Veterinary Biologics Guideline 3.29E
Safety Requirements for Veterinary Biologics
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Table of Contents
- I. Introduction
- II. Pre-Licensing Safety
- III. Application for Licensure
- IV. Post-Licensing Safety
- V. Laboratory Biosafety & Animal Use
- VI. Special Considerations for Manufacturers in the United States
- Appendix I: Permit to Release Veterinary Biologics
- Appendix II: Field Safety Trials
The purpose of this document is to advise veterinary biologics manufacturers of the safety requirements for veterinary biologics manufactured in, or imported into, Canada. This guideline is directed primarily at Canadian manufacturers and foreign manufacturers in countries other than the United States (US). The safety requirements for veterinary biologics manufactured in the US and licensed by the US Department of Agriculture are similar to Canadian requirements, as noted in Section VI.
The Canadian Centre for Veterinary Biologics (CCVB) uses a multi-step process to evaluate the safety of veterinary biologics, which includes the review and approval of documents and test data submitted by manufacturers, independent laboratory testing of master seeds, cell lines, and product serials, and post-licensure monitoring of product serial releases and adverse events. A risk-based approach is used to determine the appropriate standards, processes, laboratory tests and field trials to apply in evaluating the safety of a veterinary biologic.
More information on new product submission requirements can be found in Guideline 3.1: Guidance for Preparation of New Product Licensing (Registration) Submissions for Veterinary Biologics and references therein. Autogenous vaccines, in vitro diagnostic kits, colostrum and antibody products may have different safety requirements than those covered in this guideline. Manufacturers of these types of veterinary biologics are directed to view the relevant product-specific guideline(s) available on the CCVB website.
A. Legal Authority
CCVB is responsible for regulating veterinary biologics in Canada, including ensuring the safety of these products, under the authority of the Canadian Health of Animals Act [64.(1)(s)] and Health of Animals Regulations [Part XI - Veterinary Biologics].
Adverse Event - an observation in an animal that is unfavourable and unintended, which occurs following the use of an experimental or licensed veterinary biologic, regardless of whether or not the event is considered to be product related.
Containment - a condition under which the movement of an organism is limited by one or more of the following mechanisms:
- a set of standard practices that are generally used in microbiological laboratories;
- special procedures, equipment and laboratory installations that provide physical and other barriers, which are applied in various degrees according to the estimated biohazard, and/or
- biological barriers that limit either a) the infectivity of a vector or vehicle (plasmid or virus) for specific hosts, or b) its dissemination and survival in the environment.
Containment ensures that there is no release of an organism, or material from the organism, from a research facility to the environment.
Non-target animal - an animal belonging to a species, or group of animals (e.g. pregnant), not intended for the final use of the veterinary biologic.
Outline of Production - a detailed description of a) the process followed in preparing a veterinary biologic and any diluent to be used therewith, b) the methods and procedures to be employed in handling, storing, administering and testing a veterinary biologic and any diluent to be used therewith, and c) the tests used to establish the purity, safety, potency and efficacy of a veterinary biologic, and the purity and safety of any diluent to be used therewith.
Target animal - an animal belonging to a species, or group of animals (e.g. pregnant), intended for the final use of the veterinary biologic.
II. Pre-Licensing Safety
A. General Process
Typically, progression from inception to licensure of a product with restricted or unrestricted distribution can be accomplished in the following stages:
- Laboratory research and development under contained conditions;
- Submission to CCVB of proof of concept data;
- Controlled containment experiments using target and non-target animal species;
- Limited field trials using target species;
- Submission to CCVB of any outstanding documents and data.
Preliminary research and development work will usually be conducted under the control of institutional biohazard/biosafety personnel, following the publications listed in Section V of this guideline. After the initial submission to CCVB, researchers may find additional guidance about the design and execution of controlled animal experiments by consulting CCVB staff; however, CCVB approval is not required prior to conducting laboratory experiments in containment, provided that the vaccinated animals do not enter the food or feed chain (i.e. they are incinerated or composted). Release of a veterinary biologic from laboratory physical containment to field conditions requires CCVB approval and a Permit to Release Veterinary Biologics (refer to Appendix I). More information on field safety trials is provided below and in Appendix II.
