THANK YOU AND GOOD AFTERNOON.
AND THANK YOU SO MUCH TO THE
PEOPLE WHO HAVE SPOKEN TO US
TODAY.
I THINK HEARING THESE COMMENTS
ARE VERY IMPORTANT FOR ALL OF
US, AND I AM REALLY APPRECIATIVE
THAT YOU RECOGNIZE WHAT A
DIFFICULT DECISION WE ARE
UNDERTAKING AND HOW MUCH
COMPLEXITY THERE IS TO THE
PROBLEM.
SO, THANK YOU VERY MUCH.
TODAY I'D LIKE TO INTRODUCE A
SESSION INITIALLY BY THE WORK
GROUP.
WE HAVE A REALLY ROBUST WORK
GROUP THAT'S DONE A GREAT DEAL
OF WORK RECENTLY, AS YOU'RE
AWARE.
PARTICULARLY, I'LL LIKE TO THANK
AL, JEFF, ALLIE KEMP, LAURIE
RUBEN, WHO SIT ON THE WORK
GROUP.
BUT ALSO I'D PARTICULARLY LIKE
TO THANK TAMARA PILISHVILI, WHO
I THINK IS HERE SOMEWHERE, AND
SARA.
THERE SHE IS.
AND SARA TOMCZYK, WHO HAS DONE A
LOT OF THE WORK FOR THIS
ANALYSIS, SO WE'RE VERY
APPRECIATIVE.
JUST TO REMIND YOU OF THE TERMS
OF REFERENCE, AND I'M NOT GOING
TO READ THROUGH ALL OF THESE,
BUT I THINK THE MOST IMPORTANT
ONE ON THIS SLIDE IS THE LAST,
WHICH SAYS REVISE OR UPDATE
RECOMMENDATIONS FOR PNEUMOCOCCAL
VACCINE USE AS NEEDED, AND
THAT'S REALLY THE SOURCE OF THE
DISCUSSION THAT WE'RE GOING TO
HAVE TODAY, IS THE QUESTION OF
WHETHER OR NOT NEW EVIDENCE HAS
COME TO LIGHT THAT WE NEED TO
TAKE INTO CONSIDERATION IN
DECIDING ON VACCINE SCHEDULES.
IN PARTICULAR, WE ARE ADDRESSING
ROUTINE INFANT IMMUNIZATION
SCHEDULE FOR PNEUMOCOCCAL
CONJUGATE VACCINE, AND AS IS
MENTIONED, WE DID DISCUSS THIS
AT OUR LAST MEETING, THE
COMMITTEE REQUESTED THAT WE DO
SOME FURTHER ANALYSES
THIS INFORMATION BACK TO THE
COMMITTEE, SO THAT'S WHAT WE'RE
GOING TO DO TODAY.
BUT FIRST I'D JUST LIKE TO SET
THE CONTEXT FOR THIS DISCUSSION.
AS YOU KNOW, THERE'S BEEN
EVIDENCE SUPPORTING THE USE OF A
THREE-DOSE SCHEDULE EMERGING
THROUGHOUT THE WORLD.
THERE IS A THREE-DOSE SCHEDULE
USED AND APPROVED BY THE
EUROPEAN MEDICINES AGENCY, THE
WHO ALSO RECOGNIZES A THREE-DOSE
SCHEDULE AS AN ALTERNATIVE TO A
FOUR-DOSE SCHEDULE, AND IN MANY
LOW-INCOME COUNTRIES, THAT
SCHEDULE HAS BEEN IMPLEMENTED.
IN ADDITION, AT LEAST 21 HIGH
AND 13 UPPER-MIDDLE INCOME
COUNTRIES HAVE ALSO INTRODUCED
PCV13, OR PCV10 AS A THREE-DOSE
SCHEDULE, OR THEY'VE SWITCHED
FROM A FOUR-DOSE SCHEDULE TO A
THREE-DOSE SCHEDULE, SO IT'S
IMPORTANT TO RECOGNIZE THAT WE
ARE SEEING INCREASING EVIDENCE
OF A VALUE OF A THREE-DOSE
SCHEDULE THROUGHOUT THE WORLD.
THE SECOND ISSUE THAT IS VERY
IMPORTANT TO US IS THE
PERCEPTION THAT THE VACCINE
SCHEDULE FOR CHILDREN AND
PARTICULARLY INFANTS HAS BECOME
VERY CROWDED, AND THERE ARE SOME
SAFETY CONCERNS OVER
SIMULTANEOUS INJECTIONS BEING
GIVEN.
WE'RE CONCERNED THAT THIS MAY
LEAD AN INCREASING NUMBER OF
PARENTS TO DELAY OR REFUSE THE
RECOMMENDED VACCINES, SO
ESSENTIALLY, WE WANT TO BE
CERTAIN THAT EVERY VACCINE WE'RE
GIVING TO A CHILD IS NEEDED.
THERE HAVE BEEN SOME RARE SAFETY
ISSUES ASSOCIATED WITH COLOR
ADMINISTRATION OF ROUTINE
VACCINES AND THIS COMMITTEE HAS
HEARD REPORTS ON EACH ONE OF
THOSE ISSUES.
THE THIRD ISSUE THAT HAS REALLY
DRIVEN US TO CONSIDER THIS
CHANGE IS THAT PCV7 HAS LED TO
SUCH HUGE REDUCTIONS IN
PNEUMOCOCCAL DISEASE IN THE
UNITED STATES, AND IN PNEUMONIA
IN CHILDREN AND ADULTS.
THE PCV7 TYPES HAVE VIRTUALLY
BEEN ELIMINATED FROM ALL AGE
GROUPS, A REMARKABLE, REMARKABLE
ESTABLISHMENT.
AND NOW WE'RE WATCHING AS
DISEASE DUE TO THE ALSO REDUCI.
SO WE'VE SEEN A HUGE REDUCTION
IN DISEASE BURDEN IN THE UNITED
STATES.
WE NOW HAVE A MATURE PROGRAM
USING PCV, SO THE QUESTION HAS
RISEN, CAN A THREE-DOSE SCHEDULE
BE INCLUDED FOR THE ROUTINE
SCHEDULE FOR INFANTS, WILL IT BE
SAFE, WILL IT BE EFFECTIVE, HOW
WILL WE APPROACH THIS CHANGE IF
WE ARE TO MAKE IT?
WE HOPE TODAY TO PROVIDE MORE
INFORMATION ABOUT THIS QUESTION,
HOWEVER, WE ARE NOT GOING TO
MAKE ANY SPECIFIC
RECOMMENDATIONS TODAY.
WE'RE GOING TO REVIEW THE GRADE
EVIDENCE AND ADDRESS SOME OF THE
QUESTIONS THAT WERE RAISED IN
THE OCTOBER MEETING.
WE ALSO WILL DISCUSS SOME
CONSIDERATIONS FOR INCLUDING A
THREE-DOSE SCHEDULE FOR INFANTS.
SOME OF THE QUESTIONS THAT WE
HAVE FOR THE COMMITTEE ARE, IS
THE EVIDENCE ADEQUATE TO
CONSIDER, INCLUDING A THREE-DOSE
SCHEDULE, AND IF NOT, WHAT
ADDITIONAL DATA OR INFORMATION
WOULD BE REQUIRED?
SO, THIS IS THE AGENDA FOR
TODAY'S MEETING, FOR TODAY'S
SESSION.
MATT MOORE WILL GIVE US AN
UPDATE ON THE DIRECT AND
INDIRECT EFFECTS AND ALSO THE
VACCINE EFFECTIVENESS STUDIES.
SARA TOMCZYK WILL DISCUSS THE
GRADE REVIEW OF EVIDENCE THAT
THE WORK GROUP HAS BEEN WORKING
ON SINCE OUR LAST MEETING, AND
TAMARA PILISHVILI WILL DISCUSS
CONSIDERATIONS FOR A REDUCED
SCHEDULE FOR CHILDREN.
SO WITH THAT, TAMARA, MATT?
RIGHT, MATT.
>> THANK YOU VERY MUCH,
DR. BENNETT, AND THANKS VERY
MUCH TO THE COMMITTEE FOR YOUR
INTEREST.
I'M GOING TO BE RELATIVELY BRIEF
TODAY, BECAUSE MOST OF WHAT I
HAVE TO SHOW YOU IS A
CONTINUATION OF TRENDS AND
INFORMATION THAT YOU'VE SEEN
BEFORE, BUT AT THE POINTS WHERE
THERE'S SOMETHING TRULY NEW TO
SHARE WITH YOU ALL, I'LL MAKE A
CONCERTED EFFORT TO POINT THOSE
THINGS OUT TO YOU.
SO, THIS IS, AGAIN, JUST A
REMINDER.
YOU'VE SEEN A SLIDE LIKE THIS
BEFORE.
WE MONITOR INVASIVE PNEUMOCOCCAL
DISEASE USING ACTIVE
POPULATION-BASED AND
LABORATORY-BASED SURVEILLANCE IN
TEN AREAS AROUND THE UNITED
STATES.
THIS IS CALLED THE ACTIVE
BACTERIA COURSE PROGRAM AT CDC.
WE HAVE EVALUATED RATES OF
INVASIVE PNEUMOCOCCAL DISEASE
OVER TIME, AND AFTER THE
INTRODUCTION OF THE 13 VACCINE,
WE HAVE FOCUSED PRIMARILY ON THE
IMPACT OF THAT VACCINE ON FIVE
ADDITIONAL TYPES BECAUSE WE KNOW
THAT THE SEVEN VACCINE, THAT
ANTIGEN HAS ACTIVITY OR CROSS
PROTECTION THAT'S NOT INCLUDED
IN THE VACCINE AND THAT'S 6-A.
6-A IS ALSO INCLUDED IN THE 13
VACCINE, TO IF YOU TAKE AWAY THE
EIGHT TYPES AFFECTED BY PCV7,
YOU'RE LEFT WITH THESE FIVE.
WE'VE ALSO BEEN EVALUATING FOR
THE EVIDENCE OF TYPE
REPLACEMENT, WHAT HAPPENS
INITIALLY AT THE LEVEL WHEN
CHILDREN ARE VACCINATED WITH
PNEUMOCOCCAL CONJUGATE VACCINES.
THOSE VACCINES ELIMINATE
CARRIAGE OF VACCINE TYPES AND
THEY ARE REPLACED BY NONVACCINE
TYPES, THEN WITH THE PCV7
EXPERIENCE, WHAT WE SAW OVER
TIME IS SOME OF THE NONPCV7
TYPES BEGAN TO CAUSE INVASIVE
DISEASE AND WE'VE BEEN
MONITORING AFTER PCV13
INTRODUCTION.
THEN FINALLY, I'M JUST GOING TO
GIVE YOU A VERY BRIEF UPDATE ON
INDIVIDUAL LEVEL VACCINE
EFFECTIVENESS FROM OUR CASE
CONTROLLED PROJECT.
SO, THIS IS A SLIDE SHOWING YOU
ANNUAL TRENDS IN INVASIVE
PNEUMOCOCCAL DISEASE AMONG
CHILDREN UNDER THE AGE OF 5.
