Guidelines for Veterinary Clinical Trials

Legal basis and referenced laws

Republic Act No. 3720 (as amended by Executive Order No. 175) provides the general legal basis for regulating foods, drugs, devices and cosmetics, including veterinary drugs and related products through the regulatory framework it establishes.
Republic Act No. 6675 establishes the Generics Act of 1988.
Republic Act No. 382 is identified as the Pharmacy Act (as referenced in the Order’s legal basis).
Republic Act No. 6425 is identified as the Dangerous Drug Act of 1972 (as referenced in the Order’s legal basis).
Republic Act No. 1556 is identified as the Livestock and Poultry Feeds Act (as referenced in the Order’s legal basis).
Republic Act No. 1071 is identified as the statute regulating the sale of veterinary biologics and medicinal preparations and authorizing the Director of the Bureau of Animal Industry, subject to approval of the Secretary of Agriculture, to promulgate regulations for preparation, sale, traffic in shipment and importation of specific veterinary biologicals.
Republic Act No. 3101 is identified as authorizing the Director of the Bureau of Animal Industry to promulgate the relevant regulations described above (as referenced in the Order’s legal basis).
The Order also references a Memorandum of Agreement between the Department of Agriculture and the Department of Health on delineation of responsibilities regarding registration of veterinary drugs and products.

Purpose and community objective

The Order establishes general and scientific principles for demonstrating efficacy and for conducting, performing, and controlling clinical trials of veterinary drugs and products.
The Order focuses on authorization of new substances by requiring an evidence framework that demonstrates therapeutic effect.
The Order’s community objective is to recommend a common basis for clinical evaluation of veterinary drugs and products in the Philippines community.
The community objective is to (1) establish a basis for effective and safe products and (2) facilitate understanding and harmonization of regulatory and administrative requirements across international regions for conducting clinical trials.
The Order requires clinical tests to take account of the full range of conditions, animal management systems, disease conditions, and related factors throughout the community, even when testing is performed outside community borders.

Core definitions and concepts

“Veterinary Drugs and Products” are defined as any substance, including biological products, applied or administered to food producing, companion, aquatic, laboratory and exotic animals, whether used for therapeutic, prophylactic or diagnostic purposes or for modification of physiologic functions or behaviors.
“Established Veterinary Drugs and Products” are defined as veterinary drugs and products whose safety and efficacy have been demonstrated through long years of general use and can be found in current USP-NF and other internationally-recognized pharmacopeias.
“Clinical Trials” are defined as systematic studies in target species or in particular categories of such animals to establish therapeutic effects, including confirmation of pharmacodynamics and monitoring of adverse responses.
Clinical Trials also include studies on metabolism and the pattern of absorption, distribution, and excretion of active substances (pharmacokinetics) in target categories of animals to support efficacy evaluation.
“Efficacy” is treated as a fundamental criterion for authorization, requiring that marketing authorization be refused where a veterinary drug and product lacks therapeutic effect or where there is insufficient proof of such effect.
Therapeutic effect is understood as the effect promised by the manufacturer, including the specific claims in product literature and promotion.
Efficacy is understood as the degree to which the manufacturer’s medicinal claims are justified and are likely to be attained under practical field conditions within the community.

Clinical trial structure and rationale

Clinical trials must be designed and controlled to justify the relevant claims in each indicated target category of animals.
When controlled clinical trials using the product (preferably in the formulation intended for marketing) are not entirely possible, other means of providing efficacy data must be used, and the manufacturer must fully justify any claims drawn from inadequately controlled trials.
The Order expects that at least a proportion of the data will come from well organized, scientifically based clinical trials, and that even sound trial data from any source should be supported by information from target animals managed under conditions as similar as possible to community conditions.
Pre-clinical dose titration studies followed by dose confirmation studies serve as a precursor to clinical studies for demonstrating that the correct dosage or dosage range is recommended.
Efficacy demonstration may be supplemented by other data, such as linking pharmacokinetic information (tissue/plasma) with in vitro activity against recent and relevant field isolates of target organisms for antimicrobial products.
For ectoparasiticidal sheep dips, systemic absorption data may be of little importance compared to the persistence pattern of the active ingredient in the dip wash, within the fleece, and on the skin.
For teat dips, useful efficacy data may be obtained from in vitro tests designed to demonstrate that the recommended dilution inactivates relevant bovine mastitis organisms within a reasonable contact time.
Clinical trial design and interpretation must distinguish between effects due to the active substance itself and those due to a particular formulation.

