Where are we heading? Challenges in evidence-based severity assessment.

Evidence-based severity assessment in laboratory animals is, apart from the ethical responsibility, imperative to generate reproducible, standardized and valid data. However, the path towards a valid study design determining the degree of pain, distress and suffering experienced by the animal is lined with pitfalls and obstacles as we will elucidate in this review. Furthermore, we will ponder on the genesis of a holistic concept relying on multifactorial composite scales. These have to combine robust and reliable parameters to measure the multidimensional aspects that define the severity of animal experiments, generating a basis for the substantiation of the refinement principle.

Harm-benefit analysis - what is the added value? A review of alternative strategies for weighing harms and benefits as part of the assessment of animal research.

Animal experiments are widely required to comply with the 3Rs, to minimise harm to the animals and to serve certain purposes in order to be ethically acceptable. Recently, however, there has been a drift towards adding a so-called harm-benefit analysis as an additional requirement in assessing experiments. According to this, an experiment should only be allowed if there is a positive balance when the expected harm is weighed against the expected benefits. This paper aims to assess the added value of this requirement. Two models, the discourse model and the metric model, are presented. According to the former, the weighing of harms and benefits must be conducted by a committee in which different stakeholders engage in a dialogue. Research into how this works in practice, however, shows that in the absence of an explicit and clearly defined methodology, there are issues about transparency, consistency and fairness. According to the metric model, on the other hand, several dimensions of harms and benefits are defined beforehand and integrated in an explicit weighing scheme. This model, however, has the problem that it makes no real room for ethical deliberation of the sort committees undertake, and it has therefore been criticised for being too technocratic. Also, it is unclear who is to be held accountable for built-in ethical assumptions. Ultimately, we argue that the two models are not mutually exclusive and may be combined to make the most of their advantages while reducing the disadvantages of how harm-benefit analysis in typically undertaken.

Impact analysis of ICH S9 on non-clinical development of anticancer drugs.

Cancer presents a major healthcare challenge worldwide, with several millions new cases a year, and represents a therapeutic area with a high need for new drugs. To respond to this, the parties of the International Conference for Harmonization agreed in 2007 to develop a guideline on nonclinical requirements for oncology therapeutics' development (ICH S9), which came into effect in early 2010. This guideline includes recommendations to facilitate and accelerate the development and marketing of cancer therapeutic agents for serious and life threatening malignancies and aims to address this need through a refinement and a reduction in the use of experimental animals, following the 3Rs principles. To assess the impact of ICH S9 on drug development and reduction of animal use, we performed an analysis of Marketing Authorization Applications at the European Medicines Agency relevant to the period in which the development of the guideline was approaching the final steps and its early implementation period. From the analysis performed, a consistent trend towards a decrease in the average number of non-clinical studies performed (-40.7%) and number of animals used per development program (-58.1%) for new chemical entities has been detected, highlighting increasing compliance by companies to the recommendations of ICH S9.

Can animal data translate to innovations necessary for a new era of patient-centred and individualised healthcare? Bias in preclinical animal research.

BACKGROUND: The public and healthcare workers have a high expectation of animal research which they perceive as necessary to predict the safety and efficacy of drugs before testing in clinical trials. However, the expectation is not always realised and there is evidence that the research often fails to stand up to scientific scrutiny and its 'predictive value' is either weak or absent. DISCUSSION: Problems with the use of animals as models of humans arise from a variety of biases and systemic failures including: 1) bias and poor practice in research methodology and data analysis; 2) lack of transparency in scientific assessment and regulation of the research; 3) long-term denial of weaknesses in cross-species translation; 4) profit-driven motives overriding patient interests; 5) lack of accountability of expenditure on animal research; 6) reductionist-materialism in science which tends to dictate scientific inquiry and control the direction of funding in biomedical research. Bias in animal research needs to be addressed before medical research and healthcare decision-making can be more evidence-based. Research funding may be misdirected on studying 'disease mechanisms' in animals that cannot be replicated outside tightly controlled laboratory conditions, and without sufficient critical evaluation animal research may divert attention away from avenues of research that hold promise for human health. The potential for harm to patients and trial volunteers from reliance on biased animal data(1) requires measures to improve its conduct, regulation and analysis. This article draws attention to a few of the many forms of bias in animal research that have come to light in the last decade and offers a strategy incorporating ten recommendations stated at the end of each section on bias. The proposals need development through open debate and subsequent rigorous implementation so that reviewers may determine the value of animal research to human health. The 10Rs + are protected by a Creative Commons Attribution 3.0 Unported License and therefore may be 'shared, remixed or built on, even commercially, so long as attributed by giving appropriate credit with a link to the license, and indicate if changes were made.'

Expectations for methodology and translation of animal research: a survey of health care workers.

