Phase III and Phase IV Clinical Studies of Vaccine Candidates

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Phase III and Phase IV Clinical Studies of
Vaccine Candidates
Module 5 Vaccines PHB 4498
Joseph B. McCormick, M.D., M.S. 2004
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Iterative Steps to a Vaccine
Vaccine
Manufacture
Pivotal-Phase 3 trail
Phase 1, 2 trails
Pilot Lots
Preclinical
Process development
Pathogenesis
Basic Research
Epidemiology
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Stages of a Clinical Development Program for a
Vaccine
Phase I
Phase II
Phase III
Phase IV

• Safety
• Immunogenicity
• Proof of Principle
• N ? 50

Safety Immunogenicity Dose ranging Schedule N100
s
Pivotal Licensure Studies Safety Immunogenicity Ef
ficacy Endpoint Specific Sample Size?
Postmarketing Studies Safety Surveillance 2
endpoints Effectiveness N gt 10,000s
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Preparation of Phase III study

• Objectives of a Phase III
• To measure vaccine protective efficacy in
  intended target population(s) by comparison of
  infection and/or disease attack rates in vaccine
  and placebo recipients
• Importance of a Phase III
• must be conclusive Must measure efficacy of
  vaccine candidates already proven safe and
  immunogenic
• must be performed in target populations
• time-consuming (person-hours) long duration
  (months, years) expensive
• as little as possible left to external events
  and chance

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Epidemiology and Phase III Studies

• identification of study site and population
• choice of the type of study
• choice of the time period for study
• case definition in the choice of outcomes
• case finding
• identification of potential bias and effect
  modifiers
• estimation of sample size
• estimation of the duration of study

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Identification of study sites and populations (I)

• Objectives
• To identify a geographical area
• endemic for the disease and stable (population
  politics)
• And a target population
• at risk for the disease/infection AND responsive
  to the vaccine
• Where rigorous and robust prospective studies can
  be performed
• on-site investigatorsMinistry of Health
  laboratory and human resources logistic

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Identification of study sites and populations (II)

• Review of existing literature
• published work or unpublished reports
• Consultation with local key-epidemiologists and
  /or public health deciders
• local clinical experience (age group clinical
  signs)
• surveillance system (organisation)
• Possibilities
• existing data on site retrospective analysis
• data not available or insufficient new
  epidemiological studies will be needed

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Identification of study sites and populations
(III)

• Retrospective analysis of existing data
• gives an immediate estimation of morbidity
  (age-specific incidence) and mortality,
  seasonality, geographical variations
• BUT
• often only clinical diagnosis (e.g. typhoid,
  malaria)
• often done in sentinel centres that may not
  include the potential site
• Often incomplete (population census)
• SOMETIMES EXTREMELY VALUABLE
• e.g. surveillance of meningitis in Europe
  (age-specific and serotype-specific)
• e.g. Dengue Hemorrhagic Fever in Puerto Rico

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Identification of study sites and populations (IV)

• Data not available and/or not reliable
• Cross-sectional surveys (e.g. dengue malaria)
  age-specific seroprevalence of infection
• no information on ratio of
  infection/disease, or seasonality
• hospital-based studies (e.g. typhoid)
• indirect marker of the importance of
  disease
• selection bias more severe patients
• prospective studies
• usually too expensive for this step

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Preparation of Phase III type of study

• Gold standard
• Randomised double-blind placebo-controlled study
• Others
• Case-control, case-contact, non-randomised
  cohort studies
• rare disease (Japanese Encephalitis
  Hennessy et al., 1996)
• large epidemics (cholera Trach et al.,
  1997)

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Choice of the time period Estimation of duration

• seasonality
• e.g. malaria in The Gambia is highly seasonal
  with nearly all cases during the 6-month period
  of rainy season
• vaccination during the dry season and follow-up
  during the rainy season (dAlessandro et al.,
  1995)
• frequency of the disease
• e.g. severe dengue is a rare event
• study of 2 years or more

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Case definition and outcome (I)

