Breadcrumbs Section. Click here to navigate to respective pages.
Chapter
Chapter
switched to T. It is a criterion that takes into account within-subject variability and subject-by-formulation interaction. (See FDA Guidance, 1997, 1999b, and final Guidance, 2000, 2001.) In order to define it we need some additional notation. Let σ and σ denote the within-subject variances for T and R, respectively, σ and σ denote the between-subject variances for T and R, respectively, and σ − 2ρσ σBR , denote the subject-by-formulation interaction, where ρ is the between-subject cor-relation of T and R. The means of T and R are denoted by µ , respectively, and δ = (µ ). IBE is assessed using the following aggregate metric (FDA Guidance, 1997): (µ (7.2) max(0.04,σ ) which tests the following linearized null hypotheses: if σˆ > 0.04: H : ν = δ +σ − (1 + c ≥ 0. (7.3) If σˆ ≤ 0.04: H : ν = δ +σ − 0.04(c ) ≥ 0. (7.4) Note that the metric in (7.3) is scaled using the within-variance σˆ from the trial and (7.4) is scaled using the constant value of 0.04. We note that when calculating metrics here, and in the following, each parameter is estimated from the trial data; hence we use hatted values (e.g., σˆ ) for the calculations. When the metric is scaled using σˆ , we will refer to it as reference-scaled. When it is scaled using 0.04, we refer to it as constant-scaled. Note that if σˆ < 0 then the contribution to the numerator of (7.2) by δˆ and σˆ will be reduced. This is a potentially undesirable property and it is known such trade-offs have occurred in practice (Zariffa et al., 2000). Constant-scaling was introduced (FDA Guidance, 1997) as a means of keeping low-variability products from being held to what was felt to be an unreasonably strict standard for bioequivalence. The value c in H is a regulatory goalpost equal to 2.49 (FDA Guidance, 2000). It assumes a within-subject variance for R of 0.04 and is calculated as follows: (ln(1.25)) + (0.03) + (0.02) c = = 2.49 (7.5) 0.04 allowing for a difference in means of ln(1.25) and a variance allowance of 0.03 in the numerator for the subject-by-formulation interaction and an allowance of 0.02 for the difference in within-subject variances under the procedure proposed by the FDA (FDA Guidance, 1997). To demon-
DOI link for switched to T. It is a criterion that takes into account within-subject variability and subject-by-formulation interaction. (See FDA Guidance, 1997, 1999b, and final Guidance, 2000, 2001.) In order to define it we need some additional notation. Let σ and σ denote the within-subject variances for T and R, respectively, σ and σ denote the between-subject variances for T and R, respectively, and σ − 2ρσ σBR , denote the subject-by-formulation interaction, where ρ is the between-subject cor-relation of T and R. The means of T and R are denoted by µ , respectively, and δ = (µ ). IBE is assessed using the following aggregate metric (FDA Guidance, 1997): (µ (7.2) max(0.04,σ ) which tests the following linearized null hypotheses: if σˆ > 0.04: H : ν = δ +σ − (1 + c ≥ 0. (7.3) If σˆ ≤ 0.04: H : ν = δ +σ − 0.04(c ) ≥ 0. (7.4) Note that the metric in (7.3) is scaled using the within-variance σˆ from the trial and (7.4) is scaled using the constant value of 0.04. We note that when calculating metrics here, and in the following, each parameter is estimated from the trial data; hence we use hatted values (e.g., σˆ ) for the calculations. When the metric is scaled using σˆ , we will refer to it as reference-scaled. When it is scaled using 0.04, we refer to it as constant-scaled. Note that if σˆ < 0 then the contribution to the numerator of (7.2) by δˆ and σˆ will be reduced. This is a potentially undesirable property and it is known such trade-offs have occurred in practice (Zariffa et al., 2000). Constant-scaling was introduced (FDA Guidance, 1997) as a means of keeping low-variability products from being held to what was felt to be an unreasonably strict standard for bioequivalence. The value c in H is a regulatory goalpost equal to 2.49 (FDA Guidance, 2000). It assumes a within-subject variance for R of 0.04 and is calculated as follows: (ln(1.25)) + (0.03) + (0.02) c = = 2.49 (7.5) 0.04 allowing for a difference in means of ln(1.25) and a variance allowance of 0.03 in the numerator for the subject-by-formulation interaction and an allowance of 0.02 for the difference in within-subject variances under the procedure proposed by the FDA (FDA Guidance, 1997). To demon-
switched to T. It is a criterion that takes into account within-subject variability and subject-by-formulation interaction. (See FDA Guidance, 1997, 1999b, and final Guidance, 2000, 2001.) In order to define it we need some additional notation. Let σ and σ denote the within-subject variances for T and R, respectively, σ and σ denote the between-subject variances for T and R, respectively, and σ − 2ρσ σBR , denote the subject-by-formulation interaction, where ρ is the between-subject cor-relation of T and R. The means of T and R are denoted by µ , respectively, and δ = (µ ). IBE is assessed using the following aggregate metric (FDA Guidance, 1997): (µ (7.2) max(0.04,σ ) which tests the following linearized null hypotheses: if σˆ > 0.04: H : ν = δ +σ − (1 + c ≥ 0. (7.3) If σˆ ≤ 0.04: H : ν = δ +σ − 0.04(c ) ≥ 0. (7.4) Note that the metric in (7.3) is scaled using the within-variance σˆ from the trial and (7.4) is scaled using the constant value of 0.04. We note that when calculating metrics here, and in the following, each parameter is estimated from the trial data; hence we use hatted values (e.g., σˆ ) for the calculations. When the metric is scaled using σˆ , we will refer to it as reference-scaled. When it is scaled using 0.04, we refer to it as constant-scaled. Note that if σˆ < 0 then the contribution to the numerator of (7.2) by δˆ and σˆ will be reduced. This is a potentially undesirable property and it is known such trade-offs have occurred in practice (Zariffa et al., 2000). Constant-scaling was introduced (FDA Guidance, 1997) as a means of keeping low-variability products from being held to what was felt to be an unreasonably strict standard for bioequivalence. The value c in H is a regulatory goalpost equal to 2.49 (FDA Guidance, 2000). It assumes a within-subject variance for R of 0.04 and is calculated as follows: (ln(1.25)) + (0.03) + (0.02) c = = 2.49 (7.5) 0.04 allowing for a difference in means of ln(1.25) and a variance allowance of 0.03 in the numerator for the subject-by-formulation interaction and an allowance of 0.02 for the difference in within-subject variances under the procedure proposed by the FDA (FDA Guidance, 1997). To demon-
ABSTRACT