Safety related triggers/threshold for quality investigations/batch record reviews
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I would like seek advice on developing triggers for initiating quality investigations with biological products(eg batch record reviews) in order to identify potential quality/manufacturing related safety issue.
Can you pls provide guidance around how triggers or thresholds should be defined (ie should they be statistically based or definitively set).
There is no specific gold standard as to how triggers/thresholds should be defined for initiating quality investigations with biological products. There are various/multiple factors that can determine what would be a trigger/threshold for example just one event can trigger a signal if serious enough but set the bar too low and you end up doing batch record review for each batch, set the bar too high and you may miss something. Perhaps taking a historical perspective by looking at units produced per batch and AE numbers may help you get to an expected range of AE numbers by unit sold. From there you could provide threshold, for use as a guide. It would be very hard though to account for country differences on reporting rates (and also whether cases are being solicited). The point being that you would need a good justification document, to provide evidence of your rationale and also sign off. Not all companies use statistical tools but develop their own methodology which may vary depending on the type of medicinal product for which it is intended. Detection of signals may be performed based on a review of ICSRs, from statistical analyses in large databases, or from a combination of both. The company would be responsible for defining this and documenting their rationale and process. This question comes up frequently in biological product GMP inspections with FDA during the PV review portion, perhaps refer the question to GMP QA for an opinion too.
Useful guidance surrounding this topic are found in the Guideline on good pharmacovigilance practices (GVP) Module IX – Signal management and Eudravigilance Expert Working Group (Ev-Ewg) Guideline On The Use Of Statistical Signal Detection Methods In The Eudravigilance Data Analysis System Dec2008.