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BIOEQUIVALENCE
It is a relative term which denotes that drug substances
in two or more identical dosage forms ,reaches the
systemic circulation at the same relative rate and the
same relative extent i.e their plasma con.-time profiles
will be identical without any statistical differences.
When statistically significant difference are observed in
the bioavailibility of two or more drug products, bio-
inequivalence is indicated.
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BIOEQUIVALENT DRUG
PRODUCTS:-
Two products are bioequivalent if
they are pharmaceutically equivalent
both rate and extent after administration in the
same dose are similar to such a degree that their
effects can be expected to be essentially the same.
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Minimizes the effect of inter subject
variability.
It minimizes the carry over effect.
Requires less number of subjects to get
meaningful results.
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Requires longer time to complete the studies.
Completion of studies depends on number of formulations
evaluated in the studies.
Increase in study period leads to high subject
dropouts.
Medical ethics does not allow too many trials
on a subject continuously for a longer time.
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Requirement of BE Studies
For IND/NDAs:
To establish equivalence between:
• Early & late clinical trial formulations
• Formulations used in clinical trial & stability studies
• Clinical trial formulations & to-be-marketed drug product
• Any other comparisons, if appropriate
ANDA for a generic drug product
Change in components, composition, &/or manufacturing process
Change in dosage form (capsules to tablet)
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Objectives of BE Studies
FDA has made BE studies mandatory for all drug products
before approving those for market.
It gives assurance to patient that product give claimed
therapeutic effects and safety by manufacturers.
Determining whether chemically equivalent products by
different companies are therapeutic equivalent.
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THERAPEUTIC EQUIVALENCE
FDA classifies those products as therapeutically
equivalent which :
are pharmaceutically
equivalent
have same clinical
effect
have same safety
profile
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...
EXAMPLE:-
A 10 mg. tablet of Zocor (used to treat high cholesterol) is
therapeutically equivalent to a 10 mg. tablet of
simvastatin.
A 50 mg. tablet of Zoloft (used to treat depression) is
therapeutically equivalent to a 50 mg. tablet of sertraline.
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PHARMACEUTICAL EQUIVALENTS:-
FDA considers drug products to be pharmaceutical
equivalents if they meet these criterion:
• Shape
• Active • Labeling
ingredients • Release
• Dosage form mechanism
SAME • Route of DIFFERENT • Scoring
configuration
administration
• Strength/ • Excipient
Concentration
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When two or more drug products
contain the same labelled chemical
substance as an active ingredient in the
same amount.
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ELEMENTS OF BIOEQUIVALENCE
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Study Design
is the trials and experiments in
medical and epidemiological research in a directive,
for a better or a predetermined approach
WHY?
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Various study designs employed2 are
Completely Randomized Design
Randomized block Designs
Repeated Measures, Cross-over and Carry-over Design
Latin Square Designs
Parallel Design
Factorial Design
Cluster Design
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Completely
randomized Randomized
design block
designs
Test
Designs
Latin
square Repeated
measures,
designs cross-over
and carry-
over design
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1. Selection Criteria for Subjects
Studies should be conducted in
individuals representative of the
general population, taking into
account age, sex, and race.
Healthy subjects, above 18 years of
age.
Choice of gender based on usage &
safety criteria
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Selection Criteria for Subjects(Contd…)
If drug product is to be used predominantly in elders, then test should
include as many subjects of 60 years of age or older as possible.
Pregnant women or those taking contraceptives should not be
included in the test.
For drugs hazardous for one group of users, choice of subjects may be
narrowed down, e.g., studies on teratogenic drugs should be
conducted only on males.
For drugs primarily intended for use in only males or only females-
volunteers of only respective gender should be included in the studies.
For drugs where risk of toxicity or side effects is significant, studies may
be carried out in patients, but whose disease state is stable.
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When is Bioequivalence not necessary
(Biowaivers)
a) Parental Solution; same active substance with same concentration,
same excipient
b) Oral Solution; same active substance with same concentration,
excipient not affecting GI transit or absorption
c) Gas
d) Powder for reconstitution as solution; meets criterion (a) or (b)
e) Otic/Ophthalmic/Topical Solution; same active substance with
same concentration, same excipient
f) Inhalational Product/ Nasal Spray; administered with or w/o same
device as reference product ; prepared as aqueous solution ; same
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Exclusion Criteria
Volunteers allergy to test drug
Volunteers with liver or kidney dysfunction
Volunteers with jaundice in past 6 months
Chronic diseases eg. Asthma, arthritis
Psychiatric illness
Chronic smoker, alcohol addiction, drug abuse
Intake of enzyme modifying drug in past 3 months
Intake of OTC/Prescription drugs past 2 weeks
HIV positive
BA & BE studies in past 3 months
Volunteers with bleeding disorder 19
Study Design
Good experimental design, enhances the power of the study
Depends on: question to be answered, nature of reference
drug/ dosage form, benefit-risk ratio
As far as possible, the study should be of crossover design &
suitably randomized
Ideal design: Randomized two-period, two-sequence,
Crossover design with adequate washout period
If the half-life is long: Parallel design
For highly variable drugs: Replicate design
Any drug whose rate and extent of absorption shows
large dose-to-dose variability within the same patient 20
Completely Randomized Design
In this design all treatments are randomly allocated
among all experimental subjects.
