Wall Street Journal - March 1, 2005
Anna Wilde Mathews and John Hechinger, anna.mathews@wsj.com and John Hechinger at john.hechinger@wsj.com

With the Food and Drug Administration's handling of drug safety already under a microscope, the suspension of multiple-sclerosis drug Tysabri creates a new area for scrutiny: the agency's process for rushing out promising new treatments for the most serious conditions.

Biogen Idec Inc. and Elan Corp. yesterday announced that they would suspend Tysabri from the market and from clinical trials after confirming that one patient had died of a neurological condition called progressive multifocal leukoencephalopathy, or PML. They said a second patient also may be afflicted with it. Both patients were in clinical trials and had taken the drug in combination with another medication, Avonex.

What sets the Tysabri case apart from other recent drug-safety controversies is that it was allowed on the market through the FDA's "accelerated approval" program. Under that mechanism, a drug that treats a life-threatening disease and represents a significant improvement over available therapies can win approval with less data than typically required, though the company is supposed do a follow-up study.

Tysabri received fast approval in November after it was shown to reduce the risk of relapses of multiple sclerosis 66% compared with placebo. When it was used with Avonex, also an MS treatment, the combination cut that rate 54% compared with Avonex alone.

Now, researchers, patients and the agency itself will have to ask whether the potential danger with Tysabri could have been discovered before the drug won accelerated approval. The two cases involve patients who had taken the drug for more than two years, and Tysabri was approved based on about one year of data. If the FDA followed its more typical procedure of waiting for two-year data on multiple-sclerosis drugs, the cases might have surfaced during the review and "they probably would not have approved the drug," says Aaron Miller, chief medical officer at the National Multiple Sclerosis Society. Yet he says it isn't easy to second-guess the agency. "The FDA has a real challenge and a balancing act that they need to follow. They need to make effective drugs available sooner to people with serious diseases," he says. Tysabri "looked like a very promising drug."

The Tysabri suspension will add a difficult line of questions for the FDA, which already is under congressional scrutiny. Yesterday, Senate Finance Committee Chairman Charles Grassley, an Iowa Republican, introduced a bill with Democratic Sen. Chris Dodd of Connecticut that would force drug makers to disclose more clinical trial results. Tysabri is likely to come up in a Senate hearing on safety and the agency's drug-approval process scheduled for today. It comes as some outside researchers already were questioning whether the agency's accelerated-approval process has become too widely used, potentially allowing some drugs on the market with only limited evidence of efficacy and safety.

"All of us have to raise our expectations of when a drug is good enough to be put out there," says Silvana Martino, a clinical associate professor at the University of Southern California who heads the FDA's oncologic drugs advisory committee. "It requires time for certain toxicities to occur, and it requires more people to be treated."

Douglas Throckmorton, acting deputy director of the FDA's drug center, says that the problem that has surfaced in the patients taking Tysabri is "extremely rare," and "it's hard to imagine we would detect" it in a full approval process. It is "unlikely that a rare adverse event like this one would be seen" in the typical trials done for a drug approval, and this drug held strong benefits in a terrible disease, he says. Though "the longer you watch people, sometimes you learn things," he says. "I don't think this particular case raises any questions" about the accelerated approval process, he says.

Elan Chief Executive Kelly Martin declined to comment on whether the safety issue might have surfaced before the drug went on the market through a typical approval process. "Hindsight is 20/20," he says, but he believes the accelerated approval was appropriate.

Burt A. Adelman, Biogen executive vice president, says the expedited review of Tysabri by the FDA was warranted given the need for the drug and its strong efficacy. He also said the FDA received updated data before it approved the drug in November that included 20 months of safety data. "When this product was approved there was outstanding evidence of efficacy and a lot of safety data," he says. "I think the agency took a prudent course and we took a prudent course."

The oncologic drugs committee, which debated the accelerated-approval issue in December, is likely to discuss it again in meetings planned for Thursday and Friday. It will examine new results for the AstraZeneca PLC lung-cancer drug Iressa, which failed to extend patients' lives in a recent large clinical trial. Iressa was allowed on the market in 2003 after it helped shrink tumors in only 10% of patients in a limited study, while other studies showed no effect.

In an analysis that was presented last year at a meeting of the American Society of Clinical Oncology, and later updated, researchers found that of 26 uses for cancer drugs that won accelerated approval, six had serious new adverse events that were discovered only after they went on the market. In addition, only nine of those uses had new, fuller data reviewed after the accelerated approvals, and just six had accelerated approvals converted to full approvals. No accelerated approvals were revoked.

Charles Bennett, an author of the analysis and a researcher at Northwestern University and the Veterans Administration, says the standards for accelerated approval weren't the problem, but the FDA needs to take a tougher line on getting follow-up information for such drugs. If the study is "not done or no efficacy is shown, you should lose your approval," he says.

The FDA has long faced serious pressure from doctors and patients eager for fast access to new treatments for deadly conditions. Accelerated approval first emerged in the late 1980s, as the FDA faced demands from patients for quicker access to new AIDS drugs. In 1992, the FDA formalized the process with a new rule that allowed accelerated approval if a trial showed results that "reasonably suggest clinical benefit," even if it wasn't proven. Drug makers were expected to follow up with more studies. Since then, the agency has allowed accelerated approval of dozens of drugs, many in cancer and AIDS .

In today's Senate hearing, lawmakers are expected to hear strong calls for the FDA to avoid slowing down its process for allowing badly needed therapies on the market. "We are major, major advocates for accelerated approval," says Ellen Sigal, chair of the nonprofit Friends of Cancer Research. "We have patients dying who are in dire need of drugs."

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Laura Johannes and David Armstrong contributed to this article.

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