Dr. David Graham demonstrated considerable fortitude and integrity. The FDA and "we the people" need more like him. Contrast his testemony with the statement released yesterday by
Dr. Lester M. Crawford, acting commissioner of the Food and Drug Administration
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http://www.nytimes.com/2004/11/19/business...in&pagewanted=2November 19, 2004
F.D.A. Failing in Drug Safety, Official Asserts
By GARDINER HARRIS
WASHINGTON, Nov. 18 - Federal drug regulators are "virtually incapable of protecting America" from unsafe drugs, a federal drug safety reviewer told a Congressional panel on Thursday, and he named five drugs now on the market whose safety needs "to be seriously looked at."
In testimony before the Senate Finance Committee, Dr. David Graham, the reviewer in the Food and Drug Administration's Office of Drug Safety, used fiery language to denounce his agency as feckless and far too likely to surrender to demands of drug makers."We are faced with what may be the single greatest drug safety catastrophe in the history of this country or the history of the world," Dr. Graham concluded.
Dr. Steven Galson, the director of the F.D.A.'s Center for Drug Evaluation and Research and one of the agency's top civil servants, later said that Dr. Graham's new numbers "constitute junk science" and were "irresponsible." Dr. Graham, with more than 20 years of service at the Food and Drug Administration, cited the anti-cholesterol drug Crestor, the pain pill Bextra, the obesity pill Meridia, the asthma drug Serevent and the acne drug Accutane. Makers of each drug defended the medicines as safe.
Dr. Sandra Kweder, deputy director of the F.D.A.'s office of new drugs, told the panel that Dr. Graham was not describing "the F.D.A. that I know" and that she did not see the five drugs he cited as "more concerning than any others."The clash was a rare public airing of tensions that have simmered in the agency for decades. It is a fight between those who focus on the potential of drugs to cure the sick and dying and those who see many medicines as high-priced commercial products with potentially risky side effects, between those who view pharmaceutical makers as beneficial partners and those who see the drug makers as antagonists needing to be curbed.
"My personal view is that our system works very well," Dr. Kweder said.
The exchange came during a hearing called by Senator Charles E. Grassley, a Republican of Iowa and the chairman of the Finance Committee.
Using his broad authority over much of the government's budget, Senator Grassley and his staff have been investigating the F.D.A. for months after several controversies swept the agency this year.
The hearing focused on the last of these controversies: Merck's decision in September to withdraw Vioxx, a pain pill that became a $2.5 billion seller and one of the most widely advertised drugs in the world.
Merck withdrew Vioxx when a study it sponsored found that after 18 months of use the drug doubled the risk of heart attack or stroke.
Critics of the F.D.A. have said that studies from as early as 1999 and 2000 showed that Vioxx was a risk to the heart, and many asked why the F.D.A. had not forced the drug's withdrawal earlier.
The critics' case has been bolstered by many e-mail messages from Merck and by company documents disclosed in lawsuits by users of Vioxx. In many of the documents, Merck executives and scientists discussed the possible link between Vioxx and heart damage years before the company publicly admitted that the drug could cause harm.
Merck executives have said the documents are being taken out of context.
Raymond V. Gilmartin, Merck's chief executive, testified Thursday that his company followed a "rigorous scientific process" as it examined the risks and benefits of Vioxx.
But Dr. Graham and other witnesses severely criticized Merck, saying the company should have acted years earlier to confirm the risks of Vioxx. Dr. Graham raised his estimates of those in the United States who had suffered heart attacks or stroke as result of taking Vioxx to a range of 88,000 to 139,000, up from 28,000. As many as 40 percent of these people, or about 55,000, died as a result, he said.
Dr. Gurkirpal Singh, an adjunct clinical professor at Stanford University, said at the hearing that Merck scientists had tried to intimidate him after he publicly raised questions about the effects of Vioxx.
Dr. Singh, a rheumatologist and science officer of the Institute of Clinical Outcomes Research and Education in Woodside, Calif., said: "I was warned that if I continued in this fashion there would be serious consequences for me. I was told that Dr. Louis Sherwood, a Merck senior vice president and a former chief of medicine at a medical school, had extensive contacts within academia and could make life very difficult for me at Stanford and outside."
