Statistical Methods for Contemporary Clinical Trials
News
Webinar: Bayesian multi-criteria preference modelling for benefit-risk assessments
Jun 7, 2022
On 8th June at a NIHR benefit-risk working group webinar, Dr Ed Waddingham presented his work from his recent PhD on Bayesian estimation of preference weights for quantitative benefit-risk assessments or other multi-criteria decision problems.
Topics covered included:
· The basics of quantitative benefit-risk assessment, based on the methodology known as multi-criteria decision analysis (MCDA);
· Some commonly used deterministic methods for eliciting preferences;
· Probabilistic models that may be appropriate for preference data;
· Aggregation of preference data from multiple sources;
· The parallel application of these modelling approaches in a benefit-risk assessment.
The talk was illustrated with examples using the Bayesian MCMC approach in BUGS software.
Inaugural Meeting for TMRP Adverse Events in Clinical Trials working group (a sub-group of the Outcomes Group)
May 9, 2022
On 10th May we had our Inaugural meeting for a new group led by Rachel Phillips and Victoria Cornelius. The aim of the group is to bring together researchers interested in improving the collection, analysis, selection, and reporting of adverse events in RCTs for pharmacological and complex interventions. The first meeting had an international flavour attracted over 40 delegates from seven countries.
The meeting started with an introduction and orientation to progressing research in harms by Victoria Cornelius and Rachel Phillips. Diana Papaioannou from the University of Sheffield gave a talk on “Working towards efficient and appropriate recording of adverse events in behavioural change trials the RHABIT project”, followed by Kaspar Rufibach from Roche in Basel who gave a talk on “Stop the abuse: A plea for a more principled approach to the analysis of adverse events. The SAVVY project”.
The final session was hosted by Dr Tianjing Li from University of Colorado on determining the Groups first activity- to write a series of educations articles to promote better practice.
Estimand workshop available to watch online
May 4, 2022
On 28th and 29th April Dr Suzie Cro lead a workshop for trialists introducing estimands, which was supported by the MCR-NIHR TMRP. Speakers included clinicians and statisticians from academia and industry who covered, what an estimand is, why we need them and how to implement the estimand framework. All the sessions were recorded and are freely available to watch via the link below.
StatsCI at Great Exhibition Road Festival
Apr 26, 2022
This year we will be at the Great Exhibition Road Festival! This is a fantastic event where research teams share insights of their work with the general public. We will be hosting several activities that aim to teach you more about how a clinical trial works and some of the key concepts we use to make sure we can be confident about our answers.
We will be in the Medicine Zone, you can find out more below.
Event: What are estimands and why should we be using them?
Feb 28, 2022
Want to know what an estimand is? And why we should be using them in our clinical trials? Registration is now open to attend a free online meeting on April 28th to discuss the use of estimands in clinical trials, lead by Dr Suzie Cro. Speakers include statisticians and clinicians working in clinical trials. There is also a follow-on workshop on day 2 on How to implement the estimand framework (places prioritised for UKCRC CTU affiliation). Event funded by the MRC NIHR Trials Methodology Research Partnership (TMRP). For more details and how to register follow the link below.
New guidelines on statistical analysis plans for early phase trials published in BMJ
Feb 8, 2022
A new guidance paper for how to write Statistical Analysis Plans (SAPs) for early phase clinical trials has been published in the BMJ.
The project, led by Victoria Homer and Piers Gaunt (University of Birmingham) and co-authored by Graham Wheeler (Deputy Head of Statistics, ICTU), adapted existing SAP guidance for randomised trials for early phase and dose-findings studies.
The work included: a comprehensive search to identify existing published protocols, SAPs, and SAP guidance; a survey of clinical trial funders and regulators; a survey of current practice by statisticians within Clinical Trials Units registered with the UK Clinical Research Collaboration; a critical appraisal and expert review meeting; and a pilot of the proposed guidelines.
