Applied Clinical Trials
The prevalence of cardiovascular toxicity associated with oncology drugs has triggered a new clinical discipline that aims to promote safer drugs and better outcomes for cancer patients.
The prevalence of cardiovascular toxicity associated with oncology drugs has resulted in increased public, regulatory, and industry awareness for cardiovascular (CV) safety within oncology drug development. It has also triggered a new clinical discipline called cardio-oncology that aims to bridge the gap between cardiology and oncology and promote safer drugs and better outcomes for cancer patients.
For drug sponsors, this means rethinking the design of routine clinical trials and implementing effective CV safety strategies to evaluate potential drug induced cardiotoxicity. The benefits of an effective cardio-oncology strategy are long lasting, both from a clinical perspective (improved patient outcomes) and an economic one (getting a successful drug to market).
Advances in technology and our understanding of cardiotoxicity mechanisms have resulted in improved CV safety monitoring strategies, which include endpoints for cardiac performance (i.e., left ventricular function; LVF), cardiac electrophysiology (i.e., electrocardiograms; ECGs), and hemodynamics (i.e., blood pressure; BP). Taken together, sponsors are empowered to take a multi-pronged, comprehensive approach to CV safety in their clinical trials.
LVF, the most clinically relevant endpoint for cardiotoxicity associated with chemotherapeutic agents, is primarily assessed by imaging modalities such as echocardiography, cardiac MRI, and, to a lesser extent, MUGA and CT. Recent advances in cardiac modalities, including Tissue Doppler imaging and myocardial deformation imaging, are paving the way for increasingly sensitive detection of cardiac dysfunction.
Current FDA data indicate that oncology drugs are most frequently associated with QT prolongation (indicative of potential pro-arrhythmia) compared to other therapeutic areas. This has resulted in formal regulatory guidance, ICH-E14, issued by the International Conference on Harmonization, requiring sponsors to assess ECG QT intervals using a formal thorough QT study. The assessment of cancer drugs using this method presents unique challenges for sponsors due to high drug toxicity, narrow therapeutic windows, disease comorbidities, and placebo use. Advances in ECG technology provide sponsors and sites with increased capabilities for digital ECG acquisition, electronic data transfer, algorithm-guided analysis, and data reproducibility in support of regulatory approvals.
Targeted therapies which attack tumor vasculature can have systemic adverse effects on blood pressure, with the potential for causing acute or chronic hypertension. Advancements in blood pressure technologies enable automated and ambulatory BP endpoints to be integrated into a study protocol, providing sponsors with accurate and robust datasets for a better understanding of drug safety profiles. Additionally, the increased portability and improved functionality of BP devices enable data capture and electronic submission directly from a patient's home, increasing patient participation and protocol compliance.
With a growing number of CV safety approaches, sponsors must select and implement appropriate endpoints to determine and mitigate the risks associated with new cancer drugs. As the CV safety paradigm shifts to a more integrated approach, sponsors are relying on complimentary methodologies to gain a complete picture of a drug's safety profile. This is exemplified by the emergence of integrated CV safety services offered by centralized core labs, which can manage ECG, BP, and imaging data and have therapeutic expertise and regulatory knowledge to provide high quality data in support of safer cancer drugs.
David S. Herron Executive VP and President, Medical Imaging and Cardiac Core Lab Division, BioClinica, Inc.