Veterinary drugs

 

Introduction

Jurisdictional issues

The current regulatory and programmatic approach: strengths and weaknesses

Efficiency

Substitution

Redesign

Financing the transition

 

Introduction

The story of veterinary products has many parallels with pesticides and fertilizers.  As with those inputs, the core problem is poor farm and aquaculture designs and management, in this case to optimize animal (and fish) health within a production context (for more on aquaculture, see Goal 5 Sustainable food). It's clear, particularly, that intensive industrial production models create health problems for animals and fish. It's not that extensive farming systems automatically equate to good health, and although not well studied, there can be more challenges with water access, feed quality, predators and parasites (cf. Lund and Algers, 2003; Temple and Manteca, 2020). Nor is it the case that all health problems are a result of intensive production, since wider environmental and biological factors and deliberate or inadvertent actions can lead to poor animal health. But generally, lower intensity results in lower metabolic stress on animals, which results in better health.  Better health usually means lower reliance on problematic animal health products and veterinarians (cf. MacRae et al., 1990; Temple and Manteca, 2020).

The dominant animal production models in Canada, often with too many animals for the indoor or outdoor space available,  are heavily dependent on veterinary pharmaceuticals to limit disease pressures and maintain health in the face of high production goals - feed additives, antibiotics, ionosphores, hormones, fertility enhancement drugs, vaccines, antibody products, and in vitro diagnostic test kits. They are used prophylactically, as production aids, for prevention and for treatment. Veterinary products are delivered via injection, implants, aerosols, orally, dermally, enema and suppository, and in feed.  They can be over-the-counter (OTC) or prescription. There is a significant amount of off-label (aka extra-label) use, implicated in a number of problems, including antibiotic resistant micro-organisms (AMR).

Not all pharmaceutical classes are permitted in all farmed animals. Approved veterinary drugs are in a database with human drugs, so search parameters must be applied to determine what can be administered. Creating an integrated picture is challenging, though Health Canada states that over 2300 veterinary health products have been "notified" (what lay people would consider an approval) and of these it appears 761  are notified as part of a federal program to bring low risk products in use (see below). An August 2021 search of all marketed veterinary drugs (more specific than veterinary health products) produced 948 entries.  Each entry must be examined to identify animals on which the drug can be used and the conditions of use. Regarding what can be put in animal feed, antibiotics can be used in feed for the main farm animals, but growth hormones are not permitted (via any route of administration) in poultry, milk - producing cattle or pigs. For details on veterinary pharmaceuticals permitted in feed, see the Compendium of medicating ingredient brochures.

Veterinary products have a mixed record in regards to animal welfare (see also Goal 9, Human relations with animals).  When used for prevention and treatment, they obviously reduce pain, suffering, and mortality.  But when used to enable crowded conditions and intensified production, as is often the case with prophylactic and growth promoting administration,  they can contribute to stress and distress.  Unfortunately, Canada has a long history of using such products for such purposes and has only recently begun to implement measures to curb such uses.

Veterinary products also have impacts on human health. The biggest concern is anti-microbial resistant bacteria (though resistant viruses and fungi are also on the rise), now considered by the WHO to be a global problem. The pathways are numerous, but once a resistant population is established, resistant elements can pass to other micro-organisms and resistant organisms can end up directly in the food supply and be consumed by humans.  Once ill, the ability to treat humans with the normal suite of antibiotics can be compromised. Drug-resistant bacteria add an economic burden to the health care system. Dating back to the 1980s, there was evidence that hospital stays for those affected by an antimicrobial-resistant bacterial strain were likely to spend nearly twice as long in hospital as those infected with non-resistant strains. Mortality rates were also higher. These outcomes were attributable to treatment failures,  not just age and susceptible populations (Holmberg et al., 1984).

Although there is debate about the relative culpability of medical vs veterinary use of anti-microbials, this is both a human  and animal drug prescription issue. In 2014, approximately 82% of antimicrobials important to human medicine were distributed and/or sold for use in food-producing animals, 27% for humans, and less than 1% for companion animals and crops respectively (Public Health Agency of Canada, 2016).  This speaks to the significant levels of important antibiotic use in animal production.