The updated guidance - reviewed by academic, industry, and regulatory statisticians - specifies the minimum reporting analysis requirements, detailing extensions (11 new items) and modifications (25 items) to existing guidance. These include:
Increased details regarding statistical design methodology, and model choice where appropriate
Update of outcome definitions to include definition of estimands in line with the principles outlined in ICH E9 (R1)
Inclusion of simulation reports incorporating operating characteristics, to justify statistical design or sample size where applicable
Inclusion of code required for novel methodology
Inclusion of dose transition pathways, where appropriate
Amendments to wording to be more neutral to both frequentist and bayesian methodology, to reflect that some early phase clinical trials designs, particularly phase I, are underpinned by bayesian methods.
NIHR Pre-Doctoral Fellowship opportunities
Feb 2, 2022
Are you looking to start or advance your career in medical statistics or clinical trial design? We invite expressions of interest from individuals who would like to apply for a NIHR Pre-Doctoral Fellowship in medical statistics or clinical trial design. The NIHR Pre-Doctoral Fellowship provides funding for up to two years full time (or part time equivalent) to undertake hands on and academic training, including a master’s degree for applicants who do not have one to advance to the next level of their career. We need to hear from you by 17th February 2022, though earlier application is strongly encouraged. The deadline for applications to the NIHR is 1pm on 17th March 2022. For more details including potential supervisors and contact details please click below.
ICTU Statisticians supporting trial of needle-free vaccine for COVID-19 variants
Dec 17, 2021
This week, a study of an innovative needle-free COVID-19 vaccine (DIOS-CoVax) was opened to recruitment.
The collaborative study, led by Professor Saul Faust (University of Southampton) and Professor Jonathan Heeney (University of Cambridge), will look at the safety and signals of efficacy of the novel vaccine, which has been designed to protect against COVID-19 variants and future coronaviruses. Graham Wheeler and Matyas Szigeti, from Imperial Clinical Trials Unit, are providing statistical oversight on the study’s design, conduct and analysis.
The study’s opening received widespread media attention. In the BBC article below, Dr Rebecca Kinsley (University of Cambridge) shows how the needle-free vaccine technology works.
Interpreting statistical results in COVID-19 clinical trials
Nov 15, 2021
In November 2021, Graham Wheeler addressed the UK Government’s Antiviral Taskforce and Therapeutics Taskforce in an online seminar titled “Interpreting statistical results in COVID-19 clinical trials”.
Chaired by Dr Alex Churchill, Deputy Director of the Therapeutics Taskforce at the Department for Health and Social Care, Graham’s seminar used published frequentist and Bayesian trials to show statistical features of randomised clinical trials of therapies for treating COVID-19. These included trial design, planning and recruitment, through to interpreting research results and spotting common pitfalls and limitations in published research.
Ensuring academic trials answer the questions of interest: Implementation of the estimand framework
Oct 28, 2021
Dr Suzie Cro was successfully awarded funding in the TMRP Working Group award. She will be running a workshop to help other CTUs in the UKCRC network use an implementation tool to make sure the estimand framework is being implemented. It's important to ensure we are clear which estimand is being used in our analysis of academic trials. Currently uptake of the new framework has been very poor and it is hoped the workshop will improve uptake.
New fellowship to improve the evaluation of digital health interventions in mental health
Oct 1, 2021
This month Jack Elkes starts a 3-year doctoral fellowship, awarded by the NIHR to improve the evaluation of mental health digital health interventions in randomised controlled trials.
To test whether a digital health intervention such as an app or a website has a beneficial effect on patient health a randomised controlled trial is the gold standard study type to perform; however the level of engagement with the intervention is often not taken into account within the trial analysis. This means the relationship between how often patients engage with a mental health digital health intervention and the benefit received is poorly understood. Understanding this relationship will provide patients with an improved understanding of how much they should use such interventions and why.
Using clinical trials previously conducted in depression and psychosis as case studies, Jacks research will address (i) How to define engagement levels for mental health digital health interventions and (ii) How to adjust for engagement levels in the analysis of digital health interventions trials.
A new training course from the Clinical Trials Unit
Sep 6, 2021
This week marks the start of our brand new course, the introduction to contemporary clinical trials course. We will be introducing researchers to key concepts on how to design, setup and run a trial. The course is very practical where students develop their own study protocol throughout the 10 week course.
