Central nervous system (CNS) disorders are a diverse group of conditions that include psychiatric, neurological and substance abuse disorders. Unfortunately for patients, treatment options for CNS disorders are often limited (or non-existent). To make matters worse, comparatively few CNS drugs are in the development pipeline.
What aspects of CNS disorders contribute to lagging drug development? Read on to find out.
Why CNS Drug Development Is Crucial
Many of these disorders are common — one in four American adults today is dealing with at least one CNS condition. Additionally, according to NIMH, CNS disorders cost the U.S. over $317 billion in healthcare expenditures, lost wages, and disability benefits. If trends continue, CNS disorders are expected to make up 14.7 percent of the global disease burden by 2020 — the largest burden of any disease group.
What Makes CNS Drug Development Unpopular
CNS drugs are among the least likely treatments to gain FDA approval, making investment in them a gamble. In fact, only 8.2 percent of drug candidates are ultimately approved. Additionally, the time and expense involved in bringing a CNS drug to market is significantly greater than those of other therapeutic areas. When met with an average 8.1 years and $850 million in direct costs per drug, many major pharmaceutical companies are scaling back from CNS drug development or have exited the field altogether.
Part of this is due to the increased regulatory expectations that come with working with vulnerable populations — children, the elderly, the disabled and the mentally ill. Additionally, drugs that work directly on the CNS carry inherent safety risks, including suicidality, abuse liability, physical dependence, sexual dysfunction, and cognitive and motor impairment. All of these risks must be addressed in a clinical development plan.
To ensure patient safety, the FDA provides guidelines for CNS drug development, including specific guidance for specific disorders like Alzheimer’s and ADHD. However, regulatory guidelines can be difficult for sponsors to navigate, leading them to pursue less complex niches of drug development.
Another aspect of CNS disorders holding back R&D efforts is that the pathophysiology of these conditions remains poorly understood — it’s impossible to create targeted therapies like the ones seen in chemotherapy when the underlying molecular mechanisms of a disorder are unknown. This also causes issues when choosing neuropsychological endpoints for establishing efficacy in clinical trials.
Many existing metrics can be subjective and limited by unidentified variables along with a relative lack of available biomarkers and physical examination findings for establishing novel biochemical surrogate markers. Currently, the most powerful efficacy metric for CNS trials is neuropsychological testing. While useful, neuropsychological testing has its own issues.
How Neuropsychological Testing Is Limited
Current standards in neuropsychological testing are a major contributor to the high cost of CNS drug development. These methods are time intensive, require interpretation by experienced neuropsychologists and may involve special equipment, training, and testing environments.
Neuropsychological tests must be interpreted in the context of the patient’s age, gender, education level, and cultural background, which can all affect test performance independent of CNS disorder symptoms. Additionally, a patient’s mental or functional status can be highly variable day to day or even hour by hour. These, along with a variety of other factors, make objective evaluation of drug efficacy difficult.
And no battery of tests is perfect for all situations: When designing trial protocols, sponsors must consider the relative strengths and weaknesses of each test in terms of reliability, validity, sensitivity and specificity.
For more insights on the challenges CNS drug researchers face and the novel strategies being used to overcome them, read our white paper on patient performance in neuropsychiatric trials.