Some animal health products are controversial because of different interpretations of their health impacts on animals and the significance of residue consumption for humans. These have sometimes triggered trade disputes, often a mix of wider geo-political tensions where the veterinary product becomes a centrepiece of the dispute, and different approaches to food safety. Canada permits certain products that its trading partners have banned or restricted.  For example, producers have had trouble with beef exports to Europe because of hormones that were not permitted in the EU (even since the signing of the trade agreement with Europe since Canada has very little certified beef free of those restricted hormones, see Arnason, 2019) and with pork exports to China because of ractopamine (abandoned by Canadian producers later), a feed additive that contributes to feed conversion efficiency and leanness of meat.

There is also a large professional, scientific and economic infrastructure associated with veterinary pharmaceuticals, not to be dismissed as s significant force driving reliance on these products.  Actors in the sector have significant capacity to influence both farmers and decision makers in ways that increase consumption of veterinary drugs (see Dutescu, 2020 for an international analysis with Canadian implications). The Canadian Animal Health Institute (CAHI) is a major provincial and federal lobbyist, representing the manufacturers and distributors of animal health products. According to CAHI, getting a major animal drug to market can take 7 - 10 years  costing up to $100 million. Such costs help explain why manufacturer interests are vigorously defended. There are 5 veterinary colleges in Canada, and national and provincial associations representing their interests. Veterinary education is very expensive, for both the students and the universities that offer degrees, and this investment must be recouped in some way. Although there are shortages of vets in certain regions and specialties, there are also excesses, hence the supply of veterinarians can help create demand for certain products and services.

Jurisdictional issues

As with many other farm-related inputs, the criminal law power of the constitution provides the federal government with the authority to regulate veterinary drugs, primarily under the federal Food and Drugs Act and the Health of Animals Act for vaccines and other veterinary biologics. The primary unit responsible is the Veterinary Drugs Directorate (VDD) of Health Canada, with support from the CFIA which has authorities related to medicated animal feed (the Feeds Act and Regulations), vaccines and food safety (related primarily to drug residues in food).  Environmental assessments of new veterinary products are carried out under the New Substances Notification regulations of CEPA, by Health Canada Environmental Assessment Units. Animal pesticides for fleas, ticks, mites and intestinal parasites are regulated under the Pest Control Products Act and addressed in the Pesticides section.

The provinces and territories have some authority related to distribution and also the training and regulation of veterinarians. Provincial ministries of agriculture typically have responsibility, often under the aegis of an animal health, protection, care or diseases act, for education, prevention, inspection, surveillance and detection of animal health problems, licensing of places where livestock medicines can be sold, research, enforcement and penalties, and responses to animal health incidents of public concern, including emergency preparedness.  Many provinces have a chief veterinarian.  The Yukon also has a pertinent act.  As the provinces are responsible for land use and many aspects of food production, provincial extension services offer advice on animal production and are effectively promoters of intensive animal livestock systems that depend on veterinary drugs to maintain animal health.  Provincial responsibility for waste management also includes disposal of pharmaceuticals.

The current regulatory and programmatic approach: strengths and weaknesses

Many partnerships are required between the FPT governments, veterinary colleges and professional bodies, and the animal industries to make this dispersed system work. Consequently, some aspects function well, others do not.

Health Canada and the CFIA carry out pre-market assessment and post-market surveillance. There are different pathways for drugs vs biologics. Veterinary drugs are substances, or mixtures, for diagnosis, treatment, mitigation, or  prevention of disease, or abnormal physical state. Veterinary biologics are used to treat or prevent  infectious diseases or conditions, and include vaccines, antibody products and diagnostic  test kits. They can be derived from helminths, protozoa or micro-organisms, or be synthetically manufactured.

As with pesticides and fertilizers, the core issue is how benefits and risks are determined and elaborated. Regarding drug approvals, according to Health Canada,

For a drug to be approved for use, its benefits must outweigh its risks. A veterinary drug is approved for sale in Canada if the manufacturer has proven that the drug is:

    • safe for the animals that will be treated
    • safe for humans, if it is to be used in food-producing animals
    • effective at treating the condition for which it is approved
    • of high quality, by:
      • being manufactured according to strict specifications
      • remaining stable up to its expiry date

Health Canada reviews product labels to make sure they are clear and concise, and include the required information (Health Canada, Regulating Veterinary Drugs).

