Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs
Purpose. To provide tables of sample sizes which are required, by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), for the design of bioequivalence (BE) studies involving highly variable drugs. To elucidate the complicated features of the relationship between sam...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2011-12-01
|
| Series: | Journal of Pharmacy & Pharmaceutical Sciences |
| Online Access: | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/11612 |
| _version_ | 1797727347752828928 |
|---|---|
| author | Laszlo Endrenyi Laszlo Tothfalusi |
| author_facet | Laszlo Endrenyi Laszlo Tothfalusi |
| author_sort | Laszlo Endrenyi |
| collection | DOAJ |
| description | Purpose. To provide tables of sample sizes which are required, by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), for the design of bioequivalence (BE) studies involving highly variable drugs. To elucidate the complicated features of the relationship between sample size and within-subject variation. Methods. 3- and 4-period studies were simulated with various sample sizes. They were evaluated, at various variations and various true ratios of the two geometric means (GMR), by the approaches of scaled average BE and by average BE with expanding limits. The sample sizes required for yielding 80% and 90% statistical powers were determined. Results. Because of the complicated regulatory expectations, the features of the required sample sizes are also complicated. When the true GMR = 1.0 then, without additional constraints, the sample size is independent of the intrasubject variation. When the true GMR is increased or decreased from 1.0 then the required sample sizes rise at above but close to 30% variation. An additional regulatory constraint on the point estimate of GMR and a cap on the use of expanding limits further increase the required sample size at high variations. Fewer subjects are required by the FDA than by the EMA procedures. Conclusions. The methods proposed by EMA and FDA lower the required sample sizes in comparison with unscaled average BE. However, each additional regulatory requirement (applying the mixed procedure, imposing a constraint on the point estimate of GMR, and using a cap on the application of expanding limits) raises the required number of subjects.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. |
| first_indexed | 2024-03-12T10:58:32Z |
| format | Article |
| id | doaj.art-6538d4fc8c144dd4bb68c8dca65a6539 |
| institution | Directory Open Access Journal |
| issn | 1482-1826 |
| language | English |
| last_indexed | 2024-03-12T10:58:32Z |
| publishDate | 2011-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Journal of Pharmacy & Pharmaceutical Sciences |
| spelling | doaj.art-6538d4fc8c144dd4bb68c8dca65a65392023-09-02T06:03:42ZengFrontiers Media S.A.Journal of Pharmacy & Pharmaceutical Sciences1482-18262011-12-0115110.18433/J3Z88FSample Sizes for Designing Bioequivalence Studies for Highly Variable DrugsLaszlo Endrenyi0Laszlo Tothfalusi1University of Toronto, Toronto, ON CanadaSemmelweis UniversityPurpose. To provide tables of sample sizes which are required, by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), for the design of bioequivalence (BE) studies involving highly variable drugs. To elucidate the complicated features of the relationship between sample size and within-subject variation. Methods. 3- and 4-period studies were simulated with various sample sizes. They were evaluated, at various variations and various true ratios of the two geometric means (GMR), by the approaches of scaled average BE and by average BE with expanding limits. The sample sizes required for yielding 80% and 90% statistical powers were determined. Results. Because of the complicated regulatory expectations, the features of the required sample sizes are also complicated. When the true GMR = 1.0 then, without additional constraints, the sample size is independent of the intrasubject variation. When the true GMR is increased or decreased from 1.0 then the required sample sizes rise at above but close to 30% variation. An additional regulatory constraint on the point estimate of GMR and a cap on the use of expanding limits further increase the required sample size at high variations. Fewer subjects are required by the FDA than by the EMA procedures. Conclusions. The methods proposed by EMA and FDA lower the required sample sizes in comparison with unscaled average BE. However, each additional regulatory requirement (applying the mixed procedure, imposing a constraint on the point estimate of GMR, and using a cap on the application of expanding limits) raises the required number of subjects. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/11612 |
| spellingShingle | Laszlo Endrenyi Laszlo Tothfalusi Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs Journal of Pharmacy & Pharmaceutical Sciences |
| title | Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs |
| title_full | Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs |
| title_fullStr | Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs |
| title_full_unstemmed | Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs |
| title_short | Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs |
| title_sort | sample sizes for designing bioequivalence studies for highly variable drugs |
| url | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/11612 |
| work_keys_str_mv | AT laszloendrenyi samplesizesfordesigningbioequivalencestudiesforhighlyvariabledrugs AT laszlotothfalusi samplesizesfordesigningbioequivalencestudiesforhighlyvariabledrugs |