Bioequivalence and Bioavailability Forum • New Zealand

New Zealand [RSABE / ABEL]

posted by Helmut – Vienna, Austria, 2015-02-01 17:08 (4167 d 12:22 ago) – Posting: # 14338
Views: 26,866

Hi nobody,

❝ I wanted to learn something about the New Zealand approach to HVD mentioned in Wonnemann, 2014 (largely identical to Wonnemann, 2015 I guess, haven't read it completely yet).

There is just one paper. The epub ahead of print of July 2014 and the published version of January 2015.

❝ Unfortunately I could not find something at the NZ reg homepage,…

Wonnemann’s ref. (30) point to the 5^th edition of 2001 which is no more online. If you want I can send you a copy.

❝ …except for a brand new BE guideline,…

That’s the 6^th edition of 2014.

❝ …which, however, mentions HVD only in the context of some "isotope application or replicate design" (emphasize by me) studies, apparently without providing further details:

❝ http://www.medsafe.govt.nz/regulatory/Guideline/GRTPNZ/bioequivalence-of-medicines.pdf

No changes it section 2.5.5 anyhow.

❝ However, it apparently allows the use of sequential design "for studies expected to require a large number of subjects" (p. 20/44). But it states that it is "(n)ormally not practical to use more than 40 subjects in a bioavailability study", without any justification for this statement...

OK, this section is a little bit weired. First they tell us that a study should be designed with sufficient power “normally ≥80%”. Fine. In line with ICH E9 “The number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed”.
Now NZ states “If the calculated number of subjects appears to be higher than is ethically justifiable, it may be necessary to accept a statistical power which is less than desirable. Normally it is not practical to use more than about 40 subjects in a bioavailability study.”
On the contrary! It’s not ethical if a regulator suggests to perform a study in a sample size which will have low power to demonstrate BE. I suspect that n=40 was derived from T/R 0.95, CV 30%, 80% power in a 2×2 crossover. In a 4-period fully replicated study the same values would allow for a CV of 44%. For a CV of 63% and 40 subjects power would already be <50% [sic]. Toss a coin instead! Cheaper.

Talking about sequential designs the GL is ambiguous:

“a study is conducted on a predetermined subset of the required sample” sounds like a group sequential design. If n₁ ≠ ½n_total inflation of the TIE is possible if e.g. Pocock’s 0.0294 is applied (see the section about GSDs in a recent review article).*
“results from the first part of the study can be used to determine how many more subjects should be tested” sounds like an adaptive TSD with sample size re-estimation.
“Appropriate statistical tests (eg, sequential t-test) which make allowance for this design should be used.” Well roared, lion! Must use an adjusted α.
“The ethically justifiable maximum number of subjects should also be considered.” Sounds like a futility criterion. No issues with the TIE, but I hope they don’t mean n=40 again.

Schütz H. Two-stage designs in bioequivalence trials. Eur J Clin Pharmacol. 2015;71(3):271–81. doi:10.1007/s00228-015-1806-2

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Helmut Schütz

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Complete thread:

EMA oracle Helmut 2015-01-27 16:27
- EMA oracle nobody 2015-01-27 17:07
- Personal opinion ElMaestro 2015-01-27 17:56
- EMA oracle d_labes 2015-01-27 19:44
  - EMA oracle nobody 2015-01-28 09:04
    - EMA oracle ElMaestro 2015-01-28 13:11
- Response from Alfredo García-Arieta Helmut 2015-01-30 10:55
  - Response from Alfredo García-Arieta nobody 2015-01-30 14:55
    - Wonnemann’s Figure 4 on steroids Helmut 2015-02-01 01:35
      - Wonnemann’s Figure 4 on steroids nobody 2015-02-01 11:18
        
        Wonnemann’s Figure 4 on steroids Helmut 2015-02-01 14:49
      - General remarks ElMaestro 2015-02-01 18:43
        
        General remarks nobody 2015-02-01 22:04
        General remarks Helmut 2015-02-02 00:48
        
        General remarks nobody 2015-02-02 08:09
        
        General remarks Helmut 2015-02-02 14:06
        
        TIE: questions mittyri 2015-02-03 12:44
        
        TIE: questions Helmut 2015-02-03 13:24
        
        FDA RSABE & alpha inflation d_labes 2015-02-03 12:02
        
        FDA RSABE & alpha inflation Helmut 2015-02-03 12:22
        
        FDA RSABE & alpha inflation d_labes 2015-02-03 13:07
        
        FDA RSABE & alpha inflation Helmut 2015-02-03 13:41
- New Zealand nobody 2015-01-31 11:25
  - New ZealandHelmut 2015-02-01 16:08
    - New Zealand nobody 2015-02-01 22:08
      - New Zealand Helmut 2015-02-01 23:54
        
        New Zealand nobody 2015-02-02 08:07