How do multi-stage, multi-arm trials compare to the traditional two-arm parallel group design – a reanalysis of 4 trials

BackgroundTo speed up the evaluation of new therapies, the multi-arm, multi-stage trial design was suggested previously by the authors.MethodsIn this paper, we evaluate the performance of the two-stage, multi-arm design using four cancer trials conducted at the MRC CTU. The performance of the design at fictitious interim analyses is assessed using a conditional bootstrap approach.ResultsTwo main aims are addressed: the error rate of correctly carrying on/stopping the trial at an interim analysis as well as quantifying the gains in terms of resources by employing this design. Furthermore, we make suggestions for the best timing of this interim analysis.ConclusionMulti-arm, multi-stage trials are an effective way of speeding up the therapy evaluation process. The design performs well in terms of the type I and II error rates.

[1]  Richard J Stephens,et al.  Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial , 2007, The Lancet.

[2]  M. Parmar,et al.  Erratum: The ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVAR-2.2 trial (Lancet (2003) 361 (2099-106)) , 2003 .

[3]  Patrick Royston,et al.  Novel designs for multi‐arm clinical trials with survival outcomes with an application in ovarian cancer , 2003, Statistics in medicine.

[4]  Michael LeBlanc,et al.  Interim futility analysis with intermediate endpoints , 2008, Clinical trials.

[5]  Gareth Griffiths,et al.  Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. , 1999, Lancet.

[6]  D Machin,et al.  Survival Analysis: A Practical Approach: Second Edition , 2006 .

[7]  K. K. Lan,et al.  Discrete sequential boundaries for clinical trials , 1983 .

[8]  Yogendra P. Chaubey,et al.  Resampling Methods: A Practical Guide to Data Analysis , 2000, Technometrics.

[9]  Patrick Royston,et al.  A Menu-Driven Facility for Sample-Size Calculation in Novel Multiarm, Multistage Randomized Controlled Trials with a Time-to-Event Outcome , 2009 .

[10]  David Machin,et al.  Survival Analysis: A Practical Approach , 1995 .

[11]  I. Tannock,et al.  Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial , 2002, The Lancet.

[12]  Anastasios A. Tsiatis,et al.  Interim Monitoring of Group Sequential Trials Using Spending Functions for the Type I and Type II Error Probabilities , 2001 .

[13]  Innovation OR Stagnation.  Challenge and Opportunity on the Critical Path to New Medical Products , 2004 .

[14]  V. Torri,et al.  Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial , 2003, The Lancet.