Design and monitoring of multiarm multistage clinical trials. A groupsequential approach can be used in order to design multiarm multistage trials, using an extension to dunnetts multipletesting procedure. Current studentships ucl institute of clinical trials and. Assessing the impact of efficacy stopping rules on the. Each research arm is compared separately to the common control arm in a pairwise fashion. Participants will learn about a variety of new adaptive clinical trial designs, including multiarm multistage mams, umbrella studies and adaptive randomisation. Comparisons may be between active treatments and control treatment, or pairwise between all arms. Designing and analysing multiarm multi stage clinical trials. Dirum is an openaccess database of instruments for resource use measurement. The multiarm multistage design of stampede has a series of formal intermediate analyses for each trial arm that take place at the end of each intermediate activity stage as.
Multiarm multistage mams trials have a specific design that allows for several different treatments to be evaluated simultaneously against the standard treatment in a single trial. We used a novel multi arm, multi stage mams cluster randomised trial design to evaluate the efficacy, safety, and costs of a number of candidate interventions including hivst alone and in combination with conditional fixed financial incentives, lotteries, or phone reminders. Multiarm, multistage mams framework to speed up the evaluation of new therapies and improve success rates in identifying effective ones, we pioneered the multiarm multistage mams framework for conducting large, flexible platform trials under a single protocol. Daniel j bratton, patrick pj phillips and mahesh kb parmar, a multi arm multi stage clinical trial design for binary outcomes with application to tuberculosis, bmc medical research methodology, 10. It allows several agents or combinations of agents to be assessed simultaneously against a single control group in a randomised controlled trial rct. Multi arm multi stage mams is an east module that offers the ability to design and monitor multi arm multi stage studies with options for early stopping, dose selection, and sample size reestimation. In the early stages of drug development there often is uncertainty about the most promising among a set of different treatments, different doses of the same treatment or sets of combinations of treatments. Software for design and analysis of clinical t rials. A multiarm multistage clinical trial design for binary. This particular design compares multiple new treatments against a control in a single trial, obviating. Randomised controlled trials rcts are the gold standard for testing whether a new treatment is better than the current standard of care.
Adaptive designs and multiple testing procedures for clinical. The safety endpoint is explicitly considered in the formulation of the problem, selection of. Access to prep in the registration cohort and after week 26 will be standard of. We provide illustrative examples of the use of the package based on real trial designs. This film explores the stampede trial as an example for how mams works multiarm multistage mams trial design on vimeo. These results form the basis of most major software packages for group sequential inference with normal, binomial, and time to event endpoints. Multiarm multistage mams clinical studies provide an efficient. A generalized dunnett test for multiarm multistage clinical studies with treatment selection.
The concept of platform design had been discussed by lee and chu. Comparison of multiarm multistage design and adaptive. Multiarm evaluate multiple new treatments in a single trial against a common control arm. Optimal design for multiarm multistage clinical trials. Summaries of software for adaptive designs more generally can be found in bauer.
The trial uses nstage software for multiarm, multistage designs mams and the averted infections ratio air methodology with participants randomised i 1. They allow a shared control group, dropping of ineffective treatments before the end of the trial and stopping the trial early if sufficient evidence of a treatment being superior to control is found. An efficient solution to determine which intervention is most promising are multiarm multistage clinical studies mams. Trainees clinical trial guidance to support nihr trainees interested in getting involved in clinical trials. To do this, parameters given in table table2 2 and based on the original trial protocols were used to calculate the necessary number of control arm events e i for the first stage using the nstage program for stata. Here, we develop a multiarm multistage design for a trial with an efficacy and safety endpoint. Extending the design of multi arm multi stage clinical trials what is the project. In 2011, royston and colleagues proposed a particular class of multi arm multi stage mams designs intended to speed up the evaluation of new treatments in phase ii and iii clinical trials. Multi arm multi stage mams trials have a specific design that allows for several different treatments to be evaluated simultaneously against the standard treatment in a single trial.
The r package mams for designing multiarm multistage clinical. Multi arm, multi stage mams framework to speed up the evaluation of new therapies and improve success rates in identifying effective ones, we pioneered the multi arm multi stage mams framework for conducting large, flexible platform trials under a single protocol. The arm software written by gdm is a recognized and respected standard throughout the crop protection industry for managing plant science research data. The only package that allows the design of multiarm. Some recommendations for multiarm multistage trials james. The traditional phase iii trial design generally involves randomising.
To do this, parameters given in table 2 and based on the original trial protocols were used to calculate the necessary number of control arm events e i for the first stage using the nstage program for stata. Single stage phase ii clinical trials procedure window by expanding proportions, then one proportion, then clicking on multi stage trials, and then clicking on single stage phase ii clinical trials. The multi arm, multi stage mams design is a new efficient, adaptive approach for conducting randomised controlled trials. Design and monitoring of multiarm multistage clinical trials clinical development approaches and statistical methodologies to prospectively assess the cardiovascular risk of new antidiabetic therapies for type 2 diabetes. Issues in applying multiarm multistage methodology to a. A multistage dropthelosers design for multiarm clinical.
