Innovation in Ethical Review

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Institutional review boards (IRB) are independent organizations officially designated by the FDA to review and monitor research involving human subjects. An IRB's primary responsibility is to ensure that all appropriate steps are taken to protect the rights and welfare of humans participating as subjects in research, both before and during studies. IRBs serve a vital oversight role in the drug development and clinical trial process. In accordance with FDA regulations, the IRB has the authority to approve, require approval modifications, or disapprove research.¹

"The problem of clinical trials generating mountains of paperwork is legendary," said Louis Pozzo back in 2005² and not much has changed. The mountains of paper and the time to manage it represent an enormous expense to study sponsors, contract research organizations (CROs), and the environment.³ The review of protocols by the IRB is no different. Running the day-to-day business of an IRB requires a great deal of internal and external collaboration, managed by strict access controls. As a result, the process is incredibly document-intensive—a situation with inherent legal and compliance shortcomings, not to mention the time and money spent on document tracking, transporting, and archiving, let alone the paper itself.

Transformation process

Copernicus Group IRB (CGIRB), based in Research Triangle Park, NC, is a case in point. In 2006, 10 years after its founding, the company started an initiative that would soon make it the first large-scale IRB to transition to electronic paperless management of the entire clinical trial review process.

In 1991, FDA began discussions on the use of electronic records in lieu of paper records, resulting in the issuance of the final rule "21 CFR 11" in 1997^4,5—it took some time after that for organizations to interpret these guidelines and become truly compliant. In the case of CGIRB, by 2006, fully 96% of documents submitted to the IRB for review were received electronically via digital fax, portals, and e-mail.

New guidelines stipulated that regulatory decisions could not be made on any electronic document that did not meet Part 11 Validated System requirements. CGIRB had not yet conformed to Part 11 at this time; thus, all incoming electronic documents had to be printed out on paper and filed in the individual study and investigator files (within a regulated, access-controlled file room) for audit and archival purposes. Copies were also created and couriered to board members for review. Compounding the issue, whenever a member of the review board needed to access archival documents, a CGIRB staff member had to search through the massive paper archives and then courier printed copies to the board member. After review, the signed outcome letters were again copied and shipped to clients and sites, filed, and stored.

CGIRB was generating the equivalent of a 22-foot stack of paper every week—approximately 55,000 pages, or 2.86 million pages per year. These physical documents needed to be managed, circulated, filed, stored, and ultimately destroyed. Because research studies can continue for 10 years or more, the number of legacy paper documents that had to be kept available for review was staggering—and growing daily.

Goals of the paperless initiative

When CGIRB first began reviewing ways to reduce its production of paper documents, the company's goal was simply to develop a new way to handle incoming electronic documents. However, early in planning, CGIRB realized it was possible to become a completely paperless company throughout the entire review process, including the archives.

The goals of the project were:

• Increase organizational responsiveness

• Reduce time associated with file requests, audits, and submissions

• Enable full-text search of all live and archived documents

• Enforce security

• Provide regulatory compliance surety

• Protect and archive institutional knowledge

• Conserve personnel resources

• Reduce the need for paper for cost, shipping, storage, and environmental reasons

In the end, CGIRB scanned 1.5 million legacy documents—totaling 5 million pages—plus all outcome documents and all inbound paper and electronic documents. The company also reinvented every single process and workflow it had developed in its 10 years in operation, including extensive systems integration with its internal protocol tracking system and customer-facing portal. Perhaps most importantly, the project stimulated a new culture of change management and innovation for CGIRB's employees. Today, 98% of CGIRB's operations are managed electronically from start to finish.

New collaborative process

As an outgrowth of this conversion initiative, CGIRB was able to launch an entirely new electronic collaborative process known as CGIRB Connexus® through which study managers, CROs, and the IRB could interface. Built on the Xerox DocuShare® platform, Connexus captures and electronically manages every stage of IRB documentation—a comprehensive tracking/audit database and electronic document repository that solves the complications inherent in managing ethical review of clinical research protocols.

Acting as a "command center" for the entire IRB review process, Connexus provides CGIRB, study managers, sponsors, and CROs with 24/7 access to manage submissions in motion. It also provides study managers with unprecedented new oversight capabilities that transform the entire IRB review process. Fully FDA 21 CFR Part 11 compliant, Connexus provides a full audit trail, enabling client organizations to fulfill regulatory demands quickly and completely.

