literature monitoring for pv what are we doing at galderma elsevier webinar
TRANSCRIPT
1 / CONFIDENTIAL
Leslie GALLO – PharmD Student – TraineeJean-Dominique PIERRET – PhD – Scientific Information Expert
Competitive & Scientific Intelligence
Literature monitoring for
Pharmacovigilance
3 / CONFIDENTIAL
Weekly monitoring: Individual case safety report
• The reporting of an adverse reaction requires 4 criteria :
At least one
identifiable reporterOne single identifiable
patientAt least one suspect
medicinal product
At least one suspect
adverse reaction
Day zero is the date on which the applicant or its foreign affiliate
has received the 4 basic elements.
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Regulatory requirements for the weekly monitoring
ICH EMA FDA
Guideline ICH E2D Module VI of GVP 21CFR314.80
Monitoring frequency At least every 2 weeks Weekly Not specified
Where to look? Widely used systematic
literature reviews or
reference databases
Systematic literature
review of two widely
used reference
databases that contain
the largest number of
articles in relation to the
medicinal product
properties
Applicants can use
literature search services
(ex : Weekly Reactions)
Submission criteria - The product of the
applicant is clearly
suspected
- The product source,
brand, or trade name is
not specified
- If multiple products are
mentioned in the article,
a report should be
submitted only by the
applicant whose product
is suspected.
- The product of the
applicant is clearly
suspected
- The product source,
brand, or trade name is
not specified
- If multiple products are
mentioned in the article,
a report should be
submitted only by the
applicant whose product
is suspected.
- Same active substance as a
product marketed in the US
(even if the excipient,
dosage forms, strengths,
routes of administraction,
and indications vary)
- If multiple products are
mentioned in the article, a
report should be submitted
only by the applicant whose
product is suspected.
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Regulatory requirements for the weekly monitoring
ICH EMA FDA
Exclusions Brand or trade name of
another company can
exclude
- Brand or trade name of another
company can exclude
- The ICSR originates in a country where
the company holds a marketing
autorisation but has never
commercialised the product
- Literature ICSRs based on an analysis
from a competent authority database
or from publicly available databases
- Literature articles which summarise
results from post-autorisation studies
Brand or trade name of
another company can
exclude
Local monitoring Subsidiaries
Comments « There is no acceptable loss of recall
when searching published literature for
pharmacovigilance. » (Module VI – GVP
EMA)
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Periodic monitoring: DSUR
• DSUR = Development Safety Update Report
- Annual reporting on drugs under development
- Review and evaluation of pertinent safety information collected during the
reporting period
- Examines if the new safety information is in line with previous knowledge
• Contribution of the literature
- New and significant safety finding during the reporting period
- Non-clinical and clinical studies
- + information on drugs of the same class if relevant
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Periodic monitoring: PBRER
• PBRER = Periodic Benefit-Risk Evaluation Report
- Annual periodic report on marketed products
- Objective: enable an appraisal of the product’s benefit-risk profile by analyzing:
New safety information that could have an impact on the benefit-risk profile
(and if so, conduct an integrated B-R evaluation for approved indications)
New efficacy information
- Examines if the new safety information is in line with previous knowledge
• Contribution of the literature
- New and significant safety finding during the reporting period
- Non-clinical and clinical studies
- Wider than searches for ICSRs : studies reporting, safety outcomes in groups of
subjects…
- + information on drugs of the same class if relevant
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Periodic monitoring: NDA Annual Report Bibliography
• New Drug Application Annual Report
- Submission to the FDA within 60 days of the anniversary date of US approval of the application
- Includes:
A brief summary of significant new information from the previous year that might affect the safety,
effectiveness, or labeling of the drug product
Currently used labeling for patients and professionnals
Distribution data and authorized generic drugs
Chemistry, manufacturing and controls changes
Nonclinical laboratory studies
Clinical data
• Contribution of the literature
- Clinical information (any indications):
• Safety and effectiveness, clinical trials, clinical trial on new uses
• Biopharmaceutic, pharmacokinetic, clinical pharmacology studies;
• Epidemiologic studies or analyses of experience in a monitored serie of patients
- Nonclinical information: published reports of new toxicological findings in animal studies and in vitro
studies
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Where to look for relevant articles for pharmacovigilance?
