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Body of evidence and approaches applied in the clinical development programme of fixed‐dose combinations in the European Union from 2010 to 2016
Author(s) -
NøhrNielsen Asbjørn,
De Bruin Marie Louise,
Thomsen Mikael,
Pipper Christian Bressen,
Lange Theis,
Bjerrum Ole Jannik,
Lund Trine Meldgaard
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13986
Subject(s) - clinical trial , european union , medicine , pharmacology , pharmacokinetics , drug development , drug , business , economic policy
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.