Note: The information contained is over 20 years old. The document is intended to aid startups seeking to do their first SBIR. We find that knowing what the end product looks like is helpful to getting underway.

ACME Corporation together with consultant, [], LLC, is pleased to submit this proposal to develop a Clinical Trial Data Collection System in response to the National Cancer Institute (NCI) SBIR solicitation #123456, topic 181 for []. Also, Starfleet, is submitting a similar proposal for a data collection system to support the Treatment Trials Data Collection for the Cancer Treatment Evaluation Program (CTEP).

While we plan to use a common hand-held infrastructure for both efforts, there are unique differences between imaging and treatment trials as well as different user sites and NCI staff. We believe these differences to be substantial and have separated the efforts to ensure the highest level of performance on both. We do offer NCI the opportunity to leverage the commonalities between the two efforts during Phase I and any Phase II activities.

The background of our team is particularly appropriate for the task of developing a system to support Streamlined Clinical Trials Data Collection, Using Hand-held Technology because of our depth of experience in both the NCI’s clinical trials informatics program, our innovative hand-held technology, and NSA SPOCK certified/HIPAA compliant security product developed specifically for mobile computing applications.

Given the extraordinary sophistication of biologic and information technology that goes into research and development of new drugs and devices, it is paradoxical that, for the most part, clinical trials are conducted and managed manually – on paper. Thus, it not surprising that the average time to complete preclinical drug studies, 18 months, is substantially shorter than the five years required to complete clinical studies.1 Most of the data collection, timeliness and quality problems for clinical trials are related to this fact. The recent “Armitage Report” from the Clinical Trials Program Review Group highlighted the following major problems which were mostly relating to the current inefficiencies of data collection and methodologies:

The pharmaceutical industry has recognized similar problems. Manual data management is associated with an 8% error rate-eight case report forms (CRF) out of 100 will have a significant data error. Initial attempts to reduce the time and costs by using computerized checking of manual data entry and resulted in a 50% reduction in error rates. More recently, companies have introduced online editing and error checking of entered data using web-based remote data entry (RDE) for clinical trials CRFs. A recent survey of best practices in the pharmaceutical industry showed that data error rates fell to 0.2% after the introduction of RDE.

The introduction of RDE has nearly eliminated the problem of entering invalid or out of range data. It also has eliminated inconsistent data and has significantly improved the time to resolve remaining data errors. Using RDE to collect CRFs however does not solve all of the data management problems; there are three important, site-related issues associated with CRFs and clinical trial data.

First, creating a new research project, observational study or clinical trial usually meant that investigators had to create their own unique dataset. This has led to a proliferation of unique and not easily re-used data elements within the clinical trials community. The length of time to develop the dataset and associated databases, forms and the like is prolonged and makes it very difficult to analyze groups of clinical trials. A recent study conducted by the Office of Informatics3 at NCI found that, in four large lung cancer prevention trials, fewer than 10% of the data elements within those trials were shareable among the trials (the data elements in red in Figure 1).

1 Farley, D. How FDA approves new drugs. ASM News, 54:666-670, 1988.

2 Stemerman, Gila. Successes and Failures, Presented at Barnett Symposium on Electronic Data Capture, Philadelphia, September, 1996

In addition, an analysis of eligibility CRFs from twenty breast cancer trials resulted in over 500 unique data elements. In response the this problem, the NCI, in partnership with cooperative groups and programs, started developing a common language for NCI clinical research called Common Data Elements (CDE). They were designed to become the building blocks that enable:

As a result of enormous efforts by many NCI staff and extramural participants, there are now over 5,000 CDEs managed within the NCI’s cancer Data Standards Repository (caDSR) that cover treatment, prevention, selected aspects of imaging trials and other areas. Thus, ACRIN’s use of CDEs and common toxicity criteria (CTC) appropriate for imaging trials will significantly reduce the time to author and implement imaging study CRFs, and enable ACRIN to perform longitudinal or meta studies, of multiple ACRIN trials.

Second, clinical trials data are collected in hospitals and clinics that treat cancer patients. This may sound paradoxical, but it relates to the simple fact that clinical data, the patient’s medical record and all the electronic systems to support it, are organized to manage and document the patient’s treatment. On the other hand, clinical trials data are organized by the case report forms of a specific protocol.

Those case report forms are designed to collect and report clinical and research data to research centers for statistical analyses. The layout of those CRFs, how the data elements are grouped, and the “look and feel” of the forms, are structured to support manual data entry into study databases. These forms do not take into account how the hospital or clinic has organized its clinical data nor the local workflow for managing patients. This requires local study staff to figure out where the data needed for the CRFs are actually located: are they in the medical record file room, the laboratory, the imaging department, etc?

The way that local data is organized seldom matches the “look and feel” of the CRFs. Finally, they must translate their local data into the formats and codes required by the CRFs. Often, each study site has numerous intermediate forms to collect data from their medical records or electronic medical systems and ‘stage’ it for transcription onto paper CRFs or into RDE forms. In fact, many sites print paper copies of their electronic CRFs, transfer the data onto them and then enter the handwritten data into the web-based remote data entry “electronic” case report forms.

This problem is further compounded as each Cooperative Group and pharmaceutical company has organized their CRFs in unique ways. Sites performing clinical trials for multiple groups and pharmaceutical companies have a bewildering array of CRFs, each with separate rules for coding, layouts, reporting and the like. Site data collection staff are required to transform and transcribe their data into the multiple different.
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formats and layouts for each CRF. This is the primary reason why remote data entry, while improving the accuracy and timeliness of data for statistical centers, has not substantially improved data management problems at sites conducting the clinical trials. Simply converting paper or electronic CRFs to hand-held devices will not substantially improve the efficiency, accuracy or timeliness of clinical trials data collection from sites. One of our key innovations is a strategy that will resolve this difficulty. The Perigrine Smart CRF system will collect ACRIN clinical trial data at the point of care and from local source systems on hand-held devices. The hand-held data entry forms will use the “look and feel” of their own data , then translate that data into ACRIN trial CRFs or into the ACRIN database.

