The document discusses current regulatory guidance around medical literature monitoring (MLM) for pharmacovigilance activities. It outlines challenges faced by companies in keeping up with the increasing volume of literature and complexity of MLM. Recent regulatory initiatives by the EMA and technological solutions using automated text mining tools and integrated literature review systems aim to help companies more efficiently meet evolving MLM requirements and better evaluate product safety.

1. PharmacoVigilance Revıew • Volume 9 Number 1 • 2016 11
Supriya Desai MD, PGDBM is a
Clinical Research and
Pharmacovigilance Executive
with over 16 years of experience
in clinical practice and in various
leadership roles in the healthcare
industry, including clinical
research, drug safety and
pharmacovigilance. In her current
role as Medical Director and
Practice Head at Sciformix, she
provides scientific and
operational leadership to a global
medical team (across India,
Philippines and US) involved in
medical review activities across
pharmacovigilance, safety
writing, signal management and
allied safety surveillance
activities, spanning diverse
therapeutic areas.
Current regulatory guidance
In recent times, pharmacovigilance regulations
have focused increasingly more on medical
literature monitoring (MLM), a complex process
whose scope continues to expand and deepen.
Existing regulations provide detailed guidance on
literature searches and review to enable
reporting of those individual case safety reports
(ICSRs) not already directly reported to the
sponsor (clinical, spontaneous and solicited data)
and also help in signal detection and BRE of
products1–3.
Per the European Medicines Agency (EMA),
MAHs are required to monitor local scientific
and medical publications in countries where
they have a marketing authorisation,
irrespective of commercial status of products.
The US Food and Drug Administration (FDA)
requires submission of reports of serious,
unexpected adverse drug reactions (ADRs)
described in the scientific literature for products
with the same active moiety as products
marketed in the US, even though excipient,
dosage forms, strengths, routes of
administration and indications may vary4.
The “literature” section of the periodic benefit–
risk evaluation report (PBRER) requires a summary
of new and significant safety findings for
approved products, obtained from published peer-
reviewed scientific literature or unpublished
manuscripts during the reporting interval.
Literature searches for PBRERs should be wider
than those for individual ADRs and include studies
reporting safety outcomes in groups of subjects2.
EMA guidelines also require inclusion of relevant
applicable safety information for other active
substances of the same class as the marketed
drug. Consequently, any potentially relevant event
identified in the literature may be considered an
emerging safety issue requiring prompt immediate
analysis and, if needed, corrective and preventive
action2,3.
Furthermore, special types of safety information
that require inclusion are all pregnancy
outcomes (including termination), use in
paediatric populations, compassionate supply
and named patient use, lack of efficacy,
asymptomatic overdose, abuse or misuse,
medication error where no adverse events
occurred and important non-clinical safety
results5.
Challenges, regulatory
initiatives and technological
solutions
As regulations become more comprehensive and
stringent and regulators stricter, companies face
the challenge of incorporating ever-increasing
safety data from literature into their
pharmacovigilance efforts to ensure compliance
with applicable regulations. Given the overall
volume growth and complexity of medical
preparing for a new time in
medical literature monitoring –
exploring the regulatory
initiatives, technological trends
and more…
Supriya Desai
The quality and efficiency of the
literature monitoring process has a
significant impact on the quality of
periodic safety reports, detection of new
safety signals and eventually benefit-risk
evaluation (BRE) of medicinal products.
Importantly, shortcomings in this critical
process have the potential to impact the
marketing authorisation holder’s (MAH's)
overall pharmacovigilance activities
including regulatory compliance and
potential impact on company reputation
due to inadequate BRE of company
products leading to potential drug recalls.
This article will explore the current
guidance in place, the regulatory initiatives
and the challenges companies face to
incorporate ever-increasing safety data
from literature into their pharmacovigilance
efforts to ensure compliance.

2. 12 PharmacoVigilance Revıew • Volume 9 Number 1 • 2016
literature over the years, monitoring literature
for product citations is a huge task, involving
investment of excessive time, effort and cost for
sifting through high volumes of heterogeneous
and cross-disciplinary reports. However, there
still remains a potential risk of missing important
data due to the sheer volume of data to be
reviewed.
