he eCTD v4.0 standard has been available to be used for submissions to any ICH-participating regulatory agency since 2015, when it reached Step 4 in the International Council on Harmonisation (ICH) process. However, 10 years later, only Japan and the US have begun optional use of the new version.

The original electronic Common Technical Document (eCTD version 3.2) reached Step 4 and was approved for use 17 years ago (2008) by the ICH. Its impact on the speed and accuracy of regulatory submissions for the pharmaceutical industry has been significant, leading to simpler access for reviewers worldwide and to swifter approvals.

That same year, the US FDA started development at Health Level Seven (HL7) for a next-generation submission format, called Regulated Product Submissions (RPS), which ultimately became eCTD v4.0. (See Global Forum article “How Did We Get Here? A History of eCTD and Prospects for eCTD 4.0.”)

The delay in eCTD v4.0 implementation has likely impacted software and service vendors the most, as they have been investing in submission publishing and agency review systems, but the benefits of eCTD version 4.0 in flexibility, productivity, and communications are not being realized by the agencies and sponsor companies.

The Benefits of 4.0

There are several reasons why it has not been swiftly adopted, among them issues with development of review systems at FDA, higher priority initiatives at the European Medicines Agency (EMA) (such as implementation of the Identification of Medicinal Products (IDMP) standard, a set of five international standards developed by the International Organization for Standardization [ISO] to uniquely identify and describe medicinal products), and a perception that eCTD v4.0 doesn’t provide enough benefit to make the change worthwhile.

That last claim is a chicken-and-egg problem: We can’t see the biggest benefit of the new format until we’ve implemented it. One of the most notable potential benefits is the ability to modify the overall list of documents and files allowed in the submission—the table of contents (TOC)—without updating the main standard itself. Because of the difficulty of updating the current standard, the TOC for eCTDs has remained largely static, except for region-specific documents.

While version 3.2 of the eCTD format is based essentially on a structured, static version of the TOC for a submission, it has always been hampered by its inflexibility: The TOC can’t be updated or extended without a significant software change and lengthy regulatory agency and ICH approval processes. When it comes to innovative medicines and in crisis situations, matching the submission documentation to the eCTD TOC can be challenging (such as where to place documentation on combination device/drug products).

But eCTD v4.0 provides easier and faster ways to align the contents and the submission outline. The downside is that it would enable regulators in different countries to modify the harmonized standard outside of the “Regional” module 1, which could complicate submissions to different regions.

The version 4.0 format, to some degree, resembles the index at the back of a book. Rather than featuring the static and hierarchical TOC at the beginning, v4.0 indicates where a given subject should be found in the TOC, and how that content is stored (either in the current or a previous submission).

Apart from its utility for new drug applications, another general benefit of eCTD v4.0 lies in its use during the post-authorization life cycle—a benefit that only became apparent after several years of eCTD 3.2 use. Here eCTD v4.0 provides new opportunities by facilitating the reuse of documents across submissions and applications. This is particularly notable in Europe, where, for instance, its capability of identifying the countries for which individual documents are appropriate could simplify the handling of mutual recognition procedure (MRP) and decentralized procedure (DCP) variations, work-sharing procedures, and periodic safety update report (PSUR) single assessment procedures (PSUSA). Unfortunately, the full potential of eCTD v4.0 will require national agencies in Europe to have a common submission repository for this—a point that has long been debated but has never been fully budgeted. It is expected that by adopting eCTD v4.0, it may finally be possible to convince the national agencies to implement such a repository.

Recent Adoption of eCTD v4.0

Although adoption of the new standard has been slow, there was significant progress in 2024, with all three of the original International Conference on Harmonisation (ICH) members (EU, Japan, and US) taking steps toward full implementation:

• In December 2024, the EMA announced a three-step plan for its eCTD version 4.0 technical pilot phase, starting with an invitation to software vendors to provide mockup submissions in order to assess technical interoperability. Various vendors have compiled and submitted such pilot submissions during Q1 2025, and these are currently being evaluated by the agency. It is expected that the second step of the pilot will go ahead in Q2 2025, again mainly with the software vendors, but this time it is expected that the vendors collaborate with MAHs in the preparation of eCTD v4.0 submissions. This second part of the pilot should still focus on mock submissions of simple scenarios only; the document management lifecycle; handling of multiple file formats, pack sizes, and manufacturers; review of controlled vocabularies; updating keywords, priority numbers, and document titles; and document reuse.

  The third step, which will involve tool vendors, MAHs, and the EMA, will begin once step two has been completed and will be an expansion of step two activities. In preparation for the pilot phase, the EMA also issued a new draft version of the EU Implementation Guide v1.2 on October 4, 2024, which, among other changes, describes two scenarios for the use of eCTD v4.0 in European work-sharing and PSUSA procedures. Additionally, the agency made an updated version of EU eCTD v4.0 Controlled Vocabularies available on January 14, 2025. Further updates to both might be necessary depending on the outcome of the pilots. Mandatory use of eCTD v4.0 for European Centralised Procedure Applications is currently foreseen for 2027.

• Japan is currently accepting new submissions in the eCTD v4.0 format with a projected mandate to use it by 2026.
• FDA began accepting eCTD v4.0 on a voluntary basis as of September 16, 2024, with mandatory use projected for 2029. It will be very interesting to see how fast industry will adopt the new format during this transition phase.

