Clinical trials are the main way for scientists and doctors to test whether new treatments, such as drugs or devices, are safe and effective. Because of their pivotal importance in influencing treatment options and patient care, clinical trials must be conducted to the highest standards. For drugs, this means they are required to be proven safe and effective before they can gain government approval. Read More
The Platelet Inhibition and Patient Outcomes – or ‘PLATO’ – was a mega-trial designed to evaluate the safety and efficacy of a new antiplatelet drug called ticagrelor compared to an existing ‘gold standard’ drug called clopidogrel for the treatment of acute coronary syndrome. Coronary syndrome is a type of vascular disease that includes heart attacks.
The trial involved over 18,000 patients from all over the world at over 800 clinical sites. The manufacturer of ticagrelor financed this massive study and directly managed the majority of the study sites, in a highly unorthodox approach.
Dr Victor Serebruany from John Hopkins University and his collaborators identified unusual and sometimes misreported outcomes between what have happened in local hospitals compared to what was reported to the FDA or EMA and published PLATO results.
Overall, the PLATO trial reported that the new drug, ticagrelor, was much more effective than the old drug, clopidogrel, at preventing vascular deaths following acute coronary syndrome. It also reported that the risk of side effects, such as bleeding, was no higher for ticagrelor.
However, Dr Serebruany and his colleagues noticed differences between the results of the company-sponsored PLATO trial and other independent studies investigating the same drug. In the PLATO trial, the advantages of ticagrelor weren’t consistent between different test locations. There were also differences in results depending on the involvement of the drug sponsor in data management.
Dr Serebruany’s team analysed a subset of data from 16 PLATO research sites, including hospitals and care homes, across eight different countries, to check whether the original site records and PLATO reports matched.
The researchers found that many deaths were inaccurately reported, and that these apparent mistakes favoured the new drug, ticagrelor. Specifically, the team noticed a number of mismatches between the site records and the reported data in terms of numbers, dates, and causes of death.
Dr Serebruany found that the local sites had recorded the deaths of two patients from Poland and Korea taking ticagrelor that weren’t included the PLATO report, and that four Indonesian patients who were being treated with clopidogrel were potentially falsely reported as dead by the PLATO study.
The team also found that several deaths of patients treated with clopidogrel were listed as occurring earlier than they actually did by the PLATO report. In contrast, the deaths of two patients who were taking ticagrelor were reported as occurring later than they actually did and were excluded from the main trial results – which worked in ticagrelor’s favour.
For 12 patients treated with clopidogrel, the cause of their deaths was changed to vascular, whereas six patients who died while on ticagrelor had their cause of death changed from vascular to non-vascular.
These omissions, mistakes, and alterations all affected the overall outcome of the trial and may mean that ticagrelor is less safe or effective than the official results suggest, and that these false results were used to win FDA approval for the drug. The results have also misled the medical community and patients into believing the drug is less dangerous than it is.
The team’s rigorous analysis of clinical trial data challenges the findings of a potentially flawed study, and aims to improve patient outcomes through evidence-based medicine. Their work highlights the importance of stringent data management processes for patient safety and robust conclusions in future clinical trials.
