Literature Surveillance in

Pharmacovigilance:
Current Trends, Methods
and Challenges

Elizabeth Garrard, PharmD.

Garrard Safety Solutions
CEO and Founder
Pharmacovigilance Consultant
Disclosure

The views and opinions

expressed in the following
presentation are those of the
individual presenter and should
not be attributed to Elsevier, the
RELX Group, any regulatory
authority, or to any of my
clients.
Objectives for Today
Understand:
The regulatory obligations, best sources and
procedures for conducting literature surveillance.
When a safety signal was detected in the literature
and its impact on the lifecycle of a drug.
When to start and where to look for emerging safety
information
How to set up your search strategy
What is the impact of the new literature monitoring by
EMA?
The current methods that can increase the likelihood
of early detection of a safety issue
The challenges we face in quality, accuracy, and
completeness in the scientific literature and how best
to navigate these differences and maintain proper
vigilance.
Why search scientific and
medical literature?

Scientific & 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
When we say Medical
Literature what all is included?

Medical Literature includes:

Published abstracts or
Articles in medical/scientific journals
Unpublished manuscripts involving
case reports
Important safety findings or clinical
studies including posters, letters to the
editors, and associated communication
from scientific meetings.
 Literature volume keeps growing...

Zhiyong Lu Database 2011;2011:baq036

The Author(s) 2011. Published by Oxford University Press.

Literature is but one of many
sources of information..
Understanding the
Regulatory Obligations
Literature Searches in Pharmacovigilance
How are regulatory agencies
responding?
Health regulatory authorities (RAs) are intensifying
safety regulations and focus on Literature Monitoring
in EU and US
Marketing authorization holders are
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.
LITERATURE:ICH E2D
3.1.2 Literature
Each MAH is expected to regularly screen
the worldwide scientific literature by
accessing widely used systematic literature
reviews or reference databases. The
frequency of the literature searches should
be according to local requirements or at
least every two weeks.
Cases of ADRs from the scientific and
medical literature, including relevant
published abstracts from meetings and draft
manuscripts, might qualify for expedited
reporting. A regulatory reporting form with
relevant medical information should be
provided for each identifiable patient.
LITERATURE:
ICH E2D (cont)
3.1.2 Literature (contd)

All company offices are encouraged to be

aware of publications in their local journals
and to bring them to the attention of the
company safety department as
appropriate.
The regulatory reporting time clock starts
as soon as the MAH has knowledge that
the case meets minimum criteria for
reportability.
If the product source, brand, or trade name
is not specified, the MAH should assume
that it was its product, although the report
should indicate that the specific brand was
not identified.
If multiple products are mentioned in the
article, a report should be submitted only
by the applicant whose product is
suspected. The suspect product is that
identified as such by the article's author.
LITERATURE:
FDA
Reports of serious, unexpected adverse
experiences described in the scientific
literature should be submitted for
products that have the same active
moiety as a product marketed in the
United States. This is true even if the
excipient, dosage forms, strengths,
routes of administration, and indications
vary.

When a serious, unexpected adverse

experience is based on a foreign
language article or manuscript, the
applicant should translate the publication
into English promptly

Reference: Guidance for Industry: Postmarketing

Safety Reporting for Human Drug and Biological
Products including Vaccines:
 Literature: FDA (cont)

Serious, unexpected adverse experiences reported in

the scientific literature (or in an unpublished scientific
paper) that are known to the applicant must be
submitted as 15-day reportsApplicants can use
literature search services to identify adverse
experiences in the scientific literature.

If multiple products are mentioned in the article, an

Form FDA 3500A should be submitted only by the
applicant whose product is the suspect drug. The
suspect drug is that identified by the articles author and
is usually mentioned in the articles title. If the applicant
believes that the suspect product is different from the
one identified by the author of the article, the applicant
should indicate such information in the narrative
section of the Form FDA 3500A.

Guidance for Industry: Postmarketing Safety Reporting for

Human Drug and Biological Products including Vaccines:
LITERATURE: Health Canada
Every MAH is expected to screen
the worldwide scientific literature on
a regular basis by accessing widely
used systematic literature review or
reference databases.
It is recommended that the
frequency of the literature searches
be at least every two weeks.
A qualified healthcare professional
from the MAH should use their
clinical judgment to determine the
appropriate frequency of literature
searches based on the health
product marketed by the MAH.