METHOD OF RANDOMISATION:
Label all subjects with same number of digits.
Randomly select non repeating numbers from these
labels.
Subject them for the first treatment and then repeat
for all other treatments.
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Completely Randomized Design
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Completely Randomized Design
Pros +++++
Easy to construct.
Can accommodate any number of treatments and
subjects.
Simple to analyze even though the sample sizes
might not be same for each treatment.
Cons - - - - - - - -
Can be applied to only those situations in which there
are relatively few treatments.
All subjects must be as homogenous as possible.
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Randomized block Design
First subjects are sorted into homogenous 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
Randomization for different blocks are done
independent of each other.
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Randomized block Design
The Randomized block Design randomly divides the
experimental units into t groups of size n and
randomly assigns a treatment to each group.
Randomized block Designs divides the group of
experimental units into ‘n’ homogeneous groups
of size ‘t’.
These homogeneous groups are called blocks.
The treatments are then randomly assigned to the
experimental units in each block - one treatment
to a unit in each block.
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Example
Suppose we are interested in how weight gain (Y)
in rats is affected by Source of protein (Beef,
Cereal, and Pork) and by Level of Protein (High or
Low).
There are a total of t = 32 = 6 treatment
combinations of the two factors (Beef -High
Protein, Cereal-High Protein, Pork-High Protein,
Beef -Low Protein, Cereal-Low Protein, and Pork-
Low Protein) .
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Randomized block Design
Pros +++++
Can accommodate any number of replications.
Different treatments need not have equal sample size.
Statistical analysis is relatively simple.
The design is easy to construct.
Cons - - - - - - - -
Missing observations with in a block require more complex
analysis.
Degree of freedom of experimental error are not as large as
with a completely randomized design.
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Repeated measures Cross-over & carry over
Design
>>distortion from the accuracy due to residual effects
from the preceding treatment usually called
Carryover effects
To prevent this allow for a washout period during most
of the drug is eliminated from the body 10 elimination
half-lives.
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Two Period Cross-over Design
For two formulations
Even no. of subjects
Randomly divided into 2 equal groups.
First period, each member of one group receive a single
dose of the test formulation, each member of the other
group receive the standard formulation.
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Subjects Period 1 Period 2
1-8 T S
9-16 S T
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Replicate Cross-over Study Design
For highly variable drugs
Allows comparisons of within- subject variance
Reduce the number of subjects needed
Four period, two sequence, two formulation design(
recommended)
Three period, two sequence ( partially replicated )
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Period 1 2 3 4
Group A T R T R
Group B R T R T
Period 1 2 3
Group A T R T
Group B R T R
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Latin Square Design
A latin square design is a two-factor design with one
observation in each cell.
Rows represents subject and column represents
treatment
Such a design is useful compared to earlier when three
or more treatments are compared carry over effects are
balanced.
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Latin Square Designs
Selected Latin Squares
3x3 4x4
ABC ABCD ABCD ABCD ABCD
BCA BADC BCDA BDAC BADC
CAB CDBA CDAB CADB CDAB
DCAB DABC DCBA DCBA
5x5 6x6
ABCDE ABCDEF
BAECD BFDCAE
CDAEB CDEFBA
DEBAC DAFECB
ECDBA ECABFD
FEBADC
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Incomplete Block Designs
In the incomplete block design, each block only gets a
subset of the treatments.
An incomplete block design is one in which not all the
treatments occur in every block.
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Balance Incomplete Block Design (BIBD)
More than 3 formulations, Latin square design will not be
ethically advisable
Because each volunteer mat require drawing of too many
blood samples.
If each volunteer expected to receive at least two
formulation, then such a study can be carried out using
BIBD.
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Volunteer No. Period 1 Period 2
1 A B
2 A C
3 A D
4 B C
5 B D
6 C D
7 B A
8 C A
9 D A
10 C B
11 D B
12 D C
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EVALUATIN OF DATA
ANALYTICAL METHOD
PHARMACOKINETIC EVALUATION OF THE DATA
STATISTICAL EVALUATION OF DATA(ANOVA)
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CONCLUSION
Bioequivalence between test and reference
formulations, both in terms of rate and extension of
absorption under fasting conditions can provide a safe
and effective dosage form.
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!!All the very best!!
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