As the world comes to grips with the rise of chronic diseases—now the leading cause of death in both developed and emerging countries—the most daunting research challenges for 21st century healthcare are posed by central nervous system disorders. Causation is largely unknown and treatments are limited for most of the 600 diseases in the CNS category, which affect an estimated one billion people worldwide.[i] CNS drug development is badly in need of innovative approaches. Time and cost to approval are significantly higher than other major therapeutic categories, and CNS success rates languish at a dismal 8% compared to overall success rates of 16%.[ii] But there are hopeful signs that CNS drug innovation is improving, based on increasing knowledge of disease pathology, application of state-of-the-art technologies to  increase research efficiencies, and an emerging collaborative research environment that leverages data and innovative approaches to improve research outcomes.

A Looming Crisis in Unmet Medical Needs

The impact of central nervous system diseases is a perfect storm, with disorders that affect both the elderly and the young. Degenerative brain disorders like Alzheimer’s and Parkinson’s are diseases of aging; their prevalence is rising with the graying of the world population. Debilitating diseases like depression, psychosis, autism, epilepsy, multiple sclerosis, and traumatic brain injury impact all age groups and require repeated hospitalization, ongoing needs for rehabilitation services, and many years of diminished quality of life and productivity.

The World Health Organization (WHO) estimates that 18 million people suffer from Alzheimer’s worldwide and projects 34 million cases by 2025.[iii] In 2010, dementia costs reached $604 billion—more than 1% of global gross domestic products—prompting the World Alzheimer Report to declare dementia the greatest health and social crisis of the century.[iv] Parkinson’s with five million sufferers,[v] MS with 2.5 million,[vi] and stroke, which accounts for more than six million deaths annually,[vii] are on similar trajectories of growing prevalence and cost. Depression affects an estimated 120 million people and is the leading cause of disability worldwide.[viii] Total depression-related costs for the United States topped $83 billion in 2000.[ix]

High Research Hurdles Slow CNS Innovation

Despite this burgeoning medical need, a constellation of factors combine to slow progress in CNS treatment innovation. Approvals of novel CNS drugs have been relatively low: only 27 were approved from 2000 to 2009, compared to 49 cardiovascular drugs and 47 cancer drugs.[x] Among the 37 new molecular entities (NMEs) approved by the FDA in 2011, only three were indicated for major neurologic categories—two for epilepsy and one for depression.[xi]

Limitations in understanding neuropathologies. Without functional understanding of disease causes and processes it is difficult to select good targets for drug intervention. Advances in genetics and genomics have provided many potential targets for CNS drug development, but targets are so numerous it is difficult to know which ones to pursue.[xii] Basic tools for prediction and measurement of drug effects are lacking. In Alzheimer’s, for example, no definitive mechanism of disease causation and progression has yet been identified and few animal models exist to support preclinical development.[xiii]

Limitations in measuring efficacy and safety. Evaluation of neurologic conditions often relies on subjective measures of cognitive and physical function, which can lead to variations in reporting by both patients and investigators. The introduction of more objective diagnostic instruments—for example, brain imaging, neurological and psychiatric scoring tools, and patient reported outcomes—helps to increase scientific rigor, but improvements are needed.

Safety issues. Expanding requirements to demonstrate safety are increasing the size, duration and complexity of clinical trials. A leading reason for failure of neurologic drug candidates in this new environment is the risk of serious and possibly life-threatening side effects. Higher risk is acceptable in treatments for life-threatening diseases such as cancer, but there is a lower tolerance for risk in treatments for chronic neurologic conditions like depression, autism and Alzheimer’s.

Challenges in subject recruitment and retention. The cognitive and physical disabilities that characterize CNS diseases impact patients’ ability to participate in clinical trials. Patients may be unable to provide informed consent; many find visits to clinical sites taxing or even prohibitive. There is increasing competition for study subjects; recruitment has become the leading roadblock to successful studies, as well as a leading cost driver. Demanding inclusion and exclusion criteria mandated by study protocols can make CNS studies operationally unfeasible.[xiv]

High costs, low efficiencies.  High development costs—now estimated at $1.3 billion per approved drug[xv]—are a significant hurdle in all therapeutic areas, but CNS drug development ranks most the most time-consuming and costly. For NMEs approved by the FDA from 2003 to 2007, CNS products required 8.8 years from IND filing to approval.[xvi] According to a 2011 survey of 33 biopharmaceutical companies, Phase II trial costs for CNS agents averaged $28,197 per patient; Phase IIIa averaged $33,768; and Phase IIIb averaged $41,824. Costs were dramatically lower for both diabetes and cardiovascular trials; only cancer trials consumed more research dollars.[xvii]

Just Ahead—A New CNS Research Landscape

Noting the enormous difficulty of translating basic scientific knowledge into useful medicines, head of the National Institutes of Health Francis Collins recently challenged researchers to “build a bridge across this yawning gap.”[xviii] Advances in basic neurological science, enabled by better operational technologies and research collaborations, are beginning to bridge the wide gaps in CNS innovation.