Reference: Guidance Document for Industry: Reporting

Adverse Reactions to Marketed Health Products:
 LITERATURE:Health Canada
(cont)
For foreign literature reports, all foreign serious,
unexpected ARs involving the MAHs foreign
products with the same combination of active
ingredients irrespective of variations in the
formulation, dosage form, strength , route of
administration, or indication, that is also marketed
in Canada must be reported to MHPD in accordance
with the Regulations.

Reference: Guidance Document for Industry:

Reporting Adverse Reactions to Marketed
Health Products:
 LITERATURE : EMA
Reports of suspected adverse reactions from
the scientific and medical literature, including
relevant published abstracts from meetings
and draft manuscripts, should be reviewed
and assessed by marketing authorisation
holders to identify and record ICSRs
originating from spontaneous reports or non-
interventional post-authorisation studies.
If multiple medicinal products are mentioned
in the publication, only those which are
identified by the publications author(s) as
having at least a possible causal relationship
with the suspected adverse reaction should
be considered by the concerned marketing
authorisation holder(s).

Reference: Guideline on good pharmacovigilance practices

(GVP): Module VI-Management and of adverse events to
medicinal products:
LITERATURE :EMA
(Exclusions)
VI.C.2.2
Articles can be excluded from the reporting of ICSRs by the MAH if another
company's branded medicinal product is the suspected medicinal product.
In the absence of a specified product source or invented name, ownership of
the product should be assumed unless ownership can be excluded on the
basis of one of the following criteria:
medicinal product name
active substance name
pharmaceutical form,
batch number or
route of administration.
Exclusion based on the primary source country or country of origin of the
adverse reaction is possible if the MAH can demonstrate that the suspected
medicinal product has never been supplied or marketed in that territory.

Reference: Guideline on good pharmacovigilance practices (GVP):

Module VI-Management and of adverse events to medicinal products:
LITERATURE REPORTS:
EMA (Exclusions)
MAH can exclude from reporting if the following
conditions apply:
For ICSRs identified in the scientific and medical
literature that originate in a country where a company
holds a MA but has never commercialized the
medicinal product;
For literature ICSRs which are based on an analysis
from a competent authority database within the EU.
The reporting requirements remain for those ICSRs
which are based on the analysis from a competent
authority database outside of the EU.
For literature articles, which present data analyses
from publicly available databases or which
summarize results from post-authorization studies.
(describes adverse reactions in a group of patients or
presents data in aggregate or in tables)

Reference: Guideline on good pharmacovigilance practices (GVP):

Module VI-Management and of adverse events to medicinal products:
Safety Signals that have been
detected in the Literature

Reference: Pontes H, Clement M, Rollason V. Safety

signal detection: the relevance of literature review.
Drug Saf. 2014 Jul;37(7):471-9.
LITERATURE:
Example #1
Thalidomide-induced Phocomelia
(1961)

Obstetrician William G. Mc Bride

published a letter in the Lancet
linking the rare birth defect with the
use of thalidomide by pregnant
women

NOTE: At that time, there was no

structure for reporting of ADRs to
Regulatory

Reference: McBride WG.

Thalidomide and congenital
abnormalities. Lancet. 1961;278:
1358
 LITERATURE:
Example # 2
Granulocyte Macrophage Colony-
Stimulating Factor and Increased Risk
of Viral Replication (1998)

Literature search performed to assess

safety of use of GM-CSF in the
treatment of neutropenia in HIV patients
(off label use in US)

In vitro data suggested HIV up-

regulation by GM-CSF

Literature meta analysis showed

increased risk of viral replication by the
use of GM-CSF in patients with HIV not
currently taking antiretrovirals.

This type of safety concern would have

never been detected by spontaneous
reporting.
LITERATURE:
Example # 3
Nifedipine and Fatal Aplastic Anemia
(1998):

Article described a case-control study

linking six cases of fatal aplastic anemia
with nifedipine

Report identified a Type B ADR (bizarre

or idiosyncratic, dose independent and
unpredictable reaction)

Reference: Laporte JR, Ibanez L,

Ballarin E, Perez E, Vidal X. Fatal
Aplastic anemia associated with
nifedipine. Lancet. 1998;352: 619-20
LITERATURE:
Example #4
Tamsulosin and Floppy Iris
Syndrome (2005):

15 cases were described in the

literature in April, 2005

At the time of publication, none had

been reported to the Regulatory
Authorities!