Benefits of the initiative

Independent review boards (IRBs)

• Is entirely electronic Part 11 compliant

• Enables more efficient and precise board reviews

• Allows unprecedented Internet access to documentation

• Speeds and eases sharing and transporting massive amounts of information

• Improves review cycle times by reducing time to process requests from one hour to several minutes

• Reduces time for employees and auditors during routine FDA and sponsor audits

• Reduces time and money spent on storage space, document handling, shipping, supplies, and personnel

CROs and sponsors

• Accelerates the clinical research start up cycle, allowing companies to get drugs to market faster

• Reduces administrative tasks, allowing CROs to function more strategically

• Allows immediate 24/7 access to review status

• Provides easier study transition from startup stage to project management stage

• Improves customer service through greater transparency

• Allows the CRO to review study status and completion of site documentation

Going paperless: a staged approach

It is important to note that a very strategic staged-in approach was necessary to take an organization of this magnitude paperless while maintaining compliance, effective audit trails, and the ability to locate a document at any point in time in the process. Others embarking on this process would benefit from a similar approach.

Stage one implemented Xerox's DocuShare document management system out-of-the-box to introduce employees to the system's basic navigation and use. Non-regulated documents were used so that staff could become familiar with the system without interfering with protocol and security.

Stage two involved a massive document-scanning initiative to convert all active clinical study documents from paper to read-only PDF. A bulk upload utility transferred the documents into DocuShare, where they were available to all staff for reference purposes.

Stage three introduced 21 CFR Part 11 compliant e-signature functionality and paperless workflow to CGIRB's processes. Coupled with revised policies and procedures, this allowed CGIRB to make all regulated decisions entirely from electronic records.

Stage one: non-regulated documents. In mid-2008, CGIRB teamed with Sitrof Technologies to install the Xerox DocuShare software. During this stage, Docu-Share was configured to manage CGIRB's non-regulated documents, such as vacation requests, business development information, training information, PowerPoint presentations, spread sheets, status reports, RFIs, and contracts. The stage started with documents that did not require Part 11 compliance, giving the staff time to become familiar with DocuShare—working through process changes, customizing the software, and ensuring full buy-in before Sitrof installed its compliance module a year later.

To improve adoption, CGIRB created employee subcommittees, focus groups, best practices teams, and regular team project meetings. These subgroups examined existing standard operating procedures and processes throughout the transition. Implementing change gradually and systematically generated employee ownership and encouraged people to bring "solutions" rather than "problems" to the table.

Stage two: scanning five million pages. To become truly paperless, a major legacy scanning operation was necessary. CGIRB hired a local outsourcing firm, SCDATA, Inc., to work on-site, scanning, indexing and archiving five million pages of legacy paper documents—with more than 200,000 pages being processed per month.

Initially, the scanned documents were available through a DocuShare "e-file room" for read-only purposes. This allowed users to become familiar with the application and with electronic record management in general. But because the system was not yet Part 11 compliant for decision-making, the original paper was still routed to board members. Thus, before stage three, users had nearly a year of hands-on experience with the new system.

In addition to making a certified and trustworthy scanned duplicate, each page was converted to digital text through optical character recognition (OCR), allowing full text search of all five million pages. This strategic innovation added minimal incremental cost while significantly increasing long-term value, usability, and ROI. Adding OCR and full text search was very forward thinking at the time and dramatically streamlined the clinical research process. Each document was also compressed to within 5% of its original scanned size. The OCR and compression process continues today for all newly entered hardcopy and electronic documents.

Stage three: compliance and implementation. Much of what a review board does can be thought of as "case management." Each "case" goes through a series of status changes throughout its life cycle. Adding Sitrof's DocuShare Compliance Module provided a robust document management collaboration tool to support CGIRB's mission-critical functions. Features of this module include electronic signature capabilities and a "change status" function.

Closing out the stage was full implementation of CGIRB's proprietary Connexus system.

Dramatic results across the board

CGIRB was able to transform from a heavily paper-centric company with millions of pages of legacy documentation into a completely digital, paperless organization in less than two years. Going paperless enabled the IRB to perform more thorough, efficient reviews by providing secure access to all electronic documentation and data for current, pending, and past studies. As a result, CGIRB reduced expenses and created a greener work environment by all but eliminating paper, printing, storage, shipping, and other document handling costs.

CGIRB's paperless initiative has in turn created downstream benefits for its clients, members of its board, and its employees. Many of those benefits can be quantified as efficiencies and cost savings. Other benefits, such as a culture of innovation and change management, are less tangible—but still critical to the success of CGIRB and its ongoing system improvements.

"In a regulatory world, it's all about being accurate and on time," said Barry Mangum, Director of Clinical Pharmacology at Duke Clinical Research Unit, and one of CGIRB's clients. "We need to make sure that we have the right version control. We need to make sure that we have the right regulatory documents in the right place and engaged at the right time so we can get IRB approval."

Board reviews. The CGIRB board meets at least twice a week to deliberate new protocols and other research submissions to ensure the protection of human subjects. Deliberations often involve the review of documents containing pharmaceutical or medical terminology. Performing keyword searches electronically enables more efficient, productive reviews. Answers are found much more quickly compared to poring over paper documents—all while maintaining the benefits of a face-to-face meeting environment.

