Novel methodologies for the design of clinical trials using external control data

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

Clinical trial design in rare disease populations remains challenging. Conventional approaches to phase II and III trial design incorporating randomization are often practically prohibitive due to the limited patient population, making it difficult to deliver a robust evidence base with the number of patients required by these designs. Randomised controlled trials may also be ethically prohibitive in disease settings where no standard of care therapy exists, or where there are known poor outcomes with standard of care. The use of external controls, or digital comparators, offers an alternative approach to trial design in this setting. 

In 2023, the US Food and Drug Administration (FDA) released draft guidance on the design and conduct of externally controlled trials, recognising that no single statistical or analytical method exists that will be suitable for all trials involving external control arms. The MUK9 Optimum trial is a single arm phase II trial for patients with newly diagnosed ultra-high risk multiple myeloma, designed using a Bayesian multi-outcome multi-stage design. The trial was designed with pre-planned comparison to external control data from a recently recruited large multi-centre phase III randomised controlled trial for all patients with newly diagnosed myeloma, the Myeloma XI trial. The MUK12 trial is a randomised phase II trial for patients with relapsed refractory multiple myeloma incorporating a small, randomised calibration control arm. Combined, the MUK9, Myeloma XI and MUK12 trials provide an opportunity to explore the application and development of novel methodologies for the design of clinical trials using external control data, forming the basis of this PhD proposal.

Studentship

This project will explore the use of novel methodologies for the design and analysis of single arm phase II and III trials that utilise external control data either wholly, or partly, in place of randomised concurrent controls. Methodologies currently used include Bayesian approaches combining prior historical control data with limited concurrent control data, Bayesian approaches to single arm trials, and propensity score matching.

The project will review the current literature to determine methodologies for efficient decision making with the use of external control data in phase II and robust evidence generation in phase III trials. The project will specifically address i) application of alternative methods to the design and analysis of MUK9 ii) the impact of the choice of endpoint on design and analysis e.g. binary, continuous, time to event; iii) approaches to combining concurrent control data with external control data for the purpose of decision making;  

Data from current and recently completed clinical trials developed and delivered through the Leeds Cancer Research UK Clinical Trials Unit will provide practical examples to which novel methodologies may be applied, as previously described, providing a wealth of opportunity for the use of external control data in the form of digital comparators, non-concurrent historical control data, and hybrid approaches to combine limited concurrent control data with historical data. This will be considered in the setting of myeloma initially, with extension to the setting of colorectal cancer where patient stratification increasingly leads to smaller groups being stratified to targeted precision medicine approaches.

Supervision

Day-to-day support will be provided by Professor Sarah Brown and Andrew Hall of the Leeds Cancer Research UK Clinical Trials Unit, with expertise in the development and implementation of statistical methods in clinical trials. Co-supervision will be provided by Dr Sadie Roberts (Leeds CTU).

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