Studies of vaccine safety (Pharmacoepidemiology) V PharmD
SELECTED SPECIAL APPLICATIONS
(Doctor of Pharmacy)
SELECTED SPECIAL APPLICATIONS OF
Studies of vaccine safety
Pharmacoepidemiology and risk management
Drug induced birth defects.
STUDIES OF VACCINE SAFETY
STUDIES OF VACCINE SAFETY
Importance of vaccine safety
Methods of monitoring vaccines safety
Casual link between ADE and Vaccine
Ad Hoc Epidemiologic Studies
Automated Large-Linked Databases
Role of Immunization provider
A vaccine is a biological preparation that improves
immunity to a particular disease.
Vaccines are among the most cost-effective and prevalent
public health interventions.
Morbidity & mortality declined where immunizations are
Vaccine safety is prime for:
- Immunization providers
- Recipients of vaccines
No vaccine is completely safe or completely effective, while
all known vaccine adverse events are minor and selflimited, some vaccines have been associated with rare but
serious health effects.
Knowledge and research capacity has been limited by:
Inadequate understanding of biologic mechanisms
underlying adverse events.
Insufficient information from case reports & case series.
Limitations of existing surveillance systems to provide
evidence of causation.
To overcome these limitations:
Epidemiology is vital in providing scientific methodology
for assessing vaccine safety.
IMPORTANCE OF VACCINE SAFETY
Decrease in disease risks and increased attention on vaccine
Public confidence in vaccine safety is critical
- Higher standard of safety.
- Vaccines are generally healthy.
- Lower risk tolerance= Need to search for a rare reaction
- Vaccination is universally recommended and mandated.
Ongoing safety monitoring needed
for the development of the sound
policies and recommendations.
METHODS OF MONITORING VACCINES SAFETY
There are two methods of monitoring vaccines:
Vaccines like other pharmaceutical products,
undergo extensive safety and efficacy evaluations
in the laboratory.
Pre-licensure studies are carried out on :
If the vaccine is shown to be safe and effective
in Phase- III, the manufacturer applies for a
license from the FDA.
The FDA licenses the vaccine itself and
licenses the manufacturing plant where the
vaccine will be made.
During the application, FDA reviews:
The clinical trials results
The manufacturing plant
The manufacturing protocol
Identifies rare reactions
Monitor increases in known reactions
Identify risk factors for reactions
Identify vaccine lots with unusual rates or types of events
• Phase IV studies can be an FDA
requirement for licensure.
• These trials include tens of
thousands of volunteers and may
address questions of long-term
examine unanswered questions
identified in Phase III clinical
Adverse events following
vaccination can be classified
Frequency (Common, Rare)
Causality and Preventability
(Intrinsic to vaccine, faulty
production or faulty administration)
Adverse events are divided after vaccinations into:
3. Programmatic error
Due to intrinsic characteristic of the vaccine preparation & individual
response of the vaccine, these events would not have occurred without
E.g., vaccine-associated paralytic poliomyelitis after oral polio vaccine.
Would have occurred anyway, but were precipitated by the vaccination.
E.g., first febrile seizure in a predisposed child.
3. Programmatic error
Due to technical errors in vaccine preparation, handling, or
Associated temporally with vaccination by chance or due to
Assessment Of Causality
Analyses, Confounding & Bias
1. SIGNAL DETECTION
Vaccines are biologic rather than chemical in nature.
Variation in rate of adverse events by manufacturer or even lot
might be expected.
Surveillance systems need to detect such potential aberrations in
a timely manner.
Many vaccinations are administered to individuals:
simultaneously or as combination vaccine, unless the number of
persons who also receive that exact permutation of vaccine
exposures is known, it may be difficult if not impossible to know if
an aberration has occurred.
Vaccine safety surveillance systems:
Examine multiple exposures (e.g., different vaccine antigens,
manufacturers, lot numbers) and multiple disease outcomes.
Monitor both previously known and previously unknown adverse
2. ASSESSMENT OF CAUSALITY
Vaccine-specific clinical syndrome. e.g.myopericarditis in
healthy young adults - smallpox vaccine : must be identified
for assessing any adverse event caused by vaccine.
Information useful for assessing causality in individual case
1. Previous general experience with vaccine
Duration of licensure
Number of vaccinees, whether similar events have been observed
among other vaccinees or nonvaccinees
2. Alternative etiologies.
3. Individual characteristic of the vaccinees that may increase
the risk of the adverse event.
4. Timing of events.
5. Characteristic of the event (e.g., laboratory findings)
Misclassification of exposure status occur if there is poor
documentation of vaccinations.
Increases in number of licensed vaccines
Relative lack of combination vaccines
Leads to vaccination history misclassifications.
• Events being assessed are frequently extremely rare
(e.g., encephalopathy, GBS).
• So identifying cases for interpretation of study findings is a
• Many adverse events caused by vaccines are poorly defined
clinical syndromes.(e.g., encephalopathy,GBS)
• The poor understanding & lack of diagnostic tools for these
syndromes limits clinical & epidemiologic studies of these
5. ANALYSES, CONFOUNDING & BIAS
Since vaccines can lead to series of outcomes, cohort studies
can be considered.
In this adverse events & person-time risks are evaluated.
When outcomes are rare, these studies become time
consuming and expensive.
Case-control studies are also carried out in case of rare
Once a vaccine is licensed, it is unethical to withhold the
vaccine in subsequent randomized trials as a means to
minimize confounding and bias.
To minimize recall bias, it is best to rely on data sources
that gather information on outcomes and vaccine exposure
AD HOC EPIDEMIOLOGIC STUDIES
Ad hoc epidemiologic studies are employed to assess signals
of potential adverse events caused by :
Spontaneous reporting systems
Cohort, case–control studies : used to gather information to
measure or compare risks of an adverse event following
vaccination with risk in the absence of vaccination.
AUTOMATED LARGE-LINKED DATABASES
Automated large-linked databases provide a more costeffective and flexible framework.
Ad hoc epidemiologic studies is needed in settings without
automated large-linked databases or where the power of
the automated large-linked databases may be inadequate
to answer a question in a timely manner.
Eg: VSD by CDC
VACCINE SAFETY DATALINK(VDC)
In 1990, CDC established the Vaccine Safety Datalink
(CDC) project to improve scientific understanding of
This project involves partnerships with 10 large managed
care organizations(MCOs) to monitor vaccine safety.
Each participating organization gathers data on
vaccination (vaccine type, date of vaccination) , medical
outcomes(outpatients visits, inpatients visits, urgent care
visits), birth data and census data.