Presentation on theme: "Associate Chief, Senior Investigator"— Presentation transcript:
1 Associate Chief, Senior Investigator National Cancer Institute National Cancer Institute presents:FDA Final Rule & Revised NCI Guidelines for Expedited Reporting of Adverse EventsJan Casadei, PhDChiefRegulatory Affairs Branch, National Cancer InstituteS. Percy Ivy, MDAssociate Chief, Senior InvestigatorInvestigational Drug Branch, National Cancer Institute
2 Final Rule Implications: Investigator reporting to sponsorExpedited Filing to the FDA
3 Definitions for reporting/filing purposes Investigator – the primary investigator of a trial21 CFR 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 Sponsor FDA All Investigators Patient IRB Reports serious AEs (non-serious AEs reported per protocol non-expeditiously)SponsorReports serious and unexpected suspected Adverse Reactions (reasonable possibility drug caused event) to FDAFDAAll InvestigatorsProvides significant new findings to patientsReports unanticipated problems involving risks to subjects to the IRBPatientIRB
5 What does the Final Rule address? InvestigatorInvestigator reports (21 CFR (b))SponsorIND safety reports: Expedited (7- and 15-day) reports (21 CFR )Safety reports for bioavailability (BA) or bioequivalence (BE) studies (21 CFR (d)): Expedited reportsFDAAll Investigators
6 Overview of New Requirements Codifies FDA’s expectations for timely review, evaluation and submission of important and useful safety informationMore fully defines responsibilities of sponsors and investigatorsMore consistent with international definitions and reporting standardsClarifies confusing terminology in existing regulationsImproves the utility of IND safety reports
7 Why is the New Final Rule Needed? FDA’s viewpoint:Confusing/inconsistent terminology in current regulationsCurrent “over filing” of expedited reports dampens safety signalSponsors often report serious adverse events that:Are likely to have been a manifestation of the underlying diseaseCommonly 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 drugsA burden on the system (Investigators, Sponsors, IRBs, FDA)
8 Definition of Serious Adverse Event DeathLife-threatening event (places the patient at immediate risk of death)Requires inpatient hospitalization or prolongs hospitalizationPersistent or significant incapacity or substantial disruption of the ability to conduct normal life functionsCongenital anomaly/birth defectNOTE: 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 outcomesRevised: 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 scaleSeriousnessSeverity (Grade)Death5Life-threatening4Hospitalization3/4/5Important Medical Event (IME)Disability
10 Definition of Unexpected Adverse Event Not listed in the Investigator’s Brochure (IB) at the specificity or severity observedMentioned 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 investigationIf an IB is not required or available, the sponsor should refer to the risk information in the INDThe sponsor will determine if an adverse event (AE) is unexpected for filing purposes
11 The Universe of Adverse Events New TermsADVERSE 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 relatedAny AE for which there is a reasonable possibility that the drug is the causeImplies a lesser degree of certainty about causality than an adverse reactionAny 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 FDAKey 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 AEReasonable possibility = possibly, probably, or definitely related
13 Assigning CausalityFinal Rule outlines specific criteria for filing to the FDA:Individual occurrencesSingle occurrence of an event that is uncommon and known to be strongly associated with drug exposureAngioedemaHepatic injuryStevens-Johnson syndromeRare that causality can be assigned to drug based on single occurrence for any other type of eventOne or more occurrenceSingle 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 drugCardiac events in otherwise healthy individualsTendon rupture in young adultsAggregate 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 groupDay 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 daysIndividual SARs making up the aggregate report must be retroactively filed
14 What should be reported expeditiously to the sponsor? Adverse Event (AE)YesIs it serious?Should include an assessment of causalityNon-serious AEs are recorded and reported to the sponsor according to protocolREPORT
15 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?UnexpectedFILE
16 Other New Expedited Filing Requirements for Sponsors Study endpointsMortality or major morbidityIn general should not be filed expeditiouslyException: If there is evidence suggesting a causal relationship (e.g., death from anaphylaxis in a trial with an all-cause mortality endpoint)Increased occurrence of Serious Suspected Adverse ReactionsSponsor must file any clinically important increase in the rate of a SSAR over that listed in the protocol or IBFindings that suggest a significant human riskSponsor must file expeditiously any findings that suggest a significant risk from:Clinical, epidemiological, or pooled analysis of multiple studiesAnimal 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 investigationIND exempt Bioavailability/Bioequivalence studiesCurrent - no safety reporting requirementsNew requirement: must file ALL serious AEs
17 Key Points for Safety Surveillance Sponsors should ensure that they have in place a systematic approach for safety surveillanceShould include a process for reviewing, evaluating, and managing accumulating safety data from the entire clinical trial database at appropriate intervalsMay 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)
