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Cardiac safety concerns are the leading cause of labeling changes; late phase delays; and product recalls of drugs entering the market, all of which incur significant cost for a company. In addition to the immediate cost implications, product recalls in particular can also reduce consumer confidence and company credibility, negatively impacting a company’s revenue in the long run. As a result of the growing concern around the importance of cardiac safety, there is increasing regulatory scrutiny for all new compounds and a greater concern among pharma with regard to the potential effect of new compounds on the heart.
An outcome of this increased focus is the International Conference on Harmonization (ICH) E14 document for industry, which was issued in October 2005 and adopted by the Food and Drug Administration, European Medicines Agency, Health Canada, and the Japanese Ministry of Health. The guidance, which provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the cardiac safety of a drug, recommends that a Thorough ECG Trial (TET) should be performed, and if any cardiac safety concerns are raised, Phase II trials will require more robust or intense ECG collection. A key requirement of the ICH E14 is that a proof of concept, providing evidence that a centralized ECG system can be successfully used, must be done prior to the commencement of a TET trial.
While the increasing adoption of centralized cardiac safety laboratories, due to heightened regulatory recommendations, is a positive and necessary development, sponsors may not be aware that the benefits of using centralized ECG go beyond the sole advantage of compliance. Sponsors who adopt a centralized model will also benefit from dramatically improved data quality and accuracy, time and cost savings, access to cutting edge technologies, and improved overall efficiency of processes. With the combination of these benefits, the pharmaceutical industry is waking up to the advantages and significant return on investment of centralization.
Despite the increasing recognition of its benefits, many sponsors are discouraged from adopting the centralized model due to the misapprehension that a centralized ECG provider is more costly than a localized or internal method, primarily as a consequence of the hardware distribution involved. When a decentralized model is employed, the majority of collection, transcription, cleaning, and interpretation of ECG data are conducted by the sponsor and the individual monitoring site. As a result, the majority of companies working with this method perceive the core laboratory in a centralized system as a non-essential added expense. Contrary to this belief, a centralized approach has been proven to save costs.
When using a decentralized approach, sponsors can pay a sizeable ECG acquisition fee that includes charges for technician time and the use of ECG machines at the investigator site. This fee is reduced when using a centralized approach. In addition, the expense for labor required for both the site and sponsor/CRO personnel to manually transcribe, double-data enter, monitor, and perform quality control from multiple sites is very high. A study of investigative sites conducted by the Tufts Center for the Study of Drug Development (CSDD) in 2005 illustrates that despite initial financial concerns, there has been a shift in the perception of a centralized approach, with 70% of respondents identifying the costs of using an ECG core as less then, or equal to, the costs of using paper. These cost savings are not only attributed to the work done at the time of study conduct, but to the reconciliation of discrepancies and queries due to inconsistent interpretation during the statistical analysis and medical review phase.
Time savings and improved data quality
The use of a centralized model can also dramatically accelerate analysis time, significantly improving the accuracy and reliability of data. This increases the chance of cardiac risk being detected earlier, reducing the risk of wasted time and cost expenditure planning for a potential drug compound that is not viable. When a decentralized model is employed, ECG studies are conducted within a variety of investigator sites, using local ECG machines. Inconsistent results often occur as a consequence, with different types of instruments using varying algorithms for calculations and various interpretation guidelines and methods utilized by the local investigator or their contracted specialists. These inconsistencies can present a challenge for sponsors, who require reliable data in order to accurately assess the cardiac safety of Phase I compounds.
A centralized approach overcomes this inconsistency issue by digitally collecting data in a standardized format for assessment, with the use of consistent and validated systems. All interval duration measurements should be assessed by qualified individuals and every ECG evaluated by a qualified cardiologist who is trained to follow standardized procedures that are continually validated through a quality control program. As a result of these standardized processes, sponsors benefit not only from increased speed of analysis, but also much cleaner and more accurate data. In the CSDD report, 97% of respondents rated the central lab as more accurate and 90% viewed central labs as more efficient. Looking to the future, 89% of respondents expected the use of centralized ECG to increase in five years as a result of the more accurate and standardized data produced by ECG centralization.
Access to innovative technology
Investment in innovation and technology is vital to the continued success of a pharmaceutical company. With the adoption of a centralized method, clinical trial sponsors can utilize emergent technology, such as lightweight and compact ECG machines which have a significantly smaller footprint than existing systems and removes the challenges raised by more traditionally heavy and expensive instrumentation. In addition, these ECG devices can be much easier to maneuver and are less costly to ship and store. Due to their compact size, the cutting edge instruments can potentially offer improved service on a technical level, providing more consistency and improved accuracy while integrating with computer systems through a web application.
Making the leap
Sponsors are increasingly looking beyond the issue of regulatory compliance and recognizing the value and advantages of ECG centralization. The application of the centralized model benefits the industry in a number of important areas, including data quality, data capture, and the reduction of workload for sponsors and the ECG site, leading to significantly reduced overall costs. As indicated by the CSDD report, irrespective of regulations becoming more or less stringent, ECG centralization is increasingly being recognized as a more accurate, cost-effective, and preferable method for conducting ECG reporting within a trial.
Amy Furlong is Executive Vice President, Cardiac Safety Operations at ERT, 1818 Market Street, Suite 1000, Philadelphia, PA, e-mail: firstname.lastname@example.org.