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Feature Articles : May 15, 2005 ( )
Moving Toward System-Wide Software Suites
Overcoming Hesitation in Adopting E-Clinical Trial Systems
Electronic clinical trials are moving from standalone, point solutions toward software suites, similar to the way office applications migrated in the 1980s. Eventually, investigators will have a seamless, system-wide software suite on a single platform that can handle every trial and every patient, anywhere in the world. However, it's not there yet.
"Some people envision the ideal e-clinical trial system as a fully integrated, comprehensive software application," according to Paul Bleicher, M.D., Ph.D., chairman and founder, Phase Forward (www.phaseforward.com).
But, he continues, "holding out until the perfect system arrives makes it unlikely that it will ever arrive." Instead, "What are reasonable expectations, based on the experience of other industries?" he asks. "It's important to keep that in mind."
There is more to the pharmaceutical/biotech industries' hesitation to adopt e-clinical trials than hopes for the perfect system, however. Their concerns, according to a report by Forrester Research (www.forrester.com) Clinical Trials' EDC Endgame, are "a murky product and vendor landscape, a risk-averse culture, and organizational protectionism."
While the corporate culture and organizational protectionism is unlikely to change anytime soon, the product landscape is changing rapidly. Some of the larger software companies are cobbling together products developed from multiple companies into suites; others are developing their own from scratch, and no company as yet has a comprehensive, fully-integrated product offering.
In the meantime, interoperability is an issue even within individual companies' product offerings. "E-clinicals systems are a long way from having a global standard," says Bill Byrom, Ph.D., product strategy director, U.K, at ClinPhone (www.clinphone.com). "Although the major vendors are working toward a global standard, the existing modules still communicate using very different file formats."
CDISC's (Clinical Data Interchange Standards Consortium) ODM is frequently mentioned as a standard for data interchange, but "it's not ready for complete interoperability," Dr. Bleicher says.
"It's being piloted for some early purposes," he adds, "but some aspects of the standard require vendor-specific extensions, thus requiring coordination, rather than a seamless use of the standard."
Internet-based solutions offer one way to sidestep the issue, and are causing a paradigm shift. "Now people are leveraging the Internet as another infrastructure to connect business processes together," says Glen de Vries, CTO of Medidata Solutions (www.mdsol.com).
When he and his colleagues founded Medidata in 1999 they determined "to treat the Internet as an infrastructure that is as consistent and pervasive as the telephone, and as comfortable to use as pen and paper."
By doing so, they reasoned, "we would have an application the end-user would want to use." The result was Rave, now in version 5.2. Version 5.4, currently in beta testing and due out this summer, expects to be able to handle every clinical trial and every patient a company tracks, anywhere in the world.
ClinPhone is among the e-trial leaders with an extensive set of software tools. The firm recently web-enabled its Clinical Trial Management System, TrialWorks, which both streamlines access and allows remote access. "This allows a monitor to take a local copy and synchronize it back at the office," according to Dr. Byrom.
He emphasizes, however, that this is only one piece of a comprehensive e-clinical trials system. As his U.S. counterpart, Dave Stein, elaborates, from electronic data capture data still must be aggregated and analyzed and entered into disparate systems.
"Sponsors still need a clinical data management system. Some vendors are building tools into their EDC (electronic data capture) systems to eliminate the need for a back-end database," but trials management involves a host of such administrative details as tracking patient visits and making investigator payments based upon that, as well.
Furthermore, when a patient is enrolled in a trial, a variety of systems need to know about it, he says. Using ClinPhone's Connect for EDC Systems, data is entered once and then automatically populates the necessary systems with that information.
"This eliminates duplication of data and activities, for example, during the randomization or enrollment stages, which, in an un-integrated environment would require similar data to be entered into both EDC and IVT systems," Dr. Byrom says. "Integration has the benefit of not asking the investigator to do things twice."
Despite the growing interest in software suites, most of the e-clinical trials offerings are still point solutions. The front endpatient diariesaren't necessarily included in the emerging software suites.
"Pharmaceutical companies prefer to use best of breed solutions and expect the providers to solve the interoperability problems," says Doug Engfer, co-founder, president and CEO of Invivodata (www.invivodata.com). Electronic patient diaries are one of the applications designed to integrate seamlessly with existing clinical trial processes.
"They are the one piece of the electronic clinical trials puzzle that focuses solely on the patient," he says, "and puts the data in the context of the way they live their lives. Patient-reported data is used by 75 percent of all clinical trials and are a key aspect in understanding if a drug is safe and effective."
