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Developing a robust adverse event
capturing and reporting system

Chwee Ping Phua, Regional Head of Pharmacovigilance, Asia
Pacific
26 November 2014
Disclaimer
The views expressed in this presentation are those of the
presenter and do not necessarily represent the views of,
and should not be attributed to, Novartis Asia Pacific
Pharmaceuticals Pte Ltd.
2 | Presentation Title | Presenter Name | Date | Subject | Business Use Only
Overview of Pharmacovigilance System:

PMS &
Epidemiological
Data
Spontaneous
Reports
Clinical Trial
Follow-up
Data
Issue & Crisis

Management
Safety
Database
Literature
Reports
Data In
Regulatory
Reports
Submission
+
Study
Reports
Database
Entry
Licensing
Partners
Amend
Prescribing
Information
Data Review
Signal
Detection
Output
Enquiry
Response
Licensing
Partners
Collect
Risk
Management
Plans
Review
marketing
status
Action
World-wide
Regulatory
Reports
Expedited
& Periodic
Collate Analyse Communicate
Developing a robust adverse event capturing and

reporting system
Spontaneous case reports of adverse events submitted to
the sponsor and Health Authority, and reports from other
sources, such as the medical literature or clinical studies,
may generate signals of adverse effects of drugs.
The quality of the reports is critical for appropriate

evaluation of the relationship between the product and
adverse events.
Important to develop a robust AE capturing & reporting

system
Developing a robust adverse event capturing and

reporting system
How to overcome challenges in
Creating quality management systems for ADRs
Managing case in-flow and invalid information

Follow up requirements and procedures
Case closures
Assessing global reporting requirement

Paper reporting vs. electronic reporting
Reporting of non-serious adverse reactions
Challenge 1:
Creating quality management systems for

ADRs
Qualified PV responsible person

- Difficulty in getting
competent, appropriately
qualified and trained
personnel
- High turnover
- Resource constraint with

more stringent regulatory
requirement.
- Intensive training and

coaching for new hire with
right qualification
- Set up regional center
- Outsource/off-shore of
routine activities

Quality planning
Frequent revision of procedures due
to changes in PV legislation.
Include procedure for country in

global procedure
Record management and data retention

Insufficient storage space due to long
retention period of PV documents.
Transfer documents to ext. archiving

facilities or use electronic record
Audit
Language barrier during audit
Qualified translator during audit
Challenge 2:
Managing case in-flow & invalid information
Question
How many adverse event report does Novartis received
each year?
a. 380,000
b. 520,000
c. 450,000
d. 290,000
Managing case in-flow & invalid information

Challenges & solution
Novartis receives approximately 450,000 adverse event

reports each year.
Reported to drug safety via various media such as e-mail,

paper, fax and phone.
Reports were entered and tracked in local Affiliate system

that interface with core safety database.
Sudden influx of large volume of reports from Health

Authority
Novartis Launches Patient Safety Information Application

(PSI) in early 2013
Patient Safety Information Application (PSI)

First Electronic Adverse Event (AE) Reporting Tool
Transitioning AE reporting to an efficient, quality-driven,
electronic solution linked directly to the safety database
Cases will be collected directly from patients, HCP,
Novartis Sales people and 3rd party vendors
These events will be delivered directly into the
appropriate Affiliate site
Once the intake into Argus Affiliate is completed
they can be routed to core safety database
Latest safety information becomes available for evaluation

in the shortest possible time

Goal is to drive AE reporting through the new tool and
significantly reduce manual handling of reports
Data captured in a structured, electronic format that asks

the right questions and elicits the right information from the
stakeholder at the time it is reported
available as a Novartis iPad application for the Field Force

and an online tool via Novartis.com for HCPs and the
general public
Available for use by Patient Oriented Program vendors

available in English, French, German, Brazilian
Portuguese and Spanish
Challenge 3:
Follow-up requirements & procedures

How much information to collect and what are the number
& timeline of follow up attempts?
GVP Module VI on follow ups:

Reports should be followed-up as necessary to obtain
supplementary detailed information significant for the scientific
evaluation of the cases.
This is particularly relevant for monitored events of special interest,
prospective reports of pregnancy, cases notifying the death of a
patient, cases reporting new risks or changes in the known risks.
This is in addition to any effort to collect missing minimum

information

CIOMS V Recommendation
Priority: Serious, unexpected > Serious, expected > Nonserious, unexpected cases
Serious expected cases are potentially of epidemiological

interest in helping to identify risk factors.
Non-serious unexpected cases are also of potential

interest for detecting a new signal.
In CIOMS V, the lists of data elements are referred to as

