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The New Normal for Clinical Development


eClinical 2011: Remedies for the Clinical Trials Machine

Can the emergence of new technologies improve the miserable state of clinical trials?

By DEBORAH BORFITZ

February 1, 2011 | An assortment of emerging clinical trial technologies over the past decade are providing creative ways for pharmaceutical companies and clinical research organizations (CROs) to boost the quality, pace, and efficiency of their drug development programs. The promise is sporadically realized by companies that selectively and appropriately apply these tools and use timely and visible performance metrics as the basis for relationship-building with clinical investigators. Working recipes are not often diligently followed, however. Thus clinical trials performance, in the main, remains dreadful.

Thanks to benchmarking by the Tufts Center for Drug Development, it is widely known that five out of six trials fail to meet their enrollment targets and half of all first-time investigators never participate in another trial. Protocols have become increasingly complex and out of touch with real-world patients and clinical habits. “If clinical trials were patients, then most would require hospitalization and many the ICU,” says David Hardison, chief health scientist in the public health operations of Science Applications International Corporation. The acuity of the dysfunctions in clinical development today necessitates emergency rescue of most trials during some critical point of their execution.

Norms for how clinical trial data get collected, moved, and analyzed have fundamentally changed over the past decade. Studies once steadfastly done on paper now routinely utilize electronic data capture (EDC) and digital diaries the world over. New information-sharing and trial simulation tools have emerged for improving human productivity, keeping studies on track, and restraining costs. Accelerated acceptance of data interchange standards has also unleashed the very real possibility of using electronic health records (EHRs) to improve protocols and stop patient-recruitment log jams.

EDC is no longer just an instrument for collecting patient information on a case report form (CRF). Increasingly, it also provides near-real-time supply chain and enrollment information in lieu of freestanding interactive voice and web response systems. Some EDC systems also have some fairly robust adverse event (AE) reporting capabilities and can easily add electronic patient-reported outcomes (ePRO), says Hardison. Oracle’s Phase Forward is practically a full-fledged clinical trial management system.

Market leader Oracle now has every signal-detection and safety reporting system under its wing (see, p. 29), excepting Aris Global and Sentrix, says Steven Lefebure, Gartner life sciences analyst. Although the field of EDC companies is vast, Medidata stands out as the next largest player followed by a tier of companies—Datatrak, BioClinica (see p. 15), OmniComm, Nextrials, and KIKA—seeking better positioning with broad, suite-based offerings. Differentiation between players on core EDC is difficult to see. Solutions are typically offered on a hosted or Software-as-a-Service (SaaS) basis, for sponsors disinterested in maintaining IT infrastructure.

Clinical research organizations are selectively building their EDC expertise, wielding greater control over which tools ultimately get deployed, says Lefebure They’re also ratcheting down pricing by tapping into technologies via pay-per-use agreements. Small EDC providers that cannot differentiate or expand their “function footprints” may soon find themselves unable to compete. The exceptions include niche players like Akaza Research, whose free OpenClinica software is being used by organizations worldwide. Revenues from OpenClinica Enterprise Edition keep the company afloat.

The software code behind most eClinical technologies, once entirely proprietary, is slowly becoming more openly available. The National Institute of Health’s caBIG (cancer Biomedical Informatics Grid) has given some steam to the movement, says Hardison. The initiative links researchers, physicians, and patients throughout the cancer community in hopes of reducing costs, speeding research discoveries, and improving patient outcomes. Open source is a guiding principle and underlies caBIG tools.

Unfortunately, caBIG has become an unnecessarily expensive undertaking, argues Velos eResearch CEO John McIlwain. The National Cancer Institute (NCI), by its own admission, has spent $200 million on caBIG over the past six years and as yet only a handful of sites are fully operational. “Over the same timeframe and for far less money, Velos has been adopted by about 35% of the nation’s NCI-designated cancer centers,” says McIlwain. Were Velos serving as the EDC vendor for caBIG, all constituents in the NCI cancer research community would have access to the software for free. “Much of what caBIG is trying to build is already available within Velos.” The company was in fact selected and then abruptly deselected as a caBIG EDC vendor, replaced by industry-focused Medidata.

McIlwain reckons that EDC as we know it today will disappear in another five years. Investigative sites will instead use similar technology already in production at sites, together with data collected directly from EHRs, laboratory systems, and medical devices. This “direct data capture” approach, aided by improved data standards, has great and largely untapped potential for increasing the efficiency of clinical trials, he says.