The recent initiative of the MLM service by the
EMA (September 2015) intends to reduce
duplication of literature monitoring and review
efforts by a MAH, and potentially offset the
increased workload of the MAH to drive
improved safety monitoring of medicines. The
service, which aligns with the Guideline on Good
Pharmacovigilance Practices Module VI, will see
the EMA monitoring a total of 400 active
substance groups, including 300 chemical active
substance groups and 100 herbal active
substance groups. Literature reference
databases tracked by the EMA include Embase
covering literature from the European Economic
Area (EEA) and non-EEA countries, Elton B.
Stephens Co. (EBSCO) covering a wide variety of
resources, International Pharmaceutical
Abstracts (IPA) covering a spectrum of drug
therapy and pharmaceutical information from
over 800 journals and the Allied and the
Complementary Medicine Database (AMED)
covering alternative treatments based on
bibliographic records for articles from nearly 600
journals.
This initiative aims to improve the safety
monitoring of medicines by enhancing the
quality and consistency of data reported in
EudraVigilance. Monitoring of medical literature
and entry of relevant information into
EudraVigilance will be carried out by the EMA to
enhance the efficiency of ADR reporting, provide
a simplification for the industry, improve data
quality by reducing the number of duplicates,
contribute to industry resource savings and
support signal detection activities by National
Competent Authorities and MAHs. This is the
first of its kind and overall a very promising
initiative from the EMA, whereby ICSRs found in
the literature will be made available to MAHs so
they can include them in their safety databases
and meet their reporting obligations outside the
EEA. The list of active substance groups and a
reference to the journals covered by the
monitoring service are also available for
companies to consult6,7.
This initiative would definitely ease up literature
monitoring and literature case processing
efforts of MAHs within the EU/EEA. Yet, even
within the EU/EEA, other relevant safety
information from the perspective of aggregate
reporting, signal detection and benefit–risk
evaluation would need to be extracted by an
MAH. Further, for global organisations, other
regulatory requirements and criteria, besides
those covered by the EMA initiative, including
the way search strings are set-up, would likely
remain the same, especially for meeting US FDA
and other health authority requirements.
Today, there is a definitive need for the industry to
embrace newer, comprehensive, efficient and cost-
effective literature screening and review solutions
to meet the evolving regulatory, marketing and
strategic requirements. At the minimum, for
optimal regulatory compliance, companies need to
embrace better processes and tools that help
monitor, triage and review relevant articles from all
existing literature sources rapidly and accurately
with capacity to integrate and interrogate new
data streams as they become available without
duplication of efforts. These solutions should
enable integration of safety data from multiple
sources into a single repository across the entire
product life cycle and ensure consistent workflow
across the organisation.
Furthermore, seamless exporting of data for
case processing, regulatory submission of
reports as well as for continuous collation of
regulatory data for development of risk
mitigation strategies is required. Eventually,
such systems should be able to discern whether
a particular event is being reported multiple
times and also detect difficult-to-spot safety
signals/issues either because they are not
obvious or because they have a very low
occurrence rate.
For most companies today, literature validation
involves manual review of the retrieved abstracts
to identify valid case reports, either potential or
confirmed, before the decision is made to get a
full text PDF article for review. This manual
curation approach is often costly and time
consuming with the possibility of missing relevant
abstracts if they occur in non-indexed
publications or are based on narrow search
criteria.
Using automated text mining tools – by defining a
set of values above or below the point at which it
is highly improbable that a particular abstract will
lead to an article that contains an adverse event
to get selected abstracts – offers an effective and
economical curation approach, whereby
searching a large number of publications is
possible in less time and without risk of missing
potential adverse events. Different entries for the
same alert, multiple generations of a single record
over time and data on a single event or safety
issue detected from multiple sources (e.g.
PubMed, Embase) can be collated into a single
record, allowing automatic de-duplication of

3. PharmacoVigilance Revıew • Volume 9 Number 1 • 2016 13
reports, cutting down review time and reducing
the risk of counting a single event more than
once8.
As well as the aforementioned process
efficiencies, automated solutions would allow
integration of all relevant documents into a
centralised repository for drug safety inputs and
enable seamless tracking of the entire literature
monitoring and review process. All processing
and editing operations on each record can be
tracked and changes recorded, retaining
information from previous versions and making
the process traceable with efficient quality
control and robust audit trails. Metrics for
productivity calculation and quality control
purposes can be gathered and the right safety
information can be channelled in real-time to the
pharmacovigilance teams for further review and
analysis.
