Interchangeability

and study design

Drs. Jan Welink

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Guidance documents
http://apps.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

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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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Bioavailability

Bioavailability

Bioavailability means the rate and extent to which

the active substance or therapeutic moiety is
absorbed from a pharmaceutical form and
becomes available at the site of action.

plasma

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Bioavailability
relative bioavailability

absolute

bioequivalence

different
formulations

food-effect

interactions

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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
Bioequivalence

Bioavailability

Pharmaceutic
al equivalent

Pharmaceutic
al
alternatives
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Bioequivalence

Reference

Pharmaceutical
Equivalent
Products

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

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

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Bioequivalence

Pharmaceutical equivalent does not necessarily imply

:therapeutic equivalence
difference excipientsdifference manufacturing processother variables-

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drug
?performance

Bioequivalence

Therapeutic equivalent does not necessarily imply

:bioequivalence
sensitivitydifferent formulations (IR/CR)different active substance-

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?equivalence

Bioequivalence

pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, C max)
acceptance criteria: comparative rate and extent of absorption

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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.

comm. batch
scale up

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test

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

changed batch
variations

Bioequivalence
: Studies necessary for

Oral Immediate Release products

In general
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

in vitro
methods

!!ONLY IN EXCEPTIONAL CASE

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EXPERIMENTAL DESIGN

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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

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:tmax
time at which Cmax is observed
measure of the rate of absorption

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Plasma concentration time profile

Cmax

AUC

Tmax
time
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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

:Single dose, two-period crossover

Subjects receive in Period I and II Test/Reference

:Subjects

Healthy volunteers
randomisation
Inclusion/exclusion criteria
Number of subjects

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Bioequivalence single dose

Number of subjects!!

- Sample size calculation: e.g. Eur J Drug Metab Pharmacokinet 30 (2005) 41

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Bioequivalence fast/fed
:Administration of Test/Reference

Normally fasted state

overnight fast
drug administration ca. 240 ml water

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

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

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

In general:
follow SPC.

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Sampling

Blood sampling:
Number of samples.
Sampling times (Cmax!).
Time of sampling (extrapolated AUC max. 20%).
Washout phase long enough.

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knowledge
drug
substance

Extrapolated AUC < 20%

time
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Extrapolated AUC < 20%

time
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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

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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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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

Most submitted bioequivalence studies are:

Single dose studies.
Fasted conditions.
Crossover design.
Non replicate.

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depends on
drug
substance!

End

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