Nonclinical Safety Assessment: A Guide to International Pharmaceutical Regulations -- Contents -- List of Contributors -- Preface -- Part I: International Regulations and Nonclinical Studies for Pharmaceuticals -- 1 Introduction -- 1.1 The Global Pharmaceutical Market -- 1.2 Looking to the Future -- 1.3 Legal and Regulatory Considerations in Drug Development -- 1.4 The Drug Development Process - General Considerations -- References -- 2 ICH: History and Nonclinical Guidances -- 2.1 Introduction -- 2.2 Organization of the ICH -- 2.3 The ICH Process -- 2.4 Animal Welfare and Alternative Methods -- 2.5 ICH M3 -- 2.6 New Initiatives and Topics -- References -- 3 Food and Drug Administration: Nonclinical Program and Pharmaceutical Approval -- 3.1 Legislative Authority of the FDA -- 3.2 Nonclinical Drug Development and the FDA -- 3.3 Nonclinical Testing: General Conditions and Considerations -- 3.4 Toxicity Testing: Small Molecules and Traditional Pharmaceuticals -- 3.5 Toxicity Testing of Pharmaceuticals - The General Approach -- 3.6 First-in-Human Dosing: Results from Nonclinical Studies -- References -- 4 Nonclinical Pharmaceutical Development in MERCOSUR and Brazil -- 4.1 Introduction -- 4.2 MERCOSUR -- 4.3 Brazil -- 4.3.1 Brazilian Regulatory Aspects -- 4.3.2 Nonclinical Studies Required for Drug Registration -- 4.3.3 Comparison with Other Agencies and Harmonization Institutes -- 4.3.4 Regional Reality of Drug Registration - Final Comments -- References -- 5 Nonclinical Safety Assessment: Canada -- 5.1 Introduction -- 5.2 Organization of Health Canada -- 5.2.1 Therapeutic Products Directorate -- 5.2.2 Biologics and Genetic Therapies Directorate -- 5.2.3 Natural Health Products Directorate -- 5.3 The Regulatory Framework for Drug Approval in Canada -- 5.3.1 The Food and Drugs Act -- 5.3.2 The Food and Drug Regulations.

5.4 Nonclinical Assessment in Canada -- 5.4.1 Canada and the International Conference on Harmonization -- 5.4.2 Good Laboratory Practices in Canada -- 5.4.3 Case Studies and Summary Basis of Decision -- 5.5 Clinical Trial Applications -- 5.5.1 History and Regulations -- 5.5.2 Clinical Trial Application Overview -- 5.5.3 Pre-Submission Meetings and Consultations -- 5.5.4 CTA Content and Format -- 5.5.5 Nonclinical Aspects of the CTA/CTA-A Process -- 5.5.6 CTA-A Content and Format -- 5.5.7 CTA and CTA-A Review Process -- 5.6 Special Regulatory Considerations -- 5.6.1 Generic Drugs -- 5.6.2 Subsequent Entry Biologics in Canada -- 5.6.3 Orphan Drugs in Canada -- References -- 6 European Pharmaceutical Regulation - Nonclinical Testing Requirements -- 6.1 Introduction -- 6.1.1 Definitions -- 6.2 Regulation of Medicinal Products in the European Union -- 6.2.1 Overview -- 6.2.2 Role of the European Medicines Agency in the Regulation of Medicines -- 6.2.3 Scientific Structure of the EMA -- 6.2.4 Regulatory Process in the EU -- 6.3 Nonclinical Testing in the Support of Clinical Trials -- 6.3.1 Role of Individual Country Regulatory Agencies/Authorities -- 6.3.2 Risk Mitigation in Nonclinical Development of Medicinal Products -- 6.4 Overview -- References -- 7 South Africa -- 7.1 Introduction -- 7.2 Country Information -- 7.2.1 Description -- 7.2.2 Economy -- 7.2.3 Country Organization -- 7.2.4 The Rainbow Nation -- 7.2.5 Health and Medicines -- 7.3 The Regulatory Aspects -- 7.3.1 The Registration of Medicines: Introduction and Scope -- 7.3.2 The Legal Framework -- 7.3.3 Role, Structure and Organization of the MCC -- 7.3.4 The Regulatory Procedures -- 7.3.5 The Registration Requirements for Preparation of the Application Package -- 7.3.6 The Registration Process: Several Steps of Review -- 7.4 The Nonclinical Safety Assessment -- 7.4.1 Introduction.

7.4.2 Nonclinical Evaluation -- 7.4.3 Content of the Application for Safety Assessment -- 7.4.4 The Focus of the Nonclinical Evaluation -- 7.4.5 Pharmacology Testing -- 7.4.6 Toxicology Testing -- 7.5 Conclusion -- 7.5.1 Withdrawals -- 7.5.2 Consequences -- 7.5.3 New Safety Approach -- 8 Asia Pacific: China -- 8.1 Introduction -- 8.2 History of Drug Administration -- 8.3 The Provisions for Drug Registration -- 8.4 The SFDA -- 8.5 The SFDA Affiliated Organizations -- 8.5.1 Center for Drug Evaluation (CDE) -- 8.5.2 Center for Drug Re-evaluation (CDR) -- 8.5.3 Certification Committee for Drugs (CCD) -- 8.5.4 National Institutes for Food and Drug Control (NIFDC) -- 8.6 General Registration Procedures -- 8.7 Pharmaceutical Application -- 8.8 Import Drug Application -- 8.9 Testing Guidelines and Safety Evaluation -- 8.10 GLP Compliance in China -- 8.11 Animal Welfare Requirements -- References -- 9 Pharmaceutical Regulations for Nonclinical Safety Assessment in Japan -- 9.1 History of Regulation for Nonclinical Safety Assessment in Japan -- 9.2 Approval Application of New Drugs in Japan -- 9.2.1 Nonclinical Safety Studies Required for Drug Approval -- 9.3 Current Nonclinical Safety Guidelines Available in Japan -- 9.4 Current Trends of Conduct of Nonclinical Safety Evaluation in Japan -- 9.4.1 Single-Dose Toxicity Studies -- 9.4.2 Nonclinical Evaluation of the Potential for QT Interval Prolongation -- 9.4.3 Carcinogenicity Studies -- 9.4.4 Safety Evaluation of Drug Metabolites -- 9.4.5 Phototoxicity Studies -- 9.4.6 Skin Sensitization Studies -- 9.4.7 Nonclinical Evaluation of Paediatric Drugs -- 9.4.8 Antigenicity Studies -- 9.4.9 Safety Evaluation of Chiral Pharmaceuticals -- 9.4.10 Safety Evaluation of Impurities -- 9.4.11 Other Studies -- 9.5 Safety Assessment of Unapproved Drugs.

