1 SAE Centralized Report and Review Process April 2012

2 AE/SAE Reporting and AdEERS Effective June 4, 2012 RTOG will be utilizing the centralized reporting pathway in AdEERS. This presentation will outline how centralized reporting for AE/SAE will be done –Your role in this process (site investigator and site research associate) –The role of RTOG (AE Coordinator) –Helpful information for reporting As stated in the accompanying memo impact on clinical sites will be minimal.

3 Points to remember about Ad EERS All SAEs are required to be reported regardless of grade, attribution or expectedness, unless specified in the Specific Protocol Exceptions to Expedited Reporting (SPEER). The AdEERS Report does not require or capture a determination of expectedness from the site investigator Section 7.0 of the protocol provides specific NCI required instructions regarding the reporting of SAEs for each study. There will also be a list of expected SAEs that do not require reporting.

4 Current AdEERS Reporting Pathway The participating site submits the report directly to the NCI and the FDA (as applicable). RTOG HQ, the Study Chair and the supporting pharmaceutical company are also copied automatically on the electronic AdEERS submission.

5 NEW Centralized Reporting Pathway (effective June 4 th, 2012) The participating site submits the report directly to the RTOG and RTOG submits to the FDA (as applicable). NCI the Study Chair and the supporting pharmaceutical company are also copied automatically on the electronic AdEERS submission by RTOG.

6 Site Investigator & Research Associate The role of the site RA (aka Reporter): –Report all SAEs via AdEERS –Notify RTOG of all unexpected and reasonably related Grade 4 and 5 SAE within 24 hours of becoming aware of the event –The associated complete report must be submitted within five calendar days –Report all other SAEs to RTOG within ten calendar days. The role of the site investigator: –Assists the RA/Reporter in providing a complete and accurate summary of the event –Provides sign off and retains responsibility for the completeness and accuracy of the report

7 AE/SAE Coordinator The role of the RTOG AE Coordinator: –To coordinate the timely review of submitted information, perform necessary edits for accuracy & clarity and submit reports of all UNEXPECTED and RELATED SAEs to the NCI, pharmaceutical sponsor and to the FDA as applicable and required by regulations. –Evaluates SAEs against the IB, the ICF, and the available literature in order to assess expectedness of the event. –Queries sites to resolve discrepancies. –Submits expedited reports to Health Canada as appropriate. –Tracks serious adverse event reports

8 Centralized reporting changes summarized In order to meet regulatory reporting deadlines, a collaborative effort between the RTOG AE Coordinator and the clinical site investigator and reporter is paramount. The site reporter and investigator will need to promptly address queries to ensure the accuracy of the AdEERS report. For unexpected and reasonably related SAE, a collaboration between the AE Coordinator, the clinical site and the Study Chair is essential to evaluate events appropriate for FDA reporting.

9 The Essentials of a Good SAE Report Structured in a coherent chronological format Avoid subjective language and use concrete values to describe an event. Clearly indicate whether the event is unexpected and related. –Most SAEs do not uniquely contribute to the safety profile of the drug, the FDA wants to review only unexpected and related SAEs. –Does this individual case change the safety profile of the drug? –Does this event warrant changes to the study protocol and/or to the informed consent form?

10 How to evaluate expectedness and relatedness Is there a temporal relationship between both onset and abatement of symptoms and drug start and stop dates respectively? Is the event documented in the Investigator Brochure? Is this event of a severity greater than expected according to the IB and/or protocol? Did this event occur with the first dose and at a severe grade? Can the contribution of the study drug to the SAE be unequivocally ruled out?

11 It’s a Team Effort Only a concerted team effort will allow for the timely submission of the necessary information to ensure patient safety Please remain especially vigilant for correspondence from the AE Coordinator related to all unexpected, related SAE Reports you have submitted The Timeline clock –Begins with the initial submission to RTOG –Fatal/Life threatening SAEs require submission to outside regulatory authorities in 5 calendar days –All other SAEs require submission to outside regulatory authorities in 10 calendar days

12 AE/SAE Coordinator Sara McCartney Please feel free to contact Sara directly with any questions.