Bioequivalence and Bioavailability Forum

Hi Sukalpa,

❝

3. The within-subject standard deviation of test and reference products will be compared, and the upper limit of the 90% confidence interval for the test-to-reference ratio of the within-subject variability should be ≤ 2.5.

❝ […] 90% confidence interval for the test-to-reference ratio of the within-subject variability ≤ 2.5 were not meet the criteria for all PK variables (Cmax, AUCt and inf).

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

❝ Exercises, Observations and Analysis:

What do you mean by „Exercises”? Since the study failed are you asking for a recipe to cherry-pick? 

❝

1. We have taken subjects who have completed at least 2R or 2T in Reference Scaled Average Bio equivalence calculation (existing study).

That’s my interpretation as well. Although only the calculation of s_WR is given in Step 1 of the guidance by analogy the same procedure should be applicable for s_WT.

❝

2. We have done the exercise who have completed all four treatments and did the statistical calculation- still failing on the same criteria marginally.

Leaving cherry-picking aside: By doing so, you drop available information. One should always use all. The more data you have, the more accurate/precise an estimate will be. Have a look at the formula to calculate the 100(1–α) CI of σ_WT/σ_WR:$$\left(\frac{s_{WT} / s_{WR}}{\sqrt[]{F_{\alpha /2,\nu_1,\nu_2}}},\frac{s_{WT} / s_{WR}}{\sqrt[]{F_{1-\alpha /2,\nu_1,\nu_2}}} \right)$$We have two different degrees of freedom (ν₁, ν₁), the first associated with s_WT and the second with s_WR.

❝

3. It was observed that if the “SWT” value should be closed to SWR value or lower, then 90% CI for the test-to-reference ratio of the within-subject variability ≤ 2.5 will meet the criteria.

Of course.

❝

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.
BTW, how would you describe that in the SAP?

❝

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.

❝

3. Whether same formulation can be taken for the repeat bio-study with some clinical restrictions? If yes then what are the clinical factor to be considered?

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 s_WT/s_WR be essentially the same like in the failed study.
Reformulate.

PS: I changed the category of your post to Study Assessment yesterday and you to RSABE / ABEL today. Wrong. Don’t test my patience – your problems are definitely study-specific (see the Policy for a description of categories).

---

• Which ones are you thinking about? 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.