B. Master Seed and Cell Line Quality Control
The manufacturer is responsible for quality control testing and certification of master seeds and/or cell lines used in the production or testing of a veterinary biologic. The results of these analyses must be submitted to CCVB in support of licensure. CCVB will then arrange verification testing through a CFIA Laboratory. The quality control testing of master seeds and/or cell lines may include tests for identity, genetic content for products of biotechnology, genotypic and phenotypic stability when subcultured from the lowest to the highest passage number used in production, and purity from contaminants and adventitious agents (e.g. detection of extraneous bacteria, fungi, mycoplasmas and viruses).
C. Reversion to Virulence
For live veterinary biologics, reversion to virulence studies (also known as backpassage studies) must be performed to evaluate the genetic stability of the vaccine, to provide assurance that the product will not revert to virulence when passaged in the target animal. In these studies, a group of animals is administered an appropriate dose of the live vaccine organism via the route most likely to lead to replication and reversion. Subsequently, an attempt is made to recover the vaccine organism from these animals at the time interval and by the route (secretion or tissue) that it is most probable to recover the vaccine organism. Any recovered vaccine organism is then inoculated directly into another group of susceptible animals. After each passage, the presence and quantity of test organisms must be determined. No evidence of an increase in virulence, indicative of reversion, shall be seen with passage. The virus or microorganism isolated from the last passage must be characterized genotypically and/or phenotypically, and compared to the master seed to evaluate genetic stability and reversion to virulence. Manufacturers are encouraged to follow the procedures outlined in the US Department of Agriculture Veterinary Services Memorandum No. 800.201 and Guideline 41 of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH) entitled Target Animal Safety: Examination of Live Veterinary Vaccines in Target Animals for Absence of Reversion to Virulence regarding backpassage studies.
D. Contained Animal Toxicity Studies
Preliminary safety testing of a veterinary biologic typically includes a mouse safety test and testing in the target animal, often during the initial proof-of-concept studies. Safety tests are conducted to ensure that the veterinary biologic does not cause undue local or systemic reactions in animals. The veterinary biologic formulation employed in these safety experiments should contain a level of antigen at or near the proposed maximum allowable antigen. Contained animals studies should also address the safety of administering an overdose (typically 10x for live and 2x for inactivated) and/or repeated single doses of the experimental product.
For live veterinary biologics, data are required on the mode, rate and duration of shedding, as well as the propensity of the organism to spread to contact target and non-target animal species.
F. Bluetongue Virus Exclusion Testing
Manufacturers are required to conduct bluetongue virus exclusion tests on all live vaccines for use in ruminants that utilize non-irradiated bovine or other ruminant serum, or when the virus is grown on either primary bovine or other primary ruminant cells. Further information on bluetongue virus exclusion testing may be found in Guideline 3.6: Guideline for Bluetongue Virus Exclusion Testing of Veterinary Biologics.
G. Pseudorabies Virus Exclusion Testing
Manufacturers are required to demonstrate the absence of pseudorabies virus (Aujeszky's disease) in all live porcine virus vaccines that utilize non-irradiated porcine serum or are grown on primary porcine cells. Further information on pseudorabies testing may be found in Guideline 3.31: Guideline for Pseudorabies Virus Exclusion Testing of Veterinary Biologics.
H. Replicating Avian Leukosis Virus Testing
All embryonated eggs, chicks or chicken tissue used as ingredients in veterinary biologics must be derived from unvaccinated specific pathogen free (SPF) flocks. Testing of these veterinary biologics for lymphoid leukosis virus contamination must be performed in a manner acceptable to CCVB, and must be described in the Outline of Production (OP) or in a Special Outline (SO).
