3 1a Interchangeability Study Design

Interchangeability and study design

Drs. Jan Welink

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

Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

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)

Guidance documents

Regulatory Authority Mission

“Assure that SAFE and EFFECTIVEdrugs are marketed in the country

and are available to the people”

Bioavailability

Bioavailability means the rate and extent to whichthe active substance or therapeutic moiety is

absorbed from a pharmaceutical form andbecomes available at the site of action.

plasma

Bioavailability

relative bioavailability

absolute bioequivalence

food-effect different formulations

interactions

Bioequivalence

Bioequivalence:Two medicinal products are bioequivalents if

they are pharmaceutical equivalents or alternativesand if their bioavailabilities (rate and extent) afteradministration in the same molar dose are similar

to such degree that their effects, with respectto both efficacy and safety, will be

essential the same.

Bioequivalence

Bioavailability

Pharmaceutical equivalent

Pharmaceutical

alternatives

Bioequivalence

Reference Test

Pharmaceutical EquivalentProducts

Possible DifferencesDrug particle size, ..

ExcipientsManufacturing process

EquipmentSite of manufacture

Batch size ….

Documented Bioequivalence= Therapeutic Equivalence

(Note: Generally, same dissolution specifications)

Bioequivalence

Concept of interchangeability includes the equivalence of the dosage form as well as for the indications and instructions for use.

Therapeutic equivalence of a multiscource product can be assured when the multiscource product is both pharmaceutically equivalent/alternative and bioequivalent.

Bioequivalence

Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:

-difference excipients

-difference manufacturing process

-other variables

drug performance?

Bioequivalence

Therapeutic equivalent does not necessarily imply bioequivalence:

-sensitivity

-different formulations (IR/CR)

-different active substance

equivalence?

Bioequivalence

acceptance criteria: comparative rate and extent of absorption

pharmaceutical equivalence

method: in principle comparative pharmacokinetics (AUC, Cmax)

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.

Bioequivalence

BRIDGING STUDIES

clinical batch comm.batch changed batch

scale up variations

ref. testtest

approval innovator

approval generic

acceptance variations

innovatorgeneric bioequiv.batch comm. batch changed batch

testtest ref.test

scale up variations

acceptance 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 productsFixed-combination products with systemic absorption

where at least one of the API requires an in vivo study

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

Studies

PD studies clinicalstudies

in vitromethods

Different approach for establishing equivalence

ONLY IN EXCEPTIONAL CASE!!

EXPERIMENTAL DESIGN

Bioequivalence

Important PK parameters

area under the concentration-time curve measure of the extent of absorption

Cmax: the observed maximum concentration of a drug

measure of the rate of absorption

tmax: time at which Cmax is observed

measure of the rate of absorption

Plasma concentration time profile

Bioequivalence – single dose

minimize variability not attributable to formulations

Basic design considerations:

goal: compare performance2 formulations

minimize bias

single dose, two-period, crossover

Golden standard study design:

Reference (comparator)/Test (generic)

healthy volunteers

Single dose, two-period crossover:Subjects receive in Period I and II Test/Reference

Subjects:

Healthy volunteers– randomisation– Inclusion/exclusion criteria– Number of subjects

Number of subjects!!

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

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

Time (h)

no change in absorption: delay in absorption:

increase in absorption: decrease in absorption:

Food effect:

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.

In general:

follow SPC.

Sampling

Number of samples.

Blood sampling:

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

Washout phase long enough.

Sampling times (Cmax!). knowledge drug

substance

Extrapolated AUC < 20%

Bioequivalence – multiple dose

More relevant clinically?

Multiple dose:

Less sensitive to formulation differences!

Bioequivalence – multiple dose

Multiple dose studiesin 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

Bioequivalence – parallel design

Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required

Crossover: Parallel:

Bioequivalence – parallel design

Parallel design may be useful:Drug with very long elimination half-life

– Crossover design not practical

Number of subjectsParallel design considerations:

Adequate sample collection– Complete absorption– 72 hours sufficient in general

Bioequivalence – replicate vs. non-replicate

non-replicate

Standard approach BE study:

average bioequivalence

single administrationR and T

Bioequivalence – replicate vs. non-replicate

T and/or R administered twice

Replicate

) RRTT or RRT or TTR:(

Subject X formulation interaction

Intra-subject variability

average bioequivalence/ individual bioequivalence

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

Bioequivalence – replicate design

Disadvantages: Bigger commitment volunteers

More administrations per subject

More expensive

Bioequivalence

Single dose studies.

Most submitted bioequivalence studies are:

Crossover design.

Non replicate.

Fasted conditions. depends on drug

substance!

3 1a Interchangeability Study Design

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