Planning a future randomized clinical trial based on a network of relevant past trials

Abstract

Background: The important role of network meta-analysis of randomized clinical trials in health technology assessment and guideline development is increasingly recognized. This approach has the potential to obtain conclusive results earlier than with new standalone trials or conventional, pairwise meta-analyses.

Methods: Network meta-analyses can also be used to plan future trials. We introduce a four-step framework that aims to identify the optimal design for a new trial that will update the existing evidence while minimizing the required sample size. The new trial designed within this framework does not need to include all competing interventions and comparisons of interest and can contribute direct and indirect evidence to the updated network meta-analysis. We present the method by virtually planning a new trial to compare biologics in rheumatoid arthritis and a new trial to compare two drugs for relapsing-remitting multiple sclerosis.

Results: A trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation. Challenges of the approach include the complexity of the methodology and the need for a coherent network meta-analysis of previous trials with little heterogeneity.

Conclusions: When used judiciously, conditional trial design could significantly reduce the required resources for a new study and prevent experimentation with an unnecessarily large number of participants.

Keywords: Conditional power; Evidence synthesis; Historical data; Rheumatoid arthritis; Sample size.

Fig. 1

Network of evidence of treatments for rheumatoid arthritis. Adapted from Hazlewood et al. [15]. ABAT abatacept, ADA adalimumab, AZA azathioprine, CQ chloroquine, ETN etanercept, Ctl certolizumab, CyA cyclosporin, GOL golimumab, HCQ hydroxychloroquine, IFX infliximab, IM intramuscular, IR inadequate response, iv intravenous, LEF leflunomide, MTX methotrexate, RTX rituximab, sc subcutaneous, SSZ sulfasalazine, TOFA tofacitinib, TCZ tocilizumab, triple methotrexate plus sulfasalazine and hydroxychloroquine

Fig. 2

Power and conditional power to detect a difference in response between triple therapy vs methotrexate combined with etanercept as a function of the sample size. The difference anticipated in a new study was of OR = 0.71 in American College of Rheumatology (ACR) 50 response favoring methothrexate/etanercept. Power for a single randomized trial considered in isolation (dotted line), conditional power for a fixed effect pairwise meta-analysis (dashed line, two studies), and network meta-analysis (solid line). Expected event rate in the triple therapy was assumed equal to the average observed in the network (49%). Calculations were performed using the conditional power method [12]

Fig. 3

Network of evidence of treatments for multiple sclerosis. Adapted from Tramacere et al. [18]