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Volume 1 Issue 2

Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

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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

EDITOR Cecilia Stroe EDITORIAL MANAGER Orsolya Balogh DESIGNER Fiona Cleland BUSINESS DEVELOPMENT Richard Goodard 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: info@pharmapubs.com www.animalhealthmedia.com International Animal Health Journal – ISSN 1758-5678 is published quarterly by PHARMAPUBS.

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. 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 1 Issue 2 November 2014 PHARMA PUBLICATIONS

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06 The Growing Threat of Vector-borne Disease (VBD) in Humans and Animals The International Federation for Animal Health (IFAH), with the support of the Bill & Melinda Gates Foundation, commissioned Oxford Analytica to write a white paper looking at recommendations regarding solutions and innovations in the context of the growing threat presented by vector-borne diseases (VBDs) to both animals and people. Kim Hardie of IFAH introduces this position paper which collates the opinions of a wide range of key opinion leaders, presenting a snapshot of the situation today. 08 Beginning with the End in Mind Tom Overbay of Expedite Animal Health looks into the process of developing and registering products for use in veterinary medicine, often viewed as a quick path to revenues, especially when compared to human medicine. And he tells us what to consider when beginning the decision process regarding the development of an asset into a veterinary product. REGULATORY & MARKETPLACE 10 Canadian Animal Health Sector – An Overview of the Challenges and Opportunities The Canadian animal pharmaceutical industry represents approximately 2.5% of the global industry, within the world’s second largest land mass (larger than the US), while having a small human population which is 10.5% that of the United States. In her paper, Jean Szkotnicki, President of CAHI, explores factors impacting the Canadian animal health business and the implications these will have on it and its customers. 16 Veterinary Medicinal Products - What Might Happen if the UK Withdrew from the EU The UK’s membership of the European Union (EU) is often a topic of heated debate. While some political parties are enthusiastically in favour of a continued membership, others are lukewarm and one party in particular is vehemently opposed; and in between the “must stay in” and “get out at all costs” camps are the more restrained opinions. Without trying to do an exhaustive appraisal of the implications for the veterinary sector of the UK leaving the EU and the EEA, Dr Kevin Woodward of KNW Animal Health Consulting highlights some of the key consequences. 22 Overview of the New Draft Regulation for Veterinary Medicines The Commission published their proposals for the updating of the veterinary medicines and feed medications legislation in Europe in September, five years after starting the review process. As the regulatory bodies, industry and veterinarians have started their analysis, Paul Cooper of Assentra Limited looks into the first reactions, providing a brief outline of the main and notable provisions in the draft Regulation, and also some of the questions arising from a detailed examination of the text.

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28 New Product Development – The Intertwined Worlds of Regulations, Patents and Exclusivity The regulatory, patent and exclusivity issues as they relate to the animal health industry in the United States are complex and overlapping. Focusing in his article on drug development, Dr Sam Al-Murrani of Babylon Bioconsulting explains how the multiple regulatory hoops to jump through and the seemingly unending costs associated with patenting a new product may appear to be a dark cloud at first; however, upon a more thorough and deliberate second look the same dark cloud may end up with a very prominent silver lining. RESEARCH & DEVELOPMENT 32 Targeted Drug Delivery for Veterinary Injections Prof. Padma V. Devarajan and Anisha A. D`Souza from the Department of Pharmaceutical Sciences and Technology Deemed University, Matunga, Mumbai, discuss the challenges raised by the treatment of veterinary infections and the attractive features of nanocarriers. The recognition of the positive aspects of nanotechnology in targeted delivery could revolutionise the therapy of veterinary infections globally. 38 Pet Overpopulation: A Global Crisis Ironically, the principal problem facing domestic cats and dogs is their ability to reproduce an exponential number of offspring. For thousands of years we have chosen to breed our companion animals to serve our needs. They have ceased to be wild and have become dependent on humans for survival. If pets are indeed members of our family, Tracy Gillett of Avivagen asks what is the scope of our problem and how do we find a solution? 44 Recent Advances in Precision Livestock Farming A new take on animal farming, precision livestock farming (PLF) was born as a reaction of the pressure from world market prices, causing farmers to focus on efficiency, large-scale production and automation, while still wanting to maintain animal welfare. Dr Heiner Lehr of Syntesa addresses the obstacles to adoption of PLF, as well as 2 International Animal Health Journal

recent advances to overcome such obstacles. The main body of material comes from three EU-sponsored research projects, namely BrightAnimal, ALL-SMART-PIGS (www.allsmart-pigs.com) and EU-PLF (www.eu-plf.eu). 50 Efficient Monitoring of Antibiotic Use on Pig Farms Following the limitations on antibiotic use in pig farms across Europe since the late 1990s, it has become crucial to monitor antibiotic use on farms and their microbial status, in order to protect young and growing pigs against infectious diseases. Dr Jules Taylor-Pickard of Alltech provides insight into an audit programme which evaluates various contributing factors to on-farm productivity, including biosecurity, animal health status, mycotoxin exposure and antimicrobial use. CLINICAL STUDIES 54 The Heart of the Matter – Musings on Monitors Denny O. Day of VetPharm examines the role of clinical study monitor, the representative of the study sponsor and, as such, responsible for ensuring that the study is conducted in exact compliance with the protocol, that all study activities conform to good clinical practice (GCP) guidelines (VICH GL 9) and that all other regulatory requirements are met. If the study monitors have done their job well, there will be few, if any, surprises when the final study data is submitted to the sponsor or if one of their sites is audited by the regulatory agency. MANUFACTURING & PACKAGING 58 Animal Healthcare - Packaging & Labelling Trends Animal healthcare labelling is fast becoming more than just a functional requirement for identification of product and the fulfilment of legal obligations. In fact, shows Stephen Jarrold of Denni Brothers Ltd, labelling and packaging is playing an increasingly important role within this sector than ever before. And with an increasing number of mergers and acquisitions, manufacturers are becoming increasingly aware of the need to create packaged products for multimarket distribution.

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Foreword It`s nothing short of fascinating what has happened in the last couple of years in the animal health industry, and there is more yet to come. To end the year on a high note, IAHJ`s latest edition brings good news for those with a stake in how veterinary medicines are regulated in Europe. In September, the Commission published their proposals for the updating of the veterinary medicines and feed medications legislation in Europe, five years after starting the review process. Although there is a long way to go, since implementation is not expected before 2018, talking in his article about this “major step forward”, Paul Cooper of Assentra Limited explains why in his opinion the proposal provides a good framework for an improved regulatory landscape. And let`s not forget “The Great British trade-off”: What might happen if the UK withdrew from EU and the EEA? Some of the key consequences for the veterinary sector of such a scenario are discussed by Dr Kevin Woodward of KNW Animal Health Consulting. For good measure, Jean Szkotnicki, President of CAHI, is providing an overview of the challenges and opportunities of the Canadian animal health sector. Relatively small in terms of market size, the Canadian animal health industry will continue to play a leadership role in developing new products for the global market. It is precisely the promise of exclusive rights that gives to innovators the incentive to invest in research and development. Addressing the complex matters associated with patenting a new product in the United States, Sam Al-Murrani of Babylon Bioconsulting guides us through the regulatory “hoops” towards the “silver lining”. The process might well be very slow, costly and frustrating, but it would seem there is a way of approaching the regulatory requirements pragmatically and proactively, that makes perfect economic sense. The truth about cats and dogs is revealed by Tracy Gillett of Avivagen. Currently, the companion animal overpopulation problem has become overwhelming, and this is as a man-made disaster we are morally bound to find an answer. Discover how far animal health innovators are from delivering a realistic solution to the global pet population crisis. Even though it has been around for some time, Precision Livestock Farming (PLF) has not yet fully lived up to the initial expectations. Dr Heiner Lehr of Syntesa explains what are some of the shortcomings and why there is little doubt that SmartFarming or iFarming is the future of livestock farming; an essential part of the “livestock revolution”, and by no means just another piece of marketing hype. Our world is changing, emphasises a report commissioned by The International Federation for Animal Health (IFAH) to look at recommendations regarding solutions and innovations in the context of the growing threat presented by vector-borne diseases (VBDs) to both animals and people. Presented by Kim Hardie of IFAH, the white paper reminds us that the impact of climate change, habitat change introduced by humans, the increased movement of goods, humans, livestock and companion animals worldwide on vector distribution and VBD incidence should not be underestimated. Cecilia Stroe, Editor

Editorial Advisory Board German Graff - Project Manager Business Development at Triveritas

Sven Buckingham Buckingham QA Consultancy Ltd.

Fereshteh Barei - Health Economist & Strategy Advisor, Founder of BioNowin Santé Avenue Association

Dan Peizer - Director Animal Health at Catalent Pharma Solutions

Carel du Marchie Sarvaas - Executive Director, IFAH International Federation of Animal Health

Richard V. Myer - Vice President Global Business Development - Argenta, Ltd

Kimberly H. Chappell - Senior Research Scientist & Companion Animal Product Development Elanco Animal Health

Jean Szkotnicki President of the Canadian Animal Health Institute (CAHI)

Dr. Sam Al-Murrani - Chief Executive Officer Babylon Bioconsulting & Managing Director at Bimini LLC

4 International Animal Health Journal

Dr Kevin Woodward - Managing Director KNW Animal Health Consulting

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The Growing Threat of Vector-borne Disease (VBD) in Humans and Animals Recommendations for Optimising Solutions and Innovations across all Species and all Regions The International Federation for Animal Health (IFAH), with the support of the Bill & Melinda Gates Foundation, commissioned Oxford Analytica to write a white paper looking at recommendations regarding solutions and innovations in the context of the growing threat presented by vector-borne diseases (VBDs) to both animals and people. This white paper collates the opinions of a wide range of key opinion leaders with varied and relevant expertise, presenting a snapshot of the situation today, complete with the key challenges faced and what is therefore required to develop effective solutions in tackling vector-borne diseases globally. Initially looking at the health, welfare and economic impacts of arthropod vectors and the pathogens they transmit, the main barriers to controlling VBDs are then explored. A reflection on the lack of surveillance and disease impact data highlights that the actual significance of these diseases is often very difficult to quantify when accurate statistics remain so elusive, even in developed countries. A further important reason to improve surveillance across all regions is to allow detailed risk analysis, including the evaluation of the potential spread to new areas or the introduction of exotic species/diseases and then to see if controls implemented are actually effective. The complicated issue of ensuring pharmaceutical sector investment into developing new vaccinations and medicines for treatment is examined. The point is made that it often takes millions of dollars and many years of investment to bring a new molecule to market and as a result, there must exist a commercial market (which is often not the case for VBDs) for this to happen. Equally, the importance of educating and involving local governments, strategy implementation staff and animal owners when putting in place strategies to manage and control VBDs is stressed. For example, more donor-funded information campaigns for farmers will help them to know when it is most appropriate to use insecticides, which ones to use and how. Communities and stakeholders (e.g. local governments) need to be shown examples of success stories, and assisted in undertaking cost-benefit analysis of VBD management and control versus inaction to prompt engagement with (and therefore the success of) any control strategies. The report also highlights that our world is changing and reminds us that the impact of climate change, habitat change introduced by humans (e.g. wetland creation), the increased movement of goods, humans, livestock and 6 International Animal Health Journal

companion animals worldwide on vector distribution and VBD incidence, should not be underestimated. The opinion is shared that for many VBDs, insecticide resistance is probably the single greatest threat to traditional approaches to disease management. As a result, a recommendation that awareness of the need to minimise the development of resistance is paramount in any attempt to use insecticides to control vector populations and perhaps other strategies should be used more heavily, such as various types of physical barriers to protect hosts from vector feeding. A brief review of some of the novel techniques for the control of VBDs that are being researched identifies that this activity seems to be mainly restricted to human health (for example, vector genetic modification and the manipulation of endosymbiont bacteria). Another valuable area of research highlighted is with respect to identifying the qualities of maintaining healthy animals and management systems that foster these qualities. Especially in developing countries, improvement of basic husbandry practices can mean a significant contribution in this field. As a result of the main challenges identified, the paper considers a multi-faceted approach as the most effective way to tackle vector-borne diseases, incorporating treatments and vaccines, as well as efforts to reduce the population of the vector directly (although it is acknowledged that total eradication is often unrealistic). Incorporated into this should be a One Health approach, recognising the interdependency of environmental, human and animal health and encouraging collaboration between all health sectors to make bigger leaps in progress.

Kim Hardie, Communications Director for the International Federation for Animal Health (IFAH). IFAH represents international companies as well as associations which comprise small and medium-sized enterprises, engaged in R&D, manufacturing and commercialisation of veterinary medicines, vaccines and other animal health products. IFAH members representation approximately 80% of the global market. Email: k.hardie@ifahsec.org Volume 1 Issue 2


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Beginning with the End in Mind Developing and registering products for use in veterinary medicine is often viewed as a quick path to revenues, especially when compared to human medicine. This view is fuelled by a number of factors including the time required to gain approval, the cost of development, and the ability to conduct work in the target species to develop direct evidence of safety and efficacy among others. Some of these views can be misleading, including underestimation of the quality standards for veterinary products, overestimation of the market, and failure to appreciate the role of the animal owner in the ultimate success of the product. Human medicine recognises that patient compliance is a significant factor in the success or failure of a product to address the condition for which it is intended. Not only is this also true in treating animals, it is more important, as the ability to administer a product, or conversely its difficulty, is a leading determinant in the success or failure of a particular product. This is even more the case when treating conditions which require long-term or daily administration — the very targets attractive to drug developers and investors. Therefore, it is important to begin the decision process regarding development of an asset into a veterinary product with the end in mind. Who is the real customer? How is the drug to be delivered? How often must the product be administered? What are the side-effects, including not just adverse events but odour and appearance (is a topically administered product deemed “too greasy” for example)? When making answering these questions, convenience and compliance can spell the difference between a successfully marketed product and one which fails to meet expectations, so consideration to these points should be at the forefront of the development process. These points are evidenced when considering the successful product introductions in recent years. The ability to provide heartworm control to a dog in a presentation regarded by both the owner and the pet as a treat, being able to administer parasite control to cattle as pour-on, prevention of fleas and ticks with single, monthly topical applications instead of dips and baths, and now a new generation of flea and tick control presented in an oral presentation promising to be viewed as a treat. Certainly, the safety and efficacy of these, and other, products have positioned them well with both veterinarian and consumer. But their ease of administration, in both form and frequency, has enabled the capture of market share, the ability to command premium pricing, and the capacity to resist the introduction of competitors including those with generic active ingredients, even at lower cost per dose. In considering products for development, certainly there are stories of an individual who spent a considerable amount of money for the treatment of a beloved pet for 8 International Animal Health Journal

cancer. However, there are exponentially more examples of pet owners who also love their pet but weigh the benefit of treatment against the struggle to push a tablet into the throat of the animal. And asking the pet owner to do this two or three times per day only exacerbates the challenge. The owner may decide that the animal seems to be “doing better” after a couple of days or that the pet “is not really that sick after all” in order to justify discontinuing treatment. Certainly, discovery and development of novel products and active ingredients are exciting activities which often reward companies, entrepreneurs, and investors. By no means should these undertakings be discounted as a means to enter the veterinary market and become financially successful. However, it is equally important to consider how the product will be delivered to the animal and incorporate this feature at the onset of the development programme. No matter how well the active works, getting the product into the animal is a critical component of its effectiveness. By starting with the end in mind, the result is far more likely to yield the market share, penetration, and financial outcomes envisioned for the intended product.

Dr. Tom Overbay is one of the founders of Expedite Animal Health, a company formed to assist with the commercialization of products in the veterinary industry. Dr. Overbay has successfully brought to market a number of products arising from universities, government agencies, human hospitals, start-up, and multinational pharmaceutical and chemical companies. Email: toverbay@expediteanimalhealth.com

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Regulatory & Marketplace

Canadian Animal Health Sector – An Overview of the Challenges and Opportunities Industry Overview The animal health industry in Canada services a combined companion and production animal population, which faces both challenges along with opportunities. Our animal pharmaceutical industry represents approximately 2.5% of the global industry, within the world’s second-largest land mass (larger than the US), while having a small human population which is 10.5% that of the United States. This paper explores factors impacting the Canadian animal health business and the implications these will have on it and its customers. It considers the factors influencing the changing paradigms in the animal health sector as it relates to the generation of sales, while also elaborating on our strengths. 1) Factors Impacting Animal Health Product Sales a) Economics The Conference Board of Canada reported that consumer confidence declined in 2013. It found Canadians to be concerned about their finances and job creation, with a majority saying it was a bad time to make a major purchase. The Conference Board also reported that consumer debt at the end of 2013 was at an all-time record of 163.7% of income. This means that for every dollar earned, Canadian families owe $1.64. Canadians have been urged to reduce spending and pay down debt at a time of low interest rates, but to no avail. In the next two years it is expected that the global economy will be on a lower growth track, with Canada’s GDP to stay around 2.2%. The Canadian economy is not without good news, though. The Organization for Economic Co-operation and Development (OECD) forecasts that the Canadian economy will be one of the top performers within the G7 countries. So while Canada is likely to see declining retail activity, and indeed from the perspective of the animal health sector reduced demand for veterinary services and products, it may be less impacted than other global markets. b) Trade US trade irritants around Country of Origin Labeling (COOL) and other issues beyond agriculture have led Canada to look for increased trade and diversification away from the US, which is our major trading partner. The federal government recently announced that it completed a trade and investment deal in principle with Europe, the world’s largest common market. This could lead to export gains once the agreement is implemented. Canada also entered into the Trans Pacific Partnership (TPP) multi-lateral discussions targeted at expanding exports to large countries in Oceania, Asia and South America. The 12 countries involved in the negotiations represent 40% of the world’s economy. While there is a potential for net trade gains due to these 10 International Animal Health Journal

negotiations, there likely will be sectors which lose as a result. Certainly there are concerns within Canada’s supply managed sector about the potential for it to be dismantled. Any potential changes to supply management of agriculture would be phased in over time to allow for a stable transition. That being said, our federal government is reluctant to force change within the supply managed industries due to this sector’s political strength and economic stability. So in the near term it is expected that trade in red meats will remain stable, with limited growth until implementation of the new European trade deal, and resolution of trade irritants such as COOL and Canada’s use of production enhancers. Canada will continue to expand its trade agreements globally. Our nation has a positive image internationally in that we are able to produce safe, high-quality food to meet the various needs of our export markets. c) Population Demographics i. Immigration Canada has a small population of 35 million people comprised of a broad ethnic mix. Immigration has been increasingly important to growth in the Canadian population. The number of foreign-born persons has been steadily increasing in recent years. From 1986-2006 the number of foreign-born persons rose from 3.9 to 6.2 million. If current immigration trends continue, then the proportion of immigrants in Canada could be approximately 22% by 2017. China, the Philippines and

Immigration in Canada

India are the leading sources of new immigrants to Canada, with these three countries representing 36.7% of all new immigrants in 2012. These immigrants do not come from a tradition of pet ownership, although there are recent reports in terms of the growth of pet ownership within China. According to Packaged Facts consumer survey data, households of minority populations are slightly less likely than average to own pets. It is predicted therefore that the population growth of humans will outstrip the population growth of companion animals in the future. Market research focusing on first- and second-generation new Canadians from the Indian sub-continent and China indicates that they are less likely to own pets, and those Volume 1 Issue 2


Regulatory & Marketplace that do tend to own smaller dogs, and spend less on the pet. Different from western markets, ownership and care of these pets is not generally considered at our societal level of ‘pet parents’ and ‘fur kids’. In terms of the impact on protein consumption, from the standpoint of China, India and the Philippines it should also be noted that these immigrants are coming from backgrounds of having lower per capita meat consumption than does Canada. In 2009 Canadians consumed 94.3 kg of meat per person, whereas consumption in China, India and the Philippines was 58.2, 4.4 and 33.6 kg per person, respectively. ii. Aging Human Population and Animal Ownership The Canadian population is aging. From 1956-2006, the median age of the Canadian population went from 27.2 to 38.8 years. By 2056 the median age is expected to reach 46.9 years. It is anticipated that by 2015 the proportion of elderly will exceed the proportion of children in this country. In 2013, animal ownership rates were highest, at 75%, among 45-54-year-olds, but declined with age to 48% for 55-64-year-olds, and to 39% for those over 65. The data shows that pet ownership declines for those in the 55+ age category. However, this older segment of the population tends to be financially stable. This allows veterinary practices the opportunity to focus on increasing pet medicalization rates, additional visits to the clinic, and improved treatment compliance with this segment of the population.

Canadian Pet Ownership Rates by Age Brackets, 2013 (percent)

d) Limited Growth and Aging of the Canadian Animal Population Canada is home to approximately 6.6 million dogs and 7.9 million cats, with about 9% of Canadians owning other types of pets such as fish, small mammals, birds and reptiles. It is not expected that there will be tremendous growth in pet ownership due to economic uncertainties and population demographics related to immigration and aging.

“The demographic profile of Canadian pets shows that 35% of cats and 33% of dogs are over 8 years old and could be considered “geriatric.” Less than 8% are under 1 year old. [Reference: Perrin, T. (2009) The business of urban animals survey: the facts and statistics on companion animals in Canada.” Can. Vet. J. 50(1):48-52.]

In addition, the companion animal population is aging. The demographic profile of Canadian pets shows that 35% of cats and 33% of dogs are over eight years old and could be considered “geriatric.” Less than 8% are under one year old. With this aging pet population comes the fact that a number of pet diseases increase in prevalence with age, including arthritis, cancers, behaviour and neurological issues, etc., requiring new medicines, diagnostics and services to maintain the quality of life for these elderly dogs and cats. The food animal side of the industry is also expected to have limited growth in numbers. Production controls and domestic product pricing are critical components of Canada’s supply management regimes for dairy, poultry and egg production. These sectors of the food animal industry produce product to meet domestic demand. The red meat sector of agriculture on the other hand is export-oriented. Unfortunately, due to the incidences of diseases such as bovine spongiform encephalopathy in cattle, and, circovirus and porcine epidemic diarrhoea in hogs, combined with poor prices and trade issues around the use of productionenhancing products (zilpateral, ractopamine) and Country of Origin Labeling (COOL), there has been 5-6 years of shrinking herds that have only just stabilised. It is expected that there will be continued rationalisation and consolidation within the beef and pork feeding and packing sectors. However, with the shrinking herds there is market strength for cattle and hog producers which will likely translate to increased use of animal medications to keep animals healthy and eventually herd expansion. e) Veterinary Practice Trends A large number of factors are impacting the practice of veterinary medicine. These include: •

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The uncertain Canadian economy and limited potential for increased numbers of pets and food animals are challenges facing veterinary practices. There is also a sense that in some regions there is a saturation of veterinary practices which drives practice incomes down due to competition. The gender shift of veterinarians from male to female. The Canadian Veterinary Medical Association (CVMA) reports that there were 12,547 veterinarians in Canada in 2013, with 6,594 being female and 5,953 male. This shift is thought to put greater demands on career/life balance for practitioners, leading to limited interest in practice ownership and greater interest in flexible time. The shift from food animal to companion animal practices. Of the 3407 practices in Canada, 370 are International Animal Health Journal 11


Regulatory & Marketplace

reported to be large animal, 2106 companion animal, and 931 mixed animal practices. From an education perspective, in 2014 there were more non-Canadian-trained veterinarians licensed in Ontario than Canadian-trained veterinarians. The shift in demographics results in a saturation of clinics in Ontario with fewer pets per clinic and declining fees for service resulting from the new clinics entering the market. The above changes are resulting in new business arrangements being made whereby practice chains are established between multiple clinics in an effort to gain management and service efficiencies, to ensure the best margin to the practice. A final factor of note that influences practices is the fact that the sale of veterinary clinics by baby boomer veterinarians is the best way for the owner to realise the equity in the practice. In larger urban centres in today’s market, the real estate value of the clinic can be greater than the value of the veterinary practice, often begging the question, “is it veterinary medicine or real estate driving the consolidation?”

With all of these uncertainties, it is predicted that more challenges will lie ahead. VPI Veterinary Economics Financial Health Study, 2014, concluded that “the veterinary community will have to make dramatic and difficult changes to retain a middle class standard of living.” Impact Vet market research further revealed that pet owners are increasingly relying on “Dr Google” for the diagnosis of conditions, asking more challenging questions to veterinarians regarding their medical recommendations, or not visiting the clinic at all. Given these economic drivers and changes within the profession, it is anticipated that veterinarians will attempt to increase their revenue line using other products and services, including: •

• • •

the development of pet wellness programmes (that include consultation, diagnostics and pet care products)‎, the increased use of diagnostics to work up clinical cases, the increased use of prescription diets only available through the veterinarian, and other creative practice growers including the establishment of animal spas, etc.

