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Dear all,
In general the replicated designs are used for highly variable drugs
(CVI higher than 30%, for instance). One of the proposed approaches is
to use the Balaam design (4 sequences, 2 periods).
In which cases is it intended to use the Balaam design (4 sequences, 2
periods) for replicated BE studies? What are the pros and cons
comparing to the traditional design (4 periods, 2 sequences)?
Thank you in advance,
Rafael E. Barrientos Astigarraga
MAGABI Pesq. Clin. Farm. Ltda.
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Dear Rafael,
Your question is really interesting. A disadvantage of Balams Design
is the high sample size. Therefore I would't recommend Balams design.
For sample size see "A Note on Sample Size for Bioequivlaence Studies
with Higher-Order Cross-Over Designs" from Keh-Wei Chen, Shein-Chung
Chow and Gang Li. Pros? I don't know.
Ellen Schremmer
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The following message was posted to: PharmPK
Dear Rafael!
Cons:
FDA's guidance states: "For the majority of drug products, two-period
replicated crossover designs such as the Balaam design (which uses the
sequences TR, RT, TT, and RR) should be avoided...".
Balaam's design is less powerful than the 4x2 replicated design; see:
K.-W. Chen, S.-C. Chow and G. Li
A Note on Sample Size Determination for Bioequivalence Studies with
Higher-order Crossover Designs
J. Pharmacokinetics and Biopharmaceutics 25/6, 753-765 (1997)
Sample sizes for delta -5% (GMR 95%), power 80%
- for the conventional 2x2 design are: 8 (10% CV), 20 (20%), and 40
(30%),
- for a 4x2 replicate: 4 (10% CV), 10 (20%), and 20 (30%),
- whereas for Balaam's design: 20 (CV 10%), 72 (20%), and 156 (30%).
Pros: ?
Helmut
- Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
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Hello:
I have written a paper on pros and cons of replicate design studies,
pros and cons. You may find that paper informative. Four period, two
sequence, two period design is recommended. It is published in
American Journal of Clinical Pharmacology (2009). Sorry I do not
remember the exact citation.
Aziz Karim
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The following message was posted to: PharmPK
Dear all,
FDA states that "For the majority of drug products, two-period
replicated crossover designs such as the Balaam design (which uses the
sequences TR, RT, TT, and RR) should be avoided for individual BE
because subjects in the TT or RR sequence do not provide any information
on subject-by-formulation interaction.
However, the Balaam design may be useful for particular drug products
(e.g., a long half-life drug for which a two-period study would be
feasible but a three- or more period study would not).
You can look into the below article which describes the pros and cons of
Replicate design.
Aziz Karim, PhD, ABCP, FCP, Zhen Zhao, MS, Margaret Slater, Dawn
Bradford, MPH, Jennifer Schuster, BS and Aziz Laurent, MD. Replicate
Study Design in Bioequivalency Assessment, Pros and Cons. J Clin
Pharmacol. 2007 Jul;47(7):806-16. Epub 2007 Apr 26.
You can access this article in the following weblink.
http://www.ncbi.nlm.nih.gov/pubmed/17463215?dopt=Abstract
Regards,
Dr.S.Gunasakaran, MBBS, MD
Medical Affairs
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The following message was posted to: PharmPK
Hi Forum.
There is a well-written chapter on the precision of crossover designs
on the Pennsylvania State University website. See;
http://www.stat.psu.edu/online/courses/stat509/15_cross/08_cross_precision.htm
It gives an example of the group sizes required when inter-patient
variance is 4 times that of within-patient variance, which is not
unusual. Using standard power assumptions the group sizes are
calculated to be: 190 for the parallel, 108 for the Balaam and only 21
for the crossover design.
That has such huge implications for cost and timelines that the
crossover is much the preferred design in Phases 1 and 2 at least.
Carryover and period effects are the obvious risk but they can be
assessed by techniques like ANOVA and allowed for. My impresssion
over 100 studies has been that carryover effects are almost always so
small that they do not consitute a real risk of misinterpreting the
outcome.
Andrew Sutton
[I think I got the url right - db]
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