Safety and regulatory requirements and challenge for CNS drug development

As our recognition and understanding of diseases and disorders of the central nervous system (CNS) become more insightful, and society's concerns for the safety, efficacy, and use of such drugs become more acute, the regulatory requirements and expectations around assessing potential safety of the drug have continued to become more complex. Currently, these concerns and requirements are addressed in a time phased manner, attempting to match the advance of spending rate on assessing safety issues in alignment with advancing the moiety through development of the therapeutics. This article seeks to communicate all the critical but frequently overlooked aspects of current and pending regulatory requirements including the lesser known parts associated with impurities, active metabolites, and distribution of active components to (and subsequent clearance from) the population brain. While there are some exciting developments in treating CNS diseases with stem cells and some protein based therapies (Aboody et al., 2011), drugs meant to favorably effect, prevent, or cure a disease process within the central nervous system (CNS) are primarily small molecule and must meet a number of regulatory and scientifically mandated criteria to establish that their safety in clinical use is acceptable. This is initially done in in vivo animals or in in vitro preparations. The starting place for such nonclinical safety assessment requires some fundamental assumptions about the potential therapeutic (Ball et al., 2007; Gad, 2009; ICH S6, 2004; ICH M3 (R2), 2008). The first assumption is that the primary intended route of therapeutic administration is oral, as is indeed the case for the vast majority of both current and for most potential new drugs. Most aspects of nonclinical safety assessment do not depend on route, and we will consider the situations where the use of other routes influences requirements for nonclinical safety assessment, and why. A second general case assumption in the usual case is that drug administration frequency (or regimen) is once daily, though this assumption is less frequently made (in real life) than the oral route assumption. Regulations, costs, and acceptance of risks (Enna and Williams, 2009) along with adherence to the phased process of clinical drug development have caused the task or flow of performances of regulatory nonclinical safety assessment studies to be considered as occurring in three sequential parts (once the initial candidate screening and lead selection phase are complete). These are the studies (1) done to allow initiation of clinical trials, (2) done to allow initiation of clinical trials sufficient to support a marketing application, and (3) required to allow a marketing application. Employment of new technologies, such as in vivo imaging has aided, to both help understand specificity of delivery to target tissue sites and mechanisms of both action and undesirable actions.