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International Clinical Trials

Central Learning

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 CNS 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 (1). CNS drug development is in real need of innovative approaches. Time and cost to approval are signifi cantly higher than other major therapeutic categories, and success rates languish at a dismal eight per cent compared to overall success rates of 16 per cent (2).

Looming Crisis

The impact of CNS diseases is proving to be a perfect storm, with disorders that affect both the elderly and the young. Degenerative brain disorders such as Alzheimer’s and Parkinson’s are diseases of ageing; their prevalence is rising with the greying of the world’s population. Debilitating diseases such as depression, psychosis, autism, epilepsy, multiple sclerosis and traumatic brain injury affect all age groups and can require repeated hospitalisation and ongoing rehabilitation services, while diminishing the sufferer’s quality of life and productivity.

The World Health Organization (WHO) estimates that 18 million people suffer from Alzheimer’s worldwide, and projects that there will be 34 million cases by 2025 (3). In 2010, dementia costs reached $604 billion – more than one per cent of global gross domestic products – prompting the World Alzheimer Report to declare that dementia is the greatest health and social crisis of the century (4). According to reports, there are fi ve million Parkinson’s sufferers and 2.5 million MS sufferers, with stroke, which accounts for more than six million deaths annually, on a similar trajectory of growing prevalence and cost (5,6,7). Depression affects an estimated 120 million people and is the leading cause of disability worldwide (8). The cost of depression-related cases in the US topped $83 billion in 2000 (9).

Research Hurdles

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 (10). 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 (11).

Limitations in Understanding Neuropathologies
Without a 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 diffi cult to know which ones to pursue (12). 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 identifi ed and few animal models exist to support preclinical development (13).

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 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 rigour, 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 such as depression, autism and Alzheimer’s.

Subject Recruitment and Retention
The cognitive and physical disabilities that characterise CNS diseases affect patients’ ability to participate in clinical trials. Patients may be unable to provide informed consent and 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 primary cost driver. Demanding inclusion and exclusion criteria mandated by study protocols can make CNS studies operationally unfeasible (14).

High Costs, Low Efficiencies
High development costs – now estimated at $1.3 billion per approved drug – are a significant hurdle in all therapeutic areas, but CNS drug development ranks as the most timeconsuming and costly. For NMEs approved by the FDA from 2003 to 2007, CNS products required 8.8 years from investigational new drug filing to approval (15,16). According to a 2011 survey of 33 biopharmaceutical companies, Phase 2 trial costs for CNS agents averaged $28,197 per patient; Phase 3a averaged $33,768; and Phase 3b averaged $41,824. Costs were dramatically lower for both diabetes and cardiovascular trials; only cancer trials consumed more research dollars (17).

New CNS Research Landscape

Noting the enormous difficulty of translating basic scientific knowledge into useful medicines, Francis Collins, Head of the National Institutes of Health, recently challenged researchers to “build a bridge across this yawning gap” (18).

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 fi elds of genetics, genomics and proteomics is playing an increasing role in understanding neurological disease processes at the molecular level. For example, new fi ndings regarding genes associated with MS are helping researchers to select better targets for drug intervention (19). 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 under way to identify reliable biomarkers to aid in diagnosis and staging disease (12). In conditions such as 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 effi cacy with fewer side-effects. Several CNS agents in clinical development today target specific protein kinases – enzymes involved in intracellular and extracellular signalling (20).

Electronic Data Collection, 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 such as endpoint adjudication and remote site monitoring reduce cost, improve accuracy and enable faster study close-out.

Real-time data access produces adaptive study designs that require fewer patients and increase likelihood of successful outcomes, and provides early identification of safety signals. Cutting-edge technologies – such as 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 (21).

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 example is NeuroNEXT, the National Network for Excellence in Neuroscience Clinical Trials, created by the National Institute for Neurological Disorders and Stroke to focus on Phase 2 trials and biomarker studies. This network of 25 US clinical centres has established centralised data and coordinating centres, and a centralised 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 (22).

This collaborative research environment is the 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.

