Part 2: Concepts, Terminologies, and Structured Data Reliance

Previously we reviewed the people and process considerations during an eCTD 4.0 implementation. Here we review the impacts of new concepts, terminologies, and the increased reliance on structured data.

Socialize new concepts and terminologies

While continuing to maintain eCTD 3.2.2 submissions the transition to eCTD 4.0 will require significant investment in end-user education; socializing the new eCTD 4.0 terminologies and concepts will be an important step. Ensuring an understanding of the new context of use (CoU) concept and how these will equate to the eCTD headings and be used in conjunction with both required and optional agency and sender defined keywords, along with the requirement to use priority numbers to assign order within a CoU will be fundamental to the successful implementation.

Users will also need to adjust their understanding of life cycle which will be managed at the CoU level rather than at the document level. The new lifecycle statuses, where ‘New’ is replaced by ‘Active’ and ‘Delete’ is replaced by ‘Suspend,’ will need to be communicated with clear lifecycle examples provided. Additionally, the impact of removing the append lifecycle status and the additional flexibility for replacing documents (one document with many or many replaced by one) will need to be incorporated into updated business processes, again clear lifecycle examples showing before and after will be especially important during the transition phase.

Although likely less impactful, the new sequence code numbering, moving to a new numbering format ranging from 1 and 999999, should be understood well ahead of time.

Controlled Vocabularies

Along with many other ongoing initiatives including IDMP, DADI in the EU, and PQ CMC in the US, the reliance on structured data increases hugely with the introduction of eCTD 4.0. The increasing number of controlled vocabularies and sender-defined keywords will facilitate the review by agencies and ultimately result in a faster review cycle and an accelerated timeline for drugs to market. However, there is no single source for the controlled vocabularies; these will be defined by multiple sources including the International Council for Harmonisation (ICH), National Competent Authorities (NCA), and the Regulated Product Submission (RPS) Health Level Seven (HL7) standard. ICH will define many of the controlled vocabularies required for Modules 2 to 4 but for Module 1 these will be defined by the NCAs, additionally, eCTD 4.0 will also require MAHs to create and maintain sender-defined keywords.

Multiple Controlled Vocabularies will be introduced, and these will need to be accessible to publishing systems. For Modules 2 -4 ICH have defined 143 CoU headings, each having its own specific code for inclusion in the XML. For many of the CoU headings, keywords will need to be associated; some mandatory, some optional, some defined by ICH, and others defined by sender. In the EU SPOR Referentials will be the source for the Controlled Vocabularies and there will clearly be an overlap with IDMP.

In the table below we can see that for the repeat dose toxicity CoU, the study id_study title, document type, species and route of admin are required whereas the duration, study group order & group title are optional. Different scenarios will mandate the use of the optional values, for example where there is more than one grouping within a CoU study group order and group title will be required.

eCTD 4.0 Graph 1
Source: ICH_eCTDv4_0_CV_v4

The table below references the ICH keyword sets and the number of values contained within each e.g., Document Type contains 73 values. Each Code Set has their own set of rules; for some there are very specific uses; Route of Admin is only required for Toxicity Studies; the Study Group Order Type should only be used in conjunction with the study id/ Study Title keyword.

eCTD 4.0 Graph 2

Sender Defined Keywords

The ICH and NCAs also mandate the use of Sender defined keywords, many of those required for Modules 2 & 3 will already be defined in RIM systems e.g. Substances & Excipients, Manufacturers, Dosage Forms & Indications. To avoid duplication of effort & data misalignments it is vital that these values are obtained from a single source. Industry will need to agree on the naming conventions and define processes for ensuring that any new values or modifications are well controlled.

NCAs will define controlled values for Module 1; the FDA have defined 120 context of use values and in addition each country / region will have specific requirements.

Maintaining CVs will incur additional data administrator resources which will impact RIM teams. The increased use of structured data will require more disciplined ways of working when authoring documents, focusing less on the narrative and more on the structure incurring additional QC requirements to ensure the correct CVs have been assigned and associated.

3-point plan

  • Socialize new concepts & terminologies
  • Review ICH and NCA Controlled Vocabularies
  • Consider naming conventions and maintenance of Sender Defined keywords

Part 1: People and Processes

The timelines for the implementation of eCTD 4.0 in the major markets are approaching. Although initially the use of the new standard will be optional it is becoming increasingly important to start preparations for what will be a significant change for Regulatory Affairs and in particular, those who publish, plan, author and review the submissions.

This series will examine some of the major considerations that will need to be addressed during an eCTD 4.0 implementation, beginning with the impact to people and business processes.

People Impacts

A successful implementation is not just reliant on the technology; one of the most important considerations is to understand and communicate the impacts on the end users. In any major change management program, buy-in from the people who will be directly affected is vital. Making the time to address the most basic questions should not be overlooked; given the opportunity to discuss these questions often highlights changes in business process that may not have been fully realized.

