Body of evidence and approaches applied in the clinical development program of fixed-dose combinations in the European Union from 2010-2016.

AIM: To provide insights into the clinical development pathway for fixed-dose combinations (FDCs), to consider strategies, and to elucidate the path to approval by assessing the body of evidence, as summarized in the European Public Assessment Reports (EPARs).

METHODS: The main resource was the EPARs for 36 FDCs, which included 239 clinical trials with 157.514 patients. The analyses focused on how prior knowledge of the active substances or combination, use of pharmacokinetic-pharmacodynamic modelling, and clinical trial design choice impact the size and strategy of the clinical development program.

RESULTS: FDC products were primarily comprised of two previously approved components (21/36, 71%) and had only one approved combination (21/36, 71%). Utilizing previously approved active substances resulted in less clinical trials, arms, and patients, but not number of FDC doses studied in the clinical development program. Furthermore, dose-finding trials were performed for less than half of FDCs consisting of two previously approved active substances. The standard approach to demonstrate contribution of active substances was through a factorial or single combination study. Finally, the use of pharmacokinetic modelling showed a significant decrease in the number of FDC doses studied.

CONCLUSIONS: The field of FDCs seems to be on the rise, utilizing new molecular entities, prior knowledge, and re-profiling drugs. However, a way to move FDC development forward might be through new regulatory and scientific paradigms, in which it is encouraged to utilize model-based approaches to develop FDCs with multiple dose levels and dose ratios for exposure-based treatment that will enable personalisation.