Third, most of the clinical sites have existing medical information systems. It must be frustrating for site staff to copy patient data from their hospital, radiology, or laboratory information system(s) to paper and then walk to an RDE system and enter that same data into another computer system. Our Phase II solution will enable Peregrine Smart-CRFs to pull data from local systems to the hand-held device so that site staff will not have to reenter data that exists in a local system. They will enter only the data that does not exist in a computerized form, such as the unique research data of the clinical trial.

This approach will permit site staff to spend more time dealing with difficult data collection problems. Fortunately, radiology has been in the forefront of health information standards, developing a ubiquitous standard called DICOM to exchange medical and image data. Although there may be many different types of systems supporting ACRIN trials, the data they exchange is much more standard than in other areas of health care. It is our plan to develop tools that will map data contained in local medical imaging systems to the data specified in ACRIN CRFs using DICOM to maximum extent possible. Data collected on the Peregrine Smart-CRF system will be staged locally for submission to ACRIN databases on a schedule using CDISC standard XML documents, or it will automatically push data to ACRIN as soon as it is collected.

In addition to data management challenges described above, there are four significant technical challenges. First, the data set for a protocol may change over the course of a clinical trial. New data elements are added, some are modified and others deleted. The case report form layout often changes as well. Changes to the data set and CRFs are also implemented in the study database at the statistical center. Any system that purports to replicate any ACRIN CRF must be able to manage change and assure that all data elements and CRF changes are replicated on all hand-held devices at all sites.

Since there may be many sites performing ACRIN trials, the change management process must ensure that all sites have the same modifications to the CRFs and data elements for each protocol. As the number of hand-held devices and protocols increase at each site, the cost of keeping all the forms on each device current with the latest protocol modification becomes very labor intensive, error prone and expensive.

The innovative hand-held technology we will use to develop the Peregrine Smart-CRF system already supports central management of forms via web browser so that any authorized user in any location can create, edit and delete forms. This technology also supports automatic synchronization of forms on each hand-held device each time it is synchronized to ensure that all devices, regardless of number or location, will have the most current version of each form they are authorized to have Site medical information systems change as well. Thus, any system that collects clinical data from a site must be able to manage changes both in the structure of site provided data and to the systems that are interfaced. Again, the technology we will use for this SBIR facilitates the creation and maintenance of CRF and site form data mappings to source and to ACRIN or NCI databases.

Third, approved CDE definitions are maintained in the caDSR and, for those not yet approved CDEs, in the ACRIN data systems. One of the technical challenges will be to automatically exchange the complete set of data element definitions for all CRF data elements in an ACRIN approved trial via XML documents. We will work directly with ACRIN and NCI staff to develop the technologies needed to use and maintain the set of CDEs and DEs associated with an approved trial and will require the development of advanced terminology searching that includes NCI and ACRIN sources for data element definitions.

In addition, we will include any specifications, data requirements and standards for imaging trials that are part of the CTSU electronic reporting requirements. This will include the change management processes, exchange mechanisms, XML Schemas and software required to automate this activity. ACME plans to place any products, such as any XML Schemas, interface specifications and process or data models developed under this SBIR into the public domain to foster efficient and effective exchanges between clinical trials systems and the caDSR and ACRIN.

Fourth, moving Protected Health Information (PHI) is subject to HIPAA privacy regulations. The technology we propose for this effort meets HIPAA requirements and has obtained National Security Agency (NSA) Security Proof of Concept Keystone (SPOCK) certification. SPOCK provides the means for special government “users” to perform rigorous, hands-on testing of the vendor products to test the vendor security claims. ACME hand-held software products use a VPN product that has been through three SPOCK test demonstrations since 1995. In all tests, the special government testers upheld all claims.

The intent of this Phase I SBIR is to research and develop a system that will capture clinical trial data at the point of participation in a standardized electronic form and transfer that data to ACRIN data systems. The ACME team proposes to name the envisioned product, “Peregrine Smart CRF” for the patron saint of cancer patients. The proposed innovation, Peregrine Smart-CRF, will be “fungible” electronic ACRIN case report forms that can support mobile collection of CRF data from local data collection processes, locations and databases. The viability of the opportunity for NCI and ACRIN depends both on the contractor capabilities and the technical approach. The next two subsections provide an overview of these key indicators of viability.

1.3.1 CONTRACTOR EXPERIENCE

ACME’ consultant, [], was instrumental in developing the Common Data Elements for ] as well as its infrastructure that promotes widespread use within the cancer research community. At [], he spent over five years defining clinical trials problems and developing informatics solutions to address those problems. While [], he managed the team that developed all the [] data models, the CDEs, the design of the []. He initiated the c[] to an international standards-based metadata repository. He also supported the initial design of the Clinical Trials Support Unit (CTSU).

Through [] ground-breaking efforts, knowledge acquisition (KA) and enterprise system life-cycle activities have become de rigueur for informatics programs at NCI. He also was one of the early members and promoter of the [], an industry lead group that is implementing an XML standard for the FDA’s electronic submission requirements.

Mr. Speedy Gonzalez(ACME) is a pioneer in the development of data collection systems using hand-held technology. Mr. Gonzalez developed a hand-held data collection system called EPIC that is used to execute a 45,000-point inspection protocol for the space shuttle prior to each launch. One of the innovations resulting from this NASA SBIR is an Intelligent Form Converter (IFC). The IFC module automates the development of electronic forms. The IFC module accepts, as input, an electronic representation of the form created in a commercial word-processing program.

