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population of potential patients, but be such that they produce different effects when a patient is switched from formulation T to formulation R or vice-versa. In other words there is a significant subject-by-formulation interaction. To show that this is not the case T and R have to be shown to be IBE, i.e., individually bioequivalent. The measure of IBE that has been suggested by the regulators is an aggregate measure involving the means and variances of T and R and the subject-by-formulation inter-action. We will describe this measure in Section 7.4. In simple terms PBE can be considered as a measure that permits patients who have not yet been treated with T or R to be safely prescribed either. IBE, on the other hand, is a measure which permits a patient who is cur-rently being treated with R to be safely switched to T (FDA Guid-ance, 1997, 1999a,b, 2000, 2001). It is worth noting that if T is IBE to R it does not imply that R is IBE to T. The same can be said for PBE. An important practical implication of testing for IBE is that the 2×2 cross-over trial is no longer adequate. As will be seen, the volunteers in the study will have to receive at least one repeat dose of R or T. In other words, three-or four-period designs with sequences such as [RTR,TRT] and [RTRT,TRTR], respectively, must be used. The measures of ABE, PBE and IBE that will be described in Sec-tions 7.2, 7.5 and 7.4 are those suggested by the regulators. Dragalin and Fedorov (1999) and Dragalin et al. (2002) have pointed out some drawbacks of these measures and suggested alternatives which have more attractive properties. We will consider these alternatives in Section 7.7. All the analyzes considered in Sections 7.2 to 7.4 are based on sum-mary measures (AUC and Cmax) obtained from the concentration-time profiles. If testing for bioequivalence is all that is of interest, then these measures are adequate and have been extensively used in practice. How-ever, there is often a need to obtain an understanding of the absorb-tion and elimination processes to which the drug is exposed once it has entered the body, e.g., when bioequivalence is not demonstrated. This can be done by fitting compartmental models to the drug con-centrations obtained from each volunteer. These models not only pro-vide insight into the mechanisms of action of the drugs, but can also be used to calculate the AUC and Cmax values. In Section 7.8 we de-scribe how such models can be fitted using the methods proposed by Lindsey et al. (2000a). The history of bioequivalence testing dates back to the late 1960s and early 1970s. Two excellent review articles written by Patterson (2001a, 2001b) give a more detailed description of the history, as well as a more extensive discussion of the points raised in this section. The regulatory
DOI link for population of potential patients, but be such that they produce different effects when a patient is switched from formulation T to formulation R or vice-versa. In other words there is a significant subject-by-formulation interaction. To show that this is not the case T and R have to be shown to be IBE, i.e., individually bioequivalent. The measure of IBE that has been suggested by the regulators is an aggregate measure involving the means and variances of T and R and the subject-by-formulation inter-action. We will describe this measure in Section 7.4. In simple terms PBE can be considered as a measure that permits patients who have not yet been treated with T or R to be safely prescribed either. IBE, on the other hand, is a measure which permits a patient who is cur-rently being treated with R to be safely switched to T (FDA Guid-ance, 1997, 1999a,b, 2000, 2001). It is worth noting that if T is IBE to R it does not imply that R is IBE to T. The same can be said for PBE. An important practical implication of testing for IBE is that the 2×2 cross-over trial is no longer adequate. As will be seen, the volunteers in the study will have to receive at least one repeat dose of R or T. In other words, three-or four-period designs with sequences such as [RTR,TRT] and [RTRT,TRTR], respectively, must be used. The measures of ABE, PBE and IBE that will be described in Sec-tions 7.2, 7.5 and 7.4 are those suggested by the regulators. Dragalin and Fedorov (1999) and Dragalin et al. (2002) have pointed out some drawbacks of these measures and suggested alternatives which have more attractive properties. We will consider these alternatives in Section 7.7. All the analyzes considered in Sections 7.2 to 7.4 are based on sum-mary measures (AUC and Cmax) obtained from the concentration-time profiles. If testing for bioequivalence is all that is of interest, then these measures are adequate and have been extensively used in practice. How-ever, there is often a need to obtain an understanding of the absorb-tion and elimination processes to which the drug is exposed once it has entered the body, e.g., when bioequivalence is not demonstrated. This can be done by fitting compartmental models to the drug con-centrations obtained from each volunteer. These models not only pro-vide insight into the mechanisms of action of the drugs, but can also be used to calculate the AUC and Cmax values. In Section 7.8 we de-scribe how such models can be fitted using the methods proposed by Lindsey et al. (2000a). The history of bioequivalence testing dates back to the late 1960s and early 1970s. Two excellent review articles written by Patterson (2001a, 2001b) give a more detailed description of the history, as well as a more extensive discussion of the points raised in this section. The regulatory
population of potential patients, but be such that they produce different effects when a patient is switched from formulation T to formulation R or vice-versa. In other words there is a significant subject-by-formulation interaction. To show that this is not the case T and R have to be shown to be IBE, i.e., individually bioequivalent. The measure of IBE that has been suggested by the regulators is an aggregate measure involving the means and variances of T and R and the subject-by-formulation inter-action. We will describe this measure in Section 7.4. In simple terms PBE can be considered as a measure that permits patients who have not yet been treated with T or R to be safely prescribed either. IBE, on the other hand, is a measure which permits a patient who is cur-rently being treated with R to be safely switched to T (FDA Guid-ance, 1997, 1999a,b, 2000, 2001). It is worth noting that if T is IBE to R it does not imply that R is IBE to T. The same can be said for PBE. An important practical implication of testing for IBE is that the 2×2 cross-over trial is no longer adequate. As will be seen, the volunteers in the study will have to receive at least one repeat dose of R or T. In other words, three-or four-period designs with sequences such as [RTR,TRT] and [RTRT,TRTR], respectively, must be used. The measures of ABE, PBE and IBE that will be described in Sec-tions 7.2, 7.5 and 7.4 are those suggested by the regulators. Dragalin and Fedorov (1999) and Dragalin et al. (2002) have pointed out some drawbacks of these measures and suggested alternatives which have more attractive properties. We will consider these alternatives in Section 7.7. All the analyzes considered in Sections 7.2 to 7.4 are based on sum-mary measures (AUC and Cmax) obtained from the concentration-time profiles. If testing for bioequivalence is all that is of interest, then these measures are adequate and have been extensively used in practice. How-ever, there is often a need to obtain an understanding of the absorb-tion and elimination processes to which the drug is exposed once it has entered the body, e.g., when bioequivalence is not demonstrated. This can be done by fitting compartmental models to the drug con-centrations obtained from each volunteer. These models not only pro-vide insight into the mechanisms of action of the drugs, but can also be used to calculate the AUC and Cmax values. In Section 7.8 we de-scribe how such models can be fitted using the methods proposed by Lindsey et al. (2000a). The history of bioequivalence testing dates back to the late 1960s and early 1970s. Two excellent review articles written by Patterson (2001a, 2001b) give a more detailed description of the history, as well as a more extensive discussion of the points raised in this section. The regulatory
ABSTRACT