Volume 4 Issue 2
Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed
Applying Game Theory to One Health Modelling Human Healthcare Delivery
Regulation of Diagnostics in Animal Health Is it Needed?
Microfloral Rehabilitation Normalisation of Gut Function
Innovation and Collaboration
Combatting the Endemic Threat of Brucellosis
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CONTENTS 04 FOREWORD WATCH PAGES
Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed
MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker Project Director Clive Baigent, PhD Email: firstname.lastname@example.org EDITOR Orsolya Balogh EDITORIAL ASSISTANT Maria Dominici email@example.com DESIGNER Jana Sukenikova www.fanahshapeless.com BUSINESS DEVELOPMENT Simon Wilkins Email: firstname.lastname@example.org ADMINISTRATOR Barbara Lasco FRONT COVER © istockphoto PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: email@example.com www.animalhealthmedia.com International Animal Health Journal – ISSN 17585678 is published quarterly by PHARMAPUBS.
The opinions and views expressed by the authors in this Journal are not necessarily those of the Editor, Publisher or the Supporting Organisations which appear on the front cover. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. Volume 4 Issue 2 May 2017 PHARMA PUBLICATIONS www.animalhealthmedia.com
06 Addressing Antimicrobial Resistance Requires One Health Approach: Mind the Gap With several recent disease outbreaks potentially having implications of multi-species involvement, and the recent growth in antimicrobial resistance making bacterial diseases more difficult to treat, it is becoming increasingly urgent that governments, inter-governmental agencies and global health organisations redouble efforts aligned to a ‘One Health’ approach. In this article the Royal Veterinary College discusses how many of the research programmes are aimed at improving health outcomes for both humans and animals and are conducted in partnership with fellow researchers and academics in leading institutions around the world. 08 The Show Must Go On For Animal Health The UK’s decision to leave the EU will no doubt engender a number of changes for the veterinary medicines industry, which may lead to challenges, but also to opportunities. Our initial analysis flags up a number of areas for immediate focus, such as avoiding legal and regulatory uncertainty, harmonising licensing systems for veterinary medicines, encouraging further innovation in our sector and, most importantly, guaranteeing continued access to the necessary veterinary medicines that safeguard animal health conveys, according to Roxanne Feller, Secretary General of IFAH-Europe. 10
Precision Farming: Animal Health Treatments, Compliance & Traceability Livestock farmers and vets have long been aware of the benefits of farm specific health plans including: animal welfare, profitability and efficient farm management. Lisa Rumsfeld, Key Account Manager for veterinary products Henke Sass Wolf GmbH, says that the industry sees the need to work more intelligently, to gain via the use of data and predictive analytics. With these global trends in mind for more accountability, transparency and real time collection of health data, Henke-Sass, Wolf has launched the V-ETIC system.
REGULATORY & MARKETPLACE 12 Global Megatrends of Livestock Production and Pet Ownership The world is affected by increasing depletion of natural resources. And as the global population continues to grow, the demand for animal protein is rising in tandem with dietary changes and new challenges regarding disease transmission are emerging. Maximilian Zellmer, Policies and Stakeholder Affairs at Animal Health, Bayer, explains how global trends like this impact, and sometimes exert pressure on, the reputation and business of the animal health sector, as disease dynamics for animals and humans are becoming increasingly challenging to handle. 14 Applying Game Theory to One Health Part 2: Modelling Human Healthcare Delivery For the second and final part of his series focusing on veterinary healthcare delivery, Professor of One Health, Lloyd Reeve-Johnson MBBS, DVMS, PhD, PGCert (Business Admin), FSB, FRCVS elucidates the way typical decisions are made, using a reductionist approach to identify a small number of broad categories of participant and to ascribe general perspectives that each may have when interacting or making healthcare-related decisions. In this paper the emphasis is on breaking down the complexities of human healthcare delivery to a simple sequence of events, to understand the core transactions in healthcare delivery, as well as the points of influence or vulnerability. International Animal Health Journal 1
CONTENTS 24 Regulation of Diagnostics in Animal Health – Is it Needed? Renewed interest in the development of diagnostics for animal infections and diseases is motivated by the belief that suitable diagnostics will assist in the control of diseases; this stimulates a number of questions about the regulation of, and standards for, diagnostic evaluation and monitoring tools. This article, written by Dr Maggie Fisher BVetMed CBiol MSB MRQA DipEVPC MRCVS and Dr Peter Holdsworth AO BSc (Hon) PhD FRSB FAICD, will evidence the lack of regulation of, or standards for, veterinary diagnostics, in comparison with regulatory frameworks for veterinary pharma-ceuticals (including biologicals). It will seek to address whether any differences matter, focussing on parasitic infections of farm and companion animals in particular.
RESEARCH & DEVELOPMENT
30 Six Detrimental Effects of Mycotoxins on the Gastrointestinal Health of Poultry Contamination of feed commodities by moulds and mycotoxins is considered to be one of the most important negative factors in crop production and animal feed quality. There has been extensive research addressing the different ways in which mycotoxins can alter animal productivity. In this article, Radka Borutova, DVM, PhD, Business Development Manager, Nutriad International, illustrates six major effects of mycotoxins in the intestine that may contribute to decreased performance. In addition, the possible alteration of the microflora by mycotoxins will be explored. 34 Tackling the Worms that Turned: PARAGONE, an EU Project on Parasite Vaccines In this article, Professor Jacqueline B Matthews of Moredun Research Institute gives an insight into the PARAGONE Vaccine Development Project, the EU Horizon 2020-funded multicellular parasite vaccine consortium which includes a group of academics and commercial organisations, that are taking a collegiate approach to moving forward vaccines designed to control several major multicellular parasites of cattle, sheep and poultry. An important part of the project is the strong element of dialogue between the academic partners and the animal health company partners, in addition to several outreach activities to other end-users such as farmers, veterinarians and regulators. CLINICAL STUDIES 38 Anti-Nerve Growth Factor Monoclonal Antibodies for Chronic Pain Control in Cats and Dogs: A Review of Clinical Outcomes Chronic pain management is an area of major clinical importance. Multiple prevalent conditions in veterinary species are associated with pain and disability and the limitations of existing therapeutic options, especially in cats, have resulted in significant unmet medical need. In this white paper, Dr David Gearing of Nexvet and his team review the outcomes from pre-clinical and clinical studies of fully caninised and fully felinised anti-nerve growth factor monolocal antibodies, which support the further development of these therapies for chronic pain management in their respective species. 42 Microfloral Rehabilitation: Normalisation of Gut Function This piece by Dr Richard Murphy, Research Director at Alltech Bioscience Centre, provides new insights into the specific and reproducible effects of MRF supplementation on the composition of the bacterial community as a whole. By making changes in the overall microbial diversity within the gut, we can aim to 2 International Animal Health Journal
repair and rehabilitate the gut microflora, which can lead to reductions in pathogen load, enhance the gut’s resistance to pathogen colonisation and reduce the abundance of antibiotic-resistant strains. Improving the understanding of these comprehensive changes is now key in the poultry industry. 46 Innovation and Collaboration: Combatting the Endemic Threat of Brucellosis Brucellosis is no longer a major concern to veterinarians and farmers in most developed countries, thanks to longterm control programmes. Amy Tranzillo, Project Manager at Global Alliance for Livestock Veterinary Medicines (GALVmed) analyses how the disease still poses a major threat to both animal and human health in many lowerincome countries where veterinary infrastructure is less well developed and animal health less tightly controlled. Reducing the prevalence of brucellosis in countries where it is still endemic calls for a greater awareness, understanding and appreciation of the impact of the disease on animal and public health. MANUFACTURING AND PACKAGING 50 Profitable Modernisation for Those Who Are Used to Saving Money Marketing and financial departments analyse and calculate basic indicators which are later introduced into the company's development strategy and further investments in production. In this article, Christoph Hammer CEO of Dividella AG explains how to select packaging equipment, taking into account real current and potential future requirements (the appearance of new products, increase in production volume). She also draws attention to the main indicators which will help you save significantly on pharmaceutical manufacturers in terms of the manual process of secondary drug packaging. 52 The Revolutionary Solution Transforming the Veterinary Market – Magnesium Alloys The veterinary industry is facing the same challenges as the medical industry. A new state-of-the-art solution which has recently been developed for use in the veterinary market, for both drug delivery and in medical devices, is magnesium alloys. Magnesium alloys are now beginning to be used effectively in veterinary auto wormers; Paul Lyon, Programmes Technology Manager at Magnesium Elektron, defines what are magnesium alloy’s properties and how have they helped with recent market breakthroughs. SPECIAL FEATURE 56 Leadership Lessons from Extraordinarily Successful Executives - Part 2 Denni O. Day, BS, BSN, RN, MSPH, the founder, President, and CEO of VetPharm, Inc., presents Part 2 of Extraordinarily Successful Leaders. She sets about interviewing as many of the industry leaders as she can, to learn what skills and practices made them and their companies so successful. In this article, she explores the other five key traits: emotions, leadership traits, self-doubt, inspiration, and authenticity. Then, as an added bonus, she shares some life lessons that these executives learned from their pets. 62 A Pug’s Life In this editorial, Justine Marie Chambers, who is working in animal transport and relocation as well as being a proud pug owner, talks through pugs’ characteristics and peculiarities. Their fun-loving personalities make it easy to understand why they are so popular – which makes it seem crazy to think that, like all dogs, these pugs are descended from the mighty wolf. Pugs are very friendly characters and are known for their comical yet sensitive personalities. Volume 4 Issue 2
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FOREWORD Welcome to the Summer 2017 edition of the Journal. As regular readers will know, usually I select a few articles from each edition for editorial comment. However, on this occasion I have decided to focus on just one contribution. The decision by the United Kingdom to leave the European Union is one on the most significant political steps for the country, and for the EU, since its formal commitment at the Paris summit of October 1972. In November 2014, I published an article in Volume 1 of this Journal entitled Veterinary Medicinal Products – What might happen if the UK withdrew from the European Union? (Woodward, 2014). In 2016, the people of the United Kingdom voted in a referendum to leave the European Union. I have to confess that when I drafted the article, I did not expect this to happen – but I was in good company, as the then Prime Minister, David Cameron, also did not expect this result and he subsequently resigned. The decision to leave the EU has created a significant amount of uncertainty, both in the UK and in the EU. There should be no doubt that this uncertainty extends to human and veterinary medicines and their regulation. As noted by Professor Sionaidh Douglas-Scott: Post Brexit, would the UK continue to accept decisions by a relocated EMA until a new British equivalent had been set up, which could take several years? If there were a British equivalent, there would have to be arrangements for mutual recognition of UK and EU agency decisions, otherwise applicants would face extra costs of going through two agencies (Douglas-Scott, 2016). However, the UK already has regulatory agencies for the control of human medicines (the Medicines and Healthcare Products Regulatory Agency; MHRA) and veterinary medicines (Veterinary Medicines Directorate; VMD), so at least in that respect, there is some room for certainty. However, in all other respects, there is adequate scope for uncertainty. Article 50 of the Treaty on European Union that began the formal negotiations to leave the EU was invoked in March 2017. The Government recognised that there is a substantial body of applicable EU legislation and that this is given effect in the UK through the European Communities Act 1972 (ECA). This Act will need to be repealed on the day of Brexit as the UK leaves the EU. The government’s plan is to enable this through the implementation of the Great Repeal Bill, which will in effect convert existing EU law into UK law which can then be later amended or repealed as necessary. This appears to offer an efficient way of dealing with EU legislation – essentially convert it into UK law, keep the good bits, change the not-sogood bits and remove the bad bits. It may work well for many aspects of legislation derived from EU legislation. However, the government also recognised that it would require secondary legislation to amend laws that would no longer operate appropriately once we have left the EU and the broad approaches to these problems were discussed in the government’s White Paper of March
2017 (Department for Exiting the European Union, 2017). The regulation of human and veterinary medicines certainly fall into this category. As EU legislation makes reference to the EMA and to mutual recognition, decentralised and centralised procedures for marketing authorisation applications, then these are also written into UK legislation. They will need to be removed at Brexit. This leaves the UK without home-grown legislation on how medicines will be authorised in the future. Simply converting existing EU law into UK law will not be adequate to address the problem. This is only one of the problems relating to medicines. The British Veterinary Association has raised concerns over possible adverse effects on animal welfare due to uncertainties over the future of EU veterinarians and other professionals currently working in the UK (Waters, 2017). Similar concerns have been raised over the future status of the estimated 9000 doctors and 20,000 other health professionals from EU countries currently working in the UK (Majeed et al., 2016; Torjesen, 2017). How will these positions be filled if non-UK EU workers have to return? The concerns are not limited to the regulation of human and veterinary medicinal products. Plant protection products and food/feed additives are regulated through European regulation through the European Food Safety Authority (EFSA), biocides through the European Chemicals Agency (ECHA) and commodity chemicals under the REACH and other legislation, also through ECHA. The UK will need to put in place regulatory mechanisms for these too. Challenging times lie ahead… And the EMA will have to relocate from its current London home to some as yet unidentified city within the EU. In this issue, Roxanne Feller, Secretary General of IFAHEurope, considers some of the broader implications of Brexit for animal health, including the encouragement of future innovation and the future for regulation of veterinary medicinal products. I hope you enjoy reading her article and find it thought-provoking. I also hope you enjoy all of the other very well though out contributions to this issue.
Dr Kevin Woodward
Managing Director, KNW Animal Health Consulting 1.
2. 3. 4. 5. 6.
Department for Exiting the European Union. Legislating for the United Kingdom’s withdrawal from the European Union. Available at: https:// www.gov.uk/government/uploads/system/uploads/attachment_ data/file/604514/Great_repeal_bill_white_paper_print.pdf. S. Douglas-Scott (2016). The Great Repeal Bill: Constitutional Chaos and Constitutional Crisis? Available at https://ukconstitutionallaw. org. A. Mazeed et al. How would a decision to leave the European Union affect medical research and health in the United Kingdom? J. Royal Soc. Med., 2016, 109, 216-218. I. Torjesen. Four in 10 European doctors may leave UK after Brexit vite, BMA survey finds. BMJ, 2017, 356, j988. A. Waters. Business after Brexit: the case for keeping EU vets in the UK. Vet. Rec., 2017, 180, 432. K. N. Woodward (2014), Veterinary medicinal products – What might happen if the UK withdrew from the European Union? IAHJ, Volume 1, Issue 2, pp. 16-21.
EDITORIAL ADVISORY BOARD Germán W. Graff Research Reference Laboratory Specialist, IDEXX BioResearch Fereshteh Barei - Health Economist & Strategy Advisor, Founder of BioNowin Santé Avenue Association Carel du Marchie Sarvaas Executive Director Health For Animals Kimberly H. Chappell - Senior Research Scientist & Companion Animal Product Development Elanco Animal Health Dr. Sam Al-Murrani - Chief Executive Officer Babylon Bioconsulting & Managing Director at Bimini LLC Sven Buckingham - Buckingham QA Consultancy Ltd. Dan Peizer - Director Animal Health at Catalent Pharma Solutions Dawn Howard - Chief Executive of the National Office of Animal Health (NOAH). Jean Szkotnicki - President of the Canadian Animal Health Institute (CAHI) Dr Kevin Woodward - Managing Director KNW Animal Health Consulting Norbert Mencke - ,VP Global Communications & Public Affairs Bayer Animal Health GmbH 4 International Animal Health Journal
Volume 4 Issue 2
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Addressing Antimicrobial Resistance Requires One Health Approach – Mind the Gap With several recent disease outbreaks potentially having implications of multi-species involvement, and the recent growth in antimicrobial resistance making bacterial diseases more difficult to treat, it is becoming increasingly urgent that governments, inter-governmental agencies and global health organisations redouble efforts aligned to a ‘One Health’ approach. One Health is the principle which recognises that greater cooperation is needed between human medicine, veterinary medicine and environmental and social sciences in the fight against today’s major diseases, allied with a commitment to addressing technical, social and institution-level interventions. Many of the research programmes at the Royal Veterinary College (RVC) are aimed at improving health outcomes for both humans and animals and are conducted in partnership with fellow researchers and academics in leading institutions around the world, including the London School of Hygiene & Tropical Medicine (LSHTM), with whom the RVC runs its One Health MSc course. So how does the One Health approach work in practice? When one considers the impact of zoonotic infectious diseases from a One Health perspective, one must include multiple and wide-ranging driving forces ranging from international travel and trade, and agricultural practices, to pressing issues such as climate changes, demographic pressure and environmental pollution. It is vital that policymakers understand the interplay of the numerous factors involved in disease outbreaks in order to best understand and manage how to control them. As well as understanding the science behind public and animal health problems, it is imperative for researchers to understand the social and policy context if measures are to be implemented effectively and on a global scale. This is where we need doctors working with vets, working with economists, politicians, social scientists and environmental scientists to bring about this collaborative approach. Without the synergy that such teams bring, solutions are unlikely to emerge and none of this will have any significant impact unless there is meaningful engagement, buy-in and investment at an institutional level. Scientists have long been concerned about the threat of antimicrobial resistance and the impact it could have on the world’s population. It is estimated that 700,000 people currently die as a result of antimicrobial resistance each year. A study by Harvard University concluded that if the rising trend of antimicrobial resistance continues, then up to 10 million people will die each year as a direct result by 2050 – that’s in just 33 years. Couple this with the prediction that the cost of tackling antimicrobial resistance could be up to £80 trillion worldwide, and one can see that we are facing a threat of catastrophic proportions. Antimicrobial resistance is firmly on the agenda of the World Health Organisation (WHO), the UN, and, closer to 6 International Animal Health Journal
home, the UK government, and now it is time for action. The WHO states that “AMR is an increasingly serious threat to global public health that requires action across all government sectors and society.” To this end, colleagues from the Royal Veterinary College have taken part in a review of antimicrobial resistance to address these questions, which include: • How does resistance emerge in animals? • Does antimicrobial resistance spread through the food chain from animals to humans? • If so, how important is this pathway compared with human sources of antimicrobial resistance? • How important is the spread of antimicrobial resistance from livestock into the environment for spread to other animals and humans? Some of these questions are being answered by the RVC’s research, but the review, led by the Food and Agriculture Organisation of the United Nations (FAO) identifies substantial research gaps in the field of antimicrobial resistance which need to be addressed in order for us to be able to effectively tackle the threat. The findings were published at the end of 2016 by the FAO as a technical paper entitled Drivers, Dynamics and Epidemiology of Antimicrobial Resistance in Animal Production, and it is intended to inform vets, farmers and other stakeholders worldwide. Some examples of the gaps identified and the respective recommendations include: Volume 4 Issue 2
WATCH PAGES Gap
Better understanding of the dynamics and interactions of genes and microbes within microbiota, microbiomes and different scales of microbial ecosystems, and the transfer of resistance within those.
Use data generated by molecular techniques such as metagenomics together with epidemiological data in an integrated analysis.
Limited ability to predict the emergence and spread of resistant bacterial clones in the environment and human-agriculture interfaces will help to inform riskassessment and management strategies.
Use molecular sequencing and epidemiological studies of resistant bacteria and resistance determinants to support risk assessment and simulation studies.
Improve the efficacy of therapy and treatment and minimise the risk of antimicrobial emergence.
Use pharmacodynamic and pharmacokinetics studies to assess how antimicrobials interact with microbial populations, particularly in the context of treatment of infection.
Quantify the association between antimicrobial usage on farms and antimicrobial resistance among foodborne bacteria, as well as the relationship between antimicrobial resistance in livestock and the incidence of resistant infections in humans.
Improve data collection through robust infrastructure and capacity.
Improve intensive livestock production methods.
Identify the most efficient systems with regard to minimising environmental contamination with antimicrobial residues and resistant pathogens, taking into account local conditions and needs, and ensuring sustainability.
Better understanding of antimicrobial residues in the environment.
These should be monitored regularly in the same way as other hazardous substances.
Reduce the pressure of environmental contamination with antimicrobial residues.
Development of highly biodegradable anti-microbials should be prioritised.
Professor Pfeiffer, Professor of Veterinary Epidemiology at the RVC and Professor of One Health at Hong Kong’s City University, said: “It has been a major success that political leaders from around the world have now recognised the enormous threat for the global community associated with AMR and the challenge that it represents for all stakeholders. We are only just beginning to recognise the immense complexity of the eco-social system within which antimicrobial resistance emerges, and rather than one sector blaming the other, a truly integrated perspective based on a One Health approach is required to have a chance to deal effectively with this threat. The findings from our review very much confirm that antimicrobial usage in food production undoubtedly needs to be reduced, while acknowledging that current knowledge suggests that the vast majority of AMR affecting humans is associated with antimicrobial usage in humans.” Ben Wall, the paper’s first author and a researcher in the Veterinary Epidemiology, Economics and Public Health (VEEPH) Group, said: “It was really exciting to have the opportunity to work on this review paper as antimicrobial resistance is such a dynamic area of research at the moment, as well as it being a huge issue for all of us working with production animals. “We discovered that there are still a lot of unknowns regarding the spread of antimicrobial resistance between animals and humans. Antimicrobial usage in livestock has been associated with antimicrobial resistance in foodproducing animals. However, there is limited evidence at present concerning the number of infections in humans caused by resistant bacteria of food animal origin, or indirectly through the environment. www.animalhealthmedia.com
“Nevertheless, the prudent use of antimicrobials is still of utmost importance in mitigating the emergence of antimicrobial resistance in the first place, and this is true in human health, companion animal health and food production systems. “Due to the complexity of antimicrobial resistance epidemiology, filling the knowledge gaps will require a collaborative, multidisciplinary approach.” Armed with this research and knowledge of what we need to do to get closer to tackling antimicrobial resistance, researchers at the RVC will continue to work with colleagues in academic and governmental institutions across the world to advance our collective knowledge and understanding of this global health threat and help to save lives around the world.
