Opinion: eCTD 4.0 - Just Say No!

In 2002, the electronic common technical document (eCTD) standard changed the landscape of Global Health Authority Dossier submissions and created an opportunity to streamline and unify global dossiers.

The eCTD replaced paper dossiers with standardized PDF files in an XML structure and made preparation and submission consistent across sponsors and global health authorities.

The eCTD spawned a global community of software and operations organizations who collaborate and interact with health authorities to ensure accuracy of large pharmaceutical dossiers and enable digital exchange through electronic submissions gateways.

The eCTD was a major accomplishment and, by any measure, a radical success! While the eCTD indeed revolutionized dossier submissions, it is time for data submissions to take its place.

Twenty-two years on, there has been minimal change to the standard or the supporting technology. While a testament to the stability of the standard, that does not mean we should take a modest parallel step in the same direction. We should move to a future that utilizes big data analytics and modern system capabilities.

We should not create tomorrow’s solutions with yesterday’s technology or rebuild yesterday’s problems with today's tools.

Imagine if instead of the eCTD, a health authority had proposed more environmentally friendly, recycled cardboard covers for each printed volume of the New Drug Application. That's what eCTD 4.0 feels like. We need google maps, not paper maps that are easier to fold.

Further, anything less than revolutionary improvement to the current eCTD in 2024 may significantly delay the ability to move forward to any new platform or technology before 2029 - just about the time eCTD 4.0 would become mandatory according to several published timelines. By 2029, A 17-year-old update to a 27-year-old standard is not progress.

We will squander the opportunity, fortitude, financial and human resources, and the collective will to make changes presented by today’s possibilities and modern tools.

The eCTD, while stable, is outdated compared to the technological growth outside of the life sciences industry where modern solutions using strategic intelligence and data flow take full advantage of emerging technology advancements.

There are patients at the end of our workflow who need us to be much more efficient than we are - and much more efficient than eCTD 4.0 would allow.

“Our Age of anxiety is, in great part, the result of trying to do today’s jobs with yesterday’s tools!”?- Marshall McLuhan

The proposed eCTD 4.0 Standard will force the creation of new software, new documentation, and new processes at every organization. This will cost millions of dollars in change management, software upgrades, validation, and implementation service fees doled out by every pharma company globally - not to mention the amount of time to implement these changes. The result is exponential expenditure for infinitesimal incremental benefit.

In the twenty-two years since the eCTD came about, cloud computing, database technology, data compression, data visualization, system capacity, artificial intelligence, large language models, and computing power have exponentially increased. The eCTD is still just a set of PDF files (ePaper) wrapped in XML.

The proposed eCTD 4.0 implementation adds only minor increased value for a gigantic cost of implementation, software development, and process change – for every sponsor, health authority, and software developer.

It is a trap - a technological debt trap we will not escape.

In order to justify a change of this magnitude, sponsors, health authorities, and software vendors should instead gather these precious and finite resources to define a more appropriate and technology-driven approach to a new standard (maybe FHIR?) which will maximize the latest technology and position the industry for the next 20 years, not set us back another ten.

Our industry is a graveyard of stalled efforts and unrealized great ideas. eCTD 4.0 has been in the conversation since 2012. It is our obligation to do better with the collective knowledge of our industry's Regulatory Operations experts.

We cannot afford to delay utilization of emerging technologies which will advance the review and approval of large global dossiers and get treatments to patients faster. IDMP, for example, presents an opportunity to create a foundation of data driven submissions, assessment, and re-use but has been slow to develop.

I hope this mission statement starts a larger conversation where we - sponsors, vendors, and health authorities - can agree and decide on a data driven future and make true progress instead of an expensive minor improvement on a stable, standard.

If you made it this far, thank you for reading - please see below for a deeper dive and discussion questions.

I wish to acknowledge the tremendous efforts to get to this point. Creating implementation guides, conducting pilots, and building functional beta software – not to mention the eCTD itself -are no small effort. Let's learn from it and propel ourselves forward.

While sunk cost is a factor, we are compelled to have a productive and ongoing dialogue about the future. Let's not miss an opportunity to do this right before we are entrenched in creating and implementing unnecessary "new" technology.

Deeper Dive: Debunking recent publications and presentations touting the benefits of eCTD 4.0.

