CTD, eCTD, and Their Various Modules

To increase international harmonisation of technical requirements to ensure that safe, effective, and high-quality medicines are developed and registered, there is a joint 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 procedures.

The purpose of the 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 of July 2003 in the 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 guidelines. The interface and international specification for the pharmaceutical industry for agency transfer of regulatory information is the 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 Group. ICH eCTD is an internationally driven standard designed to reduce cost in the administration, 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 Administration 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).

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 2016.

Common Technical Document (CTD)

The CTD is categorized into 5 modules as given below6.

1. Module 1: Regional Administrative Information.
2. Module 2: Introduction, Quality Overall Summary, Nonclinical overview, Clinical overview, nonclinical written and tabulated summaries, clinical summary
3. Module 3: Quality
4. Module 4: Nonclinical Study Reports
5. Module 5: Clinical Study Reports

The CTD triangle is as shown below

Module 1: Regional Administrative Information

Module 1 of the CTD describes the administrative 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 label.

ALSO READ: Sample Product Dossier for WHO Prequalification

Module 2: Introduction, Quality Overall Summary, Nonclinical overview, Clinical overview, nonclinical written and tabulated summaries, clinical summary

Seven sections in Module 2 should be maintained in the following order:

• 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 are included in Module 4 of the dossier. The main headings in this section (that must not be altered) are as follows:

• 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

Module 5: Clinical Study Reports

Clinical reports are included in Module 5 of the dossier. The main headings in this section (that must not be altered) are as follows:

• 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. Administrative information and prescribing information
2. Common technical document summaries
3. Quality
4. Nonclinical study reports
5. Clinical study reports

Data Structure of eCTD

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 upload the sequence into their systems and hyperlink. Since all files are submitted electronically, there is no need for agencies to scan documents or the industry to print, transport and 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 time.

ALSO READ: Applicability of Module 4 to Generic Drug Products