Keywords: translational strategy, animal models, human diseases, ethics, uncertainty, 3R-principles

Transcription

1 From animal model to translational strategy On the ethical, scientific and institutional problems related to innovations in bio-medical animal research Abstract Experimenting on animals is contested in society. In spite of evidence of results in terms of understanding/ treating human diseases, there is still debate concerning the moral justification and trustworthiness of animal research, and on the validity of the used experiments including animal models. This already has resulted in many innovative activities towards new animal(free) models. The problem is that implementing such innovations appears to be difficult and does not always lead to improved human health treatments. Therefore, we hypothesize that a new approach should be taken: from improving individual experiments including animal models to building integrated translational strategies. This entails that innovation starts in the complexity of human patients who have to benefit from the research results. The research question is How can translational strategies contribute to the effectiveness and ethical acceptability of animal research and to responsible innovations in human health? Based on two case studies, the consortium investigates the hurdles and elaborate on innovative steps in animal research to build robust translational strategies. The project includes Systematic literature research to come to evidence-based translational strategies. Exploration of the research chain to trace the scientific, ethical and societal obstacles. Ethical analysis of uncertainty of outcomes of experiments as an obstacle for ethical assessment of animal research. Concrete attempts to improve the translational strategy for the case studies. The project will result in improved practical and moral understanding of current innovation problems, formulating best practices for building translational strategies, and advice to research chain partners how to deal with scientific, ethical and institutional obstacles on the road to responsible health innovation. Keywords: translational strategy, animal models, human diseases, ethics, uncertainty, 3R-principles

2 Description of the proposed research This research project aims to deliver practical guidelines to build robust translational strategies. Two case studies serve as show cases to formulate best practices for building translational strategies. This can benefit research chain partners and will contribute to responsible health innovation, including responsible animal testing. Background Academic and public debates on the justification of animal testing and on the validity of models resulted in innovations towards new (animal free) models. Nonetheless, the level of innovation is limited, implementing innovations is often difficult and innovations do not always lead to improved human health (Van der Worp et al. 2010). Furthermore, recent publications have highlighted worryingly low translational value of animal studies (Ioannidis et al. 2014, Pound & Bracken 2014; Ohl & Meijboom 2014). It is currently not possible to determine whether this low translation is caused by fundamental biological differences between species or whether it is the result of low methodological quality and inadequate design of animal studies (Ritskes-Hoitinga & Green 2014; Van der Staay et al 2009). Therefore, this project aims to explore and propose a further step in the process of innovations towards new (animal free) models. In this step, individual animal models are part of larger, integrated translational strategies. From a scientific, ethical and societal perspective it is desirable that research money is not wasted, as is discussed in the Lancet (Ioannidis et al. 2014). Moreover, as animal and human lives are involved, there is a clear legal and ethical imperative to improve the current situation in health research (Ohl & Meijboom 2014; Hooijmans & Ritskes-Hoitinga 2013; Stafleu et al. 1999). General Scientific quality The research question of this project is: What do translational strategies contribute to the effectiveness and ethical acceptability of animal research and to responsible innovations in human health? The project starts with two hypotheses. The first hypothesis is that responsible health innovation, including responsible animal testing requires an integrated approach and is the responsibility of the entire research chain. Innovation should start from a more integrative approach that brings stakeholders (pre-clinical and clinical) together. Therefore, we aim to investigate (institutional) hurdles that may frustrate innovation and deal with questions of a fair distribution of responsibility (see WP3 and 4). Furthermore, it asks for a systematic analysis of current animal models and their translational value (see WP1 and 2). A second hypothesis is that robust translational strategies start from the patient s perspective. Animal experimentation is often used for highly complex biomedical questions. As a result, there is a clear tendency to specialize into specific aspects of a research theme. For instance, a research project focuses on the influence of a specific food ingredient on