Designing multiarm multistage studies with asymptotically normal endpoints and known variance. Using the tailor trial as a motivating example, we explore a broad range of statistical issues related to multi arm multi stage trials including a comparison of different ways to power a multi arm multi stage trial. Our software is used worldwide by researchers and managers in nearly 100 countries, many companies, and hundreds of universities. An optimised multiarm multistage clinical trial design for unknown. Pdf the r package mams for designing multiarm multistage. At each interim analysis, test statistics based on all patients assessed up to that point are calculated to compare the effect of each remaining experimental treatment to control. For describing the intervention groups in clinical trials, the terms arms or groups may be used interchangeably, although the term multiarm is used for these reporting guidelines. Recommendations for the design of mams multi arm multi stage trials. Optimal design of multiarm multistage mams clinical trials. Multiarm multistage trial designs can bring notable gains in efficiency to the drug development process. Using mata to accelerate the familywise error rate. Factorial versus multiarm multistage designs for clinical.
The multiarm, multistage mams design is a new efficient, adaptive approach for conducting randomised controlled trials. Multiarm multistage designs can improve the efficiency of the drugdevelopment process by evaluating multiple experimental arms against a common control within one trial. Designing and analysing multiarm multistage clinical trials with one or more. Dec, 2011 multi arm multi stage mams trials provide gains in efficiency over separate randomised trials of each treatment. To do this, parameters given in table table2 2 and based on the original trial protocols were used to calculate the necessary number of control arm events e i for the first stage using the n stage program for stata. We build the framework for platform design in the following sequence. They allow a shared control group, dropping of ineffective treatments before the end of the trial and stopping the trial early if sufficient evidence of. Randomised controlled trials are becoming increasingly costly and timeconsuming.
When several treatments are available for evaluation in a clinical trial, different design options are available. Design issues and extensions of multiarm multistage clinical trials. Abiraterone for prostate cancer not previously treated with. A multiarm trial is defined as a randomized clinical trial that uses a parallelgroup design but has 3 or more groups. Jaki 2016 compared the sample size requirements of separate two. Issues in applying multiarm multistage methodology. This reduces the number of patients required compared to a series of trials testing. Singlestage phase ii clinical trials sample size software. A web application for the design of multiarm clinical trials bmc. In the early stages of drug development there is often uncertainty about the most promising among a set of different treatments, different doses of the same treatment, or combinations of treatments. Multiarm multistage trial designs can bring notable gains in efficiency to the drug. Flexible trial design in practice stopping arms for lackof. Daniel j bratton, patrick pj phillips and mahesh kb parmar, a multiarm multistage clinical trial design for binary outcomes with application to tuberculosis, bmc medical research methodology, 10. Recommendations for the design of mams multiarm multistage trials.
Multiarm multistage mams is an east module that offers the ability to design and monitor multiarm multistage studies with options for early stopping, dose. Extending the design of multiarm multistage clinical trials what is the project. Multiarm multistage mams is an east module that offers the ability to design and monitor multiarm multistage studies with options for early stopping, dose selection, and sample size reestimation. Here, we develop a multi arm multi stage design for a trial with an efficacy and safety endpoint. Equally important, for patients and policy makers, the multiarm trial produces contemporaneous results for all research treatments. However, for normally distributed endpoints, the determination of a design. We redesigned all four trials as though they had been run in a two stage design. The group sequential theory extended for multiarm setup gao et al. For describing the intervention groups in clinical trials, the terms arms or groups may be used interchangeably, although the term. East multi arm multi stage mams multi arm multi stage mams is an east module that offers the ability to design and monitor multi arm multi stage studies with options for early stopping, dose selection, and sample size reestimation. Exploring the innovative mams trial, which uses multiple arms to form one seamless trial. Flexible trial design in practice stopping arms for lackofbenefit and adding research arms midtrial in stampede. The multi arm multi stage mams design is a broad class of trial designs that allow for the comparison of multiple experimental treatments, including combinations of experimental treatments, against a single control group in a randomized controlled trial.
Additionally unexpected design modifications can be accounted for via the use of the conditional error approach. Some recommendations for multiarm multistage trials. The function determines the boundaries of a multi arm multi stage study for a given boundary shape and finds the required number of subjects. You may then make the appropriate entries as listed below, or open example 1 by going to the file menu and choosing open example template. An optimised multiarm multistage clinical trial design for. Multiarm multistage mams trials provide gains in efficiency over separate randomised trials of each treatment. The function determines the boundaries of a multiarm multistage study for a given boundary shape and finds the required number of subjects. Designing multiarm multistage trials with the r package mams. Multi arm multi stage trial designs can bring notable gains in efficiency to the drug development process. We redesigned all four trials as though they had been run in a twostage design. A twostage fisher exact test for multiarm studies with binary outcome variables. The multiarm multistage mams adaptive clinical trial design developed by royston et al. Multistage evaluate each arm at a series of interim.