He continues, "Our recent NDA approvals, including Amylin Pharmaceuticals' Symlin and Allergan's Acular LS, are testimonies that this technology is ready for prime time."
Historically, patient compliance with diary protocol has been a challenge. A study conducted by Arthur Stone, Ph.D., and colleagues at State University of New York at Stony Brook, found that 89% of all paper diaries were either back-or forward-filled by patients, rather than being completed at the scheduled time.
With real-world clinical studies using Invivodata's Palm-based electronic diary, DiaryPRO, however, compliance consistently reached 93%.
"The key," according to Michael Hufford, Ph.D., Invivodata's vp, scientific affairs, "is outstanding subject training that makes sure patients fully understand what's expected and how to use the technology, an easy user interface, easier than an ATM, with a proprietary compliance system with on-screen reminders if the patient is off track.
"It also can issue e-mail to alert the trial site and collect real-time data about how the patient is doing," both in terms of compliance and adverse events.
The data itself drops into drug and device development programs seamlessly, without the changes to work processes that plague many other software applications.
Dr. Hufford adds that patient groups have said they get a feeling of value and importance because the sponsor has invested in them, by providing a PDA for them for the trials.
Companies Begin to Shift
Although a handful of companies have used e-clinical trials to shepherd drugs to market, most companies are still involved with paper, at least for some trials. Wyeth Pharmaceuticals (www. wyeth.com), for example, is in transition, finishing paper trials and beginning new trials electronically.
"There are subtle differences in how electronic and paper trials are designed," according to Jerald Schindler, Dr.P.H., vp, global biostatistics and clinical trials, Wyeth Pharmaceuticals.
"Some of the early e-case reports forms were just images of the paper form, but now the industry is moving to smart forms, so questions lead to relevant questions based upon the answers. In general, some editing is built into the form," so that if data doesn't make sense, the form flags it for immediate resolution. Errors, therefore, are reduced.
"The value that can be achieved today with point solutions is significant," Dr. Bleicher says. Electronic data capture is a case in point.
Companies incorporating EDC into clinical trials "are getting faster data access, and, therefore, more timely information and better patient safety," he says. EDC allows even technophobic physicians to review thousands of data points at once, knowing who did what, when, and where. Consequently, trials can be adjusted, and patients and investigators retrained if necessary.
EDC generally is the starting point for companies interested in developing electronic trials, but "EDC is only one piece of the process," Dr. Schindler emphasizes. "We've focused on the entire systemEDC, internal cleaning, editing, analysis, interpretation and integration with other sources, including administrative data, contact info, trial progress, drug supply data, etc.," he says.
"We combined some commercial pieces with software we built ourselves," Dr. Schindler says. "There's a question among pharmaceutical companies now about whether to buy or build (e-systems). The big companies are building their own, because the (single point solutions) products don't fit well together."
A handful of companies have e-clinical suites on the market. "Most of the suites are still incomplete, so users will need to fill in the gaps," Dr. Schindler says, "which may be more challenging than implementing the initial system."
Forrester Research also reports patch results, in that applications aren't as seamless as either the customer or vendor would like.
Ease of Use
Most solutions, Dr. Schindler says, aren't yet comprehensive, so users will still need to build some of their applications. Consequently, it behooves potential purchasers to ask how the suite was designed and exactly what it requires from the user. The thought, for drug developers, is that if an application isn't as easy to use as the popular Google search engine, prospective clinical investigators may not buy in.
The return on investment (ROI) of e-clinical trials is generally considered intangible, something that changes from project to project. Foremost, Engfer says, "We're conducting clinical science. ROI must be considered within that context."
With electronic diaries, Engfer says "they are no more expensive than paper and, because of increased data integrity, trials are likely to require fewer subjects." E-diaries can eliminate statistical noise that is created when patients back-fill and forward-fill paper diaries.
According to Engfer, Sepracor, working with Invivodata, improved the quality of their patient diaries enough to reduce the number of subjects by 50%, "resulting in a 2,900 percent ROI based solely on development costs."
de Vries, also, is quick to point out that the real ROI "is that companies are getting information much earlier and have higher visibility into the trials as they're underway. For example, he says, "is a site keeping up with data entry? Are the monitors doing their jobs?"
Dr. Schindler says, "Electronic versus paper may save a couple of weeks to data lockdown, but the biggest savings is the ability to review data early, which enables adaptive, or flexible, trials."
In a comparison of paper to electronic Phase II trials, Forrester has found operational savings of $347,600. When accelerated product sales were added to the data, the savings topped $20 million. In Phase III trials, operations savings were $6.252 million. Accelerated product sales bumped the figure to about $60.6 million.
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