I APOLOGIZE THAT THESE LINES ARE
IN COLOR, BUT YOUR HANDOUTS ARE
NOT IN COLOR, SO LET ME ORIENT
YOU TO THE FIRST ONE, BECAUSE
THEY ARE FORMATTED EXACTLY THE
SAME WAY.
THE LINE AT THE TOP IN PURPLE
REPRESENTS ALL INVASIVE
PNEUMOCOCCAL DISEASE, ALL OF THE
TYPES THAT CAUSE PNEUMOCOCCAL
DISEASE IN KIDS UNDER 5.
AND THEN THIS RED LINE HERE ARE
THOSE ADDITIONAL TYPES UNIQUELY
AFFECTED BY PCV13.
THE BLUE LINE HERE REPRESENTS
THE TYPES NOT IN PCV13.
AND FINALLY, THE SEROTYPES THAT
ARE CONTINUING TO BE AFFECTED BY
THE 13 VALIENT VACCINE.
SO WHAT WE SEE ARE A REDUCTION
IN SEROTYPES AND THAT'S WHAT'S
DRIVING THIS OVERALL REDUCTION
IN INVASIVE DISEASE SHOWN IN THE
PURPLE LINE.
SO NOW THAT I'VE ORIENTED YOU TO
THAT IN KIDS UNDER 5, NOW ADULTS
18 TO 49.
BECAUSE WE DON'T THINK THERE'S
BEEN MUCH UPTAKE OF 13 VACCINE
IN ADULTS, AND NOT IN THIS AGE
GROUP, WE THINK PROBABLY MOST OF
WHAT WE'RE SEEING HERE IS A
REDUCTION RELATED TO USE IN
CHILDREN AND PREVENTION OF
TRANSMISSION OF THOSE VACCINE
TYPES FROM CHILDREN TO ADULTS,
SO AGAIN, IF WE FOCUS ON THE RED
LINE RIGHT HERE, IT WAS KIND OF
FLAT FOR SEVERAL YEARS, THEN
BEGAN DECLINING AFTER THE 13
VACCINE WAS INTRODUCED FOR
CHILDR
CHILDREN.
THE PICTURE IS SLIGHTLY
DIFFERENT, BUT ONLY SLIGHTLY.
THESE ARE THOSE ADDITIONAL
SEROTYPES IN PCV13 IN THE RED
LINE DECLINING AFTER
INTRODUCTION IN 2010, AND WE
BEGIN TO SEE PERHAPS THE
SUGGESTION OF AN INCREASE IN THE
NONVACCINE TYPES, THE TYPES NOT
IN THE 13-VALENT VACCINE AND A
SIMILAR SORT OF PATTERN IN
ADULTS 65 AND OVER.
NICE REDUCTION IN THOSE
ADDITIONAL TYPES IN THE
13-VALENT VACCINE AND PERHAPS A
SUGGESTION OF AN INCREASE.
SO WHEN WE USE OUR MODELING
APPROACH TO ESTIMATING PERCENT
CHANGES IN DISEASE IN EACH OF
THESE AGE GROUPS, THIS IS WHAT
WE SEE.
THIS IS A BIT COMPLICATED, BUT
YOU HAVE ALL THE NUMBERS IN
FRONT OF YOU.
LET ME JUST POINT OUT THE
GENERAL PATTERN.
THE GENERAL PATTERN IS WE SEE
THE LARGEST REDUCTIONS IN THE
FIRST YEAR IN VACCINE
INTRODUCTIONS, LARGEST REDUCTION
IN KIDS UNDER THE AGE OF 5, AND
THOSE REDUCTIONS ARE LOWER FOR
THE UNVACCINATED POPULATIONS,
AGAIN, THROUGH THE HERD
PROTECTION EFFECT.
SO AS YOU GO DOWN IN EACH
COLUMN, THE PATTERN IS THE SAME.
VERY LARGE REDUCTIONS IN THE
YOUNGEST AGE GROUPS, THEN
SMALLER REDUCTIONS IN THE OLDER
AGE GROUPS.
IF YOU GO ACROSS THE TABLE, WHAT
YOU SEE IS THAT EACH SUCCESSIVE
YEAR, THE REDUCTIONS ARE BIGGER
THAN THE PREVIOUS YEARS, SO WHAT
THIS IS SHOWING YOU IS WITH EACH
SUCCESSIVE YEAR OF USE OF PCV13
IN CHILDREN, WE'RE CONTINUING TO
SEE REDUCTIONS IN THOSE VACCINE
TYPES OR THOSE ADDITIONAL TYPES
AFFECTED BY PCV13.
SO THIS IS ALL VERY, VERY GOOD
NEWS.
WITH RESPECT TO THOSE NONPCV13
TYPES THAT I MENTIONED, IT'S
REALLY JUST THIS ONE AGE GROUP
AND REALLY JUST IN ONE YEAR IN
50 TO 64 YEAR OLDS, THERE IS
THIS SMALL AND STATISTICALLY
SIGNIFICANT INCREASE IN
NONVACCINE TYPES IN THAT
PARTICULAR AGE GROUP.
IT'S NOT PRESENT IN ANY OF THE
OTHER AGE GROUPS, AND WHEN WE
COMBINE ALL OF THESE DATA
TOGETHER, SO THE RESIDUAL
EFFECTS ON THE SEVEN-VALENT
TYPES, THE NEW EFFECTS ON THE
ADDITIONAL TYPES IN PCV13, EVEN
AFTER ACCOUNTING FOR THE SMALL
INCREASE AND WE LOOK AT THE
CHANGES IN ALL IPD, WE ARE STILL
MOVING IN THE RIGHT DIRECTION.
THAT IS TO SAY THAT IN EACH OF
THESE AGE GROUPS, THERE ARE
PRIMARILY STATISTICALLY
SIGNIFICANT REDUCTIONS,
ESPECIALLY AS WE GET INTO THE
LATTER YEARS IN THE OLDER AGE
GROUPS, AND SO IF THAT IS A
LITTLE BIT OF EVIDENCE OF
SEROTYPE REPLACEMENT IN THE 50
TO 64 YEAR OLDS, IT IS NOT
OVERSHADOWING THE CONTINUED
REDUCTION THAT WE'RE SEEIN
HAD BEEN PREVENTED THROUGH JUNE
OF 2012.
THIS IS NOW AN ADDITIONAL YEAR
OF DATA AND WE BELIEVE IT'S UP
TO ABOUT 30,000 CASES PREVENTED.
AND THESE ARE THE AGE GROUPS IN
WHICH THOSE HAVE BEEN PREVENTED,
ROUGHLY ONE-THIRD IN CHILDREN
UNDER THE AGE OF 5.
ABOUT A QUARTER IN PEOPLE 65 AND
OVER, AND ANOTHER QUARTER IN
PEOPLE 50 TO 64 YEARS OF AGE.
THEN WHEN WE LOOK AT THE DEATHS,
AGAIN, THIS IS AN UPDATE FROM
THE LAST TIME WE PRESENTED TO
YOU, ABOUT 2,000 DEATHS
PREVENTED OVER THE FIRST TWO
YEARS OF THE PROGRAM.
WE BELIEVE NOW IT'S ABOUT 3,000
DEATHS PREVENTED OVER THE FIRST
THREE YEARS OF THE PROGRAM.
AND, AGAIN, I MENTIONED THIS
LAST TIME, WE'RE FORTUNATE THAT
RELATIVELY SMALLER NUMBERS OF
CHILDREN ACTUALLY DIE OF
PNEUMOCOCCAL DISEASE COMPARED TO
ADULTS, AND THAT'S WHY WHEN YOU
LOOK AT THE DISTRIBUTION OF THE
DEATHS PREVENTED, MOST OF THOSE
BEING PREVENTED ARE BEING
PREVENTED IN ADULTS WHO ARE NOT
ACTUALLY RECEIVING THE VACCINE.
AGAIN, SPEAKING TO THE
PROTECTION OF THE VACCINE.
I MENTIONED THE LAST TIME WE
PRESENTED TO YOU IN OCTOBER, OUR
CASE CONTROL STUDY, VACCINE
EFFECTIVENESS USING PCV13.
AND I'LL CUT TO THE BOTTOM LINE
HERE, BECAUSE MOST OF THE OTHER
DATA THAT'S SHOWN HERE IS VERY
SIMILAR TO WHAT YOU'VE SEEN
BEFORE.
WHAT'S NEW FROM THIS TABLE
COMPARED TO WHAT YOU SAW BEFORE
IS WE NOW HAVE INDIVIDUAL LEVEL
ESTIMATES OF SEROTYPES SPECIFIC
EFFECTIVENESS, SO THE LAST TIME
YOU SAW THESE DATA, THIS NUMBER
WAS ABOUT THE SAME AND THIS
NUMBER WAS ABOUT THE SAME, THE
VACCINE EFFECTIVENESS OF ONE OR
MORE DOSES AGAINST ALL IPD AND
THEN AGAINST ALL OF THE
SEROTYPES INCLUDED IN THE
VACCINE, BUT WHEN WE LOOK AT THE
INDIVIDUAL SEROTYPES NOW, WE CAN
SEE A VACCINE EFFECTIVENESS 90%,
100% FOR 7-F AND ALL OF THESE
ARE STATISTICALLY SIGNIFICANT,
SO WE'RE ENCOURAGED TO SEE THESE
DATA AT THIS POINT.
SO IN SUMMARY THEN, REDUCTIONS
IN IPD AMONG ALL THE AGE GROUPS
AND WE THINK THAT ENCOURAGES US
OF DIRECT AND INDIRECT EFFECTS.
WE ARE SEEING EARLY EVIDENCE OF
INCREASES IN NONPCV13 SEROTYPES
IN 50 TO 64 YEAR OLDS.
THAT MAY BE INDICATIVE OF
SEROTYPE REPLACEMENT.
THAT WAS SIMILAR WITH PCV7.
WE BEGAN TO SEE REPLACEMENT IN
ADULTS RELATIVELY EARLY ON.
THOSE INCREASES IN THOSE
NONPCV13 TYPES ARE NOT
OVERSHADOWING THE REDUCTIONS IN
THE PCV13 TYPES, AND WE NOW HAVE
PRELIMINARY EVIDENCE OF
EFFECTIVENESS FOR THE THREE MOST
COMMON PCV13 SEROTYPES AND WE
HAVE LOTS OF ADDITIONAL ANALYSES
THAT WE PLAN ON DOING.
PERMISSION, I'LL STOP THERE AND
ANSWER ANY QUESTIONS YOU MIGHT
HAVE.
>> WE ARE OPEN FOR QUESTIONS.
MIKE.
>> I'M SORRY, WHICH SLIDE?
EIGHT.
>> I WOULD JUST SUBMIT THOSE
DATA SAY YOU'VE GOT AN INCREASE
IN THE LOWER THREE AGE GROUPS.
