Clinical Trial Design: Veterinary Perspectives

Tremendous potential exists for the use of the randomized clinical trial (RCT) in veterinary clinical research. Understanding the fundamentals of RCT design not only benefits clinical researchers, but it can enhance the ability of practitioners to interpret published RCT reports. In this article, the essential components of RCT design and implementation are described using examples from clinical veterinary medicine.     

Cancer clinical trials: development and implementation.

Although much of the current standard of care in veterinary oncology is based on retrospective studies or transference from the human literature, a new era of clinical trial awareness brought on by new consortia and cooperative investigative groups is beginning to change this limitation. The use of controlled, randomized, blind multicenter trials testing new cytotoxics and cytostatic agents is now becoming the norm rather than the exception. Ultimately, advanced clinical trial design applied to companion animal populations should advance veterinary-based practice and inform future human clinical trials that may follow.     

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.     

Illness Severity Scores in Veterinary Medicine: What Can We Learn?

Illness severity scores are gaining increasing popularity in veterinary medicine. This article discusses their applications in both clinical medicine and research, reviews the caveats pertaining to their use, and discusses some of the issues that arise in appropriate construction of a score. Illness severity scores can be used to decrease bias and confounding and add important contextual information to research by providing a quantitative and objective measure of patient illness. In addition, illness severity scores can be used to benchmark performance, and establish protocols for triage and therapeutic management. Many diagnosis‐specific and diagnosis‐independent veterinary scores have been developed in recent years. Although score use in veterinary research is increasing, the scores available are currently underutilized, particularly in the context of observational studies. Analysis of treatment effect while controlling for illness severity by an objective measure can improve the validity of the conclusions of observational studies. In randomized trials, illness severity scores can be used to demonstrate effective randomization, which is of particular utility when group sizes are small. The quality of veterinary scoring systems can be improved by prospective multicenter validation. The prevalence of euthanasia in companion animal medicine poses a unique challenge to scores based on a mortality outcome.     

伴侣动物用细胞毒类抗肿瘤药临床试验设计及评价要点

肿瘤已经逐渐发展成为老年伴侣动物最为常见的疾病，而目前国内并无伴侣动物专用的抗肿瘤药。细胞毒类抗肿瘤药是治疗恶性肿瘤的主要手段之一，目前有许多兽药企业致力于此类抗肿瘤药的研发。本文以EMA和FDA发布的伴侣动物抗肿瘤药指导原则为依据，结合国家药品监督管理局药品审评中心(CDE)发布的抗肿瘤药物临床试验技术指导原则对比分析，对伴侣动物使用的细胞毒类抗肿瘤药研发过程中的临床试验设计关键技术要点进行了分析，旨在为伴侣动物用细胞毒类抗肿瘤药临床评价提供参考。     

The poison-proof practice

Toxicology is the medical discipline that studies the often dramatic effects that poisons can have on living organisms. The body of toxicological information that the practicing veterinarian must deal with is growing exponentially. The veterinary clinician must come to understand the source of potential toxicants, circumstances leading up to poisoning episodes, must recognize the clinical signs of a wide variety of poisons, be able to diagnose intoxications, successfully treat and manage exposed animals, and institute strategies that educate the public and help prevent future poisonings. This is a tremendously tall order and can be not a little bit overwhelming. Fortunately, the clinicians are not alone and have tremendous resources in their corner, including veterinary schools, regional poison and drug centers, national veterinary hot lines utilizing board-certified veterinary toxicologists, local toxicologists and an ever-growing body of literature concerning small animal poisoning management. This discussion will investigate ways in which to make this seemingly daunting field much more palatable to small animal practitioners.     

