An IQ Consortium Perspective on The Scientific Committee on Health, Environmental and Emerging Risks Final Opinion on the Need for Nonhuman Primates in Biomedical Research, Production and Testing of Products and Devices (Update 2017).

The recent Scientific Committee on Health, Environmental and Emerging Risks Final Opinion on "The need for nonhuman primates in biomedical research, production and testing of products and devices" (2017 SCHEER) highlights approaches that could significantly contribute to the replacement, reduction, and refinement of nonhuman primate (NHP) studies. Initiatives that have the potential to affect NHP welfare and/or their use are expected to be appropriate, fair, and objective and publicly disseminated information focused on NHPs in biomedical research, which includes toxicologic and pathologic research and testing, should be objectively evaluated by stakeholder scientists, researchers, and veterinarians. Thus, IQ Consortium member companies convened to develop an informed and objective response, focusing on identifying areas of agreement, potential gaps, or missing information in 2017 SCHEER. Overall, the authors agree that many positions in the 2017 SCHEER Opinion generally align with industry views on the use of NHPs in research and testing, including the ongoing need of NHPs in many areas of research. From the perspective of the IQ Consortium, there are several topics in the 2017 SCHEER that merit additional comment, attention, or research, as well as consideration in future opinions.

Recent efforts to elucidate the scientific validity of animal-based drug tests by the pharmaceutical industry, pro-testing lobby groups, and animal welfare organisations.

BACKGROUND: Even after several decades of human drug development, there remains an absence of published, substantial, comprehensive data to validate the use of animals in preclinical drug testing, and to point to their predictive nature with regard to human safety/toxicity and efficacy. Two recent papers, authored by pharmaceutical industry scientists, added to the few substantive publications that exist. In this brief article, we discuss both these papers, as well as our own series of three papers on the subject, and also various views and criticisms of lobby groups that advocate the animal testing of new drugs. MAIN TEXT: We argue that there still remains no published evidence to support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials. In fact, the data in these recent studies, as well as in our own studies, support the contention that tests on rodents, dogs and monkeys provide next to no evidential weight to the probability of there being a lack of human toxicity, when there is no apparent toxicity in the animals. CONCLUSION: Based on these data, and in particular on this finding, it must be concluded that animal drug tests are therefore not fit for their stated purpose. At the very least, it is now incumbent on-and we very much encourage-the pharmaceutical industry and its regulators to commission, conduct and/or facilitate further independent studies involving the use of substantial proprietary data.

Some salt with your statin, professor?

We know that clinical trials sponsored by the pharmaceutical industry are likely to exaggerate benefit and minimise harms. But do these biases extend to their sponsorship of non-human animal research? Using systematic review and meta-analysis Bero and colleagues show that, in the case of statins, things are a little more complicated. While the conclusions of industry-sponsored studies were indeed more enthusiastic than warranted by their data, the data themselves painted a picture more conservative than was seen in non-industry-sponsored studies. This behaviour is consistent with maximising the return on investment, seeking robust data before embarking on a clinical trial, and, once that investment has been made, making every effort to "prove" that the drug is safe and effective if this is at all credible. The findings suggest that there is something different about industry-sponsored non-human animal research, perhaps reflecting higher standards than is the case elsewhere. Perhaps the academic community can learn something from our colleagues in the commercial sector.

Nonindustry-sponsored preclinical studies on statins yield greater efficacy estimates than industry-sponsored studies: a meta-analysis.

Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966-April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I(2) statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (-1.99; 95% CI -2.68, -1.31) versus studies sponsored by industry (-0.73; 95% CI -1.00, -0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study.

Consensus terminology for preclinical phases of psoriatic arthritis for use in research studies: results from a Delphi consensus study.

