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SOUTH AFRICAN COMMON TECHNICAL DOCUMENT

MEDICINES CONTROL COUNCIL

APPLICATION FOR REGISTRATION OF A MEDICINE

 South African Module 1  CTD-Modules 2 - 5

MCC Edition August 2012

South African Common Technical Document
ZA Module 1 – Administrative Information ....................................................................... 4 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11 1.12 1.13 Letter of application ................................................................................................. 4 Comprehensive table of contents............................................................................. 4 Application ............................................................................................................... 4 South African labelling and packaging ..................................................................... 4 Information about the experts .................................................................................. 4 Specific requirements for different types of applications........................................... 4 Environmental risk assessment ............................................................................... 5 Good manufacturing practice ................................................................................... 5 Details of compliance with screening outcomes ....................................................... 5 Individual patient data - statement of availability ...................................................... 5 Foreign regulatory status ......................................................................................... 5 Bioequivalence trial information ............................................................................... 6 Paediatric development programme ........................................................................ 6 Risk management plan ............................................................................................ 6

Module 2 - CTD Summaries ............................................................................................... 7 2.1 2.2 2.3 2.4 2.5 2.6 2.7 CTD Table of Contents (modules 2 to 5) .................................................................. 7 Introduction .............................................................................................................. 7 Quality Overall Summary - Introduction ................................................................... 7 Non-clinical Overview .............................................................................................. 7 Clinical Overview ..................................................................................................... 7 Non-clinical Written and Tabulated Summaries ....................................................... 8 Clinical Summary ..................................................................................................... 9

Module 3 - Quality..............................................................................................................11 3.1 3.2 3.2.S 3.2.P 3.2.A 3.2.R 3.3 Table of contents of module 3 .................................................................................11 Body of data ...........................................................................................................11 Active Pharmaceutical Ingredient (name, manufacturer) .........................................11 Pharmaceutical Product (name, dosage form) ........................................................12 Appendices .............................................................................................................13 Regional Information...............................................................................................13 Literature references...............................................................................................14

Module 4 - Non-clinical study reports ..............................................................................15 4.1 Table of contents of Module 4 .................................................................................15

Document1

August 2012

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......................Clinical Study Reports ........................17 5............3 Study reports ...................................................................................................................................17 Clinical study reports .............................................................................................4...................23 UPDATE HISTORY ...................................................................................16 Module 5 ..........................................................3 5.............................................................................15 Literature references....................................................................................................................18 APPENDIX B: The Non-clinical Tabulated Summaries – Templates ....1 5....25 Document1 August 2012 Page 3 of 25 ..........17 APPENDIX A: Examples of Tables and Figures for Written Summaries.....................................17 Tabular listing of all clinical studies ...2 5..........2 4.............................17 Literature references...................4 Table of contents of Module 5 ................................................

2.2.2.5.2.1 1.2.2.4.2.5.2.3.2 1.4.1.2 1.3 1.5.5.3.5.3 1.2.8 Application form Annexes Proof of payment Letter of authorisation for communication on behalf of the applicant/PHCR Dossier product batch information Electronic copy declaration Curriculum vitae of the person responsible for pharmacovigilance API change control EMA certificate for a Vaccine Antigen Master File (VAMF) EMA certificate for a Plasma Master File (PMF) 1.5.3.1.0 Letter of application 1.2 Application 1.6 1.3 1.5 Specific requirements for different types of applications 1.4 Information about the experts 1.2 1.1 1.2.1 1.2 1.2 1.3.1 Comprehensive table of contents 1.3 South African labelling and packaging 1.2.2.2.2.2.2.4.5 1.4 South African Package Insert Package insert Standard References Patient Information Leaflet Labels Braille 1.3 Quality Non-clinical Clinical 1.ZA Module 1 – Administrative Information 1.3 1.3.4 1.3.5.4 1.2 1.7 1.1 1.2.2.2.1 1.2.5.5 1 Literature based submissions Amendments/Variations 1 Tabulated schedule of amendments Medicines Register Details Affidavit by Responsible Pharmacist Proprietary name applications and changes Genetically modified organisms Package Insert and Patient Information Leaflet amendments/updates Amendments guideline Document1 August 2012 Page 4 of 25 .1 1.2.1 1.2 1.

