EFSA supporting publication 2015:EN-739
EXTERNAL SCIENTIFIC REPORT
Strategy support for the Post-Market Monitoring (PMM) of GM plants:
Review of existing PMM strategies developed for the safety assessment of
human and animal health1
ADAS UK ltd2
ABSTRACT
Commission Implementing Regulation (EU) No 503/2013 on applications for authorisation of
genetically modified (GM) food and feed legalised the requirement for a Post-Market Monitoring
(PMM) plan if the outcome of the risk assessment identifies a need to do so. This report provided a
systematic review of existing monitoring programmes for food, feed, human and animal health and an
inventory of data collection sources that may be useful for PMM of GM food and feed. Under the
legislative requirements PMM should confirm that specific recommendations of use are followed by
the consumer/animal owner, qualify the predicted consumption of GM food and feed and further
characterise any intended or unintended effects highlighted during the pre-market risk assessment. The
largest barriers to conducting PMM of GM food and feed in the EU were found to be the
‘unrecognisable’ nature of GM traits further down the food and feed supply chain after processing, and
the lack of appropriate consumption data at the branded/product level. EU legislation on traceability
and labelling of GMOs requires products to carry a ‘unique identifier’, however, this information is
lost once the product is further processed to become a product ‘produced from a GMO’. Consumption
data held at a product level by retailers or market research agencies was shown to be more useful for
PMM of GM food or feed than that held at the national level by public bodies. The project concludes
that several changes would be required in order to conduct comprehensive PMM of GM food and feed
in the EU, namely; greater detail on traceability requirements of GMOs, a database of which food and
feed products contain which GM traits at specific quantities, consumption data at the branded/product
level and a system for reporting the relevance and intensity of effects and unintended effects.
© [ADAS], 2015
KEY WORDS
GMO, Post-Market Monitoring, Post-Market Surveillance, trait, consumption data, composition data
DISCLAIMER
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried
out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the author(s),
awarded following a tender procedure. The present document is published complying with the transparency principle to
which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety
1
2
EFSA-Q-2013-00701
Steven Tompkins, Lottie Alves, Elizabeth Hudson, Alan Lyne, Daniel Commane (University of Reading),
Richard Weightman
Any enquiries related to this output should be addressed to GMO@efsa.europa.eu
Suggested citation: ADAS, 2015. Strategy support for the Post-Market Monitoring (PMM) of GM Plants: review of existing
PMM strategies developed for the safety assessment of human and animal health. EFSA supporting publication 2014:EN739, 117 pp.
Available online: www.efsa.europa.eu/publications
© European Food Safety Authority, 2015
Strategy support for the Post-Market Monitoring of GM Food and Feed
Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present
document, without prejudice to the rights of the authors.
EFSA supporting publication 2015: EN-739
2
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
SUMMARY
BACKGROUND AND METHODOLOGY
Commission Implementing Regulation (EU) No 503/2013 on applications for authorisation of
genetically modified (GM) food and feed legalised the requirement for a Post-Market Monitoring
(PMM) plan if the outcome of the risk assessment has identified a need to do so. Three specific
examples are given in this Regulation: 1) when the GM food or feed has altered nutritional
composition; 2) when the nutritional value of the GM food or feed differs from the conventional ones;
3) when there is a likelihood of increased allergenicity due to the genetic modification. The aim of this
project was to identify strategies, and existing monitoring or surveillance data that are collected in the
EU, and provide recommendations to assist with the development of EFSA guidance for applicants on
the design of PMM plans.
The project consisted of two main work packages focussed on gathering evidence, and a third work
package which consisted of a discussion on how PMM could be conducted in the EU using existing
data sources and the methods currently available. The methodology for WP1 and WP2 are detailed
below.
WP1 – Systematic review of existing monitoring programmes
The aim of this work package was to carry out a review of existing PMM programmes used to monitor
human and animal health. In this work package the principles of a systematic review methodology
were used to; search for, screen and present results of papers for inclusion. The review took into
account all PMM programmes, including, those for food, feed, human and animal health. Specifically,
programmes identified had a focus on either quantifying consumption of the product being monitored,
or identifying adverse/expected effects. The review used structured search criteria, which were
developed in ‘Scopus’, the largest abstract and citation database of peer-reviewed literature. The
search terms were then used in both ‘Scopus’ and ‘Web of Knowledge’ which returned a total of 3,809
records. The team then applied rigorous selection criteria in two stages, a stage one based on the title
and abstract of the paper only, and a stage 2 based on a review of the full paper. Stage 1 reduced the
total number of papers to 513 and Stage 2 reduced the total number of papers to 164. Final papers
(164) were reviewed in a MS Excel database based on key descriptors relating to the design of
programme and summarised in a discussion of results in the final report.
WP2 – Inventory of data collection methodologies
The objective of Work Package 2 was to identify and review existing survey, monitoring or
surveillance programmes for food, feed, human and animal health that may inform the design of a
PMM system for GM food or feed. The types of programmes reviewed included existing networks and
data sources on food and feed consumption, and animal and human health. Initially, informal
consultation was conducted to get an initial appreciation of the types of data collection programmes
that may be available, and to direct an internet based search.
WP1 SYSTEMATIC REVIEW RESULTS
The vast majority of the papers obtained through the systematic review process of existing monitoring
programmes were those related to Pharmacovigilance, the name given to the monitoring of adverse
effects of medical drugs. Three main stages of Pharmacovigilance were identified through the
systematic review; data collection, signal detection/evaluation and the reporting of the signal. In
Pharmacovigilance data can be collected both actively and passively. Active surveillance describes
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
methods where the operator instigates work such as conducting questionnaires/interviews with patients
or conducting post-clinical trials. Passive surveillance utilises spontaneous reporting systems to pick
up on unintended effects of drugs in general, using mediums such as consumer care lines and
healthcare professional reporting card schemes e.g. the yellow card system operational in the UK to
link adverse effects to specific products. Passive surveillance schemes are easier to conduct than active
ones as frameworks for collecting data are already operational in many countries. However, many
have criticised this approach due to large scale under reporting of adverse effects by the general public
and healthcare professionals and a lack of consistency of information recorded between countries.
Active surveillance methods allow for the monitoring of multiple outcomes within the same scheme,
and will capture adverse effects even if there is a delay between consumption and the event. The clear
disadvantage of active methods are their resource intensive nature. Similar schemes to
Pharmacovigilance operate, albeit at a smaller scale for vaccines (Vaccinovigilance) and cosmetics
(Cosmetovigilance). These schemes are similar in design to Pharmacovigilance, with country based
systems for reporting adverse effects.
Monitoring schemes are established in some countries for herbal medicines to understand adverse
effects, particularly when they are used in combination with other drugs. Currently, monitoring largely
occurs in countries such as Germany where herbal medicines are regulated in the same way as other
medicinal drugs (not ‘over the counter’), and thereby their use can be accurately known.
Novel foods are the group of products in the literature that have the most applicability to the PMM of
GM food and feed. PMM of novel foods is a useful method to clarify expected exposure to the novel
food, or novel food ingredient in ‘real world’ populations. PMM of novel foods takes two distinctive
steps, 1) clarifying the expected consumption of the food, and 2) identifying adverse effects. Methods
of PMM in novel foods have typically employed a combination of active and passive surveillance
methods. Active surveillance takes the form of cohort and case-control trials and consumption
questionnaires, while passive surveillance utilises spontaneous reporting systems largely via consumer
care lines included on the products in question. As the consumer care line is used to report any
feedback on the product such as customer complaints, many of the reports received on these lines
relate to complaints about the product (such as standards of packaging or organoleptic qualities) rather
than reports of adverse health effects from consumption of the product.
Our review found that PMM for animal feeds or veterinary products is an unexplored area, with
comparatively little focus in the literature. Pharmacovigilance for veterinary medicines operates in a
similar way to that for human drugs, however, individual animal owners are encouraged to report
adverse effects to a local veterinarian who in turn reports adverse effects.
WP2 INVENTORY OF DATA COLLECTION SOURCES RESULTS
The overall objective of Work Package 2 was to identify and describe programmes (survey,
monitoring or surveillance) that would be relevant for PMM of GM food and feed. The work package
majored on food composition and consumption data, as many networks designed to understand
adverse effects are covered by the programmes described in WP1. Our analysis started by
investigating the extent to which the existing regulatory framework on traceability and labelling may
allow a user to understand which GM traits are included in food and feed products. Traceability
legislation under Regulation (EC) 178/2002 requires Food Business Operators (FBOs) to understand
who products/ingredients are supplied from, and who they are sold to (unless the customer is the end
consumer). For GMOs, all products containing, consisting of or produced from GMOs must be
positively labelled to indicate their presence. Crucially, these requirements do not require the operator
to know exactly which GM trait(s) is included in the product. The system of unique identifiers does
require that materials ‘consisting of or containing GMOs’ are labelled with the specific code, but this
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
is not required once those materials are further processed, to constitute a product which is ‘produced
from GMOs’. This is for example the case where GM soybeans (the raw material) would be further
processed into soybean oil (an ingredient); where soybeans consist or contain a GMO, and soybean oil
is produced from a GMO. Our analysis shows that the food and feed supply chains are complex, and
‘tracking’ GM traits through the chain is difficult, and is not supported fully by regulatory
requirements.
Current food and feed composition data held at the Member State level does not identify the GM
components of a product, and are based on mean nutrient values for a range of products. Privately
available food composition data, such as that held by grocery retailers, food or feed manufacturers is
variable. For grocery retailers with ‘own-branded’ goods, data are held on provenance of the product,
but the level of information varies by product (for example more data are held on primary produce
than further processed products). Detailed food composition data may be held by the manufacturers:
However, the level of detail of this, above and beyond minimum labelling requirements, is uncertain.
For feed, composition data may be held by large feed manufacturers on specific products: However,
this information is usually commercially sensitive and thus information is not held by the livestock
producer/owner. Individual farmers will understand what they have fed to their livestock as a group,
however, this information is largely held on a herd rather than an individual animal basis. Additionally
in Europe, the least cost ration formulation system for formulation of compound feeds, means that the
actual composition of a feed product may vary from batch to batch. Therefore, even if the
concentration of the GM trait was constant, the proportions of other ingredients will probably be
varying over time, meaning it would be difficult to convincingly attribute adverse effect solely to the
GM trait in question.
Food consumption data exists in the EU at the national level by Member States (MS), and provides
good detail on foods consumed by a selectively representative sample of the population. Data are
gathered, classified by broad food group such as ‘white bread’ or ‘fruit’. Therefore in order for the
data to be useful for PMM of GM food and feed, more detail would be required on the specific food
products monitored to understand which ones contained specific GM traits. Of more value in the
context of PMM are the food purchase data collected by grocery retailers and market research
companies. In the UK, market research companies use sample households to record food purchases
using handheld barcode scanners. The scanners contain nutritional data on 100,000 food products,
either branded by manufacturers or own-brand retailer goods. Data on food purchases are also held by
retailers where consumers use a loyalty card scheme but these only reflect what is purchased at that
particular retailer, meaning it is of limited value for obtaining representative data across a whole
population. For the data collected by market research companies, demographics on the makeup of the
household are collected, however, exact consumption of the food by family member is not recorded.
For feed, no equivalent consumption database exist such as they do for food. Consumption data in the
form of feeding records may be held by individual livestock owners such as farmers. However, no
initiatives were found during this project that attempted to gather such information on livestock feeds.
Determining consumption data by individual animal may be possible for certain species, such as dairy
cows where individual feed intakes are recorded electronically.
WP3 DISCUSSION AND CONCLUSIONS
The project has shown that the largest barrier to conducting PMM for GM food and feed is the
‘unrecognisable’ nature of the GM trait further down the food supply chain. That is, GM food and feed
is sold and branded as a seed to farmer/growers to be passed through, an often complex supply chain
before being included in food or feed products often as refined ingredients. Through this supply chain
the raw material has the potential to be mixed with other similar GM food or feed, or other
conventional ingredients (such is the case with vegetable oils where there may not be one distinct
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
source of raw material). The regulatory framework for traceability and labelling on GM traits is such
that the unique identifiers prescribed to traits are no longer required once the substance is not
considered to contain the Living Modified Organism, and thus lost once the raw material is further
processed into an ingredient. The likelihood of being able to identify the GM trait after this point rests
in its visibility to users further downstream. We suggest that GM food and feed which has a specific
identity or brand would be far easier to monitor than those that are less recognised further
downstream. For example, Implementing Regulation 503/2013 details that GM traits that have a
‘higher likelihood of allergenicity’ require PMM, however, if these traits are agricultural/input and
primarily benefit the farmer/grower then it is unlikely they would be recognised on a specific trait
level after further processing. Food purchase data held by market research companies and grocery
retailers holds promise as a method to monitor consumption of GM food within a smaller sample size.
The main barrier to this is the extent to which this type of data is collected throughout the EU, as our
investigations show this is not in operation in all EU Member States. Widespread data on feed
consumption is not generally available, and if held is often at an individual farm level.
The methodologies reported for detecting adverse effects and validating expected effects of products
such as drugs, cosmetics and novel foods provide a good basis for designing a system which would
work for GM food and feed, if reliable consumption and composition data were known. Of all the
examples presented, PMM programmes for novel foods are the most relevant for GM food and feed.
These examples used a combination of approaches, such as spontaneous reports through consumer
care lines (passive surveillance) through to initiated cohort studies to test the occurrence of reported
effects in order to determine the relevance to the product in question. The project has found a large
knowledge gap regarding monitoring for adverse effects in terms of animal health. Veterinary
Pharmacovigilance is a new area of focus, and as such experience to date is limited.
Overall, it is clear that for a robust system of PMM to work, co-operation throughout the supply chain
would be required. For PMM of GM traits to work, in many cases an applicant company would need
the co-operation and resource of the final marketer of the product (be it food manufacturer, grocery
retailer or feed manufacturer) to co-ordinate monitoring of final product use and detection of effects in
the final consumer/user. We conclude that widespread PMM of GM food and feed across multiple
populations and for all products containing the trait is unlikely to be possible within the confines of
existing data collected and EU regulatory frameworks. Nevertheless, PMM may be possible on a small
scale for products in which the GM trait is known to be included, where consumption data exists or
could be generated and frameworks exist which could be used to monitor spontaneous reports of
adverse effects (e.g. customer care lines).
What would be required to conduct PMM of GM food and feed in the EU
Based on the findings from this project the following changes/items would be required to conduct
PMM of GM food and feed in the EU according to the requirements of Implementing Regulation
503/2013.
Greater detail in requirements for traceability of GMOs- This project has shown that current
traceability requirements only require the operator to detail which traits are in which batches of raw
material, ingredients or products up until the point that it is further processed to become an item
‘produced from GMOs’ (i.e. not containing the LMO). In order to accurately know which traits are
included in which final product, the unique identifier would be needed to be carried through the supply
chain to this stage.
A database of which GM food and feed products contain which GM traits, and at what proportion- In
order to accurately measure consumption of GM traits the user would need to understand in what
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
quantities they are present in the final products. This would require a database (or similar) of products
which contain GM traits, and at what level they are included in the product.
Consumption data at the branded product level- To accurately monitor consumption of particular GM
traits, robust data would be required for all branded products which contain the trait. This would likely
need to involve those further down the supply chain who are the ultimate vendors of the product
(whether food or feed).
A system for reporting the relevance and intensity of effects and unintended effects- Under the
requirements of Implementing Regulation 503/2013 the user must identify the relevance and intensity
of intended and adverse effects which are detected during the pre-market risk assessment. Approaches
such as the passive surveillance of novel foods using consumer care lines, and active surveillance with
initiated studies may be useful to identify the relevance and intensity of intended or unintended effects
of GM traits highlighted during the risk assessment.
An agreement on who is responsible for carrying out PMM- For PMM of GM traits to work, in many
cases an applicant company would need the co-operation of the final marketer of the product, (be it
food manufacturer, grocery retailer or feed manufacturer) to co-ordinate monitoring of use and
detection of effects in the final consumer/user. For PMM of GM traits to work, agreement would be
needed on who is responsible for PMM, and who would pay.
PMM METHODOLOGIES CURRENTLY FEASIBLE IN THE EU
Less detailed monitoring
Determining which products contain which GM traits, and at what proportion, as well as calculating
robust consumption figures are major difficulties in conducting a PMM programme. Less detailed
monitoring could be carried out based on import figures of GM traits as raw materials, or ingredients
into the EU. These figures could be matched with data on the quantity of generic products such as
vegetable oil consumed in the EU, including figures on the quantities of different oils consumed to
give an indication of the total amount of the GM trait consumed. This type of monitoring is foreseen to
be possible within the constraints of existing data collected within the EU, and whilst it may not
comprehensively meet all the requirements of Implementing Regulation 503/2013, could provide
knowledge as a starting point.
Small scale monitoring of GM traits
If large scale monitoring of all food and feed products containing GM traits was seen as unfeasible,
small scale monitoring of a selection of ‘reference’ products could be carried out. This system could
utilise a selection of products where robust information is held on their composition (the particular
GM traits included and at what proportion), and their consumption. Data, such as that collected by
market research agencies using hand held scanners in sample households could be used for this
purpose.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
TABLE OF CONTENTS
Abstract .................................................................................................................................................... 1
Summary .................................................................................................................................................. 3
Table of contents ...................................................................................................................................... 8
Background as provided by EFSA ......................................................................................................... 10
Terms of reference as provided by EFSA .............................................................................................. 10
Definitions .............................................................................................................................................. 11
Introduction and Objectives ................................................................................................................... 12
1.1.
Introduction ........................................................................................................................... 12
1.2.
Scope ..................................................................................................................................... 13
Materials and Methods ........................................................................................................................... 13
2. Work Package 1- Review of existing Post-Market Monitoring programmes ................................ 13
2.1.
Scope and Search Terms ....................................................................................................... 13
2.2.
Selection Criteria .................................................................................................................. 14
2.3.
Gate 1 Review ....................................................................................................................... 15
2.4.
Gate 2 Review ....................................................................................................................... 15
2.5.
Analysis, Presentation and Collation of Results ................................................................... 17
3. Work Package 2- Inventory of data collection methodologies ...................................................... 17
3.1.
Identification of programmes ................................................................................................ 17
3.2.
Analysis of programmes ....................................................................................................... 17
Results .................................................................................................................................................... 18
4. Work Package 1- Review of Existing Post-Market Monitoring Programmes: discussion of
literature review results .......................................................................................................................... 18
4.1.
Pharmacovigilance ................................................................................................................ 18
4.1.1. Data Collection ................................................................................................................. 18
4.1.1.1. Active Surveillance .................................................................................................. 18
4.1.1.2. Passive Surveillance................................................................................................. 20
4.1.1.3. Combined Surveillance Methods ............................................................................. 21
4.1.2. Signal Evaluation and Causality Assessment ................................................................... 21
4.1.3. Signal Reporting ............................................................................................................... 22
4.2.
Vaccinovigilance................................................................................................................... 22
4.3.
Cosmetovigilance.................................................................................................................. 23
4.4.
Herbal Medicines .................................................................................................................. 23
4.5.
Veterinary Pharmacovigilance .............................................................................................. 25
4.6.
Monitoring of Novel Foods .................................................................................................. 26
4.6.1. Food and Nutrient Intake Assessments............................................................................. 27
4.6.2. Assessment of Reported Adverse Events ......................................................................... 27
4.7.
Summary of existing monitoring programmes ..................................................................... 30
5. Work Package 2 - Inventory of data collection methodologies to assess food
consumption/composition and human and animal health ...................................................................... 33
5.1.
Regulatory requirements for traceability and labelling ......................................................... 33
5.1.1. Traceability requirements ................................................................................................. 33
5.1.2. Specific requirements for GMOs ...................................................................................... 34
5.2.
Assessment of food consumption ......................................................................................... 35
5.2.1. Food consumption data collected by member states and third countries.......................... 35
5.2.1.1. Data held by retailers/supermarkets ......................................................................... 36
5.2.1.2. Data held by market research companies ................................................................. 37
5.2.1.3. Data collected by private food manufacturers ......................................................... 37
5.2.2. Current data gaps to calculate food consumption ............................................................. 40
EFSA supporting publication 2015: EN-739
8
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
5.3.
Assessment of feed consumption .......................................................................................... 40
5.3.1. Feed consumption data ..................................................................................................... 40
5.3.2. Current data gaps to calculate feed consumption ............................................................. 40
5.4.
Assessment of food composition .......................................................................................... 41
5.4.1. Publicly available food composition data ......................................................................... 41
5.4.2. Privately available food composition data ........................................................................ 41
5.4.2.1. Food retailers ........................................................................................................... 41
5.4.2.2. Foodservice operators .............................................................................................. 42
5.5.
Assessment of feed composition ........................................................................................... 42
5.5.1. Feed composition data ...................................................................................................... 42
5.6.
Determining the inclusion of GM food and feed in products ............................................... 43
5.6.1. GM varieties used as feed ................................................................................................. 44
5.6.2. GM varieties used as food ................................................................................................ 45
5.7.
Data to understand adverse effects........................................................................................ 46
5.7.1. Animal health reporting schemes ..................................................................................... 46
5.7.2. Human health reporting schemes...................................................................................... 47
6. WP3 - The ability to conduct Post-Market Monitoring of GM food and feed in the EU .............. 48
6.1.
Requirements under Commission Implementing Regulation (EU) No 503/2013 ................ 48
6.2.
GM traits that would require monitoring .............................................................................. 49
6.3.
What is required for Post-Market Monitoring of GM food and feed .................................... 51
6.4.
Monitoring consumption or use of a GM food or feed in either animals or humans ............ 51
6.4.1. Inclusion of a GM trait in food or feed products .............................................................. 51
6.4.2. Food and feed consumption data ...................................................................................... 52
6.5.
Monitoring the relevance and intensity of effects and unintended effects detected during the
pre-market risk assessment ................................................................................................................ 53
Conclusions ............................................................................................................................................ 54
7. What would be required to conduct PMM of GM food and feed in the EU.................................. 55
7.1.
Greater detail in requirements for traceability of GMOs ...................................................... 55
7.2.
A database of which food and feed products contain which GM traits, and at what
proportion........................................................................................................................................... 55
7.3.
Consumption data at the branded product level .................................................................... 55
7.4.
A system for reporting the relevance and intensity of effects and unintended effects.......... 56
7.5.
An agreement on who is responsible for carrying out PMM ................................................ 56
8. PMM methodologies currently feasible in the EU ........................................................................ 56
8.1.
Less detailed monitoring ....................................................................................................... 56
8.2.
Small scale monitoring of GM traits ..................................................................................... 57
References .............................................................................................................................................. 58
Appendix/Appendices ............................................................................................................................ 69
Appendix A.
WP1 Paper Review Table........................................................................................... 69
Glossary of abbreviations ..................................................................................................................... 117
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
BACKGROUND AS PROVIDED BY EFSA
According to the Article 22 of the EFSA‟s Founding Regulation, “The Authority shall contribute to a
high level of protection of human life and health, and in this respect take account of animal health and
welfare, plant health and the environment, in the context of the operation of the internal market” and
“The Authority shall collect and analyse data to allow the characterisation and monitoring of risks
which have a direct or indirect impact on food and feed safety”. The EFSA’Science strategy 20122016’ recognises “an increasing trend for risk assessments to include assessment of issues that
require a marked broadening of the scientific discourse, such as environmental impacts, occupational
health, post-market monitoring, risk comparisons and health benefits”.
EFSA performs a centralized risk assessment for food and feed products derived from genetically
modified (GM) plants in the European (EU). The EFSA Guidance of the GMO Panel for risk
assessment of food and feed from GM plants3 (published in 24 May 2011) indicates that the proposal
for a PMM should be a hypothesis-driven scientific exercise, but does not provide detailed guidance
on how to set up a PMM in practice.
Very recently the Commission Implementing Regulation (EU) No 503/2013 on applications for
authorisation of genetically modified food and feed4 (published in 8 June 2013) legalised the
requirement of a proposal for Post-Market Monitoring (PMM) plan for the use of food and feed
derived from genetically modified (GM) plants, if the outcome of the risk assessment has identified a
need to do so. Three specific examples are given in this Regulation: 1) when the GM food or feed has
altered nutritional composition; 2) when the nutritional value of the GM food or feed differs from the
conventional ones; 3) when there is a likelihood of increased allergenicity due to the genetic
modification.
To implement the Regulation (EU) No 503/2013 in the risk assessment for GM food and feed, EFSA
is launching an open call for tenders to deliver a consolidated review, “Strategy support for the Post
Market Monitoring (PMM) of GM plants for the use as food or feed: Review of existing PMM
strategies and methodologies developed for the safety assessment of human and animal health”. The
review will identify strategies and data collection methodologies useful for further EFSA guidelines
on PMM plans for GM food and feed. The output of this procurement will be delivered within 12
months from its inception, and will be published as an External Scientific Report on the EFSA
website.
TERMS OF REFERENCE AS PROVIDED BY EFSA
This contract/grant was awarded by EFSA to:
ADAS UK ltd
Strategy support for the Post-Market Monitoring (PMM) of GM plants: Review of existing PMM
strategies developed for the safety assessment of human and animal health
Contract/grant number: OC/EFSA/GMO/2013/03
This call seeks a review on existing PMM programs in the EU and worldwide, and to analyse
strategies and methodologies for data collection and collation. The review will investigate the
3
http://www.efsa.europa.eu/en/efsajournal/pub/2150.htm
http://eur-lex.europa.eu/JOHtml.do?uri=OJ:L:2013:157:SOM:EN:HTML
EFSA supporting publication 2015: EN-739
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10
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
feasibility of transferring existing knowledge on PMM in areas other than GMOs such as novel foods
or feed additives that are relevant for the safety assessment of human and animal health.
DEFINITIONS
Raw material- refers to the primary produce from a farm-gate, such as ‘soybeans’ or ‘rapeseed’
Ingredient- refers to a component part of a final product, or a further processing of a raw material.
Examples include soybean oil or flour.
Product- refers to a finished food or feed product composed of a number of ingredients which is
purchased by consumers or animal owners.
EFSA supporting publication 2015: EN-739
11
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
INTRODUCTION AND OBJECTIVES
1.1.
Introduction
Genetically modified plants have been commercially cultivated and used across the world since 1996,
reaching a hectarage of 160 million in 2011 (James 2012) . For any genetically modified organism
(GMO) to be authorised for food and feed use, in the European Union (EU) market, an independent
safety assessment must be made by the European Food Safety Authority (EFSA) GMO Panel. The
safety assessment guidance provided by EFSA GMO panel, is used by risk managers from the
European Commission and Member States when deciding on market approval for a product5.
Pre-market risk assessment of GM food and feed is a robust process, however exposure assessment
may never be able to predict or reproduce the diversity of populations who may consume the final
product. Recently, the Commission Implementing Regulation (EU) No 503/2013 legalised the
requirement for Post-Market Monitoring of GM food and feed. Principally it is envisaged that PMM
would only be required in cases where the GM food and feed has an altered nutritional composition;
when the nutritional value of the GM food or feed differs from the conventional one; and when there is
an increased likelihood of allergenicity due to the genetic modification.
To date, few applications for approval of food or feed from GMOs have included a plan for PMM, as
the majority of GM plants approved for authorisation, within the EU, are those with simple agronomic
‘input’ traits such as herbicide tolerance, or insect resistance. Typically food and feed derived from
these GM plants would not require a PMM plan, however, new ‘novel’ GM plants with quality/output
traits such as: maize with high lysine (LY038) for use as animal feed, soybeans with modified fatty
acid structure (such as MON87705) and rice with high vitamin A content (Golden Rice), are likely to
require a PMM plan and at this stage no specific guidance exists on how this should be conducted.
The overall objective of the project was to review PMM programmes in the EU and worldwide, and to
analyse strategies and methodologies for data collection and collation in order to provide
recommendations for PMM methodologies which could be adapted/adopted for the safety monitoring
of GM food and feed in the EU.
The work was separated into three distinct work packages looking at reviewing existing PMM
methodologies, determining potential food consumption data sources and providing recommendations
for specific guidance on the PMM of GM food and feed within the EU. The relevant titles of the work
packages from the original tender document are found below.
Work Packages:
1. Review existing PMM programmes in the EU and worldwide
2. Provide an inventory of data collection methodologies to assess food/feed
consumption/composition and human/animal health
3. Provide recommendations for PMM of GM food and feed in the EU
5
See http://www.efsa.europa.eu/en/efsajournal/pub/2150.htm
EFSA supporting publication 2015: EN-739
12
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
1.2.
Scope
The scope of the report covered existing Post-Market Monitoring strategies, on a global scale, for all
products related to human and animal health, food and feed. Any programmes monitoring
environmental impacts or medical devices were excluded as they are not relevant to adverse effects
related to consumption.
MATERIALS AND METHODS
2.
WORK PACKAGE 1- REVIEW
OF
EXISTING
POST-MARKET MONITORING
PROGRAMMES
In this work package the principles of a systematic review methodology were used to; search for,
screen and present results of papers for inclusion.
The objectives of this work package were to review existing Post-Market Monitoring programmes
with specific emphasis on:
1. Distinguishing programmes from an EU and a non-EU country;
2. Distinguishing the product in question as either a food or feed, or a non-food or non-feed
product;
3. Distinguishing between general surveillance for adverse events/effects from case-specific
monitoring (where a specific hypothesis has been identified);
4. Distinguishing between mandatory and voluntary monitoring schemes.
2.1.
Scope and Search Terms
This review has taken into account all Post-Market Monitoring programmes, including, those for food,
feed, human and animal health. Programmes identified had a focus on either quantifying consumption
of the product being monitored, or identifying adverse/expected effects. Programmes that monitored
impacts on the environment, or any aspect not related to consumption such as medical devices, and
their effects on humans and animals were excluded.
Search criteria were developed and then tested in Scopus, the largest abstract and citation database of
peer-reviewed literature from multiple disciplines, and then searched for in the ‘Scopus’ and ‘Web of
Science’ databases. This allowed qualification of whether the number of results returned were similar
across multiple databases and thus if our keywords were suitable in picking up the breadth of literature
that was available. Search criteria were arranged into four main levels;
1. Terms which defined the types of programme focused on i.e. post-market or post-launch
monitoring rather than more general monitoring.
2. Additional terms which highlighted records referring to specific programmes developed e.g.
‘scheme’
3. Terms that defined the scope of programmes e.g. ‘food’
4. Terms that defined the purpose of the monitoring programme e.g. ‘intake’
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Below is the structured search string which was used to search academic, and peer reviewed literature
in ‘Scopus’ and ‘Web of Science’.
TITLE-ABS-KEY("Post-market" OR "Post Launch" OR "post-market surveillance" OR "post
launch surveillance" OR Pharmacovigilance OR Cosmetovigilance OR "postmarketing") AND
TITLE-ABS-KEY(strategy OR scheme OR plan OR programme OR initiative OR method OR
design) AND TITLE-ABS-KEY(food OR feed OR "animal feed" OR drug OR cosmetic OR
product OR gmo OR gm OR "genetically modif*" OR "herbal remedies" OR commodity) AND
TITLE-ABS-KEY("human health" OR "animal health" OR intake OR consumption OR
exposure OR risks OR consumer OR "public health" OR outcome OR impact OR allergen* OR
immunolo* OR authenticity)
This search yielded 3,258 results in Scopus and 3,791 results in Web of Science, correct as of
13/03/2014 for Scopus and 18/03/2014 for Web of Science (as numbers of results will change when
new publications are released). The number of results returned by both databases were comparable,
and the results from each database were exported to Endnote separately, and later combined into a
final database, with any duplicates identified by Endnote removed. The combined database contained
3809 results.
2.2.
Selection Criteria
A two stage process was used to select papers for review, using the same criteria at each stage. Stage 1
termed ‘Gate 1 Review’ reviewed papers for inclusion based on their title and abstract (where
available) only. Full text articles were acquired for papers passing the Gate 1 Review and also for
those for which an assessment could not be made based on the title or abstract alone. Stage 2 termed
the ‘Gate 2 Review’ used these same selection criteria, on the full text articles to select final papers for
analysis.
Table 1:
Selection criteria for Gate 1 and Gate 2 Reviews
Must answer YES to one or more of the appropriate inclusion values.
Screening Questions
Inclusion values
Question
Does study refer to monitoring consumption/intake or adverse/beneficial effects on Yes
consumers or animals?
Does study focus on a specific example, or give specific guidance on how a PMM programme Yes
should be conducted?
Does the study outline/describe PMM methodologies used?
Yes
Abstract in English
Yes
Study aims to monitor medical devices
No
Study aims to monitor environmental impacts.
No
Study focusses on outcomes of a monitoring programme, rather than design of the programme No
itself.
EFSA supporting publication 2015: EN-739
14
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
2.3.
Gate 1 Review
To conduct the Gate 1 Review two researchers independently reviewed, using Endnote, all 3809
references, based on their title and abstract (where available). References were reviewed
independently, to avoid the possibility of either consultant influencing the other’s decisions. The
Endnote results were exported into a separate Microsoft (MS) Excel document, and once a reference
was reviewed, the decision was noted in the MS Excel file. MS Excel was used in this instance, for
ease of use over Endnote.
References were coded via the following system:
Table 2:
Gate 1 Review Reference Coding System
Code
Meaning
Y
Yes
Fits inclusion criteria so through to Gate
programme/element of programme mentioned
N
No
Not relevant so excluded from Gate Review 2
M
Maybe
Unable to make an assessment based on available information, so through to
Gate Review 2
R
Review
Fits inclusion criteria so through to Gate Review 2, usually non-specific
D
Duplicate
Result missed during Endnote duplicate finding process
2
WP2
Not relevant to work package 1, but potentially relevant to work package 2
Review
2-
specific
Once all references had been reviewed by both consultants a TRUE or FALSE analysis, an example is
given below, was carried out in MS excel to compare the results.