The RVC is the UK's largest and longest established independent veterinary school, offering programmes in veterinary medicine, veterinary nursing and biosciences. RVC produces world-class research and supports the veterinary profession through its referral hospitals, including the Queen Mother Hospital for Animals, Europe's largest small animal hospital. Email: email@example.com
International Animal Health Journal 7
The Show Must Go On for Animal Health
The UK’s decision to leave the EU will no doubt engender a number of changes for the veterinary medicines industry, which may lead to challenges, but also to opportunities. Our initial analysis flags up a number of areas for immediate focus, such as avoiding legal and regulatory uncertainty, harmonising licensing systems for veterinary medicines, encouraging further innovation in our sector and, most importantly, guaranteeing continued access to the necessary veterinary medicines that safeguard animal health. Negotiations now started between the EU 27 and the UK will no doubt herald a slew of trials and tribulations for many industries at large, and it will be our job to ensure that the vital role played by the veterinary medicines industry is well-understood during the process. The one thing we must not lose sight of in this Brexit process, is that animal disease will not heed any border, be it soft or hard. Food safety standards should not be held hostage to political discussion. And, most importantly, ensuring the health and welfare of Europe’s animals through continued access to licensed medicines must not become a pawn in the game of ‘Who will get the EMA?’ This decision to detach from the EU will almost certainly change the current dynamics of the European animal health environment and the wider agri-food sector. It is likely to have as yet indeterminable repercussions on market access, trade, and regulatory standards. For UK-based companies in particular, whether the nation remains in the European Economic Area, joins the European Free Trade Association or distances itself entirely from the EU, there will clearly be ramifications for the licensing of and further innovation in veterinary medicines in the foreseeable future. Need for Continued Access to Medicines and Vaccines Veterinary surgeons, farmers and other animal owners will continue to need access to a wide range of veterinary medicines to treat and prevent the range of diseases they encounter. The message1 delivered by the European Medicines Agency and the European Commission early May was clear. Once the UK leaves the EU it becomes a ‘third country’. This means that certain legal repercussions will need to be considered in due time by animal health companies as the ‘marketing authorisation holders’. EU law requires that marketing authorisation holders are established in the EU (or EEA) and some specific activities must also be performed in the EU (e.g. related to pharmacovigilance, batch release). The notice served as a reminder that companies may be required to adapt processes or change the terms of their marketing authorisation to ensure continuous validity and use postBrexit. Under the current regulatory framework, companies can have a new product authorised by the EMA via the centralised route, leading to a marketing authorisation to sell the product in all 28 member states. As much as the industry would wish to avoid extra excessive regulatory burden, it is likely that in addition to the EU centralised 8 International Animal Health Journal
authorisation, a separate UK authorisation may need to be applied for. A further complication is that UK-based companies currently holding centrally approved EU authorisations, may need to move operations to an EU member state, in order to retain their access to the EU market. Some form of ‘mutual recognition’ may be sought and the UK may wish to adopt the full acquis on medicines, just as the EFTA countries have. EFTA members implement the EU legislation on veterinary medicines, have access to EMA activities and can participate in its committees (CVMP, CMDv). Centralised marketing authorisations also automatically cover both EU and EFTA member states. Maintaining Efficiencies and Avoiding Administrative Burden – Objective of New EU Legislation Avoiding further administrative burden and reducing regulatory uncertainty are industry’s main concerns in the authorisation process, something the current proposal for new EU legislation on veterinary medicines is trying to redress. From a regulatory perspective, given the UK’s leading role within the EU regulatory network for registering veterinary medicines, Brexit will cause a massive headache and a large regulatory burden for marketing authorisation holders. It will create a resource gap that will need to be filled by the other national competent authorities. Within the EU’s authorisation process, when it comes to new product applications, or for certain variations to marketing authorisations, the work is carried out by one or two ‘lead’ EU countries and then is generally recognised by the other EU countries. This has introduced efficiencies, reduced resource needs across the EU authorities, and even sometimes led to a reduction in the fees involved with licensing products. The UK is currently the reference member state or ‘lead’ country for more than 600 products authorised via the mutual recognition and decentralised procedures. In 2015, for example, the UK acted as reference member state in 43% of mutual recognition procedures, being the lead regulatory agency for 73 out of 168 applications. Moving forward, companies may be forced to make some tough business decisions. To which member state do they transfer the rapporteurship from the UK? Will they have to get a separate marketing authorisation for the UK, or will they decide to withdraw certain marketing authorisations from the UK entirely? Will they have to relocate manufacturing sites or their ‘qualified persons’? Will UK-based licence holders have to re-apply from scratch for marketing authorisations that have been authorised via EU systems? All of these questions sound alarm bells regarding the issue of administrative burden within the regulatory process. The current EU Directive on Veterinary Medicinal Products has been transposed into UK law but, depending on the timing of the ongoing legislative process for the future EU regulation on veterinary medicines, there may be a significant risk of divergences. The UK will be left with the old legislation that will refer to European procedures, structures and IT systems that may no longer apply, and the EU will have quite a different new regulation that aims to deliver on greater efficiencies! Volume 4 Issue 2
WATCH PAGES Retaining Expertise and Talent Diversity If, or once, the UK’s VMD are no longer part of the European regulatory network, this would mean the loss of a certain amount of expertise. Not only within the process for approving medicines but also for the ‘qualified persons’ for manufacturing authorisations or pharmacovigilance, for example. EU qualified persons for pharmacovigilance (QPPV) are required to reside in the EU. Yet another issue that must be addressed as efficiently as possible. Then there is the question of the movement of people and the workforce. We’ve already mentioned some of the impacts of losing the expertise of the VMD but there will be a need for reassurance over arrangements for the status of EU citizens working in UK-based companies and institutions and of UK nationals working in the animal medicines sector in EU countries. Ease of movement for high-qualified workers, talents and researchers will be necessary to retain a European lead on technological innovation and to further stimulate creativity. Our industry needs highly-skilled workers who can travel freely across Europe while feeling confident and secure in their jobs. The UK as a Pragmatic Scientific Reference With the UK’s strong science base, a number of British scientific institutions play important roles in many projects initiated and funded from Brussels. This is particularly applicable for food safety research. While being located in a non-member state is not a complete barrier to receiving EU funding, it will be interesting to see if there is a shift towards other member states getting a larger slice of the funding pie. The UK is considered to be a global leader for research, and is currently one of the largest recipients of EU funding. Withdrawing this financial help will certainly undermine the UK’s top-ranking position for R&D, but what would a UK withdrawal mean for the EU’s innovation prowess? Guaranteeing Consumer Protection Another concern that will arise post-Brexit, is adherence to procedures that ensure consumers across Europe are protected from residues that may occur from the use of veterinary medicines during animal-derived food production. The maximum residue limit setting is again agreed under EU law. This regulation provides the basis for setting withdrawal periods (i.e. the time between an animal receiving the last dose of a veterinary medicine and the first collection of foodstuffs, e.g. milk) and for monitoring food safety. The EU also participates in Codex, a body responsible for setting international MRLs, and helping facilitate trade in food. So, for consumer protection and continued trade of animal-sourced food products, it will be necessary to seek a mutually acceptable solution to this maximum residue limit procedure. With this in mind, food safety standards will most likely come into question. A lack of harmonised standards on vaccination of animals or health status controls may have an impact on the high levels of food safety currently enjoyed across the EU. This may also affect the freedom of movement of goods. Currently, the UK exports the majority of its agri-food products to the EU and it is also heavily reliant on food imports from the EU. To keep up this trading partnership, putting the question of trade tariffs aside, negotiations will need to cover the aspect of how future food safety will be measured and assured. Avoiding Trade Issues and Adapting to Change On the subject of the free movement of goods, the creation and maintenance of the EU single market has been one of the main reasons for companies investing in Europe. The single market ensures that there are no unnecessary barriers www.animalhealthmedia.com
to products, including veterinary medicines, being traded freely between EU/EEA member states. For governments, this means that they must not put in place tariff barriers to trade (e.g. custom duties) or non-tariff barriers to trade (e.g. unnecessary regulatory requirements). It is clear that the EU and the UK should find a solution to remain sustainable commercial partners to keep costs down for companies and to help ensure our customers’ (and the animals’) rights to access the best medicines. Any additional custom duties, import VAT and border controls will hamper trade and may have a negative effect on animal disease control and prevention. Smoothing the Transition of the EMA When it comes to the EU body holding the power to license animal medicines, the current discussion in Brussels spheres is mainly centred on which city will become the new host of the European Medicines Agency, and it seems that a new location is put forward every few weeks. The Commission is keen to ease the practical and financial burden for the experts working there, as if they stay with the agency they will have to relocate and move to another city within the EU. Our initial asks are for easy access to the host city, good local logistics, and retention of expertise. During the transition period for the EMA, our main concerns are that delays on approvals are kept to a strict minimum. Keep Calm and Carry On At a recent event organised at the EMA HQ in London, where industry and regulators meet to update on the latest developments in scientific review, regulation and marketing authorisation procedures, a journalist remarked to me that he was very surprised that Brexit was not once mentioned over the two days of the event. This, to me, is a clear demonstration of our sector’s ability and willingness to adapt and get on with business to the best of our ability. We will retain our good relationship with the UK National Office for Animal Health and continue dialogue with the negotiating teams over the various issues outlined in brief above. We don’t yet know all of the ‘where’ and ‘how’ Brexit will have an impact on our industry. But what we do know is that vets, farmers, pet lovers and other animal owners will continue to need access to a wide range of animal health products to ensure the health and wellbeing of their animals. For this reason alone, we must keep calm and carry on! 1. http://www.ema.europa.eu/docs/en_GB/document_ library/Other/2017/05/WC500226603.pdf
Roxane Feller Secretary General of IFAH-Europe, the representative body of manufacturers of veterinary medicines, vaccines and other animal health products in Europe. With membership covering 90% of the European market, IFAH-Europe represents innovators and generics alike, as well as large, medium-sized and small companies. Employing some 50,000 people in Europe, the sector is resilient and innovative. IFAH-Europe's member companies invest over €500 million in research and development each year. Email: firstname.lastname@example.org
International Animal Health Journal 9
Precision Farming: Animal Health Treatments, Compliance & Traceability Livestock farmers and vets have long been aware of the benefits of farm-specific health plans, including animal welfare, profitability and efficient farm management. This requires a commitment to precise record-keeping, manual data entry and time spent away from the herd and in the office. Faced with these choices in a busy farm environment with limited resources, detailed record-keeping has not always been the priority. Depending on the species, national legal requirements and individual veterinarian or producer, health plan practices vary. Our industry is faced with increasing legal and commercially-driven requirements on compliance and traceability of animal health plans. The choice is no longer whether, but how, to implement a true herd health compliance and traceability programme. This information needs to flow, and to be reliable, relevant, rapidly available and shared across all authorised platforms and stakeholders in real time. In the past years, many technologies have been adapted in livestock production, such as modern ventilation, automatic feeding stations and water management, with the focus on working more efficiently via automation. Today, our industry sees the need to work more intelligently, to gain via the use of data and predictive analytics. Producers small and large are embracing the IoT (Internet of Things) to collect, analyse and use data directly from the source via new precision farming technologies. With these global trends in mind for more accountability, transparency and real-time collection of health data, Henke-Sass, Wolf has launched the V-ETIC system.
The introduction of the V-ETIC system from HenkeSass, Wolf provides an easy-to-implement solution to measure, track, trace, report and optimise decisions regarding animal health treatments integrated on the familiar HSW ECO-MATIC® applicator. Whether your need is for antibiotic compliance reporting, managing vaccinations for a health passport or counting treatments, V-ETIC can be tailored for the job. Management can be done on an individual, pen/group or farm basis. V-ETIC, through the use of on-board RFID technology, provides automatic registration of animal treatments in real time. There are complementary functionalities built in that can manage animal health product inventory, usage and on-the-fly note-taking. The system is run via a simple smartphone app and cloud-based program. Users can integrate the V-ETIC app with partner apps and existing farm management software, providing a seamless view of their operation. You choose to follow the data that is important to you for decision-making and reporting. The V-ETIC is designed with the rugged farm environment in mind, mounted on the proven HSW ECOMATIC® applicator technology. The system runs on long-life batteries with 10 hours of non-stop working synchronised via Bluetooth and uploaded to the cloud via WiFi when available. No WiFi is needed in use, adding to the flexibility. V-ETIC offers: • A management tool to administer, track and trace livestock treatments • An open platform to integrate into existing or new farm management software • A suite of reports presenting key performance indicators With all stakeholders in mind, from the producer to the consumer, V-ETIC brings compliance and traceability to the treatment point. Learn more about how easy V-ETIC is to implement and use by contacting Henke Sass, Wolf. Visit our website www.henkesasswolf.de or email Stefan. Knefel@henkesasswolf.de
Lisa Rumsfeld Key Account Manager at HenkeSass, Wolf for veterinary products. A native New Yorker, she has a BA from Villanova University and a International MBA from Thunderbird. Lisa has lived and worked in Europe, the US and Asia. For the past ten years Lisa has been working globally with farmers, vets and pharmacetual companies on veterinary device management and development. Lisa Rumsfeld lives in Germany. Email: Lisa.Rumsfeld@henkesasswolf.de
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Volume 4 Issue 2
We care for companions. We love our pets and try to keep them healthy. But they can be at risk of fleas, ticks and mosquitoes. These parasites can carry dangerous diseases. Bayer Animal Health supports animal owners and veterinarians in the prevention and treatment of parasites.
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Global Megatrends of Livestock Production and Pet Ownership The world is affected by increasing depletion of natural resources. And as the global population continues to grow, the demand for animal protein is rising in tandem with dietary changes and new challenges regarding disease transmission are emerging.1 Global trends like this impact, and sometimes exert pressure on, the reputation and business of the animal health sector, as disease dynamics for animals and humans are becoming increasingly challenging to handle.
proteins will be in developing countries. Additionally, in those countries most affected by the consumption increase, production will increase too. The business model of many global food-producing companies is aimed at producing more in order to address the rising global demand for animal proteins and thus contributing to global food security. This approach is contested, as it is rather expected that developing countries will experience a sharp intensification and professionalisation of the livestock sector themselves – for instance, by enhancing productivity per animal – which in turn holds clear potential for animal health products.
The megatrends most impactful for the animal health industry:
Sustainable Livestock The projected growth in the livestock sector will only be sustainable if environmental, social, and economic challenges are addressed simultaneously. The livestock sector needs to consider and counteract challenges in the depletion of natural resources, climate change, widespread poverty, food insecurity, and global threats to animal and human health. Food security can only be met by sustainably improving productivity and resource-use efficiency. Only then will it be possible to mitigate the pressure on the earth’s natural resources and to promote socially inclusive agricultural systems.
1. Demand and production for animal protein sharply increases, particularly in Africa 2. Productivity increase per animal 3. Number of farms decreases whereas farm sizes increase 4. Changing food systems and resulting impact on farmers’ livelihoods 5. Demographic change and income increase leads to growing pet market, especially in BRICS 6. Depletion of the earth’s natural resources and increased competition for these resources 7. Emerging challenges in disease transmission
Sustainable livestock production can help to address this efficiency gap and minimise the negative environmental and social implications of livestock supply chains. The goal is to make livestock more productive without ignoring negative environmental and social impacts. The increased demand for animal-source food ultimately results in incentives for farmers to upgrade domestic livestock production. This may strengthen the role of progressive disease control, because animal wellbeing and health are prerequisites of higher productivity, since animal diseases account for a significant loss of productivity.
Dietary Change and the World Food Economy The world food economy is increasingly driven by the shift in diet and food consumption patterns towards proteins derived from animals. In tandem with human population growth, rising incomes and urbanisation, we see an increased demand for a protein-rich diet.3 The consumption of animal proteins is mainly driven by population growth in developing countries. Aspects like per capita income growth and changing consumer habits also account for the projected increase in consumption of animal proteins. Meat consumption is not expected to rise in most affluent countries over the coming years because of growing social concerns (e.g. animal wellbeing), health concerns and aging population, but in Africa and Asia, meat consumption is rising.2 Poultry is the primary driver of the growth of total meat production, followed by pig meat.5 Low production costs and lower product prices have contributed to making poultry the meat of choice for both producers and consumers in developing countries.6
Besides environmental and economic aspects, the social implications of the higher demand for livestock products are also important considerations. The growth and transformation of the sector offer opportunities for agricultural development, poverty reduction and food security gains, but the rapid momentum of change risks marginalising smallholders. Hence, systemic risks to natural resources, as well as human health and wellbeing, must be addressed to ensure sustainability. Where livestock is important to the country’s economy, there is always an incentive to invest in progressive disease control and prevention.
With the adoption of the United Nations Sustainable Development Goals (SDGs)2 by the UN Member States, sustainable development has become a strong global commitment endorsed not only by governments but also by the private sector. This may offer unprecedented opportunities for the private sector, as the commitment of multilaterals to scale up global efforts in mitigating social, environmental and economic mismatches could ultimately translate into long-term business opportunities.
Owing to lower margins and innovation hurdles, business engagement in countries where megatrends are most dominant is simultaneously the most challenging. As mentioned, the largest increase in consumption of animal 12 International Animal Health Journal
Animal Wellbeing and Good Husbandry Animal wellbeing is an issue of growing concern for consumers, pet owners, retailers, businesses, investors, regulators, civil authorities and non-governmental organisations (NGOs). However, the perception of good animal wellbeing varies immensely from region to region, owing to cultural, social and economic disparities. Similar to the One Health approach regarding the use of antibiotics, we see a growing understanding of animal wellbeing as a concept that provides a platform for fostering interdisciplinary collaboration to improve both human Volume 4 Issue 2
REGULATORY & MARKETPLACE and animal welfare (One Welfare). This concept suggests acknowledging the strong correlation between animal wellbeing and human wellbeing. Healthy and well-treated animals will help reduce the risk of food-borne and zoonotic disease as well as contributing to food security.7 As a result, food companies at all points along the supply chain, drive higher wellbeing standards in response to the demands of their customers. Consumer behaviour in more affluent societies tends to play a critical role, as animal wellbeing becomes more and more an issue of concern. The condition of farm animals is strongly associated with both the safety and the quality of food. As a result, we see a trend for greater consumer awareness, especially in Europe, but increasingly also in other markets, directly linked to a demand for products complying with animal wellbeing standards. Producers who maintain high standards have a competitive advantage as consumers are more and more prepared to pay for higher food safety norms. Achieving better lives for animals will require collaboration among stakeholders and capacitybuilding for animal owners and keepers.
health industry from various direct and indirect angles. We are facing emerging diseases, like avian influenza, Ebola or Zika, with previously unknown aspects in terms of the ecology, the distribution pattern of pathogens, interspeciestransmission, host-switching, and the symptoms of disease. The interplay between humans and wild and domestic animals and the interconnections between host reservoirs, vectors and pathogens lead to new challenges for animals and public health. Because of increasingly intensified livestock production systems, the spread of diseases is likely to increase as well. The more animals are kept on a farm, the more likely they are to be subject to infections. Thus, the demand for health management strategies to prevent parasitic, bacterial and further infection becomes a key differentiator for successful businesses. Socio-economic wealth increases companion animal ownership. The trend towards megacities further accelerates this demand, with additional pet animal species beyond the current favourites, dogs and cats. Close interaction with increasing numbers of pet animals in communities will continuously drive the demand for companion animal products, especially to prevent viral and parasitic diseases. Summary In order to safeguard the health of animals in light of megatrends emerging in livestock and pet ownership, animal disease threats need to be managed through a holistic multi-stakeholder approach and by simultaneously addressing environmental, social, and economic challenges. It is important to understand how demographic and economic changes that are likely to unfold over the coming years would affect the animal health sector and how megatrends can be addressed in the face of emerging challenges. Sustainability is becoming the number one business approach for the future to address challenges and opportunities at the same time in a rapidly changing world â€“ a world that has pledged itself to meet the needs of the generations to come. REFERENCES
1. The Food and Agriculture Organization of the United Nations (FAO), 2017. 2. http://www.un.org/sustainabledevelopment/sustainabledevelopment-goals/ , visited on 24 March 2017. 3. FAO, 2017. 4. OECD-FAO Agricultural Outlook 2016-2025, P.127. 5. OECD-FAO Agricultural Outlook 2016-2025, P. 107-109. 6. Ibid. 7. http://www.oie.int/en/animal-welfare/animal-welfare-at-aglance/, visited on 24 March 2017.
Maximilian Zellmer Land-use changes, environmental hazards and climate change cause significant disruptions within disease dynamics for humans and animals
Disease Transmission Animal health and animal disease dynamics are influenced by environmental and societal impacts. The health and wellbeing of humans and animals alike is increasingly threatened by emerging and re-emerging diseases. Furthermore, the development of societies will continuously be hindered by neglected tropical diseases (NTDs) affecting humans and animals. In addition, there is a global redistribution of disease complexes due to climate change, together with land-use changes, wildlife interaction, changes in lifestyle, livestock intensification, and globalisation. An increase in environmental hazards, as a result of climate change, for example, pervades the animal www.animalhealthmedia.com
holds a Masterâ€™s Degree in Political Science from the University of Southern Denmark and Lund University, Sweden, with a special focus on Development Studies and International Relations. He also has a diploma in Geography and Urban Studies from Mainz University, Germany. He is now working in Policies and Stakeholder Affairs at Animal Health, Bayer, prior to which he was with the United Nations Framework Convention on Climate Change (UNFCCC), and contributed to the inking of the landmark Paris Agreement on Climate Change 2015. Email: email@example.com
International Animal Health Journal 13
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Applying Game Theory to One Health: Part 2: Modelling Human Healthcare Delivery A classical economic view is that health system provision is influenced by macro-economic factors (market-led) and microeconomic factors (bottom-up/patient-led factors). Contemporary ‘complexity economics’ theories, however, are more applicable, whereby despite the macroeconomic factors imposed by governments or regulators or cumulative individual micro-economic decision processes, in practice a multitude of simultaneous decisions are occurring at many levels, which are influenced by multiple factors (which may not relate directly to the current health need) in a dynamic fashion. One classical economic assumption that would appear reasonably consistent is that most health-related decisions are made from a perspective of self-interest. However, there are vast numbers of participants with different perceptions of utility interacting daily in the highly complex system of healthcare delivery, thus the system continues to evolve to ever greater complexity of interactions. For the purposes of this paper, and to demonstrate the way typical decisions are made in healthcare delivery, a reductionist approach has been used to identify a small number of broad categories of participant and to ascribe general perspectives that each may have when interacting or making healthcare-related decisions.
Health and Social Security, insurance company, health management organisations, or the patient’s own financial constraints if the patient is also the payer). Primary influencers who tend to value effectiveness above cost and have a strong influence, often via prescriptive control over the choice of treatment (e.g. medical practitioner, nurse, dentist, paramedical professional). Innovators who consider the ultimate determinant of value to be the return on their own time and/or money invested (e.g. the pharmaceutical industry, researcher). The regulator (government agency) who places a broader societal value on the cost of treatment, and is primarily charged with protecting the safety of society and the patient population (e.g. national registration authority). Dispensers who seek to make profit from sales (e.g. retail pharmacy, wholesaler, online order, supermarkets, herbalist).
Participants can be grouped into clusters each with sub-levels, all influenced by each other (Figure 1).
Keywords: translational research; healthcare provision, One Health, healthcare economics Each category of participant in healthcare differs in the way it attempts to maximise its own utility from healthcare. In the first paper in this series, the animal healthcare delivery sequence was modelled with particular emphasis on decision-making related to market penetration for new healthcare innovations and treatments. In this paper, the emphasis is on breaking down the complexities of human healthcare delivery to a simple sequence of events to understand the core transactions in healthcare delivery, as well as the points of influence or vulnerability. The Participants in Human Healthcare: There are six main types of primary participant in any healthcare process that are directly involved ‘stakeholders’ in each specific healthcare interaction, and each perceives the ‘value’ of healthcare differently. These are summarised as: Patients who primarily value the effectiveness of treatment measured by the extent of alleviation of a medical condition. However, they have to have the cost of treatment covered by their ability to afford it, access to public or private health insurance or charitable contribution. The extent that the cost of treatment influences decisions for the patient varies with the economic environment within which the patient exists. II. Payers who are primarily concerned with controlling the costs of providing treatment (e.g. Department of I.
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Figure 1: Clusters of influence upon each participant in the healthcare process
The fundamental activity around which all the participants interact is the decision of a patient to seek treatment for either a real or perceived illness, or to promote health. Without this, nothing else would occur. Even proactive screening / case finding approaches depend upon the patient once informed, seeking treatment, although this also illustrates the power of information to prompt the sequence leading toward a treatment decision. The process can be broken down into several component parts (see Figure 2) and is common to all healthcare provision. However, the way participants interact may differ across markets according to culture, infrastructure and other local factors. There are two supporting decisions: those decisions regarding cost and those impacting lifestyle which affect compliance with treatment regimens. Each step is also amenable to external influence from media or other entities that are not primary participants (stakeholders) in the delivery of specific healthcare objectives. The perception of a healthrelated ‘need’ is the starting point in this model. The patient is the primary decision-maker at this point, but others in the patient-payer clusters are secondary influencers, such as family, friends, and co-workers who do not have a direct ‘stakeholder’ involvement. The patient perceives a problem exists due to: signs of pain or discomfort; other visual signs; change in function; suggestion, such as through mass Volume 4 Issue 2
REGULATORY & MARKETPLACE and treatment when patients present with variable symptomatology. Category 4 represents diseases where it is difficult to raise awareness and patients may also not detect signs in the early (more treatable) phases of the disease. An example may be leukaemia, where there may not be any early signs evident. Raising clinician awareness through specialist education and introducing pro-active screening to detect onset before evidence of clinical signs may be the only ways of increasing early case presentation in this much more difficult sector. Categories 1 and 2 can therefore be influenced more easily than 3 and 4, where it would be less easy to influence a patient to seek treatment. Category 3 patients are likely to be brought forward at various stages of disease, but it would more be difficult to target preventive measures for diseases in categories 3 and 4.
