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International Clinical Trials

Seamless Integration

As the benefits of centralisation become better understood, John Blakeley of ERT explores how the latest innovative technology for central labs can drive down costs and advance data quality

Centralisation within clinical trials involves the use of an outsourced vendor to provide an efficient standardised service that is not always offered by a fragmented collection of local providers or in-house personnel. Market demand for centralised laboratory services in clinical trials has grown dramatically during the past decade. In the 1990s there was a shift from ‘local’ laboratories to large ‘central’ laboratory facilities that could efficiently process high volumes of sample data. After a substantial up-front investment in facilities, information systems and laboratory personnel, centralised laboratory services provide a range of benefits not offered with the decentralised model. These benefits not only include the ability to standardise data collection instrumentation, but also consolidate laboratory results into a single database, improving consistency while reducing administrative costs.

In the past 15 years, data produced by central laboratories has represented more than 60 per cent of all data submitted in a new drug application (NDA). This percentage is expected to approach 80 per cent within the next several years (1). The key driver behind a growing reliance on central laboratory data has been FDA guidance on subject safety – in particular cardiac safety – driving the requirement for drug safety monitoring committees and post-marketing pharmacovigilance programmes. As a result there has been an increase in the need for globally standardised analytical and data management platforms when delivering safety and screening parameters for subjects enrolled in clinical trials. Another factor influencing the growth of the central laboratory industry is value-added services. These include sophisticated data management capabilities, project services, study-specific clinical trial materials, logistics services and specimen management.

This article discusses the future of centralisation and explores the introduction of new technologies to support the centralised model, with particular focus on cardiac safety.




THE TUFTS REPORT ON CENTRALISATION

The Tufts Center for the Study of Drug Development helps drug developers, regulators and policy makers improve efficiency by providing objective data on R&D practices and the current regulatory environment. The recent Tufts report on the adoption of centralised cardiac assessment measured current and anticipated adoption levels of centralised ECGs. The report describes the market as being ‘at an inflection point’ with the adoption of centralisation beginning to accelerate. Tufts’ researchers surveyed pharmaceutical sponsors and investigative sites that are experienced in both local and centralised cardiac testing. Generally, sponsors compared core labs favourably to local ECG processors, stating that centralised vendors are more “organised, accurate and standardised”, with “higher quality” results and “faster” database closures. In addition, over 52 per cent of respondents expect the use of the centralised method to Figure 1 above: ERT centralised safety laboratory increase over the next five years (2).





ECG DATA COLLECTION

Investigative sites, CROs and research sponsors routinely look for new ways to increase study conduct efficiency. ECG assessment and analysis conducted by an ECG core lab is one area where the momentum for centralisation is growing, in part due to regulatory pressure from the ICH E14 Guidance for industry issued in October 2005, adopted by the FDA, EMA, Health Canada and by the Japanese Ministry of Health. The guidance recommends that a Thorough ECG Trial (TCT) should be performed and if any cardiac safety concerns are raised, Phase 3 trials will require more intense or robust ECG collection.

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 due to the various instruments using different algorithms for calculations. A centralised approach enables clinical trial sponsors to overcome the shortcomings associated with traditional methods by allowing high quality data to be collected digitally in a standardised format for evaluation using consistent and validated systems. Every interval duration measurement (IDM) is measured by a qualified person and each ECG is evaluated by a qualified cardiologist. In addition, the use of digital ECG data collection at a centralised laboratory generates much cleaner data by using a high resolution digital methodology eliminating common transcription and misinterpretation errors. Many core laboratories also employ systems that are able to automatically check for missing visits or any changes in demography. Each ECG is evaluated by a qualified cardiologist at the core laboratory to ensure maximum data quality, integrity and consistency.

Recent technological advancements have also seen the introduction of highly compact ECG instrumentation that is just a fraction of the size of traditional systems, significantly reducing costs. These small hand-held ECG devices make the adoption of centralised systems much more accessible for companies as they are easier to manoeuvre and less expensive to ship and store. These instruments seamlessly integrate 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. Transmission of data is performed using secure internet transmission, reducing the burden of analogue/digital methods by utilising existing solutions at the site. Additionally, a live electronic inventory for immediate access to ECG waveforms can be generated in hard copy form as required for audit purposes.

STANDARDISING SPIROMETRY TESTING

The use of a centralised model is also recommended for the development of respiratory drugs – in particular the use of spirometry testing – which is one of the most important clinical endpoints. Centralised spirometry refers to the electronic transfer of the spirometry data to a centralised database, where spirometry over-read is performed and feedback to the sites regarding the quality of the spirometry is given.

In the study of respiratory drugs, the parameter FEV1 and FVC are the important spirometry values used to determine efficacy and safety of an experimental drug. However, like all other pulmonary function values, these parameters are subject to the great amount of variability inherent in the nature of testing. The validity of spirometry values is highly dependent on the cooperation of the subject, the interaction of the subject with the study coordinator and the influences of the surrounding environment. The analysis of any parameter without these factors could result in faulty or erroneous conclusions. Inconclusive results waste time and money, and ultimately may prevent the release of a promising compound or, in the worst case, release a compound that is harmful to society. As a result, it is recommended that centralised spirometry should be standard for a sponsor developing new compounds for the treatment of asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, in order to ensure high quality, standardised data.

ADDRESSING THE COST MYTH

The general assumption that centralised data collection methods are more costly than decentralised methods has resulted in reticence from some clinical trial sponsors when making the transition. In fact, the use of a core laboratory in a centralised system is a more cost-effective approach than using multiple individual monitoring sites. With the use of centralised methods, sponsors no longer suffer the burden of fees being paid to each site for technical support and qualified cardiologists. Additionally, the improved accuracy and reliability of the data being collected reduces costs even further by eliminating errors in collection and transcription of data, thus minimising the amount of re-testing that must be carried out. Due to the use of centralised equipment being an integral feature of a core laboratory, sponsors do not have to pay additional fees for machine rental or for transporting and storing heavy equipment.

Centralisation provides cost savings through 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 impact on cost reductions. The Tufts report illustrates that there has been a shift in the perception of the centralised approach, with 70 per cent of participants identifying the costs of using an ECG core laboratory as less than, or equal to, the costs of using paper.

CONCLUSION

Although a decentralised approach to data collection is still extensively used across the industry, it suffers from a number of limitations with regard to accuracy, reliability and efficiency. The Tufts study has shown that the benefits of centralisation are starting to become more understood, with 97 per cent of respondents rating core labs as an accurate and valuable way of conducting trials and 90 per cent rating them as being efficient.

The use of a centralised laboratory has proven to reduce site burden, increase access to results and achieve more consistently accurate and standardised data, which in turn facilitates the progression of the drug discovery industry. Enabling this progress is the introduction of new technology such as the hand-held digital ECG devices, which reduces costs and increases accessibility of the centralised model for trial sponsors.

References
  1. 1. Anyszek T, Hayashi E and Morrow F, Decentralising Central Laboratories, International Clinical Trials, August 2010
  2. 2. Tufts Center for the Study of Drug Development, Mapping Adoption of Centralised Cardiac Safety Assessment, http://csdd.tufts.edu


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John Blakeley is Executive Vice President and Chief Commercial Officer at ERT and has been in role since 2007. He previously served as Senior Vice President, International Operations and Sales beginning September 2006. He also served as Group Vice President, International Business Development from January 2005 to August 2006 and as Director of Business Development from May 2002 to December 2004. Prior to joining ERT, John was Managing Director of MediServe Medical UK Limited, a medical devices specialist. Email: info@ert.com
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