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Common Technical Document

The document discusses the Common Technical Document (CTD), which provides a standardized format for submitting documentation to regulatory authorities for approval of pharmaceutical products. It describes the evolution and adoption of the CTD internationally and in India. The CTD aims to streamline the drug approval process and facilitate simultaneous reviews by different regulators. It is organized into five modules covering administrative information, summaries, quality, nonclinical data, and clinical data. Widespread use of the CTD format has allowed for greater harmonization and efficiency in global pharmaceutical development and regulation.

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COMMON TECHNICAL DOCUMENT (CTD) 1 Dr. Sukanta Sen MBBS, DNB, MD, MNAMS Dept. of Clinical & Exp. Pharmacology CSTM, Kolkata
If you want to go fast go alone. If you want to go far go together. African Proverb 2
WILL DISCUSS ABOUT :What is CTD?  Evolution of CTD  Why CTD?  Preparing and organizing the CTD  What is the current status of CTD?  ICH – eCTD  Advantages of CTD  Limitations  Benefits  Conclusion  References  3
ABBREVIATIONS CDSCO: Central Drugs Standard Control Organization  CTD: Common Technical Document  DCGI: Drug Controller General of India  eCTD: Electronic Common Technical Document  FDA: Food and Drug Administration  ICH: International Conference on Harmonisation  IND: Investigational New Drug application  NDA: New Drug Application  USFDA: US Food and Drug Administration  TGA: Therapeutic Goods Administration  EMA: European Medicines Agency  4
 Substantial documentation and data are required in submissions for import/manufacture and marketing approval of drugs for human use, resulting in large, complex applications.  Till date, applicants have used many different approaches in organizing the information and the differences in organization of data in each application has made reviewing more difficult and can also lead to omission of critical data or analyses.  Such omissions can result in unnecessary delays in approvals. Thus, a common format of submission will help in overcoming these hurdles. 5
WHAT IS CTD?  Application format  The CTD is a set of specifications for a dossier for the registration of medicines (TGA)  CTD is an internationally agreed “well structured common format” for the organization of the technical requirements that is to be submitted to the regulatory authority as an application for the registration of pharmaceuticals for human use in all three ICH regions (U.S.A., Europe and Japan). 6
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Prior to the advent of the CTD, regulatory reviewers received an application from one company and spent a year or more engaged in its review.  When the review was completed, reviewers received the next application—most likely in a different format—and had to learn the structure of the new application. 1996- Industry proposed CTD but ICH regulators were hesitant  disruptive to the review process Regulators asked industry to do a feasibility study. That study, conducted in May 1996, evaluated the time it took to convert an FDA new drug application into an European Medicines Agency (EMA) submission, and the reverse. Regulators quickly saw the potential value of harmonizing submission formats. 8
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ORIGIN OF CTD… ICH EWG WAS OFFICIALLY SIGNED OFF IN NOVEMBER 2000, CTD AT 10TH ANNIVERSERY of ICH ; SAN DIEGO,CALIFORNIA. 10
CTD CTD IS A JOINT EFFORT OF 3 REGULATORY AGENCIES: 2. Food and Drug Administration (FDA, USA) and 3. Ministry of Health, Labour and Welfare (MHLW,Japan). CTD is maintained by ICH through EWG. In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and the strongly recommended format of choice for NDAs submitted to the FDA. It has been adopted by several other countries including Australia, Canada and Switzerland (2004). 11 1.European Medicines Agency (EMEA, Europe),
Any guideline which is given by ICH passes through different steps.  These different steps are called STATUS of that GUIDELINE.  STATUS FUNCTIONALITY Step 1 Development of Consensus Step 2 12 Status of CTD Text released for consultation Step 3 Consultation outside ICH Step 4 STEP 4 STATUS ACHIEVED IN NOV.2000 IN 5TH ICH CONFERENCE IN SANDIEGO.. STEP 5 STATUS ACHIEVED IN MAY.2001 IN ICH MEETING IN TOKYO. ICH guideline finalized Step 5 Implementation GUIDANCE MADE AVAILABLE TO INDUSTRY IN OCTOBER 16,2001 BY FDA.
In 2000, the 10th Anniversary of ICH, Dr. Caroline Nutley Loew of the Pharmaceutical Research and Manufacturers of America (PhRMA) wrote a report, The Value and Benefits of ICH to Industry, which detailed ICH’s creation, procedures, and guideline development in the areas of safety, efficacy, and quality.  Her report anticipated that the CTD would revolutionize the submission procedures for industry’s regulatory staff.   Dr. Loew characterized the CTD as “offering potential benefits to industry far greater than any other single ICH topic,” and predicted the CTD would afford significant savings in time and resources as complex multiple submissions were replaced by a single technical dossier submitted in the three ICH regions— 13 facilitating simultaneous submission, approval, and launch of new drugs.
 In calling the CTD “a topic whose value to industry cannot be underestimated,”  Dr. Loew noted that with full incorporation of the CTD and the electronic CTD (eCTD), ICH could turn its sights to disseminating guideline information to non- ICH countries, yielding additional benefits to both regulators and industry.  Ten years later and in anticipation of ICH’s 20th Anniversary, the value and benefits of ICH to regulators have been realized. 14
 Moreover, implementation of the CTD in 2003 promoted the involvement of drug regulatory authorities (DRAs) not initially part of ICH, thereby extending ICH’s harmonized approach.  The development of the Global Cooperation Group, which includes representatives from five regional harmonization initiatives and the newly established Regulators Forum, created to promote participation by non-ICH countries interested in implementing ICH’s strategies, have also helped incorporate the CTD into regulatory processes, creating a common regulatory language that promotes faster access to life-saving treatments to patients beyond ICH regions. 15
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EVOLUTION OF THE COMMON TECHNICAL DOCUMENT 17
In ICH Region  1995: Concept of CTD proposed by Industry.  November 2000: ICH CTD guideline finalized.  September 2002: Guideline re-edited with Numbering & Section Header changes.  Prior to July 2003: Voluntary Submission Phase in 3 ICH Region.  July 1, 2003: Mandatory Requirement in Three ICH Regions. In India  2009: CDSCO Adopt CTD format for Technical requirements for registration of biological products.  October 28, 2010: CDSCO give guideline for feedback purpose for Industry on Preparation of CTD for Import/Manufacture and Marketing Approval of New Drug for Human Use (i.e. 18 NDA) & ask for comments and suggestion within 60 days.
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This guidance is developed by CDSCO based on, - The ICH Harmonised Tripartite Guideline on “Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use”. M4, Step 4 version dated January 13, 2004, and - Drugs & Cosmetics Act 1940 and Rules made thereunder. 20
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OBJECTIVE OF ICH TO PREPARE THE CTD The primary objective of the ICH is to avoid duplicative animal and human testing and to reach a common understanding of the technical requirements to support the registration process in the three ICH regions. These objectives are achieved through harmonized guidelines and result in a more economical use of human, animal and material resources, as well as the elimination of unnecessary delays in the global development and availability of new medicines, whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health. With the development of the Common Technical Document (CTD), the ICH hopes to accomplish many of its objectives. 22
WHY CTD?  To provide a harmonized common format/template for the submission of technical requirement to the regulatory authorities (FDA) that is acceptable in all 3 ICH regions  Reduce the time and resources used to compile applications  It will ease the preparation of electronic submissions.  To facilitate simultaneous submission in three regions.  To facilitate exchange of regulatory information.  Faster availability of new medicines 23
24 Figure 1: The Drug Approval Process: Drug approval involves passing a number of steps, including preclinical and clinical studies, and later, post-marketing research.
