Veterinary Drugs Directorate Canadian Animal Health Institute Workshop Discussion of Veterinary Drug Issues May 25 and 26, 2004

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Attendees:

CAHI Members: Josee Roy, Vetoquinol; Helene Langlois, Schering-Plough; Daphne Pontbriand, Schering-Plough; Marike Dussault, Pfizer; Bruce Groves, Pfizer; Don Wilson, Bayer; Andrea Wilson, Novartis; Martin Tiemann, Merial; Lois Valli, Wyeth; Pat Whiskin, Boehringer-Ingelheim; Linda Letvenuk, Bimeda; Sue McGee, BioMedEx; Jerome Gainer, Virbac; Pat Plewman, Bioniche; Paul Dick, Elanco; Maurice Smith, Alpharma; Jean Szkotnicki, CAHI; Tracey Firth, CAHI.

VDD: C Diane Kirkpatrick; Kathy Dobbin; Denis Girard; Mike Crocker; Louis Boulay; Stan Twardowski; Ian Alexander; Sudarshan Malik; Rajinder Sharma; Arnost Vilim; Lateef Adewoye; Madeleine Marshall, Monica Gangal, Geneviève Trottier, Michelle Nicholson, Connie Rajzman, Julie Collins, Derek Ellis - Recorder.

CFIA: Susan Wilson

Others: Charlene Bender, Intervet; Susan Lahtinen, Novopharm Ltd; Choo Pin Por, Novopharm Ltd; Bert Bergen, Novopharm Ltd; Sayed Ahmed, Fort Dodge Animal Health; Richard Hameder, Rolf C. Hagen Inc; Terrance Persad, JohnsonDiversey; Andrew Medryk, JohnsonDiversey; Rita Ozolins, Centaur VA Animal Health.

Workshop Report

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 Canadian Animal Health Institute (CAHI) is the trade association representing the developers, manufacturers and distributors of animal pharmaceuticals, biologicals, feed additives and animal pesticides in Canada. CAHI is a national association, whose members are responsible for sales of approximately 95% of the animal health product market in Canada. Sales by CAHI member companies in 2002 were in excess of $480 million.

This two-day workshop was designed to provide stakeholders with the opportunity to review the two "draft guidance for industry" documents: Management of Regulatory Submissions and Preparation of Veterinary New Drug Submissions, and three "preparation for veterinary new drug submission" documents: Manufacturing and Quality Control Requirements, Human Safety Requirements, and Clinical Safety and Efficacy Data Requirements. Stakeholders are to provide feedback to VDD on areas requiring further revision or clarification, as well as to discuss VDD's initiatives in Pharmacovigilance and Bovine Spongiform Encepalopathy (BSE).

Opening Remarks

Jean Szkotnicki, President, Canadian Animal Health Institute
Ms. Szkotnicki welcomed participants to the workshop and thanked them for taking time from their busy schedules to come and share their ideas on VDD's proposed guidelines, pharmacovigilance and TSE. She noted that these issues are important to both government and industry, and it is therefore critical that solutions are found that work for all stakeholders.

Diane Kirkpatrick, Director General, Veterinary Drugs Directorate, Health Canada
Ms. Kirkpatrick observed that the workshop has been designed to enable comprehensive discussion around the draft guidelines in order to develop consensus where possible and to explore areas where further refinements may be needed. She noted that the guidelines were developed in response to stakeholder requests for improved overall management of submissions within VDD and to ensure sponsors are fully aware of data requirements.

Feedback from this workshop and other consultation venues will lead to revised documents in the fall of 2004, and final documents by spring 2005. VDD will also be developing explicit performance review standards that will be fully aligned with the requirements of the guidance document as well as Bill C212. The overall goal is a win-win environment in which everyone understands their requirements and accountabilities.

Document Review and Participant Feedback

1. Management of Regulatory Submissions

Louis Boulay, Manager, Submission and Knowledge Management Division, provided responses to questions that had been submitted by CAHI regarding the Management of Regulatory Submissions section of the proposed Guidance Document.

