Clinical trial estimands which make use of the so-called hypothetical strategy target the effect of one randomised treatment compared to another in a scenario where the corresponding intercurrent event does not happen. Historically estimation of such estimands has made use of established techniques for handling missing data, setting any observed data after the intercurrent event to missing.
In the last few years it has been shown that data after the intercurrent event can be used for estimation of such hypothetical estimands, using methods such as G-formula and G-estimation from causal inference. These offer the potential for increased statistical power, but rely on making certain assumptions about how the intercurrent event influences subsequent outcomes. In a new pre-print available on arXiv, Rhian Daniel and I examine further the role of such post intercurrent event data in estimation of hypothetical estimands.
In the paper we:
- show certain G-formula estimators are identical to certain G-estimators, something which is not obvious from their construction
- show these estimators can only improve efficiency and power by making additional assumptions not required by estimators (such as imputation missing data estimators) that do not use data observed after the intercurrent event
- show the gain in efficiency/power will typically be modest, since in most trials the rates of such intercurrent events is usually not too large
- argue that the additional assumptions necessary will often not be plausible on clinical grounds
As such, we conclude by recommending that estimation of estimands that adopt the hypothetical strategy continue to be based on estimators that do not use data after the intercurrent event occurs. This involves setting any data observed after the intercurrent event to missing and handling the resulting missing counterfactual (no intercurrent event) outcomes using missing data methods, such as multiple imputation or inverse probability weighting.