Pharmaceutical companies are required to screen scientific literature on a regular basis and this comes with many challenges, such as handling large amounts of data, building search strings and integrating EMA MLM results. Out-sourcing literature screening to service providers reduces the workload for the PV-team, but how does it impact the literature management process overall? Maybe it results in decreased oversight and additional activities like audits and reconciliation? And what about building the search strategy? During this webinar our PV expert, Dr. Joyce De Langen spoke about the following: • The importance of literature management in Pharmacovigilance and the challenges. • An evaluation of the benefits and risks of outsourcing literature management versus alternative solutions. About the speaker: Joyce de Langen, Ph.D has more than 10 years of experience in the domain of pharmacovigilance and drug safety. Through her work in the pharmaceutical industry, academia and regulatory authorities, Joyce has developed a broad perspective and knowledge in pharmacovigilance and drug safety.

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Literature Management for Pharmacovigilance:
outsourcing or in-house solution?
with Joyce de Langen
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2. 2
Handling challenges with
Literature Management for
Pharmacovigilance:
Outsourcing or in-house
solution?
Presented by: Joyce de Langen, Doctor of Pharmacy
Senior Product Solution Manager, Elsevier Life Sciences
Date: 21st of March 2017

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Need to know

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• Why screening scientific and medical literature for pharmacovigilance purposes?
• Role of scientific & medical literature in pharmacovigilance
• Challenges with screening scientific and medical literature for pharmacovigilance
• Handling challenges with screening scientific and medical literature for pharmacovigilance
– Optimize and improve precision of search strategies
– Outsourcing literature screening activities to third parties or service-provider
– Increase efficiency of process with support of IT-intelligence and software solutions
Agenda

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Why searching scientific and medical literature?
‘…Scientific and medical literature is a significant source of information for the monitoring of
the safety profile and of the risk benefit balance of medicinal products, particularly in relation to
the detection of new safety signals or emerging safety issues…
Reference: Guideline on good pharmacovigilance practices (GVP): Module VI-Management and reporting of adverse events to
medicinal products

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Role of Literature in Pharmacovigilance
• Screening scientific & medical literature to identify single adverse drug
reactions or special situations
• Systematic review of scientific & medical literature for aggregated reporting
(PSURs, PBRERs, DSUR).
• Screening literature for signal detection and assessment of validated signals.

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Literature is the 4th largest source of AE reporting
Adverse events reported in literature can have a high impact — major drug recalls
(e.g., Vioxx, Baycol) were initiated by published adverse reactions.
Often overlaps with reports from health professionals
FDA Adverse Event Reporting System (FAERS) Quarterly Data Files, Q2 and Q3 2013
Reported adverse events by report source,
Q2 & Q3 2013
N = 34,469 unique events
Overlap of adverse events sourced from
literature by reporting sources, Q2 & Q3 2013
N = 4,691 unique events

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Literature as source of ADRs: Thalidomide and congenital birth defects (1961)
McBride WG. Thalidomide and congenital abnormalities. Lancet. 1961;278:1358

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Safety information from spontaneous and literature adverse reactions reports may differ
Klose J, Fröhling S, Kroth E, Dobmeyer T, Nolting A. Safety information from spontaneous and literature adverse reactions
reports: a comparison. Ther Innov Regul Sci. 2013;47:248–55.
Extracted from Table 4
Drug
Substance
System Organ
Class
Literature Cases
(%)
Spontaneous Cases (%) % Difference
Acetylsalicylic
Acid
Nervous System
Disorders
25.6 8 17.6
Gastrointestinal
Disorders
8.4 25.4 17.0
Fentanyl
Injury, poisoning,
complications
35.9 7.5 28.3
Alendronic acid
Gastrointestinal
disorders
4.6 21.0 16.5
Injury, poisoning,
complications
28.3 5.4 22.9
Tamsulosin
Injury, poisoning,
complications
50 4.1 45.9
Etoposide
Congenital, familial,
genetic
0 24.3 24.3

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Signal from literature: Tamsulosin and ‘Floppy Iris Syndrome’ (2005)
• Intraoperative floppy iris syndrome
occurred in approximately 2% of a
cataract surgery population
• Appeared to be caused by tamsulosin, a
systemic sympathetic alpha-1A
antagonist
• Chang et al. mention 15 patients with
IFIS
• At the time of publication, none had been
reported to the Regulatory Authorities!
Intraoperative floppy iris syndrome associated with tamsulosin
Chang D.F., Campbell J.R.
Journal of Cataract and Refractive Surgery 2005 31:4 (664-673) Cited by: 285