18 Protocol-specific Requirements and Exceptions for Monitoring Serious Adverse Events Study endpointsProtocol-specific exceptions (not study endpoints) to expedited reporting or filingIdentify events and monitoring plan in the protocolLimit to events that are common in study populationSafety team or independent group monitors the rates at appropriate intervalsReport if an aggregate analysis indicates that events are occurring more frequently in the drug treatment group
19 Investigator’s Brochures Provides the investigator with information (clinical and nonclinical) about the investigational drugUsed as basis for sponsor’s determination of “unexpectedness” for filing purposesInclude AEs for which a causal relationship is suspected or confirmedNo laundry listsClinical risk informationUpdating the IB should be in concert with GCP
20 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 filingUnexpected 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 daysFollow-up reportsFile as soon as information is availableIf FDA requests any additional data or information: Submit to FDA ASAP, but no later than 15 calendar days after receiving the request (NEW)
21 Looking Forward Implementation To achieve this: Effective March 28, 2011FDA and investigators should receive fewer individual reports, but reports should be more complete and meaningful, resulting in:Better data to support clinical decision makingBetter protection of human subjectsTo 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
22 Revised NCI Guidelines for Expedited Reporting of Adverse Events
23 NCI Guidelines: Expedited Reporting of AEs from Investigator to Sponsor Reports serious AEs (non-serious AEs reported per protocol non-expeditiously)SponsorReports serious and unexpected suspected ARs (reasonable possibility drug caused event) to FDAFDAAll InvestigatorsProvides significant new findings to patientsReports unanticipated problems involving risks to subjects to the IRBPatientIRB
24 WHY Does NCI Collect EXPEDITED AE Reports? Patient SafetyAdequate Informed ConsentCompliance with FDA Regulations and consideration of concordance with ICH guidelinesRequired of the IND Sponsor (21 CFR )
25 Adverse Event EXPEDITED Reporting System: All expedited AEs for NCI IND Agents should be submitted to NCI via a web-based electronic systemAdEERS (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 requiredExpedited AE submission demonstration & training is available for key Group staff and representativesComputer-based AdEERS/caAERS training is available at: (http://ctep.info.nih.gov/protocolDevelopment/ electronic_applications/adeers.htm)
26 WHAT is reportable to NCI in an Expedited Fashion? Not ReportableALL serious AEs regardless of causality to the study drugNote: 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)
27 WHO completes an EXPEDITED AE report? InvestigatorPrincipal Investigator should review full report for completeness and accuracy; will need to provide narrative of event and select supporting materialResearch NurseClinical Research Associate
28 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 RuleThere are tables for:Phase 0Phase 1/Early Phase 2Late Phase 2/Phase 3CIP COMMERCIAL Agent Studies (based on Late Phase 2/Phase 3)AE reporting requirements for PET or SPECT IND agents were addedAn implementation date will be set for incorporating new tables into prospective studies
29 NCI Expedited AE Reporting Time-Line Requirements Report by AdEERS/caAERS within 24 hours (use telephone if internet connectivity lost) ANDComplete report within 5 calendar days for:AEs occurring within 30 days of last treatment1Serious AEs occurring >30 days after the last dose of agentPh0ALL Gr. 3-5ALL Gr. 4& 5Gr. 3 with at least a possible causalityPh1/Early Ph2Gr. 3-5 with at least a possible causalityLate Ph2/Ph3 ANDCIP commercial agentsALL Gr. 4&5Gr. 4&5 with at least a possible causalityComplete report within 10 calendar days for:AEs occurring within 30 days of last treatment1Serious AEs occurring >30 days after the last dose of agentPh0ALL Gr. 1&2Ph1/Early Ph2Gr. 1&2 hospitalizationGr. 2 hospitalization and at least a possible causalityLate Ph2/Ph3 ANDCIP commercial agentsALL Gr. 3Gr. 3 with at least a possible causality1For PET or SPECT IND agents, AEs should be monitored for 10 half-lives
30 NCI Evaluation of EXPEDITED AE Report IDB Senior Investigator reviews submitted reportRequires sufficient documentation for independent NCI evaluationHospital Summary (History and Physical)Laboratory DataEKGsRadiology Reports (e.g., scans MRI etc.)Flow SheetsVisit/ER/Progress NotesAutopsy Reports/discharge summaryIndependent review/assessment of AE, attributionDoes AE warrant expedited filing to the FDA?
31 IDB evaluation of incoming AdEERS/caAERS AE NCI IND SAFETY REPORT Process Reporting to FDA, Investigators, and Company CollaboratorsUtilize existing AdEERS/caAERS submission processes to ensure compliance with FDA regulations (21 CFR ) and ICH E2A relating to AE reporting IDB evaluation of incoming AdEERS/caAERS AE Does AE warrant expedited filing to the FDA? YesInitial Written Report generated NoAE is held for submission with Annual Report
32 “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 FDAForward IWR to company collaborator concurrent with submission to INDDistribute to pertinent NCI investigators within 1 day of submitting to IND
34 “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 ORIf 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 ORIf an AE not initially determined to be reportable in an expedited manner is now reportable, then an IWR is submitted.
