

Risk reductions for the 2.5-mg dose ranged from 16%-18% across all strata and 15%-18% in stratum 2.

The findings in all strata and stratum 2 were driven primarily by a reduction in CV deaths, particularly on the 2.5 mg dose, and to a lesser extent by a reduction in MI, Dr. Hicks said. "Compared to 2.5 mg BID [twice daily], rivaroxaban 5 mg BID increased the risk of all bleeding events without providing additional efficacy. Further, rivaroxaban 5 mg BID improved MI but not CV death, which was somewhat unexpected."

The 2.5-mg dose was associated with an all-cause mortality benefit that was nominally statistically significant. However, the 5-mg dose demonstrated no mortality advantage, and the two doses combined did not produce a statistically robust benefit. "Given the inconsistent results between rivaroxaban 2.5 mg BID and rivaroxaban 5 mg BID with respect to CV death and all-cause mortality, I do not recommend a mortality claim," Dr. Hicks said.

Significant Increases in Bleeding

On the safety side, rivaroxaban significantly increased the risk of all bleeding events, compared with placebo.

Across all strata, the 2.5-mg dose significantly increased the risk of the following TIMI classifications of bleeding: major, major or minor, life-threatening, intracranial hemorrhage, minor, clinically significant, and warranting medical attention. In stratum 2, the 2.5-mg dose significantly increased all TIMI major or minor bleeding, major bleeding, life-threatening bleeding, clinically significant bleeding, and medical attention bleeding. The 2.5-mg dose did not significantly increase the risk of TIMI major fatal bleeding or fatal intracranial hemorrhage.

In stratum 2, the 2.5-mg dose reduced the rate of the primary end point by 15% while increasing the rate of bleeding not related to coronary artery bypass graft surgery, Dr. Hicks said. "There was a twofold increase in TIMI major fatal bleeding and threefold increases in TIMI major bleeding, intracranial hemorrhage, hemorrhagic stroke, TIMI life-threatening bleeding, and TIMI major or minor bleeding. There was also an 18% increase in the risk of fatal stroke. Although the hazard ratios were increased, the absolute incidence of these events was low."

Subjects aged 75 years and older, and individuals weighing less than 60 kg, had an increased risk of bleeding events.

ACS subjects appeared to have a more pronounced tendency for liver injury than did populations studied in the atrial fibrillation and deep vein thrombosis prophylaxis studies. "Therefore, rivaroxaban, even in lower doses than what is recommended for other uses, appears possibly to cause mild liver injury in some patients. This finding likely reflects some increased susceptibility to drug-induced liver injury in patients with ACS," Dr. Hicks said.

Data Quality as a Counterargument to Approval

Dr. Hicks said that in arriving at her approval recommendation, she considered the argument that the amount of missing data from the ATLAS study weighed against approval.

Across all strata, 2,402 subjects (15.5%) discontinued the study prematurely, including 1,294 subjects (8%) who withdrew consent. "There were [more than] 1,000 subjects at the end of the trial with unknown vital status," Dr. Hicks said. Additionally, there were incomplete follow-up and uncounted deaths. "The quantity of missing data in ATLAS could affect the overall interpretability of the trial."

Nevertheless, Dr. Hicks suggested she was satisfied with the sponsors’ attempt to obtain vital status information on missing subjects and its responses to the FDA’s information requests on the issue. She also pointed to the broader problem of missing data in the setting of CV outcomes studies.

Shades of Ticagrelor

However, Dr. Thomas Marciniak, the review division’s medical team leader on the rivaroxaban application, takes a tougher stand on the issue of missing data and its ramifications for approval. In an April 26 memo, Dr. Marciniak suggests that the data quality may not support the favorable statistical results reported with the 2.5-mg dose.

The percentage of patients with incomplete follow-up in the study was high, averaging about 12%, he noted. "This percentage is far higher than the differences between the placebo and rivaroxaban arms in end point rates, which typically are about 1%-1.5%. The difference between placebo and rivaroxaban for bad follow-up rates matches these differences in end point rates. By [Johnson & Johnson’s] patient status statistics, there appears to be plenty of opportunity for incomplete data to obscure or magnify any differences in end points."

Furthermore, the rates of patients with unknown vital status exceed the reported differences in mortality rates, Dr. Marciniak said, asserting, "We cannot have confidence that the claimed mortality benefits are real."

He also challenged the sponsors’ approach to censoring patients and their classification of deaths that occurred after withdrawal of consent, saying this may have led to an overstatement of rivaroxaban’s efficacy.

"Because of the extent of missing follow-up in ATLAS, we cannot have confidence in either the calculated mortality or CV endpoint benefits," he said.

