1. Guidance for Industry M4S: The CTD-Safety
SNU College of Pharmacy
Sue Hyun Kim

2. Introduction
Recommendations for applicants preparing the ‘Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD)’– Safety Section
Provide-Organization of the information
appropriate format for the data

3. CTD Organization
Module 1 Administrative Information and Prescribing Information – Region Specific
Module 2 Common Technical Document Summaries
7sections: CTD Table of Contents/CTD Introduction/
Quality Overall Summary/Non-clinical Overview/
Clinical Overview/ Non-clinical Written and Tabulated Summaries/Clinical Summary
 M4Q, M4S, M4E
Module 3 Quality-M4Q
Module 4 Non-clinical Study Repots-M4S
Module 5 Clinical Study Reports-M4E

4. CTD M4S: General Principles
Primary Purpose
provide a comprehensive, factual synopsis of the non-clinical data
Interpretation of the data
The clinical relevance of findings
Cross-linking with the quality of the pharmaceutical
Implication of the non-clinical findings for the safe use of the pharmaceutical

5. Module 2: Non-clinical Overview
2.4.1 Overview of the Non-clinical Testing Strategy
2.4.2 Pharmacology
2.4.3 Pharamcokinetics
2.4.4 Toxicology
2.4.5 Integrated Overview and Conclusions
2.4.6 List of Literature Citations
Conclusion: supporting the safety of the product for the intended clinical use:
implications of the non-clinical findings to the safe human use of the pharmaceutical

6. Module 2: Non-clinical Written & Tabulated Summaries
Organization
Introduction
Pharmacology written summary
Pharmacology tabulated summary
Pharmacokinetics written summary
Pharmacokinetics tabulated summary
Toxicology written summary
Toxicology tabulated summary
Guidance on non-clinical written Summaries
: indicates an appropriate format for the non-clinical data acquired Focus on the needs of the regulatory authority assessor: facilitate understanding & evaluation of the results ( pages) Appendix A

7. Module 2: Non-clinical Written & Tabulated Summaries
Order of Presentation of Information Within Sections
in vitro  in vivo
ordered by species, by route, & by duration (shortest firs)
Routes of administration
The intended route for human use
Oral
I.V
I.M
I.P
S.C
Inhalation
Topical
Other
Species order
Mouse
Rat
Hamster
Other rodent
Rabbit
Dog
Nonhuman primate
Other nonrodent mammal
Nonmammals

8. Module 2: Non-clinical Written & Tabulated Summaries
Guidance of Non-clinical Tabulated Summaries
How to tabulate study results
 Appendix B (templates), C (examples)
Sufficient level of detail & concise overview of related inform
2.6 Content of Non-clinical Written and Tabulated Summaries
2.6.1 Introduction
introduce the pharmaceutical & its proposed use
pharmaceutical’s structure & pharmacologic properties
Proposed Clinical Indication, Dose, & Duration of use

9. Module 2: Non-clinical Written & Tabulated Summaries
2.6.2 Pharmacology Written Summary
Brief Summary 2-3pgs,
principal findings, description of the content of data (inclusion/exclusion)
Primary Pharmacodynamics
selectivity, safety, potency, related to other drugs in the class
Secondary Pharmacodynamics
by organ system
Safety Pharmacodynamics
Pharmacodynamic Drug Interactions
Discussion and Conclusions
Tables and Figures
2.6.3 Pharmacology Tabulated Summary(Appendix B)

10. Module 2: Non-clinical Written & Tabulated Summaries
2.6.4 Pharmacokinetics Written Summary
Brief Summary
Methods of Analysis
detection and quantification limits of an analytical procedure
validation data for the analytical method & stability of biological samples
The potential impact of different methods of analysis on the interpretation
Absorption
· Absorption
(extent and rate of absorption, in vivo and in situ studies)
· Kinetic parameters, bioequivalence and/or bioavailability
(serum/plasma/blood PK studies)

