FDA Final Rule & Revised NCI Guidelines for Expedited Reporting of Adverse Events

1. FDA Final Rule & Revised NCI Guidelines for Expedited Reporting of Adverse Events National Cancer Institute National Cancer Institutepresents: S. Percy Ivy, MD Associate Chief, Senior Investigator Investigational Drug Branch, National Cancer Institute ivyp@ctep.nci.nih.gov Jan Casadei, PhD Chief Regulatory Affairs Branch, National Cancer Institute casadeij@mail.nih.gov

2. Final Rule Implications: • Investigator reporting to sponsor • Expedited Filing to the FDA

3. Definitions for reporting/filing purposes • Investigator – the primary investigator of a trial • 21 CFR 312.3 - Investigator means an individual who actually conducts a clinical investigation (i.e. , under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. • Sponsor – the IND holder

4. Investigator • Reports serious AEs (non-serious AEs reported per protocol non-expeditiously) Sponsor • Reports serious and unexpected suspected Adverse Reactions (reasonable possibility drug caused event) to FDA FDA All Investigators • Provides significant new findings to patients • Reports unanticipated problems involving risks to subjects to the IRB Patient IRB

5. What does the Final Rule address? Investigator • Investigator reports (21 CFR 312.64(b)) Sponsor • IND safety reports: Expedited (7- and 15-day) reports (21 CFR 312.32) • Safety reports for bioavailability (BA) or bioequivalence (BE) studies (21 CFR 320.31(d)): Expedited reports FDA All Investigators

6. Overview of New Requirements • Codifies FDA’s expectations for timely review, evaluation and submission of important and useful safety information • More fully defines responsibilities of sponsors and investigators • More consistent with international definitions and reporting standards • Clarifies confusing terminology in existing regulations • Improves the utility of IND safety reports

7. Why is the New Final Rule Needed? FDA’s viewpoint: • Confusing/inconsistent terminology in current regulations • Current “over filing” of expedited reports dampens safety signal • Sponsors often report serious adverse events that: • Are likely to have been a manifestation of the underlying disease • Commonly occur in the study population independent of drug exposure (e.g., strokes or acute myocardial infarctions in an elderly population) • Are study endpoints (i.e., the study was evaluating whether the drug reduced the rate of these events) • Not useful for human subject protection or for developing the safety profiles of drugs • A burden on the system (Investigators, Sponsors, IRBs, FDA)

8. Definition of Serious Adverse Event • Death • Life-threatening event (places the patient at immediate risk of death) • Requires inpatient hospitalization or prolongs hospitalization • Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions • Congenital anomaly/birth defect • NOTE: Important medical events (IMEs) may be considered serious when, based on medical judgment, they may jeopardize the patient and require intervention to prevent one of the above serious outcomes Revised: Determination is based on the opinion of either the investigator or sponsor (i.e., if either believes it is serious, it must be considered serious)

9. Note: Serious  Severe (though they are linked) Severity is defined by a grading scale

10. Definition of Unexpected Adverse Event • Not listed in the Investigator’s Brochure (IB) at the specificity or severity observed • Mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but not mentioned as occurring with the particular drug under investigation • If an IB is not required or available, the sponsor should refer to the risk information in the IND • The sponsor will determine if an adverse event (AE) is unexpected for filing purposes

11. The Universe of Adverse Events The Universe of Adverse Events New Terms • Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related • Any AE for which there is a reasonable possibility that the drug is the cause • Implies a lesser degree of certainty about causality than an adverse reaction • Any AE caused by a drug

12. Assigning Causality • Key element in decision to file to FDA • Note: Investigator reports causality but sponsor retains final decision on causality when filing to the FDA • Key element in defining a Suspected Adverse Reaction • “Reasonable possibility” is specifically defined in Final Rule: it means there is evidence to suggest a causal relationship between the drug and AE • Reasonable possibility = possibly, probably, or definitely related

