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Hi all,
Is it possible to conduct replicate design in two periods for a
bioequivalence study and will drug regulatory accept this kind of
replicate study for highly variable drug product?
Narasimha
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Dear Narasimha
first of all what do you mean by replicate 2 periods
replicates means
half replicate as RRT, TTR
full replicates as RTRT, with its different sequences (RTTR,
TRTR,TRRT...)
so replicate may be 3 or 4 periods with different sequences
for HVD you have 2 approaches
1- increasing the sample size according to the intra subject CV% if >
30% (depending on published or pilot study) you probably need 50 subject
or more
2- if you did half replicate or full and after calculating the
intrasubject CV > 30 % you can use
Reference-Scaled Average Bioequivalence to widen the BE limits
i hope this can clarify the issue
thx
Ahmed Eshafeey, Ph.D
Associate Professor
Pharmaceutics Department
College of Pharmacy
Cairo University, Egypt.
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dear narsimha
You can explore BALAM design for BE study for two period with replicates.
Sequences will be RT. TR RR TT.but for this design you need large sample
size.
Ashwani
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Dear Narasimha
first of all what do you mean by replicate 2 periods
replicates means
half replicate as RRT, TTR
full replicates as RTRT, with its different sequences (RTTR,
TRTR,TRRT...)
so replicate may be 3 or 4 periods with different sequences
for HVD you have 2 approaches
1- increasing the sample size according to the intra subject CV% if >
30% (depending on published or pilot study) you probably need 50 subject
or more
2- if you did half replicate or full and after calculating the
intrasubject CV > 30 % you can use
Reference-Scaled Average Bioequivalence to widen the BE limits
i hope this can clarify the issue
thx
Ahmed Eshafeey, Ph.D
Associate Professor
Pharmaceutics Department
College of Pharmacy
Cairo University, Egypt.
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The following message was posted to: PharmPK
Dear Narasimha,
first I agree with what Ashwani wrote about Balaam's design.
It would be nice to know -why- you want to perform a replicate design.
Are you just interested in the performance of formulations (compare
intra-subject variances) or do you want to go with reference-scaling?
In the latter case note that FDA and EMA require two different
statistical models. EMA states in the IR guideline that you may use
either a three-period or a four-period design. Balaam's design is not
mentioned. I assume the same for the FDA since they published only code
for the partial replicate and a fully replicated design in the
progesterone guidance.
To give you an idea about sample sizes (T/R 0.95, CV 40%, 80% power):
unscaled (conventional) BE
2x2x2: 66
2x3x3 (partial replicate): 50
2x2x4 (fully replicated): 34
Balaam's design: 260 (!!)
RSABE (FDA)
2x3x3 (partial replicate): 24
2x2x4 (fully replicated): 18
According to rumors FDA wants a minimum sample size of 24 in replicate
designs...
scABEL (EMA)
2x3x3 (partial replicate): 30
2x2x4 (fully replicated): 20
I would consider Balaam's design simply unethical since you can get the
same information from other designs in much (much!) lower sample sizes.
If you are interested in some background see this recent thread:
http://forum.bebac.at/mix_entry.php?id=10178
All the best,
Helmut
-
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.at.bebac.at
web http://bebac.at/
forum http://forum.bebac.at/
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