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European Pharmaceutical Contractor

Centralising Electrocardiograms

Continuing on from her article in the December 2009 edition of EPC, Amy Furlong at ERT discusses breakthrough technology advances and the importance of centralised ECG data collection and analysis, which offers a vital tool to clinical trial sponsors

Traditionally, ECG data collection methods employ a decentralised model; however, over recent years the industry has seen a shift towards the more widespread use of a centralised model. The application of this paradigm 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.

As demand for improved accuracy and reliability in ECG studies increases, there is a clear need for innovative new instruments which can help sponsors to achieve their goals. The pharmaceutical industry is currently seeing the emergence of new, highly compact instrumentation, introduced in a bid to overcome the issues of larger ECG equipment and make a centralised approach more accessible.

This article discusses: the role of ECGs in the drug research and development process; how cost savings can be achieved; and the benefits that the centralised approach offers to clinical trial sponsors. It also looks at the future of centralisation and the introduction of new technologies and devices to support the centralised model.

THE VITAL ROLE OF ECGs

The importance of ECG studies for the drug research and development process was highlighted in May 2005 by the introduction of the tripartite core harmonised guideline, ICH E14. The ICH E14 guideline provides recommendations for the clinical evaluation of the QT/QTc interval prolongation and proarrhythmic potential of non-antiarrhythmic drugs.

An undesirable property of some non-antiarrhythmic drugs is their ability to delay cardiac repolarisation. This is an effect that can be measured as prolongation of the QT interval on the surface ECG. A delay in cardiac repolarisation creates an electrophysiological environment that favours the development of cardiac arrhythmias. The aim of the guideline is to help sponsors implement a dependable process for the design, conduct, analysis and interpretation of clinical studies in order to assess the potential of drugs to delay cardiac repolarisation.

According to the ICH E14 guideline, the assessment should include testing of the effects of new agents on the QT/QTc interval as well as the collection of cardiovascular adverse events. Drugs are expected to receive a clinical electrocardiographic evaluation early in the clinical development process in order to provide maximum guidance for later trials. This procedure typically includes a thorough ECG trial (TET), which is performed by skilled readers operating from a centralised ECG laboratory. If any cardiac safety concerns are raised upon completion of the TET, more robust and intense ECG collection is required during Phase III trials.

The guideline also specifies that the quality of the clinical ECG database depends on the use of modern equipment with a capacity for digital signal processing. By taking a centralised digital approach to ECG data collection, the TET is able to generate highly accurate and reliable ECG data.

THE POWER OF CENTRALISATION

A centralised approach uses standardised digital ECG instrumentation for data collection and a core laboratory for centralised high resolution data analysis. Each ECG is evaluated by a qualified cardiologist to ensure maximum data quality, integrity and consistency. The core laboratory is equipped with standard ECG instrumentation, the functionality of which has been validated and the systems have been programmed to suit the specific demography capture requirements of each particular study.

By using digital ECG data collection systems, common transcription and misinterpretation errors associated with a decentralised approach are eliminated, accelerating the analysis process and generating higher quality data. This also solves data-variability problems from inconsistent ECG collection and evaluation methods, which are inherent in paper-based decentralised studies. In addition, many core laboratories employ systems capable of making automatic checks for missing visits or changes in demography. This aids the data lock process as the study draws to a close.

When a decentralised model is used, ECG studies are carried out across multiple investigator sites using local ECG machines. The use of different instrument types at different sites leads to inconsistent results as not all instruments use the same algorithms for calculations. A centralised process for the collection and standardisation of quality ECG data not only reduces inconsistencies that occur from site to site, but also alleviates the userís workload. ECG data management and analysis are greatly simplified, providing sponsors with on-demand, real-time access to information.

Centralisation can 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. Holter data is generated for quantifying heart rates, ventricular and supraventricular arrhythmias and ischemia parameters, as well as qualitatively reporting cardiac rhythm information.

Regardless of the many important benefits offered by the centralised ECG approach, many clinical trials still use a decentralised paper-based method. To some extent, this can be attributed to the common misconception that centralised systems are more expensive to implement.

TACKLING THE COST MYTH

The use of a core laboratory in a centralised system is a more costeffective approach than using multiple individual monitoring sites. Sponsors no longer suffer the burden of professional fees being paid to sites for speciality consults which vary based on region and site capabilities. Additionally, the improved accuracy and reliability of digital ECG data collection help sponsors reduce costs even further. By eliminating errors in collection and transcription of ECG data, sponsors can minimise the amount of retesting that must be carried out. Unnecessary overheads are also eliminated, and since the use of centralised equipment is an integral feature of a core laboratory, sponsors do not have to pay extra for machine rental.

Centralisation provides cost savings throughout the entire study management process, alleviating resources not only from the investigator site, but also through the sponsor and CRO resources involved in the monitoring and data management of cardiac safety data. The cost savings in these areas, as well as the expedited time to database lock, have a significant effect on cost reductions.

Centralised ECG trials involve the rental, storage and shipping of the ECG machines to each investigator site. Conventional ECG machines can weigh anything between 3.2 to 4.5kg and be of substantial size, meaning that they can be expensive to transport and store, as well as time-consuming and difficult to manoeuvre and prepare for use, especially for inexperienced users. The average rental cost of such an instrument generally varies between $100 and $150 per month. Reducing the acquisition fee, which includes the amount of rental paid for the ECG instrumentation, is one way of lowering costs.

Recent technological advancements have seen the introduction of highly compact ECG instrumentation, being just a fraction of the size of traditional systems, substantially reducing costs yet still providing full ECG functionality.

ADVANCING CENTRALISED ECGs

New highly compact instruments are being developed. These small hand-held ECG devices make it easier for companies to adopt a centralised system, as they are much simpler to manoeuvre and less expensive to ship and store. Use of this new technology incorporated with the process enhancements and reduced site and sponsor burden will result in significant measurable cost savings. These instruments will also be scientifically more consistent; they can integrate seamlessly with computer systems through a web application, reducing the footprint required at the site and increasing the flexibility of a site to support multiple studies with a single platform.

Introduction of this new instrumentation will provide an online workflow solution for point-and-click demographic selection with real-time edit checks, avoiding data entry errors while saving staff time and costs. Transmission of data is performed using secure internet transmission and thus reduces the burden of analogue or digital methods by using existing solutions at the site. Additionally, a live electronic inventory for immediate access to ECG waveforms can be generated in hard copy as required for audit purposes.

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

CONCLUSION

The vital role of ECG data collection and analysis in the detection of adverse cardiac effects of drugs early in the development process has been demonstrated and is set to trigger strict regulatory scrutiny. Traditional decentralised paper-based ECG methodologies are associated with a number of important shortcomings, including data inconsistency, time inefficiencies and increased costs. A centralised approach that uses digital ECG systems for recording, transmitting, processing and reporting data is capable of overcoming all these challenges. The development of new ECG instrumentation will facilitate the use of a centralised approach, significantly minimising costs while increasing accuracy, reliability, usability and accessibility to quality results.

Reference

  1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, The Clinical Evaluation of QT/QTC Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, E14, Current Step 4 Version, www.ich.org/LOB/media/MEDIA1476.pdf, May 2005

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Amy Furlong has been Executive Vice President of Cardiac Safety Operations at ERT since December 2005 and previously served as Senior Vice President of Regulatory Compliance. She holds a BSc degree in Biology and a MSc degree in Quality Assurance and Regulatory Affairs from Temple Universityís School of Pharmacy. Amy has more than 15 years of clinical research experience specialising in regulatory compliance and computer system validation.
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