Breakthrough ECG technology facilitates improved centralised cardiac safety

By Amy Furlong, Executive Vice President Cardiac Safety Operations

In the analysis of Electrocardiogram (ECG) there remain challenges, such as data inconsistency and inaccuracy that are being incrementally solved with advances in technology. Traditionally, ECG data collection methods employed a decentralized model, however, over recent years the industry has seen a shift towards the more widespread use of a centralized model.

The application of a centralized model offers a number of substantial advantages over its counterpart including cost savings, enhanced consistency throughout the duration of a trial and a reduction in laboratory workloads. The pharmaceutical industry is currently seeking new highly compact instrumentation to support the centralized model and overcome the issues of larger ECG equipment, reducing costs and improving the reliability and accuracy of ECG data collection. These small hand-held ECG collection devices will make it easier for companies to adopt a centralized system as it integrates seamlessly and automatically with the central database, dramatically reducing both site workload and the volume of queries generated. This reduction in queries will accelerate trial timelines in the same way that EDC has improved the data collection process in clinical trials.

All new drugs and pharmaceutical products must undergo clinical testing to ensure public safety before release to market. Cardiac safety is cited as the most frequent reason for drug withdrawals from the market, labeling changes and delay, or refusal of regulatory approval. This places great importance on the accurate collection, analysis and interpretation of ECG data during clinical trials. However, this is a topic of much debate within the pharmaceutical industry.  As such, all new pharmaceutical products are required to go through stringent testing procedures to meticulously assess their impact on the cardiac health of patients. Electronic data capture and transfer technologies are making this a much more manageable endeavor. ECG data collection and analysis offers a vital tool to clinical trial sponsors enabling them to assess the effect of investigational drugs on the electrical functions of the heart.

Regulatory Overview

The majority of trials conducted worldwide still obtain ECGs the old-fashioned way. These are conducted using local ECG machines with varying algorithms and are usually collected at the beginning and end of the trial only, providing limited data about the cardiac effects of the drug being studied. However, the US Food and Drug Administration (FDA) has developed the ICH E14 document, which advises the pharmaceutical industry on how best to conduct a Thorough ECG Trial (TET) to determine the cardiac effects of a new drug on healthy subjects.

According to the guidance document, TET trials must be conducted following completion of proof of concept and they can employ a centralized ECG system. A centralized approach uses digital ECGs and a core laboratory, which handles much of the work that would be done by clinical trial sponsors, CROs and individual investigational sites. The core lab typically provides all ECG equipment to investigator sites to ensure complete consistency throughout the trial. The use of digital ECG data collection at the core laboratory speeds up the reading process and returns much cleaner data.

Centralized ECG analysis is currently utilized only in around 33% of all Phase I through to Phase IV clinical research trials1, even though nearly all TET trials are centralized. Where a TET trial raises cardiac safety concerns, relevant legislation mandates that more robust or intense ECG data collection should be conducted in Phase III of the trial – a mandate unique to the TET model. According to a study “Mapping Adoption of Centralized Cardiac Safety Assessment” by the Tufts Center for the Study of Drug Development (CSDD), which provided an independent market analysis, ECG assessment and analysis conducted by an ECG core lab is one area where momentum for centralization is increasing,

A Centralized Approach

Centralization allows for the digital collection of quality data in a standardized format for evaluation using consistent and validated systems.   Data quality, integrity and consistency are ensured since every interval duration measurement (IDM) is measured by a qualified person and each ECG is evaluated by a qualified cardiologist. Any cardiac safety concerns arise early in the process, prior to filing approval for marketing.  Further, it eliminates transcription and misinterpretation errors occurring from manual processes and improves the efficiency and quality of data collection thus reducing the time required at on-site monitoring visits. Centralization allows for proactive data monitoring and tracking in which demography and missing visits are detected automatically, thus facilitating the data lock process as studies progress.

In conjunction with a centralized cardiac safety approach, technology which improves data quality, reduces the investigator workload and improves the overall user experience at the investigative site can be implemented. This technology enables the collection of real time, consistent, quality information easing site operations for all stakeholders and delivering better value to biopharmaceutical companies. This also solves data-variability problems from inconsistent ECG collection and evaluation methods through the use of different instrument types at different sites, which are inherent in paper-based decentralized studies.

Centralization can also involve the application of best practices for digital ECG data collection, transmission and processing to enable comprehensive, regulatory-grade arrhythmia analysis. Individual safety ECGs can be also extracted and processed for interval duration measurements and cardiologist interpretation. There is however a common misconception that centralized systems are more expensive to implement and as a result many clinical trials still use a decentralized paper-based method.

