One of the most impactful changes coming up in the regulatory publishing landscape is the global implementation of eCTD version 4.0. Here, one of Calyx’s Senior RIM consultants, Diarmuid Waide, reviews the features of eCTD v4.0 and the latest timelines.
eCTD v4.0 Features
Context of Use Keywords
This new feature enables users to perform new life cycle operations on documents such as one-to-many and many-to-one. This means easier manipulation of document metadata to fix inconsistencies. Additionally, documents will be grouped under one common theme and prioritized within the dossier.
One Submission Unit
Previously eCTD featured a M1 specific XML and a M2-M5 XML. Under eCTD Version 4.0 there will be one XML that covers all modules. This decreases complexity for the end user.
Once submitted, a document may be reused by referring to its unique identifier (ID). This will be helpful to users who submit grouped submissions relating to similar products. Document reuse will speed up publishing times since the end user will be able to send a document just once and use the ID to reference the document in other submissions.
Controlled Vocabularies (CVs)
Controlled Vocabularies are a list of pre-defined terms to be used in submissions. This will aid the agencies in defining what they want to see in the metadata and can be easily updated without the need for changes in tools. This in turn reduces the time it takes to adapt to new regulatory landscapes. User defined CVs can be updated and replaced in subsequent submissions with ease.
There also has been updates to document metadata to help the user define the content of the submissions such as datasets. Increasing visibility of such documents to the reviewer can allow for efficiency gains during the review process.
Timelines for Regional Implementation
With the advantages of eCTD version 4.0 clear, it’s time to look at when you can expect this update to come to the major markets:
2023 was a busy year for eCTD v4.0. The FDA pilot, in which Calyx was proud to support a market-leading pharmaceutical company, was a key step towards implementation in the USA. In 2024, we expect to see further technical pilots in Australia and Brazil, although these dates have changed in the past and remain subject to change. We also expect to see further Implementation Guides issued by the EMA and the TGA and for the FDA to begin accepting voluntary submissions in eCTD v4.0 format.
We’ll continue to closely monitor the progress of eCTD v4.0 implementation and work with our clients on eCTD 4.0 implementation readiness. With decades of regulatory and user experience, Calyx RIM can always be relied upon to support you in continuing to meet regulatory requirements worldwide.
Learn how Calyx RIM helps you maintain compliance with all regulatory requirements.
As we enter 2024 , Calyx’s Regulatory Information Management Consultants provide their insights on what to expect and what they’re looking forward to as the global regulatory landscape continues to evolve in the new year.
Alice Merrill, RIM Consultant
I am excited to see the EMA release Nationally Authorised Products and IDMP-compliant Centrally Authorised Products for use in electronic Application Forms.
The eAF is the first time the EMA have implemented IDMP in their processes: it’s been really interesting to see how they have adapted the product information they hold internally and in xEVMPD for use in the IDMP-compliant Product Lifecycle Management portal. The challenges that they’ve faced, and the solutions they’ve found, will also be useful guidance as pharmaceutical companies develop their own processes for collecting and managing IDMP data.
Currently, the EMA say that they expect to release NAP and split CAP product data in Q1 of 2024, but we have seen this date move several times now as they have tackled issues with the structure of the product data.
Diarmuid Waide, Sr. RIM Consultant
As I specialise in publishing, I’m most excited for the increase of eCTD v4.0 submissions in 2024.
The enhanced functionality especially when it comes to being able to re-use documents from a different application is a game changer. This will make submission of groupings/work-sharings significantly easier and decrease the time needed to publish.
I am really happy to see the new context of use features of eCTD v4.0. This will drastically improve continuity in the life cycling of documents. Changing keyword values without resubmitting documents is something I would love to see used. It will really help clean up Module 3 in particular, which can become a complex nest of folders very quickly when manufacturers change or new dosage forms/dosages are added!
With all the new features included in eCTD v4.0 it’s exciting to see how sponsors will use the tools to enhance their dossier quality and publishing efficiency.
More information on eCTD 4.0 technical specifications and implementation can be found on the ICH’s official eCTD v4.0 site.