YOU DON'T HAVE A SAMPLE SIZE
LARGE ENOUGH, BUT YOUR POINT
EMPHASIS FOR ALL THREE OF THOSE
IS A POSITIVE NUMBER, SO I WOULD
CAUTION YOU NOT TO EXCLUDE THE
POSSIBILITY OF YOUR POINT
ESTIMATES NOT TELLING YOU THE
TRUTH.
I'M SORRY, I SEE WHAT YOU'RE
TALKING ABOUT.
I MEANT PHYSICALLY, THE
POSITIVE NUMBERS IN THE
RIGHT-HAND COLUMN.
THOSE ARE ALL POSITIVE POINT
ESTIMATES.
YOU SAID ONLY THE ONE IN RED
DIFFERED, BUT THAT'S NOT TRUE.
THEY ALL DIFFER, TWO OF THEM
DON'T --
>> I THINK WHAT I SAID, ONLY
THAT ONE THAT WAS STATISTICALLY
SIGNIFICANT.
BUT I THINK YOUR POINT'S WELL
TAKEN.
OTHER QUESTIONS OR
CLARIFICATION?
I HAVE A QUESTION.
IN THE NONVACCINE TYPE DISEASE,
IS THERE A TREND TOWARDS A
SPECIFIC TYPE OF ILLNESS,
PNEUMONIAS?
>> I THOUGHT WHAT YOU WERE GOING
TO ASK ME WAS WHETHER THERE WAS
A TENDENCY TOWARDS A PARTICULAR
SORT OF SEROTYPE.
>> YOU CAN ANSWER BOTH.
OKAY, THE ANSWER TO YOUR
FIRST QUESTION IS, WE HAVEN'T
LOOKED AT IT IN THAT WAY YET TO
SEE IF A PARTICULAR SYNDROME IS
RISING TO THE TOP.
WITH RESPECT TO AN INDIVIDUAL
SEROTYPE, WHAT WE'RE SEEING
RIGHT NOW ARE VERY, VERY SMALL
AND NOT PHYSICALLY SIGNIFICANT
INCREASES IN ANY INDIVIDUAL
SEROTYPE.
SO I WOULD SAY THERE ARE AT
LEAST SIX OR SEVEN THAT LOOK
LIKE MAYBE THEY ARE A LITTLE BIT
HIGHER THAN THEY WERE BEFORE,
BUT EACH OF THOSE INCREASES IS
VERY, VERY SMALL AND ONLY WHEN
YOU ADD THEM ALL TOGETHER THAT
YOU GET, AGAIN, THIS
STATISTICALLY SIGNIFICANT CHANGE
IN THAT PARTICULAR GROUP.
>> DR. GORMAN?
THIS MORNING WE HEARD SOME
DATA THAT LAST YEAR'S INFLUENZA
SEASON WAS SPECIFICALLY MORE
SEVERE THAN USUAL.
WOULD THAT HAVE HAD AN IMPACT ON
THESE NUMBERS FOR THIS YEAR?
YEAH, GREAT QUESTION.
THANKS FOR ASKING.
RYAN HAS BEEN LOOKING IN OUR
GROUP SPECIFICALLY AT THAT
ISSUE, AND IT DOES SEEM THAT IN
SOME OF OUR ABC AREAS, THERE WAS
AT LEAST A TEMPORAL RELATIONSHIP
BETWEEN INFLUENZA ACTIVITY AND
INCREASES IN SOME OF THESE
NONVACCINE TYPES, BUT IT WASN'T
CONSISTENT ACROSS ALL SIGTES.
IN FACT, SOME OF THE SITES THERE
WAS NO INCREASE IN NONVACCINE
TYPES AT ALL AND THAT WASN'T
NECESSARILY ASSOCIATED WITH AN
ABSENCE OF INFLUENZA, SO THERE
MAY BE A BEGINNING OF A SIGNAL
THERE, BUT I WOULDN'T CALL IT A
CLEAR-CUT MESSAGE.
>> THANK YOU.
THANK YOU MUCH.
THEN I THINK WE CAN HAVE DR. --
MS. TOMCZYK COME ON UP.
AND I'VE BEEN FOREWARNED WE'LL
HAVE TIME FOR CLARIFICATION
QUESTIONS AFTER THIS, BUT FOR
THE BIGGER ISSUE, I THINK WE'RE
GOING TO WAIT UNTIL THE LAST
PRESENTATION.
>> THANK YOU.
GOOD AFTERNOON.
TODAY I'LL BE PRESENTING ON THE
RESULTS OF THE GRADE PROCESS
EVALUATING THE EVIDENCE FOR THE
THREE-DOSE SCHEDULES OF THE 13
VALENT PNEUMOCOCCAL CONJUGATE
VACCINE.
SO THE POLICY QUESTION HERE IS,
SHOULD A THREE-DOSE SCHEDULE OF
PCV13 BE RECOMMENDED FOR
GENERALLY HEALTHY INFANTS IN THE
U.S.?
THIS PRESENTATION WILL ADDRESS
THE GRADE PROCESS AND THE GRADE
CONCLUSIONS ONLY.
THE NEXT PRESENTATION WILL
DISCUSS THE POLICY
CONSIDERATIONS.
THE GRADE PROCESS BEGINS WITH
DEFINING THE PICO, OR THE
POPULATION INTERVENTION
COMPARISON AND OUTCOME.
THE POPULATION OF INTEREST HERE
FOR THIS POLICY QUESTION IS
CHILDREN 2 TO 15 MONTHS OF AGE
WITH NO UNDERLYING MEDICAL
CONDITION.
THE INTERVENTIONS AND THE
COMPARISONS WERE ADDRESSED IN
TWO DIFFERENT STEPS.
IN STEP ONE, AS SEEN HERE, WE
GRADED ALL EVIDENCE FOR EACH PCV
SCHEDULE, COMPARED TO NO VACCINE
TO ASSESS THE STRENGTH OF
EVIDENCE SUPPORTING EACH
INDIVIDUAL SCHEDULE, AS IF WE
WERE TO CONSIDER POLICY
DECISIONS PRE-PCV7.
BUT THE INTERVENTION FOR STEP
ONE INCLUDED THE CURRENTLY USED
SCHEDULE OF FOUR DOSES OF PCV13,
GIVEN AT TWO, FOUR, SIX, AND 12
TO 15 MONTHS, OR THREE PLUS ONE,
AS WE WILL REFER TO IT, AND TWO
DIFFERENT THREE-DOSE SCHEDULES,
GIVEN AT TWO, FOUR, AND SIX
MONTHS, OR THREE PLUS ZERO, AND
TWO, FOUR, AND 12 TO 15 MONTHS,
OR TWO PLUS ONE.
THE COMPARISON WAS NO PCV13 OR
PLACEBO.
IN STEP TWO OF THE GRADE
PROCESS, WE GRADED ONLY STUDIES
WITH DIRECT COMPARISONS OF
SCHEDULES AVAILABLE WITHIN EACH
STUDY.
THIS INCLUDED THE THREE-DOSE
SCHEDULE OF THREE PLUS ZERO AND
TWO PLUS ONE, AS COMPARED TO THE
CURRENTLY USED FOUR-DOSE
SCHEDULE OR THREE PLUS ONE.
WE USED A MODIFIED DELFI PROCESS
TO THEN RANK THE IMPORTANCE OF
POSSIBLE OUTCOMES.
WE CONDUCTED A SURVEY OF WORK
GROUP MEMBERS AND THEIR
COLLEAGUES, PARTICULARLY
PRACTITIONERS AND PUBLIC HEALTH
PROFESSIONALS, AND THE BREAKDOWN
OF THE 48 RESPONDENTS CAN BE
SEEN HERE.
THE RESPONDENTS WERE THEN ASKED
TO RANK A LIST OF OUTCOMES, ONE
THROUGH NINE, AND THE RANKINGS
WERE USED BY THE WORK GROUP TO
SELECT CRITICAL OR IMPORTANT
OUTCOMES, FOR WHICH THE GRADE
REVIEW OF EVIDENCE WOULD BE
CONDUCTED.
OUTCOMES RATED SEVEN TO NINE
WERE DETERMINED CRITICAL FOR
DECISION MAKING, ACCORDING TO
THE GRADE GUIDELINES IN STEP
ONE.
NAMELY HERE, MORALITY, INVASIVE
PNEUMOCOCCAL DISEASE, BACTERIA
PNEUMONIA AND NONBACTERIA
PNEUMONIA AND INDIRECT EFFECTS
ON IPD.
INDIRECT EFFECTS RANKED SLOWLY
BELOW THE CRITICAL THRESHOLD,
BUT THE WORK GROUP DETERMINED IT
WAS STILL CRITICAL.
PNEUMOCOCCAL MENINGITIS AND
HOSPITALIZATIONS WERE ALSO
RANKED AS CRITICAL, BUT THEY
WERE PRIMARILY INCLUDED IN THE
IPD OUTCOME.
ADDITIONAL OUTCOMES RANKED, BUT
NOT INCLUDED BECAUSE OF LOW
RANKING, INCLUDED OFFICE VISITS
FOR PNEUMOCOCCAL DISEASE,
VACCINE-TYPE CARRIAGE, SYSTEMIC
ADVERSE EVENTS, LOCAL REACTIONS
TO THE VACCINE, AND COST
EFFECTIVENESS.
IN STEP TWO, ANY STUDIES
PROVIDING DIRECT COMPARISONS
BETWEEN SCHEDULES WERE INCLUDED
AS DETERMINED BY THE WORK GROUP.
NAMELY, ANTIBODY RESPONSE AS A
SURROGATE FOR IPD, LOWER
RESPIRATORY TRACT INFECTION.
NEXT I WILL PRESENT THE GRADE
FRAMEWORK FOR EACH STEP,
FOLLOWING THIS OUTLINE.
IN STEP ONE, I WILL PRESENT A
SUMMARY OF INCLUDED STUDIES AND
ASSESS QUALITY OF EVIDENCE FOR
EACH SCHEDULE AND OUTCOME.
RANDOMIZED CONTROL TRIALS WERE
CONSIDERED FIRST AND SELECTED
FOR EACH SCHEDULE AND OUTCOME.
WHEN DATA FROM RCTs WAS NOT
AVAILABLE, WE THEN USED
OBSERVATIONAL STUDIES.
THE DATA COMBINED FOR ALL
OUTCOMES WERE VIEWED TO
DETERMINE THE OVERALL TYPE OF
EVIDENCE FOR EACH SCHEDULE.
LASTLY, VALUES AND PREFERENCES
WERE CONSIDERED ACCORDING TO THE
RANKINGS OF OUTCOMES AND A
JUDGMENT OF RECOMMENDATION
CATEGORY OF EACH SCHEDULE WAS
MADE.
IN STEP TWO, WE FOLLOWED THE
SAME OUTLINES.
IT WAS ORGANIZED ACCORDING TO
THE FOLLOWING COMPARISONS.
BETWEEN SCHEDULES, THREE PLUS
ZERO, TWO VERSUS THREE PRIMARY
DOSES, TWO PLUS ONE VERSUS THREE
PLUS ONE, AND THE IDENTIFIED
OUTCOMES, INCLUDING DATA AS
SURROGATES FOR IPD, LOWER
RESPIRATORY TRACT INFECTION.
