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GCC BE Study

The document outlines the Gulf Cooperation Council (GCC) guidelines for bioequivalence (BE) studies, emphasizing the need for harmonization with international standards while addressing specific regional requirements. It details study design recommendations, reference and test product selection criteria, and common deficiencies found in submitted BE studies. Additionally, it highlights the importance of proper subject selection, standardized study conduct, and the necessity of validated bio-analytical methods.

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Ajithkumar S
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522 views31 pages

GCC BE Study

The document outlines the Gulf Cooperation Council (GCC) guidelines for bioequivalence (BE) studies, emphasizing the need for harmonization with international standards while addressing specific regional requirements. It details study design recommendations, reference and test product selection criteria, and common deficiencies found in submitted BE studies. Additionally, it highlights the importance of proper subject selection, standardized study conduct, and the necessity of validated bio-analytical methods.

Uploaded by

Ajithkumar S
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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GCC guidelines for BE studies

and
common deficiencies in the
submitted BE studies.

Presented by: Nabila AL-Lawati


(Ph.D)

Amman, Jordan, 15/09/2015


Gulf Cooperation Council (GCC)
Its member states are:

Bahrain

Kuwait

Sultanate of Oman

Qatar

Saudi Arabia

United Arab Emirates


GCC guidelines
present GCC guidelines (FEB /2011)
adapted from the European
Medicines Agency (EMA) guideline
on the investigation of
bioequivalence.

These guidelines have been


prepared taking into consideration
the need for worldwide
harmonization , at the same time
specific needs for the GCC
countries.
Study design

Standard design
-A randomized, two-period, two-sequence
single dose crossover design is recommended

-The treatment periods should be separated by


a wash out period sufficient to ensure that drug
concentrations are below the lower limit of
bioanalytical quantification in all subjects at
the beginning of the second period

- Normally at least 5 elimination longest half-


lives are necessary to achieve this
Study design

Alternative design.
parallel design for substances with very long half-life

Replicate designs for substances with highly variable


Reference and test product
Reference product selection:
-Original brand-name registered in the GCC

-Original brand-name registered in USA or


Europe

-Original brand-name is not available in the


market or no longer produced, then the
product which is the local market leader
Reference and test product

Reference product
The selection of the reference product is
based on assay content and dissolution
data.

The assayed content of the batch used as


test product should not differ more than 5%
from that of the batch used as reference
product determined with the test procedure
proposed for routine quality testing of the
test product.
Reference and test product

Test product
- The test product should usually originate from
a batch of at least 1/10 of production scale or
100,000 units, whichever is greater, unless
otherwise justified.

- In case of a production batch smaller than


100,000 units, a full production batch will be
required.

-The lots should be produced using the same


type of equipment and procedures
Reference and test product

Test product

-Comparative dissolution profile testing


should be undertaken on the first three
production batches.

- If full scale production batches are not


available at the time of submission, the
applicant should not market a batch until
comparative dissolution profile testing has
been completed.
Example of deficiencies in the
selection of the reference product
Test drug: Amlodipine besylate
and valsartan 10+160mg

Reference used by the company


Norvasc (Amlodipine 10mg)
Diovan (Valsartan 160mg)

Reference should be used:


Exfore (Amlodipine besylate and
valsartan Tablets 10 + 160 mg)
from Novartis
Example of deficiencies in the
selection of test product
Test drug batch size was 50.000 tablets
while production batches size were
1000, 000

10% of 1000,000 = 100, 000


Example of deficiency

Most studies lack Comparative


dissolution profile (Bio-batch and
three production batches)

Or

comparative dissolution profile


is incomplete (e.g. only one
media) (normally pH 1.2, 4.5 and
6.8)
Subjects
Number of subjects:
- The sponsor should enroll a number of subjects
sufficient to ensure adequate statistical results, which
is based on the power function of the parametric
statistical test procedure applied

- A number of subjects of less than 24 may be


accepted (with a minimum of 18 subjects) when
statistically justifiable.

- In some cases (e.g., for highly variable drugs) more


than 24 subjects are required and for parallel design
study a greater number of subjects may be required
Subjects

Selection of subjects:
- Healthy volunteers

- The inclusion/exclusion criteria should


be clearly stated in the protocol.

