Legislation
Resolution

Resolution - RE nº 484, of March 19, 2002
(Official Journal of 20/03/2002)

The Director of the Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in him under Administrative Rule 724, issued by the Director-Chairman, on October 10, 2000,

WHEREAS

paragraph 3 of article 111, of the Bylaws approved by Administrative Rule 593, of August 25, 2000, re-published in the Official Journal of the Union of December 22, 2000;

that the matter was submitted to the examination of the Collegiate Board of Directors, which approved the matter in a meeting held on March 13, 2002, decides:

Article 1 - To determine the publication of the "Guide for Designs Applicable to Bioequivalence Studies", attached.

Article 2 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

GUIDE FOR DESIGNS APPLICABLE TO BIOEQUIVALENCE STUDIES - 1/2002

1. INTRODUCTION
This guide describes the planning designs commonly used in bioequivalence studies.

2. TYPES
2.1. Crossed designs employing two drug products (T = test; R = reference);
For these designs, the interval between periods (washout) must be sufficient to ensure that there is no residual effect of the drug administered in the previous period.
2.1.1. 2X2 crossed design
This is a conventional non-replicated design with two drug products, two periods and two sequences, which may be represented as follows:

2.1.2. Replicated crossed design
For these designs, the same batches of the test drugs and reference drugs must be used for replicated administration.
The conventional 2X2 crossed design is not useful in the presence of residual effects of the drugs, as it does not produce independent estimates of intra-individual variabilities.
In order to overcome this disadvantage, in practice, it is useful to use a replicated crossed design. In this case the designs most commonly employed for comparing two drug products are:
a) Design with four sequences and two periods (Bataam design), represented as:

b) Design with two sequences and four periods, represented as follows:

c) Design with four sequences and four periods, represented as follows:

d) Design with two sequences and three periods, represented as follows:

or

A higher number of subjects is recommended for the three period design, compared to the four period design, in order to reach the same statistical power for the bioequivalence.

2.2. Crossed design employing three drug products. This is the Williams design, using T1 = test1; T2 = test2; R = reference, represented as follows:

This design must be balanced, that is:
a) each drug product is applied only once for each subject;
b) in each period, the number of subjects receiving each drug product must be the same;

2.3. Crossed design for four drug products:
This is the Williams design, using T1 = test1; T2 = test2; T3 =test3; R = reference, represented as follows:

This design must be balanced.