Vaccine safety Surveillance
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About This Presentation
Vaccine safety Surveillance
Slide Content
Chapter ... 8
VACCINE SAFETY SURVEILLANCE
+ LEARNING OBJECTIVES +
Introduction
The goal of immunization is to protect the individual and the public from vaccine
preventable diseases (PD). Although modern voccines are sale, no vaccine is entirely
without ik; adverse rections wil ecasionally occur following vaccination. Some people
experience adverse events after immunization ranging from mid side-effects to rare lie
threatening iInstes. Inthe majoriy of serious cases these events are merely e
others, they are caused bythe vaccine or by an error in the administration ora
‘vaccine, Sometimes there is no causal relationship between the vaccine and the adverse
effects. Maintaining public tust in vaccine safety, therefore, i key to the success of a
Inespectve of the cause, when adverse events folowing immunization (AEF) occur
people become confused to the extent that they refuse further immunization of their
Children, making the chidren susceptible to VPDs which are more disabling and lite
thveatening, Surveillance of AEFI, ie. systematic collection of data on events fllowing
immurization, provides valuable information to help plan and take necessary ations in order
to sustain the publ confidence and ensure smooth functioning of the programme. These
are the guidelines for managers of immunization programmes (and others responsible for
vaccine safety and quals) onthe following:
+ Strategies and systems for ensuring quality and safety of vaccines,
New dassfication of AEfls and the objectives of immunization safety/AEFis
surveillance,
Understanding vaccine reactions for better decision-making
AEFI survellance system: reporting. investigating, causally assessment and
VACCINE SAFETY SURVEILLANCE
+ LEARNING OBJECTIVES +
Introduction
The goal of immunization is to protect the individual and the public from vaccine
preventable diseases (PD). Although modern voccines are sale, no vaccine is entirely
without ik; adverse rections wil ecasionally occur following vaccination. Some people
experience adverse events after immunization ranging from mid side-effects to rare lie
threatening iInstes. Inthe majoriy of serious cases these events are merely e
others, they are caused bythe vaccine or by an error in the administration ora
‘vaccine, Sometimes there is no causal relationship between the vaccine and the adverse
effects. Maintaining public tust in vaccine safety, therefore, i key to the success of a
Inespectve of the cause, when adverse events folowing immunization (AEF) occur
people become confused to the extent that they refuse further immunization of their
Children, making the chidren susceptible to VPDs which are more disabling and lite
thveatening, Surveillance of AEFI, ie. systematic collection of data on events fllowing
immurization, provides valuable information to help plan and take necessary ations in order
to sustain the publ confidence and ensure smooth functioning of the programme. These
are the guidelines for managers of immunization programmes (and others responsible for
vaccine safety and quals) onthe following:
+ Strategies and systems for ensuring quality and safety of vaccines,
New dassfication of AEfls and the objectives of immunization safety/AEFis
surveillance,
Understanding vaccine reactions for better decision-making
AEFI survellance system: reporting. investigating, causally assessment and
Best use of sunellance data, and
Communication strategy on immunization safety forthe public andthe media.
VPOS become less visible though effective immunization programmes, more
attention vil be given to AEFI A good example is poliomyelitis, When there are many cases
of pollomyelkis in the community, the very low risk (about 1 in 3 milion) of vaccine
associated paralytic poliomyelitis (VAPP is unlikely to cause a major concern, Westen Pacific
Region has been free from polio since 2000. In countries where there is no longer any wld
poliovrus existent, VAPP have become more visible. AS a resul, VAPP has become a
sufficient concem and these countries have switched from oral (OPV) to injectable
paliomyeiti vaccine (PV)
As technology continues to improve with time, so do the qua, efficacy (level of
protection) and effectiveness (disease reduction) of the vaccines. New vaccines are being
added to the programme and the schedule becomes more tight and congested. Instead of
triple vaccine (OTP, most countries are now using either tetravalen (OTP-Hib or DTPHepE)
or pentavalent (DTP-Hep8-Hib) vaccines. Also with emerging diseases, such as MINA
influenza, demand for new vaccine has increased. An increase in vaccine use (09, mass
immunization campaigns) vil lead to more vaccine reactions as well as more coincidental
events. Immunization errors (previously known as “programme errors) may alo increase.
Reporting and investigating AEFI can be used to identify and correct immunization eros
related reactions and may help to lstinguish a coincidental event from a true AEF
Surveilance of AEM is an effecive means of monitoring immunization safety and i
ontibutes to the credibility of the immunization programme. It allows for proper
management of AEFls and avoids inappropriate responses to reports of AEFIs hat can create
Public alerness regarding vaccine safety has increased through awareness and increased
access to information through the interne. Also, the vigilance of health-care providers on
vaccine safety has increased due to strengthening of AEFI surveillance. As à resul, more
concerns on quality and safety of vaccine are highlighted and/or demanded by service
providers and the public. With this increasing complet in the immunization contes, to
determine whether a veccne is causally linked to an AEF or the AEM is a mere coincidence
that requires detailed investigation and causality assessment
In order to maintain and improve public confidence in national immunization
programmes, al health-care providers should be comprehensively amare of all aspects of
AEFIs and remain prepared to respond to publi concerns at any time. Timely response to
public concems about the safety of vaccines as well as prompt communication wil protect,
the publi and preserve he integris f te immunization programme, After recognizing the
need for such a concerted action on vaccine safety, WHO conducted a landscape analysis
Communication strategy on immunization safety forthe public andthe media.
VPOS become less visible though effective immunization programmes, more
attention vil be given to AEFI A good example is poliomyelitis, When there are many cases
of pollomyelkis in the community, the very low risk (about 1 in 3 milion) of vaccine
associated paralytic poliomyelitis (VAPP is unlikely to cause a major concern, Westen Pacific
Region has been free from polio since 2000. In countries where there is no longer any wld
poliovrus existent, VAPP have become more visible. AS a resul, VAPP has become a
sufficient concem and these countries have switched from oral (OPV) to injectable
paliomyeiti vaccine (PV)
As technology continues to improve with time, so do the qua, efficacy (level of
protection) and effectiveness (disease reduction) of the vaccines. New vaccines are being
added to the programme and the schedule becomes more tight and congested. Instead of
triple vaccine (OTP, most countries are now using either tetravalen (OTP-Hib or DTPHepE)
or pentavalent (DTP-Hep8-Hib) vaccines. Also with emerging diseases, such as MINA
influenza, demand for new vaccine has increased. An increase in vaccine use (09, mass
immunization campaigns) vil lead to more vaccine reactions as well as more coincidental
events. Immunization errors (previously known as “programme errors) may alo increase.
Reporting and investigating AEFI can be used to identify and correct immunization eros
related reactions and may help to lstinguish a coincidental event from a true AEF
Surveilance of AEM is an effecive means of monitoring immunization safety and i
ontibutes to the credibility of the immunization programme. It allows for proper
management of AEFls and avoids inappropriate responses to reports of AEFIs hat can create
Public alerness regarding vaccine safety has increased through awareness and increased
access to information through the interne. Also, the vigilance of health-care providers on
vaccine safety has increased due to strengthening of AEFI surveillance. As à resul, more
concerns on quality and safety of vaccine are highlighted and/or demanded by service
providers and the public. With this increasing complet in the immunization contes, to
determine whether a veccne is causally linked to an AEF or the AEM is a mere coincidence
that requires detailed investigation and causality assessment
In order to maintain and improve public confidence in national immunization
programmes, al health-care providers should be comprehensively amare of all aspects of
AEFIs and remain prepared to respond to publi concerns at any time. Timely response to
public concems about the safety of vaccines as well as prompt communication wil protect,
the publi and preserve he integris f te immunization programme, After recognizing the
need for such a concerted action on vaccine safety, WHO conducted a landscape analysis
The analysis provides an overview of existing structures, activities and needs of vaccine safety
stakeholders and initiatives at national and international levels. Based on the landscape
analysis, the Global Vaccine Safety Blueprin, à framework aiming to optimize the safety of
‘vaccines through effective use of state ofthe art pharmacorigilance principes and methods
as developed in a collaborative process. The Blueprint suggests three strategic goals that
identif tree areas of work at different levis, The fist goa sto ensure minimal capacity in
all counties, the second to provide enhanced capacity for specific circumstances, and the
third to establish a global support network.
"SA VACCINE PHARMACOVIGILANCE
Pharmacoviglance includes the development of standardized defnitons relevant to the
monitoring of the safety of vaccines during elnical tals and for the purposes of vaccine
pharmacevigiance inthe posticensue period
8.1. Definition
Vaccine pharmacovigiance is defined as the science and activities relating to the
detection, assessment, understanding and communication of adverse events following
immunization and other vaccine or immunization: related issues, and to the prevention of
untoward effects ofthe vaccine or immunization
The goal of vaccine pharmacoviglance is the eary detection of and appropriate and
timely response to AEFI in order to minimize negative effects to the health of individual
and lesen the potential negative impact on immunization of the population. Continuous
rsk-benefit assessment and risk management ae integral to the vaccine pharmacovgilance
There ls à very high level of safety required for vaccines. Elements to consider when
conducting vaccine pharmacovigilance include the Following:
Vaccines ar usual administered to healthy people, including infants.
‘Vaccines may be administered to the vast majority of the population or of a bith
cohort or to groups at high isk for disease complications
Subpopulations may be more susceptible to experience certain AEFIS
The age atthe time of immunization may coincide with the emergence of certain
age-related diseases (ag. neurodevelopment disorders)
[Immunization with certain vaccines is mandated in some counties.
The benefits of immunization may not be immediately visible, particularly ithe target
Due to the low acceptance of risks, intensive investigation of serious AEFS even if
rare necessary.
stakeholders and initiatives at national and international levels. Based on the landscape
analysis, the Global Vaccine Safety Blueprin, à framework aiming to optimize the safety of
‘vaccines through effective use of state ofthe art pharmacorigilance principes and methods
as developed in a collaborative process. The Blueprint suggests three strategic goals that
identif tree areas of work at different levis, The fist goa sto ensure minimal capacity in
all counties, the second to provide enhanced capacity for specific circumstances, and the
third to establish a global support network.
"SA VACCINE PHARMACOVIGILANCE
Pharmacoviglance includes the development of standardized defnitons relevant to the
monitoring of the safety of vaccines during elnical tals and for the purposes of vaccine
pharmacevigiance inthe posticensue period
8.1. Definition
Vaccine pharmacovigiance is defined as the science and activities relating to the
detection, assessment, understanding and communication of adverse events following
immunization and other vaccine or immunization: related issues, and to the prevention of
untoward effects ofthe vaccine or immunization
The goal of vaccine pharmacoviglance is the eary detection of and appropriate and
timely response to AEFI in order to minimize negative effects to the health of individual
and lesen the potential negative impact on immunization of the population. Continuous
rsk-benefit assessment and risk management ae integral to the vaccine pharmacovgilance
There ls à very high level of safety required for vaccines. Elements to consider when
conducting vaccine pharmacovigilance include the Following:
Vaccines ar usual administered to healthy people, including infants.
‘Vaccines may be administered to the vast majority of the population or of a bith
cohort or to groups at high isk for disease complications
Subpopulations may be more susceptible to experience certain AEFIS
The age atthe time of immunization may coincide with the emergence of certain
age-related diseases (ag. neurodevelopment disorders)
[Immunization with certain vaccines is mandated in some counties.
The benefits of immunization may not be immediately visible, particularly ithe target
Due to the low acceptance of risks, intensive investigation of serious AEFS even if
rare necessary.
Pramacodgiance vaccine Safety Suan
+ Nonserious AEFI also should be carefully monitored because they may signal a
potential larger problem with the vaccine or immunization, or have an impact on
he acceptability of immunization in genera. Appropriate methods are needed to
detect and assess any potential causal association of serious, ar, and/or delayed
adverse events, er of adverse events in subgroups, with immunization
Consideration of dechallenge and rechallenge difers for vaccines compared with
other medicinal products. Vaccines are frequently administered only once or with
long intervals, and serious AEFs often prevent further vaccine administration; hence
rechallenge information is only rarely avaiable, Dechalenge may not be applicable to
‘vaccines, given their long-term immunological effects.
Vaccines are often administered concomitantly with other vacines, making causal
attibution o a specific vaccine dificult
The administration of live vaccines can lead to disease caused by the attenuated
‘organisms in vaccines or their contact, his should be diferentated from coincicing
natural infec
Vaccines are complex biological product, which may include multiple antigens ve
organisms, adjuvant, and preservatives. Each component may have unique safety
implcatons Variabilty and (even small changes in the manufacturing process may
have impact on quality, protective efect, and safety. Batch information is of crucial
importance
technologies, with new adjutants and altemalve routes of administration,
necessitating adapted safety monitoring systems.
Depending on the mode and extent of use ofa vaccine, it may elicit a degree of herd
immunity to à specific disease. When assesing the risk-benefit of à vaccine, herd
immunity effects as wel as individual protection need tobe taken into account.
fective communication regarding the safely of vaccines and immunization is
challenging. Despite strong evidence that a serious adverse event isnot related to
Immunization, perceptions of harm may persist and may potentially have a negative
impact on immunization ofthe population
8.1.2 Steps for Establishing a System
then developing an immunization safety suveilance system, its advised to consi
the following steps:
+ Clari and agree on roles and responsibitis ofboth the immunization programme
and NRA in immunization safety survellnce, It is important to designate a
Surveilance implementation body,
+ Develop a protocol with cleary-defined objectives of the immunization safety
survllance: identifi strategies, actvits to be done, and availabilty of resources
+ Nonserious AEFI also should be carefully monitored because they may signal a
potential larger problem with the vaccine or immunization, or have an impact on
he acceptability of immunization in genera. Appropriate methods are needed to
detect and assess any potential causal association of serious, ar, and/or delayed
adverse events, er of adverse events in subgroups, with immunization
Consideration of dechallenge and rechallenge difers for vaccines compared with
other medicinal products. Vaccines are frequently administered only once or with
long intervals, and serious AEFs often prevent further vaccine administration; hence
rechallenge information is only rarely avaiable, Dechalenge may not be applicable to
‘vaccines, given their long-term immunological effects.
Vaccines are often administered concomitantly with other vacines, making causal
attibution o a specific vaccine dificult
The administration of live vaccines can lead to disease caused by the attenuated
‘organisms in vaccines or their contact, his should be diferentated from coincicing
natural infec
Vaccines are complex biological product, which may include multiple antigens ve
organisms, adjuvant, and preservatives. Each component may have unique safety
implcatons Variabilty and (even small changes in the manufacturing process may
have impact on quality, protective efect, and safety. Batch information is of crucial
importance
technologies, with new adjutants and altemalve routes of administration,
necessitating adapted safety monitoring systems.