Table 3:
Example MS Excel True or False Calculation
=$D2=$C2
TRUE
For those results that did not match and would therefore appear FALSE, the abstract was re-read and
discussed by both consultants and either a joint decision was reached on the outcome or a third party
reviewer was used to decide the outcome. Of the initial 3809 results, this left 513 references to go
through to the Gate 2 Review.
2.4.
Gate 2 Review
The 513 papers identified after the Gate Review 1 were collected via a number of methods. Firstly
databases such as; Science Direct and Springer Link were searched for journals and access permitting
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
papers were downloaded. Where an email address for authors could be found on Scopus, an email was
sent to ask for a copy of their paper.
Once the papers had been gathered they were screened against the selection criteria again, although
this time the full paper was read. If papers were considered irrelevant a note was made of the
reasoning and inputted into the Endnote database and the paper was removed from the analysis. Of the
513 papers from the Gate 1 Review, 164 were relevant. Relevant papers were distributed between five
separate reviewers for analysis.
Papers that were not in English, could not go through to the analysis stage without translation and
have, at this stage, not been included in the analysis. A total of 34 papers collected during this process
were not in English. The flow diagram in Figure.1 details the systematic review process.
Figure 1: Flow diagram of systematic review process
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
2.5.
Analysis, Presentation and Collation of Results
The papers that passed the Gate 2 Review were then reviewed and results collated. Papers were
distributed between five reviewers, where papers were re-read and data extracted and inputted into an
MS Excel spreadsheet. The results spreadsheet (see Appendix 1) allowed key methodological steps of
the Post-Market Monitoring methodology used, to be extracted. For example column headings
included; active vs. passive surveillance, mandatory vs. voluntary schemes, strengths and weaknesses
of methods and responsibility for reporting/monitoring. Once data were extracted, key themes were
drawn out and have been summarised in the results section below.
3.
WORK PACKAGE 2- INVENTORY OF DATA COLLECTION METHODOLOGIES
The objective of Work Package 2 was to identify and review survey, monitoring or surveillance
programmes for food, feed, human and animal health that may be suitable sources of data for a PMM
system for GM food or feed. This work package did not cover existing monitoring programmes as this
is covered under WP1. The emphasis of Work Package 2 was to understand the feasibility of
undertaking PMM for GM food and feed in Europe based on what data are currently collected.
3.1.
Identification of programmes
A combination of literature and web searching, with informal consultation was used to identify data
collection programmes that would be relevant to the PMM of GM food and feed in the EU. The scope
of programmes that may be covered under this work package was kept broad, as it was recognised that
a PMM system in the EU may need to make use of multiple sources of data to be successful. The types
of programmes reviewed included existing networks and data sources on food and feed consumption,
and animal and human health. Initially, informal consultation was conducted to get an initial
appreciation of the types of data collection programmes that may be available, and direct the internet
based search. Consultation was conducted with academic institutions, those in the food industry and
animal feed industries, and stakeholders from public institutions. Given the sensitivity of the topic we
have kept all names confidential. After this consultation a web-based search, using search engines was
conducted to source details on relevant programmes. For the purpose of this exercise, key search terms
were not used due to the flexibility needed to find all possible programmes which may operate under
different names (e.g. use company names, or have specific product names). Much of the information
in this area is not documented or is confidential (such as grocery retailers approaches to traceability in
their supply chains) and as such a large proportion of the evidence presented is based on the personal
communications described above.
3.2.
Analysis of programmes
Data collection programmes sourced are described in the results section below. The programmes
presented are only those relevant to the PMM of GM food and feed.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
RESULTS
4.
WORK PACKAGE 1- REVIEW OF EXISTING POST-MARKET MONITORING
PROGRAMMES: DISCUSSION OF LITERATURE REVIEW RESULTS
The greatest number of abstracts and papers obtained were on Pharmacovigilance, followed by papers
on Vaccinovigilance and statistical signal detection/evaluation methods e.g. disproportionality
analysis. In 1968 the World Health Organisation (WHO) set up the Programme for International Drug
Monitoring (PIDM) and since then many reports have been published with updated methodologies for
monitoring of drugs in a post-market setting (Mahmood 2011). Although Pharmacovigilance is the
oldest example of a Post-Market Monitoring scheme, there are a number of other similar initiatives
that are currently undertaken globally, these include; Cosmetovigilance and Vaccinovigilance. PostMarket Monitoring of novel foods and herbal medicines are emerging sectors and therefore a limited
number of papers regarding these topics are available. Another important area of research identified in
the literature search were nutritional/food intake studies. Within the scope of our keywords there were
a limited number of papers on nutritional uptake, as these often do not follow traditional Post-Market
Monitoring methodologies. Of the results returned from the literature review there were more papers
regarding human health, with very few relevant animal health studies identified. Each of the above
schemes/studies are discussed in more detail below with common methodologies noted. The full list of
reviewed results can be found in Annex x.
4.1.
Pharmacovigilance
Pharmacovigilance is defined by Talbot and Nilsson (1998) as, ‘the process of identifying and
responding to drug safety issues’. The major aim of Pharmacovigilance is the discovery of new or rare
Adverse Drug Reactions or (ADRs). Three main stages of Pharmacovigilance have been identified
through the systematic review; data collection, signal detection/evaluation and the reporting of the
signal (Bhosale & Gaur 2011).
4.1.1.
Data Collection
Data collection in Pharmacovigilance monitoring schemes can be split into two distinct categories;
active and passive surveillance. Active surveillance for ADRs is that which is purposefully initiated,
usually by the manufacturer of the drug to be monitored and can include work such as conducting
questionnaires/interviews with patients or post-clinical trials. Passive surveillance utilises spontaneous
reporting systems to pick up on unintended effects of drugs in general, using mediums such as
consumer care lines and healthcare professional reporting card schemes e.g. the yellow card system
operational in the UK to link adverse effects to specific products.
4.1.1.1. Active Surveillance
The use of active surveillance methods, or surveillance which is purposefully initiated, for monitoring
drugs and medicines has been gaining popularity with manufacturers over the last 20-30 years (Kay
1983, Talbot & Nilsson 1998 and McNeil et al. 1999), as further problems with drugs were discovered
after the thalidomide tragedy6 (Waller & Evans 2003) and new methods of surveillance were felt to be
6
Thalidomide was used to treat nausea in pregnant women during the 1950-60s. There was limited or no preclinical/post-clinical testing of the drug, so when it reached the market the severity of side-effects had not been
18
EFSA supporting publication 2015: EN-739
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
necessary. There are a number of different simple trial designs to monitor adverse drug reactions
actively. These include; observational studies e.g. cohort studies and case control studies and large
simple safety trials e.g. post-marketing clinical trials (Talbot & Nilsson 1998 and Berlin et al. 2008).
Cohort studies involve recruitment of individuals from a specific cohort e.g. all individuals taking a
specific drug, and then monitoring the population over time. Case-control studies are retrospective
trials comparing people who are taking a drug against those who are not, to assess whether the
presence of the drug is causing a certain adverse event. Large simple trials or post-marketing clinical
trials involve recruitment of subjects through broad selection criteria, after which they are then
randomised for different treatments and any adverse events are recorded against the treatment method.
A number of the studies analysed had used active surveillance methods to collect ADR reports. For
example; Zancan et al. 2009 describe how they compared spontaneous reporting schemes with a pilot
study, taking a more active approach. Three hundred patients were selected, from those discharged
from participating hospitals, who were prescribed drugs in the following categories; non-steroidal antiinflammatory drugs (NSAID), oral anticoagulants and antihypertensive drugs. Patients were monitored
passively for 6 months after discharge from hospital. Patient/healthcare professional reports were
collected via an adverse event reporting phoneline which was accessible 24hr/day. Active surveillance
occurred 30 days after discharge, in the form of a structured phone interview, which was completed
with all patients who had given informed consent. No calls were made to the free phoneline during the
entirety of the study, with data on adverse events collected only via the telephone interviews. Zancan
et al. (2009) discussed the advantages of active surveillance finding it to be a useful tool in
determining drug safety, but felt that the costs of conducting active surveillance trials, made it hard to
foresee widespread usage of this method.
Alemayehu et al. 2010, describe a case-control study undertaken in Zanzibar to determine the safety
effects of multi-drug administration treatments in a resource constrained setting. They describe how
children and adults meeting the eligibility criteria were allocated a treatment randomly based on the
village they were from and monitored for reactions.
Another example of active surveillance comes in the form of monitoring patients during their stay in
hospital. Hospital monitoring of adverse reactions in patients undergoing treatment were reported in
Germany, Mexico and India (Kapp et al. 1991, Juarez & Olguin 2007 and Khairnar & Gade 2011).
Hospital monitoring schemes involved; increasing awareness of both doctors and patients about
Pharmacovigilance and potential adverse reactions, and improving methods for validation of adverse
events (Kapp et al. 1991), such as better expert review systems for reviewing adverse reaction reports.
This led to improved quality and quantity of adverse event reports (Khairnar & Gade 2011). However,
often these results were short-term only (Khairnar & Gade 2011) with further investment and
incentives needed to encourage better reporting from the healthcare professionals in the future (Juarez
& Olguin 2007 and Khairnar & Gade 2011).
The benefits of an active surveillance method over spontaneous reporting, is that active methods will
capture adverse events even if there is a delay between consumption and the adverse event (Wood
1991). Active surveillance also allows for the monitoring of multiple outcomes within the same
scheme (McNeil et al. 2010). In some cases, cohort study data capture forms are created prospectively,
discovered. This led to many babies being born with limb abnormalities and triggered implementation of more
rigorous drug safety assessments (Kim & Scialli 2011).
19
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procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
before the trial begins. This means forms can be tailored so as to capture all relevant data that might
later be required (Kay 1983).
As with all methods there are limitations. In the main, the limitations of active surveillance are the
time and cost it takes to perform (Kay 1983, Wood 1991 and Weaver et al. 2009). Another significant
limitation, of active surveillance methods is the assumptions study directors have to make regarding
variance between patients. The demographic background of each patient will vary considerably, and
yet active surveillance methods have to assume, to a certain extent, that the only difference between
patients is whether or not they have taken the drug. Therefore, the event is not always necessarily
linked to taking the drug (Berlin et al. 2008).
4.1.1.2. Passive Surveillance
Traditionally post-market surveillance has largely been done via passive schemes which utilise
spontaneous reporting systems e.g. Consumer care lines and the ‘yellow card system’, for generation
of adverse event signals (McNeil et al. 1999, Barnes 2003 and Zancan et al. 2009). Reporting systems
vary across the globe, but generally information gathered from patient reporting, to dedicated support
care lines, is sent directly from the manufacturer to the regulatory agencies such as the Food and Drug
Administration (FDA) and the Medical and Healthcare products Regulatory Agency (MHRA). A more
detailed example/case study of a consumer care line is given below in section 4.6.2. Differences in
systems of collecting spontaneous adverse event reports becomes more noticeable when looking at
national healthcare professional ‘yellow card’ type schemes. In countries such as India, Nepal, Sweden
and France (Gogtay 2004, Palaian 2010 Balkrisnan 2001 and Dal Pan 2014) regional adverse drug
reaction centres collect data for their region, and this is then sent to a centralised regulatory authority.
The situation is different in the US and Germany (Dal Pan, 2014 and Talbot & Nilsson 1998), where
reports are usually made directly to the manufacturer, who then informs the regulatory authorities,
reducing contact between regulatory authorities and initial reporters. Countries who become members
of the World Health Organisation (WHO) Programme for International Drug Monitoring (PIDM)
WHO PIDM, will send their ADR reports to the WHO monitoring database ‘Vigibase’, in Uppsala
Sweden, which compiles a global list of reported ADRs (Gogtay 2004, Palaian 2010, Dogra 2013 and
Dal Pan 2014).
Once adverse event data are collected, it must be reviewed. This is often done through crossreferencing to currently available literature on potential associated ADRs and also through statistical
analysis. The most commonly used statistical analysis tool is disproportionality analysis. This involves
checking the extent to which adverse events are likely to be related to a particular drug over another
(Montastruc et al. 2011). Further detail on both literature review and statistical methods of signal
evaluation are discussed in 4.1.2.
A number of the reviewed papers stated that they believed spontaneous reporting was no longer
sufficient to successfully monitor drugs in the post-market environment (Kay 1983, Waller & Evans
2003 and McNeil 2010). This is due to a number of limitations with the spontaneous reporting system,
namely; large scale under-reporting of ADRs by the public and healthcare professionals (Inman 1981,
McNeil 1991, and Berlin et al. 2008) and a lack of consistency between the information recorded
about ADRs within and between countries. E.g. it is common for forms to be lacking required
information, making it hard later to define causality (Bennett at al. 2000 and Bandekar et al. 2010).
Other disadvantages to spontaneous reporting include; the lack of a control group making it hard to
determine whether the adverse event was the result of drug consumption or coincidence (Begaud et al.
1994), and unreliability of the method to detect new, unsuspected or delayed adverse reactions (Talbot
& Nilsson 1998, McNeil 1999 and Ahmad 2003).
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
There are, however, a number of advantages to spontaneous reporting schemes. Spontaneous reporting
can start immediately once a product is released and can be continued throughout the lifetime of the
product (Talbot and Nilsson 1998, Begaud et al. 1994 and Ahmad 2003 and Ronaldson 2011).
Reporting is not restricted to a specific cohort of the population, meaning that spontaneous reporting
can allow for the early detection of rare and severe ADRs (Wood 1991 and Ahmad 2003). One of the
main drivers for spontaneous reporting stated was that it remains the cheapest method of post-market
surveillance in Pharmacovigilance (Begaud et al. 1994 and Ahmad 2003).
4.1.1.3. Combined Surveillance Methods
A number of initiatives which aim to combine passive and active surveillance are now in place in
Europe, the US, Canada, Australia and New Zealand. Commonly termed ‘Prescription Event
Monitoring’ in the reviewed literature, these methods link prescription data to healthcare practitioner
adverse event reports (Balkrisnan et al. 2001, Eguale et al 2010, McNeil et al. 2010 and Harpaz et al.
2013). All of the above countries and many more utilise electronic health record databases, with
suggestions in the literature to make it mandatory for healthcare professionals to note changes to
prescriptions. For example changes to the dose given or the discontinuation of a prescription, with any
adverse events recorded on these systems (Balkrisnan et al. 2001 and Eguale et al. 2010). The hope is
that this will make it easier to identify the risk and prevalence of ADRs. By noting changes to dose or
the discontinuation of a specific drug treatment, the appearance of an ADR might be more easily
linked to its potential cause (Dunn & Mann 1999).
It is a general consensus among the reviewed papers that a combination approach in terms of data
collection is almost certainly going to be the most effective method for Pharmacovigilance in the
future. With many papers stating that tailor made Pharmacovigilance plans, depending on the
situation, are best (Kelman et al. 2010).
4.1.2.
Signal Evaluation and Causality Assessment
Once adverse reaction reports have been filed, signals need to be evaluated and assessed for causality.
There are generally four main features of assessing causality; time between challenge and adverse
event, de-challenge or the impact of stopping treatment, re-challenge or the impact of restarting
treatment and whether there are any other possibilities that could have caused the reaction (Bhosale &
Gaur 2011 and Sharrar & Dieck 2013). The WHO general categories for separating signals are;
Certain (definitely related), Probable/Likely, Possible, Unlikely, Conditional/Unclassified (data are not
available, or is too limited to make a judgement) (Mahmood et al. 2011). Many countries have their
own classification systems but all are similar to the WHO definitions (Bhosale & Gaur 2011).
One initial method often employed to assess causality, is a review of available medical literature to
look for similar reactions that have been reported previously (Talbot & Nielsson 1998, Ahmad 2003,
Sharrar & Dieck 2013). The method of causality assessment by comparison to historical data, is
unlikely to be available for use in GMO monitoring programmes as there is little/no previous
literature/knowledge on any known adverse reactions, over and above general intolerances and
allergies, otherwise the product would not have received authorisation.
Recent technological advances in informatics have led to the development of several statistical tools,
each of which can be used to extract data from electronic healthcare databases and look for
associations between a drug and any adverse reactions experienced (Theophile et al. 2010 and Gagne
et al. 2012). A popular method of data extraction was data-mining and more specifically a type of
data-mining called disproportionality analysis. Disproportionality analysis is conducted with a two by
two contingency table and can be used to compare the association between drug X and ADR Y. The
analysis compares the observed number of reports of ADR Y linked to drug X with the expected
EFSA supporting publication 2015: EN-739
21
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
number of reports if there was no association. This then gives a ratio of observed to expected events,
on which a chi-squared analysis can be done to test for significance (Montastruc et al. 2011). This
involves using statistics to determine if the reporting of a specific adverse event is occurring more
frequently than the reporting of other known ADRs for that particular product.
During the systematic review a number of the papers reviewed were specifically focussed on
establishing new data mining/ statistical algorithms for signal detection (Egberts et al. 2002, Fram et
al. 2003, Dasgupta & Scholl 2009, Caster et al. 2010, Fan et al. 2010, Chazard et al. 2011 and Du et al.
2013). Each method was highly detailed but one clear trend that came out of all these papers was that
signal detection informatics tools needed to be tailored to the specific need (Gagne et al. 2012).
Therefore, signal detection tools are important in the process but each method is not discussed in detail
as its use would be limited in relation to monitoring of GM foods and feeds.
4.1.3.
Signal Reporting
Once signals have been evaluated and causality has been confirmed reports are sent to regulatory
authorities or to the manufacturer of the country of origin. Where reports are inputted into a database
e.g. AERS, WHO Uppsala Monitoring Database.
Electronic forms have made reporting much easier. These systems tend to be lacking in middle to low
income countries who still rely on hard-copy reporting forms. This means that there are often physical
barriers that prevent timely reporting of adverse events (Olsson et al. 2010). There is a need therefore
to bring all systems up to a better standard, which will require significant investment (Olsson et al.
2010).
4.2.
Vaccinovigilance
The monitoring of adverse events in vaccinations is very similar to the processes used in the
monitoring of adverse drug reactions. Many countries operate similar surveillance schemes for both
drugs and vaccines e.g. the yellow card scheme in the UK. Some countries e.g. the US, Vaccine
Adverse Event Report (VAERS), Canada, Immunisation Monitoring Programme (IMP) and Brazil,
National Immunisation Programme (NIP), have specialist centres dedicated to the reporting of vaccine
adverse reactions (Davis et al. 2005, Zuber et al. 2009 and Monteiro et al. 2011). There are also a
number of international monitoring schemes in place to try and coordinate vaccine safety research. For
example the WHO set up the Global Advisory Committee on Vaccine Safety (GACVS) in 1999, to
provide countries with timely advice on vaccine safety issues (Zuber et al 2009). The SANEVA
network mentioned in the paper by Zuber et al. 2009, is a good example of international cooperation to
improve safety surveillance networks. The SANEVA network was created in 2006 between;
Argentina, Brazil, Mexico, Panama and Venezuela with the aim to create an adverse event reporting
network for Latin American, where training and active surveillance initiatives could be harmonised.
This system has been used as a guide for the recently (2012) set up Global Vaccine Safety Initiative
(GVSI), which aims to help coordinate global vaccine safety data and Pharmacovigilance trials
(Amarasinghe et al. 2013).
Methods for data collection in vaccines are the same as for other drugs. Similarly, the consensus from
the literature was that, as with drugs, spontaneous reporting of reactions was no longer considered an
entirely adequate scheme (DeStefano 2001 and Tatley et al 2008). The majority of papers reviewed on
Vaccinovigilance focussed on active surveillance methods, rather than spontaneous surveillance
methods, like drug monitoring systems. Apart from the type of surveillance used, the methods
themselves differed very little from those of Pharmacovigilance. Davis et al. 2005 and Tatley et al.
2008, discuss prospective cohort study methodologies. The Davis study used data from health
maintenance organisations, to simulate a cohort study in children. Using data on adverse reactions in
EFSA supporting publication 2015: EN-739
22
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
children before the vaccine was introduced as a control. In Tatley et al. 2008 the authors describe how
they monitored children for four weeks after immunisation and recorded all consultations, including
suspected adverse reactions.
Electronic data linkage similar to prescription event monitoring was also recorded in studies by
Farrington et al. 1995 and Destefano et al 2005.
4.3.
Cosmetovigilance
Methods to assess the causality of adverse reactions to cosmetics has been influenced by past
experiences in the pharmaceutical industry (Bons et al 2010). Therefore, adverse reaction monitoring
schemes for cosmetics are generally similar to those for drugs, although there tend to be fewer adverse
reactions reported in these schemes (Berne et al. 2008). In 2005 the European Cosmetics Association
issued guidelines on the management of un-desirable events (Bons et al. 2010), which provided
specific Post-Market Monitoring guidance to the cosmetics industry. The guidelines remain very
similar to those in place for drugs. Causality assessment criteria and scoring for Cosmetivigilance are
similar to those used in Pharmacovigilance (Bons et al. 2010).
Currently the only study into improving Cosmetovigilance that the systematic review identified is the
study by Berne et al. 2008. The study was carried out in three Swedish dermatology clinics. Patients
were enrolled in the study if they were under investigation for potential adverse reactions. Application
of different product treatments occurred via patch testing, according to the Finn Chamber technique
(Fischer & Maibach 1984). This technique involves application of liquid to a small paper disc which is
then stuck to the skin. Patches remained on the skin for 2 days and the area was assessed by
dermatologists on day 3 and day 5-7 for signs of adverse effects. Adverse reactions were recorded and
assessed for causality (Berne et al. 2008). The WHO causality definitions were used to define
causality. The study found that taking a more active approach to Cosmetovigilance could increase the
number of adverse reactions recognised and identified and could help improve reporting rates (Berne
et al. 2008).
4.4.
Herbal Medicines
WHO guidance on the safety monitoring of herbal medicines discusses the importance of including
herbal medicines in Pharmacovigilance systems (WHO guidance, 2004). The amount spent on herbal
medicines, by some 154 million US citizens in the year 2000 was $17 billion and there is currently a
trend towards greater use of herbal medicines across the globe (WHO guidance, 2004).
Herbal medicines are important to monitor for two reasons:
1) The high global levels of consumption of these medicines makes it important to know of any
potential risks associated with taking the medicine;
2) When used in conjunction with other drugs there is the potential for herbal medicines to cause
adverse reactions.
In order for programmes monitoring herbal medicines to work properly the WHO recommends
running any safety monitoring programmes in conjunction with current Pharmacovigilance techniques.
A number of limitations were listed in the WHO guidelines (2004) which would need to be addressed
in order to encourage and improve adverse event reporting in herbal medicines. Limitations that
needed addressing included: the number of case reports, the high levels of under-reporting of adverse
reactions to herbal medicines seen; the limited monitoring capacity; the lack of a standard
classification scheme; no method for information exchange systems, within and between countries;
EFSA supporting publication 2015: EN-739
23
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
and lack of communication and awareness within the general public that ‘natural’ does not always
equate to safe, for example, Kava-kava (Piper methysticum) used for its sedative properties also
caused hepatotoxicity issues and was eventually banned for use in the EU in 2002 (Barnes 2003).
A number of methods are currently used to determine the safety of herbal medicines. These methods
include: examining traditional usage data, conducting experimental studies e.g. clinical trials, and
using other human data for example case studies. Spontaneous reporting seems to be the most
common way of monitoring the adverse effects of herbal medicines (Bast et al. 2002, Barnes 2003,
Hugman 2005 and WHO guidance 2004). Where herbal medicines are regulated as drugs (e.g. in
Germany), traditional Post-Market Monitoring strategies e.g. healthcare professional adverse event
form filling, and post-market clinical trials can be conducted (Barnes et al. 2003). Some of the adverse
reactions to herbal medicines may already be captured on current Pharmacovigilance schemes if the
adverse reaction is the result of an herbal medicine: drug interaction (Bast et al. 2002). However,
many herbal medicines can be accessed ‘over the counter’, without prescription. This decreases the
likelihood of adverse event reporting, due to the lack of healthcare professional supervision and
patient understanding regarding reporting of adverse reactions to herbal medicines (Barnes et al.
2003). In the UK, to encourage increased reporting of adverse events from herbal medicines, a scheme
was implemented in the early 2000s, which allowed nurses, midwives, health visitors, pharmacists and
patients to report, in addition to doctors (Bast et al. 2002). Consumer reporting, is often the only way
to receive safety data on non-prescription drugs (WHO guidance 2004). To maintain the quality and
improve quantity of reports to help with detection of adverse reactions, further vigilance of reporting
by the patient’s healthcare professional is recommended. (Barnes 2003, WHO guidance 2004).
Manufacturer involvement is also crucial to the success of Post-Market Monitoring of herbal
medicines (Barnes 2003, Bast et al. 2002 and WHO guidance 2004). By working with consumers and
healthcare professionals, manufacturers can increase awareness not only of potential adverse reactions
associated with the product through labelling, but also of the importance of patient reporting of
suspected adverse events to a local general practitioner or relevant healthcare professional (WHO
guidance 2004).
Other methods to increase the levels of reporting of adverse reactions, to herbal medicines, was to
make the forms available online for ease of use. Generally adverse event forms include a section titled
‘other drugs’ with reference to reactions thought to be related to herbal/traditional medicines (Barnes
2003). The paper by Barnes (2003) goes onto discuss other important details that should be included in
future herbal medicine adverse event reporting forms. Specifically they focussed on gaps in current
information captured by the form. For example forms should include information, where possible, on
the formulation and identity of species found within the product and the specific processing involved
in creating the product, as this can sometimes alter the chemical composition (Barnes 2003).
Current EU Regulation on herbal medicines requires all member states to have a herbal medicine
registration scheme in place, and manufacturers are no longer allowed to sell herbal medicines without
first licensing the product7, by either holding:
7
http://www.mhra.gov.uk/Howweregulate/Medicines/Herbalmedicinesregulation/ (last modified 30th April
2014)
24
EFSA supporting publication 2015: EN-739
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
1. A full marketing authorisation license, safety and efficacy proven (standard for regular
medicinal products).
Or
2. A traditional herbal registration license, safety and quality based on traditional usage
information.
There are a number of challenges related to the monitoring of herbal medicines which are listed below:
1. Regulation; different countries have different levels of regulation in place making it hard to
globally understand the levels of adverse events associated with herbal medicines (Bast et al.
2002 and WHO guidance 2004).
2. Quality Control; if it has not been regulated properly contaminants could be an issue and
result in more adverse events being experienced and therefore reported. Often multiple
actives are used in a single product and the reverse is also true that single actives are used in
multiple products. Knowledge of the potential implications of mixing products is vital to
maintaining consumer safety.
3. Linking consumption and risk; as a high-proportion of herbal medicines enter the market as
non-prescription remedies, it makes it hard to establish risks associated with consumption, as
it is hard to determine how many individuals are taking the product and how much they are
ingesting (Barnes 2003, Bast et al. 2002 and WHO guidance 2004).
Some of these challenges can also be related to any potential monitoring programmes for GM food
and feed. The need for monitoring of GM foods and feeds in the EU will be decided on a case by case
basis according to the risk assessment and is likely to mean discrepancies in regulation between
different countries potentially making it harder to compare safety data. The lack of clear consumption
data will perhaps provide the major challenge in terms of monitoring of GM food and feed, as it will
be very hard to determine how much and how many people are consuming. Bast et al 2002 and Barnes
et al 2003 suggest the future of PharmacovigilancePost-Market Monitoring in herbal medicines is in
more active surveillance initiatives, around pharmacy-record linkage and in areas of pharmacogenetics
and increasing the awareness of the public about risks and how to report adverse events.
4.5.
Veterinary Pharmacovigilance
Comparatively fewer papers were available in the literature on veterinary Pharmacovigilance. Two
papers progressed to the final review stage, as the rest were not in scope of the selection criteria. PMM
of veterinary drugs has been based on human Pharmacovigilance systems. One difference between
human Pharmacovigilance and veterinary Pharmacovigilance is that, veterinary Pharmacovigilance not
only monitors animal health, but it also monitors the safety of animal-derived products e.g. meat and
dairy products and animal owners/practitioners who come into contact with veterinary medicines
(Iraguen et al. 2010). The International Cooperation on Harmonisation of Technical Requirements for
Registration of Veterinary Medicinal Products (VICH) outlines a spontaneous reporting system for
adverse drug reactions (Iraguen et al. 2010). Manufacturers, veterinary practitioners and owners of the
animals are all encouraged to report any potential adverse reactions, to a medicinal product, that they
observe (Iraguen et al. 2010 and Moore et al. 2005). Similarly to spontaneous reporting in human
Pharmacovigilance, once the reports have been sent to the regulatory agency, they are reviewed for
EFSA supporting publication 2015: EN-739
25
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
accuracy and completeness and any additional information required is obtained through follow-up
interviews (Moore et al. 2005).
In the paper by Iraguen et al. (2010) the authors present the results of a pilot Pharmacovigilance
programme in Chile, which makes use of a combined surveillance approach. Veterinary practices and
veterinarians were recruited and a list of the most commonly used drugs in dogs and cats were
compiled. Once this was completed, a visit was scheduled to brief the veterinarians on what was
expected of them and to provide information on the study. Vets were asked to report any ADRs they
detected in their patients as a result of treatment with a drug considered in the study list, via an ADR
reporting form. Phone, postal and email submission of an ADR report were accepted. Animal owners
were also asked to participate in reporting any ADRs they noticed in their pets. They were instructed
on potential reactions to watch for by their local veterinarian and that if they saw a reaction that they
should bring their pet to their local clinic. Only veterinarians themselves completed the ADR forms.
After the six month trial period the study organisers re-visited the clinics to review patient records and
track the number of actual adverse reactions, compared to the number reported.
Similar to human Pharmacovigilance there are a number of limitations and strengths to veterinary
Pharmacovigilance. The strengths of Pharmacovigilance tended to remain the same whether veterinary
or human. For example: The strengths of spontaneous reporting are that it is the most cost effective
method, offering the widest breadth of surveillance. In comparison the strength of active surveillance
is the ability to detect adverse events even if there is a delay between consumption and occurrence of
an adverse reaction.
Some of the limitations of the veterinary Pharmacovigilance surveillance methods are discussed. The
study by Iraguen et al. (2010) found that there were high levels of under-reporting from veterinarians,
although due to the pilot nature of the study, reporting rates may improve as veterinarians become
more familiar with the system. The review by Moore et al. (2005) discusses the variability in reporting
standards and that the number and type of reports are likely to be influenced by the reporter, which
incurs bias. Moore et al. (2005) suggest using veterinary practice databases as a method of controlling
variability in reporting standards. Standardised pull-down menus would reduce variability in entries
and promote consistency, making analysis easier. A full history of patient information would be
available and any clinical signs of an ADR as a result of a drug/vaccine treatment should be captured
via this method.
4.6.
Monitoring of Novel Foods
Post-Market Monitoring in novel foods is required on a case by case basis where the outcome of the
risk assessment deems it necessary (Alger et al. 2013). Post-Market Monitoring of novel foods is a
useful method to clarify expected exposure to the novel food, or novel food ingredients in ‘real world’
populations (Butchko et al. 1994 and Alger et al 2013). Current Post-Market Monitoring methods for
novel foods have been created using systems similar to those for drugs (Bons et al. 2010). In general
Post-Market Monitoring of novel foods requires two distinct processes to occur to be successful. One
of these is a food intake assessment and the other is the analysis of patient reported adverse effects
(Hepburn at al. 2006).
A number of studies have proposed methods for the Post-Market Monitoring of novel foods (Butchko
et all 1994, Allgood et al. 2001, Simojoki et al. 2005, Welch et al. 2011 and Willems et al. 2013).
Below the methodologies have been split by those for intake assessments and those for causality
assessment of adverse events for reporting.
EFSA supporting publication 2015: EN-739
26
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
4.6.1.
Food and Nutrient Intake Assessments
Intake assessment before and during exposure is an important assessment to make, as it allows the
elimination/determination of other potential triggers for an adverse reaction that might be seen (Welch
et al 2011).
Intake assessment in the analysed literature were obtained through active surveillance methods, in
particular quantitative questionnaire formats (Butchko et al. 1994 and Simojoki et al. 2005) and food
diaries (Butchko et al. 1994, Alger et al. 2013 and Willems et al. 2013). Questionnaires such as the US
Menu Census Survey/ National Health and Nutrition Examination Survey (NHANES) collect
consumption data from thousands of individuals. Households are asked to record all food eaten over a
two week period and these two week surveys run consecutively throughout the year. There are other
similar consumption surveys in Canada and Europe (Butchko et al. 1994, Hepburn et al. 2006). One
such study by Simojoki et al 2005 used data from 15 independent health surveys to analyse
consumption of phytosterol products e.g. ‘Flora Pro-Activ’ in Finland. Participants were selected
randomly and consumption of phytosterol spreads was determined via questions on the purchasing
choice of fat/spreads.
Willems et al. 2013 summarise results from Post-Market Monitoring on the consumption of
phytosterols e.g. Flora Pro-Activ in; Belgium, Germany, France, the Netherlands and the UK. In this
study households were recruited to cover a wide demographic. They were then issued with barcode
scanners, and every food item they bought was scanned. The scan data was stored electronically and
used to calculate household and country intake data of phytosterols. One of the limitations of this
particular study is that intake was based on overall household rather than individual consumption data
and did not take into account that some of the product may not have been consumed at all e.g. the
product was thrown away . This makes it is hard to determine how much of the purchased product the
members of the household are eating. Work done by Neuhouser et al. 2001 describes a method for
dietary assessment in individual participants. This involved an active approach where interviewers
questioned randomly selected participants about their eating habits, requiring them to estimate portion
sizes for various food groups.
