Neuroscience clinical trials present unique challenges that set them apart from other therapeutic areas. Although developing new treatments for mental health disorders has immense potential to improve lives, these trials face obstacles that impact their success rates. Whether from the increasing placebo responses to the difficulty measuring subjective outcomes, sponsors, and contract research organisations (CROs) must work together to navigate these challenges and more, leading to new treatment options.

Currently, as many as half of the world’s population will experience a mental disorder by the time they are 75. This includes depression, schizophrenia, and neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases. However, many other therapeutic areas are easier to target than many types of CNS disease.

In recent years, some companies have scaled back their central nervous system (CNS) programs because of development difficulties and high costs, while others are taking alternative approaches to overcoming barriers.

Yet, navigating these challenges in neuroscience clinical trials is possible by understanding and addressing them.

Neuroscience clinical trial challenges

A significant challenge to neuroscience clinical trials is the decrease of active drug versus placebo response, and how it affects trial outcomes. A natural phenomenon, it nevertheless interferes with researchers’ ability to measure the treatment’s effectiveness, and it makes it appear that the new treatment isn’t working, or it doesn’t show enough benefit to receive regulatory approval.

Additionally, although progress has been made recently, limited availability of validated biomarkers presents a challenge. Whereas in cancer studies or other physical diseases have obvious, measurable markers like tumors or blood markers, mental disorders, and neurodegenerative diseases are not always so clear. In their limited absence for specific indications or populations, researchers instead group patients according to their symptoms and use semi-subjective or patient-reported primary endpoints.

Compounding the difficulties, high development, and clinical trial cost coupled with difficulty finding accurate measures for success make developing treatments for mental disorders difficult to justify financially.

Training can mitigate the placebo response in clinical trials

Considering that the placebo response varies in clinical trials from 13 to 50% in antidepressant trials and 6 to 41% in schizophrenia trials, you can take steps to mitigate it to improve trial results. Since it might be largely driven by patient as well as medical care provider expectations, your priority becomes managing expectations, which begins with a well-designed patient education program during recruitment and onboarding. By helping patients understand their role in the trial and the importance of accurate symptom reporting, your clinical trials can obtain more accurate data.

The data support this idea. One study focused on placebo response mitigation with an all-placebo study of major depressive and psychotic disorders. The researchers were able to reduce the placebo effect by using a Placebo Control Reminder Script (PCRS), which provided education on placebo response.

In addition to patient education, proper and consistent psychometric assessments by selected raters is critical, making a robust training program necessary. Implementing training that follows agreed rating conventions that addresses the raters’ variabilities and potential drifts is fundamental to increasing the likelihood of success in neuroscience clinical studies.

Reduce attrition of neuroscience clinical trial study participants

Understanding why people leave studies is vital to keeping them enrolled—and completing your study. Of course, you cannot control all the reasons study participants drop out. Some leave because the treatment was not working for them, or because the treatment’s side effects were unacceptable.

However, leaving aside things that you cannot control, there are several things you can do to reduce attrition in your neuroscience clinical trial.

Simplify and streamline eligibility and trial compliance requirements

If your processes or protocols are overly complicated, you will only be able to keep the most dedicated patients, losing otherwise excellent candidates. Making the clinical trial experience as convenient for your patients as possible will help more study participants enroll and complete the trial. Here are a few ideas:

  • Make it easier to determine eligibility with online forms, because everything you do to make it easier invites more potential participants.
  • Use existing technology—like tablets and phones—to reduce paperwork and collect data instead of enormous packets. Patients can be intimidated when they have a stack of paperwork to complete for something that might help them.
  • Reduce check-in difficulty and scheduling conflicts. Offer virtual office visits instead of in-person appointments where possible. Many study participants have busy schedules, and sticking to a strict schedule of clinical appointments is difficult, especially when you factor in travel time.
  • Simplifying study visits by only including assessments that are mandatory to address the protocol hypothesis will also decrease the study subject burden but also increase sites’ acceptance of the new study.

Improve patient education and engagement

Communication prevents questions from becoming problems. Your study participants need clear communication that shows how either they or future patients will benefit from the research. In addition, the stigma connected to mental disorders does not help patient recruitment or retention. By making study participants feel part of something greater, they are more likely to stay enrolled—even if the protocols are a little burdensome. Here are a few more ways to improve education and keep your patients engaged in the process:

  • Use plain language in marketing materials and clinical literature. Make the material easy to understand, even if the topic is complex.
  • Make a two-way communication part of the study process. Engage your patients by sharing tips to help them manage their condition, information about the study progress, and other information that keeps them engaged.
  • Make online support groups available. Allow patients to reach out anonymously for advice and help.
  • When patients drop out, ask them why. Get feedback on what made them leave the trial early and what might change their mind.
  • Consider involving patient associations in selected indications from the early days when the study is designed and solicit their input to the planned study participant path.