Both the US and Japan are accepting new applications only in the version 4.0 format. This is less of an issue in Japan where the lifecycle rules require a new application for most supplements/variations, but it will certainly slow adoption, because sponsor companies will not be able to switch 100% to version 4.0 yet. The vast majority of eCTD submissions are made for lifecycle applications, not for new applications. However, limiting this to new applications could make the implementation process easier for the agencies (and perhaps for sponsors), because existing systems would not need to figure out how to link between version 3.2 and 4.0 documents. The EU plans to also include lifecycle submissions in the pilots and to test the forward-compatibility functionality that will allow version 3.2 documents from previous sequences to be referenced in the new version 4.0 submissions. It should also be noted that all agencies are yet to implement one of the key features: two-way communication. This would provide a means of delivering review comments, inquiries, and review status in the same format over electronic gateways from the agencies back to the sponsor.

Projected Adoption in 2025

According to ICH, Health Canada, Brazil’s ANVISA, and Australia’s TGA will all start eCTD v4.0 technical pilots in 2025 and SwissMedic in 2026. However, based on past performance—over the past several years, almost all ICH member agencies have repeatedly postponed their eCTD v4.0 implementation dates—it is doubtful that all of these will happen according to the currently published schedule: there has been no mention of eCTD v4.0 on the ANVISA website since 2022 or on Health Canada’s since 2019. SwissMedic has published a draft eCTD v4.0 implementation guide but has not updated it since late 2023. A technical pilot is planned for 2026. TGA in Australia is the most likely candidate, with a plan in place to invite participants to a technical pilot in the first half of 2025.

Challenges and Impact

Although processes to use the new format are nearly identical to those for eCTD v3.2, it could be argued that the lack of a mandate, and the need for a software upgrade to submission publishing vendors’ systems, reduce the value of implementing it swiftly. Such upgrades are needed to enable the additional eCTD v4.0 functionalities like one-to-many document replacements and to manage eCTD v4.0 specific features like keywords.

Most major software and service vendors should already be supporting the version 4.0 format, although details of each country’s implementations may require minor updates. While it depends on how each vendor implements the software, it could be possible for such updates to only require configuration file changes instead of significant software revisions—part of the goal of the eCTD v4.0/RPS standard (HL7 membership required for access).

Companies that are looking to change vendors for submissions and publishing systems or services should, however, look for strong support for eCTD v4.0. Companies using cloud-based systems will have a head start, as those systems may update automatically. The internal process changes that will be needed are minor, but companies should consider how to:

• Maintain identifiers for internal vocabularies such as study IDs, product names, etc.
• Determine how best to use the new lifecycle options for replacing one document with many, or many with one; for example, replacing a protocol and several amendments with an updated protocol.
• Integrate regulatory information between publishing (e.g., eCTDs) and registration tracking or, as in Europe, agency-hosted databases (SPOR) for administrative information, which should become easier with all parts of the system driving toward delivery of information built on HL7 standards.
• Enhance XML skills for debugging issues with eCTD v4.0 “backbone” files, because they will no longer have an easy-to-read hierarchical format.

One of the criticisms of eCTD v4.0 is that the format does not readily support “double-click” access: While version 3.2 documents could use an XML style sheet to directly display that submission’s table of contents, that is not practical to do with the version 4.0 format, as the hierarchy of documents is not represented in the “backbone.” However, this was never practical for other than casual review, as a single submission backbone cannot display updates to a dossier over time. Most agency and sponsor systems use the eCTD as a delivery message, essentially providing instructions on how to synchronize the dossier between both organizations.

Directions for 2025 and Beyond

2025 could be a tipping point where sponsors begin significant adoption of eCTD v4.0, and vendors push for software upgrades to support it. The full acceptance of the format by US FDA and Japan PMDA makes it a viable option, and most vendors support the format already.

It is definitely time for sponsor organizations to prepare for the US and Japan mandates and get the regulatory and IT infrastructure support in place.

Meanwhile, organizations such as DIA, the Regulatory Affairs Professionals Society (RAPS), and others should be pushing agencies to adopt eCTD v4.0 and the RPS standard for implementation of the standard across all health product registration formats. This may be hampered by the new US administration, though, as Republican leadership is less likely to create new regulatory mandates. However, it should be possible to amortize system and support costs across more agencies or agency divisions.

One very unlikely wish-list item would be that ICH begin a new project to update eCTD v4.0 (perhaps “v4.1”?) from the HL7 v3 standards to the newer HL7 FHIR specification.

Implementation of the two-way communications feature would, in the long term, improve communications of the review progress. That feature, unfortunately, would be the costliest part of the eCTD v4.0 system to implement to really gain the benefits. While version 3.2 submissions can use web-based portals so that smaller companies can submit without implementing their own gateways, two-way communication using version 4.0 really needs a gateway implemented at the sponsor in order to receive the messages containing reviewer updates and status changes. Agencies should be working on this, though, to provide sponsors with a longer-term plan for their systems. Cloud-based vendors should be able to mitigate this by serving as middlemen, processing the messages and forwarding email to appropriate staff at the sponsors indicating that an update needs to be retrieved, similar to how electronic health record systems notify patients of physician notes.

As for bigger visions for eCTD v4.0, historically, RPS was specified by the FDA and built by HL7 volunteers for wider purposes, but to date no FDA Center other than Drugs—such as medical devices or food—has announced support for RPS-formatted submissions. If eCTD v4.0 is fully embraced for pharmaceutical products, it is possible that regulators will consider extending the RPS standard to other uses. But that remains to be seen.

To learn more about this topic, plan to attend DIA’s Regulatory Submissions, Information, and Document Management Forum.