Literature Surveillance in Pharmacovigilance; Current Trends, Methods and Challenges Please join Elizabeth E. Garrard, PharmD, founder and CEO of Garrard Safety Solutions, as she reviews key issues in literature surveillance for Pharmacovigilance. Objectives: • Understand the regulatory obligations, best sources and procedures for conducting literature surveillance. • Appreciate some examples of when a safety signal was detected in the literature and its impact on the lifecycle of a drug. • Understand when to start and where to look for emerging safety information. • Setting up your search strategy, how to ensure your search strings are well balanced, recognizing the challenges between precision and sensitivity. • What is the impact of the new literature monitoring by EMA of a number of substances in selected medical literature to identify suspected adverse reactions with medicines authorized in the European Union. Early insights into successes and issues. • Discuss current methods that can increase the likelihood of early detection of a safety issue and minimize the issues surrounding. • Realize the challenges we face including wide differences in quality, accuracy, and completeness in the scientific literature and how best to navigate these differences and maintain proper vigilance.

1. Literature Surveillance in
Pharmacovigilance:
Current Trends, Methods
and Challenges
 Elizabeth Garrard, PharmD.
 Garrard Safety Solutions
CEO and Founder
 Pharmacovigilance Consultant

2. 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.

3. 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.

4. 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

5. 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.

6. Literature volume keeps growing…...
Zhiyong Lu Database 2011;2011:baq036
© The Author(s) 2011. Published by Oxford University Press.

7. Literature is but one of many
sources of information…..

8. Understanding the
Regulatory Obligations
Literature Searches in Pharmacovigilance

9. 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.

10. 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.

11. LITERATURE:
ICH E2D (con’t)
3.1.2 Literature (cont’d)
 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.

12. 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:

13. Literature: FDA (con’t)
“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 reports…Applicants 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 article’s author and
is usually mentioned in the article’s 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:

14. 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:

15. LITERATURE:Health Canada
(con’t)
“For foreign literature reports, all foreign serious,
unexpected ARs involving the MAH’s 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:

16. 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 publication’s 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:

17. 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:

18. 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:

20. 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.

21. 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

22. 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.

23. 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

24. 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

25. Literature searching: When
to start and where to look?

26. 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.

27. 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

28. Where to look?
 Well recognized scientific and medical
journals
 Embase
 Medline
 Excerpta Media
 International symposia or local journals
 Abstracts from meetings and draft
manuscripts

29. 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

30. Considerations when choosing
relevant Databases
 Accessibility
 Not all free; costs can be
high
 Coverage
 Worldwide or not
 Focus
 Orientated towards particular
medical discipline
 Overlap

31. 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?

32. Setting up an effective search strategy that can increase
the potential for detecting a safety concern early.
Methods and Search
Strategies

33. 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

34. 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

35. 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

36. 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.

37. 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

38. 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

39. 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")

40. 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’.

41. 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.

42. 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 Elsevier’s Quosa, Infotrieve, Nerac,

43. EMA Medical Literature
Monitoring (MLM)

44. 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

45. 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.

46. 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/

47. 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

48. 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

49. 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.

50. MLM Search String
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2
015/08/WC500191377.pdf

51. ICSR Workflow for MLM
http://www.ema.europa.eu/ema/index.jsp?curl=
pages/regulation/general/general_content_000
633.jsp

52. 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.
• MAH must report the ICSRs that have escaped
EMA (by screening the Green area) as QC
incidents, not as ICSRs.
Reference
Elsevier

53. 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.

54. 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
 MAH’s can access and download ICSRs from
EudraVigilance or a dedicated area of the EudraVigilance
website

55. 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

56. EMA Fee’s associated with
literature monitoring
Reference:
http://www.ema.eu
ropa.eu/docs/en_G
B/document_librar
y/Other/2015/07/W
C500190190.pdf

57. 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?
It’s 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
company’s version?
 It is possible two or more companies may do follow up in
addition to the EMA if both market the drug.

58. Challenges and Common
Inspection Findings
Of Literature Search and Review

59. 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

60. 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.

61. 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:

62. 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-ICSR’s) reported in published literature.
 Lack of training to personnel involved in literature
searching.
 Results of searches are not reproducible and tracked

63. Major audit findings by MHRA
(Apr 2014 – Mar 2015)

64. 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

65. 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 EMA’s 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
EMA’s .
 New SOPs and Work Instructions will be needed.
 Figure out whether you need to keep doing searches for
other HA’s (e.g. FDA).
 Figure out your follow up strategy with the authors. Are you
willing to wait weeks or more for EMA’s revised ICSRs after
follow up?

66. Elizabeth Garrard, PharmD
Garrard Safety Solutions
eegarrard@gmail.com

67. 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

68. References:
 European Medicines Agency, Heads of Medicines Agencies.
Guideline on good pharmacovigilance practices (GVP): module
VI—management 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
 US Food and Drug Administration. 21CFR314.80- Postmarketing
reporting of adverse drug experiences.
 US Food and Drug Administration. DRAFT Guidance for
Industry: Postmarketing Safety Reporting for Human Drug and
Biological Products Including Vaccines, March 2001
 Council for International Organizations of Medical Sciences
(CIOMS), Working Group V:Current Challenges in
Pharmacovigilance: Pragmatic Approaches
 Health Canada. Guidance Document for Industry- Reporting
Adverse Reactions to Marketed Health Products.

69. References:
Pontes H, Clement M, Rollason V. Safety signal
detection: the relevance of literature review. Drug
Saf. 2014 Jul;37(7):471-9.
Ross S. Drug -related adverse events: A readers’
guide to assessing literature reviews and meta-
analyses. Arch Int Med. 2001. 161: 1041-45.
Shetty KD, Dalal SR. Using information mining of
the medical literature to improve drug safety. J Am
Med Inform Assoc. 2011; 18: 668-674

70. Database Sources

71. Database sources (con’t)

72. Database sources (con’t)

73. Database sources (con’t)

74. |
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