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Back to the forum  Query: 2017-10-19 00:18 CEST (UTC+2h)
 
nobody
Senior

2016-10-20 10:00

Posting: # 16738
Views: 2,853
 

 Type I error inflation caused by batch-to-batch variability of Reference? [Design Issues]

Good morning everybody out there!

I'm a little slow this morning, not enough caffeine I guess, maybe someone can enlighten me:

Sandoz wants more strict BE requirements for generics to Advair Diskus 100/50 (they have tried to get marketing authorization, but apparently did not succeed yet)

http://freepdfhosting.com/56dc6751dc.pdf

on page two states:

"1) Type I error rate is adequately controlled in PK bioequivalence testing, including accounting for Type I error rate inflation caused by batch-to-batch variability of the RLD"

Hmm. Type I inflation due to high variability of Reference? Do they mean that you "by chance" ( :-D ) pick the "right" batch to show equivalence and get away with it?

They published this here on batch-to-batch variability of Reference:

https://www.ncbi.nlm.nih.gov/pubmed/27037630

...which shows substantial variability from batch to batch.

Do I get it right?

Kindest regards, nobody
Dr_Dan
Senior

2016-10-20 12:06

@ nobody
Posting: # 16739
Views: 2,494
 

 Type I error inflation caused by batch-to-batch variability of Reference?

Hi
If a RLD shows such a high in-vivo batch-to-batch variability, why should this be the problem of the generic industry?

From a regulatory point of view I would say that a batch-to-batch variability which leads to bio-in-equivalence of batches of the same product is a serious risk to public health and the product should not be approvable (how can you transfer the safety and efficacy results gained with clinical batches to marketed batches/product?). IMHO the originator should be obliged to change the product specification and demonstrate bioequivalence within his formulation.

However, if such a RLD is notwithstanding approvable then high batch-to-batch variability should not matter, right? Otherwise the logic consequence would be
alternative 1: that generics need to show bioequivalence to each originator batch, or
alternative 2: do not need to show bioequivalence at all.

In the 2015 Meeting Report entitled “Pharmacokinetics of Orally Inhaled Drug Products” a recommendation seemingly attributed to an FDA speaker states “To include batch-to-batch and intra-subject variability of the reference product, the comparison of one batch of the test product with two batches of the R product, with one R batch being repeated, was suggested.”

hmmm, if the two R products are not bioequivalent, what would be the advantage of such a design?

I guess this will lead to interesting discussions....

Kind regards and have a nice day
Dr_Dan
nobody
Senior

2016-10-20 12:14

@ Dr_Dan
Posting: # 16740
Views: 2,482
 

 Type I error inflation caused by batch-to-batch variability of Reference?

Hi back!

I tend to agree with your position, but isn't it even more strange then that a GENERIC company wants to increase the burden for generics based on lousy performance of the originators' product?

(...still not enough caffeine, I guess...)

Kindest regards, nobody
Dr_Dan
Senior

2016-10-20 12:20

@ nobody
Posting: # 16741
Views: 2,483
 

 Type I error inflation caused by batch-to-batch variability of Reference?

» Hmm. Type I inflation due to high variability of Reference? Do they mean that you "by chance" ( :-D ) pick the "right" batch to show equivalence and get away with it?

If you "by chance" picked the "right" RLD batch to show equivalence, do you also need to show in-vivo that you picked the "right" test product batch? How would you define "right"?

Kind regards and have a nice day
Dr_Dan
nobody
Senior

2016-10-20 12:27

@ Dr_Dan
Posting: # 16742
Views: 2,512
 

 Type I error inflation caused by batch-to-batch variability of Reference?

» » How would you define "right"?

Right in the sense of: I'm able to show BE (a priori or a posteriori ;-) )


I guess there are two options:

1. The originators' batches are not bioequivalent (or even bioinequivalent), but therapeutically equivalent.

Why should the generic show bioequivalence to more than one batch?

2. The originators' batches are not bioequivalent (or even bioinequivalent) AND are NOT therapeutically equivalent.

Why should such a product be allowed to be marketed?

