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Transcript
TRAINING WORKSHOP ON
PHARMACEUTICAL QUALITY,
GOOD MANUFACTURING
PRACTICE & BIOEQUIVALENCE
Introduction to the Discussion
of Bioequivalence Study
Design and Conduct
Presented by
John Gordon, Ph.D.
Consultant to WHO
e-mail: [email protected]
Kyiv, 2005-10-05
1
Background:
First Product to Market

Innovator’s Product

Quality

Safety and efficacy
– Based on extensive clinical trials
– Expensive
– Time consuming
Kyiv, 2005-10-05
2
Background:
Other products with same
medicinal ingredient

Subsequent-entry products

Generic products

Multisource products

How do these products gain
marketing authorization?
Kyiv, 2005-10-05
3
Pharmaceutical equivalence

Same amount of the same active
pharmaceutical ingredient
– Salts, esters

Same dosage form
– Comparable dosage forms
– e.g., tablet vs. capsule

Same route of administration

Is pharmaceutical equivalence enough?
Kyiv, 2005-10-05
4
Sometimes pharmaceutical
equivalence is enough

Aqueous solutions
–
–
–
–
–
–
Intravenous solutions
Intramuscular, subcutaneous
Oral solutions
Otic or ophthalmic solutions
Topical preparations
Solutions for nasal administration

Powders for reconstitution as solution

Gases
Kyiv, 2005-10-05
5
Sometimes it is not enough

Pharmaceutical equivalence by itself
does not necessarily imply
therapeutic equivalence

Therapeutic equivalence:
– Pharmaceutically equivalent
– Same safety and efficacy profiles after
administration of same dose
Kyiv, 2005-10-05
6
Pharmaceutical Equivalents
Reference
Test
Possible Differences

Drug particle size

Excipients

Manufacturing
Equipment or
Process

Site of manufacture
Could lead to differences in product performance in vivo
Kyiv, 2005-10-05
7
Additional data is required

Oral immediate release products with
systemic action
– Generally required for solid oral
dosage forms
• Critical use
• Narrow therapeutic range
• Bioavailability problems associated with
the active ingredient
• Problematic polymorphism, excipient
interaction, or sensitivity to manufacturing
processes
Kyiv, 2005-10-05
8
Additional data is required

Oral modified release products with
systemic action

Fixed dose combination products with
systemic action
– When at least one component requires study

Non-oral / non-parental products with
systemic action

Non-solution products with non-systemic
action
Kyiv, 2005-10-05
9
Marketing authorization of
multisource products

Extensive clinical trials to
demonstrate safety and efficacy
– Interchangeability?

Demonstration of equivalence to
reference (comparator) product
– Interchangeability
– Therapeutic equivalence
Kyiv, 2005-10-05
10
Marketing authorization
through equivalence

Suitable methods for assessing
equivalence:
– Comparative pharmacokinetic studies
– Comparative pharmacodynamic
studies
– Comparative clinical trials
– Comparative in vitro tests
Kyiv, 2005-10-05
11
Comparative Pharmacokinetic
Studies

In vivo measurement of active
ingredient

“Some” relationship between
concentration and safety/efficacy

Product performance is the key

Comparative bioavailability
Kyiv, 2005-10-05
12
Bioavailability

The rate and extent to which a substance or
its active moiety is delivered from a
pharmaceutical form and becomes available
in the general circulation.”
Reference:
intravenous administration = 100% bioavailability
Kyiv, 2005-10-05
13
Important Pharmacokinetic
Parameters

AUC: area under the concentration-time
curve  measure of the extent of
bioavailability

Cmax: the observed maximum concentration
of drug  measure of both the rate of
absorption and the extent of bioavailability

tmax: the time after administration of drug at
which Cmax is observed  measure of the
rate of absorption
Kyiv, 2005-10-05
14
Plasma concentration time
profile
concentration
Cmax
AUC
time
Tmax
Kyiv, 2005-10-05
15
Bioequivalence
Two products are bioequivalent if

they are pharmaceutically equivalent

bioavailabilities (both rate and extent) after
administration in the same molar dose are
similar to such a degree that their effects
can be expected to be essentially the same
Kyiv, 2005-10-05
16
Therapeutic Equivalence