Given the veterinary needs associated with these animal health products and services, the animal health industry is in a position to develop and supply these new products and services while providing continuing education to meet these various needs. f) Regulatory Climate From a regulatory perspective, both of Canada’s premarketing risk assessment bodies for pharmaceuticals (Veterinary Drugs Directorate) and biologicals (Canadian Food Inspection, Veterinary Biologics) are competitive in the services they provide with similar agencies in other 12 International Animal Health Journal

developed countries of the world. This is important in that animal owners and veterinarians need access to the same health management tools as their counterparts in other countries. Both Health Canada and the Canadian Food Inspection Agency have taken measures to be able to provide a submission review service to ensure product availability that is efficient and effective to that of other larger agencies in larger markets. The Canadian Animal Health Institute (CAHI) and its members have a good working relationship with these agencies. That being said, few new products are being developed for the animal pharmaceutical industry globally due to concerns about antimicrobial resistance, and the cost of meeting product regulatory, technical and maintenance requirements as compared to the relatively small product market size. From an innovation standpoint, Canada has strong patent protection laws for new discovery. The 20+ years provided by Canada`s patent law is critical to the success of Canadian pharmaceutical firms bringing new discoveries to the market place. Importation and use of non-approved animal health products through own use importation (OUI), and the use of active pharmaceutical ingredients (API) in dosage forms or as compounded products, continue to be non-regulated and an area of unfair competition for Canadian drug manufacturers. Health Canada is proposing oversight of OUI and API use as part of its regulatory modernisation process. The new regulation is to be introduced in 2015. An ImpactVet study prepared for CAHI in 2014 estimated OUI and API lost opportunity drug sales in 2011 to be around $50 million, which is over 10% of total drug sales ($393 million) for that year. Closure of these loopholes would be beneficial to the market success of Canadian firms. g) A New Way of Approving Low-risk Animal Health Products Canada has led the way globally in terms of the development of a mechanism to proportionally regulate companion animal low-risk products (to include natural products) through a streamlined self-affirmation process that defines the composition of the product, assures its safety through the use of a list of low-risk ingredients, and provides oversight to ensure appropriate and adequate labelling. Work is currently underway to develop a food animal version of this programme. h) Product Distribution and Sales Sales of animal health products to animal owners are made either through the veterinarian, over the counter to the animal owner, or direct to the food animal producer from the manufacturer. The veterinarian is the key customer for the animal pharmaceutical industry. Veterinary product distribution is largely the function of the five Canadian distributors, which tend to be veterinary owned and provide excellent service to the veterinary community. The distribution model has been stable for decades with product mark-ups generally being held at 12% and the purchasing or buying groups operating within a specific geographical region. There has been some expansion of the geographical territory for distributors in recent years. Volume 1 Issue 2


Regulatory & Marketplace Veterinary practices buy product from one or more of these distributors or direct from the manufacturer. In most practice business models, a portion of the services are built into the sale of medications to animal owners. There are some situations whereby product is sold from a pharmacy through veterinary prescription. i) Potential Non-traditional Product Sellers The aforementioned distribution situation is ever evolving, with major changes beginning to take hold in early 2000. Consumers have started to look at the price of pharmaceuticals and vaccines being charged by the veterinarian, versus the potential of buying cheaper product from other sources. Much of the trend for buying from other sources is being driven from the US, with major retailers like Costco, Walmart and Target starting to carry animal health products in their pharmacies. Canadians have a history of cross-border shopping in the US for goods, particularly when the Canadian dollar is at or near to par with that of the US dollar. So, US purchase of animal health medications in person or by mail is a practice many Canadian animal owners may consider. A 2014 study commissioned by the Canadian Animal Health Institute (CAHI) examined purchasing trends by animal owners. One of the study’s findings was a growing trend toward cross-border shopping for animal health products by individuals living within one to two hours of the border. It should be noted that Canadian provincial veterinary regulations enable animal owners to purchase prescription medications from sources other than the prescribing veterinarian. In many provinces the act of veterinary prescribing has been separated from the act of drug dispensing, whereby the veterinarian is required to issue a prescription for an animal, herd or flock. The animal owner can then choose to buy the product from his/her veterinarian or look to purchase it elsewhere through other sources. E-commerce is now starting to be a marketing force that consumers are gaining comfort with for their product purchases. For example, Amazon.com operates in over a dozen countries around the world. The Amazon website says, “we strive to become Earth’s most customer-centric company, we constantly look for new ways to innovate on behalf of our different customers: individuals who shop our global websites, merchants who sell on our platform, developers who use our infrastructure to create their businesses, and creators of the books, music, films, games and other content we sell through our websites. We believe that our greatest contribution to the good of society comes directly from these core business activities”. A number of companion animal health products are now listed on Amazon’s Canadian website. j) Consumer Attitudes A challenge for the animal health sector is to address new consumer demands. Today’s consumer is removed from agriculture, with agriculture representing less than 3% of the total population. Consequently, our consumers often www.animalhealthmedia.com

lack knowledge of the rationale behind modern production practices. With this, it is human nature to fear the unknown. Consumers have a strong voice and are putting demands on agriculture around animal welfare and food safety. Use of gestation crates for sows, eliminating cages for egg-layers, and rearing of animals without the use of antibiotics, are examples of areas of focus for animal activists, and, in public communications from media, food retailers and the restaurant trade. These types of messages are being heard by agriculture and resulting in changes in practices, along with the evolution of niche markets, e.g. eggs from cage-free layers, chickens fed a vegetarian diet, and antibiotic-free beef. Consumer activism is a given, but so too is the fact that global meat production is rising. It has tripled from the 1970s and risen by 20% since 2000. The main determinant of animal protein consumption appears to be wealth. As developing countries grow wealthier, so too does their demand for food animal protein. The greatest increases in production will be in poultry and pigs as well as eggs and milk. 2) Canada – Our Strengths and Opportunities Canada has a number of strengths that will provide opportunities for growth to the animal health sector as they work towards meeting global food demands and keeping our pets healthy. Our nation is resource-rich in that we have the land mass for crop production and access to abundant fresh water that can support increases in animal production. Canada has the infrastructure to support growth in food animal production. We have stable governments and regulatory regimes that are supportive of safe food animal production. Additionally, the sector is supported by a highly competent veterinary profession, producer-driven quality assurance and traceability programmes, plus transportation networks that service both domestic and export product needs. Canada has a long history of veterinary excellence, with the University of Guelph having the oldest veterinary school in North America. Other veterinary colleges exist in the provinces of Saskatchewan, Alberta, Quebec and Prince Edward Island. They are world-renowned for producing highly-skilled veterinary graduates and for their research capabilities. Besides, Canada has world-recognised agricultural colleges that are often associated with the veterinary colleges. Our agricultural colleges are based in British Columbia, Saskatchewan, Alberta, Manitoba, Ontario, Quebec and Nova Scotia, and have a long history of knowledge transfer to agrology students, as well as competence in animal production and systems research. Building upon this strong agriculture, veterinary and life science infrastructure, Canada has a large number of strengths in terms of our ability to innovate to improve the health and welfare of animals, and, in creating economic value back to its various stakeholders involved in the caring of animals. Our ability to innovate and drive the development International Animal Health Journal 13


Regulatory & Marketplace

of these new inventions and points of knowledge forward takes advantage of Canada’s innovative animal health infrastructure as outlined below: •

State-of-the-art research facilities at the academic, contract research, and government ‎level that provide access to animal populations to develop new animal health pharmaceuticals, vaccines, and other product types. World-class researchers that include veterinarians, animal scientists, and various life science researchers. When teamed with animal health company scientists, the combination makes for a powerfully synergistic force whereby both academic and industrial good is created. Supportive public granting agencies and other financial means that provide financial aid ‎in terms of turning innovative ideas into new products and services. This includes the following: • the National Science and Engineering Research Council (NSERC) that supports academic and academic/ industry shared research, • the National Research Councils, Industrial Research Assistance Program (NRC-IRAP), designed to support defined research projects with a corporate sponsor, • Agriculture Canada’s Agri-Innovation Program that enables the development of new agriculture innovations, including those involving animal health and productivity, as well as food safety and the security of the Canadian food supply, • Federal regional development programmes,

14 International Animal Health Journal

including FedDev, the Atlantic Canada Opportunities Agency (ACOA), and the Western Diversification fund that financially support and de-risk later-stage product/ service development to the point of entering the commercial market place, various provincial funding bodies including the Alberta Livestock and Meat Agency (ALMA) and funding from the Ontario Ministry of Agriculture and Food (OMAF), both of which offer financial assistance for large- and small-scale projects focused on food animal production, and the use of SRED tax credits available from the federal government providing monies back to companies, after these companies have spent significant dollars dedicated to qualified research and development projects. Enabling Animal Health Clusters located within Canada and typically associated with the various Canadian Veterinary Colleges. Of particular note is the animal health cluster in Charlottetown, ‎Prince Edward Island with its keen focus on animal health companies, natural product development, and aquaculture. Part of this particular cluster’s commitment to animal health is its creation and conduct of the VetHealth Global Conference. Held once every other year, the next in June 2015, this conference attracts global leaders of major animal health companies to discuss opportunities and matters of common concern. This conference also offers a venue in which emerging/start-up companies are able to discuss potential partnerships with the major global players. Volume 1 Issue 2


Regulatory & Marketplace •

An attractive environment for entrepreneurs (using the support as described above) to establish a startup company by typically assembling a lean team of experts, readily available in Canada, and dedicated to innovation and the creation of value for the ultimate end user of the product.

33

33 Taken together, Canada offers an attractive location to establish a new research platform, or a new research-intensive animal health company, given the myriad of enablers including: the available infrastructure and scientific/product development expertise, long periods of patent protection, attractive non-dilutive government funding opportunities and SRED tax credits, and a market place eager to adopt and utilise new technologies, products and services. Areas in which Canada has shown, and will continue to show, product development leadership include: •

ood animal therapeutics, vaccines and productivity F aids (that may also have a positive impact on the environment and the sustainability/ acceptability of animal agriculture). Companion animal therapeutics and vaccines for the young and middle-‎age pet, as well as the aging pet product market (for the management of arthritis, cancers, cognitive/behavioural disorders, etc). Wellness products and services for the companion animal (including natural health products, diagnostics, pet food and nutrition, etc). Aquaculture products targeted largely at use ‎in salmon and trout as appropriate prevent and treat disease. Product to enhance the safety and security of animal protein production when applied either pre- or postharvest. Diagnostic products to more effectively detect disease at an earlier stage to allow for faster, more effective interventions. Use of veterinary and animal production apps, big data and cloud-based computing to more effectively and efficiently raise animals.

While the Canadian animal health industry is relatively small in terms of market size, as compared with the large global business, Canada has played, and will continue to play, a leadership role in developing new products to ‎serve the needs of Canadian and global customers. The following is a summary of the animal health industry opportunities outlined in this document targeted to encourage further sectorial dialogue among industry partners with a look to being prepared for what lies ahead. 33 The Canadian Economy is targeted to be one of the top performers in the G7 countries which can factor into sustained business strength for Canadian veterinarians and food animal producers. 33 The red meat industry is experiencing record high prices which will likely lead to growth in the beef and www.animalhealthmedia.com

33

33

33

33

swine herds and increased attention to animal health needs. Global demand for animal-based protein is targeted to grow. Canada has an excellent resource base and image that will support domestic and export needs for safe, high-quality food animal products. Veterinary practices are undergoing consolidation that will help to build dynamic new business models to meet animal owner needs. The Canadian regulatory programmes for animal health products are globally competitive and strive to serve human, animal and environmental safety needs. Federal controls over importation and use of nonapproved animal drugs are anticipated and will help to serve consumer confidence in food animal products and equivalency in our food safety standards with that of our trading partners. Canadian regulatory programmes, intellectual property protection laws and research institutions are world-class and support animal health innovation. Canadian veterinarians and food animal producers are internationally recognised for their competence in delivering good veterinary medicine and food animal production regimes, respectively.

3) The Last Thought The animal health industry has many strengths and needs to collectively look to the future to manage in a climate of global economic downturn and new ways of doing business that are impacting the animal health industry and its customers. Canada has much to be proud of in terms of our‎ ability to effectively produce animals in our resource-rich and environmentally pristine landscape, while at the same time clearly recognising the value of the pet to society. Keeping our eye on the end user and the distribution system will be critical as we work to meet their respective needs, and to thereby ensure the ongoing viability and growth of the Canadian Animal Health industry.

Jean Szkotnicki is President of the Canadian Animal Health Institute (CAHI), the trade association representing companies that develop and manufacture pharmaceuticals, biologicals, feed additives and pesticides for use in companion and food animal medicine. In her capacity as President, Jean works with CAHI members to develop Institute policy and strategic directions focused on availability of safe and efficacious medicines that keep animals healthy and food safe while contributing to the economic viability of animal farmers. Liaison and communication activities with regulatory authorities, producer groups, veterinary associations, research institutions and the media are important in her role. Jean serves on a number of agricultural Boards and has a love for equine sports. She lives with her husband and son on a farm near Guelph, Ontario. Email: jszk@cahi-icsa.ca

International Animal Health Journal 15


Regulatory & Marketplace

Veterinary Medicinal Products – What Might Happen if the UK Withdrew from the European Union? Introduction The United Kingdom’s membership of the European Union (EU) is often a topic of heated debate. While some political parties are enthusiastically in favour of our continued membership, others are lukewarm and one party in particular is vehemently opposed. Somewhere in between the “must stay in” and “get out at all costs” camps are the more restrained opinions. These believe that the EU is fine as a “common market” and trading bloc, but they fear that it interferes too much in sovereign issues while encouraging further European integration. Indeed, the fear of and opposition to a federal Europe, not to mention a common currency, unite the strident “antis” with the slightly less radical Eurosceptics. As a result, there have been numerous articles written about the UK renegotiating the terms of its EU membership, while for some, only a complete withdrawal would be satisfactory. Presumably, if the UK did renegotiate its terms of membership, some things would change while others would remain unaltered. Alternatively, there has been talk of a two-speed Europe with the UK and like-minded countries enjoying some of the benefits of EU membership (such as the single market/lack of barriers to trade) but eschewing others (like open borders, monetary union, and further political and fiscal integration). Parallels are drawn with membership of the European Economic Area (EEA) which currently includes all EU countries (except Croatia which has yet to join but will do so pending ratification by all EEA states), plus three of the four European Free Trade Association (EFTA) countries, Iceland, Norway and Liechtenstein (Switzerland, the fourth EFTA country, is not a member). 1 EEA membership allows countries to participate in the EU’s internal (single) market and EEA countries adopt most (but not all) EU legislation. The Conservative Party in the UK has promised a referendum on EU membership should it win the 2015 election. The Labour Party does not presently support a referendum, but it is willing to consider the possibility in the future, while the Liberal Democrats, partners in the current coalition government are staunchly pro-EU. Were a referendum to be conducted, and a “no” (to continued EU membership) obtained, then a UK withdrawal from the EU would be a real possibility, the so-called Brexit (or Brixit) option. 2 If the UK were to adopt an arm’s length membership, or retain its membership of the EEA without being in the EU, nothing much would change. However, if the UK was to withdraw from the EU and relinquish its membership of the EEA, then the consequences for the regulatory control of many commodities, including pharmaceuticals, would be dramatic. As membership of the EEA would mean that the UK would retain what many see as the more onerous aspects of EU membership, then 16 International Animal Health Journal

it would have to have to consider other options, possibly membership of EFTA but without ties with the EEA in a manner similar to Switzerland. 3 Much of the UK’s manufacturing and export trade is covered by EU legislation. It applies to many areas including aspects of automotive products, fisheries, agriculture, aviation and food and indeed to anything where internal barriers to trade may occur and a single market is desirable. However, certain commodities are subject to strict regulation under EU legislation and among these are many types of chemical speciality. These are frequently regulated under EU directives, regulations and decisions by national competent authorities and by EU agencies, as shown below in Table 1. Regulation of Pharmaceuticals Pharmaceuticals, including veterinary medicinal products, were for a long time regulated in the UK under the Medicines Act 1968, and by Statutory Instruments made under the Act. From the UK’s joining of what was then the European Economic Community (EEC) in 1973, ensuing Statutory Instruments became more and more influenced by European pharmaceutical legislation. Following the major revision of the veterinary pharmaceutical legislation in 2004, the use of the Medicines Act was all but abandoned except for some UK-specific sections. Instead, it has been replaced by the Veterinary Medicines Regulations. The latest incarnation of these are The Veterinary Medicines Regulations 2013. These implement the requirements of the current EU legislation, namely Directive 2001/82/EC as amended by Directive 2004/28/ EC (and other EU legislation) and supplemented by UKspecific requirements and aspects of other Directives and Regulations relating to medicated feeds and additives for use in animal nutrition (http://www.vmd.defra.gov.uk/ public/vmr.aspx). The legislation is enforced in the UK by the National Competent Authority, the VMD, as indicated in Table 1. EU pharmaceutical legislation, including veterinary pharmaceutical legislation, is complex and dates back to Directive 65/65/EEC. This applied to human and veterinary medicinal products and it introduced the concept of the marketing authorisation (MA) subject to the criteria of safety, quality and efficacy. 4 Over fifteen years later, Directive 81/851/EEC was published as a comprehensive regulatory framework for veterinary medicinal products, while Directive 81/852/EEC set out the testing requirements to demonstrate safety, quality and efficacy. These two pivotal Directives were supplemented by a range of amending Directives over the ensuing years, notably by Directive 92/18/EEC which updated the data requirements originally set out in Directive 81/852/EEC. Volume 1 Issue 2


Regulatory & Marketplace Table 1. Regulation of Various Chemical Specialities in the UK Product Category

UK Competent Authority

Plant protection products

Health and Safety Executive

EU Agency European Food Safety Authority (EFSA)

Food/feed additives

Food Standards Agency

EFSA

Biocides

Health and Safety Executive

European Chemicals Agency (ECHA)

Commodity chemicals (REACH and

Health and Safety Executive

ECHA

Veterinary medicinal products

Veterinary Medicines Directorate

European Medicines Agency (EMA)

(including vaccines)

(VMD)*

Human medicinal products

Medicines and Healthcare products

(including vaccines and devices)

Regulatory Agency (MHRA)+

other legislation)

EMA

*An

agency of the Department for Environmental, Food and Rural Affairs, DEFRA

+An

agency of the Department of Health, DH Table 1. Regulation of Various Chemical Specialities in the UK

In 1990, Regulation (EEC) No 2377/90 introduced requirements for maximum residue limits (MRLs) for pharmacologically active substances intended for use in food animals. MRLs are intended to protect human consumers from potential harmful effects of residues (parent compound and/or metabolites) of pharmacologically active substances used in food animals which remain in tissues after slaughter or are present in food derived from treated animals (milk, eggs and honey). This legislation required that no pharmacologically active substance could be used in veterinary medicinal products intended for use in food animals unless MRLs had been established (or MRLs were considered unnecessary) and the legislation was applied retrospectively to all existing pharmacologically active substances. The term “pharmacologically active� is important as it applies equally to active substances and to excipients such as solvents, antioxidants, emulsifying agents and colourings, as well as to adjuvants and preservatives used in veterinary vaccines and other biological products intended for use in food animals. Up until the mid-1990s, MAs were granted by the national competent authorities and MRLs were established by the European Commission (EC) on the basis of an opinion from the then Committee for Veterinary Medicinal Products (CVMP). This changed with the arrival of Regulation (EEC) No 2309/90 which introduced the European Medicines Evaluation Agency (EMEA) and the Centralised Procedure. The CVMP became part of the structure of the EMEA and met in London instead of in Brussels, and it provided opinions on applications using the Centralised Procedure while continuing to provide opinions on MRL applications. Now MRLs and MAs considered under the centralised procedure were agreed by the EC on the basis of positive www.animalhealthmedia.com

opinions of the CVMP. At the same time the mutual recognition system was introduced, whereby national, but harmonised MAs were issued by EU/EEA countries after an initial assessment and granting of an MA by one member state (which became the reference member state, RMS) followed by assessment and eventual mutual recognition by other member states involved in the procedure (the concerned member states, CMS). In 2004, this changed again after a review of the veterinary (and human) pharmaceutical legislation, as indicated earlier. Directive 2001/82/EC was amended by Directive 2004/28/EC, while Regulation (EEC) No 2309/93 was repealed and replaced by Regulation (EC) No 726/2004. Under the amended Directive, a number of changes were introduced, including the introduction of the decentralised procedure, while a coordination group previously set up under a voluntary basis to try and resolve scientific disputes with the mutual recognition procedure was given statutory backing as the Coordination Group for Mutual Recognition and Decentralised Procedures (veterinary) (CMDv), and, as its name suggests, it now attempts to resolve issues not only for the mutual recognition procedure, but also for the decentralised procedure, a procedure broadly similar to that of mutual recognition, but which involves simultaneous submission to all countries, rather than an initial submission in one followed by subsequent submissions to the other. Both the new amending directive and the new regulation substantively upgraded the requirements for pharmacovigilance, while the CVMP became the Committee for Medicinal Products for Veterinary Use. In 2009, Regulation (EC) No 470/2009 repealed and replaced Regulation (EEC) No 2377/90, extending the International Animal Health Journal 17


Regulatory & Marketplace scope of MRLs and replacing four annexes in the old regulation with two tables – allowed substances and prohibited substances. The amalgamated lists, previously established as a large number of amending regulations under Regulation (EEC) 2377/90 were consolidated in a single regulation, Regulation (EU) No 37/2010. 5, 6 Membership of EMA Committees and Other Advisory Groups Members of the CVMP are nominated by EU/EEA member states and are frequently drawn from the national competent authorities. Thus, the UK has one member, and one alternate, both from the VMD. The CVMP has a number of working groups, as follows: • • • • • • •

Antimicrobials Working Party Efficacy Working Party Environmental Risk Assessment Working Party Immunologicals Working Party Quality Working Party Safety Working Party Scientific Working Party

The UK has representatives on most of these groups. Moreover, the UK is represented on the EMA’s Management Board, albeit by individuals from the MHRA, not from the VMD. Nevertheless, the VMD can express its views to the Management Board through MHRA members. Like the CVMP, the Management Board has representatives from EU/EEA states. The UK is represented at the Heads of Medicines Agencies (HMA) group meetings (http://www.hma.eu/ veterinary.html). This is an important group with sections for both human and veterinary medicinal issues which brings together the national competent authorities of EU/EEA countries. It has a number of functions, including the development of regulatory strategy and training and benchmarking regulatory agencies. One of its most critical roles is the provision of the statutory Coordination Groups, the CMDv mentioned earlier, and the corresponding group for human medicinal products, the CMDh, both of which work to resolve issues encountered in mutual recognition and decentralised procedures in their corresponding sectors. The HMA and CMDv have representatives of EU and EEA countries. If the UK were to withdraw from the EU but remain in the EEA, it would still enjoy the benefits enjoyed by Norway, Iceland and Liechtenstein, and it would maintain some influence within the EU while being outside. However, if the UK also withdrew from the EEA, and even if it joined EFTA, then it would relinquish that influence along with its roles with regard to the EMA, its Management Board, the CVMP and its working parties, as well as the HMA and the CMDv. The UK frequently acts as rapporteur or co-rapporteur for centralised procedures and for MRL applications, and as reference member state for mutual recognition and decentralised procedures. It also takes on responsibilities for formulating guidelines 18 International Animal Health Journal

and other documents within the working parties of the CVMP. If it withdrew from the EU and the EEA, these positions of influence (not to mention source of VMD income) would be lost. Marketing Authorisations For veterinary medicinal products, a high proportion of marketing authorisations (MAs) are national MAs granted prior to the introduction of the European procedures. In the UK, these were originally issued as product licences. However, there are now a large number of MAs issued under the mutual recognition or decentralised procedures (which of course are also national MAs), and a small number of national authorisations granted since the inception of the new procedures, but which, for a variety of reasons (e.g. company size and resources, countryspecific diseases, marketing decisions) have been registered in only one member state, negating the need for the mutual recognition or decentralised procedures. Over 170 veterinary medicinal products have been authorised through the centralised procedure (although several of these have since been withdrawn by the MAH). Consequently, on the UK market there are a variety of veterinary medicinal products authorised as solely national UK products, as products issued as national marketing authorisations under the mutual recognition or decentralised procedures, or authorised through the EU’s centralised procedure. Some of the older national MAs have been reviewed under the terms of Directive 81/851/EEC and updated, but they remain UK national marketing authorisations. Others have been subject to a referral procedure and so specific aspects of data have been subject to a CVMP opinion and a Commission Decision, usually with subsequent amendments to the SPC and product literature. If the UK were to withdraw from the EU but remain in the EEA, all of these marketing authorisations would remain valid. If the UK withdrew from the EU and the EEA, all of the national marketing authorisations would remain valid, including those authorised through mutual recognition or the decentralised procedures, although the UK would no longer need to maintain harmonised aspects of the summary of product characteristics (SPC) or labelling, or abide by any restrictions imposed as a result of the procedures. MAs granted under the centralised procedure would no longer be valid in the UK in the event of an EU and EEA withdrawal. However, the UK could presumably opt to issue a UK MA for existing centralised procedure products or even for future ones, or at least implement a fast-track procedure for the latter, without further assessment. For future national products which previously would have been considered under the mutual recognition or decentralised procedures, it would have the option of conducting a separate UK assessment prior to granting an MA, and/or adopting the SPC agreed under European procedures. If it failed to do this, and determined UK-specific indications, contraindications, posology and, in the case of food producing animals, withdrawal periods, then the MAH could face barriers to Volume 1 Issue 2


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trade with the EU/EEA e.g. with parallel exports or with trade in animal produce. The issue of withdrawal periods is extremely important in this respect. A withdrawal period (sometime called a withholding period) is the time that must elapse between drug administration and slaughter for human consumption, or before produce such as eggs, milk and honey can be collected for human consumption. They are based on the time taken for depletion of drug residues to a safe concentration, which is almost exclusively the EU MRL (see next section). If the UK were to establish its own MRL values, or if it adopted EU MRLs but calculated withdrawal periods different from those established in EU countries for the same product, or even if it permitted the use of drugs prohibited under EU legislation, then it would create potential barriers to trade in animal produce with the EU and EEA states. Regardless of the UK’s status after an EU withdrawal, it would clearly be in the interests of UK agriculture and exports, if most aspects of EU MAs were adopted or maintained in UK national MAs. These issues may appear academic, but it is important to learn lessons from the past, before the time of introduction of the EU procedures. Then it was entirely possible for a product to be authorised for dogs and cats in one country, for countries which regarded the horse as a non-food animal (such as the UK), for dogs, cats and horses, while other countries may have these species alongside various food animals, including minor food species such as rabbits, ducks and goats. In short, almost any combination could, and did, exist across the EU for any given product. Where products were indicated for use in food species, in addition to the discrepancies www.animalhealthmedia.com

between species, there were frequently differences in withdrawal periods due to differences in their methods of calculation, differences in the derivation of national MRL values, or a combination of these. The introduction of the European procedures and EU MRL values has meant that these discrepancies no longer occur. The recitals to Regulation (EC) No 470/2009 make it clear that while the prime reason for establishing EU MRLs is to protect public health, they are also “relevant to the functioning of the internal market in products of animal origin.” Were the UK to adopt different approaches to the evaluation of data pertinent to granting UK MAs, then the prospects of trade difficulties with the EU and EEA in produce of animal origin would be genuine. It would therefore be in the interests of UK agriculture if MAs for products for use in food-producing animals, at least, adopted the terms of EU MAs. MRLs EU MRLs are considered following an application to the EMA and consideration of a package of data, largely toxicology, pharmacokinetic and residues depletion data, by the CVMP, which then issues an opinion, hopefully a positive opinion, on the MRL application. MRLs are then published as Commission Implementing Regulations amending the Annex to Regulation (EU) 37/2010 in the Official Journal of the European Union. The MRL procedure is similar in many aspects to that of the centralised procedure and a rapporteur and co-rapporteur are appointed by the CVMP to handle the assessment of data and to prepare assessment reports. MRLs usually appear as numerical values in Table 1 of the Annex to the Regulation (allowed substances) such as muscle, 10 µg/kg; milk, 100 µg/kg etc. Alternatively, they may be International Animal Health Journal 19