The IFC module then automatically converts the word- processor version, including business rules and field types, into the proper electronic format for execution on a hand-held computer. The IFC eliminates the need for software engineers and database analysts to reprogram the system each time a new form is introduced into the workflow. This system also was one of the first wireless data collection and information networks in the U.S. As such, Mr. Gonzalez was an honoree at the U.S. National Inventor’s Hall of Fame and is currently a nominee for the 2003 MIT Lemelson Inventor of the Year Award.

Moreover, ACME’ work in developing the commercially successful Michaels™ Emergency Medical System (EMS) mobile computer system for pre-hospital data collection provides us with a solid grounding in the applicable technologies and the real world issues surrounding interfacing with remote, disparate databases in an industry that lacks standardization.

The extensive relevant experience of the ACME team will enable us to establish requirements for Peregrine Smart CRF and a Phase I approach that is both highly effective and totally realistic. Our work in clinical trials informatics at NCI and at cancer centers provide the deep knowledge of the current inefficiencies of data management at NCI and at the point of care where the data is created.

Our proven track record of developing innovative and scalable solutions to these problems along with hand-held technology, gives us a clear path to develop a highly usable system that will dramatically enhance error-free and efficient collection of ACRIN case report form data at the point of care, while reducing redundant data entry.

We plan to ensure that Peregrine Smart CRF is so valuable to end users that they will want to use it for all their clinical trials data collection. They will be actively involved at each stage of our “joint” project.

At the same time, we will work with NCI and ACRIN staff to ensure that the system and its data are fully compliant with CDEs and other standards defined by NCI. We plan to design our system so that it will work with the central repository for CDEs, the caDSR formerly called the Standards-based Repository, the CTSU’s Oracle clinical database and other data repositories specified by ACRIN or NCI staff.

We will proceed through the total system lifecycle process including problem definition, functional analysis, systems analysis, and system integration and testing in an iterative fashion using KA results to inform each of our steps. The Phase I product will be a working prototype of Peregrine Smart-CRF for a complete set of ACRIN CRFs for a selected ACRIN trial. The hand-held will collect subject and clinical trial data at the point of contact and point of care and will synchronize data collected on the hand-held with a database, such as the ACRIN system.

The creation of paper or computer based forms is a tedious effort. Collecting the data onto those forms and then transferring the hand written forms into a database is even more effort and requires a substantial data quality management activity, just to ensure that the data was entered correctly. Our approach for the rapid development and deployment of mobile case report forms and/or local data entry forms for use in ACRIN trials is depicted in Figure 2.

Using the approved set of CRFs, and CDEs, trial specific DEs and the rapid Form Authoring Module, the authorized user at a site will either implement ACRIN CRFs or develop local data collection forms that are compliant with the study CRFs. Data elements will then be mapped to the site database sources and to ACRIN CRFs and the ACRIN study database. Once forms are tested and approved, forms and CRFs can be published within minutes, thus distributing the forms to all approved ACRIN Study participants.

Using Peregrine Smart CRFs, it is anticipated that users will be able to author forms that transform their local data formats into CDE standard formats and codes, develop trial-specific lists of CTCs and adverse events to simplify data entry and reporting of critical AEs. One of the innovations proposed by ACME is an IFC module, similar to the IFC developed for NASA. An IFC would enable form authoring using a commercial word processor (such as MS Word) and, if successfully implemented, would significantly reduce the costs to deploy and maintain CRFs.

Using hand-held devices, data collection personnel can collect CRF data in situ; where the data actually exists, rather than writing it down on worksheets or yellow stickies. Site staff can be connected to the host PC via wireless communication links or operate the hand-held in a disconnected mode. When using the disconnected mode, users can upload the collected data when they return to their office. Both cases, either using the web or hand-held device, have the same CDE or DE definition, data edits and consistency checks that are resident in the Form database and both submit their data to the Data Entry Module.

This on-line data checking, even if the user is remote to their work area, will significantly decrease the data entry errors as data quality checking occurs during the data entry process, not after the data is entered into the database. Remote data access will be achieved using ACME NSA SPOCK and Federal Information Processing Standard 140-1 (FIPS 140-1) certified VPN technology. This technology meets the highest level of government security standards. This technology also ensures compliance with the Health Insurance Portability and Accountability Act (HIPAA) of 1996.

During our Phase I SBIR project, we will determine system (functional and technical) requirements and configuration, assess design and development feasibility, and plan for Phase II development. The technical objectives ACME has chosen for Phase I, therefore, are designed to provide the government with a complete assessment of the potential utility of the Peregrine Smart CRF design and of the Phase II Development Plan. The Peregrine Smart CRF system will meet, at a minimum, the following functional and technical requirements:

The above functional requirements will be extended by developing additional functional requirements based on knowledge acquisition activities with ACRIN end users, ACRIN and NCI staff and the team’s knowledge of clinical trials. Second, a set of technical requirements will be compared to existing hand-held computing and data management capabilities and a proof-of-concept will be prepared to demonstrate mobile data collection of ACRIN CRFs at the point of care.

As a result of our extensive KA with users, results of the demonstration and our analyses of various designs, ACME will establish the set of capabilities required to meet the requirements. The most feasible and effective design will be used to specify a sequenced plan for Phase II development and Phase III commercialization.

The results will be a well vetted design and a detailed Phase II development and implementation plan. Together, these products will provide NCI the information it needs to determine the desirability and feasibility of the proposed Phase II system development. In addition to setting the stage for Phase II, Phase I will yield a working demonstration of the Peregrine Smart-CRF system.

