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Considering the Nature of the Adverse Event

Beyond the factors listed above, the nature of the adverse event itself is an important consideration in assessing spontaneous reports. The nature of the adverse event encompasses knowledge about its naturalistic frequency of occurrence and its potential for significant morbidity or mortality.

As previously discussed, premarket clinical trials in humans have inherent limitations that significantly affect their ability to detect adverse events (Goldman et al., 1995); to have a 95 percent chance of detecting an adverse event that occurs in 1 in 1,000 people, 3,000 people must be exposed (Lewis, 1981). For adverse events that occur de novo even more rarely, such as 1 in 100,000, 300,000 people must be exposed for there to be a good chance of detection. Many of the most serious adverse events occur relatively infrequently; that is why spontaneous report systems, which are designed to cover entire populations, are able to detect rare, serious events not discovered during premarket testing.

This important outcome of spontaneous report systems for dietary supplement ingredients is the same as for other products. There are serious adverse events that by their very nature necessitate increased attention and scrutiny due to their potential for significant morbidity and/or mortality. FDA, in its recently published Proposed Rule for Safety Reporting Requirements for Human Drug and Biological Products, specifically addressed this issue by proposing a new designation, “Always Expedited Reports” for specific suspected adverse drug reactions (SADRs) of medical significance (FDA, 2003c). The following SADRs,5 regardless of expectedness, would be subject to expedited reporting due to their very nature: “congenital anomalies, acute respiratory failure, ventricular fibrillation, torsades de pointe, malignant hypertension, seizure, agranulocytosis, aplastic anemia, toxic epidermal necrolysis, liver necrosis, acute liver failure, anaphylaxis, acute renal failure, sclerosing syndromes, pulmonary hypertension, pulmonary fibrosis, confirmed or suspected transmission of an infectious agent by a marketed drug or biological product, confirmed or suspected endotoxin shock” (FDA, 2003c). Reporting of any of these adverse events in association with dietary supplement use should trigger the same degree of concern as for any other product, and the same heightened need for a timely assessment.

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Also subjected to expedited reporting within this new designation are any other medically significant suspected adverse drug reactions that FDA determines to be the subject of an always expedited report (i.e., may jeopardize the patient and/or require medical or surgical intervention to treat the patient).



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