13. Assigning Causality Final Rule outlines specific criteria for filing to the FDA: • Individual occurrences • One or more occurrence • Aggregate analysis of specific events observed in a clinical trial (e.g., such as known consequences of underlying disease, or events that commonly occur in the study population)

14. Assigning Causality Final Rule outlines specific criteria for filing to the FDA: • Individual occurrences • One or more occurrence • Aggregate analysis of specific events observed in a clinical trial (e.g., such as known consequences of underlying disease, or events That commonly occur in the study population) • Single occurrence of an event that is uncommon and known to be strongly associated with drug exposure • Angioedema • Hepatic injury • Stevens-Johnson syndrome • Rare that causality can be assigned to drug based on single occurrence for any other type of event

15. Assigning Causality Final Rule outlines specific criteria for filing to the FDA: • Individual occurrences • One or more occurrence • Aggregate analysis of specific events observed in a clinical trial (e.g., such as known consequences of underlying disease, or events that commonly occur in the study population) • Single occurrence, or a small number of occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug • Cardiac events in otherwise healthy individuals • Tendon rupture in young adults

16. Assigning Causality Final Rule outlines specific criteria for filing to the FDA: • Individual occurrences • One or more occurrence • Aggregate analysis of specific events observed in a clinical trial (e.g., such as known consequences of underlying disease, or events that commonly occur in the study population) • Events that are occurring more frequently in the agent treatment group than in a concurrent or historical control group • Day 0 is the day that the sponsor decides that the events meet the criteria for aggregate reporting and the report must be filed within 15 days • Individual SARs making up the aggregate report must be retroactively filed

17. What should be reported expeditiously to the sponsor? Is it serious? Adverse Event (AE) Yes • Should include an assessment of causality • Non-serious AEs are recorded and reported to the sponsor according to protocol REPORT

18. What should be filed expeditiously to the FDA? (1) Meets causality requirement? (2) Is serious? (3) Is not listed in the IB or other applicable safety information? Unexpected Adverse Event (AE) Suspected Adverse Reaction (SAR) Serious SAR (SSAR) Yes Yes Yes FILE

19. Other New Expedited Filing Requirements for Sponsors • Study endpoints • Increased occurrence of Serious Suspected Adverse Reactions • Findings that suggest a significant human risk • IND exempt Bioequivalence/Bioavailability studies

20. Other New Expedited Filing Requirements for Sponsors • Mortality or major morbidity • In general should not be filed expeditiously • Exception: If there is evidence suggesting a causal relationship (e.g., death from anaphylaxis in a trial with an all-cause mortality endpoint) • Study endpoints • Increased occurrence of Serious Suspected Adverse Reactions • Findings that suggest a significant human risk • IND exempt Bioequivalence/Bioavailability studies

21. Other New Expedited Filing Requirements for Sponsors • Study endpoints • Increased occurrence of Serious Suspected Adverse Reactions • Findings that suggest a significant human risk • IND exempt Bioequivalence/Bioavailability studies • Sponsor must file any clinically important increase in the rate of a SSAR over that listed in the protocol or IB

22. Other New Expedited Filing Requirements for Sponsors • Study endpoints • Increased occurrence of Serious Suspected Adverse Reactions • Findings that suggest a significant human risk • IND exempt Bioequivalence/Bioavailability studies • Sponsor must file expeditiously any findings that suggest a significant risk from: • Clinical, epidemiological, or pooled analysis of multiple studies • Animal or in vitro testing (e.g., mutagenicity, teratogenicity, carcinogenicity) • Ordinarily, results in a safety-related change in the protocol, IB, informed consent, or other aspect of the overall conduct of the clinical investigation

23. Other New Expedited Filing Requirements for Sponsors • Study endpoints • Increased occurrence of Serious Suspected Adverse Reactions • Findings that suggest a significant human risk • IND exempt Bioequivalence/Bioavailability studies • Current - no safety reporting requirements • New requirement: must file ALL serious AEs

