Developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the Electronic Common Technical Document (eCTD) is a standardised regulatory submission method. This electronic version of the original Common Technical Document – most commonly known as an eCTD – significantly streamlines the submission process with expedited regulatory life cycles and the elimination of the burden of storing paper files. The eCTD specifications define multiple requirements for the packaging and creation of submissions using XML files and lead to expedited regulatory life cycles as well as a reduction in the burden of storing paper files.

Currently, eCTD version 3.2 is the standardised submission format for applications, amendments, supplements and other regulatory documents for many global health authorities, such as the FDA (US), EMA (EU), PMDA (Japan), Health Canada (Canada) and other regions. However, 20 years after the finalisation of v3.0, the latest version, v4.0, is now implementation-ready for most regions. eCTD 4.0 will soon be the standard format, replacing v3.2, and the implementation dates for the standard vary by region. All regions that have published guidelines will mandate implementation of eCTD version 4.0 by 2028, with more regions to follow in the future.

eCTD 4.0 is highly anticipated by regulatory teams and has been in development since 2015, and the update promises to improve flexibility, robustness and stability in the long term for the regulatory submission process, increasing all-around efficiency and simplicity. As the last eCTD update and shift was over a decade ago, organisations need to prepare for the changes and requirements that will accompany eCTD v4.0. Shifting from the familiar, currently used processes to the new implementation will require some education and training. Prior to discussing implementation best practices, it is key to review the differences between eCTD 3.x and 4.0 and why this update is beneficial.

The current v3.x structure caters mainly to human pharmaceutical submissions, and it differs across the various regions and authorities. This creates unnecessary and tedious difficulties in the regulatory submission process. The new update promises to fill a majority of the current gaps, such as the ones mentioned above, seen in version 3.x.

eCTD 4.0 brings a singular format for all regions, health authorities and regulatory bodies, and it will cater to a variety of products, like medical devices, cosmetics, food additives, drugs, tobacco and veterinary products.

‘eCTD 4.0 will cater to a variety of products, like medical devices, cosmetics, food additives, drugs, tobacco and veterinary products’

This simplifies the submission formats and provides a consistent structure across submissions. This includes the reduction of structural changes as well as software releases and update cycles. With eCTD 4.0, documents can be reused without knowledge of the file path across or within an application or sequence. Rather, these documents are assigned a unique identifier (ID) across regulatory activities and applications for easy reference. Multiple documents can also be replaced with a singular document, or vice versa. The new format allows for display name, keyword or metadata definitions and structures to be easily corrected without the need to resubmit the files. One of the most beneficial aspects of eCTD 4.0 is the potential for a two-way communication mechanism between applicants and regulators. The two parties can communicate and exchange information with one another via eCTD 4.0 throughout the entire application review process, which is a much-welcomed update.

For regulators and sponsors, administrative processes are automated through data-driven structure and the use of control vocabularies (CVs). The use of CVs also streamlines new regulatory or legal modifications and requirements for the dossier structure. The overall workload and maintenance effort throughout the submission process are greatly reduced.

Eventually, eCTD 4.0 will become mandatory for all regions, and the timeline for the regions currently providing eCTD 4.0 implementation guides ranges from 2025 to 2028 based on region (though more regions will be adopting eCTD 4.0 in the future).

Japan and Europe are the first to mandate the use in 2026, although in Europe it will be required for centrally authorised products (CAPs) and nationally authorised products (NAP), while the obligatory date for mutually recognised products (MRPs) and decentralised procedures (DCPs) is still being determined. The United States and Switzerland are the next to require the use of eCTD 4.0 in 2028, while Australia and Brazil have yet to determine their respective mandatory dates. eCTD 4.0 will become more widespread throughout the global health authorities, but these mandatory implementation dates are for the health authorities that have already published guidelines. As more agencies develop guidelines, there will be additional information as to when the wider, global mandate of eCTD 4.0 will occur.

Though some global health authorities have set mandatory dates for eCTD 4.0 use, most regions have begun or planned for voluntary implementation. This will occur between 2023 and 2024 for the majority of health authorities, and most, excluding Brazil and Australia, have published regional implementation guidelines. This voluntary period will provide pharmaceutical companies with an opportunity to begin using the format without the pressure of obligatory use.

Some regions have also conducted or plan to conduct technical pilot tests, submitting test/sample submissions to determine if the process is satisfactory in the technical specification. These tests can inform any changes that need to be made prior to the acceptance of eCTD 4.0 in a production environment. As of now, only Japan has completed the technical pilot. The US technical pilot is currently in progress, and Canada, Switzerland, Brazil and Europe have planned technical pilots for later in 2023 and into 2024.

eCTD v4.0 has small variations within different regions. These differences focus on things like the M1 submission structure, M2-M5 further context of use, characters and language support, study standards, group/work-sharing submissions, group titles and forward compatibility. For example, variances in metadata and CV are also present regionally:

• CVs for application, submission and submission unit type CVs are relevant for the US, the EU and Japan
• CVs for product categories and substances CVs are relevant for Japan and the EU, but not for the US
• CV for category event submission type is relevant for Japan, and not for the US or the EU
• CVs for submission language, mode and territorial authority are relevant for the EU, but not the US or Japan.

Though eCTD 4.0 is a singular format that extends across regional health agencies, the transition from the current version to v4.0 is not entirely universal. In the US, submissions can be transitioned from the current eCTD 3.2.2 without a required transition sequence, similar to Europe, where regional submissions can transfer from eCTD 3.2.2 to v4.0.

‘The changes that eCTD 4.0 brings will meet the critical needs of the regulatory operations process, but to get to the point of use, a careful review of all guidelines and requirements is required’

Japan is an outlier, as there is no supported transition from JP 1.0 to v4.0, and the eCTD version number is maintained from initial submission through the entire life cycle to final approval. With more regions planning implementation or preparing for the release of guidelines, the necessary transitions will be reflected in the regional guidelines.

Technology, people, process and plan are essential for successful implementation. This includes preparing all PDFs as v4.0 submission-ready and training internal teams for a seamless shift.

All processes need to be carefully carried over to the new standard; the first step to implementation is to review all necessary implementation guidelines in detail. These are published so that organisations can be best equipped for the changes. It is especially important for teams to be familiar with all eCTD 4.0-related information, including any new concepts and terminology, in the same way they have grown familiar with eCTD3.x for over a decade. Training and education on all new processes are critical, especially as the coming years will be full of change for the industry. Adjusting to the latest version will take time and effort.

eCTD 3.x will need to have continued support until v4.0 is made universally mandatory, as some regions will still be utilising v3.x until 2028. Though the implementation of eCTD 4.0 is here, it will not be implemented in all regions, especially as regions without implementation guides will continue to utilise v3.x for the foreseeable future. Without support for the current standard, there will not be a solid foundation to build upon, and organisations might fall behind on relevant regulatory processes.

Expressing to teams the importance of familiarity with both versions is necessary to ensure all are on the same page. The changes that eCTD 4.0 brings will meet the critical needs of the regulatory operations process, but to get to the point of use, a careful review of all guidelines and requirements is required.