November 3, 2013 2:32 pm

US regulators probe AstraZeneca drug test

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When US regulators re-examined data used to approve a medicine launched by AstraZeneca two years ago, they found at least one patient reported dead who was in fact still alive. Now broader concerns about the clinical trial have been resuscitated by the authorities, threatening fresh financial pain to the Anglo-Swedish drug group.

Last week, the company disclosed that in late October it had received a request from the US Department of Justice to explain the conduct of Plato (Platelet inhibition and patient outcomes), a large trial of the effects of its anti-clotting drug ticagrelor (known by the brand names Brilinta and Brilique) on nearly 19,000 patients in 43 countries.

Scrutinising a clinical trial is a highly unusual step for investigators, who have more typically focused on the marketing practices of pharmaceutical companies for drugs once approved, rather than studying the underlying data that led to regulatory authorisation in the first place.

It comes at a time of continuing medical debate over the Plato trial, including questions over the more favourable results for the drug in countries where the tests were supervised directly by the company.

Pascal Soriot, chief executive of AstraZeneca, stressed: “At this stage, we are very confident with the results of the Plato trial, guided by a strong academic group who oversaw the trial. The study was reviewed extensively by the FDA which approved Brilinta.”

The treatment was authorised in Europe in 2011 and in the US the following year, and is prescribed typically for patients after a heart attack or unstable angina – chest pains linked to unstable blood flow to the heart.

Initial forecasts were optimistic, with some analysts estimating it would reach peak annual sales in the coming years of more than $2.5bn. Yet uptake has been gradual, with sales for the first nine months of this year of $191m – albeit up more than threefold from the same period in 2012. It now holds just over 6 per cent market share for new prescriptions of drugs in the category in the US.

That puts pressure on Mr Soriot, who has labelled Brilinta one of AstraZeneca’s five “growth platforms” designed to help revive a company that has been struggling to win back investor support as it seeks to replenish its pipeline of new drugs.

At this stage, we are very confident with the results of the Plato trial, guided by a strong academic group who oversaw the trial.

- Pascal Soriot, AstraZeneca CEO

In a paper in the International Journal of Cardiology published last month, the researchers James DiNicolantonio and Ales Tomek highlighted “multiple serious deficiencies in the reporting of Plato results”. They showed results for Brilinta were more favourable than Plavix in countries where the Plato study was supervised by AstraZeneca rather than by a third-party contract research organisation (including the US).

One issue has been price competition. Sanofi and Bristol-Myers Squibb’s drug Plavix (known generically as clopidogrel) was previously viewed as the “standard of care”, becoming one of the world’s top-selling drugs on revenues of more than $5bn in 2012. But it has now gone off patent, selling considerably more cheaply than Brilinta.

Brilinta’s advantage was that it appeared to work in a significant minority of patients who did not respond to Plavix. AstraZeneca developed the Plato trial to show precisely its relative benefit by comparing outcomes between the two drugs. It showed 9.3 per cent of patients had another heart attack, stroke or died from a cardiovascular disease compared with 10.9 per cent on Plavix.

Yet the results have raised questions, including the lower benefits in US patients than those studied in other countries – something AstraZeneca argued was linked to higher dosage in the US compared with other countries of aspirin, typically given alongside either of the other drugs.

Other authors, such as Victor Serebruany, have questioned the unusually high death rates in Plato of patients on Plavix, and the way side effects for the two drugs were reported. He also criticised the “family picnic” of close links between the Swedish and US academics who devised Plato, and those on the committee which reviewed the findings.

Professor Lars Wallentin at Uppsala University in Sweden, who co-chaired the Plato study, dismisses such concerns. “We feel completely comfortable with the data. Every step was completely transparent,” he said. “The questions raised are completely unfounded or we would not have been able to publish this data in some of the most highly recognised journals in the world. Brilinta has widespread confidence in the whole cardiology community.”

Andrew Baum, a pharmaceutical analyst at Citi, expresses doubts that the Plato data disputes reflect “compromised trial integrity or systematic bias”. He argues that a fresh clinical trial for Brilinta launched by AstraZeneca called Pegasus should help resolve some outstanding concerns in the future. Meanwhile, US investigators will continue to probe the past.

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