ACME has developed the Phase I work plan to achieve the technical objectives listed in the previous section. The six-month work plan is designed to be effective, be realistic, and have minimal schedule and technical risks. Figure 3 shows a six month schedule for this work plan. We have used this same approach to investigate a NASA Safety and Mission Assurance, Portable Data Collection System (Phase I and Phase II SBIR), the NASA Test Control Wireless Mobile Computing Network (Phase I and Phase II SBIR), the Federal Aviation Administration Hazardous Materials Portable Data Collection and Inspection System, and the Michaels EMS Data Collection System™ described in Section 4, “Related Work.” Each of the research tasks will be performed at ACME’ laboratory in Silver Spring, Maryland.

The proposed steps combine Quality by Design planning and the Unified Process software lifecycle techniques to minimize schedule and development risk.

3.1.1 DEVELOP DETAILED SYSTEM REQUIREMENTS

All optimized and effective system design efforts are based on a detailed and well thought out requirements document. The requirements document describes the ‘vision’ of what the system is expected to do for its users, identifies the high level use cases and specifies the functions, characteristics, limitations, and operational environment of the new system. The requirements document forms an agreement between the system developers and the users for whom the system is being developed.

Based on prior experience, it is anticipated that the requirements documents will evolve in an iterative fashion through the different phases of the project. ACME has extensive experience performing KA and developing effective requirements documents as part of critical system designs for such clients as the FAA, FHWA, NHTSA, and NASA. [] is working with ACME on two pre-hospital mobile computing projects and is developing the detailed system requirements for Arlington County’s EMS data collection system.

For the Peregrine Smart CRF data collection system, the determination of functional requirements will be driven by KA collected from users and use cases that focus on the users and what they need to accomplish in collecting CRF data. User and data requirements will be analyzed and documented by the Subject Matter Expert, [] with support from the Principal Investigator, Speedy Gonzalez. A preliminary Process Planning Road Map will be developed: project-specific planning spreadsheets will be created and used to define Peregrine “Users,” and user needs, “product” features, process features and process control features. Existing NCI use cases, data models and KA information will be used during the requirements and analysis phase to the maximum extent possible.

Typical data collection workflows, products used to collect CRF data and locations where data is collected will be analyzed from KA interviews. ACRIN and NCI staff will be interviewed to define existing data forms and formats, work flow processes, current computer usage, desired capabilities, and existing data exchanges between sites and ACRIN and ACRIN and NCI. Site users, selected by ACRIN and NCI, will be interviewed to document how those users collect CRF data currently and how hand-held data collection could be performed. Local data systems, forms and collection processes will be analyzed and mapped to those of ACRIN and NCI. Specific attention will be placed on the ready availability of CDE and DE specifications of several existing ACRIN trials and how and what CRF data moves from the site to ACRIN and then onto NCI.

In addition, NCI staff supporting the caDSR will be interviewed to understand how external entities will be able to connect directly to the CDE repository so that CDE and DE specifications can be automatically extracted and used by the Peregrine Smart-CRF system. In this later case, it will be essential to interview site and ACRIN technical staff to understand and fully model the technical specifications of ACRIN and site systems. During Phase I these technical activities will help define the requirements for automatically connecting to both system types. Analyses will be detailed in the Phase II development plan.

Requirements management and software design and development activities will be carried out using a modified Unified Process approach5. The system requirements and analysis activities will be constrained by the capabilities of existing NCI, ACRIN and local systems as the majority of Phase I and II development activities will be to extend existing mobile forms capabilities to ACRIN CRFs, to develop capabilities to map CRF data elements and attributes to local systems, and to automatically populate the local forms with existing local data.

System design and development activities will be represented in the Rational Rose Developer’s Suite™. Detailed test cases and plans will be created during design and development activities. Each component will be unit tested followed by integration testing prior to sign off and installation.

3.1.2 DEVELOP PEREGRINE SMART-CRF PROTOTYPE

For Phase I, the prototype Peregrine Smart-CRF will implement existing ACRIN CRFs. Working with ACRIN staff, a number of ACRIN CRFs will be selected from one or more ACRIN trials to be represented within the Peregrine Smart-CRF system. The hand-held forms will be able to collect CRF data at the point of care or other locations. Data collected in the hand-held will be synchronized to a test repository to demonstrate end to end data collection capabilities.

Human factors will be key to acceptance and use and therefore, this prototype will be demonstrated early to site users selected by ACRIN and NCI staff to help those users visualize potential applications of the hand-held technology. It will provide essential KA on the usability of hand-held forms and how site users will be able to adapt their local data sources and data presentation to a much smaller form factor. Merely translating 8½ x 11 “ sized case report forms to a small PDA or tablet computer will result in a product that is not used.

XML Schemas and document templates, and Extensible Style Sheet Language for Transformation (XSLT) documents will be generated for each ACRIN CRF selected for prototype implementation. The use of XML technology will base the system on an open standard that is managed by the World Wide Web Consortium. XML schemas will be used to represent approved CDEs and DEs. XML document templates will be created that represent approved CRFs.

3.1.3 DEMONSTRATE PROTOTYPE

A “field” team will visit one or more selected sites and walk users through CRF creation, downloading to hand-held devices, collecting simulated ACRIN trials data in situ and the transfer of CFR data to ACRIN database on the demo server. Constant feedback from the field team will be used to fine-tune the user interfaces, and the forms authoring and maintenance components of Peregrine Smart CRF system, as well as to assist with device selection, and deployment planning.

