Designing and analysing multi-arm multi-stage clinical trials with one or more endpoints
Lead Research Organisation:
Lancaster University
Department Name: Mathematics and Statistics
Abstract
In the early stages of drug development there is often uncertainty about the most promising among a set of different treatments. In order to ensure the best use of resources in such situations it is important to decide which, if any, of the treatments should be taken forward for further testing. An efficient solution to this problem are multi-arm clinical trials in which several active treatments are compared to a common control group. By comparing several treatments within one trial the sample size and duration required tends to be markedly smaller than if each treatment would have been evaluated separately. For added efficiency it is desirable to monitor the trial at a series of interim analyses in order to allow early stopping if efficacy is quickly established and similarly to eliminate ineffective treatments early. In confirmatory studies these designs are also useful as it has been shown that using two doses instead of a single dose can markedly improve the study's success probability.
This proposal aims to develop statistical methods to investigate how these, so called multi-arm multi-stage trials, can best be designed and analysed. The work will utilize three recently finished or currently ongoing studies in three important medical areas: HIV/AIDS, leukemia and metastatic prostate cancer. The multidisciplinary research team includes experienced clinical specialists and clinical trialists for each study from the clinical trials research unit in Leeds, the University of Liverpool and the MRC clinical trials unit as well as statisticians with experience in statistical methods for clinical trials from the University of Bremen and the Warwick medical school.
This proposal aims to develop statistical methods to investigate how these, so called multi-arm multi-stage trials, can best be designed and analysed. The work will utilize three recently finished or currently ongoing studies in three important medical areas: HIV/AIDS, leukemia and metastatic prostate cancer. The multidisciplinary research team includes experienced clinical specialists and clinical trialists for each study from the clinical trials research unit in Leeds, the University of Liverpool and the MRC clinical trials unit as well as statisticians with experience in statistical methods for clinical trials from the University of Bremen and the Warwick medical school.
Technical Summary
Multi-arm multi-stage designs are a broad class of designs in which several active treatment arms are compared to a common control. Their advantage over traditional 2-armed studies is that, on the one hand, a common control group is used yielding smaller expected sample sizes compared to multiple 2-armed trials and allowing direct comparisons of all active arms under the same study conditions and, on the other hand, that decisions about effective and ineffective treatments can be made at early interim analyses. Although some work on designing these trials in simple situations (e.g. play-the-winner designs) is available no adequate methods are available for many situations of practical interest (e.g. multiple endpoints). Moreover methods for adequately estimating the treatment effect and finding the corresponding confidence intervals in such trials are not available beyond two stages.
This proposal aims to
1. develop statistical designs for multi-arm multi-stage designs that use intermediate endpoints for treatment selection;
2. develop and evaluate methods for estimating the treatment effect and corresponding confidence intervals in multi-arm multi-stage designs with treatment selection and obtain their confidence intervals;
3. develop statistical methods for multi-arm multi-stage designs with multiple endpoints;
4. develop an open-source software package and associated training tailored to clinical trialists and applied statisticians working on clinical trials.
This proposal aims to
1. develop statistical designs for multi-arm multi-stage designs that use intermediate endpoints for treatment selection;
2. develop and evaluate methods for estimating the treatment effect and corresponding confidence intervals in multi-arm multi-stage designs with treatment selection and obtain their confidence intervals;
3. develop statistical methods for multi-arm multi-stage designs with multiple endpoints;
4. develop an open-source software package and associated training tailored to clinical trialists and applied statisticians working on clinical trials.
Planned Impact
In addition to academic beneficiaries, the work proposed in this grant will have great impact on others. By extending methodology for multi-arm multi-stage clinical trials (MAMS) to allow for differing endpoints at each stage, we shall be able to apply the theory of optimal design to a broader range of MAMS trials. This is of great benefit to patients recruited to such trials - stopping boundaries can be specified that reduce the average number of patients recruited to poor treatments, but keep effective treatments in the trial. Use of such designs will mean fewer patients are exposed to poor treatments. This will also be of interest to clinicians running and supporting the trial, who are naturally interested in ensuring their patients do not receive ineffective treatments. Funders of trials would also benefit, since fewer patients would be required on average, thus reducing the average cost. Because MAMS trials are high cost trials, even relatively small improvements in the design can lead to large savings in costs. Since this is a design issue, the benefit from this work will come in the medium-term future, when actual trials using the methodology start recruiting. In addition to the immediate benefit to patients on the trial the number of patients in the trial and hence the duration of the trial is reduced resulting in effective treatments to be put into clinical practice sooner.
Reducing bias in the estimation of treatment effects after a MAMS trial will be of great interest to those using results from a clinical trial. Those planning future trials will be able to use results to inform the design of their trial with the knowledge that the bias is minimised. Regulatory organisations such as the European Medicines Agency or the National Institute for Clinical Excellence will be able to judge the cost-effectiveness of a drug using reliable data. This area of research will have a more immediate impact since it can be applied to data from a MAMS trial designed prior to this work.
Through the extension of methodology to the exact and optimal design of MAMS trials with multiple endpoints, we shall make a greater range of efficient trials possible. This would be of interest to organisations that design and run trials, such as clinical trial units (CTUs) and pharmaceutical companies, or those who support the design of trials, such as research design services (RDSs). In addition, patients recruited to such trials will benefit because there will be clear, statistically sound, rules as to when to drop a treatment which is potentially dangerous. Since this is a design issue, the impact of this work would be in the medium-term future.
Reducing bias in the estimation of treatment effects after a MAMS trial will be of great interest to those using results from a clinical trial. Those planning future trials will be able to use results to inform the design of their trial with the knowledge that the bias is minimised. Regulatory organisations such as the European Medicines Agency or the National Institute for Clinical Excellence will be able to judge the cost-effectiveness of a drug using reliable data. This area of research will have a more immediate impact since it can be applied to data from a MAMS trial designed prior to this work.
