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FDA Official Admits 'Lapses' on Vioxx - FDA Didn't Heed Warnings on Dangers of MS Drug

Wed, 2 Mar 2005

As the Senate committee on Health, Education, Labor and Pensions prepares for the second day hearing about FDA's performance, one hopes that the committee will follow up Tuesday's hearing with some tough questions about FDA's failure to heed warning signals, thereby endangering lives.

The New York Times reports (below) that Dr. Sandra Kweder, deputy director of FDA's office of new drugs at the agency, acknowledged "the agency took too long to get information about Vioxx's heart risks into the prescribing label that is provided to physicians. More than a year passed between an advisory panel's conclusion that those risks should be highlighted and the label changes," she said.

Dr. Kweder blamed difficult negotiations with Vioxx's maker, Merck, for the delay.

Who is responsible for FDA's stealthy rescinding of the statement from antidepressant warning labels acknowledging that: "A causal role for antidepressants in inducing suicidality has been established in pediatric patients"?

This statement was part of the warning label for antidepressants that the FDA issued on March 22, and reaffirmed on October 15‹when the FDA added a Black Box warning. But on February 10, 2005, Dr. Steve Romano, vice-president of Pfizer, announced--during criminal court proceedings in which the antidepressant Zoloft figured prominently--that the FDA had rescinded the statement.

By rescinding the agreed upon language, the FDA is helping to blur the clarity and reduce the impact of the Black Box warning. Was this action taken under pressure from Pfizer?

Another example involves the MS drug, Tysabri, which the manufacturer has just withdrawn after a patient died of progressive multifocal leukoencephalopathy, or PML, a rare central nervous system disease usually seen in AIDS patients.

The Los Angeles Times reports (below) several scientists expressed concern about the drug prior to its fast-track approval.

Dr. Lawrence Steinman, a Stanford University professor and an MS specialist, said he repeatedly wrote and spoke about "the potential for serious immune-system side effects with this type of drug." Indeed, other experts in the field say the body's immune cells were a poor target for an MS drug.

Tysabri "blocks the ability of [immune cells] to get from the blood vessels to the tissue to fight infection." In the opinion of Stephen Miller, a microbiologist at Northwestern University who has collaborated with Biogen on studies in the past, "that is not the way to go."

"It's a legitimate question to ask if the FDA paid any attention to those concerns, and if not, why not?"

Souglas Throckmorton, acting deputy director of the FDA's Center for Drug Evaluation and Research (CDER), when confronted with these concerns and with FDA's failure to give Dr. Steinman an opportunity to discuss with FDA officials his concerns, Throckmorton responded: "The trials were well planned and well conducted, and the outcomes suggested a product with important scientific advances."

There is a cultural divide it seems, between FDA officials at CDER and responsible scientists for whom safety issues remain a central concern. Even scientists in the biotechnology industry acknowledge that something clearly went wrong in the agency's expedited process:

"The fast-track process, in the situation that exists, obviously is not working right," said Joseph Panetta, president of Biocom, an industry group in San Diego, where Biogen ranks among the largest biotech employers. "Something about the process needs to be restructured."

Contact: Vera Hassner Sharav
212-595-8974

THE NEW YORK TIMES
March 2, 2005
F.D.A. Official Admits 'Lapses' on Vioxx
By GARDINER HARRIS

WASHINGTON, March 1 - After the Food and Drug Administration insisted for months that it did nothing wrong in its oversight of the withdrawn pain pill Vioxx, a top agency official acknowledged "lapses" in the agency's actions before a Senate panel on Tuesday.

The official, Dr. Sandra Kweder, deputy director of the office of new drugs at the agency, also said the power to require label changes "would be very helpful."

Most witnesses testifying before the panel, the Senate Committee on Health, Education, Labor and Pensions, agreed, saying the agency should have the authority to force label changes and make companies conduct tests if safety issues arose after a drug was approved.

Dr. Steven Galson, the director of the new drug center, said after the hearing that the F.D.A. had not requested new authority over labels.

Dr. Kweder said the agency took too long to get information about Vioxx's heart risks into the prescribing label that is provided to physicians. More than a year passed between an advisory panel's conclusion that those risks should be highlighted and the label changes, she said.

