Add-on Studies in RSA [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2006-07-27 14:53 (6159 d 20:08 ago) – Posting: # 190
Views: 8,987

Dear Ahmed!

❝ Only South Africa and Japan authorities approve such a study.

...and Canada since 1991 ;-)

❝ Acc SA [...] is not clear is whether we should do the clinical part for the entire study at first (eg for all the 24) and do the analytical part for the 12 only and to perfom the study on other 12 only if the study fails.

IMHO it does not make sense to perform the clinical part of the maximum intended sample size first, because (staying with your example):
  1. evaluating part I, you calculate a necessary total sample size of 30.
  2. evaluating part I, you calculate a necessary total sample size of 16.
In case one, you have to stop the study (because you will not be able to demonstrate BE with n=24).
In case two, although you will be able to demonstrate BE, but like in case one, you unnecessarily have administered drugs to healthy subjects, which is considered unethical.

❝ If any body knows please clear.

A recent document (67kB zipped M$-Word)--for comment until 14 Aug 2006--is more precise:

3.2.1 Number of Subjects
[…] The provision for add-ons should be made in the protocol a priori clearly reflecting the maximum number of subjects to be included.
3.2.2 Drop-outs and withdrawals
[…] If the bioequivalence study was performed with the appropriate size but bioequivalence cannot be demonstrated because of a result of a larger than expected random variation or a relative difference, an add-on subject study can be performed using not less than half the number of subjects in the initial study. Combining is acceptable only in the case when the same protocol was used and preparations from the same batches were used.
Add-on designs must be carried out strictly according to the study protocol and SOPs, and must be given appropriate statistical treatment, including consideration of consumer risk.

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