AN INTRODUCTION TO THE PHARSIGHT KNOWLEDGEBASE SERVER (PKS )

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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.

Insuffi cient 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

AN INTRODUCTION TO THE

PHARSIGHT

®

_{KNOWLEDGEBASE}

SERVER™ (PKS™)

Optimizing the value of Pharmacology

Knowledge in Early Drug Development

PKS

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 scientifi c researchers must become more effi cient and productive, freeing critical skilled resources needed to learn and deploy these new technologies.

This fl ood 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

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Tripos - Pharsight PKS

“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 fi le-based systems for managing PK data and analysis activities are often not compliant with these regulations and these defi ciencies cannot easily be addressed via new standard operating procedures (SOPs) or changes to manual processes alone. Manual report preparation and review workfl ow 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™ (PKS™), PKS Reporter™, PKS 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 unifi ed 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. PKS 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.

PKS offers an integrated solution to the key challenges facing pharmacokinetic researchers and the IT/QA groups supporting them:

■ Regulatory Compliance Helping

to fulfi ll regulatory requirements as outlined in FDA’s 21 CFR Part 11 (Electronic Records & Electronic Signatures) by replacing current fi le-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 scientifi c 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 fi les and proprietary databases) with incompatible formats. Productivity

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Tripos - Pharsight PKS page 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.”

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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 unifi ed 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 signifi cant reductions in reporting backlog and productivity improvements that can free up the scientifi c resources needed to adopt these new technologies.

Benefi ts 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 scientifi c

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 is also improved in report authoring

and review/approval process by providing a unifi ed data repository, a regulatory-compliant document authoring platform, and workfl ow 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. PKS 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.

Figure 1: Inversion of the Confi dence Curve in Drug Development

Phase I Phase II Time/Money Confidence of Approval Phase III Current Desired

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“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.“

desktop tools (e.g. WinNonlin and Microsoft Word) and distributed web-based tools (e.g. PKS Administration tool, Query tool).

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 fi gures, tables, and listings and help prepare the reports needed for PK and PK/PD studies. Phoenix WinNonlin can also save any type of fi le from any application into PKS, providing regulatory-compliance via electronic signatures, reason for change, audit trail and versioning.

PKS Reporter: 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 PKS, 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 fi les and analysis runs for SAS, NONMEM, S-PLUS and SigmaPlot in Phoenix Workfl ows. It also provides access to PKS for all Phoenix-based products.

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 PKS is built with a sophisticated three-tier architecture supporting both traditional 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.

Figure 2: Pharsight Knowledgebase Server

Phoenix WinNonlin Phoenix AutoPilot

Phoenix Connect Word

Excel NONMEM SAS S-PLUS R SigmaPlot PKS Connectors Pharsight Knowledgebase Server Phoenix WinNonlin PKS Connectors

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data tables, summary statistics and comprehensive scientifi c 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 fi les, SAS Transport fi les, and Excel spreadsheets, as well as automated loading of data from ASCII fi les, SAS Transport fi les, 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 confi gured via the PKS Connectors.

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 fi les 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 Phoenix WinNonlin, Microsoft Excel, and Microsoft Word, to construct, update, review, approve, and validate any type of report. Improves scientifi c 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

PKS Data Connectors: The PKS 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. PKS Connectors can be confi gured 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 Confi guration: Administration tools to manage system security (e.g. grant access permissions for studies to users and groups of users) and to confi gure the system to meet company-specifi c needs, set defaults for system interfaces, as well as the defi nition 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

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“The Pharsight Knowledgebase Server has

been designed as a modern N-tier architecture

to support the most demanding stability and

scalability requirements.”

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 browser-based front-end. The Java-browser-based middle-tier can be deployed on Apache Tomcat and WebLogic.

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 front-ends 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 sacrifi cing data integrity. The PKS 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, PKS Reporter, functioning as a Word add-in, provides a direct connection to the PKS database, allowing researchers 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 sacrifi cing regulatory compliance.

■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

Figure 3: Overview of Pharsight Knowledgebase Server (PKS) Server Client Tier Client Tier Middle Tier PKS Application Server PKS PK/PD Data Repository PKS Database Database Tier JDBC Third Party Analysis Tools Client Tier 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 SigmaPlot PKS Reporter Phoenix WinNonlin Phoenix NLME http(s), xml Phoenix Connect Phoenix AutoPilot Web Browser R NONMEM S-Plus SAS Data Connectors

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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:

■ Management and administration of

the database infrastructure, including security and confi guration.

■ Secure data storage and retrieval to

support regulatory compliance (21 CFR Part 11) efforts.

■ 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 fi le-based exports to their native fi le formats and through Phoenix Connect.

data fi le formats. PKS 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 fi les 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.

to browse PKS studies and scenarios, inserting and updating document objects (referenced by tags inserted into the Word fi le). 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

NLME WinNonlin Connect AutoPilot Word, Excel SAS, S+, R, NONMEM, SigmaPlot ODBC, CDISC PKS Reporter

NLME

WNL

Phoenix Pharsight Knowledgebase Server

PKS

PKS Connector

Figure 4: Overview of Pharsight Knowledgebase Server Architecture

“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.“

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“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.”

■ Improved Productivity 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 benefi cial 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. PKS 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.

■ 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

Data Connectors to connect to other data sources or to add additional functionality for standard PKS Data Connectors.

Benefi ts of Pharsight Knowledgebase Server

In summary, the key benefi ts 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 fi le-based research management practices.

■ Automated tools (PKS 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 fl at fi les (including MS Excel, SAS Transport, CDISC/SDTM).

■ A template-driven report authoring

system (PKS 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 cross-study 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 PKS suite products and PK/PD modeling and analysis methodologies.

■ Installation qualifi cation and operational

qualifi cation services and tools to help speed validation of a PKS installation.

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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 +1-919-852-4685 Europe: Telephone: +49 (89) 45103036 Email: [email protected]

Web site info request:

http://www.pharsight.com/contact/Info_Request.html

About Pharsight Corporation

Pharsight, a Certara company, is market-leading provider of software products and scientifi c 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 decision-making, and regulatory strategy. Additional information on the company and its products can be found at www.pharsight.com.

Pharsight, Phoenix, and WinNonlin are registered trademarks of Tripos, L.P. Trial Simulator, Knowledgebase Server, 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.

■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 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

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.

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www.pharsight.com