HVDs? [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2008-09-23 14:52 (6112 d 13:11 ago) – Posting: # 2388
Views: 24,391

[image]Dear all!

another one from the 'Far Side':

Standard design, page 5 (lines 148-151)
'If two formulations are going to be compared, a two-period, two-sequence single dose crossover design is the design of choice. The treatment periods should be separated by an adequate wash out period.'
Alternative designs, page 6 (lines 172-175)
'Under certain circumstances, provided the study design and the statistical analyses are scientifically sound, alternative well-established designs could be considered such as [...] replicate designs e.g. for substances with highly variable pharmacokinetic characteristics (see section 4.1.10).'
Number of subjects, page 7 (lines 223-224)
'The number of subjects to be included in the study should be based on an appropriate sample size calculation. The minimum number of subjects in a cross-over study should be 12.'
Acceptance limits, page 14 (lines 561-562)
'[...] Moreover, for highly variable drugs the acceptance interval for Cmax may in certain cases be widened (see section 4.1.10).'
4.1.10 Highly variable drugs or drug products, page 16 (lines 631-641)
'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% provided that all of the following are fulfilled:
  • the widening has been prospectively defined in the study protocol
  • it has been prospectively justified that widening of the acceptance criteria for Cmax does not affect clinical efficacy or safety
  • the bioequivalence study is of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%.
This approach does not apply to AUC.
It is acceptable to apply either a 3-period or a 4-period crossover scheme in the replicate design study.'

OK, in my understanding (1) and (2) of 4.1.10 were already stated in the current NfG (2001) - although (2) was not mandatory according to the Q&A-document (CV>30% was enough), the second part of (3) had already to be demonstrated in a replicate design pilot study (Q&A) - but what do we gain from the first part of (3) = mandatory replicate design?
If scaling is not allowed, it makes no difference in terms of power to run a study in a 2x2 design in 96 subjects or in a 2x4 replicate design in 48 subjects. We only increase the chance of drop-outs due to events in the washout phases (3 as compared to 1).
Example: We assume a dropout rate of 10% / washout. In the 2x2 study in 96 subjects this means 96+10=106 (212 treatments), in the 2x4 study in 48 subjects: 48+16=64 (256 treatments). Ethically?
From a practical point of view a replicate design offers some insights on within-subject variability, but we are not allowed to exclude outliers anyway. So why all that fuzz?
One of the authors told me that he will have no problems in accepting a study combining 'everything' in one pot: replicate pilot -> HVD demonstrated -> second (BE) phase -> pooling. Is this the intention? Nice, but I would be glad if someone would tell me a valid statistical procedure (no, Bonferroni most likely will not do the job).
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