RIM Archives

This blog was written in February 2023. Please note that due to the fast-moving nature of this topic, dates are subject to change.

In January 2023, the ICH released updated Regional Implementation Information for eCTD 4.0. This is set to be a crucial year in the implementation of eCTD 4.0 with technical pilots running in a number of regions, and the FDA beginning to accept eCTD 4.0 submissions on a voluntary basis.

A snapshot of eCTD 4.0 implementation timelines worldwide, February 2023 (subject to change)

Let’s start with the FDA, which released the eCTD v4.0 Module 1 Implementation Package in September 2022. The IQ pilot began in June 2022 and runs until the end of March 2023. In 2023, CDER and CBER intend to begin accepting new eCTD v4.0 applications on a voluntary basis. Subsequent phases will cover v3.2.2 applications and two-way communication, and eCTD 4.0 will be mandatory starting in 2028. Implementation planning documents are available at fda.gov.

PMDA completed their pilot test in the second quarter of 2021 and began accepting applications in v4.0 in the year 2022. The transition phase will last through 2026 at which point eCTD v4.0 submissions will become mandatory in Japan.

Early in 2023, EMA intends to release the Implementation Guide and associated standards guidance. Timelines for voluntary and mandatory submissions are staggered based on procedure type: voluntary submissions for CAPs start in 2024 and become mandatory in 2026, while voluntary submissions for MRP/DCP and NAPs start in 2025 and 2026 respectively. The mandatory use dates for MRPs/DCPs have yet to be confirmed by the EMA. Updates are available on the EMA’s eSubmission site.

Let’s start with the FDA, which released the eCTD v4.0 Module 1 Implementation Package in September 2022. The IQ pilot began in June 2022 and runs until the end of March 2023. In 2023, CDER and CBER intend to begin accepting new eCTD v4.0 applications on a voluntary basis. Subsequent phases will cover v3.2.2 applications and two-way communication, and eCTD 4.0 will be mandatory starting in 2028. Implementation planning documents are available at fda.gov.

PMDA completed their pilot test in the second quarter of 2021 and began accepting applications in v4.0 in the year 2022. The transition phase will last through 2026 at which point eCTD v4.0 submissions will become mandatory in Japan.

Early in 2023, EMA intends to release the Implementation Guide and associated standards guidance. Timelines for voluntary and mandatory submissions are staggered based on procedure type: voluntary submissions for CAPs start in 2024 and become mandatory in 2026, while voluntary submissions for MRP/DCP and NAPs start in 2025 and 2026 respectively. The mandatory use dates for MRPs/DCPs have yet to be confirmed by the EMA. Updates are available on the EMA’s eSubmission site.

Source: EMA EUROPA

The next milestones for Health Canada have been developed based on stakeholder feedback and work with ICH partners and other regulatory authorities on the international deployment strategy for eCTD v4.0. Health Canada are planning to complete pilot testing in 2023, accept voluntary submissions in the year 2024, and will make eCTD 4.0 submissions mandatory from 2027. The guidance document, “Preparation of Regulatory Activities in eCTD Format’ will be updated to reflect the new specifications once the choice to implement eCTD v4.0 has been made. Draft guidance has been released and is available on Health Canada’s website.

Swissmedic held a public hearing on the Swiss Regional Implementation Guide back in 2020, but the final publication of the guide has yet to be made available. Meanwhile, Swissmedic plans to run a technical pilot in 2024, followed by voluntary submissions in eCTD 4.0 format the same year. Swissmedic anticipates mandating the use of 4.0 by the year 2028.

The voluntary implementation deadlines for ANVISA and TGA are 2023; a technical pilot for ANVISA is scheduled for the second quarter of 2023, while a decision is still to be made for TGA.

The MHRA, ECOWAS, and ECAs regions do not currently have any plans to deploy eCTD v4.0; they will follow suit once other regions have paved the way.

The next five years will see rapid change as national authorities complete technical pilots and begin accepting eCTD 4.0 submissions.

Learn how Calyx RIM helps you maintain compliance with all regulatory requirements.

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2022 brought many healthcare 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 most sought-after articles, white papers, webinars, and more produced by Calyx scientific, technical, and regulatory experts this 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.

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How Unintentional Unblinding Occurs in Clinical Trials

This blog series addresses the trigger points for unintentional unblinding, how partial unblinding can become full unblinding, and some controversial issues related to unintentional and partial unblinding in clinical trials.

Read the Blog Series

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Partnering to Advance CNS Treatment Development

In 2021, Calyx advanced its strategy of partnering with best-in-class technology providers to offer innovative imaging biomarkers required to find new treatments for unmet medical needs. Our groundbreaking partnership with Qynapse enables our clients to more confidently assess the full potential of treatments in development for Multiple Sclerosis, Parkinson’s, Alzheimer’s, and Huntington’s disease, as well as other neurodegenerative disorders. And our partnership with Neosoma delivers novel, improved AI-based neuro-oncology imaging assessment to clinical trial sponsors developing new treatments for gliobastoma and other life-threatening neuro-oncological diseases.

