Robert Kleiman, MD

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:

		Make go/no-go decisions for continued drug development

		Assist in identifying high-risk subgroups within the population (for example, subjects with low ejection fraction or ventricular volume)

		Screen subjects for protocol eligibility

		Monitor patients for treatment-emergent changes, which may necessitate the need for dose adjustment or treatment discontinuation

	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.

	A critical factor in patient care and data integrity

	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.

	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.

	Imaging management technology: Added transparency, reduced risk

	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.

 Imaging results are collected at the clinical site and are immediately available at the clinical institution, so safety signals can be identified at once for clinical decision-making. They are also immediately available to independent or blinded readers (BICR) so that they can make their independent assessments. The results can also be shared with other stakeholders such as sponsors, cardiac advisory boards, and data and safety monitoring committees.

Visibility to all study data in near real time.

 Trial managers and medical directors have total visibility to all study imaging data, throughout the imaging life cycle. They can:

		Measure the degree of discordance between site-based and blinded, central readers

		Track the number of cases requiring adjudication

		Monitor for selection bias in adjudicated cases

	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.

 The system delivers reminders and gives users automatic prompts so that images pass through the agreed-upon workflow from reader to reader to adjudicator as efficiently as possible. The process is not dependent upon a project manager to keep it on track.

 Image analysis software can direct a reader through the analysis of each imaging time point and even pre-process and segment anatomical structures of interest in lockstep with the study’s imaging charter and image evaluation protocol (IEP). This minimizes protocol deviations and ensures that each reader’s unique bias does not creep into the analysis process by focusing the reader on targeted endpoints whose workflows are outline in the trial-specific IEP. Artificial intelligence (AI) can be used to augment human assessment. Using AI in this way can reduce read times by as much as 50% and the need for adjudication by 20%. It would, in the process, increase speed and reduce costs.

	Active reader management: Added efficiency and effectiveness

	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:

		Ensuring that the imaging endpoints support the protocol

		Selecting a limited number of independent readers based on their training and experience

		Managing the image assessment-starting with training on the system and standardizing the imaging protocol and reading criteria

		Monitoring reader performance periodically during the study to lower variability and adjudication rates (readers are asked to re-read cases to identify performance drift)

		Reporting on imaging status and reader performance with recommendations for discussion and intervention if needed

	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:

		Look to both positive and negative results in early trials to determine the potential predictive value of cardiac endpoints.

		Identify patients at risk for cardiotoxicity and determine how to balance survival benefits with reduced cardiac risk relative to a patient’s quality of life. (There is a higher tolerance for adverse events in oncologic treatments, and the benefit/risk balancing point is different than in other disease states.)

		Clearly define the protocol-required cardiac assessments and measurement parameters to be obtained during the echocardiogram. This will help the clinical team understand patients’ clinical course and inform decisions on treatment adjustments that may be needed to maintain or restore normal cardiac function. The protocol should include details on the number of imaging findings required, together with information based on statistical analysis to assist investigators in managing patients.

		Establish a baseline of cardiac performance prior to treatment, perform serial assessments during the trial, and conduct a follow-up assessment post-therapy. 

		Pay particular attention to the technologies and processes used to ensure accuracy in how images are taken and interpreted.

	Questions to ask your imaging partner in cardiac safety trials

		Which system is used to collect imaging endpoints?

		How quickly are the data available? How easy is the analysis?

		What is the expected rate of reader discordance?

		What is the optimal number of independent readers for the trial?

		What has the adjudication rate been on similar trials?

		What process is used to monitor the timeliness and accuracy of reads?

		What process/technology is in place for creating an audit trail and ensuring compliance?

		What systems and training are in place to ensure that sites know how to follow the imaging protocol?

	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
	by 20%.

		Blaes, AH, Thavendiranathan, P, Moslehi J. Cardiac Toxicities in the Era of Precision Medicine: Underlying Risk Factors, Targeted Therapies, and Cardiac Biomarkers; 2018 

 (Print ISSN: 1548-8748 38; Electronic ISSN: 1548-8756) published by the American Society of Clinical Oncology, Inc. (“ASCO”), volume 38, p764-774	

		Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)

Articles

How new technology can impact cardiac imaging in oncology clinical trials and have broader implications for patient safety.

The Benefits of Advanced Imaging Management Systems

	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 US Food & Drug Administration (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 trials 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.

	Cardiac imaging: essential in oncology trials

	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: 

		Assist in identifying high-risk subgroups within the population (for example subjects with low ejection fraction or ventricular volume) 

		Monitor patients for treatment-emergent changes which may necessitate the need for dose adjustment or treatment discontinuation. 

	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. 

	Imaging: a critical factor in patient care and data integrity

	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, that 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 percent to 40 percent range.

	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).

