About The MarCon System for Clinical Research

The MarCon System is a fundamentally new platform for the conduct of clinical research. Here we describe the major advances offered by The MarCon System.

J2EE Platform and Scaling

The MarCon System is built using the Java 2 Enterprise Edition (J2EE) platform, the most popular enterprise platform for Internet applications available today. J2EE provides unprecedented scaling and is used for airline reserevations systems, on-line shopping applications, banking systems, real-time stock trading and other mission-critical e-business applications. J2EE is designed to handle the largest IT problems. Used in conjunction with Oracle, there is no theoretical limit to the number of users, records, trials or other entities that can be processed by The MarCon System. Additional capability can be gained by adding hardware (servers and diskspace) and bandwidth. The MarCon System scales.

J2EE and Object Orientation

The J2EE platform is "object-oriented" which means that the software is organized into objects which have attributes (data values and properties) and methods (functions or processes). So, for example, a Protocol object contains information regarding eligibility, the time and event schedule, informed consent, workflows and more.

Object orientation simplies the production of consistent code. If the system works a particular way for one service it is likely to perform exactly the same when that service is reused, because the service is provided by the same object in each case. So, for example, validity rules are specified once and can be executed on the browser or on the server. We can be sure the rules that are executed are the same, because they are produced by the same object.

Object orientation simplifies reuse. A form that was used in one protocol can be reused in another, merely by naming the form. There is no "cut and paste" or reprogramming. Reprogramming and "cut and paste" are complex, costly and introduce the possibility of errors. The MarCon System supports reuse throughout the system.

J2EE and Model-View-Controller (MVC) Architecture

Model-View-Controller Architecture, originally developed for graphical user interface applications has been adapted by the development team in support of web-based applications. Often referred to as "Model 2" in the Java literature, MVC separates three core functionalities of the application. The "Model" contains the clinial trial logic and stores the data. It operates independently of any references to the web or to other technology. It is technology independent and this makes it highly reusable and highly survivable as technology changes. The "Controller" insures that the system can be operated by processing a simple series of commands. This makes the interface interchangeable and reduces the effort required to support new devices, and languages. The "View" presents data to the user and collects input from the user. It is the least survivable of the components and is built for flexibility. It may need to be disposed or rewritten in the future as needs change and technology changes. The View in The MarCon System is written using Java Server Pages (JSPs), a JSP TagLIB (reusable software components to insure uniform display of objects such as forms and reports), and Extensible Markup Language (XML). XML permits the interface to be validated and to display using different "styles" for different circumstances (see below).

MVC and Multiple Web Interfaces

By separating the View from the Controller and the Model, MVC simplifies the work of supporting multiple interfaces. The MarCon System can support multiple languages, including languages such as Chinese and Japanese. Sponsors may find that the best interface for a community-based Phase IV trial is not the interface that would be best for a single-site Phase I trial.

MVC and Multiple Device Interfaces

By separating the View from the Controller and the Model, MVC simplifies the work of supporting multiple devices. Cell phone Wireless Access Protocol (WAP) may be useful to provide a smplified clinical trial interface for some work. Handheld devices and devices to be invented may need to provide data to the MarCon system. Alternate controllers can be built to support input from alternate devices and submit commands to the Model.

A "batch" interface can be used to send streams of commands to the system. This enables the integration of remote system data into the MarCon System while assuring that all aspects of the MarCon system - workflows, authorization, audit trail, SOPs are in force just as they are for the web interface.

Forms

The MarCon System forms are generated from data stored in Oracle. Form definitions can be created and stored and forms are displayed from their data definitions. No programming is required to create new forms. This greatly reduces set-up time, and since forms are objects, they can be instantly reused if needed. New forms can be created from old forms and modified as needed.

Forms are displayed using XML stylesheets. This allows each form to have its own "look and feel" -- different fonts, color scheme, layout, graphics. Groups of forms can easily have a consistent look and feel. So, for example, an Adverse Event Form might use an FDA style, a CRF might use a sponsor style scheme. A trial might use a custom style. The MarCon System thus separates the logic of the form from the presentation of the form. Stylesheets are reused and easily maintained.

The MarCon System forms approach has no parallel in the industry.

