Bioequivalence Studies

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FDA/Center for Drug Evaluation and Research

In reference to the Federal Register notice on "Preliminary Draft Guidance for Industry on In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches: Availability", vol. 62, No. 249, Dec. 30, 1997, the Food and Drug Administration (FDA) is announcing the availability of data that were used by the Agency in support of the proposal and the detailed description of statistical methods for individual and population approaches. One motivation for individual bioequivalence is to identify a subject-by-formulation interaction. The data sets included herein were from replicate and non-replicate in vivo bioequivalence studies submitted to the FDA, which were re-analyzed by the Agency to detect this type of interaction. As noted, the results of the analysis suggest the presence of the subject-by-formulation in some of the studies. Included are two kinds of data sets depending on the study designs: 1) bioequivalence studies with replicate designs, and 2) gender studies with non-replicate designs.

I. Studies with Replicate Designs

Drug #

1: Antianxiety agent - IR*
2: Calcium channel blocker - ER**
3: Hormone - IR
4: Anti-depressant - IR
5: Anti-inflammatory - IR
7: Beta-adrenergic blocking agent - IR
8: Beta-adrenergic blocking agent - IR
13: Antihypertensive - Patch [A, B, C]
14: MAO inhibitor - IR [A, B, C, D]
15: Hormone - IR [A, B, C, D, E, F]
16: Hormone - IR [A, B, C, D, E, F]
17: Antihypertensive - Patch [A, B, C]

* IR: Immediate Release
**ER: Extended Release

These data were analyzed using the individual bioequivalence approach proposed in the preliminary draft guidance. Below are the highlights of the results.

A. The following data are considered to have large subject-by-formulation interaction

(s_D > 0.15):

AUC: Drugs # 3d, 3e, 3f, 8, 15a, 16c, 16e, 17a

Cmax: Drugs # 1, 3c, 8, 14a, 15a, 15b, 15c, 15d, 15e, 15f, 17a

B. The following data show that the test formulation has a higher intrasubject variability than the reference formulation (s_WT /s_WR ratio > 1.5)

AUC: Drugs # 15a, 15b, 15c, 15e

Cmax: Drugs # 15a, 15c, 15e, 15f, 16e, 16f

C. The following data show that the test formulation has a lower intrasubject variability than the reference formulation (s_WT /s_WR ratio < 0.667)

AUC: Drugs # 1, 5, 7

Cmax: Drugs # 1, 7, 14c, 14d

II. Gender Studies with Non-replicate Designs

These are bioequivalence studies with non-replicated treatment design conducted in both males and females. These data were analyzed by the average bioequivalence approach.

The table, "Details of Gender Studies," provides drug class, dosage form, and other details for the studies.

The figures show the ratios of the Test/Reference (T/R) means between males and females.

Note that a large difference in the T/R ratios between genders may be indicative of a gender-by-formulation interaction. Also, gender-by-formulation interaction is an aspect of subject-by-formulation interaction.

Figure 1-A Ratio of Test/Reference Means (AUC)

Figure 1-B Ratio of Test/Reference Means (AUC)

Figure 2-A Ratio of Test/Reference Means (Cmax)

Figure 2-B Ratio of Test/Reference Means (Cmax)

Bioquiv.zip: [163 KB] All the above bioequivalence study files have been compressed and zipped for your convenience. Save this file to your computer and decompress bioquiv.zip using PKZIP or similar utility.

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Date created: August 18, 2003; last updated: June 20, 2005