One of the major issues with intake assessments is the ability of the consumer to identify a particular
novel food in a product they are eating (Kingston 2005 & Hepburn et al 2006). Unlike in the
pharmaceutical industry where professionals prescribe a fixed product and dosage, with novel foods it
is often hard for individuals to assess their level of consumption. Therefore it is much easier to
monitor branded products as consumers are more aware of the presence of novel foods. It has been
suggested that methods involving radio-tagging of un-branded products may help with these
traceability issues (Hepburn et al. 2006).
4.6.2.
Assessment of Reported Adverse Events
Assessment of reported adverse events in novel foods is similar to that for pharmaceuticals. A
combination of passive and active surveillance methods is the most commonly reported system for
monitoring of adverse reactions. Welch et al. 2011 outline guidance on conducting human intervention
studies to evaluate the health benefits of food. In relation to adverse reactions, the guidance presented
states that all adverse reactions noticed by the study leader/healthcare professional should be reported,
whether or not it is believed to be related to the consumption of the food product (Welch at al. 2011).
Other studies that used spontaneous reporting systems e.g. charge-free product care lines and
physician reports, to gather information on adverse drugs reactions include the Butchko et al. 1994
study on Aspartame and the Allgood et al. 2001 study on Olestra. Charge-free product care lines are
used by manufacturers as the most rapid method of obtaining feedback on adverse reactions
experienced by a consumer. Care lines provide extensive coverage of potential consumer groups (Wal
EFSA supporting publication 2015: EN-739
27
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
et al. 2003), as unlike active surveillance approaches, care lines can cover entire populations rather
than a demographic (Ronaldson 2011).
Using Flora Pro-Activ manufactured by Unilever as an example, best practice methods for running a
care line are discussed. Unilever developed a global charge-free customer care line to collect
consumer views on the product in an unbiased manner. The staff on the care lines were given training
so that they were able to distinguish calls that related to health complaints and to obtain detailed
information from the caller on the nature of the potential adverse reaction. This could include
information on: patient demographics, levels of consumption, the severity and duration of the reaction
and if medical assistance e.g. a hospital visit was required (Hepburn et al. 2006, Allgood et al. 2001
and Wal et al. 2003). Once the information on the adverse event had been gathered, the data could be
sent for internal and external review, by trained medical professionals e.g. toxicologists and clinicians
(Wal et al. 2003). The reports were then coded based on the level of association between the
consumption of the product and the reported symptoms (Lea & Hepburn 2006). Level of association
was coded as follows: RED, an association between intake and the occurrence of symptoms can be
explained by the known molecular properties of the product; ORANGE, an association between intake
and the occurrence of symptoms cannot be explained by the known molecular properties but causation
cannot be excluded; YELLOW, an association between intake and the occurrence of symptoms cannot
be explained by the known molecular properties but causation can be excluded; GREEN, there is no
association between intake and the occurrence of symptoms (Lea & Hepburn 2006). Two other codes
were used to indicate reports that were not relevant and those which lacked information (Lea &
Hepburn 2006). During the first year of marketing Unilever received 84,000 calls to the care line, of
which <1% were related to health complaints. Of those 227 health complaint calls, none were coded as
RED but 142 were coded as ORANGE (European Commission, 2002). The number of ORANGE
coded reports was well within the expected levels of occurrence of symptoms, within a population.
After reports had been coded, an outcome assessment summary was sent back to the consumer care
line. Every call made to the care line was monitored to check for any unknown/unexpected side-effects
and to decide whether further studies into unexpected potential adverse effects were necessary (Lea &
Hepburn 2006). Other good examples of manufacturers utilising care lines are; Proctor and Gamble
for their fat-replacement Olestra (Allgood et al. 2001) and the Nutrasweet Company for their sugar
replacement Aspartame. Active surveillance for adverse reactions was usually conducted by the
manufacturer of the brand after reports of adverse reaction to the product had been received e.g. The
Nutrasweet company for Aspartame and Procter & Gamble for Olestra (Butchko et al. 1994 and
Allgood et al. 2001). Active surveillance of novel foods in the above studies was designed as a postmarket clinical trial. In the Post-Market Monitoring of Olestra, three post-market clinical trials were
designed. These were a; re-challenge study, an acute consumption study and a six week consumption
study. The re-challenge study included patients who had previously reported an adverse reaction to
Olestra to see if the effect could be replicated. The acute consumption study was used to assess the
effect of level of consumption on potential adverse effects. Participants were allowed to eat as much or
as little as they wanted and the adverse events were recorded. The final trial was the six week
consumption study. This was a longitudinal study where households were asked to record daily chip
intake to see if Olestra had any long-term effects (Allgood et al. 2001). All trials were randomised and
contained a placebo group who did not consume any of the novel food, which is similar to the design
of the studies to assess adverse reactions to aspartame mentioned Butchko et al. 1994. Outcomes of the
Olestra trial found that there was no increased incidence of adverse events in the Olestra group over
the control group. Reporting levels were also found to be highest just after the first release of the
product (Allgood et al. 2001).
A major difficulty when monitoring potential adverse reactions to novel foods is that it is often hard to
establish whether a particular effect was the result of the consumption of the product in question (Lea
and Hepburn 2006 and Butchko et al. 1994). For example, reports of adverse events to consumer care
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
lines about Flora Pro-activ and Olestra, detailed a number of events where a causal relationship could
not be excluded, but could also not be confirmed as a direct result of the consumption of the product.
This is particularly true of gastrointestinal effects which could be due to a number of other factors
(Lea and Hepburn 2006 and Butchko et al. 1994).
Although these monitoring schemes were successful in confirming the safety of novel foods, a
consensus among the literature is that, work to develop tailored monitoring schemes for novel foods is
still required (Hepburn et al. 2006 and Alger et al. 2013) e.g. methods for defining causality (Lea and
Hepburn 2006 and Butchko et al. 1994). Developing tailored schemes for GMOs would be arguably
more difficult than for novel foods, because novel foods generally provide added value (to the
consumer), are more contained in a fewer number of products and are recognised by consumers and
vendors as a specific brand. As added value products, a premium price can be attached to the product
and tends to mean the manufacturers will market the product as a brand e.g. Flora ‘Pro-Activ’ and
Olestra. By branding the product, the manufacturer makes it much easier to track in the supply chain,
and for consumers to identify in terms of consumption and adverse events. If, for example, a product
contained GMO soybean oil in a blend with other oils, it would be much more difficult for a consumer
to identify and therefore link any adverse events back to the product. Therefore monitoring of GMOs
is potentially more complex and will require more active approaches to surveillance than novel foods
as consumer are unlikely to know that they have ingested the product.
EFSA supporting publication 2015: EN-739
29
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
4.7.
Summary of existing monitoring programmes
Table 4 has been included to provide a brief summary of how methods of Post-Market Monitoring programmes vary for the different products that they are
designed to monitor e.g. intake assessment in Pharmacovigilance for monitoring of drugs will differ considerably from post-launch monitoring for novel
foods.
Table 4:
Summary of existing monitoring programmes
Monitoring Method
Pharmacovigilance
Vaccinovigilance
Passive Surveillance
Active Surveillance
Prescription Event Monitoring
Intake Assessment
Spontaneous
reporting
of
adverse events by healthcare
professionals e.g UK yellow
card scheme and by patients e.g.
consumer care lines to the
relevant authority or license
holder
Spontaneous reporting is the
most common method of
Pharmacovigilance.
Observational studies e.g. casecontrol studies (use of nontreated patients as the control
group to compare to those of the
drug),
cohort
studies
(monitoring individuals from a
specific cohort over time) and
large simple safety trials, postmarketing clinical trials
A combination method of passive
and active surveillance which links
drug prescription data to healthcare
practitioner adverse event reports,
potentially making it easier to
determine causality.
As most drugs are
prescription only, intake
should be straightforward
to determine.
Spontaneous reporting schemes
are similar to those in
Pharmacovigilance. Countries
tend to have dedicated national
vaccine reporting centres e.g.
VAERS (USA)
Most commonly described in the
literature as the surveillance
method of choice. Use of casecontrol and cohort studies
mentioned. The design of the
studies was similar to that of
Pharmacovigilance.
Similar
process
to
Pharmacovigilance
called
‘Electronic data linkage.’ Use of
electronic data records to determine
causality.
As most vaccines are
prescription only, intake
should be straightforward
to determine.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food
Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an
output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the
rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Monitoring Method
Cosmetovigilance
Herbal Medicines
Veterinary Pharmacovigilance
Passive Surveillance
Active Surveillance
Prescription Event Monitoring
Similar to the reporting systems
for drugs. Spontaneous reporting
to Care line and by healthcare
professionals does occur but
generally reporting occurs at a
much lower rate than for drugs.
Trial design is similar to that of
the cohort studies. Patients with
potentially adverse reactions
were recruited and assessed for
dermatological skin reactions to
products. Greater levels of active
surveillance could improve
reporting rates.
Products are usually bought over the
counter so this type of surveillance
is generally not possible.
N/A
In countries like Germany where
herbal medicines are regulated
as drugs, traditional reporting
systems
e.g.
spontaneous
reporting or post clinical trials
are in place
In countries where herbal medicines
are regulated as drugs, traditional
reporting systems are in place e.g.
Germany
Usually bought over the
counter and without a
prescription determining
the actual amount taken is
hard.
Similar to Pharmacovigilance.
Veterinary practice databases used
to provide patient information and
treatment/prescription information
which can be used to help determine
causality
Based on owners being
able to dose the correct
amount but as most drugs
are prescription only
intake,
should
be
straightforward
to
determine.
Most common method of
reporting as drugs are usually
available over the counter.
Spontaneous
reporting
by
healthcare professionals and
patients. Under-reporting due to
the
lack
of
healthcare
professional supervision and
information on behalf of the
patients.
Spontaneous reporting systems
are similar to those for
Pharmacovigilance.
Although
animal owners can encouraged
to report adverse events to the
Veterinarian.
Only
the
veterinarian can report the
adverse events
EFSA supporting publication 2015: EN-739
Intake Assessment
31
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food
Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an
output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the
rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Monitoring Method
Novel Foods
Passive Surveillance
Active Surveillance
Prescription Event Monitoring
Intake Assessment
Spontaneous reporting is the
common form of monitoring.
This
usually
occurs
via
consumer care lines. This
information is processed by the
manufacturer and then sent to
the
relevant
regulatory
authorities. Some reports are
collected
from
healthcare
professionals.
Active surveillance takes the
form of cohort and case-control
trials
and
consumption
questionnaires.
Novel foods are not prescribed so
this cannot be done,
Food
diaries
and
consumption
questionnaires are used to
determine intake.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food
Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an
output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the
rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
5.
WORK PACKAGE 2 - INVENTORY OF DATA COLLECTION METHODOLOGIES
ASSESS FOOD CONSUMPTION/COMPOSITION AND HUMAN AND ANIMAL HEALTH
TO
The overall objective of Work Package 2 was to identify and describe programmes (survey,
monitoring or surveillance) that would be relevant for PMM of GM food and feed. Our approach was
to identify and describe existing data in the EU that would facilitate PMM, majoring on food
composition and consumption data. We start by giving an overview of the regulatory requirements on
food business operators for traceability and labelling, and for GMOs in particular to understand the
extent to which ‘tracking’ GM traits is possible in food and feed supply chains.
5.1.
Regulatory requirements for traceability and labelling
To fully understand the extent to which PMM of GM food and feed is possible, the EU requires an
understanding of how the requirements of other legislation can aid its implementation.
5.1.1.
Traceability requirements
Regulation (EC) 178/2002 aims to ensure the quality of foodstuffs intended for human consumption
and animal feed, as well as the free circulation of safe and secure food and feed in the internal market.
Operators are responsible for ensuring the traceability (Article 18) of substances incorporated into
foodstuffs at all stages of the supply chain, including production, processing and distribution.
The requirement relies on the ‘one step back - one step forward’ approach which details that food
business operators (FBOs) must:



Have in place a system enabling them to identify the immediate supplier(s) and immediate
customer(s) of their products.
A link must be established which gives information on which products are supplied from
which suppliers.
A link must be established which gives information on which products are supplied to which
customers. Nevertheless, food business operators do not have to identify the immediate
customers when they are final consumers.
Figure 2: system of traceability under Regulation (EC) 178/2002
The traceability requirements under Regulation (EC) 178/2002 mean that in theory, through
questioning, it is possible to trace products back to their origin. However, the following factors mean
that traceability legislation could not currently ensure an accurate system of PMM:

Regulation 178/2002 would not apply to all operators in third countries beyond the importer.
As such the ability to trace back to source requires traders and processors importing raw
materials to food businesses in the EU to have a robust understanding of the producers from
which raw materials have come from. For a system of PMM to be possible on an individual
trait level traders/processors must be able to inform the FBO in the EU which variety of plant
they have purchased as raw material.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed

Under traceability requirements FBOs do not have to provide robust data on the provenance of
their product, i.e. giving information on which GM trait is included within a batch of raw
materials.

Traceability requirements do not require FBOs to detail which customers have bought the
product if these are final consumers, i.e. a retailer does not have to keep records on every
customer which has bought a particular product.
5.1.2.
Specific requirements for GMOs
Regulations (EC) 1829/2003 and 1830/2003 set out specific requirements for controls on GMOs in
food and feed. The regulation applies to GMOs for food and feed use, as well as food and feed
produced from or containing ingredients produced from GMOs. All products covered by Regulation
(EC) 1829/2003 are subject to compulsory positive labelling, indicating whether the food or feed
contains, consists of or has been produced from GMOs (a ‘GM food’). For food, under Article 13 the
name of the ingredient (e.g. ‘soya’) must be given, however more specific information is not required
which would indicate the particular trait that has been used. The label must also mention where a GM
food is different from its conventional counterpart as regards its composition, nutritional value or
nutritional effects, intended use of the food, implications for the health of certain sections of the
population and where a food may give rise to ethical or religious concerns. Under Article 25, similar
labelling requirements are in place for feed including mentioning where a feed is different from its
conventional counterpart in terms of its composition, nutritional properties, intended use, implications
for the health of certain species or categories of animals and as specified in the authorization any
characteristic or property where a feed may give rise to ethical or religious concerns.
Under Regulations (EC) 1829/2003 and 1830/2003 wider traceability requirements for GMOs are in
place to facilitate the withdrawal of products where unforeseen adverse effects on human health,
animal health or the environment, including ecosystems, are established. Traceability requirements are
also in place to facilitate accurate labelling of these products as detailed above. The legislation sets out
the conditions for the transmission of information that products contain or consist of GMOs, and set
out the conditions for the use of unique identifiers. Commission Regulation (EC) No 65/2004 of 14
January 2004, established a system for the development and assignment of unique identifiers for
genetically modified organisms. The Regulation applies to all genetically modified organisms that will
be imported into the Community for cultivation and for human food and animal feed, except medicinal
products for human and veterinary use. The identifier is made up of 9 characters, including letters and
numbers, combined in a uniform way. If GM content exceeds legal thresholds (0.9%), the
identification code(s) must accompany shipments of GMOs. The code can be used to retrieve
information about the respective GMO from international databases. Under Regulation (EC)
1830/2003 at the first stage of placing on the market (from producer to first third party i.e. trader) of a
product consisting of or containing GMO (such as soybeans), including bulk quantities, operators must
transmit the following information in writing:

An indication that the products consist of or contain GMOs;

The unique identifiers assigned to the GMOs.
If the product is a mixture of GMOs, the operator must submit list of the unique identifiers assigned to
all the GMOs used to constitute the mixture. At all subsequent stages of the placing on the market of
these products the information above must be transmitted in writing to the operators receiving the
products. As the unique identifier must label all GM traits within a batch of material, multiple
identifiers may be placed on the same batch. Theoretically, an operator may also list multiple traits on
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
a batch whether they are included or not, just to ensure that all possible traits that could be included
are listed.
For food and feed products produced from GMOs (e.g. oils and soya lecithin) the following
information must be transmitted:

An indication of each of the food ingredients which is produced from GMOs;

An indication of each of the feed materials or additives which is produced from GMOs;

In the case of products for which no list of ingredients exists, an indication that the product is
produced from GMOs.
As such, the requirements for a unique identifier which can define one GM trait from another ends at
the stage a product is further processed to be ‘produced from GMOs’ rather than ‘consisting of or
containing GMOs’. In order to track GMOs which require PMM down the supply chain, a system
would have to ensure the unique identifier is transmitted at all stages. The legislation does not require
the operator to stipulate the proportion of a GMO in each product. Requirements for labelling of
products containing GM do not apply in isolation, and must also adhere to general EU food labelling
laws.
5.2.
Assessment of food consumption
Data collection on food consumption can be broadly split into two main categories; (1) that collected
by member state or third countries to monitor food consumption, nutritional status and nutrient intake
at a national level, and (2) data collected by market research agencies and food retailers to monitor
purchases of food, largely for commercial purposes. Table.5 gives a summary of all these programmes
and their strengths and weaknesses for monitoring GM food and feed.
5.2.1.
Food consumption data collected by member states and third countries
Food consumption databases operated at a national level are surveys of consumption, nutrient intake
and nutritional status of people in the host country. They vary in their level of detail, and extent of
foods covered. As an example, the primary national survey of dietary intake in the UK is the National
Diet and Nutrition Survey (see PHE, 2014). This is based on interviews and diet diaries recording food
intake at the individual level and combined with urinary and blood biomarkers of nutritional status and
exposure. Equivalents exist in other countries, but are not present in all member states, examples
include the German Nationale Verzehrsstudie (see BMEL, 2009), and the French Enquête Individuelle
et Nationale des Consommations Alimentaires (see ANSES, 2013). These surveys provide good detail
on food consumed by a selectively representative sample of the population. They are cognitively
demanding in that they require individuals to faithfully record foods consumed. The accuracy of the
tools for collecting food intake data are well criticised and it is unrealistic to expect that accurate data
can be pulled from such surveys reflecting the specific brand and variety of a food consumed. The
nutrient intake data in these studies is largely approximated from the records of food intake coupled to
established food composition tables such as McCance and Widdowson.
Household budget survey data are available for each of the member states and collates data on
household purchases. From a nutritional perspective, these data sets are used to estimate fruit and
vegetable consumption in member states. The drawbacks of these types of survey are that limited
detail is provided on the distribution of consumption of foods between family members and the levels
of food wastage is not available. The data collection in this type of survey may however be supported
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
by the collection of household receipts which would allow for some extrapolation back to the
individual food items purchased for the approximation of the nutritional content of purchased food.
Separate to the data on food intake and purchases collated by member states, there are also data
available on food intake from large cohort studies through the EU, the European Prospective
Investigation into Cancer and Nutrition (EPIC) study is an example of this and captures rich data on
nutritional intake and status through the Eurozone which may be linked to disease outcome measures.
The strength of the EPIC dataset is the common means of data capture used in each of the member
states involved. The dataset does however suffer the same limitations as the national diet and nutrition
surveys (see EPIC, 2014).
The data collection and exposure unit of EFSA (DATEX) collect and analyse data on food
consumption from the member states. The aim of analysing the food consumption data is to assess
exposure to hazardous chemicals. A number of short-comings with some of the other food
classification systems led DATEX to develop FoodEx in 2008 (see EFSA, 2011). FoodEx is a
hierarchical food description and classification system containing entries on approximately 1,700
foods, taking into account legislative information on maximum levels of contaminants and residues
allowed. The FoodEx system has helped to facilitate EU wide exposure assessments and accurate
matching of datasets to determine causality. One of the main benefits of the system, is that it
harmonises food consumption data entries across the EU allowing member state comparisons. It does
however have a number of limitations with regards the foods included in the system, for example, no
details are provided on branded products and very limited details are provided on food ingredients.
The EU menu survey combines aspects of both the Household budget survey and the EPIC study (see
EFSA, 2014). It is still under development, but the major aim of the survey is to standardise methods
of collecting food consumption data across all member states to help in the analysis of food
consumption data. Not all member states are currently reporting on the food consumption within their
countries. The hope is that the EU menu survey will improve the quantity and quality of food
consumption data coming from all EU member states. The reason for standardisation is because it is
currently hard to compare different country’s nutritional information data as methods of collecting
data differ. The EU menu survey will allow accurate, EU wide assessments, on the potential safety and
exposure risks of food and the nutritional status of sub-groups within Europe. The real limitation of
this survey is that it is not currently possible within this system to track brand ingredients and GM
products into food. The food consumption data is collected by the private sector.
5.2.1.1. Data held by retailers/supermarkets
Data on the food purchases of households are collected by major food retailers for commercial
purposes. Many of the major retailers trading in Europe now operate loyalty or ‘club card’ systems,
whereby consumers electronically scan a card when buying groceries in exchange for ‘points’ which
accumulate to qualify the consumer for offers or money off future shopping. Consumers provide basic
personal details and data on purchases made are held by the retailer. The data generated offers an
exhaustive list of what has been purchased by the consumer, however, this does not indicate accurately
the amount of the product consumed or hold demographic information such as the number of people in
the household and their ages etc. Furthermore, whether data are collected depends on whether the
consumer ‘scans’ his or her loyalty card at each visit to the supermarket. Card data would not
necessarily give a complete picture of all items a particular consumer had purchased if that consumer
shopped at multiple stores. Data held includes product names, which gives the possibility to work with
manufacturers or the retailer to combine this with composition data, including GM ingredients. As in
the national household budget surveys inferences regarding the distribution of dietary intakes amongst
individuals within the household are hard to draw from these data as is approximating the levels of
food wastage.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
5.2.1.2. Data held by market research companies
Independent third market research companies such as ‘Kantar’ perform market research on food
purchases in some European member states (see KantarWorldpanel, 2014). Data are typically sold to
private companies operating in the food sector to provide insights which will help their business. In
the example of Kantar, 30,000 households which are demographically weighted are used to provide a
nationally representative sample of UK food purchasing. The Kantar database holds data on the
nutritional values of 100,000 products by category, manufacturer, retailer or individual product,
assuming reference food composition data are available. Nutritional data for each product is then
linked to a range of shopper demographics such as salary, region and number of children in the
household. Survey subjects in the 30,000 households are asked to scan all food and drink products
brought into the home. These data give a detailed analysis of food available in the home which can be
linked back to individual food items, and therefore, to the provision of nutrients for the household. By
the same reductionist process the purchasing of ingredients as part of complex foods might be
identified with these datasets. In its present form the Kantar data does not give any information on
provenance of a food product, or ingredients and this would have to be built in to give any information
on the inclusion of GM food or feed. As with data held by retailers/supermarkets food wastage is not
taken into account. The Kantar dataset only captures information on products brought for consumption
in the home and has no facility to scan food consumed outside the home in the wider foodservice
sector. Kantar operates the service in the UK and Spain, however other market research companies
offer similar services which have the ability to record data on food purchases wider in the EU.
5.2.1.3. Data collected by private food manufacturers
Outside of food purchase, and market research data, data may be held on the consumption of products
by individual food companies. For many companies some level of consumption data may be collected
routinely after the launch of new products to check that consumer use patterns are as expected (van
Puijenbroek et al 2007). As this data is generally classed as commercial in-confidence no information
is held on the extent to which this is available. Based on informal consultation with the industry the
extent of more detailed consumption data are thought to be limited, as gathering it is costly, and in
many cases provides no immediate gain. Data of this nature is generally not publicly available, and
details
are
limited.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Table 5:
Summary of data collected for food consumption in the EU and its positives and negatives for the PMM of GM food and feed
Available tools
Household budget
surveys
Geographic coverage
By individual Member
State and many third
countries
Positives
Data on purchases can include identifiers for specific
products
Negatives
Purchases of food eaten out of the home poorly captured
No data on actual consumption
By individual Member
State and many third
countries
Good data on food consumption at the individual level
Food intake data is usually only available for aggregate
food items
The data collected is reliant upon awareness of the
consumer
No harmony between data collection methods between
national surveys
Many of the surveys from individual states are now dated,
not every Member State has a rolling programme
Held at EU level
Aggregation and collation of data held by member
states
Limitations are as per domestic national surveys
National diet and
nutrition surveys
FoodEx Classification
System
No harmonisation of data collection methods between
member states
An aggregate list of food items with no detail on specific
food brands
Insufficient detail to capture data on food ingredients
Very poor quality data on food eaten out of the home
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food
Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an
output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the
rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Held at EU level
Still in development
Still in development
Good data on dietary intake
Food composition databases don’t currently keep
information on brand ingredients
No system for tracking GM into food ingredients
Supplementary information on food brands may allow
some deeper analysis of exposures based on ingredients
EU menu
Harmonisation between member states
Worldwide
Data in the private
sector
Supermarkets and market research groups have good
data on household purchases
The data is on purchasing and not on intake
Data at a product and brand level may allow some
deeper analysis of exposures based on ingredients
There are few identifiers as to whom in the household is
consuming what
No data on food eaten out of the home
Data only available from large retailers, and may miss
purchasing habits of large sections of the community
using independent retailers
No harmony in data collection between member states
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food
Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an
output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the
rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
5.2.2.
Current data gaps to calculate food consumption
The diet and nutritional surveys are intended to monitor nutritional status, the potential for deficiency
or toxicity disease in the population, and the adherence to dietary guidelines, or to justify new
guidelines. The cohort study data are designed to assess links between dietary exposures and disease at
the population level. The household budget surveys principally contribute to economic planning,
whilst the private data are largely collected for market research purposes. Estimates of the intake of
nutrients can be made from these surveys with reference to food composition tables, there is a case for
integrating the data in these different types of survey to model dietary exposures where the data fails
to capture these exposures. For example, household budget survey type data can couple food
purchases to geographical regions or socioeconomic status, whilst the nutritional surveys can be used
to identify who within the household is likely to be consuming particular items of the food purchased.
This approach may also be valid for the purposes of assessing the consumption of GM foods but
would require a significant re-evaluation of the food data available. For example the abundance of a
GMO in the national diet could theoretically be estimated if data from household budget surveys
allowed for an estimation of the purchases of food items containing that GMO, the national dietary
survey could then be applied to predict who within the household was likely to be consuming that
GMO.
This approach may be of value from a public health perspective if consumption of the GMO is likely
to induce population level changes in exposure to nutrients or non-nutritive components of the diet,
particularly if there are likely to be vulnerable groups within the population, e.g. pregnant women,
those vulnerable through morbidity or infants. It would not, however, provide useful direct data on
acute adverse events associated with consuming the GMO.
The principle barriers to this strategy are that no food composition database currently contains data on
the GM content of composite food items and data capture on the consumption of whole foods is reliant
on an educated consumer in its present format. It is unlikely that most consumers/survey respondents
will universally recognise whole food GMOs and very unlikely that they will identify the GM
components of composite foods.
5.3.
Assessment of feed consumption
5.3.1.
Feed consumption data
Individual farms will, in some cases keep records of what feed, in what quantities have been fed to
livestock. The EC Feed Hygiene Regulations require farmers that mix feed on farm (without additives)
to record the source and quantity of feed used (e.g. through invoices, receipts, delivery notes and feed
labels). Feed consumption databases recording nutrient intake, as are maintained for food, do not exist
for large populations of animals in specific countries. In the UK high level information on raw
material usage and the production of compound feeds are provided by a monthly survey of animal feed
companies and of specialised integrated poultry units (see Defra, 2014).
5.3.2.
Current data gaps to calculate feed consumption
It is assumed that GM varieties developed as feed ingredients will target large market segments (e.g.
broilers, or pigs). The GM variety may be used by a feed processor, or merchant as an ingredient in a
ready mixed, or ‘compound’ feed, or may be used whole by the end user (the farmer) in his own feed
mix. The level of data on consumption of feed that is available for specific farms, will largely be
dependent on the nature of the farmer or the requirements of feed hygiene legislation. Whilst some
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by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
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individuals may keep diligent records, using technology such as feeder wagons that monitor the
amount of feed given, and its composition, other farmers may work on the principles of tradition,
simply doing business as they always have and not keeping comprehensive records. However
comprehensive consumption data may be at a farm level, it is likely that this would be for a group of
animals, rather than individuals.
5.4.
Assessment of food composition
5.4.1.
Publicly available food composition data
The food composition tables such as McCance and Widdowson in the UK provide estimates of the
composition of individual food items in terms of their nutritional and or physical composition (see
FSA, 2010). The data within these tables is often based upon approximations of the mean nutrient
content for amalgamations of a food item, which can be inaccurate. Nevertheless, inferences or
approximations of nutritional intakes are extrapolated from these databases based on information
collated in the food surveys on purchasing and intake. These tables are good for single foods (e.g.
eggs, cheese, bread and fruit) but lack accuracy for more complex dishes due to the complexity in the
number of ingredients included. As food composition tables list one generic product, they do not take
into account the variances between different products within the same category, for example a prepackaged ready meal sold in a supermarket may vary in calorie content between brands and
manufacturer. Efforts do exist at the European level to harmonise food composition data, and the
EuroFIR project draws together food composition information from 26 compiler organisations in
Europe, Australia, USA and Canada (see EuroFIR, 2014). Crucially however, in their current format
the composition databases do not specifically identify the GM components of a food or varieties of
plant included in the product and so provide limited value to PMM programmes.
5.4.2.
Privately available food composition data
Food composition data may also be held by private companies in the food sector, such as
manufacturers, retailers and food-service operators.
5.4.2.1. Food retailers
Food retailers typically use food composition tables to source nutritional data on their products to
display on the packet. Where available, retailers may also utilise analysis of nutrients directly from
manufacturers or other historical data. In terms of determining the varieties of GM food or feed in a
product, the level of composition data held by the private sector is mixed. Under Directive
2000/13/EC (repealed by Regulation (EC) 1169/2011) food labelling and packaging laws require that
if a food or drink product has 2 or more ingredients (including additives), these must be listed in order
of weight. However, this is not required for catering businesses or those who sell food loose.
Additionally labelling laws require that the product carries a notification if it contains GM ingredients
(unless their presence is accidental and 0.9% or less). As such current labelling laws would not dictate
that an operator would need to label the specific GM food or feed in their product. Major grocery
retailers across the EU collect data on the provenance of their own-brand products. The level of
information held varies from product to product, with primary products such as fruit and vegetables
where a specific supplier code provides information on the exact location where the product is grown
and information on the variety to more general product specification data (per comms). In order for a
system of PMM to be successful further data would be required in terms of the variety of raw material
used to determine its status as a GMO. Own brand foods make up a growing proportion of food and
beverage products sold by retailers across Europe.
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procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
For branded products (i.e. those carrying a brand other than the retailer’s own-label) less data are held
by retailers on composition, this being left to the specific manufacturer to maintain records
themselves.
5.4.2.2. Foodservice operators
Under food labelling laws, catering businesses are not required to provide a list of ingredients on the
food or drink they sell. The only information on composition that would be required is the name of the
food, whether ingredients have been irradiated or are GM and additions of any food additives. As
such, for foodservice operators there is likely to be a large scale of variability on the type of
information that is held on products. Whilst major restaurant chains may have detailed composition
information for specific products/meals, minor chains or single businesses are unlikely to keep or have
the facility to obtain such information.
5.5.
Assessment of feed composition
5.5.1.
Feed composition data
The composition of feed, fed to commercial livestock in many cases would be known either by a
farmer, or a manufacturer. However, there exists no central data source which holds all these data.
Where feed is mixed on-farm (with additives or premixes) the EC Feed Hygiene Regulations
(183/2005) require farmers to record information on the source and quantity of each input of feed, for
example a description of the feed used, produced or sold, the quantity, batch number, the date received
and from which supplier. If the feed has been mixed by the farm itself, depending on the nature of the
farmer, records will be kept of the proximate analysis (e.g. energy, protein, vitamin and mineral
content), in order to measure its effect on animal performance. However, as provenance data on
specific feed types are not generally known by the farmer these data would be of limited value, unless
the farmer were purchasing a specific ‘value-added’ GM product which was distinct from other feed
types. Where a farmer is buying ready mixed, or ‘compound’ feed the composition will be known by
the manufacturer/processor and the farm would record the type of feed purchased, but may not record
its ingredients (if these are known). For compound feed developed by a specific manufacturer, exact
composition data on the proportion of ingredients included is usually commercially sensitive and not
available. Where farmers are members of farm assurance schemes they may be required to record the
composition of feed offered to their animals or adhere to an ‘allowed list’.
Feed composition data for animal feeds do exist, such as the ‘Feedipedia’ project which contains
information for particular feeds (such as ‘wheat’) in relation to descriptions, feeding
recommendations, composition and nutritive value (see Feedipedia, 2013). However, these datasets
much like food composition data are generic to general feed types (such as wheat) and do not include
provenance information on whether GM traits are included.
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Table 6:
Data available by feed type
Feed type purchased by farmer/animal owner
Data available
Compound feed (a feed composed of different Detailed composition data would be held by the
raw materials) sold by a feed processor.
feed processor, however this is likely to be
commercially sensitive and not available to
determine exact quantities of GM feed used.
‘Straight’ or concentrate feeds (feeds composed Provenance data on the product is unlikely to be
of one raw material)
known unless the feed bought was a GM variety
with some added value (i.e. high oleic oil) in
which case this information may be known to the
owner.
5.6.
Determining the inclusion of GM food and feed in products
For a comprehensive system of PMM according to the requirements of Implementing Regulation
503/2013 to be possible (see Section 6.1), some degree of tracking GM traits through the feed and
food chain would be required to determine which products they are included in.
