## digging out the possible reasons of the failure [Study As­sess­ment]

❝ Failed to demonstrate BE due to the higher within-subject variability of the test product. Full stop.

Accepted.

❝ ❝ Exercises, Observations and Analysis:

❝ What do you mean by „Exercises”?

Since the study has been failed, we wanted to dig out the probable reasons for the study failure. In that process certain statistical exercises have be done officially.

❝ Although only the calculation of sWR is given in Step 1 of the guidance by analogy the same procedure should be applicable for sWT.

Accepted. Thanks.

❝ […] you drop available information. One should always use all. […]

Suggestion well accepted. Thanks.

❝ ❝

1. Which Reference Scaled Average Bioequivalence approach is acceptable in regulatory?

❝ ❝ Approach 1: Subject completed at least two test product will consider for SWT calculation and subject who completed at least two reference will consider for SWR calculation.

❝ Yes.

❝ ❝

Approach 2: Subjects who completed four period will be consider for SWR & SWT calculation.

❝ No.

❝ ❝

or both.

❝ Which one will you pick at the end if one passes and the other one fails? The passing one, right? The FDA will love that. Be aware that the FDA recalculates every study.

❝ ❝

2. which are the factors adding variability to SWT?

❝ That’s product-related. The idea behind the FDA’s reference-scaling for NTIDs is not only the narrow the limits but also to prevent products with higher variability than the reference’s entering the market.

Agreed

❝ As I wrote above, the failure to show BE was product-related. If you introduce clinical restrictions* in order to reduce within-subject variability – due to randomization – both products will be affected in the same way and sWT/sWR be essentially the same like in the failed study.

❝ Reformulate.

OK. I would like to mention one thing that, the failed study was fed one, fasting study passed quite comfortably (both ABE and SABE). Is there any possibility that the test formulation is more variable in fed condition?

❝ PS: I changed the category of your post […].

Sorry. This is the first time I am posting something in this forum. Bit confused regarding the rules and regulation of this forum.

• I don’t see how it could be possible to reduce within-subject variability by any means. Given, chaining volunteers to their beds might help.