Depending on the mode and extent of use ofa vaccine, it may elicit a degree of herd
immunity to à specific disease. When assesing the risk-benefit of à vaccine, herd
immunity effects as wel as individual protection need tobe taken into account.
fective communication regarding the safely of vaccines and immunization is
challenging. Despite strong evidence that a serious adverse event isnot related to
Immunization, perceptions of harm may persist and may potentially have a negative
impact on immunization ofthe population
8.1.2 Steps for Establishing a System
then developing an immunization safety suveilance system, its advised to consi
the following steps:
+ Clari and agree on roles and responsibitis ofboth the immunization programme
and NRA in immunization safety survellnce, It is important to designate a
Surveilance implementation body,
+ Develop a protocol with cleary-defined objectives of the immunization safety
survllance: identifi strategies, actvits to be done, and availabilty of resources
Pramacodgiance vaccine Safety Suan
« Clearly identify the role and responsibilities of each staff category involved in
immunization safety surveilance
Seek legal provision for vaccine pharmacovignce and endorsed government
Establish a national (centra) expert committee for causliy assessment and for
highest technical support and decision-making. Large countries may have state
province/egional experts committees for similar purposes and smaller counties,
here such experts are not avaiable, an identity a supporting unt frm the region,
Develop and disseminate alist of events to be reported (and investigated) and their
case defniions, standard investigation procedures, and AEFI reporting and
investigation forms,
Train staff on reporting. data analysis, and investigation and report preparation
depending on at what level each function has to be done. Develop traning materials
and training modules suitable forthe county.
Make sure the staff are aware that monitoring and evolution of activites are
important and necessary
Develop a communication plan to address issues and information based on
immunization and safety surveilance
Consider establishment of a legal framework and a compensation scheme where
applicable. Inti als if the legal frameworks a government policy
8.1.3 Role and Responsibility of NRA In Immunization Safety Surveillance
NRAS are responsible for ensuring that every pharmaceutical product - including à
vaccine - used within the country is of () good quality, (i) effective, and (i sae forthe
purpose or purposes for which itis proposed. The frst two criteria must be met before any
approval ofthe vaccine’ medical use, the issue of safety is more challenging, Strengthening
INRA activities leads to ensure vaccine safety. The Global Vaccine Safety Intitive (GUS),
through the WHO-led Vaccine Safety Blueprint Project, has already developed strategies to
strengthen NRAS, particularly in low and low-micele income-counties. The immunization
programme and NRA collectively play specif roles and responsibilities in immunization
safety suvelance. WHO considers tht in all vaccine-producing countries and in all other
countries where an NRA exists, the NRA must be involved in immurization safety
survllance, The WHO has defined sik functions tobe carried out by NRA. follows:
« Marketing authorization and licensing activities: with clear writen instruction for
licensing products and manufacturers
+ Pharmacoviglance, including survellance of AEF NRA lot release: system for lot
release
aboratory acess use of laboratory when needed
« Clearly identify the role and responsibilities of each staff category involved in
immunization safety surveilance
Seek legal provision for vaccine pharmacovignce and endorsed government
Establish a national (centra) expert committee for causliy assessment and for
highest technical support and decision-making. Large countries may have state
province/egional experts committees for similar purposes and smaller counties,
here such experts are not avaiable, an identity a supporting unt frm the region,
Develop and disseminate alist of events to be reported (and investigated) and their
case defniions, standard investigation procedures, and AEFI reporting and
investigation forms,
Train staff on reporting. data analysis, and investigation and report preparation
depending on at what level each function has to be done. Develop traning materials
and training modules suitable forthe county.
Make sure the staff are aware that monitoring and evolution of activites are
important and necessary
Develop a communication plan to address issues and information based on
immunization and safety surveilance
Consider establishment of a legal framework and a compensation scheme where
applicable. Inti als if the legal frameworks a government policy
8.1.3 Role and Responsibility of NRA In Immunization Safety Surveillance
NRAS are responsible for ensuring that every pharmaceutical product - including à
vaccine - used within the country is of () good quality, (i) effective, and (i sae forthe
purpose or purposes for which itis proposed. The frst two criteria must be met before any
approval ofthe vaccine’ medical use, the issue of safety is more challenging, Strengthening
INRA activities leads to ensure vaccine safety. The Global Vaccine Safety Intitive (GUS),
through the WHO-led Vaccine Safety Blueprint Project, has already developed strategies to
strengthen NRAS, particularly in low and low-micele income-counties. The immunization
programme and NRA collectively play specif roles and responsibilities in immunization
safety suvelance. WHO considers tht in all vaccine-producing countries and in all other
countries where an NRA exists, the NRA must be involved in immurization safety
survllance, The WHO has defined sik functions tobe carried out by NRA. follows:
« Marketing authorization and licensing activities: with clear writen instruction for
licensing products and manufacturers
+ Pharmacoviglance, including survellance of AEF NRA lot release: system for lot
release
aboratory acess use of laboratory when needed
Regulatory inspection: regular inspection of manufacturers for GMP compliance
Regulatory oversight of clinical tras evaluation of cica performances through
Role and Responsibility of Immunization Programme (Manager) in
Immunization Safety Surveillance
An effective immunization safety surveillance system is required involving health workers
at all levels in the immunizaion programme. This section identifies the key role players at
Atferent levels of the survelance system and also outlines ther roles and responsibiitis in
carrying out surveilance activites. However, their roles and responses will depend on
the operational levels in different county settings.
8.4.4.4 Immunization Service Provider Level
In these guidelines, immunization service provider level refere 10 the lowest
administrative level in the county, which provides the immunization sence to the publi
he tasks of immundation service providers are the folowing
Detection of AEFIs
Inquires should be made at the clinic hospital or in community, indhidully regarding
any AEFIs experienced ater previous vaccination from the recipient or parent/guardian of
the recipient. U treatment is necessary for a particular condition, the recipient having
Ale should be referred t the nearest hospitalet ac.
Recording of AEFL
‘Supply of neceseary forms and regitrs for immunization safety surveilancs should be
maintained. All necessary data should be entered into the forms/records/registers.
Reporting of AEFI
‘The higherup adeinistative/operationa level should be immediately informed of all
serous events, unusual AFS, and deaths. ther cases should be reported in a routine
‘ay, instructed bythe next admnistrative/operaional evel
Investigation of AEFL
IF the capacty to cary out an investigation exit, it may be done at this level All
investigations required among reported AEF as listed inthe national guidelines, need
to be done at the earliest possible time, Communication with the staff and the
«community is essential, Public should be kept informed regarding what is being done
during the investigation and, once it is over, the conclusions and results should be shared
with other members of the team and the community. Findings of investigation should be
disseminative with both service provider and next administrative / operational level
authority. If the guidlines instruct, investigation reports need to be submited to the
next adminstrativefopeational level o national level authority
Regulatory oversight of clinical tras evaluation of cica performances through
Role and Responsibility of Immunization Programme (Manager) in
Immunization Safety Surveillance
An effective immunization safety surveillance system is required involving health workers
at all levels in the immunizaion programme. This section identifies the key role players at
Atferent levels of the survelance system and also outlines ther roles and responsibiitis in
carrying out surveilance activites. However, their roles and responses will depend on
the operational levels in different county settings.
8.4.4.4 Immunization Service Provider Level
In these guidelines, immunization service provider level refere 10 the lowest
administrative level in the county, which provides the immunization sence to the publi
he tasks of immundation service providers are the folowing
Detection of AEFIs
Inquires should be made at the clinic hospital or in community, indhidully regarding
any AEFIs experienced ater previous vaccination from the recipient or parent/guardian of
the recipient. U treatment is necessary for a particular condition, the recipient having
Ale should be referred t the nearest hospitalet ac.
Recording of AEFL
‘Supply of neceseary forms and regitrs for immunization safety surveilancs should be
maintained. All necessary data should be entered into the forms/records/registers.
Reporting of AEFI
‘The higherup adeinistative/operationa level should be immediately informed of all
serous events, unusual AFS, and deaths. ther cases should be reported in a routine
‘ay, instructed bythe next admnistrative/operaional evel
Investigation of AEFL
IF the capacty to cary out an investigation exit, it may be done at this level All
investigations required among reported AEF as listed inthe national guidelines, need
to be done at the earliest possible time, Communication with the staff and the
«community is essential, Public should be kept informed regarding what is being done
during the investigation and, once it is over, the conclusions and results should be shared
with other members of the team and the community. Findings of investigation should be
disseminative with both service provider and next administrative / operational level
authority. If the guidlines instruct, investigation reports need to be submited to the
next adminstrativefopeational level o national level authority
Pramacavglance acces Suva
+ Corrective Action
Conective action, particulary related to immunization errors, should be taken
mmesitely. should be based on the findings of investigation,
Analysis of AEFL
tis recommended to keep both ine listing and detal information separately. Depending
on the capacity of staff attached at this level analysis may be limited to the basic
Public Education/Communication
Whenever an opportunity is available, the pubic should be communicated with and be
made aware of whats being done, People shouldbe educated regarding AEFI.
8.1.4.2 Intermediate Level
The use ofthe term “intermediate eve” in these guidelines wil be varied, depending on
the countries’ health-care service administration structures. À may refer to one or more
administrative levels in a country. Hence, “intermediate level” represent al levels between
‘the national and lowest administrative levels in a specific county
+ Reporting of AEFI
The national level should be informed immediately of serious events, unusual AEFS and
eats. Other cases should be reported routinely, as stipulated by national leve
author Al records on AEF surllance should be maintained
Investigation of AEFL
Al investigations required among reported AEFls, a sted in national guidelines need to
be done at the earliest possible time. In most settings, capacity to conduct à
comprehensive investigation at immunization service provider level does not exist
Therefore, collection of preliminary information of detailed investigations is often the
responsiblity at thi level Developing capacity to caery out such investigation is
necessary and logical. Findings of investigation should be dsseminative with both service
Provider and national level authorities,
Corrective Action
Comective action should be taken immediately, I should be based on the findings of
investigation. In practice, intermediate level has more responsibilties to implement
correctivo actions both logistically and administrativo. For example if any immunization
correlated reactions are observed, strengthening supportive supervision, training and
even logistic replacements could be implemented by the authorities at this level
+ Corrective Action
Conective action, particulary related to immunization errors, should be taken
mmesitely. should be based on the findings of investigation,
Analysis of AEFL
tis recommended to keep both ine listing and detal information separately. Depending
on the capacity of staff attached at this level analysis may be limited to the basic
Public Education/Communication
Whenever an opportunity is available, the pubic should be communicated with and be
made aware of whats being done, People shouldbe educated regarding AEFI.
8.1.4.2 Intermediate Level
The use ofthe term “intermediate eve” in these guidelines wil be varied, depending on
the countries’ health-care service administration structures. À may refer to one or more
administrative levels in a country. Hence, “intermediate level” represent al levels between
‘the national and lowest administrative levels in a specific county
+ Reporting of AEFI
The national level should be informed immediately of serious events, unusual AEFS and
eats. Other cases should be reported routinely, as stipulated by national leve
author Al records on AEF surllance should be maintained
Investigation of AEFL
Al investigations required among reported AEFls, a sted in national guidelines need to
be done at the earliest possible time. In most settings, capacity to conduct à
comprehensive investigation at immunization service provider level does not exist
Therefore, collection of preliminary information of detailed investigations is often the
responsiblity at thi level Developing capacity to caery out such investigation is
necessary and logical. Findings of investigation should be dsseminative with both service
Provider and national level authorities,
Corrective Action
Comective action should be taken immediately, I should be based on the findings of
investigation. In practice, intermediate level has more responsibilties to implement
correctivo actions both logistically and administrativo. For example if any immunization
correlated reactions are observed, strengthening supportive supervision, training and
even logistic replacements could be implemented by the authorities at this level
Analysis of AEFL
Carrying out data analysis is necessary. Reports need to be produced based on the
findings of data analyses and investigations.
Monitoring and Supervsion/Training
Monitoring, supervision and training are key functions at this level Authorities need to
develop the capacity at this level to any out these functions eficenty and effectively
Whenever necessary, the national level can asit intermediate level for these avi,
including providing standard formats for supportive supervision, guidelines and traning
8.1.4.3 National Level
Investigation and Causality Assessment of AEFI
Investigations that need national level experts service (eg. serious cases, deaths, AER
with pubic concerns) need to be done at the earliest possible time, Causaliy assessment
by national expert committee needs to be faciitated.1f necessary, further research needs
tobe conducted to testa hypothesis generated by the suvellance system investit
Corrective action
Corrective action should be taken immediately, I should be based on the findings of
investigation. Vaccine withdrawal or suspension should be taken only if avaiable data are
strongly supported by the causative link of the vaccines. Corrective action even can lead
to poly or/and programme strategy changes
Analysis and Sharing of AEFI Data
Reports should be produced on findings of data analyses and investigations, AEFI data
need to be shored among all the stakeholders responsible or county EPL mmunizat
programme managers, NRA, NCL, academia and, when necessary, manufactures.
Countries are encouraged to share data regionaly and globaly tough the WHO
Programme for Intemational Drug Monitoring to generate additonal and new
Public Education/Communication
Whenever needs arise, conducting public and media awareness is necessary. Developing
communication plan is also essential.
Monitoring and Supervision/Training
Monitoring and supervision of immunization services necessary. Guidance and adequate
training should be provided to the staff on AEFI survelance and good quality
immunization practices. Whenever necessary, the staff must be ce-trained. Developing
training materias and geting WHO support i necessary, should be done,
Carrying out data analysis is necessary. Reports need to be produced based on the
findings of data analyses and investigations.
Monitoring and Supervsion/Training
Monitoring, supervision and training are key functions at this level Authorities need to
develop the capacity at this level to any out these functions eficenty and effectively
Whenever necessary, the national level can asit intermediate level for these avi,
including providing standard formats for supportive supervision, guidelines and traning
8.1.4.3 National Level
Investigation and Causality Assessment of AEFI
Investigations that need national level experts service (eg. serious cases, deaths, AER
with pubic concerns) need to be done at the earliest possible time, Causaliy assessment
by national expert committee needs to be faciitated.1f necessary, further research needs
tobe conducted to testa hypothesis generated by the suvellance system investit
Corrective action
Corrective action should be taken immediately, I should be based on the findings of
investigation. Vaccine withdrawal or suspension should be taken only if avaiable data are
strongly supported by the causative link of the vaccines. Corrective action even can lead
to poly or/and programme strategy changes
Analysis and Sharing of AEFI Data
Reports should be produced on findings of data analyses and investigations, AEFI data
need to be shored among all the stakeholders responsible or county EPL mmunizat
programme managers, NRA, NCL, academia and, when necessary, manufactures.
Countries are encouraged to share data regionaly and globaly tough the WHO
Programme for Intemational Drug Monitoring to generate additonal and new
Public Education/Communication
Whenever needs arise, conducting public and media awareness is necessary. Developing
communication plan is also essential.
