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Is there any FDA or EMEA guidance on reporting observed or predicted NCA parameters?

FDA EMEA NCA

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#1 johnhood2015

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Posted 24 November 2015 - 11:37 AM

Hi Folks,

 

I'm writing an SOP1 for GLP2-compliant NCA3 and I need to state which parameters should be reported out of the XX_obs or XX_pred parameters. Personally I think that the pred should be reported as it accounts for variability around observed points and gives a more likely parameter estimate but one of my colleagues, who has been doing NCA analyses for a lot longer, states that obs estimates are more robust.

 

I've trawled the FDA and EMEA websites and the PharmPK list archive without success, so I was wondering whether anyone knew if there was any formal guidance on the matter.

 

Any pointers would be great,

Thanks,

John 

 

 

 

 

1= Standard Operating Procedure

2= Good Laboratory Practice

3= Non-compartmental Analysis



#2 Helmut Schütz

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Posted 26 November 2015 - 02:02 AM

Hi John,

I saw the discussion at David’s list and had no time to answer over there yet. I don’t concur with the majority (as usual) and strongly support your idea of using predicted values. It is my standard for 35 years and I never received a request from any agency in my 500+ studies so far. ;-)

Two references recommending the extrapolation based on Cpredz (instead of Cobsz):
  • Sauter R, Steinijans VW, Diletti E, Böhm E, Schulz H-U
    Presentation of results from bioequivalence studies
    Int J Clin Pharm Ther Toxicol 30/Suppl.1, S7–30 (1992)
  • Hauschke D, Steinijans VW, Pigeot I
    Bioequivalence studies in drug development methods and applications
    John Wiley & Sons, New York (2007)
The FDA and the WHO recommend [sic] Cobsz, but as usual nonbinding, blahblah. No specific method mentioned by the EMA. If you have a lot of spare time you can check my collection: http://bebac.at/Guidelines.htm

BTW, AUC is a lousy metric for the extent of absorption. Quote from the abstract of an antique paper (some of the authors the usual suspects from the FDA):

The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and Cmax.
(my emphasis)

Bois FY, Tozer TN, Hauck WW, Chen M-L, Patnaik R, Williams RL

Bioequivalence: Performance of Several Measures of Extent of Absorption

Pharm Res 11(5), 715–22 (1994)


If you read the paper in all of its doubtful beauty, you will see that AUC is not only more variable than AUCt (trivial), but might also be biased (depended on the number of “true” compartments and the LLOQ). I never understood why the FDA requires it at all. We know that the last observed concentration (since close to the LLOQ) likely is the most inaccurate and imprecise point of the entire profile. If we base the extrapolation on this value, all its variability will be carried over to AUC. Not a particularly good idea.
Of course my views are biased since my background is (human) BA/BE. In preclinical studies / TK ruled by GLP AUC is important indeed.

I also suggest to fiddle around in PHX in order to get Cpred in the output. Steps:
  • Send the NCA Final Parameters Pivoted to the DW
  • Exclude everything you will not need for sorting (subject, treatment, etc) and the irrelevant columns. Keep at least Tlast and Clast (if you want to check whether the calculation is correct, keep lambda_z, AUClast, and AUCpred as well).
  • In the Properties change Tlast to time.
  • Send the Result to Join Worksheets
  • Worksheet 1: Sort ad libitum; time is mandatory
  • Map whatever you need to Source
  • Worksheet 2: Summary Table of NCA, same sorts as above + time.
  • Check “Inner Join” (important!)
  • Here you are.
If you don’t trust PHX, you can add another transformation and calculate AUCinf as Predicted/lambda_z and compare it with AUCpred. In my validation runs I never saw any deviation larger than 2E-13 (see screenshot) ;-)
I have Cpred in my standard reports to make the life of reviewers easier. I would love if Certara/Pharsights adds Cpred the NCA-output…

A final remark: It’s necessary to have an SOP, but in my experience it is better to be as transparent as possible. State in the study protocol exactly what you will do – not only refer to an SOP. The protocol is reviewed and approved by the agency. Avoids discussions in the end.

Good luck,
Helmut

Nitpicking PS: The EMEA changed its name to EMA in 2005.

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Edited by Helmut Schütz, 27 November 2015 - 07:58 PM.