StatsCI Research Away Day
Aug 4, 2021
On August 5th, the StatsCI team met in person for the first time in over a year! There was lots to catch up on and we started the day with an update from Victoria Cornelius on the work of the methods group to date. This was followed by a jammed packed morning listening to updates on ongoing projects and exciting future methodological research plans.
Talks included:
- an update from Suzie Cro on her review of treatment estimands in randomised controlled trials, which forms part of her ongoing NIHR advanced fellowship
- a new project from Graham Wheeler on extensions to simulation-free design of phase I trials using the Continual Reassessment Method
- the results of Ellie Van Vogt’s MSc dissertation project looking at socio-economic determinants of pre-mature menopause
- results from Matyas Szigeti’s investigation into the use of extreme value statistics for risk assessment for patients with type I diabetes
- the findings of Francesca Fiorentino’s work with Emily Day on verification bias in trials of multiple screening tests
- a summary of the research undertaken by Giles Partington during his NIHR fellowship on the use of Bayesian methods for rare disease and small population trials
- an overview of Jack Elkes plans for a review of digital mental health RCTs, which will form the first part of his recently awarded NIHR doctoral research fellowship
- and exciting project ideas from Nicholas Johnson and Emanuela Falaschetti looking at the effect of interventions used to increase rates of type II diabetes remission and Consuelo Nohpal de la Rosa looking into imputation methods for right censored variables.
It was a great opportunity for the team to share results and ideas, and we look forward to providing updates on all of the above in the coming months.
PSI 2021
Jun 22, 2021
At this years virtual PSI conference several members of the team presented their research in talks or e-posters:
- Victoria Cornelius presented a Bayesian framework for non-inferiority evaluation of uncommon conditions in randomised controlled trials.
- Suzie Cro outlined controlled multiple imputation as an accessible flexible tool for estimating hypothetical estimands in trials with multiple intercurrent events.
- Giles Partington presented an e-poster looking at the design and analysis of small population and rare disease trials: a review of randomised trials.
- There was also a talk from alumini Anca Chis Ster who presented her work on improving analysis practice of continuous adverse event outcomes in randomised controlled trials - a distributional approach.
ICTU at the SCT conference 2021
Jun 7, 2021
In May, the 2021 SCT conference was held online, with several members of the team presenting their work during the conference:
Victoria Cornelius presented a new framework to improve the analysis of Adverse Events and improved solutions for analysing them in RCTs.
Giles Partington discussed the results of his systematic review into the use of design and analysis features in Rare Disease and Small Population trials.
Rachel Phillips presented her findings from a consensus of UK trialists and outlined recommended graphics to visualise Harm Profiles when reporting RCTs.
ICTU at the SCT conference 2021
Jun 7, 2021
In May, the 2021 SCT conference was held online, with several members of the team presenting their work during the conference:
Victoria Cornelius presented a new framework to improve the analysis of Adverse Events and improved solutions for analysing them in RCTs.
Giles Partington discussed the results of his systematic review into the use of design and analysis features in Rare Disease and Small Population trials.
Rachel Phillips presented her findings from a consensus of UK trialists and outlined recommended graphics to visualise Harm Profiles when reporting RCTs.
Current and Future Women Luminaries
Jun 7, 2021
In June, Rachel Phillips joined Imperial’s President Alice P. Gast and Professor Deborah Ashby OBE in discussion as part of the Current and Future Women Luminaries special series. This was an opportunity to share breakthroughs, innovations and aspirations to inspire those inside and outside of the College. During the conversation, Deborah and Rachel talk about their research, teaching and the life experiences and moments that shaped who and what they do today. Listen to the conversation here:
Current and Future Women Luminaries
Jun 7, 2021
In June, Rachel Phillips joined Imperial’s President Alice P. Gast and Professor Deborah Ashby OBE in discussion as part of the Current and Future Women Luminaries special series. This was an opportunity to share breakthroughs, innovations and aspirations to inspire those inside and outside of the College. During the conversation, Deborah and Rachel talk about their research, teaching and the life experiences and moments that shaped who and what they do today. Listen to the conversation here:
A systematic review to investigate engagement to digital mental health interventions.
Apr 30, 2021
Jack Elkes is undertaking a systematic review to determine whether engagement to these interventions is reported and whether it is considered in the analysis during a clinical trial. He will be answer the following research questions:
What trials of digital mental health interventions are being performed and are trial characteristics changing over time?
