>>> I THINK I'M -- I'LL JUST GO
AHEAD AND ASK DR. BOCCHINI TO
INTRODUCE THE HPV SESSION.
GOOD AFTERNOON.
IT'S WITH SOME TREPIDATION THAT
I COME TO THE -- BUT THERE IS NO
VOTE SCHEDULED FOR THE HPV WORK
GROUP VACCINE SESSION SO WE'LL
GO FORWARD.
SO TODAY'S SESSION WE'RE GOING
TO CONTINUE TO PROVIDE THE
CLINICAL TRIAL DATA FROM THE
INVESTIGATION OF 9-VALENT HPV
VACCINE AND THEN DISCUSS THE
POLICY QUESTIONS THAT HAVE BEEN
DEVELOPED BY THE WORK GROUP AND
THE APPROACH TO GRADE AND THEN
WE'LL HAVE A DISCUSSION ABOUT
CURRENT INFORMATION ON 2-DOSE
HPV VACCINE SCHEDULES.
THEN TO GIVE YOU AN UPDATE ON
VACCINE WORK GROUP ACTIVITIES,
WE ARE DOING -- WORKING TO
PREPARE FOR THE EXPECTED
LICENSURE OF THE 9-VALENT HPV
VACCINE IN LATE 2014 AND WE'RE
CONTINUING TO REVIEW THE DATA ON
2-DOSE SCHEDULES.
WE'VE HAD A GSK PRESENTATION ON
2-DOSE DEVELOPMENTAL PROGRAM IN
2013 AND RECENTLY THE WORK GROUP
DID REVIEW DATABASED ON A
PRESENTATION ON THE 2-DOSE DATA
THAT'S AVAILABLE.
HERE'S THE TIME LINE THAT THE
WORK GROUP HAS FOR CONSIDERATION
OF THE 9-VALENT HPV VACCINE.
AS YOU KNOW, IN OCTOBER AT THE
OCTOBER MEETING WE PRESENTED AN
OVERVIEW OF THE 9-VALENT
CLINICAL VACCINE -- VACCINE
CLINICAL PROGRAM AND IN FEBRUARY
OF THIS YEAR HAD A PRESENTATION
ON ATTRIBUTION OF TYPES IN HPV
ASSOCIATED DISEASE AND SOME
INITIAL CLINICAL TRIAL DATA
BEING PRESENTED BY MERK.
TODAY WE'LL HAVE ADDITIONAL
CLINICAL TRIAL DATA PRESENTED BY
MERK AND AS I MENTIONED THE
GRADE POLICY QUESTIONS.
IN OCTOBER WE EXPECT TO PRESENT
INFORMATION ON HEALTH ECONOMICS,
DO THE -- PRESENT THE GRADE
ANALYSIS AND THEN PROVIDE SOME
RECOMMENDATION OPTIONS FOR
DISCUSSION AND THEN IN FEBRUARY
OF 2015 IS WHEN WE EXPECT THE
EARLIEST POSSIBLE NEED TO HAVE A
VOTE.
SO THIS IS THE FORMAL OUTLINE OF
TODAY'S SESSION.
DR. ALAIN LUXEMBOURG FROM MERCK
WILL PROVIDE ADDITIONAL TRIAL
DATA FROM THE 9-VALENT HPV
VACCINE CLINICAL TRIALS.
THEN DR. EILEEN DUNNE WILL
FOLLOW WITH THE POLICY ISSUES
AND THEN DR. LAURI MARKOWITZ
WILL PRESENT THE INFORMATION ON
2-DOSE SCHEDULES FOR THE
BIVALENT AND QUADRI VALENT
VACCINE.
THESE ARE THE WORK GROUP
MEMBERS.
WE HAVE A NUMBER OF VERY
VIGOROUS PHONE CALLS WITH A LOT
OF DISCUSSION AND A LOT OF INPUT
FROM EACH OF THE MEMBERS, AND I
APPRECIATE ALL OF THE INPUT THAT
WE'VE RECEIVED AND I ESPECIALLY
WANT TO HIGHLIGHT LAURI
MARKOWITZ, THE CDC LEAD, WHO HAS
KEPT GOOD ORGANIZATION FOR THE
GROUP AND KEPT US MOVING
FORWARD.
SO WITH THAT, WE'LL TURN THIS
OVER TO DR. LUXEMBOURG TO BEGIN
THE INITIAL N.
GOOD AFTERNOON, EVERYONE.
THIS IS GOING TO BE THE SECOND
PART OF THE PRESENTATION OF
CLINICAL DATA FROM THE 9-VALENT
HPV VACCINE PROGRAM.
THERE ARE A FEW ABBREVIATIONS
THAT YOU CAN SEE ON YOUR
HANDOUT.
LAST TIME WE TALKED ABOUT THE
THREE DOSES IN THE PROGRAM.
2 AND 9 STUDIES IN ADOLESCENTS.
WE TALKED ABOUT CONTINUING
LONGER TERM EFFECTIVENESS IN
IMMUNOLOGY STUDIES.
TODAY WE'LL TALK ABOUT THE THREE
OTHER STUDIES THAT WE COMPLETED.
THEY ARE MORE SUPPORTIVE STUDIES
AND ONE STUDY UNIQUE TO THE
PROGRAM TO ASSESS 9-VALENT
VACCINE.
THEN WE HAVE 2 DOSE REGIMEN.
LAST TIME WE FOUND -- THEY
DEMONSTRATED IT.
THEY HAVE DOCUMENTED IT.
NO INJECTION SITE.
TODAY WE TALK ABOUT THE TWO C
CONCOMITANT STUDY.
WE TALK ABOUT EVALUATION AND
PRIORITIZATION AND FINALLY
INTEGRATED SAFETY INCLUDING ALL
SIX STUDIES.
IT'S TO ASSESS CO ADMINISTRATION
OF THE 9-VALENT WITH TWO
VACCINES THAT ARE COMMONLY USED
IN ADOLESCENTS.
ONE IS A VACCINE COMMONLY USED
IN THIS COUNTRY.
WE ALL KNOW WHAT CONCOMITANT USE
STUDY IS SO THAT'S JUST A BRIEF
SUMMARY OF THE DESIGN.
DAY ONE IN THE CONCOMITANT
COHORT.
SUBJECT RECEIVED 9-VALENT.
ALL 9-VALENT ALONE IS A
NONCONCOMITANT GROUP.
NONCONCOMITANT GROUP RECEIVES IT
ONE MONTH LATER.
ALL SUBJECTS RECEIVED AT MONTH
TWO AND MONTH SIX A DOSE OF
9-VALENT.
THE OTHER DATA -- SO WITH
RESPECT TO THE 9-VALENT HPV
VACCINE ANTIGENS, YOU SEE THE
CONCOMITANT GROUP IN GREENISH
BLUE AND THE NONCONCOMITANT IN
ORAN
ORANGE.
NOW LOOKING -- FOR ALL NINE
TIMES.
NOW LOOKING FOR SERUM CONVERSION
RATES, YOU CAN SEE THAT THEY ARE
ALL THE SAME.
AND THEN LOOKING NOW AT
CONCOMITANT ANTIGEN.
LET'S LOOK AT MINECTRA.
IT CONTAINS FOUR SERO GROUPS,
ACW 1, 3, 5 AND Y SO ALL FOUR
SERO GROUPS THE CRITERIA WAS MET
AS WELL WHICH MEANS WE HAVE
REALLY NO SUBSTANTIAL DIFFERENCE
BETWEEN CONCOMITANT AND
NONCONCOMITANT COHORT.
LOOKING AT THE ANTIGENS.
WE ARE LOOKING AT .1.
GROSS ANTIGENS THE CRITERIA IS
MET AS WELL.
WE HAVE A VERY SIMILAR
IMMUNOGENICITY IN BOTH COHORTS.
WE HAVE FOUR ANTIGEN AND THE
ABBREVIATION -- LET'S GO TO THE
EVALUATION IN PRIOR RECIPIENTS.
I'LL SPEND A LITTLE MORE TIME
BECAUSE IT'S A UNIQUE STUDY TO
THIS PROGRAM.
THIS IS PRIMARILY A SAFETY STUDY
AND WHAT WE HAD IN MIND HERE IS
HEALTH CARE PROFESSIONAL WITH
THE 9-VALENT, SHOULD THE
9-VALENT BE LICENSED AND
RECOMMENDED WHEN THEY COME TO
THE PRIMARY CARE PHYSICIAN FOR
ADVICE, THERE IS SOME DATA
BECAUSE THERE MAY BE -- THE
INDIVIDUAL HAD BEEN VACCINATED
BEFORE LOOKING FOR ADDITIONAL
COVERAGE.
PEOPLE WITH A KNOWN HISTORY OF
HP VACCINATION.
THE GOAL IS PRY MIMARILY DOCUME
THAT IT IS SAFE.
WE OBVIOUSLY LOOKED AT THE
IMMUNOGENICITY.
SO SUBJECT ARE RANDOMIZED TO
9-VALENT VACCINE OF SALINE
PLACEBO.
ONCE AGAIN IT'S A SAFETY STUDY
SO THAT ALLOWS THE SAFETY OF THE
VACCINE TO BE MORE COMPLETELY
DEFINED AND WE COLLECTED THE
USUAL END POINT FOR THE FORMULA
AND SAFETY.
STUDY WAS CONDUCTED IN GIRLS AND
YOUNG WOMEN 12 TO 26 YEARS OF
AGE BECAUSE IT'S THE MOST LIKELY
AGE FOR PEOPLE TO LOOK FOR THE
VACCINATION.
HERE'S THE STUDY DESIGNED AGAIN
MORE AS A GRAPHIC.
SUBJECTS RECEIVED THREE DOSE OF
COMMERCIAL -- AND TO BE
DOCUMENTED BY MEDICAL RECORD AND
THEN -- THERE WAS A TIME
REQUESTED OF 12 MONTHS BETWEEN
THE LAST DOSE AND THE FIRST DOSE
OF WHAT THEY ARE RECEIVING IN
THE TRIAL AND THE REASON IS THAT
WE WANTED -- WE DIDN'T WANT THE
SUBJECT AT THE PEAK OF
IMMUNOGENICITY.
IT'S HOMOGENEOUS IN TERMS OF
ANTIBODY TYPE.
12 MONTHS WAS A REASONABLE TIME
TO WAIT.
THESE ARE SAFETY DATA.
WE SHOW SAFETY FIRST BECAUSE IT
WAS A PRIMARY OBJECTIVE.
YOU CAN SEE 9-VALENT VERSUS
SALINE PLACEBO.
IT'S PRETTY CLEAR THAT THE
VACCINE NEEDS -- THERE ARE FEW
WE ARELOOKING AT THE
AND IN TERMS
INJECTION SITE SURPRISE.S IMPOR.
