Interchangeability and study design Drs. Jan Welink Training workshop: Training of BE assessors,...

Interchangeability

and study designDrs. Jan Welink

Training workshop: Training of BE assessors, Kiev, October 2009

Training workshop: Training of BE assessors, Kiev, October 20092 |

Guidance documentsGuidance 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)





Europe: http://www.emea.europa.eu

-Note for guidance on the investigation of bioavailability and bioequivalence

-Note for guidance on modified release oral and transdermal dosage form: section II.

-Question and answer documents

………………………………


BioequivalenceBioequivalence

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.



Reference Test

Pharmaceutical EquivalentProducts

Possible Differences

Drug particle size, ..

Excipients

Manufacturing process

Equipment

Site of manufacture

Batch size ….

Documented Bioequivalence= Therapeutic Equivalence



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.



Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:

-difference excipients

-difference manufacturing process

-other variables

drug performance?



Therapeutic equivalent does not necessarily imply bioequivalence:

-sensitivity

-different formulations (IR/CR)

-different active substance

equivalence?



acceptance criteria: comparative rate and extent of absorption

pharmaceutical equivalence

method: in principle comparative pharmacokinetics (AUC, Cmax)



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 studies necessary for :

Oral Immediate Release products

Oral modified release products

Fixed-combination products with systemic absorption where at least one of the API requires an in vivo study

Transdermal products with systemic action

Inhalation products



Cases when pharmaceutical equivalence is enough:

Aqueous solutions– Intravenous solutions– Intramuscular, subcutaneous solutions– Oral solutions– Otic or ophthalmic solutions

Powders for reconstitution as solution

Gases


StudiesStudies

PD studiesclinicalstudies

in vitromethods

Different approach for

establishing equivalence

ONLY IN EXCEPTIONAL CASE!!


EXPERIMENTAL DESIGNEXPERIMENTAL DESIGN



Important PK parameters

AUC :

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 profilePlasma concentration time profile

Cmax

Tmax

AUC

time


Bioequivalence – single doseBioequivalence – single dose

minimize variability not attributable to formulations

Basic design considerations:

goal: compare performance2 formulations

minimize bias


Bioequivalence – single doseBioequivalence – single dose

single dose, two-period, crossover

Golden standard study design:

Reference (comparator)/Test (generic)

healthy volunteers


Bioequivalence – single dose 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


Bioequivalence – variabilityBioequivalence – variability

Number of subjects: variability!!

Controllable variation:

-carry-over effects (use of other medicines etc.)

-time-factors (sampling time etc.)

-physiological factors (gastric emptying etc.)

Inescapable variation:

-subject difference (inter- and intra variability)

-formulations differences

-random error


Bioequivalence – fast/fed Bioequivalence – fast/fed

Administration of Test/Reference:

Normally fasted state– overnight fast– drug administration ca. 240 ml water

SPC !!!!!– with or without food– reason:

• pharmacokinetic• adverse events


SamplingSampling

Number of samples.

Blood sampling:

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

Washout phase long enough.

Sampling times (Cmax!). knowledge drug

substance


Bioequivalence – multiple doseBioequivalence – multiple dose

More relevant clinically?

Multiple dose:

Less sensitive to formulation differences!


Bioequivalence – multiple doseBioequivalence – 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 Bioequivalence – parallel design

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

Crossover: Parallel:

RR T


Bioequivalence – parallel design Bioequivalence – parallel design

Parallel design may be useful:

Drug with very long elimination half-life– Crossover design not practical

Number of subjects

Parallel design considerations:

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


Bioequivalence – replicate vs. non-replicateBioequivalence – replicate vs. non-replicate

non-replicate

Standard approach BE study:

average bioequivalence

single administrationR and T


Bioequivalence – replicate vs. non-replicateBioequivalence – 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 designBioequivalence – 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 designBioequivalence – replicate design

Disadvantages: Bigger commitment volunteers

More administrations per subject

More expensive



Single dose studies.

Most submitted bioequivalence studies are:

Crossover design.

Non replicate.

Fasted conditions. depends on drug

substance!


EndEnd

Date post:	23-Dec-2015
Category:	Documents
Upload:	gabriella-maxwell
View:	213 times
Download:	0 times

Interchangeability and study design Drs. Jan Welink Training workshop: Training of BE assessors,...

Documents