• EMA guidelines: at least 2 databases must be searched
• Databases used by the Galderma’s Competitive and Scientific Intelligence
service:
Embase.com
Which includes the references from:
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Medline/Embase
Database Medline Embase
Focus Biomedicine and healthBroad biomedical scope with in-depth coverage of
drugs and pharmacology
Date of creation 1879 1947
Time coverage 1946 to the present 1947 to the present
Produced by US National Library of Medicine Elsevier (Netherlands)
Access Available free of charge via PubMed Through institutional subscription
Content
Journal articles, mostly from peer-reviewed
journals
Journal articles, mostly from peer-reviewed journals
+ conference abstracts since 2009
Number of records Over 23 million records from 5600 journals
published in 70 countries in about 40
languages
Over 21 million records from 6100 journals
published in 70 countries in about 40 languages.
Embase.com includes all Medline records and
reaches 32 million records from 8517 journals.
Updates Daily from Tuesday to Saturday (2000-4000
records per update)
Daily from Tuesday to Saturday (6000 records per
update)
Thesaurus MeSH Emtree
Uses
- For clinical queries and biological,
genetics topics
- Similar articles are suggested (formerly
« related articles »)
- For easy keyword search
- For drug/pharmacy topics (coverage plus
subheading options)
- To pick up recent articles and conference papers
- For great basic, natural language search
- Allows proximity operators
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A focus on Embase
• Content
- In-depth coverage of pharmacology, toxicology, pharmaceutical
science and clinical research
• Geographic coverage
- More European journals are indexed
- A special attention is given to journals published outside
the main area (USA, Canada and Western Europe)
- But Medline has more journals indexed from the USA than Embase
• Conference abstracts
- Added on Embase, nonexistent on Medline
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MeSH / Emtree : key figures
Thesaurus MeSH Emtree
Database Medline Embase
Number of terms 27,883 73,000 (of which more than 30,000 are drugs
and chemicals)
Number of terms per
article
10-20 3-4 major terms, and up to 50 minor terms
_______
Medline-derived articles are not directly
indexed with Emtree terms. However MeSH
terms are mapped to Emtree terms to provide
indexing compatible with Embase indexing.
Description of terms Most terms come with a short
description or definition.
No definitions used for indexing because
according to Elsevier, « natural language
terminology means that you don’t need to
know « how » terms are defined in Emtree ».
However, Emtree contains definitions from
Dorlands dictionary for most of terms.
Synonyms 213 000 310 000 (including over 190 000 drug
synonyms)
Supplementary concept
record
232 000 0
Updates Once per year Three times per year
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MeSH / Emtree : indexing process
Medline/MeSH Embase/Emtree
Automatic indexing Nonexistent Since 2009, 3 types of articles are indexed
automatically:
- Conference abstracts
- Articles in Press
- In-Process records
Manual indexing - Federal employees or employees of
firms that have contracts with NLM
for biomedical indexing.
- An indexer must have no less than a
bachelor's degree in a biomedical
science.
- Performed by trained indexers with a
biomedical background.
- Indexers read and analyze the full text of
articles in order to identify relevant concepts,
and index them with the most specific Emtree
terms
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A focus on Emtree
Strength Weakness
Extensive pharmaceutical coverage:
- Drugs: Emtree includes chemical names, trade
names, and laboratory/research codes as well as
generic names for more than 31,000 drugs and
chemicals, including all generic names recognised by
FDA, EMA and WHO (from 2000)
- Medical devices: over 3000 specific terms
- Large number of drug subheadings (64), including
47 routes of drug administration
For each new modified descriptor: no history of
previous indexing of this concept
- The history of a term before coming to the actual
term is unknown.
