Chapter 5. Clinical Trial Design and Access to Clinical Research Studies
Melissa C. Paoloni and Chand Khanna
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 a sustained increase in the number of pet animals diagnosed with cancer and the pet-owning public’s interest in finding 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 between veterinary and human cancers. 1-5 Accordingly, well-designed clinical trials in veterinary oncology offer the opportunity to develop new drugs for use in both companion animals and people, a field known as comparative oncology.
Interestingly, the outcome for patients who are managed within a clinical trial has been consistently shown to be superior to that of patients who receive the same agents outside the setting of a clinical study. This suggests that clinical trials are of value not only for improving care of future patients, but also for those patients enrolled in a study. Through the conduct of clinical trials, our opportunities to prevent, diagnose, and 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 will welcome greater direct and indirect participation from both primary care veterinarians and veterinary specialists. The goals of this chapter are to introduce concepts of clinical trial design and conduct and to focus on the types of questions that these trials have the capability to address.
TRIAL DESIGNS
The first step in clinical trial design is to articulate the questions that the trial should address. This is generally done by asking: what are the study objectives? 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, including new drugs, radiation protocols, combination therapies, or novel technologies such as 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 lifestyle 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.
Irrespective of the intent of the trial, clinical trials are conducted in a prospective fashion and are distinctly different from retrospective studies that are commonly reported in the veterinary literature. Retrospective studies are those in which patients have already received a specified treatment or undergone a specific test, and then data are collected from their medical records for analysis. Prospective trials involve the deliberate design of a clinical trial intended to answer a specific objective or question. Patients entered into a prospective trial are managed within the constraints of a carefully designed study protocol. 6,7 This protocol design ensures accuracy and consistency of results and provides an opportunity to verify and validate results. A clinical trial protocol provides the background, specifies the objectives and describes the design and organization of the trial. All participants in a study follow the same protocol in the conduct of the clinical trial. In general, the results from prospective clinical trials are considered to be more valuable and reproducible than results from retrospective studies. Prospective trials are those most likely to make inferences about effectiveness of a new treatment. These trials are the basis of subsequent discussion.
The simplest prospective trial design in oncology is a case-series that assesses the ability of a drug to reduce the size of a measurable tumor (objective response) as the primary study endpoint. Objective response refers to an unequivocal reduction in tumor burden and is usually defined by > 50% reduction in tumor volume via World Health Organization (WHO) criteria or >30% reduction in tumor longest diameter via Response Evaluation Criteria in Solid Tumors (RECIST). Such trials allow each patient to be assessed before treatment, usually through measurement of tumor burden and then after treatment in an open-label setting, where all patients receive the active treatment or intervention. Patients are then re-evaluated at subsequent time points to determine if there has been a response (reduction in size) in the measurable tumor. Prospective clinical trials are usually included early in the development of a clinical intervention (see the next section for phases of study). Examples of such trials include the evaluation of the activity of a xenogeneic DNA vaccine for treatment of canine melanoma and of SU11654, a tyrosine kinase inhibitor in tumor-bearing dogs. 1,3,8
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. Table 5-1 outlines the most traditional phases. 9 Phase IV trials, not included in this table, are those that evaluate a drug for possible new uses or assess its market impact after it is already approved by the Food and Drug Administration (FDA). The FDA generally assesses 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.
| Phase I trials define a maximally tolerated dose (MTD) of a new drug/regimen through dose escalation. In these trials, toxicities associated with a new therapy can be defined. If a phase I trial is successful, its discovered dose moves into a phase II trial to assess efficacy and identify responding histologies. Phase III trials enroll a larger number of patients to compare the dose of the new therapy to standard of care treatment. Phase III trials can also assess if a new treatment is less toxic or less expensive with equal/improved efficacy to current standards. | |||
| Phase I | Phase II | Phase III | |
|---|---|---|---|
| Aim | Toxicity Dose finding | Efficacy Responding histologies | Comparison to standard of care |
| Patient number | Small | Large | Large |
| Dose | Escalating in cohorts | Fixed | Fixed |
| Single therapy | Yes | No | Yes or No—can be combination therapy |
| Randomization | No | Yes or No | Yes |
RANDOMIZATION AND STRATIFICATION
Randomization is the process of assigning patients to a treatment group within a clinical trial by chance, rather than by choice. Treatment groups may include the standard of care, the standard of care plus a new therapy, a new therapy alone, or, in some cases, a placebo. The goal of randomization is to reduce bias (i.e., influence) for known and unknown characteristics (e.g., age, stage of disease, previous treatments) that may influence a response to the study therapy. Random allocation can be achieved by various methods described in Chapter 4 . It is important that the sequence for randomization is concealed from clinical investigators (allocation concealment) in order to not bias the review of patient data as the study is ongoing. Therefore, during group assignment, treatment, assessment, and follow-up, it is common for the randomization of patients to be “blinded” or left unknown to participants, investigators, and statisticians. Randomization tends to produce comparable treatment groups in terms of those factors (i.e., confounders) that are not necessarily part of a study, but that may affect a treatment outcome. 9-11
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