Pharma_88
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China,
2020-03-10 06:39

Posting: # 21232
Views: 3,118
 

 NTI drugs and Full Replicate [Design Issues]

Dear All,

Greetings!!

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? Further, can we perform crossover studies for NTI by taking extra safety measurement in to the study? Further, what is the BE limit for such drugs? 2003 guidelines having information on NTI however draft 2014 doesn't have any info for NTI.

For Example, FDA suggested to perform BE for Sodium valporic acid as full replicate despite of having low ISCV. However, available PAR reports having crossover design.

Thanks,
Pharma_88
Helmut
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Vienna, Austria,
2020-03-10 13:54

@ Pharma_88
Posting: # 21233
Views: 1,131
 

 FDA: 2×2×4 design; RSABE + ABE + σwT/σwR

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


  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.

Cheers,
Helmut Schütz
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Pharma_88
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China,
2020-03-13 09:14

@ Helmut
Posting: # 21262
Views: 1,030
 

 FDA: 2×2×4 design; RSABE + ABE + σwT/σwR

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

OK

» » 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.

Yes.

» » 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.

its common for all NTI or its varies from drug to drug?


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
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Vienna, Austria,
2020-03-13 10:35

@ Pharma_88
Posting: # 21265
Views: 1,013
 

 FDA: NTID and “HVNTID”

Hi Pharma_88,

» » » 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.
»
» its common for all NTI or its varies from drug to drug?

The former. Check the guidances I linked above. Maybe there are more, do your homework.

There are exceptions: “Highly variable narrrow therapeutic index drugs”. AFAIK:2×2×4 design, conventional ABE with 80.00–125.00%, upper CL of \(\small{\sigma_{wT}/\sigma_{wR}}\) ≤2.5.
Certain inclusion criteria to decrease risk of bleeding (prothrombin time and activated partial thromboplastin time within their normal ranges, creatinine clearance ≤50 mL/min).

Cheers,
Helmut Schütz
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