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

Asbjørn Nøhr-Nielsen; Marie Louise De Bruin; Mikael Thomsen; Christian Bressen Pipper; Theis Lange; Ole Jannik Bjerrum; Trine Meldgaard Lund

doi:10.1111/bcp.13986

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

Asbjørn Nøhr-Nielsen, Marie Louise De Bruin, Mikael Thomsen, Christian Bressen Pipper, Theis Lange, Ole Jannik Bjerrum, Trine Meldgaard Lund^*

^*Corresponding author for this work

Section of Biostatistics

3 Citations (Scopus)

Abstract

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.

Original language	English
Journal	British Journal of Clinical Pharmacology
Volume	85
Issue number	8
Pages (from-to)	1829-1840
Number of pages	12
ISSN	0306-5251
DOIs	https://doi.org/10.1111/bcp.13986
Publication status	Published - Aug 2019

Keywords

clinical development, fixed-dose combination, market authorization, PK-PD modelling, regulatory science

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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. / Nøhr-Nielsen, Asbjørn; De Bruin, Marie Louise; Thomsen, Mikael et al.
In: British Journal of Clinical Pharmacology, Vol. 85, No. 8, 08.2019, p. 1829-1840.

Research output: Contribution to journal › Journal article › Research › peer-review

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abstract = "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.",

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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

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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.

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JO - British Journal of Clinical Pharmacology

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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

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