	Imaging management technology: added transparency, reduced risk

	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 percent of transcription errors. Furthermore, a consistent process is applied using standardized procedures in a common viewing platform. 

Imaging results are collected at the clinical site and are immediately available at the clinical institution, so safety signals can be identified at once for clinical decision making. They are also immediately available to independent or blinded readers (BICR) so that they can make their independent assessments. The results can also be shared with other stakeholders such as sponsors, cardiac advisory boards, and Data and Safety Monitoring Committees. 

Visibility to all study data in near real time. 

Trial managers and medical directors have total visibility to all study imaging data, throughout the imaging life cycle. They can:					

				Monitor intra/inter reader variability

				Measure the degree of discordance between site-based and blinded, central readers

				Track the number of cases requiring adjudication

				Monitor for selection bias in adjudicated cases

	            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, re-training can be provided so that the reader’s performance is consistent with others in the reader pool. 

.  The system delivers reminders and gives users automatic prompts so that images pass through the agreed-upon workflow from reader to reader to adjudicator as efficiently as possible. The process is not dependent upon a project manager to keep it on track. 

. Image analysis software can direct a reader through the analysis of each imaging time point and even pre-process and segment anatomical structures of interest in lockstep with the study’s imaging charter and image evaluation protocol (IEP). This minimizes protocol deviations and ensures that each reader’s unique bias does not creep into the analysis process by focusing the reader on targeted endpoints whose workflows are outline in the trial specific IEP. Artificial Intelligence (AI) can be used to augment human assessment. Using AI in this way can reduce read times by as much as 50 percent and the need for adjudication by 20 percent. It would, in the process, increase speed and reduce costs.  

	Active reader management: added efficiency and effectiveness 

		Ensuring that the imaging endpoints support the protocol 

		Monitoring reader performance periodically during the study to lower variability and adjudication rates (readers are asked to re-read cases to identify performance drift) 

		Reporting on imaging status and reader performance with recommendations for discussion and intervention if needed 

	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 trials is difficult, and the challenge must be addressed early in trial planning to both protect patients and the integrity of the trial itself. Sponsors should: 

		Look to both positive and negative results in early trials to determine the potential predictive value of cardiac endpoints. 

		Identify patients at risk for cardiotoxicity and determine how to balance survival benefits with reduced cardiac risk relative to a patient’s quality of life. (There is a higher tolerance for adverse events in oncologic treatments, and the benefit/risk balancing point is different than in other disease states.)  

		Clearly define the protocol-required cardiac assessments and measurement parameters to be obtained during the echocardiogram. This will help the clinical team understand patients’ clinical course and inform decisions on treatment adjustments that may be needed to maintain or restore normal cardiac function. The protocol should include details on the number of imaging findings required, together with information based on statistical analysis to assist investigators in managing patients. 

		Establish a baseline of cardiac performance prior to treatment, perform serial assessments during the trial, and conduct a follow-up assessment post therapy.  

		Pay particular attention to the technologies and processes used to ensure accuracy in how images are taken and interpreted (See Box:  Questions to Ask Your Imaging Partner). 

		Which system is used to collect imaging endpoints? 

		How quickly are the data available? How easy is the analysis? 

		What is the optimal number of independent readers for the trial? 

		What has the adjudication rate been on similar trials? 

		What process/technology is in place for creating an audit trail and ensuring compliance? 

		What systems and training are in place to ensure that sites know how to follow the imaging protocol? 
		 

	Ensuring that imaging in cardiac safety 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 percent, read times can be reduced by up to 50 percent, and adjudication rates can be cut by 20 percent.

, MD, Medical Director, Imaging, ERT and 

, MD, Vice President and Chief Medical Officer, Cardiology, ERT

Explore the growing interest in better understanding the potential for cardiovascular complications associated with cancer therapies.

Cardiac Imaging in Oncology Trials: The Benefits of Advanced Imaging Management Systems

Planning ahead can save time and money later, thanks to recent regulatory changes in cardiac safety guidance.