Cost Implications

Concerns over the cost implications have been noted as the main reason that the industry has been reluctant to change from decentralized to centralized ECG collection and interpretation. Sponsors still believe that a centralized ECG provider is more expensive than a localized or internal process, mainly because of the hardware distribution involved. This perception was also reflected in the Tufts study, where sponsors thought centralized ECG providers are more expensive, yet agree that the accuracy and ease of use of central providers justify the costs. Unfortunately, most clinical trial sponsors do not have the capacity to measure the number of ECGs collected across a drug program and to estimate the true cost of decentralized versus centralized ECGs. The general misconception is that they are already paying the site to perform and read the ECGs and that the addition of a centralized ECG reading service would be a further expense. On the contrary, a centralized approach presents sponsors with an opportunity to bring about cost savings. Using a centralized system, sponsors can decrease the ECG acquisition fee they pay. Acquisition fees typically include charges for technician time and for the use of ECG machines at the investigator site.   In addition, the labor required for the both the site and sponsor/CRO personnel to manually transcribe, double-data enter, monitor, and quality control the data from multiple sites is quite costly.

New Centralized ECG Instrumentation 

According to the ICH E14 guideline2 the quality of the ECG database can depend on the use of modern equipment with the capacity for digital signal processing leading to rapid assessment of ECGs for safety.  As a result of this, revolutionary new highly-compact instruments have been developed to enable trial sponsors to take full advantage of the benefits offered by a centralized ECG model. These small hand-held ECG devices make it easier for companies to adopt a centralized system as they are much easier to maneuver and less expensive to ship and store. These innovative instruments are also scientifically more consistent, provide improved accuracy and better reliability and they can seamlessly integrate with computer systems through a web application.

Furthermore it is increasingly required by regulators that ECG data are submitted to a central digital system to facilitate regulatory inspections for regulators to simultaneously access all data stored on the system and efficiently analyze data quality. Currently, this is not a mandatory requirement, however most clinical trial sponsors are trying to comply with it. These new centralized ECG machines will enable easy compliance with this request, as it stores all data centrally and allows for information to be simply transferred to the database as required.

Conclusion

Although the use of a decentralized approach is still used across the industry, it suffers from a number of limitations including poor accuracy, reliability and efficiency of ECG data. The introduction of the centralized model of ECG has provided the industry with significant improvements in a number of key areas including data quality and data capture in addition to reduced work loads for sponsors, lowering the cost while increasing data quality.  Clearly sponsor demand will drive faster adoption for using a central core lab. The Tufts study concluded that respondents felt that centralized core labs are a valuable way of conducting ECGs with 97% of responders rating central labs as being accurate and 90% rating them as being efficient.  It is however the regulatory pressures along with the necessity for data quality and accuracy at a faster and more efficient speed that is stimulating more rapid adoption.

The development of new ECG instrumentation will also facilitate the use of a centralized approach, significantly minimizing costs while increasing accuracy, reliability, usability and accessibility to quality results. Together with centralized cardiac safety it is now possible to improve the science of cardiac safety while helping sponsors reduce overall costs with the adoption of a fully centralized model. This new approach focusing on people, process and technology will make it easier for companies to adopt a centralized solution as it promises to deliver better science, lower sponsor costs and more convenience for all stakeholders.

The Tufts study draws parallels between the adoption of centralized cardiac safety assessment and that of blood work, lab work and electronic data capture in clinical trials. These centralized solutions took time to achieve higher levels of adoption. The adoption rate accelerated following regulatory pressure and when the benefits of centralization were better understood by industry professionals.  Centralization of ECGs could follow a similar path, with the issuance five years ago of the ICH E14 guidance and the benefits of centralization beginning to be fully understood.

A copy of the Tufts CSDD Report is available to download at www.ert.com

References

1.   Mapping Adoption of Centralized Cardiac Safety Assessment Study Report, Tufts Center for the Study of Drug Development (Tufts CSDD) March 2010
2. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, The Clinical Evaluation of QT/QTC Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, E14, Current Step 4 Version, Dated 12 May 2005, http://www.ich.org/LOB/media/MEDIA1476.pdf

About the author

About the Author: Amy Furlong, Executive Vice President, Cardiac Safety Operations - Amy has been Executive Vice President of Cardiac Safety at ERT since December 2005 and previously served as Senior Vice President of Regulatory Compliance. She holds a Bachelor of Science degree in Biology and a Master of Science degree in Quality Assurance and Regulatory Affairs from Temple University’s School of Pharmacy. Amy has more than 15 years of clinical research experience specializing in regulatory compliance and computer system validation.

About ERT

Based in Philadelphia, PA ERT (eResearchTechnology, Inc.) (www.ERT.com) is a provider of technology and services to the global biopharmaceutical and medical device industries. The company is a market leader in providing centralized core-diagnostic electrocardiographic (ECG) technology and services to evaluate cardiac safety in clinical development. The company is also a leader in providing technology and services to streamline the clinical trials process by enabling its customers to automate the collection, analysis and distribution of clinical data in all phases of clinical development.

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