KR
★    

India,
2010-04-23 08:14
(5114 d 23:26 ago)

Posting: # 5190
Views: 19,233
 

 Orlistat Bioequivalence [Regulatives / Guidelines]

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Dear all,

As per OGD guidance of orlistat, how to conduct the bioequivalence study ?

Please provide your views on the same.

Thanks,

KR
 
d_labes
★★★

Berlin, Germany,
2010-04-23 11:28
(5114 d 20:13 ago)

@ KR
Posting: # 5194
Views: 16,569
 

 To Abreviate or not to Abreviate

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Dear KR,

❝ As per OGD guidance ...


The Free Dictionary:

Acronym Definition
OGD Other Government Departments
OGD Operator Groep Delft (Dutch: Delft Operator Group; Delft, Netherlands)
OGD Old Grand-Dad (bourbon whiskey)
OGD Order of the Golden Dawn
OGD Orchid Guide Digest
OGD Osteoglophonic Dysplasia
OGD Osteoglophonic Dwarfism
OGD Organización de Gestión de Destino (Bolivia)
OGD Oesophago-Gastroduodenoscopy
OGD Open Government Document
OGD Obstacle Gain Diffraction
OGD Old Granulomatous Disease
OGD Organic Grocery Deals (web forum)

My preferred are Osteoglophonic Dwarfism because of its beautiful tone of the pronunciation and Old Grand-Dad because of its wonderful taste :-D.
SCNR.
—
Regards,

Detlew
 
ElMaestro
★★★

Denmark,
2010-04-23 11:50
(5114 d 19:51 ago)

@ d_labes
Posting: # 5195
Views: 16,371
 

 What was really meant

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Dear d_labes,

❝ Acronym Definition

❝ OGD Other Government Departments

❝ OGD Operator Groep Delft (Dutch: Delft Operator Group; Delft,

❝ Netherlands)

❝ OGD Old Grand-Dad (bourbon whiskey)

❝ OGD Order of the Golden Dawn

❝ OGD Orchid Guide Digest

❝ OGD Osteoglophonic Dysplasia

❝ OGD Osteoglophonic Dwarfism

❝ OGD Organización de Gestión de Destino (Bolivia)

❝ OGD Oesophago-Gastroduodenoscopy

❝ OGD Open Government Document

❝ OGD Obstacle Gain Diffraction

❝ OGD Old Granulomatous Disease

❝ OGD Organic Grocery Deals (web forum)


What KR really meant, I am sure, was OGD in the context of generic drugs on this webforum. That is of course Obstacle Gain Diffraction:
You run into your everyday obstacles with BE-statistics and clinical protocols and deficiency letters from member states, so you ask a question here in this forum to gain insight, but when you ask about X you get a story about Y and so the whole point diffracts like light through a slit or fizzes out like bubbles from an open bottle of beer making it an utterly dull experience.

And what can we learn from that?
I am not sure, but one suggestion would be to drink the beer as soon as it has been opened.

EM.
—
Pass or fail!
ElMaestro
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2010-04-23 14:42
(5114 d 16:58 ago)

@ ElMaestro
Posting: # 5198
Views: 16,047
 

 OGD Guidance

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Dear ElMaestro and D Labes,

besides your valuable suggestions have a look at FDA's Office of Generic Drugs Draft Guidance (02/2010) - which is really a weird piece of work. I can understand KR's questions - and have not the slightest idea what FDA wants here.
—
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Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
 
KR
★    

India,
2010-04-23 17:01
(5114 d 14:40 ago)

@ d_labes
Posting: # 5202
Views: 15,907
 

 To Abreviate or not to Abreviate

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Dear d_labes,

This it to inform you that it is the commonly used language for intelligent/smart people (like HS...!!!) as when we r talking about bioequivalence, it is obvious that OGD means "Office of Generic Drugs" and forum is for BA/BE and none of the terms mention by you is for bioequivalence mainly with reference to guidance.

So try to understand the question by mind (if u have)and then answer. It is not a forum for useless comments (like yours) but it is the forum for valuable suggetions. So if u don't have then please don't give...!!!

I hope it is sufficient for you...

KR

Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post. [Helmut]
 
d_labes
★★★

Berlin, Germany,
2010-04-23 17:47
(5114 d 13:54 ago)

@ KR
Posting: # 5203
Views: 15,863
 

 Calm and serene

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Dear KR,

just one tip:
Bioequivalence and Bioavailability Forum's
Policy / Terms of Use / FAQs
  • Etiquette
    • Be nice!
—
Regards,

Detlew
 
ElMaestro
★★★

Denmark,
2010-04-24 10:16
(5113 d 21:25 ago)

@ KR
Posting: # 5210
Views: 15,849
 

 To Abreviate or not to Abreviate

Post reply
Dear KR,

sorry if I contributed to the obfuscation of your thread.
I read briefly through the document from the OGD and it does confuse me somewhat.
As far as I can tell, this calls for an assessment of relative potency via a rudimentary dose-response curve and bootstrap. Validating a stats package for the botstrap is one hurdle in itself.

