Dr Sanet Aspinall, PhD
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
Bioequivalence = Comparative 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)
“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.”
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
consuming, expensive and exposed to
Clinical outcomes or pharmacodynamic parameters
may be involved.
Proof of bioequivalence
clinical / therapeutic equivalence and
interchangeable use of pharmaceutical
Comparative bioavailability studies
This is the cost
effective gold standard to
predict clinical equivalence of like products.
Designed to obtain comparative in vivo
= plasma drug concentration versus time data
Appropriate statistical analysis
Interpretation of results according to guidelines
produced by regulatory authorities
PK parameters used:
Describes the total amount of drug present in the
plasma, thus indicator of the
PK parameters used:
the peak plasma drug concentration (this, together with
, are indicators of
of drug absorption.)
AUC and C
are regarded as
pk parameters in bioequivalence studies
SECONDARY pk parameters
: the time (from dosing) to reach C
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
Randomized and balanced
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
Selection of subjects:
Usually healthy volunteers, with strict inclusion and
exclusion criteria (age, BMI etc.)
Enroll a few more to provide for drop
Seldom patients (only when risks/adverse events are
unacceptable to healthy volunteers).
Fasting: dosing only on empty stomach (for most
Dosing: same time of day for each subject
Fluid intake at dosing: critical to use same volume,
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.
Venous blood collected in heparinised or EDTA tubes
at predetermined intervals over predetermined time.
depends on expected t
Blood sampling (2):
depends on the expected t½ of
the drug and the sensitivity of the bio
Usually blood samples are collected for 5 x t½
Minimum required by MCC is 3 x t½ (providing 80%
Blood sampling (3):
Blood volume withdrawal limitations usually means
that a total of about 20 samples per period are
Sampling points should be chosen carefully, to result
in adequate profiles allowing accurate estimation of
relevant pk parameters.
Informed consent (comprehensive).
Allow an adequate washout period between profiles
(>5 x t½).
state (Css) studies (= multiple doses) are
sometimes required. Usually single
dose studies are
Fed vs Fasting:
Immediate release dosage forms: usually studied
whilst fasting, unless pronounced food effects
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.
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
AUC: 90% confidence intervals should
: 90% confidence intervals should
133%). (In some cases
These are calculated using log
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
Phase 1 unit
Phase 1 / BE Studies
4 and Therapeutic Clinical
Dr Sanet Aspinall
Tel: (012) 803
083 253 1260