Veterinary clinical studies are having an increasing impact on human and veterinary medicine.1–12 They are a valuable addition to our scientific knowledge and directly address a translational niche that cannot easily be filled with traditional laboratory animal–based research. Importantly, clinical studies support the concept of “replacement, reduction, and refinement,” which is integral to best practices in medical research.13 However, although the number of such studies and the support for them are currently on the rise, they can raise some difficult ethical dilemmas. For this reason, the research community must develop appropriate, efficient, and effective methods for the ethical review of veterinary clinical studies and the concomitant informed consent process. Such review is required to sustain and enhance support from veterinarians who refer patients to these studies and to advocate on behalf of participating owners and patients.
The existing regulatory environment concerning the review of veterinary clinical studies has been discussed in a few recent publications and workshops in the United States and Europe.14–16 In the United States, several governmental bodies can be involved in some, or all, aspects of these clinical studies, depending on the goal and nature of the study and sources of funding. In addition, the practice of veterinary medicine is regulated by the states through their veterinary medical boards, particularly when a veterinarian-client-patient relationship is in place, and this could impact clinical trials.17,18
Following work by its Council on Research and Animal Welfare Committee, the AVMA approved a policy in 2015 for the Establishment and Use of Veterinary Clinical Studies Committees.19 The policy is brief and does not address specific details but does confirm a link between these VCSCs and already established IACUCs. Because laboratory animal veterinarians have been intimately involved in the functioning of IACUCs, many of these veterinarians, particularly those working at academic institutions with veterinary colleges, are also involved with the functioning of VCSCs.
Through involvement with committees tasked with the overview of veterinary clinical studies, it has become clear to us that there is a need to further refine this ethical review and increase its homogeneity, while both adhering to current regulations and keeping administrative burdens to a minimum. We hope that concerned governmental and professional organizations will participate in these discussions to help establish clear, collegial, and robust guidelines.
The AWA and Regulations
The AWA, originally called the Laboratory Animal Welfare Act, was first enacted in 1966 to protect the owners of dogs and cats from theft of their pets, prevent the sale of stolen dogs and cats, and ensure that animals used in research received appropriate care. Amendments to the Act in 1970 and 1976 primarily addressed the acquisition and transportation of animals used in research. And in 1985, an amendment to the act addressed minimum housing standards and the establishment of IACUCs.20 Since then, IACUCs have been instrumental in ensuring the humane care and use of animals in research, teaching, and testing.
For each research facility, the IACUC is charged with evaluating the care and use of animals in the research program and certifying compliance with the AWA.20 Functions of the IACUC include reviewing the research facility's program for humane care and use of animals, inspecting animal facilities (with the USDA's Animal Welfare Act and Animal Welfare Regulations20 as a basis for evaluation), preparing reports of its evaluation for the institutional official in charge of the research program, reviewing and investigating concerns regarding animal care and use, making recommendations to the institutional official regarding the research facility's animal program, reviewing proposed activities (eg, research protocols) and substantial changes to ongoing activities, and suspending activities involving animals as needed to ensure their ethical use. A substantial part of the IACUC's time is devoted to reviewing procedures involving animals. This review includes evaluation of procedures to avoid or minimize pain and distress, consideration of alternatives to procedures that may cause pain or distress, and ensuring activities are not unnecessarily duplicative.
The AWA provides clear definitions of key elements of an animal care and use program. Animals are defined as any live or dead dog, cat, nonhuman primate, guinea pig, hamster, rabbit, or any other warm-blooded animal that is being used or is intended to be used for research, teaching, testing, experimentation, or exhibition purposes or as a pet. It specifically excludes birds, rats, and mice bred for use in research, horses not used for research, and farm animals used as food or for fiber. A research facility is defined as any school (except an elementary or secondary school), institution, organization, or person that uses or intends to use live animals in research, tests, or experiments and that purchases or transports live animals in commerce or receives funds under a grant, award, loan, or contract from a department or agency of the United States for the purpose of carrying out research, tests, or experiments.
