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Volume 4 Issue 4

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

PEER REVIEWED

Animal Health Delivering Solutions to Achieve a One Health World Towards an Enabling Regulatory Environment for Livestock Health Sheep Scab A Major Pest to Sheep Production Data Management in Veterinary Clinical Studies

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CONTENTS 06 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 clive@iahjmedia.com EDITORIAL MANAGER Virginia Toteva virginia@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com BUSINESS DEVELOPMENT Wilson Lemar wilson@iahjmedia.com 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

08 Sheep Scab - A Major Pest to Sheep Production Sheep scab is a disease caused by the mite Psoroptes ovis, which lives on the skin surface where it feeds. The faeces produced by the sheep scab mite cause a severe allergic dermatitis, resulting in the ‘scabby’ lesions which we associate with the later stages of the disease. Rachel Mallet at Bimeda discusses how in spite of having four medicinal active ingredients available with 16 different brands licensed and available in the UK, they are still struggling to get this disease under control. 10 Rational Use of Antimicrobials in the Dairy Industry The use of antimicrobials in food animals has long been the subject of international debate, although the relationship between their use and the development of antimicrobial resistance in bacteria is complex and unclear. Christian Scherpenzeel at GD Animal Health describes how experts combine monitoring and disease eradication programmes with practical field research projects in order to clarify and promote rational use of antibiotics. 12 Current Position in Agriculture Regarding Antibiotics Having reached our overall government antibiotic use target of 50mg/kg two years early, reducing antibiotic sales to farmers by 27% (the lowest since records began), and with critically important antibiotics also reduced (Colistin by a huge 83%), we are on the right road. Gwyn Jones, Fellow of the Royal Agricultural Society of England, discusses the great importance of reducing the use of antibiotics in animal care. REGULATORY & MARKETPLACE 14 Brexit and the UK Pet Food Industry The pet food industry holds a unique place within the food and feed sector. Whilst we are governed by the same high safety rules covering the feed industry, at the same time our consumers are those who shop in the general retail environment. In this article, Nicole Paley at PFMA discusses that although the future after the decision taken by the UK electorate in June 2016 to leave the EU is uncertain, the role of the PFMA is to ensure industry’s views are represented in all relevant negotiations and to support the members planning for what lies ahead. 16

Journal are not necessarily those of the Editor, Publisher or the Supporting Organisations which appear on the front cover. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. Volume 4 Issue 4 December 2017 PHARMA PUBLICATIONS www.animalhealthmedia.com

A Challenge to be Addressed: “Institutional Amnesia” As companies move ahead, with both internal R&D as well as external development, “institutional amnesia” is a trait which must be consciously addressed. As companies grow and globalise, the impact of amnesia increases as well. Process improvement does not always mean change. Tom Overbay at Expedite Animal Health discusses how sometimes it is going back to process that yields results.

18 Global Initiatives Promoting Good Regulatory Practices for Veterinary Medicinese The objectives of the ‘Livestock’ project correspond with Vision3 of HealthforAnimals, the global animal medicines industry association, for globally harmonised regulatory systems and their objectives to promote regulatory convergence. Rick Clayton at Healthfor-Animals International Animal Health Journal 1


CONTENTS Animals discusses how the maintaining of livestock health by improving access to veterinary medicinal products (VMPs) can minimise the negative economic impact of diseases and safeguard the livelihoods of millions of farmers around the world. 22 Animal Health: Delivering Solutions to Achieve a One Health World Effective prevention and control of infectious diseases at the animal-human-ecosystem interface is essential. It will help combat the spread of diseases in animals and humans, ensure a safe and secure food supply, and foster a more sustainable society. The One Health approach prioritises quality of life for humans and animals, and recognises that healthy animals mean healthy people and a healthier planet. But what does this mean in practice and what steps need to be taken by the different sectors involved in order to realise the One Health vision? Roxane Feller at AnimalhealthEurope reveals all for the readers.

RESEARCH & DEVELOPMENT

26 At the Frontiers of Animal Health: A European Perspective constantly presenting new possibilities for the prevention and treatment of disease. Directive 2001/82/ EC, which both sets out standards for veterinary medicinal products and outlines the authorisation procedures, focuses on the established pharmaceutical and immunological product types, and has no scope to provide a framework for innovative products that fall outside these categories. Anja Holm, independent consultant at Central VetPharma Consultancy, and Pascale Canning at Cyton Biosciences discuss how this can often frustrate and confuse companies wishing to market a product, and may be a block to useful products becoming available to veterinarians, farmers, and pet owners. 30 Homeopathy in Animals: Yesterday and Today‌ but Tomorrow? Homeopathy exists without a recognised body of evidence for its use. Furthermore, it is not based on sound scientific principles. In order to protect animal welfare, the authors Peter Lees of Veterinary Pharmacology at The Royal Veterinary College, University of London et al. regard such treatments as being complementary rather than alternative to treatments for which there is a recognised evidence base, or which are based on sound scientific principles. 36 Latest Lameness Research: A Summary Lameness is a major challenge in dairy herds globally. Digital dermatitis (DD), more commonly known as Mortellaro, is an infectious condition and one of the major causes of lameness, reducing mobility, comfort, feed intake milk yield, and fertility. This infectious condition can spread quickly through the entire herd and can reduce milk yield by at least one litre per cow per day. George Shaw at Provita Eurotech Ltd summarises key points from presentations and scientific posters from researchers across the globe that could help farmers tackle lameness in their herds. IT & LOGISTICS 40 Data Management in Veterinary Clinical Studies Data management tasks and procedures, with their direct influence on data quality and compliance, are an 2 International Animal Health Journal

Volume 4 Issue 4


CONTENTS aspect of great importance for any clinical study. Dr Brigitte Steiner and Dr Klaus Hellmann at KLIFOVET discuss that the implemented routine data management procedures should be transferable to different kinds of studies, to assist the parties involved in their tasks and help to increase efficiency in the conduct of veterinary clinical trials. FOOD & FEED 44 An Update on EFSA’s New Guidance Documents for Feed Additives These guidance documents were adopted during the last FEEDAP plenary meeting in September 2017, and will enter into force on 1 May 2018. Rocío Duchén Bocángel and Dr Hannah Lester at Pen & Tec Consulting discuss how the new guidance documents will help applicants with the preparation of feed additive submissions in each of the three sections. 46 The Potential of Feed Additives in Reducing Antibiotic Usage Over the last years, feed additives that support gut health have gained special attention from animal producers worldwide. Tim Goossens and Daniel Ramírez at Nutriad discuss how feed additives do not cure acute bacterial challenges, but prepare the gastro-intestinal tract of animals as well as possible to overcome negative consequences of certain diseases in a later life stage. As many of the effects of feed additives on bacteria are indirect, or modulate their virulence pathways, rather than having a specific bacteriostatic effect, the chance of building up resistance against these components is much less likely. 50 Helping Animal Health Companies Succeed Serving both companion and production animals, Canada’s animal health sector has developed an enviable reputation. Martin Yuill at PEI BioAlliance Inc reveals the key strengths of the Canadian sector, which include abundant resources, particularly water, to support food animal production; good infrastructure, including trans-portation networks; a stable and predictable regulatory regime; strong patent protection laws for new discovery; and a highly competent veterinary profession. LIVESTOCK 54 Giving your Herd the Best Chance for Successful Fertility Achieving high levels of reproductive performance will be a major key performance indicator on most dairy farms this winter. David Wilde at Anpario considers some nutritional factors which could have an impact on success. Mr Wilde also advises paying close attention to dietary protein levels, commenting that it is well documented that feeding excess amounts of soluble protein can reduce conception rates. 56 Towards an Enabling Regulatory Environment for Livestock Health Animal health management has important implications for poverty reduction and economic growth. Edna Kallon, K. Aleks Schaefer and Felix Frewer at Worldbank discuss the importance of good regulations to encourage the registration of quality assured products, and provide a snapshot of initial results of data collection efforts for the regulation of VMPs. 4 International Animal Health Journal

Volume 4 Issue 4


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International Animal Health Journal 11


FOREWORD Winter is upon us, at least in the northern hemisphere, and with it comes the winter 2017 issue of the Journal. In common with past issues, this one presents a variety of articles covering a range of topical subjects. Two of these caught my attention for two very different reasons. The first of these is an article by Rachel Mallet discussing sheep scab. Having been involved with sheep scab and sheep dips, in one way or another, for over 35 years, it was bound to be of interest to me. Sheep scab is a major animal welfare issue as well as being a significant cause of economic loss. If not treated appropriately, it can result in loss of condition, reduced birth weights in lambs, secondary infections, and hypothermia due to fleece loss and, in extreme cases, death. It is caused by the sheep scab mite, Psoroptes ovis and it is an allergic dermatitis. The disease is highly contagious and can be contracted from sheep to sheep contact, for example at markets or during transport, or from shearing equipment. As the mites can survive a number of days away from the animals, the disease can also be spread through clumps of isolated wool. In the United Kingdom, scab was subjected to official control measures and eradication was achieved as long ago as the 1950s. However, eventually the disease was reintroduced and relaxations in control measures resulted in the resurgence of cases. In Scotland, sheep scab was made a notifiable disease in 2010. Scab was controlled for decades by plunge dipping using organophosphorus-containing dip baths. In the UK, the popularity of these diminished because of health concerns for those involved in the dipping process and associated restrictions placed on their use while the marketing authorisations for synthetic pyrethroid dip products were suspended in 2006 due environmental concerns. As a result, it’s fair to say that there is a restricted range of products available for the treatment and control of sheep scab and, despite earlier successes, sheep scab is still a major health problem. In her article, Rachel Mallet discusses the available treatment options and the challenges encountered in attempting to combat this disease. The second article to catch my attention concerns homeopathy. As a scientist, and dutiful follower of the scientific method, I have always had serious doubts about this practice. Samuel Hahnemann developed his ideas on homeopathy in 1796. Ironically, as a physician, he was rightly concerned about the dubious nature of medical practices of

the time such as bloodletting and purging as well as some of the other treatments given including myrrh and opium. He devised a system of treatment based on ‘like cures like’ and the central principle of the ‘law of infinitesimals’, a process of serial dilutions and shaking (known as succussion) in order to increase potency. For decades scientists have attempted to discover if there is any merit in the practice of homeopathy and to examine if there is any scientific basis for the claims of its supporters. Frankly, the answer to both of these issues appears to be ‘no’ and ‘no’. Numerous studies have demonstrated that there is no evidence to support the effectiveness of homeopathy in the treatment of disease in humans. As the underlying mechanism of homeopathy is beyond scientific understanding it is impossible to determine how (if) it works. For example, at some higher dilutions, a homeopathic remedy may no longer contain any molecule of its components thus raising doubts over any therapeutic mechanism. Modern proponents have offered explanations including ‘water memory’, a dubious concept in itself, while others have drawn on ideas usurped from theoretical physics including quantum entanglement and quantum nonlocality. Whatever, what remains are a series of nonplausible explanations for a non-plausible practice. Most scientists regard homeopathy as pseudoscience. In human medicine, one of the best explanations for any effectiveness is the placebo effect. So, how might this work in animals? In September 2017, the European Academies Science Advisory Council concluded that for homeopathic veterinary practice,… there is no rigorous evidence to substantiate the use of homeopathy in veterinary medicine and it is particularly worrying when such products are used in preference to evidence-based medicinal products to treat livestock infections. Earlier this year Professor Peter Lees and colleagues published two excellent articles in the Veterinary Record comparing the effectiveness of conventional veterinary medicines and homeopathic treatments and in this issue of the Journal, they summarise their findings and conclude that homeopathy should be regarded as a complementary treatment rather than as an alternative approach. I’ll go with the view of Quackwatch (www.quackwatch.org) and regard it as the ultimate fake. Whatever your view on either of the topics I have focussed on, I can assure you that all of the articles in this issue are worthy of your attention, and I hope you enjoy reading them.

Dr Kevin Woodward

Managing Director, KNW Animal Health Consulting

EDITORIAL ADVISORY BOARD Germán W. Graff Research Reference Laboratory Specialist, IDEXX BioResearch Fereshteh Barei - Health Economist & Strategy Advisor, Founder of BioNowin Santé Avenue Association Carel du Marchie Sarvaas Executive Director Health For Animals Kimberly H. Chappell - Senior Research Scientist & Companion Animal Product Development Elanco Animal Health Dr. Sam Al-Murrani - Chief Executive Officer Babylon Bioconsulting & Managing Director at Bimini LLC Sven Buckingham - Buckingham QA Consultancy Ltd. Dan Peizer - Director Animal Health at Catalent Pharma Solutions Dawn Howard - Chief Executive of the National Office of Animal Health (NOAH) Jean Szkotnicki - President of the Canadian Animal Health Institute (CAHI) Dr Kevin Woodward - Managing Director KNW Animal Health Consulting Norbert Mencke - VP Global Communications & Public Affairs Bayer Animal Health GmbH 6 International Animal Health Journal

Volume 4 Issue 4


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WATCH PAGES

Sheep Scab – A Major Pest to Sheep Production

Dipping ceased to be compulsory in 1992, leading to a greater incidence of sheep scab with an estimated 60-fold increase in disease on UK farms.1 In spite of having four medicinal active ingredients available with 16 different brands/preparations licensed and available in the UK, we are still struggling to get this disease under control. Scab is still a major concern for UK sheep producers, as it has a significant impact on the health, welfare and productivity of affected animals.

The female mite lays 1-3 eggs per day

Eggs hatch 3 days after being laid

The developing mite feeds for 2-3 days before progressing through each nymphal stage

10-14 days after hatching the eggs mature into adults

Diagnosis First and foremost, get a diagnosis from your vet. The clinical signs of lice and sheep scab infestation can be identical – particularly in the early stages. The other complicating factor is that both diseases are contracted in the same way; through poor biosecurity. Therefore, this means there is nothing to prevent animals from being dual infected with sheep scab and lice. Just because you can visualise lice, it does not confirm that the animals are not also infected with sheep scab! Your vet can perform skin scrapes on clinically affected animals or can perform blood samples to detect antibodies to infection, before clinical signs become apparent.

f Psorop le o te c s Cy

is ov

Lif e

What is Sheep Scab?

Open bleeding wounds and ‘scabby’ lesions, Loss of condition, Death

Treatment In the UK, we have four options for controlling sheep scab (Table 1). A key consideration for parasite control strategies is ensuring that we use the correct active ingredient at the correct time. When we use dual endo- and ecto-parasiticides for sheep scab control (the macrocyclic lactones), we are targeting both internal and external parasites. When we dip (using Diazinon) we only target external parasites.

The larvae progress through the nymphal stages

The mite will spend its entire life cycle on the host where possible although it can survive for 17 days without a host. All stages are found on the surface of skin around the edge of a lesion. MCR266Sheep Scab Life Cycle

©Copyright Bimeda®

Sheep scab is a disease caused by the mite Psoroptes ovis, which lives on the skin surface where it feeds. The faeces produced by the sheep scab mite cause a severe allergic dermatitis resulting in the ‘scabby’ lesions which we associate with the later stages of the disease. The mites are transferred from animal to animal by direct contact or on ‘fomites’; pieces of wool containing sheep scab mites. These mites are able to survive for 17 days without a host to feed from, meaning it is challenging to control and the potential for re-infection is high. Infestations can be debilitating, have a detrimental impact on welfare and can lead to severe economic losses. The Sheep Health and Welfare Group report 2016 states that the annual estimated cost of sheep scab in the UK is £8.3 million!2 Clinical signs include: Restlessness, Rubbing against fence posts, Soiled/stained areas of wool, Head tossing/biting, Pulled wool appearance leading to eventual wool loss, 8 International Animal Health Journal

Table 1. Active ingredients licensed for the control of sheep scab

The highest incidence of sheep scab occurs during the winter months. At this time of year, gastrointestinal roundworms are generally present in lower burdens and are less likely to cause disease requiring treatment than during the grazing season. To continuously expose these small burdens to anthelmintics (wormers) increases the rate of development of resistance. SCOPS mirror this sentiment: “For the macrocycliclactone (clear 3-ML) wormers there has been a marked increase in recent years, probably linked to their widespread use as endectocides for the treatment of sheep scab. Action to try to preserve this group is now imperative.”3 Remember that the sheep scab mite can survive for 17 days without a host to feed from, so re-infection must be controlled by using a product/protocol which provides protection for longer than this, or by moving them to clean grazing/housing. Volume 4 Issue 4


WATCH PAGES

Prevention Good biosecurity is key to controlling this disease. It is impossible to tell simply by looking at animals if they have been recently exposed to Psoroptes ovis. In the early stages, the disease can be asymptomatic with no visible evidence of itchy sheep. Just because the animals do not appear to be itchy and do not have pulled wool/bald patches/lesions, does not mean that they are not carrying sheep scab mites.

2. Sheep Health & Welfare Report for Great Britain http:// beefandlamb.ahdb.org.uk/wp-content/uploads/2016/10/ SHAWG-report-2016-17-181016.pdf 3. Sustainable Control of Parasites in Sheep: http://www. scops.org.uk/taking-the-first-steps.html

When purchasing new animals, they should either be presumed infected and treated, or an ELISA test should be utilised to assess the risk. The flock should be kept separate from other sheep at the periphery of the farm (e.g. double fencing).

A qualified Veterinary Surgeon, who now works as a Professional Services Veterinarian for Bimeda, covering accounts in Scotland and the North of England. Rachel is passionate about animal health and about promoting best practice amongst farmers and animal owners.

REFERENCES 1. Rose H, Wall R. (2011) “Endemic sheep scab: risk factors and the behaviour of upland sheep flocks� Prev Vet Med 104 (1-2) www.animalhealthmedia.com

Rachel Mallet

Email: rmallet@bimeda.com

International Animal Health Journal 9


WATCH PAGES

Rational Use of Antimicrobials in the Dairy Industry The use of antimicrobials in food animals has long been the subject of international debate, although the relationship between their use and the development of antimicrobial resistance in bacteria is complex and unclear. The multifunctional teams of GD Animal Health experts combine monitoring and disease eradication programmes with practical field research projects in order to clarify and promote rational use of antibiotics. The majority of antimicrobials used in dairy herds are related to udder health, with two-thirds applied as dry cow therapy. In the Netherlands, approximately 90% of all dairy cows were treated with dry cow antimicrobials in the 2005–2010 period, after which the Dutch government strictly advocated prudent and restricted use of antimicrobials. Antibiotic use in the livestock industry had to be decreased by 20% in 2011 and by 50% in 2013, as compared to 2009. Realisation of these goals was the primary responsibility of the various livestock sectors themselves. Selective Dry Cow Therapy In 2011, GD Animal Health initiated a large field trial in the Netherlands for selective dry cow therapy (SDCT). It was conducted on a split-udder basis, monitoring more than 1650 dairy cows on 97 herds during the dry period and the first hundred days in lactation. Our research team of veterinary epidemiologists and technicians worked with farmers and veterinarians in the field to study the effects on udder health when reducing dry cow therapy (DCT) in low-somatic cell count cows on the dairy herds. From 2013 on, preventive use of antimicrobials was prohibited in the Netherlands, and SDCT was introduced as an alternative for blanket dry cow therapy (BDCT). Antimicrobial use for DCT accounted for 49% of the total antimicrobial use in the Dutch dairy industry. In January 2014, the Royal Dutch Veterinary Association launched guidelines to be used when implementing SDCT. Mindset There was no information on how SDCT was executed in practice and how farmers experienced it. In order to quantify this major change in mastitis management, GD Animal Health conducted another field study to gain insight into the level of implementation of SDCT, selection criteria, and the relation to mastitis and antimicrobial use. Besides this, the attitude and motivation of farmers towards SDCT was studied, and seemed surprisingly positive, although they expressed concern about the udder health situation. Total antibiotic use related to mastitis was reduced by 85%. In conclusion, our field studies showed that SDCT, as currently applied in the Netherlands, was not associated with significant deterioration of udder health and farmers managed to keep udder health at a high standard. Together with GD Animal Health’s udder health team, we apply the Udder Health Approach: aiming for healthy udders and consequently greater volume of milk and fewer financial loses. 10 International Animal Health Journal

Christian Scherpenzeel DVM PhD Christian Scherpenzeel studied veterinary medicine at Ghent University and the Faculty of Veterinary Medicine, Utrecht University. After several years of working in dairy practice, he was employed as lecturer / researcher at the Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University. He now works as a dairy specialist at GD Animal Health in Deventer, the Netherlands, since 2011. His research activities focus on udder health, antimicrobial resistance and social aspects of modern herd health management. The combination of scientific and practical expertise on udder health management triggers a lot of farm visits each year and resulted in major experience in dairy consultancy and veterinary communication skills. Dr. Scherpenzeel published a number of peer-reviewed publications in the Journal of Dairy Science. Email:c.scherpenzeel@gdanimalhealth.com

Volume 4 Issue 4


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International Animal Health Journal 11

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Current Position in Agriculture Regarding Antibiotics As this is the first in a series of columns, I should introduce myself. As you see I am Gwyn Jones and I live in West Sussex, where I have spent 35 years dairy farming. I chair the Responsible Use of Medicines in Agriculture (RUMA) Alliance and am involved in a number of other farming/government organisations in the UK and Brussels (either dairy or animal health and welfare). RUMA celebrated its 20th anniversary this year and is not only 10 years ahead of EPRUMA (which I am involved with in Brussels), but well ahead of the recent interest in this subject by the general media, politicians and pressure groups. RUMA reacted positively when our government (under David Cameron) decided to take a lead on the issue of antimicrobial resistance (AMR) – specifically antibiotic resistance; the publishing of the ‘O’Neill report’ and the pressure which had been building up for some time was a catalyst for restructuring the organisation. RUMA now has an independent scientific group of leading experts with a huge range of expertise and a ‘Targets Task Force’ of leading veterinary surgeons and farmers from each livestock sector, including fish and game-birds. Whilst the Scientific Group advise RUMA on all matters which have a scientific content, they also provide the independent expert voice on some of the scientific matters which appear in the media. RUMA has always produced responsible use guidelines for each sector (lengthy detailed ones for the veterinary profession and shorter ones for farmers) over the years and again our Scientific Group will assist us in this task. Having reached our overall government antibiotic use target of 50mg/PCU two years early, reducing antibiotic sales to farmers by 27% over the past two years, to 45mg/ PCU, the lowest since records began, as well as slashing sales of highest priority critically important antibiotics (Colistin by a huge 83%), we are on the right road. Our critics are now struggling as we forge ahead in each sector to deliver the targets set by our Targets Task Force. This will continue to drive usage down, but in a way which safeguards welfare; the critical balance which must be maintained. Poultry meat have led the way with an enormous 71% reduction in use over the past five years and many lessons can be learnt in the way they achieved this, especially for the pig sector. Poultry meat is, of course, a fully integrated system, where there is whole-chain involvement and fewer, very large players. However, the risks taken in order to ‘test’ the traditional reliance on antibiotics, the attention to infrastructure (especially water quality), removal of in-feed antibiotics and eventual removal of some highest priority antibiotics should be a lesson to us all in how to approach radical change and improvement. Why are we under such pressure to reduce antibiotics in agriculture? Politics and public pressure – not science – is driving this. We regularly see global statistics, which are a huge concern, being applied as if the same level of use (or abuse) is happening in the UK. This has led to a blame 12 International Animal Health Journal

culture, driven in the early days from the human medical fraternity including very senior, influential medics. Having joined ‘Antibiotic Guardian’ and spoken at many events and universities, I have been able to inform at least some in the medical fraternity of what goes on in farming and the role of the farmer and veterinary surgeon as the primary link in the food chain. It became clear that their information about our industry came from pressure groups and NGOs and they have no idea of the veterinary side of medicine; I repeat, no idea! We hosted a large group of very impressive and knowledgeable senior medics, including the Chief Medical Officer, on a pig farm recently and they were very surprised by certain aspects of the operation. Agriculture is, in fact, ahead of human medicine in some respects and many of those medics now speak very differently about our industry. I stress we are not seeking to absolve ourselves of responsibility, but we do need to tip the scales back to a balanced, One Health approach. There is more to do and I would encourage the veterinary profession to join us in talking about what we all do and how agriculture works. A letter in the ‘The Lancet’ (Addressing antimicrobial resistance in the UK and Europe - Dec 2017) is disappointing and somewhat lacking in the author’s understanding of the problem and lack of data. In agriculture it is vital we protect and look after the antibiotics we have; any new antibiotic development will not benefit us and, therefore, it is important we minimise use by highlighting responsible use in our sector. After all, healthy animals are more profitable and easier to look after and all farmers should be encouraged to look at how best to achieve high welfare. There is a need to recognise that we do have a cohort of farmers who are unable to invest in better infrastructure which is vital in order for them to have the same opportunity to improve animal health and welfare, cutting their use of antibiotics. As we leave the EU and the new Agricultural Bill is being drawn up, there is a need for government to take some responsibility to enable these farmers to invest and raise their game, benefiting their animals and having the chance to reduce antibiotic use.

