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Bioequivalence Studies


Dr Sanet Aspinall, PhD


Managing Director

AddClin Research

Pretoria


20 March 2009



Bioequivalence studies are usually
done to compare pharmacokinetic
parameters of generic drug products
with those of a marketed
formulation, typically an innovator
drug product.





Bioequivalence = Comparative bioavailability

BIOAVAILABILITY:

“Bioavailability means the rate and extent to

which the active pharmaceutical ingredient or

active moiety is absorbed from a

pharmaceutical form and becomes available at

the site of action.”


(FDA, EU CPMP, MCC)

BIOEQUIVALENCE:


“The absence of a significant difference in the rate and

extent to which the active pharmaceutical ingredient or

active moiety in pharmaceutical equivalents or

pharmaceutical alternatives become available at the site

of action (bioavailability) when administered at the

same molar dose under similar conditions in an

appropriately designed study.”


(FDA)


THERAPEUTIC EQUIVALENCE:




Clinical (therapeutic) trials can be done to prove that
safety and efficacy of two pharmaceutical products
are essentially the same, at the same dose.



These studies are usually avoided because they are
time
-
consuming, expensive and exposed to
difficulties.



Clinical outcomes or pharmacodynamic parameters
may be involved.


Proof of bioequivalence
normally

implies

clinical / therapeutic equivalence and

interchangeable use of pharmaceutical

products.


Comparative bioavailability studies

(bioequivalence testing):


This is the cost
-
effective gold standard to

predict clinical equivalence of like products.



Bioequivalence studies:



Designed to obtain comparative in vivo
pharmacokinetic data



= plasma drug concentration versus time data



Appropriate statistical analysis



Interpretation of results according to guidelines
produced by regulatory authorities


PK parameters used:



AUC:
A
rea
U
nder the
C
urve



Describes the total amount of drug present in the
plasma, thus indicator of the
extent

of drug
absorption.



PK parameters used:



C
max
:

the peak plasma drug concentration (this, together with
t
max
, are indicators of
rate

of drug absorption.)




AUC and C
max

are regarded as
PRIMARY

pk parameters in bioequivalence studies





SECONDARY pk parameters
include:




t
max
: the time (from dosing) to reach C
max
.



t½: terminal elimination half
-
life. This indicates the
time required for the amount of drug in the body to
decrease by half (50%).


Typical Study Design

(two formulations):




Two period



Randomized and balanced



Cross
-
over



Single dose



Laboratory
-
blind

Study subjects:


Number of subjects
:



Must be sufficient to provide 80% of power for
meeting and passing the acceptance criteria.



Can be determined from published literature.



Normally sample size is calculated by a
biostatistician.


Selection of subjects:




Usually healthy volunteers, with strict inclusion and
exclusion criteria (age, BMI etc.)



Enroll a few more to provide for drop
-
outs



Seldom patients (only when risks/adverse events are
unacceptable to healthy volunteers).


Study Standardisation:




Fasting: dosing only on empty stomach (for most
studies)



Dosing: same time of day for each subject



Fluid intake at dosing: critical to use same volume,
e.g. 200ml


Study Standardisation (2):





Food and fluid intake: standardised and supervised.




Posture and activity: controlled and supervised




No concomitant medicines, alcohol, caffeine or certain


fruit juices allowed.

Blood sampling:




Venous blood collected in heparinised or EDTA tubes
at predetermined intervals over predetermined time.



Sampling
frequency

depends on expected t
max
.



Blood sampling (2):




Sampling
duration

depends on the expected t½ of
the drug and the sensitivity of the bio
-
analytical
method used.



Usually blood samples are collected for 5 x t½



Minimum required by MCC is 3 x t½ (providing 80%
of AUC
0
-

)

Blood sampling (3):




Blood volume withdrawal limitations usually means
that a total of about 20 samples per period are
allowed.



Sampling points should be chosen carefully, to result
in adequate profiles allowing accurate estimation of
relevant pk parameters.


Other Issues:




Informed consent (comprehensive).



Allow an adequate washout period between profiles
(>5 x t½).


Steady
-
state (Css) studies (= multiple doses) are
sometimes required. Usually single
-
dose studies are
sufficient.


Fed vs Fasting:



1.
Immediate release dosage forms: usually studied
whilst fasting, unless pronounced food effects
known.


2.
Modified release dosage forms:


-

to check for any effects of food, studies are


required under both fed and fasting conditions.


-

dosing occurs immediately after a high fat meal.

Bioanalysis:



GLP, GCP, QC and SOPs.



Only validated, reliable chromatographic methods
with sufficient sensitivity to be used.



Sometimes necessary to measure active
metabolite(s) as well as parent compound.



Adverse events documented

Acceptance range for

pk parameters:



AUC: 90% confidence intervals should
usually

be
within 0,80
-
1,25 (80%
-
125%).


C
max
: 90% confidence intervals should
usually

be
within 0,75
-
1,33 (75%
-
133%). (In some cases


80%
-
125%).


These are calculated using log
-
transformed data.


Must be stated up
-
front in the protocol and may not
be changed / added retrospectively.



Generic vs proprietary prescribing or
dispensing in South Africa:



Registration of generic products by MCC will not
compromise safety and efficacy of
pharmacotherapeutic regimens.


AddClin
Research

Phase 1 unit

CONTACT DETAILS:

Phase 1 / BE Studies

AddClin Research


Phase 2
-
4 and Therapeutic Clinical
Equivalence Studies

Synexus SA


Managing Director


Laetitia Crause

Dr Sanet Aspinall


Business Development

Tel: (012) 803
-
7733


083 253 1260