Figure 2. The healthcare process
media, or increased awareness due to education (from clinician, internet, reading, advertising, etc.). Table 1 illustrates four categories which are ranked in order of the likelihood that a patient will recognise a condition and proceed to seek treatment. Ease of recognition of signs of disease by the patient
Ease of raising patient awareness to signs of disease
Table 1: Two-way table illustrating the impact of raising awareness on patient decisions to seek treatment
Category 1 represents a condition that is easily recognised by the patient based on obvious symptoms and for which it is easy to raise awareness of the disease. An example could be urinary bladder infection (cystitis). For conditions in this category, a patient-targeted educational campaign is likely to be successful at developing the commercial market for treatment. Category 2 represents the situation where it is easy to communicate the importance of the condition to the patient population but the patient may not be able to immediately detect the condition. If awareness is raised sufficiently, patients are likely to seek medical attention if they suspect the condition. An example here could be prostatic cancer, where ‘difficulty urinating’ can be easily communicated. Thus an information campaign orientated towards both the patient and clinician may be more applicable than solely targeting the general population, because patients with other urinary tract problems which do not require the treatment under consideration will also be presented. Category 3 represents conditions where it is difficult to effectively communicate the forms that the disease may manifest, such as hormonal (endocrine) problems which can present in many forms. An example might be thyroid problems where over- or under-activity, or changes in sleep patterns and motivation levels, may drive a patient to seek medical opinion. In these cases, raising clinician awareness and provision of diagnostic backup and screening tests would prove more effective ways of promoting diagnosis www.animalhealthmedia.com
Once a patient recognises a problem, the decision is whether to seek treatment, then where to seek it. The factors influencing the patient to seek treatment include: perceived potential severity of illness – death; disability; cost; accessibility; the belief that something can be done. Once the decision to proceed with medical care has been made, the payer becomes a primary decision-maker. Where the payer is the patient, the patient can maintain decision-making power. The decision at this level is influenced by cost, access and belief that a certain type of provider can help. Where the payer is another body, e.g. insurance company, health management organisation or government, the decision is influenced by “programme rules”, which restrict access to some types of providers and restrict treatment options available to the patient. The patient may also decide to become the payer to regain control of their healthcare decisions. The payer’s decisions are influenced by considerations of their own total cost and perceived treatment quality, which is rationalised in terms of cost versus benefit. Socio-economic status and belief systems are therefore relevant (Table 2) when trying to distinguish between highcost, high-quality treatment and low-cost, low-quality treatment. In serious conditions, it is likely that the balance of opinion will favour high-quality treatment if their belief is that the condition is curable. In less urgent or less severe conditions, alternatives may be sought (e.g. pharmacy advice or self-medication) and the trade-off may be consciously made to seek a lower cost and lower perceived quality (and possibly effectiveness) of treatment by both the patient and the payer. Cost of visiting provider High
Perceived quality of treatment
2 or 3
2 or 3
Table 2: Two-way table illustrating likely treatment quality preferences based upon the cost of a healthcare visit
Once the presenting complaint of the patient has been evaluated, a diagnosis should follow. If the patient has decided to seek treatment within the medical provider network, the primary decision-maker based upon their expertise becomes a healthcare professional (e.g. a doctor). In markets where patients can readily self-treat, or where a problem is not perceived as severe and where over-the-counter products are available, this role may be filled by a pharmacist or para-medical healthcare provider. The factors influencing the medical practitioner’s diagnosis International Animal Health Journal 15
REGULATORY & MARKETPLACE are: experience, continuing professional development education, influence by pharmaceutical manufacturers, professional bodies, payers and the general media. The concept of complexity economics is well illustrated in these scenarios which correlate with the patient’s selfperception/self-diagnosis of their problem, which is a function of personal experience, education, word of mouth, trust in healthcare providers and the wider clusters of influence (see Figure 1) notably including media influence. Once a diagnosis or differential diagnoses have been generated, a treatment plan is established. The treatment plan, in some cases, creates a loop back to the “seek treatment” decision (see Figure 2), such as when the treatment plan of a medical practitioner comprises referral to another professional or where an alternative/ differential diagnosis will be followed up. The treatment plan from medical practitioners can include a combination of: pharmaceutical interventions (both prescription or nonprescription); nutritional changes; behavioural modification; surgery, or referral to another provider. These options are not all available to a patient without involvement of a medical practitioner. The patient influences the practitioner by providing information concerning personal wishes or the likelihood of compliance with the treatment plan. Yet the medical provider’s treatment plan decision has to be cognisant of likely effectiveness, safety and cost. The payer exerts influence on the medical provider and patient and may restrict the use of certain interventions, or require a specific sequence of treatment interventions. The payer’s programme rules focus on cost, efficacy and safety and, if a public funding agency or private insurer, typically aim at limiting overall cost from a population perspective (as opposed to a case by case). The regulator’s decisions are also designed to maximise the utility of the total population, rather than individuals. These decisions are a function of the “risk” the regulator is willing to take. The regulator can either take the risk that a valuable, safe treatment is kept off the market, or they can take the risk that an unsafe treatment is placed on the market (i.e. a type 1 or type 2 error). Regulators are also very cognisant of cost and use a variety of costbenefit, cost-minimisation and qualitatively-based costeffectiveness studies to determine public funding models for medical technologies. These in turn significantly influence the incentive for medical research directions. Aware that not all benefits can be neatly captured as a financial figure, subjective measures such as Quality Adjusted Life Years (QALY’s) are used to give weighting to value perceptions by society. However, in OECD countries, where governments typically cover 80% of individual healthcare costs and spend over 15% of government revenue on the healthcare of citizens, cost is a limiting factor and will in future years be a major determinant of the scope of publically funded health provision. When a pharmaceutical product is part of the treatment plan, there are three relevant decisions to be made by the practitioner: a. which class of drugs is appropriate for the plan? b. which specific molecule is appropriate? c. which brand in a generic environment (based on cost/brand recognition) The product that the provider will choose is influenced by the effectiveness of treatment, the cost of treatment and the ease of distinguishing a product from other products with the same or similar indications of use. Tables 3 and 4 give examples of the ways pharmaceutical innovators are influenced by market conditions to maximise the uptake and profitability of a new product. 16 International Animal Health Journal
Efficacy of treatment
Cost of treatment
Table 3: Two-way table illustrating a ease of market penetration (1 = easy, 4 = very difficult) based upon criteria of treatment cost and efficacy
Ideal for the patient would be a highly efficacious, lowcost treatment (category 1), however, highly efficacious products are generally premium-priced (category 2). A high-cost, low-efficacy product would not be well received by the market, given accurate information. If distinction cannot be made based on cost as in Table 3, branding strategy and advertising will play an increasingly important role in distinguishing one product from another (Table 4). Cost of treatment versus rival product High
Ease of distinguishing product from rivals
Table 4: Two-way table illustrating ease of market penetration based upon branding and treatment cost
Thus, in order to influence the level of demand for a new product, some basic criteria need to be fulfilled: 1= Easily distinguishable option with few or no rival products and preferential pricing or superior efficacy. 2= Where there are many generic rival products of equivalent efficacy, the product needs to represent an easily discernible option or cost less. 3= Where there is little direct competition, but many alternatives, clear product distinction will have to outweigh relative costs. 4= In a high-competition market, with many alternatives and where pricing is not favourable, this represents a very difficult market environment in which innovative focus has to be upon production and manufacturing processes to decrease cost of production. The patient’s decision to comply with a treatment plan is an important determinant of outcome and it is important that the plan is agreed between all involved participants in advance to ensure it is sustainable. Pharmaceutical innovators target the needs of the patient, medical provider and payer in an attempt to balance the cost of development against the anticipated sales and opportunity cost of other projects not progressed in consequence. Keeping a balanced portfolio is an important part of managing the risk of product development. Where several leads are generated from the same innovation platform and only a couple can be pursued, the implication is that the opportunity cost might be as large for the candidate which is not chosen for development as for the lead candidate. Table 5 illustrates the type of prioritisation process required when balancing research and development costs against potential market value. Market value Cost of development (measured in time and finance required)
Table 5: Two-way table illustrating the overriding aim of research and development activities Volume 4 Issue 2
International Animal Health Journal 17
REGULATORY & MARKETPLACE There is a trade-off when balancing high cost and high market value against low cost and low market value (both prioritised as category 2). This decision will be partly based upon the cost: benefit ratio of each, the opportunity cost and risk management in terms of probabilised success, portfolio management and overall potential earnings of the project given similar profitability. The delivery of a service or a product is instructed in the treatment plan. The delivery of a pharmaceutical product to a patient according to a treatment plan includes three things: the drug, a delivery mechanism and information about the drug. The primary participant at this stage is the dispenser. The dispenser can be a retail dispenser – which includes a stand-alone pharmacy or a pharmacy as part of another retail business (grocery, department store, etc.), a medical practice, a hospital, a specialist practice, online order, etc. The influence the dispenser has is a function of which type of dispenser they are and the local regulations governing their activity: a. Retail dispensers generally have no decision-making authority. They can influence the patient when the product is multi-sourced and will inform the patient about cost or plan options when relevant. b. The medical practitioner as a dispenser has decision-making authority over delivery of the drug. This decision-making ability may be constrained by the payer through social security or insurance reimbursement rules. c. Online/internet dispensers have influence similar to that of a retail dispenser. The influence on drug delivery decisions is primarily a function of the dispenser type’s profitability. In other words, if a dispenser has the freedom to influence a patient, how they choose to influence a patient is driven by what is most profitable for the dispenser. The dispenser may also be influenced by concerns for the patients’ cost in a competitive market. The delivery decisions influenced by the dispenser are primarily decided on by the payer and the patient. The regulator has decision-making authority over the types of pharmaceutical dispensers that exist in a given market. A key determinant of success for a pharmaceutical company is developing an ability to target, understand and in some cases influence each of the decisions in the transaction. Figure 3 is a worked example, where the probability of each set of decision choices has been set at parity (e.g. 50% chance of choosing to treat versus not treat, or a 33% chance of choosing between three possible providers of treatment, etc.). The exact trend can be established by local market research and each of these sets of decisions can be adapted according to concurrent trends. Through education or awareness campaigns, it can be made more likely that once ‘breast lumps’ are detected by a woman, treatment will be sought. With appropriate preventive health strategies, this decision could realistically be raised to over 95% seeking some form of advice or treatment versus 5% those choosing to ignore the ‘lumps’ completely, with a further 5% choosing either ‘self-treatment’ or a non-medical provider. In the case of treatment for mild urinary tract symptoms, however, education campaigns could also be used to influence people not to initially seek treatment from a medical provider and the option, set arbitrarily at 33%, may become only 10% when patients are aware of a threshold of symptoms that require medical intervention rather than home-based management. In doing so, self-medication could be increased to account 18 International Animal Health Journal
for the majority of treatments, increasing over-the-counter sales and taking the expense of medical consultation out of the system and freeing up medical capacity. The rate and types of product adoption can therefore be influenced. This type of model, even in the scenario suggested by complexity economics, can rationalise behaviours and help target resources to maximum effect. In the medium term, this game-theory approach will become increasingly evident as efforts are made to constrain increasing costs within stagnating public healthcare budgets. Figure 4 uses typical decision proportions as based upon our medical practice and illustrates how the probability of different outcomes can be greatly altered, mainly via patient education and the attitude of the influencer (ie doctor or non-medical provider). The proportion not receiving a formal medical procedural work-up was halved (14%) in this example, which is important in potentially serious medical conditions like breast cancer, and the number of interactions that resulted in a medical procedure* was increased by well over five-fold (76%). The probably of no treatment or further investigation was decreased from 56% to 10%, which may better reflect the low-risk subset of young women with benign ‘normal’ fibro-adenomatous breast changes. The influence could just as easily have been used in the opposite direction to decrease medical interventions. A good example of this in our practice has been the substantial decrease in rate of antimicrobial prescriptions and increase in alternative management methods via targeted strategies aimed at influencing demands of patients and payers and the attitudes of the influencing healthcare professionals. During a treatment plan and after completion, there must be evaluation of the plan’s effectiveness in solving the problem identified during diagnosis. The patient is the primary decision-maker with regard to whether or not a treatment plan has worked, and evaluates efficacy in relation to their expectation and the Figure 3: Worked example of a decision cascade from the point of perception of illness through to dispensing of therapy with all decision probabilities set at parity. Figure 3: Worked example of a decision cascade from the point of perception of illness through to dispensing of therapy with all decision probabilities set at parity. SelfProbability of treatment 1.0 NOT utilising a Self0.33 Probability medical of treatment 1.0 NOT utilising a procedure* 0.5 0.33 0.5 medical = 31% Non-medical 0.33 procedure* Perceive Seek 0.5 practitioner 0.5 = 31% illness treatment Non-medical 0.33 provider 0.25 Perceive Seek practitioner 0.33 illness treatment Probability of provider 0.25 0.5 0.5 utilising a 0.33 Probability of Medical medical 0.5 0.25 0.5 utilising a Practitioner procedure* Medical medical provider 0.25 = 13% Probability of Practitioner procedure* 0.25 no treatment provider = 13% 0.25 Probability = 56% of 0.25 no treatment 1.0 0.25 = 56% Referral 1.0 Referral
Figure 3: Worked example of a decision cascade from the point of perception of illness through to dispensing of health therapy with decision Figure 4: Illustration of an ‘influenced’ decision cascade showing how outcomes can beall altered to favour medical procedural follow-up (e.g. breast lumps detected by patient) probabilities set at parity. Figure 4: Illustration of an ‘influenced’ decision cascade showing how health outcomes can be altered to favour medical procedural follow-up (e.g. breast lumps detected by patient) SelfProbability of treatment 1.0 NOT utilising a Self0.05 Probability medical of treatment 1.0 NOT utilising a procedure* 0.05 0.1 medical 0.95 = 14% Non-medical 0.05 procedure* Perceive Seek 0.1 0.95 practitioner = 14% illness: treatment Non-medical 0.05 provider 0.1 Perceive Seek Detection practitioner 0.9 treatment of illness: breast provider Probability of 0.1 0.9 Detection lumps 0.05 utilising a 0.9 of breast Probability 0.9 Medical medical of 0.8 lumps 0.05 utilising a Practitioner procedure* Medical medical 0.8 provider = 76% Probability of Practitioner procedure* 0.05 no treatment provider = 76% 0.05 Probability of = 10% 0.05 no treatment 1.0 0.05 = 10% Referral 1.0 Referral
Figure 4: ‘medical Illustration ofequates an ‘influenced’ decision cascade *where procedure’ to a controlled medical intervention such asshowing imaging, how pathological sampling, surgery or use to of aprescription only products health outcomes can be equates altered to favour medical procedural follow-up *where ‘medical procedure’ controlled medical intervention such as imaging, sampling, surgery or use prescription only products (e.g. pathological breast lumps detected byofpatient) 13 13
Volume 4 Issue 2
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International Animal Health Journal 19
International Animal Health Journal 11
REGULATORY & MARKETPLACE total cost of treatment plan (including opportunity cost and impact on lifestyle). Patient evaluations are based on: symptomatic relief, ability to resume normal activities or demonstrable change in the condition (e.g. tumour shrinkage). The clinician co-evaluates a treatment plan based on their medical evaluation, the patientâ€™s own evaluation, repeat investigations and empirically upon whether any better outcome could be hoped for using existing alternative treatments. The clinician only has the potential to evaluate a plan if the patient returns to the provider after the treatment plan was implemented. So, in many cases the clinician must assume a result which may over-estimate efficacy with the common assumption that lack of re-presentation of a patient equates to a cure. Discussion The patient has a great deal of influence over the entire process and typically controls whether or not a healthcare transaction proceeds at all. If the patient does not perceive a problem exists, nothing happens. But just because an illness exists and is recognised, it does not mean treatment will be sought. Lack of awareness of solutions, denial and fear of the consequences are all relevant factors (ReeveJohnson, 2003). The more difficult a problem is to perceive, the less likely treatment will be sought. When it comes to deciding where to seek treatment, the patient has a variety of choices and can choose to stop and exit the healthcare provision system any time. Medical practitioners in general practice are important influencers, with substantial numbers of patients waiting to receive treatment, however, having sufficient time to explain the disease, to share the options for treatment and internalise the decision into a collaborative disease management effort in which the
20 International Animal Health Journal
patient is fully engaged and therefore more likely to comply with the regimen, is important. It is helpful at this time to discuss the realistic expectation for benefits and sideeffects, as well as the consequences of not completing treatment. By virtue of improving compliance with the treatment protocol, the patient is more likely to benefit to the full extent from the treatment. Pharmaceutical companies are fully aware of the transactional nature of healthcare, yet many other participants in the system may not perceive the economic fundamentals as clearly. The patient has a very large amount of influence over the transaction as a whole. If a problem is not perceived, or treatment is not sought, then no sale will occur and innovation will not be utilised. The patientâ€™s decision-making capability or influence is constrained by clinicians and payers, but in different ways for different reasons. The clinicianâ€™s influence over the patient is primarily due to either their expertise or through access to products limited by prescription. The patient believes he is not qualified to identify and solve certain medical problems, and so gives control of this decision to the expert. The clinician tends to be the decision-maker at the diagnosis stage and to be the primary decisionmaker at the treatment plan stage, but is constrained by the payer. Clinicians can influence patient selection at the perception or seek treatment stage through screening (e.g. faecal occult blood screening, PAP screening, blood profiling, etc.). The level of information provided on the treatment options has a large effect at this stage. Table 6 summarises the key decision-makers at each level of the healthcare transaction and who influence the progression though a series of decisions common to most modalities of healthcare.
Volume 4 Issue 2
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International Animal Health Journal 21
REGULATORY & MARKETPLACE supply of treatments influence the way new products and interventions are utilised. • Central to healthcare provision is the individual adoption process of the patient, which includes the perception of illness, the decision to treat, diagnosis, setting up the treatment plan, the delivery of the drug and evaluation of the effectiveness of the treatment plan which impacts compliance. Each of these steps is a potential point of influence and can be used to influence the choice and extent of medical intervention to either increase population health or manage demand within the capacity constraints of the healthcare systems.
Table 6: Summary of the primary decision-makers and main influencers during the healthcare process
The patient allows the payer to exert influence for economic reasons and cedes a degree of control to the payer in return for the payer’s role in bearing some of the patient’s costs. The payer, however, does not make decisions on a real-time basis, like the patient and provider. The payer acts on the decision in advance, through a set of programme rules. Healthcare provision systems are dynamic and evolve towards greater complexity as the number of influencing factors accumulate in the absence of any single macroeconomic control point. Because new possibilities are always presented (innovations, management efficiencies, disease outbreaks, capacity issues, funding, communications, regulations, etc.), the system can never reach stable equilibrium. Changes occur regularly and those that do not broadly increase utility for all participants will ultimately be rejected. Summary • Provision of healthcare is fundamentally a complex transaction between a relatively small number of core stakeholders and a multitude of external influences, including belief systems which do not necessarily relate directly to the immediate healthcare need. • The participants in healthcare interact and rationalise their perspectives of utility through a form of economic exchange which is constantly evolving to greater complexity to cater to increasingly diverse influences. • Interactions between social, psychological, environmental and physical determinants of health mean that for patient education to be effective, it has to be targeted to cater to messages that are easily communicated, signs that are easily recognisable and messages that are contiguous with belief systems and perceptions that may not relate directly to the current healthcare issue. • Patients and healthcare professionals may be less aware of the underlying economic imperatives and ways these are influenced, than pharmaceutical companies, dispensers, insurance and government funders who have evident economic motives. • In the healthcare industry, demand generally preexists and education, awareness, media constructs and 22 International Animal Health Journal
• Complexity economic models are highly relevant to health delivery because healthcare systems are dynamic and continually evolving to accommodate new possibilities through innovation, efficiencies, funding changes, communication and other factors. A stable equilibrium is never attained and changes which reduce the utility of any participant group are likely to be rejected. REFERENCES 1.
Reeve-Johnson, L. (2003) Quantifying and maximizing the value of innovation in the pharmaceutical industry. J. Vet. Pharmacol. Therap. 26 (Suppl 1). 19-55. 2. Reeve-Johnson, L. (2015) Translational Research: putting the right price on innovation. Vet. Record 173: 312-313. 3. Reeve-Johnson, L. Chapter in Practical Veterinary Forensics, ed. Bailey D. (2016) Macro-economic incentives for Translational research and One Health collaborations. CABI publishing, Cambridge. 4. Reeve-Johnson, L. (2017) Applying Game Theory to One Health: Part 1: Modelling Veterinary Healthcare Delivery. IAJH. Vol 3. Issue 4. 16-21
Acknowledgement P. Johnson, Eli Lilly and Company for guidance.
Lloyd Reeve-Johnson BVM&S, MBBS, DVMS, PhD, DipECVPT, PGCert(Business Admin), CBiol, FRSB, FRCVS is Professor of One Health at the University of Sunshine Coast in the Faculty of Science, Health, Education and Engineering in Queensland, Australia he also held an Adjunct Professor position at the Institute of Health and Biomedical Innovation at the Queensland University of Technology and until recently was a Principal Research Fellow at the flagship Translational Research Institute in Brisbane. He remains committed to a full clinical caseload as a doctor and continues to apply skills leaned previously in veterinary medicine to bridge translational research gaps between human and animal health. He is a former Dean of the Queensland Veterinary College and Director of European Research and Development with Elanco Animal Health. He is President of the Australasian Society of Biology and passionate about One Health and global disease management, having worked in over 100 countries on projects related to human and animal health. Email: firstname.lastname@example.org
Volume 4 Issue 2
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www.therqa.com International Animal Health Journal 23
REGULATORY & MARKETPLACE
Regulation of Diagnostics in Animal Health – Is It Needed? At a time when evidence-based medicine is encouraged, and where evaluation and monitoring are key components of the cycle of health management, there is an increasing dependence on diagnostics. Renewed interest in the development of diagnostics for animal infections and diseases is motivated by the belief that suitable diagnostics will assist in the control of diseases. This stimulates a number of questions about the regulation of, and standards for, diagnostic evaluation and monitoring tools, particularly in comparison to pharmaceuticals involved in the action to manage health problems that may be identified (Fig. 1). This article will evidence the lack of regulation of, or standards for, veterinary diagnostics, in comparison with regulatory frameworks for veterinary pharmaceuticals (including biologicals). It will seek to address whether any differences matter, focussing on parasitic infections of farm and companion animals in particular.
calf, be faecal egg counts (FECs), pepsinogen levels or antihelminth antibody titres. Interpretation may be confounded by the relationship between the parameter of interest and the chosen surrogate. Once calves have grazed for a period of approximately two months, and as immunity develops, the direct relationship between FECs and worm burden disappears, with worm burdens being under-represented by the FEC result (Shaw et al. 1998). Conversely, a reliance on antibody titres may over-estimate a parasite burden, because antibody titres often respond slowly to a reduction in the parasite burden, for example after parasiticide treatment. There are ambitions to take diagnoses of parasite infections a stage further by linking them to production parameters (Charlier et al. 2014). These examples illustrate how the results of diagnostic tests may have profound implications for anything from the care of an individual animal to strategic management decisions for a herd or larger population. Ideally, diagnostics should be sensitive and specific, with a lack of cross-reactivity (false positivity) in similar disease conditions. Tests should ideally be easy to run and produce unambiguous results. For devices, inter- and intra-batch consistency should have been convincingly demonstrated; a further consideration is their long-term stability during anticipated travel or storage conditions. Diagnostics can be broadly categorised as techniques or devices. Techniques typically involve multiple steps and may include a degree of expertise to assess the test sample, such as that involved in examining a faecal sample under a microscope to speciate and enumerate the parasite eggs. Devices that permit in vitro tests to be conducted may be simplified one-step devices or may involve a complex series of steps before producing a result. Interpretation of the result in the context of the animal(s) involved and evaluation of the best course of action is a critical further step.
Figure 1: Cycle of health management (adapted from Tisdall et al. 2017)
Integrity and Utility of Diagnostics for Parasitic Infection and Disease Confirmation of internal or external parasitism of farm or companion animals relies on accurate diagnosis, and is an implicit part of evidence-based medicine. Diagnosis underpins treatment and prevention programmes that may rely on parasiticide usage. Diagnostics may be used most simply as a qualitative test, and for some parasites such as Sarcoptes scabiei var. canis, where there is zero tolerance for the parasite, this level of information may be sufficient. In other situations, for example to estimate the magnitude of helminth infections in calves, enumeration of parasites may be important. It is often necessary to rely on an available surrogate for the measurement of interest, which may, in the example of the 24 International Animal Health Journal
Whether developed as techniques or devices, there is an initial research phase, followed by method development and verification, validation stages and, where appropriate, manufacturing and/or user studies (Fig. 2). In the case of devices, validation includes, for example (where relevant): • • • • • • •
Robustness Limits of detection and quantitation determinations Sensitivity and specificity Positive and negative predictive values Cross-reactivity and/or interferences Intra-batch and inter-batch variation Accelerated and real-time stability studies.
Diagnostic Sample Life Cycle The success or failure of a diagnostic test does not rely solely on the processing of the sample; rather it relies on a series of steps from sample collection to the utilisation of results, to inform the actions necessary to treat, prevent or control infections (Fig. 3). At any of these stages, integrity of the sample and its resulting data relies upon appropriate Volume 4 Issue 2
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International Animal Health Journal 25
REGULATORY & MARKETPLACE handling throughout the process. There may be a restriction to qualified personnel, such as veterinary surgeons, when collecting some types of sample, such as blood or tissue, which are normally collected under veterinary surgery regulations.
by veterinarians in practice include faecal flotation, onsite immunochromatographic and coproantigen tests, while serological techniques such as IFAT, ELISA and PCR are often outsourced to external laboratories (Kramer 2016). In either case, it is important to know how to obtain and preserve samples correctly as well as how to interpret results (Kramer 2016). Tests using canine blood samples for detection of dirofilariosis (heartworm) include DiroCHEK ELISA and for lungworm (Angiostrongylus vasorum) AngioDetect, while tests based on faecal samples include FLOTAC (Del Prete et al. 2015). Regulations Within the cycle of diagnosis and management (Fig. 1), highly regulated veterinary pharmaceuticals will often feature at the action stage; an overview of the regulation of veterinary pharmaceuticals and (human) clinical diagnostics are provided below to serve as a benchmark for comparison with regulation of veterinary diagnostics.
Figure 2: Development of veterinary pharmaceuticals and diagnostics
Veterinary Pharmaceuticals Veterinary pharmaceuticals are highly regulated during development, with the process (Fig. 2) in Europe involving submission to the European Medicines Agency or the relevant national authority to demonstrate evidence of the quality, safety and efficacy of the treatment before it is approved for supply. The formal application by the pharmaceutical sponsor company also contains specifications of the anticipated side-effects, claims and other characteristics that will ultimately appear in the summary of product characteristics, the package leaflet and the product labelling. The review process includes assessment of the instructions and advice to be provided to the end user of the pharmaceutical. In the event that the end user will be a farmer or companion animal owner, considerable efforts are made to ensure that the instructions are clear and unambiguous, with significant time spent on linguistic review to ensure that translation into different languages within Europe remain accurate. This strategy has been used successfully in safeguarding cats from the potential harm of pyrethroid products indicated for administration to dogs. Following a successful assessment, the sponsor company receives a marketing authorisation for the pharmaceutical. The marketing authorisation defines the route to market which may, in many cases, be limited to professional use only, including by pharmacists and veterinary surgeons who are trained to understand the instruction language and the methods of administration. Post-authorisation monitoring is mandatory and consists of a well-developed pharmacovigilance system. Whilst differing in detail, similar regulations exist for the development, validation, approval and marketing of veterinary biologicals and feed additives. DIAGNOSTICS
Figure 3: The diagnostic sample life cycle. It is worth noting that laboratory results may undergo QA or senior scrutiny before sign-off and release.
Tests may be run in the field (â€œpen sideâ€?), within the local veterinary practice or by remote, specialised laboratories. In companion animals, for example, tests typically used 26 International Animal Health Journal
Regulation of Laboratory Techniques With a few exceptions, for example Good Laboratory Practice (GLP) accreditation, laboratory regulation of veterinary diagnostic laboratories is absent. Some laboratories, for example those that undertake analysis of samples for preclinical studies, where GLP compliance is mandatory and subject to inspection, will be subject to regulatory GLP inspection. In the UK this oversight is provided by the Medicines Healthcare Regulatory (MHRA) Agency of the Department of Health. Volume 4 Issue 2
REGULATORY & MARKETPLACE Regulation of Human and Veterinary Medical Devices There is no regulation that applies to veterinary medical devices in Europe, however regulation of medical devices for human use exists. Within the EU, a medical device is defined as: "Any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: • diagnosis, prevention, monitoring, treatment or alleviation of disease • diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap • investigation, replacement or modification of the anatomy or of a physiological process • control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.” This definition covers implanted devices such as hip replacements as well as in vitro devices. The boundaries are not clear cut and the document: http://ec.europa.eu/consumers/sectors/medicaldevices/files/meddev/2_1_3_rev_3-12_2009_en.pdf has been developed to define the items within the overlapping areas between the Medical Devices Directive 93/42/EEC (MDD)3, the Active Implantable Medical Device Directive 90/385/EEC (AIMDD)4 and the Medicinal Products Directive 2001/83/EC5 (MPD). In vitro diagnostics are regulated by Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. OJ L 331 of 7 December 1998. In order to be placed on the market, in vitro diagnostics (IVDs) in the EU must be Conformité Européene (CE) marked. There are a number of classes of IVDs, from simple, relatively harmless tests/methods to those covering potentially life-threatening and/or highly infectious disease diagnosis. The former may be CE marked by the producer, provided the company is accredited under ISO Standard EN13485 to do so. For the latter class of IVDs, the product sponsor nominates an organisation mandated to review applications for CE mark approval and submits a dossier, and in some cases product destined for sale. In the USA, a similar raft of legislation and regulations is overseen by the Food and Drug Administration. IVDs of differing levels of risk must go through either a 510[k] review process or pre-market approval (PMA) before they are allowed to be sold. In summary, there is no formal evaluation and approval process for veterinary diagnostics and no requirement for training of the end user or ensuring that the end user is suitably trained and retains competency. Standards A lack of mandatory regulation means that some veterinary laboratories and veterinary IVD diagnostics producers have identified relevant standards and have sought to implement them and have them recognised, where possible. Veterinary diagnostic laboratories may be GLP, Good Laboratory Clinical Practice (GLCP) or ISO Standard 17025 accredited, for example. While these standards www.animalhealthmedia.com
differ in their detail, all work to ensure that procedures are standardised and appropriate and carried out by suitably informed/trained personnel. Similarly, manufacturers of veterinary IVD tests may be Good Manufacturing Practice (GMP) accredited or ISO 13485 accredited, and may elect to apply or obtain CE marks for individual tests, although there are no background legislation nor regulations to cover such situations. Adoption of agreed standards is consistent with the World Health Organisation recommendations (WHO 2003). Evidence for the Integrity and Utility of Diagnostics Correct diagnosis of parasite infection is crucial, with methods being either simple and carried out on farm or in veterinary practices, or complex and needing the use of specialised laboratories (Kramer 2016). Veterinary clinicians rely heavily on laboratory analyses for diagnosis and monitoring of treatment (Bell et al. 2014). Current guidance on best practice for parasite control in pets (ESCCAP 2010) recommends that all pets of all ages are screened at least four times per year for gastro-intestinal helminth infections. Similarly, best practice guidance on Sustainable Control of Parasites in Sheep (SCOPS) and Control of Worms Sustainably (COWS) recommend that the production species sheep and cattle, respectively, are monitored for parasite burdens and their requirements for parasite management and treatment based on this information. Diagnosis forms an integral part of evidencebased medicine (Fig. 1). There are a large number of veterinary diagnostic tests and devices are currently used to identify and monitor parasite infections, and it is beyond the scope of this article to review every test. Instead, the widely used FEC technique will be used as an example of a commonly used technique where there have been initiatives to create standard kits to conduct the test and to make the technique more readily available to farmers and other animal keepers. It is notable that there is no single FEC technique, with various different methodologies and a lack of between-laboratory standardisation. It has been recognised for some time (Stoll 1930) that the accuracy of FECs depends not only on the analytical sensitivity of the chosen flotation solution but also on the “personal factor” (Levine et al. 1960), an undefined source of variation that centres on technical proficiency, even when personnel conducting the test are following the same set of directions. Sample handling is another factor that can affect the apparent performance of all flotation techniques. It has been demonstrated (Foreyt 1986; Rinaldi et al. 2011) that many faecal preservation methods influence the detection of various parasite elements. Consensus as to centrifugation time when processing faecal samples for faecal flotation methods has not been established, in part, because the time will be influenced by the flotation media (Ballweber et al. 2014). Use of new methods without providing validation and quality control (QC) assessments should be discouraged (Ballweber et al. 2014). The purpose of the exercise, cost-effectiveness, and technical capacity can also greatly influence the choice of method (Ballweber et al. 2014). Interpretation of the results requires an appreciation of the likely effects of age and grazing history, for example, on the FEC (Charlier et al. 2016). Efforts to make a FEC in kit form include Fecpak and Fecpak mark 2 (G2). Some devices (e.g. Ovassay Plus (Zoetis Synbiotics) and Fecalyzer (Vetquinol USA)) incorporate a built-in specimen container and a flotation tube with a sieving basket and flat top for good contact International Animal Health Journal 27
REGULATORY & MARKETPLACE with the coverslip (Alcaino and Baker 1974; Egwang and Slocombe 1981). McCoy et al. (2005) demonstrated that the Fecpak system (using the McMaster method) was a reliable and accurate means of performing FECs in the hands of highly skilled and experienced operators, but was much less accurate when performed by flock owners, despite them having been trained in its use. They went on to state that it is necessary for anyone advocating the use of on-farm diagnostics to ensure that the skill of the operator is matched to the technique and equipment used and that a mechanism for QC be incorporated into the testing system to ensure accuracy and reproducibility. This point was highlighted again by Gates and Nolan (2009), who concluded that there is no substitute for good training, methodical approach and continuing education. In various regions of the world, the absence of regulatory oversight of veterinary laboratory testing has been identified as a risk requiring addressing. In 2006, the Committee for Quality Assurance and Standards of the Society for Veterinary Clinical Pathology formulated a comprehensive document for QC standards applicable to all veterinary laboratories (www.asvcp.org/publications/ qas-guidelinemenu.html). In Europe, the development and implementation of more complete QC programmes were recently identified as areas for improvement by a group of European veterinary medical laboratories seeking ISO 15189 certification (Freeman et al. 2006). Lack of regulation in veterinary testing is one factor in QC monitoring not being well practised in veterinary hospital facilities, resulting in most users being left to follow the recommendations of suppliers of diagnostic instrumentation (Westgard QC 2015).