Lists A, B and C:
A containing the least and C the most called-for information.
Follow-up is recommended only when the data elements

on the Lists are missing or incomplete
Minimum desired case information

(CIOMS V Recommendation)
List A
List B
country of occurrence
an identifiable reporter
an identifiable patient
source type (e.g., physician, lawyer,
regulatory authority, etc.)
a suspect drug or drugs
one or more adverse event.
Daily dose of suspected medicinal

product and regimen
Route of administration
Indication(s) for which suspect
medicinal product was prescribed
If serious, criterion or criteria for
regarding the case as serious
Full description or reaction(s)
including body site and severity
Starting date of onset of reaction
(or time to onset)
Time lag if ADR occurred after
cessation of treatment
Patient outcome : Information on
recovery and any sequalae.
Dechallenge/Rechallenge
information (if any)
For a fatal outcome, cause of death
and a comment on its possible
relationship to the suspected
reaction(s)
Causal relationship assessment
Other relevant etiological factors
List C
Stopping date and time or duration
of treatment
For concomitant medications:
Daily dose and regimen
Stopping date and time or
duration of treatment
Specific tests and or/treatment
required and their results
Setting (e.g., hospital, outpatient
clinic, home, nursing home)
Any autopsy or other post-mortem
findings
Whether or not the hospital
discharge summary is available if
the patient was hospitalized.
Anything relevant to facilitate
assessment of the case such as
medical history, relevant drug
history including allergies, drug or
alcohol abuse, family history.
Timeline
(CIOMS V Recommendation)
Unexpected deaths or life-threatening events

Every effort should be made to follow-up within 24 hours
Serious unexpected case or a non-serious unexpected

case
If first written follow-up attempt fails to generate a satisfactory
response, second follow-up letter should be sent no later than four
weeks after the first letter. When the reporter does not respond or is
incompletely cooperative, the two follow-up letters should reflect
sufficient diligence.
For non-serious expected cases

only one letter (or equivalent communication) should suffice.

How long should a case be followed by a company to
determine the outcome?
no guidelines on how long a company should continue and what
constitutes a reasonable effort.
Recommended approached from CIOMS V :

Serious unexpected case : continue follow-up until the outcome has
been established or the condition is stabilized
Currently Novartis follows recommendation in CIOMS V

concerning follow up and has applied self imposed
number of follow up attempts to demonstrate due
diligence as outlined in GVP Module VI.

Novartis Follow-up process
*Not mandatory, a reminder letter may be sent for non serious cases if deemed appropriate

Challenges of this approach
Resource intensive to make a labelling assessment at case receipt
to determine the number of follow up required.
Undertaking a local labelling step has a high degree of risk. If the
local labelling contradicts the global assessment this would result in
inspection findings.
CIOMS V recommends approach against CDS, but countries maybe

using local labelling document leading to contradictory assessments.
Basing a system on CIOMS V is not keeping with current trends and
regulations in the PV system and legislation where there is a finite
amount of resource, so resource should be deployed in the areas of
most risk and which bring the most value.

A paper1 that examined the effect of re-contacts on
response rates stated that it was insufficient to measure
response rate as a sole measure, but measure the quality
that the response creates.
It was concluded that after one re-contact there was not a

significant increase in quality of response.
Number of re-contacts a total rise in quality
This is akin to the PV system, a reply stating no further

information will be provided does not add any quality to the
case therefore does not bring any value to assessing for
safety signals.
1
Gordon B et al Med Care 2013;51: 945948


A study was conducted in Novartis to determine the case
quality and number of follow up conducted
The results demonstrated that percentage quality against

percent score decreased with each follow up attempt:
5% quality gain for the third follow up attempt for serious

cases (PMS & SR).
9% quality gain for first follow up attempt for non-serious
cases (PMS & SR)
Considering the challenges and risk of non compliant,

reduction in follow up attempts is recommended

Solution
To simplify the current follow up scheme to make it most

clear, understandable and easy to be followed.
To focus the efforts (in terms on number of followattempts) in RMP events, Serious Fatal and Life
Threatening(F/LT) Cases/Serious Cases:
As per GPV Module VI follow ups are particularly relevant for
monitored events of special interest, and cases notifying the
death of a patient