Through the extension of methodology to the exact and optimal design of MAMS trials with multiple endpoints, we shall make a greater range of efficient trials possible. This would be of interest to organisations that design and run trials, such as clinical trial units (CTUs) and pharmaceutical companies, or those who support the design of trials, such as research design services (RDSs). In addition, patients recruited to such trials will benefit because there will be clear, statistically sound, rules as to when to drop a treatment which is potentially dangerous. Since this is a design issue, the impact of this work would be in the medium-term future.
Publications
Bowden J
(2012)
Identifying combined design and analysis procedures in two-stage trials with a binary end point.
in Statistics in medicine
Wason JM
(2012)
Optimal design of multi-arm multi-stage trials.
in Statistics in medicine
Jaki T
(2013)
Considerations on covariates and endpoints in multi-arm multi-stage clinical trials selecting all promising treatments.
in Statistics in medicine
Magirr D
(2013)
Simultaneous confidence intervals that are compatible with closed testing in adaptive designs.
in Biometrika
Choodari-Oskooei B
(2013)
Impact of lack-of-benefit stopping rules on treatment effect estimates of two-arm multi-stage (TAMS) trials with time to event outcome.
in Trials
Wason JM
(2013)
Planning multi-arm screening studies within the context of a drug development program.
in Statistics in medicine
Wason JM
(2014)
A comparison of Bayesian adaptive randomization and multi-stage designs for multi-arm clinical trials.
in Statistics in medicine
Magirr D
(2014)
Flexible sequential designs for multi-arm clinical trials.
in Statistics in medicine
Bowden J
(2014)
Empirical Bayes estimation of the selected treatment mean for two-stage drop-the-loser trials: a meta-analytic approach.
in Statistics in medicine
Wason JM
(2014)
Correcting for multiple-testing in multi-arm trials: is it necessary and is it done?
in Trials
Description | Short-course Oxford |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Improved understanding of available tools for more efficient clinical trials |
Description | A Practical Adaptive and Novel Designs Toolkit |
Amount | £100,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 06/2019 |
End | 06/2020 |
Description | Developing efficient perpetual platform trials to study multiple treatments and multiple biomarkers |
Amount | £228,041 (GBP) |
Funding ID | MR/N028171/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2017 |
End | 01/2020 |
Description | Marie Curie ITN |
Amount | € 3,639,394 (EUR) |
Funding ID | 633567 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 01/2015 |
End | 12/2018 |
Description | Methodology Research Panel - Estimation project |
Amount | £345,000 (GBP) |
Funding ID | MR/M005755/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2015 |
End | 12/2017 |
Description | NIHR Senior Research Fellowship |
Amount | £653,526 (GBP) |
Funding ID | SRF-2015-08-001 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 01/2016 |
End | 12/2020 |
Description | Adaptive designs MUW |
Organisation | Medical University of Vienna |
Department | Centre for Medical Statistics, Informatics and Intelligent Systems |
Country | Austria |
Sector | Academic/University |
PI Contribution | Joint research |
Collaborator Contribution | Joint research |
Impact | Publications. |
Start Year | 2011 |
Description | NWHTMR |
Organisation | University of Liverpool |
Department | Department of Biostatistics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Joint research and support in implementation of methods |
Collaborator Contribution | Joint research and implementation of methods |
Impact | Joint papers, funding applications |
Start Year | 2009 |
Title | MAMS package |
Description | Software to design multi-arm multi-stage designs in the statistical software R |
Type Of Technology | Software |
Year Produced | 2013 |
Open Source License? | Yes |
Impact | Increased uptake of the methodology |
URL | http://cran.r-project.org/web/packages/MAMS/index.html |
Description | 8th International Conference on Multiple Comparison Procedures, Southampton, UK, Sept 2013 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited presentation at 8th International Conference on Multiple Comparison Procedures, Southampton, UK, Sept 2013 |
Year(s) Of Engagement Activity | 2013 |
Description | Adaptive and Bayesian Methods Course |
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 | Annual Short course on adaptive and Bayesian methods |
Year(s) Of Engagement Activity | 2015,2016,2017,2018 |
Description | Conference of the Austro-Swiss Region of the International Biometric Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited presentation at Conference of the Austro-Swiss Region of the International Biometric Society |
Year(s) Of Engagement Activity | 2013 |
Description | Design of Experiments in Drug Development open for business |
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 | Discussion event around improving drug development through adaptive designs. |
Year(s) Of Engagement Activity | 2015 |
Description | International Biometric Conference, Florence, Italy |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited conference presentation at International Biometric Conference |
Year(s) Of Engagement Activity | 2014 |
Description | International Conference on Simultaneous Inference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited presentation at International Conference on Simultaneous Inference |
Year(s) Of Engagement Activity | 2013 |
Description | NCRI CTU annual meeting 2015 |
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 | Workshop on "Novel trial designs for phase II oncology" at NCRI CTU annual meeting 2015 |
Year(s) Of Engagement Activity | 2015 |
Description | SCT Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited Conference talk at the Society for Clinical Trials conference |
Year(s) Of Engagement Activity | 2015 |
Description | Short 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 | Several short-course for professionals and students that are based on the undertaken research Wider uptake of methods |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015,2016 |
Description | Statistical Innovations in Clinical Trials Workshop 2015 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Workshop on Statistical Innovations in Clinical Trials Workshop 2015 by PSI |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.psiweb.org/events/event-item/2015/06/29/default-calendar/one-day-meeting---adaptive-desig... |