FDA Whistleblower Has His Say

Dr. David Graham, associate director of science for the office of drug safety at the center for drug evaluation and research for the Food and Drug Administration testifies before the Senate Finance Committee hearing on 'The FDA, Merck and Vioxx: Putting Patient Safety First?' on Capitol Hill in Washington Thursday, Nov. 18, 2004.
A Food and Drug Administration whistleblower who had complained the agency was trying to muzzle him was allowed to go before a pair of advisory committees Thursday to warn of dangers with at least one popular painkiller and perhaps others.

The painkiller Vioxx — now off the market — posed a risk of hundreds to thousands of additional heart attacks, said Dr. David Graham.

Graham, a medical officer at the FDA's Center for Drug Evaluation and Research, said he believes there is also a heart hazard from using Celebrex at high doses, adding the problem may cover the whole class of drugs, which also includes Bextra.

Celebrex and Bextra remain on the market and their maker, Pfizer Inc., has defended their safety.

Graham had complained that the FDA ordered him not to discuss a pair of studies that cast doubts on the safety of Vioxx because those reports were preliminary and had not yet been officially published.

But he included information from those studies in his talk to the advisory committees, which are holding a three-day meeting to assess the safety of this type of drugs. Opening his speech, Graham thanked Acting FDA Director Lester Crawford for allowing him to speak.

Both studies, called Ingenix and Medi-Cal, showed an increased risk of heart attack for users of Vioxx, Graham noted.

"We're talking about small levels of risk that turn out, at the population level, to be enormously important," he said.

He said various studies indicate a range of increased heart attack risk which translates to as few as 400 or as many as 10,800 additional heart attacks per million men aged 65 to 74 at low doses of the drug, and up to 40,000 at higher doses.

Vioxx was pulled off the market Sept. 30 by its maker, Merck & Co., after a long-term study indicated an increased risk of heart problems and stroke beginning at 18 months of use.

Responding to Graham, Merck released a statement calling his estimated speculative.

Determination of what caused any patient's heart attack or stroke can only be made on a case by case basis, the company said.

Graham said "patients enrolled in clinical trials are generally healthier than patients in the real world, so models underestimate the actual population impact."

The typical user of this type of painkiller is someone in their 60s, not only men, with other health problems, Graham said. That person already had a one-in-50 risk of heart attack, he said.

As Graham finished, meeting chairman Alistair J.J. Wood of the Vanderbilt University Medical Center asked if he had given the panel the whole picture or was leaving anything out.

"I've been able to present what I thought it was important to present," Graham said.

An official of Merck said at Wednesday's hearing that the problem appears to affect the whole class of drugs, while Pfizer Inc., the maker of maker of Celebrex and Bextra argued those products are safe.

When Merck withdrew Vioxx on Sept. 30 the company acted because it feared some problem with the drug itself was leading to the strokes and heart trouble.

But Dr. Ned S. Braunstein, senior director of Merck Research Laboratories, told the panels that since then studies suggesting similar problems with Celebrex and Bextra have changed his mind.

"The data strongly suggest it is a class effect" for all drugs of that type, Braunstein said.

The drugs, designed to help people in chronic pain from conditions such as arthritis, are known as Cox-2 inhibitors. At least two other Cox-2 drugs are awaiting approval from the FDA, Arcoxia from Merck and Lumiracoxib from Novartis Pharmaceuticals.

The Cox-2 drugs have become blockbuster sellers over the past 15 years, offering relief from chronic pain without causing the stomach and intestinal troubles that plague many other pain killers.

The advisory committees are holding a three-day session to gather data on the safety of Cox-2 inhibitors and to make recommendations regarding their future use.

Recommendations could range from limiting these drugs to people not known to be at risk of heart problems, reducing the dose or duration of use, requiring tougher warning labels and even taking the drugs off the market.