VB-GL-3.17: Efficacy studies for veterinary biologics

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1. Introduction

The purpose of this document is to advise veterinary biologics (VB) manufacturers and researchers of the efficacy requirements for VB manufactured in, or imported into, Canada.

The Canadian Centre for Veterinary Biologics (CCVB) uses a multi-step process to evaluate the efficacy of VB. This includes the review and approval of technical reports and test data submitted by manufacturers for preliminary studies with working seeds, cell lines, experimental product serials, and pre-licensing serials, and post-licensure monitoring of product serial releases and adverse events. A risk-based approach is used to determine the appropriate standards, processes, tests, and laboratory and field studies to apply in evaluating the efficacy of a VB.

This guideline is directed primarily at Canadian manufacturers and foreign manufacturers in countries other than the United States (U.S.). The efficacy requirements for VB manufactured in the U.S. and licensed by the U.S. Department of Agriculture (USDA) are similar to Canadian requirements.

Information and submission requirements to license new VB can be found in VB-GL-3.1: Preparation of new product licensing (registration) submissions for veterinary biologics and references therein. In vitro diagnostic kits, colostrum and antibody products may have different efficacy requirements than those covered in this guideline. Manufacturers of these types of VB are directed to view the relevant product-specific guideline(s).

1.1 Legal authority

1.2 Definitions

Adverse event

means any observation in animals, whether or not it is considered to be product related, that is unfavourable and unintended and that occurs after any use of veterinary biologic(s)

Containment

means a condition under which the movement of an organism is limited by 1 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.

Outline of Production

is a detailed description of:

the process followed in preparing a veterinary biologic and any diluent to be used with it
the methods and procedures to be employed in handling, storing, administering and testing a veterinary biologic and any diluent to be used with it, and
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 with it

Target animal

is an animal belonging to a species, or group of animals (for example, pregnant), intended for the final use of the veterinary biologic

2. General requirements

The manufacturer must demonstrate that a VB is efficacious according to the proposed label claim in the target animal. The efficacy of a VB is evaluated using laboratory-based or containment-based vaccination-challenge studies. Field studies with a natural challenge may be used to make licensing decisions, if laboratory-based disease models in the target animal are not available for the study. The CCVB does not release or authorize a VB product for field efficacy or field safety studies without the previous submission and acceptance of the following information:

a draft Outline of Production
a summary of purity, potency and safety test results from the experimental serial(s)
data from a laboratory-based vaccination-challenge efficacy study

Protocols for both laboratory and field efficacy studies should be prepared in the specified format. If the efficacy study is also to be used in support of VB product safety, then a description of the responses and clinical observations used to measure safety should be included in the protocol for the efficacy study.

The proposed study protocol and the draft Outline of Production should be sent for review to the CCVB prior to the start of the study, allowing a minimum of 60 days for review. The study should not be started until the study protocol has been accepted by the CCVB. The CCVB may arrange to monitor various parts of the study. Copies of the purity, potency and laboratory safety results of the experimental serial to be used in the efficacy study should be sent to the CCVB prior to the start of the study.

Copies of all efficacy study results (for example, studies to select dose, antigen level, adjuvant, definitive or repeated studies) relating to a VB product submission, whether or not the VB product was shown to be effective, should be maintained by the manufacturer and be available for inspection at all times.

The manufacturer is required to notify the CCVB in writing of changes to a CCVB-approved protocol for an efficacy study in advance of the study start date or at any time during the study. The following information should be provided in detail:

a summary of the necessary changes with reference to each part, page, paragraph, or subparagraph being changed
an explanation of the reason for the change(s)
a copy of the amended page(s) of the protocol

The manufacturer is required to notify the CCVB if a CCVB-approved study is cancelled and does not take place as scheduled.