Dr. Kweder blamed difficult negotiations with Vioxx's maker, Merck, for the delay. "We don't have the authority to tell a company, 'This is how your label has to look,' " she said. "We have to negotiate with the company the specific language of how things should be worded, the placement, those kinds of things, after talking to them."

The other lapse, Dr. Kweder said, was "the failure of that information somehow to be in the forefront of the consciousness of the prescribing physician."

Millions of people took Vioxx in the years after its risks to the heart became apparent. As a result, as many as 55,000 patients may have died from heart attacks and strokes induced by the drug, according to estimates by drug safety officials at the F.D.A. Merck withdrew the drug from the market in September, after a test showed that it doubled the risk of heart attack and stroke.

Dr. Kweder's admission could cause difficulties for Merck, which is battling more than 800 lawsuits filed by thousands of patients claiming that they were injured by Vioxx.

Casey Stavropoulos, a Merck spokeswoman, responded, "We worked diligently with F.D.A. to do all requested analyses and develop labeling that provided physicians with the most accurate and appropriate information."

An F.D.A. advisory panel concluded last month that Celebrex and Bextra, similar pills made by Pfizer, also cause heart problems. The panel concluded that all of these drugs should have labels with strong warnings about their heart risks.

Senator Michael B. Enzi, a Wyoming Republican who is chairman of the health committee, said he had not decided what changes, if any, he would propose for the agency. But he said examining problems at the F.D.A. was "not only critical, but it's also a hot issue right now."

Senator Patty Murray, Democrat of Washington, asked Dr. Kweder during the hearing if Merck had rejected F.D.A.'s initial proposals to warn of Vioxx's heart risks on its label. "They rejected many of our proposals, and we similarly rejected many of the proposals they sent to us," Dr. Kweder said.

The negotiations began in February 2001 and were not resolved until April 2002, a period that Dr. Kweder said was unusually long. "Usually it's just a matter of a few back-and-forths and getting the language right," she said.

Dr. Kweder also said the Bush administration's proposal to add $5 million to the agency's budget in the 2006 fiscal year for tracking the safety of drugs once they are approved represented "a good down payment."

The F.D.A. has almost no ability to uncover dangers once drugs are approved if risks are common problems like heart attacks, top agency officials have said. Every witness who went before the panel on Tuesday said the agency must do a better job of uncovering such dangers using existing computer databases.

One witness argued that the agency did not need more power. Dr. Scott Gottlieb, a former top official at the agency who is now at the American Enterprise Institute, a conservative research group, said the agency "doesn't use its existing authority very well."

Dr. Gottlieb said that the agency's initial proposals to change drug labels often "aren't worded very well," and that they improve greatly after suggestions from drug companies.

William Schultz, another former top official at the F.D.A., said the agency should be given the power to limit or ban drug advertising for a period after a drug's initial approval and limit prescriptions of some medicines to certain specialists.

THE LOS ANGELES TIMES
March 2, 2005
Warning Didn't Slow Approval of MS Drug

A specialist in the disease repeatedly questioned Tysabri's safety before a patient's death.
By Ricardo Alonso-Zaldivar and Denise Gellene, Times Staff Writers

WASHINGTON ‹ A multiple sclerosis drug pulled off the market after a patient died was approved by the Food and Drug Administration even though a prominent neurobiologist and a top medical journal had questioned the drug's safety.

When the FDA gave the drug, Tysabri, so-called fast-track approval in November, "there was already somebody out there saying 'Whoops,' " Arthur Levin, director of the New York-based Center for Medical Consumers, said Tuesday.

"It's a legitimate question to ask if the FDA paid any attention to those concerns, and if not, why not?"

Dr. Lawrence Steinman, a Stanford University professor and an MS specialist, said he repeatedly wrote and spoke about the potential for serious immune-system side effects with this type of drug. The MS patient who died while taking Tysabri suffered from progressive multifocal leukoencephalopathy, or PML, a rare central nervous system disease usually seen in AIDS patients.

"I was really worried this would cause opportunistic infections," Steinman said. "I was largely on the sidelines, issuing jeremiads and negative predictions that this would lead to troubles."

Steinman - whose career as a developer of drugs for multiple sclerosis makes him a potential competitor to Tysabri's manufacturers - began raising his concerns long before the New England Journal of Medicine published an editorial in early 2003.

