3 October 2024

eCTD 4.0 Explained: What It Is and How to Transition

In case your time is short

The electronic Common Technical Document (eCTD) standard has evolved many times over the past fifteen years and its current version, v3.2.2, will soon be supplemented with the introduction of the next major version – eCTD v4.0.

The FDA's CDER and CBER are accepting new regulatory applications in eCTD v4.0 format as of September 16, 2024. More information can be found on the agency's eCTD page.

Future implementation phases will address forward compatibility for existing v3.2.2 applications and two-way communication.

Key changes include:

  • Bi-directional communication: Currently, sponsors can only submit eCTD sequences to regulatory agencies. In a future phase, eCTD v4.0 will support two-way communication, allowing agencies to send documents like requests for information back to sponsors as eCTD sequences.
  • Document reuse: Regulatory professionals will find their work simplified through the ability to reuse documents across applications. With eCTD v4.0, each document is assigned a unique ID, allowing it to be referenced for future applications as long as it remains in the agency's system.
  • Controlled vocabularies: A critical component of eCTD v4.0, controlled vocabularies ensure clear and consistent communication between systems exchanging XML messages. These vocabularies will be managed by entities such as ICH, regional authorities like the FDA, and third-party organizations.
  • New XML schema: eCTD v4.0 introduces a new XML schema designed to enhance the system’s robustness, flexibility, and long-term stability.
  • Collaboration with Standards Development Organizations (SDOs): eCTD v4.0 was developed in collaboration with organizations like HL7 through the Regulated Product Submission (RPS) project. The final version will be published as an ISO standard. This closer alignment between eCTD dossiers and structured data, such as in the ISO IDMP standard, offers benefits like more efficient regulatory reviews, faster decision-making through finer data granularity, and a proactive approach to patient safety.

Jump to:

The latest version of the Electronic Common Technical Document (eCTD), known as eCTD v4.0, has been finalized and is now being implemented worldwide. This updated version brings significant advancements in the submission handling process for sponsors and regulatory bodies. All major regulatory authorities must adapt to these improvements by 2028, with earlier deadlines in many regions.

eCTD v4.0 is primarily a format change that will provide users with new capabilities. This guide briefly explores the evolution of the eCTD format, the upcoming changes in the next major version, and the objectives and focal points of eCTD v4.0.

Additionally, we will outline the benefits and challenges associated with transitioning from eCTD v3.2.2 to v4.0 from both technical and regulatory perspectives.

Brief Background: eCTD v3.2.2 to eCTD v4.0

In the 1980s, transferring regulatory information to health authorities involved a laborious process of printing and storing paper submissions. However, in 1997, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) formed the ICH M8 Expert Working Group/Implementation Working Group (EWG/IWG), which created the Common Technical Document (CTD) to standardize applications submitted to regulatory authorities.

This led to the adoption of the original eCTD by health authorities and sponsors in the U.S. and internationally in 2003. The current default version, eCTD v3.2.2, was established in 2008.

In November 2010, the ICH M8 EWG/IWG was reestablished to oversee the next eCTD update. The goal was to create a more robust, flexible, and longer-term messaging system between sponsors and regulatory agencies. After several versions were developed through collaboration and change requests, eCTD v4.0 was finalized in 2022.

Per the FDA Data Standards Catalog, the electronic submission of eCTD v4.0 to FDA's CBER and CDER is supported for new NDA, BLA, ANDA, IND, and MFs beginning September 16, 2024. As of now, only new applications may be submitted in v4.0, forward compatibility functionality is not yet available.

The FDA will provide advance notice of when the agency will begin supporting electronic submission only in eCTD v4.0. Please see the FR Notice, Data Standards Catalog, eCTD v4.0 Submission Standards for details.

What is eCTD Changing With v4.0?

eCTD v4.0 aims to make communication between sponsors and regulatory agencies more efficient and streamlined. However, this significant update, coming after twenty years, also presents a complex transition for stakeholders.

A New Submission Structure

In eCTD v3.2.2, submissions are web-based, consisting of multiple XML files. eCTD v4.0, on the other hand, adopts a data-driven format, reducing the need for frequent structural updates and software release cycles.

This new approach eliminates the traditional hierarchy of the table of contents and instead introduces a flat structure that uses keywords, Context of Use terminology, and sender-defined listings to organize and display submission units.

Data-Driven Submissions

With the introduction of Controlled Vocabularies and sender-defined keywords, sponsors gain more control over how they refer to and organize regulatory information. This makes the submission process more flexible and efficient, while also simplifying the review process for regulatory authorities.