BACKGROUND: Health care workers (HCW) often perform, promote, and advocate use of public funds for animal research (AR); therefore, an awareness of the empirical costs and benefits of animal research is an important issue for HCW. We aim to determine what health-care-workers consider should be acceptable standards of AR methodology and translation rate to humans. METHODS: After development and validation, an e-mail survey was sent to all pediatricians and pediatric intensive care unit nurses and respiratory-therapists (RTs) affiliated with a Canadian University. We presented questions about demographics, methodology of AR, and expectations from AR. Responses of pediatricians and nurses/RTs were compared using Chi-square, with P < .05 considered significant. RESULTS: Response rate was 44/114(39%) (pediatricians), and 69/120 (58%) (nurses/RTs). Asked about methodological quality, most respondents expect that: AR is done to high quality; costs and difficulty are not acceptable justifications for low quality; findings should be reproducible between laboratories and strains of the same species; and guidelines for AR funded with public money should be consistent with these expectations. Asked about benefits of AR, most thought that there are sometimes/often large benefits to humans from AR, and disagreed that "AR rarely produces benefit to humans." Asked about expectations of translation to humans (of toxicity, carcinogenicity, teratogenicity, and treatment findings), most: expect translation >40% of the time; thought that misleading AR results should occur <21% of the time; and that if translation was to occur <20% of the time, they would be less supportive of AR. There were few differences between pediatricians and nurses/RTs. CONCLUSIONS: HCW have high expectations for the methodological quality of, and the translation rate to humans of findings from AR. These expectations are higher than the empirical data show having been achieved. Unless these areas of AR significantly improve, HCW support of AR may be tenuous.

Strategic focus on 3R principles reveals major reductions in the use of animals in pharmaceutical toxicity testing.

The principles of the 3Rs, Replacement, Reduction and Refinement, are being increasingly incorporated into legislations, guidelines and practice of animal experiments in order to safeguard animal welfare. In the present study we have studied the systematic application of 3R principles to toxicological research in the pharmaceutical industry, with particular focus on achieving reductions in animal numbers used in regulatory and investigatory in vivo studies. The work also details major factors influencing these reductions including the conception of ideas, cross-departmental working and acceptance into the work process. Data from 36 reduction projects were collected retrospectively from work between 2006 and 2010. Substantial reduction in animal use was achieved by different strategies, including improved study design, method development and project coordination. Major animal savings were shown in both regulatory and investigative safety studies. If a similar (i.e. 53%) reduction had been achieved simultaneously within the twelve largest pharmaceutical companies, the equivalent reduction world-wide would be about 150,000 rats annually. The results point at the importance of a strong 3R culture, with scientific engagement, collaboration and a responsive management being vital components. A strong commitment in leadership for the 3R is recommended to be translated into cross-department and inter-profession involvement in projects for innovation, validation and implementation. Synergies between all the three Rs are observed and conclude that in silico-, in vitro- and in vivo-methods all hold the potential for applying the reduction R and should be consequently coordinated at a strategic level.

The cost of self-imposed regulatory burden in animal research.

U.S. federal regulations and standards governing the care and use of research animals enacted in the mid- to late 1980s, while having positive effects on the welfare and quality of the animals, have resulted in dramatic increases in overall research costs. In addition to the expenses of housing and caring for animals according to the standards, establishing the requisite internal compliance bureaucracies has markedly driven up costs, in both institutional monetary expenditures and lost research effort. However, many institutions are increasing these costs even further through additional self-imposed regulatory burden, typically characterized by overly complex compliance organizations and unnecessary policies and procedures. We discuss the sources of this self-imposed burden and recommend strategies for avoiding it while preserving an appropriate focus on animal well-being and research success.

They see a rat, we seek a cure for diseases: the current status of animal experimentation in medical practice.

The objective of this review article was to examine current and prospective developments in the scientific use of laboratory animals, and to find out whether or not there are still valid scientific benefits of and justification for animal experimentation. The PubMed and Web of Science databases were searched using the following key words: animal models, basic research, pharmaceutical research, toxicity testing, experimental surgery, surgical simulation, ethics, animal welfare, benign, malignant diseases. Important relevant reviews, original articles and references from 1970 to 2012 were reviewed for data on the use of experimental animals in the study of diseases. The use of laboratory animals in scientific research continues to generate intense public debate. Their use can be justified today in the following areas of research: basic scientific research, use of animals as models for human diseases, pharmaceutical research and development, toxicity testing and teaching of new surgical techniques. This is because there are inherent limitations in the use of alternatives such as in vitro studies, human clinical trials or computer simulation. However, there are problems of transferability of results obtained from animal research to humans. Efforts are on-going to find suitable alternatives to animal experimentation like cell and tissue culture and computer simulation. For the foreseeable future, it would appear that to enable scientists to have a more precise understanding of human disease, including its diagnosis, prognosis and therapeutic intervention, there will still be enough grounds to advocate animal experimentation. However, efforts must continue to minimize or eliminate the need for animal testing in scientific research as soon as possible.

The a3 problem solving report: a 10-step scientific method to execute performance improvements in an academic research vivarium.

