Europe Seeking Clarity in Complex Clinical Trials

Even before COVID stimulated renewed urgency in mechanisms to promote rapid and efficient product development, the drive for innovative–and more complex–clinical trials was already well underway in Europe and beyond. The response to the pandemic has, however, given new momentum to many ongoing reflections on getting a better– and faster–bang from the bucks (or more elegantly, more patient benefit from platform trials) in clinical development.

Large-scale platforms

While the classic RCT may remain the preferred approach for many regulators, there is growing concern over its costs and delays, and a reinforced appetite to overcome the associated challenges in subject recruitment, and in patients finding the right trial for their needs. One of the key tasks of HERA, the European Union's newly-announced strategy for tackling health risks, is to work with the European Medicines Agency "to create a long-term and large-scale EU platform for multi-center clinical trials and corresponding data platforms." This 'European Health Emergency preparedness and Response Authority', unveiled in mid-September, will incentivize "advanced research, innovation and development of relevant technologies and countermeasures–including diagnostics, therapeutics, and vaccines," says the official announcement, and will promote data sharing arrangements that "can lead to breakthrough discoveries and accelerate the development of health solutions." It will, it says, rely heavily on European clinical trial networks and platforms "to accelerate trials and connect all development stakeholders for designing and conducting trials." These platforms should, it adds, be easily adjustable to respond to a broad range of potential threats, and should reduce current lead times.

Fragmented Europe

EU officials acknowledge that the trial landscape in response to the pandemic has been fragmented, with a multitude of small, national trials, struggling to generate robust and actionable clinical data, with great duplication of efforts and direct competition for shared resources and participant populations. Action has already been taken to build a COVID therapeutics network, based on three large-scale multi-center, adaptive platform trials– REMAPCAP, EU-SolidAct and DisCoVeRy. When these are combined, they will encompass around 200 trial sites across half of the EU member states. Another early initiative in this context is VACCELERATE–the first EU-wide network for COVID vaccine trials, which is collaborating with EMA to ensure these trials provide relevant evidence fast for a marketing authorization assessment, and is currently designing three trials that aim to inform future COVID vaccination strategies. HERA envisages that all these networks will be brought together into "a large-scale EU platform for multi-center clinical trials to avoid fragmentation."

But as officials also acknowledge, these trials are demonstrating yet again how hurdles relating to innovative trial designs, long regulatory approval processes and complex site administration lead to delays and underachievement. These must be tackled at European and national level to guarantee the availability of the best clinical management options, they recognize. "Efforts are needed to better address identified barriers and challenges, to ensure the necessary agility and speed of large-scale multi-country trials across the EU," according to an invitation to an official EU meeting planned for October to seek solutions and to build "increased and mutual trust with regard to the implementation of adaptive platform trials."

Wider than COVID

In parallel to these specifically COVID-related activities, there are plenty of moves within the European clinical trials community to explore and expand understanding of the challenges of matching clinical trials design to the exigencies and opportunities of scientific advances. The European drug industry worked on complex clinical trials in 2020 with researchers in the European Organization for Research into Treatments for Cancer and specialists in the Association of Clinical Research Organizations, as well as with the European Union's Clinical Trial Expert Group, composed of national health ministry officials. This built-in part upon the 2019 recommendation paper on the initiation and conduct of complex clinical trials from the Clinical Trial Facilitation and Coordination Group, a working group of the EU Heads of Medicines Agencies, which covered enrichment designs, adaptive designs, master protocols, and use of historical controls in clinical trials. The EMA Regulatory Science Strategy to 2025 finalized in March 2020 also recognized the need to foster innovation in clinical trials as a priority focus area–a position supported further by Europe's national medicines agencies' network in their strategy to 2025.

Meanwhile, an EU-funded research project with industry input–EU-PEARL–is one of several aiming to make clinical trials more efficient and patient friendly, through adaptive platforms which allow multiple companies to test their candidate drugs simultaneously against a shared placebo group. It is exploring how an adaptive platform trial with a single master protocol can allow new treatment groups to be added at any time, and candidate drugs that prove ineffective to be dropped. Other similarly-funded EU projects include ADAPT SMART, looking at evidence generation throughout the product life cycle and making best use of real world/registry data, GetReal, which is focused on including RWE in drug development using innovative trial designs, and EPAD, which is pioneering a flexible adaptive design for Alzheimer’s disease treatments.

Wider than Europe

On a broader geographic scale, the US FDA Complex Innovative Trial Design Pilot Program was set up in 2018, and in 2019 FDA released final guidance on Adaptive Designs for Clinical Trials of Drugs and Biologics. The US-based Clinical Trials Transformation Initiative is developing resources that will guide the appropriate use of the master protocols on which complex trials depend. And the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is developing guidelines on Adaptive Clinical Trials with a timeline of 2023, and on Good Clinical Practice Renovation to address the increasing diversity of clinical trial designs and data sources. And in September the University of Maryland Center of Excellence in Regulatory Science and Innovation organized a workshop on Complex Innovative Trial Design in Advancing the Development of Pediatric Therapeutics to discuss opportunities for leveraging complex and innovative trial designs, and to develop solutions on overcoming challenges, particularly in the use of bridging biomarkers in extrapolation and of Bayesian techniques in pediatric studies.

It is against this background that the European drug industry is sponsoring a multi-stakeholder workshop in October to develop shared solutions for the use of complex clinical trials to optimize drug development in Europe. As the industry grouping EFPIA says, "Complex clinical trials have the potential to accelerate drug development and enable patients to get timely access to transformative therapies." Its workshop is aiming to develop shared solutions in terms of simplified and standardized definitions, and in agreed responses to the challenges faced by regulators, health technology assessment bodies and payers, academia, patients’ organizations and industry. It hopes to define action plans to gain acceptance of complex trials supporting regulatory decision-making. The need may be obvious, but the sempiternal diversity of approaches to health–and particularly to medicines–in Europe may make achieving the objective more elusive than merely agreeing the agenda.