But, actually, in order to assess relative potency I would believe that something more complex than a three-arm study would be needed, so I cannot tell you exactly which groups to have. I cannot tell if the FDA wants to see just the dose-response for Ref and then a single point of Test. If they will accept it, it would to me seem to be three arms and should be easy, but does the Emax model given in the document really allow for that?

Best regards
EM.
 
KR
★    

India,
2010-04-26 08:03
(5111 d 23:37 ago)

@ ElMaestro
Posting: # 5223
Views: 15,825
 

 To Abreviate or not to Abreviate

Post reply
Dear EM,

Thanks for the reply. The main problem is how does the Emax model given in the OGD guidance give the output as the same dose (i.e. 60 mg tid or 2 x 60 mg tid) for both test and reference will be given to all the volunteers and hence, how to establish dose response relationship ?

Thanks...

KR

Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post. [Helmut]
 
GSTATS
☆    
Homepage
India,
2010-05-27 20:30
(5080 d 11:11 ago)

@ KR
Posting: # 5389
Views: 15,959
 

 To Abreviate or not to Abreviate

Post reply
Dear KR,

As per my understanding, if i am not wrong FDA wants you to conduct a three way crossover study with two doses of reference and then fitting an Emax model (as given in recommendation) for reference which will provide estimated values of parameters used in model.
Put those estimated values again in model for test product as response and find relative bioavailability (F) of test with respect to reference.

And 90% confidence intervals for "F" can be calculated by repetitive sampling method using Bootstrap procedure.

I hope this will help you.

Regards,
GSTATS
http://gstatsolutions.com/Medical%20Research.html
—
Let Noble Thoughts come from Every Side: RIG VEDA
 
ElMaestro
★★★

Denmark,
2010-05-28 02:54
(5080 d 04:47 ago)

@ GSTATS
Posting: # 5390
Views: 15,631
 

 My lack of understanding

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Hi GSTAT,

❝ As per my understanding, if i am not wrong FDA wants you to conduct a three way crossover study with two doses of reference and then fitting an Emax model (as given in recommendation) for reference which will provide estimated values of parameters used in model.

❝ Put those estimated values again in model for test product as response and find relative bioavailability (F) of test with respect to reference.


This is more or less also what I can make out of it, but note that the Emax model contains three unknowns: E0, Emax and ED50 plus of course the relative potency itself.
In order to make a fair fit to that model for ref., you need at least 3+ dose levels, if I am not mistaking?

The only thing I could imagine with two levels of Ref and one level of Test would be:
  1. Construct a straight line through the two Ref points
  2. Measure the vertical distance from the single Test point to the regression line.
  3. Convert the vertical distance, by means of the slope we got from (1), to a horizontal distance, which is then taken as a measure of the relative potency under a sh!tload (pardon my French) of assumptions which cannot be qualified by this design itself.
Somehow I don't get the details of all this.
Can you tell?

Many thanks for clarification and best regards,
EM.
—
Pass or fail!
ElMaestro
 
GSTATS
☆    
Homepage
India,
2010-05-28 19:03
(5079 d 12:37 ago)

@ ElMaestro
Posting: # 5396
Views: 15,639
 

 My lack of understanding

Post reply
Dear Elmaestro

❝ In order to make a fair fit to that model for ref., you need at least 3+ dose levels, if I am not mistaking?


Yes, you are right.
And we can use Baseline response in the absence of the drug as third dose level and make a fair fit to that model for ref.

Regards,
GSTATS
http://www.gstatsolutions.com/Clinical%20Research.html
—
Let Noble Thoughts come from Every Side: RIG VEDA
 
ElMaestro
★★★

Denmark,
2010-05-29 05:32
(5079 d 02:08 ago)

@ GSTATS
Posting: # 5397
Views: 15,565
 

 My lack of understanding

Post reply
Hi Gstats,

❝ And we can use Baseline response in the absence of the drug as third dose level and make a fair fit to that model for ref.


I am afraid I am not able to see the practical applicability of that; for any data point associated with ref. there will be two dose levels, or perhaps three if you're right this will only be the case if we assume Emin is the same for both test and ref. (reasonable, if you ask me) and equal to the effect at run-in. The latter lacks qualification and I would really be surprised if the FDA would allow that kind of assumption. It would not fit into my image of those gents.


Mystified and still curious to see how this would work in practise.
EM.
—
Pass or fail!
ElMaestro
 
GSTATS
☆    
Homepage
India,
2010-05-29 07:28
(5079 d 00:12 ago)

@ ElMaestro
Posting: # 5398
Views: 15,525
 

 My lack of understanding

Post reply
Hi Elmaestro,

❝ I am afraid I am not able to see the practical applicability of that; for any data point associated with ref. there will be two dose levels, or perhaps three if you're right this will only be the case if we assume Emin is the same for both test and ref. (reasonable, if you ask me) and equal to the effect at run-in. The latter lacks qualification and I would really be surprised if the FDA would allow that kind of assumption. It would not fit into my image of those gents.


Emin or E0 is same for both test and reference as it is a value obtained in run in period when dose level is zero and FDA has mentioned in there recommendation that "This modified model is based on assumption that both E0 and Emax are the same for the test and reference products".