PREPARING & ORGANIZATION OF CTD It is organized into: Module 1: General Information  Module 2: CTD summaries  Module 3: Quality  Module 4: Nonclinical study reports  Module 5: Clinical study reports 25
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MODULE 1. Administrative information and prescribing information. Document specific to each region. E.g. Application form Proposed label for use in the region 27
MODULE 1: GENERAL INFORMATION 1.1 Covering letter & comprehensive table of contents (modules 1 to 5) 1.2 Administrative information 1.2.1 Brief introduction about the applicant company 1.2.2 Duly filled and signed application in Form 44 and Treasury Challan 1.2.3 Legal and Critical Documents 1.2.3.1 Copy of Clinical Trial/BE. No Objection letters issued by CDSCO 1.2.3.2 For import and marketing of finished products a. Copy of drug sale license in Form 20B / 21B b. Copy of Free Sale Certificate (FSC) and/or Certificate of Pharmaceutical Products (CPP) issued by the Regulatory 28 Authority of the country of origin
c. Batch release certificate issued by National Regulatory Authorities d. Copy of Form 11 for imported drug product for testing purpose 1.2.3.3 For manufacture and marketing of finished products a. Copy of existing manufacturing license in Form 25 / 28 / 26 b. Copy of Form-29 1.2.3.4 Undertaking or Declaration as per Annexure II 1.2.3.5 Certificate of Analysis 29
1.2.4 Coordinates related to the application 1.2.4.1 Name, address, telephone, fax, e-mail of applicant of drug product 1.2.4.2 Name, address, telephone, fax, e-mail of manufacturer of drug substance 1.2.4.3 Name, address, telephone, fax, e-mail of the responsible official 1.2.4.4 Name, address, telephone, fax, e-mail of other manufacturer(s) involved in the production process 1.2.4.5 Name, designation, address, telephone, fax, e-mail of the official responsible for releasing batches of drug product 1.2.4.6 Name, address, telephone, fax, e-mail of the authorized agent in India: (for imported drug products) 1.2.4.7 Name, address, telephone, fax, e-mail of the manufacturing premises holding Market Authorization of the drug product (for imported drug 30 products)
1.3 GENERAL INFORMATION ON DRUG PRODUCT 1.3.1 A brief description of the drug and the therapeutic class to which it belongs 1.3.2 Non-proprietary name or generic name of drug 1.3.3 Composition (As per label claim) 1.3.4 Dosage form 1.3.5 Strength per dosage unit 1.3.6 Dispensing requirements 1.3.7 Route of administration 1.3.8 Commercial presentation 1.3.9 Conditions of storage or conservation 1.3.10 Full Prescribing Information (Package insert) 1.3.11 Product Labeling: Proposed draft labels and cartons have to be provided. 1.3.12 Summary of the packaging procedures for Indian shipments  31
1.4 SUMMARY OF TESTING PROTOCOL(S) FOR QUALITY CONTROL TESTING together with a complete impurity profile and release specifications for the product should be submitted.  1.5 Regulatory status in other countries 1.5.1 List of countries where proposed drug is Marketed 1.5.2 List of countries where proposed drug is Approved for Marketing 1.5.3 List of countries where proposed drug is Approved as IND 1.5.4 List of countries where proposed drug is Withdrawn (if any, with reasons for withdrawal) 1.5.5 Details of any restrictions on use, in any country where it is marketed /approved  32
 1.6 Domestic price of the drug followed in the countries of  1.7 A brief profile of the manufacturer’s research activity  1.8 A brief profile of the manufacturer’s business activity in domestic as well as global market  1.9 Information regarding involvement of experts, if any  1.10 Samples of drug product  1.11 Promotional materials 33
MODULE 2. CTD SUMMARIES 2.1 Table of content of module 2 2.2 Introduction 2.3 Quality overall summaries 2.4 Non-clinical overview 2.5 Clinical overview 2.6 Non-clinical summaries 2.7 Clinical summaries 34
Module Content 2.1 Common technical document table of contents (Modules 2–5) 2.2 CTD introduction 2.3 Quality overall summary 2.4 Nonclinical overview 2.5 Clinical overview 2.6 Nonclinical written and tabulated summaries Pharmacology Pharmacokinetics Toxicology 2.7 Clinical summary Biopharmaceutic studies and associated analytical methods Clinical pharmacology studies Clinical efficacy Clinical safety Literature references Synopses of individual studies 35
2.3 QUALITY  OVERALL SUMMARIES In general, the Quality Overall Summary (QOS) is an outline of data presented in Module 3.  Please do not provide the entire information present in Module 3 corresponding sections, but, provide brief information picked from relevant sections.  This QOS normally should not exceed 40 pages of text, excluding tables and figures. 36
2.3.S Summary of drug substance 2.3.S.1 General Information (name, manufacturer) 2.3.S.2 Manufacture (name, manufacturer) 2.3.S.3 Characterisation (name, manufacturer) 2.3.S.4 Control of Drug Substance (name, manufacturer) 2.3.S.5 Reference Standards or Materials (name, manufacturer) 2.3.S.6 Container Closure System (name, manufacturer) 2.3.S.7 Stability (name, manufacturer) 2.3.P SUMMARY OF DRUG PRODUCT 2.3.P.1 Description and Composition of the Drug Product (name, dosage form) 37
2.3.P.2 Pharmaceutical Development (name, dosage form) 2.3.P.3 Manufacture (name, dosage form) 2.3.P.4 Control of Excipients (name, dosage form) 2.3.P.5 Control of Drug Product (name, dosage form) 2.3.P.6 Reference Standards or Materials (name, dosage form) 2.3.P.7 Container Closure System (name, dosage form) 2.3.P.8 Stability (name, dosage form) 2.3.A appendices 38
2.4 NON-CLINICAL OVERVIEW  Nonclinical overview should present an integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicological evaluation of the pharmaceutical.  In general, it should address the interpretation of data, the clinical relevance of findings, cross-linking with quality aspects of the pharmaceutical, and the implications of nonclinical findings for the safe use of the pharmaceutical. 39
2.4.1 Introduction and GLP statement A brief introduction about the contents of this section and a comment on the GLP status of the studies submitted should be provided 2.4.2 Overview of the Non Clinical Testing Strategy 2.4.3 Pharmacology 2.4.4 Pharmacokinetics 2.4.5 Toxicology 2.4.6 Integrated Overview and Conclusions 2.4.7 List of Literature References 40
2.5 CLINICAL OVERVIEW Summary and analysis of the clinical data Provide a brief overview of the clinical findings, including important limitations (e.g., lack of comparisons with an especially relevant active comparator, or absence of information on some patient populations, on pertinent endpoints, or on use in combination therapy).  Analyse the benefits and risks of the medicinal product in its intended use based upon the conclusions of the relevant clinical studies 41
