How new technology can impact cardiac imaging in oncology clinical trials and have broader implications for patient safety.
As cancer patients are surviving longer, there is growing interest in better understanding the potential for cardiovascular complications associated with cancer therapies. Indeed, over four decades, clinical data have shown that oncology treatments-from chemotherapies to targeted immunotherapies-can negatively impact heart health. Risks include ischemia, vascular disease, cardiomyopathy, myocarditis, hypertension, heart failure, arrhythmias, QT prolongation, and thrombosis.
Often, patients face a tradeoff of the benefits and risks of treatment. Herceptin, for example, revolutionized the treatment of breast cancer, but also produced congestive heart failure in many patients.
Thus, the FDA requires cardiac safety monitoring in oncology trials. And experienced clinical development teams understand and apply the evolving body of clinical research and therapeutic-level recommendations to clinical trial protocols in order to monitor for these cardiac conditions. Yet, the imaging required to monitor for cardiotoxicities during clinical development can, at times, be treated as a perfunctory task.
The fact is, for cardiac safety trials, as in all clinical studies involving imaging, it matters how images are taken, how they are analyzed, and how the process is monitored. The quality and capabilities of the imaging management system-the process and tools used to collect, share, interpret, and store images-has an appreciable impact on patient safety as well as trial costs and timelines.
Imaging is commonly used as a biomarker for safety in oncology development and, in many trials, is the primary efficacy endpoint. Echocardiography is used to assess symptomatic and asymptomatic cardiac dysfunction in oncology patients and to grade the severity of the condition; the results are surrogate markers for cardiac safety.
The availability of high-resolution and sensitive imaging techniques allows for the identification of potential pathological changes earlier (e.g., decline in left ventricular ejection fraction (LVEF), acute myocarditis, and valve leaflet thickening).
Such assessments are performed in order to:
The study team will recommend the monitoring frequency based on an understanding of the drug’s mechanism of action, the intended patient population(s), the drug toxicity profile, and a review of prior clinical and non-clinical data.
Early detection and diagnosis of cardiotoxicity is, of course, important, as the goal is to be able to medically intervene, prevent delayed effects, and improve outcomes for the patients. And, should the investigational product need to be re-engineered in the lab, it is better to determine this as early as possible in the development path.
Increasingly, echocardiography is the primary assessment tool for cardiac safety assessments, given its advantages of wide availability, lower cost, and the improved detection three-dimensional methods afford.
Several factors can impact the quality of data produced through echocardiography, as with other imaging modalities.
First, the sonographer’s skill, experience, and knowledge can influence the quality of the image. Second, there can be variations in how the image is acquired, such as the display or resolution, which are related to the equipment itself. And, third, how individual readers interpret the images can-and does-vary. Studies conducted since 1947 have measured diagnostic discordance in the 25% to 40% range.4,5
Indeed, wide variability in both quantitative and qualitative echocardiography assessments is recognized in recent guidance publications offered by both the European Society of Cardiology (ESC) and the American Society of Echocardiography (ASE).
Errors and inconsistencies can have a direct impact on patient care, as well as on the chance of regulatory approval for the investigational product. Thus, there’s a need for a comprehensive approach to ensuring that image acquisition techniques are standardized, that images are appropriately collected to the highest quality standard across multiple sites, and that the images are evaluated consistently to support the study protocol endpoints. That’s why imaging management systems and active reader management practices are critical. Additionally, the recent ASE Echocardiography Report recommends the use of a centralized echo-reading laboratory in multicenter clinical trials.6
Today’s imaging technology platforms can help reduce the chance of human error, speed the assessment process, increase objectivity and consistency, and improve patient safety. A single system is used to collect the source data (which is input directly by the clinical trial site staff), manage image analysis, report on the results, and archive records. Because the data are always contained in the same system, there are no delays or errors caused by transferring it between different platforms to perform various operational tasks. This, in fact, eliminates virtually 100% of transcription errors. Furthermore, a consistent process is applied using standardized procedures in a common viewing platform.
The best systems available provide:
Such insight into reader workloads and performance makes it possible to quickly address issues around reader drift, variability, and bias, thus minimizing their impact. If, for example, it becomes clear from the metrics that a reader’s approach has changed, retraining can be provided so that the reader’s performance is consistent with others in the reader pool.
An imaging core lab will be concerned with all of the controllable factors that impact data quality, from data collection to image review and data analysis. The best practices of an imaging core lab include:
The lab’s ability to monitor reader performance and oversee imaging progress is dependent upon the capabilities of the imaging management software.
Ensuring the validity of cardiac imaging data points in oncology clinical trials is difficult, and the challenge must be addressed early in study planning to both protect patients and the integrity of the trial itself. Sponsors should:
Ensuring that imaging in cardiac safety clinical trials is managed expertly and with the benefit of the latest technology and careful oversight has broad implications for patient safety as well as trial cost and timing. Overall error rates can be reduced by as much as 20%, read times can be reduced by up to 50%, and adjudication rates can be cut
Joseph Pierro, MD, Medical Director, Imaging, ERT; Robert Kleiman, MD, Vice President and Chief Medical Officer, Cardiology, ERT