Bioequivalence and Bioavailability Forum

Hi Shata,

❝ ❝ Any test at level \(\small{\alpha}\) has an unavoidable false positive rate. Do you want to exclude \(\small{(100\times\alpha)\%}\) of subjects although they are in (pseu­do) steady state?

❝

❝ I will not exclude any subjects from analysis, I just need to check achievement of steady state in compliance with EMA guideline.

Under the premise of linear PK, the superposition principle holds, i.e., \(\small{AUC_{0-\infty}=AUC_{0-\tau}}\). In simple terms, we must compare bioavailabilites either after a single dose or in steady-state. If steady-state is not achieved, a comparison is not correct.
What will you do if your ‘check’ fails? Since you don’t want to exclude subjects, would you throw the entire study into the waste container?

❝ The guideline didn't specify the verification method.

Correct.

• 5.1. Pharmacokinetic studies (p. 10)
  Whenever multiple dose studies are performed it should be demonstrated that steady state has been reached. Achievement of steady-state is assessed by comparing at least three pre-dose concentrations for each formulation, unless otherwise justified.
  
• 6.1.1.2. Multiple dose studies (p. 19)
  Whether the steady-state has been achieved is assessed by comparing at least three pre-dose con­cen­tra­tions for each formulation. The apparent half-life should also be taken into account.

Section 5 is applicable for hybrid applications and Section 6 for generics. Don’t know why the half-life entered the scene here and not in Section 5 as well. If we cross the border of flip-flop PK (\(\small{k_\textrm{a}\leq k_\textrm{e}}\)), it will just take longer to reach steady state (i.e., designing the study based on \(\small{k_\textrm{e}}\) would be wrong).

❝ I have reviewed the comments raised for this guidance, the proposed changes in page 53 and page 54 include visual inspection of the last three pre-dose concentrations to verify steady state achievement and the feasibility to use the last 2 pre-dose concentrations and the Ctau instead of the last 3 pre-dose concentrations.

❝ EMA has evaluated the comments.

Yep. Note that though the overview of comments are dated with 17 October 2019 and according to the EMA’s website were published on 29 October 2019, the PDF was modified on 18 May 2020…
On 30 April 2014¹ Jan Neu­hau­ser of the Austrian agency AGES and mem­ber of the CHMP Pharmacokinetics Working Party announced that

»the overview of comments will be published within the next two weeks«.

5½ years ≠ two weeks.

❝ They mentioned in page 4 that clarifications on steady state evaluation was included in the final guidance following stakeholder comments.

If fail to find that in page 4 and anywhere else.

❝ I searched for this final guidance but I didn't find it, the published effective version is still the one came into effect in 2015.

That’s the final one.

❝ Is it feasible to verify steady state visually?

As I wrote in the article:

In 2013² members of the EMA’s Pharmacokinetics Working Party confirmed unanimously that a test is not expected by the agencies. ‘Demonstration of steady state’ should not be understood in the statistical sense. In­stead, individual pre-dose concentrations should be reported together with spaghetti plots and plots of geometric means. In the discussion it became clear that common sense should prevail.

In an earlier meeting³ nothing was mentioned at all.

For 10+ years I’m presenting only summary tables, individual and spaghetti plots. All regulatory assessors were fine with that.

❝ ❝ ❝ Helmert transformation method …

❝ ❝

❝ ❝ Do you have a reference demonstrating its application in PK?

❝

❝ No, I don't have references. It was suggested as the best method for steady state verification by a reviewer during protocol preparation two years ago and accordingly documented in the protocol.

I can’t follow you here. You stated something in the protocol without knowing how to perform the method? Ask the reviewer for help and report back here. I’m curious.

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1. EMA/EGA. Joint workshop on the impact of the revised EMA Guideline on the Pharma­co­kinetic and Clinical Eva­lu­ation of Modified Release Dosage Forms. London, UK. 30 April 2014.
   
2. EUFEPS. BABP Network Open Discussion Forum on the Revised European Guideline on Phar­ma­co­ki­netic and Clinical Evaluation of Mo­di­fied Release Dosage Forms. Bonn, Germany. 17–18 June 2013.
   
3. EUFEPS. BABP Network Open Discussion Forum. Revision of BE Requirements for Modified Release Products Barcelona, Spain. 23–24 February 2011.