7.2 1.3 1.statement of availability 1.7. 1.6.7.4.10 Foreign regulatory status 1.7.1 1.8 Details of compliance with screening outcomes 1.4.7.10.3 Confirmation of submission of sample Batch manufacturing record of the sample CoA of the sample 1.7 1.7.10.1 1.7 Good manufacturing practice 1.11 Certified copy of a permit to manufacture specified Schedule 5.6.7.7.4 Data set similarities Document1 August 2012 Page 5 of 25 .10.7.10.7. Schedules 6.7.7.7.4.3 1.7.2 1.10.2 Non-GMO (genetically modified organisms) GMO 1.1 1.6 Environmental risk assessment 1.6 1.12 Inspection flow diagram 1.9 Individual patient data .7.4.7.2 Registration certificate or marketing authorisation 1. 7 and 8 substances.7.3 Foreign prescribing and patient information 1.1.1 1.10.8 1.4 1.10.7.4 1.5 1.1 List of countries in which an application for the same product as being applied for has been submitted 1.13 Organogram 1.9 Date of last inspection of each site Inspection reports or equivalent document Latest GMP certificate or a copy of the appropriate licence Release API IPIs Finished Product Release Control (FPRC) tests Finished Product Release Responsibility (FPRR) criteria Confirmation of contract CPP (WHO Certification scheme) SAPC registration Registration with Registrar of Companies Other documents relating to the Applicant/PHCR 1.2 1.7.10 Sample and Documents 1.7.

9 Date of final report 1.1.2 Protocol and study numbers 1.3 Investigational products (test and reference) details 1.11.7 Sponsor and responsible sponsor representative: details name and address. duration.11.12 Paediatric development programme 1.11.4 Confirmation that the test product formulation and manufacturing process is that being applied for 1.11. contact 1.11.13 Risk management plan Document1 August 2012 Page 6 of 25 .11 Bioequivalence trial information 1.11.11. dose and subject population of each study) 1.6 Name and address of the Research Organisation(s) / Contract Research Organisation(s) where the bioequivalence studies were conducted 1.11.1 Study Title(s) (or brief description giving design.5 Proof of procurement of the biostudy reference product 1.8 Duration of Clinical phase: dates of dosing and last clinical procedure 1.11.

1 2.3.3.1 CTD Table of Contents (modules 2 to 5) 2.S. manufacturer) Characterisation (name.Introduction 2.A.4 Non-clinical Overview 2.P. dosage form) Quality Overall Summary .2 2.5 2.P.S.S. manufacturer) Excipients 2.5 Clinical Overview 2.3.P.S.7 2.P. manufacturer) Adventitious agents safety evaluation (name.2 2.4 2. manufacturer) Reference Standards or Materials (name.Module 2 .3.1 2.Appendices Facilities and equipment (name.2 2.3.3 2.2 2. dosage form.P 2.A.S.3.3.3 2. dosage form) Control of Pharmaceutical Product (name.3.4 2.3.6 2.3.3.3 Quality Overall Summary .1 2.3.S.Finished Pharmaceutical Product (name.P.3.P. manufacturer) Manufacture (name.3 2.3.2 Introduction 2. dosage form) Reference Standards or Materials (name.3.CTD Summaries 2. manufacturer) Stability (name.3.P.3 Quality Overall Summary . manufacturer) Quality Overall Summary . dosage form) Control of Excipients (name.S 2.3.A 2. dosage form) Stability (name.5. dosage form) Pharmaceutical Development (name.5.A.5.S.6 2.7 2. dosage form) Container Closure System (name.3.P. dosage form) Manufacture (name.5. dosage form) Description and Composition of the Pharmaceutical Product (name. manufacturer) Control of Active Pharmaceutical Ingredient (name.5 2.4 Product Development Rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology Overview of Efficacy Document1 August 2012 Page 7 of 25 .Active Pharmaceutical Ingredient (name.3.1 2.8 2.3. manufacturer) Container Closure System (name.3. manufacturer) General Information (name.