Apoptosis: A review of pro‐apoptotic and anti‐apoptotic pathways and dysregulation in disease

Objective – To review the human and veterinary literature on the biology of apoptosis in health and disease. Data Sources – Data were examined from the human and veterinary literature identified through Pubmed and references listed in appropriate articles pertaining to apoptosis. Human Data Synthesis – The role of apoptosis in health and disease is a rapidly growing area of research in human medicine. Apoptosis has been identified as a component of human autoimmune diseases, Alzheimer's disease, cancer, and sepsis. Veterinary Data Synthesis – Research data available from the veterinary literature pertaining to apoptosis and its role in diseases of small animal species is still in its infancy. The majority of veterinary studies focus on oncologic therapy. Most of the basic science and human clinical research studies use human blood and tissue samples and murine models. The results from these studies may be applicable to small animal species. Conclusions – Apoptosis is the complex physiologic process of programmed cell death. The pathophysiology of apoptosis and disease is only now being closely evaluated in human medicine. Knowledge of the physiologic mechanisms by which tissues regulate their size and composition is leading researchers to investigate the role of apoptosis in human diseases such as cancer, autoimmune disease and sepsis. Because it is a multifaceted process, apoptosis is difficult to target or manipulate therapeutically. Future studies may reveal methods to regulate or manipulate apoptosis and improve patient outcome.     

Hyperbaric oxygen therapy. Part 2: application in disease

Objective – Review the mechanisms of action and clinical application of hyperbaric oxygen therapy (HBOT) based on human and veterinary clinical and experimental literature. Data Sources – Pubmed and Veterinary Information Network databases were searched for human and veterinary journal articles on hyperbaric therapy in clinically applicable situations. Historical reference searches on several articles in addition to basic physiologic concepts were also reviewed. Human Data Synthesis – HBOT has gained acceptance as an adjunctive treatment in clinical conditions other than diving‐related injuries, such as select problem wounds and central nervous system diseases, in human medicine. Access to hyperbaric therapy has increased and ongoing research has furthered understanding of the mechanisms and potential therapeutic uses of HBOT. Veterinary Data Synthesis – Several animal models have been utilized to examine the effects of HBOT; primarily rodents (mice, rats) and rabbits but also dogs, cats, and pigs. Data related to animal model research as it pertains to clinical application of HBOT is reviewed. Conclusions – There is a substantial body of literature that has examined the adverse and beneficial effects of HBOT in animal models. As technology becomes more readily available to clinical practice and more clinical trials are performed to define its effectiveness, HBOT may be considered as an additional therapeutic option in many conditions including select problem wounds, spinal cord injury, and cerebral ischemic injury. Understanding the mechanisms by which HBOT exerts its effects will help guide research and use of the modality in clinical patients.     

The use of intravenous lipid emulsion as an antidote in veterinary toxicology

Objective – To review the use of IV lipid emulsion (ILE) for the treatment of toxicities related to fat‐soluble agents; evaluate current human and veterinary literature; and to provide proposed guidelines for the use of this emerging therapy in veterinary medicine and toxicology. Data Sources – Human and veterinary medical literature. Human Data Synthesis – Human data are composed mostly of case reports describing the response to treatment with ILE as variant from mild improvement to complete resolution of clinical signs, which is suspected to be due to the variability of lipid solubility of the drugs. The use of ILE therapy has been advocated as an antidote in cases of local anesthetic and other lipophilic drug toxicoses, particularly in the face of cardiopulmonary arrest and unsuccessful cardiopulmonary cerebral resuscitation. Veterinary Data Synthesis – The use of ILE therapy in veterinary medicine has recently been advocated by animal poison control centers for toxicoses associated with fat‐soluble agents, but there are only few clinical reports documenting successful use of this therapy. Evidence for the use of ILE in both human and veterinary medicine is composed primarily from experimental animal data. Conclusions – The use of ILE appears to be a safe therapy for the poisoned animal patient, but is warranted only with certain toxicoses. Adverse events associated with ILE in veterinary medicine are rare and anecdotal. Standard resuscitation protocols should be exhausted before considering this therapy and the potential side effects should be evaluated before administration of ILE as a potential antidote in cases of lipophilic drug toxicoses. Further research is waranted.     

