Transcript Biometrics from 2005 until 2008

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: Area Under the Curve
Describes the total amount of drug present in the
plasma, thus indicator of the extent of drug
absorption.
PK parameters used:
Cmax :
the peak plasma drug concentration (this, together with
tmax, are indicators of rate of drug absorption.)
AUC and Cmax are regarded as PRIMARY
pk parameters in bioequivalence studies
SECONDARY pk parameters
include:
• tmax: the time (from dosing) to reach Cmax.
• 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 tmax.
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 AUC0-∞)
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%).
• Cmax: 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
Dr Sanet Aspinall
Tel: (012) 803-7733
Laetitia Crause
Business Development
083 253 1260