Prepare Now for EU Clinical Trial Regulation Go-Live Date

In this blog post, Rina Kacha, senior regulatory affairs manager, explains the significance of the European Union (EU) Clinical Trial Regulation (CTR) 536/2014 to drug developers. With the go-live date of 31 January 2022, rapidly approaching, sponsors will face a myriad of changing regulations that will create new challenges for drug development. PPD’s cross-functional EU CTR readiness team continues to keep a close eye on the new EU CTR and its potential impacts, working to embrace this change and to ensure sponsors are ready from day one.

The new EU Clinical Trial Regulation (CTR) go-live date is drawing closer – Are you prepared?

One contributor to the cost and complexity of pharmaceutical product development is the variance in national regulatory requirements for the approval of clinical trials across EU member states. The EU CTR is aimed at mitigating some of this complexity by harmonizing procedures for the authorization, assessment, and supervision of clinical trials between EU member states. While this worthwhile effort will address these variances, it comes with substantial adjustments in the way clinical trial application (CTA) submissions will be made.

Three important changes for sponsors include:

1) Defined options for submitting new CTAs

Within the first year of the implementation, sponsors will have the option of submitting new trials under the current Directive (2001/20/EC) or the EU CTR before submissions under the EU CTR will become mandatory. The EU CTR will allow sponsors to submit one combined CTA to the Competent Authorities (CAs) and Ethics Committees (ECs) for all EU countries intended to participate in a given trial, via the Clinical Trial Information System (CTIS). The application will entail a two-part process:

• Part I:  Scientific Assessment coordinated by a reporting member state (RMS)
• Part II:   Member state specific assessment

Parts I and II of the dossier can be reviewed in parallel or sequentially, depending on sponsor preference. Clinical trial approvals will be released as a single member state opinion following both, CA and EC assessment per country, rather than the current process of separate CA and EC approvals, in accordance with individual country process and timelines. Optimally, this efficiency would condense milestones for site activations in the EU. However, careful strategic consideration will need to be made regarding the right approach.

2) Transition timeline for ongoing clinical trials

Transition of all ongoing clinical trials to the new EU CTR needs to be completed within three years of its implementation as part of a clinical trial development plan. Documents such as the protocol, investigators brochure and Investigational Medicinal Product Dossier will need to be harmonized or consolidated across the EU prior to transition.

3) Reduced flexibility in Substantial Modifications

The EU CTR will have less flexibility in the way Substantial Modifications (SMs) are submitted. Under the new regime, SMs will take up to 94 days to be approved. No additional SMs can be submitted in this time. This includes the addition of EU member states, making country selection and the associated submission strategy, key factors for success.

Companies, regardless of size, are currently reporting an average of 4.1 planned and 3.7 unplanned mid-study amendments per clinical trial, with very high variance.¹ Experience suggests a substantial proportion of these amendments will be classified as substantial modifications.

Breaking this down by company size, larger companies are reported to have a higher average number of mid-study amendments, smaller companies reported fewer updates, but more variance was observed around their mean number of updates.¹ Thus, the new rules for submission of substantial modifications could result in Good Clinical Practice (GCP) compliance issues reducing the ability to adapt trials based on data or results as a trial progresses, as well as potentially longer and more costly clinical trials. Tactical, advanced planning of SMs will be key with this regard.

Substantial benefits expected

• While it will take effort to adjust to these changes, substantial benefits are expected. One of these is greater transparency under the new regulation. The EU CTR strongly promotes the transparency of clinical trial data and the Clinical Trial Information System will aid in this goal, allowing the public access to information on the complete lifecycle of a clinical trial in the EU.

One exception to this is commercially sensitive information such as the Investigational Medicinal Product Dossier. The EU CTR will afford the opportunity to provide copies of documents with redacted confidential information in addition to the complete document for review. Sponsors will be able to manage the deferral of the publication of data for up to seven years depending on the category of the trial type.

• Another expected benefit is more clarity for lay persons. The EU CTR requires sponsors to provide a Clinical Summary Report as well as a summary of clinical trial results in a format that is understandable for lay persons. 

If the trial is still ongoing in third countries and data from that portion of the trial are not available, a justification should be provided in the protocol, specifying when the results are going to be submitted. This will require consideration in the development plan of the Investigational Medicinal Product.

Time to Prepare

Delays in the implementation of the EU CTR have made it a challenge for various stakeholders such as sponsors and EU agencies to maintain the commitment to preparation. Big changes and a lot of work will be required, adapting to new processes, systems and timelines. It is important to act now by seeking a right first-time approach, implementing robust strategic planning to ensure mitigation of any risk of hurdles through the life cycle of the development of a product. A high-level global scientific, regulatory and operational strategy is required to be ready for these significant shifts in the regulatory landscape.