3. Laboratory biosafety and animal use

The manufacturer is responsible for ensuring that the appropriate biocontainment level is used to handle any live organisms used in the development and evaluation of the VB. All aspects of the development and evaluation of a VB must meet the standards and regulations for laboratory biosafety and animal use described in the documents listed below, along with the relevant provincial legislation, and local safety and animal care authorities:

Canadian Biosafety Standard (CBS), Canadian Biosafety Standard, Third Edition, Public Health Agency of Canada
Containment Standards for Facilities Handling Aquatic Animal Pathogens, Office of Biohazard Containment and Safety, Canadian Food Inspection Agency
Primary Containment for Biohazard: Selection, Installation and Use of Biological Safety Cabinets, Second Edition, Centre for Disease Control and Prevention and National Institute of Health
Canadian Biosafety Handbook, Public Health Agency of Canada

4. Considerations for manufacturers in the United States

U.S. manufacturers, and "permittees" in the U.S. of foreign manufacturers, may apply to license in Canada a VB product already licensed by the USDA. In this situation, the CCVB will review all pertinent USDA documentation (scientific data and correspondence) and will notify the manufacturer of any additional efficacy requirements. The CCVB will consider requests initiated by the U.S. manufacturer to include a Canadian laboratory or field efficacy site to support a pending or future Canadian licence application on a case by case basis.

Test results for pre-licensing serials reported on the Animal and Plant Health Inspection Service Form APHIS 2008 – Veterinary biologics production and test report must be provided to the CCVB.

5. Format of the experimental protocol

5.1 Title page, table of contents, participants

The title page should contain the following:

assigned or scientific name of the VB product
trade name
VB establishment licence number
name of the manufacturer
unique study identifier number
study title
anticipated start and completion dates of the study
preparation date and version of the protocol
name and contact information for person responsible for the protocol
proposed label claim to be assessed during the study

A table of contents should follow the title page and outline the sections of the protocol.

The protocol must list the names, addresses, phone numbers, email addresses, and responsibilities of the principle participants in the study. It should include a list of the key collaborators (producers, veterinary clinics, farms, veterinarians, and so on). The qualifications and experience of the key personnel should be outlined in an appendix to the protocol.

5.2 Description of disease and rational for vaccination

This section should summarize the scientific and veterinary medical rationale for using the product under review to control, treat, or prevent a disease in the target species. This should be supported by peer-reviewed scientific publications, and should include a brief description of the current knowledge of the disease (clinical signs, pathogenesis, epidemiology). Provide only key references, and do not review the subject extensively. Include a list of references with a hyperlink to an online publication or copies of each of the references in an appendix.

5.3 Objective of the study

The objective of an efficacy study is to demonstrate that a VB product is efficacious in the target animal species, according to the label claim made by the manufacturer. Efficacy data should be established for each clinical form of a disease, each route of administration (intramuscular, subcutaneous, intranasal, and so on), and each species recommended in the label claim.

The efficacy study should be conducted in fully susceptible animals of the youngest age for which the product is recommended. If the youngest age recommended for vaccination is still expected to have levels of maternal antibody, then the efficacy of the product should be established in the face of the expected levels of maternal antibody. If this data is not available, labelling should indicate that the product is for the vaccination of susceptible animals of the minimum age used in the efficacy study, and recommend re-vaccination at appropriate intervals until such animals reach an age when interfering levels of maternal antibody would no longer be present.

Specific label claims concerning the onset of immunity must be supported by acceptable efficacy data.

When recommending vaccination of adults to provide passive immunization of offspring, the efficacy must be established in the offspring of a significant number of vaccinated adults.

Serological data are generally not acceptable for establishing the efficacy of a product. They should only be used when reasonable data exists to demonstrate that the serological results are indicative of protection.

The objectives of the study should be described in detail and include:

a general overview
a specific description of the efficacy objectives in terms of the experimental response(s) to be measured, the times of measurement, and the methods

For many products and infectious diseases, efficacy objectives are listed in the Code of Federal Regulations 9 (9CFR) of the United States or in the European Pharmacopoeia (Ph. Eur.). For information on products not listed in the 9CFR or the Ph. Eur., the specific clinical signs, pathologic, serologic, and/or immunologic responses required for licensing, as well as the time periods over which they must be measured can be obtained from the CCVB.

For example:

General Objective

To demonstrate the efficacy and immunogenicity of an infectious bovine rhinotracheitis vaccine, killed virus.