2 2.4.2.4.1 2.4.2.4.4.2.2 2.6.10 2.4 2.8 2.4.6.4 2.6.1 2.3 2.5.6.3 2.6.6.6.5 2.4.9 2.6.1 2.6.6.6 2.6.2.6.6.1 2. Document1 August 2012 Page 8 of 25 .6.2 2.5 2 Introduction Pharmacology Written Summary 2 Brief Summary Primary Pharmacodynamics Secondary Pharmacodynamics Safety Pharmacology Pharmacodynamic Medicine Interactions Discussion and Conclusions Tables and Figures (See Appendix A) Pharmacology Tabulated Summary (See Appendix B) Pharmacokinetics Written Summary 2 Brief Summary Methods of Analysis Absorption Distribution Metabolism (interspecies comparison) Excretion Pharmacokinetic Medicine Interactions Other Pharmacokinetic Studies Discussion and Conclusions Tables and Figures (See Appendix A) Pharmacokinetics Tabulated Summary (See Appendix B) Toxicology Written Summary 2 Brief Summary Single-Dose Toxicity Repeat-Dose Toxicity (including supportive toxicokinetics evaluations) Genotoxicity Carcinogenicity (including supportive toxicokinetics evaluations) Typically in the eCTD this logical document should consist of a single file.7 Overview of Safety Benefits and Risks Conclusions Literature References 2.6.6 2.6.6.5 2.6.6.6 2.6.6.6.6.3 2.7 2.2.6.5.6.6.3 2.5 2.6.6.7 2.5 2.6.6.5.6 2.6. The CTD defines these further heading levels and navigation should be provided within the document to these subheadings.4.4 2.2.2 2.4.4.6.2.4 2.2.6 Non-clinical Written and Tabulated Summaries 2.6.

7.9 2.2 2.7.2.7.7.1 2.2 2.7.7.3. The CTD defines these further heading levels and navigation should be provided within the document to these subheadings.1.7.4 2.6.4 2.1 2.6.4.7.7.4 2.1.2 2.2 2.6.1 2.2.3 2.2 2.2.3.1.7.1.7.6.3.4 2.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods 3 Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Appendix Summary of Clinical Pharmacology Studies 3 Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Special Studies Appendix Summary of Clinical Efficacy – Indication 3 Background and Overview of Clinical Efficacy Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Study Populations Comparison of Efficacy Results of All Studies Comparison of Results in Sub-populations Analysis of Clinical Information Relevant to Dosing Recommendations Persistence of Efficacy and/or Tolerance Effects Appendix Summary of Clinical Safety 3 Exposure to the Medicine Overall Safety Evaluation Plan and Narratives of Safety Studies 3 Typically in the eCTD this logical document should consist of a single file. Document1 August 2012 Page 9 of 25 .2.2.7.1.7.3 2.3 2.3.3.7.7.6 2.6.6.4.5 2.7.3 2.2.3.7.3.1 2.6.1 2 7.7 Reproductive and Developmental Toxicity (including range-finding studies and supportive toxicokinetics evaluations) Local Tolerance Other Toxicity Studies (if available) Discussion and Conclusions Tables and Figures (See Appendix A) Toxicology Tabulated Summary (See Appendix B) 2.7.1 2.7 Clinical Summary 2.7.6 2.3.3.6.3.6.7.3.7.10 2.5 2.6.3 2.8 2.7.6.7.7 2.3.