 Address particular efficacy or safety issues encountered in development, and how they have been evaluated and resolved.  Explore unresolved issues, explain why they should not be considered as barriers to approval, and describe plans to resolve them.  Explain the basis for important or unusual aspects of the prescribing information 42
 2.5.1 Product Development Rationale  2.5.2 Overview of Biopharmaceutics  2.5.3. Overview of Clinical Pharmacology  2.5.4 Overview of Efficacy  2.5.5 Overview of Safety  2.5.6 Benefits and Risks Conclusions  2.5.7 Literature References 43
2.6 NON-CLINICAL SUMMARIES Summary of pharmacokinetic, pharmacological and toxicology studies – in-vivo/in-vitro, species, route and duration Appropriate age and gender related effects 44
2.6.1 Introduction  2.6.2 Written Summary of Pharmacology  2.6.2.1 Brief Summary  2.6.2.2 Primary Pharmacodynamics  2.6.2.3 Secondary Pharmacodynamics  2.6.2.4 Safety Pharmacology - defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.  2.6.2.5 Pharmacodynamic Drug Interactions  2.6.2.6 Discussion and Conclusions  2.6.3 Tabulated Summary of Pharmacology  2.6.4 Written Summary of Pharmacokinetics  45
2.6.4 Written Summary of Pharmacokinetics 2.6.4.1 Brief Summary  2.6.4.2 Methods of Analysis  2.6.4.3 Absorption  2.6.4.4 Distribution  2.6.4.5 Metabolism  2.6.4.6 Excretion  2.6.4.7 Pharmacokinetic Drug Interactions  2.6.4.8 Other Pharmacokinetic Studies  2.6.4.9 Discussion and Conclusions  2.6.4.10 Tables and Figures  2.6.5 Tabulated Summary of Pharmacokinetics 46
2.6.6 Written Summary of Toxicology  2.6.6.1 Brief Summary  Study type and duration Route of Species administration Compound Compound administered* Single-dose toxicity po and iv Rat and mouse Parent drug Single-dose toxicity po and iv Rat and mouse Metabolite X 1 month po Rat and dog Parent drug 6 months po Rat “ “ 9 months etc. po Dog “ “ Repeat-dose toxicity 47
2.6.6.2 Single-Dose Toxicity  2.6.6.3 Repeat-Dose Toxicity (including supportive toxicokinetics evaluation)  2.6.6.4 Genotoxicity Studies should be briefly summarised in the following order: in vitro non-mammalian cell system in vitro mammalian cell system in vivo mammalian system (including supportive toxicokinetics evaluation) o 2.6.6.5 Carcinogenicity (including supportive toxicokinetics evaluations) Short- or medium-term studies Long-term studies 48  2.6.6.6 Reproductive and Developmental Toxicity  2.6.6.7 Local Tolerance 
2.7 CLINICAL SUMMARIES This section is intended to provide a detailed, factual summarization of all of the clinical information in the CTD. This includes:    information provided in clinical study reports; information obtained from any meta-analyses or other cross- study analyses for which full reports have been included in Module 5; and  post-marketing data for products that have been marketed in other regions 49
 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods  2.7.1.1 Background and Overview  2.7.1.2 Summary of Results of Individual Studies  2.7.1.3 Comparison and Analyses of Results Across Studies  2.7.2 Summary of Clinical Pharmacology Studies  2.7.2.1 Background and Overview  2.7.2.2 Summary of Results of Individual Studies  2.7.2.3 Comparison and Analyses of Results Across Studies 50  2.7.2.4 Special Studies
 2.7.3 Summary of Clinical Efficacy  2.7.3.1 Background and Overview of Clinical Efficacy  2.7.3.2 Summary of Results of Individual Studies  2.7.3.3 Comparison and Analyses of Results Across Studies  2.7.3.3.1 Study Populations  2.7.3.3.2 Comparison of Efficacy Results of all Studies  2.7.3.3.3 Comparison of Results in Sub-populations  2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations  2.7.3.5 Persistence of Efficacy and/or Tolerance Effects 51
2.7.4.2.1.3 Other S2.7.4 Summary of Clinical Safety  2.7.4.1 Exposure to the Drug  2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies  2.7.4.1.2 Overall Extent of Exposure  2.7.4.2 Adverse Events  2.7.4.2.1 Analysis of Adverse Events  2.7.4.2.1.1 Common Adverse Events  2.7.4.2.1.2 Deaths  erious Adverse Events  2.7.4.2.1.4 Other Significant Adverse Events  2.7.4.2.1.5 Analysis of Adverse Events by Organ System or Syndrome  2.7.4.2.2 Narratives  2.7.4.3 Clinical Laboratory Evaluations  2.7.4.4 Vital Signs, Physical Findings, and Other Observations 52 Related to Safety 
o 2.7.4.5 Safety in Special Groups and Situations o 2.7.4.5.3 Drug Interactions o 2.7.4.5.4 Use in Pregnancy and Lactation o 2.7.4.5.5 Overdose 2.7.4.5.6 Drug Abuse 2.7.4.5.7 Withdrawal and Rebound 2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability o o o  2.7.4.6 Post-marketing Data  2.7.5 Literature References  2.7.6 Synopses of Individual Studies 53
MODULE 3 QUALITY The Quality section of the Common Technical Document (M4Q) provides a harmonised structure and format for presenting CMC (Chemistry, Manufacturing and Controls) information in a registration dossier. Module 3 content Module Content 3.1 Module 3 table of contents 3.2 Body of data 3.3 Literature references 54
3.2 BODY OF DATA  3.2.S DRUG SUBSTANCE(S)  3.2.S.1 General information (name, manufacturer)  3.2.S.1.1 Nomenclature (name, manufacturer)  3.2.S.1.2 Structure (name, manufacturer)  3.2.S.1.3 General Properties (name, manufacturer)  3.2.S.2 Manufacture of Drug Substance (name, manufacturer) 3.2.S.2.1 Manufacturer(s) (name, manufacturer)  3.2.S.2.2 Description of Manufacturing Process and Process Controls (name, manufacturer)  3.2.S.2.3 Control of Materials (name, manufacturer)  3.2.S.2.4 Controls of Critical Steps and Intermediates  3.2.S.2.5 Process Validation and/or Evaluation (name, manufacturer) 55  3.2.S.2.6 Manufacturing Process Development (name, manufacturer) 
3.2.S.3 Characterization of Drug Substance  3.2.S.4 Quality control of Drug Substance  3.2.S.5 Reference Standards or Materials 3.2.S.6 Container Closure System 3.2.S.7 Stability of Drug Substance  3.2.P DRUG PRODUCT (NAME, DOSAGE FORM)  3.2.P.1 Description and Composition of the Drug Product  3.2.P.2 Pharmaceutical Development  3.2.P.3 Manufacture of Drug Product  3.2.P.4 Control of Excipients  3.2.P.5 Control of Drug Product  3.2.P.6 Reference Standards or Materials  3.2.P.7 Container Closure System  3.2.P.8 Stability of drug product  56
MODULE 4: NON-CLINICAL STUDY REPORTS Module 4 describes the format and organisation of the nonclinical (pharmaco-toxicological) data relevant to the application.  4.2 STUDY REPORTS  4.2.1 Pharmacology  4.2.2 Pharmacokinetics  4.2.3 Toxicology  4.3 literature references 57