I. Materials of Animal Origin
In order to minimize the risk of introducing animal transmissible spongiform encephalopathy (TSE) agents or other contaminants into Canada through veterinary biologics, all materials of animal origin (MAO) used in the development and production of a veterinary biologic must be identified, along with the species and tissue of origin, supplier, and source country, in a SO referenced in the OP. Manufacturers of veterinary biologics are responsible for ensuring that any MAO contained within their products are acquired from suppliers who can confirm that the MAO were derived from sources considered to be safe from animal TSE infection or contamination. In particular, veterinary biologics must not contain any material defined as specified risk material (SRM). The manufacturer must provide a certificate from each supplier indicating the supplier's actions with respect to minimizing the risk for contamination of their product by animal TSE agents. Further information regarding MAO requirements and the Declaration of Compliance may be found in Guideline 3.32: Guideline for Minimising the Risk of Introducing TSE Agents through Veterinary Biologics.
J. Field Safety Trials
Field safety trials are conducted prior to licensure to demonstrate that a veterinary biologic is safe for use in the target animal and does not cause unexpected adverse events and/or mortality when used as recommended by the manufacturer. The field safety trial provides a degree of confidence with respect to the rate of occurrence of adverse events, and identifies reactions that may require precautionary statements on the product label. Veterinary biologics (typically more than one pre-licensing serial) are usually tested for field safety at three geographically distinct locations, with enough animals vaccinated on each premise to be statistically relevant (exact number depends on the product), and with a third of the animals tested being at the minimum age indicated for vaccination. Pre-licensing serials are not released for field trials without the previous submission and acceptance of the documentation outlined in Appendix II by CCVB. Appendix II also contains information on the reporting of field safety trials.
To release the organism into the environment, researchers and developers must obtain a Permit to Release Veterinary Biologics prior to conducting a field trial. This permit authorizes the use of a veterinary biologic product for "Investigational Use Only", to generate field safety data in support of a licence application. Requirements for a Permit to Release Veterinary Biologics are listed in Appendix I.
K. Environmental Assessment
As a condition of the Permit to Release Veterinary Biologics, all live veterinary biologics derived through biotechnology, as well as products containing organisms considered novel to Canada, must have a detailed Environmental Assessment (EA). This document contains information on the molecular and biological characteristics of the novel vaccine, target animal and non-target animal safety, human safety, environmental considerations and risk mitigation measures. An outline of the EA can be found in Guideline 3.2: Regulation of Veterinary Biologics Produced by Biotechnology. The manufacturer must submit all relevant data to aid the CCVB reviewer in preparing the EA. The CCVB reviewer will also independently research any potential safety issues, and may consult with other federal and provincial government departments with expertise in areas of concern. The EA must be completed before authorizing the release of the organism in a field safety trial.
L. Consistency of Production
The production of safe, pure, potent and efficacious vaccines requires quality assurance procedures to ensure the uniformity and consistency of the production process. Prior to completing licensure, the manufacturer should produce in its facilities three consecutive pre-licensing serials (normally of at least a third of the size of serial that will be produced upon licensure) of completed product according to the product OP, to evaluate batch-to-batch uniformity. The manufacturer must test each of these serials for safety, purity and potency as described in the product OP.
III. Application for Licensure
The material required from Canadian manufacturers in support of a Veterinary Biologics Product Licence, together with a list of supplemental documentation required of foreign manufacturers, is specified in Guideline 3.1: Guidelines for Preparation of New Product Licensing (Registration) Submissions for Veterinary Biologics and is further described in other relevant guidelines.
B. Testing by a CFIA Laboratory
As part of the licensing process, manufacturers must submit samples of the master seed(s) and cell line(s) used in the development and production of a veterinary biologic, as well as samples of the pre-licensing serials of the product to a CFIA Laboratory. The Laboratory will conduct independent tests to verify the quality control testing of the master seeds and cell lines, to confirm the manufacturer's product safety and purity testing, and to examine the potency of the veterinary biologic.
