## misunderstanding [RSABE / ABEL]

hi Mikalai,

» Hi Mitturi,
       ^^^^
is my nick so difficult to copy and paste?

» » Republic of what?
» This is from the Star Wars.

looks like rewording, cannot recall that

» I think there is no misunderstanding. I never said that in ABEL/RABE trials TIE should not be controlled. What I worry is the control TIE may invalidate the whole method, because in a big number studies the reduction in sample size can be negligible but risks can double for subjects.

I cannot find the arguments for doubling risks for subjects. What risks are higher?

» I also afraid that this can be assesd only post-hoc.

really? and what about the limits? do you know them before the study?

» Do we have a decisicion tree for ethic committees?

see Helmut's lectures for schemes

» Who set up rules of games in this case? Moreover TIE as consumer protection metric is very controversial. Have we asked people about this convention? Do we have good feedback mechanisms with consumers? Do we incorporate qulitative studies in our regulatory documetns. How can we represent consumers if we do not speak with them?

what answer do you want to get? "Yes, we are interested in TIE control"
"No, 5% is too much for us, gimme 6%"

» It seems that people tolerate much higher risks than we use currently. Look at alternative medicine. They have millions customers and don't bother with any statistics.

some people does. Believe or not but the people trust decisions of regulators.
Placebos exist on the market, is that bad? Sometimes yes, sometimes not.

» » It should be controlled everywhere, not only in ABEL
» It is Utopia, and good luck with this. See my comments above. But I can give another argument.

so you blame ICH docs?

» At the heart of bioequivalence lie the concept that products are different.

you are playing with words. different but still have comparable action

» Have manufacturing processes of different manufactures have ever been compared.

how to assess the differences in overall and how are they inflate the bioequivalence? If you have an answer - go with an initiative to EMA, they will be happy to hear it I think.

» And what about TIE deflating factors like industrial statisticians, industrial spies, angry sacked employees from original producers, the same equipment and the same supppliers.

sorry, who is industrial statistician?
if you have any proposals regarding making the products more comparable - go to the initiative group and propose your solutions. I see only remarks. I don't understand why do you want to start a wholywar here.

» Might be that the TIE inflation risk is a bit overestimated

a bit? what will trigger you to say it is not overestimated? There will always be sceptics/conservators, irrespective of initiatives. Especially on the slippery zone of risk/benefit of generic drugs.

» This is why if something is widely used and is a reason to rejection, it should be mentioned in regulatory documents.

EMA and FDA mention 5%. Have you read the lectures? If we want to keep that value at the level of 5%, we should keep in mind TIE inflation. If you have another opinion - stop reading that

» » Please define 'win'. You didn't win until null hypothesis(es) is rejected.
»
» If somebody shoot all alpha level and pass bioequivalence at the first stage.

aha, stage! OK, so you are playing in the 2-stage game? Did you take into account the corrected alphas there? Do you remember 2-stage designs and corrected alphas irrespective of the results of 1st stage?

» It seems that the issue is still not clear for most regulators. It also seems that this issue is afloat for more 7 years. Also, where are results of the inflated TIE? Where are unsafe and inefficient drugs.

where are the results of inefficient drugs started when Cmax had limits 75-133? If it is bad, why did the regulators change it? why that drugs are still on the market?

» There are no stupid questions there are either not good answers or ignorance. Sorry ...

at least I did not asked something stupid! excellent! I am not surprised that you are not happy with my answers since even detailed Helmut's answers were rejected by you.
For sure you can ignore TIE inflation for yourself until some request will knock your door. It is up to you to prepare yourself or just keep trying to neglect it

Kind regards,
Mittyri