Capturing the Patient Perspective

Like EDC, digital diaries offered by outfits like Invivodata and PHT are now in the mainstream, says Hardison. “Even the FDA says reliability of [ePRO] data is sufficient to support a submission. This is in contrast to issues with paper just a few years ago, when you would hear stories like, ‘I saw a patient filling out a month’s worth of diary data in the parking lot prior to their visit.’ Now, if an indication is conducive to ePRO, it’s written into every clinical trial protocol.”

Quintiles’ ePRO partner Invivodata, together with PHT and CRF Health, collectively control the majority of the ePRO market that is device-driven, says Lefebure. EDC vendors like Oracle are offering Web-based ePRO solutions. Software developer Merge Healthcare has ePRO options for collecting patient data via phone, device, or the Web. And Exco InTouch has a cell phone-based ePRO solution.

The interests of science should dictate which ePRO approach is the “best fit,” says Ken Kolenik, director of product management at Invivodata. E-diaries have, until recently, been the only option and remain his recommendation for most trials requiring patients to self-collect data at home. In addition to proven “equivalency” with paper-based measurement, he says, single-purpose ePRO devices are patient-centric in design and functionality and suitable for any demographic. Most recently, cell phone technology has automated data transfer and eliminated reliance on patients to dock diaries on a dedicated cradle.

Web-based solutions are still largely untested, says Kolenik. Variability in screen size means patients may have to scroll through questions rather than view them all at once, potentially influencing responses. In some countries, Web access is also relatively limited. On the other hand, Web-based ePRO may be an economical alternative for some post-approval trials where patient demographics are less important, or to gather data that will not face regulatory review.

Information-Sharing Simplified

On the collaboration front, email is no longer the last option standing, says Hardison. Skype, social networking sites like Facebook and YouTube, and Microsoft’s ubiquitous SharePoint portal technology provide options aplenty for keeping even the most technologically challenged colleagues connected. “We’re moving into the phase where enterprises are ready to start using these tools rather than look for the next big breakthrough,” says Hardison.

Major pharma companies have been making the shift to SharePoint over the past 12-18 months, primarily as a portal for internal information-sharing and communication between study monitors and investigators, says Guido Roumans, global director of life sciences services at TechTeam Global. The regulatory solutions of NextDocs are fittingly SharePoint focused, adds Lefebure. And last summer, QUMAS made a major update to its product suite to accommodate the growing popularity of SharePoint tools. BioClinica has smartly based its entire platform on the user-friendly, easily integrated application.

Companies like CSC are building document management and collaboration solutions (FirstDoc and FirstPoint) that capitalize on SharePoint’s familiar user interface. Other SharePoint-based tools are giving visibility to protocol details such as actual-to-target patient enrollment, says Egbert Schröer, industry manager for Microsoft’s manufacturing and resources team. “A clinical trial management solution comprises several [such] portal views, each customized with relevant information relating to specific team members and tasks.” Trial progress can be tracked by study, site, and staff member from one centralized place, streamlining administrative processes while providing sites with online access to essential information and documents.

In terms of enabling critical information flows for engaging participants in the trial process, Gartner last year named IntraLinks (along with Pramata and Virtify) a “cool vendor” in the life sciences. The newly-public company, with a proven history in the financial services industry, provides a SaaS platform for securely sharing sensitive documents and tracking information flow associated with clinical trial management. More than 60,000 investigative sites are using IntraLinks to access study documents and communicate with multiple sponsors across multiple studies online with one username and password.

IntraLinks gives sponsors the wherewithal to quickly pull together information—including feasibility surveys, financial and confidentiality agreements, informed consent documents, and 1572 Statement of Investigator forms—from sites around the world, facilitating study start-up, says VP product marketing, Alison Shurell. It can also immediately alerts sites of protocol amendments and safety concerns once a study is underway. Tasks lists, due dates, and reminders can all be automatically generated with the latest release of IntraLinks, removing the risk of human error. Sponsors also gain a real-time dashboard view of study progress by and across sites, so study monitors know where to focus their attention. The platform is a connection point to IRBs and CROs as well.

Many trials still rely on email for document exchange between sites and sponsors, but that could be changing. A recent IntraLinks study found most sites willing to try an online study management tool. Large companies sometimes rely on internal IT expertise to create a Web interface for information sharing, but managing end user support tends to get “overwhelming.”

Capitalizing on EHR data

Sponsors everywhere are still struggling to find qualified study participants. Companies are increasingly turning to Facebook and Twitter to aid their recruitment efforts; Pfizer even has its own YouTube channel (http://www.youtube.com/user/PfizerClinicalTeam) for enlisting people into trials, says Roumans. But compared to the industry it regulates, the FDA is a social media connoisseur. Only a handful of pharma companies have active blogs.

