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International Clinical Trials

Data Dynamics

The digital pen might look like a ballpoint pen, but the technology looks set to accelerate the speed of clinical trials, while helping to reduce the cost. Petter Ericson at Anoto AB investigates

In its 2011 outlook on pharmaceutical and biopharmaceutical trends, the Tufts Center for the Study of Drug Development predicts that drug developers will struggle to replace revenues from a large number of prescription drugs which are set to lose patent protection over the next few years. It raises the question of whether drug developers can bring enough new drugs to market quickly enough to remain profitable, not to mention the challenge of coming up with so-called ‘blockbusters’ that bring in annual revenues of $1 billion and above (1).

Between 2005 and 2009, sponsors in the US spent more than $300 billion on R&D, but only 34 new products were approved by the FDA (2). At a time when the cost of developing a new drug is running at $1.3 billion, this means pharmaceutical companies are under even greater pressure than ever to cut down on the time and cost of development (1).

Clinical trials are an obvious target in this search for efficiencies, as they are generally estimated to make up around 60 per cent of total drug development costs. A major share of this cost is associated with collecting and analysing large amounts of data in case report forms (CRFs).

In recent years, electronic data capture (EDC), or eCRF, has become more widely used for recording patient data. Anecdotal evidence suggests that about half of all trials now use EDC, mainly in the shape of web-based data entry, or webEDC. However, a large share of clinical trial data is still captured on paper CRFs, and re-entered manually into backend systems for further processing. It is this duplication of effort that contract research organisations (CROs) and sponsors are keen to reduce or in some cases remove completely.

Digital pen and paper (DPP) is winning industry support as an alternative to webEDC. The technology automatically captures handwritten information in paper CRFs and other forms, such as medical diaries, converting it directly into digital data so that notes no longer have to be re-typed.

There is mounting proof from the field that DPP can help speed up data entry and improve data accuracy compared with paper-based methods and webEDC. More importantly, the use of digital pens has led to a step change in how clinical trials are conducted, enabling an adaptive approach to clinical trials that can cut development time and costs dramatically.

EASE OF USE & SPEED DRIVE ADOPTION

Academic and field usability research in general support the case that DPP is significantly more user-friendly, quicker and more accurate compared with using a keyboard – or mobile alternatives such as tablets or PDAs (3). Digital pen users require less training, can set up the technology swiftly and generally find digital pens easy to use (4,5). At regional breast cancer screening centres in France, doctors grew so accustomed to the digital pens that they sometimes accidentally used their own biros to fill in clinical forms (6).

With the number of procedures per enrolled patient rising, it is also worth considering the comfort of the patient (7). In spite of proven benefits, using technology often gets in the way of the relationship between clinicians and patients, creating a feeling of distance between them. For example, there is evidence that laptops are more disruptive to meetings than pen and paper (8).

The digital pen looks and works like a ballpoint pen with a tiny infrared camera at its tip that tracks the pen strokes relative to a pattern of barely visible dots printed on the form, recording and storing what is being written. The dot pattern is laserprinted onto standard paper and makes each form – CRF or otherwise – unique and traceable. It is easy to track the specific trial, investigator, patient, time and date of each test.

Once investigators have completed a form, the pen data is transferred to a PC or backend system via USB or using bluetooth and a mobile phone. CRF data is then converted digitally, enabling investigators to view, clean, analyse and code clinical trial data more quickly than previously possible.

As CROs are increasingly moving into emerging markets, DPP also has the benefit that you do not need access to a PC or terminal immediately. For example, the UN Food and Agriculture Organization, which helps developing countries improve agriculture, forestry and fishery practices, uses DPP technology for its livestock disease control in rural Africa. The pen can store the equivalent of 40 A4 pages of data, allowing UN field workers to keep collecting data until they have access to a mobile network or an internet-enabled PC for downloading and transferring the information (9).



MAKING THE IMPOSSIBLE POSSIBLE

A range of pharmaceutical companies and CROs have incorporated DPP technology into their clinical trials processes and services, as a tool for speeding data collection and study monitoring.