Regulatory & Marketplace listed as “no MRL required”, a category usually reserved for relatively innocuous substances (or those rapidly metabolised to innocuous substances by the treated animals). Table 2 (prohibited substances) of the Annex contains a small number of drugs (or groups of drugs) whose use in food animals is not permitted on consumer safety grounds. 7 Other agents, including those with thyrostatic action, β-agonists and the growth-promoting anabolic steroids are prohibited for use in food-producing animals (although therapeutic uses of some of these are permitted) under separate EU legislation (Directive 96/22/EC as amended by Directives 2003/74/EC and 2008/97/EC). Irrespective of where companies are based or where products are made, manufacturers must abide by the legislation on MRLs if MAs are to be granted for foodproducing animals in the EU/EEA. However, if the UK were no longer a member of the EU or EEA, it would be in a position to adopt its own form of MRLs and if desired, authorise products containing substances prohibited in the EU/EEA. However, as described earlier, this would raise potential problems for trade in food of animal origin with the Community, possibly similar to those which have arisen because of the (legal) use of anabolic and other production-enhancing drugs in the United States. 8 In practice, it would probably be simpler and safer for the UK to adopt EU MRL values and the requirements of other EU legislation prohibiting the use of certain drugs in food animals. Residues Surveillance Each year, EU member states conduct surveillance of food commodities of animal origin to determine the presence of residues, or more particularly of violative residue (above the MRL or residues of prohibited drugs) in accordance with the requirements of Directive 96/23/ EC. This Directive requires member states to examine food of animal origin for the presence of residues of certain classes of drugs including those with an anabolic effect, antimicrobial substances, anthelmintics, sedatives and non-steroidal anti-inflammatory drugs, as well as other substances and environmental contaminants such as chemical elements (e.g. cadmium and arsenic), organochlorine compounds and some mycotoxins. The Directive requires member states to draw up a national residues monitoring plan, which needs to comply with its Annex IV which establishes the sampling frequencies, and the types of animal and commodities to be tested. The Directive required the submission of an initial surveillance plan, followed by subsequent annual plans to be submitted to the Commission for scrutiny and approval. In the UK, this work constitutes the Statutory Surveillance Programme. It is supplemented by a NonStatutory Surveillance Scheme which looks for similar violations of residues, mainly in imported foods. If the UK were to leave the EU and EEA, it would no longer need to conduct this work which is overseen by the VMD. However, the results, which are published on the website of the Veterinary Residues Committee 20 International Animal Health Journal

(http://www.vmd.defra.gov.uk/vrc/) would no longer be available to reassure consumers of the safety of food of animal origin. In effect, the UK would become a third country under the terms of the Directive, and would still need to submit a surveillance plan and conduct residues surveillance in compliance with Article 29, if it wished to export its produce to the EU. Consequently, withdrawal from the EU and the EEA would have little effect on the UK’s residues surveillance programme. Pharmacovigilance One of the major requirements in the EU/EEA for the conduct of pharmacovigilance is that for the appointment of a Qualified Person for Pharmacovigilance (QPPV), and one of the major requirements for the QPPV is that he or she should reside in the Community. 9 In Volume 9B of the Rules Governing Medicinal Products in the European Union, it is made clear that Community in this respect means the EU and EEA. So for example, the QPPV could reside in Norway or Iceland as well as in other EEA/EU countries. Thus, any company employing a QPPV in the UK could continue to do so if the UK remained in the EEA. However, if the UK left the EU and EEA, then with the exception of any interim arrangements that might be put into place, the QPPVs currently working in the UK would need to relocate to a country within the EU or EEA. In fact, this would apply equally to QPPVs working in pharmacovigilance of human medicinal products. This would not result in major consequences for many companies which already have offices and operations in these countries, but it could result in logistical problems for those without these facilities. The conduct of a pharmacovigilance operation in the UK would not exempt it from EU pharmacovigilance inspections if products were marketed in the EU or EEA. The UK would then be regarded as a third country, and UK companies or subsidiaries marketing products within the EU would be subjected to the requirements for third countries as set out in paragraph 2.5.9 of Volume 9B. Manufacturing Veterinary medicinal pharmaceutical and biological products for sale and supply within the EU and EEA must be manufactured in accordance with the principles of good manufacturing practice (GMP) as required by Article 51 of Directive 2001/82/EC (as amended). Moreover, the manufacturer must hold a manufacturing authorisation (ManA). ManA applications are made to the VMD except for those manufacturers which produce veterinary and human medicinal products where applications are made to the MHRA. Manufacturing sites in the UK are subject to GMP inspections by the VMD (or MHRA) to ensure compliance. 10 For manufacturing sites in other (third) countries such as the USA, Australia or New Zealand, a GMP inspection may be carried out by an EU/EEA state, prior to authorisation of products made there, and imported into the EU. The manufacturer must appoint at least one Qualified Person and the QP has statutory duties, especially for release of product for sale and use. One of the requirements under the Directive is that the Volume 1 Issue 2


Regulatory & Marketplace QP must reside in the EU or EEA. If the UK were to leave both the UK and EEA, the manufacture of veterinary medicinal products need not be adversely affected. However, the manufacturing facilities would need to comply with the requirements of EU legislation, would need to hold a ManA, would need to be GMP-compliant and would be subject to inspection from EU competent authorities. The QP would need to relocate to an EU/EEA country, rather like the situation with the QPPV described earlier. Conclusions This is not meant to be an exhaustive appraisal of the consequences for the veterinary sector of the UK leaving the EU and the EEA. Rather, it is intended to highlight some of the key consequences. If the UK left the EU but remained in the EEA, then nothing much would change for most practical purposes although EEA members have less influence in the formulation of EU policy and legislation. However, if the UK withdrew from the EU and the EEA, substantive changes or adaptations would be needed in a number of areas, as described above. Many of these changes, with the obvious exception of MRLs, would also apply to human medicinal products. Withdrawal from the EU and the EEA would mean that the UK would lose influence in decision-making bodies such as the EMA, its Management Board, and its expert committees such as the CVMP. However, it would also lose wider influence as a result of its loss of membership of the European Commission and the Council of Ministers. The UK would also relinquish the United Kingdom Permanent Representative to the European Union (UKRep) and membership of the Committee of Permanent Representatives (COREPER) in the Council of the EU. Clearly, it would no longer have Members of the European Parliament (MEPs) and it would lose its place in the Parliament’s influential committees such as the Environment, Public Health and Food Safety Committee which has a responsibility for a number of areas including animal health and chemical safety. It must be emphasised that there has been no suggestion that the UK would not remain as an EEA country. However, with Iceland preparing to accede to the EU, will there be an EEA to remain a member of? As the members of the EU are also members of the EEA, the answer is likely to be yes, but as more countries join the EU (and therefore the EEA) will there be any point in having the EEA at all? Moreover, to avoid some of the obligations that the UK regards as onerous, then leaving the EEA would seem a logical step. This could leave the UK with the only option of joining the European Free Trade Area (EFTA) to garner trading partners. EFTA members currently include Iceland, Norway, Liechtenstein and Switzerland but this is a reduced membership since Denmark left EFTA after it acceded to the EU. In fact, the founder members of EFTA were Portugal, Austria, Denmark, Norway, Sweden, Switzerland and the UK, but as countries joined the EU and left EFTA, membership declined. Although EFTA www.animalhealthmedia.com

countries have bilateral agreements with the EU, unlike EEA countries they do not enjoy the close association with EU processes that EEA countries do. So, if the UK opts to leave the EU, then Europe could indeed become more “isolated”.  References 1. A. Teasdale and T. Bainbridge. The Penguin Companion to European Union, 4th ed., Penguin, London, 2012. 2. A. Bagehot. Brixit looms. The Economist, June 21, 2012. 3. I. Mansfield. A Blueprint for Britain: Openness not Isolation. Institute of Economic Affairs, London, 2014. 4. J. Lisman and C. Schoonderbeek. An Introduction to EU Pharmaceutical Law. Brookwood Medical Publications, London, 2005. 5. K. N. Woodward. Veterinary pharmacovigilance in the European Union in K. N. Woodward (ed.) Veterinary Pharmacovigilance. Adverse Reactions to Veterinary Medicinal Products. Wiley-Blackwell, Chichester, 2009, pp. 19-46. 6. K. N. Woodward. Regulation of veterinary medicines. In K. N. Woodward (ed.) Toxicological Effects of Veterinary Medicinal Products in Humans. Volume 1, RSC Publishing, Cambridge, 2013, pp. 21-39. 7. K. N. Woodward. Consumer safety – maximum residue limits. In K. N. Woodward (ed.) Toxicological Effects of Veterinary Medicinal Products in Humans. Volume 1, RSC Publishing, Cambridge, 2013, pp. 40-80. 8. J. K. Leighton. Center for Veterinary Medicine’s perspective on the beef hormone case. Veterinary Clinics of North America: Food Animal Practice, 1999, Vol. 15, 167-180. 9. K. N. Woodward. The role of the QPPV in EU veterinary pharmacovigilance. Regulatory Rapporteur, 2011, Vol. 8, 16-20. 10. Veterinary Medicines Directorate. Veterinary Medicines Guidance Note No 15. Manufacturing Authorisations, July 2013. Available from www.vmd. defra.gov.uk.

Dr Kevin Woodward is an independent consultant in veterinary regulatory affairs. His areas of expertise include toxicology, residues, user safety and pharmacovigilance. Kevin has previously held senior positions in TSGE Consulting, Intervet/Schering-Plough Animal Health and the Veterinary Medicines Directorate. He was a member of several expert committees including the CVMP and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and was an active member of IFAH-Europe regulatory and technical committees. Kevin has authored or edited three books and published over 100 scientific articles and book chapters. He is a qualified toxicologist and a Fellow of the Royal College of Pathologists. E-mail: knw@knwanimalhealthconsulting.com International Animal Health Journal 21


Regulatory & Marketplace

Overview of the New Draft Regulation for Veterinary Medicines So we have them at last! The Commission published their proposals for the updating of the veterinary medicines and feed medications legislation in Europe in September, five years after starting the review process. The regulatory bodies, industry and veterinarians have started their analysis and the first reactions are emerging. Stakeholders quickly took all of the available remaining places at the TOPRA veterinary symposium in Brussels in October to hear from the Commission, exchange views and ask questions. There is universal welcome of the recognition that the veterinary medicines sector is very different from the human, and the formal separation of their legal frameworks is a major step forward. The Commission’s position is that this is intended to reduce the administrative burden and promote availability, but in reality how far is this achieved in these proposals? As expected and to the stakeholder’s general satisfaction, Directive 2004/82 will be replaced by a Regulation which will incorporate the veterinary provisions of Regulation 726/2004. Member states will lose the flexibility that allowed national nuances in implementation, and marketing authorisation holders and applicants will have a more predictable, harmonised regulatory environment, as they wished. This satisfaction is tempered by the realisation that the proposals have left much unsaid or undefined. To my ear, the last (casual yet enigmatic) remark that the Commission’s representative Martinus Nagtzaam made at the TOPRA symposium was the most important. He emphasised that the draft Regulation is the ‘basic act’ which makes almost no reference to guidance, but instead to unpublished implementing or delegating acts that will provide the tightly described detail in the structure of the new environment. I counted 17 different references to implementing acts, directed inter alia at fees, labelling, variations and particularly antimicrobial resistance. I’m sure there will be consultation before they are final, but will there be enough detail to inform the stakeholder’s comments on the main Regulations, and to direct the lobbying to the Parliament and the Council? Once the Regulations are final, how far and how significantly will we be able to influence the important details in these Acts? The Commission points to significant changes that, according to their figures, will reduce the administrative burden by some 140 million Euros, or 25%. IFAH Europe has been quick to point out that to reach the proportional administrative cost of human medicines, the reduction would need to be doubled. The major administrative burdens were identified, 22 International Animal Health Journal

in order of magnitude, in packaging and labelling, variations, marketing authorisation procedures, renewals and pharmacovigilance, and the Commission has used these as a priority list for the measures. Packaging and labelling has been subjected to a ‘major simplification’, with reduced compulsory information, especially on inner and small packaging and adoption of ‘approved’ pictograms and abbreviations to reduce text for translation. National languages will no longer be required on marketed packs, but the member states will be able to opt for other languages. Industry has long called for such changes to reduce the cost of placing products on the smaller markets, and the changes should further facilitate multi-country packaging. However, the extensive work by CMDv and industry task forces in recent years, reducing to a minimum the packaging constraints within current rules, have not really had any significant impact on availability in smaller markets so far. Twenty five percent of the identified burden was around variations. Changes to marketing authorisations will be simplified and divorced from the variations Regulation 1234/2008. A risk-based approach is proposed; only changes that affect ‘animal health, public health or the environment’ (including an impact on safety, efficacy or the SPC) should be subject to scientific assessment, and the Commission will establish a positive list of changes that require assessment. Other changes will be made on a ‘do and tell’ basis, recorded by the marketing authorisation holder in a newly-established product database within 12 months of implementation. What will be included in the list? As an example, for immunologicals it is difficult to see how most of the changes related to manufacturing or quality could be assumed to be without effect on safety or efficacy without an assessment. The changes (variations) are one of the areas where the details will be through implementing acts, and one where all stakeholders will be paying close attention. The relaxation of pre-assessment is counterbalanced by an emphasis on verifying compliance by inspection and this will simply move the burden. Competent authorities will be required to inspect, on a risk basis, at all stages from manufacture and application to supply, and the Commission will audit this process. One can see the competent authorities’ assessment teams being replaced by inspectors. Despite significant effort by IFAH Europe, all four routes to authorisation will remain. The Commission has taken the view that a single expensive and resourcedemanding pan-European process would disadvantage SMEs, so the national route plus mutual recognition for Volume 1 Issue 2


Regulatory & Marketplace geographical extensions are necessary. The decentralised procedure is available for access to a limited number of member states and the centralised procedure for the innovative and pan-European products. Although the Commission claims that simplification will remove some of the barriers to a true single market, on the face of it this is not addressing its objective of reducing the bureaucratic burden and a single market still seems some way distant, to me at least. The framework for dossier content, application, validation and assessment timetables are common across the procedures, and the Commission has stressed that there will be only one assessment for a new authorisation or for a change, either at a national, pan-national or European level, with decision by a simple majority in the MRP or DCP. Applicants may appeal the assessment, and competent authorities (but not authorisation holders) may refer concerns ‘in the interest of the Union’ (public or animal health or the environment related to the quality, safety or efficacy) to EMA. Further re-assessment for geographical extension is not allowed, so the initial assessment in an MRP or DCP with a few concerned member states will be followed by a purely administrative rollout procedure to others. This seems to be causing some disquiet among the national competent authorities, where true trust and confidence in one another’s abilities is still incomplete and the spirit of ‘mutual recognition’ is absent. IFAH Europe, having missed its goal of a single process and full European authorisation, has indicated that it sees the single assessment with decision by majority vote as its ‘big win’ and will strongly defend this important detail in the lobby. It would seem that there are battles of principle to be fought over the coming months, and the outcome will be fundamental to the shape of the regulatory landscape. The centralised procedure remains the prescribed route for innovative products including new actives, biotechnologies and growth enhancers (although this list may be changed though a delegated act) but it has been opened to all who wish to use it and can afford the higher fees and associated costs inherent in a pan-European authorisation. The new CP will even allow generics of a nationally authorised product provided there is no other authorisation in the Community. Authorisations will no longer need to be renewed, as they will be of unlimited duration – but of course the competent authorities may amend, suspend or withdraw if the benefit/risk balance is unfavourable. The ‘sunset clause’, whereby products off the market for three years would lose their authorisations, has also been removed. Good manufacturing practice remains for veterinary medicinal products and active ingredients as expected, but its scope appears to have been extended to cover intermediate products and excipients. If confirmed, is this extension of manufacturing requirements really necessary? The Commission has indicated that pharmacovigilance www.animalhealthmedia.com

will be simplified, through an ‘updated, targeted approach’ and single management process, with a reduced administrative burden and a risk-based focus on the products of concern. More reliance will be placed on electronic systems and a dedicated Europe-wide pharmacovigilance database will be established into which all adverse events in the Union will be recorded and shared. The database will have variable access for competent authorities, marketing authorisation holders and the public. This will make surveillance at the Union level practicable, and should impose a consistent approach across the countries and authorisation routes. There will be a pharmacovigilance Masterfile linked to the marketing authorisation holder, rather than the product, and the periodic safety update report will be abandoned. Instead, there will be a requirement on authorisation holders and competent authorities alike to record all adverse events – human or animal, serious or mild – within 30 days into the database. Surveillance by competent authorities will focus on signal detection, and the Regulation provides various mechanisms to allow and promote sharing of responsibilities between authorities and targeting of products or groups of products of concern. Competent authorities will be required to promote adverse event reporting by veterinarians and owners. All sectors of industry have consistently argued that the great majority of the estimated 30,000 existing marketing authorisations must be brought to wider access across the member states in an administrative process that preserves the existing indications and target species, while acknowledging that some products may require assessment. At first glance the draft Regulation allows just this, with an administrative process for ‘similar products’ authorised before 2004 which maintains the higher common denominator for species and indications and the shortest withdrawal period. The CVMP, however, must identify the groups of products where a re-assessment should, in their view, be carried out. The reassessment will then be mandated by further implementing acts by the Commission. Will the competent authorities easily accept harmonising to the shortest withdrawal period without reassessment? The words ‘similar products’ here are significant – essentially the harmonisation will be across all products with the same active substance composition and pharmaceutical form in the Union, not for the same product authorised by one MA holder in different member states. This ‘class harmonisation’ has already attracted the attention of IFAH Europe, which is strongly opposed. The Commission claims to have taken a balanced approach to data protection, now referred to as ‘protection of technical documentation’, in order to maintain innovation and competition, and encourage better availability. The global marketing authorisation principle is maintained and protection for listed species – cattle, sheep, pigs, chickens, dogs and cats but not salmonidae – is set for 10 years, for antimicrobials and International Animal Health Journal 24


Corporate Profile We have a full-time archivist, and in-house information technology support. Our staff are active in many professional organisations and we actively encourage and support the pursuit of continuing education opportunities.

Kingfisher International Inc. (KFI) is a Canadian veterinary contract research organisation (CRO) whose sole purpose is to improve the lives of companion animals. We do this by exclusively specialising in product development and regulatory studies (GLP/GCP) for dogs and cats. We pride ourselves on our vigour, our teamwork, our study quality, and our ability to meet or exceed our sponsor’s timelines. We are good listeners and we strive to understand our sponsors’ expectations. Maintaining the highest standards of animal welfare is critical to what we do.

We have two facilities, totalling 15,000 sq. ft., both of which have been purpose-built to our specifications since 2010. In addition to vivarium space (we have room for approximately 100 dogs and 120 cats) we have a fully-validated clinical pathology laboratory, gross post-mortem suite, surgery suite, and treadmill lab. Our facilities are accredited in Good Animal Practice® by the Canadian Council on Animal Care. Kingfisher International Inc. has conducted GLP target animal safety studies for FDA, EPA, and EMEA submission. We have a solid track record of regulatory acceptance, typically on first pass review. We take pride in ensuring concise, comprehensive, quality submissions that smoothly negotiate the regulatory process. While not all of our studies are GLP, we nonetheless maintain a GLP environment every day. We do, however, routinely conduct non-GLP pilot studies in areas such as pharmacokinetics, bioequivalence, tolerance, and surgical and non-surgical models. At KFI we believe that pilot studies are crucial to establishing appropriate endpoints and determining estimates of statistical variability.

Our company was incorporated in 2004 and since then, we have conducted both GLP and non-GLP studies on behalf of eight of the top ten companion animal health companies. Our exclusive dedication to the animal health industry means that we are very familiar with regulatory agency requirements and guidelines (CVM/ EPA/VDD/EMEA). Working in this industry allows us to engage with like-minded professionals who see dogs and cats as the target client, and are just as committed as we are to ensuring animal welfare is at the forefront of our research. We are acutely aware that the research we do and our findings have a direct impact on final labelling. Our staff of 25 people include: veterinarians, PhDs, registered veterinary technicians, quality assurance professionals, study coordinators, laboratory technicians, and animal care attendants.

Our bioequivalence studies are conducted in compliance with GLP regulations and CVM bioequivalence guidelines to support abbreviated new animal drug applications. While we do not have in-house bioanalytical capability, we manage all aspects of bioequivalence studies including, but not limited to: in-vivo phase; bioanalytical method development; validation and sample analysis; pharmacokinetics and statistical analysis; final study report; and archiving. At Kingfisher International Inc., we take seriously the “single point of control” maxim of GLP. We strive to take complete ownership over our studies and provide the sponsor a “turnkey” approach to study management. We do not like surprises and ensure that the sponsor’s experience is as stress-free as possible. We are large enough that we have sufficient resource for complex study designs, yet small enough to ensure that study directors and test facility management are intimately aware of study activities. We understand how sponsors can sometimes feel “out of the loop” when their studies are outsourced and we strive to ensure they are kept fully abreast of study activities. We encourage sponsor audits and value the constructive feedback we receive. Since we are located close to Toronto, Canada we are readily accessible to North American and overseas travel. We are close to several major hotels and many fine restaurants in one of the world’s most multicultural cities. Please contact us to discuss your animal health product development needs! Contact Info: Jonathan Hare, DVM, PhD VP, Research Kingfisher International Inc. 165 Mostar Street, Unit 8, Stouffville, Ontario, Canada L4A 0Y2 Phone: (905) 642-3712 Email: jhare@kingfisherint.com www.kingfisherint.com

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International Animal Health Journal 25


Regulatory & Marketplace There is no decoupling of prescribing and supply in the draft (at least, not at this stage, before the parliamentary review) but veterinarians will be allowed to supply antimicrobials only for animals under their care and only as much as necessary for treatment. Antimicrobial and other products with special properties (such as anabolics, hormones and psychotropics, but also antiinflammatories) may only be handled by companies specifically authorised to do so, and additional recordkeeping provisions apply.

unlisted species 14 years, and bees 18 years. Further, protection may be increased by one year for listed species, four years for other species to a maximum of 18 years and in addition five years for clinical trials for MRLs. I have the impression that neither the generic nor the reference companies are too happy with this outcome, so perhaps the Commission has got the balance about right. Benefit-risk analysis may allow reduced data dossiers for authorisations for minor species and for markets of limited size (geographical or for infrequently occurring diseases), but these will be re-assessed after three, then every five, years. Where there are no licensed products for a condition veterinarians will be able to prescribe alternative products (authorised in same / other species, other member states, for humans) based on clinical judgement of need, without reference to a ‘cascade’. Of course, the choice for off-label use in food species is limited to products with MRLs and conservative but practical withdrawal periods based on a multiple of existing withdrawal periods. Clinical trials are to be regulated at a European level for the first time, with the principles of the ‘3Rs’ to be applied as a legal obligation. However, one area of concern is the strict wording forbidding all food animals in trials involving substances without MRLs from entering the food chain. This seems against 3R principles as well as being a disincentive for innovation. Mitigating the risk of development of antimicrobial resistance is a clear aim of the draft Regulation, which provides the legislative channel for the Commission to tightly control veterinary antimicrobials from authorisation to administration. Several implementing or delegating acts cover antimicrobials, including lists of antibiotics restricted to human medicine, data gathering on antimicrobial use and off-label restrictions. Antimicrobial resistance is now an integral part of the benefit-risk analysis, with refusal where the perceived risk for public health of development of antimicrobial resistance outweighs the benefits of the product to animal health. 26 International Animal Health Journal

In the separate draft Regulation on Medicated Feeds, preventive use (not yet defined) of antimicrobials will be banned, animals must be examined by the prescriber, and strict limits on carryover and homogeneity will be enforced. These latter provisions may see many of the feed manufacturers withdraw from handling medicated feeds. Distribution and supply of all veterinary medicines are closely controlled, but authorised distributors and retailers will be able to carry out their business throughout the Union, including retail by internet. Internet sales will be regulated using the UK model, with authorised retailers displaying a common logo denoting their status, and they will be able to supply in another member state. Space permits only this brief outline of the main and notable provisions in the draft Regulation, which stretches to 150 Articles and 82 ‘whereas’; many have gone unremarked in this article. Nevertheless, the Commission’s draft Regulation contains a lot that is positive. Of course, questions arising from detailed examination of the text are being raised – for example, are fermentation products or insulin classed as ‘biological products’? What exactly are the requirements for generics regarding environmental assessments? Answers may emerge during the co-decision procedure, but so will many more questions and amendments that could significantly change the eventual legal text. Implementation is not expected before 2018 (nine years after the process was started). There is a long way to go but in my opinion the proposal provides a good framework for an improved regulatory landscape. The views expressed in this article are my own and not necessarily those of any organisation with which I am associated. Paul Cooper is an independent consultant in Veterinary Regulatory Affairs. Paul is currently Vice President of the Association of Veterinary Consultants and Chair of the British Veterinary Association’s Medicines Group. Paul has previously held senior regulatory roles in Merial and was an active member of IFAH Europe regulatory and safety committees. Email: paul.cooper@assentra.com Volume 1 Issue 2


Services for the Animal Health and Nutrition Industry Veterinary Clinical Studies Regulatory Affairs Product Development

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Regulatory & Marketplace New Product Development – The Intertwined Worlds of Regulations, Patents and Exclusivity The regulatory, patent and exclusivity issues as they relate to the animal health industry in the United States are complex and overlapping. Given the scope and breadth of this subject matter, the discussion here will focus on drug development. Other product types such as devices, diagnostic or otherwise, and foods, are not discussed here and may be revisited in future articles. However, some generalities can be made that cover all product types within the industry.