Therapeutic equivalence:
– Pharmaceutically equivalent
– Same safety and efficacy profiles after
administration of same dose:
bioequivalent

Interchangeability
Kyiv, 2005-10-05
17
Comparative
Pharmacodynamic Studies

Not recommended when:
– active ingredient is absorbed into the
systemic circulation
– pharmacokinetic study can be
conducted

Local action / no systemic absorption
Kyiv, 2005-10-05
18
Comparative Clinical Studies

Pharmacokinetic profile not possible

Lack of suitable pharmacodynamic
endpoint

Typically insensitive
Kyiv, 2005-10-05
19
Comparative in vitro Studies

May be suitable in lieu of in vivo
studies under certain circumstances

Requirements for waiver to be
discussed
Kyiv, 2005-10-05
20
When are bioequivalence
studies employed?

Multisource product vs. Innovative
product

Pre-approval changes
– Bridging studies

Post-approval changes

Additional strengths of existing
product
Kyiv, 2005-10-05
21
Bioequivalence Studies:
Basic Design Considerations

Minimize variability not attributable to
formulations

Minimize bias

REMEMBER: goal is to compare
performance of the two products
Kyiv, 2005-10-05
22
“Gold Standard” Study
Design

Single-dose, two-period, crossover

Healthy volunteers

Subjects receive each formulation
once

Adequate washout
Kyiv, 2005-10-05
23
Multiple-dose Studies

More relevant clinically?

Less sensitive to formulation
differences
Kyiv, 2005-10-05
24
Multiple-dose Studies may be
employed when:

Drug is too potent/toxic for
administration in healthy volunteers
– Patients / no interruption of therapy

Extended/modified release products
– Accumulation using recommended
dosing interval
– In addition to single-dose studies
Kyiv, 2005-10-05
25
Multiple-dose Studies may be
employed when:

Non-linear pharmacokinetics at
steady-state (e.g., saturable
metabolism)

Assay not sufficiently sensitive for
single-dose study
Kyiv, 2005-10-05
26
Crossover vs. Parallel
Designs

Crossover design preferred
– Intra-subject comparison
– Lower variability
– Generally fewer subjects required

Parallel design may be useful
– Drug with very long half-life
– Crossover design not practical
Kyiv, 2005-10-05
27
Parallel Design
Considerations

Ensure adequate number of subjects

Adequate sample collection
– Completion of Gastrointestinal transit
/ absorption process
– 72 hours normally sufficient
Kyiv, 2005-10-05
28
Fasted vs. Fed Designs

Fasted study design preferred
– Minimize variability not attributable to
formulation
– Better able to detect formulation
differences
Kyiv, 2005-10-05
29
Fed Study Designs may be
employed when:

Significant gastrointestinal (GI)
disturbance caused by fasted
administration

Product labeling restricts
administration to fed state
Kyiv, 2005-10-05
30
Fed Study Design
Considerations

Fed conditions depend on local diet
and customs

Dependent on reason for fed design
– Avoiding GI disturbance
• Minimal meal to minimize impact
– Required due to drug substance /
dosage form
• Modified-release products
Kyiv, 2005-10-05
31
Fed Study Design
Considerations cont.
– Required due to drug substance /
dosage form
• Complicated pharmacokinetics
• Known effect of food on drug substance

Fed conditions designed to promote
maximal perturbation
– High fat
– High Calorie
– Warm
Kyiv, 2005-10-05
32
Replicate vs. non-replicate
designs

Standard approach
– Non-replicated
– Single administration of each product
– Average bioequivalence
Kyiv, 2005-10-05
33
Replicate Designs

Typically four-period design
– Each product administered twice

Intra-subject variability

Subject X formulation interaction

Different approaches possible
– Average bioequivalence
– Individual bioequivalence
Kyiv, 2005-10-05
34
Replicate Designs

Advantages
– More information available
– Different approaches to assessment
possible

Disadvantages
– Bigger commitment for volunteers
– More administrations to healthy
volunteers
– More expensive to conduct
Kyiv, 2005-10-05
35
Discussion

Questions

Comments

Opinions
Kyiv, 2005-10-05
36