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AstraZeneca’s Ticagrelor Faces New Scrutiny Over Data Integrity in Pivotal Trial
A new investigation published by The BMJ has raised fresh doubts about the reliability of the pivotal PLATO clinical trial that led to the global approval of ticagrelor (Brilinta/Brilique), a popular anti-platelet drug marketed by AstraZeneca. Despite the drug costing the United States over $750 million annually, concerns are mounting about the integrity of the trial data that supported its approval.
The investigation, led by The BMJ senior editor Peter Doshi, reveals significant issues with data reporting, casting a shadow over the trial’s credibility. Doshi’s findings are based on primary records from the PLATO trial and previously unpublished data acquired through a freedom of information request.
The PLATO Trial: Initial Findings and Controversies
Published in 2009 in the New England Journal of Medicine (NEJM), the PLATO trial studied more than 18,000 patients across 43 countries. The trial’s conclusion was that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared to the older anti-platelet drug clopidogrel (Plavix). However, the results for US patients were troubling, showing a higher death rate among those on ticagrelor, leading to an initial rejection of AstraZeneca’s application for FDA approval.
The FDA’s medical officer, Thomas Marciniak, described AstraZeneca’s resubmission as “the worst in my experience regarding completeness of the submissions.” Despite these concerns, the FDA approved ticagrelor in 2011 for the treatment of acute coronary syndrome, sparking a long-standing dispute over the reliability of the PLATO trial’s data.
Growing Skepticism and Calls for Reappraisal
Since its approval, several other studies have failed to replicate PLATO’s positive results, fueling skepticism within the medical community. Experts such as Victor Serebruany, a researcher at Johns Hopkins University, initially lauded the PLATO findings but grew increasingly skeptical after noticing data inconsistencies. In 2013, Serebruany helped guide a US Justice Department investigation into the trial.
Eric Bates, a co-author of the US guidelines that recommend ticagrelor, has also expressed concerns over the trial’s credibility. He stated that the results of subsequent studies “were not dramatically positive in any way,” and now calls for a reassessment of ticagrelor’s place in clinical guidelines.
Disparities in Trial Oversight and Reporting
The BMJ investigation further uncovers troubling discrepancies in the trial’s oversight and reporting. While PLATO co-chairs Robert Harrington and Lars Wallentin maintain that there is no reason to suspect that trial oversight influenced the outcomes, the investigation points out that a statistical paper cited by the trial authors did not fully analyze the primary endpoint results for patients at sites monitored by contract research organizations (CROs) versus those monitored by AstraZeneca itself.
Moreover, the investigation raises questions about the accuracy of patient death reporting in the trial. Discrepancies in the number, causes, and dates of deaths suggest that there may have been unblinding, where patients or researchers could have been aware of treatment allocations—potentially compromising the trial’s integrity.
The Road Ahead
Despite these concerns, AstraZeneca has declined to comment further on the findings, pointing to its 2014 public statement in response to the US Department of Justice’s investigation. Co-chairs Harrington and Wallentin have also not responded to The BMJ’s requests for comment.
As the investigation continues to unfold, Victor Serebruany remains doubtful that scientific inquiries alone will resolve the questions surrounding PLATO’s data integrity. He believes the only way forward is a renewed investigation by the US Department of Justice, calling for a deeper look into the trial’s oversight and the practices of those involved.
Fifteen years after PLATO’s publication, Serebruany’s call for justice remains unanswered. “We need to give the Justice Department another chance to look at the case, issue new civil investigative demands, and ensure accountability in the pharmaceutical industry,” he said.
The BMJ’s investigation highlights the urgent need for further scrutiny of one of the most significant trials in modern cardiovascular medicine. As the debate over ticagrelor’s effectiveness and safety continues, experts are calling for a reappraisal of the drug’s role in clinical guidelines and a deeper examination of the data that led to its widespread use.
Reference: “Doubts over landmark heart drug trial: ticagrelor PLATO study” by Peter Doshi, 11 December 2024, BMJ. DOI: 10.1136/bmj.q2550