Reference: Chang DF, Campbell

JR,. Intraoperative floppy iris
syndrome associated with
tamsulosin. J Cataract Refract
Surg. 2005;3: 664-73
Literature searching: When
to start and where to look?
When to Start and Stop

For the period between submission and granting

of a marketing authorization, literature searching
should be conducted to identify published articles that
provide information that could impact on the risk-
benefit assessment of the product under evaluation.
Literature searches should be conducted for all
products with a marketing authorization, irrespective of
commercial status.
Bottom line: It is expected that literature
searching would start on submission of a
marketing authorization application and continue
while the authorization is active.
What types of new emerging
safety information should you
be searching for..
New, unexpected serious and non-serious ICSR reports
with a reasonable causal association with the product.
AND..non-ICSR safety
information
Pregnancy outcomes (including termination) with no
adverse outcomes
Use in pediatric populations
Compassionate supply, named patient use
Lack of efficacy
Asymptomatic overdose, abuse or misuse
Medication error where no adverse events occurred
Important non-clinical safety results
Where to look?

Well recognized scientific and medical

journals
Embase
Medline
Excerpta Media
International symposia or local journals
Abstracts from meetings and draft
manuscripts
Medical Databases and Search
Engines for Literature Screening
Database Search Engines

Medline Pubmed

Embase Quosa

BioSys Previews Ovid

Cochrane Library ISI Web of Knowledge

CINAHL Scopus

SEDBASE Google Scholar

Considerations when choosing
relevant Databases

Accessibility
Not all free; costs can be
high
Coverage
Worldwide or not
Focus
Orientated towards particular
medical discipline
Overlap
Considerations when choosing
Literature Search Engines
Costs
Free or has access costs associated with it.
Is the user interface easy to navigate or complex?
How dependable and reliable are the outputs?
Can the search engine return de-duplicated
results?
Can the user make selections for the most relevant
articles and store your selected citations?
Can the user be notified when certain articles of
interest are available?
Methods and Search
Strategies
Setting up an effective search strategy that can increase
the potential for detecting a safety concern early.
Methods and Signal Search
Strategies
Database/search engine selection
Approach to record retrieval
Establishing a search strategy
Creating a search string
Selection of relevant terms or text
Application of limits
Use of automated methods
LITERATURE:
Search Strategy
Recommendations from CIOMS V & EMA
Target the search to publications that appear in
internationally recognized databases
Search at least two suitable databases
Constuct search string with terms likely to solicit
relevant information
Utilize consistent and balanced search strategies
(INN as keyword for retrieval)
Searches should be scheduled with a frequency
appropriate to the drug [& as required by the local
RA]
Review search results for ICSRs and non ICSR
safety data. Consider separate searches for each.
Make sure local database searches are being
conducted
Non-ICSR relevant data
Exposure during pregnancy or lactation (including pregnancies
with no adverse outcomes)
Use of the product in pediatric populations, elderly or organ-
impaired individuals
Occupational exposure
Lack of therapeutic efficacy
Asymptomatic overdose, abuse, or misuse
Medication error where no adverse events occurred (near
misses)
Off-label use
Suspected transmission of infectious agents
Compassionate supply, named-patient use
Clinical trial results/conclusions
Important non-clinical safety results (including in vitro/in vivo
laboratory studies)
Information on the risk-benefit
Counterfeit product
Potential Diversion
Other data of interest
Choice of the Search
Construction and Search Terms:
Precision and Recall
The success of a search can be measured
according to precision and recall (also called
sensitivity)
Recall is the proportion of records retrieved ("hits")
when considering the total number of relevant
records that are present in the database.
Precision is the proportion of "hits" that are
relevant when considering the number of records
that were retrieved.
Good search construction should result in an
output with low recall and high precision.
Representative list of possible terms
for adverse

