FDA Takes Slow Road Toward Withdrawal of Drug Approved With Fast-Track Process

Abstract

THE US FOOD AND DRUG ADMINistration (FDA) is apparently continuing to slow its withdrawal procedure for a drug that was granted access to the market through the agency’s accelerated approval process. At issue is midodrine hydrochloride, which received accelerated approval in 1996 for the treatment of symptomatic orthostatic hypotension. The approval was based on studies showing an improvement in the surrogate end point of 1-minute standing systolic blood pressure—a marker considered likely to correspond to clinical benefits, chiefly relief of symptoms and improved ability to perform activities of daily living. In granting accelerated approval, the FDA expects the manufacturer to conduct postmarket studies of clinical benefits and to determine adverse events. Such studies on midodrine were never submitted to the FDA, and on August 16 of last year, the agency began a process that could lead to the drug’s withdrawal from the market—the first such removal of a drug granted accelerated approval. On September 10, 2010, the FDA issued a clarification of its withdrawal process, saying a hearing would be granted to the drug’s sponsor, Shire Pharmaceuticals, at which time the company could present data to the agency supporting clinical benefit of midodrine. The clarification came, in part, to reduce the concerns of physicians, patients, and representatives of professional organizations who apparently consider midodrine to be effective and who were concerned that withdrawal was imminent. About 100 000 individuals are taking the drug, the FDA said. But no hearing date has been set. On January 11, the FDA issued a memorandum (http://tiny.cc/nay0z) to aid potential researchers in designing 2 studies that might adequately determine the clinical benefit of midodrine. One suggested study is a randomized, doubleblind, placebo-controlled trial establishing the effects of a single dose of midodrine on the symptoms of orthostatic hypotension. Such a study could be short-term in an acute setting, such as using a tilt-table test. The other could be a randomized, double-blind, placebocontrolled withdrawal study in patients who have used midodrine for at least 2 weeks to determine whether benefits in controlling symptoms are sustained. The memo made the point that the agency was not requiring additional safety testing and that the necessary studies are intended specifically to assess effectiveness. Ellis F. Unger, MD, deputy director of the FDA’s Office of Drug Evaluation I, said the accelerated approval process is designed so as not to require further safety studies. “With accelerated approval, the issue is the evidence of effectiveness; we accepted a surrogate end point, but there is an expectation that safety has been demonstrated here,” Unger said. “It is not like we will not look at safety information, but then we always look at safety issues.” Also on January 11, the FDA opened a public document seeking comments on the proposed study designs and inviting submissions of existing controlled studies that verify the clinical benefit of midodrine in treating orthostatic hypotension (http://tiny.cc /ylb34). The deadline for comments and submissions is July 11. For Rita Redberg, MD, MSc, a professor of medicine at the University of California, San Francisco, and editor of Archives of Internal Medicine, the FDA’s action on policing midodrine is taking too long. “The FDA has had 15 years of waiting for data; it has sent 3 letters to