Innovation in the EHR space may well open the recruitment floodgates. Until now, EHRs haven’t proven particularly useful for clinical research purposes because data are recorded to maximize reimbursement rather than meet the exactitudes of science. But in its unique collaboration with the Mayo Clinic, one clinical services company seems to have crossed the digital divide. Centerphase Solutions has developed a proprietary methodology for tapping more than 7 million de-identified Mayo Clinic patient records to optimize trial protocols and the study feasibility process. Early results (see “Seeking Solutions”) indicate that Centerphase could vastly improve trial enrollment by translating the results of the feasibility analysis into pre-qualified subjects who can be approached for study participation.

Standards to the Rescue

Clinical research is increasingly being standardized, thanks largely to the efforts of the Clinical Data Interchange Standards Consortium (CDISC). “Significant progress has been made toward eCRFs with an agreed-upon format regardless of EDC vendor and protocol standards, which together can optimize workflow from protocol authoring to final study reports and regulatory submission,” says Hardison, former CDISC board chair. Nextrials still has the only EDC product (Prism) supporting the CDISC Healthcare Link Initiative focused on EHR/EDC interoperability. Potentially huge efficiencies can be realized by integrating workflows for clinical research and clinical care in terms of information sharing, reduced data entry, and improved data accuracy (see p. 18).

“There is still a lot of custom interfacing between applications in the clinical study landscape,” says Lefebure. Although CDISC’s Operational Data Model (ODM) and other standards have enabled a lot of plug-and-play type of applications, they can’t erase all integration issues, he notes. “There may be data points not in the ODM standard or an extension added to it or information about the data—the metadata—that needs to be shared [and] requires interpretation by data managers.” Standards in general are in a “never ending race” with next-generation IT.

Data exchange standards are enabling the Cleveland Clinic, in partnership with health care informatics company Explorys, to create a set of analytic tools to do clinical trial protocol modeling and patient selection from within the institution. For the first time this year, the value of standards in improving the speed and quality of clinical research will undergo large-scale testing by a fledgling collaborative of AMCs, pharma companies, and health IT organizations known as the Partnership to Advance Clinical electronic Research (PACeR). (The collaborative is being sponsored by the Healthcare Association of New York State as part of its larger goal to create a self-sustainable health care IT infrastructure.)

The idea is for hospitals participating in PACeR to build out their EHRs to be more valuable to both clinical care and clinical research, says David Leventhal, director of health care informatics at Pfizer. Merck, Bayer, Roche, Johnson & Johnson, and Quintiles have joined Pfizer as participants, helping to underwrite the cost of the initial EHR “gap analysis” and integration of clinical trial data elements by a start-up group of hospitals in New York State. The hospitals will ultimately reap revenues from any pharma company wanting access to the enhanced and de-identified patient data to improve protocol design and patient recruitment. PACeR is expected to expand into other states in lockstep with EHR implementation. Adherence to CDISC and HL7 standards will allow co-mingling of data across institutions. Industry will gain access to between 11 and 15 million research-optimized patient records this year alone, Leventhal predicts.

First movers in PACeR get not only early access to the data but the opportunity to proactively face the steep change management curve implied by “right sizing [protocol] eligibility criteria in the presence of real-world data,” Leventhal says. “The value proposition couldn’t be clearer,” he adds, given the volume of protocol amendments bloating trial budgets and cycle times industry-wide. Within Pfizer, he is personally endeavoring to better align the language of clinical research with ICD-9 codes and lab values the clinical care community uses to identify patients and define diagnoses.

The tactic of GlaxoSmithKline over the last few years has been to proactively identify EHR-enabled sites that can help it optimize protocol feasibility, site selection, and patient recruitment, says Philip Burstein, VP health care data optimization. “Some [investigative] sites are able to take a protocol, tell us approximately how many patients they can identify for possible recruitment, and then utilize their EHR systems to do [that recruiting] with varying degrees of success. We do think this will be heavily used in the future.”

Room for Improvement

Currently, about half of the time and dollars spent on data management is consumed simply getting data from disparate sources ready to be analyzed (via well-vetted tools like SAS and Spotfire) by statisticians, medical directors, study monitors, and project managers over a trial, says Hardison. Applications based on service-oriented architecture allow for functionality across multiple systems and thus more immediate insights from tsunamis of incoming data—and at a fraction of the cost of writing “bespoke interfaces” to connect silos of point solutions. eClinical technology vendors have been “slow to keep up with best practices in other industries around system architecture, but we’re starting to see evidence that they’re catching up,” he adds. But even the largest pharma firms still rely heavily on Excel spreadsheets to track and report on clinical trial activity.

