Bioequivalence and Bioavailability Forum

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.

•  BE/BA—General Considerations. Rev.1, March 2003: ABE 80.00–125.00%, additional quality measures.
  
• BE ANDA Draft, December 2013: Nothing.
  
• BA/BE NDA/IND Draft, March 2014: Nothing.
  
• BA/BE NDA/IND Final, February 2019: Nothing.
• Some of the product-specific guidances: 2×2×4 design, method & conditions see above.
  • Warfarin Sodium Draft, December 2012
    
  • Tacrolimus, Draft July 2014
    
  • Phenytoin Sodium, Draft Rev.1, December 2014
    
  • Carbamazepine, Draft Rev.1, September 2015.
       Whether the recommended single dose study is most sensitive is debatable at least.²
    
  • Digoxin Draft Rev.1, August 2017
    
  • Valproic acid Final, August 2017
    
  • …

❝ 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 C_max:

• Tacrolimus: AUC 90.00–111.11%, C_max 80.00–125.00%
  
• Everolimus
  • Oncologic-only indication: AUC and C_max 80.00–125.00%
    
  • Transplant-only indication: AUC 90.00–111.11%, C_max 80.00–125.00%
• Sirolimus: AUC 90.00–111.11%, C_max 80.00–125.00%
  
• Colchicine: AUC 90.00–111.11%, C_max 80.00–125.00%

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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.