Statistical methods for next-generation clinical trials

Lead Research Organisation: University of Cambridge

Abstract

Clinical trials are used to test the effectiveness and safety of new treatments. In recent years they have become more and more expensive and have high rates of failure. Methods for reducing the cost of clinical trials and improving the chances of finding the truth are important. New technology means that new approaches to clinical trials are needed. This programme will conduct research into statistical methods for improving clinical trials.

The programme will cover three main areas. The first is research for including the large amount of biological information that can be measured for patients. The purpose of this is that different patients may benefit more from a treatment than others: we would like to be able to find this if it is true. The second is to explore how clinical trials can be more efficient by allowing new treatments to be added as they go along. This will reduce the cost and provide opportunities to ensure patients on a trial get the most suitable treatment for them. A third area is to improve the statistical analysis of trials which use complicated ‘composite endpoints’ which measure several things at once. This reduces the cost of clinical trials.

By working with doctors as well as statisticians we will make sure that this research is used in real clinical trials to benefit patients and decision-makers.

Technical Summary

The process of developing and testing a new treatment or intervention takes a long time, a lot of money, and often ends in failure. The high cost is primarily due to expensive clinical trials, which are required to show that the treatment is safe and effective. Improving the efficiency of clinical trials, to make maximum use of limited resources, is a priority research area.
This research programme will develop statistical methodology to ensure that clinical trials have the tools necessary to cope with current and future challenges.
The first area of focus is statistical methodology for best using the increasing amount of high-dimensional biomarker data in clinical trials. With increasing availability of routinely collected biomarker data, modern clinical trials urgently require suitable methods to incorporate them prospectively. Current approaches rely on less efficient statistical methods such as testing each variant one-by-one in a logistic regression, and classifying patients as high-risk if they are positive for a certain number of biomarker. By combining novel adaptive designs and state-of-the-art high-dimensional statistical methods such as Bayesian sparse regression we can improve on this. Through working with clinicians, this novel methodology will be available for use in real trials for areas such as cardiovascular diseases and oncology.
A second area of focus is methodology for ongoing trials that test multiple treatments and biomarkers. In an ongoing trial new treatments and biomarkers are added in continually as treatments are found sufficiently promising to move to phase III trials, or are dropped due to lack of effectiveness. Some real trials are already doing this due to the considerable logistical and administrative advantages. This programme will focus on statistical issues in ongoing trials. This includes how to optimally choose decision criteria for dropping or progressing a drug to phase III and how to optimally plan phase III trials that result. Collaborations with a multidisciplinary set of statisticians and clinicians will allow us to implement developed methods in practice.
A third area of focus is to improve the analysis of trials using composite endpoints. In this case it is possible to gain considerable power by fitting a suitable model to the data. These methods will be applied to a variety of disease areas including oncology trials, rheumatoid arthritis and lupus.

Publications

10 25 50

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Grayling MJ (2017) Group sequential designs for stepped-wedge cluster randomised trials. in Clinical trials (London, England)

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Grayling MJ (2018) Blinded and unblinded sample size reestimation in crossover trials balanced for period. in Biometrical journal. Biometrische Zeitschrift

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Grayling MJ (2018) Blinded and unblinded sample size reestimation procedures for stepped-wedge cluster randomized trials. in Biometrical journal. Biometrische Zeitschrift

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Grayling M (2018) Group Sequential Clinical Trial Designs for Normally Distributed Outcome Variables in The Stata Journal: Promoting communications on statistics and Stata

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Grayling MJ (2018) An optimised multi-arm multi-stage clinical trial design for unknown variance. in Contemporary clinical trials

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McMenamin M (2018) Improving the analysis of composite endpoints in rare disease trials. in Orphanet journal of rare diseases

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Michiels S (2019) Overestimated treatment effects in randomised phase II trials: What's up doctor? in European journal of cancer (Oxford, England : 1990)

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McClure ME (2019) Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis. in Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases

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Robertson DS (2019) Conditionally unbiased estimation in the normal setting with unknown variances. in Communications in statistics: theory and methods

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Grayling MJ (2019) Admissible multiarm stepped-wedge cluster randomized trial designs. in Statistics in medicine

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Antoniou M (2019) Biomarker-guided trials: Challenges in practice. in Contemporary clinical trials communications

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Lee KM (2019) Design of experiments for a confirmatory trial of precision medicine. in Journal of statistical planning and inference

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Gallagher F (2020) Imaging breast cancer using hyperpolarized carbon-13 MRI in Proceedings of the National Academy of Sciences

 
Description A platform clinical trial approach to the management of Mycobacterium abscessus complex
Amount $2,100,000 (AUD)
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 11/2018 
End 10/2023
 
Description Health Technology Assessment
Amount £1,792,088 (GBP)
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 02/2017 
End 12/2021
 
Description Improving the robustness of complex and structured study designd for clinical trials
Amount £158,598 (GBP)
Organisation Biometrika Trust 
Sector Private
Country United Kingdom
Start 12/2018 
End 12/2021
 
Description Methodology Research Programme
Amount £226,204 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC/NIHR Methodology Research Programme
Sector Academic/University
Country United Kingdom
Start 02/2017 
End 01/2020
 