Marciniak’s criticisms about ATLAS are reminiscent of his attacks on the pivotal efficacy study for AstraZeneca PLC’s ticagrelor (Brilinta). During a July 2010 advisory committee review of the antiplatelet agent, Dr. Marciniak criticized the sponsor for inadequate end point and vital status follow-up in the 18,624-patient PLATO trial.

Dr. Marciniak’s criticisms were even more strenuous in his written reviews, in which he cited inadequate data collection and analyses, poor follow-up, faulty adverse event reporting, failure to adjudicate potential end points, an inappropriate primary end point, and censoring problems. The review division approved ticagrelor in July 2011 despite Dr. Marciniak’s recommendation against approval.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee will be asked at a May 23 meeting whether the advantage seen with Johnson & Johnson/Bayer HealthCare AG’s Xarelto (rivaroxaban) in acute coronary syndromes is undermined by the extent of missing data in the pivotal trial.

In background briefing materials released May 21, the FDA said the pivotal ATLAS ACS 2-TIMI 51 trial had substantial missing data, including lack of vital status, because of the withdrawal of consent. In its draft questions for discussion, the FDA’s Division of Cardiovascular and Renal Drug Products seeks the committee’s views on how the missing data affected interpretation of the ATLAS efficacy results. In that study, rivaroxaban was associated with a statistically significant reduction in the risk of the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, though with significantly increased bleeding.

The review division appears interested in using rivaroxaban as the platform for a broader discussion on issues surrounding missing data in cardiovascular studies. According to the draft questions, the committee will be asked whether the agency should prespecify trial standards for data quality in the same way it prespecifies standards for demonstrating statistical significance.

The committee will be asked to vote on whether rivaroxaban should be approved in ACS and, if so, how it should be labeled.

Finally, the division plans to ask committee members the unusual question of whether, if the ACS claim is approved, they will use rivaroxaban for such patients in clinical practice.

Three Indications, Three Advisory Committees

Johnson & Johnson’s Janssen Pharmaceuticals division is seeking approval of the Factor Xa inhibitor to reduce the risk of thrombotic CV events in patients with acute ACS – defined as ST elevation myocardial infarction (STEMI), non-STEMI, or unstable angina – in combination with aspirin alone or aspirin plus clopidogrel or ticlopidine. The proposed dose is 2.5 mg twice daily.

The supplemental new drug application is undergoing a priority review, with a June 29 Prescription Drug User Fee Act (PDUFA) date. If approved, the ACS indication would be the third for rivaroxaban. The drug gained its initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery. In November, it added a claim for stroke risk reduction in patients with atrial fibrillation.

The ACS claim marks the third advisory committee meeting for rivaroxaban; the cardiorenal panel previously recommended approval for the deep vein thrombosis prophylaxis and atrial fibrillation indications.

ACS Claim Rests on the Shoulders of ATLAS

The proposed indication is based on the phase III, 15,526-patient ATLAS trial, the results of which were published in the New England Journal of Medicine in November (2011;366:9-19 [doi:10.1056/NEJMoa1112277]).

The trial randomized ACS patients to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo; patients were stratified based upon whether they received concomitant aspirin alone (stratum 1) or aspirin with a thienopyridine (stratum 2). In her April 30 clinical review, medical officer Karen Hicks said stratum 2 was the most clinically relevant stratum for U.S. ACS patients.

Dr. Hicks said she recommended approval of rivaroxaban in ACS, finding efficacy to have been demonstrated under numerous different analyses.

"In all strata, including subjects treated with aspirin (stratum 1) and subjects treated with aspirin plus a thienopyridine (stratum 2), on-treatment plus 30 days (sponsor’s modified intent to treat) and intent to treat analyses ... demonstrated that rivaroxaban (combined, 2.5 mg twice daily, and 5 mg twice daily) significantly reduced the occurrence of the composite primary end point of cardiovascular death, myocardial infarction or stroke, compared with placebo, in ACS subjects stabilized 1-7 days post index event," Dr. Hicks said. "Numerous sensitivity analyses confirmed these results."

These efficacy results were statistically significant, regardless of whether data from three Indian clinical trial sites were included or excluded. The sponsors proposed to exclude the sites because of Good Clinical Practice violations.

Risk reductions for the 2.5-mg dose ranged from 16%-18% across all strata and 15%-18% in stratum 2.

The findings in all strata and stratum 2 were driven primarily by a reduction in CV deaths, particularly on the 2.5 mg dose, and to a lesser extent by a reduction in MI, Dr. Hicks said. "Compared to 2.5 mg BID [twice daily], rivaroxaban 5 mg BID increased the risk of all bleeding events without providing additional efficacy. Further, rivaroxaban 5 mg BID improved MI but not CV death, which was somewhat unexpected."