• Which main outcome?
• Infection ? (e.g. measles)
• Disease? (e.g. tetanus)
• Severe case ? (e.g. malaria dengue)
• Which case definition ?
• In clinical practice, confirmation is not always
  necessary for the treatment of patients.
• BUT
• In phase III only confirmed cases can be counted
  in the analysis
• e.g. typhoid, malaria, dengue, S.pneumoniae

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Case definition and outcome (II)

• Which site-specific case definition?
• e.g. malaria case definition depends on level of
  endemicity
• The Gambia fever parasitaemiagt6,000/?l
  (dAlessandro et al., 1995)
• whereas in Thailand fever parasitaemia
  (without cut-off point) (Nosten et al., 1996)
• Which site-specific differential diagnosis?
• e.g. typhoid and malaria in Kenya
• e.g. typhoid and dengue in Vietnam

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Case definition and outcome (III)

• Confirmation of the diagnosis
• isolation of infectious agents by culture
• PCR species and serotype-specific
• On-site issues in the confirmation of diagnosis
• amount of blood capillary vs venous puncture
• logistic transport, process, storage of samples
  
• Note
• pre-phase III studies aim at providing a clear
  case definition and at testing and finding the
  easiest method for confirmation of cases.

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Preparation of Phase III prospective studies (I)

• The objectives of a cohort study prior to the
  Phase III are
• to optimise case finding and case confirmation
• to estimate the incidence of the main outcome
• to estimate the drop-out rate
• to identify potential bias and confounders
• Design prospective follow-up of the targeted
  population for a minimum of one year.

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Preparation of Phase III prospective studies (II)

• Case finding
• rare and severe disease passive case detection
  hospital network
• mild disease passive case detection general
  practitioners, primary health centres,
  home-visitors
• infection active case detection schools
  teachers, home visitors.
• Case confirmation
• study on sensitivity and specificity of clinical
  and laboratory findings

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Preparation of Phase III prospective studies
(III)

• Incidence and drop-out
• Numerator, counting cases (case finding)
• denominator from enrollment to outcome or
  withdrawal or death.
• Regular and uniform follow-up (daily
  weekly monthly)
• Identification of risk factors
• for further analysis of sub-groups
• questionnaires/ clinical/laboratory measures of
  exposure factors and their relationship with
  outcome

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Estimation of sample size

• incidence of the outcome in the study population
• from pre-vaccine prospective study
• Expected protective efficacy
• from previous phases and experts consensus
• Power confidence level of the study
• table with various power and confidence level
• Drop-out
• from pre-vaccine prospective study

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Oversight and Safety Data Monitoring During
Clinical Development
Phase I
Phase II
Phase III
Phase IV
IRB OPRR IND FDA Safety Reports
IRB OPRR IND FDA Safety Reports
Postmarketing Studies VAERS Govt. Studies Company
studies Case reports IOM Reviews Press Interest
groups Parents/Vaccine FDA/CDC/NIH Physician Compa
ny NVICP
IRB OPRR IND FDA AE profile SAEs
Investigators Nurse Clinical Monitor Company
Statistician Medical Monitor Independent
Monitor QA/OC Peer review
Safety Monitoring Committee Or Data
Safety Monitoring Board
DSMB
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Model of Net Cash Flow Over Product Lifetime
Phase IV

Preclinical
Clinical
-
Phase I
Phase II
Phase III
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Detection of Rare Events
1000 100 10 1 0.1 0.01 0.001
Risk per thousands
1 10 100 1000
10, 000 100,000 1,00,000
Number of subjects
Sample size needed to reduce the maximum true
proportion to a certain level when no adverse
event is observed (p0.05) Gedde-Dahl TW, NIPH
Annals, 14.92-93,1991
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Overview Data Collectionand Data Management

• Collecting data is the primary activity of
  research
• Must be relevant
• Collect only what you trust and will evaluate
• Must be practical and simple
• Precise and accurate (reproducible)
• Verifiable
• Permanent record
• timely

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Data Collectionand Data Management