28 International Animal Health Journal
Quality assurance is defined in ISO 8402 as: “all the planned and systematic activities implemented within the quality system and demonstrated as needed, to provide adequate confidence that an entity will fulfil requirements for quality” (ISO1994). Study results (Rishniw et al. 2012) suggested that the performance of “in clinic” biochemical analysers was significantly worse than that of reference laboratories, and commonly used in clinic analysers periodically and unpredictably failed quality assurance checks. 4075%; 20% and 40% respectively of test errors occurred in the pre-analytic; analytic and post-analytic phase of diagnostic laboratory procedures respectively (Westgard QC 2015; Braun et al. 2015). In a 2007 survey of point of care instrumentation, analysis and quality assurance in veterinary practice, the majority of practices (316/374) utilised manufacturer-provided reference intervals without further adjustment or assessment, while one-third (126/374) used reference intervals from textbooks, which is discouraged by the American Society for Veterinary Clinical Pathology (Bell et al. 2014). Current opinions on the regulation of medical devices, including in vitro tests in Europe, appear to reveal a concern that transparency and evidence-based data is lacking within the EU regulatory system as it is currently constructed (Eikermann et al. 2013). For example, the lack of a centralised registry means that post-marketing surveillance is fragmented. Eikermann et al. (2013) refer to the Poly Implant Prosthèse (PIP) case as an example of the problems associated with following up problems. Although unrelated to IVD, the similarity of the systems for implants
Volume 4 Issue 2
REGULATORY & MARKETPLACE and IVDs suggests that similar situations could arise for IVDs. Discussion A review of the literature assessing the fitness for purpose of medical device regulation in Europe intimates that European regulation has not addressed all concerns. There is a sense that the USA regulation has some benefits over the European system. This may change with new European in vitro device regulations for medical devices due to be released in April or May 2017. Regulation may have negative consequences; for example, it may increase the cost of bringing new products to market and, in doing so, inhibit innovation and decrease the number of new tests reaching the market. The development of platforms, such as lateral flow devices, that can be used to develop pen side tests may mean that there are more tests available to the end user (the farmer, pet owner or local veterinarian), which means that such tests are out of the hands of professional laboratory techniques with their traditional laboratory management and report approval processes. Conclusion There are fundamental differences between the stringent regulation of veterinary medicines and the absence of regulation of veterinary diagnostics. Whilst there is a lack of clarity about the impact of the lack of regulation, or indeed the implications of introducing regulation, in an era of one health (OIE) for humans and animals, the differences between regulation of human and veterinary diagnostics merit further attention. REFERENCES 1. 2.
3. 4. 5. 6.
7. 8. 9.
Alcaino, H.A. and Baker, N.F. ‘Comparison of two flotation methods for detection of parasite eggs in feces’ J. Am. Vet. Med. Assoc .164 (1974) 620-622 Ballweber, L.R., Beugnet, F., Marchiondo, A.A. and Payne, P.A. ‘American Association of Veterinary Parasitologists’ review of veterinary fecal flotation methods and factors influencing their accuracy and use – Is there really one best technique?’ Veterinary Parasitology 204 (2014) 73-80 Bell, R., Harr, K., Rishniw, M. and Pion, P. ‘Survey of point-of-care instrumentation, analysis, and quality of care in veterinary practice’ Veterinary Clinical Pathology (2014) 185-192 Braun, J.P., Bourgès-Abella, N., Geffré, A., Concordet, D. and Trumel, C. ‘The preanalytic phase in veterinary clinical pathology’ Veterinary Clinical Pathology 44 (2015) 8-25 Camus, M.S. ‘Quality control for the in-clinic veterinary laboratory and pre-analytic considerations for specialized diagnostic testing’ The Veterinary Journal 215 (2016) 3-9 Charlier, J., De Waele, V., Ducheyne, E., van der Voort, M., Vande Velde, F. and Claerebout, E. ‘Decision making on helminths in cattle: diagnostics, economics and human behaviour’ Irish Veterinary Journal (2016) 69:14 Charlier, J., van der Voort, M., Kenyon, F., Skuce, P. and Vercrysse, J. ‘Chasing helminths and their economic impact on farmed ruminants’ Trends Parasitol. (2014) 361-367 COWS http://www.cattleparasites.org.uk/ Del Prete, L.D., Maurelli, M.P., Pennacchio, S, Bosco, A., Ciuca, L., Cringoli, G. and Rinaldi, L. ‘Dirofilaria immitis and Angiostrongylus vasorum: the contemporaneous detection in kennels’ BMC Veterinary Research (2015) Egwang, T.G. and Slocombe, J.O.D. ‘Efficiency and sensitivity of techniques for recovering nematode eggs from bovine feces’ Can. J. Comp. Med. 45 (1981) 243-248 Eikermann, M., Gludd, C., Perleth, M., Wild, C., Sauerland, F., GutierrezIbarluzea, I., Antoine, S., Demotes-Mainard, J. and Neugebauer, E.A.M. ‘Commentary: Europe needs a central, transparent, and evidence based regulation process for devices’ BMJ (2013) 346 ESCCAP 2010 http://www.esccap.org/page/ G1+Worm+Control+in+Dogs+and+Cats/25/#.WN4fSlXyvIU Foreyt, W.J. ‘Recovery of nematode eggs and larvae in deer: evaluation of fecal preservation methods’ J. Am. Vet. Med. Assoc. 189 (1986) 1065-1067
14. Freeman, K.P., Bauer, N., Jensen, A.L. and Thorensen, S. ‘Introduction to ISO 15189: a blueprint for quality systems in veterinary laboratories’ Vet. Clin. Pathol. (2006) 157-171 15. Gates, M.C. and Nolan, T.J. ‘Risk factors for endoparasitism in dogs: retrospective case-control study of 6578 veterinary teaching hospital cases.’ J Small Anim Pract. (2009) 50(12):636-40. 16. ISO 1994 https://www.iso.org/standard/16534.html 17. Kramer, L. ‘Science and innovation in parasite diagnostics in companion animals’ Companion Animal (2016) 316-322 18. Levine, N.D., Mehra, K.N., Clark, D.T. and Aves, J. ‘A comparison of nematode egg counting techniques for cattle and sheep feces’ Am. J. Vet. Res. 21 (1960) 511-515 19. McCoy, M.A., Edgar, H.W.J., Kenny, J., Gordon, A.W., Dawson, L.E.R. and Carson, A.F ‘Evaluation of on-farm faecal worm egg counting in sheep’ Veterinary Record 156 (2005) 21-23 20. OIE One health http://www.oie.int/en/for-the-media/onehealth/ 21. Rinaldi, L., Coles, G.C., Maurelli, M.P., Musella, V. and Cringoli, G. ‘Calibration and diagnostic accuracy of simple flotation, McMaster and FLOTAC for parasite egg counts in sheep’ Veterinary Parasitology 177 (2011) 345-352 22. Rishniw, M., Pion, P.D. and Maher, T. ‘The quality of veterinary in-clinic and reference laboratory biochemical testing’ Vet. Clin. Pathol. (2012) 92-109 23. SCOPS http://www.scops.org.uk/ 24. Shaw, D.J., Vercruysse, J., Claerebout, E. and Dorny, P. ‘Gastrointestinal nematode infections of first-grazing season calves in Western Europe: associations between parasitological, physiological and physical factors’ Veterinary Parasitology (1998) 133-151 25. Stoll, N.R. ‘On methods of counting nematode ova in sheep dung’ Parasitology 22 (1930) 116-136 26. Westgard QC http://www.westgard.com/testing-error-rates.htm 27. WHO Medical Device Regulations: Global overview and guiding principles (2003)
Acknowledgements Phil Goodwin of Biocheck-UK and Will Drury of Cyton Biosciences are both thanked for their constructive comments on the manuscript. Hannah Fisher is acknowledged for the figures, compilation and review.
Dr Maggie Fisher BVetMed CBiol MSB MRQA DipEVPC MRCVS graduated in 1986 from the Royal Veterinary College and now runs three businesses (a parasitology consultancy, a CRO/ laboratory and a veterinary project management facility). Dr Fisher has been active in the establishment and advancement of a number of animal health associations including WAAVP, EVPC, AVC and ESCCAP. Email: firstname.lastname@example.org
Dr Peter Holdsworth AO BSc (Hon) PhD FRSB FAICD was the founding Chief Executive Officer of Animal Health Alliance (Australia) Ltd – the peak industry body in Australia representing R,D&E companies, registrants, manufacturers and marketers of veterinary medicines, veterinary chemicals and biologics in Australia. Dr Holdsworth is the immediate past president of WAAVP and a former president of the Australian Society for Parasitology. Email: email@example.com
International Animal Health Journal 29
RESEARCH AND DEVELOPMENT
Six Detrimental Effects of Mycotoxins on the Gastrointestinal Health of Poultry Sophie Vermaut <S.VERMAUT@nutriad.com>
Six Detrimental Effects of Mycotoxins on the Gastrointestinal Health of Poultry decreased performance. In addition, the possible alteration Contamination of feed commodities by moulds
of the microflora by mycotoxins will be explored.
Author: Radka isBorutova, PhD. Business and mycotoxins considered DVM, to be one of the most Development Manager, Nutriad International, important negative factors in crop production and 1. Mycotoxins affect the intestinal mucosa Belgium animal feed quality.
The gastrointestinal tract represents the first barrier against ingested chemicals, feed contaminants, and natural Contamination of feed commodities by moulds and toxins. mycotoxins is considered to mycotoxin-contaminated be one of the Following ingestion of It is well documented that factors mycotoxinin consumption feed, and intestinal epithelial can be exposed most important negative crop production animal feed cells quality. It is well to high causes a decrease in performance as well as decreased concentrations of toxins. This is especially important when documented that mycotoxin consumption causes considering a decrease in performance as well as growth rate and poor feed efficiency (Pestka, 2007; Hanif toxins that have poor intestinal absorption, growth and poor feed Hanif et al., 2008). The Direct most intestinal et decreased al., 2008). The mostrate important source of efficiency mycotoxins (Pestka, such as2007; fumonisin B1 (Bouhet et al., 2004). is feed. It is known that 95% of all mycotoxins come from damage can be caused by the biological actions of important source of mycotoxins is feed. It is known that 95% of all mycotoxins come from the the field. More than 300 mycotoxins have been shown to mycotoxins. Trichothecenes affect actively dividing cells, field.signs Moreofthan 300in mycotoxins have been shown to induce signslining of toxicity in mammals andThere are induce toxicity mammals and avian species, such as those the gastrointestinal tract. and this number increasing. It has been estimated that of trichothecenes protein synthesis in avian species,is and this number is increasing. It hasdirect beeneffects estimated that 25% ofonthe world’s 25% of the world’s crop production is contaminated with eukaryotic cells due to the interaction with the ribosomal crop production contaminated with mycotoxins and either Mezes, 2005).of The most mycotoxins (Surai and is Mezes, 2005). The most significant units,(Surai preventing initiation protein synthesis or mycotoxins in naturally-contaminated foods and feeds elongation of the polypeptidic chains (Ueno, 1984). It should significant mycotoxins in naturally-contaminated foods and feeds are aflatoxins (Afla), are aflatoxins (Afla), ochratoxin A (OTA), zearalenone be noted that the gastrointestinal tract is also sensitive to ochratoxin A (OTA), zearalenone (ZEN), T-2 toxin, deoxynivalenol (DON) and fumonisins (FUM). (ZEN), T-2 toxin, deoxynivalenol (DON) and fumonisins trichothecene-induced apoptosis, affecting mainly the In many cases, these canbebefound found combination in contaminated feed. The (FUM). In many cases, thesemycotoxins mycotoxins can in ingastric mucosa, gastric granular epithelium, and intestinal combination in contaminated feed. The effectsimportant of the most mycotoxins crypt cell epithelium (Bondy and Pestka, 2000). The toxic effects of the most economically in different poultry categories economically important mycotoxins in different poultry action of trichothecenes results in extensive necrosis of oral (broilers,(broilers, layers and are usually: reduction in feed consumption and weight categories layersbreeders) and breeders) are usually: mucosa and gizzard lesions (Leeson et al., gain, 1995). The T-2 reduction in feedresistance consumptiontoand weight gain,-decreased toxin inhibits DNA, RNA, and synthesisand in eukaryotic decreased pathogens immunosuppression, reduced eggprotein production resistance to pathogens - immunosuppression, reduced cells, affecting the cell cycle and inducing apoptosis both hatchability, decreased semen volume and testes weights, fatty livers and enlarged spleens, egg production and hatchability, decreased semen volume in vivo and in vitro (Rocha et al., 2005). It should also be rickets, weakness, impaired quality and different kinds and testes leg weights, fatty livers and shell enlarged spleens, mentioned that of thelesions primary(oral, effect skin, of T-2kidney, toxin is executed rickets, shell quality and different by its contact the mouth liver leg andweakness, gizzard).impaired Major mechanisms of mycotoxin toxicity are with described in epithelium picture 1.(beak Therecavity and kinds of lesions (oral, skin, kidney, liver and gizzard). tongue). has mechanisms been extensive research addressing the different ways important in whicheffect mycotoxins can alter such as Major of mycotoxin toxicity are described in Another of some mycotoxins, picture 1. There has been extensive research addressing fumonisin B1 and ochratoxin A, is that they alter animal productivity. In this article, the emphasis is on six major effects of mycotoxins in thethe barrier the different ways in which mycotoxins can alter animal function of the intestinal epithelium, which is measured as intestine In that contribute to decreased performance. In addition, the possible alteration productivity. thismay article, the emphasis is on six major a decrease in the transepithelial electrical resistance. It is effects of mycotoxins themycotoxins intestine thatwill maybe contribute to likely that the environment surrounding the tight junctions of the microflorainby explored.
Mycotoxins Lipid peroxidation, membrane structure and function alteration – Most of mycotoxins
Inhibition of protein, DNA, RNA synthesis, damages to DNA OTA, T-2, AFB1
Induction of programmed cell death - Most of mycotoxins
Effects on gene expression - Most of mycotoxins
Immunosupression, hepatotoxicity, nephrotoxicity, neurotoxicity, genotoxicity
Picture 1: Major Mechanism of mycotoxin toxicity (Adapted from Suraj and Dvorska, 2005 30 International Animal Health Journal
Volume 4 Issue 2
RESEARCH AND DEVELOPMENT is somehow altered by continuous exposure to fumonisin B1 (Bouhet et al., 2004; McLaughlin et al., 2004). Poults fed grains naturally contaminated with fusarium mycotoxins had decreased villus height in the duodenum, and decreased villus height and villus surface in the jejunum during the starter period. In turkeys fed the same diet contaminated with fusarium mycotoxins, the width and villus surface of the duodenum, villus height and surface of jejunum, and submucosal thickness of ileum were decreased during the grower phase (Girish and Smith, 2008). Broilers fed diets contaminated with 0.5 mg deoxynivalenol/ kg had shorter and thinner villi, which resulted in lighter small intestines compared to birds fed control diets (Awad et al., 2006). 2. Mycotoxins affect intestinal secretions Aflatoxins fed to broiler chickens decreased the production of pancreatic secretions, whereas aflatoxins fed to layers produced an increase in the production of pancreatic enzymes (Osborne and Hamilton, 1981; Richardson and Hamilton, 1987). Intestinal morphology (intestinal crypt depth) and the specific activity of intestinal disaccharidase and maltase were also altered by feeding aflatoxin B1 (AFB1) (Applegate et al., 2009).
and pathogenic bacteria that causes the most devastating effects (Kumar et al., 2003). Gross and histopathological lesions of birds inoculated with E. coli were also more severe in birds that received a diet containing 2 ppm of ochratoxin than in birds that received a diet with no significant levels of mycotoxins (Kumar et al., 2004). Parasitic infections are more severe in combination with mycotoxins. It has been demonstrated that birds treated with lasalocid developed clinical coccidiosis when the levels of T-fusariotoxin exceeded 0.5 ppm (Varga and Ványi, 1992). 6. Mycotoxins alter intestinal motility Subchronic ingestion of DON, comparable with concentrations occurring in contaminated food and feed, was reported to impair the intestinal transfer and uptake of nutrients. Black sticky diarrhoea was reported in a flock of 6700 laying hens in India after the consumption of a feed batch contaminated with fumonisin B1 (6.5 mg/kg feed) and aflatoxin B1 (0.1 mg/kg). Haemorrhages of the proventriculus and accumulation of fluid in the intestine were commonly seen in the postmortem examinations. The disease was then experimentally reproduced in day-old chicks and in laying hens by feeding the contaminated diet (Prathapkumar et al., 1997).
3. Mycotoxins affect intestinal nutrient absorption In addition to the morphological changes induced to the intestinal villi by DON, it is suggested that this mycotoxin inhibits Na+ transport and Na+-D-glucose co-transport in the jejunum of layers. This results in a reduction of glucose uptake when the intestine is exposed to DON concentrations of 10 mg /L (Awad et al., 2005a; 2007). Similarly, in layers, DON affects the intestinal absorption of the amino acids that are co-transported with sodium, such as L-Proline (Awad et al., 2005b).
By combining the different areas covered in this article, it becomes clear that the intestinal microflora could be affected by mycotoxin ingestion via the following ways:
4. Mycotoxins and intestinal microflora Direct microbial toxicity of several mycotoxins has already been reported. E. coli, and S. aureus are susceptible to AfB1. This toxin inhibits the growth of these bacteria by up to 60%, depending on the bacterial strain. Bacteria that are more resistant to antibiotics have a tendency to be more resistant to the effect of mycotoxins (Tiwari et al., 1986). B. brevis, B. cereus, B. megaterium, B. subtilis, B. thuringiensis, B. pumilus and Listeria ivanovii are also sensitive to several mycotoxins (Madhyastha et al., 1993). Streptomyces vinaceous, S. olivoreticuli, S. lavendulae, S. roseochromogenes, S. virginiae, Nocardia leishmanii and N. coelica were also inhibited to certain degrees by aflatoxins, at concentrations ranging from 10 to 100 μg/mL (Tadashi et al., 1967). In addition to the direct toxic effects of mycotoxins on bacteria, there may be additional indirect effects. There is reported communication between the intestinal cells and microflora. If the capability of epithelial cells to synthesise proteins is reduced, a change in the signals that the enterocytes are transmitting to the microflora may be hypothesised.
2) Mycotoxins affect intestinal secretions: This generates a change in the chemistry of the luminal environment. The bacteria that are most suitable to the new luminal environment will have more chances of successfully multiplying.
5. Pathogen colonisation is enhanced by mycotoxins Although some bacterial strains are affected by mycotoxins, there is evidence that mycotoxins increase pathogenic bacterial colonisation of the intestinal tract in poultry and other animal species. Similarly, layer chickens treated with 3mg/kg of ochratoxin A had higher susceptibility to a Salmonella challenge compared to the control group (Fukata et al., 1996). E. coli challenge in broilers receiving an experimental diet containing 2 ppm of ochratoxin more than doubled the mortality compared to birds that received the bacterial challenge and a diet without mycotoxins. No birds died in the group that received the mycotoxin alone diet, demonstrating that it is the combination of mycotoxins www.animalhealthmedia.com
1) Mycotoxins affect the intestinal mucosa: Necrotic tissue released into the lumen changes the local environment. Receptor sites are lost and inflammatory cells get to the injured site and secrete toxic metabolites. In addition, mucus production is increased, changing the quality of nutrients available in the lumen.
3) Mycotoxins affect nutrient absorption in the intestine: The quality and quantity of nutrients available in the intestinal lumen changes since absorption capacity is altered. It is likely that species of bacteria that can successfully ferment the new “luminal diet” will predominate in the lumen. 4) Bacteria are affected by mycotoxins: It is reported that several genera of bacteria are sensitive to at least one mycotoxin. Species of bacteria that are more resistant to the mycotoxins will probably replicate at an increased rate, changing the ecosystem of the microflora. 5) Pathogen colonisation is enhanced by mycotoxins: This is probably a consequence of a weakened immune system plus altered microbial ecosystem (dysbiosis). 6) Mycotoxins alter intestinal motility: The quality and quantity of nutrients available for fermentation in a determined location are dependent on the flow rate, thus the bacterial population will readapt to the new environment. In addition, increased motility will physically eliminate the bacteria that have their niche closer to the tips of the villi, compared to those that find a more favourable environment towards the bottom of the villi (villi probably serve as a mechanical barrier). For bacteria that live predominantly close to the top section of the villi, a rapid reproduction rate will give them higher chances of survival under increased transit rate. International Animal Health Journal 31
RESEARCH AND DEVELOPMENT Mycotoxin Management Although agronomic and other practices are aimed at decreasing or eliminating mycotoxins in the field, there are still considerable reasons to look at post-harvest ways to counteract mycotoxins in grains and other commodities. Costs and limitations of physical and chemical treatments prompted the search for other solutions concerning the mycotoxin hazard. The best practical way to control mycotoxin levels is to use rapid test kit systems for the analysis of mycotoxins in raw ingredients which are not yet in silos. Different rapid test kit systems are validated for different mycotoxins and commodities offering a very quick and effective way of raw material screening before they enter the feed mill. Once the levels are known, every feed mill can estimate the quality of its raw ingredients in terms of mycotoxin contamination and can effectively and more precisely (by dosage adjustment) apply feed additives during feed production. Another strategy of mycotoxin risk management is to test for the presence of mycotoxins in finished feeds including total mixed ration (TMR) and silages. This method has some advantages and disadvantages. Since each raw ingredient can bring its own mycotoxins into the finished feed, the most important advantage is that the presence of raw ingredients with a low inclusion rate (510%) – which can still cause significant contamination of the finished feed but can be inadvertently overlooked if not tested - can be identified by testing the finished feed. The most important disadvantage is that analysis of finished feed takes quite a long time, such that the tested feed is likely to have been fed to the animals by the time the results from the analysis are known. Storage mycotoxin contamination (ochratoxins, aflatoxins) can be prevented by keeping temperature and moisture content in silos low, whilst aerating the grain regularly. In cases where perfect storage conditions cannot be guaranteed, the use of mould inhibitors and silage inoculants is highly recommended. The application of specific feed additives (mycotoxin deactivators) which are able to help reduce the negative effects of different mycotoxins in dairy cows is highly recommended. REFERENCES 1. 2. 3.
