BIOEQUIVALENCE STUDIES

1. z
BIOEQUIVALENCE
STUDIES

2. z
Need/Objectives
 If a new product is intended to be a substitute
for an approved medicinal product as a
pharmaceutical equivalent or alternative, the
equivalence with this product should be
shown or justified.
 In order to ensure clinical performance of such
drug products, bioequivalence studies should
be performed. Bioequivalence studies are
conducted if there is:
 A risk of bio-inequivalence and/or
 A risk of pharmacotherapeutic failure or
diminished clinical safety.

3. z
Bioequivalence studies are conducted if ..
 A risk of bio-inequivalence and/or
 A risk of pharmacotherapeutic failure or
diminished clinical safety.

4. z
IMPORTANT TERMS
Equivalence: It is a relative term that
compares drug products with respect to
a specific characteristic or function or
to a defined set of standards. There are
several types of equivalences.
 Chemical Equivalence: It indicates that
two or more drug products contain the
same labelled chemical substance as an
active ingredient in the same amount

5. z
IMPORTANT TERMS
 Pharmaceutical Equivalence: This term
implies that two or more drug products are
identical in strength, quality, purity, content
uniformity and disintegration and
dissolution characteristics; they may
however differ in containing different
excipients.
 Bioequivalence: It is a relative term which
denotes that the drug substance in two or
more identical dosage forms, reaches the
systemic circulation at the same relative
rate and to the same relative extent i.e. their
plasma concentration-time profiles will be
identical without significant statistical
differences.

6. z
IMPORTANT TERMS
 Therapeutic Equivalence: This term
indicates that two or more drug
products that contain the same
therapeutically active ingredient
elicit identical pharmacological
effects and can control the disease to
the same extent.

7. z
IMPORTANT TERMS
 Therapeutic Equivalence: This term
indicates that two or more drug
products that contain the same
therapeutically active ingredient
elicit identical pharmacological
effects and can control the disease to
the same extent.

8. z
Oral immediate release products with systemic action
 Indicated for serious conditions requiring assured response
 Narrow therapeutic margin
 Pharmacokinetics complicated by absorption < 70% or
absorption window, nonlinear kinetics, presystemic elimination
> 70%
 Unfavourable physiochemical properties, e.g. low solubility,
metastable modifications, instability, etc.
 Documented evidence for bioavailability problems
 No relevant data available, unless justification by applicant that
in vivo study is not necessary.
2. Non-oral immediate release products.
3. Modified release products with systemic action.
In vivo bioequivalence studies are conducted in the usual
manner as discussed for bioavailability studies, i.e. the
pharmacokinetic and the pharmacodynamic methods

9. z
In vitro Bioequivalence Studies
1.The drug product differs only in strength of
the active substance it contains, provided all
the following conditions hold –
 Pharmacokinetics are linear
 The qualitative composition is the same
 The ratio between active substance and the excipients
is the same, or (in the case of small strengths) the ratio
between the excipients is the same
 Both products are produced by the same manufacturer
at the same production site
 A bioavailability or bioequivalence study has been
performed with the original product

10. z
In vitro Bioequivalence Studies
1.The drug product has been slightly
reformulated or the manufacturing method
has been slightly modified by the original
manufacturer in ways that can convincingly
be argued to be irrelevant for the
bioavailability.
2.The drug product meets all of the following
requirements –
 The product is in the form of solution or solubilised
form (elixir, syrup, tincture, etc.)
 The product contains active ingredient in the same
concentration as the approved drug product.
 The product contains no excipients known to
significantly affect absorption of the active ingredient.

11. z
In vitro Bioequivalence Studies
1.An acceptable IVIVC and the in vitro
dissolution rate of the new product is
equivalent with that of the already approved
medicinal product.
Moreover,
 The product is intended for topical administration
(cream, ointment, gel, etc.) for local effect.
 The product is for oral administration but not intended
to be absorbed (antacid or radio-opaque medium).
 The product is administered by inhalation as a gas or
vapour.
The criteria for drug products listed above indicate
that bioavailability and bioequivalence are self-evident.

