Report of the Fifth Veterinary Drugs Directorate Stakeholder Committee Meeting, Ottawa, November 3 - 4, 2004

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Ottawa, Ontario, November 3-4, 2004

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Table of Contents

Introduction
Part 1: VDD Progress Report
Part 2: International Harmonization/Cooperation
Part 3: Prudent Use of Antimicrobials - A shared Responsibility
Part 4: The Canadian Sheep Industry (Stakeholder Profile)
Part 5: Priority Drug Review Task Force
Part 6: Next Step/Agenda Setting

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Introduction

The Veterinary Drugs Directorate (VDD) is part of the Health Products and Food Branch of Health Canada. The VDD is responsible for ensuring the safety of foods such as milk, meat, eggs, fish and honey from animals treated with veterinary drugs. It also ensures that veterinary drugs sold in Canada are safe and effective for animals.

The VDD Stakeholder Committee provides a high-level forum for obtaining input on key issues that fall under the purview of the Directorate. The Fifth Stakeholder Committee meeting was held in Ottawa on November 3 and 4, 2004. The objective of the meeting was to provide an update on VDD initiatives and to focus discussion around two key issues: International Harmonization/Cooperation, and Prudent Use of Antimicrobials. The meeting also included a progress report from the Priority Drug Review Task Force and a presentation from the Canadian Sheep Federation.

This report provides summaries of presentations, key discussion points and suggested recommendations for action/next steps.

Part 1: VDD Progress Report

Diane Kirkpatrick, Director General, VDD

Ms. Kirkpatrick reported that efforts to reduce the backlog of submissions are continuing, and significant progress has been achieved. The current target for fiscal year 2004-2005, is to complete the review of 90 percent of all data packages received over 18 months ago (i.e., packages received prior to October 1, 2002), and she is confident that this is possible. The report of the Priority Review Task Force has been submitted to VDD, and is now being reviewed.

Two draft guidance documents to assist industry in preparing and managing new drug submissions are being revised to incorporate stakeholder feedback. VDD hopes to publish the Guidance for Industry on Preparation of Veterinary New Drug Submissions and Guidance for Industry on Management of Regulatory Submissions in the spring of 2005, with implementation by summer 2005.

VDD also continues to add to the list of Administrative Maximum Residue Limits (AMRLs)/Maximum Residue Limits (MRLs), with up to eight new AMRLs/MRLs expected to be completed before the end of the fiscal year. VDD has compiled a comparative listing of Canadian and US limits/tolerances, which will assist in harmonization efforts.

The NOC (Notice of Compliance) Database will soon be up and running. It will provide improved access and search capabilities for users. VDD's Pharmacovigilance Unit has also launched a new website to provide easy access to issue-specific safety information on veterinary drugs. Recent postings included advisories regarding Proheart 6 and Micotil. At recent VICH (International Co-operation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products) meetings, further progress was made on harmonization around requirements for adverse reaction reporting. Canada continues to offer leadership and support on pharmacovigilance issues at the international level.

VDD efforts and progress continue in a number of key policy and regulatory development areas:

• Antimicrobial Resistance (AMR): The 2^nd Annual CIPARS (Canadian Integrated Program for Antimicrobial Resistance Surveillance) Report is expected by the end of the year. VDD provided a presentation on AMR to the Health Products and Food Branch's Public Advisory Committee in October 2004. VDD is also in the process of establishing an Expert Advisory Committee which will further explore and consult on public education actions on AMR issues. First meetings will be held in the new year. VDD continues to take a leadership role on this issue, both domestically and internationally.
  
• Bovine Spongiform Encephalopathy (BSE): VDD has drafted an appendix to HPFB's common guidance document, Minimizing the Risk of Transmission of Transmissible Spongiform Encephalophathies (TSEs) via Health Products, to provide information relating to veterinary products. Further work on this will continue, including consultation with stakeholders and ongoing research.
  
• Unapproved Drugs: A three-pronged approach that focuses on importation of unapproved veterinary drugs; compounding; and Active Pharmaceutical Ingredients (APIs) has been adopted. A regulatory change has been proposed to prohibit personal importation of unapproved veterinary drugs for use in food producing animals.
  
