Vaccine safety surveillance

Vaccine Pharmacovigilance
• Definition- According to the CIOMS/WHO working group on
vaccine pharmacovigilance, Vaccine pharmacovigilance 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 effect of the vaccine or immunization.
 Adverse event following immunization
(AEFI)
Definition
• An AEFI is any untoward medical occurrence which follows
immunization and which does not necessarily have a causal
relationship with the usage of the vaccine. The adverse event
may be any unfavourable or unintended sign, abnormal
laboratory finding, symptoms or disease.
 Importance of vaccine safety

• Decreases in disease risk and increased attention on vaccine

risks

• Public confidence in vaccine safety is critical

• Low tolerance for vaccine risks

• – Higher standard of safety is expected
• – Vaccines generally healthy
• – Lower risk tolerance = need to search for rare reaction
 Terminology

– AEFI: adverse events following immunisation, without

necessarily having a causal relationship with the usage
of vaccine
– Immunisation: the process of making a person immune
– Vaccination: administration of a vaccine
 Steps of vaccine pharmacovigilance

• Detect signal suggesting AEFI is related to vaccine.

• Develop hypothesis about causal association between

an AEFI and vaccination

• Test hypothesis through appropriate epidemiological

method
• Nationally against 9 diseases
– Diphtheria
– Pertussis
– Tetanus
– Polio
– Measles
– Rubella
– severe form of Childhood Tuberculosis, Hepatitis B and Meningitis
& Pneumonia caused by Hemophilus Influenza type B
• Sub-nationally against 3 diseases –
– Rotavirus diarrhoea
– Pneumococcal Pneumonia
– Japanese Encephalitis;
of which Rotavirus vaccine and Pneumococcal Conjugate vaccine are in
process of expansion while JE vaccine is provided only in endemic districts.
• Other vaccines......
•  Pneumococcal vaccine
•  Rotavirus vaccine
•  Hepatitis A
•  MMR
•  Influenza
•  Meningococcal
•  Cholera
•  JE
•  HPV
•  Varicella
•  Typhoid
 Source for vaccine safety

• Local health workers

• Health education campaigns
• Visiting experts
• Online resources and communication network
• Religious and/or community leader
• Parents, guardians and vaccine
• Radio and television
• printed material
• Video or DVD
 Which AEFIs should be reported?
• Serious AEFI

• Signal and events associated with newly introduced vaccine

• AEFI that may have been caused by an immunization error

• Significant events of unexplained cause occurring within 30

days after a vaccination

• Swelling, redness, soreness at the injection site IF it lasts for

more than 3 days or swelling extended beyond nearest joint
 Classification of AEFIs

• Vaccine product-related reaction – An AEFI that is caused or

precipitated by a vaccine due to one or more of the inherent
properties of the vaccine product. Extensive limb e.g. swelling
following DTP vaccination.

• 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 inducing its administration
device as provide by the manufacturer.

– Ex. Failure by the manufacturer to completely inactivate a lot of

inactivated polio vaccine leads to cases of paralytic polio
• Immunization error-related reaction – An AEFI that is caused
by inappropriate vaccine handling, prescribing or
administration.
 Ex. Transmission of infection by contaminated multidose vial.

• Immunization anxiety-related reaction – An AEFI from

anxiety about the immunization.
e.g. Vasovagal syncope in an adolescent following vaccination.
• Coincidental event- An AEFI that is caused by something
other than the vaccine product, immunization error or
immunization anxiety.

– e.g. A fever after vaccination (temporal association) and malarial

parasite isolated from blood
Two type of vaccine reaction-
• Minor reaction
• Severe reaction
Minor reaction
• Usually occur within a few hours of injection.
• Resolve after short period of time and pose little danger.
• Local (includes pain, swelling or redness at the site of
injection).
• Systemic (includes fever, malaise, muscle pain, headache or
loss of appetite).

Severe reaction
• Usually do not result in long-term problems.
• Can be disabling
• Are rarely lives threatening
• Include seizures and allergic reactions caused by the body’s
reaction to a particular component in a vaccine.
Elements consider when conducting Vaccine Pharmacovigilance

• Usually administered healthy Patients

• Vaccine may be administered to birth cohort (Specific

population) or to groups at high risk for disease complication

• Sub population may be more susceptible for certain AEFI’s

• The age at that time of immunization may coincide with the

emergence of some age related disease
• Immunization with certain vaccine is mandate in some
countries

• Benefit of immunization may not be visible immediately

particular if target disease incidence is low

• Due to low acceptance of risk, intensive investigation of

serious AEFI, even if rare is necessary

• Non serious AEFI should be carefully monitored because they

may signal a potential large problem with vaccine
• Appropriate methods are needed to detect and assess any
potential association of serious, rare, delayed adverse event

