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Using observational data and/or single arm studies to inform trial design: can we make our trials smaller and shorter?

   Institute of Clinical Trials and Methodology (ICTM)

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  Dr Siobhan Crichton  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Background to the project: The gold standard for evaluating the efficacy and safety of new treatments versus existing treatments (standard of care) is a phase III randomised controlled trial (RCT). However, such trials are large, expensive, take time and are not always feasible. Thus there is growing interest in other approaches to generating evidence, particularly in children (where treatment lags behind adults and the numbers are often smaller). For a new drug for children, a small phase II pharmacokinetic (PK) study is carried out to evaluate dosing and collect some safety and efficacy data at the same time. Once these data are available, serious consideration needs to be given to whether a subsequent full-scale phase III RCT is needed.

Dolutegravir (DTG)-based antiretroviral therapy (ART) was first approved for treatment of adults and adolescents aged ≥12 years living with HIV in 2013. The ODYSSEY trial, led by the MRC CTU, evaluated DTG-based ART versus standard of care in children newly starting or switching ART following treatment failure. This full scale RCT started recruitment in 2016, and the first results were not available until the end of 2020. The trial ran alongside a small phase II dose-finding study in children taking DTG, which included PK and limited efficacy and safety data. ODYSSEY also included PK and safety in a subset of children in the DTG group of the trial.

At the MRC CTU we lead the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC) which pools patient level data on children and adolescents living with HIV treated in routine care settings across Europe and Thailand. These cohorts provide ‘real world’ high quality data on the uptake, effectiveness and safety of new drugs.

What the studentship will encompass: The student is likely to begin with a review of the growing literature on emulating randomised clinical trials with non-randomised real-world observational cohort studies. This will help identify key assumptions required for successful use of observational data in this way. The student will then explore alternative approaches to using data from small PK studies, observational cohort data and other trial data to inform treatment in children, potentially reducing the need for large-scale efficacy trials.

First, the student will aim to emulate the ODYSSEY trial in the EPPICC observational cohort, by defining appropriate inclusion/exclusion criteria, considering an appropriate primary outcome and by using causal inference methods to adjust for biases, including selection bias in observational studies and better adherence in trials. Secondly, this will be built upon by combining data on the ODYSSEY PK study with a simulated standard-of-care arm from EPPICC to evaluate treatment outcomes. Outcomes will be compared to those reported in the main ODYSSEY RCT. Finally, the student will consider whether using Bayesian approaches to borrowing information from the existing published randomised controlled trials of DTG in adults could have reduced the size of the ODYSSEY trial, potentially to just PK/safety studies with contemporaneous controls (either from trial or observational data). 

Depending on their interests, the student may also carry out a small qualitative study to explore views of clinical investigators, trialists and statisticians on the validity of results generated using external controls or from emulated trials.

The supervisors are based at the MRC CTU and bring together a wealth of expertise in use of real world and trial data and statistical methods, within a friendly and supportive team. Siobhan Crichton (EPPICC senior statistician) and Jeannie Collins’ (epidemiologist and EPPICC co-lead) research interests focus on the use of observational data primarily to describe epidemiology and treatment outcomes of children living with HIV and other infections. Man Chan (statistician) has experience working across RCTs evaluating treatment efficacy and safety in children living with HIV, and observational studies of virological outcomes and viral reservoirs; and Becky Turner’s (statistical methodologist) research interests include Bayesian methods, meta-analysis and adjustment for biases.

Candidates should have a strong background in maths/statistics, ideally bachelor’s degree in mathematics and/or statistics with an MSc in Statistics.


You are applying for a PhD studentship from the MRC TMRP DTP. A list of potential projects and the application form is available online at:

Please complete the form fully. Incomplete forms will not be considered. CVs will not be accepted for this scheme.

Please apply giving details for your first choice project. You can provide details of up to two other TMRP DTP projects you may be interested in at section B of the application form.

Before making an application, applicants should contact the project primary supervisor to find out more about the project and to discuss their interests in the research.

The deadline for applications is 4pm (GMT) 18 February 2022. Late applications will not be considered.

Completed application forms must be returned to: [Email Address Removed]

Informal enquiries may be made to [Email Address Removed]

Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend (stipend to include London Weighting where appropriate). We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.
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