Applegate T.J., G. Schatzmayr, K. Prisket, C. Troche and Z. Jiang. 2009. Effects of aflatoxin culture on intestinal function and nutrient loss in laying hens. Poult. Sci. 88:1235-1241. Awad, W.A., J. Böhm, E. Razzazi-Fazeli and J. Zentek. 2005a. In vitro effects on electrical properties of intestinal mucosa of laying hens. Poult. Sci. 84:921-927. Awad, W.A., H. Rehman, J. Böhm, E. Razzazi-Fazeli and J. Zentek. 2005b. Effects of luminal deoxynivalenol and L-proline on electrophysiological parameters in the jejunums of laying hens. Poult. Sci. 84:928-932. Awad, W.A., J. Böhm, E. Razzazi-Fazeli and J. Zentek. 2006. Effects of feeding deoxynivalenol contaminated wheat on growth performance, organ weights, and histological parameters of the intestine of broiler chickens. J. Anim. Physiol. Anim. Nutr. 90:32-37. Awad, W.A., J.R. Aschenbasch, F.M. Setyabudi, E. Razzazi-Fazeli, J. Böhm and J. Zentek. 2007. In vitro effects of deoxynivalenol on small intestinal D-glucose uptake and absorption of deoxynivalenol across the isolated jejuna epithelium of laying hens. Poult. Sci. 86:15-20. Bondy, G.S. and J.J. Pestka. 2000. Immunomodulation by fungal toxins. J Toxicol. Environ. Health Part B Crit. Rev. 3: 109-143. Bouhet, S., E. Hourcade, N. Loiseau, A. Fikry, S. Martinez, M. Roselli, P. Galtier, E. Mengheri and I.P. Oswald. 2004. The mycotoxin fumonisin B1 alters the proliferation and the barrier function of porcine intestinal epithelial cells. Toxicological Sc. 77:165-171. Fukata, T., K. Sasai, E. Baba and A. Arakawa. 1996. Effect of ochratoxin A on Salmonella typhimurium-challenged layer chickens. Avian Dis. 40(4):924-926. Girish, C.K. and T.K. Smith. 2008. Effects of feeding blends of grains
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naturally contaminated with Fusarium mycotoxins on small intestinal morphology of turkeys. Poult. Sci. 87:1075-1082. 10. Hanif, N.Q., G. Muhammad, M. Siddique, A. Khanum, T. Ahmed, J.A. Gadahai and G. Kaukab. 2008. Clinico-pathomorphological, serum biochemical and histological studies in broilers fed ochratoxin A and a toxin deactivator (Mycofix® Plus). B. Poult. Sci. 49(5):632642. 11. Huwig A., Freimund S., Kappeli O. and H. Dutler. 2004. Mycotoxin detoxication of animal feed by different adsorbants. Toxicol. Lett. 122: 179 – 188. 12. Kumar, A., N. Jindal, C.L. Shukla, Y. Pal, D.R. Ledoux and G.E. Rottinghaus. 2003. Effect of ochratoxin A on Escherichia coli– challenged broiler chicks. Avian Diseases 47:415-424. 13. Kumar, A., N. Jindal, C.L. Shukla, R.K. Asrani, D.R. Ledoux and G.E. Rottinghaus. 2004. Pathological changes in broiler fed ochratoxin A and inoculated with Escherichia coli. Avian Pathology 33(4):413417. 14. Leeson S., G.J. Diaz and J.D. Summers. 1995. Poultry metabolic disorders and mycotoxins pp. 190-216. University Books. Guelph, Ont., Canada. 15. Madhyastha, M.S., R.R. Marquardt, A. Masi, J. Borsa and A.A. Frohlich. 1993. Comparison of toxicity of different mycotoxins to several species of bacteria and yeasts: use of Bacillus brevis in a disc diffusion assay. J. of Food Protection 57(1):48-53. 16. McLaughlin, J., P.J. Padfield, J.P. Burt and C.A. O’Neill. 2004. Ochratoxin A increases permeability through tight junctions by removal of specific claudin isoforms. Am. J. Physiol. Cell Physiol. 287:C1412-1417. 17. Osborne, D.J. and P.B. Hamilton. 1981. Decreased pancreatic digestive enzymes during aflatoxicosis. Poult. Sci. 60:1818-1821. 18. Pestka, J.J. 2007. Deoxynivalenol: toxicity, mechanisms, and animal health risks. Animal Feed Science and Technology 137:283-298. 19. Prathapkumar, S.H., V.S. Rao, R.J. Paramkishan and R.V. Bhat. 1997. Disease outbreak in laying hens arising from the consumption of fumonisin-contaminated food. Br. Poult. Sci. 38(5):475-479. 20. Richardson, K.E. and P.B. Hamilton. 1987. Enhanced production of pancreatic digestive enzymes during aflatoxicosis in egg-type chickens. Poult. Sci. 66:640-644. 21. Rocha O., K. Ansari and F.M. Doohan. 2005. Effects of trichothecene mycotoxins on eukaryotic cells: a review. Food Addit. Contam. 22:369-78. 22. Surai, P.F. and J.E. Dvorska. 2005. Effects of mycotoxins on antioxidant status and immunity. In: The Mycotoxins Blue Book, Ed. By Duarte Diaz. Nottingham University Press, pp. 93-137. 23. Surai, P.F. and M. Mezes. 2005. Mycotoxins and immunity: Theoretical Considerationh and Practical Applications: Review. Praxis veterinaria 53 (1-2) 71-88, 2005. 24. Tadashi, A., T. Ito and Y. Koyama. 1967. Antimicrobial activity of aflatoxins. J. Bacteriol. 93(1):59-64. 25. Tiwari, R.P., G. Singh and D.V. Vadehra. 1986. Drug resistance patterns and susceptibility to aflatoxin B1 of strains of Escherichia coli and Staphylococcus aureus. J. Med. Microbiol. 22:115-118. 26. Ueno, Y. 1984. Toxicological features of T-2 toxin and related trichothecenes. Fundam. Appl. Toxicol. 4:S124-S132. 27. Varga I. and A. Ványi. 1992. Interaction of T-2 fusariotoxin with anticoccidial efficacy of lasalocid in chickens. Int. J. Parasitology 22(4):523-525.
Radka Borutova DVM, PhD. Business Development Manager, Nutriad International, Belgium. Radka Borutova graduated from University of Veterinary Medicine in Kosice, Slovakia and was awarded Doctor’s degree in Veterinary Medicine ( DVM) in 2005. For 5 years she worked at the Institute of Animal Physiology, Slovak Academy of Sciences, Slovakia followed by the Ministry of Agriculture of the Slovak Republic as Chief state counsellor. After 4 years at Biomin Holding GmbH as Product manager for MycofixR product line, she joined NutriAd International NV as Business Development Manager Mycotoxins. Email: firstname.lastname@example.org
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RESEARCH AND DEVELOPMENT
Tackling the Worms that Turned: PARAGONE, an EU Project on Parasite Vaccines The Need for Multicellular Parasite Vaccines Multicellular parasites are common disease agents of livestock. Important groups of parasites that affect the health and welfare of ruminant livestock include the helminths (i.e. nematodes, flukes and tapeworms) and the ectoparasitic mites. Parasitic helminths are the cause of some of the most important production-limiting diseases of grazing ruminants. Generally, all herds or flocks in grass production systems are exposed to helminths and intensification of farming increases the risk of exposure to, and infection with, helminths. These parasites can cause severe clinical disease, but they have most impact through their sub-clinical effect on production, reducing growth rate, fertility, meat quality and/or wool/milk production. In particular, when farm profit margins are low, due to increases in production costs and fluctuating output prices, even relatively small helminth-associated effects on biological efficiency can have a major impact. There is a lack of data on the precise cost of helminth-associated disease in different systems; the information that is published tends to describe impacts only in regionally restricted terms. For example, one 2005 analysis described the annual cost of nematode infections to the UK sheep industry as ~€99M.1 In the same year, the annual cost of bovine liver fluke in Switzerland was estimated as ~€52M.2 In addition to these types of analysis, epidemiological-based studies in cattle have consistently demonstrated negative correlations between diagnostic test results indicating helminth infection and measures of productivity.3-5 Added to their effects on welfare and production, some helminth species, for example Fasciola hepatica, have indirect impacts by affecting the diagnosis of other important disease such as bovine tuberculosis.6 Of further concern is the fact that in recent years, climate changes in parts of the EU have been linked to an increase in the frequency of helminthassociated disease in ruminants.7 This is because of a preponderance in the type of environmental conditions more conducive to the survival and development of helminth developmental stages that live outside the host on pasture. All of the aforementioned issues are exacerbated by the fact that resistance to commonly used antiparasitics is being increasingly reported in helminth species that infect cattle and, in particular, sheep.8-10 Indeed, anthelmintic resistance is a major threat to the livestock industry. Added to this are consumer concerns regarding antiparasitic residues in food and their possible detrimental environmental impact. Ectoparasitic (scab) mites also represent a welfare and production concern for ruminant and poultry farmers worldwide. These parasites cause intense itching in infected animals and birds. Psoroptes ovis is a relatively common scab mite that infects sheep and cattle. Over a decade ago, the economic cost of infestation with this mite in sheep was estimated at > €10M per annum in the UK alone.1 In cattle, beef breeds tend to be more susceptible to P. ovis infection, in particular, the Belgian Blue breed. In some parts of the EU, mange caused by this mite is the most common skin disease of cattle. Chemical treatment options that are licensed for control of P. ovis are limited. Furthermore, resistance to antiparasitic compounds in P. ovis has been suspected. The poultry red mite, Dermanyssus gallinae, is the most economically-important parasite in commercial egg 34 International Animal Health Journal
production facilities worldwide. 11 It has been estimated that infections with this mite cause annual losses in the region of €130M in Europe alone.11 The numbers of mites that can infest a single bird can be very high (up to several hundred thousand); thus, the welfare implications of infection are immense, as the parasites cause intense itching, weight loss and anaemia. A decrease in egg quality is also a symptom of infestation. These poultry mites have also been implicated as vectors of viral and bacterial diseases. Current control strategies for poultry red mite involve the spraying of hen houses with pesticides; these practices provide short-lived protection against infection and, similar to helminth infections, parasite resistance to the chemicals used for control is reported.12 For all of the reasons above, sustainable, non-chemical solutions need to be identified to address the diminishing supply of effective antiparasitics to control multicellular parasite infections in different classes of livestock. Vaccines are the obvious candidates for this; these prevent rather than cure infection, have more durable protection, have no associated meat, milk or egg residue issues and represent more environmentally-friendly forms of control than the current antiparasitics. Sub-unit Vaccines for Multicellular Parasites The development of commercially-viable effective subunit vaccines for multicellular parasites has proved a real challenge to the global animal health research community.13 There are several issues linked to the complexity of the associated host/parasite interactions that have provided barriers to successful vaccine discovery programmes. For example, numerous studies have demonstrated that helminths have the capacity to modulate host immune responses to those that favour infection by producing ‘immunosuppressive’ molecules in their host niche; this provides a major obstacle to stimulating effective immune responses in the face of infection. It has also been indicated that very young ruminants (the main target for the effective deployment of vaccines) do not respond well at the immunological level to worm challenge in the gastrointestinal tract. Added to these fundamental obstacles are technical issues associated with trying to define what are the host-protective components that exist within these highly complex multicellular worms and mites. In many cases, where extracts from the parasites themselves (so-called ‘native’ vaccines) have provided protection by vaccination, synthetic versions of molecules identified within these extracts have not afforded anything near the same levels of protection. This has been a recurring theme in multicellular parasite vaccine research for many years. Native vaccines require that animals be used for production and a cold chain is needed for distribution, both of which are features that restrict deployment across wide geographic regions, making such vaccines commercially unattractive. For these reasons, recombinant protein (sub-unit) vaccines offer the most attractive option for commercially feasible means to control multicellular parasites. Recent scientific advances have been made to address the hurdles defined above. These advances include the Volume 4 Issue 2
RESEARCH AND DEVELOPMENT design of sub-unit multi-component (‘cocktail’) vaccines that contain several parasite components that span different developmental stages of the pathogens. Such vaccines have been tested in trials and have been shown to afford significant levels of protection against parasite challenge; for example, an eight-protein ‘cocktail’ vaccine developed to combat the sheep brown stomach worm, Teladorsagia circumcincta, has been shown on several occasions to induce significant levels of protection against challenge when worm burdens and egg-shedding in vaccinates were compared to those in challenge control sheep.14,15
Electron micrograph of the brown stomach worm, Teladorsagia circumcinta
Prototype vaccines such as this one have been devised by exploiting an in-depth knowledge of the associated host/parasite relationship with the aim of developing a ‘smart’ vaccine designed to bypass worm intra-host survival strategies. For parasites for which vaccine development pipelines have not yet been established, or are in their infancy (for example, vaccines against ectoparasitic mite infections), research urgently needs to be undertaken to understand host/parasite interactions to pinpoint which components of the host immune response are protective. Once these are defined, they can be used as tools to identify potential vaccine candidates in the mites. Vaccine delivery systems also need to be tested to ensure that effective host responses are being stimulated in the appropriate host environment to counter parasites at challenge. Crucial to all of these aspirations is an interdisciplinary research approach that allows wide-ranging streams of activity to come together to address the complex questions being addressed.
In PARAGONE, the research partners are undertaking further pen or field trials using prototypes previously identified as showing promise in inducing protection against helminth infections in order to examine variability in host responsiveness. For parasites for which effective sub-unit vaccines have proved difficult to develop or have not yet been developed, fundamental science studies are being undertaken to understand key host responses that need to be stimulated to induce immunity against infection. Here, state-of-the-art technologies are being harnessed to understand host/parasite interactions to define key signatures of immunity, which will be used to inform the identification of vaccine constituents or vaccine delivery. In these studies, a systems approach is being undertaken to explore host/parasite interactions in detail. This involves next generation sequencing of transcripts in biological samples obtained from a number of model systems, combined with cutting-edge bioinformatics analyses. The consortium is taking a trans-disciplinary approach whereby the bioinfomatic outputs are being combined with data from detailed immunological and parasitological experiments for the parasite systems under study. Other research strands are aimed at determining the level of polymorphism in the genes that encode the vaccine components’ previously identified prototypes. This work is being performed to examine if the current prototypes will be effective across geographic scales or if they need to be modified to take into account sequence diversity between populations. These streams of research are being combined with the study of novel adjuvant and delivery systems with the aim of further improving protection levels in vaccinates. Together, the consortium is working on vaccine prototypes to control the following multicellular parasites: Ostertagia ostertagi and Cooperia spp. in cattle, Cooperia spp. in sheep, Teladorsagia circumcincta in sheep, Fasciola hepatica in cattle and sheep, Psoroptes ovis in cattle and Dermanyssus gallinae in poultry. PARAGONE’s approach goes beyond the scope of previous vaccine projects, many of which followed ‘single protein/single parasite’ design strategies that did not work. For each of the vaccines, the academic partners are working closely with the commercial partners to exploit the best prototypes coming out of the research studies. In this way, the programme forms a virtual ‘conveyor belt’ of vaccine development by using knowledge on host/ parasite interactions, from gene characterisation to interanimal investigations to the use of novel adjuvant/delivery systems to housed or field trials in the appropriate host.
The PARAGONE Vaccine Development Project The EU Horizon 2020-funded multicellular parasite vaccine consortium, PARAGONE (http://www.paragoneh2020.eu), is addressing the challenges defined above. This group of academics and commercial organisations are taking a collegiate approach to moving forward vaccines designed to control several major multicellular parasites of cattle, sheep and poultry. The consortium (funded to a value of ~€9 million) comprises 17 partners, including academic members from six European countries and Uruguay and four commercial partners from across the EU. Of the commercial partners, two are leading animal health companies, one is a biotech company focused on novel bioinformatic development pipelines and one is a company that develops and manufactures immunological tools. www.animalhealthmedia.com
International Animal Health Journal 35
RESEARCH AND DEVELOPMENT An important part of the project is the strong element of dialogue between the academic partners and the animal health company partners, in addition to several outreach activities to other end-users such as farmers, veterinarians and regulators. These activities are being used to obtain feedback on how the prototype vaccines could be best implemented in the field in future and provide a clear pathway towards the future commercialisation and uptake of the prototypes under study. Another important aspect of the project is the transfer of knowledge across disciplines and partners; the activities include several training workshops for students and post-doctoral scientists on the project and some of these are open to external applicants who can benefit from the knowledge being generated within the programme (please check out the website for further information on PARAGONE training opportunities). In summary, vaccines are probably the only valid option for long-term control of multicellular parasitic infections given the potential ubiquity of antiparasitic resistance. For these reasons, the development of any sub-unit multicellular parasite vaccine to the point of practical application would be a ground-breaking step.
Acknowledgements The PARAGONE project is funded by the European Union’s Horizon 2020 Research and Innovation programme (http:// cordis.europa.eu/project/rcn/193331_en.html) under Grant Agreement No 635408. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Nieuwhof and Bishop 2005. Animal Sci. 81:23-9. Schweizer et al. 2005. Vet Rec. 157:188-193. Charlier et al. 2005. Vet Parasitol. 129:67–75. Mezo et al. 2011. Vet Parasitol. 180:237–42. Dank et al. 2015. J Dairy Sci. 98:7741–7. Claridge et al. 2012. Nat Commun. 3:853. Verschave et al. 2016. Trends Parasitol. 32:724-38. Fairweather 2011. Vet Parasitol. 180:133-43. Kaplan and Vidyashankar 2012. Vet Parasitol. 186:70-8 Rose et al. 2015. Vet Rec. 176:546. Sparagano et al. 2009. Exp Appl Acarol. 48:3-10. Sparagano et al. 2014. Annu Rev Entomol. 59:447-66. Matthews et al. 2016. Parasite Immunol. 38:744-753. Nisbet et al. 2016. Parasitology 143:1055-1066. Nisbet et al.2013. Vaccine 31:4017-4023.
PARAGONE project partners at first Consortium Meeting in Edinburgh, 2015
Jacqueline B Matthews Moredun Research Institute, Edinburgh. After qualifying in veterinary medicine at the University of Glasgow, Jacqui’s career has been in helminthology research. Her research spans immunology, vaccine development and diagnostics to support sustainable worm control in ruminants and horses. She has obtained over £13 million in competitive grant funding to support her research and has published >120 associated peer-reviewed research papers. In addition to support from Scottish Government, her research has been/is funded by BBSRC, Wellcome Trust, DEFRA-VMD, Horserace Betting Levy Board, Horse Trust, Pilkington Trust, Donkey Sanctuary, Perry Foundation, animal health companies and EU H2020. Currently, Jacqui is Coordinator of a 9 million euro EU Horizon 2020 project. Jacqui holds an Honorary Professorship at the Royal (Dick) School of Veterinary Studies, University of Edinburgh, and is Translational Facilitator of the University of Edinburgh’s Centre of Immunity, Infection and Evolution. Email: firstname.lastname@example.org
36 International Animal Health Journal
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International Animal Health Journal 37
Anti-Nerve Growth Factor Monoclonal Antibodies for Chronic Pain Control in Cats and Dogs: A Review of Clinical Outcomes
Chronic pain management is an area of major clinical importance. Multiple prevalent conditions in veterinary species are associated with pain and disability and the limitations of existing therapeutic options, especially in cats, have resulted in significant unmet medical need. In human Phase III clinical studies, monoclonal antibody (mAb) therapies targeting the hormone nerve growth factor (NGF) have been shown to be highly effective in managing chronic pain. We review here outcomes from preclinical and clinical studies of fully caninised and fully felinised anti-NGF mAbs, which support the further development of these therapies for chronic pain management in their respective species. Degenerative Joint Disease and Current Approved Treatments in Dogs and Cats In veterinary medicine, the mainstay of drug therapy for the alleviation of clinical signs associated with degenerative joint disease (DJD, including osteoarthritis) -associated pain in dogs and cats are non-steroidal anti-inflammatory drugs (NSAIDs). This may be partly due to the fact that there are no other classes of drug approved by the Food and Drug Administration’s Center for Veterinary Medicine (FDA CVM) for the control of DJD-associated pain in dogs. In cats, the NSAID meloxicam is currently approved in Europe for use in treating chronic pain, but has not been approved for this use in the United States. There are no other approved medications for the long-term treatment of chronic pain in the cat, despite a clear need for such a treatment. Although some studies have demonstrated efficacy of other drug classes for DJD-associated pain in dogs (Lascelles et al. 2008), evidence indicates that NSAIDs are still currently considered the most effective therapy for pain (Innes et al. 2010; Aragon et al. 2007; Sanderson et al. 2009). However, NSAIDs are not always sufficiently effective in dogs (Lascelles et al. 2008) and concerns about side-effects result in a large unmet need in the treatment of canine DJD-associated pain. In cats, there are greater concerns about the use of NSAIDs for long periods of time, especially as the majority of cats presenting with DJD-associated pain have evidence of chronic kidney disease (Marion et al. 2013), and NSAIDs may interfere with renal function (Sparkes et al. 2010). Indeed, only two placebo-controlled, blinded clinical studies of the efficacy of meloxicam in cats have been published (Gruen et al. 2015; Lascelles et al. 2007). Because of these concerns, doses lower than the European-approved dose of meloxicam (0.05mg/kg) have been assessed, with evidence from one blinded, placebo-controlled study demonstrating that 0.035mg/kg daily produced measurable improvement over a threeweek period of administration (Gruen et al. 2015). An Alternative Approach: Targeting Nerve Growth Factor (NGF) Nerve growth factor (NGF) has emerged as a potentially useful therapeutic target for pain control. NGF was identified as a protein growth factor critical for the development and maintenance of sensory and sympathetic neurons in the 38 International Animal Health Journal
developing nervous system. However, it is now clear that NGF has an important role in pro-nociception (reviewed in: Hefti et al. 2006). NGF binds to the high-affinity NGF-specific receptor TrkA, resulting in autophosphorylation of the TrkA intracellular domain and activation of subsequent downstream signalling cascades (Hefti et al. 2006). In nerves, this results in post-translational changes in the transient receptor potential vanilloid receptor 1 (TRPV1) cation channel, lowering its threshold for stimulation. NGF-induced upregulation of other proteins also increases the excitability of the primary afferent fibre (Hefti et al. 2006). NGF also activates mast cells, which can further sensitise neurons as a result of the mast cell products released (Kawamoto et al. 2002). Given its role in nociception, various methods of preventing activation of TrkA have been explored, including blocking NGF binding to TrkA and preventing activation of TrkA (Eibl et al. 2012). Of these approaches, monoclonal antibodies (mAbs) that target and neutralise NGF (blocking binding to receptor) have been developed first (Figure 1).
Peripheral Sensitization Pain Signal
Ranevetmab or Frunevetmab
Inhibition of NGF function via anti-NGF antibodies markedly reduces hyperalgesia and behavioural indicators of pain in various animal models of inflammatory arthritis (Shelton et al. 2005; Ghilardi et al. 2012). In human clinical studies, several anti-NGF mAbs have been shown to reduce pain and improve function in patients with OA, and these antibodies are currently in late-stage (Phase III) clinical development (Balanescu et al. 2014; Tiseo et al. 2014; Sanga et al. 2013; Brown et al. 2012; Lande et al. 2010). Development of Anti-NGF Antibodies for Chronic Pain Control in Cats and Dogs Antibody drugs are large glycoproteins that need to be species-specific, so as to prevent the body developing an immune response to the drug (immunogenicity). Biotechnology company Nexvet has developed an efficient way of creating species-specific antibodies using a process termed PETization (see “About PETization” at Nexvet.com). Briefly, in order to convert anti-NGF antibodies generated in rats (donor mAbs) into cat- and dog-specific antibodies, changes were made to the donor mAb heavy and light chain (NGF-binding) variable domain sequences. These changes were chosen by alignment of the donor framework sequences with a collection of predicted protein sequences encoded by expressed antibody DNA sequences from the target species (cat or dog), followed by substitution of the most suitable amino acids into the protein sequence. This process ensures retention of the antibody’s affinity for NGF and reduces the immunogenic potential of Volume 4 Issue 2
CLINICAL STUDIES the donor mAb in the cat or dog. By this process, the rat donor framework sequences are completely “caninised” or “felinised”, with minimal changes made from the donor antibody, thus improving the likelihood that converted mAbs retain their affinity and potency. Further engineering of mAb heavy and light chain constant domains enabled the construction of the complete antibodies for dogs and cats, respectively (Gearing et al. 2013; 2016).
measure, which assesses overall owner experience with the treatment course, achieved statistical significance at the single timepoint at which it was measured, D28. Statistically significant improvements on the assessed level of pain as measured using CBPI treatment success/fail criteria were also seen between enrolment and D14, D28 and D56. No adverse safety signals were associated with anti-NGF mAb administration in this study.
Anti-NGF Monoclonal Antibody for Chronic Pain in the Dog A canine-specific mAb against NGF (ranevetmab or NV01) was generated via PETization and has demonstrated high affinity and potency, no immune cell effector activity, a long half-life and low immunogenic potential (Gearing et al. 2013). An exploratory clinical study provided evidence that NV-01 (0.2 mg/kg intravenously (IV)) alleviated the signs of pain in dogs with OA using a validated pain and mobility assessment questionnaire (the Canine Brief Pain Inventory (Brown et al. 2008)) with owners blinded to the time of administration of the antibody (Webster et al. 2014). Subsequently, a randomised, double-blinded, placebocontrolled clinical study assessed pain control and effects on mobility of NV-01 in dogs with DJD-associated pain using pain and mobility assessment questionnaires and actimetry (activity monitoring using collar-mounted accelerometers) (Lascelles et al. 2015). Twenty-six dogs with DJD-associated pain received a single dose of NV-01 (0.2 mg/kg IV) or placebo on day 0 and were then assessed at two and four weeks postdosing. In addition to objective actimetry measures, owners completed various subjective pain and mobility assessment questionnaires (client-specific outcome measures [CSOM], canine brief pain inventory [CBPI] and Liverpool osteoarthritis in dogs index [LOAD]) on D0, D14 and D28. CBPI scores significantly (P<0.05) improved in the NV-01treated group compared to the placebo-treated group at D14 and D28. The magnitude of the effect was similar to that previously observed with NSAID treatment. CSOM and LOAD scores showed similar improvement in the NV-01-treated group at D14 and D28. No adverse side-effects were noted and neutralising anti-NV-01 antibody responses were not detected. The accelerometer data demonstrated that the average daily activity of animals in the NV-01-treated group increased over the study period compared to placebo, and significant differences were observed during the daytime (9am-5pm). These pilot data supported further clinical assessment of the anti-NGF mAb as an analgesic in dogs suffering from DJD-associated pain.
Anti-NGF Monoclonal Antibody for Chronic Pain in the Cat Following the encouraging outcomes seen in early canine studies of NV-01/ranevetmab, a felinised version of an anti-NGF antibody was designed (termed NV-02/ frunevetmab). Similar to the canine antibody, NV-02 has high affinity and potency and was found to be safe with favourable pharmacokinetics in pre-clinical testing in cats. In a placebo-controlled, blinded clinical study, thirty-four client-owned cats with DJD-associated pain and mobility impairment were randomised to a single SC treatment with NV-02 (n=23) or placebo (n=11). Activity was measured objectively using collar-mounted accelerometers, and subjectively by owners completing two clinical pain and mobility questionnaires (CSOM and feline musculoskeletal pain index [FMPI]) on days 0 (at screening), 14 (baseline, NV-02 administration), 35, 56 and 77. NV-02 significantly increased activity overall and at two, three, four, five and six weeks following treatment compared with placebo. CSOM scores were significantly improved three weeks following administration with antibody (Gruen et al. 2016). At D77, 83% of the owners in the NV-02-treated group correctly identified the treatment administered (NV-02 or placebo) compared to 45% of owners in the placebo group. No treatment-related adverse effects were identified. These pilot data demonstrated a positive analgesic effect of sixweek duration following anti-NGF antibody administration to the cats.