In order to track products through the food and feed chains, the co-operation of multiple stakeholders
throughout the supply chain is a pre-requisite. GM traits that will require PMM are, in most cases sold
as a seed to a farmer/grower for cultivation.
For this example we assume a GM variety (soybean) is cultivated in a third country, and subsequently
shipped to the EU where it has an approval for use as food and/or feed, and is further processed into
multiple products before reaching the consumer. Figure.3 details the first stage of the supply chain,
from farmer to trader and processor, green arrows indicate where information on the GM variety is
passed through the supply chain, red indicates that keeping information on the GM variety is not
currently practiced. It is assumed that an applicant company would keep records of seed sold to
particular customers and that a farmer buying a GM variety would be aware of the variety that had
been purchased, and later sown. After a GM variety has left the field as an agricultural raw material
(such as soybeans or corn), under the requirements of Regulation (EC) 1830/2003 it must carry a
unique identifier which details the trait that is included in the batch. Where multiple traits are included
in the same batch all unique identifiers for the trait should be labelled (see Section 5.1.2). Traders may
import the raw material to a processor in the EU who would turn the raw material into an ingredient
(such as oil). Alternatively the processor may have the facility to process raw materials into
ingredients themselves and do this in the third country, or the EU country where the commodity is
imported to. As detailed in Section 5.1.2, once the raw material which is ‘consisting of or containing
GMOs’ becomes an ingredient which is ‘produced from GMOs’ it no longer requires the unique
identifier to be transmitted through the supply chain.
These ingredients will still require segregation of GM and non-GM to facilitate the positive labelling
of GM food and feed, but information would not be held on the specific variety. In the example of
soybeans further identification of the GM components may be possible after the raw material becomes
an ingredient if it has some higher value further down the supply chain. For example oil with high
oleic properties derived from ‘high oleic soybeans’ may be kept segregated for their added value to
users downstream, however it should be appreciated that this oil could consist of more than one
variety of GM ‘high oleic soybeans’. For a GM trait that does not confer any added value further down
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
the food chain (i.e. input traits) the GM component would be identifiable through labelling, however
not at a specific variety level or with a known proportion of the product.
Figure 3: The supply chain- producer to trader/processor
Once imported into the EU, a GM plant variety destined as food or feed will pass through multiple
stages before reaching the end-consumer. The two supply chains are discussed in detail below.
5.6.1.
GM varieties used as feed
Feed processors or merchants in the EU will typically purchase imports of a particular agricultural
product (soybeans, corn etc) and further process this with other products into compound feed for
different livestock. The final product could be as pellets, crumbles or meal and could include a variety
of grains such as soybean, corn, oats and barley etc. This means that in effect one particular type of
compound feed sold by a merchant/processor could contain more than one GM variety. In order for a
system of Post-Market Monitoring to be successful, a merchant or processor would have the know
exactly which GM varieties are contained within the finished product, and preferably at what
proportion.
The finished product would then go to a farmer who would need to keep records of which compound
feeds had been fed to his or her livestock. In effect, after all these conditions had been obeyed it may
be possible to confirm the effects of the GM variety in accordance with a PMM scheme.
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Figure 4: The supply chain for feed- post import
5.6.2.
GM varieties used as food
Agricultural products will be bought by food processors in the EU for further processing, and in
limited cases may also be bought in their current state (i.e. there is a limited food market for whole
soybeans). In the case of soybeans, it is likely that further processing will extract multiple by-products
such as soybean oil and lecithin which then could be sold to a final processor or manufacturer to be
used as ingredients in multiple other food products. The ability of a system whereby consumption of
particular GM varieties could be monitored will be dictated by the ability of the final manufacturer to
know which variety of soybean has been used in a particular product. If this can be achieved then this
information could be included in food composition data, and subsequently utilised in food
consumption data (see Section 5.2).
EFSA supporting publication 2015: EN-739
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Figure 5: The supply chain for food- post import
5.7.
Data to understand adverse effects
5.7.1.
Animal health reporting schemes
Animal health monitoring is carried out by public agencies in the EU, and at an international level to
monitor for emerging diseases and the trends with particular known diseases (such as mastitis). The
data underpinning these schemes are often provided by vets that have coverage of a particular Member
State. For schemes that operate at an international level, organisations that may provide information
include High Commissions and Embassies overseas, reference laboratories for animal health,
reference publications on animal health, the World Organisation for Animal Health (Office
International des Epizooties) and veterinary administrations of Member States. These schemes have
the potential to pick up instances of disease, or adverse effects which may have been triggered by
consumption of feed containing GMOs, however it is not clear the extent to which the effect could be
related to GMOs, or how many livestock would have to be affected to trigger a notification under such
schemes. In addition, whilst Member States have a responsibility to report certain notifiable diseases
(e.g. Bluetongue), it is uncertain the extent to which other diseases information is gathered on, and are
reported.
In commercial livestock farming, animal performance may be the best indicator of health status. If a
farmer was using a feed mix, containing GMOs which had negative effects on the performance of his
stock, there is always a risk that he would simply change the feed mix, rather than reporting the
effects. As such the extent to which adverse nutritional effects of using GMO varieties would be
recognised in animals is uncertain. Where a compound feed has been sold that has been produced by a
large processor this may be sold direct through the processor themselves, or through an intermediary
merchant. In all cases there is likely to be some channel for which the farmer purchaser can record
complaints or comments. This may be through an individual sales representative of the processor or
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
merchant, or could be to a central switchboard directly at the company from which the feed was
purchased. If the processor is able to collate adverse effects and link this with detailed composition
data of the compound feed sold then a system of cause and effect, such as that practiced in
Pharmacovigilance, may be possible. However, the system would rely on accurate compositional and
consumption data.
For detection of unintended effects in animals, again this will largely be dependent on the individual
farm. It is reasonable to conclude that most livestock farmers will utilise the services of a vet, however
this may only be in response to particular issues such as prevalence of a ‘well known’ disease, rather
than overall health monitoring. Technologies do exist for monitoring animal health on a farm level
(see data collection sources database), however only a subset of farmers would likely to be using it.
Overall it can be said that each farm is individualistic, and the amount of information held will be
largely dependent on the individual farmer.
Initiatives are underway to develop ‘sentinel’ surveillance networks for monitoring adverse effects in
primary production. An external scientific report completed for EFSA by Mönkemeyer & Schmidt
(2014) presents the results of a feasibility study to investigate whether farmer/producer associations/
federations can serve as sentinel surveillance networks for the detection of adverse events in the health
of agricultural plants and animals and the safety of new agricultural products in primary production.
The MARLON project aims to create an inventory of which epidemiological and monitoring
initiatives exist, both within and outside the EU, which could provide useful data for the purpose of
monitoring for health impacts of animal feeds, in particular those containing GM ingredients, on
livestock animals (see http://web.spi.pt/marlon/about.html#sthash.AeCuUq6V.dpuf).
5.7.2.
Human health reporting schemes
Example monitoring programmes that are used to detect unintended effects have been presented in
Section 2, and are applied for a number of drugs, vaccines and cosmetics as well as herbal medicines
and novel foods. Methods for gaining data on the effects of the product in the wider population include
actively initiated programmes by the manufacturer such as conducting questionnaires/interviews with
patients or post-clinical trials. Surveillance is also in place to respond to safety issues that may occur at
any time, and utilises methods such as consumer care-lines and professional reporting card schemes.
For almost all of these programmes, the product which is being monitored is often recognisable to
consumers, or has a controlled prescription, so causes are often linked more easily by consumers to
specific products. For example, in the case of novel foods, plant sterols in yellow fat spreads were
monitored by the applicant after product launch. However, the novel food was limited to a specific
product (Unilever’s ‘Flora Pro-Activ’) which was easily identifiable by the consumer. For foods
containing GMOs, the identification of adverse effects by consumers becomes more difficult, as the
GMO would in most cases be an ingredient in a food product. In this case, whilst label information
may state that the product contained GMOs, more detailed information on which GMOs may not be
given. Additionally, the reporting of adverse effects would need to be underpinned by robust
consumption and composition data.
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
DISCUSSION
6.
WP3 - THE ABILITY TO CONDUCT POST-MARKET MONITORING OF GM FOOD AND
FEED IN THE EU
6.1.
Requirements under Commission Implementing Regulation (EU) No 503/2013
Commission Implementing Regulation (EU) No 503/2013 set the conditions in which a proposal for
PMM should be submitted by an applicant. It states that:
“Post-Market Monitoring should only be considered in cases where, notwithstanding the fact that the
safety of genetically modified food and feed has been demonstrated, it is appropriate to confirm the
expected consumption, the application of conditions of uses or intended effects. This is for example the
case when the genetically modified food or feed has altered nutritional composition or when that its
nutritional value differs from the conventional food or feed that it would replace or when there is a
likelihood of increased allergenicity due to the genetic modification8”
The Regulation further elaborates on the role of PMM as an outcome of the risk assessment process.
In accordance with the outcome of the risk assessment, it is appropriate to confirm:
a) that specific recommendations of uses are followed by the consumer/animal owner;
b) the predicted consumption of the genetically modified food or feed; or
c) the relevance and intensity of effects and unintended effects detected during the pre-market risk
assessment which can only be further characterised by post-market monitoring.
PMM can therefore be split into two main sub-sections; (a) the calculation of consumption or use of a
GM food or feed in either animals or humans, which would lead to information to satisfy whether
recommendations of use are followed by the consumer/animal owner, and (b) to confirm any intended,
or unintended effects which have been identified during the pre-market risk assessment. Please note
that the scope of the legislation does not allow for monitoring of any unintended effects which have
not been highlighted at the risk assessment stage. As the Implementing Regulation concerns
requirements for specific applications it can be inferred that monitoring is required by specific trait,
rather than overall product. For example where two different traits confer a similar outcome, such as
high oleic oil derived from genetically modified soybeans, PMM would be required separately for
both traits. Given that all questions posed by the Implementing Regulation are prompted by specific
questions raised, and only focuses on monitoring effects and unintended effects which are highlighted
in the pre-market risk assessment, it can be classified as case-specific monitoring. As the legislation
does not allow for PMM to detect unexpected effects which are not detailed in pre-market risk
assessment, general surveillance monitoring is not foreseen under this legislation.
The Implementing Regulation does not make any mention of the length of time an applicant would be
required to monitor GM traits for.
8
Commission Implementing Regulation (EU) No 503/2013 (19)
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
The aim of this section is to determine the feasibility of conducting PMM of GM food and feed under
the requirements of the Implementing Regulation within the existing framework of available data
sources and programmes that currently exist in the EU.
6.2.
GM traits that would require monitoring
In order to assess the feasibility of PMM it is pertinent to suggest which GM traits would be covered
by the Implementing Regulation, namely:
1. GM food or feed with an altered nutritional composition
2. GM food or feed where the nutritional value differs from the conventional food or feed it
would replace
3. GM food or feed with an increased likelihood of allergenicity due to the genetic modification
A previous review for EFSA by Tompkins et al (2013) identified a list of ‘novel’ GM traits9 that may
require market authorisation in the EU as food or feed in the foreseeable future. These included both
quality/output traits, likely to have an altered nutritional composition or complex/input traits that
benefit the farmer/grower and as a result of the modification have an increased likelihood of
allergenicity. For traits (1) and (2) as listed above these would largely be classed as quality/output
traits and could include traits such as those with compositional changes to carbohydrates, proteins,
fatty acid profile and secondary metabolites to benefit the consumer. In some cases more
developmental traits such as those which have an altered maturation or growth may be found to have
different nutritional profiles. Given that these traits benefit the consumer or end-market user it is likely
that they may be more recognisable further down the supply chain as they confer a higher value to the
user. For type (3) this could potentially be any GM trait, including agricultural/input traits which
benefit the producer rather than end user. For these agricultural/input traits, as they do not primarily
benefit the end user or consumer it is likely they will be less recognisable to users further down the
supply chain and thus are harder to track. Informal consultation carried out as part of this project
suggests that it is unlikely traits with a higher likelihood of allergenicity would request, or be granted
an authorisation under the current EU risk assessment process and thus the likelihood of these traits
requiring PMM programmes is minimal. Given the information above, it is reasonable to assume that
the higher the added value or differentiation that a GM trait provides its end user (either consumer or
animal owner), the more recognisable it will be within the supply chain, and therefore the easier it will
be to conduct a PMM programme on the product. Table.7 gives examples of the types of GM traits
and their ease of monitoring.
9
GM traits with substantial modifications to the composition, metabolism and physiology of the plant.
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Table 7:
Types of trait that may require PMM
Ease of monitoring
Trait
Description
‘Flavr Savr’ Tomatoes/GM tomato paste.
Tomato with delayed ripening.
When sold the tomato was
further processed into a single
branded product sold in retailers
under an own-brand label and
recognisable to consumers.
Soybeans with high oleic acid.
Soybeans with a modified seed
fatty acid composition. Trait
confers higher value to end
markets for its use in food
applications. However soybeans
are placed into multiple
products with or without distinct
branding and are thus harder to
track.
Agricultural/input traits
Various agricultural input traits
could potentially fall under the
scope of Regulation 503/2013 if
they are considered to have a
higher
likelihood
of
allergenicity. These traits are
not recognised once further
processed and would thus be
much harder to monitor.
Traits requesting authorisation as food and Some traits destined for nonfeed due to the possibility of adventitious food uses may require an
presence.
approval as food or feed in the
eventuality
of
adventitious/accidental presence
in the food chain. In this case it
would be likely that presence
would be unknown and thus
monitoring
would
be
impossible.
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by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
6.3.
What is required for Post-Market Monitoring of GM food and feed
In order to achieve the outcomes of PMM as detailed in the Implementing Regulation there are a
number of factors which must be known:
1. The user must know which food and feed products contain the GM trait which is to be
monitored (food and feed composition data).
2. The user must know the level of consumption of these products by humans and animals (food
and feed consumption data).
3. The user must then have a system/methodology to identify the relevance and intensity of
intended and unintended effects.
6.4.
Monitoring consumption or use of a GM food or feed in either animals or humans
To satisfy the requirements of Regulation 503/2013 it is necessary to confirm that specific
recommendations of use of a GM food or feed are followed, and that predicted consumption as set out
in the pre-market risk assessment is as expected. This requires the applicant to understand (1) which
food and feed products their trait is included in, (2) the level of consumption of those products and (3)
any qualitative details to prove whether users are following product recommendations (for example
preparation guidelines or maximum daily allowances). These are discussed in turn below.
6.4.1.
Inclusion of a GM trait in food or feed products
Our analysis has shown that the current EU regulatory requirements surrounding traceability and
labelling of GM food and feed, and food more generally goes some way to ensure information is
known about which GM traits are in which products, however, there are gaps.
The system of unique identifiers for GM traits is an internationally harmonised system which allows
for traceability of GMOs throughout the supply chain. It requires all products consisting of or
containing mixtures of GMOs to carry the unique identifier. This documentation must be transmitted
in writing to all operators subsequently receiving the item. This system works in harmony with wider
traceability requirements for all food, where each operator in the supply chain must know whom he
has purchased material from, and who this has been sold to (unless this is to final consumers). For
food and feed ingredients or products ‘produced from GMOs’ (such as oils) operators must only
transmit information indicating which of the material or ingredient is produced from GMOs. As such
written documentation on the unique identifier is transmitted through the supply chain until the point
at which a raw material consisting of or containing a GMO becomes an ingredient or product produced
from a GMO. This is for example the case where GM soybeans (the raw material) would be further
processed into soybean oil (an ingredient); where soybeans consist or contain a GMO, and soybean oil
is produced from a GMO. For PMM to be successful the final manufacturer of the food or feed
product to be bought by consumers or animal owners must know exactly which GM trait is included in
his particular product. Where the final manufacturer is purchasing raw materials consisting of or
containing GMOs this would be possible under Regulation 1830/2003, however, where the
manufacturer is purchasing in ingredient produced from GMOs, information on the unique identifier
would not legally be required. As such, in order to fully understand which GM traits are included in
which products to be sold to consumers or animal owners the unique identifier would need to be
passed on at every step of the supply chain, even for ingredients or products produced from GMOs.
Whilst operators may understand which GM traits are included in which products, regulatory
requirements do not provide for information to be gathered on the amount of a GM food or feed
EFSA supporting publication 2015: EN-739
51
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
included in a final product. This is particularly problematic where a product produced from GMOs is
incorporated with another, for example high oleic oil derived from GM soybeans may be blended with
other high oleic vegetable oils which are not GM. Additionally in the example above, the product may
contain multiple GM traits of the same type.
Current food and feed composition data held at the Member State level does not identify the GM
components of a product, and is based on mean nutrient values for a range of products. Privately
available food composition data, such as that held by grocery retailers, food or feed manufacturers is
variable. For grocery retailers with ‘own-branded’ goods, data are held on provenance of the product,
but the level of information varies by product (for example more data are held on primary produce
than further processed products). Detailed composition data may be held by food manufacturers,
however, the variability of this, above and beyond minimum labelling requirements is uncertain. For
feed, composition data may be held by large feed manufacturers on specific products, however, this
information is usually commercially sensitive and thus information is not held by the animal owner.
Individual animal owners/farmers will likely understand what they have fed to their animals, however,
this information is largely held on an individual animal owner basis.
6.4.2.
Food and feed consumption data
National dietary and nutritional surveys (NDNS) operated by competent bodies at the Member State
level provide good detail on foods consumed by a selectively representative sample of the population.
They are cognitively demanding in that they require individuals to faithfully record foods consumed.
Data are gathered by broad food group such as ‘white bread’ or ‘fruit’, therefore in order for the data
to be useful for PMM of GM food and feed more detail would be required on the specific food
products monitored to understand which ones contained specific GM traits. As the NDNS is based on
self-declared data on the types of product consumed, analysis at this level is currently not available as
products are not further defined by participants than by broad type (e.g. fruit). The data underpinning
the surveys is predominantly nutrient intake data, which is largely approximated from the records of
food intake coupled to established food composition tables such as those developed by McCance and
Widdowson in the UK. Of more value in the context of PMM is the food purchase data collected by
grocery retailers and market research companies. In the UK, market research companies use sample
households to record food purchases using handheld barcode scanners. The scanners contain
nutritional data on 100,000 food products, either branded by manufacturers or own-brand retailer
goods. Data on food purchases is also held by retailers where consumers use a loyalty card scheme,
however, this only reflects what is purchased at that particular retailer. For the data collected by
market research companies, demographics on the makeup of the household are collected, however, the
exact level of consumption of the food by each family member is not recorded. Other organisations
offer approaches whereby food purchase data are modelled by data held on nutrient intake in the
NDNS surveys to approximate the level of intake by demographic group. In order for food purchase
data to be useful for PMM, the data on food purchases would need to be linked to data on whether a
particular trait is included in the food product, along with data or assumptions on the amount per
packet/portion. Crucially, it is uncertain the level to which this market research data on food purchases
occur in all EU countries, and thereby robust monitoring by Member State may not be possible.
For feed, no equivalent consumption database such as the NDNS exist. Consumption data in the form
of feeding records may be held by individual animal owners such as farmers, however there are no
initiatives found during this project that have attempted to gather such information. Determining
consumption data by individual animal may be possible for certain species, such as dairy cows where
individual feed intakes are recorded electronically. Where livestock are kept extensively or in large
quantities (such as pigs and poultry) determining the individual feed intake of particular animals
EFSA supporting publication 2015: EN-739
52
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
would be difficult. If the scope of PMM includes fish then PMM by this group of animals is unlikely
to be possible due to the unknown numbers of animals.
6.5.
Monitoring the relevance and intensity of effects and unintended effects detected
during the pre-market risk assessment
To satisfy the requirements of Regulation 503/2013 it is necessary to identify the relevance and
intensity of intended and unintended effects that are detected during the pre-market risk assessment.
The literature sourced in the systematic review (Work Package 1) gives a comprehensive overview of
existing PMM programmes, for products such as: drugs, cosmetics, vaccines, novel foods and herbal
medicines, which are primarily used to report adverse reactions in those using the product. The
examples give detail on how systems are operated, how reports of adverse effects are collected and
how the cause of an adverse event can be attributed, or not, to the product in question. Both active (a
study is initiated to test effects) and passive (spontaneous reports are collected) methods are used to
collect adverse event data.
In all programmes, unlike GM food and feed those conducting the monitoring have robust information
on which products contain the item that is being monitored. For drugs and vaccines, and in some cases
herbal medicines, these are prescribed products and as such, exact information is available on the level
of consumption and composition. In all other instances (novel foods, herbal medicines and cosmetics)
the item to be monitored is usually contained in a limited number of products which are distinctly
branded to be recognisable to vendors and consumers. Consumer care lines are often utilised in these
products, as a means by which consumers can report any adverse events they experience. Wellestablished systems, for healthcare professional reporting of adverse events, caused by drugs and
vaccines are in operation in many countries. The major criticism of ‘vigilance’ PMM programmes for
drugs, vaccines and cosmetics which use passive surveillance approaches, is the consistent level of
under-reporting of adverse drug reactions (ADRs), by both consumers and healthcare professionals.
The benefits of taking an active approach to monitoring are that these methods will capture adverse
events even if there is a delay between product consumption and the event, and allow for the
monitoring of multiple outcomes within the same scheme. As active surveillance generally involves
establishing a robust study with more intensive monitoring, it is of course more time consuming and
costly. The review showed that the consensus among authors was, that a combination between active
and passive surveillance methods is likely to be of most benefit. A major barrier to the implementation
of the types of schemes described above for GM food and feed is the scale at which inclusion of these
traits occurs within these products. For the examples given above, all items whether medicinal or food
based are only included in a limited number of products meaning that monitoring efforts can be
relatively directed. For GM food and feed, the trait is often included in varieties of basic commodity
crops e.g. soybean, which could be used as an ingredient in multiple food and feed products at
different levels of inclusion. This makes establishing a reliable system of PMM more difficult.
For animals the literature review found comparatively little evidence on the existence of PMM
programmes. The few papers identified, focussed on veterinary Pharmacovigilance of medicines
administered to animals. The International Cooperation on Harmonisation of Technical Requirements
for Registration of Veterinary Medicinal Products (VICH) have developed guidelines for
Pharmacovigilance in this context, however, given the number of papers found on PMM in animal
situations it is reasonable to conclude that this is not a well-developed area and more evidence is
required. More general animal health monitoring occurs at a national level to monitor for disease
occurrence, and possible outbreaks of exotic diseases. These programmes are operated at a country
level and use regionally based vets as reporters. These schemes have the potential to pick up instances
of disease, or adverse effects which may have been triggered by consumption of feed containing
EFSA supporting publication 2015: EN-739
53
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
GMOs, however, it is not clear the extent to which the effect could be related to GMOs, or how many
livestock would have to be affected to trigger a notification under such schemes. In addition, whilst
Member States have a responsibility to report certain notifiable diseases (e.g. Bluetongue), it is
uncertain the extent to which other diseases information is gathered on, and are reported. Overall
monitoring adverse or intended effects in an animal population has received much less focus than in
human populations and existing programmes would most likely need focus in order to be a reliable
method of reporting adverse effects in livestock due to the consumption of specific GM traits.
CONCLUSIONS
This project has provided a comprehensive review of the design of PMM programmes that exist across
the world relating to food or feed intake, human and animal health as well as a review of existing data
which is collected in the EU and could aid the implementation of PMM of GM food and feed.
It is concluded that the largest barrier to conducting PMM for GM food and feed is the
‘unrecognisable’ nature of GM traits further down the food supply chain, that is GM food and feed is
sold and branded as a seed to farmer/growers to be passed through a complex supply chain before
being included in food or feed products. Through this supply chain the raw material has the potential
to be mixed with other similar GM food or feed, or other conventional ingredients (such is the case
with vegetable oils where there may not be one distinct source of raw material). The regulatory
framework for traceability and labelling on GM traits does not allow for identification of specific traits
once the raw material is further processed to become a product. The likelihood of being able to
identify the GM food and feed after this point rests in its visibility to users further downstream. For
example, soybeans with a high oleic oil profile may be recognised further downstream as ‘high oleic
soybean oil’ and could be monitored as such. The ability to achieve this rests in how the product is
used further downstream and its potential to be mixed with other products. Table.7 gives an overview
of which type of GM traits may be easier to monitor than others, with those sold as a distinct and
recognisable product being the easiest. A food or feed manufacturer may keep detailed raw material
specifications on their products to understand the proportion of certain ingredients included, however,
the information known on these ingredients in many cases may not extend to the specific GM trait
included. For compound feeds produced by large manufacturers, detailed composition data other than
a basic proximate analysis is generally not made available and is commercially sensitive information.
This is a large barrier to the PMM of GM feed as potentially it is not possible to understand which GM
traits are in which products, and to what proportion.
For consumption data this project has shown that data held at the national level, collected by public
bodies for food is of only limited use to a system of PMM for GMOs. This is largely as the data held is
in reference to ‘generic’ products such as ‘white bread’, rather than specific products or branded
goods. As a result of this, the extent to which the product referenced contains the specific GM traits to
be monitored is unknown. Food purchase data held by market research companies and grocery
retailers holds promise as a method to monitor consumption of GM food, however, these data are not
nationally representative in most Member States. Widespread data on feed consumption are not
generally available, and if held is often at an individual farm level. Where particular farms exist in
which robust consumption data are available per animal, this may hold promise to carry out PMM of
GM feed on a small scale.
Given these barriers it is reasonable to conclude that widespread PMM of GM food and feed across
multiple populations and for all products containing the trait is unlikely to be possible without changes
to the requirements around traceability, and efforts to pull together additional data on products
containing GM traits. These requirements are detailed below in Section 7.
EFSA supporting publication 2015: EN-739
54
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
If reliable consumption and composition data are known, the monitoring programmes detailed in WP1
of this project give a basis for designing PMM programmes to characterise the relevance and intensity
of effects and unintended effects detected during the pre-market risk assessment. Of all the examples
presented, PMM programmes for novel foods are the most relevant for GM food and feed. These
examples used a combination of approaches, such as spontaneous reports through consumer care line
(passive surveillance) through to initiated cohort studies to test the occurrence of reported effects in
order to determine the relevance to the product in question. Pharmacovigilance and similar
programmes are not easily translated to GM food and feed as a) in the case of pharmaceuticals and
vaccines the exact dose of the product is known, and b) they are designed to identify adverse effects
which are not detected in any pre-market risk assessment. The project has found a large knowledge
gap in terms of the experience in monitoring for adverse effects with regards to animal health.
Veterinary Pharmacovigilance is not widely used, and comparatively little experience is found in this
area.
7.
WHAT
EU
WOULD BE REQUIRED TO CONDUCT
PMM
OF
GM
FOOD AND FEED IN THE
Based on the findings from this project this section gives detail on what would be required to conduct
PMM for GM food and feed in the EU according to the requirements of Implementing Regulation
503/2013.
7.1.
Greater detail in requirements for traceability of GMOs
In order to monitor the occurrence of specific GM traits in food and feed products, greater complexity
in traceability requirements for GMOs would be needed. We have shown in this project that current
traceability requirements only require the operator to detail which traits are in which batches of raw
material, ingredients or products up until the point that it is further processed to become an item
‘produced from GMOs’ (i.e. not containing the LMO). In order to accurately know which traits are
included in which final product, the unique identifier would be needed to be carried through the supply
chain to this stage. This would require more complex traceability requirements, resulting in greater
administrative burden on operators further down the supply chain.
7.2.
A database of which food and feed products contain which GM traits, and at what
proportion
In order to accurately measure consumption of GM traits the user would need to understand at what
proportion they are present in the final products. This would require a database (or similar) of products
which contain GM traits, and at what level they are included in the product. For some products this
may be easier than others. Of particular difficulty is determining this for products whose composition
may change due to various external factors. For example a bottle of vegetable cooking oil may contain
the oils of multiple vegetables, and the exact quantities of oil from each vegetable may change
depending on the price of the commodity, and its quality at any given period.
7.3.
Consumption data at the branded product level
To accurately monitor consumption of particular GM traits, robust data would be required for all
branded products which contain the trait. This would likely need to involve those further down the
supply chain who are the ultimate vendors of the product (whether food or feed). In this report we
have listed sources of consumption data where they exist, however for all data there are caveats on
calculating exact consumption of a product. In many cases, where purchase data is known, exact
consumption of the product by all members of the household/individual animals and the amount of
wastage is uncertain.
EFSA supporting publication 2015: EN-739
55
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
7.4.
A system for reporting the relevance and intensity of effects and unintended effects
Under the requirements of Implementing Regulation 503/2013 the user must identify the relevance
and intensity of intended and adverse effects which are detected during the pre-market risk
assessment. This may involve the use of active or passive surveillance models which have been
detailed in WP1 of this project. Of these the PMM strategies developed for novel foods are of most
relevance, models for Pharmacovigilance and its equivalents can be helpful, but are not directly
comparable as in the case of pharmaceuticals and vaccines the dose of the product is usually known to
a precise level. The remit of the legislation does not require the user to monitor for unintended effects
of a GM trait, which have not been highlighted at the pre-market risk assessment stage, and thus the
passive surveillance models of Pharmacovigilance schemes to pick up Adverse Drug Reactions
(ADRs) are of only limited use. Nevertheless, approaches such as the passive surveillance of novel
foods using consumer care lines and active surveillance, with initiated studies may be useful to
identify the relevance and intensity of intended or unintended effects of GM traits highlighted during
the risk assessment.
7.5.
An agreement on who is responsible for carrying out PMM
Overall, it is clear that for a robust system of PMM to work, co-operation throughout the supply chain
would be required. The wording of Implementing Regulation 503/2013, taken from Regulation (EC)
1829/2003 stipulates that a proposal for PMM must be submitted by the applicant. In many cases,
applicant companies for GM traits are those engaged in the selling of seeds to farmers, and whilst the
traits they develop may be intended to benefit a user further down the supply chain, these companies
will often not be marketing the end-product. As co-operation is needed throughout the supply chain in
order for a system to work effectively, clearly this will also have resource implications for
stakeholders other than the applicant company (such as grocery retailers and food manufacturers). In
the case of novel foods, those conducting PMM have been the ones who developed the novel food, but
were also engaged in marketing it as a final product (an example being Unilever who marketed
phytosterol-esters in the branded spread, ‘Flora Pro-Activ’). For PMM of GM traits to work,
agreement would be needed on who is responsible for PMM, and who would pay.
8.
PMM METHODOLOGIES CURRENTLY FEASIBLE IN THE EU
The points above show what changes would be required to conduct effective PMM according to the
requirements of legislation. These changes would likely take time to enact and as such the below
sections give an overview of the design of PMM schemes that could be conducted within the
constraints of existing data collected in the EU at the present time. The level of detail and granularity
required in PMM will dictate its effectiveness, and the points below detail ways in which PMM could
be carried out to a less detailed extent, but with less administrative burden.
8.1.
Less detailed monitoring
Determining which products contain which GM traits, and at what proportion, as well as calculating
robust consumption figures are major difficulties in conducting a PMM programme. Less detailed
monitoring could be carried out based on import figures of GM traits as raw materials, or ingredients
into the EU. For example figures detailing the quantities of bulk soybeans or soybean oil from a
particular GM trait could be presented, as at this stage the item would still hold the 9 digit unique
identifier. These figures could be matched with data on the quantity of generic products such as
vegetable oil consumed in the EU, including figures on the quantities of different oils consumed to
give an indication of the total amount of the GM trait consumed. This monitoring would give no
specific information on the amount of the GM trait consumed by individual humans or animals, and
thus would not give robust information on questions such as whether the trait was replacing other
products in the diet, or changing consumption patterns. This type of monitoring is foreseen to be
EFSA supporting publication 2015: EN-739
56
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
possible within the constraints of existing data collected within the EU, and whilst it may not
comprehensively meet all the requirements of Implementing Regulation 503/2013, could provide
knowledge as a starting point.
8.2.
Small scale monitoring of GM traits
If large scale monitoring of all food and feed products containing GM traits was seen as unfeasible,
small scale monitoring of a selection of ‘reference’ products could be carried out. This system could
utilise a selection of products where robust information is held on their composition (the particular
GM traits included and at what proportion), and their consumption. Data, such as that collected by
market research agencies using hand held scanners in sample households could be used for this
purpose. This system is similar to the type of monitoring carried out for novel foods, which utilises
market research data. Small scale monitoring of GM traits could serve to provide a set of data and
results which may inform the design of less detailed monitoring as discussed in Section 8.1. More
work would need to be done to develop this area to ensure that a set of reference products could be
included which were representative of the use of GM traits overall. For PMM of feed containing GM
traits this would likely be more difficult, as data sources are not as prevalent for food. Additionally,
this review has shown that market research data is collected more widely in some EU MS than others.
EFSA supporting publication 2015: EN-739
57
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
REFERENCES
Abenhaim L Moore N Begaud B, 1999. The role of pharmacoepidemiology in pharmacovigilance: A
conference at the 6th ESOP Meeting, Budapest, 28 September 1998. Pharmacoepidemiology and
Drug Safety, 8, S1-S7.
Agorastos T Chatzigeorgiou K Brotherton JML Garland SM, 2009. Safety of human papillomavirus
(HPV) vaccines: A review of the international experience so far. Vaccine, 27, 7270-7281.
Ahmad SR, 2003. Adverse drug event monitoring at the Food and Drug Administration - Your report
can make a difference. Journal of General Internal Medicine, 18, 57-60.
Alberman E, 1986. Post-marketing surveillance of oral contraceptives. Human Reproduction, 1, 433434.
Alemayehu D Andrews EN Glue P Knirsch CA, 2010. Considerations for the design and conduct of a
pharmacovigilance study involving mass drug administration in a resource-constrained setting.
PLoS Neglected Tropical Diseases, 4.
