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is rarer), fewer case reports are needed to perceive causality (Auriche and Loupi, 1993). For rare4 serious adverse events, such as toxic epidermal necrolysis, coincidental medical product-event associations have been found to be so unlikely that they merit little concern in spontaneous reporting, with more than three reports seen to represent a signal necessitating further study (Begaud et al., 1994). Further, it has been suggested that the combination of a temporal relationship between medical product and adverse event, positive dechallenge, and rechallenge can make individual reports conclusive as to product-event association (Temple et al., 1979).

Notwithstanding, there is no definitive number of cases for generating a signal of safety concern. It is dependent on the characteristics of the individual adverse event itself, including such factors as clinical manifestations and severity, potential for significant morbidity (reversible and irreversible) or mortality, potential populations at risk, and the overall risk to public health.

In judging any association to be causal, biological plausibility and reasonable strength of association are useful (Rawlins, 1995). However, given the outlined limitations of spontaneous reports, achieving certain proof of causality through postmarketing surveillance is unusual (Auriche and Loupi, 1993). Attaining a prominent degree of suspicion is much more likely, and, given that it may be deemed an ample basis for regulatory decisions on drugs (Auriche and Loupi, 1993), it is an ample basis for regulatory decisions on dietary supplement ingredients.

Regarding factors that can be useful in assessing the strength of association between any medical product and a reported adverse event, international consensus produced the following list (CIOMS, 1990):

  • The chronology of administration of agent, including beginning and ending of treatment and adverse event onset,

  • The course of the adverse event when the suspected agent stopped (dechallenge) or continued,

  • The etiologic roles of agents and diseases in regard to an adverse event,

  • Response to readministration (rechallenge) of the agent, and

  • Laboratory test results.

4  

The United States has no regulatory definition that explicitly delineates events as common, infrequent, or rare based on their frequency of occurrence; the Council of International Organizations of Medical Sciences (CIOMS) III/V working groups have recommended the following standard categories of frequency: common (frequent): > 1/100 and < 1/10 (> 1 and < 10 percent); uncommon (infrequent): > 1/1,000 and < 1/100 (> 0.1 percent and < 1 percent); rare: > 1/10,000 and < 1/,1000 (> 0.01 and < 0.1 percent) (CIOMS, 1999).



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