Serious adverse events causality

In a systematic review of clinical trials, published case reports and pharmacovigilance reporting center data, Huntley and Ernst (2003) concluded that black cohosh is generally safe. If products are taken for a limited amount of time, the risk of adverse events is slight and the events are usually mild and transient, with gastrointestinal upset and rashes being the most common events reported. The reviewers noted that some serious adverse events have been reported, including hepatic and circulatory conditions, but due to limited information on cases, causality could not be determined (Huntley and Ernst 2003). 

Considerable uncertainty was raised in Germany in 1996 by reports in the popular press that several deaths due to anaphylaxis had occurred over the previous six years in patients taking Echinacea preparations. However, investigations by the federal health authorities failed to establish causality between the deaths and Echinacea in view of the variety of other treatments being administered [39]. While positive IgE antibodies have been reported in up to 5% of patients taking Echinacea preparations [40], this must be set against the millions of packages sold annually without reports of serious adverse events. 

Observational studies In October 2003 the Advisory Committee on Immunization Practices (ACIP) recommended influenza immunization for all children aged 6-23 months [30 ]. The safety of this recommendation has been evaluated using the Vaccine Adverse Event Reporting System (VAERS) to study serious adverse events reported between 1 July 2003 and 30 June 2006 in children aged 6-23 months who had been given trivalent inactivated influenza vaccine. There were 104 serious adverse events at a median time after immunization of 1 day. The two most common serious adverse events were fever (52 reports) and seizures (35 reports). Causality assessment suggested that none was definitely related to influenza vaccine. No new or unexpected concerns were identified. 

Signal Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. 

Adverse events following immunization can be causally related to the inherent properties of the vaccine, linked to errors in administration, quality, storage, and transport of the vaccine (programmatic errors), but also occurring coincidentally after immunization. It is therefore necessary to investigate and evaluate AEFI, particularly those that are serious or unknown. 

The essential elements of pharmacovigilence during clinical trials of an investigational compound span from adverse event identification through characterization and analysis. Identification is focused on treatment-emergent adverse events. These events can then be characterized by incidence, prevalence, severity, seriousness, and relationship to the study drug (causality). The data can then be examined to identify potential risk factors and markers with which to anticipate the occurrence of an adverse event. 

Adverse events are non-linear and unpredictable products of the functioning of the entire system and indicators have serious challenges capturing non-linear causal relations. 

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