Monitoring and Supervision/Training
Monitoring and supervision of immunization services necessary. Guidance and adequate
training should be provided to the staff on AEFI survelance and good quality
immunization practices. Whenever necessary, the staff must be ce-trained. Developing
training materias and geting WHO support i necessary, should be done,
18.2 VACCINATION FAILURE
The development of sustainable immunization programmes delivering safe and effective
vaccines to human populations has been proven to be highly successful. However, vacines
are neither 100% efcacious nor 100% effective (where efficacy is determined in clinical al
usually pre-hcensure, and effectiveness is determined in practical use, Le. posticensur)
Various case definitions for vaccination fllre are being used in different settings eg for
reporting to regulatory authorities or in epidemiological studies. Vaccination falure can be
defined by a variety of endpoint criteria (eg. disease prevention, disease mitigation or
mmune response) Different terms are also used inconsistently to designate vaccination
failure, eg. lack of vaccine efficacy or lack of adequate protection.
À major issue regarding any definition of vaccination failure i the question of the clinica
endpoint against which a specific vaccine should protect, ie. infection versus disease versus
exis (complicated) disease. These issues could potential be solved by proposing general
Aefinitions for types af vaccination failure complemented by specific definitions or a given
vaccine, Vaccination failure can be due to: (1) vaccine failure or (2) failure to vaccinate, Le
that an indicated vaccine was nat administered appropriately for any raso
8.2.4 Vaccine Failure
24.4 Reasons for Vaccination Failure are Manifold and include, but are
not restricted to the following
Vaccine-related (host related):
+ immunodeficiency (ending to suboptimal or even absent immune response after
[Age-related maturation and senescence of immune responsiveness
Insufficient or suboptimal immune response (other than a defined immunodeficiency
to one or more antigenic vaccine components or vaccine stains or serotypes this
may or may not be meacurable by standard laboratory tests such as serum antibody
Interference due to other infectious agents (eg. wild type enterovinus infection
causing interference with the immune response to oral poliompelti vaccine (OPV);
Waning immunity
Suboptimal health stats (eg. undertying disease, nutrition)
Immunological interference (eg matemal antibodies, administration of
immunoglobuie's
Pre-existing infection with pathogen targeted by the vaccine (eg. with specific HPV
‘genotypes or immunization during incubstion period (after exposure to pathogen
Immunosuppressiv therapy.
The development of sustainable immunization programmes delivering safe and effective
vaccines to human populations has been proven to be highly successful. However, vacines
are neither 100% efcacious nor 100% effective (where efficacy is determined in clinical al
usually pre-hcensure, and effectiveness is determined in practical use, Le. posticensur)
Various case definitions for vaccination fllre are being used in different settings eg for
reporting to regulatory authorities or in epidemiological studies. Vaccination falure can be
defined by a variety of endpoint criteria (eg. disease prevention, disease mitigation or
mmune response) Different terms are also used inconsistently to designate vaccination
failure, eg. lack of vaccine efficacy or lack of adequate protection.
À major issue regarding any definition of vaccination failure i the question of the clinica
endpoint against which a specific vaccine should protect, ie. infection versus disease versus
exis (complicated) disease. These issues could potential be solved by proposing general
Aefinitions for types af vaccination failure complemented by specific definitions or a given
vaccine, Vaccination failure can be due to: (1) vaccine failure or (2) failure to vaccinate, Le
that an indicated vaccine was nat administered appropriately for any raso
8.2.4 Vaccine Failure
24.4 Reasons for Vaccination Failure are Manifold and include, but are
not restricted to the following
Vaccine-related (host related):
+ immunodeficiency (ending to suboptimal or even absent immune response after
[Age-related maturation and senescence of immune responsiveness
Insufficient or suboptimal immune response (other than a defined immunodeficiency
to one or more antigenic vaccine components or vaccine stains or serotypes this
may or may not be meacurable by standard laboratory tests such as serum antibody
Interference due to other infectious agents (eg. wild type enterovinus infection
causing interference with the immune response to oral poliompelti vaccine (OPV);
Waning immunity
Suboptimal health stats (eg. undertying disease, nutrition)
Immunological interference (eg matemal antibodies, administration of
immunoglobuie's
Pre-existing infection with pathogen targeted by the vaccine (eg. with specific HPV
‘genotypes or immunization during incubstion period (after exposure to pathogen
Immunosuppressiv therapy.
Vaccine-reated:
Vaccine is not 100% efficacious against included antigens
Incomplete coverage of strains, serotypes, genotypes, antigenic variants or escape
mutants that can cause a vacine-preventabe disease
Antigenic interference or other vaccine-vaccine interactions in case of co
Manufacturing related (e, batch variations, qualty defect
1.2 Failure to Vaccinate
Usage issues:
or suboptimal rout, inadequate dose, incorrect liven
scination series incomplete, on complince with recommended
Schedule, including lack of recommended booster vaccinations) (allure to
vaccinate rather than “vaccination file”)
Storage-elted (eg. cold chain
1.3 Immunization Programme-related Issues
+ Suboptimal recommendations regarding number and time points of primary and/or
booster vaccinations:
+ Shortage of vaccine leading to no or incomplete vaccination.
{One or more ofthese reasons listed under vaccine fur or failure o vaccinate may lead
to individual vaccination failure. They are not part of à ase definition and may or may net be
discovered in the process of analyzing individual suspected vaccination falure. A data
checklist to ad in collecting dato that can help identify reasons for vaccination failure in an
indhidualis provided
ADVERSE EVENTS FOLLOWING IMMUNIZATION
Any untoward medical occurrence which follows immunization and whieh does not
necessarily have a causal relationship withthe usage ofthe vaccine. The adverse event may
be any unfavourable ar unintended sign, abnormal laboratory finding. symptom or disease
These definitions and related information are Li out in tre par:
+ AGF general and cause-specific definitions and associates concepts:
+ Explanatory notes regarding the contextual application ofthe definitions: and
+ Lists of underÿing mechanisms foreach AEF cause-specfc definition
8.3.4.4 Vaccine Product-elated Reaction
‘An AEFI that is caused or precipitated by a vaccine due to one or more of the inherent
properties ofthe vaccine product Underying mechanisms could be the same whether or not
ETES
Vaccine is not 100% efficacious against included antigens
Incomplete coverage of strains, serotypes, genotypes, antigenic variants or escape
mutants that can cause a vacine-preventabe disease
Antigenic interference or other vaccine-vaccine interactions in case of co
Manufacturing related (e, batch variations, qualty defect
1.2 Failure to Vaccinate
Usage issues:
or suboptimal rout, inadequate dose, incorrect liven
scination series incomplete, on complince with recommended
Schedule, including lack of recommended booster vaccinations) (allure to
vaccinate rather than “vaccination file”)
Storage-elted (eg. cold chain
1.3 Immunization Programme-related Issues
+ Suboptimal recommendations regarding number and time points of primary and/or
booster vaccinations:
+ Shortage of vaccine leading to no or incomplete vaccination.
{One or more ofthese reasons listed under vaccine fur or failure o vaccinate may lead
to individual vaccination failure. They are not part of à ase definition and may or may net be
discovered in the process of analyzing individual suspected vaccination falure. A data
checklist to ad in collecting dato that can help identify reasons for vaccination failure in an
indhidualis provided
ADVERSE EVENTS FOLLOWING IMMUNIZATION
Any untoward medical occurrence which follows immunization and whieh does not
necessarily have a causal relationship withthe usage ofthe vaccine. The adverse event may
be any unfavourable ar unintended sign, abnormal laboratory finding. symptom or disease
These definitions and related information are Li out in tre par:
+ AGF general and cause-specific definitions and associates concepts:
+ Explanatory notes regarding the contextual application ofthe definitions: and
+ Lists of underÿing mechanisms foreach AEF cause-specfc definition
8.3.4.4 Vaccine Product-elated Reaction
‘An AEFI that is caused or precipitated by a vaccine due to one or more of the inherent
properties ofthe vaccine product Underying mechanisms could be the same whether or not
ETES
the reaction is due to an inherent property ofthe vaccine ora quality defect in manufacture
Thus, mechanisms for product-related reactions and quality defeckteated reactions are
combined into a single category in his section and include but are not limited to the Ist
provided in this report.
Vaccines are designed to induce a response by the immune system which involves a
complex interaction between the vaccine antigens, the adjuvant (if present antigen
presenting cell, lymphocytes and multiple immune mediator (cytokines). The interaction is.
important to the development of the desired immunity against the specf vaccine
preventable disease. However, the immune response in a vaccine may manifest a relatively
common and mild adverse reactions to the vaccines), such as injection site redness and
Sweling or fever. Homeosttic mechanisms usually limit the inflammatory response, 50 that
such reactions ae shor-Ived and have no lasting consequence. Uncommonly, the immune
response to one or more vaccine components may resul in a longer-lasting and more severe
verse reaction, Rarely, the immune response may cause aife-threatening allergic reaction.
Reaction associated with the route and/or ste of administration of the vaccine product
or vaccine-specifc characteristics:
+ Bei palsy following intranasal administration ofa specific influenza vaccine where
the causative mechanism was atibuted to the vaccine composition combined with
the mode of administration
+ Pain atthe time of injection and associated physiologic responses
2.2.4.2 Immuno-mediated Vaccine Reactions
(@) Local reaction, with involvement of injection site, due to one or more vaccine
‘components
Non granulomatous inflammation with or without regional ymphadentis
Extensive limb sweling eg post-DTP vaccination,
Mid, moderate or severe local inflammation, manifesta one or more of swelling,
redness, pain, local tenderness and induration. Examples of the mechanism
underlying more severe reactions include:
Subcutaneous injection of a vaccine (eg. alum adsorbed) recommended for
intramuscular administration,
Localized antigen-antibody reaction (antibody excess) aluminium adjuvan
hypersensitivity, or infection.
i) Granulomatous infammation at the injection site with or without regional
Iymphadenits (most commonly related to BCG vaccine)
(©) Muttisystem (generalized) reaction due to one or more vaccine components
+ Systemic inflammatory response, eg, fever or lethargy,
Thus, mechanisms for product-related reactions and quality defeckteated reactions are
combined into a single category in his section and include but are not limited to the Ist
provided in this report.
Vaccines are designed to induce a response by the immune system which involves a
complex interaction between the vaccine antigens, the adjuvant (if present antigen
presenting cell, lymphocytes and multiple immune mediator (cytokines). The interaction is.
important to the development of the desired immunity against the specf vaccine
preventable disease. However, the immune response in a vaccine may manifest a relatively
common and mild adverse reactions to the vaccines), such as injection site redness and
Sweling or fever. Homeosttic mechanisms usually limit the inflammatory response, 50 that
such reactions ae shor-Ived and have no lasting consequence. Uncommonly, the immune
response to one or more vaccine components may resul in a longer-lasting and more severe
verse reaction, Rarely, the immune response may cause aife-threatening allergic reaction.
Reaction associated with the route and/or ste of administration of the vaccine product
or vaccine-specifc characteristics:
+ Bei palsy following intranasal administration ofa specific influenza vaccine where
the causative mechanism was atibuted to the vaccine composition combined with
the mode of administration
+ Pain atthe time of injection and associated physiologic responses
2.2.4.2 Immuno-mediated Vaccine Reactions
(@) Local reaction, with involvement of injection site, due to one or more vaccine
‘components
Non granulomatous inflammation with or without regional ymphadentis
Extensive limb sweling eg post-DTP vaccination,
Mid, moderate or severe local inflammation, manifesta one or more of swelling,
redness, pain, local tenderness and induration. Examples of the mechanism
underlying more severe reactions include:
Subcutaneous injection of a vaccine (eg. alum adsorbed) recommended for
intramuscular administration,
Localized antigen-antibody reaction (antibody excess) aluminium adjuvan
hypersensitivity, or infection.
i) Granulomatous infammation at the injection site with or without regional
Iymphadenits (most commonly related to BCG vaccine)
(©) Muttisystem (generalized) reaction due to one or more vaccine components
+ Systemic inflammatory response, eg, fever or lethargy,
Pramacovgance cine Sle Suveace
Mast cel degranulation,
IgE mediated hypersensvit (anaphyiaxs,
Non ige mediated hypersensitivity (reactions in this group are commonly referred to
Disseminated granulomatous reaction, e. disseminated BCG in immunodeficient
hosts
+ Immune complex mediated resction (Serum Sickness Reaction)
Organ-specific reaction due to one or more vaccine components
+ Autoimmane or undefined mechanism,
+ CNSeg.demeinating conditions such as GBS por influenza vaccination (30.
+ Blood e.g, rombocytopenia post MR vaccination,
+ Skin eg. rashes after vaccination including urticaria,
Consequence of replication of vaccine-associated microbial agents) in the vaccine ora
close contact ofthe vaccine. The microbial agents) could be:
+ Attonsated vaccine agent.
= Wid type vaccine agent due to insufficient inactivation during the manufacturing
process
‘Contaminant introduced into vaccine during the manufacturing process
Direct toxic efect of vaccine component or contaminant (e.g. quality defect)
8.3.1.3 Vaccine Quality Defect Related Reaction
An AEFI that is caused or precipitated by a vaccine that is due to one or more quality
defects of the vaccine product including its adminisvation device as provided by the
Since the emphasis for AEF falling in this category is on their preventable nature, the
mechanisms focus on the nature ofthe error cathe than on the biologic process giving ri
to the speciic AEFI), Stil, many of the AEFIs inthis category 8 result from the same or
similar processes underhing vaccine productrelated or vaccine quality defec-related
For example, when an individual has a documented hypersensithity to one or more
components of a vaccine but a vaccine provider fais to adhere to what is a known
contraindication, the resulting anaphyias is due to an errr in vaccine prescribing,
Error in vaccine handling:
(@) Exposure to excess hest or cold as a result of inappropriate transport, storage or
handling ofthe vaccine (and its cliuent where applicable.
+ Failure to vaccinate a a result of inactivation ofthe active vaccine components
Mast cel degranulation,
IgE mediated hypersensvit (anaphyiaxs,
Non ige mediated hypersensitivity (reactions in this group are commonly referred to
Disseminated granulomatous reaction, e. disseminated BCG in immunodeficient
hosts
+ Immune complex mediated resction (Serum Sickness Reaction)
Organ-specific reaction due to one or more vaccine components
+ Autoimmane or undefined mechanism,
+ CNSeg.demeinating conditions such as GBS por influenza vaccination (30.
+ Blood e.g, rombocytopenia post MR vaccination,
+ Skin eg. rashes after vaccination including urticaria,
Consequence of replication of vaccine-associated microbial agents) in the vaccine ora
close contact ofthe vaccine. The microbial agents) could be:
+ Attonsated vaccine agent.