Specific Objective

In vaccinate and control animals to describe the daily changes in clinical signs of respiratory disease and body temperature on each of 14 days following challenge with virulent infectious bovine rhinotracheitis virus.

If the efficacy study is also to be used in support of the product safety, then this section should also include a detailed description of the safety objectives of the study, including both a general overview, and a specific description of the safety objectives, experimental response(s) to be measured, the times of measurement, and the methods.

5.4 Experimental design

This section should include the following:

General overview of the experimental design

Provide a general outline of the study, describing the treatments, test animals, sampling, timing of events, and so on.

Allocation of animals to treatment groups

This section should include: a description of the treatment groups (including any stratification or blocking factors used in the experimental design, such as: antibody titre, age, sex, weight, litter, and so on), their sample sizes, the alpha and power of the study, the method used to randomly allocate the experimental animals to the treatment groups, and the randomization plan for the study. The statistical formulae used to estimate the sample sizes should be referenced. For many products the method of allocating animals to treatment groups are specified in the 9CFR or the Ph. Eur.

Response variables and scoring method

For many products, the response to be measured, and the definition of a positive response are outlined in the 9CFR or the Ph. Eur. For products in which this is not the case, this section should describe the biological responses and the scoring systems that are to be used to measure the efficacy of the product, including the range of values to be considered a positive or negative response.

If the manufacturer decides to use a composite score or index of clinical or pathological signs to demonstrate a significant difference between the vaccinate and control animals, they should also describe and statistically evaluate each response making up the score or index, separately.

If the efficacy study is also to be used in support of product safety, then this section should describe the biological responses and scoring systems being used to measure the safety of the product. As with the response variables for efficacy, this should include the range of values to be considered a positive or negative response.

Blinding the study

This section should describe the methods used to blind the study in order to ensure unbiased results. It should include a list of the various aspects of the study which are blinded and the personnel who will be blinded.

5.5 Study schedule

The study schedule should list the key experimental days, their corresponding dates, and the event(s) which take place (arrival, acclimatization, vaccination, challenge, sampling, observations, and so on).

5.6 Description of the test materials

The composition of the VB product used in the pre-licence laboratory or field efficacy study should be that of the VB product intended for sale or distribution. It should be 1 of 3 experimental serials produced in a licensed facility in accordance with a previously filed Outline of Production. If the experimental serials are produced on a smaller scale in a research facility, the manufacturer must establish that they represent the product which will be produced for sale in the licensed production facilities. The manufacturer is responsible for establishing the validity of the experimental serial used to demonstrate the efficacy of a product by submitting to the CCVB, the summary test results of the serial for purity, potency and laboratory safety as described in the Outline of Production. For both the experimental serial and the placebo test materials used in the efficacy study, describe:

the composition, including antigenic mass, per mL and per dose
method of production and standardization
date of production
date of use in the efficacy study
assigned or scientific product name and trade name, if known
serial or batch number
method of use (dose, route, and frequency) in the efficacy study
purity, potency and laboratory safety results

Describe the method by which the level of potency of the experimental serial to be used in the efficacy study will be measured. This should be the same as that described for serial release in the Outline of Production.

The experimental serial used in the efficacy study should be at a potency level equal to that proposed in the Outline of Production at the release of the product for sale.

The experimental serial used in the efficacy study should be produced at the highest passage from the master seed, and if of cell culture origin, in cells at the highest passage from the master cell stock allowed by the Outline of Production.

For the experimental serial used in the efficacy study, identify and account for all material prepared, used, distributed, and returned.

Describe the method proposed to dispose of the unused veterinary biological experimental serial and placebo.

Provide a copy of the labelling intended for both the experimental serial and the placebo test material.

5.7 Description of the test animals

This section should describe the test animals to be used in the efficacy study. It should include the following:

Selection/exclusion criteria

Describe the source, age, breed, sex, reproductive status and any other distinguishing features of the animals used in the study.

Method of animal identification

Housing and environmental conditions

Include a description of when treatment groups are in contact with one another, co-mingled, or kept separate.

