lizhao
☆    

US,
2014-09-11 01:21
(3486 d 22:12 ago)

Posting: # 13478
Views: 13,289
 

 cortisol suppression as clinical endpoint [Design Issues]

Hi

I am study bioequivalence testing of inhaled corticosteriods using cortisol suppression as the metric. I just want to know what would be the study design suggested by EMA. Since there is cortisol is an endo­ge­nous compound in human body, the baseline needs to be substracted from post-treatment AUC of cortisol.

I can think of two kinds of study designs:
  1. baseline1 → Test treatment → washout period → baseline2 → Reference treatment

  2. baseline → Test treatment → Reference treatment
Can somebody tell me which one is the right one? If either one is correct, can you please tell me the study design recommended by EMA or FDA?

Thanks


Edit: Category changed. [Helmut]
ElMaestro
★★★

Denmark,
2014-09-11 01:42
(3486 d 21:51 ago)

@ lizhao
Posting: # 13479
Views: 11,794
 

 cortisol suppression as clinical endpoint

Dear lizhao,

❝ I can think of two kinds of study designs:

❝ 1. baseline1 → Test treatment → washout period → baseline2 → Reference treatment


❝ 2. baseline → Test treatment → Reference treatment


The first suggestion is a potential winner. You'll always have pre-dose samples so no reason not to address the baseline in it.
But on the other hand, what do you know about wash-out and potential for carryover? Some companies lean towards parallel designs. It is a very complicated matter.

My sixth sense tells me you might be working on an inhaled formulation? In that case, to be honest: At the moment many, many, many companies including some from the world's top 10 are outright failing their Cortisol suppression studies even though they have invested lots and lots of resources in formulations, good CROs (actually they seem to pick cheap ones over good ones) and expensive experts to help them. The literature is no help, you will not see what doesn't work in papers. So take my advice: Don't do it. If you are in a situation where your formulation needs a CS study there is probably a reason behind it such as a failed safety PK study, a desire for a children's indication or other stuff which just spells trouble.

❝ Can somebody tell me which one is the right one? If either one is correct, can you please tell me the study design recommended by EMA or FDA?

  1. Don't do it.
  2. If you ignore pt. 1, then at least take scientific advice / protocol assistance at the authority to get the design right. If your boss tells you that there is no time or no budget for it, then you need a new boss.
Check out this link and refs in the paper it links to.

Pass or fail!
ElMaestro
nobody
nothing

2014-09-11 10:45
(3486 d 12:48 ago)

@ lizhao
Posting: # 13482
Views: 11,660
 

 cortisol suppression as clinical endpoint

As a starter: Take some 20 healthy volunteers and simply determine the cortisol profile over, let's say 5 days. With these data have a look at your "baseline" and then you will know, why these studies fail.

Kindest regards, nobody
lizhao
☆    

US,
2014-09-12 01:00
(3485 d 22:33 ago)

(edited by Dr_Dan on 2014-09-12 08:08)
@ nobody
Posting: # 13489
Views: 11,588
 

 cortisol suppression as clinical endpoint

Because it is not well reproducible? variability is too high? taking the average should be helpful, I think?


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! [Dr_Dan]

Edit: Please follow the Forum’s policy. [Helmut]
nobody
nothing

2014-09-12 15:59
(3485 d 07:34 ago)

@ lizhao
Posting: # 13497
Views: 11,506
 

 cortisol suppression as clinical endpoint

Is cortisol suppression a bug or a feature for inhaled steroids?

You know something called "signal-noise ratio"?

Kindest regards, nobody
ElMaestro
★★★

Denmark,
2014-09-12 16:56
(3485 d 06:37 ago)

@ nobody
Posting: # 13498
Views: 11,452
 

 cortisol suppression as clinical endpoint

Hi nobody,

❝ Is cortisol suppression a bug or a feature for inhaled steroids?


Clearly a feature invented by the originator industry to block generic entry :-D

Pass or fail!
ElMaestro
nobody
nothing

2014-09-12 18:00
(3485 d 05:33 ago)

@ ElMaestro
Posting: # 13500
Views: 11,484
 

 cortisol suppression as clinical endpoint

:-D

...on the other hand: Teva and others succeeded with BE data alone apparently, got some Risk Management Plan with suppression to be studied, iirc the Assessment Report. So apparently not really needed, this fancy cortisol thing.

