Issue Identification Paper
Work In Progress: Extra-label Drug Use In Animals (ELDU)
Developing a Common Understanding

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Updated:
October 26, 2004

Table of Contents

Purpose

Acknowledgement

I. Background
Extra-Label Drug Use in Animals
Recent Developments
Regulating ELDU in Canada
Canadian Industry and Veterinarian Views on ELDU
Scope of ELDU in Canada
Factors Contributing to ELDU in Canada
Factors Affecting the Control of ELDU in Canada
ELDU in Other Jurisdictions

II. Issue Identification
Assessing The Risks

A. Lack of knowledge about ELDU in Canada
Lack of quantitative practice information
Lack of access to collated and quantitative information
Lack of practice information: what drugs are used
Lack of practice information: how is ELDU practised
Lack of awareness of potential impact of ELDU
Lack of information on the user
Lack of information on potential impact of ELDU
Other gaps

B. Risks associated with ELDU practice
ELDU and AMR
ELDU and violative food residues
ELDU and occupational/environmental health hazards
ELDU and lack of efficacy of products
B.1 Mitigating risks related to ELDU

III. Issue Identification
Developing Risk Management Strategies/Policies
Health Care System
Legal
Ethical
International Trade
Political
Accountability and Liability
Physical Environment
Public Perceptions and Expectations
Stakeholder Perceptions and Positions
Economic
Agri-Food System

Appendix A: ELDU Advisory Committee

Appendix B: Examples Of Extra-label Drug Use In Animals

Appendix C: Health Canada's Policy On ELDU In Animals

Appendix D: Indirect Indicators

Appendix E: Total Canadian Agricultural Production

Appendix F: References

For more information on ELDU, visit the VDD's Web site.

Purpose:

This paper has two purposes: first, to document explicitly salient information on the subject of Extra-Label Drug Use in Animals (ELDU) in Canada and secondly, to begin the process of documenting key issues related to both the assessment of the risk(s) of ELDU and the development of risk management strategies and policies.

Acknowledgement:

We thank the VDD Risk Management/ELDU Team and the members of the ELDU Steering Committee¹ for their collaboration in the development of this paper.

I. Background

Extra-Label Drug Use in Animals:

1. In this document, "Extra-Label Drug Use ", often referred as "off-label use", refers to the actual use or intended use of any drug², whether it is a prescription drug or over-the-counter (OTC) drug, in an animal³ in a manner that is not in accordance with the approved label⁴ or the package insert of the drug approved by Health Canada (HC). This includes the use of all unapproved drugs ( including unapproved bulk pharmaceutical substances and compounded drugs) i.e., those that do not have a Canadian approved label. [See Appendix B for examples of ELDU.]

2. In general, the practice of extra-label drug use in Canada is not restricted to veterinarians. As a result, it can be done by a variety of people, including veterinarians and layperson, intermediate health professionals such as pharmacists, animal health technicians (AHTs), feedmill operators, feedlot managers, wildlife officers, animal breeders, pet owners , pet shop owners and employees.

3. ELDU has always been a part of veterinary medicine⁵, for the proper and humane care of sick animals, since it gives veterinary practitioners access to drugs which may be registered for human use or which have limited registration for veterinary use.

4. In addition to animal health concerns, there are two primary public health concerns which may be associated with ELDU: violative⁶ drug residues in food products derived from animals⁷ and the potential for the development and spread of antimicrobial resistance (AMR) when antimicrobials are used in an extra-label manner⁸.

5. Concerns about the potential for ELDU abuse/misuse in Canada were highlighted by the second mission to Canada undertaken by the European Union's (EU) regulatory auditors (Food and Veterinary Office [FVO], Health and Consumer Protection Directorate-General [SANCO])⁹. The delegation visited from September 19-29, 2000, to evaluate the control of veterinary drug residues in live animals and animal products for purposes of Canada's exports of these products to the EU¹⁰. Among other things, an area of key concern to the EU included the extent to which a national approach for the effective control of extra-label use of veterinary drugs existed in Canada¹¹.

6. Market access into other countries requires that Canada be responsive to evolving requirements of export markets and be vigilant in the integrity of its regulations and their implementation through inspection and certification programs. As well, domestic consumer protection requires the continuous improvement of the food safety and public health systems which form the foundation for the traditional positive reputation of Canadian products abroad.

Recent Developments:

7. Canada's response to the EU audit noted that its policy¹² on ELDU of veterinary drugs recommends that extra-label drug use be performed under the supervision of a veterinarian¹³ with an established Veterinary-Client-Patient Relationship (VCPR)¹⁴. Furthermore, ELDU should be restricted to therapeutic purposes only where no other therapy exists. ELDU may be used in food-producing animals provided that appropriate withdrawal times and safety standards are established. This ELDU must not result in the violative levels of drug residues in animals sent to slaughter.

8. In addition to clarifying and strengthening controls on ELDU, Health Canada (HC) committed to undertake a series of actions which included: updating a survey of veterinary practitioners on ELDU (and adding livestock producers associations to it); expediting risk assessments of specified drugs and where appropriate, restricting the sale to veterinarians only; expanding human safety risk assessment to include horses; enhancing the control of ELDU through the combined force and impact of federal and provincial legal and regulatory frameworks and strengthened partnerships; and enhancing the educational program for veterinarians and livestock producers associations on ELDU in Canada.

9. As a result, HC proceeded to develop a nation-wide study aimed at assessing drug use in animals in Canada. The objective was to gather up-to-date and comprehensive information and understanding of the nature and scope, as well as the impacts, of both label and extra-label drug use in animals in Canada, to highlight areas for further consultation, and to allow for the identification of gaps in the accessibility of veterinary drugs. A contract for the study was awarded on October 9, 2002. To assist the contractor and the department with expert advice and guidance in various aspects of the project, HC established a Steering Committee consisting of sixteen members with broad representation from animal industries (dairy, pork, beef, poultry), the Canadian Veterinary Medical Association, the Canadian Food Inspection Agency (CFIA) and academia.

10. After considerable work in creating different questionnaires for the different users of veterinary drugs, it was determined that this approach was complex, costly and - even if completed - would not likely yield the required information. In November 2003, VDD decided to suspend the study temporarily, but to continue working with the Steering Committee and other partners and stakeholders to develop an alternative cost-effective approach to gathering data. As well, HC in consultation with the Steering Committee would pursue a policy development track, identifying the gaps in ELDU controls and ELDU's impact on public health and what can be done to fill the gaps. This Issue Identification is a critical first step in the policy development process.