Overall, data quality has “much improved” over the past decade but expectations have also risen, says Lefebure. Many of the quality gaps can be tied to reporting requirements in study protocols that fail to capture data precisely or with the right tools.

Trial simulation software, which could help companies plan and control trial resources and costs, remain grossly under-utilized, he adds.

Few sponsors today are doing “end-to-end” study management by thinking through a holistic set of work activities during the planning stage and then managing against that multi-disciplinary blueprint, says Lefebure. But industry overall rated the practice as having “breakthrough potential” in a 2010 Gartner survey. ClearTrial has unique and useful software for integrating and managing clinical trial operations, he notes, giving sponsors a means to intelligently parcel out limited resources. BioClinica has a clinical trial supply forecasting tool (Optimizer) that both simulates and optimizes trial activity. Even generalized analytical tools, like IBM Cognos, can help sponsors achieve a healthier balance between study planning and execution.

Companies might also want to integrate their IT and logistics support during trials, says Roumans, so sites and monitors can stop calling multiple help desks. This is displeasing to already hard-to-recruit investigators and can add to trial delays by making over-arching issues hard to detect, leading to support duplications and inefficiencies. But the tide appears to be turning. TeachTeam Global has or soon will integrate 24/7 support for three of its 12 industry clients to cover all eClinical technologies for site personnel, study monitors, and sponsor study management, effectively turning the help desk into a “clinical research operational contact center.”

The performance deficiencies are so great that sponsor movement on any of the improvement opportunities would have the effect of moving the bar at least a tad north of abysmal. “Sponsors and CROs might do well to apply some of the principles learned from supply chain optimization,” says Hardison. This would naturally involve helping investigators gain intimate knowledge of their patients, including what attracts them to participate and what keeps them enrolled. “Remember that a chain is only as strong as its weakest link.”

Seeking Solutions

Centerphase Solutions serves as the Mayo Clinic’s single external channel for industry-funded studies and assembles recruitment and communication plans on its behalf. To ensure a protocol is feasible, inclusion and exclusion criteria first get analyzed quantitatively against de-identified patient information in Mayo’s expanding Enterprise Data Trust. Chart reviews and subject matter experts then qualitatively evaluate the factors impacting subject willingness to participate in the trial. The result is a more confident enrollment projection as well as pointers to which sites are likely to perform well and improvements in the site selection process.

President/CEO Gary Lubin notes that Centerphase has to date conducted more than 25 protocol reviews across study phases and therapeutic areas for ten pharma companies. In the first of four studies started at Mayo, Centerphase took 155 days to get the first patient enrolled in a phase IIb neurological study—well below the 210-day median for all studies—and could have done so in 81 days but for contractual delays. The 21-day period between site activation and first patient enrolled was notably compressed relative to the 90-day median.

Impressively, the Mayo Clinic principal investigator (PI) enrolled patients 30% faster than the other 150 sites on the study, and within the shortest relative timeline (1.2 months), says Centerphase chief clinical officer Beth Harper. Eleven of the 12 patients screened were ultimately enrolled. The enrollment period closed earlier than expected, she notes, preventing the PI from achieving his target of 15 subjects. The study effectively substantiated the predictability of the Centerphase-Mayo Clinic model, with actual versus planned pre-screen, consent loss, and screen fail ratios within 10 percentage points.

Enrollment statistics on a subsequent phase III gastroenterology study with the same sponsor are yet more compelling. Mayo was among the first wave of sites initiated—a rarity for an academic medical center (AMC) with its own institutional review board (IRB)—and shaved another three weeks from the site activation timeline relative to its initial efforts. Mayo enrolled three times as many patients as the average site and did so at a 50% faster rate.

The Centerphase vision is to build a nationwide network of AMCs and medical systems as study “centers of excellence,” says Lubin. A second AMC is in the process of coming on line, with Centerphase in “serious discussions” with three other AMCs as it plans for the build out. Theoretically, data can be extracted in the aggregate across disparate EHR systems as long as Health Level Seven (HL7) and other standards for interoperability are followed and definitions of data are consistently applied. But integrating the EDT with other major data sources could prove tricky, says Hardison, who serves on Centerphase’s advisory board. Mayo is one of few provider organizations that have put business processes in place to ensure EHR data can be exploited for clinical development.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
This article also appeared in the January-February 2011 issue of Bio-IT World Magazine. Subscriptions are free for qualifying individuals. Apply today.
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