Gwyn Jones Gwyn Jones was born into a hill farming family in Snowdonia, North Wales. Gwyn trained as an engineer with Rolls Royce in Shropshire, and worked in London for a specialist engineering company before deciding to go back to agriculture, working on a large estate in North Wales whilst attending college (Llysfasi and Aberystwyth). Gwyn is now immersed in off farm activity as well as farming with his daughter Gwenan (past three years) at Boughton Dairy, Tillington, near Petworth, West Sussex. Email: wealdclay@btinternet.com

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Please contact us for any information. We provide support wherever you are in the world.

GD Animal Health, P.O. Box 9, 7400 AA Deventer, The Netherlands, T. +31 (0)570-63 33 91 www.animalhealthmedia.com www.gdanimalhealth.com, info@gdanimalhealth.com

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Brexit and the UK Pet Food Industry

The Pet Food Manufacturers’ Association (PFMA) is the united voice of the UK pet food industry. Our 76 members account for over 90% of the market. The decision taken by the UK electorate in June 2016 to leave the EU has profound implications for our Association’s members. Whilst the future is uncertain, the role of the PFMA is to ensure industry’s views are represented in all relevant negotiations and that we support our members in planning for what lies ahead. Pet Food Uniquely Positioned The pet food industry holds a unique place within the food and feed sector. Whilst we are governed by the same high safety rules covering the feed industry, at the same time our consumers are those who shop in the general retail environment. This presents unique challenges; we have many commonalities with the feed sector and we can present a united voice on certain Brexit issues, but we also have our own, very distinct needs. We move forward building alliances, yet ensuring the voice of our industry is heard. The UK Pet Food Sector Vital statistics about the pet food industry: • • • • • • • •

12 million (44%) UK households have pets The total pet population is 54 million The UK market is valued at £3 billion PFMA members currently access 500m consumers in the EU single market The European pet food market is valued at 15 billion euros 80% of pet food ingredients are sourced from the UK

Key Issues for the UK Pet Food Industry In March 2017, PFMA launched its Brexit Manifesto, which we developed following a survey of the membership. We identifi ed fi ve priority areas: 1. Animal Health & Welfare 2. Raw Materials Supplies 3. Regulatory Regime 4. Market Access 5. Workforce In the UK we have some of the highest animal health and product safety standards in the world. This is underpinned by stringent legislation on what raw materials we can use and how pet food is manufactured. It also relies on supervision by offi cial vets and meat hygiene inspectors, as well as safeguards to handle any disease outbreaks. On top of this, we have developed a complex set of guidelines through our European association, FEDIAF, which ensures our members follow best practice to meet, and even go beyond, the strict regulation. We must ensure 14 International Animal Health Journal

these standards and high animal health levels remain as strong as ever, not only to satisfy our UK customers but also to ensure UK pet food remains highly regarded when we trade globally. Animal welfare: The pet food sector is in a unique position when it comes to animal welfare. We are not only keen to ensure the highest welfare of our pets; through providing the best possible nutrition, we also support livestock having the best possible life as well as end of life. Maintaining high levels of farm animal welfare post-Brexit is critical. This is a cost to farmers that must not be undermined by importing products from markets which operate under lower welfare standards. Raw materials: We are proud of our contribution to sustainability in the agri-food sector. Pet food companies utilise those parts of the animal surplus to the requirements of the human food chain (around 600,000 tonnes in 2016). This gives value to farmers who would otherwise have to dispose of that high-quality material. Similarly, right at the other end of the life cycle, only 0.7% of pet food is thrown away by consumers. Compare this to an average 30% of all other food purchased being thrown away. Our members currently source 80% of their raw materials from the UK and we are keen for this to continue. A strong UK agricultural policy is key to this, and is also important for ensuring the high welfare and safety standards. Non-tariff barriers: Much of the discussion on future trading arrangements with the EU focuses on the impact of tariffs. For the pet food sector, it is the impact of nontariff barriers which is likely to be more critical. These include the requirement for export health certifi cates (signed by offi cial vets), the requirement to prove the origin of the raw material used in pet food, and the need for veterinary inspection at the border. All of these will take time, add cost, and require suffi cient numbers of qualified vets. The veterinary workforce: The British Veterinary Association (BVA) and Royal College of Veterinary Surgeons (RCVS) are working with government to address the issue of the veterinary workforce and there are calls to have vets placed on the Shortage Occupation List. Approximately 85% of offi cial state vets working in abattoirs and up to 30% of all vets come from the EU. Without their continued presence, the health and welfare of our pets and the quality of their food could be impacted. PFMA supports the lobbying endeavours of these vet bodies, and this is just one example of sectors working together to achieve common goals for a common good. Regulations: PFMA members have worked intensely with EU partners to establish rules and regulations which underpin the Single Market and have facilitated trade. We will need to consider whether to implement new legislation currently under negotiation but not yet in force. For now, we need to maintain legislation in line with the EU. Volume 4 Issue 4


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Coalition on Welfare Issues PFMA is active in the All Party Parliamentary Group for Animal Welfare (APGAW). APGAW is an all-party group made up of MPs, peers and associate animal welfare organisations or groups with a specifi c interest in this area. The aim of the Group is to promote and further the cause of animal welfare to the Parliaments at Westminster and in Europe. This group is highly relevant and has become even more so for PFMA in light of Brexit. Other broader pet-related considerations include the PETS travel scheme. Many UK nationals resident in the EU are concerned about their pets’ future rights of movement. From a leisure perspective, owners have become accustomed to taking their pets abroad and there needs to be clarity on what will happen going forward. UK Pets Didn’t Vote for Brexit Whatever your views on Brexit, the 54 million pets in the UK www.animalhealthmedia.com

did not vote for it. PFMA is working with its members and other organisations to ensure quality, safety and welfare is maintained. Join the conversation at: https://www.pfma. org.uk/brexit-pfma

Nicole Paley PFMA Communications Manager and runs the PFMA Press Office. Nicole also sits on the Communications Working Group of the European Pet Food Federation, FEDIAF and participates in the communications discussions of the Global Pet Food Alliance, GAPFA. Email: nicole@pfma.org.uk

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A Challenge to be Addressed: The “Institutional Amnesia” As companies move ahead, with both internal R&D as well as external development, “institutional amnesia” is a trait which must be consciously addressed. As companies grow and globalise, the impact of amnesia increases as well. Process improvement does not always mean change. Sometimes it means going back to process that yields results. One of the most valuable, and difficult to quantify, assets is “institutional memory.” This is true of virtually any industry as well as with regulatory bodies. Animal health is no exception with both companies and the regulatory bodies overseeing the industry relying, in no small part, on this knowledge. While institutional knowledge affects all parts of a business, from knowing one’s customers to the art that accompanies the science of manufacturing commercial product, it is the development and approval process that this article will address. Within a regulatory body, “institutional knowledge” is often referenced as precedence. While subject to changes in regulations and advances in science, prior decisions have an influence on whether a product will be approvable and the pathway to such an approval. In fact, with novel products, it may benefit the company to choose a regulatory path that sets the standard for future approvals as the model by which a product is approved. Products coming to the market as competitors may likely have to meet a similar requirement, which may prove more protective to the asset than patents or other forms of intellectual property and know-how. From a business perspective, it is important to know which agencies will govern an application. There can be vast differences between biologicals and pharmaceuticals within a country, not to mention between countries. With increased globalisation of both companies and opportunities, submissions are being made less on a sequential country-by-country basis but rather simultaneously across critical territories. This requires appreciation of the various similarities and important distinctions to enable an efficient development plan to be executed. Failure to take into account these issues can result in excessive costs from additional or duplicate studies, delayed approvals, or labels that do not fully capture the commercial prospects. Understanding and implementing a strategy to take advantage of existing synergies and planning for addressing the dissimilarities is a critically important trait that often presents itself in the form of experience beyond that found from a “reading” of the applicable regulations – in other words, institutional memory. With institutional memory being a critically valuable asset, then “institutional amnesia” can be an equally serious challenge. As companies merge and grow, it is not uncommon for long-time employees to take advantage of early retirement or fail to find a fit in the new organisation. With their physical exit comes a departure of developmental know-how as well. This can be especially 16 International Animal Health Journal

challenging as companies find themselves participating in new therapeutic categories, species, or territories. A historically strong company in vaccines may suddenly find itself a global leader in pharmaceuticals, or vice versa. Strength in the United States may abruptly be balanced by an equally important presence in Europe, for example. And, while there is great effort to rationalise and align product lines and R&D pipelines, the know-how to do so may be lost. The execution of a timely and financially efficient development plan is dependent on two general areas – why and how. Knowing why a project is important to an organisation and how it fits into the overall strategy of the company plan is essential to achieving company goals. Failure to do so risks having commitment to individual projects take precedence over the true task at hand, which is a pipeline that results in meeting organisational expectations. And, while “why” is valuable, knowing how is equally essential. And “how” generally comes from experience – both successes and failures. Experience that is unique to animal health. Interaction with Regulatory Bodies Animal health is a highly regulated industry, with a variety of agencies having jurisdiction. And while the regulations of those agencies are written in black and white, the interpretation is far less clear-cut. This is further complicated by the advancement of science at a rate that outpaces the ability of regulations (and regulators for that matter) to keep up. Therefore, early interaction with regulators to position development of an asset cannot be underestimated. Using the precedence of prior regulatory decisions, some which are not so obviously linked, can be a powerful tool in gaining favourable treatment regarding the process which will govern approval. Being knowledgeable of precedence is a tool which cannot be found in any document but can be used to gain agreement on a plan which is likely to result in approval. Regulatory bodies also have a language of their own. Crafting documents which comply with the preferred format and use appropriate terminology are moved along more quickly than those which fail to do so. For example, submission of a development plan set up in a manner customary for the Food and Drug Administration Center for Veterinary Medicine (FDA CVM) is likely to be rejected if submitted to the United States Department of Agriculture Center for Veterinary Biologics (USDA CVB). Or perhaps worse, it may result in establishing requirements which would make the development much more expensive and longer to achieve approval, or cause a product to fail to achieve approval after resources of time and money have been expended. Additionally, construction of a development plan impacts the commercial claims and the conditions under which a product is manufactured, so an inappropriate approval could result in excessive cost of goods or a label that is less than ideal. And this is between agencies in the same country! Manufacturing Current Good Manufacturing Practices (cGMP) are the same the world around. However, the practices are subject Volume 4 Issue 4


REGULATORY & MARKETPLACE to local interpretation, which creates some interesting challenges to a development plan. Does a company simply build to the most stringent requirements based on the commercialisation plans? Or does a company license manufacturing in different territories in order to be in a cost competitive position? Or is there a hybrid approach with split manufacturing to enable both cost-effectiveness along with compliance with regulations which interpret cGMP differently. There is even more variation in vaccines. The USDA CVB follows a guideline which does not rely on cGMP but on a process that utilises an outline of production and finished product testing in order to approve and release products. While USDA CVB inspects facilities, there is also a licensing process whereby the site is granted a facility licence. Any vaccine sold in the United States must either be manufactured in a licensed facility or, if manufactured outside the United States, be imported under a permittee strategy that is best performed by a company whose facilities are USDA CVB licensed. And the facilities differ from those producing pharmaceuticals with the knowledge of this highly impacting the cost of both facilities and products. Sourcing material from sources which have been successfully inspected or which, based on an audit, are capable of having a favourable inspection, is another area where experience can be invaluable. Having an active pharmaceutical ingredient (API) with an acceptable drug master file (DMF) can save companies years in development time along with the associated expense. Then there are the questions about which pharmacopeia are acceptable and if concerns exist over any genetic manipulations of ingredients. Knowing that issues have been raised, for example, as to whether a flavouring has been sourced from a genetically modified crop (or proving that it has not) can help to streamline the approval process. Animal Studies Perhaps no component of a development plan is as heavily influenced by institutional memory, or as negatively affected by institutional amnesia, as is the conduct of animal studies. The design of animal studies is the critical determinant to a successful development plan. Setting the appropriate outcomes and getting agreement from the regulatory authorities defines the likelihood of successfully satisfying safety and efficacy requirements and, ultimately, the approved label. This process is dependent upon skillful negotiation based on an understanding of prior decisions regarding case definition and the measurements acceptable for submission. Knowing when and how hard to push to achieve the desired outcome further ensures success of the plan and the product. The actual conduct of animal studies can also be an art form. Much of this work is conducted through a network of contract service providers including, among others, the actual animal sites, laboratories for performance of reagent development and assay performance, and data collection entities. The coordination of these in a manner which promises to deliver the best outcome is a skill honed over time. Collection and reporting of data in a format desired by the regulatory reviewers is most likely to minimise the possibilities of incomplete letters and get the product on the market as soon as possible. Coordination While the various subject matters in product development benefit from institutional memory, the coordination of these, www.animalhealthmedia.com

in itself, profits as well. The knowledge of how to coordinate the moving pieces in such a manner as to best utilise the available human and financial resources can augment development of the pipeline. The intersection of “how” and “why” certainly resides at this level in the organisation. Harmonisation of vaccines, pharmaceuticals, species, and territories in order to meet company performance criteria is a key driver to company success. Experience across the various disciplines, including discernment in areas in which direct knowledge is lacking, is irreplaceable.

Dr. Thomas D. Overbay He serves as a business development and technical consultant to the international animal health industry. He founded Expedite Animal Health which is a company formed to discern opportunities in animal health then assist with product development across pharmaceuticals, biologicals, devices, and diagnostics. Expedite’s clients span the globe and include the largest multinational animal health companies, the smallest of startup companies, and the financial community including venture capital and private equity. Dr. Overbay brings over 25 years of experience in the veterinary pharmaceutical industry. He has served as the senior business development officer and executive committee member for a major animal health company and has served in similar roles with a contract services provider and start-up animal health companies in the US and internationally. In addition to business development, Dr. Overbay’s background of veterinary practice, technical services, and sales management provides him with a unique perspective of the scientific, financial, and legal aspects of innovative technologies. Dr. Overbay has successfully brought to market a number of products arising from universities, government agencies, human hospitals, start-up companies (both human and veterinary), and multinational pharmaceutical and chemical companies. Dr. Overbay holds his veterinary degree from the Virginia-Maryland Regional College of Veterinary Medicine and resides in Louisburg, Kansas. Email: toverbay@expediteanimalhealth.com

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Global Initiatives Promoting Good Regulatory Practices for Veterinary Medicines In this edition the World Bank Group (WBG) reports on its long-term project ‘Enabling the Business of Agriculture’ (EBA)1. The driving force behind this project is the importance of agriculture to the WBG’s twin goals of ending poverty by 2030 and boosting shared prosperity. Since 2013, the project has collected data from 62 countries on laws and regulations that impact the business environment for agriculture across 12 topic areas. The 3rd project report was published by WBG in February 20172, and for the first time includes a chapter on ‘Livestock’ covering the regulatory environment for the market control of veterinary medicinal products (VMPs). The objectives of the ‘Livestock’ project correspond with the Vision3 of HealthforAnimals, the global animal medicines industry association, for globally harmonised regulatory systems and its objectives to promote regulatory convergence. So the opportunity is taken to briefly review what other projects and organisations are actively seeking to promote good regulatory practices for the benefit of animal health and all those who depend on their pets and livestock. The Importance of Agriculture to Human Health The importance of agriculture cannot be over-stated. The demand for food is increasing 20% annually to feed a growing world population that may reach 9 billion by 20502. The largest increases in demand are projected in Sub-Saharan Africa, South Asia and East Asia. Boosting the productivity, profitability and sustainability of agriculture is essential to support this growth. But agriculture is not just important for a secure food supply. For some 500 million smallholder farmers, it is their economic and social life-blood; and for subsistence farmers in developing countries it is essential to their survival and the largest source of incomes, jobs and food security. That is why the World Bank Group’s ‘Enabling the Business of Agriculture’ (EBA) project is such an important tool to improve prosperity and end extreme poverty. The world needs more productive, sustainable and efficient ways to grow food. We need systems to support the resilience of farmers and food supply chains while simultaneously reducing the environmental footprint of agriculture. These systems cannot function properly without a framework of good regulations and infrastructure, which can create well-functioning markets, fostering growth in agribusinesses.

In short, the world needs a food system that can feed every person, every day, everywhere with a nutritious and affordable diet, delivered in a climate-smart, sustainable way.

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Livestock and the Regulation of Veterinary Medicines If you are raising livestock, you need access to certain ‘inputs’, including feed, water and disease control. Disease is estimated to cause 20% of livestock production losses globally4. This can have knock-on effects and put public health at risk by impacting food security and because 70% of all new human diseases are zoonotic, often originating from animals5. Maintaining livestock health by improving access to veterinary medicinal products (VMPs) can minimise the negative economic impact of diseases and safeguard the livelihoods of millions of farmers around the world. For this we need an enabling regulatory environment that encourages and does not hinder product registrations; we need effective market control to enforce quality standards and prevent fraud; we need the necessary infrastructure for supply and distribution; and we need good veterinary services for disease identification and to ensure effective and safe use of the VMPs. Open borders, inadequate legal frameworks and poor law enforcement can lead to counterfeit and substandard VMPs in the market. Counterfeit VMPs are a major threat to animal health and disease control. For the regulatory framework to support a reliable market in effective and safe VMPs of guaranteed quality, it needs to cover the full supply chain of manufacture, registration, import, distribution, sale and/or administration of livestock medicinal products. Enabling the Business of Agriculture Project This is why the WBG, with its twin goals of ending poverty by 2030 and boosting shared prosperity – as well as the Sustainable Development Goals – has invested significant effort in the EBA project. The main aim is to measure and monitor regulations that affect the functioning of agribusinesses, covering all aspects across 12 topics, from seeds to machinery to finance. The extensive and thorough nature of this World Bank survey, which aims to expand to cover 80 countries in 2018, makes it an important and influential tool in the drive to reach this goal through global convergence towards regulatory best practice. Their governments should make good use of this valuable benchmarking. The EBA 2017 report2 catalogues the level of transparency, predictability and efficiency of the regulatory systems in a wide sample of countries. These factors influence private sector decisions to supply a market with VMPs, and thus directly affect their availability to veterinarians. It is important that countries have the systems and infrastructure in place to legally register VMPs, to control the marketplace, and protect consumer health. Other Regulatory Convergence Projects HealthforAnimals has been running similar, albeit smaller, projects aimed at promoting regulatory good practice and regulatory harmonisation, through its series of five-yearly Global Regulatory Benchmarking Surveys6. HealthforAnimals is also a driving force behind a series of Global Animal Health Conferences and workshops7,8, sponsored by the Bill and Melinda Gates Foundation, and global harmonisation initiatives such as VICH9. Volume 4 Issue 4


REGULATORY & MARKETPLACE The most important player, when it comes to promoting global animal health, is The World Organisation for Animal Health (OIE), which was established in 1924 in recognition of the need to fight animal diseases by coordinating at a global level. Of equal influential standing is the World Health Organisation, which is developing guidelines for national regulatory authorities on good regulatory practices10. Examples of Good Regulatory Practices • • • • • • •

Develop regulations that are flexible, Use risk management principles, Be consistent in guidance and decision-making, Be efficient in information and records management, Measure and maintain performance and transparency, Be approachable, open to dialogue and reach out to stakeholders, Be aware of changing regional and global factors in R&D and access to drugs.

All these activities are reviewed below. However the starting point for HealthforAnimals was the elaboration of its “Global Vision”. The HealthforAnimals Vision The HealthforAnimals “Global Vision for the harmonised Regulation of Veterinary Medicines across the World2” ‘identifies 10 key elements (see below), but can be concisely captured as: “Efficient regulatory systems that result in harmonized, science-based decisions in predictable timeframes, resulting in the wide availability of safe and effective veterinary medicines.” The ten-point plan supporting the HealthforAnimals Vision 1.

Authorisation decisions are science-based solely on evaluation of benefit and risks. 2. Predictable regulatory timeframes, with a maximum of 24 months for a new product. 3. Regulation that is efficient for industry and regulators, with no unnecessary administrative burden. 4. More countries/regions co-operating on the core assessment of the same product, or mutually recognising assessments from other countries/ regions. 5. A fair return on investment for innovation. Maintaining confidentiality of data and awarding appropriate periods of protection of data. 6. Regulatory frameworks and regulatory staff which can manage highly innovative products/new technologies. 7. Ability for companies to undertake global developments, with a core set of data and studies meeting the needs of all countries/regions. VICH conducted studies being accepted by all countries. 8. Ability to locate manufacturing anywhere in the world, operating to a single set of standards. More mutual recognition agreements on inspections. 9. A single global system of pharmacovigilance with requirements and approach aligned with the relevant VICH guidelines and the Guide to the Essentials for Veterinary Pharmacovigilance7. 10. Countries to have legal frameworks which includes management of urgent off-label use and a legal basis to deal with illegal (or illegally supplied) veterinary medicines.

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To maximise innovation and the availability of medicines to animals and customers, it is important to remove unnecessary administrative burdens and to achieve regulatory convergence between countries/regions. The HealthforAnimals Global Benchmarking Survey Reports, which preceded the World Bank surveys, provide some good pointers for the challenges that need to be addressed and identify the future needs for well-functioning global regulatory systems. Global Benchmarking Surveys Every five years since 1996, HealthforAnimals has commissioned a global survey to review and benchmark, from the perspective of its member companies, the status of the different regional regulatory frameworks for veterinary medicines and the impacts these have on the industry’s ability to invest in veterinary medicinal product development. The reports identify global best practices and reveal the most common regulatory barriers shared by animal health markets worldwide. The most recent Global Benchmarking Survey (GBS) report, published in June 2016, covers six countries and one region (Australia, Brazil, Canada, China, Japan, USA and EU). The report reveals significant differences between countries or regions, for example in terms of maturity of the regulatory framework, the different types of application procedures available, the different ways in which changes to products are managed, the approach to monitoring safety and efficacy of products after registration, the transparency of the authorities and resources available to the authorities. Many of the differences are fundamental and are based on different philosophies and a level of trust placed in the veterinary pharmaceutical industry. It is not simply that some authorities have lightweight versions of the framework used in other regions; the frameworks themselves differ. The veterinary pharmaceutical industry continues to consolidate through mergers and acquisitions. Funding for research and development (R&D) is under intense pressure, particularly to support veterinary medicines serving small markets, whether in certain countries, for certain species or for particular diseases. The cost of development of a new veterinary medicine for use in food animals is very high. In addition, a proportion of the available R&D budget in companies must be used to maintain the licences of existing products (known as ‘defensive R&D’); this is a particular problem in Europe (see graph), and regulations should aim to limit this to the level absolutely necessary.

