IXICO: Progressing a scientific GRID project to an endtoend solution

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 90012000
• 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
Grid DemonstratorA Dynamic Brain Atlas
(2001-2002)?
Image database
Patient scan
registration
create atlas
transformation
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
8
IXI components

• 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

• Workflow engine
• Workflow language to combine image analysis
  services

• XML workflow file

10
IXI components

• Web interface to launch workflows
• Grid applications to design workflows and to
  control the execution

11
IXI components

• 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
Application Automatic delineation of bones
calcaneus
Reference image
Subject image
Computed boundary of calcaneus
Manual segmentation
13
Business idea
Baseline

• Automated image analysis for the Drug Development
  Process
• Measurement in Rheumatoid Arthritis eg. grade of
  bone erosion

Start of treatment using drug candidate
14
From the idea to a business plan ...
Founders of IXICO
Prof. David Hawkes
Prof. Jo Hajnal
Prof. Derek Hill
Prof. Daniel Rueckert
15
Business plan

• The Market
• The industry
• Product Unique Selling Preposition
• Sustainable advantage
• The team
• Intellectual Property
• Finance (forecast, funding requirements)?
• Exit strategy

16
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
The Market

• The customers are the pharmaceutical and biotech
  companies
• What does an imaging biomarker product look
  like?

18
Image Analysis in clinical trials
Imaging supplier
Data transfer metadata
Results for database upload
19
Potential revenue growth
Potential Market compared to projected sales
Total Market 161.9m
180
160
140
CNS Oncology 124.6m
120
100
m
80
60
40
IXICO ??m
20
0
2006
2007
2008
2009
2010
Years
20
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
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
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
USP
Due diligence conducted by the Capital Fund
identified unique combination of


Technology
Know-how
Quality system

Image acquisition
Image analysis
24
The team
Prof. Derek Hill
Dr. Thomas Hartkens
Dr. Kate McLeish
James Cameron
Richard Brooman
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 90012000 certification
• Software Validation
• e.g. V-model

28
Audit trail produced by Workflow System
29
Task submission
IWD 1 Coarse Registr. 2 Bias
Correction 3 QC interface
30
Task processing
IWD 1 Coarse Registr. 2 Bias
Correction 3 QC interface
31
Automatic task
IWD 1 Coarse Registr. Date11.12.2006
1345 ResultTransformation Server234.232.43.2
2 Bias Correction 3 QC interface
32
Task processing
IWD 1 Coarse Registr. Date11.12.2006
1345 ResultTransformation Server234.232.43.2
2 Bias Correction 3 QC interface
33
Task processing
IWD 1 Coarse Registr. Date11.12.2006
1345 ResultTransformation Server234.232.43.2
2 Bias Correction Date13.12.2006 359
ResultImage Server234.256.43.8 3 QC interface
34
Manual task
IWD 1 Coarse Registr. Date11.12.2006
1345 ResultTransformation Server234.232.43.2
2 Bias Correction Date13.12.2006 359
ResultImage Server234.256.43.8 3 QC interface
Date15.12.2006 945 ResultComment PersonKate
McLeish
Kate McLeish
35
IXICO's Electronic Audit Trail
36
21 CFR Part 11Electronic 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 Electronic Paper Trail
IXICO's Workflow System
Report Analysis has shown that XY of all
cases ....
IWD 1 Coarse Registr. 2 Bias
Correction 3 QC interface
IWD 1 Coarse Registr. Date11.12.2006
1345 ResultTransformation Server234.232.43.2
2 Bias Correction 3 QC interface
IWD 1 Coarse Registr. Date11.12.2006
1345 ResultTransformation Server234.232.43.2
2 Bias Correction Date13.12.2006 359
ResultImage Server234.256.43.8 3 QC interface
IWD 1 Coarse Registr. Date11.12.2006
1345 ResultTransformation Server234.232.43.2
2 Bias Correction Date13.12.2006 359
ResultImage Server234.256.43.8 3 QC interface
Date15.12.2006 945 ResultComment PersonKate
McLeish
Kate McLeish
40
ISO 90012000 based QMS
41
ISO 90012000

• 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

• Write down what you are doing.
• Follow what you have written down.
• Improve documentation in a controlled way.
• Preserve and improve knowledge base

43
ISO 90012000 certification

• Does NOT certify a product
• But
• certifies that the company works according to the
  ISO 90012000 standard

44
ISO 90012000 based QMS
45
Written procedures
46
Written procedures

• 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
IXICO's QMS
ISO 90012000
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 lt-gt production system
• Electronic company cannot be implemented as a
  business without quality standards.
• Exciting journey

58
Thank you!
59
Traceability
Software Design Specification
60
IXICO Milestones
06/04
01/07
01/05
06/05
01/06
06/06
First business plan written
Incorporated
Licenced Imperial IPR
Licenced KCL IPR
Lead investment completed
Started trading
YFM investment offer letter signed
UCL option agreement signed
around 5m of investment
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 -gt 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
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