GSTATS
http://www.gstatsolutions.com/Clinical%20Research.html
—
Let Noble Thoughts come from Every Side: RIG VEDA
 
KR
★    

India,
2010-05-31 10:51
(5076 d 20:50 ago)

@ GSTATS
Posting: # 5402
Views: 15,522
 

 My lack of understanding

Post reply
Dear GSTATS and Elmaestro,

Thanks for the reply.

Would you please provide some more clarification/explaination to conduct the pharmacodynamic and statistical analysis considering the practical applicability in mind ?

Thanks again...

KR
 
ElMaestro
★★★

Denmark,
2010-06-01 18:13
(5075 d 13:28 ago)

@ KR
Posting: # 5407
Views: 15,933
 

 My lack of understanding

Post reply
Dear KR,

❝ Would you please provide some more clarification/explaination to conduct the pharmacodynamic and statistical analysis considering the practical applicability in mind ?


There's an old Chinese proverb that goes like this:
If in doubt about BE-statistics, ask d_labes.

As a pure amateur from the lowest rank of scum, here's what I imagine would be a possible approach:
Your starting point is a dataset consisting of n subjects. On each subject, you have 4 pharmacodynamic data points: Run-in, test, ref-lo, ref-hi. Then...
  1. Put all numbers 1...n into a hat.
  2. Ask a NLYW to pull out one of these numbers n times. Everytime she pulls out a number she notes the sampled number down and puts the number back in the hat.
  3. Once she has done it you take the piece of paper she has written which contains n numbers of which some might be identical. With this piece of papers you construct your sample dataset as Run-in, test, ref-lo, and ref-hi for each subject number she pulled out of the hat (remember: one subject's data might occur more than once in the sampled dataset).
  4. On this sample dataset you fit your ref data to the model in the guideline.
  5. Knowing the nominal strength of the test, you can now calculate a relative potency from the sample. You write down that reltive potency.
  6. You give the NLYW a new and blank piece of paper, sharpen her pencil, and steps 2...5 are now repeated a lot of times. The more the better. I do not know the minimum, but I'd put the lower limit at 500 because FDA has used that limit in other bootstrap applications.
  7. You now have 500 (or whatever) recordings on relative potency. Now you go to the library and figure out the BCA from those 500 (or whatever) numbers.
  8. You submkit your data to the Organic Grocery Deals and await approval.
Note: This should be done using validated systems. This implies that the NLYW and her interaction with the hat should be qualified.

Best regards
EM.
—
Pass or fail!
ElMaestro
 
sangeeta
☆    

India,
2011-11-29 18:58
(4529 d 11:43 ago)

@ ElMaestro
Posting: # 7750
Views: 14,626
 

 Calculation

Post reply
Dear EM,

❝ 4. On this sample dataset you fit your ref data to the model in the guideline.


I tried to fit the model as in guideline by pooling all subjects for mean of PD response for reference. Here I have only 3 observations, 2 observations for reference since we have 2 doses and 1 observation for baseline (0 mg). I could not fit the model in SAS since I have only 3 observations. I am not clear here while taking means from guideline perspective.

Can you please help me out in this ? :confused:

Thanks,

Sangeeta.
 
ElMaestro
★★★

Denmark,
2011-11-29 19:09
(4529 d 11:31 ago)

@ sangeeta
Posting: # 7751
Views: 14,669
 

 Calculation

Post reply
Hi sangeeta,

❝ I tried to fit the model as in guideline by pooling all subjects for mean of PD response for reference. Here I have only 3 observations, 2 observations for reference since we have 2 doses and 1 observation for baseline (0 mg). I could not fit the model in SAS since I have only 3 observations. I am not clear here while taking means from guideline perspective.


I think you have to do bootstrapping. So no averaging. Sample full data sets from the in vivo data listing 500 times with resampling and evaluate 500 times etc.
—
Pass or fail!
ElMaestro
 
sangeeta
☆    

India,
2011-11-29 19:30
(4529 d 11:11 ago)

@ ElMaestro
Posting: # 7752
Views: 14,643
 

 Calculation

Post reply
Hi Em,

❝ I think you have to do bootstrapping. So no averaging. Sample full data sets from the in vivo data listing 500 times with resampling and evaluate 500 times etc.


Thanks for your reply. Did you mean fitting model for individual subjects data?
But as per the guideline we should fit for mean of PD response for each dose.

Thanks,

Sangeeta.
 
ElMaestro
★★★

Denmark,
2011-11-30 12:35
(4528 d 18:05 ago)

@ sangeeta
Posting: # 7753
Views: 13,827
 

 Calculation

Post reply
Hi sangeeta,

❝ Thanks for your reply. Did you mean fitting model for individual subjects data?

❝ But as per the guideline we should fit for mean of PD response for each dose.


I think you will have to resample your dataset 500 etc times. For each resample you fit the model and extract an F. On basis of the 500 etc F values you derive your bootstrap confidence interval.

Good luck.
—
Pass or fail!
ElMaestro
 
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