Neuroscience Trials of the Future: Proceedings of a Workshop (2016)

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1 Introduction1 Although major strides have been made over the past two decades in basic neurosciences, translation into more effective treatments has eluded the field (Kaitin, 2012). Among the many factors contributing to this re- ality are the standard clinical trial methods that have barely changed dur- ing this time, with the exception of increased use of electronic data acquisition and analysis. Clinical trials for diseases of the central nervous system (CNS) suffer from high failure rates due, in part, to the limited understanding of dis- ease pathophysiology and lack of well-validated targets (Pankevich et al., 2014; Wegener and Rujescu, 2013). In addition, even in the hands of ex- perienced investigators, poor assay sensitivity2; the lack of reliable, vali- dated, and clinically meaningful endpoints; high placebo or non-specific responses; high variability among participants and sites; poor treatment adherence; and inadequate recruitment and retention have adversely af- fected pharmaceutical and device development (Ereshefsky et al., 2016; Gupta, 2012; Silberman, 2009). One of the net effects of these challenges has been to simply increase the trial sample size in an attempt to control type II error (false-negative results) (Becker and Greig, 2009; Button, 2013). Yet, promising early clinical data are often not replicated in large regis- 1 The planning committee’s role was limited to planning the workshop, and the Pro- ceedings of a Workshop has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus. 2 For examples of recent terminated trials in Parkinson’s disease and Huntington’s disease due to futility, please go to http://www.ninds.nih.gov/disorders/clinical_trials/2CARE- Early-Study-Closure.htm; https://nccih.nih.gov/research/extramural/crest-e; and https://parkin sontrial.ninds.nih.gov/netpd-LS1-study-termination.htm (accessed June 2, 2016). 1 

2 NEUROSCIENCE TRIALS OF THE FUTURE tration trials, resulting in Phase III failure rates that are among the high- est in medicine (Kesselheim et al., 2015). The apparent unsustainability of the current clinical development pipeline has driven many large phar- maceutical companies to significantly decrease investments in neurosci- ence (Abbott, 2011; Miller, 2010; Riordan and Cutler, 2011), although, there is some evidence that this trend is reversing (Herper, 2015; Tracy, 2015). Of drug development projects started between 2000 and 2004, the number of new medical entities (NMEs)3 generated each year was less than half the number of NMEs generated by projects started between 1990 and 1999. However, within each therapeutic area, the productivity was similar, indicating that lower productivity reflected a shift to areas where there is greater medical need, but higher risk, such as neuroscience and oncology (Pammolli, 2011). In comparison to oncology, there are far fewer clinical trials for nervous system disorders, yet in 2015 the Food and Drug Administration (FDA) approved 19 drugs in oncology and 9 in neuropsychiatry, suggesting greater efficiency in the neuroscience area, said Perry Nisen, chief executive officer of Sanford Burnham Prebys Medical Discovery Institute. Quite apart from the business perspective, the fact that many early- stage clinical trials misleadingly provide a false-positive signal (a type I error) raises the question of whether volunteering for these trials is in the best interest of trial participants (Button et al., 2013; Cohen et al., 2007). Better methods, from clinical study design through execution and evaluation, could help restore the integrity, feasibility, acceptability, effi- ciency, and economic viability of clinical neuropsychiatric drug devel- opment. However, in order to use innovative approaches to address these challenges, buy-in and acceptance from the regulatory community will be important (Parekh et al., 2015). For example, adaptive trials, in which trial parameters are modified based on interim data, could offer a more efficient means of addressing experimental questions involving multiple uncertainties, although they are often infrequently used (Wang et al., 2011). In addition, understanding the utility of wearable and patient mon- itoring devices (and the data generated) in neuroscience clinical trials is important (Capone, 2015; Desgrousilliers and Keet, 2015; Kumar et al., 2013). 3 Drugs that contain an active moiety that has not been previously approved by the FDA. 

INTRODUCTION 3 WORKSHOP OBJECTIVES On March 3–4, 2016, the National Academies of Sciences, Engineer- ing, and Medicine’s Forum on Neuroscience and Nervous System Disor- ders held a workshop in Washington, DC, bringing together key stakeholders to discuss opportunities for improving the integrity, effi- ciency, and validity of clinical trials for nervous system disorders (see Box 1-1). Participants in the workshop represented a range of diverse perspectives, including individuals not normally associated with tradi- tional clinical trials, added co-chair Atul Pande, chief medical officer and executive vice president of Tal Medical. The purpose of this workshop was to generate discussion about not only what is feasible now, but what may be possible with the implementation of cutting-edge technologies in the future, according to workshop co-chair Richard Keefe, professor of psychiatry and behavioral sciences at Duke University School of Medi- cine. Thus, workshop participants were asked to consider solutions that could be implemented immediately or over the short term, as well as in- novations that will change the way clinical trials look over the next 10 years. Potential solutions offered by several participants addressed the need to simplify and decrease the costs of trials. Keefe noted that all in- novations, whether technological or methodological, should be tested with empirical data, and such data should drive adoption. Robert Califf, Commissioner of Food and Drugs at the FDA, stated that the best medi- cal outcomes occur when health care providers and patients are armed with high quality-based evidence to make medical decisions, which is most likely to happen when clinical trials are conducted in practice. ORGANIZATION OF PROCEEDINGS The following proceedings summarizes the workshop presentations and discussion. Chapter 2 provides an overview of the challenges and opportunities for 21st century neuroscience clinical trials noted by many workshop participants. Chapter 3 outlines novel research and clinical trial design approaches to address heterogeneity and expedite the devel- opment of biomarkers and other drug development tools, including clini- cally meaningful outcome measures. The potential impact of technological innovations on clinical trials is discussed in Chapter 4. Chapter 5 focuses on regulatory challenges with an international perspec- tive and the potential implications for 21st century clinical research in- 

4 NEUROSCIENCE TRIALS OF THE FUTURE novations. Ethical considerations, including data protection and human subjects’ protection, are addressed in Chapter 6. Finally, the evidence base for real-world use and reimbursement issues are discussed in Chap- ter 7. BOX 1-1 Statement of Task An ad hoc committee planned and conducted a 2-day public workshop to explore opportunities to improve the efficiency and va- lidity of clinical trials for nervous system disorders. The workshop will bring together key stakeholders to consider ways to advance therapeutic development for nervous system disorders by using inno- vative clinical trial designs; improving patient selection, engagement, and retention; and enhancing clinical monitoring to help decrease the failure rate of drugs and devices in development. Presentations and discussions will be designed to: • Examine assay sensitivity challenges in clinical trials for nervous system disorders, including causes of poor signal detection and type II error. • Explore opportunities to improve clinical trial methodology for nervous system disorders, including strategies for: o Guiding the selection of patient populations, such as us- ing endophenotyping to increase the yield of responders and using genomics, proteomics, and imaging bio- markers to “stage” nervous system disorders. o Increasing patient engagement through all phases of the clinical trial (i.e., recruitment, screening, and posttrial) and improving adherence and retention. o Using patient-centric technologies (e.g., wearables) and integrating such real-world, real-time data with tradi- tional clinical data. o Improving monitoring during clinical trials. o Leveraging recent advances in diagnostics, biomarkers, and endpoints to develop more efficient clinical trials.  Using novel trial designs (e.g., adaptive, enrich- ment, and platform design studies) for nervous sys- tem disorders, including associated regulatory challenges and opportunities. .