With regards to veterinary clinical studies, the AVMA states that, “Just like a clinical study in people, a veterinary clinical study involves research that gains information from animal patients. Clinical studies are intended to advance animal health care by identifying the most effective therapies and practices for a given condition, or by advancing our basic understanding of the disease. There are two main types of clinical studies: clinical trials (also called interventional studies) and observational studies. The AVMA Animal Health Studies Database includes both interventional and observational studies as well as including epidemiologic surveys.”21
Clinical trials are critical in veterinary medicine to advance our understanding of the diagnosis, treatment, and prevention of various ailments. However, the oversight of clinical studies is not clearly stated in the regulations governing animal care and use in research. The OLAW, which develops and monitors compliance oversight relative to the Public Health Service's Policy on Humane Care and Use of Laboratory Animals, provides guidance on when IACUC review of clinical trials is necessary, stating that IACUC review is required for clinical trials funded by the Public Health Service.22
Adhering strictly to the definitions of a research facility provided in the AWA, if a clinical trial does not involve the purchase or transport of live animals or does not receive funding from a governmental agency, the activity would not fall under the auspices of the AWA and would not be covered by it. This interpretation is supported by both the USDA and OLAW as highlighted in a 2009 article entitled “Protocol review: clinical study or research activity?”23 A hypothetical scenario presented in the article involved a veterinary neurologist performing CT and MRI at a local human hospital on client-owned dogs suspected to have had a stroke, with funding for the study provided by a foundation. The USDA guidance on this scenario focused on the acquisition of the animals and on whether government funding was used, and the determination was that because the animals were client-owned and the funding was from a foundation, the study was not subject to the AWA. Similarly, the OLAW stated that because no Public Health Service funding was used, IACUC oversight was not required.
More recent guidance from the USDA24 reinforces the idea that live animals (of species covered by the AWA) used for clinical studies are regulated if acquired by the institution. The guidance specifically refers to teaching activities, but because teaching and research have equal consideration under AWA regulations,20 the guidance clearly applies to clinical and translational studies as well. The USDA's Animal Welfare Inspection Guide also provides information regarding activities occurring in the context of a veterinarian-client-patient relationship, as defined by the AVMA.18 Activities occurring in the context of a valid veterinarian-client-patient relationship are not generally regulated under the AWA, because these animals are considered patients receiving treatment. However, there are many situations that are not simple to categorize and require case-by-case evaluation. For example, the inspection guide outlines special circumstances that may require further review, such as situations when animals not owned by the facility are housed at the facility for an extended period.25 However, the examples in the inspection guide are not exhaustive. Additional examples that may merit further evaluation include clinical trials involving healthy, client-owned animals as controls undergoing invasive sham procedures and instances when invasive or high-risk procedures performed on client animals may not have a confirmed or potential medical benefit to the animals, because these situations call into question their status as patients receiving treatment. Situations where the veterinarian-client-patient relationship is not clear would also warrant further consideration.
AVMA Guidance
The AVMA provides guidance on veterinary clinical trials and on enrolling patients. The association stresses that investigators should provide adequate information for owners to provide informed consent on the basis of potential risks and benefits, and that this consent is documented in writing. Further, the AVMA recommends that the IACUC determine whether the study involves any activity that would not otherwise be performed and that would therefore be subject to regulatory oversight. However, several aspects of a clinical study may not fall under the formal oversight of an IACUC, and in these situations, the AVMA suggests that the study be performed with the oversight of a VCSC,19 stating that “Animals undergoing standard-of-care treatment within a veterinarian-client-patient relationship that is not influenced by their involvement in a clinical study may be overseen by Veterinary Clinical Studies Committees (VCSC). The VCSC serves to ensure informed consent and to protect animals from conflict of interest issues.” Note that the VCSC is not meant to replace the IACUC, and that the VCSC should include a representative from the IACUC to help ensure appropriate practices are in place. Oftentimes, this representative will be the attending veterinarian for the institution's laboratory research program, who can be expected to have knowledge of the regulatory requirements for animal research.
Institutions can choose how they want to manage veterinary clinical trials. Although some institutions have policies and practices requiring IACUC review of all clinical trials, others may defer that oversight to a VCSC, and still others may use a combination of the two. Proposed veterinary clinical trials may not have undergone scientific peer review similar to the review process for studies funded by grants from the National Institutes of Health. Thus, although scientific review of the trial's rationale is not within the purview of the IACUC, the IACUC review process may benefit from such review to allow committee members to make a more informed decision. If oversight is deferred to a VCSC, someone knowledgeable of the USDA regulations should be part of the review process to ensure that trials are not subject to USDA or OLAW regulations. The VCSC should ensure that the scientific rationale is sound, selection criteria are clear, and informed consent is obtained and maintained (because informed consent is an ongoing process). A combination approach may involve VCSC review, including scientific review, of the clinical trial, with oversight by the IACUC. As an example, Colorado State University uses a tiered approach. Investigators provide the IACUC administrator and attending veterinarian with a description of a proposed project, which includes a project overview and information on funding sources and sources of animals. These individuals then make a determination as to whether the project is regulated by the USDA and whether it meets the definition of a clinical trial. If it does meet the criteria for a clinical trial, it is referred to the VCSC for review. If it does not meet the definition of a clinical trial, it is referred to the IACUC for review. If it requires IACUC review but client-owned animals are also involved, then it is reviewed by both the VCSC and the IACUC. In instances when it is difficult to determine which committee should review a project, the project is reviewed by both the IACUC and the VCSC. The Ohio State University and Cornell University have similar review processes.26
Case Examples
As a way to illustrate the complex issues that can arise when reviewing proposed clinical trials to determine whether IACUC approval would be needed, the authors considered several examples of real and potential studies. For all of these examples, we assumed that there was no funding from the Public Health Service or any other governmental agency, only client-owned animals would be enrolled in the study, informed owner consent would be received, and the study had been reviewed by a VCSC. We provide the opinion of the authors who are academicians (LVK, VKB, RLP, and PJRB) and the results of an evaluation by the USDA APHIS (NP) to illustrate the potential differences in interpretation.