Source: Webinar in 2013 - Searching Adverse Events on Embase:

http://www.slideshare.net/rocheam/embase-webinar-ard-25-sep-2013
LITERATURE:
Search Construction
Precision and recall- ideal is low
recall & high precision
Adding index terms can increase
precision and return records that are
of relevance to PV but use with
caution
Search term construction is a
balancing act- too many hits vs
omission of relevant records
Creating the search string
Creation of a search string is a very delicate balancing act, as
you want to ensure the best recall with the most precision.
Some Examples are below:
MESH.EXACT("generic -- adverse effects") OR
MESH.EXACT ("generic -- poisoning") OR
MESH.EXACT("generic -- contraindications") OR
MESH.EXACT("generic -- toxicity")
OR
(truncated generic&2 or generic other or TradeName1 or
TradeName2 or other active substance or etc) near/15
ti,ab(adverse or allerg&2 or anomaly or causal or
carcinogen&5 or complication&1 or congenital or
contraindicat&4 or death&1 or mortality or mutagen&5 or
oncogen or overdos&3 or poison&3 or pregnan&2 or
reaction&1 or risk&1 or safe&1 or side or disabl&3 or
disability or failure or fatal&3 or iatrogen&2 or ineffective or
interact&3m or intoxicat&3 or "lack of efficacy" or lethal or
error&1 or misuse or morbidity or teratogen&5 or toxic&3 or
unexpected or unintended or unintentional or untoward or
unwanted or analyphyla&3 or interact&5 or overdos&3 or
intoxicat&3 or poison&3 or error&1 or "off label use")
Use of Search Limits
Should be relevant to the search criteria and purpose of
the search
Should be applied to produce results for date ranges
Should also retrieve all records added in that period, and
not just those initially entered or published during the
specified period
Use of publication type limits is not robust for the
detection of ICSRs, because an ICSR might be
presented within review articles or study publications that
are not usually indexed as case reports.
Examples of the relevance of
search limits in Literature
Screening

Reference: Pontes H, Clement M, Rollason V. Safety signal detection: the relevance

of literature review. Drug Saf. 2014 Jul;37(7):471-9.
Automated Methods
Use of literature search automated system that provides
Searches in relevant databases
Ability to set search limits, customize search strings and use free
text to find adverse effects
Email alerts
All results stored electronically.
The electronic text files of searches performed and the archive of
full text articles are readily available for internal or regulatory
inspection.
Examples include Elseviers Quosa, Infotrieve, Nerac,
EMA Medical Literature
Monitoring (MLM)
EMA Literature Monitoring
The agency decided to monitor a
range of substances including
herbals and the selection was
made based on being active
ingredients for products with high
numbers of MAHs in the EU
The total number of substance
groups to be included in the
literature-monitoring service is
depending on allocated budget.
The service was fully operational
as of 1 September 2015
The European Medicines Agency
(EMA) has outsourced the
monitoring of literature to a
service provider
Monitored list URL:
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/03/WC500163678.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/03/WC500163679.pdf
Key principles for why
EMA decided to
implement MLM
Alleviate the burden on maximum number of MAHs.

Innovative medicinal products should not be covered.

Avoid partial service that would necessitate

duplicative efforts by MAHs.

Provide quality controlled literature-monitoring

services.

Establish a process so that MAHs can comply with the

worldwide regulatory requirements.
Expected Benefits of the
EMA Literature Monitoring
The monitoring of medical literature and the entry of
relevant information into EudraVigilance will be carried
out by EMA in order to:
Enhance the efficiency of adverse reactions reporting;
Provide a simplification for the pharmaceutical industry;
Improve data quality by reducing the number of duplicates;
Contribute to resource savings for the pharmaceutical
industry;
Support signal detection activities by national competent
authorities and marketing-authorisation holders.

Website for list of EMA monitored products:

http://www.c3ihc.com/blog/monitoring-medical-literature-eu-
changes/
Which MAHs are going to
benefit?
The Agency defined a range of active substances
including herbal active substances contained in
medicinal products for which a high number of
marketing authorizations were granted to various
MAHs in the EEA
More than 3,500 MAHs in the EEA will benefit from
the MLM Service for the 300 substance groups
selected by the Agency
More than 640 MAHs in the EEA will benefit from the
MLM Service for the 100 herbal substance groups
selected by the Agency
The list of MAHs benefitting from the service will be
published on the EMA website
What databases are being used
by EMA for their Literature
Monitoring
Journal/Reference Databases that are monitored by
EMA
Embase - a large, comprehensive and widely
used, daily updated and indexed biomedical
reference database covering literature from EEA
and non-EEA countries
EBSCO - covering a wide variety of resources,
including Medline Plus, International
Pharmaceutical Abstracts (IPA) and The Allied
and the Complementary Medicine Database
(AMED)

