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GMDS 2012: 57. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e. V. (GMDS)

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie

16. - 20.09.2012, Braunschweig

Stopping one of two sister trials early for futility: Evaluation of futility monitoring tools

Meeting Abstract

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  • Patricia Glomb - Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Deutschland
  • Birgit Gaschler-Markefski - Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Deutschland

GMDS 2012. 57. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS). Braunschweig, 16.-20.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12gmds157

DOI: 10.3205/12gmds157, URN: urn:nbn:de:0183-12gmds1575

Published: September 13, 2012

© 2012 Glomb et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

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In most therapeutic areas of pharmaceutical research at least two well-conducted confirmatory trials are required for the submission and approval of new drug applications. Despite being increasing in size, duration and costs, the success rate of phase III registration trials remains very low. This is particularly true for Oncology. Stopping a clinical trial early that is very unlikely to be successful can therefore reduce substantial recourses, save time and effort. For that reason an interim analysis for futility is often implemented at a pre-specified point in time. A futility analysis is typically conducted by a Data Monitoring Committee (DMC) and causes a trial to be terminated if evidence shows that the results at the end of the trial are likely to be negative.

Conducting two confirmatory Phase III sister-trials in parallel for both of which a futility analysis is planned, the scenario can arise where based on the interim results one trial will emerge promising but the other considered futile. Although set up in parallel, due to different recruitment rates and other trial specific behaviour the interim analysis of one trial can become due only several months after the futility analysis of the first trial was conducted.

Given the futility analysis of the first trial is positive (results indicate that the new treatment is likely to beat the control) but the futility analysis of the second trial is negative (results indicate that the new treatment is unlikely to beat the control), several questions arise while making an overall judgement on the substance’s effect:

a) At the time of the later conducted futility analysis of the second trial, how should the information from the first non-futile trial be taken into account?
b) Which methods and additional information can be used in order to confirm the futility decision of the second trial?

We aim to investigate these questions within the framework of typical phase III oncology trials. In oncology progression-free survival (PFS) is taking the leading role as a surrogate endpoint for overall survival (OS) and is being used as the primary efficacy endpoint. PFS provides the basis for interim futility decisions.The fundamental methods for futility monitoring are (1) formal futility boundaries based on group sequential methods and (2) conditional power approaches including frequentist methods (stochastic curtailment), partially Bayesian methods (predictive power) and fully Bayesian methods (predictive probability).

Based on simulated scenarios of the afore-mentioned two trials situation we evaluate the common methods in order to answer the above questions a) and b). Re-sampling methods and retrospective analyses of the first trial are considered to gain higher evidence about the substance’s treatment effect. Three-state modelling is considered in order to make use of the dependence between PFS and OS.

Preliminary results illustrate that additional information from the past and data from the sister trial can be used to support the DMC decision in the afore-mentioned situation. Inspection of different futility measures retrospectively over the course of time can further give deeper insight before deciding on stopping for futility or not.