By Deborah Borfitz

August 26, 2019 | Dozens of global pharmaceutical companies and contract research organizations (CROs) are giving the EU Clinical Trials Regulation (CTR) a "test run" in advance of its long-anticipated launch, now targeted for mid-2021. As a "gesture of goodwill," national competent authorities (NCAs) and ethics committees in Germany have an ongoing pilot allowing clinical trial applicants to run the paces with the new procedure, says Thorsten Ruppert, M.D., senior manager of research, development and innovation for the Association of Research-Based Pharmaceutical Companies (vfa) in Berlin.

It's a risk-free undertaking for applicants, who can drop out if the going gets rough and return to existing national rules that come with significantly less deadline pressure, Ruppert says. When EU-CTR is in force, they will have only 10 to 12 calendar days to react to any feedback on their submission—or be forced to repeat the entire application process, inclusive of all associated fees.

The tight timeline has been one of the chief obstacles for pilot participants in Germany, as well as those in similar pilots taking place in other European countries such as Belgium, Austria and France, Ruppert says. So has the slow response time of study sites to document requests by applicants.

EU-CTR creates a harmonized, European-wide authorization approach for trials that promises to rescue sponsors from the tedious, time-consuming task of consolidating multiple national feedbacks until "everyone" agrees with the clinical trial, says Ruppert. It was enacted in 2014 and originally scheduled to go live in May 2016. Current information suggests that the EU-CTR will enter into force no sooner than 2021.

Holdups in the development of a fully functional EU clinical trials portal and database is behind a succession of postponements, he says. While frustrating, the delays have provided a window of opportunity to work out the kinks in operationalizing EU-CTR, including how to deal with differences in the standard of care among European countries.

"Huge Step Forward"

The German pilot phase is, by design, a "role model" for the new EU-CTR application procedure, says Ruppert. It was jointly developed by the nation's two NCAs and 33 of its 53 ethics committees—the ones who will be taking part in the new authorization process—and has them evaluating clinical trial applications together in "close accordance" with EU-CTR's stipulations and deadlines. But it also stays within the legal guardrails of the still-relevant German Medicines Act and German Ordinance on Good Clinical Practice.

A survey of vfa member companies conducted last January found 65% are engaged in the pilot phase, Ruppert says, including German branches of international pharmaceutical companies in Switzerland and the US. Untold numbers of CROs and academic sponsors are also involved and they may be particularly challenged to meet the deadline for responding to reviewers' questions given the added layers of communication required to prepare their answers.

The good news is that approval timelines foreseen under the pilot procedure are between 50 and 75 days, depending on whether documents were missing—what Ruppert terms a "huge step forward" relative to historic norms. Currently, the overall timeline for formally completed applications is 135 days or 159 days according to German law if all process timelines are used fully, he says.

The long timelines are due largely to the generous time cushion built into German drug law, Ruppert explains. Ethics committees have 60 days to complete their assessments and, if they have questions, sponsors are given 90 days to respond.

Full data sets were registered for 86 applications in the pilot, which represents 69% of all applications under the pilot procedure at that time. Of these 86 applications, 67 were approved and three were rejected, Ruppert says. Based on the 67 application approvals, the total process timeline was an average 44.6 days—with individual process times ranging from 18 to 71 days. Among these were complex pediatric multicenter studies with multiple versions of informed consent documents, he notes, not just less complex phase I trial applications.

Five sponsors withdrew their application and another five ended due to "insufficient remedial measures" by the applicant, he says. The pilot procedure ended for two applicants due to non-adherence with the pilot process by ethics committees who directly approached sponsors with their feedback versus doing so collaboratively with the NCA. Four applications were still making their way through the pilot procedure at the time of the survey.

What's Next

One of the learnings from the pilot to date is that trial sites are unevenly prepared to give sponsors the complete and properly prepared documents they need to meet deadline expectations, says Ruppert. An initial burst of sponsor enthusiasm to better train sites died off due to the repeated delays in implementing EU-CTR. Until there's clarity on when the new regulation will be in place, the pilot procedure is the best available learning lab for the future process, he says.

While an overarching, pan-European pilot is out of the question, Ruppert continues, a cross-border pilot involving German and Austrian NCAs and ethics committees is currently open for applications because they share a common language. The idea is to align the document review process despite potentially dissimilar concerns raised by groups in the two countries. In addition to the national pilots, the NCAs in Europe are still conducting their Voluntary Harmonisation Procedure (VHP), another collaborative approach.

Based on conversations with colleagues in Austria and Belgium, Ruppert says procedural problems between NCAs and ethics committees may differ somewhat country to country but is "not harming the overall approach or idea behind the pilots." The bigger worry is how they will find "common ground" on such matters as what constitutes standard medical treatment given country-specific clinical practices and guidelines.

Attempted creation of a harmonized European approach to defining standard treatment is one project of a European working group consisting of the EU Commission, European health ministries, the NCAs and national ethics committees, says Ruppert. Per EU-CTR, the last word on such matters will ultimately fall to a "reporting member state" that will serve as a central NCA to work collaboratively with European countries where trial sites are located.

Editor's Note: Ruppert will be presenting at the upcoming Summit for Clinical Trials Operations Executives (SCOPE) Europe, being held in Barcelona, Spain Sept. 17-18, on how industry can prepare for EU-CTR via the pilot procedures. Attendees can expect to hear more about differences between the old and new EU systems and lessons learned from completed applications in the German pilot, he says.