Alger HM Maffini MV Kulkarni NR Bongard ED Neltner T, 2013. Perspectives on how FDA
Assesses Exposure to Food Additives When Evaluating Their Safety: Workshop proceedings.
Comprehensive Reviews in Food Science and Food Safety, 12, 90-119.
Allgood GS Kuter DJ Roll KT Taylor SL Zorich NL, 2001. Postmarketing surveillance of new food
ingredients: Results from the program with the fat replacer olestra. Regulatory Toxicology and
Pharmacology, 33, 224-233.
Amarasinghe A Black S Bonhoeffer J Carvalho SMD Dodoo A Eskola J Larson H Shin S Olsson S
Balakrishnan MR Bellah A Lambach P Maure C Wood D Zuber P Akanmori B Bravo P Pombo M
Langar H Pfeifer D Guichard S Diorditsa S Hossain MS Sato Y, 2013. Effective vaccine safety
systems in all countries: A challenge for more equitable access to immunization. Vaccine, 31,
B108-B114.
Anon., 1983. Monitoring of drugs after marketing. The Journal of the Royal College of General
Practitioners, 33, 438-441.
Anon., 2005. International Conference on Harmonisation; guidance on E2E Pharmacovigilance
Planning; availability. Notice. Federal register, 70, 16827-16828.
Anon., 2007. The Erice Manifesto: for global reform of the safety of medicines in patient care. Drug
safety : an international journal of medical toxicology and drug experience, 30, 187-190.
Anon., 2012. Pharmacovigilance and communicating safety information. Drug and therapeutics
bulletin, 50, 138-140.
ANSES (Agence nationale de sécurité sanitairede l’alimentation, de l’environnement et du travail),
2013.
Individual
and
national
study
on
food
consumption.
https://www.anses.fr/en/content/individual-and-national-study-food-consumption-inca-study.
Arimura K Nakagawa M Izumo S Usuku K Itoyama Y Kira J-I Osame M, 2007. Safety and efficacy of
interferon-alpha in 167 patients with human T-cell lymphotropic virus type 1-associated
myelopathy. Journal of Neurovirology, 13, 364-372.
Arlett PR Kurz X, 2011. New approaches to strengthen pharmacovigilance. Drug Discovery Today:
Technologies, 8, e15-e19.
EFSA supporting publication 2015: EN-739
58
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Balkrishnan R Furberg CD, 2001. Developing an optimal approach to global drug safety. Journal of
Internal Medicine, 250, 271-279.
Bandekar MS Anwikar SR Kshirsagar NA, 2010. Quality check of spontaneous adverse drug reaction
reporting forms of different countries. Pharmacoepidemiology and Drug Safety, 19, 1181-1185.
Banerjee AK Okun S Edwards IR Wicks P Smith MY Mayall SJ Flamion B Cleeland C Basch E,
2013. Patient-Reported Outcome Measures in Safety Event Reporting: PROSPER Consortium
Guidance. Drug Safety, 36, 1129-1149.
Barnes J, 2003. Pharmacovigilance of herbal medicines - A UK perspective. Drug Safety, 26, 829-851.
Bast A Chandler RF Choy PC Delmulle LM Gruenwald J Halkes SBA Keller K Koeman JH Peters P
Przyrembel H De Ree EM Renwick AG Vermeer ITM, 2002. Botanical health products,
positioning and requirements for effective and safe use. Environmental Toxicology and
Pharmacology, 12, 195-211.
Beck-Peccoz P Minuto F Leal-Cerro A Zabransky M Stalla G, 2012. Rationale and design of PATRO
Adults, a multicentre, noninterventional study of the long-term efficacy and safety of Omnitrope®
for the treatment of adult patients with growth hormone deficiency. Therapeutic Advances in
Endocrinology and Metabolism, 3, 85-91.
Begaud B Moride Y Tubertbitter P Chaslerie A Haramburu F, 1994. FALSE-POSITIVES IN
SPONTANEOUS REPORTING - SHOULD WE WORRY ABOUT THEM. British Journal of
Clinical Pharmacology, 38, 401-404.
Bencheikh RS Benabdallah G, 2009. Medication errors: pharmacovigilance centres in detection and
prevention. British Journal of Clinical Pharmacology, 67, 687-690.
Bennett CL Nebeker JR Lyons EA Samore MH Feldman MD McKoy JM Carson KR Belknap SM
Trifilio SM Schumock GT Yarnold PR Davidson CJ Evens AM Kuzel TM Parada JP Cournoyer D
West DP Sartor O Tallman MS Raisch DW, 2005. The Rresearch on Adverse Drug Events and
Reports (RADAR) project. Jama-Journal of the American Medical Association, 293, 2131-2140.
Bennett CL Nebeker JR Yarnold PR Tigue CC Dorr DA McKoy JM Edwards BJ Hurdle JF West DP
Lau DT Angelotta C Weitzman SA Belknap SM Djulbegovic B Tallman MS Kuzel TM Benson
AB Evens A Trifilio SM Courtney DM Raisch DW, 2007. Evaluation of serious adverse drug
reactions: A Proactive Pharmacovigilance Program (RADAR) vs safety activities conducted by the
Food and Drug Administration and pharmaceutical manufacturers. Archives of Internal Medicine,
167, 1041-1049.
Bergman U, 1992. Second thoughts. Pharmacoepidemiological Perspectives. Journal of Clinical
Epidemiology, 45, 313-317.
Berlin JA Glasser SC Ellenberg SS, 2008. Adverse event detection in drug development:
Recommendations and obligations beyond phase 3. American Journal of Public Health, 98, 13661371.
Berne B Tammela M Färm G Inerot A Lindberg M, 2008. Can the reporting of adverse skin reactions
to cosmetics be improved? A prospective clinical study using a structured protocol. Contact
Dermatitis, 58, 223-227.
Bhosale VV Gaur SPS, 2011. Adverse drug reaction monitoring. Current Science, 101, 1024-1027.
Bian J Topaloglu U Yu F, 2012. Towards large-scale twitter mining for drug-related adverse events.
25-32.
Blake KV Smeraldi C Kurz X Arlett P Blackburn S Fitt H, 2011. The European network of centres for
EFSA supporting publication 2015: EN-739
59
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
pharmacoepidemiology and pharmacovigilance: Application to diabetes and vascular disease.
British Journal of Diabetes and Vascular Disease, 11, 304-307.
BMEL (Bundesministerium für Ernährung und Landwirtschaft), 2009. National Nutrition Survey
Two. http://www.was-esse-ich.de/index.php?id=44
Bond RA, 2006. A proposal for a national program reporting beneficial drug responses, analogous to
the existing program to detect adverse drug responses. Medical Hypotheses, 66, 10-13.
Bons B Audebert F Bitaudeau C Cachin N Colson L Farr C Fix LA Gilmour N Gorni R Griffiths M
Harris B Holle V Kirk S Meredith E Pari C Poinsot P Renner G, 2010. Assessment of undesirable
events in cosmetic market surveillance: Background, description and use of a causality assessment
method in cosmetovigilance. Regulatory Toxicology and Pharmacology, 58, 349-353.
Bousquet PJ Demoly P Romano A Aberer W Bircher A Blanca M Brockow K Pichler W Torres MJ
Terreehorst I Arnoux B Atanaskovic-Markovic M Barbaud A Bijl A Bonadonna P Burney PG
Caimmi S Canonica GW Cernadas J Dahlen B Daures JP Fernandez J Gomes E Gueant JL
Kowalski ML Kvedariene V Mertes PM Martins P Nizankowska-Mogilnicka E Papadopoulos N
Ponvert C Pirmohamed M Ring J Salapatas M Sanz ML Szczeklik A Van Ganse E De Weck AL
Zuberbier T Merk HF Sachs B Sidoroff A, 2009. Pharmacovigilance of drug allergy and
hypersensitivity using the ENDA-DAHD database and the GA2LEN platform. The Galenda
project. Allergy: European Journal of Allergy and Clinical Immunology, 64, 194-203.
Breckenridge A, 2008. Post-marketing strategies for medicines [1]. Clinical Pharmacology and
Therapeutics, 83, 24-25.
Bren L, 2003. FDA's response to food, dietary supplement, and cosmetic adverse events. FDA
Consumer, 37.
Brewer T Colditz GA, 1999. Postmarketing surveillance and adverse drug reactions current
perspectives and future needs. Journal of the American Medical Association, 281, 824-829.
Bright RA Nelson RC, 2002. Automated support for pharmacovigilance: a proposed system.
Pharmacoepidemiology and Drug Safety, 11, 121-125.
Buchbinder R March L Lassere M Briggs AM Portek I Reid C Meehan A Henderson L Wengier L
Van Den Haak R, 2007. Effect of treatment with biological agents for arthritis in Australia: The
Australian Rheumatology Association Database. Internal Medicine Journal, 37, 591-600.
Burk M Moore V Glassman P Good CB Emmendorfer T Leadholm TC Cunningham F, 2013.
Medication-use evaluation with a Web application. American Journal of Health-System Pharmacy,
70, 2226-2234.
Butchko HH Kotsonis FN, 1991. Acceptable daily intake vs actual intake: The aspartame example.
Journal of the American College of Nutrition, 10, 258-266.
Butchko HH Tschanz C Kotsonis FN, 1994. Postmarketing surveillance of food additives. Regulatory
Toxicology and Pharmacology, 20, 105-118.
Butler SF Budman SH Licari A Cassidy TA Lioy K Dickinson J Brownstein JS Benneyan JC Green
TC Katz N, 2008. National Addictions Vigilance Intervention and Prevention Program
(NAVIPPRO™): A real-time, product-specific, public health surveillance system for monitoring
prescription drug abuse. Pharmacoepidemiology and Drug Safety, 17, 1142-1154.
Caster O Norén GN Madigan D Bate A, 2010. Large-scale regression-based pattern discovery: The
example of screening the WHO global drug safety database. Statistical Analysis and Data Mining,
3, 197-208.
EFSA supporting publication 2015: EN-739
60
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Castle GH Kelly B, 2008. Global harmonization is not all that global: Divergent approaches in drug
safety. Food and Drug Law Journal, 63, 601-622+i.
Chazard E Ficheur G Bernonville S Luyckx M Beuscart R, 2011. Data Mining to Generate Adverse
Drug Events Detection Rules. Ieee Transactions on Information Technology in Biomedicine, 15,
823-830.
Chee BW Berlin R Schatz B, 2011. Predicting adverse drug events from personal health messages.
AMIA Annual Symposium proceedings / AMIA Symposium AMIA Symposium, 2011, 217-226.
Cicero TJ Dart RC Inciardi JA Woody GE Schnoll S Munoz A, 2007. The development of a
comprehensive risk-management program for prescription opioid analgesics: Researched Abuse,
Diversion and Addiction-Related Surveillance (RADARS (R)). Pain Medicine, 8, 157-170.
Clark DWJ Coulter DM Besag FMC, 2008. Randomized controlled trials and assessment of drug
safety. Drug Safety, 31, 1057-1061.
Coloma PM Trifiro G Patadia V Sturkenboom M, 2013. Postmarketing Safety Surveillance Where
does Signal Detection Using Electronic Healthcare Records Fit into the Big Picture? Drug Safety,
36, 183-197.
Cook MN, 2006. Estimating national drug consumption using data at different points in the
pharmaceutical supply chain. Pharmacoepidemiology and Drug Safety, 15, 754-757.
Crowther M, 2013. Phase 4 research: what happens when the rubber meets the road? Hematology / the
Education Program of the American Society of Hematology American Society of Hematology
Education Program, 2013, 15-18.
Curtis LH Weiner MG Boudreau DM Cooper WO Daniel GW Nair VP Raebel MA Beaulieu NU
Rosofsky R Woodworth TS Brown JS, 2012. Design considerations, architecture, and use of the
Mini-Sentinel distributed data system. Pharmacoepidemiology and Drug Safety, 21, 23-31.
Czarnecki A Maciejczyk A, 1997. Pharmacovigilance in Poland. Pharmacoepidemiology and Drug
Safety, 6, 277-281.
Dal Pan GJ, 2014. Ongoing Challenges in Pharmacovigilance. Drug Safety, 37, 1-8.
Dart RC, 2009. Monitoring risk: Post marketing surveillance and signal detection. Drug and Alcohol
Dependence, 105, S26-S32.
Dasgupta N Schnoll SH, 2009. Signal detection in post-marketing surveillance for controlled
substances. Drug and Alcohol Dependence, 105, S33-S41.
Davis RL Kolczak M Lewis E Nordin J Goodman M Shay DK Platt R Black S Shinefield H Chen RT,
2005. Active surveillance of vaccine safety: A system to detect early signs of adverse events.
Epidemiology, 16, 336-341.
De Vries ST Mol PGM de Zeeuw D Haaijer-Ruskamp FM Denig P, 2013. Development and Initial
Validation of a Patient-Reported Adverse Drug Event Questionnaire. Drug Safety, 36, 765-777.
Defra (Department for Environment, Food & Rural Affairs), 2014 Latest animal feed production
statistics. https://www.gov.uk/government/statistics/animal-feed-production.
DeStefano F Vaccine Safety Datalink Res G, 2001. The Vaccine Safety Datalink project.
Pharmacoepidemiology and Drug Safety, 10, 403-406.
Dieck GS Sharrar RG, 2013. Preparing for safety issues following drug approval: Pre-approval risk
management considerations. Therapeutic Advances in Drug Safety, 4, 220-228.
Dikshit RK Desai C Desai MK, 2008. Pleasures and pains of running a pharmacovigilance center.
EFSA supporting publication 2015: EN-739
61
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Indian Journal of Pharmacology, 40, S31-S34.
Dogra R Garg R Kumar V Verma V Tripathi V, 2013. Detection, assessment, understanding and
prevention of adverse effects: Pharmacovigilance: A review. International Journal of
Pharmaceutical Sciences Review and Research, 20, 71-86.
Du W Lehr VT Lieh-Lai M Koo W Ward RM Rieder MJ Van Den Anker JN Reeves JH Mathew M
Lulic-Botica M Aranda JV, 2013. An Algorithm to Detect Adverse Drug Reactions in the Neonatal
Intensive Care Unit. Journal of Clinical Pharmacology, 53, 87-95.
Dunn N Mann RD, 1999. Prescription-event and other forms of epidemiological monitoring of sideeffects in the UK. Clinical and Experimental Allergy, 29, 217-239.
EuroFIR, 2014. EuroFIR website. http://www.eurofir.org/?page_id=3
Edwards IR, 1998. Safety monitoring of new anti-malarials in immediate post-marketing phase.
Medecine tropicale : revue du Corps de sante colonial, 58, 93-96.
Edwards IR, 2000. Spontaneous ADR reporting and drug safety signal induction in perspective - To
honour Professor Jens Schou. Pharmacology & Toxicology, 86, 16-19.
Edwards IR, 2012. Pharmacovigilance. British Journal of Clinical Pharmacology, 73, 979-982.
Edwards R Faich G Tilson H, 2005. Points to consider: the roles of surveillance and epidemiology in
advancing drug safety. Pharmacoepidemiology and Drug Safety, 14, 665-667.
EFSA (European Food Safety Authority), 2011. The food classification and description system
FoodEx 2. http://www.efsa.europa.eu/en/supporting/pub/215e.htm.
EFSA
(European
Food
Safety
Authority),
http://www.efsa.europa.eu/en/datexfoodcdb/datexeumenu.htm.
2014.
EU
Menu.
Egberts ACG Meyboom RHB van Puijenbroek EP, 2002. Use of measures of disproportionality in
pharmacovigilance - Three Dutch examples. Drug Safety, 25, 453-458.
Egberts TCG, 2007. Signal detection: Historical background. Drug Safety, 30, 607-609.
Eguale T Tamblyn R Winslade N Buckeridge D, 2008. Detection of adverse drug events and other
treatment outcomes using an electronic prescribing system. Drug Safety, 31, 1005-1016.
Eguale T Winslade N Hanley JA Buckeridge DL Tamblyn R, 2010. Enhancing pharmacosurveillance
with systematic collection of treatment indication in electronic prescribing: A Validation study in
Canada. Drug Safety, 33, 559-567.
EPIC (European Prospective Investigation into Cancer and Nutrition), 2014. EPIC study webpage.
http://epic.iarc.fr/
Evans JMM MacDonald TM, 1999. Record-linkage for pharmacovigilance in Scotland. British Journal
of Clinical Pharmacology, 47, 105-110.
Faden LB Milne C-P, 2008. Pharmacovigilance activities in the United States, European Union and
Japan: Harmonic convergence or convergent evolution? Food and Drug Law Journal, 63, 683-700.
Faich G Morris J, 2012. Adverse Reaction Signaling and Disproportionality Analysis: An Update.
Drug Information Journal, 46, 708-714.
Fan K Sun X Tao Y Xu L Wang C Mao X Peng B Pan Y, 2010. High-Performance Signal Detection
for Adverse Drug Events using MapReduce Paradigm. AMIA Annual Symposium proceedings /
AMIA Symposium AMIA Symposium, 2010, 902-906.
EFSA supporting publication 2015: EN-739
62
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Farrington P Pugh S Colville A Flower A Nash J Morgancapner P Rush M Miller E, 1995. A new
method for active surveillance of adverse events from diphtheria-tetanus-pertussis and measles
mumps rubella vaccines.. Lancet, 345, 567-569.
Feedipedia, 2013. Link to Feedipedia website homepage. http://www.feedipedia.org/
Fernandopulle RBM Weerasuriya K, 2003. What can consumer adverse drug reaction reporting add to
existing health professional-based systems? Focus on the developing world. Drug Safety, 26, 219225.
Fischer T, Maibech H, 1984. Finn chamber patch test technique. Contact Dermatitis, 11, 137-140.
Fleuranceau-Morel P, 2002. How do pharmaceutical companies handle consumer adverse drug
reaction reports? An overview based on a survey of French drug safety managers and officers.
Pharmacoepidemiology and Drug Safety, 11, 37-44.
Fox B, 2012. Closing the information gap: Informing better medical decisionmaking through the use
of post-market safety and comparative effectiveness information. Food and Drug Law Journal, 67,
83-101+iii.
Fram DM Almenoff JS Dumouchel W, 2003. Empirical Bayesian data mining for discovering patterns
in post-marketing drug safety. 359-368.
Frauger E Moracchini C Le Boisselier R Braunstein D Thirion X Micallef J French C-AN, 2013.
OPPIDUM surveillance program: 20 years of information on drug abuse in France. Fundamental &
Clinical Pharmacology, 27, 672-682.
FSA (Food Standards Agency), 2010. Background to the composition of foods review.
http://tna.europarchive.org/20110116113217/http://www.food.gov.uk/science/dietarysurveys/dietsu
rveys/backgrdcofr
Fujiwara Y Kobayashi K, 2002. Oncology drug clinical development and approval in Japan: the role
of the pharmaceuticals and medical devices evaluation center (PMDEC). Critical Reviews in
Oncology Hematology, 42, 145-155.
Gagne JJ Glynn RJ Rassen JA Walker AM Daniel GW Sridhar G Schneeweiss S, 2012. Active Safety
Monitoring of Newly Marketed Medications in a Distributed Data Network: Application of a SemiAutomated Monitoring System. Clinical Pharmacology & Therapeutics, 92, 80-86.
Gagne JJ Rassen JA Walker AM Glynn RJ Schneeweiss S, 2012. Active safety monitoring of new
medical products using electronic healthcare data: Selecting alerting rules. Epidemiology, 23, 238246.
Ghosh AK De A Bala NN, 2011. Current problems and future aspects of pharmacovigilance in India.
International Journal of Pharma and Bio Sciences, 2, 15-28.
Gogtay NJ Dalvi SS Kshirsagar NA, 2003. Safety monitoring: An Indian perspective. International
Journal of Risk and Safety in Medicine, 16, 21-30.
Griffin MR Braun MM Bart KJ, 2009. What Should an Ideal Vaccine Postlicensure Safety System
Be? American Journal of Public Health, 99, S345-S350.
Haerian K Varn D Vaidya S Ena L Chase HS Friedman C, 2012. Detection of PharmacovigilanceRelated Adverse Events Using Electronic Health Records and Automated Methods. Clinical
Pharmacology & Therapeutics, 92, 228-234.
EFSA supporting publication 2015: EN-739
63
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Hall RF, 2007. The risk of risk reduction: Can postmarket surveillance pose more risk than benefit?
Food and Drug Law Journal, 62, 473-492.
Harpaz R Vilar S DuMouchel W Salmasian H Haerian K Shah NH Chase HS Friedman C, 2013.
Combing signals from spontaneous reports and electronic health records for detection of adverse
drug reactions. Journal of the American Medical Informatics Association, 20, 413-419.
Hepburn P Boeing H Cockburn A Constable A Davi A Howlett J de Jong N Moseley B Oberdorfer R
Robertson C Verhagen H Wal J-M, 2006. Utility of post-market monitoring of novel foods.
Toxicology Letters, 164, S49-S49.
Hilmer SN Gnjidic D Abernethy DR, 2012. Pharmacoepidemiology in the Postmarketing Assessment
of the Safety and Efficacy of Drugs in Older Adults. Journals of Gerontology Series a-Biological
Sciences and Medical Sciences, 67, 181-188.
Hoffmann A Hippius M Sicker T, 1998. Adverse drug reaction monitoring in Jena - experiences of a
regionalized pharmacovigilance centre. Experimental and Toxicologic Pathology, 50, 453-457.
Howlett J Edwards DG Cockburn A Hepburn P Kleiner J Knorr D Kozianowski G Mueller D
Peijnenburg A Perrin I Poulsen M Walker R, 2003. The safety assessment of novel foods and
concepts to determine their safety in use. International Journal of Food Sciences and Nutrition, 54,
S1-S32.
Hugman B, 2005. From the Uppsala Monitoring Centre: A review of Viewpoint part 1 and part 2.
Drug Safety, 28, 645-646.
Inman WHW, 1981. Postmarketing surveillance of adverse drug reactions in general practice. I.
Search for new methods. British Medical Journal, 282, 1131-1132.
Iragueen D Urcelay S Martin BS, 2011. Pharmacovigilance in veterinary medicine in Chile: a pilot
study. Journal of Veterinary Pharmacology and Therapeutics, 34, 108-115.
Isah AO Pal SN Olsson S Dodoo A Bencheikh RS, 2012. Specific features of medicines safety and
pharmacovigilance in Africa. Therapeutic Advances in Drug Safety, 3, 25-34.
Ishaq GM Shah MY Koul PA Tanki SA, 2004. Adverse drug reaction monitoring with a Kashmiri
perspective - Need for an urgent initiative. JK Practitioner, 11, 85-87.
James C, 2012. Global status of commercialized biotech/GM crops: ISAAA Brief 44.
Johansson S Wallander MA De Abajo FJ Rodríguez LAG, 2010. Prospective drug safety monitoring
using the UK primary-care general practice research database: Theoretical framework, feasibility
analysis and extrapolation to future scenarios. Drug Safety, 33, 223-232.
Juarez-Olguin H Perez-Guille G Flores-Perez J, 2007. Pharmacovigilance and pharmacoepidemiology
of drugs in a Mexican pediatric hospital. A proposed guide. Pharmacy World & Science, 29, 43-46.
KantarWorldpanel,
2014.
Webpages
on
http://www.kantarworldpanel.com/global/Consumer-Panels
consumer
panels.
Kapp JF Zentgraf R Widmer A Schopf E, 1991. A NEED TO INTENSIFY DRUG SURVEILLANCE
IN GERMANY. Klinische Wochenschrift, 69, 775-779.
Karande S Gogtay NJ Kshirsagar NA, 2003. Improving drug safety monitoring. Indian pediatrics, 40,
1167-1175.
Kelman C, 2010. Pharmacology Researcher Biographical Sketches and Research Summaries. An
EFSA supporting publication 2015: EN-739
64
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Australian model for a national medicines monitoring system. Mihaylov Z and Stoyanov G, (eds)
Nova science publishers. 205-206
Khairnar A Gade PR, 2011. Interventional improvement in hospital based intensive monitoring of
adverse event. Research Journal of Pharmacy and Technology, 4, 1443-1448.
Khattri S Balamuralidhara V Pramod KTM Valluru R Venkatesh MP, 2012. Pharmacovigilance
regulations in India: A Step forward. Clinical Research and Regulatory Affairs, 29, 41-45.
Kim JH, Scialli AR, 2011. Thalidomide: The tragedy of birth defects and the effective treatment of
disease. Toxicological Sciences, 122, 1-6.
Kingston R, 2005. Challenges in collecting, accessing and evaluating post market surveillance AERS
in patients receiving dietary supplements. Thrombosis Research, 117, 137-144.
Kristal AR Vizenor NC Patterson RE Neuhouser ML Shattuck AL McLerran D, 2000. Precision and
bias of food frequency-based measures of fruit and vegetable intakes. Cancer Epidemiology
Biomarkers & Prevention, 9, 939-944.
Kubota K, 1999. A design for Prescription-Event
Pharmacoepidemiology and Drug Safety, 8, 447-456.
Monitoring
in
Japan
(J-PEM).
Layton D Hazell L Shakir SAW, 2011. Modified prescription-event monitoring studies: a tool for
pharmacovigilance and risk management. Drug safety : an international journal of medical
toxicology and drug experience, 34, e1-9.
Lea LJ Hepburn PA, 2006. Safety evaluation of phytosterol-esters. Part 9. Results of a European postlaunch monitoring programme Food Chem Toxicol, 44, 1213–1222
Mahmood KT Amin F Tahir MUl Haq I, 2011. Pharmacovigilance - A need for best patient care in
Pakistan. A review. Journal of Pharmaceutical Sciences and Research, 3, 1566-1584.
Mann RD, 1998. Prescription-event monitoring - recent progress and future horizons. British Journal
of Clinical Pharmacology, 46, 195-201.
Markowitz LE Hariri S Unger ER Saraiya M Datta SD Dunne EF, 2010. Post-licensure monitoring of
HPV vaccine in the United States. Vaccine, 28, 4731-4737.
Martinez-Frias ML, 2007. Postmarketing analysis of medicines - Methodology and value of the
Spanish case-control study and surveillance system in preventing birth defects. Drug Safety, 30,
307-316.
Mazzitello C Esposito S De Francesco A Capuano A Russo E De Sarro G, 2013. Pharmacovigilance in
Italy: An overview. Journal of Pharmacology and Pharmacotherapeutics, 4, S20-S28.
McClure DL Glanz JM Xu S Hambidge SJ Mullooly JP Baggs J, 2008. Comparison of epidemiologic
methods for active surveillance of vaccine safety. Vaccine, 26, 3341-3345.
McClure DL Raebel MA Yih WK Shoaibi A Mullersman JE Anderson-Smits C Glanz JM, 2014.
Mini-Sentinel methods: Framework for assessment of positive results from signal refinement.
Pharmacoepidemiology and Drug Safety, 23, 3-8.
McNeil JJ Grabsch EA McDonald MM, 1999. Postmarketing surveillance: Strengths and limitations.
The flucloxacillin-dicloxacillin story. Medical Journal of Australia, 170, 270-273.
McNeil JJ Piccenna L Ronaldson K Ioannides-Demos LL, 2010. The value of patient-centred
registries in phase IV drug surveillance. Pharmaceutical Medicine, 24, 281-288.
Mehta U Dheda M Steel G Blockman M Ntilivamunda A Maartens G Pillay Y Cohen K, 2014.
Strengthening pharmacovigilance in South Africa. South African Medical Journal, 104, 104-106.
EFSA supporting publication 2015: EN-739
65
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Mönkemeyer W Schmidt, K, 2014. Use of farmer/producer associations/federations to form sentinel
surveillance
networks
for
adverse
effects
in
primary
production.
http://www.efsa.europa.eu/it/search/doc/543e.pdf
Montastruc JL Sommet A Lacroix I Olivier P Durrieu G Damase-Michel C Lapeyre-Mestre M
Bagheri H, 2006. Pharmacovigilance for evaluating adverse drug reactions: value, organization,
and methods. Joint Bone Spine, 73, 629-632.
Montastruc JL, Sommet A, Bagheri H, & Lapeyre-Mestre M, 2011. Benefits and strengths of the
disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance
database. British Journal of Clinical Pharmacology, 72, 905–908.
Monteiro SAMG Takano OA Waldman EA, 2011. Evaluation of the Brazilian surveillance system for
adverse events following vaccination. Revista brasileira de epidemiologia = Brazilian journal of
epidemiology, 14, 361-371.
Moore GE Frana TS Guptill LF Ward MP Lewis HB Glickman LT, 2005. Postmarketing surveillance
for dog and cat vaccines: new resources in changing times. Javma-Journal of the American
Veterinary Medical Association, 227, 1066-1069.
Mutebi A, 2012. Patient-reported outcomes in the post-approval environment: Opportunities and
challenges. Pharmaceuticals Policy and Law, 14, 83-91.
Neuhouser ML Patterson RE Kristal AR Eldridge AL Vizenor NC, 2001. A brief dietary assessment
instrument for assessing target foods, nutrients and eating patterns. Public Health Nutrition, 4, 7378.
Neuhouser ML Patterson RE Kristal AR Rock CL Neumark-Sztainer D Thornquist MD Cheskin LJ,
2000. Do consumers of savory snacks have poor-quality diets? Journal of the American Dietetic
Association, 100, 576-579.
Olsson S Pal SN Stergachis A Couper M, 2010. Pharmacovigilance activities in 55 low-and middleincome countries: A questionnaire-based analysis. Drug Safety, 33, 689-703.
Palaian S Ibrahim MIM Mishra P Alam K Shankar PR Thapa BB, 2010. Pharmacovigilance Activities
in Nepal. Drug Safety, 33, 889-890.
Payne DC Franzke LH Stehr-Green PA Schwartz B McNeil MM, 2007. Development of the Vaccine
Analytic Unit's research agenda for investigating potential adverse events associated with anthrax
vaccine adsorbed. Pharmacoepidemiology and Drug Safety, 16, 46-54.
Prabhakar U Edwards B, 2010. Postmarketing safety surveillance: Issues with data collection for
postmarketing pharmacovigilance. Pharmaceutical Medicine, 24, 343-348.
PHE (Public Health England), 2014. National diet and nutrition survey: results from years 1-4.
https://www.gov.uk/government/statistics/national-diet-and-nutrition-survey-results-from-years-1to-4-combined-of-the-rolling-programme-for-2008-and-2009-to-2011-and-2012. Jointly funded by
Public Health England and Food Standards Agency.
Reynolds RF Lem JA Gatto NM Eng SM, 2011. Is the large simple trial design used for comparative,
post-approval safety research?: A review of a clinical trials registry and the published literature.
Drug Safety, 34, 799-820.
Robb MA Racoosin JA Sherman RE Gross TP Ball R Reichman ME Midthun K Woodcock J, 2012.
The US Food and Drug Administration's Sentinel Initiative: Expanding the horizons of medical
product safety. Pharmacoepidemiology and Drug Safety, 21, 9-11.
Ronaldson KJ, 2009. The new age of pharmacovigilance. Medical Journal of Australia, 191, 132-134.
EFSA supporting publication 2015: EN-739
66
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by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Ronaldson KJ, 2011. Maintaining and enhancing the value of spontaneous reporting programmes.
Pharmaceutical Medicine, 25, 83-86.
Sautebin L, 2008. Understanding the adverse effects of cosmetics: A pilot project in cosmetovigilance.
Drug Safety, 31, 433-436.
Savage RL Kunac DL Johansson J, 2009. Appraising the post-marketing safety of medicines: A
description of national and international pharmacovigilance with a focus on medicines used in
chronic pain. Current Anaesthesia and Critical Care, 20, 215-220.
Schuchat A Bell BP, 2008. Monitoring the impact of vaccines postlicensure: new challenges, new
opportunities. Expert Review of Vaccines, 7, 437-456.
Sharrar RG Dieck GS, 2013. Monitoring product safety in the postmarketing environment.
Therapeutic Advances in Drug Safety, 4, 211-219.
Simojoki M Luoto R Uutela A Rita H Boice Jr JD McLaughlin JK Puska P, 2005. Use of plant stanol
ester margarine among persons with and without cardiovascular disease: Early phases of the
adoption of a functional food in Finland. Nutrition Journal, 4.
Steenburg C, 2006. The Food and Drug Administration's use of postmarketing (phase IV) study
requirements: Exception to the rule? Food and Drug Law Journal, 61, 295-384.
Talati AR Gurnani AK, 2009. Dietary Supplement Adverse Event Reports: Review and Analysis.
Food and Drug Law Journal, 64, 503-513.
Talbot JCC Nilsson BS, 1998. Pharmacovigilance in the pharmaceutical industry. British Journal of
Clinical Pharmacology, 45, 427-431.
Tatley MV Kunac DL McNicholas A Zhou L Ballantyne S Ashton J Stehr-Green P Galloway Y Reid
S, 2008. The Intensive Vaccines Monitoring Programme (IVMP): An electronic system to monitor
vaccine safety in New Zealand. Vaccine, 26, 2746-2752.
Theophile H Arimone Y Miremont-Salame G Moore N Fourrier-Reglat A Haramburu F Begaud B,
2010. Comparison of Three Methods (Consensual Expert Judgement, Algorithmic and Probabilistic
Approaches) of Causality Assessment of Adverse Drug Reactions An Assessment Using Reports
Made to a French Pharmacovigilance Centre. Drug Safety, 33, 1045-1054.
Theophile H Laporte J-R Moore N Martin K-L Begaud B, 2011. The Case-Population Study Design
An Analysis of its Application in Pharmacovigilance. Drug Safety, 34, 861-868.