	 	Drugs that produce torsade de pointes, a potentially fatal arrhythmia, also prolong the QTc interval measured on the electrocardiogram (ECG). The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), which brings together global regulatory authorities and the pharmaceutical industry to clarify scientific and technical aspects of drug registration, adopted the ICH E14 guidance in 2005 to address this important safety issue. Since then, regulatory bodies like the FDA, EMA, and more recently the PDMA have mandated the evaluation of a new drug’s effect on QTc in a formal Thorough QT (TQT) trial.	 	In December 2015, the ICH E14 Working Group released an update to the ICH E14 Guidance for Industry as a “Q&A” document. This anticipated revision discusses the use of concentration-QTc effect modeling (also referred to as Pharmacokinetic/Pharmacodynamic or PK-PD modeling) of data obtained during Phase I single and multiple ascending dose SAD/MAD clinical studies to characterize a new compound’s effects on QTc. In the right circumstances, the ICH update indicates that such data may be adequate to replace a TQT trial for regulatory submission and review â which is welcome news for biopharmaceutical companies looking for ways to reduce development time and costs.	 	This strategy is not new, but the guidance revision offers new options to consider in development. Since 2005, regulatory bodies have required a TQT trial for new compounds with the exception of drugs for which a TQT study is not feasible, most notably for cytotoxic oncologic agents, atypical antipsychotics, and some biologics. In these cases, the industry has assessed QTc liability via PK-PD analysis during Phase I ascending dose studies. What is new is simply that the ICH now acknowledges that these techniques which have been used on oncologic and other agents are robust enough for use on less toxic drugs.	 	The new ICH E14 revision gives you the option of using either Phase I SAD/MAD data or data from a standard TQT trial to assess the QTc liability of new agents. Since the cost of adding the required ECG collection to a SAD/MAD trial are a tiny fraction of the cost of a TQT trial, this is a great opportunity to potentially collect QT data earlier while also reducing costs. However, as only a small percentage of compounds that have a SAD/MAD trial progress to Phase III and drug approval, it is important to work with an experienced advisor so as to not increase overall costs even though the cost for a particular compound will be less.	 	Robert Kleiman, MD is Chief Medical Officer and Vice President of Global Cardiology for ERT	 	 	For more information download our free report on Cardiac Assessment 

An updated release to the ICH E14 Guidance could indicate that data be used to replace a TQT trial for regulatory submission and review. The result of such a change would be a reduction in development time and costs for biopharma companies.

Are You Prepared to Replace the Thorough QT Study?

How Sponsors Can Prevent Unnecessary Exclusions

	Subject recruitment is one of the largest challenges in pharmaceutical clinical research. This can be more challenging in the case of oncology trials, where only an estimated 3% of potential patients volunteer to participate as subjects. Sponsors of trials evaluating new oncologic drugs need every eligible subject they can get – and cannot risk unnecessarily excluding potential subjects due to inaccurate cardiac safety measurement results when determining patient eligibility.

	Many clinical trials of oncologic agents utilize electrocardiogram (ECG) machine measurements of QTc for inclusion / exclusion and dosing decisions, though their reliability in this setting has not been established. Concurrently, there is a general perception that ECG machine measurements of QTc are accurate and precise. However, it is less widely known that ECG machine algorithms may significantly under-measure or over-measure the QT interval and heart rate, leading to errors in the derived value of QTc.

	A recent study was performed to compare machine-generated ECG measurements (which rely on automated algorithms) versus high-precision ECG analysis generated through centralized cardiac safety measurement. The study was a retrospective, blinded evaluation of more than 270,000 consecutive ECGs collected from 299 clinical oncology trials. It compared decentralized, ECG machine-generated QTc measurements collected by various devices and analyzed via automated, device-based algorithms with measurements obtained through centralized cardiac safety services. The centralized ECG measurements were collected by standardized ECG devices across investigative sites, analyzed via a semi-automated methodology and reviewed by trained cardiologists. The results of the study demonstrated significant differences between the two measurement/analysis approaches, which may impact subject recruitment and retention.

	While on average, ECG machine-measured QTc values were very similar to the central core lab measurements, there were very significant discrepancies – up to 45% of patients who would have been excluded from enrollment based on machine QTc measurements were eligible after correct centralized measurement. These results suggest that many patients who are excluded from participation in clinical trials due to an elevated ECG machine-generated QTc measurement may actually have been eligible for study participation. In addition, up to 77% of patients who would have had medication doses withheld based on machine QTc measurements were actually able to continue dosing based on the centralized measurements. By unnecessarily excluding potential subjects or withholding doses from patients who are actually still eligible to receive medication, this denies access to potentially lifesaving investigational therapies for patients who may have exhausted all conventional therapies in their battle against cancer.

	The study, “Benefits of Centralized ECG Reading in Clinical Oncology Studies” which was conducted by ERT and published in Therapeutic Innovation & Regulatory Science (TIRS), August 2015 can be found 

	Robert Kleiman, M.D., Chief Medical Officer and Vice President, Global Cardiology, ERT

Results from an analysis of oncology trials suggest that many patients who are excluded from participation in clinical trials due to an elevated ECG machine-generated QTc measurement may actually have been eligible for study participation.

Robert Kleiman, MD

Articles

The Benefits of Advanced Imaging Management Systems

Cardiac Imaging in Oncology Trials: The Benefits of Advanced Imaging Management Systems

Are You Prepared to Replace the Thorough QT Study?

In Oncology Trials, Every Subject Counts