If you have been in the industry as long as some of us, (haha) then eCTD v. 4.0 has been coming for a long time. 😉 Some agency regions are already accepting and piloting v. 4.0. For many emerging and smaller pharma, you may be questioning "what’s in it for me"? Or, "doesn’t my CRO/vendor/software take care of it?!" However, there are some important things to know that can improve submission quality and review time.
A Quick History
It’s been 20 years since the eCTD XML format was adopted. Over the years industry has evolved to push the current eCTD XML standards to handle more types of submissions. Other formats have been discussed, such as RPS (Regulated Product Submission) created by HL7. RPS includes veterinary, device and tobacco products as well as human drugs/biologics. eCTD v. 4.0 is the natural next step from the current version 3.2.2. The XML in the current eCTD allows a directory structure, individual files and the XML backbone with a style sheet. The current version, 3.2.2, is a straightforward viewing and navigation solution with relationships by lifecycle operators for documents. The fact that so many countries and regions accept the 5-module structure is a major feat in and of itself.
ICH started developing eCTD v 4.0 in 2010. Implementation guides started surfacing in 2016. The ICH endorsed a full package of controlled vocabularies, schemas, transition plan and various other technical files in 2015. V.4.0 is based off the HL7 standards and RPS. We are now seeing agencies starting to accept v. 4.0 on a voluntary basis at US FDA and Japan PMDA.
The latest version, v. 4.0, extends the functionality of XML by making it more flexible in the ways to work with document reuse as well as updates to software for regulatory changes. The ability to change the DTD and not update any software is a huge advantage to both agencies and sponsors. The XML contains more data elements with controlled vocabulary (CV) based off standards, Content of Use (CoU) and other built in technical communications. Additionally, the eCTD package will contain one .xml file inclusive of regional M1 and M2-5 documentation. No longer will the M1 regional information contain its own .xml. From a technical perspective, a single dossier streamlines the submission process. By using more standards, the submissions are truly closer to harmonization across the globe.
|The intent of eCTD v.4.0 is to increase speed, flexibility and communications in regulatory submissions for and between agencies and sponsors.
How does eCTD 4.0 affect me?
As with the standards and requirement updates that came before, eCTD v.4.0 will be here soon. Implementation timelines are starting now. Mandatory dates are still a few years off, around 2028 for most agencies. At the very least, now is the time to educate yourself and your team on the terminology and basic concepts.
For executives and regulatory leaders, the business drivers are simple: better quality submissions with faster review times at the agency. eCTD 4.0 encompasses several technical components that lend itself to that objective. From internal sponsor teams creating and processing error-free, smaller submissions in less time than before through the re-use of content and flexibility to make changes easily to regulatory reviewers seeing a priority list of content; eCTD v. 4.0 can deliver results.
For executives, the key motivators include:
- Eliminating costly software upgrades due to simpler DTD updates.
- Reducing submission workload burden by reuse of content.
- Streamlining global submissions.
For regulatory affairs and operations, the new format means:
- Reducing regulator review time by grouping and prioritizing content.
- Minimizing rework due to inaccuracies or mistakes in file name.
- Faster submission creation for multi-region .
What are the full benefits of eCTD 4.0?
Through the concepts and functions enabled below, the updated version provides a platform to tailor submissions per sponsor while also conforming to multiple regional requirements at the same time.
- Submit in the same format across ICH regions.
- Change document granularity while maintaining lifecycle relationships.
- Set the order of documents within a CTD section and/or set a priority.
- Identify submission content for additional processing (e/g.datasets).
- Reuse documents submitted previously.
- Use of controlled vocabularies.
- Attributes and metadata can be corrected easily.
- Group documents within a CTD section in a consistent way across ICH regions.
- Software upgrades uncoupled from DTD updates.
What do I need to do differently for eCTD 4.0?
For most of the technical pieces, your regulatory publishing software or outsourcing vendor will do the heavy lifting. As an executive, regulatory leader or end user, monitoring the vendor via oversight activities ensures compliance. New or changed concepts essential to use your software or work with a partner comprise of new lifecycle operators, controlled vocabulary options, context of use and re-use of content.
Below we will cover a few critical new concepts at a high level.
Reuse of Content
Unique Identifiers (UUID) for each document allow reuse of content across sequences, regulatory activities and different applications. Sponsors may refer to previously submitted content and reduce the size of new sequences. Confusion over duplicate content is removed. Since the UUID is accepted globally, true harmonized submissions across agencies will become a reality.
One challenge for the sponsors to meet is tracking and tagging the original content submitted in the internal document management solution (EDMS). As the application progresses through its lifecycle, ensuring the “link” to the original document is maintained becomes critical. Best practice: utilize an EDMS to harness the power of the CTD lifecycle linked to specific content in a coherent manner for future use. One solution would be to incorporate the UUID within the EDMS in the metadata fields.
New lifecycle operators
Flexibility is key when it comes to the lifecycle operators. Sponsors control how to use the new operators in conjunction with Content of Use (CoU) and groups to update information for the reviewers. Here are the new operators:
- Active, Replace and Suspend (previously New, Replace, Delete)
- Replace one with one
- Replace one with many
- Replace many with one
- Lifecycle relationship is maintained on all Docs
The replace function will track the changes made to the submission contents when one document (referenced by a context of use) is replaced by one, many, or many to one.