Regulating ELDU in Canada:

11. In Canada, ELDU is a complex multi-jurisdictional issue involving the federal government and the various provinces and territories. HC does not regulate the use of drugs: that use per se comes under the "practice of veterinary medicine", a provincial jurisdiction. Currently, there are no federal Canadian regulations defining the requirements for permitting the practise of ELDU, except for medicated feeds¹⁵. However, in as much as there is federal legislative authority for regulating the approval, sale and labelling of veterinary drugs, HC can take into account how a drug is or may be used on or extra-label (off-label) in determining whether a drug's labelling is sufficient for it to be safe and effective (in the sense required by the Food and Drugs Act and Regulations for it to be sold). In this regard, recent legal opinion has confirmed that if a specific extra-label (off-label) use risk is identified, the Food and Drugs Act and Regulations do provide authority for HC to require that a product be labelled with an express warning or contraindication against extra-label (off-label) use.

12. One area of federal regulation that does attempt to track medications used in food-producing animals is CFIA's "Modernized Poultry Inspection Program" with its requirement for "flock sheets" that accompany the poultry and transfer mandated information (including listing all vaccines used and all non-feed medications used for which a withdrawal time applies) to the next levels in the food chain¹⁶. Under the Meat Inspection Regulations, all lots of poultry presented for slaughter at federally registered establishments must be accompanied by these flock information documents. CFIA is now proposing to amend the Regulations to extend the requirement for all food animals¹⁷.

13. The federal Food and Drugs Act and Regulations prescribe matters pertaining to the approval and sale of drug products in Canada. Within provincial boarders, in each province has the authority to further restrict the sale, distribution and dispensing of approved drugs¹⁸, ¹⁹,²⁰ .

14. Each province in Canada is responsible for the regulation of the practice of veterinary medicine and has established standards of conduct for veterinary practitioners²¹. A recent review²² indicated that every province allows extra-label administration of prescription or over-the-counter drugs by veterinarians or in some cases by animal owners, provided public safety and animal welfare are not threatened, and violative drug residues are not present in food derived from animals treated in this way. Among other findings, it reported that provincial legislatures and veterinary licensing bodies control ELDU indirectly, through: (i) regulation of the way in which veterinarians practice veterinary medicine; and (ii) regulation of the dispensing and sale of veterinary drugs by veterinarians and others, including drugs for extra-label use.

15. In Ontario, since no specific authority in any legislation/regulations is granted to producers for off-label use in their livestock, it is deemed to be a default prohibition excluding producers from the practice of ELDU²³

Canadian Industry and Veterinarian Views on ELDU:

Position of Canadian Veterinary Medical Association (CVMA) on ELDU²⁴

16. The CVMA issued a general position or policy statement in November 2002 regarding ELDU and its justification in the Canadian environment for application by its members:

The CVMA encourages Canadian veterinarians to use and prescribe approved veterinary drugs as per label indications and dosage.

The CVMA recognizes that ELDU is justified if the prescribing veterinarian has scientific evidence that it is in the best interest of the animal, and the circumstances of the use are in accordance with the provincial veterinary association's policy or guidelines on ELDU.

The CVMA believes that only veterinarians are qualified to order ELDU in animals.

ELDU by veterinarians must only be performed within the confines of VCPR²⁵.

When prescribing ELDU to food-producing animals, veterinarians must educate themselves and their clients on appropriate withdrawal times and the liabilities associated with non-approved use.

Further, veterinarians must not use any drugs that are prohibited ²⁶ for use in food-producing animals.

Position of Food-Animal Producing Groups

17. Some producer groups have stated positions on the ELDU issue: e.g., the Canadian Cattlemen's Association recommends avoiding off-label or ELDU, but if necessary, it should be done only under a veterinary prescription²⁷. A number of groups (including the Canadian Cattlemen's Association) have worked with the Government of Canada to develop On-Farm Food Safety Programs²⁸. The Dairy Farmers of Canada's program workbook describes the best management practices by recommending "a written veterinary prescription for all treatments given extra-labelly"²⁹. The Canadian Pork Council's policy states that "medications should be used only on the advice of a veterinarian, following recommended treatment levels"³⁰.

18. In developing their On-Farm Food Safety Programs , producer organizations such as the aforementioned have incorporated principles and practices based on the Hazard Analysis Critical Control Point (HACCP)³¹ system with the intent to reduce the incidence of violative residues in food³².

19. On-Farm Food Safety Programs in Canada are run on a voluntary basis with no regulatory provisions or mandate. While voluntary at this time, market forces may eventually drive universal producer participation and adherence.

Position of Feed Industry

20.The Food and Drug Regulations and the Feeds Regulations require a veterinary prescription when a drug is used extra-labelly in feed³³. Thus ELDU by the feed industry is regulated. However, major concerns exist regarding the liability of feed manufacturers in filling any prescription, especially ELDU when the feed manufacturer has no previous experience or information. ELDU also complicates the feed industry's ability to comply with the pending Regulations Respecting the Making of Medicated Feeds (RRMMF). These regulations are process-based and deal with contamination, medicated product reformulation, sequencing and flushing. The more medications and combinations a feed manufacturer has to deal with, the more challenging and costly it is to comply with the RRMMF³⁴.

Scope of ELDU in Canada

21.The scope of ELDU in Canada has been estimated through direct (i.e., survey) and indirect methods.

22. A 1990 survey was undertaken by ResCan Consultants, commissioned by HC in connection with a wider investigation of antimicrobial resistance³⁵. (As noted above in paragraph 10, the recent plans to conduct a subsequent survey have been suspended.)

23. The ResCan survey involved mailing questionnaires to 1100 veterinary practitioners. Only 310 questionnaires were returned. The survey results revealed that 260 of the 310 respondents had practised extra-label use of veterinary drugs. These practices specifically involved:

1. the administration of drugs, mostly antibiotics, at a dosage higher than what is instructed by the labelling.
2. the administration to species not indicated by the drug label.

24. At the time of the survey, in small animal practice, the drugs most frequently prescribed for extra-label use were Ivermectin (Ivomec) and megestrol acetate (Ovaban). Ivermectin (Ivomec), indicated for the treatment of parasites in large animals, was used in small animals and birds. Megestrol acetate (Ovaban), approved as a contraceptive for dogs, was used for treatments of abnormal behavioural in cats.

