Bioequivalence and Bioavailability Forum • Overpowering

Overpowering [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2013-07-30 17:51 (4707 d 16:24 ago) – Posting: # 11125
Views: 9,608

Hi vasup,

first I agree with what ElMeestro and John stated.

❝ […] use the more number of subjects than required".

My emphasis. The crucial point here is the term “required”. Some guidelines suggest 80–90% power (US-FDA, Canada-HPFB/TGD, Japan-NIHS, Brazil-ANVISA,…), whereas EMA uses the ambiguous phrase “appropriate”.

❝ For example based on the calculation and to get required power 50 subjects are sufficient what will be fate of the study if i use 100 subjects.

Let’s assume you want 90% power with expected CV of 29% and a ratio of 0.95. 50 subjects will give you 90.8% power. If your run the study in 100 – your assumptions are correct and you have no drop-outs – power will be 99.5%. On the other hand, it allows to still have >80% power if the ratio drops to 0.89. The main problem will be IEC-approval. The IEC is concerned with the safety of subjects in the study. Why should they approve a protocol with such a high sample size only minimizing the producer’s risk?

❝ Is acceptable to regulatory agencies.

Some issues:

Submitting of the protocol: At least agencies with a statement about power (≤90%), might reject the protocol. They might also be concerned about “forced bioequivalence”, i.e., although you expect to have a “bad” ratio but don’t officially (!) base your sample size on it (some kind of camouflage tactic).
If the protocol was approved by the agency + IEC and the study was performed in 100 subjects other issues enter the scene:
- The PE is 0.95 (or even closer to 1 and/or lower CV) the study is extremely overpowered. Given that post hoc (aka retrospective) power is not part of the bioequivalence decision, there should be no problem with acceptance. You only wasted money and dosed more subjects than necessary – an ethically problematic situation you should avoid in the future.
- The PE is 0.89* (or even lower if the CV is lower as well) technically you have demonstrated BE. With a PE of 0.85 and a CV of 26% you still have a chance of 51% to show BE. Now put yourself in an assessor’s position: Imagine they have already approved other products with differences of <±5% to the reference in <50 subjects. Assessors decide on the whole body of evidence and “guidelines are guidelines are guidelines”. Do you think they will approve a product with a ratio 10% worse than the other generics on the market? I would not take that for granted. You might end up in a referral and a lot of nasty legal stuff with rather unpredictable outcome.

Confirming what you secretly expected but didn’t state in the protocol because it looks so awful.

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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
- OverpoweringHelmut 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 CV Helmut 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