IV. Post-Licensing Safety
A. Serial Release Testing
1. Testing by the Manufacturer - The manufacturer is required to conduct all appropriate tests (including bluetongue virus exclusion, pseudorabies virus exclusion or replicating avian leukosis virus testing where appropriate) described and agreed upon in the OP prior to the release of each serial of a licensed veterinary biologic that is produced or sold in Canada. Such testing often includes inoculating target and/or non-target animals with the product in order to verify the safety of the serial. For Canadian manufacturers and foreign manufacturers from countries other than the US, the results from such tests must be communicated to CCVB via signed copies of a Manufacturer's Serial Release Test Report, and must be retained in the manufacturer's records for a minimum of six years. In addition, samples of each serial must be stored by a manufacturer for at least six months past the expiry date.
2. Testing by a CFIA Laboratory - Manufacturers must submit samples of each serial to a CFIA Laboratory according to Guideline 3.22: Guidelines for the Submission, Testing and Reporting of Biological Samples. For products/serials selected by CCVB, the Laboratory may conduct, among other tests, the serial release safety tests described by the manufacturer in the OP.
B. Adverse Event Monitoring
The Health of Animals Regulations require every holder of a veterinary biologic licence or permit (manufacturers, commercial importers, veterinarians, or diagnostic laboratories) to report, in writing, any information concerning, or any evidence of, a significant deficiency in safety, potency or efficacy of a veterinary biologic within 15 days after the date on which that information or evidence is known to the holder or is generally known to the industry. Upon receipt of an adverse event complaint by CCVB, the manufacturer is asked to investigate and prepare a report for the owner's veterinarian and the CFIA. If the problem is resolved to the satisfaction of the veterinarian/client, no further action is usually requested by CCVB. However, if the outcome is not satisfactory, CCVB may initiate regulatory action depending on the case, which may include further safety testing, temporary stop sale, product recall, or product withdrawal from the market. For more information on the responsibilities of veterinary practitioners and veterinary biologics companies for reporting and investigating suspected adverse events, please refer to Guideline 3.15: Reporting Suspected Adverse Events to Veterinary Biologics.
Note 1: While holders of import permits are not required to report each separate adverse event which has occurred in another country, they are required to report any information or adverse event which may indicate a significant deficiency in the safety, potency or efficacy of a product being distributed in Canada.
V. Laboratory Biosafety & Animal Use
All aspects of the development and evaluation of a veterinary biologic must meet the standards and regulations for laboratory safety and animal use described in the documents listed below, along with the relevant provincial legislation, and local safety and animal care authorities.
- Containment Standards for Veterinary Facilities originally written by Agriculture and Agri-Food Canada and adopted by the CFIA.
- Laboratory Biosafety Guidelines and other applicable publications available through the Public Health Agency of Canada.
Note 2: Although the Laboratory Biosafety Guidelines does not reference all animal pathogens, the manufacturer is responsible for ensuring that the appropriate containment level is used to handle any live organisms used in the development and evaluation of the veterinary biologic.
- Guide to the Care and Use of Experimental Animals and other relevant guidelines published by the Canadian Council for Animal Care
VI. Special Considerations for Manufacturers in the United States
US manufacturers, and "Permittees" in the US of foreign manufacturers, may apply to license in Canada a veterinary biologic product already licensed by the US Department of Agriculture (USDA). In this situation, CCVB will review all pertinent USDA documentation (scientific data and correspondence) and will notify the manufacturer of any additional safety requirements.
If the master seed(s) and cell line(s) used in the production and evaluation of a veterinary biologic have previously been tested and approved by the USDA Center for Veterinary Biologics (CVB) Laboratory, or by another appropriate laboratory, in a manner accepted by CCVB, the latter may waive the requirement for confirmatory testing by CFIA, as long as the master seed(s) and cell line(s) have not been manipulated in any way since their approval. Similarly, CCVB may also grant a veterinary biologic product manufactured in the US an exemption from CFIA testing of pre-licensing and post-licensing serials, provided that these serials are tested and released by the USDA-CVB in a manner acceptable to CCVB.