11. Module 2: Non-clinical Written & Tabulated Summaries
Distribution
· Tissue distribution studies
· Protein binding and distribution in blood cells
· Placental transfer studies
Metabolism (interspecies comparison)
· Chemical structures and quantities of metabolites in biological samples
· Possible metabolic pathways
· Presystemic metabolism (GI/hepatic first-pass effects)
· In vitro metabolism including P450 studies
· Enzyme induction and inhibition
Excretion
· Routes and extent of excretion
· Excretion in milk

12. Module 2: Non-clinical Written & Tabulated Summaries
Pharmacokinetic Drug Interactions
in vitro and/or in vivo
Other Pharmacokinetic Studies
nonclinical models of disease (e.g., renally impaired animals)
Discussion and Conclusions
Tables and Figures
2.6.5 PHARMACOKINETICS TABULATED SUMMARY (SEE APPENDIX B)

13. Module 2: Non-clinical Written & Tabulated Summaries
2.6.6 Toxicology Written Summary
* Brief Summary 6pgs
Toxicology evaluation in relation to the poposed clinical use
Comment on GLP status
Tabulation example

14. Module 2: Non-clinical Written & Tabulated Summaries
Single-Dose Toxicity
Order by species and by route
Repeat-Dose Toxicity
order by species, by route, and by duration
methodology & highlighting important findings
(e.g., nature and severity of target organ toxicity, dose (exposure)-response relationships, no observed adverse effect levels).
Nonpivotal studies in less detail
Genotoxicity
· In vitro nonmammalian cell system
· In vitro mammalian cell system
· In vivo mammalian system
· Other systems
Carcinogenicity
rationale of study & the basis for high-dose selection
· Long-term studies (in order by species)
· Short- or medium-term studies
· Other studies

15. Module 2: Non-clinical Written & Tabulated Summaries
Reproductive and Developmental Toxicity
· Fertility and early embryonic development
· Embryofetal development
· Prenatal and postnatal development, including maternal function
· Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
Local Tolerance
order by species, by route, and by duration
Other Toxicity Studies (if available)
· Antigenicity
· Immunotoxicity
· Mechanistic studies (if not reported elsewhere)
· Dependence
· Studies on metabolites
· Studies on impurities
· Other studies

16. Module 2: Non-clinical Written & Tabulated Summaries
Discussion and Conclusions
Tables and Figures
2.6.7 TOXICOLOGY TABULATED SUMMARY (SEE APPENDIX B)

17. Module 4: Non-Clinical Study Reports
Appropriate location for the individual animal data
4.1 Table of Contents: lists all Non-clinical Study Reports & their locations in the CTD
4.2.1 Pharmacology
Primary Pharmacodynamics
Secondary Pharmacodynamics
Safety Pharmacology
Pharmacodynamic Drug Interactions
4.2.2 Pharmacokinetics
Analytical Methods and Validation Reports (if separate reports are available)
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic Drug Interactions (nonclinical)
Other Pharmacokinetic Studies

18. Module 4: Non-Clinical Study Reports
4.2.3 Toxicology
Single-Dose Toxicity (in order by species, by route)
Repeat-Dose Toxicity
(in order by species, by route, by duration, including supportive toxicokinetics evaluations)
Genotoxicity
In vitro
In vivo (including supportive toxicokinetics evaluations)
Carcinogenicity (including supportive toxicokinetics evaluations)
Long-term studies
Short- or medium-term studies
Other studies

19. Module 4: Non-Clinical Study Reports
Reproductive and Developmental Toxicity
Fertility and early embryonic development
Embryofetal development
Prenatal and postnatal development, including maternal function
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
Local Tolerance
Other Toxicity Studies (if available)
Antigenicity
Immunotoxicity
Mechanistic studies (if not included elsewhere)
Dependence
Metabolites
Impurities
Other

20. Thank you!
Thank you!