24. Key Points for Safety Surveillance • Sponsors should ensure that they have in place a systematic approach for safety surveillance • Should include a process for reviewing, evaluating, and managing accumulating safety data from the entire clinical trial database at appropriate intervals • May be carried out by a data safety monitoring board or safety team, preferably independent with external representation (may already be common practice-briefly mentioned in FDA’s 2006 DMC guidance)

25. Protocol-specific Requirements and Exceptions for Monitoring Serious Adverse Events • Study endpoints • Protocol-specific exceptions (not study endpoints) to expedited reporting or filing • Identify events and monitoring plan in the protocol • Limit to events that are common in study population • Safety team or independent group monitors the rates at appropriate intervals • Report if an aggregate analysis indicates that events are occurring more frequently in the drug treatment group

26. Investigator’s Brochures • Provides the investigator with information (clinical and nonclinical) about the investigational drug • Used as basis for sponsor’s determination of “unexpectedness” for filing purposes • Include AEs for which a causal relationship is suspected or confirmed • No laundry lists • Clinical risk information • Updating the IB should be in concert with GCP

27. Immediate Filing Timeframes for Sponsors • IND Safety Reports (15-day) • File within 15 calendar days after the sponsor determines that the AE or other risk information qualifies for filing • Unexpected fatal or life-threatening SAR Reports (7-day) • Notify FDA within 7 calendar days after sponsor’s initial receipt of information (phone, fax, or electronic) • Initial Written Report (IWR) from NCI is filed within 7 days • Follow-up reports • File as soon as information is available • If FDA requests any additional data or information: Submit to FDA ASAP, but no later than 15 calendar days after receiving the request (NEW)

28. Looking Forward • Implementation • Effective March 28, 2011 • FDA and investigators should receive fewer individual reports, but reports should be more complete and meaningful, resulting in: • Better data to support clinical decision making • Better protection of human subjects • To achieve this: • Protocols may need to be more specific (i.e., protocol specific exceptions to expedited reporting should be included when possible) • Sponsor will have more overt responsibility for aggregation and analysis of AEs

29. Revised NCI Guidelines for Expedited Reporting of Adverse Events

30. NCI Guidelines: Expedited Reporting of AEs from Investigator to Sponsor Investigator • Reports serious AEs (non-serious AEs reported per protocol non-expeditiously) Sponsor • Reports serious and unexpected suspected ARs (reasonable possibility drug caused event) to FDA FDA All Investigators • Provides significant new findings to patients • Reports unanticipated problems involving risks to subjects to the IRB Patient IRB

31. WHY Does NCI Collect EXPEDITED AE Reports? • Patient Safety • Adequate Informed Consent • Compliance with FDA Regulations and consideration of concordance with ICH guidelines • Required of the IND Sponsor (21 CFR 312.32)

32. Adverse Event EXPEDITED Reporting System: • All expedited AEs for NCI IND Agents should be submitted to NCI via a web-based electronic system • AdEERS (implemented 2001) • caAERS (scheduled to replace AdEERS in 2011?) • All open protocols using NCI-sponsored IND agents will be listed in AdEERS/caAERS and will indicate expedited AE reporting is required • Expedited AE submission demonstration & training is available for key Group staff and representatives • Computer-based AdEERS/caAERS training is available at: (http://ctep.info.nih.gov/protocolDevelopment/ electronic_applications/adeers.htm)

33. WHAT is reportable to NCI in an Expedited Fashion? Reportable Not Reportable • ALL serious AEs regardless of causality to the study drug • Note: All expedited AEs (reported via AdEERS/caAERS) must also be reported via routine reporting mechanisms (e.g., CRF, CTMS, and/or CDUS) • Non-serious AEs (instead, recorded and reported to NCI according to the protocol)

34. WHO completes an EXPEDITED AE report? • Investigator • Principal Investigator should review full report for completeness and accuracy; will need to provide narrative of event and select supporting material • Research Nurse • Clinical Research Associate

