Safety of drugs not known for years, study says

FDA says analysis overstates problem

The safety of new drug agents cannot be known with certainty until a drug has been on the market for many years, according to research published in the May 1 issue of the Journal of the American Medical Association (JAMA).

Researchers, led by Karen E. Lasser, MD, MPH, at Cambridge Hospital and Harvard Medical School in Cambridge, MA, found that through Kaplan-Meier analyses, the estimated probability of a new drug acquiring black box warnings or being withdrawn from the market over 25 years was 20%. The findings led the researchers to suggest that the Food and Drug Administration (FDA) should consider raising its threshold for approving new drugs when safe, effective therapies already exist, or when the new drug treats a benign condition.

The researchers also recommend that clinicians avoid using new drugs when older, similarly efficacious agents are available. Patients who must use new drugs should be informed of the drug’s limited experience and safety record, and be observed for possible hepatic, hematologic, or cardiac toxicity.

To do their study, the researchers identified black box warnings through a manual search of all 26 annual volumes of the Physicians’ Desk Reference (PDR) from 1975 to 2000 and also calculated the frequency and timing of drug withdrawals during this time. The PDR is a compendium of the FDA-approved professional product labeling for selected drugs. Of the 548 new drugs that were approved in 1975-1999, 56 (10.2%) acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) acquired one or more black box warnings, and 16 (2.9%) were withdrawn from the market.

In addition, 81 major changes to drug labeling in the PDR occurred including the addition of one or more black box warnings per drug, or drug withdrawal. In Kaplan-Meier analyses, half of these changes occurred within seven years of drug introduction; half of the withdrawals occurred within two years.

The FDA responds

Although premarketing trials in a few thousand patients do not detect all of a drug’s adverse effects, especially relatively rare ones, frequent postmarketing labeling changes are inevitable and should be anticipated, counters Robert J. Temple, MD, and Martin J. Himmel, MD, MPH, of the FDA’s Center for Drug Evaluation and Research Policy. Temple’s and Himmel’s comments are published in an accompanying editorial in JAMA.

Using the PDR to determine the timing of the labeling change is not the most accurate measure, they say, because the Physicians’ Desk Reference cannot change between editions, while labeling does change.

A physician contemplating prescribing a new drug should consider carefully the reason for the choice, particularly when an equally effective alternative is available, as there is always some risk of an undiscovered adverse drug reaction (ADR), they say. "But it is incorrect to describe the introduction of unsafe drugs as frequent; the analysis of drugs by Lasser et al actually demonstrates that ADRs of sufficient importance to change the role of a drug in practice are uncommon. If there is sound reason to use a recently approved drug, the physician need not deny the patient this treatment."

Temple and Himmel also question what the researchers mean by the FDA "raising the threshold" for approving new drugs when safe, effective therapies already exist. "It is not clear whether the authors believe superiority of a new drug, as opposed to equivalence, should be established, more data should be required, or something else is needed. It is worth observing that existing therapy does not always prove to be completely safe and fully satisfactory and that there is value in having alternatives."

The Pharmaceutical Research and Manufacturers of America (PhRMA) in Washington, DC, also spoke out against the drug safety study. "The article by Lasser et al is misinformed and misleading. Findings of the FDA and the data presented in the article both contradict the authors’ conclusions that serious adverse drug reactions commonly emerge after FDA approval and that the safety of new agents cannot be known with certainty until a drug has been on the market for many years," says Jackie Cottrell, PhRMA spokeswoman. "Likewise, we note that Dr. Lasser et al state that the benefit/risk ratio of new medicines sometimes shifts as new information is acquired after marketing, but they fail to state that it often shifts to the benefit side. For example, cholesterol-lowering drugs have been found after marketing to have significant additional benefits."

Recent changes in drug development should help protect against some of the most important past causes of drug withdrawal, Temple and Himmel say. Drugs are now evaluated in both animals and humans for their effect on cardiac repolarization, and drugs that do so are not approved or are approved with labeling that points to the need for close monitoring or attention to concomitant therapy. Similarly, the ability of drugs to inhibit hepatic metabolizing enzymes and interact with other drugs is now thoroughly examined. In addition, early signals of hepatotoxicity are better assessed. "Thus, there is reason to believe that some of the more common causes of significant toxicity will be less likely in the future."

They acknowledge, however, that no improvements will completely eliminate the risk of unexpected events. "The FDA continues to rely on reporting of ADRs by physicians, other health care professionals, and others to help uncover these risks as rapidly as possible."