Speeding up the Evaluation of New Agents in Cancer

Affiliations of authors: MRC Clinical Trials Unit, London, UK (MKBP, MS, RL, RK, AMS, WQ, PR); Institute of Psychiatry, King’s College London, London, UK (FMSB); NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada (EE); School of Public Health and Health Professions, University at Buffalo, Buffalo, NY (MB); CR-UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK (NJ); Fox Chase Cancer Center, Philadelphia, PA (MAB)
Journal of the National Cancer Institute (Impact Factor: 12.58). 10/2008; 100(17):1204-14. DOI: 10.1093/jnci/djn267
Source: PubMed


Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented.

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    • "If an experimental arm passes the final stage of the study then it is deemed to be superior (or non-inferior, depending on the objective) to the control. The efficiency of this procedure can be greatly increased by using an outcome in the intermediate stages which is observed earlier and on the causal pathway to the final, definitive outcome of the trial, although it does not necessarily have to be a surrogate [8,9]. For example, the MAMS design may be used for a seamless phase II/III trial where the intermediate outcome is that used in a phase II trial while a phase III outcome is of primary interest in the final stage. "
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    ABSTRACT: Randomised controlled trials are becoming increasingly costly and time-consuming. 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. Their design, which controls the type I error rate and power for each pairwise comparison, discontinues randomisation to poorly performing arms at interim analyses if they fail to show a pre-specified level of benefit over the control arm. Arms in which randomisation is continued to the final stage of the trial are compared against the control on a definitive time-to-event outcome measure. To increase efficiency, interim comparisons can be made on an intermediate time-to-event outcome which is on the causal pathway to the definitive outcome. We adapt Royston's MAMS design to binary outcomes observed at the end of a fixed follow-up period and analysed using an absolute difference in proportions. We apply the design to tuberculosis (TB), an area where many new drugs are in development, and demonstrate how it can greatly accelerate the evaluation of new TB regimens. We use simulations to support the extensions to the methodology and to investigate the amount of bias in the estimated treatment effects of arms in which randomisation is ceased at the first interim analysis and arms which continue to the final stage of the trial. The proposed seamless phase II/III TB trial designs are shown to greatly reduce sample size requirements and trial duration compared to conducting separate phase II and III trials. The bias in the estimated treatment effects for the definitive outcome is shown to be small, especially when treatment selection is based on an intermediate outcome or when a reanalysis is performed at the planned end of the trial after all recruited patients have completed follow-up. The proposed designs are practical and could be used in a variety of disease areas. They hold considerable promise for speeding up the evaluation of new treatments particularly in TB where many new regimens will soon be available for testing in phase II and phase III trials.
    BMC Medical Research Methodology 11/2013; 13(1):139. DOI:10.1186/1471-2288-13-139 · 2.27 Impact Factor
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    • "The multi-arm, multi-stage (MAMS) design [1,2] is one example of a flexible, seamless phase II/III randomized controlled trial. Detail on the general rationale for the MAMS design has been published elsewhere [3], but in brief, this approach allows for several research approaches to be assessed simultaneously against a common control group. Accrual resources are directed away from arms that show either insufficient activity on an intermediate primary outcome measure or unacceptable toxicity so that recruitment becomes increasingly focused towards the more promising research arms and the control arm. "
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    ABSTRACT: Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial. STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate 'activity' stages (focus: failure-free survival), and a final 'efficacy' stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims. (1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies. The STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner. ISRCTN78818544, NCT00268476First patient into trial: 17 October 2005First patient into abiraterone comparison: 15 November 2011.
    Trials 09/2012; 13(1):168. DOI:10.1186/1745-6215-13-168 · 1.73 Impact Factor
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    • "Furthermore, if all arms stop early, the trial has successfully closed off multiple avenues of research allowing other approaches to be examined more speedily. Further detail on the general rationale for the MAMS design has been published elsewhere[3]. "
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    ABSTRACT: The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases. STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously. The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity. It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials. ISRCTN78818544, NCT00268476.
    Trials 07/2009; 10(1):39. DOI:10.1186/1745-6215-10-39 · 1.73 Impact Factor
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