EU Clinical Trial Regulation: Get Ready to Adapt!

Around the Globe

EU Clinical Trial Regulation:
Get Ready to Adapt!

Ruediger Pankow

Danu Pamungkas

Beate

Roder

Bettina Goldberg

Parexel® Regulatory and Access, Clinical Trial Regulatory Services
@Parexel

T

he European Union Clinical Trial Regulation 536/2014 (EU CTR) aims to standardize and harmonize the conduct and management of interventional clinical trials across the European Economic Area (EEA), with legally binding rules on requirements and increased transparency.

This long-anticipated legislation uses one single electronic web-based Clinical Trials Information System (CTIS) to:

Submit, evaluate (scientific and ethical review), and authorize clinical trial applications (CTAs);
Submit any trial-related notifications, reports, and results, up to the clinical study report; and
Serve as the single communication channel between the sponsor and the Member States Concerned (MSC) in the clinical trial.

The new EU-CTR promises a harmonized, simplified process designed to decrease the burden resulting from idiosyncratic interpretations of the current EU-CTD. But it also poses new operational challenges to many clinical trial sponsors.

The EU-CTR came into effect on January 31, 2022. From this date until January 30, 2023, sponsors can choose to submit CTA requests for new trials under the current EU Clinical Trials Directive 2001/20/EC (EU-CTD) or under the EU-CTR; however, after January 31, 2023, all new CTAs must follow EU-CTR processes. Sponsors must transition ongoing trials to EU-CTR by January 30, 2025.

Preparing for the EU-CTR requires wide-ranging cross-company initiatives. Companies that have started their preparations early understand very well that they must mobilize all stakeholders to analyze current business processes, upgrade information technology systems, and restructure operations to avoid disruptions to start-up, conduct, and maintenance of ongoing and new trials.

To Reap Efficiencies, Sponsors Must Sow Operational Changes

The new EU-CTR promises a harmonized, simplified process designed to decrease the burden resulting from idiosyncratic interpretations of the current EU-CTD (Table 1). These promised efficiencies include all-electronic submissions and communication, improved collaboration between MS, increased process transparency, and uniform review timelines. Although core activities and data sets for trials in the EEA will not change, management of study start-up activities, request for information (RFI) responses, and modifications to the CTA dossier need to change. For example, one of the significant operational changes needed is for sponsors to establish processes for document redaction. Companies will also need to undertake other essential preparations, including:

Figure 1: What sponsors should consider when preparing for the EU-CTR. Provided by Parexel.

Analyze processes across your portfolio: To maximize efficiency, sponsors need to assess processes across their portfolio lifecycle. Early on, sponsors should engage with internal stakeholders and external outsourcing partners to communicate clearly defined processes and workflows that ensure business continuity and full compliance under the EU-CTR. They may need to employ different resourcing models to address varying circumstances. Sponsors should prepare for EU-CTR using a cross-departmental approach (Figure 1).
Focus on first-time quality: Under the EU-CTR, the success of a CTA depends on the first-time quality of the dossier to a greater extent than ever before. A CTA will not pass the validation phase in any MSC unless it receives clearance to proceed in all MSCs. You must complete the authorization procedure for an initial application before you can submit an additional MSC. This greater interdependency amongst MSCs in the trial demands that sponsors get applications right the first time.
Choose countries wisely: Under the EU-CTR, the study start-up strategy will need to change from “first EEA country ready” to a holistic approach to EEA country readiness. Part I of an EU-CTR CTA dossier evaluation is a joint assessment from all MSCs led by the Reporting Member States (RMS), proposed by the sponsors. However, if a CTA contains elements or provisions at odds with the RMS’s national laws, a negative Part I conclusion will affect all MSCs. Experts with local knowledge can tailor the country list. Choosing the right RMS and MSC will be critical.
Centralize CTA management: An industry-wide EU-CTR trend is centralization of CTIS management. Communication exclusively via CTIS and the short RFI response timelines call for a focused team that monitors the CTIS for incoming communications, handles document/data entry and download for trial master file compliance, and closely monitors timelines.
Upgrade IT infrastructure: Most companies will need to upgrade their electronic trial master file, regulatory information management, and clinical trial management systems to meet the new demands of EU-CTR. However, companies should realize that procuring and upgrading such systems can take anywhere from six to 12 months, and you can only upgrade effectively after a comprehensive impact assessment. It is vital to get the right insight and information about your current IT system and what you will need going forward.
Tighten timing: Under the EU-CTR, sponsors will need to coordinate initial applications—and all modifications—closely. Missed timelines may result in legal consequences, such as lapsed applications, for sponsors. Sponsors will need a strategic plan for management and oversight of timing the permitted and nonpermitted overlapping initial, substantial modification, and additional MSC applications.

