An Underrecognized Challenge in Evaluating Postmarketing Drug Safety

Abstract

he withdrawal of the cyclooxygenase (COX)-2-specific inhibitor rofecoxib (Vioxx; Merck) has generated a high-profile debate in the medical and lay press over when a signal suggesting the potential for harm from this drug was first apparent and what steps the medical community, the US Food and Drug Administration, and the pharmaceutical sponsor took and should have taken to address this issue. 1,2 This debate, however, has glossed over a fundamental problem that the withdrawal of the drug serves to highlight-not how best to deal with a potential signal once it is described, but rather how to identify such important and initially unanticipated effects after a drug is marketed.

Drug-Induced Long QT Syndrome

“…These concepts have now been incorporated into the drug development process. As the discussion above makes clear, this has created a tension between those who feel excellent candidate drug molecules are being withheld from the development process because of an indefinable and possibly vanishingly small risk, and those who feel that current and new screening technologies can protect the public from the catastrophic scenario of marketing a drug with a moderate risk of unexpected and serious toxicity (Roden, 2005). It is conceivable that with advances in personal genomics will come the ability to predict with high accuracy risk for adverse drug effects.…”

A randomized database study in general practice yielded quality data but patient recruitment in routine consultation was not practical

“…Due to the limitations of randomized clinical trials (in particular, lack of generalizability due to limited sample size, exclusion criteria, and protocol-driven assessment), postmarketing observational studies are necessary to study safety and effectiveness of new drug treatments [1]. Observational studies on drug effects are usually conducted by using claims or medical record databases [2].…”

A systematic review on the application of pharmaco­epidemiology in assessing prescription drug-related adverse events in pediatrics

“…Prescription drugs' regulatory approvals are often based on the evidences from well-designed pre-marketing RCTs 4,5 . However, the number of subjects enrolled in the pre-marketing RCTs is usually inadequate to detect rare adverse drug events (ADEs) [2][3][4][5] . Study subjects are likely to be unrepresentative of, and healthier than, the general population likely to be treated [2][3][4][5] .…”

“…However, the number of subjects enrolled in the pre-marketing RCTs is usually inadequate to detect rare adverse drug events (ADEs) [2][3][4][5] . Study subjects are likely to be unrepresentative of, and healthier than, the general population likely to be treated [2][3][4][5] . Most premarketing trials are also too brief to allow the study of long-term drug safety [2][3][4][5] .…”

“…Study subjects are likely to be unrepresentative of, and healthier than, the general population likely to be treated [2][3][4][5] . Most premarketing trials are also too brief to allow the study of long-term drug safety [2][3][4][5] . Given these limitations, pharmacoepidemiology has been widely used to complement RCTs in the assessment of drug safety.…”