Introduction

Clinical studies (or trials) are essential to support a wide range of veterinary health applications in farm and companion animals. It brings about new treatments, pharmaceutical or biological products, therapeutic diets, devices, and diagnostic tools needed to advance animal health and improve quality of life for both animals and their owners.

However, clinical studies can be challenging in a veterinary setting. Designing and conducting clinical studies can be complicated, costly, time-consuming, and resource intensive. Patient enrolment can be challenging due to many factors, including the disease-state the complexity of required study procedures, and the requirement to adhere to the relevant regulatory requirements and quality standards. Additionally, to ensure that research maintains its quality, it must undergo rigorous and comprehensive quality assurance (QA) procedures that can be laborious for many organisations to perform in-house.

So — what’s actually involved in veterinary clinical research, and what should pharmaceutical developers consider when moving into the clinical environment?

Clinical studies in veterinary medicinal products development

Developing veterinary medicinal products (VMPs) involves several different types of clinical studies. These begin with pilot or proof-of-concept studies (which can take place in either a field or experimental (or semi-experimental) setting) and progress to pivotal or confirmatory studies, which usually take place in the field.

• Pilot/exploratory/proof-of-concept studies are used to assess preliminary safety, efficacy, and effectiveness.
• Pivotal studies are used to assess the safety and effectiveness of a product in target species animals and are performed in support of a VMP achieving approval or registration.

Unlike human clinical studies, veterinary clinical studies are not formally referred to as Phase I, II, III or IV. Instead, the appropriate terms are target animal safety studies (TASS) and target animal effectiveness studies (TAES). TASS are used to assess whether a veterinary product is safe for use in the target species under experimental or semi-experimental conditions and compliance of either the good laboratory practice (GLP) or the good clinical practice (GCP) quality standards, while TAES are carried out to assess effectiveness in target animals with the condition or disease of interest, typically in client-owned animals under field conditions and compliance of the GCP quality standards.

Trial stage aside, what do VMP developers need to consider when designing a clinical study?

First and foremost, clinical studies must be appropriately designed to achieve objectives and record valid data over a clinically relevant duration. In terms of design, clinical studies can take various forms depending on the research objectives.

The gold standard veterinary clinical study is a controlled, randomised, double-blinded, multi-centre prospective trial. This involves research taking place at multiple veterinary clinics (multi-centre) comparing the VMP with a reference or control product (controlled), where the participating animals are randomly assigned to the treatment groups (randomised), without either their owner nor the veterinarian participating as investigator knowing to which group the animal has been assigned (blinded). And always with a signed consent of the animal's owner obtained prior to the initiation of the study.

Any clinical trial requires an adequate sample size mainly to ensure that the trial has enough power to detect a true effect of the treatment. This means the study can reliably identify differences between treatment groups if they exist. Accurate estimates of key parameters are essential to ensure the sample size is appropriate. Equally, clinical endpoints must be selected appropriately and measured at relevant time intervals, and the selected methods of data analysis — whether exploratory, descriptive, diagnostic, prescriptive or predictive — should suit these endpoints.

These key elements of trial design are crucial not only for the study's success but also for compliance with animal welfare requirements. When considering the animal welfare principles of a trial, reviewers consider — among other things — the benefits, risks, and alternatives of the intervention being studied, as well as the consequences of doing nothing. Guidance in the European Union (EU) states that the number of animals used should be kept to a minimum while still obtaining valid results, with non-animal methods used where possible, and research practices refined to minimise stress and improve welfare for study animals.

To achieve success in animal clinical research, it’s key to sustain a carefully managed study design and implement strong QA and quality control (QC) procedures throughout the clinical study lifecycle. By doing so, developers can ensure that the highest quality and integrity is maintained throughout their study, streamlining the development process as they move their product towards successful approval.

“Quality assurance plays a critical role throughout the entire clinical study pathway or lifecycle” says Kristen Ryan, Senior QA Officer at Argenta. “It involves a comprehensive review of processes and procedures related to all aspects of the clinical study, including data collection and management. QA activities typically include verifying compliance with the study protocol, assessing the adequacy of study staff training, auditing study activities, reviewing the performance of subcontractors and third parties, evaluating data management practices, and confirming adherence to regulatory requirements. Ultimately, QA activities are one of the fundamental pillars to ensuring that the integrity of the study data is maintained throughout the clinical study life cycle.”