Figure 1: Proportion of R&D budgets spent on ‘defensive R&D’ in VICH regions

Global Animal Health Workshops Other organisations interested in promoting animal health through good regulatory systems, such as OIE, GALVmed and the regulatory bodies that are part of VICH (USDA, FDA, EMA and JMAFF), have recognised the importance of good governance in the regulation and control of veterinary products and the part this plays in supporting socioeconomic development, public health and animal health. International Animal Health Journal 19


REGULATORY & MARKETPLACE This serves the wider aim of promoting the One Health approach towards human and animal health. With this common set of objectives in mind, HealthforAnimals has worked with these bodies to develop conferences and workshops for the African and the South Asia region. The aim was to share knowledge and understanding of good regulatory practices and to promote further close cooperation amongst a regional network of regulatory agencies (see box below).

Themes addressed in the Global Animal Health Workshops • • • • •

The essential elements of a regulatory system for the registration of veterinary products, The opportunities for stimulating the entry of new quality assured, safe and effective products on the market, The roles of legislation and guidance documents, and alignment with international standards, Good manufacturing practices (GMP), authorisation procedures for veterinary products and pharmacovigilance, The benefits and hurdles of mutual recognition of marketing authorisation processes from other regions with internationally recognised regulatory systems, including GMP, The benefits and hurdles of the formation of regional organisations to pool resources and the advantages of alignment with international standards, The processes necessary for market control of veterinary products and how to tackle falsified products.

VICH VICH is a trilateral (EU-Japan-USA) programme, formed under the auspices of OIE, with active participation also from four observer countries (Canada, Australia, New Zealand and South Africa), with the purpose of ‘International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products’ (to give VICH its full name). The role of VICH is to develop harmonised guidelines on the technical details of the studies to be submitted in the data dossier for applications for marketing authorisation (also known as ‘product registration’). The benefit of having harmonised guidelines is to avoid studies being duplicated or repeated for products being registered in more than one country. Typically, a VICH guideline describes how a study should be conducted to satisfy quality, safety or efficacy data requirements. In the period from its establishment in 1996 to November 2017, VICH has published 56 harmonised guidelines (www. vichsec.org), with a further six guidelines in preparation. The guidelines cover the areas: • • •

For pharmaceuticals: quality, safety (toxicology, target animal safety, antimicrobial safety, environmental safety and residues) and efficacy. For biologicals: quality, target animal safety and batch safety testing. In addition, there is one general guideline on Good Clinical Practice (GCP), one guideline on the electronic format for electronic submission of dossiers, and five pharmacovigilance guidelines.

The underlying themes were two-fold: firstly, the relationship between animal health and access to veterinary products, and the need to ensure the regulatory environment is enabling for manufacturers of veterinary products; and secondly, the value, in terms of efficient use of resources and encouraging market development, of working to international standards and guidelines and regulatory convergence, particularly on a regional basis.

VICH Outreach Forum One of the primary objectives of VICH is to provide a basis for the wider international harmonisation of technical requirements, improve information exchange and raise awareness of the VICH guidelines outside of the participating countries. This has always been achieved using the OIE’s channels of communication to OIE member countries, but in 2006 more direct lines of communication were opened up with the creation of the VICH Outreach Forum. This allows country delegates to interact directly with VICH Steering Committee members in a workshop-style setting and to also network with each other.

Other Areas of Industry Standardisation In addition to the regulatory framework, there are other interesting areas connected to bringing veterinary medicines to the market where HealthforAnimals is actively promoting a single harmonised approach. For example, it has developed:

The VICH Outreach Forum is composed of countries and regional organisations that have an operational regulatory system, have expressed an interest in the work of VICH, and are motivated to participate in the activities of the VICH Outreach Forum. Currently 20 countries and four regional organisations are participating.

• • • •

Regional templates for the contents of the data dossiers required for an application for marketing authorisation, A harmonised approach to pharmacovigilance based on the VICH guidelines, A unified approach to the use of a 2D matrix barcode for product labelling, A copyright-free set of species pictograms for use on product labelling.

HealthforAnimals is also actively promoting a harmonised approach to GMP inspections through the PIC/S organisation and a harmonised approach to the protection of proprietary data submitted to competent authorities in the marketing authorisation dossiers. 20 International Animal Health Journal

The VICH Outreach Forum meets in conjunction with VICH Steering Committee meetings, which take place every nine months in one of the VICH member countries/regions. The Forum meetings are chaired by the VICH host country in collaboration with OIE, recognising the OIE’s membership in VICH as well as its broader mandate. OIE Harmonising the regulatory systems to improve the availability of quality assured veterinary products is just one part of the jigsaw. True product availability is not achieved unless there is also a good infrastructure of veterinary services within a country, to distribute the products and to ensure they are correctly prescribed and used. This is where the OIE has a major role. Volume 4 Issue 4


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The OIE is the intergovernmental organisation responsible for improving animal health worldwide and is recognised as a reference organisation by the World Trade Organization (WTO). It plays a major role in two ways: firstly, by bringing international harmonisation through its worldwide reach – it has 181 member countries – and its activities setting international codes and standards; and secondly, through its activities in strengthening veterinary services, monitoring animal diseases, and setting standards on animal welfare. The WTO members base their disease prevention and control measures on OIE’s codes and manuals (both terrestrial and aquatic). Perhaps the best known of the OIE’s missions is to improve knowledge of the global animal disease situation, including zoonoses, which it achieves through a unique tool, the OIE World Animal Health Information System, WAHIS. Using its worldwide network of national experts, the OIE collects and analyses the latest scientific information on prevention and control of animal diseases, which is then made available to its member countries so that they can apply the most effective disease control methods. The experts are organised in national ‘OIE Focal Points’ and ‘OIE Reference Centres’. The OIE helps its members to strengthen and improve the structure of their national animal health systems, particularly the national veterinary services, diagnostic laboratories and veterinary education. These support services are an essential part of a well-regulated and functioning market for veterinary medicinal products. OIE also help developing and emerging countries deal effectively with health threats, by providing customised support within the framework of its PVS (Performance of Veterinary Services) Pathway. REFERENCES 1.

2. 3.

Kallon, E., Aleks Schaefer, K. & Frewer, F. Towards an Enabling Regulatory Environment for Livestock Health. International Journal of Animal Health, Volume 4, 4 November (2017) Enabling the Business of Agriculture 2017, World Bank Group, February 07, 2017 http://eba.worldbank.org/ reports Global Vision for Regulation of Veterinary Medicines,

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HealthforAnimals, September 01, 2016, https:// healthforanimals.org/resources-and-events/ resources/publications.html “Feeding the World Better by Controlling Animal Diseases.” OIE, http://www.oie.int/for-the-media/ editorials/detail/article/feeding-the-worldbetter-bycontrolling-animal-diseases/ Wang, L. & Crameri, G. Emerging Zoonotic Viral Diseases. OIE Scientific and Technical Review, 33 (2), 569–81 (2014) Global Benchmarking Survey 2015 Report, HealthforAnimals, June 28, 2016 https:// healthforanimals.org/resources-and-events/ resources/publications.html Clayton, R. Global Animal Health Conference Addresses Regulatory Barriers to Disease Control, International Animal Health Journal, Volume 2.3, September 11, 2015 Clayton, R. An Asian perspective on how to improve market access for authorised veterinary medicines, International Animal Health Journal, Volume 4.1, February 27, 2017 Harmonising the global processes for authorising veterinary medicines, International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (‘VICH’), http://www.vichsec.org/ WHO, Good regulatory practices: guidelines for national regulatory authorities for medical products, WHO Working document QAS/16.686, October 2016

Rick Clayton The Technical Director for HealthforAnimals, Belgium, the industry association representing manufacturers of veterinary pharmaceuticals, vaccines and other animal health products throughout the world, as well as the associations that represent companies at national and regional levels. Email: rick@healthforanimals.org

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Animal Health: Delivering Solutions to Achieve a One Health World Effective prevention and control of infectious diseases at the animal-human-ecosystem interface is essential. It will help combat the spread of diseases in animals and humans, ensure a safe and secure food supply, and foster a more sustainable society. The World Organisation for Animal Health (OIE) reports that at least 60% of all human infectious diseases have their origin in animals, and that increased transparency of animal health situations globally can contribute to better public health. The animal medicines industry shares this view and it is one that has also been recognised by the European Commission and other international bodies in recent policy decisions – such as the 2016 EU Regulation on transmissible animal diseases and the 2017 EU One Health Action Plan against Antimicrobial Resistance. These One Health policies will have a role to play in how we address the emergence of multi-species health concerns and the spill-over of infectious diseases, and will ensure that appropriate control and prevention measures are taken. The One Health approach prioritises quality of life for humans and animals and recognises that healthy animals mean healthy people and a healthier planet. But what does this mean in practice and what steps need to be taken by the different sectors involved in order to realise the One Health vision? Animals and Humans are Mutually Dependent As people, we depend on animals for companionship, assistance and leisure as well as for food and other products, such as wool and leather. No matter how well we care for our animals, just like us, animals get sick and we have a responsibility to care for them and provide them with the correct care and treatment they need in order to get better. Our entire food chain could simply not function without animal medicines to prevent and treat disease. Without these medicines it would be impossible to raise livestock or to care for family pets and assistance animals while maintaining public health. Farmers, vets, the food industry and pet owners rely on the animal medicines industry to keep animals healthy and protect their welfare. Thanks to the health protection that their solutions provide, we are able to raise livestock efficiently and effectively and to produce quality, animal products such as milk, meat and eggs that form some of the essential ingredients of a nutritious diet. The reciprocal relationship between animal health and people’s lives today can be even better understood when we consider that over the past three decades, approximately 75% of new emerging human infectious diseases have been zoonotic, meaning they can pass from animals to people. This was certainly the case with recent diseases such as Middle East respiratory syndrome-coronavirus (MERSCoV), severe acute respiratory syndrome (SARS), and Zika virus, which have hit news headlines across the globe. Preventing and controlling zoonotic disease is essential in 22 International Animal Health Journal

protecting people and animals and is a core priority for the animal medicines industry. In sum, medicines which keep animals healthy also keep people healthy, allowing for close companionship with pets and ensuring sustainability throughout the food chain from farms and the rural economy, right through to the food products we buy and consume every day. Innovation is Essential The sheer variety of species and range of diseases and treatments means that innovation in animal medicines and vaccines is crucial. Not only is it vital for the sustainability of European agriculture, but for the sustainability of our whole society. Finding a balance between the interests of animals and people is essential. Certainly we have a responsibility to use veterinary medicines correctly and indeed, 24% of all medicines sold in Europe are vaccines used to prevent disease and suffering in animals. As outlined in the EU Animal Health Strategy (2009–2013), we believe that prevention is better than cure in ensuring the health of both humans and animals. Keeping ahead of the curve and being prepared to respond to new diseases and strains that emerge is an ongoing challenge for society and the animal medicines industry. Our increasingly global economy and food chain means that we are facing new threats, such as African swine fever and lumpy skin disease, and the avian flu variants on a regular basis. These need to be managed efficiently and effectively in order to maintain optimal health for all species. And health is not the only concern here. Control measures imposed, such as the culling of animals, and the ensuing carcass management and risk reduction practices, can have an impact on the environment. Other associated costs, such as trade restrictions or bans placed on selling animal produce after disease outbreaks, can also have a major impact on the wider economy. The recent emergence of lumpy skin disease (LSD), for example, led to the culling of around 6000 animals in Greece in 2016 alone. And at the height of the disease’s spread in Europe, affected countries registered up to 200 outbreaks, which led to significant economic losses – due to drops in milk production and reduced quality of skins – and the death of up to around 15 per cent of the affected herds, according to the United Nations Food and Agriculture Organisation (FAO). Following mass vaccinations, the European Food Safety Authority reported that the LSD outbreak in Europe was contained in April 2017, but authorities in Albania, Greece and Macedonia have been reporting a disease resurface in recent months. With such outbreaks, the importance of animal disease knowledge and the availability of preventive tools and widespread implementation of control measures are essential, along with the ever-important monitoring of disease occurrences. In the case of LSD, the FAO is recommending that countries that have not been affected by the disease so far but are considered at risk, need to Volume 4 Issue 4


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International Animal Health Journal 23


REGULATORY & MARKETPLACE carry out risk-based vaccination to avert the spread of the disease, which can have devastating consequences for farmers, particularly for smallholders. Maintaining existing solutions to address regular disease occurrences is important, and ensuring that new tools to address new diseases are available to vets, farmers and pet owners, is vital. The world evolves, and so do bacteria and pathogens. Diseases travel, mutate, jump species, new ones are born, and some have as yet not been able to be treated. This means that the existing medicines available need to be handled responsibly – as little as possible, as much as necessary. However, it also means that the European and global animal health industry needs to keep developing new and innovative products. It is also crucial to understand where the gaps in knowledge lie, and to know how to prioritise research. In Europe, DISCONTOOLS (www.discontools.eu) was set up to do just that. It is a platform, initially funded by the EU, and led by AnimalhealthEurope (at the time IFAH-Europe), which started in 2008 to help drive the delivery of new and improved diagnostics, vaccines and pharmaceuticals to improve our ability to control animal diseases. Deploying new technologies in the animal health area as rapidly as possible is another of the platform’s objectives and it is developing a blueprint for the identification and evaluation of new technologies. The use of biotechnology and cutting-edge research means that in the future, new vaccines can be developed – e.g. against diseases for which it is currently impossible to vaccinate. It will allow more effective and simple ways to protect animals against two or more diseases with just one product, enabled through a wide variety of administration routes (water, baits, air spray, eye inoculation, intra-nasally, through skin (needle-free), etc). The use of biotechnology will also provide improved stability of animal health products which can reduce the need for the cold chain, which in turn means that more animals can be included in vaccination programmes in developing countries – thereby helping to eradicate diseases, increase food availability and secure the livelihood of farmers. However, finding solutions to meet our One Health vision requires an environment which stimulates innovation. At the moment it takes between eight and 10 years to bring a product to market. This is speeded up in cases of disease outbreaks, where the authorities and regulators can cut through the paperwork and red tape, and muchneeded vaccines, for example, can be on the market in two years. However, even then there are limits, as the products are only given temporary licences to deal with the outbreak. The administrative burden involved in bringing veterinary medicines and vaccines to the market under the current EU regulatory framework is, to put it bluntly, not stimulating innovation and needs to be addressed. Strong Legislation can Bring Speed and Wider Treatment Options So how do we safeguard and encourage innovations to protect and promote this virtuous circle? Well, we need to start with a positive and encouraging legislative environment and a regulatory process that safeguards consumers. This is vital to ensure innovation and the availability of animal medicines which protect both animal and human health. It is also essential in driving business performance and contributing to a vital industry. 24 International Animal Health Journal

AnimalhealthEurope and its members are working alongside the EU institutions to ensure that the industry can operate in an environment which is well managed and regulated and which gives companies the confidence to invest in the development and marketing of new products and technologies. In Europe, we have a well-established system where veterinary medicines only reach the marketplace after thorough testing to assure their efficacy, safety and quality, and of course after review by the relevant government authorities. This process is currently under review and the revision of the regulations on Veterinary Medicinal Products and Medicated Feed promise to be very supportive of the One Health, One Europe approach. The updated legislation must streamline procedures and so relieve some of the administrative burden while also speeding up the whole process of bringing innovations to market. The intention must be to foster innovation and prompt a wider choice of treatment options – supporting the animal health industry to innovate more and supporting a wider availability and scope of treatments. The animal health industry in Europe is committed to delivering on its objectives to further invest in innovation to ensure the availability of a reliable arsenal of animal medicines for more sustainable prevention and treatment of animal disease. This can be aided, of course, by the European institutions who are working to ensure that the forthcoming legislation on animal medicines and medicated feed will meet the objectives set out by the European Commission, which are to: • • • •

Increase availability of veterinary medicines in all markets, for all species; Reduce administrative burden; Improve the functioning of the internal market; Address the public health risk of antimicrobial resistance (AMR).

Fostering innovation through a more harmonised system, where resources are invested in R&D instead of in administrative tasks, will be an important first step. It will mean that new medicines can be developed to fill the gaps in animal treatment options that at present either don’t exist or are not available in certain markets. By putting in place more efficient procedures to authorise medicines in exceptional situations, this paves the way for greater preparedness in the case of disease outbreaks in the future. This has got to be good news for all of Europe’s citizens, whether they have skin, feathers or fur, and whether they walk on two legs or four.

Roxane Feller Secretary General of Animalhealth Europe (formerly IFAH-Europe), the representative body of manufacturers of animal medicines, vaccines and other animal health products in Europe. With membership covering 90% of the European Market, AnimalhealthEurope represents innovators and generics alike, as well as large, mediumsized and small companies. Email: info@animalhealtheurope.eu

Volume 4 Issue 4


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International Animal Health Journal 25


RESEARCH AND DEVELOPMENT

At the Frontiers of Animal Health: A European Perspective In animal health, as in human health, scientific discoveries and technological innovations are constantly presenting new possibilities for the prevention and treatment of disease. Harnessing, commercialising and eventually reaping the benefits of these innovative products, however, poses particular challenges. A large proportion of such discoveries originate in academia, research organisations or SMEs – which, in contrast with large established companies within the industry, often do not have any experienced regulatory personnel nor dedicated internal processes to bring their discoveries into development. There is also the very real issue of legislation and guidance not ‘keeping step’ with innovation. Directive 2001/82/EC (the EU Directive which both sets out standards for veterinary medicinal products and outlines the authorisation procedures) focuses on the established pharmaceutical and immunological product types, and has no scope to provide a framework for innovative products that fall outside these categories. It has also been the case for a considerable time that so-called ‘borderline’ products in the EU face regulatory uncertainty where no relevant legislation for certain product types exists on the veterinary side. Although some member states have nominated experts, and some competent authorities have dedicated national review and registration processes for borderline products, it is still the case that opinion on the same product (usually as medicinal versus non-medicinal) can be dramatically different from member state to member state. This can often frustrate and confuse companies wishing to market a product, and may be a block to useful products becoming available to veterinarians, farmers, and pet owners. The bulk of the other animal health-related legislation and guidance is also in the rather restricted pharmaceutical vs. immunological products vein. The situation is such that, at present, legislative development is largely being driven by scientific progress: novel products are often coming to market with regulation being applied on a case by case basis. In recognition of this complicated state of affairs, the EU regulatory agencies have put in place various networks, working groups and informal consultative procedures. The aim is to maximise dialogue between the regulators and industry, from as early a stage as possible. Initiatives are in place that recognise the challenges faced by researchers and SMEs wishing to develop a novel therapy, in negotiating the regulatory landscape and meeting costs. Innovators can be guided towards obtaining data that could support an eventual product authorisation. Early dialogue also enables regulators to become aware of new kinds of treatment as they appear on the horizon. The scope of this article is two-fold. We wish to identify the particular regulatory infrastructure that currently exists to support innovation in animal health products in the EU, 26 International Animal Health Journal

and how this may be used most productively by innovators. We also discuss some of the product types which have come into being more recently; the potential benefits that they could offer if eventually made available on the market, and what difficulties are faced by innovators and regulators in trying to achieve this. The EU Innovation Network (EU-IN), and the EMA Innovation Task Force (ITF) Although some of the EU national competent authorities (NCAs) have had their own innovation offices for a number of years, in 2015 the EU Innovation Network (EUIN) was established with the stated aim of supporting medicine innovation and early development of new medicines in the EU. These innovation offices, and the EUIN generally, are open to enquiries and discussion around applying new technology in both human and animal health, in recognition of the fact that such innovations may eventually be applied in either or both fields. Meetings of the innovation offices occur a few times a year via telephone conference, and annually face-toface. The EU-IN mandate8, adopted and published in September 2016, encourages dialogue between the individual innovation offices and across the network. Those in the process of developing new therapies can engage with the network in a couple of ways. They can contact the innovation office in their own country, on an informal basis to have meetings and discussions, if they are based in an EU member state which has such an office (it is not compulsory to have an innovation office and not all member states have one, but the majority now do5). This can certainly be a useful first step, especially for initial dialogue, since travelling to a meeting is less arduous within one’s own country and speaking one’s own language! It may well be the case that a meeting with the European Medicines Agency’s (EMA) Innovation Task Force will be more productive, however, since the ITF can draw on the scientific expertise of its members across the EU. Although scientific knowledge and experience of emerging trends are shared throughout the network, as well as discussion of case studies (only with sponsor permission, of course), the relevant expertise for the product in question may not necessarily be available within each national innovation office. The ITF encourages future applicants, particularly those which are SMEs or are within academia, to engage with the regulators early on: both to assist the innovators in finding the appropriate road to market, and to flag to the ITF and its associated network what regulatory challenges are emerging with the development of new technologies. For truly innovative products, the ITF offers briefing meetings, free of charge, where scientific, technical and regulatory issues can be discussed informally. Following receipt of a request, they will confirm when a meeting can be arranged, and identify the experts recruited to attend. The actual meeting can take place in person or by video conference. Volume 4 Issue 4


RESEARCH AND DEVELOPMENT Ad Hoc Expert Group on Veterinary Novel Therapies (ADVENT) ‘Novel therapies’ in the context of ADVENT refers to therapies that are new to the veterinary domain, although they may already be well-known in research, and possibly in the context of human medicine; equally they may be entirely novel to both the human and veterinary fields. ADVENT is a small core group drawn primarily from the EMA’s Committee for Medicinal Products for Veterinary use (CVMP). Its purpose is to provide scientific guidance on novel therapies, which it does by releasing problem statements for consultation, consulting topic experts, and following up with published question and answer documents.

breakthroughs, although the first one was authorised in Canada in 2005 against infectious hematopoietic necrosis virus in fish.

The group has recently published its first guidance documents on extraneous agents and sterility of stem cells for veterinary use. Current problem statements at the time of writing include target animal safety for allogenic stem cell products, and monoclonal antibodies for veterinary use. ADVENT invites not only opinions and comments on the published problem statements, but also suggestions on novel therapy-related subject areas that would benefit from the provision of scientific guidance. The guidance documents, problem statements and contacts for comments and suggestions to the group are all available on the “Novel therapies” page, which can be found using the search function on the EMA website.

Clynav was the first veterinary DNA vaccine to be recommended for marketing authorisation in the EU. It is authorised to protect farmed Atlantic salmon against salmon pancreas disease (SPD) caused by an alphavirus, which damages the heart, pancreas and skeletal muscle and can lead to death of the salmon6.

Scientific Advice from EMA/CVMP For innovative products, applicants often face the situation that there is no relevant guidance available. Occasionally a human guideline is published on the topic, but it may not be feasible to follow it due to divergent risk factors in animal health, target species differences, or cost issues that are much more prominent when developing veterinary products. Moreover, when experience is lacking, the assessors become risk-aversive and may be overly cautious in their assessment. To increase the predictability for applicants and to reduce the risk early in the development process, the CVMP can give scientific advice on specific products, studies, and processes. An application with questions and the applicant’s background and suggested solutions is submitted to CVMP’s Scientific Advice Working Party (SAWP-v). Within 2–3 months an answer is returned with acceptance or proposals that the applicant can work on. Occasionally a meeting is held between the applicant and the SAWP-v, primarily to clarify the topic before the final answer is given. Although the advice is not legally binding, the rule is that it is adhered to by all assessors and regardless which authorisation route the applicant pursues, i.e. centralised, decentralised, mutual recognition, or national.

A DNA vaccine consists of a genetic sequence, typically circular bacterial DNA, with inserts of single genes from a pathogenic organism. After injection, the genes are translated to proteins directly inside the cells of the vaccinated animal. These proteins resemble the pathogenic organism and stimulate the host’s immune system to create an immunological response (for example antibodies), enabling the host to fight off a subsequent infection with the pathogenic organism itself.

