As Forum member Jeffrey Drazen noted, “Adverse events associated with treatments represent a major hurdle that is very difficult to overcome in the setting of the randomized clinical trials that are done when a drug gets approved for marketing. There is almost no other way … to see how the drug functions in the real world.”

There are significant concerns about the process by which drugs are subject to assessment of their safety. While all drugs must undergo pre-market studies examining effectiveness and safety before they receive FDA approval, these tests are conducted on a limited number of subjects and often do not investigate long-term outcomes (Ray and Griffin, 1993). In addition, drugs are not always used in practice the same way they were used in the studies that led to their approval. For example, patients taking the medication may differ from the population in which it was studied; the treated population may not be as closely monitored as the patients in the clinical trials; or drugs may be prescribed for off-label use, the common practice in which physicians prescribe a medication for a use other than that for which it was tested and approved. In addition, during the initial period after the introduction of a new drug, the likelihood of inappropriate dosing, failure to follow directions, and contraindicated use is high (Smalley et al., 2000; Graham et al., 2001; Griffin et al., 2004).

A rare adverse event, one that occurs in fewer than 1 in 1,000 treated patients (for example, aplastic anemia), may not be identifiable in the premarket data and generally becomes apparent only after the drug is in wide use after its approval by the FDA (Okie, 2005). Other adverse events are first recognized through case reports in the literature, for example, the association of cisapride and torsades de pointes (Ray, 2003). Additionally, if the drug increases the rate of a common condition—for example, if it increases the risk for an adverse vascular event such as heart attack or stroke—this may be identifiable only when many thousands or even millions of people have used the drug.

Postmarketing surveillance can address some of these concerns by studying use by a larger group of patients over a longer period of time than in the premarket phase. Postmarketing research also provides the opportunity for a more comprehensive evaluation of drug utilization in the clinical practice environment.

A limitation in postmarket observational studies is the potential for findings to be due to systematic differences between patients in the treatment and comparison groups, rather than to the drug that is the subject of the study. There are statistical techniques that can be employed to control for confounding factors, but they are only effective when the relationships are known in advance and the data are available (Hunter, 2006). Controlling for confounding factors is also difficult in studies involving causes of mortality. The contribution of medication effects to the overall



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement