Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP

The ARRIVE guidelines have been implemented in BJP for 4 years with the aim of increasing transparency in reporting experiments involving animals. BJP has assessed our success in implementing them and concluded that we could do better. This editorial discusses the issues and explains how we are changing our requirements for authors to report their findings in experiments involving animals. This is one of a series of editorials discussing updates to the BJP Instructions to Authors

Video

To view the video on the ARRIVE guidelines, visit: https://www.youtube.com/watch?v=DYXoUAnhoPM     

Improving planning, design, reporting and scientific quality of animal experiments by using the Gold Standard Publication Checklist, in addition to the ARRIVE guidelines

Several studies have demonstrated serious omissions in the way research that use animals is reported. In order to improve the quality of reporting of animal experiments, the Animals in research: reporting in vivo experiments (ARRIVE) Guidelines were published in the British Journal of Pharmacology in August 2010. However, not only the quality of reporting of completed animal studies needs to be improved, but also the design and execution of new experiments. With both these goals in mind, we published the Gold Standard Publication Checklist (GSPC) in May 2010, a few months before the ARRIVE guidelines appeared. In this letter, we compare the GSPC checklist with the ARRIVE Guidelines. The GSPC describes certain items in more detail, which makes it both easier to use when designing and conducting an experiment and particularly suitable for making systematic reviews of animal studies more feasible. In order to improve not only the reporting but also the planning, design, execution and thereby, the scientific quality of animal experiments, we strongly recommend to all scientists involved in animal experimentation and to editors of journals publishing animal studies to take a closer look at the contents of both the ARRIVE guidelines and GSPC, and select the set of guidelines which is most appropriate for their particular situation.     

Ethical review of regulatory toxicology guidelines involving experiments on animals: the example of endocrine disrupters.

The safety assessment of new chemicals (including medicines, pesticides, food additives, and industrial chemicals) relies on the results of animal experiments. Because the safety of those exposed to these products and the welfare of the experimental animals used are considered critically important, both testing requirements and the welfare of experimental animals are controlled by law. In the U.K., projects that propose to use animals for experimental purposes, including for the testing of chemicals, have been controlled by law for over a century, with the most recent legislation (Animals [Scientific Procedures] Act of 1986) requiring a cost/benefit assessment before it may proceed. New regulations introduced in 1998 will require an ethical review process for all projects from April 1999. Such ethical review will have to take account of the toxicity testing methods and schemes that are required by the legislation aimed at protecting human health. Neither national nor international proposals for toxicity testing methods and schemes are generally subjected to ethical review from the point of protecting animal welfare. The international nature of the chemical and pharmaceutical industry means that testing requirements from one of the major national regulatory agencies (USA, EU, or Japan) or the international organizations (Organization for Economic Co-operation and Development [OECD]or the International Conference on Harmonization [ICH]) have an impact on the testing carried out by industrial organizations in all countries. The recent proposals for screening and testing chemicals to identify endocrine disrupters (ED) from the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) of the U.S. Environmental Protection Agency (EPA) are used as an example of the interaction between regulatory proposals and animal welfare issues. The current proposals are the most extravagant in the use of animals. Between 0.6 and 1.2 million animals would be required for each 1000 chemicals tested. The EPA, before incorporating them into regulation, is subjecting the recommendations to further review. This will undoubtedly moderate the number of animals actually used from the worst-case calculation. The variables that have the greatest impact on the number of animals required for testing are the prevalence of ED chemicals in the chemicals to be tested, and the sensitivity and specificity of the testing methods. The modeling demonstrates, for example, that increasing the prevalence from 10 to 50% reduces the number of animals used to detect one ED from 10,000 to 2700. Knowledge of the prevalence of EDs in the chemicals to be tested would allow rational selection of tier one screening based on the sensitivity and specificity of the screening tests. The EDSTAC proposals are difficult to justify from an ethical perspective, as equally effective detection rates may be achieved with fewer animals. National and international regulatory testing proposals should be subjected to formal independent ethical review before they are finalized, with a view to improving animal welfare.     

