1. Copyright © 2005 Rockwell Automation, Inc. All rights reserved. 1 Clinical Trials Supply Management Kevin Walls Rockwell Automation Life Sciences Global Industry Consultant

2. 2 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Agenda 1. Clinical Supply Industry Drivers 2. Reducing Risk 3. Increasing Efficiency 4. Optimizing the Clinical Material Supply Chain 5. Conclusion

3. 3 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. What’s Keeping You Up at Night? How can I optimize my clinical supply chain? How can we ease compliance to regulatory authorities? What will it take to integrate all of my data and systems? Is my study data secure? How can I ensure safety down to patient level? Clinical Supply Excellence How should I interact with my business partners? Would a partner help solve my business issues faster and better? How can I increase the accuracy of my demand forecast? How can I drive global business? Am I getting a long term cost effective solution? How can I lower Operational costs?

4. 4 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Life Sciences Industry Challenges In the Industry’s Own Words: “Redefining our discovery and development process to yield new products more efficiently” “Reduce spending per by 15 to 20% in the U.S.” “Reducing inventory by $400 million and saving $1.2 billion in procurement by 2008” “Redesigning all of our end-to-end processes” “Strengthened capabilities in vertical integration to secure future cost competitiveness” “Scale in manufacturing and infrastructure in low cost regions” “Integration of a global manufacturing network” “Globalization, centralization and standardization of clinical trial operations and data management” “Creation of one Pharmaceutical Development “center of excellence” between R&D and Manufacturing” Source: Various life sciences manufacturing's investor relations presentations

5. 5 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. R&D Spend for New Drug Approval Increasing R&D spending with less output Increase of R&D costs by 400% over the last 20 years Decreasing output of approved new drugs Spending per new drug significant increased Failing studies becomes more expensive

6. 6 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. New Drug Application: Trials and Patient Numbers Increasing number and complexity of Clinical Trials Number of clinical trial per NDA doubled over the last 20 years Number of needed patients tripled Clinical trials have trended steadily higher in both cost and complexity Clinical Supplies have to handle more and more throughput

7. 7 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. CTM Material Waste Bulk dose overage Patient kit overage Source: Managing the Impact of Personalized Drugs on Clinical Trial Supply Operations, F nk Schulze, 2004 Best in Class companies reduce material overage by 4-5 times average Companies are producing in average 30% - 50% material overage Best in Class companies are able to lower overage

8. 8 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Working with Business Partners % of Activity outsourced by companies Source: Managing the Impact of Personalized Drugs on Clinical Trial Supply Ope tions, F nk Schulze,.2004 Outsourcing requires the right information exchange platform Companies are still looking for the “golden” outsourcing strategy Virtual companies are outsourcing almost 90% of all activities

9. 9 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Agenda 1. Clinical Supply Industry Drivers 2. Reducing Risk 3. Increasing Efficiency 4. Optimizing the Clinical Material Supply Chain 5. Conclusion

10. 10 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Potential Risk in Clinical Supply Seeing complexity of the clinical supply chain … –Aligning the supply strategy to the short shelf life of biological IMP –Complying with regulatory rules of multiple countries –Country specific import and export regulations –Late changes of the protocol –Inconsistent patient recruitment process –Country specific labeling requirements … leads to higher business risk –De-blinding risk of the study –Out of stock situation at the investigator site –Inconsistencies in lacking individual patient data throughout process –Expensive supply of IMP

11. 11 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Clinical Supply Risk Mitigation Manage the risk by: –Providing transparency to the clinical supply processes –Balancing flexibility vs. optimization –Taking capabilities from the API down to the patient –Effective material demand planning –GMP compliant execution of Manufacturing and Packaging –Ensuring study blinding with Randomization and tailored Clinical Supply labeling

12. 12 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. An Integrated Process Reduces Risk Input for NDA Report Destruction of kits Fast input over web application Automatic gene tion of study reconciliation report 10 Returns of kits Interface to IVRS, EDC Fast input over web application 9 Patients (kit dispense) Interface to IVRS, EDC Fast input over web application 8 IMP control on the investigator site Inventory Management Retest, Recall-Management 7 Shipment Fast input over web request Efficient prepe tion and status control Interface to external systems 6 Clinical Packaging Just in time labelling triggered over WEB or IVRS 5 Bulk MFG Integ ted supply chain planning from API to KIT 4 Chemical/ pharmaceutical Development / API MFG Expand flexibility for GLP Restricted for GMP Interface (PLC, PCS) Process 3 Study and protocol setup Fast input over web request Interface to external systems Approval 2 New Project Efficient project planning over all tasks / milestones Automatic update over process & web Everyone works to the same plan using a cent l deposit 1 Project planning Approvals Material control

