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22/06/2012 Slide 1
Overview of Adverse Reaction
Reporting Requirements inClinical Trials
IMB Clinical Trials Seminar, 19thJune 2012
Clare Brennan PhD
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Introduction
Legislation
Definitions
Assessing adverse events/reactions causality &expectedness
SAE/SAR/SUSAR reporting requirements
Methods for reporting to the IMB
Eudravigilance
Methods for reporting to Eudravigilance
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Legislation and Guidance Documents
Legislation
Directive 2001/20/EC
S.I. No. 190 of 2004Guidance documents
Eudralex Volume 10 Clinical Trial Guidelines - Chapter II
Detailed guidance on the collection, verification andpresentation of adverse event/reaction reports arising fromclinical trials on medicinal products for human use
Guide to Clinical Trial Applications(IMB website)
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What is an adverse event (AE)?
Any untoward medical occurrence in a patient or clinical trial
subject administered a medicinal product and which does notnecessarily have a causal relationship with this treatment.
May be serious or non-serious and may/may not be related to investigational
product(s)
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What is a Serious Adverse Event (SAE)?
Any untoward medical occurrence or effect that at any dose results in:
death,
is life-threatening,
requires hospitalisation or prolongation of existing hospitalisation,
results in persistent or significant disability or incapacity,
or is a congenital anomaly or birth defect.
is serious per criteria and may/may not be related to investigational product(s)
NB: Important medical events which jeopardise the subject or may require anintervention to prevent one of the serious criteria listed above should also beconsidered serious
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What is a Serious Adverse Reaction (SAR)?
All untoward and unintended responses to an investigationalmedicinal product, related to any dose administered
Is serious per criteria, expected per the Investigators Brochure/SmPC and
is related to investigational product(s)
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What is a SUSAR?
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A suspected, unexpected serious adverse reaction.
Is serious, is unexpected/not listed in the Investigators Brochure/SmPC
and is related to investigational product(s)
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Who assesses causality and how?
Causality assessment must be made by the Investigator
Made using knowledge of biological, pharmacologicalproperties of the IMP/comparator, clinical and scientificjudgement
Investigator must report all SAEs to the Sponsor within 24hours
Causality assessment cannot be downgraded by theSponsor
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Who assesses expectedness and how?
Expectedness assessment must be made by the Sponsor
Expectedness assessment is made using the reference safetyinformation applicable version at time of the reaction
Reference safety information Investigator Brochure or SmPC
Expectedness should be determined from the perspective ofreactions previously reported unexpected unless documented in
the RSI
NB: Reports which add significant information on the specificity,increase in occurrence or severity of a known, documented seriousadverse reaction constitute unexpected events
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CA, EVEC , Inv
24 h 7/15 days
SUSAR
SponsorInvestigator
CA Competent Authority
EV - Eudravigilance
EC Ethics Committees
Inv - Investigators
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When should I unblind?
SUSARs must be unblinded prior to submission per guidance
Waivers on unblinding - needs to be proposed and agreed atauthorisation stage of application DSMB recommended
Points to consider
Defined process for unblinding to be in place prior to commencing trial Access to unblinding codes
Maintaining blind for relevant personnel
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Overview of Reporting
Ev e n t / r e ac t io n n o t e dby i nves t i ga t o r a t s i t e
Subm i t t ed t oSponsor fo rassessment
SAE
DSUR
SAR
DSUR
SUSAR
I MB EVEth ics
C om m i t t eesA l l o ther
i n ves t i ga to rsDSUR
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Wh f b b i d h
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What type of report must be submitted to the
IMB and Eudravigilance by the Sponsor?
Suspected Unexpected Serious Adverse Reactions (SUSARs)
Points to consider before submission
Do I have the minimum criteria for a valid report (reporter, subject, drug &
reaction)?
Have I unblinded the report?
Have I provided the EudraCT number and IMB CT number?
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Ti li f ti SUSAR t IMB d EV b
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Timelines for reporting SUSARs to IMB and EV by
Sponsor
All SUSARs
Fata l and l i fe -t h r ea t en ing
SUSARs
7 ca lendardays f r om f i r s tno t i f i ca t i on t o
Sponsor
A f u r t he r 8days fo r
com p le t edr epo r t
A l l o the rSUSARs
15 Calendardays f r om f i r s tno t i f i cat i on t o
Sponsor
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H d th S b it SUSAR t th
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How does the Sponsor submit SUSARs to the
IMB?
Electronic reporting of SUSARs is mandatory per Directive
2001/20/EC
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What is the Eudravigilance database?
