1. www.rtog.org 1 MARCH 2012 REGULATORY MANAGEMENT Marie D’Amico, CCRP Manager, RTOG Regulatory Affairs

2. www.rtog.org 2 Disclaimer The following presentation is being given for RTOG studies only. The information represented here while current may change due to changes within RTOG internal processes or because of federal regulatory guidelines. Therefore, you may not reproduce or distribute any of the presentation without obtaining RTOG’s prior written consent.

3. www.rtog.org 3 Discussion Points Regulatory Documents & the CTSURegulatory Documents & the CTSU Drug Procurement & AccountabilityDrug Procurement & Accountability RTOG SAE Safety ReportingRTOG SAE Safety Reporting –Site initiated Internal SAE Reporting –Pharmaceutical/NCI initiated External Safety Reports

4. www.rtog.org 4 MARCH 2012 Regulatory Documents & the CTSU

5. www.rtog.org 5 Regulatory Documents All regulatory documents for US, Canadian & Non North American sites are submitted to the CTSU for cataloguing and data entry –Continuing Reviews –Approvals of amendments –IRB initial study approvals –IRB approved consent forms (translation required for Non English speaking countries/provinces)

6. www.rtog.org 6 Continuing IRB Approval IRB approval must continue untilIRB approval must continue until Finite StudiesFinite Studies –All subjects accrued have completed treatment and follow up Non Finite StudiesNon Finite Studies –All subjects are deceased Additional requirements for both finite & non finite studiesAdditional requirements for both finite & non finite studies –No further accrual is anticipated –All data forms have been submitted –All queries to date have been resolved –RTOG approves the site for early closure (see form) IRB approval remains necessary, even after RTOG study closure and until RTOG termination unless all the above criteria/requirements have been metIRB approval remains necessary, even after RTOG study closure and until RTOG termination unless all the above criteria/requirements have been met Only RTOG can classify a study as "terminated" (Database locked)Only RTOG can classify a study as "terminated" (Database locked) Notification of Study Termination will be received via broadcastNotification of Study Termination will be received via broadcast A formal request is required for early closure when all criteria metA formal request is required for early closure when all criteria met

7. www.rtog.org 7 Form to Request Early IRB Closure http://www.rtog.org/ResearchAssociates/RegulatoryInformation/EarlyIRBClosure.aspx http://www.rtog.org/ResearchAssociates/RegulatoryInformation/EarlyIRBClosure.aspx

8. www.rtog.org 8 Requests for Early IRB Closure Request form must be submitted to and approved by RTOGRequest form must be submitted to and approved by RTOG The Form has Multiple purposesThe Form has Multiple purposes –Request consideration for early closure with IRB –Request closure with IRB when no patients enrolled on study –Transfer IRB responsibilities RTOG response with approval of the request is required prior to taking any closure actionRTOG response with approval of the request is required prior to taking any closure action Internal multi department review at RTOG HQ can take 7-10 business days to completeInternal multi department review at RTOG HQ can take 7-10 business days to complete Sites will still be required to respond to queries even after study closure with the IRBSites will still be required to respond to queries even after study closure with the IRB

9. www.rtog.org 9 Continuing IRB Approval IMPORTANT NOTE Full member institutions that have affiliates that use the Full Member IRB as their IRB of record must ensure that those affiliate/ Joint Center institutions had also never put any patients on studies they are considering closing with the IRB. If they have, then the main IRB must keep this study open for annual review.IMPORTANT NOTE Full member institutions that have affiliates that use the Full Member IRB as their IRB of record must ensure that those affiliate/ Joint Center institutions had also never put any patients on studies they are considering closing with the IRB. If they have, then the main IRB must keep this study open for annual review.

10. www.rtog.org 10 Special Handling Handling of all other study specific regulatory documentation is detailed in Sections 5.0 or 7.0 of the protocolHandling of all other study specific regulatory documentation is detailed in Sections 5.0 or 7.0 of the protocol Study Agent Shipment Form (SASF) Sponsor required documentation Questionnaires Training Certifications RT Certifications Non English speaking Canadian & Non North American sites are required to supply the Certified/Verified English translation and native language copy of the IC with their regulatory approvalsNon English speaking Canadian & Non North American sites are required to supply the Certified/Verified English translation and native language copy of the IC with their regulatory approvals Other special procedures may exist for Non North American sitesOther special procedures may exist for Non North American sites

11. www.rtog.org 11 Correlative Components Each participating institution must be prepared to participate in all correlative components/have a plan in place to facilitate participation and must offer every patient the opportunity to participate in these components.Each participating institution must be prepared to participate in all correlative components/have a plan in place to facilitate participation and must offer every patient the opportunity to participate in these components. ONLY THE PATIENT can decline to participate in the correlative components of a studyONLY THE PATIENT can decline to participate in the correlative components of a study The majority of RTOG studies require varying degrees of specimen collection as part of eligibility, stratification or protocol treatment.The majority of RTOG studies require varying degrees of specimen collection as part of eligibility, stratification or protocol treatment. Sites are encouraged to become more organized in their efforts and coordinate tissue banking collections with other protocol required specimen collections whenever possible.Sites are encouraged to become more organized in their efforts and coordinate tissue banking collections with other protocol required specimen collections whenever possible. In the event tissue is collected/residing at another facility RTOG expects a good faith effort to obtain the retrospective specimens but the site will not be penalized if it is not possible.In the event tissue is collected/residing at another facility RTOG expects a good faith effort to obtain the retrospective specimens but the site will not be penalized if it is not possible. Prospectively the site must inform the collecting entity that future specimens collected are expected to be forwarded along with the appropriate submission form for tissue banking as noted in the protocol.Prospectively the site must inform the collecting entity that future specimens collected are expected to be forwarded along with the appropriate submission form for tissue banking as noted in the protocol.

