Death Tied to Experimental MS Drug Stirs Debate
A year ago, Anita Louise Smith died from effects of Tysabri -- a drug that was supposed to help her cope with multiple sclerosis.
Within days, drug makers yanked Tysabri off the market, devastating many people with multiple sclerosis who had hoped that the intravenous treatment would bring them relief.
Now, as makers of the drug prepare to seek approval to put Tysabri back on the market, some prominent neurologists contend that Smith shouldn’t have been taking it to begin with -- because, they say, she didn’t have MS.
Smith’s case dramatizes a new debate over how multiple sclerosis drugs are tested: In recent years, drug companies have been trying out medicines on people with mild symptoms or none at all at the time of treatment, several experts say, including some who, like Smith, might not have the disease. These trials broadened the market for MS drugs but, critics say, put patients who don’t need powerful new medicines at risk.
Smith, 46, was taking the drug as part of a clinical trial that regulators had required when they granted Tysabri fast-track approval. Most of the 1,171 patients in her trial suffered no disabilities, according to Food and Drug Administration documents.
“People with no active disease -- in other words, people who are doing fine -- shouldn’t be given an experimental drug with unknown risks,” said Stanford University neurology professor Lawrence Steinman, a co-inventor of Tysabri who has previously spoken out about the drug’s dangers.
This week, Steinman and another Stanford neurologist, Annette Langer-Gould, urged the FDA to tighten criteria for selecting patients in MS drug trials.
“We are concerned that not only were patients put at risk by Tysabri, but we feel that the risk was absolutely unnecessary to assume,” they said in an e-mail to the agency.
Biogen Idec Inc. and Elan Corp. hope to win government permission as soon as next month to resume sales of Tysabri. They say that it is an effective treatment for multiple sclerosis and that the risks can be managed by carefully selecting and monitoring patients.
Biogen Idec spokeswoman Amy Brockelman said privacy requirements prevented the company from commenting on Smith’s case. But all aspects of the Tysabri clinical trials were approved by the FDA and by oversight boards at the medical centers where the studies were conducted, she said.
FDA spokeswoman Susan Cruzan said the agency would not comment on matters regarding Tysabri before an advisory panel meets March 7 to discuss the drug’s possible return to the market. This week the FDA allowed the companies to resume clinical trials in MS patients who had been receiving the drug, a step that would provide added information about the risks of Tysabri.
Experts see the drug as a potential boon in the battle against multiple sclerosis, a disease in which errant white blood cells destroy the coating that protects cells in the brain and spinal cord. About 400,000 Americans have the disease.
For most patients, the disease is marked by flare-ups and remissions. Many experience only minor symptoms, such as numbness or tingling. But though the disease is seldom fatal, about half of MS patients become disabled -- such as comedian Richard Pryor, who was unable to speak, swallow or get out of bed unassisted in the years before his death late last year.
Though not a cure, Tysabri was designed to prevent or delay progression of the disease by blocking the white blood cells that damage the brain.
A once-monthly medicine, administered through an intravenous infusion in a doctor’s office, Tysabri received fast-track approval in late 2004 -- on condition that clinical trials continue -- because the FDA deemed it a significant advance over existing treatments. Researchers in one study noted that Tysabri nearly doubled patients’ chance of infection, although the overall risk was tiny.
Despite an annual price tag of $23,500, initial sales of Tysabri were strong. When the drug was withdrawn, 5,000 patients were taking it and 15,000 more were awaiting insurance verification and their first dose. The companies needed just 20,000 patients to break even on the drug.
Biogen Idec, based in Cambridge, Mass., and Elan, based in Dublin, Ireland, saw Tysabri as a potential blockbuster, and Wall Street expected sales to one day reach $3 billion. Now analysts are forecasting annual sales of as much as $1 billion should the drug return to the U.S. market and receive approval in Europe.
Questionable Diagnosis
Smith, who lived in Colorado Springs, Colo., was diagnosed with multiple sclerosis in 2000 after a bout of weakness in her right leg, followed by blurred vision -- both common symptoms of MS.
Although the symptoms disappeared, she started taking injections of Avonex, another Biogen Idec drug for MS. Insurance covered some of the cost, but Smith still had to pay $1,000 a month, her husband, Walter, said.
Smith started taking Tysabri in 2002 in addition to Avonex as part of a clinical trial looking at how the drugs worked in combination, according to her husband and a product-liability lawsuit he has filed against the drug companies. Her motivation for entering the trial was largely financial, he said.
