Bioequivalence and Bioavailability Forum • Regulators view of HVD drugs

Regulators view of HVD drugs [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2017-05-16 17:01 (2867 d 23:29 ago) – Posting: # 17358
Views: 23,274

Hi David,

❝ For the sake of curiosity, in your opinion should a regulator approve a generic submited as "highly variable" although all the previous trials reported low CV's? Technically, the criteria are well defined and no objection should be raised in principle. However, should a study that reports an high variation, when all the previous information reports otherwise, be considered scientifically sound for the demonstration of bioequivalence?

Is the high variability enough to trigger an inspection? Likely. See Section 2 of the EMA’s CMDh Guidance on triggers for inspections of bioequivalence trials: Quick scan.

Question 6.
Are there any observations which raise concerns about the quality or validity of the reported study data in general? E.g.:
- study data too clean / too messy;
- data/results in contradiction to published and known data (e.g. distribution and/or characteristics of volunteers) on this product/active substance;
- conflicting results between studies regarding pharmacokinetic parameters or overall/intra-subject variability.
General considerations
Although response to these questions may not always be easily found, the issues raised should be taken seriously.
Issues should generally be judged based on proper knowledge on bioequivalence testing methodologies.
In case it is known, the conduct and outcome of the study may be compared with previous studies in order to check for potential issues.

Can an inspection reveal bad study conduct increasing the variability? Possibly not.
Regulators should assess studies based on the “whole body of evidence”. Would an assessor have the guts to reject an application without relevant findings in an inspection and risk to be overruled by the CHMP in a referral? Duno.

❝ Ideally, regulators would publish in their product-specific guidelines which compounds could be considered "highly variable"...

True. Takes a while. As of today there are only 36 (adopted + draft). Reference-scaling recommended for capecitabine, levodopa/carbidopa/entacapone, posaconazole. In all other cases applicants are left out in the rain with this footnote:

As intra-subject variability of the reference product has not been reviewed to elaborate this product-specific bioequivalence guideline, it is not possible to recommend at this stage the use of a replicate design to demonstrate high intra-subject variability and widen the acceptance range of Cmax. If high intra-individual variability (CVintra > 30 %) is expected, the applicants might follow respective guideline recommendations.

IMHO, this is a vicious circle

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Complete thread:

Highly Variable Drug BE Justification jag009 2017-03-20 04:42 [Regulatives / Guidelines]
- Highly Variable Drug BE Justification ElMaestro 2017-03-20 06:55
  - Study costs: Replicate vs. 2×2×2 Helmut 2017-03-20 13:12
    - Study costs: Replicate seems to be cheaper VStus 2017-03-21 12:49
      - Study costs: Replicate seems to be cheaper Dr_Dan 2017-03-21 13:06
        
        Study costs: Replicate seems to be cheaper Helmut 2017-03-21 14:50
        
        expected power d_labes 2017-03-21 15:16
        Doesn't hurt! VStus 2017-03-23 14:24
    - Study costs: Replicate vs. 2×2×2 mahmoud-teaima 2017-03-23 08:17
    - Study costs: Replicate vs. 2×2×2 M.tareq 2017-05-07 21:21
      - Replicate vs. 2×2×2 (ethics?) Helmut 2017-05-08 14:21
        
        Replicate vs. 2×2×2 (ethics?) nobody 2017-05-08 14:52
        
        Applicability of reference-scaling Helmut 2017-05-10 14:10
        
        Replicate vs. 2×2×2 M.tareq 2017-05-14 23:04
        
        Replicate vs. 2×2×2 Helmut 2017-05-15 19:07
        
        Replicate vs. 2×2×2 M.tareq 2017-05-15 21:02
        Regulators view of HVD drugs DavidManteigas 2017-05-16 12:41
        
        Regulators view of HVD drugsHelmut 2017-05-16 15:01
        What's the problem? ElMaestro 2017-05-17 03:30
        
        What's the problem? nobody 2017-05-17 07:48
        
        What's the problem? nobody 2017-05-17 09:31
        
        What's the problem? DavidManteigas 2017-05-17 11:25
        
        What's the problem? ElMaestro 2017-05-17 12:07
        
        What's the problem? kumarnaidu 2017-07-11 14:43
        
        What's the problem? ElMaestro 2017-07-11 14:56