• Extra-Label Drug Use (ELDU): The ELDU issue identification document is in its final revision stage, based on input from stakeholders. Next steps include expanding membership on the ELDU Advisory Committee, identifying priority issues for analysis and options development; and the development of policy and risk management strategies.
  
• Natural Health Products (NHPs): As a first step in the development of a regulatory framework, VDD and the HPFB Inspectorate, with input from stakeholders, are drafting an interim compliance approach that would identify criteria to be applied in prioritizing and implementing compliance actions.
  
• International Cooperation/Harmonization: VDD continues to be active on various VICH and CODEX¹ committees, and participates in bilateral discussions on pharmacovigilance, safety, and other issues.

VDD participates in numerous interdepartmental committees and working groups dealing with horizontal issues, such as legislative renewal and the creation of the new Canada Health Protection Act, Smart Regulations, External Charging and the New Users Fee Act, Public Health Agency implications, and the National Food Policy. VDD is committed to consulting on these issues and keeping stakeholders informed of new developments and progress.

Part 2: International Harmonization/Cooperation

Presentations

Brief presentations and question and answer sessions outlined the perspectives around issues related to international harmonization and cooperation of various stakeholder groups, including producers, drug manufacturers, consumers, and animal welfare groups. Following the same format, VDD provided an overview of the issue and context.

Producer Association Perspective
David Plett, Canadian Cattlemen's Association (CCA)

Mr. Plett presented on behalf of beef, pork, dairy, poultry, sheep and equine producers. For producers, international harmonization/cooperation means "equivalency for access and use of veterinary drugs through standardized approval processes and regulatory principles between international animal and meat trading partners." The top three issues for producers are:

• Harmonization of policies, procedures and available products between Canada and the U.S.
• Priority of veterinary products for food animals before companion animals and new products before label extensions.
• The overall process has become so onerous for Canadian applicants that manufacturers do not place a priority for getting products approved in Canada.

Industry efforts to build harmonization have included frequent ongoing meetings with U.S. counterparts as well as Mexico, Australia and New Zealand. Producer associations have supported the Chief Veterinary Officer for Canada in deliberations at the OIE (World Organisation for Animal Health) and in bilateral and multilateral trade negotiations.

Producer organizations recommend the creation of a permanent Policy Advisory Council, comprised of industry and government, to facilitate a cooperative and collaborative forum for moving forward on international harmonization issues, with priority focus on establishment of an international system for information sharing, MRL equivalency between countries that trade in live animals and products, and development of an international standard for veterinary drug approval and use.

Drug Manufacturer Perspective
Paul Doig, Canadian Animal Health Institute (CAHI)

Mr. Doig emphasized that international harmonization is essential to the survival of a Canadian veterinary drug industry. Canada cannot have a "for Canada only" approach. New products are now all globally driven. Because of the relative small size of the Canadian market, Canada's regulatory requirements and the time to bring a new product to market, there are some products that would be beneficial to animal food producers which are currently not being registered in Canada. The status quo is not an option - harmonization/cooperation would help alleviate this situation.

CAHI participates in VICH and global pharmacovigilance programs. Canada should adopt international approaches wherever possible and promote joint/single product reviews. The aim should be to achieve full transparency in the regulatory submission process, such that VDD sees what other countries have reviewed and approved.

CAHI supports the development of a three- to five-year plan for moving forward, with stakeholders and VDD working together at the international level to achieve international harmonization and SMART regulations.

Consumer Perspective
Jennifer Hillard, Consumer Interest Alliance Inc. (CIAI)

CIAI supports international harmonization, as it provides consumers with a better selection of products by simplifying and streamlining regulatory processes and reduces the cost of products by enabling more competition and freer trade.

However, harmonization must not be to the lowest common denominator. It should not remove protective measures. International harmonization may not be applicable to all regulations or to all parts of a regulation - specific Canadian requirements should be maintained if the need can be justified.

Bureaucratic unwillingness to accept scientific assessments from other qualified scientists is insufficient reason not to harmonize. International harmonization should begin with the U.S., then progress to other OECD (Organisation for Economic Co-operation and Development) countries to maintain high standards.