12. www.rtog.org 12 CTSU Forms & Guidance Can be found on the RTOG website www.rtog.org www.rtog.org under RA/Regulatory Info/CTSU Filing Requirements –IRB Certification Forms –310 Certification Form –IRB Transmittal Forms –Guidance for completing the forms –RSS Flow sheet NCI Required Forms are also available here –FDA 1572 –CTEP Supplemental Investigator Data Form (IDF) –CTEP Financial Disclosure

13. www.rtog.org 13 Proper Labeling Ensures Proper Processing Please identify all information submitted to the CTSU with the institution’s NCI Code on the transmittal/certification formPlease identify all information submitted to the CTSU with the institution’s NCI Code on the transmittal/certification form If the submission covers more than one institution or an entire CCOP all assigned individual NCI institution codes covered under the approval must be listed on the transmittal/certification form or supplemental pageIf the submission covers more than one institution or an entire CCOP all assigned individual NCI institution codes covered under the approval must be listed on the transmittal/certification form or supplemental page

14. www.rtog.org 14 CTSU Forms Transmittal/Certification

15. www.rtog.org 15 Resolving Regulatory Issues All issues for U.S., Canadian and Non North American sites with submitted regulatory documents should be handled directly through the CTSU.All issues for U.S., Canadian and Non North American sites with submitted regulatory documents should be handled directly through the CTSU. RTOG does not have access to copies of regulatory documents that have been submitted to the CTSU.

16. www.rtog.org 16 Checking Registration Status Visit the CTSU Website: https://www.ctsu.org/public/ https://www.ctsu.org/public/ Requires a CTSU username & passwordRequires a CTSU username & password Sites are identified by NCI CodeSites are identified by NCI Code Lists all requirements for studyLists all requirements for study Lists items not in complianceLists items not in compliance Now available for Non North American sitesNow available for Non North American sites

17. www.rtog.org 17 To obtain a CTSU password…

18. www.rtog.org 18 Points of Contact for the CTSU Help Desk: 1-888-823-5923Help Desk: 1-888-823-5923 Regulatory Help Desk: 866-651-CTSU (2878)Regulatory Help Desk: 866-651-CTSU (2878) E-mail for questions: ctsucontact@westat.comE-mail for questions: ctsucontact@westat.comctsucontact@westat.com For Regulatory Submissions: Fax Number: 215-569-0206Fax Number: 215-569-0206 E-mail : CTSURegulatory@ctsu.coccg.orgE-mail : CTSURegulatory@ctsu.coccg.org CTSURegulatory@ctsu.coccg.org Mailing Address: Mailing Address: CTSU Regulatory Office Coalition of National Cancer Cooperative Groups 1818 Market Street, Suite 1100 Philadelphia, PA 19103 Website: http://members.ctsu.org/Website: http://members.ctsu.org/http://members.ctsu.org/

19. www.rtog.org 19 Record Retention According to the NCI Investigator Handbook: 10.3 Retention of Records10.3 Retention of Records FDA regulations require that all research records (including patient charts, case report forms, x-rays and scans that document response, IRB approvals, signed informed consent documents and all agent accountability records) must be kept by the investigator for at least 2 years after an NDA or BLA has been approved for that indication or the CTEP IND has been closed. CTEP will notify investigators when these events occur. This requirement is an explicit part of the FDA Form 1572, http://ctep.cancer.gov/handbook/index.html For NON IND Studies:For NON IND Studies: The point of reference used to determine the length of time required for record retention for non IND studies would be RTOG’s termination date for the study, which is when the database is locked and no further information would be required. The recommended timeframe for record retention is 3 years past termination The institution’s (and IRB’s) guidelines would also need to be considered.

20. www.rtog.org 20 Password Protected Documents on the RTOG Website An RTOG user name and password may be required to gain access to some password protected documentsAn RTOG user name and password may be required to gain access to some password protected documents The username and password used for web registration will permit access to these documentsThe username and password used for web registration will permit access to these documents The application to obtain a username & password is now web based. Paper submissions will no linger be accepted. Complete the online application at the following link: http://www.rtog.org/AboutUs/RTOGPasswordApplication.aspxThe application to obtain a username & password is now web based. Paper submissions will no linger be accepted. Complete the online application at the following link: http://www.rtog.org/AboutUs/RTOGPasswordApplication.aspx http://www.rtog.org/AboutUs/RTOGPasswordApplication.aspx The usual turnaround time for password authorization requests is two business daysThe usual turnaround time for password authorization requests is two business days

21. www.rtog.org 21 Informed Consent Concerns RTOG provides an NCI and ACR IRB Approved consent template for each protocolRTOG provides an NCI and ACR IRB Approved consent template for each protocol RTOG prefers no changes be made other than to add local contextRTOG prefers no changes be made other than to add local context IRB requested additions to the document for clarity are permittedIRB requested additions to the document for clarity are permitted The Deletion of any information should be avoided to preserve the integrity of the documentThe Deletion of any information should be avoided to preserve the integrity of the document The essential elements of the RTOG Informed Consent Template must remain intactThe essential elements of the RTOG Informed Consent Template must remain intact IRB required deletions of risks and alternative procedures will require written justificationIRB required deletions of risks and alternative procedures will require written justification Please refer to RTOG Guidance Document for making changes to the informed consent template (revised 5/2010)Please refer to RTOG Guidance Document for making changes to the informed consent template (revised 5/2010) http://www.rtog.org/LinkClick.aspx?fileticket=d5UGGw5pEjc%3d&tabid=309http://www.rtog.org/LinkClick.aspx?fileticket=d5UGGw5pEjc%3d&tabid=309http://www.rtog.org/LinkClick.aspx?fileticket=d5UGGw5pEjc%3d&tabid=309

22. www.rtog.org 22 Informed Consent Approval It remains your IRB’s responsibility to review and approve the informed consent content and any changes made at the site levelIt remains your IRB’s responsibility to review and approve the informed consent content and any changes made at the site level A CERTFIED or VERIFIED English & native language translation of the IC is required for Non English speaking Canadian & Non North American sitesA CERTFIED or VERIFIED English & native language translation of the IC is required for Non English speaking Canadian & Non North American sites Please note the RTOG Regulatory Compliance Department does not review consents. All consent content will be reviewed at time of audit.Please note the RTOG Regulatory Compliance Department does not review consents. All consent content will be reviewed at time of audit. Problems and deficiencies with IRB approved consents found during the audit will be reported as appropriate.Problems and deficiencies with IRB approved consents found during the audit will be reported as appropriate.

23. www.rtog.org 23 Broadcasts & Summary of Changes Information relating to protocol updates and amendments can be found on the RTOG web site: www.rtog.orgInformation relating to protocol updates and amendments can be found on the RTOG web site: www.rtog.orgwww.rtog.org RTOG suggest sites check the website regularly to assure they have received all broadcast informationRTOG suggest sites check the website regularly to assure they have received all broadcast information NCI requires that cooperative groups provide a Summary of Changes which describes all of the changes made to a protocol, and indicates whether the changes are administrative (update) or treatment related (amendment)NCI requires that cooperative groups provide a Summary of Changes which describes all of the changes made to a protocol, and indicates whether the changes are administrative (update) or treatment related (amendment) On the website select Clinical Trials/Protocol Table, then the protocol number:On the website select Clinical Trials/Protocol Table, then the protocol number: – Select “Summary of Changes” under Protocol Documents scroll through the document to see all previous –Select “Broadcasts”, from left column, a list of protocol specific broadcasts will open.

24. www.rtog.org 24 Finding Broadcasts & Amendments On The Website

25. www.rtog.org 25 Protocol Updates Updates are editorial/administrative changes that RTOG is allowed to make without prior NCI approval (updates are sent to NCI for their information).Updates are editorial/administrative changes that RTOG is allowed to make without prior NCI approval (updates are sent to NCI for their information). Examples of protocol updates might include:Examples of protocol updates might include: –correction of typos –changes/additions to administrative processes –change in the address for data submission –change in a Co-Chair’s contact information. Per NCI, an update cannot involve patient treatment or anything that would impact patient safety.Per NCI, an update cannot involve patient treatment or anything that would impact patient safety. The RTOG broadcasts indicate “IRB review of an update is not required; however, these changes must be reported to the site IRB”The RTOG broadcasts indicate “IRB review of an update is not required; however, these changes must be reported to the site IRB”

26. www.rtog.org 26 Protocol Amendments All treatment or safety related changes to protocols are amendments,All treatment or safety related changes to protocols are amendments, Amendments are sent by RTOG to NCI for review and approval.Amendments are sent by RTOG to NCI for review and approval. As “Per CTMB Guidelines, amendments must be reviewed and approved by local IRBs within 90 days.As “Per CTMB Guidelines, amendments must be reviewed and approved by local IRBs within 90 days. For Canadian sites the broadcast of Health Canada’s approval of the amendment begins the 90 day timeframeFor Canadian sites the broadcast of Health Canada’s approval of the amendment begins the 90 day timeframe Full board IRB review is required If patients at the site are in active treatment on the studyFull board IRB review is required If patients at the site are in active treatment on the study When using the CIRB, facilitated review by your local IRB may still be required for all Phase III amendmentsWhen using the CIRB, facilitated review by your local IRB may still be required for all Phase III amendments

27. www.rtog.org 27 IRB Approvals Please review the full content for 45 CFR 46 §46.110 + Category List from OHRP Website at the following link: http://ohsr.od.nih.gov/guidelines/45cfr46.html#46.114Please review the full content for 45 CFR 46 §46.110 + Category List from OHRP Website at the following link: http://ohsr.od.nih.gov/guidelines/45cfr46.html#46.114 http://ohsr.od.nih.gov/guidelines/45cfr46.html#46.114

28. www.rtog.org 28 MARCH 2012 Drug Procurement & Accountability

29. www.rtog.org 29 Possible Sources of Drug Supply Pharmaceutical CompaniesPharmaceutical Companies Third Party DistributorThird Party Distributor NCI-Pharmaceutical Management Branch (PMB)NCI-Pharmaceutical Management Branch (PMB) Commercially available productsCommercially available products * More than one may apply in certain studies.

30. www.rtog.org 30 Canadian Review Board (CRB) Purpose: To identify barriers, specifically related to drug availability and in the various member provinces early in the development of the protocol when there is the potential to address these issues.Purpose: To identify barriers, specifically related to drug availability and differing RT standards in the various member provinces early in the development of the protocol when there is the potential to address these issues. Initiated in April 2009Initiated in April 2009 Representation: a provincial board member from each member province was appointed by the Canadian vice chair.Representation: a provincial board member from each member province was appointed by the Canadian vice chair. Please remember to share all drug or RT related protocol concerns with your provincial board member as early as possible.Please remember to share all drug or RT related protocol concerns with your provincial board member as early as possible.