During the prototype demonstrations, ACME will incorporate a performance assessment module into the hand-held This utility, similar to the one developed by ACME for its Phase I NASA EPIC SBIR, will be used to assess number and types of errors, and statistical data resulting from use of the prototype. These data will be fed back to the ACME team to continuously evolve the design. This assessment will also be used to assess data collection efficiency gains and proficiency in using both the hand-held to collect data and the forms authoring components of Peregrine Smart CRF.

In addition, ACME will perform an initial usability study of site and ACRIN users at work while they perform steps of a selected task. These initial usability results will inform Phase II user interface and component development. We will perform an initial review of work flow and decision-making for the various steps of the CRF authoring, and most frequent data collection processes, to support Phase II scooping. We will also assess doctrines and principals regarding the design and operation of the information display. Our objective is to ensure ease of use, to minimize training and user fatigue. This investigation will culminate in the development of a series of heuristic-based work assistant tools that will be based on human decision-making algorithms that will be a key part of Phase II Development.

3.1.4 SYNTHESIZE CANDIDATE PEREGRINE SMART-CRF SYSTEM DESIGNS

At the completion of the initial KA phase and the field exercises, ACME will have prepared high level system design requirements. These design requirements will be further refined as the results of building the prototype and demonstrating it to site users, ACRIN and NCI staff. These requirements will be developed into conceptual designs for the system.

In particular, the early system design will address the ability of a site to develop data forms that collect all the data in a set of ACRIN CRFs. We will research the feasibility of an IFC to convert CRFs presented in a commercial word processor into an electronic form that will reduce the need to author forms on the DFH server. This initial design will be incorporated into the Phase II development plan. This design will propose an interface to the caSDR that will obtain CDE and DE specifications and will manage PHI in fully HIPAA compliant fashion. System designs will be represented in Rational Rose and will use existing object structures defined by Center for Bioinformatics to the extent possible.
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3.1.4.1 SELECT HAND-HELD FOR PHASE I TESTING

ACME will augment its existing database of hand-held computing and communication technologies that it has accumulated in its pre-hospital data collection projects. The initial task of the District of Columbia EMS Data Collection project was to perform a survey of existing and near-term technologies that could be applied to the problem of providing lightweight and ruggedized hand-held computers.

The problem is very analogous to a hospital setting and has similar requirements. Thus the ACME team brings extensive expertise to the Phase I research in connecting hand-helds to both wired and wireless infrastructure. We will research the best communication solution based on existing and future infrastructure. We also considered security requirements including the use of biometrics to authenticate the users, as well as HIPAA requirements for patient care records.

ACME expects that the most feasible technology solution will involve a combination of wired and detached computing. Our solution will be sensitive to cost issues as some sites may have an existing wireless infrastructure and others may not be able to afford to deploy even a small one in their site. Our innovative approach supports wireless transfer of data when time is essential to completing tasks, like the initial registration of a new study participant. For other tasks, like collecting data from records, ACRIN trials data can be stored on the hand-held and synchronized when the data collector returns to their office by docking the hand-held.

Even limiting the option of radio communications systems, leaves many potential combinations of data exchange schemes such as an infrared or a wired interface to an Internet or LAN using a docking system. In this task, ACME will research the latest technologies that may be applicable to the Peregrine CRF system. We will consider the latest hand-held, communication, security, and user interface technologies to insure that we select the optimum technology for Peregrine and will consider evolving wireless technologies. We anticipate that by the completion of the Phase II effort, wireless technology will be faster, more reliable and less expensive. Thus the proposed solution must accommodate the evolution of this technology.

3.1.5 FEASIBILITY ANALYSIS

There are four components to ACME feasibility analysis: expected system performance, cost, development risk (including the ability to conduct a valid and reliable test of the system), and user acceptability. We are confident that a working version of Peregrine Smart-CRF for selected ACRIN CRFs can be developed and used to demonstrate data collection at point of care. We will investigate the feasibility of using an IFC capable of automatically converting forms developed in a standard word processor into an electronic form including all of the business rules associated with each field. This innovation will significantly reduce the cost to introduce and maintain CRFs and local forms. This innovation will also enable local users to use Peregrine Smart-CRF for other types of clinical trials, particularly pharmaceutical company trials CRFs.

Expected system performance here will be assessed during CRF and local forms authoring activities, CRF data collection during patient activities at the point of participant contact and points of care, and transfer of collected data to ACRIN databases. Using Peregrine Smart CRFs it anticipated that users will be able to author forms that transform their local data formats into CDE standard formats and codes and to develop trial-specific lists of CTCs and adverse events to simplify data entry and reporting of critical AEs. Site data collection staff will be able to collect ACRIN trial data with substantially less effort and less errors.

Real-time linkages with wireless data entry at the point of participation may also yield increased participation in ACRIN trials as eligibility determinations can be performed much more quickly and patient or physician questions could be answered while the patient in within the care location. These benefits will require site process changes to be fully realized. ACRIN staff should observe a lower data error rate, more timely CRF submissions, and the opportunity to manage data quality as an interactive, ACRIN to site joint effort resulting in reduced turn around times for data issue resolutions.

Estimation of the development risk is based on the maturity and availability of the technology, as well as the complexity of the system development. We will base complexity Judging the complexity of a development effort is more subjective, especially without a detailed design, but we will base this metric on the relative number of significant new, unproven functions that must be devised and implemented for each configuration, and the technology readiness level of the components being used.

We will also include in the development risk the ability to conduct a realistic and meaningful test of a prototype of the system. Some promising designs may be extremely difficult or even impossible to verify adequately Phase I. We are explicitly reducing the project’s development risk by using technologies that have been developed and that are based on commercial off the shelf technologies. The Dynamic Form Hand-held Server is based on Oracle’s Mobile Server which provides an ‘industrial strength’ database management system.