Challenges in veterinary clinical studies

Moving from pre-clinical into a clinical setting brings many challenges. If these aren’t anticipated ahead of time, sponsors risk having to delay their research, discount valuable data, or even potentially needing to re-do an entire trial. These include:

Patients' recruitment

As mentioned previously, sample size is a core part of trial success, but the study design and the definition of the appropriate criteria for evaluating efficacy and safety are equally crucial, as they directly inform the primary endpoint, which is the basis for the sample size calculation. Once this key element has been defined, sponsors face a challenge: recruiting animal patients. Sufficient patients must be enrolled to reach the required sample size, all must meet criteria on whether they are eligible for inclusion in the trial (inclusion/exclusion criteria), and all must be relevant for the given indication.

To aid the recruitment of sufficient patients, it's important to have a strong network of veterinarians, who are interested in taking part in clinical studies. These clinical investigators need to have the right organisational set-up, time and attention to detail to properly execute the study, supported by designated Clinical Research Associates (CRAs) and Monitors, Project Managers from the sponsor or a designated contract research organisation (CRO).

Recruiting investigators and supporting them with patient enrolment can be a difficult and time-consuming exercise for sponsors, potentially delaying research progress. Working with a specialised CRO can accelerate this process.

Protocol writing

The study protocol holds all the key information needed to conduct the trial: the rationale and objectives, animal inclusion/exclusion criteria, the schedule of study procedures, and more.

Crucially, the protocol should be clear on what is and is not a deviation, as significant deviations may force valuable data to be excluded. It must capture all aspects of data generation and collection. For example, is the length of the trial appropriate for the indication — for chronic conditions, for instance? Will data be collected at suitable time intervals? Are the endpoints appropriate and clinically relevant? Writing a good study protocol is far from easy and represents a core challenge facing those designing veterinary clinical trials.

The risk of protocol deviations increases when the protocol becomes more complex and difficult to implement. This is also true of data collection forms, which are included in the protocol and the design and content of which is critical to success. The simpler and clearer the study protocol, endpoints, and data collection forms, the easier the study will be conducted, and data will be to collect, lowering the risk of protocol deviations.

Study personnel training

Unlike in the pre-clinical stage, in clinical studies the treatment or intervention is administered, and data collected and recorded by veterinarians, veterinary nurses, and/or animal owners in field conditions, who may not have prior experience in a clinical studies environment, so they are not always fully aware of the regulatory and documentation requirements.

Because of this, it’s crucial to ensure that study site personnel are sufficiently trained and recognise the importance of closely following not only the protocol but also applicable scientific, ethical and quality standards and specific standard operating procedures (SOPs). Poor training can lead to protocol deviations (e.g. not collecting data within a given timeframe) and cause data to be discounted — which is looked upon poorly by regulators.

Adherence to international quality standards  

As previously mentioned, clinical trials must be performed in compliance with the international good clinical practice (VICH-GCP) guideline as a gold quality standard, to ensure the integrity of data, protection of animal welfare, safety of study personnel, preservation of the environment, and safeguarding of both human and animal food chains. Additionally, raw data recorded during the study (written or electronic) must follow the ALCOA principles for data integrity: namely, that data is attributable, legible, contemporaneous, original, and accurate.

While these guidelines provide an overall guidance to industry that appears to be straightforward to implement, the interpretation by regulatory authorities can vary between countries, which can present challenges when conducting field trials across different regions. Here, well-planned QA procedures can support compliance and ensure that operational and regulatory quality standards are met all along the clinical pathway. QA is a core part of confirming that all the processes used in clinical development are fit for purpose. It takes a systematic approach to assuring that all QC steps are followed across clinical research, data management, training, monitoring, and regulatory submission (including for any sub-contractors or partner organisations).

Addressing differences in regulatory requirements

Although both the US and EU are subject to the VICH-GCP guidelines, regulatory requirements may still differ from region to region. Requirements may slightly diverge, even within EU, as they are subject to local and national variations across Member States.

The key US regulation comes from the US Food and Drug Administration (FDA)'s Center for Veterinary Medicine (CVM). In the EU, this regulation instead comes from the European Medicines Agency (EMA). Both agencies harmonise wider legislation and guidelines for GCP, GLP, and good manufacturing practice (GMP) for VMPs. Different specific regulatory guidance is applicable depending on the type of intervention being tested (a medical device versus a vaccine or feed additive, for instance).

This is a fluid landscape, with regularly emerging updates. As a prominent recent example, in 2019, the EU published two new regulations surrounding the manufacture and marketing of VMPs (2019/6) and medicated feed (2019/4). These came into effect in 2022. (In fact, to help developers navigate this ever-changing area, Argenta experts deliver a workshop on the changing regulatory landscape each year for those involved in the development of animal health products. Access insights from our 2024 workshop, or register your interest for our 2025 event.)