CIAI works to promote the acceptability of harmonization and to counter the arguments that harmonization means lower standards or that it threatens Canadian sovereignty. Harmonization should mean a raising or maintaining of standards, not erosion or lowering.

Animal Welfare Perspective
Clément Gauthier, Canadian Council on Animal Care (CCAC)

International harmonization of standards is a key priority for the CCAC Guidelines Development Program. It involves agreement between countries on fundamental principles, such as animal testing requirements, international scientific collaboration and global acceptance of research data. It also has implications for international trade.

The underlying basis of all CCAC guidelines and policies is "Reduction, Replacement, Refinement." The harmonization of test requirements presents opportunity for implementation of the "three Rs."

CCAC is a recognized health effects expert and works with OECD and ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) on issues related to international test guidelines. Constructive dialogue and communication is important amongst those who develop and implement regulatory requirements, those who conduct animal testing, and those who regulate animal testing.

Developing a Common Understanding of Terms/Definitions Related to International Harmonization/Cooperation
Diane Kirkpatrick, Director General, VDD

International harmonization is a priority of the federal government and a key result area of VDD's strategic plan. It is closely linked to other issues and priorities, including Smart Regulations, timely access to safe and effective drugs and innovation. It encompasses informal and formal sharing of scientific information, participation in international organizations, and sharing of submission data and drug evaluations.

Challenges include Canada's regulatory framework, international agreements and conventions, varying ways of interpretation of scientific data between jurisdictions, confidentiality and conflicting priorities.

Health Canada/VDD continues to move forward on international harmonization issues by participating in bilateral meetings and international organizations, increasing the Directorate's capacity, and by building and strengthening networks and relationships with counterparts in other jurisdictions. The development of an international regulatory cooperation framework is currently underway, and will have stakeholder feedback. Canada is often asked to take a lead role in international deliberations and consensus building.

Stakeholder Feedback

In small table groups, committee members discussed the following questions:

• What are the targeted outcomes that we can strive to achieve?
• What are the timeframes expected?
• Who should be involved?

In plenary, stakeholders suggested that an overall goal should be to facilitate improved access to products in a timely manner that is supported by equivalency in standards amongst regulatory agencies. In this context, stakeholders emphasized issues related to common submission practices and review methodology.

An important first step would be to move forward on the development of a synchronized submission process, in which countries and companies agree that all parties receive information at the same time. Such a process would include common data requirements for content, common format, and electronic submissions. This would provide timely information and data that would help enable equivalency and support peer review. Peer review figures prominently in international harmonization, and stakeholders noted that to be valid, both parties must receive the same data package, and the reviewers' assessments must be accepted.

Stakeholders suggested that an initiative be undertaken to identify commonalities in review processes between countries and to accept assessments. This could include assessing review processes in discrete terms (by product and by commodity), and focussing on separate parts individually, rather than attempting to harmonize the whole process from the outset.

Stakeholders suggested that a conference or forum be held to facilitate the sharing of information on how data is interpreted by a country - what are the guiding principles, foundations and frameworks that influence and shape decisions? Stakeholders noted that effective regulatory policy tools should be developed.

The long-term goal would be to put in place legislative changes that facilitate the use of data/approvals generated by major trading partner agencies.

A strong VDD is essential to moving toward this goal. Canada's credibility and reputation means VDD is well positioned to take even a greater leadership role in moving issues forward at both national and international levels, contributing to Canadian innovation within a smart regulatory approach.

VDD should continue to work closely with VICH, the regulatory authorities of other countries, and strengthen its leadership role on various committees and working groups. It is important to promote Canada's sound science-based regulatory approach, our safe food status and animal welfare principles with the international community. Stakeholder input and participation will continue to be important to moving international harmonization and cooperation issues forward.

Stakeholders suggested the following guiding principles:

A Strong VDD: VDD is an efficient, effective science-based organization with the leadership and resources to deliver on its mandate with authority and expediency. It is an important part of Canada's regulatory framework.

A Collaborative System: Industry, governments (international, federal and provincial) and consumers support a collaborative approach based on transparency and disclosure. Information is shared across jurisdictions to facilitate the approval process, reduce duplication and ensure timely access.