Test results for pre-licensing serials are reported on the Animal and Plant Health Inspection Service Form APHIS 2008 - Veterinary Biologics Production and Test Report and must be provided to CCVB.
Appendix I: Permit to Release Veterinary Biologics
A Permit to Release Veterinary Biologics contains information on the nature of the veterinary biologic product, the conditions for use, and any restrictions. Where applicable, the information required by CCVB in order to issue the permit may include:
- The name of the person or body responsible for the proposed release and the name of the person who will be in charge of carrying out the release, as well as the name of the attending veterinarian(s).
- The proposed starting date, time period and site(s) of the release.
- The serial number(s) to be covered by the permit, along with the serial number(s) and number of doses to be used at each facility.
- The assigned name of the veterinary biologic, as well as a description of the product and any diluent used with the product.
- In the case of a live genetically modified veterinary biologic, a) a description of the donor organism and the methods of incorporation of the genes from the donor organism into the host, b) a description of the live genetically modified veterinary biologic, including details relating to expression of the new gene and the stability of its incorporation, and c) a comparison of the characteristics of the live genetically modified organism with those of the unmodified organism.
- The Outline of Production describing the preparation of the veterinary biologic and any diluent to be used with it. This should include a list of the materials of animal origin used in the production of the product and a statement confirming freedom from TSE contamination.
- The results of tests used to establish the safety, purity, potency and efficacy of the experimental veterinary biologic, and the safety and purity of any diluent used with it.
- The procedures to be followed in handling, storing, administering, testing, releasing and disposing of the veterinary biologic and any diluent to be used with it.
- The purpose of the proposed release, and a detailed experimental protocol when used for research purposes.
- A description of the type of animal (species, breed, age, sex, other relevant information) in which the product will be used.
- Proposed measures to mitigate any risk of harm to the environment or to human or animal health.
- For novel veterinary biologics, all information required by the CCVB reviewer to prepare an environmental assessment, which will be compiled and approved prior to issuance of the release permit.
- Any other information with respect to the veterinary biologic that is relevant to identifying any risk of harm to the environment or to human or animal health.
Upon review of the above information, CCVB will specify certain conditions for use of the unlicensed veterinary biologic. These conditions will be determined on a case-by-case basis and may include (but are not limited to):
- The product must not be sold or distributed to anyone other than the named facilities and/or licensed veterinarians;
- All records pertaining to the distribution, use and disposal of the product must be maintained by the manufacturer and/or attending veterinarian for a minimum of six years. These records must be made available to CCVB upon request;
- The permittees uses the veterinary biologic at their own risk and assumes responsibility for all consequences resulting from the possession or use of this product;
- Veterinarians, animal owners and any personnel under their authority must be informed that the product is intended for investigational use only, or for emergency use only, and no licence has been issued pursuant to the Health of Animals Act and Regulations;
- Written consent from all parties must be obtained and kept on file by the manufacturer;
- The product must bear a label approved by CCVB and copies of the labels must be maintained by the manufacturer for a minimum of six years;
- A pre-determined withdrawal time (typically between 21 to 60 days depending on the nature of the adjuvant) is required prior to slaughter for food;
- All waste, including needles, gloves, product containers and unused product must be treated as biomedical waste and disposed of properly;
- All aspects of the proposed use of the animal must meet the standards and regulations for the care and maintenance of experimental animals as described by the Canadian Council of Animal Care, along with relevant provincial and local animal care authorities;
- The Workplace Hazardous Materials Information System (WHMIS) and other Canadian Labour Code requirements for the provision of safe working conditions must be followed;
- The veterinary biologic must be packaged in appropriate shipping containers to prevent accidental spillage of contents during transportation, and must be shipped in accordance with Transport Canada's regulations regarding the transportation of dangerous goods. A copy of the signed release permit should accompany the unlicensed product during shipping;
- All relevant federal, provincial and municipal environmental requirements must be fulfilled;
- For large scale studies or for pre-licensing serials, a CCVB reviewer may require that an appropriate number of samples of the experimental serial(s) be submitted to a CFIA laboratory for testing;
- The permit holder must report, in writing, to CCVB any information concerning or any evidence of, a significant deficiency in safety, potency or efficacy or a veterinary biologic within 15 days after the date on which that information or evidence is known to the holder or is generally known to the industry. In case of significant adverse events attributable to the product, usage should be stopped;
- The Permit to Release Veterinary Biologics may be cancelled or suspended if there is reason to believe that failure to do so could result in harm to the environment or to human or animal health;
- Date until which the permit is valid.
