ISSN:1054-3406    

DOI:10.1080/10543409708835161

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

ISSN:1054-3406    

DOI:10.1080/10543409708835162

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

ISSN:1054-3406    

DOI:10.1080/10543409708835163

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

摘要:

The idea of defining bioequivalence in terms of the proportion of individuals exhibiting a drug formulation discrepancy that does not exceed some prespecified limit seems natural enough. Since the derivation of formal statistical procedures for testing the associated hypotheses is more or less straightforward, it is surprising that the approach was pursued in a systematic manner not earlier then in 1990 [by Anderson and Hauck (1) and Wellek (2,3)]. In discussing the relative merits of the approach we will stress the importance of a careful understanding of its conceptual basis. It will be argued that the most severe limitation on the usefulness of such probability-based criteria of individual bioequivalence arises from the fact that large intraindividual formulation discrepancies provide evidence against equivalence only in definite absence of period effects.

ISSN:1054-3406    

DOI:10.1080/10543409708835164

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

摘要:

We review and discuss some technical statistical issues and practical implementation issues associated with the use of individual as opposed to population average bioequivalence to express the relative bioavailabilities of alternative formulations of a drug. A number of promising methods for addressing individual bioequivalence have been described. Individual bioequivalence calculations can be done using standard crossover designs, although more sophisticated assessments that compare test-reference variability to reference-reference variability require more complex designs. However, more experience about the clinical implications of various degrees of individual bioinequivalence as expressed by various metrics should be accumulated before definitive regulations are set forth mandating the use of individual bioequivalence for expressing relative bioavailabilities.

ISSN:1054-3406    

DOI:10.1080/10543409708835165

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

摘要:

Regulatory requirements for average bioequivalence have been internationally harmonized (1,2), which is by no means the case for the more recent concept of individual bioequivalence (3–9). The main reason for introducing more complex replicate designs and bioequivalence criteria are the highly variable drugs, for which the setting of suitable bioequivalence ranges poses a major problem and scaling of the bioequivalence criteria by the intrasubject variability has been suggested (10–12). The shortcoming of the present two-treatment, two-period (2 × 2) crossover design to detect subject-by-formulation interaction provides a second argument in favor of the more complex replicate designs (13). A unified approach of proposed statistical procedures for the replicate design has been given by Schall (6,8). However, the availability of these methods and understanding of them seems to be limited to a small working group, so a broader international awareness of the problems and potentional solutions is desirable.

ISSN:1054-3406    

DOI:10.1080/10543409708835166

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

ISSN:1054-3406    

DOI:10.1080/10543409708835167

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

ISSN:1054-3406    

DOI:10.1080/10543409708835168

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

摘要:

In this paper we propose a two one-sided tests procedure for assessment of individual bioequivalence based on the concept of individual equivalence ratios proposed by Anderson and Hauck (5). The proposed procedure is derived under the normality assumption for the logarithmic transformation of pharmacokinetic responses obtained from a standard two-sequence, two-period crossover design. We show that the hypotheses for individual bioequivalence are equivalent to the hypotheses for testing whether the upper (or lower)pth quantile of the distribution of the differences between the test and reference formulations from the same subject is not greater (or not smaller) than some prespecified equivalence limits. Under this setting, we examine the relationship between average and individual bioequivalence. There exists the uniformly most powerful invariant test for each of the two one-sided hypotheses. In addition, the proposed two one-sided tests procedure is a test of size α(i.e.,≤ α) We demonstrate that the determination of critical values, the enumeration of power, and the estimation of sample sizes requires noncentralt-distributions but does not necessarily require the estimation of unknown population mean and variance for noncentrality parameters. We discuss possible extensions to other crossover and replicated crossover designs. A numberical example illustrates the proposed procedure.

ISSN:1054-3406    

DOI:10.1080/10543409708835169

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor

摘要:

The bioavailability and bioequivalence between drug products has become an important subject in drug development. The average bioavailability of the test (T) and the reference (R) products is currently specified in the FDA guidelines to be used for assessing the bioequivalence of the drug products. However, it has been recognized that the safety for the substitution of a reference drug product with a test drug product in patients, whose concentration may have been titrated to a steady efficacious and safe level, could be a concern. Therefore, it is suggested that individual bioequivalence within each subject be assessed to assure the safety of the drug switchability. This paper examines the statistical properties of TIER procedure that Anderson and Hauck (1) proposed to assess individual bioequivalence. It is shown that Anderson and Hauck's procedure could be improved by imposing some distribution assumption such as lognormal distribution for assessment of individual bioequivalence. This paper also compares the relative performance of the individual bioequivalence based on TIER procedure and the average bioequivalence based on two one-sided tests procedure suggested by Schuirmann (2). The relationship between equivalence limits for the improved TIER procedure and average bioequivalence is also examined.

ISSN:1054-3406    

DOI:10.1080/10543409708835170

出版商:Marcel Dekker, Inc.    

年代:1997

数据来源: Taylor