Table of Contents. Edition 1.4, June 2021

Foreword and important disclaimers

1    Global labeling governance
  1.1 The purpose of global labeling governance
  1.2 Different approaches
  1.3 Need for rules
  1.4 Reach of governance

2    Company Core Data Sheet and Company Core Safety Information
  2.1 Company Core Data Sheet
    2.1.1 Definition
    2.1.2 CCDS content
    2.1.3 Tailoring CCDS content to specific markets
    2.1.4 CCDS for inactive products
    2.1.5 CCDS scope and structure
    2.1.6 Additional CCDS features
  2.2 Company Core Safety Information
    2.2.1 Definition
    2.2.2 Typical strict implementation policy for CCSI
    2.2.3 Typical elements of CCSI
    2.2.4 Defining CCSI by section?
  2.3 CCDS and CCSI as reference information for labeling governance
  2.4 CCDS and CCSI as reference information for periodic safety reporting
  2.5 Alternatives to CCDS and CCSI

3    Basic business practices for global safety labeling governance
  3.1 Implementation fidelity-related expectations
    3.1.1 Markup of CCDS content and associated implementation expectations
  3.2 Speed-related implementation expectations

4    Target labeling and labeling development
  4.1 Definitions
    4.1.1 Target labeling
    4.1.2 Target product profile
    4.1.3 Development labels, Development Core Data Sheet
  4.2 Creating and maintaining target labeling
    4.2.1 Benefits
    4.2.2 Requirements
    4.2.3 Content of a target labeling document

5    Adverse reactions - Introduction
  5.1 Adverse reactions - The users’ information needs
  5.2 Conflicting regulatory definitions of “adverse reaction”
  5.3 “Reaction to” or “effect of”

6    Deciding what qualifies to be an “adverse reaction for labeling”

  6.1 Two factors to weigh

  6.2 Analysis of regulatory definitions
    6.2.1 A non-regulatory definition for reference
    6.2.2 The definition in the US prescription drug labeling regulation
    6.2.3 The “definition” in the European Union’s SmPC guideline
    6.2.4 Other regulatory definitions for the purposes of labeling

  6.3 Towards a better understanding of the threshold for inclusion
    6.3.1 Terminology issues
    6.3.2 Visualization of the threshold for inclusion
    6.3.3 Visualization of threshold criteria in regulatory definitions for labeling
    6.3.4 Comparison with the threshold criteria proposed by the CIOMS III/V
    6.3.5 Still sitting on the fence?
    6.3.6 Comparison with the ICH threshold criteria for potential and identified risks
    6.3.7 Unsuitable definitions from the universe of safety reporting

  6.4 How to determine the level of confidence and relevance
    6.4.1 Determining the level of confidence in a causal association
    6.4.2 Determining the relevance of a potential adverse effect
    6.4.3 Judgment and bias

  6.5 Class reactions

  6.6 Term grouping and more
    6.6.1 Using MedDRA terms
    6.6.2 Diagnosing
    6.6.3 Diagnostic grouping
    6.6.4 Lexical grouping
    6.6.5 Term selection for headings
    6.6.6 Need for early planning

  6.7 Illustrating the likelihood of adverse effects
    6.7.1 Some general principles
    6.7.2 Some standard approaches
    6.7.3 Assessing worldwide harmony
    6.7.4 What to do in CCDS and CCSI?

  6.8 Some frequently asked question
    6.8.1 Can I omit less important adverse reactions?
    6.8.2 Only adverse effects to a product or all adverse effects to using a product?
    6.8.3 Should I have separate adverse reaction tables/lists for different indications/uses?

7    Interactions
  7.1 Definitions and some general principles
    7.1.1 Pharmacokinetic and pharmacodynamic interactions
    7.1.2 Clinically significant (clinically relevant) interactions
    7.1.3 Desirable and undesirable interactions
  7.2 Criteria for including clinically significant undesirable interactions in labeling
    7.2.1 Basic approach
  7.3 Triviality of pharmacodynamic interactions
  7.4 To label interactions in both directions?
  7.5 Talking about classes and listing examples
  7.6 Which label section?
  7.7 Precautionary measures and other recommendations

8    Interference with laboratory tests and other diagnostic tests

9    Deleting adverse effects from labeling

10    When to elevate a risk to the warnings and precautions level
  10.1 The nature of a Warnings & Precautions section
  10.2 Elevating information to Warnings & Precautions in a CCDS
    10.2.1 Level of confidence in a causal association
    10.2.2 Relevance
  10.3 Relationship to the ICH concept “important risk”
  10.4 Boxed warnings and CCDS or CCSI
  10.5 Warnings text

11    Delineating the target population for use and describing other conditions of use
  11.1 Some definitions
    11.1.1 Indication, target condition of use and intent of use
    11.1.2 Non-indication
    11.1.3 Absolute contraindication
    11.1.4 Relative contraindication
    11.1.5 Prohibited/discouraged action
    11.1.6 Target population of use
  11.2 Comparison with clinical trial inclusion and exclusion criteria
  11.3 General principles
    11.3.1 Explicitness and strictness of advice
    11.3.2 Using positive or negative language
  11.4 Elements of the description of the target population and their location in labeling
    11.4.1 Strict descriptors
    11.4.2 Soft descriptors of the target population
    11.4.3 Using strict and soft descriptors as a tool to guide user decisions
  11.5 No silence topics
  11.6 Other conditions of use and burden of use
  11.7 FDA’s “limitations of use”
    11.7.1 Type 1 LoUs: Explaining the reason for the limits of an indication
    11.7.2 Type 2 LoUs: Discouraged uses worth mentioning in the Indications and Usage section
    11.7.3 Type 3 LoUs: Other conditions to be mentioned in the Indications and Usage section
    11.7.4 Additional aspects
    11.7.5 Implications for CCDS and CCSI

12    When and how to contraindicate
  12.1 Definitions
  12.2 General principles
  12.3 US FDA’s guidance on when to contraindicate

  12.4 Hypersensitivity contraindications

13    Providing the reason for advice

14   Glossary
15   References