Download Guidelines

Prequalification programme:
Priority essential medicines
Training Workshop for evaluators from National
Medicines Regulatory Authorities in the East African
Community:
Evaluation of quality and inter-changeability
of medicinal products.
Dar Es Salaam
United Republic of Tanzania
10 – 14 September 2007
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Training Workshop on
Evaluation of quality and interchangeability of medicinal products.
Marketing authorisation trough equivalence
documentation
Presenter: Drs. J. Welink
Senior pharmacokineticist
Medicines Evaluation Board, NL
WHO adviser
E-mail: [email protected]
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Guidance documents
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Guidance documents
http://mednet3.who.int/prequal/
* Note to applicants on the choice of comparator products for
the prequalification project
* Guideline on generics
- Annex 7 (Multisource (generic) pharm. products: guidelines on
registration requirements to establish interchangeability)
- Annex 11 (Guidance on the selection of comparator pharm. products for
equivalence assessment of interchangeable multisource (generic)
products)
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Guidance documents
 Multisource (generic) pharmaceutical products: guidelines on
registration requirements to establish interchangeability (1)
 Proposal to waive in vivo bioequivalence requirements for WHO
Model List of Essential Medicines immediate-release, solid oral
dosage forms (2)
 Additional guidance for organizations performing in vivo
bioequivalence studies (3)
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Guidance documents
 Multisource (generic) pharmaceutical products: guidelines on
registration requirements to establish interchangeability (1)
 Proposal to waive in vivo bioequivalence requirements for WHO
Model List of Essential Medicines immediate-release, solid oral
dosage forms (2)
 Additional guidance for organizations performing in vivo
bioequivalence studies (3)
 Guidance on the selection of comparator pharmaceutical products
for equivalence
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Guidance documents
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Regulatory Authority Mission
“Assure that SAFE and EFFECTIVE
drugs are marketed in the country
and are available to the people”
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Bioequivalence
Bioequivalence
Bioavailability
Pharmaceutical
equivalent
Pharmaceutical
alternatives
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Bioequivalence
Bioequivalence:
Two medicinal products are bioequivalents if
they are pharmaceutical equivalents or alternatives
and if their bioavailabilities (rate and extent) after
administration in the same molar dose are similar
to such degree that their effects, with respect
to both efficacy and safety, will be
essential the same.
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Bioequivalence
Pharmaceutical Equivalent
Products
Reference
Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution specifications)
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Bioequivalence
Dissolution, solubility, and intestinal permeability are the
three major factors that govern the rate and extent of
absorption of a drug that is stable in the GI tract
Fluid volume
pH
hydrodynamics
surface tension
other….
TIME (hours)
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Bioequivalence
Therapeutic equivalence of a multiscource product can be
assured when the multiscource product is both
pharmaceutically equivalent/alternative and bioequivalent.
Concept of interchangeability includes the equivalence of the
dosage form as well as for the indications and instructions for
use.
TE = PE + BE
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Bioequivalence
Pharmaceutical equivalent does not necessarily imply
therapeutic equivalence:
- difference excipients
- difference manufacturing process
- other variables
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drug
performance?
Bioequivalence
Therapeutic equivalent does not necessarily imply
bioequivalence:
- sensitivity
- different formulations (IR/CR)
- different active substance
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equivalence?
Bioequivalence
pharmaceutical equivalence
method: in principle comparative pharmacokinetics
acceptance criteria: comparative rate and extent of absorption
IR tablets and capsules considered the same pharmaceutical form
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Bioequivalence
BA and BE are generally required for approvals of innovator
and generic (multiscource) products.
BE based on blood level determination of Cmax and AUC has
become the most commonly used and successful biomarker for
safety and efficacy of the drug product.
BE products can be substituted for each other without any
adjustment in dose or other additional therapeutic monitoring.
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Bioequivalence
BRIDGING STUDIES
variations
scale up
innovator
clinical batch
comm.batch
ref.
test
changed batch
ref.
test
acceptance
variations
approval
innovator
approval
generic
generic
test
ref.
acceptance
variations
test
bioequiv.batch
ref.
test
comm. batch
scale up
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changed batch
variations
Bioequivalence
Important PK parameters
Cmax:
the observed maximum concentration of a drug
 measure of the rate of absorption
AUC:
area under the concentration-time curve
 measure of the extent of absorption
tmax:
time at which Cmax is observed
 measure of the rate of absorption
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Plasma concentration time profile
concentration
C
max
AUC
Tmax
time
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Bioequivalence
Studies necessary:
 Oral Immediate Release products
–
–
–
–
Critical use medicines
Narrow therapeutic range drug products
Documented BA or BE problems related to API
Scientific evidence suggesting polymorphs of API, excipients,
and/or process affecting BA
– Non-oral, non-parenteral products designed to act systemically
 Oral Modified Release products
 Fixed-combination products with systemic absorption
where at least one of the API requires an in vivo study
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Bioequivalence
Cases when pharmaceutical equivalence is enough:
 Aqueous solutions
–
–
–
–
–
–
Intravenous solutions
Intramuscular, subcutaneous solutions
Oral solutions
Otic or ophthalmic solutions
Topical products prepared as solutions
Aqueous solution for nebulizer inhalation or nasal sprays
 Powders for reconstitution as solution
 Gases
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Studies
Different approach for
establishing equivalence
PD studies
clinical
studies
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in vitro
methods
PD studies
Comparative
PD studies
In case of local action/
no systemic
absorption
Not recommended when:
- active ingredient is absorbed
into the systemic circulation
- pharmacokinetic study can be
conducted
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PD studies
Comparative
PD studies
PD measures more variable than PK
response relevant
efficacy/safety
placebo effect
method: validated
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PD studies-example
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Clinical studies
Comparative
clinical studies
in case PK or PD studies
can not be performed
However:
- requires large number of subjects
- methodology establishing equivalence has not yet evolved
extensively as for PK BE trials
- insensitive
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Clinical studies-example
dissolution matrix
Topical/local acting:
diffusion to skin
penetration
str. corneum
penetration
sebum
diffusion and penetration
epidermis
diffusion trough dermis
too blood capillair
absorption blood
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In vitro studies
Comparative
in vitro studies
BCS approach for
biowaivers
However:
- acceptability in general?