Due to the innovative nature and the content of the product (genetic material), and because it is used in fish-farms in open water cages, a complex environmental assessment was performed. Moreover, an evaluation of safety for the consumer of vaccinated salmon was drawn up based on input from the European Food Safety Agency, as was an assessment of the possibility of integration/nonintegration of the DNA from the vaccine into the genome of the salmon. Despite the general understanding in the scientific community that DNA vaccines are very safe, the authorisation of the first one of these vaccines in the EU proved to be a very lengthy and demanding procedure3. The CVMP’s guideline for DNA vaccines is currently under review, with expected release in 2018. Monoclonal Antibodies Monoclonal antibodies (mAbs) are immunoglobulins (Ig) with a defined specificity derived from a single clone of cells. Their biological activities are determined by a specific binding characteristic to an antigen. Monoclonal antibodies may be produced by recombinant DNA technology, hybridoma technology, B lymphocyte immortalisation, or genetically engineered animals. Since 2014, several mAbs have been authorised in human medicine against e.g. cancer or rheumatoid arthritis.

The fee for scientific advice may be waived or reduced for specific applications, or if the applicant is a registered SME.

ADVENT recently identified areas that would benefit from further consideration and guidance in the form of question and answer documents, specifically regarding quality specifications, target animal safety, and reproductive safety.

Scientific advice can be of huge benefit for innovative products to clarify the necessary data package, for example if the manufacturing resembles a vaccine production, but the mode of action resembles a pharmaceutical product. In general, applicants must be ready to explain the science in detail to assure the assessors of the properties and risks of the intended product.

In April 2017, Cytopoint was authorised as the first monoclonal antibody for veterinary use in the EU. It contains Lokivetmab that attaches to interleukin-31, a protein that plays an important role in triggering atopic dermatitis in dogs, a common allergic skin disease. By blocking this protein, Lokivetmab reduces itchy skin and inflammation associated with atopic dermatitis.

DNA Vaccines DNA vaccines have been researched for more than two decades for their positive potential, with limited

Stem Cells Stem cells are non-terminally differentiated, self-renewing cells that harbour the ability to produce mature, diffe-

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International Animal Health Journal 27


RESEARCH AND DEVELOPMENT rentiated daughter cells. Stem cells serve to regulate or participate in normal tissue homeostasis and embryonic and foetal development. The use of stem cell-based products in the veterinary sector is raising questions for manufacturers, authorities, and users. In 2016, ADVENT issued four problem statements regarding stem cells; stem cell sterility, extraneous agents, tumorigenicity, and target animal safety. At the time of writing, the Q&As on extraneous agents (EMA/CVMP/ADVENT/803494/2016) and sterility (EMA/CVMP/ADVENT/751229/2016) were adopted. Because stem cell-based products are novel therapies, different from both pharmaceutical and immunological products, relevant and feasible parameters in relation to different safety concerns need to be considered. When tackling the challenges of stem cells, the deficits of the current veterinary legislation become obvious. In human medicines in EU, stem cells entered the scene in 2014, where Holoclar was recommended as a treatment for burns to the eye(s), and later with, e.g. Zalmoxis, aiding in the treatment of blood cancer. The initial assessment of human advanced therapy medicinal products (ATMP) is typically carried out by the Committee for Advanced Therapies (CAT) in EMA. A similar committee does not exist on the veterinary side. Bacteriophages Bacteriophages are virus-like agents with antibacterial properties. They have been used to treat bacterial infections in humans for almost a century in some parts of the world. Bacteriophage therapy is used in some parts of Europe, but there are currently no authorised bacteriophage medicinal products. In 1923, the idea of bacteriophage therapy was developed as prophylactic and/or therapeutic use of selected bacteriophages in the destruction of pathogenic bacterial cells, while being harmless for the host’s cells. In recent years, the rise of bacterial resistance to many antimicrobial drugs has spurred renewed interest in bacteriophages, and voices increasingly state that bacteriophage therapy has a place within the therapeutic armamentarium against bacterial infections. However, legislative change and regulatory flexibility will be required to address the unique aspects of bacteriophage development, because bacteriophage therapy is usually adjusted to the individual infection. To our knowledge, no specific guideline is available as yet, but in the US, bacteriophages are generally regarded as safe (GRAS), and have been approved as food additive or food ingredient in human food by the FDA9. Efforts should be joined to develop this area and not to burden a promising approach to treating antibiotic resistant microorganisms. This may require innovative solutions, as are available for autogenous vaccines or multistrain dossiers. Probiotics and Alternative Products Antimicrobial resistance (AMR) continues to be a hot topic, and there is a great deal of pressure for the quantities of antimicrobial substances currently used in veterinary medicine (particularly with respect to food-producing/ farm animals) to be reduced. Use of antimicrobials for growth promotion has been banned in the EU since 20054 and restricted in the US recently7. Treatment with antimicrobials in cases of disease outbreak is now closely monitored in many countries. It is generally accepted that 28 International Animal Health Journal

antibiotics should remain as an option for treatment in animal health; there are, however, many difficulties and limitations associated with their use. It is recognised that the dose rate that appears on the label of older veterinary antimicrobials is not always adequate, since antimicrobial resistance may have increased and better understanding of the antimicrobial’s mechanism of action may have emerged since the time of initial authorisation. This creates knock-on problems, since administration of a higherthan-recommended dose may impact on the withdrawal period in the case of a food-producing animal, and may also affect tolerance in the treated animal and an altered environmental impact11. It is very burdensome in regulatory terms to revise all the recommendations linked to posology. Older antimicrobial substances do not offer very big profit margins for manufacturers, and it is unlikely that any new classes of antibiotics will become available for veterinary use in the near future: it is almost certain that they will be reserved for treating humans. Given all of the above, antimicrobial veterinary medicines are looking less and less attractive to manufacturers and licence holders as time goes on. Farmers, of course, still need to be able to protect their livestock from disease too, and be able to treat them should they become severely infected; they also want to maximise production from their animals. This drive to divest from the use of traditional antimicrobials has meant an increased interest in products that may have been seen as ‘alternative’ until quite recently. An ingredient derived from pineapple stems, Anatara’s ‘Detach’1 has shown much promise in clinical trials in preventing scour (diarrhoea in piglets), which is currently treated with antibiotics. A US firm is focusing their research efforts on algae, having found a candidate compound in it that they hope to develop as an alternative to antibiotics used for growth promotion2. Probiotics (‘live microorganisms that, when administered in adequate amounts, confer a health benefit on the host’, according to the FAO/WHO definition) are becoming more mainstream in animal husbandry globally, with certain substances having proven results in lowering disease susceptibility, improving productivity10. Summary and Conclusions It is clear that the regulatory bodies in the EU/EEA are well aware of the need for the Community legislation and guidelines – and the practical procedures involved in authorising new therapies – to be in close dialogue with those at the cutting edge of innovation in animal health. The continuing expansion and development of the Innovation Network, and its remit of sharing experience gained and identifying need for training or recruitment of specific expertise, is a recognition of the fact that regulation is often lagging behind research and academia. Animal health is also often secondary to human health, with legislation for some technologies entirely absent on the veterinary side (medical devices, for example). Scientific innovations usually break into human healthcare first too; but it is nevertheless quite common for companies that have managed to obtain a licence for an effective new therapy in humans to then consider widening their market to include animals, where the treatment is relevant. The shift away from use of antimicrobials, with continued reduction anticipated, has created an incentive for companies to develop new products with similar functions that have the potential to replace them. Multi-faceted Volume 4 Issue 4


RESEARCH AND DEVELOPMENT approaches to combating disease are also being explored, with innovative classes of products showing promise, but as yet not being widely trialled or applied, nor giving consistent results. Looking ahead from the current frontiers of animal health, there are clearly some emerging ‘front-runners’ amongst the new and innovative treatments, some of which have been identified in the discussion. It is safe to say though – as with everything in life – the only certainty is change. Glossary ADVENT

Ad-hoc expert group on Veterinary Novel Therapies (ADVENT)

AMR

Antimicrobial resistance

CAT

Committee for advanced therapies

CVMP

Committee for medicinal products for veterinary use

EC

European Commission

EEA

European Economic Area

EFSA

European Food Safety Agency

EMA

European Medicines Agency (the central agency for human

EPAR

European Public Assessment Report

EU

European Union

FAO

Food and Agriculture Organisation

FDA

Food and Drug Administration (the agency for human and

GRAS

Generally regarded as safe

HMA

Heads of medicines agencies

IN/EU-IN

European Union Innovation Network

ITF

Innovation Task Force

and veterinary medicines regulation for the EU)

veterinary medicines regulation for the USA)

MS

Member state

NCA

National competent authorities (the national agencies

located in the EU Member States)

SAWP-v

Scientific advice working party (veterinary)

SME

Small or medium-sized enterprise

VMP

Veterinary medicinal product

WHO

World Health Organisation

REFERENCES 1.

ABC News, Rachel Brown (2016) - "Pineapple extract used to treat deadly diarrhoea in piglets, replaces need for antibiotics". http://www.abc.net.au/news/201606-23/pineapple-extract-used-to-treat-deadlydiarrhoea-in-piglets/7536762 (accessed 16/10/17) 2. Animal Pharm / Sian Lazell (2017) - "ZIVO algal platform holds potential for 'endless supply of bioactive compounds' https://animalpharm. agribusinessintelligence.informa.com/AP013054/ZIVOalgal-platform-holds-potential-for-endless-supplyof-bioactive-compounds?vid=Agri&processId=29b 18d77-f996-4a53-bedc-4ce7573bfba4 (accessed 05/10/2017) 3. EFSA (2016) - "Assessment of the potential integration of the DNA plasmid vaccine CLYNAV into the salmon genome". https://www.efsa.europa.eu/en/efsajournal/ pub/4689 (accessed 16/10/17) 4. European Commission (2005) – Press Release "Ban on antibiotics as growth promoters in animal feed enters into effect" http://europa.eu/rapid/press-release_IP05-1687_en.htm (accessed 02/10/2017) www.animalhealthmedia.com

5. European Medicines Agency - EU Innovation Offices Network: E-mail addresses for users (2017) - http:// www.ema.europa.eu/ema/index.jsp?curl=pages/ regulation/general/general_content_000334. jsp&mid=WC0b01ac05800ba1d9# (accessed 21/08/17) 6. European Medicines Agency/Committee for Veterinary Medicinal Products (2016) - Clynav European Public Assessment Report, http://www.ema.europa. eu/docs/en_GB/document_library/EPAR_-_ Public_assessment_report/veterinary/002390/ WC500231720.pdf (accessed 20/09/2017) 7. Food and Drug Administration (2016) - Notification " FDA Reminds Retail Establishments of Upcoming Changes to the Use of Antibiotics in Food Animals "https://www. fda.gov/animalveterinary/newsevents/cvmupdates/ ucm507355.htm (accessed 02/10/2017) 8. Heads of Medicines Agencies / European Medicines Agency (2016) - "Mandate of the European Innovation Network". http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2017/03/WC500223627.pdf (accessed 18/08/2017) 9. Peek, R. and Rajender Reddy, K. (2006) - "FDA Approves Use of Bacteriophages to be Added to Meat and Poultry Products" in Gastroenterology (Accessed online at https://www.ncbi.nlm.nih.gov/pubmed/17067600 , 31/10/17) 10. PEW Charitable Trusts (2017) - "Alternatives to Antibiotics in Animal Agriculture", http://www.pewtrusts.org/en/ research-and-analysis/reports/2017/07/alternativesto-antibiotics-in-animal-agriculture (accessed 02/08/2017) 11. Schefferlie, J. (2017) - "CVMP-Industry work on dose optimisation for established veterinary antibiotics". Presentation given at the 2017 TOPRA Symposium.

Anja Holm She is an independent consultant with 18 years of unique experience from the EMA and a national authority in evaluation of veterinary medicines and vaccines. She is a veterinarian and has scientific, leadership, communication, and regulatory expertise combined with strong understanding of start-up companies and novel therapeutics. Email: anjaholm@centralvetpharma.com

Pascale Canning She has worked at Cyton Biosciences for around seven years, supporting and project-managing regulatory procedures on behalf of Cyton's clients in the animal health industry, and carrying out regulatory intelligence research. More recently, she has also been involved in Cyton's business development activities, and organised regulatory affairs training courses in collaboration with the co-author of this paper, Anja Holm. Email: pcanning@cyton.com

International Animal Health Journal 29


RESEARCH AND DEVELOPMENT

Homeopathy in Animals: Yesterday and Today … But Tomorrow? The Royal College of Veterinary Surgeons (RCVS), the UK veterinary profession’s regulatory body, has recently issued a position statement on homeopathic product use in animals, which includes the following:

the ‘Law of Similars’, the ‘Law of Infinitesimals’ and the ‘Law of Succussion’. In summary, these are: •

“…we expect that treatments offered by veterinary surgeons are underpinned by a recognised evidence base or sound scientific principles... Homeopathy exists without a recognised body of evidence for its use. Furthermore, it is not based on sound scientific principles. In order to protect animal welfare, we regard such treatments as being complementary rather than alternative to treatments for which there is a recognised evidence base or which are based in sound scientific principles.  It is vital to protect the welfare of animals committed to the care of the veterinary profession and the public’s confidence in the profession that any treatments not underpinned by a recognised evidence base or sound scientific principles do not delay or replace those that do.”  Why has the RCVS done this? In a recently published veterinary textbook, Taylor and Gough1 stated:

“Misconceptions abound regarding homeopathy. Such is the effectiveness of homeopathic ‘spin’, many users are convinced it is safe and effective and has firm scientific evidence behind it. Others may assume it is akin to herbal medicine, using small amounts of natural material to treat disease. In fact homeopathy is none of these; it is actually one of the most improbable and deeply strange manifestations of CAM [complementary and alternative medicine] in existence today. Its use has resulted in the deaths of humans and animals, yet in trials against blank placebo controls it is found to be utterly ineffective in treating disease.” So why is homeopathy still being practised, on both people and animals, today? History: Homeopathy was invented by Samuel Hahnemann, a medically qualified German doctor, around 1796. His invention, which we now know to be ineffective, must be seen in the context of his time. The late 18th century has been described as the period of ‘heroic medicine’, and the rationale underlying much of medical treatment was the ancient belief that illness resulted from an imbalance of the four bodily humours – blood, yellow bile, black bile and phlegm2,3. On this basis, the major medical treatments used were purging, bleeding, sweating, emesis and blistering. In addition was the use of plants and their extracts (Materia Medica). At the time, a surgeon’s skill related mainly to speed of cutting. Much of this treatment was ineffective, and some of it positively harmful. To these, Hahnemann added homeopathy which, at least, had the benefit of doing no harm. The three Laws: Hahnemann predicated homeopathy on three ‘laws’ that continue to underlie the whole of homeopathy today; 30 International Animal Health Journal

Similars: The word ‘homeopathy’ is derived from the Greek for ‘similar suffering’, and the Law of Similars is often paraphrased as ‘like-cures-like’. The concept is that, if a substance in large doses can cause the symptoms of an ailment, in much smaller doses it can cure or prevent those symptoms. For example, coffee is a stimulant, but in preparing the homeopathic product Coffea cruda from coffee, its action is converted into a cure for insomnia, a sedative action. This would be miraculous, if it was to happen, but there is no evidence to support the notion. It is rather an example of what is described by anthropologists as ‘sympathetic magic’, a belief system almost universal in human culture throughout history4. Infinitesimals: The starting material is successively diluted, 1:10 or 1:100, usually many times, until in most remedies there is not a single molecule of the starting material or substance remaining. Succussion: At each stage of dilution there has to be vigorous shaking or tapping (to coin a phrase ‘shaken not stirred’) in order to ‘potentise’ or ‘energise’ the remedy. With each round of dilution and succussion, the healing effect is believed to become more powerful.

These three laws were invented by one man at a time well before the modern understanding of biology, disease and medicine – before Pasteur, Virchow, Koch and Darwin. Each law is arbitrary in the sense that it bears no relation to the modern understanding of biology and disease; there is no scientific reason to think that ‘like-cures-like’, or that dilution and succussion will reverse the effect of the undiluted starting substance and activate its healing properties. In other words, these laws are matters of faith. Each ‘Law’ is itself implausible, but the absolute requirement to obey all three Laws in preparing each remedy compounds the implausibility – to an infinite degree. The procedures used in preparing homeopathic products are claimed to achieve ‘potentisation’; that is steadily increasing potency at each step with decreasing numbers of molecules of the starting material, with the potentisation continuing in the absence of any molecules. These beliefs are totally incompatible with modern scientific knowledge, not only in the disciplines of biochemistry, physiology, pharmacology and microbiology but in physics and chemistry also. For example, the key principle of 20th and 21st century pharmacology is that, with few exceptions, e.g. the phenomenon of hormesis5,6,7, more drug produces greater effect – up to a maximum attainable response. In stark contrast, homoeopathists insist that less (even absence of) substance produces increasing effect. The tenets of homeopathy and drug-based therapeutics are polar opposites. Homeopathy is pseudoscientific and, to be effective, would require the existence of some force beyond scientific understanding or the laws of nature, i.e., a truly supernatural force. Volume 4 Issue 4


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International Animal Health Journal 31

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RESEARCH AND DEVELOPMENT Constituents: The components of homeopathic products are: •

• • • •

Commonly less than one molecule of the original “active”, depending on the magnitude (1:10 or 1:100) and number (commonly 12 or 30, sometimes over 1000) of serial dilutions. “Energised” diluent – usually water and/or alcohol. In some products sugar also (but with no claim for efficacy for it). Dissolved atmospheric gases, various impurities, including both inorganic and organic molecules. Microorganisms (most homeopathic products are not sterile).

Some of the more bizarre starting materials, which may be of animal, plant, microbial or mineral origin, include clingfilm, meadow grass, duck offal, light from the planet Venus, organophosphates, car exhaust fumes and the Berlin Wall. Homeopathic remedies made from each of these materials can be purchased from homeopathic pharmacies. Homeopaths’ proposals on mechanism of action: Homeopaths have been bound to provide explanations, in a modern world, of how their products might work. They have to explain how the action possessed by the starting material is converted to a polar opposite action (onions induce lachrymation and therefore the derived homeopathic product cures or relieves symptoms of a common cold) and how this is achieved by dilution and succussion in such a way that the curative effect operates – in many cases – with no molecules of that starting material remaining. Hahnemann’s view was that illnesses in humans and animals are a result of an imbalance of the body’s ‘vital force’. He believed that homeopathy utilises the same ‘vital force’ or ‘life energy’ that is present in the substances that the remedies are produced from – indeed, apparently, present in all substances – and that this ‘vital force’ is manipulated by homeopaths in the creation of their remedies in such a way as to ‘heal’ or ‘balance’, in an unspecified way, the vital force of the patient. Many modern homeopaths appear to hold this view, as demonstrated by an internet search of these terms with ‘homeopathy’ and by reading modern homeopathy texts (e.g. 8, 9, 10). However, in our scientific age, some homeopaths have attempted to provide more-or-less scientific explanations. Clearly, claims for molecules acting on receptors (the fundamental basis of pharmacology) cannot be made, as there are no molecules of the starting material remaining in ultra-dilute remedies. Resort has been made to other mechanisms; electromagnetism, quantum effects and nanoparticles have been invoked to explain claimed effects. Each has been found wanting and there remains no rational, scientific explanation of how homeopathic remedies achieve their alleged efficacy. Many laboratory-based in vitro and in vivo experiments have been reported that claim to demonstrate a biological action of ultra-dilute remedies. Unfortunately, these studies have generally been poorly designed and controlled and, to date, there has been no laboratory demonstration of a positive effect of an ultra-dilute remedy that can be reliably replicated11, 12. Evidence for efficacy of homeopathic products: Effective drugs exercise a therapeutic effect by specific mechanisms. In addition, there are often non-specific effects of giving drugs, which can make effective drugs appear more effective than 32 International Animal Health Journal

they truly are, or make an ineffective drug appear effective12,13. The most well-known of these non-specific effects is the placebo effect. Further, other factors occurring concurrently with a treatment can confound assessment of the efficacy of the drug, again usually acting to make the drug appear more effective than it actually is. These include the natural history of the disease – if the drug is given just before the patient starts to recover naturally from an acute infection, the drug can appear effective when it is actually ineffective. Similarly, in chronic illnesses with fluctuating signs – for example osteoarthritis – patients tend to be presented when the signs are particularly bad and so there is a natural tendency for the signs to improve after treatment because they are regressing to the mean. Drugs may also appear more effective than they actually are to observers, such as doctors, veterinary surgeons or animal owners, because of expectation effects and biases in the observers themselves12,13. Because of all these confounding effects, it is easy to believe that ineffective treatments are truly effective. Regardless of underlying mechanism(s) of action, the key question is, do homeopathic products actually work, when evaluated in robust studies and, if so, can the results be replicated? The gold standard trial design for assessment of therapeutic interventions is the randomised blinded controlled clinical trial (RCT), in which a treatment is compared to a control treatment, usually a placebo. The rationale of RCTs is precisely to separate the specific effects of a treatment from all the confounding non-specific effects, concurrent variations in disease signs, and observer biases. However, such trials are difficult to design and carry out to high standards. For this reason, objective criteria exist for the assessment of published RCTs14,15,16. Systematic reviews and meta-analyses of RCTs carried out using such objective criteria represent the highest level of evidence for therapeutic interventions. Many RCTs of homeopathy have been performed, in both human and veterinary medicine. The small number of systematic reviews and meta-analyses in both human and veterinary medicine have found that relatively few of the many RCTs meet the required stringent standards, particularly in veterinary medicine. These systematic reviews and metaanalyses have provided no clear indication that homeopathy has any benefit over placebo; those reviews and metaanalyses that have reported small apparent positive effects in favour of homeopathy all recognise that the apparent effect could be due to residual confounding factors remaining as a result of imperfect design and performance of the best-quality RCTs available12,13,17,18,19,20. The ethics of homeopathy in animals: Despite the lack of any specific therapeutic effect of homeopathic remedies, many scientists and clinicians accept that some benefit can accrue in human patients from psychological and psychophysiological effects of the homeopathic consult itself and from placebo effects associated with the remedies in some instances12,13. Even so, there are ethical issues associated with the use of ineffective/placebo treatments in humans21,22. In veterinary medicine, it will be extremely rare, unless specifically organised by prior conditioning of the animal, that a placebo effect will occur on treatment of the animal. If, therefore, there is neither placebo benefit nor any specific effect (in the presence of few or no molecules of starting Volume 4 Issue 4


RESEARCH AND DEVELOPMENT substance) then the use of homeopathic products cannot be acceptable in animals on ethical grounds. A further concern is that animal owners can have ‘caregiver placebo effects’ that can make them believe that there is improvement in an animal when there is none23,24,25,26. An additional ethical concern is that a homeopathic product might be used in preference to a drugbased product that has been licensed following a detailed evaluation to establish its quality, safety and efficacy. For an animal that is suffering as a result of a disease that could be effectively treated, the use of an ineffective treatment in place of an effective one would result in avoidable suffering. In human cancer patients, the use of alternative therapies in place of conventional treatments has been associated with increased mortality27,28,29. Legal status of homeopathic remedies: Once formulated after many dilutions and succussions, there are essentially no additional costs to marketing homeopathic products, only very limited regulatory requirements to be negotiated. For example, no comparative studies against other products, homeopathic, placebo or drug-based, are required by regulatory authorities. These authorities universally recognise that the products are lacking in constituents with specific actions. Therefore, specific medicinal claims are disallowed. Furthermore, it is assumed that no toxicity will arise in the absence of any active. Hence, it is further assumed that there can be no residues in edible tissues of food-producing species and consequently no meat/milk withholding periods are required. The legal status of homeopathic products in the EU is currently under consideration by the Committee for Veterinary Medicinal Products, a committee of the European Medicines Agency. British Veterinary Association position on homeopathy: In the UK, diagnosis and treatment of animals, including homeopathy, can only be carried out by veterinary surgeons. Over the last couple of decades there has been a great deal of discussion within the UK veterinary profession about the practice of homeopathy on animals by veterinary surgeons, and this concern has increased over the last few years. The British Veterinary Association, the national representative body for the UK veterinary profession, has long held the position that homeopathic products should not be recommended for use in animals30: “We cannot endorse the use of homeopathic medicines, or indeed any medicine making therapeutic claims, which have no proven efficacy. As with any medicine, we believe that veterinary medicinal products must be evidence-based, with any medicinal claims made by a manufacturer supported.” Summary: The use of homeopathy presents us with two hypotheses, only one of which can be correct. One proposes that homeopathic products are genuinely effective, through specific actions that are not just unknown to science, but appear incompatible with scientific understanding. This hypothesis is extremely implausible and is lacking in support from the bestquality evidence from RCTs and systematic reviews which, as discussed above, indicate that homeopathy is ineffective. The second hypothesis is that homeopathy has no effect beyond placebo in humans and no effect at all in animals, and that homeopaths’ judgement of the efficacy of their products is incorrect as a result of the numerous factors, described above, that act to confound physicians’ assessment of treatment efficacy. This latter hypothesis is simple and highly plausible and is consistent with all available evidence. In conclusion, it is www.animalhealthmedia.com

clear why the RCVS felt it necessary to produce its new position statement, in order to protect animals from potential welfare harms. REFERENCES

1. 2. 3. 4. 5.

