Guidelines for Preparing

Core Clinical-Safety Information

on Drugs

Second Edition
Report of CIOMS Working Groups III and V
Including New Proposals
for Investigator's Brochures

Geneva
 TABLE OF CONTENTS

Page

VISION 7

PREFACE 9

1. INTRODUCTION 11
a. Background 11
b. Historical Perspective 14
c Basic Principles 16
d. Objectives and Strategies 17
e. Membership and Process of CIOMS Working Group III .. 18

2. GENERAL GUIDELINES 19
a. The Life Cycle of a Drug
and its Company Core Safety Information (CCSI) 19
b. The First CCSI 20
c. Updating the CCSI 21
d. Different Presentations and Uses of Medicinal Products .. 22
e. Excipients and Other Substances 22
f. National Differences in Data Sheets 22

3. WHAT? 23
a. Introduction 23
b. What Not to Include 24
c. Legal Considerations: "Duty to Warn"
and Advisability N q t t o Warn 25
d. The CCSI and General Medical Knowledge 26
e. Lack of Efficacy .." 27

4. WHEN? ...: 27
a. Introduction 27
b. The Concept of Threshold 28
c. Threshold Criteria and Their Order of Importance 28
d. The Importance of Well-Documented Cases 30
e. The Threshold and Clinical Utility 31
f. Considerations of Seriousness
of an Adverse Drug Reaction 31
g. Availability of Other Treatments 31
h. Role of Indication for Treatment and Extent of Use 32
i. When to Add Hypersensitivity Reactions 32
j . When to Delete or Downgrade Safety Information 33
5. HOW? — GOOD SAFETY INFORMATION PRACTICES .... 34
a. General Formatting Principles 34
b. Class Labeling 34
c. Format of Initial Company Core Safety Information 34
d. Frequency of Adverse Drug Reactions 36
e. Good Safety Information: Ten General Principles 37

6. WHERE? 39
a. Introduction 39
b. Posology (Dosing) and Method of Administration 40
c. Contraindications 40
d. Special Warnings and Special Precautions for Use 40
e. Interaction With Other Medicaments
and Other Forms of Interaction 41
f. Pregnancy and Lactation 42
g. Effects on Ability to Drive Vehicles
and Operate Machinery 45
h. Undesirable Effects (Adverse Reactions) 46
i. Overdose 46
j . Pharmacological Properties 46
k. Preclinical Safety Data 47

7. WHO? — SUGGESTED RESPONSIBILITIES 47

a. The Company 47
b. Shared Responsibility 48

8. DEVELOPMENT CORE SAFETY INFORMATION (DCSI) .. 49

a. Introduction 49
b. Specific Proposals 51
c. Administrative Considerations for DCSI 57

9. SUMMARY OF PROPOSALS 58
General Guidelines 58
What? 59
When? 59
How? 60
Where? 60
Who? — Responsibilities 61
Development Core Safety Information 62

10. UNRESOLVED ISSUES 62

11. FIGURES 64
1. Drug Safety in Relation to Phase of Drug Development .. 64
2. Initial and Evolving DCSI and CCSI 65
12. TABLE: Ranking of Threshold Criteria 66

13. APPENDICES 68
APPENDIX 1: European Summary of Product Characteristics
(SPC) and U.S. FDA Requirements for Labeling 68
APPENDIX 2: Membership and Process
of CIOMS Working Groups III and V 77
APPENDIX 3: Some illustrative drug scenarios used
by the Working Group 79
APPENDIX 4: Fictitious example of CIOMS III proposals .. 83
APPENDIX 5: "Investigator's Brochure," Chapter 7
of ICH Harmonized Tripartite Guideline for Good
Clinical Practice, 1996, IFPMA,Geneva 90
APPENDIX 6: Survey of CIOMS Working Group V
on ADR Expectedness In Investigator's Brochures 97