THE FINAL RECOMMENDATION
CATEGORY WAS JUDGED FOR EACH
THREE-DOSE SCHEDULE, THREE PLUS
ZERO OR TWO PLUS ONE, AS
COMPARED TO THE THREE PLUS ONE
SCHEDULE.
WE WILL START WITH STEP ONE TO
PRESENT THE GRADE OF EVIDENCE
FOR EACH SCHEDULE COMPARED TO NO
VACCINE TO ASSESS THE STRENGTH
OF EVIDENCE SUPPORTING EACH
SCHEDULE.
IN STEP ONE, I WILL START WITH A
THREE PLUS ONE SCHEDULE IN
INVASIVE PNEUMOCOCCAL DISEASE
AND PNEUMONIA.
FOUR RCTs WERE INCLUDED, IN THE
U.S., THE U.S. NAVAJO COMMUNITY,
FINLAND, AND BRAZIL.
THESE STUDIES EVALUATED THE
ETHICACY OF PCV7 AND PCV10.
FOR IPDs RANGED FROM 83% TO
100%.
VACCINE ETHICACY FOR
X-RAY-CONFIRMED PNEUMONIA RANGED
AND WE FOCUSED ON CHEST
PNEUMONIA FOR OUTCOME DATA
LISTED HERE.
FOR ESTIMATES OF BASELINE
DISEASE INCIDENTS AMONG THE
NONVACCINATED OF PCV13-TYPE OR
ALL CAUSED PNEUMONIA AMONG U.S.
CHILDREN LESS THAN 2 YEARS OF
AGE.
WE APPLIED THE POOLED ESTIMATES
FOR VACCINE-TYPE IPDs AND
PNEUMONIA BASED ON THE STUDIES
PRESENTED IN THE PREVIOUS SLIDE
TO THE BASELINE INCIDENTS TO
ESTIMATE THE INCIDENTS AMONG THE
VACCINATED FOR 100,000
POPULATION.
USING THESE DATA, WE THEN
CALCULATED THE ABSOLUTE RISK
DIFFERENCE PER PERSON AND THE
NUMBERS NEEDED TO TREAT OR
VACCINATE.
ON A THREE PLUS ONE SCHEDULE,
PCV HAD A 94% VACCINE ETHICACY
FOR IPD AND 11% ETHICACY FOR
PNEUMONIA.
THE NUMBERS NEEDED TO TREAT OR
VACCINATE SHOWED THAT 613 PEOPLE
NEEDED TO BE VACCINATED IN ORDER
TO PREVENT ONE CASE OF IPD.
THE VACCINE EFFICACY ESTIMATE.
TO EVALUATE THE EFFECTS OF PCV
INTRODUCTION ON IPD ON THE
POPULATION LEVELS, WE USED DATA
FROM A POOLED ANALYSIS FROM 21
DATA SETS AMONG COUNTRIES WITH
DIFFERENT PCV7 SCHEDULES.
THIS GRAPH SHOWS VACCINE-TYPE
IPD AMONG ADULTS DURING THE
THIRD YEAR POST INTRODUCTION OF
THE VACCINE IN THE U.S., CANADA,
CALGARY, AND THE NETHERLANDS,
WHICH HAVE USED THE THREE PLUS
ONE SCHEDULE.
THE "X" AXIS SHOWS THE ADULT AGE
GROUPS AND THE "Y" AXIS SHOWS
THE RATIOS.
DESPITE SURVEILLANCE METHOD AND
EXPENSE OF CATCHUP, YOU CAN NOTE
THE EFFECT ESTIMATE BETWEEN ALL
COUNTRIES HERE ARE BETWEEN 0.20
OR 0.80 AMONG ADULTS.
DESPITE A FEW ESTIMATES THAT ARE
NOT STATISTICALLY SIGNIFICANT.
AS YOU CAN SEE, PCV USE IN
CHILDREN HAS LED TO LARGE
INDIRECT EFFECTS ON IPD AMONG
ADULTS OF ALL AGE GROUPS IN
COUNTRIES USING A THREE PLUS ONE
SCHEDULE.
SO THAT WAS THE SUMMARY OF THE
THREE PLUS ONE DATA.
I WILL NOW DESCRIBE HOW WE
DETERMINED THE EVIDENCE TYPE FOR
THIS THREE PLUS ONE SCHEDULE
DATA.
IN THE GREAT PROCESS, THIS IS
DONE BY FIRST ASSIGNING AN
INITIAL EVIDENCE TYPE AS
FOLLOWS.
TYPE ONE IS MAINLY RCTs, OR
OVERWHELMING EVIDENCE FROM
OBSERVATIONAL STUDIES.
TYPE TWO IS RCTs WITH IMPORTANT
LIMITATIONS OR EXCEPTIONALLY
STRONG EVIDENCE FROM
OBSERVATIONAL STUDIES.
TYPE THREE IS OBSERVATIONAL
STUDIES OR RCTs WITH NOTABLE
LIMITATIONS, AND TYPE FOUR IS
CLINICAL EXPERIENCE AND
OBSERVATION, OBSERVATIONAL
STUDIES WITH IMPORTANT
LIMITATIONS, OR RCTs WITH
SEVERAL MAJOR LIMITATIONS.
NEXT, THAT INITIAL EVIDENCE TYPE
CAN BE DOWNGRADED OR UPGRADED
ACCORDING TO THE FOLLOWING
PRESPECIFIED GRADE CRITERIA,
WHICH INCLUDES THE FOLLOWING,
RISK OF BIAS, INCONSISTENCY,
INDIRECTNESS, IMPER SIX, AND
OTHER CONSIDERATIONS, SUCH AS
STRENGTH OF ASSOCIATION, DOSE
RESPONSE, OR BIAS.
EVIDENCE CAN BE DOWNGRADED MINUS
ONE OR MINUS TWO WHEN ANY OF THE
GRADE CRITERIA IS SERIOUS OR
VERY SERIOUS.
IT CAN BE UPGRADED PLUS ONE OR
PLUS TWO IF THE STRENGTH OF
ASSOCIATATION IS LARGE OR VERY
LARGE AND THERE IS NO APPARENT
RISK OF BIAS.
THUS, FOR THE THREE PLUS ONE
SCHEDULE, THE TYPE OF EVIDENCE
WAS ASSESSED ACCORDING TO THE
GRADE CRITERIA AS SEEN IN THE
COLUMN HEADING.
BOTH FOR IPV AND PNEUMONIA, YOU
WILL NOTE WE STARTED WITH THREE
RCTs AND THERE WERE NO SERIOUS
CONCERNS, SO THE TYPE OF
EVIDENCE FOR BOTH OUTCOMES WAS
DETERMINED TO BE ONE.
FOR INDIRECT EFFECTS, THE THREE
SURVEILLANCE DATA SETS WERE PART
OF A POOLED ANALYSIS, SO THE
INITIAL TYPE OF EVIDENCE WAS
THREE, AND IT WAS UPGRADED BY
ONE DUE TO THE STRENGTH OF
ASSOCIATION AND NO APPARENT RISK
OF BIAS FOR A FINAL EVIDENCE
TYPE OF TWO.
AND THE KEY POINT HERE TO TAKE
AWAY IS THAT THERE IS HIGH
QUALITY EVIDENCE, WHICH SHOWS
THAT PCV THREE PLUS ONE SCHEDULE
IS EFFECTIVE AGAINST IPV AND
PNEUMONIA AND, IN ADDITION, HAS
DEMONSTRATED LARGE AND DIRECT
EFFECTS.
NEXT, I WILL PRESENT THE
EVIDENCE ON A THREE PLUS ZERO
PCV SCHEDULE.
FOR INVASIVE PNEUMOCOCCAL
DISEASE AND PNEUMONIA, THREE
RCTs WERE INCLUDED.
THESE WERE CONDUCTED IN SOUTH
AFRICA, GAMBIA, AND THE
PHILIPPINES.
THESE STUDIES EVALUATED THE
EFFICACY OF PCV9 AND PCV11.
AGAINST IPV RANGED FROM 77% TO
83%.
AND FOR X-RAY CONFIRMED
PNEUMONIA, IT RAISED FROM 23% TO
37%.
AS BEFORE, THE DATA FROM
INCLUDED STUDIES WERE USED TO
OBTAIN A POOLED VACCINE EFFICACY
ESTIMATE FOR EACH OUTCOME, WHICH
WAS THEN APPLIED TO THE BASELINE
PREPCV7 INCIDENT RATES FOR
CHILDREN LESS THAN 2 YEARS OF
AGE.
TO CALCULATE INCIDENTS AMONG THE
VACCINATED FOR 100,000
POPULATION.
PCV HAD A 74% VACCINE EFFICACY
FOR IPD.
EXCUSE ME.
AND A 26% VACCINE EFFICACY FOR
PNEUMONIA.
THE NUMBERS NEEDED TO TREAT OR
VACCINATE ESTIMATES SHOWED THAT
779 PEOPLE NEEDED TO BE
VACCINATED IN ORDER TO PREVENT
ONE CASE OF IPD AND 370 PEOPLE
NEED TO BE VACCINATED IN ORDER
TO PREVENT ONE CASE OF
PNEUMONIA.
TO EVALUATE THE INDIRECT EFFECTS
OF PCV INTRODUCTION AND IPV AT
THE POPULATION FOR THREE PLUS
ZERO, WE USED THE SAME POOLED
ANALYSIS OF 21 SURVEILLANCE DATA
SETS.
THIS INCLUDED AUSTRALIA, WHICH
HAVE USED THE THREE PLUS ZERO
SCHEDULE.
THE "Y" AXIS REFLECTS THE RATE
RATIOS AMONG ADULTS DURING THE
THIRD YEAR POST INTRODUCTION AND
THE "X" AXIS REFLECTS THE AGE
GROUPS.
YOU CAN NOTE THE EFFECT
ESTIMATES RANGE FROM 0.20 AND
0.50, OR 50% TO 80% REDUCTION IN
IPV RATES.
THE KEY POINT HERE IS THE USE OF
PCV ON A THREE PLUS ZERO
SCHEDULE AMONG CHILDREN IN
AUSTRALIA ALSO RESULTED IN LARGE
REDUCTION IN IPD AMONG ADULTS OF
ALL AGE GROUPS.
WE THEN USED THE ABSTRACTED DATA
TO DETERMINE THE EVIDENCE TYPE
FOR THREE PLUS ZERO SCHEDULE.
FOR BOTH IPD BASED ON TWO RCTs
AND PNEUMONIA BASED ON THREE
RCTs, THERE WERE NO SERIOUS
CONCERNS FOR ANY CRITERIA, SO
THE TYPE OF EVIDENCE WAS
DETERMINED TO BE ONE.
FOR INDIRECT EFFECT, BASED ON
SURVEILLANCE DATA FROM ONE
COUNTRY, USING THE THREE PLUS
ZERO SCHEDULE, THE INITIAL
EVIDENCE TYPE WAS THREE, BUT IT
WAS UPGRADED BY ONE DUE TO THE
STRENGTH OF ASSOCIATIONS AND
LACK OF BIAS FOR A FINAL
EVIDENCE TYPE OF TWO.
