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Unpublished manuscripts involving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 (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.

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 (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:

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

(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:

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:

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:

FDA EMA CIOMS ICH

Frequency Not identified Weekly Monthly Bi-weekly

Literature ‘scientific

literature’

‘scientific and

medical literature’

CIOMS discusses

all terms used by

RAs- ‘worldwide’,

‘scientific/medical’

, and literature

‘worldwide’

Attribution/

Causality

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.

only those which

are identified by

the publication’s

author(s) as

having at least a

possible causal

relationship with

the suspected

adverse reaction

…positive

attribution by

either the author

or company and/

or regulator

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.

Reporting Serious/

Unexpected only

Serious & Non-

serious

Discusses

expedited

reporting

Regulatory clock

starts when MSI

are identified

Exclusions All active moiety

(no exclusions)

Exclusions apply

(see Guideline)

Brand or trade

name can

exclude

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?

Setting up an effective search strategy that can increase

the potential for detecting a safety concern early.

Methods and Search

Strategies

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 Elsevier’s 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.

• MAH must report the ICSRs that have escaped

EMA (by screening the Green area) as QC

incidents, not as ICSRs.

Reference

Elsevier

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

MAH’s 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 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

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.

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-ICSR’s) 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 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?

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 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.

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

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