We can concentrate on the specific needs of mobile CRF form design and data collection and not spend time or effort trying to recreate an already robust capability. Out of the box, Oracle databases and data management tools provide enterprise-wide scaling and high assurance data integrity. Moreover, the CTSU uses Oracle Clinical and over 90% of hospital data resides in an Oracle database, thus mitigating in part the technical challenges of connecting to source data.

User acceptability will be judged by how well the prototype supports the data collection needs as defined by actually using the system during the prototype phase and how it meets requirements determined from user needs. Other technical specifications include size, weight, operational requirements, battery life, and aesthetics. As part of this assessment, a judgment must be derived of the likelihood that the user will use the device sufficiently frequently to achieve the expected benefits.

Each of the metrics will provide input into the overall feasibility score. The system design configuration that is determined to be the most feasible will be further developed, and form the basis of the phase II proposal. In case of equivalent scores, ACME will both solicit the COTR's input and consider our team's strongest capabilities in choosing the design configuration to recommend for Phase II development.

3.1.6 DETAILED DESIGN OF RECOMMENDED SYSTEM

The recommended system configuration will be expanded into a more detailed system design. This is required to accurately scope the development effort to be proposed for Phase II. This design will address both hardware and software required for the system.

For the hardware design, ACME will identify specific products, and their vendors. Where possible, a second source will be identified. As hardware evolves rapidly, we will continue to update our database of hand-held technologies to optimize cost and performance against users needs.

The software design is based on Oracle’s mobile application server technology. It is a web based, multi- tier solution that handles all the heavy lifting of managing forms, security, deploying the applications, maintaining data integrity for both CRFs and CRF data (as they are both stored in the database), managing user accounts and authorizations (who can create/edit/use what forms, tools, etc) and handling all the data mappings and transforms.

ACME uses a 3-tier software architecture for software development. A 3-tier software architecture approach helps to clearly delineate the boundaries between the presentation of information, the business rules that drives the application, and the data repository. Any database used by the application resides within tier 1, the data source/repository layer. Database design and development is driven by the requirements and use cases developed for the system. Data fields, tables and relationships extracted from use cases and requirements are used to build a data model and the database schema.

ACME has extensive experience with interfacing and integrating with disparate databases through the use of proxy agents at the data source layer in a 3-tier architecture. If needed, these agents can be used in Phase II to interface with a specific database. The agent knows how to input and output data from a specific database. They can accept data required to be stored in a database in a standard format such as XML, and transform the data from XML to the format required for storage in the database. A proxy agent can also extract and transform the data into a standard format such as XML for use by other systems.

3.1.7 DESIGN REVIEW

The ACME team believes it will be desirable to brief the COTR and NCI and ACRIN staff on the best candidate design configurations, the feasibility analysis, and the recommended design. This will allow us to incorporate government's comments, concerns, and desires into the design and the development plan.

3.1.8 PHASE II DEVELOPMENT PLAN

In this task, the ACME team will specify a plan for Phase II development. The plan will identify the technical objectives, work tasks, and schedule. Development risks will be identified and quantified. The result will be less detailed than the actual Phase II proposal but it will discuss project feasibility and key risks to completion, a result that is the primary goal of the Phase I efforts.

3.1.9 FINAL REPORT

A comprehensive final report will be prepared that will document the work performed, results obtained, and provide an estimate of the technical feasibility for completing Phase II. The report will present conclusions and recommendations for the Peregrine Smart-CRF system. Each section of the report will correspond to the tasks listed in the work plan. A draft of each section will be written as each task is completed. At the end of the project, ACME will combine the sections with our conclusions and recommendations to form the final report. A draft of the final report will be submitted to the COTR three weeks before the end of Phase I. The final version of the report will be delivered at the six-month mark.

ACME and [] have been working together on several different pre-hospital hand-held data collection projects including the A[]System. The team works well together, and is well balanced with Dr. [] clinical trials experience and the point of participation community, and ACME’s extensive experience and capabilities in hand-held computing, wireless networks, and information security. A brief overview of ACME projects should provide an indication of our capabilities.

For the [] is deploying hand-held pre-hospital EMS data collection applications. We also are providing requirements analysis and assisting each customer in redefining their business processes to take advantage of automation. ACME also developed sophisticated software for another hand-held application called AutoDocs GPS that includes a custom multimedia user interface and for the proprietary GPS processing software consisting of a kinematic, Differential Global Positioning System (DGPS) Kalman filter. Developed under a National Highway Traffic Safety Administration (NHTSA) SBIR, AutoDocs GPS has received a U.S. patent.

Dr. [] was instrumental in defining, designing and building out many of the new informatics capabilities at []. His unique experience as a national leader in bringing informatics principals and practices to clinical trials assures that the team will effectively address key challenges. He and a[] is revolutionizing how clinical trials are authored, monitored and conducted. He has also developed the innovative dynamic forms – hand-held server technology that will be used in conjunction with ACME hand-held tools to permit users to create and maintain forms and the linkages of data elements on those forms to ACRIN databases.

ASSURANCE INSPECTION SYSTEM (EPIC)

ACME developed a customized, wireless data collection system to support Safety and Mission Assurance (S&MA) inspections of each Space Shuttle prior to launch. Prior to the development of this system, NASA relied on a paper-based 45,000-point inspection procedure for system checkout of the Space Shuttle. The Phase I and Phase II NASA SBIRs included re-engineering and automating the manual and paper-intensive Space Shuttle S&MA Inspection Process.

EPIC is comprised of a Central Database Server (CDS), Inspector’s Smart Stamps ™, Routers and Ethernet Adapters, system databases, and a custom-developed Graphical User Interface (GUI). EPIC is a fully automated, electronic version of the mission inspection process, which exactly mimics NASA business practices. This solved the problem of 15% error introduced into space shuttle checkout processing, due to manual data collection processes and data re-keying.

