Clinical Trial Design & the Role of the Practitioner
ACVIM 2008
Melissa C. Paoloni, DVM, DACVIM (Oncology)
Bethesda, MD, USA

Introduction

Clinical trials in veterinary oncology are growing in scope and importance. Trials that evaluate novel therapies for pet animals with cancer have the opportunity to improve the outcome and quality of life for veterinary patients, as well as human patients with cancer. The demand for clinical trials has been fueled by the rapid growth in pet animals treated for cancer and the pet owning public's interest in effective and well-tolerated treatments for their pets. Interest from the human cancer drug development industry is based on a need for more reliable ways to evaluate new cancer drugs and the strong similarities established between veterinary and human cancers. Accordingly, well-designed clinical trials in veterinary oncology offer the opportunity to develop new drugs in both species. Interestingly, the outcome for patients who are managed within a clinical trial has been consistently shown to be superior to patients who receive the same agents outside the setting of a clinical study. This suggests the value of clinical trials not only to future patient care but also to the actual patient who is involved in a study. Through the conduct of clinical trials our opportunities to prevent, diagnose or treat cancer will continue to improve. It is likely that the availability of clinical trials in veterinary oncology will continue to expand. This expansion will require and welcome greater direct and indirect participation from both primary care veterinarians and veterinary specialists.

Trial Designs

The first step in the design of a clinical trial is to articulate the questions that the trial should address. This is generally done by asking: what is the primary study objective? Based on a combination of primary and secondary objectives, investigators will define the optimal trial design for a specific study. There are three general types of clinical trials:

 Therapeutic trials test new therapies, such as new drugs, radiation protocols, combination therapies or novel technologies like gene therapy or cancer vaccines.

 Prevention trials assess new approaches to reduce the risk of developing certain types of cancer. These are less common in veterinary medicine but can be thought of as those that involve life style changes for pets, such as diet changes or supplement administration. In the future these trials may assess the ability of an intervention to reduce the risk of cancer development in high-risk animals, i.e., breeds at high risk for specific cancers.

 Screening trials evaluate novel tests that diagnose or define the stage of a cancer. These tests may involve new imaging techniques, such as positron emission tomography (PET) scans, magnetic resonance imaging (MRI) or new molecular tests like polymerase chain reaction (PCR) to confirm a diagnosis of leukemia in a patient with lymphocytosis.

Phases of Clinical Trials

Most clinical research in human oncology is very well defined and the testing of new therapies proceeds in a step-wise process. Clinical trials are broken up into three phases so that the questions they answer are distinct. Phase I trials are geared toward assessments of safety and are dose finding, phase II trials must demonstrate activity or define an indication for a new agent, where phase III trials strictly evaluate a new therapy vs. the present standard of care. Phase IV trials, which are a newer concept, are those that test a drug for possible new uses after it is already approved by the FDA. They generally assess new indications, dosages or delivery methods of a drug. Although the named phases of clinical trials are not always used in veterinary oncology trials, many of our studies aim to answer the same questions of safety, efficacy and comparison to conventional therapy.

Power

Power is a measure of the ability of a study to identify statistically significant differences between treatment groups. If the difference between treatment groups is small, the number of patients included in a trial needs to be large. The size of the patient population is a primary determinant of its power. By increasing the statistical power in a study, the chance of demonstrating statistically significant differences between treatment groups is increased. It is important to note that the size of a study (i.e., number of participants) should be defined before a clinical trial is initiated.

Endpoints

Endpoints are selected to answer the primary and secondary objectives of a trial and reflect the specific measures that will be followed in a study. Common endpoints in clinical trials include defining a maximally tolerated dose (MTD) to assess safety and evaluating tumor response, disease free interval (DFI) and survival time (ST) to measure activity. Criteria for safety and toxicity have been recently established for veterinary patients through the Veterinary Cooperative Oncology Group (VCOG-CTCAE). These published guidelines list a number of maladies that may be noted in the evaluation of an animal in a clinical trial and allow the categorization of the severity of these maladies using a grade from I (least severe) to IV (most severe). These guidelines allow consistency in the reporting of safety/toxicity endpoints in clinical trials. Reporting of the safety/toxicity of a new agent assessed in a clinical trial is of significant importance. The effectiveness of a new cancer agent can be measured in several ways. These include response rates in measurable/macroscopic disease, DFI and overall survival as mentioned above and quality of life (QOL) assessments. Endpoints differ depending on the type and objectives of a study and are defined prospectively in the study protocol. Biological endpoints, such as pharmacokinetic and pharmacodynamic assessments, are becoming increasingly important in veterinary oncology clinical trials. These biologic endpoints have been incorporated into study designs to better understand the mechanisms and biological effects of novel therapies/interventions.

Ethical Considerations

There are key ethical standards employed in clinical trial design and it is the goal of all clinicians to ensure these standards are met when presenting the option of a trial to a client or enrolling a patient within a clinical trial. The motivation for clients to enter clinical trials include the lack of other effective treatments for their pet's cancer, side effects that may limit their interest in pursuing conventional treatments, or cost of conventional therapy. For the most part, clinical trials are provided at no cost or at limited cost to clients. In almost all trials, the cost of the study drug is not the responsibility of the client. It is increasingly important to include the option of clinical trials when presenting the medical options available for a specific patient. In many cases, an owners' motivation to choose a clinical trial is influenced by their desire to help their pet and to improve outcomes for future pets or people with cancer.

Informed consent is required for all patients to enroll in a clinical trial. This is a written acknowledgement created by a trial's principal investigators and signed by a client, indicating that both the potential benefits and the adverse effects associated with clinical trial participation have been discussed. This informed consent defines a trial's purpose and the requirements of the client to return with their pet for future follow-up procedures/appointments. It ensures that the relationship and responsibilities of all parties involved in the trial are clear. Although, adverse events outside of those described are always possible, informed consent ensures that clients understand that in many trials the outcome/side effects are yet unknown.

Practitioner Involvement in Clinical Trials

The active engagement of veterinary general practitioners in conducting oncology clinical trials is integral to their success. These clinicians are the ones who first diagnose a pet with cancer and can act as the front line to educate clients on the availability of clinical trials as part of the options available to a family. Reassuring clients about the myriad of treatment options available today to pets with cancer and removing the mystery surrounding clinical trials is one of the most important steps in developing new techniques to fight cancer in companion animals. It is also proven that involving patients in clinical trials provides the best care to patients in both the short and long term.

Clinical trials are often conducted through academic veterinary teaching hospitals or referral centers, and increasingly include direct involvement from private practitioners. It may not be feasible for patients to return to tertiary care centers for recheck examinations, hence these are often handled locally by their referring veterinarians. The timely reporting of these rechecks to the study center site and accurate record keeping are necessary for the reporting of clinical trial results. This includes all possible long-term adverse events (side effects) from a new therapy, as well as outcome data.

There are a number of resources available to practitioners to find information regarding oncology clinical trials. As suggested, it is certain that the availability of clinical trial options for pet owners will expand in the coming years. These options will in many cases be the "desired" option for a client/family to pursue for their pet. As a trusted source of information, the primary care veterinarian plays an important role in describing the advantages and disadvantages of all treatment options available for a pet with cancer. In many cases these options will include clinical trial participation.

References

1.  Hansen K, et al. Eur J Cancer 2004;40, 858.

2.  Vail DM. Vet Comp Oncol 2004;2,194.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Melissa Paoloni, DVM, DACVIM (Oncology)
Washington, DC


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