臨床試験規制と CTIS への備えと今後の展望

The three-year transitional period is underway for the new EU Regulation No 536/2014 for the Clinical Trials Regulation (CTR) and the Clinical Trials Information System (CTIS) database. Since Fortrea started supporting CTR submissions in early 2022, we now have 49 active applications in the CTIS, 213 country submissions and have received 28 approvals.

To help the drug development sponsors understand the latest expectations and how to fully support their submissions, this article shares our experiences and lessons learned from the EU CTR.

A brief background

Since January 31, 2023, all new clinical trial applications (CTAs) must be submitted under the new regulation, while any ongoing trials are allowed to operate under the former directive. After this second transition period ends on January 31, 2025, all existing trials must be transitioned over to the new regulation.

Setting up the Clinical Trials Information System (CTIS)

CTIS user management involves navigating several detailed steps before submission. Sites must be pre-registered in the Organisation Management System (OMS). Our team at Fortrea recommends facilitating discussions with sites at pre-study visits(PSV) to ensure all registrations are in place ahead of submission.

To avoid potential delays, our team also checks that early registration of the product name in the eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) with the product code. If the product name is not available, this must be added ahead of CTIS compilation.

Understanding documentation requirements

There is no legal basis under EU CTR to submit post-consent patient-facing documents in the research dossier Part II documentation package.[1] It’s important for sponsors to know that:

The local customized and translated documents are not included in the initial CTA submission but prepared for the time of RFI (Request for Further Information).
The Informed Consent Form (ICF) is submitted but our team at Fortrea has found that patient-facing documents should be prepared in case the regulators ask to review them.
Labels must comply to the new EU CTR requirements by displaying a “period of use,” expiry or retest date at primary packaging labeling.
The protocol synopsis must be prepared in a way that redaction is not needed; the synopsis will be displayed on a public-facing database and cannot have personal protected data or commercially confidential information (CCI).

Securing early site engagement

For the research dossier Part II documentation, early site engagement is key to gather contracts, insurance and curriculum vitae (CVs). Collecting these documents as soon as possible will help prepare for an on-time submission.

Enabling rapid responses for Requests for Information (RFIs)

The timeline for initial CTA submission to approval is between 60 and 106 days for a standard Investigational Medicinal Product (IMP). However, applicants only have up to 12 calendar days to respond to RFIs. If a response deadline is missed, the application is considered lapsed. And, if a member state (MS) fails to meet an interim deadline, it will constitute tacit approval of that stage of the process.

To help sponsors quickly answer these requests, we created a Fortrea Rapid Response Team with subject matter experts assigned to support different areas such as ICFs, CMC (chemistry, manufacturing and controls), medical writing and translations. With this custom team and detailed responsibilities, we can help our sponsors generate complete responses within the 12-day timeline.

Understanding revised transparency rules

It is important to note that in the Guideline EMA/263067/2023 Revised CTIS Transparency Rules dated 05 October 2023, revised rules for publication of structured data and documents will apply when an updated CTIS public website will become live, which is expected in the second quarter of 2024. For now, deferral rules are still in place, however, sponsors should assume that trial category 2 and 3 documents—such as protocol, synopses, patient-facing documents, summaries of product characteristics (SmPCs), ICFs and patient information sheets, recruitment arrangements, including procedures for inclusion and copies of advertisement materials—will become public at the time of the first Member State concerned (MSC) decision. For trial category 1, protocol, synopses and patient-facing documents will be published upon submission of results and 30 months after EU/EEA end of trial for pediatric and/or Pediatric Investigation Plan (PIP) and adult studies, respectively.

Additionally, according to Accelerating Clinical Trials EU Q&A on the protection of Commercially Confidential Information and Personal Data while using CTIS, which was released on 29 November 2023, EMA has advised that in the interim period, between now and Q2 2024, sponsors can immediately follow the principles of the revised rules in initial applications, and have provided guidance for the “historical” trials (i.e., trials submitted to CTIS before the new transparency rules are implemented).

Working with an experienced partner

Throughout this transition, Fortrea continues to monitor guidance from the European Medicines Agency (EMA) as well as national country legislation and procedures. We are active participants in the EMA CTIS Master Trainer Forum and related workshops, a member of the Association of Clinical Research Organizations (ACRO), attend European and national webinars on aspects of CTR implementation and provide input at EMA stakeholder meetings.

[1] Clinical Trials Regulation (EU) No 536/2014 Questions & Answers Version 6.6. September 9, 2023. https://health.ec.europa.eu/system/files/2023-09/regulation5362014_qa_en.pdf Accessed 08 December 2023.

臨床試験規制と CTIS への備えと今後の展望