3 gut health or on the function of one specific protein on the development of diabetes. As a consequence the animal models turn out be very specific. This is understandable, but a reductionist perspective quite often does not match with the holistic problem that individual patients are confronted with. Furthermore, most diseases are multi-factorial and probably not caused by, for instance a single protein. This is problematic, because the final research aim often is to contribute to human health and wellbeing. Therefore, the project aims to bring the reductionist approach that often characterizes research in line with the more holistic nature of health questions of patients. The concrete health questions should be leading in building models. This implies a (normative) analysis of the concepts of translatability and complexity (WP3 and 4), but also making concrete steps towards strengthening the translational power of concrete research models (WP5 and 6). The aim of the project is (a) to deliver step stones for practical guidelines to build robust translational strategies, (b) to design innovative experiments (including animal models) for Cystic Fibrosis (CF) and/ or improve current models for Rheumatoid arthritis (RA), and (c) develop a translational strategy for the two designated human health problems as a showcase. The interdisciplinary consortium and especially the companies in the team already have ample experience with and run models for the mentioned diseases and explicitly aim to bridge animal-human research. Therefore, WP5 is dedicated to improve research models in order to build a translational strategy and analyses how companies could improve their strategy to offer/ use models with the best translational strategy. WP1: Getting grip on animal models (Central role for Postdoc 1; experts at private partners; support senior researchers) Several studies have shown that the selection of animal models is not always evidence-based (e.g., de Vries et al. 2012). Practical reasons tend to play as important a role as anticipated predictive value and the selection is often not the result of an explicit and extensive comparison between different potentially suitable models. Systematic reviews support an evidence-based choice of animal model by providing a comprehensive overview of models used so far, including their respective advantages and disadvantages. Therefore, in this WP a systematic review of animal studies will be performed to analyse the literature in order to choose the most optimal experimental design for the case studies (CF and RA) based on the available evidence. Subgroup analyses in the meta-analysis can greatly help in determining which animal model is, in the relevant aspects, most similar to the human disease. Deliverables: Scientific paper on the Systematic Review on the two case studies, direct practical input for WP 5. WP2 Quality versus translational value (Central role for Postdoc 1; experts at private partners; support senior researchers)

4 The methodological quality of animal studies is generally low: measures to reduce the risk of bias, such as randomisation and blinding, are often not applied (Kilkenny et al. 2009). There is already some evidence that a lack of randomisation and/or blinding leads to a substantial overestimation of the true effect of an intervention (Macleod et al. 2008). This overestimation may explain the differences in results between animal and human studies. A second systematic review will be performed in order to collect further empirical evidence for a correlation between a higher quality of execution and reporting of animal studies and a more successful translation of animal data to humans. Our hypothesis is that higher quality studies are more likely to be translatable, based on the situation of carcinogenicity studies that use a rigorous experimental design protocol and have better translational value (Huff 1999). Studies in animals and humans that examine a similar mechanism in rheumatoid arthritis, and the same drug and the same disease outcome parameters (efficacy studies) will be compared in meta-analyses. Statistical analysis will reveal whether the results in animals and humans are significantly different or not. Subgroup analyses will be used to examine the correlation between study quality (and other variables) and predictive value. Deliverables: Scientific paper on the Systematic Reviews and meta-analyses on the two case studies, direct practical input for WP 5. WP3: Exploring the research chain (Central role for PhD and PostDoc1; valorisation panel and experts at private partners; support senior researchers) It already has been stressed in the literature that translational research implies a change in science (e.g., Duyck, 2003; Lancet 2014; Macleod et al, 2008; Maienschein et al. 2008). However, about what changes are needed there is less agreement. Therefore, in parallel to WP 1 and 2, this WP will explore and analyse current (institutional) hurdles and obstacles that may frustrate such a change in science and therefore discourage further innovation. This includes explicit attention to the (plurality of) normative assumptions with respect to animal research and health innovation in the research chain. It aims to analyse how a better understanding of the institutional and normative background of the research chain helps to improve translational power of animal research models. Furthermore, it analyses views on distribution of responsibility in the research chain. The used methods are literature study, semi-structured interviews with experts, and stakeholder meetings. Deliverables: Scientific papers with analysis of the research chain from an institutional and an ethical perspective; Paper that translates the findings to stakeholders in the research chain; direct input for WP 6. WP4: Uncertainty as key concept (Central role for PhD; support senior researchers) Most of the literature on ethics of animal experimentation focuses on what we owe to animals and on ethical assessment of experiments (cf. Meijboom et al. 2009). Although this forms the background of the need for innovation, the discussions on translatability show the importance of

