This document discusses using literature databases like Embase to conduct post-authorization safety studies (PASS) through systematic literature reviews and meta-analyses. It provides an example PASS on the drug brentuximab vedotin that identified adverse events like peripheral neuropathy and infections. The document reviews how to structure a literature search using the PICO framework and Embase's in-depth indexing of concepts, relationships, and causality to comprehensively identify safety outcomes reported for a drug.

1. 1
Searching literature databases
for Post-authorisation Safety
Studies
Presented by:
Dr. Joyce de Langen
Sr Solution Manager Pharmacovigilance
Dr. Ivan Krstic
Sr Product Development Manager, Embase
Elsevier Life Sciences
Date: 15th of June 2016

2. 2
Agenda
Part I – Post-authorisation Safety Study (PASS)
– Definition and Key Objectives
– Systematic literature review and Meta-analysis as PASS
Part II – Example of PASS
Part III - Literature search for a literature PASS using Embase

3. 3
Agenda
Part I – Post-authorisation Safety Study (PASS)
– Definition and Key Objectives
– Systematic literature review and Meta-analysis as PASS
Part II – Example of PASS
Part III - Literature search for a literature PASS using Embase

4. 4
What is a PASS?
A post-authorization safety study (PASS) is any study related to an
authorized medicinal product which is conducted with the aim of:
 Identifying, characterizing or quantifying a safety hazard
 Confirming the safety profile of the medicinal product
 Measuring the effectiveness of risk management measures
PASS may be started, managed or financed by a marketing
authorization holder (MAH) voluntarily, or pursuant to an obligation
imposed by a competent authority.

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PASS
GVP Module VIII (rev 1) concerns PASS which are clinical trials and
non-interventional studies
PASS is non-interventional when:
 Medicinal product is prescribed in accordance with marketing
authorization terms
 Assignment of patient to a particular therapeutic treatment falls within
current practice
 Prescription of medicinal product is independent from the inclusion
 No additional diagnostic or monitoring procedures are applied to
patients
 Epidemiological methods are used for the analysis of the collected data

6. 6
Non-interventional PASS
Design: Primary Data
Collection
 Prospective observational
studies
 Registries
Design: Use of Secondary
data
 Case-control studies
 Cross-sectional
 Cohort
 Other

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Key Principles of PASS
• Quantify potential or identify risk
• Evaluate risks of medicinal product used in specific patient
population
• Evaluate risks of medicinal products after long-term use
• To provide evidence about the absence of risks
• To assess patterns of drug utilisation
• To measure effectiveness of risk minimisation measures

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ENCePP – European Network Centres for
Pharmacoepidemiology and Pharmacovigilance
• GVP guidelines recommend study registration and protocol posting before
start of data collection
• The legislation requires that protocols and abstracts of results of PASS
imposed as an obligation are published in a publicly available register
• Registration for imposed studies
must be made no later than at the
time of the final study report
• Final report of imposed studies
must provide the date of
registration in the register
• For non imposed studies, no legal
obligation to register but
recommended http://www.encepp.eu/encepp_studies/indexRegister.shtml

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Systematic literature review and Meta-analysis as PASS
Systematic Review
A comprehensive collation of primary research studies with explicit objectives and
methods, and conducted according to explicit and reproducible methods.
Meta-analysis
The quantitative synthesis of the data within the studies of a systematic review
Whereas the PASS design should be appropriate to address the
study objective does not depend on the type of design if it fulfils the
criteria.
Systematic literature review or a meta-analysis may be
considered as PASS depending on their aim.
GVP-Module VIII Post-authorisation Safety Studies

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Systematic literature review and Meta-analysis as PASS
Particularly Useful to quantify the risk for
– Non-common serious adverse events (SAE)
– Small or moderate relative risk increase of an SAE
– Specific Subgroups of patients
– Class effects

11. 11
Agenda
Part I – Post-authorisation Safety Study (PASS)
– Definition and Key Objectives
– Systematic Literature and Meta-analysis as PASS
Part II – Example of PASS
Part III - Literature search for a literature PASS using Embase

12. 12
Example of a post-authorisation observational safety study
Post-authorisation observational safety study of brentuximab vedotin in
relapsed/refractory hodgkin lymphoma and systemic anaplastic large cell
lymphoma: Arroven study
Linton K., Ayto R., D'Amore F., Moestl M., Chau I., Paneesha S., Kinley J., Huebner D., Porter J.,
Exter B., Wang B., Tymoszczuk J., Arumainathan A.
Hematological Oncology 2015
Introduction:
Brentuximab vedotin has conditional approval in Europe (October 2012) for adult patients
with:
• (relapsed/refractory (R/R) CD30+) Hodgkin lymphoma (HL) or
• (systemic) anaplastic large cell lymphoma (sALCL)

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Post-authorisation observational safety study of brentuximab vedotin
in relapsed/refractory hodgkin lymphoma and systemic anaplastic large
cell lymphoma: Arroven study
ARROVEN is an ongoing, multi-centre, post-authorisation safety study required by the
European Medicines Agency to further evaluate brentuximab vedotin's safety profile in a
real-world patient population.

