Transcript Non-animated Presentation on AE Reporting and Final Rule 3-28-2011 (suitable for printing)

National Cancer Institute
National Cancer Institute
presents:
FDA Final Rule & Revised NCI Guidelines
for Expedited Reporting of Adverse
Events
Jan Casadei, PhD
Chief
Regulatory Affairs Branch, National
Cancer Institute
[email protected]
S. Percy Ivy, MD
Associate Chief, Senior Investigator
Investigational Drug Branch, National
Cancer Institute
[email protected]
Final Rule Implications:
Investigator reporting to sponsor
Expedited Filing to the FDA
National Cancer Institute (NCI)
March 28, 2011
2
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
3
Investigator
Sponsor
FDA
Reports serious AEs
(non-serious AEs
reported per protocol
non-expeditiously)
Reports serious and
unexpected suspected
Adverse Reactions
(reasonable possibility drug
caused event) to FDA
All Investigators
Provides significant new
findings to patients
Patient
National Cancer Institute (NCI)
Reports unanticipated problems
involving risks to subjects to the IRB
IRB
March 28, 2011
4
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
National Cancer Institute (NCI)
All Investigators
March 28, 2011
5
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
6
Why is the New Final Rule Needed?
FDA’s viewpoint:
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)
National Cancer Institute (NCI)
March 28, 2011
7
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
8
Note: Serious  Severe
(though they are linked)
Severity is defined by a grading scale
Seriousness
Death
Life-threatening
Hospitalization
Important Medical Event (IME)
Disability
National Cancer Institute (NCI)
Severity (Grade)
5
4
3/4/5
3/4/5
3/4/5
March 28, 2011
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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
National Cancer Institute (NCI)
March 28, 2011
10
The Universe
of Adverse
EventsEvents
The
Universe
of Adverse
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
National Cancer Institute (NCI)
March 28, 2011
11
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
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Assigning Causality
Final Rule outlines specific criteria for filing to the FDA:

Individual occurrences




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 of an event that is uncommon and known to be strongly associated with drug exposure
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
13
What should be reported expeditiously to the sponsor?
Adverse Event (AE)
Is it serious?
Should include an
assessment of causality
REPORT
National Cancer Institute (NCI)
Non-serious AEs are
recorded and reported to
the sponsor according to
protocol
March 28, 2011
14
What should be filed expeditiously to the FDA?
Adverse Event (AE)
Suspected Adverse
Reaction (SAR)
Yes
Yes
(1) Meets causality requirement?
(2) Is serious?
Serious SAR (SSAR)
Yes
Unexpected
(3) Is not listed in the IB or other
applicable safety information?
FILE
National Cancer Institute (NCI)
March 28, 2011
15
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


