November 10, 2023
In this article we draw on real data from our own experience to help you understand the new scenario so that you can establish your own clinical trial submission strategy through CTIS. These data – anonymized – correspond to 7.1% of all commercial clinical trials submitted through CTIS up to August 2023, which are the ones we have managed at Sermes CRO. These figures involve more than 2,700 participating sites and a total of 536 countries.
Assessment and approval timelines foreseen in EU CTR 536/2014
The assessment of an initial clinical trial application is divided into three phases: the validation, the assessment itself, and the decision. Member States Concerned (MSC) have, theoretically, up to 60 days to issue a decision on an application for initial approval, provided there are no RFIs (requests for information).
As can be seen in the picture, validation takes 10 days. This period can be increased by an additional 15 days if there is an RFI: 10 days for the sponsor to respond to the considerations and a further 5 days for the Member State to assess it. In the case of multi-country clinical trials, it will be necessary to choose a Reporting Member State (RMS) to lead the Part I assessment process. The country that will act as the RSM will be confirmed by the Member States at this stage of study validation.
The Part I and Part II assessments are carried out in parallel and have a maximum duration of 45 days, but can be extended by an additional 31 days if there is an RFI. There are two possible strategies here: either submit Parts I and II simultaneously, or submit them consecutively. If the application for Parts I and II for a country is made simultaneously, both parts will be assessed in parallel, after which the decision for both parts will be obtained, so that as soon as the authorization is obtained, the study can start in the country. However, if an application is made in which Part I is submitted and Part II is submitted for some countries but not for others, the whole dossier will be assessed only in those Member States where the sponsor submitted the complete application (Part I and Part II), and once positive decisions are issued for these Member States Concerned, a clinical trial may be initiated in these countries. The remaining Member States for which Part II was not submitted will only assess Part I together with the rest of the participating countries and will only receive the conclusion on Part I. This conclusion is valid for 2 years, within which time Part II of those countries that had not submitted it must be submitted. Only when the Member State has issued a positive decision on the complete application (Part I and Part II), the sponsor may start trials in these countries. If the sponsor does not submit Part II in these Member States within 2 years, the conclusion on Part I will be deemed to have lapsed for these countries.
Part I assessment examines the scientific documentation associated with the study, such as the protocol, the medicinal product, the investigational brochure, safety, efficacy, etc. This part is assessed by all the countries concerned, but is coordinated by one of them, the RMS.
The assessment of Part II is carried out by each Member State Concerned, and local/national aspects such as the informed consent form, patient recruitment and reimbursement, sites, data protection, etc. are assessed.
Once Part I and Part II have been assessed, countries have 5 days to issue a decision on the study, i.e. whether to authorize, authorize with conditions or not to authorize.
In conclusion, if we add up all the phases (validation, assessment and decision), the result is that we will receive a response from CTIS in 106 days. However, there are a number of issues that can make this number of days longer. Let’s see what they are and how they are influencing the actual time data.
A detail to be taken into account when analyzing the best date to submit a clinical trial for CTIS is the so-called stop clock. These are the cases in which the established timelines (shown in the image) do not apply because the clock stop days have to be added to them:
The due date of a task that applies to Member States: the due date has to fall on a working day.
New clinical trials via CTIS: examples of actual timelines
Of the 20 new clinical trials we have submitted through CTIS, we have received approval for 11 to date. We have calculated the average number of days until approval and the result is 120 days, i.e. 14 days more than the theoretical time established by the regulation, which, as we said earlier, is 106 days. The cause, in this case, has been the clock stop at Christmas and the bank holidays of the Member States Concerned. The Reporting Member States most frequently chosen for these assessments were Italy and Germany.
Transition of clinical trials to CTIS: examples of actual times
Just as new clinical trial applications through CTIS can take up to 106 days, transitions from clinical trials to CTIS can take up to 82 days to be approved.
Of the 57 clinical trials whose transition we have requested through CTIS, we have received approval for 38 to date. Based on our experience, we have calculated the average number of days until approval and the result is 88 days, i.e. 6 days more than the theoretical time established by the regulation, which, as we have mentioned, is 82 days. The cause, in this case, has also been the clock stop at Christmas and the bank holidays of the Member States Concerned. The Reporting Member State most often chosen for these assessments was Germany.
As we have seen, the actual approval timelines for clinical trials by CTIS are not exactly the theoretical timelines foreseen by the EU CTR 536/2014 regulation. Therefore, in order to manage clinical trials on the new European platform, we hope our advice will be useful. The most important thing is to plan your strategy well!