Description Multiple Interventions for Diabetic Foor Ulcer Treatment (MIDFUT) Trial
Amount £7,745 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2017 
End 12/2021
 
Description Australian platform trial collaboration 
Organisation University of Queensland
Country Australia 
Sector Academic/University 
PI Contribution I was invited to be a co-investigator on a clinical trial submission to the Australian Medical Research Council. I provided input to the application. My role will be to provide methodology input to the design and analysis of the trial.
Collaborator Contribution Professor Claire Wainwright led the application and will be the chief investigator of the trial.
Impact Successful application to Australian national health and medical research council, with just over $2m funding.
Start Year 2017
 
Description Basket of Baskets trial 
Organisation Fundacio Institut d'Investigacio Oncologica Vall Hebron (VHIO)
Country Spain 
Sector Hospitals 
PI Contribution VHIO are leading a European wide Basket trial which will investigate novel targeted oncology treatments for different tumour types. Cambridge Cancer Centre are involved and I am providing the statistical input to this trial.
Collaborator Contribution VHIO have led the development of the trial and have successfully attracted several million euros worth of funding from Roche.
Impact Trial has not yet started so no outcomes yet.
Start Year 2017
 
Description Methodology advisor for Healthy Campuses trial 
Organisation University of Kyoto
Country Japan 
Sector Academic/University 
PI Contribution I helped advise Professor Toshi Furukawa on the design of a factorial trial in Japan, which will investigate which components of a CBT app are most beneficial to depressed undergraduate students.
Collaborator Contribution I contributed to the statistical design and analysis plan of the trial.
Impact Protocol paper is to be submitted soon.
Start Year 2017
 
Description AZ-MRC Science Symposium 2017 on 'All Data Great and Small' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact In conjunction with the AstraZeneca Biometrics Group, BSU organised a jointly sponsored science symposium on 'All Data Great and Small: Advancing clinical research through quantitative science'. 150 attendees from a cross-section of organisations came to the complimentary event, where various talks from external eminent speakers took place.

The symposium provided an opportunity to advance knowledge and understanding on data driven research, and establish new contacts and potential new collaborations for future research.

James Wason, Programme Leader Track, sat on the symposium organising committee - provided valuable ideas and contributions to develop the finalised agenda and format for the symposium.
Year(s) Of Engagement Activity 2017
 
Description Armitage Lectures 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Annual workshop and lecture created and hosted by the MRC Biostatistics Unit, to honour the immense contributions of Professor Peter Armitage who was at the unit from 1947 to 1961, and whose work is recognised throughout the world as achieving a successful balance between methodological rigour and applied commonsense, to which all statisticians aspire. An eminent medical statistician visits for a week and works with members of the unit. The highlight is the Armitage Lecture, where more than 100 delegates attend. This event raises the unit research profile and creates new collaborations.
Year(s) Of Engagement Activity 2016,2017
URL https://www.mrc-bsu.cam.ac.uk/news-and-events/armitage-lectureships-and-workshops/
 
Description Article in The Times - START Trial 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact James Wason co-author on paper published in Lancet (http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(18)30001-4/fulltext) about START Trial - findings published in The Times
Year(s) Of Engagement Activity 2018
URL https://www.thetimes.co.uk/article/costly-child-therapy-linked-to-higher-crime-risk-multisystemic-th...
 
Description Australian Adaptive Designs Courses 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We ran three 2-day workshops on Adaptive Clinical Trials in Australia (Melbourne, Brisbane and Sydney). This was organised by the Australian Clinical Trials Alliance.
Year(s) Of Engagement Activity 2019
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Each year BSU participate in Cambridge Science Festival - members of the general public explore and discuss issues of scientific interest and concern, through a series of different events. The festival also aims to raise aspirations by encouraging young people to consider a career in science, technology, engineering or mathematics.

BSU take part over two full days - 'Science Saturday' and the 'Cambridge Biomedical Campus' day. The unit presents a stand with 4 - 5 interactive activities that each communicate a basic statistical method or idea, representing one of the four research themes in the unit. Each year a new activity is developed and delivered requiring scientific input from staff and students across the unit. Over the two days, BSU engage with approximately 500 adults and children who visit the festival.
Year(s) Of Engagement Activity 2016,2017
 
Description Stimulus scheme - Volunteering in schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact PhD student, Martina McMenamin, volunteering at St Matthew's Primary School in Cambridge - 1 hour per week in maths classes. Encouraging and inspiring young children about maths - making maths fun. Part of University of Cambridge Stimulus scheme.
Year(s) Of Engagement Activity 2017,2018
URL https://stimulus.maths.org/content/
 
Description Talk at NIHR statistics group meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I was invited to give a talk on methodology research to the annual meeting of the NIHR Statistics Group
Year(s) Of Engagement Activity 2017
 
Description Talk at patients event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact I was invited to give a talk about novel design in clinical trials to a event focused on patients with polycystic kidney disease.
Year(s) Of Engagement Activity 2017
 
Description Talk to pharmaceutical statisticians meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact I was invited to give a talk to a PSI meeting on Bayesian methods in trials.
Year(s) Of Engagement Activity 2018