1. Monitoring the Progress of Trials and the Safety of Participants Don Workman, PhD Victor Santana, MD St. Jude Children’s Research Hospital

2. A continuous ongoing review of the conduct of the trial Shared responsibility – –Research Team/Principal Investigator – –Institutional Officials – –Oversight Committees (IRB, DSMB) Monitoring the Progress of Trials and the Safety of Participants

3. Partnership in Research Investigator IRB Institutional Officials Participant

4. A Systematic Approach to the Problem Defining what needs to be monitored and reported Defining role of DSMB and role of IRB Developing infrastructure to report, evaluate and act upon safety concerns in a timely fashion

5. Monitoring Elements as Summarized in the NCI Clinical Data Update System Patient-Specific Data – demographics– treatment status (received therapy) – date of entry– off-therapy reason(s) subgroup on protocol – –eligibility– performance status – –prior therapy– disease code (diagnosis, SNOMED) treatment by course – –Course ID – Start date – –Rx assignment (ph I) – BSA or weight dose of agent – –agent– dose modification – total dose/course adverse even reporting – –type– grade – –attribution– reporting response – –evaluable– best response at time of evaluation

6. Monitoring Type or Phase of Trial Monitoring Interval Reports to Subcommittee Number of Patients to be Monitored Phase ICentral Elements Continuously Missing Data Reports Monthly QuarterlyFirst 3 patients enrolled, plus 1 patient per dose level Phase IIEligibility and Consents Continuously Central Elements Quarterly Missing Data Reports Quarterly* AEs Quarterly Response coding semiannually, or at appropriate protocol time points Semiannually, or as required in the protocol First 2 patients enrolled, plus at least 10% of total patients accrued

7. Monitoring Type or Phase of Trial Monitoring Interval Reports to Subcommittee Number of Patients to be Monitored Phase IIIEligibility and Consents Continuously Central Elements Quarterly Missing Data Reports Quarterly* Response coding semiannually Other primary objectives Annually Semiannually, or as required in the protocol DSMP First 2 patients enrolled, plus at least 10% of total patients accrued ST JUDE holds IND/IDE Per study-specific monitoring planPer study phasePer study phase, or study-specific monitoring plan

8. The Problem of AE/SAE Reporting and IRB Review Problems in reporting: – –Over-reporting (reporting of anticipated adverse events) – –Increased research in drugs and biologics – –Increased federal scrutiny—OHRP, FDA – –Saturation effects – –Lack of denominators in Safety Reports, lack of normative data for population under study

9. The Problem of AE/SAE Reporting and IRB Review Problems in review: – –External events reports often sketchy summaries—no opportunity for questions/clarifications – –IRB is not DMC/DSMB – –IRB is not FDA with single IND file – –IRB needs to rely on local investigator to interpret the meaning of the events reported

10. PI Reports & Categorizes Adverse Events Electronic Submission IRB Office of RA Office of VP Clinical Trials External Reporting: OHRP CTEP NIH FDA RAC SPONSORS Internal Reporting Other Committees Institutional (DSMB, CPSRMC) Feedback Follow-up

11. An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs Project Development – –18 months from design to implementation – –Began with Implementation of a Form, designed like screen-shots to include checkboxes and fill-in the blanks – –Development of flow-diagram for Web-based Reporter – –Security versus Access issues – –Need for electronic “signature” other title 11 issues

12. An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs Project Development – –Integration with existing databases Verifiable identities/access list Internal reports: subjects/medical record numbers – –Links to registered protocols – –Information stream to other PIs External reports: radio buttons for selecting protocol(s) for reporting of events (sometimes multiple studies on single safety report) – –E-mail notification to PIs

13. An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs Functional Outcomes – –Real-time IRB reporting: time stamping – –Forced choice, smart forms, no incomplete submissions – –Ease of access—any system signed onto intranet – –Ability to generate single-incident reports – –Ability to generate reports entered in specified time period

14. An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs Functional Outcomes – –Quicker reporting times – –Ability of IRB Office to generate reports based on protocols, type of events, across subjects – –Able to generate internal denominators – –Use of standardized NCI toxicity tables – –Able to record IRB actions, and updates from Investigators onto previous reports

15. An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs Process Improvements – –More timely reporting—able to demonstrate overall compliance – –Better communication between investigators and IRB – –Able to manipulate information into reports – –Improved information summary presentation for reviewers – –Easy access to history of events on any protocol

16. An Intranet-Based Solution for Collecting and Processing AE/SAE/UPIRSOs Process Improvements – –No need for generating additional correspondence – –PI can generate time-stamped “receipt” by IRB and determinations from the Committee – –Requires PI input on judgments re. Seriousness, relationship (related/not related), and expected/unexpected – –Requires PI judgments regarding need for revision/amendment to consent/protocol

17. DEMONSTRATION

26. Dr Teddy Bear

29. Conclusions Technology can be used to improve process for collection and review of information regarding adverse events Web-based applications can facilitate cross-talk between various databases Well-designed systems may allow for a single report in an inpatient hospital to generate incident reports, ADR reports, medwatch reports, and AE/Safety reports

30. Acknowledgments Don Workman, Ph.D., IRB Administrator (2003) Donna Hogan, IRB Office, CIP Mickey Weeks, Clinical Informatics Donald Sanderlin, Clinical Informatics Victor Santana, M.D