Statistical methods for next-generation clinical trials

Lead Research Organisation: MRC Biostatistics Unit

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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Kunz CU (2017) Two-stage phase II oncology designs using short-term endpoints for early stopping. in Statistical methods in medical research

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

 
Description New adaptive design mentioned as 'research highlight' in Nature Reviews Clinical Oncology
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.nature.com/nrclinonc/journal/v12/n9/full/nrclinonc.2015.138.html
 
Description Biometrika Fellowship
Amount £96,860 (GBP)
Organisation Biometrika Trust 
Sector Private
Country United Kingdom
Start 11/2014 
End 09/2016
 
Description Gates Foundation - Dora Pereira
Amount £5,818 (GBP)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 04/2016 
End 03/2018
 
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 MRC- Alistair Coles
Amount £56,487 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 06/2020
 
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 UCL -Peter Fonagy
Amount £1,459,421 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 11/2015 
End 10/2020
 
Description AstraZeneca rheumatoid arthritis and SLE collaboration 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution The Biostatistics unit funded a PhD student to work under my supervision on methodology for applying the augmented binary method, an improved analysis technique for composite outcomes, to rheumatoid arthritis and systemic lupus erythematosus. The PhD student, Martina McMenamin started in October 2016.
Collaborator Contribution AstraZeneca has provided expertise from Anna Berglind and Martin Jenkins and access to clinical trial datasets in each disease. This has helped a lot with showing the methodology is useful in real life.
Impact So far we have published a paper in Rheumatology, prior to Martina starting.
Start Year 2016
 
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 CRUK grant 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided expertise in efficient statistical analysis of phase II oncology trials using the RECIST criteria.
Collaborator Contribution Individuals at the University of Birmingham provided clinical and applied statistical expertise that has helped us jointly develop a programme of work for a grant application.
Impact With individuals at the University of Birmingham, I have successfully applied for a Cancer Research UK grant, to start in Jan 2015.
Start Year 2013
 
Description MAMS grant 
Organisation Lancaster University
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided input to multiple submitted papers, including two in 2013/2014, that covered multi-arm multi-stage trials and phase II oncology trials. I provided input into writing a grant that was funded by the MRC methodology research panel. I was a co-investigator on this grant.
Collaborator Contribution Dr Thomas Jaki has provided complementary expertise into the writing of papers and the grant application.
Impact Multiple papers published since 2012 (recorded under publications). Successful grant application.
Start Year 2011
 
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 Philips Research Cambridge collaboration 
Organisation Philips Research Cambridge
Country United Kingdom 
Sector Private 
PI Contribution I am the academic supervisor for a Ph.D. student on the subject of 'Adaptive designs for telehealth trials'
Collaborator Contribution Individuals at Philips Research Cambridge have provided expertise on telehealth trials and have hosted the student for a research visit. They also provided a financial contribution to the EPSRC case award that funds the studentship.
Impact The student (Lisa Law) started in October 2013 and has been upgraded to full Ph.D. student status in October 2014. During her time as a student, Lisa published two papers. Unfortunately Lisa chose to drop out of the PhD programme in 2016 and submitted what she had done up to that point for a MPhil degree, which she received successfully.
Start Year 2012
 
Description SMARTer trial collaboration 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided expertise on statistical design of adaptive clinical trials to develop a suitable clinical trial design for the needs of the collaborators.
Collaborator Contribution Input on the design and clinical expertise. They have also written a grant application to fund the trials.
Impact We have submitted a paper on the trial design and a grant application to the HTA efficient trial design call (currently at outline stage).
Start Year 2012
 
Title OptGS R package 
Description This is a publically available R package for finding optimal group-sequential clinical trial designs. It is available from the CRAN repository (which involves validation steps). 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact The software package description and documentation has been published in the Journal of Statistical Software. 
URL https://cran.r-project.org/web/packages/OptGS/index.html
 
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 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 Imaging workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I was invited to give a talk to a mixture of PhD students and postdocs working in imaging research on "Introduction to statistics for clinical trial design". This was part of a course on clinical trials for that group.
Year(s) Of Engagement Activity 2015
 
Description Media enquiry - 'Trust Me I'm a Doctor' 
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, Programme Leader Track, provided background research on clinical trials research for BBC 2 documentary 'Trust Me I'm a Doctor'
Year(s) Of Engagement Activity 2016
 
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