US lawyers investigate trial that secured license for AstraZeneca’s antiplatelet drug
BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f6727 (Published 08 November 2013) Cite this as: BMJ 2013;347:f6727
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The outcome of this investigation will prove to be extremely interesting given the criticism from various sources, particularly that of Marciniak. It highlights the need for more transparency within the US Food and Drug Administration and for detailed discussion of disagreements on an open platform. The administration has previously been described as a “house divided” by senior scientist David Graham who worked within the FDA's Office of Drug Safety (1). The outcome of this investigation will likely reignite debate regarding the FDA’s approach to handling disagreements within the administration.
It seems foolish that Stockbridge would out rightly refute Marciniak’s claims without more in depth investigation. One cannot deny some of the figures, such as significantly more patients on ticagrelor (3.1%, n = 289 patients) had incomplete vital status follow-up versus clopidogrel (2.6%, n = 242 patients, p = 0.04 for the difference) (2). Nonetheless, it is promising to see the US Department of Justice initiate the investigation quite rapidly in the wake of criticism. It should be made clear what in particular led to this investigation and what aspects of the trial are being called into question.
That there are 98 regulatory approvals to date for ticagrelor indicates the weight of the investigation. Given the increasing body of evidence demonstrating the implications of anti-platelet drug ‘resistance’ (3), more physicians are turning to new drugs like ticagrelor to reduce the risk of further thrombotic events. It is therefore imperative that licensing bodies adopt the most stringent strategies possible when analysing trials like that of the Platelet Inhibition and Patient Outcomes (PLATO) trial (4).
References
(1) Leung, R. (2009). FDA: Harsh Criticism From Within . Available: http://www.cbsnews.com/2100-500164_162-674293.html. Last accessed 8th Nov 2013
(2) Dinicolantonio JJ, Tomek A. Misrepresentation of vital status follow-up: challenging the integrity of the PLATO trial and the claimed mortality benefit of ticagrelor versus clopidogrel. Int J Cardiol2013;168:4076-80
(3) Marco Cattaneo, Resistance to anti-platelet agents, Thrombosis Research, Volume 127, Supplement 3, February 2011, Pages S61-S63, ISSN 0049-3848
(4) Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med2009;361:1045-57.
Competing interests: No competing interests
PLATO Executive Committee welcomes the U.S. Department of Justice decision to close its investigation into the PLATO clinical trial.
“Over the past years the academic leaders of the PLATO trial have repeatedly refuted allegations on the conduct and analyses of the PLATO trial which also were highlighted in an article in BMJ in November 2013 (BMJ 2013;347:f6727). We therefore welcome the news that the U.S. Department of Justice has closed its investigation of the PLATO trial and will take no further action” says one of the study co-chairman professor Lars Wallentin, Uppsala Clinical Research Center, Uppsala, Sweden. “This decision should remove any remaining doubts about the reliability of the trial results and thereby support the implementation of the tested new treatment, not least in the United States,” says the other co-chairman professor Robert A. Harrington, Stanford Medical Center, Stanford, California, USA. “Now we can focus even more on providing new knowledge on how to best deliver this life-saving treatment to our patients with heart attacks.”
The Platelet Inhibition and Patient Outcomes (PLATO) trial compared the new blood clot-preventing drug ticagrelor (Brilinta) from AstraZeneca with the previous routine treatment clopidogrel (Plavix) in 18,624 patients with myocardial infarction or unstable angina from 41 countries. The results were presented and published for the first time in 2009 and showed improved survival and a lower risk of recurrent myocardial infarction during the one year of treatment without any increase in risk of major bleeding although there was a slight increase in spontaneous bleeds. The PLATO study group has thereafter published a long series of carefully performed analyses to better understand the effects and to tailor ticagrelor treatment to better fit the needs of the individual patient. The results have led to the approval of ticagrelor for treatment of myocardial infarction in more than 100 countries worldwide and ticagrelor is now recommended as a first-line treatment of myocardial infarction in European and US guidelines.
Over the last years, a few individuals have repeatedly questioned the validity of the PLATO results and accused the PLATO trial of irregularities in study conduct, analyses and reporting. As previously disclosed on October 31, 2013 AstraZeneca received a civil investigative demand from the US Department of Justice seeking documents and information related to the PLATO trial. AstraZeneca has cooperated with the government enquiry, which focused on questions that have been raised previously in public about the trial. Similar questions have been responded to by the independent PLATO Executive Committee, which led the clinical trial. On Tuesday August 19 2014 the United States Department of Justice informed that it is closing its investigation into PLATO and that the government is not planning any further action. Based on this decision, coupled with previous disclosure of all documents from regulatory agencies, the extensive publication of the results in international peer-reviewed scientific journals, and the open discussion and debate, the PLATO group hopes that the raised allegations can finally be put to rest. The two PLATO co-chairmen emphasize that ”now is the time to switch from investigation to implementation of ticagrelor in the majority of patients with heart attacks in order to improve their survival and reduce the risk of recurrent events.”
Competing interests: The authors are the academic members of the executive committee of the PLATO trial and have receive institutional grants from the sponsor AstraZeneca for performance and reporting of the trial.