Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies
Pilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguabl...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/5/1430 |
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| author | Sara Carolina Henriques João Albuquerque Paulo Paixão Luís Almeida Nuno Elvas Silva |
| author_facet | Sara Carolina Henriques João Albuquerque Paulo Paixão Luís Almeida Nuno Elvas Silva |
| author_sort | Sara Carolina Henriques |
| collection | DOAJ |
| description | Pilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguably more sensitive to variability. The aim of this work is to propose alternative approaches to the average bioequivalence methodology, in a way to overcome and reduce the uncertainty on the conclusions of these studies and on the potential of test formulations. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling. Each simulated BA/BE trial was analysed using the average bioequivalence approach. As alternative analyses, the centrality of the test-to-reference geometric least square means ratio (GMR), bootstrap bioequivalence analysis, and arithmetic (A<sub>mean</sub>) and geometric (G<sub>mean</sub>) mean ƒ<sub>2</sub> factor approaches were investigated. Methods performance was measured with a confusion matrix. The G<sub>mean</sub> ƒ<sub>2</sub> factor using a cut-off of 35 was the most appropriate method in the simulation conditions frame, enabling to more accurately conclude the potential of test formulations, with a reduced sample size. For simplification, a decision tree is also proposed for appropriate planning of the sample size and subsequent analysis approach to be followed in pilot BA/BE trials. |
| first_indexed | 2024-03-11T03:24:43Z |
| format | Article |
| id | doaj.art-c427f9bef4db4b399490080b556f7ebd |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T03:24:43Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-c427f9bef4db4b399490080b556f7ebd2023-11-18T02:51:28ZengMDPI AGPharmaceutics1999-49232023-05-01155143010.3390/pharmaceutics15051430Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence StudiesSara Carolina Henriques0João Albuquerque1Paulo Paixão2Luís Almeida3Nuno Elvas Silva4Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalBlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalBlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalPilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguably more sensitive to variability. The aim of this work is to propose alternative approaches to the average bioequivalence methodology, in a way to overcome and reduce the uncertainty on the conclusions of these studies and on the potential of test formulations. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling. Each simulated BA/BE trial was analysed using the average bioequivalence approach. As alternative analyses, the centrality of the test-to-reference geometric least square means ratio (GMR), bootstrap bioequivalence analysis, and arithmetic (A<sub>mean</sub>) and geometric (G<sub>mean</sub>) mean ƒ<sub>2</sub> factor approaches were investigated. Methods performance was measured with a confusion matrix. The G<sub>mean</sub> ƒ<sub>2</sub> factor using a cut-off of 35 was the most appropriate method in the simulation conditions frame, enabling to more accurately conclude the potential of test formulations, with a reduced sample size. For simplification, a decision tree is also proposed for appropriate planning of the sample size and subsequent analysis approach to be followed in pilot BA/BE trials.https://www.mdpi.com/1999-4923/15/5/1430bioequivalencegeneric medicinal productspilot studiesƒ<sub>2</sub> factorbootstrappharmacokinetics |
| spellingShingle | Sara Carolina Henriques João Albuquerque Paulo Paixão Luís Almeida Nuno Elvas Silva Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies Pharmaceutics bioequivalence generic medicinal products pilot studies ƒ<sub>2</sub> factor bootstrap pharmacokinetics |
| title | Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies |
| title_full | Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies |
| title_fullStr | Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies |
| title_full_unstemmed | Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies |
| title_short | Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies |
| title_sort | alternative analysis approaches for the assessment of pilot bioavailability bioequivalence studies |
| topic | bioequivalence generic medicinal products pilot studies ƒ<sub>2</sub> factor bootstrap pharmacokinetics |
| url | https://www.mdpi.com/1999-4923/15/5/1430 |
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