As with many Health Canada assessment processes, the human and animal health assessments and post-market surveillance systems are generally stronger than the environmental ones, though not without problems. Certainly, there have been many apparent benefits to the use of these products, especially for treatment of sick animals. Economic losses for farmers associated with animal disease and death have been reduced in many cases. Reduced levels of disease have often assured higher food quality for consumers. All these benefits are significant and important.

However, numerous problems exist. There is a list of banned pharmaceuticals not permitted in food producing animals, but many of these were on the market for many years before being banned, a process that always raises questions about the effectiveness of the regulatory system. The use of antibiotics in feed was introduced post WWII with relatively weak knowledge about long-term effects on animals and humans.  There are also significant questions about the ability of the regulatory system to address chronic and subtle impacts of human consumption of animal products with low-level presence of antibiotics and metabolites. Not always well documented effects of veterinary drug residues in food (including aquaculture products) include hypersensitivity reactions, a range of cellular impacts including carcinogenic, mutagenic and teratogenic effects, immune system suppression, and disruptions to intestinal flora (the microbiome) resulting in digestive problems (Okocha et al., 2018). These kinds of adverse reactions from low level residues raise questions about the suitability of MRLs for veterinary drugs and CFIA monitoring programs for domestic and imported foods.  Canada has been much slower than many European states to remove antibiotics and growth promotants from use, which also calls into question both pre- and post-market systems. A significant regulatory failure was the Health Canada attempt, ultimately unsuccessful, to approve recombinant Bovine Growth Hormone (see Get Started, Advocates for change, Case studies, and Goal 4 Genetic Engineering).

It is notable that the above Health Canada summary statement makes no mention of environmental impacts. This is a weak area of the regulatory system. There is limited consideration of the direct impacts of medicated feed waste, inefficiency antibiotic uptake in aquaculture systems, excreted veterinary medicines and production aids, and question marks around veterinary product disposal by farmers, and even less assessment of the environmental implications of intensive animal production systems and how veterinary drugs facilitate their management. Many veterinary drugs are poorly absorbed in the guts of animals and a significant percent of the  drug or its metabolites is excreted in feces and urine with negative impacts on non-target organisms, especially from antimicrobials (Schiffer et al., 2001; Sarmah et al., 2006).  Such problems are likely to be more significant in intensive operations with higher densities of animals and disease pressures.  Application of residue - laden manure can result in inhibition of soil organisms and processes resulting in additional fertility challenges (cf. Toth et al., 2011). Plant root growth and other metabolic processes may also be affected (cf. Li et al., 2011; Opris et al., 2013).  Aquatic systems can be negatively impacted by antibiotic administration to farmed seafood (Okocha et al., 2018).  It would appear, given approvals, that such problems are considered manageable by regulators, but mounting evidence  suggests that regulatory approaches are not adequately considering during assessments the expanding scale and scope of the problems.

The approval process for veterinary biologics is built on the same kind of risk assessment platform for drugs and is operated by the CFIA (see CFIA veterinary biologics). There are requirements specified by the CFIA regarding the safety, purity, potency, and efficacy of a product. In general, vaccines are seen to be more desirable than prophylactic administration or treatment with antibiotics, since vaccines by design are more focused on disease prevention and thereby can reduce antibiotic consumption (for a review, see Hoelzer et al., 2018a).  However, vaccines are not without potential problems. Not all of them optimize safety, efficacy, with durable protection against a broad spectrum of pathogens. Administration costs can be high with low user friendliness. Vaccines are not available for all common diseases (Hoelzer et al., 2018a). There can be risks for people involved in vaccine manufacture, distribution and administration. Vaccines for  gram-negative diseases can cause adverse reactions in animals and as a result using more than two at a time is not recommended (Derksen, 2021).  It means that vaccines must be carefully employed as part of a wider disease prevention strategy.

