Complex Clinical Trials – A decade of innovation in clinical research

"Patients with unmet needs are longing for innovative treatments to be approved. Especially rare disease patients, where only 5-6% have approved treatments, need a new strategy to speed up research and provide new opportunities to access innovative drugs. Complex clinical trials can be the change that patients want to see".
Claas Röhl, chairman of NF Patients United

‘To ensure that patients have faster access to innovative and transformative therapies’, that is the overall goal of EFPIA’s Regulatory Road to Innovation. An important area for action within the existing legislative framework is the use of more advanced clinical trials in order for medicines to reach patients more rapidly. These types of clinical trials are called complex clinical trials (CCTs)[1].

The increased understanding of both human genetics, patients’ DNA, and the genetics known to be associated to various diseases has created the current reality that traditional clinical trial designs are no longer suited to answer medical questions within the timeframe that the patients are expecting to gain access to new therapies[2]. Complex (and innovative) clinical trials can allow multiple new treatments to be investigated in parallel in various diseases or patient groups. This will enable more patients to be given the opportunity to join a trial and it will result in shorter timelines to get the data to decide if a medicine is effective and safe and considered by regulators to be approved. CCTs designs have been used for over a decade in drug development, examples include the application of master protocols covering platform, umbrella and basket trials; the enrichment of trial populations through the use of biomarkers, incorporating historical control arms and more advanced adaptive trial designs. CCTs and innovation in trial designs have so far been used by 80% of EFPIA companies and have become a key component in generating clinical data[3],[4]. The use of CCTs should be encouraged but key stakeholders, such as regulatory agencies and Health Technology Assessment bodies, need to accept the use of CCTs for new treatments to find their way to the right patients in an efficient manner[2].

How does this benefit the patient?

The decision to participate in CCTs is one that should be made by the patient in close communication with the physician. Patients in clinical trials play a key role in drug development and discovery; CCTs contribute important knowledge on potential new treatments for treating and preventing diseases.

First and foremost participants can help others who are suffering from the same medical conditions by contributing to medical research which has the goal to improve public health. Above all, patients who take part in a CCT may benefit from the treatment(s) they receive and will be seen regularly by a healthcare professional.

How can patients continuously be engaged from beginning to end?

Since there is a desperate need for new and innovative treatments in areas of significant unmet medical need, it is crucial that CCTs, with innovative trial design, are broadly adopted to enable an acceleration of clinical trials in Europe and beyond [1],[4]. The emphasis should not just be on data collected from patients regarding their medical conditions. It is as equally important to understand the viewpoint of the patient and how their condition affects their everyday life. Moreover, patients need to feel comfortable in joining a CCT and need to be able to visualise how they are contributing to the bigger picture where their data could enable a potential new therapy to treat and/or prevent disease. CCTs design should recognise the needs and expectations of patients. The goal is for participants to experience more patient-friendly trials, from start to finish. Digital technologies can support this goal by making trial participation less burdensome and brings more options in how patient care is delivered. Ensuring positive experiences for patients facilitates participation and retention in CCTs[2],[3].

How do CCTs need to evolve?

CCTs have been increasing in their use in recent years, so it is important that lessons are learned from these recent experiences to further evolve CCTs. Building on the COVID pandemic and the use of  master protocols to search new COVID therapies, identifies the need of fostering innovation in Clinical trials [2]. Moreover, COVID trials have shown that different stakeholders, including academics, Pharmaceutical Industry, regulators and HTAs can align on CCTs supporting innovative strategies for evidence generation [3]. New tools and technologies, and improved clinical trial processes will pave the way towards higher patient centricity including diverse patient populations and patient engagement strategies across the development ecosystem.

All of this together will enable patients to have faster access to innovative and transformative therapies that best fits their specific disease. Much progress has been achieved in recent years but there is more to be done to align all stakeholders to accept complex clinical trials.

[1] EFPIA Regulatory Road to Innovation.

[2] Multi-stakeholder workshop on complex clinical trials, October 2021

[3] Make the regulatory system fit for the future of medical innovation, a Blog from Nathalie Moll 

[4] EFPIA Regulatory Road to Innovation, Leaflet

Chrissie Fletcher

Chrissie is the Vice President and Head for Speciality & Primary Care Statistics at GlaxoSmithKline. She leads...
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Mireille Muller

Mireille Muller is currently Executive Regulatory Policy Director at Novartis, focusing on clinical trials, advanced...
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