Sukalpa Biswas ☆ India, 20190806 09:15 (edited by Sukalpa Biswas on 20190807 09:07) Posting: # 20475 Views: 632 

This is regarding NTI drug Bio equivalence study Statistical approach. As per regulatory,
All the above criteria has been met except 90% confidence interval for the testtoreference ratio of the withinsubject variability ≤ 2.5 were not meet the criteria for all PK variables (Cmax, AUCt and inf). Exercises, Observations and Analysis:
Kindly respond. Edit: Please follow the Forum’s Policy. Category changed; see also this post #1. [Helmut] 
Helmut ★★★ Vienna, Austria, 20190807 11:09 @ Sukalpa Biswas Posting: # 20482 Views: 522 

Hi Sukalpa, » 3. The withinsubject standard deviation of test and reference products will be compared, and the upper limit of the 90% confidence interval for the testtoreference ratio of the withinsubject variability should be ≤ 2.5. » […] 90% confidence interval for the testtoreference ratio of the withinsubject variability ≤ 2.5 were not meet the criteria for all PK variables (Cmax, AUCt and inf). Failed to demonstrate BE due to the higher withinsubject 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 cherrypick? » 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 cherrypicking 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 (ν_{1}, ν_{1}), 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 testtoreference ratio of the withinsubject variability ≤ 2.5 will meet the criteria. Of course. » 1. Which Reference Scaled Average Bioequivalence approach is acceptable in regulatory? 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 productrelated. The idea behind the FDA’s referencescaling 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 biostudy 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 productrelated. If you introduce clinical restrictions* in order to reduce withinsubject 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 yesterday and you to today. Wrong. Don’t test my patience – your problems are definitely studyspecific (see the Policy for a description of categories).
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Sukalpa Biswas ☆ India, 20190809 06:11 @ Helmut Posting: # 20488 Views: 441 

» Failed to demonstrate BE due to the higher withinsubject 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 s_{WR} is given in Step 1 of the guidance by analogy the same procedure should be applicable for s_{WT}. 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? » 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. Thanks for your suggestion. » » 2. which are the factors adding variability to SWT? » That’s productrelated. The idea behind the FDA’s referencescaling 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 productrelated. If you introduce clinical restrictions* in order to reduce withinsubject 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. 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. »
Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut] 
Helmut ★★★ Vienna, Austria, 20190809 12:36 @ Sukalpa Biswas Posting: # 20489 Views: 405 

Hi Sukalpa, » » 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? That’s quite possible. An extreme example of the past: The first PPIs were monolithic gastricresistant formulations. Crazy variability, both fasting and fed. Current formulations are capsules with gastricresistant pellets. Variability still high but way better than the monolithic forms. Of course, when the capsules were introduced, BE studies were performed. All PK metrics passed but by inspecting the profiles you could clearly see the lower variability of the capsules. OK, these are easy drugs (now many are already OTCs). Imagine that they would be NTIDs and the formulation change the other way ‘round (capsule → monolithic). No way ever to pass the s_{wT}/s_{wR} criterion. In your case this means again to reformulate. Don’t ask me how (I’m not a formulation chemist). Maybe dissolution testing in the various stinking FeSSIF “biorelevant” media helps. » This is the first time I am posting something in this forum. Bit confused regarding the rules and regulation of this forum. Some hints in the Policy. — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 