ACME developed mission-specific "inspection” forms using Visual Basic 4.0, Visual C++, and Microsoft Access. The mission databases are updated in real time, thus, eliminating any data latency and allowing NASA to perform remote certification of Space Shuttle Systems. EPIC also interfaces with a number of remote and disparate databases located throughout the KSC campus. This system won NASA’s 1997 Most Innovative SBIR Product of the Year Award (Software Category).

Under a NHTSA SBIR, ACME developed a hand-held and wireless data collection system that significantly enhances the speed and accuracy of crash scene documentation. AutoDOCS-GPS consists of a portable computer, a customized, turn-key software package using a Graphical User Interface (GUI), GPS receivers, and GPS antennas. Using AutoDOCS, a single surveyor is able to accurately and rapidly measure and document a crash scene. The system uses highly accurate, kinematic, DGPS measurements to geo- locate crash scene elements and reference points.

To perform the crash scene measurements, a hand-held or laptop computer is used in conjunction with the customized turnkey software. The turnkey software features a user friendly GUI that provides step-by- step prompts. The processing software takes the raw GPS data from both receivers and determines the relative position of each point to centimeters in accuracy. The AutoDOCS software automatically develops a Computer Aided Drafting (CAD) quality graphical representation of the scene. The AutoDOCS software then calls the word processing program, Microsoft Word to automatically complete a text report.

The National Highway Traffic Safety Administration (NHTSA) performs research on the causes and circumstances of automobile and truck crashes. One of the most important sources of data for this research comes from the analysis of crash scenes. The position and orientation of vehicles relative to each other and roadway features is important to attempt to determine the crash dynamics and cause. Skid mark positions and lengths also provide clues. Prior to the development of AutoDOCS, crash scene measurements were done manually with wheel and tape measures. The data is recorded by hand and the analysis is done through manual calculations.

Phase I SBIR work included developing the system requirements, performing feasibility testing, system design, and a feasibility analysis.

Phase I will develop detailed requirements for the Peregrine CRF system based on actual clinical trials, actual site and ACRIN and NCI staff experiences with prototype electronic CRFs, and testing of critical requirements using existing hand-held computers from the ACME inventory. ACME will use the system requirements to develop candidate design configurations that will be analyzed for feasibility. The most feasible and desirable design will be further defined to facilitate a Phase II System Development Plan identifying resource levels and risk.

Phase I defines the scope and plan for Phase II, and positions ACME to rapidly and efficiently produce prototype ACRIN CRFs and IFC. The hardware and software specifications will be finalized after checking the market for new, more capable hand-held computers to fulfill the requirements developed in Phase I. The products will be procured and integrated together. Simultaneously, software development will proceed to extend the current Form Authoring and Data Entry Modules to meet requirements defined in Phase I.

We anticipate developing tools that are compliant with the underlying mobile architecture that support site-to- CDE or ACRIN DE mapping so that coding can occur in situ where data problems should be identified and resolved. We expect to develop an interface that will enable the Forms database and Authoring Module to connect to the caDSR for automatic retrieval of CDE specifications. A detailed test plan will be developed, and laboratory and controlled site and ACRIN tests will be conducted. Modifications suggested by the testers will be incorporated before a Government Acceptance Test. A final report will completely document the design, software, test procedures, test results, and conclusions and recommendations.
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New drug development is an extraordinarily costly endeavor. The cost to bring a single drug from discovery to approval for use in humans averages near $500 million. There is tremendous pressure to develop new drugs that harvest the astounding new genetic discoveries. Unfortunately, we need ten times more patients on clinical trials than we have today - just to test the currently available drugs. The explosion of promising target compounds will overstress today’s clinical trials systems and result in many promising drugs lying fallow until we can “get around to them.”

Most efforts to improve this situation are focused on reducing the paper logjam. Leading pharmaceutical and biotechnology companies are sponsoring remote data entry of case report forms directly into their study centers. The FDA is promoting electronic submissions of all drug information. Still, there is a “data gap” between the trials information systems of the pharmaceutical industry, NCI and ACRIN that deal with protocols on the one hand and the hospital and imaging information systems that deal with treating patients on the other. As described above in the Background and Opportunity sections, the organization of clinical trials data does not currently support graceful, let alone effortless, data collection or extraction of clinical information that may already exist in a computer system.

Based on our deep knowledge of the problems and over five years developing a well structured solution to them, the Peregrine Smart CRF system is designed specifically to fill this data chasm. Our approach will have tremendous potential value to both NCI and ACRIN trials and to the private sector.

First, NCI has spent millions developing the CDE and its infrastructure and untold hours building the processes and procedures to create and maintain them. It still lacks efficient and effective delivery mechanisms to use this resource directly in authoring clinical trials and in collecting CRF data at clinical sites. We have made solving this problem one of our team’s highest priorities. The reason is simple: if our system and approach helps NCI and ACRIN foster widespread use of CDEs, then ACRIN sponsored clinical trials will be much easier to do, cost much less (as the data collection effort will be substantially less expensive and much faster), and become the benchmark for clinical research. There are substantial down stream advantages as well. As CDEs become ubiquitous, they will become essential for the efficient performance of clinical trials. This dramatically reduces the cost of entry for other companies to exploit a boom area in what is otherwise a down economy.

The ACME team is committed to developing and publishing in the public domain all the change management processes, exchange mechanisms, XML Schemas interface specifications and process or data models. Indeed, we believe that these products will be our most valuable contribution to NCI and ACRIN. Lastly, there is nothing truly unique about cancer clinical trials. We believe that the products above and our solution will be useful to other trials groups at NCI and Institutes at NIH.

