title: Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 3: Design considerations.
abstract: Ongoing safety monitoring of clinical trials of investigational treatments must operate at levels that range from the minute and detailed - namely, mathematical treatment of trial data - to the philosophical and societal - namely, ethical concerns for individuals and populations. Between those two poles lies a realm of environmental and pragmatic considerations that reflect the goals, biases, risk-tolerance, and constraints of study sponsors and organizers. These factors, while more difficult to quantify or, at times, to justify, also have a meaningful impact on the approach to safety monitoring and the resulting actions and outcomes. This paper considers the influence and interaction of two such factors, study design and statistical framework, on continuous safety monitoring procedures. Group sequential designs have been generally preferred for clinical trials over continuous sequential designs because of practical considerations. The group means and greater time for deliberation when using a group sequential procedure, as opposed to a continuous sequential procedure, can improve the quality of the analyses with minimal loss in sensitivity. However, undertaking any sequential analysis within a frequentist framework provokes considerable theoretical and practical difficulties. Continuous monitoring with a likelihood based method, on the other hand, has the advantages that all available information, including new data, can be used; sample sizes need not be fixed; and decisions can be made at any time without statistical penalty, irrespective of trial design. Such responsive statistical rules are needed to provide guidance to the human beings charged with trial monitoring.
authors.affiliation: Astellas Pharma Global Development, 3 Parkway N, Deerfield, IL 60015, USA. greg.ball@us.astellas.com
authors.forename: Greg
authors.initials: G
authors.lastname: Ball
authors.forename: Michael H
authors.initials: MH
authors.lastname: Silverman
mesh_terms: D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials / Q000191:economics; D006801:Humans; D009874:Operations Research; D061214:Patient Safety / Q000592:standards; D018579:Patient Selection; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards; D012107:Research Design / Q000592:standards*; D018401:Sample Size; D016037:Single-Blind Method