THE KEY POINT HERE IS THAT THERE
IS AGAIN HIGH QUALITY EVIDENCE
THAT SHOWS PCV THREE PLUS ZERO
SCHEDULE IS EFFECTIVE AGAINST
IPD AND PNEUMONIA AND THERE ARE
STRONG INDIRECT BENEFITS USING
THIS SCHEDULE.
NEXT I WILL PRESENT THE EVIDENCE
REVIEWING THE TWO PLUS ONE
SCHEDULE.
FOR THE IPD OUTCOME, WE INCLUDED
ONE RCT CONDUCTED IN FINLAND,
EVALUATING THE EFFICACY OF
PCV10.
VACCINE EFFICACY FOR IPD HERE
WAS 92%.
STUDIES IN CANADA AND POLAND
EVALUATED THE IMPACT OF PCV7
INTRODUCTION IN CHILDREN.
THE LEFT GRAPH SHOWS THE STUDY
IN QUEBEC DEMONSTRATING A 72%
REDUCTION ON LOW-BAR PNEUMONIA
BEFORE AND AFTER THE
INTRODUCTION ON PCV7 ON A TWO
PLUS ONE SCHEDULE.
THE RIGHT GRAPH SHOWS THE STUDY
IN POLAND AND THERE WAS ALSO A
REDUCTION IN X-RAY CONFIRMED
IT WAS 65% IN ZERO TO 1 YEAR V7
OLDS.
LASTLY, THE STUDY IN ITALY WAS A
LARGE COHORT STUDY WHICH SHOWED
A 65% VACCINE EFFICACY ESTIMATE
FOR X-RAY CONFIRMED PNEUMONIA.
AS PRESENTED FOR THREE PLUS ONE
AND THREE PLUS ZERO, VACCINE
EFFICACY ESTIMATES FOR EACH
OUTCOME WERE APPLIED TO THE
BASELINE PREPCV7 INCIDENTS OF
IPD AND ALL CAUSE PNEUMONIA
AMONG U.S. CHILDREN LESS THAN 2
YEARS OF AGE.
TO CALCULATE INCIDENTS AMONG THE
VACCINATED FOR 100,000
POPULATION.
PCV HAD A 96% VACCINE EFFICACY
AGAINST IPD, A 70% VACCINE
EFFICACY AGAINST PNEUMONIA, AND
THE NUMBERS NEEDED TO TREAT OR
VACCINATE ESTIMATE SHOWED THAT
600 PEOPLE NEED TO BE VACCINATED
IN ORDER TO PREVENT ONE CASE OF
IPD AND 139 PEOPLE NEED TO BE
VACCINATED IN ORDER TO PREVENT
ONE CASE OF PNEUMONIA.
TO EVALUATE THE INDIRECT EFFECTS
OF PCV INTRODUCTION ON IPV AT
THE POPULATION LEVEL FOR TWO
PLUS ONE, WE AGAIN USE THE SAME
POOLED ANALYSIS OF 21
SURVEILLANCE SETS.
THIS GRAPH SHOWS THE RATE RATIOS
ON THE "Y" AXIS AMONG ADULTS
DURING THE THIRD YEAR POST
INTRODUCTION AND AGE GROUPS BY
COUNTRY USING THE TWO PLUS ONE
SCHEDULE ON THE "X" AXIS.
YOU CAN NOTE THAT THE EFFECT
ESTIMATES ACROSS ALL COUNTRIES
ARE BETWEEN 0.20 AND 1.20, OR
80% REDUCTIONS TO NO CHANGE IN
ALL CASES, DESPITE A FEW
ESTIMATES IN SWITZERLAND,
DENMARK, AND SCOTLAND THAT,
AGAIN, WERE NOT STATISTICALLY
SIGNIFICANT.
ALTHOUGH THERE IS SOME
VARIABILITY, YOU CAN STILL SEE
THAT THERE IS GOOD EVIDENCE,
THAT THE USE OF PCV ON A TWO
PLUS ONE SCHEDULE LEADS TO LARGE
REDUCTIONS IN IPD AMONG ADULTS.
WE THEN USED THE ABSTRACTED TWO
PLUS ONE DATA TO DETERMINE THE
EVIDENCE TYPE FOR THE TWO PLUS
ONE SCHEDULE.
FOR IPD, THE EVIDENCE RELIES ON
ONE RCT.
AND THERE WERE NO SERIOUS
CONCERN FOR ANY CRITERIA, SO THE
TYPE OF EVIDENCE WAS ONE.
FOR PNEUMONIA AND INDIRECT
EFFECTS, OBSERVATIONAL STUDIES
WERE USED, BUT THE TYPE OF
EVIDENCE WAS UPGRADED BY ONE DUE
TO STRENGTH OF ASSOCIATION AND A
LACK OF BIAS FOR A FINAL
EVIDENCE TYPE OF TWO.
SO AGAIN, THE KEY POINT HERE, IS
THAT THERE IS HIGH QUALITY
EVIDENCE.
AGAIN, WHICH SHOWS THAT PCV USE
ON A TWO PLUS ONE SCHEDULE IS
EFFECTIVE AGAINST IPD AND
PNEUMONIA AND HAS STRONG
INDIRECT EFFECTS, WHICH HAVE
BEEN OBSERVED IN SEVERAL
COUNTRIES USING THE TWO PLUS ONE
SCHEDULE.
NEXT I WILL BRIEFLY ADDRESS THE
MORTALITY OUTCOMES.
I WILL NOT GO THROUGH THIS TABLE
IN DETAIL, BECAUSE IT IS IN YOUR
HANDOUT TO LOOK AT MORE, BUT THE
TAKEAWAY POINT FOR MORTALITY IS
DEATHS DUE TO IPD ARE LOW IN
HIGH INCOME COUNTRIES, INCLUDING
THE U.S.
NONE OF THE STUDIES WERE POWERED
TO DETECT THE IMPACT OF ANY
SCHEDULE ON THIS OUTCOME, SO WE
ARE UNABLE TO ASSESS THE IMPACT
OF PCV SCHEDULES ON MORTALITY.
THE LAST OUTCOME WAS ASSESSED
THROUGHOUT ALL SCHEDULES AND BY
DOSE WHEN POSSIBLE.
THREE DIFFERENT TYPES OF
EVIDENCE WERE USED TO GRADE THIS
OUTCOME.
EVIDENCE COMPARING PCV13 TO NO
VACCINE WERE NOT AVAILABLE,
THUS, DATA COMPARING PCV13 TO
PCV7 AS PART OF THE PCV13
LICENSURE FROM ONE RCT CONDUCTED
IN THE U.S. WERE USED.
ADDITIONALLY, AN OBSERVATIONAL
STUDY WAS INCLUDED TO LOOK AT
THE INCIDENTS AND TIMING OF
ASSOCIATED WITH PCV13 ALONE AND
WHEN COADMINISTERED WITH THE
INFLUENZA VACCINE. USING THE
DATA FROM THE LICENSURE
APPLICATION, THIS TABLE FIRST
SHOWS THE COMPARISON OF
INCIDENTS OF DEATHS AND OVERALL
SERIOUS ADVERSE EVENTS BETWEEN
PCV13 AND PCV7 GROUPS.
THERE WAS THREE DEATHS IN THE
PCV13 GROUP AND ONE DEATH IN THE
PCV7 GROUP.
IN THE PCV13 GROUP, THE DATE OF
DEATHS INCLUDED, THREE DAYS POST
DOSE ONE, 14 DAYS POST DOSE TWO,
AND 76 DAYS POST DOSE THREE.
IN THE PCV7 GROUPS, THE DATE OF
DEATH INCLUDED 13 DAYS POST DOSE
ONE.
FOR OVERALL SERIOUS ADVERSE
EVENTS, THERE WERE SMALL
DIFFERENCES BETWEEN THE TWO
GROUPS, AS YOU WILL SEE HERE.
AND INVESTIGATORS BELIEVE THAT
THESE SERIOUS ADVERSE EVENTS
WERE RELATED TO THE VACCINE.
THIS TABLE COMPARES TO INCIDENTS
OF DEATH IN THE PCV7 GROUP AS
COMPARED TO THE CONTROL GROUP.
IN THE PCV7 GROUP, THERE WERE
FOUR DEATHS.
OR 0.2 CASES PER 1,000 CHILDREN.
IN THE CONTROL GROUP, THERE WERE
EIGHT DEATHS.
OR 0.4 CASES TO 1,000 CHILDREN.
ALTHOUGH INVESTIGATORS REPORTED
THAT THESE DEATHS WERE NOT
RELATED TO THE VACCINE.
WE ALSO REVIEWED A PUBLISHED
STUDY USING THE VACCINE SAFETY
DATA LINK PROJECT DATA, WHICH
EVALUATED THE RISK OF SEIZURES
IN CHILDREN FOLLOWING A
COADMINISTRATION OF THE
INFLUENZA VACCINE AND PCV13.
THE BOTTOM BROWN LINE SHOWS RISK
DIFFERENCES FOR THE INFLUENZA
VACCINE ONLY BY MONTHS OF AGE.
THE MIDDLE GREEN LINE SHOWS
PCV13 ONLY, AND THE TOP BLUE
LINE SHOWS PCV13 AND THE
INFLUENZA VACCINE ADMINISTERED
TOGETHER.
RISK DIFFERENCE ESTIMATES VARIED
BY AGE, DUE TO THE VARYING
BASELINE RISK FOR SEIZURES IN
YOUNG CHILDREN, WITH THE HIGHEST
ESTIMATES OCCURRING AT 16
MONTHS, AROUND THE TIME WHEN THE
PCV BOOSTER IS ADMINISTERED.
THE RISK DIFFERENCE PEAKS AT
13.7 PER 100,000 DOSES FOR PCV13
WITHOUT THE COADMINISTRATION OF
THE INFLUENZA VACCINE.
AND 44.9 PER 100,000 DOSES FOR
BOTH THE INFLUENZA VACCINE AND
PCV13.
THE LOWEST ESTIMATES OCCURRED AT
59 MONTHS.
OVERALL, THERE ARE MANY UNIQUE
VACCINE COMBINATIONS, SO IT MAY
BE DIFFICULT TO ESTIMATE THE
RISK FOR EACH COMBINATION DUE TO
LACK OF STATISTICAL POWER.
ADDITIONAL ANALYSES LOOKING INTO
DIFFERENT VACCINE COMBINATIONS
AND COMPARING RISKS WITHIN
DIFFERENT AGE GROUPS IS
FORTHCOMING AND WILL BE
PRESENTED TO THE COMMITTEE AT A
FUTURE DATE.
NEXT WE DETERMINED THE EVIDENCE
TYPES FOR THE SERIOUS ADVERSE
EVENTS.
WE INCLUDED 14 RCTs.
FOR AN EVIDENCE TYPE ONE,
HOWEVER, DUE TO INDIRECT
COMPARISONS WHERE WE COMPARED
PCV13 TO PCV7, AND PCV7 TO A
CONTROL VACCINE, WE DOWNGRADED
THE EVIDENCE TYPE BY ONE FOR A
FINAL EVIDENCE TYPE OF TWO.
