guidance for industry m4s : the ctd-safety snu college of pharmacy sue hyun kim

Guidance for IndustryM4S: The CTD-Safety

Guidance for IndustryM4S: The CTD-Safety

SNU College of PharmacySue Hyun Kim

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

CTD Organization

Module 1 Administrative Information and Prescribing Information – Region Specific

Module 2 Common Technical Document Summaries7sections: 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

CTD M4S: General Principles

Primary Purposeprovide 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

Module 2: Non-clinical Overview

2.4 NON-CLINICAL OVERVIEW2.4.1 Overview of the Non-clinical Testing Strategy2.4.2 Pharmacology2.4.3 Pharamcokinetics2.4.4 Toxicology2.4.5 Integrated Overview and Conclusions2.4.6 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

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 (100-150 pages) Appendix A


Order of Presentation of Information Within Sectionsin vitro in vivo

ordered by species, by route, & by duration (shortest firs)

Species order

Mouse

Rat

Hamster

Other rodent

Rabbit

Dog

Nonhuman primate

Other nonrodent mammal

Nonmammals

Routes of administration

The intended route for human use

Oral

I.V

I.M

I.P

S.C

Inhalation

Topical

Other


Guidance of Non-clinical Tabulated SummariesHow 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 Introductionintroduce the pharmaceutical & its proposed use

• pharmaceutical’s structure & pharmacologic properties• Proposed Clinical Indication, Dose, & Duration of use


2.6.2 Pharmacology Written Summary

• 2.6.2.1 Brief Summary 2-3pgs, principal findings, description of the content of data (inclusion/exclusion)

• 2.6.2.2 Primary Pharmacodynamicsselectivity, safety, potency, related to other drugs in the class

• 2.6.2.3 Secondary Pharmacodynamicsby organ system

• 2.6.2.4 Safety Pharmacodynamics

• 2.6.2.5 Pharmacodynamic Drug Interactions

• 2.6.2.6 Discussion and Conclusions

• 2.6.2.7 Tables and Figures

2.6.3 Pharmacology Tabulated Summary(Appendix B)


2.6.4 Pharmacokinetics Written Summary

• 2.6.4.1 Brief Summary

• 2.6.4.2 Methods of Analysisdetection 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

• 2.6.4.3 Absorption

· Absorption

(extent and rate of absorption, in vivo and in situ studies)· Kinetic parameters, bioequivalence and/or bioavailability (serum/plasma/blood PK studies)

• 2.6.4.4 Distribution

· Tissue distribution studies· Protein binding and distribution in blood cells· Placental transfer studies

• 2.6.4.5 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

• 2.6.4.6 Excretion

· Routes and extent of excretion· Excretion in milk


• 2.6.4.7 Pharmacokinetic Drug Interactionsin vitro and/or in vivo

• 2.6.4.8 Other Pharmacokinetic Studiesnonclinical models of disease (e.g., renally impaired animals)



• 2.6.5 PHARMACOKINETICS TABULATED SUMMARY (SEE APPENDIX B)


2.6.6 Toxicology Written Summary

* 2.6.6.1 Brief Summary 6pgsToxicology evaluation in relation to the poposed clinical useComment on GLP statusTabulation example


• 2.6.6.2 Single-Dose ToxicityOrder by species and by route

• 2.6.6.3 Repeat-Dose Toxicityorder by species, by route, and by durationmethodology & 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

• 2.6.6.4 Genotoxicity· In vitro nonmammalian cell system· In vitro mammalian cell system· In vivo mammalian system· Other systems

• 2.6.6.5 Carcinogenicity rationale of study & the basis for high-dose selection· Long-term studies (in order by species)· Short- or medium-term studies · Other studies


• 2.6.6.6 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

• 2.6.6.7 Local Toleranceorder by species, by route, and by duration

• 2.6.6.8 Other Toxicity Studies (if available)· Antigenicity· Immunotoxicity· Mechanistic studies (if not reported elsewhere)· Dependence· Studies on metabolites· Studies on impurities· Other studies




• 2.6.7 TOXICOLOGY TABULATED SUMMARY (SEE APPENDIX B)


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

4.2.1.1 Primary Pharmacodynamics4.2.1.2 Secondary Pharmacodynamics4.2.1.3 Safety Pharmacology4.2.1.4 Pharmacodynamic Drug Interactions

4.2.2 Pharmacokinetics

4.2.2.1 Analytical Methods and Validation Reports (if separate reports are available)

4.2.2.2 Absorption4.2.2.3 Distribution4.2.2.4 Metabolism4.2.2.5 Excretion4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)4.2.2.7 Other Pharmacokinetic Studies

4.2.3 Toxicology

4.2.3.1 Single-Dose Toxicity (in order by species, by route)

4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration, including supportive toxi

cokinetics evaluations)

4.2.3.3 Genotoxicity

4.2.3.3.1 In vitro

4.2.3.3.2 In vivo (including supportive toxicokinetics evaluations)

4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations)

4.2.3.4.1 Long-term studies

4.2.3.4.2 Short- or medium-term studies

4.2.3.4.3 Other studies


4.2.3.5 Reproductive and Developmental Toxicity

4.2.3.5.1 Fertility and early embryonic development4.2.3.5.2 Embryofetal development4.2.3.5.3 Prenatal and postnatal development, including maternal funct

ion4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/

or further evaluated

4.2.3.6. Local Tolerance

4.2.3.7. Other Toxicity Studies (if available)

4.2.3.7.1 Antigenicity4.2.3.7.2 Immunotoxicity4.2.3.7.3 Mechanistic studies (if not included elsewhere)4.2.3.7.4 Dependence4.2.3.7.5 Metabolites4.2.3.7.6 Impurities4.2.3.7.7 Other


Thank you!Thank you!

guidance for industry m4s : the ctd-safety snu college of pharmacy sue hyun kim

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