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FDA Final Rule & Revised NCI Guidelines for Expedited Reporting of Adverse Events. National Cancer Institute National Cancer Institute presents:. S. Percy Ivy, MD Associate Chief, Senior Investigator Investigational Drug Branch, National Cancer Institute [email protected]

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Fda final rule revised nci guidelines for expedited reporting of adverse events

FDA Final Rule & Revised NCI Guidelines for Expedited Reporting of Adverse Events

National Cancer Institute National Cancer Institutepresents:

S. Percy Ivy, MD

Associate Chief, Senior Investigator

Investigational Drug Branch, National Cancer Institute

[email protected]

Jan Casadei, PhD

Chief

Regulatory Affairs Branch, National Cancer Institute

[email protected]


Final Rule Implications: Reporting of Adverse Events

  • Investigator reporting to sponsor

  • Expedited Filing to the FDA


Definitions for reporting/filing purposes Reporting of Adverse Events

  • 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


Investigator Reporting of Adverse Events

  • 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


What does the final rule address
What does the Final Rule address? Reporting of Adverse Events

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

All Investigators


Overview of new requirements
Overview of New Requirements Reporting of Adverse Events

  • 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


Why is the new final rule needed
Why is the New Final Rule Needed? Reporting of Adverse Events

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)


Definition of serious adverse event
Definition of Reporting of Adverse EventsSerious 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)


Note: Serious Reporting of Adverse Events Severe (though they are linked)

Severity is defined by a grading scale


Definition of unexpected adverse event
Definition of Reporting of Adverse EventsUnexpected 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


The universe of adverse events
The Universe of Adverse Events Reporting of Adverse Events

The Universe of Adverse Events

New Terms

  • 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


Assigning causality
Assigning Causality Reporting of Adverse Events

  • 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


Assigning causality1
Assigning Causality Reporting of Adverse Events

Final Rule outlines specific criteria for filing to the FDA:

  • Individual occurrences

  • One or more occurrence

  • 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)


Assigning causality2
Assigning Causality Reporting of Adverse Events

Final Rule outlines specific criteria for filing to the FDA:

  • Individual occurrences

  • One or more occurrence

  • 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)

  • 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


Assigning causality3
Assigning Causality Reporting of Adverse Events

Final Rule outlines specific criteria for filing to the FDA:

  • Individual occurrences

  • One or more occurrence

  • 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)

  • 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


Assigning causality4
Assigning Causality Reporting of Adverse Events

Final Rule outlines specific criteria for filing to the FDA:

  • Individual occurrences

  • One or more occurrence

  • 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


What should be reported expeditiously to the sponsor
What should be reported expeditiously to the sponsor? Reporting of Adverse Events

Is it serious?

Adverse Event (AE)

Yes

  • Should include an assessment of causality

  • Non-serious AEs are recorded and reported to the sponsor according to protocol

REPORT


What should be filed expeditiously to the fda
What should be filed expeditiously to the FDA? Reporting of Adverse Events

(1) Meets causality requirement?

(2) Is serious?

(3) Is not listed in the IB or other applicable safety information?

Unexpected

Adverse Event (AE)

Suspected Adverse Reaction (SAR)

Serious SAR (SSAR)

Yes

Yes

Yes

FILE


Other new expedited filing requirements for sponsors
Other New Expedited Filing Requirements for Sponsors Reporting of Adverse Events

  • Study endpoints

  • Increased occurrence of Serious Suspected Adverse Reactions

  • Findings that suggest a significant human risk

  • IND exempt Bioequivalence/Bioavailability studies


Other new expedited filing requirements for sponsors1
Other New Expedited Filing Requirements for Sponsors Reporting of Adverse Events

  • 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)

  • Study endpoints

  • Increased occurrence of Serious Suspected Adverse Reactions

  • Findings that suggest a significant human risk

  • IND exempt Bioequivalence/Bioavailability studies


Other new expedited filing requirements for sponsors2
Other New Expedited Filing Requirements for Sponsors Reporting of Adverse Events

  • Study endpoints

  • Increased occurrence of Serious Suspected Adverse Reactions

  • Findings that suggest a significant human risk

  • IND exempt Bioequivalence/Bioavailability studies

  • Sponsor must file any clinically important increase in the rate of a SSAR over that listed in the protocol or IB


Other new expedited filing requirements for sponsors3
Other New Expedited Filing Requirements for Sponsors Reporting of Adverse Events