25. In large animal practice, flunixin meglumine (Banamine) and penicillin were most frequently employed for extra-label use. Both drugs were used in the treatment of dairy cattle. Flunixin meglumine (Banamine) is a non-steroidal anti-inflammatory drug (NSAID). In 1990, this drug was indicated solely for equine use in Canada; in 2003, however, flunixin meglumine (Banamine) received approval for use in cattle. The extra-label use of penicillins involved the application of a higher dosage than label indication.

26. There are several limitations to the ResCan Survey:

27. Survey Design. The survey questions were qualitative and did not capture the frequency that each respondent administered a specific drug product.

28. Sample Selection. The survey sample group was restricted to Canadian veterinarians and did not represent the range of individuals who might practice ELDU such as AHTs, food producers, farm operators, horse owners, lay persons etc. The survey also focussed on small animal, large animal, mixed and equine practices and did not specifically address aquaculture or apiaries.

29. Sample Size. The ResCan report did not provide specific details of sample size, only that 1,100 veterinary practitioners were selected from ResCan's "Canadian Veterinary Mailing Atlas"³⁶ listing 2,226 clinics across Canada. The estimation of total population of veterinary practitioners remains open to conjecture, since it is not mentioned in the report³⁷.

30. Survey Return Rate. The return rate (310 of 1100 questionnaires) is statistically low.

31. In addition, the 1990 survey results are no longer current.

Other Contextual Information

32. With regard to indirect indicators, ELDU practice in Canada may be affected by the numbers of Canadian veterinary practitioners, by changing agrarian practices for food animals, and by the number of drug products available to both Canadian and global markets. [See Appendix D for further discussion of these points.]

33. Another factor that could affect the potential for ELDU is the number of drug products available in Canada.

Factors Contributing to ELDU in Canada

Some of the most common reasons veterinarians prescribe drugs in an extra-label manner include the following:

34. Access to sufficiently varied approved drugs: The total number of pharmaceutical drugs (human, veterinary, and disinfectant) marketed in Canada has increased from 17,210 in 1987³⁸ to 24,133 in 2004 ³⁹. Currently, there are over 2,500 approved veterinary products⁴⁰. This greater number of drug products could either (i) decrease the potential for ELDU by providing a new approved therapy for a condition previously treated by ELDU or (ii) increase the potential for ELDU by providing a greater selection of drug products not indicated for a specific species or condition.

35. A serious limitation is the availability of relatively few approved drugs for minor uses and use in "minor species"⁴¹ such as sheep, goats, game and wildlife animals. The broad range of species and conditions that could be treated in the course of a veterinarian's practice or professional activities makes the use of only approved drugs an almost impossible requirement to meet for each individual animal's needs and clinical situation. To fulfill his/her duty of care, the veterinarian will often have to use a drug product that is not approved for the animal species or condition being treated. Further, some approved or unapproved drugs may be recognized to be highly effective in the treatment and management of diseases for which approval has not been sought by pharmaceutical manufacturers or in species or age groups for which the drug(s) was (were) not originally approved. In some instances, label claims may be more extensive for a product in another regulatory jurisdiction. In the present market environment, there are few financial incentives for a pharmaceutical company to seek approval in Canada for additional uses of an approved product or for an unapproved product for which there is limited market demand and where sale of the product occurs under the rubric of ELDU. A frequent assertion is that ELDU is more common in minor species because there are so few drugs approved for use in these species; the lack of approved drugs is also thought to affect major food-producing animal species in Canada, albeit to varying degrees.

36. The situation is affected by the proximity of the American market where the imminent passage of the Minor Use and Minor Species (MUMS) Animal Health Act is intended to increase the availability of new therapies for animals, including zoo animals and some pets for which treatments for many ailments currently do not exist or are not available⁴². The US legislation will establish two new ways to market lawfully new animal drugs while safeguarding public health and make available incentives, such as grants, for certain new animal drugs for MUMS (i.e., more MUMS drugs can be expected to become available, known to Canadian veterinarians, but not be registered in Canada as the same incentives to register do not currently apply here).

37. Perceived superiority of unapproved⁴³ drug products: Based on anecdotal information, it is apparently common practice for drugs to be used in an extra-label manner or for unapproved drug products imported from other countries to be used in major food-producing species in situations in which these products are perceived to be more efficacious than drugs approved in Canada.⁴⁴

38. Ineffectiveness of approved product at label directed dosages: Some drugs may not be optimally effective and efficacious when used according to the approved product label directions. The 1990 Rescan survey indicated that the drugs most likely to be used in an extra-label manner were antibiotics procaine penicillin is a common example of when effectiveness could be reached only at dosages several times the dosage recommended on the label. Most antibiotics approved in Canada are for use at a single dosage rather than the varying dosages or a range of dosages found on U.S. labels. Thus, label claims may be more extensive for a product in another jurisdiction.

39. Economic and other considerations: Beyond extra-label use of products registered in Canada (DIN), and as noted in paragraph 35, the use of unapproved products occurs under the rubric of ELDU. Under the current regulatory framework, many drugs, natural health products and other pharmacologically active substances can be imported into Canada for "personal use" (i.e., not for resale). Animal owners are permitted to import veterinary drugs for administration to their own animals. In addition, HC does not currently have a regulatory framework to control the entry and use of Active Pharmaceutical Ingredients⁴⁵ (APIs). Thus, producers have access to a variety of drug products from other countries, sometimes perceived as less expensive or providing superior efficacy, safety or other benefits⁴⁶. Potential risks to public health arise from the inability to assess the impact of unapproved drugs used in food-producing animals. Currently, there is an initiative underway in HC to address the importation, traceability and quality of drug products used in animals.

40. Lack of suitable dosage forms or delivery vehicles of approved products: This constitutes a form of ELDU whereby the delivery form of a drug can be altered for convenience and practical administration to animals. Compounding for veterinary use has been defined as the reformulation of an active pharmaceutical compound to address the unique physiological needs of an individual animal, as determined under a valid VCPR, which cannot be met by current, commercially available (i.e., approved) product formulations⁴⁷. Examples include making a solution from a solid dosage form, making oral dosage forms from injectable products, mixing two or more drug products into a single product, etc. Compounding by pharmacies or veterinarians may involve human drugs, approved or unapproved drug products, or APIs to produce drugs for veterinary use. Compounding may also be used so that drugs can be obtained at more economical prices. HC is collaborating with the CVMA and NAPRA (National Association of Pharmacy Regulatory Authorities) to establish national guidelines for legitimate compounding of animal drugs in Canada.