- currently no biowaiver in prequalification project, except for
additional strength and solutions
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Bioequivalence – single dose
Basic design considerations:
minimize variability not
attributable to formulations
minimize bias
goal: compare performance
2 formulations
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Bioequivalence – single dose
Golden standard study design:
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)
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Bioequivalence – single dose
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Bioequivalence – multiple dose
Multiple dose:
More relevant clinically?
Less sensitive to
formulation differences!
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Bioequivalence – multiple dose
Multiple dose studies
in case of…..
Drug too potent/toxic for healthy volunteers
–patients/ no interruption therapy
Extended/modified release formulations
– accumulation / unexpected behavior
Non-linear PK at steady state
Analytical assay sensitivity
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Bioequivalence – parallel design
Crossover:
Crossover design preferred:
- intra-subject comparison
- lower variability
- fewer subjects required
Parallel:
R
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T
Bioequivalence – parallel design
Parallel design may be useful:
 Drug with very long elimination half-life
– Crossover design not practical
Parallel design considerations:
 Number of subjects
 Adequate sample collection
– Complete absorption
– 72 hours sufficient in general
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Bioequivalence – replicate vs. non-replicate
Standard approach BE study:
non-replicate
single administration
R and T
average bioequivalence
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Bioequivalence – replicate vs. non-replicate
Replicate
(RRTT or RRT or TTR):
T and/or R administered twice
Intra-subject variability
Subject X
formulation interaction
average bioequivalence/
individual bioequivalence
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Bioequivalence – replicate design
Scientific advantages:
Comparison within-subject
variances T and R
Indicate whether T exhibits lower or
higher within-subject variability
More information
(performance/S*F interaction)
Reduce number of subjects
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Bioequivalence – replicate design
Disadvantages:
Bigger commitment
volunteers
More administrations per subject
More expensive
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Bioequivalence – fast/fed
Food effect:
delay in absorption:
Plasma Conc. mg/L
Plasma Conc. mg/L
no change in absorption:
Time (h)
Time (h)
decrease in absorption:
Plasma Conc. mg/L
Plasma Conc. mg/L
increase in absorption:
Time (h)
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Time (h)
Bioequivalence – fast/fed
Food effect due to change in:
• gastric emptying time
• acid secretion
• intestinal motility
• bile secretion
• enzyme secretion
• active absorption process
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Bioequivalence – fast/fed
If the SPC of the reference product
contains specific recommendations in
relation with food intake related to food
interaction effects the study should be
designed accordingly
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Bioequivalence – fast/fed
 If the recommendation of food intake is based on pharmacokinetic
properties such as higher bioavailability, then a bioequivalence study
under fed conditions is generally required
 If the recommendation of food intake is intended to decrease adverse
events or to improve tolerability, a bioequivalence study under fasting
conditions is considered acceptable although it would be advisable to
perform the study under fed conditions.
 If the SPC leaves a choice between fasting and fed conditions, then
bioequivalence should preferably be tested under fasting conditions as
this situation will be more sensitive to differences in pharmacokinetics.
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Bioequivalence – fast/fed
 The composition of the meal should be described and taken into
account, since a light meal might sometimes be preferable to mimic
clinical conditions, especially when the fed state is expected to be less
sensitive to differences in pharmacokinetics.
 For products with release characteristics differing from conventional
immediate release (e.g. improved release, dissolution or absorption),
even if they cannot be classified as modified release products with
prolonged or delayed release, bioequivalence studies may be
necessary in both the fasted and fed states.
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Bioequivalence – fast/fed
 Different modified release formulations of the same drug substance
may differ with respect to food interaction. Hence, the influence of food
on the bioavailability of oral modified release formulations must be
investigated for safety and efficacy purposes.
 The optimal experimental conditions to produce a food effect include
the ingestion of a predefined high fat meal immediately before dosing.
For the assessment of food effect besides AUC and Cmax, it may also
be valuable to compare the modified release characteristics.
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Bioequivalence – fast/fed example
Diclofenac 50 mg studies
 Study I: 2-way cross-over study administered after intake
of a high fat breakfast, sampling for 12 hours
 Study 2: 2-way cross over study administered after intake
of a high fat breakfast, sampling for 24 hours
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Bioequivalence – fast/fed example
Diclofenac 50 mg short study
3000
04.210.8
2500
treatment=R
2000
1500
1000
500
0
0
1
2
3
4
5
6
7
Time after dosing on Day 1 (hr)
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8
9
10
Bioequivalence – fast/fed example
Diclofenac 50 mg short study
3000
04.210.8
2500
treatment=T
2000
1500
1000
500
0
0
1
2
3
4
5
6
7
Time after dosing on Day 1 (hr)
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8
9
10
Bioequivalence – fast/fed example
Diclofenac 50 mg long study
Reference
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Bioequivalence – fast/fed example
Diclofenac 50 mg long study
Test
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Bioequivalence – fast/fed example
Diclofenac 50 mg normalised on Tlag
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Bioequivalence – fast/fed
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End
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