The journals covered by the reference databases are further

described in the document Description of the MLM
Journal/Reference databases published at the EMA website
What specific types of safety
information are being sought for
MLM
The purpose of the screening, review and assessment
process is to identify valid Individual Case Safety Reports
(ICSRs) related to:
suspected adverse reactions originating from
spontaneous reports and solicited reports in humans;
special situations such as use of a medicinal product
during pregnancy or breastfeeding, use of a medicinal
product in a pediatric or elderly population, reports of off-
label use, misuse, abuse, overdose, medication errors
and occupational exposure with suspected adverse
reactions;
lack of therapeutic efficacy;
suspected adverse reactions related to quality defects or
falsified medicinal products;
suspected transmission via a medicinal product of an
infectious agent.
MLM Search String

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2
015/08/WC500191377.pdf
ICSR Workflow for MLM

http://www.ema.europa.eu/ema/index.jsp?curl=
pages/regulation/general/general_content_000
633.jsp
MLM : Pharmacovigilance
Dream or Nightmare?
MAH is fully responsible for executing literature
screening for ICSRs (Yellow and Green area).

MHA must report ICSRs detected on literature

from Yellow area.

MAH must not report ICSRs from Blue area.

MAH must incorporate the cases detected by

EMA from the Blue area in their safety
management systems.
Reference
MAH must report the ICSRs that have escaped
Elsevier
EMA (by screening the Green area) as QC
incidents, not as ICSRs.
Ways to avoid having a nightmare!
As soon as possible, find a way to detect your Yellow
area, and screen it while EMA is screening the Green
area.

Pay regular attention to the Blue area, i.e., those

references and sources that never crossed your radar. Do
the ICSRs matter? What does your Risk and Signal
Detection have to say about them?

Although MLM targets a very narrow set of generic

medicinal products, no drug exists isolated in its own
universe. Either as a concomitant drug, as part of a drug-
drug interaction or as an optional suspect drug, all MAHs
will, every once in a while, be referenced in the MLM
ICSR List.
ICSR Timelines
ICSRs are created within the following timelines:
Suspected serious adverse reactions originating from
the EEA or in third countries immediately and no
later than seven calendar days from day zero.
Non-serious adverse reactions originating from the
EEA within 21 calendar days from day zero.
The ICSRs related to serious and non-serious adverse
reactions are submitted within one calendar day to the
concerned NCA in accordance with the reporting
requirements of ICSRs as outlined in GVP Module VI
MAHs can access and download ICSRs from
EudraVigilance or a dedicated area of the EudraVigilance
website
Follow-up on ICSRs by the
Agency
In principle, one attempt to follow-up with the primary
author is made for suspected serious adverse reactions
based on a risk-based approach
Follow-up is pursued for those ICSRs where outcome is
unknown or important clinical information is missing
New information will be added in a follow-up ICSR
All attempts to obtain additional follow-up is documented
MLM website publishes date follow-up is initiated
EMA Fees associated with
literature monitoring

Reference:
http://www.ema.eu
ropa.eu/docs/en_G
B/document_librar
y/Other/2015/07/W
C500190190.pdf
MLM final thoughts..
The burden seems to be on the companies now to go the
site, probably every working day, as it would not be
advisable to have serious ICSRs available to the public
before the company.
Non-indexed local journals are excluded from the
Agency's monitoring activities and remain under the
responsibility of the MAHs.
What about disagreements on causal or expectedness?
Its not clear how the company will handle those cases
where they disagree with the causality and/or
expectedness.
It is also not clear whether the company can or should do
follow up on their own even if the EMA has already done
so.
Will the EMA update its database (EudraVigilance) with a
companys version?
It is possible two or more companies may do follow up in
addition to the EMA if both market the drug.
Challenges and Common
Inspection Findings
Of Literature Search and Review
LITERATURE:
Challenges in Screening &
Review of Articles
Ensuring that the search string is robust enough to
capture all relevant hits and not so overly inclusive
that you capture irrelevant information.
Data is often presented in tables, without identifiable
MSI (% of patients experienced [adverse event])
Case reports present the suspicion of the reporter;
often opinion based, not a proven association
Drug reactions may have confounding factors
(comorbid illness, patient population, concomitant
medications)
Drug reactions may be the result of patient non-
compliance, medication error, or other factors
 LITERATURE:
Challenges in Screening &
Review of Articles
Lack of population exposure data
Social Media Bias
Authors may have or not reported the case to the MAH or the
regulatory authority
Authors may have first published the single case report
followed by the publication of a case series
Authors may have presented the case in conferences and
thus the case was published as proceedings of the
conference followed by publications in a peer reviewed
journal
Authors may have published in local journals followed by
publication in a peer reviewed journal
Drug safety reviews may cross refer to the publications of
ICSRs or the same case may have been indexed in many
databases in a slightly different manner.
LITERATURE:
Challenges in Screening &
Review of Articles
Published reports have been submitted to a third-
party and might lack clarity with respect to drug-
event attribution (especially with study reports)
Published papers may not specifically describe or
discuss attribution- adverse events are mentioned
without much discussion
Spontaneous reports are prompted by a suspicion
of drug-related harm/injury (implied causality),
while publications containing adverse event data
cannot necessarily be categorized as having
presumed drug-causality

