FDA Final Rule & Revised NCI Guidelines for Expedited Reporting of Adverse Events S. Percy Ivy, MD...
-
Upload
dwight-surgener -
Category
Documents
-
view
216 -
download
0
Transcript of FDA Final Rule & Revised NCI Guidelines for Expedited Reporting of Adverse Events S. Percy Ivy, MD...
FDA Final Rule & Revised NCI Guidelines for Expedited Reporting
of Adverse EventsS. Percy Ivy, MD
Associate Chief, Senior Investigator
Investigational Drug Branch, National Cancer Institute
National Cancer Institute
National Cancer Institute presents:
Jan Casadei, PhDChief
Regulatory Affairs Branch, National Cancer [email protected]
National Cancer Institute (NCI) March 28, 2011
2
Final Rule Implications:Investigator reporting to sponsorExpedited Filing to the FDA
National Cancer Institute (NCI) March 28, 2011
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
National Cancer Institute (NCI) March 28, 2011
4
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
National Cancer Institute (NCI) March 28, 2011
5
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?
National Cancer Institute (NCI) March 28, 2011
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
National Cancer Institute (NCI) March 28, 2011
7
Why is the New Final Rule Needed?
1) Confusing/inconsistent terminology in current regulations
2) 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:
National Cancer Institute (NCI) March 28, 2011
8
Definition of Serious Adverse Event
1. Death
2. Life-threatening event (places the patient at immediate risk of death)
3. Requires inpatient hospitalization or prolongs hospitalization
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
5. Congenital anomaly/birth defect
6. 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)
National Cancer Institute (NCI) March 28, 2011
9
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)
3/4/5
Disability 3/4/5
National Cancer Institute (NCI) March 28, 2011
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
National Cancer Institute (NCI) March 28, 2011
11
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
National Cancer Institute (NCI) March 28, 2011
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
National Cancer Institute (NCI) March 28, 2011
13
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
National Cancer Institute (NCI) March 28, 2011
14
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
National Cancer Institute (NCI) March 28, 2011
15
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
National Cancer Institute (NCI) March 28, 2011
16
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
National Cancer Institute (NCI) March 28, 2011
17
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)
National Cancer Institute (NCI) March 28, 2011
18
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
National Cancer Institute (NCI) March 28, 2011
19
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
National Cancer Institute (NCI) March 28, 2011
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 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)
National Cancer Institute (NCI) March 28, 2011
21
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
National Cancer Institute (NCI) March 28, 2011
22
Revised NCI Guidelines for Expedited Reporting of
Adverse Events
National Cancer Institute (NCI) March 28, 2011
23
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
NCI Guidelines: Expedited Reporting of AEs from Investigator to Sponsor
National Cancer Institute (NCI) March 28, 2011
24
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)
National Cancer Institute (NCI) March 28, 2011
25
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)
National Cancer Institute (NCI) March 28, 2011
26
WHAT is reportable to NCI 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 NCI according to the protocol)
Reportable Not Reportable
National Cancer Institute (NCI) March 28, 2011
27
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
National Cancer Institute (NCI) March 28, 2011
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 Rule
There are tables for:1) Phase 0
2) Phase 1/Early Phase 2
3) Late Phase 2/Phase 3
4) 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
National Cancer Institute (NCI) March 28, 2011
29
NCI Expedited AE Reporting Time-Line Requirements
AEs occurring within 30 days of last treatment1
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 commercial 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 treatment1
Serious AEs occurring >30 days after the last dose of agent
Ph0 ALL Gr. 1&2
Ph1/Early Ph2 Gr. 1&2 hospitalization Gr. 2 hospitalization and at least a possible causality
Late Ph2/Ph3 AND CIP commercial agents
ALL Gr. 3Gr. 1&2 hospitalization
Gr. 3 with at least a possible causality Gr. 2 hospitalization and at least a possible causality
1For PET or SPECT IND agents, AEs should be monitored for 10 half-lives
National Cancer Institute (NCI) March 28, 2011
30
NCI Evaluation of EXPEDITED AE Report
IDB Senior Investigator reviews submitted report
Requires sufficient documentation for independent NCI 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?
National Cancer Institute (NCI) March 28, 2011
31
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
National Cancer Institute (NCI) March 28, 2011
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 FDA
Forward IWR to company collaborator concurrent with
submission to IND
Distribute to pertinent NCI investigators within 1 day of
submitting to IND
National Cancer Institute (NCI) March 28, 2011
33
“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.