From the private sector perspective, pharmaceutical companies are very interested in established and proven technologies that reduce the time from drug discovery to market. As strange as it may seem, cost savings in performing clinical trials is not as significant a factor. Getting an additional six months of patent protection for their blockbuster drug, because the clinical trials closed faster, yields an additional $1-2 billion for the company. Clearly this is high incentive for all the players in the pharmaceutical industry, including clinical research organizations, IT solution vendors to name just a few. It is also important for clinical sites. Peregrine Smart CRF will be a horizontal technology and will work for any clinical trial.

The cancer centers who are early adopters of our technology can translate the reduced cost of data management into a marketing strategy to drug companies – our center can predictably reduce the time and cost of performing your clinical trial. That the drug companies will receive clean and pure data, in the form and format they want, will seal the deal. If our approach does enhance recruitment onto trials, that will be even more incentive for drug companies and NCI to sponsor research in centers using Peregrine Smart CRF.

Lastly, in our Phase III efforts, we plan to push the data entry window to a host of wireless, portable devices such as cell phones, Blackberries, etc so that we can deliver mini-Smart CRFs that will collect a portion of clinical trial data directly from the participants, where ever they may be. Our technical architecture will scale to other than PDA devices without having to rewrite all our applications.

Personnel from ACME include the proposed PI and a Sr. Software/Systems Engineer. Resumes also include ACME consultant, [].

Education: J.D., Catholic University of America, 2001; B.E.E.E, City College of New York, 1988. Qualifications: Mr. Gonzalez possesses more than 15 years experience in design, test, integration, and maintenance of public safety related computer software and wireless communication products.

Experience:

Founder / CEO, ACME Corporation —Mr. Gonzalez’s experience includes software design and coding, development of software to requirements, and software testing and independent validation. He led the development of software for the National Aeronautics and Space Administration (NASA), the Federal Aviation Administration (FAA), U.S. Coast Guard, Volpe Research Center, NAVCOM Systems, Inc., and SENTEL Corporation. He was principal investigator for four different Phase I and Phase II SBIRs including one for the development of a “Computer System for Collection of Quality-Assurance Data” (now called EPIC™) won NASA’s 1997 Most Innovative Software Product of the Year Award.

Gonzalez also won the 1989 Most Innovative Design of the Year Award for the design and development of the FAA’s Mini-Telecommunications Demarcation System (MTDS). The MTDS units are currently installed in every aviation facility in the U.S., a total of over 8,300. In addition, Gonzalez is an honoree at the U.S. National Inventor’s Hall of Fame for inventing the MTDS system and NASA’s EPIC™ system.

Mr. Gonzalez has extensive experience in research and product development for the Department of Defense, Department of Transportation, NASA, and the commercial market. He has also been involved in the invention of ACME’s core products, which include RAPIDS™ and Michaels Fire and EMS™. RAPIDS™ is a hand-held computer system used in housing and building code enforcement. RAPIDS™ computers are linked using wireless networking technology, which gives inspectors in the field instant access to information on properties, building codes, and other resources in real-time. Michaels™ is a state-of-the-art hand-held pre-hospital data collection and medical charting system. Michaels™ provides Emergency Medical Service (EMS) information delivery with date, time and data validation features, and video-capture capabilities for voice and video collaboration with emergency room staff. Currently, the system is being installed in every ambulance in Washington, D.C. and is imminent in Arlington County, Virginia.

Mr. Gonzalez is also the subject of a PBS documentary, “Voices of Vision” which is scheduled to air nationwide on November 24, 2002.

Engineering Director, SENTEL Corporation —As an Engineer and Engineering Director with SENTEL Corporation and as a Systems Engineering Manager for NavCom Systems, Mr. Gonzalez was responsible for design of the FAA’s Loran/GPS Site Evaluation System (LSES). LSES is used to test the integrity of LORAN and GPS signals at airport locations throughout the country. The system uses GPS to determine if the airport is safe for approaching aircraft. Mr. Gonzalez also was the senior design engineer responsible for design of an Aviation Blink System (ABS). The ABS monitors LORAN navigation signals, identifies faulty signals, and notifies pilots of those unreliable signals.

Selected Publications:

1. Gonzalez E., Yogi, D., Stovepipe Communications System—Barriers to Effective Emergency Networks. First Responder Magazine, November 2002.

[], will be a consultant for this Phase I SBIR. [] will serve as the subject matter expert and will perform a maximum of 33% of the work. D[] efforts will include delineating realistic and effective system requirements, including applicable use scenarios, operational techniques, and human factors, as well as providing the Dynamic Forms Hand-held Server technology.

During Phase II, we anticipate bringing additional consultants to the team. These consultants may include individuals from D[], who are highly experienced in NCI clinical trials data models.

ACME will perform all Phase I activities at its 15,000 square-feet facility in Silver Spring, MD. Our facility is equipped with a Rapid Application Development (RAD) laboratory, and extensive computing assets. The facility includes offices for technical and support personnel, two conference rooms, and a hardware test and assembly room that has test equipment for hardware development and troubleshooting. ACME also has software and equipment available for requirements/mission testing during this phase.

ACME provides a high-speed Internet connection for all technical employees. ACME is a Microsoft Certified Software Developer with access to all Microsoft beta software, technical support, and development environments. ACME uses Rational Rose for software design, documentation, project control, and testing. The office meets all state and federal environmental laws and regulations.

Field testing and demonstration will be performed at academic institutions such as Johns Hopkins, Pittsburgh Cancer Center, etc., as selected by ACRIN and NCI staff. ACME and Starfleet are currently involved in another hand-held data collection opportunity with Johns Hopkins.

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