Dr. Graham said that in his years at the F.D.A., he had recommended that 12 drugs be withdrawn. Only two are still being sold, he said.
His list of the five most worrisome drugs angered pharmaceutical makers, although objections to most of these drugs have long been known. For instance, Accutane, a drug for severe acne, can cause birth defects. The drug's label has warnings about this risk, and the F.D.A. has long been trying to get physicians to confine prescriptions to those women who cannot become pregnant or who are taking birth control.
Dr. Graham said that the F.D.A. needed to do a better job restricting the drug's sales.
Carolyn Glynn, a spokeswoman for Roche, which makes Accutane, said that her company had worked with the F.D.A. for years to "address the risk of birth defects."
Dr. Graham mentioned Crestor because, he said, it was the only cholesterol-lowering drug on the market that caused acute kidney failure. And the drug is more likely to cause a serious muscle-weakening disease than similar drugs, he said.
AstraZeneca introduced Crestor last year, but sales have been disappointing largely because of worries about the drug's safety. Public Citizen, a Washington advocacy group, has called for it to be withdrawn.
"We are confident in the safety profile of Crestor," said Rachel Bloom-Baglin, a spokeswoman for AstraZeneca. "To date, the F.D.A. has not given us any indication of a major concern regarding Crestor."
But Dr. Kweder of the F.D.A. told the panel that Crestor's risks are "something that we are in the process of and have been evaluating very, very closely."
Studies of the painkiller Bextra, also mentioned by Dr. Graham, have shown that it increases the risks of heart attack in patients undergoing cardiac surgery. In rare cases, the drug can also cause a fatal skin reaction. Despite these risks, Bextra, which is similar to Vioxx, has never been proved to be any more effective at reducing pain or protecting the stomach than older medicines like ibuprofen that are a fraction of the price and pose none of these suggested or proven risks.
Susan Bro, a spokeswoman for Pfizer, the maker of Bextra, said that the drug "has been found to be safe and effective when used as indicated to treat osteoarthritis, rheumatoid arthritis and menstrual pain." She said the F.D.A. planned to ask a panel of experts early next year to examine the safety of Bextra and Celebrex, a Pfizer pain drug.
Meridia is a weight-loss pill, made by Abbott Laboratories, that can cause substantial increases in blood pressure in some patients. Public Citizen has called for Meridia's withdrawal because it has been associated with 124 reports of serious cardiovascular problems, including 49 deaths, said Dr. Sidney Wolfe, director of Public Citizen's health research group.
Dr. Graham testified that few patients were able to withstand Meridia's side effects long enough to benefit from its use. "What's the utility of the drug?" he asked.
Laureen Cassidy, a spokeswoman for Abbott, said, "Science continues to support the safe use of Meridia as a treatment for obesity."
The fifth drug named by Dr. Graham was Serevent, an asthma medication made by GlaxoSmithKline, which stopped a large trial last year after an interim analysis revealed an increased risk of asthma-related deaths and life-threatening episodes among those given the drug.
"We have case reports of people dying clutching their Serevent inhaler," Dr. Graham said.
After the study was released, the F.D.A. placed a "black box" warning, its most severe, on the drug's label. The agency concluded that the drug's benefits outweighed its risks.
In a statement Thursday, GlaxoSmithKline said that it "stands firmly behind Serevent, which is safe and effective when used appropriately and in accordance with labeling and treatment guidelines."
Dr. Galson of the F.D.A. emphasized that the drugs mentioned by Dr. Graham "are all approved and are safe and effective like other drugs that are approved, recognizing that safe does not mean risk-free."
Dr. Kweder of the F.D.A. defended the agency's handling of Vioxx and said that Merck had "acted responsibly" when it sold Vioxx. She said that Dr. Graham's estimates of Vioxx's toll were simply mathematical guesses and "not real deaths." And she said that it was not unusual when a drug went on the market "to have ongoing concerns about particular aspects of its safety."
