Harish Kaushik
☆    

India,
2015-02-02 13:16
(3342 d 17:29 ago)

Posting: # 14350
Views: 9,421
 

 Individual/Population Bioequivalence [General Sta­tis­tics]

Hello HS & Forum members

I have read in a BEBAC forum posted by HS that the concept of Individual/Population Bioequivalence is no longer considered by FDA/other regulatory agencies, Is it true?

If I understand rightly, FDA/EMEA considers only Average bioequivalence for establishing the BE of formulations?

Correct me if iam wrong, may be this is reason why in bear software we don't have option to calculate IBE/PBE

Finally, I would like to hear from experts out there, about the status of IBE/PBE statistical analysis, Does it have any relevance now?

Regards
Kaushik
Helmut
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Vienna, Austria,
2015-02-02 14:30
(3342 d 16:15 ago)

@ Harish Kaushik
Posting: # 14352
Views: 8,228
 

 Population/Individual Bioequivalence

Hi Kaushik,

❝ I have read in a BEBAC forum posted by HS that the concept of Individual/Population Bioequivalence is no longer considered by FDA/other regulatory agencies, Is it true?


AFAIK, yes.
  • FDA abandoned PBE/IBE more than a decade ago. PBE/IBE is not mentioned in CFR21/320. Not a single word in the current drafts for ANDAs (2013) and NDAs/INDs (2014). Only: We re­com­mend that appli­cants use the average BE method of analysis with these study designs for es­tab­lish­ing BE.”
  • In Europe PBE/PBE was never implemented.

❝ Finally, I would like to hear […] about the status of IBE/PBE statistical analysis, Does it have any relevance now?


No. If the FDA is concerned, parts of the methodology enter the scene through the back door, e.g., com­paring within-subject variances of NTIDs (warfarin guidance) and the subject-by-formulation inter­action (ER methylphenidate guidance).

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Harish Kaushik
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India,
2015-02-03 06:52
(3341 d 23:53 ago)

@ Helmut
Posting: # 14356
Views: 8,071
 

 Population/Individual Bioequivalence

Hello HS,
Thanks for your quick reply and clearing my doubts about regulatory acceptance of IBE/PBE.
Your answer made me to think further about, the issues of Switchability and Prescribability.
How do we tackle/address these issues, Is it relevant to evaluate the generic to generic switchability impact, as none of the guidelines talk about these, Is there any specific method to explore this issue of switchability impact considering the fact that the markets are getting flooded with "N" number of generics

I have seen methods such as Indirect Treatment comparision/Network meta analysis published in the literature and being used for this by Canadian FDA/EMEA

I would like to know from people like you, what's your opinion
  1. on assesing the impact of generic to generic switchability by a statistical method
  2. As a researcher is there any way out to statistically evaluate these growing number of generics getting flooded in the market
Regards
Kaushik


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! [Helmut]
jag009
★★★

NJ,
2015-02-27 01:30
(3318 d 05:15 ago)

@ Harish Kaushik
Posting: # 14507
Views: 7,693
 

 Population/Individual Bioequivalence

Hi,

Email Dr. Laszlo Endrenyi, my grad professor. He will be more than happy to give you his side of views. You can find his email address in one of his scientific article.

John
Helmut
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Vienna, Austria,
2015-02-27 17:37
(3317 d 13:08 ago)

@ Harish Kaushik
Posting: # 14513
Views: 7,884
 

 Switching in theory & practice

Hi Kaushik,

❝ How do we tackle/address these issues, Is it relevant to evaluate the generic to generic switchability impact, as none of the guidelines talk about these, Is there any specific method to explore this issue of switchability impact considering the fact that the markets are getting flooded with "N" number of generics


Good question.

❝ I have seen methods such as Indirect Treatment comparision/Network meta analysis published in the literature …


I guess you are talking about Arne Ring’s paper?1 Interesting ideas. Robert Schall is one of the pioneers of PBE/IBE. See their Fig.1:

[image]


The common approach is A). Note that the arrows are bidirectional. In approval BE is established for T1,…,N R but not the other way ’round. This is not a problem in ABE because we could re­verse the procedure. There might be already a problem with reference-scaled ABE. If the vari­ances of T and R are not equal the decision is not reversible any more.

In B) substitute the tests by major variations of the reference (each supported by a BE study with the previous product). The WHO faced serious problems identifying reference products which were as close as possible to the formulation used in phase III. Another obstacle: The first generic might be tested to an “old” reference and later ones to newer ones.
Heretic question I : Would be R3 bioequivalent to R0?
Heretic question II: How many minor variations (supported by in vitro data) can one expect until the re­fe­rence would be no more bioequivalent to the original product?

In clinical practice we face something beyond A):

[image]


Only the blue comparisons were performed (BE established) but the red switches might take place as well. With four generics we have four established BEs but six potential switches which were never tested for ABE. With ten generics we have 45 and with twenty an amazing 190. A lesson in com­bi­na­torics.

