Landmark Ticagrelor Trial Faces Renewed Scrutiny Over Data Integrity

An investigation by The BMJ has cast fresh doubts on the landmark PLATO clinical trial that led to the worldwide approval of ticagrelor查看药品详情 (Brilinta/Brilique), an anti-platelet drug manufactured by AstraZeneca查看公司主页. The investigation reveals potential issues in data reporting and accuracy that raise questions about the drug's efficacy and safety, especially when compared to its cheaper, off-patent rivals like clopidogrel查看药品详情.

Concerns Over Data Reliability

Peter Doshi, senior editor at The BMJ, obtained primary PLATO trial records and unpublished data through a freedom of information request, uncovering discrepancies in the number, causes, and dates of patient deaths. These inconsistencies raise concerns about the accuracy of reporting to the FDA and the possibility of unblinding during the trial.

The PLATO trial, published in the New England Journal of Medicine in 2009, involved over 18,000 patients across 43 countries. It initially reported that ticagrelor查看药品详情 reduced the risk of vascular death, heart attack, or stroke (搜索)搜索该疾病 compared to clopidogrel查看药品详情. However, a subgroup analysis revealed that US patients on ticagrelor experienced higher mortality rates, leading to the FDA's initial rejection of AstraZeneca查看公司主页's application.

FDA Approval Amidst Internal Objections

Despite these concerns, the FDA eventually approved ticagrelor查看药品详情 in 2011. This decision came despite strong reservations from FDA medical officer Thomas Marciniak, who described AstraZeneca查看公司主页's resubmission as "the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests." Marciniak recommended against approval due to concerns over the basic reliability of PLATO trial data.

Failure to Replicate PLATO's Results

Since its approval, numerous studies have failed to replicate PLATO's positive findings, prompting experts to question the trial's validity and call for a reappraisal of guidelines recommending ticagrelor查看药品详情. Eric Bates at the University of Michigan, a co-author of the US guidelines, expressed increasing concern over the lack of consistently positive results in subsequent trials.

Monitoring and Data Integrity

Critics have also pointed out that ticagrelor查看药品详情 performed worse at trial sites monitored by third-party contract research organizations (CROs) compared to those overseen directly by AstraZeneca查看公司主页. While PLATO co-chairs Robert Harrington and Lars Wallentin have dismissed any influence of monitoring organization on study outcomes, The BMJ found that the cited statistical analysis did not directly compare primary endpoint results between CRO-monitored and sponsor-monitored sites. Furthermore, the lead author of the statistical paper was AstraZeneca's former chief statistician, a fact not disclosed in the publication.

Unresolved Questions and Calls for Re-evaluation

The controversy surrounding PLATO has persisted for years, with critics like Victor Serebruany at Johns Hopkins University raising concerns about inconsistencies and anomalies in the data. Serebruany, who initially found the trial results impressive, guided a US Justice Department investigation into PLATO in 2013. While the investigation was later terminated, Serebruany believes that re-engagement from the Justice Department is the only way to resolve the lingering questions about data integrity.

With generic versions of ticagrelor查看药品详情 soon expected in the US, the renewed scrutiny of the PLATO trial raises important questions about the evidence supporting its widespread use and the need for a thorough re-evaluation of its place in clinical guidelines.