title: Biometrical issues in the analysis of adverse events within the benefit assessment of drugs.
abstract: The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.
authors.affiliation: Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, Germany.|Faculty of Medicine, University of Cologne, Cologne, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bender
authors.affiliation: Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Beckmann
authors.affiliation: Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lange
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data; D000736:Androstenes / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002986:Clinical Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D017277:Drug Approval / Q000379:methods / Q000706:statistics & numerical data*; D004345:Drug Industry / Q000379:methods / Q000706:statistics & numerical data*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000401:mortality*; D005260:Female; D005500:Follow-Up Studies; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D010880:Piperidines / Q000009:adverse effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000401:mortality; D011799:Quinazolines / Q000009:adverse effects; D015996:Survival Rate / Q000639:trends; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000401:mortality
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; C089740:abiraterone; C452423:vandetanib
keywords: adverse events; benefit assessment; censoring; contingency tables; time-to-event data