Veterinary trials and tribulations.

Dog owner Jodi Ware makes the case for transparency in companion animal research.

Development of a core outcome set for therapeutic clinical trials enrolling dogs with atopic dermatitis (COSCAD'18).

BACKGROUND: For decades, the efficacy of interventions in clinical trials enrolling dogs with atopic dermatitis (AD) relied on heterogeneous evaluations of skin lesions and pruritus using unvalidated tools. Although some instruments for clinical signs were validated later, there was little impact on standardizing outcome measures resulting in difficulties in comparing treatment efficacy between trials and impeding meta-analyses. RESULTS: Participants in the Outcome Measures subcommittee of the International Committee of Allergic Diseases of Animals (ICADA) collaborated for two years to develop a core outcome set (COS) for canine AD, the COSCAD. This project involved several steps, constantly-re-assessed during online exchanges, to define the scope of this COS, to identify the relevant stakeholders, the domains to be evaluated, the instruments available for measuring agreed-upon domains and how to express outcome measures. This COSCAD'18 was designed principally for therapeutic-but not preventive or proactive-clinical trials enrolling dogs with chronic, nonseasonal (perennial), moderate-to-severe AD. Selected domains were skin lesions, pruritus manifestations and perception of treatment efficacy. Instruments to evaluate these domains were the CADESI4 or CADLI, the 10-point pruritus visual analog scale (PVAS10) and the Owner Global Assessment of Treatment Efficacy (OGATE), respectively. The COSCAD'18 has three outcome measures: the percentages of dogs with veterinarian-assessed skin lesions or owner-rated pruritus manifestation scores in the range of normal dogs or those with mild AD; the third is a good-to-excellent global assessment by the pet owners of their perception of treatment efficacy. Importantly, this COSCAD'18 is not meant to represent the sole-or primary-outcome measures evaluated in a trial; authors are always free to add any others, which they deem will best assess the efficacy of tested interventions. Benchmarks to define a threshold for treatment success were not set, as what constitutes a clinically-relevant therapeutic efficacy is expected to vary greatly depending interventions. CONCLUSIONS: This COSCAD'18 should help veterinarians and owners compare the benefits of treatments in future trials. This COS should also facilitate the combination of trial results in future systematic reviews, thereby producing more reliable summary estimates of treatment effects and enhancing evidence-based veterinary dermatology.

The Use of Liposomes and Nanoparticles as Drug Delivery Systems to Improve Cancer Treatment in Dogs and Cats.

BACKGROUND: Cancer remains a leading cause of death in companion animals. In human medicine, liposomes and nanoparticles have been extensively investigated as drug delivery systems (DDS) for anticancer agents due to their ability to target cancerous cells and reduce the negative side effects of free cytostatic drugs. In this review, the authors discuss the results of clinical trials using liposomes and polymer-based nanoparticles as DDS to improve cancer treatment in dogs and cats, indicating which ones seem worth further evaluation. The authors then overview ongoing animal cancer clinical trials, evaluating nano-DDS registered on the American Veterinary Medical Association Animal Health Studies Database. Finally, the authors indicate the nano-drugs that require further in vivo evaluation based on the encouraging results obtained from in vitro studies. CONCLUSIONS: Liposomes have been the most investigated nano-DDS in veterinary medicine. The lack of cardiotoxicity of the commercially available liposomal doxorubicin (Doxil/Caelyx) suggests it should be used in dogs with cardiac disorders, rather than using free doxorubicin. Cisplatin-incorporated hyaluronic acid nanoparticles, nanocrystals of cisplatin, and paclitaxel are the most promising nano-drugs for potent applications in treating various canine cancers (e.g. oral melanoma, oral sarcoma, and anal gland adenocarcinoma) and their translation into the treatment of human diseases.

Quality assurance and best research practices for non-regulated veterinary clinical studies.

Veterinary clinical trials generate data that advance the transfer of knowledge from clinical research to clinical practice in human and veterinary settings. The translational success of non-regulated and regulated veterinary clinical studies is dependent upon the reliability and reproducibility of the data generated. Clinician-scientists that conduct veterinary clinical studies would benefit from a commitment to research quality assurance and best practices throughout all non-regulated and regulated research environments. Good Clinical Practice (GCP) guidance documents from the FDA provides principles and procedures designed to safeguard data integrity, reliability and reproducibility. While these documents maybe excessive for clinical studies not intended for regulatory oversight it is important to remember that research builds on research. Thus, the quality and accuracy of all data and inference generated throughout the research enterprise remains vulnerable to the impact of potentially unreliable data generated by the lowest performing contributors. The purpose of this first of a series of statement papers is to outline and reference specific quality control and quality assurance procedures that should, at least in part, be incorporated into all veterinary clinical studies.

Attitudes of small animal practitioners toward participation in veterinary clinical trials.