THE KEY POINT HERE IS THAT THE
PCV APPEARS TO BE SAFE ACROSS
ALL SCHEDULES.
NEXT WE COMBINED ALL OF THE
EVIDENCE TYPES JUST PRESENTED
PER OUTCOME FOR EACH SCHEDULE TO
ASSESS OVERALL EVIDENCE TYPES BY
SCHEDULE.
THE LOWEST EVIDENCE QUALITY FROM
CRITICAL OUTCOMES ASSESSED FOR
EACH SCHEDULE WAS USED.
THUS, EACH SCHEDULE IS SUPPORTED
BY A TYPE TWO OR S PREFERENCES.
WORK GROUP MEMBERS DETERMINED
THAT THE VALUES AND PREFERENCES
WERE HIGH FOR IPD, PNEUMONIA,
AND SERIOUS ADVERSE EVENTS, BUT
OF RELATIVELY LOWER VALUE FOR
INDIRECT EFFECTS.
LASTLY, WE PUT OUR ASSESSMENT
DATA TOGETHER TO MAKE A JUDGMENT
OF THE RECOMMENDATION CATEGORY
FOR EACH SCHEDULE IN STEP ONE.
WE ASKED THE WORK GROUP MEMBERS
TO RESPOND TO THE FOLLOWING FOUR
QUESTIONS, IS THE EVIDENCE
QUALITY LOW?
THE WORK GROUP DETERMINED THAT
THE EVIDENCE QUALITY SUPPORTING
EACH SCHEDULE WAS HIGH.
ARE THE NET BENEFITS LOW, OR IS
THERE UNCERTAINTY ABOUT THE
BALANCE OF BENEFITS VERSUS HARM?
THE WORK GROUP DETERMINED THAT
THERE WAS NO UNCERTAINTY ABOUT
EACH SCHEDULE PROVIDING
PROTECTION AGAINST CRITICAL
OUTCOMES.
IS THERE VARIABILITY OR
UNCERTAINTY IN WHICH OUTCOMES
ARE IMPORTANT TO PREVENT?
THE WORK GROUP HAD REACHED
CONSENSUS ON WHICH OUTCOMES ARE
IMPORTANT.
AND IS THERE UNCERTAINTY ABOUT
WHETHER THE NET BENEFITS ARE
WORTH THE COST?
WE DETERMINED THAT THE
INTERVENTION WAS COST EFFECTIVE.
COST EFFECTIVENESS STUDIES FOR
PCV HAVE BEEN CONDUCTED AND
PUBLISHED AS PREVIOUSLY
PRESENTED TO THIS COMMITTEE IN
OCTOBER, AND FOR THE SAKE OF
TIME, WE DID NOT PRESENT DATA
AGAIN HERE.
THESE ANSWERS INDICATE THAT EACH
SCHEDULE IS SUPPORTED BY A
CATEGORY "A" RECOMMENDATION,
WHICH IS A RECOMMENDATION FOR
WHICH THE DESIRABLE EFFECTS
CLEARLY OUTWEIGH THE UNDESIRABLE
EFFECTS.
OVERALL, THE GRADE PROCESS
SUGGESTS THAT IF WE HAD TO MAKE
POLICY DECISIONS TO RECOMMEND
PCV ON EITHER SCHEDULE FOR THE
FIRST TIME, THE DATA WOULD
I WILL NOW PRESENT STEP TWO PR
THE STUDIES WITH DIRECT SCHEDULE
COMPARISONS ONLY.
MOST OF THE DIRECT SCHEDULE
COMPARISONS WERE OBTAINED FROM
STUDIES.
WE ABSTRACTED DATA AND ANTIBODY
CONCENTRATIONS AND THE
PROPORTION ACHIEVING RESPONSE OF
CONCENTRATIONS OF GREATER THAN
OR EQUAL TO 0.35 MICROGRAMS PER
MILLILITER FOLLOWING THE PRIMARY
SERIES OF PCV OR A BOOSTER DOSE
OF EACH SCHEDULE.
A THRESHOLD OF 0.35 IS A
REFERENCE POINT WHICH WAS
DEVELOPED FOR ANTIBODY
COMPARISONS IN INFANT VACCINE
SCHEDULES TO SUPPORT AN IPD
INDICATION.
COMPARISONS BETWEEN SCHEDULES
WERE ALSO MADE BY LOOKING AT THE
RISK RATIOS PREPARING THE
PORTION GREATER THAN OR EQUAL TO
0.35 BETWEEN GROUPS AND THE
RATIO OF COMPARING GEOMETRIC
MEANS CONCENTRATION IN EACH
GROUP.
FOR STEP TWO, RCTs WITH DIRECT
SCHEDULE COMPARISONS INCLUDED
THOSE CONDUCTED IN ISRAEL, THE
UK, ONE ACROSS EUROPE, IN FIJI,
IN ICELAND, AND IN THE GAMBIA.
FOUR STUDIES COMPARED -- HAD
COMPARISONS, BETWEEN TWO PLUS
ONE OR THREE PLUS ZERO VERSUS
THREE PLUS ONES, AND TWO STUDIES
HAD COMPARISONS BETWEEN TWO
VERSUS THREE PRIMARY DOSES.
PCV7, 9, AND 10 WERE EVALUATED
IN THESE STUDIES.
THE FIRST TABLE PRESENTS THE
COMPARISON OF DATA FOR THREE
PLUS ZERO VERSUS THREE PLUS ONE.
AND IT SHOWS THE PROPORTIONS OF
ANTIBODY LEVELS GREATER THAN OR
EQUAL TO 0.35 FOR EACH GROUP IN
THE MIDDLE TWO COLUMNS AND THE
RISK RATIO COMPARING THE
PERCENTAGE ABOVE THIS THRESHOLD
AND GMC RATIOS FOR THREE PLUS
ZERO AND THREE PLUS ONE IN THE
LAST TWO COLUMNS.
ANTIBODY LEVELS FOR THE THREE
PLUS ZERO SCHEDULE WERE ASSESSED
POST PRIMARY OR APPROXIMATELY
SEVEN MONTHS AND FOR THREE PLUS
ONE WERE ASSESSED POST BOOSTER
AT APPROXIMATELY 13 MONTHS.
THREE TYPES, 6B, -F AND 1
LOWER PROPORTIONS ABOVE THE 0.35
THRESHOLD IN THE THREE PLUS ZER
THREE PLUS ONE.
FOR ALL TYPES, s WERE
SIGNIFICANTLY LOWER FOR THE ZE.
THESEHLIGHT A STRONG
BOOSTING EFFECT OBSERVED WHEN
THE LAST DOSE IS GIVEN IN THE
SECOND YEAR OF LIFE FOLLOWING A
PRIMARY SERIES.
HOWEVER, I WOULD LIKE TO NOTE
THAT IN THE MIDDLE TWO COLUMNS
IN BOTH GROUPS, THEY HAD HIGH
PROPORTIONS ABOVE THE 0.35
CUTOFF.
THE SECOND TABLE PRESENTS
SIMILAR COMPARISONS FOR TWO
VERSUS THREE PRIMARY DOSES.
THE RESPONSE IN EACH GROUP WAS
MEASURED APPROXIMATELY ONE MONTH
POST LAST DOSE.
NO TYPES DIFFERENCES BY
PERCENTAGES ABOVE THE
THRESHOLDS, AND TWO SEROTYPES,
6-B AND 23-F HAD SIGNIFICANTLY
LOWER GMCs FOR TWO, COMPARED TO
THREE, DOSES.
HOWEVER, AGAIN, BOTH GROUPS HAD
HIGH PROPORTIONS ABOVE THIS 0.35
CUTOFF.
THE LAST TABLE OF OUTCOME DATA
SHOWS COMPARISONS FOR TWO PLUS
ONE VERSUS THREE PLUS ONE.
ONLY ONE SEROTYPE, 6-B, HAD A
SIGNIFICANTLY LOWER PROTECTION
ABOVE 0.35 CUTOFF FOR THE TWO
PLUS ONE SCHEDULE, AS COMPARED
TO THREE PLUS ONE.
AND TWO SEROTYPES, 6-B AND 18-C,
HAD SIGNIFICANTLY LOWER GMC
RATIOS, BUT BOTH GROUPS HAD HIGH
PROPORTIONS ABOVE THE 0.35
CUTOFF.
I REALIZE THIS IS A LOT OF DATA
TO DIGEST, SO I PROMISE WE'RE
NEARING THE END, BUT TO HELP YOU
OUT MORE, WE THOUGHT WE WOULD
TRY TO DESCRIBE SOME OF THE KEY
POINTS.
THE FOLLOWING CAN BE SUMMARIZED.
THE PROPORTIONS GREATER THAN OR
EQUAL TO 0.35 ARE HIGH FOR
SCHEDULES WITH THREE AND
TWO-DOSE PRIMARY SERIES.
POST PRIMARY, THE THREE-DOSE
SCHEDULE APPEARS TO BE BETTER
THAN THE TWO-DOSE SCHEDULE.
FOR SOME SEROTYPES, ACCORDING TO
THE GMC RATIO DATA.
IN THE SECOND YEAR OF LIFE,
PREBOOSTER AND POST BOOSTER
DOSE, THERE WERE SMALL BUT
SIGNIFICANT DIFFERENCES FOR SOME
SEROTYPES ACCORDING TO THE GMC
RATIO DATA.
THE DIFFERENCES APPEAR TO BE
MORE PRONOUNCED AT THE PRIMARY
SERIES AND WHEN COMPARING GMC
VALUES OR RATIOS RATHER THAN
PROPORTIONS GREATER THAN OR
EQUAL TO 0.35.
HOWEVER, WE ALSO WANTED TO DRAW
YOUR ATTENTION TO SOME CAVEATS
WITH THIS DATA THAT NEED TO BE
CONSIDERED WHEN INTERPRETING.
REGARDING A CUTOFF OF 0.35
MICROGRAMS PER MILLILITER, THE
WORLD HEALTH ORGANIZATION HAD
DETERMINED THIS CUTOFF VALUE
THAT CORRELATED WITH PROTECTION
AGAINST IPD THROUGH VARIOUS
STAGES.
FIRST, THE RESULTS OF A U.S.
TRIAL WHICH SHOWED A 0.2 CUTOFF
POST DOSE THREE CORRELATED WITH
97.3% VACCINE EFFICACY AGAINST
IPD.
LATER, DATA FROM TWO RCTs WERE
ADDED, ONE PCV7 TRIAL AMONG THE
AMERICAN INDIANS, WHICH SHOWED A
CUTOFF VALUE OF 1.0, WHICH
CORRELATED WITH 76.8% VACCINE
EFFICACY, AND ONE PCV9 TRIAL IN
SOUTH AFRICAN INFANTS WHICH
SHOWED A CUTOFF VALUE OF 0.68,
WHICH CORRELATED WITH 90%
VACCINE EFFICACY.
