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Dear All,
What is the purpose of doing 4X4 BE studies?
Regards,
Dr.Sridhar
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Dear Sridhar
The 4 X 4 Bioequivalence studies come under "Replicate Crossover
Dosing" whereby the same reference and the same test are each given
twince to the same subject.
The purposes to carry out 4 X 4 Bioequivalence studies are to:
1. determine of individual bioequivalence
2. estimate within-subject variance for both the Test and Reference
drug products
3. provide an estimate of the variance for the subject-by-formulation
interaction
(Lenon Shargel et al in Applied Biopharmaceutics and Pharmacokinetics,
McGrea-Hill, New York, 2005. pp 473)
Another Source on the subject is
Bolton S and Bon C. Pharmaceutical Statistics - practical and clinical
applications., Marcel Dekker, INC. 2004, p 345 - 355.
++
Nadeem Irfan Bukhari
Lecturer Pharmaceutical Technology,
International Medical University,
Bukit Jalil 57000, Kuala Lumpur, Malaysia
Web: http://www.imu.edum.my
Tel: +60 3 8656 7228, Ext. 1186; Fax: 86567229
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Dear Sridhar,
According to my knowledge, 4x4 crossover BE study is done to compare
different test formulations with one reference.
That is, three test fornulations with one reference.
regards,
Srinivasa Reddy,
Research Analyst.
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Dear Dr. Sridhar,
Replicate study designs (test and reference formulations are each
administered twice) offers several scientific advantages such as:
1) It allow comparisons of within-subject variances for the test and
reference products
2) It provide more information about the intrinsic factors underlying
formulation performance
3) It reduces the number of subjects participating in the BE study.
Hope this helps
Regards,
Vikesh S
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Hi
4x4 Bioequivalenec study refers to a crossover study between 1
reference
and 3 tests and not a replicate design(as discussed by many). You can
compare many tests with one reference in one study instead of conducting
many two way studies. The comparison should be only between the test and
reference. This is different from a replicate design wherein two
formulations are treated as the same treatment.
Replicate design offers many advantages and reduces
variability to
a great extent which a 4x4 design cannot. A 4x4 design is a more
complex one
as there are more number of interactions which one has to take care of
during analysis.
Regards
Sulagna
Biostatistician
Veeda Clinical Research
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Dear sridjar,
Replicate designs are typically four period designs. Each product
administered twice.
regards,
Srinivasa Reddy,
Research analyst
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A replicate design BE study is one in which the test and reference
compounds are each given on two occasions. This is a 4x2 design, which
means 4 periods and 2 treatments. The usual sequences for this (which
can be found in the January 2001 FDA Guidance Statistical Approaches to
Establishing Bioequivalence) are: TRTR and RTRT
A 4x4 crossover design implies 4 periods and 4 treatments. This is
usually done as a Latin square one example of which could be:
ABCD
BCDA
CDAB
DABC
Where typically there are 3 tests and 1 reference, that is A=T1, B=T2,
C=T3 and D=R (for example). Often these are used for BA approach rather
than BE. In this case you might see an IV, Oral solution, and two
different tablet formulations, for example.
Mike Davenport
Dir Biometrics Clin Pharm
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Dear All,
For crossovers with more than 2 formulations, a better alternative to a
classical Latin square is a Williams design, i.e. a Latin square
balanced for eventual first-order carry-over effects.
An example of Williams design for a 4x4 crossover would be
ADBC/BACD/CBDA/DCAB.
With this kind of design, each treatment is preceeded once by each the
three other treatments or is given as the first treatment of the study.
In the classical Latin square design (ABCD/BCDA/CDAB/DABC), each
treatment (when not the first occurrence) is always preceeded by the
same treatment (B by A, C by B, and D by C), which can bias the
estimates in presence of differential 1st-order carry-over.
Further discussion about Williams designs and their analysis can be
found in sections 2.5.5 and 10.3 in:
Chow SC and Liu JP (1992).
Design and Analysis of Bioavailability and Bioequivalence Studies.
Marcel Dekker Inc. New York, NY.
Fabrice Nollevaux,
SGS Life Science Services,
Pharmacokinetic Analysis and Outcomes Research Manager
www.sgs.com/clinicalresearch
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