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.

Neuroenhancement - perspectives of Swiss psychiatrists and general practitioners.

QUESTIONS UNDER STUDY: Although the ethical and health implications of neuroenhancement have been intensely discussed over the past years, little is known about the experiences and attitudes of physicians confronted with requests for neuroenhancing substances. The aim of this study was to explore general practitioners' and psychiatrists' familiarity with such requests and their willingness to prescribe these products. METHOD: A nation-wide cross-sectional survey among general practitioners and psychiatrists in Switzerland was conducted. A questionnaire was developed, pre-tested and sent out to a pre-defined sample of 1,600 Swiss practising physicians in the fields of psychiatry and general practice/internal medicine in the German-speaking and French-speaking part of Switzerland. RESULTS: A total of 393 questionnaires were returned (response rate: 24.7%). 80.2% of study participants were encountered requests for neuroenhancing products in their own practice, mostly not exceeding 1-2 times a year. A total of 41.1% were undecided when asked if they categorically against neuroenhancement, 49% would decide on a case-by-case basis, and 9.6% would decide according to patients' wishes. CONCLUSIONS: Swiss psychiatrists and general practitioners are confronted with requests for neuroenhancement, albeit not very frequently. Most participants embrace a pragmatic position towards neuroenhancement, although there is also a considerable degree of uncertainty about the appropriateness of a categorical refusal. A minority would follow a consumer model that leaves the decision about the use of neuroenhancers to the client, even though this conflicts with legal requirements regarding drug prescriptions.

Developing explicit positive beers criteria for preferred central nervous system medications in older adults.

BACKGROUND: The Beers criteria have been extensively used over the past decade to identify and evaluate potentially inappropriate medication use in adults 65 years of age and older in the United States. In contrast to the Beers criteria, the purpose of this pilot initiative was to develop a new set of explicit criteria for determining preferred (rather then potentially inappropriate) medications to use in older adults, using similar methodology as used in the three iterations of the Beers criteria. This initiative organized its evaluations around classes of medications that are both frequently used and associated with drug-related problems in older adults-central nervous system (CNS) medications. METHODS: This pilot study used a modified Delphi method-a set of procedures and methods for reaching group consensus for a subject matter in which precise information is lacking-to determine medications that are preferred for use in persons 65 years of age or older known to have specific medical conditions. Medications were selected as preferred because they are both effective, based upon a thorough evaluation of the clinical evidence, and pose less risk for older persons compared with alternative medications for the condition. Expert panelists evaluated 78 individual medications within four medical conditions (dementia, depression, Parkinson's disease, and psychosis). RESULTS: This study identified 13 preferred medications to be used in older adults with these conditions. CONCLUSIONS: This study expands explicit criteria to more precisely define preferred medication use in older adults. This refinement of the Beers criteria will enable providers to select medications with the greatest benefit-to-risk ratio for older adults, thereby minimizing drug-related problems. These criteria will need to be expanded to include other medication classes and medical conditions frequently encountered in older adults.