SAE Reporting
Pan European Clinical Trials under current EU regulations
London, 24 Jan 2008
Trude Butterfaß-Bahloul
EURAMOS 1 Intergroup Safety Desk
Centre for Clinical Trials (ZKS, formerly KKS) Münster, Germany
This course, as part of the European Science Foundation EUROCORES Programme ECT,
is supported by funds from the EC Sixth Framework Programme, under Contract no: ERAS-CT-2003-980409.
Aims of SAE reporting system
Assuring the patients‘ safety
1. Timely overview within the trial: SAE including
fatal cases
2. Early detection of serious unexpected
adverse reactions
– Contribution of the trial to overall pharmacovigilance
and drug safety by SUSAR reporting
London, 24 Jan 08
Overview
1. What is an SAE, SAR, SUSAR?
2. Investigators: what to report, how to report and
when?
3. Safety Desk: What does the Safety Desk do
with SAE reports?
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
Definitions
1. Adverse event (AE)
2. Adverse reaction (AR)
3. Serious adverse event/reaction (SAE / SAR)
4. Unexpected adverse reaction
5. Suspected unexpected serious adverse
reaction (SUSAR)
– Defined in: Directive 2001/20/EC, Detailed Guidance
ENTR/CT 3, ICH-E2A
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
1. Adverse event (AE)
• Any untoward medical occurrence in a patient
or clinical trial subject administered a medicinal
product and which does not necessarily have a
causal relationship with this treatment
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
2. Adverse reaction (AR)
• All untoward and unintended responses to an
investigational medicinal product related to
any dose administered
• Judged by either the reporting investigator or the
sponsor as having a reasonable causal relationship to
a medicinal product → worst case
• Reasonable causal relationship: to convey in general
that there is evidence or argument to suggest a causal
relationship
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
Adverse reaction, Investigator‘s judgement
Is SAE related to EURAMOS trial medication?
Yes No
Reasonable causal relationship
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
3. Serious adverse event/reaction (SAE/SAR)
• Any untoward medical occurrence or effect that
at any dose
– Results in death
– Is life-threatening
– Requires hospitalisation or prolongation of existing
inpatients’ hospitalisation
– Results in persistent or significant disability or
incapacity
– Is a congenital anomaly or birth defect
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
Also serious:
• Important adverse events/reactions
• that are not immediately life-threatening or do not result
in death or hospitalisation
• but may jeopardise the subject or may require
intervention to prevent one of the other outcomes listed
• According to investigator’s medical judgement
– E.g. treatment in an emergency room or at home for
allergic bronchospasm
– E.g. convulsions that do not result in hospitalisation
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
Difference between serious and severe!
• Serious: based on patient / event outcome or
action criteria
• Severe: describes intensity (severity)
– Mild / moderate / severe
– CTC / CTCAE
Examples: severe headache / mild heart attack
CTCAE grades < 4 may also be serious
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
4. Unexpected adverse reaction
• Nature or seriousness or severity or outcome …
is not consistent with the applicable product
information
– Investigator's brochure or summary of product
characteristics (SmPC)
Not on the basis of what might be anticipated
from the pharmacological properties!
• ICH-E2A
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
5. Suspected unexpected serious adverse
reaction (SUSAR)
• “Triple-yes”
Serious
Related to investigational medicinal product
Unexpected
Suspicion is enough!
London, 24 Jan 08
What is an SAE, SAR, SUSAR?
AE
→ SAE form
SAE
SAR
SUSAR
London, 24 Jan 08
Investigators: what, how, and when to report?
Directive 2001/20/EC
London, 24 Jan 08
Investigators: what, how, and when to report?
DEFINITIONS and EXCEPTIONS for EURAMOS:
• All deaths including death due to disease
progression during protocol treatment and for 30
days after the last protocol treatment, including
treatment with pegylated interferon α-2b, will be
reported as an SAE.
• Death due to progression of disease will not
constitute a SAE if it occurs at least 30 days
after the last protocol treatment.
London, 24 Jan 08
Investigators: what, how, and when to report?
• Hospitalization …
a) Hospitalization for chemotherapy is not reported as an
SAE. In addition expected side effects of chemotherapy,
which are listed in the product information, will not be
reported on an SAE form for the purposes of this clinical
trial unless in the opinion of the investigator they
unexpectedly prolonged the hospitalization or required
intensive care therapy.
b) Hospitalization for procedures required by the protocol
e.g. biopsy or surgery are not considered serious
adverse events until one of the above criteria are met.
London, 24 Jan 08
Investigators: what, how, and when to report?
• Hospitalization…
c) Hospitalization due to signs and symptoms
associated with disease progression are not
considered an SAE unless outcome leads to
DEATH during protocol treatment and for 30
days after the last protocol treatment, including
treatment with pegylated interferon α-2b.
d) Elective hospitalization for a pre-existing
condition that has not worsened does not
constitute a SAE.
London, 24 Jan 08
Investigators: what, how, and when to report?