• Consideration of dechallenge and rechallenge differ for

vaccine compared to other medicine

• Vaccine are often administered concomitantly with other

vaccine making attribution to a specific vaccine difficult

• A vaccine are complex biological products may include

antigen, live organism, adjuvant, preservatives. Each
component may have unique safety implications.
• The administered of live vaccines can lead to disease caused
by the attenuated organism in vaccine. This should be
differentiated from coinciding natural infection

• New vaccine increasing based on new production and

administered technology – necessity safety monitoring system

• Depending on mode and extent of use of vaccine, it may elicit

degree of HERD immunity to specific disease. When assessing
the risk-benefit of vaccine, herd immunity effects as well as
individual protection need to be taken into account.
 Vaccination failure

• Definition : May be defined on clinical endpoints or

immunological criteria, where correlates or surrogate marker
for disease protection exist

• Primary failure – Lack of seroconversion ( lack of developing

antibody) or seroprotection

• Secondary failure – waning Immunity (less immunity)

• Vaccine failure due to vaccine failure and failure to vaccinate
(Not administered)

• Vaccine failure are two types i.e Vaccinee related (Host

related) and Vaccine related
Vaccinee related (Host related)

• Immunodeficiency

• Age related maturation and difference of immune responsiveness

• Insufficient or suboptimal immune response

• Interfere due to other infections agents

• Warning immunity (Decreasing immunity)

• Suboptimal health status

• Immunological interference

• Pre existing infection with pathogen targeted the vaccine

• Immunosuppressive therapy
Vaccine related

• Vaccine is not 100% efficacious against included antigen

• Incomplete coverage of strain, serotypes, genotypes, antigenic

variants or escape mutants that can cause a vaccine
preventable disease

• Antigenic interference or other vaccine- vaccine interactions

in case of co-administered vaccines

• Manufacturing related (Quality/defects/batch variations)

Failure to vaccine
Two types : Usage and immunization program related
issues
Usage Issue
• Administration error (Wrong/suboptimal dose/incorrect
diluents)
• Vaccination series incomplete
• Non compliance with recommended schedule
• Lack of recommended booster vaccination
• Storage related
• Vaccine beyond expiry date used
Immunization program related issue

• Suboptimal recommendation regarding number and time

points of primary/booster vaccination

• Shortage of vaccine leading to no or incomplete vaccination

AEFI Frequency terminology
Vaccine Evaluation

Pre-licensing
• Randomized, Blinded, Controlled Clinical Trials
• Vaccine efficacy: Protective Effect under Idealized Conditions
• RCT: controlled experiments, simple interpretation

Post-licensing
• Observational Studies
• Vaccine effectiveness
• Protective Effect under Ordinary Conditions of a public health
programme
• Prone to bias, more complex interpretation
 Pharmacovigilance methods

Objectives:

• To establish a functional reporting system to monitor

the safety of all medicines

• To learn more about the safety profile of new

medicines in the early post-marketing phase

• To learn more about the ADR profile of a specific

medicine(s) in your population
Cont…

• To estimate the incidence of a known ADR to a

specific medicine in your population

• To gather more information on the safety profile of a

new chemical entity in early post-marketing phase

• To make use of existing electronic health records and

registries to support pharmacovigilance activities
Methods
• Passive surveillance
Spontaneous reports
Case series
• Stimulated reporting
• Active surveillance
Sentinel sites
Drug event monitoring
Registries
• Targeted clinical investigations
• Comparative observational studies
Cross sectional study
Case control study
Cohort study
• Descriptive studies
Natural history of disease
Drug utilization study
 Spontaneous Reports
• A communication by consumers or healthcare professionals to
a company or Regulatory Authority, that describes one or more
ADR in a patient, who has given the drug.

• It plays a major role in the, identification of safety signals

once the drug is marketed.

• Gives alerts on rare AEs that were not detected in earlier

clinical trials or pre marketing studies.

• Provides important information on at risk groups, risk factors

and clinical features of known serious ADRs.
Case series
• Series of case reports can provide evidence of an
association of a drug and AEs.

• Generally more useful for generating hypothesis than

for verifying an association between drug exposure and
outcome.

• Certain distinct adverse events occur more frequently

with drug therapy, such as anaphylaxis, aplastic anemia
and Stevens-Johnson syndrome events such as these
are spontaneously reported for detailed and rapid
follow-up.
 Stimulated Reporting
• A method used to encourage and facilitate reporting
by health professionals for new products, or for
limited period.

• Online reporting of AE, systematic stimulation of

reporting of AEs.

• Drawbacks- data are often incomplete. Not useful to

generate accurate incidence rates.
Active surveillance

• To ascertain completely the no. of AEs via a

continuous pre-organized process.
– E.g. follow up of patient treated with a particular drug.

