1. IXI(CO): Progressing a scientific GRID project to an end-to-end solution Thomas Hartkens, CTO

2. Overview A brief history of IXI From the idea to a business plan Challenges in the first two years – GCP – Maintaining an audit trail and FDA 21 CFR part11 – Quality Management System / ISO 9001:2000 – Software validation Conclusion

3. Why using Grid in Automated Medical Image Analysis? Huge volume of image data –hospitals typically produce several tera bytes per year –results of automated image analysis can be few times larger Computationally demanding algorithms - sophisticated image analysis of one single image can take several hours (or even days) Multiple processing steps (Workflows) - one solution consists often out of many single applications Collaboration of different insitutions - is often required in clinical trials or research studies

4. Image database Grid Demonstrator: A Dynamic Brain Atlas (2001-2002) registration create atlas Atlas Patient scan transformation Computational expensive ! DB query

5. Opening of the National e-Science Centre (NeSC), April 2002

6. Grid-enabled image registration and segmentation for medical research: – to assess scalability of Dynamic Brain Atlas – to extend to data from outside the brain – to build an application interface 3 year project funded by e-science core programme & GSK, Philips Medical Systems, Dunhill Charitable Trust

7. IXI components IXI Portal GT3 Index Service IXIWorkflow service IXI insertion Service IXI Core Service Compute Resources Service Provider #1 IXI Core Service Compute Resources Service Provider #2 Medical Image Database Available ServicesAggregations of MICL SDEs Workflow submission Invocations & Notifications Result management GridFTP

8. IXI components IXI Portal GT3 Index Service IXIWorkflow service IXI insertion Service IXI Core Service Compute Resources Service Provider #1 IXI Core Service Compute Resources Service Provider #2 Medical Image Database Available ServicesAggregations of MICL SDEs Workflow submission Invocations & Notifications Result management GridFTP Algorithms wrapped as grid services for medical image analysis, e.g. image segmentation image registration non-rigid registration: run-time on single CPU between 10 minutes and 24 hours

9. IXI components IXI Portal GT3 Index Service IXIWorkflow service IXI insertion Service IXI Core Service Compute Resources Service Provider #1 IXI Core Service Compute Resources Service Provider #2 Medical Image Database Available ServicesAggregations of MICL SDEs Workflow submission Invocations & Notifications Result management GridFTP Workflow engine Workflow language to combine image analysis services XML workflow file

10. IXI components IXI Portal GT3 Index Service IXIWorkflow service IXI insertion Service IXI Core Service Compute Resources Service Provider #1 IXI Core Service Compute Resources Service Provider #2 Medical Image Database Available ServicesAggregations of MICL SDEs Workflow submission Invocations & Notifications Result management GridFTP Web interface to launch workflows Grid applications to design workflows and to control the execution

11. IXI components IXI Portal GT3 Index Service IXIWorkflow service IXI insertion Service IXI Core Service Compute Resources Service Provider #1 IXI Core Service Compute Resources Service Provider #2 Medical Image Database Available ServicesAggregations of MICL SDEs Workflow submission Invocations & Notifications Result management GridFTP large data set of MRI brains ~550 normal volunteers age range 20-80 years T1, duel echo (proton density and T2 weighted) acquired at 3 different sites publicly available to research community

12. Reference image Subject image Rigid + non-rigid registration Manual segmentation Computed boundary of calcaneus Application: Automatic delineation of bones calcaneus Elastic Transformation Apply transformation

13. Business idea 3 months later6 months later 9 months later Automated image analysis for the Drug Development Process Measurement in Rheumatoid Arthritis: eg. grade of bone erosion Baseline Start of treatment using drug candidate

14. From the idea to a business plan... Prof. David Hawkes Prof. Jo Hajnal Prof. Derek Hill Prof. Daniel Rueckert Founders of IXICO:

15. Ixico Present ation Business plan The Market The industry Product & Unique Selling Preposition Sustainable advantage The team Intellectual Property Finance (forecast, funding requirements) Exit strategy

16. Ixico Present ation A crisis in drug discovery & development Imaging can help… Imaging is a key technology for assessing, accelerating the development of, and guiding the use of new therapeutic options George Mills, FDA It is estimated that between $10m and $30m could be saved per drug program through the use of advanced imaging technologies which could guide go/no go decisions. Business Insights Journal, May 2006

17. Ixico Present ation The Market The customers are the pharmaceutical and biotech companies What does an imaging biomarker product look like?