New FU process
*For NVx key event cases, the number of follow ups can be more than 3 as per the NVx procedure. CPO would be informed through
the responsible PVE/PVL
** +/- 2 calendar days

Busy healthcare professionals (HCPs) may be difficult to
contact to complete the follow up.
HCPs may be more willing to offer further

details if questions are asked on important
information in clinically important cases.
Use event or product specific checklist
Follow-up encounters should optimally take place only

once; therefore, plans should be made to obtain as much
information as possible the first time around.
Follow-up information can be obtained in writing, via a

telephone call, or a site visit as appropriate.
Challenge 4:
Case Closures
Case Closures
Challenges
Ensure that all reports are complete prior to case closure.

if all attempts to obtain follow-up information have failed,
case to close out.
Difficult for central processing site to determine if the case

is complete with no further information or lost to follow up
or incomplete with no further follow up attempt .
Difficult for country to track and monitor prospective

pregnancy outcome as the Expected Delivery Date (EDD)
may be many months from the initial report.
Case Closures
Solution
The outcome of all follow up attempts should be properly

documented in the source document and in safety
database.
If there will be no more FU attempts, country will add a

note in local Affiliate system to indicate if the case is Lost
to FU or Case complete to facilitate case closure at
central site.
Distribute monthly listing of prospective pregnancy cases

without outcome by central site to all countries
Perform follow up on the outcome or
Transmit appropriate status of case to central processing site.
Case Closures
solution
Periodic Monitoring by Central Site

Follow-up activities
- Ensure compliance of frequency & timeliness of FU
attempts.
Prospective Pregnancy Outcome after EDD

- Ensure cases are followed-up to capture missing
outcome & cases lost to follow-up are documented.
A single country is monitored 3 times a year i.e. every 4

months, the same group is monitored again
Case Closures
Solution
The result of monitoring is analyzed by Central site and

any deviation from internal procedures, related to
timeliness or frequency of FU attempts or missing
pregnancy outcome, is addressed with the respective
country.
Challenge 5:

Challenges
Non-harmonized PV Legislations and PV requirements

vary widely from country to country
Some countries in the Asia Pacific region do not have

well-defined pharmacovigilance regulations
Differences in language in different countries

In many regions, the regulations are being revised and
updated (e.g, European Economic Area or EEA) and it is
essential to keep pace with these changes
Keep abreast and comply with the global regulations that

are applicable in the countries where the companies
products have authorizations

How to overcome the challenges
Harmonized to internationally recognized standards

If the regulation is unclear, the local Authorities will be
contacted for clarification by the local Drug Safety
Responsible (DSR).
All local pharmacovigilance requirements must be

reported to central site via email.
Local DSR should inform central site as soon as a new or

changed regulation is published or about any locally
imposed pharmacovigilance RMP commitment.

If company has no local office in a country, they can enter
into business agreements with local companies that will
monitor and provide local pharmacovigilance requirements
and updates.
Central site will incorporate new or changed requirements

and commitments into the Regulatory Requirements Table.
If there is a change in current ICSR reporting to Health

Authorities, information is also entered in a country-specific
Argus configuration table.
Central site approves the new expediting rule and issues a

change requests to Pharmacovigilance Systems. The
configuration in safety database will be changed.

On a quarterly basis, central site will circulate the
regulatory requirements table to all DSRs, the QPPV office
for information, review and update.
In addition to the reconciliation of requirements, central

site periodically reconcile the Argus configuration with the
regulatory ICSR requirements and any specific
commitments.
Any inconsistency will be documented and followed up

and necessary actions taken to investigate the deviation
and rectify any missing reporting.

T- REX (Tracking & Managing Regulatory Requirements & Argus
Expediting Configurations)
New Novartis application (T-REX) which will be launched

to track, communicate, manage and document regulatory
ICSR requirements and to ensure the corresponding ICSR
expediting configuration in Argus is implemented.
Challenge 6:
Stage 1 B.C. before CIOMS

No defined format or report form that is
compatible with more than one authority.
Stage 2 - 1990: CIOMS 1

CIOMS I global standard for expedited reports.