The information infrastructure that supports evidence-based veterinary medicine: a comparison with human medicine

In human medicine, the information infrastructure that supports the knowledge translation processes of exchange, synthesis, dissemination, and application of the best clinical intervention research has developed significantly in the past 15 years, facilitating the uptake of research evidence by clinicians as well as the practice of evidence-based medicine. Seven of the key elements of this improved information infrastructure are clinical trial registries, research reporting standards, systematic reviews, organizations that support the production of systematic reviews, the indexing of clinical intervention research in MEDLINE, clinical search filters for MEDLINE, and point-of-care decision support information resources. The objective of this paper is to describe why these elements are important for evidence-based medicine, the key developments and issues related to these seven information infrastructure elements in human medicine, how these 7 elements compare with the corresponding infrastructure elements in veterinary medicine, and how all of these factors affect the translation of clinical intervention research into clinical practice. A focused search of the Ovid MEDLINE database was conducted for English language journal literature published between 2000 and 2010. Two bibliographies were consulted and selected national and international Web sites were searched using Google. The literature reviewed indicates that the information infrastructure supporting evidence-based veterinary medicine practice in all of the 7 elements reviewed is significantly underdeveloped in relation to the corresponding information infrastructure in human medicine. This lack of development creates barriers to the timely translation of veterinary medicine research into clinical practice and also to the conduct of both primary clinical intervention research and synthesis research.     

Antiviral therapy for ocular viral disease.

Ophthalmic manifestations of viral disease are commonly encountered in veterinary practice. Although the number of antiviral agents is rapidly increasing, the efficacy of many of these drugs against animal viral pathogens may not be known. Furthermore, some of these newer medications may, in fact. be toxic to animal patients. Continued research on the efficacy of these medications in treating viral diseases of veterinary importance is warranted.A thorough review of the ever-growing body of literature is imperative before instituting any new or unknown antiviral therapy.At this time, feline HSV-1 infections remain the most well understood of the ocular viral infections that veterinary practitioners may be called on to treat. Ironically, the number of antiviral agents proven to be effective in naturally occurring clinical cases of FHV-I remains quite limited. With new medications being investigated, this paucity of information on efficacious antiviral therapeutic agents will hopefully improve.     

Evidence‐Based Medicine in Canine Reproduction: Quality of Current Available Literature

The objective of this study was to evaluate the quality of published literature on reproduction in dogs. A systematic search in online databases revealed 287 papers that met the inclusion criteria. For evaluation a questionnaire comprising 40 criteria regarding materials and methodology, study design, statistics, presentation and information content, applicability and conclusions was developed. In a pre‐test including seven independent scientists the applicability and explanatory power of the questionnaire and its results were validated. Out of 287 publications evaluated, 90 (31.4%) were classified as clinical trials. The remaining 197 publications were case reports or contained information based on personal experience. Not a single meta‐analysis was found. Sixty (66.7%) of the 90 clinical trials included a control group. Randomization was conducted in 23 and blinding in eight articles respectively. In total five articles were determined as randomized, controlled and blinded clinical trials. Information content of the publications was variable concerning details on included animals, type or dosage of used remedies or conducted interventions. For example, in 99.7% of the articles, the exact number of animals was given, but in 79.8%, housing and feeding of the animals were not described. Statistical procedures of clinical trials were determined adequate in 55.6%. However, the data of 67.9% of the articles were evaluated to be not sufficient to draw valid conclusions. This study revealed evidence of deficits in the field of canine reproduction. The demand for more high quality clinical research is obvious. Requisite for the further implementation of the evidence‐based veterinary medicine is an improvement of the quantity and the quality of well‐designed, conducted and reported clinical trials. The practitioner should always assess the quality of information before implementing results into practice to provide best available care for the animals.     

Physical agent modalities.

The purpose of this article is to review the use of cold, heat, therapeutic ultrasound, and electrical stimulation in small animal rehabilitation.The material in this article is a compilation from the veterinary and hu-man literature. Additional information is needed on how to adapt the techniques used in human beings to small animals and then to establish the efficacy of these techniques in animals.     

Thromboembolic therapies in dogs and cats: an evidence-based approach.

In veterinary medicine, we are forced to make use of less than ideal "evidence," such as extrapolation from experimental studies in dogs and cats without naturally occurring diseases and from clinical trials in other species (particularly human clinical trials), as well as limited information gained from veterinary clinical experience, small clinical trials, case studies, and anecdotal reports. In this article, specific treatment recommendations are made for each of the common thromboembolic conditions seen in dogs and cats. These recommendations are made with the important caveat that, to date, such suggested therapeutic approaches are based on limited evidence.     