18. Ixico Present ation Imaging supplier Image Analysis in clinical trials Results for database upload Data transfer metadata Image scoring and analysis Procedures Study set-up, regulatory charter, Site management (training, SOPs…)

19. Ixico Present ation Potential revenue growth Potential Market compared to projected sales Total Market £161.9m IXICO £??m CNS & Oncology £124.6m 0 20 40 60 80 100 120 140 160 180 20062007200820092010 Years £m

20. Ixico Present ation Image analysis suppliers Dominated by small number of companies that specialise in traditional radiological reading Fastest growth is in more sophisticated methods – Regulator push for methods that are less subjective – Industry need for more precise measures for better, faster, cheaper decision making

21. Ixico Present ation Product Advice on image acquisition parameters Automated image analysis service Quality control of analysis results Quality Management System Electronic audit trail Site Management Data logistics Imaging charter for regulators (FDA)

22. Ixico Present ation Product Advice on image acquisition parameters Automated image analysis service Quality control of analysis results Quality Management System Electronic audit trail Site Management Data logistics Imaging charter for regulators (FDA)

23. Ixico Present ation USP Image acquisitionImage analysis + Due diligence conducted by the Capital Fund identified unique combination of: TechnologyKnow-howQuality system ++

24. The team Dr. Thomas Hartkens Dr. Kate McLeish James Cameron Richard Brooman Prof. Derek Hill Ian Alexander

25. IXICO's non executives Peter Morgan – Chairman – Executive career with IBM and experience on several company boards – Formerly Director General of the Institute of Directors in London. Prof. Sir Michael Brady –Track record of building successful entrepreneurial companies using academic technology (most recently Mirada, acquired by CTI) Prof. Sir Colin Dollery –Clinical pharmacologist and leading authority on Clinical Trials –Senior consultant in GlaxoSmithKline (GSK): adviser to Dr Yamada the Chairman of Research and Development and member of the committees that review all protocols for human research, on the Development Investment Board and on the Global Safety Board Peter Ellis –Executive Director of People in Health and previously senior partner in Ernst & Young's Global Consulting life sciences practice.

26. Challenges in the first two years

27. Good Clinical Practise (GCP) Audit Trail Electronic audit trail compliant with FDA 21 CFR part 11 Quality Management System ISO 9001:2000 certification Software Validation e.g. V-model

28. 28 Audit trail produced by Workflow System Reference + Image data

29. 29 Task submission IWD 1 Coarse Registr. 2 Bias Correction 3 QC interface

30. 30 Task processing IWD 1 Coarse Registr. 2 Bias Correction 3 QC interface

31. 31 Automatic task Image analysis application IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction 3 QC interface Results & Audit trail information

32. 32 Task processing IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction 3 QC interface

33. 33 Task processing IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction Date:13.12.2006 3:59 Result:Image Server:234.256.43.8 3 QC interface

34. 34 Manual task Custom-made interface IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction Date:13.12.2006 3:59 Result:Image Server:234.256.43.8 3 QC interface Date:15.12.2006 9:45 Result:Comment Person:Kate McLeish Kate McLeish Results & Audit trail information & Digital Signature

35. 35 IXICO's Electronic Audit Trail Result images Electronic Audit Trail IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction Date:13.12.2006 3:59 Result:Image Server:234.256.43.8 3 QC interface Date:15.12.2006 9:45 Result:Comment Person:Kate McLeish Kate McLeish

36. 21 CFR Part 11 Electronic records; electronic signatures Designed to provide FDA assurance that electronic records / signatures are – Trustworthy – Reliable Equivalent to paper records and handwritten signatures Applies to all FDA regulated industries

37. 21 CFR part 11

38. Requirements Electronic records Controls aimed at security and integrity of records What information needs to be included with a signed electronic record How the signature must be linked to the record Electronic signatures Unique to an identified individual Components of an electronic signature (in general, 2) Security and integrity of ID codes and passwords Software validation