Although regulators in both geographies have the same goal — overseeing the development of and approving safe and effective therapeutics — there are differences in how GCP guidelines are regulated and interpreted. In the US, protocol concurrence is required from the FDA before commencing a trial. Conversely, while regulatory approval is required to conduct a study in Europe, the EU does not provide pre-approval of the protocol, so developers must know how to accurately interpret regulations.

US and EU regulators also vary in stance when it comes to endpoints. Different endpoints — e.g. biomarkers, clinical — are preferred for evaluation by investigators in each region. For example, when assessing a drug to lower blood pressure, the FDA does not accept blood pressure figures as the primary endpoint and instead wants to see a clinical impact (e.g. extended life or improved quality of life). While there are guidelines for endpoint selection, this process is not standardised, and the choice is ultimately the trial developer’s decision.

“There are many things to consider in veterinary clinical research, and many aspects to juggle to ensure that your study is well designed, well conducted, and complies with all applicable standards and country-specific regulations. Therefore, the more experience one has in conducting global veterinary clinical studies, the greater the chances of success in obtaining consistent, reliable and valid results, and the lower the risk of having to repeat the study, with the resulting waste of time and money." says David Sabaté, General Manager, Argenta San Sebastian

The benefits of working with an expert CRO partner

As described above, the development of clinical studies may be rough — but there are certainly ways to make it smoother.

One such way is to bring external experience and expertise on board by partnering with a CRO. This is a great way to streamline and de-risk the clinical study development process. As experts in the sector, CROs can act as a one-stop shop throughout the entire process or simply support where needed, offering the flexibility to meet changing business needs and manage studies effectively. A CRO partnership can ensure an efficient and effective development path, leading to high-quality data and fast, successful product approval. This is especially the case for CROs that are specifically focused on animal health, with such CROs possessing focused expertise and comprehensive knowledge of the relevant industry and regulatory landscape.

By working with an expert CRO, developers can access:

• A deep, comprehensive understanding of regulations and their requirements, including expertise in the nuances of US and EU guidance and strong relationships with regulators. This regional understanding can go beyond knowledge of the regulations themselves and extend to experts able to work in different local languages — a key consideration for those looking to work internationally and a huge benefit when supporting client interactions, site training, and more.
• Dedicated QA experts with significant experience in veterinary clinical research. Many organisations lack the capacity to sustain comprehensive QA capabilities in-house — and so outsourcing this to a CRO can bring tremendously valuable expertise and guidance that may otherwise be lacking.
• Established relationships with clinical sites and personnel that are already trained to conduct studies and gather and handle valid, high-quality data. This can accelerate the recruitment and training process, and result in fewer trial delays or costly protocol deviations.
• A knowledgeable team with significant experience training veterinary personnel and an understanding of the common VMP development pitfalls — and how to avoid them.
• Highly flexible services to suit individual development needs. Some or all study activities can be outsourced. Certain CROs have specialised teams or facilities that can fill in-house skills or knowledge gaps; for instance, regulatory teams able to support dossier completion, or GMP-compliant facilities that can manufacture a product for trials or, following approval, commercially.

By leveraging the expertise, network, resources, and QA capabilities of an expert CRO, companies can increase the likelihood of their clinical trials succeeding, and ultimately maximise their chances of bringing new therapies to market quickly and efficiently.

Future-proofing the success of veterinary clinical trials

Global veterinary medicine markets continue to grow year on year, with a sustained demand for new VMPs. To continue advancing veterinary medicine and improving animal health, it’s essential that we conduct the clinical studies needed to ascertain that new VMPs are safe and effective for their target animals.

However, guiding a new VMP from pilot stage through to the commercial market is a colossal challenge, with many hurdles cropping up to delay progress and disrupt a product’s route to registration.

An effective way to streamline this process is to work with an expert CRO partner — one able to support you as you design and conduct high-quality clinical trials and generate valid, sufficient data to comply with regulation and good practice guidelines. By working with an experienced CRO, VMP developers can accelerate their product’s path to market and ensure clinical research success: essential to improve animal health and develop better veterinary therapies.

Do you want to know more about how Argenta can accelerate your veterinary clinical studies and support you in your QA? Watch our on-demand webinar 'Ensuring excellence: Implementing quality in veterinary clinical trials'. In this webinar we address the importance of quality assurance and control measures in veterinary clinical trials. It offers valuable insights into maintaining quality at every stage of a trial and is designed for professionals involved in veterinary clinical trials, including clinical researchers, quality assurance officers, study directors, and anyone interested in advancing their knowledge of quality implementation in the veterinary field.

Watch the on-demand webinar here.