eCTD 4.0: The Next Step in Regulatory Submissions and Publishing

Regulatory submissions have evolved significantly, from paper-based processes to fully electronic formats. The electronic Common Technical Document (eCTD) has been the cornerstone of this evolution, enabling structured, standardised submissions across global health authorities, with the next major advancement, eCTD 4.0, upcoming.

The ICH M8 and HL7 RPS guidelines define eCTD 4.0, which is expected to bring significant changes to the way regulatory submissions are managed globally. Unlike earlier versions that relied on multiple XML files and rigid folder structures, eCTD 4.0 introduces a data-centric, granular approach to document management. It leverages structured XML metadata and controlled vocabularies for Context of Use and keywords, shifting the focus from static hierarchies to dynamic relationships between documents. This new architecture enables modular content blocks, allowing partial updates without resubmitting entire documents, significantly improving efficiency and flexibility.

eCTD 4.0 represents a step change in regulatory publishing: greater adaptability, enhanced lifecycle management, and harmonisation across regions. For regulatory professionals, mastering these changes is essential to remain compliant and competitive in an increasingly digital landscape.

What’s new in eCTD 4.0?

eCTD 4.0 introduces several key enhancements designed to improve efficiency and interoperability:

• Unique Document Identifiers. Each document in eCTD 4.0 will receive a unique identifier within the build’s metadata, enabling reuse across applications submitted to the same health authority. This should reduce duplication and potentially accelerate review timelines.
• Terminology Changes. With the introduction of eCTD 4.0, some key terminology has evolved. In eCTD 3.2.2, we commonly referred to a dossier and individual sequences for each submission build. Under eCTD 4.0, these terms will be replaced by the application and submission unit, respectively. Additionally, eCTD 4.0 introduces a new lifecycle status called “update,” which specifically handles metadata changes without requiring resubmission of physical files.
• Simplified Sequence Numbering. Initial sequence numbers start at 1 rather than the four-digit baseline 0000. Existing sequences from eCTD v3.2.2 (e.g., seq XXXX) will not be renumbered retroactively. Instead, when transitioning to eCTD 4.0, the next available sequence number will continue incrementally but in the new single-digit format.
• No More Study Tagging Files for FDA. This change aligns FDA requirements with other health authorities, promoting global harmonisation.
• Harmonised Submission Unit. Previous versions of eCTD have required various XML files for the presentation of content, whereas eCTD 4.0 provides a single XML exchange message including all content from Module 1 through to Module 5.

Key enhancements in eCTD 4.0

The upgrade to eCTD 4.0 addresses gaps identified during the implementation of eCTD 3.2.2 and introduces capabilities that support modern regulatory needs:

• Document Reuse. Under eCTD 4.0, it will be possible to submit a document once and reference it in future submissions to the same authority using its unique identifier, provided it remains valid with the authority.
• Document and Metadata Lifecycle Management. Instead of rigid folder hierarchies, eCTD 4.0 uses rich metadata to describe documents. Metadata includes details like document type, study ID, manufacturer, and regulatory intent, acting as “coordinates” for regulators, improving searchability and lifecycle traceability. eCTD also makes it possible to update previously submitted document information, for example, to fix a typo or to change an erroneous detail and replace documents in three new approaches: one to one, many to one, and one to many. The replacement function allows you to use a single function to make multiple updates or changes.
• Context of Use Group Management. Under eCTD 4.0, the system places group-related documents (e.g., clinical study report components) within a Context of Use and tags them with keywords to improve organisation and lifecycle control. Keywords replace many attributes from v3.2.2 and define how documents are grouped and displayed.
• Modular Content and Granularity. eCTD 4.0 presents data in smaller, reusable content blocks rather than in potentially large static documents, supporting modular content. Each module also has its own metadata, version history, and approval status. This enables precise updates without also resubmitting entire documents, streamlining lifecycle management.

Global timelines

Health authorities are moving forward with the implementation of eCTD 4.0, and while initially it will not be mandatory in all regions:

• EMA: Voluntary submissions are expected by the end of 2025; mandatory for CAPs by 2027.
• FDA: Voluntary now; mandatory by 2029.
• PMDA (Japan): Deadline for transfer is April 2026.
• Health Canada & Swissmedic: Pilots anticipated 2027–2029.

Conclusion

DLRC is proud to provide end-to-end support for global eCTD publishing and submission and will strive to support our clients’ transition to eCTD 4.0 with confidence and efficiency. Our experienced team brings over 75 years of combined expertise to manage the complexities of electronic submissions using advanced platforms such as Veeva Vault and DocuBridge 5.

To learn more about how DLRC can support you with your current and future regulatory submissions, contact us at hello@dlrcgroup.com.