AN INTRODUCTION TO THE PHARSIGHT KNOWLEDGEBASE SERVER (PKS )

Transcription

1 AN INTRODUCTION TO THE PHARSIGHT KNOWLEDGEBASE SERVER ( ) Optimizing the value of Pharmacology Knowledge in Early Drug Development 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 decision-making 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

2 For drug development organizations, the challenge of managing and leveraging the intellectual capital and maximizing the return on the investment in creating it, often boils down to collecting and managing clinical data effi ciently and in compliance with strict FDA regulations. 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. Challenges Addressed In response to the challenges described above, Pharsight, the leading developer of pharmacokinetic and pharmacodynamic (PK/PD) modeling and analysis tools, including Phoenix WinNonlin and Phoenix NLME, has developed a new type of research knowledge management system. This system is based on Pharsight Knowledgebase Server ( ), Reporter, Data Connectors, and the Phoenix-based family of analysis tools such as Phoenix WinNonlin, Phoenix Connect, Phoenix NLME and the PK Automation product AutoPilot. Pharsight Knowledgebase Server, as the core of this solution 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. provides productivity tools, integration with common data management systems and desktop environments, and a platform for automating and standardizing common tasks such as data transformations/loading and authoring of reports for regulatory submissions. 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 regulatorycompliant pharmacokinetic research management system for data collection and transformation, PK/PD modeling and analysis, report preparation and review, and later data mining and metaanalysis. 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 page 2

3 Pharsight Knowledgebase Server offers an integrated solution to the key challenges facing pharmacokinetic researchers and the IT/QA groups supporting them: Regulatory Compliance, Increased Researcher Productivity, and Knowledge Management for Early Drug Development. 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. 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. 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. Pharsight Knowledgebase Server provides a key infrastructure component needed to effectively leverage intellectual capital created early in drug development. Providing secure, regulatory-compliant Confidence of Approval 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 Server 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. Desired Current Phase I Phase II Time/Money Phase III Figure 1: Inversion of the Confi dence Curve in Drug Development page 3

4 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 confi dence in making program design decisions much earlier in the drug development process. Phoenix WinNonlin Phoenix AutoPilot desktop tools (e.g. WinNonlin and Microsoft Word) and distributed webbased tools (e.g. Administration tool, Query tool). Connectors Phoenix Connect Pharsight Knowledgebase Server Word NONMEM SAS S-PLUS R SigmaPlot Excel Phoenix WinNonlin: Phoenix WinNonlin is the industry-standard for PK and PD modeling, noncompartmental analysis, data management and transformation, and analysis automation. In addition, Phoenix WinNonlin can generate the figures, tables, and listings and help prepare the reports needed for PK and PK/PD studies. Phoenix WinNonlin can also save any type of file from any application into, providing regulatory-compliance via electronic signatures, reason for change, audit trail and versioning. Figure 2: Pharsight Knowledgebase Server 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. Key Functional Areas in Pharsight Knowledgebase Server Pharsight Knowledgebase Server consists of several integrated components: Pharsight Knowledgebase Server: Pharsight Knowledgebase Server provides a regulatory-compliant data management system for PK/PD data and the results of analysis and reporting activities. The is built with a sophisticated three-tier architecture supporting both traditional Reporter: 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, accessing data and modeling results saved by Phoenix WinNonlin, as well as data and graphics from other analysis tools and data sources. Phoenix Connect: Phoenix Connect manages files and analysis runs for SAS, NONMEM, S-PLUS and SigmaPlot in Phoenix Workflows. It also provides access to for all Phoenix-based products. page 4

5 Data Connectors: The Data 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. Connectors can be configured to work with common data management systems, such as Clintrial, Oracle Clinical, or customers 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 companyspecific 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, Phoenix WinNonlin, and to SAS, NONMEM, S-PLUS, R, and SigmaPlot through Phoenix Connect, 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. Reporter allows researchers to use familiar tools, such as Phoenix 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. 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 Phoenix WinNonlin) 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 Connectors. page 5