9-VALENT
COHORT, WE HAVE RECEIVED 6 DOSE
OF HPV VACCINE IN THEIR LIFE.
IS IT SAFE?
SO LET'S LOOK FURTHER IN
INJECTION SITE AND, YOU KNOW,
YOU CAN SEE THAT FREQUENCY OF
INJECTION SITES ARE, IF YOU
REMEMBER, CONSISTENT WITH WHAT
WE'VE SEEN IN PRODUCT 1 LAST
TIME WITH PAIN, SWELLING, AND
EREYTHEMA BEING BY FAR THE MOST
COMMON.
HERE THE INJECTION SITE, IT
APPEARED ACCEPTABLE.
LET'S LOOK NOW AT IMMUNOGENIC Y
IMMUNOGENICITI
IMMUNOGENICITIES.
E YOU CAN LOOK AT SERUM
SEE THAT BOTH IN THE GIRL
AND THE YOUNG WOMEN SUBSET THE
SERUM CONVERSION RATES ARE HIGH,
WHICH MEANS THE VACCINE IS VERY
IMMUNOGENIC IN BOTH POPULATIONS.
LOOKING AT GMT.
SO YOU WANT TO LOOK FIRST AT THE
FOUR ORIGINAL TYPES, TYPES 6-11
AND 6-18.
WHAT YOU CAN SEE IS AT DAY ONE
THERE IS ALREADY A SUBSTANTIAL
GMT.
NOT A SURPRISE.
THEY ARE ALL PART OF THE
RECIPIENTS.
AT MONTH TWO WE HAVE A
SUBSTANTIAL INCREASE AND AFTER
TWO MORE DOSE THERE IS NOT MUCH
OF A CHANGE, WHICH MEANS YOU GET
MOST OF THE INCREASE AFTER THE
FIRST DOSE.
IT'S NOT A SURPRISE IT IS A
MEMORY RESPONSE AND WE -- YOU
KNOW, IT'S VERY CLEAR HERE.
EVEN THOUGH IT'S THE ADDITIONAL
TYPES, THE PICTURE IS DIFFERENT.
IN GENERAL THERE IS NO OR VERY
LITTLE ANTIBODY AT DAY ONE AND
THEN THERE IS SUBSTANTIAL
INCREASE AFTER THE FIRST DOSE
AND THERE IS FURTHER INCREASE
AFTER THE THIRD DOSE WITH SOME
OF THE TYPES WHERE, YOU KNOW, WE
HAVE MORE THAN HALF A LOG
DIFFERENCE.
THERE IS A BENEFIT IN MORE THAN
ONE DOSE FOR THE ADDITIONAL
TYPES.
THIS IS IN GIRLS.
WE SHOW THE GIRLS AND YOUNG
WOMEN DIFFERENTLY.
YOUNG WOMEN, NOT GOING TO SPEND
MUCH TIME.
THE PROFILE IS PRETTY MUCH THE
SAME.
MEMORY RESPONSE FOR THE ORIGINAL
TYPES, NEW TYPES.
MORE PATTERN THAT LOOKS LIKE A
PRIMARY RESPONSE.
SO SUMMARY.
WE HAVE AN ACCEPTABLE SAFETY
PROFILE AND THE VACCINE IS
HIGHLY IMMUNOGENIC.
THE QUESTION THAT COMES VERY
OFTEN, THE STUDY INVESTIGATED
THREE DOSE OF GALDASIL FOLLOWED
BY THREE DOSE OF 9-VALENT.
INVESTIGATE THREE REGIMEN,
PARTIAL DOSE, THAT WAS NOT THE
GOAL.
ALSO IT WAS PRIMARILY SAFETY
STUDY SO WE DON'T DO
IMMUNOGENICITY COMPARISON LET'S
SAY IN SUBJECT WHO RECEIVED
THREE DOSE OF COULD HE VALENT,
NINE DOSES OF COULD HE VALENT
VERSUS SUBJECT WHO RECEIVED
9-VALENT ALONE.
OBVIOUSLY WE ARE INTERESTED IN
THE COMPARISON, BUT IT HAS TO BE
ACROSS THE COMPARISON.
SO WE DID THAT AND COMPARING
IMMUNOGENICITY AFTER THREE DOSE
IN PRODUCT SIX VERSUS WHAT
HAPPENS IN ALL STUDIES IN THE
PROGRAM.
AND SO THE GOAL WAS TO COMPARE A
CROSS STUDY SO WHY DID WE DO
THAT?
IT'S BECAUSE IT'S KNOWN THE
PREVIOUS ANTIGENIC ENCOUNTER CAN
AFFECT THE IMMUNOGENIC RESPONSE.
AND WHAT WE HAVE TO KEEP IN MIND
IS THAT ALL THESE HPV TYPES, WE
USED THE N 1 PROTEIN.
THE N1 PROTEIN HAS A VERY
HIGH -- THERE IS A VERY HIGH
IMMUNOLOGY BETWEEN TYPES.
YOU KNOW, WE GIVE YOU EXAMPLE
BETWEEN TYPE 16 AND TYPE 33 --
I'M SORRY, TYPE 16 AND TYPE 31,
THERE IS APPROXIMATELY 83% WHICH
MEANS THAT YOU CANNOT SAY THAT
SUBJECT WILL PRIORITIZE THE
RECIPIENT.
IT'S OF INTEREST TO LOOK AT
WHAT'S GOING ON.
WE REMEMBER THE ORIGINAL ANTIGE
IT CAN BE EFFECTIVE.
LET'S LOOK AT THE DATA.
FIRST LET'S LOOK AT SERUM
CONVERSION RATES.
SO YOU SEE 9-VALENT VACCINE.
THIS IS FOR 6.
YOU SEE ALL THE SUBJECT IN THE
PROGRAM AND THE TWO GROUPS ARE
NOT DISTINGUISHABLE IN T
SERUM CONVERSION RATES.
VERY, VERY IMMUNOGENIC IN BOTH
GROUPS.
NOW LET'S LOOK AT GMT.
THE GMT IN YOUNG WOMEN IN BLUE
WE HAVE THE COHORT RECEIVING
9-VALENT AND 4 VALENT.
IN ORANGE WE SEE THE COHORT
RECEIVING 9-VALENT ONLY AND THE
ELO IS NATURAL HPV INFECTION.
LET'S FOCUS FIRST ON THE
ORIGINAL TYPES.
HERE WHAT WE SEE IS THAT THE GMT
IN SUBJECT RECEIVE 9-VALENT
AFTER 4-VALENT IS HIGHER THAN
WHAT WE'VE SEEN IN THE COMBINED
OTHER STUDIES WHERE SUBJECTS
RECEIVED 9-VALENT ALONE.
IT'S CONSISTENT WITH MEMORY
RESPONSE ONCE AGAIN.
LOOKING NOW AT THE NEW TYPES.
HERE WE SEE THAT THE PICTURE IS
REVERSED AND THE IMMUNOGENICITY
IS LOWER WITH RESPECT TO THE NEW
TYPES AND YOU HAVE THE GMT RATIO
AT THE BOTTOM WHICH IS
CONSISTENT WITH WHAT I TRIED TO
INTRODUCE, YOU KNOW.
AND SO THE GMT IN THE 9-VALENT
AFTER THE 4-VALENT GROUP IS
LOWER THAN 9-VALENT ALONE BUT
HIGHER THAN WITH NATURAL HPV
INFECTION.
THIS IS A COMPARISON WITH YOUNG
WOMEN, YOU KNOW?
AND IF WE LOOK AT GIRLS RECEIVED
9-VALENT AFTER 4-VALENT COMPARED
TO WOMEN WHO RECEIVED 9-VALENT
ONLY.
SO WOMEN RECEIVED 9-VALENT ONLY.
THEN THE DIFFERENCE IS LESS IN
RESPECT TO THE ADDITIONAL TYPES.
FOR SOME TYPES THE GMT IS
SLIGHTLY LOWER.
FOR THE ORIGINAL TYPES GMTs ARE
HIGHER.
SO IN SUMMARY, THIS IS ACROSS
THE COMPARISONS SO THE RESULTS
NEED TO BE INTERPRETED AS
CAUTION, AS EXPLORATORY.
IT'S CONSISTENT WITH PRIOR
OBSERVATION THAT IF YOU ARE
EXPOSED TO AN ANTIGEN AND THEN
FOLLOWING THAT WITH AN ANTIGEN
VARIANT, THERE IS A CHANCE THAT
YOU HAVE A LOWER IMMUNOGENICITY.
THE PRODUCT SEQUENCE ARE
LIMITED.
WE'VE DEMONSTRATED THAT THE
SERUM CONVERSIONS ARE HIGH.
WE HAVE DIFFERENCE OF GMT
BETWEEN THE GROUPS, THE
SIGNIFICANCE OF THE DIFFERENCES
ARE KNOWN BECAUSE THERE IS NO
KNOWN THRESHOLD OF ANTIBODY
PROTECTION.
ALSO IN ONE STUDY WE'VE SHOWN
THAT TITHERS ARE NOT LOWER.
ONCE AGAIN, THAT BRINGS TO MIND
THE FLU AND IN THAT FIELD IT'S
BEEN DEMONSTRATED THAT WITH
VACCINATION ASSOCIATED WITH
LOOKING NOW AT THE O IMPACT LI
SAFETY.
I KNOW YOU'VE SEEN DATA OR
YOU'VE BEEN INFORMED OF THE
RESULTS OF SIX STUDIES.
LET'S LOOK AT INTEGRATED SAFETY
FOR ALL SIX STUDIES AND BEFORE
GETTING THERE LET'S -- JUST AS A
REMINDER, YOU KNOW, WHAT
WE'VE -- WHAT YOU'VE BEEN SHOWN
LAST TIME IS COMPARING THE
9-VALENT AND THE 4-VALENT, THE
PROFILE WAS COMPARABLE.
SAFETY PROFILE WAS COMPARABLE
ONLY HIGHER FREQUENCY OF
INJECTION SITES AS I MENTIONED
MUST BE -- THAT'S WHAT
SEEN LAST TIME IN 7,000 --
APPROXIMATELY 7,000 SUBJECTS IN
EACH COHORT.
NOW LOOKING AT THE INTEGRITY
DATABASE.
LOOKING AT 13,000, OVER 13,000
SUBJECTS.
SAFETY PROFILE IS COMPARABLE TO
WHAT WE'VE SEEN SO FAR IN
PRODUCT 1.
VACCINE WAS ACCELERATED IN MOST
OF THE VACCINE SITES AND THERE
ARE VERY FEW -- INJECTION SITES,
PAIN, SWELLING, ERYTHEMA ARE THE
MOST COMMON.