Read the Announcements

Improving how we Evaluate Treatment Response in Oncology Research

The Journal for ImmunoTherapy of Cancer recently published ‘Comparison of tumor assessments using RECIST 1.1 and irRECIST, and association with overall survival,’ marking the first time immune-related criteria show correlation with Overall Survival as its most meaningful endpoint in the treatment of cancer patients.

The publication demonstrates the benefit to a subgroup of patients who otherwise would have foregone treatment and survival benefit when relying solely on RECIST 1.1 instead of irRECIST, as irRECIST takes the entire tumor burden including new tumor growth into consideration.

In this webinar, co-authors Peter Eggleton of Merck and Oliver Bohnsack of Calyx – leading experts on RECIST and irRECIST – discuss the implications of these findings, what it means for oncology clinical development and treatment decision-making, and why irRECIST easily can and shall replace outdated RECIST 1.1 on all solid tumor trials going forward.

View the Webinar

150 Orphan Drug Indication Approvals Trusted to Calyx IRT

In rare disease trials, it is critical that trial supplies are available when patients are identified, and that drug overage is minimized – a real challenge due to larger numbers of investigative sites typically required to meet trial enrollment levels. Which is why we’re honored that so many sponsors of orphan drug-designated trials have entrusted their RTSM needs to Calyx IRT and continue to rely on our expertise as they bring safe and effective treatments to patients in critical need. Learn more about Calyx IRT.

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The Practicalities of Implementing eCTD 4.0

This blog series reviews the factors regulatory affairs professionals should consider as they prepare for eCTD 4.0 implementation, beginning with people and business processes, the impacts of new concepts and terminologies, and the challenges to be expected.

Read the Highly Requested Blog Series

The Siren Song of Deferred IRT Functionality

What are the consequences of deferring IRT functionality to meet clinical trial start dates? In this Applied Clinical Trials article, Calyx’s Craig Mooney reviews the inefficiencies and potential quality / regulatory risks likely to occur.

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Leading CROs join Calyx Partner Program

At Calyx, we have a long history as part of a CRO, so we know how a CRO functions, the challenges you’re up against, and the importance of keeping your customers satisfied. This inside knowledge affects every aspect of our CRO relationships and makes us more efficient and easier to work with.

Our Activate Solutions for CRO Partners Program enables CROs of all shapes and sizes to partner with Calyx and extend our advanced technology and proven services to drive success for their customers. In 2022 we added more CROs to the program – get to know some of them and learn how they’re partnering with Calyx to deliver more value.

Meet the Partners

Reducing Overage with Calyx IRT: Minimize Monitoring Burden while Optimizing Supplies

80 sites enrolling 150 patients: How do you minimize overage without burdening your supply team? Learn how one of Calyx IRT’s advanced trial management options solved the complex in this case study.

Read the Case Study

Seeing the Patient beyond the Data

In this episode of the Calyx Café, Patient Advocate Emily Epstein discusses the importance of supporting clinical trial patients’ mental health and the impact that clinical trial technologies – including DCTs – may have on patient welfare.

Watch the Interview

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CTMS Functionalities

Your clinical trials deserve every chance to succeed. And your monitors deserve the most effective tools to improve trial efficiencies. This brochure describes why Calyx CTMS is the solution.

Read the Brochure

We’ll be delivering more valuable content throughout 2023 to help you achieve your clinical development and regulatory objectives. Subscribe to make sure you don’t miss out!

Upgrade to Calyx RIM on Microsoft Azure drives efficiencies and patient safety

Nottingham, England and Morrisville, NC – August 2, 2022 – Calyx, the eClinical and Regulatory solutions and services provider relied on for solving complex data challenges in clinical research, today announced that long-term client, Krka – one of the world’s leading generic pharmaceutical companies – is expanding its investment in the Calyx Regulatory Information Management (RIM) system for an additional five years.

“We chose to continue our relationship with Calyx based on our successful experience working with their regulatory experts over the past decade, and our trust in the robustness of the Calyx RIM system,” said Krka. “We’re excited about the investment Calyx has made in innovating the system with reliable cloud technology, which will help us to ensure patient safety, even during system updates.”

Since 2011, Krka has relied on Calyx RIM to comply with increasingly complex global publishing requirements and for the management and tracking of detailed product information, registrations, and authorizations. Krka’s contract extension includes an upgrade to Calyx RIM on Microsoft Azure for increased efficiencies, including simplified activities and tailored, direct delivery of system updates to minimize operational disruptions.

“We value the trust that Krka continues to place in Calyx RIM and are delighted to extend our relationship as they strive to comply with evolving worldwide regulations and ensure patient access to much needed medical treatments,” said Jo English, Vice President, Regulatory Information Management, Calyx

More than 20 million regulatory records have been seamlessly migrated into the Calyx RIM system, representing over 1 million global submissions to date. Notably, over 100 COVID-19 vaccine authorizations have been granted by worldwide regulatory bodies based on clinical trial data submitted via Calyx RIM.

Click here for more information on the benefits of Calyx RIM.

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 30 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 Calyx.ai or at LinkedIn, Twitter, or Facebook.