39. IXICO's Workflow System IXICO's Electronic Paper Trail Automatic Task IWD 1 Coarse Registr. 2 Bias Correction 3 QC interface IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction 3 QC interface IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction Date:13.12.2006 3:59 Result:Image Server:234.256.43.8 3 QC interface IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction Date:13.12.2006 3:59 Result:Image Server:234.256.43.8 3 QC interface Date:15.12.2006 9:45 Result:Comment Person:Kate McLeish Kate McLeish IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2 2 Bias Correction Date:13.12.2006 3:59 Result:Image Server:234.256.43.8 3 QC interface Date:15.12.2006 9:45 Result:Comment Person:Kate McLeish Kate McLeish Derek Hill Manual Task Automatic Task Report Analysis has shown that XY% of all cases....

40. ISO 9001:2000 based QMS

41. ISO 9001:2000 Does NOT say anything about the quality of the product. BUT guarantees a constant product quality or an improvement of quality over time.

42. Idea of QMS 1.Write down what you are doing. 2.Follow what you have written down. 3.Improve documentation in a controlled way. Preserve and improve knowledge base

43. ISO 9001:2000 certification Does NOT certify a product But certifies that the company works according to the ISO 9001:2000 standard

44. ISO 9001:2000 based QMS 4. Quality Management System 5. Management responsibilities 6. Resource management 7. Product realization 8. Measurement, analysis and improvement

45. Written procedures System deployment procedure

46. Written procedures System deployment procedure Contract Agreement Contract Amendment Contract Processing Overview Site Management Site Training Protocol Optimization Adverse Findings Data Transfer Data Admission Data Export Data Delivery Software Design Workflow System Deployment Workflow design Software Transfer Control of documents Control of records Internal audit Issue tracking Control of Nonconformity, Corrective and Preventive Action Customer Feedback Document Review Document Version Control Training Recruitment Purchasing Risk Assessment IP Transfer

47. Document control

48. Document server

49. Documents and records

50. Internal or external audit ISO 9001:2000 IXICO's QMS 1. 2.

51. Management responsibility To define measurable objectives Involvement of people: creates an environment where people become fully involved in achieving the organization's objectives Leadership: is needed to provide unity of purpose and direction Review

52. Product realization Customer-related processes –Determination / review of product requirements –Customer communication Design and development –Definition of inputs and outputs of design –Planning –Verification and Validation Purchasing Production and service provision Control of service provision; Validation of service Identification and traceability of product

53. FDA: Software validation Diagram by Alford Taylor, Director, Devision of Electrical and Software Engineering, CDRH / FDA

54. Software design procedure: V-model

55. Traceability Matrix

56. End-to-end solution

57. Conclusion Innovations in the technology might not be selling point Research implementation production system Electronic company cannot be implemented as a business without quality standards. Exciting journey

58. Thank you!

59. Traceability Software Design Specification Functional Specification Software Req. Spec.

60. Ixico Present ation IXICO Milestones around $5m of investment First investment round First business plan writtenIncorporatedLicenced Imperial IPRLicenced KCL IPRLead investment completedStarted tradingYFM investment offer letter signedUCL option agreement signed 06/0401/0701/0506/0501/0606/06

61. Summary Business plan (3 months) Negotiations with colleges and IP license agreements (6 months) First investment round (12-18 months) setting up first office (1 week) Quality Management System – writing initial Quality Manual & Procedures (4 months) – setting up document control & non-conformity tracking (2 months) – establishing processes and procedures (8 months) FDA 21 CFR part 11 (4 months)

62. Conclusion business model research implementation and production system timeline, QoS, provenance, Innovations realized the technology might not be selling point Stability of technology; company needs to be based on reliable technology. exciting journey electronic company -> cannot be implemented as a business without the quality standards.

63. Management review Quality Management System Customer complaints and feedback Results of internal and external audits Progress of corrective and preventive actions IXICO's policy, objectives, and targets

64. Resolving non-conformities

65. Ixico Present ation The Image Analysis market Includes Acquisition design Imaging protocol (charter) for regulator Site management Data logistics Image analysis (scoring or automatic) Excludes Recruiting patients Scanning patients Clinical assessment of patients