7.3 2.5 2.7 2.4.2.7.4.7.4.7.4.5.5.1.4.7 2.2 7.4 2.5.7.2 2.2.7.4.1 2.3 2.5.2.4.1.1.4.7.7.3 2.7.1.3 2.7.7.7.2.1.4.4.2 2.4.7.5 2.2.4. Physical Findings and Other Observations related to Safety Safety in Special Groups and Situations Intrinsic Factors Extrinsic Factors Medicine Interactions Use in Pregnancy and Lactation Overdose Medicine Abuse Withdrawal and Rebound Effects on Ability to Drive of Operate Machinery or Impairment of Mental Ability Post-marketing Data Appendix Literature References Synopses of Individual Studies Document1 August 2012 Page 10 of 25 .6 Overall Extent of Exposure Demographic and Other Characteristics of Study Population Adverse Events Analysis of Adverse Events Common Adverse Events Deaths Other Serious Adverse Events Other Significant Adverse Events Analysis of Adverse Events by Organ System or Syndrome Narratives Clinical Laboratory Evaluations Vital Signs.4.4.7.4.4.7.7.1 2.1 2.4.6 2.5.4.4 2.2 2.4 2.7.6 2.2 2 7.2.7.5.5.4.2 2.4.4.1.4.7.2.1.5 2.7.4.7.8 2.7.5 2.7.5.

4.S.2. manufacturer) Impurities (name. manufacturer) Stability Data (name.S. manufacturer) Specifications (name.3. manufacturer) Process Validation and/or Evaluation (name.2 Body of data 3.1 3. manufacturer) Structure (name.5 3.4.4 3.S. manufacturer) Controls of Critical Steps and Intermediates (name. manufacturer) 3.1 Table of contents of module 3 3.1 3.7. manufacturer) Manufacturing Process Development (name.S.1 3.2.2.7 3.2. manufacturer) General Properties (name.2.2.7. manufacturer) Analytical Procedures (name. manufacturer) Control of active pharmaceutical ingredient (name.2.Module 3 .2.S.S. manufacturer) Validation of Analytical Procedures (name.3.S.2.2.2. manufacturer) Manufacturer(s) (name.2. manufacturer) Justification of Specification (name.2 3. manufacturer) Reference Standards or Materials (name.2.S. manufacturer) Manufacture (name. Control of Materials (name.1 3.2.S.S.Quality 3. manufacturer) Batch Analyses (name.3 General information (name.5 3.2.2 3.2.S.3 3. manufacturer) Container Closure System (name.S Active Pharmaceutical Ingredient (name.S.4.S.2 3.1.S.2. manufacturer) Stability (name. manufacturer) Post approval stability protocol and stability commitment (name. manufacturer) Document1 August 2012 Page 11 of 25 .2.S.2.2 3.2.S.7.2.4 3. manufacturer) Characterisation (name.S.S.1. manufacturer) Elucidation of Structure and other Characteristics (name.3 3. manufacturer) Stability summary and conclusions (name.4 3.2.1.4.2.2.2.2.2.S.S.S.S.S.4.5 3.3 3.2.3 3.2.6 3.S.S.2.2 3.S.1 3.1 3.2 3. manufacturer) Nomenclature (name.2.2.2. manufacturer) Description of manufacturer) Manufacturing Process and Process Controls (name.6 3.