OBJECTIVE To determine attitudes of small animal practitioners toward veterinary clinical trials and variables influencing their likelihood of participating in such trials. DESIGN Cross-sectional survey. SAMPLE Small animal practitioners with membership in 1 of 2 online veterinary communities (n = 163 and 652). PROCEDURES An online survey was developed for each of 2 veterinary communities, and invitations to participate were sent via email. Each survey included questions designed to collect information on the respondents' willingness to enroll their patients in clinical trials and to recommend participation to clients for their pets. RESULTS More than 80% of respondents to each survey indicated that they spend no time in clinical research. A high proportion of respondents were likely or extremely likely to recommend clinical trial participation to clients for their pets when those trials involved treatments licensed in other countries, novel treatments, respected investigators, or sponsoring by academic institutions, among other reasons. Reasons for not recommending participation included distance, time restrictions, and lack of awareness of ongoing clinical trials; 28% of respondents indicated that they did not usually learn about such clinical trials. Most respondents (79% to 92%) rated their recommendation of a trial as important to their client's willingness to participate. CONCLUSIONS AND CLINICAL RELEVANCE Participation in veterinary clinical trials by small animal practitioners and their clients and patients appeared low. Efforts should be increased to raise practitioner awareness of clinical trials for which patients might qualify. Specific elements of trial design were identified that could be modified to increase participation.

A systematic review of adverse event reporting in companion animal clinical trials evaluating cancer treatment.

OBJECTIVE To evaluate methods used to ascertain, define, and report adverse events (AEs) in companion animal clinical trials involving cancer treatment. DESIGN Systematic review. SAMPLE English-language articles describing prospective clinical trials involving dogs and cats with naturally occurring cancer published in peer-reviewed journals between 2008 and 2014. PROCEDURES Reports were identified via MEDLINE and CAB database searches combined with a hand-searching strategy. General article characteristics were abstracted and summarized. Data for AE reporting were collected with a 14-item checklist adapted from the 2004 CONSORT extension for reporting harms. Study characteristics associated with the AE reporting checklist score were identified by means of linear regression analysis. RESULTS 168 articles with data for 6,132 animals were included. Standardized terminology was significantly more likely to be used to describe AEs for trials that included chemotherapy (92/115 [80.0%]) than for trials that did not (16/53 [30.2%]). Median AE reporting checklist score was 5 out of 14 (range, 0 to 12). Poorly reported items included methods and time frame of AE ascertainment, AE data analysis, and reasons for treatment discontinuation and death. Trials with industry funding, a single-arm design, and treatment with chemotherapy were associated with a significantly higher quality of AE reporting. CONCLUSIONS AND CLINICAL RELEVANCE Reporting of adverse events in veterinary clinical trials evaluating cancer treatment was selective and heterogeneous. Harms associated with cancer treatments could be underestimated because of suboptimal collection and reporting of AE data. Findings supported the adoption of a higher standard for AE surveillance and reporting in veterinary patients.

Conduct, Oversight, and Ethical Considerations of Clinical Trials in Companion Animals with Cancer: Report of a Workshop on Best Practice Recommendations.

Development of effective and safe treatments for companion animals with cancer requires the collaboration of numerous animal health professionals and the full engagement of animal owners. Establishing 'Best Practice Recommendations' for clinical trials in veterinary oncology represents an important step toward meeting the goal of rigorous clinical trial design and conduct that is required to establish valid evidence. Likewise, optimizing patient welfare and owner education and advocacy is crucial to meet the unique ethical obligations to both owners and animals enrolled in these clinical trials and to ensure trust in the team conducting the research. To date, 'Best Practice Recommendations' for clinical trial conduct have not been reported for veterinary oncology. This document summarizes the consensus of a workshop held in November, 2014 to identify relevant ethical principles and to ensure responsible conduct of clinical research in companion animals with cancer. It is intended as a working document that will be updated as advances in science and ethical considerations require. To the extent possible, existing guidelines for the conduct and oversight of clinical trials in humans have been adapted for veterinary trials to avoid duplicative effort and to facilitate integration of clinical trials such that translational research with benefits for both companion animals and humans are encouraged.

Ethical principles for novel therapies in veterinary practice.

OBJECTIVES: To present insights to aid decision-making about novel veterinary treatments from regulations concerning animal experimentation and human clinical medical trials. MATERIALS AND METHODS: EU Directive 2010/63/EU on the protection of animals used for scientific purposes and EU Regulation 536/2014 on clinical trials on medicinal products for human use were analysed, evaluated and "translated" into relevant principles for veterinary surgeons. RESULTS: A number of principles are relevant, relating to treatment expectations, thresholds and objectives; client consent; minimising harms; personnel; review committees; assessment and publication. CLINICAL SIGNIFICANCE: These principles should assist veterinary surgeons to make good ethical decisions about novel treatments.

Technical note: A method for assigning animals to treatment groups with unequal count per group that equalizes mean animal weight among groups.

Pastures available for grazing studies may be of unequal size and may have heterogeneous carrying capacity necessitating the assignment of unequal numbers of animals per pasture. To reduce experimental error, it is often desirable that the initial mean BW be similar among experimental units. The objective of this note is to present and illustrate the use of a method for assignment of animals to experimental units of different sizes such that the initial mean weight of animals in each unit is approximately the same as the overall mean. Two alternative models were developed and solved to assign each of 231 weaned steers () to 1 of 12 pastures with carrying capacity ranging from 5 to 26 animals per pasture. A solution to Model 1 was obtained in which the mean weights among pastures were approximately the same but the variances among pastures were heteroskedastic, meaning that weight variances across pens were different (-value < 0.05). An alternative model was developed (Model 2) and used to derive assignments with nearly equal mean weights and homoskedastic variances among pastures.

Species differences in tumour responses to cancer chemotherapy.

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.