A senior FDA official has told a US investigation that the country is "virtually defenceless" against another withdrawal because of safety concerns similar to that of Merck's painkiller Vioxx.

The company's $2.5 billion arthritis blockbuster was withdrawn at the end of September this year after it was found long-term use doubled the risk of heart attacks and strokes.

Giving evidence to the Senate finance committee Dr David Graham, associate director of the FDA's Office of Drug Safety (ODS), said the Vioxx case was a "national disaster" and a "terrible tragedy and profound regulatory failure".

Committee chairman Senator Chuck Grassley said the Vioxx case seemed to indicate the FDA had lost its way when it came to drug safety, and that it may have allowed itself to be manipulated by Merck on labelling changes that became necessary after its VIGOR trial in 2000.

Dr Graham led an agency-sponsored study in 1999 that estimated Vioxx could have caused at least 28,000 heart attacks or deaths, although writing recently in the New England Journal of Medicine, Cleveland Clinic's Dr Eric Topol, said the drug could have caused as many as160,000 heart attacks or strokes.

Defending his company at the hearing Merck chief executive Raymond Gilmartin said the FDA had approved Vioxx after extensively studying the medicine, using rigorous scientific processes at each step of the process.

This picture of the agency contrasted sharply with Dr Graham's portrayal of the FDA's current configuration as "broken" and "incapable of protecting America against another Vioxx".Most controversially, he singled out five major drugs on the market which could be withdrawn in a similar fashion to Vioxx.  

Dr Graham listed Abbott Laboratories' obesity drug Meridia; AstraZeneca's Crestor (cholesterol); Roche's Accutane (a severe acne treatment); Pfizer's Bextra (in the same Cox-II class as Vioxx) and GlaxoSmithKline's Serevent (asthma) as having safety problems.

Despite AstraZeneca's strong defence of its statin Dr Graham said Crestor was "the only cholesterol-lowering drug that causes acute renal failure along with muscle-wasting side-effects".

He added that Accutane was a "20-year FDA regulatory failure" saying that pregnant women were still allowed to use the acne treatment, despite evidence it caused birth defects in children. Meanwhile, he said GSK's asthma treatment Serevent may be linked to asthmatic deaths and Pfizer's Cox-II Bextra needed serious safety studies to disprove the possibility it increased the risk of heart problems.

He said the biggest obstacles to effectively dealing with serious drug safety issues was caused by conflicts of interest within the FDA's Center for Drug Evaluation and Research (CDER) and its Office of New Drugs (ONS) ­ the office that approves new drugs - as well as lack of regulatory power or authority in his own office.

"The same group that approved the drug is also responsible for taking regulatory action against it post-marketing. This is an inherent conflict of interest," Dr Graham said.

Dr Graham said there had been numerous safety lapses but cited diabetes drug Rezulin as an example of ONS regulatory failure, which "probably led to thousands of Americans to be severely injured or killed by the drug".

In this case the drug caused acute liver failure and was taken off the UK market at the end of 1997 but the ONS, "relying on utterly ineffective risk management studies" delayed withdrawing Rezulin from the US market until March 2000.

He added that the 95% burden of proof needed to show a drug was unsafe was also too high, using a graphic Russian roulette gun analogy to highlight his point.

"Using CDER standards, only when you have 95 bullets or more in the gun will you agree that the gun is loaded and a safety problem exists," he said.

The eventual outcome of the investigation is far from clear, but could conceivably lead to stricter standards in the FDA's approval and post-marketing monitoring of drugs, which would in turn spell a more hazardous and expensive regulatory environment for the industry.

Related articles:

Markets stunned as Merck withdraws blockbuster Vioxx

Friday , October 01, 2004

pharmafocus@wiley.co.uk