How to get the plausible and precise safety data, maintaining the highest ethical standards during clinical development? KCR’s article presents critical points in safety monitoring and reporting at different stages of the clinical trial, as well the main difficulties faced by medical personnel and clinical team during their everyday practice.

1. Safety monitoring and reporting
in clinical trials – ensuring
quality and effectiveness
Author: Magdalena Matusiak
Manager, Clinical Development
Pharmacovigilance Team Lead, KCR
Adverse event reporting to authorities
product in EU:
• Sponsor must obtain EudraCT number
and MedDRA access
• Sponsor must be registered with Eudravigi-
lance database (EV registration procedure
usually takes about 20 working days to be
-
quest submission together with an applica-
ble
document)
• Sponsor must be registered with the
eXtended EudraVigilance Medicinal Product
Dictionary (XEVPRM)
• Safety management procedures have to be
in the clinical trial are aware of their
responsibilities
SUSAR reports may be submitted:
- via Eudravigilance database only
- via Eudravigilance database and
additionally electronic submission to local
Competent Authorities may be required
- in some countries only paper versions of
safety reports are acceptable still - submit-
ted by post/courier or submitted in person
CONCLUSIONS:
Pharmacovigilance systems have become
recently more and more regulated due to hard
work of global and national health agencies.
New requirements have been established to
assure that patients’ safety is properly moni-
tored, all safety data is valid and credible, and
the process of safety reporting is fast and
Despite the number of guidelines and recom-
mendations released for national regulators,
clinical trial Sponsors, CRO companies with
regard to pharmacovigilance processes,
common human errors, report omissions,
reporting process still appear to be the most
important factors potentially leading to
patients’ safety threats, protocol deviations,
Human mistakes and failures made at early
stages of the safety reporting procedure may
safety and may lead to improper conclusions
is more, it may become a potential global
threat to patients' safety and public health
in the future.
by Sponsors and CRO companies at the clinical
site level could have an enormous impact on
-
covigilance system for the entire clinical trial
duration.
REFERENCES:
EMA, Guidelines on Good Pharmacovigilance
Practices (GVP) available at: www.ema.eu-
ropa.eu/ema/index.jsp?curl=pages/regulation/-
document_listing /document_listing_000345.jsp
Communication from the Commission — De-
and presentation of adverse event/reaction re-
ports arising from clinical trials on medicinal
products for human use (‘CT-3’) 2011/C 172/01,
European Commission 2011;
-
tion and standards for expedited reporting
E2E 1994;
ICH, Good Clinical Practice E6(R1) 1996;
WHO, The importance of pharmacovigilance
safety monitoring of medicinal products, 2002
Adverse event reporting to sponsor
After receipt of the SAE report from the investi-
gator a medical review of the report is per-
formed to verify completeness and quality of
data. After assessing the SAE reports obtained
during the clinical trials conduct, the most
common omissions are analyzed. Graph no 1
-
ciencies. Table no 2 summarizes the key factors
and timelines.
Potential risk to be minimized Key element to consider Recommendation
Patients may not fully
understand the risk related
to the study drug
Informed Consent Form/
Patient’s Information
Patients should be informed in a detailed, clear and
understandable manner not only about possible
adverse reactions, but also about any symptoms
patients may experience, which conditions should
be particularly observed.
Patients may not remember
about potential threat
to their health
Re-consent
option (especially during long-term clinical trials).
Re-consent is obligatory if new safety information
is available.
Patients may not remember
about adverse events
occurred between visits
Patient diaries,
Phone contacts
Paper patient’s diaries, commonly used, might be
lost or forgotten by patient. An electronic patient’s
and store safety data, allows for the safety monitor-
ing at the time the entry was made. Phone contacts
with patients between visits may be crucial for
monitoring patient’s safety status.
Patients may not understand
what information is crucial
for the investigation
Detailed interview with
patient during the visit
Patient’s perception of information and level of un-
-
cantly. Each patient should be treated individually.
medical data to feel comfortable with sharing their
private information with investigators.
not be available if patient is hos-
pitalized or after patient’s death
Patient’s family
members
Patient’s family member may be a valuable source
of medical information, especially if patient’s health
condition is very poor, or after patient’s death.
Table no 1:
Potential risk to be minimized Recommendation
Seriousness criteria not
recognized by investigators
Detailed training on seriousness criteria should be conducted for investiga-
the situations should be considered serious. Independent medical review of
patient’s safety parameters in study database should be every day practice
during clinical research.
Missing minimum information
criteria on the SAE report report template making them more visible. Detailed step-by-step SAE report-
process.
on the SAE report, hospital
discharge or other documents
send to the Sponsor/CRO
All site study personnel involved in the trial should be regularly trained in
and dedicated fax for safety reporting should be limited and controlled.
Bad quality of scanned SAE report Equipment and software crucial for safety reporting should be tested and
validated before the study. Back-up methods of safety reports transmission
should be always available.
Use of obsolete version of SAE
report template or SAE report
template dedicated for other trial
Obsolete versions of safety reports should be removed from sites. Sites
should be provided with pre-printed with site and project details templates,
Table no 2:
IMP batch
number
Outcome
of the event
Patient’s
medical history
Action
taken
with study
drug
Study drug
information
(dose, route)
Relationship
to study drug
35%
19%
17%
11%
11%
7%
Graph no 1: The most frequent SAE reports
source: KCR)
PATIENT
INVESTIGATOR medicinal product
on the market
CRO, SPONSOR COMPETENT
AUTHORITIES
PATIENT PATIENT PATIENT
Adverse events detection
Adverse events reporting Risk assessment and
marketing approval
Adverse
events reporting
OBJECTIVE:
The main goal of the article is to present critical
points in safety monitoring and reporting at dif-
ferent stages of the clinical trial, with a main
focus on the early stages of the process. The
by medical personnel and clinical team during
their everyday practice, and attempts to identi-
fy relevant solutions and answer the question
how to get the plausible and precise safety data
maintaining the highest ethical standards
during clinical development.
RESULTS:
Safety monitoring processes start at the level
of observing patient’s symptoms as well as
performed by investigators. Table no 1
adverse event detection.
METHOD:
Based on KCR’s knowledge and experience in
clinical monitoring, medical monitoring and
pharmacovigilance, the most important aspects
and processes of safety monitoring and report-
ing have been assessed.
Copyright © 2015 KCR S.A.
All rights reserved.
Quality of data, time of data obtainment and
for proper safety reporting processes.
Almost 20 years of clinical experience have
made KCR an expert for identification and
in-depth analysis of those critical points that
may influence negatively on patients' safety, as
well as for implementation of effective tools to
assure that safety and wellbeing of patients are
adequately maintained and controlled during
clinical trials.