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CTD and eCTD CTD and eCTD Sri Harsha Gonnuru

Student of online Professional degree in pharmaceutical regulatory affairs (PDPRA), James Lind Institute, India The objective of this paper is to outline CTD, eCTD and their various modules

CTD and eCTD: To increase international harmonisation of technical requirements to ensure that safe, effective, and high-quality medicines are developed and ed there is a t initiative involving both regulators and research‐based industry representatives of the European Union, Japan and the USA in scientific and technical discussions of the testing procedures1. The purpose of Common technical document (CTD)is to provide a harmonized structure and format for new drug applications. The CTD was agreed upon in November 2000 in San Diego USA and the use of CTD is mandatory as from July 2003 in European Union and Japan. The CTD is not intended to indicate what studies are required but the focus of the CTD is to provide a common format for the preparation of a well-structured submission according to the modular framework described in the ICH guidelines3. The interface and international specification for the pharmaceutical industry to agency transfer of regulatory information is electronic common technical document (eCTD). This is based on the Common Technical Document (CTD) format and was developed by the International Council for Harmonisation (ICH) Multidisciplinary Group 2 Expert Working Group3. ICH‐eCTD is an internationally driven standard designed to reduce cost in the istration, assessment and archiving of applications for marketing authorization of medicinal products for human use, to reduce the use of paper and streamline the assessment process making the system more efficient. On May 5, 2015, the U.S. Food & Drug istration published a final, binding guidance document requiring certain submissions in electronic (eCTD) format within 24 months. The projected date for mandatory electronic submissions is May 5, 2017 for New Drug Applications (NDAs), Biologic License Applications (BLAs), Abbreviated New Drug Applications (ANDAs) and Drug Master Files (DMFs)4. The E.U. and its European Medicines Agency began accepting eCTD submissions in 2003.However, in February 2015, the "EMA announced it would no longer accept paper application forms for products applying to the centralized procedure beginning 1 July 2015."The EMA verified on that date that it would no longer accept "human and veterinary centralized procedure applications" and that all electronic application forms would have to be eCTD by January 20165.

CTD and eCTD Common Technical Document (CTD): The CTD is categorized into 5 modules as given below6.  Module 1: Regional istrative Information.  Module 2: Introduction, Quality Overall Summary, Nonclinical overview, Clinical overview, nonclinical written and tabulated summaries, clinical summary  Module 3: Quality  Module 4: Nonclinical Study Reports  Module 5: Clinical Study Reports The CTD triangle is as shown below6

CTD and eCTD Module 1: Regional istrative Information Module 1 of the CTD describes the istrative information and prescribing information (for example, the application form, the proposed product information and labelling). Module 1 is not strictly included in the CTD since it contains documents that are specific to each region, e.g. application forms or the proposed label7. Module 2: Introduction, Quality Overall Summary, Nonclinical overview, Clinical overview, nonclinical written and tabulated summaries, clinical summary There are seven sections in Module 2 that should be maintained in the following order8:  2.1 Table of contents  2.2 Introduction  2.3 Quality Overall Summary  2.4 Non-clinical Overview  2.5 Clinical Overview  2.6 Non-clinical Written and Tabulated Summaries  2.7 Clinical Summary Module 3: Quality Chemistry, Manufacturing, and Controls reports for the product are included in Module 3 of the registration dossier. Sections on both drug substance and drug product are included in this module. The main headings in this section (that must not be altered) are as follows:  3.1 Table of contents of Module 3  3.2 Body of data  3.2.S Drug Substance  3.2. P+ Drug Product  3.3 Literature references used in Module 3 Module 4: Non-clinical study reports Non-clinical reports included in Module 4 of the dossier. The main headings in this section (that must not be altered) are as follows8:  4.1 Table of contents of Module 4  4.2 Study reports  4.2.1 Pharmacology  4.2.2 Pharmacokinetics  4.2.3 Toxicology  4.3 Literature references used in Module 4

CTD and eCTD Module 5: Clinical study reports Clinical reports included in Module 5 of the dossier. The main headings in this section (that must not be altered) are as follows8:  5.1 Table of contents of Module 5  5.2 Tabular listing of all clinical studies  5.3 Clinical study reports  5.3.1 Reports of biopharmaceutic 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.  Electronic Common technical Document (eCTD): The eCTD has five modules as given below: 1. 2. 3. 4. 5.

istrative information and prescribing information Common technical document summaries Quality Nonclinical study reports Clinical study reports

Data Structure of eCTD9: The eCTD is a message specification for the transfer of files and metadata from a submitter to a receiver. The primary technical components are:    

A high-level folder structure (required) An XML "backbone" file that provides metadata about content files and lifecycle instructions for the receiving system An optional lower level folder structure (recommended folder names are provided in Appendix 4 of the eCTD specification) Associated document type definitions (DTDs) and stylesheets.

For quick referencing of information, the XML backbone allows agencies to automatically the sequence into their systems and hyper-linking. Since all files are submitted electronically there is no need for agencies to scan documents or industry to print, transport and

CTD and eCTD store masses of paper. Changes and updates to the dossier are easy for reviewers to identify, and, with electronic submission portals, can be presented to the authorities within minutes of completion, drastically reducing processing time10.

References: 1.

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"Guidance for Industry, ICH M4: Organization of the CTD" U.S. Department of Health and Human Services Food and Drug istration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) August 2001 CTD AND ECTD. (n.d.). Retrieved from http://www.authorstream.com/Presentation/manohar.kasturi-1570061-ctd-ectd/ Common Technical Document. (2019, August 14). Retrieved from https://en.wikipedia.org/wiki/Common_Technical_Document Guidance for Industry: Providing Regulatory Submissions in Electronic Format—Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. (2006). Biotechnology Law Report, 25(1), 35-45. doi:10.1089/blr.2006.25.35 “Electronic Application Forms Mandatory for EU Centralized Procedure.” Regulatory Affairs Professionals Society (RAPS), www.raps.org/regulatory-focus%E2%84%A2/newsarticles/2015/7/electronic-application-forms-mandatory-for-eu-centralized-procedure.

“CTD.” ICH, www.ich.org/products/ctd.html. Jordan, Debbie. “An Overview of the Common Technical Document (CTD) Regulatory Dossier.” Medical Writing, vol. 23, no. 2, 2014, pp. 101–105., doi:10.1179/2047480614z.000000000207. 8. Australian Government Department of Health. “CTD Module 1.” Therapeutic Goods istration (TGA), Australian Government Department of Health, 10 July 2019, www.tga.gov.au/ctd-module-1. 9. “Electronic Common Technical Document.” Wikipedia, Wikimedia Foundation, 7 Jan. 2019, en.wikipedia.org/wiki/Electronic_common_technical_document. 10. “What Is Regulatory Affairs?” Trac Services, www.tracservices.co.uk/what-is-regulatoryaffairs/.