How is engagement defined and summarised in randomized evaluations of digital mental health interventions?
How often is the intervention effect adjusted for engagement and what methods are used to do so in the analysis of randomised evaluations of digital mental health interventions?
ICTU Shoot for the Moon
Mar 31, 2021
This month we started a new moving challenge. In November last year we aimed to travel the length of the UK, this time we are trying to fly to the moon! With a small conversion of 1KM = 100KM in rocket distance we will need to travel 3,805KM or 380,005KM (Rocket Miles).
Keep checking back to see our progress.
Cochrane US Network: Virtual Methods Symposium
Mar 8, 2021
Over February and March 2021, Dr Tianjing Li of the University of Colorado hosted a three day virtual methods symposium looking at advanced methods and innovative technologies for evidence synthesis on behalf of the Cochrane US Network funded by the US Agency for Healthcare Research and Quality. The symposium aimed to disseminate research into systematic reviews as a means to improve the quality, effectiveness, and appropriateness of healthcare by synthesizing existing evidence and facilitating the translation of research findings. Speakers included Rachel Phillips who presented work on the advantages of visualisations to evaluate and communicate adverse event information in randomised controlled trials in the session on synthesising harms of interventions. Other presenters included Dr Evan Mayo Wilson (Indian University Bloomington), Riaz Qureshi (Johns Hopkins Bloomberg School of Health), Dr Roger Chou (Oregon Health and Science University). You can watch all of the talks here:
We welcome…Spring 2021
Mar 7, 2021
We are delighted to welcome two new members to ICTU at the start of 2021.
In February we welcomed Dr Leila Janani as a Research Fellow in Medical Statistics who will be working the TREAT trial for treating severe paediatric asthma and working with Professor Tony Gordon on Critical Care research studies.
In March we welcomed Dr Graham Wheeler as Senior Lecturer in Medical Statistics, and Deputy Head of Statistics for ICTU. He joins us from Cancer Research UK & UCL Cancer Trials Centre where he was leading on several early phase oncology studies. His research is focused on novel adaptive designs for clinical trials and improvements for their use in practice.
eCritical Care Reviews 2021 Conference
Jan 23, 2021
On 20th – 23rd January, eCCR 2021 held its annual three day Critical Care Conference. Victoria Cornelius joined Fernando Zampieri, Jon Silversides, Andrew Althouse and Marion Campbell for a panel discussion on the often misunderstood area of Pilot Studies in Critical Care trials at the Critical Care Reviews 2020 Conference. The discussion covered what pilot trials are and what they are not, how to determine an appropriate sample size, the differences between internal and external pilots, and how to assess if the trial has been a success. The discussion is covered on day 2 at 7 hours 50mins.
Travel the length of the UK
Nov 1, 2020
This month we have motivated the department to help us run the length of the UK. We have asked everyone to record how much exercise they do each day, then see how far we travel collectively between us. Our team member Jack Elkes also built an R Shiny app to help us track our progress, follow the link below to check this out!
Wanted: members of the public to advise our clinical trials research
Oct 19, 2020
We are setting up a group of public members to discuss how we can improve the information reported from clinical trials, so that it is more meaningful and usable for patients and the public. Often the numbers and statistics reported from trials are not well understood and we would like to understand how we can improve this. For more information on this opportunity and how to get involved please see the poster linked below.
Presentation at UKCRC CTU Network Statistics group meeting
Oct 4, 2020
The UKCRC Registered CTU Network held its bi-annual statisticians meeting on 8th October. At this meeting Suzie Cro gave a talk on handling unplanned disruptions and missing data in randomised trials ongoing during Covid-19. Richard Emsley (KCL) also gave a talk on departures from random allocation in trials ongoing during Covid-19. For members of the UKCRC CTU network a recording of the talks can accessed by logging into the below link.
NIHR Fellowships
Aug 31, 2020
We are pleased to announce the start of 2 new NIHR fellowships. Ms Eleanor Van Vogt starts a 2-year pre-doctoral fellowship supervised by Dr Suzie Cro, Dr Victoria Cornelius and Dr Karla Diaz-Ordaz. She begins year 1 by undertaking the MSc in health data science and machine learning at Imperial College, school of public health and will undertake a research project with ICTU in year 2.