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Post-authorisation observational safety study of brentuximab vedotin
in relapsed/refractory hodgkin lymphoma and systemic anaplastic large
cell lymphoma: Arroven study
Methods: The objectives of ARROVEN are to evaluate the occurrence of serious adverse
events (SAEs) and AEs of special interest considered related to brentuximab vedotin:
• peripheral neuropathy,
• neutropenia,
• infections,
• hyperglycaemia, and
• hypersensitivity reactions.

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Post-authorisation observational safety study of brentuximab vedotin
in relapsed/refractory hodgkin lymphoma and systemic anaplastic large
cell lymphoma: Arroven study
Results:
Between June 2013 and January 2015, 62 patients received a median of 4 treatment
cycles (range 1-12).
AEs were reported in 45 patients, the most common (n ≥ 4) included:
• peripheral neuropathy (n = 18),
• infections (n = 14),
• neutropenia (n = 13),
• hypersensitivity reactions (n = 4), and
• lethargy (n = 4).
No hyperglycaemia events were reported.

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Post-authorisation observational safety study of brentuximab vedotin
in relapsed/refractory hodgkin lymphoma and systemic anaplastic large
cell lymphoma: Arroven study
Results (continuation):
Twenty-one patients had SAEs, including 11 with drug-related SAEs; the most common (n ≥
2) were
• infection (n = 9) and
• peripheral neuropathy (n = 4).
No cases of progressive multifocal leukoencephalopathy, Stevens-Johnson syndrome, toxic
epidermal necrolysis or acute pancreatitis were reported.

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Post-authorisation observational safety study of brentuximab vedotin
in relapsed/refractory hodgkin lymphoma and systemic anaplastic large
cell lymphoma: Arroven study
Conclusions:
These data indicate brentuximab vedotin is associated with a manageable safety profile
in the conditionally approved indications.
The severity and frequency of toxicities observed are consistent with the known safety
profile and pivotal phase 2 studies of brentuximab vedotin.
ARROVEN is ongoing.

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Systematic literature review

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What are Systematic Reviews?
Finding the best evidence
High-level overviews of
primary research on a
particular research question
that tries to
• identify,
• select,
• synthesize and
• appraise
all high-quality research
evidence relevant to that
question in order to answer it.

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Preparing a Systematic Review
The Cochrane Handbook outlines eight general steps for preparing a
systematic review:
1. Defining the review question(s) and developing criteria for including studies
2. Searching for studies
3. Selecting studies and collecting data
4. Assessing risk of bias in included studies
5. Analyzing data and undertaking meta-analyses
6. Addressing reporting biases
7. Presenting results and "summary of findings" tables
8. Interpreting results and drawing conclusions

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How does Embase support SRs/EBM?
Embase is recommended by the Cochrane Collaboration as a key international general
healthcare databases to use — a search of MEDLINE alone is not considered adequate.
Embase − Over 8,600 Journals
Embase
MEDLINE
• Indexing of trial- and study types, reviews
and meta-analysis
• Selection based on abstract and index
terms and dozens of filters
• Ability to save, share and edit complex
search strategies with a group
• +6,500 conferences covered
• Unique coverage of non-English RCTs
2,800 journals not available
on MEDLINE

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Using the PICO Framework to Structure a Question
P = Patient
I = Intervention
C = Comparison/control
O = Outcome
PICO is a method used to structure the elements (concepts) of the review question
into a search strategy and process. Goal is as high recall as possible.

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P (Patient, Problem or Population)
A generic formula for this search strategy is:
1. Disease Emtree term
‘name of the disease’/de
2. Disease term as free text search
‘name of the disease’ OR ‘synonyms for the disease’
3. #1 OR #2

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I (Intervention)
A generic formula for this search strategy is:
1. Drug Emtree term
‘name of the drug’/de
2. Drug term as free text search
‘name of the drug’ OR ‘synonyms for the drug’
3. #1 OR #2

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C (Comparison or Control)
The aspects of this concept may include absence of risk or treatment,
placebo or alternative therapy. This component may not apply to all
review questions.

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O (Outcome)
The aspects of this concept may include risk, mortality, morbidity,
quality of life and utilities, in our case it will be occurrence of
adverse events.
Sometimes this component is not searchable and/or it is advisable to
ignore it in the search process.