The purpose of this study was to illustrate the application of A3 Problem Solving Reports of the Toyota Production System to our research vivarium through the methodology of Continuous Performance Improvement, a lean approach to healthcare management at Seattle Children's (Hospital, Research Institute, Foundation). The Report format is described within the perspective of a 10-step scientific method designed to realize measurable improvements of Issues identified by the Report's Author, Sponsor and Coach. The 10-step method (Issue, Background, Current Condition, Goal, Root Cause, Target Condition, Countermeasures, Implementation Plan, Test, and Follow-up) was shown to align with Shewhart's Plan-Do-Check-Act process improvement cycle in a manner that allowed for quantitative analysis of the Countermeasure's outcomes and of Testing results. During fiscal year 2012, 9 A3 Problem Solving Reports were completed in the vivarium under the teaching and coaching system implemented by the Research Institute. Two of the 9 reports are described herein. Report #1 addressed the issue of the vivarium's veterinarian not being able to provide input into sick animal cases during the work day, while report #7 tackled the lack of a standard in keeping track of weekend/holiday animal health inspections. In each Report, a measurable Goal that established the basis for improvement recognition was present. A Five Whys analysis identified the Root Cause for Report #1 as historical work patterns that existed before the veterinarian was hired on and that modern electronic communication tools had not been implemented. The same analysis identified the Root Cause for Report #7 as the vivarium had never standardized the process for weekend/holiday checks. Successful outcomes for both Reports were obtained and validated by robust audit plans. The collective data indicate that vivarium staff acquired a disciplined way of reporting on, as well as solving, problems in a manner consistent with high level A3 Thinking.

Quality of reporting of experimental research in implant dentistry. Critical aspects in design, outcome assessment and model validation.

OBJECTIVE: The aim was to assess the quality of reporting of experimental research in implant dentistry by a critical evaluation of study design, outcome assessments and model validation. MATERIAL & METHODS: An online search was performed using the MEDLINE. Experimental studies performed in both animals and humans were included. A’stratified random sample of the included studies was extracted and used for quantitative and qualitative analyses. Modified versions of the ARRIVE guidelines were used for quality assessment. RESULTS: A total of 982 papers were eligible and used for quantitative analyses. A’stratified random sample of 193 publications was extracted. The dog model was the most used experimental model whereas experimental studies on humans were few. Intra-oral experimental sites dominated in human, monkey, dog and mini-pig studies. Extra oral sites dominated in rabbit, rodent and goat/sheep studies. Studies on the pathogenesis and treatment of peri-implant diseases were few. CONCLUSION: Different animal models, experimental protocols and methods of analysis have been used to address different areas of experimental research in implant dentistry. Standardized designs for investigations within this type of experimental research seem to be lacking. Furthermore, in many of these studies there were limitations in reporting on methodology and statistical methods.

Quality assessment of reporting of animal studies on pathogenesis and treatment of peri-implant mucositis and peri-implantitis. A systematic review using the ARRIVE guidelines.

OBJECTIVES: To address the following focused question: What is the quality of reporting of pre-clinical research for the study and treatment of mucositis/peri-implantitis? MATERIALS AND METHODS: Electronic databases of the PubMed and the Cochrane Library were searched for animal studies reporting on pathogenesis or therapy of either peri-implant mucositits or peri-implantitis and completed by dual manual searches in duplicate between 1992 and May 2011. Quality assessment (i.e. grading of a checklist of 20 items in different categories) of selected full-text articles was performed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. RESULTS: Following screening, 75 publications were eligible for the review. For publications reporting on pathogenesis (n = 7) and therapy (n = 1) of peri-implant mucositis, minimum gradings were assigned to items 5 (Methods/Ethical Statement), 9 (Methods/Housing and husbandry), 11 (Methods/Allocation animals to experimental groups), 14 (Results/Baseline data), and 17 (Results/Adverse events). For publications reporting on pathogenesis (n = 34) and therapy (n = 33) of peri-implantitis, minimum grades were mainly assigned to items 9, 11, 14, and 17. CONCLUSIONS: This systematic review has identified missing information in the publications on pre-clinical research for the study and treatment of mucositis/peri-implantitis.

Animal models and medical countermeasures development for radiation-induced lung damage: report from an NIAID Workshop.

Since 9/11, there have been concerns that terrorists may detonate a radiological or nuclear device in an American city. Aside from several decorporation and blocking agents for use against internal radionuclide contamination, there are currently no medications within the Strategic National Stockpile that are approved to treat the immediate or delayed complications resulting from accidental exposure to radiation. Although the majority of research attention has focused on developing countermeasures that target the bone marrow and gastrointestinal tract, since they represent the most acutely radiosensitive organs, individuals who survive early radiation syndromes will likely suffer late effects in the months that follow. Of particular concern are the delayed effects seen in the lung that play a major role in late mortality seen in radiation-exposed patients and accident victims. To address these concerns, the National Institute of Allergy and Infectious Diseases convened a workshop to discuss pulmonary model development, mechanisms of radiation-induced lung injury, targets for medical countermeasures development, and end points to evaluate treatment efficacy. Other topics covered included guidance on the challenges of developing and licensing drugs and treatments specific to a radiation lung damage indication. This report reviews the data presented, as well as key points from the ensuing discussion.