AN INTRODUCTION TO THE PHARSIGHT KNOWLEDGEBASE SUITE

Transcription

1 AN INTRODUCTION TO THE PHARSIGHT KNOWLEDGEBASE SUITE Optimizing the value of Pharmacology Knowledge in Early Drug Development White Paper September 2005 Pharsight Corporation East Evelyn Avenue, 3rd Floor Mountain View, California Tel: Copyright Pharsight Corporation

2 The Challenge of Leveraging Pharmacology Data in Early Drug Development Pharmacokinetics and pharmacodynamics the study of how drugs reach their active site and the effects they produce is occupying an increasingly important role in the drug development cycle. Major effort is being directed at measuring, modeling, and summarizing the concentration-vs.-time and concentration-vs.-effect data that characterize the kinetics and dynamics of a drug. Insufficient utilization or access to pharmacokinetic knowledge is one of the primary factors for the 80 % attrition rate reported by the FDA for new molecules in clinical development. While recent analytical advances support more rapid and more detailed collection of pharmacokinetic data at the component / mechanistic levels of absorption, distribution, metabolism, and excretion (ADME), not much progress has been made in effectively handling this information on an enterprise level (i.e. on the level of a complete development program or indication). Adopting new in-silico methodologies and technologies also promises to make decisionmaking better informed however, the current work activities of skilled scientific researchers must become more efficient and productive, freeing critical skilled resources needed to learn and deploy these new technologies. This flood of new data relating to both existing compounds and new chemical entities must be stored, managed, analyzed, summarized, and in the case of successful development programs, submitted to regulatory authorities. While existing systems, such as Documentum -based document management systems or Oracle -based LIMS and clinical data management systems, may handle some types of data consumed or generated by drug modeling and pharmacokinetic / pharmacodynamic (PK/PD) analysis activities, these systems do not adequately address the need for a centralized, secure repository for the intellectual capital generated by early-phase drug development. In addition, regulations issued by the FDA 21 CFR Part 11 (Electronic Records & Electronic Signatures) require that research organizations maintain much stricter controls over electronic data being used in support of regulatory submissions. Current file-based systems for managing PK data and analysis activities are often not compliant with these regulations and these deficiencies cannot easily be addressed via new standard operating procedures (SOPs) or changes to manual processes alone. Manual report preparation and review workflow also may represent a critical gap in compliance with Electronic Signature/Records regulations (21 CFR Part 11). Drug development organizations face the problem of managing and leveraging the intellectual capital this type of research science produces in a way that maximizes the return on the investment in creating it and they must do so while collecting and managing that data in compliance with strict FDA regulations. Copyright Pharsight Corporation 2

3 Challenges Addressed In response to the challenges described above, Pharsight, the leading developer of pharmacokinetic and pharmacodynamic (PK/PD) modeling and analysis tools, including WinNonlin and WinNonMix, has developed a new type of research knowledge management system. This system includes the Pharsight Knowledgebase Server (PKS), the PKS Reporter, PKS Connectors, WinNonlin Enterprise, a series of PKS Clients for Microsoft Word and Excel, S-PLUS, SigmaPlot, NONMEM and SAS, as well as custom tools to automate routine analyses. The Pharsight Knowledgebase Server (PKS), as the core of this suite of integrated products, provides a unified repository for modeling and analysis activities, including the capture and maintenance of computed model parameters and other derived information, across a large set of compounds and development phases. The PKS suite provides productivity tools, integration with common data management systems and desktop environments such as Oracle Clinical and Microsoft Office, and a platform for automating and standardizing common tasks such as data transformations/loading and authoring of reports for regulatory submissions. The Pharsight Knowledgebase suite offers an integrated solution to the key challenges facing pharmacokinetic researchers and the IT/QA groups supporting them: Regulatory Compliance Helping to fulfill regulatory requirements as outlined in FDA s 21 CFR Part 11 (Electronic Records & Electronic Signatures) by replacing current file-based practices with a regulatory-compliant pharmacokinetic research management system for data collection and transformation, PK/PD modeling and analysis, report preparation and review, and later data mining and meta-analysis. Increased Researcher Productivity Increasing scientific productivity by cutting down on long data preparation cycles for PK analysis, interpretation and presentation, report preparation and management. Productivity is also improved by reducing the overhead, and resulting QA effort, of data collation and transformation of fragmented source data coming from multiple heterogeneous systems (e.g. clinical data management systems, Toxicology, Bioanalysis, LIMS, spreadsheet files and proprietary databases) with incompatible formats. Productivity is also improved in report authoring and review/approval process by providing a unified data repository, a regulatory-compliant document authoring platform, and workflow tools to optimize report review and approval processes including management of electronic signatures. Productivity in performing clinical trial simulations can often be markedly improved by providing ready access to relevant PK/PD data. Knowledge Management for Early Drug Development Providing central access to the wealth of information related to drug modeling and analysis generated in discovery, lead optimization, and early development. The PKS suite supports the assembly and review of pharmacokinetic information within an organized knowledge management framework during pre-clinical and clinical development and can in turn facilitate the optimization of clinical trial designs and clinical development programs via modeling and simulation. Copyright Pharsight Corporation 3