= Wid type vaccine agent due to insufficient inactivation during the manufacturing
process
‘Contaminant introduced into vaccine during the manufacturing process
Direct toxic efect of vaccine component or contaminant (e.g. quality defect)
8.3.1.3 Vaccine Quality Defect Related Reaction
An AEFI that is caused or precipitated by a vaccine that is due to one or more quality
defects of the vaccine product including its adminisvation device as provided by the
Since the emphasis for AEF falling in this category is on their preventable nature, the
mechanisms focus on the nature ofthe error cathe than on the biologic process giving ri
to the speciic AEFI), Stil, many of the AEFIs inthis category 8 result from the same or
similar processes underhing vaccine productrelated or vaccine quality defec-related
For example, when an individual has a documented hypersensithity to one or more
components of a vaccine but a vaccine provider fais to adhere to what is a known
contraindication, the resulting anaphyias is due to an errr in vaccine prescribing,
Error in vaccine handling:
(@) Exposure to excess hest or cold as a result of inappropriate transport, storage or
handling ofthe vaccine (and its cliuent where applicable.
+ Failure to vaccinate a a result of inactivation ofthe active vaccine components
+ Systemic or local reactions due to changes In the physical nature ofthe vaccine such
as agglutination of aluminium based excipients in freze-sensiive vaccines,
(©) Use of product after the expiy date
+ Failure to vaccinate as a result of loss of potency or non-vabilty of an attenuated
product,
Error in vaccine prescribing or non-adherence to recommendations for use:
(6) Faure to adhere to a contraindication
+ Anaphyiase folowing administration of 2 vaccine to an individual known to have an
immune-mediated hypersensiivity to one or more components
‘seminated infection with an attenuate lve vacine agent folowing administration
+ Vaccine-associsted paralytic polio in an immunocompromised household contact of
à child given oral palo vaccine
(2) Fahre to consider appropriately warnings or precautions for vaccine use.
(<) Faure to adhere to vaccine indications or prescription
Systemic and/or local reactions following administration of incorrect dose
Systemic and/or local reactions following administration of wrong product or
administration to an individual in an incorrect age group.
Vaccinefalure 1 Ive attenuated produc ie given too soon ater blood products or
at an age when maternally transfered antibody could interfere with replication
required to induce an immune response
Neurologic, muscular, vascular or bony injury due to incorrect injection ste
equipment or technique
Error in administration:
Use ofan incorect diluents or injection ofa product other than the intended vaccine
allure to vaccinate due to incorrect evens
Reaction due tothe inherent properties of whatever was administered other than the
intended vaccine or cvent.
Incorrect tele technique or inappropriate procedure wih a mulidose val
infection a the ste of injection due to a microbial contaminant introduced during
Infection beyond the site of injection due to a microbial contaminant introduc
during administration of the vaccine.
Failure to ensure a safe environment during and immediately fllowing immunization
Head injury during a syncopal episode post immunizaton
as agglutination of aluminium based excipients in freze-sensiive vaccines,
(©) Use of product after the expiy date
+ Failure to vaccinate as a result of loss of potency or non-vabilty of an attenuated
product,
Error in vaccine prescribing or non-adherence to recommendations for use:
(6) Faure to adhere to a contraindication
+ Anaphyiase folowing administration of 2 vaccine to an individual known to have an
immune-mediated hypersensiivity to one or more components
‘seminated infection with an attenuate lve vacine agent folowing administration
+ Vaccine-associsted paralytic polio in an immunocompromised household contact of
à child given oral palo vaccine
(2) Fahre to consider appropriately warnings or precautions for vaccine use.
(<) Faure to adhere to vaccine indications or prescription
Systemic and/or local reactions following administration of incorrect dose
Systemic and/or local reactions following administration of wrong product or
administration to an individual in an incorrect age group.
Vaccinefalure 1 Ive attenuated produc ie given too soon ater blood products or
at an age when maternally transfered antibody could interfere with replication
required to induce an immune response
Neurologic, muscular, vascular or bony injury due to incorrect injection ste
equipment or technique
Error in administration:
Use ofan incorect diluents or injection ofa product other than the intended vaccine
allure to vaccinate due to incorrect evens
Reaction due tothe inherent properties of whatever was administered other than the
intended vaccine or cvent.
Incorrect tele technique or inappropriate procedure wih a mulidose val
infection a the ste of injection due to a microbial contaminant introduced during
Infection beyond the site of injection due to a microbial contaminant introduc
during administration of the vaccine.
Failure to ensure a safe environment during and immediately fllowing immunization
Head injury during a syncopal episode post immunizaton
+ Inadvertent administration of vaccine to someone for whom it was not intended,
129, via a needle stick jury or splash tothe eye.
Immunization error related reaction:
= An AEF that is caused by inappropriate 25 vaccine handling. prescribing or
administration and thus by its nature is preventable. The types of reactions caused by
immunization arvity include but re not ited to:
Vasovagal mediated reactions
Hyperventiation mediates reactions
Stress related psychiatrie disorders
Immunization anxiety-related reaction:
+ An AEFL arising from anviety about the immunization
Coincidental event:
‘+ A AEFI that is caused by something other than the vaccine product, immunization
129, via a needle stick jury or splash tothe eye.
Immunization error related reaction:
= An AEF that is caused by inappropriate 25 vaccine handling. prescribing or
administration and thus by its nature is preventable. The types of reactions caused by
immunization arvity include but re not ited to:
Vasovagal mediated reactions
Hyperventiation mediates reactions
Stress related psychiatrie disorders
Immunization anxiety-related reaction:
+ An AEFL arising from anviety about the immunization
Coincidental event:
‘+ A AEFI that is caused by something other than the vaccine product, immunization
Chapter ... 9
PHARMACOVIGILANCE METHODS
+ LEARNING OBJECTIVES +
9.0 SURVEILLANCE
Langmuir defines suveilan fulness over the distribution ond trends
ofthe incidence of 0 disease through the 3 lection, consolidation ond evaluation of
morbidity and mortality reports and other relevant deta” Hence, itis necessary to collect the
data on diseases that are considered reportable by state statute and regulation. State and
ical heath departments of a country are responsible for this. Most local city, and state
health departments require physicians and other heath care professionals working in towns,
hools, hospitals and in laboratories are to report diseases. Such surveillance is called
passive surveilance. The pasive surveillance systems have some limitations.
PASSIVE SURVEILLANCE
hysicians frequently do not report cases and are not aware of the reportable diseases 0
may think that the report would be a breach of confidentiality. As à result, the delay in
receiving laboratory test resus occurs and affects the timeliness ofthe report. In passive
survellance, criteria are established for reporting diseases risk factors or health-related
events. Heath practioner are notified of the requirements and they report events as they
come to their attention. This is Ihe more common type of survalance.
port by contacting the local heath department and then provides the detls as required
for a case of measles. Here, the local heath department relies on the phy
PHARMACOVIGILANCE METHODS
+ LEARNING OBJECTIVES +
9.0 SURVEILLANCE
Langmuir defines suveilan fulness over the distribution ond trends
ofthe incidence of 0 disease through the 3 lection, consolidation ond evaluation of
morbidity and mortality reports and other relevant deta” Hence, itis necessary to collect the
data on diseases that are considered reportable by state statute and regulation. State and
ical heath departments of a country are responsible for this. Most local city, and state
health departments require physicians and other heath care professionals working in towns,
hools, hospitals and in laboratories are to report diseases. Such surveillance is called
passive surveilance. The pasive surveillance systems have some limitations.
PASSIVE SURVEILLANCE
hysicians frequently do not report cases and are not aware of the reportable diseases 0
may think that the report would be a breach of confidentiality. As à result, the delay in
receiving laboratory test resus occurs and affects the timeliness ofthe report. In passive
survellance, criteria are established for reporting diseases risk factors or health-related
events. Heath practioner are notified of the requirements and they report events as they
come to their attention. This is Ihe more common type of survalance.
port by contacting the local heath department and then provides the detls as required
for a case of measles. Here, the local heath department relies on the phy
Passive surveillance is simple to conduct and in most cases, once the procedures are
established (who to reporto, case definition, and laboratory confirmation) It isnot a huge
burden on the reporter. However, passive reporting ls susceptible to incompleteness.
9.4.4 Spontaneous Reports
A spontaneous report is a voluntary communication by healthcare professionals or
consumers to a company, regulatory authority or other organization (e., WHO, Regional
Centres Poison Control Centre) that describes one or more adverse drug reactions in a
patient, who was given one or more medicinal products and that does not derive from a
study or any organized data collection scheme
Spontaneous report play a major role inthe identification of safety signals once a drug
ls marketed. In many cases, a company can be alerted to rare adverse events that were n
detected in eane clinical trials or other pre marketing studies. Spontaneous report can also
provide important information on at-risk groups, risk factors, and cinical features of known
serious adverse drug reactions Caution should be exercised in evaluating spontaneous
reports, especialy when comparing drugs. The data accompanying spontaneous reports are
‘often incomplete, and the rate at which cases are reported is dependent on many factors
induding the time since launch, pharmacoviglance-elated regulatory activity, media
attention and the indication for use ofthe drug
9.1.2 Systematic Methods for the Evaluation of Spontaneous Reports
More recent, systematic methods for the detection of safety signals from spontaneous
reports have been used. Many of these techniques are still in development and their
useluness for identifying safety signals is being evaluated. These methods include the
Calculation of the proportional reporting ratio, as well as the use of Bayesian and other
techniques for signal detection, Data mining techniques have also been used to examine
drug-drug interactions. Data mining techniques should always be used in conjunction with,
and not in place of, analyses of single case reports. Data mining techniques facilitate the
evaluation of spontaneous reports by using statistical methods to detect potential signals for
further evaluation, This too! does not quanti the magnitude of risk and caution should be
exerised when comparing drugs. Further, when using data mining techniques, consideration
should be given to the threshold established for detecting signals since this will nave
implications forthe sensitivity and specificity of the method (a high threshold is associated
with high specfity and low sensitivity), Confounding factors that influence spontaneous
adverse event reporting are not removed by data mining. Results of data mining should be
interpreted with the knowledge ofthe weaknesses ofthe spontaneous reporting system an,
established (who to reporto, case definition, and laboratory confirmation) It isnot a huge
burden on the reporter. However, passive reporting ls susceptible to incompleteness.
9.4.4 Spontaneous Reports
A spontaneous report is a voluntary communication by healthcare professionals or
consumers to a company, regulatory authority or other organization (e., WHO, Regional
Centres Poison Control Centre) that describes one or more adverse drug reactions in a
patient, who was given one or more medicinal products and that does not derive from a
study or any organized data collection scheme
Spontaneous report play a major role inthe identification of safety signals once a drug
ls marketed. In many cases, a company can be alerted to rare adverse events that were n
detected in eane clinical trials or other pre marketing studies. Spontaneous report can also
provide important information on at-risk groups, risk factors, and cinical features of known
serious adverse drug reactions Caution should be exercised in evaluating spontaneous
reports, especialy when comparing drugs. The data accompanying spontaneous reports are
‘often incomplete, and the rate at which cases are reported is dependent on many factors
induding the time since launch, pharmacoviglance-elated regulatory activity, media
attention and the indication for use ofthe drug
9.1.2 Systematic Methods for the Evaluation of Spontaneous Reports
More recent, systematic methods for the detection of safety signals from spontaneous
reports have been used. Many of these techniques are still in development and their
useluness for identifying safety signals is being evaluated. These methods include the
Calculation of the proportional reporting ratio, as well as the use of Bayesian and other
techniques for signal detection, Data mining techniques have also been used to examine
drug-drug interactions. Data mining techniques should always be used in conjunction with,
and not in place of, analyses of single case reports. Data mining techniques facilitate the
evaluation of spontaneous reports by using statistical methods to detect potential signals for
further evaluation, This too! does not quanti the magnitude of risk and caution should be
exerised when comparing drugs. Further, when using data mining techniques, consideration
should be given to the threshold established for detecting signals since this will nave
implications forthe sensitivity and specificity of the method (a high threshold is associated
with high specfity and low sensitivity), Confounding factors that influence spontaneous
adverse event reporting are not removed by data mining. Results of data mining should be
interpreted with the knowledge ofthe weaknesses ofthe spontaneous reporting system an,
more special, the large differences in the ADR reporting rate among diferent drugs and
the many potential biases inherent in spontanacus reporting. Al signals should be evaluated
recognizing the possibilty of false positives In addition, the absence of a signal does net
mean that a problem does not exist
Case series of case reports can provide evidence of an association between a drug and an
adverse event. but they are generally more useful for generating hypotheses than for
veriÿing an association between drug exposure and outcome. There are certain distinc
adverse events known to be associated more frequently with drug therapy, such as
snaphylas, aplastic anaemia, toxic epidermal necrolysis and Stevens Johnson Syndrome,
Therefore, when events such as these are spontaneously reported, sponsors should place
more emphasis on these reports fr detailed and rapid folow-up.
9.2 STIMULATED REPORTING
Several methode have been used to encourage and facitate reporting by heath
professionals in specie stuations (e. in-hospital settings) for new products or or limited
time periods, Such methods induce on-line reporting of adverse events and systematic
stimulation of reporting of adverse events based on a pre-designed method. Although these
methods have been shown to improve reporting. they are not devoid ofthe limitations of
passive surveillance, especially selective reporting and incomplete information.
During the early postmarketing phase, companies might actively provide heath
products and the submission of spontaneous reports when an adverse event is identified. &
plan can be developed before the producti launched (eg. through ste vists by company
representatives, by direct malings or faxes, etc). Stimulated adverse event reporting inthe
any post-marketing phase can lead companies to noti healthcare professionals of new
therapies and provide safety information early in use by the general population (eg. Early
ost marketing Phase Vigilance, EPPY in Japan). This should be regarded as à form of
Spontaneous event reporting, and thus data obtained from stimulated reporting cannot be
sed to generate accurate incidence rates but reporting rates can be estimated
9.3 ACTIVE SURVEILLANCE - SENTINEL SITES, DRUG EVENT
MONITORING AND REGISTRIES
Active suveilace, in contrast to passive surveillance, seeks to ascertain completely the
number of adverse events via à continuous pre-organized process. An example of active
surveilance is the followup of patients treated with a particular drug through a risk
the many potential biases inherent in spontanacus reporting. Al signals should be evaluated
recognizing the possibilty of false positives In addition, the absence of a signal does net
mean that a problem does not exist
Case series of case reports can provide evidence of an association between a drug and an
adverse event. but they are generally more useful for generating hypotheses than for
veriÿing an association between drug exposure and outcome. There are certain distinc
adverse events known to be associated more frequently with drug therapy, such as
snaphylas, aplastic anaemia, toxic epidermal necrolysis and Stevens Johnson Syndrome,
Therefore, when events such as these are spontaneously reported, sponsors should place
more emphasis on these reports fr detailed and rapid folow-up.
9.2 STIMULATED REPORTING
Several methode have been used to encourage and facitate reporting by heath
professionals in specie stuations (e. in-hospital settings) for new products or or limited
time periods, Such methods induce on-line reporting of adverse events and systematic
stimulation of reporting of adverse events based on a pre-designed method. Although these
methods have been shown to improve reporting. they are not devoid ofthe limitations of
passive surveillance, especially selective reporting and incomplete information.
