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FDA and Drug Approval Overview

Vioxx was one of the most widely used prescription drugs in the world and, for many, it may have been a killer. The Food and Drug Administration (FDA) is supposed to guarantee the safety of the medicines we take, but some say it may have disregarded warnings from its own scientists about this looming public health disaster. NOW's BAD MEDICINE explores the drug approval process and talks with FDA whistleblower, Dr. David Graham, who reveals how his FDA managers tried to silence him and quash evidence that indicated Vioxx was unsafe.

Approval Process

The drug approval process overseen by the FDA has been subject to complaints from many sides. In the 1990s it was criticized for being too slow — keeping potentially life-saving drugs off the market and adding to development costs. The most recent controversies come from another perspective, questioning whether the process is too quick and relies too much on information from the pharmaceutical industry.

Approving prescriptions drugs is the job of FDA's Center for Drug Evaluation and Research (CDER). The process begins when a manufacturer has tested a new drug on animals and concluded three phases of testing on humans. The results from this process forms the basis of a "new drug application" (NDA), which the company submits to the CDER.

The NDA is then reviewed by CDER scientists who evaluate both the efficacy and safety of the drug and its risk/benefit ratio. The CDER reviewers may request more information from the developer and seek additional opinions from outside experts. CDER also checks the label information and investigates the manufacturing plant. The CDER director completes a final review and decides if the drug is ready for market. View an interactive graph of the process from CDER.

Some of the criticism Dr. Graham has leveled at the FDA process relates to what happens after a drug is approved. The FDA is also charged with monitoring drug safety of drugs on the market. The FDA tracks "adverse events" or negative "side effects" of drugs through the Office of Drug Safety, also a part of CDER. An adverse effect is a reaction which "results in death, disability, hospitalization, is life-threatening, causes a congenital anomaly, or requires treatment to prevent permanent damage."

Doctors and other healthcare personnel usually report these occurrences to the drug companies which are in turn required to notify the FDA of any serious incidents within 15 days of the original report. If a drug is new, the company must forward all reports quarterly for three years. After that time, all reports are filed annually. In addition, the FDA maintains a system of voluntary reports called MedWatch. Here, consumers and health care workers can submit reports which are then sent on to staff for evaluation.

In his November 2004 testimony before Congress, Dr. Graham suggested that the FDA is reluctant to admit that there are problems with drugs it has already approved. The FDA responded to Dr. Graham's testimony with a public rebuttal. In December 2004, THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (JAMA) echoed some of Graham's criticism, publishing a series of papers which question the relationship of drug companies to the approval process. According to THE ECONOMIST, the makers of some of the drugs mentioned by Dr. Graham are feeling a financial effect. AstraZeneca's share price fell by 10%. Shares in GlaxoSmithKline fell by 6%. And as for Merck, the maker of Vioxx, traders have made a $40 billion reduction in the company's value. (Read Dr. Graham's testimony and the JAMA articles.)

Drug Trial Reporting

One of the elements of the drug approval process to come under heightened criticism recently is the reporting of clinical trial results, especially those sponsored by the pharmaceutical industry itself. According to the American Medical Association (AMA), the industry funded over 70% of such studies in 2002. Experts point out that the underreporting of all clinical results — favorable, unfavorable or inconclusive — prohibits a larger picture from being created of both drug safety and effectiveness.

Pressure has recently been put on those who conduct clinical trials to open up their results. New York Attorney General Eliot Spitzer filed a lawsuit in June 2004 against GlaxoSmithKline (GSK) alleging that the company had suppressed negative results of four studies of its anti-depressant Paxil. As part of a negotiated settlement GSK posted summaries of all clinical trials done after December 27, 2000 on its Web site. (Read the Attorney General's and GSK's statements.)

Soon after the settlement was announced in September 2005, the International Committee of Medical Journal Editors, among them the editors of the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (JAMA), the NEW ENGLAND JOURNAL OF MEDICINE (NEJM), the LANCET and 11 other prestigious medical journals published a joint editorial calling for increased openness in trial result reporting. Specifically, they called for a database of trial results. The group said that after mid-2005 they would not publish the results of any trials which had not been registered in a publicly-accessible independent database open to the public such as the National Institutes of Health's On January 6, 2005, the BBC reported that a number of the world's leading drug companies have promised to publish more data in such a manner. Research groups and government agencies are expected to follow suit. The BBC notes that "drug firms are only required to publish trials a year after they have been approved. There is no requirement to publish data on trials on drugs that do not make it to the market and it will not be retrospective either."

Suggested Solutions

THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION and Dr. Graham have both suggested that some of the process problems could be solved by removing post-approval monitoring duties from the FDA and giving them to a new independent agency. Critics of this plan say that this would only add another layer of bureaucracy and additional costs to the process.

Another solution may be to follow the example of the European Union. There the European Agency for the Evaluation of Medicinal Products (EMEA) reauthorizes (or not) drugs after five years on the market. This supervisory power allows the agency to make sure that company promises to do follow-up safety studies are carried out and provides a clearing house for evidence of efficacy and safety. The ECONOMIST recently reported that unlike their European counterparts, US companies have completed less than 50 percent of the post-approval studies they have promised to the FDA.

For more information visit our Pharmaceutical Research Resources. Also, learn more about the regulation of direct-to-consumer drug advertising.

Sources: BBC News, THE NEW YORK TIMES, THE ECONOMIST, American Council on Science and Health and U.S. Food and Drug Administration Center for Drug Evaluation and Research.

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