Legislative Renewal: Regulations are reviewed and updated as needed to support a strong VDD and cross jurisdictional collaboration. Regulations are supported by enhanced tools to balance risk and expediency.

Part 3: Prudent use of Antimicrobials - A shared Responsibility

Presentations

Presentations outlined the health risks and challenges associated with the use of antimicrobials and the efforts of some stakeholder groups to address AMR issues.

Explaining the issue of "Prudent Use" - An Outline of Health Risks and Challenges
Dr. Michèle Doucet, University of Montreal

Dr. Doucet provided a "primer" on the issues, including definitions, the scope of antimicrobial resistance (AMR), and how various players can contribute to controlling AMR.

Infectious agents include parasites, bacteria, viruses and prions. She emphasized that not all bacteria are bad. The term antimicrobial refers to both natural and synthetic substances like antibiotics and disinfectants which can kill or inhibit the growth of microorganisms (bacteria, yeast, protozoa, algae and virus). ("Antibiotics" kill or inhibit bacteria, but the term is often used in place of "antimicrobial(s)".) Antimicrobial resistance occurs when an antimicrobial substance, or agent, is no longer effective in killing or inhibiting the growth of a particular microorganism. "Resistance" is the ability of microorganisms to resist the antimicrobial designed to kill or inhibit it. This resistance may be intrinsic (i.e., a normal evolutionary process) or acquired.

AMR risk factors include the use of broad spectrum antibiotics, low doses for long periods, incomplete administration of the prescription, inappropriate drug choices, doses and extra label drug use, and excessive household use of disinfectants.

AMR is an important public health issue worldwide. The growth and proliferation of resistant bacteria may outpace our ability to control their effect on our health.

Rational antibiotic use is the cornerstone of controlling AMR. The right dose and frequency must be used, and these will vary with the drug used and its concentration, the pathogen being treated and the patient. The clinician prescribing an antimicrobial must carefully consider these parameters.

Prudent use is everyone's business. Veterinarians and doctors can assist by adopting rational antibiotic use protocols, educating clients/patients, and limiting transmission of resistant microorganisms through proper hospital hygiene and preventative measures such as vaccines. Producers can work with vets to ensure rational antimicrobial drug use, follow specific label instructions, and maintain safe and clean on-farm environments. Consumers can limit use of products that claim to fight bacteria in the home, dispose of unused or outdated drugs appropriately, and not consume potentially contaminated or non-pasteurized products. Industry can work to develop new molecules. Government can promote prudent use, establish microbiological MRLs, and ensure labels carry sufficient and explicit directions that include warnings regarding AMR.

Antimicrobial Use in Animals: Building on Prudent Use Initiatives to Minimize Antimicrobial Resistance Risks
Dr. Lateef Adewoye, Team Leader, Policy and Programs Human Safety Division, VDD

The discovery and availability of antimicrobial agents have made it possible to treat and control bacterial infections in humans and animals. Increasing emergency of AMR is a serious threat to human and animal health. Organisms resistant to one antimicrobial agent may become resistant to other agents consequently limiting the number of effective agents.

Mitigating AMR risks requires an integrated approach given the epidemiological complexity of AMR. Antimicrobial use in any environment creates the selective pressure for the emergence and spread of AMR and significantly increases the risk of infections with resistant bacteria.

The World Health Organization has urged member states to develop measures to encourage appropriate and cost effective use of antimicrobials and to reduce the use of antimicrobials in food animal production. Canada has created a number of initiatives to tackle AMR, including the Canadian Committee on Antibiotic Resistance (CCAR), the National Information Program on Antibiotics (NIPA), a multi-stakeholder project called "Do Bugs Need Drugs?", as well as numerous provincial and university programs.

The Canadian Veterinary Medical Association (CVMA) has developed species-specific prudent use guidelines.. This initiative aims to protect human and animal health by maximizing therapeutic efficacy of antimicrobials and minimizing the emergence of resistance to antimicrobials.

Ongoing education and promotion activities, along with prudent use, are key priorities in risk management of AMR. Development of education programs by professional associations and producer organizations should continue. Other needed actions include research on cost-effective and efficacious alternatives to antimicrobials and the creation of a multi-stakeholder task force to monitor and ensure effectiveness of prudent use measures and education programs.