During the early postmarketing phase, companies might actively provide heath
products and the submission of spontaneous reports when an adverse event is identified. &
plan can be developed before the producti launched (eg. through ste vists by company
representatives, by direct malings or faxes, etc). Stimulated adverse event reporting inthe
any post-marketing phase can lead companies to noti healthcare professionals of new
therapies and provide safety information early in use by the general population (eg. Early
ost marketing Phase Vigilance, EPPY in Japan). This should be regarded as à form of
Spontaneous event reporting, and thus data obtained from stimulated reporting cannot be
sed to generate accurate incidence rates but reporting rates can be estimated
9.3 ACTIVE SURVEILLANCE - SENTINEL SITES, DRUG EVENT
MONITORING AND REGISTRIES
Active suveilace, in contrast to passive surveillance, seeks to ascertain completely the
number of adverse events via à continuous pre-organized process. An example of active
surveilance is the followup of patients treated with a particular drug through a risk
Pramacocgiance Pharmacodplace Methods
management programme, Patients who fil prescription for this drug may be asked to
complete a brief survey form and give permission for later contact. In genera, itis more
feasible to get comprehensive data on indhidual adverse event reports through an active
Sumveilance system than through a passive reporting system
9.3.4 Sentinel Site
Active suveilance can be achieved by reviewing medical records or interviewing patients
and/or physicians in sample of sentinel sites to ensure complete and accurate data on
reported adverse evens from these sites The selected sits can provide information, such as
data from specific patient subgroups that would not be available in a passive spontaneous
reporting system. Further, information on the use of a drug. such as abuse, can be targeted
a selected sentinel sites. Some of the major weaknesses of sentinel sites are problems with
selection bias, small numbers of patients, and increased costs. Active surveillance wth
sentinel sites is most ecient for those drugs used mainly in institutional serings such as
hospitals, curing homes, haemodialyss centres, et. Institutional settings can have a greater
frequency of use for certain drug products and can provide an infrastructure for dedicated
reporting In addition, automatic detection of abnormal laboratory values from computerized
laboratory reports in certain clinical settings can provide an efficient active surveilance
system. Intensive monitoring of sentinel ites can aso be helpful in identiing risks among
patients taking orphan drugs
9.3.2 Drug Event Monitoring
Drug event monitoring is a method of active pharmacovgiance suneillance. In drug
event monitoring. patients might be identified from electronic prescription data or
automated health insurance claims. A follow-up questionnaire can then be sent to each
prescribing physician or patient at pre-spected intenals to obtin outcome information.
Information on patient demographics, indication for treatment, duration of therapy
including start dates), dosage, clinical events, and reasons for discontinuation can be
included in the questionnaire, limitations of drug event monitoring can include poor
physician and patient response rates and the unfocused nature of data collection, which can
‘obscure important signals. In addition, maintenance of patient confidentiality might be à
concem, On the other hand, more detailed information on adverse events from a large
number of physicians and/or patients might be collected
9.3.3 Registries
A registry is list of patients presenting withthe same characteristics). This characteristic
can be à disease (disease regist) or à specific exposure (drug registry. Both types of
management programme, Patients who fil prescription for this drug may be asked to
complete a brief survey form and give permission for later contact. In genera, itis more
feasible to get comprehensive data on indhidual adverse event reports through an active
Sumveilance system than through a passive reporting system
9.3.4 Sentinel Site
Active suveilance can be achieved by reviewing medical records or interviewing patients
and/or physicians in sample of sentinel sites to ensure complete and accurate data on
reported adverse evens from these sites The selected sits can provide information, such as
data from specific patient subgroups that would not be available in a passive spontaneous
reporting system. Further, information on the use of a drug. such as abuse, can be targeted
a selected sentinel sites. Some of the major weaknesses of sentinel sites are problems with
selection bias, small numbers of patients, and increased costs. Active surveillance wth
sentinel sites is most ecient for those drugs used mainly in institutional serings such as
hospitals, curing homes, haemodialyss centres, et. Institutional settings can have a greater
frequency of use for certain drug products and can provide an infrastructure for dedicated
reporting In addition, automatic detection of abnormal laboratory values from computerized
laboratory reports in certain clinical settings can provide an efficient active surveilance
system. Intensive monitoring of sentinel ites can aso be helpful in identiing risks among
patients taking orphan drugs
9.3.2 Drug Event Monitoring
Drug event monitoring is a method of active pharmacovgiance suneillance. In drug
event monitoring. patients might be identified from electronic prescription data or
automated health insurance claims. A follow-up questionnaire can then be sent to each
prescribing physician or patient at pre-spected intenals to obtin outcome information.
Information on patient demographics, indication for treatment, duration of therapy
including start dates), dosage, clinical events, and reasons for discontinuation can be
included in the questionnaire, limitations of drug event monitoring can include poor
physician and patient response rates and the unfocused nature of data collection, which can
‘obscure important signals. In addition, maintenance of patient confidentiality might be à
concem, On the other hand, more detailed information on adverse events from a large
number of physicians and/or patients might be collected
9.3.3 Registries
A registry is list of patients presenting withthe same characteristics). This characteristic
can be à disease (disease regist) or à specific exposure (drug registry. Both types of
registres, which only der by the type of patent data of interest, can collect a battery of
information using standardized questionnaires in prospective fasion, Disease registries,
such as registres for blood dyscravas, severe cutaneous reactions, or congenital
malformations can help collect data on drug exposure and other factors associated with à
clinical condition. A disease registy might leo be used as a base for a case-control study
comparing the drug exposure of cases identified fom the registry and controls selected from
‘ether patent with another condition within the registry or patients outside the regis.
Exposure (rug) registries address populations exposed to drugs of interest (eg, registry
‘of houmatoid artis patents exposed to biological therapies) o determine i à drug has à
special impact on this group of patients. Some exposure (drug) registres address drug
exposures in specific populations, such as pregnant women. Patients can be followed over
time and included in à cohort study to collet data on adverse events using standardized
questionnaires, Single cohort studies can measure incidence, but, without a comparison
group. cannot provide proof of association However, they can be useful for signal
amplficanon, particular for rae outcomes. This type of registry can be very valuable when
‘examining the safety ofan orphan drug indicated for a specific condition.
9.4 COMPARATIVE OBSERVATIONAL STUDIES - CROSS SECTIONAL
STUDY, CASE CONTROL STUDY AND COHORT STUDY
Traditional epidemiologic methods are à key component inthe evaluation of adverse
events There are a number of observational study designs that are useful in valcaing
signals from spontaneous reports or case series. Major types of these designs are cross
sextional studies, case-control studies, and cohort studies (both revospective and
prospective
9.4.4 Cross-Sectional Study (Survey)
Data collected on a population of patients at a single pont in time (or interval of time)
regardless of exposure or disease status constitute a cross-sectional study. These types of
studies are primarily used to gather data for surveys or for ecological analyses. The major
drawback of cross-sectional studies thatthe temporal relationship between exposure and
‘outcome cannot be direct addressed, These studies are best used to examine the
prevalence of à disease at one time point or to examine trends over time, when data for
serial time points can be captured. These studies can also be used to examine the crude
association between exposure and outcome in ecologic analyses. Cross-sectional studies are
best utlired when exposure do not change overtime
information using standardized questionnaires in prospective fasion, Disease registries,
such as registres for blood dyscravas, severe cutaneous reactions, or congenital
malformations can help collect data on drug exposure and other factors associated with à
clinical condition. A disease registy might leo be used as a base for a case-control study
comparing the drug exposure of cases identified fom the registry and controls selected from
‘ether patent with another condition within the registry or patients outside the regis.
Exposure (rug) registries address populations exposed to drugs of interest (eg, registry
‘of houmatoid artis patents exposed to biological therapies) o determine i à drug has à
special impact on this group of patients. Some exposure (drug) registres address drug
exposures in specific populations, such as pregnant women. Patients can be followed over
time and included in à cohort study to collet data on adverse events using standardized
questionnaires, Single cohort studies can measure incidence, but, without a comparison
group. cannot provide proof of association However, they can be useful for signal
amplficanon, particular for rae outcomes. This type of registry can be very valuable when
‘examining the safety ofan orphan drug indicated for a specific condition.
9.4 COMPARATIVE OBSERVATIONAL STUDIES - CROSS SECTIONAL
STUDY, CASE CONTROL STUDY AND COHORT STUDY
Traditional epidemiologic methods are à key component inthe evaluation of adverse
events There are a number of observational study designs that are useful in valcaing
signals from spontaneous reports or case series. Major types of these designs are cross
sextional studies, case-control studies, and cohort studies (both revospective and
prospective
9.4.4 Cross-Sectional Study (Survey)
Data collected on a population of patients at a single pont in time (or interval of time)
regardless of exposure or disease status constitute a cross-sectional study. These types of
studies are primarily used to gather data for surveys or for ecological analyses. The major
drawback of cross-sectional studies thatthe temporal relationship between exposure and
‘outcome cannot be direct addressed, These studies are best used to examine the
prevalence of à disease at one time point or to examine trends over time, when data for
serial time points can be captured. These studies can also be used to examine the crude
association between exposure and outcome in ecologic analyses. Cross-sectional studies are
best utlired when exposure do not change overtime
9.4.2 Case-Control Study
In a case-control study, cases of disease (or events) are identified, Controls, or patients
without the disease or event of interest, are then selected from the source population that
¿ave is o the cases. The controls shouldbe selected in such a way that the prevalence of
exposure among the controls represents the prevalence of exposure in the source
population. The exposure status of the two groups is then compared using the odds ato,
which is an estimate of the relative risk of disease in the two groups. Patients can be
identified from an existing database or using data collected special for the purpose of
ho study of interest. I safety information is sought for special populations, the cases and
controls can be stated according to the population of interest (the elder, children
pregnant women, ele). For rare adverse event, existing large population-based databases
are uselul and efficent means of providing needed drug exposure and medical outcome
data in a relatel short period of ime. Case-control studies are particular useful when the
goal isto investigate whether there i an association between a drug (or drugs) and one
pectic race adverse event, a well as to identify rick factors for adverse events. Risk actors
an include conditions such as renal and hepatic dysfunction, that might modify the
relationship between the drug exposure and the adverse event Under specific conditions, a
case control study can provide the absolute incidence rate ofthe event. al cases of interest
(or 3 wel-defined traction of cases) nthe catchment area are captured and the fraction of
controls from the source population s known, an incidence rate can be calculated
9.4.3 Cohort Study
In a cohort study, population-atrisk for the disease (or event) is fllowad overtime for
the occurrence of the disease (or event) Information on exposure status is known
throughout the follow-up period for each patent, A patient might be exposed to a drug at
one time during followup, but non-exposed at another time point Since the population
exposure during follow-up is known. incidence rates can be calculated. In many cohort
studies involing drug exposure, comparison cohorts of interest are selected an the bass of
drug use and followed over time. Cohort studies ae useful when there isa need to know the
incidence rates of adverse events in addition o the relative risks of adverse events. Multiple
adverse events can also be investigated using the same data source in a cohort study
However, it can be dif to recruit suficent numbers of patients who are exposed to à
drug of interest (such as an orphan drug) or to study very rare outcomes. Ike case-control
studies, the identification of patients for cohor studies can come fiom large automated
databases or from data collected specifically forthe study at hand. In addition, cohort studies
In a case-control study, cases of disease (or events) are identified, Controls, or patients
without the disease or event of interest, are then selected from the source population that
¿ave is o the cases. The controls shouldbe selected in such a way that the prevalence of
exposure among the controls represents the prevalence of exposure in the source
population. The exposure status of the two groups is then compared using the odds ato,
which is an estimate of the relative risk of disease in the two groups. Patients can be
identified from an existing database or using data collected special for the purpose of
ho study of interest. I safety information is sought for special populations, the cases and
controls can be stated according to the population of interest (the elder, children
pregnant women, ele). For rare adverse event, existing large population-based databases
are uselul and efficent means of providing needed drug exposure and medical outcome
data in a relatel short period of ime. Case-control studies are particular useful when the
goal isto investigate whether there i an association between a drug (or drugs) and one
pectic race adverse event, a well as to identify rick factors for adverse events. Risk actors
an include conditions such as renal and hepatic dysfunction, that might modify the
relationship between the drug exposure and the adverse event Under specific conditions, a
case control study can provide the absolute incidence rate ofthe event. al cases of interest
(or 3 wel-defined traction of cases) nthe catchment area are captured and the fraction of
controls from the source population s known, an incidence rate can be calculated
9.4.3 Cohort Study
In a cohort study, population-atrisk for the disease (or event) is fllowad overtime for
the occurrence of the disease (or event) Information on exposure status is known
throughout the follow-up period for each patent, A patient might be exposed to a drug at
one time during followup, but non-exposed at another time point Since the population
exposure during follow-up is known. incidence rates can be calculated. In many cohort
studies involing drug exposure, comparison cohorts of interest are selected an the bass of
drug use and followed over time. Cohort studies ae useful when there isa need to know the
incidence rates of adverse events in addition o the relative risks of adverse events. Multiple
adverse events can also be investigated using the same data source in a cohort study
However, it can be dif to recruit suficent numbers of patients who are exposed to à
drug of interest (such as an orphan drug) or to study very rare outcomes. Ike case-control
studies, the identification of patients for cohor studies can come fiom large automated
databases or from data collected specifically forthe study at hand. In addition, cohort studies
can be used to examine safety issues in special populations (the elderly, children, patients
with co-morbi conditions, pregnant women) through over-sampling of these patients or by
stratifying the cohon if sufficient numbers of patients exis.
There are several automated databases available for pharmacoepidemiologí studies
They include databases which contain automated medical records or automated
accounting/illng systems. Databases that are created rom accounting/biling_ systeme
might be linked to pharmacy claims and medical claims databases. These dataets might
include milions of patients, Since they ate created for administrative or bilng purposes they
might not have the detailed and accurate information needed for some research, such as
validated diagnostic information or laboratory data. Although medical records canbe used to
ascertain and validate test results and medical diagnoses, one should be cognizant ofthe
privacy and confidentiality regulations that apply to patient medical records
95 TARGETED CLINICAL INVESTIGATIONS
‘When significant risks are identified rom pre-approval clinical was, further clinical
studies might be calles for to evaluate the mechanism of action forthe adverse reaction In
some instances, pharmacodynamic and pharmacokinetic studies might be conducted to
determine whether à particular dosing instruction can put patients at an increased risk of
‘adverse events. Genetic testing can aso provide dues about which group of patients might
be at an increased risk of adverse reactions. Furthermore, based on the pharmacological
properties and the expected use of the drug in general practice, conducting specifi studies
to Investigate potential drug-drg interactions and food-drug interactions might be called
for. These studies can include population pharmacokinetic studies and drug concentration
monitoring inpatients and normal volunteers
Sometimes, potential risks or unforeseen benefits in special populations might be
‘denied from pre-approval nical trials, but cannot be fuly quantified due to small sample
sites or the exclusion of subpopulations of patients from these clica studies. These
populations might include the elder, children, or patients with renal or hepatic disorder.
hieren, the elder, and patients with co-morbid conditions might metabolize drugs
iferent than patients typically enrole in clinical tals. Further clinical trials might be used
to determine and to quantily the magnitude ofthe sk (or benefi in such populations
To elucidate the benefirisk prfie of a drug outside of the formalraitonal cinical
il setting andr to fully quantity the tsk of a critical but relatively rare adverse event. a
Large simplified trial might be conducted. Patients envoled in a large simplified tial are
with co-morbi conditions, pregnant women) through over-sampling of these patients or by
stratifying the cohon if sufficient numbers of patients exis.
