Focused on Pulmonology and Hepatology PSDM 22 May 2008 Focused on Pulmonology and Hepatology SAE RECONCILIATION: Determining how much to reconcile Introduction DM CRO working with the CRO DS unit Biotech DM working with internal DS unit; coding person Sponsor oversee SAE and coding process Now, Sponsor performing SAE discrepancy identification and resolution; coding lead (sep 2006) Jennifer Juntado, Sr. Manager, Data Management Confidential. Property of InterMune, Inc. Any unauthorized review, use, disclosure or distribution is prohibited.

Typical Data Flow SIMPLE FLOW CHART The CRFs are filled out and monitored then sent to Covance document control The data on the CRFs is double data entered, meaning it is keyed in twice by different operators and compared Before we can do anything else with the data, the system has to run “BATCH VALIDATION” which includes integrity checks and the edit checks. A lot of different types of cleaning happens to the data Two tasks that are important to a study are Coding and SAE Recon

SAE Collection and Reconciliation

Typical SAE Collection Period Patient withdraws from study early: SAE collection period ends at earlier of below two time points 1) Time of study withdrawal 2) 28 days after last dose of study treatment: ICF Signed: SAEs only reported if related to protocol procedure Study drug initiated: All AE/SAEs reported per protocol Final Follow-up Visit: End of SAE collection period

SAE/AE Collection Period Examples Patient discontinues drug and the next day withdraws from study, but agrees to vital status: Any SAEs occurring after the withdrawal date will not be collected Patient discontinues drug and 35 days later withdraws from study: Any SAE occurring after the 28th day following study drug discontinuation will not be collected Patient permanently discontinues drug on 01 August 2007 and experiences an SAE on 12 Sept 2007: SAEs are to be collected until the end of study (Final Follow-up Visit) Patient experiences an SAE of Pneumonia on 01 June 2007 and discontinues study drug the same day. Patient then withdraws from study on 15 June 2007 with the pneumonia still ongoing: Pneumonia will be followed to resolution by DSRM

Documentation CRFs – Data Management CRF Completion Guidelines – Clinical Operations SAE Report Form – Drug Safety SAE Reconciliation Plan – Drug Safety Coding Guidelines – Data Management Data Handling Report – Data Management To document the evaluation and resulting action of data discrepancies between the Drug Safety serious adverse event (SAE) database and the Clinical adverse event (AE) database between database soft lock and hard lock To document how “Handling Discrepancies between SAE and AE Databases” deviates from the study’s Serious Adverse Event Reconciliation Plan in the Data Management Plan.

SAE Reconciliation Flow Chart Quarterly Prior to milestones: Data Review snapshot; soft lock; hard lock

SAE Reconciliation Cheat Sheet DM and DSRM takes every opportunity to conduct training at Clinical Operations sponsored events. For example, Study Monitor Training, Study Coordinator Training, and at Investigator Meetings. We make it a point to know what the site is being instructed in completing AE CRFs and SAE Report Forms. Besides querying events that are not in SAE and in AE or vice versa, we provide a SAE RECONCILIATION CHEAT SHEET. Here, I would like to address some fields we are having a lot of queries on. (click) Item 4: The term on the AE CRF has to logically match the Primary Event Term on the SAE REPORT FORM. (click) Item 6: The start date of the event on the AE CRF that is marked SERIOUS must match the DATE BECAME SERIOUS on the SAE REPORT FORM. This can be confusing as there are other dates on the SAE FORM. (click) Item 8: It is very important that the relationship to study drug matches because this may trigger a report to the regulatory agencies. (click) Item 9: Action Taken regarding the study drug and (click) Item 10: Primary Outcome is important because this data needs to be accurate so it can be tabulate what is really going with the patient, the study, etc.

SAE Reconciliation Because the terminology on the AE CRF and the SAE Report can be different, the back of the CHEAT SHEET tells you which codes on the AE CRF match up with on the SAE Report.

Data Management goes beyond typical SAE Reconciliation 10 10

Beyond SAEs: Other Data Patient Disposition: Termination of Study Treatment Date of last study drug Termination due to AEs (or Serious AE) or Reasons where it might be an AE If an AE or SAE states that treatment was discontinued, then this data must correlate. If early termination of study treatment is due to an AE (or Serious AE, if applicable), then the AE must be captured with consistent information. Study Completion/Early Discontinuation from Study Date of study discontinuation Discontinuations due to AE (or Serious AE) or Reasons where it might be and AE Mortality Date of death Primary cause of death

Snapshot of the listing – level 1 In AE not in SAE In SAE not in AE Serious should be marked YES SAEF reported term is not consistent with AE verbatim term Causality does not match Outcome does not match Action taken to study treatment is not consistent between SAEF, AE, End of Study Treatment Action taken to study treatment is not consistent between SAEF and AE SAEF dates and AE CRF do not correlate: SAEF date serious < or > Serious AE start date, AE start date is > SAEF date serious and onset of symptoms date; AE start date = onset of symptoms date and not = date became serious Early End of Study Treatment CRF was submitted when not applicable ISSUES THAT WILL/SHOULD BE CAUGHT DURING ROUTINE DM CLEANING: Serious is marked YES however seriousness criteria is missing Serious is marked NO however seriousness criteria is present Primary cause of death missing on mortality CRF AE number needs to be fixed End of Treatment CRF missing ISSUES THAT WILL/SHOULD BE CAUGHT DURING ROUTINE DSRM REVIEW: SAEF onset of symptoms date blank SAEF date became serious is blank

Snapshot of the listing – level 2

Snapshot of the listing – level 3

Approaching database lock… now what? What’s got to give: 15 15

Prior to database lock 16

What other data points can remain discrepant, yet assuring our regulatory obligations and maximizing subject safety? What’s got to give: 17 17

Questions? This is not only regarding CODING and SAE RECONCILIATION, it’s critical for patient disposition and drug dosing/accountability.