Rheumatoid Arthritis Drug Not Withdrawn Despite Safety Concerns

The Arthritis Advisory Committee to the Food and Drug Administration (FDA) recently rejected a petition to remove a rheumatoid arthritis drug from the market due to severe liver toxicity. The committee decided that the benefits of Arava (generic name: leflunomide) outweighed any risks. The committee's decision favored Arava, despite the fact that the FDA's own experts determined that the drug put one in 200 users at serious risk for acute liver injury. All FDA advisory committees are primarily made up of outside experts, and their recommendations are usually followed by the agency.

The FDA approved Arava in 1998 to reduce symptoms of rheumatoid arthritis and to slow damage to the joints. By March 2002, Sidney Wolfe, MD, director of Public Citizen, filed a petition with the FDA requesting immediate withdrawal of the drug from the market and stating that Arava was associated with 130 severe liver reactions, including 56 hospitalizations and 22 deaths, two of whom were people in their twenties. These adverse reactions occurred between 1998 and 2001.

During the public comment period of the committee meeting held last month, Dr. Wolfe pointed out that his safety concerns are supported by two in-house FDA experts, Drs. Banelle and Graham, who had conducted their own thorough review of all adverse reaction reports associated with Arava. Dr. Wolfe, whose organization has been an effective FDA watchdog for over 30 years, began his remarks by asking why neither FDA expert was allowed to attend this meeting and present their views.

He went on to cite a Public Citizen survey of FDA medical officers in which 14 instances were identified where they reported being "told not to present information at FDA Advisory Committees that was unfavorable to the possible approval of a drug." That said, Dr. Wolfe went on to summarize the FDA in-house review which found 16 cases of acute liver failure and 38 cases of severe liver injury. Dr. Wolfe concluded his remarks with his findings that the older rheumatoid arthritis drug methotrexate is safer than Arava.

But the Arthritis Advisory Committee's final decision appeared to be based on the presentation by Larry Goldkind, MD, who is a gastroenterologist and deputy director of the FDA Division of Anti-inflammatory Analgesic and Ophthalmic Drug Products. Dr. Goldkind said he conducted "an exhaustive" reassessment of liver injuries, citing clinical trials, the FDA's adverse drug event reporting system called Medwatch, and several other databases. Altogether these sources reported the experiences of thousands of people taking Arava.

Dr. Goldkind found only one definite case of acute liver failure as a result of Arava use, and cases of "probable" Arava-induced acute liver failure, but "there are additional cases that vary from possible to unlikely." In the majority, he said, other explanations could be found for the liver injuries. The chief problem associated with the drug, according to Dr. Goldkind, is its high rate of false alarms from the recommended liver function tests. He explained that Arava is associated with elevations of liver enzymes in a significant number of patients, but they are generally reversible.

At the end of the meeting, committee member Dr. Allan Gibofsky addressed Dr. Wolfe's charges against the FDA, saying that they cast a pall over the proceedings. He invited any FDA officer with a conflicting viewpoint to Dr. Goldkind's to state his or her case before the committee reached its final decision. There was no response to the invitation.

For More Information:
The transcripts of this meeting of the Arthritis Drug Advisory Committee, held March 4-5, 2003, can be read at the FDA Web site (www.fda.gov). Click into "advisory committees" and then "New Documents." On the same home page of the FDA, see "Medwatch: Safety Information and Medical Product Reporting."

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