AFTER ADDING DATA FOR THESE
THREE TRIALS, THE AGGREGATE
CUTOFF WAS DETERMINED AND RAISED
TO 0.35.
SO WHAT THIS DATA TELLS US, IS
THAT CHILDREN AT A HIGHER RISK
FOR PNEUMOCOCCAL DISEASE MAY
REQUIRE HIGHER ANTIBODY LEVELS
TO ACHIEVE AN EQUIVALENT
PROTECTIVE EFFICACY.
BUT THE KEY POINT FOR THE U.S.
POPULATION IS THAT THE CUTOFF
FOR IPD OF 0.35 MICROGRAMS PER
MILLILITER IS LIKELY HIGHER THAN
NECESSARY FOR A U.S. POPULATION
OF GENERALLY HEALTHY INFANTS.
OVERALL, THE CUTOFF OF 0.35
SHOULD BE INTERPRETED WITH
CAUTION.
IT WAS DEVELOPED AS AN AGGREGATE
CUTOFF FOR ALL SEROTYPES
COMBINED AND ITS CLINICAL
SIGNIFICANCE IS NOT ESTABLISHED
FOR INDIVIDUAL SEROTYPES, POST
BOOSTER MEASUREMENTS OF ANTIBODY
LEVELS, AND FOR NONIPD.
IN ADDITION, GMC RATIOS WERE
PRESENTED TO COMPARE THE
SCHEDULES SHOULD ALSO BE
INTERPRETED WITH CAUTION,
BECAUSE THEY DO NOT TAKE INTO
ACCOUNT ABSOLUTE VALUES FOR THE
ANTIBODY LEVELS OF THE GROUPS
COMPARED.
FOR EXAMPLE, TWO VERSUS FOUR
MICROGRAMS PER MILLILITER AND
0.35 VERSUS 0.7 HAVE THE SAME
GMC RATIOS.
SO THE KEY POINT IS THAT IT'S
IMPORTANT TO INTERPRET THE
DIFFERENCES WITH CAUTION AND
LOOK AT BOTH THE PERCENTS OF
GREATER THAN OR EQUAL TO 0.35
AND THE ABSOLUTE VALUE.
THAT'S FOR ALL COMPARISONS, THE
TYPE OF EVIDENCE IS ONE.
BECAUSE WE STARTED WITH RCTs AND
THERE WERE NO SERIOUS CONCERNS
NOTED ACROSS CRITERIA.
WE ALSO IDENTIFIED TWO
OBSERVATIONAL STUDIES WITH
DIRECT SCHEDULE COMPARISONS IN
THE U.S. USING PCV7 ON LOWER
RESPIRATORY TRACT INFECTIONS OR
LRTI AND AOM.
ALTHOUGH IT SHOULD BE NOTED THAT
AOM WAS NOT RANKED AS ONE OF THE
CRITICAL OUTCOMES IN STEP ONE.
THE FIRST OBSERVATIONAL STUDY
USING A PROPENSITY SCORE MATCHED
COHORT DESIGN IN THE U.S.
EVALUATED THE RATE OF
HOSPITALIZATIONS AND AMBULATORY
VISITS FOR PNEUMONIA IN A 2002
COHORT, COMPARING TWO VERSUS
THREE PRIMARY DOSES.
COMPARISONS BETWEEN SCHEDULES
WITH TWO AND THREE PRIMARY DOSE
SERIES BEFORE BOOSTER ARE SHOWN
ON THE LEFT GRAPH, AND AFTER
BOOSTER ON THE RIGHT GRAPH.
THE "Y" AXIS SHOWS THE HOSPITAL
ADMISSIONS AND "X" AXIS SHOWS
THE FOLLOW-UP MONTHS.
THE TOP SOLID BLACK LINE
REPRESENTS SCHEDULES WITH TWO
DOSES IN THE PRIMARY SERIES AND
THE BOTTOM DOTTED LINE
REPRESENTS THREE DOSES.
AND THIS STUDY FOUND THAT THERE
WAS A STATISTICALLY SIGNIFICANT
RATE DIFFERENCE OF 7.8 CASES PER
1,000 CHILDREN, OR FEWER
PNEUMONIA-RELATED
ADMINISTRATIONS IN THOSE WHO
RECEIVED THREE DOSES VERSUS TWO
DOSES.
HOWEVER, THIS DIFFERENCE
DISAPPEARED AFTER THE BOOSTER
DOSE WAS ADMINISTERED.
THIS TABLE SHOWS THE DATA FROM
THE SAME STUDY, BUT WHAT WAS
REPEATED FOR THE 2003.
POST PRIMARY, THREE PLUS ONE HAD
A GREATER INCIDENT AS COMPARED
TO TWO PLUS ONE, BUT THE
ABSOLUTE RATE DIFFERENCE WAS NOT
STATISTICALLY SIGNIFICANT.
POST BOOSTER, THREE PLUS ONE HAD
A LOWER INCIDENT AS COMPARED TO
TWO PLUS ONE, BUT AGAIN, THE
ABSOLUTE RATE DIFFERENCE WAS NOT
STATISTICALLY SIGNIFICANT.
IT IS DIFFICULT TO INTERPRET
THESE RESULTS GIVEN THE TWO-DOSE
PRIMARY SERIES HAD LOWER RATES
AND POST BOOSTER, THE THREE-DOSE
PRIMARY SERIES HAD LOWER RATES,
AND AS MENTIONED, NONE OF THE
DIFFERENCES WERE AS
STATISTICALLY SIGNIFICANT.
THE AUTHORS OF THE PAPER
CONCLUDED THERE WERE NO
DIFFERENCES OBSERVED BETWEEN
SCHEDULES FOR THIS 2003 COHORT.
THEY HYPOTHESIZED BY 2003, HERD
EFFECTS HAD LESSENED THE
DIFFERENCE BETWEEN THE TWO
GROUPS.
THE SECOND OBSERVATIONAL STUDY
COMPARING THE DIFFERENCES IN
CHILDREN BORN IN 2002 WHO
RECEIVED TWO OR THREE DOSES IN
THE PRIMARY PCV7 SERIES USING
PROPENSITY SCORE MATCH DATA FROM
AN INSURANCE CLAIMS DATA BASE,
THE STUDY ASSESSED O CUTE MEDIA
AFTER COMPLETION OF THE PRIMARY
SERIES AND BEFORE THE BOOSTER
DOSE, WHICH IS THE FIGURE ON THE
LEFT.
AND AFTER THE BOOSTER DOSE,
WHICH IS THE FIGURE ON THE
RIGHT, UNTIL FOUR YEARS OF AGE.
THE RESULTS SHOWED THAT THE
PREBOOSTER DOSE INCIDENTS RATES
WERE 0.38 FOR CHILDREN RECEIVING
TWO DOSES AND 0.35 PER PERSON
FOR CHILDREN RECEIVING THREE
DOSES, BUT THESE RATES WERE NOT
STATISTICALLY DIFFERENT.
POST BOOSTER INCIDENT RATES WERE
ALSO NOT STATISTICALLY DIFFERENT
BETWEEN THE GROUPS.
THE KEY POINT HERE IS THAT THERE
WERE NOT STATISTICALLY
SIGNIFICANT DIFFERENCES BETWEEN
SCHEDULES WITH TWO VERSUS THREE
DOSES IN THE PRIMARY SERIES
PRE OR POST BOOSTER.
THE DIRECT COMPARISONS OF
CLINICAL PNEUMONIA RELATED
HOSPITALIZATIONS AND ACUTE
OTITIS MEDIA, THE EVIDENCE TYPE
OF BOTH STARTED AS THREE AND
REMAINED THIS TYPE BECAUSE NO
GREAT CRITERIA WERE APPLIED FOR
UPGRADING OR DOWNGRADING THE KEY
POINT HERE IS THERE'S
UNFORTUNATELY LIMITED STUDIES
WITH DIRECT HEAD-TO-HEAD
COMPARISONS AND CLINICAL END
POINTS.
USING THE EVIDENCE TYPE TABLES
PRESENTED BY SCHEDULE AND BY
OUTCOME, WE THEN DETERMINED THE
OVERALL EVIDENCE TYPE FOR EACH
SCHEDULED COMPARISON.
THE LOWEST EVIDENCE QUALITY FROM
CRITICAL OUTCOME ASSESSED FOR
EACH SCHEDULE COMPARISON WAS
USED, THUS ALL SCHEDULED MEMBER
DETERMINED THAT THE VALUES AND
PREFERENCES WERE HIGH FOR
PNEUMONIA, BUT HAVE RELATIVELY
LOWER VALUE FOR ACUTE OTITIS
MEDIA.
DATA WAS RANKED AS RELATIVELY
LOWER VALUE BECAUSE THE CLINICAL
SIGNIFICANCE OF THE SURROGATE
DATA IS NOT ESTABLISHED FOR
NON-IPD OUTCOMES, POST BOOSTER
DOSE, OR INDIVIDUAL SEROTYPES.
LASTLY, WE PUT OUR ASSESSMENT
DATA TOGETHER TO MAKE A JUDGMENT
OF RECOMMENDATION CATEGORY FOR
EACH SCHEDULE.
WE ASKED THE WORK MEMBERS TO
RESPOND TO THE FOLLOWING FOUR
QUESTIONS, IS THE EVIDENCE
QUALITY LOW?
IT WAS DETERMINED THAT THE
EVIDENCE QUALITY SUPPORTING EACH
THREE-DOSE SCHEDULE COMPARED TO
A FOUR-DOSE SCHEDULE WAS LOW,
BECAUSE LIMITED HEAD-TO-HEAD
COMPARISONS WERE AVAILABLE AND
THE AVAILABLE DATA WERE USED AS
SURROGATES FOR IPD, BUT NOT FOR
OTHER CRITICAL OUTCOMES.
ARE THE NET BENEFITS LOW, OR IS
THERE UNCERTAINTY ABOUT THE
BALANCE VERSUS BENEFITS AND
HARM?
THE WORK GROUP DETERMINED THAT
THERE WAS SOME UNCERTAINTY ABOUT
THE BALANCE, GIVEN THE OBSERVED
DIFFERENCES FOR SOME SEROTYPES
AND ANTIBODY RESPONSE AND THE
CLINICAL RELEVANCE OF THESE
DIFFERENCES.
IS THERE VARIABILITY -- IS THERE
VARIABILITY OR UNCERTAINTY IN
WHAT OUTCOMES ARE IMPORTANT TO
PRESENT?
THE WORK GROUP REACHED A
CONSENSUS ON WHICH OUTCOMES WERE
IMPORTANT TO PREVENT.
LASTLY, IS THERE UNCERTAINTY
ABOUT WHETHER THE NET BENEFITS
ARE WORTH THE COST?
AS MENTIONED EARLIER, COST
EFFECTIVENESS ANALYSIS COMPARING
THE TWO PLUS ONE SCHEDULE TO
THREE PLUS ONE WAS PRESENTED
LAST OCTOBER TO THIS COMMITTEE.
THE STUDY WAS PUBLISHED AND
BASED ON THE RESULTS, IT WAS
DETERMINED THAT THE THREE PLUS
ON COMPARED TO
THE TWO PLUS ONE, WAS LESS COST
EFFECTIVE.
