MEDICINES CONTROL COUNCIL

Transcription

1 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

2 South African Common Technical Document ZA Module 1 Administrative Information Letter of application Comprehensive table of contents Application South African labelling and packaging Information about the experts Specific requirements for different types of applications Environmental risk assessment Good manufacturing practice Details of compliance with screening outcomes Individual patient data - statement of availability Foreign regulatory status Bioequivalence trial information Paediatric development programme Risk management plan... 6 Module 2 - CTD Summaries CTD Table of Contents (modules 2 to 5) Introduction Quality Overall Summary - Introduction Non-clinical Overview Clinical Overview Non-clinical Written and Tabulated Summaries Clinical Summary... 9 Module 3 - Quality Table of contents of module Body of data S Active Pharmaceutical Ingredient (name, manufacturer) P Pharmaceutical Product (name, dosage form) A Appendices R Regional Information Literature references Module 4 - Non-clinical study reports Table of contents of Module ZA_CTD_Jul12_v5 August 2012 Page 2 of 25

3 4.2 Study reports Literature references Module 5 - Clinical Study Reports Table of contents of Module Tabular listing of all clinical studies Clinical study reports Literature references APPENDIX A: Examples of Tables and Figures for Written Summaries APPENDIX B: The Non-clinical Tabulated Summaries Templates UPDATE HISTORY ZA_CTD_Jul12_v5 August 2012 Page 3 of 25

4 ZA Module 1 Administrative Information 1.0 Letter of application 1.1 Comprehensive table of contents 1.2 Application 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) 1.3 South African labelling and packaging South African Package Insert Package insert Standard References Patient Information Leaflet Labels Braille 1.4 Information about the experts Quality Non-clinical Clinical 1.5 Specific requirements for different types of applications Literature based submissions Amendments/Variations 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 1 Amendments guideline ZA_CTD_Jul12_v5 August 2012 Page 4 of 25

5 1.6 Environmental risk assessment Non-GMO (genetically modified organisms) GMO 1.7 Good manufacturing practice 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 Sample and Documents Confirmation of submission of sample Batch manufacturing record of the sample CoA of the sample Certified copy of a permit to manufacture specified Schedule 5, Schedules 6, 7 and 8 substances Inspection flow diagram Organogram 1.8 Details of compliance with screening outcomes 1.9 Individual patient data - statement of availability 1.10 Foreign regulatory status List of countries in which an application for the same product as being applied for has been submitted Registration certificate or marketing authorisation Foreign prescribing and patient information Data set similarities ZA_CTD_Jul12_v5 August 2012 Page 5 of 25

6 1.11 Bioequivalence trial information Study Title(s) (or brief description giving design, duration, dose and subject population of each study) Protocol and study numbers Investigational products (test and reference) details Confirmation that the test product formulation and manufacturing process is that being applied for Proof of procurement of the biostudy reference product Name and address of the Research Organisation(s) / Contract Research Organisation(s) where the bioequivalence studies were conducted Sponsor and responsible sponsor representative: name and address, contact details Duration of Clinical phase: dates of dosing and last clinical procedure Date of final report 1.12 Paediatric development programme 1.13 Risk management plan ZA_CTD_Jul12_v5 August 2012 Page 6 of 25