There are several automated databases available for pharmacoepidemiologí studies
They include databases which contain automated medical records or automated
accounting/illng systems. Databases that are created rom accounting/biling_ systeme
might be linked to pharmacy claims and medical claims databases. These dataets might
include milions of patients, Since they ate created for administrative or bilng purposes they
might not have the detailed and accurate information needed for some research, such as
validated diagnostic information or laboratory data. Although medical records canbe used to
ascertain and validate test results and medical diagnoses, one should be cognizant ofthe
privacy and confidentiality regulations that apply to patient medical records
95 TARGETED CLINICAL INVESTIGATIONS
‘When significant risks are identified rom pre-approval clinical was, further clinical
studies might be calles for to evaluate the mechanism of action forthe adverse reaction In
some instances, pharmacodynamic and pharmacokinetic studies might be conducted to
determine whether à particular dosing instruction can put patients at an increased risk of
‘adverse events. Genetic testing can aso provide dues about which group of patients might
be at an increased risk of adverse reactions. Furthermore, based on the pharmacological
properties and the expected use of the drug in general practice, conducting specifi studies
to Investigate potential drug-drg interactions and food-drug interactions might be called
for. These studies can include population pharmacokinetic studies and drug concentration
monitoring inpatients and normal volunteers
Sometimes, potential risks or unforeseen benefits in special populations might be
‘denied from pre-approval nical trials, but cannot be fuly quantified due to small sample
sites or the exclusion of subpopulations of patients from these clica studies. These
populations might include the elder, children, or patients with renal or hepatic disorder.
hieren, the elder, and patients with co-morbid conditions might metabolize drugs
iferent than patients typically enrole in clinical tals. Further clinical trials might be used
to determine and to quantily the magnitude ofthe sk (or benefi in such populations
To elucidate the benefirisk prfie of a drug outside of the formalraitonal cinical
il setting andr to fully quantity the tsk of a critical but relatively rare adverse event. a
Large simplified trial might be conducted. Patients envoled in a large simplified tial are
usualy randomized to avoid selection bias. In this type of trial, though the event of interest
vil be focused to ensure convenient and practical study. One limitation of his method is
that the outcome measure might be too simplified and this might have an impact on the
quality and ultimate usefloess ofthe ial Large, simple tal are also resource intensive.
Descriptive Studies
Descriptive studies are an important component of pharmacovigance,athough not for
the detection or verification of adverse events associated with drug exposures. These studies
are primary used to obtain the background rate of outcome events and/or establish the
prevalence ofthe use of drugs in specified populations
vil be focused to ensure convenient and practical study. One limitation of his method is
that the outcome measure might be too simplified and this might have an impact on the
quality and ultimate usefloess ofthe ial Large, simple tal are also resource intensive.
Descriptive Studies
Descriptive studies are an important component of pharmacovigance,athough not for
the detection or verification of adverse events associated with drug exposures. These studies
are primary used to obtain the background rate of outcome events and/or establish the
prevalence ofthe use of drugs in specified populations
Chapter .. 10
COMMUNICATION IN
PHARMACOVIGILANCE
+ LEARNING OBJECTIVES +
0.0 COMMUNICATION IN PHARMACOVIGILANCE
Modern medicines have changed the way in which diseases are managed and
However, despite al their benefits, evidence continues to mount that averse reactions to
medicines are a common, yet often preventable cause of illness, sabity and even death. In
€ countries, adverse drug reactions (ADRS) rank among the top 10 leading causes of
mortality. Aside from the intrinsic dangers associated with the products themselves
individual patents may exhibit particular and unpredictable senstties to certain medicines
In addition, if more than one medicine is prescribed, there is always a risk of negative
interactions. The selection and use ofthe best and safest medicines) for a given individual
out ofthe many choices available thus requires considerable ski on behalf ofthe prescrbing
practitioner. In order to prevent or reduce harm to patients and thus improve public health
mechanisms for evalating and monitoring the safety of medicines in clinical use ae vital In
practice this means having in place 2 wellorganized pharmacovigiance system
Pharmacovigiance - an umbrella term used to describe the processes for monitoring
evaluating ADRS - is a key component of effective drug regulation systems, clinical practice
and publi heath programmes.
Why Pharmacovigilance is needed
The processes involved inthe cinical development of medicines are illustrated in Fig...
‘Once put into the market. a medicine leaves the secure and protected scientific environment
of clinical tials and is legally set free for consumption by the general population. At ths
point, most medicines wil only have been tested for short-term safey and efficacy on à
limited number of careful selected individual, In some cases as few as 500 subjects, and
rarely more than 5000, wil have received the product prio o its release. For good reason
COMMUNICATION IN
PHARMACOVIGILANCE
+ LEARNING OBJECTIVES +
0.0 COMMUNICATION IN PHARMACOVIGILANCE
Modern medicines have changed the way in which diseases are managed and
However, despite al their benefits, evidence continues to mount that averse reactions to
medicines are a common, yet often preventable cause of illness, sabity and even death. In
€ countries, adverse drug reactions (ADRS) rank among the top 10 leading causes of
mortality. Aside from the intrinsic dangers associated with the products themselves
individual patents may exhibit particular and unpredictable senstties to certain medicines
In addition, if more than one medicine is prescribed, there is always a risk of negative
interactions. The selection and use ofthe best and safest medicines) for a given individual
out ofthe many choices available thus requires considerable ski on behalf ofthe prescrbing
practitioner. In order to prevent or reduce harm to patients and thus improve public health
mechanisms for evalating and monitoring the safety of medicines in clinical use ae vital In
practice this means having in place 2 wellorganized pharmacovigiance system
Pharmacovigiance - an umbrella term used to describe the processes for monitoring
evaluating ADRS - is a key component of effective drug regulation systems, clinical practice
and publi heath programmes.
Why Pharmacovigilance is needed
The processes involved inthe cinical development of medicines are illustrated in Fig...
‘Once put into the market. a medicine leaves the secure and protected scientific environment
of clinical tials and is legally set free for consumption by the general population. At ths
point, most medicines wil only have been tested for short-term safey and efficacy on à
limited number of careful selected individual, In some cases as few as 500 subjects, and
rarely more than 5000, wil have received the product prio o its release. For good reason
Pramacovglance Communion in Pamscoigiance
therefore, it is essential that new and medically sl evohing treatments are monitored fr
their effectiveness and safety under reife conditions post release. More information is
general} needed about use in specific population groups notably children, pregnant women
nd the elder, and about the efficacy and safety of chronic us, especially in combination
with other medicines. Experience has shown that many adverse elects, interactions (ie. with
foods or other medicines) and risk factors come to light only during the years after the
Over the last decade, it has been increasingly recognized that the scope of
pharmacovglance needs to be extended beyond the sic confines of detecting new signal
of safety concems, Globalization, consumerism, the resulting explosion in free trade and
communication across borders, and increasing use of the Internet have all contributed to à
change in the way people access medicinal products and information about them, These
‘hanging patterns in drug use require a sh in Ihe approach to pharmacovigance, more
special, towards one thats more closely linked, and thus better able to respond, to the
precaling pattems of drug use within society
10. EFFECTIVE COMMUNICATION IN PHARMACOVIGILANCE
Centra to effective and Umely communication between FDA and sponsors is the ailty
to communicate clear, both orally and in writing, inside and outside the formal meeting
format, Communication via any ofthe following best practices and communication methods
(except meetings where numerous atendees participate) should be conducted via the FDA
project manager, ypial the review division RPM, rather than FDA reviewers, tam leaders,
‘or senior management to ensure thatthe advices appropriately vetted and documented
10.1.4 Meetings between FDA and Sponsors
Sponsors can request meetings with FDA at any time during drag development to
resolve questions and issues These meetings may also help to minimize wasteful
expendiures of time and resources and thus help to speed the drug development and
evaluation process. FDA strongly encourages sponsors to request cal milestone meetings
such as pre-IND, end-of-phase 1 (EOPI), end-of-phase 2 (EOP2), and pre-NDA/BLA
meetings. FDA provides feedback to sponsors va th formal meeting process in three main
formats: face-to-face meetings, teleconferences, and written response only (WRO). FDA
guidances (ls reer to the specific guidances for drugs and biosimars) describe detailed
information about meeting requests, packages, schedulng, preparation, conduct
documentation and timelines for FDA feedback
10.1.2 Written Correspondence from FDA
FDA project managers will use established letter templates 10 ensure consistency and
accuracy in regulatory communications. Project managers should send a courtesy copy of
written FDA correspondence to sponsors when such communications are time-sensitive or
therefore, it is essential that new and medically sl evohing treatments are monitored fr
their effectiveness and safety under reife conditions post release. More information is
general} needed about use in specific population groups notably children, pregnant women
nd the elder, and about the efficacy and safety of chronic us, especially in combination
with other medicines. Experience has shown that many adverse elects, interactions (ie. with
foods or other medicines) and risk factors come to light only during the years after the
Over the last decade, it has been increasingly recognized that the scope of
pharmacovglance needs to be extended beyond the sic confines of detecting new signal
of safety concems, Globalization, consumerism, the resulting explosion in free trade and
communication across borders, and increasing use of the Internet have all contributed to à
change in the way people access medicinal products and information about them, These
‘hanging patterns in drug use require a sh in Ihe approach to pharmacovigance, more
special, towards one thats more closely linked, and thus better able to respond, to the
precaling pattems of drug use within society
10. EFFECTIVE COMMUNICATION IN PHARMACOVIGILANCE
Centra to effective and Umely communication between FDA and sponsors is the ailty
to communicate clear, both orally and in writing, inside and outside the formal meeting
format, Communication via any ofthe following best practices and communication methods
(except meetings where numerous atendees participate) should be conducted via the FDA
project manager, ypial the review division RPM, rather than FDA reviewers, tam leaders,
‘or senior management to ensure thatthe advices appropriately vetted and documented
10.1.4 Meetings between FDA and Sponsors
Sponsors can request meetings with FDA at any time during drag development to
resolve questions and issues These meetings may also help to minimize wasteful
expendiures of time and resources and thus help to speed the drug development and
evaluation process. FDA strongly encourages sponsors to request cal milestone meetings
such as pre-IND, end-of-phase 1 (EOPI), end-of-phase 2 (EOP2), and pre-NDA/BLA
meetings. FDA provides feedback to sponsors va th formal meeting process in three main
formats: face-to-face meetings, teleconferences, and written response only (WRO). FDA
guidances (ls reer to the specific guidances for drugs and biosimars) describe detailed
information about meeting requests, packages, schedulng, preparation, conduct
documentation and timelines for FDA feedback
10.1.2 Written Correspondence from FDA
FDA project managers will use established letter templates 10 ensure consistency and
accuracy in regulatory communications. Project managers should send a courtesy copy of
written FDA correspondence to sponsors when such communications are time-sensitive or
Prannacovipane Communion in Pamaconglance
10.1.3 Submissions from Sponsors
FDA regulations describe general principles of, as well as content and format
requirements for INDs. Complete and well-organized sponsor submissions can increase the
efficiency of FDA review. FDA encourages sponsors to identify issues or areas of concern in
their submissions by describing them fully and solicting feedback on specific areas of
concem where further progression in drug development depends largely on receiving FDA
feedback if sponsors om important information, do not identify the regulatory intent ofthe
tulbmission, or provide insufficient deta, they run the risk of not receiving timely FDA
feedback In addition, sponsors must adhere to required timelines for their submission
Some submissions have regulatry-mandated timelines for reviewing and. providing
feedback to the sponsor hat are described by statute or regulation (e. some safety-related
submissions, complete response to clinical hold) while other submissions have FDA.
established goals for review and feedback (eg. in a MAP), Timelines for FOA feedback
regarding IND submissions are discussed in MAP? 60303,
10.4.4 Acknowledging Receipt of Communications
FDA project managers will send writen acknowledgment of receipt of certain
submissions that have review timelines. They will lso stive to acknowledge receipt of
questions received from sponsors via telephone cals, emails, and other submissions within 3
business days of receipt by the project manager, The acknowledgment may include the
response salí an estimated response time fame; notification that the questions) have been
consuled to other offices/centers wth an undetermined response time fame: a
recommendation to submit the questions via a formal meeting request or redirection 10
another specialized functional area in FDA. Sponsors should likewise acknowledge receipt of
FDA information request and provide an estimated response time. Delays in responding, or
lack of response to FDA information requests can negatively affect later development.
Sponsors should acknowledge receipt of FDA's information requests, and provide the RPM
th an estimated response tine
10.4.5 Email between FDA and Sponsors
Sponsors should establish secure email with FDA to allow for informal communications
that may include commercial confidential information. Use of secure email allows transparent
and complete communication between FDA and sponsor, However, itis not a substitute for
formal submissions (eg. new INDE and amendments) Formal submissions should be
submitted to the respective centers document room (paper submissions) or via the
electronic gateway as aplicable
10.1.6 General Telephone Calls between FDA and Sponsors
Genera or administrative questions are suitable fr informal telephone communications
between sponsors and FDA project managers. However, when complex. regulatory. oF
CTI
10.1.3 Submissions from Sponsors
FDA regulations describe general principles of, as well as content and format
requirements for INDs. Complete and well-organized sponsor submissions can increase the
efficiency of FDA review. FDA encourages sponsors to identify issues or areas of concern in
their submissions by describing them fully and solicting feedback on specific areas of
concem where further progression in drug development depends largely on receiving FDA
feedback if sponsors om important information, do not identify the regulatory intent ofthe
tulbmission, or provide insufficient deta, they run the risk of not receiving timely FDA
feedback In addition, sponsors must adhere to required timelines for their submission
Some submissions have regulatry-mandated timelines for reviewing and. providing
feedback to the sponsor hat are described by statute or regulation (e. some safety-related
submissions, complete response to clinical hold) while other submissions have FDA.
established goals for review and feedback (eg. in a MAP), Timelines for FOA feedback
regarding IND submissions are discussed in MAP? 60303,
10.4.4 Acknowledging Receipt of Communications
FDA project managers will send writen acknowledgment of receipt of certain
submissions that have review timelines. They will lso stive to acknowledge receipt of
questions received from sponsors via telephone cals, emails, and other submissions within 3
business days of receipt by the project manager, The acknowledgment may include the
response salí an estimated response time fame; notification that the questions) have been
consuled to other offices/centers wth an undetermined response time fame: a
recommendation to submit the questions via a formal meeting request or redirection 10
another specialized functional area in FDA. Sponsors should likewise acknowledge receipt of
FDA information request and provide an estimated response time. Delays in responding, or
lack of response to FDA information requests can negatively affect later development.