The concept of psoriatic arthritis (PsA) prevention is gaining increased interest owing to the physical limitation, poor quality of life and low remission rates that are achieved with current therapies for PsA. The psoriasis-to-PsA transition offers a unique opportunity to identify individuals at increased risk of developing PsA and to implement preventive strategies. However, identifying individuals at increased risk of developing PsA is challenging as there is no consensus on how this population should be defined. This Consensus Statement puts forward recommended terminology from the Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) for defining specific subgroups of individuals during the preclinical and early clinical phases of PsA to be used in research studies. Following a three-round Delphi process, consensus was reached for three terms and definitions: 'increased risk for PsA', 'psoriasis with asymptomatic synovio-entheseal imaging abnormalities' and 'psoriasis with musculoskeletal symptoms not explained by other diagnosis'. These terms and their definitions will enable improved identification and standardization of study populations in clinical research. In the future, as increasing evidence emerges regarding the molecular and clinical features of the psoriasis-to-PsA continuum, these terms and definitions will be further refined and updated.

Validating animal models for preclinical research: a scientific and ethical discussion.

The use of animals to model humans in biomedical research relies on the notion that basic processes are sufficiently similar across species to allow extrapolation. Animal model validity is discussed in terms of the similarity between the model and the human condition it is intended to model, but no formal validation of models is applied. There is a stark contrast here with the use of non-animal alternatives in toxicology and safety studies, for which an extensive validation is required. We discuss both the potential and the limitations of validating preclinical animal models for proof-of-concept studies, by using an approach similar to that applied to alternative non-animal methods in toxicology and safety testing. A major challenge in devising a validation system for animal models is the lack of a clear gold standard with which to compare results. While a complete adoption of the validation approach for alternative methods is probably inappropriate for research animal models, key features, such as making data available for external validation and defining a strategy to run experiments in a way that permits meaningful retrospective analysis, remain highly relevant.

The SCHER report on non-human primate research - biased and deeply flawed.

The European Commission's Scientific Committee on Health and Environmental Risks (SCHER) recently issued an Opinion on the need for non-human primate (NHP) use in biomedical research, and the possibilities of replacing NHP use with alternatives, as part of the Directive 86/609/EEC revision process. Here, we summarise our recent complaint to the European Ombudsman about SCHER's Opinion and the entire consultation process. It is our opinion that the Working Group almost entirely failed to address its remit, and that the Group was unbalanced and contained insufficient expertise. The Opinion presumed the validity of NHP research with inadequate supporting evidence, and ignored substantial evidence against the need for NHP research and examples of valid alternatives that could replace the use of NHPs. Because the European Commission and others might base their approach to NHP research directly on the inquiry's findings during the revision of Directive 86/609/EEC, the implications of a flawed analysis of the efficacy of NHP research are extremely serious, both for animal welfare and for human health and safety. The conduct of the SCHER inquiry, and its published Opinion, should therefore be of major and widespread concern, and should not be given any political, scientific or legislative credibility.

Designing Preclinical Studies in Germline Gene Editing: Scientific and Ethical Aspects.

Human germline gene editing is often debated in hypothetical terms: if it were safe and efficient, on what further conditions would it then be ethically acceptable? This paper takes another course. The key question is: how can scientists reduce uncertainty about safety and efficiency to a level that may justify initiation of first-time clinical trials? The only way to proceed is by well-designed preclinical studies. However, what kinds of investigation should preclinical studies include and what specific conditions should they satisfy in order to be considered well-designed? It is argued that multispecies and multigenerational animal studies are needed as well as human embryo editing without implantation. In order to be possible to translate to first-time clinical trials, animal studies need to satisfy strict conditions of validity. Moreover, embryo studies intended for translation to first-time clinical trials need to correspond to the animal studies in experimental design (with exception of implantation). Only in this way can uncertainty about risk for harm (safety) and prospect of benefit (efficiency) in first-time clinical trials be reduced to a modest level. If uncertainty is not reduced to such a level, first-time clinical trials in germline gene editing should not be initiated.

New insect system for testing antibiotics.

