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Literature Management for Pharmacovigilance:

outsourcing or in-house solution?with Joyce de Langen

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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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questions and comments

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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

Disorders25.6 8 17.6

Gastrointestinal

Disorders8.4 25.4 17.0

FentanylInjury, poisoning,

complications35.9 7.5 28.3

Alendronic acid

Gastrointestinal

disorders4.6 21.0 16.5

Injury, poisoning,

complications28.3 5.4 22.9

TamsulosinInjury, poisoning,

complications50 4.1 45.9

EtoposideCongenital, familial,

genetic0 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

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/AuditsMonitoring 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 PracticeSpontaneous 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 reportsThe 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?

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

26

Outsourcing PV activities to Asia & Latin America

20122010

27

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?

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

34

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

36

Introducing QUOSA PV

Empowering rapid, transparent literature surveillance and case triage

Conference

Documents

Online literature

database

Journal RSS

Feeds

PSURs

ICSRs

OTHER

SAFETY &

COMPLIANCE

REPORTSA 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

37

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

Thank you for your attention