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EMA : Signals from literature in 2014 and 2015
Description 2014 2015
Total number of signals 2,030 2,372
Signals from Eudravigilance 86.7% 87.8%
Signals from Scientific Literature 8.6% 8.7%
Other regulatory authorities (FDA, WHO, Health
Canada)
3.2% 2.3%
Other sources 1.5% 1.2%
http://www.ema.europa.eu/docs/en_GB/document_library/Annual_report/2016/05/WC500206482.pdf

12. Challenges in literature screening for
pharmacovigilance

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What are the biggest challenges with Literature Screening?
Differences in
regulations
Building the
perfect Search
Strategy
Large Volume of
scientific literature
Inspections/Audits
Monitoring Local
Language
Journals
Implementing
EMA MLM Results

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Guidelines for literature screening may differ between authorities

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A. Good reporting Practice
Spontaneous case reports of adverse events submitted to the sponsor
and FDA, 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. FDA
recommends that sponsors make a reasonable attempt to obtain
complete information for case assessment during initial contacts and
subsequent follow-up, especially for serious events, and encourages
sponsors to used train…
VI.B.1.1.2. Literature reports
The scientific and medical literature is a significant source of
information for the monitoring of the safety profile and of the risk
benefit balance of medicinal products, particularly in relation to the
detection of new safety signals or emerging safety issues. Marketing
authorization holders are therefore expected to maintain awareness of
possible publications through a systematic literature review of widely
used reference databases (e.g. Medline, Excerpta Medica or Embase)
no less frequently than once a week. The marketing authorization
holder should ensure that the literature review includes the use of
reference databases that contain the largest reference of articles in
relation to the medicinal product properties
Marketing authorization holders are therefore
expected to maintain awareness of possible
publications through a systematic literature
review of widely used reference databases
(e.g. Medline, Excerpta Medica or Embase)
no less frequently than once a week.
The quality of the reports is critical for
appropriate evaluation of the relationship
between the product and adverse events.
Challenges in Literature screening for PV: Increased regulatory focus on
role of literature in PV

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Challenges in Literature screening for PV: Differences between regulatory requirements
EMA FDA CIOMS ICH
Frequency of
screening literature At least weekly Not specified Monthly According to local
requirements or at
least bi-weekly
Which Literature to
screen?
Scientific and
medical literature
Scientific literature Discusses all
terminology used
by different
Regulators
Worldwide
literature
Reporting
requirements
Serious and non-
serious
Serious and
unexpected
Expedited reporting
being discussed
Day 0 is when
Medical safety
information is
identified
Exclusions No Yes Not applicable Brand or trade
name

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Challenges in Literature screening for PV: Building the perfect search strategy?
Recall
Precision
• Balancing between recall and precision = balancing between
‘capturing all relevant information’ and ‘avoiding all noise’
• Ideally the goal would be to build a search strategy with high recall
with high precision
• In real-life the goal of building a search strategy is to keep precision
as high as possible while recall is maximized

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Challenges in Literature screening for PV: Increasing amount of scientific literature
Data retrieved from www.Embase.com
0
5
10
15
20
25
30
35
1975 1980 1985 1990 1995 2000 2005 2010 2011 2012 2013 2014 2015 2016
Number of records in Embase per Year
(in millions)

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Challenges in Literature screening for PV: Inspections and audits
• Increased attention of regulators for literature screening since introduction of GVP modules in
2012
• Proportion of major and minor findings related to literature screening has increased since 2012
But it is not only about ‘not missing articles:
– List of journals & reference databases
– SOP(s)
– Search strategy
– Integration of EMA MLM results in your companies workflow
– Local language journals
– Oversight CRO/Service Providers
– Traceability

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Challenges in Literature screening for PV: EMA Medical Literature Monitoring
• EMA MLM Service: 300 active substances, 100 herbals
• Since launch (July, 2015) 115,550 literature references reviewed by EMA
• In total 1,464 Adverse Drug Reactions were identified, involving 756 individual patients
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/05/WC500186732.pdf

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Challenges in Literature screening for PV: Integrating EMA MLM Results into MAH’s
workflow
• MAHs should still fulfill reporting requirements outside EU
• MAHs are still responsible for literature screening for aggregated safety reporting
• MAHs are still responsible for monitoring scientific and medical publications in local language
journals
• MAHs need to integrate the dataflow resulting from the EMA MLM Service into their existing
workflow for literature management and ICSR-management

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Challenges in Literature screening for PV: Screening Foreign Language Literature
List of Local Language Journals
 Do you know where to look to identify all relevant local language journals?
 Are you sure the company’s list of local language journals is exhaustive?

23. Outsourcing Literature Management For PV

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When does outsourcing helps?
• In times of high workload, and no additional in-house resources are available on short term
• When companies need to be flexible due to varying workloads
• Outsourcing approach of ‘pay as you go’ allows you to respond fully to regulatory obligations,
without the need of retaining a full pharmacovigilance team on the payroll
• The benefits of outsourcing include reduced costs because less effort is needed for staff
recruitment, management and training. With stricter regulatory requirements, the hiring of
experienced safety personnel has become highly competitive.

