European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part I: assessment.

In 2011 a working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines for Tourette syndrome (TS). Now, we present an updated version 2.0 of these European clinical guidelines for Tourette syndrome and other tic disorders, part I: assessment. Therefore, the available literature has been thoroughly screened, supplemented with national guidelines across countries and discussions among ESSTS experts. Diagnostic changes between DSM-IV and DSM-5 classifications were taken into account and new information has been added regarding differential diagnoses, with an emphasis on functional movement disorders in both children and adults. Further, recommendations regarding rating scales to evaluate tics, comorbidities, and neuropsychological status are provided. Finally, results from a recently performed survey among ESSTS members on assessment in TS are described. We acknowledge that the Yale Global Tic Severity Scale (YGTSS) is still the gold standard for assessing tics. Recommendations are provided for scales for the assessment of tics and psychiatric comorbidities in patients with TS not only in routine clinical practice, but also in the context of clinical research. Furthermore, assessments supporting the differential diagnosis process are given as well as tests to analyse cognitive abilities, emotional functions and motor skills.

The current status of exposure-driven approaches for chemical safety assessment: A cross-sector perspective.

For the purposes of chemical safety assessment, the value of using non-animal (in silico and in vitro) approaches and generating mechanistic information on toxic effects is being increasingly recognised. For sectors where in vivo toxicity tests continue to be a regulatory requirement, there has been a parallel focus on how to refine studies (i.e. reduce suffering and improve animal welfare) and increase the value that in vivo data adds to the safety assessment process, as well as where to reduce animal numbers where possible. A key element necessary to ensure the transition towards successfully utilising both non-animal and refined safety testing is the better understanding of chemical exposure. This includes approaches such as measuring chemical concentrations within cell-based assays and during in vivo studies, understanding how predicted human exposures relate to levels tested, and using existing information on human exposures to aid in toxicity study design. Such approaches promise to increase the human relevance of safety assessment, and shift the focus from hazard-driven to risk-driven strategies similar to those used in the pharmaceutical sectors. Human exposure-based safety assessment offers scientific and 3Rs benefits across all sectors marketing chemical or medicinal products. The UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) convened an expert working group of scientists across the agrochemical, industrial chemical and pharmaceutical industries plus a contract research organisation (CRO) to discuss the current status of the utilisation of exposure-driven approaches, and the challenges and potential next steps for wider uptake and acceptance. This paper summarises these discussions, highlights the challenges - particularly those identified by industry - and proposes initial steps for moving the field forward.

Opportunities to Apply the 3Rs in Safety Assessment Programs.

Before a potential new medicine can be administered to humans it is essential that its safety is adequately assessed. Safety assessment in animals forms an integral part of this process, from early drug discovery and initial candidate selection to the program of recommended regulatory tests in animals. The 3Rs (replacement, reduction, and refinement of animals in research) are integrated in the current regulatory requirements and expectations and, in the EU, provide a legal and ethical framework for in vivo research to ensure the scientific objectives are met whilst minimizing animal use and maintaining high animal welfare standards. Though the regulations are designed to uncover potential risks, they are intended to be flexible, so that the most appropriate approach can be taken for an individual product. This article outlines current and future opportunities to apply the 3Rs in safety assessment programs for pharmaceuticals, and the potential (scientific, financial, and ethical) benefits to the industry, across the drug discovery and development process. For example, improvements to, or the development of, novel, early screens (e.g., in vitro, in silico, or nonmammalian screens) designed to identify compounds with undesirable characteristics earlier in development have the potential to reduce late-stage attrition by improving the selection of compounds that require regulatory testing in animals. Opportunities also exist within the current regulatory framework to simultaneously reduce and/or refine animal use and improve scientific outcomes through improvements to technical procedures and/or adjustments to study designs. It is important that approaches to safety assessment are continuously reviewed and challenged to ensure they are science-driven and predictive of relevant effects in humans.

Making progress and gaining momentum in global 3Rs efforts: how the European pharmaceutical industry is contributing.

Animal research together with other investigational methods (computer modeling, in vitro tests, etc) remains an indispensable part of the pharmaceutical research and development process. The European pharmaceutical industry recognizes the responsibilities inherent in animal research and is committed to applying and enhancing 3Rs principles. New nonsentient, ex vivo, and in vitro methods are developed every day and contribute to reducing and, in some instances, replacing in vivo studies. Their utility is however limited by the extent of our current knowledge and understanding of complex biological systems. Until validated alternative ways to model these complex interactions become available, animals remain indispensable in research and safety testing. In the interim, scientists continue to look for ways to reduce the number of animals needed to obtain valid results, refine experimental techniques to enhance animal welfare, and replace animals with other research methods whenever feasible. As research goals foster increasing cross-sector and international collaboration, momentum is growing to enhance and coordinate scientific innovation globally-beyond a single company, stakeholder group, sector, region, or country. The implementation of 3Rs strategies can be viewed as an integral part of this continuously evolving science, demonstrating the link between science and welfare, benefiting both the development of new medicines and animal welfare. This goal is one of the key objectives of the Research and Animal Welfare working group of the European Federation of Pharmaceutical Industries and Associations.