Identifying each role and providing regular oversight of the ‘What, Why, When and How’ will help to establish positive end user engagement. Encouraging ownership of the changes by identifying lead users to support the messaging and to coordinate questions, concerns, and feedback will start to build trust and confidence.


“In any major change management program, buy-in from the people who will be directly affected is vital.”

– Karen Harry, Director Regulatory Information Management, Calyx

Business Processes

The management of processes across submission planning, authoring, publishing, and archiving requires a significant number of documents, varying from high level policies & SOPs to detailed step by step work instructions to be maintained.

eCTD 4.0 will require updates to existing processes and in preparation identifying documents that need to be updated by conducting a review of in-scope SOPs, Work Instructions and Quick Reference Guides will provide a starting point to help recognize potential gaps and the amount of work that will be needed to be eCTD 4.0-ready.

Because there will be a need to support both eCTD 3.2.2 and eCTD 4.0, both sets of documents will need to be available. Specifically for eCTD 4.0, thought should be given to new business processes with respect to the management and maintenance of structured data, impacts to the authoring processes, and additional requirements for reviewers.

Having made these assessments, a plan can be developed; identifying authors, reviewers, and the timelines for the updates. Coordinating the upload of the new processes in Learning Management Systems and identifying the impacted roles will also need to be considered to ensure that all end users have completed the training within the required timeframe.

The need to complete additional training and to update documentation will require time away from daily activities which may result in additional time pressures for end users, so it is important to factor these into the overall implementation plan.

User Awareness

Identify the audiences, the relevant content, and the cadence for awareness sessions in advance, make sure that attendance at the sessions is prioritized. Engage the lead user network to encourage attendance and to raise questions and topics to discuss in advance.

Among many other areas, understanding the practicalities of the hand-off content and the associated controlled vocabularies will need to be addressed along with any update to the reviewing process and impacts on submission planning timelines.

For companies that outsource publishing activities, communication will be crucial to ensure that the third-party companies are working with their teams to raise awareness of the forth coming changes and for the vendors to have a full understanding of the strategic plan for the company’s implementation of eCTD 4.0.

Don’t miss Part 2 of the series which focuses on socialising the new concepts, terminologies and the increased dependence on structured data.

2021 brought with it many healthcare advances – the most monumental being the availability of numerous COVID vaccines to bring an end to the global pandemic. The year also brought many other advances, and opportunities for life science professionals to stay up to date on the research, technologies, and processes that are driving change in how new medical treatments are developed and ultimately approved for worldwide use.

So here, in case you missed them, are the ten most downloaded articles, white papers, webinars and more produced by Calyx scientific, technical, and regulatory experts last year. Each provides direction and perspective on optimizing and accelerating the clinical development and approval of medical treatments. We hope you find them as insightful and valuable to you now as they were the first time around.

Behind the Breakthrough

When breakthrough therapy designation is granted, the challenges of clinical trial imaging increase. This white paper presents an insider’s view of what happens when the stakes, scrutiny, and demands of clinical trial imaging are sky-high, to help you get medical imaging done right in your accelerated trial.

While Direct-to-Patient (DtP)shipping offers potential advantages in improving clinical trial patient engagement, this approach is not as simple as it sounds. This article from International Clinical Trials outlines the pros, cons, and factors to consider when designing decentralized or hybrid clinical trials that include a DtP approach.

Focusing on the use of PET and addressing key problem areas in response assessment seen frequently in clinical trial settings, this virtual panel of IMWG 2016 authors and imaging experts answered questions about optimizing imaging-related assessments in multiple myeloma trials and shared their expertise in imaging as well as the clinical parameters in myeloma response assessment for running successful myeloma trials.

Listen in and learn how clinical trial management systems can adapt to support positive industry changes, including advances in user interfaces, integrations, and the ability to use CTMS as a data hub to better surface clinical trial risks.

Calyx’s Craig Mooney reflects on recent changes in the regulatory landscape that emphasize the investigative site’s ownership of IRT data collected during clinical trials, and considerations for making progress toward this goal.

Regulatory publishing is the backbone of any pharmaceutical, biotech, or medical device business. Do you know what needs to be considered as you bring publishing activities in-house? This guide outlines everything you need to know.

What biomarker to target? Is Blinded Independent Central Review necessary? Should we ‘Collect & Hold’? In this live panel, Calyx medical imaging experts answered questions about how to succeed in early phase oncology.

You won’t want to miss this episode of the Calyx Cafe where our host explains how AI can benefit randomization and trial supply management processes. You’ll never believe who’s asking the questions!

Learn how to prevent data variability and potential clinical trial delays by normalizing local labs data with advanced EDC systems.

Understand the various factors that drive drug wastage in clinical trials and the different IRT approaches that can be used to reduce each in this ultimate guide.

