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Br J Clin Pharmacol. 2019 Dec 27. doi: 10.1111/bcp.14195. [Epub ahead of print]

Beyond "Intent-to-treat" and "Per protocol": Improving assessment of treatment effects in clinical trials through the specification of an estimand.

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European Medicines Agency, Domenico Scarlattilaan 6, Amsterdam, HS, 1083, the Netherlands.
Medical Statistics, Universita' della Campania Luigi Vanvitelli, Naples, 80138, Italy.
Medicines and Healthcare products Regulatory Agency, 10 South Colonnade, London, E14 4PU, UK.
Dutch Medicines Evaluation Board, College ter Beoordeling van Geneesmiddelen, Graadt van Roggenweg 500, Utrecht, AH, 3531, the Netherlands.
Department of Health Evidence, Section Biostatistics, Radboud University Medical Centre, Geert Grooteplein 21, Nijmegen, GA, 6525, the Netherlands.


There is a key problem in randomised clinical trials as outcomes can be distorted due to informative post-randomisation events. This is inadequately addressed by the use of traditional intention-to-treat or per protocol analysis sets and often either ignored or wrongly labelled as missing data. As a consequence, the treatment effects of interest in a clinical trial are not well defined and their estimates might be misinterpreted. The estimand framework should help all those planning, conducting and analysing clinical trials as well as those interpreting the results to better define, estimate and understand the treatment effects of interest. This framework is described in the addendum to ICH E9 and addresses precisely this problem. It is relevant for regulatory drug trials and academic-run trials, as well as for trials of nonpharmacological interventions.


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