VDD's Draft Guidance for Industry - Management of Regulatory Submissions provides the requirements for the key steps in the submission process, defines how VDD manages regulatory submissions and related information, and describes the process that sponsors must follow for all submission related activities. The objectives of the document are to improve the quality of submissions as well as the efficiency and cost-effectiveness of VDD, leading to improved timeliness of decisions.

He noted that the document would initially apply to New Drug Submission (NDS); Administrative NDS, including submissions filed in support of corporate and brand name changes; Supplemental New Drug Submission (S/NDS); Abbreviated New Drug Submission (ABNDS); Abbreviated Supplemental New Drug Submission (ABS/NDS); and Notifiable Change (NC). Other types of submissions would be covered in subsequent editions or appendices, or new documents.

Mr. Boulay emphasized the importance of the ongoing efforts to reduce the backlog of submissions to the overall improvement of effective management of new drug approval submissions.

Mr. Boulay indicated the prototype for submission tracking process to be in place June 12, 2004 and delivered by January 1, 2005 with on-line tracking available by next fiscal year.

The following comments highlight areas where clarification and/or further development are needed, as well as industry preferences and suggestions.

• A list of priorities for future guidance documents should be developed (e.g., guidance for submissions for Investigational New Drug Submissions (INDS), applications for Drug Identification Numbers (DIN), submission classification, labeling, ABNDS, etc.).
• All information that impacts the review process or interaction between industry and government should be available to stakeholders through the VDD website. "Housekeeping" elements or activities need not be provided.
• Industry would like feedback/updates on how the process is working in terms of timelines, number of pre-submission meetings, number of recommendations, etc.
• Information regarding submissions and approvals in other jurisdictions is not part of VDD's data requirements. Nor is it acceptable in lieu of required data. However, it is useful for reviewers.
• 90 days should be allowed for industry to respond to requests for additional information (without "clock stopping"). Industry recommended that VDD consider the "stop clock" system used efficiently by other regulatory agencies.
• The effectiveness of the processes outlined in the guidance document should be regularly reviewed and revised as required.
• Timeframes for screening and reviewing must be transparent, predictable, well articulated and monitored. Industry recommends that any regulatory changes should provide the establishment of a default timeframe for those not already specified in the Food & Drugs Act and Regulations and used by other Health Canada Departments.
• Clarification is needed on label submission timeframes. VDD will try to minimize revisions to final labels after the NOC has been approved.
• Timeframes for implementing new labels following a company name and/or address change will be investigated. Jean Szkotnicki will review the U.S. FDA model for application to Canada, and provide comments to VDD.
• Industry is seeking predictability of all submission timelines.
• Further discussion is needed to define process and timelines for sponsors to update submission manufacturing packages prior to the initiation of the review (i.e., to provide sponsors the opportunity to update a submission that has been in the queue and is about to be picked up for review).

2. Preparation of Veterinary New Drug Submissions

Mr. Boulay provided clarification and answers to CAHI questions that had been previously submitted to VDD. In response, VDD will move forward on the following items:

• A submission certificate form will be developed.
• A template letter for the wording of the Letter of Authorization will be developed.
• The practices for submission and product summaries followed by other directorates will be reviewed, as well as Module 2 of the CTD, for adaptation to VDD use.
• The current section on tissue site irritation data will be moved and specific guidelines will be created for ABNDS and SABNDs.

3. Clinical Safety and Efficacy Requirements

Dr. Ian Alexander, Chief, Clinical Evaluation Division, provided clarification around the clinical safety and efficacy requirements of the proposed guidance document.

He noted that guidance on occupational safety issues may be obtained from the current Guide for the Labeling of Drugs for Veterinary Use, as well as Workplace Hazardous Materials Information System (WHMIS) and Material Safety Data Sheets (MSDS). In the absence of specific guidance, VDD will consider requirements on a case-by-case basis. In addition, the Clinical Evaluation Division will provide clarification in the guidelines regarding occupational safety relative to drugs intended for use in companion animals and the Human Safety Division will provide guidance regarding occupational safety relative to drugs intended for use in food producing animals.