13. 13 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. GMP Challenges in Clinical Supply Ensure compliance to cGMP for investigational drug products –Apply appropriate cGMP controls for the manufacture of investigational drugs during development –Providing a complete set of GMP documentation Coping with regional differences within Good Manufacturing requirements –European Guide to Good Manufacturing Adhere to cGMPs for placebos used in investigational studies Ensure complete tracking and audit till capabilities meet regulatory requirements

14. 14 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Key GMP Principals Addressed by a Clinical Supply Solution Quality –Integrated material testing –Documentation of process and quality issues with Electronic Batch Recording –Labeling for the API’s intended use Equipment and Facility –Support of Equipment calibration and cleaning with integrated Dispensing and EBR –Material handling to minimize the risk of contamination and cross-contamination enabled by material identification and material tracking Production –Documentation in batch records, providing information of use materials, equipment, processing and scientific observations supported by MBR Change control –Documentation of every change in the production and specification procedures provided by approval workflow and audit tracking Documentation –Ensure that information gained during the development is documented and available with MBR

15. 15 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Electronic Batch Recording for Compliance and Efficiency Interactive electronic work instruction guides the operator through manufacturing and packaging processes and eliminates documentation errors Automated identification with barcode and RFID process speeds up the manufacturing and packaging processes Automated recording of deviation reduce the documentation effort Mobile solution optimize operational processes and increase efficiency

16. 16 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. EBR Document Reductions Documents –Pages30 - 50% reduction in pages –Entries30 - 60% reduction in entries –Creation25 - 40% reduction in document creation / revision time –Number10 - 25% reduction in number of documents

17. 17 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Clinical Supply and Patient Risk Wrong medication packed and shipped in patient kits Inconsistent processes for tracking and tracing from patient kit to API and backwards Potential wrong information in emergency labels or emergency letters Improper label context in regards to –Direction for use –Warning phrases Expired material Lack of drug at sites is a risk to patient health

18. 18 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Key Patient Risks Mitigated with a Clinical Supply Solution Avoid mis-packed material by controlling instances during the packaging process CTM unique medication identifier provides verification that the right medication is assembled for the individual patient kit CTM creates a complete material genealogy down to the individual medication throughout the manufacturing and packaging processes The material genealogy is the source for any emergency labels or letters ensuring the right information which are integrated in the CTM labeling capabilities Complete approval workflows significantly lower the risk of releasing improper information integration of the labeling content with the packaging execution assures the use of the correct label text phrases

19. 19 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Example: Reducing Patient Risk with Visit Box Control 2. Scann visit box (unique barcode number) 3. Scan each component e.g. bottles 4. System check – bottle matches visit box Alert! If wrong bottle scanned 1. initialization order step displays patient list on mobile scanner 5. Update visit box and patient information

20. 20 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Other Risks in Clinical Trials Inherent risks to the security of study data with clinical supply activities –Insufficient Randomization algorithm could lead to a biased assignment of patient/kits to treatments –The missing quality of clinical labels, especially for re-supplies, could cause unblinding of patient blocks or a whole study –Uncontrolled access to data, especially Randomization data, is a threat to keep the blinding

21. 21 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Lowering Bias and Unblinding Risk Extensive Randomization capabilities reduce risk –Proper Randomization is required to generate unbiased comparison groups in controlled trials –Management of several Randomization per study –Symmetric and asymmetric Randomization –Consecutive and non-consecutive Randomization –Multiple patient sets –Stratification Integrated Labeling tools reduce risk –Automated tracking and allocation of printed labels for the packaging process ensures the use of the “right” labels –Simple re-reprint capabilities for re-supplies lowers unblinding risks

22. Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Integrated Label Creation Reduces Risk Output: Printed labels Output: Printed labels Check labeling system set up Complete label documentation Print labels check quality and count Quality control Randomization generation process Output: Random list Output: Random list Biometrics Label approval Clinical, Distribution site Set up and program label text in labeling system approved phrases from text library CPO - Clinical Protocol Outline: Drafted and approved including fixed supplies information. Internal order for labels. Final approved CPO Input:

23. 23 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Agenda 1. Clinical Supply Industry Drivers 2. Reducing Risk 3. Increasing Efficiency 4. Optimizing the Clinical Material Supply Chain 5. Conclusion

24. 24 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Challenges to Clinical Supply Efficiency Extensive operator involvement with manufacturing and packaging processes Intensive quality control requirements Unplanned material overages Lengthy paper based approval processes Low equipment efficiency Manual and time consuming documentation processes Time intensive quality control of documentation Untimely data collection from diverse global environments

25. 25 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Increase Efficiency in Dispensing Dispensing solution ensures the right use of material with batch identification and eliminates loss of batches Guided dispensing capabilities reduce number of operators errors Automated tracking and electronic signature capabilities reduces number of operators in the weighing cabins Automated integration of Weighing protocol into the Batch Record

26. 26 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Typical Dispensing Operation

27. 27 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Impact of Automated Weigh & Dispense

28. 28 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Lower Operational Costs Quality review –Review by exception speeds up the Batch record review process Workflow support –Workflow orientated approval processes of master recipes speeds up idle time of processes –Reusable text libraries speeds up the label text translation –Global web based approval workflow for clinical label layouts Scheduling –Finite scheduling of resources increase the efficiency of equipment, room and operator use

29. 29 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Agenda 1. Clinical Supply Industry Drivers 2. Reducing Risk 3. Increasing Efficiency 4. Optimizing the Clinical Material Supply Chain 5. Conclusion

30. 30 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Time to Market Accelerating a product launch by 2 years could increase the revenue by $600 million An effective Clinical Trial Supply management can help to improve the product launch date What are delays costing you? $1M, $2M, or more?

31. 31 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. The cost of 1 day Total cost of project staff and operations, internal and external: –average $70 thousand per day Advance 1 day towards expiry date (risk further delay) Advance 1 day further through seasonality of indication (risk full year delay) Delayed revenue in patent life –$500 million drug: 1 lost day costs $1.3 million+ –$1 billion drug: 1 lost day costs $2.7 million+ Costs of delayed revenue is unrecoverable at end of patent life

32. 32 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Streamlined Clinical Supplies Releases Earlier Product Revenue Improving the manufacturing, packaging and shipping processes by factor 3 could accelerate revenues by $100 Million for a $1 billion drug Speed up your Clinical Supply chain with your Clinical Supply solution

33. 33 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Clinical Trial Forecasting Clinical Trial forecasting utilize many complex factors like: –Varying enrollment rates –Drop percentages –Existing distributed inventory –Re-test dates –Study design (Dose escalation, Crossover, Titration,…) –Country specific start times of studies Typical MRP systems are not able to handle all of these factors

34. 34 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Demand-Planning in Clinical Supply Solutions and ERP (MRP) Demand table PP/MM MRP CTM Clinical Forecast ERP (MRP) Purchase Orders Planned Orders Production Planning Inventory bookings Execution Master data Distribution Master data material master data CTMS Estimated Demand (Item-Quantity & Date) Advice for incoming material Investigator/Patient screening Distribution routes Predictive Forecast Lead Time Initial/Safe Stock reorder points Simulation Inventory Project Cost controlling Inventory Study Information Countries Recruitment rate dropout rate

35. 35 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Integrated IT systems improve demand forecasting Kit Structure Kit Structure Study Modelling Study Modelling Study Enrollment Plan Study Enrollment Plan Inputs –Detailed study protocol –Sites and countries involved in the study –Recruitment rate dropout rate –Expire/retest dates –Packaging size –Distribution routes –Shipment size –External/internal resources Outputs –Forecast demand for IMP kits (Pack types) Dosage form Component materials Drug substance –Production schedule –Distribution schedule –Inventory Re order points IT Systems Complex Studies require IT support for successful SCM Distribution strategy

