General Considerations

Imputation Methods

The term "imputation method'' can be defined as any monitoring procedure based on individual patient test results, the aim of which is to differentiate a monitored product cause from other causes for an AE. Throughout health care product surveillance, imputation-derived procedures (e.g. causality assessments) are either mandated by regulation (Code of Federal Regulations), or are encouraged by international agreements, such as those pertaining to expedited individual patient AE reporting (ICH E2A) or periodic safety update reports (ICH E2C) (European Agency for the Evaluation of Medicinal Products, 1995, 1997). However, while well accepted in the regulatory sense, imputation-based methodology has never been well rationalized epidemiologically, and a definitive theory through which imputation-based methodology can be implemented has not yet evolved. A useful alternative, as is followed in this chapter, is to view imputation methodology functionally, i.e. relative to its purpose within a comprehensive AE surveillance scheme. The parameters of imputation-based methodology can then be discussed in terms of their intended effect, such as their appropriateness for implementing a particular step in the signalling process.

From the surveillance perspective, two general uses for imputation can be identified (see Table 18.2 and Figure 18.1). The first, imputation screening, involves the automated examination of product-specific report databases with imputation-based instruments in order to find "interesting" product-AE pairs (Venulet, 1992). Like all identification signalling methods, screening imputation examines collections of AE reports, selecting only certain product-AEs for subsequent scrutiny (see the section Imputation Screening (Causality) Assessments in Chapter 19). The second, case series imputation, applies imputation methods to a product-AE case series to see if evidence favoring

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