The FDA, in general, and the CVM have certainly, from my experience in the past several years, emphasised the need for early engagement. That is to say, to increase the predictability of the regulatory requirements an entity should not wait late into the full development process to request a pre-submission conference to agree on a development plan with the FDA/ CVM, which is then followed up with the full submission of protocols, studies, data…etc.

If a company, whether new or established, is in the process of developing new products, two major considerations must be taken into account. One, the regulatory environment that could potentially govern the product in question and two, the prevailing intellectual property landscape that could pose a significant barrier to entry if not explored and understood upfront. Both aspects are complex, expensive and have an enormous impact on any company’s bottom line. Although patenting something is still somewhat of a choice that an entity can exercise some degree of control over, the regulatory requirements governing a particular product are not. They must be complied with and pose more of a risk if the company does not.

During the pre-development timeframe or during the early development process and prior to the start of full development of any product, companies are encouraged to seek informal meetings with the FDA/CVM. Those meetings should be used to provide as much early information as possible to the FDA/CVM. This information can be based on short-term studies with fairly narrow scientific focus providing justifications, pharmacological and toxicity information, supporting literature and any available pilot studies. All this early information can then form the basis for the “official” pre-submission conference and flow into the Investigational New Animal Drug file. These early communications should also be used to gather information, identify and leverage existing resources, identify issues and gaps of knowledge and perform a risk analysis with the ultimate aim of making a well-informed decision that if left to be made based on the traditional process could end up being extremely costly in time and money.

Within the United States the regulatory bodies that govern animal health products include the United States Department of Agriculture (USDA) and the Food and Drug Administration Center for Veterinary Medicine (FDA/CVM). For certain product categories the United States Environmental Protection Agency (EPA) may also be involved. Within the USDA the Center for Veterinary Biologics oversees the development of products that are extracted from biological sources and have medicinal or therapeutic properties (biologics). The FDA/CVM on the other hand is responsible for regulating drugs, devices and foods. Traditionally speaking, the process of engaging any regulatory body for any reason usually induces the “roll of the eye” reflex. That the process can be very costly, slow and frustrating is very true, but as the saying goes “you need two to tango”. Approaching the regulatory requirements pragmatically and proactively is not only good for limiting the stress associated with the exercise but also makes perfect economic sense. The principle here is very simple and transcends the type of industry or product involved, if predictability of a process is increased, risk is reduced and the returns become more attractive. This is particularly important given the fact that a blockbuster drug in the animal world only brings in a fraction of the revenue usually associated with a blockbuster drug in the human world. Having said that, there is plenty of economic value still to be had, and with planning and proactive work the regulatory process may not be as daunting or costly and therefore, adding to the overall economic return of a product. 28 International Animal Health Journal

This idea of a proactive approach and increased consultation and communication at an earlier stage with the FDA/CVM is not necessarily novel but it’s seldom practised. Regulations are unavoidable, and if applied more widely and uniformly, a proactive approach will mitigate the risk and cost of failure and help streamline the approval of new drugs at a faster rate. Similar to the regulatory process, the process for patenting something can be complex, costly and very frustrating, yet for a highly competitive industry with strong growth potential such as the animal health industry, having a robust and successful intellectual property strategy is essential. Until recently, the United States was the only country in the world with a first-to-invent system versus a first-tofile system. However, in 2011, the United States Congress passed a law that changed the patent system to a first-to-file system, therefore joining the rest of the world. Having said that, the United States still has a special rule that essentially states that if you disclose the invention at a conference or elsewhere, you have a one-year grace period to file a patent for it within the United States. This means that a disclosure will prevent someone else from getting a patent on your invention in the meantime. However, that is a double-edged sword because disclosure may hurt the chances of patenting the same invention elsewhere in the world. Volume 1 Issue 2


Regulatory & Marketplace Regardless of which side of the fence you live on, whether for or against patents, from a social point of view the economic impact of a well-developed patent portfolio or even a well-placed single patent can give a drug company a big boost in the market place. Given the amount of time and resources to put a single molecule drug, for example, out on the market, the costs of any associated patent or patents may pale into insignificance. Furthermore, although patents can be challenged and in certain cases circumvented by other clever inventors, having some protection may afford the company that holds the patent some time to recoup some of the costs of bringing the drug to market in the first place. Furthermore, only a small fraction of the drugs researched actually make it to market and because of the costs associated with researching all of those “failed” drugs, having patent protection on one or two drugs that are successful in the market place will more than likely guarantee enough uncontested return to encourage continued future investments in other like products, which is essential to the survival of the overall industry. Patent strategies must be crafted to provide operating space in a very crowded industry sector. The engagement of a competent law firm is only one step in the strategy. Deciding what needs to be protected by a patent and how to design the claims to effectively exclude competitors from the immediate subject matter at the heart of the patent are other aspects that are central to a successful overall strategy. Very few companies approach the issue of patenting in their early stages, mainly because of the costs associated with the patenting process. However, if left until later stages, the patent strategy is more likely to be reactive rather than proactive and may not be as effective in providing exclusivity when the chips fall. Patents confer exclusivity of use of the subject matter to the patentee, however, there are other instruments that could be employed and that provide exclusivity, albeit for a shorter period of time compared to the protection time covered by an issued patent. Patents are granted by the patent and trademark office and can encompass a wide range of claims. However, the FDA can grant exclusive marketing rights upon approval of a drug. Those “exclusivity” rights can run concurrently with an existing patent or not. Exclusivity here is a statutory provision and is granted if certain statutory requirements are met. Exclusivity was designed to promote a balance between new drug innovation and generic drug competition. The Generic Animal Drug and Patent Term Restoration Act of 1988, known as GADPTRA, amended the Federal Food, Drug, and Cosmetic Act to provide for the approval of generic copies of animal drug products that have been previously approved and shown to be safe and effective when used in accordance with their labelling. If evidence is provided that a generic animal drug product has the same active ingredients, in the same concentration, as the approved animal drug product, and that it is bioequivalent to the approved animal drug product, the generic drug may be approved under the GADPTRA. www.animalhealthmedia.com

All animal drugs that were approved for safety and effectiveness on November 16, 1988, or have been approved since that date, that have not been withdrawn from the market and are not subject to a Notice of Hearing published in the “Federal Register” and are not protected by patent or exclusivity, can be copied under the provisions of the GADPTRA. The FDA/CVM publishes a list of animal drug products that can be copied as generics (Green Book) to meet the requirements of the law. The law allows a period of three years of marketing exclusivity for a new use of an animal drug and five years of marketing exclusivity for an animal drug that has not been previously approved in any new animal drug application. During those two periods, respectively, no abbreviated applications for a generic copy may be approved for the new use and no abbreviated applications may be submitted. The law also provides another type of exclusivity referred to as “Patent Term Restoration”. This provision extends the period of protection by US patent for an animal drug, or its method of use, that was approved after November 16, 1988, to compensate for the time that was required for investigation and regulatory review of the animal drug prior to its approval. Patent term restoration is not related to the exclusivity periods described above and may overlap those exclusivity periods. An outside observer can look at the combined economic impact of the regulations and patent protection mechanisms from two very different points of view. On one hand the regulations and patents can be viewed as counterproductive and a burden on the economy, providing only a net negative in the long run. The other side of this argument would be that approached wisely and methodically at the inception of a new product development cycle; the various regulations, patent protections and exclusivity provisions can in fact enhance the value of a company’s products by many fold over a long period of time. Under those circumstances, and if applied across a whole industry sector, an overall positive economic impact cannot be ignored or underestimated. The multiple regulatory hoops to jump through and the seemingly unending costs associated with patenting a new product may appear to be a dark cloud at first; however, upon a more thorough and deliberate second look the same dark cloud may end up with a very prominent silver lining. References: 1) www.fda.gov

Dr. Sam Al-Murrani Chief Executive Officer Babylon BioConsulting LLC, a human and animal health-based business consultancy firm. He is also Managing Director for Bimini LLC, a privately owned pet health company manufacturing pet dose-form health supplements and a newly introduced line of pet health treats Email: murrani@babylonbioconsulting.com

International Animal Health Journal 29


Corporate Profile Catching up with Zoetis Canada What does it mean to be an independent global animal health company? It means that Zoetis has the enthusiasm of a startup, yet we’re building on six decades of experience — delivering quality medicines and vaccines, diagnostic products, genetic tests, and a range of relevant services. It means that Zoetis works hard on the real-world challenges facing those who raise and care for animals, helping to improve outcomes and productivity while bringing new medicines and vaccines to veterinarians. The Zoetis name derives from the word “zoetic”, which means “pertaining to life.” It signals our company’s dedication to supporting veterinarians, livestock producers, and all those who raise and care for the farm and companion animals on which we depend. The Zoetis vision: That our products, services, and people will be the most valued by animal health customers around the world. The Zoetis mission: We build on a six-decade history and singular focus on animal health to bring customers quality products, services, and a commitment to their businesses. Zoetis provides vaccines, parasiticides, anti-infectives, medicated feed additives, and other pharmaceuticals. Our complementary businesses include diagnostics and genetics, as well as services such as dairy data management, hatchery in ovo injection equipment, e-learning, and professional consulting. Zoetis experts also provide extensive customer service, technical education, and business support across seven core species (cattle, horses, poultry, sheep, pigs, cats, and dogs). We aim to help our clients manage their businesses more effectively. Putting our customers first: We strive every day to put our customers first. Zoetis field representatives lead the way by developing beneficial business relationships with customers that endure for years. Technical and veterinary specialists, who provide in-depth technical expertise and disease education, support these relationships. With extensive on-the-ground presence, Zoetis can react quickly to local-market needs and be well positioned to help our customers continually increase their business productivity and sustain longterm success. When our customers thrive, we thrive. A Singular Focus on Animal Health It’s who we are and what we do. And with this singular focus, Zoetis puts customers first and assists them in making a real difference in the world. We’re dedicated to the business of animal health so that our customers can be dedicated to theirs. We know how deeply the 30 International Animal Health Journal

world depends on animals, so animals — and the people who care for them — can depend on us. Research and Development Zoetis is focused on continuous innovation to develop animal health. R&D is at the core of our efforts to provide innovative outcomes that anticipate the future needs of veterinarians and livestock producers in their local markets around the globe. Our new product R&D leverages relevant discoveries from the agribusiness, pharmaceutical, and biotechnology industries. Combining this capability with the most promising discoveries from existing Zoetis R&D generally yields a faster, less expensive, and more predictable process and more sustainable pipeline as compared to human health R&D. Zoetis R&D for existing products focuses on broadening and enhancing our existing portfolio through the addition of new species or claims, securing approvals in additional countries, or creating new combinations and reformulations that extend Zoetis innovations to a growing range of those who raise and care for animals worldwide. R&D Areas of Focus Our research is fuelled by both innovation within Zoetis and collaboration with external partners. We apply our research to a broad and diverse range of species, therapeutic areas, and geographic regions, with research that encompasses vaccines and medicines. In addition, our R&D activities include the development of genetic and diagnostic products as well as biodevices and engineering investments for in ovo poultry applications. Vaccines: Zoetis is a global leader in the research and development of products that help prevent infectious diseases in companion animals and livestock, including poultry and aquaculture. Our research includes modified-live, inactivated and gene-modified approaches to disease prevention. Zoetis’ technical expertise, innovative models, and global presence facilitate rapid response to address new and emerging infectious diseases. Medicines: Zoetis is the leader in the identification, research, and development of small and large molecules for therapeutic use in companion animals, and for therapy and improvement of production efficiencies in livestock, poultry, and aquaculture. We seek approaches that improve animal health with a keen eye to environmental sustainability, safety, and food security. Genetics: Zoetis Genetics R&D delivers comprehensive, state-of-the-art genetic information and support Volume 1 Issue 2


Corporate Profile

Our regional footprint, supported by our in-country and global market research, is at the core of our ability to respond rapidly and accurately when emerging infectious diseases spread and threaten the lives of people, animals, and livelihoods. Zoetis Canada, At a Glance Cattle and companion animals are the leading divisions at Zoetis Canada. Zoetis Canada oversees the care of 10.3 million beef cows and 2 million dairy cows throughout the country, while 8.5 million cats and 6.4 million dogs comprise the companion animal population in Canada.

services that deliver genetic predictions and solutions to beef, dairy, and sheep producers. From breeding through to marketing, our solutions address real-world needs and help customers unlock the value of an animal’s genetic potential.

Looking after 1.2 million sows and 685 million birds, the swine and poultry divisions are important industry leaders in Canada; as is the equine division, which ensures the health of over 1 million horses, nationwide. Zoetis Canada markets 270 products in Canada; the top sellers in this portfolio are:

Diagnostics: Zoetis R&D offers a world-class portfolio of immunodiagnostic products that utilise such technologies as enzyme-linked immuno-sorbent assay (ELISA), Rapid Immuno Migration (RIM™) tests, and agar gel immuno-diffusion (AGID) tests. Our Diagnostics portfolio consists of more than 90 diagnostic tests, including those that veterinarians can use at point-ofcare and for use in diagnostics-reference laboratories.

1. Revolution — a topical solution for the treatment and control of fleas, ear mites, sarcoptic mange mites, ticks, and heartworm.

Biodevices: Zoetis R&D offers a novel and innovative pipeline of automated bio-mechanical solutions to the poultry industry that include cutting-edge technologies for in ovo vaccination of embryonated eggs prior to hatch; identification of embryonated egg status, including live and non-live and other related needs. Our Poultry Biodevice portfolio consists of devices for both the large and small poultry producer and the manufacturer of egg-based vaccines for either human or veterinary use.

3. Excenel — for the treatment and control of respiratory disease in cattle and swine and foot rot in dairy cattle.

R&D Capabilities Expertise: The Zoetis R&D organisation is comprised of scientific experts across numerous disciplines in science and veterinary medicine. These experts leverage stateof-the-art research facilities, and the latest technologies and innovative approaches to deliver complete health solutions to veterinarians and livestock producers. Worldwide presence: In addition to our global R&D headquarters in Kalamazoo, Michigan, the Zoetis research network includes R&D teams throughout the United States (California, Iowa, Maryland, Missouri, Nebraska, New Jersey, and North Carolina), Europe (Belgium and Spain), Australia, and in key emerging markets (Brazil, India, and China). This worldwide network allows us to listen to livestock producers and veterinarians, region by region, and translate their challenges into practical and costeffective innovations tailored to meet their needs. www.animalhealthmedia.com

2. Draxxin — a single-dose low-volume antibiotic for the treatment of bovine and swine respiratory disease, infectious bovine kerato conjunctivitis and bovine foot rot.

4. Bovishield — a range of viral respiratory and reproductive cattle vaccines. 5. Vanguard — a vaccine that aids in preventing canine distemper caused by canine distemper virus. Zoetis Canada has the industry’s leading animal health professionals, including 25 technical service veterinarians. Zoetis’ colleagues, from sales, technical services and enabling functions are totally dedicated to animal health. Working Closely with Each Customer We have the local presence and knowledge to serve the needs of each individual customer, as well as the global reach and resources to help advance animal health around the world. First and foremost, we strive to form deep, enduring relationships with our customers through the largest direct sales force in the industry. Our sales teams and veterinarians provide expertise and disease education on the ground in more than 70 countries. We’re in the clinic, on the ranch, and just a click or phone call away. At Zoetis, it’s always: For animals. For health. For you.

International Animal Health Journal 31


Research & Development Targeted Drug Delivery for Veterinary Infections 1. Introduction Domestic livestock are primary drivers for the livelihood of 600 million farmers in developing countries and contribute to about 30-35 per cent of agricultural gross domestic product 1 . Devastating outbreaks of new diseases and re-emergence of old infections in animals with almost 61% of transmissible zoonotic infections are of paramount importance for livestock keepers2,3. More than 200 zoonoses have been defined4 and attributed to ~2.2 million deaths/ year and ~ 2.4 billion cases of human illness globally5. Delayed detection is often associated with spread of the infection to entire herds and humans. Some zoonoses have spread beyond geographical boundaries and are globalised, e.g. H1N1, swine flu, Ebola, etc., and are threats for bio-security and bioterrorism. The World Organization for Animal Health adopts the policy of “Stamping out (Cull and Kill), vaccination, or a combination of the two”6. In countries where such strategies are not legally permitted, livestock keepers are constrained to remain in close contact with the infectious animal, thereby endangering themselves. Drug resistance to existing therapies, insufficient drug potency, side-effects and drug residues in animal products compound the woes7,8,9. The problems escalate further, when the infections are intracellular. 2. Intracellular Infectious Diseases Intracellular infectious diseases are caused by pathogens that reside within the primary immune defence mechanism of the host, generally comprising macrophages from different reticuloendothelial organs (liver, spleen, lymphoid tissues, etc). They are more difficult to eradicate. Extracellular pathogens in contrast survive on epithelial surfaces and extracellular spaces of the body that release specific proteins or toxins triggering body immune mechanism, and are generally more accessible to treatment. Interestingly, intracellular infection results when the organism outsmarts the body’s defence system. Phagocytosis of organisms following recognition is a natural defence strategy to kill the pathogen. Nevertheless, smart pathogens develop various adaptive mechanisms, survive destruction, and harbour safely within the reticuloendothelial system (RES). Common zoonotic infections and their major locations in the RES are listed in Table 1. 3. Adaptive Mechanism A number of strategies are adopted by smart pathogens to evade death. Bypassing of normal phagocytosis and internalisation into macrophages by alternative pathways, parasitophorous vacuole or receptor-mediated pathways such as clathrin is an important approach37. Secretion of endolysosomolytic enzymes or endotoxins that break down endosome membrane favour direct entry into the nutrientrich cytosol38, 39 by passing phagolysosomal destruction40, 41. Interference with the phagolysosome formation by either preventing acidification of phagosome, delayed fusion with lysosome, enzymatic breakdown, reduced levels of proton ATPase, disturbances in forming lipid rafts or altering host signal is yet another possibility42, 31. Virulent pathogens also 32 International Animal Health Journal

have general resistance that permits survival in low pH, lytic enzymes, oxidants and various other harsh conditions43. These mechanisms are depicted in Figure 1.

Figure 1: Uptake and adaptive mechanisms of intracellular pathogens by macrophages 4. Nanotechnology – A Solution Conventional drug delivery strategies rely on diffusion of drug across cell membranes to build up intracellular concentrations. On the other hand, nanocarriers can be designed to follow the same pathway as the virulent organism to enable high drug payloads within the cell. More importantly, nanocarriers also overcome other confronting challenges, namely drug efflux through efflux pumps and Cyp-mediated metabolism. Targeted delivery of nanocarriers thus presents a promising therapeutic strategy in infectious diseases more specifically. 5. Targeted Drug Delivery The challenges posed for the successful therapy of veterinary infections differ significantly from human infections, not so much in the eradication of the infections, but more so with drug concentration in non-target locations. Indeed, secretion of drug in milk of lactating animals and residual drug concentrations in meat pose significant hurdles in veterinary therapy. The concept of targeting goes back to the early twentieth century when the Nobel Laureate Paul Ehrlich proposed the magic bullet. The concept, however, has been exploited, although to a limited extent for human therapy, primarily for cancer treatment (e.g. Doxil®). AmBisome® explored for leishmaniasis and fungal infections is the first success story, confirming the major role nanocarriers could play in the improved therapy of infections44. Targeting to the RES can provide a key solution for most livestock intracellular infections. Passive and active targeting strategies can be exploited to target macrophages. Passive targeting would rely on the body’s natural phagocytic ability to engulf the nanocarriers and would be significantly influenced by surface properties, mainly particle size, charge, shape and hydrophilicity. Active targeting using appropriate ligands to facilitate endocytic uptake can further enhance intracellular drug levels. Targeting Volume 1 Issue 2


Research & Development Diseases

Causative organisms

Foci of infection

Adaptive mechanism

Reference

Diseases of bacterial origin Actinomycosis

Actinomyces bovis

Lung, bone and muscles, lymphatic systems

Block phagocytosis

Anthrax

Bacillus anthracis

Lymph node and spleen

Brucellosis

Brucella spp.

Spleen, liver, lung, kidney, lymphatic system, bone marrow, intestine, CSF, seminal vesicles, testicles and epididymis

Develops spores preventing breakdown Forms beta- 1,2 glucans and disturbs normal formation of lipid rafts

Ehrlichiosis

Ehrlichia spp.

Leukocytes and retain in systemic circulation

Inhibit phagolysosome fusion, and survive

Johne’s disease

Mycobacterium paratuberculosis

Lymph nodes, liver, GI tract

Replicates in macrophage phagosomes that fail to mature

Streptococcus agalactiae Yersinia pseudotuberculosis

Alveolar cells and macrophages Lung, liver and lymphatic system

Coxiella burnetii, Clostridium spp.,

Lung and liver

Mastitis Pseudotuberculosis Q fever Tuberculosis Tularemia

Mycobacterium tuberculosis Francisella tularensis

Lung, lymph nodes Bone, lung

10

Formation of capsule

11,12,13 14, 15

16 17, 18 19

Virulence inhibits phagocytosis Survives in phagolysosomes, uptake by non-phagocytic pathway Disrupts phagolysosome and breakdown by enzymes Disrupts phagolysosome

20, 21 4 22, 23 24

Diseases of viral origin Avian influenza (H5N1)

Influenza A, H5N1

Lungs

Ebola virus infection

Ebola virus

Kidneys, spleen, and liver

Aujeszky’s disease

Pseudorabies virus

Malignant catarrhal fever

Herpes viridae

Pseudorabies

Alpha herpes virus of swine

Liver, spleen, adrenal glands, lymph nodes, brain Peripheral blood leukocytes, liver, kidney, lymph node, liver and brain Lymphatic system, lungs, neurons

Rabies

Rabies virus

Spleen, lymphoid, brain

Severe Acute Respiratory Syndrome (SARS)

Severe acute respiratory syndrome (SARS) coronavirus

Liver, spleen, lymphatic

Compromised functional capacity Utilises micropinocytosis through Rac-1/Pak-1– dependent membrane ruffling Phagosome-lysosome fusion failure

25 5 26, 27 28

Resistant to pH changes Phagosome-lysosome fusion failure Virulence factors increases cytokine production

27 29

Enter a non-Interferon-αproduction

30

Activation of IL-12 and IFN-γ, decreasing macrophage population

31

Development of cysts

32

Forms endocytic parasitophorous vacuole

33

Liver, lung and CNS

Forms hydatid cyst

34

Spleen, liver, lymph node, bone marrow, liver

Prevents activation of macrophages, survives breakdown, alters signalling

Diseases of parasitic origin Babesiosis

Babesia equi, Babesia microti

Bovine besnoitiosis

Besnoitia besnoiti

Chagas disease

Trypanosoma cruzi

Echinococcosis

Echinococcus granulosus

Leishmaniasis

Leishmania donovani

Blood and spleen Endothelial cells of blood vessels and lymphatic system Liver, spleen and lymph node

35, 36

Table 1: Major zoonotic diseases and their major locations in the RES www.animalhealthmedia.com

International Animal Health Journal 33


Research & Development strategy would therefore enable high drug concentrations at the site of infection and this can be achieved using a range of nanocarriers45, 46.

