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Keywords: Estimands, subsequent therapy, hypothetical strategy, trial failure, oncology
Industry has expressed concerns about the standard “ITT” approach to TTE evaluation. Subsequent therapy in a trial may itself be experimental and not reflect real-world clinical practice. Use of non-clinical-practice treatment as subsequent therapy may lead to inconclusive results.
The estimands framework focuses trials on answering clearly defined research questions predicting future real-world clinical practice. It defines events affecting interpretation of results, such as subsequent therapy, as intercurrent events, and discusses alternative strategies to address them.
Under this approach, the “ITT” approach, with corresponding follow-up requirements, becomes a treatment policy strategy.
When subsequent therapy is itself experimental, particularly when it consists of the study drug or another drug in the same class, then the trial conduct itself does not reflect clinical practice. Real-world patients neither receive placebos nor follow drug failure with another drug in the same class.
A hypothetical strategy asks what would have happened if an intercurrent event had not occurred. It may be particularly appropriate in this context. Where the exigencies of a trial require departure from real-world clinical practice, it may be scientifically appropriate to ask what would have happened if real-world practice were followed. Accordingly, a hypothetical clinical trial objective may be a scientifically reasonable, and a hypothetical strategy to address it may be appropriate.
Additional estimands strategies may also be useful.
Inconclusive results of primary ITT analyses result in failure of potentially beneficial treatments. The estimands framework provides an opportunity to discuss alternatives and to better assess the real-world value of novel therapies.
Presented on behalf of the Pharmaceutical Industry Working Group on Estimands in Oncology.