Sukalpa Biswas ☆ India, 20200526 12:47 (806 d 03:02 ago) Posting: # 21468 Views: 1,459 

For NTI product for USFDA, we follow product specific guidance where 4WC study is mandatory with statistical criteria discussed below, Un scaled Average Bioequivalence approach • Primary pharmacokinetic parameter(s) for the 90% confidence interval of the geometric least square means must fall within 80.00% to 125.00% (both inclusive). Reference Scaled Average Bioequivalence • SWR will be determined for Primary pharmacokinetic parameter(s) of Cmax, AUC0t and AUC0∞. The following criteria will be estimated for Primary pharmacokinetic parameter(s): • The 95% upper confidence bound for (μTμR)2θ*S2WR must be ≤ 0 Where μT and μRare mean of test and reference formulations on lntransformed scale, respectively, and θ = (In (1.11111)/ (σW0)2 (Scaled average BE limit); where σW0 = 0.10 (regulatory limit). • The point estimate of the Test/Reference geometric mean ratio must fall within [0.80, 1.25] 90% CI for the ratio of the within subject SD of Test product to Reference product σWT/σWR • 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. For NTI product of ANVISA studies, 1. if 95% CI need to be ensured within 80125, then can we prefer doing 2WCstudies(ISCV<30%)? 2. If ISCV>30%, can we go for full replicate/partial replicate design? If yes then what will be the statistical approach? 3. Is it necessary to get the statistical approach approved from ANVISA regulatory prior initiation of the study. Edit: Please follow the Forum’s Policy. [Helmut] 
Helmut ★★★ Vienna, Austria, 20200526 13:39 (806 d 02:10 ago) @ Sukalpa Biswas Posting: # 21470 Views: 1,076 

Hi Sukalpa, » For NTI product of ANVISA studies, » 1. if 95% CI need to be ensured within 80125, then can we prefer doing 2WCstudies(ISCV<30%)? Calculating a 95% CI (instead of the common 90% CI) was dropped a while ago and for good reasons. It does not decrease the patient’s risk. That was a misconception by the ANVISA. Only a narrower acceptance range (EMA and most other agencies) or reference scaling acc. to the method of the FDA does. See the draft of 27 Dec 2019 (in Portuguese). Inofficial Translation: Chapter VI, Section V, Narrow therapeutic index drugs (NTID) » 2. If ISCV>30%, can we go for full replicate/partial replicate design? If yes then what will be the statistical approach? It is extremely unlikely that an NTID shows high variability. The only ones I know are dagibatran and rivaroxaban. Whether you opt for a 2×2×2 or a replicate design, up to you. The evaluation has to be done for ABE. If you expect AEs in healthy volunteers and a high dropout rate, I would avoid a replicate design. » 3. Is it necessary to get the statistical approach approved from ANVISA regulatory prior initiation of the study. The protocol has to be approved by the ANVISA anyway. It is up to you to give a clinical justification for the limits (C_{max}, AUC, both). Examples from the EMA’s productspecific guidances:
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