2.2 3.2.5 3. dosage form) Control of Inactive Pharmaceutical Ingredients (name.P.P.4 3. dosage form) Manufacture (name.P. dosage form) Microbiological attributes (name. dosage form) Document1 August 2012 Page 12 of 25 .2 3.2.3 3.2.P.4.2.2.1 3.2.3.3 3.2.2.P.1 3. dosage form) Components of the Pharmaceutical Product (name.2.P. dosage form) Manufacturing process development (name.2. dosage form) Batch formula (name.3 3.4. dosage form) Description of manufacturing process and process controls (name. dosage form) Controls of critical steps and intermediates (name. dosage form) Pharmaceutical Development (name.2.5.P.5.2.P.2.2 3.P.2.2.P. dosage form) Overages (name.2.1.2.2.4.3.2.2.2.2.3.2 3.2 3.P.2.1 3.4. dosage form) Container closure system (name.2.5.6 3.P.P.2.2.P. dosage form) Novel excipients (name.P.4 3.2.2.4 3.3 3. dosage form) Control of pharmaceutical product (name.P. dosage form) Active Pharmaceutical Ingredient(s) (name. dosage form) Analytical procedures (name.2 3. dosage form) Excipients (name. dosage form) Analytical procedures (name.2.P.2. dosage form) Compatibility (name.5 3.P.2. dosage form) Justification of specifications (name. dosage form) Batch analyses (name. dosage form) 3.2.3.2. dosage form) Validation of analytical procedures (name.4.P.4.5.P.5 3.P.2.1 3.P.1 3.3 3. dosage form) Process validation and/or evaluation (name. dosage form) Characterisation of impurities (name.2.2. dosage form) Manufacturer(s) (name. dosage form) Justification of specifications (name.P.5.5 3.5 3.3.P.2.2. dosage form) Specification(s) (name.2.2.1 3.2.5.3.3 3.1.P.4 3. dosage form) Physicochemical and biological properties (name.P.P.2.P.2.1 3. dosage form) Final pharmaceutical product (name. dosage form) Formulation development (name.2.P.2.6 3.4 3. dosage form) Specifications (name.P. dosage form) Excipients of human or animal origin (name.2.P.P Pharmaceutical Product (name.2.6 Description and Composition of the pharmaceutical product (name.P.2 3.P. dosage form) Validation of analytical procedures (name.

2.1.2.R.2. dosage form.3.1. dosage form) Stability data (name. manufacturer) Excipients 3.2.R.2 3.1.1 3.R.1.8 3.A.2.2.1.2.R.R.R.R.2.1.9 3.1.1.8 3.8. 3.7 3.2.2.R.2.10 3.R.2.P.8.7 3.R.3 Document1 August 2012 Page 13 of 25 .R.1 3.2.P.1.R.2.12 3.R.1.3 Reference standards or materials (name.2. dosage form) Stability summary and conclusion (name.1.2.2.4 3.3 3.1.1.2.1.1.14 3.A Appendices 3.1.2.15 3. if applicable Motivation for the use of the particular reference product Motivation for the use of a pharmaceutical alternative or lower strength Tabular summary of the information pertaining to the study products The formulation of each of the dosage strengths of the test product(s) in tabular form in the case of a biowaiver of proportionally similar dosage strengths A discussion and conclusion of the outcomes of each of the studies and other relevant information to support and justify acceptance of product efficacy An overall conclusion References Reference product/s (local and foreign) Certificates of Analysis 3.1.2.16 3.2.1.2.1.6 3.1.2.P.2.1.A. dosage form) Container closure system (name.R.6 3.1.2.R.2 3.P.13 Pharmaceutical and Biological availability Overview Country where developed.R Regional Information 3.2.1 3. dosage form) Post-approval stability protocol and stability commitment (name.R.1.2.P.R.1.1.2. company developed by.2.2.8.1.2.1.2.R.R.R.1. test product synonyms The type of study(ies) submitted in support of efficacy The purpose of the study or studies The status of the reference product A description of the type of study(ies) Confirmation that the data submitted have been obtained with the formulation and manufacturing process being applied for Confirmation that the test product (all strengths) was manufactured by the same manufacturer and site applied for Confirmation that the test product was manufactured with manufactured by the same manufacturer(s) as being applied for API(s) A statement whether in vivo-in vitro correlation from the data was obtained by the method/s used.1 3.1.1.A.P. manufacturer) Adventitious agents safety evaluation (name.1.1.5 3.3 Facilities and equipment (name.1. dosage form) Stability (name. dosage form) 3.2 3.1 3.1.1.11 3.