THE FREQUENCIES ARE CONSISTENT
WITH WHAT WE'VE SEEN PREVIOUSLY
IN PRODUCT 1.
AND HERE FOR THE INTEGRATED DATA
MOST INJECTION SITES ARE MILD TO
MODERATE IN INTENSITY.
VACCINE RELATED SYSTEM WITH AN
INCIDENCE OF MORE THAN 1% IT'S,
AGAIN, A SHORT LIST.
A LIST OF EVENTS, EVERYDAY LIFE
EVENTS AND COMMON IN ANY VACCINE
WE HAD THECCINE
F THEM
THEY ALL RESOLVEDTHAT YOU KNOW,
4-
SO IN TERMS OF SAFETY, THAT
VACCINE PROFILE IN CERTAIN
SUBJECT, FEW DISCONTINUATION,
FEW VACCINE RELATED, NO VACCINE
RELATED DEATHS AND THE ADVERSE
EXPERIENCE PROFILE IS GENERALLY
COMPARABLE TO THE 4-VALENT.
WE'VE SEEN ALSO THAT THE
9-VALENT VACCINE WAS GIVEN TO
PRIOR RECIPIENTS.
IT'S WELL TO LOOK AT SUB GROUP
BY AGE, RACE, ETHNICITY.
WE DID NOT SEE MUCH DIFFERENCE
EITHER.
SO OVERALL SCENARIO OF PART 1
AND PART 2 DEMONSTRATED
NONFAILURE RESPONSE WITH RESPECT
TO THE ORIGINAL TYPES COMPARED
TO THE COULD HE VACCINE.
HIGH EFFICACY AGAINST THE
DISEASE ASSOCIATED WITH THE NEW
FINDINGS, THE COULD BE
EXTENDED IMMUNOGENICITY IN AND
WAS -- 9-VALENT CAN BE
CO-ADMINISTERED.
AS IT REMAINS, AN INVESTIGATION
AND A REVIEW BY
THE
THANK YOU VERY MUCH.
>> THANK YOU.
SHOULD WE MOVE TO THE NEXT AND
COVER THE 9-VALENT QUESTIONS LT?
IS THAT -- DR. DUNNE.
>> GOOD AFTERNOON.
IN THIS PRESENTATION WE'RE
SETTING THE STAGE FOR GRADE
REVIEW OF 9-VALENT HPV VACCINE
IN OCTOBER OF THIS YEAR.
IN ORDER TO FRAME THE POLICY
QUESTIONS I'D LIKE TO REVIEW
AGAIN THE ATTRIBUTION OF HPV
TYPES TO CERVICAL PRECANCERS AND
CANCERS, AND THIS WAS PRESENTED
TO ACIP IN FEBRUARY OF THIS
YEAR.
DISCUSSED 9-VALENT VACCINE
POLICY QUESTIONS FOR
CONSIDERATION AS WELL AS THE
AVAILABLE 9-VALENT HPV VACCINE
STUDIES.
THE CONCLUSIONS FROM THE WORK
GROUP ON CRITICAL OUTCOMES, THE
PICO FOR THE PRIMARY POLICY
QUESTIONS, COST-EFFECTIVENESS
CONSIDERATIONS AND OUR NEXT
STEPS.
SO THIS IS THE HPV TYPE
ATTRIBUTION BY CANCER SITE IN
THE U.S. AND IN RED IS THE
ATTRIBUTION TO HPV TYPE 16 AND
18 AND YELLOW IS THE ADDITIONAL
FIVE TYPES THAT ARE PREVENTED BY
9-VALENT HPV VACCINE.
IN GREEN ARE OTHER HPV TYPES AND
GRAY ARE HPV NEGATIVE.
AND AS YOU CAN SEE, HPV 16-18 IS
ATTRIBUTED TO MOST CANCERS.
THE FIVE ADDITIONAL TYPES ARE
ATTRIBUTED TO BETWEEN 14 AND 18%
CERVICAL AND VAGINAL CANCERS AND
6 TO 9% OF ANAL, PENILE, AND
ORAL PHARYNGEAL CANCERS.
THIS IS AN OVERVIEW OF HPV 16-18
AND AT TRIB BECAUSES TO CIN 2
PLUS AND INVASIVE CANCERS.
ABOUT 50% OF CIN 2 ARE
ATTRIBUTABLE TO HPV 16-18 AND
25% TO THE FIVE ADDITIONAL
TYPES.
AS FAR AS HPV ASSOCIATED
INVASIVE CANCERS, 62% ARE
ATTRIBUTED TO HPV 16-18 AND THIS
IS SIMILAR FOR FEMALES AND
MALES.
11% -- AN ADDITIONAL 11% OF
CANCERS ARE ATTRIBUTED TO THE
FIVE ADDITIONAL TYPES IN
9-VALENT HPV VACCINE AND THIS IS
DIFFERENT FOR FEMALES AND MALES
WITH 14% IN FEMALES AND 5% IN
MALES.
I'D LIKE TO SUMMARIZE THE
9-VALENT HPV VACCINE QUESTIONS.
THE QUESTIONS ARE SHOULD
9-VALENT BE RECOMMENDED
ROUTINELY FOR 11 OR 12-YEAR-OLDS
AND SHOULD 9-VALENT BE
RECOMMENDED FOR FEMALES AGE 13
THROUGH 26 YEARS AND MALES AGE
13 TO 21 YEARS SO NOT INITIATED
OR COMPLETED THE VACCINE SERIES?
THE HPV WORK GROUP WAS
INTERESTED IN CONSIDERING THESE
POLICY QUESTIONS FOR MALES AND
FEMALES AT THE SAME TIME FOR
PROGRAMMATIC REASONS.
ALTHOUGH BECAUSE THE OUTCOMES
ARE DIFFERENT IN FEMALES AND
MALES AS WELL AS THE
ATTRIBUTABLE FRACTION DUE TO
NINE TYPES, THE PICO WOULD BE
CONSIDERED SEPARATELY FOR MALES
AND FEMALES.
THE WORK GROUP WOULD LIKE TO
CONSIDER A RECOMMENDATION FOR
ADULT MALES WITH AVAILABLE DATA
IN OCTOBER OF THIS YEAR EVEN
THOUGH THERE WOULD NOT BE AN
ADULT MALE INDICATION FOR
9-VALENT HPV VACCINE AT THE TIME
OF FIRST LICENSURE.
OTHER POLICY QUESTIONS INCLUDED
GIRLS AND YOUNG WOMEN WHO
RECEIVED THREE DOSES OF QUAD
VALENT HPV VACCINE BE
REVACCINATED WITH 9-VALENT HPV
VACCINE AND SHOULD 9-VALENT HPV
VACCINE BE RECOMMENDED FOR MEN
WHO HAVE SEX WITH MEN THROUGH
AGE 26 YEARS?
SO YOU'VE SEEN THE SLIDE BEFORE
SUMMARIZES 9-VALENT HPV
VACCINE STUDIES FOR THE INITIAL
FILING.
STUDIES INCLUDE THE EFFICACY IN
ADULT FEMALES, WHICH WAS
PRESENTED EARLIER TO THE ACIP
AND EARLIER THIS YEAR.
ALSO IMMUNOGENICITY STUDIES IN
BOYS AND GIRLS AS WELL AS YOUNG
WOMEN.
THE CONCOMITANT USE STUDIES AS
WELL AS THE STUDY THAT WAS
HIGHLIGHTED EARLIER TODAY, WHICH
IS THE SAFETY STUDY OF 9-VALENT
HPV VACCINE IN PRIOR HPV 4
QUADREY VALENT VACCINE
RECIPIENTS.
AN ADDITIONAL STUDY WILL LIKELY
BE AVAILABLE IN OCTOBER AS I
HIGHLIGHTED EARLIER OF
IMMUNOGENICITY IN ADULT MALES.
SO I WOULD LIKE TO HIGHLIGHT
SOME FEATURES OF THE DATA
AVAILABLE FOR THE POLICY
QUESTIONS.
AS A REMINDER, THE MAIN TRIAL
WAS A COMPARISON OF QUADRI
VALENT VACCINE, THE PLACEBO ARM.
FOR ADULT FEMALES IT WILL BE
EFFICACY AND IMMUNOGENICITY
DATA.
IN ADULT MALES IT WILL BE
IMMUNOGENICITY DATA.
AS FAR AS THE DATA ON
RE-VACCINATION WITH 9-VALENT HPV
VACCINE IN FEMALES, THAT DATA IS
AVAILABLE IN FEMALES ONLY.
AND THE IMMUNIZATION SCHEDULE IN
THE TRIALS WAS 0, 2 AND 6
MONTHS.
IN ORDER TO ADDRESS THE CRITICAL
OUTCOMES TO CONSIDER FOR GRADE
WE SURVEYED THE HIV, HPV WORK
GROUPS IN MAY OF THIS YEAR ON
KEY OUTCOMES.
THIS INCLUDED SCORING OUTCOMES
IN FEMALES AND MALES AND
BENEFITS AND HARM.
WE RECEIVED 21 RESPONSES AND THE
FOLLOWING SLIDES SUMMARIZE THE
OPINIONS ON CRITICAL OUTCOMES.
WE ALSO SURVEYED AIM MEMBERS AND
RECEIVED 26 RESPONSES AND THE
FEEDBACK WAS CONSISTENT WITH THE
GROUPS.
LISTS
CRITICAL OUTCOMES FOR FEMALES.
THESE INCLUDE CERVICCANCER,
CERVICAL PRECANCER, ANAL CANCER,
VAGINAL VUL VAR CA CIN,
DEFINITIVE THERAPIES AND/OR ROW
AS A REMI MANY OF THES
OUTCOMES
INICAL TRIALS SOE WE'VE LISTED
OUTCOMES IN WHICH THERE'S DIRECT
DATA INCLUDING CERVICAL
PRECANCER, CIN, DEFINITIVE
THERAPIES, SAE AND ANAPHYLAXIS.
CERVICAL PRECANCER,
IMMUNOGENICITY AND VAGINAL
VULVAR PRECANCERS.
FOR MALES THE CRITICAL OUTCOMES
INCLUDED ANAL CANCER,
OROPHARYNGEAL CANCER, SAE AND
AN
ANAPHYLAX
ANAPHYLAXIS.
THERE WILL BE DIRECT DATA FOR
SAE AND ANAPHYLAXIS.
INDIRECT WILL INCLUDE
IMMUNOGENICITY.
FOR THE NEXT TWO SLIDES I'LL
SUMMARIZE THE PICO FOR THE
PRIMARY POLICY QUESTIONS OR THE
POPULATION INTERVENTION
COMPARISON AND OUTCOMES.
FOR THE QUESTION OF ROUTINE
VACCINATION AT 11 OR 12 YEARS
THE POPULATION OF FEMALES
IMMUNIZED AT AGES 8 AND 12, THE
COMPARISON IS QUAD DRI VALENT
VACCINE.
