Nathalie T
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Belgium,
2020-05-08 16:40
(138 d 10:31 ago)

(edited by Nathalie T on 2020-05-08 17:22)
Posting: # 21409
Views: 2,362
 

 BE XR OD vs IR BID - which Cmax for IR? [Regulatives / Guidelines]

Dear All,
I would like to have the help of the forum participants on a tricky question, ie which IR Cmax should be considered to assess the potential bioequivalence between an IR formulation administered BID and an XR formulation administered OD on day 1 and at steady-state. This is for a submission to FDA.
I double-checked the “Bioavailability Studies Submitted in NDAs or INDs — General Considerations Guidance for Industry” draft February 2019, and it is written (page 13)

C.1.a. A new ER formulation compared to an IR product that is already approved
For drugs with linear pharmacokinetics over the therapeutic dose range: A fasting study should be conducted comparing the ER product administered as a single dose at the highest strength to the IR reference administered over the least common time interval to achieve equivalent total dose as for the ER product.28 […]


28 For example, when a 150-milligram (mg) ER product administered once daily (QD) is being developed that gives an approved 50-mg IR reference product administered three times a day (TID) or a 75-mg product administered two times a day (BID), a comparison of the 150-mg ER product administered as a single dose could be compared to either the 50-mg IR reference product administered TID or 75-mg IR reference product administered BID.

In this case, the least common time interval is 24 hours.

Based on this, I think that the first day dosing interval should be considered as a whole and that on both day 1 and at SS, the highest Cmax over the least common dosing interval should be taken for the reference, whether it is the first or the second Cmax.
I would be very interested of having others opinion
Best regards
Nathalie T


Edit: Guidance linked. [Helmut]
Helmut
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Vienna, Austria,
2020-05-09 11:54
(137 d 15:17 ago)

@ Nathalie T
Posting: # 21410
Views: 1,665
 

 FDA ER vs. IR: Global Cmax

Hi Nathalie,

» […] which IR Cmax should be considered to assess the potential bioequivalence between an IR formulation administered BID and an XR formulation administered OD on day 1 and at steady-state. This is for a submission to FDA.
»
» 28 For example, when a 150-milligram (mg) ER product administered once daily (QD) is being developed that gives an approved 50-mg IR reference product administered three times a day (TID) or a 75-mg product administered two times a day (BID), a comparison of the 150-mg ER product administered as a single dose could be compared to either the 50-mg IR reference product administered TID or 75-mg IR reference product administered BID.
»
» In this case, the least common time interval is 24 hours.

Correct.

» Based on this, I think that the first day dosing interval should be considered as a whole…

Correct.

» …and that on both day 1 and at SS, the highest Cmax over the least common dosing interval should be taken for the reference, whether it is the first or the second Cmax.

SS correct. What do you mean by “day 1”? Do you want to sample full profiles in the multiple dose study both after the first dose and in steady state? That’s not required. The guidance recommends two studies: SD and MD. If you want to collapse the SD and MD studies into one, you may drain the subjects.

Even if the drug has a short half-live (i.e., little accumulation), for the IR formulation the Cmax after the last dose in the interval will likely* be the global Cmax anyhow. I performed studies like that (OAD XR vs. BID IR, European submission and for Health Canada). The t½ was <3 h, accumulation <1%. In all studies the second Cmax was the global one.
Another hint why the FDA requires the global Cmax only: For multiphasic products the FDA requires partial AUCs but only one Cmax (example). That’s different to the EMA, where additionally Cmax-values in each interval are required.


  • Exception: High intra-subject variability.

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Nathalie T
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Belgium,
2020-05-11 15:59
(135 d 11:12 ago)

@ Helmut
Posting: # 21419
Views: 1,588
 

 FDA ER vs. IR: Global Cmax for Day 1 too?

Hi Helmut,

Thank you for your very useful answer.