5 reflection on uncertainty and trust in science (cf. Fung & Kerridge 2013). Uncertainty of future outcomes of experiments forms a severe obstacle for the moral assessment of animal research, the relevance of animal models, and desirable institutional frameworks (Grimm 2014; Sandoe et al 2004). This asks for analysis of (a) how a better understanding of uncertainty and trust improves ethical assessment of research, (b) the possibility to ascribe responsibilities regarding innovation in contexts of uncertainty, and (c) whether is it morally legitimate to restrict (academic) freedom to improve the quality of research? This Work Package provides (1) a conceptual and normative analysis of concepts that are central to the approach of translational strategies (e.g., translation, uncertainty) and (2) an normative ethical analysis of questions of responsibility, of what translational power is needed to improve trust in and acceptability of research, and the legitimacy to restrict individual freedom to improve the quality of research. The used methods are literature study, philosophical analysis and systematic ethical reflection. Deliverables: Scientific papers the concepts of uncertainty and responsibility in the context of animal research; direct input for WP 6. WP5: Building Translational Strategy (Central role for PostDoc2 and the experts at private partners; support senior researchers) Based on the outcomes of WP1-4, this WP will make concrete steps in order to develop new models and/ or improve current models that fit in an integrated translational strategy for one of the mentioned case studies. This includes performing an animal study according to the ideal experimental design. This means that animal studies are planned, executed and reported by using the Gold Standard Publication Checklist (Hooijmans et al. 2010). This is in line with how the medical field came to improve the inadequacies in performing clinical trials (the Dublin trial). Even though real translational activities are beyond the scope of this project (as it would require a clinical trial too), the hypothesis is that an improved quality leads to more relevant results for humans (Huff 1999). Deliverables: Design and performance of experiments including animal studies that have strong translational value based on the two case studies. Scientific papers that present and discuss the results of the experiments; The results of the ideal animal study in relation to the human situation will be discussed with experts and published in scientific journals. Direct input for WP 6. WP6: Implementation and valorisation (Central role for senior researchers, PhD and the experts at private partners; support members of valorisation panel) The results from WP1-5 will be first discussed with key-stakeholders in the research chain. Next, we aim to formulate concept guidelines that help individual researchers in choosing their experimental design. Furthermore, we aim to translate the results of the project to the templates that are used by animal experimentation. This implies that both researchers and the committees that perform the ethical assessments may benefit from

6 the results. In the end, we define step stones towards a revised golden standard for future experiments taking into account the possibilities and challenges that result from this project. Deliverables: An integration of the results in new or existing guidelines for research groups that aim to contribute health innovation; A translation of the results to the context of the Animal Experimentation Committee(s); Step stones towards a revised golden standard for future experiments. Scientific quality within the Responsible Innovation (MVI) frameworks To run this project input from different disciplines is necessary. We aim for a continuous interplay between α, β and γ perspectives: innovations start in ethical assumptions, ask for scientific research to propose innovations, which again ask for reflection, and (lab-animal) scientists who are willing to invest in the development of models. For each of the steps that constitute the project a multidisciplinary approach is needed. For instance, writing systematic reviews always requires multidisciplinary teams in order to write meaningful reviews. With the current consortium we have a group that is willing and capable of dealing with the various dimensions of defining best practices for animal research. Especially, the private partners will play a crucial role. They feel the need to improve the current models and to build a more robust strategy for human health questions. The CRO and the company focused on development of drugs to treat genetic disorders have the competence and the infrastructure to make the steps from theory to practice that are needed to (a) answer the research question, (b) deliver innovative animal models for the designated case studies, but also (c) to test and validate the recommendation with respect to translational strategies at the end of the project. Research group / embedding of the research The consortium and the research team reflects the interdisciplinary character of the question at stake and includes many relevant fields of expertise, such as laboratory animal science, expertise in the field of the 3Rs, veterinary medicine, systematic reviews of animal studies, and philosophical ethics. The combination between Utrecht University and the Radboud university medical center brings together the two Netherlands universities that have many years of experience with and competence in laboratory animal science. Both universities have a chair in this field, and have research groups that perform biomedical research that includes animal experimentation and clinical trials. Because of the intern network of the consortium members information and experience from these groups can be used in this project and will bridge animal research and human medicine. On top of this, via the in-kind contribution of the two private partners and their network a lot of know-how with respect designing and performing animal studies will become available. Furthermore, the close link to the private sector guarantees a good entry to other private partners the research chain. This is essential in for the valorisation of the project and the distribution of the result in the research chain.

