Is the FDA's drug review process breaking down?

Since 1997 the US FDA has banned use of 11 prescription drugs because of serious side effects. The FDA says it's not the drug approval process but inappropriate prescribing that is responsible.

By | December 20, 2000

The US Food and Drug Administration (FDA) has withdrawn 11 prescription drugs from the market since 1997. Serious side effects and patient deaths have forced these withdrawals.

Is the FDA's drug review process breaking down? According to Sidney Wolfe, Director the Health Research Group (part of Ralph Nader's Public Citizen advocacy organisation), "Changes in FDA review and approval policies in the past several years appear to have led to a significant decline in the safety and efficacy standards for new drugs." Under congressional pressure the FDA has accelerated its review process. In 1997, the Congress passed the Food and Drug Administration Modernization Act expanding use of 'fast track' approval mechanisms for drugs to treat life-threatening conditions and allowing use of surrogate endpoints in clinical trials. It also included a number of mechanisms for accelerating FDA review and changed the legal standard for new drug approval to a single clinical trial instead of two.

In the fiscal year 2000, average FDA new drug application review time was 14.6 months compared to 34.3 months in 1993. Drugs deemed 'breakthroughs' get a special fast track six-month review process. Also, pharmaceutical companies that pay special fees to the FDA can buy the fast track process for their drugs.

Critics say these measures have resulted in the FDA approving new drugs too rapidly. As a result, problems, particularly serious patient side effects, are going undetected until significant numbers of patients suffer. FDA officials deny this, noting that few of the recently banned drugs received fast track approval. FDA Commissioner Jane Henney has said the percentage of drug withdrawals is unchanged from when reviews were slower. Another concern is that only 82 FDA regulators monitor occurrence of medical problems once a drug is on the market. Congress has repeatedly refused to approve additional funds to upgrade this $12 million program. In addition, the program depends on voluntary reports from physicians that their patients are experiencing problems.

Once it does identify a problem with a drug, the FDA issues a warning. Increasingly, however, these warnings seem to be ignored. For example, for two years the FDA warned doctors that prescribing the heartburn drug Propulsid to people with kidney or heart disease or those who take certain antibiotics or other drugs could cause lethal irregular heartbeats. Despite the warnings, 80 deaths resulted and the FDA was forced to order Propulsid withdrawn from the market last summer.

Warnings on the diabetes drug Rezulin required that physicians test patients for liver damage; for months, FDA regulators complained that tests weren't being done. FDA officials say the primary cause of seven drug bans was not the drug itself but that doctors ignored or never read FDA warnings — warnings that could have prevented deaths. As a result, Janet Woodcock, Director of the FDA's Center for Drug Evaluation and Research, said, "Additional effective drugs are likely to be withdrawn, and some drugs may never become available in the first place."

The most recent ban, on Lotronex, was announced three weeks ago — nine months after its release. Lotronex, for treatment of irritable bowel syndrome, was causing severe intestinal side effects. Five other drugs have been withdrawn roughly one year after approval. These include Trovan, an antibiotic approved in 1998 and banned in 1999 after causing liver failure. Currently, the FDA allows only hospitals and nursing homes to prescribe Trovan. Another banned drug is Rotashield, a childhood diarrhoea vaccine approved in 1998 and banned in 1999 after causing bowel obstruction. Posicor, a blood pressure medicine approved in 1997 was banned in 1998 because it caused potentially deadly interactions with 25 other medicines. In 1998 liver damage was the reason for banning Duract, an anti-inflammatory painkiller after its 1997 approval. Patient heart damage resulted in the 1996 ban of Redux; a diet drug approved in 1996 and used in combination with an older diet drug called fenfluramine (the fen-phen drug combination).

Three other drugs have been banned only two years after FDA approval. Antihistamines Seldane and Hismanal were banned in 1998 and 1999, respectively, because they caused lethal interactions with numerous other medications. The antibiotic Raxar, approved in 1997 was withdrawn two years later after causing deadly irregular heartbeats in some patients.

Sidney Wolfe recommends that the FDA should ban drugs more quickly, as the current warning system isn't effective. Why aren't physicians reading the FDA's warnings and following their recommendations? Some physicians say they lack the time and learn about new drugs from pharmaceutical salesmen (who seldom spend much time discussing risks). Others can't remember all the warnings they do read. Sometimes the fliers pharmacies distribute with drug prescriptions do not list all the side effects. Some health care organisations and pharmacies use computer systems that theoretically can identify drugs likely to cause serious side effects. Shortly before the banning of Propulsid, however, Raymond Woolsey — a leading drug safety expert and Georgetown University cardiologist — found one such system that allowed prescription of a hazardous combination of Propulsid and an antibiotic.

Possible solutions to the problem include limits on early sales of new drugs and restricting some drugs from being prescribed by certain doctors. Experts suggest that measures of this sort should be applied in 2001 to the acne pill Accutane, which can cause serious birth defects. Patients should take a more active role in their treatments. When a physician prescribes a drug, patients should ask their doctor to discuss risks and explain why they chose one drug over another.

Clinical pharmacologist Alastair Wood of Vanderbilt University has suggested, "After a marketed drug is withdrawn or development of a new drug is terminated because of adverse toxic effects, an open public attempt to define what happened and why is an important element in improving the drug development and safety monitoring process … such an open dialogue could also take place immediately under the auspices of the scientific societies dedicated to the affected discipline." Wood and colleagues have recommended establishment of an independent drug safety board, analogous to the US National Transportation Safety Board, which investigates airline crashes.

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