Canadian Veterinarians and AMR - A Long Term Concern
Dr. Conrad L'Ecuyer, CVMA

The Canadian Veterinarian Medical Association has issued guidelines on the prudent use of antimicrobial drugs in animals. The guidelines take a common sense approach and cross all species and uses.

The Advisory Committee on Animal Uses of Antimicrobials and Impact on Resistance and Human Health recommends the adoption by veterinarians, provincial licensing bodies, and on-farm food safety programs of practice guidelines that are species and drug specific and based on sound information (accurate diagnosis supported by pathology reports, etc.).

However, practice and use guidelines are only as effective as their application and "enforcement." Guidelines have to be put into effect by veterinarians, producers and their respective organizations and licensing bodies.

Canadian Approach to On-farm Food Safety - Its Evolution, Current Successes and Future Challenges
Albert Chambers, Coordinator, Canadian On-Farm Food Safety (COFFS) Working Group

Canadian producers have taken a proactive approach to on-farm food safety through the introduction of Hazard Analysis and Critical Control Point (HACCP)-based on-farm food safety programs. Commodity-specific voluntary programs include on-farm requirements for record keeping, training and management systems, conformity assessment, auditor training, risk management and official recognition.

The COFFS Working Group initiatives include training modules for auditors, templates for program management systems, risk management planning guide, and official recognition programs.

The success of the commodity COFFS programs has led to the development of pre- and post-farm gate HACCP or HACCP-based programs that have been adopted by members of the supply chain from input supplier to final marketer. Initiatives include the Canadian Supply Chain Food Safety Coalition, Canadian Partnership for Consumer Food Safety Education, CAN-TRACE and Canadian Livestock Identification Agency.

Future challenges include moving to full implementation, sustainable and affordable infrastructure mechanisms, international recognition, and adaptation and expansion of programs to encompass other management system requirements, such as environment and animal welfare. Future success depends on demonstrating value to farmers and customers, and continued collaboration amongst farm groups and with government.

Stakeholder Feedback

An extensive plenary discussion served to build a better understanding of issues around antimicrobial resistance.

Committee members noted that there are important labelling issues that need to be resolved. For example, many over-the-counter antibiotics are labelled in such a way as to promote under dosages being used. A possible solution would be to have all antimicrobials available by prescription only. The question of the need for legislation on extra-label drug use was raised.

There is need for more research and surveillance to increase the database and understanding of AMR, and to ensure evidence-based decisions. However, concern was raised regarding who should fund these research/surveillance efforts. It was suggested that the drug renewal application process be used to monitor AMR, by including an AMR risk assessment in the review.

Committee members emphasized that improving awareness and knowledge through education will be critical to controlling AMR. Information on prudent use, proper storage, dosage, etc., should be aimed at various groups, including pet owners, producers, veterinarians and consumers. Messages should be easy to understand and convey the importance of the prudent use of antimicrobials to both human and animal health.

Members noted that there seems to be a lack of focus on AMR in on-farm food safety programs. The connection of AMR to food safety and the inclusion of prudent use procedures in on-farm food safety programs would be beneficial, as would the creation of tools for veterinarians. They also noted that consumers were not involved in the range of involved stakeholders.

Stakeholders noted that the prudent use of antimicrobials is a long-term issue that will continue to be of interest to the committee and VDD can play a leadership role.

Part 4: The Canadian Sheep Industry (Stakeholder Profile)

Jonathan Wort, Canadian Sheep Federation

As a new member of the committee, Mr. Wort provided an overview of the Canadian sheep industry. Five percent of all Canadian farms have sheep, with 13,000 having an average of 74. Canadian raised sheep supply about 50% of domestic demand. There has been a 25% increase in per capita consumption since 1996. In 2002, per capita annual consumption was 1 kg.

The Canadian Sheep Federation's mandate is to represent all sheep producers at a national level, and implements activities such as the Food Safe Farm Practices Program and the Canadian Sheep Identification Program. The Canadian Sheep Breeders' Association encourages the production of high quality breeding stock and promotes programs and good production practices for maintaining sheep health.

