joyjac
★    

Philippines,
2006-05-23 03:50

Posting: # 134
Views: 5,965
 

 Conduct / Assessment of BE [Design Issues]

Dear HS,

How would you conduct/assess BE of 2 drug products of the same active ingredient but of different dosage formats and strengths i.e. immediate-release, 130 mg per tablet versus sustained-release, 200 mg per tablet? Thanks.
Helmut
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Vienna, Austria,
2006-05-28 13:28

@ joyjac
Posting: # 141
Views: 5,155
 

 BE of MR versus IR?

Hi Joy!

» How would you conduct/assess BE of 2 drug products of the same active ingredient but of different dosage formats and strengths i.e. immediate-release, 130 mg per tablet versus sustained-release, 200 mg per tablet?

It’s not possible to show bioequivalence between an immediate release and a modified release form – although the extent of BA may be the same, just by definition the rate of BA should be different.
Another point in the definition of BE requires administration of the same molar dose. Since the least common multiple of 200 and 130 ist 2600, it would mean comparison of 20 IR tablets v.s. 13 SR tablets.
I’m afraid, in this case the cards are stacked against you…

At least if your drug shows linear pharmacokinetics within 130 mg and 200 mg you may perfom a comparative bioavailability study and normalize dose-dependent PK parameters of the 200 mg formulation to 130 mg; but remember, this is not BE.

Cheers,
Helmut Schütz
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drks
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2006-12-18 15:21

@ Helmut
Posting: # 411
Views: 4,958
 

 Comparative BA versus BE?

» At least if your drug shows linear pharmacokinetics within 130 mg and 200 mg you may perfom a comparative bioavailability study and normalize dose-dependent PK parameters of the 200 mg formulation to 130 mg; but remember, this is not BE.

Dear Helmut,

In different references we come across, various researchers have used the terms "comparative bioavailability" and "bioequivalence" for the similar studies. However, as far as i understand, these imply to different kind of studies. the former (C BA) referring to all the studies involving comparison of bioavailability, while latter one (BE) refer to only those where a test product is being compared with the innovator's formulation (having same molar dose) only. This implies that, if we are comparing two generic products, the study should be termed as comparative bioavailability, not bioequivalence study. How about it?
Can we say that all BE studies are comparative BA studies, but all comparative BA studies are not BE? or,
Can we use the two terminology interchangeably?
Please quote some references (preferably from regulatory bodies), if possible.

Regards,

Kshitij
Helmut
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Vienna, Austria,
2006-12-18 15:54

@ drks
Posting: # 412
Views: 4,939
 

 Comparative BA versus BE?

Dear Kshitij!

» In different references we come across, various researchers have used the terms "comparative bioavailability" and "bioequivalence" for the similar studies.

Yes, some people like the sloppy use of terms. Sometimes you find “Comparative BA” in the title, “BE” in the abstract, and both terms in the article. ;-)

» However, as far as i understand, these imply to different kind of studies. the former (C BA) referring to all the studies involving comparison of bioavailability, while latter one (BE) refer to only those where a test product is being compared with the innovator's formulation (having same molar dose) only.

Exactly!

» This implies that, if we are comparing two generic products, the study should be termed as comparative bioavailability, not bioequivalence study. How about it?

Yes, that’s the correct term.

» Can we say that all BE studies are comparative BA studies,…

Yes, BE is a subset of comparative BA. You already gave the correct definition of BE above.

» …but all comparative BA studies are not BE?

Not quite.
Even if you have used the same molar dose, the innovator’s product as reference, etc., and all PK metrics found in the study were within commonly applied acceptance ranges – if your study was not planned to demonstrate BE (i.e., going for an abbreviated submission) it’s not a BE study.
Comparative BA studies report confidence intervals in a descriptive manner only; they are not confirmatory (as BE studies are).

So for bioequivalence we have three points to be fulfilled:
  • Comparative BA,
  • Designed to demonstrate BE,
  • Reference = Innovator’s product.

» …can we use the two terminology interchangeably?

No.

» Please quote some references (preferably from regulatory bodies), if possible.

One “classical paper“* starts its summary with the sentence:

The role of comparative bioavailability trials in testing for the bioequivalence of different formulations of a drug is discussed and the statistical aspects of the design and analysis of such trials are reviewed.


The European Note for Guidance on BA/BE states at 3. Design and Conduct of Studies, 2nd paragraph:

A bioequivalence study is basically a comparative bioavailability study designed to establish equivalence between test and reference products.

Similar wordings are given in other regulations.


  • Westlake WJ. Statistical Aspects of Comparative Bioavailability Trials. Biometrics. 1979;35(1):273–80. doi:10.2307/2529949.

Cheers,
Helmut Schütz
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