These pilot study results were confirmed in a larger pivotal efficacy and field safety study which enrolled 262 dogs with naturally-occurring osteoarthritis. This randomised, double-blind, placebo-controlled study involved administration of three doses of 0.2 – 0.4 mg/ kg of NV-01/ranevetmab delivered at 28-day intervals by subcutaneous injection (SC). Dogs were randomly assigned to receive either NV-01 or placebo at a 2:1 ratio. CSOM and CBPI were the primary assessment tools, conducted at days 0 (pre-first dose), 14, 28, 56 and 84. A statistically significant improvement in pain score was observed in the antibody-treated group compared to the placebo group using pre-determined CSOM improvement success/fail criteria between enrolment and day 28 (this was the primary endpoint of the study as agreed under protocol concurrence with FDA CVM). Statistical significance (P<0.05) by this measure was also seen on days 56 and 84. Median change in CSOM scores also showed significant improvement in the antibody-treated dogs for D0 to D28 and D0 to D56 (p<0-05). The CSOM global assessment www.animalhealthmedia.com
A larger placebo-controlled, double-blinded pilot field study which enrolled 126 cats with naturally-occurring osteoarthritis was conducted, and further supported the safety and efficacy of NV-02/frunevetmab. This study used CSOM and FMPI as primary assessment tools, at screening, day 0 (first dosing) and days 14, 28, 42 and 56. Two doses of 0.1 – 0.28 mg/kg NV-02/frunevetmab were administered with a 28-day interval between doses. Cats randomly received either NV-02 or placebo at a 2:1 ratio. IV and SC administration were examined: both routes of administration were highly effective and the groups were combined for analysis. Analysis of the combined NV-02-treatment groups compared to placebo yielded a number of statistically significant (P <0.05) improvements, including the assessed level of pain as measured using pre-determined CSOM improvement success/fail criteria between enrolment and both D42 and D56. There were also statistically significant reductions in the assessed level of pain as measured using changes in median total CSOM score between enrolment and day 42 and day 56. A statistically significant difference between NV-02/frunevetmab-treated cats and placebo was seen for the CSOM global assessment on both days it was measured: D28 and D56. Pre-determined FMPI improvement success/fail criteria also showed statistically significant improvement on the assessed level of pain between enrolment and both D42 and D56. Reductions in median FMPI total score showed statistically significant improvement over placebo on the assessed level of pain at D42 and D56. No adverse safety signals associated with NV-02/frunevetmab administration were seen in this study. International Animal Health Journal 39
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50 40 Day Day 28 14Day Day 56 28Day 82 Day 56
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Conclusion These pre-clinical and clinical studies support the hypothesis that species-specific anti-NGF monoclonal antibodies can control pain in dogs and cats, when administered by monthly injection. The high prevalence of conditions that cause chronic pain and disability in these species, combined with a need for differentiated pain management therapeutic options, makes this approach a promising area of development. Note: The monoclonal antibodies NV-01/ranevetmab and NV-02/frunevetmab remain in clinical development and have not yet been approved for use by a regulatory agency REFERENCES 1.
5. 6. 7.
11. 12. 13.
Aragon CL, Hofmeister EH, Budsberg SC. Systematic review of clinical trials of treatments for osteoarthritis in dogs. J Am Vet Med Assoc. 2007;230:514–21 Balanescu AR, Feist E, Wolfram G, Davignon I, Smith MD, Brown MT, et al. Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multi-centre phase III randomised clinical trial. Ann Rheum Dis. 2014;73:1665–72. Brown DC et al. Ability of the Canine Brief Pain Inventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Assoc. 2008: 233(8): 1278–1283. Brown MT, Murphy FT, Radin DM, Davignon I, Smith MD, West CR. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J Pain. 2012;13:790–8. Eibl JK, Strasser BC, Ross GM. Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int. 2012;61:1266–75. Gearing DP, Virtue ER, Gearing RP, Drew AC. A fully caninised antiNGF monoclonal antibody for pain relief in dogs. BMC Vet Res. 2013;9:226. Gearing DP, Huebner M, Virtue ER, Knight K, Hansen P, Lascelles BDX, Gearing RP, Drew AC. In vitro and in vivo characterization of a fully felinized therapeutic anti-nerve growth factor antibody for the treatment of pain in cats. J. Vet. Int. Med. 2016, 30: 1129-1137. Ghilardi JR, Freeman KT, Jimenez-Andrade JM, Coughlin KA, Kaczmarska MJ, Castaneda-Corral G et al. Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint. Arthritis Rheum. 2012;64:2223–32. Gruen ME, Griffith EH, Thomson AE et al. Criterion Validation Testing of Clinical Metrology Instruments for Measuring Degenerative Joint Disease Associated Mobility Impairment in Cats. PLoS ONE, 2015, 10:e0131 Gruen ME, Thomson AE, Griffith EH, Paradise H, Gearing DP, Lascelles BDX. A feline specific anti-nerve growth factor antibody improves mobility in cats with degenerative joint disease-associated pain: A pilot proof of concept study. J. Vet. Int. Med. 2016, 30:1138-1148. Hefti FF, Rosenthal A, Walicke PA, Wyatt S, Vergara G, Shelton DL et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci. 2006;27:85–91. Innes JF, Clayton J, Lascelles BDX. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Rec. 2010;166:226–30. Kawamoto K, Aoki J, Tanaka A, Itakura A, Hosono H, Arai H et al. Nerve growth factor activates mast cells through the collaborative interaction with lysophosphatidylserine expressed on the membrane surface of activated platelets. J Immunol. 2002;168:6412–9. Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD et al. Tanezumab for the treatment of pain from osteoarthritis
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80 70 60 50 40
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CSOM Success (%)
CSOM Success (%)
CSOM Success (%)
50 40 Day 28 Day 42 Day 56 Day 14 Day 28 Day 42
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of the knee. N Engl J Med. 2010;363:1521–31. 15. Lascelles BDX, Gaynor JS, Smith ES, Roe SC, Marcellin-Little DJ, Davidson G et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med. 2008;22:53–9. 16. Lascelles BDX, Knazovicky D, Case B, Freire M, Innes JF, Drew AC, Gearing DP. A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. BMC Veterinary Research. 2015 Apr 30;11(1):101. 17. Lascelles BDX, Hansen BD, Roe S et al. Evaluation of Client-Specific Outcome Measures and Activity Monitoring to Measure Pain Relief in Cats with Osteoarthritis. J Vet Intern Med. 2007;21:410. 18. Marino CL, Lascelles BDX, Vaden SL et al. Prevalence and classification of chronic kidney disease in cats randomly selected from four age groups and in cats recruited for degenerative joint disease studies. J. Feline Med. Surg. 2013 16:465–72. 19. Nexvet website: “The PETization platform”. http://www.nexvet.com/ our-science/petization-platform. 20. Sanderson RO, Beata C, Flipo R-M, Genevois J-P, Macias C, Tacke S et al. Systematic review of the management of canine osteoarthritis. Vet Rec. 2009;164:418–24. 21. Shelton DL, Zeller J, Ho W-H, Pons J, Rosenthal A. Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. Pain. 2005;116:8–16. 22. Sanga P, Katz N, Polverejan E, Wang S, Kelly KM, Haeussler J et al. Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain. Pain. 2013;154:1910–9. 23. Sparkes AH et al. ISFM and AAFP Consensus Guidelines, Long-term use of NSAIDs in cats. Journal of Feline Medicine and Surgery. 2010. 12: 521-538. 24. Tiseo PJ, Kivitz AJ, Ervin JE, Ren H, Mellis SJ. Fasinumab (REGN475), an antibody against nerve growth factor for the treatment of pain: results from a double-blind, placebo-controlled exploratory study in osteoarthritis of the knee. Pain. 2014;155:1245–52. 25. Webster RP, Anderson GI, Gearing DP. Canine brief pain inventory scores for dogs with osteoarthritis before and after administration of a monoclonal antibody against nerve growth factor. Am J Vet Res. 2014;75:532–5.
Dr. David Gearing Nexvet co-founder with more than 20 years experience in the biopharmaceutical sector. From January 2000 to September 2007, David served as the Chief Research Officer and Director of Research at CSL Ltd, a specialty biopharmaceutical company based in Melbourne, Australia. He served as Vice President and Founder at Millennium Biotherapeutics, Inc., a biopharmaceutical company and as Director of Molecular Biology at SyStemix, a stem cell and gene therapy company. Email: email@example.com Co-authors: Tom C. Donovan, Samantha J. Busfield, Jane Eagleson and Colin J. Giles
Volume 4 Issue 2
Better digestion for better feed efficiency
Add the power of • A unique blend of herbs, essential oils and functional ﬂavors Phytogenics to • Proven in science and practice your diet: • Tailored to the animal’s needs
International Animal Health Journal 41
Microfloral Rehabilitation: Normalisation of Gut Function Intestinal Health Gut health and its management is an intricate and complex area governed by numerous factors, including nutrition, microbiology, immunology and physiology. When gastrointestinal health is compromised, nutrient digestion and absorption are affected, feed conversion becomes reduced, susceptibility to disease is heightened and, ultimately, these issues result in a negative economic impact. The comprehensive community of microorganisms in the gut is referred to as the microbiome and is recognised as a very diverse community of bacteria, fungi, protozoa and viruses. Its diversity varies along the different regions of the gastrointestinal (GI) tract, with some regions having less tolerable conditions and therefore containing reduced microbial diversity in comparison to regions more favourable to microbial growth. The gastrointestinal microbiome plays a pivotal role in nutritional, physiological and immune functions. Poor intestinal health is associated with increased pathogen colonisation and susceptibility to infectious disease, which can ultimately lead to poor weight gain and increased mortalities.
immune system. In addition, the intestinal microbiome can influence host growth rates by producing extra nutrients through the breakdown of less digestible nutrients. Profiling and understanding the role of intestinal microbial communities is important for the development and understanding of new and existing feed additives, thus allowing the manipulation of diets to improve performance, health and welfare. Dietary supplements, which focus on rehabilitating or repairing the gut microfloral diversity in order to aid intestinal health and decrease the animal’s susceptibility to disease, can be broadly classed as either prebiotics or probiotics. Through the use of techniques based on molecular sequencing technologies, difficulties associated with cultivating intestinal bacteria have been overcome, providing detailed insights into the malleable nature of the microbiome. Over the last number of years, a focus has been placed on identifying the populationmodulating effects of dietary supplementation with yeast cell wall-based prebiotics (such as mannose rich fractions (MRF). In particular, the role of overall microbial diversity in influencing health and performance has come under increased scrutiny. Ultimately, the goal with nutritional intervention is to normalise gut function through a process of microbial repair and rehabilitation.
In general, the development of the adult gut microbiota begins on hatching or on birth, whereby microbes are picked up predominantly from the post-hatch/delivery environment and from feed or drinking water. From a management point of view, humans can also be a source of microbes, and care needs to be taken not to inadvertently introduce pathogenic species. The time it takes for the establishment of the stable adult microbiota will depend on many factors, including the size of species, type of feeding regime and management practices in place. Within the GI tract, there are multiple interactions between the host, intestinal environment and microbial cells, in addition to feed components. These interactions underline the critical role of the microbiota in the health and wellbeing of the host, although the exact way in which this is achieved is not yet fully understood.
Figure 1. Microbial diversity: the key to gut health
The diversity within the microbiome plays a critical role in gut health, with beneficial microbes forming a protective barrier lining the gut that prevents the growth of pathogenic bacteria such as Salmonella, Campylobacter, Clostridia and Escherichia, amongst others. There are numerous theories on how the beneficial microbes prevent pathogen colonisation. Some theories suggest that potential attachment sites on the gut cells become occupied, thereby reducing the opportunity for attachment and colonisation by pathogens. Another proposed mechanism is that the intestinal microbiota secrete compounds such as volatile fatty acids (VFAs), organic acids and natural antimicrobials that either inhibit the growth of or make the environment unsuitable for less favourable bacteria.
Rehabilitation of the Microbiome From a nutritional standpoint, there are many feed supplements focused on stabilising the gut microflora to aid intestinal health and decrease the animal’s susceptibility to disease. These include products that are designed to regulate and support the gut environment and its microflora: • Coccidial vaccines • Probiotics • Competitive exclusion products • Feed enzymes • Functional nutrients, such as nucleotides • Organic acids and feed hygiene products • Organic minerals • Plant-based products, such as herbs, spices and essential oils • Prebiotics, such as yeast MRF
Studies using germ-free animals have further demonstrated that the intestinal microbiome is also critical to the stimulation, development and maturation of the
Of the functional ingredients currently in use for microbial control, MRFs isolated from the yeast cell wall (MRFs) are widely used in animal nutrition and have been
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CLINICAL STUDIES shown to improve animal performance in a manner similar to antibiotic-like growth promoters, suggesting they are a viable non-antibiotic alternative. MRF products have been commercially available since the early 1990s. Since 1999, the use of MRF in animal feed has become more prominent, mainly due to the European ban on prophylactic antibiotic growth promoters in animal feed. Most MRF products are derived from the cell wall of the yeast Saccharomyces cerevisiae. Given their ability to bind and limit the colonisation of gut pathogens, MRF have proven to be an effective solution for antibioticfree diets as well as providing support for immunity and digestion. The effects of MRF supplementation on health and performance have been studied comprehensively, and they have proven effective at improving weight gain and feed conversion efficiencies while also protecting against pathogen colonisation of the gut. While the effects of MRF supplementation on bird health and performance have been studied comprehensively, newer studies have focused on the effects on the overall bacterial community of the poultry gut — not just specific bacteria — and such work has shown that supplementation with MRF can significantly alter the intestinal microflora, the so-called microbiome (Corrigan et al., 2015). This analysis, which was carried out using so-called deep-sequencing technology, allows for the effects of MRFs in modulating the microbial population at varying phylogenetic levels to be studied. One specific study (Corrigan and Murphy, 2016b) focused on a number of commercial broiler trials and identified consistent alterations in the cecal microbiota of broilers, demonstrating increases in the phylum Bacteroidetes and decreases in the phylum Firmicutes (Figure 2).
Figure 2. Consistent alterations in broiler cecal diversity following supplementation with MRF (Corrigan et al., 2016b)
Of particular interest in this study was the noted effect of supplementation on the overall microbial diversity of the cecal microbiota, with a significant increase in overall phylum-level diversity being consistently noted in poultry receiving MRF in the diet. Such increases in microbial diversity are documented in the literature as being associated with an increased resistance to pathogen colonisation. On further examination, the studies also showed a consistent reduction in the overall prevalence of a specific phylum known as the Proteobacteria, which includes such wellknown pathogens as Escherichia and Salmonella. Additional analysis and studies have focussed on the microbiome-potentiating effects of MRFs to reduce the prevalence of a pathogen with particular resonance for consumer health: Campylobacter. A recent research trial demonstrated the additional benefits accruing from enhancing microbial diversity and the potential for reducing the Campylobacter load in the cecum (Figure 3, Corrigan and Murphy, 2016). www.animalhealthmedia.com
Figure 3. Modulation of Campylobacter colonisation by MRF
In essence, the use of MRF aids in the repair and rehabilitation of the gut microflora by increasing the overall diversity, reducing pathogen load and enhancing the gut’s resistance to pathogen colonisation. These studies are the first of their kind and represent a breakthrough in our understanding of how nutrition is intricately linked with the overall health and welfare of poultry. Considering how human health is intimately linked with the food produce we consume, one can also appreciate the additional benefits accruing from pathogen control in poultry production. Anti-microbial Resistance Antibiotic resistance has the potential to become one of the greatest problems of our generation, given the everincreasing rise in bacterial strains that are less and less sensitive to existing treatments. Currently, there is political pressure worldwide to restrict the use of antibiotics in animals to therapeutic use only, following the 2006 European Union ban on the use of antibiotics for all non-therapeutic use, such as antibiotic growth promoters (AGPs). The public is also aware of the increasing problem of antibiotic resistance, and this has led to heightened awareness regarding bacterial prevalence in meat products. The statistics behind the rise in resistance are startling, with almost 23,000 people dying in the US each year due to infections caused by antibiotic-resistant bacteria. Even more alarming is that since 1998, the US Food and Drug Administration (FDA) has only approved two new classes of antibiotics, with the vast majority of today’s antibiotics developed before the 1970s. Antimicrobial resistance arising in agriculture can negatively impact public health. Treatment of animals with antimicrobials important in human medicine or drugs of the same family or class can select for drug resistance in zoonotic pathogens (e.g., Salmonella, Campylobacter) that can be transmitted to humans through direct contact or indirectly through food or water. Resistant bacteria from animals or plants are part of a larger antimicrobialresistant ecosystem, and their resistant genes could find their way through a variety of poorly understood, indirect pathways to human pathogens. Bacteria from animals can be spread to food products during slaughter and processing, and this spread has been extensively documented for conventional foodborne pathogens such as Salmonella, Campylobacter and E. coli. More recent studies have indicated the emergence of enterococci resistant to antimicrobials, with direct transmission of resistant enterococci between animals and farm workers also being identified. More importantly, these studies have found identical or closely related subtypes in animals, food and humans, supporting the hypothesis that International Animal Health Journal 43
CLINICAL STUDIES the foodborne route of antibiotic resistance transmission is of significance. An increase in food safety concerns resulting from extensive antibiotic use has seen the poultry and livestock industries challenged in recent years, as meat free from antibiotics and disease has become a requirement within the European Union. Consumer demand for antibiotic-free meat has also increased within the US and other antibioticusing countries as a result of concerns about the rise in antibiotic resistance, making it necessary for producers to find suitable replacements for antibiotic growth promoters. Globally, it is recognised that there is no so-called “silver bullet” to replace antibiotic use in animal production, and producers will also have to focus on incremental improvements in hygiene and husbandry to address the issue. One drawback of the use of antibiotics is their nonspecific effects on the gut microbiome and the reduction in overall gut microfloral diversity (Vrieze et al., 2014). Without intervention, the use of antibiotics can lead to a vicious cycle in which their use can reduce overall microfloral diversity and select for the expansion of resistant species to the detriment of non-resistant commensal strains. This reduced diversity allows for the continued proliferation of resistant species and without intervention can have negative impacts on health and performance. One strategy to combat the negative consequences of antibiotic use is to repair and rehabilitate the microfloral diversity after their administration. Given the ability of MRF to enhance the overall gut microfloral diversity, it is an ideal solution to combat the negative consequences of diversity reduction. While there is still much to be learned — in particular, the mode of action — in the long term, such findings will have significant practical value in commercial production settings and will also have beneficial impacts on consumer health and wellbeing. The Microbiome and Metabolism Profiling microbial diversity within the gut is a key tool for studies trying to understand these microbial communities, but it does not provide direct evidence of the microbiome’s functional capabilities. The development of advanced computational approaches in the last couple of years has begun to allow us to predict what the effect of altering the bacterial community structure is on the overall function of the gut. This approach was recently used (Corrigan et al., 2015), and the study highlighted that numerous biological metabolic pathways were found to be affected as a result of supplementation with MRF (Figure 4). Some of the
pathways that were predicted to be enriched as a result of MRF supplementation included those associated with energy metabolism and were attributed to the observed increases in the Bacteroidetes group. In a general sense, we can now begin to attribute cause and effect when considering the way in which nutrients affect changes in the gut microflora, which are ultimately responsible for digestion and metabolite production. Summary This work provides new insights into the specific and reproducible effects of MRF supplementation on the composition of the bacterial community as a whole, rather than looking at specific beneficial or detrimental bacterial species. By making changes in the overall microbial diversity within the gut, we can aim to repair and rehabilitate the gut microflora, which can lead to reductions in pathogen load, enhance the gut’s resistance to pathogen colonisation and reduce the abundance of antibiotic-resistant strains. Improving the understanding of these comprehensive changes in bacterial community composition and how they might contribute to host health and performance is now key in the poultry industry. REFERENCES 1.
Corrigan, A. and Murphy, R. (2017). Effect of yeast mannan-rich fractions on reducing Campylobacter concentration in broiler chickens. Journal of Applied Poultry Research. (in press) Corrigan, A. and Murphy, R. (2016a). Effect of yeast based interventions on reducing Campylobacter spp., colonisation broilers. 67th Annual Meeting of the European Federation of Animal Science, Belfast, Ireland Corrigan, A. and Murphy, R. (2016b). Effect of dietary mannan-rich fractions on bacterial communities, a new approach with old data. 67th Annual Meeting of the European Federation of Animal Science, Belfast, Ireland Corrigan, A., de leeuW, M., Penaud-Frézet, S., Dimova, D. and Murphy, R.A. (2015). Phylogenetic and functional alterations of bacterial community composition in the broiler caecum as a result of mannan oligosaccharide supplementation Applied and Environmental Microbiology. AEM.04194-14 Vrieze, A., Out, C., Fuentes, S., Jonker, L., Reuling, I., Kootte, R.S., van Nood, E., Holleman, F., Knaapen, M., Romijn, J.A., Soeters, M.R., Blaak, E.E., Dallinga-Thie, G.M., Reijnders, D., Ackermans, M.T., Serlie, M.J., Knop, F.K., Holst, J.J., van der Ley, C., Kema, I.P., Zoetendal, E.G., de Vos, W.M., Hoekstra, J.B., Stroes, E.S., Groen, A.K. and Nieuwdorp, M. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. Journal of Hepatology, Volume 60, Issue 4, 824-831
Dr. Richard Murphy Research director at the Alltech European Bioscience Centre in Dunboyne, Ireland. He received a bachelor’s degree in biochemistry in 1994 from the National University of Ireland, Galway. Subsequently, he received a research scholarship from Alltech and earned his doctorate in the Department of Biochemistry at the National University of Ireland, Galway in 1999. Murphy maintains strong links with numerous universities and research institutions and has been appointed as an adjunct professor on the faculty of science and health studies at Dublin City University. He has also served as an external examiner for undergraduate degree programs and sits on the board of management of the National Institute for Cellular Biology at Dublin City University, where he is the external chairman.
Figure 4. Heat map reflecting hierarchical clustering of samples classified into clusters of orthologous groups of proteins metabolic pathways (Corrigan et al., 2015) 44 International Animal Health Journal
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International Animal Health Journal 45
Innovation and Collaboration: Combatting the Endemic Threat of Brucellosis Brucellosis is no longer a major concern to veterinarians and farmers in most developed countries, thanks to long-term control programmes. However, the disease still poses a major threat to both animal and human health in many lowerincome countries where veterinary infrastructure is less well developed and animal health less tightly controlled. Infection is endemic at high levels in large countries and regions, such as India, China and sub-Saharan Africa, and also in emerging livestock systems such as the peri-urban dairy farms, which have been expanding in Africa to supply milk and dairy products to urban populations. The World Health Organization estimates that around 400,000 people are infected each year by contaminated food and there are also many cases as a result of direct contact with infected animals.1
the prevalence to manageable levels, brucellosis can be eliminated by means of test and slaughter of infected animals. But this second strategy is very costly. “In high-income countries where the disease was once endemic, this approach has worked very well and brucellosis is now largely controlled. But there are a number of factors which mean that the same strategy is not so easy to apply elsewhere.” Barriers to Eradication Schemes in Low- and Middleincome Countries One essential difference is the characteristic of the production system and the degrees of central control and organisation that can be applied. “Brucellosis can be caused by different species of the bacteria that have a preference for different hosts. In several high-income countries that successfully eliminated brucellosis, the main problem was Brucella abortus in cattle, whereas in some of the regions where brucellosis is currently endemic, Brucella melitensis in goats and sheep is the main issue, and this species is actually more pathogenic to humans than the species that infects cattle. “In some of these settings, small ruminants are often kept in nomadic or pastoralist flocks and there is no identification system or movement control, so you can start to see why it is more difficult to apply a vaccination programme which covers the majority of animals. We are talking about places where animals can be moved and traded freely with no identification.”
The impact of the disease on smallholder farmers who rely on cattle and small ruminants as a source of income and food can be particularly devastating. Although the true prevalence of the disease is not known in most countries, it is estimated that the cost to smallholder farmers in South Asia and sub-Saharan Africa alone is around US $500 million per year.2 So can anything be done to control this important disease in those countries where it is endemic?
Since a test-and-cull programme relies on movement restrictions, tight controls by the veterinary services and commitment from local authorities are required in order for such a programme to be truly successful. The other main barriers to the success of control programmes in LMICs are farmers’ unwillingness to cull animals, and a general lack of disease awareness. Many smallholder farmers in LMIC countries rely on relatively small herds of goats or sheep for their livelihoods and as a food source, and so without compensation for culled animals, their livelihoods would be at risk – and they would be unlikely to co-operate with the system. In terms of disease awareness, many smallholder farmers and veterinarians do not fully understand the extent or impact of brucellosis on either animals or humans – often due to the lack of pathognomonic symptoms. As a result, the disease and vaccination may not be a high priority.
Professor Javier Guitián from the Royal Veterinary College (RVC) in London is a member of the Veterinary Epidemiology, Economics and Public Health Group and has a specific interest in the control of neglected zoonoses, including brucellosis. He believes that a number of factors need to be addressed before the disease can be successfully controlled in low- and middle-income countries (LMICs):
Talking About Solutions: Reducing Prevalence Through Vaccination “In my view we need to talk more about reducing prevalence, rather than elimination,” explains Professor Guitián. “And the main way to reduce prevalence is through vaccination. This is how it has been done in high-income countries and how it can be done in endemic areas.
“Successful control of brucellosis in developed countries has used two basic strategies. First you have to reduce the prevalence of the disease by vaccinating ruminants; that may take some years. Then, once you have reduced
“But to be successful you have to vaccinate over a period of time. It is not enough to vaccinate once or twice and just stop. Discontinuation has been a huge issue in some countries, simply because they lack the resources.
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CLINICAL STUDIES Professor Guitián comments: “Improved efficacy would be good – we are always looking for more effective vaccines – but the safety issue and the willingness of farmers to use the vaccine, and of governments to support its use, is more critical right now.”