Findings that suggest a significant human risk



Sponsor must file any clinically important increase in the rate of a SSAR over that listed in the protocol or IB
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
16
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
17
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
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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
National Cancer Institute (NCI)
March 28, 2011
19
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
20
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
21
Revised NCI Guidelines for Expedited
Reporting of
Adverse Events
National Cancer Institute (NCI)
March 28, 2011
22
NCI Guidelines: Expedited Reporting of AEs from
Investigator to Sponsor
Investigator
Sponsor
FDA
Reports serious AEs
(non-serious AEs
reported per protocol
non-expeditiously)
Reports serious and
unexpected suspected ARs
(reasonable possibility drug
caused event) to FDA
All Investigators
Provides significant new
findings to patients
Patient
National Cancer Institute (NCI)
Reports unanticipated problems
involving risks to subjects to the IRB
IRB
March 28, 2011
23
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
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Adverse Event EXPEDITED Reporting System:
 All expedited AEs for NCI IND Agents should be submitted to NCI via a webbased 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
25
WHAT is reportable to NCI in an Expedited Fashion?
Reportable
 ALL serious AEs
regardless of causality to
the study drug
Not Reportable
 Non-serious AEs (instead,
recorded and reported to
NCI according to the
protocol)
 Note: All expedited AEs
(reported via
AdEERS/caAERS) must
also be reported via
routine reporting
mechanisms (e.g., CRF,
CTMS, and/or CDUS)
National Cancer Institute (NCI)
March 28, 2011
26
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
27
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
28
NCI 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
treatment1
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
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
Complete report within 10 calendar days for:
AEs occurring within 30 days of
last treatment1
1For
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. 3
Gr. 1&2 hospitalization
Gr. 3 with at least a possible causality
Gr. 2 hospitalization and at least a possible causality
PET or SPECT IND agents, AEs should be monitored for 10 half-lives
National Cancer Institute (NCI)
March 28, 2011
29
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
30
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
No
Initial Written
Report generated
AE is held for submission
with Annual Report
National Cancer Institute (NCI)
March 28, 2011
31
“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
32
“Initial Written Report” Form
IND SAFETY REPORT: INITIAL WRITTEN REPORT
TO: Division of Drug Oncology Products, Center for Drug
Evaluation and Research, FDA
1. IND NUMBER
FAX: 301-796-9845
2. AGENT NAME
3. DATE
, 2008
4. SPONSOR
Division of Cancer Treatment and Diagnosis, National Cancer Institute
5. REPORTER’S NAME, TITLE, AND INSTITUTION
6. PHONE NUMBER
, MD - Associate Branch Chief for Investigational
Therapeutics I, Investigational Drug Branch, CTEP, DCTD, NCI
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
33
“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
34
ADDITIONAL INFORMATION
National Cancer Institute (NCI)
March 28, 2011
35
ACRONYMS
AdEERS
AE
AR
BA
BE
caAERS
CAEPR
CDUS
CFR
CIP
CRF
CTMS
IB
ICD
ICH
IDB
IDE
IME
IND
IRB
IWR
SAR
SSAR
Adverse Event Expedited Reporting System
Adverse Event
Adverse Reaction
Bioavailability
Bioequivalence
Cancer Adverse Event Reporting System
Comprehensive Adverse Events and Potential Risks
Clinical Data Update System
Code of Federal Regulations
Cancer Imaging Program
Case Report Form
Clinical Trial Management System
Investigator’s Brochure
Informed Consent Document
International Conference on Harmonization
Investigational Drug Branch
Investigational Device Exemption
Important Medical Event
Investigational New Drug
Institutional Review Board
Initial Written Report
Suspected Adverse Reaction
Serious Suspected Adverse Reaction
National Cancer Institute (NCI)
March 28, 2011
36
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
37
REVISED NCI AE REPORTING TABLES
National Cancer Institute (NCI)
March 28, 2011
38
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) Death
2) 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
39
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.
National Cancer Institute (NCI)
March 28, 2011
40
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
Grade 1 and 2 Timeframes
Grade 3-5 Timeframes
10 Calendar Days
24-Hour
5 Calendar Days
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
41
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
Hospitalization
Grade 1 and 2 Timeframes
Grade 3-5 Timeframes
Resulting in Hospitalization  24 hrs
10 Calendar Days
24-Hour
5 Calendar Days
Not resulting in Hospitalization
 24 hrs
Not Required
24-Hour
5 Calendar Days
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
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies
under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention1
and
CIP Commercial Agent Studies: Expedited Reporting Requirements for Adverse Events that Occur in a CIP NonIND/IDE trial within 30 Days of the Last Administration of a Commercial Imaging Agent1
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-Hour
5 Calendar Days
Not resulting in Hospitalization
 24 hrs
Not Required
10 Calendar Days
24-Hour
5 Calendar Days
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
SAEs that occur more than 30 days after the last administration of
investigational agent/intervention require reporting as follows:
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.
For SAEs with an attribution of possible, probable, or definite:
Phase 1 and Early Phase 2
Studies
Expedited 24-hour notification followed by complete report within 5 calendar days for:
All Grade 3, 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
For SAEs with an attribution of possible, probable, or definite:
Late Phase 2 and Phase 3
Studies
AND
CIP Commercial Agent Studies
National Cancer Institute (NCI)
Expedited 24-hour notification followed by complete report within 5 calendar days for:
All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
Grade 3 adverse events
March 28, 2011
44
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
45
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
Grade 1
Grade 2
Unexpected
and
Expected
Unexpected
Expected
Unlikely
Unrelated
Not required
Not required
Possible
Probable
Definite
Not required
10 Calendar
Days
Attribution
National Cancer Institute (NCI)
Grade 3
Grade 3
Grade 4 & 5
Unexpected
Expected
Unexpected
and
Expected
with
hospitalization
without
hospitalization
with
hospitalization
without
hospitalization
Not required
10 Calendar Days
Not required
10 Calendar
Days
Not required
24-Hour
5 calendar Days
Not required
24-Hour
5 calendar Days
24-Hour
5 calendar
Days
10 Calendar
Days
Not required
24-Hour
5 calendar Days
March 28, 2011
46
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
Grade 1
Grade 2
Unexpected
and
Expected
Unexpected
Expected
Unlikely
Unrelated
Not required
Not required
Possible
Probable
Definite
Not required
10 Calendar
Days
Attribution
National Cancer Institute (NCI)
Grade 3
Grade 3
Unexpected
Expected
Grade 4 & 5
Unexpected
Expected
Not required
10 Calendar
Days
10 Calendar
Days
Not required
24-Hour
5 calendar
Days
10 Calendar
Days
with
hospitalization
without
hospitalization
with
hospitalization
without
hospitalization
Not
required
10 Calendar
Days
Not required
10 Calendar
Days
Not
required
10 Calendar
Days
10 Calendar
Days
10 Calendar
Days
March 28, 2011
47
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
48
INFORMATION ON COMPREHENSIVE ADVERSE
EVENTS AND POTENTIAL RISKS (CAEPR)
National Cancer Institute (NCI)
March 28, 2011
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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 NCI to be included, but are left to IRB discretion
 Always used within NCI'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 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)
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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 conjunction
with an Action Letter
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