Structure of the Common Technical Document (CTD)- M4 Guideline

What is the Common Technical Document (CTD)?

The Common Technical Document (CTD) format or dossier was designed by the ICH and was agreed upon as a common format between three major regulatory regions, i.e.  European Union (EU), USA, and Japan for submission of technical documentation included in an application for the registration of a human pharmaceutical product.

Background and Objective:

A marketing application submission typically requires a huge amount of information. Generally, comparable scientific and clinical information is required to be submitted in countries where the manufacturer or sponsor plans to market the drug.  Historically, submissions were in the paper format, which would need huge sponsor and agency resources as well as signifigant storage space. Most regions also had their own set of guidelines and format for submission of a regulatory dossier to obtain marketing approval for a new drug or a variation to an existing license. For example, in Japan, the GAIYO format was required. In the US, the Food and Drug Administration (US-FDA) had guidance documents regarding the format and contents of a New Drug Application (NDA). In Europe, Expert Reports and Summaries were required, additionally, countries within EU had their own guidelines and formats, which made the process more time-consuming and repetitive.

The CTD format was mainly implemented as a way to harmonize the content of the submission required for each of these major regions, this effort would greatly reduce the time and resources needed to compile applications for pharmaceutical products, as also making the whole submission process much more efficient in terms of global applications. The CTD indicates the content and organization of technical data when submitted to an Agency for their marketing approval.

Overview of Electronic CTD or eCTD submissions:

USFDA had been accepting paper CTD application only until 2003, making the electronic submission or electronic CTD (eCTD) mandatory from May 2017. Most E-submission requirements have been phased in the recent years, including the New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) submissions, Drug Master Files (DMFs), Investigational New Drug application (IND) and Biologics License Applications (BLAs).

With an eCTD, each document is separate (granular) and named as per ICH specifications. Each submission has its own eCTD XML backbone file, which allows the FDA to receive, archive and review the submission smoothly.

Currently, apart from US, EU and Japan, most regulatory agencies around the world such as HAS (Singapore), Health Canada (Canada), MFDS (Republic of Korea), NMPA (China), Swissmedic (Switzerland) have already implemented and highly recommend electronic submissions or eCTD format for most regulatory submissions.

Refer to the ICH M8 guideline on Electronic Common Technical Document (eCTD), for additional details on the eCTD and implementation status of the eCTD in major countries.

Organization of the Common Technical Document:

The general principle that is followed for any CTD document is that the information within the application must be unambiguous and transparent, in order to ensure efficient review of the data. Refer to the M4_R4 guideline (Source: https://database.ich.org/sites/default/files/M4_R4__Guideline.pdf) for more detailed formatting principles to be followed for the CTD document.

The Common Technical Document (CTD) dossier is organized into 5 Modules:

Module 1: Administrative Information and Prescribing Information

Module 1 contains documents specific to a region, example, application forms, and proposed label for use in the region. This Module is mostly specific for each region, and is thus, not harmonized as the other Modules.

Module 2: Common Technical Document Summaries

Module 2 typically consists of 7 sections as outlined below and contains summaries of Quality, Non-clinical and Clinical data that are provided in Module 3, Module 4, and Module 5 respectively.

• CTD Table of Contents
• CTD Introduction
• Quality Overall Summary
• Nonclinical Overview
• Clinical Overview
• Nonclinical Written and tabulated Summaries
• Clinical Summary

Module 3: Quality

Module 3 presents the chemistry, manufacturing, and controls reports for the product presented in the dossier. This Module gives complete detail of the manufacturing of the Active pharmaceutical ingredient or the drug substance and the drug product such as manufacturer details, product development, manufacturing steps, critical process parameters and in process controls as well as details related stability of the product, drug substance, raw materials and other excipients and analytical validation process as relevant to the product.

The main headings of this Module are as below:

3.1 Table of Contents for 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/ Safety

 Module 4 also known as the Safety Module, consists of all the study reports and assessments indicating safety of the product. The data in this module pertains to non-clinical or pre-clinical studies conducted for the drug product. This Module typically includes studies related to Pharmacology, Pharmacokinetics, Pharmacodynamics, Toxicology as relevant to the drug product.

The main sections of this Module are as below:

4.1 Table of Contents for 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/ Efficacy

Module 5, also known as the Efficacy module, indicates all the study reports and assessments that prove that the product shows efficacy for the target indication. This Module is the most extensive, the length of which depends on the number of clinical studies conducted (Phase 1, Phase 2, and Phase 3 study data). The data within this Module pertains to complete details of clinical study reports, cross-study analyses, post-marketing data, clinical pharmacology, biopharmaceutic studies, clinical efficacy, and clinical safety as relevant to the product.

Refer to the ICH CTD page, for additional details on the content and format of each Module outlined above.

 Today, as the CTD format is widely used and accepted, sponsors have been able to use one common format to submit their marketing applications to major markets across the world. Thus, as a company, if you are dealing with a pharmaceutical product or a biological product, you will most certainly use the CTD format for most of the applications.

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References:

• ICH M4 CTD page, https://www.ich.org/page/ctd
• Organization of the CTD document, https://database.ich.org/sites/default/files/M4_R4__Guideline.pdf
• The CTD Triangle, https://admin.ich.org/sites/default/files/2021-02/CTD_triangle_color_Proofread.pdf
• M4Q CTD on Quality, https://database.ich.org/sites/default/files/M4Q_R1_Guideline.pdf
• M4S CTD on Safety, https://database.ich.org/sites/default/files/M4S_R2_Guideline.pdf
• M4E CTD on Efficacy, https://database.ich.org/sites/default/files/M4E_R2__Guideline.pdf
• M8 eCTD, https://ich.org/page/ich-electronic-common-technical-document-ectd-v322-specification-and-related-files