A Barabaraig pastoralist child holds a goat so her young can feed in Mureru village, Tanzania – ©GALVmedKarel Prinsloo
“In some cases control programmes ‘on paper’ are not really being implemented, or implementation becomes erratic and is discontinued if resources are not available. There can also be a discrepancy between the theoretical vaccination coverage and actual coverage if veterinarians and farmers are reluctant to vaccinate.” According to Professor Guitián, one factor contributing towards a reluctance to vaccinate is that some veterinarians and farmers have concerns over the safety of current Brucella vaccines, and this is a key factor that needs to be addressed. “The current vaccines are live, so anyone administering them can accidentally infect themselves if they are not careful. Also, if you vaccinate pregnant animals, they can abort. This really limits the usefulness of the vaccine, because if people think it is not safe, and they do not perceive brucellosis as a major problem in their animals, then not surprisingly they are reluctant to use it. Understanding and consideration for farmers’ needs, perceptions and incentives are key considerations when developing a control plan.” The need for a safer vaccine was one of the catalysts for a recently announced US $30 million competition, the Brucellosis Vaccine Prize. An initiative of AgResults (a collaboration between the governments of Australia, Canada, the UK and US and the Bill & Melinda Gates Foundation), and implemented by the Global Alliance for Livestock Veterinary Medicines (GALVmed), it incentivises animal health innovators to develop and register a new vaccine that is efficacious, safe and viable for use against Brucella melitensis in small ruminants across endemic areas. www.animalhealthmedia.com
Beyond Vaccination: Towards a Landscape of Change As well as the development of an improved vaccine, research aiming to ascertain the incidence and impact of the disease in both animals and humans is currently being carried out by the RVC team in endemic areas in the Middle East, North India and West Africa. This work is also trying to ascertain the practices and attitudes of farmers and veterinarians. “The baseline data gathered from these activities can be used to formulate potential control programmes incorporating, for example, the strategic use of vaccines. We use simulation and economic modelling to find out which strategies would be most suitable for different areas,” says Professor Guitián. The expansion of livestock systems, such as the periurban dairy farms in Africa, and the absence in many cases of official control systems or surveillance capability, means that the epidemiology of brucellosis in many areas is not yet understood and its true burden remains hidden. Professor Guitián is involved in a project under the ZELS (Zoonoses and Emerging Livestock Systems) initiative. The aim of the project is to enhance capacity for diagnostics and veterinary epidemiology in West African countries and to fill important gaps that currently preclude the implementation of control programmes. Professor Guitián explains: “We are conducting fieldwork to determine the burden of disease, and testing pilot control programmes in periurban dairy farms. This should facilitate countries in the region establishing better surveillance and control in their peri-urban dairy farms, which are an expanding livestock system in which Brucella is known to be present.” Local economic and political factors are obviously important in many of the LMICs and have resulted in the discontinuation of control programmes in some countries. The key is to set realistic targets, says Professor Guitián. International Animal Health Journal 47
CLINICAL STUDIES the safety and efficacy of current B. melitensis vaccines in developing countries. Considerations for the MVP include: • Species: B. melitensis in sheep or goats • Safe: Safe for pregnant animals (less than 5% abortion) • Efficacious: More than 80% animals protected • Convenient: Single vaccination annually • Smallholder Farmer Friendly: Affordable cost, long shelf-life
A goat herder at the farm , Mara outside the Kenyan city of Eldoret, ©GALVmedKarel Prinsloo
“In my experience you have to have a realistic objective for control; I think we need to be more modest with objectives, such as reducing prevalence rather than aiming for elimination. Elimination from a country requires animal identification, the ability to implement movement restrictions, good surveillance and diagnostic capabilities that are often not available in endemic countries. For this reason, elimination in the short term is not a realistic objective.” Simply reducing the prevalence of brucellosis in countries where it is still endemic but resources are limited may be a more realistic target but is still far from easy. It calls for a greater awareness, understanding and appreciation of the impact of brucellosis on animal and public health. It also requires a collective will and determination by the local authorities to implement and continue a realistic and sustainable long-term programme of control measures, built around a safe and effective vaccine, and including suitable incentives to encourage buy-in from farmers and veterinary services. Finally, the chances of success will be greatly enhanced by the development of a vaccine which meets the practical needs and realities of LMICs and thus will be acceptable and used by local veterinarians and farmers. REFERENCES 1.
WHO estimates of the global burden of foodborne diseases: http:// www.who.int/foodsafety/areas_work/foodborne-diseases/ferg/ en/ 2. Bill & Melinda Gates Foundation, Economic Impact Estimate, July 2014. Includes annual productivity, reproduction, and mortality losses
Brucellosis Vaccine Prize The devastating economic and public health impact of brucellosis in endemic countries has prompted the development of a US $30 million competition, aimed at incentivising the development of a new vaccine. The AgResults Brucellosis Vaccine Prize competition is making a total of US $30 million available to organisations that can develop a suitable vaccine that is efficacious, safe and viable for use against Brucella melitensis in small ruminants across the developing world. The winning vaccine will need to meet all the requirements set out in the minimum viable product (MVP), and will ideally overcome all current hurdles that inhibit 48 International Animal Health Journal
For the grand prize of US $20 million, the winning vaccine will need to both meet the requirements of the MVP and obtain regulatory registration in any one of the following regions/countries: EU, Japan, USA, Canada or Australia. The competition is likely to be of interest to animal health, biotech and pharmaceutical companies, as well as academic and research institutes. It is expected to last at least 10 years. Brucellosis is a costly and highly contagious disease, which affects production animals such as cattle, sheep, goats and pigs, causing abortions, reduced milk production, weight loss, infertility and lameness. The effects of the disease are particularly devastating for smallholder farmers in low-income countries, where small ruminants are a crucial source of income and food. Wholesale vaccination of livestock can be a costeffective way of controlling the disease and limiting its impact on both human and animal health. However, the existing brucellosis vaccines are not safe or efficacious enough to use in developing countries. Current vaccines do not provide protection across different species of animal hosts, are unsafe for use in pregnant animals, have variable efficacy, and can harm humans. A new vaccine that addresses these shortcomings would deliver lasting benefits to smallholder farmers’ health and livelihoods. Applications for the first phase of the competition are now open, with 10 Milestone 1 payments of US $100,000 available to potential solvers. These will be awarded to the best applications on a quarterly basis (ending in November 2017), so solvers are encouraged to submit applications as early as possible in order to increase the chance of being accepted. Full details and an application form can be found at www.brucellosisvaccine.org.
Amy Tranzillo Project Manager at Global Alliance for Livestock Veterinary Medicines (GALVmed) an international notfor-profit organization, where she manages the implementation of the Brucellosis Vaccine Prize Competition. Prior to joining GALVmed, Amy spent 18 years at Zoetis where she has held management roles in new product development, regional marketing, and global marketing analytics. While at Zoetis, she worked to develop and commercialize livestock vaccines, feed additives and pharmaceuticals in Europe, USA, Australia, New Zealand, Brazil, India and Latin America. Amy holds a B.S. Degree in Animal Science and Agricultural Business from the University of Delaware, and is a certified Yoga teacher. Email: firstname.lastname@example.org
Volume 4 Issue 2
APPLY NOW FOR THE US $30 MILLION BRUCELLOSIS VACCINE PRIZE Help transform lives by combatting brucellosis
The AgResults Brucellosis Vaccine Prize, a US $30 million prize competition, invites vaccine developers (‘Solvers’) to submit their proposals for – and ultimately develop – a suitable vaccine that is efficacious, safe and viable for use against Brucella melitensis in small ruminants across the developing world.
LEARN MORE AND APPLY ONLINE:
THE AGRESULTS INITIATIVE IS A PARTNERSHIP BETWEEN:
International Animal Health Journal 49
This is not an official competition document, all prizes and all requirements regarding the competition are subject to the official Competition Rules
MANUFACTURING AND PACKAGING
Profitable Modernisation For Those Who Are Used to Saving Money The decision to buy something new, whether new furniture for the home or, on an industrial scale, replacing old equipment with more efficient equipment, or even a radical shift from manual labour to automatic, is always linked with a fundamental analysis, and simply in terms of convention, with a calculation of the expediency of such changes. It is appropriate to take into account all factors, to weigh everything sensibly, and to adopt the most suitable decision as the end result â€“ but this is not the most trivial decision. Marketing and financial departments analyse and calculate, depending on market conditions and market potential in a given country, basic indicators which are later introduced into the company's development strategy and further investments in production. In this article, we explain how to select packaging equipment, taking into account real current and potential future requirements (the appearance of new products, increase in production volume). We also draw your attention to the main indicators which will help you save significantly on pharmaceutical manufacturers in terms of the manual process of secondary drug packaging. It is important from the start to resolve the issue of the packaging material itself. It must be determined in which form the packaged product will be most reliably protected, most convenient, and physically available for use by the
50 International Animal Health Journal
end user, whether there will be a guaranteed indicator of initial opening, protection from children in accordance with GMP standards, whether the package will be ecologically and easily developed, and simply if the information on the package itself about the product and its usage conditions will be adequate (the manufacturer, the number of parts, the release date, the expiry date, the dose, the conditions for use, the contraindications, the storage conditions, and information for visually impaired patients). All of these packaging properties directly hold important information on the product contents for the patient/end user. Without a doubt, the cost of the packaging material itself is important, and it in turn depends on the level of complexity of the packaging, the thickness of the box, its quality, finishing, and, of course, on the quantity. Everyone knows that acquiring new equipment is connected with a serious investment and it must always be justified. In the standard business plan calculation by financial experts, everything leads to a definite ROI indicator, the coefficient for the return on investment. This indicator is one of the main ways to measure the efficacy of your investments. An important parameter in deciding about purchasing new packaging equipment is the existing or estimated volume of production. If medical items (syringes, ampoules, injectable pens, needles, inhalers, vials, tubes) in their various combinations are packaged in quantities from 100,000 packages but no more than 1,000,000 packages per year, then it makes sense to talk about the advisability of using manual labour. If the production volumes from the start are directed at the release and packaging of more
Volume 4 Issue 2
MANUFACTURING AND PACKAGING than 1 million product packages per year, then it is clearly reasonable to talk about the semi-automation of the packaging line. The principle of the semi-automatic line of work lies in the fact that the creation and sealing of packages will occur automatically, while the insertion of medical products will be done by hand. The partial replacement of manual labour by semi-automatic packaging systems allows small investments to guarantee the replication of quality packaging, an increase in the quantity of packages, decreased staffing expenses and increased production efficiency. If the pharmaceutical production plans are sufficiently ambitious and the expected production volume is in the range of 3 million to 5 million packages per year, then it is impossible to avoid automatic packaging lines. Such production volumes are difficult to ensure merely with staff packagers. The replication of quality will also be doubtful, as the human factor will undoubtedly significantly influence the efficiency of packaging production, the expenses for staff will be considerable, and additional expenses will increase. Let's examine, as an example, the pharmaceutical market in India and analyse how, even under the conditions of quite low salaries (on average, a worker in a pharmaceutical manufacturing company earns 1200 euros per year), production modernisation and the replacement of manual labour by machine labour results in positive economic performance, and investments in quality European equipment pay for themselves in five to seven years, taking into account only the replacement of manual labour and the decrease in the end cost of the package itself, without taking into account the economic effect from the production of products and the effect on ROI of the cost of the product itself. And if we look at European pharmaceutical manufacturers, then packaging equipment directed at large volumes enables a considerable decrease in spending on staff and packaging. Packaging lines, depending on the intensity and volume of their workload, are paid off (break even) within one to five years; that is, the investment in packaging equipment itself is justified and the line begins to earn profits. When the production volume is from 5 million to 24 million pharmaceutical packages per year, ensuring product packaging for this production may only be done by fully automatic, high-speed packaging lines. The return on investment for such equipment will in the long run lead to covering the production volume, decreasing the cost of the packaging materials and, of course, decreasing the expenditures on staff, which, depending on the country, allows for savings from hundreds of thousands to millions of euros per year. And those are serious figures, requiring deeper analysis and calculation. From all of the information above, it seems we have several particularly important parameters which must be taken into account when calculating general production expenses, expenses for production and packaging, and the ROI on equipment: a) the cost of the packaging material (it affects the ROI of the packaging equipment itself); b) the volume of estimated or actual pharmaceutical production (the quantity of packages per year); c) the staff expenses (main and supplementary). The choice and decision are up to you, and we, the producers of packaging equipment, will help you make those decisions in a competent, reasonable manner. www.animalhealthmedia.com
Christoph Hammer CEO of Dividella AG since 2015, previously held the position of Chief Technical Officer and Deputy CEO at Dividella in Grabs for 14 years. He holds a lot of experience in the food and pharmaceutical packaging industry in the fields of engineering and consulting. His expertise covers the capital equipment industry, and through extensive sales activities he has an excellent knowledge of international markets. Christoph was educated as an electrical engineer with additional degrees in Business and Production Technology. Email: email@example.com
International Animal Health Journal 51
MANUFACTURING AND PACKAGING
The Revolutionary Solution Transforming the Veterinary Market – Magnesium Alloys The veterinary market in the UK alone has grown by 1.9% annually since 2012 (CVS Group plc, 2017) and, looking at other geographies, US Animal Health Institute member companies spend around 10-12% of their sales investing in new innovations in animal health (AHI, 2010). Scientists and those working in the veterinary industry are continuing to look for improvements to maintain the health of animals, whether this be through drug delivery or the implementation of medical implants. The veterinary industry, however, to some extent, is facing the same challenges as the medical industry. Owners of pets and animals are investing more and it is therefore important that the best possible products reach market through the discovery of innovative solutions to medical and healthcare problems. A new state-of-the-art solution which has recently been developed for use in the veterinary market, for both drug delivery and in medical devices, is magnesium alloys. Magnesium alloys have already been successfully developed and used in CE marked cardiovascular scaffold implants in humans and are now beginning to be used effectively in veterinary auto wormers, allowing a drug to be delivered over specific intervals rather than at one time. So, what are magnesium alloy’s properties and how have they helped with recent market breakthroughs, such as in veterinary auto wormers? Magnesium for Applications in Animals Bioresorbable materials, such as magnesium alloys, are beginning to be tested more and more for use within the animal health and veterinary industries. These bioresorbable materials are advantageous and can be used to address a number of challenges, as they achieve optimum healing by resorbing at a steady rate. Other examples of bioresorbable materials include polymers; however, polymers are often associated with low strength, and have been known to cause foreign body reactions. Further disadvantages are the time polymers can take to resorb compared to other resorbable materials. Magnesium alloys bring to the market a revolutionary alternative to polymers. Magnesium, unlike polymers, is a naturally occurring element within the body. Although it has previously been associated with the aerospace industry, it is biocompatible and has now begun to be tested for and used in a variety of medical devices in both animals and humans. Research into magnesium is a continuous process; however, it is already clear that magnesium demonstrates bio-compatibility, as well as biosafety. It is proven that magnesium can be used in the treatment of animals, and we now know what the outcome will be and that the material has the potential to be used in a wider range of applications for animals. 52 International Animal Health Journal
Studies of human blood following the use of magnesium within the body revealed little change to the composition and no disorder to the liver or kidneys (Zhang et al. 2009). Tests with magnesium alloy implants among rabbits have also revealed that the magnesium scaffold performed very well during degradation and osteogenesis, rendering magnesium a useable material for orthopaedics (Liu et al. 2014). This demonstrates its use among both humans and animals. Magnesium has faced challenges, including its potential to degrade too quickly under physiological conditions. However, the recent advances in magnesium alloy technology mean that magnesium can be tailored to degrade at specific rates, taking advantage of the degradation process. This means that magnesium can now be used within animals for a variety of different applications. The Manufacturing Process A manageable step-by-step process is implemented for the manufacturing of magnesium alloys, which can then be used within medical applications for animals. A good example of a company implementing a rigid process for magnesium alloy manufacturing is Magnesium Elektron, a Manchester, UK-based developer, manufacturer and supplier of magnesium, across markets including biomedical and pharma. The bespoke Magnesium Elektron manufacturing process results in the SynerMag® magnesium alloy product for biomedical applications. The SynerMag product is developed in the company’s SynerMag® Technology Centre, built as part of a $2.5M investment in 2012. The centre is a dedicated manufacturing facility, incorporating state-ofthe-art laboratories, casting, extrusion and heat-treatment facilities. Magnesium Elektron worked to achieve ISO 13485 certification in 2014. The certification is an internationally recognised quality standard for medical devices. SynerMag’s alloy designs, manufacturing and business processes – including supplier controls, traceability and documentation – are fully compliant with medical industry standards. The process begins with magnesium heated in a furnace until molten. The alloying elements are then added to magnesium, with all raw materials selected based on their impurity content. The magnesium used in this process is of the highest grade of commercial volumes available on the market. Once this step has been implemented, the metal is then cleaned to remove any traces of impurities. Then the molten alloy is cast into billets (a casting produced in the foundry that will need further processing before the finished good is manufactured). The casting parameters are critical in determining the structure of the material. This, in turn, affects the mechanical properties and corrosion rate. Magnesium Elektron uses computer modelling to simulate the casting parameters, in order to develop the very best cooling conditions for each alloy. The next step of the process involves the cast billets being machined to a smooth surface. They are then Volume 4 Issue 2
MANUFACTURING AND PACKAGING Examples of Use Magnesium alloys have been used effectively within animals for a number of different applications, including osteosynthesis and for drug delivery. Osteosynthesis applications have previously, typically been produced from titanium and stainless steel, however, these are permanent materials and often require removal with secondary operations. Polymers are bioresorbable materials which have been used in this application; yet polymers, as well as taking longer to degrade than magnesium, have the potential to intake water during degradation, which leads to a loss in structural integrity, as well as size (Hofmann et al. 2009). For drug delivery, it was hitherto very difficult to control the release of a drug into an animalâ€™s system at set intervals, with a drug often released upon entry into the body. An effective example of magnesiumâ€™s use in osteosynthesis in comparison with polymers was by Marukawa et al. (2016) using Magnesium Elektronâ€™s alloy, SynerMag, to evaluate the effectiveness of the magnesium alloy implants in comparison to PLLA polymer implants, within beagle tibia fractures. The study discovered that 100% of the PLLA screws were broken within the timeframe. In comparison, only one in 24 magnesium screws broke. It also found that four out of six PLLA screws loosened within four weeks, whereas all magnesium screws remained tight. This shows both the strength and obvious mechanical benefits of magnesium, which can be used in high loadbearing areas; the study also found magnesium to have good biocompatibility.
ultrasonically inspected to locate any defects. Following this, the billets are then ready for extrusion and they are heated to a carefully determined temperature. They are placed in a heated extrusion press and then pushed through a die. The die and extrusion press are also at critical temperatures. The heat parameters combined with the speed of extrusion determine the change in mechanical properties of the extruded material, comparative to the cast. Once the extrusion has occurred, the material is cut into the correct lengths and samples are taken for testing. During melting, casting and extrusion, all the parameters are logged in real time by a central computer system. These parameters are then compared to the end test results for statistical process control. The summary of product characteristics (SPC) was a key aspect in fine-tuning the manufacturing process and removing variation within the product. All of these processes, from the supply chain, through manufacturing and testing are risk-assessed, set up and controlled according the ISO 13485 standards. So, following the manufacturing process, which applications for animals have magnesium alloys been used in? www.animalhealthmedia.com
Figure 1. (a) Shows the monolithic magnesium screws, (b) shows the anodised magnesium screw, (c) shows the PLLA screw. Below (d-f), the first two screws (d and e made from magnesium) stayed intact, whereas the PLLA fractures at four weeks after implantation (Marukawa et al. 2015).
A second example once again used SynerMag and was conducted with biodegradable magnesium plate/screw osteosynthesis systems implanted onto the frontal bone of adult miniature pigs. Results showed the implants kept their shape during implantation and stayed in place with no screw loosening (Schaller et al. 2016). Furthermore, a pilot study conducted by Windhagen et al. (2013) found that resorbable magnesium screws were radiographically and clinically on a par with titanium screws. They also found that magnesium did not cause any foreign body, osteolysis or inflammatory reaction. Within drug delivery, magnesium has been equally as successful. A specific example is in veterinary auto wormers, in which a galvanic cell is used. This uses the process of magnesium corrosion to release oxfendazole, over a controlled, set period. In this particular case, an iron weight is coupled with a magnesium rod to form a galvanic cell. International Animal Health Journal 53
MANUFACTURING AND PACKAGING This is held in a polymer cylinder containing several drug capsules. The galvanic corrosion forces the magnesium rod to shorten over time, creating an aperture for drug release. Each capsule releases its load at set intervals as the magnesium rod continues to corrode shorter.
Figure 2. Veterinary auto wormers use magnesium corrosion to give timed delivery of drugs. The device also utilises a galvanic couple (Mg and Fe) to design where the device corrodes first.
Although magnesium alone has a quick resorption time, corrosion can be controlled through alloy design, processing and the coating of the alloy. It is therefore likely to replace problematic polymers in certain applications (Song, 2006), specifically in high-impact areas. As seen in use by Marukawa et al. (2015), the PLLA screws were prone to breakage. Conclusion Magnesium is therefore a material which can be used within multiple veterinary applications. This includes, among others, for osteosynthesis and drug delivery and offers great promise for other veterinary applications. Magnesium demonstrates biocompatibility, as well as biosafety, and can resorb over specified periods of time. This therefore means it is advantageous for use in animals over other bioresorbable materials such as polymers. Using magnesium, instead of titanium or steel, also eliminates the need for re-operation, saving time and money. https://www.magnesium-elektron.com/global-downloads/ REFERENCES 1.
