Bioequivalence and Bioavailability Forum • regulators don’t care?

regulators don’t care? [RSABE / ABEL]

posted by Helmut – Vienna, Austria, 2013-03-26 22:18 (4451 d 07:37 ago) – Posting: # 10291
Views: 25,194

Hi Martin!

❝ totally agree: If the inflation of the type-I-error is real = serious risk to public health (to quote a famous colleague of mine).

Is this the same guy who is (in)famous for publicly calling some approaches “bullshit”?

BTW, α-inflation is not unknown. See the figures and table 1 of the two Lászlós.¹

❝ PS.: IMHO - a-priori specification of the method should control the type-I-error (i.e. CV from historical data or more stringent the corresponding lower confidence limit should be greater than 30% to allow scaling).

I would also say so. Already noted in the past:

Besides, it is not clear at present what kind of regulatory policy will be followed when several σ_WR estimates (i.e. results of previous submissions) are available to a drug regulatory agency. If regulators use all available data, then they can get an improved estimate for σ_WR, and possibly can draw a different conclusion from the sponsor.²

But likely it is wishful thinking to expect a list of acceptance ranges or CVs of reference formulations.

Endrényi L, Tóthfalusi L. Regulatory Conditions for the Determination of Bioequivalence of Highly Variable Drugs. J Pharm Pharmaceut Sci. 2009;12(1):138–49. free online
Tóthfalusi L, Endrényi L, García Arieta A. Evaluation of Bioequivalence for Highly Variable Drugs with Scaled Average Bioequivalence. Clin Pharmacokinet. 2009;48(11):725–43. doi:10.2165/11318040-000000000-00000

Edit: EMA’s data set I (full replicate, n₁ 36, n₂ 37, CV_WR 0.4696) needs no α-adjustment, pBE 0.012061. If the two outliers are excluded (n₁ 34, n₂ 37, CV_WR 0.3216) we require an adjusted α of 0.03149 in order to maintain the consumer’s risk. The 93.70% CIs of 106.03–126.16% (Method A) and 106.10–126.24% (Method B) lie still within the scaled acceptance range of 78.79–126.93%, but it is a close shave…

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Complete thread:

‘alpha’ of scaled ABE? d_labes 2013-03-15 15:56 [RSABE / ABEL]
- ‘alpha’ of scaled ABE? Helmut 2013-03-15 17:27
  - ’alpha’ of scaled ABE: design d_labes 2013-03-16 20:10
    - N=24, 48 d_labes 2013-03-18 08:11
      - adaptive design without adjustment martin 2013-03-25 20:47
        
        α adjustment? Helmut 2013-03-26 15:21
        
        iteratively adjusted alpha martin 2013-03-26 16:19
        
        throw away our sample size tables? Helmut 2013-03-26 18:02
        
        if real martin 2013-03-26 19:44
        
        regulators don’t care?Helmut 2013-03-26 21:18
        
        adjusting α Helmut 2013-08-11 16:19
        
        missing letter apapanas 2024-10-31 06:02
        
        PowerTOST: sampleN.scABEL.ad() Helmut 2024-10-31 08:41
        
        PowerTOST: sampleN.scABEL.ad() apapanas 2024-11-08 10:48
        
        Molins et al. (2017) Helmut 2024-11-08 14:34
        
        target α in sim’s? Helmut 2013-03-27 15:38
        
        target α in sim’s? martin 2013-03-27 16:36
        
        If it is real: results Helmut 2013-03-28 23:20
        
        having alpha martin 2013-03-28 15:08
        
        fixed swr Helmut 2013-03-28 23:34
        
        fixed swr martin 2013-03-29 15:07
        
        Yes but no but yes but no but… Helmut 2013-03-29 16:10