It can be problematic to find old articles if the
way of indexing before is unknown.
Scopes notes seem to be less systematic than in the
MeSH
Limited use of subheadings
- The subheadings cannot be used for every kind of
descriptors. Subheadings can qualify drugs, diseases
or medical devices only, contrary to the MeSH with
which the descriptors can almost always be
associated to subheadings
17 / CONFIDENTIAL
Comparison Embase/Medline
• Several tests performed on Embase.com and PubMed
• Problematic: shall we search for Medline articles on PubMed with the MeSH or can we keep
searching for Medline articles on Embase.com with the Emtree?
• Findings:
1. Loss of subheadings during the automatic mapping of articles from Medline on
Embase.com
2. The use of some terms differs between the MeSH and the Emtree
3. False negatives on Embase.com
- Some articles weren’t indexed with adverse effects terms whereas the articles were about
adverse effects.
4. False positives on PubMed
- Some drugs were indexed with the « adverse drug reaction » subheading whereas the article did
not mention any adverse event caused by the drug in question.
Conclusion : it would be more reliable to search for Medline on PubMed with the MeSH
20 / CONFIDENTIAL
Comparison Embase/Medline : example
• Several tests performed on Embase.com and PubMed
• Problematic: shall we search for Medline articles on PubMed with the MeSH or can we keep
searching for Medline articles on Embase.com with the Emtree?
• Findings:
1. Loss of subheadings during the automatic mapping of articles from Medline on
Embase.com
2. The use of some terms differs between the MeSH and the Emtree
3. False negatives on Embase.com
- Some articles weren’t indexed with adverse effects terms whereas the articles were about
adverse effects.
4. False positives on PubMed
- Some drugs were indexed with the « adverse drug reaction » subheading whereas the article did
not mention any adverse event caused by the drug in question.
Conclusion : it would be more reliable to search for Medline on PubMed with the MeSH
21 / CONFIDENTIAL
Comparison Embase/Medline
Subheading Emtree definition MeSH definition
« Adverse effects » dd_ae: “Adverse drug reaction” :
Used as a drug subheading to identify a
drug for which an undesired side effect is
reported (when used at therapeutic dose
ranges in humans)
AE : Used with drugs, chemicals, or biological agents in
accepted dosage - or with physical agents or manufactured
products in normal usage - when intended for diagnostic,
therapeutic, prophylactic, or anesthetic purposes.
It is used also for adverse effects or complications of
diagnostic, therapeutic, prophylactic, anesthetic, surgical, or
other procedures, but excludes contraindications for which
"contraindications" is used.
« Toxicity » dd_to: “Drug toxicity” :
Used as a drug subheading to identify a
drug or chemical that is toxic in animals
(including LD50 tests), in animal or human
cells and tissues, and in other toxicity
studies.
In humans, used to signal toxicity at non-
therapeutic dose ranges, or when lasting
damage is caused at therapeutic dose
ranges.
TO : Used with drugs and chemicals for experimental human
and animal studies of their ill effects. It includes studies to
determine the margin of safety or the reactions
accompanying administration at various dose levels. It is
used also for exposure to environmental agents. Poisoning
should be considered for life-threatening exposure to
environmental agents.
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Comparison Embase/Medline
• Several tests performed on Embase.com and PubMed
• Problematic: shall we search for Medline articles on PubMed with the MeSH or can we keep
searching for Medline articles on Embase.com with the Emtree?
• Findings:
1. Loss of subheadings during the automatic mapping of articles from Medline on
Embase.com
2. The use of some terms differs between the MeSH and the Emtree
3. False negatives on Embase.com
- Some articles weren’t indexed with adverse effects terms whereas the articles were about
adverse effects.
4. False positives on PubMed
- Some drugs were indexed with the « adverse drug reaction » subheading whereas the article did
not mention any adverse event caused by the drug in question.