Tompkins S Hudson E Gimson A Halford N Weightman R, 2013. Review of the strategies for the
comprehensive food and feed safety and nutritional assessment of GM plants per se.
http://www.efsa.europa.eu/en/supporting/pub/480e.htm
Torvi JR Hunashal R, 2011. Pharmacovigilance. International Journal of Pharma and Bio Sciences, 2,
95-103.
Van Grootheest K De Graaf L De Jong-van Den Berg LTW, 2003. Consumer adverse drug reaction
reporting: A new step in pharmacovigilance? Drug Safety, 26, 211-217.
Van Hunsel F Haermark L Pal S Olsson S van Grootheest K, 2012. Experiences with Adverse Drug
Reaction Reporting by Patients An 11-Country Survey. Drug Safety, 35, 45-60.
Van Puijenbroek EP Hepburn PA Herd TM Van Grootheest AC, 2007. Post launch monitoring of food
products: what can be learned from pharmacovigilance. Regulatory Toxicology and Pharmacology.
47, 213-220.
Waller PC, 1991. Postmarketing surveillance: The viewpoint
pharmacoepidemiology. Drug Information Journal, 25, 181-186.
EFSA supporting publication 2015: EN-739
of
a
newcomer
to
67
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Waller PC, 2006. Making the most of spontaneous adverse drug reaction reporting. Basic & Clinical
Pharmacology & Toxicology, 98, 320-323.
Waller PC Coulson RA Wood SM, 1996. Regulatory pharmacovigilance in the United Kingdom:
Current principles and practice. Pharmacoepidemiology and Drug Safety, 5, 363-375.
Waller PC Evans SJW, 2003. A model for the future conduct of pharmacovigilance.
Pharmacoepidemiology and Drug Safety, 12, 17-29.
Weaver J La Grenade L Kwon H Avigan M, 2009. Finding, evaluating, and managing drug-related
risks: approaches taken by the US Food and Drug Administration (FDA). Dermatologic Therapy,
22, 204-215.
Welch RW Antoine JM Berta JL Bub A De Vries J Guarner F Hasselwander O Hendriks H Jäkel M
Koletzko BV Patterson CC Richelle M Skarp M Theis S Vidry S Woodside JV, 2011. Guidelines
for the design, conduct and reporting of human intervention studies to evaluate the health benefits
of foods. British Journal of Nutrition, 106, S3-S15.
Westerholm B, 1987. The rationale for a post-marketing surveillance. Human Reproduction, 2, 41-44.
WHO (World Health Organisation), 2004. WHO guidelines on safety monitoring of herbal medicines
in pharmacovigilance systems. Geneva.
Wiktorowicz M Lexchin J Moscou K, 2012. Pharmacovigilance in Europe and North America:
Divergent approaches. Social Science & Medicine, 75, 165-170.
Willems JI Blommaert MAE Trautwein EA, 2013. Results from a post-launch monitoring survey on
consumer purchases of foods with added phytosterols in five European countries. Food and
Chemical Toxicology, 62, 48-53.
Wood SM, 1991. Postmarketing surveillance: Viewpoint from a regulatory authority. Drug
Information Journal, 25, 191-195.
Zakaryan A Martin IG, 2012. Regulation of Herbal Dietary Supplements: Is There a Better Way?
Drug Information Journal, 46, 532-544.
Zancan A Locatelli C Ramella F Tatoni P Bacis G Vecchio S Manzo L, 2009. A new model of
pharmacovigilance? A pilot study. Biomedicine & Pharmacotherapy, 63, 451-455.
Zuber PLF Autran B Asturias EJ Evans S Hartigan-Go K Hussey G John TJ Lambert PH Law B
Midthun K Nohynek H Salmaso S Smith PG Bentsi-Enchill A Caric A Pfeifer D Duclos P Wood
D, 2009. Global safety of vaccines: Strengthening systems for monitoring, management and the
role
of
GACVS.
Expert
Review
of
Vaccines,
8,
705-716.
EFSA supporting publication 2015: EN-739
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by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
APPENDIX/APPENDICES
Appendix A.
WP1 Paper Review Table
The below table summarises the results of all papers that were included in the final review as part of Work Package 1, review of existing PMM programmes.
Date
Published
Authors
Title
Location
1999
Abenhaim L,
Moore N &
Begaud B
The
Role
Pharmacoepidemiology
Pharmacovigilance
2009
Agorastos T,
Chatzigeorgio
u
K,
Brotherton
JML
&
Garland SM
Safety of human papillomavirus
(HPV) vaccines: A review of
the international experience so
far
EFSA supporting publication 2015: EN-739
of
in
Aim
Global
To look at the benefits and role of
pharmacoepidemiology
in
Pharmacovigilance.
Global
To report on the international
experience with the safety of
prophylactic HPV vaccines
Monitoring method
Discusses spontaneous reporting and epidemiology studies.
Spontaneous reporting case identification is described as
investigator independent, whereas epidemiology study case
identification
is
described
as
investigator
driven.
Pharmacoepidemiological methods discussed include field casecontrol studies, record linkage databases, practice databases and
field cohort studies. Uses include: determining causality of an
adverse event, assessing the risks in the absence of an epidemic
e.g. reports occur spontaneously within the population and preemptively when there is no alert e.g. a new drug or when there are
suspicions.
Literature review looking for reported adverse effects. Most
systems in vaccine surveillance are passive, relying on selfinitiated reporting. These systems can be influenced by things e.g.
media attention which could affect reporting rates. Active
surveillance can be conducted, by extracting safety information
from health systems databases and reviewing the scientific
literature to confirm cases. The report then showed examples of
how different countries monitored the HPV vaccine. Australia, the
USA, Europe and Canada all used passive surveillance monitoring
methods, where data was collected (regionally or centrally) and
reviewed by experts to determine causality. In Canada active
surveillance was also recorded on certain paediatric wards in
several hospitals.
69
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
USA
Describe the FDA's PMS program
and highlight the importance of
physicians in this task, with the hope
of increasing reporting.
2003
Ahmad SR
Adverse Event Monitoring at
the
Food
and
Drug
Administration
1986
Alberman E
Post-marketing surveillance of
oral contraceptives
UK
effects on reproduction of preconceptional oral contraception
2010
Alemayehu
D, Andrews
EN, Glue P &
Knirsch CA
Considerations for the Design
and
Conduct
of
a
Pharmacovigilance
Study
Involving
Mass
Drug
Administration in a ResourceConstrained Setting
Tropical/
Resource
Constrained
Conduct and reporting of multi drug
administration studies and the main
features that distinguish these trials
from typical clinical trials.
EFSA supporting publication 2015: EN-739
Monitoring method
Spontaneous reports from pharmaceutical companies and
physicians/pharmacists on adverse events are collected and
scrutinised by Food & Drug Administration (FDA) safety
evaluators. Evaluators look for additional cases in (Adverse Event
Reports) AERS database and medical literature. Then searches
begin for common trends, patterns of events to identify risk
factors. Confirmation of signals is done using large claims
databases and through foreign regulatory agencies and World
Health Organisation (WHO) Uppsala Monitoring Centre.
Confirmation of signal is followed by regulatory action e.g.
changing of warning label/ removal of drug from market
Discusses routine monitoring of trends in mortality and morbidity;
retrospective case-control studies and longitudinal studies.
Longitudinal studies work by continuous follow-up of patients
from the time of first exposure to a specific drug and by
comparing the incidence and nature of adverse drug reactions in
exposed and control patients. Little bit of information on the
benefits of retrospective studies over longitudinal e.g. cheaper and
easier to run.
Pharmacovigilance- Randomized, open label, community based
cohort trials. Both active and passive systems should be put in
place, although passive systems may be easier in a resourceconstrained setting. Questionnaires and case-report forms should
be simple and easy to use for efficient reporting and electronic
records are preferable. It is the investigators responsibility to
extract all the relevant information from the patient e.g.
demographics and concomitant drugs to help inform causality
assessment.
70
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author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2013
2001
2012
Authors
Alger
HM,
Maffini MV,
Kulkarni NR,
et al.
Allgood GS,
Kuter
DJ,
Roll KT, et al.
Amarasinghe
A, Black S,
Bonhoeffer J,
et al.
Title
Perspectives on How FDA
Assesses Exposure to Food
Additives When Evaluating
Their
Safety:
Workshop
Proceedings
Postmarketing Surveillance of
New Food Ingredients: Results
from the Program with the Fat
Replacer Olestra
Effective
Vaccine
safety
systems in all countries: A
challenge for more equitable
access to immunization.
EFSA supporting publication 2015: EN-739
Location
Mainly US but
did
consider
systems around
the world
USA
Global
Aim
Monitoring method
To discuss FDA's approach to
assessing safety of food additives
The paper is a report of a workshop attended by more than 70
experts from academia, government, industry, and public interest
groups to discuss the U.S. Food and Drug Administration's
(FDA's) approach to assessing safety of food additives.
Participants generally agreed that there were opportunities for
FDA to improve the current system for ensuring the safety of
substances in food. 3 major topics emerged for improving
exposure assessments: Food consumption data, Greater
consideration of subpopulations and cumulative dietary exposure
and better interagency communication, collaboration, and
coordination.
To describe the results of postmarketing surveillance program
Proctor and Gamble were required
to carry-out on Olestra as part of the
approval process
Three key methods: 1) spontaneous consumer reporting 2) info
obtained was subject to in/external medical evaluation 3)
Continuation of clinical studies in 'real-world' populations.
Clinical studies included; a re-challenge study- those who had
reported (Gastro-Intestinal) GI effect, were used to see if effect
could be replicated, the acute consumption study- consumers
could eat as much as they wanted to prove effects of level of
consumption, six week-consumption study- households recorded
daily chip intake to see if olestra had any long-term effects.
To minimize occurrence of vaccineassociated adverse events, to
provide care to those affected.
Situation and landscape analysis, in-depth analysis of the vaccine
safety landscape. Worked in four key steps: Situation analysis e.g.
what’s already out there; developing a blue print (building on
what’s already out there); reviewing and endorsement of the
blueprint and finally the implementation of the improved system.
Three key findings were the need to standardise signal detection
and reporting, improve communication between stakeholders and
also to better use active surveillance systems in the monitoring of
vaccines.
71
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2007
2011
2001
2001
2001
2001
Authors
Arimura K,
Nakagawa M,
Izumo S, et
al.
Arlett PR &
Kurz X
Balkrishnan R
&
Furberg
CD
Balkrishnan R
&
Furberg
CD
Balkrishnan R
&
Furberg
CD
Balkrishnan R
&
Furberg
CD
Title
Safety
and
efficacy
of
interferon-α in 167 patients
with
human
T-cell
lymphotropic virus type 1–
associated myelopathy
Location
Japan
Aim
Monitoring method
A postmarketing surveillance study
was undertaken to investigate the
safety and efficacy of interferon-α
for human T-cell lymphotropic virus
type
1
(HTLV-1)-associated
myelopathy (HAM) under routine
treatment conditions
Patients undergoing treatment invited to enrol in study, and when
each patient was enrolled they were examined by a healthcare
specialist and a standardised questionnaire was conducted with
them to obtain information on their demographics, any other
conditions they had and any other drugs they were taking. During
the course of the drug treatment healthcare professionals from the
patient’s hospital would collect data on any improvements or
declines in the patients’ health. Including drug-related health
events which were then assessed for causality.
New approaches to strengthen
pharmacovigilance
EU
Find adverse reactions
Spontaneous adverse reaction (individual case safety) reports,
observational data, clinical trials and meta-analyses. Discusses
how spontaneous reporting was/is the traditional method of
pharmacovigilance but now they are looking at developing some
other methods. For example: using electronic healthcare
databases, as sources of observational data, used for quick
response to new adrs; large simple randomised trials which are
useful because outcomes can be measured during routine care
processes and epidemiological methods e.g. questionnaires on
discharge from hospital.
Developing
an
optimal
approach to global drug safety
Global
NA
Discusses the different methods of postmarket monitoring of
drugs in different countries around the world. (see below entries)
Developing
an
optimal
approach to global drug safety
France
report adrs
Pharmacovigilance
Developing
an
optimal
approach to global drug safety
New Zealand
report adrs
The intensive medicines monitoring program (IMMP)
Developing
an
optimal
approach to global drug safety
UK
report adrs
Prescription event monitoring (PEM)
EFSA supporting publication 2015: EN-739
72
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2001
2001
Authors
Balkrishnan R
&
Furberg
CD
Balkrishnan R
&
Furberg
CD
Title
Monitoring method
United States
report adrs
The adverse event reporting system (AERS)
Developing
an
optimal
approach to global drug safety
Sweden
report adrs
Swedish drug surveillance efforts
Global
To study and analyse the suspected
adverse reaction drug reporting form
of different countries to assess if
forms capture all data.
Survey of Spontaneous ADR (adverse drug reaction) reporting
forms.
n/a
Improve safety reporting by better
incorporating the perspective of the
patient
Patient-reported outcome of adverse event (PRO-AE): A PRO-AE
is any untoward medical occurrence, whether or not considered
treatment/intervention related, which is reported or transmitted
directly by the patient without interpretation by a clinician or
anyone else. PRO-AEs may be collected by both structured and
unstructured reports.
UK
Provide a critical overview of the
current state of pharmacovigilance
of herbal medicines in the UK, and
to discuss the particular challenges
that this area presents.
Methods for Pharmacovigilance of Herbal Medicines include:
spontaneous reporting schemes (e.g. UK national spontaneous
reporting scheme; WHO/Uppsala monitoring centre traditional
medicines project; Herbal sector initiated spontaneous reporting
schemes;
intensive
monitoring
schemes)
and
other
Pharmacoepidemiological study designs.
2010
Quality check of spontaneous
adverse drug reaction reporting
forms of different countries.
2013
Banerjee AK,
Okun
S,
Edwards IR,
et al.
Patient-Reported
Outcome
Measures in Safety Event
Reporting:
PROSPER
Consortium Guidance
Barnes J
Aim
Developing
an
optimal
approach to global drug safety
Bandekar
MS, Anwikar
SR
&
Kshirsagar
NA
2003
Location
Pharmacovigilance of Herbal
Medicines
EFSA supporting publication 2015: EN-739
73
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2002
2012
Authors
Title
Bast
A,
Chandler F,
Choy PC, et
al.
Botanical health products,
positioning and requirements
for effective and safe use
Beck-Peccoz
P, Minuto F,
Leal-Cerro A,
et al.
Rationale and design of
PATRO Adults, a multicentre,
non-interventional study of the
long-term efficacy and safety of
Omnitrope® for the treatment
of adult patients with growth
hormone deficiency
1994
Begaud
B,
Moride
Y,
Tubert-Bitter
P, et al.
2009
Benchelkh RS
&
Benabdallah
G
False-positives in spontaneous
reporting: should we worry
about them?
Medication
errors:
pharmacovigilance centres in
detection and prevention
EFSA supporting publication 2015: EN-739
Location
Aim
Monitoring method
Global
Summarise legislation of botanical
products e.g. safe products which
are non-toxic
The report mentions that the use of epidemiological studies and
patient case report data can be useful indicators of a safety issue.
The report then discusses how operational systems of
pharmacovigilance for herbal medicines still need to be
developed. One of the challenges is that herbal medicines are
often sold over the counter and therefore it is hard to determine
how much product is actually being consumed and consumers are
likely to report any adverse events directly to the manufacturer of
the product.
European
Countries
To describe the rationale and design
of PATRO Adults, a postmarketing
surveillance study of the long-term
efficacy and safety.
A postmarketing surveillance study of the long-term efficacy and
safety of somatropin (Omnitrope®) for the treatment of
adult patients with GHD. The study is part of the post-approval
pharmacovigilance plan for Omnitrope. Eligible patients were
adults receiving treatment with Omnitrope® and who provided
informed consent.
Theoretical
The aim of this paper is to determine
how likely coincidental associations
are to occur in the postmarketing
surveillance setting.
Morocco
International
To develop an extended role for
national
centres
of
pharmacovigilance, to include the
collection of information on the
incidence of adverse events related
to medication errors.
/
Spontaneous reporting. Pharmacovigilance system. Discusses
some of the limitations of spontaneous reporting e.g. underreporting, difficulty in describing users and patterns of use in the
reporting population. The paper used a statistical model to see if
reports could be coincidental and the results suggested that this
was not the case unless the symptom was very common among
the population.
Pharmacovigilance centres were sent questionnaires regarding
medication errors and adverse drug reactions. Root-cause analysis
can be used to determine if the adverse reaction is due to
medication errors or not. It works by looking at the underlying
causes and environmental context in which an incident related to a
medication error occurred. Names the different types of rootcause and how pharmacovigilance centres can help to prevent
medication errors occurring e.g. education of healthcare
professionals.
74
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2005
2007
1992
2008
Authors
Title
Bennett CL,
Nebeker JR,
Lyons EA, et
al.
The Research on Adverse Drug
Events and Reports (RADAR)
project
Bennett CL,
Nebeker JR,
Yarnold PR,
et al.
Evaluation of Serious Adverse
Drug Reactions: A proactive
pharmacovigilance
program
(RADAR) vs safety activities
conducted by the food and drug
administration
and
pharmaceutical manufacturers
Bergman U
Second
Thoughts
Pharmacoepidemiological
Perspectives
Berlin
JA,
Glasser SC &
Ellenberg SS
Adverse Event Detection in
Drug
Development:
Recommendations
and
Obligations Beyond Phase 3
EFSA supporting publication 2015: EN-739
Location
Aim
Monitoring method
USA
RADAR focused on uncovering
previously unrecognized adverse
drug (and device events).
After identifying a serious and unexpected clinical event, RADAR
postulated clinical hypotheses and derived case series and
incidence estimates from physician queries, published and
unpublished clinical trials, published case reports, FDA databases,
and manufacturer sales figures.
United States
Comparing safety efforts for
evaluating serious ADRs conducted
by the FDA and pharmaceutical
manufacturers vs the RADAR
project
RADAR pharmacovigilance program, possible adr is reported, it
is then reviewed by radar staff. After review if the adr is novel &
significant it goes for further investigation e.g. additional FDA
case reports. Case reports are reviewed to inform hypotheses and
data collection tools. Once reviewed they are assessed for
causality associations according to WHO criteria. Data is
disseminated via FDA, manufacturers and journals.
Global
Discussion of potential methods of
pharmacovigilance.
Article based on a paper presented at the WHO Drug Research
Group Meeting in Oslo, Norway, September 1987, discusses
methods of pharmacovigilance e.g. pharmacoepidemiological
studies (cohort and case control), post-market clinical trials and
spontaneous reporting systems. Also discusses record-linkage
databases, where patient data is anonymised and validation of
exposure and diagnosis are then completed. Discusses the benefits
of using record linkage e.g. speed and they provide objective
patient history for use in causality assessments. Touches on
prescription event monitoring in the UK.
USA
To review the strengths and
limitations
of
postmarketing
surveillance of drugs and to make
recommendations for means of
continued
evaluation
after
marketing.
Review of strengths and limitations of postmarketing surveillance
including methods such as spontaneous reporting, electronic
databases, observational studies and large simple safety trials.
75
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2008
2011
2011
2011
Authors
Title
Berne
B,
Tammela M,
Farm G, et al.
Can the reporting of adverse
skin reactions to cosmetics be
improved?
A
prospective
clinical study using a structured
protocol.
Bhosale VV
& Gaur SPS
Adverse
monitoring
drug
Location
reaction
Bian
J,
Topaloglu U
& Yu F
Towards Large-scale Twitter
Mining
for
Drug-related
Adverse Events
Blake
KV,
Smeraldi C,
Kurz X, et al.
The European Network of
Centres
for
pharmacoepidemiology
and
Pharmacovigilance: application
to
diabetes and vascular disease
EFSA supporting publication 2015: EN-739
Aim
Monitoring method
Sweden
To improve the reporting of adverse
reactions to cosmetics.
Structured standardized protocol during clinical investigation,
including skin patch testing, followed by a causality assessment.
Some examples
of ADR in India
Information on some recent label
changes of drugs, withdrawals from
the market and standard methods of
adverse drug reaction (ADR)
monitoring with examples.
The National Pharmacovigilance Programme (NPP)12 encourages
the reporting of all suspected drug-related adverse events,
including those suspected to have been caused by herbal,
traditional and alternative remedies. ADR monitoring involves: (i)
collecting the ADR data, (ii) assessing the causality between
drugs and suspected reactions, and (iii) reporting ADRs to
pharmacovigilance centres/ADR regulating authorities.
Global
An approach to find drug users and
potential
adverse
events
by
analysing the content of twitter
messages
utilizing
Natural
Language Processing (NLP) andto
build Support Vector Machine
(SVM) classifiers.
They collected a stream of Tweets which was organized by a
timeline. The raw Twitter messages were trawled using the
Twitter’s user timeline API [29] that contains information about
the specific Tweet and the user.
Europe
Provide a unique point of access for
all involved stakeholders, including
industry or regulatory authorities,
who are seeking collaboration for
the
commissioning
or
the
performance of post-authorisation
studies.
The European Network of Centres for Pharmacoepidemiology and
Pharmacovigilance (ENCePP) is an initiative led by the European
Medicines Agency (EMA) aimed at further strengthening the
post-authorisation monitoring of medicinal products in Europe by
facilitating the undertaking of multi-centre, independent, studies
focusing on safety and on benefit/risk.
76
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Aim
Monitoring method
Bond RA
A proposal for a national
program reporting beneficial
drug responses, analogous to
the existing program to detect
adverse drug responses.
Finding post-marketing additional
beneficial uses for drugs using
existing monitoring for ADRs.
Use existing Government sponsored system for the reporting of
adverse drug responses but looking at alternative forums for
collecting information on adverse drug reactions e.g. web-based
forums where off-label uses are often discussed.
2010
Bons
B,
Audebert F,
Bitaudeau C,
et al.
Assessment of undesirable
events in cosmetic market
surveillance:
Background,
description and use of a
causality assessment method in
cosmetovigilance
N/A
Propose a pragmatic causality
assessment method which has been
developed by the cosmetic industry
with the purpose to specifically
address the case of cosmetic
products.
Causality assessment method in cosmetovigilance. Causality
analysis started with a review of the presence of evocative
symptoms. This then guided the cosmetovigilance practitioner to
follow the decision tree in function of the available information on
chronological criteria. The decision tree takes into account the
need for additional investigations and re-challenges results prior
to arriving at a final causality score.
2009
Bousquet P-J,
Demoly
P,
Romano A, et
al.
Pharmacovigilance of drug
allergy and hypersensitivity
using
the
ENDA–DAHD
database and the GA2LEN
platform. The Galenda project
European
To highlight benefits of better
collection of data and co-ordinated
database
The paper describes setting up databases for collection of data on
allergy and hypersensitivity - not a report of trial
2006
Authors
Title
Location
2012
Brashier DBS
& Sharma S
An adverse drug reaction clinic:
Breathing fresh life into the
pharmacovigilance programme
India
Report ADRs
2008
Breckenridge
A
Post Marketing Strategies for
Medicines (letter to the editor)
NA
NA
EFSA supporting publication 2015: EN-739
Pharmacovigilance Programme of India (PvPI)- discusses setting
up a national centre for pharmacovigilance which will deal with
all adverse event reports. Passive surveillance and active
surveillance methods are discussed. Passive surveillance systems
are spontaneous reporting forms and active surveillance will be
follow-up call with patients.
NA - article is a letter to the editor discussing the concept pf a
life-cycle approach to drug safety and risk management strategies
which are used throughout the life of the drugs' use in clinical
practice.
77
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
Monitoring method
Adverse Event Reporting System (Food and Drug Administration
Centre for Food Safety and Applied Nutrition). Will allow better
reporting of adverse events for food and nutritional supplements.
Complaint data received via telephone, email or fax will be
inputted into the system and real-time reporting features will
allow the quick dissemination of information.
Spontaneous reporting systems such as MEDWATCH. Health
care professionals are encouraged to report serious events
suspected to be caused by medications, medical devices, special
nutritional products, and other products regulated by the FDA.
Serious events are those that lead to death, hospitalization,
significant or permanent disability, or congenital anomaly or
require medical or surgical intervention to prevent 1 of these
events.
2003
Bren L
FDA's response to food, dietary
supplement
and
cosmetic
adverse events.
USA
Determine cause of incidences and
help prevent their recurrence
1999
Brewer T &
Colditz GA
Postmarketing Surveillance and
Adverse
Drug
Reactions:
Current Perspectives and Future
Needs
N/A
General review
2002
Bright RA &
Nelson RC
Automated
support
for
pharmacovigilance: a proposed
system
USA
To develop a new strategy for the
review and analyses of adverse
event reports received by FDA
Pharmacovigilance. It was considered vital to place
pharmacovigilance first, with all else (filing, tracking,
compliance, administration) secondary. All historical and new
reaction data would be coded with the new MedDRA (Medical
Dictionary for Regulatory Activities) scheme.
2007
Buchbinder
R, March L,
Lassere M, et
al.
Effect of treatment with
biological agents for arthritis in
Australia:
the
Australian
Rheumatology
Association
Database
Australia
To describe setting up of database
and report some preliminary results
Briefly describes the Australian spontaneous reporting system and
some of advantages and disadvantages of spontaneous reporting.
Discusses the development of a database including information on
data collection, data validity and recruitment of patients.
EFSA supporting publication 2015: EN-739
78
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2013
1991
Authors
Burk
M,
Moore V, P
Glassman, et
al.
Butchko HH
& Kotsonis
FN
Title
Medication-use evaluation with
a Web Application
Acceptable Daily Intake vs
Actual Intake: The Aspartame
Example
EFSA supporting publication 2015: EN-739
Location
USA
Global
Aim
Monitoring method
Describing a web-based application
for coordinating medication-use
evaluation (MUE) initiatives within
the veterans’ affairs (VA) health
care system.
VAMedSAFE- VA centre for medical safety, use of MUE
(medication use evaluation) reports on patient pharmacotherapy. It
is a national centre promoting medical safety and conducting
pharmacovigilance. Uses spontaneous reporting systems and
integrated databases. Uses electronic healthcare data to design
MUE Tracker (MUET). This systems; collects, analyses, reports
and responds (incorporating human response) to assess
medication use. Database contain info on demographics,
prescription data, diagnoses, provider encounters, hospitalisations,
lab data and procedure codes. MUET is used to identify at risk
groups of patients to aid pharmacovigilance.
It is the purpose of this article to
discuss the topics surrounding
acceptable daily intake using
aspartame (APM), a widely used
food additive as an example.
Five different methods, 2 USA, 1 Canada, 1 Germany and 1
Finland
1) USA- MRCA: Menu Census Survey, 14 day dietary intake
diaries. All food eaten in and outside of the home are recorded for
every member of the family. Intake= no. of times individual
consumes product containing aspartame x portion size (age & sex)
x
amount
of
ingredient
in
product
2) USDA Survey of food intakes by individual: 1 day diary
surveys
of
1500
adult
females
3) Canada: Survey of 5000 individual chosen as representative of
Canadian population. 7 day consumption diary kept in winter and
summer. 4)Germany: 1 day dietary survey of 2300 individual
5)Finland: Consumption by diabetic adolescents evaluated over
48hr period
79
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Butchko HH,
Tschanz C &
Kotsonis FN
Postmarketing surveillance of
food additives
2008
Butler
SF,
Budman SH,
Licari A, et
al.
National addictions vigilance
intervention and prevention
program (NAVIPPROTM): a
real-time,
product-specific,
public
health
surveillance
system
for
monitoring
prescription drug abuse
2010
Caster
O,
Norén
GN,
Madigan D &
Bate A
Large-Scale Regression-Based
Pattern
Discovery:
The
Example of Screening the
WHO Global Drug Safety
Database
Castle GH &
Kelly B
Global Harmonization Is Not
All That Global: Divergent
Approaches in Drug Safety
1994
2008
EFSA supporting publication 2015: EN-739
Location
Aim
Monitoring method
Summary of surveillance for consumption and medical effects,
plus clinical trials e.g. menu census surveys, food diaries postclinical trials and toll-free care lines. Discusses menu-census
surveys to determine levels of consumption, with surveys
conducted over a 14 day period across 5000 households. It also
discusses the use of food diaries in the UK and Canada as
methods of determining consumption. They found more reports of
adverse events close to the first release of the product and
numbers reduced over time.
The National Addictions Vigilance Intervention and Prevention
Program (NAVIPPROTM) is a risk management program for
scheduled therapeutics. NAVIPPROTM provides post-marketing
surveillance, signal detection, signal verification and prevention
and intervention programs. The focus of this paper is on
NAVIPPROTM surveillance, the Addiction Severity IndexMultimedia Version1 (ASI-MV1) Connect. NAVIPPROTM is a
continuous, real-time, national data stream which assesses
pharmaceutical abuse by patients entering substance abuse
treatment clinics. Data collection includes product-specific,
geographically-detailed information.
Mainly US but
includes some
global
information
To present consumption, safety data
to indicate aspartame is safe and
system used is applicable to other
food additives
National, USA
The primary focus of this article is
to describe the ASI-MV Connect,
one of the system’s continuous, realtime
data
streams
and
to
demonstrate its ability to effectively
monitor
product-specific
prescription opioid abuse within a
sentinel population.
82
countries,
Worldwide
Implement
shrinkage
logistic
regression for large-scale pattern
discovery
and
evaluate
its
usefulness in real-world data.
Shrinkage logistic regression for large-scale pattern discovery and
evaluate its usefulness in real-world data. Example used is the
WHO Global Individual Case Safety Report database, VigiBase,
maintained and analysed by the WHO Collaborating Centre for
International Drug monitoring in Uppsala, Sweden.
To highlight deficiencies in global
systems
General review of different pharmacovigilance systems, with
definitions of adverse reactions, examples of implanting
pharmacovigilance in Europe and the US e.g. spontaneous
reporting directly to the healthcare professional (EU) or to the
manufacturer (US).
Global
80
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
Monitoring method
Some European
Aims at automatically discovering
ADEs that occurred in inpatients.
Data Mining, natural language processing. Data are extracted
from several hospitals’ electronic health records and must include
information on: patient demographics, diagnoses, medical
procedures, drugs administered etc. Aggregation engines
transform the data into a set of events, which can then be analysed
by the data mining tools. This is supposed to simplify the process
of pharmacovigilance.
USA
Explore the use of online health
forums as a source of data to
identify drugs for further FDA
scrutiny
Machine-learning classifiers to compare messages containing
watch list drugs’, pre-regulatory action to other messages
containing drugs with no regulatory action.
USA
Detection of abuse of OxyContin
and other commonly prescribed
opioid analgesics at the three-digit
ZIP code level across the country
utilizing a number of different
detection systems.
Proactive surveillance program to monitor and characterize abuse,
named the Researched Abuse, Diversion and Addiction Related
Surveillance (RADARS) System.
Discusses that randomized clinical trials (RCTs) are usually
designed to provide evidence of efficacy in a disease and
population, compared with the control. Details the types of
reactions usually captured during a trial and discusses some other
alternative methods of pharmacovigilance currently available.
This paper provides an overview of ongoing initiatives exploring
data from electronic healthcare records (HER) for signal detection
vis-a`-vis established spontaneous reporting systems (SRS)
2011
Chazard
E,
Ficheur
G,
Bernonville
S, et al.
Data Mining to Generate
Adverse Drug Events Detection
Rules
2011
Chee
BW,
Berlin R &
Schatz B
Predicting
Adverse
Drug
Events from Personal Health
Messages
2007
Cicero
TJ,
Dart
RC,
Inciardi JA, et
al.
The
Development
of
a
Comprehensive
RiskManagement
Program
for
Prescription Opioid Analgesics:
Researched Abuse, Diversion
and
Addiction-Related
Surveillance (RADARS)
2008
Clark DWJ,
Coulter DM
&
Besag
FMC
Randomized Controlled Trials
and Assessment of Drug Safety
N/A
Discuss randomized controlled trials
and their effectiveness on the
assessment of drug safety.
2013
Coloma PM,
Trifirò
G,
Patadia V &
Sturkenboom
M
Postmarketing
Safety
Surveillance:
Where
does
Signal
Detection
Using
Electronic Healthcare Records
Fit into the Big Picture?
Global coverage
Review existing systems and make
comments
EFSA supporting publication 2015: EN-739
81
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
2006
Cook MN
Estimating
national
drug
consumption using data at
different
points
in
the
pharmaceutical supply chain
2013
Crowther M
Phase 4 research: what happens
when the rubber meets the
road?
2012
Curtis
LH,
Weiner MG,
Boudreau
DM, et al.
Design
considerations,
architecture, and use of the
Mini-Sentinel distributed data
system
1997
Czarnecki A
& Maciejczyk
A
Pharmacovigilance in Poland
2014
Dal Pan GJ
Ongoing
Challenges
Pharmacovigilance
EFSA supporting publication 2015: EN-739
in
Aim
Monitoring method
Pharmaceutical companies with products on the European market
are obligated to provide national competent authorities,
particularly in the context of pharmacovigilance, with ‘all data
relating to the volume of sales of the medicinal product, and any
data in his possession relating to the volume of prescriptions’ Article 23a in Directive 2004/27/EC)
Comment on need for improved Phase 4 (Post market
surveillance) systems and databases, by discussing current
systems including their limitations and detailing new innovative
methods that could be used for data capture and provides
examples.
Global
To describe present systems that
drug companies use to collect data
on drug usage and how could be
improved
North America
To highlight need for better PM
surveillance
USA
The objective of Mini-Sentinel is to
inform
and
facilitate
the
development
of
an
active
surveillance system for monitoring
the safety and safe use of medical
products, including drugs, biologics,
and devices.
