fda final rule & revised nci guidelines for expedited reporting of adverse events s. percy ivy,...

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

[email protected]

National Cancer Institute

National Cancer Institute presents:

Jan Casadei, PhDChief

Regulatory Affairs Branch, National Cancer [email protected]

National Cancer Institute (NCI) March 28, 2011

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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 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:


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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)


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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


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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 NCI 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

NCI Guidelines: Expedited Reporting of AEs from Investigator to Sponsor


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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)


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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)


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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


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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 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


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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


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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?


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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


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“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


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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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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


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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 NCI AE REPORTING TABLES


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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.


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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:


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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.


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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



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Hospitalization Grade 1 and 2 Timeframes Grade 3 Timeframes Grade 4 & 5 Timeframes

Resulting in Hospitalization 24 hrs 10 Calendar Days 10 Calendar Days


Not resulting in Hospitalization 24 hrs Not Required 10 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



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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:


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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 NCI 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

hospitalizationwithout

hospitalizationwith


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


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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 Expected

Unexpected Expectedwith


hospitalizationwith


hospitalization

UnlikelyUnrelated

Not required Not requiredNot

required10 Calendar

DaysNot required

10 Calendar Days


Days10 Calendar

Days

PossibleProbableDefinite


DaysNot

required10 Calendar

Days10 Calendar

Days10 Calendar

DaysNot 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]

mailto:[email protected]

mailto:[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 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


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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

fda final rule & revised nci guidelines for expedited reporting of adverse events s. percy ivy,...

Documents

national cancer institute

serious slide

serious adverse events

fda slide

adverse event ae

filing of expedited

investigators fda

primary investigator