35. Comparison of Old vs. New Tables • No reporting distinctions based on causality or expectedness (unless SAE occurred >30 days after last dose administration) • Only consideration is seriousness, as outlined in the Final Rule • There are tables for: • Phase 0 • Phase 1/Early Phase 2 • Late Phase 2/Phase 3 • CIP COMMERCIAL Agent Studies (based on Late Phase 2/Phase 3) • AE reporting requirements for PET or SPECT IND agents were added • An implementation date will be set for incorporating new tables into prospective studies

36. NCI Expedited AE Reporting Time-Line Requirements • Report by AdEERS/caAERSwithin 24 hours (use telephone if internet connectivity lost) AND • Complete report within 5 calendar days for: • Complete report within 10 calendar days for: 1For PET or SPECT IND agents, AEs should be monitored for 10 half-lives

37. NCI Evaluation of EXPEDITED AE Report • IDB Senior Investigator reviews submitted report • Requires sufficient documentation for independent NCI evaluation • Independent review/assessment of AE, attribution • Does AE warrant expedited filing to the FDA? • Hospital Summary (History and Physical) • Laboratory Data • EKGs • Radiology Reports (e.g., scans MRI etc.) • Flow Sheets • Visit/ER/Progress Notes • Autopsy Reports/discharge summary

38. NCI IND SAFETY REPORT Process Reporting to FDA, Investigators, and Company Collaborators Utilize existing AdEERS/caAERS submission processes to ensure compliance with FDA regulations (21 CFR 312.32) and ICH E2A relating to AE reporting IDB evaluation of incoming AdEERS/caAERS AE Does AE warrant expedited filing to the FDA? Yes Initial WrittenReport generated No AE is held for submission with Annual Report

39. “Initial Written Report” NCI Processing Timelines Initial Written Report (IWR) faxed to relevant FDA division within 3-5 calendar days of receipt at NCI(once determined AE warrants expedited filing)  Submit IWR to IND within 1 day after faxing to FDA  Forward IWR to company collaborator concurrent with submission to IND  Distribute to pertinent NCI investigators within 1 day of submitting to IND

40. “Initial Written Report” Form

41. “Follow-up Written Report” Process • Based on subsequent AE-related information from site, one of the following is submitted to the IND, company collaborator, and relevant investigators: • An “ADVERSE EVENTS ASSESSMENT” summary detailing time course, laboratory and radiological assessments, IND experience, and assessment of attribution is prepared as a Follow-up Written Report OR • If AE is no longer considered related to the investigational agent/regimen, the IWR form is revised accordingly and submitted as a Follow-up Written Report OR • If an AE not initially determined to be reportable in an expedited manner is now reportable, then an IWR is submitted.

42. ADDITIONAL INFORMATION

43. ACRONYMS AdEERS Adverse Event Expedited Reporting System AE Adverse Event AR Adverse Reaction BA Bioavailability BE Bioequivalence caAERS Cancer Adverse Event Reporting System CAEPR Comprehensive Adverse Events and Potential Risks CDUS Clinical Data Update System CFR Code of Federal Regulations CIP Cancer Imaging Program CRF Case Report Form CTMS Clinical Trial Management System IB Investigator’s Brochure ICD Informed Consent Document ICH International Conference on Harmonization IDB Investigational Drug Branch IDE Investigational Device Exemption IME Important Medical Event IND Investigational New Drug IRB Institutional Review Board IWR Initial Written Report SAR Suspected Adverse Reaction SSAR Serious Suspected Adverse Reaction

44. URLS for Final Rule and Guidance Documents http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf

45. REVISED NCI AE REPORTING TABLES

47. Expedited AE reporting timelines are defined as: o “24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.

48. Phase 0 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention1 1For studies using PET or SPECT agents, the AE reporting period is limited to 10 radioactive half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.

49. Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention1 1For studies using PET or SPECT agents, the AE reporting period is limited to 10 radioactive half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.

50. Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention1 and CIP Commercial Agent Studies: Expedited Reporting Requirements for Adverse Events that Occur in a CIP Non-IND/IDE trial within 30 Days of the Last Administration of a Commercial Imaging Agent1 1For studies using PET or SPECT agents, the AE reporting period is limited to 10 radioactive half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.