mahmoud-teaima
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2017-05-22 15:55
(2502 d 02:54 ago)

Posting: # 17387
Views: 5,248
 

 Sample Size calculation and setting of BE limit base on Cmax or AUC [Power / Sample Size]

Dear all,
Please, advise on sample size estimation and setting of BE limits in the following situations where ISV for Cmax and AUC are far apart.

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Greetings.

Mahmoud Teaima, PhD.
Helmut
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2017-05-22 17:16
(2502 d 01:34 ago)

@ mahmoud-teaima
Posting: # 17388
Views: 4,611
 

 PK metric with largest variability – generally – drives the sample size

Salam Mahmoud,

❝ Please, advise on sample size estimation and setting of BE limits in the following situations where ISV for Cmax and AUC are far apart.


You have to demonstrate BE for both. Since in your example Cmax seems to be highly variable I assumed a T/R-ratio of 0.9 (and not the observed despite that it is close to 1) and the same for AUC. Target power 80%.
Two options for the EMA:
  1. Reference-scaling acceptable (widening of the limits for Cmax clinically justifiable), RTRT|TRTR design.

        Design method metric   GMR    CV     LL     UL  n  power  GMRlo
     RTRT|TRTR   ABEL   Cmax 0.900 0.336 0.7799 1.2822 34 0.8040   <NA>
     RTRT|TRTR    ABE    AUC 0.900 0.202 0.8000 1.2500 34 0.9613 0.8717

    Regulator: EMA (ABEL applicable if CVwR of Cmax >0.3).
    PK metric ruling the sample size: Cmax
    Sample size: 34 (ABEL, power: 0.8040)
    Power of AUC (ABE): 0.9613
    Lowest GMR of AUC which will give power 0.8: 0.8717
    Total number of treatments in study: 136


  2. Reference-scaling not acceptable (conventional ABE)

    1. RTRT|TRTR design.

          Design method metric   GMR    CV     LL     UL  n  power  GMRlo
       RTRT|TRTR    ABE   Cmax 0.900 0.336 0.8000 1.2500 50 0.8132   <NA>
       RTRT|TRTR    ABE    AUC 0.900 0.202 0.8000 1.2500 50 0.9938 0.8586

      PK metric ruling the sample size: Cmax
      Sample size: 50 (ABE, power: 0.8132)
      Power of AUC (ABE): 0.9938
      Lowest GMR of AUC which will give power 0.8: 0.8586
      Total number of treatments in study: 200


    2. TR|TR design.

      Design method metric   GMR    CV     LL     UL  n  power  GMRlo
        RT|TR    ABE   Cmax 0.900 0.336 0.8000 1.2500 98 0.8046   <NA>
        RT|TR    ABE    AUC 0.900 0.202 0.8000 1.2500 98 0.9928 0.8593

      PK metric ruling the sample size: Cmax
      Sample size: 98 (ABE, power: 0.8046)
      Power of AUC (ABE): 0.9928
      Lowest GMR of AUC which will give power 0.8: 0.8593
      Total number of treatments in study: 196

For the FDA you could try reference-scaling (no justification needed, applicability depends on swR). RTRT|TRTR design.

    Design method metric   GMR    CV     LL     UL  n  power  GMRlo
 RTRT|TRTR  RSABE   Cmax 0.900 0.336 0.7468 1.3390 28 0.8064   <NA>
 RTRT|TRTR  RSABE    AUC 0.900 0.202 0.8000 1.2500 28 0.9168 0.8984

Regulator: FDA (RSABE applicable to PK metrics with CVwR ≥0.3).
PK metric ruling the sample size: Cmax
Sample size: 28 (RSABE, power: 0.8064)
Power of AUC (RSABE): 0.9168
Lowest GMR of AUC which will give power 0.8: 0.8810
Total number of treatments in study: 112

For ABE the outcome is the same as for the EMA’s 2.a and 2.b. above.

You can see that the variability of Cmax (even for reference-scaling) drives the sample size. However, you get an incentive. Power for AUC will be (much) higher than the target. Hence, its T/R-ratio can deviate more from 1 than expected (as shown above in the column GMRlo) or its CV can be higher whilst still maintaining the target level.

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mahmoud-teaima
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2017-05-23 14:31
(2501 d 04:18 ago)

@ Helmut
Posting: # 17392
Views: 4,555
 

 Regulatory guidance versus literature data

Salam Helmut,
Thank you for the detailed, evidence-proofed explanation.

The problem here is that literature data archiving the PKs and output of previous BE studies on simvastatin show border ISV with CV around 30% (29% - 33%).

On the contrary, till the moment, the FDA guidance for BE study on Simvastatin doesn't involve reference scaling
https://www.fda.gov/downloads/Drugs/.../Guidances/ucm086171.pdf
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm089636.pdf

So, the straightforward question is:
Does the BE study of Simvastatin involve reference scaling due the border ISV of simvastatin derived from literature though the regulator doesn't imply that?

Greetings.

Mahmoud Teaima, PhD.
Helmut
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2017-05-23 15:15
(2501 d 03:35 ago)

@ mahmoud-teaima
Posting: # 17394
Views: 4,612
 

 FDA: If RSABE not recommended in product-specific guidance

Salam Mahmoud,

❝ The problem here is that literature data archiving the PKs and output of previous BE studies on simvastatin show border ISV with CV around 30% (29% - 33%).


❝ On the contrary, till the moment, the FDA guidance for BE study on Simvastatin doesn't involve reference scaling https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm089636.pdf


Note that this guidance was recommended in August 2008 – way before the FDA considered reference scaling acceptable (Progesterone, April 2010).

❝ Does the BE study of Simvastatin involve reference scaling due the border ISV of simvastatin derived from literature though the regulator doesn't imply that?


Until the FDA updates the product-specific guidance, it is still worthwhile to give it a try. See the draft guidance “Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA” lines 119–121 and footnote 10. For the FDA you have to submit the protocol for review anyway. See also Section VI.B. of “ANDA Submissions – Refuse-to-Receive Standards”.

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mahmoud-teaima
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2017-05-23 18:20
(2501 d 00:29 ago)

@ Helmut
Posting: # 17400
Views: 4,400
 

 FDA: If RSABE not recommended in product-specific guidance

Salam Helmut,

❝ submit the protocol for review anyway.


Totally, agree with that.

Many thanks for advise.

Greetings.


Edit: Standard quotes restored; see also this post #8. [Helmut]

Mahmoud Teaima, PhD.
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