The 2.5-mg dose was associated with an all-cause mortality benefit that was nominally statistically significant. However, the 5-mg dose demonstrated no mortality advantage, and the two doses combined did not produce a statistically robust benefit. "Given the inconsistent results between rivaroxaban 2.5 mg BID and rivaroxaban 5 mg BID with respect to CV death and all-cause mortality, I do not recommend a mortality claim," Dr. Hicks said.

Significant Increases in Bleeding

On the safety side, rivaroxaban significantly increased the risk of all bleeding events, compared with placebo.

Across all strata, the 2.5-mg dose significantly increased the risk of the following TIMI classifications of bleeding: major, major or minor, life-threatening, intracranial hemorrhage, minor, clinically significant, and warranting medical attention. In stratum 2, the 2.5-mg dose significantly increased all TIMI major or minor bleeding, major bleeding, life-threatening bleeding, clinically significant bleeding, and medical attention bleeding. The 2.5-mg dose did not significantly increase the risk of TIMI major fatal bleeding or fatal intracranial hemorrhage.

In stratum 2, the 2.5-mg dose reduced the rate of the primary end point by 15% while increasing the rate of bleeding not related to coronary artery bypass graft surgery, Dr. Hicks said. "There was a twofold increase in TIMI major fatal bleeding and threefold increases in TIMI major bleeding, intracranial hemorrhage, hemorrhagic stroke, TIMI life-threatening bleeding, and TIMI major or minor bleeding. There was also an 18% increase in the risk of fatal stroke. Although the hazard ratios were increased, the absolute incidence of these events was low."

Subjects aged 75 years and older, and individuals weighing less than 60 kg, had an increased risk of bleeding events.

ACS subjects appeared to have a more pronounced tendency for liver injury than did populations studied in the atrial fibrillation and deep vein thrombosis prophylaxis studies. "Therefore, rivaroxaban, even in lower doses than what is recommended for other uses, appears possibly to cause mild liver injury in some patients. This finding likely reflects some increased susceptibility to drug-induced liver injury in patients with ACS," Dr. Hicks said.

Data Quality as a Counterargument to Approval

Dr. Hicks said that in arriving at her approval recommendation, she considered the argument that the amount of missing data from the ATLAS study weighed against approval.

Across all strata, 2,402 subjects (15.5%) discontinued the study prematurely, including 1,294 subjects (8%) who withdrew consent. "There were [more than] 1,000 subjects at the end of the trial with unknown vital status," Dr. Hicks said. Additionally, there were incomplete follow-up and uncounted deaths. "The quantity of missing data in ATLAS could affect the overall interpretability of the trial."

Nevertheless, Dr. Hicks suggested she was satisfied with the sponsors’ attempt to obtain vital status information on missing subjects and its responses to the FDA’s information requests on the issue. She also pointed to the broader problem of missing data in the setting of CV outcomes studies.

Shades of Ticagrelor

However, Dr. Thomas Marciniak, the review division’s medical team leader on the rivaroxaban application, takes a tougher stand on the issue of missing data and its ramifications for approval. In an April 26 memo, Dr. Marciniak suggests that the data quality may not support the favorable statistical results reported with the 2.5-mg dose.

The percentage of patients with incomplete follow-up in the study was high, averaging about 12%, he noted. "This percentage is far higher than the differences between the placebo and rivaroxaban arms in end point rates, which typically are about 1%-1.5%. The difference between placebo and rivaroxaban for bad follow-up rates matches these differences in end point rates. By [Johnson & Johnson’s] patient status statistics, there appears to be plenty of opportunity for incomplete data to obscure or magnify any differences in end points."

Furthermore, the rates of patients with unknown vital status exceed the reported differences in mortality rates, Dr. Marciniak said, asserting, "We cannot have confidence that the claimed mortality benefits are real."

He also challenged the sponsors’ approach to censoring patients and their classification of deaths that occurred after withdrawal of consent, saying this may have led to an overstatement of rivaroxaban’s efficacy.

"Because of the extent of missing follow-up in ATLAS, we cannot have confidence in either the calculated mortality or CV endpoint benefits," he said.

Marciniak’s criticisms about ATLAS are reminiscent of his attacks on the pivotal efficacy study for AstraZeneca PLC’s ticagrelor (Brilinta). During a July 2010 advisory committee review of the antiplatelet agent, Dr. Marciniak criticized the sponsor for inadequate end point and vital status follow-up in the 18,624-patient PLATO trial.

