March 2, 2005
Los Angeles Times
By Ricardo Alonso-Zaldivar and Denise Gellene, Times Staff Writers
A specialist in the disease repeatedly questioned Tysabri's safety before a patient's death.
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 … 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 …. 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."