• Translates information of different types
• to standardized formats (data elements)
• Creates a verifiable permanent record
• Contains all elements for data analysis
• Essential for study management and
• subject tracking

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Who Uses Data(Both Interim and Final Reports)

• Principle Investigator
• Data analysis personnel (Biostatistician,
• Programmers, Data managers)
• Research personnel (Nurses, other investigators
  and monitors)
• IRB, DMSC, Regulatory agencies
• Sponsors

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Good Clinical Practice
A standard for the design, conduct, performance,
monitory, auditing, recording, analysis, and
reporting of clinical trials that provides
assurance that the data and reported results are
credible and accurate, and that the rights,
integrity and confidentiality of trial subjects
are protected.
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Creation of Good ClinicalPractices Guidelines

• Impetus from the international conference on
  harmonization (ICH)
• A collaborative collaboration between government
  and industry in U.S., Japan and the European
  union
• Goal to facilitate mutual acceptance of data from
  clinical trials by improving quality and
  standardization
• Involves human subjects guarantees
• FDA has adopted and is committed to implementing
  the harmonized tripartite guidelines for GCP
  published in the federal register in May, 1997

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Essential Elements in DataManagement

• Standard operating procedures (sops)
• Case report forms (data collection instruments)
• Data dictionary
• Computer files
• QA- Validity checks
• Data analysis plan

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Need to diagram all subject Contacts, sources of
data, And create a data collection Flow chart
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Data Collection Forms(CRF)

• Essential study component (often multiple CRF per
  subject, e.g. clinical, lab, epi)
• Design to parallel protocol objectives
• Be simple and graphically clear
• Coordinate entry of all clinical,
• epidemiologic and lab data components
• (linkage usually by common ID number)

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CRF Elements

• Make precise definitions
• Time periods
• During the 2 weeks prior to evaluation, were any
  antibiotics given? Vs. were any antibiotics
  given?
• Specify Terms
• Define what is an antibiotic?
• Specify Units
• Days, hours
• Specify conventions
• 12 hour clock vs. 24 hour clock
• Date time (conventions), e.g., mm/dd/yy or
  dd/mm/yyyy

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Standard Operating Procedures (SOPs)

• Defines data management procedures
• for each study
• Provides standardization
• Incorporates guidelines of FDA (Us Food and Drug
  Administration) and ICH
• (International Conference on
• Harmonisation)

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Identification of Elements

• Use a unique numbering System
• Not language dependent
• Easy to reference
• Used in
• Forms
• Data dictionaries
• Program
• Reports

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Identifiers

• Patient name
• Not unique
• Medical record number
• May not be available Subject to errors
• National ID number identifier
• May not be available Subject to errors

• Need Unique identifier number/letter
• Links different records
• Can allow personal identifiers
• to be discarded

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Prepare Interim Reports

• Internal monitoring of progress
• Monitor adherence to protocol
• Monitor adherence to SOPs IRB
• Sponsors
• Regulatory Agencies

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Data Accuracy

• Train personnel
• Design good forms and procedures
• Set-up screen entry to limit errors
• Range checks
• Logic checks
• Use automated programs for data checks
• Double entry or compare to CRF
• All data and data entry forms are subject to
• audit by the FDA

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Range Checks

• Codes
• Gender, Race
• E.g. 1 Yes 2 No
• Dates
• E.g. Start and stop dates of medications
• Results
• Temperature measurement at injection site

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Logic Checks

• Question has several responses
• Temperature and route should both be
• Entered
• If a condition is true, then a response
• is required
• if subject experienced any symptoms should exist

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Serious Event Form
SERIOUS EVENT FORM (Page 2 of 2)
Medications
DOB / /
Cohort
A or B
CHARACTERISTICS OF SERIOUS ADVERSE EVENT
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Monitoring and RegulatoryOversight

• Independent monitors protocol
• Compliance with good clinical practice
• Review consent practices and IRB overview
• Validates all data collected (e.g. audit)
• Monitors reporting of adverse events
• Interface between sponsor and investigators, or
  sponsor and FDA

