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

FDA Final Rule & Revised CTEP 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 Cancer Therapy Evaluation Program (CTEP)

presents:

Jan Casadei, PhDChief

Regulatory Affairs Branch, National Cancer [email protected]

NCI /Cancer Therapy Evaluation Program (CTEP) 2

Final Rule Implications:Investigator reporting to sponsorExpedited Filing to the FDA


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


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


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?


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


Why is the New Final Rule Needed?

1) Confusing/inconsistent terminology in current regulations2) 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:


Definition of Serious Adverse Event

1. Death2. Life-threatening event (places the patient at immediate risk of

death)3. Requires inpatient hospitalization or prolongs hospitalization4. Persistent or significant incapacity or substantial disruption of

the ability to conduct normal life functions5. Congenital anomaly/birth defect6. 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 Severe (though they are linked)Severity is defined by a grading scale

Seriousness Severity (Grade)Death 5Life-threatening 4Hospitalization 3/4/5Important Medical Event (IME)

3/4/5

Disability 3/4/5


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


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


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


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


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


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


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


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)


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

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

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

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


Revised CTEP Guidelines for Expedited Reporting of

Adverse Events


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

CTEP Guidelines: Expedited Reporting of AEs from Investigator to Sponsor


WHY Does CTEP 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)


Adverse Event EXPEDITED Reporting System: All expedited AEs for CTEP IND Agents should be submitted to CTEP

via a web-based electronic system AdEERS (implemented 2001) caAERS (scheduled to replace AdEERS in 2011?)

All open protocols using CTEP-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 CTEP 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 CTEP according to the protocol)

Reportable Not Reportable


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


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 02) Phase 1/Early Phase 23) Late Phase 2/Phase 34) CIP Studies (identical to Late Phase 2/Phase 3)

An implementation date will be set for incorporating new tables into prospective studies


CTEP Expedited AE Reporting Time-Line Requirements

AEs occurring within 30 days of last treatment

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 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 treatmentSerious AEs occurring >30 days after the last dose of agent

Ph0 ALL Gr. 1&2

Ph1/Early Ph2 Gr. 2 w/ hospitalization Gr. 2 w/ hospitalization and at least a possible causality

Late Ph2/Ph3 AND CIP agents

ALL Gr. 3Gr. 2 w/ hospitalization

Gr. 3 with at least a possible causality Gr. 2 w/ hospitalization and at least a possible causality


CTEP Evaluation of EXPEDITED AE Report

IDB Senior Investigator reviews submitted report Requires sufficient documentation for independent CTEP 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?


CTEP 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” CTEP Processing Timelines

Initial Written Report (IWR) faxed to relevant FDA division within 3-5 calendar days of receipt at CTEP(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

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.


“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.


ADDITIONAL INFORMATION


ACRONYMSAdEERS 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


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






REVISED CTEP AE REPORTING TABLES


Grade 1 and 2 Timeframes Grade 3-5 Timeframes

10 Calendar Days 24-Hour5 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/Intervention


Hospitalization Grade 1 Timeframes Grade 2 Timeframes Grade 3-5 Timeframes

With Hospitalization 24 hrs Not Required 10 Calendar Days 24-Hour

5 Calendar Days

Without Hospitalization

24 hrsNot Required Not Required 24-Hour

5 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/Intervention


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

With Hospitalization

24 hrsNot Required 10 Calendar Days 10 Calendar Days 24-Hour

5 Calendar Days

Without Hospitalization

24 hrsNot Required Not Required 10 Calendar Days 24-Hour

5 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/Intervention andCIP Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under a CIP Non-IND/IDE trial within 30 Days of the Last Administration of a Commercial Imaging Agent


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 CTEP 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

Attribution

Grade 1 Grade 2 Grade 3 Grade 3 Grade 4 & 5

Unexpectedand

ExpectedUnexpected Expected

Unexpected Expected Unexpectedand

Expectedwith hospitalization

without hospitalization

with hospitalization

without hospitalization

UnlikelyUnrelated Not required Not required Not required 10 Calendar Days Not required 10 Calendar

Days Not required 24-Hour 5 calendar Days

PossibleProbableDefinite

Not required 10 Calendar Days Not required 24-Hour

5 calendar Days

24-Hour 5 calendar

Days

10 Calendar Days Not required 24-Hour

5 calendar Days


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 ExpectedUnexpected Expectedwith

hospitalizationwithout

hospitalizationwith

hospitalizationwithout

hospitalization

UnlikelyUnrelated Not required Not required Not

required10 Calendar

Days Not required 10 Calendar Days Not required 10 Calendar

Days10 Calendar

Days

PossibleProbableDefinite

Not required 10 Calendar Days

Not required

10 Calendar Days

10 Calendar Days

10 Calendar Days Not required

24-Hour 5 calendar

Days

10 Calendar Days


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]


INFORMATION ON COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS

(CAEPR)


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 CTEP to be included, but are left to IRB discretion

Always used within CTEP's agent-specific protocol templates


Sources for CAEPR Information

Primary Source: Investigator’s Brochure

Secondary Sources: Company Communications Package Insert Publications and Abstracts AdEERS/caAERS Reports


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


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 CTEP-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?

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