  • Simon Davis likes this

 Best regards,
Helmut

https://forum.bebac.at/


#3 johnhood2015

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Posted 27 November 2015 - 01:53 PM

Hi John,

 

I saw the discussion at David’s list and had no time to answer over there yet. I don’t concur with the majority (as usual) and strongly support your idea of using predicted values. It is my standard for 35 years and I never received a request from any agency in my 500+ studies so far. ;-)

 

Two references recommending the extrapolation based on Cpredz (instead of Cobsz):

  1. Sauter R, Steinijans VW, Diletti E, Böhm E, Schulz H-U
    Presentation of results from bioequivalence studies
    Int J Clin Pharm Ther Toxicol 30/Suppl.1, S7–30 (1992)
  2. Hauschke D, Steinijans VW, Pigeot I
    Bioequivalence studies in drug development methods and applications
    John Wiley & Sons, New York (2007)

The FDA and the WHO recommend [sic] Cobsz, but as usual nonbinding, blahblah. No specific method mentioned by the EMA. If you have a lot of spare time you can check my collection: http://bebac.at/Guidelines.htm

 

BTW, AUC is a lousy metric for the extent of absorption. Quote from the abstract of an antique paper (some of the authors the usual suspects from the FDA):

The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and Cmax.
(my emphasis)

Bois FY, Tozer TN, Hauck WW, Chen M-L, Patnaik R, Williams RL

Bioequivalence: Performance of Several Measures of Extent of Absorption

Pharm Res 11(5), 715–22 (1994)

 

If you read the paper in all of its doubtful beauty, you will see that AUC is not only more variable than AUCt (trivial), but might also be biased (depended on the number of “true” compartments and the LLOQ). I never understood why the FDA requires it at all. We know that the last observed concentration (since close to the LLOQ) likely is the most inaccurate and imprecise point of the entire profile. If we base the extrapolation on this value, all its variability will be carried over to AUC. Not a particularly good idea.

Of course my views are biased since my background is (human) BA/BE. In preclinical studies / TC ruled by GLP AUC is important indeed.

 

I also suggest to fiddle around in PHX in order to get Cpred in the output. Steps:

  1. Send the NCA Final Parameters Pivoted to the DW
  2. Exclude everything you will not need for sorting (subject, treatment, etc) and the irrelevant columns. Keep at least Tlast and Clast (if you want to check whether the calculation is correct, keep lambda_z, AUClast, and AUCpred as well).
  3. In the Properties change Tlast to time.
  4. Send the Result to Join Worksheets
  5. Worksheet 1: Sort ad libitum; time is mandatory
  6. Map whatever you need to Source
  7. Worksheet 2: Summary Table of NCA, same sorts as above + time.
  8. Check “Inner Join” (important!)
  9. Here you are.

If you don’t trust PHX, you can add another transformation and calculate AUCinf as Predicted/lambda_z and compare it with AUCpred. In my validation runs I never saw any deviation larger than 2E-13 (see screenshot) ;-)

I have Cpred in my standard reports to make the life of reviewers easier. I would love if Certara/Pharsights adds Cpred the NCA-output…

 

A final remark: It’s necessary to have an SOP, but in my experience it is better to be as transparent as possible. State in the study protocol exactly what you will do – not only refer to an SOP. The protocol is reviewed and approved by the agency. Avoids discussions in the end.

 

Good luck,

Helmut

 

Nitpicking PS: The EMEA changed its name to EMA in 2005.

Thanks Helmut! I find it interesting how much disagreement there appears to be around this topic.



#4 Helmut Schütz

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Posted 27 November 2015 - 01:59 PM

Hi John,

 

Thanks Helmut! I find it interesting how much disagreement there appears to be around this topic.

 

Yep. The annual flame-war (Clearance vs. rate-constants) started at David’s list. As my father used to say: “If you are a believer, go to church.”

 

Helmut


 Best regards,
Helmut

https://forum.bebac.at/


#5 johnhood2015

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Posted 27 November 2015 - 02:07 PM

Yeah, it's getting a bit heated...



#6 Simon Davis

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Posted 30 November 2015 - 09:51 PM

Helmut, Nice workflow discussion for Cpred, although when using the join you don't need to rename Tlast but can instead just use a Sort Map, then you get to keep Tlast as a variable name that might be advantageous.

 

 Simon



#7 Simon Davis

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Posted 16 January 2019 - 01:50 PM

I forgot to follow up on this topic that with Phoenix 8.0's enhancements to NCA you now get Clast_pred;
(QC 4831 Request for a Pred Clast in the final parameters sheet)

as well as the option to request the conc at any specified time etc.

Also, if you haven't seen it yet, these free sessions from Certara University could be handy to explore some of the other useful new features.

https://www.certarau...w-in-phoenix-80

https://www.certarau...ix-winnonlin-81

Simon.

Edited by Simon Davis, 16 January 2019 - 01:56 PM.






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