Nanocarriers

Schematic representation

Liposome

6. Nanocarriers for Targeted Drug Delivery Attractive features of nanocarriers include enhanced bioavailability, desired tissue selectivity, and high drug payload at desired sites. More importantly, drug concentrations at other sites can be effectively decreased. This could provide a specific advantage in the therapy of veterinary infections, decreased secretion of drug in milk, and/or decreased accumulation in meat. A variety of nanocarriers may be resorted for targeted delivery. Some important carriers are summarised in Table 2. 7. Applications of Nanocarriers a. Nanomedicine Polymeric drug delivery systems and lipid drug delivery systems have been explored for infectious diseases. Depending upon the targeted site, properties of nanocarriers such as surface chemistry and size have been modulated. Modifying shape could direct nanocarriers to spleen, a major aspect of macrophagic infection47, 48. Various nanocarriers exploited for targeting livestock infections have been summarised in Table 3. Nano drug delivery systems have also been explored for delivery of minerals e.g. Selenium, for improving digestive process, animal production and improved immunity49, 50, 51. b. Nano-vaccines Veterinary vaccines are different from human vaccines. Vaccination should increase the immunity in herd rather than the individual and control infections in animals. A less reactive and biodegradable vaccine is of high priority, especially if the animals are bred for human consumption. Besides, high genetic diversity with limited knowledge of targeting molecules (immune modulators and surface markers) in wildlife species is to be addressed78. During epidemics, marker vaccines should also be able to differentiate vaccinated animals and infected ones7. Subunit vaccines, DNA vaccines, vectored vaccines and recombinant vaccines have replaced the traditionally used killed or live modified vaccines. Earlier vaccines used adjuvants such as aluminum hydroxide to improve immune response, which has its own disadvantages of immunity, inflammation, etc. 79. Nanoparticles for Trichinosis (caused by consumption of pork meat contaminated with Trichinella spiralis) revealed adequate induction against immune response in Trichinellainfected mice80. Liposomes for oral and intranasal delivery of recombinant B subunit of cholera toxin or IgA have been studied in mice81, 82. Needle-free nanoemulsion (droplet size ~ 40 nm) of hepatitis B antigen has been studied in mice, rats and guinea pigs 49. ISCOM (Immunostimulatory complexes) and ISCOMATRIXTM based adjuvants composed of antigen incorporated into lipid vesicles and admixtures with particulate adjuvant are widely researched for vaccines 83 . Most of the research involved in study of vaccine delivery, target to the antigen presenting cells and Peyer’s patches. Incorporation of antigens within particulate delivery protects and provides enhanced immunogenicity, increased antigenic uptake, and control antigen release84. It activates pattern recognition receptors (initiating innate immune response), 34 International Animal Health Journal

Features  Spherical phospholipid vesicles  Fluidity can be adjusted using combination of liposomes  Enclosing an internal aqueous volume with one or more concentric hydrophobic bilayers  Unilamellar (single bilayer) or multilamellar (many bilayers) or multivesicular  Encapsulates both hydrophilic and hydrophobic drug  Rigid nanoparticles made of natural / synthetic polymers or lipids  Drugs loaded within matrix are ‘nanocapsule’; Drugs loaded throughout matrix are ‘nanosphere’  Release of drug through matrix diffusion or degradation of matrix  Ease for surface modification  Combination of lipid and polymer  Polymers enhance loading of hydrophilic drugs and lipids favour hydrophobic drug loading  Improved stability, ease to anchor ligands  Coating with lipids mimic bio-interface

Polymeric or lipid nanoparticles

Lipid-polymer hybrid nanoparticles

 Star polymers  Chemical polymers similar to bio-molecules  Surface functionalisation on surface to tailor drugs and ligand

Dendrimer

 Amphiphilic block or graft copolymers  Self-assemble to form micelles, vesicles or gels  Enhances solubility of poorly soluble drugs

Polymeric micelles

 Single or multi-walled layer of rolled grapheme/ graphite sheets capped by fullerene  Penetrate through barriers by ‘nano-needle’ mechanism

Carbon nanotubes

II

SPIONS

Fe O 2

Quantum dot

Metallic nanoparticles

III

+

m-

 Hydrotalcite (M nM (OH)2+2n) (A )1/m.x H20 (n=2– II III 4), Where M M represents a divalent and trivalent mmetal cation respectively and A represents an anion  Cationic charge of LDH enhances loading of anionic actives

Layer double hydroxide (anionic clay)

3

 Super paramagnetic iron oxide nanoparticulates (SPIONS) and ultra super paramagnetic iron oxide nanoparticulates composed of magnetite, Fe 3O4, or maghemite  Application directed by external magnetic field  Semiconductors from II-VI or III-V of the periodic table  ZnS, ZnSe, ZnO, InAs, GaAs, CdTe, CdSe, CdS  Broad absorption spectra, unique electronic luminescence and optical properties  Gold, silver and platinum nanoparticles  Controllable optical properties termed surface plasmon resonance  Anti-infective and other bioactivities of gold and silver itself

Table 2: Different nanocarriers used in veterinary medicine

up-regulates antigen-presenting cells (increasing T cells activation), control residence time, location and dose of antigen (maintaining immunity levels and translocation to lymph nodes) and maintains depot for prolonged release. It is reported that 40 animal diseases have nanoparticles developed or under development85. c. Nano-diagnostics Early detection of pathogens with high accuracy is vital to prevent long-term complication and epidemic outbreaks, develop pandemicity, and preserve public health. Classical techniques of culturing and biochemical-based tests for pathogen detection, enzyme-linked immunosorbent assay and polymerase chain reaction are time-consuming with limited sensitivity. Nanomaterial-based devices have also been designed for detection of tuberculosis from sputum samples86. Biosensors based on Au/Si hetero-nanorod functionalised with anti-Salmonella antibodies have been used for detection of infectious diseases in food as well as in diagnosis87. Change in estradiol blood level of animals can be determined by implanting carbon nanotube-based sensors88. Carbon nanotubes bind to estradiol antibodies, track estrus Volume 1 Issue 2


Research & Development in animals, and accordingly actuate breeding. Veterinary drug residues in milk, bovine urine such as sulfamethazine, progesterone, clenbuterol, etc., are being detected online using nano-based new optical biosensors working on the principle of surface plasmon resonance89, 90, 91. Quantum dots, carbon nanotubes and nanoshells can be explored for imaging using fluorescence, X-rays, ultrasound or magnetic resonance. Nanosensors and cantilever arrays have also been used for diagnosis of a specific target sequence92. Lab-onchip recognises gene mutations, DNA mutation, pathogenic strains, and chemical pathogens with high sensitivity14. Implanted sensors can also assist in gaining information about physiological parameters such as temperature, heart rates, blood pressure, etc.93.

macrophages. Immunology letters 93, 137-142 (2004). 19.

Hebert, A., Sayasith, K., Senechal, S., Dubreuil, P. & Lagace, J. Demonstration of intracellular Staphylococcus aureus in bovine mastitis alveolar cells and macrophages isolated from naturally infected cow milk. FEMS microbiology letters 193, 57-62 (2000).

20.

Malone, F.E. et al. A serological investigation of caseous lymphadenitis in four flocks of sheep. Irish veterinary journal 59, 19-21 (2006).

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Rosqvist, R., Bolin, I. & Wolf-Watz, H. Inhibition of phagocytosis in Yersinia pseudotuberculosis: a virulence plasmid-encoded ability involving the Yop2b protein. Infection and immunity 56, 2139-2143 (1988). Sturgill-Koszycki, S. et al. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science (New York, N.Y.) 263, 678-681 (1994). Schroeder, G.N. & Hilbi, H. Molecular pathogenesis of Shigella spp.: controlling host cell signaling, invasion, and death by type III secretion. Clinical microbiology reviews 21, 134-156 (2008). Santic, M., Asare, R., Skrobonja, I., Jones, S. & Abu Kwaik, Y. Acquisition of the vacuolar ATPase proton pump and phagosome acidification are essential for escape of Francisella tularensis into the macrophage cytosol. Infection and immunity 76, 2671-2677 (2008).

22.

23.

24.

8. Future Prospects Targeted delivery of drugs for veterinary infections provides great promise for both short-term and long-term treatment strategy. The rate-limiting features concerned are the technology scale-up challenges and the possible new toxicities. Nevertheless, due recognition of the positive aspect of nanotechnology in targeted delivery could revolutionise the therapy of veterinary infections globally.  

25.

29.

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Pols, J.W. Studies on bovine Besnoitiosis with special reference to the aetiology. Onderstepoort Journal of veterinary research 28 (1960).

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de Souza, W., de Carvalho, T.M. & Barrias, E.S. Review on Trypanosoma cruzi: Host Cell Interaction. International journal of cell biology 2010 (2010).

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Sleeman, J.M. et al. Johne’s disease in a free-ranging white-tailed deer from Virginia and subsequent surveillance for Mycobacterium avium subspecies paratuberculosis. Journal of wildlife diseases 45, 201-206 (2009). Wormser, G.P. et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 43, 1089-1134 (2006).

1.

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3.

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Mumy, K.L. et al. Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils. Infection and immunity 76, 3614-3627 (2008).

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Bloom, W.L., Watson, D.W. & et al. Studies on infection with Bacillus anthracis; preparation and characterization of an anthracidal substance from various animal tissues. The Journal of infectious diseases 80, 41-52 (1947). Salles, II, Tucker, A.E., Voth, D.E. & Ballard, J.D. Toxin-induced resistance in Bacillus anthracis lethal toxin-treated macrophages. Proceedings of the National Academy of Sciences of the United States of America 100, 12426-12431 (2003). CFSPH in Brucellosis (Center for Food Security and Public Health, Iowa; 2009).

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Swanson, M.S. & Isberg, R.R. Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Infection and immunity 63, 3609-3620 (1995). Berger, K.H. & Isberg, R.R. Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Molecular microbiology 7, 7-19 (1993). Swanson, M.S. & Fernandez-Moreira, E. A microbial strategy to multiply in macrophages: the pregnant pause. Traffic (Copenhagen, Denmark) 3, 170-177 (2002). Kubica, M. et al. A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus phagocytosed by human monocyte-derived macrophages. PloS one 3, e1409 (2008). Meunier, F., Prentice, H.G. & Ringden, O. Liposomal amphotericin B (AmBisome): safety data from a phase II/III clinical trial. The Journal of antimicrobial chemotherapy 28 Suppl B, 83-91 (1991). Torchilin, V.P. Drug targeting. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 11 Suppl 2, S81-91 (2000). Vasir, J.K., Reddy, M.K. & Labhasetwar, V.D. Nanosystems in Drug Targeting:

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Devarajan, P.V. et al. Particle shape: a new design parameter for passive targeting in splenotropic drug delivery. Journal of pharmaceutical sciences 99, 2576-2581 (2010). Patil, R.R., Gaikwad, R.V., Samad, A. & Devarajan, P.V. Role of Lipids in Enhancing Splenic Uptake of Polymer-Lipid (LIPOMER) Nanoparticles. Journal of Biomedical Nanotechnology 4 (2008). Shi, L. et al. Effect of sodium selenite, Se-yeast and nano-elemental selenium on growth performance, Se concentration and antioxidant status in growing male goats. Small Ruminant Research 96, 49-52 (2011). Zhou, X. & Wang, Y. Influence of dietary nano elemental selenium on growth performance, tissue selenium distribution, meat quality, and glutathione peroxidase activity in Guangxi Yellow chicken. Poultry science 90, 680-686 (2011). Romero-Perez, A. et al. Designing and evaluation of sodium selenite nanoparticles in vitro to improve selenium absorption in ruminants. Veterinary research communications 34, 71-79 (2010). Bielinska, A.U. et al. Mucosal immunization with a novel nanoemulsion-based recombinant anthrax protective antigen vaccine protects against Bacillus anthracis spore challenge. Infection and immunity 75, 4020-4029 (2007). Fountain, M.W., Weiss, S.J., Fountain, A.G., Shen, A. & Lenk, R.P. Treatment of Brucella canis and Brucella abortus in vitro and in vivo by stable plurilamellar vesicle-encapsulated aminoglycosides. The Journal of infectious diseases 152, 529535 (1985). Nicoletti, P., Lenk, R.P., Popescu, M.C. & Swenson, C.E. Efficacy of various treatment regimens, using liposomal streptomycin in cows with brucellosis. American journal of veterinary research 50, 1004-1007 (1989). Hamouda, T. et al. A novel surfactant nanoemulsion with broad-spectrum sporicidal activity against Bacillus species. The Journal of infectious diseases 180, 1939-1949 (1999). Hamouda, T. & Baker, J.R., Jr. Antimicrobial mechanism of action of surfactant lipid preparations in enteric Gram-negative bacilli. Journal of applied microbiology 89, 397-403 (2000). MacLeod, D.L. & Prescott, J.F. The use of liposomally-entrapped gentamicin in the treatment of bovine Staphylococcus aureus mastitis. Canadian journal of veterinary research = Revue canadienne de recherche veterinaire 52, 445-450 (1988). He, P., Wang, Z., Zhang, L. & Yang, W. Development of a label-free electrochemical immunosensor based on carbon nanotube for rapid determination of clenbuterol. Food Chemistry 112, 707-714 (2009). Norville, I.H. et al. Efficacy of liposome-encapsulated ciprofloxacin in a murine model of Q fever. Antimicrobial agents and chemotherapy 58, 5510-5518 (2014). El-Ridy, M.S., Mostafa, D.M., Shehab, A., Nasr, E.A. & Abd El-Alim, S. Biological evaluation of pyrazinamide liposomes for treatment of Mycobacterium tuberculosis. International journal of pharmaceutics 330, 82-88 (2007). Kumar, G., Sharma, S., Shafiq, N., Khuller, G.K. & Malhotra, S. Optimization, in vitro– in vivo evaluation, and short-term tolerability of novel levofloxacin-loaded PLGA nanoparticle formulation. Journal of pharmaceutical sciences 101, 11 (2012). Booysen, L.L. et al. In vivo/in vitro pharmacokinetic and pharmacodynamic study of spray-dried poly-(dl-lactic-co-glycolic) acid nanoparticles encapsulating rifampicin and isoniazid. International journal of pharmaceutics 444, 10-17 (2013). Esmaeili, F. et al. Preparation and antibacterial activity evaluation of rifampicinloaded poly lactide-co-glycolide nanoparticles. Nanomedicine : nanotechnology, biology, and medicine 3, 161-167 (2007). Fatunmbi, O.O., Newman, J.A., Sivanandan, V. & Halvorson, D.A. Efficacy of avridine and liposomes as adjuvants for avian influenza virus antigens in turkeys. Avian pathology : journal of the W.V.P.A 21, 225-237 (1992). Rao, M., Bray, M., Alving, C.R., Jahrling, P. & Matyas, G.R. Induction of immune responses in mice and monkeys to Ebola virus after immunization with liposomeencapsulated irradiated Ebola virus: protection in mice requires CD4(+) T cells. Journal of virology 76, 9176-9185 (2002). Knudsen, R.C., Card, D.M. & Hoffman, W.W. Protection of guinea pigs against local and systemic foot-and-mouth disease after administration of synthetic lipid amine (Avridine) liposomes. Antiviral research 6, 123-133 (1986). 67. Padmaja, R.J., Akshath, U.S., Abhijith, K.S., Halami, P.M. & Thakur, M.S. Gold nanoparticle-based immunodetection of Staphylococcus aureus leukotoxin M/F[prime or minute]-PV in subclinical samples of bovine mastitis. Analytical Methods 6, 5214-5220 (2014). Kende, M., Alving, C.R., Rill, W.L., Swartz, G.M., Jr. & Canonico, P.G. Enhanced efficacy of liposome-encapsulated ribavirin against Rift Valley fever virus infection in mice. Antimicrobial agents and chemotherapy 27, 903-907 (1985). Pimentel, T.A. et al. Peptide nanoparticles as novel immunogens: design and analysis of a prototypic severe acute respiratory syndrome vaccine. Chemical biology & drug design 73, 53-61 (2009). Timofeev, B.A. et al. Liposomal diamidine (imidocarb): preparation and animal studies. Journal of microencapsulation 11, 627-632 (1994). Morilla, M.J. et al. Intravenous liposomal benznidazole as trypanocidal agent: increasing drug delivery to liver is not enough. International journal of pharmaceutics 278, 311-318 (2004). Wen, H. et al. Pharmacology and efficacy of liposome-entrapped albendazole in experimental secondary alveolar echinococcosis and effect of co-administration with cimetidine. Parasitology 113 ( Pt 2), 111-121 (1996). Marques, C. et al. Efficacy of the liposome trifluralin in the treatment of experimental canine leishmaniosis. Veterinary journal (London, England : 1997) 178, 133-137 (2008).

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naturally infected by Leishmania (Leishmania) chagasi following treatment with a liposome formulation of meglumine antimoniate. Antimicrobial agents and chemotherapy 52, 2564-2572 (2008). 75.

Borborema, S.E., Schwendener, R.A., Osso, J.A., Jr., de Andrade, H.F., Jr. & do Nascimento, N. Uptake and antileishmanial activity of meglumine antimoniatecontaining liposomes in Leishmania (Leishmania) major-infected macrophages. International journal of antimicrobial agents 38, 341-347 (2011).

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Padma V. Devarajan, PhD (Tech), is Professor in Pharmacy and Head, Department of Pharmaceutical Sciences and Technology at the Institute of Chemical Technology (ICT), Mumbai, India. Her research interests include nano drug delivery for cancer and infectious diseases, bioenhancement strategies, mucosal drug delivery systems and protein and nucleic acid delivery. Email: pvdevarajan@gmail.com Anisha A. D’Souza has completed her PhD (Tech) in Pharmaceutics from Institute of Chemical Technology (ICT), Mumbai, India. Her research interests include Nano Drug Delivery and vaccine delivery strategies. Email: anisha149@gmail.com

Ribeiro, R.R. et al. Reduced tissue parasitic load and infectivity to sand flies in dogs

36 International Animal Health Journal

Volume 1 Issue 2


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Research & Development Pet Overpopulation: A Global Crisis Ironically, the principal problem facing domestic cats and dogs is their ability to reproduce an exponential number of offspring. Having long since been removed from the wild and the pressures of natural selection that once limited their population, more puppies and kittens now survive to become sexually mature and reproduce.

A Global Issue The 2014 Winter Olympics in Sochi brought worldwide attention to the overwhelming pet overpopulation problem that exists in Russia, with many athletes attempting to bring pets home to their own countries. Russia and the US are not alone, however, with pet overpopulation being a global issue.

We now bear the responsibility for this state of affairs. For thousands of years we have chosen to breed our companion animals, especially dogs, to serve our human needs. They have essentially ceased to be wild and have become dependent on humans for survival.

Euthanasia as a means of animal population control in countries such as the US, the UK and the EU, is performed in a humane fashion by qualified veterinary staff. In many countries, however, stray dogs and cats are seen as vermin and carriers of disease and parasites. As such, companion animals are often not treated with respect and empathy, and euthanasia techniques are often barbaric and inhumane in nature.

In many ways, we are accepting and passionately acting on our responsibilities. The vast majority of people now consider their companion animals as “family members�,1 with significant attachment to them as domestic pets. In a 2001 study, it was found that many people would not trade their dog even if offered a million dollars or more, and if the care of their animal was guaranteed. This confirms that for many people pets are seen as family members rather than possessions.2 If pets are indeed members of our family, what is the scope of our problem and how do we find a solution? The Size of the Problem In the US alone, 30 million puppies and kittens are born each year. This is a ratio of seven pets born for every human birth. At this rate, there will simply never be sufficient available homes for all those loving companion animals. Estimates now suggest that only one out every 10 animals born will find a permanent home.3 The current estimate of homeless dogs worldwide is over 500 million,4 with the number of homeless cats likely even greater. In the United States, approximately six to eight million dogs and cats enter shelters annually, from which they are either adopted into new homes, re-united with their families or euthanised.5 It is estimated that, of these animals, only 24.9% of dogs and 23.4% of cats in shelters are adopted each year.6 The remaining animals are either housed in nokill shelters or euthanised. According to the Humane Society, three to four million animals are euthanised due to the lack of adoptive homes. In light of these figures, overpopulation is the number one killer of companion animals in the United States. According to a study performed by the University of Appalachia (North Carolina), one unaltered female dog and her offspring can produce 67,000 puppies in a six-year period. Being an induced ovulator, combined with the ability to birth two to three litters per season, the statistics are even more dramatic in cats. In a seven-year period, one female cat and her offspring can produce a staggering 370,000 kittens.7 Unaltered males, especially cats, obviously have the capacity to reproduce an immeasurable number of offspring.

38 International Animal Health Journal

Human Health Consequences Relinquishment of pets to shelters is also a major contributor for the number of animals entering shelters. A common reason cited by owners for surrendering their dogs to a shelter is behavioral issues, such as biting, which accounts for 26.4% of animals surrendered.8 In the US, there are 4.7 million dog bites per year.9 It is notable that unsterilised dogs are 2.6 times more likely to bite than sterilised dogs.10 Thus sterilisation is not only of paramount importance in the management of companion animal populations, but is also a public health and safety issue. Fear of homeless animals, especially dogs, carrying and spreading diseases to humans is also a very real concern. According to the World Health Organisation, canine rabies potentially threatens over 3 billion people in Asia and Africa, with tens of thousands of people dying from the disease every year.11 The greater the number of stray dogs, the greater is the potential risk posed to human health. One study in Gabon suggests that dogs can become infected with Ebola. In a 2002 outbreak, after witnessing dogs eating infected dead animals, researchers tested dogs for the Ebola virus. Of the 337 dogs tested, 9 to 25 per cent showed antibodies to Ebola, a sign they were infected or exposed to the virus.12 As recently as October 2014, a Spanish dog, Excalibur, in Madrid was euthanised due to fear of potentially carrying the deadly virus, Ebola. Excalibur’s owner tested positive for carrying the disease and the dog was euthanised as a preventative measure. In this case, it has not been proven whether Excalibur is infected with Ebola or not, but given the deadly nature of the disease, officials are not willing to take the chance. Disease outbreaks such as these will put increasing pressure on authorities to control stray dog populations through lethal methods. A Complex Problem Companion animal overpopulation is a problem of human Volume 1 Issue 2


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Research & Development creation, and one for which we are morally indebted to find a solution. The complexities of the issue abound, from human health and the potential spread of zoonotic disease to the financial burdens placed on nations globally. Companion animal overpopulation is nothing short of a manmade disaster. Most significantly, however, the ultimate price is being paid by the cats and dogs of the world surviving without a loving home. We owe it to our valued companion animals to find a solution to the problem we created. An Imperfect Solution: Spay and Neutering Programmes The current shelter systems of most nations are overwhelmed and ineffective in reducing their pet overpopulation problems. With only a small percentage of the animals that enter shelters being found permanent homes, the majority are left to face euthanasia or long-term confinement within no-kill institutions. Alternatively, stray and feral companion animals are left to fend for themselves, often becoming the victims of abuse and starvation, and potentially becoming sources for the spread of disease. Euthanasia has become a solution in many countries, which comes at a high price. Not only are the financial burdens to local governments onerous; the moral predicament of systematically and routinely euthanising millions of healthy cats and dogs weighs heavily on societies, which value their companion animals deeply. The veterinary staff and shelter workers who are charged with the task of performing the euthanasia procedures are those most affected. Psychological, emotional and physical illness including ulcers, high blood pressure, unresolved grief, depression, and suicide have been reported among those responsible for the regular euthanasia of companion animals.13 It is well accepted and supported that the only long-term effective and humane means of pet population control is through targeted, affordable spay and neutering programmes. Veterinarians are well-known for passionately supporting such programmes, often offering discounted procedures as a way to give back to the community and improve animal welfare for the individual. Organisations such as World Vets run programmes for volunteer veterinarians and technicians to travel to countries such as Nicaragua and Paraguay to perform large-scale spay and neuter programmes. These programmes are to be commended and make a real and lasting difference to the local communities. The inherent limitations to such programmes, however, include their high cost, and the need for facilities, supplies and skilled personnel. A recent feline trap, neuter, release (TNR) programme, undertaken by the University of Florida, found that a targeted approach helped effectively manage the feral cat population and reduce shelter euthanasia rates in the targeted area. Participants neutered an estimated 54% of the feral cat population in the target area and subsequently reported a 70% decline in animal control cat intake within the study area and a 13% decline in the surrounding areas. Euthanasia rates also declined by 95% in the target area, and by 30% in surrounding areas.14

In Canada in 2012, a cat overpopulation research initiative was performed by the Canadian Federation of Humane Societies. When asked the question “What would be the best way to deal with the cat overpopulation problem in Canada?â€? the one overwhelmingly clear recommendation of animal welfare organisations was to ensure that sterilisation (currently spay and neuter surgeries) is affordable and accessible to everyone.15 The message is unequivocally clear: the most effective solution to companion animal overpopulation is widespread sterilisation. However, the issue with stray and feral companion animals is that execution of widespread surgical spay and neuter programmes are prohibitively costly to local and national governments. The Ontario Veterinary Medical Association of Canada estimates the average cost of a male cat castration to be $447 and a female cat spay to be $547. The costs for a male dog castration are estimated at $571, with a female dog spay estimated to be $626.16 Even for pets with homes, the costs associated with spay and neutering procedures can be unaffordable for many owners. Of the animals surrendered to shelters, only 10% are sterilised. This is in contrast with the non-surrendered pet, where over 80% of pets are sterilised.17 Alternatives to Surgical Spay Procedures The invention of a non-surgical, affordable means of sterilisation of companion animals would provide a practicable and realistic solution to the global pet population crisis. Such is the need that there is an organisation, Found Animals, which offers a substantial prize for such an invention. Founded by philanthropist Dr Gary Michelson, Found Animals is a privately funded foundation, which is working to achieve a singular goal - to find a solution to help reduce the number of pets euthanised each year in shelters. Found Animals offers grants to scientists to pursue non-surgical sterilisation technologies for companion animals and will award a $25M prize to the first entity that agrees to surrender rights to a product that meets its contest criteria. Not only is there a need for a more cost-effective method of sterilisation, but given the extent of the population problem, a non-surgical method would offer a much more efficient method of sterilisation on a global scale. Emerging Technologies With an urgent need for a non-surgical sterilisation procedure, animal health innovators globally continue to search for a solution to the pet overpopulation crisis. Ark Science recently launched their zinc-based ZueretinTM sterilisation injection for male dogs. The mode of action of Zeuterin™ involves destruction of spermatozoa in all stages of maturation in the seminiferous tubules and in the epididymis. Ark Science have launched the product in the US and are certifying veterinarians in the use of the product through training programmes.18 A Canadian-based Animal Health company, Avivagen

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Volume 1 Issue 2


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International Animal Health Journal 41 vetpharm.com


Research & Development Inc., is currently completing a proof-of-concept study into a novel, drug-based technology for the permanent sterilisation of female mammals. The inventor is Dr Duncan Hockley, Director of the Veterinary Medical Centre of the University of Saskatchewan. The study will measure the effects of multiple potential drug actives at several doses versus a negative control group. The primary endpoint of the study will be a definitive count of all viable follicle types in the ovary, allowing an assessment of immediate fertility as well as reproductive reserves. The aim would be to produce a drug-based means of accomplishing permanent sterilisation in female mammals. Small Efforts Add Up As a veterinarian, I am personally aware of the issues facing stray and feral domestic animals. My cat, Oliver, was a tiny four-week-old stray kitten when he was brought into the vet school in Australia where I was a student at the time. He, of course, came home with me and the rest is history. It is a common story, as veterinarians and technicians, that we open our homes to homeless animals in order to avoid the heartbreak of yet another inevitable euthanasia. But the issue of pet overpopulation is far greater than I ever imagined, and it is fair to label it nothing short of a global crisis. The animal health industry as a whole is a wonderful sector to work in, providing a rewarding and stimulating workplace for thousands of employees worldwide. Whether you are a veterinarian, a sales representative or a shelter worker, our ultimate responsibility is to the animals our industry serves. As a collective group we have the gift to be able to educate the greater public on the issues and responsibilities surrounding pet ownership and the consequences of pet overpopulation. By encouraging people to consider rehoming a pet from an animal shelter, strongly recommending pet sterilisation and supporting new pet owners to avoid relinquishment of pets, we are making a small difference which has the potential to have a major impact on this vast animal welfare issue. References 1. Hirschman, E. C. 1994. Consumers and their animal

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5. 6.