THE CRITICAL ELEMENTS WERE
HIGHLIGHTED EARLIER.
THE PRIMARY OBJECTIVE IS
EVALUATION OF HPV 6, 11, 16, 18
EE GIVE LENTSZ OR
NONINFERIORITY.
EVALUATION OF HPV 31, 45, 52
SUPERIORI
SUPERIORITY.
FOR MALES IT'S MALES IMMU
NIGHTED AT 11 OR 12 AND THE
CRITICAL OUTCOMES AGAIN WERE
HIGHLIGHTED EARLIER.
THE PRIMARY OBJECTIVE FOR THE
MALE EVALUATION WILL BE
EVALUATION OF 6, 11, 16, 18
EQUIVALENT.
WE DID NOT ELECT TO EVALUATE
SUPERIORITY OF THE FIVE HPV
TYPES OF MALES SUCH AS ANAL
CANCER AND OROPHARYNGEAL CANCER
IS LIMITED.
FOR THE OR THE QUESTION IN
OLDER FEMALES INCLUDES
OPULATION OF
IMMUNIZED FROM 13 TO 26 WITH TH
VATICAL OUTCOMESIGHLIGHTED BEFO
AGAIN, THE OBJECTIVE IS THE
EVALUATION OF HPV 6, 11, 16, 18
EQUIVALENT AS WELL AS FIVE TYPE
SUPERIORITY.
FOR MALES THIS IS SLIGHTLY
DIFFERENT.
MALES IMMUNIZED AT AGE 13
THROUGH 21 WITH THE SAME
INTERVENTION AND COMPARISON.
CRITICAL OUTCOMES WERE
HIGHLIGHTED BEFORE.
THE OBJECTIVE FOR MALES IS
EVALUATION.
THAT'S HPV 6, 11, 16, 18
EQUIVALENT.
AND I HAVE HIGHLIGHTED THE DATA
NUMEROUS TIMES BUT THIS IS,
AGAIN, THE DATA EVALUATED THAT
WILL BE EVALUATED FOR THE
PRIMARY POLICY QUESTIONS THAT
INCLUDES EFFICACY AND
IMMUNOGENICITY IN ADULT FEMALES.
IMMUNOGENICITY IN BOYS AND GIRLS
AND IMMUNOGENICITY IN ADULT
MALES.
AGAIN, A REMINDER THAT THE DATA
FOR IMMUNOGENICITY IN ADULT
MALES IS LIKELY TO BE AVAILABLE
IN OCTOBER OF 2014 FOR OUR GRADE
CONSIDERATION BUT IT WILL BE
PENDING FDA APPROVAL FOR ADULT
MAIL INDICATIONS A THE THE TIME
OF PRIMARY LICENSURE.
SO COST EFFECTIVENESS IS
CONSIDERED, AS YOU KNOW, FOR
GRADE.
FOR 9-VALENT HPV VACCINE WE'LL
PRESENT COST EFFECTIVENESS FOR
MALES AND FEMALES SEPARATELY AND
COMBINED IN OCTOBER OF THIS
YEAR.
COST EFFECTIVENESS OF
REVACCINATION WITH 9-VALENT
AFTER RECEIPT OF THREE DOSES OF
QUAD VALENT VACCINE WILL BE
PRESENTED AS WELL.
A VARIETY OF MODELS WILL BE
SUMMARIZED, BOTH CDC AND
EXTERNAL MODELS THAT USE U.S.
DATA.
IN SUMMARY, WE'RE HOPEFULLY
PROVIDING THE FOUNDATION FOR OUR
NEXT PRESENTATION TO
CONSIDERATION.
THE QUALITY QUESTIONS IN PICO
HAVE BEEN DEVELOPED AND AS FAR
AS NEXT STEPS ARE CONCERNED,
WE'LL DEVELOP TABLES OF EVIDENCE
ON 9-VALENT HPV VACCINE AND
PRESENT TO THE WORK GROUP AND
WE'LL ALSO PREPARE FOR
PRESENTATION ON COST
EFFECTIVENESS AND GRADE TO THE
HIP IN OCTOBER OF 2014 FOR
POSSIBLE RECOMMENDATION IN EARLY
2015 SO THANK YOU.
LET'S SEE IF THERE'S ANY
QUESTIONS OR COMMENTS ON THE
LAST TWO?
YES.
DR. KARYN.
>> YES, I HAVE ONE FOR DR. DUNNE
AND ONE FOR DR. LUXEMBOURG.
SO FOR YOU, DR. DUNNE, THE
QUESTION WAS -- I KNOW IN
PREVIOUS PRESENTATION YOU HAD
SPOKEN ABOUT ETHNIC RACIAL
DISPARITIES IN TERMS OF THE 5
VAIL LENT, I DIDN'T KNOW IF THAT
WAS FOR CARRIAGE, CI O2 OR
CANCER.
>> IN OUR PREVIOUS PRESENTATION
IN FEBRUARY IT WASN'T ME.
WE ALL LOOK THE SAME SOMETIMES
UP HERE.
WE PRESENTED ATTRIBUTION TO FIVE
TYPE AND IT'S THE NINE TYPES TO
CIN 2 PLUS AND CANCERS AND THERE
WERE RACE ETHNICITY DIFFERENCES
FOR THE CERVICAL PRECANCERS IN
PARTICULAR AND SO -- BUT
PRIMARILY FOR THE INVASIVE
CANCERS THE ATTRIBUTION OF 16-18
IS THE SAME ACROSS RACE
ETHNICITIES.
>> AND THE QUESTION I HAD FOR
DR. LUXEMBOURG IS WHEN WILL
THERE BE DATA AVAILABLE ON THE
2-DOSE REGIMEN FOR THE 9-VALENT
VACCINE?
SO WE ANTICIPATE THIS TO BE
CONDUCTED BEFORE THE END OF NEXT
YEAR.
DR. SCHEFFNER?
DR. HARRISON?
>> YOU SHOWED THE CHANGE IN
ANTIBODY TITHER BETWEEN DOSES 1
AND 3 BUT HOW ABOUT BETWEEN 2
AND 3?
>> IT WAS NOT SHOWN IN THIS
PARTICULAR STUDY.
IN PRODUCT 1 WE DID POST DOSE 2
AND POST DOSE 3 AND THERE WAS AN
INCREASE BUT IT'S RELATIVELY
SMALL.
YOU KNOW, PROBABLY AROUND 30%,
SOMETHING LIKE THAT.
>> DR. VASQUEZ?
YES, SIMILAR QUESTION.
WHEN YOU SHOWED IMMUNOGENICITY
DATA IN THE CROSS STUDY, THAT'S
COMPARING WHAT HAPPENED TO
INDIVIDUALS AFTER THREE DOSES OF
THE 9-VALENT.
DO YOU HAVE INFORMATION ON ONE
DOSE OR TWO DOSES?
WE DON'T HAVE THAT TYPE OF
INFORMATION FOR CROSS STUDY
COMPARISON.
WE STUDIED ONLY POST DOSE 1.
IN THE OTHER WE STUDIED ONLY
POST DOSE 2.
DR. ENGOLD?
>> YEAH.
I MEAN, I WAS WONDERING IF YOU
COULD ELABORATE A LITTLE BIT ON
THE DECISION NOT TO LOOK AT THE
CRITICAL OUTCOME OF MALES AND
I'M SURE THE DATA ARE SCANTY,
BUT I'M JUST CURIOUS IF THAT
REALLY IS NOT POSSIBLE.
>> IT ABSOLUTELY IS POSSIBLE BUT
THE FOCUS OF THE WORK GROUPS WAS
THE ATTRIBUTION -- MAYBE I
SHOULD SHOW THAT PREVIOUS SLIDE
AGAIN OF THE ATTRIBUTION TO THE
SPECIFIC FIVE TYPES IS LESS FOR
MALES THAN FOR FEMALES.
CERTAINLY THIS ISN'T SEPARATING
MALES AND FEMALES.
THE ATTRIBUTION FOR MALES IS 5%
OVERALL.
WE HAVE NOT YET PRESENTED COST
EFFECTIVENESS DATA AND I THINK
THAT WILL BE PRESENTED IN
OCTOBER OF THIS YEAR AND --
WHICH BRINGS UP ADDITIONAL
QUESTIONS OF COST EFFECTIVENESS
OF 9-VALENT FOR MALES AS WELL AS
FEMALES.
DR. KAREN?
>> SORRY.
I JUST WANTED TO ASK DR.
LUXEMBOURG A FOLLOW-UP QUESTION.
I JUST WANT TO UNDERSTAND.
I KNOW THERE IS A FORMAL SETTIN
THERE EXISTING DATA FOR NAIVE
INDIVIDUALS GETTING TWO DOSES OF
9-VALENT VACCINE PERHAPS IN
THE -- I MEAN, MAYBE THEY
RECEIVED THREE BUT YOU HAVE
IMMU
IMMUNOGENICITY DATA AFTER TWO
DOSES.
DID THOSE DATA ALREADY EXIST OR
DID THEY NOT EXIST AND YOU'RE
ANTICIPATING GETTING THEM WITH
AN UPCOMING STUDY?
THE ONLY DATA WE HAVE GOTTEN
IS PRODUCT 1, YOUNG WOMEN, 16 TO
26.
I THINK IT'S NOT COMPLETELY
RELEVANT TO WHAT THE ACIP WOULD
BE INTERESTED FOR TWO REASONS.
IT'S NOT THE GROUP THAT 2-DOSE
WOULD BE CONSIDERED.
AND THE OTHER IS THAT THE
SCHEDULE IS DIFFERENT ALSO FROM
WHAT WOULD BE CONSIDERED BECAUSE
SUBJECT RECEIVED AT DAY ONE
MONTH TWO AND MONTH SIX.
SO 2-DOSE -- ANY SUBJECT
RECEIVING 2-DOSE.
IT'S VERY DIFFERENT.
SO THAT LONG EXPANSION TO SAY,
NO, WE DO NOT HAVE RELEVANT DATA
AT THIS TIME.
>> OKAY.
LET'S MOVE ALONG TO DR.
MARKOWITZ.
WELL THE PURPOSE OF TODAY'S
MEETING IS TO INFORM THE
COMMITTEE ON 2-DOSE HPV VACCINE
SCHEDULES AND WHAT I'D LIKE TO
DO FIRST IS PROVIDE SOME
BACKGROUND AND THEN REVIEW SOME
RECOMMENDATIONS AND REGULATORY
APPROVALS AROUND THE WORLD, THEN
I WILL PRESENT THE DATA ON
2-DOSE SCHEDULES.
