Non-concurrent control use in confirmatory platform trials

One full scholarship is available in the Leeds Institute of Clinical Trials Research in the School of Medicine in 2024/25.

This scholarship is open to UK applicants and covers fees plus £19,237 maintenance. This fully funded PhD place provides an exciting opportunity to pursue postgraduate research in cancer clinical trials methodology within the Leeds Cancer Research UK Clinical Trials Unit at the Leeds Institute of Clinical Trials Research. The Institute is an international leader in the field of clinical trials and the CRUK Unit is one of the largest in the UK being one of only 7 clinical trials units to receive a prestigious infrastructure award from Cancer Research UK. We conduct national and international early phase and late phase clinical trials specialising in blood cancers, treatment with radiotherapy, and colorectal cancer, and this PhD will integrate into these portfolios.

We invite applications from prospective postgraduate researchers who wish to commence study for a PhD in the academic year 2024/25 for the CRUK Clinical Trials Unit Scholarship. The award is open to full-time or part-time candidates (UK only) who meet the eligibility for a place on a PhD degree at the School of Medicine.

Background

The use of non-concurrent controls in randomised trials is a controversial topic. (1) However, there are scenarios where the use of appropriate-chosen non-concurrent controls could be advantageous. For example, in a platform study which has added a new experimental arm during recruitment such as FLAIR (2), comparisons could be more efficient if we include information from controls enrolled in a platform before the addition of the new arm. Similarly, in a study that stratifies tumours into, increasingly rare, molecular sub groups such as FOCUS-4 (3), the feasibility of undertaking randomised comparisons with concurrent controls reduces. Appropriately incorporating non-concurrent controls in situations such as these could provide adequately robust evidence that could enhance randomised comparisons and make them more practical and more efficient. 

There are a number of analysis methods (4) that have been proposed for use in these situations in both the frequentist and Bayesian paradigms. For example, p-value combination methods, regression-based adjustment methods and power prior methods have been used. However, the appropriate method to use in different situations is currently not well understood. Furthermore, the implications of the use of these methods in statistical design is not clear. For example, the appropriate weight to assign to information obtained in the historical period as compared to the concurrent period, and how this relates to different tuning parameters in the statistical methods, is not obvious. If this was better understood, it would allow the prospective determination of sample size for a given design that makes use of non-concurrent controls.

Studentship

The plan for this work would be to update the scoping review of the methodological literature and review published confirmatory cancer clinical trials that have made use of non-concurrent controls to understand current practice. The extension of these methodologies may also be considered if that is the interest and skillset of the student. The methods would then be evaluated in a simulation study designed to emulate platform trials where adding an arm, or molecular stratification take place. Variables of interest to consider in these simulations would include: the proportion of non-concurrent to concurrent controls and elements describing the similarity of the non-concurrent group, such as their calendar age. The focus of the simulation study will be to assess the performance of these different methods, particularly with reference to key clinical trial design and statistical quantities such as bias, coverage and frequentist power. In addition, there are example clinical trials in the Leeds Cancer Research UK CTU Haematology (Myeloma XI) and Colorectal Cancer Portfolios (FOxTROT) that can be used to evaluate these methods whilst supporting the development of the statistical analysis plan of impactful ongoing clinical trials. 

The intention is that this work will disseminate recommendations on how to design confirmatory clinical trials which use non-concurrent controls using existing analysis methods so that they can be added a priori into clinical trial protocols for scrutiny by important stakeholders such as trial funders, regulators and health technology assessors.

Supervisors

Day-to-day support will be provided by Professor David Cairns and of the Leeds Cancer Research UK Clinical Trials Unit, with expertise in the design and analysis of confirmatory platform trials. Co-supervision will be provided by Prof. James Wason (TBC)

How to apply

To apply for this scholarship opportunity applicants should complete an online application form and attach the following documentation to support their application.

• a full academic CV
• degree certificate and transcripts of marks
• Evidence that you meet the University’s minimum English language requirements (if applicable)

To help us identify that you are applying for this scholarship project please ensure you provide the following information on your application form;

• Select PhD in Medicine as your programme of study
• Give the full project title and name the supervisors listed in this advert
• For source of funding please state you are applying for a CRUK CTU Scholarship

Eligibility

Applicants to this scholarship should normally have an Undergraduate degree of 2:1 or above (or international equivalent) in a relevant subject area. A Masters degree is desirable but not essential.

If English is not your first language, you must provide evidence that you meet the University’s minimum English language requirements. The minimum English language entry requirement for the Faculty of Medicine & Health is an IELTS of 6.5 overall with at least 6.0 in each component or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

Other Conditions:

• Applicants must not have already been awarded or be currently studying for a doctoral degree
• Awards must be taken up by 1st November 2024
• Applicants must live within a reasonable distance of the University of Leeds whilst in receipt of this scholarship