Vito Anthony Losito

As pharmaceutical companies face intense pressures from looming patent expirations, weak drug pipelines, and heightened competition, they are implementing new technologies to improve operational efficiencies in clinical trials and speed drugs to market. Document workflows in a clinical trial environment require coordination of tasks and people from multiple organizations including the study sponsors, CROs, investigator sites, academic institutions, and research ethics boards. During study start-up and throughout the course of a trial, a number of essential regulatory documents have to be processed in a short period of time. Most recently, CTMS and investigator portals have automated trial master files (TMF) and regulatory workflows and played a central role in enabling companies to expedite study start-up while significantly reducing costs, improving collaboration and data management, and speeding site/study initiation.  

A TMF consists of thousands of pages, and includes everything from regulatory documents, correspondence, and data to documentation that supports compliance with local regulations. With paper-based TMF systems, managing documentation is a time-consuming and cumbersome task that often involves eliminating duplicates (generated in multi-center clinical trial environments where documents reside in various organizations and/or across geographical regions), replacing lost documents, scanning, indexing, and filing. Ensuring that all required documents are included in the final TMF, with required approvals, and managing metadata also become arduous tasks when using a paper-based system. With an eTMF solution, however, all documentation—including documents from sponsors, subsidiaries, CROs, and field-based personnel—is located in a centralized place, making it readily available for viewing and tracking by trial personnel from any geographic location. eTMF solutions also allow assembly of the TMF to occur gradually during the course of the study. As such, eTMFs accelerate the production, review, approval, and submission stages in addition to eliminating time-consuming and costly processes that diminish clinical trial efficiency.  

EntraLogix, a site management organization that developed an investigator portal solution for its own needs, which is now commercialized, reports cutting study site initiation time from an average of 102 days to an average of 49 days through the use of its investigator portal system. By automating the clinical development process and cutting down the days to site initiation, CROs and sponsors can potentially gain valuable time to market their approved compounds under patent protection. 

Second generation investigator portals are web-based collaboration platforms designed to aid in TMF management. The TMF consists of regulatory documents as well as artifacts related to the clinical trial that permit the evaluation of the trial conduct and quality of the data produced. The latest portal technologies leverage enterprise-level collaboration, document management, electronic forms, and digital signature technology to integrate the TMF with investigator site files (ISF), data, and metadata. These new clinical trial applications handle documents electronically throughout the entire document lifecycle, and cover all steps from site selection to study close out. Third generation investigator portals are designed and developed specifically for TMF requirements. Using enterprise level portal/application technology such as Websphere or Weblogic, the clinical trial web applications offer a full set of features for online collaboration, regulatory document processing, and data integration. Through document workflow and task management capabilities combined with electronic forms and digital signatures, organizations are using these investigator portals to streamline operations while significantly shortening timelines, reducing costs, and speeding development.  

With investigator portals, life science companies are also meeting the desire of regulatory authorities to have clinical documents submitted electronically. One of the key initiatives of investigator portals is referred to by the FDA as "Leaving the Paper-Based World Behind—Creating an All-Electronic Environment for Managing Data on FDA-Regulated Products."

  The Agency has been developing standards and systems that will enable the electronic receipt, management, and storage of FDA-regulated product information. The FDA will use the Janus data warehouse to store and manage study data about the products it regulates, as well as clinical study information. Further, data exchange standards are being developed to provide a consistent way for information across organizations to be handled and to ensure that sending and receiving systems both understand what information is being exchanged. This is a significant leap forward as it demonstrates direct exchange of data from the systems of life science companies to the FDA's system. Whereas transmission of scanned PDF documents provides information that is static, difficult to query, and non-relational, electronic forms allow end users to enter, retrieve, and display data, while digital signatures are used to authorize it.  

In the past 12 months, EntraLogix has been using an eTMF system built on enterprise level portal web application technology, electronic forms, and digital signatures. The company started eight new clinical trials and reduced its average study start-up from 102 days to 49 days from initial site contact to site initiation. EntraLogix's regulatory documents remain in electronic format from conception to archiving. Digital signatures are a key part of the solution because investigators sign documents from their computers, regardless of their geographic location. Equally important, digital signatures allow maintenance of an eTMF without the need to digitize documents. Figure 1 uses a financial disclosure form to demonstrate how documents are processed electronically. 

 Figure 1. Investigator portal process broken down into five steps.			

Investigator portals have evolved from information gateways to web-based automated eTMF applications that allow online collaboration, centralization of documents, and control over the regulatory process. These systems are built on business process automation, and the integration of disparate applications, workflows, and data.  

Possibly the most important factor to consider when evaluating an eTMF solution is the portal's adherence to standards. An eTMF solution must be able to easily integrate with disparate applications. To be able to integrate, the portal technology used needs to comply with Java Portlet Specification (JSR) 168. This enables interoperability among portlets and portals by defining a set of APIs for portlets and addresses standardization for preferences, user information, portlet requests, responses, deployment packaging, and security. Examples of compliant portal technologies are: BEA Weblogic, IBM Websphere Portal, and Oracle Portal. 

 Instrumental to business process automation is the electronic form. Aside from eliminating the hassle and cost associated with printing, distributing, and archiving paper forms, electronic forms can be completed more quickly because they can automatically format, calculate, look up, and validate information for the user. Further, with digital authorization and routing via  secure web server, review and approval cycle times can be significantly reduced.  

Electronic forms initially emerged as a means to replicate a paper document on a computer screen. Today, electronic forms provide a richer, interactive environment for end users. For instance, an investigator attempting to complete a financial disclosure form can be guided through the process of completing the form. After investigators have completed the electronic form they simply submit it online. The next person in the business process, such as the sponsor's document reviewer, is then automatically notified to review and approve the form online.  

