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Are Animal Models Needed to Discover, Develop and Test Pharmaceutical...
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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: closed (15 May 2020) | Viewed by 33302

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 submissions that pass pre-check are 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 semimonthly 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 2400 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 (7 papers)

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Editorial

Jump to: Research, Review, Other

7 pages, 217 KiB  
Editorial
Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?
by Pandora Pound
Animals 2020, 10(12), 2455; https://doi.org/10.3390/ani10122455 - 21 Dec 2020
Cited by 14 | Viewed by 4033
Abstract
Despite many decades of research, much of which has focused on studies in animals, we humans continue to suffer from multiple diseases for which there are no cures or treatments [...] Full article
(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?)

Research

Jump to: Editorial, Review, Other

18 pages, 993 KiB  
Article
Patient-Derived Xenograft vs. Organoids: A Preliminary Analysis of Cancer Research Output, Funding and Human Health Impact in 2014–2019
by Lindsay J. Marshall, Marcia Triunfol and Troy Seidle
Animals 2020, 10(10), 1923; https://doi.org/10.3390/ani10101923 - 20 Oct 2020
Cited by 18 | Viewed by 3822
Abstract
Cancer remains a major threat to mortality and morbidity globally, despite intense research and generous funding. Patient-derived xenograft (PDX) models—where tumor biopsies are injected into an animal—were developed to improve the predictive capacity of preclinical animal models. However, recent observations have called into [...] Read more.
Cancer remains a major threat to mortality and morbidity globally, despite intense research and generous funding. Patient-derived xenograft (PDX) models—where tumor biopsies are injected into an animal—were developed to improve the predictive capacity of preclinical animal models. However, recent observations have called into question the clinical relevance, and therefore the translational accuracy, of these. Patient-derived organoids (PDO) use patient tumor samples to create in vitro models that maintain aspects of tumor structure and heterogeneity. We undertook a preliminary analysis of the number of breast, colorectal, and lung cancer research studies using PDX or PDO published worldwide between 2014–2019. We looked for evidence of impacts of this research on human health. The number of publications that focused on PDO is gradually increasing over time, but is still very low compared to publications using PDX models. Support for new research projects using PDO is gradually increasing, a promising indicator of a shift towards more human-relevant approaches to understanding human disease. Overall, increases in total funding for these three major cancer types does not appear to be translating to any consequential increase in outputs, defined for this purpose as publications associated with clinical trials. With increasing public discomfort in research using animals and demands for ‘alternative’ methods, it is timely to consider how to implement non-animal methods more effectively Full article
(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?)
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Review

