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 Establish
Interchangeability
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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 assessment
4. 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 vivo studies
In vitro studies
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 trials
13. In vitro dissolution
Part Four. In vitro dissolution 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 vivo equivalence 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 abbreviations
Appendix 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?
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•
•
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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 and must 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?
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•
•
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Comparative bioavailability (bioequivalence) studies
Comparative pharmacodynamic studies in humans
Comparative clinical trials
In vitro dissolution 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 use
e) 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 to
reference product.
Also, bioequivalence studies may be waived for compositionally similar
strengths 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 exists
b) 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 nonsystemic 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
•
•
•
•
•
•
•
•
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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
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•
•
•
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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 CMAX of the test to
reference product should be between 80-125%. Since CMAX is
recognized 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 more
than 5% from that of the reference product, the parameters may be
normalized for potency.
• TMAX may be important for some drugs
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Some statistical considerations
• A priori specification of methods
Statistical methods to be used must be specified beforehand in
the protocol
• Number of subjects
Take into consideration error variance of parameter, desired
significance level and acceptable deviation from reference
product
Minimum 12 subjects. Usually 18-24 subjects sufficient.
• Log-transformation
AUC and CMAX should be analyzed after log-transformation
Satisfies assumption of Analysis of Variance (ANOVA model is
additive rather than multiplicative)
• Outliers
Must be valid medical reason to drop outlier from analysis
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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 innovator’s product
• 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
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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 confidence
intervals, Diletti E et al. Int J Clin Pharmacol Ther Toxicol1991, 29:1-8
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Statistical method:
A comparison of the two one-sided tests procedure and the power approach for assessing
the equivalence of average bioavailability, Schuirman DJ, J Pharmacokinet Biopharm,
1987, 15:657-680.
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Drug characteristics:
American Hospital Formulary Service Drug Information
Physician’s Desk Reference
•
Comprehensive text:
Generics and Bioequivalence, Ed. A.J. Jackson, CRC Press, 1994
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Conclusion
• Multisource products should meet the same
standards of quality, safety and efficacy as the
reference products AND must be interchangeable
• Bioequivalence to a reference product
demonstrates safety and efficacy of the
multisource product and is a good indicator of
interchangeability
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