Example 1
Proposed study—A clinician proposes collecting blood samples from client-owned animals to determine the prevalence of antibodies against a common pathogen in the region and identify potential risk factors for disease. Only surplus samples left over from blood samples collected for other reasons would be used.
Academicians' interpretation—There was no consensus for this situation. The argument for not requiring IACUC review was that blood samples used in the study would have been collected for diagnostic testing anyway, in adherence with the current standard of care, and that using patient information to identify risk factors would potentially aid in the future prevention of disease. However, some argued that IACUC review would be required, because blood sample collection may not have been routine for animals with this condition, even under the current standard of care, and that, regardless, extra blood would have to be collected for use in the proposed study.
USDA interpretation—Note that according to USDA guidelines and provided a valid veterinarian-client-patient relationship was established, the study as outlined in this scenario would likely not be considered a regulated activity under the AWA, because it would not involve animals acquired by the institution, would appear to have potential benefits for enrolled animals in regard to diagnostic testing, and could provide information that would lead to prevention of disease. However, if the blood samples were marketed or sold, then the study would become a regulated activity, because the institution would then be acting as a dealer as defined by the AWA.
Example 2
Proposed study—In a proposed study, owners of healthy dogs would be asked to attach a physical activity monitor to their dog's collar, which would measure their dog's regular activity. Owners would keep a log of special events, such as removal of the collar, and any technical difficulties that were encountered. The purpose of the study was to compare various physical activity monitors on the market.
Academicians' interpretation—As with the previous scenario, there was no consensus for this situation. Although this was a noninvasive study, there was no medical purpose for having dogs wear these monitors. The argument for not requiring IACUC review was that the dogs were not procured by the institution and the project was not funded by the government. The argument for requiring IACUC review was that because these were healthy dogs, wearing an activity monitor was not medically necessary. Thus, the study could be interpreted to be a research project, which the IACUC should oversee.
USDA interpretation—Notably, although medical benefit (ie, clinical purposes) is addressed in the USDA's guidance,23 “medical necessity” is not, nor is it addressed in the Animal Welfare Inspection Guide. In this scenario, there would appear to be some potential benefit to enrolled patients if activity monitors are considered useful adjuncts to managing animal health. However, as outlined in the guidance, medical benefit, ownership, and funding source must be considered in determining whether IACUC review is necessary. The scenario involves a noninvasive study on client-owned animals and, provided that the activity monitors are already commercially available and not novel devices undergoing safety testing, would not appear to be a regulated activity under the AWA, according to the USDA. However, if there were safety concerns such as ingestion hazards or toxic components that have not been evaluated for safety, the activity could be considered a regulated activity involving testing, as opposed to being a study designed to determine medical benefit to the animals in the context of a valid veterinarian-client-patient relationship.
Example 3
Proposed study—A proposed study involves evaluating a novel stem cell therapy as a treatment for dogs with naturally occurring osteoarthritis.
Academicians' and USDA interpretation—There was a consensus that this scenario would not require IACUC oversight. Although the treatment would be experimental, it would involve treating a medical condition under the guidance of a veterinarian in the context of a veterinarian-client-patient relationship. That said, the FDA could be concerned and could potentially place some restrictions on the study and require evidence of the treatment's safety and efficacy.
Example 4
Proposed study—A clinician wants to conduct a pharmacokinetic study of buprenorphine in healthy ferrets and is proposing to conduct the study on client-owned ferrets rather than ordering ferrets from a commercial supplier. The ferrets would be housed at the clinic for 72 hours for drug administration and sample collection.
Academicians' and USDA interpretation—There was a consensus among the authors that the study would require IACUC review and approval. There would be no medical reason for the ferrets to receive the buprenorphine, and it is likely that at least some animals would never benefit from the study. In addition, the institution or hospital would be housing the ferrets for a prolonged period (72 hours).
