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 1: National drug regulatory legislation: guiding principles for small drug regulatory authorities 1 : Appendix 3. References and selected bibliography

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. References and selected bibliography

REFERENCES

(1) Guidelines for developing national drug policies. WHO, Geneva, 1988.

(2) Guiding principles for small national drug regulatory authorities. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first report. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 790).

(3) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996 (WHO Technical Report Series, No. 863).

(4) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992 (WHO Technical Report Series, No. 823).

(5) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-third report. Geneva, World Health Organization, 1993 (WHO Technical Report Series, No. 834).

(6) WHO Expert Committee on the Use of Essential Drugs. Sixth report. Geneva, World Health Organization, 1995 (WHO Technical Report Series, No. 850).

(7) WHO International Nonproprietary Names (INN) for Pharmaceutical Substances, Geneva, World Health Organization, 1996.

(8) Wehrli A. “Generic names for drugs: The WHO process for assigning INNs, Drug News and Perspectives, Vol. 1 (2), 1988, pp 105-108.

(9) Ethical criteria for medicinal drug promotion. Geneva, World Health Organization, 1988.

(10) WHO Expert Committee on the Use of Essential Drugs. Seventh report. Geneva, World Health Organization, 1997 (WHO Technical Report Series, No. 867).

The Regulation of Pharmacists and Pharmacies. A Draft Act for Adaptation by Small National Drug Regulatory Authorities, PHARM/94.272, 1994

SELECTED BIBLIOGRAPHY
(in addition to the above references)

1981

WHO, Report of a Consultation on Basic Elements of Drug Legislation and Regulatory Control for Developing Countries. Unpublished WHO document, DAP/81.3.

1985

WHO: The rational use of drugs. Report of the Conference of Experts, Nairobi, 1985

Jayasuriya DC. Regulation of Pharmaceuticals in Developing Countries: Legal Issues and Approaches, Geneva, WHO, 1985.

1988

WHO, The World Drug Situation, Geneva, 1988.

1990

WHO, The Role of the Pharmacist in the Health Care System (WHO/PHARMA/DAP/90.1), 1990

1991

United Nations, Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or Not Approved by Governments, New York, 1991.

1992

WHO, Essential Drugs, World Health, March-April 1992.

WHO, Registration of Pharmaceuticals: Tanzania (WHO/DAP/92.12).

WHO/IFPMA, Counterfeit Drugs: Report of a Joint WHO/IFPMA Workshop, 1-3 April 1992, WHO, Geneva.

WHO, Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances (reproduced in WHO Drug Information, Vol. 6(2), 1992, pp. 14-15.

1993

Bankowski Z, Levine RJ.(eds.) Ethics and Research on Human Subjects: International Guidelines, Geneva, CIOMS, 1993.

Dunne JF. “Global Harmonization of Regulatory Requirements: World Health Organization” in Sixth International Conference of Drug Regulatory Authorities: Report of the Conference Proceedings, (WHO/DMP/ICDRA/93.1), pp. 81-82.

UNDCP/WHO, Joint UNDCP-WHO Technical Consultation Meeting on Parallel Distribution Systems for Narcotic Drugs and Psychotropic Substances at the National Level: Report, 1993.

Wehrli A. “The International Drug: What Kind of Passport?”, Paper Presented at the Twenty-Fifth International Seminar of the French Society of Pharmaceutical Sciences and Technology, Montpellier, France, 10-12 June 1993.

World Bank, World Development Report 1993, Washington D.C., 1993.

WHO, “Drug Regulation and Developing Countries”, WHO Drug Information, Vol. 7 (1), 1993, pp. 1-3.

1994

Quality Pharmaceutical care - benefits for governments and the public, WHO second meeting on the role of the pharmacist, Tokyo, Japan, 31 August- 3 September 1993, WHO/PHARM/94.569

Idänpään-Heikkilä JE. WHO, ICH and Global Harmonization of Registration Requirements for Pharmaceutical Products. Proceedings of the Second International Conference on Harmonization, Orlando, 1993, Queen’s University of Belfast, 1994

IFPMA, The IFPMA Compendium on Regulation of Pharmaceuticals for Human Use, IFPMA, Geneva, 1987 (1989 Supp.)

1996

Idänpään-Heikkilä JE., WHO and Harmonization of Pharmaceutical Regulation, WHO Drug Information, 10: 125-126, 1996

Good Pharmacy Practice (GPP) in Community and Hospital Settings, WHO/PHARM/DAP/96.1

EXAMPLES OF NATIONAL LEGISLATION ADOPTED SINCE 1988

Albania

The Drug Law, Date of enactment: 20 April l994

Bulgaria

Degree No. 109 of 17 April 1995 promulgating the Law on medicaments and pharmacies with regard to human medicine
(see also International Digest of Health Legislation (IDHL), 1996, 47(1): 56-60, Bulg. 96.1)

Estonia

(Medicinal Products Act of 19 December 1995)

Ghana

The Pharmacy Act, 1994 (dated 30 December 1994)
(see also International Digest of Health Legislation (IDHL), 1996, 47(1): 63, Ghana, 96.2)

Republic of Korea

The Pharmaceutical Act, as amended up to 7 January 1994
(see also International Digest of Health Legislation (IDHL), 1995, 46(3): 352, ROK 95.1)

Latvia

Law of 27 April l993 of the Republic of Latvia on pharmaceutical activities
(see also International Digest of Health Legislation (IDHL), 1995, 46(2): 220, Lat. 95.1)

Myanmar

Drug Law of 30 October 1992

Malawi (Drug Act of 1988)

Sierra Leone

Pharmacy and Drug Act, 1988