41. Unknown use of ELDU in the every day traditional practice of veterinary medicine: The practice of ELDU by veterinarians may result from learning from experience. For example, the use of drugs by veterinarians may be influenced by the clinical practices learned from respected mentors. In this way, veterinarians may unknowingly contribute to ELDU.

Factors Affecting the Control of ELDU in Canada:

Availability of veterinary drugs and drug substances in Canada

42. Prior to drugs being permitted on the Canadian market, HC evaluates them for quality, efficacy, animal safety and human safety and determines their conditions of sale and label requirements. Once approved at the federal level, the provinces/territories can further regulate the sale and distribution of drugs in their province. After that, drugs for animal use may then be distributed through veterinarians, pharmacists, feed companies and retail outlets (i.e., often referred as over-the-counter (OTC) sales).

43. In addition, unapproved drug products can be sold in Canada to veterinary practitioners through the Emergency Drug Release (EDR) Program⁴⁸ administered by Health Canada for the treatment of a medical emergency of animals under their direct care or supervision. Applicants have to provide credible residue, human safety and other required pharmacological data in order to access the unregistered drug. Special authorization for investigational studies in the form of Experimental Studies Certificates (ESCs)⁴⁹ or Investigational New Drugs (INDS)⁵⁰ from HC may also govern the sale of drugs for experimental purposes in animals.

ELDU in Other Jurisdictions:

44. The aims of regulations in other countries are similar⁵¹;

1. Ensure that stock and produce from stock are residue-free before entering the food chain
2. Minimize the development of antibiotic resistance,
3. Provide legislative consistency among States (USA), States and Territories (Australia and New Zealand) or Member States (European Union).

45. While the aims of regulation in these countries are similar, each jurisdiction has adopted varying approaches and control. However the key role of the veterinarian is constant, in that by law no other person but a veterinarian is permitted to practice ELDU.( For more information please consult websites listed in the footnote⁵² )

II. Issue Identification:
Assessing The Risks

A. Lack of knowledge about ELDU in Canada

46. While some qualitative knowledge exists about Canadian ELDU practices, there are significant gaps in the quantitative evidence about Canadian ELDU practices. This undoubtedly affects the ability to quantitatively assess the benefits and risks associated with ELDU and to predict the future impacts of ELDU on animal and public health, but these gaps should nevertheless not be viewed as an impediment to policy development.

The following information gaps can be identified:

Lack of quantitative practice information: why/when ELDU is practised

47. confirmation and significance of generic reasons for ELDU and specific ELDU patterns;

48. availability or lack of availability of specific drugs for specific indications in specific species;

49. suitability of existing approved products for veterinary medical needs available in Canada and the extent of their effectiveness for approved uses;

50. relationship between increased drug availability for one animal species and ELDU occurrences, in other animal species.

51. incidence, prevalence and types of intended vs. non-intended ELDU use applications;

52. changes in therapeutic needs for good veterinary practise and the availability of approved veterinary drugs in response;

53. efficacy/effectiveness range of drugs most commonly used in an ELDU manner.

Lack of access to collated and quantitative information:

54. relationship between drug costs and efficacy as a driver for ELDU;

55. producers using ELDU to reduce their costs;

56. on how producers/companion animal owners use drugs;

57. loopholes in current regulatory framework;

58. familiarity with other products not approved in Canada.

Lack of practice information: what drugs are used:

59. ELDU patterns, their incidence and prevalence in different animal species, in food-producing vs. non-food-producing animals, different age groups, applicability to production stages, etc.;

60. incidence and prevalence of specific drug product use or specific therapeutic category use, especially those of interest to public health e.g., the extent of the use of growth promoters in food animals; prophylactic use of antibiotics;

61. list of drugs most commonly used by veterinarians and/or producers in an extra-label manner⁵³.

Lack of practice information: how is ELDU practised:

62. lack of understanding by some end users as to what constitutes ELDU during the preparation of the national survey.

63. sources of information relative to drug use for animals and ELDU use decision-making;

64. sources of information consulted by end users re. animal efficacy and animal drug safety for ELDU applications and their prevalence in ELDU decision-making.

Lack of awareness of potential impact of ELDU:

65. sources of information consulted by end users for establishing accurate⁵⁴ withdrawal periods/withholding times for food products resulting from ELDU and the prevalence of use of these sources in ELDU decision-making.

Lack of information on the user (who practises ELDU):

66. socio-economic and drug use education profiles of decision-makers, end users and providers of information about the use of drugs in animals, concerning general drug use and specifically ELDU;

67. purchase and use of drugs in animals by lay persons, especially the extent to which they are involved in ELDU decision-making and application.

Lack of information on potential impact of ELDU:

68. causality relationship between findings of residue violations and the root cause(s) e.g., relative contribution of ELDU, non-observance of withdrawal period or withholding time, other reasons;

69. frequency of residues and overall incidence;

70. causality relationships between incidence of ELDU patterns and the nature of violative residues in food products derived from treated animals;

71. while it is anticipated that the implementation of HACCP-based⁵⁵ inspection programs (HIP) and On-Farm Food Safety Programs⁵⁶ will reduce the incidence of residue violations for individual food commodity groups, data to substantiate this are not available;

72. causality relationship between findings of food-borne AMR pathogens and the root cause(s) e.g., relative contribution of ELDU, inappropriate use of antibiotics, other reasons;

73. relative contribution of ELDU in the potential development, transfer and dissemination of AMR from animals to animals and from animals to humans;

74. worldwide gap also relates to the inverse relationship, i.e., from humans to animals.

75. incidence, prevalence and types of adverse reactions in animals and humans as a result of ELDU;

76. relationship between perceived lack of controls over the sale of drugs in Canada to ELDU.

Other gaps: putting ELDU into context:

77. incidence and prevalence of drug usage in Canada based on drugs in a finished form, compounded form, bulk APIs (loose) etc.;

78. percentage of drug sales to/by veterinarians vs. over-the-counter sales; sales volume for APIs, drugs for personal use, or drugs obtained via Internet and other importation sales;

79. drug usage in Canada based on approved drug products vs. non-approved drug products imported from other countries;

80. availability sources and distribution channels of drugs used in animals, and their relative significance and contribution to ELDU.

