Pooling in Integrated Safety Databases
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POOLING IN INTEGRATED SAFETY DATABASES DAMIANJ. MCENTEGART, BSc, MSc, FIS Biostatistics and Data Management, BASF Pharma, Nottingham, United Kingdom
New Drug Applications require the formation of an integrated safety summary as part of the license submission. The objective of this summary is to identify important serious adverse events and to characterize more common, nonserious adverse events. This review typically involves pooling the data across different studies and comparing the event rates on the drug and a common comparator (placebo or active). The most common approach is to collapse data from all studies and summarize them as if they came from a single study. From a scientific viewpoint this is not optimal as between study variability is not accounted fox The dangers of simple pooling are demonstrated with a real example. It is argued that where appropriate, more use should be made of statistical techniques that account for between-study variability; this will be particularly relevant when the treatment allocation ratio is unbalanced across studies. Key Word: Integrated safety summary; Pooling; Meta-analysis
INTRODUCTION
such events, for example, demographic or disease subgroups, dose or plasma level charREGULATORY GUIDELINES AND good acteristics, concomitant medications, and depractice require the formation of an integree of exposure. A further objective is to grated safety summary (ISS) for a new drug characterize the nonserious, common adapplication. Regarding safety data, the Interverse events. national Conference on Harmonization With respect to the nonserious, common (ICH) E9 guidelines (1) state that: “the readverse events, past regulatory advice has sults from trials which use a common companot implied a need for great sophistication. rator (placebo or specific active comparator) The Food and Drug Administration (FDA) should be combined and presented separately architect of the ISS wrote that: “the actual for each comparator providing sufficient outcome is almost never critical to approval data.” The primary objectives of such presenand great precision is not required”(2). The tations are to identify and estimate the inci1988 FDA guidelines (3) stated that: “minor dence of important adverse reactions and to differences ( . . . . between treatments) are identify factors that predispose patients to not of interest and need not be pursued with rigorous statistical methods.” These statements reflect the fact that the most important Reprint address: Mr. Damian J. McEntegart, Biostatispart of the safety assessment for most drugs tics and Data Management, BASF Pharma, St. Nicholas Court, 27 Castle Gate, Nottingham, NGI 7AR, United is the evaluation of generally unanticipated, Kingdom. E-mail: damian.mcentegart@basf-pharma. less frequent or even rare, serious adverse co.uk. reactions. 495
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