regulators don’t care? [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2013-03-26 21:18 (2969 d 21:35 ago) – Posting: # 10291
Views: 18,177

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 σWR 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 σWR, 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.

  1. 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
  2. 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, CVWR 0.4696) needs no α-ad­just­ment, pBE 0.012061. If the two outliers are excluded (n1 34, n2 37, CVWR 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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