FDA: 2×2×4 design; RSABE + ABE + σwT/σwR [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2020-03-10 14:54 (1534 d 03:30 ago) – Posting: # 21233
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Hi Pharma_88,

❝ For NTI drugs, USFDA suggested to perform full replicate design despite of having low to moderate ISCV. My question is that is there any specific guidance is available from FDA behind this rationale?

All of the product-specific guidances contain a section ‘Explanation’. See also Yu et al.1

❝ Further, can we perform crossover studies for NTI by taking extra safety measurement in to the study?

You can. Whether that is necessary in healthy volunteers depends on the drug.

❝ Further, what is the BE limit for such drugs?

It depends on \(\small{s_{wR}}\) observed in the study, i.e., reference-scaling is applied. Furthermore – irrespective of passing the scaled limits – the study has to pass 80.00–125.00% as well and the upper confidence limit of \(\small{\sigma_{wT}/\sigma_{wR}}\) has to be ≤2.5.

❝ 2003 guidelines having information on NTI however draft 2014 doesn't have any info for NTI.

I think that you are mixing up ANDA with NDA/IND. Furthermore, any product-specific guidance overrules general ones.

❝ For Example, FDA suggested to perform BE for Sodium valporic acid as full replicate despite of having low ISCV.

Yep. Actually it is the other way ’round. NTIDs have (by definition) a steep dose-response curve. In order to get approved, the phase III studies must have ‘worked’ without serious safety/efficacy problems. That’s only possible if the CV is low to moderate.

❝ However, available PAR reports having crossover design.

PAR is a European term and the classification of particular drugs might differ and also depend on the indication. The EMA requires for NTIDs ABE (2×2×2 is sufficient) with narrower limits of 90.00–111.11%. In all studies I’m aware of, valpoic acid was not classified as an NTID.

In some cases narrower limits are only required for AUC but not for Cmax:

  1. Yu LX, Jiang W, Zhang X, Lionberger R, Makhlouf F, Schuirmann DJ, Muldowney L, Chen M-L, Davit B, Conner D, Woodcock J. Novel Bioequivalence Approach for Narrow Therapeutic Index Drugs. Clin Pharmacol Ther. 2015; 97(3): 286–91. doi:10.1002/cpt.28.
  2. Tóthfalusi L, Endrényi L. Approvable generic carbamazepine formulations may not be bioequivalent in target patient populations. Int J Clin Pharmacol Ther. 2013; 51(5): 525–8. doi:10.5414/CP201845.

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