Dr. Marciniak’s criticisms were even more strenuous in his written reviews, in which he cited inadequate data collection and analyses, poor follow-up, faulty adverse event reporting, failure to adjudicate potential end points, an inappropriate primary end point, and censoring problems. The review division approved ticagrelor in July 2011 despite Dr. Marciniak’s recommendation against approval.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee will be asked at a May 23 meeting whether the advantage seen with Johnson & Johnson/Bayer HealthCare AG’s Xarelto (rivaroxaban) in acute coronary syndromes is undermined by the extent of missing data in the pivotal trial.

In background briefing materials released May 21, the FDA said the pivotal ATLAS ACS 2-TIMI 51 trial had substantial missing data, including lack of vital status, because of the withdrawal of consent. In its draft questions for discussion, the FDA’s Division of Cardiovascular and Renal Drug Products seeks the committee’s views on how the missing data affected interpretation of the ATLAS efficacy results. In that study, rivaroxaban was associated with a statistically significant reduction in the risk of the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, though with significantly increased bleeding.

The review division appears interested in using rivaroxaban as the platform for a broader discussion on issues surrounding missing data in cardiovascular studies. According to the draft questions, the committee will be asked whether the agency should prespecify trial standards for data quality in the same way it prespecifies standards for demonstrating statistical significance.

The committee will be asked to vote on whether rivaroxaban should be approved in ACS and, if so, how it should be labeled.

Finally, the division plans to ask committee members the unusual question of whether, if the ACS claim is approved, they will use rivaroxaban for such patients in clinical practice.

Three Indications, Three Advisory Committees

Johnson & Johnson’s Janssen Pharmaceuticals division is seeking approval of the Factor Xa inhibitor to reduce the risk of thrombotic CV events in patients with acute ACS – defined as ST elevation myocardial infarction (STEMI), non-STEMI, or unstable angina – in combination with aspirin alone or aspirin plus clopidogrel or ticlopidine. The proposed dose is 2.5 mg twice daily.

The supplemental new drug application is undergoing a priority review, with a June 29 Prescription Drug User Fee Act (PDUFA) date. If approved, the ACS indication would be the third for rivaroxaban. The drug gained its initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery. In November, it added a claim for stroke risk reduction in patients with atrial fibrillation.

The ACS claim marks the third advisory committee meeting for rivaroxaban; the cardiorenal panel previously recommended approval for the deep vein thrombosis prophylaxis and atrial fibrillation indications.

ACS Claim Rests on the Shoulders of ATLAS

The proposed indication is based on the phase III, 15,526-patient ATLAS trial, the results of which were published in the New England Journal of Medicine in November (2011;366:9-19 [doi:10.1056/NEJMoa1112277]).

The trial randomized ACS patients to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo; patients were stratified based upon whether they received concomitant aspirin alone (stratum 1) or aspirin with a thienopyridine (stratum 2). In her April 30 clinical review, medical officer Karen Hicks said stratum 2 was the most clinically relevant stratum for U.S. ACS patients.

Dr. Hicks said she recommended approval of rivaroxaban in ACS, finding efficacy to have been demonstrated under numerous different analyses.

"In all strata, including subjects treated with aspirin (stratum 1) and subjects treated with aspirin plus a thienopyridine (stratum 2), on-treatment plus 30 days (sponsor’s modified intent to treat) and intent to treat analyses ... demonstrated that rivaroxaban (combined, 2.5 mg twice daily, and 5 mg twice daily) significantly reduced the occurrence of the composite primary end point of cardiovascular death, myocardial infarction or stroke, compared with placebo, in ACS subjects stabilized 1-7 days post index event," Dr. Hicks said. "Numerous sensitivity analyses confirmed these results."

These efficacy results were statistically significant, regardless of whether data from three Indian clinical trial sites were included or excluded. The sponsors proposed to exclude the sites because of Good Clinical Practice violations.

Risk reductions for the 2.5-mg dose ranged from 16%-18% across all strata and 15%-18% in stratum 2.

The findings in all strata and stratum 2 were driven primarily by a reduction in CV deaths, particularly on the 2.5 mg dose, and to a lesser extent by a reduction in MI, Dr. Hicks said. "Compared to 2.5 mg BID [twice daily], rivaroxaban 5 mg BID increased the risk of all bleeding events without providing additional efficacy. Further, rivaroxaban 5 mg BID improved MI but not CV death, which was somewhat unexpected."

