An investigation published by The BMJ today raises new concerns over the landmark clinical trial (PLATO) that was used to gain worldwide approval for the anti-platelet drug ticagrelor (Brilinta in the US and Brilique in Europe), manufactured by AstraZeneca.
Peter Doshi, senior editor at The BMJ, reveals new details that show problems in data reporting after obtaining primary PLATO trial records and unpublished data through a freedom of information request.
The PLATO trial was published in the New England Journal of Medicine (NEJM) in 2009. Assessing over 18,000 patients in 43 countries, investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in US patients, PLATO's results showed higher deaths in the ticagrelor group, and AstraZeneca's first application for FDA approval failed.
FDA medical officer Thomas Marciniak reviewed AstraZeneca's resubmission, but called it "the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests." Marciniak became deeply concerned over the basic reliability of PLATO trial data and recommended against approval.
But the FDA approved ticagrelor over these objections, sparking a long and rancorous dispute over PLATO. However, since the 2011 approval for acute coronary syndrome, a host of other studies have failed to replicate PLATO's positive results, prompting experts to question its validity and call for a reappraisal of guidelines that recommend ticagrelor.
Victor Serebruany at Johns Hopkins University was initially impressed by the trial results, but became sceptical after noticing inconsistencies and anomalies in the data and guided a US justice department investigation into PLATO in 2013.
Eric Bates at the University of Michigan, and a co-author of the US guidelines that recommend ticagrelor, also said he was "increasingly disturbed by how trial after trial came out as being not dramatically positive in any way." Bates is now calling for a reappraisal of ticagrelor's place in guidelines.
Others contend that PLATO's results were not credible from the start, pointing out that ticagrelor fared worse at trial sites monitored by third party contract research organisations (CROs) than at sites overseen by AstraZeneca.
PLATO co-chairs Robert Harrington and Lars Wallentin have argued that "there is no reason to suspect an influence of monitoring organization on the study outcomes," citing an analysis by "two senior academic statisticians."
But The BMJ has found that the cited statistical paper did not analyze overall primary endpoint results for patients at sites monitored by CROs compared with sites monitored by the sponsor, and that the paper was led by AstraZeneca's former chief statistician without disclosing his former employment.
The BMJ investigation also reveals discrepancies in the number, causes, and dates of patient deaths provided by PLATO investigators, raising further questions about the accuracy of reporting to FDA and possibility of unblinding.
AstraZeneca declined to be interviewed. A spokesperson said by email that the company has "nothing to add," and directed The BMJ to its 2014 public statement following the US Department of Justice's investigation into PLATO. Trial co-chairs Harrington and Wallentin did not respond to The BMJ's requests for comment.
The BMJ's analysis also found omissions in the number of deaths reported in the NEJM paper. The NEJM did not dispute the error and said it would attempt to contact the authors, but added "if we are unable to reach them or they are unable to access the data, we would most likely not proceed with corrections."
Fifteen years after PLATO, Serebruany continues to publish critiques, but in an interview with The BMJ he expressed little hope that scientific levers will resolve questions about data integrity in PLATO.
The only way forward, in his opinion, is reengagement from the US Department of Justice. "There are many good people in the justice department and we need to give them another chance to look at the case, issue new civil investigative demands, and stop the flirting, dealing, and wheeling in exchange for future high profile jobs in big pharma. Then the American people will receive justice."
