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Since 1992, the US Food and Drug Administration (FDA) has offered an accelerated approval process designed to make available new drugs to treat dire conditions that lack alternative therapies. To achieve speed, the FDA allows approval based on a lower standard than required for the regular approval process. That laxity in initial oversight is supposed to be followed by rigorous postmarketing studies that validate the efficacy and safety of the drug. Some charge that officials with the US Food and Drug Administration are too lenient in requiring the proper rigorous follow-up studies needed to confirm the efficacy and safety of pharmaceuticals entering the market through the accelerated approval process. But the system does not always work as planned. A company with a product that was approved this way and that is already generating revenue has little incentive to conduct a postmarketing study that may or may not validate the drug. And even if a company cannot produce a postmarketing trial showing efficacy, the FDA will still have a hard time removing a drug from the market, as patients, who may believe the drug is helping them, make their worries known to the agency, the media, and elected officials. The case of one such drug, midodrine hydrochloride, exemplifies this conundrum. Midodrine was granted accelerated approval in 1996 to treat orthostatic hypotension, a condition marked by a drop in blood pressure that causes dizziness or fainting when a person stands. To date, no postmarketing study showing the drug's efficacy has been accepted by the FDA. On August 12, the FDA announced that it had begun a process that could ultimately lead to midodrine becoming the first drug removed from the market because of the manufacturer's inability to produce rigorous postmarketing data confirming efficacy (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm222580.htm). The FDA's announcement prompted an immediate outpouring of concern and worry from some of the 100 000 patients already taking the medication or its generic equivalents. In press accounts, these patients, and some of their physicians, said the drug was the only therapy that allowed them to overcome the effects of orthostatic hypotension and live normal lives. This public concern prompted the FDA to clarify its decision, and in a September 10 update, the agency explained that its announcement did not herald an immediate withdrawal of the medication. The agency said, “It represented a step in the regulatory process—a step that reflects both the regulatory requirement for manufacturers to verify the clinical benefit of accelerated approval products and the agency's position that more data about the benefits of midodrine would help doctors and patients understand who can benefit from the drug and how best to use it.” The FDA went on to say a public hearing would be held at the request of the manufacturer, Shire Pharmaceuticals, so the company could present data supporting the clinical benefit of the drug and an advisory committee could review those data (http://www.fda.gov/Drugs/DrugSafety/ucm225444.htm). Shortcuts The accelerated approval process was launched in 1992 to expedite the approval of new drugs that are designed to treat serious or life-threatening illnesses and are expected to provide meaningful therapeutic benefit over existing therapies. The process was fueled by the needs of HIV/AIDS patients who could not wait the years required to show efficacy and safety of potentially lifesaving medications. But the program introduced shortcuts to the usual drug approval process. Pharmaceutical manufacturers no longer had to spend millions of dollars enrolling hundreds or thousands of patients over long periods to get a drug to market. The companies only had to show that a drug succeeded based on a surrogate end point, using fewer patients over a short period. And once a drug was on the market, it became difficult to spur pharmaceutical companies—who were already earning revenues from sales of the drug—to conduct follow-up studies showing efficacy on hard clinical end points, in part because patients may be reluctant to join a trial in which they may receive a placebo or alternative medication instead of the drug that they presume works. Midodrine has been on the market for 14 years without a single rigorous study to show its efficacy. Harlan M. Krumholz, MD, a professor of cardiology, epidemiology, and public health at Yale University School of Medicine in New Haven, Conn, said the problems associated with the accelerated approval process demonstrate the larger problem of approving drugs based on surrogate end points. “With fast-track [approval], you take a small number of patients or develop surrogate outcomes to show a benefit, and once that benefit is shown, people will become convinced it works, and if you take it away from them, they will have adverse effects,” Krumholz said. “So you end up with people fairly convinced of a drug's benefits; it could be placebo, or it could be real, but we are left without the data to show true benefit.” John K. Jenkins, MD, director of the FDA's Office of New Drugs, said the accelerated approval process puts the agency in a tough spot, forcing it to balance between getting a drug with a promise of efficacy quickly to a population in dire need and then ensuring that that promise is fulfilled. “These are very complex cases,” Jenkins said. “If this is the only available therapy, it is a very complex decision to remove that from physicians and patients as an option unless you identify a real safety concern, or if the drugs have not shown benefit but harm, or something else comes along to replace it.” Jenkins said the FDA has done a good job in handling the accelerated approval process and cited the agency's comments published in a November 2009 Government Accountability Office (GAO) report on using surrogate end points for drug approval (http://www.gao.gov/new.items/d09866.pdf). The report found that for the 90 drugs granted accelerated approval through late 2008, about two-thirds of the required confirmatory postmarket studies had been closed (drug sponsors had met FDA requirements for these studies or the FDA had determined that the studies were no longer needed or feasible), with more than half of these drugs being converted to regular approval. “It is important to emphasize that this has been a successful program giving patients access to drugs early, and in the majority of cases, having the efficacy of these drugs confirmed,” Jenkins said. But others do not characterize the accelerated approval process as a success. Indeed, the positive comments by the FDA were made in response to a GAO report highly critical of the process. In that report, the GAO argued that the FDA needed to enhance its oversight of drugs approved on the basis of surrogate end points and that the agency needed to clarify the conditions under which it would use its authority to expedite the withdrawal of drugs granted accelerated approval. The FDA disagreed with the GAO's argument. The authors of the GAO report said that the FDA did not routinely review pharmaceutical company annual submissions of the status of studies in a timely manner, that it lacked enough accessible and comprehensive data to monitor postmarketing study progression, and that it did not consider such oversight a priority. The report also noted that while the FDA has authority to withdraw a drug if a postmarketing study is not completed with due diligence or it fails to confirm clinical benefit, the agency has not specified the circumstances that would prompt it to act on removal. Sidestepping Steven E. Nissen, MD, chairman of the Cleveland Clinic Foundation's Department of Cardiovascular Medicine, said drug companies understand the situation and use accelerated approval to sidestep the regular and more onerous path to bringing a medication to market. “To qualify for fast-track status, a drug has to treat serious disease and fill an unmet medical need,” Nissen said. “When I look at the drugs on the fast track, I am not sure the majority meet those requirements. Fast tracking should be used sparingly.” Curt D. Furberg, MD, PhD, professor of public health sciences at the Wake Forest University School of Medicine in Winston-Salem, NC, said the passage of the Food and Drug Administration Amendments Act of 2007 should have given the agency more regulatory ammunition to push companies to comply with conducting postmarketing studies. “The problem prior to the act's passage was that some of the commitments to complete postmarketing studies had no deadlines, so it was hard to claim they were delinquent. And clearly there have been no consequences and no one at the FDA paid attention to this problem,” Furberg said. “The changes in the regulations should help, but when I look at the list of studies on the accelerated approval list, some have been conducted and some are pending, and to me it is hard to say the situation has improved.” Nissen remains frustrated with the inaction by FDA leadership to improve the accelerated approval process. “The people at the FDA approving drugs are very pharma friendly; they view pharmaceutical manufacturers as their principal clients. So we see this lack of enforcement over and over,” Nissen said. “I do not think we need tough laws; we need tougher regulators.”
JAMA – American Medical Association
Published: Oct 27, 2010
Keywords: drug approval
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