literature monitoring for pv what are we doing at galderma elsevier webinar

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Leslie GALLO – PharmD Student – TraineeJean-Dominique PIERRET – PhD – Scientific Information Expert

Competitive & Scientific Intelligence

Literature monitoring for

Pharmacovigilance

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Weekly and Periodic monitorings

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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


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)


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


- 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


- 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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Sources of literature for pharmacovigilance

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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

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Comparison Embase/Medline

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• 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

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Comparison Embase/Medline : example

• PubMed

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• Embase

Loss of subheadings

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• Findings:


Embase.com




adverse effects.





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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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• PubMed

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• Embase

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• Findings:


Embase.com




adverse effects.





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• PubMed

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• Embase.com

False negative

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• Findings:


Embase.com




adverse effects.





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• Embase

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• Embase

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• Embase

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• PubMed

False positive

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• Findings:


Embase.com




adverse effects.




Conclusion: it would be more reliable to search for Medline articles on PubMed with the MeSH

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Literature monitoring process

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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

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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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EMA guidelines

(GVP)


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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EMA guidelines

(GVP)


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)

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- 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

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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

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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)

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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

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Thank you for your attention!

literature monitoring for pv what are we doing at galderma elsevier webinar

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