6. 7. 8. 9. 10.

11.

12.

13.

Taylor, N. & Gough, A. No Way to Treat a Friend – Lifting the Lid on Complementary and Alternative Veterinary Medicine. 5M Publishing, Sheffield (2017). Porter, R. Greatest Benefit to Mankind; A Medical History of Humanity from Antiquity to the Present. Harper Collins, London (1997). Wootton, D. Bad Medicine: Doctors doing Harm Since Hippocrates. Oxford University Press, Oxford (2006). Fraser, J.G. Chapter 3. Sympathetic Magic. In The Golden Bough: A Study in Magic and Religion. MacMillan, New York (1922). Calabrese, E.J. Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences. Environ Pollut 138, 379-411 (2005). Calabrese, E.J. & Baldwin, L.A. Hormesis: U-shaped dose responses and their centrality in toxicology. Trends Pharmacol Sci 22, 285-291 (2001). Vandenberg, L.N. Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol a as a case study. Dose Response 12, 259-276 (2014). Kayne, S.B. Homeopathic pharmacy theory and practice, 2nd Ed. Elsevier, Philadelphia (2006). Nicolai, T. Important concepts and the approach to prescribing. In: Kayne, S. Ed. Homeopathic Practice. Pharmaceutical Press, London pp 43-61 (2008). Owen, D. What is health? In: D. Owen, ed. Principles and Practice of Homeopathy: The therapeutic and healing process. Jessica Kingsley Publishers, London. pp3-17 (2015). Witt, C.M., Bluth, M., Albrecht, H., Weisshuhn, T.E., Bautmgartner, S. & Willich, S.N. The in vitro evidence for an effect of high homeopathic potencies - a systematic review of literature. Complement Ther Med 15,128-138 (2007). Lees, P., Chambers, D., Pelligand, L., Toutain, P.-L. Whiting, M. & Whitehead M.L. Comparison of veterinary drugs and veterinary homeopathy: part 2. Vet Rec 181,198-207 (2017). Lees, P., Chambers, D., Pelligand, L., Toutain, P.-L. Whiting, M. & Whitehead, M.L. Comparison of veterinary drugs and veterinary homeopathy: part 1. Vet Rec 181,170-176 (2017). International Animal Health Journal 33


RESEARCH AND DEVELOPMENT 14. Higgins, P.T. & Green, S. eds; Cochrane handbook for systematic reviews of intervensions v5.1.0. Cochrane Collaboration, Oxford (2011). http://handbook. cochrane.org/ 15. Zoonoses & Public Health special issue: Systematic reviews and meta-analysis in animal agriculture and veterinary medicine. Zoonoses and Public Health 61 Suppl 1, 1-63 (2014). 16. PRISMA Preferred reporting items for systematic reviews and meta-analyses (PRISMA) website (2017). http:// www.prisma-statement.org/Default.aspx visited on 7 November 2017. 17. Shang, A., Huwiler-Muntener, K., Nartey, L., Juni, P., Dorig, S., Sterne, J.A., Pewsner, D. & Egger, M. (Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet 366, 726-732 2005). 18. Mathie, R.T., Lloyd, S.M., Legg, L.A., Clausen, J., Moss, S., Davidson, J.R.T. & Ford, I. Randomised placebocontrolled trials of individualized homeopathic treatment: systematic review and meta-analysis. Syst Rev 3:142 (2014). 19. Mathie, R.T. & Clausen, J. Veterinary homeopathy: systematic review of medical conditions studied by randomised placebo-controlled trials. Vet Rec 175, 373-381 (2014). 20. Mathie, R.T. & Clausen, J. Veterinary homeopathy: meta-analysis of randomised placebo-controlled trials. Homeopathy 104, 3-8 (2015). 21. Shaw, D.M. Homeopathy is where the harm is: five unethical effects of funding unscientific 'remedies'. J Med Ethics 36, 130-131 (2010). 22. Smith, K. Against homeopathy – a utilitarian perspective. Bioethics 26(8), 398-409 (2012). 23. Conzemius, M.G. & Evans, R.B. Caregiver placebo effect for dogs with lameness from osteoarthritis. J Am Vet Med Assoc 241, 1314-1319 (2012). 24. Talbot, W.A., Pinchbeck, G.L., Knottenbelt, D.C., Graham, H. & McKane, S.A. A randomised, blinded, crossover study to assess the efficacy of a feed supplement in alleviating the clinical signs of headshaking in 32 horses. Equine Vet J 45, 293-297 (2013). 25. 25. Gruen, M.E., Griffith, E., Thomson, A., Simpson, W. & Lascelles, B.D.X. Detection of clinically relevant pain relief in cats with degenerative joint disease associated pain. J Vet Intern Med 28, 346-350 (2014). 26. Gruen, M.E., Dorman, D.C. & Lascelles, B.D.X. Caregiver placebo effect in analgesic clinical trials for cats with naturally occurring degenerative joint diseaseassociated pain. Vet Rec 180, 473-479 (2017). doi 10.1136/vr104168. 27. Chang, Y.E., Glissmeyer, M., Tonnes, S., Hudson, T. & Johnson, N. Outcomes of breast cancer in patients who use alternative therapies as primary treatment. Am J Surg 192,471-473 (2006). 28. Han, E., Johnson, N., DelaMelena, T., Glissmeyer, M. & Steinbock, K. Alternative therapy used as primary treatment for breast cancer negatively impacts outcomes. Ann Surg Oncol 18:912-916 (2011). 29. Johnson, S.B., Park, H.S. Gross, C.P. & Yu, J.B. (2017) Use of Alternative Medicine for Cancer and its Impact on Survival. J Natl Cancer Inst (2018) 110(1) (2018). doi: 10.1093/jnci/djx145 30. https://www.bva.co.uk/News-campaigns-andpolicy/Policy/Medicines/Veterinary-medicines/, visited on 7 November 2017. 34 International Animal Health Journal

Peter Lees He is a specialist in veterinary pharmacology and is now Emeritus Professor of Veterinary Pharmacology at The Royal Veterinary College, University of London. He has served terms on the Veterinary Products Committee and as European Editor of Journal of Veterinary Pharmacology and Therapeutics. Email: plees@rvc.ac.uk

Danny Chambers He graduated from University of Liverpool in 2008 and currently works at Langford Vets, University of Bristol. He is a member of the BVA Policy Committee and an elected member of RCVS Council. He has spent his career in practices all over the UK and New Zealand. Danny is regularly involved with One Health projects involving rabies eradication, working horses and livestock in India, Iraq, Morocco and The Gambia. Email: danny.chambers@live.com

Ludovic Pelligand He is a veterinary anaesthesia and clinical pharmacology specialist. He is joint Head of the Anaesthesia and Analgesia Service at the Royal Veterinary College, University of London. He has served on the British Small Animal Veterinary Association’s scientific committee. Email: lpelligand@rvc.ac.uk

Pierre-Louis Toutain A specialist in veterinary pharmacology and formerly Professor at Toxalim, Ecole Nationale Veterinaire de Toulouse, France. He is current President of the European Association for Veterinary Pharmacology and Therapeutics and Distinguished Visiting Professor of Veterinary Pharmacology at The Royal Veterinary College. Email: pltoutain@wanadoo.fr

Martin Whitehead A veterinary surgeon at Chipping Norton Veterinary Hospital in Oxfordshire, UK. He is a Royal College of Veterinary Surgeons accredited Advanced Practitioner in Small Animal Medicine, runs a radiotherapy unit for hyperthyroid cats, and has served on the British Small Animal Veterinary Association’s Scientific Committee. Email: martincnvets@gmail.com

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International Animal Health Journal 35


RESEARCH AND DEVELOPMENT

Latest Lameness Research: A Summary Provita Animal Health recently took part in several conferences which delved into the current research on lameness, amongst other topics. These included: the 19th International Symposium and 11th Conference on ‘Lameness in Ruminants’ which was held in Munich, Germany on 7th–9th September 2017, AVSPNI (Association of Veterinary Surgeons Practising in Northern Ireland) in October 2017 and CAVI (Veterinary Ireland) Annual Conference, October 2017. This article summarises key points from presentations and scientific posters from researchers across the globe that could help farmers tackle lameness in their herds. Lameness is a major challenge in dairy herds globally. Digital dermatitis (DD), more commonly known as Mortellaro, is an infectious condition and one of the major causes of lameness reducing mobility, comfort, feed intake milk yield, fertility. This infectious condition can spread quickly through the entire herd and can reduce milk yield by at least one litre per cow per day. At the International Lameness Conference in Munich, GJ Remnant reported that the levels of lameness overall ranged from 7% to 61%. Likewise David Tisdall, at the AVSPNI conference mentioned that lameness can range from 0% to 79.2% and overall levels are increasing with a reported average 36.8% of lameness incidence. From the percentages stated, it is evident that lameness can be controlled, however too many lameness protocols on farm are substandard. It was suggested at AVSPNI conference that the main obstacles to controlling lameness were time and labour restrictions, plus the unpopularity and tedium of the job itself. Furthermore, if lameness levels reach a noticeably high level, farmers may feel it is irreversible and too difficult to reduce. Thus, it is paramount that veterinarians and farm consultants provide reassuring on-farm assistance, robust protocols and regular follow-up to manage such scenarios. Keynote speeches at the Munich conference were delivered by very reputable researchers within the ruminant lameness field. One such speech by Dr Arturo Gomez from Spain discussed “Lameness: could it be driven by inflammation?” which posed some interesting questions on the relationship between lameness and inflammation. Arturo said cow behaviour and stress can promote inflammatory states so he questioned whether we should be adopting low-stress handling in cattle? He highlighted the transition stage to be a key time of a cow’s lactation which can greatly impair the immune system, and that special focus should be put on transiting cows, and a specific lameness goal approach given to cows depending on their stage of lactation. An interesting debate with practical implications for veterinarians, farmers and hoof-trimmers was whether to bandage or not bandage Mortellaro infections. One philosophy is that bandages can leave the skin soft and 36 International Animal Health Journal

compromised if left on for longer than three days; however, they do allow sustained contact time for any topical product to work such as Konquest hoof gel (see images 1&2). Research led by Dr Klawitter from University of Bern, Switzerland, showed that bandaging leads to a 71%–86% treatment rate within one month, but absence of a bandage successfully treated 30–44% of lesions. However, it must be noted the techniques used were complex, comprising large amounts of cotton gauze, a bandage wrap and tar sealant. This was in addition to replacing every week during a four-week period. This may not be a practical option for all farms, but it could be a warranted approach for a few difficult cases.

Image 1

Image 2

Also of interest for the day-to-day management of Mortellaro was a longer-term study led by Coatney from USA, which showed that the majority of infections treated with either a single or triple (one week apart) application of topical antibiotic redeveloped again at 120 days, despite appearing healed at 60 days. This would confirm the necessity for a treatment and control strategy to be used together, i.e. topical product applications and footbathing. Footbathing is an effective control measure, therefore it will help to reduce the incidence of new infections and improve the condition of the hoof. For maximum results, it is recommended to run a footbath after every milking, every day. Renowned cattle veterinarian, Roger Blowey MCRVS, has often stated that many dairies will realise a greater economic benefit from regular footbathing than any other change on farm. Effective hoof-trimming was discussed at both the AVSPNI conference and the CAVI conference. It was stated that effective trimming resulted in 25% less lameness on farm, and the following suggestions on improving trimming were made: • • • •

Earlier trimming leads to 50% less incidence of lameness; One shoe size does not fit every animal, so dorsal wall length should be varied per cow – larger cows may need 80 mm to 90 mm; The first cut should not draw blood as this can be a route of infection by DD and lead to toe necrosis; The use of NSAID drug, in conjunction with trimming and blocking, doubled the cure rate to 56% compared to 24% for trimming only. Volume 4 Issue 4


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International Animal Health Journal 37


RESEARCH AND DEVELOPMENT

Provita Animal Health had co-authorship on an oral and scientific poster presentation at the conference in Munich. The oral presentation was presented by Dr Nick Bell from England on the repeatability of visual scoring of Mortellaro lesions. The purpose of this study was to determine if there was scoring agreement among lameness researchers and professionals in the identification of DD lesions using the widely adopted M-system (see image 3). Surprisingly, the level of agreement was satisfactory, only highlighting the need for more training and education on the M-system. To help farmers complete M-scoring, there have been significant advancements in technology. Currently there are two systems available; Zinpro’s DD Check and the Provita Animal Health DD App. The DD Check App requires training and good knowledge of the M-system, whereas Provita Animal Health DD App simply requires the user to make three observations on colour, size and profile of lesions, and to input these into the app. The app converts observations and categorises them into early, acute, healing, chronic DD lesions. Once the data has been submitted, a full report and specific recommendations for the farm are generated (see image 4).

Image 4

by 45% (see figure 1). Cleaner medicated footbaths allow greater contact time on the hoof and improved hoof hygiene. The use of permanent footbaths (e.g. concrete, stainless steel) resulted in less loss of footbath solution than temporary footbaths (e.g. plastic). As the number of observed cow defecations in pre-wash footbaths and medicated footbaths were similar during the study, it could be that the pre-wash bath has a beneficial cleaning effect on cows’ feet. It was noted that a larger study will be required to verify and expand on these observations. % Dry matter contamination

At the Munich Lameness conference, the main consideration voiced was the appropriateness of trimming techniques that were specific to the herd. Over-trimming is certainly a practice to avoid, since it can affect the sole thickness and biomechanics of the feet, thus impacting the lameness susceptibility. Trimming at dry-off needs to be correctly done, as the changes in hoof conformation at calving are multiple. It was described how the cow’s pedal bone sinks at calving, pushing more pressure on the digital cushion, often the primary site of infectious lesions like DD. Additionally, digital cushion thickness is at its thinnest one week after calving, due to the repositioning of fat, in the same way body condition is lost which can predispose claw horn lesions like sole haemorrhages and ulcers. Therefore, it may be the case to implement specific lameness management for freshly calved groups, and this was heavily endorsed by many presenters. Although research is still sparse to give any concrete recommendations, I am confident many projects will begin to investigate this further.

12 10 8 6 4 2 0

Pre-wash

No Pre-wash

Footbath set up Percentage dry matter in footbath with or without pre-wash set up The use of pre-wash baths reduced the level of dry matter contamination in the chemical footbath by 45%.

Figure 1

In conclusion, a great diversity and knowledge was presented at all of the recent conferences and a common trend from them is that lameness is still a major problem globally. That said, with deeper examination it has revealed lameness to certainly be controllable and treatable if the correct measures are in place. The initial recognition and identification of the lameness levels are vitally important; following advice on hoof-trimming; having a permanent footbath in place; treating and controlling digital dermatitis effectively and having reviewable farm-specific lameness protocols in place are important measures needed for success. REFERENCES 1.

Image 3

Another study by Provita Animal Health aimed to help farmers decide on using a pre-wash footbath that was presented again at the International Lameness conference, Munich 2017. The use of a pre-wash set-up reduced the level of dry matter contamination in medicated footbaths 38 International Animal Health Journal

Gomez A. ‘Lameness: could it be driven by inflammation?’ Proceedings of 19th Symposium and 11th Conference, Lameness in Ruminants, Munich, Germany, 2017. 2. Armstrong T., Bell N., Shaw G. ‘Effects of a pre-wash footbath and footbath capacity loss observations’, Proceedings of 19th Symposium and 11th Conference, Lameness in Ruminants, Munich, Germany, 2017. 3. Bell NJ. et al. ‘Repeatability of a Visual Scoring of Digital Dermatitis from Photographs of Standing Animals’, Proceedings of 19th Symposium and 11th Conference, Lameness in Ruminants, Munich, Germany, 2017. 4. Coatney J. et al. ‘Prospective Randomized Clinical Trial Comparing Therapeutic Interventions for Complete Healing of Advanced Bovine Digital Dermatitis Lesions Volume 4 Issue 4


RESEARCH AND DEVELOPMENT

in Dairy Cows’, Proceedings of 19th Symposium and 11th Conference, Lameness in Ruminants, Munich, Germany, 2017. 5. Klawitter M. et al. ‘To bandage or Not bandage: The Curative Effect Of Bandaging Digital Dermatitis Lesions’, Proceedings of 19th Symposium and 11th Conference, Lameness in Ruminants, Munich, Germany, 2017. 6. Newsome RF. et al. ‘A Prospective Cohort Study of Digital Dermatitis Cushion Thickness, Body Condition and Claw Horn Lesions in Holstein Dairy Cattle’, Proceedings of 19th Symposium and 11th Conference, Lameness in Ruminants, Munich, Germany, 2017. 7. Tisdall D. ‘Taking steps towards a proactive approach to managing bovine lameness at individual animal level’, AVSPNI Conference, Newcastle, Co Down, Northern Ireland, October 2017. www.animalhealthmedia.com

George Shaw MPharm MPSNI is Technical Adviser for Provita Eurotech Ltd. He graduated from Queen’s University Belfast in 2011 with a Masters in Pharmacy and registered with Pharmaceutical Society of Northern Ireland in 2012.  George has a keen interest in the promotion of animal health naturally and practices it wherever possible on his family owned beef farm. Email: george.shaw@provita.co.uk

International Animal Health Journal 39


IT & LOGISTICS

Data Management in Veterinary Clinical Studies Data management tasks and procedures with their direct influence on data quality and compliance are an aspect of great importance for any clinical study. Standards and guidelines define basic requirements for data management but provide little detail on requirements for hardware equipment and specific software specification. There are multiple options and solutions available, all promising to provide the ultimate productivity and effectiveness for data management. However, the devil is in the detail depending on the objectives of a study, the environment to work in and the day-to-day challenges related to the conduct of veterinary clinical studies. Data managers have to consider a lot of opportunities and solutions for setting up data management routines. Computerised systems, regardless of whether they are in the context of a veterinary clinical study or not, will consist of individual components, unless a complete (software) package offering all parts of such a system is used. For an electronic data capture (EDC) system, requirements regarding traceability and integrity are the same as for processing data ‘conventionally’ on paper. In the EU, major exigencies detailing requirements for data management procedures are provided in VICH GL9 ‘Guideline on good Clinical Practices (GCP)’, that is linked to legislation via the European Commission Directive 2001/82/EC, as amended by Directive 2009/9/EC. In the US, VICH GL9 is also applicable. There the Food and Drug Administration’s (FDA) 21 CFR part 11, amongst others, defines criteria for (electronic) records and requires mandatory signatures within clinical studies. Additionally, several associated ‘Guidance for Industry’ documents released by the FDA provide recommendations for various issues of data processing, including software validation. Other available guidance documents were initially issued for use in data management of human clinical studies, such as ‘Good Practices for Computerized Systems in regulated ‘GxP’ environments’ from the Pharmaceutical Inspection Co-Operation Scheme (PIC/S) and ‘Good Clinical Data Management Practices’ published by the ‘Society for Clinical Data Management’. Their recommendations and guidance may be very useful to facilitate good data management practices for veterinary clinical studies. The European Commission’s Guide to ‘Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 11: Computerised Systems’ also provides appropriate guidance and is transferrable to use in veterinary clinical studies. This article will briefly illuminate some aspects of data management procedures within a clinical study, from initial planning to providing the final data pack. Planning a clinical study, the team establishing the protocol and related procedures should always involve a well trained and experienced data manager from the very beginning. Designing a clinical study, possibly the first topic with relevance for data management should be the decision 40 International Animal Health Journal

of which medium for raw data collection will be used for data capture: shall it be the traditional way of recording the data on paper (paper-based) or is it justified to use an electronic data capture system for immediate recording (EDC-based). Decision-making criteria whether to use paper-based or EDC-based data capture will need to consider various aspects of the study design, but also feasibility and practical aspects. When deciding to use an EDC system, certain aspects need to be taken into account, as today there is a variety of EDC systems available on the market. A certain number of EDC solutions were initially designed for data capture in human clinical studies and can also be used in veterinary clinical studies: All allow the registration of individual animals, as this is comparable to the requirements of a Phase III study in human medicine. While very suitable for use in small and companion animal studies, adaption of such systems to the study environment on farms may sometimes be impossible due to the data structure these systems provide. So first of all, the location of generating raw data, in a veterinary practice, under laboratory conditions or on a farm, will make a relevant difference. Far away from urban infrastructure, internet availability and transfer rates may also become an issue when intending to use an EDC system in remote areas. Secondly, the study design plays an important role, e.g. when individual animals are enrolled one by one, the processes that basically all EDC systems support by their structure for individual subject registrations may be a good fit. But if cases are rather enrolled by larger groups or flocks at once, or where varying time points require high flexibility, this may reduce the options for use of an EDC system significantly. In certain livestock or poultry studies, animals are to be enrolled in batches, per pen or even as a complete barn/house together, followed by group/ pen-wise treatment. Parallel to group registration, the individual animal’s data will need to be captured precisely, as finally for data analysis the experimental unit will be the individual animal. As flexibility of some EDC solutions is limited, workarounds for pen- or batch-wise registration instead of individual animal registration may need to be taken into account. However, single EDC systems offer the flexibility to handle great animal figures and allow subgroup registration together with individual data capture. Any EDC solution that can cover all such options will definitely be of great help, but will indeed require a huge effort in setting it up accordingly prior to the start of such a study. If such a study is conducted in a multicentric setting, and workflows at each farm are different, this will complicate any use of an EDC system even further. Wherever an EDC system is intended to be used, before deciding on a solution, the available computer system as well as internet infrastructure at site, especially regarding data transfer rates, will require thorough checking to be able to ensure adequate performance during the course of the clinical study. Nevertheless, there is no doubt of the attractiveness of using an EDC system providing the possibility to capture data immediately at site, without subsequent transcription or data entry, as a paper-based data capture model would require. While the setup time and costs may be higher for Volume 4 Issue 4