Recent production trends have pointed to a need for greater accountability for drug use and investigation of production-related diseases. There is a lack of drugs for use in dairy sheep, which leads to off-label use. In addition, there are a number of vaccines that are being effectively used in other countries but which are not as yet approved for use in Canada, which leads to increased use of drugs.

The sheep industry supports VDD's Minor Use/Minor Species initiative as a positive first step. The extension of label claims for sheep, acceptance/harmonization of approved products of major trading partners (U.S., New Zealand, Europe), will help provide the required drugs.

Part 5: Priority Drug Review Task Force

Presentations

Report of the Priority Drug Review Task Force
Dr. Conrad L'Ecuyer

The Priority Drug Review Task Force asked commodity groups to provide a list of medical conditions and the associated drugs needed to fill major gaps in veterinarian treatment. The criteria for listing these drugs were: animal health; food safety; animal welfare; environmental protection; and public health. Listed items must also have been for food producing animals and therapeutic drugs (i.e., production enhancing drugs were not to be included). The Task Force received submissions from eight commodity groups. The content of the lists were not made public, due to confidentiality considerations.

The Task Force reviewed the submissions to identify common items (i.e., drugs sought by more than one commodity group) and those listed as a top priority by a commodity group.

The resulting list of 17 products for priority review was submitted to VDD as a starting point for priority review. The Task Force noted that it was unable to provide a more specific order of priority, as it lacked information on the status of these products within the drug submission and review process.

Analysis of the Report of the Priority Drug Review Task Force
Louis Boulay, Manager

In November 2003, VDD and the Stakeholder Committee agreed that there was a need for priority review and established principles to support a priority review process. These included:

• Priority review of a drug submission would be on a case-by-case and exceptional basis and for health and safety reasons.
• Priority review would not change submission requirements nor the level of scientific scrutiny.
• Clear conditions and criteria would be established for granting priority status to a submission.

Of the list provided by the Task Force, eight of the 17 products are currently in the VDD review process, with four targeted for completion by March 2005, and the other four to be given priority in the next review cycle. The other nine products have no submissions filed for the requested use, although seven have been approved for other species.

Confidentiality versus transparency remains a key issue in the development of the priority review process. Next steps for VDD include the revision of the draft priority review policy and the creation of a mechanism for receiving ongoing input and advice from affected stakeholders.

Stakeholder Feedback

VDD confirmed that four of the products on the Priority Drug Review Task Force's list would be marked for completion by March 2005 as part of VDD's 90% target. Another four products, which are also already in the review system, would be marked as priority for completion in the next review cycle.

The question remains, however, as to how to deal with the other nine products for which there is no applicable submission. It was suggested that VDD could inform each commodity of the therapeutic class and condition for which there is no submission (i.e., provide a list of gaps by commodity). This information can then be relayed to industry in terms of "this is where there is a need."

VDD agreed to move forward on the Priority Drug Review Task Force's list of drugs and categorize them by therapeutic group for priority review, as appropriate. In addition, to support the ongoing need for priority review of drugs, a new formalized, transparent policy for priority review will be developed by VDD for consultation with stakeholders.

Part 6: Next Steps/Agenda Setting

The next meeting of the VDD Stakeholder Committee will be held on May 4 and 5, 2005. A two-day agenda of presentations and discussion is planned. The agenda will focus on:

Day 1

• MUMS (Minor Use/Minor Species).
  • Half day session.
  • Jonathan Wort, Canadian Sheep Federation, will assist with development of this agenda item.
• Submission Review Update /Label Expansion
  • Jenny Hilliard, Consumer Interest Alliance Inc., and Liz Samis, Quality Assurance Ontario Pork Council (TBC), will work with VDD on this agenda item.
• AMR/CIPARS
  • Information/education; Rebecca Irwin to be invited to make a presentation.

Day 2

• Extra Label Drug Use (ELDU)
  • Perspectives of Canada, US and other jurisdictions; challenges and opportunities, etc.
• Stakeholder profiles from:
  • Animal Welfare (Stephanie Brown).
  • Society for Environmentally Responsible Livestock Operation (of Alberta) - Sherry Brock (TBC).

Footnotes