Recommendations from a global cross-company data sharing initiative on the incorporation of recovery phase animals in safety assessment studies to support first-in-human clinical trials.

An international expert group which includes 30 organisations (pharmaceutical companies, contract research organisations, academic institutions and regulatory bodies) has shared data on the use of recovery animals in the assessment of pharmaceutical safety for early development. These data have been used as an evidence-base to make recommendations on the inclusion of recovery animals in toxicology studies to achieve scientific objectives, while reducing animal use. Recovery animals are used in pharmaceutical development to provide information on the potential for a toxic effect to translate into long-term human risk. They are included on toxicology studies to assess whether effects observed during dosing persist or reverse once treatment ends. The group devised a questionnaire to collect information on the use of recovery animals in general regulatory toxicology studies to support first-in-human studies. Questions focused on study design, the rationale behind inclusion or exclusion and the impact this had on internal and regulatory decisions. Data on 137 compounds (including 53 biologicals and 78 small molecules) from 259 studies showed wide variation in where, when and why recovery animals were included. An analysis of individual study and programme design shows that there are opportunities to reduce the use of recovery animals without impacting drug development.

Target organ profiles in toxicity studies supporting human dosing: an assessment of recovery and chronic dosing.

We have previously reported the profile of toxic effects with respect to target organs (defined as organs showing histopathological changes) observed in rodent and non-rodent toxicity studies conducted prior to first time in man (FTIM) for 77 AstraZeneca candidate drugs (CDs) across a range of therapy areas. The main objectives of the current study were twofold; to determine which target organs observed in the FTIM studies recovered after a dose free recovery period and to determine which additional target organs were observed in subsequent chronic (⩾3month) studies required to support longer term clinical dosing. The analysis showed that ⩾86% of findings in studies supporting FTIM either fully or partially resolved at the end of the recovery period, with profiles of recovery that were similar whether the CD progressed into man or not and across different therapy areas. Compared to observations in FTIM studies, chronic studies identified toxicities in an additional 39% of target organs. Overall these data demonstrate that chronic studies in both rodents and non-rodents provide valuable information for the risk assessment for longer term dosing in humans. In addition, the high levels of recovery demonstrated in this analysis suggest that inclusion of recovery assessments on FTIM studies should be on a case-by-case basis driven by a positive indication of need. This is in line with ICH non-clinical guidance that states that reversibility of severe nonclinical toxicities of potential clinic relevance should be assessed 'when appropriate', but that the evaluation can be based on a study of reversibility or on a scientific assessment.

Assessment of toxicological effects of blood microsampling in the vehicle dosed adult rat.

UNLABELLED: Historically, satellite groups are often used for rodent toxicokinetic profiling because of the haematological consequences of blood sampling. If microsampling is shown to be toxicologically benign, its adoption in rat studies would enable comparison of exposure and toxicity in individual animals (as happens in non-rodent studies) as well as obviating need for satellite groups. METHODS: Groups of 10 male (200-300g) and female (150-250g) rats aged 10weeks were vehicle dosed and either left unsampled, conventional blood volume sampled (6×200µL) or microsampled (6×32µL) on Days 1 and 14. At termination on Day 15, clinical pathology plus liver and spleen weights and histopathology were obtained. RESULTS: All clinical pathology parameters were within background range. However, compared to unsampled controls, conventional volume sampled rats showed a statistically significant (p<0.001) decrease in haemaglobin, haematocrit and red blood cell count, an increase in reticulocytes (at least p<0.01), increased AST and GLDH and, in males only, an increase in monocytes and neutrophils. In contrast, microsampled animals showed no changes except for a slight, toxicologically insignificant decrease in haemoglobin concentration (15.0g/dL compared to the unsampled group mean of 14.4g/dL) in females (p<0.05) and a small increase in monocytes (p<0.05) in males. CONCLUSION: Microsampling of adult rats is possible without adverse toxicological consequences.

Reducing attrition in drug development: smart loading preclinical safety assessment.

Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca's potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping ('stopping toxicities') showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase. This will reduce animal use overall, save significant R&D costs and improve drug pipeline quality.

A global pharmaceutical company initiative: an evidence-based approach to define the upper limit of body weight loss in short term toxicity studies.

Short term toxicity studies are conducted in animals to provide information on major adverse effects typically at the maximum tolerated dose (MTD). Such studies are important from a scientific and ethical perspective as they are used to make decisions on progression of potential candidate drugs, and to set dose levels for subsequent regulatory studies. The MTD is usually determined by parameters such as clinical signs, reductions in body weight and food consumption. However, these assessments are often subjective and there are no published criteria to guide the selection of an appropriate MTD. Even where an objective measurement exists, such as body weight loss (BWL), there is no agreement on what level constitutes an MTD. A global initiative including 15 companies, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), has shared data on BWL in toxicity studies to assess the impact on the animal and the study outcome. Information on 151 studies has been used to develop an alert/warning system for BWL in short term toxicity studies. The data analysis supports BWL limits for short term dosing (up to 7days) of 10% for rat and dog and 6% for non-human primates (NHPs).

