Spontaneous reporting systems such as AERS are the most common, effective, and relatively inexpensive methods used in pharmacovigilance to identify new or rare adverse events. Data from AERS are first scrutinized by the FDA's postmarketing safety evaluators for previously unrecognized (unlabeled) serious adverse events, which may represent potential “signals.” Most helpful in this process are “good” adverse event reports that contain information such as: a complete description of the adverse outcome; baseline status of the individual; laboratory values and biopsy report, where applicable; temporal relationship with the suspect drug; information about dechallenge (event abates when drug is discontinued) and rechallenge (event recurs when drug is restarted); and information about confounding drugs or conditions. Even a single “good” adverse event report can qualify as a potential “signal” that requires further research.
When a “signal” is noted, the safety evaluators, who are specially trained clinical pharmacists, routinely try to find additional cases in AERS and medical literature or from foreign regulatory agencies. A case definition may be developed and repeatedly refined as new cases are collected. After assembling a series of cases, the safety evaluators search for any common trend, causal relationship, or pattern of events to identify potential risk factors or any other peculiarities. Usually, they look for signs such as: temporal association (the suspect drug was taken before the occurrence of adverse outcome); coherence with existing information or biological plausibility; similar effect in drugs of the same class; dose-response relationship; consistency of the association (replicability of results); and specificity of association.
One of the limitations of spontaneous reports is that, in general, they are poorly documented, and the safety evaluator may need to contact the event reporter, either directly or through the manufacturer, in order to secure follow-up information.
Another limitation of spontaneous reporting is that it captures only a small fraction of the adverse events that actually take place. The extent of under-reporting is unknown, and depends on the severity of the adverse event, among other factors. One group of researchers estimated that the FDA receives reports of less than 1% of serious adverse events, whereas another group gave this estimate as between 8% and 13%.8,9
Since it is not possible to calculate from the available information the actual incidence of adverse events, the FDA's epidemiologists frequently estimate the reporting rate (number of case reports of adverse outcome of interest divided by estimated total number of prescriptions) of adverse events with a suspect drug, and compare it with the background rate at which the same event occurs in a population not treated by the suspect drug. A reporting rate that is higher than the background rate is an indication of a possible causal relationship between the adverse event and the drug.