4 Benefits for Clinical Pharmacology and PK Groups In addition to meeting regulatory compliance needs, the creation of a comprehensive and accessible pharmacology data warehouse is essential to applying advanced modeling and simulation technologies as part of a more rational and cost-effective drug development process, improving both scientific productivity and reducing information management overhead. The Pharsight Knowledgebase Suite provides a key infrastructure component needed to effectively leverage intellectual capital created early in drug development. Providing secure, regulatory-compliant access to a cross-program drug development data warehouse allows R&D organizations to form the foundation for the optimization of decision processes throughout the drug development process. With the integration of all drug development data sources into a unified knowledge management framework, companies will be able to fully capitalize on emerging in-silico techniques like trial simulation. The Pharsight Knowledgebase Suite can support standardization and automation efforts leading to significant reductions in reporting backlog and productivity improvements that can free up the scientific resources needed to adopt these new technologies. Figure 1 - Inversion of the Confidence Curve in Drug Development Investing in an infrastructure for early drug development will ultimately cut development costs and accelerate development time by increasing the level of knowledge and the confidence in making program design decisions much earlier in the drug development process. Copyright Pharsight Corporation 4

5 Figure 2 The Pharsight Knowledgebase Suite Key Functional Areas in Pharsight Knowledgebase Suite The Pharsight Knowledgebase Suite consists of several integrated components: Pharsight Knowledgebase Server (PKS) The Pharsight Knowledgebase Server provides a regulatory-compliant data management system for PK/PD data and the results of analysis and reporting activities. The PKS is built with a sophisticated three-tier architecture supporting both traditional desktop tools (e.g. WinNonlin and Microsoft Word) and distributed web-based tools (e.g. PKS Administration tool, Query tool). WinNonlin Enterprise WinNonlin is the industry-standard for PK and PD modeling, Noncompartmental Analysis, data management and transformation, and analysis automation. In addition, WinNonlin can generate the figures, tables, and listings and help prepare the reports needed for PK and PK/PD studies. WinNonlin can also save any type of file from any application into the PKS database, providing regulatory-compliance via electronic signatures, reason for change, audit trail and versioning. PKS Reporter The PKS Reporter provides an automated system for the authoring, updating, and review/approval of standardized or customized reports and documents. It operates as a Microsoft Word add-in and is directly integrated with the Pharsight Knowledgebase Server (PKS), accessing data and modeling results saved by WinNonlin Enterprise, as well as data and graphics from other analysis tools and data sources. Copyright Pharsight Corporation 5

6 PKS Clients for Word and Excel The PKS Clients for Word and Excel provide secure document management and regulatory compliance for files created or edited by these Microsoft Office productivity tools. When installed, the PKS Clients provide additional options on the Word and Excel file menus to save or open documents stored in the PKS database. PKS Client for SAS, NONMEM, S-PLUS and SigmaPlot The PKS Client is a desktop tool for managing data, code and analyses using the secure storage and version tracking features of the Pharsight Knowledgebase Server (PKS). The PKS Client manages files and analysis runs for SAS, NONMEM, S-PLUS and SigmaPlot. It stores data and analysis results in the PKS, where they are available to share with WinNonlin and other Pharsight tools. Customers who also own the PKS Reporter can report output from PKS Client sessions in Microsoft Word documents. PKS Connectors The PKS Connecters provide automated loading of study data from various sources such as data management systems, LIMS (laboratory information management systems), legacy databases, and other data sources. PKS Connectors can be configured to work with common data management systems, such as Clintrial, Oracle Clinical, or customer s in-house database systems. Together, these components provide a broad range of functionality to support regulatory compliance and improve productivity: Study-Oriented Database Management and Configuration Administration tools to manage system security (e.g. grant access permissions for studies to users and groups of users) and to configure the system to meet company specific needs, set defaults for system interfaces, as well as the definition and management of study/protocol metadata. Data Analysis and Visualization Tool Interfaces Direct bi-directional interfaces to Pharsight s main PK/PD modeling and analysis tool, WinNonlin Enterprise, and to SAS, NONMEM, S-PLUS and SigmaPlot through the PKS Client, along with export/import interfaces supporting other analysis and simulation tools. Export interfaces to third-party software such as NONMEM and SAS, including the ability to re-import selected derived parameters from the output files generated by these programs. Export facilities support data export for use with standard database reporting and data exploration tools (e.g., Microsoft Excel). Report/Document Authoring and Productivity via Standardization Manages the process of producing reports for internal use or regulatory submission, including transforming data, creating tables and graphs, laying out and editing documents, validating data references and analysis, and updating documents when new data are received. PKS Reporter allows researchers to use familiar tools, such as WinNonlin, Microsoft Excel, and Microsoft Word, to construct, update, review, approve, and validate any type of report. Improves scientific productivity, reduces QA overhead, and provides a template-driven scriptable system to standardize and automate routine document authoring tasks. Copyright Pharsight Corporation 6