EMAs centralised adverse reaction database (Dec 2001)
Is maintained by the EMA
The EV Post Authorisation Module (EVPM) Individual Case SafetyReports (ICSRs)
The EV Clinical Trial Module (EVCTM) SUSARs
http://eudravigilance.ema.europa.eu/highres.htm
Points to consider
Registration with Eudravigilance required prior to study commencement
Prior training & testing required before access is granted to production
phase
ICH E2B (R2) compliant pharmacovigilance system in place
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Methods for reporting to EVCTM by the Sponsor
I do not have access to a compliant PhV system. Are
there alternatives routes for electronically submitting
my SUSAR reports and meeting reporting
requirements?
EVWEB Web interface for secure transmission of SUSARs
Points to consider
More manual procedure than E2B compliant EV submission Also requires registration with EMA and training
http://eudravigilance.ema.europa.eu/human/evweb01.asp
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Exceptional Circumstances
Is there any support for submission of SUSARs to
EVCTM?
Provided for small, non commercial, investigator led trials
Prior arrangement and agreement by e-mail
([email protected]) Trial by trial basis
Points to consider
Shorter timeline for reporting to IMB
IMB will only facilitate onward reporting ofNational SUSARs
Intended for exceptional circumstances and specific needs
Not an indefinite solution
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I th ifi IMB t l t SAE f
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Is there a specific IMB template SAE form
available?
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Processing Other Reports
Submission of other reports?
SAEs - DSUR
SARs - DSUR
Line listings (quarterly/6 monthly) - for EthicsCommittees not routinely required by the IMB
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Further Information
Where can I get further information and access online
forms?
IMB: Guide to Clinical Trial Applicationshttp://www.imb.ie/EN/Publications/Publications/Guide-to-Clinical-Trial
Applications.aspx?page=1
IMB: SAE form
http://www.imb.ie/EN/Medicines/Clinical-Trials/Serious-Adverse-Event
form.aspx
IMB: Guide to Electronic Transmission of ICSRs and SUSARs
http://www.imb.ie/EN/Publications/Publications/Guide-to-Electronic
Transmission-of-ICSRs-and-SUSARs-associated-with-the-use-of-Human
Medicines.aspx?page=1&year=0&categoryid=36&letter=&q=
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http://www.imb.ie/EN/Publications/Publications/Guide-to-Clinical-Trial-Applications.aspx?page=1http://www.imb.ie/EN/Publications/Publications/Guide-to-Clinical-Trial-Applications.aspx?page=1http://www.imb.ie/EN/Medicines/Clinical-Trials/Serious-Adverse-Event-form.aspxhttp://www.imb.ie/EN/Medicines/Clinical-Trials/Serious-Adverse-Event-form.aspxhttp://www.imb.ie/EN/Publications/Publications/Guide-to-Electronic-Transmission-of-ICSRs-and-SUSARs-associated-with-the-use-of-Human-Medicines.aspx?page=1&year=0&categoryid=36&letter=&qhttp://www.imb.ie/EN/Publications/Publications/Guide-to-Electronic-Transmission-of-ICSRs-and-SUSARs-associated-with-the-use-of-Human-Medicines.aspx?page=1&year=0&categoryid=36&letter=&qhttp://www.imb.ie/EN/Publications/Publications/Guide-to-Electronic-Transmission-of-ICSRs-and-SUSARs-associated-with-the-use-of-Human-Medicines.aspx?page=1&year=0&categoryid=36&letter=&qhttp://www.imb.ie/EN/Publications/Publications/Guide-to-Electronic-Transmission-of-ICSRs-and-SUSARs-associated-with-the-use-of-Human-Medicines.aspx?page=1&year=0&categoryid=36&letter=&qhttp://www.imb.ie/EN/Publications/Publications/Guide-to-Electronic-Transmission-of-ICSRs-and-SUSARs-associated-with-the-use-of-Human-Medicines.aspx?page=1&year=0&categoryid=36&letter=&qhttp://www.imb.ie/EN/Publications/Publications/Guide-to-Electronic-Transmission-of-ICSRs-and-SUSARs-associated-with-the-use-of-Human-Medicines.aspx?page=1&year=0&categoryid=36&letter=&qhttp://www.imb.ie/EN/Medicines/Clinical-Trials/Serious-Adverse-Event-form.aspxhttp://www.imb.ie/EN/Medicines/Clinical-Trials/Serious-Adverse-Event-form.aspxhttp://www.imb.ie/EN/Publications/Publications/Guide-to-Clinical-Trial-Applications.aspx?page=1http://www.imb.ie/EN/Publications/Publications/Guide-to-Clinical-Trial-Applications.aspx?page=17/31/2019 Adverse Reaction Reporting Requirements for Clinical Trials - Clare Brennan
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Thank you
?
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