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

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

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

Investigator Sponsor FDA All Investigators Patient IRB 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

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

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

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)

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)

Note: Serious  Severe (though they are linked) Severity is defined by a grading scale Seriousness Severity (Grade) Death 5 Life-threatening 4 Hospitalization 3/4/5 Important Medical Event (IME) Disability

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

The Universe of Adverse Events New Terms ADVERSE EVENTS (AE) Suspected Adverse Reactions (SAR) Adverse Reactions (AR) 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

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

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)

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

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

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

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

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

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

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 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)

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

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

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

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)

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

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

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)

Looking Forward Implementation To achieve this: 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

Revised CTEP Guidelines for Expedited Reporting of Adverse Events

CTEP Guidelines: Expedited Reporting of AEs from Investigator to Sponsor 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

WHY Does CTEP 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)

Adverse Event EXPEDITED Reporting System: All expedited AEs for CTEP IND Agents should be submitted to CTEP via a web-based electronic system AdEERS (implemented 2001) caAERS (scheduled to replace AdEERS in 2011?) All open protocols using CTEP-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)

WHAT is reportable to CTEP in an Expedited Fashion? 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 CTEP according to the protocol)

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

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 Studies (identical to Late Phase 2/Phase 3) An implementation date will be set for incorporating new tables into prospective studies

CTEP Expedited AE Reporting Time-Line Requirements Report by AdEERS/caAERS within 24 hours (use telephone if internet connectivity lost) AND Complete report within 5 calendar days for: AEs occurring within 30 days of last treatment Serious AEs occurring >30 days after the last dose of agent Ph0 ALL Gr. 3-5 ALL Gr. 4& 5 Gr. 3 with at least a possible causality Ph1/Early Ph2 Gr. 3-5 with at least a possible causality Late Ph2/Ph3 AND CIP agents ALL Gr. 4&5 Gr. 4&5 with at least a possible causality Complete report within 10 calendar days for: AEs occurring within 30 days of last treatment Serious AEs occurring >30 days after the last dose of agent Ph0 ALL Gr. 1&2 Ph1/Early Ph2 Gr. 2 w/ hospitalization Gr. 2 w/ hospitalization and at least a possible causality Late Ph2/Ph3 AND CIP agents ALL Gr. 3 Gr. 3 with at least a possible causality

CTEP Evaluation of EXPEDITED AE Report IDB Senior Investigator reviews submitted report Requires sufficient documentation for independent CTEP 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

 IDB evaluation of incoming AdEERS/caAERS AE CTEP 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 Written Report generated  No AE is held for submission with Annual Report

“Initial Written Report” CTEP Processing Timelines Initial Written Report (IWR) faxed to relevant FDA division within 3-5 calendar days of receipt at CTEP (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

“Initial Written Report” Form

“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.

ADDITIONAL INFORMATION

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

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

REVISED CTEP AE REPORTING TABLES

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/Intervention Grade 1 and 2 Timeframes Grade 3-5 Timeframes 10 Calendar Days 24-Hour 5 Calendar Days

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/Intervention Hospitalization Grade 1 Timeframes Grade 2 Timeframes Grade 3-5 Timeframes With Hospitalization  24 hrs Not Required 10 Calendar Days 24-Hour 5 Calendar Days Without Hospitalization  24 hrs

Without Hospitalization 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/Intervention and CIP Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under a CIP Non-IND/IDE trial within 30 Days of the Last Administration of a Commercial Imaging Agent Hospitalization Grade 1 Timeframes Grade 2 Timeframes Grade 3 Timeframes Grade 4 & 5 Timeframes With Hospitalization  24 hrs Not Required 10 Calendar Days 24-Hour 5 Calendar Days Without Hospitalization

LEGACY TABLES Legacy tables should continue to be used for all studies at the present time The revised reporting tables will only be applied to studies not yet approved by CTEP by an implementation date yet to be determined

without hospitalization Legacy Phase 1: Reporting Requirements for Adverse Events that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 1 Studies Attribution Grade 1 Grade 2 Grade 3 Grade 4 & 5 Unexpected and Expected with hospitalization without hospitalization Unlikely Unrelated Not required 10 Calendar Days 24-Hour 5 calendar Days Possible Probable Definite 24-Hour 5 calendar Days

without hospitalization Legacy Phase 2/3: Reporting Requirements for Adverse Events that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 Studies Attribution Grade 1 Grade 2 Grade 3 Grade 4 & 5 Unexpected and Expected with hospitalization without hospitalization Unlikely Unrelated Not required 10 Calendar Days Possible Probable Definite 24-Hour 5 calendar Days

AdEERS Help Technical Help Desk Phone: 301-840-8202 Fax: 301-948-2242 Email: ncictephelp@ctep.nci.nih.gov Adverse Event Content Help Desk Phone: 301-897-7497 Fax: 301-230-0159 Email: adeersmd@tech-res.com Email for CTCAE v4.0 questions: ncictcaehelp@mail.nih.gov

INFORMATION ON Comprehensive Adverse Events and Potential Risks (CAEPR)

Purpose of Comprehensive Adverse Events and Potential Risks (CAEPR) Provides a single source document listing the AEs at least possibly associated with an investigational agent When sufficient patient experience (e.g., 100 patients) is available, CAEPR provides the relative AE frequency for the Informed Consent Document (ICD) Risk List Provides comprehensive list of all AEs to be included in the ICD ALL AEs must be included in the ICD with the exception of AEs in the “Reported but Undetermined” attribution CAEPR category: they are not required by CTEP to be included, but are left to IRB discretion Always used within CTEP's agent-specific protocol templates

Sources for CAEPR Information Primary Source: Investigator’s Brochure Secondary Sources: Company Communications Package Insert Publications and Abstracts AdEERS/caAERS Reports

What the CAEPR is Not CAEPRs are NOT regulatory documents but simply a tool to help the clinical sites prepare their ICD CAEPRs do not consider severity CAEPRs do not normally include data from combination trials, UNLESS the AE can be attributed as at least possibly associated with the investigational agent Does not usually include routine AE information (e.g., CDUS data), since not all of this information is reviewed/confirmed by the IDB Senior Investigator

Purpose of the Specific Protocol Exceptions to Expedited Reporting (SPEER) Section of the CAEPR Formerly known as the Agent Specific Adverse Events List (ASAEL) Provides a subset of high-frequency AEs (~10%) that are to be considered expected for the investigational agent (Adverse Reactions) Filtering out high-frequency AEs allows IDB to focus on incoming AEs that: Are unexpected Are causally related to the investigational agent Are serious Future plans: all CTEP-sponsored trials will include AEs in the SPEER as protocol-specific exceptions to expedited reporting Would reduce the time the clinical sites must spend reporting, in an expedited fashion, common/expected AEs

When is a CAEPR Revised? Reviewed/revised at least annually in accordance with cGCP Reviewed/revised upon release of a new version of the IB Upon receipt of new safety information from our pharmaceutical collaborator At the request of the IDB Sr. Investigator in conjunction with an Action Letter