for Human Pharmaceuticals Kyung-Chul Choi D.V.M., Ph.D. ICH Safety Guidelines for Human Pharmaceuticals 2008년 10월 15일 Kyung-Chul Choi D.V.M., Ph.D. College of Veterinary Medicine Chungbuk National University Email: kchoi@cbu.ac.kr Blog: blog.daum.net/vetimmune

ICH Introduction * Source : http://www.ich.org

ICH Introduction * Source : http://www.ich.org

ICH Introduction * Source : http://www.ich.org

ICH Introduction * Source : http://www.ich.org

ICH Guidelines The ICH topics are divided into four categories and ICH topic codes are assigned according to these categories. Quality Guidelines Harmonisation achievements in the Quality area including stability studies, impurities testing and a more flexible approach to pharmaceutical quality based on GMP risk management Safety Guidelines Safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity and reprotoxicity. Recent work : non-clinical testing strategy for assessing the QT interval prolongation liability Efficacy Guidelines The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials. Multidisciplinary Guidelines Cross-cutting topics which do not fit uniquely into one of the Q, S and E categories. It includes MedDRA, CTD and the development of Electronic Standards for the Transfer of Regulatory Information (ESTRI). * Source : http://www.ich.org

ICH Guideline = ICH Products * Source : http://www.ich.org

ICH (http://www.ich.org)

Carcinogenecity Studies ICH Safety Guidelines Carcinogenecity Studies S1A – S1C

Carcinogenecity Studies (S1A) TABLE OF CONTENTS 1. Introduction 2. Historical Background 3. Objective of the guideline 4. Factors to consider for carcinogenicity testing 4.1 Duration and Exposure 4.2 Cause for Concern 4.3 Genotoxicity 4.4 Indication and Patient Population 4.5 Route of Exposure 4.6 Extent of Systemic Exposure 4.7 Endogenous Peptides and Protein Substances or Their Analogs 5. Need for Additional Testing

Carcinogenecity Studies (S1B) TABLE OF CONTENTS 1. OBJECTIVE 2. BACKGROUND 3. SCOPE OF THE GUIDELINE 4. THE GUIDELINE 4.1 Preamble. 4.2 Experimental approaches to testing for carcinogenic potential. 5. MECHANISTIC STUDIES 5.1 Cellular changes. 5.2. Biochemical measurements. 5.3. Considerations for additional genotoxicity testing 5.4. Modified protocols. 6. GENERAL CONSIDERATIONS IN THE CHOICE OF AN APPROPRIATE SPECIES FOR LONG TERM CARCINOGENICITY TESTING 6.1. Information from surveys on pharmaceuticals. 6.2. Potential to study mechanisms. 6.3. Metabolic disposition. 6.4. Practicality. 6.5. Testing in more than one species. 6.6. Exceptions.

Carcinogenecity Studies (S1C) TABLE OF CONTENTS 1. INTRODUCTION 1.1 General Considerations for the Conduct of Dose-Ranging Studies 1.2 Toxicity Endpoints in High Dose Selection 1.3 Pharmacokinetic Endpoints in High Dose Selection 1.4 Criteria for Comparisons of AUC in Animals and Man for use in High Dose Selection 1.5 Saturation of Absorption in High Dose Selection 1.6 Pharmacodynamic Endpoints in High Dose Selection 1.7 Maximum Feasible Dose 1.8 Limit Dose 1.9 Additional Endpoints in High Dose Selection 1.10 Selection of Middle and Low Doses in Carcinogenicity Studies 2. SUMMARY

ICH Safety Guidelines Genotoxicity Studies S2

Genotoxicity Studies (S2) TABLE OF CONTENTS 1. INTRODUCTION 1.1 OBJECTIVES OF THE GUIDELINE 1.2. Background 1.3. Scope of the Guideline 1.4 General Principles 2 THE STANDARD TEST BATTERY FOR GENOTOXICITY 2.1 Rationale 2.2 Description of the Two Options for the Standard Battery 2.3 Modifications to the Test Battery 2.4 Detection of Germ Cell Mutagens 3. RECOMMENDATIONS FOR IN VITRO TESTS 3.1 Test Repetition and Interpretation 3.2 Recommended Protocol for the Bacterial Mutation Assay 3.3 Recommended Protocols for the Mammalian Cell Assays