3.R.2.4.8 Pharmaceutical availability studies Dissolution studies.3.3 3.R.1.4. data and reports Other Parent API manufacturer with various sites Certificate(s) of suitability with respect to the Ph.R.4.2.2.R.4 3.2.4.2.2 3.R.2.2.2.4.2.1.3 3.R.1.2.1 3.7 3.1 3.2.R.R.R.2.R.5 3.R.Eur.2.4. (CEPs) Multiple API manufacturers Comparative API manufacturers study report Comparative results Confirmation of compliance with guidelines Certificates of analysis Medical device Materials of animal and/or human origin Batch records of samples Other 3.6 3.3 Literature references Document1 August 2012 Page 14 of 25 .R.R.2.4 3.4 3.2.R.2 3.

2.1 4. including range-finding studies that cannot be appropriately included under repeat-dose toxicity or pharmacokinetics) Short or medium term studies (including range finding studies that cannot be appropriately included under repeat-dose) Other studies Reproductive and developmental toxicity (including range-finding studies and supportive toxicokinetics evaluations) (If modified study designs are used.2.2.Module 4 .2.2.5.Non-clinical study reports 4.5.5.2.7 4.3 4.2 4.2.2.3.2 4.3.2.1.1.2.4.2.2.2 4.4.2.2 Study reports 4.1.2.2.3.2.4 Document1 August 2012 Page 15 of 25 . including supportive toxicokinetics evaluations) Genotoxicity In vitro In vivo (including supportive toxicokinetics evaluations) Carcinogenicity (including supportive toxicokinetics evaluations) Long-term studies (in order by species.1 4. by route) Repeat dose toxicity (in order by species.3.1 4.3 4.2.2.4 4.3.3.3.3 4.4 4.3.2 4.3 4. by route.2.3. the following subheadings should be modified accordingly) Fertility and early embryonic development Embryo-foetal development Prenatal and postnatal development.2.2.2.3.6 4.3.5 4.2.4. by duration.3.4 4.2.2 4.3.5 4.2.2.2 4.1 4.2.3.5.1 4.3.3 4.2.2.2 4.3 4.2.1 4.1.2.2. including maternal function Studies in which the offspring (juvenile animals) are dosed and/or further evaluated 4.3.1 Pharmacology Primary pharmacodynamics Secondary pharmacodynamics Safety pharmacology Pharmacodynamic medicine interactions Pharmacokinetics Analytical methods and validation reports Absorption Distribution Metabolism Excretion Pharmacokinetic medicine interactions (non clinical) Other pharmacokinetic studies Toxicology Single-dose toxicity (in order by species.1 Table of contents of Module 4 4.2.2.2.

3.2.2.3.4 4.7 Local tolerance Other toxicity studies (if available) Antigenicity Immunotoxicity Mechanistic studies (if not included elsewhere) Dependence Metabolites Impurities Other 4.7.2.3.7.3.2.3.7.7.2.2.4.3 Literature references Document1 August 2012 Page 16 of 25 .3.6 4.2.2.2 4.3.6 4.7 4.1 4.2.3.7.3 4.5 4.3.7.7.