7.

companions. Journal of Consumer Research, 20, 616– 632. doi: 10.1086/209374 Frank, J. 2001. “A new economic paradigm for addressing dog overpopulation and the effectiveness of policy alternatives,” Doctoral Dissertation, Rensselaer Polytechnic Institute, Troy, NY. The National Humane Education Society. http://www.nhes. org/articles/view/696 Hsu, Y., Severinghaus, L. and Serpell, J. 2003. Dog keeping in Taiwan: Its contribution to the problem of free-roaming dogs. Journal of Applied Animal Wel- fare Science 6(1): 1–23. The National Humane Education Society. http://www.nhes. org/articles/view/696 44. Natl. Council Pet Population Study & Policy, Frequently Asked Questions, http:// www.petpopulation.org/faq.html (updated Mar. 4, 2009) [hereinafter Frequently Asked Questions]. Coleman, P. et al. 2011. Stetson Law Review, Volume 40, Winter 2011, Number 2. It’s raining cats and dogs. Differential Licensing Laws generate revenue, reduce costs,

42 International Animal Health Journal

protect citizens and save lives. 8. Arkow, P. & Dow, S. 1984. The ties that do not bind: A study of the human–animal bonds that fail. In R. K. Anderson, B. L. Hart, & L. A. Hart (Eds.), The pet connection: Its influence on our health and quality of life (pp. 348–354). Minneapolis: Center to Study Human–Animal Relationships and Environments. 9. Kenneth Phillips, Dog Bite Law, Statistics, http://www. dogbitelaw.com/PAGES/ statistics.html (last modified Jan. 15, 2011) (citing Ctrs. Disease Control & Prevention, Nonfatal Dog Bite-Related Injuries Treated in Hospital Emergency Departments—United States, 2001, 52(26) Morbidity & Mortality Wkly. Rep. 605, 605) (July 4, 2003) (available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5226a1. htm) 10. Delise, supra n. 9, at 13–14; see also Jamey Medlin, Student Author, Pit Bull Bans and the Human Factors Affecting Canine Behavior, 56 DePaul L. Rev. 1285, 1308–1309 (2007) 11. http://www.who.int/mediacentre/factsheets/fs099/en/ 12. Allela, L. et al. 2005. Emerging Infectious Diseases, www.cdc. gov/eid, Vol. 11, No. 3, March 2005, Ebola Virus Antibody Prevalence in Dogs and Human Risk, Loïs Allela et al., (Accessed 9/10/14) http://wwwnc.cdc.gov/eid/article/11/3/ pdfs/04-0981.pdf 13. Rolf, V. & Bennett, P. 2005. Perpetration-Induced Traumatic Stress in persons who euthanize nonhuman animals in surgeries, animal shelters, and laboratories. Soc Anim. 2005;13:201–219. 14. Levy, J., Gale, D. & Gale, L. A. 2003. Evaluation of the effect of a long-term trap-neuter-return and adoption program on a free-roaming cat population. Journal of American Veterinary Medical Association, Vol 222, No. 1, January 1, 2003. 15. Canadian Federation of Humane Societies, A Comprehensive Report on the Cat Overpopulation Crisis, 2012 16. OVMA Handbook, The Cost of owning a Cat or Dog in 2013, (accessed 9/10/14) http://publications.ovma.org/i/123911 17. The National Humane Education Society, http://www.nhes. org/articles/view/696 18. h t t p : / / w w w . a r k s c i e n c e s . c o m / f a q s . html#veterinarians#faqnoanchor (Accessed 9/10/14)

Tracy Gillett BVSc joined Avivagen Inc, as Marketing and Technical Services Manager in 2011. Since graduating from the University of Queensland, Australia, in 2000 with a Bachelor of Veterinary Science, Tracy spent ten years in small animal practice in Australia and the UK. Following her time in practice she joined Bayer Animal Health as Technical Services Manager in New Zealand. A move to Vancouver, Canada in 2011, saw Tracy join the team at Avivagen. Avivagen is a Canadian Animal Health company founded on the discovery of a unique active ingredient, OxC-beta, which supports the healthy functioning of the immune system of both pets and livestock. Avivagen’s most recent project involves R&D into a potential non-surgical means of sterilization of female mammals. Tracy enjoys the natural beauty that British Columbia has to offer and lives there with her husband and young son. Email: t.gillett@avivagen.com Volume 1 Issue 2


temperature, humidity & shock monitoring • Testo data loggers are delivered with a calibration certificate traceable according to ISO 17025 • With testo data loggers, the well being of the livestock can be monitored during transportation and on arrival • Comprehensive alarm management, allows the setting of multiple alarm limits • The Saveris system, measures the temperature and humidity values of goods in processes and during transportation.


Research & Development

Recent Advances in Precision Livestock Farming Abstract Precision Livestock Farming (PLF) or SmartFarming is a new take on animal farming, similar to a management change in the ‘80s. At this time, firms started to employ employee motivation and the concept of the ‘firm as a family’ in order to make better firms. PLF is an attempt at making a similar change in animal farming: by detecting the needs of animals as early as possible and helping the farmers to sat-isfy those needs, animal wellbeing will increase. It is hoped that in turn this will increase socio-economic benefits of animal farming, i.e. make better farms. Precision Livestock Farming1, 2, 3, 4, 5, 6 was born in an attempt to help farmers cope with the challenges they are facing today. Modern livestock farming is expected to produce more and more to satisfy the growing intake of animal protein whilst at the same time increasing animal health and welfare, reducing energy use and environ-mental footprint and coping with fewer and fewer suitable workers for the farms. PLF is a reaction of the pressure from world market prices, causing farmers to focus on efficiency, large-scale production and automation, while still wanting to maintain ani-mal welfare. PLF can offer different technologies to assist the farmer (e.g. surveillance systems to discover lameness) but also to improve the efficiency (e.g. optimise the feeding of the individual animal) and finally to reduce the labour cost or improve the flexibility at the farm (e.g. automatic milking systems). Precision Livestock Farming has been around for some time but it has not yet fully lived up to expectations. There are many reasons, not least of which is the complexity of animals – as compared to plants and precision agriculture. Among the reasons why PLF has not yet become more widely accepted are the difficulties associated with mak-ing PLF technologies work reliably on commercial farms. Some are related to the suit-ability of the developed techniques and technologies. Others are related to a lack of awareness, education and training of farmers and consumers, coupled with the pursuit of PLF more as an academic discipline than a practical farming development platform. However, in many areas of the world the main reason behind the lack of adoption is that labour is cheap and available – although skilled labour is in short supply almost everywhere. The need for PLF is best understood when labour is short and expensive and where animal welfare is a consumer concern. This contribution wishes to discuss obstacles to adoption of Precision Livestock Farming, as well as recent advances to overcome such obstacles. The main body of material comes from three EU-sponsored research projects, namely BrightAnimal, ALL-SMART-PIGS (www.all-smart-pigs.com) and EU-PLF (www.eu-plf.eu).

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What’s in a Name: SmartFarming, Precision Livestock Farming, iFarming It was one of the conclusions of the ground-laying EU-funded project BrightAnimall7 that the term “Precision Livestock Farming” is not well chosen for marketing the sub-ject to farmers and consumers. It was believed that the term suggests a field full of engineers rather than producers and marketing experts. As a consequence, neither farmers nor consumers are attracted to the field. It was the impression that farmers think that PLF means “more time spent behind the computer rather than in the barn.” Although modern farmers in Europe – less so in Asia and Africa – understand and appreciate the value of management systems, they miss spending time with the animals. The term “precision” does not attract them. Consumers on the other hand are very much removed in their thinking from modern farming. Pictures of animals running free on green grass very much dominate con-sumer thinking. Technology and animals don’t really go together in consumers’ minds. As a consequence, it was felt that a new name was essential for the implementation of Precision Livestock Farming. The BrightAnimal group suggested the term “SmartFarming” or Smart Animal Farming 7. In a parallel effort, the company Fancom launched the name iFarming or Intelligent Farming. The name suggests that PLF allows farmers to use their intelligence to care for their animals and at the same time provide evi-dence for intelligent buying decisions by consumers. The name targets young, digital and entrepreneurial farmers that wish to act as trend setters and enjoy having full con-trol over their production. Originally trademarked, the name has been released into the public domain in an attempt to make the brand available to all. None of the names has yet found widespread adoption, but it is clear that Precision Livestock Farming refers more to the scientific field, whereas both SmartFarming and iFarming refer to the practical aspects of animal and farm-centric livestock production. In the following the terms will be used interchangeably. What is PLF? SmartFarming is an essential part of the “livestock revolution” 8 , i.e. the necessary increase in productivity to cope with higher protein consumption and growing world population with limited resources, while maintaining the welfare of the animals. SmartFarming has the obligation to contribute to providing solutions • through an animal and farm-centric approach that seeks a balance between production, welfare and Volume 1 Issue 2


Research & Development health mproving living conditions and avoiding illness improving genetics and the reproduction cycle optimising feed usage along the supply chain avoiding the emission of greenhouse gases to the atmosphere.

in modern livestock farming12. EU-PLF is designing valuecreation models both on farm13 and in the supply chain to address point 6. ALL-SMART-PIGS is conducting cost-benefit analysis in Smart Pig Farm-ing on four farms (two in Spain, two in Hungary) in order to derive socio-economic valuecreation models.

SmartFarming is an essential part of European competitiveness and of Europe’s contri-bution to global food security.

Integration of Farmers and Other Stakeholders into the Development of SmartFarming Products The current challenge for SmartFarming is to penetrate the market (mainly farmers) with a set of new technologies and services. There are at least four key dimensions in industrial marketing (Webster, 1992): 1. Identifying customer needs, which requires understanding the economics of the customer’s operations, the structure of the industry within which they operate, and how they compete. 2. Selecting customer groups for emphasis, the classic problem of market seg-mentation, which takes on special meaning in industrial markets because of the high degree of buyer-seller interdependence after the sale. 3. Designing the product/service package, where there is seldom a standard product, the accompanying bundle of services is often more important than the product itself. Industrial marketing aims for improved profit performance, where sales volume and market share per se is not as important as in consumer marketing.

• • • •

BrightAnimal defined the essentials of SmartFarming as 7: Essentials of SmartFarming 1. Smart animal farming is the approach to farming that aims to achieve economical-ly, environmentally and socially sustainable farming through the observation, be-havioural interpretation and control of the smallest possible group of animals. 2. Smart farming considers the bi-directional exchange of essential data and employs traceability for that purpose. 3. Smart farming is a discipline where farmers, engineers, biologists and economists work together to achieve the best possible results. 4. Smart animal farming has profound respect for the individual animal and tries to de-tect its needs in as timely a manner as possible. Main Obstacles to Adoption BrightAnimal concluded that there are a number of obstacles to adoption7, such as: 1. Consistent marketing of PLF/SmartFarming/iFarming 2. Lack of direct cooperation between engineers, biologists, economists and farmers 3. Too much focus on sensing and too little on interpretation and control 4. Lack of a service sector with suitable business models 5. Technology aversion of consumers as a result of too large a distance between consumers and modern livestock farming 6. Consistent value-creation models on farm and in the feed-animal-food supply chain 7. Awareness and education After having analysed these obstacles, the EU-sponsored project EU-PLF (www.eu-plf.eu) attempts to increase collaboration between engineers, biologists and economists through a large and well-balanced consortium. The EU-sponsored project ALL-SMART-PIGS (www.all-smart-pigs. com) uses the LivingLab methodology (www.enoll.eu) to increase collaboration between farmers, feed companies and slaughterhouses9; see below. EU-PLF attempts to lay the basis for a future service sector in PLF by creating a validated blueprint (to be finalised in 2016). At the same time, the project validates the blueprint by creating spin-offs through a coaching and competition process10, 11. ALL-SMART-PIGS has dedicated some resources in col-laboration with the EUsponsored project CommNet (www.commnet.eu) and the Brit-ish Nutrition Foundation to educating schoolchildren www.animalhealthmedia.com

In ALL-SMART-PIGS we find the Living Lab (LL) methodology useful for accomplishing the needs for risk reduction and user acceptance in the efforts of bringing research and technology developments within PLF to a specific market – in this case European pig farmers. Each LL farm will act as an open innovation milieu, where innovations are developed by adopting a research-intense and stakeholderdriven approach. The focus lies on co-creation of innovations on the basis of users’ real needs and by involving the whole value chain. Living Labs (LL) are currently heavily discussed in the European research community. Most of the discussions focus on open and publically available infrastructures to test and implement new products and services. Partners in the European Network of Open LivingLabs (ENOLL) claim that there are a number of different models that can be used for LL collaborations. However, most LLs summarised in the ENOLL community depend on government and public funding and there is a clear lack of suitable alternative business models. In addition to European level harmonisation and definitions, there is now an emerging movement to tailor an LL concept for various user groups and appli-cation sectors. The focus of each LL is: • Continuous and open co-operation among different involved stakeholders • Development of innovations based on user needs, desire and preference This can only be obtained by: • Engaging and empowering users to take an active part in International Animal Health Journal 45


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• •

the creation of valuable innovations Interacting with users in their real-world context (i.e. on real farms) Correlating user involvement activities with ongoing research and social trends

• • • • •

The ALL-SMART-PIGS Living Lab process can be seen as a spiral in which the focus and shape of the design become clearer, while the attention of the evaluation broadens from a focus on concept and usability aspects to a holistic view on the use of the sys-tem. There are four iterative cycles that each consist of a repetition of three phases; see Figure 1. The three repetitive phases in the ALL-SMART-PIGS Living Lab concept are: • Appreciating opportunities (co-creation with users) • Design (exploration and experimentation) • Evaluation These three phases (a-c) are repeated in four iterative cycles (1-4): • Concept design • Prototype design • Final system design • System demonstration

Contactless weight measurement14 Dispensed feed per pen15 Cough index as indicator for respiratory health16, 17 Activity and occupation index (distribution of animals within the pen and movements therein) Environmental parameters, such as ammonia concentration, temperature, humidity etc18

In interviews with farmers it became apparent that not all value created by these technologies can be measured in pure economic gain. There is a combination of measurable economic gain, non-measurable economic gain and “soft value”. Measur-able economic gain refers to an impact of the technology that we know how to meas-ure in money terms. Non-measurable economic gain is an area where there is a gen-eral agreement that value is created, but it is not yet clear how to measure it in money terms. An example would be early respiratory disease detection. Although economic gain for this can be modelled, it is very hard to measure on farm. “Soft values” refer to social values, such as satisfaction of workers that represent a value that cannot easily be measured in money terms. In the project, we have conducted interviews with farmers after each fattening round using a standardised questionnaire where we collected economic farm data according to a simplified economic model of pig farms developed in the EU-PLF project13, qualitative data evaluating sense of control and detection of incidents (e.g. outbreak of disease) and soft values. After farmer interviews and our analysis of farm data, it became clear that the contin-uous weighing of pigs using video analysis14 is the clearest case for measureable economic return. Measurable economic return stems mainly from a better detection of the ideal moment for slaughter, because (a) the weight growth curve slows down or (b) the ideal slaughter weight is reached within the precision of the measuring technology.

Figure 1 The iterative LivingLab process used in ALLSMART-PIGS In ALL-SMART-PIGS the above iterative process is used (i) to design a technology prod-uct/service package that appeals to European pig farmers and provides them with a clear value proposition, and (ii) to design and trial a traceability system with the pur-pose of preparing the development of a commercial offering at a subsequent stage. Given that the development of a commercial system for the exchange of data depends heavily on the acceptability, within the project we only attempt to collect first experi-ences with a limited number of players in order to better identify areas of valuecreation. Socio-economic Analysis of Smart Pig Farming ALL-SMART-PIGS has set out to implement and evaluate five base SmartFarming tech-nologies on four European pig farms (two in Spain, two in Hungary):

46 International Animal Health Journal

Figure 2 shows the price of a carcass as a function of its

Figure 1 The price at slaughter for a Spanish slaughterhouse with a first-order approximation of benefit

weight, from a real slaughter-house in Spain (blue line). Also shown is a first-order approximation of the benefit (red line); this approximation is not good for very large weights where it should be lower than shown. Determination of ideal slaughter weight (around 85kg

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carcass weight for the above slaughterhouse) is subject to an error in estimating the weight. Particularly with nar-rower weight distributions (i.e. where most of the pigs have very similar weights), the precision is very important. If weight is determined incorrectly, the farmer suffers an opportunity loss and/or a price penalty at the slaughterhouse. In Figure 3 (left) we show the optimal gain of one farm

Figure 1 On the left, optimal gain per pig as a function of the standard deviation of the weight distribution. On the right, optimal savings per 1000 animals when using a PLF technology with 1kg error as opposed to visual estimation with about 5kg error.

Figure 3 On the left, optimal gain per pig as a function of the standard deviation of the weight distribution. On the right, optimal savings per 1000 animals when using a PLF technology with 1kg error as opposed to visual estimation with about 5kg error.

delivering to the above slaugh-terhouse as a function of the standard deviation of the pig weight. As can be seen clearly, a lower standard deviation leads to better financial results. It is a known fact 19 that several factors impact the width of the weight distribution, health issues being one of them. We are convinced that technologies such as respirato-ry health detection, activity measurements and feed dispensed measurements have the potential to demonstrate their measurable economic value from this curve. How-ever, it is still unclear how to isolate the impact of early warnings. On the right hand side we show the savings per 1000 animals assuming that the PLF technology measures weight with 1kg error and the visual estimation of weight has an error of 5kg, as reported by farmers. The 1kg error is supported www.animalhealthmedia.com

by on-farm measure-ments of the contactless weighing technology cited above. It can clearly be seen that SmartFarming has an impact on those farms that attempt to optimise their returns – and at the same time wish to monitor welfare of the animals (which in Spain has currently little economic incentive). With 2.5 fattening rounds per year, a 1000-animal farm can improve its result by almost 9000€ per year, which cer-tainly gives rise to an investment case for the weighing technology. PLF and Supply Chain Value-creation However, the ALL-SMART-PIGS project wanted to go one step beyond simple data cap-ture and on-farm visualisation for more efficient management that normally is consid-ered the focus of Precision Livestock Farming. The project explored the value of ex-changing data using traceability between supply chain partners (see Figure 4), in par-ticular between: • • •

Feed providers Farms Slaughterhouses/cutting rooms

Due to the lack of access to real data, feed manufacturers have to rely on test or re-search farms, farmers have to rely on experience and the offering of the feed industry, and slaughterhouses have little influence on the meat quality, with the exception of fines for off-spec animals. Given that even slight decreases of feed need make huge differences on micro and macro levels, the current approach is not optimal. The starting point was our suggestion for a privately-run system where carcass compo-sition data is made available to farmers for their individual animals. Farmers would then (via an electronic system) make averaged data available to the respective feed producers who can aggregate this data with that from other farms to judge the per-formance of their International Animal Health Journal 47


Research & Development farms clearly shows that the technologies have to improve their robustness. Reliance on the internet for data transmission is a particularly tedious problem. Other more mundane problems include, for example, the depositing of fly faeces on camera lenses, which impacts weight and activity measurements. There is a clearly measurable value in some technologies. In fattening animals the easiest directly measurable economic impact is related to determining the slaughter weight correctly and/or shortening the fattening period once growth flattens out.

Figure 4 Feed(back) on the feed-animal-food chain 7

However there are many SmartFarming technologies whose value is clear, but not yet directly quantifiable. Most of these have an impact on animal health and welfare, where the hard economics need to be substituted by softer values. Further socio-economic research, currently being carried out in the EU-PLF project, will make value-creation on farm and in the supply chain more concrete. Models are under

feed compositions9, 20. Based on real and massive data, feed producers can on one hand optimise their products and on the other hand offer better products to Table 1 Validated concept for information exchange along the feed - animal - food chain individual farms. The Danish Catellae System is an example where such an approach has been used, in this case for poultry. After some initial resistance, the system is now used by 100% of the Danish poultry farmers thanks to pressure by larger buyers, but also due to the optimisation potential that such a system allows21. Through the open co-creation method described above, ALL-SMART-PIGS was able to confirm the value of such a feed-animal-food traceability system. In particular, the parameters shown in Table 1 have been considered to be of interest by feed compa-nies, farmers and slaughterhouses. This research is now being continued within the EU-PLF project and an economic eval-uation of such information elements will be published in due time. Conclusions Technology uptake is increasing in all areas of humankind, and there is very little doubt that this will extend in the future to livestock farms. SmartFarming or iFarming is certainly the future of livestock farming, in particular since it addresses the balance between practicality (efficiency, economic return) and acceptability (concern for ani-mal health and welfare). Experience of installation of Smart Pig Farming technologies on commercial 48 International Animal Health Journal

Feed provider to farmer Purpose • Historic cost of feed per kg of meat • Target growth curve for service agreement • Service level (e.g. % protein, minimum % corn etc) Main data • Historic cost of feed per kg of meat elements • At beginning of fattening period growth curve (set of data points, potentially as a function of target start and end weights) • Updated nutritional profile per delivery Other data Feed identification (feed type, delivery identifier/date and a farm/silo) Farmer to feed provider Purpose Manage changes in composition with respect to farm indicators such as weight gain and feed consumption Main data Per feed identifier (may require a link between pen and silo; for project we can assume one feed per elements farm) and per day • Avg. weight (kg) • Avg. feed dispensed per animal (kg) • Avg. activity index • Avg. cough index • Avg. effective temperature • Change in ammonia concentration with respect to 1-2 days before Other data Number of pigs per pen over time Farmer to farmer Purpose Understand the performance of the farm relative to peers (weight gain at a particular age, incidences of respiratory diseases, variability of pig weight and lean meat %, activity indexes (under certain environmental conditions and/or feed composition), mortality Main data • Deliver to the system: weight gain at day of production, weight variance, cough index, activity elements index, variance in lean meat % at end of cycle, mortality • Receive from system: offset from average of the above indicators Farmer to slaughterhouse/cutting room Purpose • Quality control (and risk control) • Being able to offer differentiated products Main data • Transport date, time and duration elements • Transport type (smooth road or unpaved path, ventilated/non-ventilated lorry) • Time of last feeding • Genetics • Feed type • Cough index • Treatments Slaughterhouse/cutting room to farmer Purpose • Weight and composition data to optimise the feeding process • Understanding non-compliances Main data • Per pig: live weight, carcass weight, carcass classification and lean meat % elements • Observations meat quality • Vet report/quality department report Slaughterhouse/cutting room to feed provider Purpose Weight and composition data to optimise the feeding process (on average over farms) Main data Via farm: Avg. pig weight, carcass classification and lean meat % elements Other data • Environmental conditions • Farm age • Type of production systems • Health problems before fattening (e.g. diarrhoea in piglet)

Table 1 Validated concept for information exchange along the feed - animal - food chain Volume 1 Issue 2


Research & Development development that will allow a more direct cost-benefit calculation. There is also clear value in the exchange of on-farm measurement data, in particular with feed companies. The main reasons for the interest are collected in Table 2.