Other gaps: extrapolating from other jurisdictions:

81. linkages between ELDU controls (regulations) and the incidence of ELDU in general and/or specific ELDU patterns in other regulatory jurisdictions;

82. types of ELDU controls via regulatory approaches versus ELDU compliance levels in other regulatory jurisdictions;

83. data requirements for review of animal drug products in other regulatory jurisdictions where there are currently different types of regulatory controls on ELDU.

B. Risks associated with ELDU practice:

84. There are potential human health risks relating to ELDU despite the clear benefits of this practice⁵⁷. Major concerns include the development or persistence of AMR in food-borne bacteria as well as violative drug residues in foods⁵⁸.

ELDU and AMR

85. Any use of antimicrobial agents is inherently associated with the development of AMR. Minimizing the use of antimicrobial agents is a key strategy to combat and contain AMR⁵⁹.

86. The extra-label use of antimicrobial agents in animals has the potential to increase the development and persistence of AMR in target bacterial pathogens as well as in food-borne pathogens and thus increase the potential spread of resistant bacteria among animals as well as from animals to people through the food chain.

87. One of the major concerns about ELDU practice is the potential for emergence of multiple drug resistance in several important food-borne pathogens such as Salmonella spp, Campylobacter spp., Enterococcus spp. and pathogenic Escherichia coli. This may result from increased antimicrobial drug use and consequent increase in selective pressure for emergence or persistence of AMR⁶⁰.

88. The extra-label use of antibiotics in animals can contribute to an increase in the reservoir of antibiotic-resistant bacteria, which may facilitate the persistence and spread of resistant bacteria in either food-producing or companion animals and humans.

89. Importantly, increased AMR in target pathogens could also lead to reduced effectiveness of appropriate antimicrobial agents in animals; it may also lead to treatment failure or increased burden of illness in humans⁶¹.

ELDU and violative food residues:

90. A key imperative from a public health perspective in prescribing drugs for or administering them to food-producing animals is that the use must not result in violative drug residues in food products derived from such animals.

91. Violative drug residues in food could arise from a variety of factors including ELDU.

92. Extra-label use of approved drugs or the use of compounded drugs in food-producing animals may increase the potential for violative drug residues in food⁶².

93.There is increased difficulty in monitoring drug residue levels due to ELDU. As well, maximum residue limits (MRLs) or administrative MRLs (AMRLs) for drugs used in an extra-label manner may not be available for further health risk assessment and/or compliance/enforcement activity by regulators/inspectors.

ELDU and occupational/environmental health hazards:

94. Any use of a drug potentially poses occupational/environmental health hazards. A drug that is prescribed or used as ELDU could potentially affect the handler(s) of the drug product during its preparation, formulation, storage and administration (e.g., inhalation dust from loose bulk chemicals incorporated into a medicated premix). The risk may be further increased by the absence of safe handling instructions from approved sources.

95. A drug that is prescribed or used in an extra-label manner can potentially contribute to a detrimental impact on the environment (e.g., in aquaculture or from manure or urine excretion and further spreading or infiltration into the environment). This may result particularly from the absence of well-controlled studies or scrutiny of such studies by mandated regulatory agencies to ensure that it meets environmental safety standards, as prescribed under Canadian law.

96. Certain veterinary drug residues have been detected in the environment in Canada and in other countries⁶³. ELDU could potentially increase adverse impacts on the environment.

ELDU and lack of efficacy of products:

97. The efficacy of products used in an extra-label manner has not been proven. This lack of efficacy, or reduced unknown efficacy, is concern when a product is used in different species, for different diseases, and/or by an alternative route of administration than may have been approved on its label.

98. Veterinarians may practise ELDU based on limited information coming from scientific reports, academic sources, pharmaceutical companies, and/or anecdotal reports. They may lack the necessary knowledge of pharmacological principles and the pharmacokinetic differences between species (often as closely related as poultry and ducks) to use a substance safely and effectively in an extra-label manner. The specific formulation of a product might not be effective if administered in a different way (e.g., oral vs. injection vs. intra-mammary).

B.1 Mitigating risks related to ELDU:

99. To prevent the emergence, spread or persistence of AMR for the purposes of minimizing negative human health impacts, the ELDU of specific veterinary antimicrobial agents may be prohibited or restricted. For instance, due to concern for the development of resistance, the ELDU of specific fluoroquinolone antimicrobial agents is expressly contraindicated in some jurisdictions, including Canada (as a warning on the product label).

100. The issuance of an authorisation for drugs via the EDR program⁶⁴ and the issuance of an ESC by HC represents an authorization of sale of an unapproved drug to a licensed practitioner and/or qualified investigator.

101. The CVMA General Position Statement on ELDU⁶⁵ and the Canadian On-Farm Food Safety Program (COFFSP)⁶⁶ contribute to mitigating risks associated with ELDU. CFIA is proposing a regulatory amendment to make its Food Safety Enhancement Program (FSEP) mandatory for all federally registered meat and poultry establishments⁶⁷. FSEP can be described as the CFIA's approach to encourage the development, implementation and maintenance of HACCP systems in all federally registered establishments. Provincial On-Farm Food Safety Programs are also being implemented (e.g., in Alberta, Ontario and Prince Edward Island).⁶⁸

102. Canada joined the global Food Animal Residue Avoidance Databank (gFARAD) program in the fall of 2002⁶⁹. Based at the Western College of Veterinary Medicine in Saskatoon, SK, and the Faculté de médecine vétérinaire at St-Hyacinthe, QC, the Canadian gFARAD provides information on residue avoidance to veterinarians. FARAD was developed to provide information related to approved animal drugs, and also on ELDU and environmental toxins. Member countries have web-based access to the FARAD database and in return, share all relevant drug and chemical information and tolerance data. The Canadian gFARAD centres provide expert-mediated decision support for any inquiry related to drug or chemical residues in food animals; assist veterinarians or government agencies with inquiries related to animal exposures to environmental contamination; and provide extra-label drug withdrawal information only to veterinarians authorized to practice in Canada. The purpose of the Canadian gFARAD is not to promote extra-label drug use, but to protect the food supply when necessary for veterinarians to use drugs in an extra-label manner. Utilizing information from gFARAD does not absolve the user from responsibility.

103. Voluntary efforts by the food industry to restrict the use of drugs in animals may also help to mitigate risks posed by ELDU.⁷⁰

III. Issue Identification: Developing Risk Management Strategies/Policies

104. A broad range of health and other related issues must be taken into consideration in developing effective risk management strategies and policies on ELDU.

