Bioequivalence

Dr Mohammad Issa Saleh

 Bioequivalence
• Two medicinal products are bioequivalent
if they are pharmaceutically equivalent
or pharmaceutical alternatives and if
their bioavailabilities after administration in
the same molar dose are similar to such a
degree that their effects, with respect to
both efficacy and safety, will be essentially
the same.
 Pharmaceutical equivalents and
alternatives
• Medicinal products are pharmaceutically equivalent if
they contain the same amount of the same active
substance(s) in the same dosage forms that meet the
same or comparable standards
• Medicinal products are pharmaceutical alternatives if
they contain the same active moiety but differ in
chemical form (salt, ester, etc.) of that moiety, or in the
dosage form or strength
• It is well known that pharmaceutical equivalence does
not necessarily imply bioequivalence as differences in
the excipients and/or the manufacturing process can
lead to faster or slower dissolution and/or absorption.
 Bioequivalence
• Bioequivalence is defined as the absence
of a significant difference in the rate and
extent to which the active ingredient or
active moiety in pharmaceutical
equivalents or pharmaceutical alternatives
becomes available at the site of drug
action when administered at the same
molar dose under similar conditions in an
appropriately designed study.
 Therapeutic equivalence
• A medicinal product is therapeutically equivalent with
another product if it contains the same active substance
or therapeutic moiety and, clinically, shows the same
efficacy and safety as that product, whose efficacy and
safety has been established.
• In practice, demonstration of bioequivalence is generally
the most appropriate method of substantiating
therapeutic equivalence between medicinal products,
which are pharmaceutically equivalent or pharmaceutical
alternatives, provided they contain excipients generally
recognized as not having an influence on safety and
efficacy and comply with labeling requirements with
respect to excipients.
 Therapeutic equivalence
• However, in some cases where similar
extent of absorption but different rates of
absorption are observed the products can
still be judged therapeutically equivalent if
those differences are not of therapeutic
relevance.
• A clinical study to prove that differences in
absorption rate are not therapeutically
relevant will probably be necessary
 Design and conduct of
bioequivalence studies
• Crossover design and alternatives
• Single- vs. multiple-dose studies
• Pharmacokinetic characteristics
• Subjects
• Statistical models
 Standard 2×2 Crossover design
Period

I II
Randomization

Sequence 1 Reference Test

Washout
Subjects

Sequence 2 Test Reference

Standard 2×2 Crossover design
• A bioequivalence study should be designed in such a
way that the formulation effect can be distinguished from
other effects. In the standard situation of comparing a
test formulation (T) with a reference formulation (R), the
two-period, two-sequence crossover design is the RT/TR
design.
• Subjects are randomly allocated to two treatment
sequences; in sequence 1, subjects receive the
reference formulation and test formulation in periods 1
and 2, respectively, while in sequence 2, subjects
receive the formulations in reverse order.
• Between period 1 and period 2 is a washout period,
which has to be sufficiently long to ensure that the effect
of the preceding formulation has been eliminated.
 Alternative designs
• Under certain circumstances and provided
that the study design and the statistical
analyses are scientifically sound,
alternative designs could be considered
such as a parallel group design for
substances with a very long half-life and
replicate designs for substances with
highly variable disposition.
 Two-group parallel design

Randomization Group 1 Reference

Subjects

Group 2 Test
 Two-group parallel design
• Each subject receives one and only one
formulation of a drug in a random fashion.
• Usually each group contains the same
number of subjects.
• Higher subject numbers compared to a
cross-over design, since the between-
subject variability determines sample size
(rather than within-subject variability).
 Two-group parallel design
• Advantages
– Clinical part (sometimes) faster than crossover.
– Straigthforward statistical analysis.
– Drugs with long half life.
– Studies in patients.

• Disadvantages
– Lower statistical power than crossover (rule of thumb:
subject number should at least be doubled).
– Phenotyping mandatory for drugs showing
polymorphism.
Single- vs. multiple-dose studies
• In general, single-dose studies will suffice
• Steady-state studies may be required in:
– The case of dose- or time-dependent
pharmacokinetics.
– The case of some modified release products
(prolonged release formulations and transdermal drug
delivery systems), steady-state studies are required in
addition to the single-dose investigations.
• Steady-state studies can be considered:
– If problems of sensitivity preclude sufficiently precise
plasma concentration measurements after single
dose administration
 Subjects
• The subject population for bioequivalence studies should
be selected with the aim of minimizing variability and
permitting detection of differences between
pharmaceutical products.
• Therefore, the studies should normally be performed
with healthy volunteers. Subjects could belong to either
sex; however, the risk to women of childbearing potential
should be considered on an individual basis.
• In general, subjects should be between 18–55 years old,
of weight within the normal range, preferably
nonsmokers, and without a history of alcohol or drug
abuse.
• They should undergo a routine screening of clinical
laboratory tests and a comprehensive medical
examination.
 Subjects
• If the investigated active substance is known to have
adverse effects and the pharmacological effects or risks
are considered unacceptable for healthy volunteers, it
may be necessary to use patients instead, under suitable
precautions and supervision.
• Phenotyping and/or genotyping of subjects should be
considered for exploratory bioavailability studies and all
studies using parallel group design. If the metabolism of
a drug is known to be affected by a major genetic
polymorphism, studies could be performed in panels of
subjects of known phenotype or genotype for the
polymorphism in question.
 Statistical models
• Average bioequivalence
• Population bioequivalence
• Individual bioequivalence
 Average bioequivalence
• Based upon the two-period, two-sequence
crossover design, average bioequivalence
is concluded if the two-sided 90 %
confidence interval for the test/reference
ratio of population means is within the
appropriate bioequivalence acceptance
range, for example (0.80, 1.25).
 Population bioequivalence
• Population bioequivalence encompasses equivalence
of the entire distributions of the respective metric
between test and reference
• Since the lognormal distribution is fully described by
the median and the variance, population
bioequivalence is commonly restricted to the
equivalence of population medians and variances for
test and reference
• Hence, the conventional RT/TR crossover design may
be used to assess bioequivalence in a stepwise
approach. Starting with average bioequivalence,
population equivalence will be considered only if
average equivalence is approved
 Individual bioequivalence
• The primary objective for introducing
individual bioequivalence is to account for
subject by- formulation interaction, and to
use the comparison of the reference
formulation to itself as the basis for the
comparison of test and reference.
• In contrast to average and population
bioequivalence, individual bioequivalence
compares within-subject distributions of the
respective bioavailability metrics, and thus,
needs at least replication of the reference
formulation