Special Issue "Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?"

A special issue of Animals (ISSN 2076-2615). This special issue belongs to the section "Animal Ethics".

Deadline for manuscript submissions: 15 May 2020.

Special Issue Editor

Dr. Pandora Pound
E-Mail Website
Guest Editor
Safer Medicines Trust, PO Box 122, Kingsbridge, TQ7 9AX, UK
Interests: preclinical animal research; animal models; clinical translation; new approach methodologies

Special Issue Information

Dear Colleagues,

Despite many decades of research, much of which has focused on studies in animals, humans continue to suffer from a multiplicity of diseases and illnesses for which there are no cures or treatments. It is now clear that insights provided by animal studies do not often translate to humans, explaining the very high failure rate observed when new medicines are evaluated in human clinical trials. In addition, there is increasing evidence that animal studies are frequently conducted so poorly that no clear conclusions may be drawn from them. Some claim that if only the quality of animal studies was improved, and animal models were made to more faithfully capture the relevant human disease, then these models would begin to translate and deliver clinical benefits. Others argue that research focusing on humans is necessary to gain a better understanding of human disease and to develop safe and effective drug treatments. These scientists point to developments in human biology during the last decade that have yielded in vitro and in silico techniques capable of providing novel insights into human disease mechanisms, as well as human-relevant disease models for developing and testing drug treatments for humans. Against this backdrop, the Netherlands and the US have recently announced concrete proposals for significantly reducing laboratory animal use by 2025 and 2035 respectively, whilst accelerating a transition towards, human-focused methodologies. A key question is whether there is value in refining animal models, or whether these should be relinquished in favour of new, human-focused research approaches.

Original manuscripts that address this point are invited for this special issue. Associated topics, for example, papers discussing the use of both animal and human-focused approaches, are also of interest.

Dr. Pandora Pound
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Animals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Clinical translation

New approach methodologies

Human focused methods

Human biology

In vitro

In silico

Animal models

Animal research

Published Papers

This special issue is now open for submission, see below for planned papers.

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

  • The Use of Animals in Alzheimer, Breast and Prostate Cancer Research: Translational Failures and the Importance to Monitor Return on Investment

Francesca Pistollato, Camilla Bernasconi, Ivana Campia, Clemens Wittwehr and Maurice Whelan

European Commission, Joint Research Centre (JRC), Ispra, Italy

Abstract: Animal models of Alzheimer’s disease (AD), breast cancer (BC) and prostate cancer (PC) have been traditionally used to recapitulate human disease features and develop new drugs, as they are generally purported to resemble some of the major hallmarks of these human diseases. However, animal models do not physiologically develop the disease as it occurs in humans, and their use has not often, in some cases never, paved the way to the development of drugs effective in human patients. Despite conspicuous research and economical endeavours, the clinical failure rate in drug development remains still very high, with an overall likelihood of approval from Phase I of about 9.6%. On the other hand, the expanding toolbox of non-animal methods, accounting for e.g., induced pluripotent stem cells derived from patients, next-generation sequencing, omics and integrated computer modelling can be used to study human diseases in human-based settings, identify new potential druggable targets, and evaluate treatment effects. The rise of new technological tools and models in life science, and the increasing need for multidisciplinary approaches, have encouraged many research initiatives and the launch of new EU calls for proposals. In particular, research proposals on AD, BC and PC based on the use of both animal and/or non-animal approaches have been extensively funded in the last two decades. Nowadays, it is becoming pivotal to define and apply indicators suitable to measure return on investment of research funding strategies to monitor contribution to innovation, retrospectively assess public health trends, and readdress funding strategies when needed. Here we discuss such issues, describing a list of indicators to measure return on investment in biomedical research, considering AD, BC and PC as case studies.