Opportunities to minimise animal use in pharmaceutical regulatory general toxicology: a cross-company review.

Toxicity studies in animals are carried out to identify the intrinsic hazard of a substance to support risk assessment for humans. In order to identify opportunities to minimise animal use in regulatory toxicology studies, a review of current study designs was carried out. Pharmaceutical companies and contract research organisations in the UK shared data and experience of standard toxicology studies (ranging from one to nine months duration) in rodents and non-rodents; and carcinogenicity studies in the rat and mouse. The data show that variation in study designs was primarily due to (i) the number of animals used in the main study groups, (ii) the use of animals in toxicokinetic (TK) satellite groups, and (iii) the use of animals in off-treatment recovery groups. The information has been used to propose a series of experimental designs where small adjustments could reduce animal use in practice, while maintaining the scientific objectives.

Preventing abuse in accommodation services: from procedural response to protective cultures.

This article reviews current approaches of disability accommodation services to addressing the abuse and neglect of people with intellectual disability who live in them. We review international literature and provide practice examples from accommodation services for people with intellectual disability in Australia to develop a framework of current research, policy and practice in this area. The results of this review show that dominant policy and practice approaches do not give adequate consideration to the prevention and protection of people from harm, focusing primarily on responding to individual instances of maltreatment. Managerial, compliance-based systems may be deflecting attention from recognizing and responding more effectively to abuse and neglect at individual, systemic and structural levels. The current dominant approach fails to develop a culture of prevention and protection for people with intellectual disability. Further, some systemic and structural preconditions are set which make abuse and neglect less likely to be prevented.

The value of acute toxicity studies to support the clinical management of overdose and poisoning: a cross-discipline consensus.

Acute toxicity studies are no longer required to support first clinical trials of pharmaceuticals in man. However, it is unclear in the wording of the revised ICH M3 whether acute toxicity studies are required later in drug development (e.g., phase 3) in order to support the management of overdose. The NC3Rs held a workshop in January 2010 with representatives from international poison centres, the pharmaceutical and chemical industries, and regulatory and government bodies to explore further whether acute toxicity studies are used to support the clinical management of overdose of pharmaceuticals and whether this work can be translated to other sectors such as the chemical industry. The consensus formed at the workshop was that acute toxicity studies are not used for managing overdose of pharmaceuticals and are of little value in treating human poisoning from chemicals. In this paper, the authors describe the key considerations in treating human overdose and poisoning, challenge the value of the classification and labelling process of chemicals for this purpose and discuss how acute toxicity studies can be improved to better inform risk assessment.

A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development.

Regulatory guidelines indicate acute toxicity studies in animals are considered necessary for pharmaceuticals intended for human use. This is the only study type where lethality is mentioned as an endpoint. The studies are carried out, usually in rodents, to support marketing of new drugs and to identify the minimum lethal dose. A European initiative including 18 companies has undertaken an evidence-based review of acute toxicity studies and assessed the value of the data generated. Preclinical and clinical information was shared on 74 compounds. The analysis indicated acute toxicity data was not used to (i) terminate drugs from development (ii) support dose selection for repeat dose studies in animals or (iii) to set doses in the first clinical trials in humans. The conclusion of the working group is that acute toxicity studies are not needed prior to first clinical trials in humans. Instead, information can be obtained from other studies, which are performed at more relevant doses for humans and are already an integral part of drug development. The conclusions have been discussed and agreed with representatives of regulatory bodies from the US, Japan and Europe.

Holistic health promotion: putting the art into nurse education.

The role of the arts in health care and health promotion is enjoying belated attention as a way of promoting people's mental health and well-being. Canterbury Christ Church University offers a course which examines how nurses can use the arts to enhance the health care experience for both staff and patients. The Holistic Health Promotion course is compulsory for all final year pre-registration Bachelor degree students in Adult and Child Nursing. The content and process of the course are described, and the findings from the evaluation data are discussed. Through the use of autobiographical literature, active learning in the classroom, visiting speakers and visits within the local community, the course provides a positive learning experience for many students and broadens their perceptions of how to carry out mental, emotional and spiritual health promotion.

Use of telemedicine to follow special needs children.

Two remote telemedicine clinics were established linked to a tertiary care center to improve access for special health care needs children (SHCNC). The remote clinics were established at Lamar University's School of Nursing (1996) and Stephen F. Austin University's School of Nursing (1997), and they were linked to the pediatric interdisciplinary team at the University of Texas Medical Branch. These clinics were evaluated to determine if the tertiary interdisciplinary team could effectively assess and plan interventions for SHCNC and to assess patient and caregivers satisfaction with this intervention. The interdisciplinary team and the patients and their families were highly satisfied with this arrangement.