National Cancer Institute (NCI) March 28, 2011
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 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.
National Cancer Institute (NCI) March 28, 2011
35
ADDITIONAL INFORMATION
National Cancer Institute (NCI) March 28, 2011
36
ACRONYMS
AdEERS 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
National Cancer Institute (NCI) March 28, 2011
37
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
National Cancer Institute (NCI) March 28, 2011
38
REVISED NCI AE REPORTING TABLES
National Cancer Institute (NCI) March 28, 2011
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 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing
hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal
life functions 5) A congenital anomaly/birth defect. 6) 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 312.32; 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.
National Cancer Institute (NCI) March 28, 2011
40
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.
Expedited AE reporting timelines are defined as:
National Cancer Institute (NCI) March 28, 2011
41
Grade 1 and 2 Timeframes Grade 3-5 Timeframes
10 Calendar Days24-Hour
5 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/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.
National Cancer Institute (NCI) March 28, 2011
42
Hospitalization Grade 1 and 2 Timeframes Grade 3-5 Timeframes
Resulting in Hospitalization 24 hrs 10 Calendar Days24-Hour
5 Calendar Days
Not resulting in Hospitalization 24 hrs Not Required
24-Hour5 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/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.
National Cancer Institute (NCI) March 28, 2011
43
Hospitalization Grade 1 and 2 Timeframes Grade 3 Timeframes Grade 4 & 5 Timeframes
Resulting in Hospitalization 24 hrs 10 Calendar Days 10 Calendar Days
24-Hour5 Calendar Days
Not resulting in Hospitalization 24 hrs Not Required 10 Calendar Days
24-Hour5 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/Intervention1
andCIP 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.
National Cancer Institute (NCI) March 28, 2011
44
Phase 0 Studies Expedited 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 Studies
For 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 hospitalization
Late Phase 2 and Phase 3 Studies
ANDCIP Commercial Agent Studies
For SAEs with an attribution of possible, probable, or definite:
Expedited 24-hour notification followed by complete report within 5 calendar days for:All Grade 4, and Grade 5 AEsExpedited 10 calendar day reports for:Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse events
SAEs that occur more than 30 days after the last administration of investigational agent/intervention require reporting as follows:
National Cancer Institute (NCI) March 28, 2011
45
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 NCI by an implementation date yet to be determined
National Cancer Institute (NCI) March 28, 2011
46
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
hospitalizationwithout
hospitalizationwith
hospitalizationwithout
hospitalization
UnlikelyUnrelated
Not required Not required Not required 10 Calendar Days Not required10 Calendar
DaysNot required
24-Hour 5 calendar Days
PossibleProbableDefinite
Not required10 Calendar
DaysNot required
24-Hour 5 calendar Days
24-Hour 5 calendar
Days
10 Calendar Days
Not required24-Hour
5 calendar Days
National Cancer Institute (NCI) March 28, 2011
47
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 Expected
Unexpected Expectedwith
hospitalizationwithout
hospitalizationwith
hospitalizationwithout
hospitalization
UnlikelyUnrelated
Not required Not requiredNot
required10 Calendar
DaysNot required
10 Calendar Days
Not required10 Calendar
Days10 Calendar
Days
PossibleProbableDefinite
Not required10 Calendar
DaysNot
required10 Calendar
Days10 Calendar
Days10 Calendar
DaysNot required
24-Hour 5 calendar
Days
10 Calendar Days
National Cancer Institute (NCI) March 28, 2011
48
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]
National Cancer Institute (NCI) March 28, 2011
49
INFORMATION ON COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS
(CAEPR)
National Cancer Institute (NCI) March 28, 2011
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 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 NCI to be included, but are left to IRB discretion
Always used within NCI's agent-specific protocol templates
National Cancer Institute (NCI) March 28, 2011
51
Sources for CAEPR Information
Primary Source: Investigator’s Brochure
Secondary Sources: Company Communications
Package Insert
Publications and Abstracts
AdEERS/caAERS Reports
National Cancer Institute (NCI) March 28, 2011
52
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
National Cancer Institute (NCI) March 28, 2011
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 unexpected
Are causally related to the investigational agent
Are serious
Future plans: all NCI-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
National Cancer Institute (NCI) March 28, 2011
54
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