Shilpa Tikare, Sr. RIM Consultant
I’m interested to see further international use of the eCTD submission standards. The Economic Community of West African States (ECOWAS) started accepting submissions in eCTD for centralised procedure applicants in November 2023. This is currently voluntary, and an alternative eSubmission format can be used until 1 May 2026.
Five of the fifteen nations – Ghana, Nigeria, Cote d’Ivoire, Benin and Cabo Verde – will also begin a pilot phase for national procedures from 30 June 2024.
Initially, ECOWAS is implementing the ICH eCTD v3.2.2 but have stated their intention to migrate to eCTD v4.0 in future implementation plans.
The use of eCTD by all fifteen member countries is expected to facilitate easy submissions, reduce the cost of both submission and assessment, improve collaboration and information exchange among regulators, shorten registration life cycles, and ultimately improve access to critical and essential medicines in the region.
More information on the ECOWAS eCTD implementation project can be found on the ECOWAS eCTD site.
Daniel Smith, Sr. RIM Consultant
I’m based in the UK, so I monitor the evolving regulatory framework at the MHRA very closely. As of 1 Jan 2024, the International Recognition Procedure (IRP) will replace the European Commission Decision Reliance Procedure (ECDRP). The Mutual Recognition / Decentralised Reliance Procedure (MRDCRP) will also be incorporated under the umbrella of IRP.
The IRP will be open to applicants that have already received an authorisation for the same product from one of MHRA’s seven specified Reference Regulators (RRs), who include the EMA and US FDA. It will allow the MHRA to take into account the expertise and decision-making of trusted regulatory partners for the benefit of UK patients.
The IRP can be used for initial MAA submissions. There are two recognition timetables, 60 days or 110 days, during which the MHRA say they will “conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust”. IRP can also be used for post-authorisation procedures including line extensions, variations, and renewals.
Darren Oakes, Sr. RIM Consultant
I’ve been closely monitoring developments in IDMP, and I’m very interested to see how this continues to evolve in 2024. The EMA and FDA have both hosted recent events on the topic of IDMP implementation – the EMA Product Lifecycle Management (PLM) Value Stream Deep-Dive Webinar, which included content on the Product Management Service (PMS), and the FDA hosted Toward Global IDMP Implementation: A Focus on Global Use Cases.
Both of these events showed that regulatory agencies are continuing to focus on IDMP and its implementation – although we may be some way off FHIR messages, we are certainly seeing regulatory agencies embrace the core concepts of IDMP.
Lael McCune, RIM Publishing Consultant
I am looking forward to seeing agencies continue to work towards transparency and global harmonization.
Health Canada will be releasing version 5.2 of their validation rules for eCTD. Master files have been added to multiple xml checks. More information about this guidance, which will be effective April 2024, can be found on Health Canada’s site.
The FDA released a list of proposed legislation for 2024. Topics include change in agent regulatory oversight responsibility for certain products, requiring full disclosures for drugs to promote generic competition, and enhancing FDAs authority to better protect infants and young children. A complete list of proposed legislation can be found in the FDA’s Summary of Legislative Proposals download.
Finally, the EMA will be enhancing their regulatory process with eCTD EU Module 1 Specification V3.1, Validation Criteria V7.1, and updates to accepted file formats. The guidance is open for comment until January 12, 2024. More information can be found on the eSubmission site.
2023 brought many healthcare advances and opportunities for life science professionals to stay current 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, videos, case studies, 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.
De-risking Medical Imaging in Solid Tumor Trials
During anti-tumor treatment development, imaging modalities, criteria, and regulators’ expectations change frequently. Without the direction of imaging scientists who work day in and day out in clinical trial imaging, it would be difficult, if not impossible to keep track of and react to changes during these critical and often, lengthy trials.
Successful medical imaging in solid tumor trials requires professionals with therapeutic experience, expertise in the modalities required to demonstrate safety and efficacy, and first-hand insight into what global regulators will look for in your submissions.
This blog presents examples of scientific advances and regulatory changes that are currently impacting anti-tumor treatment research, demonstrating the need for an imaging partner who is immersed in the regulations, scientific learnings, and trends that could impact the success of your development program.
