1. CTEP, NCI Adverse Event Reporting Programmatic & Workflow Processes Prepared by: Ann Setser May 24, 2010

2. Agenda Conceptual overview of NCI AE reporting CTEP Adverse Event Reporting Systems – Multiple mechanisms for AE data submission Routine via CTMS; CDUS; CDS Expedited via AdEERS AE Reporting Workflow – Variable practices Issues to consider for integration of PRO- CTCAE

3. NCI AE Reporting Overview Methodology varies widely among sites, modalities, specialties, practices There are no guidelines or uniform methods for how to capture, present and interpret AE data Within NCI, requirements differ – Paper CRF – Multiple data systems (Groups, Centers, CTEP, contractors, others) At the patient encounter, most clinician- documented AE / symptom data are not CTCAE terms and often include notes that do not promote straightforward translation to CTCAE Grade (severity indicator)

4. NCI AE Reporting Overview… From patient encounter to sponsor analysis and publication, many layers of ‘interpretation and translation’ of AE terms and severity indicators occur. CTCAE data is a collection of secondary endpoints used to generate an overall picture or general safety profile of a given treatment, to identify gross trends and differences between studies, arms, groups, etc.

5. CTEP Adverse Event Reporting Systems 1.Clinical Data Update System CDUS Primary resource of clinical trial data for NCI DCTD and DCP Types of Data Sets – Abbreviated CDUS (Phase 3 - no AE data) – Complete CDUS (Phase 1, 2 AE data) Methods of Data Submission – ftp data transfer – web Contents of data set – Cumulative data per protocol

6. CTEP Adverse Event Reporting Systems… CDUS Data Submission Early Phase 1 – via CTMS (Clinical Trials Monitoring System) File Transfer Protocol (FTP) Monthly Other Phase trials: – via CDUS Lead Group or Lead Institution submits data set FTP or web Quarterly

7. Adverse Events Screen

8. Steps

9. CTEP Adverse Event Reporting Systems…AdEERS Adverse Event Expedited Reporting System Expedited AE reporting tool for CTEP sponsored trials Expedited reporting (AdEERS) is always in addition to Routine Reporting All AEs (meeting the CDUS reporting requirements) must be submitted as part of routine reporting AdEERS does not replace Routine Reporting

10. CTEP Expedited AE Reporting AdEERS CTEP-specific rules as a sponsor reporting to FDA The foundation of AdEERS is CTCAE – Unlike industry (verbatim coded to MedDRA) AdEERS ‘rules’ based on CTCAE depend on Phase of Trial

11. Example: CTEP AdEERS ‘Rules’

12. CTEP Expedited AE Reporting AdEERS Because of timeline requirements, AdEERS data is usually closer to patient encounter Requires extensive patient level data entry each time a report is generated Data reviewed by CTEP almost real-time – 24 hours – 5 days – 10 days Next slide: Screensnap of AdEERS with Sections of Report

13. Screensnap of AdEERS with Sections of Report

14. CDUS-reported and AdEERS-reported AEs 1.Design and expectations of two systems are very different CDUS = summary cumulative AE data by quarter AdEERS = detailed AE data in real-time 2. Initially there was no expectation for comparison of data from the two systems Programmatic data element requirements differ Different staff with different AE expertise submit to the different systems 3. AdEERS-CDUS Reconciliation implemented April 1, 2006 Comparison of the data reported to the 2 systems All Grade 5 discrepancies must be resolved All other discrepancies result in a CDUS caution

15. Workflow Processes for reporting Routine AEs - Paper 1.At the patient encounter clinician documents AEs / symptoms – On paper Patient chart / Progress Note Trial-specific ‘cheat sheet’ / AE CRF – Electronic Electronic Health Record Remote Data Capture System 2.Nurse, CRA, or Data Manager retrospectively reviews source data – Translates symptoms into CTCAE terms and grades and transcribes onto trial-specific AE CRF

16. Workflow Processes for reporting Routine AEs - Paper… 3.Site personnel submit paper CRF to Cooperative Group or Lead Organization 4.Cooperative Group or Lead Organization personnel enter AE data into data system 5.Technical staff prepare and submit electronic data to CTEP via CDUS ftp

17. Workflow Processes for reporting Routine AEs - Electronic… 1.Site access to RDC, CDMS, etc. 2.Site technical staff program local data file transfer to Group data system 3.Group technical staff prepare CTEP- required subset of all Group data and reprograms for submission to CTEP CDUS

18. Going Forward with PRO-CTCAE 1.Understand strengths and limitations of current AE data systems and processes—from patient encounter to sponsor to regulators to publication 2.With awareness of the varied processes (paper, electronic), how best might PROs be integrated and help achieve more real-time AE reporting? 3.How will PRO data be analyzed / utilized relative to clinician-reported AE data? 4.How can we achieve a common method to summarize and communicate overall AE burden?

19. Acronyms AdEERSAdverse Event Expedited Reporting System CDUSClinical Data Update System (FTP submission) CDSClinical Data System (Web submission) CDMSClinical Data Management System CTCAECommon Terminology Criteria for Adverse Events CTEPCancer Therapy Evaluation Program CRAClinical Research Associate CRFCase Report Form CTMSClinical Trials Monitoring System DCPDivision of Cancer Prevention DCTDDivision of Cancer Treatment and Diagnosis FTPFile Transfer Protocol RDCRemote data capture

20. Discussion