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International Clinical Trials

Proof Positive

Embracing technology to make measurable improvements to timelines, data quality and patient safety has been at the heart of accelerating the clinical trial process. One of the solutions that is emerging as critical to speedier product development is electronic source data, generally referred to as eSource.

The key feature of eSource is it eliminates paper source documentation, allowing for more accurate and faster data collection, even in locales with limited infrastructure. Once captured, eSource data and documents are available online for remote review and monitoring. With this capability, clinical trials are unfolding at a quicker pace than traditional paper-based methods of collecting source data that later require transcription into electronic data capture (EDC) systems.

Removing the transcription step means fewer errors will be introduced into the study database, resulting in cleaner trial data from the time of fi rst data collection. This cuts out the need for 100% source data verification by study monitors, as data collected electronically flow directly to the sponsor’s clinical trial database and do not have to be matched to a paper source.

Transforming Studies

This capability is being encouraged by the FDA and EMA, both having issued publications attesting the value of eSource (1,2). Complementing this regulatory push is a recent white paper by the Society for Clinical Data Management, which describes the move to eSource as transformational. It comments that, with the preservation of requisite data standards, the process of data collection is being reinvented (3).

As it becomes more widely accepted, drug developers are realising that the benefits of eSource extend well beyond cost savings and condensed timelines. Particularly valuable is how it opens the door to innovative approaches in clinical research, such as risk-based monitoring (RBM) and adaptive design earlier in the trial process. This makes real-time or near-time viewing of clinical data possible, allowing for interim analysis and earlier decision-making about the direction of studies. Case studies outlined here illustrate the advantages this can bring for vaccine, central nervous system (CNS) and dermatology trials.

Regulatory Support

To understand the role of eSource, it is meaningful to start with a definition, such as that given in the 2013 FDA guidance, Electronic source data in clinical investigations (1). According to the guidance, eSource data refers to data initially recorded in electronic format. It states that access to source data is critical to the review and inspections of trials; and that eSource eliminates unnecessary duplication of data, reduces transcription errors, and facilitates remote data monitoring.

A few years earlier, in 2010, the EMA released a Reflection Paper on eSource (2). This document acknowledges that, with the growing use of technology in pharmaceutical R&D, there is a need for clear guidance on the use of eSource and transcribed data, as these elements were originally developed to be managed with paper. In moving to electronic format, the Reflection Paper describes how data captured by electronic case report forms, electronic patient reported outcomes devices and other modalities need specific requirements, so that processes can be implemented and accepted with confidence, and the benefits of these systems fully realised.

Further regulatory guidance from the FDA and EMA on the benefits of eSource comes in the form of publications describing adaptive trial design and RBM (4-7). Collectively, they highlight the growing use of electronic solutions and mention that sponsors should consider adopting these methodologies to improve the trial process.

Vaccines Development

All of the regulatory support for integrating eSource into clinical trials provides encouragement for changing how some vaccines are developed, particularly in remote areas of the world. Of late, significant attention has been focused on producing a vaccine to prevent the Ebola virus which, says the World Health Organization (WHO), is experiencing its worst outbreak in history, causing more than 6,000 deaths in West Africa (8). A recent WHO statement claims that effective treatments and vaccines would make a dramatic difference (9).

Other critical unmet needs include developing an effective vaccine for tuberculosis (TB), which the WHO reports developed in 9 million people in 2013 (10). Of the infected population, more than half (56%) were in the southeast Asia and western Pacific regions, and 25% in Africa, which also had the highest rates of cases and deaths relative to population. In 2013, more than 1.5 million died from this largely preventable disease.

According to the WHO, more than a dozen TB vaccine candidates are in clinical trials. However, despite years of concerted effort, a key barrier to their development is the limited infrastructure and connectivity in many isolated and rugged locations where TB prevails, which makes regulated clinical research difficult.

TB Case Study

To address this issue, the Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) received limited grant funding to test a promising TB vaccine in 2012. Seven sites were selected in Tanzania and South Africa, based on the significant number of TB cases in those areas, even though there was limited connectivity and site experience of conducting trials according to Good Clinical Practice (GCP).

PanACEA was particularly concerned with sites’ ability to ensure that source documents would be maintained, clinical data would be monitored regularly for appropriate oversight, and that sites would comply with the protocol in line with GCP. PanACEA and Triclinium, a South African-based CRO, selected an eSource platform to enable the African sites to capture source data electronically and permit European medical institutions to review and monitor source documents remotely. To effectively support this study, fully mobile tablets were provided to sites – each equipped with intuitive electronic forms with the look and feel of paper in terms of usability, but incorporating sophisticated real-time data validations. Prior to the study visit, site users would download the necessary forms for offline use, which allowed some users to conduct research and collect data at subjects’ homes or off-site locations. After capturing data, site users would return to a location with an internet connection to securely upload both documents and data for monitors to review remotely.

Breaking Barriers

Although there was limited clinical research experience among sites in this study, eSource made it possible for more than 300 users to collect data from 634 subjects. Built-in protocol guidance, coupled with the intuitive nature of the electronic forms, ensured quality data and protocol execution. As evidence, less than five customer support requests were received per month. Using eSource eliminated the need for sites to re-enter clinical data into an EDC system, and minimised source data verification by providing monitors with remote review of original site documents and data.

After three months, PanACEA was able to cancel the data management contract with a third-party CRO because the eSource data were already validated and clean at the time they were entered.

This study demonstrates how eSource can dramatically lower the barriers to conducting research in isolated and remote locations. In addition, the availability of both source documents and data permitted a higher percentage of scarce study research dollars to be allocated to recruiting and enrolling patients, rather than monitoring and data management overhead activities.

