Estimates of subgroup treatment effects in overall nonsignificant trials: To what extent should we believe in them?

Pharmaceutical Statistics
Julien TanniouKit C B Roes

Abstract

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall "failed" trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial ...Continue Reading

References

Aug 5, 2005·Journal of Biopharmaceutical Statistics·Jean-Marie GrouinJohn Lewis
Jan 1, 2008·The International Journal of Biostatistics·Xiaogang SuSong Yang
Jul 30, 2010·Clinical Trials : Journal of the Society for Clinical Trials·Stephen J RubergYanping Wang
Aug 5, 2011·Statistics in Medicine·Jared C FosterStephen J Ruberg
Jan 8, 2014·Journal of Biopharmaceutical Statistics·Armin Koch, Theodor Framke
Jan 8, 2014·Journal of Biopharmaceutical Statistics·Ilya Lipkovich, Alex Dmitrienko
Jan 23, 2014·Statistical Methods in Medical Research·Julien TanniouKit Cb Roes
Feb 20, 2016·BMC Medical Research Methodology·Julien TanniouKit C B Roes
May 28, 2016·Biometrical Journal. Biometrische Zeitschrift·Gerd K Rosenkranz
Sep 1, 2016·The New England Journal of Medicine·Stuart J Pocock, Gregg W Stone

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Citations

Jun 18, 2019·Therapeutic Innovation & Regulatory Science·Christoph MuysersStephanie Roll
Jul 31, 2020·The Journal of Thoracic and Cardiovascular Surgery·Volkmar Falk, Tim Friede

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