人体生物医学研究国际道德指南

本指南是自1982年以来的第三个版本，由来自非洲，亚洲 拉丁美洲，欧洲，美国和CIOMS秘书处的10名专家共同商议起草，由21条指导原则及其注释组成。与1982年和1993年的两个版本一样，2002版指南旨在规范各国的人体生物医学研究政策，根据各地情况应用伦理标准，以及确立和完善伦理审查机制。     

Benchmark dose approaches in chemical health risk assessment in relation to number and distress of laboratory animals

Use of benchmark dose (BMD) approaches is expected to increase substantially, with growing awareness among researchers and inclusion in regulatory testing guidance documents such as REACH. The BMD approach has clear advantages over the No-Observed-Adverse-Effect-Level (NOAEL) approach in defining toxicological thresholds, risk levels, and points of departure as the basis for setting guidance and limit values. Several aspects of the BMD may increase the use of laboratory animals; the optimal number of dose groups for BMD calculation is between five and ten, rather than the current standard of four; also, experiments with more animals will result in narrow confidence intervals. However, this paper presents several counterarguments suggesting that design of experiments suited for BMD analyses might be used to decrease the distress and use of laboratory animals. If experiments are performed with unequal group size, with fewer animals in the high response dose groups and more animals close to toxicological threshold, the aggregated distress might be reduced. In addition, there is a need to evaluate how the total number of animals affects the quality of BMD (e.g. in terms of confidence intervals). Development of strategies for optimal design of experiments requires tools which evaluate experimental designs from an ethical perspective; a concept of distress-adjusted number of animals is suggested.     

酒精使用相关障碍的临床治疗指南综述

酒精是世界范围内使用最广泛的精神活性物质之一,而酒精的有害使用也造成了巨大的疾病、社会及经济负担,因此目前酒精使用相关障碍受到广泛的关注。本文将综述国内外相关临床指南对酒精使用相关障碍的治疗方案及建议,为临床实践提供更清晰的理论基础。     

Antipsychotics in clinical practice: guidelines for safe and effective use

Antipsychotic drugs have made a significant contribution to the treatment of schizophrenia but the older drugs in particular have significant side-effects. The newer atypical drugs are effective for the treatment of both positive and negative symptoms and they also have significantly fewer serious side-effects. However, these drugs are considerably more expensive that the older drugs and this has generated intense debate about their cost effectiveness. There is now good evidence that when all factors are taken into consideration the atypical drugs are both cost effective and improve the quality of life of patients with schizophrenia. Despite the importance of these drugs there is widespread variation in their use and a national consensus on this important issue is long overdue.     

Evidence-based guidelines for pediatric clinical trials: focus on StaR Child Health

Clinical trials in children are challenging and filled with important ethical considerations that differ from adults. Given difficulties associated with pediatric clinical trials, off-label prescribing is a common practice in pediatrics, which can lead to adverse safety events and efficacy failures. To overcome these consequences, in the past 15 years, legislation in the USA and Europe has provided incentives to industry and increased government funding to conduct pediatric trials. Pediatric trial networks have also been formed to decrease the knowledge gap. However, challenges to performing pediatric trials and lack of standardization and guidelines regarding studies in children still exist. Standards for Research (StaR) in Child Health, begun in 2009, aims to improve the design, conduct and reporting of pediatric trials. This organization uses a consensus guideline approach involving academic, government and industry stakeholders to identify and disseminate best practices for pediatric trials. Six out of 11 planned standards are currently published.     

Pharmacogenomics guidelines: Current status and future development

Genetic polymorphisms impact biological responses to drugs. Current pharmacogenomics guidelines formulated by different countries, such as the Clinical Pharmacogenetics Implementation Consortium, the Dutch Pharmacogenetics Working Group, the Canadian Pharmacogenomics Network for Drug Safety, and the French National Network (Réseau) of Pharmacogenetics, play important roles in clinical practices. However, the standards for these guidelines vary significantly, resulting in differences in recommendations. The present article discusses these differences by head‐to‐head comparison of the existing pharmacogenomics guidelines and proposes new strategies for their future development.     

Comparison of EMA and FDA guidelines for drug interactions: An overview

In 2013, the regulatory authorities of the European Union and the US issued, almost simultaneously, new editions of the industry guidelines for the requirements of drug testing during their development for drug–drug and drug–food interactions. That being said, there are significant differences in the requirements set by both guidelines, and the aim of this article is to point out those differences. In this review, the author carefully and comprehensively compared the publicly available guidelines via the official Food and Drug Administation’s (FDA) and European Medicine Agency’s (EMA) websites, highlighting the differences between the two sets. Unlike the guidelines provided by the FDA, the EMA guidelines lack set requirements for testing interactions with therapeutic proteins as well as with the usage of pharmacodynamics end-points. It also does not set standards for the use of the ‘no interaction’ declaration in the summary of product characteristics. On the other hand, the FDA currently lacks guidance for testing drug–food interactions, the use of the Relative Induction Score correlation method, and proving existence of reversible inhibition and mechanism-based inactivation. It is important to note that, while there are differences in the requirements for the FDA’s and the EMA’s drug interaction guidelines, they are not substantial and are mostly relating to the scope of requirements and precision of the standards set.     

