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International Clinical Trials
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Bringing greater efficiency to the clinical trial process has been a battle cry for more than a decade. Touting the benefi ts of technology to streamline trials has been an intense industry focus, and while technology has brought disruptive change, especially in the form of electronic data capture (EDC), the industry is evolving to the next horizon: electronic source data, commonly known as eSource.
eSource streamlines clinical research by resolving one of the key challenges of EDC – the need to transcribe source documents into case report forms (CRFs). Embracing eSource, however, is a massive step forward, and one that is strongly encouraged by US and European regulators.
FDA guidance issued in 2013 promotes the use of eSource to streamline trials by eliminating unnecessary duplication of data, and improve data quality and reliability (1). The guidance "promotes capturing source data in electronic form, and it is intended to assist in ensuring the reliability, quality, integrity, and traceability of data from electronic source to electronic regulatory submission".
Similarly, the EMA published a Reflections Paper in 2010 on the use of electronic collection of source data in accordance with 12 user requirements of source data established by the Clinical Data Interchange Standards Consortium (CDISC) (2,3). The EMA states: "With increasing use of IT in pharma development, there is a need to have clear guidance on the use of electronic source data and transcribed data and the principles that should apply to them… to ensure the processes can be used and accepted with confidence when such requirements are complied with, and the benefits these systems offer can be fully utilised."
What is eSource?
The FDA guidance defines electronic source data as data initially recorded in electronic format. According to the guidance, data obtained at a study visit can be entered directly into an electronic system and validated – a process that has the advantage of eliminating errors by cutting out the paper transcription step.
EMA's Reflection Paper also describes eSource. It mentions that various types of electronic tools can house directly entered source data, such as electronic case report forms (eCRFs), electronic patient reported outcomes devices, and electrocardiogram instruments. In addition, to be of acceptable quality, eSource data must be in compliance with Good Clinical Practice.
Complementing this push from the FDA and EMA towards eSource is a greater understanding among stakeholders that this technology enables remote viewing of the actual source documents back to the beginning of the data stream.
In a thoughtful piece by Mitchel and Markowitz, the authors explain that this capability not only offers greater operational efficiencies to sponsors, CROs and sites, it also assists regulators in performing risk-based pre-approval inspections of high-enrolling sites during pivotal trials (4). This approach is a timesaver and provides a realistic picture of how well a trial is being conducted.
Beyond Transcription
The concept of eSource has been around for more than a decade (5,6), but its uptake is just starting to gain momentum as stakeholders recognise the benefits. “eSource will revolutionise how we do trials, but most people do not know about it yet,” says Leonard Chuck, Medical Director at Diablo Clinical Research.
Alison Crook, a contract monitor based in the UK, is familiar with the benefits of eSource too. She explains that source data are owned by the site; and with eSource, there is documented evidence of case histories, as well as the data needed for a study that can be transferred directly to the sponsor’s clinical database. “This eliminates the need for the traditional CRF, and is huge for the site. They collect the data at source, and there is no need to transpose it or re-enter it into a CRF,” she says. Crook adds, however, that initially some data, such as medical histories, may come from outside sources in paper format, so there may be a mixture of paper and electronic data entry at first.
Meeting the Protocol
Chuck notes that while many stakeholders are focusing on the ability of eSource to eliminate transcription and the associated errors, the change in process it offers is key to improving operational efficiency. A major benefit comes from its ability to help users properly execute a protocol. “With eSource, you can mandate the sequence by which you gather data from the site. You can put in criteria that mandate you do one step before another step, so the study is conducted in accordance with the protocol. This is a major value to the site, sponsor, CRO and auditors,” he explains.
He adds that the right eSource technology – for example, systems such as SureSource that use a mobile tablet and a special electronic pen – allows investigators to make notes that document how the data were collected. This is useful as investigators are responsible for maintaining case histories and supporting data (6) – factors that are reviewed during inspections. According to Chuck, “the FDA needs to verify that we gathered the data appropriately. The documents and the notes we can create with [eSource technology] can show the study is in line with the protocol".
Risk-Based Monitoring
Over the past few years, the clinical trials industry has been exploring risk-based monitoring (RBM), a methodology that allows for identification of risk at sites and allocation of monitoring resources to mitigate risk while ensuring clinical trial data quality.
A range of articles has discussed its value and questioned the continued practice of 100% source data verification (SDV). In 2011, a piece appeared in CenterWatch trying to determine the value of 100% SDV and commenting that its ongoing use is somewhat surprising, given its high cost and the fact that there is no evidence it improves data quality (7). It stated: “Industry and regulatory leaders have expressed concern that monitoring methods focusing on SDV may not be the best way to evaluate the quality of studies. In particular, significant resources often are dedicated to SDV of data that has little or no impact on study conclusions."
Furthermore, 100% SDV may not result in absolute accuracy. Guidance on good clinical data management practices from the Society for Clinical Data Management suggests that the error rate for human inspection of data is 15% (8).
Better approaches allow monitors to focus on critical study-related questions, patient safety, and whether the protocol is being followed, instead of spending time determining whether a lab result is 75 or 76. Alternatives to 100% SDV include partial SDV and statistical risk-based algorithms based on fixed risks tied to the protocol or study site; or dynamic risks at the site level, such as number of adverse events, and number of protocol deviations (9). According to Clive Ballard, an investigator at King's College London: “It will probably be accepted that there has to be RBM. It will lead to better use of time, ease of running reports, and an increase in quality of data."