  • A Systematic Review Comparing Experimental Design between Animal and Human Methotrexate Efficacy Studies for Rheumatoid Arthritis: Lessons for the Translational Value of Animal Studies

CHC Leenaars, FR Stafleu, DH de Jong, M van Berlo, T Geurts, CJJ Coenen-de Roo, A Bleich, RBM de Vries, FLB Meijboom and M Ritskes‐Hoitinga


Abstract: This paper will describe our results from a systematic review of methotrexate studies, in which we compare several aspects of clinical trial design between animal and human studies. We will discuss the findings in light of the value of animal studies for development of human drugs. Besides, we will discuss the value and limitations of systematic reviews.

  • Taking out the Xenograft- Making Cancer Research more Human-Relevant.

Lindsay Marshall and Marcia Triunfol

School of Life and Health Sciences, Aston University, Birmingham, UK

Abstract: Cancer is the number one cause of death for Europeans aged between 45 and 64 and was responsible for 1.75 million deaths in 2012, with 3.45 million new cases diagnosed in the same year.  The most common causes of death are lung cancers, followed by colorectal and breast cancers and the World Health Organisation has estimated that there will be over 22 million new cases of cancer by 2030.  In 2019, Carlos Moedas, in his role as the European Commission’s commissioner for Research, Enterprise and Science, in announcing the ambitious ‘Cancer Mission’ element of the Horizon Europe funding programmes, declared that “cancer has evolved…” and yet it is apparent that the methodologies for assessing chemotherapeutic efficiency have not.  Cancer drugs have the lowest likelihood of success, with failure rates as high as 97%.  There is still a heavy reliance on the immunocompromised nude mouse, with these animals used as incubators for human tumours, despite an increased understanding of the importance of the (host-specific) tumour microenvironment and recent research revealing the development of significant phenotypic changes in human cancers implanted into animals.

This review will compare and contrast the impact of the so-called ‘patient derived xenograft’ animal-based approach with the more human-relevant patient-derived organoids.  We will consider the use of both methodologies in the development and assessment of possible cancer treatments in order to determine likely translational failures or successes of each approach.  We estimate costs of funding dedicated to both approaches and evaluate their likelihood of success in terms of clinical trials, novel drugs in clinic and improved understanding of disease mechanisms.  We make urgent recommendations that funding no longer focuses on the failing animal models and that the EU’s Cancer Mission takes this opportunity to lead the way, making a firm commitment to support the human relevant methods that are already offering personalised solutions for cancer patients and are faster and more efficient in terms of providing treatment regimes.

  • The Use of Non-Human Primates in Research: Is It Worth It or Is It Time to Stop It?

Candida Nastrucci; et al

Abstract: According to the latest EU published Statistics on animals’ use regarding the year 2017 in Europe in the published EU documents [1] and [2] the total number of non human-primates used were 8235. Numbers increased by 12.1% (996 more primates) from 2015 (7136 in total) and by 13.3% (1099 more primates) from 2016 (723 9 in total).

In 2017 a large 31.7% of primates were born in China and a larger 52.6% in Africa, only 12.8% were born at a registered breeder in EU. Cynomologus monkeys represented 87.7% of primates used: 7227 individuals out of 8235 total were subjected to experimentation in 2017, 59% of them were born in Africa (4290 subjects) and 36% in Asia (2591 subjects).

Looking at the areas of use, for 2017, 64.7% of non-human primates uses (7509) were to satisfy legislative requirements for medicinal products for humans (regulatory requirements, therefore mandatory use according to international regulations), while their use in basic (1190, 10.2%), translational and applied research (1705; 14.6%) accounted for 25%. In basic research 27% of primates was used to study the nervous system, 30.4% for other biological research, 12.6% for ethology, animal behaviour/biology and 9.24% for endocrine system/metabolism. In applied and translational research, 46% of primates were used to study human infectious disorders, 22% for non-regulatory toxicology, and 12% for the nervous system and mental disorders.