Kindest regards, nobody
Dr_Dan
Senior

2016-10-20 12:49

@ nobody
Posting: # 16743
Views: 2,487
 

 Type I error inflation caused by batch-to-batch variability of Reference?

Correct, I totally agree
RLD batches not bioequivalent, but therapeutically equivalent => no PK/PD relationship and consequently batch-to-batch variability does not matter.
RLD batches not bioequivalent AND are NOT therapeutically equivalent => serious risk to public health. You kill the originator after establishing your product on the market :-D

Kind regards and have a nice day
Dr_Dan
nobody
Senior

2016-10-20 14:27

@ Dr_Dan
Posting: # 16746
Views: 2,451
 

 Type I error inflation caused by batch-to-batch variability of Reference?

» RLD batches not bioequivalent AND are NOT therapeutically equivalent => serious risk to public health. You kill the originator after establishing your product on the market :-D

...hmmm, would such a "Generic" get marketing authorization? Would you have to show "better" batch-to-batch performance for your generic formulation? I'm inclined to say: The originator has to get his quality issues under control (recall lousy batches from the market?) and no generic should be allowed AT ALL in the meantime.

This whole story reminds of the good old days when BE was invented to keep companies from marketing lousy products with erratic biopharmaceutical properties. Maybe it is time to get a little tougher on this inhalation-stuff?

Kindest regards, nobody
DavidManteigas
Regular

Portugal,
2016-10-21 10:44

@ nobody
Posting: # 16749
Views: 2,355
 

 Type I error inflation caused by batch-to-batch variability of Reference?

I'm feeling really dumb in this discussion since I can't figure it out how batch-to-batch variability migth be accounted for in bioequivalence trials in a smart way.

When I was in University studying pharmaceutical development I remember to hear about the Design Space when we talked about quality by design and as far as I remember batch-to-batch variability is expected within the design space. Even the test formulation will have that kind of variability and different batches of test and reference products may, or may not be bioequivalent. However, as far as both formulations keep the amount API within the approved design space (which I believe is defined based on the pk-pd relationship of the specific product) and bioequivalence has been proved by the traditional way, there is no increase in the chance of having more than 5% of bio-inequivalent products in the market. Batch-to-batch variability is "random noise" imo, and I don't see how one might control for it. Using different batches of reference product will increase the variability of the reference product and increase the sample size required for BE studies. Conducting an additional BE study in a different batch of the reference product will increase costs of an industry in which price is the competitive advantage without any significant advantage for patients.

Will we in the near future discuss how one should account for pill-to-pill variability? :-D

I think there are problems in clinical operations that inflate a lot more type I error rather than manufacturing issues. Subject behaviour between periods, subject behaviour during confinement, subject physical activity, the weather...
Helmut
Hero
Homepage
Vienna, Austria,
2016-10-24 17:12

@ DavidManteigas
Posting: # 16752
Views: 2,234
 

 Type I error inflation caused by batch-to-batch variability of Reference?

Hi David,

you raised good points!

» Batch-to-batch variability is "random noise" imo, …

Yep. At least the EMA’s BE-GL specifically asks for products which are “similar” in their measured content (Δ ≤5%). Of course – due to inaccuracy/imprecision of the analytical method – even “suitable” batches might have a larger true difference. However, this will not affect the Type I Error – only increases the producer’s risk; Type II Error).

Is the risk for a patient to switch from Reference to Test substantially larger than between different batches of the reference (which happens all the time)? Duno. Educated guess: No.*
We must not forget that batch-to-batch variability (if theoretically tested in BE studies powered at 80%) will lead to failure in 1/5 of studies. And: Failure to demonstrate BE does not imply inequivalence.
IIRC, at the BioInternational ’94 (Munich) Les Benet suggested small (n=6) BE-studies evaluated by Bayesian methods for batch-release. Was not further considered due to the shouts of innovators. ;-)


  • Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haidar SH, Patel DT, Yang Y, Yu LX, Woodcock J. Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug Administration. Ann Pharmacother. 2009; 43(10): 1583-97. doi 10.1345/aph.1M141

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Helmut Schütz 
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