Average bioequivalence

Patterson SD, Zariffa NM, Montague TH, Howland K Nontraditional study designs to demonstrate average bioequivalence for highly variable drug products. Eur. J. Clin. Pharmacol. (2001) 57 663—670. 

Tothfalusi, L. and Endrenyi, L., Limits for the scaled average bioequivalence of highly variable drugs and drug products, Pharmaceutical Research, Vol. 20, No. 3, 2003, pp. 382-389. 

Karalis, V., Symillides, M., and Macheras, P., Novel scaled average bioequivalence limits based on GMR and variability considerations, Pharmaceutical Research, Vol. 21, No. 10, 2004, pp. 1933-1942. 

Patnaik, R.N. Lesko, L.J. Chen, M.L. Individual bioequivalence. New concepts in the statistical assessment of bioequivalence metrics. FDA individual bioequivalence working group. Clin. Pharmacokine. 1997, 33 (1), 1-6. Midha, K.K. Rawson, M.J. Hubbard, J.W. Individual and average bioequivalence of highly variable drugs and drug products. J. Pharm. Sci. 1997, 86 (11), 1193-1197. 

Classically, the assessment of BE relies on the concept of average bioequivalence (ABE)... 

It has been also suggested that the regulatory criterion of ABE, in the case of HV drugs, could be scaled by a standard deviation, leading to an approach known as scaled average bioequivalence (ABEsc) (59,60). The acceptance criterion is then defined as... 

Schall R. A unified view of individual, population, and average bioequivalence. In Blume H, Midha K, eds. Bio-intemational 2 Bioavailability, Bioequivalence and Pharmacokinetic Studies. Stuttgart Medpharm Scientific Publishers, 1995 91-106. 

This is another historical curiosity. At one time it was proposed that, in addition to satisfying the requirement for average bioequivalence, the bioavailability of the test drug should be proved to be within 75% of that for the reference for 75% of the subjects. The intention of this, perhaps, was to address the issue of individual bio availability. This sort of requirement suffers from the same difficulties covered by the requirement for 15% FEVi bronchodilation in Chapter 8. 

Steinijans VW, Hauschke D, Schall R (1995) International harmonization of regulatory bioequivalence requirements for average bioequivalence and current issues in individual bioequivalence. Drug Information Journal 29 1055-1062. 

The current evaluation criteria are based on the two one-sided test approach, also commonly referred to as the Confidence Interval Approach or Average Bioequivalence, which determines whether the average values for the pharmacokinetic parameters measured after the administration of test and reference products are comparable. This approach involves the calculation of a 90% confidence interval about the ratio of the averages of T and R products for AUC and values. To establish bioequivalence, the AUC and of the T product should not be less than 0.80 (80%) or greater than 1.25 (125%) of the R product based on log-transformed data (i.e., a bioequivalence limit of 80 to 125%). For some time prior to the use of log-transformed data, the nontransformed data were used to assess bioequivalence. In 1989, it was realized that log transformation of the data enables a comparison based on the ratio of the two averages rather than the difference between the averages in an additive manner." Moreover, most biological data correspond to a log-normal distribution rather than to a normal distribution. 

More recent proposals discussed for evaluating bioequivalence are based on approaches termed Individual Bioequivalence and Population Bioequivalence. The average bioequivalence approach focuses only on the comparison of population averages (p, p ) of a bioequivalence metric of interest and not on the variances of the metric for the T and R products. The individual bioequivalence approach not only compares the population averages (pj, p ), but also assesses the within-subject variability (o t, o r ) as well as the subject-by-formulation interaction (Od ). The population bioequivalence approach is designed to assess the total variability, i.e., within- and between-subject variability (o, Oxr ) of the pharmacokinetic parameter (metric) in the population. The individual and population bioequivalence... 

In relation to residues in food-producing species, it is important to recognize that demonstration of average bioequivalence does not obviate the need for separate residue depletion studies for a generic product. There are several reasons why this is so ... 

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