Although not necessarily required, human drugs are often evaluated for safety and pharmacology attributes (ADME) in lab animal models prior to entering human studies. The veterinary drug development process may take into account lab animal studies, but veterinary drug registration is contingent on studies supporting target animal safety and effectiveness. The target animal is the species in which the product is intended to be labeled for use. For instance, to obtain a veterinary registration for dogs, the effectiveness and safety must be evidenced in the dog.
Key DifferencesVeterinary Clinical Trials Compared to Human Clinical Trials
Unlike human clinical studies, confirmatory veterinary clinical studies are not formally referred to as Phase I, II, III or IV. Phase I-IV are terms used for human clinical trials intended to support a NDA or BLA or during post-marketing. Veterinary studies are sometimes referenced as Phase I, II, III or IV in the literature, but these terms are inaccurate in the context of the veterinary approval process. The appropriate terms are Target Animal Safety Studies (TASS) and Target Animal Effectiveness Studies (TAES).
Veterinary medicine is not subject to The Health Insurance Portability and Accountability Act (HIPAA). However, owner and patient information obtained during the course of a veterinary clinical study may be subject to certain obligations of the Sponsor, regulatory agency, clinic, and/or other stakeholders involved in the veterinary clinical study and registration process. With that stated, certain states consider veterinary patient medical records subject to obligations of protected health information (PHI).
Types of Veterinary Clinical Studies
Veterinary clinical trials generally fall into several categories, ranging from small pilot studies (proof of concept (POC) veterinary studies) to confirmatory studies in support of a veterinary product registration. Study sponsors that are just beginning their veterinary research endeavors may benefit from having a good understanding of the registration process and types of veterinary clinical trials required for each agency.
Pilot: Proof of Concept Veterinary Clinical Studies
Before starting pivotal / confirmatory veterinary clinical studies, many companies will conduct pilot clinical trials in the target species to:
- obtain preliminary data of safety, efficacy, and effectiveness
- determine optimal dosing schedule, and/or
- obtain data to attract investors and strategic partners.
It is important obtain guidance before starting any study in a target species, as certain studies may be subject to state and federal authorizations before starting.
Good Clinical Practice: Veterinary clinical studies intended to support a veterinary registration must be conducted under strict conditions and the clinical trials sites are subject to regulatory agency auditing. One resource is the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) VICH GL9- Good Clinical Practice (PDF – 356KB).
Pivotal: Confirmatory Veterinary Clinical Trials
Target Animal Safety Studies (TASS) are conducted to assess the safety of a veterinary product in the target species. Safety studies may also include dose escalation in the target species depending on the type of product being evaluated (drug vs. biologic). Often, target animal safety studies are performed by veterinary contract research organizations (CROs). Veterinary safety is also evaluated during larger field efficacy studies in client-owned animals with the disease of interest.
Target Animal Effectiveness Studies (TAES) – Target animal effectiveness studies are performed in the target species having the disease or condition of interest. These are normally conducted in client-owned animals under Good Clinical Practice (GCP) conditions. Target animal effectiveness (efficacy) studies used to support registration require authorization and protocol concurrence with either by the FDA-CVM or USDA-CVB.
Veterinary Study Sites
Veterinary Trial Site Selection
Veterinarians often get little training on veterinary research and conducting clinical studies. As such, many veterinary clinics are not familiar with conducting studies or the elements of Good Clinical Practices. Therefore, it is important that sponsors, site management organizations, and/or veterinary contract research organizations select the right sites in order to perform the veterinary study. With that stated, there are a number of private practices that have a strong track record of being involved with field effectiveness studies and are routinely involved with veterinary pilot and pivotal studies.
Feasibility of Veterinary Studies
Veterinary CROs should qualify veterinary clinical trials sites; which often begins with a feasibility assessment. The feasibility assessment may involve a site qualification visit (SQV) and/or site questionnaire to verify the site has sufficient resources, training and expertise to conduct the veterinary study. In addition to the site’s expertise and resources, the site feasibility should determine if the site has an adequate patient population, estimated patient accrual rates, hours of operation, and other factors before activating a clinical trial site (more information below).
Veterinary Study Personnel
Veterinary Clinical Study Investigators
Sponsors should qualify investigators based on a number of factors, including their training, experience, and familiarity with conducting veterinary clinical trials under Good Clinical Practice conditions. Most sites will have a Principal Investigator (PI) that can further delegate responsibilities to site specific veterinary study team personnel. These responsibilities are often reflected in a Delegation of Authority (DOA) log, signed by each veterinary clinical study team member. The veterinary PI is ultimately responsible for all study activities at their respective veterinary trial site, but often have sub-Investigators who can manage the majority of the clinical procedures and other obligations occurring at the veterinary clinical trial site.
Veterinary Study Coordinators and Monitors
Veterinary Clinical Research Coordinators play a key role on the veterinary clinical trial team. The veterinary clinical study coordinator is often assigned by the veterinary PI, and can provide study support through owner consenting, and patient screening, scheduling, data capture, source documentation and care.
