TY - JOUR
T1 - Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016
AU - Nøhr-Nielsen, Asbjørn
AU - De Bruin, Marie Louise
AU - Thomsen, Mikael
AU - Pipper, Christian Bressen
AU - Lange, Theis
AU - Bjerrum, Ole Jannik
AU - Lund, Trine Meldgaard
PY - 2019
Y1 - 2019
N2 - Aims: 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. Methods: The main resource was the European Public Assessment Reports 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 programme. Results: FDC products primarily comprised 2 previously approved components (21/36, 71%) and had only 1 approved combination (21/36, 71%). Utilizing previously approved active substances resulted in fewer clinical trials, arms and patients, but FDC doses studied in the clinical development programme. Furthermore, dose-finding trials were performed for less than half of FDCs consisting of 2 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 personalization.
AB - Aims: 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. Methods: The main resource was the European Public Assessment Reports 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 programme. Results: FDC products primarily comprised 2 previously approved components (21/36, 71%) and had only 1 approved combination (21/36, 71%). Utilizing previously approved active substances resulted in fewer clinical trials, arms and patients, but FDC doses studied in the clinical development programme. Furthermore, dose-finding trials were performed for less than half of FDCs consisting of 2 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 personalization.
KW - clinical development, fixed-dose combination, market authorization, PK-PD modelling, regulatory science
U2 - 10.1111/bcp.13986
DO - 10.1111/bcp.13986
M3 - Journal article
C2 - 31077427
VL - 85
SP - 1829
EP - 1840
JO - British Journal of Clinical Pharmacology, Supplement
JF - British Journal of Clinical Pharmacology, Supplement
SN - 0264-3774
IS - 8
ER -