Dragging the Clinical Trials Community into Conformity

It's three months since the European Union's clinical trials regulation came fully into force (and eight years since the legislation was adopted), but knowledge and understanding of the new rules is still—to say the least—patchy, and compliance, consequently, far from guaranteed. The European authorities are, however, taking a softly-softly approach to getting the clinical trials community up to speed, and since January the European Medicines Agency (EMA) has been providing weekly titbits of information and advice about the regulation, in order to woo trial sponsors into learning to live with it. The metrics of this service provide an interesting surrogate endpoint for measuring engagement of those who need to know.

The so-called Clinical Trials Information System (CTIS) was launched on Jan. 31, when the legislation entered into force. Sponsors could, from that date, log in to use CTIS to draft and submit new clinical trial applications, and could also transfer into CTIS trials that were initiated under the now superseded Clinical Trials Directive. It had a slow start. Over the first week, the number of logins to CTIS was just 1,260 a day, and just 53 draft applications were made, with just one actual application submitted—small beer in a region where some 4,000 clinical trials a year are conducted, according to the EU.

However, by the following week, logins were running at 2,000 a day, 87 applications were in draft form, and there were three submitted applications—one of which was the first multinational clinical trial in the system, and also the first trial to use CTIS to transition from the regime of the old directive to the new regulation. By late February, there were 4,000 logins a day, 185 draft applications, and seven applications submitted—including the first by a large pharmaceutical company. In addition, three of the applications passed validation by the regulatory authorities—the first step in the clinical trial application evaluation process in CTIS, when a check is made that the application dossier documentation is complete. The trend continued: as of mid-March, over 6,000 logins to CTIS had been recorded, more than 220 applications were in draft,and14 clinical trial applications for assessment by the regulatory authorities had been submitted—most of them from academic sponsors.

Inaugural study

By early April, with numbers still rising steadily, the first clinical trial was authorized through the new system. This trial had been ongoing under the clinical trials directive and was transferred to the regime of the clinical trials regulation. And in line with the provisions of the CTIS, details were publicized indicating that it was a randomized Phase III trial in Sweden of vasopressin and steroids in addition to adrenaline in cardiac arrest. The sponsor was Tiohundra AB, a Swedish healthcare company listed as "non-commercial." CTIS also provided details on the inclusion and exclusion criteria for recruitment, primary endpoints, the full trial protocol, the planned number of subjects, the trial sites, the informed consent form, and the CV of the investigator. The information is open and accessible to all—patients, healthcare professionals (HCPs) and clinical researchers—and equally to the general public.

One of the key elements of CTIS is the additional transparency it brings to trials. Part of CTIS is a searchable database (euclinicaltrials.eu) that is open to patients, HCPs, and the general public. Patients can find clinical trials that are recruiting participants within their country and therapeutic area of interest and can obtain sponsor contact information to request more information about joining specific trials. And when trials have ended, the sponsor must upload a summary of the results of the trial in lay language, making clinical trial results easily understandable to the public.

Late April saw a continuing rise in engagement, with 13,000 logins a day, 366 draft applications, 31 submitted applications, and one more authorized application—this time for a completely new trial rather than a transition from the previous regime. And, again, details were listed on the public section of the CTIS website.

This time the trial is a prospective Phase II study of calcium electroporation in combination with irreversible electroporation and immunotherapy in patients with pMMR metastatic colorectal cancer, conducted by Zealand University Hospital in Denmark. It is described as an investigator-initiated study involving CE approved devices and an EMA approved drug, to determine the efficacy and safety of Ca-EP performed concurrently with IRE followed by a PD-1 inhibitor (pembrolizumab). CTIS also lists eight secondary endpoints, and recruitment is due to start in June.

Other info divulged

The CTIS listing provides for similarly public information (as it becomes available) on unexpected events and urgent safety measures, as well as summary results, a lay person’s summary, and clinical study reports. Reports on any corrective measures and the results of inspections are also provided for.

As from May, monthly reports will replace the weekly bulletins that EMA has been publishing in order to familiarize the clinical trials community with the new system, to offer alerts to obligations and rights, and to track the evolution of take-up. But EMA will continue to provide the range of advisory services that have been set up to ease the implementation of the new system.

And for anyone apprehensive about the extent of information being divulged to the public, some reassurance—or at least clarity—may be found in provisions that allow sponsors to upload “for-publication” and “not-for-publication” versions of certain documents, including the protocol and the investigator brochures so as to protect personal data and commercially confidential information.EMA is currently preparing guidance on this protection in CTIS, and has published a draft document for open consultation, with a deadline of Sept. 8 for comment.