  • Study endpoints

  • Increased occurrence of Serious Suspected Adverse Reactions

  • Findings that suggest a significant human risk

  • IND exempt Bioequivalence/Bioavailability studies

  • 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


Other new expedited filing requirements for sponsors4
Other New Expedited Filing Requirements for Sponsors Reporting of Adverse Events

  • Study endpoints

  • Increased occurrence of Serious Suspected Adverse Reactions

  • Findings that suggest a significant human risk

  • IND exempt Bioequivalence/Bioavailability studies

  • Current - no safety reporting requirements

  • New requirement: must file ALL serious AEs


Key points for safety surveillance
Key Points for Safety Surveillance Reporting of Adverse Events

  • 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)


Protocol specific requirements and exceptions for monitoring serious adverse events
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


Investigator s brochures
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


Immediate filing timeframes for sponsors
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)


Looking forward
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



Nci guidelines expedited reporting of aes from investigator to sponsor
NCI Guidelines: Expedited Reporting of AEs from Investigator to Sponsor

Investigator

  • 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


Why does nci collect expedited ae reports
WHY Does NCI Collect EXPEDITED AE Reports? to Sponsor

  • 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)


Adverse event expedited reporting system
Adverse Event EXPEDITED Reporting System: to Sponsor

  • 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)


What is reportable to nci in an expedited fashion
WHAT is reportable to NCI in an Expedited Fashion? to Sponsor

Reportable

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)


Who completes an expedited ae report
WHO completes an EXPEDITED AE report? to Sponsor

  • 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


Comparison of old vs new tables
Comparison of Old vs. New Tables to Sponsor

  • 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


NCI Expedited AE Reporting Time-Line Requirements to Sponsor

  • Report by AdEERS/caAERSwithin 24 hours (use telephone if internet connectivity lost) AND

  • Complete report within 5 calendar days for:

  • Complete report within 10 calendar days for:

1For PET or SPECT IND agents, AEs should be monitored for 10 half-lives


Nci evaluation of expedited ae report
NCI Evaluation of EXPEDITED AE Report to Sponsor

  • IDB Senior Investigator reviews submitted report

  • Requires sufficient documentation for independent NCI evaluation

  • Independent review/assessment of AE, attribution

  • Does AE warrant expedited filing to the FDA?

  • 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


Nci ind safety report process reporting to fda investigators and company collaborators
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


Initial written report nci processing timelines
“Initial Written Report” NCI Processing Timelines Investigators, and Company Collaborators

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


Initial written report form
“Initial Written Report” Form Investigators, and Company Collaborators


Follow up written report process
“Follow-up Written Report” Process Investigators, and Company Collaborators

  • 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.


Additional information
ADDITIONAL INFORMATION Investigators, and Company Collaborators


Acronyms
ACRONYMS Investigators, and Company Collaborators

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


Urls for final rule and guidance documents
URLS for Final Rule and Guidance Documents Investigators, and Company Collaborators

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


Revised nci ae reporting tables
REVISED NCI AE REPORTING TABLES Investigators, and Company Collaborators


Expedited AE reporting timelines are defined as: Investigators, and Company Collaborators

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.


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.


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.


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

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.


SAEs that occur Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Interventionmore than 30 days after the last administration of investigational agent/intervention require reporting as follows:


Legacy tables
LEGACY TABLES Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention

  • Legacy tables should continue to be used for all studies at the present time

  • The revised reporting tables will only be applied to studies not yet approved by NCI by an implementation date yet to be determined


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


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


Adeers help
AdEERS Help that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 Studies

Technical Help Desk


Information on comprehensive adverse events and potential risks caepr
INFORMATION ON that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 StudiesComprehensive Adverse Events and Potential Risks (CAEPR)


Purpose of c omprehensive a dverse e vents and p otential r isks caepr
Purpose of that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 StudiesComprehensive 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


  • Sources for caepr information
    Sources for CAEPR Information that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 Studies

    • Primary Source:

      • Investigator’s Brochure

    • Secondary Sources:

      • Company Communications

      • Package Insert

      • Publications and Abstracts

      • AdEERS/caAERS Reports


    What the caepr is not
    What the CAEPR is Not that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 Studies

    • 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


    Purpose of the s pecific p rotocol e xceptions to e xpedited r eporting speer section of the caepr
    Purpose of the that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 StudiesSpecific Protocol Exceptionsto 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


    When is a caepr revised
    When is a CAEPR Revised? that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 Studies

    • 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


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