Concurrent medication/vaccination

Describe any concurrent medications, and vaccinations that will be received by the animals used in the efficacy study, and the frequency and timing of their administration. This should include anaesthetics, analgesics, immobilizing agents and tranquillizers, and so on.

Treatment of adverse reactions

Describe anticipated adverse reactions and the methods that will be used to treat animals experiencing these reactions.

5.8 Disposition of study animals and their milk

Describe the criteria for removal of an animal during the study, and the disposition of study animals at the end of the study. Specify the applicable withdrawal times for the experimental serial and any concurrent medications that are administered during the study.

Manufacturers are required to notify the CCVB in writing, at least 2 weeks prior to the shipment of experimental animals to slaughter so that the regional veterinarian and the inspection staff of the establishment can be informed. The following information must be provided:

the name of the experimental VB product
the intended use of the experimental VB product
the name and address of the investigator responsible for the study
the dates of the commencement and completion of the study
the date(s) of all treatments or vaccination
the number of animals and their identification
the name and address of the federally inspected slaughter house where animals would be sent for slaughter

Note that for meat animals a withdrawal time of at least 21 (or more depending on the type of adjuvant) days is required for VB products before the animals can be shipped for slaughter. Some of the immobilizing agents used for animal restraint in the different species may have longer withdrawal times.

5.9 Target animal challenge model

Summarize the scientific rationale for using this target animal challenge model to support VB product efficacy. This should be supported by publications in the scientific literature, and should include a brief description of the current knowledge of the challenge model.

Provide a detailed description of the materials and methods of the challenge, as well as information on its development, and repeatability. Specifically define a successful challenge in terms of the efficacy response(s) to be measured.

5.10 Data collection procedures

This section of the protocol should describe the methods used to collect data and biological samples for measuring each response (blood, serum, post mortem, and so on) throughout the duration of the study. Samples of the finalized record and data collection forms should be appended to the study protocol. Records should clearly document all observations in an objective manner. Abbreviations or acronyms must be defined and consistently used on all records. The records must include the initials or signature of person responsible for an action or an observation. Proper correction of recording errors (single line cross-out with the correct result and initials of person responsible for the correction) must be applied.

5.11 Statistical methods

This section should outline the strategy that will be used to carry out the statistical analysis to determine the efficacy and/or safety of a VB product. The analysis should reflect the experimental design, including the randomization scheme and the type of outcome variables measured. It should include a description of the statistical tests to be used, the groups to be compared, the response variables to be used in the comparisons, a statement of whether the scores are to be analyzed as ordinal categories or continuous variables, and the time periods over which the comparisons will be made.

The statistical methods and computer software being used to carry out the calculations should be listed and/or referenced.

6. Format of the study report and conclusions

The final study report should include a separate title page and table of contents. If the efficacy study is also to be used in support of product safety then the data for safety objectives of the study should be reported in a separate study report using the same sections and reporting format as described below.

6.1 Summary

The summary should describe the purpose of the efficacy study, the basic procedures used and the main findings (specific data and their statistical significance). The main findings should be linked to the proposed label claim.

6.2 Results

The results should include:

summary tables of individual animal data, sorted by treatment group
- all animals entering the study should be accounted for in the report, as well as in the written records
copies of the data collection record form(s), appended to the report
- original data collection record form(s) should be kept on file by the manufacturer and be available upon request
descriptive statistics showing the measures of central tendency (means, medians), and the distributions (tables, histograms, bar charts, scattergrams, boxplot or similar) for the efficacy response variables by relevant sub-group
inferential statistics (ANOVA, Mantel-Haenszel) demonstrating the statistically significance difference between the control and vaccinated groups for the efficacy response variables
study deviations with explanations and discussion of potential implication on the study outcome

6.3 Conclusion and discussion

The discussion should emphasize the important aspects of the efficacy study, and the conclusions that follow from them. Include the implications of the findings and their limitations. Link the conclusions with the proposed label claim and objectives of the efficacy study, but avoid unqualified statements and conclusions not completely supported by the efficacy data. Do not allude to work that has not been completed.

7. Additional information

Contact the CCVB if you have additional questions or need clarification on regulations and requirements for veterinary biologics efficacy studies.

Date modified:: 2024-01-05

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