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Dear Colleagues,
I came across a cross-over bioequivalence study (2 products, 2 periods, 2 sequences) where, due to
the large number of drop-offs, a second group of subjects was added (essentially the study was
repeated about one month later with a smaller group of volunteers). The pK data from the 2 groups
were statistically analyzed for bioequivalence together (as if we had only one group). Is it
correct? Thank you.
Sincerely,
Konstantinos Avgoustakis, PhD
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Dear Konstantinos,
replacement of drop-outs after completion of an initial part of a study is often done and depends on
the respective definition in the study protocol. The overall sample size must not be increased by
the replacement, and of course the results of those individuals who initially completed the study
must not be known when the drop-outs are replaced.
If for unexpectedly high variability the sponsor wants to increase the sample size, a two-stage
design for bioequivalence studies may be acceptable for some of the regulatory agencies including
the EMA if:
- this is defined a priori in the study protocol
- appropriate measures are taken to maintain overall alpha
(see EMA BE guideline for details)
Best regards,
Uwe
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Dear Konstantinos,
What was the main reason of drop-outs? side effects? statistical outliers?
If these are side-effects, are they related mostly to one of the products?
If this is true, subject-by-formulation interaction should be excluded.
If a new group was dosed, it means new period(s) was(were) added. The data cannot be just combined.
This new design should be treated differently by the ANOVA. Please consider a statistician.
Best regards,
Zeev
Zeev Elkoshi, PhD, Senior Director, Biopharmaceutics, Global R & D
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1) prove that the two group are the same then collapse the groups into one
2) drive the proof by founded SOP
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