6 The Pharsight Knowledgebase Server has been designed as a modern N-tier architecture to support the most demanding stability and scalability requirements. Third Party Analysis Tools Pharsight Tools Standard PK/PD Analysis & Reporting Data Sources, e.g. Watson LIMS ClinTrial Oracle Clinical CDISC/SDTM Flat Files, e.g., SAS.xpt, Excel Data Connectors Client Tier SAS Client Tier Web Browser Middle Tier Figure 3: Overview of Pharsight Knowledgebase Server () Server User-friendly Regulatory-Compliant Data Management: User-friendly spreadsheet-style and dialog-based data entry facilities in Phoenix WinNonlin 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 S-Plus Phoenix AutoPilot Database Tier NONMEM Phoenix WinNonlin Phoenix NLME http(s), xml Application Server JDBC Database R Phoenix Connect SigmaPlot Reporter PK/PD Data Repository offering the ease-of-use of a typical Windows program, such as Microsoft Excel, the combination of and WinNonlin maintains user productivity (and leverages existing user knowledge of WinNonlin) without sacrificing regulatory compliance. Leveraging Modern Technology for Productivity and Compliance Pharsight Knowledgebase Server has been designed as a modern N-tier architecture to support the most demanding stability and scalability requirements. This architecture is implemented using an open industry standard, the Oracle database system, as the backend and a combination of Windows clients and a web browserbased front-end. The Java-based middletier can be deployed on Apache Tomcat and WebLogic. uses an Oracle-based implementation of security and data integrity features to help ensure a fully regulatory-compliant operation, by either using the supplied front-ends or third-party tools to access and update data. A middle-tier, based on XML transactions, provides a transactionlevel interface to support integration of data sources and other data management systems without sacrificing data integrity. The is directly linked to Phoenix WinNonlin, a 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. For sophisticated document authoring support, Reporter, functioning as a Word add-in, provides a direct connection to the database, allowing researchers page 6

7 The Pharsight Knowledgebase Server 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. Phoenix NLME NLME WNL WinNonlin AutoPilot Connect ODBC, CDISC SAS, S+, R, NONMEM, SigmaPlot Word, Excel Deploying Pharsight Knowledgebase Server Pharsight Knowledgebase Server 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 Pharsight Knowledgebase Server provides: Connector Pharsight Knowledgebase Server Reporter 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. Figure 4: Overview of Pharsight Knowledgebase Server Architecture to browse 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. Common analysis tools like SAS and NONMEM are also supported through the use of Phoenix Connect by providing import/export interfaces to their native data file formats. Data 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, Phoenix WinNonlin provides a facility that allows files of any type (ASCII, JPG, DOC, etc.) to be saved to or retrieved as part of a Phoenix project, supporting regulatory-compliant capture of output from a wide variety of visualization and analysis tools. Extension of existing Phoenix WinNonlin 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 and through Phoenix Connect. page 7

8 In summary, the key benefi ts of deploying the Pharsight Knowledgebase Server within a clinical pharmacology organization are: Regulatory Compliance, Improved Productivity, Data Integration and Analysis, Optimized Development Programs, and Advanced Technology and Scalability, Built with Industry Knowledge by experts in pharmacokinetics and pharmaceutical research. Automated tools ( Data Connectors) for importing PK information directly from multiple external data management systems (e.g. LIMS and clinical data management systems such as Oracle Clinical) and flat files (including MS Excel, SAS Transport, CDISC/SDTM). A template-driven report authoring system ( Reporter) for automating the construction and regeneration of compound documents in standardized formats for review and submission. Data mining and data merging tools 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 crossstudy and cross-compound data mining. In addition, Pharsight and its partners can provide services, including: Training classes, either on-site or in a Pharsight facility for the suite products and PK/PD modeling and analysis methodologies. Installation qualification and operational qualification services and tools to help speed validation of a 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. Customized development of Data Connectors to connect to other data sources or to add additional functionality for standard Data Connectors. Benefits of Pharsight Knowledgebase Server In summary, the key benefits of deploying the Pharsight Knowledgebase Server within a clinical pharmacology organization are: Regulatory Compliance 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 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 Pharsight Knowledgebase Server provides an 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. Data 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. page 8

9 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. Advanced Technology and Scalability Pharsight Knowledgebase Server is designed around a component-based and multitiered web/xml architecture supported by the reliability of an Oracle database leveraging the best of current and emerging technologies. And 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 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 the Pharsight sales team using one of the following methods: Phone: Americas Europe: Telephone: +49 (89) [email protected] Web site info request: About Pharsight Corporation Pharsight, a Certara company, is market-leading provider of software products and scientific consulting services to help pharmaceutical and biotechnology companies improve their drug development process, regulatory compliance and strategic decision-making. Established in 1995, Pharsight helps customers reduce the time, cost and risk of drug development, as well as optimize the post-approval marketing and use of pharmaceutical products. Pharsight leverages expertise in its software tools and in the discipline s of pharmacology, drug and disease modeling, human genetics, biostatistics, strategic decisionmaking, and regulatory strategy. Additional information on the company and its products can be found at Pharsight, Phoenix, and WinNonlin are registered trademarks of Tripos, L.P. Trial Simulator, Knowledgebase Server, and 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. page 9

10 Copyright Tripos, L.P. 2011