1. Highlights from ExLPharma’s Proactive GCP Compliance March 29-31, 2010 Arlington, VA

2. GCP in Emerging RegionsEthics, Quality, and Compliance 1

3. The Objectives of Clinical Research To Contribute to Public Health To Contribute to Health Science To Contribute to Economic Development

4. Good Clinical Practice A Set of Responsibilities ‘a process that makes all parties to a study responsible for patient safety and study quality’

5. US & EU Objectives inHarmonizing GCP(3 August 2009, Launch of a Bilateral GCP Initiative) To achieve common understandings and practices To share standards and methodologies To share knowledge To share resources To improve human subjects protections

6. Challenges to GCP Harmonization The extensive reach of clinical trials The complexity of law and regulation Lack of an internationally agreed code of ethics for human research protections The progress of medical science The lack of appropriately representative platforms

7. Current Ethical Challenges to GCP in Clinical Trials (1) The use of control arms (placebo) ‘Standard of care’ Informed consent process Community consultation Individual and community access to research The role & responsibility of ethics committees (IRBs/ECs) Compensation for trial injury Patient/Participant Confidentiality and Privacy Locating phase I, II, and III trials Pharmacovigilance

8. Current Ethical Challenges to GCP in Clinical Trials (2) Medical treatment during the course of research Product availability Sponsorship Liability & Insurance Tissues Stem Cell Research Data Protection Monitoring (DMCs) Data Ownership Proprietary Information/Knowledge Publishing Clinical Trial Information and Results Botanical/Traditional Medicines

9. Dimensions of GCP General Frameworks WHO GCP ICH GCP Regional/Applied Frameworks EU GCP US CFR National/Applied GCP Guidelines China, India, Russia, Singapore, Malaysia, Indonesia, South Korea Argentina, Brazil, Mexico, South America, South Africa, Turkey

10. The Way Forward for GCP Further National & Regional Development(e.g., CTTI, The AfroGuide Project) A Broader Scope to Include All Health Research Modernizing Guidance to Meet New Developments (e.g., Registries, Results Publication, DMCs, Insurance, Regulatory Science) Appropriate National, Regional, & International Platforms A Broad and Comprehensive Vision Complimented by Small Steps

11. Proactive GCP ComplianceInvestigator Responsibilities Guidance& A Few Comments on AE Reporting

12. CI Responsibilities Guidance Supervision of the Conduct of a Clinical Investigation What Is Appropriate Delegation of Study-Related Tasks? What Is Adequate Training? What Is Adequate Supervision of the Conduct of an Ongoing Clinical Trial? What Are an Investigator’s Responsibilities for Oversight of Other Parties Involved in the Conduct of a Clinical Trial? Protecting the Rights, Safety, and Welfare of Study Subjects

13. Investigator Longevity(Length of time in active 1572) Source: CenterWatch Analysis 2001

14. Migration of Clinical Trials into the Private Sector

15. Standard Operating Procedures Site Solutions Summit 2009 Survey

16. Quality Assurance Program Site Solutions Summit 2009 Survey

18. Number of CRF pages increases from 55 to 180 pages

19. Controlling for treatment duration, cycle times increased substantially

20. 12% longer protocol readiness to FPFV

21. 70% longer from protocol readiness to data lock

22. Enrollment rates worsened

23. Screen to randomized dropped from 75% to 59%

26. Whether study staff received adequate training on how to conduct the delegated tasks and were provided with an adequate understanding of the study

28. IRB questioning the acceptability of a persons credentials

29. Sponsors looking more seriously at who will do what, during the pre site visit

30. Investigator signing off on I/E source document But it’s more then a list, it’s knowing who CAN do what and who SHOULD do what

32. Training files – GCP & study specific

33. Which brings up - How many times must one complete GCP training?

34. Training tab in each regulatory binder

36. Evidence of meetings with sponsor monitor

37. Monitor letter – reviewed, signed and preferably responded to

38. PI & CRA meeting minutes*

39. Set of SOPs to Guidance requirements & GCPs

40. Evidence of Investigator involvement in the study

41. Appropriate signature on lab results

42. Signature on I/E source documentation worksheet

44. Evidence of subject's Primary Care Physician having been informed (with subject's consent)

45. Evidence of Investigator's presence throughout the study

47. Investigators still get these “large volumes of reports, often lacking in context and details”

49. Site Report Card Site Solutions Summit 2009 Survey

50. Ask For What You Want Site Solutions Summit 2009 Survey

51. Proactive GCP Compliance

52. Overview The typical reaction to a finding from a Good Clinical Practice (GCP) audit or inspection is a quick fix to: Update the wording in a Clinical Standard Operating Procedure (SOP), or Provide more training But this does not guarantee that the: Process will be more effective, SOPs will be followed, or that Activities will prevent similar issues from occurring

