searching literature databases for post authorisation safety studies (pass)

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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

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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

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Agenda



– Systematic literature review and Meta-analysis as PASS



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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

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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

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Agenda



– Systematic Literature and Meta-analysis as PASS



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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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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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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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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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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

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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

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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:

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

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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

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Fatigue

108

Drug

interaction

Drug

comparison

Drug

therapy

Adverse

drug

reaction

Drug

combination

Peripheral T

cell lymphoma

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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

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Manually

extracted

semantic

relationships

Brentuximab

vedotin

Thrombocytopenia

83

Hyperglycemia

38

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In-depth indexing for high precision (causality)

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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

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Thank you!

Any questions?

Dr. Joyce de Langen

Sr Solution Manager Pharmacovigilance

[email protected]

Dr. Ivan Krstic

Sr Product Development Manager Embase

[email protected]

searching literature databases for post authorisation safety studies (pass)

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