globally, with its most common indication for use being prevention of cardiovascular disease in postmenopausal women. Many years after the therapy was marketed, however, both the HERS (Heart and Estrogen/ progestin Replacement study) Trial and the Women’s Health Initiative demonstrated its association with an excess of vascular events (Hulley et al., 1998; WHI Steering Committee, 2004). As a second example, the COX-2 (cyclo-oxygenase-2) inhibitors were expected to be a safer alternative to nonsteroidal anti-inflammatory drugs (NSAIDs). Vioxx and Bextra (among others), however, were removed from the market after the FDA Advisory Committee meeting in February 2005. Some experts believed the true balance of benefit and risk was not known for any of the COX-2 inhibitors (Psaty and Furberg, 2005). Perhaps even more startling, it was pointed out at the hearing that the same could be said for the traditional NSAIDs, which had been considered safe enough to sell over the counter. As a final example, a variety of antihypertension drugs have been developed and marketed as superior to the older, generic drugs used for this indication. However, when the National Institutes of Health (NIH) funded a pragamatic clinical trial involving more than 40,000 patients, it was found that the newer drugs provided no greater protection against stroke, heart failure, or death than the generic drug chlorthalidone (ALLHAT, 2002). Given that these examples involve some of the most commonly used and intensively studied drugs, there is uncertainty that drugs receiving less attention are better characterized. Since the only way to be confident about the balance of benefit and risk is empirical measurement, this information is lacking for most prescriptions that are written, especially those for chronically administered drugs.

The above issues are magnified in certain populations that bear much of the risk of drug prescription and administration:

  • The majority of prescriptions written for children are off label,1 with no empirical demonstration of safety and efficacy (Roberts et al., 2003). The Best Pharmaceuticals Act for Children has stimulated a major increase in clinical trials in children, but the legacy of sparse evidence remains substantial, and few of these trials have provided definitive information about indications and doses for the drugs involved. Pediatric oncology has been at the forefront in terms of enrolling a significant number of children in trials and could possibly be used as a model for other drug categories.

  • Almost nothing is known about the balance of benefit and risk in the fastest-growing segment of the population—those over age 80. These patients have only recently been enrolled in clinical trials (Alexander and


The FDA permits the prescribing of approved medications for other than their intended indications. This practice is known as off-label use.

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