More evolved literature review solutions,
connected to larger safety reporting databases
and signal detection systems, can help
investigate unexpected ADRs with unclear
causality, unconfirmed reports from sources
outside the literature, and other potential
signals. Furthermore, relevant drug safety data
can be connected to specific regulatory concerns
and recommendations and facilitate
retrospective literature searches for specific
associated signals. This can enable review of past
interpretations of certain events in light of new,
more recent information in such integrated
systems. Availability and access to all this
information would help companies to do more
than simply meet pharmacovigilance regulatory
requirements.
In addition to shedding light on potential
problems with an existing drug on the market, all
this post-marketing safety data can be mined
when embarking on a drug development
programme for a similar compound or
mechanism of action, or a drug repurposing
effort8.
Summary and conclusions
Scientific and medical literature is an important
source of information on suspected adverse
reaction case reports. As the regulatory pressure
and focus on literature monitoring and review
continues and the number of data sources for
mining and analysis increases,
pharmacovigilance teams need to rethink
existing traditional literature monitoring and
review mechanisms and embrace new-age
solutions to make best use of the limited
pharmacovigilance resources while staying
compliant to regulatory requirements and for
optimal benefit–risk evaluation of company
products.
References
1. European Medicines Agency. DRAFT detailed guide
regarding the monitoring of medical literature and the
entry of relevant information into the EudraVigilance
database by the European Medicines Agency.
EMA/161530/2014. London, UK: Inspections and
Human Medicines Pharmacovigilance Division, EMA;
26 May 2014. Available at: http://www.ema.europa.
eu/docs/en_GB/document_library/Regulatory_and_pr
ocedural_guideline/2014/06/WC500167985.pdf
[Accessed 16 December 2015].
2. European Medicines Agency. ICH guideline E2C (R2) on
periodic benefit-risk evaluation report (PBRER). Step
5. EMA/CHMP/ICH/544553/1998. London, UK: EMA;
January 2013. Available at: http://www.ema.europa
.eu/docs/en_GB/document_library/Regulatory_and_p
rocedural_guideline/2012/12/WC500136402.pdf
[Accessed 16 December 2015].
3. Heads of Medicines Agency. Guideline on Good
Pharmacovigilance Practices (GVP): Module VI –
Management and Reporting of Adverse Reactions to
Medicinal Products (Rev. 1) EMA/873138/2011 Rev 1.
London. UK: HMA, EMA; 8 September 2014. Available
at: http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2014/09/WC50
0172402.pdf [Accessed 16 December 2015].
4. Heads of Medicines Agency. Guideline on Good
Pharmacovigilance Practices (GVP): Module VII – Periodic
Safety Update Report (Rev. 1). EMA/816292/ 2011 Rev 1.
London, UK: HMA, EMA; 9 December 2013. Available
at: http://www.ema.europa .eu/docs/en_
GB/document_library/Scientific_guideline/2013/04/WC5
00142468.pdf [Accessed 16 December 2015].
5. US Food and Drug Administration. Guidance for
Industry Postmarketing Safety Reporting for Human
Drug and Biological Products Including Vaccines. Silver
Spring, MD, USA: FDA; March 2001. Available at:
http://www.fda.gov/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidanc
es/Vaccines/ucm074850.htm [Accessed 16/12/2015].
6. European Medicines Agency. Detailed guide regarding
the monitoring of medical literature and the entry of
relevant information into the EudraVigilance database
by the European Medicines Agency. EMA/161530/2014.
London, UK: Inspections and Human Medicines
Pharmacovigilance Division, EMA; 12 May 2015.
Available at: http://www.ema.europa.eu/docs
/en_GB/document_library/Other/2015/05/WC5001867
31.pdf [Accessed 16 December 2015].
7. European Medicines Agency. Monitoring of medical
literature and entry of adverse reaction reports into
EudraVigilance. London, UK: EMA. Available at:
http://www.ema.europa.eu/ema/index.jsp?curl=page
s/regulation/general/general_content_000633.jsp.
[Accessed 16 December 2015].
8. Elsevier. Pharmacovigilance: Rethinking Literature
Monitoring and Review – 5 Strategies to Streamline
the Process and Ease the Pain. Amsterdam, The
Netherlands: Elsevier; 2015. Available at:
http://www.elsevier.com/rd-solutions/industry-
insights/pharma-and-life-sciences/pharmacovigilance-
rethinking-literature-monitoring-and-review
[Accessed 16 December 2015].