Kindest regards, nobody
lizhao
☆    

US,
2015-11-12 03:15
(3059 d 19:18 ago)

@ nobody
Posting: # 15629
Views: 10,769
 

 cortisol suppression as clinical end­point

I know this is an old post, but I have a follow-up question. Instead of cortisol suppression, do you guys think cortisol might be a better metric? I mean just compare cortisol profiles of Test and cortisol profiles of Reference....


Edit: Please follow the Forum’s policy. 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]
nobody
nothing

2015-11-12 09:27
(3059 d 13:05 ago)

@ lizhao
Posting: # 15630
Views: 10,730
 

 cortisol suppression as clinical end­point

...and then do exactly WHAT with these profiles? ;-)

Kindest regards, nobody
lizhao
☆    

US,
2015-11-12 12:07
(3059 d 10:25 ago)

@ nobody
Posting: # 15632
Views: 10,710
 

 cortisol suppression as clinical end­­point

❝ ...and then do exactly WHAT with these profiles? ;-)


We can still get a Test/Reference ratio for cortisol (not cortisol suppression) and then see if it is within (0.8, 1.25). Does it make sense? :confused:
nobody
nothing

2015-11-12 17:06
(3059 d 05:27 ago)

@ lizhao
Posting: # 15633
Views: 10,741
 

 cortisol suppression as clinical end­point

Scientific rational for your borders chosen? What do you evaluate? AUC?

What if cortisol fails, but your other BE passes?

I would invest some days and go to the basics before you shoot yourself in the knee with a protocol full of nonsense (as you might learn in the end). ;-)

Kindest regards, nobody
ElMaestro
★★★

Denmark,
2015-11-13 19:39
(3058 d 02:54 ago)

@ lizhao
Posting: # 15636
Views: 10,589
 

 cortisol suppression as clinical end­point

Hi lizhao,

❝ We can still get a Test/Reference ratio for cortisol (not cortisol suppression) and then see if it is within (0.8, 1.25). Does it make sense?: confused:


That would be the theory yes, but it is a nightmare in practice. You will not find much about it in the literature, because companies don't like to publish it when they fail. That's a problem. But everytime 20 companies try to do something along those lines, 19 or so will fail.

Just to give you an idea: Cortisol measurements usually involve a blood sample. And even though we are all nice and calm when somebody takes a blood sample off of us, our corticol levels will react in an unpredictable manner. Depending on circumstances all this will be quite unrelated to the drug you are testing.... Then you can resort to urinary cortisol which is in another league of trouble.

Personally I would rather swim to the North pole, eat plutonium and have my appendix removed with a rusty fork than do any of this stuff. But that's just me, of course.

Finally, perhaps you are asking because you already have one or more failed PK studies. They failed because of something. Power, formulation, CRO, etc etc. Whatever it was, spend your money and time on fixing it and then redo your PK. If it requires a reformulation then so be it. A reformulation that is costly and which takes a lot of time may still be a much wiser decision.

Pass or fail!
ElMaestro
lizhao
☆    

US,
2015-11-13 21:56
(3058 d 00:37 ago)

@ ElMaestro
Posting: # 15637
Views: 10,503
 

 cortisol suppression as clinical end­point

Thank you all for your kind input!!! :-D:-D
I really appreciate them!


Edit: Full quote removed (like in all your replies so far). Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! Is it really so difficult? [Helmut]
lizhao
☆    

US,
2015-12-03 00:00
(3038 d 22:33 ago)

@ ElMaestro
Posting: # 15688
Views: 9,117
 

 cortisol suppression as clinical end­point

Dear all,

what I am doing right now is using population based clinical trial simulations to prove that cortisol suppression is not a good clinical endpoint to show systemic bioequivalence.

My simulator could simulate crossover BE trials including both PK profiles and the corresponding cortisol profiles. Right now, based one the simulation results, even if I set Test and Reference products to be exactly the same, the probability of passing BE using cortisol suppression as a clinical endpoint is still very low.



I do need your guys' input so I am confident that I am doing the bioequilvance test in the right way.

My questions are 1: when compare cortisol suppression profiles of Test and Reference products, should I compare directly the cortisol suppression profiles of these products, or I have to do the "dose-scale" approach. Which means translate cortisol suppression back onto PK scale using dose-response curve?



2. What doses are usually being used for conducting cortisol suppression? ED50?


Thanks!!!!

Li
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