53. Overview To have sustainable compliance across clinical trials, a set of underlying mechanisms should be in place for: Building effective clinical processes, Managing continuous improvement, and Holding staff accountable for day to day quality and compliance

55. not intended to imply actual costsPrevention Costs + Detection Costs + Rework Costs = Total Cost of Quality

56. The Focus – Clinical Trial Operations 33 Compliance Activities Implementation Activities Foundation Processes Process Management Activities Clinical / Service Processes Training SOPs Monitoring TMF

57. The Foundation Processes Mar 30, 2010 How to manage initiatives and process changes effectively Process Mgmt Activities How to proactively build lessons learned, improvements, new skills, management involvement and measures of success into organization How to collect, report, trend and prioritize issues and propose changes / resolutions on global basis Plan Assess Implementation Activities Compliance Activities Do

58. Roles and Accountabilities Quality Control (QC): Daily hands on activities to ensure operations and associated deliverables meet quality standards and metrics Quality/Compliance: Oversight for process development, inspection readiness, compliance oversight, continuous improvement, quality metrics, compliance communications and engine for QMS Management Support / Governance/CI: Oversight of strategic direction of compliance activities, tactical assessments, priority of issues, measurement/ enforcement of compliance and implementation of CAPA/process improvements Research into, implementation of and support for compliance issues, proposed changes and expected outcomes Audit: Independent examination by sponsor or contracted resource to determine whether the sampled trial activities were conducted, recorded, analyzed and reported according to all requirements Oversight of regulatory inspections

59. Roles: Governance/CI Teams Clinical/Service Processes Foundation Processes Assessment Board Process Team Process Team Process Team Process Team Process Team Process Team Process Team Process Team Process Team Process Team Process Team Process Team Process Team Initiatives CAPAs Policies SOPs GDs Systems Training Process Team Initiatives CAPAs Policies SOPs GDs Systems Training Mgmt Sponsor Process Lead(s) = = Process SMEs Training Rep Executive Governance Quality Cost Time

61. Collect Data

62. Identify Possible Causes

63. Identify Root Causes

64. Recommend and Implement Solutions37

66. Brainstorm the issues

67. Flowcharting

68. Fishbone Analysis – Cause /Effect Diagrams

69. 5 Whys technique

70. Force Field Analysis

71. Pareto Charts

72. Run Charts

73. Six Sigma Analysis (DMAIC) 38

74. Structured Investigation Method 1. Define the performance problem (DEFINE) 2. Collect Existing Data (MEASURE) 3. Identify Possible Causes (ANALYZE) 4. Test Possible Causes (ANALYZE) 5. Identify Root Causes (ANALYZE) 6. Determine Best Solution (IMPROVE) 7. Verify Solution (CONTROL)

76. Usually a team activity; allows for different points of view

77. Expands the scope of the investigation; mitigates against focusing / targeting too soon

78. Identifies areas that need further analysis (e.g., review of data, experimentation); does not pinpoint root cause.40

79. Fishbone Diagram - Example Major cause categories Process Training No adequate training to staff regarding the new lab kits Validation done at Lab Supplies, Lab kits sent from distribution for re-assembly and distribution Wrong Kits assembled and sent to investigation sites Miscommunication between sites Inattention to work order requirements Human Root cause 41

81. Develop compliance objectives/metric

82. Routinely perform analyses for recurring trends

83. Prioritize and work on trends with biggest impact/risks

84. Shift focus from reporting issues to understanding causes

85. Implement cross-functional process improvements/lessons learned

86. Staff/Culture

87. Assess, and increase, dedicated compliance resources, as needed

88. Promote resolutions across programs

89. Hold staff accountable through evaluations/ratings

90. Promote error free culture

91. Develop and implement effective communications of issues/solutions

93. Implement software for documenting, tracking and training on processes

94. Establish effective compliance forums / governance committee(s)

95. Centralize oversight / tracking of process improvement initiatives and link to SOP updates

96. Process

97. Transition from SOP training to effective learning across processes

98. Build QC steps into all future process changes

99. Add temp resources to complete backlog of process improvements/SOPs

100. Restructure Initiative/SOP teams