Challenges
Paper reporting
Use of paper
Issues on records management e.g. Archiving facilities & space

Resources required for data (re-)entry activities as paper reports
must be manually converted into electronic formata costly and
time-consuming process.
Time consuming to prepare
aggregation of safety data for
analysis
Delayed acknowledgement and

feedback from regulatory authorities
Time consuming to send multiple
reports to multiple countries and license partners

Stage 3 late 1990s: ICH Guidelines

ICH E2B, M2 and M1 guidance signed off.
Electronic reporting
Electronic submission of ICSRs is a cost effective, efficient
alternative to paper-based reporting.
Electronic report also allows harmonized exchange of

drug safety information between all stakeholders
(regulators, life sciences organizations and other parties in
the life sciences business) across the world.
Stage 4: Reporting ICSRs

Adoption of electronic reporting of ICSRs
- has this moved us forward?
Electronic reporting
Challenges
Considering the large number of potential participants in a

world-wide exchange of information, there should be a
standard format that is capable of accommodating direct
database-to-database transmission using standardized
message transfers.
Technical capabilities required.

Budget $$$
Electronic reporting E2B

Solution
Successful electronic transmission of information relies on

the consistent and uniform interpretation of definitions for
common data elements and standard transmission
procedures.
Therefore, the adoption of a standardized electronic

message across regions, regulatory agencies, and other
participants is of paramount importance.
In some countries, ICSRs were submitted on line to HA as

ICH-E2B format (XML file- eXtensibleMarkup Language)
Challenge 7:

Challenges
Inconsistent requirements among EU countries during

transition phase

SOPs to be in place to ensure that the appropriate cases
are sent to the appropriate agencies throughout the EU
Difficult to get investigators from Non-Interventional

Studies (NIS) to report non-serious adverse reactions in
expedited basis to company.
Clinical database owner to run an extract and transfer (ET)

procedure to take AEs from the NIS study database on
monthly basis and report as monthly batches.
Want to Learn More?

Dont Miss the Chance to Attend:
18th 19th November 2015, Singapore

Featuring the heads of PV from across Asia, including:
Sushrut Bhatt
Area Medical Governance and Pharmacovigilance
Miranda Wang
Head for Country Pharmacovigilance, China
GlaxoSmithKline Pharmaceuticals Limited
Bristol-Myers Squibb
Jean Christophe Delumeau

Head of Pharmacovigilance Asia Pacific and China
Bayer HealthCare / Bayer South-East Asia
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Developing a robust adverse event

capturing and reporting system

2 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Overview of Pharmacovigilance System:

Issue & Crisis

Collate Analyse Communicate

3 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Developing a robust adverse event capturing and

The quality of the reports is critical for appropriate

Important to develop a robust AE capturing & reporting

4 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

5 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

6 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Developing a robust adverse event capturing and

Managing case in-flow and invalid information

Assessing global reporting requirement

7 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Creating quality management systems for

8 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Creating quality management systems for ADRs

Qualified PV responsible person

- Resource constraint with

- Intensive training and

Creating quality management systems for ADRs

Include procedure for country in

Record management and data retention

Transfer documents to ext. archiving

10 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Qualified translator during audit

Managing case in-flow & invalid information

11 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

12 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Managing case in-flow & invalid information

Novartis receives approximately 450,000 adverse event

Reported to drug safety via various media such as e-mail,

Reports were entered and tracked in local Affiliate system

Sudden influx of large volume of reports from Health

Novartis Launches Patient Safety Information Application

Patient Safety Information Application (PSI)

14 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Patient Safety Information Application (PSI)

Latest safety information becomes available for evaluation

Patient Safety Information Application (PSI)

Data captured in a structured, electronic format that asks

available as a Novartis iPad application for the Field Force

Available for use by Patient Oriented Program vendors

Patient Safety Information Application (PSI)

17 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Patient Safety Information Application (PSI)

18 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Patient Safety Information Application (PSI)

19 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Patient Safety Information Application (PSI)

20 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Patient Safety Information Application (PSI)

21 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Follow-up requirements & procedures

22 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Follow-up requirements & procedures

GVP Module VI on follow ups:

This is in addition to any effort to collect missing minimum

23 | Presentation Title | Presenter Name | Date | Subject | Business Use Only