MODULE 5: CLINICAL STUDY REPORTS Module 5 describes the format and organisation of the clinical data relevant to the application. 5.3.1 Reports of Biopharmaceutical Studies  5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials  5.3.3 Reports of Human Pharmacokinetic (PK) Studies  5.3.4 Reports of Human Pharmacodynamic (PD) Studies  5.3.5 Reports of Efficacy and Safety Studies  5.3.6 Reports of Post-Marketing Experience  5.3.7 Case Report Forms and Individual Patient Listings  5.4 literature references o 58
GUIDANCE FOR THE INDUSTRY  Divided in 4 guidance document M4Q M4 CTD 59
ECTD 6 months behind CTD  May, 2001, Tokyo, Step 2 of the eCTD ICH process was agreed by Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG). Specifications developed by ICH M2 EWG Maintained by eCTD IWG Electronic submission from applicant to regulator 60
M2 EWG – developed change control process to monitor implementation process & provide solutions and added flexibility found necessary during implementation Addressed and resolved - study report structure - lifecycle management - consistency with CTD 61
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Paper CTD eCTD 63 File 1 File 2 File 3 File 4 / 19
ECTD:ELECTRONIC - CTD Developed by M2 EWG (Multidisciplinary 2 Expert Working Group) of ICH. 64 Industry <-----> Message <------> Agency Paper submission has been replaced by electronic submission / 19
CHARACTERISTICS OF ECTD:1. Files Referenced in the XML Backbone(s) 65 (Extensible Markup Language) REASONS: 1.It manages the large data for the entire submission and for each document within the submission. 2.This XML backbone allows the eCTD submission to be viewed via a web browser and can be loaded on a Web server. / 19
66 2.The file formats that can be included in the eCTD are Portable Document Format (PDF) and XML. However other formats can be used for graphs and images. JPEG PNG GIF -may be used for higher resolution. / 19
3. All eCTD Submissions Include Module 1 67 Module 1 Identifies following important information:       Company Name Drug Name Submission Type Submission Date Application Number Sequence Number / 19
NOMENCLATURE FOR FILES AND ECTD SUBMISSION. EXAMPLE:- MODULE 2 FILE NOMENCLATURE AND eCTD submission Description File Name 2.2 introduction 22-intro 2.3 Quality overall summary 23-qos 2.4 Non clinical Overview 24-nonclin-over 2.5 Clinical Overview 25-clin-over 2.6 Non clinical Written and Tabulated Summaries 26-nonclin-sum 2.7 Clinical summary 27-clin-sum 68 / 19
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ADVANTAGES OF CTD To make the reviewing of each application more easy and also to avoid omission of critical data or analyses. Omissions of such data can result in unnecessary delays in approvals.  To save time and resources  To facilitate regulatory review and communications  Appropriate format for the data  Easy to understand and evaluation of data  Applicable to all types of products (NCE, radiopharmaceuticals, vaccines, herbals, etc.)  70
SILENT BENEFITS OF THE CTD  More “reviewable” applications  Complete, well-organized submissions  More predictable format  More consistent reviews  Easier analysis across applications  Easier exchange of information  Facilitates electronic submissions 71
LIMITATIONS………  CTD is only a format, its not a single dossier with a single content.  Legal requirements differ in the different regions  ICH guidelines have not yet harmonized in all requirements  Pharmacopoeias are not harmonized  Applicant may have regional preferences. 72
•The eCTD has proved critical to improving application submission efficiencies as well as reviewer efficiency. •Besides delivering submission material to the reviewer in an expedited manner, the eCTD format has made it easier to develop standardized reviewer e-templates and review tools for each of the review disciplines. 73
IS CTD MANDATORY FOR ALL TYPE OF SUBMISSIONS? CTD is mandatory for all.  Import and/or manufacture and marketing approval of new drugs (New chemical entity, new indication, new dosage forms, new route of administration etc.), as a finished pharmaceutical product, for first time submission and for subsequent applications until 4 years.  Modified release formulations (even after 4 years of approval by CDSCO)  Fixed Dose Combinations under item (a) of Appendix VI of Schedule Y of Drugs and Cosmetics Rules 1945. 74
CONCLUSION  Whilst the realization of the CTD took many years, there is now a common format for the submission of Marketing Authorizations Applications across the three ICH regions Europe, Japan and the USA.  This should facilitate pharmaceutical companies to make simultaneous filings in the ICH regions as it will eliminate the extensive work previously required to convert, for example, a US dossier to an EU dossier and vice versa. 75
REFERENCES 1. Molzon J; “The Common Technical Document: the changing face of New Drug Application”; Nature Reviews – Drug Discovery; Volume 2, January 2003;Page 7174. 2. “Guidance for Industry on Preparation of Common Technical Document for Import / Manufacture And Marketing Approval Of New Drugs For Human Use (New Drug Application – NDA)”. Available at http://cdsco.nic.in/CTD_Guidance%20-Final.pdf 3. Roth I R; “Preparing the Common Technical Document for Registration of Pharmaceuticals for Human Use (CTD) – Insight and Recommendations”; Drug Information Journal; Volume 42; 2008; Page149-159. 4. “The Common Technical Document- Quality (CTDQ)”. Available at http://www.ema.europa.eu/ . 5. “Guideline M4: The Common Technical Document”. Available at http://www.ich.org/products/ctd.html 6. Smith C G, O’donnell J T; “The Process of New Drug Discovery & Development”; 2nd Edition; Informa Health Care USA, Inc.; Page 477. 7. “ICH Harmonised Tripartite Guideline: Organisation Of The Common Technical Document For The Registration Of Pharmaceuticals For Human Use M4”.  Available at http://www.ich.org/fileadmin 76
REFERENCES (CONTINUE):www.ich.org 77 www.cdsco.nic.in http://www.fda.gov/cder/regulatory/ersr/ectd.htm http://esubmission.eudra.org/ http://www.mhlw.go.jp/english/index.html http://www.tga.gov.au/docs/html/eugctd.htm / 19
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Common Technical Document

  • 1.
    COMMON TECHNICAL DOCUMENT (CTD) 1 Dr.Sukanta Sen MBBS, DNB, MD, MNAMS Dept. of Clinical & Exp. Pharmacology CSTM, Kolkata
  • 2.
    If you wantto go fast go alone. If you want to go far go together. African Proverb 2
  • 3.