Conclusion : it would be more reliable to search for Medline on PubMed with the MeSH
27 / CONFIDENTIAL
Comparison Embase/Medline
• Several tests performed on Embase.com and PubMed
• Problematic: shall we search for Medline articles on PubMed with the MeSH or can we keep
searching for Medline articles on Embase.com with the Emtree?
• Findings:
1. Loss of subheadings during the automatic mapping of articles from Medline on
Embase.com
2. The use of some terms differs between the MeSH and the Emtree
3. False negatives on Embase.com
- Some articles weren’t indexed with adverse effects terms whereas the articles were about
adverse effects.
4. False positives on PubMed
- Some drugs were indexed with the « adverse drug reaction » subheading whereas the article did
not mention any adverse event caused by the drug in question.
Conclusion : it would be more reliable to search for Medline on PubMed with the MeSH
32 / CONFIDENTIAL
Comparison Embase/Medline
• Several tests performed on Embase.com and PubMed
• Problematic: shall we search for Medline articles on PubMed with the MeSH or can we keep
searching for Medline articles on Embase.com with the Emtree?
• Findings:
1. Loss of subheadings during the automatic mapping of articles from Medline on
Embase.com
2. The use of some terms differs between the MeSH and the Emtree
3. False negatives on Embase.com
- Some articles weren’t indexed with adverse effects terms whereas the articles were about
adverse effects.
4. False positives on PubMed
- Some drugs were indexed with the « adverse drug reaction » subheading whereas the article did
not mention any adverse event caused by the drug in question.
Conclusion: it would be more reliable to search for Medline articles on PubMed with the MeSH
34 / CONFIDENTIAL
Weekly literature monitoring
• Search strategy for the weekly monitoring:
- INN (free-text + corresponding Emtree term)
- Brand names and trade names in all languages (free-text)
+ Pre-selection:
- Active ingredient corresponding
- Galenic form corresponding
- Human
35 / CONFIDENTIAL
Periodic literature monitoring
• Search strategy for the periodic monitoring:
1. Safety query: ‘product’/exp/dd_ae,dd_to
‘drug class’/exp/dd_ae,dd_to
2. Interactions query: ‘product’/dd_it
‘drug class’/dd_it
3. Benefit-risk query: product query AND benefit-risk query
drug class query AND benefit-risk query
Bold = suggestions for additions
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Periodic literature monitoring SOP
• Search strategy for the periodic monitoring :
- Benefit-risk query (1) :
EMA guidelines
(GVP)
Concepts Terms currently used in the query Terms that could be added
Generalities General terms on the
benefit/risk
Risk benefit analysis
Drug surveillance program
Pharmacoepidemiology
Treatment effect Therapy effect
Drug effect
Treatment outcome
Benefit Efficacy Clinical effectiveness
Patient satisfaction
Risk Inefficacy Treatment failure Drug substitution
Drug withdrawal
Drug resistance
Free-text :
Ineff*
Lack of efficacy
Drug effect decreased
Nonresponse, unresponse
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Periodic literature monitoring SOP
• Search strategy for the periodic monitoring :
- Benefit-risk query (2) :
EMA guidelines
(GVP)
Concepts Terms currently used in the query Terms that could be added
Risk Adverse effect Adverse drug reaction
Side effect OR ‘Side effect’/lnk
Risk/safety data Risk
Safety
Drug safety
Risk assessment
Patient safety
Iatrogenic disease
Intoxication, toxicity and
fatality
Drug toxicity and intoxication
(this term includes « drug fatality,
« drug intoxication » and « drug
toxicity »)
Death
Suicide
Abuse Drug abuse
Drug overdose
Medication error Medication error
Misuse Drug misuse
Hypersensitivity Drug hypersensitivity
Tolerance Drug tolerance Drug tolerability
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Periodic literature monitoring SOP
