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EVALUTION OF DOSSIERS IN WHO-PREQUALIFICATION PROJECT

MULTISOURCE HIV/AIDS-DRUGS

Evaluation of bioavailability/bioequivalence data

Based, with some changes on a presentation by Anna-Karin Hamberg

Medical products agency, Sweden

Presented byHans Kemmler

Consultant to WHO(Clinical Reviewer, Swissmedic, Switzerland)

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Why do we need Bioequivalence studies?

No clinical studies have been performed in

patients with the Generic Product to support

its Efficacy and Safety.

With data to support similar in vivo

performance (= Bioequivalence)

Efficacy and Safety

data can be extrapolated from the Innovator

Product to the Generic Product.

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Overview

Definition of some important Bioequivalence [BE] terms

Key issues in the WHO Manual Annex 3 “Guidelines on Requirements to Establish Interchangeability”

Major Deficiencies in BE-Studies identified within the WHO Procurement, Quality and Sourcing Project: HIV/Aids Drugs

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Overview

A Note on Choice of Reference

Products

Present new WHO Template for

Assessment of Bioequivalence data

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Bioavailability

“ .. the extent and the rate at which a

substance or its active moiety is delivered

from a pharmaceutical form and becomes

available in the general circulation.”

Reference:

intravenous administration = 100% bioavailability

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Plasma concentration time profile

Cmax

Tmax

AUC

time

concentration

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Important Pharmacokinetic Parameters

AUC: area under the concentration-time curve measure of the extent of bioavailability

Cmax: the observed maximum concentration

of drug measure of both the rate of absorption and the extent of bioavailability

tmax: the time after administration of drug at

which Cmax is observed measure of the

rate of absorption

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Bioavailability

Absolute bioavailability (F):

Relative bioavailability (Frel)

larextravascu

ravenousint

ravenousint

larextravascu

DoseDose

AUCAUC

F

1larextravascu

2larextravascu

2larextravascu

1larextravascurel Dose

DoseAUCAUC

F

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Bioavailability: Same Dose

Absolute bioavailability (F):

Relative bioavailability (Frel)

larextravascu

ravenousint

ravenousint

larextravascu

DoseDose

AUCAUC

F

1larextravascu

2larextravascu

2larextravascu

1larextravascurel Dose

DoseAUCAUC

F

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Pharmaceutical Equivalents

contain the same amount of the same active

substance in the same dosage form

meet the same or comparable standards

intended to be administered by the same

route

Pharmaceutical equivalence by itself does not

necessarily imply therapeutic equivalence

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Pharmaceutical Equivalents

Possible Differences

Drug particle size

Excipients

Manufacturing

Equipment or

Process

Site of manufacture

Test Reference

Could lead to differences in product performance in vivo

Possible Bioinequivalence

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Bioequivalence

Two products are bioequivalent if

they are pharmaceutically equivalent

bioavailabilities (both rate and extent) after

administration in the same molar dose are

similar to such a degree that their effects

can be expected to be essentially the same

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Therapeutic equivalence

Two products are therapeutically equivalent if

pharmaceutically equivalent

their effects, with respect to both efficacy and

safety, will be essentially the same as derived

from appropriate studies– bioequivalence studies– pharmacodynamic studies– clinical studies – in vitro studies

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Interchangeable pharmaceutical products

If a product is demonstrated to be

therapeutically equivalent to a reference

product, then the products are considered

interchangeable.

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Bioanalytical Method Validation

Quantitative determinations of drugs

in biological samples, such as blood

or plasma, play a significant role in

evaluation and interpretation of

bioequivalence data.

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Bioanalytical Method Validation

Essential to use a well-characterised

and fully validated analytical method

to yield reliable results.

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Bioanalytical Method Validation

Method Validation should include– Accuracy– Precision– Sensitivity– Specificity– Recovery– Stability

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Bioanalytical Method Validation

Accuracy

Closeness of determined value to the true value.

The acceptance criteria is mean value 15% deviation from true value.

At LOQ, 20% deviation is acceptable.

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Bioanalytical Method Validation

Precision

The closeness of replicate determinations of a sample by an assay.

The acceptance criteria is 15% CV. At LOQ, 20% deviation is acceptable.

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Bioanalytical Method Validation

Sensitivity

The limit of quantitation (LOQ) is the lowest concentration which can be measured with acceptable accuracy and precision.

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Bioanalytical Method Validation

Specificity (selectivity)

Ability of the method to measure only what it is intended to measure in the presence of other components in the sample. Blank samples of the biological matrix should be tested for interfering peaks.

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Bioanalytical Method Validation

Recovery

The extraction efficiency of an analytical process, reported as a percentage of the known amount of an analyte carried through the sample extraction and processing steps of the method. Recovery does not have to be 100%, but the extent of recovery of an analyte and of the internal standard should be consistent.

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Bioanalytical Method Validation

Stability Stability of the drug in the biological matrix during

the collection process,

the sample storage period and

sample analysis,

should be established.

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Bioanalytical Method Validation

Useful references:

FDA Guidance for Industry

Bioanalytical Method Validation (May 2001)(http://www.fda.gov/cder/guidance/4252fnl.pdf)

Published Workshop Reports

Shah, V.P. et al, Pharmaceutical Research: 1992; 9:588-592

Shah, V.P. et al, Pharmaceutical Research: 2000; 17: 1551-1557