Alzheimer's Data

Recent data from the Alzheimer’s Association indicate that an estimated 5.2 million Americans suffer from this disease; that number is expected to triple by 2050, unless effective therapies are developed to halt or slow its progress (11). Worldwide, the number of people with dementia has reached 44.4 million (12). Given this substantial burden, it is not surprising that clinicaltrials.gov lists in excess of 1,500 studies for Alzheimer's.

Trials for CNS disorders, such as Alzheimer’s disease, often involve complex paper-based assessment scales administered by raters to determine a potential patient’s eligibility or outcomes at study visits. These often large, global studies are particularly challenging due to the level of difficulty to ensure data quality and consistency – two critical success factors.

In October 2014, a Phase 2 Alzheimer’s study testing an investigational therapy selected eSource to capture data at 75 clinical research sites located in North America and Europe. At the time of writing, the study was attempting to enrol more than 600 subjects over an 18-month period, and to capture data electronically using nine customised scales in more than 12 languages.

Using a purpose-built eSource platform, electronic scales were developed to replace traditional paper scales and the bias sometimes associated with them. The electronic forms incorporate built-in logic, automated scoring and integrated audio recording to ensure data consistency and improve the assessment of critical efficacy end-points. The electronic scales also help simplify the complexities of scale administration through smart form design that guides protocol execution by identifying any data entry errors to correct while the subject is still present; and incorporating guide text directly in the forms to help ensure raters are administering the questionnaire appropriately (13,14).

Dermatology Patients

eSource technology has also been used in the dermatology field. A pharma company conducting a Phase 3 study of an investigational ointment required a solution that could support remote monitoring, image capture and video uploads, while ensuring proper protocol execution and streamlining clinical R&D. Using a purpose-built platform, the sponsor was given customised eSource that included built-in guidance to mandate the sequence by which sites would collect study data.

Using tablets equipped with the eSource study, site users captured data electronically during the subject visit. Each eSource study was embedded with an instructional video that demonstrated proper application of study medication to aid proper protocol execution. A bi-directional data exchange between the eSource platform and an interactive voice response system (IVRS) database provided site users with push-button randomisation. After filling out the eSource form, users simply pushed a button and the IVRS was automatically populated with relevant subject data necessary to perform the randomisation and kit assignment. Using the tablet’s built-in camera, photos were taken to record the patient’s response to the investigational medication, and immediately uploaded to a dedicated section in the eSource form. This remote access to study data and images enabled monitors to note improvements and grade lesions in real-time.

Relevance Today

As these case studies suggest, the ability to collect both eSource documents and data on mobile tablets at the point of care has clear implications for improving the clinical trial process. It not only minimises costs and timelines, but also facilitates high-quality, secure clinical development in the most remote regions of the world with minimal infrastructure. This is particularly relevant today as pharma companies race to produce a vaccine for Ebola.

eSource technology delivers real-time, remote access to source documents and data from anywhere in the world to make earlier decisions and interim analysis supporting innovative approaches like adaptive study design. For dermatology studies, the ability to capture images, play videos and record audio is especially useful for RBM and adaptive designs. And for Alzheimer’s and other CNS therapies, where outcomes are highly dependent on subtle data quality factors, eSource can remove bias and ensure more consistent, high-quality data across sites.

The versatility of studies using eSource across divergent therapeutic areas, along with encouragement by regulatory agencies, speaks to the benefits of adopting this approach to innovate clinical research and speed development of much needed therapies.

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. King L et al, eSource implementation in clinical research: A data management perspective, Society for Clinical Data Management, 12 June 2014. Visit: www.scdm.org/sitecore/content/be-bruga/scdm/publications/~/media/be%20bruga/scdm/documents/esource%20 white%20paper%2006122014%20FINAL.ashx
4. FDA draft guidance: Adaptive design clinical trials for drugs and biologics, 2010. Visit: www.fda.gov/downloads/drugs/.../guidances/ucm201790.pdf
5. EMA Reflection Paper on methodological issues in confirmatory clinical trials planned with an adaptive design, 2007. Visit: www.ema.europa.eu/docs/en_GB/document_library/scientific_guideline/2009/09/WC500003616.pdf
6. 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
7. 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
8. 2014 Ebola outbreak in West Africa – Case counts, Centers for Disease Control and Prevention, December 2014. Visit: www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html
9. Ethical considerations for use of unregistered interventions for Ebola viral disease: Report of an advisory panel to WHO. Visit: http://apps.who.int/iris/bitstream/10665/130997/1/WHO_HIS_ KER_GHE_14.1_eng.pdf
10. Baddeley A et al, Global Tuberculosis Report 2014, WHO. Visit: http://apps.who.int/iris/bitstream/10665/137094/1/9789241564809_eng. pdf?ua=1
11. 2014 Alzheimer’s disease facts and figures, Alzheimer’s Association. Visit: www.alz.org/downloads/facts_figures_2014.pdf
12. Dementia statistics, Alzheimer’s Disease International. Visit: www.alz.co.uk/research/statistics
13. Wajman JR et al, Educational bias in the assessment of severe dementia: Brazilian cutoffs for severe MiniMental State Examination, Arq Neuropsiquiatr 72(4): pp273-277, 2014
14. Schultz R et al, Magnitude and causes of bias among family caregivers rating Alzheimer’s disease patients, Am J Geriatr Psychiatry 21(1): pp14-25, 2013

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Ann Neuer MBA is President of Medical deScriptions, a recognised provider of writing and qualitative market research services to the biopharma sector. Her specialism is in the clinical trials niche, where she has written extensively on technologies that improve trial efficiency, as well as patient recruitment and site selection. She also focuses on cloud computing, comparative effectiveness and outcomes research.
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