German cancer research specialist, Indivumed, opted for a DPP-based system following a review of EDC technologies, including PDAs and advanced form scanning. Before the introduction of the digital pens, it took up to 90 minutes for nurses to fill in patient forms – 27 pages with 1,600 data fields – and then input the same information into the trial management system. Thanks to the digital pens, patient data now only has to be recorded once, reducing the time needed for each form to around half an hour. As the digital pens largely work in the same way as normal pens, nurses did not have to change their existing working practices.

In addition to boosting productivity by up to 70 per cent, the data is available to everyone involved in monitoring the trial instantly. Each CRF is imprinted with a unique dot pattern to ensure that data recorded on different days by different people is linked to the correct patient (10).

In Italy, Solvay Pharma used digital pens to carry out a nationwide study of 1,200 patients, unusually involving 250 family doctors as investigators. The objective was to gather information on the prevalence of androgen insufficiency in men over 45 suffering from metabolic syndrome. As part of this noninterventional study, the doctors identified suitable patients and noted down the results of their examinations with the digital pens. For this, they only received a 20-minute training session.

In past studies of this nature, doctors would have to gather the information on paper, either to be collected by a study monitor or posted, and then this data had to be re-typed electronically. This was not only time-consuming and errorprone, but also caused a significant delay between data being collected and becoming available for review and analysis.

With the digital pens, the family doctors simply filled in the CRF and docked the pen to download the stored data, which was then transferred automatically to the eCRF clinical trial data management System. This meant, for example, that monitors could flag mistakes for immediate correction, ensuring all 1,200 data sets were valid for analysis. Using the traditional approach, a large-scale study of this nature would have required significantly greater resources and may have even been impossible to realise, underscoring the step change DPP technology can bring to clinical trials (6).

BOOSTING DATA ACCURACY

Achieving high levels of accuracy is one of the most time-consuming and costly areas of trial monitoring and site management during a clinical trial, with about 65 per cent of a monitor’s time normally devoted to source data verification (SDV). The industry has put a lot of focus on reducing the need for SDV, whether it is by reducing the number of fields that require checking, focusing verification efforts on areas where accuracy is particularly critical, or by trying to do away with SDV altogether (11).

Traditionally, clinical trial data has been collected manually and then entered electronically by two different people, before being verified by the study monitor. WebEDC has become a popular alternative. Here, validation tools are used to avoid the need for a verifier. This is less expensive but it also lacks accuracy. Optical mark recognition (OMR) overcomes these problems but involves a prolonged scanning process that makes it inefficient.

Using DPP technology now enables study monitors to use eCRFs as source data. As the paper transcription stage is no longer required, there is no need to compare electronic study data to the original paper CRFs. For example, Health Decisions chose to combine digital pens with OMR. Here, digital pens are used to enter patient data on OMR paper forms imprinted with the dot pattern. This combined approach was found to be four times more accurate than webEDC, leading to fewer post-entry corrections. Furthermore, far fewer people need to ‘touch’ the data during entry and validation. Compared to webEDC and paper, the DPP system was also considerably faster – at least two weeks quicker than webEDC – and less expensive (12). The CRO found that using eCRFs as source data can lead to savings of up to 50 per cent of study monitoring budgets (11).

TAKING AN ADAPTIVE APPROACH TO MONITORING

The speed of data collection means that, once the pen data has been downloaded and the research data has been extracted, the latter can be shared more quickly between the CRO and the sponsor. Consequently, both parties have much greater visibility of what is going on in the field and can exert tighter control over the trial as it progresses than previously possible.

This immediacy has disruptive implications for the overall design and management of clinical trials. Using a traditional, paper-based approach can lead to problems and errors only becoming apparent at an advanced stage in the study. Having to make adjustments at that point can mean missed deadlines, soaring costs and, in the worst case scenario, a missed opportunity if a competitor’s product gets to market first. With the help of DPP, CROs and sponsors can take an adaptive approach to monitoring their study, which effectively gives them the ability to nip problems in the bud before they can spiral out of control.

