What is already known about this subject? Serious and unexpected adverse drug reactions (ADRs) have been reported shortly after marketing of a number of drugs. Review of ADR cases by the regulatory authorities has resulted in suspension of drugs or restrictions in product information. What this study adds? Information about serious and unexpected ADRs of three drugs with reported serious ADRs was already present in the registration files. Observations of these ADRs were not investigated further before marketing. A more active utilization of the ADR information in premarketing studies could probably prevent the appearance of unexpected and serious ADR cases after marketing. AIMS: Spontaneous reports of adverse drug reactions (ADRs) are often the only documentation used to justify the recall of drugs from the market. The purpose of this study was to investigate whether it would have been possible to foresee serious ADR cases based on available information on ADRs reported in Phase II and III clinical trials before marketing. METHODS: We conducted a retrospective analysis of reported ADR data in Phase II/III clinical trials in the registration material for three different ADR scenarios: (i) trovafloxacin/alatrofloxacin and hepatotoxicity; (ii) tolcapone and hepatotoxicity and neuroleptic malignant syndrome; and (iii) rituximab and cytokine release syndrome. We chose the scenarios because they were of serious character and caused great damage to the patients and because of different outcomes of the scientific discussions in the regulatory agencies. RESULTS: In all three cases, the registration material contained observations of ADRs, but there had been no follow-up on these observations. ADRs were mentioned in the summary of product information (SPC) purely as information, to some extent accompanied by recommendations. The information was not converted into new knowledge and remained tacit knowledge embedded in the SPCs disseminated to health professionals/prescribers. CONCLUSIONS: The registration material analysed contained information about ADRs that were reported later, meaning that it would have been possible to foresee the occurrence of the ADRs at the time of licensing. More active utilization of the information from Phase II/III clinical trials is recommended to prevent the appearance of unexpected ADRs and further emphasis in SPC warnings to doctors about possible serious ADRs.
Keywords: Adverse Drug Reaction Reporting Systems; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Pharmaceutical Preparations; Product Surveillance, Postmarketing; Retrospective Studies