Bioequivalence and Bioavailability Forum • ICH M13A: Changes to Step 2

ICH M13A: Changes to Step 2 [BE/BA News]

posted by Helmut – Vienna, Austria, 2024-09-06 10:04 (31 d 03:43 ago) – Posting: # 24188
Views: 1,446

Dear all,

a tricky part.

Draft (4. DOCUMENTATION, page 27)
Module 2.7.1 of the CTD should list all relevant BE studies conducted regardless of the study outcome. Full study reports should be provided for the BE study(ies) upon which the applicant relies for approval. For all other studies, synopses of the study reports (in accordance with ICH E3) are sufficient. However, complete study reports for these studies should be available upon request.
Final (page 22)
Unchanged.

In the Questions and Answers (page 16) we find:

Question
If the relevant BE studies conducted with the same formulation under the same study conditions result in different BE outcomes, what action should be taken?
Answer
M13A recommends that all relevant BE studies conducted, regardless of the study outcome, should be provided. If, for a particular formulation at a particular strength, multiple pivotal studies result in inconsistent BE conclusions, the totality of the evidence should be considered. The applicant should discuss the results and justify the BE claim. When relevant, a combined analysis of all studies may be considered as a sensitivity analysis in addition to the individual study analyses. It is not acceptable, however, to pool studies which fail to demonstrate BE without a study that passes.
If there are differences in the study conditions, e.g., sampling times, fasting or fed conditions, or method of administration, pooling is not justifiable. A different number of subjects is not considered a difference in study conditions.

The first paragraph is essentially similar (pun!) to the EMA’s guideline (4.1.8 Evaluation – Presentation of data, page 16):

If for a particular formulation at a particular strength multiple studies have been performed some of which demonstrate bioequivalence and some of which do not, the body of evidence must be considered as a whole. Only relevant studies […] need be considered. The existence of a study which demonstrates bioequivalence does not mean that those which do not can be ignored. The applicant should thoroughly discuss the results and justify the claim that bioequivalence has been demonstrated. Alternatively, when relevant, a combined analysis of all studies can be provided in addition to the individual study analyses. It is not acceptable to pool together studies which fail to demonstrate bioequivalence in the absence of a study that does.What might be considered »relevant« according to the Q&A to justify pooling of studies? See also this post for problems arising if one reports a confidence interval.

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Helmut Schütz

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Complete thread:

ICH M13A: Changes to Step 2 Helmut 2024-07-31 13:16 [BE/BA News]
- ICH M13A: Changes to Step 2 Helmut 2024-07-31 14:19
  - AUCres mittyri 2024-08-05 21:08
    - ‘Percentage covered’ Helmut 2024-08-05 22:13
  - ICH M13A: Changes to Step 2 BEQool 2024-09-09 05:48
    - fixed or mixed effects model Helmut 2024-09-09 07:04
      - fixed or mixed effects model BEQool 2024-09-09 10:18
        
        fixed or mixed effects model Helmut 2024-09-09 11:13
        
        fixed or mixed effects model BEQool 2024-09-10 07:35
      - fixed or mixed effects model Helmut 2024-09-10 08:12
- ICH M13A: Changes to Step 2 Helmut 2024-08-05 12:53
- period within group and formulation mittyri 2024-08-05 20:42
  - period within group and formulation Helmut 2024-08-05 22:29
- ICH M13A: Step 4 → 5 Helmut 2024-08-08 11:57
  - Formal ICH Procedure Helmut 2024-08-09 09:45
- ICH M13A: Changes to Step 2Helmut 2024-09-06 08:04