36. 36 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Using Simulation to Improve the Clinical Supply Chain Simulation of clinical supply chain –Visualizing of the entire CTM process including all of its assumptions, variability, interdependencies, and conflicts –Analyzing the trial progress in advance Titration scenarios, recruitment rate, approval times,.. and the effects on the resource levels (material, workload of the CTSU, contractors,..) and processes using a powerful dynamic, flexible simulation capability –Decrease inventory, secure supply readiness and save costs by making decisions and changes knowing in advance the most probable result

37. 37 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Clinical Supply is a Global Business Lack of worldwide harmonization of the clinical supply processes –Each site is not able to act as back up of each other one for full or partial process –Resources needs to be managed in common tools & databases Trend to run Clinical Trials in Asia/Pacific area Limitation of being able to deliver clinical material to Asia area, based on incapability to print labels in Chinese, Japanese, Indian languages, …. Most top 10 Pharma Companies utilize worldwide Clinical Supply units New challenges created by globalization and expanding trials in Asia

38. 38 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Communication is the Key WEB based requests harmonize how clinical supply customer formulates their needs One central database provides visibility to all sites One central data repository provides a common communication platform for all stakeholders Logical separation of data by site Cont ctors CRO Biometric Statistics Biometric Statistics Distributors Clinic Centers Study Coordinator Investigators Affiliates Medical/ Monitor Medical/ Monitor Clinical Supply Site USA Clinical Supply Site Germany Clinical Supply Site Japan Qualified Person cent l database Repository

39. 39 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Labeling for Global Customer Unicode support for all label text libraries Capabilities to easily print clinical supply labels in Asia/Pacific languages

40. 40 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Drive Tangible Benefits in a Global Clinical Supply Chain One system for all clinical sites is driving common business processes No timely and error prone information and data transfer necessary using one common data repository Global data visibility is supporting the right business decisions Optimized use of GLOBAL resources Printing labels in native languages for all countries in the world Consistent information drives global business performance

41. 41 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Outsourced Supply Chain Management Planning Shipping Synthesis Shipping Packaging Formulations Shipping Packaging and Labeling Formulations Packaging and Labeling Outsourced In-house Need to support the business object outsourcing order All material movements must be tracked within the outsourcing order Complete material genealogy incorporates outsourced activities Outsourcing order

42. 42 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Challenge Areas Around Outsourcing Outsourcing needs a high degree of coordination and information exchange especially in the areas of: –Process - What gets done Where –Performance - How is the cont ct manufacturer performing –Organization - Who is responsible –Information Systems - Get information in time to make decisions Missing information linkage creates error prone, manual and timely processes to handle contract manufactures

43. 43 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. IT Challenges with Business Partners Information exchange of Clinical Supply unit and Contract Manufacturers is based on many sources, e.g. Descriptions on paper Communication via Email notifications, phone calls… Electronic information in various systems of varying data formats Different material / batch numbers And sometimes there is no information exchange at all, e.g. material shipped out without any announcement … How to trace material? How to get Real Time Status Information ?

44. 44 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Example Clinical Supply Solution - IVRS Information Flow – Complex! Clinical Supply Solution Project information Study information Study design Clinical ResearchAddresses Warehouse/Distribution Center Material randomization Supply request Material availability Batch data (Status/Retest) Shipping (Consignment) request Shipping (Consignment) order Shipping (Consignment) receipt Patient dispensing Unblinding (Patient kit) Destroy Back Shipping IVRS Project information Study information Study design Clinical ResearchAddresses Warehouse/Distribution Center Material randomization Supply request Material availability Batch data (Status/Retest) Shipping (Consignment) request Shipping (Consignment) order Shipping (Consignment) receipt Patient dispensing Unblinding (Patient kit) Destroy Back Shipping 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

45. 45 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Integrated Systems Improve Trial Supply Operations and Reduce Complexity  Status update triggered via IVRS arrival message

46. 46 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Agenda 1. Clinical Supply Industry Drivers 2. Reducing Risk 3. Increasing Efficiency 4. Optimizing the Clinical Material Supply Chain 5. Conclusion

47. 47 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Summary Reduce the expense and improve efficiency Mitigate the risk Shorten the timeline of clinical trials through properly managed clinical material supply Do material planning Link systems to assure that drug supply continuously meets demand Optimize supply for your clinical trials

48. 48 Copyright © 2005 Rockwell Automation, Inc. All rights reserved. Thank You Rockwell Automation has the solutions to meet your Clinical Supply Chain Needs