Histamine: metabolism, physiology, and pathophysiology with applications in veterinary medicine

Objective – To review the human and veterinary literature on histamine physiology and pathophysiology and potential applications for clinical use in veterinary critical care. Data Sources – Human and veterinary clinical studies, reviews, texts, and recent research in histamine receptor and antagonist therapy. Human Data Synthesis – Recent progress in molecular biology has led to a more complete understanding of the enzymes involved in histamine metabolism and histamine receptor physiology. The past decade of research has confirmed the role of histamine in the classical functions (contraction of smooth muscle, increase in vascular permeability, and stimulation of gastric acid secretion) and has also elucidated newer ones that are now under investigation. Data on the roles of histamine in angiogenesis, circadian rhythm, bone marrow regeneration, bacterial eradication, and cancer are emerging in the literature. Newer histamine antagonists are currently in drug trials and are expected to advance the clinical field in treatment of allergic, gastrointestinal, and cognitive disorders. Veterinary Data Synthesis – Veterinary histamine research is directed at identifying the effects of certain pharmacological agents on blood histamine concentrations and establishing the relevance in clinical disease states. Research demonstrates important species differences in regards to histamine receptor physiology and tissue response. Studies in the area of trauma, sepsis, anaphylaxis, allergy, and gastrointestinal disorders have direct applications to clinical veterinary medicine. Conclusions – Histamine plays a key role in the morbidity and mortality associated with allergy, asthma, gastric ulcers, anaphylaxis, sepsis, hemorrhagic shock, anesthesia, surgery, cardiovascular disease, cancer, CNS disorders, and immune‐mediated disease. Histamine antagonism has been in common use to block its adverse effects. With recent advances in the understanding of histamine receptor physiology, pharmaceutical agents targeting these receptors have increased the therapeutic options.     

Evidence based medicine in veterinary daily practice

The veterinary practitioner should base decisions concerning diagnostic procedures and treatments in practice on recent, valid and clinically relevant information. He may rely on journal papers, colleagues, the internet or other sources. It is a great challenge to find appropriate information in a reasonable time. Furthermore, the practitioner has to judge the information regarding its actuality and validity. Ideally, such information should provide a high level of evidence. This means that this information is more likely to be "correct". Good information can be obtained through high quality trials, such as randomized and blinded controlled clinical trials. Universities, publishers and professional organizations should promote editing of scientific information to support practitioners in decision making.     

The use of vasopressin for treating vasodilatory shock and cardiopulmonary arrest

Objective – To discuss 3 potential mechanisms for loss of peripheral vasomotor tone during vasodilatory shock; review vasopressin physiology; review the available animal experimental and human clinical studies of vasopressin in vasodilatory shock and cardiopulmonary arrest; and make recommendations based on review of the data for the use of vasopressin in vasodilatory shock and cardiopulmonary arrest. Data Sources – Human clinical studies, veterinary experimental studies, forum proceedings, book chapters, and American Heart Association guidelines. Human and Veterinary Data Synthesis – Septic shock is the most common form of vasodilatory shock. The exogenous administration of vasopressin in animal models of fluid‐resuscitated septic and hemorrhagic shock significantly increases mean arterial pressure and improves survival. The effect of vasopressin on return to spontaneous circulation, initial cardiac rhythm, and survival compared with epinephrine is mixed. Improved survival in human patients with ventricular fibrillation, pulseless ventricular tachycardia, and nonspecific cardiopulmonary arrest has been observed in 4 small studies of vasopressin versus epinephrine. Three large studies, though, did not find a significant difference between vasopressin and epinephrine in patients with cardiopulmonary arrest regardless of initial cardiac rhythm. No veterinary clinical trials have been performed using vasopressin in cardiopulmonary arrest. Conclusion – Vasopressin (0.01–0.04 U/min, IV) should be considered in small animal veterinary patients with vasodilatory shock that is unresponsive to fluid resuscitation and catecholamine (dobutamine, dopamine, and norepinephrine) administration. Vasopressin (0.2–0.8 U/kg, IV once) administration during cardiopulmonary resuscitation in small animal veterinary patients with pulseless electrical activity or ventricular asystole may be beneficial for myocardial and cerebral blood flow.     