Vaccines  are less likely to be shed in animal manures than antibiotics and other production aids.  Attenuated vaccines, in general, have low likelihood of reversion to  wild virus virulence though there have been cases of this occurring. Live vaccines  have a risk of horizontal and/or vertical transmission, sometimes with outbreaks (Hoelzer et al., 2018a).  The regulatory system assesses the likelihood of such events, but given these negative events, not always successfully. Impacts on the environment are generally low.  However, there is no indication that vaccines are being assessed within a sustainability and health promotion framework, since CFIA assessments do not challenge the dominant production models. This is significant because the use of both vaccines and antibiotics can indirectly preference other disease organisms that are more difficult to manage (Hoelzer et al., 2018a), particularly in the absence of a wider strategy to optimize animal health.

Development of vaccines can be slow and expensive. According to Hoelzer et al. (2018a):

Commercial interest in developing vaccines for animal diseases is a critically important driver of innovation, but in reality often remains limited. Reasons include the relatively high cost of production for many vaccines, the costs and time associated with laborious administration protocols, in particular if multiple booster vaccinations are required, and the limited cost-effectiveness compared to other available control options including antibiotics.

The regulation of veterinary health products that are not drugs, vaccines, biologics and diagnostics is relatively recent and still in evolution.  It is based on some of the same regulatory principles as the system brought in during the early 2000s for human natural health products.  The system is being put in place to add low risk veterinary health products that could assist with animal health and potentially reduce the need for anti-microbials.  Until recently, such products have not been authorized for sale, largely "because of the difficulty manufacturers have in generating sufficient scientific data respecting the safety and efficacy of the drug to meet the existing regulatory requirements for a “new drug” (which would require the filing of a new drug submission as per Division 8 of the FDR)". Some products that could be used in veterinary were approved for humans, but were not authorized for animals because of the more onerous conditions of the FDR. Changes put in place from 2017 (Veterinary health product regulatory amendments 2017) are designed to make it less onerous to import and sell low risk VHPs for food-producing animals.

The Extra Label Drug Use (ELDU) program is controversial.

The practice of ELDU in Animals in Canada is not confined to veterinarians and may be performed by multiple users including intermediate health professionals (e.g., pharmacists, animal health technicians, etc.) and laypersons (e.g., animal owners, livestock producers, etc.). VDD acknowledges that ELDU is an important tool in the practice of veterinary medicine. Decisions to use ELDU may include a potential lack of efficacy of approved products, lack of approved products to address specific needs and economic considerations (Health Canada).

Part of the rationale for these earlier programs was to take pressure off veterinarians, especially for emergencies.There is evidence the program has been abused and contributed to the AMR problem. Resistance has been recognized as a serious problem with agricultural linkages since at least the 1980s with a number of reports documenting levels of antibiotic resistance in the 80s and 90s (cf. Addison, 1984; Nolan et al. 1991; Poppe et al. 1995). There are long standing criticisms of Canada's approach to addressing AMR, and it is only recently that Health Canada has slowly clamped down on own-use provisions (Health Canada and PHAC 1999-2012 evaluation). According to HC and PHAC audits, Canada is behind Western Europe and Australia on may aspects of programming to reduce AMR.

Ultimately, if we design animal production around sustainability, animal welfare, human health and equity, how does the benefit / risk equation shift for veterinary drugs and biologics and what products will we need? This is a foundational question not yet being substantially addressed.

Financing the transition

There is little to no financial modelling of the changes proposed here.

At the farm level, there are likely to be savings on input costs and veterinary services. Manufacturers will have to pivot to different products and services that will likely be less profitable and / or more expensive to develop, and with fewer animals on the landscape, sales will decline. However, given the size of the dominant actors, they are generally in good standing to adapt to new realities.

With animals healthier and fewer of them, there will be less demand for certain kinds of veterinary services and potentially fewer vets overall, especially considering declines in both pets and food-producing animals.  Colleges and universities will have to manage enrolment in different ways. Tuition fees will likely be reduced with lower government grants, however, the costs of operating veterinary programs may also decline.

A revamped regulatory system could mean review savings since a more limited (and possibly more targeted) array of products will be submitted to regulators. Reduced reliance on veterinary drugs may also reduce post-market surveillance, inspection and enforcement costs.