Veterinary Clinical Study Monitors are used by the Sponsor or veterinary contract research organization to routinely monitor clinical trial sites. Veterinary study monitors may visit the veterinary trial sites to review records, source documents, and other materials which are important for ensuring the integrity of the study. Monitoring visits should occur before, during, and after a study has completed enrollment.
Additional Info: Veterinary Clinical Studies
Clinical Study Costs (Target Animal Safety and Effectiveness): The cost of conducting a veterinary clinical studies can range from several thousand dollars to several hundred thousand dollars. Veterinary study costs are often broken down into fixed and variable expenses. Fixed costs can include site fees, document preparation, monitoring fees, data tabulation, and report generation while variable costs are often directly associated with patient procedures. Veterinary clinical study costs are often influenced by several factors, including but not limited to:
Study Conditions: non-GCP, GCP or GLP. Proof of concept studies may often involved only a few number of subjects (10-30), and are often performed under non-GCP conditions. Pivotal studies that are used to support a products approval are most commonly performed under GCP or GLP conditions, and are typically more expensive owing to the degree of documentaiotn and QA/QC involved in these studies.
Duration: The duration of a veterinary clinical study can vary, from days to years, depending on the investigational product being evaluated. For instance, a product that may only be used for acute and critical care situations or that may only be used once can often be evaluated over a few days. Other products that are anticipated to be used frequently over extended periods of time are often studied for months or longer.
Number of Subjects: Pilot studies often involve only a few number of veterinary patients, so the patient specific costs are often lower to complete the study. Confirmatory studies (safety and efficacy) may require a larger number of patients, sometimes several hundred patients.
Outcomes for Assessment: The outcomes for assessment often drive the information which will be used to evidence safety or efficacy. There are a variety of subjective and objective data that can be obtained through physical exams, bloodwork, special diagnostics, imaging, etc.
What is the total cost of developing a new animal drug or new animal biologic? The registration process for a new veterinary drug or veterinary biologic in the United States may take 4-6 years of development work for companion animals, and may take longer for food production animals. Although there are not published expenditures, Woods Consulting, LLC estimates the cost for conducting companion animal TAS and TEA studies are between $3-7 million dollars depending on the species, duration of treatment, and anticipated label claims. This does not take into account the cost of drug/biologic failures or other factors such as licensing fees, etc. The costs for developing minor use minor species (MUMS) products may be lower.
Feasibility: Veterinary clinical trial feasibility is essential in determining if a study and the anticipated sites have sufficient resources, veterinary subjects, training, etc. to effectively and efficiently perform the veterinary clinical study. A veterinary clinical study should have a feasibility assessment that takes into account the overall study program, the sites, and the personnel involved in the veterinary clinical study.
- the availability of comparator treatments to be used in the study,
- patient inclusion and exclusion,
- study data capture and management (electronic data capture methods),
- veterinary acceptance of study related research procedures,
- risks and benefits of the study intervention (veterinary study treatment),
- logistics and operations of the study, and
- competitive studies which may interfere with veterinary clinical trial patient recruitment.
- existing patient population,
- site resources, equipment and overall facilities,
- hours of operation,
- investigational product security and storage capabilities, and
- allocation of sufficient space to store veterinary clinical study documents (regulatory binders, patient binders, etc.).
- Common Acronyms used in Human and Veterinary Clinical Trials
ADR: Adverse Drug Reaction AE: Adverse Event ALCOA: Attributable, Legible, Contemporaneous, Original, Accurate API: Active Pharmaceutical Ingredient CAPA: Corrective and Preventive Action CBER: Center for Biologics Evaluation and Research CDER: Center for Drug Evaluation and Research CDRH: Center for Devices and Radiological Health CFR: Code of Federal Regulations CMO: Contract Manufacturing Organization CRF: Case Report Form CRO: Contract Research Organization DHHS: Department of Health and Human Services eCRF: Electronic Case Report Form EDC: Electronic Data Capture EHR: Electronic Health Record EMR: Electronic Medical Record FDA: Food and Drug Administration FWA: Federal-wide Assurance GCP: Good Clinical Practice GDP: Good Documentation Practice HIPAA: Health Insurance Portability and Accountability Act ICF: Informed Consent Form ICH: International Council for Harmonization IDE: Investigational Device Exemptions IND: Investigational New Drug (Application) IRB: Institutional Review Board PHI: Protected Health Information PI: Principal Investigator QC: Quality Control SAE: Serious Adverse Event SMO: Site Management Organization SOE: Schedule of Events SOP: Standard Operating Procedure ANADA: Abbreviated New Animal Drug Application NADA: New Animal Drug Application INAD: Investigational New Animal Drug Application IACUC: Institutional Animal Care and Use Committee SIV: Site Initiation Visit SQV: Site Qualification Visit QA: Quality Assurance CMC: Chemistry, Manufacturing and Controls VSM: Veterinary Service Memorandum OLAW: Office of Lab Animal Welfare CVM: Center for Veterinary Medicine CVB: Center for Veterinary Biologics USDA: United States Department of Agriculture