References

1. World Health Organization, 2007, Neurological disorders affect millions globally: WHO report. Visit: www.who.int/mediacentre/news/releases/2007/pr04/en/index.html
2. DiMasi JA, Feldman L, Seckler A and Wilson A, Trends in risks associated with new drug development: success rates for investigational agents, Clin Pharmacol Ther 87(3): pp272-277, 2010
3. World Health Organization, Mental health and substance abuse facts and fi gures, Alzheimer’s disease: the brain killer. Visit: www.searo.who.int/en/Section1174/Section1199/Section1567/Section1823_8066.htm
4. Alzheimer’s Disease International, World Alzheimer report 2010: global economic impact of dementia. Visit: www.alz.co.uk/research/files/WorldAlzheimerReport2010.pdf
5. Dorsey ER, Constantinescu R, Thompson JP et al, Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030, Neurology 68(5): pp384-386, 2007
6. National Multiple Sclerosis Society – multiple sclerosis facts. Visit: www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx
7. World Health Organization – cardiovascular diseases (CVDs) fact sheet No 317 (Sep 2011). Visit: www.who.int/mediacentre/factsheets/fs317/en/index.html
8. World Health Organization – Mental Health: Depression. Visit: www.who.int/mental_health/management/depression/definition/en9. 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 64(12): pp1,465-1,475, 2003
10. Kaitin Ki, DiMasi JA, Pharmaceutical innovation in the 21st century: new drug approvals in the fi rst decade, 2000-2009, Clin Pharmacol & Thera 89(2): pp183-188, 2011
11. Traynor K, New drug and biological product approvals 2011, In American Society of Health-system Pharmacists’ Pharmacy News,
1 February 2012. Visit: www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=3661
12. Preskorn S, CNS drug development Part III: future directions, J Psychiatr Pract 17(1): pp49-52, 2011
13. Prichard JF, Risk in CNS drug discovery: focus on treatment of Alzheimer’s disease, BMC Neuroscience 9 (Suppl 3): S1, 2008
14. Craven R, The risky business of drug development in neurology, Lancet Neurol 10(2): pp116-117, 2011
15. DiMasi JA and Grabowski HG, The cost of biopharmaceutical R&D: is biotech different? Manage Decis Econ 28: pp469-479, 2007
16. Kaitin KI, Deconstructing the drug development process: the new face of innovation, Clin Pharmacol Ther 2010; 87(3): pp356-361
17. Silverman E, Clinical trials costs are rising rapidly. Pharmalot.com, 21 July, 2011. Visit: www.pharmalot.com/2011/07/clinical-trialcosts-for-each-patient-rose-rapidly
18. Wang S, Bridge the gap between basic research and patient care, NIH head urges, Wall Street Journal Health Blog, 11 April 2012. Visit: http://blogs.wsj.com/health/2012/04/11/bridge-the-gap-between-basic-research-and-patient-care-nihhead-urges/?mod=WSJBlog&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+wsj%2Fhealth%2Ffeed+%28WSJ.com%3A+Health+Blog%29
19. Sawcer S et al, Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis, Nature; 476(7359): pp214-219, 2011
20. Chico LK, Van Eldik LJ and Watterson DM, Targeting protein kinases in central nervous system disorders, Nat Rev Drug Discov 8(11):
pp892-909, 2009
21. 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 38 (1): pp239-251, 2004
22. Lancet Neurology, NeuroNEXT: accelerating drug development in neurology 11(2): p 119, 2012

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Mark Shapiro has more than 15 years of experience spanning virtually all aspects of drug development. Mark completed an MBA at Duke University’s Fuqua School of Business. Prior to that, he carried out Masters and Doctoral work in pharmacology and biomolecular pharmacology at the Boston University School of Medicine. He received a BSc in Chemistry at Virginia Tech. He has received several professional distinctions including Duke University’s Certificate in Health Sector Management, and professional certifi cations in both regulatory affairs and clinical research from the Regulatory Affairs Professional Society and Association of Clinical Research Professionals.
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