bioavail_equiv2.ppt

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MARKETING AUTHORIZATION OF PHARMACEUTICAL

PRODUCTS WITH SPECIAL REFERENCE TO MULTISOURCE(GENERIC) PRODUCTS: A MANUAL FOR DRUG REGULATORY

AUTHORITIES

Annex 3:*Multisource (Generic) Pharmaceutical Products:

Guidelines on Registration Requirements to EstablishInterchangeability


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Table of Contents of Annex 3

Introduction

Glossary

Part One. Regulatory assessment of interchangeable multisource Pharmaceutical products

1. General considerations

2. Multisource products and interchangeability

3. Technical data for regulatory assessment4. Product information and promotion

5. Collaboration between drug regulatory authorities

6. Exchange of evaluation reports

Part Two. Equivalence studies needed for marketing authorization

7. Documentation of equivalence for marketing authorization

8. When equivalence studies are not necessary

9. When equivalence studies are necessary and types of studies required

In vivostudies

In vitrostudies

Part Three. Tests for equivalence

10. Bioequivalence studies in humans

Subjects

Design

Studies of metabolites

Measurements of individual isomers for chiral drug substance products

Validation of analytical test methods

Sample retention

Statistical analysis and acceptance criteria

Reporting of results

11. Pharmacodynamic studies

12. Clinical trials13. In vitrodissolution

Part Four. In vitrodissolution tests in product development and quality control

Part Five. Clinically important variations in bioavailability leading to non-approval of the product

Part Six. Studies needed to support new post-marketing manufacturing conditions

Part Seven. Choice of reference product

Authors

References

Appendix 1 Examples of national requirements for in vivoequivalence studies for drugs included in the WHO Model List of Essential

Drugs (Canada, Germany and the USA, August 1994).

Appendix 2 Explanation of the symbols used in the design of bioequivalence studies in humans, and other commonly used

pharmacokinetic abbreviationsAppendix 3 Technical aspects of bioequivalence statistics


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Overview

Why is bioequivalence needed?

What are the ways of demonstrating bioequivalence?

When are bioequivalence studies needed/not needed

or may be waived by a regulatory agency?

Design of comparative bioavailability studies

Bioequivalence standards (acceptance ranges)

Some statistical considerations

Other issues - selection of reference product,

extended-release delivery systems, stereoisomers Critical parameters to look into when evaluating dossiers

with respect to bioequivalence studies

Some useful reference materials


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Why is bioequivalence needed?

Pharmaceutical equivalence does not necessarily mean

therapeutic equivalence

Multisource drug products should conform to the same

standards of quality, safety and efficacy required of the

reference product andmust be interchangeable

Differences in excipients or manufacturing process may

lead to differences in product performance. Also, in vitro

dissolution does not necessarily reflect in vivo

bioavailability.


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What are the ways of

demonstrating therapeutic

equivalence?

Comparative bioavailability (bioequivalence) studies

Comparative pharmacodynamic studies in humans

Comparative clinical trials

In vitrodissolution tests


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Bioequivalence studies are not needed when

the multisource product is:a) an aqueous solution for parenteral use

b) a solution for oral use

c) a gas

d) a powder for reconstitution as a solution for oral or parenteral usee) an otic or ophthalmic solution

f) a topical aqueous solution

g) an inhalation product or nasal spray as an aqueous solution

For e, f and g, formulation of multisource product must be similar toreference product.

Also, bioequivalence studies may be waived for compositionally similarstrengths when one strength in a range has been studied.


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Bioequivalence studies are particularly needed for

pharmaceutical products for systemic action such as:a) Oral immediate release when one or more of the following criteria

apply:

i)indicated for serious conditions requiring assured therapeutic response

ii)narrow therapeutic window/safety margin; steep dose-response curve

iii)complicated pharmacokinetics

iv)unfavourable physicochemical properties, e.g., low solubility

v)documented evidence for bioavailability problems related to the drug

vi)where a high ratio of excipients to active ingredients existsb) Non-oral and non-parenteral, such as transdermal patches, suppositories

c) Modified release

d) Fixed combination


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Products for non-systemic use

Comparative clinical or pharmacodynamic studies are required to prove

equivalence for non-solution pharmaceutical products that are for non-

systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc.

application) and are intended to act without systemic absorption.