Appendix II: Field Safety Trials
The purpose of a field safety trial is to assess the safety of a veterinary biologic in its target population under the conditions of its intended use. Field safety trials can detect adverse events of unexpected type or frequency that might indicate a need for further investigation, or warrant a precautionary statement in the labelling. Field safety trials may be monitored by the CFIA.
B. Approval by CCVB
All field safety trials require approval from CCVB prior to their commencement. In support of a licensing application and prior to starting the field trial, investigators must submit the following documents for review by CCVB:
- Outline of Production - Manufacturers must submit an OP, including any relevant SOs, detailing the methods used to manufacture and test the veterinary biologic. More information on the preparation of these documents can be found in Guideline 3.7: Guideline for Preparation of Outlines of Production, Special Outlines and Summary of Changes for Veterinary Biologics.
- Purity, Potency, and Safety Data - Manufacturers must accumulate and submit data demonstrating the purity, potency, and laboratory safety of the pre-licensing serial(s) to be used in the field safety trial.
- Efficacy Data - Results of a laboratory-based vaccination-challenge efficacy study should be included as part of the submission.
- Environmental Assessment - Manufacturers must submit all relevant information to aid CCVB reviewers in preparing the environmental assessment for a veterinary biologic produced through biotechnology, or containing an organism that would be novel to Canada. An outline of an environmental assessment is included in Guideline 3.2: Regulation of Veterinary Biologics Produced by Biotechnology.
- Labelling - A draft copy of the labelling, packaging and any product information sheets that will accompany the veterinary biologic during the field safety trial must be submitted to CCVB for approval. The label of the pre-licensing serial must clearly include the statements, "For Investigational Use Only" and "Not For Sale". For more details on labelling requirements, please refer to Guideline 3.3: Labelling of Veterinary Biologics.
- Experimental Protocol - The proposed experimental protocol must be detailed in Part I of the Field Safety Trial Report, which is further described below.
C. Field Safety Trial Report: Part I - Experimental Protocol
Part 1 of the Field Safety Trial Report, which is submitted to CCVB for approval prior to conducting the field safety trial, must include the following information:
- Title Page - The title page of the report should contain the a) scientific name and, if known, the trade name of the veterinary biologic, b) name of the manufacturer, c) manufacturer's veterinary biologics establishment licence number, d) trial title, e) anticipated start and completion dates of the trial, f) preparation date of the report, g) name, address, phone number, fax number, and email address of the person to contact regarding the trial, and h) any proposed label claim(s) and precautionary statement(s). In addition, the scientific and trade names of the veterinary biologic, the manufacturer's veterinary biologics establishment licence number, and the preparation date of the report should appear on each subsequent page of the report.
- Objectives - The general and specific objectives of the field safety trial must be described.
- Background - A brief background should be included to justify the field study and convey an understanding of the specific objectives, placing it in the context of the veterinary biologic product's developmental stage and any specific safety claims (e.g. safety during pregnancy).
- Participants - The manufacturer must submit to CCVB a list of the names, contact information, qualifications and responsibilities of each of the principal participants involved in the field safety trial. In addition, the proposed recipients (veterinarians, etc.) of the experimental veterinary biologics, as well as any animal owners must be identified (list all locations). The anticipated quantity of the product destined for each location should also be indicated.
