Application procedures and Timelines under the EU Clinical Trials Regulation

Background

With the implementation of the Clinical Trials Regulation (CTR) (No 536/2014), the European Commission hopes to realise its ambition to create a favourable environment to conduct clinical trials within the EU. The CTR is the new regulation that governs all interventional clinical trials conducted in the EU with medicinal products for human use. CTR aims to harmonise submission and assessment processes, improve cooperation and transparency in and between Member States and enhance overall safety standards. In this series of blogs, we have and will further examine the key changes and challenges faced and the potential competitive benefits for organisations that CTR introduces.

If you have an interest in our previous blogs on CTIS you can find them
here:

1. Introduction to the Clinical Trials Regulation
2. Legal representation set out in the EU Clinical Trials Regulation
3. User management in the Clinical Trials Information System

In our fourth blog, we provide an overview of the key considerations around submissions of clinical trial applications.

MSCs have 10 days following the submission of an initial application to validate the application, taking into account whether the clinical trial falls in scope of the Regulation and whether the application dossier is complete. If this 10-day period is exceeded, then the trial will be validated automatically. Once an application has been validated, it will go through a two-part assessment. Both parts run in parallel to each other, with part I being assessed by all MSCs and part II only by the relevant MSC. Following the assessment, a decision is made and communicated by the RMS. The conclusion of the Part I assessment is deemed to be supported by all MSCs.

Following the authorization of an initial application, a Sponsor can make amendments via non-substantial or substantial modifications. Non-substantial modifications can be made without resubmitting the application. However, substantial modifications, defined as “any change…which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial”, require a resubmission and reassessment of the relevant part of the application (i.e. Part I, Part II or Part I & II). In addition to a reassessment of the relevant part, there is a validation phase to assess whether the submitted SM is referring to the correct part of the application.

Furthermore, a Sponsor may want to include an additional MSC. In this case, Part II for that respective MSC must be submitted and assessed. While the additional MSC is only required to assess Part II of the application, they can raise considerations for Part I which can lead to a reassessment of this part.

Timelines for all three application procedures are strict and must be met in order to proceed with the application. In addition, Requests for Information (RFI) can influence the timelines for an initial application, substantial modification and an additional MSC. If RFIs come in, Sponsors have 12 days to respond (unless otherwise indicated by the Member State but this will not exceed 12 days), after which the Reporting Member State has 19 days to assess the response. Failure to respond to an RFI within the set timeline can result in a lapsed application. It is therefore important to monitor incoming RFIs to ensure they are responded to in a timely manner. Important to highlight is the fact that CTIS does not send alerts or reminders outside of the system, someone with a CTIS user role therefore needs to monitor incoming RFIs on a regular basis.

The EMA has published several rules regarding the due dates for CTR/CTIS tasks (see Figure 2). A task is to start on a working day and the due date of tasks cannot fall on weekends or public holidays. If that is the case, then it will be moved to the next working day. Despite these rules, public holidays and weekends can influence the number of days available to respond to tasks and can result in tight timeframes. We anticipate that there could well be challenges when responding to an RFI particularly in a scenario where you have multiple steps before submitting it to CTIS, for example if an RFI requires you to reach out to a number of affiliates or CROs. An example where this could be particularly difficult is the Easter weekend (see Figure 3). If an RFI comes in on the Thursday before Easter weekend then the time to respond to the RFI starts on the following working day (Friday). A Sponsor will then only have 6 working days to respond to the RFI considering the holiday weekend. In this example, a standard 12-day response time is applied however Member States can choose to shorten this timeline.

Another important consideration is the fact that CTIS does not allow parallel submissions. Requests for substantial modifications cannot be submitted while any other assessment is still ongoing such as an initial application, application for another substantial modification and an application for the addition of a MSC. This may influence the timing of the clinical trial and may require further coordination within organisations.

Final remarks

While the EU CTR harmonises clinical trial assessment procedures by introducing CTIS, it does require organisations to be mindful of several new considerations namely stricter timelines, responses to RFIs and no parallel submissions. By being aware of these considerations, organisations can take them into account when preparing for the transition to EU CTR. In our next blog we will zoom in on Transparency of clinical trial information under EU CTR.

How can Deloitte support you?

We have extensive experience in supporting regulators and top pharmaceutical companies to prepare for new Life Science Regulations, and since 2014 we have been helping organisations prepare for the implementation of the Clinical Trial Regulation. We are skilled with differentiating and setting up regulatory frameworks in challenging and diverse jurisdictions. We pride ourselves in supporting organisations in defining and executing optimal strategies for CTR implementation and ensuring they are and remain responsible businesses. Want to know more? Find our contact details below.