New and efficient methods to screen antibiotics are needed to counter increased antibiotic resistance in pathogens and the emergence of new diseases. Here we report a new insect model for screening antibiotics in vivo using the grasshopper Romalea microptera. The system is inexpensive, efficient, and flexible, avoids animal-welfare problems, and can be used to test against most major pathogenic groups. We employed this system to test 11 commercial antibiotics against a pathogenic Encephalitozoon species (Microsporidia). Oral treatment with fumagillin or thiabendazole significantly reduced pathogen spore counts, whereas spore counts of grasshoppers fed with albendazole, ampicillin, chloramphenicol, griseofulvin, metronidazole, sulfadimethoxine, or tetracycline were not significantly different from the infected controls. Quinine produced a distinct, but nonsignificant, reduction in spores, and streptomycin a nonsignificant increase in spores. Although 2 antibiotics significantly reduced spore counts, in no case was the pathogen totally eliminated. This study demonstrates the validity of this system as a method to screen antibiotics. It also corroborates the difficulty researchers and physicians have had in treating microsporidia infections, and suggests that quinine and related alkaloid compounds should be further examined as possible therapeutic agents against this group of ubiquitous pathogens. In addition, streptomycin and related compounds should be tested to determine if this widely used antibiotic enhances microsporidiosis.

Ethical issues on the "synthetic" phosphoethanolamine clinical trial.

Notwithstanding its approval by the National Committee for Ethics in Research (Conep) on April 19, 2016, a trial of the so-called "synthetic" phosphoethanolamine (syn-phospho) pill in cancer patients raises ethical concerns. An analysis by a laboratory contracted by the Ministry of Science, Technology and Innovation (MCTI) revealed that syn-phospho contained a great amount of impurities and did not meet standards of pharmaceutical quality required for an investigational drug. Cytotoxicity against human tumor cell lines and in vivo rodent xenograft tumor assays consistently failed to demonstrate a potential anticancer activity of syn-phospho. Preclinical safety studies of syn-phospho were also insufficient to support a trial of this investigational drug in cancer patients. Moreover, the ethical approval decision apparently overlooked two previous findings that suggested a possible enhancement of mammary carcinoma cell proliferation by phosphoethanolamine, and an apparent increase in lung metastases (rat implanted tumor assay) by syn-phospho. The syn-phospho risk-benefit ratio is clearly unfavorable and, thus, this trial in cancer patients does not fulfill a key requirement to make a clinical research ethical. There are also concerns regarding whether the study design is robust enough (scientific validity), and the social value of the trial of syn-phospho in cancer patients is questionable.

Development of Novel Antibiotic Lysocin E Identified by Silkworm Infection Model.

In this symposium, we reported the identification and mechanistic analysis of a novel antibiotic named lysocin E. Lysocin E was identified by screening for therapeutic effectiveness in a silkworm Staphylococcus aureus infection model. The advantages of the silkworm infection model for screening and purification of antibiotics from the culture supernatant of soil bacteria are: 1) low cost; 2) no ethical issues; 3) convenient for evaluation of the therapeutic effectiveness of antibiotics; and 4) pharmacokinetics similar to those of mammals. Lysocin E has remarkable features compared with known antibiotics such as a novel mechanism of action and target. Here, we summarize our reports presented in this symposium.

Screening, brief intervention, and referral to treatment for opioid and other substance use during infertility treatment.

Opioid use and misuse have reached epidemic proportions in the United States, especially in women of childbearing age, some of whom seek infertility treatments. Substance use is much more common than many of the conditions routinely screened for during the preconception period, and it can have devastating consequences for the woman and her family. Substance use can worsen infertility, complicate pregnancy, increase medical problems, and lead to psychosocial difficulties for the woman and her family. The reproductive endocrinologist thus has an ethical and medical duty to screen for substance use, provide initial counseling, and refer to specialized treatment as needed. This article provides an overview of screening, brief intervention, and referral to treatment (SBIRT), a public health approach shown to be effective in ameliorating the harms of substance use.

The use of non-human primates in regulatory toxicology: comments submitted by FRAME to the Home Office.