THIS IS NOT A COMPREHENSIVE
REVIEW OR EVIDENCE REVIEW, BUT
IT'S PROVIDING AN OVERVIEW OF
THE LANDSCAPE OF THE DATA
AVAILABLE FOR THE COMMITTEE.
THEN I'LL REVIEW DATA ON
COUNTRIES USING 2-DOSE SCHEDULES
CONSIDERED FOR THE U.S. AND THE
WORK GROUP PLAN.
AS BACKGROUND WE HAVE TWO
LICENSED PRODUCTS IN THE U.S.
I THINK EVERYBODY KNOWS THE
QUADRI VAI LIPT AND THE
BIVALENT.
THEY USE THE L1 PROTEINS.
THEY CONTAIN DIFFERENT
ADJUVANTS.
THE LICENSE IS THREE DOSE
SCHEDULE WITH THE SECOND DOSE
GIVEN ONE OR TWO DOSES AFTER THE
FIRST AND THE THIRD DOSE SIX
MONTHS AFTER THE FIRST DOSE.
FOR LICENSURE OF THE CURRENTLY
AVAILABLE VACCINES LARGE
EFFICACY TRIALS HAVE BEEN
PERFORMED IN 15 TO 26-YEAR-OLD
FEMALES AND THEN BRIDGING
IMMUNOGENICITY STUDIES WERE
CONDUCTED IN 9 TO 15-YEAR-OLDS
IN AGE GROUPS IN WHICH EFFICACY
TRIALS WERE NOT FEASIBLE.
LICENSURE WAS BASED ON THE
NONINFERIOR ANTIBODY RESPONSE
COMPARED TO THE AGE GROUP OF
WOMEN WHO HAD BEEN IN THE
EFFICACY TRIALS.
NOW OVER 99% OF VACCINATIONS
DEVELOPED ANTIBODIES.
THE HE HAVE SEFFICACY TRIALS, T
FIGURES FROM 2007, GMTS FROM 6,
11, 16, 18 ONE MONTH AFTER THE
THIRD DOSE BY AGE IN ENROLLMENT
FROM 9 TO 23 YEARS, YOU CAN SEE
FOR ALL OF THESE TYPES THE GMTss
WERE HIGHEST IN THE YOUNGEST
GROUPS AND DECREASED WITH AGE OF
VACCINATION.
VERY SIMILAR FINDINGS BY AGE ARE
AVAILABLE FOR THE BIVALENT
VACCINE FOR THE HPV 16 AND 18.
NOW THE MAIN BASIS OF PROTECTION
IS FELT TO BE NEUTRALIZING
ANTIBODY BUT THEN THE MINIMAL
PROTECTIVE ANTIBODY THRESHOLD IS
NOT KNOWN.
THE HIGH EFFICACY FOUND IN THE
VACCINE TRIALS HAS PRECLUDED
IDENTIFICATION OF A PROTECTOR
TITHER.
VACCINATION PRODUCES ANTIBODY
TITERS THAN AFTER NATURAL
INFECTION.
CLINICAL TRIALS OF THE
QUADRIVALENT, THEY LOST
DETECTABLE ANTIBODY.
THERE WAS NO LOSS OF PROTECTION
AGAINST THE END POINTS IN THE
TRIALS.
NOW I THINK EVERYONE KNOWS
THERE'S BEEN GLOBAL INTEREST IN
SIMPLIFIED SCHEDULES FOR HPV
VACCINE.
THIS WOULD BE MORE COMMON FOR
PROVIDERS AND VACCINEES.
IT WILL FACILITATE
IMPLEMENTATION.
ALSO DECREASED RESOURCE NEEDS.
THE HIGH EFFICACY FOUND IN THE
TRIALS PROMPTED REDUCED DOSE
SCHEDULES.
BEFORE I GO INTO THE DATA I WANT
TO MENTION A FEW MORE THINGS AS
BACKGROUND, AND ONE IS WHAT'S
CONSIDERED THE IMMUNOLOGIC BASIS
OF THE HPV VACCINE SCHEDULE.
THE THREE-DOSE SCHEDULE CAN BE
CONSIDERED A PRIME PRIME BOOST
SCHEDULE WITH THE FIRST TWO
DOSES BEING THE PRIMING DOSES
AND THE THIRD BEING THE BOOST.
AND A TWO-DOSE SCHEDULE AT 0-6
MONTHS CAN BE CONSIDERED A PRIME
BOOST WITH THE SECOND PRIME
HAVING BEEN DROPPED.
MEMORY D CELLS REQUIRE FOUR TO
SIX MONTHS TO MATURE AND
DIFFERENTIATE INTO HIGH DID HE
FIN KNIT AT THIS B CELLS.
WHO'S STRATEGIC ADVISORY GROUP
OF EXPERTS ARE SAGE ON
IMMUNIZATION CONSIDER A 2-DOSE
HPV VACCINE SCHEDULE IN FEBRUARY
OF 2014.
AT THAT MEETING THEY RECOMMENDED
A 2-DOSE VACCINATION SCHEDULE
FOR GIRLS IF VACCINATION IS
INITIATED PRIOR TO 15 YEARS OF
AGE.
THE MINIMUM INTERVAL BETWEEN THE
TWO DOSES BEING SIX MONTHS, THE
INTERVAL CAN BE SENT BACK.
A THREE-DOSE REMAINS NECESSARY
AFTER THE 16th BIRTHDAY AND
THREE-DOSE REMAINS RE78DED FOR
IMMUNOCOMPROMISED INDIVIDUALS
INCLUDING THOSE KNOWN TO BE
H.I.V. INFECTED.
I WILL REVIEW SOME OF THE DATA
FOD IN SYSTEMATIC REVIEW
OF THE LITERATURE AND THE EMA
ASSESSMENT REPORT AND BOTH OF
THESE ARE AVAILABLE ON THE WHO
WEBSITE.
I WANT TO MENTION THAT THE
MANUFACTURERS HAVE SUBMITTED
DATA ON 2-DOSE SCHEDULES.
THE BIVALENT VACCINE HAS
REGULATORY APPROVAL.
IN THE E.U. AND FIVE OTHER
COUNTRIES AS WELL AS COUNTRIES
IN LATIN AMERICA, ET CETERA, HAS
APPROVAL FOR THE USE OF THE TWO.
WHAT IS THE CURRENT STATUS OF
REGULATORY APPROVAL IN THE U.S.?
BIVALENT VACCINE THERE IS
SUBMISSION TO FDA FOR THE
QUADREY VALENT VACCINE, THERE
ARE NO PLANS FOR SUBMISSION
BECAUSE MERCK IS FOCUSING ON THE
9-VALENT VACCINE WHICH YOU HEARD
TODAY WHICH IS CURRENTLY -- THEN
THERE'S NO DATA ON 2 DOSES UNDER
CONSIDERATION BY FDA ALTHOUGH
TWO VERSUS THREE HAS BEEN
SUBMITTED.
I'LL REVIEW THAT LATER IN THIS
PRESENTATION.
WITH THAT BACKGROUND I'M GOING
TO REVIEW SOME OF THE DATA ON
TWO DOSE SCHEDULES FOR THE
BIVALENT QUADREY VALENT
VACCINES.
MOST OF THE DATA ARE FROM
IMMUNOGENICITY STUDIES.
THERE IS LIMITED DATA FROM POST
HAWK ANALYSES AND THERE ARE NOW
DATA FROM LICENSURE
EVALUATION.
FIRST I'M GOING TO REVIEW THE
IMMUNOGENICITY DATA AND MUCH OF
THIS WAS PRESENTED AT THE SAGE
MEETING.
THIS SLIDE SHOWS IMMUNOGENICITY
STUDIES COMPARING TWO AND THREE
DOSE STUDIES.
FOR EACH STUDY IT WAS THE
COUNTRY WHERE IT WAS PERFORMED,
THE VACCINE THAT WAS USED, THEA
FOLLOW-UP.
THERE ARE THREE STUDIES OF THE
BIVALENT VACCINE AND THE QUADREY
VALENT STUDY.
OTHER GROUPS WERE INCLUDED OTHER
THAN THOSE INDICATED HERE.
THERE ARE TWO PUBLICATIONS FROM
THIS STUDY.
THE MOST RECENT PUBLISHED LAST
MONTH HAVING A 48-MONTH
FOLLOW-UP.
THE SECOND STUDY IS ALSO GSK
SPONSORED STUDY CONSIDERED BY
GSK AS INCENTIVES OF TWO DOSES.
THESE DATA HAVE BEEN PRESENTED
AT TWO INTERNATIONAL MEETINGS IN
THE LAST EIGHT MONTHS AND THE
DATA HAVE ALSO BEEN SUBMITTED TO
REGULATORY AGENCIES.
AND THE THIRD STUDY IS A STUDY
CONDUCTED BY RESEARCHERS IN
MEXICO.
THERE ARE TWO STUDIES OF THE
QUADREY VAI LENGTH.
THE FIRST ONE HERE IS NEITHER OF
THESE WERE INDUSTRY SPONSORED.
THE FIRST ONE IS THE DOBSON
STUDY CONDUCTED IN CANADA.
THIS IS THE MAIN PUBLISHED STUDY
THAT WE HAVE ON THE QUADREY
VALENT VACCINE.
IT HAS BEEN PUBLISHED BY MERCK.
THIS LAST STUDY WAS CONDUCTED IN
INDIA.
IT WAS ORIGINALLY PLANNED AS A
RANDOMIZED TRIAL OF QUADREY
VALENT VACCINE WITH OVER 20,000
GIRLS 10 TO 18 YEARS OF AGE.
THE ORIGINAL DESIGN WAS GOING TO
EVEVALUATE THIN OUTCOMES.
THE PLAN WAS HALTED BY THE
GOVERNMENT.
AT THE PRESENT TIME DATA ARE
ONLY AVAILABLE IN A SUBSET FOR
IMMUNOGENICITY.
THE RANDOMIZED STUDY HAS BEEN
COMPROMISED.
FOUR OF THE STUD YISZ HAD A
GROUP THAT INCLUDED THE STANDARD
GROUP STUDY WHICH IS THE AGE
GROUP OF THE WOMEN IN THE
EFFICACY TRIALS.
THIS IS THE MAIN COMPARISON THAT
WAS MADE BETWEEN ANTIBODY IN
THIS GROUP WITH THE EXPERIMENTAL
2-DOSE SCHEDULES AND THE YOUNG
ADOLESCENTS.
FOUR STUDIES WERE DESIGNED TO
ALLOW A DIRECT COMPARISON
BETWEEN THE 2-DOSE SCHEDULE AT
0-6 MONTHS AND THE THREE-DOSE
SCHEDULE IN THE SAME AGE GROUP.
ONE STUDY OF THE BIVALENT
VACCINE COMPARED TWO DIFFERENT
2-DOSE SCHEDULES, 0-6 MONTHS AND
SHORTER SCHEDULE OF 0-2 MONTHS.