IT & LOGISTICS an EDC system, it will help to save resources of all involved parties overall in many cases, the advantage of direct data availability for monitoring and plausibility checks included. When deciding to use paper-based DCFs, it has to be kept in mind that appropriate setup for (double) data entry and related quality control will have to be provided for. After considering all these facts, it is strongly recommended to summarise all required data management tasks and their timelines in a data management plan. This allows for transparency and traceability, but even more for reliability of the agreed process. While the data management plan should define in sufficient detail all relevant processes, it must be shared with all parties involved in the clinical study to ensure the professional conduct of the clinical study and the collection and generation of true, accurate and integer data. The first use of EDC solutions in veterinary clinical studies was made in the second half of the first decade of this century. These studies were all pet studies, allowing individual animal registration and data collection. In today’s versions of certain EDC systems specifically designed for use in veterinary clinical studies, additional features necessary for use in studies on farm or under laboratory conditions are included. A lot of the initial challenges for using them under such conditions have been addressed in the meantime. In these more flexible EDC solutions, the data manager has the possibility to choose from different designs when setting up an individual study. For data capture, scenarios based on pens or batches are available and for data processing, with respect to analysis, the final focus is on the individual animal’s data. Having reviewed more than 10 available systems for their use in veterinary medicinal studies, the use in companion animal studies is possible in any EDC solution in order to handle multicentric field studies; they offer the possibility to define and keep separately different study sites, different roles of people to be involved, archiving and data transfer. It is obligatory that an EDC system provides options for randomisation and blinding to treatment towards any treatment. A very useful functionality is an online randomisation tool. Different approaches are implemented; many EDC systems offer an upload of a predefined randomisation list. Based on that, following the completion of a key value, allocation to treatment group is done. In some EDC solutions, a realtime randomisation is implemented. Data managers have to consider carefully which solution is more appropriate for the chosen study, as both have their advantages. Realtime randomisation leaves aside the risk of upload errors or breaking the blinding code by inadvertently showing predefined randomisation information to anyone involved who must not know. Uploading complete randomisation lists prepared outside the EDC system, either individually for each centre (site randomisation) or together for all sites (global randomisation) leaves the option to provide the study sites with sealed printout copies that can be used as a fall-back position in case of e.g. internet failure. Choosing the ‘conventional’ paper-based system, data managers will have to set up and provide appropriate data entry tools for digitalisation of data captured on hardcopy into electronic data by any kind of data entry. EDC systems may be used as data entry platforms for manual input from distant locations; some EDC solutions are already prepared www.animalhealthmedia.com

for double data entry with immediate data comparison, with the results displayed in the (web) user interface. Apart from using existing EDC solutions for manual data entry from paper forms, various scenarios for transferring the data in digitalised form are possible. Simple or complex data entry spreadsheets are quite commonly used, as well as data entry masks representing a user-friendly front-end to a relational database. Automatic recognition systems with transfer of data in a database are also still used. No matter which data entry tool is finally used, it will have to be set up in a way that one can trust the process to correctly reflect the raw data: All setups need to be validated. This is applicable equally for a study-specific EDC setup, a spreadsheet or a database-associated solution. Usually, unless the underlying software is validated by the vendor, validation for the intended purpose is required. In all cases, study-specific setups with their project-related masks and functionalities will need to undergo testing and approval. Post-approval adaptions of study-specific setups will require change management procedures including appropriate documentation. All EDC systems known by the authors offer a full audit trail including change control; which allows the control of changes of data initially entered and modified, but also allows tracing of any later changes. Some also include in the audit trail the setup history of visits, forms and fields which provides the currently highest standard of transparency for documenting changes within an EDC system. Any kind of electronic data capture system, whether an EDC solution or internally built components, should allow data managers and clinical monitors to check data under different aspects. Ideally, a system allows the implementation of immediate checks for presence/absence of values for mandatory parameters, and to set up checks for plausibility of entered values. Any implementation of checks should not prevent or restrict data being collected by the responsible person from entering such (realistic) data. Many EDC systems also provide communication tools to allow and facilitate direct communication between the person entering the data and the clinical monitor, the sponsor or any other person authorised; this also includes flagging or closing queries. Additional features that assist data managers and monitors in routine work (predefined scenarios) are offered. These features are, e.g., functionalities that allow the creation of individual data summaries, general and subject-specific study schedules, and complex checks of dependent or related parameters within a single data entry mask or amongst different forms and setup of email notifications. The latter may include notification of when a new subject has been enrolled, when an adverse event form has been completed, or outstanding next visits by patients. Performing ‘traditional’ monitoring and parallel or subsequent retrospective data entry from hardcopy may require covering the above (applicable) issues by individual components as time points in workflow may vary. Data managers and project managers or monitors will have to coordinate their actions accordingly. Once data in the database is clean, no further corrections are required due to the intensive quality control during the process, including checking for plausibility and solving all queries. Any data captured or digitalised in another language than English may need to be translated. Where required, coding of selected parameters may have to be performed using standardised coding dictionaries (ex. VeDDRA, ATCvet). Some EDC systems offer coding functionalities that already can be included in the data capture process and include common coding libraries. Data management solutions not International Animal Health Journal 41


IT & LOGISTICS routines from plausibility checks to coding – whatever is required and useful. After finalising the clean data pack, this data pack will have to be transferred into a format suitable for further processing by the statistician. Several EDC systems already offer the export of data to SAS, XML or other formats. Where no such prepared functionalities are available, data managers may need to develop appropriate routines. The ultimate objective will remain that data integrity and accuracy is maintained during data transfer, as well as security and confidentiality of the data needing to be assured. All of these topics are influenced by local IT infrastructure of the parties involved. In summary, EDC solutions on the market offer a variety of options. It is worthwhile comparing systems for their scope of available features. They do offer easy and transparent options for data management in veterinary clinical studies. Data management needs to ensure accurately described processes that need thorough planning, transparent setup and validation before release. This includes a full audit trail for tracking of any changes made. Starting with careful consideration of which data needs to be captured (and what), a data management plan should always address the following questions: Who, Where and How it shall be done. It should also include all processes that ensure the objective of a clean data pack, and detail routines that allow safe transfer of correct, accurate and integer data to the partners for analysis. In general, implemented routine data management procedures should be transferable to different kinds of studies, assist involved parties in their tasks, and help to increase efficiency in the conduct of veterinary clinical trials.

Dr Brigitte Steiner

taking advantage of such libraries may require individual approaches. There may also be other data produced which it may be valuable to have available in the central database. Most of the time, this data is generated by a laboratory, performing certain tests and also generating such test results electronically. Laboratory analysis data is usually part of statistical analysis, so it becomes necessary to import such data into the database before finalising the data pack. Other data that may be part of the final data pack may also be X-ray or ultrasound related files, or automatically recorded data like milk yield, cell counts or feed consumption data. Any data import needs to be planned well in advance, in fact prior to the collection of such data in systems that are not under the control of the data manager or a study monitor. Similar criteria applicable for validation of an EDC system are also applicable for any software collecting or generating raw data. It is highly recommended to address these topics during the planning phase of a study. Finally, after setup and approval of import routines, imported data should be handled like other study data and undergo all 42 International Animal Health Journal

She is a veterinarian with over 14 years’ experience in the animal health industry. After a couple of years in veterinary practice, she joined KLIFOVET as a project manager for veterinary clinical studies. In 2010, she moved into data management and focused on data management procedures, development and validation of EDC systems specifically developed for animal health. Since 2017, Brigitte has been heading the Data Management and IT group at KLIFOVET AG. Email: brigitte.steiner@klifovet.com

Dr Klaus Hellmann He is a veterinarian with over 23 years’ experience in the animal health industry. Prior to starting Klifovet in 1997 as a CRO, he worked in veterinary practice, science and the animal health industry. He is a Board-certified veterinary pharmacologist, Diplomate of the European College of Veterinary Pharmacology and Toxicology and holds the title of an Auditor (European Organisation of Quality). Email: klaus.hellmann@klifovet.com

Volume 4 Issue 4


www.animalgenetics.eu Avian

• Sexing • Disease Testing

Canine

• • • • •

Coat Colours Length Genetic Disorders Individual ISAG profiles Parentage Verification

Equine

• Coat Colours • Genetic Disorders • Individual ISAG Profiles • Parentage Verification Contact Details

www.animalgenetics.eu contact@animalgenetics. eu +44(0)1726 247788 www.animalhealthmedia.com

International Animal Health Journal 43


FOOD & FEED

An Update on EFSA’s New Guidance Documents for Feed Additives On 17 October 2017, the EFSA FEEDAP Panel published three new guidance documents to help applicants with the preparation of feed additive submissions: • • •

Guidance on the identity, characterisation and conditions of use of feed additives Guidance on the assessment of safety of feed additives for the consumer Guidance on the assessment of the safety of feed additives for the target species

These guidance documents were adopted during the last FEEDAP plenary meeting in September 2017 and will enter into force on 1 May 2018. EFSA is also working on updating a fourth guidance (Guidance on the characterisation of microorganisms used as feed additives or as production organisms), expected to be adopted during the next FEEDAP meeting. Draft guidance documents on the assessment of the safety of feed additives for the environment and guidance on the assessment of the efficacy of feed additives are being developed and are on the agenda to be discussed at the next FEEDAP meeting. Prior to the adoption of the three new guidance documents, draft versions were made available for public consultation, whereby interested parties could comment & provide feedback. Pen & Tec submitted feedback on all three documents and some of the key changes proposed by Pen & Tec are discussed below. Guidance on the Identity, Characterisation and Conditions of Use of Feed Additives This new guidance will substitute feed additive category guidance documents currently in use (for technological, sensory, nutritional, zootechnical additives and cocciodiostats and histomonostats). In order to make the application procedure more efficient, Pen & Tec suggested that information and data requirements could be more concise. For example, giving a simple generic description of the production process, with key steps of feed additive manufacture, instead of the “detailed description” required by the guidance. Also, a shorter study duration to assess the stability in water (12 or 24h instead of 48h), depending on the practical use of the additive and quality of the water; or the possibility of using one single batch or pilot batches, when testing concentration of newly-produced feed additives for which five different commercial lots are not available (measuring intra-batch variability instead of batch-to-batch variability). Pen & Tec also advised to specify the “feed dilution technique” as a possibility for analysing the active substance in premixtures. It is already accepted by the EURL and it only requires the premixtures to be adequately diluted and then analysed for the active substance with the same analytical method used for feed, so that no extra method validation/verification process is needed. EFSA has taken all of these comments into consideration 44 International Animal Health Journal

and addressed them in the recently published Identity Technical Report. Guidance on the Assessment of Safety of Feed Additives for the Consumer The aim of this guidance is to reduce the use of laboratory animals in oral toxicity studies for microorganisms and production strains, replacing them by in vitro safety studies and analysis using modern genomic techniques (WGS, bioinformatic analysis, and phenotypic testing). In addition, reduced safety study packages were suggested for genetically modified strains whose parent strains were already proven safe (provided that genetic modifications do not raise additional safety issues), and to active substances and their combinations previously evaluated in the EU, or other geographic areas with well-established regulatory frameworks (e.g. USA). Methodologies for dietary exposure assessments that reduce the use of experimental animals should also be taken into account, especially if there is a long-term exposure risk, but only via infrequent food consumption. Pen & Tec also pointed out the need for more harmonised approaches to gather consumption data, following standard methods and recognised by other agencies (EMA, US FDA, etc.). This would help avoid discrepancies in safety assessments and in the determination of maximum residue levels (MRLs). Moreover, consistency between the approach used in this guidance to determine MRL values, and other accepted models such as EFSA’s pesticide residue intake, and JECFA model for veterinary residues, would prevent overly conservative exposure estimates. All comments, together with the reply from EFSA, are listed in the Consumer Safety Technical Report. Guidance on the Assessment of the Safety of Feed Additives for the Target Species This guidance document will replace the current EFSA technical guidance on tolerance and efficacy studies in target animals. The scope of the new guidance covers the assessment of safety in target species. A separate guidance will be developed for efficacy. The main changes made to this guidance document were as follows: As a first step in demonstrating the safety of a feed additive, the guidance proposes conducting an extensive literature search. The guidance says that the literature search should be conducted in a structured manner and cover at least the last 20 years. The references should be compiled using appropriate reference management software provided in .RIS format and copies of all relevant papers should be provided. This is a positive step, as if sufficient evidence can be found to support the safety of a product, then in vivo studies may not be required. Not only will this approach save the applicant time and money, it is also a positive step towards the “3Rs” (reduce, refine and replace the use of animals in science). For  all additives  (except microorganisms), safety for target animals can be derived from suitable toxicological Volume 4 Issue 4


FOOD & FEED studies with oral administration in laboratory animals. This means that expensive in vivo  target animal safety (TAS) studies may not be required. When  in vivo  target animal safety studies are required, the number of trials needed will depend on the target species for which the application is made. For example, data from broilers can be extrapolated to turkeys. If the application covers all pigs and poultry, the requirement is limited to a total of three studies. Again, this approach will potentially save many companies time and money, while following the “3Rs” approach (reduce, refine, replace in vivo animal studies). Study Design and Reporting  The new guidance says that TAS trials, when required, “should be compliant with the criteria established by a recognised, externally audited, quality assurance scheme (e.g. Good Laboratory Practice)”. Currently, such a quality assurance scheme is recommended but it looks like it may become compulsory for all contract research organisations/labs after the new guidance is implemented. Good Laboratory Practice (GLP) studies are more stringent in the way in which study data are collected, audited and reported, which makes them more expensive, so this could have an impact on an applicant’s budget. However, EFSA clarified that GLP is not mandatory, though trials should comply with the guidance and should be conducted at contract research organisations that have an in-house quality assurance team and are externally audited. EFSA are becoming stricter on study design and statistical requirements. For example; the guidance asks that the rationale for the selection of the number of animals/ replicates used (sample size calculation) is provided along with a power analysis. Whilst in practice this should always be done, it is not always reported. The guidance also requires that the protocol and any amendments/ deviations be reported in the final study report. To date, EFSA have not required this information. This type of reporting is more in line with the requirements of GLP or Good Clinical Practice. EFSA define the experimental unit as the smallest entity to which a treatment is applied. As such, if all animals in a pen share the same feed source, the pen is the statistical unit for all parameters. Pen & Tec proposed that when animals are weighed and sampled individually, then those individual data may be considered as individual replicates for statistical purposes. The only parameters for which the pen is the only possible statistical unit would be feed intake and feed gain. In the OECD/GLP guidelines, all  other parameters (e.g. body weight, clinical signs, haematology, blood and urine biochemistry, organ weights, pathology, etc.) are considered as individual values. In relation to the use of a randomised block design, Pen & Tec suggested that flexibility be considered for certain cases where control animals need to be housed separately from treated animals (e.g. coccidiostat studies). EFSA responded by pointing out that guidance allows applicants to use other study designs where appropriate, as long as the approach is justified. In addition, Pen & Tec commented that innovation is driving new uses of feeds and feed additives (e.g. the use of feed additives in nutrients delivered from 18 days in ovo and in the period through hatching, delivery of chicks to farms, and acclimatisation of chicks at farms), therefore, EFSA safety (and efficacy) guidance documents may need to be adapted further as these innovations are taken into account, or become common industry practices.

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Guidance on the Characterisation of Microorganisms Used as Feed Additives or as Productions Organisms This guidance is expected to replace several EFSA guidance documents related to the same subject (e.g. Compatibility of zootechnical microbial additives with other additives showing antimicrobial activity, Microbial Studies, Assessment of bacterial susceptibility to antimicrobials of human and veterinary importance, Bacillus spp. safety, Enterococcus faecium safety). An important modification to be introduced is the requirement of using whole genome sequence analysis (WGS) for the characterisation of bacterial and yeast strains, as well as for the search of antimicrobial resistance (AMR). Consequently, Pen & Tec asked EFSA to specify its preferred databases for comparison of commonly used sequences, and its preferred method for taxonomic identification (e.g. 16S rRNA gene or house-keeping genes). At the same time, Pen & Tec suggested replacing the full WGS analysis request by a step-wise approach, where a previous investigation of minimum inhibitory concentrations (MICs) would determine the need of a WGS analysis (only if MIC > cut-off value for one or more antimicrobials, further investigation via WGS to determine the nature of the resistance would be required). EFSA has also been asked to indicate in the guidance if there are sufficient grounds not to provide the WGS. EFSA expects to discuss these comments and possibly adopt the guidance during the next FEEDAP meeting. Pen & Tec’s input on the guidance documents support the use of the “3Rs” for animal welfare. We are also in favour of adopting a pragmatic and more universal approach to data collection in order to keep the application process within reasonable time frames, maintaining the quality of the data provided for EFSA assessment, and rationally conveying information sources and procedures accepted by other important feed regulatory bodies worldwide.

Dr Hannah Lester A research scientist with over 10 years’ experience in running veterinary clinical trials for regulatory approval. She has a PhD in parasite epidemiology and an MSc in Veterinary Public Health. Hannah has managed Contract Research Organisations in the UK, and has also worked for government, providing veterinary policy advice. Email: hannah@pentec-consulting.eu

Rocío Duchén Bocángel An analytical chemist. She holds a Degree in Chemistry and a Master Degree in Forensic Chemistry, as well as a Master Degree in Translation Studies (scientific/technical translation from English to Spanish). Rocío has worked in research and has also collaborated as a specialist consultant in the food industry. Email: rocio@pentec-consulting.eu

International Animal Health Journal 45


FOOD & FEED

The Potential of Feed Additives in Reducing Antibiotic Usage Over the last years, feed additives that support gut health have gained special attention from animal producers worldwide. Especially during the last decade, in many regions interest has been further nourished by regulatory ambitions to restrict the use of antibiotics, either as antimicrobial growth promoter (AGP) or as veterinary drugs. Attention should be given to the similarities and differences between the gut health promoting feed additives and antibiotics, if we want to understand the potential of these additives to reduce antimicrobial usage. Microorganisms, such as bacteria, fungi and parasites, can develop resistance against antimicrobial substances, such as antibiotics, antifungals and anthelminthics. As a result, these antimicrobial substances become ineffective in limiting the growth of resistant microorganisms. The occurrence of antimicrobial resistance (AMR) is not a new phenomenon; in fact, it is a natural selection process that has been going on for billions of years. In recent years, however, microorganisms have been isolated that have developed AMR against a wide range of medically important drugs. As such, these ‘superbugs’ have become an increasing threat to human healthcare. Antimicrobial Resistance and Feed Additives The misuse and overuse of antimicrobials is accelerating this process. While it is recognised that the human use of antibiotics is the largest contributor to AMR in human pathogens, the over-use in intensively-produced farm animals is now believed to play a considerable role in this global problem as well. For this reason, governmental administrations and food animal producing organisations worldwide are looking into the possibility of reducing antimicrobial use, either as veterinary drug or as antimicrobial growth promoter (AGP), in animal production. In this context, special attention is given to several strategies aiming to minimise the need to apply antibiotics to food animals, such as an increased focus on veterinary support, biosecurity measures, production management and nutritional interventions like the use of functional feed additives. Indeed, certain feed additives can have a beneficial effect on gut health in animals, and can mitigate the damage caused by intestinal pathogens, thereby reducing the need to routinely use veterinary drugs applied to tackle enteric infections. In addition, gut health will stimulate animal performance in general, and additives that strengthen the digestive tract can therefore be employed as part of a strategy replacing AGPs. Gut Health Additives and Antibiotics: Similarities and Differences However, in order to correctly evaluate the potential of gut health promoting additives as alternatives to antibiotics, it should be pointed out that the characteristics of both groups of active molecules are very different, which has consequences to their proper application. Often, when animal producers are faced with the need or the wish to reduce AGP supplementation for the first time, they are 46 International Animal Health Journal

looking for ways to remove the antibiotics in the feed, just to replace them by other active ingredients which they hope will have the same effect. Similarly, some producers who want to minimise veterinary interventions, might try to apply feed additives as a way to cure an upcoming disease, expecting they will act in similar ways as drug. These approaches, however, deny the fact that additives have a different mode of action compared to AGPs/antibiotics, and that knowledge of these mechanisms is needed to correctly use those additives, as well as to have realistic expectations on their potential. To illustrate this, in Figure 1, some of the modes of action of AGPs and gut health promoting feed additives are listed. Both classes of compounds can be said to have the same goal: improving intestinal health and function, thereby increasing animal performance. AGPs are hypothesised to do so by directly affecting the intestinal microbiota, and perhaps by having anti-inflammatory properties. The additives, on the other hand, can have different working mechanisms; typically, some of them are overlapping with those of AGPs, while others are distinctive. Some coated butyrate products, for instance, will have a direct or indirect effect on intestinal microbial species (see below), but often without directly killing them, or inhibiting their growth, as antibiotics do. Butyrate has also strong anti-inflammatory properties, while it also has the potential to trigger several physiological pathways, when it is delivered throughout the entire intestinal tract by means of a coating that sets butyrate free gradually after ingestion (ADIMIX®Precision, a Precision Delivery Coated Butyrate, PDCB). Intestinallydelivered butyrate can trigger signalling pathways which are not (or less) activated by antibiotics: for instance, it can fortify the epithelial lining of the digestive tract, it can increase the secretion of digestive fluids, and it might be used by other organs, such as the liver, as energy source and as modulator of metabolic and detoxification processes.

Figure 1: AGPʹs and gut health promoting feed additives have modes of action that are partially similar, and partially different

The fact that AGPs and PDCB have underlying modes of action that are partially similar and partially distinct, means that PDCB can be used to reduce dependency on AGPs: both products can be used in combination with each other, or, when the use of AGPs is forbidden or needs to be restricted, PDCB will be needed to fill this void, for example by mitigating the effect of pathogenic intestinal bacteria, albeit via a different route. Volume 4 Issue 4


FOOD & FEED Below, some examples are given on how researching different application of PDCB can shed light on how this product can be employed to support animal health and production in a production context where less antibiotics are used. Mitigating the Effects of Necrotic Enteritis Necrotic enteritis (NE) is an important enteric disease in poultry, caused by the overgrowth of certain Clostridium perfringens strains, which evokes intestinal tissue damage. In its acute clinical form, the disease is characterised by a sudden increase in flock mortality, and gross lesions that are usually, but not always, restricted to the small intestine. In the sub-clinical form, no peak mortality is observed, but intestinal damage will lead to decreased nutrient digestion and absorption, thereby negatively affecting performance parameters such as growth-rate and feed conversion ratio. Especially since the ban of antibiotic growth promoters (AGPs), the increased incidence of this sub-clinical form is estimated to have a substantial impact on animal welfare and on the profitability of poultry production. In a model for necrotic enteritis in broilers, 800 broilers were allocated to four treatment groups in a 2x2 factorial design: birds were supplemented with PDCB or not, and were either orally infected with a NE-associated C. perfringens strain right after IBD-vaccination (day 14), or were left unchallenged. After 35 days, birds that were infected with C. perfringens were significantly lighter than the control group, while their FCR was numerically higher1. In the challenged group, PDCB-fed birds outperformed the control group, with zootechnical characteristics comparable to those of the unchallenged birds. Importantly, also in unchallenged birds, supplementing feed with PDCB resulted in a significant increase in final weight and a reduction of FCR.

downregulate genes in Salmonella that are important for epithelial invasion and colonisation3. To have any significant effect in vivo, butyrate therefore needs to be delivered in the animal hindgut, where Salmonella resides. As butyrate is a small molecule that is readily absorbed in the first part of the digestive tract, this means that the gastric bypass and intestinal delivery characteristics of PDCB are critical to exert any anti-Salmonella effect inside the animal2. Likewise, butyrate has been shown to protect intestinal cell from Campylobacter invasion and translocation in vitro4. Recently, an extensive in vivo study was set up, in which broilers were orally infected with Campylobacter jejuni and were fed one of 24 feed additives, including (monoglycerides of) short- and medium-chain fatty acids and phytogenic substances (Fig. 3)5,6. Strikingly, the compounds that could have been predicted to be most efficacious based on their antimicrobial properties in vitro (monoglycerides of short/medium-chain fatty acids and essential oil components), weren’t the groups that outperformed the others in the in vivo test. In fact, only two treatments were linked to a significant reduction in mean caeca Campylobacter counts at all sampling moments: a PDCB, included at 3 kg/T, and only one out of the seven monoglyceride treatments tested, included at 8 kg/T. These results suggest that when evaluating effective feed additives to be used in a production programme where the use of antibiotics is minimised, it is imperative to look beyond direct antimicrobial effects. Similarly, it should be clear that gut health feed additives

Interestingly, supplementing challenged birds with PDCB had limited effects on the enumeration of Clostridium perfringens in the intestinal tract. However, PDCB-treatment birds had lower necrotic lesion scores (Figure 2). These results are in line with the hypothesis that PDCB doesn’t have a direct bacteriostatic effect against Clostridium, but that it prevents or repairs intestinal epithelial damage, thereby limiting nutrient loss and inflammation and, as such, restricting conditions that would favour the intestinal overgrowth of Clostridium in later life stages.