Overcoming Oncology RTSM Challenges with Advanced IRT
Sponsors of oncology trials face unique randomization and trial supply management (RTSM) challenges, including:
- Central vs. local sourcing of standard-of-care treatments
- Unknown patient treatment duration
- Impact of rescue medication on study drug expiration
- High cost of treatments / need to reduce excessive drug wastage
Learn about these and other supply challenges and how a flexible IRT system can reduce errors, ensure patient safety, and meet changing RTSM during lengthy oncology trials in this article by Calyx’s Malcolm Morrissey, published in International Clinical Trials®.
Exceeding Timelines for Accelerated Approval: Calyx Medical Imaging
In oncology clinical development, every day matters. Even more so when your compound has been fast-tracked for approval by global regulators.
Which is why so many clinical trial sponsors rely on Calyx Medical Imaging. Calyx’s collaborative approach, ability to meet each sponsor’s unique needs, and expertise in image acquisition and analysis have repeatedly been proven to help clinical development programs succeed.
Like in this example, where Calyx Medical Imaging delivered critical imaging data in advance of deadlines on an already expedited timeline to help a leading pharmaceutical company receive accelerated FDA approval for a Multiple Myeloma treatment.
How IRT Expertise Surfaces – and the Difference it Makes
An IRT system is a critical part of a clinical trial. The implications for failing to get it right can be impactful not only to study goals but to participants as well.
Here, Calyx’s Craig Mooney gives examples of the consequences that can arise if a study’s IRT system isn’t implemented with insight and precise focus on the protocol’s needs and why expertise matters throughout the clinical trial lifecycle.
Calyx RIM Supports Successful FDA eCTD 4.0 Pilot
Calyx RIM has been successfully used by a global market-leading pharmaceutical company in FDA’s eCTD 4.0 implementation pilot program.
Calyx’s regulatory experts worked closely with this leading company and the FDA throughout the pilot and advanced Calyx RIM based on their feedback and lessons learned.
Learn why you can rely on Calyx RIM as you adopt eCTD 4.0 as part of your global regulatory processes.
Neuroimaging in Alzheimer’s Disease Trials
As our understanding of Alzheimer’s Disease (AD) pathophysiology continues to evolve, we’re seeing advanced approaches for assessing treatment effects in clinical development, including AI/machine learning to measure subtle changes that are difficult for the human eye to detect.
Calyx Medical Imaging delivers neuroimaging expertise to help sponsors meet the unique and emerging needs of early to late-phase AD clinical trials. This paper outlines Calyx’s capabilities and experience, which includes confirmation of eligibility and brain safety assessments with rapid turn-around times as well as advanced quantitative analyses for PET and MRI data to help your AD trial succeed.
Mitigate Unblinding Risks with Calyx IRT
Every clinical trial runs the risk of unintentional unblinding. With 30 years of experience designing reliable RTSM solutions and the processes behind it, Calyx IRT is the solution you can rely on to minimize these risks and ensure the integrity of your clinical trial.
The solution design and technical experts behind Calyx IRT have published a variety of papers, webinars, and blogs to demonstrate where and how unblinding can occur and more importantly, how to minimize those risks.
Calyx CTMS Select: Scalable for Small/Mid-sized Biopharma and CROs
The features of Calyx CTMS deliver significant benefits for studies of all shapes and sizes. However, not all studies have the same needs.
Enter Calyx CTMS Select, a pre-configured and validated clinical trial management system for small to mid-tier biopharmaceutical companies and CROs who want reliability and global support but don’t require CTMS customization.
Calyx CTMS Select enables SMID organizations to scale as their operations require and includes the rich features required for clinical trial management oversight and monitoring at lower costs than comparable solutions.
Cookie Cutter Solutions don’t Cut it in Clinical Trial Imaging
When medical imaging is used as a clinical trial biomarker, your centralized core lab provider needs therapeutic/modality and operational expertise to help you meet your development objectives, regardless of where you are in the clinical development spectrum.