Compliance. The application of electronic signatures through a validated compliance module in the document management system meets requirements of 21 CFR Part 11. CGIRB employees who previously hand signed hundreds or even thousands of paper outcome documents may now sign them electronically by using a unique username and password.

Reduced shipping costs. CGIRB's clients may access all study documents through a secure web portal via Connexus. A Connexus alert function sends an e-mail to study contacts when a submission is completed/filed within the document management system. The e-mail prompts the client to log into Connexus and access the documents. In contrast, shipping hardcopy approvals can cost $15 to $20 per site, so savings quickly add up for the study sponsor if a clinical trial has a large number of sites.

Efficient file requests. In 2006, CGIRB's document control team received and filled 6,676 file requests. In 2007 file requests increased by 28%, with the average time required to fill them increasing by 40%. By contrast, once the paperless transition project was completed, in 2009 the document control team filled only 260 requests. For 2010, the team received no requests whatsoever—CGIRB staff is relying completely on the paperless system for searches, retrievals, and document queries.

Prior to implementation of the paperless system, three document control staff members worked full time filling file requests and refiling documents in the file room. These people were reassigned to other more business-critical tasks.

Audit improvements. Audits by outside clients are a common and frequent occurrence in a regulated industry. Before the paperless transition, two full-time document control employees would spend a total of approximately 80 hours for each audit, locating and sorting files and preparing file folders. Today, just one full-time employee spends only one to two hours preparing for each audit—a reduction in time of roughly 98%.

Submission processing time reduction. An analysis of 100 submissions for new principal investigators—submitted to CGIRB via traditional methods such as fax, e-mail, or hardcopy—showed that an average of 104 minutes passed between receipt and creation of the submission package by staff. This time dropped to just 3.4 minutes (N=100) when the submission was made through Connexus. Submissions that arrived via e-mail (N=21) used to wait an average of 128 minutes before creation of the submission package. Today, new protocols submitted via Connexus wait only 2.1 minutes.

Equipment and supply savings. The CGIRB paperless initiative quickly created dramatic cost savings in equipment and supplies. When CGIRB performed paper-based reviews, documents, or e-mails had to be printed in order to get them into a manual workflow. These print jobs consumed large quantities of paper and toner. More than 1,000 cases of paper were purchased in a typical year. Today, annual paper purchases have decreased by over 75%, to 240 cases.

CGIRB used to incur significant shipping and courier costs prepared for its twice-weekly board meetings. Board members received a package every Friday (Saturday for out-of-town board members) containing paper documents to review at upcoming meetings. Courier fees and fees for overnight and Saturday deliveries totaled $1,000 per month. In addition, to prepare the board members' packets, CGIRB staff used a photocopier whose monthly lease and maintenance fees totaled $1,700. By contrast, Connexus has allowed CGIRB to eliminate courier and shipping fees and the photocopier, resulting in annual cost savings of more than $30,000. In total, CGIRB estimates that its annual savings on office supplies (e.g., shipping, postage, paper, and toner) will be $160,000.

Lifetime savings: $2.6 million. CGIRB estimates its total cost savings will be more than $2.6 million. This figure includes office savings (courier/shipping, postage, and associated supplies) and increased productivity. That figure is expected to increase as more data becomes available to reflect efficiencies realized by the use of CGIRB Connexus®.

Conclusion

To safeguard the rights, safety and welfare of human subjects, clinical research is a shared responsibility among sponsors, investigators, CROs, and IRBs. More expedient collaboration, sharing of documents, and quick review of protocols will ensure new products safely get to market in a timely fashion.

Efficiency, cost-savings, compliance, competitiveness, eco-friendliness—all are dramatic benefits that a paperless solution brings to the review process. In the end, the most important benefactors of this kind of paradigm-breaking initiative are the clinical trials subjects themselves.

Jennifer Sodrel is Director of Information Management at Copernicus Group IRB, PO Box 110605, Research Triangle Park, NC, e-mail: [email protected].

References

1. US Department of Health and Human Services. "Guidance on IRB Approval of Research with Condition" (http://www.hhs.gov/ohrp/policy/conditionalapproval2010.html)

2. Louis Pozzo and Glen De Vries, " Paperless Progress," Applied Clinical Trials, October 2005, 66-67.

3. Ken Lownie, "In Search of Paperless Clinical Trials," Infonomics Magazine, July/August 2009.

4. Food and Drug Administration, Electronic Records; Electronic Signatures, Title 21 Code of Federal Regulations (21 CFR Part 11).

5. John Farrell and Michael Cooper, "Navigating the New 21 CFR 11 Guidelines," Applied Clinical Trials, March 2004, 67-70.