fda final rule & revised ctep guidelines for expedited reporting of adverse events
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FDA Final Rule & Revised CTEP Guidelines for Expedited Reporting of Adverse Events. National Cancer Institute Cancer Therapy Evaluation Program (CTEP) presents:. S. Percy Ivy, MD Associate Chief, Senior Investigator Investigational Drug Branch, National Cancer Institute [email protected]. - PowerPoint PPT PresentationTRANSCRIPT
FDA Final Rule & Revised CTEP Guidelines for Expedited Reporting
of Adverse EventsS. Percy Ivy, MD
Associate Chief, Senior Investigator
Investigational Drug Branch, National Cancer Institute
National Cancer Institute Cancer Therapy Evaluation Program (CTEP)
presents:
Jan Casadei, PhDChief
Regulatory Affairs Branch, National Cancer [email protected]
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Final Rule Implications:Investigator reporting to sponsorExpedited Filing to the FDA
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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
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Provides significant new findings to
patients
Reports serious and unexpected suspected
Adverse Reactions (reasonable possibility drug caused event) to
FDA
Reports serious AEs (non-serious AEs
reported per protocol non-expeditiously)
Investigator
Sponsor
Reports unanticipated problems involving risks to
subjects to the IRB
All Investigators
Patient
FDA
IRB
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IND safety reports: Expedited (7- and 15-day) reports (21 CFR 312.32)
Investigator reports (21 CFR 312.64(b))
Investigator
Sponsor
Safety reports for bioavailability (BA) or bioequivalence (BE) studies (21 CFR
320.31(d)): Expedited reports
All InvestigatorsFDA
What does the Final Rule address?
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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
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Why is the New Final Rule Needed?
1) Confusing/inconsistent terminology in current regulations2) 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)
FDA’s viewpoint:
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Definition of Serious Adverse Event
1. Death2. Life-threatening event (places the patient at immediate risk of
death)3. Requires inpatient hospitalization or prolongs hospitalization4. Persistent or significant incapacity or substantial disruption of
the ability to conduct normal life functions5. Congenital anomaly/birth defect6. 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)
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Note: Serious Severe (though they are linked)Severity is defined by a grading scale
Seriousness Severity (Grade)Death 5Life-threatening 4Hospitalization 3/4/5Important Medical Event (IME)
3/4/5
Disability 3/4/5
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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
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The Universe of Adverse Events
ADVERSE EVENTS (AE)
Suspected Adverse Reactions
(SAR)
Adverse Reactions
(AR)
The Universe of Adverse Events
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
New Terms
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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
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Assigning Causality Final Rule outlines specific criteria for filing to the
FDA: Individual occurrences
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 One or more occurrence
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
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
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What should be reported expeditiously to the sponsor?
Yes
Adverse Event (AE)
Is it serious?
REPORT
Should include an assessment of causality
Non-serious AEs are recorded and reported to the sponsor according to protocol
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What should be filed expeditiously to the FDA?
Yes
Yes
Yes
Adverse Event (AE) (1) Meets causality
requirement?
(2) Is serious?
(3) Is not listed in the IB or other applicable safety information?
Suspected Adverse Reaction (SAR)Serious SAR (SSAR)
Unexpected
FILE
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Other New Expedited Filing Requirements for Sponsors
Study endpoints 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) Increased occurrence of Serious Suspected Adverse Reactions
Sponsor must file any clinically important increase in the rate of a SSAR over that listed in the protocol or IB
Findings that suggest a significant human risk 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
IND exempt Bioavailability/Bioequivalence studies Current - no safety reporting requirements New requirement: must file ALL serious AEs
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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)
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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
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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
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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)
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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
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Revised CTEP Guidelines for Expedited Reporting of
Adverse Events
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Provides significant new findings to
patients
Reports serious and unexpected suspected
ARs (reasonable possibility drug caused
event) to FDA
Reports serious AEs (non-serious AEs
reported per protocol non-expeditiously)
Investigator
Sponsor
Reports unanticipated problems involving risks to
subjects to the IRB
All Investigators
Patient
FDA
IRB
CTEP Guidelines: Expedited Reporting of AEs from Investigator to Sponsor
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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)
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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)
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WHAT is reportable to CTEP in an Expedited Fashion?
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)
Reportable Not Reportable
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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
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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:
1) Phase 02) Phase 1/Early Phase 23) Late Phase 2/Phase 34) CIP Studies (identical to Late Phase 2/Phase 3)
An implementation date will be set for incorporating new tables into prospective studies
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CTEP Expedited AE Reporting Time-Line Requirements
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& 5Gr. 3 with at least a possible causality
Ph1/Early Ph2 ALL Gr. 3-5 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
Report by AdEERS/caAERS within 24 hours (use telephone if internet connectivity lost) AND
Complete report within 5 calendar days for:
Complete report within 10 calendar days for: AEs occurring within 30
days of last treatmentSerious 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. 3Gr. 2 w/ hospitalization
Gr. 3 with at least a possible causality Gr. 2 w/ hospitalization and at least a possible causality
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CTEP Evaluation of EXPEDITED AE Report
IDB Senior Investigator reviews submitted report Requires sufficient documentation for independent CTEP evaluation
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
Independent review/assessment of AE, attribution Does AE warrant expedited filing to the FDA?
