Clinical Research: Phase 1 - Phase 4

Operational Challenges of Neuroscience Clinical Trials, Part 1: Overview

With billions of neurons, the brain is the most complex organ in the body, so it’s not surprising that neuroscience clinical trials—more so than trials in other medical specialties—face major challenges, both conceptual and practical. In this new blog series, we’ll look at the challenges sponsors face when operationalizing clinical trials and share lessons from our extensive experience in this therapeutic area over the years.

High burden, few treatment options

One-quarter of Americans have at least one CNS disorder, and this number seems to be on the rise.[1] Brain disorders are also a major cause of disability and death, not to mention a source of significant economic burden. Unfortunately, despite a great deal of effort, effective treatments are generally scarce or nonexistent for the most common brain disorders.

For example, people living with Alzheimer’s disease, epilepsy, depression, and post-traumatic stress disorder often find little relief from treatments. There are no disease-modifying therapies for neurodegenerative diseases and no effective treatments for the core symptoms of autism and schizophrenia. In psychiatry especially, the majority of the most effective treatments have been around since the 1950s, with few new molecular targets since the 1980s.

Trial tribulations

The need for better neuroscience therapeutics is high, yet the disproportionately high R&D costs and failure rates of novel neurological and psychiatric therapeutics have made many pharmaceutical companies reluctant to invest in neuroscience indications. According to the Tufts Center for the Study of Drug Development, not only do CNS drugs take 18 percent more time to develop than other drugs, but only 6 percent of those that enter clinical testing are eventually approved (less than half the rate of 13 percent for other drugs).[2]

The most common reason for failure is not toxicity, but lack of efficacy. Sadly, these statistics are discouraging pharmaceutical companies from investing in neuroscience indications. Substantial cutbacks and, unfortunately, even complete dissolution of neuroscience R&D programs abound.

Challenges to success: conceptual and operational

Executing and delivering quality clinical trials in neuroscience is very difficult for a number of reasons. Many of the conceptual challenges have been explored in the Institute of Medicine’s Forum on Neuroscience and Nervous System Disorders, an ongoing series of collaborative workshops that brings together key stakeholders in an effort to accelerate translational neuroscience.

Major conceptual challenges include the fact that diagnostic classifications of brain disorders are still based solely on symptoms and signs, with causes and mechanisms varying across patients within existing diagnostic categories. In addition, because the pathophysiological mechanisms of CNS disorders are generally much less well understood than other areas of medicine, this makes molecular target identification difficult.

The development of animal models has also lagged due to this lack of understanding of disease mechanisms. In general, animal models of CNS disorders have low predictive validity and reproducibility and aren’t able to fully replicate the complexity of the human disorders they model.

In addition to these conceptual barriers to neuroscience trial success, a number of practical challenges also exist, many of which are unrelated to the effect of the drug being studied.

In future posts in this blog series, we’ll take a closer look the top three operational challenges in neuroscience trials that are inspiring the next generation of novel tactics, creative processes, trial designs, and even niche providers. The first challenge is the high rate of placebo response. A second operational challenge is patient recruitment and the struggle to find participants that will yield quality data, and the third is the subjective nature of assessments conducted during neuroscience trials. Join us in the coming weeks to learn more about the details of these challenges and what can be done to combat them, or contact us today for more information.

Part 2: High Placebo Responses

Part 3: Patient Recruitment

Part 4: Assessment Subjectivity

[1] National Institute of Mental Health. (2018, January). Statistics. Retrieved from

[2] Tufts Center for the Study of Drug Development. (2014, November/December). CNS Drugs Take Longer to Develop, Have Lower Success Rates, Than Other Drugs. Retrieved from