7 Module 2 - CTD Summaries 2.1 CTD Table of Contents (modules 2 to 5) 2.2 Introduction 2.3 Quality Overall Summary - Introduction 2.3.S 2.3.S S S S S S S P 2.3.P P P P P P P P.8 Quality Overall Summary - Active Pharmaceutical Ingredient (name, manufacturer) General Information (name, manufacturer) Manufacture (name, manufacturer) Characterisation (name, manufacturer) Control of Active Pharmaceutical Ingredient (name, manufacturer) Reference Standards or Materials (name, manufacturer) Container Closure System (name, manufacturer) Stability (name, manufacturer) Quality Overall Summary - Finished Pharmaceutical Product (name, dosage form) Description and Composition of the Pharmaceutical Product (name, dosage form) Pharmaceutical Development (name, dosage form) Manufacture (name, dosage form) Control of Excipients (name, dosage form) Control of Pharmaceutical Product (name, dosage form) Reference Standards or Materials (name, dosage form) Container Closure System (name, dosage form) Stability (name, dosage form) 2.3.A 2.3.A A A.3 Quality Overall Summary - Appendices Facilities and equipment (name, manufacturer) Adventitious agents safety evaluation (name, dosage form, manufacturer) Excipients 2.4 Non-clinical Overview 2.5 Clinical Overview Product Development Rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology Overview of Efficacy ZA_CTD_Jul12_v5 August 2012 Page 7 of 25

8 2.5.5 Overview of Safety Benefits and Risks Conclusions Literature References 2.6 Non-clinical Written and Tabulated Summaries Introduction Pharmacology Written Summary 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 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 Brief Summary Single-Dose Toxicity Repeat-Dose Toxicity (including supportive toxicokinetics evaluations) Genotoxicity Carcinogenicity (including supportive toxicokinetics evaluations) 2 Typically in the ectd this logical document should consist of a single file. The CTD defines these further heading levels and navigation should be provided within the document to these subheadings. ZA_CTD_Jul12_v5 August 2012 Page 8 of 25

9 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 Clinical Summary Summary of Biopharmaceutic Studies and Associated Analytical Methods Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Appendix Summary of Clinical Pharmacology Studies Background and Overview Summary of Results of Individual Studies Comparison and Analyses of Results Across Studies Special Studies Appendix Summary of Clinical Efficacy Indication 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 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. The CTD defines these further heading levels and navigation should be provided within the document to these subheadings. ZA_CTD_Jul12_v5 August 2012 Page 9 of 25

10 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, 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 ZA_CTD_Jul12_v5 August 2012 Page 10 of 25

11 Module 3 - Quality 3.1 Table of contents of module Body of data 3.2.S Active Pharmaceutical Ingredient (name, manufacturer) 3.2.S S S S.1.3 General information (name, manufacturer) Nomenclature (name, manufacturer) Structure (name, manufacturer) General Properties (name, manufacturer) 3.2.S S.2.1 Manufacture (name, manufacturer) Manufacturer(s) (name, manufacturer) 3.2.S.2.2 Description of Manufacturing Process and Process Controls (name, manufacturer) 3.2.S S S S.2.6 Control of Materials (name, manufacturer) Controls of Critical Steps and Intermediates (name, manufacturer) Process Validation and/or Evaluation (name, manufacturer) Manufacturing Process Development (name, manufacturer) 3.2.S S S S S S S S S S S S S S S.7.3 Characterisation (name, manufacturer) Elucidation of Structure and other Characteristics (name, manufacturer) Impurities (name, manufacturer) Control of active pharmaceutical ingredient (name, manufacturer) Specifications (name, manufacturer) Analytical Procedures (name, manufacturer) Validation of Analytical Procedures (name, manufacturer) Batch Analyses (name, manufacturer) Justification of Specification (name, manufacturer) Reference Standards or Materials (name, manufacturer) Container Closure System (name, manufacturer) Stability (name, manufacturer) Stability summary and conclusions (name, manufacturer) Post approval stability protocol and stability commitment (name, manufacturer) Stability Data (name, manufacturer) ZA_CTD_Jul12_v5 August 2012 Page 11 of 25