31. www.rtog.org 31 CRB Provincial Representation & Contact Information

32. www.rtog.org 32 Important Note About Non North American Sites Non North American Institutions are advised not to submit a study for approval by their local regulatory body until their participation has been confirmed in the written notice of an approved Letter of Intent (LOI) from RTOG HQ.Non North American Institutions are advised not to submit a study for approval by their local regulatory body until their participation has been confirmed in the written notice of an approved Letter of Intent (LOI) from RTOG HQ. All Non North American Institutions must submit an LOI to RTOG HQ indicating their interest in participating in any RTOG Study.All Non North American Institutions must submit an LOI to RTOG HQ indicating their interest in participating in any RTOG Study. Formal Approval of the LOI will be received via e-mail with IMPORTANT specific instructions for moving forwardFormal Approval of the LOI will be received via e-mail with IMPORTANT specific instructions for moving forward Once the LOI has been approved, documentation of completion of all applicable regulatory pre-registration requirements as noted in the protocol must be submitted directly to the CTSU before enrollment can begin.Once the LOI has been approved, documentation of completion of all applicable regulatory pre-registration requirements as noted in the protocol must be submitted directly to the CTSU before enrollment can begin.

33. www.rtog.org 33 Important Note About Non North American Sites Participation will not be possible if any part of the study specific requirements outlined in the protocol conflict with your country's Ministry of Health regulations.Participation will not be possible if any part of the study specific requirements outlined in the protocol conflict with your country's Ministry of Health regulations. It is your institution's responsibility to understand and comply with all national Ministry of Health Regulations.It is your institution's responsibility to understand and comply with all national Ministry of Health Regulations. Translation of documents is critical. The cost of all translation would be your institution's responsibility. All regulatory documents, data and supporting documentation (when required) would need to be provided in English with certified/verified translation documentationTranslation of documents is critical. The cost of all translation would be your institution's responsibility. All regulatory documents, data and supporting documentation (when required) would need to be provided in English with certified/verified translation documentation Your institution will be responsible for acquiring any drug noted in the protocol as commercially available.Your institution will be responsible for acquiring any drug noted in the protocol as commercially available. Non North American participation in studies with a drug component will only be permitted if RTOG can procure and provide a supply of the study agent for your regionNon North American participation in studies with a drug component will only be permitted if RTOG can procure and provide a supply of the study agent for your region

34. www.rtog.org 34 International Letter of Intent (Pages 1& 2 of 3)

35. www.rtog.org 35 International Letter of Intent (page 3 of 3) “****Please review important information attached with response****”. This portion of the form will be returned to the site by RTOG HQ noting approval or disapproval A second very important document will also be provided with the approval, entitled International Letter of Intent to Participate Response, outlining expectations and requirements This document must be retained as a checklist to assure preregistration compliance prior to patient registration/enrollment.

36. www.rtog.org 36 Finding International Forms on the Website International Letter of Intent (LOI)International Letter of Intent (LOI)

37. www.rtog.org 37 Pharmaceutical Company Supplied Drug Procurement Procedure can vary by study.Procedure can vary by study. Detailed instructions for obtaining drug can be found in Section 7.0 of each protocolDetailed instructions for obtaining drug can be found in Section 7.0 of each protocol First step a pre-registration requirement, as noted in Section 5.0, submit the Study Agent Shipment Form (SASF) to CTSUFirst step a pre-registration requirement, as noted in Section 5.0, submit the Study Agent Shipment Form (SASF) to CTSU Processing of this form approves the site as eligible to receive drugProcessing of this form approves the site as eligible to receive drug –Registration/Randomization is the trigger for the initial shipment

38. www.rtog.org 38 SAMPLE (SASF) Study Agent Shipment Form

39. www.rtog.org 39 Finding RTOG SASFs On the Website Clinical Trials/Protocol Table/Select Study/Regulatory Resources

40. www.rtog.org 40 Pharmaceutical Company Supplied Drug Procurement Submitting your SASF for processing as soon as the individual responsible for the drug at your institution has been identified will assist you in: –avoiding delays in the initial drug shipment –alleviating frustration and inconvenience for yourself and most importantly the patient

41. www.rtog.org 41 Pharmaceutical Company Supplied Drug Procurement Realistic Treatment Start DatesRealistic Treatment Start Dates –If the SASF has already been processed, drug is received much faster, generally for overnight or two day delivery. –Most distributors will not ship prior to a weekend or holiday. –Shipments are generally restricted between December 23 and January 1. –Canadian sites should take into consideration the possibility of customs delays

42. www.rtog.org 42 NCI Drug Procurement –The Pharmaceutical Management Branch (PMB) of the NCI is responsible for supplying study agent for studies where the NCI holds the IND. –When the PMB supplies the drug for a study they are also responsible for providing the Investigator Brochure. –NIH Form 986/Clinical Drug Request is used to order study drug for NCI sponsored trials –All NCI Forms are available on the NCI website at http://ctep.cancer.gov/forms/index.html Clinical Drug Request (NIH Form 986) Investigational Drug Accountability Record Form (DARF) Drug Return Drug Transfer –The Pharmaceutical Management Branch (PMB) of the NCI is responsible for supplying study agent for studies where the NCI holds the IND. –When the PMB supplies the drug for a study they are also responsible for providing the Investigator Brochure. –NIH Form 986/Clinical Drug Request is used to order study drug for NCI sponsored trials –The Pharmaceutical Management Branch (PMB) of the NCI is responsible for supplying study agent for studies where the NCI holds the IND. –When the PMB supplies the drug for a study they are also responsible for providing the Investigator Brochure. –NIH Form 986/Clinical Drug Request is used to order study drug for NCI sponsored trials –All NCI Forms are available on the NCI website at http://ctep.cancer.gov/forms/index.html Clinical Drug Request (NIH Form 986) Investigational Drug Accountability Record Form (DARF) Drug Return Drug Transfer –The Pharmaceutical Management Branch (PMB) of the NCI is responsible for supplying study agent for studies where the NCI holds the IND. –When the PMB supplies the drug for a study they are also responsible for providing the Investigator Brochure. –NIH Form 986/Clinical Drug Request is used to order study drug for NCI sponsored trials –All NCI Forms are available on the NCI website at http://ctep.cancer.gov/forms/index.html Clinical Drug Request (NIH Form 986) Investigational Drug Accountability Record Form (DARF) Drug Return Drug Transfer

