Bayesian Sequential Design for Identifying and Ranking Effective Patient Subgroups in Precision Medicine in the Case of Counting Outcome Data with Inflated Zeros.

Precision medicine is revolutionizing health care, particularly by addressing patient variability due to different biological profiles. As traditional treatments may not always be appropriate for certain patient subsets, the rise of biomarker-stratified clinical trials has driven the need for innovative methods. We introduced a Bayesian sequential scheme to evaluate therapeutic interventions in an intensive care unit setting, focusing on complex endpoints characterized by an excess of zeros and right truncation. By using a zero-inflated truncated Poisson model, we efficiently addressed this data complexity. The posterior distribution of rankings and the surface under the cumulative ranking curve (SUCRA) approach provided a comprehensive ranking of the subgroups studied. Different subsets of subgroups were evaluated depending on the availability of biomarker data. Interim analyses, accounting for early stopping for efficacy, were an integral aspect of our design. The simulation study demonstrated a high proportion of correct identification of the subgroup which is the most predictive of the treatment effect, as well as satisfactory false positive and true positive rates. As the role of personalized medicine grows, especially in the intensive care setting, it is critical to have designs that can manage complicated endpoints and that can control for decision error. Our method seems promising in this challenging context.

Simulation study for evaluating an adaptive-randomisation Bayesian hybrid trial design with enrichment.

Background: As we enter the era of precision medicine, the role of adaptive designs, such as response-adaptive randomisation or enrichment designs in drug discovery and development, has become increasingly important to identify the treatment given to a patient based on one or more biomarkers. Tailoring the ventilation supply technique according to the responsiveness of patients to positive end-expiratory pressure is a suitable setting for such a design. Methods: In the setting of marker-strategy design, we propose a Bayesian response-adaptive randomisation with enrichment design based on group sequential analyses. This design combines the elements of enrichment design and response-adaptive randomisation. Concerning the enrichment strategy, Bayesian treatment-by-subset interaction measures were used to adaptively enrich the patients most likely to benefit from an experimental treatment while controlling the false-positive rate.The operating characteristics of the design were assessed by simulation and compared to those of alternate designs. Results: The results obtained allowed the detection of the superiority of one treatment over another and the presence of a treatment-by-subgroup interaction while keeping the false-positive rate at approximately 5\% and reducing the average number of included patients. In addition, simulation studies identified that the number of interim analyses and the burn-in period may have an impact on the performance of the scheme. Conclusion: The proposed design highlights important objectives of precision medicine, such as determining whether the experimental treatment is superior to another and identifying wheter such an efficacy could depend on patient profile.

Enrichment Bayesian design for randomized clinical trials using categorical biomarkers and a binary outcome.

BACKGROUND: Adaptive clinical trials have been increasingly commonly employed to select a potential target population for one trial without conducting trials separately. Such enrichment designs typically consist of two or three stages, where the first stage serves as a screening process for selecting a specific subpopulation. METHODS: We propose a Bayesian design for randomized clinical trials with a binary outcome that focuses on restricting the inclusion to a subset of patients who are likely to benefit the most from the treatment during trial accrual. Several Bayesian measures of efficacy and treatment-by-subset interactions were used to dictate the enrichment, either based on Gail and Simon's or Millen's criteria. A simulation study was used to assess the performance of our design. The method is exemplified in a real randomized clinical trial conducted in patients with respiratory failure that failed to show any benefit of high flow oxygen supply compared with standard oxygen. RESULTS: The use of the enrichment rules allowed the detection of the existence of a treatment-by-subset interaction more rapidly compared with Gail and Simon's criteria, with decreasing proportions of enrollment in the whole sample, and the proportions of enrichment lower, in the presence of interaction based on Millen's criteria. In the real dataset, this may have allowed the detection of the potential interest of high flow oxygen in patients with a SOFA neurological score ≥ 1. CONCLUSION: Enrichment designs that handle the uncertainty in treatment efficacy by focusing on the target population offer a promising balance for trial efficiency and ease of interpretation.