105. The issues identified below are based on the current understanding of ELDU. Projects underway in HC and other areas may shed light on other key issues. Some of these issues fall within the purview of HC; some are the responsibility of other partners.

Health Care System:

106. Since ELDU has important actual and potential public health impacts, Canada's health care system is implicated in a variety of ways.

107. AMR has already been identified as an issue with respect to human prescription drugs. The availability of effective antibiotic therapies (known as "miracle drugs" when they were first developed, early in the 20th century) has greatly reduced morbidity and mortality from bacterial pathogens. However, as drug-resistant strains of bacteria emerge, physicians are being advised to exercise caution in prescribing antibiotics, particularly to children. While the Canadian Medical Association (CMA) cites inappropriate use of antibiotics as the primary cause⁷¹, it has been noted earlier in this document (para. 86), that extra-label use of antimicrobial agents in food-producing animals also has the potential to increase the development and persistence of AMR by transfer of resistant bacteria from animals to humans through the food chain.

108. Furthermore, new antibiotics⁷² are almost always far more expensive than the older formulations, placing added pressure on health care costs (of which pharmaceutical prices are a major component). It is estimated that AMR at least doubles the cost of treating a susceptible infection and adds between $40 million and $52 million per year to direct and indirect health care costs in Canada.⁷³

Legal:

109. Legal issues around ELDU arise from interpreting the relative authority of different jurisdictions.

110. Articles 91 to 95 of the Canadian Constitutional Law of 1867⁷⁴ set out the powers of the federal and the provincial governments. The practice of veterinary medicine is primarily an area of provincial responsibility, whereas protection of the public against health hazards and drug product deception is part of the federal "duty of care" mandate under the Food and Drugs Act and Regulations. The use of drugs by veterinarians, including ELDU, belongs to the practice of veterinary medicine, but the policy and regulatory issues arising from these uses fall within the public health mandate.

111. Guidance from federal authorities may be used by provincial regulatory bodies to determine acceptable standards of practice for their members. Accordingly, licensed professionals (veterinarians and pharmacists) whose practices contradict federal regulations would be subject to disciplinary action.

112. The federal role generally takes precedence when the issue becomes a subject for criminal law⁷⁵. For instance, there are already prohibitions relative to the sale and administration of specific drugs under the Food and Drug Regulations, if and when residues of specific drugs endanger public health.

Ethical:

113. Animal welfare considerations, which are regarded as inherent duty of care under the veterinarians' professional code of ethics, require that when a drug is prescribed in an extra-label manner, it is done to relieve the animal's suffering (pain), to benefit the animal's health and to compensate for the lack of availability or suitability of approved animal drugs.

114. Since the practice of ELDU is often based on limited clinical studies or even, at times, nonexistent information, animal safety could be put at risk from one or more types of adverse drug reactions.

115. Professional ethics dictate that when a veterinarian decides to prescribe a drug to animals in an extra-label manner, there is enough information or documentation on hand to justify clinically the medical/veterinary use for ELDU. ELDU is expected to be practised within a valid VCPR and veterinarians must ensure that no harm to the animals or unnecessary impediment to their treatment is caused.

116. Apart from the VCPR, there are broader ethical dimensions to ELDU with respect to protecting the public from exposure to risks of which they are unaware. The Veterinarian's Oath⁷⁶ provides a moral obligation for veterinarians to be mindful of public health and to apply their practice to the benefit of society.

117. ELDU practised by lay people (e.g., farmers and animal owners) who lack specialized knowledge of a drug's risks and benefits is another matter. Lay people sometimes take the initiative in administering medicinal products to animals outside of labelled (or prescribed) directions. This may pose increased risks if the end-user of the drug is not sufficiently aware of potential impacts on food safety, public health and animal welfare.

International Trade:

118. As a member of the World Trade Organization (WTO), Canada is obligated under the Sanitary and Phytosanitary Measures Agreement (SPS Agreement) to control veterinary drug residues in foods⁷⁷. This agreement encourages the use of international standards while allowing member countries to set their own higher standards when justified by science. International standards for food safety are recognized in the SPS Agreement as those established by the Codex Alimentarius Commission (CAC). The CAC has endorsed standards for residues of veterinary drugs in foods, including Guidelines for the Establishment of a Regulatory Programme for Control of Veterinary Drug Residues in Foods and Maximum Residue Limits for Veterinary Drugs in Foods and Recommended International Code of Practice for Control of the Use of Veterinary Drugs CAC/RCP 38-1993.⁷⁸

119. ELDU in food-producing animals could initiate trade restrictions in those cases where Canadian laws on extra-label use are not harmonized or equivalent with those of Canada's trading partners. If violative drug residues were found in Canadian exported food products derived from locally treated animals, our international trading partners could apply the "equivalence" provisions (Article 4) of the SPS Agreement, resulting in trade implications for Canadian producers.

120. Beyond WTO agreements, Canada and the EU signed the Veterinary Agreement in 1998, to govern the bilateral trade in live animals, animal products, fish and fish products⁷⁹. This agreement outlines a mechanism for mutual recognition of the equivalency of sanitary measures between Canada and the EU. It is intended to create common requirements for certification, resulting in fewer inspections and fewer trade delays, without compromising Canada's human and animal health standards.

121. In connection with the Veterinary Agreement, EU regulatory auditors visited Canada in May 1998 and September 2000 to evaluate the control of veterinary drug residues in live animals and animal products. The findings for the September 2000 visit⁸⁰ concluded that the Canadian residues control programme is not equivalent to the EU system and that certain drugs must be excluded from ELDU when products derived from treated animals are to be exported to the EU.

Political:

122. There is potential for the federal government's position on ELDU to influence international political issues. Based on trade agreements for food products, a decision could be implemented by a trading partner to ban the importation of a specific food product originating in Canada. An export ban on a food product would additionally cause political issues among provincial/territorial and federal government levels.

Accountability and Liability:

123. The veterinarian incurs legal liability each time he or she prescribes a drug for an extra-label use (usually due to unavailability of appropriate veterinary therapies or unsuitability of available drugs). The unproven safety and efficacy of the extra-label application could leave the practitioner open to liability action. This is of particular concern in the treatment of minor species for which there are a very limited number of approved drugs in Canada.

124. Compounding as a form of ELDU is a further area of potential professional liability, since the veterinarian is effectively assuming the complete responsibility for safety, quality and efficacy of the end product.⁸¹

125. Other areas where there might be some accountability and/or liability considerations include the role of animal owners or those charged with the care of animals (e.g., farmers, livestock producers, small animal owners) in the choice and direct administration of extra-label treatments.