The 2.5-mg dose was associated with an all-cause mortality benefit that was nominally statistically significant. However, the 5-mg dose demonstrated no mortality advantage, and the two doses combined did not produce a statistically robust benefit. "Given the inconsistent results between rivaroxaban 2.5 mg BID and rivaroxaban 5 mg BID with respect to CV death and all-cause mortality, I do not recommend a mortality claim," Dr. Hicks said.

Significant Increases in Bleeding

On the safety side, rivaroxaban significantly increased the risk of all bleeding events, compared with placebo.

Across all strata, the 2.5-mg dose significantly increased the risk of the following TIMI classifications of bleeding: major, major or minor, life-threatening, intracranial hemorrhage, minor, clinically significant, and warranting medical attention. In stratum 2, the 2.5-mg dose significantly increased all TIMI major or minor bleeding, major bleeding, life-threatening bleeding, clinically significant bleeding, and medical attention bleeding. The 2.5-mg dose did not significantly increase the risk of TIMI major fatal bleeding or fatal intracranial hemorrhage.

In stratum 2, the 2.5-mg dose reduced the rate of the primary end point by 15% while increasing the rate of bleeding not related to coronary artery bypass graft surgery, Dr. Hicks said. "There was a twofold increase in TIMI major fatal bleeding and threefold increases in TIMI major bleeding, intracranial hemorrhage, hemorrhagic stroke, TIMI life-threatening bleeding, and TIMI major or minor bleeding. There was also an 18% increase in the risk of fatal stroke. Although the hazard ratios were increased, the absolute incidence of these events was low."

Subjects aged 75 years and older, and individuals weighing less than 60 kg, had an increased risk of bleeding events.

ACS subjects appeared to have a more pronounced tendency for liver injury than did populations studied in the atrial fibrillation and deep vein thrombosis prophylaxis studies. "Therefore, rivaroxaban, even in lower doses than what is recommended for other uses, appears possibly to cause mild liver injury in some patients. This finding likely reflects some increased susceptibility to drug-induced liver injury in patients with ACS," Dr. Hicks said.

Data Quality as a Counterargument to Approval

Dr. Hicks said that in arriving at her approval recommendation, she considered the argument that the amount of missing data from the ATLAS study weighed against approval.

Across all strata, 2,402 subjects (15.5%) discontinued the study prematurely, including 1,294 subjects (8%) who withdrew consent. "There were [more than] 1,000 subjects at the end of the trial with unknown vital status," Dr. Hicks said. Additionally, there were incomplete follow-up and uncounted deaths. "The quantity of missing data in ATLAS could affect the overall interpretability of the trial."

Nevertheless, Dr. Hicks suggested she was satisfied with the sponsors’ attempt to obtain vital status information on missing subjects and its responses to the FDA’s information requests on the issue. She also pointed to the broader problem of missing data in the setting of CV outcomes studies.

Shades of Ticagrelor

However, Dr. Thomas Marciniak, the review division’s medical team leader on the rivaroxaban application, takes a tougher stand on the issue of missing data and its ramifications for approval. In an April 26 memo, Dr. Marciniak suggests that the data quality may not support the favorable statistical results reported with the 2.5-mg dose.

The percentage of patients with incomplete follow-up in the study was high, averaging about 12%, he noted. "This percentage is far higher than the differences between the placebo and rivaroxaban arms in end point rates, which typically are about 1%-1.5%. The difference between placebo and rivaroxaban for bad follow-up rates matches these differences in end point rates. By [Johnson & Johnson’s] patient status statistics, there appears to be plenty of opportunity for incomplete data to obscure or magnify any differences in end points."

Furthermore, the rates of patients with unknown vital status exceed the reported differences in mortality rates, Dr. Marciniak said, asserting, "We cannot have confidence that the claimed mortality benefits are real."

He also challenged the sponsors’ approach to censoring patients and their classification of deaths that occurred after withdrawal of consent, saying this may have led to an overstatement of rivaroxaban’s efficacy.

"Because of the extent of missing follow-up in ATLAS, we cannot have confidence in either the calculated mortality or CV endpoint benefits," he said.

Marciniak’s criticisms about ATLAS are reminiscent of his attacks on the pivotal efficacy study for AstraZeneca PLC’s ticagrelor (Brilinta). During a July 2010 advisory committee review of the antiplatelet agent, Dr. Marciniak criticized the sponsor for inadequate end point and vital status follow-up in the 18,624-patient PLATO trial.

Dr. Marciniak’s criticisms were even more strenuous in his written reviews, in which he cited inadequate data collection and analyses, poor follow-up, faulty adverse event reporting, failure to adjudicate potential end points, an inappropriate primary end point, and censoring problems. The review division approved ticagrelor in July 2011 despite Dr. Marciniak’s recommendation against approval.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.