Simple flow-thru swivel for infusions into unrestrained animals

Infusion of fluids into unrestrained animals requires the use of a flow-thru swivel. A method is described for the construction of a simple efficient swivel assembled from disposable plastic syringes and needles.     

European guidelines for workplace drug testing in urine

These European Guidelines for Workplace Drug Testing in Urine have been prepared and updated by the European Workplace Drug Testing Society (EWDTS). The first version of these urine guidelines was published in 2002. Since then, the guidelines have been followed by many laboratories in different European countries and their role has been essential particularly in countries lacking legislation for workplace drug testing. In 2014, the EWDTS started a guidelines updating project and published a new version of the urine guidelines in 2015. Here we represent this updated version of the urine guidelines. The European Guidelines are designed to establish best practice procedures whilst allowing individual countries to operate within the requirements of national customs and legislation. The EWDTS recommends that all European laboratories that undertake legally defensible workplace drug testing should use these guidelines as a template for accreditation. Copyright © 2017 John Wiley & Sons, Ltd.     

Guidelines for European workplace drug testing in oral fluid

Over the past decade, oral fluid has established itself as a robust testing matrix for monitoring drug use or misuse. Commercially available collection devices provide opportunities to collect and test oral fluid by the roadside and near-patient testing with both clinical and criminal justice applications. One of the main advantages of oral fluid relates to the collection of the matrix which is non-invasive, simple, and can be carried out under direct observation making it ideal for workplace drug testing. Laboratories offering legally defensible oral fluid workplace drug testing must adhere to national and international quality standards (ISO/IEC 17025); however, these standards do not address issues specific to oral fluid testing. The European Workplace Drug Testing Society (EWDTS) recognizes the importance of providing best practice guidelines to organizations offering testing and those choosing to use oral fluid drug testing to test their employees. The aim of this paper is to present the EWDTS guidelines for oral fluid workplace drug testing.     

Guidelines for European workplace drug and alcohol testing in hair

Drug and alcohol abuse is a concern for many European companies, especially those having safety‐critical jobs. It is not uncommon for European companies to establish a drug policy with little or no provision for drug testing. The European Union (EU) has launched a number of initiatives in its fight against drugs. There is, however, no specific EU legislation and no generally accepted guidelines. Since the outcome of workplace drug testing (WDT) can have serious consequences for the employee, it is of utmost importance that WDT be performed in a defined quality standard and in a legally secured way. In order to fulfil this, the European Workplace Drug Testing Society (EWDTS) has formulated WDT guidelines in order to ensure that the entire drug testing process is of high quality, accredited, and legally defensible, hence giving accurate and reliable information about employee drug use while respecting the privacy of the employee. The aim of this paper is to present the recently formulated guidelines for workplace drug testing in hair. Copyright © 2010 John Wiley & Sons, Ltd.     

European guidelines for workplace drug and alcohol testing in hair

Guidelines for Legally Defensible Workplace Drug Testing have been prepared and updated by the European Workplace Drug Testing Society (EWDTS). They are based on the 2010 version published by Pascal Kintz and Ronald Agius (Guidelines for European workplace drug and alcohol testing in hair. Drug Test. Anal. 2010 , 2, 367) and in concordance with the Society of Hair Testing guidelines (Society of Hair Testing guidelines for drug testing in hair. Forensic Sci. Int. 2012 , 218, 20‐24). The European Guidelines are designed to establish best practice procedures whilst allowing individual countries to operate within the requirements of national customs and legislation. The EWDTS recommends that all European laboratories that undertake legally defensible workplace drug testing use these guidelines as a template for accreditation. Copyright © 2016 John Wiley & Sons, Ltd.     

