1. Associate Chief, Senior Investigator
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
S. Percy Ivy, MD
Associate Chief, Senior Investigator
Investigational Drug Branch, National Cancer Institute

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

3. Definitions for reporting/filing purposes
Investigator – the primary investigator of a trial
21 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)
Sponsor
Reports serious and unexpected suspected Adverse Reactions (reasonable possibility drug caused event) to FDA
FDA
All Investigators
Provides significant new findings to patients
Reports unanticipated problems involving risks to subjects to the IRB
Patient
IRB

5. What does the Final Rule address?
Investigator
Investigator reports (21 CFR (b))
Sponsor
IND safety reports: Expedited (7- and 15-day) reports (21 CFR )
Safety reports for bioavailability (BA) or bioequivalence (BE) studies (21 CFR (d)): Expedited reports
FDA
All Investigators

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

7. Why is the New Final Rule Needed?
FDA’s viewpoint:
Confusing/inconsistent terminology in current regulations
Current “over filing” of expedited reports dampens safety signal
Sponsors often report serious adverse events that:
Are likely to have been a manifestation of the underlying disease
Commonly occur in the study population independent of drug exposure (e.g., strokes or acute myocardial infarctions in an elderly population)
Are study endpoints (i.e., the study was evaluating whether the drug reduced the rate of these events)
Not useful for human subject protection or for developing the safety profiles of drugs
A burden on the system (Investigators, Sponsors, IRBs, FDA)

8. Definition of Serious Adverse Event
Death
Life-threatening event (places the patient at immediate risk of death)
Requires inpatient hospitalization or prolongs hospitalization
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
Congenital anomaly/birth defect
NOTE: Important medical events (IMEs) may be considered serious when, based on medical judgment, they may jeopardize the patient and require intervention to prevent one of the above serious outcomes
Revised: Determination is based on the opinion of either the investigator or sponsor (i.e., if either believes it is serious, it must be considered serious)

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)
Disability

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

11. The Universe of Adverse Events
New Terms
ADVERSE EVENTS (AE)
Suspected Adverse Reactions (SAR)
Adverse Reactions
(AR)
Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
Any AE for which there is a reasonable possibility that the drug is the cause
Implies a lesser degree of certainty about causality than an adverse reaction
Any AE caused by a drug

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

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

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

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?
Unexpected
FILE

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

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)

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

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

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)

21. Looking Forward Implementation To achieve this:
Effective March 28, 2011
FDA and investigators should receive fewer individual reports, but reports should be more complete and meaningful, resulting in:
Better data to support clinical decision making
Better protection of human subjects
To achieve this:
Protocols may need to be more specific (i.e., protocol specific exceptions to expedited reporting should be included when possible)
Sponsor will have more overt responsibility for aggregation and analysis of AEs

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)
Sponsor
Reports serious and unexpected suspected ARs (reasonable possibility drug caused event) to FDA
FDA
All Investigators
Provides significant new findings to patients
Reports unanticipated problems involving risks to subjects to the IRB
Patient
IRB

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 )

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: ( electronic_applications/adeers.htm)

26. WHAT is reportable to NCI in an Expedited Fashion?
Not Reportable
ALL serious AEs regardless of causality to the study drug
Note: All expedited AEs (reported via AdEERS/caAERS) must also be reported via routine reporting mechanisms (e.g., CRF, CTMS, and/or CDUS)
Non-serious AEs (instead, recorded and reported to NCI according to the protocol)

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

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:
Phase 0
Phase 1/Early Phase 2
Late Phase 2/Phase 3
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

29. 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
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
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. 3 with at least a possible causality
1For 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 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?

31.  IDB evaluation of incoming AdEERS/caAERS AE
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 ) and ICH E2A relating to AE reporting
 IDB evaluation of incoming AdEERS/caAERS AE
 Does AE warrant expedited filing to the FDA?
 Yes
Initial Written Report generated
 No
AE is held for submission with Annual Report

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

33. “Initial Written Report” Form

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.

35. ADDITIONAL INFORMATION

36. ACRONYMS AdEERS Adverse Event Expedited Reporting System
AE Adverse Event
AR Adverse Reaction
BA Bioavailability
BE Bioequivalence
caAERS Cancer Adverse Event Reporting System
CAEPR Comprehensive Adverse Events and Potential Risks
CDUS Clinical Data Update System
CFR Code of Federal Regulations
CIP Cancer Imaging Program
CRF Case Report Form
CTMS Clinical Trial Management System
IB Investigator’s Brochure
ICD Informed Consent Document
ICH International Conference on Harmonization
IDB Investigational Drug Branch
IDE Investigational Device Exemption
IME Important Medical Event
IND Investigational New Drug
IRB Institutional Review Board
IWR Initial Written Report
SAR Suspected Adverse Reaction
SSAR Serious Suspected Adverse Reaction

37. URLS for Final Rule and Guidance Documents

38. REVISED NCI AE REPORTING TABLES

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:
Death
A life-threatening adverse event
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
A 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/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.

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/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
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.

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/Intervention1
and
CIP 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
Hospitalization
Grade 1 and 2 Timeframes
Grade 3 Timeframes
Grade 4 & 5 Timeframes
Resulting in Hospitalization  24 hrs
10 Calendar Days
24-Hour
5 Calendar Days
Not resulting in Hospitalization
 24 hrs
Not Required
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.

44. 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.
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 AEs
Expedited 10 calendar day reports for:
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
Late Phase 2 and Phase 3 Studies
AND
CIP Commercial Agent Studies
All Grade 4, and Grade 5 AEs
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
Grade 3 adverse events

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

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 Studies
Attribution
Grade 1
Grade 2
Grade 3
Grade 4 & 5
Unexpected
and
Expected
with hospitalization
without hospitalization
Unlikely
Unrelated
Not required
10 Calendar Days
24-Hour 5 calendar Days
Possible
Probable
Definite
24-Hour 5 calendar Days

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 Studies
Attribution
Grade 1
Grade 2
Grade 3
Grade 4 & 5
Unexpected
and
Expected
with hospitalization
without hospitalization
Unlikely
Unrelated
Not required
10 Calendar Days
Possible
Probable
Definite
24-Hour 5 calendar Days

48. AdEERS Help Technical Help Desk Phone: 301-840-8202 Fax: 301-948-2242
Adverse Event Content Help Desk
Phone:
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 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

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

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

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

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 conjunction with an Action Letter