Figure 3: Overview of caecal Campylobacter reduction result in a study evaluating the effect of 24 feed additives

Figure 2: Lesion score in NE-challenged birds

Restricting Hindgut Colonisation of Salmonella and Campylobacter Similarly, PDCB can restrict the colonisation of Campylobacter and Salmonella in the intestinal tract of production animals2. This effect is most likely not the result of a direct bacteriostatic effect of butyrate on Salmonella in the digestive tract. Rather, butyrate is documented to www.animalhealthmedia.com

cannot be used as an antibiotic drug to be applied in the final production stage, to eradicate zoonotic pathogens just before the animals are slaughtered. This is demonstrated by an experiment, where the effect of PDCB on caecal Campylobacter colonisation was evaluated in more detail. Zero or three kg/T of PDCB was added to several feeds of broilers infected with Campylobacter jejuni in the growing stage (Figure 4). When PDCB was added to all feeds, or from the moment onwards that birds were orally infected, caecal Campylobacter loads were significantly reduced compared to birds from the control treatment. However, inclusion of PDCB in only the starter feed and/or the finisher feed had a less profound impact on caecal Campylobacter counts. These results demonstrate that PDCB, in addition to its effects on animal performance, can be of value in a programme reducing zoonotic pathogens, but that it is not a ‘quick fix’ to be applied during the end of production, exerting a specific antibacterial effect. International Animal Health Journal 47


FOOD & FEED

Figure 4: Mean Campylobacter counts (day 39) in caeca from infected broilers supplemented with 0 or 3 kg/T PDCB in the starter-grower-finisher diets

Conclusion In conclusion, antibiotics, whether applied as drugs or AGPs, most likely exert a specific and direct effect on enteric bacteria. The downside of this approach is that bacteria can build up resistance against certain drugs, jeopardising future treatment of humans and animals with antibiotics. Functional feed additives such as PDCB, on the other hand, do not cure acute bacterial challenges, but prepare the gastrointestinal tract of animals as well as possible to overcome negative consequences of certain diseases in a later life stage. As many of the effects of feed additives on bacteria are indirect, or modulate their virulence pathways, rather than having a specific bacteriostatic effect, the chances of building up resistance against these components is much less likely to happen. As such, feed additives can be a safer way of raising animals without AGPs, while they can also optimise intestinal integrity, thereby helping in reducing the need for veterinary application of antibiotics. These examples also demonstrate that additives can never be a ‘quick-fix’, as replacer of antibiotics without careful consideration as to how the application of these products should be implemented in a production context that acknowledges that reducing dependency on antibiotics requires a multifaceted management approach. REFERENCES 1.

Awaad, M., et al., The Efficacy of Na-Butyrate Encapsulated in Palm Fat on Experimentally Induced Necrotic Enteritis and Enumeration of intestinal resident Clostridium perfringens in Broiler Chickens. IOSR Journal of Agriculture and Veterinary Science, 2014. 7(1): p. 40-44. 2. Van Immerseel, F., et al., Supplementation of coated butyric acid in the feed reduces colonization and shedding of Salmonella in poultry. Poultry science, 2005. 84(12): p. 1851-6. 3. Gantois, I., et al., Butyrate specifically down-regulates salmonella pathogenicity island 1 gene expression. Applied and environmental microbiology, 2006. 72(1): p. 946-9. 4. Van Deun, K., et al., Butyrate protects Caco-2 cells from Campylobacter jejuni invasion and translocation. The British journal of nutrition, 2008. 100(3): p. 480-4. 5. Gracia, M.I., et al., Efficacy of feed additives against Campylobacter in live broilers during the entire rearing period: Part B. Poultry science, 2015. 95(4): p. 886-92. 6. Guyard-Nicodeme, M., et al., Efficacy of feed additives against Campylobacter in live broilers during the entire rearing period. Poultry science, 2015. 95(2): p. 298-305. 48 International Animal Health Journal

Tim Goossens He studied biotechnology at Ghent University, and subsequently worked as a researcher in the Laboratory of Molecular Biotechnology at the University of Antwerp. Subsequently, he moved to the KU Leuven, where he obtained a PhD in Biomedical Sciences. He joined Nutriad to work as an R&D Engineer, and later as a Business Development Manager. He focuses on the technical and commercial development of feed additives supporting gut health and animal performance in production animals. Email: t.goossens@nutriad.com

Daniel Ramírez He received degrees in veterinary medicine and animal production in the UAM and UNAM universities in Mexico, and completed an MBA at the Porto Business School in Portugal. He has several years of experience as a veterinary expert in research programmes and as a senior commercial manager in the feed industry. In 2016, he joined Nutriad to team up with Tim Goossens in supporting the Digestive Performance portfolio. Email: d.ramirez@nutriad.com

Volume 4 Issue 4


Driving quality and integrity in scientific research and development We continue to meet the needs of our members by: • Promoting quality standards in scientific research and development • Facilitating knowledge sharing through events, publications and networking

As a not-for-profit association we have around 2,300 members of which 44% are based outside of the United Kingdom and located in 58 countries worldwide, with many of our members working in an international environment and to international standards.

• Liaising with regulatory agencies in the development and interpretation of regulations and guidance • Offering professional development opportunities • Working in partnership/ cooperation with other organisations. Our membership caters for professionals including managers, scientists, auditors, inspectors and practitioners concerned with the quality and compliance of research and development. Our members focus on the safety and efficacy of pharmaceuticals, biologicals, medical devices, agrochemicals and chemicals in man, animals and the environment. More information on all of our first class services and products can be viewed on our website.

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T: +44 (0)1473 221411 E: rqa@therqa.com International Animal Health Journal 49


FOOD & FEED

Helping Animal Health Companies Succeed

Serving both companion and production animals, Canada’s animal health sector has developed an enviable reputation in a number of areas, including: • • •

• • •

food animal therapeutics, vaccines and productivity aids; companion animal therapeutics and vaccines; wellness products and services for the companion animal market, including natural health products, diagnostics, pet food and nutrition; aquaculture products targeted mainly for use in disease treatment and prevention; diagnostic products to more effectively detect disease at an earlier stage to allow for faster, more effective interventions; and veterinary and animal production apps, big data and cloud-based computing to more effectively and efficiently raise animals.

Key strengths of the Canadian sector include abundant resources, particularly water, to support food animal production; good infrastructure, including transportation networks; a stable and predictable regulatory regime; strong patent protection laws for new discovery; a highly competent veterinary profession; world-class research facilities and researchers; and public granting agencies that financially support innovative ideas and new products. Within Canada, one of the foremost animal health clusters is to be found in Prince Edward Island. With a focus on animal health companies, natural product development, and aquaculture, this cluster boasts more than 50 companies and over 1500 employees. Under the leadership of the Prince Edward Island (PEI) BioAlliance Inc., this eastern Canadian cluster spawned the International VetHealth Global Conference. Held once every other year, this event attracts global leaders of major animal health companies to discuss opportunities and matters of common concern. This conference also offers a venue to showcase up-andcoming animal health startups, and provides a forum for these ventures to discuss potential partnerships with the major global players. Not coincidentally, Prince Edward Island is also home of the Emergence Bioscience Business Incubator, an initiative that offers strong support to startup and scale-up companies in the animal health sector across Canada.

located in Canada, while also providing a “soft landing” for innovative international animal health ventures seeking to start up or establish themselves in, or expand into, North America. One of its clients is Aim OA Sys - a UK startup that has developed a new, cloud-based electronic decision-making tool for managing canine arthritis. This revolutionary new system enables veterinary practices to create effective, individualised multimodal plans for each patient. The digitised process is based on the Aim OA system, which has been developed and used in arthritis management for over 15 years by some of the world’s leading authorities in canine arthritis. The system also records interventions and monitors outputs. AIM OA is in the process of setting up operations in Prince Edward Island with a view to managing its North American market entry from what locals fondly refer to as “the mighty island”! The company is also seeking to leverage the expertise at the Atlantic Veterinary College at the University of Prince Edward Island in Charlottetown as a source of talent for the business and for its network of veterinarians across North America. Animal Ethics is another Emergence client - an Australian research and development company specialising in the development of wound care and pain relief products for humans, livestock, and companion animals. Animal Ethics was the first company, globally, to have a topical pain relief product registered for use on farm animals. Their vision is that highly effective, safe, affordable and practical pain relief products are developed and made widely available to prevent pain and minimise suffering associated with surgical husbandry procedures and traumatic wounds in humans, livestock and companion animals. Animal Ethics projects a market potential of $412 million for their first product, Tri-Solfen, a  pain product which recently gained approval in New Zealand for sheep and cattle husbandry procedures. In 2016, Animal Ethics received an $18.2 million investment from UK-listed Dechra Pharmaceuticals PLC, which has acquired a global license to sell Tri-Solfen internationally. The company is working towards a US and Canadian registration by mid-2019. Both companies have benefitted from the soft-landing and market entry services that Emergence offers to international ventures.

Under the BioAlliance umbrella, Emergence is just three years old, but has already secured a reputation as one of the country’s leading enablers of new company formation and growth in the animal health sector. Emergence currently serves a portfolio of 67 mostly startup and early-stage client companies, which between them raised over $48 million in follow-on funding over the last year, racked up revenues of $29 million, and grew their full-time employment by 75%. A virtual (rather than physical) incubator, Emergence serves high-potential companies wherever they are 50 International Animal Health Journal

Volume 4 Issue 4


FOOD & FEED Building on the traditional strengths of the PEI Bioscience Cluster and its expertise in the animal health space, Emergence provides programming that supports the commercialisation of innovative animal health technologies; the formation and growth of disruptive animal health companies; and the development of new entrepreneurs. The incubator’s primary focus is on assisting Canadian entrepreneurs, startups, and growth stage ventures to develop and commercialise products and services for the global market; improve their export preparedness and readiness; improve their international market access; de-risk their developmental, regulatory and investment pathways; advance their business plans; and acquire follow-on financing by improving their investmentreadiness. The Emergence model is based on long-term relationships, and provides clients with access to the knowledge and resources they need to grow. The Emergence team understands that growing successful innovation-based businesses is a complex process. With each phase of development, entrepreneurs are faced with new challenges. Emergence is therefore not a cohortbased programme, but offers a continuous intake model and programming designed to provide clients with the long-term support they need to respond to their dynamic and demanding environments. As such, Emergence client companies enjoy access to a range of customised development services. Chief among these is mentorship – both one-on-one and team mentorship. Through this pillar, entrepreneurs are allocated business advisors, who provide regular feedback and guidance on issues related to the viability of their idea, regulatory requirements, the best route to commercial success, and capital formation strategy advice and contacts. With an enviable team of world-class mentors drawn from across Canada and the United States, the Emergence incubator also provides clients access to their “Critical Path Team Mentorship” programme, which benefits from the many years of experience and learning of the programme’s mentorship partner, the MIT Venture Mentoring Service. This business advice is designed to help entrepreneurs de-risk their ventures, improve their investor-readiness, and successfully navigate the challenges of bringing their new products and services to the global market. The Emergence team mentorship programme matches entrepreneurs in this sector with experienced volunteer mentors and, when necessary, ad hoc specialist mentors. The programme matches founders with groups of three to five mentors who provide practical, day-to-day professional advice and business coaching. Mentorship support is given across a broad range of business activity, including product development, regulatory, marketing, intellectual property, finance, human resources, and founders’ issues. The Critical Path Team Mentorship programme is a flagship programme of the incubator, and is offered selectively to clients on a highgrowth trajectory. Currently, a full 50% of the ventures in the team mentorship programme have female founders and co-founders. Lisa Pfister, a recent engineering graduate from New Brunswick, Canada has launched her startup, Pfera, with www.animalhealthmedia.com

the goal of making equine reproduction management easier, cheaper and healthier for the horses. Lisa says she’s benefitted from the in-depth mentorship she has received. Lisa’s first product – a biotech chemistry plus IT solution that allows breeders to more accurately predict birthing in mares – was born from her personal need as a horsebreeder. Today, her patent-pending product includes technology that interprets milk analysis of mares and reduces the variability of results from 61% down to 3–7%. This kind of accuracy means that breeders will no longer need to monitor their mares for up to six weeks around estimated birthing time. Pfera’s technology will predict birthing time up to four days in advance, within an eight-hour window. But Pfister isn’t stopping with just one product. She’s already moving onto more innovative applications for the equine industry, including technology to improve breeding management records and create graphical information for breeders and veterinarians. This kind of technology doesn’t currently exist and will be extremely helpful in monitoring the reproductive health of mares. “I am so grateful for the support I have received through Emergence,” Lisa says. “Technical skills are one thing, but the challenges of being a new entrepreneur, bringing a new product to the market, have proven to be much more challenging. I have been helped in my journey by the fantastic mentorship and coaching I have received, as well as by the many other services that I have been able to take advantage of as a client of Emergence.” In addition to mentorship, incubator clients are able to benefit from a pool of funds that support what are called Specialist Services Projects. This pillar of the incubator cofunds, alongside the client, defined projects that are critical to the company progressing along its “critical path” of commercialisation. For Specialist Services projects, an expert is engaged to provide third-party consulting and strategic advisory services and guidance to supplement the client company’s internal skills and build their internal competencies. Projects focus on providing clients with the additional support they require to develop their business plans and product prototypes, gain a better understanding of their regulatory pathways, access follow-on funding, and develop marketing and sales strategies. Both Pfera and SomaDetect, also from the province of New Brunswick, have received support from Emergence to complete their product development and move to working prototypes. SomaDetect has developed an innovative herd health solution for the global dairy industry, which involves new advanced technology that detects the presence of progesterone, protein, fat, trace antibiotics and somatic cell counts in raw milk without the need for reagents or consumables. Using this technology, farmers will be able to monitor the reproductive status and health of their herd, and ensure high-quality milk for consumers. SomaDetect has enjoyed a year of remarkable success, from being announced as one of the “top 20 most innovative companies in Canada”, to being selected as one of “22 transformative early-stage companies” selected to participate in the 2017 Ag Innovation Showcase in St Louis, Missouri, where they captured the prize for “best pitch”, to walking away with the US$1 million first prize at the 43North competition in Buffalo, New York. International Animal Health Journal 51


FOOD & FEED

Drawing on the full resources of Emergence, SomaDetect has seen their first year in business catapult them into the international spotlight. “Working with an incubator programme like Emergence has enabled us to draw upon the expertise and valuable mentorship of others who have been there and done that,” says SomaDetect Founder, Bethany Deshpande. “This has been crucial to keeping us focused on the issues important to our commercialisation ‘critical path’, while access to funding when we needed it most helped us to optimise the development of our prototype, and accelerate our path to market.” Clients of Emergence also take advantage of the programme’s Market Intelligence Service. This provides access to critical market intelligence to help move businesses forward. Through a partnership with the MaRS Accelerator in Toronto, Emergence clients have ready access to thousands of reports covering key technology clusters from global research firms such as Frost & Sullivan, GlobalData, Bloomberg New Energy Finance and Lux Research. MicroSintesis Inc. is a startup company that has taken advantage of this service. A new animal health company that has, for the past five years, been researching a novel probiotic technology which has the potential to significantly impact the way animals are treated for gut health and intestinal distress, MicroSintesis is creating a platform of novel anti-infectives from probiotics. The company operates a research and development lab as well as scaleup manufacturing in PEI, and recently signed an exclusive distribution agreement with a Canadian veterinary distributor to distribute their first product. By taking advantage of the Market Intelligence Service, MicroSintesis was able to access top-tier research reports as well as expert analysts with industry knowledge of the animal health sector. This helped founder Hannah McIver address questions about market segmentation, size of market, growth rates, types of business models, purchasing habits, demographic data, customer segmentations, and industry trends, all of which she was able to use to prepare investor presentations, develop a launch strategy, and investigate international market entry. “For a cash-starved startup, this service was incredibly valuable,” says McIver, who also credits the incubator with providing strategic- and operational-level input to her venture at a time when she needed it most. In addition to accessing in-house expertise, Emergence clients enjoy access to legal, financial, risk mitigation and 52 International Animal Health Journal

intellectual property advisory services through partnerships with top-tier professional service providers. “Emergence provided us direct access to some of the best legal and tax advice available,” says AIM OA’s David Prydie. “This is so important for a young company like ours that is taking its first steps into new markets.” Programme participants also benefit from facilitated access and linkages to international business networks; are able to tap into support with their media, public relations and social media campaigns; and get assistance hiring the world-class talent they need to grow through the incubator. By offering entrepreneurs the tools, connections, training, education, coaching, mentorship, and professional expertise and services they need to succeed, Emergence is supporting the growth of some of Canada’s most innovative animal health startups. Based on the programme’s impact metrics to date, Emergence is already having a significant impact on the successful formation, commercialisation, funding, and export- and investment-readiness of animal health companies across Canada.

Martin Yuill He serves as Director of Incubation Services at the PEI BioAlliance Inc. and as Director of the Emergence Bioscience Business Incubator, a role he has held since February 2016. During this time, the Emergence program has more than tripled in size and attracted client companies from across Canada and internationally. He has a track record of success building innovation clusters, developing entrepreneurial ecosystems, growing angel investment networks, and launching business incubation initiatives. Web: www.emergencebioincubator.com

Volume 4 Issue 4


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International Animal Health Journal 53


LIVESTOCK

Giving Your Herd the Best Chance for Successful Fertility

Achieving high levels of reproductive performance will be a major key performance indicator on most dairy farms this winter. David Wilde, Ruminant Technical Manager with Anpario, considers some nutritional factors which could have an impact on success. “The reasons why dairy cows do not get in-calf are numerous and complex,” Mr Wilde comments. “In most cases, infertility will be a multifactorial issue rather than one single problem. Genetics, semen quality, management, feeding, housing, stress and heat detection will all have an influence.” “Repeat oestrus cycles are not just due to a cow not conceiving. In many cases there may have been successful fertilisation of the egg and initial implantation of the embryo before this fails, leading to a new cycle. It is not unusual for there to be plenty of bulling activity but a lot of repeats.” Mr Wilde, a qualified Cow Signals Master Trainer, says it is important to consider the basic physiology, commenting that the average signs of oestrus last for just 8 hours with an average of just one standing event per hour. He says ideally insemination needs to take place about 12 hours after the first standing event with ovulation 24–28 hours after the first standing event. “This early insemination allows the sperm to ‘get in to place’ and there is evidence that they form a reservoir in the oviduct. They can survive quite happily for 3–4 days, waiting for the egg to arrive before fertilisation.” He says nutrition can have a direct impact on the fine balance within the cow, which can determine the success of an insemination. “There is a common belief that high-yielding cows are less fertile than low-yielding cows and there is a grain of truth in this, relating to the hormone status of the cow and the roles of progesterone and prostaglandin. After ovulation, the corpus luteum produces progesterone to maintain everything for implantation. High levels of progesterone also serve to provide a barrier to the next wave of eggs being produced for the next oestrus cycle, assuming the current one is not fertilised or fails to implant.” After fertilisation there is a window of just 14–16 days in which implantation can occur. Mr Wilde says once the embryo successfully implants, it releases another hormone – interferon-tau – that signals to the cow that the embryo is there and she needs to look after it. “Sadly, it takes the developing embryo around 8-13 days to become big enough to produce this signal meaning this can coincide with the uterus now thinking that pregnancy has not happened, leading to it producing prostaglandin (PGF2α). This hormone suppresses the progesterone and terminates that specific cycle, allowing a fresh oestrus cycle to start. PGF2α is a powerful hormone and if the interferontau from the embryo is not strong enough, it will override it and the pregnancy will terminate.” “High-yielding cows have a much higher flow of blood, resulting in a faster clearance of progesterone via the liver and consequently lower circulating levels. Less 54 International Animal Health Journal

progesterone means the PGF2α is more likely to suppress the cycle. Reduced progesterone concentrations also mean that eggs that do ovulate will tend to be smaller and poorer quality.” Mr Wilde says one management approach is to suppress the production of PGF2α by feeding long-chain omega 3 fatty acids, either linolenic acid (from linseed oil) or EPA and DHA from fish oils. Work at the University of Florida demonstrated that while linolenic acid could reduce the PGF2α secretion by about 22%, EPA and DHA from fish oils are far more effective, reducing it by around 60%. He says adding these fats could help in the establishment and maintenance of early pregnancy. “Many forages and feed ingredients are naturally low in omega 3s so it can be beneficial to add a supplement high in these fatty acids, such as Optomega, which is a rich source of DHA and EPA, the most biologically active omega 3 fatty acids.” Mr Wilde also advises paying close attention to dietary protein levels, commenting it is well documented that feeding excess amounts of soluble protein can reduce conception rates. He says many diets are formulated with an incorrect balance of protein seen as excess nitrogendependent metabolisable protein (MPN) values in rations, or too much rumen digestible protein (RDP). This could be a particular challenge with many grass silages being higher in protein than usual, which will contribute to high MPN levels. “The rumen microbes are unable to effectively capture the soluble nitrogen, leading to the excesses being converted to ammonia in the rumen and absorbed directly into the bloodstream. Raised blood ammonia levels have the undesirable effect of altering the uterine pH which in turn reduces the chance of successful implantation of the embryo.” “It is important to monitor potential problems and milk urea is a useful tool. The problem is that milk urea results are for the whole herd, not the cow you are trying to get in calf. However, keep an eye on milk urea levels and take action if they creep above 300mg/l. If possible, look to reduce overall crude protein levels but at the same time, improve the supply of by-pass proteins to ensure the supply of useable, metabolisable protein meets requirements.” In conclusion, carefully monitoring the nutritional intake of a herd can have a significant impact on overall health and the subsequent fertility. Simply supplementing the herd’s diet with fatty acids can make a big difference to the profit and loss. Increased consumption of fatty acids such as DHA and EPA means increased fertility, resulting in increased profits. Averebes mei se parbit. Entem nesu quam

David Wilde Technical Product Manager – Ruminants Telephone: +44 (0) 7793 835173 Email: david.wilde@anpario.com

Volume 4 Issue 4


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LIVESTOCK

Towards an Enabling Regulatory Environment for Livestock Health

The World Bank Group (WBG) has initiated a flagship programme called “Enabling the Business of Agriculture” (EBA) that examines and monitors regulations impacting agriculture and agribusiness around the world. Earlier this year, the EBA released its third report, covering 12 topic areas across 62 countries.1 The livestock chapter within the EBA2017 report focused on select regulations affecting the market supply of veterinary medicinal products (VMPs). This paper describes the issues covered by the EBA Livestock topic, discusses the importance of good regulations to encourage the registration of quality assured products, and provides a snapshot of initial results of data collection efforts for the regulation of VMPs. Animal Health Risk and Access to VMPs Animal health management has important implications for poverty reduction and economic growth. Infectious diseases cause at least 20% of all livestock production losses globally.3 Livestock production accounts for around 40% of agricultural output in the developing world.2 Approximately one in every five people (including the extreme poor) depends on the livestock sector as a primary source of income.3 Livestock infectious diseases therefore pose a significant risk to economic gains and livelihoods. Animal diseases also generate health costs at the human-animal-environment interface, including reductions in food safety, food security, and maternal and child health. The top 13 zoonotic diseases (transmitted between animals and humans) account for over a billion human cases and a million deaths annually.4 Animal diseases may also affect biodiversity by changing wildlife population dynamics for the infected animal groups, as well as for other organisms and species in shared ecosystems.5 Access to veterinary medicinal products (VMPs) is a key factor in mitigating the risks associated with animal diseases. In many countries, especially in the developing world, access to safe, quality and effective VMPs remains low. While a diversified mix of large companies, small- and medium-sized enterprises (SMEs), breeders’ organisations, and veterinarians work to supply VMPs to livestock producers, large companies constitute the biggest market share of VMP manufacturing. Given that most VMP manufacturing facilities are established and owned by companies located in Europe, the USA, and China, countries outside of these

Figure 1 56 International Animal Health Journal

regions rely heavily on VMP imports for market supply. Figure 1 depicts the average annual value of imported veterinary biologicals (one of two sub-categories of VMPs) in each country between 2010 and 2014. Least developed countries account for only 2.7% of total imports, despite representing a greater share of global livestock production and the animal disease burden. Access to VMPs alone is insufficient to reduce animal health risks; quality matters. Counterfeit VMPs are also major threats to animal health and disease controls in some countries. According to the International Institute of Research Against Counterfeit Medicines (IRACM), more than 50% of veterinary medicines marketed in Africa are fake.6 Moreover, if used improperly, VMPs — even if efficacious — may have limited effect or even lead to adverse health outcomes. The Importance of a Regulatory Framework The regulatory environment can enable access to safe, quality and effective VMPs by encouraging (and not hindering) product registration and effectively enforcing standards and quality control processes along the entire supply chain from manufacture, registration, import, distribution, sale and administration. Given the importance of the private sector at all points along the VMP supply chain, it is important that regulations are streamlined and efficient in order not to discourage suppliers from entering and operating in markets, particularly in countries with agro-based economies. The relationship between regulation and market supply for VMPs is neither abstract nor theoretical. Figure 2 depicts the impact of the introduction of regulations on market entry and circulation of VMPs in four countries (Nigeria, Nicaragua, Tanzania and Vietnam); these countries have historically been net importers of VMPs (Table 1) over the period of 1996 to 2015. In each panel of Figure 2, values of veterinary vaccine imports are plotted from 1996 to 2015. The vertical solid bars represent the year in which a key regulatory document impacting import decisions was enacted in the country. The two dotted lines in each panel of the Figure depict the linear trend in imports prior to and after a key regulatory document was enacted. As illustrated, the trend line following the introduction of the regulatory document lies above the pre-legislation trend in each country, suggesting that imports increased following the introduction of new or reformed regulations.