Dr Suzie Cro starts a 3-year advanced fellowship to develop accessible statistical methods to determine treatments effects that matter to patients and prescribing physicians in randomised controlled trials. This includes statistical development of controlled Multiple Imputation methods for estimating hypothetical estimands in clinical trials. Details on the fellowship schemes are available below.
NISS Meeting on Estimands and Missing Data
Aug 31, 2020
On September 1st, the National Institute of Statistical Science (NISS) held an online meeting to investigate topics related to methods or strategies for mitigating disruptions in trials during covid-19, as part of their Ingram Olkin Forum Series. Presenters included Suzie Cro who explored a strategy for handling unplanned disruptions in the analysis of trials using missing data methods. Other presenters included Mouna Akacha (Novartis), who discussed the value of the estimand framework (ICH 2019) in being able to support the proper analysis and interpretation of trials disrupted by covid-19, and David Murray, (Office of Disease Prevention) who provided examples from the Health Care Systems Collaboratory Project and reviewed how these trials adapted in response to various disruptions.
Recommendations to visualise treatment harm profiles in Randomised Controlled Trials – a national consensus
Jul 5, 2020
In collaboration with the UKCRC CTU Statistics Operation group, Rachel Phillips, Victoria Cornelius and Suzie Cro hosted three half day meetings to develop a national consensus of recommendations to display harm events in Randomised Controlled Trials. The meeting was attended by national senior statisticians from academia and industry, and delegates with info-graphic expertise. The groups’ aim is to develop practical guidelines to support clinical trial researchers in their choice of visualisations for communicating AE data in publications. The next stage will seek input from clinicians and patients and the group will be publishing their work for trialists later this year.
A dose-finding design for early phase trials with continuous re-assessment
Jun 24, 2020
As part of the NIHR Statistics – Early Phase Trials Group webinar series on “Practical applications of advanced designs in Phase I Trials” Suzie Cro shared her recent experience of designing a dose finding study. The trial requires two agents to be combined where one has discrete dose levels and the other having doses that are patient specific. In the presentation Suzie Cro and Pavel Mozgunov from Lancaster University explained how they will evaluate the different discrete doses of the primary agent and allow for different ranges of the patient specific doses of the second agent.
NIHR Statistics Group Virtual Conference
Jun 11, 2020
As part of the 2020 NIHR Statistics Group virtual conference Rachel Phillips and Victoria Cornelius hosted a workshop on the use of visualisations to communicate information on harms in RCTs. In the workshop they demonstrated the use of four graphical displays and contrasted the visual summaries with data presented in the original published journal articles demonstrating impact for interpretation. Delegates provided feedback on the applications across settings. The responses in this session will contribute to the development of practical guidance for communicating harm data.
Evidence of unexplained discrepancies between planned and conducted statistical analyses
May 28, 2020
Different methods of analysis applied to the same clinical trial data set can lead to different conclusions. It is therefore important that the statistical analysis approach for a randomised controlled trial is pre-specified, and any changes or additions to the planned analysis should be flagged alongside trial results. This provides full transparency and allows for a thorough evaluation of the results. In a new review of trials published in high impact journals, we identified a large proportion of trials (61%) with one or more undisclosed change to the planned primary analysis approach. To see more results click the below link for the full open access publication of the review.
New Tutorial: Controlled Multiple Imputation for Missing Data Sensitivity Analysis in Clinical Trials
May 17, 2020
In clinical trials it is most typical that some participant outcomes will not be available. This may be due to missed participant visits, trial withdrawal or other unplanned and uncontrollable events. Therefore often some required data will be missing from the analysis. When there are missing data, it is important that the primary analysis of the trial is conducted under the most plausible assumption for the missing data. Sensitivity analysis under a range of different credible assumptions should then be undertaken to assess how robust the trial results are. One method which readily enables contextually relevant sensitivity analysis, and has recently seen increased discussion and developments in the statistical literature, is Controlled Multiple Imputation. In this new tutorial article, an overview of Controlled Multiple Imputation procedures, and a practical guide to their use for sensitivity analysis of a continuous outcome is provided. Worked examples and Stata code are included to facilitate adoption of such methods, to enable robust evaluation of clinical trial results.
