Applying the estimands framework to non-inferiority trials: guidance on choice of hypothetical estimands for non-adherence and comparison of estimation methods
arxiv(2023)
摘要
A common concern in non-inferiority (NI) trials is that non adherence due,
for example, to poor study conduct can make treatment arms artificially
similar. Because intention to treat analyses can be anti-conservative in this
situation, per protocol analyses are sometimes recommended. However, such
advice does not consider the estimands framework, nor the risk of bias from per
protocol analyses. We therefore sought to update the above guidance using the
estimands framework, and compare estimators to improve on the performance of
per protocol analyses. We argue the main threat to validity of NI trials is the
occurrence of trial specific intercurrent events (IEs), that is, IEs which
occur in a trial setting, but would not occur in practice. To guard against
erroneous conclusions of non inferiority, we suggest an estimand using a
hypothetical strategy for trial specific IEs should be employed, with handling
of other non trial specific IEs chosen based on clinical considerations. We
provide an overview of estimators that could be used to estimate a hypothetical
estimand, including inverse probability weighting (IPW), and two instrumental
variable approaches (one using an informative Bayesian prior on the effect of
standard treatment, and one using a treatment by covariate interaction as an
instrument). We compare them, using simulation in the setting of all or nothing
compliance in two active treatment arms, and conclude both IPW and the
instrumental variable method using a Bayesian prior are potentially useful
approaches, with the choice between them depending on which assumptions are
most plausible for a given trial.
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