Sponsors should acknowledge receipt of FDA's information requests, and provide the RPM
th an estimated response tine
10.4.5 Email between FDA and Sponsors
Sponsors should establish secure email with FDA to allow for informal communications
that may include commercial confidential information. Use of secure email allows transparent
and complete communication between FDA and sponsor, However, itis not a substitute for
formal submissions (eg. new INDE and amendments) Formal submissions should be
submitted to the respective centers document room (paper submissions) or via the
electronic gateway as aplicable
10.1.6 General Telephone Calls between FDA and Sponsors
Genera or administrative questions are suitable fr informal telephone communications
between sponsors and FDA project managers. However, when complex. regulatory. oF
CTI
technical issues are discussed via telephone between the sponsor and the FDA project
manager, the caler should follow-up with a writen communication to document the
discussion and/or respond to information requested during the conversation,
10.1.7 Faxes between FDA and Sponsors
Although it is aot a substitute for formal submissions, a fax can be used when secure
email has not been established between FDA and sponsors Before transmitting the fax
sponsors and FDA projet managers should contact tei especive counterparts o arrange
fer confirmation of recep
Use of Out-of- Office Messages by FDA and Sponsors:
IND sponsors and FDA staff should alert others to their unavalabity by using email and
voicemail out-ofoffce messages. Keep in mind that questions that may appear to the
sponsor to be simple or cantying questions are often more complex and necessitate
significant review and communication among FDA review team members, inclu
As COERS pre-eminent resource for communicating human drug information, the
Centers Office of Communications (OCOMM) serves atthe nexus of vitally every drug
safety issue, question, or ensis that CDER faces. With near 100 staf members including
heath professionals, communications specialists and web and graphic designers, OCOMM
fulls CDERS intemal and external communication needs, including providing strategic
communication advice to Center and Agency leadership, developing and coordinating
overarching pubic communication initiatives and educational activites, and employing
comprehensive communication approaches to ensure consistent branding, messaging, and
strategic direction of CDERS communication products—allertical aspects of drug product
safety,
Expert Responses to Public Queries:
À team of pharmacists, consumer safety officers and nurses respond to public inguiies
from around the world, providing expert guidance and responses to questions about human
drug products. More than 65.000 requests for information are received annually, many of
which involve some aspect of drug safety, from how mach or how litle of a medicine to
safely use, to sale prescribing or dispensing practices, to responses on medi-trending drug
safety concerns. Queries are via phone, electronic mal, and letter, from an aray of
stakeholders, including consumers, health care professionals, academia foundations and
research organizations, and the pharmaceutical industry. Safety inquires can nvove complex
«ciente or regulatory issues; in those cases, OCOMM coordinates extensive research and
consultation needs with the subject matter experts needed to craft accurate and balanced
responses. Another variation in public inquiy are national write-in campaigns, which are
manager, the caler should follow-up with a writen communication to document the
discussion and/or respond to information requested during the conversation,
10.1.7 Faxes between FDA and Sponsors
Although it is aot a substitute for formal submissions, a fax can be used when secure
email has not been established between FDA and sponsors Before transmitting the fax
sponsors and FDA projet managers should contact tei especive counterparts o arrange
fer confirmation of recep
Use of Out-of- Office Messages by FDA and Sponsors:
IND sponsors and FDA staff should alert others to their unavalabity by using email and
voicemail out-ofoffce messages. Keep in mind that questions that may appear to the
sponsor to be simple or cantying questions are often more complex and necessitate
significant review and communication among FDA review team members, inclu
As COERS pre-eminent resource for communicating human drug information, the
Centers Office of Communications (OCOMM) serves atthe nexus of vitally every drug
safety issue, question, or ensis that CDER faces. With near 100 staf members including
heath professionals, communications specialists and web and graphic designers, OCOMM
fulls CDERS intemal and external communication needs, including providing strategic
communication advice to Center and Agency leadership, developing and coordinating
overarching pubic communication initiatives and educational activites, and employing
comprehensive communication approaches to ensure consistent branding, messaging, and
strategic direction of CDERS communication products—allertical aspects of drug product
safety,
Expert Responses to Public Queries:
À team of pharmacists, consumer safety officers and nurses respond to public inguiies
from around the world, providing expert guidance and responses to questions about human
drug products. More than 65.000 requests for information are received annually, many of
which involve some aspect of drug safety, from how mach or how litle of a medicine to
safely use, to sale prescribing or dispensing practices, to responses on medi-trending drug
safety concerns. Queries are via phone, electronic mal, and letter, from an aray of
stakeholders, including consumers, health care professionals, academia foundations and
research organizations, and the pharmaceutical industry. Safety inquires can nvove complex
«ciente or regulatory issues; in those cases, OCOMM coordinates extensive research and
consultation needs with the subject matter experts needed to craft accurate and balanced
responses. Another variation in public inquiy are national write-in campaigns, which are
Hiequent organized around a particular fact of medication safety. OCOMM organizes and
manages CDER response to these campalgns-in the last 18 months alone, OCOMM has.
sent over 2000 emails and letters to 16 diferent campaigns
Social Media and Online Tools OCOMM serves as CDERS public interface in using
muliple digital tools and platforms to provide drug safety outreach and education. The
highlights below reflect 2015-2016 milestones in these communications arenas.
Facebook: CDER became the frst Center to engage the public on FDA's Facebook page,
with 128 drug-related posts reaching over 4 milion Facebook users.
Twitter: COER became the fst FDA Center with à Turter account (FDA Drug Info)
616 Tweets were sent and 40,764 new followers were gained over the last 18 months to
reach a total of more than 200000 Twitter followers. OCOMM organized aná led the fist
CDER Twitter Chat, LungChat. which engaged major oncology organizations, patients
Advocates and health care profesional about lung cancer treatments, and lve-tweeted
three of Center Director Janet Woodcock’ recent Congressonalestimonies
Podcasts: FDA Drug Safety Podcasts provide Drug Safety Communications in audio form
and are available on Tunes and ReachWD radio—46 Drug Safety Podcasts have seen 31,846
transcript visits and 135.388 audio downloads in 2015 and through the fst quarter of 2016.
Webinars: OCOMM hosted 27 webinars over 2015 and to date in 2016, several of which
‘offered information and traning on drug safety programmes and initiatives:
Introduction to Post Marketing Drug Safety Surveillance: Pharmacovigilance in
FDACDER.
Introduction to FDA’ MedWatch Adverse Reporting Programme,
Professional Labeling: The Prescribing Information
FDA Online Drug Information Resources for Students and Clinicians,
Introducing the REMS@FDA Website.
Xow Your Source: Protecting Patients rom Unsafe Drugs
Video:
FDA Drug info Rounds Videos target pharmacists and other health care provider and are
promated to State Board of Pharmacy, pharmacy school, and posted on YouTube. Many of
the Drug info Rounds Videos produced in 2015 and 2016 focus on aspect of drug safety
+ REMSOFDA Tutorial presents the new and improved REMS website called
REMSEFDA
Emergency Preparedness - Keeping Medications Safe discusses the importance of
having a plan in place for keeping medications safe as part of emergency
preparedness
CTI
manages CDER response to these campalgns-in the last 18 months alone, OCOMM has.
sent over 2000 emails and letters to 16 diferent campaigns
Social Media and Online Tools OCOMM serves as CDERS public interface in using
muliple digital tools and platforms to provide drug safety outreach and education. The
highlights below reflect 2015-2016 milestones in these communications arenas.
Facebook: CDER became the frst Center to engage the public on FDA's Facebook page,
with 128 drug-related posts reaching over 4 milion Facebook users.
Twitter: COER became the fst FDA Center with à Turter account (FDA Drug Info)
616 Tweets were sent and 40,764 new followers were gained over the last 18 months to
reach a total of more than 200000 Twitter followers. OCOMM organized aná led the fist
CDER Twitter Chat, LungChat. which engaged major oncology organizations, patients
Advocates and health care profesional about lung cancer treatments, and lve-tweeted
three of Center Director Janet Woodcock’ recent Congressonalestimonies
Podcasts: FDA Drug Safety Podcasts provide Drug Safety Communications in audio form
and are available on Tunes and ReachWD radio—46 Drug Safety Podcasts have seen 31,846
transcript visits and 135.388 audio downloads in 2015 and through the fst quarter of 2016.
Webinars: OCOMM hosted 27 webinars over 2015 and to date in 2016, several of which
‘offered information and traning on drug safety programmes and initiatives:
Introduction to Post Marketing Drug Safety Surveillance: Pharmacovigilance in
FDACDER.
Introduction to FDA’ MedWatch Adverse Reporting Programme,
Professional Labeling: The Prescribing Information
FDA Online Drug Information Resources for Students and Clinicians,
Introducing the REMS@FDA Website.
Xow Your Source: Protecting Patients rom Unsafe Drugs
Video:
FDA Drug info Rounds Videos target pharmacists and other health care provider and are
promated to State Board of Pharmacy, pharmacy school, and posted on YouTube. Many of
the Drug info Rounds Videos produced in 2015 and 2016 focus on aspect of drug safety
+ REMSOFDA Tutorial presents the new and improved REMS website called
REMSEFDA
Emergency Preparedness - Keeping Medications Safe discusses the importance of
having a plan in place for keeping medications safe as part of emergency
preparedness
CTI
MediWath Tips and Tools presents resources aullble o heath care profesional to
make reporting to MedWatch easier than ever.
Breakthrough Therapy discusses the breakthrough therapy designation, an exiting
new programme to expedite drug development while maintaining safety oversight in
the development process (Bronze Tel Award).
FAERS provides background information about the FDA Adverse Event Reporting
System (FAERS) database.
REMS presents the many components of Risk Evaluation and Mitigation Strategies
(REMS) and how they can help manage a drug product with known or potent
+ Disposal of Unuted Medicines discusses cafe medication disposal option.
Drug Safety Communications (DSCs)
Patients, caregivers, health care professionals, and the public ae updated on new drug
safety information with Drug Safety Communications (PSC). These messages. and
“announcements can range from new or emerging risks associated with concurren conditions
(for example, pregnancy or existing Ive or kidney disease), or cautions about potenti
medication erors. DSCs contain actionable recommendations for patients and healthcare
professionals that can help them make more informed decisions, and prevent or mitigate
drugrrelsted harm, DSCS are usual issued in conjunction with regulatory actions such
‘Safety Labeling Changes fr a number of reasons, including issues affecting a large number
of patient, potentially serious or life-threatening adverse events, or medication error that
may result in serious or lie threatening adverse reactions. The Drug Safety Communication
web page i the most visited page on the FDA’ website, Forty-six DSC were isued between
January 1, 2015, and July 26, 2016, and during that time the DSC home page and the 46
individual DSC web pages received over a millon page views. Outreach was significant
‘greater than that, however, as DSCs are much more brasdly culated through a variety of
other channel, including several large Istserved, emai nevaletrs, podcasts, socal and
traditional media, nd targeted outreach to media healthcare professionals, advocacy groups
and other stakeholders
Safety Labeling Changes (SLCs)
New and Improved Access to Safety Information: When a drug is
marketing, not every safety concern or risk potential can be identified. As this report
highlights, postmarket safety oversight is therefore essential to learning more about the
effects of a medicine when used by a large number of people over a long period of time. I
mew safety concems emerge after à medicine is used in a real-world seting, CDER may
require a “Safety Labeling Change” or SLC These changes can focus in one or more specifi
make reporting to MedWatch easier than ever.
Breakthrough Therapy discusses the breakthrough therapy designation, an exiting
new programme to expedite drug development while maintaining safety oversight in
the development process (Bronze Tel Award).
FAERS provides background information about the FDA Adverse Event Reporting
System (FAERS) database.
REMS presents the many components of Risk Evaluation and Mitigation Strategies
(REMS) and how they can help manage a drug product with known or potent
+ Disposal of Unuted Medicines discusses cafe medication disposal option.
Drug Safety Communications (DSCs)
Patients, caregivers, health care professionals, and the public ae updated on new drug
safety information with Drug Safety Communications (PSC). These messages. and
“announcements can range from new or emerging risks associated with concurren conditions
(for example, pregnancy or existing Ive or kidney disease), or cautions about potenti
medication erors. DSCs contain actionable recommendations for patients and healthcare
professionals that can help them make more informed decisions, and prevent or mitigate
drugrrelsted harm, DSCS are usual issued in conjunction with regulatory actions such
‘Safety Labeling Changes fr a number of reasons, including issues affecting a large number
of patient, potentially serious or life-threatening adverse events, or medication error that
may result in serious or lie threatening adverse reactions. The Drug Safety Communication
web page i the most visited page on the FDA’ website, Forty-six DSC were isued between
January 1, 2015, and July 26, 2016, and during that time the DSC home page and the 46
individual DSC web pages received over a millon page views. Outreach was significant
‘greater than that, however, as DSCs are much more brasdly culated through a variety of
other channel, including several large Istserved, emai nevaletrs, podcasts, socal and
traditional media, nd targeted outreach to media healthcare professionals, advocacy groups
and other stakeholders
Safety Labeling Changes (SLCs)
New and Improved Access to Safety Information: When a drug is
marketing, not every safety concern or risk potential can be identified. As this report
highlights, postmarket safety oversight is therefore essential to learning more about the
effects of a medicine when used by a large number of people over a long period of time. I
mew safety concems emerge after à medicine is used in a real-world seting, CDER may
require a “Safety Labeling Change” or SLC These changes can focus in one or more specifi
sections of a drug label including contraindications, warnings and precautions, adverse
reactions, or boxed wamings (widely known as “black box warnings). Although SLCS have
been availabe online for many years, they were aggregated and posted on a monthly basis.