THIS COMPARISON WAS MADE IN
SEVERAL AGE GROUPS.
THE NEXT FEW SLIDES ARE GOING TO
BE FIGURES FROM THE SYSTEMATIC
AND THIS PARTICULAR SLIDE OR
SHOWS DIFFERENCES IN THE
PROPORTION SERO CONVE
SERO POSITIVE BETWEEN GIRLS WHO
RECEIVED 2 DOSES AND THE WOMEN
WHO RECEIVED THREE DOSES AND
THEY'RE CONSTRUCTED SIMILARLY.
ESTIHT FAVOR 2
DOSES AND ON THE LEFT FAVOR
THREE DO
THE DASH IS THE NONINFERIORITY
MARGIN.
FOUR STUDIES, TH
BIVALENT AND THE QUADREY VALENT.
THERE ARE MANY MORE DATA POINTS
BECAUSE 16 AND 18 ARE SHOWN
SEPARATELY AND THERE ARE ALSO
DATA POINTS FROM DIFFERENT
FOLLOW-UP PERIODS.
THEY'RE ALSO SEPARATED INTO HIGH
AND LOW INCOME COUNTRIES. COMPLO
LOOK AT.
THE TOP HALF OF THE SLIDE SHOWS
HPV 16.
FRISONS THERE WAS NO
DIFFERENCES IN SERO CONVERSION
OR SERO POSITIVITY BETWEEN
GIRLS WHO RECEIVED TWO DOSES AND
THE WOMEN WHO RECEIVED THREE.
FOR HPV 18 ON THE BOTTOM OF THE
SLIDE YOU CAN SEE THERE WAS NO
N FACT THE --
FOR HPV 18 ON THE ONE OF
THE QUADREY VALENT ACTIVITY,
SERO POSITIVITY WAS HIGHER AT 24
AND 36 MONTHS FOR GIRLS TO
RECEIVE 2 DOSES COMPARED TO
WOMEN WHO RECEIVE 3 DOSES
ALTHOUGH THIS WAS NOT
SIGNIFICANT.
AND THIS SLIDE SHOWS THE
GEOMETRIC MEAN CONCENTRATIONS
FROM THE SAME STUDIES I SHOWED
IN THE PREVIOUS SLIDE COMPARING
GIRLS WHO RECEIVED TWO DOSES AND
THOSE WHO RECEIVED THREE DOSES.
FOUR STUDIES CONTRIBUTED TO
THIS.
THREE OF THE BIVALENT, ONE OF
THE QUADREY VALENT.
AS YOU CAN SEE ON THE IT'S
SHOWN HPV 16 AND IN ALL OF THESE
TRIALS NONINFERIORITY CRITERIA
WERE MET.
AND FOR MOST OF TH
THE SCHEDULE IN GIRLS AND
SAME FOR THE HPV 18.
THE NEXT TWO SPOTS ARE
COMPARISONS OF GIRLS OF THE SAME
AGE RECEIVING EITHER THE 2-DOSE
OR THE 3-DOSE SCHEDULE.
THIS SHOWS DIFFERENCES IN
CONVERTING SERO POSITIVE AND
ONLY TWO STUDIES CONTRIBUTED TO
THIS ANALYSIS, ONE OF THE BIAND
ONE OF THE QUADREY VAI LANT.
FOR HPV 16 THERE WAS NO
DIFFERENCE BETWEEN THE AND SCH.
FOR 18 IN THE ONE ST
WASQUADRI VALENT, SERO
POSITIVITY WAS HIGHER AT 24 AND
36 MONTHS WHEN THE GIRLS WHO
RECEIVED THREE DOSES COMPARED
THOSE WHO RECEIVED TWO.
THE OVERALL WAS THE
NONINFERIORITY MOTION.
THIS IS THE PLOT SHOWING THE
GEOMETRIC MEAN CONCENTRATIONS IN
GIRLS THE SAME AGE WHO RECEIVED
TWO OR THREE DOSES ONE MONTH
AFTER THE LAST DOSE.
FOR HPV 16 THE FIRST TRIAL IS
THE BIVALENT VACCINE.
YOU CAN SEE THE GEOMETRIC MEAN
CONCENTRATION IS SOMEWHAT LOWER
BUT NOT SIGNIFICANTLY.
FOR THE QUADREY VALENT VACCINE
THE ESTIMATES WERE NOT MUCH
DIFFERENT ONE MONTH AFTER THE
LAST DOSE.
FOR HPV 18 FOR BOTH THE BIVALENT
AND QUADREY VALENT VACCINE,
GEOMETRIC MEAN CONCENTRATIONS
AFTER TWO DOSES WERE LOWER BUT
NOT INFERIOR TO THREE DOSES.
AND THE LAST -- ON THE GRAPH YOU
SEE THE STUDY FROM INDIA WHERE
HERE TWO DOSES ACTUALLY SEEMED
TO GIVE THE GEOMETRIC MEAN
CONCENTRATIONS OR THE HIGHER
THAN THE 3-DOSE SCHEDULE.
FINALLY THIS IS THE LAST FOREST
PLOT I'M GOING TO SHOW.
THIS SHOWS A COMPARISON BETWEEN
THE SCHEDULES WITH TWO DIFFERENT
INTERVALS BETWEEN THE TWO DOSES.
ALL OF THESE DATA POINTS ARE
FROM THE SAME STUDIES AS THE
BIVALENT VACCINE BUT WHAT'S
SHOWN HERE ARE THE DIFFERENT AGE
GROUPS THAT WERE COMPARED AND
YOU CAN SEE FOR ALL THE AGE
GROUPS AND BOTH FOR 16 AND 18
SCHEDULES WITH THE 0-6 MONTH
INTERVAL RESULTED IN HIGHER
GEOMETRIC MEAN CONCENTRATIONS
THAN THOSE WITH THE 0-2 MONTH
INTERVAL BETWEEN THE TWO DOSES.
NOW WHAT I'D LIKE TO DO IS
REVIEW SEPARATELY BIVALENT AND
QUADREY VALENT SO YOU CAN SEE
THE DATA THAT'S AVAILABLE FOR
EACH VACCINE.
FOR THE BIVALENT THIS WILL
INCLUDE SOME OF THE DATA THAT
WERE IN THE FOREST PLOT THAT
INCLUDE IMMUNOGENICITY DATA FROM
STUDY 48 WHICH WAS THE
CANADIAN/GERMANY STUDY AND 070
WHICH WAS THE MULTI-NATIONAL
STUDY.
THESE WERE THE DATA SUBMITTED TO
REGULATORY AGENCIES.
I WILL ALSO PRESENT DATA FROM
TWO POST HAWK ANAL
EFFICACY TRIALS THAT PROVIDE
EVIDENCE ON 2-DOSE TRIALS.
THIS WAS INCLUDED IN THE FOREST
PLOT OF THE SAGE REVIEW.THIS IS
ALSO CALLED MANY IN
THEREVIEW.
THIS WAS A DOSE RANGING TRIAL AS
WELL AS A 2 VERSUS 3-DOSE TRIAL.
THERE WAS A 48-MONTH FOLLOW-UP
THAT WAS PUBLISHED LASTTH AND T
JUST THE LICENSE FORMULATION IN
TWO GROUPS.T IS THE MOST IGROUP
14-YEAR-OLDS AND THREE DOSES IN
15 TO 26-YEAR-OLDS.
FINDINGS THAT ALL PEOPLE
REMAIN SERO .
THE GEOMETRIC TITERS WERE
DIFFERENT BETWEEN THE TWO DOSE
AND THE THREE DOSE. SHOWS THE I
KINETICS FOR TWO GROUPS WHERE
A PLATEAU.OF TIBODYAFTER THE L
YOU CAN SEE THE LINES ARE ALMOST
COMPLETELY SUPERIMPOSED FOR THE
TWO GROUPS.
THIS WAS THE DESIGN OF THE 070
WHICH WAS CONSIDERED
CONFIRMATORY TRIAL, THE LARGER
TWO VERSUS THREE TRIAL.
THE DESIGN WAS SLIGHTLY
DIFFERENT.
THERE ARE TWO DIFFERENT
EXPERIMENTAL GROUPS IN THE 9 TO
14 GROUPS, 0-6 MONTH AND 0-2
MONTH.
THERE WAS A CONCURRENT GROUP.
THESE ARE THE DATA FROM THAT
STUDY AND ON THE LEFT IN THE
BLUE BARS WHAT'S SHOWN IS -- ARE
THE GEOMETRIC TITERS ONE MONTH
AFTER THE LAST DOSE IN THE THREE
STUDY GROUPS.
ON THE FAR LEFT IS THE
15-25-YEAR-OLD WOMEN WHO
RECEIVED THREE DOSES.
THEN THE 14- -- 9-14-YEAR-OLD
GIRLS RECEIVED TWO AND THE
9-14-YEAR-OLD GIRLS RECEIVED 12.
YOU CAN SEE THERE IS NO
DIFFERENCE IN GEOMETRIC MEAN
TITERS BETWEEN THE THREE GROUPS.
THE ORANGE BARS SHOWED THE
LONGEST FOLLOW-UP TO DATE WHICH
IS SIX MONTHS AFTER THE LAST
DOSE AND THE DATA HERE ARE ONLY
AVAILABLE FOR THE WOMEN 15-25
AND THE 0-6 MONTH GROUP.
GEOMETRIC MEAN TITERS WERE LOWER
BUT NOT SIGNIFICANT CAN'TLY AND
THE GIRLS RECEIVED TWO DOSES AND
NONINFERIORITY TITERS WERE NOT
MET.
EFFICACY DATA ARE AVAILABLE FROM
TWO POST HAWK ANALYSES.
I THINK WE'VE SHOWN SOME OF
THESE DATA TO ACIP BEFORE.
IT'S IMPORTANT TO KNOW THEY WERE
NOT DESIGNED TO LOOK AT THE
NUMBER OF DOSES BUT TO
THE EFFICACY OF THREE DOSES.
IT'S THE POST HAWK EVALUATION OF
EFFICACY FROM PERSISTENT
INFECTION.
AMONG WOMEN ENROLLED IN THIS
RCT, 20% RECEIVED LESS THAN
THREE DOSES.
THIS POST HAWK ANALYSIS THE END
POINT WAS INSTANT PERSISTENT
INFECTION.
THIS IS PIVOTAL RANDOMIZED
CONTROLLED TRIAL FOR THE
MANUFACTURER PATRICIA.
IN THIS LARGE TRIAL OF 15 TO
25-YEAR-OLD WOMEN COMPLIANCE
WITH 3-DOIRS SCHEDULE IS HIGH.