❝ … and being used for this by Canadian FDA/EMEA


Surprises me. Do you have a reference?

❝ […] what's your opinion

❝ 1. on assesing the impact of generic to generic switchability by a statistical method


IBE would help in theory.

❝ 2. As a researcher is there any way out to statistically evaluate these growing number of generics getting flooded in the market


If we leave IBE aside I don’t think so. Or should generic #21 perform 21 ABE studies (against R and T1,…,20)? Although from a theoretical perspective switching is not covered by ABE there seem to be no major problems – unless we talk about NTIDs, where switching is not acceptable in some regulations (e.g., in Denmark) or not recommended by medical specialists.

See another interesting paper.2 From the conclusions:

Two generic products (T1 and T2) can be switched from one to another when the T1/R and T2/R ratios are close to the same value, the CVw of the drug is low, and each BE study of T1–R and T2–R was conducted using a relatively large number of subjects.



    References:
  1. Ring A, Morris TBS, Hohl K, Schall R. Indirect bioequivalence assessment using network meta-analyses. Eur J Clin Pharmacol. 2014;70(8):947–55. doi 10.1007/s00228-014-1691-0
  2. Karalis V, Bialer M, Macheras P. Quantitative assessment of the switchability of generic products Eur J Pharm Sci. 2013;50:476–83. doi 10.1016/j.ejps.2013.08.023

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ElMaestro
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Denmark,
2015-02-27 18:07
(3317 d 12:38 ago)

@ Helmut
Posting: # 14514
Views: 7,670
 

 theory & practice.... & practice

Hi all,

all those theoretical considerations are of course interesting but are they really practical?

It is exceedingly rare to see a problem arising from average BE due to switching in real life.
Of course several originator companies have jumped on the opportunity to throw dirt at the generics. Think epilepsi medications and what not. So you get a bunch of journals flooded with scaremongering about subjects suffering episodes in situations where they switched from an originator to a generic. But when originators have tried to quantify it with a fair control group, then the evidence disappears completely. And they have tried a lot, believe me.
The variation from an original to a generic is most often not more than from one batch of the originator to the next batch of the same originator.

The problem is twisted information in the public domain and not switching.

Pass or fail!
ElMaestro
nobody
nothing

2015-02-27 20:56
(3317 d 09:49 ago)

@ ElMaestro
Posting: # 14515
Views: 7,663
 

 theory & practice.... & practice

... Hi again!

Ask German public health ensurers: A generic is "switchable" whenever the ensurer does not pay for something else.

Welcome to reality 2015...

The whole concept of bioequivalence is highly political, as you can see more detailed in the discussions on biosimilars.

Have a nice weekend!

Οὐδείς









PS: Maestro, can you please keep away these awfull ice/snow showers from the E45, nearly killed me recently...

Kindest regards, nobody
ElMaestro
★★★

Denmark,
2015-02-27 22:04
(3317 d 08:41 ago)

@ nobody
Posting: # 14516
Views: 7,606
 

 theory & practice.... & practice

Hi nobody,

❝ Ask German public health ensurers: A generic is "switchable" whenever the ensurer does not pay for something else.


Haha, this is excellent. I hope it qualifies for the bebac quote of the day, some day.


❝ PS: Maestro, can you please keep away these awfull ice/snow showers from the E45, nearly killed me recently...


I am doing my best, nobody, but the powers that be show no mercy.
Hey, if you are ever on the Danish part of E45 then please drop by at the Elmaestrolophystic residence for a cup of coffee until it stops snowing.

As a long term solution I hope we can get nuclear power banned and rely on burning coal and fossile fuels for a good number of years. That should expedite the global warming, all of E45 will be like Ocean Avenue on a sunny day, and we'll all be happy. What could possibly go wrong? :-D

Pass or fail!
ElMaestro
nobody
nothing

2015-02-27 22:34
(3317 d 08:12 ago)

@ ElMaestro
Posting: # 14517
Views: 7,651
 

 theory & practice.... & practice

❝ As a long term solution I hope we can get nuclear power banned and rely on burning coal and fossile fuels for a good number of years. That should expedite the global warming, all of E45 will be like Ocean Avenue on a sunny day, and we'll all be happy. What could possibly go wrong? :-D


But then Fanö would be gone.... Hope not in my lifetime... :-(

btw. Denmark and Austria both were clever enough never to start production of highly enriched nucleare waste. Will be a big plus in the long run, believe me. And all the fancy wind turbines will keep you warm and cosy :-D

E45 stopover? Maybe not tomorrow, but we should plan that for the future, definitely, although these travel-days are... some kind of crowded... ;-)

Sorry for OT, but to be back:

In Germany all customers of large public health insurers are provided with one generic at special price, of course the suppliers are switched from time to time, to allways keep the CHEAPEST product...

Kindest regards, nobody
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