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(Re)Designing schizophrenia trials: Lessons from the frontlines of CNS research

Our recent webinar with industry experts focused on the opportunities for innovation and the necessity of true collaboration to achieve it. Small actions can build strong bridges between sponsors, CROs,  sites and patients, driving engagement and delivering meaningful outcomes. 

The webinar, entitled “Get ready for a new wave of clinical trials in schizophrenia: How sites and sponsors can avoid conceptual mistakes,” brought together a panel of seasoned experts including: 

  • Dr. David Walling, Chief Clinical Officer, CenExel CNS
  • Dr. Louisa Steinberg, Senior Director, Drug Development Solutions, Psychiatry at ICON
  • Dr. Peter Schüler, Senior Vice President, Drug Development Solutions, Neurosciences, ICON. 

Here we outline some of the key discussion points.

A promising pipeline with unique challenges

Recent scientific progress offers reasons for optimism in schizophrenia trials. As Dr. David Walling explained, new mechanisms of action, such as muscarinic receptor agonists and TAAR1 modulators, are broadening therapeutic possibilities for patients who have not responded to traditional dopamine-targeting drugs.

“This is a really exciting time,” said Dr David Walling. “We have multiple new medications being developed for multiple areas of schizophrenia, and each presents its own unique challenge.”

Alongside these advances, however, come operational hurdles. For example, increasing placebo responses, complex protocols, subjective endpoints, low adherence to the therapy and high dropout rates and even the risk of duplicate patients. Innovation alone won’t carry trials across the finish line. To succeed, sponsors and CROs must invest in early, active partnerships with research sites and the patient community.

Why schizophrenia needs a new clinical trial playbook

When attendees were polled during the webinar, a striking 95% said they believe there is more room for improvement in schizophrenia trials than in studies for depressive disorders.

“This observed gap is not just about trial mechanics,” noted Dr. Peter Schüler. “We always have to look around and ask what’s the reality outside of the research world? What happens in clinical care? Amongst all the other CNS indications, schizophrenia trials have very specific challenges. They target acutely ill patients as well as cognitively impairment ones with negative symptoms.”

That alignment between the clinical and research environments is critical, and it starts with early and consistent engagement between stakeholders.

Designing trials for sites and participants

A recurring theme in the discussion was the need to make trials feasible not just for participants, but for the sites delivering them. Excessively rigid inclusion/exclusion criteria, long assessment days, and underappreciated operational burdens can all derail a trial before it begins.

“Remember, these are patients suffering from an illness which impacts their ability to function in day to day life said Dr. Louisa Steinberg. “We have to make sure we’re not expecting superhuman feats from them.”

Dr. Walling reinforced the importance of meaningful value for participants. “If it’s a true innovation, enrolment is easier. If it’s just another ‘me-too’ drug, patients are harder to convince.”

This underscores the need to build patient-centred protocols in partnership with sites and caregivers to leverage the insight from those who best understand the population and its needs.

Site voices matter

Panellists agreed that site feedback should be sought as early as the synopsis stage of protocol design, not after the protocol is finalised. This ensures that the protocol is feasible, accessible and accounts for operational hurdles. 

“You can take or leave my feedback,” said Dr Walling, “but my coordinators give even better feedback on the real-life operations of the protocol.”

Whether it’s scheduling conflicts, medication timing, or consent procedures, coordinators and site staff offer frontline knowledge that can significantly improve trial design and execution. CROs and sponsors who solicit input and listen to these voices early reduce the risk of costly amendments, recruitment and retention issues, and delays down the line.

Rater training needs to evolve

Schizophrenia trials often rely on subjective outcome measures, meaning consistent, quality raters are crucial to mitigate variability and bias. While experienced raters often undergo repetitive, generic training, new raters are sometimes thrown in without adequate support. The panel called for a more tailored approach that would match the training to the trial’s therapeutic focus and the rater’s level of experience. Even within schizophrenia trials, there can be a wide variation between rater requirements. For example, negative symptoms trials require a different skillset than cognition or acute schizophrenia. 

ICON, for example, is increasingly using performance data to tailor rater training. But as Dr. Schüler noted, “Good rater training is still needed upfront to avoid mistakes before they happen.”

Small changes making big impacts

Some of the most powerful improvements in schizophrenia trials come from small, relationship-driven adjustments that ripple across the entire study experience.

One long-standing challenge in CNS research is managing placebo response. While central raters were once considered a potential solution, the panel noted they haven’t consistently outperformed site-based raters and often introduce unnecessary cost and complexity. Increasingly, the focus is shifting back to what matters most: human connection. Ensuring that everyone at the site, from reception staff to principal investigators, understands how to minimize placebo effects simply by their own behaviour and explicitly explaining the purpose of the trial to the participants. Dr. Schüler gave the example: “Simply tell the patients there is no reason to please the doctor by saying they feel better – unless they actually do so”.

Dr. Walling gave another practical example: “We show the ward and their room to candidates for a trial that requires a period of hospitalization– so they can make a more educated decision whether that is fine for them”. He also pointed to the problem of duplicate participants. Aside existing databases and analytics which search for unusual similarities in the subject’s clinical data, familiarity with participants’ histories are often the first lines of defence against this issue that can potentially skew trial results.

Beyond screening and assessments, the relationship between the site and the participant drives long-term success. Retention, Dr Walling stressed, depends heavily on consistency and care. In one 90-day outpatient study with frequent visits, his team lost only one participant thanks in large part to regular personal check-ins. “Every time a subject came in, we’d confirm their next visit and get their commitment,” he said. “That personal connection makes a huge difference.”

Caregivers, too, play a vital role. Including them in site tours and ongoing communications helps foster trust, ease uncertainty and support the participant’s continued involvement. In trials where the human factor is often the most unpredictable variable, these simple, people-first strategies can make all the difference.

Redefining success through partnership

Ultimately, the message from all three speakers was clear: schizophrenia trials succeed when stakeholders collaborate. Ideally, sponsors respect site knowledge, CROs facilitate feedback loops, and participants and caregivers are treated as true partners in research.

As Walling put it, “Partner with sites, with patients, with your CRO. We all want the study to succeed.”

At ICON, that spirit of collaboration is central to how we support CNS studies from protocol design through execution. Our teams are committed to working side-by-side with sites and sponsors to build better trials, smarter processes, and ultimately, better outcomes.

 

Connect with us to learn more about designing and optimising schizophrenia trials with deeper site and participant engagement. 

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