The Home Office have circulated a document that summarises the discussions of a Primate Stakeholders Forum. The Forum took place in January 2004, and was convened to address the issues raised and the recommendations made in the Animal Procedures Committee 2002 report on the use of primates under the Animals (Scientific Procedures) Act 1986. The report emphasises the need for more resources focused on alternatives to toxicological testing in primates, including harmonising worldwide regulatory requirements, investigating the relevance of primate models, and improving the retrospective analysis of procedures involving primates. The document called for reasoned comments about the report to be submitted to the Home Office. In response, FRAME submitted a comprehensive paper, which evaluated each of the Animal Procedures Committees recommendations, along with the Home Office Forums comments. FRAME believes that, in coming to a decision as to whether primates should be used for regulatory testing, there must be full consideration of all the information available, including whether the ethological needs of any given species can be met prior to, during and following experimental use. Where these needs cannot be met, there must be a concerted effort to develop alternative models for research and testing. However, this should not detract from the ultimate goal of phasing out primate research altogether.

Refinement, reduction, and replacement of animal use for regulatory testing: future improvements and implementation within the regulatory framework.

Many are critical of how regulatory testing practices have evolved and become established--critical both of the scientific rational and the animal welfare costs. The test of whether we are more enlightened than our predecessors will be whether, armed with more powerful scientific insights and a better understanding of animal welfare, we can ensure that the best animal welfare and the best science drive and shape future developments in regulatory testing. Conducting the most humane animal-based regulatory testing requires establishing and maintaining a constructive dialogue between stakeholders and acknowledging the common ground that unites. Inclusive processes with stakeholders prepared to offer public, rational justifications for their policies and processes are essential if best practice is to be identified and implemented. There is general agreement that the best animal welfare results in the best science; that regulatory requirements based on an understanding of mechanisms and early relevant biomarkers result in elegant and valid science. Thus, "alternative" methods enabling replacement, reduction, or refinement (the 3Rs) are in reality often more scientifically "advanced" and scientifically valid methods. These principles provided the incentive and framework for recent initiatives in the United Kingdom to enhance the quality of the data prepared for regulatory submission while better protecting the welfare of the animals used. Some remaining 3R opportunities are explored in this paper, and some of the commonly encountered myths about regulatory testing and perceived barriers to change are challenged. Current "threats" may indeed offer opportunities for ensuring that sound science and the best animal welfare underpin developments in regulatory testing.

Chocolate, an effective means of oral drug delivery in rats.

Oral gavage is an important procedure for drug discovery and efficacy studies using rodents. However, there are welfare issues related to the use of the method by inexperienced persons or for long-term studies. The authors describe an effective method of administering drugs to rats by mixing the drug with chocolate to provide a consistent and reliable method of oral drug delivery to large groups of rats for a long period of time.

Animal models of chemically induced intestinal inflammation: predictivity and ethical issues.

The debate about the ethical and scientific issues regarding the use of animals in research is mainly focused on these questions: a) whether preclinical studies in animals are still ethically acceptable; b) whether it is possible to establish more soundly their predictivity; c) what measures should be taken to reduce the clinical attrition often due to biased preclinical assessment of potential efficacy of new drugs. This review aims at a critical revision of animal models of chemically induced intestinal inflammation in drug development. These models, notwithstanding differences among species, still represent a major source of information about biological systems and can have undisputable translational value, provided that appropriate measures are taken to ensure that experiments are both scientifically and ethically justified. These measures include: a) more stringent application to preclinical experiments of standards used in clinical studies (such as sample size, randomization, inclusion/exclusion criteria, blinding); b) selection of the animal model after careful pathophysiological scrutiny bearing in mind inherent limitations of each model (e.g. acute self-limiting vs chronic disease, animal species, role of the intestinal immune system and microbiome); and c) experimental design duly considering the specific pharmacological profile of each agent to be screened (such as bioavailability, route of administration, full consideration of the pharmacological spectrum). In this perspective, the new European legislation is an opportunity to fully apply these standards so that in vivo animal models can provide an invaluable mean to study complex physiological and biochemical interactions, which cannot be completely simulated in silico and/or in vitro.