Digital signatures allow source documents to be signed and maintained electronically without ever introducing paper into the process. They eliminate the cumbersome processes of printing, routing, scanning, and archiving paper documents solely for the purpose of obtaining signature authorizations. Further, digitally-signed electronic records are compliant with worldwide regulations including the FDA 21 CFR, Part 11. As a result, they provide legally enforceable electronic records that are recognized by sponsor organizations and regulatory authorities. Organizations that implement automated eTMF solutions with digital signatures benefit from expedited business processes and significant cost reduction, while maintaining legal and regulatory compliance.  

It is essential to understand the difference between "digital signatures" and "electronic signatures." Digital signatures are a sub-category of electronic signatures that provide heightened levels of integrity and non-repudiation. Whereas proprietary (closed-system) electronic signatures can only be trusted and verified within a specific application, standard digital signatures allow any party to verify the signature for signer identity and intent, and content integrity, regardless of the system(s) they are using. In eTMF solutions, digital signatures have various advantages, including: open system trust, where signed electronic records are portable, sustainable, and completely self-contained; security, where non-repudiation is ensured and indication of tampering is always provided; and compliance with the strictest industry regulations. 

Investigator portals with integrated digital signature capabilities enable the various participants in a clinical trial, including sponsors, CROs, investigators, and IRBs, to sign the documents that constitute TMFs. These documents include NDAs, financial disclosures, 1572s, CVs, protocols, IRB approvals, informed consents, trial agreements, contracts, certifications, safety letters, drug shipment and handling forms, delegation of duties forms, and others. Digital signatures are also being used to authorize project plans, internal audit reports, archiving forms and expense reports, as well as in other clinical activities such as site monitoring reporting and site close out reports. By enabling the participants in a clinical trial to digitally sign off on these electronic documents, delays, costs and low-level security associated with paper-based documentation are eliminated. In addition, since the documents are being created, signed, and distributed electronically using standard digital signatures, any party with access to the documents can verify the signer's identity and document content integrity—inside or outside of the investigator portal. 

When evaluating the digital signature solution in use with an automated eTMF system, it's important to ensure that the signature solution is intuitive for site personnel. A digital signature solution that requires extensive training will not be adopted as easily or quickly as one that is intuitive and simple for end users to adopt. This carries the risk of reintroduction of paper into the regulatory workflow for signature authorization purposes, which would consequently delay site initiation and other processes in addition to incurring added costs. It is also important for the digital signature system to allow for easy system administration including the ability to quickly add signing permissions to remote personnel, and also remove signing capabilities once the signing requirements and/or study are completed. 

The use of eTMF is well underway, and certainly beyond the early adoption stage. Well-designed eTMF solutions that make it easier for organizations to manage the investigator site file and related documents have been well-received and easily implemented across hundreds of sites.  

The bigger challenge to adoption of eTMF solutions are the life science companies. With workflows and processes that span many disparate systems, hundreds to thousands of users, various departments, different geographic locations, and well-established standard operating procedures, implementing an eTMF solution naturally seems daunting. Thankfully, experience with eTMF solutions has shown that there is a golden path for successful implementation within life sciences organizations.  

The first step is to develop a vision for your organization. Implementing a good eTMF solution is a gated process that takes between two to five years. The eTMF solution should be a transactional system that includes electronic forms and digital signatures, and captures data in a relational database system. The system should be a robust, external-facing portal web application with functions for all clinical service providers including investigators, site personnel, IRBs, auditors, and third-party vendors. Further, it should include integration with existing internal-facing document management systems and data exchange with organizations such as the FDA.  

With a vision in place, it is possible to start developing the requirements that your organization needs to achieve the end goal. List, in no specific order, all the functions your eTMF solution must be able to do. In addition to a functional requirements list, you also need to consider the technical requirements. There are a number of important technical items to consider when looking at purchasing or developing an eTMF solution that are consistent with the industry's migration to paperless clinical trials. First, the future of clinical trials will depend heavily on data interchange; as such, your eTMF solution must be designed and built for data interchange. The solution must have electronic forms that produce pure XML. Also, the electronic forms must be able to capture data in a relational database. The electronic forms must be compliant with ODM and HL7 standards. Lastly, the electronic forms must be integrated with a compliant digital signature solution. Second, your solution should be J2EE compliant as there are a number of important advantages to this architecture. With J2EE servlets and portlets, the solution can use server-side to process all requests such that the client only needs a web browser. Also, J2EE is a services oriented architecture with compliance with a number of important standards, making integration with back-end document management systems and data interchange much simpler. 

With functional and technical requirements in place, it is now time to investigate the eTMF solutions available on the market. If you can find a commercial eTMF solution that meets the top 80 percent of your requirements out of the box, the chances of successfully implementing the system are very high. With your solution selected, it is time to plan the implementation gates for key functions. When it comes time to start implementing your eTMF solution, start with the most fundamental piece: a portal for all the TMF documents. Documents that must be printed for signatures are digitized during the study and placed in the eTMF. The first stage of implementation should include functions for all the clinical service providers to track and manage their documents electronically. The second stage of implementation should include the implementation of electronic forms and digital signatures. This will significantly reduce the need to digitize, index and file documents. Document, workflow, and task management is now completely electronic and spans the entire spectrum of clinical service providers regardless of organization or time zone. This is when significant gains are made in productivity and study start-up times are significantly shortened. The final stage of eTMF implementation is integration with existing internal document management systems and data exchange. 

Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products

 is Director, Clinical Trial Systems at EntraLogix Systems Inc., 38 Prospect Street, Newmarket, ON, L3Y 3S9, e-mail: 

, is FDA and USDA Markets Manager at ARX.

*To whom all correspondence should be addressed. 

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