126. With respect to the role and accountability of HC, there are areas where liabilities might be incurred: for example, product labels containing instructions for the use of approved products are regulated by HC. Extra-label applications do not - by definition - appear on the label, but there have been instances where HC required a manufacturer to issue a warning on the product label against ELDU. The implications of this and other potential HC actions within its mandate to protect public health and safety are a further consideration in assessing the potential for accountability and liability.

127. Finally, liability issues may arise in the generation and dissemination of information relative to ELDU by manufacturers of both human and animal health pharmaceuticals.

Physical Environment:

128. The impacts of ELDU on the physical environment are indirect, but could be significant. Drug residues generally enter the environment when excreted by humans and/or animals, who may have consumed the drug directly or through food or feed containing these residues.

129. Drug residues may also enter the environment as a result of inappropriate disposal, including products administered through ELDU (as well as APIs or unapproved drug products). Further environmental impacts may occur from the release of these drugs or metabolites through the application of manure as fertilizers in agriculture, or from the dumping of urine/faeces/carcasses of animals which may be infected with resistant organisms as a result of ELDU.

130. Drug residues in the physical environment also result from human use and excretion or disposal of unadministered pharmaceuticals. Where the same drug may be prescribed for human or animal use, it would be virtually impossible to attribute the sources (i.e., from ELDU or from human use/disposal) of drug residues in the physical environment.

Public Perceptions and Expectations:

131. The nature and extent of public awareness of ELDU is not known, but information gleaned from polls, surveys and qualitative studies reveals that Canadians have high expectations of their governments to establish and enforce standards that will ensure quality and safety of the food supply.

132. A Canada-wide survey conducted by Ipsos-Reid in March 2001 reported that 68 percent of respondents are concerned about the safety of the food they eat.⁸²

133. A spring 2001 Canada Information Office opinion poll reported that food safety as a priority issue increased to a high of 78 percent. At the same time, Canadians' opinion of the Government of Canada's performance in the field of food safety also increased.⁸³

134. In July 2003, The Consumers Council of Canada surveyed its newly created Public Interest Network, a group of some 500 grassroots opinion leaders who are influential in their areas of interest; 88 per cent cited food safety as the country's most important consumer issue.

135. A focus group study on food irradiation, carried out for HC in 2001, asked participants about their more general views on food issues. Participants were largely positive when asked about the safety of Canada's food supply, but many expressed some level of concern about technological interventions used in food production and marketing. Specific concerns mentioned included:

• use of chemicals and chemical preservatives
• genetically-modified foods
• use of antibiotics, steroids and hormones
• mass production - pressure to increase the number and size of animals might be at the expense of human health
• efforts to extend the shelf life of products
• irradiation.

136. Activities or responsibilities that participants in the focus groups frequently associated with the government included inspection of the food production process, standards setting, control of imports, research on food safety and quality, laws on labelling, providing information, and responding to specific problems or disease outbreaks. Most rated government performance as good or very good, although many acknowledged that they had little evidence on which to base their views. Typically, people felt that the Canadian government fared well in comparison with other countries insofar as its performance on these matters.

Stakeholder Perceptions and Positions:

137. [It is our hope to receive this input from representatives of stakeholder groups, including pharmaceutical companies, the agri-food industry and veterinarians.]

Economic:

138. The restriction of ELDU may have economic effects for the following stakeholders:

139. Agri-Food System. ELDU control measures may result in outbreaks of disease that could otherwise have been contained if the practice of ELDU had been allowed. A disease outbreak in livestock would have a far-reaching effect on food-producing animals (as in the recent cases of BSE and avian flu) with potentially large financial losses to the industry. The prohibition of ELDU may also lead to an increase in animal production costs, which in turn would be passed on to the consumer.

140. Pharmaceutical Industry. The restriction of ELDU would require pharmaceutical companies to seek HC's approval of new indications for approved drugs. There is an associated economic cost when companies prepare clinical evidence to support such an approval. In the absence of ELDU control measures, drug companies may also currently profit from the extra-label use of drugs where their efficacy has not been established by sufficient clinical evidence. For example, a 2003 study by Knight-Ridder Newspapers⁸⁴ reported significant sales figures resulting from the extra-label prescribing of human prescription drugs in the US.

141. An absence of ELDU control measures beyond HC's 1992 policy on ELDU could result in export trade restrictions or the increased perception by Canadian consumers that drug residues are inadequately controlled in animal food products. Both of these scenarios could have negative economic effects.

Agri-Food System:

142. The establishment of ELDU controls would present many issues to the entire range of the Agriculture-Food system:

143. Information. One issue is the education and awareness of all possible users/administrators of drugs in Canada. Because of the lack of understanding about what ELDU means in day-to-day practice⁸⁵, many Canadian users (veterinarians, livestock producers/farmers and pharmacists) require information regarding what actions constitute ELDU, and the impact of their actions when they prescribe or use a drug in this manner.

144. Animal husbandry. Also of consideration is the capacity for adhering to voluntary or mandatory quality drug use standards in the context of on-farm food safety quality assurance programs or other. Under the Canadian Food Safety and Quality Program (CFSQP), the veterinarian will assist food producers to develop and apply good farming practices. It is anticipated that this will provide greater opportunity for veterinarians to explain to producers the risks associated with ELDU, and consequently reduce the pressure for drug therapies.⁸⁶

145. Systems that protect animal welfare. In controlling ELDU practice, there is a need to ensure that animal welfare will not be compromised. Animal welfare is a responsibility that encompasses all aspects of animal well-being, including proper housing, management, nutrition, disease prevention, responsible care, humane handling, and where necessary, humane euthanasia.⁸⁷

Appendix A: Eldu Advisory Committee

Appendix B: Examples Of Extra-label Drug Use In Animals

"Extra-label use" of a drug may take many forms, such as, but not limited to, the following:

• The use of a drug product in a different dosage than what is approved on the label;
  
  
• The use of a drug with a greater or lesser frequency of administration than what is approved on the label;
  
  
• The use of a drug for a different indication (i.e., different disease or condition) than what is stated on the label;
  
  
• The use of a drug for a longer or shorter duration of treatment than what is indicated on the label;
  
  
• The use of a drug by different routes of administration (e.g., oral versus injectable);
  
  
• The use of a drug in a different species than what is indicated on the label (e.g., a drug approved in cattle could be administered to sheep);
  