• Search strategy for the periodic monitoring :
- Benefit-risk query (3) :
EMA guidelines
(GVP)
Concepts Terms currently used in the query Terms that could be added
Interaction Drug interaction
Clinical studies (with
a number of
subjects high
enough)
Major clinical study
Multicenter study
Off-label use Off label drug use Case report (may be very broad)
Particular
populations
Pregnant women Pregnancy
Drug exposure
Pregnancy outcome
Pregnancy disorder
Lactation
Breast feeding
(Compassionate use) (Not useful for current Galderma products) (compassionate use)
39 / CONFIDENTIAL
Periodic literature monitoring SOP
• Search strategy for the periodic monitoring :
- Benefit-risk query : 'risk benefit analysis'/de OR 'drug surveillance program’/exp OR
'pharmacoepidemiology'/exp OR 'therapy effect'/exp OR 'drug effect'/exp OR
'treatment outcome'/exp OR 'patient satisfaction'/exp OR 'clinical effectiveness'/exp
OR ‘adverse drug reaction’/exp OR ‘side effect’/exp OR ‘side effect’/lnk OR 'treatment
failure'/exp OR 'drug substitution'/exp OR ‘drug withdrawal’/exp OR ‘drug
resistance’/exp OR ineff* OR ‘lack of efficacy’ OR nonresponse OR ‘non response’ OR
‘no response’ OR unresponse OR ‘drug effect decreased’/exp OR 'risk'/exp OR
'safety'/de OR 'drug safety'/de OR 'risk assessment'/de OR ‘patient safety’/exp OR
‘iatrogenic disease’/exp OR 'drug toxicity and intoxication'/exp OR 'death'/exp OR
'suicide'/exp OR 'drug abuse'/exp OR 'drug overdose'/exp OR 'withdrawal
syndrome'/exp OR 'vitamin D intoxication'/exp OR ‘retinol intoxication’/exp OR
'toxic epidermal necrolysis'/exp OR 'toxicity'/exp OR 'medication error'/exp OR ‘drug
misuse’/exp OR 'drug hypersensitivity'/exp OR 'drug tolerance'/exp OR ‘drug
tolerability’/exp OR ‘drug interaction’/exp OR ‘major clinical study’/exp OR
‘multicenter study’/exp OR 'case report'/exp OR 'off label drug use'/exp OR
'pregnancy'/exp OR 'drug exposure'/exp OR 'pregnancy outcome'/exp OR ‘pregnancy
disorder'/exp OR 'lactation'/exp OR 'breast feeding'/exp
Bold = suggestions for additions
40 / CONFIDENTIAL
Periodic literature monitoring
• Search strategy for the periodic monitoring:
- Benefit-risk query: tests were performed to evaluate the new query
• The new query was tested in association to the adapalene query
• Old query: 825 results ; New query: 1,100 results (+25%)
• Analyze of the relevance of the articles found with the new query:
Among the 275 articles found with the new query and that were not found with the old
query, 67% of the articles are relevant for the benefit/risk assessment
8%
17%
34%4%
4%
29%
4%
Pediatric population
Clinical study
Off-label use
Interaction
Inefficacy
Not pertinent for the B/R
General article
41 / CONFIDENTIAL
Free-text/thesaurus
• Problematic: Would it be useful to search for the keywords in free-text, in
addition to the descriptors corresponding to the keywords on the thesaurus?
The tests performed showed that the search with free-text was not useful
(noise). Keep in mind that we gather the literature twice: once during the
weekly monitoring and once during the periodic monitoring.
• The free-text is only useful when the concept does not exist in the thesaurus
(example: « lack of efficacy » can be used with free-text)
42 / CONFIDENTIAL
Quality key elements to document
• Useful for the weekly monitoring: - List of products to monitor and associated queries- Changements tracking with :• Modification type (addition/modification/withdrawal)• Date of request• Date of implementation• New query
• Execution of the weekly or periodic literature monitoring: - Type of request (weekly monitoring/DSUR/PSUR/PBRER)- Reference of the search- Date of execution- Name of the documentalist who performed the monitoring- Period covered by the search- Queries used- Number of results found (including the products for which 0 result was found)*- Number of results kept
*for the weekly search only