- Pre-licensing Serials - The pre-licensing veterinary biologic to be used in the field safety trial must be described in this section. Specifically, manufacturers should indicate the assigned scientific name and, if known, trade name of the product, the composition of the product, including any adjuvants, the method of production (or cite the OP on file with CCVB), the serial number, and the date of serial production. More than one pre-licensing serial (batch) of the veterinary biologic should be tested for field safety (typically two pre-licensing serials are used). The pre-licensing serials must be produced in a licensed production facility according to the methods described in the OP. The potency of the pre-licensing serial must be above the minimum potency standard indicated in the OP, and should be at the maximum allowable antigen titre if specified in the approved OP.
- Experimental Design Overview - The manufacturer must provide a synopsis of the field safety trial design, describing the treatments, test animals, timing of events, parameters to be monitored, etc.
- Sequence of Events - The trial schedule must list the key experimental milestones, their anticipated dates, and the events that take place at each occasion.
- Blinding - Whenever possible, observations should be made without knowing the status of the animal being observed. This section should describe the blinding methods to be used in the field safety trial, or justify the absence of blinding observations.
- Description of Test Animal
- Sample Size - The number of animals required for a field safety trial is determined on a case-by-case basis, based on the type of product, the probability of detecting adverse events, the label claims made by the manufacturer, and the risk of harm to animal or human health, or the environment.
- Treatment Groups - A description of the treatment groups (including any stratification or blocking factors used in the experimental design) must be provided, along with the method used to (randomly) allocate the test animals to each of the treatment groups.
- Type of Animals - The breed, age, sex, gestation and/or lactation status, and any other distinguishing features of the animals to be used in the field safety study should be indicated. All types of animals included in the manufacturer's label recommendations should be represented in the animals selected for the field safety trial. In particular, a sufficient number of animals (typically 1/3) should be at the minimum age indicated for vaccination. Any criterion for the inclusion and/or exclusion of a test animal from the study must be described.
- Method of Animal Identification - The methods used to identify the test animals must be specified.
- Housing and Environmental Conditions - The animals selected for a field safety trial should be from a minimum of three geographically distinct 6. locations, preferably with differing environments, and housed under various conditions of animal husbandry.
- Treatment of Adverse Events - The anticipated adverse events and the methods used to treat affected animals should be stated.
- Concurrent Medication / Vaccination - If the animals are expected to receive medication (e.g. anaesthetics, analgesics, tranquillizers) or additional vaccination during the field trial, these should be indicated.
- Product Administration - The veterinary biologic should be administered according to the product label, including the administration of multiple doses and/or alternate routes of administration if indicated.
- Observation Period - This section should outline the frequency and duration of observations, personnel making observations, and the procedures to abide by upon detection of a suspected adverse event. Animals should be observed by a qualified person (e.g. veterinarian or trained specialist) during the immediate post-vaccination period, and also at specified key points following vaccination. Typically any adverse events are monitored until resolution. In the case of mortality, attempts to identify the cause of death should be made.
- Data Collection - Copies of the reporting forms that are to be given to field investigators and, if applicable, animal owners, should be provided in an appendix. Manufacturers should ensure that all records are legible and include the initials or signature of the person responsible. Any recording errors may be corrected using a single line cross-out so that the error remains legible, with the correction and the initials of the person responsible for the change clearly visible. Any abbreviations or acronyms must also be defined. If tissue samples need to be collected during the field safety trial, or at the slaughter of the test animal, this section should also include the procedures to be used when collecting the samples.
- Data Analysis - A strategy to analyse the data from the field safety trial, including any proposed statistics, should be offered.
- Disposal - The procedures to be used for the disposal of test animals, as well as any remaining veterinary biologic product, must be described. Under certain circumstances, manufacturers may be required to notify CCVB in writing prior to the shipment of experimental animals for slaughter. For meat animals, depending on the nature of the product, a withdrawal time of between 21 to 60 days is required for veterinary biologics before the animal can be sent for slaughter.