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Conclusions on DataCollection and Management

• Quality of a study is reflected in the data
  quality
• Data analysis plan is essential
• Optimize study management
• New Technologies

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Epidemiology and Vaccine Efficacy

• Vaccine Efficacy is the measure of the proportion
  of an expected number of infections or illnesses
  prevented by the vaccine

Vaccine efficacy (Incidence in Unvaccinated
population-Incidence in Vaccinated population)
X100 Incidence in Unvaccinated
population

• Thus 10 cases in a population of 100 exposed
  unvaccinated individuals,
• and 1 case in a population of exposed vaccinated
  individuals results in
• VE(10/100-1/100) X 100 9/100 X100 90
  ()
• 10/100 10/100

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Epidemiology and Vaccine Efficacy
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Measles Vaccine Efficacy
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Measles Vaccine Efficacy
Secondary Attack Rates in Families

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Measles Vaccine Efficacy
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Vaccine Efficacy by Screening Method

PCV Percentage of cases vaccinated - PPV
Percentage of population vaccinated
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Summary
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The SPf66 malaria vaccine candidate (I)

• Malaria is the most significant human parasitic
  disease
• Age-group at risk morbidity and mortality case
  definition depend on the level of transmission
• Distribution of Plasmodium species host factors
  depend on geographical areas.
• MALARIA IS A Multivariable DISEASE AND ITS
  CONTROL MUST BE SITE-, SPECIES- AND HOST-SPECIFIC

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The SPf66 malaria vaccine candidate (II)

• Peptide vaccine with alum, directed against
  asexual blood stage of the parasite (i.e.
  anti-disease)
• Development in Colombia by Manuel Pattaroyo.
• First field studies non-randomised
  placebo-controlled trials performed in South
  America
• double-blind randomised placebo-controlled trials
• Africa and Asia
• various ages and case definitions
• main outcome first clinical P.falciparum malaria
  episode

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The SPf66 malaria vaccine candidate (III)
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The SPf66 malaria vaccine candidate (IV)
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The SPf66 malaria vaccine candidate (V)
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The SPf66 malaria vaccine candidate (VI)

• 20,230 subjects in 3 continents
• use of nearly all potential study sites
• use of important human and budget resources
• no evidence of protective efficacy of SPf66
  against clinical malaria
• recent studies have shown a lack of correlates of
  protection between humoral and cellular responses
  to SPf66 antigens and clinical disease (Al-Yaman
  et al., 1995 1997)

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SPf66 trial in Thailand pre-vaccine studies

• 1992 two cohorts (5-15y all ages) followed for
  one year
• comparison weekly vs monthly active case
  detection
• combination of active and passive case detection
• age and species-specific incidence of malaria
• ratio symptomatic/asymptomatic malaria infections
• risk factors for malaria
• (Luxemburger et al., 1996)

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SPf66 trial in Thailand pre-vaccine studies

• 1990-1992 surveillance of all malaria cases in
  the village and analysis of hospitalised cases
• case definitions for uncomplicated/severe malaria
• mortality rates (Luxemburger et al.,
  1997)
• 1993 enrolment and 6-month follow-up of 1530
  children 2-15y to be enrolled in vaccine trial
• differential diagnosis
• case confirmation (Luxemburger et al.,
  1998)

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SPf66 trial in Thailand pre-vaccine studies

• Isolates from 1991 to 1996
• genetic diversity of parasites
• (Paul et al., 1999)
• distinction between first and recrudescent
  episode
• (Brockman et al., 1999)

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SPf66 trial in Thailand Phase III

• 1348 children from 2 to 15 years of age
• followed for 6 (vaccination schedule) and 12
  months (assessment of efficacy)
• daily detection of fever or related symptoms in
  subjects suspected of malaria
• confirmation of case by using double reading of
  Giemsa-stained blood smears
• no evidence of protective efficacy of SPf66
  vaccine against clinical malaria

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Phase III

• Trials may last several years. A few hundred to
  tens of thousands volunteers may be involved.
• If the proposed vaccine checks out for safety and
  effectiveness, the manufacturer applies for a
  license from the Food and Drug Administration
  (FDA).