» What do you mean by “day 1”? Do you want to sample full profiles in the multiple dose study both after the first dose and in steady state? That’s not required. The guidance recommends two studies: SD and MD. If you want to collapse the SD and MD studies into one, you may drain the subjects.

Indeed we are combining SD and MD studies into one, and we are going to collect full profiles on both days, and given the bioanalytical method, the volume we take is OK for the subjects.

So I have the same question for the concentrations on day 1. The IR is administered BID to be in conformittee with the previous cited FDA guideline. In my opinion the least common interval needs to be considered as a whole, here 24h, and the highest Cmax over this day 1 interval should be taken as the reference for the IR. And this is specific to the FDA.

Do you agree with that?


Edit: Standard quotes restored; see also this post #8[Helmut]
Helmut
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2020-05-11 17:51
(135 d 09:20 ago)

@ Nathalie T
Posting: # 21421
Views: 1,560
 

 Global Cmax (MD and SD)

Hi Nathalie,

» Indeed we are combining SD and MD studies into one, and we are going to collect full profiles on both days, and given the bioanalytical method, the volume we take is OK for the subjects.

I see. Of course, scientifically this design is than better than two separate studies because you could assess whether you have linear PK (MD AUC0–τ ≈ SD AUC0–∞; evaluated as a paired design). However, only “nice to know”.

» So I have the same question for the concentrations on day 1. The IR is administered BID to be in conformittee with the previous cited FDA guideline. In my opinion the least common interval needs to be considered as a whole, here 24h, and the highest Cmax over this day 1 interval should be taken as the reference for the IR. And this is specific to the FDA.
»
» Do you agree with that?

Sure. BTW, that’s the same approach I used in my studies for the EMA.
One minor warning. Since the FDA in the NDA/IND guidance specifically recommends two studies, you risk a Refuse-to-Receive. Given, that’s for ANDAs but a controlled correspondence with the OGD will not hurt.

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jag009
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NJ,
2020-05-11 06:29
(135 d 20:42 ago)

@ Nathalie T
Posting: # 21417
Views: 1,616
 

 BE XR OD vs IR BID - which Cmax for IR?

» I would like to have the help of the forum participants on a tricky question, ie which IR Cmax should be considered to assess the potential bioequivalence between an IR formulation administered BID and an XR formulation administered OD on day 1 and at steady-state. This is for a submission to FDA.

Not sure if the following will answer your Q exactly and whether it still exists on FDA website (or they blacked out the results):
Look for Ultram ER at [email protected]
Similar approach (Don't ask how I know :))

J
Nathalie T
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Belgium,
2020-05-11 16:02
(135 d 11:09 ago)

@ jag009
Posting: # 21420
Views: 1,581
 

 BE XR OD vs IR BID - which Cmax for IR on day 1?

Hi Jag,

Thanks for the answer.

» Look for Ultram ER at [email protected]

I did have a look at it, and it seems to be in agreement for steady-state, but does not help for the first day of administration.

Any idea?
jag009
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NJ,
2020-05-12 21:16
(134 d 05:55 ago)

@ Nathalie T
Posting: # 21430
Views: 1,498
 

 BE XR OD vs IR BID - which Cmax for IR on day 1?

Hi

» I did have a look at it, and it seems to be in agreement for steady-state, but does not help for the first day of administration.

I don't recall but I did a single dose study there (sorry I didn't read your post fully. You mean a single-dose to steady state study (one study)?)

J
Nathalie T
☆    

Belgium,
2020-05-18 16:23
(128 d 10:48 ago)

@ jag009
Posting: # 21452
Views: 1,214
 

 BE XR OD vs IR BID - which Cmax for IR on day 1?

Hi,

» I don't recall but I did a single dose study there (sorry I didn't read your post fully. You mean a single-dose to steady state study (one study)?)

It is indeed SD + steady-state in one study, hence the question is for the Cmax on day 1 and the Cmax at steady-state.

Regards

Nathalie
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