Article

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

ABSTRACT

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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    • "The relative advantages of both methods depend on the accrual rate and the delay between individual recruitment and outcome assessment. Parmar et al.[40]motivated the use of MAMS designs in oncology but stated that they should only be used if the final endpoint, or some suitable intermediate endpoint, is observed relatively quickly. The same is true for AR designs, and a phase II trial where the final endpoint is observed quickly is the ideal setting for using the designs discussed in this paper. "
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    ABSTRACT: When several experimental treatments are available for testing, multi-arm trials provide gains in efficiency over separate trials. Including interim analyses allows the investigator to effectively use the data gathered during the trial. Bayesian adaptive randomization (AR) and multi-arm multi-stage (MAMS) designs are two distinct methods that use patient outcomes to improve the efficiency and ethics of the trial. AR allocates a greater proportion of future patients to treatments that have performed well; MAMS designs use pre-specified stopping boundaries to determine whether experimental treatments should be dropped. There is little consensus on which method is more suitable for clinical trials, and so in this paper, we compare the two under several simulation scenarios and in the context of a real multi-arm phase II breast cancer trial. We compare the methods in terms of their efficiency and ethical properties. We also consider the practical problem of a delay between recruitment of patients and assessment of their treatment response. Both methods are more efficient and ethical than a multi-arm trial without interim analyses. Delay between recruitment and response assessment attenuates this efficiency gain. We also consider futility stopping rules for response adaptive trials that add efficiency when all treatments are ineffective. Our comparisons show that AR is more efficient than MAMS designs when there is an effective experimental treatment, whereas if none of the experimental treatments is effective, then MAMS designs slightly outperform AR. © 2014 The Authors Statistics in Medicine Published by John Wiley & Sons, Ltd.
    Full-text · Article · Jun 2014 · Statistics in Medicine
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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.
    Full-text · Article · Nov 2013 · BMC Medical Research Methodology
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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.
    Full-text · Article · Sep 2012 · Trials
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