Genotoxicity Studies (S2) TABLE OF CONTENTS (Cont….) 4. RECOMMENDATIONS FOR IN VIVO TESTS 4.1 Tests for the Detection of Chromosome Damage In Vivo 4.2 Other In Vivo Genotoxicity Tests 4.3 Dose Selection for In Vivo Assays 4.4 Demonstration of Target Tissue Exposure for Negative In Vivo Test Results 4.5 Sampling Times for In Vivo Assays 4.6 Number of Animals Analyzed 4.7 Use of Male/Female Rodents in In Vivo Genotoxicity Tests 4.8 Route of Administration 4.9 Use of Positive Controls for In Vivo Studies 5. GUIDANCE ON EVALUATION OF TEST RESULTS AND ON FOLLOW-UP TEST STRATEGIES 5.1 Assessment of Biological Relevance 5.2 Evaluation of Results Obtained in In Vitro Tests 5.3 Evaluation of Results Obtained from In Vivo Tests 5.4 Follow-up Strategies for Positive Results 5.5 Follow-up Genotoxicity Testing in Relation to Tumor Findings in a Carcinogenicity Bioassay

Toxicokinitics and Pharmacokinetics ICH Safety Guidelines Toxicokinitics and Pharmacokinetics S3A – S3B

Toxicokinitics and Pharmacokinetics (S3A) TABLE OF CONTENTS 1. Introduction 2. The objectives of toxicokinetics and the parameters 3. General principles to be considered 3.1 Introduction 3.2 Quantification of exposure 3.3 Justification of time points for sampling 3.4 Contribution to the setting of dose levels in order to produce adequate exposure 3.5 Extent of exposure assessment in toxicity studies 3.6 Complicating factors in exposure interpretation 3.7 Route of administration 3.8 Determination of metabolites 3.9 Statistical evaluation of data 3.10 Analytical methods 3.11 Reporting

Toxicokinitics and Pharmacokinetics (S3A) TABLE OF CONTENTS (Cont…) 4. Toxicokinetics in the various areas of toxicity testing - specific aspects 4.1 Introduction 4.2 Single-dose toxicity studies 4.3 Repeated-dose toxicity studies 4.4 Genotoxicity studies 4.5 Carcinogenicity (oncogenicity) studies1 4.6 Reproductive toxicity studies 5. Supplementary Notes 6. References (other ICH Guidance)

2. Circumstances Under Which Repeated Dose Tissue Toxicokinitics and Pharmacokinetics (S3B) TABLE OF CONTENTS 1. Introduction 2. Circumstances Under Which Repeated Dose Tissue Distribution Studies Should be Considered 3. Design and Conduct of Repeated Dose Tissue Distribution Studies 4. Summary

ICH Safety Guidelines Toxicity Testing S4

TABLE OF CONTENTS (Cont…) 1. Objectives 2. Scope 3. Background Toxicity Testing (S4) TABLE OF CONTENTS (Cont…) 1. Objectives 2. Scope 3. Background 4. GUIDANCE ON DURATION OF CHRONIC TOXICITY TESTING FOR TRIPARTITE DEVELOPMENT PLAN

Reproductive Toxicology ICH Safety Guidelines Reproductive Toxicology S5

Reproductive Toxicology (S5) TABLE OF CONTENTS 1. Introduction 1.1 Purpose of the Guideline 1.2 Aim of studies 1.3 Choice of studies 2. Animal Criteria 2.1 Selection and number of species 2.2 Other test systems 3. General Recommendations Concerning Treatment 3.1 Dosages 3.2 Route and frequency of administration. 3.3 Kinetics 3.4 Control groups 4. PROPOSED STUDY DESIGNS - COMBINATION OF STUDIES 4.1 The most probable option 4.2 Single study design (rodents) 4.3 Two study design (rodents) 5. STATISTICS

Biotechnological Products ICH Safety Guidelines Biotechnological Products S6

Biotechnological Products (S6) TABLE OF CONTENTS 1. INTRODUCTION 1.1 Background 1.2 Objectives 1.3 Scope 2. SPECIFICATION OF THE TEST MATERIAL 3. PRECLINICAL SAFETY TESTING 3.1 General Principles 3.2 Biological Activity/Pharmacodynamics 3.3 Animal Species/Model Selection 3.4 Number/Gender of Animals 3.5 Administration/Dose Selection 3.6 Immunogenicity 4. SPECIFIC CONSIDERATIONS 4.1 Safety Pharmacology 4.2 Exposure Assessment 4.3 Single Dose Toxicity Studies 4.4 Repeated Dose Toxicity Studies 4.5 Immunotoxicity Studies 4.6 Reproductive Performance and Developmental Toxicity Studies 4.7 Genotoxicity Studies 4.8 Carcinogenicity Studies 4.9 Local Tolerance Studies

ICH Safety Guidelines Pharmacology Studies S7A – S7B

Pharmacology Studies (S7A) TABLE OF CONTENTS 1. INTRODUCTION 1.1 Objectives of the Guideline 1.2 Background 1.3 Scope of the Guideline 1.4 General Principle 1.5 Definition of Safety Pharmacology 2. GUIDELINE 2.1 Objectives of Studies 2.2 General Considerations in Selection and Design of Safety Pharmacology Studies 2.3 Test Systems 2.4 Dose Levels or Concentrations of Test Substance 2.5 Duration of Studies 2.6 Studies on Metabolites, Isomers and Finished Products 2.7 Safety Pharmacology Core Battery 2.8 Follow-up and Supplemental Safety Pharmacology Studies……..