Mini-Sentinel is a major component of the Sentinel Initiative, the
response of the US Food and Drug Administration (FDA) to a
congressional mandate to create an active surveillance system
accessing electronic health data for 25 million people by 2010 and
100 million people by 2012.
Poland
To increase awareness of the need
for drug safety monitoring.
Government reporting programme, including polish ‘yellow
reporting card’ for spontaneous reports. Discusses the future of
pharmacovigilance in Poland e.g. regional centres, based on the
French pharmacovigilance system.
Global
To address ongoing challenges in
pharmacovigilance
N/A- some information on +ves & -ves of spontaneous reporting
and information on the use of informatics in PMM methodologies.
82
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
Monitoring method
Pharmacosurveillance of CNS drugs, with brief information
relating to spontaneous reporting and its limitations,
epidemiological studies and assessing drug abuse.
USA
The primary goal of postmarketing
surveillance
is
to
provide
information for risk assessment of a
drug.
2009
Dart RC
Monitoring risk: Post marketing
surveillance
and
signal
detection
2009
Dasgupta N
& Schnoll SH
Signal detection in postmarketing surveillance for
controlled substances
USA
focus on signal detection in the postmarketing setting
2005
Davis
RL,
Kolczak M,
Lewis E, et al.
Active Surveillance of Vaccine
Safety: A System to Detect
Early Signs of Adverse Events
US
To analyse existing data and suggest
better surveillance
2013
de Vries ST,
Mol PGM, de
Zeeuw D, et
al.
Development
and
Initial
Validation of a PatientReported Adverse Drug Event.
The Netherlands
To develop and test a generic
questionnaire to identify adverse
drug events.
2001
DeStefano F
The Vaccine Safety Datalink
Project
USA
Primary purpose of rigorously
evaluating concerns about the safety
of vaccines.
2008
Dikshit RK,
Desai C &
Desai MK
Pleasures and pains of running
a pharmacovigilance centre.
India
NA
EFSA supporting publication 2015: EN-739
The design of surveillance systems and development of methods
for signal determination begin with development of the specific
goals and objectives of a risk management program.
Used a database to simulate an active surveillance system, after
vaccination children were followed for four weeks to look for any
signs of adverse reaction. The vaccinated children were compared
to children that had not yet had the vaccine and these acted as the
control group. Outcomes were classified according to a
standardised system.
Generic questionnaire, content validation, causality scale,
cognitive debriefing plus a reliability calculation (Cohen's kapp
and proportion of positive agreement (PPA).
Vaccine Safety Datalink (VSD) project, mainly discusses results
of the project with a small section on methods. Data is collected
on a computerised system from lots of different health
maintenance organisation and evaluates vaccine safety hypotheses
using spontaneous reporting and literature data under joint
analytical protocol.
Review article - review of the National Pharmacovigilance
Program (NPVP). Discusses the role of the centre, organisation
and running and measures taken to increase reporting by
healthcare professionals. It also covers the highs and lows of
creating the programme.
83
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
Monitoring method
India
Review of pharmacovigilance with
specific relevance to India.
Gives a detailed overview of pharmacovigilance in general
including definitions and background details. Does discuss some
of the methodologies for India specifically. States they are still
quite backward in terms of development of pharmacovigilance.
Mentions spontaneous reporting as the cornerstone of signal
detection. Report forms would be filled out by healthcare
practitioners and sent to the relevant authority e.g. national
pharmacovigilance programme and monitored by the Office of
Drug Controller General for India, who would encourage
reporting of all suspected ADRs. The forms should be completed
to the highest quality and returned to the same Pharmacoviglance
centre they were obtained from. Once obtained the forms then
need to be assessed for causality, with data-mining to show
product-event linking. State there is a need for more active
surveillance but don't go into much detail. The same is true for
pharmacoepidemiological studies.
USA
The objective of this study was to
develop a data-driven algorithm that
will provide a valid, reliable, and
easy-to-use tool for the detection of
ADRs specific in the NICU
population.
Data-driven algorithm that will provide a valid, reliable, and easyto-use tool for the detection of ADRs specific in the NICU
population.
Review of post marketing surveillance of drugs, including
spontaneous adverse drug reporting, prescription event
monitoring, case-control studies, cohort studies, and use of the
Drug Safety Research Unit database, record linkage and
randomized clinical trials.
Dogra
R,
Garg
R,
Kumar V, et
al.
Detection,
Assessment,
Understanding and Prevention
of
Adverse
Effects:
Pharmacovigilance: A Review
Du W, Lehr
VT, Lieh-Lai
M, et al.
An algorithm to detect adverse
drug reactions in Neonatal
Intensive Care Unit (NICU) – A
new approach
1999
Dunn N
Mann RD
Prescription-event and other
forms
of
epidemiological
monitoring of side-effects in the
UK.
UK
To
review
monitoring
1998
Edwards IR
Safety monitoring of new antimalarials in immediate postmarketing phase
Global
Report ADRs
2013
2013
&
EFSA supporting publication 2015: EN-739
prescription-event
Spontaneous case reports- discusses advantages
cost/simplicity and disadvantages e.g. under-reporting.
e.g.
84
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Edwards IR
Safety monitoring of new antimalarials in immediate postmarketing phase
2000
Edwards IR
Spontaneous ADR Reporting
and Drug Safety Signal
Induction Perspective
2012
Edwards IR
2005
Edwards R,
Faich G &
Tilson H
2002
Egberts ACG,
Meyboom
RHB & van
Puijenbroek
EP
1998
2007
Egberts TCG
Aim
Monitoring method
Report ADRs
Pharmacoepidemiology: case control and cohort studies allow for
controlled comparison. Also briefly mentions the use of
prescription event monitoring in New Zealand and the UK.
Global
Improve public health
Suspected ADR signal generation and formation of hypotheses;
analysis of the signal (confirm hypothesis/size of risk/susceptible
patients); changed benefit-to-risk issues in therapy; communicate
to health professionals and patients; consequence evaluation.
An agenda for UK clinical
pharmacology
pharmacovigilance.
UK
To review Pharmacovigilance in
broad terms.
Review of pharmacovigilance including pharmacoepidemiology,
data mining, and use of communication and systems technology.
Points to consider: the roles of
surveillance and epidemiology
in advancing drug safety
Global
To set out 10 principles important to
monitor PMS
The paper sets out 10 principles considered important to consider
for PM Surveillance of drugs - arose from Workshop in 2003
Netherlands
Present three Dutch examples of the
use
of
a
measure
of
disproportionality in quantitative
signal
detection
in
pharmacovigilance.
Three Dutch examples are described in which a measure of
disproportionality is used in quantitative signal detection in
pharmacovigilance: (i) the association between a single drug and a
single event; (ii) the association between two drugs and a single
event (drug-drug interaction); and (iii) the association between a
single drug and multiple events (syndrome).
Report ADRs
Discusses the development of signal detection from use of human
intellect to newer techniques e.g. disproportionality analysis. Also
discusses improvements to current signal detection methods e.g.
selection of appropriate control groups and restriction to subsets
of people/reports.
Use
of
Measures
Disproportionality
Pharmacovigilance
Signal Detection
Background
EFSA supporting publication 2015: EN-739
of
in
Historical
Global
Global
85
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2008
Authors
Eguale
T,
Tamblyn R,
Winslade N
& Buckeridge
D
Title
Detection of Adverse Drug
Events and Other Treatment
Outcomes Using an Electronic
Prescribing System
2010
Eguale
T,
Winslade N,
Hanley JA, et
al.
Enhancing
Pharmacosurveillance
with
Systematic
Collection
of
Treatment
Indication
in
Electronic Prescribing
1999
Evans JMM
and
MacDonald
TM
Record-linkage
for
pharmacovigilance in Scotland
EFSA supporting publication 2015: EN-739
Location
Aim
Monitoring method
Canada
To determine the accuracy of an
electronic prescribing and drug
management system in documenting
orders for discontinuation and dose
changes of prescription drug
treatment, and in identifying the
reasons for the drug discontinuation
and dose change.
Detail what prescription event monitoring is and how it is an
improvement/good addition to spontaneous reporting. They
prospectively assessed the accuracy of electronic prescription
records for dose change and discontinuation by comparing them
with changes in treatment that were documented by physicianfacilitated medical chart review. They propose using a real-time
surveillance electronic prescribing systems.
Canada
1) Determining the sensitivity and
positive predictive value (PPV) of
using an electronic
prescribing
system to document treatment
indications at the time of prescribing
2) Investigating the use of treatment
indication data to evaluate on/off
label prescribing in primary -care
practice
Used electronic prescribing system MOXXI (Medical Office for
the XXI Century). Trialling a system where it is compulsory for
physicians to select one treatment indication for each prescribed
drug. Treatment indications are specific to a drug and are used to
populate patient health care records. This allows a physician to
see and will give notifications of potential drug-drug and drugdisease interactions. Making it easier to track adverse reactions.
Scotland
The contribution of record-linkage
in Scotland to medical research is
described
Collaborative project between Medicines Monitoring Unit
(MEMO) and Information and Statistics Division (ISD), which
draws upon MEMO's expertise in pharmacovigilance and ISD's
experience in probabilistic matching.
86
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2008
2012
2010
Authors
Title
Faden LB &
Milne C-P
Pharmacovigilance Activities in
the United States, European
Union and Japan: Harmonic
Convergence or Convergent
Evolution?
Faich G
Morris J
Adverse reaction monitoring
and disproportionality analysis:
an update
&
Fan K, Sun X,
Tao Y, et al.
High-Performance
Signal
Detection for Adverse Drug
Events
using
MapReduce
Paradigm
EFSA supporting publication 2015: EN-739
Location
Aim
US, EU, Japan
To compare system in US, UK &
Japan
USA, but also
Globally
Highlighting recent developments in
signal detection and management as
well as providing cautions related to
biases that affect reporting and
analyses of adverse event databases.
USA
To investigate the possibility of
using MapReduce principle to speed
up biomedical data mining tasks
using this pharmacovigilance case
as one specific example.
Monitoring method
The paper details the main features of the current
pharmacovigilance systems in the U.S., the EU, and Japan,
especially post-marketing surveillance (PMS), risk management,
and post-approval research (PAR). It goes on to discuss efforts to
harmonize these systems and then presents a comparison of
pharmacovigilance in the three regulatory regions with an
emphasis on PAR. Finally the paper provides some conclusions
about how much the changes taking place are related to the world
getting smaller (i.e., harmonic convergence) or the problem
getting bigger (i.e., convergent evolution).
Spontaneous reports are submitted by healthcare practitioners,
industry
and
patients
directly
to
regulatory
authorities/manufacturers. Most reporting in the US occurs
verbally via care lines. Reports are classed as signals and are used
as a preliminary indication of causal relationship. Drugs are
selected for adverse event evaluation based on suspicions of
causality. Data mining is used as a technique to monitor and
evaluate signals. Most commonly used technique is
disproportionality analysis, or comparing the observed level of a
drug-adverse event occurrence to the expected drug-adverse event
occurrence in a comparison group. Events with a low (close to 1)
disproportionality numbers are thought to be less likely to be
linked to the drug.
A parallel programming model, MapReduce has been introduced
by Google to support large-scale data intensive applications. This
study proposes a MapReduce-based algorithm, for common ADE
detection approach to datamine for Adverse Drug Events (ADE)
in FDA records.
87
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
1995
2003
2002
Authors
Title
Farrington P,
Pugh
S,
Colville A, et
al.
A new method for active
surveillance of adverse events
from
diphtheria/tetanus/pertussis and
measles/mumps/rubella
vaccines.
Fernandopull
e RBM &
Weerasuriya
K
What can consumer adverse
drug reaction reporting add to
existing health professionalbased systems?
FleuranceauMorel P
How
do
Pharmaceutical
companies handle consumer
adverse drug reaction reports?
An overview based on a survey
of French drug safety managers
and officers
EFSA supporting publication 2015: EN-739
Location
5 districts
England
in
Aim
Monitoring method
New method for active postmarketing surveillance of vaccine
safety based on patient records.
New epidemiological and statistical method based on the linkage
of routinely available computerised hospital admission records
with vaccination records. An active surveillance method was used
to assess the attributable risk of a convulsion after
diphtheria/tetanus/pertussis (DTP) and Measles, Mumps &
Rubella (MMR) vaccines and to investigate the relation between
MMR vaccine and idiopathic thrombocytopenic purpura (ITP) in
children under 2 years in five districts in England.
Mainly
developing
world
1) To determine the limitations of
the
current
system
2) Suggest potential for allowing
consumer reports to inform drug
withdrawals
France
Detailing
results
of
the
questionnaire sent to drug safety
officers and discussion of active
consumer adr reporting
Currently physician spontaneous reporting. But they suggest
setting up an online, independent consumer reporting system, so
that patients can report their own ADRs. They use a number of
case studies which illustrate how consumers have contributed to
drug surveillance by getting drugs withdrawn which have caused
adverse reactions. Case studies are from; Australia and
Philippines.
Detailed how pharmaceutical companies deal with ADR reports
from patients. Drug Safety officers from different pharmaceutical
companies were sent a short-survey on how they dealt with
consumer adverse reaction reports. Initially the reports went
through to the secretary who directed them to the relevant
authority on that particular drug usually a drug safety officer. The
drug safety officer would then collect adequate info on the patient,
treatment and the event to be able to confirm the report. However
it was felt that consumer reports could only be considered in the
signal detection process if they were confirmed by a medical
source.
88
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
2012`
Fox B
Closing the Information Gap:
Informing
Better
Medical
Decision making through the
Use of Post-Market Safety and
Comparative
Effectiveness
Information
2003
Fram
DM,
Almenoff JS
&
DuMouchel
W
Empirical
Bayesian
Data
Mining
for
Discovering
Patterns in Post-Marketing
Drug Safety
2013
Frauger
E,
Moracchini
C,
Le
Boisselier R,
et al.
OPPIDUM
surveillance
program:
20
years
of
information on drug abuse in
France.
Fujiwara Y &
Kobayashi K
Oncology
drug
clinical
development and approval in
Japan: the role of the
pharmaceuticals and medical
devices
evaluation
centre
(PMDEC)
2002
EFSA supporting publication 2015: EN-739
Location
Aim
Monitoring method
means
of
The paper discusses the need for this type of safety information,
outlines various methods to generate and manage postmarket
safety and effectiveness information. And discusses the
communication of safety and effectiveness information to the
medical community.
US
To set out better
information gathering
USA
Report on the joint effort by Lincoln
and GSK to define, design,
implement, test, and deploy a web
based
visual
data
mining
environment for pharmacovigilance.
WebVDME data mining has been used to assist with safety
screening as part of day-to-day pharmacovigilance and risk
management practice, and to carry out special projects for
hypothesis generation and refinement as an adjunct to formalized
methods (clinical trials, pharmacoepidemiological studies).
France
To
describe
the
OPPIDUM
surveillance (Observation of Illegal
Drugs and Misuse of Psychotropic
Medications)
Specific population surveys, collecting anonymous data from
various regional drug centres using a questionnaire which patients
fill out. Questionnaires include info on patient demographics and
info on the type, frequency, ingestion method and amount of
drugs taken by the patient. The reports are sensed checked and the
results presented to the French drug agency.
Japan
Discuss the current system for drug
approval, discuss the post-approval
re-examination and re-evaluation
system, conditions under which
development and review may be
expedited, and mechanisms for
approval of off-label usage.
Japan has instituted two systems for assessing the safety and
efficacy of drugs in a wider postmarketing setting. 1) Drug reexamination (Sai-shinsa) system (post-approval phase III study),
2) Drug re-evaluation (Sai-hyouka) system.
89
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
Monitoring method
US
To test monitoring system based on
algorithms
Authors developed a semi-automated active monitoring system
that uses sequential matched-cohort analyses to assess drug safety
across a distributed network of longitudinal electronic health-care
data. The approach involves (i) identifying new users of a medical
product, (ii) matching them by PS to new users of a comparator
product, (iii) tabulating results across the distributed databases,
and (iv) applying an automated alerting algorithm selected from
an earlier simulation study In this study, they evaluate whether the
system would generate alerts for three drug–outcome pairs
USA
Simulated serially accruing matched
cohort data and compared the
performance of alerting algorithms.
Compared the performance of five classes of algorithms in
simulated data using a sequential matched-cohort framework, and
applied the results to two electronic healthcare databases to
replicate monitoring of cerivastatin-induced rhabdomyolysis.
2012
Gagne
JJ,
Glynn
RJ,
Rassen JA, et
al.
Active Safety Monitoring of
Newly Marketed Medications
in a Distributed Data Network:
Application
of
a
SemiAutomated Monitoring System
2012
Gagne
JJ,
Rassen
JA,
Walker AM,
et al.
Active safety monitoring of
new medical products using
electronic healthcare data:
Selecting alerting rules.
2011
Ghosh AK,
De A & Bala
NN
Current problems and future
aspects of Pharmacovigilance in
India.
India
Analytical study of current problems
and
future
aspects
of
pharmacovigilance in India.
2003
Gogtay NJ,
Dalvi SS &
Kshirsagar
NA
Safety monitoring: An Indian
perspective
India
Article is a review of the country's
perspective of ADR monitoring.
2009
Griffin MR,
Braun MM &
Bart KJ
What should an ideal vaccine
post licensure safety system be?
USA
Article is summary of conference
presentations.
EFSA supporting publication 2015: EN-739
No specific methods discussed. General Review. Gives definitions
of terms used in pharmacovigilance and details some of the
current problems with pharmacovigilance in India and how they
plan to develop pharmacovigilance in India in the coming years.
Review of existing ADR and the background/history to it.
Discusses the two post-market surveillance centres and details
how intensive adr monitoring in hospital remains the major source
of information on adrs. Discusses the need to improve levels of
spontaneous reporting and also stricter monitoring of
herbal/alternative medicines.
Summary of conference presentations regarding post-license
evaluation of vaccine safety, including active and passive
surveillance.
90
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2012
Authors
Title
Location
Aim
Monitoring method
Haerian
K,
Varn
D,
Vaidya S, et
al.
Detection
of
Pharmacovigilance-Related
adverse
Events
Using
Electronic Health Records and
automated Methods
New
York
Presbyterian
Hospital, USA
Assess the sensitivity and specificity
of the method by comparing the
classification results to a gold
standard.
ADR signal detection using a Medical Language Extraction and
Encoding System (MedLEE), a clinical NLP system developed at
Columbia University.
Mentions
US
but could apply
globally.
Questioning the value of enhanced
postmarket surveillance systems.
Discusses the three different elements of pharmacovigilance very
basically.
1) data collection: info input system, to detect risks not previously
identified
2) data analysis: looking for patterns of issues, new issues and
increasing
frequency
of
anticipated
events
3) field safety actions: once causality is defined what are the
actions you take to keep the public safe e.g. withdrawals
The paper then goes onto look at when PMM can cause harm e.g.
unnecessary actions cause patients to stop taking a drug where the
benefits of taking it outweigh the risks of not taking it. The paper
states that an inappropriate field action e.g. inserting a black box
onto the product can cause more harm than good by stopping
people taking the product and getting worse as a result.
USA
Signal-detection
strategy
that
combines
the adverse
event
reporting system (AERS) of the
Food and Drug Administration and
Electronic Health Records (EHRs).
Signal detection strategy - Leverage EHRs and explicitly combine
them with spontaneous reports to facilitate uninformed,
hypothesis-free signal detection. Conforming to standard practice
in AERS-based analysis, used the MGPS DPA algorithm (via
Oracle’s Empirica Signal V.7.3) to generate ADR signals in the
AERS portion of this study.
2007
Hall RF
The risk of reduction: Can
Postmarket surveillance pose
more risk that benefit?
2013
Harpaz
R,
Vilar
S,
DuMouchel
W, et al
Combing
signals
from
spontaneous
reports
and
Electronic health records for
detection of adverse drug
reactions.
EFSA supporting publication 2015: EN-739
91
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2006
Authors
Hepburn P,
Howlett
J,
Boeing H, et
al.
Title
The application of post-market
monitoring to novel foods
Location
N/A
Aim
Monitoring method
Review the literature on PMM
methodologies for novel foods
Contact Centres - established by food companies to interact with
consumers via telephone, mail, email and face to face. Trends and
signals can appear through this method when a particular subject
is brought up repeatedly and contact centres can serve as early
warning systems for possible product problems. In addition,
contact centres can ask consumers to participate in surveys which
enables information to be gathered on a specific topic, thus
helping a product to detect problems after launch.
2011
Hilmer SN,
Gnjidic D &
Abernethy
DR
Pharmacoepidemiology in the
Postmarketing Assessment of
the Safety and Efficacy of
Drugs in Older Adults.
USA but could
apply globally
Providing an overview on the role of
pharmacoepidemiological studies in
determining the safety and efficacy
of drugs in older adults.
1998
Hoffman A,
Hippius M &
Sicker T
Adverse
drug
reaction
monitoring
in
Jena
experiences of a regionalized
pharmacovigilance centre
Jena, Germany
Pharmacovigilance
project
to
monitor adverse drug reactions at
the wards
2003
Howlett
J,
Edwards DJ,
Cockburn A,
et al.
The safety assessment of novel
foods
and
concepts
to
determine their safety in use.
Global
Discusses best practice methods to
ensure the safety of novel foods and
ingredients
EFSA supporting publication 2015: EN-739
Discussed many different methods of pharmacovigilance
including: postmarketing trials e.g. randomized clinical trials,
drug-drug interaction studies, case-control, observational,
pharmacoepidemiology.
Talked about using current
pharmacoepidemiological methods and tailoring them for older
adults. Gave the pros/cons for various pharmacovigilance
methods.
Use of three regionalised pharmacovigilance centres and
monitoring admissions to the hospitals for potential adverse drug
reactions. Suspicious cases are referred to a specialised physician.
Cases assessed using a predefined set of screening criteria
Talks mainly about methods of pre-marketing risk assessment, but
does have a small section on PLM of novel foods. Details use of
consumer care lines as the main source of information on adverse
reactions, where consumers are directly in contact with the
manufacturer. It also briefly discusses how the general care line
questionnaire format for receiving consumer complaints can be
modified to fit the purpose of adverse event monitoring. It also
discusses the use of marketplace surveys as a good non-invasive
method for discovering adverse reactions, as panel members are
not aware which foods are monitored and it give a truthful look
into consumer purchasing patterns.
92
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
2005
Hugman B
From the Uppsala Monitoring
Centre A Review of Viewpoint
Part 1 and Part 2
1981
Inman WHW
Postmarketing surveillance of
adverse drug reactions in
general practice
N/A
Review the yellow card system and
discuss the search for new methods
2010
Iragüen
D,
Urcelay S &
San Martin B
Pharmacovigilance
in
veterinary medicine in Chile: a
pilot study
Chile
To carry out a validation type study
to see if Veterinary PMM can be
carried out in Chile.
2011
Isah AO, Pal
SN, Olsson S,
et al.
Specific features of medicines
safety and pharmacovigilance
in Africa
Africa
Review of factors challenging
pharmacovigilance in Africa
2004
Ishaq
GM,
Shah
MY,
Koul PA &
Tanki SA
Adverse
drug
reaction
monitoring with a Kashmiri
perspective- need for an urgent
initiative
Global
To review current PMM and to
suggest its use in Kashmiri
EFSA supporting publication 2015: EN-739
N/A
Review the 2 parts of Viewpoint
Monitoring method
The review of the two parts of the publication. Viewpoint
represents a pioneering effort to provide easily accessible
information on international pharmacovigilance for lay and
specialist readers.
Discusses the advantages and disadvantages of the Yellow card
system. Covers topics such as under-reporting and therefore the
possibility of a delay in discovering adverse reactions, but also,
mentions the positives e.g. remains the cheapest and easiest
method of postmarketing surveillance on the market.
After identifying the most commonly prescribed drugs by
interviewing veterinarians using a survey questionnaire, they then
carried out a pilot PMM study in 19 practices across 14 districts in
Santiago. Vets were given documents describing how to report an
ADR and owners were given details on adrs from their vet. An
ADR form was drawn up based on European standards and vets
were asked to complete the form and send it to the authors of the
study. Once the study was over a visit to the clinic was organised
to collect data on the number of cats and dogs treated during the
trial and also to check the records for potential ADRs which had
gone un-reported.
Review of factors challenging pharmacovigilance in Africa e.g.
presence and use of many counterfeit/herbal medicines and a lack
of resources. Majority of reporting in African pharmacovigilance
schemes is done via spontaneous reporting
UK Yellow card and black triangle schemes. Also state that it is
hard to do PMM in Kashmiri due to off-label drug use and the
availability of drugs that have not had formal approval.
93
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
2010
Johansson S,
Wallander MA, de Abajo
FJ
&
Rodriguez
LAG
Prospective
Drug
Safety
Monitoring Using the UK
Primary-Care General Practice
Research Database
UK
To assess the feasibility of proactive
monitoring of an electronic medical
record system, in combination with
an
independent
endpoint
adjudication committee, to detect
adverse events among users of
selected drugs.
2007
Juarez-Olguin
H,
PerezGuille G &
Flores-Perez J
Pharmacovigilance
and
pharmacoepidemiology
of
drugs in a Mexican paediatric
hospital, A proposed guide.
Mexico
Proposed guide for monitoring in
children’s hospital
1991
Kapp
J-F,
Zentgraf R,
Widmer A &
Schöpf E
A Need to Intensify Drug
Surveillance in Germany
Germany
Catch serious adverse effects via
more intensive monitoring.
2003
Karande
S,
Gogtay NJ &
Kshirsagar
NA
Improving
Monitoring
India
To promote better surveillance for
adverse drug effects in children
EFSA supporting publication 2015: EN-739
Drug
Safety
Monitoring method
Used patient information gained from the General Practice
Research Database who had newly been prescribed
amoxicillin/clavulanic acid during Oct 2005-march 2006. During
Oct-march 3 monthly standing enquiries were set up and
information inputted into the GPRD was sent to the Spanish
Centre for Pharmacoepidemiological research (CEIFE), where the
data was checked by an external board of experts who identified if
patients had acute liver disorder. The number of new patients
required to detect the signal was also calculated. This depended
on the target incidence of a specific AE and the uptake of the
study product in the database.
Proposed guide for monitoring in children’s hospital. Data on the
adverse response is collected in a report form including: patient
data, time elapsed after consumption before reaction and other
drugs administered etc. If the event was considered serious it was
sent to the relevant information collection system and compared
to a bibliography. Briefly discusses epidemiological studies too
including a couple of sentences on analysis.
Spontaneous reporting is still the most commonly used
postmarketing surveillance tool. In the report they suggest that
more intensive surveillance of 40% of hospital beds should be
sufficient to detect adverse reactions. Discuss the need for pilot
studies of this more intensive monitoring and give some details of
how causality would be assessed.
Examination of reports from others, mostly discussing specific
adrs relating to certain drugs. Does have a section at the end of the
report on improvements to the surveillance system e.g. more
proactive management and encouragement for spontaneous
reporting and the use of electronic healthcare databases for
causality assessment and ease of use.
94
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Monitoring
marketing
1983
Kay CR
2010
Kelman CW,
Pearson S-A,
Day RO, et al.
2011
Khairnar
Gade PR
A,
2012
Khattri
S,
Balamuralidh
ara
V,
Pramod
KTM, et al.
of
Location
drugs
after
Evaluating medicines: let’s use
all the evidence
Interventional Improvement in
Hospital
Based
Intensive
Monitoring of Adverse Event
Pharmacovigilance regulations
in India: A step forward
EFSA supporting publication 2015: EN-739
Aim
Monitoring method
UK
To describe PMM system in 1980s
Sets out basis of PMM as of 1980s, including information on
study design of prospective cohort study, case-control study and
retrospective cohort study. Also details advantages e.g. in
prospective studies the ability to design reporting forms to ensure
capture of all useful data and disadvantages e.g. cost and time.
Australia
Limitations of the current system of
monitoring medicines and propose
an updated method that takes
advantage of the capabilities of
information technology.
Propose an expanded and integrated system of medicines
regulation for Australia, based on a surveillance system that
improves safety monitoring by complementing existing systems,
making best use of routinely collected data, and leveraging the
power of information technology.
India
Assessing the effect of training on
drug safety monitoring.
2
parts:
Part A: Data collection: During daily rounds physicians were
asked to collect data on any adverse reactions their patients may
have had. If a potential adverse event was found data on
demographics, suspected drug, allergies and concomitant
medicines was obtained. The causality and severity of reports was
assessed
using
WHO
guidelines.
Part B: The data on patients suffering adverse reactions was
evaluated, using lit reviews and studies of the adr, by a team of
health practitioners supervised by a pharmacovigilance officer.
Part B was run as a knowledge transfer scheme to encourage
better physician reporting.
India
To discuss the areas of Indian
pharmacovigilance that require
reform, and recommendations for an
improved reporting system.
NA - review article discussing the areas of Indian
pharmacovigilance that require reform, and recommendations for
an improved reporting system.
95
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2005
2009
Authors
Kingston R
Kristal AR,
Vizenor NC,
Patterson RE,
et al.
Title
Challenges
in
collecting,
accessing and evaluating post
market surveillance AERS in
patients
receiving
dietary
supplements
Precision and Bias of Food
Frequency-based measures of
Fruit and Vegetable Intakes
EFSA supporting publication 2015: EN-739
Location
USA
USA
Aim
Monitoring method
Review
Various types discussed with an emphasis on spontaneous
reporting, this is because there is not the same surveillance system
in place for dietary supplements as there is for drugs. Spontaneous
reports are likely to be sent in by consumers to manufacturers,
where there is no standardised adverse event reporting form.
Often supplements will have multiple ingredients at unknown
concentrations which makes it hard to attribute causality. The use
of care lines or telephone reporting of adrs is also detailed with
discussion on the advantages and disadvantages of this technique.
Examining the bias and precision of
the two commonly used food
frequency questionnaire approaches
to measuring fruit and veg intake.
Looked at three different methods for evaluating consumption of
fruit
and
vegetables.
1) The 5 A Day method: total veg/fruit intake calculated as
servings of veg/fruit. All of those that took part completed a
mailed questionnaire (recalling intake over the past month), with a
subset selected at random to complete a telephone interview too
(24hr
recall).
2) Summation method: simple sum of all servings of all relevant
foods. Participants asked to complete baseline 100/144-item food
frequency
questionnaire.
3) Four/24hr food records/dietary recall: multiple component
foods are broken down into their relevant parts for nutritional
analysis. Generally completed via phone call. Development of
computer algorithms to determine consumption of fruit & veg
eaten alone and as component parts.
96
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
1999
Kubota K
A Design for PrescriptionEvent Monitoring in Japan (JPEM)
2011
Layton
D,
Hazell L &
Shakir SAW
Modified
Prescription-Event
Monitoring Studies
EFSA supporting publication 2015: EN-739
Location
Aim
Japan (vs UK)
To compare Japan with UK
UK
To
review
how
Modified
Prescription-Event
Monitoring
(PEM) system has benefitted
surveillance
Monitoring method
Sets out PMM system in Japan as of 1999 as compared with UK,
discussing strengths and weaknesses of both. The report also
details a pilot prescription event monitoring project run in Japan.
Pharmacists were recruited and asked to fill in patient forms for
individuals prescribed a specific drug and send them to the centre
of pharmacoepidemiology in Tokyo. Six months after first
prescription, questionnaires were sent to the pharmacist and
prescribing physician. The physician form also included questions
on whether an adverse events were suspected/had occurred.
Discusses traditional prescription event monitoring (PEM) and
newer modified prescription event monitoring (MPEM).
Traditional PEM studies work as non-interventional observational
cohort designs. Six months after initially prescribing a drug, a
questionnaire is sent to the prescribing physician requesting
information on the patient and any significant events which might
have occurred. The MPEM questionnaire is similar to the PEM
questionnaire but includes more detailed questions on specific
outcomes and can be tailored to the study. Current MPEM studies
are listed.
97
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2006
Authors
Lea LJ &
Hepburn PA
Title
Safety evaluation of phytosterol
esters. Part 9: Results of a
European
post-launch
monitoring programme.
2011
Mahmood
KT, Amin F,
Tahir M &
Haq IU
Pharmacovigilance – A Need
for Best Patient Care in
Pakistan.
A review
2007
Manifesto
signed
by
many
The Erice Manifesto For Global
Reform of the Safety of
Medicines in Patient Care
EFSA supporting publication 2015: EN-739
Location
Europe mainly
but
globally
applicable
Pakistan
Global
Aim
Monitoring method
Report their approach to PLM and
to present the findings of the
programme monitoring phytosterolester spreads in Europe.
Done using consumer care lines and marketplace surveys to check
consumer usage is what it should be. Used independent market
research companies in; Netherlands, UK, Belgium, France and
Germany. Consumers are asked to scan bought food items as they
place them into cupboards, which then transfers the data to a
centralised market research database. The company used their
well-established product care lines (across all countries) to gather
data on potential adverse effects. Care line staff were trained in
order that they could identify and collect the relevant information.
Data was then assessed by clinicians and toxicologists for
causality according to a colour coded system. Red: there is an
association, orange: there is an association but cannot be
explained by known properties of product, causal relationship
cannot be excluded, yellow: there is an association but cannot be
explained by known properties of product, causal relationship can
be excluded, green: no association.
The present review paper is
presented
with
the
basic
To highlight the significance and
need of Pharmacovigilance, in
Pakistan, for ensuring best patient
care.
Very little in the way of pharmacovigilance in Pakistan. They do
have a standardised reporting form but do not have a national
pharmacovigilance database and need to invest in better
pharmacovigilance centres. The report does list the three main
types of reporting; spontaneous reporting surveillance (mentions
systems in other countries e.g. 'yellow card scheme' in the UK,
voluntary reporting and mandatory reporting. Gives brief detail on
signal detection methods although nothing specific. The rest of the
report tended to focus on the background to pharmacovigilance
rather than specific methods.
report adrs
Very broad discussion, only really details that it is important to
develop new and innovative methods and to encourage
involvement of patients and healthcare professionals in the
pharmacovigilance process.
