Introduction

Why do we conduct clinical research? For whose benefit? The most straightforward answer to these questions are that we conduct clinical research to improve diagnostic methods and treatments, which in the end will benefit the general dog and cat population and their owners. Although this is probably true for many research projects, the reality is probably more complex. The last 20 years, original research designed for studying a clinical entity or medical treatments has gradually increased, as indicated by the increased number of publications and the complexity of studies. I have been fortunate to have been an active researcher during this very dynamic time period. This presentation is aimed at, to some extent, illustrate the development of different types of studies conducted in small animals. I, as many other people engaged in clinical research, wonder if our studies truly made a difference in the end for owners, pets and practitioners.

New Technologies and Integrity

The rate at which technical innovations are introduced field is high, but there are examples of studies where new technologies are introduced that may not add much extra information to what is already known through case history, physical examination and routine clinical tests. There is a saying about these technologies: "Another method desperately seeking an application." Some of these technologies may be expensive, which means that researchers feel compelled to conduct studies. There are other examples where researchers need publications for their academic career or for prestige. In some instances, the reason for the publication is simply for marketing reasons. In these cases, the integrity of the researchers is paramount to ensure that the results are correctly outlined in a non-biased manner and that negative results are also published. Here it is the responsibility of the specialists that are engaged in the study to press the sponsor for a clause in the contract that states that the investigators have full right to proceed with publishing the trial regardless of the outcome.

Different Questions to Answer Require Different Clinical Studies

Clinical studies do not need to be large and expensive to provide clinical valuable information. Good new ideas and the formulation of questions to answer is a scarce commodity, and only the ingenuity sets the limits. An example of studies that were very inexpensive and simple to perform includes the studies of sleeping and resting respiratory rates in normal dogs and cats and in those with heart disease. These studies were very cheap to conduct, but provided valuable information how to effectively home monitor dogs and cats with heart disease. Other studies, particularly those aimed at evaluating responses to treatment, require large study population, blinding and randomization which is expensive. The most challenging types of studies include chronic medication over a long time-period. It is tempting to extract as much information as possible from these expensive trials, and a common problem is that they are designed with too many questions to answer and too complicated study protocol. The more questions to answer, the greater the chance is that the results become diluted and non-informative, and the compliance among clinicians and owners decrease with study protocol complexity. Therefore, the questions to be answered should be as few as possible and pertinent, and the study protocol should only include data that are needed for evaluating the primary outcome variable.

Some studies might not have been of direct benefit for the animals or owners but are needed to better characterize and define diseases. Case series are very common in veterinary medicine and they are limited in value. For example, they cannot provide strong evidence of treatment effect unless a certain treatment lead to an outcome that never happens otherwise, but they serve to raise the awareness of a certain disease, and might be suggestive of a need for future studies. Studies of disease progression and staging might not either lead to a direct benefit. However, these types of studies constitute the foundation of large clinical trials that could not be appropriately designed without them. Epidemiological studies might serve to quantify a health problem within a breed and raise the awareness among clinicians, breeders and owners, but they do not provide a direct benefit for anyone. They are however essential in the next step for clinical decision making and for preventive measures aimed at reducing the occurrence of the disease. However, further studies might be needed before preventive measures are initiated. For example, breeding restrictions should not be applied unless evidence of inheritance is available. There are many examples where this vital information is missing and measures are based on assumed inheritance.

Clinical Trials in Dogs

For interventional studies, it is of vital importance to have very strict and defined outcome variables. Having diagnostic imaging or laboratory variables as surrogates of genuine clinical success is usually not appropriate, when the aim is to investigate if a certain treatment benefit dogs and cats by improving quality of life and survival. Drug trials are the most challenging types of interventional studies, the reason being that they require many cases included, clear inclusion and exclusion criteria, and well-defined endpoints (outcome variables). Endpoints in the area of small animal cardiovascular medicine usually include quality of life variables assessed by attending clinician and owner, duration of preclinical period and survival. Drug trials in dogs with preclinical myxomatous mitral valve disease (MMVD) are challenging trials. However, due to the lengthy nature of the preclinical period, any therapy effective in prolonging this period could have a major impact on longevity and quality of life of affected dogs. It has therefore been of great interest to find a treatment that has a preventive effect on progression of MMVD, alternatively offers a prolonged preclinical period. The challenges include establishing inclusion and exclusion criteria that lead to a study population that is representative of the target population (the dogs that will be receiving this particular treatment in the future). Because of the lengthy preclinical period, a clinical trial, aimed at studying progression in treatment groups, must plan for how to handle dogs developing other disease and possibly initiation of medication other than the test substances, and how to handle treatment gaps and dropout of included dogs. Safety is a very important issue in long-term trials in dogs without clinical signs of disease. The study needs to be designed in such manner that potential detrimental effects of the test substance are detected during the study.

Designing Studies Concerning Feline Cardiomyopathy

There have been some drug trials conducted in cats with hypertrophic cardiomyopathy (HCM), but few of them have been published, presumably owing to non­significant differences between treatment groups. Feline cardiomyopathy is a group of myocardial diseases where it may be difficult to distinguish one form from the other. Some cats may also share features of all forms. The situation has also been complicated by a lack of robust reference intervals for echocardiographic measurements, which are vital for diagnosing heart disease, HCM in particular. Fortunately, sometimes help can come from those who will ultimately benefit from the study, which was the case when new body weight dependent reference ranges were recently published. The reference ranges were based on almost 20,000 echocardiographic screens of pure-bred cats, and the management of the screen reports and entering them all into a database was all done on a voluntary basis for the PawPeds organization. The cost for this study was very low, but demanded a very large amount of voluntary work. These reference intervals will help specialists into better defining disease, and thereby presumably help in establishing better defined study populations in interventional studies.

Concluding Remarks

Studies are conducted for many reasons and motifs. Depending on type of study, and quality in design and performance, they help indirectly by better disease definitions or better understanding of the pathophysiology, or they can benefit dogs and cats directly. Does it matter? I think it does, but some studies matter more than others.

References

1.  Rishniw M, Ljungvall I, Porciello F, et al. Sleeping respiratory rates in apparently healthy adult dogs. Res Vet Sci. 2012;93:965–969.

2.  Ljungvall I, Rishniw M, Porciello F, et al. Sleeping and resting respiratory rates in healthy adult cats and cats with subclinical heart disease. J Feline Med Surg. 2014;16:281–290.

3.  Häggström J, Andersson AO, Falk T, et al. Effect of body weight on echocardiographic measurements in 19,866 pure-bred cats with or without heart disease. J Vet Intern Med. 2016;30:1601–1611.

4.  Boswood A, Häggström J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study - a randomized clinical trial. J Vet Intern Med. 2016;30:1765–1779.

5.  Häggström J, Boswood A, O’Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. J Vet Intern Med. 2008;22:1124–1135.

6.  Cowie MR, Filippatos GS, Alonso Garcia ML, et al. New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment. Eur J Heart Fail. 2017.