Bioequivalence and Bioavailability Forum • CL of CV

CL of CV [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2013-09-06 17:42 (4669 d 00:08 ago) – Posting: # 11453
Views: 8,973

Hi Jay,

❝ Is this method i.e. Upper CI of CV, should be considered while calculating sample size everytime?

I would say so – unless you have a bunch of studies with similar CVs.

❝ We use highest CV of Cmax, Auc0-t or AUCinf observed in pilot or from any literature.

Remember the CV is an estimate itself which carries some degree of uncertainty. This value is not set in stone.
BTW, you can easily see from the formula that the CV from a smaller study is more uncertain (i.e., higher CL due to the lower degrees of freedom) than the one from a larger study. Therefore, the price you have to pay (= sample size penalty if you use the CV’s upper CL) is higher if the pilot study was small.

❝ And is this use of upper CI of CV in sample size calculation commonly used in BE Studies?

Regrettably not. A sensitivity analysis in sample size planning is suggested in ICH-E9 (Section 3.5). Sponsors and CROs don’t care* and the former complain afterwards. :no:

❝ As much unawareness about its usage in Sample size calculation is not here.

–1 × –1 = +1?

Too bad. Imagine you (falsely) believe that the CV is some kind of a natural constant. Since it is an estimate, the true value lies somewhere within its confidence interval. If you plan a study with the “carved from stone” CV you have a 50% chance that the value in the study will be higher. Maybe you fail to show BE (sample size too low). If the value is lower – though you loose money (sample size higher than necessary) – you still show BE. Bingo.

— Sponsors have a tendency to be overly optimistic (Our product is great! Why should we expect a higher CV? Our ratio will be 1 – for sure!) and are always looking for the cheapest “solution”, forgetting that repeating a failed study is not very economic.
— CROs in secret love failed studies (Hey, we might get another – even larger – one!)…

Both views are ethically questionable and bad statistical practice as well (ICH-E9: The number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed.)

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

Sample size vasup 2013-07-29 08:37 [Regulatives / Guidelines]
- Sample size ElMaestro 2013-07-29 10:00
- Sample size jag009 2013-07-29 15:57
- Overpowering Helmut 2013-07-30 15:51
  - Overpowering ElMaestro 2013-07-30 16:37
    - Overpowering jag009 2013-07-30 16:45
      - Overpowering ElMaestro 2013-07-30 16:51
        
        Overpowering jag009 2013-08-01 20:08
        
        Overpowering kumarnaidu 2013-09-02 12:22
        
        Conservative study planning Helmut 2013-09-02 12:42
        
        Conservative study planning kumarnaidu 2013-09-02 14:36
        
        Conservative study planning Ohlbe 2013-09-02 18:44
        
        confidence limit of the CV Jay 2013-09-06 13:55
        
        CL of CV Helmut 2013-09-06 15:02
        
        CL of CV Jay 2013-09-06 15:21
        
        CL of CVHelmut 2013-09-06 15:42
        
        PE consideration Jay 2013-09-11 11:02
        
        PE consideration Dr_Dan 2013-09-11 12:07
        
        PE consideration Jay 2013-09-11 13:09
        PE consideration kumarnaidu 2013-09-11 13:22
        
        Sockpuppet? Helmut 2013-09-11 14:13
        PE consideration kumarnaidu 2013-09-12 13:04