39 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR )An adverse event is considered serious if it results in ANY of the following outcomes:DeathA life-threatening adverse eventAn adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hoursA persistent or significant incapacity or substantial disruption of the ability to conduct normal life functionsA congenital anomaly/birth defect.Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR ; ICH E2A and ICH E6).ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within the timeframes detailed in the appropriate tables.
40 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.
41 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/Intervention1Grade 1 and 2 TimeframesGrade 3-5 Timeframes10 Calendar Days24-Hour5 Calendar Days1For 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.
42 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/Intervention1HospitalizationGrade 1 and 2 TimeframesGrade 3-5 TimeframesResulting in Hospitalization 24 hrs10 Calendar Days24-Hour5 Calendar DaysNot resulting in Hospitalization 24 hrsNot Required1For 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.
43 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/Intervention1andCIP 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 Agent1HospitalizationGrade 1 and 2 TimeframesGrade 3 TimeframesGrade 4 & 5 TimeframesResulting in Hospitalization 24 hrs10 Calendar Days24-Hour5 Calendar DaysNot resulting in Hospitalization 24 hrsNot Required1For 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.
44 SAEs that occur more than 30 days after the last administration of investigational agent/intervention require reporting as follows:Phase 0 StudiesExpedited 24-hour notification followed by complete report within 5 calendar days for :ALL Grade 4 and 5 AEs and Grade 3 AEs with at least a possible attribution.Phase 1 and Early Phase 2 StudiesFor SAEs with an attribution of possible, probable, or definite:Expedited 24-hour notification followed by complete report within 5 calendar days for:All Grade 3, 4, and Grade 5 AEsExpedited 10 calendar day reports for:Grade 2 AEs resulting in hospitalization or prolongation of hospitalizationLate Phase 2 and Phase 3 StudiesANDCIP Commercial Agent StudiesAll Grade 4, and Grade 5 AEsGrade 2 adverse events resulting in hospitalization or prolongation of hospitalizationGrade 3 adverse events
45 Legacy TablesLegacy tables should continue to be used for all studies at the present timeThe revised reporting tables (slides 39-41) will only be applied to studies not yet approved by NCI by an implementation date yet to be determined
46 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 StudiesAttributionGrade 1Grade 2Grade 3Grade 4 & 5UnexpectedandExpectedwith hospitalizationwithout hospitalizationUnlikelyUnrelatedNot required10 Calendar Days24-Hour 5 calendar DaysPossibleProbableDefinite24-Hour 5 calendar Days
47 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 StudiesAttributionGrade 1Grade 2Grade 3Grade 4 & 5UnexpectedandExpectedwith hospitalizationwithout hospitalizationUnlikelyUnrelatedNot required10 Calendar DaysPossibleProbableDefinite24-Hour 5 calendar Days
48 AdEERS Help Technical Help Desk Phone: 301-840-8202 Fax: 301-948-2242 Adverse Event Content Help DeskPhone:Fax:for CTCAE v4.0 questions:
49 INFORMATION ON Comprehensive Adverse Events and Potential Risks (CAEPR)
50 Purpose of Comprehensive Adverse Events and Potential Risks (CAEPR) Provides a single source document listing the AEs at least possibly associated with an investigational agentWhen sufficient patient experience (e.g., 100 patients) is available, CAEPR provides the relative AE frequency for the Informed Consent Document (ICD) Risk ListProvides comprehensive list of all AEs to be included in the ICDALL 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 NCI to be included, but are left to IRB discretionAlways used within NCI's agent-specific protocol templates
51 Sources for CAEPR Information Primary Source:Investigator’s BrochureSecondary Sources:Company CommunicationsPackage InsertPublications and AbstractsAdEERS/caAERS Reports
52 What the CAEPR is NotCAEPRs are NOT regulatory documents but simply a tool to help the clinical sites prepare their ICDCAEPRs do not consider severityCAEPRs do not normally include data from combination trials, UNLESS the AE can be attributed as at least possibly associated with the investigational agentDoes not usually include routine AE information (e.g., CDUS data), since not all of this information is reviewed/confirmed by the IDB Senior Investigator
53 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 unexpectedAre causally related to the investigational agentAre seriousFuture plans: all NCI-sponsored trials will include AEs in the SPEER as protocol-specific exceptions to expedited reportingWould reduce the time the clinical sites must spend reporting, in an expedited fashion, common/expected AEs
54 When is a CAEPR Revised?Reviewed/revised at least annually in accordance with cGCPReviewed/revised upon release of a new version of the IBUpon receipt of new safety information from our pharmaceutical collaboratorAt the request of the IDB Sr. Investigator in conjunction with an Action Letter