    WILL DISCUSS ABOUT:What is CTD?  Evolution of CTD  Why CTD?  Preparing and organizing the CTD  What is the current status of CTD?  ICH – eCTD  Advantages of CTD  Limitations  Benefits  Conclusion  References  3
  • 4.
    ABBREVIATIONS CDSCO: Central DrugsStandard Control Organization  CTD: Common Technical Document  DCGI: Drug Controller General of India  eCTD: Electronic Common Technical Document  FDA: Food and Drug Administration  ICH: International Conference on Harmonisation  IND: Investigational New Drug application  NDA: New Drug Application  USFDA: US Food and Drug Administration  TGA: Therapeutic Goods Administration  EMA: European Medicines Agency  4
  • 5.
     Substantial documentation anddata are required in submissions for import/manufacture and marketing approval of drugs for human use, resulting in large, complex applications.  Till date, applicants have used many different approaches in organizing the information and the differences in organization of data in each application has made reviewing more difficult and can also lead to omission of critical data or analyses.  Such omissions can result in unnecessary delays in approvals. Thus, a common format of submission will help in overcoming these hurdles. 5
  • 6.
    WHAT IS CTD?  Applicationformat  The CTD is a set of specifications for a dossier for the registration of medicines (TGA)  CTD is an internationally agreed “well structured common format” for the organization of the technical requirements that is to be submitted to the regulatory authority as an application for the registration of pharmaceuticals for human use in all three ICH regions (U.S.A., Europe and Japan). 6
  • 7.
  • 8.
    Prior to theadvent of the CTD, regulatory reviewers received an application from one company and spent a year or more engaged in its review.  When the review was completed, reviewers received the next application—most likely in a different format—and had to learn the structure of the new application. 1996- Industry proposed CTD but ICH regulators were hesitant  disruptive to the review process Regulators asked industry to do a feasibility study. That study, conducted in May 1996, evaluated the time it took to convert an FDA new drug application into an European Medicines Agency (EMA) submission, and the reverse. Regulators quickly saw the potential value of harmonizing submission formats. 8
  • 9.
  • 10.
    ORIGIN OF CTD… ICH EWG WASOFFICIALLY SIGNED OFF IN NOVEMBER 2000, CTD AT 10TH ANNIVERSERY of ICH ; SAN DIEGO,CALIFORNIA. 10
  • 11.
    CTD CTD IS AJOINT EFFORT OF 3 REGULATORY AGENCIES: 2. Food and Drug Administration (FDA, USA) and 3. Ministry of Health, Labour and Welfare (MHLW,Japan). CTD is maintained by ICH through EWG. In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and the strongly recommended format of choice for NDAs submitted to the FDA. It has been adopted by several other countries including Australia, Canada and Switzerland (2004). 11 1.European Medicines Agency (EMEA, Europe),
  • 12.
    Any guideline whichis given by ICH passes through different steps.  These different steps are called STATUS of that GUIDELINE.  STATUS FUNCTIONALITY Step 1 Development of Consensus Step 2 12 Status of CTD Text released for consultation Step 3 Consultation outside ICH Step 4 STEP 4 STATUS ACHIEVED IN NOV.2000 IN 5TH ICH CONFERENCE IN SANDIEGO.. STEP 5 STATUS ACHIEVED IN MAY.2001 IN ICH MEETING IN TOKYO. ICH guideline finalized Step 5 Implementation GUIDANCE MADE AVAILABLE TO INDUSTRY IN OCTOBER 16,2001 BY FDA.
  • 13.
    In 2000, the10th Anniversary of ICH, Dr. Caroline Nutley Loew of the Pharmaceutical Research and Manufacturers of America (PhRMA) wrote a report, The Value and Benefits of ICH to Industry, which detailed ICH’s creation, procedures, and guideline development in the areas of safety, efficacy, and quality.  Her report anticipated that the CTD would revolutionize the submission procedures for industry’s regulatory staff.   Dr. Loew characterized the CTD as “offering potential benefits to industry far greater than any other single ICH topic,” and predicted the CTD would afford significant savings in time and resources as complex multiple submissions were replaced by a single technical dossier submitted in the three ICH regions— 13 facilitating simultaneous submission, approval, and launch of new drugs.
  • 14.
     In calling theCTD “a topic whose value to industry cannot be underestimated,”  Dr. Loew noted that with full incorporation of the CTD and the electronic CTD (eCTD), ICH could turn its sights to disseminating guideline information to non- ICH countries, yielding additional benefits to both regulators and industry.  Ten years later and in anticipation of ICH’s 20th Anniversary, the value and benefits of ICH to regulators have been realized. 14
  • 15.
     Moreover, implementation ofthe CTD in 2003 promoted the involvement of drug regulatory authorities (DRAs) not initially part of ICH, thereby extending ICH’s harmonized approach.  The development of the Global Cooperation Group, which includes representatives from five regional harmonization initiatives and the newly established Regulators Forum, created to promote participation by non-ICH countries interested in implementing ICH’s strategies, have also helped incorporate the CTD into regulatory processes, creating a common regulatory language that promotes faster access to life-saving treatments to patients beyond ICH regions. 15
  • 16.
  • 17.
    EVOLUTION OF THECOMMON TECHNICAL DOCUMENT 17
  • 18.
    In ICH Region 1995: Concept of CTD proposed by Industry.  November 2000: ICH CTD guideline finalized.  September 2002: Guideline re-edited with Numbering & Section Header changes.  Prior to July 2003: Voluntary Submission Phase in 3 ICH Region.  July 1, 2003: Mandatory Requirement in Three ICH Regions. In India  2009: CDSCO Adopt CTD format for Technical requirements for registration of biological products.  October 28, 2010: CDSCO give guideline for feedback purpose for Industry on Preparation of CTD for Import/Manufacture and Marketing Approval of New Drug for Human Use (i.e. 18 NDA) & ask for comments and suggestion within 60 days.
  • 19.
  • 20.
    This guidance isdeveloped by CDSCO based on, - The ICH Harmonised Tripartite Guideline on “Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use”. M4, Step 4 version dated January 13, 2004, and - Drugs & Cosmetics Act 1940 and Rules made thereunder. 20
  • 21.
  • 22.
    OBJECTIVE OF ICHTO PREPARE THE CTD The primary objective of the ICH is to avoid duplicative animal and human testing and to reach a common understanding of the technical requirements to support the registration process in the three ICH regions. These objectives are achieved through harmonized guidelines and result in a more economical use of human, animal and material resources, as well as the elimination of unnecessary delays in the global development and availability of new medicines, whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health. With the development of the Common Technical Document (CTD), the ICH hopes to accomplish many of its objectives. 22
  • 23.
    WHY CTD?  To providea harmonized common format/template for the submission of technical requirement to the regulatory authorities (FDA) that is acceptable in all 3 ICH regions  Reduce the time and resources used to compile applications  It will ease the preparation of electronic submissions.  To facilitate simultaneous submission in three regions.  To facilitate exchange of regulatory information.  Faster availability of new medicines 23
  • 24.