If the study were to be performed in ferrets that had undergone surgery and received buprenorphine for postoperative analgesia, with blood collected to confirm therapeutic buprenorphine concentrations, then IACUC review would not be required because all procedures would be performed for therapeutic purposes.
Example 5
Proposed study—A clinician wants to perform kidney transplantation on a client-owned cat with chronic renal failure, using a kidney from a donor cat that would be expected to survive following surgery to acquire the kidney.
Academicians' and USDA interpretation—The consensus was that this surgical procedure did not require IACUC review because it would be used to treat a condition in a client-owned cat. However, depending on the source of the donor cat, IACUC review may be necessary. If the donor cat were to be purchased specifically for kidney donation, then IACUC review would be required. Thoughtful consideration of the disposition of the donor cat following surgery would also be required. If the donor cat belonged to the owner or to another individual, the procedure would not require IACUC review.
Although client-owned donor animals undergoing invasive procedures that are not of medical benefit are generally considered special circumstances requiring review, in this instance, we looked to human donation guidelines, under which procedures for the donor and recipient would both be considered part of and essential to the medical intervention for the recipient. Therefore, we believe that activities involving client-owned donor animals would not be regulated under the AWA, provided that all activities were in the context of a valid veterinarian-client-patient relationship. However, there are clearly numerous ethical and welfare concerns in this example. Although the AWA and its regulations are silent on informed consent, obtaining informed owner consent would be especially important in this scenario.
Example 6
Proposed study—A clinician wants to collect blood samples from healthy dogs to serve as control samples for a study evaluating potential biomarkers in dogs with heart disease. The blood samples would be in addition to any blood samples collected for routine veterinary care but would be collected at the same time blood samples were collected for routine diagnostic testing.
Academicians' interpretation—The consensus was that the use of animals would require IACUC oversight. There would be no medical need for the additional blood to be collected and doing so would not serve any diagnostic or therapeutic purpose.
USDA interpretation—Evaluation of USDA guidelines could offer an alternative interpretation. If the owners were present during blood sample collection, the owners provided their consent for collection of additional blood without their being present, or collection of additional blood was not considered an invasive or high-risk procedure with no actual or potential medical benefit,25 then the activity would not be regulated, regardless of whether the samples were collected at the same time as blood samples were collected for routine diagnostic testing or as a separate procedure. Nevertheless, having informed consent is recommended for minimally invasive procedures such as blood sample collection that are not of clear or certain benefit to the animal, as is having the owner present for the procedure, if feasible. This ensures that owners have real-time information on the welfare of their animals and can make informed decisions regarding their welfare.
Future Directions
Determining whether activities conducted under the auspices of a clinical study are regulated by the USDA or OLAW, and thus require IACUC oversight, is not always a clear and simple issue. Institutions should develop their own guidance on how the IACUC oversees—or does not oversee—clinical trials. The AVMA's policy on VCSCs should be further elaborated and strengthened. Ethical review of clinical studies is a necessity and presents many advantages. Although establishing policies and procedures may be relatively straightforward for academic institutions, given that they are likely already registered with the USDA and have an IACUC, researchers and clinicians in the private sector should be aware of when USDA or OLAW oversight is needed. It behooves the veterinary profession to take the lead in this matter through discussions of IACUC and VCSC responsibilities and by working with regulatory agencies. Further discussions on and review of the ethical components of clinical studies by concerned parties is needed.
ABBREVIATIONS
| AWA | Animal Welfare Act |
| IACUC | Institutional animal care and use committee |
| OLAW | Office of Laboratory Animal Welfare |
| VCSC | Veterinary clinical studies committee |
References
1. Park JS, Withers SS, Modiano JF, et al. Canine cancer immunotherapy studies: linking mouse and human. J Immunother Cancer 2016;4:97–108.
2. Gavazza A, Lubas G, Fridman A, et al. Safety and efficacy of a genetic vaccine targeting telomerase plus chemotherapy for the therapy of canine B-cell lymphoma. Hum Gene Ther 2013;24:728–738.
3. Mason NJ, Gnanandarajah JS, Engiles JB, et al. Immunotherapy with a HER2-targeting Listeria induces HER2-specific immunity and demonstrates potential therapeutic effects in a phase I trial in canine osteosarcoma. Clin Cancer Res 2016;22:4380–4390.
4. AVMA. Therapeutic use of stem cells and regenerative medicine. Available at: www.avma.org/KB/Policies/Pages/Therapeutic-Use-of-Stem-Cells-and-Regenerative-Medicine.aspx. Accessed Sep 23, 2017.