Here we review how a small biotech captured the imaging data needed to secure funding and advance their early-stage research on a rare neurological disease compound. And, how a top 5 global pharma captured reliable primary efficacy endpoint data in a pivotal phase III study to achieve regulatory approval on a prostate cancer compound. All supported by Calyx Medical Imaging.
The United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) has announced a new route for expedited pre-and post-authorisation procedures. The International Recognition Procedure (IRP) is a new framework that will replace the EC Decision Reliance Procedure (ECDRP) and incorporate the Mutual Recognition/Decentralised Reliance Procedure (MRDCRP) starting from January 1, 2024. It aims to expedite access to safe and effective medicines for patients in the UK by recognizing trusted regulatory partners.
The IRP allows the MHRA to consider the expertise and decision-making of regulatory authorities from other countries. It will be open to applicants who have already received authorization for the same product from one of MHRA’s specified Reference Regulators (RRs – see below). The same product is defined as having the same qualitative and quantitative composition, active substances, excipients, and pharmaceutical form.
The MHRA has approved seven countries/regions as Reference Regulators; Australia, Canada, European Commission (replaces ECDRP), Japan, Switzerland, Singapore, and the USA.
The Reference Regulators play a crucial role in the IRP. Applicants seeking approval from the MHRA can apply through the IRP if they have already received authorization for the same product from one of the specified Reference Regulators. The MHRA will conduct a targeted assessment of an IRP application based on the expertise and decision-making of these Reference Regulators.
The IRP can be used for various types of marketing authorisation applications (MAAs), including chemical and biological new active substances, generic applications, hybrid applications, biosimilar applications, and new fixed combination product applications.
Traditional Herbal Registrations, Homoeopathic Registrations (Simplified Registration Scheme), Homeopathic National Rules Authorizations (National Rules Scheme), and bibliographic applications are excluded from IRP. Post-authorization procedures such as line extensions, variations, and renewals are also eligible for IRP.
There are two types of recognition procedures: Recognition A and Recognition B. Recognition A is suitable for products with overseas regulatory approvals granted within the previous 2 years and without significant complex factors. The processing window for this type of application is 60 days. Recognition B is ideal for more complex cases and has a processing window of 110 days.
The official guidance from the MHRA states that they will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust.
For more information about Reference Regulators and the International Recognition Procedure, you can refer to the official guidance published by the MHRA on their website.
International Recognition Procedure allows your products to reach the UK market faster for the patients that need them. All of which can be tracked and published in Calyx RIM today, using out-of-the-box functionality. With decades of regulatory and user experience, Calyx RIM can always be relied upon to support you in continuing to meet regulatory requirements worldwide.
Advancements to Calyx RIM prove effective at meeting evolving, global regulatory requirements
Nottingham, England and Billerica, MA – August 8, 2023 – Calyx, the eClinical and regulatory solutions and services provider relied on for solving complex data challenges in clinical research, today announced a major accomplishment in the evolution of its Regulatory Information Management (RIM) system. Calyx has been successfully used by a global market-leading pharmaceutical company to submit key regulatory information to the FDA during its recently completed electronic common technical document (eCTD) 4.0 implementation pilot program.
eCTD 4.0 is a standard format for submitting applications, amendments, supplements, and reports to FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER). eCTD 4.0 submission pilots that enable select pharmaceutical companies to evaluate their eCTD 4.0 readiness are being conducted by multiple worldwide regulatory agencies and are crucial to the success of both industry and health authorities alike.
“We worked closely with this leading pharmaceutical company and the FDA during the pilot program to continue advancing Calyx RIM based on ongoing feedback and lessons learned,” said Jo English, Vice President and General Manager, Enterprise Technology, Calyx. “We’re proud that the advancements we’ve made to Calyx RIM enabled this market leading company to succeed during the pilot program and that all of our clients can rely on Calyx RIM as they adopt eCTD 4.0 as part of their global regulatory processes.”
Visit calyx.ai/RIM for more information on Calyx RIM and its compliance with evolving global eCTD 4.0 regulations.
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.
Christine Tobin | Christine.Tobin@Calyx.ai | +1 412-628-8598
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.
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.