Evaluating the Performance of the ICH Guidelines for Shelf Life Estimation

The goal of shelf life estimation is to determine the storage time during which the entire product meets specification with acceptably high probability. The estimated shelf life should be “applicable to all future batches” (ICH Q1E, International Conference on Harmonization, 2003b). There is compelling evidence of issues with the International Conference on Harmonization (ICH) guidelines for shelf life estimation. Issues include fixed batch effects, poolability tests, and confidence intervals for the mean. Two conclusions from evaluating the ICH procedure are that batch effects should be random and that focus should be on a quantile. A procedure is needed that combines random batches with the ICH objective of estimating the minimum batch shelf life.     

Dosage guidelines for the use of vancomycin based on its pharmacokinetics in infants

Summary The purpose of this study was to characterize the pharmacokinetics of vancomycin and to develop optimal dosage guidelines in infants. Thirteen infants between the ages of 13 to 183 days were enrolled. All had been born prematurely, and average gestational age, postconceptional age, and actual body weight were 29.8 weeks, 38.2 weeks, and 2.1 kg respectively. Multiple blood samples were obtained from each patient after 72 h of therapy. Serum inhibitory and bactericidal titres were determined for peak and trough samples.There were good correlations between total body clearance of vancomycin and both postconceptional age (r=0.86) and actual body weight (r=0.87). This information was used to develop vancomycin dosage guidelines in premature infants. The regression line for vancomycin daily dosage requirements vs postconceptional age may be useful for determining initial dosage recommendations.There were also good correlations between vancomycin serum concentrations and serum inhibitory and cidal titres. Peak and trough concentrations in the therapeutic range (peak, 25–35 µg/ml; trough, 5–10 µg/ml) corresponded to titres of 1:8 and 1:2 to 1:8 respectively.Based on these data we suggest the following dosage guidelines for vancomycin: 10 mg/kg 12 hourly for 30–34 weeks postconceptional age and <1.2 kg actual body weight; 10 mg/kg 8 hourly for 30–42 weeks postconceptional age and >1.2 kg actual body weight; 10 mg/kg 6 hourly for >42 weeks postconceptional age and >2.0 kg actual body weight.Thus, doses which are lower than currently recommended are needed for infants born prematurely. Furthermore, the initial dose of vancomycin can easily be determined using an infant's postconceptional age.SML was a Fellow at Children's Hospital at the time of study and is now at Rutgers University, College of Pharmacy, Piscataway, NJ, USA     

探讨中国、美国及欧洲高血压防治指南中有关药物治疗的问题

高血压治疗,药物的选择是关键,我国临床应用的降压药物种类,包括中西药及各种复方制剂有几百种之多,但我国高血压的治疗率和控制率都很低,高血压防治形势不容乐观。本文对中国、美国及欧洲高血压防治指南中有关药物治疗方面的差异进行比较,并对高血压药物临床选择的原则进行探讨。中、美、欧指南均认为不同类别的降压药物在某些治疗效果或特殊的人群中确实存在差异,因此对特定的强制性适应症应采用特定类别的降压药物。三个指南都强调合并用药的益处,并建议采用能维持24 h的长效药物或制剂。但三个指南在是否推荐一线治疗药物上存在明显分歧,美国指南建议噻嗪类利尿剂可作为大多数无并发症高血压患者的首选药,而欧洲指南和中国指南均未推荐一线药物,认为几个主要类别的降压药均可用于高血压的起始治疗和维持治疗。中医药是我国特有的宝贵资源,各种降压中成药在临床上有广泛的应用,但由于缺乏高质量证据,2004年中国高血压防治指南中缺少中成药部分。临床上降压药物的选择首先取决于药物的疗效和安全性,在疗效与安全性相差不大的情况下,应优先选择相对价廉的药物。对于我国大多数高血压患者,如果没有必需使用其他药物的适应症,低剂量噻嗪类利尿药可以作为治疗的首选方案。2004年中国高血压防治指南的出台,对我国高血压防治工作具有重要的意义,现阶段应加强指南的推广和实施,促进临床高血压药物的合理使用,提高血压控制率。     

抗结核药物药效学非临床研究技术指南

摘要：研发新型抗结核药物极具挑战性,难度大,周期长,非临床研究的数据是开展临床试验的前提。全面充分的结核分 枝杆菌体外和在动物体内的药效学评价是临床试验前的重要步骤和关键内容。本技术指南主要适用于治疗由结核分枝杆菌引起 的肺结核病药物的研发,旨在为创新抗结核药物的临床前药效学研究提供参考。