Multivariate Analysis of Adverse Events
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Robert Goldberg-Alberts, MA Suiiior Pi-iiicipctl Skifisticiciii. Cliii iccil Bios f ci f i s f ics , U/!.rlh Rus ecii-ch, ColleAridlr. Puiiiisylvcitiici
Som Poge Associcile. Liqiiic/ffiib. /tic., Kitig of Pi-ussici.
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Clinical trial reports typically provide univariate data on adverse events in the form of rates. Little or no consideration is given to providing data on syndromes or constellations of adverse events in clinical trials. We describe three methods for analyzing adverse events; these methods focus on constellations of events within the same patient. A computer algorithm enumerates the constellations of adverse events in the data and counts the number of patients in each con-
INTRODUCTION Clinical trials provide evidence of the safety of new therapeutic agents by collecting data from a fundamental safety triad: (1) safety end points, ( 2 ) clinical laboratory values, and ( 3 ) reports of adverse events. The clinical protocol mandates the ascertainment of safety end points for every patient randomly assigned to the study. Furthermore, the protocol provides a prospective definition of safety end points and dictates the method by which these end points are determined. The clinical interpretation of clinical laboratory values is well defined (1). During the analysis of the study, clinical laboratory values are summarized at each patient visit and are analyzed for differences between study treatments. The laboratory values are analyzed in two ways: (1) by defining extreme laboratory values as clinically significant and calculating rates of occurrence for each clinically significant value by treatment group, and (2) analysis ofcovariance (ANCOVA) using treatment as a factor and the baseline value as a covariate. Both of these measurements, safety end points and clinical laboratory values, provide focused, objective measures of the safety of study medication. Adverse events, however, are broadly defined to include a wide range of medical events. The following definition of adverse events is from the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (2):
stellation. The proposed algorithm also preserves the identifiers ofpatients in the constellation and other covariates forfurther analysis. A log-linear model is used to estimate the magnitude of association of two or more adverse events by analyzing the count ofpatients in each of the possible subsets of the constellation. These methods make a unique contribution to the determination of safety in the development of new therapeutic agents.
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
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