43. www.rtog.org 43 Canadian Drug Accountability There is a PMB approved Canadian Drug Accountability Form, which can be used by Canadian institutions for both PMB and pharmaceutically supplied drug.There is a PMB approved Canadian Drug Accountability Form, which can be used by Canadian institutions for both PMB and pharmaceutically supplied drug. This form is available on the RTOG website with the other Canadian resourcesThis form is available on the RTOG website with the other Canadian resources

44. www.rtog.org 44 NCI Drug Procurement Investigators must be registered with the NCI and have an Investigator NCI Number to receive drug from the NCI. Maintenance of this NCI Investigator Number requires the annual submission of: –FDA 1572 with CVs –signed Supplemental Investigator Data Form (IDF) –Financial Disclosure Form NCI/PMB Contact Information: Phone: (301) 496-5725 Fax: (301) 402-0429

45. www.rtog.org 45 NCI On-Line Drug Procurement http://ctep.info.nih.gov/branches/pmb/agent_order_processing.htm

46. www.rtog.org 46 Drug Accountability Record Forms NCI RTOG

47. www.rtog.org 47 Finding RTOG Accountability Records on the Website Clinical Trials/Protocol Table/Select Study/Regulatory Resources

48. www.rtog.org 48 Commercially Available Products Supplied free of charge through pharmaceutical support directly from the pharmaceutical company or via a third party distributor OR Obtained via prescription from the physician

49. www.rtog.org 49 End of Study Drug Disposition Can vary by sponsor/protocolCan vary by sponsor/protocol Records of accountability documentation may require submissionRecords of accountability documentation may require submission –Receipt of Drug –Dispensation of Drug –Disposition of Drug (returned/destroyed used/unused) Instructions usually documented in the protocol Institutional Drug Destruction Policy or SOPInstitutional Drug Destruction Policy or SOP –Required for site drug destruction

50. www.rtog.org 50 Return/Destruction of Study Drug When applicable, unexpired, unused, unopened, nontransferable agents remaining after a study has been permanently closed to accrual by RTOG must be returned to the distributor within 90 days of the RTOG closure broadcast.When applicable, unexpired, unused, unopened, nontransferable agents remaining after a study has been permanently closed to accrual by RTOG must be returned to the distributor within 90 days of the RTOG closure broadcast. If end of study drug destruction is noted in the protocol it must be carried out within 90 days of study closure and accountability records must be retained.If end of study drug destruction is noted in the protocol it must be carried out within 90 days of study closure and accountability records must be retained. If the institution lacks a written policy or SOP pertaining to drug destruction, drug must be returned to the distributor for destruction within 90 days of study closure.If the institution lacks a written policy or SOP pertaining to drug destruction, drug must be returned to the distributor for destruction within 90 days of study closure.

51. www.rtog.org 51 Blinded Studies RTOG saw a increase it drug errors on blinded RTOG saw a marked increase it drug errors on blinded RTOG studies particularly RTOG 0825. Please take the time to consider the importance of reviewing drug administration and safety policies with related staff in an effort to eliminate these errors. RTOG suggests a double or even triple check of the drug label and patient ID or a two person check similar to hospital drug transfusion policies. Contact RTOG HQ if you would like assistance with training your research pharmacy or staff.

52. www.rtog.org 52 Case & Point

53. www.rtog.org 53 Blinded Studies Important Points to remember: The number of RTOG blinded drug studies is increasing.The number of RTOG blinded drug studies is increasing. The order of the initials entered during registration significantly impacts our ability to quickly unblind a case in an emergency situationThe order of the initials entered during registration significantly impacts our ability to quickly unblind a case in an emergency situation Initials must be entered as First Middle Last (FML) or F-L if there is no middleInitials must be entered as First Middle Last (FML) or F-L if there is no middle The full DOB (MM/DD/YYYY) is also required for all blinded studies to allow us to confirm we have the right patient during unblinding in the event there are cases with the same initialsThe full DOB (MM/DD/YYYY) is also required for all blinded studies to allow us to confirm we have the right patient during unblinding in the event there are cases with the same initials

54. www.rtog.org 54 Emergency Unblinding Procedures “Decisions to break the code will only be considered for life threatening events or extraordinary clinical circumstances where it can be demonstrated knowledge of the drug treatment assignment will affect clinical judgment.” During RTOG business hours (8:30AM-5PM ET) call RTOG HQ at 215-574-3150 and ask to speak to a statistician.During RTOG business hours (8:30AM-5PM ET) call RTOG HQ at 215-574-3150 and ask to speak to a statistician. After hours (5PM-8:30AM ET) call 215-459-3576After hours (5PM-8:30AM ET) call 215-459-3576 Calls received after hours or during weekends and holidays will be returned as soon as possible. Please leave your name, contact information, the first and last name of the patient who experienced the event, the study & case number and the reason for the unblinding request.Calls received after hours or during weekends and holidays will be returned as soon as possible. Please leave your name, contact information, the first and last name of the patient who experienced the event, the study & case number and the reason for the unblinding request. If the unblinding request pertains to RTOG 0825 and tumor progression, please contact Treena Trotman at 215-940-8913 during regular business hoursIf the unblinding request pertains to RTOG 0825 and tumor progression, please contact Treena Trotman at 215-940-8913 during regular business hours

