Feds launch probe of AstraZeneca's controversial late-stage Brilinta study

When EP Vantage went back to look over some of the bullish peak sales projections made for a new generation of medicines, its analysts pulled out AstraZeneca's blood-thinner Brilinta as one of the industry's top duds. Once expected to crest at $2.52 billion a year, most analysts now don't see it hitting the $1 billion blockbuster mark, with a poor impact in the U.S. market dragging down projections.

Now AstraZeneca ($AZN) has another Brilinta headache to deal with. In its third-quarter earnings release the company revealed that the U.S. Justice Department's civil division is probing PLATO, its big clinical trial of Brilinta. The feds demanded "documents and information" on the study. And the pharma giant noted briefly that it will be cooperating with investigators.

While the company offers no details about exactly what the feds are after, the PLATO study has been subjected to some harsh criticism from James DiNicolantonio, Pharm.D., and Dr. Ales Tomek, of Charles University in Prague. The two raised serious questions about the study results last summer in a report published in the International Journal of Cardiology. They highlighted concerns that study results reviewed by an independent CRO demonstrated a worse outcome for the drug--ticagrelor--than the clopidogrel arm compared to the positive results reported by AstraZeneca's investigators.

They also reported that almost half of the favorable results for Brilinta were drawn from just two Eastern European countries, Hungary and Poland. Reporting on cardiovascular events appeared to favor Brilinta and "an estimated 23 definite or possible cardiovascular events or deaths on ticagrelor (Brilinta) were either not submitted for adjudication, inactivated, deleted or were downgraded to 'softer' endpoints (this was not shown in the FDA review for clopidogrel), and four FDA reviewers voted for non-approval of ticagrelor."

"The FDA report highlights what appear to be multiple serious deficiencies in the reporting of the PLATO results, which clinicians will not have gleaned from the primary publication alone," they wrote, according to a report in MedPage Today. "Individual clinicians may therefore wish to carefully reconsider their practice of ticagrelor prescription for this indication. Guideline bodies should also evaluate the information in its totality."

In a Q3 update for analysts, AstraZeneca CEO Pascal Soriot noted that he is "very confident" in the data that came from the study, according to a report from The Wall Street Journal. He added that a "very strong academic group" and an independent safety-monitoring board oversaw the trial.

One of the principal investigators, Lars Wallentin of Uppsala Clinical Research Center in Sweden, has fought back against the accusations leveled against PLATO.

"Since the publication ... of the PLATO trial results in August 2009 and the presentation of the FDA documents in 2011, Mr. DiNicolantonio and/or his collaborators have produced 25 to 30 manuscripts for various journals, criticizing the PLATO trial, its investigators, sponsor, and the regulators from similar perspectives without providing any new valid data as support for their allegations…," Wallentin wrote in an email to MedPage Today. "Any reader of scientific articles should be able to review the results critically, draw conclusions, and translate the results for clinical practice. In doing so, the reader should be confident that the reported data derived from meticulously performed clinical trials are correct and reported with minimal bias. Unfortunately, DiNicolantonio and [Victor Serebruany, M.D., Ph.D., a co-author one of the papers] report selected data derived from various sources using improper statistics. The data provided in the commentary are a biased selection of an extensively peer-reviewed and published series of articles."

- here's the AstraZeneca release on Q3
- see the abstract from the International Journal of Cardiology
- read the report from MedPage Today
here's the story from The Wall Street Journal (sub. req.)