Reference: CIOMS V:
Common Regulatory Inspection
Findings Related to Literature
Inadequacies in the construction of, or process used for,
literature searching (sources used, adequacy of scope of
search with respect to search objective, local literature
scanning, language restrictions, lack of QC).
Not all relevant articles that had been newly distributed in
the database in the week of search had been identified
therefore articles were omitted from literature review
(MHRA finding).
Waiting to search the literature at data lock for PSUR
instead of searching proactively.
Failure to discuss in PSURs significant safety findings
(non-ICSRs) reported in published literature.
Lack of training to personnel involved in literature
searching.
Results of searches are not reproducible and tracked
Major audit findings by MHRA
(Apr 2014 Mar 2015)
In Summary.
Ensure you select the most relevant publication databases for
your product
Systematically monitor publications at a frequency consistent with
regulatory obligations.
Systemically monitor all active substances for which you hold MA
within the EU (where not listed by the EMA)
Monitor articles published locally in each territory where your
product is marketed
Route the results of this activity to the appropriate departments
within your company
Understand and comply with the time deadlines that apply to
ICSR Literature Screening even if a third party is completing
your screening
Avoid reporting duplicate ICSRs within literature
Describe and analyze any new and significant safety findings in
the medicinal products PSUR
Understand and comply with the requirement to immediately
notify regulators of new safety information from screening
Further Suggestions:
Anyone involved in literature searches for pharma
companies must pay careful attention to this as it evolves.
Study the relevant documents, read the SOPs, get into
EudraVigilance and understand what is happening.
See which of your drugs are covered and which are not. It is
not totally clear how/when they will add products. Check the
website every day!
Do not stop doing literature searches even if they seem to be
duplicative of the EMAs searches. See how this plays out
and see if both searches pick up the same cases or whether
some are missed. Compare your search strings to the
EMAs .
New SOPs and Work Instructions will be needed.
Figure out whether you need to keep doing searches for
other HAs (e.g. FDA).
Figure out your follow up strategy with the authors. Are you
willing to wait weeks or more for EMAs revised ICSRs after
follow up?
Elizabeth Garrard, PharmD
Garrard Safety Solutions
eegarrard@gmail.com
References
Regulation (EU) No 658/2014 of the European Parliament and of
the Council of 15 May 2014 on fees payable to the European
Medicines Agency for the conduct of pharmacovigilance activities
in respect of medicinal products for human use:
http://ec.europa.eu/health/files/eudralex/vol-
1/reg_2014_658/reg_2014_658_en.pdf
Regulation (EC) No 726/2004 of the European Parliament and of
the Council of 31 March 2004 laying down Community procedures
for the authorisation and supervision of medicinal products for
human and veterinary use and establishing a European Medicines
Agency:
http://ec.europa.eu/health/files/eudralex/vol-
1/reg_2004_726/reg_2004_726_en.pdf
Directive 2001/83/EC of the European Parliament and of the
Council 6 November 2001 on the community code relating to
medicinal products for human use:
http://ec.europa.eu/health/files/eudralex/vol-
1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf
References:
European Medicines Agency, Heads of Medicines Agencies.
Guideline on good pharmacovigilance practices (GVP): module
VImanagement and reporting of adverse reactions to
medicinal products.
European Medicines Agency, Heads of Medicines Agencies.
DRAFT detailed guide regarding the monitoring of medical
literature and the entry of relevant information into the
EudraVigilance database by the European Medicines Agency.
May 2014
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