On the severity of suffering, the report shows in 2017 that 54% of non-human primates were used in mild-severe and 1.6% in severe procedures. Research projects in basic, applied and translational research are still funded today, despite warnings by the IUCN Red list [3], environmental issues, ethical concerns, and the evidence of the serious impact that laboratory conditions and procedures have on primates’ life. It is well known and documented that primates are intelligent and close to humans in sensitivity, ability to understand and living in organized and interactive communities, using tools and performing complex tasks. Despite analogies with humans, retrospective analysis of results shown that non-human primates do not generally represent a good model for our species. Significant number of publications are not followed by real progress in medicine for humans, and much of funded research does not translate into therapies or drugs useful for humankind, despite their use being legally required. Moreover, civil society is very concerned about primates welfare and many countries are moving fast towards the end of primates' research in EU and internationally. This paper aims to provide an overview on non-human primates’s reaserch, a global picture on what primates are used for and why in EU and in the world, with a vision for a new ethical research without the use of non-human primates.

  • Development and validation of methods for identification and quality assessment of in vitro research

Emma Wilson1, Florenz Cruz2, Jing Liao1, Sarah McCann2, Malcolm Macleod1, Emily Sena1
1.    University of Edinburgh, Edinburgh, UK
2.    Charité - Universitätsmedizin Berlin, Berlin, Germany

Abstract: In the last decade, in vitro systems have increasingly garnered traction as models to reduce and place the use of animals in scientific research. Despite this, the robustness of in vitro models has not been subjected to systematic scrutiny. Systematic review and meta-analysis of in vivo literature has highlighted high risks of bias and overestimation of efficacy. Highlighting these findings has had a positive impact on reporting quality of in vivo research. Our recent assessment of publications describing in vitro research conducted as part of the Nature Publishing Group – Quality in Publication (NPQIP) study suggested that reporting of measures to reduce the risk of bias are even lower in in vitro compared with in vivo research. We believe that in vitro research is of high risk of bias, and that systematic review and meta-analysis of in vitro research could bring similar benefits to this field.
Systematic review methods developed for clinical studies and adapted to in vivo studies generally used title-and-abstract-only searching for citation screening. Unfortunately, studies performing both in vivo and in vitro experiments often do not report the in vitro experiments in titles and abstracts. These limitations in how these studies are reported and indexed can result in these studies unintentionally being excluded from systematic reviews. Systematic review methods must be further adapted to fit in vitro research. A key challenge in this is the computational power and resources required to perform full text searches instead of title and abstract.
In this study, we aimed to validate methods for identification and quality assessment of in vitro research. We took a random sample of 2,000 papers from PubMed Central and screened their full texts for reporting of in vitro experiments. We used this dataset first to train a machine learning algorithm to identify in vitro research. To assess quality, we then trained a machine to identify reporting of risk of bias measures including randomisation, blinding, and sample size calculation. Once we validated these algorithms to run with over 85% accuracy, we used the machine to both identify in vitro research and assess trends in reporting measures to reduce the risk of bias on a larger sample of papers from PubMed Central.

  • Animal research: necessary evil or frivolous enterprise?

Guilherme Ferreira
Universiteit Utrecht, The Netherlands


Abstract: Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and the public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often lacklustre. Several initiatives to address the internal validity and reporting quality of animal studies (e.g. ARRIVE and PREPARE guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Here, we discuss the latest developments to tackle the evaluation of the predictive value of animal models themselves: the Framework to Identify Models of Disease (FIMD) was the first step to standardise the assessment, validation and comparison of animal models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of models more likely to predict human response. Moreover, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between models quantitatively. Finally, we explore whether external validity is a factor in animal model selection in the Investigator’s Brochure (IB), and we use the IB-Derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data to early clinical development. Similar to internal validity, we show how we can address external validity to evaluate animal models’ translatability/scientific value. Whereas these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. Only when we promote and adopt a high-quality study design and reporting as well as a thorough assessment of animal models’ translatability, we will have robust data to challenge and improve the current paradigm.

Back to TopTop