Safety Reporting

Shirley Jankelevich, MD
IND Sponsor Clinical Safety Office
IMPAACT 2011 Training Meeting
May 5,2016
Objectives
• Reporting Adverse Events for IMPAACT 2011
• Reporting time periods forAEs
• Solicited vs unsolicited AEs
• Definitions of solicitedAEs
• Which solicited AEsrequire expeditedreporting
• Grading of solicited AEs
• Rules for recording solicited AEs
• Events that required expedited reporting
• Unanticipated problems (UPs) and reporting of UPs
• General Safety Oversight of study
• Pausing and Stopping Rules
Surveillance for Adverse Events

• “All events that occur during IMPAACT 2011 protocol-

specified AEreporting periods should be evaluated as a
potential:
• expedited AE(per DAIDS)or
• unanticipated problem (UP) (Section 7.4)
 Recording and Reporting Time Periods for AEs
Period of Enrollment
Apr 1 Oct 14
Inoculation
Reporting D 0-28 D 29-56 D 56 -Oct 31 Nov 1-Mar 31 Apr 1-Apr 30
time Acute Phase Post-Acute RSVSeason Post-RSV Season
Pre-RSVSeason
period Phase
All SAEs All SAEs Only SAEsand All SAEs Only SAEsand
CRFRecording Solicited AEs AEs≥ Gr 3 related to Fever, LRI, URI, and/or OM AEs≥ Gr 3 related to
Requirements Unsolicited AEs procedures performed that are medically procedures performed
during attended during
Pre-RSV Season Study Post-RSV Season Study
Visit Visit
CRFReporting DAERS DAERS DAERS
Requirements

Unresolved AE with onset date during Day 0 to midnight on 28th day after inoculation
Unresolved SAE with onset date prior to midnight on 56th day following inoculation
Throughout study
Unresolved SAE with onset date during RSV Surveillance Period
Time Periods for RecordingAEs
Table 3: AE CRF Recording Requirements; Section 7.2
Study Phase at time of AE onset
Day 0 to 12 MN of 28th day after inoculation
(Acute Phase)
12:01 am on 29th day post inoculation to12 MN 
of 56th day following inoculation
(Post-Acute Phase)
 Grade ≥3AEs or SAEs with onset after Day 56 and prior to RSV Surveillance Period related to Pre-RSV
>Day 56 day following inoculation up to Oct 31
in year of inoculation)
Nov 1 – Mar 31
(RSV Season SurveillancePeriod)
Apr 1-30
(Post-RSV Season)
Throughoutstudy
AEs to record onCRFs
• All SAEs
• All solicitedAEs that meetAppendix IV criteria
• All unsolicitedAEs (Grades 1 to 4), exceptdiaper rashes, teething pain, and spitting up that are not Rx’d
with prescription or OTCmeds
All SAEs
Season Study Visitprocedures
 Fever,LRI, URI, and/or otitis media that are medically attended
 All SAEs
ONLY Grade ≥3AE or SAE deemed related to Post-RSV Season Study Visit procedures
UnresolvedAE with onset date during Day 0 to midnight on 28th day after inoculation
Unresolved SAE with onset date prior to midnight on 56th day following inoculation
Unresolved SAE with onset date during RSV Surveillance Period
 Adverse Events: Solicited vs UnsolicitedAEs
• In IMPAACT 2011, AE’s are categorized by whether theyare:
• Solicited (see App IV)
• solicited AE= AEthat occurs during the period of time that RSV
vaccine virus replicates after inoculation
• occurs within the 1st 28 days after inoculation=ACUTEPERIOD
• protocol specific grading tables (Tables 4 and 5) used to determine
severity
or
• Unsolicited
• due to other causes at any time during thestudy
• Use DAIDSAEGrading Table used to determineseverity
Adverse Events:

Definitions of SolicitedAEs
occurring from Day 0 to
midnight on 28th day
following inoculation.
(see Appendix IV; Section8.1.1)

