Pharmaceutical Research

, Volume 33, Issue 11, pp 2805–2814 | Cite as

Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence, and a Method for its Control

Research Paper

Abstract

Purpose

To verify previously reported findings for the European Medicines Agency’s method for Average Bioequivalence with Expanding Limits (ABEL) for assessing highly variable drugs and to extend the assessment for other replicate designs in a wide range of sample sizes and CVs. To explore the properties of a new modified method which maintains the consumer risk ≤0.05 in all cases.

Methods

Monte-Carlo simulations of three different replicate designs covering a wide range of sample sizes and intra-subject variabilities were performed.

Results

At the switching variability of CVwR 30% the consumer risk is substantially inflated to up to 9.2%, which translates into a relative increase of up to 84%. The critical region of inflated type I errors ranges approximately from CVwR 25 up to 45%. The proposed method of iteratively adjusting α maintains the consumer risk at the desired level of ≤5% independent from design, variability, and sample size.

Conclusions

Applying the European Medicines Agency’s ABEL method at the nominal level of 0.05 inflates the type I error to an unacceptable degree, especially close to a CVwR of 30%. To control the type I error nominal levels ≤0.05 should be employed. Iteratively adjusting α is suggested to find optimal levels of the test.

KEY WORDS

bioequivalence European Medicines Agency highly variable drugs Monte-Carlo simulation reference-scaling 

ABBREVIATIONS

(A)BE

(Average) bioequivalence

ABEL

Average bioequivalence with expanding limits

AUC

Area under the curve

CI

Confidence interval

Cmax

Maximum observed concentration

CVwR

Within-subject coefficient of variation of the reference treatment

EMA

European Medicines Agency

FDA

(United States) Food and Drug Administration

GMR

Geometric means ratio

HVD(P)

Highly variable drug (product)

k

Regulatory constant

L

Lower expanded acceptance limit for bioequivalence

N

Sample size

n1,2

Number of subjects in sequence 1, 2

R

Reference product

RSABE

Reference-scaled average bioequivalence

T

Test product

TIE

Empiric type I error (probability of α, consumer risk)

U

Upper expanded acceptance limit for bioequivalence

α

Nominal level of the statistical test

αadj

Adjusted α

θ

True T/R ratio

Supplementary material

11095_2016_2006_MOESM1_ESM.doc (994 kb)
ESM 1(DOC 994 kb)
11095_2016_2006_MOESM2_ESM.xls (203 kb)
ESM 2(XLS 203 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Cooperative Clinical Drug Research and Development AGNeuenhagenGermany
  2. 2.BEBAC – Consultancy Services for Bioequivalence and Bioavailability StudiesViennaAustria

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