It is not an exaggeration to state that pharmaco-vigilance is the cornerstone of postmarketing drug safety activities in the United States, and will likely remain so for the foreseeable future. Nearly all postmarketing labeling changes related to drug toxicity are based on spontaneous case reports. The same holds true for drug withdrawals. Since 1980, there have been 18 major prescription drug withdrawals in the United States. Of these, spontaneous case reports and their analysis were a critical informational component contributing to the withdrawal decision in 16. The two exceptions were encainide and flosequinan, where randomized clinical trials identified the increased mortality risk conferred by these approved drugs (Echt et al., 1991; Massie et al., 1993). This should not be a surprise because patients with cardiac arrhythmias under treatment for those arrhythmias will sometimes experience sudden death due to arrhythmias, and death is not infrequent among patients with congestive heart failure. In situations where the underlying disease being treated and the ADR resulting from treatment are the same, only a well-conducted randomized trial will convincingly establish the drug-ADR association.
While the utility of case reports is undeniable, there is much that might be done to improve and expand their value. Strategies to improve the level of reporting of serious ADRs need to be developed. The proverb about "strength in numbers'' also applies to pharmacovigilance. A few reports may provide a sufficient basis upon which to modify a product's label. However, important information regarding the magnitude and duration of risk as well as risk factors for ADR occurrence is more easily and reliably discovered through careful analysis of a larger series of cases. Hand in hand with the value of a larger numbers of serious case reports is improved quality and completeness of those reports. The more clinically detailed a series of reports is, the greater the range of analytic possibilities. The value of this for regulatory decision-making and risk management efforts cannot be overstated. How to achieve these goals in an environment of immense time constraints and litigation fear is an important challenge for the future.
Another area of potentially great public health value is the expansion of current pharmacovigi-lance practice to include other venues and types of ADRs. In the United States, the focus of pharmacovigilance has been on the rapid identification of serious unlabeled events. Many, if not most of these fall into the category of "unexpected" or "idiosyncratic" and have been referred to as type B reactions (Meyboom et al., 1997). This is an important endeavor but from a population perspective, the bulk of drug-related morbidity and mortality is due to type A reactions, that is, those that represent an extension of the drug's pharmacology. The problem is great enough to represent one of the leading causes of mortality in the United States (Lazarou et al., 1998).
Pharmacovigilance strategies in this arena might lead to the identification of "problem areas" and provide the basis for more effective intervention and prevention.
Finally, advances in technology over the past decade and the advent of the ICH process have created an environment where global pharmaco-vigilance is now conceivable. A remaining challenge is to make this a reality.
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