Improving disease models. Knowledge emerging from the fields of genetics, genomics and proteomics is playing an increasing role in understanding neurological disease processes at the molecular level. For example, new findings regarding genes associated with MS are helping researchers select better targets for drug intervention.[xix] Advances in this fundamental knowledge also improve drug screening and early identification of drug candidates with the best potential for success in development.

Developing biomarkers. Major efforts are underway to identify reliable biomarkers to aid in diagnosis and disease staging.12 In conditions like Alzheimer’s and autism, identifying early-stage disease may offer opportunities to slow or halt disease progression. Biomarkers are invaluable tools to evaluate drug effectiveness; in CNS studies, replacing traditional subjective measures with objective biomarkers as study endpoints promises to make clinical trials more informative and efficient.

Aiming for targeted therapies. Reliable models of neurological disease processes and associated biomarkers will make it possible to develop more targeted CNS therapies. Targeted drugs deliver greater efficacy and safety based on identifying subpopulations of patients who will benefit from greater efficacy with fewer side effects. Several CNS agents now in clinical development target specific protein kinases—enzymes involved in intracellular and extracellular signaling.[xx]

Technology: EDC, real-time data, and Internet-based research. Internet-based technologies are delivering dramatic clinical trial efficiencies. Electronic data collection came of age in the 2000s; now the Internet is driving faster, lower-cost processes for data collection, data mining, and research communications to advance trial operations and safety reporting.  Automated systems for functions like endpoint adjudication and remote site monitoring reduce cost, improve accuracy, and enable faster study close-out. Real-time data access enables adaptive study designs that require fewer patients and increase likelihood of successful outcomes, and provides early identification of safety signals. Cutting edge technologies—like patient recruitment through online social networks and remotely conducted clinical trials in which patients can participate in studies from home—promise to be especially useful in CNS research.[xxi]

Building collaborations. A growing number of major collaborations point to the evolution of a new CNS research environment based on shared knowledge, data, and operational resources among drug developers in industry, government and academia. One is NeuroNEXT, the National Network for Excellence in Neuroscience Clinical Trials, created by the National Institute for Neurological Disorders and Stroke (NINDS) to focus on Phase II trials and biomarker studies. This network of 25 U.S. clinical centers has established centralized data and coordinating centers and a centralized institutional review board—a major advantage that eliminates the time and cost inefficiencies that result from multiple review boards at each participating research institution. Investigators can apply to use the NeuroNEXT infrastructure to overcome barriers associated with lack of experience in conducting clinical studies and limited access to eligible patients.[xxii]

This collaborative research environment is our best path to bridging the gap between the new knowledge of neurological disease processes and improving the lives of patients. Shared resources—enabled by advanced information technologies—will shape both the clinical trial process as well as safer and more effective CNS therapies.

[i]World Health Organization, 2007. Neurological disorders affect millions globally: WHO report. Available at:

[ii] DiMasi JA, Feldman L, Seckler A, Wilson A. Trends in risks associated with new drug development: success rates for investigational agents. Clin Pharmacol Ther. 2010;87(3):272-277.

[iii] World Health Organization. Mental health and substance abuse facts and figures. Alzheimer’s disease: the brain killer. Available at:

[iv] Alzheimer’s Disease International. World Alzheimer report 2010: global economic impact of dementia. Available at:

[v] Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384-6.

[vi] National Multiple Sclerosis Society. Multiple sclerosis facts. Available at:

[vii] World Health Organization. Cardiovascular diseases (CVDs) fact sheet No 317 (Sep 2011). Available at:

[viii] World Health Organization. Mental Health: Depression. Available at:

[ix] Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003; 64(12):1465-75.

[x] Kaitin Ki, DiMasi JA. Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009. Clin Pharmacol & Thera. 2011; 89(2):183-188.

[xi] Traynor K. New drug and biological product approvals 2011. In American Society of Health-system Pharmacists’ Pharmacy News, February 1, 2012. Available at:

[xii] Preskorn S. CNS drug development Part III: future directions. J Psychiatr Pract. 2011;17(1):49-52.

[xiii] Prichard JF. Risk in CNS drug discovery: focus on treatment of Alzheimer’s disease. BMC Neuroscience. 2008;9(Suppl 3):S1.

[xiv] Craven R. The risky business of drug development in neurology. Lancet Neurol. 2011;10(2):116-7.

[xv] DiMasi JA, Grabowski HG, 2007. The cost of biopharmaceutical R&D: is biotech different? Manage Decis Econ. 2007;28:469-479.

[xvi] Kaitin KI. Deconstructing the drug development process: the new face of innovation. Clin Pharmacol Ther. 2010;87(3):356-61.

[xvii] Silverman E. Clinical trials costs are rising rapidly., July 21, 2011. Available at:

[xix] Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214-219.

[xx] Chico LK, Van Eldik LJ, Watterson DM. Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov. 2009;8(11):892-909.

[xxi] Ellenberg K, Hoover A, Rutherford M, et al. From informed consent through database lock: an interactive clinical trial conducted using the Internet. Drug Information Journal. 2004; 38 (1) 239-251.

[xxii] Lancet Neurology. NeuroNEXT: accelerating drug development in neurology.2012;11(2):119.