Bioequivalence and Bioavailability Forum 13:20 CEST

Main page Policy/Terms of Use Abbreviations Latest Posts

 Log in |  Register |  Search

Mikalai
Junior

Belarus,
2018-08-01 12:05

Posting: # 19121
Views: 370
 

 Cmax is out of the range [Study As­sess­ment]

Dear all,
We recently conducted a BE trial. It was a classical 2-period, 2-sequence study of a drug that consists of a combination of two active substances. Unfortunately, results one of analytes, a parent drug, fell sightly outside of the 80-125% range, below 80% for Cmax. CV was below 30% and post-hoc power was less than 80% for this analyte. Are there any ways we can defend bioequivalence without conducting another BE trail? All other analytes fell within 80-125%. Specifically, what should we put in the protocol or in a supporting letter to justify our lower border of CI around 79% for Cmax?
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-08-01 13:37

@ Mikalai
Posting: # 19122
Views: 321
 

 Bad luck

Hi Mikalai,

» […] Unfortunately, results one of analytes, a parent drug, fell sightly outside of the 80-125% range, below 80% for Cmax.

Bad luck. If you planned the study for assumed CV, T/R-ratio, and a dropout-rate for a desired power π the chance that you fail to demonstrate (if all assumptions turn out to be correct) is β = 1 – π. In other words, if you aimed at 80% power, 15 of studies of products which are BE will fail by pure chance. That’s part of the game.

» […] and post-hoc power was less than 80% for this analyte.

Although post-hoc power is irrelevant, if you planned for 80% and fail to show BE it will be <80%. As expected.

» Are there any ways we can defend bioequivalence without conducting another BE trail?

I don’t know how your agency deals with that. For the EMA and the FDA chances are close to nil.

» All other analytes fell within 80-125%.

Nice, but you have to demonstrate BE for all.

» Specifically, what should we put in the protocol …

You can’t change the protocol once the study is done, right?

» … or in a supporting letter to justify our lower border of CI around 79% for Cmax?

I don’t see how you could do that.
Example: Study planned for CV 25%, T/R-ratio 0.95, 80% power ⇒ n 28. All as expected, except a worse T/R 0.88  ⇒ 90% 78.66–98.45%. If you play around with α you will see that the patients’ risk will be 7.97% instead of ≤5%. I don’t think that any agency will accept that.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Mikalai
Junior

Belarus,
2018-08-01 13:50

@ Helmut
Posting: # 19123
Views: 319
 

 Bad luck

Hi Helmut

» You can’t change the protocol once the study is done, right?

I meant the final report not the protocol, sorry. I thought that something like clinical pharmacology of the drug may, to some extent, reassure our NCA that safety and efficacy are not at risk?
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-08-01 15:01

@ Mikalai
Posting: # 19124
Views: 296
 

 Cherry-picking

Hi Mikalai,

» I thought that something like clinical pharmacology of the drug may, to some extent, reassure our NCA that safety and efficacy are not at risk?

OK, you missed the lower limit of Cmax for one API. It depends on the drug whether this imposes a risk to the patients. Efficacy is in many cases more related to AUC than to Cmax. Exceptions are f.i. painkillers where Cmax (and tmax!) is important. Safety is generally related to the upper limit of Cmax.

Now for the big but: If you consider the conventional limits of 80–125% Cmax being too strict, you should have stated wider limits (or aim at reference-scaling in a replicate design if CVwR >30%) already in the protocol and discussed that with the agency before performing the study.
It smells of cherry-picking if you fail to show BE according to the protocol and afterwards :blahblah: about a patient’s risk which you consider not relevant for any reason. :cherry picking:

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
jag009
Hero

NJ,
2018-08-02 17:56

@ Mikalai
Posting: # 19128
Views: 222
 

 Cmax is out of the range

Hi,

» We recently conducted a BE trial. It was a classical 2-period, 2-sequence study of a drug that consists of a combination of two active substances. Unfortunately, results one of analytes, a parent drug, fell sightly outside of the 80-125% range, below 80% for Cmax. CV was below 30% and post-hoc power was less than 80% for this analyte...

Sorry, there is no way for you to argue.
John
Back to the forum Activity
 Thread view
Bioequivalence and Bioavailability Forum |  Admin contact
18,606 posts in 3,959 threads, 1,212 registered users;
online 21 (0 registered, 21 guests [including 13 identified bots]).

“Data! Data! Data!” he cried impatiently.
“I can’t make bricks without clay!”    Arthur Conan Doyle

The BIOEQUIVALENCE / BIOAVAILABILITY FORUM is hosted by
BEBAC Ing. Helmut Schütz
HTML5 RSS Feed