3.3.3.1 5.1 5.5 5.1 5.1 Table of contents of Module 5 5.Module 5 .2.5.3.3.5 5.3 Clinical study reports 5.2 5.3.3.2 5.3.1.3 5.2.3.3.3.3.3.3 5.Clinical Study Reports 5.5.3.3.4 5.4.6 5.1.3.3 5.5.1.3.4 5.3.3.3.2 5.2 5.1 5.2 Tabular listing of all clinical studies 5.1.7 Reports of biopharmaceutic studies Bioavailability (BA) Study Reports Comparative BA and Bioequivalence (BE) Study Reports In vitro-in vivo correlation study reports Reports of bioanalytical and analytical methods for human studies Reports of studies pertinent to pharmacokinetics using human biomaterials Plasma Protein Binding Study Reports Reports of Hepatic Metabolism and Medicine Interaction Studies Reports of Studies Using Other Human Biomaterials Reports of human pharmacokinetic (PK) Studies Healthy Subject PK and Initial Tolerability Study Reports Patient PK and Initial Tolerability Study Reports Intrinsic Factor PK Study Reports Extrinsic Factor PK Study Reports Population PK Study Reports Reports of human pharmacodynamic (PD) studies Healthy Subject PD and PK/PD Study Reports Patient PD and PK/PD Study Reports Reports of efficacy and safety studies Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication Study Reports of Uncontrolled Clinical Studies Reports of Analyses of Data from More than One Study Other Study Reports Reports of Post-marketing experience Case report forms and individual patient listings 5.3.3.3.4.4 5.3.3.4 5.3 5.3.3 5.3.4 Literature references Document1 August 2012 Page 17 of 25 .3.3.2 5.1 5.2 5.1 5.2.3.5.

Document1 August 2012 Page 18 of 25 . Study references should be included in the table or text.APPENDIX A: Examples of Tables and Figures for Written Summaries The tables and figures in Appendix A are presented merely as examples. Tables should include statistics. if appropriate. Applicants should provide tables and figures using a format appropriate to the product.

v..e. 25 mg/kg p.v. Hypotensive effect of saline i. aSHR= spontaneous hypertensive rate (n=5 per group) Document1 August 2012 Page 19 of 25 .01.o.. 3 mg/kg i.05. for 7 (l) or 14 (n) days. Values represent mean ± s. Saline pretreated statistical significances: p<0. for 7 (m) or 14 (p) days or X. all other points after challenge p<0.o. infusion to SHR pretreated twice daily with saline. infusion over 5 min (s) compared to X. 1 mL/kg p.m.Blood pressure following chronic dosing with X to SHRa[ref].

Document1 August 2012 Page 20 of 25 .

Numbers in parentheses represent ratios of exposure in animals to those in patients. and 1 year dog study). Data for man are extrapolated from dose normalised data obtained in male and female patients following t.calculated from the total daily dose assuming a bodyweight of 50 kg for man.AUC0-6 in the mouse.i.Data presented are for male and female animals and are after daily repeated oral administration (at the end of the 60-day mouse study.d. Document1 August 2012 Page 21 of 25 . AUC0-t in the rat and in the dog and dose normalised AUC0-τ x 24 in man. # . regimen. $ . 14 day rat study. * .

Document1 August 2012 Page 22 of 25 .

6.6.7 2.3.6.6.7 2.3. Module 2.7.6.4 Pharmacology Pharmacology: Overview Primary Pharmacodynamics* Secondary Pharmacodynamics* Safety Pharmacology Pharmacodynamic Medicine Interactions* Pharmacokinetics Pharmacokinetics: Overview Analytical Methods and Validation Reports* Pharmacokinetics: Absorption After a Single Dose Pharmacokinetics: Absorption after Repeated Doses Pharmacokinetics: Organ Distribution Pharmacokinetics: Plasma Protein Binding Pharmacokinetics: Study in Pregnant or Nursing Animals Pharmacokinetics: Other Distribution Study Pharmacokinetics: Metabolism In Vivo Pharmacokinetics: Metabolism In Vitro Pharmacokinetics: Possible Metabolic Pathways Pharmacokinetics: Induction/Inhibition of Medicine-Metabolizing Enzymes Pharmacokinetics: Excretion Pharmacokinetics: Excretion into Bile Pharmacokinetics: Medicine-Medicine Interactions Pharmacokinetics: Other Toxicology Toxicology: Overview Toxicokinetics: Overview of Toxicokinetics Studies Toxicokinetics: Overview of Toxicokinetics Data Toxicology: Active Pharmaceutical Ingredient Document1 August 2012 Page 23 of 25 .8 2.3 2.5 2.6.6. edition 2003 for examples of templates 2.6.6.12 2.3 2.6.16 2.14 2.5.3.5.6.5.6.4 2.6.5.6.5.9 2.5.6.6.6.7.5.6.1 2.6. NTA.6.3 2.2 2.6.5.5 2.5.5.6.5 2.5.1 2.6 2.5.15 2.6. Vol.3 2.6.13 2.2 2.7.7.APPENDIX B: The Non-clinical Tabulated Summaries – Templates Refer to the European Commission.5. 2B-CTD.5.10 2.6.6.3.4 2.1 2.6.2 2.6.11 2.5.3.5.