At that point, Tysabri was in what is known as a Phase II trial in which a relatively small number of people taking the drug were studied for six months. The Journal said that "firm conclusions about safety Š must await the results of much larger" studies.

Those larger, Phase III studies haven't yet been completed. Nonetheless, the drug was approved under an accelerated program for breakthrough medicines that the FDA sees as offering extraordinary benefits to patients.

"This was a product that absolutely fit the criteria for accelerated approval," said Dr. Douglas Throckmorton, acting deputy director of the FDA's Center for Drug Evaluation and Research. "The trials were well planned and well conducted, and the outcomes suggested a product with important scientific advances."

Throckmorton said he didn't know whether agency scientists saw an article Steinman wrote last summer in the journal Science, in which he warned that "there is at least a theoretical concern that recipients of the therapy would become generally compromised in their ability to fight infection."

But Throckmorton said he was confident that FDA scientists knew about, and considered, such a theoretical risk. He stressed that in almost 3,000 patients involved in clinical trials before Tysabri was approved, there were no cases of PML or life-threatening immune system reactions.

"It's clear that other drugs used for MS have effects on the immune system, and I'm sure the office thought about those same issues when they looked at this new entity," he said. "I am certain the division looked at that."

A spokeswoman for Biogen Idec Inc., which developed the drug with Elan Corp., said Steinman never met with the company to share his concerns. "Our focus now is on patients," said Amy Brockelman. "Our concern is for their safety and that is what is guiding our actions."

Some in the biotechnology industry said something clearly went wrong in the agency's expedited process, which has been criticized in the past for rushing drugs to the market before they have been thoroughly scrutinized.

"The fast-track process, in the situation that exists, obviously is not working right," said Joseph Panetta, president of Biocom, an industry group in San Diego, where Biogen ranks among the largest biotech employers. "It needs to be looked at Š. Something about the process needs to be restructured."

MS affects some 400,000 Americans and leaves about half of its victims permanently disabled. The cause of the disease is unknown, but scientists believe it is rooted in a malfunction of the immune system, which prompts immune system cells to attack the brain and spinal cord.

The FDA approved Tysabri based on results from the first year of two Phase III clinical trials, each of which was designed to last for two years. The first-year results of those trials showed that the drug reduced the frequency of MS attacks by as much as 66%.

The drug is believed to work by binding to certain immune system cells, preventing them from traveling to the brain where they can cause damage. The fast-track clearance was hailed as a breakthrough for MS patients, who had not seen a new drug in a decade. Usually the agency requires the completion of clinical trials before granting approval.

On Feb. 17, Biogen announced that it had completed one of the two-year clinical trials and that the results confirmed the positive one-year outcome. But the next day the makers of the drug reported to the FDA that one patient taking Tysabri as part of the studies had developed PML and that there was a second suspected case.

There is no known effective treatment for PML, which often leads to death. One of the patients died Thursday, four days before the drug was recalled. Biogen previously said the patient had died Feb. 18. Company executives said they learned of the two patients after its pre-dawn Feb. 17 announcement about the trial, but refused to be more specific.

Researchers familiar with Tysabri said they weren't surprised to learn that patients had become infected with the deadly virus. Emmanuelle Waubant, a neurologist at UC San Francisco, said PML didn't show up in the one-year data because such infections take long to develop.

"In patients with HIV, it takes several years of having their immune system compromised to develop this virus," she said. "It is not surprising it took two years in each [Tysabri] case," she said. "There is a reason why these studies were designed to take two years."

Waubant said she would not have approved the drug without seeing two years' worth of data, but she was loath to criticize the FDA because the drug also appeared beneficial. Waubant was one of the academics who helped conduct the clinical trial for Biogen and Elan.

"You are always more intelligent after the fact," she said. "It is hard to blame the FDA."

Stephen Miller, a microbiologist at Northwestern University who has collaborated with Biogen on studies in the past, said the body's immune cells were a poor target for an MS drug. Tysabri "blocks the ability of [immune cells] to get from the blood vessels to the tissue to fight infection," he said. "In my opinion, that is not the way to go."

Alonso-Zaldivar reported from Washington and Gellene from Los Angeles.

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