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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 WrittenReport
generated
No
AE is held for submission with Annual Report
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“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
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“Initial Written Report” Form
IND SAFETY REPORT: INITIAL WRITTEN REPORT TO: Division of Drug Oncology Products, Center for Drug
Evaluation and Research, FDA
FAX: 301-796-9845
1. IND NUMBER
2. AGENT NAME
3. DATE
, 2008 4. SPONSOR Division of Cancer Treatment and Diagnosis, National Cancer Institute 5. REPORTER’S NAME, TITLE, AND INSTITUTION
, MD - Associate Branch Chief for Investigational Therapeutics I, Investigational Drug Branch, CTEP, DCTD, NCI
6. PHONE NUMBER
301-496-1196 7. FAX NUMBER
301-402-0428 8. PROTOCOL NUMBER (AE #)
9. PATIENT IDENTIFICATION
10. AGE
11. SEX
12. DESCRIPTION OF ADVERSE EVENT There is a reasonable possibility that the experience may have been caused by the drug. [to be inserted as last sentence of this section] 13. DOSE, ROUTE, AND SCHEDULE 14. DATES OF TREATMENT
15. ACCRUAL AND IND EXPERIENCE
16. COMMENTS
AT THIS TIME, NO OTHER INFORMATION IS AVAILABLE. IF UPON FURTHER INVESTIGATION RELEVANT INFORMATION BECOMES AVAILABLE, THEN A FOLLOW-UP REPORT WILL BE SUBMITTED IN ACCORDANCE WITH 21CFR 312.32(d)(2). DISCLAIMER per 21 CFR 312.32(e): THIS SAFETY REPORT DOES NOT NECESSARILY REFLECT A CONCLUSION OR ADMISSION BY THE CTEP IDB SENIOR INVESTIGATOR/ SPONSOR THAT THE INVESTIGATIONAL AGENT/THERAPY CAUSED OR CONTRIBUTED TO THE ADVERSE EXPERIENCE BEING REPORTED.
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“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.
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ADDITIONAL INFORMATION
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ACRONYMSAdEERS Adverse Event Expedited Reporting SystemAE Adverse EventAR Adverse ReactionBA BioavailabilityBE BioequivalencecaAERS Cancer Adverse Event Reporting SystemCAEPR Comprehensive Adverse Events and Potential Risks CDUS Clinical Data Update SystemCFR Code of Federal RegulationsCIP Cancer Imaging ProgramCRF Case Report FormCTMS Clinical Trial Management SystemIB Investigator’s BrochureICD Informed Consent DocumentICH International Conference on HarmonizationIDB Investigational Drug Branch IDE Investigational Device ExemptionIME Important Medical EventIND Investigational New DrugIRB Institutional Review BoardIWR Initial Written ReportSAR Suspected Adverse ReactionSSAR Serious Suspected Adverse Reaction
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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
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REVISED CTEP AE REPORTING TABLES
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Grade 1 and 2 Timeframes Grade 3-5 Timeframes
10 Calendar Days 24-Hour5 Calendar Days
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
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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 hrsNot Required Not Required 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
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Hospitalization Grade 1 Timeframes Grade 2 Timeframes Grade 3 Timeframes Grade 4 & 5 Timeframes
With Hospitalization
24 hrsNot Required 10 Calendar Days 10 Calendar Days 24-Hour
5 Calendar Days
Without Hospitalization
24 hrsNot Required Not Required 10 Calendar Days 24-Hour
5 Calendar Days
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 andCIP 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
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Legacy Tables Legacy tables should continue to be used for all
studies at the present time
The revised reporting tables (slides 39-41) will only be applied to studies not yet approved by CTEP by an implementation date yet to be determined
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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 3 Grade 4 & 5
Unexpectedand
ExpectedUnexpected Expected
Unexpected Expected Unexpectedand
Expectedwith hospitalization
without hospitalization
with hospitalization
without hospitalization
UnlikelyUnrelated Not required Not required Not required 10 Calendar Days Not required 10 Calendar
Days Not required 24-Hour 5 calendar Days
PossibleProbableDefinite
Not required 10 Calendar Days Not required 24-Hour
5 calendar Days
24-Hour 5 calendar
Days
10 Calendar Days Not required 24-Hour
5 calendar Days
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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 3 Grade 4 & 5
Unexpectedand
ExpectedUnexpected Expected
Unexpected ExpectedUnexpected Expectedwith
hospitalizationwithout
hospitalizationwith
hospitalizationwithout
hospitalization
UnlikelyUnrelated Not required Not required Not
required10 Calendar
Days Not required 10 Calendar Days Not required 10 Calendar
Days10 Calendar
Days
PossibleProbableDefinite
Not required 10 Calendar Days
Not required
10 Calendar Days
10 Calendar Days
10 Calendar Days Not required
24-Hour 5 calendar
Days
10 Calendar Days
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AdEERS Help
Technical Help Desk Phone: 301-840-8202 Fax: 301-948-2242 Email: [email protected]
Adverse Event Content Help Desk Phone: 301-897-7497 Fax: 301-230-0159 Email: [email protected] Email for CTCAE v4.0 questions: [email protected]
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INFORMATION ON COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS
(CAEPR)
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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
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Sources for CAEPR Information
Primary Source: Investigator’s Brochure
Secondary Sources: Company Communications Package Insert Publications and Abstracts AdEERS/caAERS Reports
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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
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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
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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 conjunctionwith an Action Letter