A Surveillance Program for Serious Adverse Events During Phase III Drug Development Studies
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Drug Information J o u m l . Vol. 35, pp. 1301-1314, 2001
Copyright 0 2001 Drug Information Association Inc.
Printed in h e USA. All rights reserved.
A SURVEILLANCE PROGRAM FOR SERIOUS ADVERSE EVENTS DURING PHASE I11 DRUG DEVELOPMENT STUDIES PHILIP HOUGAARD Novo Nordisk, Bagsvaerd, Denmark
A new, simple approach to surveillance of serious adverse events during Phase III is suggested. The large-scale Phase III studies are typically double-blind comparisons of the drug with placebo, or a control, pelformed in order to assess the risk of frequent adverse events. The risk of rare and severe adverse events cannot be assessed with sufJicient precision, but the events must be monitored in order to stop the trials if there is a major safety problem. This paper suggests a cumulative sum (CUSUM)approach, where the events in the treatment group are cumulated, adjusting for the expected numbers based upon the total number of serious adverse events. Thus, if there are many events in the treatment group compared to the control group, there will be an alarm. The procedure requires unblinding the treatment for serious adverse events, but no other information from the ongoing studies. Exact probability properties of this sequential Bernoulli procedure can be evaluated by means of Markov chain methods. Optimizing the surveillance program with respect to the mean time to alarm (the standard in CUSUM applications) leads to a design that depends upon the alternative considered, whereas the optimum solution based on the probability of alarm within the expected course of the study is independent of the alternative. The procedure was applied to adverse events for NNC 46-0020, a partial estrogen receptor agonist. The finding of too many adverse events led to closure of the study. Key Words: Bernoulli; CUSUM; Markov chain; Optimal; Sequential
INTRODUCTION PHASE I11 OF A CLINICAL development program is the large-scale application of the new drug to patients. The desired effect of the drug is evaluated in Phase 11. The aim of Phase 111 is to confirm the effect of the recommended dose of the final formulation and to evaluate the risk of the adverse events, both those that are expected from earlier
Reprint address: Philip Hougaard. Biostatistics, Novo Nordisk, Novo AIIC, Building 9DS, DK-2880 Bagsvaerd, Denmark. E-mail: pho9novonordisk.com.
work on the drug, and those that are unexpected. vpically, the studies in this phase are double-blind comparisons of the new drug versus a control, which is placebo, or the best existing product. In this phase, many new side effects are detected. Even though the studies involve thousands of patients, they are usually underpowered for evaluating the more serious and rare events. However, there is still a need to monitor these events, and if they are too frequent, the drug development program must be stopped. Under the expedited reporting system, clinical centers are required to report serious
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