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Design of comparative bioavailability studies

Studies should be carried out in accordance with

provisions of guidelines on Good Clinical Practice, Good

Manufacturing Practice, Good Laboratory Practice

Most common design is single-dose, randomized, two-way

crossover study (non-replicated)

Other designs possible, e.g. parallel design for drugs with

long half-lives or in patients, steady-state studies for some

non-linear drugs


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Factors to consider in the design of a study Protocol must state a priori, the study objectives and methods to be used

Study formulation should be representative of formulation to be marketed

Subjects

- number

- health status

- age, weight, height

- ethnicity- gender

- special characteristics e.g. poor metabolizers

- smoking

- inclusion/exclusion criteria specified in protocol

Randomization

Blinding

Sampling protocol

Washout period

Administration of food and beverages during study

Recording of adverse events


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Assay validation

specificity

accuracy

precision

sensitivity

stability

must cover before- and within-study phases

calibration range must be appropriate


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Bioequivalence standards (acceptance ranges)

The 90% confidence interval of the relative mean AUC of the test to

reference product should be between 80-125%.

The 90% confidence interval of the relative mean CMAXof the test to

reference product should be between 80-125%. Since CMAX isrecognized as being more variable than the AUC ratio, a wider

acceptance range may be justifiable.

These standards must be met on log-transformed parameters calculated

from the measured data

If the measured potency of the multisource formulation differs by morethan 5% from that of the reference product, the parameters may be

normalized for potency.

TMAXmay be important for some drugs


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Other issues

Selection of a reference product

-should be a product for which the safety, efficacy and quality

are well established, usually the innovatorsproduct

Modified-release delivery systems-greater safety concern due to possibility of dose-dumping

-may be more difficult to establish equivalence

Stereoisomers

-multisource product must have same proportion of enantiomers

in the formulation

-non-stereospecific assay usually adequate in determination of

bioequivalence


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Critical parameters to look into when

evaluating bioequivalence studies Is the reference product suitable?

Was the study design such that variability due to factors

other than the product was reduced? Other design issues

e.g. sample size, sampling protocol

Assay validation adequate?

Pharmacokinetic analysis appropriate?

Statistical analysis appropriate? Acceptance criteria met?


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Some References WHO bioequivalence guideline:

Marketing Authorization of Pharmaceutical Products with Special Reference to

Multisource (Generic) Products. A Manual for a Drug Regulatory Authority (WHO)

Assay validation:

Conference report on analytical methods validation: Bioavailability, Bioequivalence

and Pharmacokinetic Studies, Pharmaceutical Research Vol.9, No.4, 1992

Sample size calculation in comparative bioavailability studies:

Sample size determination for bioequivalence assessment by means of confidenceintervals, Diletti E et al.Int J Clin Pharmacol Ther Toxicol1991, 29:1-8

Statistical method:

A comparison of the two one-sided tests procedure and the power approach for assessingthe equivalence of average bioavailability, Schuirman DJ,J Pharmacokinet Biopharm,

1987, 15:657-680.

Drug characteristics:

American Hospital Formulary Service Drug Information

PhysiciansDesk Reference

Comprehensive text:

Generics and Bioequivalence, Ed. A.J. Jackson, CRC Press, 1994


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Conclusion

Multisource products should meet the samestandards of quality, safety and efficacy as the

reference products AND must be interchangeable

Bioequivalence to a reference productdemonstrates safety and efficacy of themultisource product and is a good indicator ofinterchangeability

bioavail_equiv2.ppt

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