CDISC

The MarCon System supports CDISC input and export. Any form, or collection of forms can be exported into CDISC format (CDISC format is an XML format) for transport or input into another system supporting CDISC input. A CDISC "document" can contain one or more CDISC forms. The MarCon System supports CDISC input by creating MarCon form objects for each CDISC form and signable unit in the CDISC document. A new (empty) protocol will be created if needed and associated with the input forms. A default time and event chart (see below) is created which can then be edited to create workflows and time periods.

Authorization

The MarCon System contains a new and powerfully simple authorization system for controlling access of users to workflows. All work in The MarCon System is defined in terms of workflows. To perform a workflow, the user must have an appropriate Role. For example, Tom may have "Data Entry" role which permits Tom to view empty forms, enter data into forms and view completed forms. The role may not authorize editing of forms, which may be reserved for a different role. Roles may be customized and created in response to study needs. Roles may contain other roles. Roles will vary from sponsor to sponsor, and from trial to trial, allowing different organization of the wrok as needed.

Each role has a scope which defines the objects on which the role may operate. So Tom's Data Entry role may have scope "Site=152" while another users Data Entry role may authorize multiple sites using a different scope. Since Scope and Role are objects, they are easily reused.

The MarCon System authorization features are the most sophisticated in the clinical trial industry and will support every combination of user, role, scope and workflow. The system may be the most flexible authorization solution yet designed for access control software with applications in hospital information systems, financial systems, and commercial systems.

The Protocol as Software

The MarCon System uses a protocol object to define and execute the clinical trial. The protocol object contains the following objects.

• X-chart The time and events schedule for a clinical trial is called an X-chart in The MarCon System due to the common industry practice of representing the schedule using time periods across the top, workflows along the rows and "X"'s in the table to indicate that the workflow should be performed in the indicated time period. The X-chart defines the workflows for the trial, the time-periods for the trial and the relationship of workflows to time-periods.
• Eligibility Rule The eligibility rule for the protocol is stored as a software object. All rules in The MarCon System use the same underlying object to insure consistent performance. The eligibility rule can be applied to study subject data using the "Deterine Eligibility" act. Using the modular approach, The MarCon System can support the determination of eligibility in an entry workflow, as seen in INVEST, following a screening visit, in the background as lab or other results are obtained or in any part of the trial.
• Randomization Method The type of randomization that will be used in the protocol. Other randomization methods are easily added.
• Protocol text The full text of the protocol and any suporting documents are stored.

Since the protocol is an object, it is version controlled and audited as with any other The MarCon System object. This greatly simplifies the programming logic needed to enable different study sites to use different versions of the protocol. This is often desirable in large clinical trials where local IRBs may approve versions at different times.

Query Management

While web-based data entry at the study sites with front-end validation greatly reduces the need for queries and their management, The MarCon System provides a full-featured query management system fully-integrated with the rest of the system. Data managers can use the query management features to search for suspicious data values and tag them, then track the resolution of the query for each data value. Data values can be marked with query information and value histories can be obtained showing how and when each value came to be in the database.

Addresses

The MarCon System contains sophisticated contact information management features for storing address information. Unlimited types of addresses can be defined and stored without programming. For example, an investigator might have an office, home, shipping, billing, and summer address. Each address can have parts that can be defined as needed. International addresses are supported as well as any combination of address parts such as cell phone, mobile phone, fax number, pager, alternate cell, car phone, and any other. Address parts can be defined, stored and used without additional programming. An address can have an unlimited number of named address parts.

Addresses can be read and written, sent and received, in V-card format defined in Internet Request for Comments (RFC) documents RFC 2424 and RFC 2426 which define Internet-standards for representing address information using XML. Many applications support the transfer of contact information using V-cards. Microsoft OutLook, for example, sends and receives V-Cards.

Addresses are used throughout the system as contact information must be managed for sites, investigators, subjects, users, and contacts (prospective sites).

Documents

The MarCon System contains an integrated document management system which can store documents in any format including Microsoft Word, XML, plain text, PDF, HTML, and images and images.