98
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
1998
2010
2007
Authors
Mann RD
Markowitz
LE, Hariri S,
Unger ER, et
al.
MartinezFrias ML
Title
Prescription -event monitoringrecent progress and future
horizons
Post-licensure monitoring of
HPV vaccine in the United
States
Postmarketing Analysis of
Medicines Methodology and
value of the Spanish casecontrol
study
surveillance
system in preventing birth
defects
EFSA supporting publication 2015: EN-739
Location
UK
US
Spain
Aim
Monitoring method
To briefly review the methodology
of PEM and the current/planned
activities relating to this technique.
PEM monitoring. Non-interventional observational cohort-study.
Each PEM study begins as soon after drug approval in England as
possible and must contain a min of 10,000 patients. 6 months after
the start of treatment doctors are sent a green card which seeks
information on any events the patient might have experienced.
The green forms are sent to the DRSU (Drug safety research unit
and an interim analyses are conducted after every 2500 patients.
This includes monthly lists of any events reported.
To review current system and
identify improvements
Review of existing systems of data collection of adverse effects.
Immunisation information systems (IIS) and national
immunisation surveys (NIS) provide sources of data regarding
potential adverse reactions associated with vaccination. Discusses
the passive surveillance vaccine adverse event reporting systems
(VAERS), where reports are submitted voluntarily by patients,
healthcare professionals and manufacturers. Also describes the
vaccine safety datalink (VSD) and the clinical immunisation
safety assessment as ways of monitoring vaccine safety.
Describing the research programme
on the potential effects of drugs
taken during pregnancy run by the
ECEMC
The Spanish collaborative study of congenital malformations
(ECEMC) used a continuous hospital-based, case control study
and surveillance system to monitor the effect of drug use during
pregnancy on congenital malformations. ECEMC consisted of the
data-collecting group and the coordinating group. Paediatricians
assessed new-borns for both case (all information on deformities
recorded and described in detail) and control (next same sex baby
born in the hospital) groups, interviewing mothers to collect
demographic information. This information is then sent to the
coordinating group in Madrid, with defects coded for analysis.
Analysis of the potential impact of drugs during pregnancy was
done using secular analysis methods comparing controls to cases.
99
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
2013
Mazzitello C,
Esposito
S,
De Francesco
AE, et al.
Pharmacovigilance in Italy: an
overview
2008
McClure DL,
Glanz JM, Xu
S, et al.
Comparison of epidemiologic
methods for active surveillance
of vaccine safety
Location
Aim
Monitoring method
Italy
To
examine
the
legislative
framework
concerning
pharmacovigilance in Italy
NA - review article examines the legislative framework
concerning pharmacovigilance in Italy.
US
To use simulation to identify most
effective monitoring system
This was a simulation study to compare four study designs
[(matched-cohort, vaccinated only (risk-interval) cohort, case–
control, and self-controlled case-series (SCCS)] in the context of
vaccine safety active surveillance.
PMM methodologies, describes PMM as three-stage process;
signal generation, signal refinement and signal evaluation.
Mainly goes into detail about the second stage or the signal
refinement. Defined as 'the assessment of predefined exposure
outcome pairs to determine whether there is evidence of
association.'
Key
Steps:
1)
Develop
a
product-specific
assessment
plan
2)Review data validity, descriptive stats and analytic computer
programmes
3)Conduct
secondary
analysis
4)Consider
quantitative
bias
analysis
5)
Interpret
and
assess
report
Move onto signal evaluation...
Paper advocating that 'spontaneous' reporting is inadequate and
more robust PMM monitoring is required using systematic
monitoring of cohorts
2014
McClure DL,
Raebel MA,
Yih WK, et
al.
Mini-Sentinel
methods:
framework for assessment of
positive results from signal
refinement
Global but US
To determine if a positive
association can be explained by
something other than a cause and
effect
relationship,
such
as,
information bias, selection bias or
confounding after conducting signal
refinement.
1999
McNeil
JJ,
Grabsch EA
& McDonald
MM
Postmarketing
surveillance:
strengths and limitations: The
flucloxacillin-dicloxacillin story
Australia
but
references to NZ
& UK
To
promote
surveillance
EFSA supporting publication 2015: EN-739
better
active
100
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
2010
McNeil
JJ,
Piccenna L,
Ronaldson K
& IoannidesDemos LL
The value of patient-centred
registries in phase IV drug
surveillance
2014
Mehta
U,
Dheda
M,
Steel G, et al.
Strengthening
pharmacovigilance
Africa
2006
Montastruc
JL, Sommet
A, Lacroix I,
et al.
Pharmacovigilance
for
evaluating
adverse
drug
reactions: value, organisation
and methods
EFSA supporting publication 2015: EN-739
in
South
Aim
Monitoring method
Global
To highlight benefits and limitations
of drug registries
South Africa
To
outline
findings
and
recommendations from a national
pharmacovigilance workshop held
in South Africa in 2012.
France
To
give
an
overview
pharmacovigilance in France
of
Presents review of drug registries to provide better surveillance
than just spontaneous surveillance and gives the advantages and
disadvantages of drug registries. Registries facilitate prospective
cohort studies and allow the researchers to determine the
incidence of multiple outcomes at once. Good at determining drug
safety in specific populations but to avoid bias control groups
must be chosen carefully.
Improvements to the current pharmacovigilance programmes
running in South Africa. Currently they have targeted spontaneous
reporting (specific drugs or patient groups) and some active
surveillance using cohort studies and cohort event monitoring.
Confirmed that they needed: a national and centralised
pharmacovigilance system, which should contribute to policy
decision making. The system should incorporate both active and
passive surveillance and understand the importance of both.
Investment in training and communication with stakeholders to
ensure
the
success
of
the
programme.
Current progress in national system for targeted spontaneous
reports with all spontaneous reports reviewed by sub-district
health teams.
The paper describes a number of different methods including;
spontaneous reporting (in France this is mandatory), active
surveillance including, longitudinal cohort studies and case
control studies and it also mentions the use of electronic
prescribing databases to improve detection and quantification. It
also details the roles of regional pharmacovigilance centres in
collecting, evaluating (causality assessed using probabilistic
approaches e.g. intrinsic and extrinsic causality) and exploiting
data on ADRs. Reports are then sent to a national centre for
collation before being sent to the WHO.
101
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
2011
Monteiro
SAMG,
Takano OA &
Alves
Waldman E
Evaluation of the Brazilian
surveillance system for adverse
events following vaccination
2005
Moore
GE,
Frana
TS,
Guptil LF, et
al.
Postmarketing surveillance for
dog and cat vaccines: new
resources in changing times
2012
Mutebi A
Patient- reported outcomes in
the post-approval environment:
Opportunities and challenges
EFSA supporting publication 2015: EN-739
Location
Aim
Monitoring method
Brazil
To describe and evaluate the
Brazilian
system
of
passive
surveillance of adverse events
following immunization (PSAEFI).
Collection of data from health professionals followed by analysis.
Evaluation was done by analysing reported adverse events to
vaccines, using a methodology developed by the centre for disease
control.
Mainly US
Discussing current PMM methods
for vaccines and discussing potential
future surveillance methods for
vaccines.
Discussing spontaneous reporting methods and epidemiological
follow-up investigations. Discusses using veterinary practice
databases to provide information for postmarketing surveillance.
Also discusses strengths and weaknesses of surveillance methods.
USA
Exploring the opportunities and
challenges of collecting and using
patient-reported outcomes in the
post-approval environment.
Looks at utilising Patient Reported Outcomes (PRO) data. Gives a
few examples of where this might be useful e.g. comparing new
therapies with existing therapies because you have real-time
patient data and using PRO data with existing claims data to
potentially confirm signals, meaning PRO data could become a
very useful tool for practitioners, researchers and policy makers.
102
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
2012
N/A
2000
Neuhouser
ML, Patterson
RE,
Kristal
AR, et al.
Title
Pharmacovigilance
communicating
information
Location
and
safety
Do consumers of savory snacks
have poor-quality diets?
EFSA supporting publication 2015: EN-739
Aim
Monitoring method
Europe-wide
(UK focus)
Providing an explanation of the on
the process of pharmacovigilance
and how new information on
adverse events is communicated to
healthcare professionals.
Post-marketing
trials,
prescription
event
monitoring,
pharmacoepidemiological studies, spontaneous reporting e.g.
Yellow card scheme in the UK, literature reviews. Healthcare
professionals and the public report adverse effects to the MHRA
where it is added to the MHRA drug database. The MHRA
monitor the database and the literature to determine if any new
adverse reactions are being reported and can have causality
attributed
to
a
specific
drug.
Previously in the UK drugs that required more intensive
monitoring had a black triangle placed on the label.
Use of the Eudravigilance database (European database on
adverse effects) as a centralised adverse event reporting centre
across
Europe
to
reduce
complexity.
Mandatory additional monitoring programmes and scope of
reporting using 'yellow card scheme' extended to include
overdose, medication errors, occupational errors etc.
US
Purpose of this report is to assess
associations of overall diet quality
with consumption of high-fat,
reduced fat and fat-free savoury
snacks.
Used Telephone surveys and clinic questionnaires to work out
nutritional intake and snack food questionnaires. Diet quality was
calculated based on scoring against Diet and Health
recommendations for healthy eating. Score 0 was healthy score 3
was unhealthy.
103
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2000
2010
2010
Authors
Title
Location
Aim
Monitoring method
Neuhouser
ML, Patterson
RE,
Kristal
AR, et al.
A brief dietary assessment
instrument for assessing target
foods, nutrients and eating
patterns.
USA
To develop and validate the new
dietary assessment tool, focussed
recall.
Used focussed recall methods in a large population based study to
assess intake of olestra. Participants were asked to take part in
focussed recall questionnaires and a larder inventory. The
focussed recall was split into 6 sections corresponding to different
times of the day and interviewers asked whether participants has
eaten fruit or veg during the day. Trying to get portion sizes for
those items where a mixed level of different fruits or vegetables
may have been consumed. After completion of the focussed and
larder questionnaires a 24hr dietary recall was administered.
Interviews were trained and used a standard script, fruit and veg
consumption was calculated using automated food grouping
systems.
Olsson S, Pal
SN,
Stergachis A
& Couper M
Palaian
S,
Ibrahim
MIM, Mishra
P, et al.
Pharmacovigilance Activities in
55 Low- and Middle-Income
Countries: A QuestionnaireBased Analysis
Global
To assess current and planned
pharmacovigilance activities in low
and middle-income countries
Questionnaire to representatives from 114 countries to gather
information on pharmacovigilance activities within those
countries.
Pharmacovigillance activities in
Nepal
Nepal
NA
NA - Letter to the Editor
EFSA supporting publication 2015: EN-739
104
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2007
2010
Authors
Payne
DC,
Franzke LH,
Stehr-Green
PA, et al.
Prabhakar U
& Edwards B
Title
Development of the Vaccine
Analytic Unit's research agenda
for
investigating
potential
adverse events associated with
anthrax vaccine.
Postmarketing
safety
surveillance Issues with Data
Collection for Postmarketing
Pharmacovigilance
EFSA supporting publication 2015: EN-739
Location
USA
Global
Aim
Monitoring method
To describe the development
process the VAU used to research
the anthrax vaccine safety
A collaboration between the Department of Defence (DoD) and
the Centres for disease control and prevention (CDC) with input
from the FDA, formed the Vaccine Analytic Unit (VAU). They
wanted to look at potential adverse effects experienced after
administration of anthrax vaccines in military personnel. They
used the DMSS a longitudinal surveillance database to collect
historical health data on the military personnel and decided on a
list of potential adverse reactions which could be associated with
the vaccine. This list would then be prioritised using 6 criteria for
further areas of research. The 6 criteria were; Feasibility,
Frequency of Occurrence, Severity of effect, Programmatic
interventions, Likelihood of association and public health
concern. One criteria were established the adverse effects were
reviewed and the top 11 priority considerations were decided
during independent review by VAU staff. Next steps will be to
monitor these 11 more closely for signs of possible association.
Discussing spontaneous reporting,
methods, current issues
and
improvements
Discusses spontaneous reporting in detail, although not much on
actual collection of reports. Talks about reporting forms and
differences between UK (reports mainly go to regulatory
authorities) and the US & Germany (reports mainly go to
manufacturers first.) Mentions yellow card scheme and adverse
incident reporting schemes, although doesn't detail what the forms
entail. When interviewers are going through forms with patients,
structured questioning should be encouraged by providing a
structured questionnaire to make sure all the relevant information
is obtained including; drug-food interactions, medication errors,
drug-use in pregnancy, abuse and misuse, drug withdrawal, dose
escalation or reduction and lack of efficacy.
105
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2011
Authors
Reynolds RF,
Lem
JA,
Gatto NM &
Eng SM
Title
Is the Large Simple Trial
Design Used for Comparative,
Post-Approval
Safety
Research?
Location
US
Aim
Monitoring method
Consider if large simple trial is most
suitable study design
To evaluate whether large simple trials (LSTs) are used for
comparative safety evaluation and if the design is, in fact,
advantageous compared with other designs, a review of the
published literature (1949 through 31 December 2010) was
conducted and the ClinicalTrials.gov registry (2000 through 31
December 2010). Thirteen ongoing or completed safety LSTs
were identified. The design has rarely been used in comparative
drug safety research, which is due to the operational, financial and
scientific hurdles of implementing the design. The studies that
have been completed addressed important clinical questions and,
in some cases, led to re-evaluation of medical practice. It
concludes that the design has demonstrated utility for comparative
safety research of medicines and vaccines if the necessary
scientific and operational conditions for its use are met
2012
Robb
MA,
Racoosin JA,
Sherman RE,
et al.
The US Food and Drug
Administration's
Sentinel
Initiative:
Expanding
the
horizons of medical product
safety.
USA
Give an overview of the minisentinel initiative.
Mainly discusses the introduction of the mini-sentinel scheme by
the FDA and how they will use data currently collected for claims
databases or electronic health databases to actively monitor for
adverse drug reactions in real-time. The process involves three
stages.
1) Signal generation- using statistical methods to identify drugadverse
effect
associations.
2) Signal Refinement- identified potential safety signals are
further
investigated
3) Signal evaluation- implementing full epidemiological analysis
to
fully
evaluate
causality.
Spontaneous reporting is briefly mentioned as the previous
cornerstone of pharmacovigilance.
2011
Ronaldson KJ
Maintaining and enhancing the
value of spontaneous reporting
programmes
Global
To discuss the benefits and potential
future benefits of using spontaneous
reporting systems.
Spontaneous reporting programmes (SRPs). Discusses the general
benefits and potential future uses of spontaneous reporting in
combination with other reporting systems.
EFSA supporting publication 2015: EN-739
106
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2009
2008
2009
2008
Authors
Title
Location
Ronaldson KJ
The
new
age
pharmacovigilance
Sautebin L
Understanding the Adverse
Effects
of
Cosmetics
A
pilot
project
in
cosmetovigilance
Savage RL,
Kunac DL &
Johansson J
Appraising the post-marketing
safety
of
medicines:
A
description of national and
international pharmacovigilance
with a focus on medicines used
in chronic pain
Schuchat A &
Bell BP
of
Monitoring the Impact of
Vaccines Postlicensure: New
Challenges, New Opportunities
EFSA supporting publication 2015: EN-739
Aim
Monitoring method
Looking at improving/ supplementing pharmacovigilance passive
surveillance systems in Australia by using additional information
gained from active surveillance forms e.g. epidemiological
approaches like randomised-control trials, registries of new drugs,
data-linkage and case-control studies. Does discuss spontaneous
reporting as the major mechanism for adverse drug reaction
reporting.
Dermatologists and pharmacists were enrolled to help develop a
standard reporting form for adverse effects for cosmetics. Once
the form was completed they were asked to notify the study
directors using the form of any adverse events that were reported
to them by their patients/consumers. Reports were then validated
and evaluated by the study directors for completeness and
relevance with any extra info required obtained from the
pharmacists/dermatologists.
Australia
Give an opinion on the TGA
strengthening pharmacovigilance,
without implementing strategies to
encourage
the
conduct
of
epidemiological research
Italy
To trial a pilot project testing the
effectiveness of a notification
system for adverse events from
cosmetics.
New Zealand
To
describe
the
role
of
pharmacovigilance in detecting and
evaluating evidence of adverse drug
reactions.
Voluntary reporting systems, cohort event monitoring, specific
monitoring of medication error, data-mining, health care
databases, general practice records.
Address key aspects of postlicensure
surveillance for VPDs with an
emphasis on the US experience
Postlicensure surveillance for vaccine-preventable diseases
(VPDs). Surveillance can be carried out by either passive or active
methods. Passive surveillance constitutes the default for most
public-health systems and may be sufficient for evaluation of
trends in disease and characterization of clinical and
epidemiologic features of illness. Active systems generally
involve soliciting case reports from all participating components
of the system (e.g., laboratories, hospitals, clinics or schools) and
typically involve reporting of zero cases when no episodes have
been detected.
USA
107
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Sharrar RG &
Dieck GS
Monitoring product safety in
the postmarketing environment
Global
Review of pmm
Review- details methods for active and passive surveillance. Also
contains information on disproportionality analysis. Gives pros
and cons of spontaneous reporting. No specific methodologies.
2005
Shuren
(FDA)
International Conference on
Harmonisation
(ICH);
Guidance
on
E2E
Pharmacovigilance Planning;
Availability
EU, Japan and
US
Conference summary.
Not much information but discusses observational studies.
2005
Simojoki M,
Luoto
R,
Uutela A, et
al.
Finland
Purpose of this post-marketing study
is to characterize users of plant
stanol ester margarine with and
without cardiovascular disease.
Fifteen independent health surveys conducted by the National
Public Health Institute in Finland between 1996 and 2000 were
combined into study cohort. Subjects who reported myocardial
infarction, stroke, hypertension, heart failure, angina pectoris or
intermittent claudication were classified as having cardiovascular
disease.
To examine the 35 years of phase IV
trial obligations.
Long report covering: pre-marketing approval, history of phase
IV, and the authority of the FDA over regulations in drugs safety
and
persuading
drugs
companies
to
run
trials.
Talk about spontaneous reporting and how legally manufacturers
are required to pass on any reporting forms, from healthcare
professionals which detail the adverse event experienced by the
patient.
Talk about different phase IV studies that could be undertaken:
additional studies to capture other adverse effects, large scale and
long-term studies to see the impact of the drug on mortality and
morbidity, additional clinical trials as supplementary information,
clinical trials in patient groups not well studied in phase III and
clinical trials where there is an indication that once the drug is
approved it will be used in those areas.
2013
2006
Steenburg C
J
Use of plant stanol ester
margarine among persons with
and without cardiovascular
disease: Early phases of the
adoption of a functional food in
Finland
The
Food
and
Drug
Administration's
Use
of
Postmarketing (Phase IV) Study
Requirements:
Exception to the Rule?
EFSA supporting publication 2015: EN-739
Location
USA
Aim
Monitoring method
108
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
2009
Talati AR &
Gurnani AK
Dietary Supplement Adverse
Event Reports: Review and
Analysis
1998
Talbot JCC &
Nilsson BS
Pharmacovigilance
in
Pharmaceutical Industry
2008
Tatley MV,
Kunac
DL,
McNicholas
A, et al.
Location
the
The
Intensive
Vaccines
Monitoring
Programme
(IVMP): An electronic system
to monitor vaccine safety in
New Zealand
EFSA supporting publication 2015: EN-739
Aim
Monitoring method
USA
Importance of tracking serious
adverse events with respect to
dietary supplements that have
already been marketed.
The MedWatch Adverse Event Reporting (AER) procedure. A
serious adverse event must be reported to FDA by manufacturers
or distributors of dietary supplements using Form 3500A.
Voluntary reporting of an adverse event may be done using
MedWatch Form3500.
EU/USA
Discussion
of
current
pharmacovigilance methods and the
future of pharmacovigilance
Reviews a number of current methods including: spontaneous
reporting, published case reports, cohorts studies, post marketing
clinical trials
New Zealand
An electronic system to monitor
vaccine safety in New Zealand. The
main aims of the IVMP were to
provide an early alert mechanism of
unexpected adverse events occurring
with the meningococcal vaccine and
to measure the incidence of clinical
conditions requiring a health care
consultation in the 6-week period
following vaccination with the
meningococcal vaccine and/or other
routine childhood immunisation
schedule vaccines.
Intensive Vaccines Monitoring Programme (IVMP). Adverse
Events Following Immunisation (AEFIs) were monitored in a
cohort of children receiving vaccinations in primary care. The
IVMP cohort was established from 30 general practitioner led
medical centres, known as ‘sentinel practices’, recruited from
1000 such practices across New Zealand. Details of all
vaccinations in the sentinel practices are routinely
recorded in the practice management system.
109
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author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2010
Authors
Theophile H,
Arimone Y,
MiremontSalamé G, et
al.
Title
Comparison of three methods
(Consensual Expert Judgement,
Algorithmic and Probabilistic
Approaches)
of
Causality
Assessment of Adverse Drug
Reactions
An assessment using reports
made
to
a
French
pharmacovigilance centre.
EFSA supporting publication 2015: EN-739
Location
France
Aim
Monitoring method
The aim of the study was to
compare this novel method, an
operational
algorithm
and
consensual expert judgement taken
as reference.
Compared three different causality assessment methods: expert
opinion, evaluation using the algorithm and evaluation using the
logistic
method.
1) Expert opinion: A panel of 26 experts was set up to evaluate
the adverse event reports. A panel of three experts per pair of
reports was set up (picked on their specialisms) and assessment of
reports was done independently. If the results didn't match a
second group of experts would reanalysis to come to a consensus.
2) The French algorithm uses, evaluation of seven criteria
belonging to 2 groups (chronological (C) and semiological (S)) to
assess causality. Each criteria category has a score once both C &
S scores have been added together they form the intrinsic score.
These relate to whether the likelihood of association is, not related
to
highly
likely.
3) The logistic method uses seven causality criteria, but unlike the
French algorithm it tries to replicate the expert opinion. The
weight given to each criteria is therefore computed by linear
regression. A lack of relevant information gives a middle score
which means causality can't be accepted or rejected.
110
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
2011
Theophile H,
Laporte J-R,
Moore N, et
al.
The Case-Population Study
Design
An analysis of its application in
pharmacovigilance
2011
Torvi JR &
Hunashal R
Pharmacovigilance
2003
van
Grootheest K,
de Graaf L
and de Jongvan den Berg
LTW
Consumer
Adverse
Drug
Reaction Reporting - A New
Step in Pharmacovigilance?
EFSA supporting publication 2015: EN-739
Location
Aim
Monitoring method
Europe
Multiple
aims:
1) To present case-control studies to
non-statisticians
2) To propose an easy method that
can be used in pharmacovigilance
3) To propose a simple formulae for
calculating OR confidence intervals
4) Applying the approach to real-life
examples
5) Discussion of pros and cons (reallife context)
Population based case-cohort study, comparing odds of exposure
to a studied factor (consumption of a particular drug) in a caseseries. Contingency tables are used to calculate the odds of
exposure. During the given study period, all or a highly
representative sample of adverse reactions within the catchment
population should be obtained to remove selection bias. You must
first calculate the proportion of those exposed in the population
and then the amount of exposed and not exposed person time.
Once these have been calculated using the contingency table the
estimation of relative risk can occur. The control group are the not
exposed members of the catchment population.
India
To prepare a plan to improve
pharmacovigilance in India.
Review of national programme of pharmacovigilance in India.
Spontaneous reporting is listed as the main method of collecting
postmarketing safety information. Discusses issues with underreporting and gives some useful definitions on pharmacovigilance.
Various
Overview of experiences with
consumer reporting in various
countries of the world.
Many countries have set up national pharmacovigilance systems,
which, as a rule, function on the basis of spontaneous reporting by
physicians and pharmacists. This paper looks at the advisability of
direct reporting of potential adverse drug reactions by patients.
111
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Title
Location
Aim
Monitoring method
van Hunsel,
Härmack L,
Pal S, et al.
Experiences with Adverse Drug
Reaction Reporting by Patients
Australia,
Canada,
Denmark,
Netherlands,
New Zealand,
Norway,
Malaysia,
Philippines,
Sweden,
UK,
US
To review the methods of patient
reporting
of
Adverse
Drug
Reactions (ADRs) in 11 countries
worldwide and to compare different
aspects of their experiences.
A survey based on telephone interviews, e-mail discussions and
field visits of existing practices in consumer and patient reporting
of ADRs was performed in the second half of 2010.
2006
Waller PC
Making
the
Most
of
Spontaneous Adverse Drug
Reaction
Reporting
Global
Identify any adverse effects
1991
Waller PC
Postmarketing
surveillance:
The viewpoint of a newcomer
to Pharmacoepidemiology
England
Monitor all new chemical entities
that are used in general practice in
the United Kingdom.
2003
Waller PC &
Evans SJW
A model for the future conduct
of pharmacovigilance
UK
To describe a model to improve the
process of pharmacovigilance in the
future.
2012
Authors
EFSA supporting publication 2015: EN-739
Spontaneous Reporting (SR)- details the history and purpose of
SR and how to carry out effective SR. It then goes onto to discuss
current regulations and how the process of SR could be improved
in the future.
Prescription-event monitoring (PEM)- details the major aims of
PEM. Data collection involved providing photocopies of
prescriptions for the patients enrolled in the study and between 412 months after prescription green forms were sent out to their
doctors and they are asked to detail any adverse reactions the
patient may have experienced. Initial follow-up of serious reports
occurred by the GP.
Methods suggested include: observational
research,
randomized
clinical
trials,
pharmacogenetics.
epidemiological
meta-analysis,
112
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
Monitoring method
UK
To identify and investigate methods
of drug safety problems
Spontaneous reporting data, drug usage data, post-marketing
safety studies, record linkage, marketing authorization holders,
periodic safety updates, links with other regulatory authorities,
published literature, registries/mortality statistics, signal
generation procedures, intensive monitoring, screening procedures
and literature monitoring.
Discusses a number of methods of pharmacovigilance:
spontaneous reporting forms, large simple safety trials,
epidemiological studies e.g. case-control and cohort studies, and
discusses the use of registries as a data source for cohort studies.
1996
Waller
PC,
Coulson RA
& Wood SM
Regulatory Pharmacovigilance
in the United Kingdom: current
principles and practice
2009
Weaver
J,
Grenade LL,
Kwon H &
Avigan M
Finding,
evaluating
and
managing drug-related risks:
approaches taken by the US
Food and Drug Administration.
USA
To provide examples of approaches
taken by the FDA in identifying and
managing risks associated with the
use of marketed pharmaceuticals.
2011
Welch RW,
Antoine J-M,
Berta J-L, et
al.
Guidelines for the Design,
Conduct and Reporting of
Human Intervention Studies to
Evaluate the Health Benefits of
Foods
N/A
To provide guidelines for the
design, conduct and reporting of
human intervention studies.
The paper provides suggestions for guidelines of what should be
included in health studies and provide guidelines for the design,
conduct and reporting of human intervention studies.
Westerholm
B
Westerholm
B
Westerholm
B
Westerholm
B
Westerholm
B
The rationale for
marketing surveillance
The rationale for
marketing surveillance
The rationale for
marketing surveillance
The rationale for
marketing surveillance
The rationale for
marketing surveillance
Some countries.
Identify any adverse effects
Spontaneous reporting
Some countries.
Identify any adverse effects
Intensive monitoring
Some countries.
Identify any adverse effects
Health registers can be used to trace cases for case-control studies.
Some countries.
Identify any adverse effects
Prospective studies is an informative way to obtain results.
Some countries
Identify any adverse effects
Data on drug utilization.
1987
1987
1987
1987
1987
EFSA supporting publication 2015: EN-739
a
post-
a
post-
a
post-
a
post-
a
post-
113
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
Authors
Title
Location
Aim
Monitoring method
Global
To give details on how to apply
pharmacovigilance practices to
herbal medicines.
World health organisation document which gives definitions on
herbal medicines and also discusses pharmacovigilance generally.
The report then moves on to talk about pharmacovigilance of
herbal medicines, including the different reports that can be
obtained on adverse reactions to herbal medicines and some of the
challenges involved in collecting reports on herbal medicines. It
also discusses the WHO coding systems for case reports and
provides details on how to use the different codes to assess
adverse event case reports for herbal medicines.
2004
WHO
WHO guidelines on safety
monitoring of herbal medicines
in pharmacovigilance systems
2012
Wiktorowicz
M, Lexchin J
& Moscou K
Pharmacovigilance in Europe
and North America: Divergent
approaches
Global
Identify safety issues through
epidemiologic
analyses
of
healthcare databases
2013
Willems JI,
Blommaert
MAE
&
Trautwein EA
Results from a post-launch
monitoring survey on consumer
purchases
of
foods
with
added
phytosterols in five European
countries
Netherlands,
Belgium, United
Kingdom,
France
and
Germany
Reports findings from the 2011
post-launch monitoring survey on
consumer purchase behaviour of
foods with added phytosterols.
1991
Wood SM
Postmarketing
surveillance:
viewpoint from a regulatory
authority
UK
Review of Postmarket surveillance
EFSA supporting publication 2015: EN-739
Discusses the differences between pharmacovigilance systems in
the US/Europe, including regulatory policy and regulatory
processes. Suggest that in the EU (mainly UK and France) they
remain too driven by industry designed surveillance strategies.
Post Launch Monitoring (PLM)- data was collected by two
independent market research companies. Once recruited panellists
were asked to scan purchases (via a household barcode reader
provided during the study) when they returned from the
supermarket to provide information on purchases. Products
included in the study had to contain phytosterol esters and
included; yoghurt drinks, salad dressing and spreads. Data from
the households was scaled up to country level. Using the
estimated phytosterol concentration of the product, the household
purchase data and the estimated daily intake of phytosterols per
household, intake was determined per country.
Methods are reviewed very briefly and their importance
discussed. Methods mentioned include; spontaneous reporting,
published literature, registries, cohort studies, prescription event
monitoring and record linkage. The most information is provided
about spontaneous reporting giving limitations of different
systems.
114
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2012
2009
Authors
Zakaryan A
& Martin IG
Zancan
A,
Locatelli C,
Ramella F, et
al.
Title
Location
Regulation of Herbal Dietary
Supplements: Is There a Better
Way?
A
new
model
pharmacovigilance? A
study
EFSA supporting publication 2015: EN-739
of
pilot
Various
Italy
Aim
Outlines the importance of herbal
dietary supplements regulation by
providing a brief overview of
history of supplement regulation in
the US with emphasis placed on
passage of the 1994 Dietary
Supplement Health and Education
Act (DSHEA)
Aim of the present study was to
build a procedure to actuate the new
model of pharmacovigilance and to
compare the ADR incidence
recorded using the two different
models
Monitoring method
Review of the Dietary Supplement Health and Education Act
(DSHEA)
and
post-DSHEA
enforcement
actions.
Identification of risk by the FDA relies primarily on post-market
surveillance practices such as monitoring serious adverse event
reports.
Manufacturers of dietary supplements, unlike manufacturers of
pharmaceuticals, are not required to provide evidence of safety
and efficacy based on rigorous pre-market clinical testing.
Compared traditional method of spontaneously reported ADRs,
with active surveillance methods. Patients were followed after
discharge from hospital for 6 months. After 30 days out of
hospital a telephone questionnaire was completed and files logged
in patient data tracking. Passive surveillance ongoing throughout
study.
115
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
Date
Published
2009
Authors
Zuber PLF,
Autran
B,
Asturias EJ,
et al.
Title
Global safety of vaccines:
strengthening
systems
for
monitoring, management and
the role of GACVS
EFSA supporting publication 2015: EN-739
Location
Various
Aim
Monitoring method
Review the models and systems that
have been developed to monitor and
respond to concerns regarding
vaccine safety
Brief review on a number of methods of passive and active
surveillance. Passive surveillance systems include: 1) The UK
Yellow Card system which is a mechanism for reporting a broad
spectrum of suspected safety issues related to use of medicines,
including vaccines. 2) In the USA, the Vaccine Adverse Event
Reporting System (VAERS). 3) In Australia, the Adverse Drug
Reactions Advisory Committee database is a well-established
AEFI surveillance system. 4) In Brazil, the national immunization
program coordinates an adverse events reporting system. 5) The
WHO collaborating centre for international drug monitoring.
The Global Advisory Committee on Vaccine safety (GACVS)
was set up 10 years ago and charged to provide the WHO with
independent advice on vaccine safety issues.
116
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the
author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European
Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Strategy support for the Post-Market Monitoring of GM Food and Feed
GLOSSARY OF ABBREVIATIONS
ADR- adverse drug reaction
EFSA – European Food Safety Authority
EU – European Union
EU MS – European Union Member States
GACVS- Global Advisory Committee on Vaccine Safety
GM – genetically modified
GMO – genetically modified organism
IMP- Immunisation Monitoring programme
LMO – living modified organism
MS - Microsoft
NIP – National Immunisation programme
NSAID – Non-steroidal anti-inflammatory drugs
PIDM - Programme for International Drug Monitoring
PMM – Post-Market Monitoring
VAERS- Vaccine Adverse Event Reporting Scheme
VICH - International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary
Medicinal Products
WHO – World Health Organisation
EFSA supporting publication 2015: EN-739
117
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the
context of a contract between the European Food Safety Authority and the author(s), awarded following a tender procedure. The present document is published
complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food
Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to
the rights of the authors.