• Disability is defined as a substantial disruption
in a person’s ability to conduct normal life
functions (e.g. blindness, deafness). Disability
resulting from tumor surgery does not constitute
an SAE.
London, 24 Jan 08
Investigators: what, how, and when to report?
• Other medically important conditions are ….
• Secondary malignancies are also considered to
be medically important e.g. skin cancers,
myelodysplastic syndrome (MDS) and are
reportable on an SAE form during protocol
treatment and for 30 days after the last protocol
treatment, including treatment with pegylated
interferon α-2b.
London, 24 Jan 08
Investigators: what, how, and when to report?
• Other medically important conditions
• Abnormal biological or vital signs commonly occur under
chemotherapy and will only be reported as serious when
considered CLINICALLY RELEVANT BY THE
INVESTIGATOR (unexpected) e.g. severe nephrotoxicity
(CTCAE Grade 4) or severe cardiac toxicity (CTCAE
Grade 4). Expected serious adverse reactions (SAR)
such as hematological toxicity or increase in liver
enzymes under methotrexate which resolve are
examples of SARs which are not considered reportable
on an SAE Form by the investigator.
London, 24 Jan 08
Investigators: what, how, and when to report?
EURAMOS 1: SAE reporting per country (Dec 07)
Patients recruited SAEs
400 352
300
193
200
101
100
25 14 28 36 20 30
6 2 8 17 11 3 5
0
B DK D NL NOR SWE UK USA
No SAEs received from:
AUS (7 patients recruited), CAN (32), FIN (1), H (11), NZ (6), CH (17)
London, 24 Jan 08
Investigators: what, how, and when to report?
• The highest reporting rates (2004 total
population) can be found in Sweden, Ireland,
Norway, Denmark, the UK, France, and the
Netherlands.
• Assessment of the European Community System of
Pharmacovigilance, Frauenhofer ISI, Final Report Nov. 2005
Same experience in the EURAMOS 1 trial
May reporting rates be harmonized by applying
to the reporting rules in the protocol?
London, 24 Jan 08
Investigators: what, how, and when to report?
How to report an SAE:
1. Become aware of adverse event
2. Assess as serious
3. Assess as reportable according to protocol
4. Complete SAE-form with as much information
as possible (preferably in English)
5. Identify patient by patient ID no., never by
name (on attached documents as well!)
6. Sign and date by investigator
London, 24 Jan 08
Investigators: what, how, and when to report?
How to report an SAE:
7. Fax to Safety Desk immediately
(within 1 working day of knowledge)
8. Await confirmation of receipt / query
(within 1 more working day)
9. Answer query soon
(otherwise: trial site will be suspended 21 d after query!)
10. Further follow-up information may be faxed at
any time, sometimes more queries may come
(eg outcome, or questions from Schering Plough)
London, 24 Jan 08
Investigators: what, how, and when to report?
SAE form Version 2.0
Please use new version
– Otherwise: query for details of medication
Electronically fillable form available
– May prevent query due to readability reasons
Form to be found on www.euramos.org
London, 24 Jan 08
London, 24 Jan 08
Investigators: what, how, and when to report?
London, 24 Jan 08
Investigators: what, how, and when to report?
When to report?
• Immediately: 24 h/1 business
day after knowledge
• Early report more important
than complete report
EURAMOS 1:
London, 24 Jan 08
Safety Desk: What do we do with SAE reports?
1. First Inhouse review → Registration: SAE no.
2. If PegIntron given: Fax to Schering Plough
3. Data entry, coding (MedDRA, ATC)
4. Complete Inhouse review
5. Fax to investigator: Confirm. of receipt / Query
All this to be completed within 1 business day
London, 24 Jan 08
Safety Desk: What do we do with SAE reports?
6. Fax to Chief Investigator (Assessment until d 3)
7. Reporting form incl. narrative
8. Fax to National Coordinators/Data Centers (d3)
9. If SUSAR: Fax also to all Competent
Authorities and to Ethics Committee of country
where SAE occurred
(No more SUSAR reports from other trial received)
10. For follow-up information: repeat previous
steps, as applicable
London, 24 Jan 08
Safety Desk: What do we do with SAE reports?
EURAMOS 1: Assessment of SAEs
(n=101, Dec 07)
SAR
79
78%
SUSAR SAE
11 11
11% 11%
London, 24 Jan 08
Safety Desk: What do we do with SAE reports?
Investigator
SAE 1 businessday
Safety Desk Chief invest.
COSS
(SAE)
SUSAR
Nat. Coord.
Data Centres
Competent Ethics
authorities Investigators Committee
London, 24 Jan 08
Safety Desk: What do we do with SAE reports?
Annual Safety Report
• All SAR (including SUSARs) will be summarized
in the Annual Safety Report
3rd EURAMOS 1 ASR submitted in October 2007
London, 24 Jan 08
Thank you!
Aims of SAE reporting system
• Early detection of unknown reactions
• Timely overview of patients’ safety in the trial
• Ensuring the safe use of medicines
… can be archieved
London, 24 Jan 08