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PICO - Logical Operators
Use the Boolean OR operator to search the relationship within each
individual concept.
The formula for using AND Boolean logical operators to search the
relationship between the concepts is:
P-elements
AND
I-elements
AND
C-elements
AND
O-elements
27

28. 28
PICO search for high recall

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Setting the stage: Patient and Intervention
Safety profile of
brentuximab
vedotin
in
hodgkin
lymphoma
and
anaplastic large
cell lymphoma

30. 30
Post-authorisation observational safety study of
brentuximab vedotin in relapsed/refractory hodgkin
lymphoma and systemic anaplastic large cell lymphoma:
Arroven study
Results:
AEs were reported in 45 patients, the most common (n ≥ 4) included:
• peripheral neuropathy (n = 18)
• infections (n = 14)
• neutropenia (n = 13)
• hypersensitivity reactions (n = 4)
No hyperglycaemia events were reported.
Embase: let’s look for those outcomes.

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Outcome: occurrence of neutropenia (adverse drug
reaction)

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Outcome: occurrence of infections (adverse drug reaction)

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Outcome: occurrence of hypersensitivity (adverse drug
reaction)

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Outcome: occurrence of hyperglycaemia (adverse drug
reaction) - there are reports in literature after approval

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Post-authorisation observational safety study of brentuximab
vedotin in relapsed/refractory hodgkin lymphoma and systemic
anaplastic large cell lymphoma: Arroven study
Results (continuation):
Twenty-one patients had SAEs, including 11 with drug-related SAEs; the most common (n ≥
2) were
• infection (n = 9)
• peripheral neuropathy (n = 4)
No cases of:
• progressive multifocal leukoencephalopathy
• Stevens-Johnson syndrome
• toxic epidermal necrolysis
• acute pancreatitis
were reported.
Embase: let’s look for those outcomes.

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There are reports of progressive multifocal
leukoencephalopathy

37. 37
There are reports of progressive multifocal
leukoencephalopathy - details

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There are reports of Stevens Johnson syndrome

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There are reports of toxic epidermal necrolysis

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There are reports of acute pancreatitis

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In-depth indexing for high precision
(relationship)

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Indexing for Embase is a manual process
performed by trained indexers with a biomedical
background, with the exception of articles designated
for automatic indexing.
Indexers read and analyze the full text of articles in
order to identify relevant concepts, and index them with
the most specific Emtree terms.
Index terms are controlled by the Emtree thesaurus
resulting in consistent coverage of concepts that
may be expressed in many different ways in the
literature.
Indexing principles

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In-depth indexing: triple-linking
Triple-indexing is a three level indexing of the full text of an article,
and it consists of:
‒ Concept (drug or device or disease)
‒ Semantic relationship (key subheading)
‒ Linked concept (e.g. neutropenia, hypertension, stroke, nausea)
Important
Definition
Brentuximab
vedotin
Neutropenia
Adverse drug
reaction

44. 44
Fatigue
108
Drug
interaction
Drug
comparison
Drug
therapy
Adverse
drug
reaction
Drug
combination
Peripheral T
cell lymphoma
39
Vinblastine
38
Dacarbazine
43
Doxorubicin
66
Bleomycin
4
Rifampicin
5
Ketoconazole
5
Vinblastine
6
Doxorubicin
7
Bleomycin
7
Large cell
lymphoma
269
Hodgkin
disease
466
Peripheral
neuropathy
125
Neutropenia
143
Manually
extracted
semantic
relationships
Brentuximab
vedotin
Thrombocytopenia
83
Hyperglycemia
38

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In-depth indexing for high precision (causality)

46. 46
Results in the literature on Embase
For brentuximab vedotin there are
(manually indexed) reports of:
• peripheral neuropathy
• infections
• neutropenia
• hypersensitivity reactions
But also events of hyperglycaemia.
As well cases of:
• progressive multifocal leukoencephalopathy,
• Stevens-Johnson syndrome,
• toxic epidermal necrolysis or
• acute pancreatitis
were reported.

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Next steps in preparing a systematic review
The Cochrane Handbook outlines eight general steps for preparing a
systematic review:
1. Defining the review question(s) and developing criteria for including
studies
2. Searching for studies
3. Selecting studies and collecting data
4. Assessing risk of bias in included studies
5. Analyzing data and undertaking meta-analyses
6. Addressing reporting biases
7. Presenting results and "summary of findings" tables
8. Interpreting results and drawing conclusions

48. 48
Thank you!
Any questions?
Dr. Joyce de Langen
Sr Solution Manager Pharmacovigilance
j.delangen@elsevier.com
Dr. Ivan Krstic
Sr Product Development Manager Embase
i.krstic@elsevier.com