Table 2 Main value-creation potential as a function of the supply chain step Acknowledgements The authors gratefully acknowledge the European Community for financial participa-tion in Collaborative Project EU-PLF KBBE.2012.6-311989 and ALL-SMART-PIGS KBBE.2012.1.402-311989 under the Seventh Framework Programme. The author would like to thank in particular the Living Lab participants for their continued and fruitful collaboration. Contributions by all project partners are kindly acknowledged. References 1. T. B. Banhazi, J. J. Black, H. Cabtree, P. Schofield, M. Tscharke and D. Berckmans, “Precision Livestock Farming: An international review of scientific and commercial aspects,” Int J Agric & Biol Eng, vol. 5, p. 1ff, 2012. 2. S. Cox, Ed., Precision Livestock Farming, Wageningen: Wageningen Academic Publishers, 2003. 3. S. Cox, Ed., Precision Livestock Farming, Wageningen: Wageningen Academic Publishers, 2005. 4. S. Cox, Ed., Precision Livestock Farming, Wageningen: Wageningen Academic Publishers, 2007. 5. S. Cox, Ed., Precision Livestock Farming, Wageningen: Wageningen Academic Publishers, 2009. 6. C. Lokhorst and D. Berckmans, Eds., Precision Livestock Farming, Prague: Czech Center for Science and Society, 2011. 7. I. G. Smith and H. Lehr, Eds., Multidisciplinary Approach to Acceptable and Practical Precision Livestock Farming, Halifax: Vicarage, 2011. 8. [“A special report on feeding the world,” The Economist, 24 February 2011. 9. H. Lehr, B. Lenvig and E. Fàbrega, “Traceability in the feed-animal-food chain,” in Precision Livestock Farming ‘13, Leuven, 2013. 10. H. Lehr, J. van den Bossche, M. Mergeay and D. Rosés, “Developing SmartFarming entrepreneurship - first results from EU-PLF,” in Proceesings from EC-PLF, Leuven, 2013. 11. H. Lehr, J. van den Bossche, M. Mergeay and D. Rosés, “Developing SmartFarming entrepreneurship. II Preparing PLF spin-offs,” in European Association of Animal Production, Copenhagen, 2014. 12. H. Lehr, “SmartPig Farming - How the ALL-SMART-PIGS technologies improve animal welfare,” British Nutrition Foundation (CommNet), London, 2014. www.animalhealthmedia.com

13. C. Kamphuis and H. Hogeveen, “Economic modelling to evaluate the benefits of precision livestock farming,” in European Association of Animal Production, Copenhagen, 2014. 14. T. M. Banhazi, M. Tscharke, W. Ferdous, C. Saunders and S. Lee, “Improved image analysis based system to reliably predict the live weight of pigs on farm: Preliminary results,” Australian Journal of Multi Disciplinary Engineering, vol. 8, no. 2, p. 107, 2011. 15. T. M. Banhazi, D. Rutley, B. Parkin and B. Lewis, “Field evaluation of a prototype sensor for measuring feed disappearance in livestock buildings,” Field evaluation of a prototype sensor for measuring feed disappearance in livestock buildings, vol. 7, p. 27, 2009. 16. V. Exadaktylos, M. Silva, J.-M. Aerts and D. Berckmans, “Real-time recognition of sick pig cough sounds,” Computers and Electronics in Agriculture, p. 207–214, 2008. 17. M. Hemeryck and D. Berckmans, “Pig cough monitoring in the EU-PLF project: first results,” in European Association for Animal Production 2014, Copenhagen, 2014. 18. T. B. Banhazi and J. L. Black, “Precision livestock farming: A suite of electronic systems to ensure the application of best practice management on livestock farms,” Australian Journal of Multi-disciplinary Engineering, vol. 7, no. 1, pp. 1-14, 2009. 19. J. L. Black, L. R. Giles, P. C. Wynn, A. G. Knowles, C. A. Kerr, M. R. Jone, N. L. Gallagher and G. J. Eamens, “A review - factors limiting the performance of growing pigs in commercial environments,” in Manipulating Pig Production VIII, Adelaide, Australasian Pig Science Association, 2001, pp. 9-36. 20. H. Lehr, “Practical and acceptable Precision Livestock Farming: results from BrightAnimal,” in Proceedings of the 5th EC-PLF conference, Leuven, 2011. 21. H. Bunkenborg, “Lyngsoe Systems – Supply Chain Division, presentation held at LivingLab session in Vic (Spain) 13/06/2013,” Vic, 2013. 22. F. E. Webster, “The Changing Role of Marketing in the Corporation,” Journal of Marketing, vol. 4, pp. 1-17, 1992.

Dr Heiner Lehr is a partner of Syntesa, a firm working in bringing innovation to the market. Heiner has been involved with Precision Livestock Farming since 2008. He was the co-ordinator of the ground-laying BrightAnimal project and continues his work now in the projects ALL-SMART-PIGS where Syntesa is the co-ordinator and in EU-PLF, where he leads the work packages on value creation and on spin-off creation. Email: heiner@syntesa.eu International Animal Health Journal 49


Research & Development

Efficient Monitoring of Antibiotic Use on Pig Farms Following the limitations on antibiotic use in pigs farms across Europe since the late 1990s, it has become crucial to monitor antibiotic use on farms and their microbial status, in order to protect young and growing pigs against infectious diseases. As research continues to provide commercial producers with knowledge regarding challenges to animal health and performance, the checklist of risk factors continues to grow regarding what biosecurity measures are required to keep diseases off farm, as well as environmental challenges that are ubiquitous, for example soil-borne organisms and mycotoxins. Alltech provides an audit programme which evaluates various contributing factors to on-farm productivity, including biosecurity, animal health status, mycotoxin exposure and antimicrobial use. From such individual surveys, and comparisons against research and commercial trial data, recommendations can then be given for both nutritional and management solutions that will minimise the reliance on antimicrobial treatments. The survey includes both internal and external biosecurity (Biocheck), current levels of antibiotic reliance (ABcheck) and, via the PigASSIST progamme, animal health status and productivity. This allows identification of any animal health challenges that can then be targeted and minimised. In addition, feed and bedding (e.g. straw) samples are analysed for mycotoxin risk. Example of an On-farm Audit Indoor and outdoor pig units face very different types of challenges to animal health and productivity. For the purposes of this paper, the example of an outdoor unit is used. Many farms have good external biosecurity, for example wheel and foot baths for visitors, however internal biosecurity can be more lax, leading to challenges from feed, bedding and personnel on internal biosecurity, and overall biosecurity was below average. For all facilities, quarantine areas for purchased animal stock are recommended to monitor any incubating disease and offer treatment before mixing animals with others already on the farm. The quality of drinking water should also be taken into account – as this can be a major vector for pathogens which cause digestive disease, scours, poor productivity and even higher mortality. Farms sourcing water from bore holes are at particular risk of these and other disease-causing organisms, which infect via faecal and soil contamination. Common On-farm Threats to Growing Pigs Sows and growing pigs face various threats on farm – from both internal and external sources. These threats include biosecurity management systems, i.e. limiting risk factors coming onto the farm. However, some threats to animal health and performance are ubiquitous and difficult to exclude or avoid – and hence various steps can be taken to reduce their negative impact on the welfare and health of the pigs and the economics of the farm. Fungal growth in feed materials and bedding leads to the exposure of pigs to the 50 International Animal Health Journal

toxins they produce. Mycotoxins cause a variety of diseases in pigs, notably major reproductive problems, including poor fertility and lactation, higher empty day rates in sows and lower piglet numbers per litter. Other problems tend to be sub-clinical and hard to diagnose, and include poor feed efficiency and higher variability in herds, leading to extra costs for drafting pigs in an all-in/all-out system. Gut-active feed ingredients, including mannan-based supplements, have been shown to affect the development and acquisition of immunity in young pigs. Sows fed mannanrich fractions (MRF) had increased colostrum production, higher IgG concentrations and better colostrum nutrient quality, which in turn boosts the suckling piglets’ immunity, reducing pre-wean mortality, lowers the incidence of piglet scours, increasing weaning weights and also reducing the need for medication. MRF binds pathogens in the intestinal tract, and reduces the pathogen load in the sow, often reducing wean to oestrus interval. Working in synergy, these two solutions would reduce both the mycotoxin load and bacterial infection, which is currently affecting birth, weaning weights, pre-weaning mortality from scouring piglets, and sow reproductive performance. In addition this would affect herd antimicrobial (AM) use on this unit, and would give pigs an improved start when weaned and shipped to new premises, affecting feed intake, growth rate, post-weaning mortality, morbidity, disease profile and AGP use on the nursery unit. Practical Monitoring The on-farm monitoring for both the Biocheck and Alltech Pig-Assist Program includes scoring for both external and internal biosecurity threats that lead to higher antibiotic reliance. External threats which are monitored include the purchase of animals and semen, transport of animals, manure and dead animals off farm, cleanliness of feed, water and personnel, control of visitors, vermin and bird control and local environmental conditions. Internal threats monitored include current disease management, farrowing and suckling conditions, rearing facilities, control of animal movements, cleanliness of equipment and general cleaning and disinfection routines. All of these factors are scored on-farm using the Biocheck system and compared with averages from other units in order to ‘rank’ the current biosecurity measures used. In general, several practices are recommended to improve biosecurity on pig farms. Firstly, a quarantine area should be set up for all animals coming onto the farm, and gilts should be held for three weeks away from the main animal housing to ensure they are disease-free. In addition, for outdoor units, this is an opportunity to slowly adapt them to outdoor living conditions, which can otherwise cause stress. Secondly, drinking water quality should be monitored and appropriately treated to ensure this is not a vector for disease. All visitors to the piggery must be signed in and out, and should be provided with clean clothing and boots to wear on the unit. Foot and wheel baths should be used at all access Volume 1 Issue 2


Research & Development points to the pigs. The Alltech Pig-Assist Program can be used to gauge the current status of performance and health on pig farms by monitoring litter numbers and health alongside costs for rearing litters including sow empty days. This is then compared against targets for economical production on that unit – allowing the identification of areas in management and productivity where improvements can be made. This is then included in an economics model, whereby all costs of piglet production are taken into account, as are improvements (taken from research and commercial pig trial responses). This can be used to take into account any extra in-feed supplements or other costs that have been recommended from the individual farm information, and return on investment calculated.

as ensuring better return on investment for pig production, leading to higher profitability per pig, even in outdoor farming systems. References Connolly A., Antibiotic free animal production, 2010. Pig Progress, Vol 26 Nr 6. Gillepsie, T. 2013. The next step when pigs get sick. PorkNetwork. www.PorkNetwork. com. Landeau E., Le Dividich J. 2013. Effect on pig birth weight of including mannanoligosaccharides (MOS) in reproductive sow diets. Poster, Journees de la Recherche Porcine, Paris, 2013 McArdle T.M., Nollet L. 2013. Effects of Actigen during gestation, lactation and starter phases on sow and piglet performance to 40 kg. Poster, Alltech 29th Symposium, Lexington, KY, USA. Samuel R.S., Brennan K.M. 2012. Effect of Actigen™ supplementation in gestation and lactation on sow and piglet performance, colostrum Ig level and milk

The levels of antibiotics used on farm are now regulated in European pig farms, and most have to be administered under veterinary supervision. In our example using an outdoor farm, fluoroquinolone was being used, which is not recommended and should be replaced by another product, such as a thirdgeneration cephalosporin. For this farm, the model for reducing reliance on AGPs by supplementing diets with MRF products was included.

composition. J. Anim. Sci. 90(Suppl. 1):391. Brennan K.M., Graugnard D.E., Paul M., Xiao R. 2013. Effect of maternal Actigen supplementation during gestation and lactation on piglet gut development and gene expression. J. Anim. Sci.90(Suppl. 1):390. Che T.M., Song M., Kelley K.W., Van Alstine W.G., Dawson K.A., Pettigrew J.E. 2011. Actigen improves growth efficiency and immune responses in pigs experimentally infected with PRRSV virus. 44th Midwestern Sectional Meeting, Mar 14-16, Des Moines, IA.

The example farm used in this paper had mycotoxins present in both the straw bedding used in sow accommodation and in the feed. Thermal imaging showed fungal growth in straw bales as well as in bulk feed bins, due to poor clean out, and also leakage of water into storage areas. The greatest risks from analysing samples from this farm were identified from type B tricothecenes. These are associated with poorer feed intake and weight loss, due to lesions and other damage within the digestive tract. Sows are known to have poorer conception rates and poorer immunity (including transfer of immunoglobulins to piglets) when exposed to type B tricothecenes. In addition, lower levels of type A tricothecenes, penicillium and aspergillus toxins were detected, which reduce performance and immunity. The fact that multiple mycotoxins were found on this farm shows that pigs were at a higher risk of ingestion and exposure. From these findings, it is recommended that mycotoxin binders be used in feed to remove the threat of toxin contamination, as well as a complete clean out of both animal and feed areas at a minimal six-monthly period. The cost benefit analysis (using the current outdoor farm example) showed that, by taking on the recommended feed supplementation, a return on investment of 2.6:1 was calculated. Conclusions Modern scoring systems, analysis of major risk points, comparisons with responses seen in commercial and research trials and including cost benefit analysis are available for direct application on active pig farms. These will help with general biosecurity measures, as well as identifying where problems are currently occurring that will be inhibiting performance and animal health, and increasing reliance on antibiotic use. By using such systems, pig farmers will be better able to maintain their farm management practices to stay in line with retailer and consumer requirements, as well 51 International Animal Health Journal

Che T.M., Johnson R.W., Kelley K.W., Dawson K.A., Pettigrew J.E. 2011. Effects of feeding Actigen on the ex vivo immune responses of porcine leukocytes. J. Anim. Sci. 89:405, 2011 Che T.M., Song M., Liu Y.,Johnson R.W., Kelley K.W., VanAlstine W.G., Dawson K.A.,Pettigrew J.E. 2012. Mannanoligosaccharide increases serum concentrations of antibodies and inflammatory mediators in weanling pigs experimentally infected with porcine reproductive and respiratory syndrome virus. J Anim Sci.90:2784-2793 Che T.M., Song M., Johnson R.W., Kelley K.W., Van Alstine W.G., Dawson K.A., Pettigrew J.E. 2011. Actigen increases serum levels of cytokines and haptoglobin in pigs experimentally infected with PRRSV virus. 44th Midwestern Sectional Meeting, Mar 14-16, Des Moines, IA. Che T.M., Song M., Johnson R.W., Kelley K.W., Van Alstine W.G., Dawson K.A., Pettigrew J.E. 2011. Effects of Actigen on peripheral blood immune cells in pigs experimentally infected with porcine reproductive and respiratory syndrome virus (PRRSV). J. Anim. Sci. 89:14, 2011 http://www.biocheck.ugent.be/v4/about/pig/ http://www.abcheck.ugent.be/v2/audit/

Dr Jules Taylor-Pickard : a nutritionist, obtained her Ph.D. specializing in piglet gut health, physiology and immunity. Taylor-Pickard is currently the solutions deployment team manager and the pig unit business director for Alltech Europe. Within these roles, she directs the European commercial swine and research strategies, provides technical support to the salesforce, and initiates, supports and interprets multi-species research activities, focusing on providing natural solutions to optimize animal performance and efficiency. Previous roles she has held within Alltech include global Mycosorb® manager and pig technical manager for Europe. Prior to Alltech, she worked with pharmaceutical applications in the monogastric sector. Email: jpickard@alltech.com Volume 1 Issue 2


Corporate Profile

Dividella’s TopLoading Concept Proves Convincing in South Korea. First NeoTop x for CAVAC. The Dividella project team convinced the customer of the benefits of the TopLoading solution for packaging vials in boxes in record time. Contact was made shortly before Interpack 2014 - and the FAT is scheduled for midDecember Customer portrait: CAVAC, Choong Ang Vaccines Laboratories Location: Daejeon, South Korea Portfolio: Bio-pharmaceutical veterinary products Market leader in vaccines for livestock in Southeast Asia The customer’s requirement: For packaging its products, including Suishot (vaccine for pigs), the customer requires a packaging solution that guarantees comprehensive product protection in addition to low volumes for cost-efficient cold-chain distribution. In addition, different pack sizes are to be produced on a GMP-compliant packaging line with a capacity of up to 450 vials/min. The solution: Dividella very quickly developed a packaging and machine concept for a total of four different pack formats, all

of which can be packaged on the NeoTop x using the TopLoading method. The NT x is equipped with feeds for different vial formats and leaflets. Customer benefits: Compared to the original packaging in blister trays in a side-load box, the Dividella (NeoTOP) packaging solution significantly reduces costs for cold-chain distribution thanks to the much lower volume. The use of monomaterial in turn lowers the TCP (total cost per package) and hence the TCO (total cost of ownership). Fast, toolless format changes allow the customer to package different formats on one machine and to respond quickly to the requirements of the market. In the veterinary sector too, there is a trend towards shrinking lot sizes and pack variants forspecific target groups. However, in addition to small orders the NTx concept allows the production of large quantities - a decisive competitive advantage, especially in the case of vaccines. Expert advice and quick production of samples led to success. In an interview, the Dividella project team, consisting of Wolfgang Nimmerfroh, Area Sales Manager and Andreas Summer, Project Manager Engineering for the design and consultation phase, report on how the customer was finally convinced of the benefits of the TopLoading solution. Facts: How was contact made with the customer? Wolfgang Nimmerfroh (wni): The customer enquiry was very much targeted at us specifically, i.e. we obviously have a good reputation in the market. Also, the information and details that we supplied to the customer at their request

From 3D Templates... 52 International Animal Health Journal

...to the actual samples boxes Volume 1 Issue 2


Corporate Profile very promptly. Fast feedback was received following our initial efforts, so we jointly continued to adapt the packaging to the customer’s needs. From a cardboard box which was optimised for volume to a pack whichnprovides the best protection for the product but still has a significantly reduced volume. For the customer, this is an optimal combination.

Vaccines in different vial formats are to be packaged on a packaging line.

were so convincing that an additional representative of the customer travelled from South Korea to Interpack in DĂźsseldorf. This new TopLoading NeoTOP x cartoner could be seen working there. About two weeks later we had the order. Andreas Summer (as): Then everything happened very quickly. We created the initial 3-D packaging concepts based on product photos and vial dimensions and sent them to the customer.

In your view, what were the most important arguments for the customer choosing Dividella? wni: I think the good advice and the speed with which we were able to present different designs to the customer and implement his requirements were decisive. Our colleagues from Engineering have done a lot of work. In the final analysis the customer is not just buying a Machine, but choosing a packaging concept. as: Yes, modern engineering tools with 3D templates and interactive drawings, in which the customer himself can make adjustments, greatly supported coordination. And what now for the project? wni: The project manager was on site with the customer at the end of July to discuss the technical details and the timely provision of materials for operating trials. We have adopted a schedule which provides for the FAT as early as midDecember 2014. If cooperation continues to be so harmonious, I see no problems here at all. We are very pleased with this project – our first NeoTOP for South Korea.

How was the cooperation with the customer during the design phase? as: Very professional and open, and decisions were taken

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International Animal Health Journal 53


Clinical Studies The Heart of the Matter – Musings on Monitors

“Begin an exciting career in clinical research as a study monitor! Generous compensation, flexible schedules, work from home, and pick your studies! Don’t miss this opportunity. Call now!” Ask a study monitor why they do what they do, and they’ll quickly tell you that they love being involved in clinical research. Then, they’ll usually add that they were lured by the money, the flexibility, and the variety. While one or more of these reasons may prompt someone to become a monitor, their success in the field depends on an entirely different set of factors. Some of the necessary skills can be learned in school, especially if the course of study was in one of the physical sciences. Other skills can be taught as part of the new monitor’s onboarding and at individual study training sessions. However, of equal and perhaps greater importance are the individual’s personal commitment to excellence and the amount of actual field experience. Those are the factors that distinguish great monitors from all of the rest. Clinical study monitors are representatives of the study sponsor and, as such, are responsible for ensuring that the study is conducted in exact compliance with the protocol, that all study activities conform to Good Clinical Practice (GCP) guidelines (VICH GL 9, available at http://www.fda. g ov / d o w n l o a d s / A n i m a l Ve te r i n a r y / GuidanceComplianceEnforcement/GuidanceforIndustry/ ucm052417.pdf), and that all other regulatory requirements are met. The study monitor oversees the performance of each investigator, assists site personnel, ensures the authenticity and integrity of all study data, and serves as the principal liaison for all communications between the study sites and the sponsor. If they have done their job well, there will be few, if any, surprises when the final study data are submitted to the sponsor or if one of their sites is audited by the regulatory agency. Finding Study Monitors According to VICH, section 5.1, “The monitor should have scientific training and experience to knowledgeably oversee a particular study. The monitor should be trained in quality control techniques and data verification procedures. The monitor should understand all applicable protocol requirements and be able to determine whether the study was conducted in accordance with the protocol and relevant SOPs.” Finding a good study monitor is no different from finding a good candidate for any other position. Deciding what to look for is easy: aptitude, education, experience, and commitment. Assessing an individual candidate against those four parameters, though, can be challenging. Does the candidate have the innate ability to absorb new material? Do they have formal education in a scientific field? 54 International Animal Health Journal

Some sponsors look for at least a baccalaureate degree in one of the life sciences to demonstrate basic understanding and familiarity with medical terminology. Do they have relevant past experience (laboratory research, academic or privatepractice veterinary hospital, human clinical research)? Do their track record and/or references indicate a commitment to success? In today’s environment of employee privacy, it may be difficult to obtain reliable references beyond basic employment information. Can they work well with a wide diversity of people? Have they demonstrated an ability to solve problems and meet deadlines? The higher a candidate scores on these and other factors will determine the likelihood of superior performance in the field…after onboarding and study-specific training! Training Study Monitors As with any new employee, a new study monitor first should be introduced to company policies and procedures. They then should be trained in their new company’s standard operating procedures for conducting clinical research. Some companies give the new monitor the protocol from a previous study and selected site data to review, and then use the results as a guide for further training. Others assign the new monitor to “shadow” an experienced monitor to gain some supervised experience before being sent out on their own. Some companies also give the new monitor a detailed checklist and then test their understanding of that checklist while role-playing a site visit. Whichever method or combination of methods is used, the goal is to prepare the new monitor to attend study-specific protocol training and then to successfully monitor investigative sites under that protocol. Monitoring Activities Clinical study monitors have three principal responsibilities. First and foremost is the review of study data and documentation from each of the investigative sites, as well as the issuance and resolution of queries regarding any data that are missing, out of the protocol’s acceptable range, inconsistent with other data, incorrect, improperly formatted, or otherwise requiring clarification or further action (e.g., reporting of adverse events). The monitor’s second principal responsibility is to document, review, and catalogue all study communications, whether verbal, written, or electronic. All study-related conversations, telephone calls, emails, faxes, reports, notices, correspondence, and file notes must be retained as part of the study’s permanent record. This record tells the story behind the data, much as a libretto supports an opera, and is a necessary component of a successful study. The monitor’s third principal responsibility is to oversee the study activities at each of their assigned investigative sites and to periodically visit each site to confirm that their performance complies in all respects with the protocol’s Volume 1 Issue 2


Clinical Studies

requirements. The frequency of site monitoring visits will be determined through a combination of the sponsor’s initial monitoring plan, the complexity of the study, the pace of enrolment at each site, and the performance of each investigator as indicated by the quality of their data, the number and type of protocol deviations, and the number and type of queries. There are four principal types of site monitoring visits: site qualification visits, site initiation visits, interim site monitoring visits, and site close-out visits. Following the completion of each site visit, the study monitor should file a report documenting their activities during the site visit, their findings, instructions given to the investigator and/or site personnel, and any follow-up action that may be required. The purpose of a site qualification visit is to determine whether (a) the investigator and participating clinic staff are sufficiently capable and motivated to complete their study activities in accordance with the protocol, GCPs, and all regulatory requirements, and (b) the clinic is adequatelystaffed, well-organised, and equipped with the necessary technology, supplies, and properly-calibrated equipment to successfully complete the study. During this visit, the monitor also will detail the investigator’s responsibilities that are included in VICH GL 9, Section 3 and assess their understanding of the protocol. They also will review the clinic’s standard operating procedures to ensure that they will support superior study performance. Lastly, the monitor will inspect the clinic’s medical records and, depending on the targeted indication, confirm that the clinic has a sufficient patient population with the target indication to enable prompt enrolment of the required number of study subjects.

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The site initiation visit allows the study monitor to evaluate the investigator’s understanding of all of the material presented during study training, to reconfirm their availability for the duration of the study, and to verify that the correct amount of test article and any necessary supplies have been delivered and are properly stored. Monitors often find it beneficial to review the protocol’s schedule of activities, enrolment criteria, test article accounting, and other study details with the investigator and participating site personnel to ensure that everyone is very clear on their responsibilities, procedures to be followed, and required documentation. The monitor also should review the process for reporting and documenting protocol deviations and adverse events. If possible, some monitors schedule their site initiation visits to coincide with each site’s first enrolment or, when that is not feasible, to occur before additional study subjects are enrolled. This format provides an excellent opportunity to observe the investigator and participating site personnel under actual study conditions and to determine whether remedial training is warranted. It also gives the study monitor a chance to assess the site’s recruitment strategy and project if and when the site might meet its enrolment quota. After study training, the site initiation visit is a key determinant of site performance. Additional time spent at this early stage of the study will pay big dividends later on. Interim site monitoring visits are periodic check-ups on each site’s performance. They are scheduled according to a monitoring plan approved by the sponsor prior to the start of the study. However, individual site results may dictate additional visits to address a problem or fewer visits at lowenrolling sites or those with minimal queries. In addition, sites with successful past performance may receive fewer interim International Animal Health Journal 55


ChapterStudies Clinical Title monitoring visits than newer, less experienced sites. During each interim site monitoring visit, the study monitor verifies protocol compliance, reconciles test article inventory, and reviews all required study documentation. They also review each study subject’s medical record to ensure compliance with the protocol’s inclusion/exclusion criteria and check for data entry discrepancies. For studies employing electronic data capture (EDC), the monitoring plan may allow for some interim site monitoring visit activities to be completed remotely. In those instances, the study monitor can review site data in real time through the EDC system, and then issue and resolve queries electronically. However, there is no substitute for hands-on verification to ensure that all of the protocol’s requirements are being met. Therefore, the study monitor should complete at least one interim site monitoring visit at each site.

5.

6.

7.

8. A site close-out visit is scheduled after the last subject enrolled at each site has completed its last study visit. During the close-out visit, the study monitor will resolve any outstanding data queries, confirm that the site’s study binder is properly organised with all required documents, and instruct the investigator and participating site personnel in their ongoing study responsibilities for document and data retention. The monitor then will make certified copies of any documentation that must be retained by the site and pack all document originals for shipment to the sponsor. The monitor also will perform a final reconciliation of the test article inventory and review the documented resolution of any discrepancies. In most instances, the monitor will assist site personnel with the packaging and return of test article to the sponsor and with the return or destruction of laboratory kits and supplies. Before leaving the site, the study monitor will discuss audit readiness and review the procedures to be followed should the site receive notice of a pending FDA site audit. Comprehensive training can prepare a new study monitor to perform all of their responsibilities, and time invested in such training will reap rewards once the monitor is assigned to an actual study and travels to sites in the field. However, truly exceptional performance is rare until a new monitor’s skills have been honed by years of experience. Bonus: Ten Tips for Masterful Monitoring 1. Before a study starts, introduce the assigned monitor to each site’s staff to ensure that everyone is compatible and committed to superior results. Monitor-site staff rapport is essential to successful site performance. 2. Assign only full-time monitors and, to the extent possible, allow only participating site personnel who are available for the duration of the study. 3. Review the protocol and case report forms with all assigned and back-up monitors before the investigator training meeting to uncover any potential problems or bottlenecks and to clarify and reinforce monitor responsibilities. 4. Establish a monitoring communication plan which details what needs to be communicated, by whom, to whom, and when. Whenever possible, create communication 56 International Animal Health Journal

9.

