Clinical trial estimands - from definition to estimation

Randomised clinical trials represent the gold standard approach for testing whether new treatments for diseases work better than existing treatments and quantifying the magnitude of the benefit. In principle the analysis of such trials is simple - one compares the chosen outcome measure of patients in one group with the patients in the other group. In practice a number of complications may arise which make this comparison difficult to interpret or impossible even to calculate. One example is trials in which patients may change from the treatment that they were randomly assigned to receive during the follow-up period, either to the alternative treatment, no treatment at all, or they may start taking additional treatment(s). A second example is in trials which aim to compare (for example) cholesterol treatments in terms of their effects on death due to cardiovascular disease. This comparison is complicated by the fact that some patients may die of other causes, such as cancer. In a simple analysis comparing the number of patients who died due to cardiovascular disease between the two groups, a new treatment could for example reduce the chances of death due to cardiovascular disease, but only by virtue of the fact it increases death due to cancer. A third example is trials in cancer where interest lies in comparing treatments both in terms of their ability to prevent cancer recurrence and in terms of their adverse side effects, which may impact on the patient's quality of life. Any comparison of the treatments' effects on patient quality of life measures is complicated by the fact that inevitably such measures will be unavailable for some patients in each treatment group because they have died.

In the context of such issues, in recent years there has been increased scrutiny from drug regulatory agencies regarding how clinical trials specify how they will handle such complications in their design and statistical analysis. Specifically, there is an increased demand for trials to clearly specify exactly what kind of effect of treatment they seek to quantify (the so called estimand) and to choose a method of statistical analysis that handles these issues in a sensible and plausible manner.

The aim of this research is to investigate how such complications can best be handled using concepts and methods developed in the field of so called 'causal inference theory'. This theory offers a mathematical language to precisely describe what we mean by the effect of treatment in the presence of complicating factors such as the ones described earlier. Moreover, a large range of statistical methods have been developed for estimating treatment effects defined using these concepts, under different assumptions. This research will use causal inference theory to precisely define treatment effects (estimands) in the presence of the various issues described earlier. It will then investigate which statistical methods developed in causal inference theory are best suited for application to the analysis of clinical trial data.

The outputs of this research will help statisticians involved in clinical trials to use causal inference concepts and language to clearly specify the treatment effect which their trial intends to estimate. It will give them guidance and recommendations as to which statistical methods they can use to estimate such effects. The research will also produce software to implement the new statistical methods to enable trial statisticians to use the methods in their trials. Together these outputs will mean that patients can be offered more meaningful and accurate measures of expected treatment effects and that clinicians can make more informed decisions about patient care. The research will enable drug regulators and payer authorities to make fairer comparisons between treatments in regards their efficacy, safety, and cost-effectiveness, leading to improved decisions about which treatments to license and make available to patients.