FRIDAY, March 3, 2006 (HealthDay News) -- Two experts are questioning whether a woman who died of a rare infection after participating in a trial for the multiple sclerosis (MS) drug Tysabri should have been included in the study in the first place.
The patient was suspected of having MS but showed no symptoms, and was later found not to have had MS. Now, a commentary in the March 4 issue of The Lancet paints a cautionary tale of what went wrong, and asks whether the woman should have received Tysabri at all, when other safe and effective agents were at hand.
The piece, penned by Stanford University neurologists Dr. Annette Langer-Gould and Dr. Lawrence Steinman, adds fuel to the debate over Tysabri (natalizumab), which has been linked to three cases of a rare, dangerous infection called progressive multifocal leukoencephalopathy (PML). Two of those cases proved fatal.
Researchers quickly halted the trial last February after the PML cases emerged. At the same time, Biogen Idec and Elan Corp., the drug's makers, heeded a U.S. Food and Drug Administration advisory and withdrew Tysabri from the market, just three months after its fast-track approval for cases of especially tough-to-treat MS.
However, research published this week in the New England Journal of Medicine found the drug to be safe and effective, at least for the short term. And after a yearlong investigation, an FDA advisory committee recently announced that it will meet Tuesday and Wednesday to consider the company's request to return the drug to the market.
In the Lancet commentary, Steinman and Langer-Gould criticize how the original trial was conducted.
"When you test a drug that is potentially dangerous and, in this case, carries a risk of one per 1,000 of fatality or serious injury, one ought to be careful that the subjects in the study have a fair risk-benefit balance," explained Steinman, a professor of neurobiology and neurological sciences who helped develop Tysabri.
In fact, the woman who died, Anita Louise Smith, had been diagnosed with MS, even though she had no symptoms. In the end, it was determined that Smith did not have MS. "But that can happen," Steinman said. "MS is a notoriously difficult disease to diagnose."
However, whether or not an asymptomatic patient such as Smith should have been included in the trial to begin with points to the crux of the problem, according to Steinman.
"One needs to reexamine the justifications for putting someone on an experimental MS drug when they have no disability," he said, adding that the criteria for including patients in such a trial needs to be re-evaluated.
Steinman does believe the FDA should let Tysabri go back on sale. "If I were the FDA commissioner, I would let it back -- with warnings about the risk," he said. "I would leave it up to physicians and their patients to make the decision."
However, Steinman believes the drug will -- and should -- be used mainly for patients who are not doing well, and not for patients in the early phases of MS.
"It's hard to justify looking a person in the eye and saying that 'You have all these approved drugs that are safe -- or [you have] this drug, which might be more effective. However, it carries a chance that you can die from it or have a really serious neurologic injury,'" he said.
Langer-Gould, who treated the MS patient who survived PML, believes the risk of developing the infection while receiving Tysabri is greater than reported. But, she explained, "all you need to have is three more cases, and the estimate becomes one in 500."
In addition, Langer-Gould doesn't think Tysabri is significantly more effective than other, safer MS drugs. "This drug does nothing more than [add] a 4 percent reduction in disability, which is nothing," she said.
However, Langer-Gould said she, too, would like to see Tysabri back on the market. "I'd like to have this drug as an option for patients who are sicker," she said. "But I'd have to tell them that I have no data to support the use of the drug, because most of the patients at risk for disability were excluded from the trial."
"We have so little for these patients," she noted. If nothing else is working, Tysabri might be worth a try, she reasoned: "At that point in their disease, there is nothing to lose."
Langer-Gould is concerned, however, that if Tysabri returns to pharmacy shelves, there is a high risk of it being wrongly prescribed. "There are still many clinicians out there saying that they are going to use it as first-line treatment," she said. "They have a misunderstanding of both the efficacy and the safety of the drug."
"Physicians have to be willing and ready to accept the fact that it may kill or permanently disable their patients if they are going to use this drug," Langer-Gould said. "They need to ask themselves if that's a decision they are going to be willing to live with."
One expert thinks the ongoing Tysabri controversy distracts from other promising work in MS treatment.
"Steinman and Langer-Gould make some interesting points," said Nicholas LaRocca, the director of Health Care Delivery and Policy Research at the National Multiple Sclerosis Society.
"Over the years, the whole science of clinical trials in MS has been evolving," LaRocca said. "We are way ahead of where we were 20 years ago. This is not a field that is standing still."
He added that there's always been controversy as to whether or not doctors should actively treat patients who appear to be doing well. "If you talk to a number of neurologists, you will get differing opinions," LaRocca said.
One neurologist who took issue with the Lancet commentary illustrates that point.
"The accusation that this lady was put at risk inappropriately is specious, callous and vicious in its condemnation of standard of practice for clinical neurology research," said Dr. Norm Kachuck, an associate professor of neurology at the University of Southern California Keck School of Medicine. "It is sad and tragic that anyone is injured in medical care, in medical research. With the best of intentions, the most careful physician can do harm with the two-edged swords of our armamentarium."
"There is no reason except the obvious -- that research is a search into the unknown, with only roughly estimated risks -- that this woman, and all of the other courageous folks who contribute their bodies and souls to medical research, would not have been made a subject in this and other trials which we do to help understand and cure human disease," Kachuck said.
The amount of attention Tysabri has gotten is striking, LaRocca added.
"It sort of obscures the broader picture of MS research, and some of the other exciting things that are happening in MS research," he said. "We hope that we can get back to focusing people's attention on some of the exciting things that are happening in the MS field."
More information
For more on MS, head to the National Multiple Sclerosis Society.