In a clinical trial looking to establish the predictive accuracy of a new human papilloma virus test, DPP was used to collect trial data across 46 US sites. Expert projections had shown that the study would require more than 50,000 subjects and cost $50 million using a traditional approach. With the digital penbased adaptive system, the size of the trial was cut down to 4,100 subjects because of the ability to immediately determine who could provide useful information, and costs were reduced to less than 35 per cent of the expert estimate. Most importantly, the fast access to data allowed the sponsor to beat a major multinational competitor to market by 2.5 years.

With important data becoming available in real-time thanks to the digital pens, strategic decisions about the direction of the trial could be made quicker than was usually possible. Information was shared instantaneously between on-site investigators, the CRO and the sponsor. The ability to review results as they arrived, make corrections and provide feedback instantly to investigators enabled sponsors to guide and adjust the study as it progressed.

Potential sources of errors and delays could be managed proactively. The transparency and immediacy of data access allowed the CRO to pinpoint and address problems at study sites before they could affect data quality or timelines. Monitoring quality was also improved, all while reducing the frequency of site visits needed, and the real-time stream of metrics meant that the CRO could address many issues without having to travel to the site (13).

CONCLUSION

While its use in clinical trials is fledgling, this review of DPP technology and its applications in the field has shown that it has disruptive potential in terms of fundamentally changing how the industry runs clinical trials. Real-time access to data as it is being collected means having greater control over the progress of a trial, with the ability to root out problems early and adapt the trial if the original design proves flawed. With the promise of saving tens of millions of dollars and taking years off the innovation cycle, digital pen technology could become an important building block for changing the dynamics of clinical trials.

References
  1. The Tufts Center for the Study of Drug Development, Drug Developers Are Aggressively Changing the Way They Do R&D, 5 January 2011, http://csdd.tufts.edu/news/complete_story/ pr_outlook_2011
  2. Pharmaceutical Research and Manufacturers of America, Pharmaceutical Industry Profile, March 2010
  3. Boldt R and Raasch J, Analysis of current technologies and devices for mobile data capture, A qualitative usability study for comparison of data capture via keyboard, tablet PC, personal digital assistant, and digital pen and paper, University of Applied Sciences, Hamburg, 2008
  4. Estellat C, Tubach F, Costa Y et al, Data Capture by digital pen in clinical trials: a qualitative and quantitative study, Contemporary Clinical Trials 29(3): pp314-323, 2007
  5. Anoto, Enabling broad epidemiological study, October 2009
  6. Digital pen supports breast screening in France, eHealthEurope, 7 November 2007
  7. The Tufts Center for the Study of Drug Development, Drug Developers Actively Improving Efficiency of Clinical Trials, 26 April 2011, http://csdd.tufts.edu/news/complete_story/ rd_pr_apr_2011
  8. Newman W and Smith EL, Disruption of meetings by laptop use: is there a 10 second solution?, CHI 2006
  9. Anoto, Playing an important part in disease control, November 2008, http://bit.ly/lW7iGb
  10. Anoto, Digital Pen and paper solution increases research efficiency by up to 70 per cent, October 2008 (bit.ly/kMQwIN)
  11. Health Decisions, Adaptive Operations: Taking Adaptive a Step Further (White Paper), 2007, www.healthdec.com/resources/white-papers.php
  12. Anoto, Providing fast and accurate data in clinical trials, March 2007 (http://bit.ly/iyhoLx) and personal communications with Michael Rosenberg, CEO, Health Decisions
  13. Health Decisions, Case Study: Molecular Diagnostics: HPV; and personal communications with Michael Rosenberg, May 2011


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Petter Ericson is the co-inventor of digital pen and paper technology. Having studied Engineering Physics at Lund Institute of Technology, he joined C Technologies – now Anoto – in 1997 as Head of Software Development. In 1998 the world’s first consumer hand-held image processing device, the C-Pen, was launched. At present, Petter is Anoto’s Chief Technology Officer, spearheading the company’s R&D activities. He has filed patents for over 40 inventions in the fields of image processing and DPP. Email: clinicaltrials@anoto.com
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