Aims: To support the selection of dose combination(s) of solifenacin and mirabegron for further development using a transparent and standardized approach, and to characterize the added value of the combination compared to the respective monotherapies. This was accomplished by performing a multi-criteria decision analysis (MCDA) evaluating the clinical utility of the combination use of solifenacin and mirabegron.
Methods: MCDA is used to optimize decision making in situations requiring simultaneous evaluation and trade-off of multiple, qualitatively different criteria. Building on the expert knowledge required for complex decision making, MCDA provides a transparent framework in which to interpret and compare the relevant benefits and risks in a quantitative fashion.
Efficacy and key safety data obtained in a phase II study (study 178-CL-100) were used for the MCDA. Reported surveys and informal discussions with European and US urologists, as well as patient opinions, were used to identify crucial attributes and their relative importance. A component utility function was defined for each attribute, describing the contribution to the overall utility of the combination of solifenacin and mirabegron. The utility functions were based on historical results from monotherapy trials. Factors associated with efficacy, safety and tolerability were balanced, using the MCDA, to determine the clinical utility of different dose combinations. Improvements in efficacy (e.g. increased mean voided volume) and improvements in safety and tolerability (e.g. reduced dry mouth) resulted in a higher clinical utility. Sensitivity analyses were performed to assess the effect of varying the relative attribute weights, thus testing the robustness of the results.
Results: The clinical utility of different dose combinations of solifenacin and mirabegron is presented in the figure below. In this figure, the relative contribution for each attribute is shown and the sum represents the clinical utility score. The error bars represent the 95% confidence interval of the total clinical utility score.
Conclusion: The combinations of solifenacin 5 mg and mirabegron 25 mg and mirabegron 50 mg had the highest clinical utility score in the primary analysis and supported combination therapy development of solifenacin and mirabegron for phase III clinical development at these dose regimens. This case study illustrates how a MCDA approached can integrate the benefit risk assessments of clinical experts as well as patient opinions to support a clinical drug development program in a transparent and standardized manner.
de Greef-van der Sandt, I et al. A quantitative benefit-risk assessment approach to improve decision making in drug development: Application of a multicriteria decision analysis model