November 19, 2010 7:18 pm
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A report sent to the FDA questions the data in a study AstraZeneca is relying on for US approval of its potential new antiplatelet blockbuster Brilinta.
Before it makes an approval decision, the US drug regulator has been searching for explanations as to why Brilinta’s effectiveness in US patients differs unfavourably from that of the combined rest of the world.
AstraZeneca told Pharmawire it is confident in the trial results, but was unable to comment further as the drug is currently under FDA review. The FDA said it cannot comment on pending application matters.
If approved, Brilinta (ticagrelor) will rival Bristol-Myers Squibb’s big selling antiplatelet Plavix (clopidogrel) and Eli Lilly’s Effient (prasugrel). Brilinta is a key asset for AstraZeneca as it could reach peak sales of USD 1.4bn by 2017, according to Biopharm Insight data. Analysts have noted its success is crucial for AstraZeneca, who like many of its peers, faces increasing erosion in sales of some of its top selling drugs now that cheaper, copycat versions have become available.
An FDA Advisory Committee voted in July to approve Brilinta for patients with acute coronary syndromes (ACS) but the FDA has since extended its decision date to 16 December 2010.
FDA still wavering on US approval decision
Regulators recommended approval of ticagrelor in Europe (where it is called Brilique) in September. Yet certain FDA decision makers in the US are still not happy with Brilinta’s data package, a source claimed. “There are huge things going on behind the scenes,” the source said, who remained uncertain of the outcome.
“It seems a lot is unclear with the data,” another person familiar with the situation confirmed, but called the issues “minor.”
In a Phase III trial called PLATO, Brilinta showed superior effectiveness over the current industry standard Plavix, in reducing heart attack or stroke events, or death (from vascular causes).
Yet the US patients in this global study actually had an increase in these event rates - including higher death - if they were treated with Brilinta. According to FDA reviewers, “extensive analyses” were performed, but a definitive explanation for this regional difference was not found.
“If US population differs sufficiently from the rest of the world, a US trial may be needed to further evaluate the efficacy of Brilinta in US subjects,” FDA reviewers said.
Platelet expert Dr Victor Serebruany, HeartDrug Research Laboratories and Johns Hopkins University Osler Medical Center, Maryland, said he has since worked to help the FDA to better “understand” the regional differences. Serebruany said he issued his report on 26 October and presented the FDA with his findings.
A major focus of his report is clinical sites in Poland (2,666) and Hungary (1,267) enrolled 21% of the patients on the trial, but yielded 46% of the events favoring Brilinta. Statistically, Poland and Hungary also notably stand out from the other 41 countries in PLATO, he noted.
Thrombosis and haemostasis expert, professor Job Harenberg, University of Heidelberg, Germany, noted that if the FDA review investigates individual countries for the quality of the data then this becomes a “very difficult situation.”
Professor Dan Atar, head of cardiology, Oslo University Hospital, Norway, said that the data are within what could be the result of natural variability. “I think the situation will eventually land softly and smoothly,” he said.
One clinician familiar with PLATO said that many currently approved drugs have had geographical differences in the results that were not fully understood. “It’s a recurring finding [in global trials] which is one reason for making them so big,” he said.
In addition to the US, results also favoured Plavix for 11 other individual countries: Argentina, Israel, Austria, Norway, Russia, South Korea, Georgia, Canada, Denmark, Taiwan and Australia.
“The PLATO results are really robust and I have no concern,” the clinician said. The FDA review documents state that even when the large centers (Poland and Hungary) that showed a significant treatment effect favoring Brilinta were excluded from the statistical analysis, the overall result still favored Brilinta, he added.
Digging into the data
Serebruany pointed to the FDA’s observation that one of the “dead” patients in PLATO was actually later found to be alive and questioned whether such an error was limited to this one case. He reasoned that the difference in reported deaths between the US and Europe is at least 1% and said the 4.86% combined fatality rate in PLATO is “abnormally high” compared to other similar studies which all have death rates below 4%.
It is understood that the FDA sent clinical site monitors to Poland and Hungary, yet they found nothing out of the ordinary. The FDA monitors only checked the electronic records, Serebruany said.
This news service has reported previously on the FDA’s increasing resolve to dig deeper into the integrity of clinical data, particularly from emerging market regions, before approving a new drug.
Serebruany’s report questioned how Brilinta managed to achieve a “huge” all-cause death reduction with 107 fewer deaths - especially as almost half the patients were pretreated with Plavix - and highlighted other points that question the death result in PLATO.
The 5.9% all-cause death in patients who took Plavix was the highest reported for Plavix in a trial in the last 10 years, he said. Death in Brilinta patients was 4.5% and the difference between Plavix and Brilinta was highly significant. Yet in the US, 3.22% of Plavix patients and 3.84% of Brilinta patients died, the report noted.
Moreover, Brilinta’s superior death benefit over the comparator (Plavix) is not apparent immediately, but grows over time, a pattern which has never been observed for any drug in an ACS trial before and is “odd” because patients’ death risk markedly decreases over time, Serebruany said.
Clinicians interviewed pointed out that many theories have been proposed in the medical community to explain some of the above points regarding Brilinta’s performance and the US data difference has sparked particular debate.
Hypotheses revolve around the higher Plavix ‘loading’ dose that some patients received; Brilinta’s novel mode of action; the difference in treatment practices between the US and Europe; and use of different Aspirin doses in the different regions.
FDA review documents state that even though the Aspirin theory seems to be the biggest contributing factor, out of more than 30 factors the FDA and AstraZeneca have been looking into, the interpretability of the results that support this theory remain “very much uncertain”.
AstraZeneca further commented, “PLATO was a large, well-conducted study undertaken with an executive committee with responsibility for overseeing the medical, scientific, and operational conduct and has been published in peer-reviewed medical journals.”
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