Paperless Progress

The problem of clinical trials generating mountains of paperwork is legendary. Stories of semi-tractor-trailer trucks pulling up to FDA-certified warehouses to unload literally tons of paper forms containing clinical trial data are no exaggeration. Consequently, the FDA has published white papers explaining and endorsing a concept called eSourcing: capturing clinical data electronically at the "source"—patient diaries and case report forms (CRFs). Indeed, the FDA is not only endorsing eSourcing methodology, but it is taking this "all-electronic" approach to data capture a step further by encouraging completely paperless submissions of clinical trial results.

Nevertheless, eSourcing remains the exception to how most drug companies conduct clinical trials today. eSourcing has been tried, but too often patient and/or doctor discomfort or displeasure with the computer interface has ultimately undermined the results. There are other risks as well with eSourcing that must be successfully eliminated or mitigated, including:

• Total compliance with 21 CFR Part 11 regulations governing the security and reliability of electronic data;

• The security and durability of the computers investigator sites use;

• The need to seamlessly synchronize trial-site data with a central data management system;

• The need for high availability of the data at all times in both directions, from the site to the center data-management (DM) server and back from the DM server to the site.

The Nuts and Bolts

Ambitious advance

Despite these risks, Janssen Pharmacuetica, a division of Johnson & Johnson, has implemented eSourcing since 2002 to improve cost efficiencies and time to market. Over the years, the company has slowly grown the number and scope of the paperless trials it has sponsored. These efforts culminated in 2004 with a program to use a complete, end-to-end eSourcing system for two separate clinical trials involving approximately 230 sites that have enrolled 900 patients to date. Both trials, for two new drugs, are 100 percent paperless.

Doctors are able to travel from room-to-room entering data directly into dedicated laptops; the patient data is then uploaded over a secure Internet connection to a central server managed by Medidata Solutions, a provider of clinical trials data capture and management software, as well as hosting services. All data from the two trials is managed by Rave, Medidata's core platform technology. The data is synchronized and organized for review by Janssen as well as by third-party trial monitors through a secure Web portal. Monitors are able to send edit checks and protocol changes to the trial sites via the portal.

Several security issues are also typically a concern to eSourcing users, but the centralized architecture system minimizes the risk of data loss from a broken laptop. At the end of each visit, a standard operating procedure (SOP) followed by site investigators is to synchronize with the central server, which copies all original source data downloaded from the laptop.

The server itself is protected by high-availability architecture, including redundant processing and frequent backup of its data. In the event a laptop needs replacing, the most current data can quickly and easily be uploaded remotely from the server.

Another SOP is that sites lock up laptops every night, just as they would drugs or a CRF binder. As a result, Janssen has reported only a one percent hardware-loss rate from either a broken or stolen laptop—and a zero percent data-loss rate across both trials.

A less obvious regulatory element is the 21 CFR Part 11 compliance of the software, which helps ensure data integrity via time stamps and audit trails for all information gathered. The time-stamped data offers a side benefit, too: discouraging log-keeping procrastination—the so-called "parking lot effect" of people filling out information in the parking lot prior to an office visit.

Satisfying users

Because many of the sites that signed on were technology-naîµ¥—for some it was their first clinical trial—a simple user-friendly interface is crucial to successful eSourcing. Doctors and nurses using the software must be able to complete a CRF, for example, with a minimal investment of time in formal training. Plus, automated functions such as data-validation checks needed to be unobtrusive and not slow data entry.

Key to this process is the translation of paper-based trial processes and information formats to electronic processes and formats. For example, when initiating a clinical study, electronic CRFs (eCRFs) can be created as flexibly as if they were created on paper. When viewed on-screen, the eCRF appears as it would on paper.

To complement ease-of-use, training is critical to guide users to ask the right questions and properly design the Web-based pages for collecting the necessary patient information. The protocol-design process overall is similar to a paper-based trial, but with the key advantage of speed afforded by the electronic medium.

Because user satisfaction with the technology would determine long-term success, Janssen surveyed its physicians to evaluate their experience. A strong majority of the doctors indicated they would rather not return to paper-based trials.

The ROI

The cost per page of data gathered during trials has decreased for Janssen, but greater ROI has emerged around data quality and data accessibility.

The eSource model has dramatically changed the way Janssen's trial monitors work. Rather than travel to numerous sites nationally or globally conducting protocol-compliance checks, monitors now examine the data being collected and fully manage trial processes from their home or office via a secure Web portal. They can, for example, query sites and generate data-correction forms with near-real-time speed. Monitors still usually visit investigator sites to initiate or end a trial, but their travel costs have been reduced significantly.

Also, fewer queries and data corrections need to be issued from monitors because automated edit-checking functions in the investigator's software intercept data-entry errors before they are logged. On-the-fly cleaning of data, which is immediately indexed and fully searchable, is estimated to permit Janssen to close its database two to four weeks earlier than previously possible with paper-based trials.

A faster database lock will enable Janssen to submit a new drug application (NDA) for FDA approval faster, or publish a Phase IV trial follow-up study sooner. This time saved is money saved—potentially millions of dollars in opportunity costs.

Spreading eSource

Janssen initially considered building its own eSource software, but recognized that conducting clinical trials was not its core competency. Marrying the technology and the clinical experience would be difficult.

Moreover, such in-house development would require large investments in support infrastructure and services. The industry adage is that efficient and effective EDC is 30 percent technology and 70 percent process. It was more economical and practical to engage Medidata to host the system in its own data center and provide help-desk support to users and continue to invest in future functionality.

Janssen collaborated on the development of Medidata Rave Remote and provided requirements that ensured the software met all of Janssen's parameters and were fully field-tested. The two companies have agreed to make the software available to other pharmaceutical firms that wish to leverage the advantages of eSourcing.

Louis Pozzo is manager of clinical trials and relationship management with Janssen Pharmaceutica, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, (609) 730-2000, fax (609) 730-2323, www.janssen.com.

Glen de Vries is chief technology officer with Medidata Solutions, Inc., 79 Fifth Ave., 8th floor, New York, NY 10003, (212) 918-1800, fax (212) 918-1818, www.medidatasolutions.com.