The following changes will be made to the draft document:

• "Subchronic" replace "subacute or" in Item 3.1.2.2.
• The reference to "Bioequivalence Guidance" will be updated to reflect the 2002 FDA document.
• As mentioned above, separate guidelines will be created for ABNDS and SABNDS and VDD stated they will consider what is being done in other jurisdictions in developing these.

4. Human Safety Requirements

Dr. Rajinder Dharma, Team Leader, Human Safety Division, noted that the final guidance document would reference all six toxicity studies.

In response to a CAHI question regarding the data requirements for Competitive Exclusion (CE) and Direct Fed Microbial Products in 2.2, he noted that the requirements differ from those in 2.1 because the products are different. Participants noted that clarification is needed to define what is "different" between the two types of products. CE products will be dealt with on a case-by-case basis. Concerns about identifying the responsible department/agency were also raised by participants (i.e., Health Canada/VDD vs. CFIA). Further discussion will be needed to develop questions/technical requirements that meet the needs of both sponsors and regulators around CE products. VDD will consult with industry and move forward on developing an MOU between CFIA and Health Canada.

Issues surrounding the requirements for overdose studies were raised. VDD noted that the overdose studies have been set to provide additional safety measures. The Directorate is seeking industry feedback on how to update and harmonize these requirements with those of other countries. Industry agreed to attempt to provide suggestions by the end of June.

Data on consumption patterns is useful for establishing maximum residue levels (MRLs). However, the most recent national food consumption survey was conducted in the early 1970s. VDD is actively working with other government areas, such as Health Canada and Stats Can, to acquire more up-to-date information.

Industry and stakeholder input is also sought on the classification of antimicrobial drugs. The classifications in the proposed document were designed to provide a starting point for discussion and are based on the importance of each drug class to human health. Only a few examples of each category have been provided in the current draft.

Concern was expressed that the classification scheme is a defacto risk assessment that does not fully consider all factors. A case-by-case risk management approach may be more appropriate. There is fear that needed products will not be accessible under a classification process. It was noted that the U.S. Guideline 152 is currently under review, with a report expected by the end of the summer. VDD should work with the U.S. as it moves forward to develop a final guidance document.

The choice between qualitative and quantitative risk assessment depends on a number of factors based on available science. Potential adverse human health impacts of animal uses of individual antimicrobial products are a key factor in any risk assessment. The benefits of using individual antimicrobial products would also be considered. An Expert Advisory Committee is being established by VDD to provide ongoing and timely expert advice to VDD on assessment of the antimicrobial resistance risks attributable to new and existing antimicrobial products.

5. Manufacturing and Quality Control

Dr. Denis Girard, Acting Chief, Manufacturing and Quality Control, noted that acronyms would be consistent across all divisions. A glossary will be included in the guideline.

VDD is seeking to develop a formal way for manufacturers to report changes or confirm that no changes have occurred to products that have been on the market for a number of years. Industry input will be sought in establishing approach, criteria and process for reevaluation of marketed products.

Health Canada's Therapeutic Products Directorate will lead the revision of the guideline regarding Drug Master Files (DMF) in the near future. Consultations will be a part of this process. Issues of concern include use of the FDA format for filing the DMF report. Information on submitting a DMF to VDD will be included in the guidance document (address to submit information, letter of access, fee information, etc).

Participants noted that the labeling guideline needs to be updated and clarified, for example, around VDD's interpretation of "manufacturer's standards" regarding labeling. Clarification is also required around shelf life, stability and active ingredients, as well as guidance on whether a Notifiable Change would be required.

Further discussion on the requirement for summarizing developmental studies should be undertaken. Summaries are used in the EU, but are not required in the U.S. It was suggested that the guidance document state that while a summary is not mandatory, it is useful for both the sponsor and the regulator. The EU approach is preferred and would provide a model for reference.