EU-CTR will require tight process coordination by sponsor study teams. All contributors must synchronize activities—lifecycle planning for each trial as well as across all studies with the same product—because an ongoing assessment in one MSC will block further substantial modifications to Part I, or Parts I and II, for all MSCs. Sponsors should attempt to minimize in-process changes to a clinical trial and ask: Will this action impact the submission of another action?

If sponsors prepare well in advance, they will find that initiating and conducting clinical trials in a timely fashion will be manageable under the EU-CTR.

New Challenges to Many Clinical Trial Sponsors

Emerging biotech companies outside Europe are facing additional challenges in expanding their clinical trials in European Economic Area countries now that the new EU-CTR is in effect. These companies are often very limited in their internal resources and lack in-depth knowledge of the requirements under EU-CTR and the system functionality within CTIS; this implies the need for CTIS User Administration management and highly trained staff managing CTIS daily. In addition, sponsors are often not aware of new document and master database registration requirements and transparency rules imposed by the EU-CTR.

Many small biotech companies may benefit from getting support from an experienced adviser to ensure they get ready for their first trial under EU-CTR. These EU-CTR experts can support sponsors by proposing best practices for EU-CTR readiness and providing guidance for trial submission content and timeline planning as well as advice on MSC selection. This is an important component to protect forecasted development timelines.

Not Yet Business as Usual: Plan Transitions Well in Advance

During times of wide-ranging regulatory and operational changes in clinical trials, business continuity and regulatory compliance must be maintained to ensure patient safety and well-being. The applicability of the EU-CTR requires mindset changes from all stakeholders. Preparations should start earlier than current practice to ensure sufficient time for sponsors to prepare all required documents in line with EU-CTR standards, register in all relevant source databases, and develop a strategy to manage the transparency rules under EU-CTR. Sponsors who need to transition trials to EU-CTR should start strategic planning well in advance of the mandatory cutoff date.

Table 1. EU Clinical Trials Directive Versus EU Clinical Trials Regulation

EU-CTD
EU Clinical Trials Directive 2001/20/EC

EU-CTR
EU Clinical Trials Regulation 536/2014

RA application and approval, country by country

One application via CTIS to all MSCs; one decision per MSC, including scientific and ethical evaluation, based on availability of:

Part I (core scientific data dossier): Assessment report by RMS (with contribution by each MSC)
Part II (country-specific documents*): Assessment report by each MSC separately

*Informed consent documents, site suitability, etc.

EC application and opinion, country by country

No separate EC applications and opinions (central or local); these are integrated into the process above

Response timelines to RFI vary across countries

RFI must be answered within maximum of 12 calendar days or the application is lapsed

Submission communication method is country-specific

Electronic communication via CTIS only

Trial sites or countries can be added, or protocols amended, at any time in a parallel process independent of ongoing applications

Ongoing review of an application (for example, substantial modifications within a MSC or the addition of a new MSC) prevents further applications

Assessment processes and deadlines vary by country

All applications assessed in the same way, with the same timelines

Acronyms: CTIS: Clinical Trials Information System; EC: Ethics Committee; MSC: Member State Concerned; RA: Regulatory Authority; RFI: Request for Information; RMS: Reporting Member State.

EEA Countries: Austria, Belgium, Bulgaria, Croatia, Republic of Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, and Sweden.