Tricky FDA Debate:
Should a Risky Drug
Be Approved Again?
By ANNA WILDE MATHEWS and SYLVIA PAGÁN WESTPHAL
February 24, 2006; Page B1
Next month, Food and Drug Administration advisers will take up one of the most difficult questions the agency ever faces: Should a promising drug that carries a known and deadly side effect still be allowed on the market?
Tysabri was seen as a life-changing drug for the nation's 400,000 multiple-sclerosis patients and a potential blockbuster for its makers, Biogen Idec Inc. and Elan Corp. But last February, it was abruptly withdrawn after being linked to a rare but often fatal brain infection called progressive multifocal leukoencephalopathy, or PML. Two patients died of the condition, while a third survived but was significantly impaired and no longer able to work.
Now the companies hope to convince an FDA advisory committee, and the agency itself, that Tysabri should be back on the market. A two-day meeting set for March 7 and 8 will focus on whether the drug should return -- and what limits should be set on its use if it does.
The meeting also will provide the latest setting for debate over how the FDA should balance medicines' efficacy and safety. On one side, the FDA generally weighs the seriousness of the condition involved, the effectiveness of the drug and whether there are alternative medications. On the other side, the agency evaluates the frequency and severity of side effects and whether they can be easily detected, prevented or cured. The FDA also considers whether a drug's label warnings are sufficient, or whether other restrictions are needed, a tack that has become increasingly common during the past several years.
Sometimes, "a considerable toxicity is acceptable because the benefit of the drug is great, and you try to minimize the harm to people," says Robert Temple, director of the FDA's office of medical policy. The agency last week signaled that it believes Tysabri holds value for at least some patients by ending a freeze on Biogen's clinical trials of the drug. "We consider MS a very serious disease, and people might take risks to get an effective treatment," Dr. Temple says.
Dr. Temple says that "every case is different." In treatments for certain conditions, such as cancer, possible deadly side effects are accepted. "You have to use those kinds of remedies to get any effect at all," he says. By contrast, the arthritis pain treated by Merck & Co.'s withdrawn Vioxx isn't seen as a life-threatening condition for most people.
The FDA is believed to have allowed only one drug -- GlaxoSmithKline PLC's Lotronex -- back on the market after being withdrawn for safety reasons. The medication, a treatment for irritable bowel syndrome, was reintroduced in 2002 after being recalled in 2000 after reports of intestinal problems that led to a few deaths. Some patients pushed hard for the drug's return because they felt they had no alternative treatments. The FDA imposed significant restrictions: Lotronex can be prescribed only by doctors enrolled in a special program, and patients must sign consent forms.
Because it showed powerful effectiveness in treating MS, Tysabri also has strong backing from a vocal group of MS patients. "Frankly, I'm willing to take the chance," says Marcy Canavan, an Accokeek, Md., retiree who plans to speak at the FDA committee meeting. Ms. Canavan, who says she has no ties to Biogen or Elan, was scheduled to start on Tysabri before it was withdrawn. She believes the drug will help ease worsening MS symptoms that include walking difficulties. Other symptoms of MS can include vision problems and numbness, but most people with the disease have a normal or almost-normal life expectancy.
Tysabri won accelerated approval from the FDA in November 2004. One trial had shown that the drug reduced the rate of MS relapses, or flare-ups, by 66%. Just three months later, however, the companies suspended sales of Tysabri. All three cases of PML occurred in clinical trials -- two in MS patients and a third in a patient with Crohn's disease, an intestinal illness. About 3,000 people had taken Tysabri through studies.
James Mullen, chief executive of Biogen, says if the drug comes back the company will "strongly warn" about the brain infection, although he declined to provide specifics because he says those details likely would be worked out with the FDA next month. "We are not telling people that we think we solved it and that we are not going to see it," he says.
Among the issues confronting the FDA: Is Tysabri appropriate for all MS patients or should it be limited to those who haven't gotten results from other treatments? Should people get it only when their MS is advanced? Biogen says Tysabri should be available for a broad spectrum of patients. Some neurologists have told the company that they may still prescribe it for newly diagnosed MS patients, because of the drug's superior efficacy.
Other doctors say they would use it only for advanced MS. "The risk is not acceptable" for MS patients with mild forms of the disease, says Annette Langer-Gould, a neurologist at Stanford University who treated one of the Tysabri PML patients.
Another question will be whether Tysabri poses a danger only when combined with other medicines that damp the immune system. Mr. Mullen says Biogen will likely "caution against" using Tysabri with other such drugs. Two of the cases of PML occurred in people taking another immune-suppressive drug, while the third had previously taken such medicines.
Though doctors can't tell in advance which patients may be prone to developing PML, Biogen is likely to argue that the condition's worst effects can be headed off. If doctors intervene early to treat signs of PML, "the outcomes can be pretty good," Mr. Mullen says.
But committee members may question how much of PML's impact can truly be prevented, and whether physicians will be able to easily separate its early symptoms from those of MS itself. "Maybe you can slow or partially arrest the disease," says Jerry Wolinsky, a professor at the University of Texas in Houston, but "once it's active in your brain, you're probably in trouble." Dr. Wolinsky has consulted for Elan and Biogen.
The committee and the FDA also will focus on whether, if Tysabri is allowed back on the market, its use should be restricted beyond the warnings on the label. Two drugs that cause birth defects, acne treatment Accutane and thalidomide, or Thalomid, approved for use in leprosy, have very tough restrictions. For example, women taking Accutane must take a pregnancy test each month, with a negative result, and use two forms of birth control. The FDA has said that in both cases the serious risks merited the stiff restrictions.
Write to Anna Wilde Mathews at firstname.lastname@example.org