Other areas requiring further clarification, definitions or consultation include:

• A definition of "distributor" is required. It was suggested that a statement such as "the entity legally responsible in Canada for the release of the product" be added.
• Section 2.3.4 will be revised to clarify the validation requirements (whether Phase I or Phase II).
• It was suggested that requirements for broached vial studies be added to the Preparation of Veterinary New Drug Submissions: Manufacturing and Quality Control Requirements guidance document (section 2.6). Validation guidelines for terminal sterilization processes are currently under revision by the HPFBI GMP committee. They will be consulted on.

VDD Presentations and Stakeholder Discussion

Pharmacovigilance and Adverse Drug Reaction Reporting

Geneviève Trottier, Manager, Pharmocovigilance Program
The World Health Organization defines pharmacovigilance as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem." An "adverse drug reaction," for regulatory purposes, includes adverse or unintended symptoms in animals after labeled or extra-label use, adverse symptoms in humans exposed to veterinary products and lack of efficacy.

While it is a shared responsibility with government, manufacturers have the primary responsibility to ensure marketed drugs are safe and efficacious and must report all suspected adverse drug reactions. The timeframe for reporting depends on the seriousness and expectedness (labeled or unlabeled side effect) of the symptoms.

The Adverse Drug Reaction Database has been in operation since March 2003. All new ADR reports are entered, and historical data is added as resources permit. The database enables the preparation of multiple-variable reports and investigation according to drug class and demographic profiles. Reactions related to exposure to veterinary drugs in humans are also collected and assessed.

VDD represents Canada on the VICH Expert Working Group on Pharmacovigilance and participates in information sharing and policy issue sessions. A meeting of pharmacovigilance regulators from the United States, the European Union, Australia and Canada was held in Ottawa in March 2004. Outcomes of that meeting included a position paper for harmonizing pharmacovigilance practices and a proposal to establish an informal pharmacovigilance network among regulators for information sharing.

Drug safety is a collaborative effort that requires the participation of drug manufacturers, veterinarians and the animal health community, end-users of veterinary products and Health Canada and other regulators. Health Canada and VDD are committed to transparency, consultation with stakeholders, development of national and international standards and guidelines, improved communication of safety data and awareness and educational programs.

Adverse Events

Dr. Susan Wilson, Veterinary Biologics Section, CFIA
The Veterinary Biologic Section (VBS) of the Animal Health and Production Division, Canadian Food Inspection Agency (CFIA), is responsible for licensing veterinary biologics in Canada. This licensing program forms an integral part of Canada's National Animal Health Program, which strives to protect the health of food producing animals, domestic pets, and the Canadian public by preventing the introduction and spread of certain important animal diseases.

To meet the requirements for licensing, veterinary biologics must be shown to be pure, potent, safe, and effective when used in the target species according to the manufacturer's label recommendations. In addition, the licensing submission must also contain supporting data demonstrating that the product can be manufactured and used without adversely affecting animal health, human health, food safety or the environment.

The Health of Animals Regulations requires that any information or evidence of a significant deficiency in safety, potency or efficacy of a veterinary biologic be reported within 15 days. "Adverse events" are defined as those that have a serious impact on the health, productivity, or marketability of an animal. Veterinarians and the public can report suspected adverse events (SAEs) to the Veterinary Biologics Section (VBS) of CFIA, which then contacts the manufacturer and/or importer and request an investigation. Further information on how to report suspected adverse events can be found at the following web site:  Canadian Food Inspection Agency Guidelines and Forms

Open Forum Discussion

Post marketing surveillance is an essential part of the drug review process that will help with pre-market evaluation. VDD noted that post market information will not replace data for current submissions, but it does provide information that is very helpful for reviewers, thereby streamlining the process and building improved efficiency.

Although progress is being made, more efforts are required by all stakeholders to collect, analyze and communicate information about adverse drug reactions, extra label drug use, and prescribing practices amongst veterinarians, industry and regulators. However, raw data without interpretation is not useful. Similarly, distinctions need to be made between Canadian events and events in other countries, particularly in relation to varying label requirements.