CVS Group plc. - https://www.ibisworld.co.uk/market-research/ veterinary-services.html 2. AHI - http://www.ahi.org/about-animal-medicines/industrystatistics/ 54 International Animal Health Journal
3. Zhang E, Xu L, Pan F, Yu G, Yang L and Yang K. In vitro and in vivo evaluation of the surface bioactivity of a calcium phosphate coated magnesium alloy. 2009. Biomaterials, Volume 30, Issue 8, Pages 1512-1523 4. ResearchGate, Liu et al. - https://www.researchgate.net/ publication/264637365_An_animal_experimental_study_of_ porous_magnesium_scaffold_degradation_and_osteogenesis 5. Hofmann D, Entrialgo-Castano M, Kratz K and Lendlein A. Knowledge-based approach towards hydrolytic degradation of polymer-based biomaterials. 2009. Advanced Materials. 21, 32373245. 6. Marukawa E, Masato T, Takahashi Y, Hatakeyama I, Sata M et al. Comparison of magnesium alloys and poly-l-lactide screws as degradable implants in canine fracture model. J Biomed Mater Res Part B 2016:104B:1282-1289. 7. Schaller B, Saulacic N, Imwinkelried T, Beck S, Wei Yang Lui E et al. In vivo degradation of magnesium place/screw osteosynthesis implant systems: Soft and hard tissue response in calvarial model in miniature pigs. Journal of Cranio-Maxillo-Facial Surgery 44 (2016) 309-317. 8. Windhagen H, Radtke K, Weizbauer A, Diekman J, Noll Y, Kreimeyer U, Schavan R, Stukenborg-colsman C and Waizy H. Biodegradable magnesium-based screw clinically equivalent to titanium screw in hallux valgus surgery: short term results of the first prospective, randomized, controlled clinical pilot study. 2013. Biomed Eng Online 12:62. 9. Song G. Control of biodegradation of biocompatible magnesium alloys. Corrosion Science (2006:49:4 1696-1701)
Paul Lyon Programmes Technology Manager for Magnesium Elektron, a Manchester, UK-based developer, manufacturer and supplier of magnesium. In his role as Programmes Technology Manager, Paul is responsible for overseeing the development of bespoke magnesium alloys for use in a range of diverse markets including biomedical, pharma and aircraft interiors. He has more than 25 yearsâ€™ experience leading teams in alloy development and promotion and is a member of the Senior Leadership Team at Magnesium Elektron. Paul holds a first-class honours degree in metallurgy, and is a chartered engineer. Paul is also the author of numerous magnesium alloy publications in the USA & Europe and patent-holder of several magnesium alloys. Email: firstname.lastname@example.org
Volume 4 Issue 2
Teaming up for animal health
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International Animal Health Journal 55
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Leadership Lessons from Extraordinarily Successful Executives - Part 2 Welcome back for Part 2 of Extraordinarily Successful Leaders! As I explained in my introduction to Part 1, I had long wondered why certain companies in our industry were very successful while others were not. Over time, I uncovered a host of reasons. However, a common factor that appeared in almost every case was effective senior leadership. So, I set about interviewing as many of those leaders as I could to learn what skills and practices made them and their companies so successful. I uncovered ten key traits. In Part 1, I examined the first five: productivity, delegation, coaching, dispute resolution, and personnel challenges. In this article, I explore emotions, leadership traits, self-doubt, inspiration, and authenticity. Then, as an added bonus, I share some life lessons that these executives learned from their pets! So, let’s get started. Managing Emotions Some people believe that emotions have no place in the workplace. Others feel that real success is impossible without passion. So, the appropriate expression…or suppression…of emotion can be a challenge for any leader. Aaron Schacht tries to anticipate which team members might have an emotional attachment to an issue because he knows that those emotions eventually will surface during discussions. “I try to think first, act next, and feel last.” If you reverse that order, Aaron says, your decisions may be more emotional than logical and, consequently, might feel good but play out in ways that are less than optimal. Aaron’s team includes people with strong personalities and firm convictions. “That’s a very positive dynamic,” he notes. “The challenge comes when those personalities and convictions are in conflict. As a leader, I have to sincerely acknowledge their beliefs but then focus their energy on the key business issue. I become a facilitator to get each team member to view the issue from different, but nonetheless rational, perspectives.” Aaron acknowledges that his efforts toward reconciliation are not always successful. “In those cases, I let everyone know that I’ve heard their opinion and then I make the decision. I can live with disagreement, but not misalignment.” Craig Wallace allows emotional discussions “until I feel an edge that’s personal.” He expects his team to “leave their egos at the door and do what’s right” and intervenes when discussions get personal. Don Chew wants his team to be “passionate and engaged, but not at the expense of other people.” Whenever emotions need to be tempered, he directs his team to “focus on the issues, not on the person. Focus on what we want to accomplish.” Jim Herbert sometimes lets the discussions run their course because he feels that “emotions need to be 56 International Animal Health Journal
respected, even if they sound childish.” He sees his role as that of a guide helping his team navigate through emotionally-charged issues. When the team reaches an apparent impasse, he often suggests that they stop, think about the issue overnight, and then get back together the next morning. Larry Miller views emotions as a big positive. “If people are engaged emotionally, it creates energy, and that’s a good thing. It means that people really care about the issue.” Like Aaron and Craig, Larry encourages his team to focus on the company’s goals and reframe the emotional issue in terms of a company priority. For him, it’s more important to “see where the issue fits in the bigger picture.” Mark Heffernan observes that people in science and development can be very passionate. When confronted with an emotionally-charged situation, “my immediate thought is how do we solve this. It’s a matter of working around to find the right solution. And that means looking at it from everyone’s perspective.” Niclas Lindstedt believes that there is room for emotion and passion in business. “People can be extremely productive when they are emotionally engaged. Animal health people are doing good and helping by solving problems and issues for vets, animal owners, and animals. So, for Niclas, emotion and passion drive people’s heart and mind to good outcomes. Lisa Conte also supports emotions in the workplace, particularly if the workplace is a startup company. “You’re asking so much of people. If they care and are passionate, you need to honour that…to show them that it's not just a job. We're doing something more here.” In fact, when Lisa identifies a team member who lacks passion, she urges them to “catch the excitement.” If they don’t, she “weeds them out.” Choosing Leaders A good leader is worth their weight in gold. However, not everyone measures up. So, what makes a good leader? Authenticity, integrity, and a drive for growth. For Aaron Schacht, the two most essential attributes are listening and courage. “They’re linked.” A leader must be willing to listen to what other people have to say. Then, the leader must have the courage to act on what he’s heard even though he may not have all of the facts. Aaron also notes that “you become a much better leader when you care less about getting credit and more about giving credit.” Carsten Hellmann looks for authenticity in leaders. “Since most executive-level people have similar credentials, I look for those who are honest and open with their teams, who can engage their teams toward goals.” For Craig Wallace, trust is the foundation of leadership. “Trust is such an important element of any relationship and such a critical value in terms of leadership.” Craig knows that sharing trust occasionally can be disappointing, but he thinks it naïve to expect that disappointments won’t Volume 4 Issue 2
SPECIAL FEATURE happen. Some folks aren’t ready, while others aren’t capable. Integrity, honesty, and doing the right thing are essential traits for Don Chew. “Work hard and treat others how they want to be treated. Understand the business, analyse the issues, and then solve the problems. Earn the respect of peers and those with whom you work.” If Don were to advise a search committee charged with replacing him, he would tell them to find a person “who has the requisite skills and experience, who believes in servant leadership, and who will dedicate themselves to the organisation in an unselfish way.” Jim Herbert knows he’s found the right leader when that person demonstrates the ability to listen. “We were given two ears and one mouth for a reason. Good leaders are those who listen to the other side.” He advises companies to create a system that will foster and encourage good leaders. Those leaders then need to hire people they respect. Larry Miller looks for leaders who understand the entire organisation and have “an appreciation of how the whole choir needs to sing together.” They certainly must have the required technical skills, but they also must be honest, reliable, and accountable. “These are table stakes.” Larry also feels that a true leader has empathy. “Never ask anyone to do anything you wouldn’t do or haven’t done.” Successful leaders don’t care what’s in it for them. Instead, they focus on developing their team members and building their company. That creates an environment that attracts more good people. “A leader must have passion and drive for whatever they’re doing,” says Mark Heffernan. “They also need really strong emotional intelligence. They’re dealing with complex intra- and inter-organisational relationships. They can’t be someone who comes in, bangs on the table, and then expects things to get done.” Experience has been an important success factor for Mark. It has enabled him to quickly assess situations and adjust his approach accordingly. “It helps to have dealt with challenging individuals…including those who can be quite destructive to an organisation.” Niclas Lindstedt adheres to his core value of honesty. “There are certain things I wouldn’t reveal, but I never lie just to get something done.” To illustrate the relevance of his point, he says, “Look at dogs. They can sniff out who is genuine, who is really your friend, and who is just pretending. People will eventually sense if you’re genuine.” For Rob Joseph, vulnerability is a critical leadership skill. “If you project the sense that everything you do is right, you run the risk of alienating the people around you. People know that, sometimes, everybody makes mistakes and everybody gets things wrong.” Rob notes that high productivity entails occasional failure and ads that true acceptance of failure requires vulnerability. Without that vulnerability, it is hard to get everyone to work together to overcome the failure. “One of the most important aspects of leadership is relentless problem-solving,” says Lisa Conte. She doesn’t accept “no” until all alternatives have been explored. “For me, ‘no’ is just a strong ‘maybe.’ At the end of the day, after you've looked at all possibilities, ‘no’ may in fact be ‘no.’ But I don't just accept it right off the bat.” Self-doubt Doubt plagues every decision-maker at one point or www.animalhealthmedia.com
another. Leaders doubt if they hired the right person for a key position or approved the right strategy for their company. The key to overcoming self-doubt is whether the leader treats it as a lens or a wall. Aaron Schacht recalls doubting if he hired the right person. While the extra resource was desperately needed, his gut told him it was the wrong person. “A quick solution that may have a fatal flaw is not a good solution. It’s always better to take the time to find the good solution. In this case, the expedient ‘solution’ cost me a lot of time, and I still didn’t get all the work done. Ignoring the doubt…my gut…creates energy vampires.” Carsten Hellmann admits to doubting himself at times. Everybody makes the wrong decision at some point. The key is to learn from each one. “Success is making fewer mistakes than good decisions. Take balanced risks.” Craig Wallace doesn’t doubt his decisions as much as he doubts the potential outcome. Like Aaron, he’s sometimes had a gut feeling that a decision wasn’t the right one, and later regretted that he didn’t honour that feeling. “I question a lot before we make the decision. However, once the decision is made, the questions are behind me. If we’ve gone through the questioning process, then we’ve reached a conclusion that makes sense for the organisation.” Jim Herbert is a man of action. When he must make a decision, he considers all factors, weighs alternatives, assesses shortcomings, and evaluates obstacles and pitfalls. He then picks a course of action, and moves forward. Don Chew relies on a core group to provide input for major decisions. He contends that this improves their decision-making process. However, whenever he doubts a decision, he leans on his fundamental beliefs and values. He knows that his team is “trying to do the right thing with honesty and integrity. We may not make the right decision every time, but at least we’re going to think through the issue and give it our best effort. If we always do the right thing, our business will grow and prosper.” Like Don, Larry Miller asks his team for honest feedback. He also examines how the potential decision will impact others. “The more of the horizon you can see, the better you can craft your response in a sensitive and proactive manner.” In addition to his team, Mark Heffernan also relies on his advisors, all of whom have deep experience. Since big decisions often have big consequences, he makes sure he considers all aspects before moving forward. Niclas Lindstedt recalls that “when I was a student, I thought I knew something. When I became an engineer, I found that I didn’t know much. And, when I became a vice president, I realised that nobody else knew everything, either.” Believing is sometimes seeing, not always the other way around. Being humble about what he knows and honest about what he doesn’t allows him to ask the right questions. “It’s more about accepting that I don’t always know.” Rob Joseph makes decisions intuitively. “The organisation looks to its leadership for certainty. They want them to define the vision, define the future, and to remain confident in their choices. Leaders who vacillate and waver engender fear.” Rob characterises himself as a Type A leader. “That’s not the only leadership style, but it works for me. Any leader should consider input from those International Animal Health Journal 57
SPECIAL FEATURE around them. The reality of leadership is that it’s neither a democracy nor an autocracy. At some point, someone has to make the call. Many decisions are made collectively. But for the really tough ones, someone has to say that this is the direction we’re going.” While Lisa Conte admits to frequently doubting her decisions, “that doesn't mean I'm not productive and that I don't deal with something that is thrown at me, make a decision, and move on. Nonetheless, it's constant selfexamination.” A high level of self-confidence allows her to re-examine her decisions. “Almost any mistake can be fixed or learned from.” When she was a child, Lisa’s godmother always forgave her mistakes “as long as you learned something.” “My parents wouldn't forgive me, but she always would forgive me.” Inspiration Inspiration can enhance the level of anyone’s performance. But should leaders provide that inspiration…or rely on team members to find their own? Aaron Schacht surrounds himself with people who are self-motivated. “If you constantly have to motivate people to just get the basics done, you probably don’t have the right people. The leader spends all of their time mitigating that. It’s an energy vampire.” However, with the right people, Aaron can challenge them with riskier projects to build skills and create value. For himself, Aaron loves “making a significant difference in the health of creatures on this earth through technology. I now realise what pets mean to people. My current work is every bit as gratifying as working on a human condition. And, in some ways, it’s more important.” Carsten Hellmann inspires his team to be “stronger, faster, and better.” However, he cautions them that not all efforts result in success. “If we fail, we try to fail fast!” He encourages his team to acknowledge the failure, stop and fix it, and then move on. Failure examined is knowledge. Failure accepted is true failure. For Craig Wallace, inspiration comes from seeing his team grow and prosper. “I get a real charge from watching people experience success and develop in their career.” He loves creating opportunities for his people to improve their lives by helping animals and strengthening the humananimal bond. When failure strikes, Don Chew reminds himself and his team of “our vision and mission, and all of the great accomplishments we’ve had.” Don cites past successes as proof of their ability to meet the challenges of tomorrow. “Just because something doesn’t work now, doesn’t mean that we don’t have the ability to support the organisation and do many more great things.” Jim Herbert is inspired by “doing well for our shareholders by doing good for the customers we serve.” He reminds his team that they can, at any time, improve the status quo. However, he also cautions them that they “don’t always have to be right and…shouldn’t worry about being wrong occasionally.” Larry Miller visualises what the future can be and what his company can achieve. He evaluates what they can control, what assets and resources they have, and how much untapped potential exists. “When you look at those things, you always see opportunity to do things differently. The vision of where we can go, what people can contribute, is inspiring. To have been part of it at Point A, help it get 58 International Animal Health Journal
to Point B, and then see it go to Point C is inspiring.” If an effort fails, Larry leads his team to evaluate what was good, bad, and unexpected. He then sets a new course of action, which helps to get people re-engaged. “Defining new roles and priorities to complete the mission and visualising what success looks like” helps focus everyone’s energies. Mark Heffernan is a self-proclaimed high-energy person. As such, he’s often thinking of new, creative ways to do things. “My energy rubs off on the team. They feel that they’re on a unique and interesting journey. Everyone develops an energy and passion for what we’re doing. And that creates a culture that attracts like-minded people to join the team.” “Failure is just a part of life,” Niclas Lindstedt commented. He inspires his team by pointing out that, after failure, they know at least one thing that doesn’t work. “I’m very competitive, and I hate to lose. When I’ve done everything that I thought was right, and fail, I figure out where I went wrong and learn from it. Then, I lick my wounds and go forward.” Rob Joseph feels that recovery from failure starts with the leader. “Leadership really earns its money in times of crisis and failure.” To rekindle inspiration, a leader must provide clarity and direction. “It’s very important to give people a sense for moving forward.” Rob also believes that integrity and loyalty each play a role. “You have to build an organisation that attracts people whose values align with those of the organisation. They have a guiding light.” For Lisa Conte, “Bringing innovative medicine to the world is remarkably rewarding. It’s not just a job.” That philosophy inspires her team. It also keeps them focused on the goal when things don’t go as planned. Their solution? “Back up and find a way around the wall.” Lisa always gives her team time to analyse what went wrong. Meanwhile, she works on “Plan B, Plan C, and Plan D.” Authenticity It is impossible to be true and transparent to others if you are not first true to yourself. Living one’s core values is the essence of authenticity. Aaron Schacht’s guiding principle is integrity. “It all stems from that. If something is not integral to what I’m about, or what I said I would do, or where I come from, or what I believe in, it’s not going to get any of my time. Ultimately, if I’m true to myself, I cannot fail in all my other endeavours, even if someone calls what I do ‘failure’.” “I believe in people until they prove me wrong,” says Carsten Hellmann. He believes that people want to do their best if they have the right circumstances. However, “if I find out that people are here for the wrong reasons, they’re not part of my team anymore.” Craig Wallace looks for the good in people. “You really work to show people that you care about them and that you trust them. And that gets balanced with expectations.” It’s a very simple equation. “It is very difficult to be true and transparent to others if you are not first true to yourself,” says Don Chew. “I’m a very trusting person. As an organisation, we’ve been very trusting. Unfortunately, we have had to learn some painful lessons. Those lessons remind us to honour our values and develop good processes and controls.” Volume 4 Issue 2
SPECIAL FEATURE Jim Herbert wants this on his tombstone: “He was fair, he was honest, and he was as hard on himself as he was on others.” He also misses the time when a handshake was a bond and people recognised that. He nonetheless expects people to be true to their word. Larry Miller frequently asks himself if he’s doing the right thing. He also encourages his team to treat people like they would want to be treated, and to be honest, hard-working, and ethical. The essential value for Mark Heffernan is respect for others, including both peers and subordinates. “Whatever you do, and with whomever you interact, be respectful. Also, maintain your integrity. At the end of the day, you don’t want your reputation tarnished in any way.” Like Larry, Niclas Lindstedt treats people the way he likes to be treated. Being the boss doesn’t mean a leader can treat anyone badly. “The best leadership manual is the mirror. I know I can’t change people. The only thing I can try to change is the guy in the mirror.” Doing the right thing is Lisa Conte’s mantra. “We have many values, but ‘do the right thing always’ is the most important. Just look inside yourself and do the right thing.” Life Lessons from Pets Like many people, I have learned important lessons over the years from my many pets. So, what lessons have these successful leaders learned from their pets? Rob Joseph feels that pets are so valuable to people. During an engagement with the French behavioural psychologist, Clotaire Rapaille, he learned about the relationship between people and their pets. “He told us that pets allow each of us to be the ideal ‘me.’ We often talk about loyalty and love without conflict. That’s true, but it’s actually a manifestation of ourselves. Pets tell us to not judge ourselves because they do not judge us. Leadership is very stressful. There is an enormous amount going on every day. Pets give us that moment of solitude, that moment of escape from everything around us. When we engage with our pets, we receive enormous therapeutic and cathartic benefit. We close off the world around us and just have a moment with our pet. From a stress management perspective, I absolutely can say that this is extraordinarily important.” For Craig Wallace, the lessons are very simple…and humorous. “Don’t mess on the floor. Don’t miss the litter box. Show loyalty and devotion at home and at work.” “Animals have been very influential in making me who I am,” says Lisa Conte. “If you need to chill out, you get that unconditional love. You pet them and everything calms down and comes into perspective. Another lesson they’ve taught me is to never give up. I have www.animalhealthmedia.com
Jack Russel Terriers. They have enthusiasm for everything they do, and never, ever give up. We take them on vacations. When we're walking through the airport with them, every single person who looks at those two dogs smiles because they're so excited. It's contagious to your team and everyone in the work environment when you're like that. You're smiling and enthusiastic, and you don't accept ‘no,’ and you show a little sense of humour when someone is irrational rather than responding to them in kind.” Don Chew marvels at his dog’s unconditional love. “It doesn’t matter how bad a day I’ve had, or how little interest I show, they come back with unconditional love. They help me keep everything in perspective. Plus, they are so forgiving about everything.” Niclas Lindstedt thinks that pets always demonstrate love. He believes that a dog truly can be a man’s best friend. “Any dog owner will probably struggle to remember when their dog wasn’t good. They’ll only remember the joy they brought.” Niclas’ dog has taught him to be happy and celebrate successes in small things. “When you celebrate your successes, you rise to the next level.” Jim Herbert learned the true meaning of loyalty from his dog. “They are loyal no matter how they’re treated. Dogs have shaped our lives in a lot of ways.” Mark Heffernan delights in the effect that the mere presence of an animal can have on people. “My appreciation of animals has really grown in the last few years. You really do see their impact. You can’t put a value on pets in your life. And, having pets in a meeting changes the whole dynamic. It calms people. It’s just incredible. I don’t think that you can underestimate their influence. In fact, I encourage people who are having a tough time in their life to get a pet because that bond will be life-changing for them. It’s amazing!” By observing animals, Larry Miller has learned about persistence and awareness. “Keep pushing forward to where the boundary is. Animals are so intuitive and aware of their surroundings. Like animals, we should have all of our senses alert and working together to assess whatever situation we’re in.” Aaron Schacht grew up as a cat person. He loved their independence and amazing agility and how they seemed to be completely in control of their destiny. As a family International Animal Health Journal 59
man, he’s lived with dogs. “I’m the alpha of the pack. When I come home, the first thing I encounter is my dogs. They’re waiting at the door, their attention is completely on me, and they treat me like I’ve been gone for ten years. Dogs teach unconditional love and commitment to their owner. I try to be that way to my wife so that every time she walks in the door, I treat her like she’s been gone for a month. We all should be more puppy-like to the people who matter the most to us.”
6. Understand that mistakes and disappointments will occur. Learn from them and move forward. 7. Be yourself…always. 8. Have fun!
Carsten Hellman has horses and a West Highland Terrier. By working with his horses, he knows the value of training and consistency and has learned to “never give up.” But his Westie has shown him something much more important: happiness. “Westies are just happy dogs. Seeing the effect of this, it’s so positive. Their little tail is always going. They’re eager to meet the world. Westies also trust. While there may be an occasional disappointment, they just move on. And, no matter what you do, 99.99% of the time, you get love back.” So, Carsten says, “do the Westie thing.”
• Donald Chew, President and Chief Executive Officer, PBI-Gordon, the parent company of Pegasus Laboratories and PRN Pharmacal • Lisa Conte, President and Chief Executive Officer, Jaguar Animal Health • Mark Heffernan, Chief Executive Officer, Nexvet • Carsten Hellmann, Chief Executive Officer, Merial • James Herbert, Chairman and Chief Executive Officer, Neogen Corporation • Robert Joseph, Chief Executive Officer, Parnell Veterinary Pharmaceuticals • Niclas Lindstedt, Vice President, Orion Pharma Animal Health • Larry Miller, Chief Operating Officer, Phibro Animal Health • Aaron Schacht, Vice President, Global Research and Development, Elanco Animal Health • Craig Wallace, Chief Executive Officer and North America|Pacific Zone Director, Ceva Animal Health
I am so very grateful to each of the contributors to this article for sharing their thoughts and experiences. I learned a lot…and had a good time doing it! And, after speaking with all of them, it is easy to understand why they’ve risen to their current positions.
Denni O. Day
When I started this project, I expected that one or more of the leaders would reveal some novel perspective or complex process that contributed to their success. I was both disappointed (there is no “secret sauce”) and heartened (most of their advice is common sense). The key difference between these leaders and the rest of us is their complete…and relentless…adherence to a few basic concepts. To be an extraordinarily successful leader, you must: 1. Know what you want, where you want to go, and why. 2. Acknowledge that you cannot achieve your objective alone. 3. Recruit the best “helpers” you can find. 4. Tell your team what you want, where you want to go, and why…and then get their agreement. 5. Trust, support, and reward your team. 60 International Animal Health Journal
Acknowledgments I am extremely grateful to the following executives who were most generous with their time and thoughtful in their insights:
BS, BSN, RN, MSPH is the founder, President, and CEO of VetPharm, Inc., a leading contract research organisation dedicated exclusively to animal health. VetPharm offers a complete menu of clinical trial support services including protocol development, data form design, investigator recruitment, site qualification, enrolment enhancement, study administration, site monitoring, data management, biostatistics, medical writing, and regulatory support in the United States and Europe. VetPharm employs a comprehensive study management system and a consortium of study-ready investigators that facilitate rapid study initiation, accelerated enrolment, and superior results. Email: firstname.lastname@example.org
Volume 4 Issue 2
International Animal Health Journal 61
A Pug’s Life
If you are a pug owner, you will know their characteristics already – a mixture between a fourlegged clown and a toddler, which is among the many reasons why we all love them. Pugs are believed to originate from China where they were prized companions for the emperors, so it is no surprise that these little dogs strut around like kings and queens of the house. Ancient records included descriptions of these flat-faced dogs with short legs, which leads us to believe they existed in China within the royal family, and only the very important people would be able to own a pug. Pugs seemed to have stayed within the royal families as they soon moved their way over to the Netherlands, having been discovered by the Dutch when they started trading with China. There are stories of a famous heroic pug which has now become the official dog of the House of Orange, because of how he alerted Prince William of an invasion. One night when William was asleep, an assassin tried to enter his chambers, but his brave little pug, Pompey, alerted the prince to the intrusion, thereby saving the prince’s life. These days pugs seem to be everywhere, whether it’s in the park, printed on a t-shirt or in a movie. They are classed as ‘toy breeds’ or ‘designer dogs’, which also makes them very popular, even with celebrities. Their fun-loving personalities make it easy to understand why they are so popular – which makes it seem crazy to think that, like all dogs, these pugs are descended from the mighty wolf. Pugs are very friendly characters and are known for their comical yet sensitive personalities. The most visible trait is their stubbornness; a pug always knows what he wants and will try different ways to get it, whether it is to wait it out, or turn on the charm and give cuddles – either way very amusing to a pug lover. Pugs can be harder to train because of their stubborn ways but, as long as you are persistent and work out what motivates them – which 99% of the time is food – then there is no reason why they cannot be trained like any other dog. Although they are big eaters, pugs are also very lively and full of beans; they love a mad five minutes, which will always puts a smile on your face. Exercise is always welcomed by a pug, since they are not as lazy as they look they would never turn down a Sunday lie-in. Pugs generally get on well with both humans and other dogs, being by no means shy or submissive, and loving to socialise. A pug is like a child, sulking when being told off and very sensitive to harsh tones – it will take a while to win them round again. The pug was bred to be a lap dog, therefore they are very loyal and always like to be nearby. They are true family dogs who will expect a place on the sofa or bed next to you. The pug, like the bulldog, is a brachycephalic breed, meaning flat-faced. While this does add to their cuteness, it can also lead to serious health problems. The throat and passageways of these dogs are usually undersized, making it harder for them to breathe compared to most other dogs. If exposed to extreme heat or stress it can mean a very dangerous situation for them. 62 International Animal Health Journal
The way that pugs have been bred has led to them having an elongated soft palate, which makes it harder for them to breathe when exercising, stressed or overheating as they are unable to take long deep breaths. When this starts to happen to the pug, it can then cause more anxiety for the dog. Symptons that the dog is having problems are if the pug is engaging in noisy, open-mouthed panting or breathing, extending its neck to try to open the airways, or even cyanosis, which is turning blue due to lack of oxygen and eventually the dog collapsing. It is possible to have surgery to help a pug or other snub-nose breed which their breathing; vets can try methods to widen the nostrils and remove excess tissue around the airways to create better airflow for them. To avoid causing breathing problems, it is recommended to avoid stressful environments and overheating. Pugs cannot be left out in the heat. Try to walk when it cools down in the evening or first thing in the morning, for short walks if necessary. Avoid using collars that can push on their airways and try to maintain the guided body weight for your pug – if you are not sure, please ask your vet. It is also advisable to carry a bottle of water and a lightweight bowl so they can stop for a drink to rehydrate and cool off if they are finding it a bit hot on their walk. If your dog is very hot, you should try to cool it down with cool water on the ears and the feet, and move them to a cool area whilst offering them cool water to drink. Pugs are prone to a few other health problems due to their features. The pug’s eyes can have issues with ulcers and entropion of the eye, a condition where the eyelid rolls inwards. Another common problem is ‘dry eye’ or conjunctivitis. This is not just pugs, but other breeds too; however, it is just one of several problems they can suffer from, which is why it is important to do your research when looking to take on a pug. Having researched the breed thoroughly, your next step would be looking for a breeder. There are a lot of breeders out there from all different backgrounds, so you need to ask questions and see the parents of the puppies. Ask about the history of the bloodline; a good breeder should welcome questions and genuine interest in the puppy, which should also reassure them their puppies are going to a sensible owner. Volume 4 Issue 2
SPECIAL FEATURE a rabies vaccine, so if your new puppy comes with a Pet Passport, please check with your vet. This is not saying that all puppies imported are illegal, but it is on the rise. If pets are imported into the UK illegally, or there are errors on the paperwork, the animals will be quarantined until the issue is resolved. This will incur quarantine charges and result in the puppy being away from their owners. If you are thinking of travelling overseas with your pug, it may be difficult, depending on the destination. Most airlines will not carry brachycephalic dogs as they do not want to carry these high-risk breeds, so you may wish to plan ahead. If you are looking to purchase a puppy online, be aware of puppy scams. Scammers are usually using free websites to advertise puppies that don’t exist. Breeds like bulldogs and pugs are offered at an attractive price, or even offered for adoption in return for covering the costs of transport. The advertiser will send you pictures and check that you are a suitable owner for their precious puppies that need homes. If the offer seems too good to be true, it usually is, and they will lure you in with cute pictures of puppies that may not even be real. You should not buy a puppy you have never seen, and if you do get as far as seeing a puppy, be sure it is a genuine breeder and not stolen, or part of a buying and selling scam. Ask for documentation like a vaccine card and receipt of purchase – even better, ask to speak to their vet. Hopefully, by the end of the process you will have a healthy, genuine and lovable new puppy to add to the family, ready to have many fun times and fond memories.
When looking for pugs there are a few things to look out for other than puppy personalities; one being their eyes. Check that they are not bulging, watery or glazed, as this could be a sign of future problems. Next would be to assess their breathing – if you can, listen to the puppy’s breathing to make sure it is not chesty or rattling. When the puppy is calm, is it a noisy breather and having to breathe through its mouth? They should be able to breathe with their mouth closed at rest with no problem. If you are not sure, speak to your vet for advice and signs to look out for before going to view. As pugs are becoming more and more popular, it is becoming more common that they are sold on the internet. This can bring both good and bad news for the buyer. Now that the rules and regulations of bringing pets into the UK (see www.gov.uk) have been relaxed, with a microchip, a pet passport and rabies vaccine, bringing in a puppy or two from abroad can be an easy money-maker for some people who are buying and selling these designer dogs. This is why it is so important to know their history and go to see the puppies. The Pet Travel Scheme is in place to ensure pets travelling in and out of the UK are regulated, and to ensure that healthy, disease-free animals are coming into the country, whether by air or road. As toy breeds like pugs are in high demand, it has been known that they have been brought into the country, illegally, way too young, ready to be sold again in the UK to unsuspecting new pug owners. All pets need to be at least 12 weeks of age before having www.animalhealthmedia.com
Justine Marie Chambers Currently working in animal transport and relocation and have been pet shipping for over five years, mainly dealing with the exports of family pets around the world. Assisting people with meeting the Pet Travel Scheme and arranging the flights for their pets. As well as working with animals, also a proud pug owner. Email: email@example.com
International Animal Health Journal 63
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Alltech Henry Schein Animal Health Asahi Calpis Wellness Co. Ltd. Bayer AG
Cyton Biosciences Ltd.
GD Animal Health
Henke-Sass, Wolf GmbH
IDEXX Laboratories Inc.
Page 21 OBC
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Volume 4 Issue 2
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International Animal Health Journal 65
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Volume 4 Issue 2