From the EU Implementation Guide:

The new version of the eCTD implementation based on the HL7 RPS Standard will offer:

• Options to accommodate regulatory changes without delay and major technical changes as content related changes can be achieved by updates of controlled vocabularies or modification of keywords. Author's Note: How often does this occur and is it enough, and or not possible, to do this with existing eCTD Specification?
• Applicability of the same technology for all types of regulated products. Author's Note: While this is compelling, a minor DTD change could potentially accommodate the needs of devices and other regulated products. Also, these use cases might be in the most advantageous position to leapfrog technology.
• Use of controlled vocabularies to a wide extent. Author's Note: Compelling, but is it worth the cost instead of waiting to implement this on a much more advanced platform?
• Use of keywords for organising content. Author's Note: Couldn't this be achieved with a viewer by parsing the existing eCTD Metadata and creating a different view?
• Improvement of life cycle operations by simplification due to execution on the contextOfUse element only. Author's Note: The current lifecycle operations are adequate and not overly burdensome.
• Flexibility of dossier granularity and grouping of documents. Author's Note: Couldn't this be achieved with a viewer by parsing the existing eCTD metadata and creating a different view?
• Referencing documents across applications. Author's Note: This is already possible in the current paradigm if the health authorities would give us the mapping to our various applications. At the worst, it's a reference link - again, is the juice worth the squeeze for this ability?
• Re-use of documents. Author's Note: If you have good document management processes, this should be easy to do either by reference or simply re-adding the document to the new sequence/application. Also, document re-use is only useful if you are using documents instead of data - let's move to data. In addition, document re-use would require other significant changes in health authority infrastructure and does not benefit sponsor process as documents are updated per submission to enable one-stop-shop review and archival to avoid confusion and version issues; This has been an option for many years without significant uptake or benefit over current practice.

From a recent ICH Industry presentation which stated the benefits of 4.0:

With eCTD v4.0, you can...

• Reuse documents submitted previously Author's Note: Or you could just refer to it with a hyperlink as is the current practice. See previous comment.
• Correct information (e.g., display name or document title) easily Author's Note: This can already be done with a new sequence and replace the element.
• Group documents within a CTD section in a consistent way across ICH regions. Author's Note: Couldn't this be achieved with a viewer by parsing the existing eCTD metadata and creating a different view?
• Change document granularity while maintaining life cycle relationships. Authors Note: This can already be done with a new sequence and replace the element.
• Set the order of documents within a CTD section. Author's Note: Couldn't this be achieved with a viewer by parsing the existing eCTD Metadata and creating a different view?
• Identify submission content (e.g., datasets) for additional processing, and Life cycle and reuse of v3.2.2 content. Author's Note: Couldn't this be achieved with a viewer by parsing the existing eCTD Metadata and creating a different view?

Discussion Questions:

Am I missing something? Am I way off base? Is the eCTD 4.0 standard a necessary stepping stone to data submissions or can we leapfrog it?

Were any of the stated benefits of eCTD 4.0 on the radar as key issues of the current eCTD? Is eCTD 4.0 a pain killer or a vitamin?

Opportunity Cost - Software vendors have no choice - they must stay in compliance. Development for eCTD 4.0 will dictate their investments for the foreseeable future while becoming a source of revenue for implementation and upgrades. Do we want them to spend their resources developing 4.0 when current eCTD tools are stable? Do we want eCTD 4.0 development to slow the pace and supersede features and functionality of our current tools?

Could a minor DTD update be a bridge to the future instead of eCTD 4.0? Would IDMP be a better start?

Do we need two-way communication (which was de-scoped in the pilot and will not be implemented in 4.0) or can we live with email and other portal solutions until the modern data submission of the future is in place?

Is the need for eCTD 4.0 for all other types of regulated products - which currently have no solution - a driver which supersedes the change management needed for existing eCTD in pharma?

Disclaimer: This article is the opinion of the author and does not reflect those of their organizations, system vendors, or service providers. However, it is the culmination of numerous informal discussions with trusted and brilliant industry colleagues.

Photo Credit: https://smoeschen.substack.com/p/not-a-memo-a-mission-statement

Useful Links:

ML7 FHIR: https://www.hl7.org/fhir/overview.html

https://www.intelinotion.com/home.html

https://www.dnanexus.com/precision-health-data-platform

https://precision.fda.gov/challenges/consistency

https://www.calyx.ai/journal/ectd-4-0-update-and-timeline/

Knowledge-aided Assessment & Structured Application (KASA): https://www.fda.gov/media/162865/download

Accumulous Synergy: https://www.accumulus.org/why-it-matters/

Upcoming Webinar on the topic: https://astrixinc.com/news/astrix-webinar-data-driven-content-fhir-and-the-future-of-regulatory-submissions/