12. z
Bioequivalence Experimental Study
Design
 Completely randomised designs
 In a completely randomised design, all treatments
(factor levels) are randomly allocated among all
experimental subjects.
 Method of randomisation
 Label all subjects with the same number of digits,
for e.g., if there are 20 subjects, number them from
1 to 20. Randomly select non-repeating random
numbers (like simple randomisation) with among
these labels for the first treatment, and then repeat
for all other treatments.

13. z
Bioequivalence Experimental Study
Design
 Advantages
1)The design is extremely easy to
construct.
2)It can accommodate any number of
treatments and subjects.
3)The design is easy and simple to analyse
even though the sample sizes might not
be the same for each treatment.

14. z
Bioequivalence Experimental Study
Design
 Disadvantages
1) Although the design can be used for any number
of treatments, it is best suited for situations in
which there are relatively few treatments.
2) All subjects must be as homogeneous as
possible.
3) Any extraneous sources of variability will tend to
inflate the random error term, making it difficult
to detect differences among the treatment (or
factor level) mean responses.

15. z
Bioequivalence Experimental Study
Design
 Randomised block designs
 First, subjects are sorted into homogeneous
groups, called blocks and the treatments are
then assigned at random within the blocks.
 Method of Randomisation
 Subjects having similar background
characteristics are formed as blocks. Then
treatments are randomised within each
block, just like the simple randomisation.
Randomisations for different blocks are
done independent of each other.

16. z
Bioequivalence Experimental Study
Design
 Advantages
1) With effective and systematic way of grouping, it can provide
substantially more precise results than a completely randomised
design of comparable size.
2) It can accommodate any number of treatments or replications.
3) Different treatments need not have equal sample size.
4) The statistical analysis is relatively simple. The design is easy to
construct.
5) If an entire treatment or block needs to be dropped from the
analysis for some reason, such as spoiled results, the analysis is
not thereby complicated.
6) Variability in experimental units can be deliberately introduced to
widen the range of validity of the experimental results without
sacrificing the precision of results.

17. z
Bioequivalence Experimental Study
Design
 Disadvantages
1)Missing observations within a block
require more complex analysis.
2)The degrees of freedom of experimental
error are not as large as with a
completely randomised design.

18. z
Repeated measures, cross-over and
carry-over designs
1. Repeated measures design is a type of
randomized block design.
2.Same subjects are used for all
conditions (treatments or time points).
3.This reduces individual differences
between subjects.
4.The design can involve multiple
treatments or a single treatment over
time.
5.Crossover design applies treatments
one after another to the same group.

19. z
Repeated measures, cross-over and
carry-over designs
1.Crossover design needs wash-out period to
avoid carry-over effects.
2.Wash-out period allows elimination of drugs
from the body.
3.Wash-out period typically lasts 10 elimination
half-lives
4.Repeated measures design is advantageous
for reducing variability due to individual
differences.
5.Crossover design is more efficient than
repeated measures design when many
treatments are involved.

20. z
Repeated measures, cross-over and
carry-over designs
1.Crossover design is not suitable for
treatments with long-lasting effects.
2.The order of treatments in a crossover
design can be randomized or fixed.
3.Statistical analysis of crossover designs
needs to account for carry-over effects.
4.Alternative methods to wash-out periods can
be used to minimize carry-over effects, such
as statistical adjustments.
5.Repeated measures design and crossover
design are both valuable tools for clinical
research.

21. z
 Method of Randomisation
 Complete randomisation is used to randomise the order of treatments for each
subject. Randomisations for different subjects are independent of each other.
 Advantages
1) They provide good precision for comparing treatments because all sources of
variability between subjects are excluded from the experimental error.
2) It is economic on subjects. This is particularly important when only a few subjects
can be utilized for the experiments.
3) When the interest is in the effects of a treatment over time, it is usually desirable to
observe the same subject at different points in time rather than observing different
subjects at the specified points in time.
 Disadvantages
1) There may be an order effect, which is connected with the position in the treatment
order.
2) There may be a carry-over effect, which is connected with the preceding treatment
or treatments.