Clinical Trial Management & Part 11 Compliance

1. Clinical Trial Management & Part 11 Compliance Ginger Clasby, MS Exec. VP, Business Development gclasby@promedica-intl.com

2. BackgroundWhat is Good Clinical Practice? A process enabling reliable decisions about allowing a medical product to be marketed

3. Product Approval Factors • Product is safe • Treatment is effective for disease or condition it is meant to treat

4. Clinical Research Project Principles • Control bias in subject selection • Compensate for placebo effect • Reduce examiner bias • Objectively compare results to other treatments or controls • Produce sufficient statistical power

5. The Study Protocol • Explains problem & proposes treatment hypothesis • Describes key variables to assess safety & efficacy • Specifies & justifies study sample size • Describes study population

6. The Study Protocol • Identifies exams and allowable measurement intervals • Specifies clinical and data endpoints • Explains how data collected will be analyzed

7. Study Team Study SiteSponsor/CRO

8. Protocol Implementation • Qualified study sites • Appropriate equipment & instrumentation • Adequate training of study team • Appropriate data collection instruments • Adequate data storage mechanism • Adequate study monitoring

9. Monitoring Study Progress • Subject enrollment • Subject accountability at study exams • Data recorded & collected

10. Standard Study Data Documents • Source documents • Data capture forms (CRFs) • Data query forms

11. Source Document Initial capture of clinical history data, impressions, diagnoses and plans of care • Hospital records • Clinic/office charts • Lab reports • Subject Diaries

12. Source Document Required to substantiate data submitted to sponsor via CRFs

13. Data Capture Forms • Case Report Form (CRF) • Electronic Data Capture (e-CRF)

14. Case Report Form Completion • Formally authorized staff for CRF entries • Complete all fields in (black) ink • No unnecessary marks or notations • Data changes must not obliterate original entry • Changes must be initialed and dated • Investigator signs CRFs after finalization

15. Data Flow at Site Site sees subject, records exam data on source doc Site transcribes source data to CRF Study monitor verifies data capture & submits to sponsor

16. Data Flow at Sponsor/CRO Sponsor/CRO enters data to database (#1) Sponsor/CRO enters data to database (#2) – “verifies” Sponsor/CROvisually reviews CRF data/logic checks

17. Data Query Forms • After CRFs reviewed by sponsor/CRO, further verification or clarification may be required • Provide traceability regarding data changes

18. Data Queries • Data queries generated by sponsor/CRO for resolution by site • Formally authorized staff for query responses • Completed queries must be signed by investigator or authorized staff • Copy of completed data queries filed at site • Query records in sponsor’s permanent database

19. Data Queries

20. Data Query Flow Sponsor/CROvisually reviews CRF data/logic checks Sponsor/CROgenerates data query form & sends Siteresponds to query & returns Sponsor/CROrevises database entry as necessary

21. Using Computerized Systemsin Clinical Trials

22. General PrinciplesSystem Definitions • Protocol should identify when computerized system is used • Documentation should identify hardware & software used

23. General PrinciplesSource Documents • Retain to reconstruct & evaluate trial • Investigators retain originals or certified copies • When original observations entered directly, e-record is “source”

24. General PrinciplesData Accountability • All info for each subject attributable to that subject • Record changes shouldn’t obscure original info • Record changes should be indicated & means provided to check prior entry • Necessity of audit trail – who changed & why?

25. General PrinciplesThoughtful System Design • Matches data capture requirements (kg. vs. lb.) • Precludes errors in modification, maintenance, archiving, retrieval or transmission • Ensures record keeping & retention are in-line with paper systems

26. General PrinciplesSecurity Measures • To prevent unauthorized access to data • To prevent unauthorized access to computerized system

27. General PrinciplesFDA Records Access May inspect all records intended to support submissions

28. e-Data Flow at Site Site sees subject, records exam data on source doc Site inputs data to computer & “commits”

29. e-Data Flow at Sponsor/CRO Study monitor visually reviews “committed” data vs. “source” Sponsor/CROreviews CRF data/applies logic checks

30. Data Processing Responsibility

31. Additional Site Qualification Questions • Previous experience/comfort level with e-data collection activities? • Computer/high-speed internet accessibility? • On-site technical support capabilities?

32. Additional Site Management Planning • Site & subject training and documentation for e-data capture • Ongoing monitor communication & support • Technical “Help Desk” • E-signature management

33. Add’l Systems Design IssuesData Entry • Prompts for clinical terms & measurements • Prompts for out of range data • Electronic diaries & e-CRFs designed to allow annotations • Features to facilitate data review & identify changes • Sponsor access to data during study

34. Add’l Systems Design IssuesElectronic Signatures • Individual enters signature at start of data entry session • Attributability of signatures • Passwords changed at established intervals

35. Add’l Systems Design Issues Date/Time Stamps • Controls to ensure correct system date/time (yr, mo, day, hr, min) • Limited ability (with documentation) to change date/time

36. Add’l Systems Design IssuesControls • SOPs to maintain system integrity in light of changes • Revalidation for changes exceeding operation limits/design specs • Documentation of software versions • SOPs for contingency plans

37. Add’l Systems Design IssuesControls • SOPs for backup & recovery of e-records • Logs to assess nature & scope of data loss in the event of system failure • Secure storage of backup records

38. Consider Speed of Data Capture vs. Costs Incurred

39. Clinical Project Planning • Skilled, regularly available technical support • Detailed hazard/failure analyses • Skilled, regularly available monitoring/training support • Increased budget for site participation • Adequate schedule “padding” for things to go wrong