Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities - Regulatory Support Series No. 005: ANNEXES: Annex 3: *Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability 1 : Appendix 3. Technical aspects of bioequivalence statistics

Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities - Regulatory Support Series No. 005
(1998; 213 pages)

Table of Contents

PREFACE
I. INTRODUCTION
II. PROVISIONS AND PREREQUISITES FOR REGULATORY CONTROL
	A. Political will and commitment
	B. Legislation
	C. Accountability
	D. Resources for the marketing authorization function
	E. Fees and cost recovery
	F. Inventory of existing products on the market
	G. Rational selection of products
	H. Special access schemes
	I. Postmarketing activities
III. OPERATING ACTIVITIES
	A. Transparency
	B. Policies
	C. Administrative procedures
	D. Guidelines for applicants
	E. Model application form
	F. Communication among departments within the DRA
	G. Relationship of evaluators with GMP inspectors
	H. Relationship of evaluators with the quality control laboratories
	I. Functional relationship of the evaluators with the expert advisory body
	J. Relationship of evaluators with the pharmaceutical industry and confidentiality of data
	K. Meetings with applicants
	L. Procedures for appeals
	M. Collaboration with other DRAs
	N. Collaboration with WHO
	O. Use of external experts as evaluators
	P. Timeframes for processing of applications
	Q. Publication of marketing authorization decisions
IV. REVIEW OF APPLICATIONS FOR MARKETING AUTHORIZATION OF MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS
	A. Applicability
	B. Initial decisions on options for premarket evaluation
	C. Evaluation of data on quality
	D. Quality of starting materials
	E. Container labelling
	F. Toxicological, pharmacological and clinical data
	G. Product Information
	H. Interchangeability
V. ISSUE OF WRITTEN MARKETING AUTHORIZATION
VI. VARIATIONS
VII. PERIODIC REVIEWS
VIII. SUSPENSION AND REVOCATION OF MARKETING AUTHORIZATION
GLOSSARY
ABBREVIATIONS
REFERENCES
ANNEXES
	Annex 1: National drug regulatory legislation: guiding principles for small drug regulatory authorities¹
		1. Introduction
		2. Drafting national legislation: points for consideration
		3. Defining the scope of the marketing authorization procedure for medicinal products
		4. Example of a legislative scheme for regulating medicinal products.
			4.1 General considerations
			4.2 Model Legislative text and commentary (in italics)
				I. Administration
				II. Provisional registration/marketing authorization and inventory of medicinal products
				III. Screening of products and issuance of product licences/authorizations
				IV. Other activities requiring authorization/licensing
				V. General provisions
				VI. Interpretation
		Appendix 1. Example of a legislation scheme for registration of pharmacy personnel
		Appendix 2. Guidelines, documents and other regulatory instruments established by WHO to support drug regulatory authorities
		Appendix 3. References and selected bibliography
	Annex 2: *Guidelines for Implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce¹
		1. Provisions and objectives
		2. Eligibility for participation
		3. Requesting a certificate
		4. Issuing a certificate
		5. Notifying and investigating a quality defect
		References
		Appendix 1. Model Certificate of a Pharmaceutical Product
		Appendix 2. Model Statement of Licensing Status of Pharmaceutical Product(s)
		Appendix 3. Model Batch Certificate of a Pharmaceutical Product
		Appendix 4. Glossary and index (not intended to be a formal part of the Scheme).
	Annex 3: *Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability¹
		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
				Measurement 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 symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
		Appendix 3. Technical aspects of bioequivalence statistics
	Annex 4: Model Guidelines on Conflict of Interest and Model Proforma for a Signed Statement on Conflict of Interest
	Annex 5: Model Contract between a Regulatory Authority and an External Evaluator of Chemistry, Pharmaceutical and Bioavailability Data
	Annex 6: Model Application Form for new Marketing Authorizations, Periodic Reviews and Variations, with Notes to the Applicant
	Annex 7: Detailed Advice on Evaluation of Data by the Drug Regulatory Authority
	Annex 8: Ethical criteria for medicinal drug promotion¹
		Resolution WHA41.17 adopted by the Forty-first World Health Assembly, 13 May 1988
		Introduction
		Objective
		Ethical criteria
		Applicability and implementation of criteria
		Promotion
		Advertising
		Medical representatives
		Free samples of prescription drugs for promotional purposes
		Free samples of non-prescription drugs to the general pubic for promotional purposes
		Symposia and other scientific meetings
		Post-marketing scientific studies, surveillance and dissemination of information
		Packaging and labelling
		Information for patients: package inserts, leaflets and booklets
		Promotion of exported drugs
		Appendix: Sample drug information sheet²
	Annex 9: Model marketing authorization letter
	Annex 10: Model List of Variations (Changes) to Pharmaceutical Aspects of Registered Products which may be made without Prior Approval
	Annex 11: *Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms¹
		General
		Definitions
		1. Stability testing
		2. Intended market
		3. Design of stability studies
		4. Analytical methods
		5. Stability report
		6. Shelf-life and recommended storage conditions
		References
		Official, international and national guidelines
		Appendix 1: Survey on the stability of pharmaceutical preparations included in the WHO Model List of Essential Drugs: answer sheet
		Appendix 2: Stability testing: summary sheet

Appendix 3. Technical aspects of bioequivalence statistics

The pharmacokinetic characteristics to be tested, the test procedure and the norms to be maintained should be specified beforehand in the protocol. A post hoc change of the methods specified for the statistical evaluation is acceptable only if adherence to the protocol would preclude a meaningful evaluation and if such change of procedure has been fully justified.

Concentration dependent data such as AUC and C_max should be log transformed prior to statistical analysis in order to satisfy the fundamental assumption of variance that effects in the model in an additive rather than a multiplicative manner.

Acceptance ranges for main characteristics

AUC-ratio

The 90% confidence interval for this measure of relative bioavailability should lie within a bioequivalence range of 0.80-1.25 (see page 118). If therapeutic range is particularly narrow, the acceptance range may need to be reduced. A larger acceptance range may be acceptable if clinically appropriate.

C_max-ratio

This measure of relative bioavailability is inherently more variable than, for example, the AUC-ratio, and a wider acceptance range may be appropriate. The range used should be justified taking into account safety and efficacy considerations.

t_max-diff

Statistical evaluation of t_max only makes sense if there is a clinically relevant claim for rapid release or action or signs for a relation to adverse effects. The non-parametric 90% confidence interval for this measure of relative bioavailability should lie within a clinically relevant range.