M4

DABT Study Guide ICH Guidelines M4

1. M4 : The Common Technical Document ORGANISATION OF THE COMMON TECHNICAL DOCUMENT FOR THE REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

2. M4 Harmonized the electronic submission of industries for presenting CMC (Chemistry, Manufacturing and Controls) Registration of applications for new pharmaceuticals (including biotechnology-derived products) Enabled the Implementation of good review practices Mandatory in EU (European Medicines Agency or EMEA) and Japan (Ministry of Health, Labour and Welfare) Recommended by FDA in USA

3. CTD Triangle Five modules Module 1: Region specific (Administrative and Prescribing Information) Module 2: Overview and Summaries Modules 3 to 5) Module 3: Quality – also called (M4Q) Module 4: Non Clinical Reports (Safety) – (M4S) Module 5: Clinical Studies (Efficacy) – (M4E)

4. Module 1 – Administrative Information and Prescribing Information Documents specific to region Prescribing information Proposed Label Certificate of Analysis Description of Drug Non-propriety name Dosage Dosage form Route of Administration Regulatory status in other countries Domestic price Promotional materials Specified to the relevant regulatory agencies

5. Module 2 - CTD (Quality) Summaries Module 2 should contain 7 sections in the following order : CTD Table of Contents CTD Introduction Quality Overall Summary Nonclinical Overview Clinical Overview Nonclinical Written and Tabulated Summaries Clinical Summary

6. QOS It is only summary of module 3 or overview of Module 3 for reviewer. QOS should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD. Cross reference should be provided Include justification where guidelines are not followed qualification of impurities via toxicological studies discussed under the CTD-S module

7. Module 3 - M4Q(R1): Quality For all Drugs, New Chemicals and biotech products comes under ICH Guidelines Q 6 A ("NCE – New Chemical Entity") and ICH Guideline Q 6 B ("Biotech") Drug substance Name, Structure, Manufacture, Characterization, Control of Drug Substance, Reference standards, Container, Stability Drug Production Composition, pharmaceutical development , manufacturing process, Characterization, Control of Drug Substance, Reference standards, Container, Stability

8. Module 2 - Nonclinical Written Summary pharmacologic, pharmacokinetic, and toxicologic evaluation Except for biotechnology-derived products, an assessment of the impurities and degradants present in the drug substance and product should be included. proposed impurity limits For biotechnology derived products, comparability of material used in nonclinical studies, clinical studies, and proposed for marketing should be assessed

9. Module 2 - Nonclinical Written Summary-2 Content and Structural Format The Nonclinical Overview should be presented in the following sequence: Overview of the nonclinical testing strategy Pharmacology Pharmacokinetics Toxicology Integrated overview and conclusions List of literature references

10. Summary-3 The evaluation of toxicology studies should be arranged in a logical order animal species used numbers of animals used routes of administration employed dosages used duration of treatment or of the study systemic exposures in the toxicology species at no observed adverse effect levels and at toxic doses, in relation to the exposures in humans at the maximum recommended human dose. Tables or figures summarising this information are recommended. the effect of the drug substance observed in nonclinical studies in relation to that expected or observed in humans

11. Non- clinical written and tabulated summaries in vitro and then in vivo ordered by species, by route, and then by duration studies should precede in vivo studies Species should be ordered as follows: • Mouse • Rat • Hamster • Other rodent • Rabbit • Dog • Non-human primate • Other non-rodent mammal • Non-mammals

12. Toxicology Summary Routes of administration should be ordered as follows : • The intended route for human use • Oral • Intravenous • Intramuscular • Intraperitoneal • Subcutaneous • Inhalation • Topical • Other

13. The following order is recommended: • Introduction • Written Summary of Pharmacology • Tabulated Summary of Pharmacology • Written Summary of Pharmacokinetics • Tabulated Summary of Pharmacokinetcs • Written Summary of Toxicology • Tabulated Summary of Toxicology

14. Toxicology Written Summary The sequence of the Toxicology Written Summary should be as follows: Brief Summary Single-Dose Toxicity Repeat-Dose Toxicity Genotoxicity Carcinogenicity Reproductive and Developmental Toxicity Studies in Juvenile Animals Local Tolerance Other Toxicity Studies Discussion and Conclusions Tables and Figures (either here or included in text)

15. Module 4: M4S(R2): Safety Nonclinical Study Reports critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluation

16. Module 5 - M4E(R2): Efficacy Clinical Study Reports