9.6 Necessity of 3Rs (Reduction/Refinement/Replacement) of Animal Studies -- 9.7 Attitude of Japanese Pharmaceutical Companies and the Regulatory Agency toward Nonclinical Safety Assessment -- References -- 10 Indian Regulatory Process for Nonclinical Drug Development -- 10.1 Introduction -- 10.2 Drug Development -- 10.3 Quality Systems -- 10.4 Nonclinical Drug Development - Key Regulatory Requirements -- 10.5 Nonclinical Safety Assessment - Key Approval Requirements -- 10.6 Data Required for Clinical Study Approval -- 10.6.1 Animal Toxicity Studies as Mandated by Clinical Phases -- 10.6.2 Animal Toxicity Studies as Mandated by Proposed Route and Duration of Administration -- 10.7 Animal Toxicology -- 10.7.1 Systemic Toxicity Studies -- 10.7.2 Male Fertility Study -- 10.7.3 Female Reproduction and Developmental Toxicity Studies -- 10.7.4 Local Tolerance Studies -- 10.7.5 Allergenicity/Hypersensitivity -- 10.7.6 Genotoxicity -- 10.7.7 Carcinogenicity -- 10.8 Animal Pharmacology -- 10.8.1 General Principles -- 10.8.2 Specific Pharmacological Actions -- 10.8.3 General Pharmacological Actions - Essential Safety Pharmacology -- 10.8.4 Follow-up and Supplemental Safety Pharmacology Studies -- 10.8.5 Conditions under which Safety Pharmacology Studies are not Necessary -- 10.8.6 Timing of Safety Pharmacology Studies in Relation to Clinical Development -- 10.9 Safety Assessment Requirements: Indian Schedule Yand International Guidelines -- 10.10 Good Laboratory Practice Quality System in India -- 10.10.1 Indian National Compliance Monitoring Authority (NGCMA) -- 10.10.2 Mutual Acceptance of Data (MAD) -- 10.11 Safety Assessment Test Facilities in India -- 10.12 Investigational New Drug Application for Undertaking Clinical Trials -- References -- 11 Asia Pacific: Australia -- 11.1 Introduction -- 11.2 Australian Therapeutic Goods Administration (TGA).

11.2.1 Introduction -- 11.2.2 Legislative Backing -- 11.2.3 Information to be Supplied to the TGA to Support Inclusion of Therapeutic Goods in the ARTG -- 11.2.4 Evaluation Categories -- 11.2.5 Evaluation Fees and Timeframes -- 11.3 Clinical Trials in Australia -- 11.3.1 Introduction -- 11.3.2 Clinical Trial Schemes in Australia -- 11.3.3 Clinical Trial Process -- 11.3.4 CTN Scheme -- 11.3.5 CTX Scheme -- 11.3.6 Conducting Clinical Trials in Australia -- 11.4 Nonclinical Data to Support the Conduct of Clinical Trials in Australia and Marketing Application to the TGA -- 11.4.1 Introduction -- 11.4.2 Chemistry, Manufacturing and Controls -- 11.4.3 Nonclinical Pharmacology and Pharmacokinetics -- 11.4.4 Nonclinical Toxicology -- 11.4.5 Nonclinical Toxicology Studies -- References -- Part II Toxicology Studies Supporting Clinical Development -- 12 Repeated-Dose Toxicity Studies in Nonclinical Drug Development -- 12.1 Introduction -- 12.2 General Considerations -- 12.2.1 Duration and Timing of Repeated-Dose Toxicology Studies -- 12.2.2 Anticancer Therapeutics -- 12.2.3 Assessment of Systemic Exposure -- 12.2.4 Qualification of Drug Substance and Product -- 12.2.5 Other Types of Applications/Submissions -- 12.3 Study Design Considerations -- 12.3.1 Selection of Animal Model -- 12.3.2 Size of Treatment Groups -- 12.3.3 Dose and Administration -- 12.3.4 Dose Selection -- 12.3.5 Test Article (Drug Substance) and Drug Formulation -- 12.4 Study Observations and Assessments -- 12.4.1 General -- 12.4.2 Clinical Observations -- 12.4.3 Food Consumption/Body Weight -- 12.4.4 Clinical Chemistry -- 12.4.5 Haematology -- 12.4.6 Urinalysis -- 12.4.7 Ophthalmologic Examinations -- 12.4.8 Electrocardiographic Examinations -- 12.4.9 Macroscopic Examination -- 12.4.10 OrganWeights -- 12.4.11 Histopathology -- 12.4.12 Additional Parameters -- 12.4.13 Medical Devices.

Acknowledgement.