FDA guidance provides this example below:
Context of Use
Context of Use (CoU) is similar to the leaf title. It determines placement of document in the CTD structure and associated keywords. Content of Use indicates the lifecycle of the document. Combining Content of Use groups, document type and keyword replace the STF by organizing multiple files relating to a single study in M4 and M5. Additionally, Context of Use allows the advanced lifecycle operations described above to replace one with many and many with one.
Controlled vocabularies (CVs) further describe and define content within the submission when combined with the content of use. Five types of CVs established are accepted for eCTD v4.0: ICH, HL7, Regional, sender defined and external organizations-ISO Country Codes.
Examples include ICH CV for species: mouse, and rat. US regional CV includes NDA, IND and ANDA. New CVs introduced for v.4.0 provide additional content or replace older values. Examples are Category Event, Document Type and Study Group Order.
Sponsors define (sender defined) keywords like the name of a manufacturer (fictional example: ABC CDMO) or the name of the drug. Since the keywords are included in the XML packages, all regions will receive the same message.
ICH describes in detail the use of both Content of Use and Keyword combinations to place and describe M3 Drug Substance content.
Below is an example CMC Amendment mapped to content of use, keywords and other required areas of the new structure based on the ICH implementation guidelines. A new contract manufacturer is being added; ABC CDMO. ABC CDMO manages the creation and distribution of the drug substance, DS.
By moving towards a more data driven approach, sorting and editing the information about the submission becomes a simplified easy process. V. 4.0 creates a path towards a more flexible submission structure for sponsors and streamlined review for agencies.
Corrections are much easier using keywords. Typos in attributes and keywords are easy fixes, where previously sponsors were required to submit a new document with the correct file name.
Order and Group Documents in a Section
Using priority numbering, regulatory leaders now control the order of documents in a section. Giving clear priority to content for reviewers expedites reading timelines and creates efficient responses to information. Even better, grouped documents and ordering within a study further organizes the M4 and M5 content for the reviewers. Order and Groups replace the STF .
Table of Contents
Gone are the days of the hierarchy. Documents and files are delivered in a flat structure. Within the file name Context of Use (CoU) and keywords place the content in the correct location and keywords provide additional detail to the content of use (CoU).
In the older versions a style sheet was included. Users could open the .xml file in a web browser and see/navigate a submission as a standalone sequence. With v. 4.0, this is no longer the case. An eCTD viewing tool will be required, either integrated within an EDMS or publishing solution or standalone.
What stays the same?
Documents: Sponsors will still be writing documents in the ICH granular format in WORD. Conversion to PDF format is still required. Authors continue to utilize the granular ICH CTD documents for each appropriate section of the five (5) modules.
EDMS, Regulatory Operations Publishing and RIM: Reliance on systems, especially EDMS, will continue and become more important to track documents submitted. Regulatory Publishing solutions need to adapt for the XML formats and support the various Controlled Vocabularies required inclusive of sponsor generated CVs. Currently many EDMS and publishing integrations include sharing of submission metadata. RIM solutions that may encompass both of these solutions in addition to various other function for tracking, preparing, and reporting on regulatory activities. Data standards and governance management is one the 14 capabilities of a RIM solution. By incorporating the CVs into the RIM and distributing the metadata across the cross-functional areas, consistency, adherence to the standards and submission excellence can be achieved. By integrating and incorporating the additional keywords, content of use and CVs to meet the demand of users in the market.
How do I prepare?
In our last article we previewed the implementation timelines of the ICH participating agencies. Japan PMDA and US FDA are accepting eCTD v. 4.0 on a voluntary basis. Participating during the voluntary time period is an option to learn with the agency. With the FDA, the process starts with a conversation with a project manager and determining a process. FDA will start accepting production eCTD v. 4.0 submissions in Q1 2024. It is never too early to start your team on the educational journey!
Key steps and areas to focus:
- Educate yourself and your team on the new metadata and concepts like context of use.
- Build, align and incorporate a sponsor keyword list to your systems now. Ex. Use EDMS metadata to drive compliance.
- Keep the new guidance in mind as a requirement when upgrades or new technology solutions are presented.
- Consider participating with a pilot during the voluntary time period.
Lastly, we- technology providers, regulatory agencies and sponsors- are all on the journey together towards eCTD v. 4.0. The more we can share each other's experiences and learn, the better the entire industry will be. Attend the conferences, watch the webinars, read the guidance, and we'll be on our way to harmonization!
- ICH eCTD v4.0 Implementation Package (also accessible at https://www.ich.org/page/ich-electronic-common-technical-document-ectd-v40)
- ICH M8 technical specification, eCTD v4.0 IWG Question and Answer and Specification Change Request Document.(https://ich.org/page/ich-electronic-common-technical-document-ectd-v40)
- FDA Electronic Common Technical Document (eCTD) v4.0 Technical Conformance Guide (https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-ectd-v40)