(6189 d 01:41 ago)
Posting: # 324
since at the Regulatory Workshop on BE/Dissolution in Budapest there was a debate concerning the appropriate size of a pilot study (some participants advocated still a sample size of 6 subjects), I prepared a little example.
You may use the data to 'play around' in your own piece of software. Although raw data are given, all calculations were obtained after log-transformation (multiplicative model).
Let's start with a balanced 2×2 cross-over in 24 subjects (the main study) and extract 4 subsets of size 6 and 2 subsets of size 12 (the artificial pilot studies). The CV was 20%, which is quite common in BE. Please note that such a procedure is for illustrative purpose only.
In the following some results are presented;
Bioequivalence was demonstrated in the main study (N: 24), but we may also notice two points:
Now what can we learn from the examples?
Or have a look at
Both subsets of size 12 lead to more consistent results. If you have stated such a procedure in your protocol, even BE may be claimed in both subsets, and no further study is necessary. If you want to use the upper CL in sample size estimation, you also get more consistant values.
If you have some hints of high intra-subject variability (>30%), I would recommend a pilot study size of at least 16 subjects.
Small sample sizes (let's say <12) are useful in checking the sampling schedule and the appropriateness of the analytical method, but are not reasonable for the purpose of sample size planning. Q.E.D.
Some regulators tend to have a biased perspective, because they see only examples working with n=6. Unfortunately luck is not a statistical category.
On the other hand I have seen many failed studies following small pilots; at least the failed study was large enough to get a better estimate for a repeated study
According to the implemented European GCP-directive I have seen IECs rejecting approval of small pilot studies 'because the size of the study is too limited to get a reliable estimate of variability'.
I know one of the generic 'global players' setting the internal rule to a minimum size of 16.
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
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