LRI events require ExpeditedReporting

Adverse Events (AEs): Grading of SolicitedAEs
2 Specific Tables are Used to Grade Solicited AEs
Table 4: Grading Table for SolicitedAEs
Severity Definition
Grade (0) None Not applicable
No medical intervention required; may include use of over-the-counter
Grade (1) Mild
medications managed by the caregiver for treatment of symptoms
Outpatient medical intervention by a health care provider required; may
Grade (2) Moderate
include use of over-the-counter and/or prescription medications
Grade (3) Severe Prolonged medical intervention and/or hospitalizationrequired
Grade (4) Life
Illness requiring hospitalization with intensivecare
threatening
Grade (5) Death Event resulting in fatal outcome to theparticipant
Table 5: Fever Grading
Severity Definition
Grade (0) ≥100.0ºF but <100.4ºF (≥37.8ºC but <38ºC)
Grade (1) ≥100.4ºF but ≤101.4ºF (≥38ºC but <38.6ºC)
Grade (2) ≥101.5ºF but ≤102.4ºF (≥38.6ºC but ≤39.1ºC)
Grade (3) ≥102.5ºF but ≤104.8ºF (≥39.2ºC but ≤40.4ºC)
Grade (4) ≥104.9ºF (≥40.5ºC)
Adverse Events: Rules for Recording SolicitedAEs
on CRFs
• Solicited AEselicited by history but Unconfirmed by Clinical
Assessment
• Do NOTrecord onCRFs
• Solicited AEselicited by history but no Clinical Examdone:
• if description meets “definition” in the column criteria in
Appendix IV:
• record on CRFs asAEs
• if description fails to meet the “definition” in the column
criteria in AppendixIV:
• record only on the source document and NOT on the CRF
Adverse Events: Expedited Reporting Requirements (Section7.3.2)

• SAEs(as per protocol instructions)

• All Solicited events in LRI category during Day 0 – 28 (AppendixIV)

• Timeline for Reporting

• Report via DAERSno later than 3 reporting days after site awareness of theevent
• For IRB, report as per IRB requirements
 Unanticipated Problems (UPs)
• Definition of UP(Section 7.4)
• Any incident, experience, or outcome thathave the following 3 characteristics
1. unexpected in terms ofnature, severity, or frequency in relation to:
• the research procedures that are described in the protocol and IC or other studydocuments
and
• the characteristics of the participant population beingstudied
1. possibly, probably, or definitely related to participation in the research
2. places participants or others at a greater risk of harm (including physical,
psychological, economic, or social harm) than was previously known or recognized.
• Reporting of UPs
• All UPs----report to IRBs
• UPs that are Non-serious AEs---report to OCRPROClinical SafetyOffice
• ≤ 7 calendar days after site investigator becomes aware of event
• UPs that are Serious AEs---report in DAERSas Expedited Adverse Event (EAE)
 General Safety Oversight
• Protocol Safety Review Team (PSRT)
• includes:
• Protocol Chair or Vice Chair, Data Manager, NIAID/DCR Medical Monitor, DAIDS or NICHD
Medical Officer the ProtocolStatistician
• will closely monitor participant safety through routine review of safety data
reports generated by the SDMC
• will review aggregate data every 2 weeks during the first 56 days after the last
infant is immunized and then atleast every 4 weeks
• will be notified of events that met the protocol pausing or stopping criteria
• Data and Safety Monitoring Board (DSMB)
• will monitor safety through reviews of study data
• reviews take place ~ 6 months
• review data if stopping criteria is triggered or as requested by the DSMB
12
Pausing Rules (Section 8.2)

• Protocol will be paused ifone of the following AEsoccur

• Day 0 through MN of 28th day following inoculation:
• LRI per Appendix IV (SolicitedAE)
OR

• Fever of Grade 4
OR
• Grade 3 or above solicited AE(other than fever)
• Day 0 through MN of 56th day following inoculation:
• SAEthat:
• cannot be attributed to a specific etiology unrelated to RSVvaccine
or
• cannot be attributed to a cause unrelated to RSVvaccine
Pausing Rules (MOP Section6.3)
• If a site identifies that pausing criterion has been met, site will perform
following steps:
• Notify IMPAACT team (with description) at impaact.team2011@fstrf.org,
within 24 hours of event ID
• Determine if local IRB requires reporting for a studypause
• Report SAEsand LRIs via the DAERSreporting system
• Continue to conduct theprotocol-specified evaluations on previously
enrolled/active participants
• IMPAACT team notifies all sites to suspend enrollmentand inoculations
• FSTRFcloses accrual
• IMPAACTteam notifies sites via email when/if the study enrollment and
inoculations may resume.
• It is imperative that sites follow the pausing steps so that the event can
be assessed expeditiously and not delay furtherenrollment
 Stopping Rule Criteria (Section 8.2)
• Enrollment and inoculations will be suspendedif:
• 1 or more participants who received active RSVvaccine develops orexperiences:
• SAEthat cannot be attributed to an etiology or cannot be attributed to a cause unrelated to study vaccine
OR

• LRI associated with shedding of vaccine virus at the time of LRI (even if another pathogen is identified,
unless the RSVis confirmed to be wt RSV)
OR

• LRI that is not explained by a diagnosis unrelated to vaccine virus

OR

• Grade 4 fever or any Grade 3 or Grade 4 solicited AEother than fever associated with shedding of vaccine
virus
OR

• Any pattern of research laboratory values or clinical symptoms is observed that is considered asignificant
safety issue for participants

• DSMB will make recommendations to Protocol Chair

• Sponsor and PSRTwill determine if enrollment can resume, or if the study needs to be stopped.