A caution on the use of IPTW in small randomised trials
Mar 23, 2020
Recently Inverse Probability of Treatment Weighting (IPTW) using the propensity score has been proposed as an alternative to standard regression methods for baseline covariate adjustment in the analysis of randomized trials (Williamson et al. 2013). Motivated by some recent small trial analyses we explored the properties of IPTW for covariate adjustment within small trial settings. A simulation study and a re-analysis of a pediatric eczema trial involving 60 children revealed the performance of the IPTW variance estimator proposed by Williamson et al. was sub-optimal with smaller sample sizes. We therefore caution against the use of IPTW in small sample settings without small-sample modifications when the sample size is less than 150 and particularly when the sample size <100. In larger samples IPTW using the propensity score method can however be a useful tool for adjustment. When IPTW is used with large samples we demonstrate how the bootstrap variance may be a simpler route to variance estimation, given this incorporates the estimation of the propensity score.
Anca presents at PHASTAR office
Feb 11, 2020
Anca went to visit the London PHASTAR team in Chiswick for their monthly company meeting to present some of the research that’s been going on at ICTU, as well as her systematic review that investigates how rescue medication is defined, reported, and adjusted for in randomised controlled trials. It was also amazing to hear Jennifer Roger’s presentation describing her experience with her BBC Watchdog appearance, where companies within a different industry were ranked to establish who was the best and who was the worst when considering factors such as complaints, customer satisfaction, and cost.
Do early skincare interventions prevent eczema and food allergy?
Feb 10, 2020
The protocol for an individual patient data meta-analysis to establish whether early skin care interventions, such as moisturisers, can prevent eczema or food allergy is now available. Published in the Cochrane database, this protocol provides details of the planned analyses that will be conducted by Suzie Cro and Victoria Cornelius. The primary analysis will estimate the pooled treatment policy effect of early skincare interventions on eczema and food allergy. Sensitivity analysis will also explore the pooled effect of complying with early skin care intervention. Subgroup analyses will explore whether risk for atopy, based on genotype and family history are associated with the pooled treatment effect. Results coming later this year!
PSI Visualisation Special Interest Group
Feb 7, 2020
PSI have recently launched a new visualisation special interest group (SIG). The group aims are to train statisticians and quantitative scientists about effective visualisations to look beyond tables alone. This group is led by Alexander Schacht of UCB and includes our own Rachel Phillips as a core member. The SIG’s first initiative, “Wonderful Wednesdays” will teach participants about visualisation principles and allow them to apply the techniques they learn to examples from the field of healthcare. To learn more about the initiative and how to get involved follow the link below:
MRC-NIHR Trials Methodology Research Partnership Statistical Analysis Working Group
Jan 31, 2020
The new MRC-NIHR Trials Methodology Research Partnership Statistical Analysis Working group (SAWG) is now open to expressions of interest to join. If you are researching/interested in developing and applying methods for the statistical analysis of clinical trials we encourage you to join. This group is being co-led by Richard Emsley (KCL) and Tim Morris (UCL) and includes our own Suzie Cro as one of the core members. Additional details on the groups remit can be found at the below link.
Featured in Imperial People
Jan 1, 2020
One of our team members, Jack Elkes, was featured in the Imperial College London blog which is a look behind the scenes with the staff who make the College tick called Imperial People.
Reference‐based multiple imputation for missing data sensitivity analyses in trial‐based cost‐effectiveness analysis
Dec 17, 2019
In randomised trials, sensitivity analyses are required to assess the implications of different missing data assumptions on the trial results, including in cost‐effectiveness analysis. In their new paper, Leurent, Gomes, Cro et al. extend and illustrate the reference‐based multiple imputation approach for cost‐effectiveness sensitivity analysis. Reference‐based multiple imputation provides an attractive approach for conducting such sensitivity analyses, because missing data assumptions are framed in an intuitive way by making reference to other trial arms. The method is illustrated using the CoBalT trial which evaluated cognitive behavioural therapy for treatment‐resistant depression and Stata code is provided.