12 3.2.P Pharmaceutical Product (name, dosage form) 3.2.P P P P P P P P P P P P P.2.6 Description and Composition of the pharmaceutical product (name, dosage form) Pharmaceutical Development (name, dosage form) Components of the Pharmaceutical Product (name, dosage form) Active Pharmaceutical Ingredient(s) (name, dosage form) Excipients (name, dosage form) Final pharmaceutical product (name, dosage form) Formulation development (name, dosage form) Overages (name, dosage form) Physicochemical and biological properties (name, dosage form) Manufacturing process development (name, dosage form) Container closure system (name, dosage form) Microbiological attributes (name, dosage form) Compatibility (name, dosage form) 3.2.P P P P P P P P P P P P P P P P P P P P.5.6 Manufacture (name, dosage form) Manufacturer(s) (name, dosage form) Batch formula (name, dosage form) Description of manufacturing process and process controls (name, dosage form) Controls of critical steps and intermediates (name, dosage form) Process validation and/or evaluation (name, dosage form) Control of Inactive Pharmaceutical Ingredients (name, dosage form) Specifications (name, dosage form) Analytical procedures (name, dosage form) Validation of analytical procedures (name, dosage form) Justification of specifications (name, dosage form) Excipients of human or animal origin (name, dosage form) Novel excipients (name, dosage form) Control of pharmaceutical product (name, dosage form) Specification(s) (name, dosage form) Analytical procedures (name, dosage form) Validation of analytical procedures (name, dosage form) Batch analyses (name, dosage form) Characterisation of impurities (name, dosage form) Justification of specifications (name, dosage form) ZA_CTD_Jul12_v5 August 2012 Page 12 of 25

13 3.2.P P P P P P.8.3 Reference standards or materials (name, dosage form) Container closure system (name, dosage form) Stability (name, dosage form) Stability summary and conclusion (name, dosage form) Post-approval stability protocol and stability commitment (name, dosage form) Stability data (name, dosage form) 3.2.A Appendices 3.2.A A A.3 Facilities and equipment (name, manufacturer) Adventitious agents safety evaluation (name, dosage form, manufacturer) Excipients 3.2.R Regional Information 3.2.R R R R R R R Pharmaceutical and Biological availability Overview Country where developed, company developed by, 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) 3.2.R Confirmation that the data submitted have been obtained with the formulation and manufacturing process being applied for 3.2.R Confirmation that the test product (all strengths) was manufactured by the same manufacturer and site applied for 3.2.R Confirmation that the test product was manufactured with API(s) manufactured by the same manufacturer(s) as being applied for 3.2.R A statement whether in vivo-in vitro correlation from the data was obtained by the method/s used, if applicable 3.2.R Motivation for the use of the particular reference product 3.2.R Motivation for the use of a pharmaceutical alternative or lower strength 3.2.R Tabular summary of the information pertaining to the study products 3.2.R 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 3.2.R A discussion and conclusion of the outcomes of each of the studies and other relevant information to support and justify acceptance of product efficacy 3.2.R An overall conclusion 3.2.R References 3.2.R R.1.3 Reference product/s (local and foreign) Certificates of Analysis ZA_CTD_Jul12_v5 August 2012 Page 13 of 25

14 3.2.R R R Pharmaceutical availability studies Dissolution studies, data and reports Other 3.2.R.2 Parent API manufacturer with various sites 3.2.R.3 Certificate(s) of suitability with respect to the Ph.Eur. (CEPs) 3.2.R.4 Multiple API manufacturers 3.2.R.4.1 Comparative API manufacturers study report 3.2.R.4.2. Comparative results 3.2.R.4.3 Confirmation of compliance with guidelines 3.2.R.4.4 Certificates of analysis 3.2.R.5 Medical device 3.2.R.6 Materials of animal and/or human origin 3.2.R.7 Batch records of samples 3.2.R.8 Other 3.3 Literature references ZA_CTD_Jul12_v5 August 2012 Page 14 of 25

15 Module 4 - Non-clinical study reports 4.1 Table of contents of Module Study reports 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, 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 (in order by species, 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, the following subheadings should be modified accordingly) Fertility and early embryonic development Embryo-foetal development Prenatal and postnatal development, including maternal function Studies in which the offspring (juvenile animals) are dosed and/or further evaluated ZA_CTD_Jul12_v5 August 2012 Page 15 of 25

