HSM: Estimation of intervention effects for adaptive enrichment design RCTs that incorporate identification of predictive biomarkers

Lead Research Organisation: University of Warwick
Department Name: Warwick Medical School


Advances in medicine have led to the acknowledgement that differences in patient characteristics may lead to differences in how patients respond to therapies such as drugs. Patient characteristics that have had much medical research interest recently are those based on the genetic make-up. For example, patients may be categorised as those who express a certain genetic make-up and those who do not. The term generally used is biomarker, with the patients who express a certain genetic make-up referred as being biomarker positive and those who do not referred as biomarker negative. The term is usually not restricted to genetics and so could be used, for example, to categorise patients into those below and those above a certain age.

This project is concerned with settings where the biomarker may interact with a therapy, that is, patients' responses to a therapy depends on whether they are biomarker positive or negative. If a patient's response depends on whether he/she is biomarker positive or negative, the biomarker is said to be a predictive biomarker.

Stratified medicine is the branch of medicine where testing of new therapies allows for the possibility of differences in therapy effects in different subpopulations defined by biomarker status. One strategy is to have two separate trials. The first trial consisting of patients from the full population and its aim is to use a predictive biomarker to select the subpopulation that will benefit from the new therapy. The second trial recruits patients from the selected subpopulation and its aim is to use the data collected to get a definitive estimate of the size of the effect (benefit) of the new therapy in this subpopulation.

An efficient strategy is to have a single trial that includes an interim analysis partway through the trial to select the subpopulation that benefits from the new therapy. After the interim analysis, more patients are recruited from the selected subpopulation and their data, together with data used in the interim analysis, are used is to get a definitive estimate of the size of the effect of the new therapy in the selected subpopulation. Such designs are commonly referred to as adaptive enrichment designs. They are efficient because fewer patients would be required to test a new therapy.

Estimating the size of the effect of the new therapy when an adaptive enrichment design is used needs to adjust for the fact that the interim data used to select the subpopulation are also used in estimating the effect. If this is not done and the standard methods are used, the effect will be overestimated because the larger effect observed in the selected subpopulation using the interim analysis data may have occurred by chance. This is undesirable because definitive estimates of the size of the effect of new therapies are used by many stakeholders to make a decision on whether to adopt a therapy.

Only one appropriate method for estimating effects of therapies, and which is for a specific design, has been developed for adaptive enrichment designs. This is one of the barriers of using these designs. The aim of this project is to remove this barrier by developing new methods for estimating size of effects while adjusting for subpopulation selection made using a predictive biomarker.

The difference between the existing method and this work is that we will consider different forms of biomarkers, such as having more than one biomarker, and we will also consider a common type of patient outcome data in stratified medicine: time to event data such as overall survival for patients.

This work will increase the use of adaptive enrichment designs. Consequently, this will save resources while testing new therapies and lead to more rapid development of safe effective treatments.

Technical Summary

The aim of this work is to develop point and interval estimators following randomised clinical trials (RCTs) that are conducted using adaptive enrichment designs in the context of stratified medicine.

In stratified medicine, it is acknowledged that patients with different characteristics such as different genetic biomarkers, may respond to treatments in different ways so that an intervention may only benefit a subpopulation of the full patient population. Testing of new interventions allow for this possibility.

We will consider adaptive enrichment designs where a RCT includes an interim analysis. Using a predictive biomarker, that is a biomarker that determines how a patient responds to a treatment, the interim analysis is used to select the subpopulation that benefits from the new therapy. After the interim analysis, patients are recruited from the selected subpopulation. Definitive analysis includes data collected before and after interim analysis.

Interim analysis data induce selection bias and so point and interval estimators need to adjust for this. Very little work exists that adjust for selection bias and so more research is required. We will develop point estimators for three settings: (1) Patient data are normally distributed and the biomarker is continuous with several candidate threshold values, (2) Same setting as above but for time to event data, and (3) A panel of biomarkers is used to make selection. Data collected after the interim analysis are unbiased and we will use them to get unbiased estimators, which we then Rao-Blackwellise to obtain unbiased estimators that have smaller variances.

We will also develop two interval estimators for the first setting; one based on p-value inversion and the second based on the density of the statistic in the selected subpopulation.

By enabling unbiased point and interval estimation, we will increase the use of these efficient adaptive enrichment designs.

Planned Impact

Who will benefit from this research?

This research will benefit UK and global regulatory bodies and individuals who want to use estimates from clinical trials to make decisions on whether to adopt or not adopt therapies. The research will also benefit any institution that conducts and analyses clinical trials such as the pharmaceutical industry and public sector research institutions. Finally, the ultimate aim of this research work is intended to benefit patients and the general public.

How will they benefit from this research?

The aim of this research is to develop methods for obtaining unbiased estimates following clinical trials conducted using adaptive enrichment designs in the context of stratified medicine. Currently, appropriate methods for hypothesis testing are available but methods for obtaining unbiased estimates are lacking. As well as well as hypothesis testing, unbiased estimates are important to decision makers as they quantify the size of effect for therapies. This research will fill the current gap associated with lack of methods for obtaining unbiased estimates. This will enable regulatory bodies and individuals who want to make decisions to have better understanding of the benefits of therapies tested using adaptive enrichment designs.

Pharmaceutical industry and public sector research institutions will benefit because they will be able to obtain unbiased estimates and confidence intervals with right coverage probabilities when they use adaptive enrichment designs to conduct their clinical trials. This will increase uptake of adaptive enrichment designs. Consequently, it will become cheaper for institutions to conduct clinical trials.

The patients will benefit because adoption of adaptive enrichment designs means that effective and safe therapies will become available more quickly. The general public will also benefit because clinical trials that are funded through taxes will become cheaper. The money saved may be used to conduct more trials or to provide other services.


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Description Collaboration with Dr Lindsay Renfro from Mayo Clinic in the US 
Organisation Mayo Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution This collaboration was proposed in the grant application. The collaboration has been successfully established. Our contribution to the collaboration is several years expertise in developing statistical techniques that can be used to analyse trials that include selection of patients based on biomarkers. Mayo Clinic conduct such trials and will benefit by having appropriate statistical methods to analyse them.
Collaborator Contribution The partner has already provided input into the designs that we have considered while developing new statistical methods. The partner uses the designs and patient outcomes that we will assume for the new statistical methods in the second work package. The partner has promised to provide real clinical trial data to demonstrate how to apply the new statistical methods in this work package.
Impact (1) I had a research visit in October 2017 at the partner's site where I presented methods developed in work package 1. (2) Research partner provided input in terms of statistical expertise and application of methods in clinical trials on a paper that has been resubmitted after reviewers' comments. (3) I have had a discussion with the partner on getting real data to apply to the methods to be developed in Work Package 2.
Start Year 2016