    24 Figure 1: TheDrug Approval Process: Drug approval involves passing a number of steps, including preclinical and clinical studies, and later, post-marketing research.
  • 25.
    PREPARING & ORGANIZATION OF CTD Itis organized into: Module 1: General Information  Module 2: CTD summaries  Module 3: Quality  Module 4: Nonclinical study reports  Module 5: Clinical study reports 25
  • 26.
  • 27.
    MODULE 1. Administrative informationand prescribing information. Document specific to each region. E.g. Application form Proposed label for use in the region 27
  • 28.
    MODULE 1: GENERALINFORMATION 1.1 Covering letter & comprehensive table of contents (modules 1 to 5) 1.2 Administrative information 1.2.1 Brief introduction about the applicant company 1.2.2 Duly filled and signed application in Form 44 and Treasury Challan 1.2.3 Legal and Critical Documents 1.2.3.1 Copy of Clinical Trial/BE. No Objection letters issued by CDSCO 1.2.3.2 For import and marketing of finished products a. Copy of drug sale license in Form 20B / 21B b. Copy of Free Sale Certificate (FSC) and/or Certificate of Pharmaceutical Products (CPP) issued by the Regulatory 28 Authority of the country of origin
  • 29.
    c. Batch releasecertificate issued by National Regulatory Authorities d. Copy of Form 11 for imported drug product for testing purpose 1.2.3.3 For manufacture and marketing of finished products a. Copy of existing manufacturing license in Form 25 / 28 / 26 b. Copy of Form-29 1.2.3.4 Undertaking or Declaration as per Annexure II 1.2.3.5 Certificate of Analysis 29
  • 30.
    1.2.4 Coordinates relatedto the application 1.2.4.1 Name, address, telephone, fax, e-mail of applicant of drug product 1.2.4.2 Name, address, telephone, fax, e-mail of manufacturer of drug substance 1.2.4.3 Name, address, telephone, fax, e-mail of the responsible official 1.2.4.4 Name, address, telephone, fax, e-mail of other manufacturer(s) involved in the production process 1.2.4.5 Name, designation, address, telephone, fax, e-mail of the official responsible for releasing batches of drug product 1.2.4.6 Name, address, telephone, fax, e-mail of the authorized agent in India: (for imported drug products) 1.2.4.7 Name, address, telephone, fax, e-mail of the manufacturing premises holding Market Authorization of the drug product (for imported drug 30 products)
  • 31.
    1.3 GENERAL INFORMATIONON DRUG PRODUCT 1.3.1 A brief description of the drug and the therapeutic class to which it belongs 1.3.2 Non-proprietary name or generic name of drug 1.3.3 Composition (As per label claim) 1.3.4 Dosage form 1.3.5 Strength per dosage unit 1.3.6 Dispensing requirements 1.3.7 Route of administration 1.3.8 Commercial presentation 1.3.9 Conditions of storage or conservation 1.3.10 Full Prescribing Information (Package insert) 1.3.11 Product Labeling: Proposed draft labels and cartons have to be provided. 1.3.12 Summary of the packaging procedures for Indian shipments  31
  • 32.
    1.4 SUMMARY OFTESTING PROTOCOL(S) FOR QUALITY CONTROL TESTING together with a complete impurity profile and release specifications for the product should be submitted.  1.5 Regulatory status in other countries 1.5.1 List of countries where proposed drug is Marketed 1.5.2 List of countries where proposed drug is Approved for Marketing 1.5.3 List of countries where proposed drug is Approved as IND 1.5.4 List of countries where proposed drug is Withdrawn (if any, with reasons for withdrawal) 1.5.5 Details of any restrictions on use, in any country where it is marketed /approved  32
  • 33.
     1.6 Domestic priceof the drug followed in the countries of  1.7 A brief profile of the manufacturer’s research activity  1.8 A brief profile of the manufacturer’s business activity in domestic as well as global market  1.9 Information regarding involvement of experts, if any  1.10 Samples of drug product  1.11 Promotional materials 33
  • 34.
    MODULE 2. CTD SUMMARIES 2.1Table of content of module 2 2.2 Introduction 2.3 Quality overall summaries 2.4 Non-clinical overview 2.5 Clinical overview 2.6 Non-clinical summaries 2.7 Clinical summaries 34
  • 35.
    Module Content 2.1 Common technical documenttable of contents (Modules 2–5) 2.2 CTD introduction 2.3 Quality overall summary 2.4 Nonclinical overview 2.5 Clinical overview 2.6 Nonclinical written and tabulated summaries Pharmacology Pharmacokinetics Toxicology 2.7 Clinical summary Biopharmaceutic studies and associated analytical methods Clinical pharmacology studies Clinical efficacy Clinical safety Literature references Synopses of individual studies 35
  • 36.
    2.3 QUALITY  OVERALL SUMMARIES Ingeneral, the Quality Overall Summary (QOS) is an outline of data presented in Module 3.  Please do not provide the entire information present in Module 3 corresponding sections, but, provide brief information picked from relevant sections.  This QOS normally should not exceed 40 pages of text, excluding tables and figures. 36
  • 37.
    2.3.S Summary ofdrug substance 2.3.S.1 General Information (name, manufacturer) 2.3.S.2 Manufacture (name, manufacturer) 2.3.S.3 Characterisation (name, manufacturer) 2.3.S.4 Control of Drug Substance (name, manufacturer) 2.3.S.5 Reference Standards or Materials (name, manufacturer) 2.3.S.6 Container Closure System (name, manufacturer) 2.3.S.7 Stability (name, manufacturer) 2.3.P SUMMARY OF DRUG PRODUCT 2.3.P.1 Description and Composition of the Drug Product (name, dosage form) 37
  • 38.
    2.3.P.2 Pharmaceutical Development(name, dosage form) 2.3.P.3 Manufacture (name, dosage form) 2.3.P.4 Control of Excipients (name, dosage form) 2.3.P.5 Control of Drug Product (name, dosage form) 2.3.P.6 Reference Standards or Materials (name, dosage form) 2.3.P.7 Container Closure System (name, dosage form) 2.3.P.8 Stability (name, dosage form) 2.3.A appendices 38
  • 39.
    2.4 NON-CLINICAL OVERVIEW  Nonclinicaloverview should present an integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicological evaluation of the pharmaceutical.  In general, it should address the interpretation of data, the clinical relevance of findings, cross-linking with quality aspects of the pharmaceutical, and the implications of nonclinical findings for the safe use of the pharmaceutical. 39
  • 40.
    2.4.1 Introduction andGLP statement A brief introduction about the contents of this section and a comment on the GLP status of the studies submitted should be provided 2.4.2 Overview of the Non Clinical Testing Strategy 2.4.3 Pharmacology 2.4.4 Pharmacokinetics 2.4.5 Toxicology 2.4.6 Integrated Overview and Conclusions 2.4.7 List of Literature References 40
  • 41.