Trial protocol requirements

Clinical trials must be planned so that specific problems are thoroughly considered and chosen solutions are justified on scientific and ethical grounds.
Responsibility for the trials lies with the registrant/sponsor and the overall supervisor, as well as the actual individual investigators.
Trials should be planned and designed as part of a logically constructed chain of investigations, moving from limited numbers of animals in near-experimental-type studies to substantial numbers of animals in near-marketing-type field studies.
Even if results are generally acceptable regardless of location, the BAI may require additional trials when scientifically justified, such as when normal husbandry or environmental conditions differ markedly from reported test conditions.
A trial protocol must be completed before the trial is initiated and must be worked out and adhered to, with proper instruction given to all investigatory staff.
Responsibilities of the registrant/sponsor, overall supervisor, investigator(s), and collaborators must be clearly defined before the start of the clinical trial.
A trial protocol must include, where relevant, the following elements:
- General information, including project title; names and contact points of investigators and participants and their professional background; registrant/sponsor identity and contact point; and identity of the farm/department/group where the trial will take place.
- Justification and objectives, including aim and reason for execution, and relevant problem background tied to literature.
- Schedule, including commencement date and time, investigation period, observation period, and termination date, with justification of schedule and waiting period before slaughter; waiting periods must be established for all animals removed from the trial.
- Design, including type of trial; randomization method and practical arrangements; trial design (parallel/cross-over) and blinding technique (double blind/single blind/open); and bias-reducing factors.
- Subject selection, including animal type specifications (species, age, sex, breed, category, prognostic factors); diagnostic admission criteria; and inclusion/exclusion and withdrawal criteria.
- Treatment, including precise identification of product(s) likely for marketing; justification of doses; description of control group treatments; route, dose, dosing schedules, treatment periods; rules for concomitant treatment; operator safety measures; and compliance monitoring.
- Assessment of efficacy, including effects to be achieved before efficacy can be claimed; measurement and recording methods; observation/recording timing; and special analyses/tests.
- Adverse reaction/side effects, including recording methods; provisions for dealing with reactions; handling of trial code for emergencies; and reporting details and designated recipient.
- Operational matters, including step-by-step control/monitoring plan; anticipated protocol deviations (e.g., therapeutic failure) and instructions; team duties and coordination; staff instructions; contact details; and confidentiality problems to be considered.
- Handling of records, including record processing procedures; availability of procedures to maintain records for each individual/test group for ready identification; and inclusion of a copy of the recording form.
- Evaluation, including scoring system/clinical response evaluation; computation and calculation methods; handling/reporting of animals withdrawn/removed; and quality control of evaluation procedures.
- Statistics, including statistical methods; planned number of animals and sample-size reasoning (including power and clinical justification, and justification for changes); statistical unit; level of significance; and rules for trial termination.
- Summary and supplements, including comprehensive summary and supplements such as information to animal owners, staff instructions, and special procedure descriptions.
- References, including a list of relevant literature included in the protocol.

Investigators’ qualifications and safety focus

Animal protection in trials must be the primary concern of every person responsible for implementing clinical trials.
Persons administering veterinary drugs and products and any consumer of animal products from trial animals must be protected through high concern for safety of the environment and trial administration.
Every investigator must demonstrate professionalism in observation and reporting.
The overall supervisor must hold veterinary qualifications, be clinically competent, and have sufficient experience in clinical evaluation of veterinary drugs and products and in the conditions under investigation.
The overall supervisor must have access to competent toxicologists, environmental biologists, and medical advice to maintain safety of the trials.
Site supervisors for individual trials at particular locations must have expertise in the biology and clinical handling of the specific disease or condition under study.
Ethical standards, independence, and professional integrity of all investigators must be beyond reproach.

Pre-clinical and target-animal requirements

Pre-clinical requirements demand relevant chemical, pharmaceutical, experimental animal pharmacology, and toxicological data professionally evaluated before clinical trials in target species.
The registrant/sponsor must obtain exhaustive, complete, and relevant information through the overall supervisor.
Experimental animal data must include laboratory animal species plus target and other domestic species examined under experimental conditions.
Before clinical trials in food producing animals, a secure waiting period before slaughter or taking of produce must be established and justified by pre-clinical trials.
The extent of pre-clinical trials must relate to the waiting time intended to be used during clinical trials, with more detail required when waiting time is shorter, especially when large numbers of animals are involved.
For target animal pharmacology, all existing research data in the target species and relevant target categories must be considered.
Effects on other important organ systems must be studied at relevant dosage levels.
Kinetic studies of the active ingredient and intended formulation, potentially with several routes of administration, must be included.
Dosage selection must include results of dose/response and/or concentration/effect relationships and safety studies.
Investigators must account for interactions with other concurrently administered products.

Reporting, records, and labeling

Reporting of trial outcomes must be carefully planned and agreed upon by all participants.
A policy for publication in scientific journals or elsewhere must be considered as part of cooperation between the parties involved.
Suspected adverse reactions/side effects must be reported as quickly as possible to the competent authority, usually organized through the overall supervisor.
In cases of serious adverse effects, investigation or animal owner reporting must be made directly.
The competent authority must be informed in writing if any major deviation from a previously submitted trial protocol is contemplated.
If a trial does not begin or is interrupted before its purpose is achieved, the reason must be conveyed in writing to the BAI.
After completion, the BAI must be informed of results, including suspected adverse reactions/side effects, through a formal report that includes a short, comprehensive summary of essential findings and methodology.
All clinical and experimental data, including records of the complete formulation used in each trial, must be kept safely by the overall supervisor and/or the sponsor for five (5) years or more after completion of the trial, and retained in an archive until beyond the time of issue of the relevant marketing authorization to validate results later and/or submit documentation for inspection if requested.
Labeling rules apply by analogy to labeling of all veterinary drugs and product(s) or placebo(es) used in clinical trials.
Labeling must include the words “For Veterinary Clinical Trial Only” (or similar wording), the identity of the overall supervisor responsible for the trial or the manufacturer sponsoring the trial, and an assessment of safety on which a waiting time prior to slaughter must be based.
Labeling must also include warning statements relevant to safety of the animal, the operator, or the environment.

Notification/approval and environmental safeguards

Clinical trial conduct must give due regard to the product’s effect on the environment.
Clinical trial conduct must give due regard to residues in produce of treated animals.
Clinical trial conduct must give due regard to the eventual fate of animals used for food production.