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13 pages, 457 KiB  
Review
Levelling the Translational Gap for Animal to Human Efficacy Data
by Guilherme S. Ferreira, Désirée H. Veening-Griffioen, Wouter P. C. Boon, Ellen H. M. Moors and Peter J. K. van Meer
Animals 2020, 10(7), 1199; https://doi.org/10.3390/ani10071199 - 15 Jul 2020
Cited by 43 | Viewed by 4700
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 general public now question whether there is still a justification for conducting animal [...] Read more.
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 general 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 unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, 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 in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm. Full article
(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?)
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28 pages, 10359 KiB  
Review
Alzheimer’s Disease, and Breast and Prostate Cancer Research: Translational Failures and the Importance to Monitor Outputs and Impact of Funded Research
by Francesca Pistollato, Camilla Bernasconi, Janine McCarthy, Ivana Campia, Christian Desaintes, Clemens Wittwehr, Pierre Deceuninck and Maurice Whelan
Animals 2020, 10(7), 1194; https://doi.org/10.3390/ani10071194 - 14 Jul 2020
Cited by 14 | Viewed by 5584
Abstract
Dementia and cancer are becoming increasingly prevalent in Western countries. In the last two decades, research focused on Alzheimer’s disease (AD) and cancer, in particular, breast cancer (BC) and prostate cancer (PC), has been substantially funded both in Europe and worldwide. While scientific [...] Read more.
Dementia and cancer are becoming increasingly prevalent in Western countries. In the last two decades, research focused on Alzheimer’s disease (AD) and cancer, in particular, breast cancer (BC) and prostate cancer (PC), has been substantially funded both in Europe and worldwide. While scientific research outcomes have contributed to increase our understanding of the disease etiopathology, still the prevalence of these chronic degenerative conditions remains very high across the globe. By definition, no model is perfect. In particular, animal models of AD, BC, and PC have been and still are traditionally used in basic/fundamental, translational, and preclinical research to study human disease mechanisms, identify new therapeutic targets, and develop new drugs. However, animals do not adequately model some essential features of human disease; therefore, they are often unable to pave the way to the development of drugs effective in human patients. The rise of new technological tools and models in life science, and the increasing need for multidisciplinary approaches have encouraged many interdisciplinary research initiatives. With considerable funds being invested in biomedical research, it is becoming pivotal to define and apply indicators to monitor the contribution to innovation and impact of funded research. Here, we discuss some of the issues underlying translational failure in AD, BC, and PC research, and describe how indicators could be applied to retrospectively measure outputs and impact of funded biomedical research. Full article
(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?)
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21 pages, 3557 KiB  
Review
A Systematic Review Comparing Experimental Design of Animal and Human Methotrexate Efficacy Studies for Rheumatoid Arthritis: Lessons for the Translational Value of Animal Studies
by Cathalijn Leenaars, Frans Stafleu, David de Jong, Maikel van Berlo, Tijmen Geurts, Tineke Coenen-de Roo, Jan-Bas Prins, Rosalie Kempkes, Janneke Elzinga, André Bleich, Rob de Vries, Franck Meijboom and Merel Ritskes-Hoitinga
Animals 2020, 10(6), 1047; https://doi.org/10.3390/ani10061047 - 17 Jun 2020
Cited by 7 | Viewed by 5106
Abstract
Increased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of methotrexate for rheumatoid arthritis, comparing trial design between 147 animal and 512 human studies. Animal studies generally [...] Read more.
Increased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of methotrexate for rheumatoid arthritis, comparing trial design between 147 animal and 512 human studies. Animal studies generally included fewer subjects than human studies, and less frequently reported randomisation and blinding. In relation to life span, study duration was comparable for animals and humans, but included animals were younger than included humans. Animal studies often comprised males only (61%), human studies always included females (98% included both sexes). Power calculations were poorly reported in both samples. Analyses of human studies more frequently comprised Chi-square tests, those of animal studies more frequently reported analyses of variance. Administration route was more variable, and more frequently reported in animal than human studies. Erythrocyte sedimentation rate and c-reactive protein were analysed more frequently in human than in animal studies. To conclude, experimental designs for animal and human studies are not optimally aligned. However, methotrexate is effective in treating rheumatoid arthritis in animal models and humans. Further evaluation of the available evidence in other research fields is needed to increase the understanding of translational success before we can optimise translational strategies. Full article
(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?)
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16 pages, 250 KiB  
Commentary
Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?
by Dania Movia and Adriele Prina-Mello
Animals 2020, 10(8), 1259; https://doi.org/10.3390/ani10081259 - 24 Jul 2020
Cited by 22 | Viewed by 4765
Abstract
Respiratory diseases constitute a huge burden in our society, and the global respiratory drug market currently grows at an annual rate between 4% and 6%. Inhalation is the preferred administration method for treating respiratory diseases, as it: (i) delivers the drug directly at [...] Read more.
Respiratory diseases constitute a huge burden in our society, and the global respiratory drug market currently grows at an annual rate between 4% and 6%. Inhalation is the preferred administration method for treating respiratory diseases, as it: (i) delivers the drug directly at the site of action, resulting in a rapid onset; (ii) is painless, thus improving patients’ compliance; and (iii) avoids first-pass metabolism reducing systemic side effects. Inhalation occurs through the mouth, with the drug generally exerting its therapeutic action in the lungs. In the most recent years, orally inhaled drugs (OIDs) have found application also in the treatment of systemic diseases. OIDs development, however, currently suffers of an overall attrition rate of around 70%, meaning that seven out of 10 new drug candidates fail to reach the clinic. Our commentary focuses on the reasons behind the poor OIDs translation into clinical products for the treatment of respiratory and systemic diseases, with particular emphasis on the parameters affecting the predictive value of animal preclinical tests. We then review the current advances in overcoming the limitation of animal animal-based studies through the development and adoption of in vitro, cell-based new approach methodologies (NAMs). Full article
(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?)
12 pages, 229 KiB  
Conference Report
Improving Translation by Identifying Evidence for More Human-Relevant Preclinical Strategies
by Merel Ritskes-Hoitinga, Cathalijn Leenaars, Wouter Beumer, Tineke Coenen-de Roo, Frans Stafleu and Franck L. B. Meijboom
Animals 2020, 10(7), 1170; https://doi.org/10.3390/ani10071170 - 10 Jul 2020
Cited by 14 | Viewed by 3361
Abstract
Preclinical animal studies are performed to analyse the safety and efficacy of new treatments, with the aim to protect humans. However, there are questions and concerns about the quality and usefulness of preclinical animal research. Translational success rates vary between 0 and 100%, [...] Read more.
Preclinical animal studies are performed to analyse the safety and efficacy of new treatments, with the aim to protect humans. However, there are questions and concerns about the quality and usefulness of preclinical animal research. Translational success rates vary between 0 and 100%, and no clear relationship has been found with possible predictive factors such as animal species or field of research. Therefore, it is not yet possible to indicate what factors predict successful translation. Translational strategies were therefore discussed at an international conference held in the Netherlands in November 2019, aiming to develop practical guidelines for more robust animal-to-human translation. The conference was organised during the course of a research project funded by the Dutch Research Council (313-99-310), addressing possible solutions for the low translational values that had been published for a multitude of animal studies in human health care. This article provides an overview of the project and the conference discussions. Based on the conference results and the findings from the research project, we define four points of attention that are crucial in the search for improved translational success rates: (a) optimising the methods and design of studies; (b) incorporation of the complexity of the human patient in research; (c) start with the patient rather than existing animal models as the gold standard; and (d) more and better collaboration within the chain from funding to pharmacy. We conclude that this requires improved organization and use of procedures, as well as a change of attitude and culture in research, including a consideration of the translational value of animal-free innovations and human-relevant science. Full article
(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?)
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