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Back to the forum  Query: 2018-04-25 02:57 CEST (UTC+2h)
 
sudy
Junior

India,
2018-03-28 07:09

Posting: # 18598
Views: 748
 

 FDA-Subject by formulation interaction (Switchability) [Regulatives / Guidelines]

Dear all,

I have a discussion point regarding switchability criteria for methylphenidate 54mg tabs (specially). For lower strength, they have removed this criterion.

As per guideline, we have to meet the ABE criteria and additionally meet 95% UB for switchability.

Now, as we are doing a fully replicate study as suggested by OGD recommendation on methylphenidate, can we use RSABE approach in case if we get ISCV-reference > 30% for any one of the PK parameter Cmax or partial AUCs, instead of using 90% CI calculation to prove the bioequivalence?

The OGD recommendation did not discuss anything about this case, as we know that methylphenidate is not a HVD. But incase if we got CV-R more than 30%, can we apply RSABE?

Your suggestion will be highly appreciated.

Regards,
Sudy
Helmut
Hero
Homepage
Vienna, Austria,
2018-03-28 11:25

@ sudy
Posting: # 18599
Views: 636
 

 Risking Refuse-to-Receive

Hi sudy,

» […] can we use RSABE approach in case if we get ISCV-reference > 30% for any one of the PK parameter Cmax or partial AUCs, instead of using 90% CI calculation to prove the bioequivalence?

The guidance clearly states:

The 90% confidence intervals of the geometric mean test/reference (T/R) ratios for the above five Cmax and AUC metrics (Cmax, AUC0-T1, AUCT1-T2, AUCT2-T3, AUC0-∞) should fall within the limits of 80-125%.


Without a controlled correspondence you will risk an RTR because according to
  • B. Alternate BE Studies:
    • FDA will RTR an ANDA if the ANDA contains one or more in vivo studies that were not recommended in the BE guidance, without adequate justification. Adequate justification should include justification for an approach that deviates from FDA posted guidance, including data (Module 2.7 and Module 5) and appropriate references.

» The OGD recommendation did not discuss anything about this case, as we know that methylphenidate is not a HVD.

In my experience you will get the highest CV in the first partial AUC of the fasting study. I never saw a high CV of Cmax… A CVwR >30% of AUC0-3 is extremely unlikely.

@John: Other experiences?

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Helmut Schütz 
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sudy
Junior

India,
2018-03-28 12:13

@ Helmut
Posting: # 18600
Views: 626
 

 Risking Refuse-to-Receive

Dear Helmut,

Thanks for your reply.

Regards,
sudy
jag009
Hero

NJ,
2018-03-28 21:35

@ Helmut
Posting: # 18608
Views: 551
 

 Risking Refuse-to-Receive

Hi Helmut!

» In my experience you will get the highest CV in the first partial AUC of the fasting study. I never saw a high CV of Cmax… A CVwR >30% of AUC0-3 is extremely unlikely.
»
» @John: Other experiences?

Yes the culprit is the first partial AUC. However, if the coating on your delayed release bead is acting funny then it's possible for you to see high CV on the 1st and 2nd partial AUCs...

John
jag009
Hero

NJ,
2018-03-28 21:33

@ sudy
Posting: # 18607
Views: 549
 

 FDA-Subject by formulation interaction (Switchability)

» Now, as we are doing a fully replicate study as suggested by OGD recommendation on methyl­phenidate, can we use RSABE approach in case if we get ISCV-reference > 30% for any one of the PK parameter Cmax or partial AUCs, instead of using 90% CI calculation to prove the bio­equivalence?

Yes. Reason is that it is possible for one of those PK parameters to show ISCV > 30%.
As an added bonus, even if a BE guidance states that crossover studies are required but you have data to support that the drug of interest is HVD (ISCV>30%, provided that the high ISCV is not because your formulation is crap) then you can run the studies as replicates. I have done 2 projects in the past already.

P.S. You woke me up from my hibernation Helmut... :-)

John
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