55. www.rtog.org 55 Emergency Unblinding Requests to unblind either case in the situation of a corruption or crossover in drug administration will likely result in both cases being removed from the studyRequests to unblind either case in the situation of a corruption or crossover in drug administration will likely result in both cases being removed from the study The Emergency Unblinding line is for true emergencies onlyThe Emergency Unblinding line is for true emergencies only Please do not leave messages pertaining to anything but emergency unblindingPlease do not leave messages pertaining to anything but emergency unblinding This is NOT a catch all after hours office lineThis is NOT a catch all after hours office line Messages left for any other reason will not be forwarded or receive a responseMessages left for any other reason will not be forwarded or receive a response

56. www.rtog.org 56 Minimum Required Information for Emergency Unblinding Request The unblinding officer will contact you for further information.

57. www.rtog.org 57 Protocol Deviations CTEP has a policy in place related to the issuance of waivers for protocol deviations:CTEP has a policy in place related to the issuance of waivers for protocol deviations: The policy applies to all components of CTEP-approved protocols, including eligibility criteria, treatment schedules, dose modifications, toxicity assessment, response criteria, and statistical aspects.The policy applies to all components of CTEP-approved protocols, including eligibility criteria, treatment schedules, dose modifications, toxicity assessment, response criteria, and statistical aspects. Link to Policy: http://ctep.cancer.gov/protocolDevelopment/policies_deviation s.htmLink to Policy: http://ctep.cancer.gov/protocolDevelopment/policies_deviation s.htm http://ctep.cancer.gov/protocolDevelopment/policies_deviation s.htm http://ctep.cancer.gov/protocolDevelopment/policies_deviation s.htm CTEP does not issue or approve any waivers for protocol deviationsCTEP does not issue or approve any waivers for protocol deviations

58. www.rtog.org 58 NCI Deviation Policy

59. www.rtog.org 59 MARCH 2012 RTOG SAE Safety Reporting

60. www.rtog.org 60 NCI Guidelines for AE Reporting RTOG Data Management is responsible for and provides basic instruction and NCI based training and guidance regarding the reporting of adverse events (AE) and Protocol Specific Special Reporting (PSSR) via the for and provides basic instruction and NCI based training and guidance regarding the reporting of adverse events (AE) and Protocol Specific Special Reporting (PSSR) via the Adverse Event Expedited Reporting System (AdEERS)

61. www.rtog.org 61 Current AdEERS Reporting Pathway (Decentralized) Centralized changes coming soon…

62. www.rtog.org 62 Centralized SAE Reporting Coming Soon…

63. www.rtog.org 63 The NEW FDA Final Rule for Expedited Reporting The Final Rule:The Final Rule: 21 CFR Parts 312 and 320 [Docket No. FDA-2000-N-0108] (formerly Docket No. 00N-1484)21 CFR Parts 312 and 320 [Docket No. FDA-2000-N-0108] (formerly Docket No. 00N-1484) RIN 0910-AG13RIN 0910-AG13 Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in HumansInvestigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans http://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdfhttp://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdfhttp://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdfhttp://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdf This regulation requires changes to expedited serious adverse event reporting requirements for investigators to IND sponsors such as NCI/CTEPThis regulation requires changes to expedited serious adverse event reporting requirements for investigators to IND sponsors such as NCI/CTEP

64. www.rtog.org 64 Pharmaceutical/Industry SAE Reporting Requirements Special considerations when reporting on pharmaceutically supported studies using the AdEERS system Pharmaceutically supported studies often require additional reporting over and above that which is required by the NCI.Pharmaceutically supported studies often require additional reporting over and above that which is required by the NCI. Complying with pharmaceutical standards will require bypassing the “reporting not required” screen in AdEERS and going on to complete and submit the report.Complying with pharmaceutical standards will require bypassing the “reporting not required” screen in AdEERS and going on to complete and submit the report.

65. www.rtog.org 65 SAE Definition A Serious Adverse Event (SAE) is defined by the Code of Federal Regulations (CFR) as: Any untoward medical occurrence that at any dose results in death is life threatening requires inpatient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. The phrase “at any dose” should be replaced with “during protocol treatment and 30 days after” for RTOG purposes to capture SAEs that occur during any part of protocol therapy including radiation therapy or surgery. Please note reporting outside the 30 day window is required when the event is determined to be possibly, probably or definitely related to any part of protocol treatment.

66. www.rtog.org 66 Important Points Hospitalization is defined as an admission to an inpatient bed for at least 24 hours.Hospitalization is defined as an admission to an inpatient bed for at least 24 hours. Grade, attribution or expectedness are not a consideration for RTOG in the reporting of SAEs, simply meeting the criteria in the SAE definition makes the event an SAE.Grade, attribution or expectedness are not a consideration for RTOG in the reporting of SAEs, simply meeting the criteria in the SAE definition makes the event an SAE. The use of the CTEP CTCAE Grading Scale instead of the SAE criteria in the reporting of AEs that may also be considered serious can become confusing in some instances and allow certain SAEs to go unreported (e.g., when a patient is hospitalized for a grade 2 event).The use of the CTEP CTCAE Grading Scale instead of the SAE criteria in the reporting of AEs that may also be considered serious can become confusing in some instances and allow certain SAEs to go unreported (e.g., when a patient is hospitalized for a grade 2 event). The new FDA Final Rule RE: Expedited Reporting now also requires all SAEs be reported unless the protocol states otherwiseThe new FDA Final Rule RE: Expedited Reporting now also requires all SAEs be reported unless the protocol states otherwise