AND SO TO CONCLUDE THE FINDINGS
OF THE GRADE REVIEW, IN STEP
ONE, THERE WAS STRONG EVIDENCE
SUPPORTING EACH INDIVIDUAL
SCHEDULE COMPARED TO NO VACCINE.
IN STEP TWO, THERE WAS MORE
LIMITED EVIDENCE WITH FEW
STUDIES SHOWING DIRECT SCHEDULE
COMPARISONS.
THUS, THE GRADE PROCESS SUPPORTS
A CATEGORY-B RECOMMENDATION FOR
EACH THREE-DOSE PCV SCHEDULE,
TWO PLUS ONE AND THREE PLUS ZERO
AS COMPARED TO THREE PLUS ONE OR
THE FOUR-DOSE SCHEDULE, MEANING
A RECOMMENDATION FOR WHICH THE
DESIRABLE CONSEQUENCES PROBABLY
OUTWEIGH THE UNDESIRABLE
OUTCOMES.
THE NEXT PRESENTATION WILL
INCORPORATE THESE GREAT
CONCLUSIONS, ALONG WITH
ADDITIONAL DATA AND
CONSIDERATIONS AND PRESENT THE
WORK GROUP CONCLUSIONS THUS FAR.
AND I JUST WANT TO ACKNOWLEDGE
ALL OF THE PNEUMOCOCCAL WORK
GROUP FOR ALL OF THE HARD WORK
THAT WENT INTO THE GRADE PROCESS
AND THANK YOU FOR STICKING WITH
US, BECAUSE WE REALIZE IT'S A
LOT OF DATA, AS WELL.
AND I THANK YOU.
I THINK I HAVE A FEW MINUTES FOR
QUESTIONS, AS WELL.
THANKS FOR A VERY COMPLETE
DISCUSSION, KIND OF LOOKING AT A
VERY NUANCED APPROACH HERE.
DR. HARRISON, DO YOU HAVE A --
YEAH, IN TERMS OF ANTIBODY
RESISTANCE, YOU SHOWED DATA, I
BELIEVE, THROUGH 13 MONTHS FOR
SOME OF THE SCHEDULES, BUT ARE
THERE LONGER TERM PERSISTENCE
DATA FOR ALL THREE SCHEDULES,
COMPARING THE THREE?
>> CORRECT ME IF I'M WRONG, BUT
WE DID NOT FIND ANY OF THESE
DATA.
YEAH, AND MEASUREMENTS THAT WE
DID SHOW WAS LIMITED TO WHAT WAS
AVAILABLE IN THE STUDIES.
>> I'M THINKING OF DATA FROM THE
UK WITH THE MENINGOCOCCAL C
CONJUGATE VACCINE, THE
ACCELERATED THREE PLUS ZERO
SCHEDULE HAD A LIMITED
RESISTANCE OF ANTIBODY AND
EFFICACY WENT AWAY AFTER ONE
YEAR.
>> I DON'T KNOW, DID ANYONE WANT
TO COMMENT ON THAT STUDY IN
PARTICULAR?
I GUESS WE'D JUST SAY,
COMPLETELY DIFFERENT VACCINE AND
YOU'RE RIGHT, IF I'M NOT
MISTAKEN, THE ACCELERATED
SCHEDULE IS MORE LIKE A TWO,
FOUR, 12 OR TWO, FOUR, SIX.
I HAVE A QUESTION REGARDING
THE IMPORTANCE IN BETWEEN THE
VACCINE.
THE SCHEDULE YOU'RE PROPOSING
WOULD BE TWO, FOUR, AND I'M
THINKING, WHEN YOU THINK
ABOUT -- I CERTAINLY UNDERSTAND,
MY CLINICAL TRIALS GIVE YOU THAT
INFORMATION, BECAUSE THEY ARE
EXPERIMENTAL, BUT THE
EFFECTIVENESS TENDS TO BE LOWER
THAN EFFICACY, AND IN THE TRIALS
THAT YOU'RE SHOWING, THE
INTERVALS ADHERED TO
CONTROLLED STUDIES AND I'M
THINKING ABOUT SORT OF REAL
WORLD WHERE AS WE GO TO THE
TWO-ONE SCHEDULE, SOMEBODY MIGHT
GET A TWO-MONTH VACCINE, NOT GET
ANOTHER ONE UNTIL THEY ARE TEN
MONTHS OR NINE MONTHS, THEN COME
BACK POTENTIALLY FOR THEIR
BOOSTER, AND I'M THINKING IF
THAT INITIAL INTERVAL, SHORT
INTERVAL, IS IMPORTANT, WE WON'T
KNOW WHETHER THEY ARE OUT OF THE
RECOMMENDED INTERVAL WORK AS
WELL OR NOT.
YEAH, I THINK THAT'S A REALLY
GOOD POINT, AND WE DIDN'T
ADDRESS THE INTERVAL AND THE
GRADE PROCESS IN PARTICULAR.
THANK YOU.
>> THANK YOU FOR THAT TOUR
DE FORCE THROUGH THE DATA.
IF YOU COULD GO BACK TO SLIDES
22 THROUGH 25.
>> ALL RIGHT, GOES A BIT SLOW.
THANK YOU.
>> YOUR CONTROLLED INCIDENCE IS
THE UNITED STATES INCIDENCE AND
NOT THE DISEASE IN THOSE
COUNTRY, IS THAT CORRECT?
>> CORRECT.
INCIDENCE AMONG U.S. CHILDREN.
>> SO IF THE INCIDENCE OF THESE
DISEASES IN THESE COUNTRIES
WHERE THE STUDY WAS DONE WAS
HIGHER THAN THE NUMBER TO TREAT,
MIGHT AS WELL FALLEN?
YEAH, CORRECT.
>> IF YOU CAN GO TO THE NEXT
SLIDE, PLEASE?
>> 25?
25.
SO YOU HAVE A RATE RATIO.
NOW, IS THAT THE SAME RATE AGAIN
AS THE UNITED STATES RATE, OR
WERE THOSE THE RATES SPECIFIC
FOR THOSE COUNTRIES, BOTH BEFORE
AND AFTER THE INTRODUCTION OF
THE VACCINES?
THESE ARE SPECIFIC TO THESE
COUNTRIES BECAUSE THEY ARE FROM
A COMPLETELY SEPARATE STUDY OF
SPECIFIC COUNTRY DATA SET.
THANK YOU.
>> DOCTOR?
MY QUESTION COMES ALONG SLIDE
48.
YOU HAD SAID THERE WAS A
STATISTICALLY SIGNIFICANT
INCREASE IN HOSPITAL ADMISSIONS
FOR LOWER TRACT INFECTIONS
DURING THE PRIMARY SERIES UNTIL
THE BOOSTER IS DONE, IS THAT
CORRECT?
>> RIGHT, PREBOOSTER.
AND YOU EXPECT THAT TO HOLD
UP NOW THAT SOME HERD IMMUNITY
IS AROUND?
>> YEAH -- I DON'T KNOW, DID
ANYONE WANT TO COMMENT ON THAT,
AS WELL?
IF YOU WANT TO JUST GO TO
YOUR NEXT SLIDE.
I THINK THAT WILL HELP.
>> SARA MENTIONED IN THIS
PARTICULAR STUDY THAT THE
ASSOCIATION IS NOT RIGHT AND
INTERPRETED TO MEAN ONCE THEY
KICK IN, THE DIFFERENCE BETWEEN
SCHEDULES ARE SMALLER.
>> DR. BRADY?
I HAVE TWO THINGS.
FIRST OF ALL, I THINK THE GRADE
SYSTEM WORKS WELL FOR GRADING
EVIDENCE, BUT SOMETIMES IT
DOESN'T HELP YOU WITH THE
CONCLUSION.
AND WHEN YOU LOOK AT THE
INVASIVE PNEUMOCOCCAL DISEASE
WITH THE THREE PLUS ZERO AND THE
VACCINE EFFICACY WAS ONLY 74%
AND THE TWO PLUS ONE AND THREE
PLUS ONE WERE IN THE MID 90s, I
DON'T THINK YOU CAN SAY THEY ARE
EQUIVALENT.
I THINK IF YOU'RE LOOKING AT
DOES THREE PLUS ZERO PREVENT
PNEUMOCOCCAL, YES.
IS IT EQUIVALENT TO THE OTHER
ONE, NO.
THE OTHER QUESTION I HAVE IS,
MOST OF THESE STUDIES WERE
DONE -- NOW, THE THREE PLUS ZERO
WERE DONE IN AFRICAN COUNTRIES.
WE'VE DONE A REALLY NICE JOB IN
THE UNITED STATES OF ELIMINATING
THE DIFFERENCE IN DISPARITY IN
PNEUMOCOCCAL DISEASE IN
AFRICAN-AMERICAN CHILDREN.
AND I WOULD HATE TO FIND THAT WE
ACTUALLY DO NEED HIGHER LEVELS
OF ANTIBODY TO PROTECT
AFRICAN-AMERICAN CHILDREN AND IF
WE WENT TO A SCHEDULE THAT WAS
EITHER TWO PLUS ONE AND RETURNED
HAVING A DISPARITY, I WOULD BE
VERY UNCOMFORTABLE WITH THAT, SO
I THINK THAT'S ONE OF THE ISSUES
THAT NEEDS TO BE ADDRESSED,
BECAUSE WHEN YOU LOOK AT MOST OF
THE COUNTRIES, THEY DON'T HAVE
THE LEVEL OF AFRICAN-AMERICAN
CHILDREN AND IF YOU NOTICE FROM
THE NATIVE AMERICAN POPULATION,
THEY NEED A MUCH HIGHER LEVEL TO
GET VACCINE EFFICACY, AND I
DON'T KNOW IF WE KNOW WHAT IT IS
IN AFRICAN-AMERICANS, BUT I
WOULD BE VERY UNCOMFORTABLE IF
WE WERE TO SEE A CHANGE.
>> POINT TAKEN.
THANK YOU.
>> IF I COULD JUST THROW IN ONE
CAVEAT AROUND THAT, AND IT ALSO
SPEAKS TO THE POINT ABOUT THE
INTERVALS.
THE TRIALS IN AFRICA WERE DONE
ON SCHEDULE OF SIX, TEN, AND 14
WEEKS, AND WE KNOW WITH
PNEUMOCOCCAL VACCINE YOU GET A
BETTER RESPONSE IF YOU SPREAD
OUT.
TWO MONTHS IS BETTER THAN ONE
MONTH.
I THINK THE BALANCE WE NEED TO
STRIKE HERE, THOUGH, IS WE DON'T
WANT TO SPREAD IT OUT TOO FAR
BECAUSE WE DON'T THINK A SINGLE
DOSE GIVES YOU ENOUGH
PROTECTION, SO IT'S ONE POSSIBLE
DIFFERENCE THAN THE AFRICAN
DATA LOOK DIFFERENT THAN THE
TRIALS.
ANY ADDITIONAL QUESTIONS FOR
CLARIFICATION?
ALL RIGHT.