10.

templates to standardise documentation. Keep the sponsor informed at all times about all issues. Establish a monitoring team conference-call schedule to review the results of each monitoring visit (qualification, initiation, interim, and close-out) so monitors can share experience and collaborate on problem solutions. Develop a monitoring visit schedule for each site, tailored to their clinical trial experience, familiarity with the study’s target indication, and projected enrolment. Some sites may warrant more visits than others, depending on their respective enrolment pace, number of protocol deviations, data quality, and query volume. Create an enrolment timeline by site and report site enrolment status weekly. Before the study starts, plan enrolment enhancement strategies for those sites which lag behind their timeline. Establish and maintain study data review schedules, whether data are collected via paper case report forms or an electronic data capture system. Review data forms and issue queries promptly to catch protocol deviations and adverse events as soon as possible and to identify sites needing remedial training. Before the study starts, develop a proactive inventory control plan to prevent discrepancies from occurring. Reconcile test article inventory on a regular schedule, but no less frequently than every monitoring visit. Resolve discrepancies immediately and quickly report any unresolved discrepancies to the sponsor. Role-play various study and site visit scenarios to anticipate problems, develop preventive measures, and plan courses of corrective action. Identify resources that may be needed and determine their cost and availability.

In many ways, clinical study monitors are like traffic cops. They keep the study moving, look out for problems, give instruction where needed, assist at and report on “accidents,” and stop those who don’t follow the “rules of the road.” They ensure that all study data and required documentation are complete, consistent, and accurate, thereby playing a crucial role in the approval process for new therapies which improve the health and wellbeing of all animals. And that is the heart of the matter.

Denni O. Day, 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, a consortium of study-ready investigators, and an animal conditions database which facilitate rapid study initiation, accelerated enrolment, and superior results. For more information, please visit www.vetpharm. com or contact Denni Day at (585) 249-1090 ext. 209 or email: dday@vetpharm.com Volume 1 Issue 2


Corporate Profile

Prevtec microbia: Innovation and Expertise for Sustained Animal Health

launch in other major markets. To that effect, Prevtec microbia recently submitted a dossier to European regulatory authorities for the approval of Coliprotec F4.

Prevtec microbia is a Canadian biotechnology company specialising in developing and bringing to market products designed to help improve the health of food-producing animals in order to increase production, performance and food safety.

Our pipeline of future products is as exciting as our currently marketed entities and includes innovative solutions to animal health concerns. In this regard, Prevtec microbia has joined the ranks of thriving animal health companies with activities in various parts of the world. And we are privileged to count two of the top animal health companies in the world as our distributors.

At Prevtec microbia, we believe in taking a proactive approach to animal health, focusing on disease prevention. Our activities are founded on the universally-held values of health, safety and responsibility. The company’s mission is to be a world leader in the development and commercialisation of vaccines and other biologicals. From the laboratory to the global market, our in-depth understanding of animal health challenges and solutions has led to a portfolio of performance-proven products for commercialisation around the world. As the world’s food ecology evolves as a result of limited resources and other realities that threaten animal health, it is now more important than ever to identify ways to optimise food production processes and output. Less waste, more food and efficiency-improving technologies: Prevtec microbia is working on ways to achieve all this – and more. Innovation Strategy Prevtec microbia’s core strength lies in our strategic assets, namely, our track record, our technologies and our people. At Prevtec microbia, we believe that research & development spells the future of the animal health industry. With R&D facilities and corporate headquarters located in the Greater Montreal area of Quebec – known as a Canadian pharmaceutical hub – the Prevtec microbia team is comprised of specialised veterinarians and industry experts. As a testament to the company’s success, since 2008 Prevtec microbia has sold more than 8 million doses of its Coliprotec®F4 – an E.coli vaccine for swine – in Canada. This vaccine is also registered in Brazil, Russia and Kazakhstan with plans for

Connectivity: Contributing to Future Success Prevtec microbia’s success in an increasingly competitive global market is due in large part to our belief in the power of synergistic partnerships. Our innovation strategy is based on connectivity. We feel strongly that pursuing dialogue with like-minded corporations will propel us to even greater heights. We enjoy access to a worldwide network of scientists, university academics, manufacturers and distributors. These partners are well positioned to align with Prevtec microbia in generating new avenues of growth and distribution channels through the development and acquisition of new technologies and biologicals. Our future plans include strengthening our presence in existing markets while making our products available in as yet untapped geographical areas. Leveraging our veterinary, scientific and management expertise, together with our commercial activities, will translate into new opportunities to make a practical difference in animal health. We look forward to embracing new opportunities in a spirit of interaction and cooperation. In the coming years we expect to announce game-changing ways of approaching challenges in animal health, with technologies and products that will translate into tangible problem-solving solutions. For more information about Prevtec microbia and how we contribute better ways to feed the planet, visit www.prevtecmicrobia.com.


Manufacturing & Packaging

Animal Healthcare - Packaging & Labelling Trends Currently valued at around US$ 27.8 million and expected to reach US$ 41.3 million by 2019, animal healthcare is currently a keen area of focus for drug manufacturers. In recent years, the industry has experienced a high level of mergers and acquisitions and just 10 major manufacturers account for 75% of the market share.

• By comparison with human healthcare drugs and pharmaceuticals, animal healthcare products are manufactured and distributed in much smaller volumes. However, in recent times, there has been significant innovation in the range of treatments available for the treatment of animals. There are a number of factors that indicate that demand for veterinary healthcare products looks set to rise substantially: •

• •

Longevity – with improved knowledge and healthcare products both humans and animals are enjoying longer life spans than ever before. The global population is on the increase. Demand for foodstuffs and production animals bred

for meat and milk-related products is therefore on the increase. Furthermore, we are generally becoming a lot more health-conscious so demands for protein-rich foods are on the increase, which has resulted in an increase in the number of animal farms globally. Income levels are on the rise, with more and more people being encouraged to adopt pets. (In 2012, 13% of all households in Germany had at least one dog and 16% had at least one cat.) Global transportation has become much more effective than in years gone by, which means the importation of more exotic species is more commonplace. This places a higher demand on veterinary practices and the need for specialist healthcare products.

Furthermore, development of drugs and medications for companion pets may well be down to investments towards private animal healthcare. An increasing population (UK) are investing in pet insurance (Pet Care estimate around 30% of the UK population has cover). Much of this is to cover conditions such as diabetes and arthritis and other acute conditionsa. What are the types of animal healthcare products on the market? The industry split animal healthcare products into three main categories: 1. Feed additives, 2. Pharmaceuticals, & 3. Vaccines. With increasing levels of both companion and production animals, there is a need for targeted medicines. In the case of pets, the emphasis is on preserving the long-term health of the animal. This is often in the form of a vaccine for preventative purposes, or perhaps antibiotics to help treat ailments and conditions. Where production animals are concerned, animal healthcare products may also come in the format of feed additives such as nutritional additives, amino acids and vitamins and minerals. What are the anticipated challenges within this industry? First and foremost, manufacturers are taking a keen interest in the development of drugs and vaccinations more than ever before. The European Food Safety Authority (EFSA) estimate 320,000 cases of food-borne and zoonotic diseases annually within the EU. In 2012, 220,209 people in the EU were affected by campylobacteriosis, the most-commonly observed zoonosis in animals, due to the consumption of infected broiler meatb.

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Manufacturing & Packaging Additionally, the animal breeding industry cannot afford to suffer losses against epidemics as they have in the past such as foot and mouth disease. It is therefore very much in the interest of both the industry and the economy interest to continue to seek out solutions to protect and vaccinate against such diseases.

What this means for manufacturers of packaged products is that very clear instructions on usage, indications and contra-indications must be outlined within the packaging; a particular challenge when packs of drugs may have to be split and re-packaged into smaller dosages, or when the drug has been packaged and intended for use on another species.

Prescription Challenges Where animal health products are concerned, only a qualified veterinary surgeon is legally permitted to write a prescription for a controlled drug or a medicine classified as a POM-V. It is therefore imperative that all of the necessary information is clearly outlined on the packaging and labelling so that other staff members involved in this process are clear on the directions of use.

The Extended Role of Packaging in Animal Healthcare Products: Animal healthcare labelling is fast becoming more than just a functional requirement for identification of product and the fulfilment of legal obligations. In fact, labelling and packaging is playing an increasingly important role within this sector than ever before. Manufacturers can see the importance of streamlining this area to improving efficacy in product communication, plus with the latest technology and careful planning, far greater benefits can be derived.

What information needs to be included? • The name, address and telephone number of the person prescribing the product. It is considered good practice to include the registration number for the veterinary surgeon (MRCVS), pharmacist or SQP writing the prescription • The qualifications of the person writing the prescription • The name and address of the owner or keeper of the animal • The identification (including the species) of the animal or group of animals to be treated • The premises at which the animal(s) is kept if this differs from the address of the owner or keeper • The date that the prescription is written • The signature of the person writing the prescription • The name and amount of the medicine prescribed • The dosage and administration instructions • Any necessary warnings. A Cascading Challenge: Veterinary surgeons within the UK may opt to choose from a range of both animal health and also potential human health products, should they see fit under the Veterinary Cascade guidelines. The guidelines have remained largely unchanged since 1995. However, a revision by the European Direction and the subsequent Veterinary Medicines Regulation has tightened up the guidelines. However, there is clearly a level of interpretation as well as knowledge and experience required here. The danger is that misinterpretation can in itself have the potential for errors to be made, something that must be avoided at all costs, regardless of whether it is a human or animal life in the balance. The Label is an Underestimated Form of Communication with the Consumer: What’s written on the label can also be far more underestimated than we might think, particularly where companion healthcare is concerned. Once the surgeon or dispenser has handed the medication over, it is up to the carer to interpret the instructions on the label. Clearly laid out userinstruction and product details are much better understood than those that might lead to confusion.

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Multi-market Distribution of Animal Healthcare Products: With an increasing number of mergers and acquisitions, including the recent acquisition of Novartis by Eli Lilly, manufacturers are becoming increasingly aware of the need to create packaged products for multi-market distribution. Country-specific packaging is not only limiting but requires additional storage space and handling if products are to be aimed at, for example, a Europe-wide market.

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Manufacturing & Packaging

Couple this with the need for increasing amounts of information on the packaging itself, and manufacturers are likely to consider alternative methods of labelling and packaging. But sometimes there simply isn’t enough space for all of this information, especially where a number of languages need to be included on the packaging. The Role of Leaflet Labels in Animal Healthcare Products: One method of ensuring all of the information can be fitted into the container or pack is the use of leaflet labels. Combining a self-adhesive label alongside a printed and folded leaflet offers anywhere between two right up to 100 additional pages for complex user-instruction, in one or more language/s, as well as any necessary charts, diagrams or even pictograms. Product Labelling for Improved Production Communication: There are further benefits of opting for a leaflet label system which can be translated into improvements within the production processes. Leaflet labels are supplied on reels and therefore can be applied directly onto the product or container at high speed using standard label application equipment. A leaflet label may be used in a number of ways to assist with the production processes: Security and Anti-counterfeiting Measures: Counterfeit medicines cost the global economy an estimated $1000bn annually. Additionally, they undermine public trust and integrity in brands, and at worst could cause a fatality. Like most forms of labelling and packaging, there are a variety of optional security and anti-counterfeit measures that can be incorporated into the leaflet label. 60 International Animal Health Journal

Anti-counterfeit technology may be incorporated into the artwork of both the label and the leaflet, either overtly or covertly, allowing for quick and easy detection of genuine products within the supply chain. A trust-seal or hologram may be added to the product or even a simple tamperevident strip extending the label onto the lid or closure of the container. Specialist User-instruction for Seagreens Products: By example, Anglo-Scandinavian seaweed specialists Seagreens recently utilised a leaflet label on the lids of their pet & equine products as an addition to their packaging to educate the customer of the benefits of the product range. This entailed 18 pages of images and information, all printed complete with a tamper strip on the lid. 1. Packaging Enhancement – the most common reason for switching to a leaflet label is when a manufacturer simply has too much information to include on the label. 2D matrix, pharmaceutical and bar codes, as well as variable data such as batch codes and serial data, can all be added directly onto the leaflet label following strict production guidelines. Scanning equipment ensures correct leaflet to label matching, resulting in fault-free product. 2. Cost-reduction – leaflet labels are frequently used to help a manufacturer reduce production costs. A loose leaflet and carton may be replaced with a single multiply label including all the necessary product information in several languages too. This can reduce procurement costs, minimise inventory and also eliminate additional production processes. Volume 1 Issue 2


Manufacturing & Packaging One of the main concerns a manufacturer will have when considering switching to a leaflet label solution is the effects it may have on the packing line. Loss of production means a loss of output and revenue, something that no manufacturer can afford. Multi-page labels are supplied on reels and so can be applied using standard label application equipment just like a normal label, with little or no effect on line speeds. Conclusions: There are many benefits to be had by choosing to use a multipage label on your product, and they are not just restricted to solving packaging problems. Multi-page labels can enhance

3. This Tick & Flea spray by Bob Martin (South Africa) is an illustration of how this can be achieved. A simple fourpanel label has been applied to the front of the spray pump, containing all of the necessary product and user information. There are both manufacturer and consumer benefits to be had here. Firstly, the consumer has all of the information attached to the product for reference both initially and throughout the course of medication. Secondly, consumers have a tendency to discard any outer packaging and loose leaflets initially as this information is securely attached the manufacturer is less likely to receive a customer call or query. 4. Over-labelling – frequently leaflet labels are incorporated onto drugs and medicines that have been parallelimported. This avoids the costly measure of having to remove existing labelling or even re-package vast quantities of product. Leaflet labels can be produced to fit neatly over an existing product label, avoiding consumer confusion and adhering to re-sale guidelines. 5. The Drive for Sustainable Packaging Solutions packaging line efficiencies, packaging reduction and the need to source sustainable packaging materials have fast become priorities for manufacturers. Not only does this help to raise awareness of the brands’ green credentials, but more importantly it aids in keeping costs down and often results in significant long-term returns on investment. Multi-page labels provide additional pages for the inclusion of well-laid-out user guidance and copy, and remain securely attached to the product or host container throughout the cycle of the medicine being taken. Furthermore, they help to simplify and reduce packaging and can be offered in a range of formats to keep costs down. A single leaflet can have anywhere from two to 100 or more pages of patient information, user guidance and instruction in one or several languages.

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the appearance of the packaging as well as informing the consumer of vital user-instruction and encouraging correct usage for the pet or animal. Remember, the label on the packaging is the only form of communication you have once the medication has been handed over to you by the veterinary surgeon or dispenser. References a. Pet Care/ August Equity. b. Transparency Market Research.com - animal-healthcareindustry report.

Stephen Jarrold, Sales and Marketing Director - Denny Bros Ltd. Stephen is head of sales and marketing at Denny Bros - a leading UK label printing specialist and originator of the Fix-aForm leaflet label concept. With over 30 years of experience, he is responsible for the business development across a range of sectors including the animal healthcare, pharmaceutical and clinical industries. For more information visit www.dennybros.com or Email: fix-a-form@dennybros.com International Animal Health Journal 61


News Pages The Dangers of Giving Pets Human Medication According to a new study from Direct Line Pet Insurance, in the last year, more than three-quarters (78%) of vets treated pets that have ingested human medication. The insurer is calling on owners to be more vigilant and not expose their animals to human medication as it can cause serious illness, or even death. Among the vets surveyed, some 243 cases of accidental ingestion in the last year were reported. More than a quarter (28%) of vets surveyed reported cases where owners have deliberately given their pet human medication in an attempt to help them. Some vets described incidents of owners believing paracetamol will help conditions like arthritis and limping. But giving paracetamol to a cat can cause death, as they are unable to break down the medication. In one case an owner gave their cat a quarter of paracetamol every day in an attempt to stop its pain, which instead resulted in the cat dying. “It is concerning to see so many cases of pets ingesting human medication. Human medication is extremely dangerous to pets and often results in them being treated with medication to induce vomiting or a fluid treatment, which may cause them great distress. If you suspect that your pet has ingested human medication, it is essential that they see a vet immediately,” says Madeline Pike, veterinary nurse at Direct Line Pet Insurance. The majority (76%) of cases involved dogs; however, incidents involving cats, rabbits and guinea pigs were also reported. Source: MedicalNewsToday Dogs, Hogs and Dairy Cows: ‘Animal Pharm’ Catches Wall Street’s Attention Cancer drugs for cats, pain relief for dogs, diarrhoea drugs for hogs and hormones for dairy cattle: the “animal pharm” industry is increasingly drawing the interest of Wall Street investors. “There is a lot of enthusiasm for animal health,” says Tim Lugo, an analyst at William Blair & Company, which has helped manage two recent animal health IPOs. “Vets in general are starving for new innovative therapies.” The animal health industry globally is pegged at $92 billion to $102 billion, with the subsector of animal medicines and vaccines seen at $22 billion annually, according to a report by Technology Acceleration Partners, a private capital development firm targeting animal health, food and agriculture ventures. From 2011 to 2016, the animal medicines and vaccines sector is expected to grow by 5.7% per year, the report states. Investors like the fact that regulatory approval of products for animals can move faster at less cost than with drugs for people. While a drug for humans can take 10 years and more than $1 billion to develop, one for animals can reach market in half that time for about $10 million, industry experts say. Until 18 months ago, animal drug development companies were largely off the radar screen, either divisions of much larger humanfocused pharmaceutical companies or start-ups struggling for cash. That changed in January 2013 when Pfizer Inc. spun off its animal health business Zoetis, raising $2.2 billion. Shares have climbed more than 40 per cent since then, to around $38. Stan Baker, a lawyer for Husch Blackwell, which provides legal counsel for animal health companies, called the industry’s rise “explosive.” However, industry observers say it is too early to tell how well the animal health companies will do in the public investment spotlight, since few of them have meaningful track records.”Is it a bubble? Maybe,” says Technology Acceleration’s chief executive officer, Michael Helmstetter. “We’ll know in the next few years.” Source: Reuters Antibiotics May Help Salmonella Spread in Infected Animals, According to Stanford Scientists About 80% of all antibiotics used in the United States are given to livestock - mainly cattle, pigs and chickens - because doing so increases the animals’ growth rates, and experts have already voiced concerns about how this practice contributes to the rise of drug-resistant pathogens. But a new study, published in Proceedings of the National Academy of Sciences by a team of investigators from the Stanford University School of Medicine, highlights an entirely different concern. “We’ve shown that the immune state of an infected mouse given antibiotics can dictate how sick that mouse gets and also carries implications for disease transmission,” says Denise Monack, PhD, associate professor of microbiology and immunology and the study’s senior author. “If this holds true for livestock as well - and I think it will - it would have obvious public health implications. We need to think about the possibility that we’re not only selecting for antibiotic-resistant microbes, but also impairing the health of our livestock and increasing the spread of contagious pathogens among them and us.” When the scientists gave oral antibiotics to mice infected with Salmonella typhimurium, a bacterial cause of food poisoning, a small minority - so called “superspreaders” that had been shedding high numbers of salmonella in their faeces for weeks - remained healthy; they were unaffected by either the disease or the antibiotic. The rest of the mice got sicker instead of better and, oddly, started shedding like superspreaders. The findings point to a reason for superspreaders’ ability to remain asymptomatic. They also pose ominous questions about the widespread, routine use of sub-therapeutic doses of antibiotics in livestock. Source: MedicalNewsToday Zoetis and Easter Bush Research Consortium Establish Centre for Surveillance and Identification of Emerging Infectious Diseases in Europe A new European research centre, comprising a collaborative network of veterinarians, scientists and technical specialists with a coordinating hub in Edinburgh, Scotland, aims to identify emerging diseases in livestock and companion animals, and enhance the ability to control them.A collaboration between the Easter Bush Research Consortium (EBRC) and global animal health company Zoetis, this cluster brings together expertise in pathology, rapid genetic sequencing and molecular biology from University of Edinburgh’s Roslin Institute and Royal (Dick) School of Veterinary Studies; laboratory diagnostic and surveillance expertise from Scotland’s Rural College (SRUC); and high contaminant-level laboratories and expertise in infectious diseases from the Moredun Research Institute, integrating them with the research and development and specialised infectious disease capabilities of Zoetis. Theo Kanellos, Associate Director at Pfizer Animal Health, says: “This collaborative approach between academia, research institutes and industry, provides a unique methodology for combating emerging diseases for the benefit of animal and human health and puts this partnership at the cutting edge of animal research in Europe.” Source: FierceAnimalHealth 62 International Animal Health Journal

Volume 1 Issue 2


News Pages Partnership Brings “Star Trek technology” to University A Kansas State University veterinary medicine team is working with Lawrence Livermore National Laboratory to bring “Star Trek technology” to the university and improve diagnostic tools for infectious diseases. “Lawrence Livermore National Laboratory is developing some of the top technology tools in the field. The idea is to take some of this ‘Star Trek technology’ and bring it to diagnostic laboratories and the clinical practice level,” says Raymond “Bob” Rowland, professor of diagnostic medicine and pathobiology in the university’s College of Veterinary Medicine. This advanced technology includes an “everything test” called the microbial detection array. The test is a comprehensive diagnostic test that Lawrence Livermore National Laboratory developed to check a single sample for 8000 different microbes, such as viruses, bacteria and fungi. Rowland and his research team are applying some of the national laboratory’s technology to studying porcine diseases, which are the focus of Rowland’s research. The microbial detection array can test any sample, including blood, dirt, tissue, or a nasal or saliva swab. “We want to figure out how to apply this test and make it useful for the veterinarian, the livestock producer or the clinician,” Rowland adds. Source: FierceAnimalHealth Report: Pet Owners Jump on the Probiotics Bandwagon North Americans spent $3.1 billion on probiotic-infused products in 2013, according to data compiled by Fast Company. The pet industry has traditionally lagged behind trends on the human side by seven years, but that’s no longer the case, and industry experts are predicting probiotics will invade animal health products in the next year or two. “A lot of the ideas for pet supplements are simply transposed from human supplements,” says Philip Brown, a veterinarian and consultant. “If people take them, it’s easier to sell them” for use in pets, he adds. Spending by Americans on supplements for pets is expected to explode from $750 million a year to $1 billion by 2017, says market researcher Packaged Facts. An estimated 7% of pet foods and supplements currently contain probiotics, according to Fast Company. Source: FierceAnimalHealth Lawsuit Targets FDA Approval of Controversial Animal Drugs Used in Food Production In November, the Center for Food Safety, the Center for Biological Diversity and Sierra Club filed a lawsuit against the US Food and Drug Administration for approving several controversial animal drugs used in food production without fully examining how they affect people, animals and the environment. The controversial drug ractopamine is fed to pigs, cattle and turkeys to cause rapid weight gain. An estimated 60% to 80% of pork sold in US supermarkets comes from pigs treated with the drug. The lawsuit, filed under the National Environmental Policy Act and Administrative Procedures Act, challenges the FDA’s approval of 11 ractopamine-based drugs without first analysing the environmental and public health risks of their use. “FDA is basing controversial drug approvals on incomplete and inadequate environmental analyses,” says Paige Tomaselli, senior attorney for the Center for Food Safety. “These drugs in our food supply impact the environment, thousands of farm workers, millions of consumers, and billions of animals. FDA cannot continue to abdicate its responsibility to do its job.” The European Union, China and Russia have all banned US pork from pigs that have been fed ractopamine. Source: FierceAnimalHealth A New OIE Guide to Better Surveillance and Detection of Health Risks Related to Animals The Guide to Terrestrial Animal Health Surveillance is a practical handbook developed by international experts in surveillance methodology and takes into account the complexity of animal health management, the diversity of the animal kingdom, and the variety of situations in the 180 OIE member countries. On becoming an OIE member, each country undertakes to report in a timely and transparent manner on the health status of its territory in terms of animal diseases, including zoonoses. Within the framework of its mandate, the OIE then disseminates the information to all other member countries to enable them to protect themselves. This exchange of information is based on the OIE World Animal Health Information System, WAHIS, which enables the degree of importance of events to be validated, in the face of a constant stream of information, most of which does not require any specific response. The Guide is published in English and will soon also be available in French and Spanish. Source: FierceAnimalHealth New TB Testing Arrangements for England and Wales Due in 2015 The Animal and Plant Health Agency (APHA) is introducing new arrangements for the delivery of TB testing in England and Wales. From April 2015, APHA will manage TB testing through delivery partners who have successfully tendered for the work. These delivery partners will be responsible for testing in one or more geographical regions of England and Wales. A tendering exercise is underway and announcement of the successful delivery partners is planned for early 2015. On-farm TB testing is currently done by vets working for private businesses who are trained, appointed and paid by APHA to do the work. Over 650 veterinary businesses currently perform this role and well over 2000 individual vets are approved testers. Animal keepers will still be responsible for arranging the testing and will need to liaise with the delivery partner for their geographical region. Delivery partners will then allocate and monitor the quality of this work. Simon Hall, APHA’s Veterinary Director says: “Testing will always be performed by a fully qualified vet but the new arrangements will help ensure that on-farm testing is as effective as it is possible to be in detecting disease, and that the taxpayer is only being asked to pay what is necessary for the testing.” Source: APHA

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International Animal Health Journal 63


Chapter Title

Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

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FOR ANIMALS FOR HEALTH FOR YOU At Zoetis, we’re able to put our customers first and assist them with making a real difference in the world. From helping veterinary businesses succeed and livestock producers raise healthy animals, we’re dedicated to the business of animal health so that our customers can be dedicated to theirs. We know how deeply the world depends on animals, so animals—and the people who care for them—can depend on us. To see how we do it, visit us at zoetis.ca.

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