About Krka

Krka (LJSE:KRKG) was established in 1954 and has developed into one of the leading generic pharmaceutical companies in wider Europe. Globally, it ranks among the top 20 generic companies, and is present in overseas markets and Asia. Krka has a broad portfolio of effective and innovative medicines and a strong development pipeline of 170 products. Krka’s medicines are available in unique strengths and combinations, innovative dosage forms, including sustained release dosage forms, and are manufactured in advanced and patented technological processes. Our flexibility allows us to be agile and first to market. Krka has grown to become an international company with 12 thousand employees and global presence in more than 70 markets around the world. In addition to the 47 subsidiaries and representative offices abroad, the company’s international presence is consolidated through its own production plants in Slovenia, Poland, the Russian Federation, Croatia, Germany, and now in China. Krka’s products are marketed under our own brand names, ensuring market recognition. New products are constantly being added to the wide Krka product range, reinforcing the company’s ability to enter new therapeutic areas. Krka’s group business model is based on a high degree of vertical integration at all levels of its operation.

Contact:

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

Considerations for Life Sciences and Vendors

In our previous blogs we discussed the people and process considerations as well as the impacts of new concepts, terminologies, and the increased reliance on structured data during an eCTD 4.0 implementation. In this final blog in the series, we review some of the challenges for implementation and longer-term adoption both from a life sciences and vendor perspective

Timelines

The timelines for implementing eCTD 4.0 across the different markets and regions is varied and subject to change. In the July 2022 ICH updates Canada moved the dates for voluntary implementation from 2023 to 2024 and for final implementation from 2026 to 2027. These timeline changes mean that it is often difficult for pharma companies to effectively plan their implementation; having to take a risk-based approach in assigning resources and prioritization. Additionally, the long lead times between voluntary and mandatory submissions coupled with the need to comply with other future regulatory requirements such as IDMP & PQ CMC make it difficult to prioritize and plan for eCTD 4.0.

For several in-scope countries e.g., Brazil and Australia and for Non Centrally approved products in the European Union, timelines for mandatory implementation are not yet known, which further complicate plans to move forward. While in some cases countries such as Thailand, South Africa and the Gulf Cooperation Council region have not provided any plan for their 4.0 implementation. In summary the implementation of eCTD 4.0 looks to be a protracted process which will continue to evolve way into the 2030s.

“Long lead times between voluntary and mandatory submissions coupled with the need to comply with other future regulatory requirements make it difficult to prioritize and plan for eCTD 4.0.”

– Karen Harry, RIM Expert

Below is a representation of the current timelines for voluntary and mandatory timelines (correct as of July 2022).

Transition

Another important area of discussion will be in deciding the plan for transition. As referenced above there are lengthy timelines from optional submission to mandatory submissions and there will need to be capabilities to manage a single application in both eCTD 3.3.2 and 4.0

This will require some very detailed planning and co-ordination with submission planners, publishers and authors alike. It will clearly be critical to have a well-defined plan for transition; a couple of considerations in helping to inform these decisions could include the prioritization of applications where there are minimal updates planned.

Working in close collaboration with submission planners, especially in larger organizations must be a priority, having access to the submission schedule and visibility of any variations to it will be critical.

Another obvious option to facilitate the transition would be to identify a subset of publishers with eCTD 4.0 subject matter expertise to manage the follow up submissions post transition. It would also make sense to target any new MAAs as candidates for eCTD 4.0 from the beginning of their lifecycle.

Vendors

Vendors will clearly be pivotal in providing eCTD 4.0 capabilities in their publishing solutions and in supporting future submissions in the new format while still maintaining support for current eCTD specifications, NEES, and paper publishing. New assembly templates will need to be provided to support the new 4.0 structure and updates to DTDs will also be required.

Validation tools will need to be updated to ensure that all criteria including the rules relating to the association of controlled vocabularies and sender defined keywords are included. Vendors will also need to focus on viewing tools, ensuring that the capabilities to review both the content and the structure of the eCTD 4.0 format are provided.

Other requirements that will need to be satisfied include the need to link to multiple controlled values and for those companies that have an integrated registrations and publishing utilization of the same list of values for both IDMP and publishing will be hugely beneficial, along with any future initiatives requiring those same values.

As with other ongoing initiatives there will be a reliance on FHIR (Fast Health Interoperability Resources) to generate the single XML backbone.

Although out of scope for the initial submissions, in the future vendors will also need to consider the need to support two-way communication so that agency feedback can be included. This in itself will introduce changes to business process to ensure visibility to the regulatory affairs team who are typically in receipt of such communications.

Importantly, vendors will also be expected to collaborate with industry to support agency pilots prior to the formal implementation of eCTD 4.0. These pilots will be crucial to the success for both industry and health authorities alike.

Learn how Calyx RIM can help you get eCTD 4.0-ready!

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.

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

Read Part 3 of the series which focuses on timelines and strategies for implementation

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, RIM Expert

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 the next installments to the series. Part 2 focuses on socialising the new concepts, terminologies and the increased dependence on structured data. Part 3 focuses on timelines and strategies for implementation.