Introduction

Since the systematic recording of pharmaceutical product-related adverse events (AEs) was first proposed by Finney after the thalidomide tragedy, regulators, public health organizations, and manufacturers have been faced with the difficult task of interpreting postmarketing AE signals that arise from health care product surveillance programs (Finney, 1963, 1964, 1965). Health care product monitoring is based on data from four major data sources: spontaneous reports, medical literature case reports or case series, human studies, and pharmacologic or toxicologic experiments (European Agency for the Evaluation of Medicinal Products, 1995, 1997) (see Table 19.1). Of these, spontaneous reporting is typically the largest contributor (Faich et al., 1987; Faich, 1996). The term "spontaneous" refers to unsolicited AE reports that are forwarded to manufacturers or regulators, pertain to individual patients, and are not derived from either the medical literature or studies. Spontaneous reporting systems have become the foundation of postmarketing surveillance programs because of the high volume of information they supply, their low maintenance costs, and their demonstrated usefulness when supervised by experienced evaluators (Begaud et al., 1994a). This chapter summarizes and integrates the published literature pertaining to spontaneous signalling methods and AE surveillance program design.

While the emphasis in this chapter is on how spontaneous reports can be used to generate signals, safety professionals should note that the terms "spontaneous" and "signalling" are not equivalent. Spontaneous reports are only one data source from which postmarketing AE signals can be generated. With the exception of the circumstance in which a safety outcome is hypothesized a priori and then tested using a study design, any source of relevant data with a bearing on a marketed product's risk profile can give rise to postmarketing AE signals (Meyboom et al, 1997a; Waller and Lee, 1999).

Table 19.1. Data sources for AE surveillance programs.

Spontaneous reports

• To manufacturers

• To regulatory agencies

Literature case reports

• Single case reports

• Case report series

Studies (published or unpublished)

• Clinical studies

• Epidemiologic studies

Pre-clinical and toxicological data

• In vitro experiments

• Animal models

• Toxicologic studies speculative at their outset. Consequently, prior to wide acceptance, spontaneous assessments require demonstration of consistency using multiple methods, and may require confirmation from non-spontaneous data sources. Spontaneous methodology should therefore not be regarded as generating precise estimates (the calculation of incidence rates, for example), but, rather, as providing the constituents of signalling arguments (Goldman, 1998) (see Figure 19.1). In the public health literature, such activities are sometimes referred to as ''pre-epidemiology'' to distinguish them from the more formalized logic of observational studies (Wartenberg and Greenberg, 1993).

This point also extends to signalling logic itself, since similar signalling methods can often be applied to AE information arising from different data sources. This is particularly true for individual patient reports from spontaneous, literature, and study environments, all three of which are subject to report forwarding under the same general regulatory scheme, and are usually organized by manufacturers and regulators in the same ''spontaneous'' database. Thus, safety evaluators should recognize that, while this discussion focuses on signalling from spontaneous reports, overlap is considerable among the various postmarketing data sources and the signalling methods that are applied to them.

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