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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Standard

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; Pipper, Christian Bressen; Lange, Theis; Bjerrum, Ole Jannik; Lund, Trine Meldgaard.

In: British Journal of Clinical Pharmacology, Vol. 85, No. 8, 2019, p. 1829-1840.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Nøhr-Nielsen, A, De Bruin, ML, Thomsen, M, Pipper, CB, Lange, T, Bjerrum, OJ & Lund, TM 2019, 'Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016', British Journal of Clinical Pharmacology, vol. 85, no. 8, pp. 1829-1840. https://doi.org/10.1111/bcp.13986

APA

Nøhr-Nielsen, A., De Bruin, M. L., Thomsen, M., Pipper, C. B., Lange, T., Bjerrum, O. J., & Lund, T. M. (2019). Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016. British Journal of Clinical Pharmacology, 85(8), 1829-1840. https://doi.org/10.1111/bcp.13986

Vancouver

Nøhr-Nielsen A, De Bruin ML, Thomsen M, Pipper CB, Lange T, Bjerrum OJ et al. Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016. British Journal of Clinical Pharmacology. 2019;85(8):1829-1840. https://doi.org/10.1111/bcp.13986

Author

Nøhr-Nielsen, Asbjørn ; De Bruin, Marie Louise ; Thomsen, Mikael ; Pipper, Christian Bressen ; Lange, Theis ; Bjerrum, Ole Jannik ; Lund, Trine Meldgaard. / Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016. In: British Journal of Clinical Pharmacology. 2019 ; Vol. 85, No. 8. pp. 1829-1840.

Bibtex

@article{44c8f2b57fe44f41a3815684cd8c8251,
title = "Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016",
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.",
keywords = "clinical development, fixed-dose combination, market authorization, PK-PD modelling, regulatory science",
author = "Asbj{\o}rn N{\o}hr-Nielsen and {De Bruin}, {Marie Louise} and Mikael Thomsen and Pipper, {Christian Bressen} and Theis Lange and Bjerrum, {Ole Jannik} and Lund, {Trine Meldgaard}",
year = "2019",
doi = "10.1111/bcp.13986",
language = "English",
volume = "85",
pages = "1829--1840",
journal = "British Journal of Clinical Pharmacology. Supplement",
issn = "0264-3774",
publisher = "Wiley-Blackwell",
number = "8",

}

RIS

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

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 -

ID: 226073487