Clinical trial management system delivers heightened data security, open connectivity, and improved trial efficiencies

Nottingham, England and Morrisville, NC – December 14, 2021 Calyx, the eClinical and Regulatory solutions and services provider most relied on for solving complex data challenges in clinical research, today announced an extended partnership with one of the world’s Top 5 clinical research organizations (CRO). The arrangement enables the leading CRO to continue providing Calyx’s proven clinical trial management system (CTMS) and services to its global biopharmaceutical customers for an additional three years.

Calyx CTMS delivers robust features that simplify the oversight of clinical trial operations, improve data quality, and reduce trial timelines and cost. The leading CRO selected Calyx CTMS based on its use of Microsoft’s Azure cloud technology, which improves clinical trial efficiencies while addressing the significant privacy, security, and compliance challenges that face the pharmaceutical industry today.

“Calyx is committed to delivering high integrity services and enabling our customers to leverage open, interoperable, and flexible connectivity that best fits their business needs,” said Serena Barker, Vice President of eClinical at Calyx. “We’re delighted to extend our partnership with this leading organization and to continue delivering the central CTMS solution and services its many diverse customers are leveraging to achieve more efficient, successful clinical trials and bring treatments to patients faster.”

Calyx CTMS is underpinning the entire development process for this CRO, enabling its 8,000+ users to boost productivity through the system’s 60+ integrations, centralize operational data for informed decision making, and improve the management of today’s clinical trials with tools that address the complexities of traditional and decentralized trials.


Click here for more information on Calyx CTMS.

About Calyx

Through innovative eClinical and Regulatory solutions and services, Calyx turns the uncertain into the reliable, helping bring new medical treatments to market reliably. With deep expertise in clinical development and more than 25 years supporting trial sponsors and clinical research organizations, Calyx harnesses its intelligence and experience to solve complex problems, deliver fast insights, and get new drugs to market every day.

Medical Imaging | IRT | CTMS | EDC | RIM

Take your trials further with intelligent insights at or at LinkedIn, Twitter, or Facebook.


Christine Tobin | [email protected] | +1 412-628-8598

Regulatory Professional readers who recognise the following image can surely appreciate just how far we have come in the last 25 years.

Let’s recall the dark old days when major marketing applications for local affiliates arrived from head office ready-printed, on paper, literally on the back of a truck.

From my own experience, working in the Australian subsidiary of one of the largest global pharma companies, adjustments to meet local requirements would inevitably need to be made. This meant a large (or very large) repagination effort of the dossier, using the above torture device.

Eventually, all was well, all was complete, and the submission was sent off to the Therapeutic Goods Administration. On another truck.

Figure 1: A numbering machine

Presently, we remain heavily reliant on documentation to communicate and exchange information around drug development. Slowly but surely, however, we are moving inextricably away from documents and towards data.


The volume and complexity of submissions are increasing exponentially. For example – there are a couple of orders of magnitude differences in the number of data points in XEVMPD and the complete ISO IDMP schema.

With the preparation for IDMP, a lot of effort over the last several years has involved finding the source of truth for a great many additional pieces of information required in this new standard.

Each company has had to identify which of their internal departments owns the information, and the format in which that information currently resides. Often, the information needed sits in a dusty warehouse, in an archive. On paper.

Varying proportions of manual work and technology, including optical character recognition and artificial intelligence (e.g., natural language processing, machine learning) have been deployed, with varying degrees of success, to extract structured data from the unstructured data in documents.

Structured content authoring, where existing data is used to create the still-required documents of today, might perhaps be viewed in the future as a ‘holding technology’ which eases current outdated document shuffling, not unlike my digital photocopier of twenty years ago.


“Ongoing initiatives to transform regulatory data exchange will drive improved efficiencies and transparency while reducing costs and review times, bringing new medicines to patients sooner.”

– Sandra Vignes, Technical Solutions Director, Calyx

Certainly, because documents remain important today, it makes sense to invest in the best DMS to meet your needs, knowing that it will become less important in regulatory affairs as time moves on.

The drive from documents to data is unrelenting. We are likely to see the end of the dossier in the coming years.

Projects are already underway to transform the way regulatory data is exchanged, to bring indirect data interchange via the cloud, between marketing authorization holders and regulatory agencies. This will drive efficiencies and cost savings, better transparency, and reduced review times, bringing new medicines to patients sooner.

As has been already the trend, datasets will become larger and larger. This combined with more global standardization, like multi-regional IDMP adoption, means safety signals will be generated earlier. Regional interoperability, such as cooperation on international prescriptions, and against drug counterfeiting, will be very much enhanced.

Combined with artificial intelligence tools, such as the Alphafold project by Deepmind, the utilization of data will continue to expand. Solutions to one challenge will open opportunities to solve many more.

Fasten your seat belts.

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