    2.5 CLINICAL OVERVIEW Summaryand analysis of the clinical data Provide a brief overview of the clinical findings, including important limitations (e.g., lack of comparisons with an especially relevant active comparator, or absence of information on some patient populations, on pertinent endpoints, or on use in combination therapy).  Analyse the benefits and risks of the medicinal product in its intended use based upon the conclusions of the relevant clinical studies 41
  • 42.
     Address particular efficacyor safety issues encountered in development, and how they have been evaluated and resolved.  Explore unresolved issues, explain why they should not be considered as barriers to approval, and describe plans to resolve them.  Explain the basis for important or unusual aspects of the prescribing information 42
  • 43.
     2.5.1 Product DevelopmentRationale  2.5.2 Overview of Biopharmaceutics  2.5.3. Overview of Clinical Pharmacology  2.5.4 Overview of Efficacy  2.5.5 Overview of Safety  2.5.6 Benefits and Risks Conclusions  2.5.7 Literature References 43
  • 44.
    2.6 NON-CLINICAL SUMMARIES Summaryof pharmacokinetic, pharmacological and toxicology studies – in-vivo/in-vitro, species, route and duration Appropriate age and gender related effects 44
  • 45.
    2.6.1 Introduction  2.6.2Written Summary of Pharmacology  2.6.2.1 Brief Summary  2.6.2.2 Primary Pharmacodynamics  2.6.2.3 Secondary Pharmacodynamics  2.6.2.4 Safety Pharmacology - defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.  2.6.2.5 Pharmacodynamic Drug Interactions  2.6.2.6 Discussion and Conclusions  2.6.3 Tabulated Summary of Pharmacology  2.6.4 Written Summary of Pharmacokinetics  45
  • 46.
    2.6.4 Written Summaryof Pharmacokinetics 2.6.4.1 Brief Summary  2.6.4.2 Methods of Analysis  2.6.4.3 Absorption  2.6.4.4 Distribution  2.6.4.5 Metabolism  2.6.4.6 Excretion  2.6.4.7 Pharmacokinetic Drug Interactions  2.6.4.8 Other Pharmacokinetic Studies  2.6.4.9 Discussion and Conclusions  2.6.4.10 Tables and Figures  2.6.5 Tabulated Summary of Pharmacokinetics 46
  • 47.
    2.6.6 Written Summaryof Toxicology  2.6.6.1 Brief Summary  Study type and duration Route of Species administration Compound Compound administered* Single-dose toxicity po and iv Rat and mouse Parent drug Single-dose toxicity po and iv Rat and mouse Metabolite X 1 month po Rat and dog Parent drug 6 months po Rat “ “ 9 months etc. po Dog “ “ Repeat-dose toxicity 47
  • 48.
    2.6.6.2 Single-Dose Toxicity 2.6.6.3 Repeat-Dose Toxicity (including supportive toxicokinetics evaluation)  2.6.6.4 Genotoxicity Studies should be briefly summarised in the following order: in vitro non-mammalian cell system in vitro mammalian cell system in vivo mammalian system (including supportive toxicokinetics evaluation) o 2.6.6.5 Carcinogenicity (including supportive toxicokinetics evaluations) Short- or medium-term studies Long-term studies 48  2.6.6.6 Reproductive and Developmental Toxicity  2.6.6.7 Local Tolerance 
  • 49.
    2.7 CLINICAL SUMMARIES Thissection is intended to provide a detailed, factual summarization of all of the clinical information in the CTD. This includes:    information provided in clinical study reports; information obtained from any meta-analyses or other cross- study analyses for which full reports have been included in Module 5; and  post-marketing data for products that have been marketed in other regions 49
  • 50.
     2.7.1 Summary ofBiopharmaceutic Studies and Associated Analytical Methods  2.7.1.1 Background and Overview  2.7.1.2 Summary of Results of Individual Studies  2.7.1.3 Comparison and Analyses of Results Across Studies  2.7.2 Summary of Clinical Pharmacology Studies  2.7.2.1 Background and Overview  2.7.2.2 Summary of Results of Individual Studies  2.7.2.3 Comparison and Analyses of Results Across Studies 50  2.7.2.4 Special Studies
  • 51.
     2.7.3 Summary ofClinical Efficacy  2.7.3.1 Background and Overview of Clinical Efficacy  2.7.3.2 Summary of Results of Individual Studies  2.7.3.3 Comparison and Analyses of Results Across Studies  2.7.3.3.1 Study Populations  2.7.3.3.2 Comparison of Efficacy Results of all Studies  2.7.3.3.3 Comparison of Results in Sub-populations  2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations  2.7.3.5 Persistence of Efficacy and/or Tolerance Effects 51
  • 52.
    2.7.4.2.1.3 Other S2.7.4Summary of Clinical Safety  2.7.4.1 Exposure to the Drug  2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies  2.7.4.1.2 Overall Extent of Exposure  2.7.4.2 Adverse Events  2.7.4.2.1 Analysis of Adverse Events  2.7.4.2.1.1 Common Adverse Events  2.7.4.2.1.2 Deaths  erious Adverse Events  2.7.4.2.1.4 Other Significant Adverse Events  2.7.4.2.1.5 Analysis of Adverse Events by Organ System or Syndrome  2.7.4.2.2 Narratives  2.7.4.3 Clinical Laboratory Evaluations  2.7.4.4 Vital Signs, Physical Findings, and Other Observations 52 Related to Safety 
  • 53.
    o 2.7.4.5 Safety inSpecial Groups and Situations o 2.7.4.5.3 Drug Interactions o 2.7.4.5.4 Use in Pregnancy and Lactation o 2.7.4.5.5 Overdose 2.7.4.5.6 Drug Abuse 2.7.4.5.7 Withdrawal and Rebound 2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability o o o  2.7.4.6 Post-marketing Data  2.7.5 Literature References  2.7.6 Synopses of Individual Studies 53
  • 54.
    MODULE 3 QUALITY TheQuality section of the Common Technical Document (M4Q) provides a harmonised structure and format for presenting CMC (Chemistry, Manufacturing and Controls) information in a registration dossier. Module 3 content Module Content 3.1 Module 3 table of contents 3.2 Body of data 3.3 Literature references 54
  • 55.
    3.2 BODY OFDATA  3.2.S DRUG SUBSTANCE(S)  3.2.S.1 General information (name, manufacturer)  3.2.S.1.1 Nomenclature (name, manufacturer)  3.2.S.1.2 Structure (name, manufacturer)  3.2.S.1.3 General Properties (name, manufacturer)  3.2.S.2 Manufacture of Drug Substance (name, manufacturer) 3.2.S.2.1 Manufacturer(s) (name, manufacturer)  3.2.S.2.2 Description of Manufacturing Process and Process Controls (name, manufacturer)  3.2.S.2.3 Control of Materials (name, manufacturer)  3.2.S.2.4 Controls of Critical Steps and Intermediates  3.2.S.2.5 Process Validation and/or Evaluation (name, manufacturer) 55  3.2.S.2.6 Manufacturing Process Development (name, manufacturer) 
  • 56.