D. Field Safety Trial Amendments
Should changes to the experimental protocol describing the field safety trial be necessary, the manufacturer must notify CCVB in writing by providing the following:
- a summary of the necessary changes with reference to each part or page and each paragraph or subparagraph being changed,
- an explanation of the reason for the change(s), and
- a copy of the amended page(s). Amended pages should be numbered the same as those being superseded. They should bear the date prepared, and the date of the pages being superseded. If one page is superseded by multiple pages, the pages should have the page number followed a letter.
E. Field Safety Trial Report: Part II - Results and Conclusions
Part II of the Field Safety Trial Report, which is submitted to CCVB in support of an application for licensure, contains the following information:
- Title Page - same as in Part I
- Summary - The summary should restate the purpose of the field safety study and the basic procedures used, state the main findings, and link the main findings to the proposed label claims and/or precautionary statements.
- Deviations from Original Protocol - All deviations from the original protocol must be identified and their potential impact upon the results or interpretation of the trial discussed. In particular, this section must explain the reasons for which an animal was removed from the study, and describe any additional treatments received by an animal during the course of the study.
- Adverse Events Reporting - Data related to the incidence, severity, and duration of local and systemic adverse events must be compiled from the field study. Adverse events may be categorized according to standardized low-level terms developed by the Veterinary Dictionary for Drug Regulatory Activities (VEDDRA). This database is currently maintained by the European Medicines Agency (EMEA) and is published on EMEA's website as CVMP-VEDDRA List of Clinical Terms for Reporting Suspected Adverse Reactions in Animals to Veterinary Medicinal Products (EMEA/CVMP/413/99-Rev.4). All suspected adverse events must be reported, regardless of the individual making the observation. If a firm wishes to conclude that an adverse event is not related to the veterinary biologic, such a claim must be supported in the report by a follow-up evaluation and/or diagnosis by a veterinarian, and if possible, laboratory test results.
- Summary Tables - All animals entering the field trial must be accounted for in the report, as well as in written records. Although the original data collection forms generated by the field study must be kept on file by the manufacturer and be available upon request, the results of the field safety trial may be presented in summary tables of individual animal data sorted by treatment group in the field report.
- Descriptive Statistics - Measures of distribution (histograms, scattergrams, boxplot, etc.), central tendency (means, medians, etc.), and dispersion (standard deviation, etc.) of the data should be performed for the appropriate safety response variables by relevant sub-group.
- Inference Statistics - Where applicable, inference statistics such as Analysis of Variance should be employed to demonstrate statistical significance between relevant treatment groups.
- Label Precautions - For each type of adverse event for which the animals were monitored, the manufacturer should make a statement estimating the maximum percent of the population that could be susceptible to that particular adverse reaction, for 95% and 99% confidence levels (based on an approximation to the binomial distribution), given the number of animals that were observed in the field trial with no reaction.
Table 1: Estimates of the maximum percent of the population that could be susceptible to a particular adverse event given the number of animals that were observed in a field safety trial with no reaction, for 95% and 99% confidence levels (based on an approximation to the binomial distribution).
Number of Animals Tested with no Reactions Maximum Percent Susceptible 95% (C.L.) 99% (C.L.) 100 3.0 4.6 200 1.5 2.3 300 1.0 1.5 400 0.7 1.1 500 0.6 0.9 1000 0.3 0.5
- Conclusions and Discussions - This section of the report should indicate the extent to which the study objectives have been satisfied, and may address limitations of the field safety trial that might impact upon the interpretation of the results. By linking the findings of the field safety trial with other available safety data, a notion of overall product safety should be established for the veterinary biologic. The significance of the results towards the product's development and application for licensure should also be discussed. Importantly, the process used to interpret the data in order to generate or substantiate any proposed label claims and/or precautionary statements must be made clear.
- Study Validation and Quality Assurance Declaration - The principal investigator of the study must provide a signed, written declaration certifying that the final report accurately reflects the study observations, and is complete and correct.
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