Table 1: Average Annual Trade in Veterinary Vaccines (1996–2015) Volume 4 Issue 4


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International Animal Health Journal 57


LIVESTOCK Tanzania $3,500,000

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Post-Legislation Trend

$2,500,000

Post-Legislation Trend

$2,500,000 $2,000,000 $1,500,000 $1,000,000

Pre-Legislation Trend

Pre-Legislation Trend

$500,000

$500,000

$0

$0

Nigeria $7,000,000

Vietnam $80,000,000

National Agency for Food and Drug Administration and Control Act

$70,000,000

$6,000,000 $5,000,000

Post-Legislation Trend

$4,000,000 $3,000,000 $2,000,000

$1,000,000

Pre-Legislation Trend

Labeling Rules for Veterinary Medicines

Post-Legislation Trend

$60,000,000

Veterinary Vaccine Imports (US$)

Veterinary Vaccine Imports (US$)

Technical Regulation of Central America

$3,000,000

$3,000,000

$50,000,000

$40,000,000 $30,000,000 $20,000,000

Pre-Legislation Trend

$10,000,000

$0

$0

Figure 2

The Enabling the Business of Agriculture (EBA) Project The World Bank Group “Enabling the Business of Agriculture” (EBA) project collects data on regulations influencing the agriculture sector in an effort to encourage an enabling environment for agribusiness. The EBA 2017 report covers 12 topics across 62 geographies and presents globally comparable data and indicators that measures legal barriers faced specifically by agribusinesses to enter and operate in markets. Two types of indicators are developed by the EBA project: legal indicators and efficiency indicators. Legal indicators are derived from the reading of relevant laws and regulations. Efficiency indicators reflect the time and cost imposed by regulatory systems on private sector entities in adhering to the regulatory framework in countries. Data and indicators provided by the EBA project can be used by governments, large companies, small and medium enterprises, investors, researchers and others interested in information provided by the project. For example, policymakers within governments can utilise EBA data to identify barriers that impede the growth of the agriculture sector in their respective countries, compare themselves with other countries and to make informed decisions on reform. In the EBA 2017 survey and subsequent report, the focus of the livestock chapter is on VMPs specifically, with a sub-categorisation into veterinary biologicals and pharmaceuticals. The topic assesses regulations impacting the private sector’s ability to supply safe, quality and effective VMPs. The topic covers three major regulatory areas affecting VMPs: 1. VMP registration, 2. authorisation of importers, and 3. marketing requirements. Within each of these regulatory areas, a set of “global good practices” (Table 2) is identified that should be part of a country’s regulatory framework. 1. VMP Registration To ensure that VMPs conform to safety and other standards, most countries require that registration (or marketing authorisation) via an official registration process is obtained 58 International Animal Health Journal

before a VMP can be placed on the market. Though necessary, the product registration system can be prone to bottlenecks. As a result, private sector entities seeking to register VMPs may face unnecessary burdens, such as the time and costs associated with adhering to regulations. The absence of a good registration mechanism acts as a disincentive to market entry using officially mandated channels. In addition, lack of formal requirements gives rise to concerns regarding proprietary rights and counterfeit products flooding the market. Data is collected on the structure and efficiency of regulatory institutions to measure these costs. For example, all else equal, having to compile and submit dossiers to multiple regulatory authorities throughout the registration process can result in duplicative efforts for the applicant (and the regulatory authorities). Data is also collected on specific procedures required of applicants during the registration process. Unnecessary or ill-defined requirements for the registration process can create backlogs and delay market access for valuable products. Moreover, poor security of applicants’ confidential information and intellectual property can lead to discovery of product formulation and other trade secrets by competitors discouraging the use of official registration processes. Finally, data is collected on the existence of a registry of authorised VMPs. The extent to which veterinarians and livestock producers use quality VMPs depends in large part on their awareness regarding product availability and the ability to confirm a product is legally authorised. The existence of a list has legal consequences as, in most countries, only approved products are allowed to enter the market. 2. Authorisation of Importers Import permits and import licenses are two of the most Volume 4 Issue 4


LIVESTOCK widely used regulatory instruments to manage the import of VMPs. Import permits are a tool to provide tighter control on VMPs entering the country. These permits require that importers obtain authorisation for each shipment or consignment of products being imported into a country. Import licences, on the other hand, are a tool to provide tighter control on the entities importing VMPs. Licensing refers to the formal authorisation of legal business entities engaging in (or seeking to engage in) the importing of VMPs. Import licensing is used to keep track of importers and to ensure that importers have the required credentials and facilities to handle VMPs. To assess the impact of regulations on import, the EBA 2017 Livestock survey collects data on the use of these regulatory instruments and whether importers are required to employ specialised staff. 3. Marketing of VMPs Labelling requirements on the packaging and leaflet inserts of marketed VMPs provide information to distributors and veterinary pharmacists regarding handling and storage requirements. They also provide information to veterinarians and livestock producers about proper administration. Package labelling should provide information such as the active substance(s) per dosage or weight, the proper handling and storage conditions, the dosage and the route of administration. The EBA 2017 Livestock survey collects data on the type of information required to be included on product packaging.

If a country’s registration system is not transparent, it can deter the private sector from attempting the process of registering VMPs. Applicants need to be aware of all the registration requirements and to easily obtain this information. Thus, for the predictability of the process, it is important that: (a) information on registration requirements is published and is clear, so the company can be sure that all necessary documentation is included in the application package (or ‘dossier’); and (b) the timeframe by which the registration will be completed is also published. The vast majority (95%) of the surveyed countries had legislation requiring VMP registration, but four of these countries do not provide information on dossier requirements on the registration authority’s website (see Table 3).

Table 3: Countries that currently do not provide on-line information on dossier requirements from EBA2017 report

Table 2: Some examples of countries with elements of good regulatory practice from the EBA2017 report

Summary of Key Findings Results for each regulatory area reveal a gap between regulatory reality and global good practice in many countries. Three of the 62 countries included in the sample of EBA countries (Burundi, Lao PDR, and Mozambique) do not have a regulatory framework for VMP registration. These three countries are either in the process of developing a legislative framework or are yet to start the process of developing relevant legislation. www.animalhealthmedia.com

In most countries, the dossier evaluation process is delayed, because each time the regulatory authority requires additional information from an applicant, the registration process is put on hold. To improve efficiency, the dossier should be checked for completeness prior to the start of evaluation. This process check is required in 17 EBA countries either via legislation (e.g. Mexico) or guidelines (e.g. Armenia). According to the relevant regulatory document, the official timeframe within which the International Animal Health Journal 59


LIVESTOCK regulatory authority can contact the applicant for missing documents is 23 days on average, but ranges from three days (in the Kyrgyz Republic) to 60 days (in Bosnia and Herzegovina). New product launches and associated marketing communications require forward planning, particularly for seasonal products. Therefore, awareness of how long the registration process will take is important to the private sector. The expected registration times will depend upon the type of registration process adopted in a country, with some countries implementing a full dossier assessment complete with the testing of products, while others may rely on the use of reference countries and other parameters. Regardless of the registration process followed in a country, applicants should be provided with an expected timeframe and that expectations are adhered to. Of the 57 countries actively registering VMPs, 38 (67%) have published an estimation of how long the registration process should take either in a regulatory document or guideline. The estimation of how long the registration process should take for veterinary biologicals and pharmaceuticals ranges from 30 days (Cambodia) to 365 days (Jordan and Kenya). Estimation of the actual time in which VMPs are registered, provided by companies that have registered VMPs, varied in countries. For example, with veterinary pharmaceuticals, the average days for registering VMPs ranged from just 29.5 days (in Georgia) to 860 days (in South Korea). The information provided on the packaging (typically a bottle label, package leaflet and outer carton) is critical to ensure the correct and safe use of the product, and should therefore be part of the legal requirements. As reflected in Table 4, not all countries follow “good practices” on labelling. For example, only 18 of the 57 countries require that precautions on disposal of unused or waste materials are included on the labelling of VMPs in any of the packaging locations.

Conclusion The identification of barriers to agribusiness development is a critical step towards global improvements to animal health. The transparency, predictability, and efficiency of the regulatory system influence private-sector decisions to supply the market with health-promoting technologies. Thus, the legal framework is particularly important for agroeconomies where farmers are economically dependent upon their livestock. The objectives of the EBA 2017 Livestock topic dovetail with other international and regional efforts to encourage regulatory convergence to international standards. The Organisation for World Animal Health (OIE) runs the PVS Pathway Programme — a global programme for the sustainable improvement of countries’ veterinary service compliance with international standards on the quality of veterinary services.7 HealthforAnimals has ongoing projects aimed at promoting regulatory good practice and regulatory harmonisation, through its series of five-yearly Global Regulatory Benchmarking Surveys.8 The Global Alliance for Livestock Veterinary Medicine (GALVmed) engages in similar efforts for regulatory harmonisation with respect to vaccine registration in select African countries.9 And finally, there is the VICH programme developing harmonised guidelines for the technical requirements for veterinary product registration.10 There is much work to be done. Infrastructure improvements and the increased provision of veterinary services must be made alongside legal reforms. Infrastructure improvements facilitate supply and distribution. Improved access to quality veterinary services is necessary to diagnose, monitor, report and treat disease, and to ensure the correct use of VMPs. Moreover, the health of an animal is intricately linked to diet, genotype, and husbandry practices. For the purposes of livestock production, increased access to VMPs is of limited use if not coupled with high-quality feed resources and an effective breed improvement strategy. Over the 2018–2019

Table 4: Examples of Labelling Requirements for VMP for EBA2017 report 60 International Animal Health Journal

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LIVESTOCK livestock/docs/2016/LGA-Brochure-revMay13th.pdf 4. Grace, Delia et al. 2012. “Mapping of poverty and likely zoonoses hotpots.” p 14. https://cgspace.cgiar.org/ bitstream/handle/10568/21161/ZooMap_July2012_ final.pdf?sequence=4&isAllowed=y 5. FAO. “Chapter 10: Animal health and the environment.” Guidelines for strengthening animal health services in developing countries. Rome, 1991. http://www.fao.org/ docrep/U2200E/u2200e0d.htm 6. International Institute for Research Against Counterfeit Medication. 2017. http://www.iracm.com/en/historical/ 7. PVS Pathway Programme, World Organisation for Animal Health, http://www.oie.int/support-to-oiemembers/pvs-pathway/ 8. Global Benchmarking Survey 2015 Report, HealthforAnimals, June 28, 2016 https:// healthforanimals.org/resources-and-events/ resources/publications.html 9. Regulatory Harmonisation for Vaccine Registration, Global Alliance for Livestock Veterinary Medicine, https://www.galvmed.org/work/policy-andadvocacy/regulatory-harmonisation-for-vaccineregistration 10. International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products, http://www.vichsec.org/

Edna Kallon She leads the livestock topic for the World Bank Enabling the Business of Agriculture programme. Before joining the World Bank, Edna worked with the Iraq county office of the UN Food and Agriculture Organization and with the Corporate Executive Board, a global best practice insights and technology company providing businesses worldwide with products and services. Email: ekallon@worldbank.org

K. Aleks Schaefer He joined the World Bank EBA livestock topic team in May 2017. In January 2018, Aleks will join the Royal Veterinary College, University of London, as a lecturer in agribusiness. He holds a PhD in Agricultural and Resource Economics from the University of California, Davis. Email: kschaefer@worldbank.org project cycle, the EBA will expand to cover 80 geographies and will include additional regulatory indicators for animal nutrition and animal genetic resources. REFERENCES 1. 2. 3.

Enabling the Business of Agriculture 2017, World Bank Group, February 07, 2017 http://eba.worldbank.org/ reports Impact of Animal Disease on Meat and Milk Production, World Organisation for Animal Health. http://www.rrafrica.oie.int/en/news/index.html Livestock Global Alliance. 2016. “Livestock for Sustainable Development in the 21st Century.” http:// www.livestockdialogue.org/fileadmin/templates/res_

www.animalhealthmedia.com

Felix Frewer He was a member of the EBA livestock topic team from 2014 to 2017. Before joining the EBA in 2014, Felix worked with the UN Food and Agriculture Organization (FAO) on agricultural policies in Latin America and the Competitive Cashew Initiative (ComCashew) on strengthening the West Africa cashew value chain. Email: ffrewer@worldbank.org

International Animal Health Journal 61


NEWS EU Delays Blanket Ban Decision on Neonicotinoids The European Commission has delayed a vote on the banning of three neonicotinoids to include all outdoor crops.

Dr Rees said: “The existing skin test is based on the animal’s immune response, and takes three days to produce a result, but more worryingly is known to miss about 20 per cent of infected animals.

Member states met at the European Commission on 12-13 December to propose an extension of the ban to all outdoor crops.

“Our new test is unique as it is the only test that directly detects live bacteria in blood or milk and is fast, specific and highly sensitive. Additionally the test can distinguish between a vaccinated and an infected animal (DIVA test) paving the way for new types of disease control in the future when vaccines are available.”

Four years ago, the EU restricted use of three neonicotinoids in the spring and on flowering crops. The Standing Committee on Plants, Animals, Food and Feed (Scopaff) discussed proposals to set out a blanket ban, but no vote was taken. The issue is expected to be on the agenda again in early 2018. The UK government has overturned its previous convictions on neonicotinoids and now say and outright ban is needed due to their supposed harm to pollinators. By: IAHJ – Staff Reporter Trilanco Announce Exclusive Trade Distribution Deal of Westgate EFI Brands Trilanco has agreed exclusive trade sales and distribution rights of Westgate EFI (WEFI) brands. Under the deal, Trilanco will distribute WEFI’s own brands including The Mark Todd Collection, Gatehouse, Jumper’s Horse Line (JHL), JHL Pro-Steel, Rodney Powell, Saddlecraft, StableKit and Plus Equine. Additional ranges will also be available from January 2018. Martin Balmer, Trilanco’s managing director, said: “I’m delighted to announce the addition of WEFI’s brands to our product catalogue. They really enhance our offering to the varied needs of equestrian retailers.” The deal adds to Trilanco’s growing catalogue of 16,000 products, which includes a comprehensive range of products for both horse and rider. Bruno Goyens de Heusch, managing director of Westgate EFI, said: “We recognised our individual strength as a manufacturer. Trilanco has an impressive new warehouse and distribution operation and this partnership will allow us to focus on the continued development of our brands.” Mr Balmer added: “Our aim is to provide retail customers with the best products and service in the industry. Bringing together great brands at competitive prices with excellent sales support, helps to create a fantastic buying experience for our trade customers.” By: IAHJ – Staff Reporter PBD Biotech Launches Actiphage TB Test Kit Actiphage TB, a new test for bovine tuberculosis (bTB), will soon be available from start-up PBD Biotech  based in Suffolk. The company said  its move brings fresh hope for the dairy industry which has seen over 30,000 cows slaughtered this year after contracting the disease.

PBD Biotech has been successful in raising finance to create and manufacture test kits based on the phage technology developed by Dr Rees. By: IAHJ – Staff Reporter Organic Derogation Extension Provides Certainty for Pig and Poultry Producers The decision to extend two derogations for organic pig and poultry for a further 12 months will provide much-needed certainty for the industry, the NFU and NPA said after successful calls to the European Commission to extend the permissions. Due to tight supplies of organic proteins, the extension allows farmers to continue feeding their pig and poultry up to five per cent non-organic proteins. The derogation also allows for farmers to buy in pullets of up to 18 weeks old, where organically-reared pullets are not available, provided they have been managed under the organic feed and veterinary standard. NFU deputy president Minette Batters said: “It is incredibly important for the organic pig and poultry industry that these derogations were extended, to provide certainty to producers. “The NFU, along with industry, called for these derogations to be extended and it is fantastic news that the European Commission has listened to our concerns. By: IAHJ – Staff Reporter Calls for Urgent Action on Organic Derogations The NFU, NPA and stakeholders across the industry are urging the European Commission to extend two derogations for organic pig and poultry which are coming to an end on December 31, 2017. Farmers are currently allowed to feed their pig and poultry up to five per cent non-organic protein. They are also allowed to buy in pullets up to 18 weeks old, provided they have been managed under the organic feed and veterinary standard. Without Commission intervention, these derogations will revert back to original regulation, which requires a 100 per cent organic diet.

PBD Biotech said the new test can detect live bacteria in blood or milk in just six hours, allowing affected cattle to be identified quickly before the infection spreads.

NFU deputy president Minette Batters said this will not only have severe consequences to the organic sector, such as being unable to source the right nutrition, but will be a major welfare concern for young birds who are extremely vulnerable to predators.

The test is based on research conducted at the University of Nottingham by Drs Cath Rees and Ben Swift, co-founders of PBD Biotech.

Ms Batters said: “It is vital for the organic poultry sector that an extension to these derogations is granted as soon as possible. Producers are planning now for 2018 and

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NEWS currently have no certainty whether these derogations will be in place.

reinforce the relationship between the two associations and to discuss issues of common interest.

“Organic producers would like nothing more than to use 100 per cent organic feed but they don’t want to do this at the expense of their animals’ health and welfare, which is why an extension is so important.”

High on the agenda was the challenge faced by both UK and EU based member companies from the UK’s EU Exit, at a time when the new EU Veterinary Medicines Regulation is close to becoming a reality. NOAH’s vision for an environment that delivers a thriving animal medicines sector applies both nationally and internationally; it will be critical that products continue to be traded in order to safeguard animal health and welfare, public health and food safety – both here in the UK and across Europe. Business continuity will require a closely aligned regulatory environment and close co-operation between the two associations will be vital in order to make this a reality.

By: IAHJ – Staff Reporter Fresenius Pulls off Sterile Injectables Double Whammy, snags Akorn as Well as Merck KGaA's Biosimilars Business With deals for U.S. generics maker Akorn and the biosimilars business of Merck KGaA, Fresenius appears to be mimicking the approach taken by sterile injectables leader Hospira, which Pfizer bought in 2015 for $15 billion. Fresenius’ new CEO has pulled off a dealmaking double play, committing more than $5.4 billion to expand its reach in sterile generics as well as in the rapidly expanding area of biosimilars. The Germany-based company today announced two deals. In the first, it reached a $4.3 billion agreement in its previously announced talks to buy U.S.-based generics maker Akorn, also assuming $450 million in debt. The deal, expected to close in early 2018, will add three U.S. manufacturing sites and one in India to Fresenius’ network, as well as about 2,000 employees. Separately, Fresenius said it will buy the biosimilars portfolio of Germany-based Merck KGaA for €170 million upfront and up to €500 million in milestone payments, about $729.2 million total. Manufacturing of biosimilars will continue at Merck's two plants in Switzerland as part of that deal. “Akorn brings to Fresenius Kabi specialized expertise in development, manufacturing and marketing of alternate dosage forms, as well as access to new customer segments like retail, ophthalmology and veterinary practices,” John Ducker, CEO of Fresenius Kabi USA said in a statement. By: IAHJ – Staff Reporter NOAH Welcomes new UK Chief Vet Christine Middlemiss Christine Middlemiss has been appointed as the new UK chief Veterinary Officer (CVO), taking over from Nigel Gibbens who is stepping down at the end of February 2018 after 10 years in the position. NOAH Chief Executive Dawn Howard said: “NOAH welcomes Christine to her new role. We look forward to working with her in the future, particularly as we are negotiating the UK’s exit from the EU, to ensure the availability of animal medicines to secure the health and welfare of UK animals in the future”.

Wijnand de Bruijn welcomed Gaynor Hillier’s commitment that NOAH will remain an active and valued member of AnimalhealthEurope. By: IAHJ – Staff Reporter AHI STATEMENT: FDA Report on Sales of Antibiotics for Use in Food Producing Animals Antibiotic sales – whether they go up or down – are not predictors of public health impact. While today’s sales report is an interesting piece of the story, we are more encouraged by the recent data from the National Antimicrobial Resistance Monitoring System that shows that for those pathogens that might transfer from animals to humans, resistance rates in people have been stable or declining. Over the 20-year life of the program, Salmonella resistance in humans has steadily declined. This trend of reduced resistance began long before implementation of FDA’s judicious use program and is evidence that producer supported antimicrobial responsible use programs have been working. We are committed to the One Health goal that antibiotic use in all settings, human or veterinary, should be judicious. That’s why we worked in collaboration with the Food and Drug Administration to implement the Judicious Use program, eliminating the use of medically important antibiotics for promoting growth in food animals, and making sure all remaining uses are under the supervision of a licensed veterinarian. Public policy that focuses only on reducing the amount of antibiotic used has not reduced antibiotic resistant rates in humans and can result in more animal disease and death. We will continue to work with customers, veterinarians and other stakeholders to preserve a safe food supply and protect public health through the careful and judicious use of antibiotics to keep food animals healthy. By: IAHJ – Staff Reporter

By: IAHJ – Staff Reporter NOAH remains committed to working with AnimalhealthEurope UK and European animal health associations NOAH and AnimalhealthEurope met at London Vet Show today to underline the continuing importance of veterinary medicines for our animals. AnimalhealthEurope President, Wijnand de Bruijn, and Secretary General, Roxane Feller, met with NOAH Chair, Gaynor Hillier, and Chief Executive, Dawn Howard, to www.animalhealthmedia.com

International Animal Health Journal 63


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