Meyer, EL,
Mesenbrink, P,
Dunger-Baldauf, C, et al.
Decision rules for identifying combination therapies in open-entry, randomized controlled platform trials.
Pharmaceutical Statistics.
2022;
21(
3):
671–
690. doi:
10.1002/pst.2194
Platform trials are clinical trials in which several treatments are investigated in parallel. The goal of platform trials generally is to test as many investigational treatments as possible over the shortest duration. They should be set up in such a way that reliable conclusions about the treatments’ efficacy and safety are reached as quickly as possible. To achieve this aim, it is necessary to specify how patients will be allocated to the investigational treatments. This is an important aspect of the design of the trial. The researchers investigated the design of platform trials in the context of combination therapies, where new treatments are combined with a common (so-called backbone) monotherapy (which can also be applied alone). In this context, a platform trials allows re-usage of certain data points, which means that the efficacy of therapies can be evaluated faster and fewer patients need to be allocated to standard of care.
However, there are still many unanswered questions about how to design platform trials – such as the impact of decision rules (here algorithms that lead to advancing or stopping further investigation of a compound) and the concrete method of data sharing across different groups, among others. In platform trials, defining operating characteristics (performance measures) is not straightforward because operating characteristics that would apply in standard clinical trials do not necessarily apply here.
For a platform trial comparing combination therapies to different monotherapies and standard-of-care, the researchers defined a set of error rates and operating characteristics and then used these to compare a set of design parameters and assumptions using simulations. When setting up the simulations, they tried to make the trajectories as realistic as possible, e.g. in case a compound is found to be superior to standard-of-care, it could replace standard-of-care in future cohorts.
Their results indicate that the method of data sharing, exact specification of decision rules and quality of the biomarker used to make interim decisions all strongly contribute to the operating characteristics of the platform trial. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics, this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage.
This research was publicly funded by the Innovative Medicines Initiative and is part of the EU-PEARL project. For more information, on the EU Patient-cEntric clinicAl tRial pLatforms, please see the project’s website here.
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