16 Local tolerance Other toxicity studies (if available) Antigenicity Immunotoxicity Mechanistic studies (if not included elsewhere) Dependence Metabolites Impurities Other 4.3 Literature references ZA_CTD_Jul12_v5 August 2012 Page 16 of 25

17 Module 5 - Clinical Study Reports 5.1 Table of contents of Module Tabular listing of all clinical studies 5.3 Clinical study reports 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 5.4 Literature references ZA_CTD_Jul12_v5 August 2012 Page 17 of 25

18 APPENDIX A: Examples of Tables and Figures for Written Summaries The tables and figures in Appendix A are presented merely as examples. Applicants should provide tables and figures using a format appropriate to the product. Study references should be included in the table or text. Tables should include statistics, if appropriate. ZA_CTD_Jul12_v5 August 2012 Page 18 of 25

19 Blood pressure following chronic dosing with X to SHRa[ref]. Hypotensive effect of saline i.v. infusion over 5 min (s) compared to X, 3 mg/kg i.v. infusion to SHR pretreated twice daily with saline, 1 ml/kg p.o., for 7 (m) or 14 (p) days or X, 25 mg/kg p.o., for 7 (l) or 14 (n) days. Saline pretreated statistical significances: p<0,05, all other points after challenge p<0,01. Values represent mean ± s.e.m. ashr= spontaneous hypertensive rate (n=5 per group) ZA_CTD_Jul12_v5 August 2012 Page 19 of 25

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21 Data presented are for male and female animals and are after daily repeated oral administration (at the end of the 60-day mouse study, 14 day rat study, and 1 year dog study). Data for man are extrapolated from dose normalised data obtained in male and female patients following t.i.d. regimen. # - AUC0-6 in the mouse, AUC0-t in the rat and in the dog and dose normalised AUC0-τ x 24 in man. $ - calculated from the total daily dose assuming a bodyweight of 50 kg for man. * - Numbers in parentheses represent ratios of exposure in animals to those in patients. ZA_CTD_Jul12_v5 August 2012 Page 21 of 25

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23 APPENDIX B: The Non-clinical Tabulated Summaries Templates Refer to the European Commission, NTA, Vol. 2B-CTD, Module 2, edition 2003 for examples of templates 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 ZA_CTD_Jul12_v5 August 2012 Page 23 of 25

24 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- and Postnatal Development, Including Maternal Function (Pivotal) Studies in Juvenile Animals a Local Tolerance Other Toxicity Studies * : Tabulated Summary is optional. It is preferable to include text tables and figures with the Nonclinical Written Summary. a : When a juvenile animal study has been conducted, it should be tabulated using the template appropriate for the type of study and located in Section ZA_CTD_Jul12_v5 August 2012 Page 24 of 25

25 UPDATE HISTORY Date Reason for update Version & publication November 2009 First publication released for pilot implementation v2 Nov 2009 June 2010 Released for implementation v2 June 2010 March 2011 Amended after first pilot submissions and workshop with industry Amended module headings , , , added , Added , 1.7.2, 1.7.3, added new 1.7.1, & 1.7.2; 1.7.5, 1.7.6, 1.7.7, 1.7.8, 1.7.9, removed , Removed Renumbered , Added new Removed , Removed to R.1, 3.2.R.1.1 Removed 3.2.R.1.2 and renumbered 3.2.R.1.1.8, 3.2.R R R.1.1.2, 3.2 R Removed 3.2.R Renumbered 3.2.R.4, renumbered; Removed 3.2.R R.2 Moved 3.2.R.6 to 3.2.R.3 and renumbered 3.2.R.4, 3.2.R.4.2, 4.3.R.4.4, added 3.2.R R.6, 3.2.R.7 1 June 2011 Date for implementation August 2011 Amendment to 1.7.7/8/9 for immediate implementation August 2012 Amendment to for immediate implementation v3 March 2011 v4 August 2011 v5 August 2012 ZA_CTD_Jul12_v5 August 2012 Page 25 of 25