SHOWN HERE ARE THE 2 AND 3 DOSE
EFFICACY AGAINST 6-MONTH
PERSISTENT INFECTION WITH 16 AND
18.
YOU CAN SEE THE NUMBERS ARE VERY
SMALL HERE.
THE EFFICACY WAS 100% FOR TWO
DOSES, 93.7 FOR THREE DOSES.
NOW I'D LIKE TO GO ONTO THE QUAD
DRI VALENT VACCINE AND GO INTO
MORE DATA ON THAT.
THE MAIN DATA AVAILABLE FOR TWO
DOSES ARE THE IMMUNOGENICITY
DATA FROM A STUDY IN CANADA AND
TWO DOSES IN YOUNGER ADOLESCENTS
AND THREE IN OLDER WOMEN.
I WILL ALSO MENTION DATA
AVAILABLE FROM A RANDOMIZED
CONTROL TRIAL OF DIFFERENT THREE
SCHEDULES -- I'M SORRY, OF
DIFFERENT THREE-DOSE SCHEDULES
IN GIRLS 11 TO 13 YEARS OLD THAT
PROVIDES SOME DATA ON TWO-DOSE
SCHEDULES.
AGAIN, THIS STUDY WAS ALSO PART
OF THE SAGE SYSTEMATIC REVIEW
AND I'M JUST REVIEWING THEM HERE
IN MORE DETAIL.
THIS IS THE -- THE DESIGN OF THE
STUDY 9-13-YEAR-OLD GIRLS WERE
RANDOMIZED TO RECEIVE VACCINE AT
0-6 OR THESTANDARD 0-26.
THIS ALLOWED TWO DIFFERENT
COMPARE SOCHBS.
THIS COMPARED TO WOMEN AS WELL
GROUP THAT
RECEIVED A THREE-DOSE
THESE ARE THE RESULTSIS
STUDY.
THE MAIN COMPARISON WAS FOR THE
TWO-DOSE SCHEDULE IN THE GIRLS
COMPARED TO THE THREE-DOSE
SCHEDULE IN THE WOMEN AND YOU
CAN SEE HERE THAT NONINFERIORITY
CRITERIA WERE MET FOR ALL TYPES.
IN FACT, THE ANTIBODY RESPONSE
WAS HIGHER IN THE GIRLS WHO
RECEIVED TWO DOSES WITH
GEOMETRIC MEAN TITER RATIOS
GREATER THAN ONE.
THIS WAS THE MAIN END POINT FOR
THE TRIAL.
IN THE DIRECT COMPARISON OF THE
TWO AND THREE-DOSE SCHEDULE IN
THE 9-13-YEAR-OLDS YOU CAN SEE
THE GEOMETRIC MEAN TITERS
LESS THAN 1.
AND NONINFERIORITY WAS LOST FOR
HPV 18 BY 24 MONTH AND FOR HPV 6
BY 36 MONTHS.
THESE GRAPHS SHOW GEOMETRIC MEAN
TITERS FOR THIS TRIAL FOR HPV 16
AND 18 AND YOU CAN SEE THAT
ACTUALLY EVEN THOUGH THERE WERE
DIFFERENCES THE ANTIBODIES
FOLLOW THE SAME KINETICS IN ALL
SCHEDULES.
ANTIBODY REACHES A PEAK AT ONE
MONTH AFTER THE LAST DOSE AND
DECLINES AND REACHES A PLATEAU
AND FOR BOTH THE 2 AND 3-DOSE
GIRLS SHOWN IN RED AND BLACK,
THEY MAINTAINED A PLATEAU LEVEL
THAT WERE HIGHER THAN THOSE IN
THE YOUNG ADULT WOMEN SHOWN IN
GREEN.
LAST I WANT TO MENTION THE
RANDOMIZED TRIAL OF ALTERNATIVE
THREE-DOSE SCHEDULES FOR QUADREY
VALENT VACCINE.
THIS STUDY WAS CONDUCTED IN
VIETNAM.
11-13-YEAR-OLD GIRLS WERE
RANDOMIZED TO RECEIVE THE
STANDARD REGIMEN 026 OR EXTENDED
INTERVALS 039, 0, 6, 12, 24.
ONE MONTH AFTER THE 0 3 9 AND 0,
6, 12, IN A FOLLOW-UP STUDY AT
MONTH 29 TO 32 NONINFERIORITY
CRITERIA WERE MET FOR ALL OF THE
SCHEDULES FOR ALL OF THE TYPES.
NOW IN THIS TRIAL A SEROLOGY
SAMPLE WAS OBTAINED BOTH PREAND
POST DOSE THREE.
THIS SLIDE SHOWS GEOMETRIC MEAN
TITERS.
YOU CAN SEE THERE WAS A TREND
FOR HIGHER ANTIBODY LEVELS
BEFORE THE THIRD DOSE WITH
INCREASING LEVELS BETWEEN DOSE 1
AND DOSE 2 RANGING FROM 657 IN
THE STANDARD SCHEDULE TO 1581 IN
THE 0, 12, 24 SCHEDULE.
AND OF NOTE, B BECAUSE THE
SCHEDULES WERE DIFFERENT,
ACTUALLY THE TIME BETWEEN
VACCINATION AND BLOOD DRAW AFTER
THE SECOND DOSE ALSO VARIED, FOR
EXAMPLE IN THE 0, 2, 6-MONTH
SCHEDULE, THE TIME IS FOUR
MONTHS WHILE IN THE OTHER
SCHEDULES THEY WERE LONGER, IN
SPITE OF THIS WE STILL SEE THAT
HIGHER ANTIBODY TITER WITH A
LONGER INTERVAL BETWEEN DOSE
AND DOSE 2.NOW I'D LIKE TO REVI
EFFECTIVENESS DATA THAT ARE
AVAILABLE FROM POST LICENSURE
MONITORING STUDIES.
THERE ARE NOW DATA FROM POST
LICENSURE MONITORING STUDIES AND
POPULATION IMPACT ON SOME EARLY
OUTCOMES HAS BEEN DEMONSTRATED
IN COUNTRIES WITH HIGH AS WELL
AS MODERATE OR LOW COVERAGE.
I'M NOT GOING TO GO OVER THESE
BUT I JUST LISTED THE VARIETY OF
COUNTRIES THAT HAVE LOW IMPACT
EARLY IN THE VACCINATION
PROGRAM.
BUT I WOULD LIKE TO REVIEW THOSE
STUDIES THAT VACCINE
EFFECTIVENESS STUDIES THAT HAVE
TRIED OR LOOKED AT VACCINE
EFFECTIVENESS BY NUMBER OF DOSES
AND SHOWN ON THIS SLIDE ARE THE
FOUR STUDIES THAT DO PROVIDE
SOME INFORMATION ON VACCINE
EFFECTIVENESS BY NUMBER OF
DOSES.
THERE ARE THREE FOR QUADREY
VALENT AND ONE FOR BIVALENT.
THE FIRST THREE WERE DATA
LINKAGE STUDIES THAT USE DATA
REGISTRY INFORMATION FOR THOSE
COUNTRIES.
THE LAST WAS A SERIAL CROSS
SECTIONAL STUDY OF THE HPV
PREVALENCE.
TWO EVALUATED CERVICAL
ABNORMALITIES AND ONE TYPE
SPECIFIC PREVALENCE.
I SHOULD MENTION THERE ARE A
VARIETY OF OTHER VACCINE
EFFECTIVENESS STUDIES ONGOING
INCLUDING ONE IN THE U.S.
LOOKING AT EFFICACY AGAINST
CONDOLOMA.
THERE ARE A VARIETY OF
CHALLENGES BEFORE I PRESENT THE
DATA.
FIRST OF ALL, EARLY IN THE
PROGRAMS THESE EFFECTIVENESS
STUDIES ARE EVALUATING OUTCOMES
THAT ARE IN THE CATCHUP
POPULATION, NOT THOSE THAT WERE
VACCINATED IN THE TARGET AGE.
MANY PEOPLE WERE INFECTED BEFORE
VACCINATION.
SECOND, THERE ARE DIFFERENCES
BETWEEN TWO AND THREE-DOSE
RECIPIENTS.
THIRD, THAT THE DO
NOT EXAMINE THE 0-6 MONTH
TWO-DOSE SCHEDULE BUT RATHER
PEOPLE WHO ARE ON THE
TRADITIONAL SCHEDULES MAY NOT
HAVE COMPLETED -- THAT DID NOT
COMPLETE THEIR THIRD
I'LL GO THROUGH THESE BRIEFLY.
AUSTRALIA.
THE OUTCOME WITH CERVICAL
ABNORMALITIES.
THEY LOOKED AT 3 CINAND WHAT Y
SLIDE, BUT THE HAZARD RATIO FOR
N IS .53 ANDCEIVED THREE
RECEIVED DOSES WAS .87 WHICH
WAS NOT SIGNIFICANTLY DIFFERENT
FROM THE UNVACCINATED AND FOR
CIN 2 THE HAZARD RATIO IS FOR T
THOSE WHO RECEIVED ONLY TWO
DOSES.
NOW THE AUTHORS POINT OUT THE
MANY LIMITATIONS OF THIS STUDY.
EVEN THOUGH THEY CONTROL FOR THE
DIFFERENCES THERE COULD BE SOME
RECITY SID DUAL CONFOUNDING AND
THEY POINT OUT WOMEN WHO
RECEIVED TWO DOSES ARE YOUNGER.
OLDER AT VACCINATION AND HAD
LOWER SOCIOECONOMIC STATUS.
THIS IS THE SECOND STUDY FROM
AUSTRALIA.
IT HAD A DIFFERENT STUDY DESIGN
BUT ALSO LOOKED AT CERVICAL
ABNORMALITIES AND HERE I
PRESENTED RESULTS FOR THE ENTIRE
AGE RANGE.
THEY LOOKED AT11-27-YEAR-OLDS
AS WELL AS RESTRICTED TO THE 15
TO 18-YEAR-OLDS.
FOR THE ENTIRE AGEHERE
WAS ALSO A DIFFERENCE HERE FOUND
BETWEEN TWO AND THREE DOSE
VACCINEES WITH THE ODDS RATIO
BEING .54 FOR DOSES
AND .79 FOR TWO DOSES.S SIGNIFI.
AND FOR THE 15-18-YEAR-OLDS THE
ADJUSTED ODD RATIO IS .43
SHOWING HIGHER EFFICACY IN THIS
AGE GROUP THAN THE EXTENDED AGE
GROUP AND ALSO FOR TWO
DOSES .77.
AGAIN, THE SAME LIMITATIONS HERE
APPLY THAT I EXPLAINED FOR THE
OTHER STUDY IN AUSTRALIA.
NOW THIS STUDY OF THE QUADREY
VALENT VACCINE EFFECTIVENESS FOR
CONDO LOMA IN SWEDE DONE IS AN
OPEN COHORT OF ALL WOMEN LIVING
IN SWEDEN.
