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Guidance FDA (2001) using a REML UN model. Then, this estimate is asymptotically normally distributed, unbiased with E[νˆ ] = δ +σ − (σ )− 0.04(c ) and has variance of Var[νˆ ] = 4σ δ + l + 2l − 2l + 2l To assess PBE we ‘plug-in’ estimates of δ and the variance components and calculate the upper bound of an asymptotic 90% confidence interval. If this upper bound is below zero we declare that PBE has been shown. Using the code in Appendix B and the data in Section 7.4, we obtain the value −0.24 for log(AUC) and the value −0.19 for log(Cmax). As both of these are below zero, we can declare that T and R are PBE. 7.6 ABE for a replicate design Although ABE can be assessed using a 2× 2 design, it can also be as-sessed using a replicate design. If a replicate design is used the number of subjects can be reduced to up to half that required for a 2 × 2 de-sign. In addition it permits the estimation of σ and σ . The SAS code to assess ABE for a replicate design is given in Appendix B. Using the data from Section 7.4, the 90% confidence interval for µ is (−0.1697,−0.0155) for log(AUC) and (−0.2474,−0.0505) for log(Cmax). Exponentiating the limits to obtain confidence limits for exp(µ ), gives (0.8439,0.9846) for AUC and (0.7808,0.9508) for Cmax. Only the first of these intervals is contained within the limits of 0.8 to 1.25, there-fore T cannot be considered average bioequivalent to R. To calculate the power for a replicate design with four periods and with a total of n subjects we can still use the SAS code given in Section 7.3, if we alter the formula for the variance of a difference of two obser-vations from the same subject. This will now be σ +σ instead of σ , where σ is the subject-by-formulation interaction. Note the use of σ rather than 2σ as used in the RT/TR design. This is a result of the estimator using the average of two measurements on each treatment on each subject. One advantage of using a replicate design is that the number of sub-jects needed can be much smaller than that needed for a 2×2 design. As an example, suppose that σ = 0, and we take σ = 0.355 and α = 0.05, as done in Section 7.3. Then a power of 90.5% can be achieved with only 30 subjects, which is about half the number (58) needed for the 2 × 2 design.
DOI link for Guidance FDA (2001) using a REML UN model. Then, this estimate is asymptotically normally distributed, unbiased with E[νˆ ] = δ +σ − (σ )− 0.04(c ) and has variance of Var[νˆ ] = 4σ δ + l + 2l − 2l + 2l To assess PBE we ‘plug-in’ estimates of δ and the variance components and calculate the upper bound of an asymptotic 90% confidence interval. If this upper bound is below zero we declare that PBE has been shown. Using the code in Appendix B and the data in Section 7.4, we obtain the value −0.24 for log(AUC) and the value −0.19 for log(Cmax). As both of these are below zero, we can declare that T and R are PBE. 7.6 ABE for a replicate design Although ABE can be assessed using a 2× 2 design, it can also be as-sessed using a replicate design. If a replicate design is used the number of subjects can be reduced to up to half that required for a 2 × 2 de-sign. In addition it permits the estimation of σ and σ . The SAS code to assess ABE for a replicate design is given in Appendix B. Using the data from Section 7.4, the 90% confidence interval for µ is (−0.1697,−0.0155) for log(AUC) and (−0.2474,−0.0505) for log(Cmax). Exponentiating the limits to obtain confidence limits for exp(µ ), gives (0.8439,0.9846) for AUC and (0.7808,0.9508) for Cmax. Only the first of these intervals is contained within the limits of 0.8 to 1.25, there-fore T cannot be considered average bioequivalent to R. To calculate the power for a replicate design with four periods and with a total of n subjects we can still use the SAS code given in Section 7.3, if we alter the formula for the variance of a difference of two obser-vations from the same subject. This will now be σ +σ instead of σ , where σ is the subject-by-formulation interaction. Note the use of σ rather than 2σ as used in the RT/TR design. This is a result of the estimator using the average of two measurements on each treatment on each subject. One advantage of using a replicate design is that the number of sub-jects needed can be much smaller than that needed for a 2×2 design. As an example, suppose that σ = 0, and we take σ = 0.355 and α = 0.05, as done in Section 7.3. Then a power of 90.5% can be achieved with only 30 subjects, which is about half the number (58) needed for the 2 × 2 design.
Guidance FDA (2001) using a REML UN model. Then, this estimate is asymptotically normally distributed, unbiased with E[νˆ ] = δ +σ − (σ )− 0.04(c ) and has variance of Var[νˆ ] = 4σ δ + l + 2l − 2l + 2l To assess PBE we ‘plug-in’ estimates of δ and the variance components and calculate the upper bound of an asymptotic 90% confidence interval. If this upper bound is below zero we declare that PBE has been shown. Using the code in Appendix B and the data in Section 7.4, we obtain the value −0.24 for log(AUC) and the value −0.19 for log(Cmax). As both of these are below zero, we can declare that T and R are PBE. 7.6 ABE for a replicate design Although ABE can be assessed using a 2× 2 design, it can also be as-sessed using a replicate design. If a replicate design is used the number of subjects can be reduced to up to half that required for a 2 × 2 de-sign. In addition it permits the estimation of σ and σ . The SAS code to assess ABE for a replicate design is given in Appendix B. Using the data from Section 7.4, the 90% confidence interval for µ is (−0.1697,−0.0155) for log(AUC) and (−0.2474,−0.0505) for log(Cmax). Exponentiating the limits to obtain confidence limits for exp(µ ), gives (0.8439,0.9846) for AUC and (0.7808,0.9508) for Cmax. Only the first of these intervals is contained within the limits of 0.8 to 1.25, there-fore T cannot be considered average bioequivalent to R. To calculate the power for a replicate design with four periods and with a total of n subjects we can still use the SAS code given in Section 7.3, if we alter the formula for the variance of a difference of two obser-vations from the same subject. This will now be σ +σ instead of σ , where σ is the subject-by-formulation interaction. Note the use of σ rather than 2σ as used in the RT/TR design. This is a result of the estimator using the average of two measurements on each treatment on each subject. One advantage of using a replicate design is that the number of sub-jects needed can be much smaller than that needed for a 2×2 design. As an example, suppose that σ = 0, and we take σ = 0.355 and α = 0.05, as done in Section 7.3. Then a power of 90.5% can be achieved with only 30 subjects, which is about half the number (58) needed for the 2 × 2 design.
ABSTRACT