Periodic Summary Update Reports (PSURs) provide concise data on targeted drugs and are assessed in combination with adverse reaction reports and other available safety data. The international PSUR format is the recommended standard. CAHI will provide feedback to CFIA and VDD on industry perspective regarding PSUR reporting.

Concern was expressed that there seems to be an inequitable burden of responsibility on industry while other areas related to veterinary drug use remain unregulated. VDD agreed that regulations cannot be aimed only at the "responsible industry," and noted that there are many concurrent activities underway to deal with other areas of veterinary drug use, including importation of unapproved drugs, compounding, use of active pharmaceutical ingredients (APIs), etc. The importance of industry and government working together is crucial for maintaining consumer confidence in the safety of the food production system and in moving forward on these important issues.

A participant commented that the proposed submission guidelines may have the effect of increasing regulatory burden and costs on industry, and may lead to a lack of new drugs in the marketplace. VDD emphasized that one of the objectives of the guidelines is to provide clear processes and expectations that will help create a level playing field. In addition, the guidelines are very much consistent with the requirements of other jurisdictions. Participants noted that to be truly effective, the overarching result of the guidelines must be a faster timeline for approval.

Manufacturing and Chemical Evaluation Division

Recent BSE (bovine spongiform encephalopathy) in North America have heightened concerns regarding potential public exposure to TSEs (transmissible spongiform encephalopathies). As part of its response, Canada has prohibited the entry of bovine specified risk materials (SRMs) into the human food chain. SRM prohibition to food does not specifically address the use of bovine derived materials in veterinary drugs.

VDD's approach to minimizing the potential risks to the health and safety of Canadians posed by TSE include:

• undertaking a situation analysis and identification of risk factors;
• gathering information, identifying risk in certain types of ingredients, development of a database to capture this information for active pharmaceutical ingredients, excipients and auxiliary reagents derived from bovine sources; and
• development of a guidance document.

Many factors need to be considered in minimizing the risk of transmission of TSE agents, such as the source of the raw materials (age of animal, genus and species, country of origin, type and quantity of tissues and/or body fluids), potential for cross contamination and substantiation of any claims regarding inactivation of TSE agents in the manufacturing process.

The proposed scope of the guidelines will include New Drug Submissions (NDS, ABNDS, SNDS, SABNDS, NC).

VDD is seeking stakeholder feedback as it moves forward in this important and challenging area.

Open Forum Discussion

The BSE/TSE issue is far larger than VDD - other areas of Health Canada and CFIA are also actively pursuing it, and have been doing so well before the initial North American outbreaks. For example, CFIA has been developing a table of ruminant products and products with components of ruminant origin.

VDD clarified that Health Canada's guidance document for TSE should be completed by the fall. VDD indicated that they would think about looking at already marketed products at some point in the future but that for now the primary focus of the guidance document was new drugs. It was also indicated that upgrades to the guidance document would be made if new science emerged. The guidance will take a cascading approach to requirements based on potential risk. The document will be a collaborative effort within Health Canada and will apply to products intended for both human and veterinary use, with appendices dealing with specific applications/product lines.

Participants sought clarification on the department/agency that will be responsible for export/import certification, as CFIA had done this in the past. VDD will provide CAHI members with an initial point of contact and provide redirection as necessary.

There was general agreement that there is a need for clarification and updating regarding pet food manufacturing.

Closing Comments

Jean Szkotnicki, President, Canadian Animal Health Institute
Ms. Szkotnicki noted that very good progress on a large number of issues had been made over the course of the workshop. She observed that it is only the beginning. Many issues have been identified and areas for further discussion. There is clear commitment on the part of VDD to continue to work together with industry to move these issues forward.

Diane Kirkpatrick, Director General, Veterinary Drugs Directorate, Health Canada
Ms. Kirkpatrick thanked participants for their involvement and ongoing input. She observed that the candidness and thoughtfulness of participants' comments are appreciated. Through ongoing cooperation and collaboration we will achieve our mutual goals for improved processes, greater efficiencies and improved access to veterinary drugs.