Documents can be uploaded and downloaded, version controlled, audited, and attached to objects to provide additional information for users of the system. For example, standard operating procedures (SOPs) can be attached to workflows so that the current audited procedure for executing the workflow is always available. Other specialized documents such as Informed Consents, Protocol text, Investigator brochure, Investigator 1572 forms can be managed using the MarCon System.

The document management features in the MarCon system are fully integrated with the clinical research process. This is new for the industry. By fully integrating documents and workflow, the MarCon system provides unprecendented access and management to trial documents in a regulated environment and with a simple and consistent interface. By providing these features in the clinical research platform, the MarCon System eliminates the need for complex, costly, stand-alone systems for document management.

Calendar

Completed work is recorded. Proposed work is represented on the X-chart. For any combination of completed and proposed work, the MarCon System can present a calendar -- of work completed, work to be completed, or both. Calendars contain hot-links to the work.

Site Management Organization (SMO) Features

Sites, Investigators, Subjects and Studies are all objects in the system along with their natural associations (StudySubject, StudySite, StudyInvestigator). Performance of Sites is tracked to create Site dossiers which can be used to attract sponsors and reward high performing sites. Automatically entered and maintained metrics regarding system, site, study and investigator performance can be added to the system as they are defined

Conlon and Marks are working with industry leaders to develop metrics for clinical trial performance. As metrics emerge from this process, they can be added to the MarCon System.

Digital Signatures

Digital signatures in compliance with 21 CFR 11 which are non-reputable, authentic and attributal are supported at the CDISC Signable Unit level along with support for FDA signature meaning codes.

Validated System

The MarCon System The MarCon System is fully validated for work in regulated studies, meeting and exceeding FDA standards.

Informed Consent Management

Approved informed consent documents are maintained for each study site.

Statistical System Integration

The MarCon System The MarCon System is integrated with the R language, a comprehensive open-source, non-licensed statistical computing environment. This gives the MarCon System full access to the powerful capabilities of R including statistical aggregation functions, statistical analysis functions and statistical graphics.

XML

The Extensible Markup Language (XML) is an Internet-standard for representing data and documents. XML documents can be "validated" meaning they can be held to conform to a specification. Such a specification is called a schema. The CDISC standard is an XML schema. XML documents are displayed using a stylesheet. By separating the content of the document from its appearance, XML documents can be displayed in a variety of formats. The same XML document may be run through a style sheet to produce a PDF document or run through a different stylesheet to produce a web page in HyperText Mark-up Language (HTML).

The MarCon System uses XML throughout its design to simplify its processing, produce consistent results and provide flexibility. In particular, XML is used as described below.

• Interface. The MarCon System The MarCon System web interface is generated using XML and stylesheets. This insures valid presentation, consistent presentation and easily changed presentation.
• Forms. Study forms are rendered using XML. This permits forms to each have their own style as required by the work. Groups of forms can use a common style to give a common look and feel to forms from a particular study or for a particular sponsor. Using stylesheets, forms can use artwork, layout, fonts and graphical themes as needed. No other system currently uses this approach.
• CDISC. Study data can be imported and exported via CDISC, an XML schema for representing clinical trial information.
• Addresses. Addresses can be imported and exported via V-card, an XML schema for representing contact information.
• Documents. Documents stored in XML format can be rendered with stylesheets in real-time and validated for structure. This makes XML an ideal format for SOPs and other formal documents. The document you are reading was produced in XML, validated using the DocBook schema and rendered into PDF for printing using a stylesheet. DocBook is a popular XML DTD for technical documents.
• Study Archive. Entire studies with all attributes and audit trail can be archived using XML format.

Audit Trail

The MarCon System The MarCon System audit trail provides full access to all previous versions of data, as well as full tracking of all work done on all studies.

Standard Operating Procedures (SOPs)

Standard Operating Procedures are documents that describe how the clinical trial will be conducted and how the system supporting the clinical trial will be operated. Standard Operating Procedures are the backbone of Good Clinical Practice (GCP) and compliance with federal regulations (21CFR11). The MarCon System The MarCon System integrates SOPs and their management into the fabric of the clinical research system, insuring SOPs exist and providing tools for their management.

The MarCon System supports an unlimited number of SOPs, protocol and sponsor specific SOPs and reuse of SOPs as appropriate.

Integration of SOPs with existing sponsor SOP management processes will be supported.