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Expected Growth Global PV market size results in trend to outsourcing
https://www.gminsights.com/industry-analysis/pharmacovigilance-market

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Outsourcing PV activities to Asia & Latin America
20122010

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Most commonly outsourced drugs safety activities
https://www.ashfieldhealthcare.com/wp-content/uploads/2015/06/Safety-on-a-Budget.pdf
3/21/2017

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What kind of Literature Services do CRO’s Provide?
• Screening Literature for Identification of Individual Case Safety Reports (ICSRs) and Special
Situations
• Targeted Literature Screening For Safety Assessments And Benefit Risk Analysis
But also:
• Entry of identified cases onto a validated safety database
• Full medical review of ICSRs
• Regulatory reporting of ICSRs
• Signal Detection and Benefit risk analysis
• Medical Assessment of safety issues

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Outsourcing Literature Management for PV
• CRO’s usually provide flexible end-to-end literature search and review solutions that assist
companies and individuals to meet their regulatory goals.
• Literature review help users to stay updated in their research.
• Provides complete picture of today’s global clinical research in clinical medicine which is
enabled by broad coverage with numerous access point, extensive search capabilities and
coverage of immense data.
• Save research time by providing one source for variety of research data including abstracts,
author’s name, contact details and information per bibliographic record than in other
resources.

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Conditions & Challenges for outsourcing Literature Management for PV
• The service provider has the qualification for the pharmacovigilance services.
• Contractual agreement includes well defined responsibilities.
• Transparency maintained at project start.
• Do you have oversight over the CRO activities?
• How much time do you spend on reconciling the data?
• Do you know who the CRO validates/optimizes the search strategy?

31. In-house Software Solutions for
literature management challenges

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Software solutions: in-house solution to solve challenges with literature
management
• In-house software solutions provide oversight on users
• Increase of efficiency (reduction of costs) due to automated deduplication & generating
ICSRs from the tool
• Improve the Quality & Compliance of the whole literature review process as:
– A software solution structures data-flow >> decreased risk of missing information.
– Increased oversight on the workload and possibility to manage/structure the workload
– Increased oversight on CRO activities

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Literature management solutions: decrease risk of missing
information without redundant reviewing
Make sure all relevant
articles are captured
• Capture data from
most comprehensive
source of journals/
conference abstracts
• Develop custom
search strategies to
find all relevant data
Avoid redundant reviews
of the same input
• Save time and avoid
redundant reviewing with
automatic deduplication
of articles
Save time and
stay current
• Stay current and
work more efficiently
with automated
article curation
process

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Literature management solutions: improve workflow
management and regulatory compliance
Track review process
in case of audit
• Demonstrate procedures
done correctly and
on time with traceable
review process
Improve article pipeline
management
• Identify most relevant
articles with text mining
• Ensure appropriate
personnel receive/
review required data
with alert system
Capture metrics behind
article reviews
• Calculate efficiency
and ensure strict
quality control by
capturing metrics

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Introducing QUOSA PV
Empowering rapid, transparent literature surveillance and case triage
Conference
Documents
Online literature
database
Journal RSS
Feeds
PSURs
ICSRs
OTHER
SAFETY &
COMPLIANCE
REPORTS
A browser-based tool that enables pharmacovigilance
teams to save time and money by centralizing and
automating the literature review and triage process
Receive alerts to
rapidly identify
adverse events
in literature
Review and
annotate articles
from a scalable
central library
Use pre-formatted
output to easily
create reports

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Introducing QUOSA PV
Empowering rapid, transparent literature surveillance and case triage
Conference
Documents
Online literature
database
Journal RSS
Feeds
PSURs
ICSRs
OTHER
SAFETY &
COMPLIANCE
REPORTS
A combination of software and services that allows customers to
reduce risk, remain compliant and ensure that workgroups have
the latest scientific literature
Supervisors
Track deadlines
And bottlenecks
• Automatic alerts import
• Article deduplication
• E2B case data export
• Document listing
exports in Vancouver
format for PSURs
Administrators
View all aspects of
the review process

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Take Home Message
• Scientific and medical literature is a relevant source of safety information
• Literature screening for single adverse drug reactions may indeed:
– improve patient safety
– impact the life cycle of a drug
• MAHs are facing a number of challenges with regard to literature management
for pharmacovigilance
• Outsourcing pharmacovigilance and investment in software solution may
support pharmaceutical companies in handling the challenges with literature
management for pharmacovigilance.
• Using software solutions like QUOSA PV allow you to have oversight on your
CRO and outsource (part of) the workload

38. Thank you for your attention