This article is the second in a series of three providing a background and primer to radiologists and imaging professionals interested in clinical trials. It offers background on regulatory approval and on the use of surrogate endpoints and imaging biomarkers, as well as touching on the administration of medical imaging in clinical trials.
Medical imaging has become a significant tool in the development of clinical-trial protocols. Diagnostic imaging enables sponsors to obtain a rapid diagnosis by using truly quantitative assessment, as well as qualitative assessment. Paramount to understanding the utility of medical imaging in clinical trials is an understanding of biomarkers as imaging endpoints.
The definitions of these key elements of trial mechanics were developed and distributed by the Biomarkers Definition Working Group of the National Institutes of Health (NIH). 1 The key determination point in a clinical trial is called a clinical endpoint.
A clinical endpoint specifically refers to a characteristic or variable such as a sign, symptom, laboratory abnormality, or disease that represents one of the targets of the trial. It often represents how an enrolled patient feels, functions, or survives. The results of a clinical trial most often try to represent the number of patients who reach the clinical endpoint during the study, in comparison with the total number of patients who are enrolled. When patients enrolled in the trial reach the clinical endpoint, they are often excluded from other facets of the trial, so the definition and determination of the endpoint are critical.
For example, a clinical trial testing the ability of a drug to prevent deep-vein thrombosis could use leg pain as the clinical endpoint. A person enrolled in the trial who develops this symptom would be categorized as having met the clinical endpoint.
The use of classic clinical endpoints, however, often can lead to lengthy trials—and, based on design, nonspecific correlation with the true effect of the therapy that is being evaluated. Therefore, clinical-trial methodology experts and researchers began to investigate alternative techniques to assist them in improving the elapsed time, quality, and statistical power of clinical trials This investigation led to the development of surrogate endpoints.
To substitute for a clinical endpoint, a surrogate endpoint or surrogate marker is used. In the majority of instances, surrogate endpoints have been shown to decrease the length of trials, as there is more rapid assessment of whether a drug has clinical benefits.
An endpoint that is simply correlated with a clinical endpoint that is being studied might not always be a suitable surrogate, as the surrogate is expected to predict the benefit (or lack thereof) that the treatment has on the clinical endpoint. 1 The NIH has defined two specific criteria in relation to surrogate endpoints.
First, a surrogate endpoint is, specifically, a biomarker intended to substitute for a clinical endpoint. 2 ,3
Second, a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic response to a therapeutic intervention. 1
Over the course of the early 1990s, the FDA began approving trials that used a test or result that measured and evaluated a biological process, pathogenic process, or pharmacologic response to a treatment or drug rather than requiring a classic clinical endpoint. An example of a biomarker is prostate-specific antigen (PSA), used in evaluating the response to therapy for prostate cancer. A trial can be designed to use a decrease in PSA (the biomarker) as a surrogate endpoint for response to therapy.
With the use of biomarkers and surrogate endpoints over the past decade, researchers have been able to use smaller group sizes to obtain quicker results while maintaining the necessary statistical power. 4Imaging Biomarkers
Specific to radiology, imaging biomarkers are a subtype of biomarker that enhances the methodology of a clinical trial. An imaging biomarker specifically uses a characteristic that is objectively measured using an imaging technique; this indirectly serves to represent the pharmacological response to the therapy being administered.
The benefit of using medical imaging (correctly interpreted) is the ability to reveal subtle changes that demonstrate the effectiveness of therapy—and that are often