7 Graphics-based Review and Evaluation Standard views of summary parameter and experimental data tables and associated forms support retrieval of data tables, summary statistics and comprehensive scientific graphing (via WinNonlin Enterprise) for reporting and submission. Retrieval and display/visualization facilities (as formatted tables and graphs) are able to handle special characteristics of summary parameter information (e.g. ranges or merging of discrete and continuous data) and explore the PK/PD data with statistical information (i.e. descriptive statistics) calculated on demand. Data Loading, Import, and Transformation Import of summary parameter data from ASCII files, SAS Transport files, and Excel spreadsheets, as well as automated loading of data from ASCII files, SAS Transport files, and Oracle-compatible databases to support the integration of data from LIMS systems, clinical databases, and data received in electronic format from CRO s and external laboratories. Automated web-based batch loading of study and lab data from commercial clinical data management and laboratory information systems such as Oracle Clinical or the Watson LIMS can be configured via the PKS Connectors. User-friendly Regulatory-Compliant Data Management User-friendly spreadsheet-style and dialog-based data entry facilities in WinNonlin Enterprise can be used to specify information about compounds and studies, as well as enter raw (source) data, analysis or modeling results, and summary parameter records from non-electronic sources and relevant literature data. While offering the ease-of-use of a typical Windows program, such as Microsoft Excel, the combination of PKS and WinNonlin maintains user productivity (and leverages existing user knowledge of WinNonlin) without sacrificing regulatory compliance. Figure 3: Overview of Pharsight Knowledgebase Server (PKS) suite Copyright Pharsight Corporation 7

8 Leveraging Modern Technology for Productivity and Compliance The Pharsight Knowledgebase Server has been designed as a modern N-tier architecture to support most demanding stability and scalability requirements. This architecture is implemented using an open industry standard, the Oracle 8i/9i database system, as the backend and a combination of native 32-bit Windows clients and a web browser-based front-end. The middle-tier can be deployed on a Tomcat and WebLogic. The PKS uses an Oracle-based implementation of security and data integrity features to help ensure a fully regulatory-compliant operation, by either using the supplied frontends or third-party tools to access and update data. A middle-tier, based on XML transactions, provides a transaction-level interface to support integration of data sources and other data management systems without sacrificing data integrity. The PKS is directly linked to WinNonlin Enterprise, a 32-bit Windows application, permitting the regulatory-compliant capture of source PK/PD data and results, including detailed reasons for changes to individual data cells and full audit trails. PKS Suite includes standalone clients for managing data using PKS; currently, we have clients that operate through the Word and Excel menus, as well as a stand-alone PKS Client for S-PLUS, SigmaPlot, SAS, and NONMEM. For more sophisticated document authoring support, the PKS Reporter, also functioning as a Word add-in, provides a direct connection to the PKS database, allowing researchers to browse PKS studies and scenarios, inserting and updating document objects (referenced by tags inserted into the Word file). All of these add-ins support full versioning, electronic signatures, audit trails, and reason for change capture. Figure 4: Overview of Knowledgebase Server (PKS) Architecture Copyright Pharsight Corporation 8

9 Common analysis tools like SAS and NONMEM are also supported by providing import/export interfaces to their native data file formats. PKS Connectors and documented APIs (via an XML middle tier) support automated loading of data from clinical data management systems and other drug development systems and databases. In addition, WinNonlin Enterprise provides a Document Manager facility that allows file of any type (ASCII, JPG, DOC, etc.) to be saved to or retrieved from the PKS, supporting regulatory-compliant capture of output from a wide variety of visualization and analysis tools. Deploying the Pharsight Knowledgebase Suite The Pharsight Knowledgebase Suite provides both the necessary database management system and the software tools needed to support the creation, administration, and ongoing use of a central data repository of early drug development knowledge. Deployment of the Pharsight Knowledgebase Suite provides: Management and administration of the database infrastructure, including security and configuration. Secure data storage and retrieval to support regulatory compliance (21 CFR Part 11) efforts. Extension of existing WinNonlin Enterprise functionality to support server-aware data entry/editing, tracking of derived data elements, capture of audit trail entries and electronic signatures, and management of multiple analysis approaches for a single source data set. Integration with analysis software (including Excel, S-PLUS, SigmaPlot, SAS, and NONMEM) via file-based exports to their native file formats using WinNonlin Enterprise. Direct integration of Microsoft Office tools (Word and Excel) and desktop data analysis tools (S-PLUS, SigmaPlot, SAS and NONMEM) via PKS Clients and the PKS Reporter, with the Pharsight Knowledgebase Server providing a secure, regulatory-compliant repository for Office documents. Automated tools (PKS Connectors) for importing PK information directly from multiple external data management systems (e.g. LIMS and clinical data management systems such as Oracle Clinical). A template-driven report authoring system (the PKS Reporter) for automating the construction and regeneration of compound documents in standardized formats for review and submission. Data mining tools (the Query Tool provided in the PKS web interface) to support and automate comprehensive cross-study and cross-analysis queries for use in later meta-analysis activities. An open and accessible data model to allow any Oracle-capable third-party data query tool for additional cross-study and cross-compound data mining. Copyright Pharsight Corporation 9

