Case Series

The most common approach to signal development is based on the evaluation of a series of case reports. Although several criteria (described above) are used in this review, no formal causality assessment algorithm is followed. A number of such algorithms have been reported in the literature, but these suffer from important liabilities including inflexibility, lack of sensitivity and lack of validation (Pere et al., 1986; Frick et al., 1997). They are also oftentimes difficult and time consuming to use, may tend to discount even remotely confounded cases and may place excess weight on the presence of positive rechallenge.

Because the AERS database draws on the cumulative experience of over 270 million people, it is a rich source of clinical material. A physician in practice may see one case of a rare or unusual drug reaction, and may perhaps even publish the case. The advantage of a centralized ADR repository is that it offers the potential of much greater case numbers, and with that comes the capacity to describe the spectrum and natural history of the reaction and to identify risk factors for its occurrence.

Several examples help to illustrate this. Based on a review of 121 cases of seizure reported with alprazolam, the importance of the duration of drug use and the sudden cessation of therapy were identified as risk factors for seizure occurrence (Graham, 1989). The "epidemic curve'' derived from these case reports strongly suggested benzo-diazepine withdrawal as the underlying mechanism (Figure 17.1). Evaluation of 95 reported cases of hemolysis with use of the antibiotic temafloxacin resulted in the discovery of hemolytic-uremic syndrome with this drug and identified prior fluoroquinolone use as a strong risk factor for development of this life-threatening complication (Blum et al., 1994). More recently, a review of 43 cases of acute liver failure reported with the use of troglitazone described the clinical spectrum and natural history of this disorder (Graham and Green, 1999). Of note, this analysis provided evidence of the inability to predict who was at risk or how to prevent this often fatal reaction. In another instance, a review of 58 case reports

Days since last dose

Figure 17.1 Reported cases of seizure by time since stopping alprazolam use.

Days since last dose

Figure 17.1 Reported cases of seizure by time since stopping alprazolam use.

suggested a possible association between use of the antifungal, itraconazole, and the development of congestive heart failure (Ahmad et al., 2001). No evidence of a similar signal was observed with the other azole fungicides.

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