This meant that fa new safety concern was reflected in an approved labeling change early in
a month, that information was not publicly posted until early in the following month—three
to four weeks later As web and database technologies evolved, CDER recognized a need to
apply new digital functionalities that would not only shorten the me between an SLCS
approval and when is safety information becomes avalable on the FDA website, but to
generally enhance an online vistors experience by improving the SLC web platlom's clarity
access and navgabiity
Risk Communications Research
OCOMM houses a number of ongoing research studies that will allow better
understanding of CDER audiences’ knowledge. perceptions, needs, desire, and behaviours
related to a variety of drug safety information. Evidence now being generated will provide
date that can be used to improve CDER communications and expand disseminstion of
coment and materials in order to help target audiences understand the health and safety
information that CDER provides. These research efforts also provide the publ, including
people with limited health Meracy or who face disparities in accessing health services,
opportunites fr input onthe efeciveness of CDER drug safety information, In ate 2015, à
study of medial countermeasures messaging (aunched in 2012) was completed, offering
insight and recommendations for developing effective communication initiatives for public
heath emergencies. A second phase of hs study wil be undertaken in 2016 to test the
study findings. Other OCOMM risk communication research conducted in 2015 and through
aly 2016 includes
+ À study to enhance FDA communications addressing opioids and other potentially
addictive pain medications, scheduled to be completed in 2027.
Research exploring issues of uncertainty and unintended consequences associated
with presion drug communications
A survey projet building on prior focus group research that tests Drug Safety
Communications to better understand consumer recall, understanding of rk, and
behavioural intentions related to OSC content and formating
703 COMMUNICATING WITH REGULATORY AGENCIES, BUSINESS
PARTNERS, HEALTHCARE FACILITIES AND MEDIA
10.3.1 Pharmacovigitance in the Regulation of Medicines
Robust regulstory arrangements provide the foundation for a national ethos of medicine
safety, and for publ confidence in medicines. To be effective, he remit of drug regulatory
reactions, or boxed wamings (widely known as “black box warnings). Although SLCS have
been availabe online for many years, they were aggregated and posted on a monthly basis.
This meant that fa new safety concern was reflected in an approved labeling change early in
a month, that information was not publicly posted until early in the following month—three
to four weeks later As web and database technologies evolved, CDER recognized a need to
apply new digital functionalities that would not only shorten the me between an SLCS
approval and when is safety information becomes avalable on the FDA website, but to
generally enhance an online vistors experience by improving the SLC web platlom's clarity
access and navgabiity
Risk Communications Research
OCOMM houses a number of ongoing research studies that will allow better
understanding of CDER audiences’ knowledge. perceptions, needs, desire, and behaviours
related to a variety of drug safety information. Evidence now being generated will provide
date that can be used to improve CDER communications and expand disseminstion of
coment and materials in order to help target audiences understand the health and safety
information that CDER provides. These research efforts also provide the publ, including
people with limited health Meracy or who face disparities in accessing health services,
opportunites fr input onthe efeciveness of CDER drug safety information, In ate 2015, à
study of medial countermeasures messaging (aunched in 2012) was completed, offering
insight and recommendations for developing effective communication initiatives for public
heath emergencies. A second phase of hs study wil be undertaken in 2016 to test the
study findings. Other OCOMM risk communication research conducted in 2015 and through
aly 2016 includes
+ À study to enhance FDA communications addressing opioids and other potentially
addictive pain medications, scheduled to be completed in 2027.
Research exploring issues of uncertainty and unintended consequences associated
with presion drug communications
A survey projet building on prior focus group research that tests Drug Safety
Communications to better understand consumer recall, understanding of rk, and
behavioural intentions related to OSC content and formating
703 COMMUNICATING WITH REGULATORY AGENCIES, BUSINESS
PARTNERS, HEALTHCARE FACILITIES AND MEDIA
10.3.1 Pharmacovigitance in the Regulation of Medicines
Robust regulstory arrangements provide the foundation for a national ethos of medicine
safety, and for publ confidence in medicines. To be effective, he remit of drug regulatory
authorities needs to go further than the approval of new medicines, to encompass a wide
range of issues relating tothe safety of mecicines, namely.
+ Clinical tas
+ The safety of complementary and traditional medicines, vaccines and biological
+ The development of lines of communication between all parties which have an
interest in medicine safety, ensuring that they are able to function efficient and
In order to achieve ther respective objectives, pharmacoviglance programmes and drug
regulatory authorities must be mutually supporting, On the one hand, pharmacoviglance
programmes need to maintain strong links withthe drug regulatory authorities to ensure
that the latter are well briefed on safety issues in everyday clinica practice, whether these
issues are relevant to future regulatory action or to concerns that emerge in the public
domain, On the other, regulators need to understand the specialzed and pivta role that
pharmacovigiance play in ensuring the ongoing safety of medicinal products
10.3.2 Pharmacovigilance In Practice
CCevivastatin was fist approved asa lipid-egulating agent in 1997. By 2000, a total of 548
cases of rhabdomyolysis associated with crvastain use had been reported to the WHO
Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. Consequently, a
signal wat issued regarding an association between cerhastatn, myopathy and
‘habdomyolysis. In November 1999 in the United States, and in March 2000 in Canada,
precribing information was changed to include a contraindication forthe combined use of
cervastatn and gemfibrozil, another lipidregulating medicine. A similar action was taken in
Australia in February 2001, and a warning issued to alert prescribers to the possibilty of
‘habdomyolysis occurring with al statins. In June 2001, Europe-wide regulatory action was
taken to contraindicate Ihe combined use of cerivastatin and gemfibrozil On 8 August 2001,
the manufacturer voluntarily withdrew cerivastatin from the market on the grounds of an
increased risk of rhabdomyolysis, particularly when used in combination with gemfirozi
10.3.3 Pharmacovigilance in Clinical Practico.
Safety monitoring of medicines in common use should be an integral part of clinical
practice. The degree to which cinians are informed about the principles of
phammacovglne, and practise according to them, has a large impact on the quaity of
heath care. Education and training of health profesional in medicine safe, exchange of
information between natonal pharmacovigiance centres, the coordination of such exchange,
and the linking of clinical experience of medicine safety with research and heath poly, ll
range of issues relating tothe safety of mecicines, namely.
+ Clinical tas
+ The safety of complementary and traditional medicines, vaccines and biological
+ The development of lines of communication between all parties which have an
interest in medicine safety, ensuring that they are able to function efficient and
In order to achieve ther respective objectives, pharmacoviglance programmes and drug
regulatory authorities must be mutually supporting, On the one hand, pharmacoviglance
programmes need to maintain strong links withthe drug regulatory authorities to ensure
that the latter are well briefed on safety issues in everyday clinica practice, whether these
issues are relevant to future regulatory action or to concerns that emerge in the public
domain, On the other, regulators need to understand the specialzed and pivta role that
pharmacovigiance play in ensuring the ongoing safety of medicinal products
10.3.2 Pharmacovigilance In Practice
CCevivastatin was fist approved asa lipid-egulating agent in 1997. By 2000, a total of 548
cases of rhabdomyolysis associated with crvastain use had been reported to the WHO
Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. Consequently, a
signal wat issued regarding an association between cerhastatn, myopathy and
‘habdomyolysis. In November 1999 in the United States, and in March 2000 in Canada,
precribing information was changed to include a contraindication forthe combined use of
cervastatn and gemfibrozil, another lipidregulating medicine. A similar action was taken in
Australia in February 2001, and a warning issued to alert prescribers to the possibilty of
‘habdomyolysis occurring with al statins. In June 2001, Europe-wide regulatory action was
taken to contraindicate Ihe combined use of cerivastatin and gemfibrozil On 8 August 2001,
the manufacturer voluntarily withdrew cerivastatin from the market on the grounds of an
increased risk of rhabdomyolysis, particularly when used in combination with gemfirozi
10.3.3 Pharmacovigilance in Clinical Practico.
Safety monitoring of medicines in common use should be an integral part of clinical
practice. The degree to which cinians are informed about the principles of
phammacovglne, and practise according to them, has a large impact on the quaity of
heath care. Education and training of health profesional in medicine safe, exchange of
information between natonal pharmacovigiance centres, the coordination of such exchange,
and the linking of clinical experience of medicine safety with research and heath poly, ll
Pramacovgance Communion in Pamscoigiance
serve to enhance effective patient cae. A regular flow and exchange of information in this
way means that national pharmacogilance programmes are ideally paced to identify gaps
in ourunderstanding of medicine induced diseases.
10.3.4 Pharmacovigilance in Disease Control Public Health Prot
The monitoring of medicine safety in countries where there is no regulatory or safety
monitoring system in place, or in remote areas with litle or no health care survelance or
infrastructure, has been identified as a matter for concem. The problems are especialy
apparent in situations that involve the use of medicines in pectic communities, for example,
for the treatment of tropical diseases such as malaria ishmanioss and schistosomiasis, and
for the treatment of HIVAIDS and tuberculosis. In some settings several disease control
iniativos invoking the administration of medicines to large communities are being
implemented within the same population wit litle knowledge of, or regard to, how these
Various medicines could interact with each other, Pharmaconiglance should be a priority for
every country with a pubic health disease control programme
Malaria an example of pharmacavigilance in pubic heath In view of the increasing
resistance to existing antimalarial medicines, several counties have Switched to Using
Combinations of various artemisinin derivatives as her frst- and second-ine treatment fr
malaria. The change to artemisinin combination therapies (ACTS) has provided a timely
‘opportunity to introduce a pharmacoviglance system in those countries that hitherto had no
established systems for safety monitoring of medicine. In 2003, participants from five
African counties were trained in the basic methods of medicine safety monitoring with à
view to faiitating the introduction of à common system of pharmacoviglance for new
Antimalrlal treatments. Since then ‘wo of these counties have formally established à
pharmacovigilarco contre; the others are also making progress in monitoring antimalarial
medicines
404 COMMUNICATING THE OUTCOME OF PHARMACOVIGILANCE |
I is not sufficient for the experts to be satisfied with the safety evidence for a given
medicine. The public perception of the hazards associated with medicines is an equally
important factor. How safe is safe enough? Which risks ore acceptable? These are critical
questions that providers of mediines need to consider when communicating with patients
and the general public. The pharmaceutical industry, governments and health-care providers
have a cuy to buld public trust through effective communication of ik Tis can only be
achieved once the public mindset has been examined and fully understood. Available
methods for communicating messages about the safety of medicines are listed in Table 12.
Medical journals and websites maintained by national agencies are other methods of
communication, The choice of method employed tends to depend on the urgency and
seriousness ofthe issue in question
serve to enhance effective patient cae. A regular flow and exchange of information in this
way means that national pharmacogilance programmes are ideally paced to identify gaps
in ourunderstanding of medicine induced diseases.
10.3.4 Pharmacovigilance in Disease Control Public Health Prot
The monitoring of medicine safety in countries where there is no regulatory or safety
monitoring system in place, or in remote areas with litle or no health care survelance or
infrastructure, has been identified as a matter for concem. The problems are especialy
apparent in situations that involve the use of medicines in pectic communities, for example,
for the treatment of tropical diseases such as malaria ishmanioss and schistosomiasis, and
for the treatment of HIVAIDS and tuberculosis. In some settings several disease control
iniativos invoking the administration of medicines to large communities are being
implemented within the same population wit litle knowledge of, or regard to, how these
Various medicines could interact with each other, Pharmaconiglance should be a priority for
every country with a pubic health disease control programme
Malaria an example of pharmacavigilance in pubic heath In view of the increasing
resistance to existing antimalarial medicines, several counties have Switched to Using
Combinations of various artemisinin derivatives as her frst- and second-ine treatment fr
malaria. The change to artemisinin combination therapies (ACTS) has provided a timely
‘opportunity to introduce a pharmacoviglance system in those countries that hitherto had no
established systems for safety monitoring of medicine. In 2003, participants from five
African counties were trained in the basic methods of medicine safety monitoring with à
view to faiitating the introduction of à common system of pharmacoviglance for new
Antimalrlal treatments. Since then ‘wo of these counties have formally established à
pharmacovigilarco contre; the others are also making progress in monitoring antimalarial
medicines
404 COMMUNICATING THE OUTCOME OF PHARMACOVIGILANCE |
I is not sufficient for the experts to be satisfied with the safety evidence for a given
medicine. The public perception of the hazards associated with medicines is an equally
important factor. How safe is safe enough? Which risks ore acceptable? These are critical
questions that providers of mediines need to consider when communicating with patients
and the general public. The pharmaceutical industry, governments and health-care providers
have a cuy to buld public trust through effective communication of ik Tis can only be
achieved once the public mindset has been examined and fully understood. Available
methods for communicating messages about the safety of medicines are listed in Table 12.
Medical journals and websites maintained by national agencies are other methods of
communication, The choice of method employed tends to depend on the urgency and
seriousness ofthe issue in question
40.5 WHO PROGRAMME FOR INTERNATIONAL DRUG MONITORING
As a means of pooling existing data on ADRs, WHO's Programme for International Drug
Monitoring was started in 1968. Ina a plot project in 10 countries with established
national reporting systems for ADRS, the network has since expanded sigailiantly as more
countries worldwide developed national pharmacoviglance centres for the recording of
ADRS, Currently, 86 countries participate in the programme, which coordinated by WHO
ther wth is collaborating centre in Uppsala, Sweden (Fi. 1.2). The cllaborating centre
s responsible for maintaining the global ADR database, Vigihase At present the database
contains more than tree millon ADR report. The WHO Collaborating Centre analyses the
reports in the database to
identify early warning signals of serious adverse reactions to medicines
+ Gralate the hazard
+ Undertake research into the mechanisms of action to aid the development of safer
and more efectire medicines
Through an advisory committee, WHO plays an important rl in the provision of expe
advice on all matters relating to the safety of medicines. The Committee alo exits
facilitate consistent polices and action among member countries and to advise those who
‘may be concerned about ation taken in another country. The success of WHO's Internationa
Drug Monitoring Programme is entre dependent on the contibutions of national
phamacoviglance centres Such centres provide an essential pool of experience and
Competence which has been instrumental in the continuous development of the WHO
programme and of pharmacovigiance as à whole. Ideally every county should have à
As a means of pooling existing data on ADRs, WHO's Programme for International Drug
Monitoring was started in 1968. Ina a plot project in 10 countries with established
national reporting systems for ADRS, the network has since expanded sigailiantly as more
countries worldwide developed national pharmacoviglance centres for the recording of
ADRS, Currently, 86 countries participate in the programme, which coordinated by WHO
ther wth is collaborating centre in Uppsala, Sweden (Fi. 1.2). The cllaborating centre
s responsible for maintaining the global ADR database, Vigihase At present the database
contains more than tree millon ADR report. The WHO Collaborating Centre analyses the
reports in the database to
identify early warning signals of serious adverse reactions to medicines
+ Gralate the hazard
+ Undertake research into the mechanisms of action to aid the development of safer
and more efectire medicines
Through an advisory committee, WHO plays an important rl in the provision of expe
advice on all matters relating to the safety of medicines. The Committee alo exits
facilitate consistent polices and action among member countries and to advise those who
‘may be concerned about ation taken in another country. The success of WHO's Internationa
Drug Monitoring Programme is entre dependent on the contibutions of national
phamacoviglance centres Such centres provide an essential pool of experience and
Competence which has been instrumental in the continuous development of the WHO
programme and of pharmacovigiance as à whole. Ideally every county should have à
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