10 In addition, Pharsight and its partners can provide services, including: Training classes, either on-site or in a Pharsight facility for the PKS suite products and PK/PD modeling and analysis methodologies. Installation qualification and operational qualification services and tools to help speed validation of a PKS installation. Services to build and deploy automation systems for common analysis and reporting tasks. Systems-integration services to connect other data management systems and analysis systems to the PKS. Customized development of PKS Connectors to connect to other data sources or to add additional functionality for standard PKS Connectors. Benefits of the Pharsight Knowledgebase Suite In summary, the key benefits of deploying the Pharsight Knowledgebase suite within a clinical pharmacology organization are: Regulatory Compliance The Pharsight Knowledgebase Server offers a fully 21 CFR Part 11 compliant repository for pharmacokinetic and related data. Built-in security and full Audit Trail mechanisms ensure the integrity and traceability of your valuable data, permitting drug development organizations to move away from current noncompliant file-based research management practices. Improved Productivity The PKS Reporter can help substantially reduce the overhead, backlog, and QA effort associated with producing documents and reports for internal use and regulatory submission. Pharmaceutical R&D organizations expend considerable staff resources transforming data, creating tables and graphs, laying out and editing documents, validating data references and analysis, and updating documents when new data are received. Often this work must be performed by skilled researchers, taking them away from more productive and beneficial work. While this activity is necessary, much of the overhead, repetition, and potential for error can be minimized by moving to an automated, standardized system to produce regulatory reports. Data Integration and Access The Pharsight Knowledgebase Server provides a integrated, easily-accessible data management system for leveraging a wide range of preclinical, toxicological, and pharmacology data in early drug development organizations, and providing a hub to collect and share data between development phases and disciplines. PKS Connectors can automate this integration process, providing batch-loading facilities for common data management systems, and can be customized to connect to specialized data sources. Optimized Development Programs The central and well-structured storage of PK/PD data and drug models in the Pharsight Knowledgebase Server offers unprecedented support for modeling and simulation activities by reducing the overhead of locating and reusing pharmacokinetic data needed to build, validate, and utilize PK/PD and trial simulation models. Copyright Pharsight Corporation 10

11 Advanced Technology and Scalability The Pharsight Knowledgebase Server is designed around a component-based and multi-tiered web/xml architecture supported by the reliability of an Oracle database leveraging the best of current and emerging technologies. And PKS is designed to be a highly scalable data management system, providing a repository for storing all PK/PD and modeling related data about compounds from hundreds of studies in one central repository. Built with Industry Knowledge The Pharsight Knowledgebase Server is developed by the leading PK/PD analysis tool vendor, Pharsight Corporation, and incorporates extensive experience in pharmacokinetics and pharmaceutical research, as well as building on our experience in pioneering clinical trial simulation with many leading pharmaceutical companies. Contact Information For further information regarding the Pharsight Knowledgebase Server, or to arrange for an on-site demonstration please contact: James Hayden jhayden@pharsight.com Phone: About Pharsight Corporation Pharsight Corporation is a public company (OTCBB.PHST) that develops and markets integrated software products and services to help pharmaceutical and biotechnology companies improve the drug development process. Pharsight s solutions combine proprietary computer-based simulation, modeling, statistical, and data analysis tools with the sciences of pharmacology, drug and disease modeling, human genetics and biostatistics. Pharsight Corporation is headquartered in Mountain View, California with a satellite office in Cary, North Carolina and staff throughout the United States and Europe. Additional information on the company and its products can be found at Pharsight, WinNonlin and WinNonMix are registered trademarks of Pharsight Corporation. Trial Simulator, Knowledgebase Server, PKS Client and PKS Reporter are trademarks of Pharsight Corporation. Other company or product names mentioned herein may be trademarks or registered trademarks of their respective companies. This brochure is for information purposes only. Pharsight makes no warranties, express or implied, herein. Copyright Pharsight Corporation 11