5. Burton J, Khanna C. The role of clinical trials in veterinary oncology. Vet Clin North Am Small Anim Pract 2014;44:977–987.
6. Fürdös I, Fazekas J, Singer J, et al. Translating clinical trials from human to veterinary oncology and back. J Transl Med 2015;13:265–272.
7. Weintraub A. Heal: the vital role of dogs in the search for cancer cures. Toronto: ECW Press, 2015.
8. Natterson-Horowitz B, Bowers K. Zoobiquity: the astonishing connection between human and animal health. New York: Vintage Books, 2013.
9. MacDonald H. What animals taught me about being human. The New York Times Magazine. Available at: www.nytimes.com/2017/05/16/magazine/what-animals-taught-me-about-being-human.html. Accessed Sep 23, 2017.
10. Nature. Pet projects need a helping hand. Available at: www.nature.com/news/reform-regulations-to-make-pet-clinical-trials-easier-1.21103. Accessed Nov 9, 2017.
11. National Association for Biomedical Research. Available at: www.nabr.org/biomedical-research/laboratory-animals/species-in-research/dogs/. Accessed Sep 23, 2017.
12. Grimm D. Can clinical trials on dogs and cats help people? Available at: www.sciencemag.org/news/2016/08/can-clinical-trials-dogs-and-cats-help-people. Accessed Nov 9, 2017.
13. Russell WMS, Burch RL. The principles of experimental technique. London: Methuen and Co, 1959. [Reissued, 1992. Universities Federation for Animal Welfare, Herts, UK. Available at: altweb.jhsph.edu/pubs/books/humane_exp/het-toc. Accessed Sep 23, 2017.]
14. Gordon I, Paoloni M, Mazcko C, et al. The Comparative Oncology Trials Consortium: using spontaneously occurring cancers in dogs to inform the cancer drug development pathway. PLoS Med 2009;6:e1000161.
15. The National Academies. The role of clinical studies for pets with naturally occurring tumors in translational cancer research: workshop summary. Available at: www.nationalacademies.org/hmd/Reports/2015/The-Role-of-Clinical-Studies-Pets-Naturally-Occuring-Tumors-Transitional-Cancer-Research.aspx. Accessed Sep 23, 2017.
16. Page R, Baneux P, Vail D, et al. Conduct, oversight, and ethical considerations of clinical trials in companion animals with cancer: report of a workshop on best practice recommendations. J Vet Intern Med 2016;30:527–535.
17. AVMA. Defining relationships. Available at: www.avma.org/News/JAVMANews/Pages/170601a.aspx. Accessed Sep 23, 2017.
18. AVMA. VCPR: the veterinarian-client-patient relationship. Available at: www.avma.org/KB/Resources/Reference/Pages/VCPR.aspx. Accessed Oct 26, 2017.
19. AVMA. Establishment and use of veterinary clinical studies committees. Available at: www.avma.org/KB/Policies/Pages/Establishment-and-use-of-veterinary-clinical-studies-committees.aspx. Accessed Apr 5, 2017.
20. Animal Care, USDA APHIS. Animal Welfare Act and Animal Welfare Regulations. Available at: www.aphis.usda.gov/animal_welfare/downloads/AC_BlueBook_AWA_FINAL_2017_508comp.pdf. Accessed Jun 25, 2018.
21. AVMA. AVMA Animal Health Studies Database: learn about veterinary clinical studies. Available at: ebusiness.avma.org/aahsd/more_info/veterinary_clinical_studies.aspx. Accessed Sep 23, 2017.
22. Office of Laboratory Animal Welfare. Frequently asked questions: PHS policy on the humane care and use of laboratory animals. Available at: grants.nih.gov/grants/olaw/faqs.htm#527. Accessed Apr 5, 2017.
23. Silverman J. Protocol review: clinical study or research activity? Lab Anim 2009;38:185–187.
24. Animal Care, USDA APHIS. Animal welfare inspection guide. Section 7–51: guidance for veterinary schools and veterinary technician programs for the inspector. Available at: www.aphis.usda.gov/animal_welfare/downloads/Animal-Care-Inspection-Guide.pdf. Accessed Jun 25, 2018.
25. Animal Care, USDA APHIS. Animal welfare inspection guide. Section 7–52: special circumstances that may require registration. Available at: www.aphis.usda.gov/animal_welfare/downloads/Animal-Care-Inspection-Guide.pdf. Accessed Jun 25, 2018.
26. Baneux PJ, Martin ME, Allen MJ, et al. Issues related to institutional animal care and use committees and clinical trials using privately owned animals. ILAR J 2014;55:200–209.
