Interchangeability

and study design

Drs. Jan Welink

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

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 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

food-effect different
formulations

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

Pharmaceutical
Equivalent
Reference 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 excipients-
drug
difference manufacturing process- ?performance
other variables-

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 Bioequivalence

Therapeutic equivalent does not necessarily imply

:bioequivalence

sensitivity-
)different formulations (IR/CR- ?equivalence
different active substance-

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 Bioequivalence

pharmaceutical equivalence

)method: in principle comparative pharmacokinetics (AUC, Cmax

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
scale up variations
innovator

clinical batch comm.batch changed batch

ref. test ref. test

acceptance
approval
variations
innovator

approval acceptance
generic variations
test ref. test ref.
generic

test

bioequiv.batch comm. batch changed batch

scale up variations

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 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

clinical in vitro
PD studies
studies 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 :tmax

⇒ measure of the extent of absorption time at which Cmax is observed
⇒ measure of the rate of absorption

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 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:
no change in absorption: delay in absorption:

Plasma Conc. mg/L

Plasma Conc. mg/L

T im e (h ) T ime (h )

increase in absorption: decrease in absorption:

Plasma Conc. mg/L

Plasma Conc. mg/L

Time (h) Tim e (h)

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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

In general:
follow SPC.

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 Sampling

Blood sampling:

Number of samples.

Sampling times (Cmax!). knowledge

drug
Time of sampling (extrapolated AUC max. 20%). substance

Washout phase long enough.

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 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 design preferred:

- intra-subject comparison
- lower variability
- fewer subjects required
:Crossover :Parallel

R T

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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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 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. depends on

drug
Crossover design. substance!

Non replicate.

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 End

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