ashokraj
☆    

India,
2015-07-22 16:26
(3172 d 19:26 ago)

Posting: # 15124
Views: 4,963
 

 Restriction on widened limit -AUC of HVD [RSABE / ABEL]

Hi all

Can any one through some light on why EMA do not allow widening of CI limits for AUC of HVDs? Whereas RSABE is applicable for AUC as well by USFDA.

rgds/Ashokraj
d_labes
★★★

Berlin, Germany,
2015-07-22 18:03
(3172 d 17:49 ago)

@ ashokraj
Posting: # 15125
Views: 4,188
 

 No scaled ABE for AUC

Dear Ashokraj!

"The Lord moves in mysterious ways."

Regulators are a strange bunch of people.
IMHO there are no scientific reasons behind this decision. Helmut once called it "pure politics". And politics must not be reasonable.

Search the Forum. We had already occasionally exactly that theme.

Regards,

Detlew
Helmut
★★★
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Vienna, Austria,
2015-07-22 18:26
(3172 d 17:26 ago)

@ ashokraj
Posting: # 15128
Views: 4,265
 

 History lesson

Hi Ashokraj,

❝ Can any one through some light on why EMA do not allow widening of CI limits for AUC of HVDs? Whereas RSABE is applicable for AUC as well by USFDA.


There is no scientific justification for it at all. The background is a mishmash of history and politics.

In the dark ages of BE a few products were approved in Europe with a widened (pre-specified) acceptance range of up to 70–143% (i.e., a 30% difference was considered not clinically relevant) for AUC. These were rare exceptions. However, widening for Cmax was pretty common (without requiring a clinical justification). The 2002 NfG stated for AUC “In rare cases a wider acceptance range may be acceptable if it is based on sound clinical justification“. In 2006 EMA backpedaled and stated that widening is acceptable only for Cmax and limited it to 75–133% (if high variability was demonstrated in a replicate design). Given the background of many products on the market approved for an AR of 70–143% for Cmax, EMA decided to cap the scaling at a CVwR of 50% in their 2010 GL. Do you see the similarity in the numbers?

   Dark ages        ABELmax    
70.00 – 142.86   69.84 – 143.19

Obviously EMA didn’t trust in their limited experience with wider limits for AUC – and ignores what’s going on across the pond.

Timeline and summary for AUC:
  • 3CC15a, Jun 1992
    The 90% confidence interval for this measure of relative bioavailability should lie within a bioequivalence range of 0.80–1.25. […] A larger acceptance range may be acceptable if inevitable and clinically accept­able.
  • NfG, Jan 2002
    The 90% confidence interval for this measure of relative bioavailability should lie within an acceptance interval of 0.80-1.25. […] In rare cases a wider acceptance range may be acceptable if it is based on sound clinical justification.
  • Concept paper “Evaluation of BE of HVDs and HVDPs”, Apr 2006
    (removed in Oct 2007 from EMA’s website)
    At the EU level, no clear regulatory guidance exists on how to proceed, especially for AUC, when the reference product is deemed to behave as a HVDP. This leads to different regulatory practices among Member States. The current document is designed to bring some harmonisation in this regard.
  • Q&A, Jul 2006
    The possibility offered here by the guideline to widen the acceptance range of 0.80–1.25 for the ratio of Cmax (not for AUC) should be considered exceptional and limited to a small widening (0.75−1.33).
  • Draft GL, Jul 2008
    In certain cases, Cmax is of less importance for clinical efficacy and safety compared with AUC. When this is applicable, the acceptance criteria for Cmax can be widened to 75-133% […] This approach does not apply to AUC.
  • Overview of comments on the Draft GL, Jan 2010
    C: Consideration of extending the approach to the comparison of AUCs is recommended.
    R: AUC is presently not considered as clinically irrelevant as Cmax. Therefore, scaling for AUC has not been agreed.
    C: Propose same criteria used to widen Cmax bounds also be allowable for AUC.
    R: Clinical irrelevance is a prerequisite. But it is not enough to allow a widening.
  • GL, Aug 2010
    The possibility to widen the acceptance criteria based on high intra-subject variability does not apply to AUC where the acceptance range should remain at 80.00–125.00% regardless of variability.
  • MR-GL, Nov 2014
    The bioequivalence approach considering usual acceptance limits (80.00 – 125.00%) is applicable for generic MR products […]. Any widening of the acceptance criteria for Cmax should follow the re­com­men­dations on highly variable drug products in the Guideline on the Investigation of Bioequivalence […].
    A similar approach can be used for widening the acceptance criteria for Cmax,ss, Cτ,ss, and partialAUC.

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