The MarCon System The MarCon System will be operated and managed by MarCon staff in accordance with Standard Operating Procedures developed to insure compliance with 21CFR11.

Workflow

All work in the MarCon System The MarCon System is done by workflows. Workflows may contain other workflows. Atomic work that can not be subdivided is called an act. Workflows consist of one or more acts or other workflows. The authorization system authorizes users to perform workflows.

The system contains several basic acts -- randomize, determine eligibility, show form, show report, send email, and others. These can be combined into workflows to represent visits, adverse event reporting, closeout and other typical workflows in clinical trials. As more acts are built, the span of work that can be performed by combining acts into workflows will grow.

Workflows are configured, acts are programmed. Workflows are referenced in the time and events chart (X-chart) of the protocol. Workflows are objects, so they can be copied and reused, modified. Workflows are audited so previous versions of the workflow can be accessed.

Workflows create the opportunity to represent protocol defined work in a flexible and reusable manner. Version 1 implemented half a dozen hard-coded workflows. The MarCon System has configurable workflows which can be created without programming. The MarCon System can store an unlimited number of workflows.

Workflows open up new business opportunities for MarCon. By adding acts for new domains, the MarCon System can be used for many purposes.

Study Conduct

The MarCon System creates unlimited opportunities for study conduct through application of the act and workflow concepts in concert with the authorization system and standard operating procedures. Screening, closeout, medical summary, randomization, data entry, reporting, informed consent, prescribing, titration, payment, consent, workflow summary, and eligibility determination are all acts which can be combined in flexible workflows to service the broadest range of clinical protocol requirements.

Future Capabilities

The MarCon System is well-designed for expansion and adoption of new technologies and the provision of new services. In particular, the following capabilities are anticipated:

• Web Services. Emerging Internet standards for a new type of Internet interaction is emerging under the title "web services." Web services are standardized interfaces to systems to permit their use to by modularized and assembled nto web portals for customers. With Web Services, a financial system, an HR system, a clinical system and a clinical research system might each provide services which can be assembled into a consistent customer application. The MarCon System will be available as a series of web services as standards mature.
• Microsoft Dot-Net is an an emerging technology for deploying and integrating Internet-based applications using a common authentication and authorization scheme owned by Microsoft and hosted as the Passport service. Passport is used by large e-businesses Travelocity, e-Bay, others) to provide single sign-on across e-business apps. Should the industry embrace Dot-Net and Passport, the MarCon system will integrate with it to provide a seamless user experience across e-business applications.
• Shibboleth. An open standard for single-sign across e-business applications is being developed by the Internet 2 consortium. Code named "Shibboleth" the system is designed to address the same underlying need as Microsoft's Passport system. Should Shibboleth gain ground as a common authentication mechanism, the MarCon System will support it.
• Public Key Infrastructure (PKI) Various groups, incudng the Internet 2 consortium and the Federal Government are examining Public Key Infrastructure (PKI) as a means of developing "certificates" which could be issued to individuals and used by individuals to assert electronic identity and gain access to computer systems. Using PKI, a user presents their credentials (using appropriate software interfaces and possibly a smart card to store the credentials) to gain access to a computer system rather than using a userid and password. Userid and password are easily shared, certificates are not. As the Federal Government moves forward with PKI, the MarCon System will add capabilities to support it.
• Clinical Research Program With its object-oriented structure, the MarCon System is well-positioned to add features leading to management of a portfolio of trials in a clinical research program.
• New Drug Application (NDA) Building on the management of clinical research programs and integrating in statistical reports and other elements, the MarCon System is well-positioned to add features leading to generation of a complete NDA.

There are many more features and foundations of the MarCon System that provide it with the power to scale and the power to be simple.

By using configurable workflows, rules, forms and permissions, the MarCon System is ultimately flexible and reusable. Combined with a powerfully simple web interface, the MaerCon System represents a fundamentally new platform for clinical research.

Email:   info@marconglobal.com Voice: (352) 264-7505 Fax: (352) 264-7401		Revised: 2001/09/14 18:26:31 Today: 2001/09/17 08:21:53 User: demo
Copyright © 2001	MarCon Global Data Solutions, Inc.	All Rights Reserved.