Helmut
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Vienna, Austria,
2005-09-20 14:58

Posting: # 33
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 European NfG Update? [Regulatives / Guidelines]

There have been rumors during last week's IIR's 'Dissolution, Biovailability & Bioequivalence 2005' conference in Amsterdam about a planned Update of the European NfG (Note for Guidance) on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98).

Potential candidates for a change are:
3.1 Design
where for HVDs a steady-state study in order to reduce variability may not be acceptable any more. A replicate design should be considered instead.
A maximum number of subjects (e.g., n=40 as in New Zealand’s Guideline) is also under discussion.
3.6.2 Acceptance range for pharmacokinetic parameters
which according to the current NfG may be widened from 0.8–1.25 if prospectively defined and justified based on clinical grounds (i.e., safety or efficacy concerns for patients switched between formulations). This procedure provoced a good deal of discussions between applicants and regulators; dropping the widened acceptance range would lead to harmonization with the FDA, where not exceptions are allowed.

Hopefully, the picture will be sharpened next month at the Bio-International 2005 in London.

Cheers,
Helmut Schütz
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Helmut
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Vienna, Austria,
2006-05-25 12:15

@ Helmut
Posting: # 136
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 Concept Paper for Addendum to NfG: HVDs

Dear all,

EMEA recently published a

'Concept paper for an Addendum to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence: Evaluation of Bioequivalence of Highly Variable Drugs and Drug Products'.


For more informations see this post.

Cheers,
Helmut Schütz
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Helmut
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Vienna, Austria,
2006-08-16 19:18

@ Helmut
Posting: # 221
Views: 6,335
 

 Q&A Document to European NfG

Dear all,

after almost two years of rumors, today a 'Question and Answers Document' to the European BA/BE-Note for Guidance was published by EMEA - dated 27 July 2006. ;-)

I added the link to the Guidance page; here is the direct link (118kB PDF) to the document as well.

Main points of the document are
  1. Introduction
  2. Wider acceptance range for Cmax (generally discouraged, only in rare cases, limited to 0.75–1.33)
  3. Outliers. Forget it.
  4. One confidence limit outside 0.80 or 1.25: not bioequivalent, but must be seen within the pharmacokinetic / pharmacodynamic context.
  5. Nonparametrics for parameters other than tmax. See my personal remarks below :angry:
  6. Use of metabolite data (still ambiguous conditions ar given).
  7. Widening of Cmax-limits for metabolites (same conditions as given in #2 but even more restrictive).
  8. Definition of a HVD / HVDP (30% intra-subject CV).
  9. Selection of strenghts for drugs with non-linear PK.
  10. Urinary PK data in BE.
  11. Standardization of food intake.
My personal favorite is Section 2 concerning Cmax:

‘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).’

… which is in contradiction to the NfG, which states for the AUC-ratio:

‘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.’

So by a little sidestep widening of the acceptance range for AUC is now prohibited! ;-)

Another nice one comes from Section 5:

‘Parametric testing using ANOVA on log-transformed data should be the rule. Results from non-parametric statistical methods or other statistical approaches are nevertheless welcome as sensitivity analyses. Such analyses can provide reassurance that conclusions from the experiment are robust against violations of the assumptions underlying the analysis strategy.’

The problem with ANOVA is the non-robustness against violations of assumptions. IMHO it’s simply a bizarre idea to show robustness of ANOVA with a nonparametric analysis.

Cheers,
Helmut Schütz
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Jaime_R
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Barcelona,
2006-08-18 15:54

@ Helmut
Posting: # 224
Views: 6,139
 

 Q&A Document to European NfG

Hi Helmut,

after browsing through the document, I'm a little bit confused...

Are the rumors of a nostalgic 'Habsburgian' conspiracy with some Hungarian/Spanish/Dutch touch true? ;-)

What makes me wonder is the fact that it took nine drafted versions to proceed from one adopted NfG on BA/BE (1992) to the last one (2001): endless discussions, presentations at international conferences, etc.

The MR-NfG obviously remains 'stuck' at Draft #15 from 1999, and now we have a Q&A document which was (secretly?) prepared by an anonymous 'Therapeutic Subgroup on Pharmacokinetics (EWP-PK)': no drafted versions, no public discussion, etc.

I'm asking myself whether the EWP-PK (with its eight members, again according to rumors...) is representative of the European Regulatority Authorities?

But possibly preparing such a document is just a displacement activity for the real important stuff: two separate guidances for BA and BE!

Regards, Jaime
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