Preparing for eCTD 4.0: What FDA Submitters Need to Know

Why Early Planning Matters for Regulatory Operations

While it's only been a handful of years since eCTD Version 3.2.2 became the standard submission format for all major components of US regulatory applications, changes are on the horizon for eCTD. In September 2024, FDA announced support for eCTD Version 4.0. While the Agency is currently accepting new regulatory applications in eCTD 4.0 on a voluntary basis and does not yet support forward compatibility for applications submitted in prior versions of the eCTD format, we’re only a few years away from eCTD 4.0 becoming the industry standard. Prior experience with eCTD transitions tells us that the runway ahead of us will pass quickly and eCTD 4.0 will be here before we know it. Now is the time to plan and strategize your organization’s transition and ProPharma has added expertise and resources to help prepare your operations for the implementation of eCTD 4.0.

What’s New in eCTD 4.0?

The eCTD 4.0 Technical Specification describes the enhancements and new functionality included in the 4.0 version release but here’s a quick rundown of the notable changes:

Greater Flexibility

Perhaps the most significant change to eCTD is the increased flexibility of Version 4.0. The us-regional.xml and DTD files have been replaced with a single eCTD submission file known as the Submission Unit. Each Submission Unit is comprised of one or multiple Contexts of Use which are flexible, user-defined components of the submission. Submissions are no longer constrained to the pre-defined regional table of contents, and this change will allow for faster updates to the specification as new document types are needed. Further, regional controlled vocabulary codes will allow for improved flexibility as schema data elements are all managed in external code sets. Changes or updates to the schema can now be implemented through updates to controlled vocabulary without requiring major revisions to eCTD publishing tools.

Improved Document Management Capabilities

eCTD 4.0 offers submitters expanded document management capabilities, specifically standardized document reuse. This feature was available in version 3.2.2 and used frequently in certain use cases such as ad/promo submissions. Changes to the eCTD 4.0 structure will allow for increased reuse of previously submitted regulatory documents along with improved visibility for Agency reviewers. Additionally, eCTD 4.0 adds the capability for one-to-many and many-to-one document linking and updating. Submitters can now upload a single document to multiple active contexts of use or upload multiple documents to a single active context of use, depending on the use case and business need.

Two-Way Communication

One of the more intriguing features of eCTD 4.0 is one that isn’t yet included in the US version of the technical specification. eCTD 4.0 allows for two-way communication between submitters and regulatory bodies. A January 2021 revision to the FDA technical specification notes that two-way communication was removed and has not yet been restored to the US-based implementation. Operations teams should continue to monitor changes to the eCTD 4.0 specification going forward. While the Agency has not signaled an implementation date for two-way communication, the potential implications represent a significant change for regulated Industry.

What Can Submitters Do Now to Prepare?

While eCTD 4.0 isn't scheduled to become mandatory for US FDA submitters until 2029 at the earliest, operations and submissions teams can and should use this time to prepare. These are some suggested steps to take today to prepare for a successful transition to eCTD 4.0.

• Familiarize your operations with the changes outlined in the published FDA technical specifications and implementation guides. Keep in mind that the specification can change and it is important to monitor updates as the mandatory implementation date approaches.

• Review and analyze your current publishing procedures. Use the runway ahead as an opportunity to ensure your operations can fully leverage the new functionalities and capabilities available in eCTD 4.0.

• Talk to your publishing vendor and learn how they intend to implement eCTD 4.0. Identify their development schedule and when they plan to support publishing for each component of your regulatory applications.

• Plan to submit test submissions to FDA. The process for submitting test submissions is published on FDA's website.

• Review lessons learned from prior eCTD transitions; identify best practices and resources that can be leveraged to ensure a successful transition to eCTD 4.0.

Your Trusted Regulatory Operations Partner

The transition to eCTD 4.0 represents more than a technical upgrade, it is a strategic inflection point for regulatory operations. Organizations that use this transition period to assess processes, modernize publishing workflows, and align internal teams will be best positioned to take full advantage of eCTD 4.0's flexibility and enhanced functionality.

ProPharma partners with regulatory and submission teams to navigate change with confidence. Our regulatory operations experts bring deep experience supporting prior eCTD transitions, FDA test submissions, and complex publishing environments across the product lifecycle. From readiness assessments and process optimization to vendor coordination and hands-on submission support, we help organizations prepare today for the regulatory standards of tomorrow.

As eCTD 4.0 adoption accelerates, early planning can reduce risk, minimize disruption, and create long-term operational efficiencies. With ProPharma as your partner, you can approach the transition strategically, ensuring your regulatory operations are not only compliant, but future-ready.