- The subjects should be screened for


suitability by means of clinical laboratory
tests, a medical history, and a physical
examination

-Both sex can include in the study


Deficiency in subjects selection

All of the recruited subjects


were vegetarians in fed study

???
Deficiency in subjects screening
procedure

The gap between screening and the


actual study was about six months in
anti diabetic test drug

Major deficiency in
the study
Study conduct
Standardization
The test conditions should be
standardized in order to
minimize the variability of all
factors involved except that of
the products being tested.
Therefore, it is recommended to
standardize diet, fluid intake
and exercise.
-
Study conduct
- Subjects should fast for at least 8 hours prior to
administration of the products, unless otherwise
justified

-The test and reference products should be


administered with a standardized volume of
fluid

- It is recommended that water is allowed as


desired except for one hour before and one
hour after drug administration and no food is
allowed for at least 4 hours post-dose
Fast and fed studies
In general, a bioequivalence study should be conducted
under fasting conditions as this is considered to be
the most sensitive condition to detect a potential
difference between formulations

For products where the SPC recommends intake of


the reference medicinal product on an empty
stomach or irrespective of food intake, the
bioequivalence study should hence be conducted
under fasting conditions.

For products where the SPC recommends intake of


the reference medicinal product only in fed state,
the bioequivalence study should generally be
conducted under fed conditions.
Sampling times
-A sufficient number of samples should
be collected to adequately describe
the plasma concentration-time profile

-Frequent sampling around predicted


tmax

-Avoid Cmax being the first point of a


concentration time curve
Deficiencies in study conduct

When SPC recommends intake of the


reference standard in fed state, BE study was
conducted on Fast state.

The study was not


accepted and was ask
to conduct a new study
on fed state as per the
GCC guidelines
Characteristics to be investigated
Pharmacokinetic parameters

In studies to determine bioequivalence


after a single dose, AUC(0-t), AUC(0-∞),
Cmax and tmax should be determined

In studies to determine bioequivalence


for immediate release formulations at
steady state, AUC(0-τ), Cmax,ss, and
tmax,ss should be determined.
Strength to be investigated

If several strengths of a test product


are applied for, it may be sufficient to
establish bioequivalence at only one
or two strengths, depending on the
proportionality in composition
between the different strengths and
other product related issues described
below.

The strength(s) to evaluate depends


on the linearity in pharmacokinetics of
the active substance.
General biowaiver criteria
The following general requirements must be met where a waiver
for additional strength(s) is claimed:

a) The pharmaceutical products are manufactured by the same


manufacturing process,

b) The qualitative composition of the different strengths is the


same,

c) The composition of the strengths are quantitatively


proportional, i.e. the ratio between the amount of each
excipient to the amount of active substance(s) is the same for all
strengths

d) Appropriate in vitro dissolution data should confirm the


adequacy of waiving additional in vivo bioequivalence testing.
Deficiencies in the bio-waived
strengths
When claiming for strength bio-waiver :
Comparative dissolution testing should be conducted on
12 dosage units each of all strengths of the test with each
of all respective strengths of either reference or test
products.

A common Or to submit
deficiency is not incomplete
to submit comparative
comparative dissolution
dissolution profile profile
Bio-analytical methodology

The bio-analytical methods used must be


fully validated and documented to yield
reliable results that can be satisfactorily
interpreted. Within study validation
should be performed using Quality
control samples in each analytical run.
Bio-analytical Method
Development and Validation

Fundamental parameters for this


validation include the following:

selectivity
Accuracy, Precision and recovery
Calibration curve
Sensitivity
Reproducibility
Stability
Deficiencies in the bio-analytical
validation
Stability testing should evaluate the stability of the
analytes during sample collection and handling,
after long-term and short-term (bench top, room
temperature) storage, and after freeze and thaw
cycles.

In some application, the long term stability (frozen at


intended temperature) is not performed or
performed under other temperatures that were not
used in storage.
Also the stability may not cover whole storage
period.
Other common deficiencies
-Protocol and its amendment not
included in the dossier
- Protocol deviations not included
- Agreement between sponsor and
CRO is missing or incomplete
- 20% of the analytical
chromatograms not included
- Information consent form (ICF) of
volunteers is missing
Sultanate of Oman
.

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