Smith’s neurologist, Dr. Patricia Fodor of Colorado Springs, told the couple that as a clinical trial participant, she would receive Avonex free, he said.
“Dr. Fodor more or less said if you get on this study -- this clinical trial -- we will pay for all the Avonex you need,” Walter Smith said. “She sent home some papers and Anita signed.”
The couple, who operated a towing business, made “a decent living -- it wasn’t like we couldn’t afford it,” he said. But “it sounded good not to pay for it.”
Although she sometimes became fatigued, Smith had enough energy to shop, play with her Dalmatians and vacation in Las Vegas with her daughter, now 26, and son, 22.
But her condition took an unexpected turn in November 2004. Writing and typing became difficult, and she had problems with speech. A month later, her right side became numb and she grew increasingly forgetful.
By mid-February she was admitted to a hospital, where tests showed Smith had developed progressive multifocal leukoencephalopathy, or PML -- a disease now recognized as a possible side effect of Tysabri. Another MS patient, a San Francisco man participating in the same clinical trial as Smith, also developed PML; he survived but suffered severe disabilities.
Moved to a hospice near her home, Smith died Feb 24. Four days later Tysabri’s makers pulled it off the market. In reaction, Biogen Idec’s stock dropped 43% and Elan shares plunged 70%.
Fodor, the neurologist who had diagnosed Smith with multiple sclerosis, declined to discuss her former patient. “We have no comment on anything to do with Anita Smith or the Tysabri study,” said Debbie DeBaun, Fodor’s practice manager.
But a July report on the case in the New England Journal of Medicine led many experts to contend that Smith did not have MS.
Dr. Bette KleinschmidtDeMasters, lead author of the article, said in an interview that she had found no evidence of the disease during her postmortem examination of Smith, though it was possible that the PML had obliterated signs of MS.
Some neurologists, after reading the journal report, concluded that Smith was misdiagnosed. The fleeting symptoms she had first experienced may have been due only to fatigue.
“For me -- and a lot of other MS experts -- there is no doubt that at least this patient did not have MS,” said Dr. Thomas Berger, head of neuroimmunology at Innsbruck Medical University in Austria. Berger and a colleague said in a letter to the New England Journal of Medicine that Smith did not appear to have MS.
Writing in the British Medical Journal this week, Dr. Abhijit Chaudhuri, a London neurologist who conducted one of the earliest clinical tests of Tysabri, called Smith’s diagnosis “questionable.” He also called for stricter enrollment criteria for clinical trials and said independent reviewers should monitor patient selection.
Walter Smith’s lawsuit against the two drug companies contends that his wife did not belong in the trial and that the companies failed to confirm that she had multiple sclerosis. In court documents, the companies contend that Smith’s doctor was responsible for selecting her for the trial and for warning her about the risks.
At the root of the question is how patients are selected for multiple sclerosis drug trials. A decade or so ago, experimental MS drugs were tested in sicker patients. Those with no current symptoms -- with normal eye movement, coordination and sensation -- were not selected.
The practice changed in recent years as more neurologists began treating patients at the first sign of disease, hoping to slow its course.
Harvard Medical School neurology professor Dr. David A. Hafler, an expert on MS, said risks are an unavoidable part of drug research and that it was reasonable to test Tysabri in patients with mild as well as somewhat advanced cases of MS. “All drugs work better when used early on,” he said.
Recruitment Factor
Dr. Howard L. Weiner, also an MS expert at Harvard Medical School, said it was appropriate to enroll patients with no current physical symptoms in clinical trials if an MRI confirmed that disease was causing damage.
He cited a practical reason for including patients with mild as well as more advanced disease in trials: A broad patient group makes recruitment into trials easier, he said, saving time and money.
But other neurologists were critical of current practice.
Stanford University’s Langer-Gould said Biogen Idec helped lead the push toward earlier treatment with a study six years ago of Avonex in patients who didn’t meet the clinical definition of MS that was in effect at the time. Although the trial, which showed that Avonex could delay relapses, benefited patients because it led to earlier treatment, it also benefited Biogen Idec by expanding the market for Avonex, she said.
Langer-Gould said the Avonex study didn’t raise concerns because the drug was already on the market and considered safe. But she worries that patients with mild cases of MS face potentially greater risks from an experimental drug than from their illness.
“What was the rush to treat these patients?” she asked.
Chaudhuri, the London neurologist, shares her concern. “Patients with mild MS and who are fairly stable generally don’t get that bad,” he said. “Why on Earth would you go into a treatment trial with the possibility of side effects and complications when you don’t expect to get much worse?”
