Spontaneous event reporting numbers

The dossier contains data from case report forms collected from hospitals. The number of cases is around 3000-4000 observations, reporting prescriptions on a routine basis (survey of use). Safety information comes from this particular survey and from spontaneous ADR reporting (serious events reports and the synthesis of the periodic safety update reports). Of course, information on measures taken during the period should be added (modification of the data sheet, etc.), as well as updated information regarding approval of the drug in foreign countries. 

Because ARMS is a form of passive surveillance that is based on spontaneous reports, it has a number of limitations. Most importantly, it cannot establish a definitive, causal relationship between the ingestion of an incriminated substance and the occurrence of symptoms. Since people are exposed daily to a myriad of food ingredients, it is inherently difficult to attribute an adverse event to a specific food substance. Moreover, symptoms reported are often vague or general in nature. Other confounders, which were discussed by Bradstock et al. (1986), include ... 

The absolute numbers of spontaneous reports relating to any particular clinical event are dependent on a number of fairly obvious factors. 

The absolute numbers of spontaneous reports relating to any particular clinical event are dependent on a number of fairly obvious factors. The extent to which a drug is used is clearly important, but may be complicated by the pathological mechanism of the adverse reaction. The significance of prescription volume is different for reactions associated with the initiation of treatment from reactions that do not become apparent until the drug has been taken for an extended period. 

In the past decade there has been increased emphasis on drug safety, and more public visibility of safety problems. The volume of reports now exceeds 250 000 spontaneous reports per year, and adverse events have been highlighted in the medical sector and also in the media. In parallel, the FDA has focused more intently on this area in both NDA reviews and in the postmarketing period. This has accompanied withdrawals of a number of products, such as cisapride, phenylpropanolamine and terfenadine, and special scrutiny of products associated with particular adverse events, such as cardiac arrhythmias (torsades de Pointes ) and hepatic necrosis. The result has been an emphasis on the concept of risk management of a product. This concept, which is due to be described in forthcoming FDA recommendations, stresses the need to identify potential... 

Measures like (23.7) suffer from the disadvantage that where the expected number of events is large, statistical significance can occur without there being much excess risk. Furthermore, since such spontaneous reporting systems are subject to various biases, the fear may be that all that has been detected is a reporting bias. 

Many reported cases of spontaneous (homogeneous) nucleation are found on careful examination to have been induced in some way. Indeed, it is generally accepted that true homogeneous nucleation is not a common event. For example, a supercooled system can be seeded unknowingly by the presence of atmospheric dust which may contain active particles (heteronuclei). Aqueous solutions as normally prepared in the laboratory may contain >10 solid particles per cm of sizes <1 pm. It is virtually impossible to achieve a solution completely free of foreign bodies, although careful filtration can reduce the numbers to <10 cm and may render the solution more or less immune to spontaneous nucleation. 

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