    3.2.S.3 Characterization ofDrug Substance  3.2.S.4 Quality control of Drug Substance  3.2.S.5 Reference Standards or Materials 3.2.S.6 Container Closure System 3.2.S.7 Stability of Drug Substance  3.2.P DRUG PRODUCT (NAME, DOSAGE FORM)  3.2.P.1 Description and Composition of the Drug Product  3.2.P.2 Pharmaceutical Development  3.2.P.3 Manufacture of Drug Product  3.2.P.4 Control of Excipients  3.2.P.5 Control of Drug Product  3.2.P.6 Reference Standards or Materials  3.2.P.7 Container Closure System  3.2.P.8 Stability of drug product  56
  • 57.
    MODULE 4: NON-CLINICALSTUDY REPORTS Module 4 describes the format and organisation of the nonclinical (pharmaco-toxicological) data relevant to the application.  4.2 STUDY REPORTS  4.2.1 Pharmacology  4.2.2 Pharmacokinetics  4.2.3 Toxicology  4.3 literature references 57
  • 58.
    MODULE 5: CLINICALSTUDY REPORTS Module 5 describes the format and organisation of the clinical data relevant to the application. 5.3.1 Reports of Biopharmaceutical Studies  5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials  5.3.3 Reports of Human Pharmacokinetic (PK) Studies  5.3.4 Reports of Human Pharmacodynamic (PD) Studies  5.3.5 Reports of Efficacy and Safety Studies  5.3.6 Reports of Post-Marketing Experience  5.3.7 Case Report Forms and Individual Patient Listings  5.4 literature references o 58
  • 59.
    GUIDANCE FOR THEINDUSTRY  Divided in 4 guidance document M4Q M4 CTD 59
  • 60.
    ECTD 6 months behindCTD  May, 2001, Tokyo, Step 2 of the eCTD ICH process was agreed by Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG). Specifications developed by ICH M2 EWG Maintained by eCTD IWG Electronic submission from applicant to regulator 60
  • 61.
    M2 EWG –developed change control process to monitor implementation process & provide solutions and added flexibility found necessary during implementation Addressed and resolved - study report structure - lifecycle management - consistency with CTD 61
  • 62.
  • 63.
    Paper CTD eCTD 63 File 1 File2 File 3 File 4 / 19
  • 64.
    ECTD:ELECTRONIC - CTD Developed by M2EWG (Multidisciplinary 2 Expert Working Group) of ICH. 64 Industry <-----> Message <------> Agency Paper submission has been replaced by electronic submission / 19
  • 65.
    CHARACTERISTICS OF ECTD:1.Files Referenced in the XML Backbone(s) 65 (Extensible Markup Language) REASONS: 1.It manages the large data for the entire submission and for each document within the submission. 2.This XML backbone allows the eCTD submission to be viewed via a web browser and can be loaded on a Web server. / 19
  • 66.
    66 2.The file formatsthat can be included in the eCTD are Portable Document Format (PDF) and XML. However other formats can be used for graphs and images. JPEG PNG GIF -may be used for higher resolution. / 19
  • 67.
    3. All eCTDSubmissions Include Module 1 67 Module 1 Identifies following important information:       Company Name Drug Name Submission Type Submission Date Application Number Sequence Number / 19
  • 68.
    NOMENCLATURE FOR FILESAND ECTD SUBMISSION. EXAMPLE:- MODULE 2 FILE NOMENCLATURE AND eCTD submission Description File Name 2.2 introduction 22-intro 2.3 Quality overall summary 23-qos 2.4 Non clinical Overview 24-nonclin-over 2.5 Clinical Overview 25-clin-over 2.6 Non clinical Written and Tabulated Summaries 26-nonclin-sum 2.7 Clinical summary 27-clin-sum 68 / 19
  • 69.
  • 70.
    ADVANTAGES OF CTD Tomake the reviewing of each application more easy and also to avoid omission of critical data or analyses. Omissions of such data can result in unnecessary delays in approvals.  To save time and resources  To facilitate regulatory review and communications  Appropriate format for the data  Easy to understand and evaluation of data  Applicable to all types of products (NCE, radiopharmaceuticals, vaccines, herbals, etc.)  70
  • 71.
    SILENT BENEFITS OFTHE CTD  More “reviewable” applications  Complete, well-organized submissions  More predictable format  More consistent reviews  Easier analysis across applications  Easier exchange of information  Facilitates electronic submissions 71
  • 72.
    LIMITATIONS………  CTD is onlya format, its not a single dossier with a single content.  Legal requirements differ in the different regions  ICH guidelines have not yet harmonized in all requirements  Pharmacopoeias are not harmonized  Applicant may have regional preferences. 72
  • 73.
    •The eCTD hasproved critical to improving application submission efficiencies as well as reviewer efficiency. •Besides delivering submission material to the reviewer in an expedited manner, the eCTD format has made it easier to develop standardized reviewer e-templates and review tools for each of the review disciplines. 73
  • 74.
    IS CTD MANDATORYFOR ALL TYPE OF SUBMISSIONS? CTD is mandatory for all.  Import and/or manufacture and marketing approval of new drugs (New chemical entity, new indication, new dosage forms, new route of administration etc.), as a finished pharmaceutical product, for first time submission and for subsequent applications until 4 years.  Modified release formulations (even after 4 years of approval by CDSCO)  Fixed Dose Combinations under item (a) of Appendix VI of Schedule Y of Drugs and Cosmetics Rules 1945. 74
  • 75.
    CONCLUSION  Whilst the realizationof the CTD took many years, there is now a common format for the submission of Marketing Authorizations Applications across the three ICH regions Europe, Japan and the USA.  This should facilitate pharmaceutical companies to make simultaneous filings in the ICH regions as it will eliminate the extensive work previously required to convert, for example, a US dossier to an EU dossier and vice versa. 75
  • 76.
    REFERENCES 1. Molzon J;“The Common Technical Document: the changing face of New Drug Application”; Nature Reviews – Drug Discovery; Volume 2, January 2003;Page 7174. 2. “Guidance for Industry on Preparation of Common Technical Document for Import / Manufacture And Marketing Approval Of New Drugs For Human Use (New Drug Application – NDA)”. Available at http://cdsco.nic.in/CTD_Guidance%20-Final.pdf 3. Roth I R; “Preparing the Common Technical Document for Registration of Pharmaceuticals for Human Use (CTD) – Insight and Recommendations”; Drug Information Journal; Volume 42; 2008; Page149-159. 4. “The Common Technical Document- Quality (CTDQ)”. Available at http://www.ema.europa.eu/ . 5. “Guideline M4: The Common Technical Document”. Available at http://www.ich.org/products/ctd.html 6. Smith C G, O’donnell J T; “The Process of New Drug Discovery & Development”; 2nd Edition; Informa Health Care USA, Inc.; Page 477. 7. “ICH Harmonised Tripartite Guideline: Organisation Of The Common Technical Document For The Registration Of Pharmaceuticals For Human Use M4”.  Available at http://www.ich.org/fileadmin 76
  • 77.
  • 78.