Reduce the operational burden on study sites

As neuroscience trial protocols become more complex, some study sites might struggle to meet requirements. Those sites are sometimes under-staffed with budget concerns and other operational hurdles like technology limitations or lack of experience with clinical trials.

CROs like CliniRx can help manage challenges and mitigate the operational burden by providing support through their network of qualified vendors. Reducing the overall operational burden means more sites can take part, which gives you easier access to qualified study participants.

Reduce the operational burden with these ideas:

  • Use clear communication methods to keep everyone informed.
  • Provide sites with effective pre-screening support and training. Preparing sites ahead of the trial can reduce hiccups in procedures and increase protocol compliance.
  • Ensure clarity and specificity in your protocol’s schedule of activities and any amendments.
  • Reduce the onboarding burden by making sure that technology you require sites to use has thorough online learning resources.
  • Invest into strategic relationships with sites rather than transactional only. This will allow sites to plan in advance for potential new studies ahead of time and increase sites’ availability for your new project.

Improve neuroscience trials patient selection criteria

For all our scientific advancements, our understanding of the pathophysiology behind mental disorders is still limited, and for up to 60% of patients response to treatment can be suboptimal, insignificant or none.

With few known biological markers, trial protocols depend heavily on patient-reported outcomes.

However, there are things you can develop to improve the patient selection criteria for your next neuroscience clinical trial:

  • Patient education programs to help collect more accurate information.
  • Strategies to select more homogeneous yet diverse groups for trials.
  • Develop and validate translational biomarkers for pharmacodynamic assessments and patient selection.

Improve future neuroscience trial outcomes by addressing current challenges

To successfully complete clinical neuroscience trials, your team will have to take a multifaceted approach. While the placebo response rates, limited biomarkers, and operational difficulties are hurdles, strategic solutions can improve the outcomes.

By adopting enhanced patient education programs, streamlining procedures, and improving site support, sponsors, and CROs can work together to improve data quality and minimise patient attrition and placebo response.

In a Phase II/III clinical study in chronic schizophrenia, an evolving regulatory strategy caused our sponsor to increase the sample size three times. Unfortunately, the contracted central lab could not meet the revised requirements within the designated timeline. We pivoted and adopted a country-specific approach, contracting with local labs instead. The sponsor announced topline results and plans to advance to the next phase. Our team’s quick action and ability to execute a rapid course change saved the study.

References:

Age of onset and cumulative risk of mental disorders: a cross-national analysis of population surveys from 29 countries. McGrath, John JAguilar-Gaxiola, Sergio et al. The Lancet Psychiatry, Volume 10, Issue 9, 668 – 681

Gribkoff, V. K., & Kaczmarek, L. K. (2017). The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology120, 11–19. https://doi.org/10.1016/j.neuropharm.2016.03.021

Holper L. (2020). Raising Placebo Efficacy in Antidepressant Trials Across Decades Explained by Small-Study Effects: A Meta-Reanalysis. Frontiers in psychiatry11, 633. https://doi.org/10.3389/fpsyt.2020.00633

Rief, W., Nestoriuc, Y., Weiss, S., Welzel, E., Barsky, A. J., & Hofmann, S. G. (2009). Meta-analysis of the placebo response in antidepressant trials. Journal of affective disorders118(1-3), 1–8. https://doi.org/10.1016/j.jad.2009.01.029

Kinon, B. J., Potts, A. J., & Watson, S. B. (2011). Placebo response in clinical trials with schizophrenia patients. Current opinion in psychiatry24(2), 107–113. https://doi.org/10.1097/YCO.0b013e32834381b0

Cohen, E.A., Hassman, H.H., Ereshefsky, L. et al. Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders. Neuropsychopharmacol. 46, 844–850 (2021). https://doi.org/10.1038/s41386-020-00911-5

Howes, O.D., Thase, M.E. & Pillinger, T. Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry 27, 58–72 (2022). https://doi.org/10.1038/s41380-021-01200-3

 

RFI form

Please submit your RFI/RFP here. Our team will revert at the earliest