Keeping Radiology on the Cutting Edge
Over the past two decades, imaging has undergone revolutionary and evolutionary changes in both the clinical and nonclinical spheres. Part of this evolution has been the acceptance of imaging as an endpoint or marker for evaluation of the efficacy of therapy in clinical trials. As a result, new doors have opened for the involvement of radiologists in shaping the future of new therapies. This three-article series will review trial methodology, the role of imaging in clinical trials, and potential future developments for the use of imaging in clinical trials. A clinical trial, at its most basic level, is a biomedical or health-related research study that is conducted in human beings and that follows a predefined set of steps or a protocol. In general, there are two types of clinical trials: interventional and observational studies. The former are executed through the assignment of research subjects, by an investigator, to a treatment or other intervention, after which their outcomes are measured. An observational study is one where individuals are observed and their outcomes are measured by investigators. Trial Types and Phases Within these general divisions of trials, there are various subsets and types of trials. Prevention trials attempt to examine new methods to prevent disease and typically use medication, vaccines, or alteration of habits. Diagnostic trials are performed to elucidate better methods for diagnosing diseases. Treatment trials attempt to study experimental treatments, adjunct therapies with novel combinations of drugs, or new approaches to conventional therapies. Screening trials attempt to ascertain the most efficient manner of detecting diseases. Supportive-care trials investigate methods for improving the quality of life of patients with chronic illness. All clinical trials are conducted in various phases. At each phase of the trial, the process attempts to answer a different (but specific) question. The phases are generally numbered I through IV, with a recent rise in the popularity of phase-0 trials (human microdosing). In a phase-I trial of (for instance) an experimental drug, investigators select a small group of people (fewer than 100) and try to evaluate drug safety while determining a safe dose, as well as identifying any side effects. In phase II, the experimental drug or treatment is given to a larger group of people (100 to 400), and further determination is made of its safety profile and treatment effectiveness. In phase III, investigators administer the drug to a larger cohort of patients (thousands) and compare the test drug with other conventional treatments. In addition, a safety-and-efficacy profile is studied. In phase IV, the FDA seeks to evaluate the drug after it has reached the market and has been used by the medical community. Radiology’s Investigative Role A biomarker is defined as a detectable biological feature that provides information about the source from which it came. Specifically, an imaging biomarker represents a feature that can be detected, evaluated, and followed using imaging modalities. For example, the detection of a dynamically enhancing mass in the liver, on MRI, can represent an imaging biomarker. For a clinical trial that is investigating the efficacy of a novel antitumor agent, the shrinkage of a liver tumor can represent an excellent imaging biomarker. The use of biomarkers (or surrogate endpoints) represented a shift in the methodology and thinking of regulatory bodies. Traditionally, endpoints (typically morbidity and mortality) were used to measure differences in groups within a clinical trial. As these endpoints can take significant time to reach, clinical trials began investing the use of biomarkers as surrogate endpoints—and specifically, the use of imaging biomarkers, given their precision and their objective (rather than subjective) capabilities. In 1996, the FDA released a bulletin addressing the issue of using imaging as a biomarker or surrogate endpoint. It stated, “FDA will begin to rely more on partial responses, such as shrinkage of a tumor, when considering drugs for accelerated approval. Through simpler clinical trials, manufacturers can more quickly demonstratethese partial responses than they can improvements in survival and quality of life. By basing accelerated approval on these partialresponses, and allowing more definitive data to be developed after approval, FDA will make more cancer therapies available to patients more quickly.”¹ This bulletin was followed, in 1997, by the FDA Modernization Act, which was designed to improve the regulatory process for medical products. In section 112 of the act, authority was given to expedite approval for drugs that provide therapy for conditions, given that the therapy is shown to have an effect on a surrogate endpoint that indicates a clinical benefit. There are other provisions in the act that enable companies to monitor products, following FDA approval, to study and ensure the efficacy of the surrogate endpoint that was used. It has become evident that the FDA is now committed to establishing programs that promote the development and use of surrogate endpoints for serious illnesses and diseases. This acceptance of surrogate endpoints has begun a shift that is expanding the roles of radiology, radiologists, and the imaging chain in helping to guide drug discovery and development. Clinical trials are an important part of the discovery and development of new therapies, and traditionally, radiology has not participated in the process. With the advent of imaging biomarkers and imaging endpoints for evaluating and testing therapeutic agents, however, we—as imaging experts—are poised to help guide the future of drug discovery. Amit Mehta, MD, FRCP, is a radiologist with South Texas Radiology Group in San Antonio and is a consulting radiologist for a contract-research organization. He welcomes comments and questions at dramitmehta@IntrinsicCRO.com.