The REFLECT Statement: Reporting Guidelines for Randomized Controlled Trials in Livestock and Food Safety: Explanation and Elaboration†

Concerns about the completeness and accuracy of reporting of randomized clinical trials (RCTs) and the impact of poor reporting on decision making have been documented in the medical field over the past several decades. Experience from RCTs in human medicine would suggest that failure to report critical trial features can be associated with biased estimated effect measures, and there is evidence to suggest that similar biases occur in RCTs conducted in livestock populations. In response to these concerns, standardized guidelines for reporting RCTs were developed and implemented in human medicine. The Consolidated Standards of Reporting Trials (CONSORT) statement was first published in 1996, with a revised edition published in 2001. The CONSORT statement consists of a 22‐item checklist for reporting a RCT and a flow diagram to follow the number of participants at each stage of a trial. An explanation and elaboration document not only defines and discusses the importance of each of the items, but also provides examples of how this information could be supplied in a publication. Differences between human and livestock populations necessitate modifications to the CONSORT statement to maximize its usefulness for RCTs involving livestock. These have been addressed in an extension of the CONSORT statement titled the REFLECT statement: Methods and processes of creating reporting guidelines for randomized control trials for livestock and food safety. The modifications made for livestock trials specifically addressed the common use of group housing and group allocation to intervention in livestock studies; the use of deliberate challenge models in some trials and the common use of non‐clinical outcomes, such as contamination with a foodborne pathogen. In addition, the REFLECT statement for RCTs in livestock populations proposed specific terms or further clarified terms as they pertained to livestock studies.     

The perioperative management of small animals with previously implanted pacemakers undergoing anaesthesia

ObjectiveThere is little information in the veterinary literature about the perioperative management of small animal patients with previously implanted pacemakers undergoing elective or emergency non-cardiac procedures. The purpose of this article is to review the current literature with regard to human patients, with previously implanted pacemakers, undergoing general anaesthesia. Using this and the current information on pacemakers and anaesthesia in dogs and cats, we provide recommendations for small animal patients in this situation.Databases usedGoogle Scholar, PubMed and CAB Abstracts using and interlinking and narrowing the search terms: “dog”, “cat”, “small animals”, “anaesthesia”, “pacemaker”, “perioperative”, “transvenous pacing”, “temporary pacing”. Scientific reports and human and small animal studies from the reference lists of the retrieved papers were reviewed. In addition, related human and veterinary cardiology and anaesthesia textbooks were also included to create a narrative review of the subject.ConclusionsThe best perioperative care for these animals comes from a multidisciplinary approach involving the anaesthetist, cardiologist, surgeon and intensive care unit team. When such an approach is not feasible, the anaesthetist should be familiar with pacemaker technology and how to avoid perioperative complications such as electromagnetic interference, lead damage and reprogramming of the device. The preanaesthetic assessment should be thorough. Information regarding the indication for pacemaker placement, complications during the procedure, location, type and programming of the pacemaker should be readily available. The anaesthetic management of these veterinary patients aims to preserve cardiovascular function while avoiding hypotension, and backup pacing should be available during the perioperative period. Further prospective studies are needed to describe the best perioperative care in small animals with a previously implanted pacemaker.     

Clinical Evaluation of Methods of Treatment

Veterinary clinicians can make a significant contribution to the knowledge of the practical value of using alternative treatment methods by conducting clinical trials. By following a logical sequence of steps the clinician can design and participate in a clinical trial in his clinic without interfering with his normal practice. The successive stages of a field trial were presented along with an example to demonstrate the application of the principles involved. These stages are: design and planning, implementation, collection of data, and analysis of data.

The veterinary clinician who initiates clinical trials to answer questions plaguing him provides two services to the veterinary profession. First, he helps answer questions facing private practitioners throughout the profession. Second, he can demonstrate that not all research must be done in a laboratory setting isolated from “real world” complications. Seeing the results that can be derived from individual practicing veterinarians participating in clinical trials should act as a stimulus to other veterinarians to logically organize the data coming from their practices.