Linking eSource and RBM
The functionality offered by eSource is just starting to be appreciated and, as part of that trend, is increasingly tied to RBM. Stakeholders are looking to RBM as both a costeffective measure and a sharper way to utilise monitoring resources. Moving to RBM represents a profound change from the long-held practice in the clinical trials industry of 100% SDV – a gruelling task, but the advent of eSource makes this possible.
For starters, recent direction from the FDA and EMA encouraging greater use of eSource is coupled with new guidance from the FDA and a recent EMA Reflection Paper on the benefits of RBM. This new FDA guidance states: "There is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% data verification to ensure subject protection and overall study quality. For example, incorporation of centralised monitoring practices, where appropriate, should improve a sponsor’s ability to ensure the quality of clinical trial data" (10).
However, the guidance is not specific as to how sponsors are to conduct monitoring, so a range of approaches is acceptable, including risk-based. Moreover, it states that the FDA encourages greater use of centralised monitoring, which is enabled by electronic solutions, leading to growing numbers of electronic source documents available to the sponsor remotely.
The subsequent EMA Reflection Paper on RBM comments that current practices in clinical research, such as 100% SDV, are not proportionate to risk, nor in keeping with the desired goal of accelerating clinical development timelines (11). It states further that risk aversion is a signifi cant problem, making it difficult to change processes. As the paper describes, the need for monitoring to be more of a risk-mitigation strategy is made possible with the growing presence of electronic trial data.
Validation and Queries
Alison Crook explains that RBM has been around for some time now. eSource has the ability to offer built-in validation of data. “The data you see is a true refl ection of the source data. You are actually monitoring source data.”
Tying the availability of these data to RBM, Crook says it becomes easy to raise queries and look at query rates. “With eSource, you could select to look at a particular visit for a number of patients simultaneously, and maybe pick up trends quicker and more easily. In addition, if patients were, for example, coughing at a specific visit, you may notice it sooner because you can monitor the data earlier and do not have to wait for an on-site visit,” she says. Clive Ballard, who has conducted studies using eSource, also notes that it reduces queries and has an impact on the style of monitoring. “eSource increases the effi ciency of RBM; we have seen it reduce queries, maybe up to 70%.”
Moving Forward
As stakeholders turn their attention to methods of improving operational efficiency, the need to produce clean, reproducible clinical trial data from the site remains a bedrock for the industry. Technology is enabling this transition, with eSource key to addressing the root cause of problems linked to capturing data on paper and then transcribing into an EDC system.
This is a period of transition. The functionality of eSource is making RBM more feasible, yet the industry is just starting to understand the best approach. Recent research has identified various RBM approaches, comparing them to traditional 100% SDV with a number of cost analyses (3). The intent is to use fewer data points for SDV that pack a greater punch when it comes to efficacy and safety analysis.
eSource is here to stay. As Crook says: “Even with my limited experience with eSource, I am sold on the idea. I can see source data in real time. I love the flexibility, and it is easy to cross-check data on different forms. You feel that you are doing a really effective job – and this should improve the quality of the research.”
References
1. FDA Guidance for Industry: Electronic source data in clinical investigations, September 2013. Visit: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ UCM328691.pdf
2. EMA Reflection Paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials, June 2010. Visit: www.ema.europa.eu/docs/en_GB/document_library/regulatory_and_procedural_guideline/2010/08/WC500095754.pdf
3. Leveraging the CDISC standards to facilitate the use of eSource data within clinical trials, CDISC Electronic Source Data Interchange Group, 2006. Visit: www.cdisc.org/stuff/contentmgr/files/0/2f6eca8f0d f7caac5bbd4fadfd76d575/miscdocs/esdi.pdf
4. Mitchel JT and Markowitz JMS, Time for change, International Clinical Trials, February 2012. Visit: www.samedanltd.com/magazine/13/issue/172/article/3228
5. Bleicher P, eSource redux, Applied Clinical Trials, 2002. Visit: www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=83559
6. 21 Code of Federal Regulations Part 312.62(b) – Responsibilities of sponsors and investigators: Investigator recordkeeping and retention
7. Koreith K, The high cost and questionable impact of 100% SDV, CenterWatch Monthly 18(2), 2011
8. Little C et al, Good clinical data management practices, Version 4, Society for Clinical Data Management, 2005. Visit: https://ncisvn.nci.nih.gov/webSVN/filedetails.php?repname=ctms-forum&path=%2F2-analyst_folders%2Fmichele_working%2Fgcdmp_v4.pdf
9. Franco P et al, Risk-based monitoring: Reduce clinical trial costs while protecting safety and quality, PricewaterhouseCoopers, March 2013
10. FDA Guidance for Industry: Oversight of clinical investigations – A risk-based approach to monitoring, August 2013. Visit: www.fda.gov/downloads/drugs/.../guidances/UCM269919.pdf 11. EMA Reflection Paper on risk-based quality management in clinical trials, November 2013. Visit: www.ema.europa.eu/docs/en_GB/ document_library/scientific_guideline/2011/08/WC500110059.pdf
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