67. www.rtog.org 67 Medically Significant Events Medical and scientific judgment should be exercised in deciding whether reporting as an SAE is appropriate in other situations, such as important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the SAE definition.Medical and scientific judgment should be exercised in deciding whether reporting as an SAE is appropriate in other situations, such as important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the SAE definition. ExamplesExamples –the development of a new malignancy –allergic bronchospasm – blood dyscrasias – convulsions

68. www.rtog.org 68 Site Initiated SAE/Safety Reporting Reporting Serious Adverse Events (SAE) AdEERS is the required reporting format for SAEs on all NCI supported RTOG studiesAdEERS is the required reporting format for SAEs on all NCI supported RTOG studies A study specific SAE form will be used for upcoming Foundation Studies (3500 series studies) for transcription by RTOG into the FDA MedWatch FormA study specific SAE form will be used for upcoming Foundation Studies (3500 series studies) for transcription by RTOG into the FDA MedWatch Form All events that meet the criteria for an SAE must be reported regardless of grade or attributionAll events that meet the criteria for an SAE must be reported regardless of grade or attribution SAE/Safety Reporting is separate, and in addition to Data Management AE reporting (on the CRF)SAE/Safety Reporting is separate, and in addition to Data Management AE reporting (on the CRF) All SAEs must be reported to your IRBAll SAEs must be reported to your IRB

69. www.rtog.org 69 SAE Serious Adverse Events (SAEs) are defined by FDA and therefore seriousness (not severity) serves as a guide for defining regulatory reporting obligations for patient/subject safety. ‘Seriousness’ is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning. FDA Federal Regulations require IND sponsors to report serious adverse events via Expedited reporting. The two terms “serious” and “severe” are not interchangeable and their meanings should not be confused.

70. www.rtog.org 70 24 Hour AdEERS Notification Requirements Phase II & III Studies: hospitalizations grade 4 or > and all grade 4 & 5 events regardless of relationshipPhase II & III Studies: hospitalizations grade 4 or > and all grade 4 & 5 events regardless of relationship Phase I & early Phase II Studies: hospitalizations grade 3 or > and all grade 4 & 5 events regardless of relationshipPhase I & early Phase II Studies: hospitalizations grade 3 or > and all grade 4 & 5 events regardless of relationship The timeframe for the complete AdEERS Report associated with any 24 Hour AdEERS Notifications is 5 days.The timeframe for the complete AdEERS Report associated with any 24 Hour AdEERS Notifications is 5 days. All other SAEs that do not require the submission of a 24 Hour AdEERS Notification will be reported via AdEERS using the 10 day reporting timeline.All other SAEs that do not require the submission of a 24 Hour AdEERS Notification will be reported via AdEERS using the 10 day reporting timeline.

71. www.rtog.org 71 Foundation Study SAE Report Form 24 Hour Notification Requirements Phase II & III Studies: hospitalizations grade 4 or > and all grade 4 & 5 events regardless of relationshipPhase II & III Studies: hospitalizations grade 4 or > and all grade 4 & 5 events regardless of relationship Phase I & early Phase II Studies: hospitalizations grade 3 or > and all grade 4 & 5 events regardless of relationshipPhase I & early Phase II Studies: hospitalizations grade 3 or > and all grade 4 & 5 events regardless of relationship The timeframe for the complete Report associated with any event requiring 24 Hour Notifications is 5 days.The timeframe for the complete Report associated with any event requiring 24 Hour Notifications is 5 days. All other SAEs that do not require the submission of a 24 Hour Notification will be reported using the 10 day reporting timeline.All other SAEs that do not require the submission of a 24 Hour Notification will be reported using the 10 day reporting timeline.

72. www.rtog.org 72 Timelines The time frame for submitting the required type of report will vary from FIVE to TEN CALENDAR DAYS Please refer to the protocol for specificsThe time frame for submitting the required type of report will vary from FIVE to TEN CALENDAR DAYS Please refer to the protocol for specifics The day the event is reported is counted as day one.The day the event is reported is counted as day one. The reporting deadline is required to allow for RTOG and/or pharmaceutical sponsors to fulfill their external regulatory reporting obligations.The reporting deadline is required to allow for RTOG and/or pharmaceutical sponsors to fulfill their external regulatory reporting obligations.

73. www.rtog.org 73 Table of Timelines Revised 3/2012 in alignment with centralized reporting & the new FDA Final Rule for Expedited Reporting

74. www.rtog.org 74 Proper Identification Proper identification of follow-up or amended reports, supporting source documentation and/or other information relevant to the SAE is imperative and must always include the RTOG study and case number Please use the RTOG Case Number as the Patient ID in the AdEERS System * DO NOT ADD LEADING ZEROSPlease use the RTOG Case Number as the Patient ID in the AdEERS System * DO NOT ADD LEADING ZEROS Please follow the specific instructions on the SAE Report Form for Foundation (3500 series) studiesPlease follow the specific instructions on the SAE Report Form for Foundation (3500 series) studies

75. www.rtog.org 75 What type of other documentation must be submitted with the an SAE Report? AdEERS: Only documentation noted by the reporter as being provided in the additional information section of AdEERS need be submitted initiallyAdEERS: Only documentation noted by the reporter as being provided in the additional information section of AdEERS need be submitted initially Foundation (3500 series)SAE Report Form: None unless specifically requestedFoundation (3500 series)SAE Report Form: None unless specifically requested If the pharmaceutical company requires further documentation or clarification, RTOG will contact you via e-mail with the query/ requestIf the pharmaceutical company requires further documentation or clarification, RTOG will contact you via e-mail with the query/ request The NCI may also contact you directly to request specific information or documentationThe NCI may also contact you directly to request specific information or documentation