In his testimony, Mr. Gilmartin of Merck retraced many of the steps his company had undertaken and noted that while some early studies suggested that the drug might be a risk to the heart other studies found no problems. He said he believed so thoroughly in the drug that his wife took it until the day the company withdrew it.
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http://www.nytimes.com/2004/11/18/business/18hearing.htmlNovember 18, 2004
F.D.A. Leader Says Study Tied to Vioxx Wasn't Suppressed
By GARDINER HARRIS
Top federal drug reviewers immediately recognized the importance of a study showing the cardiovascular risks of the painkiller Vioxx, according to a statement released yesterday by Dr. Lester M. Crawford, acting commissioner of the Food and Drug Administration. The drug was withdrawn from the market by Merck in late September.
Dr. Crawford released the statement ahead of a Senate hearing today and in response to criticism that his agency tried to stifle the conclusions of one of its own drug safety experts that Vioxx was unsafe. Dr. Crawford also backed away from statements last week by agency officials that Dr. Curt Furberg, a professor of public health sciences at Wake Forest University, had been removed from an advisory committee because he had publicly questioned the safety of Bextra, a drug in the same class as Vioxx, called COX-2 inhibitors.
The advisory committee is scheduled to meet early next year to discuss the safety of Celebrex and Bextra, two painkillers made by Pfizer, which are also COX-2 drugs. Dr. Furberg recently co-authored a study concluding that Bextra may increase the risk of heart attacks, as Vioxx has been found to do, and he was quoted in The New York Times saying that Pfizer was trying to "suppress" this information.
On Friday, an F.D.A. spokeswoman said that Dr. Furberg's removal from the committee was a "routine procedure" that resulted from an "intellectual" conflict of interest. Critics of the agency pointed out that airing intellectual differences is the point of holding an advisory committee hearing.
Dr. Crawford wrote in his statement that "the advisory committee preparation process is still under way, so it was premature for any F.D.A. official to suggest that Dr. Furberg could not participate in the upcoming meeting."
Dr. Crawford's six-page defense of his agency was released before a Senate hearing today being held by Senator Charles E. Grassley, Republican of Iowa, the chairman of the Senate Finance Committee.
One key witness will be Dr. David Graham, an F.D.A. drug safety reviewer who co-authored a study critical of Vioxx and then complained in e-mail messages that his supervisors denigrated his conclusions.
The hearing comes as the F.D.A. faces increasing criticism on several fronts. In recent months, the agency has been severely criticized for failing to conclude sooner that antidepressant drugs can cause children and teens to become suicidal. It was also criticized for being surprised when British health regulators withdrew their approval in October for Chiron to make flu vaccines at a plant in Liverpool. The British action reduced the anticipated supply of flu vaccine in the United States by half.
And when Merck announced that it was withdrawing Vioxx after a study found that it doubled the risk of heart attacks, critics said the F.D.A. should have known of the risks three or four years ago.
Four separate Congressional hearings this week will examine the agency's decisions involving the flu vaccine and the Vioxx safety questions.
In his statement, Dr. Crawford pointed out that the agency underwrote and supported Dr. Graham's study of Vioxx. And he indicated that when Dr. Graham concluded that Vioxx increased the risks of heart attacks "supervisors immediately recognized the importance" of the study.
But he also noted that the agency should not be criticized for failing to take Dr. Graham's conclusions seriously because agency supervisors did not see his report before Merck's withdrawal of the drug on Sept. 30.
Dr. Crawford also pointed out that he had asked the Institute of Medicine, the government's premier scientific review agency, to analyze the agency's drug safety system. And he will soon set up a formal system in which reviewers who disagree with their bosses can have their views considered by an independent panel.
Dr. Graham's testimony today will be followed by that of two physicians, Dr. Gurkirpal Singh of Stanford University Medical School and Bruce M. Psaty of the University of Washington, who will testify about their analysis of the early studies of Vioxx.
They will be followed by Dr. Sandra Kweder, deputy director of F.D.A.'s office of new drugs, and Raymond V. Gilmartin, Merck's embattled chief executive.