Pharmacology Studies (S7B) TABLE OF CONTENTS 1. INTRODUCTION 1.1 Objective of the Guideline 1.2 Background 1.3 Scope of the Guideline 1.4 General Principles 2. GUIDELINE 2.1 Objectives of S7B Studies 2.2 Considerations for Selection and Design of Studies 2.3 Non-clinical Testing Strategy 2.4 Timing of S7B Non-clinical Studies and Integrated Risk Assessment in Relation to Clinical Development 3. TEST SYSTEMS 3.1 Considerations for Test Systems

Immunotoxicology Studies ICH Safety Guidelines Immunotoxicology Studies S8

Immunotoxicology Studies (S8) TABLE OF CONTENTS 1. INTRODUCTION 1.1 Objectives of the Guideline 1.2 Background 1.3 Scope of the Guideline 1.4 Overview 2. GUIDELINE 2.1 Factors to Consider in the Evaluation of Potential Immunotoxicity 2.2 Weight of Evidence Review 3. SELECTION AND DESIGN OF ADDITIONAL IMMUNOTOXICITY STUDIES 3.1 Objectives 3.2 Selection of assays 3.3 Study Design 3.4 Evaluation of Additional Immunotoxicity Studies and Need for Further Studies 4. TIMING OF IMMUNOTOXICITY TESTING IN RELATION TO CLINICAL STUDIES

Nonclinical Evaluation for Anticancer Pharmaceuticals S9 ICH Safety Guidelines Nonclinical Evaluation for Anticancer Pharmaceuticals S9

Nonclinical Evaluation for Anticancer Pharmaceuticals (S9) TABLE OF CONTENTS 1. INTRODUCTION 1.1 Objectives of the Guideline 1.2 Background 1.3 Scope 1.4 General Principles 2. STUDIES TO SUPPORT NONCLINICAL EVALUATION 2.1 Pharmacology 2.2 Safety Pharmacology 2.3 Pharmacokinetics 2.4 General Toxicology 2.5 Reproduction Toxicology 2.6 Genotoxicity 2.7 Carcinogenicity 2.8 Immunotoxicity 2.9 Photosafety testing

Nonclinical Evaluation for Anticancer Pharmaceuticals (S9) TABLE OF CONTENTS (Cont…) 3. NONCLINICAL DATA TO SUPPORT CLINICAL TRIAL DESIGN AND MARKETING 3.1 Start Dose for First Administration in Humans 3.2 Dose Escalation and the Highest Dose in a Clinical Trial 3.3 Duration and Schedule of Toxicology Studies to Support Initial Clinical Trials 3.4 Duration of Toxicology Studies to Support Continued Clinical Development and Marketing 3.5 Combination of Pharmaceuticals 3.6 Nonclinical Studies to Support Trials in Pediatric Populations 4. OTHER CONSIDERATIONS 4.1 Conjugated Products 4.2 Liposomal Products 4.3 Evaluation of Drug Metabolites 4.4 Evaluation of Impurities

Photosafety Evaluation ICH Safety Guidelines Photosafety Evaluation S10

Photosafety Evaluation (S10) TABLE OF CONTENTS 1. INTRODUCTION 1.1. Objectives of the Guideline 1.2. Background 1.3. Scope of the Guideline 1.4. General Principles 2. FACTORS TO CONSIDER IN THE PHOTOSAFETY EVALUATION 2.1. Photochemical Properties 2.2. Tissue Distribution/Pharmacokinetics 2.3. Metabolite Considerations 2.4. Pharmacological Properties 3. NONCLINICAL PHOTOSAFETY TESTING 3.1. General Considerations 3.2. Photoreactivity Testing Using Chemical Assays 3.3. Phototoxicity Testing Using in vitro Assays 3.4. Photosafety Testing Using in vivo Assays and Systemic Administration 3.5. Photosafety Testing Using in vivo Assays and Dermal Administration 3.6. Photosafety Testing Using in vivo Assays and Ocular Administration

Photosafety Evaluation (S10) TABLE OF CONTENTS (Cont…) 4. CLINICAL PHOTOSAFETY ASSESSMENT 5. ASSESSMENT STRATEGIES 5.1. Recommendations for Testing of Pharmaceuticals Given via Systemic Routes 5.2. Recommendations for Testing of Pharmaceuticals Given via Dermal Routes 5.3. Recommendations for Testing of Pharmaceuticals Given via Ocular Routes