As the worlds largest biometrics cro, we improve our customers chances of success through expert trial design and planning, quality implementation and accurate clinical data handling and analysis. Pdf designing multiarm multistage trials with the r. Designing multiarm multistage clinical studies springerlink. Multiarm multistage trials can improve the efficiency of. Performance of different clinical trial designs to evaluate. Many such routines are now available in standard statistical software, with. Specialising in the development of improved designs for clinical trials. The r package mams for designing multi arm multi stage clinical trials. To aid the wider implementation of multiarm clinical trial designs, we have. East multiarm multistage mams multiarm multistage mams is an east module that offers the ability to design and monitor multiarm multistage studies with options for early stopping, dose selection, and sample size reestimation. We used a novel multiarm, multistage mams cluster randomised trial design to evaluate the efficacy, safety, and costs of a number of candidate interventions including hivst alone and in combination with conditional fixed financial incentives, lotteries, or phone reminders. An efficient solution to determine which intervention is most promising are multi arm multi stage clinical studies mams. Multiarm multistage trials can improve the efficiency of the drug development process when multiple new treatments are available for testing. However, traditional rct designs can take a long time and are often expensive.
Let x denote the treatment arm, where x 0 is the control arm, and x 1, k denote k distinct new drugs to be tested. Designing and analysing multiarm multistage clinical trials. Blinded and unblinded sample size reestimation procedures for steppedwedge cluster randomized trials. It is the first trial of this design to use multiple arms and stages. The r package mams for designing multiarm multistage. Reporting of multiarm parallelgroup randomized trials. We compare multiarm multistage with factorial designs, and in particular, we will consider a 2.
Multi arm multi stage mams clinical studies provide an efficient solution to determine which intervention is most promising. The simons twostage design to determine sample size is one that is widely used and accepted in phase ii cancer trials. We are leading the way in developing methodology for sample size, design and analysis of steppedwedge and other. Mar 27, 2016 east user group meeting 2016 featured presentation cyrus mehta, cytel president and cofounder, unveils multiarm multistage mams trial capabilities in east version 6. Evaluation of a multiarm multistage bayesian design for. However, for normally distributed endpoints, the determination of a design typically depends on the assumption that the patient variance in response is known. By comparing several treatments within one trial the sample size and duration required tends to be markedly smaller than if. Description usage arguments details value authors references examples.
The multiarm multistage mams design is a broad class of trial designs that allow for the comparison of multiple experimental treatments, including combinations of experimental treatments, against a single control group in a randomized controlled trial. Multiarm multistage mams trials are a very broad class of design. Singlestage phase ii clinical trials procedure window by expanding proportions, then one proportion, then clicking on multistage trials, and then clicking on singlestage phase ii clinical trials. Multiarm multistage mams designs mams designs are aimed at accelerating the evaluation of new therapies over more conventional approaches. Seamless phase iiiii multiarm clinical trials that compare several active treatments. Similarly to groupsequential designs for two arm studies, efficiency can be gained by the inclusion of interim analyses.
Admissible multiarm steppedwedge cluster randomized trial designs. The steppedwedge cluster randomised trial is a comparatively new design that is becoming increasingly popular. A multistage dropthelosers design for multiarm clinical trials james wason 1, nigel stallard2, jack bowden, and christopher jennison3 1mrc biostatistics unit, cambridge 2warwick medical school, university of warwick, coventry. In 2011, royston and colleagues proposed a particular class of multiarm multistage mams designs intended to speed up the evaluation of new treatments in phase ii and iii clinical trials. A multi stage dropthelosers design for multi arm clinical trials james wason 1, nigel stallard2, jack bowden, and christopher jennison3 1mrc biostatistics unit, cambridge 2warwick medical school, university of warwick, coventry. May 02, 2019 designing multi arm multi stage studies with asymptotically normal endpoints and known variance. Hiv selftesting alone or with additional interventions. Using design parameters motivated by a recently completed phase ii. To do this, parameters given in table 2 and based on the original trial protocols were used to calculate the necessary number of control arm events e i for the first stage using the n stage program for stata.
It allows several agents or combinations of agents to be assessed simultaneously against a single control group in a. In addition, recently several authors have also explored the extent to which multiarm. For simplicity, let us consider a balanced design, although any imbalanced fixed design could be considered. As well as learning about how to design adaptive trials we will cover the implications of the design. Throughout, stata programs are created and updated to accommodate the use. The group sequential theory extended for multi arm setup gao et al. An efficient solution to this problem are multiarm clinical trials in which several active treatments are compared to a common control group. Feb 20, 2017 when several treatments are available for evaluation in a clinical trial, different design options are available. A comparison of bayesian adaptive randomization and multi.
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