  
• The use of a drug in a different age group (e.g., weanling);
  
  
• The use of a drug in a different stage of the animal's production cycle (e.g., dried-out cows versus lactating dairy cows);
  
  
• The use of a drug in a different dosage form (e.g., a tablet may be crushed into powder and incorporated into a gel, i.e., by "Compounding");
  
  
• The use of a drug approved in humans to treat an animal;
  
  
• The use of a drug(s) in a medicated feed outside of Medicated Ingredient Brochure (MIB) listing;⁸⁸
  
  
• Compounding is considered a form of ELDU. Compounding for veterinary use has been defined as the reformulation of an active pharmaceutical compound to address the unique physiological needs of an individual animal, as determined under a valid VCPR, which cannot be met by current, commercially available (i.e., approved) product formulations;⁸⁹
  
  
• The use of a drug in a different formulation e.g., two drugs being mixed in the same syringe i.e., by "Compounding";
  
  
• The use of unapproved drugs in animals, or of bulk pharmaceutical substances, also called Active Pharmaceutical Ingredients (API), which have been formulated by compounding or can be administered as is.

Appendix C: Health Canada's Policy On Eldu In Animals

• ELDU should be avoided unless no other alternative therapy exists.
  
  
• The primary concern... is that drugs which are used in animals are safe to both animals and [the] humans handling those drugs.
  
  
• The administration of drugs to food animals must not result in residues which are dangerous to humans consuming food derived from those animals.
  
  
• Potential occupational hazards should also be assessed and addressed in decisions involving extra-label drug use.
  
  
• [There are] concerns regarding the risk of adverse reactions to off label drug use, and that [the] drugs selected may not be effective in the clinical situation.
  
  
• The professional abilities of veterinarians, and their right to prescribe drugs to be used in animals [are recognized].
  
  
• [It is] further recognize[d] that there will be instances where it will be necessary for drugs to be used in an extra-label manner.
  
  
• It is also important to have established a VCPR when distributing drugs especially if it is recommended that drugs are to be used off label. This assumes that the practitioner assumes the responsibility for clinical judgements, and has sufficient knowledge of the animals to make the diagnosis, recommend treatment and be available for follow-up evaluation.

^{[Ritter, L. & Alexander, I. op. cit 202:(10)]}

Appendix D: Indirect Indicators

Indirect Indicators Which May be Affecting ELDU Practice in Canada:

• Since ELDU is a tool of practising veterinary medicine, consideration of the growth of that particular profession can be useful. In 1874 when the Ontario Veterinary Medical Association was formed, it had 27 members. Today, Ontario has over 3,300 licensed veterinarians and over 1,150 veterinary practices⁹⁰. Across the country, by 1959 there were about 1,600 veterinarians, a thousand more than in 1949⁹¹. Today, there are approximately 9,000 veterinarians in Canada. (These numbers includes practitioners and researchers, teachers, administrators and government.)
  
  
• Over the 60 years between 1941 and 2001, farm size in Canada steadily increased in terms of land area and also in terms of herd size ⁹². Between 1971 and 2001, the average number of dairy cows per farm more than tripled while the average number of pigs per farm increased by more than tenfold⁹³. In 1998, more than 40 percent of all farms were "food-producing animal" farms.

Farm Types

Farm types, Canada:94	1998
	# of farms	% of all farms
cattle	63,395	27.5
dairy	20,255	8.8
hog	7,175	3.1
poultry & egg	4,210	1.8
	95,035	41.2

• Between 1990 and 1998, while the cattle sector expanded, dairy and hog farms declined in number, because restructuring in these two sectors resulted in fewer but larger farms. For the same time period, agricultural production overall became increasingly concentrated on commercial farms with revenues of $250,000 and over, particularly on very large farms. The share of total production by very large farms increased substantially from 23.2% to 40.8% of total agricultural production. For example, in 1998, very large farms produced 73.5% of the poultry and egg farm production and 21.8% of dairy farm production.
  
  
• Recent production numbers for a range of food animals in Canada indicate that, while cattle populations have not significantly changed over the past five years, there have been notable increases in swine, chicken, turkey, and other poultry production [see Appendix E] . Aquaculture has also experienced a sharp growth in production since 1999. On the companion animal side, it is estimated that in 2002 there were about 4.3 million dogs and 6.8 million cats in Canada.⁹⁵

Appendix E: Total Canadian Agricultural Production

Total Canadian Agricultural Production

	Before 2000	2000	2001	2002	2003
Cattle1	N/A	15.0M cattle (July 1, 2000)	15.4M cattle (July 1, 2001)	15.4M cattle (July 1, 2002)	15.7M cattle (July 1, 2003)
Beef Cows	N/A	4.7M cattle (July 1, 2000)	4.8M cattle (July 1, 2001)	4.8M cattle (July 1, 2002)	4.9M cattle (July 1, 2003)
Dairy Cows2	1.15M cattle (1999)	1.10M cattle	1.09M cattle	1,08M cattle	1.07M cattle
Milk3			73M hectolitres	71.7M hectolitres	74.5M hectolitres
Swine - Hogs4	23,269.8K (1999)	24,191.6K	26,187.9K	27,994.8K	N/A
Swine - Pigs	12,227.3K (1999)	13,014.5K	13,673.4K	14,399.2K	14,566.1K
Chicken5	847.6M kg (1999)	880.7M kg	930.1M kg	938.9M kg	N/A
Turkey (All Categories)6	139.1M kg (1999)	151.7M kg	148.5M kg	145.7M kg	N/A
Chicken Eggs			46.3M dozen 25.4M layers7	47.1M dozen 25.8M layers8	47.5M dozen 25.8M layers
Other Poultry9 (incl. geese, ducks, roosters, ostriches, emus, pheasants, quail, wild turkeys)	3.32M birds (1996)		5.31M birds
Sheep10	N/A	1.11M sheep (July 1, 2000)	1.25M sheep (July 1, 2001)	1.25M sheep (July 1, 2002)	1.25M sheep (July 1, 2002)
Goats11	125,819 (1996)		182851
Horses and Ponies	443,889 (1996)		460569
Rabbits	285,366 (1996)		255762
Honey Products	76.4M pounds (1999)12	69.4M pounds13	70M pounds14	73.4M pounds15	74M pounds16
Aquaculture Products	113,228 (1999)17	12723418	15252319	17669620

M = million

Appendix F: References