Sequence Structure Organization

eCTD v4.0 replaces the previous "file-tags" with Document Types, which follow the same principles but allow for a more flexible organization of data under additional headings. Sponsors can create and manage sender-defined lists across all active submissions. These lists only need to be created once, although resubmissions are allowed if corrections, like fixing typos or adding terms, are needed. This creates a more dynamic keyword system that fosters better collaboration between sponsors and health authorities.

Flexibility and Harmonization

One of the key improvements in eCTD v4.0 is its flexibility, particularly in harmonizing submission processes across different regions. Documents no longer need to be replaced for every submission; instead, each document is assigned a unique number through Object Identifiers and Universally Unique Identifiers (UUIDs), making it easier to reference them in future submissions. New features, such as content grouping and prioritization, help to establish a less rigid submission structure compared to eCTD v3.2.2.

Future eCTD Features

Additional features are expected to roll out with future versions of eCTD v4.0:

  • Two-way communication: This will allow regulatory authorities to send information directly to sponsors, facilitating better communication between agencies and sponsors.
  • Grouped submissions: Depending on the region, sponsors will be able to submit multiple components within a single submission.
  • Forward compatibility: While eCTD v4.0 is currently used for new applications, forward compatibility will enable submissions from eCTD v3.2.2 to transition smoothly to the new standard. This will allow for document reuse and lifecycle management, ensuring a seamless review process.

The Benefits of the eCTD 4.0 Standard

To understand the advantages of the new eCTD 4.0 standard, it's important to recognize the limitations of version 3.2:

  • The structure only supports human pharmaceutical submissions.
  • Submission formats vary by region and regulatory authority.
  • Changes to metadata or the table of contents often require structural updates.

Given these limitations, eCTD 4.0 brings significant improvements:

  • The structure now supports all product types, including veterinary, tobacco, cosmetics, drugs, medical devices, food additives, and more.
  • A single format is used across all regions, agencies, and centers.It reduces the need for structural changes and frequent software updates.
  • Harmonized submission units—all content from Module 1 to Module 5 is included in one exchange message (an XML file covering ICH, regional, and study information).
  • Metadata, such as drug substance/product names, manufacturers, and group titles, can be easily corrected without resubmitting physical files.
  • Users can set document order and priority within a section over time.
  • Advanced lifecycle management allows one document to be replaced by multiple documents, or vice versa.
  • Document granularity can be adjusted while preserving lifecycle relationships.
  • Previously submitted documents can be reused by referencing their unique identifier (ID) across submissions, regulatory activities, and applications.
  • Controlled vocabularies (CVs) make it easier to update allowed values without system or tool updates.
  • Documents can be grouped consistently across ICH regions using a group title.

Additionally:

  • Version 3.2.2 content can still be reused.
  • Extra document metadata can be added as required by region for further processing.
  • Future capabilities may include two-way communication between applicants and regulatory agencies.

eCTD 4.0 overcomes the limitations of eCTD 3.x and transforms the regulatory submission process. However, successful implementation requires careful preparation to ensure a smooth transition.

How to Prepare for eCTD v4.0

It is crucial that sponsors give themselves plenty of time to prepare for the upcoming implementation.

Here's a high-level look at a ten-step strategy.

  1. Align current submission processes with eCTD v4.0 implementation packages. Ensure your workflows and procedures are updated to meet the new standards.
  2. Review metadata: Evaluate and update the metadata used in your submissions to ensure compatibility with eCTD v4.0 requirements.
  3. Agree on sender-defined keywords: Collaborate with your team to define and agree on the keywords that will be used to organize and reference documents effectively.
  4. Conduct a gap analysis: Assess your current processes, systems, and team readiness against eCTD v4.0 requirements to identify areas needing improvement.
  5. Ensure document management and publishing software compliance: Confirm that your software can produce technically compliant documents and validated e-submissions before your region’s mandatory date.
  6. Provide training for your team: Ensure that all relevant staff—including regulatory, IT, and submission teams—are trained on the new eCTD v4.0 processes, including new metadata, UUIDs, and document management practices.
  7. Establish a testing phase: Conduct test submissions to validate your document management and publishing software. This will allow you to identify and resolve technical or process issues early.
  8. Engage in discussions with vendors and IT groups: Plan accordingly by working with your publishing vendors and IT teams to develop a transition strategy.
  9. Monitor regulatory updates: Stay informed on any updates from regulatory authorities regarding timelines, technical requirements, and changes that might affect your submission strategy.
  10. Engage with industry groups and peers: Participate in webinars, forums, and other industry events to share best practices and learn from others who are also transitioning to eCTD v4.0.

For a listing of eCTD v4.0 Implementation Guides, Specifications, Validations, Technical Conformance Guide, and Supportive Files, refer to the FDA's eCTD Submission Standards for eCTD v4.0 and Regional M1.

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