eCTD 4.0: FDA Implementation Plans

The adoption of the Electronic Common Technical Document (eCTD) by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) marks a significant milestone in regulatory practices.

This innovative system not only provides a convenient and environmentally friendly alternative to traditional paper dossier submissions but also addresses the substantial costs associated with shipping expenses.

In this blog, Dan Flynn examines the transformative impact of eCTD on pharmaceutical regulatory processes.

The eCTD format is comprised of a regional Module 1 and the harmonized Modules 2-5, as demonstrated by the CTD triangle figure.

Version 3.2.2 of eCTD was introduced in July 2008. ⁽¹⁾

In 2015, the adoption of the eCTD submission format gained momentum, with the U.S. Food and Drug Administration (FDA) requiring its use for all new drug applications. Subsequently, in 2017 ⁽²⁾, the FDA made eCTD submissions mandatory for all new drug applications.

Figure 1: eCTD Structure ⁽³⁾

In recent years, the ICH has spearheaded the transition to a data-driven updated version of eCTD, known as eCTD 4.0.

This iteration brings significant enhancements to the eCTD submissions process.

While maintaining the core content structure of regional Module 1 and harmonized Modules 2-5, eCTD 4.0 implements technical modifications based on feedback from sponsors and regulatory authorities accumulated throughout the lifecycle of eCTD 3.2.2.

These improvements aim to streamline the review process, facilitate content reuse, enhance documentation management, enable easier metadata corrections, and markedly advance lifecycle management capabilities.

eCTD 3.2.2 vs eCTD 4.0 – Major Changes to Note ⁽⁴⁾⁽⁵⁾

XML

eCTD 3.2.2 utilizes multiple XML files, namely the regional XML, the index XML, and study XMLs. eCTD 4.0 aims to simplify this by incorporating a singular standardized XML file for use in any region.

Introducing Compatibility with Other Products

While eCTD 3.2.2 is restricted to pharmaceutical products for human use, eCTD 4.0 introduces structural changes, enabling a broader range of products to be accommodated. This includes pharmaceutical products for use in veterinary medicine, cosmetics, medical devices, food additives, and beyond. ⁽⁶⁾

Document Re-use

One major inconvenience of eCTD 3.2.2 was the repetitive use of the documents within an application’s lifecycle. eCTD 4.0 aims to address this issue by assigning a more efficient Universal Unique Identifier to each document. This allows for easier referencing in future sequences, eliminating the need for reference leaves and file path locations.

Content Management

In eCTD 3.2.2, replacing one document with another is limited to singular replacements, often leading to awkward submission-building scenarios.

As the need arises to replace one document with many or vice versa, it results in a progressively intricate naming and folder structure, which becomes cumbersome with each additional submission.

eCTD 4.0 eliminates this issue by enabling the replacement of one document with many. This feature could prove particularly valuable in scenarios where multiple concurrent versions of documents for different variations are under review simultaneously, allowing for their replacement with a single approved version in the end.

Table of Contents (TOC)

In contrast to the hierarchical structure based on definitions used in eCTD 3.2.2, eCTD 4.0 will introduce a ‘flat structure’ table of contents. This system will utilize the context of use and keywords to locate documentation within a submission. This shift promises to enhance navigation of the eCTD dossier.

Study Tagging Files (STF)

eCTD 4.0 will replace STF with document groups, fostering a harmonized standard across markets. This change will facilitate easier cloning of documentation across different regions.

Controlled Vocabulary

eCTD 4.0 aims to streamline communication between sponsors and regulatory authorities by introducing controlled vocabulary lists. The implementation, requiring action in publishing systems, will prevent unnecessary confusion stemming from inconsistent vocabulary use between involved parties. With clear definitions established, all contributors to the dossier submission will have a mutual understanding of the communicated information.

Implementation timeframe – USA FDA

The FDA has outlined the first phase of its eCTD 4.0 implementation. This is set to commence voluntarily in 2024 for new applications following the completion of a successful small-group technical pilot program with selected pharmaceutical companies.⁽⁷⁾

It will be interesting to observe how this major market handles this introduction, especially as it moves towards mandatory use of eCTD 4.0 in 2029. Additionally, it will be worth monitoring how other regulatory agencies leverage the FDA experience in their implementation plans.

Global Timelines

A summary of the current implementation plans available for some major global markets is outlined below.

Figure 2: Table of Planned Global Implementation Timelines for eCTD 4 ⁽⁸⁾

Conclusion

The transition to eCTD 4.0 marks a significant yet welcome adjustment for the industry.

With new technical features facilitating data-driven submissions, it promises a more streamlined process for submitting, amending, and reviewing submissions, reducing approval times.

This transition is further supported by efficient two-way communication with regulatory authorities, a development being embraced globally through pilot programs.

References

1. https://admin.ich.org/sites/default/files/inline-files/eCTD_Specification_v3_2_2_0.pdf
2. https://www.efpia.eu/media/636610/ectd-white-paper_final-20-dec-21.pdf
3. https://admin.ich.org/sites/default/files/2021-02/CTD_triangle_color_Proofread.pdf
4. eCTD 4.0: What is changing? (with Paul Ireland from DocShifter) https://www.linkedin.com/pulse/video-recording-ectd-40-what-changing-geert-van-peteghem/
5. eCTD 4.0: Key Changes & Impact on Submission Content Preparation https://www.linkedin.com/pulse/ectd-40-key-changes-impact-submission-content-geert-van-peteghem/
6. https://www.iqvia.com/-/media/iqvia/pdfs/library/white-papers/ectd-4-0-implementation-including-understanding-of-regional-differences-and-benefits.pdf
7. https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-ectd-v40
8. https://www.ich.org/page/ich-electronic-common-technical-document-ectd-v40