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One License Wont DoThere Have to be Two

• The FDA gives a biologic license for the vaccine
  itself
• A separate license is also needed for the
  manufacturing plant where the vaccine is made.

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Every Lot of Vaccine is Tested and Sampled

• After a vaccine is approved, samples of each lot
  of a vaccine must be submitted to the FDA before
  it can be released for use.
• Tested for safety, potency, and purity

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Phase IV Tracks Vaccines After Licensing

• Continual tracking of tens of thousands of people
  who have been immunized with the vaccine under
  study.
• Gives valuable information about the vaccines
  long-term safety and effectiveness.

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Vaccine Safety Studies Post-Licensure

• Passive reporting systems
• Causality assessment difficult
• Appropriate (unvaccinated) controls?
• Controlled Epidemiologic Studies
• Ad hoc
• Phase IV

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Post-Licensure Monitoring

• Vaccine Adverse Events Reporting System (VAERS)
• Vaccine Safety Datalink (VSD) Project
• Clinical Immunization Safety Assessment
  (CISA) Centers
• Institute of Medicine (IOM) Vaccine Safety
  Reviews

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In prelicensure trials of the tetravalent
rhesus-based recombinant rotavirus vaccine,
(RotaShield, Wyeth Lederle) intussusception
occurred in five of 10,054 recipients. One case
was reported in 4633 controls. The association
was not statistically significant, and was
concluded to be temporal rather than
causal. However ACIP recommended post-licensure
surveillance for this adverse event, and in
August 1998 RotaShield was licensed for routine
use.
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Post licensure surveillance
By July 1999, 15 cases of intussusception had
been reported in vaccine recipients. This rose
later to a total of 102 cases (estimated 1.5
million doses given) Risk of intussusception
increased by 60 in recipients (plt0.0003) Effect
maximal in first 3-7 days after first
dose. (25-fold increased risk)
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Rule of Three
95 confidence interval includes as its upper
limit approximately 3/30 or 10
With more observations the denominator expands
and the upper limit falls Thus with 100
observations the upper limit is approx 3/100 or
3 1,000 3/1000 or 0.3 10,000 3/10,000 or
0.03, and so on To detect the association of
intussusception with the vaccine the sample size
in Phase III would have had to be increased 17
fold (plt0.05). That is 85 cases in 171,923
recipients
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Detection of Rare Events
1000 100 10 1 0.1 0.01 0.001
Risk per thousands
1 10 100 1000
10, 000 100,000 1,00,000
Number of subjects
Sample size needed to reduce the maximum true
proportion to a certain level when no adverse
event is observed (p0.05) Gedde-Dahl TW, NIPH
Annals, 14.92-93,1991
70
Model of Net Cash Flow Over Product Lifetime
Phase IV

Preclinical
Clinical
-
Phase I
Phase II
Phase III
71
Rare events will not be seen until after licensure
What about the developing world?
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Oversight and Safety Data Monitoring During
Clinical Development
Phase I
Phase II
Phase III
Phase IV
IRB OPRR IND FDA Safety Reports
IRB OPRR IND FDA Safety Reports
Postmarketing Studies VAERS Govt. Studies Company
studies Case reports IOM Reviews Press Interest
groups Parents/Vaccine FDA/CDC/NIH Physician Compa
ny NVICP
IRB OPRR IND FDA AE profile SAEs
Investigators Nurse Clinical Monitor Company
Statistician Medical Monitor Independent
Monitor QA/OC Peer review
Safety Monitoring Committee Or Data
Safety Monitoring Board
DSMB
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Cheng et al. Pediatrics, July 2001
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Search for excess cases of intussusception,
during rotavirus vaccination
81 cases were identified during the vaccination
period 78 cases occurred during the
pre-vaccination period This means there were 3
excess cases A risk of 1.8 (previous studies)
should have yielded 12 excess cases
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