Beruflich Dokumente
Kultur Dokumente
ORIGINAL PAPER
Lopes N, BPharm, MBA, b Ruas K, BPharm, a Serra CHdR, BPharm, MSc, PhD, a Porta V, BPharm, MSc, PhD
a
Department of Pharmacy, Universidade de So Paulo, So Paulo
b
Subrosa Consultoria Ltda, So Paulo
Abstract
The introduction of generic medicines brings about the debate around drug efficacy and safety, where
bioavailability and bioequivalence play an important role. In recent years, many questions have emerged
regarding utilisation of average bioequivalence as the only criterion of evaluating bioequivalence for all
drug categories. In this scenario, population and individual bioequivalence were presented as alternative
criteria. This paper aims to discuss some of the main questions concerning average bioequivalence as criterion of evaluating bioequivalence, especially in the interchangeability aspect, and emphasises the main
differences among these three methodologies: average, population and individual bioequivalence.
Keywords: average bioequivalence; individual bioequivalence; population bioequivalence; interchangeability; generic drugs
Introduction
Debate around generic drugs efficacy and safety is not a recent
issue. In the very beginning of the last century, the US Congress approved the Biologics Control Act dating from July 1st
1902, it established the need for annual licensing of companies
that manufactured and sold vaccines and serum derivatives.
From that time on, labels for such products were required to
contain the manufacturers name and licence number, and
production was to be supervised by qualified professionals.1
The introduction of generic medicines in the US market came
in 1984, through the Drug Price Competition and Patent
Restoration Act (also known as Hatch-Waxman Act). By then,
several discussions on drug efficacy and safety had been
raised, with the concepts of bioavailability and bioequivalence
as centre topics.1
Since the American Food and Drug Administration (FDA) introduced regulations for bioequivalence and bioavailability studies
in 1977, methodology and criteria for proof of bioequivalence
have been the object of many debates and improvements,2
having served as regulatory milestones for different countries.
In Brazil, for instance, the Generic Drug Law3 was introduced
on February 10th 1999, with the technical regulation originally
issued by the local regulatory agency, ANVISA (Agncia
Nacional de Vigilncia Sanitria), on August 9th 1999.4 In 1992,
the FDA published its first guide on statistical procedures for in
vivo bioequivalence studies and established average bioequivalence as the criterion for bioequivalence assessment between
the test drug and the reference drug.5 Similarly, the same
criterion was adopted by ANVISA in 2003.6
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In spite of great improvements over the last years, many debates have been raised around the usage of average bioequivalence as the sole criterion for all drug categories, mainly for
those which have a narrow therapeutic range and also for those
which display great intra- or inter-subject variability. For such
categories, population and individual bioequivalence have appeared as alternative criteria for bioequivalence assessment.5,7-9
In 1999, FDA issued a Draft Guidance concerning several
criteria for bioequivalence proof the Average, Population and
Individual Approaches to Establishing Bioequivalence.10 In 2001,
it also published a guide covering statistical aspects of average,
population and individual bioequivalence the FDA Guidance
on Statistical Approaches to Establishing Bioequivalence.11
This article discusses some of the issues concerning the use
of average bioequivalence as criterion for bioequivalence (BE)
evaluation and also highlights the main differences among the
three bioequivalence methodologies average (ABE), population (PBE) and individual (IBE).
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ORIGINAL PAPER l
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ORIGINAL PAPER
Final considerations
Although bioequivalence might not be a recently established parameter, there are still debates in search of more precise evaluation criteria. As such criteria are able to tackle efficacy and
safety issues, frequently raised by clinical practice; they could be
incorporated in further discussions by regulatory agencies.
Meanwhile, in spite of publications commenting on the limitations of average bioequivalence, it remains the most frequently
recommend criterion by regulatory agencies.6,11,19 ABE limitations
for highly variable drugs and narrow therapeutic drugs are known
and may be addressed by modification of the acceptance limits20.
However, studies with replicate design have been considered to
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Evaluation criteria
(T- R) BE*
(T - R)2+ (sTT2 - sTR2)
sTR2
IBE
Population averages (T; R)
2
2
2
2
Intra-subject variances (SWT2, SWR2) (T- R) + (sWT - sWR ) + SD
Subject-by-formulation interaction
variance (SD2)
sWR2
BE*
BE*
evaluate highly variable drugs/drug products,20 which is an indication that the use of population and individual bioequivalence may
be an alternative to ABE for specific drug products. At the present
time, they are recommended by the FDA only under special
circumstances, when there is need for more precise bioavailability
measurements than those resulting from the ABE criterion.11r
References:
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