7 With respect the staff: for the first two work packages we deliberately chose for a Postdoc. Performing Systematic reviews for the designated case studies requires the contribution at the level of a Postdoc. The envisaged person for Postdoc1 has already ample expertise with performing systematic reviews and has experience with the field of animal research. Given the level of required expertise for designing animal studies together with the private partners, and the relatively short period in which the animal studies have to performed, we also chose for WP5 for a Postdoc. Finally, we consider it to be essential to get grip on the institutional and ethical context in which the steps towards best practices for defining translational strategies are taken. This part runs parallel with the systematic reviews and the concrete search for ideal experimental design. For this part, we will recruit a PhD who has a background in ethics and has experience with or interest in animal research and philosophy of science. The supervisors and the other senior researchers in the team, as well as the members of the valorisation panel will guarantee the entry to the field of responsible animal research. 17. Summary for laymen [in Dutch only] Het uitvoeren van dierexperimenten roept in de samenleving nog altijd veel vragen en discussie op. Ondanks dat de inzet van dieren de afgelopen decennia heeft bijgedragen aan een beter inzicht in ziektes en aan de behandeling van diverse aandoeningen, blijven er vragen. Die vragen richten zich op de ethische aanvaardbaarheid van de dierproeven, de betrouwbaarheid van de onderzoeksketen en de validiteit van de gebruikte modellen. Deze langlopende discussies hebben geleid tot diverse innovatie-initiatieven om nieuwe en betere dier(vrije) onderzoeksmodellen te ontwikkelen. Toch blijkt in praktijk het implementeren van deze innovaties uiterst lastig en wordt lang niet altijd de gewenste gezondheidswinst geboekt. Dit projectvoorstel wil de maatschappelijke discussie serieus nemen, maar ook de problemen met betrekking tot innovatie een stap verder helpen. Daarom is de hypothese dat er een nieuwe aanpak nodig is. In dit project staat de stap centraal van innovatie op het niveau van individuele (dier)experimenten naar het formuleren van zogenaamde translationele strategieën. Dit houdt in dat (a) de gehele onderzoeksketen (dier en humaan) wordt meegenomen bij het bepalen van de optimale onderzoeksstrategie en dat (b) de patiënt en zijn/ haar gezondheidsvraag centraal staat. De onderzoeksvraag is: Hoe kan de ontwikkeling van translationele strategieën bijdragen aan de effectiviteit en de ethische aanvaardbaarheid van gezondheid innovaties, inclusief dierproeven? Aan de hand van twee case studies zal het onderzoeksteam de mogelijkheden en onmogelijkheden van goede translationele strategieën verkennen en analyseren. Het project omvat 6 werkpakketten, waarin via verschillende methodes (o.a. Systematic Reviews, ethische reflectie, interviews en

8 focusgroepen, vernieuwend experimenteel dieronderzoek) tot een wetenschappelijk onderbouwde en praktisch toepasbare translatiestrategie gezocht wordt. De cases richten zich op Taaislijmziekte (cystische fibrose (CF)) en Reuma (Reumatoïde artritis (RA)). Met de uitkomsten van het project zal het mogelijk zijn om (a) beter grip te krijgen op de institutionele en ethische problemen, waardoor innovaties bij dierproeven niet worden geïmplementeerd of niet leiden tot gezondheidswinst. (b) concrete stappen te maken in het optimaliseren van (dier)onderzoek bij de twee cases CF en RA. (c) Bouwstenen en best practices te formuleren voor het opzetten van translationele strategieën. Het onderzoek zal in nauw overleg met experts en stakeholders in het veld van o.a. dieronderzoek en medisch onderzoek worden uitgevoerd. De resultaten zullen worden gedeeld met de praktijk, o.a. via onderwijs, bijdrage aan standaardprotocollen voor onderzoek en ethische toetsing.