• More feasible to get comprehensive data on

individual AE reports.
Sentinel Sites

• Active surveillance carried out at Institutions,

Nursing Homes and Hospitals etc. provides
information such as data from specific patient
subgroups, drug abuse etc.
Drug Event Monitoring
• Patients are identified by electronic prescription data
or automated health insurance claims.

• A follow up questionnaire can be sent to each

physician or patient at specified intervals.
Information on patient demographics, indication for
treatment, duration of therapy, dosage, clinical events,
and reasons for discontinuation can be included in the
questionnaire.
Registries

• A registry is a list of patients presenting with same

characteristics.
– E.g. Disease registry, drug registry, pregnancy registry etc.
Differs from each other depending on type of patient.
Comparative Observational Studies

• Traditional epidemiologic methods are a key

component in the evaluation of AEs.

• Observational study designs are useful in validating

signals from spontaneous reports or case series.
Cross Sectional Studies

• Data collected from a population of patients at a

single point in time regardless of exposure or disease
status.

• Primarily used to gather data for surveys or for

ecological analysis. Best used to examine the
prevalence of a disease at one time point or to
examine trends over time, when data for serial time
points can be captured.
Case Control Study:

• In this case of disease are identified. Controls

or patients without the disease or event of
interest, are selected from the source
population.
• Exposure status of the two groups is compared
using the odds ratio.
Cohort Study

• A population at risk for the disease is followed over a

time for the occurrence of the disease or events.
Information on exposure status is known throughout the
follow up and hence incident rates can be calculated.

• Comparison cohorts of interest are selected on the basis

of drug use and followed over time. Multiple AEs can
also be investigated using the same data source in a
cohort study
 Targeted Clinical Investigations
• When significant risks are identified from pre-approval
clinical trials, further clinical studies might be called, to
evaluate the mechanism of action for ADRs.

• PK and PD studies might be conducted.

• Specific studies to investigate potential drug-drug interactions

and food-drug interactions might be called.
Descriptive Studies
• Primarily used to obtain the background rate of
outcome events and/or to establish the prevalence of
the use of drugs in specified populations.

• Natural History of Disease- Focused on the natural

history of disease, including the characteristics of
diseased patient and the distribution of disease in
selected populations, as well as estimating the
incidence and prevalence of potential outcomes of
interest.
Drug Utilization Study

• These studies provide data on specific populations,

such as the elderly, children, or patients with hepatic
or renal dysfunction, often stratified by age, gender,
concomitant medication, and other characteristics.
Communication in Pharmacovigilance
 Principles of Good Pharmacovigilance Communication

• Relate the messages to the audience’s perspective

• Avoid comparisons which trivialize the concern
• Ensure completeness of the message
• Be balanced, honest and sympathetic
• Focus on the specific issue that needs to be handled
• Pay attention to what the audience already knows
• Be respectful of people’s right to be concerned
• Be honest about the limits to scientific knowledge
• Acknowledge uncertainty
• Evaluate the impact of your message
Effective Communication in Pharmacovigilance
• One can achieve effective way of communication just by
following the principles of good pharmacovigilance
communication.
Why do we need to improve our communication?
• Improve patient care and understanding
• Eradicate disease / improve disease control
• Promote transparency and accountability

Why do Communications matter in Drug Safety?

• For Welfare of millions of people worldwide
• To overcome Extreme dangers of failure
• Communications are commonly poorly executed,
second-rate and ineffective, so to improve the quality.
Communication Challenges:
• The importance of ADRs and reporting them
• Information about benefit – harm and effectiveness –
risk
• Encouraging rational drug use/adherence
• Communicating uncertainty
• Dealing with traditional beliefs and practices
• Involving patients; reaching informed consent
• Preventing or resolving crises
 Problematic issue in Drug Safety: all reliant on
communications for safety

• Adverse effects: ‘no drug 100% safe’

• Risk as a concept in medicine
• Safety and medicines (prescribing, dispensing)
• Benefit-harm
• Effectiveness-risk
• Public health and commercial goals
• Public health and individual welfare
• Access to medicines
• Uncertainty
What is an Effective Communication?
 Communication with Media
Who are the media?
• Print -magazines, newspapers, community
newspapers
• Electronic -radio, TV, internet
• Local and national levels
Some basic questions a reporter will ask you….
• WHO-is affected, responsible
• WHAT-has happened and what is being done about it
• WHERE-has it happened
• WHEN-did it happen
• WHY-did it happen
• WILL-it happen again
Communications practices to avoid
 “Spinning”! (distortion or decoration of facts for beneficial effects)

 All communications are subjective, but do not be manipulative or dishonest

 Avoid “No comment”–rather say why there’s nothing to say and what is
being done

 Avoid confusing statistics

 Do not avoid taking responsibility

 Don’t attack the messenger/accuser

 Don’t deny, justify or excuse your mistakes