76. www.rtog.org 76 Dedicated SAE Fax Line 215-717-0990 All necessary supporting source documentation relating to the SAE noted as being supplied in the Additional Information Section of the AdEERS Report must be properly labeled with the RTOG Study and Case Number as well as the date and Ticket Number of the corresponding event and provided within the allotted timeframe or as soon as it becomes available. Information pertaining to Foundation (3500 series) Studies must also be properly labeled with the Study and Case Number as well as the date of the event

77. www.rtog.org 77 May 27, 2008

78. www.rtog.org 78 Guidance and/or Assistance with the AdEERS System  It may be helpful to view the AdEERS Tutorial at the following link: http://ctep.info.nih.gov/reporting/AdEERS_CBT_v3/welcome.html  Problems or issues with the AdEERS System for reporting AE/SAEs may also be referred to the following contacts:  For all medical and policy related issues, please contact the AdEERS Coordinators by email at AdEERSMD@tech-res.com or telephone (301) 897-7497. mailto:AdEERSMD@tech-res.com  For all technical and training related issues please contact the NCI CTEP Help Desk by email at ncictephelp@ctep.nci.nih.gov or telephone (301)840-8202. mailto:ncictephelp@ctep.nci.nih.gov  RTOG AdEERS Coordinator: Sandy McDonald [ smcdonald@acr.org or 215-717-0857] smcdonald@acr.org

79. www.rtog.org 79 Guidance and/or Assistance with the Foundation (3500 series) SAE Report Form  You can view both the Foundation SAE Report Form and Guidance for use/completion on the RTOG website www.rtog.org. www.rtog.org  The Foundation SAE Report Form and Guidance are study specific and will be located under the study specific Regulatory Resources tab on the website  The RTOG SAE Coordinator: Sara McCartney[ smccartney@acr.org or 267-940-9404 can also provide assistance with using the Foundation SAE Report Form smccartney@acr.org

80. www.rtog.org 80 NCI/Pharmaceutical Initiated/External Safety Reports (ESR) Events detailed in safety reports originating from the NCI or pharmaceutical company can reference a more global use of the drugEvents detailed in safety reports originating from the NCI or pharmaceutical company can reference a more global use of the drug These safety reports are intended to inform treating physicians regarding events that have occurred in the interim that will be included in the next revised Investigator BrochureThese safety reports are intended to inform treating physicians regarding events that have occurred in the interim that will be included in the next revised Investigator Brochure No action other than providing these reports to your IRB is required unless indicatedNo action other than providing these reports to your IRB is required unless indicated Any questions regarding the overall significance of events reported in these safety reports should be directed to the NCI or the pharmaceutical company that initiated the report.Any questions regarding the overall significance of events reported in these safety reports should be directed to the NCI or the pharmaceutical company that initiated the report.

81. www.rtog.org 81 External Safety Report (ESR) IRB Review Local IRB policy can limit the review of ESRsLocal IRB policy can limit the review of ESRs –Auditors will require a copy of the written IRB policy or SOP In the event the Local IRB elects not to review all ESRsIn the event the Local IRB elects not to review all ESRs –ESRs must still be reviewed by the PI or designee –The reviewer should indicate review by signing and dating the report –All ESRs must still be maintained as part of the study file for review during a site audit. Sites who previously relied on the CIRB review of ESRs for Phase III studiesSites who previously relied on the CIRB review of ESRs for Phase III studies –This review is now accomplished by way of review of the RTOG Data Monitoring Committee (DMC) reports for both Phase IIR & III studies

82. www.rtog.org 82 Finding Safety Reports on the Website Safety Reports can be found under the study specific broadcasts on the RTOG website (Clinical Trials > Protocol Table > Study Details > Broadcasts)Safety Reports can be found under the study specific broadcasts on the RTOG website (Clinical Trials > Protocol Table > Study Details > Broadcasts) Safety reports are sent via e-mail broadcast to individuals from participating institutions who are listed on the RTOG Broadcast ListSafety reports are sent via e-mail broadcast to individuals from participating institutions who are listed on the RTOG Broadcast List If you would like to be added/removed from the RTOG broadcast list or wish to update your e-mail address, send a message to RTOG-UserAccounts@acr.orgIf you would like to be added/removed from the RTOG broadcast list or wish to update your e-mail address, send a message to RTOG-UserAccounts@acr.orgRTOG-UserAccounts@acr.org Sites should not reply directly to any broadcast. Institutions can share a comment or ask a question by accessing the appropriate department at RTOG Headquarters on the RTOG web site at www.rtog.org then select the member information tab and click HQ Information & Telephone Listings. Sites can also call 1-800-227-5463 ext. 4189, which provides prompts to reach each departmentSites should not reply directly to any broadcast. Institutions can share a comment or ask a question by accessing the appropriate department at RTOG Headquarters on the RTOG web site at www.rtog.org then select the member information tab and click HQ Information & Telephone Listings. Sites can also call 1-800-227-5463 ext. 4189, which provides prompts to reach each departmentwww.rtog.org Canadian research staff should be sure to request they be added specifically to the Canadian Broadcast List to assure the receipt of all broadcast information relevant to Canadian participation

83. www.rtog.org 83 Safety Report Broadcasts Clinical Trials > Protocol Table > Study Details > Broadcasts

84. www.rtog.org 84 On a Lighter Note…

85. www.rtog.org 85 Regulatory Staff

86. www.rtog.org 86