7.12 2.6.6.6.16 2.6.15. Document1 August 2012 Page 24 of 25 .7 2.7. it should be tabulated using the template appropriate for the type of study and located in Section 2.6.6.7.6.7.7.7.6.6.7.5 2.7.7.13 2.6.11 2.and Postnatal Development.7.6 2.6.6.10 2.6.2.7. Nonclinical Written Summary.17 Single-Dose Toxicity Repeat-Dose Toxicity: Non-pivotal Studies Repeat-Dose Toxicity: Pivotal Studies Genotoxicity: In Vitro Genotoxicity: In Vivo Carcinogenicity Reproductive and Developmental Toxicity: Non-pivotal Studies Reproductive and Developmental Toxicity: Fertility and Early Embryonic Development to Implantation (Pivotal) Reproductive and Developmental Toxicity: Effects on Embryofoetal Development (Pivotal) Reproductive and Developmental Toxicity: Effects on Pre.9 2. a : When a juvenile animal study has been conducted.7.15 2.14 2. Including Maternal Function (Pivotal) Studies in Juvenile Animals a Local Tolerance Other Toxicity Studies It is preferable to include text tables and figures with the * : Tabulated Summary is optional.7.6.7.8 2.

7.2.2.4.2.1.1 – 4 Renumbered 3.2.R. 3.R. 1.3.3.7/8/9 1. 1.7.2.2.1.2.1.4 – added new 1.R.4.1.2.2.2.5.R. 1.7.1.R.13 Added new 1.6 to 3. & 1.4.2.2 – added 1.1.R.2. 1. 3.10.7.5.R.1.2.2.3.5 Removed 3.1. 1.10.7.4.2 Removed 1.2.11 3.7.9. 3.5 for for immediate immediate v4 August 2011 v5 August 2012 pilot submissions and Version & publication v2 Nov 2009 v2 June 2010 v3 March 2011 Amended module headings Document1 August 2012 Page 25 of 25 . 1.2. renumbered.7.11.5.3. 1.10 – removed 1.5.1.7. 3.2.R.6.3.R.1. 1.2.7.2. 1.6.8.2 – 3. 1.1.2.2. 3. 1.1.7. 1.7.4.R.1 – 5 3.2.R.2 1.R.1 Added 1.1.R.6.1. added 3. Removed 3.1.2.2.4.R.R.1. 4.7.2.5 1.7.3.7.1.7.3 3.1.UPDATE HISTORY Date November 2009 June 2010 March 2011 Reason for update First publication released for pilot implementation Released for implementation Amended after first workshop with industry 1.2. 1.6 Removed 1.R.3 and renumbered 3.2.13 Removed 1.1.11 Renumbered 1.1 to 7 3.12.8 1.3.1.2.R.7. 1.7. 1.7 1 June 2011 August 2011 August 2012 Date for implementation Amendment to implementation Amendment to implementation 1. 1.10.R.2.1.2 and renumbered 3.R.16.7.1.4.2 R.5.7.8.2.7.7.2 Moved 3.10.1 Removed 3.