IT WAS A LARGE STUDY USING
POPULATION BASE REGISTERS.
OVER 1 MILLION WOMEN WERE
INCLUDED AND OVER 20,000 CASES
OF GENITAL WARTS.
AND INCIDENCE WAS SIGNIFICANTLY
REDUCED FOR ONE, TWO, THREE DOSE
VACCINEES COMPARED TO THOSE
UNVACCINATED BUT THE INCIDENCE
RATIO DIFFERED IN THEIR PRIMARY
ANALYSIS WITH THE INCIDENCE
RATIO FOR THREE DOSES BEING .18
AND THE OTHER BEING .29.
THIS DEMONSTRATED IMPACT BY THE
THREE-DOSE SERIES.
THE AUTHORS POINT OUT THAT THE
MAIN ANALYSIS WAS DONE WITH AN
INTERVAL OF 24R50E MONTHS
BETWEEN VACCINATION AND CASE
COUNTING WITH A LONGER PERIOD
BETWEEN VACCINATION AND CASE
COUNTING, MORE GENITAL WARTS CAN
BE EXCLUDED THAT MIGHT BE DUE TO
EXPOSURE PRIOR TO VACCINATION
AND WITH A PERIOD OF FIVE MONTHS
INSTEAD OF THREE MONTHS A
SIGNIFICANT DIFFERENCE IN THE
CONDOLOMA WAS NO LONGER
OBSERVED BETWEEN TWO AND
THREE-DOSE VACCINEES.
THIS SHOULD HAVE BEEN UP WHEN I
JUST REVIEWED THAT.
THE LAST EFFECTIVENESS WAS OF
THE BIVALENT VACCINE.
CROSS SECTIONAL STUDY OF WOMEN
20 TO 21 YEARS OF AGE PRESENTING
FOR CERVICAL CANCER SCREENING
AND THEY LOOKED AT HPV
PREVALENCE.
THE DATA WERE LINKED TO
IMMUNIZATION REGISTRIES.
HERE YOU SEE THE ADJUSTED ODDS
RATIOS WAS DIFFERENT, .43 FOR
THREE DOSES AND .68 FOR TWO
DOSES.
SO IN SUMMARY, THIS IS JUST A
SUMMARY OF THE IMMUNOGENICITY,
EFFECTIVENESS DATA, THE
GEOMETRIC FOR BOTH VACCINES, THE
TITERS WERE NONINFERIOR FOR TWO
DOSES COMPARED TO THREE DOSES IN
THE ROUTINE SCHEDULE FOR WOMEN
15-26 YEARS OF AGE.
GEOMETRIC MEAN TITERS WERE LOWER
BUT NONINFERIOR AFTER TWO DOSES
COMPARED TO THREE DOSES ONE
MONTH AFTER THE LAST DOSE.
SOME QUADREY VALENT VACCINES DID
BOOST NONINFERIORITY FOR TWO
TYPES AT LATER TIME POINTS.
FOR BOTH VACCINES GEOMETRIC MEAN
TITERS ARE HIGHER FOR LONGER
INTERVALS BETWEEN A TWO-DOSE
SCHEDULE.
FOR EFFICACY, THERE ARE TWO
SMALL POST HAWK ANALYSES FOR THE
BIVALENT VACCINE THAT FOUND HIGH
EFFICACY.
FOR THE QUADREY VALENT, THERE
MAY BE MORE INFORMATION IN THE
FUTURE.
FOR EFFECTIVENESS, THERE ARE
FOUR POST LICENSURE
EFFECTIVENESS EVALUATIONS THAT
HAVE LOOKED AT THE NUMBER OF
DOSES, THREE FOR THE QUADREY
VALENT AND FOUR FOR THE HIGHER.
THERE ARE REALLY MANY
LIMITATIONS AND CHALLENGES WITH
POST LICENSURE EFFECTIVENESS
EVALUATIONS AT THIS POINT IN THE
VACCINATION PROGRAMS AND I HAVE
V
REVIEWED THOSE ALREADY.
THERE ARE A VARIETY OF REMAINING
QUESTIONS.
I'VE JUST LISTED ONE HERE.
THE MAIN QUESTION IS THE
DIFFERENCES IN DURATION OF
PROTECTION IF THERE IS INITIAL
EFFICACY.
WE KNOW THAT SOME LONGER FALLS
WILL BE AVAILABLE FROM SOME
STUDIES.
MODELING EFFORTS HAVE LOOKED AT
THIS.
WE HAVE SOME INFORMATION OR SOME
INFORM TO INFORM US FROM THOSE
MODELING STUDIES AND TWO STUDIES
SUGGEST THAT IF TWO-DOSE
SCHEDULES PROTECT FOR 20 YEARS
AND THE BENEFITS OF THE THIRD
DOSE ARE SMALL, IF THEY PROTECT
FOR TEN YEARS THEN THE THIRD
DOSE MAY PREVENT AS MANY CANCERS
AS THE THIRD DOSES.
WE INTEND TO LOOK AT THIS IN THE
U.S. FOR LATER PRESENTATION TO
ACIP.
I MENTIONED EARLIER THAT SAGE
HAS RECOMMENDED A TWO-DOSE
SCHEDULE FOR HPV VACCINATION.
BEFORE THAT SEVERAL COUNTRIES
HAD CHANGED TO TWO DOSE
SCHEDULES OR SOME THE EXTENDED
THREE-DOSE SCHEDULE.
THE PURPOSE OF THE EXTENDED
THREE-DOSE SCHEDULES WAS TO
ALLOW IMPLEMENTATION OF THE
VACCINATIONS.
THAT WAS IF IT WAS DECIDED THE
THIRD DOSE WASN'T NEEDED.
AND THESE ARE THE COUNTRIES,
JUST SOME OF THEM, THERE ARE
MORE, BUT I JUST WANTED TO
HIGHLIGHT THESE.
QUEBEC WAS THE FIRST
JURISDICTION TO IMPLEMENT THIS.
THEY IMPLEMENTED THAT IN 2008
AND THEY CHANGED TO A TWO-DOSE
SCHEDULE LAST SUMMER.
BRITISH COLUMBIA CHANGED FROM A
KWAUD DRI VALENT THREE DOSE
SCHEDULE TO THE EXTENDED
THREE-DOSE SCHEDULE IN 0.
THEY'RE REVIEWING THEIR
RECOMMENDATIONS NOW.
MEXICO HAS BEEN USING EXTENDED
THREE DOSE SCHEDULE SINCE THEIR
NATIONAL PROGRAM IN 20112.
I KNOW THERE ARE PEOPLE FROM
MEXICO AND THEY CAN UPDATE THIS
IF THERE'S MORE INFORMATION.
SWITZERLAND CHANGED FROM A
THREE-DOSE TO A TWO-DOSE FROM 11
TO 14-YEAR-OLDS IN 2012.
ENGLAND RECENTLY ANNOUNCED THAT
THEY WILL CHANGE FROM A QUADREY
VALENT THREE DOSE SCHEDULE TO A
QUADREY VALENT TWO DOSE SCHEDULE
FOR THEIR SCHOOL-BASED PROGRAM
IN THE FALL OF THIS YEAR.
AND, AGAIN, THERE'S MANY
OTHER -- MANY OTHER TWO-DOSE
SCHEDULES AS JUST AN EXAMPLE OF
MANY OF THEM THAT WE'RE AWARE
OF.
COMING BACK TO THE U.S. WHICH I
MENTIONED EARLIER, THERE'S BEEN
NO SUBMISSION OF DATA TO FDA FOR
THE BIVALENT.
THERE ARE NO PLANS TO SUBMIT
DATA FOR THE QUADREY VALENT
BECAUSE THEY'RE FOCUSING ON THE
INVESTIGATIONAL 9-VALENT
TRIAL -- PROGRAM.
AND THERE'S NO DATA ON TWO DOSES
IN THE BLA UNDER CONSIDERATION
BUT A TRIAL HAS BEEN INITIATED
BY THE MANUFACTURER.
THIS IS THE -- SOME INFORMATION
FROM THE TRIAL WHICH IS
REGISTERED ON A CLINICAL
TRIALS.GOV.
IT'S AN IMMUNOGENICITY STUDY.
IT STARTED IN DECEMBER 2013 AND
ACCORDING TO THE WEBSITE, THE
LAST VISIT OF THE LAST PERSON
ENROLLED WILL BE IN JULY 2015.
WE ASSUME IT WILL TAKE SEVERAL
MONTHS TO ANALYZE THE DATA AND
WE WOULD HAVE DATA AVAILABLE TO
LOOK AT IN THE FALL OF 2015.
THERE ARE FIVE ARMS IN THIS
TRIAL.
THERE ARE THREE EXPERIMENTAL
GROUPS.
THERE'S A TWO-DOSE GROUP AT 0-6
GROUPS IN 9-14 GIRLS.
A TWO-DOSE GROUP IN
9-14-YEAR-OLD BOYS.
TWO DOSES AT 0-12 MONTHS IN
9-14-YEAR-OLDS.
THE THREE-DOSE GROUP IN THE
9-14-YEAR-OLDS AND THE THREE
DOSE GROUP IN THE 15-26-YEAR-OLD
WOMEN.
NOW I WANT TO MENTION A LITTLE
BIT ABOUT THE PLANS OF THE WORK
GROUP.
OUR PLANS HAVE BEEN TO REVIEW
AND CONSIDER AND STILL ARE TO
REVIEW AND CONSIDER THE 9-VALENT
VACCINE AT THE THREE-DOSE
SCHEDULE AND TO CONSIDER
TWO-DOSE SCHEDULES WHEN DATA
FROM THE TWO VERSUS THREE-DOSE
TRIAL OF 9-VALENT VACCINE ARE
AVAILABLE.
HOWEVER, WE HAVE HAD OTHER
DISCUSSIONS ABOUT OTHER OPTIONS
AND THE MAIN ONE, OF COURSE, IS
TO CONSIDER A 2-DOSE SCHEDULE
NOW FOR BIVALENT QUADREY VALENT
VACCINE IN 9-14-YEAR-OLDS.
I WANT BE TO EMPHASIZE FOR OLDER
INDIVIDUALS THE THREE-DOSE
SCHEDULE IS TO BE RECOMMENDED.
BECAUSE OF THE INTERSECTION OF
THE 9-VALENT AND 2-DOSE, IT'S A
BIT MORE COMPLICATED.
ONE OF THE THINGS WE DISCUSS IS
IF A 2-DOSE SCHEDULE IS
CONSIDERED, WHAT WOULD BE THE
OPTIONS?
THIS INCLUDES WAITING UNTIL
THERE ARE DATA FOR A 2-DOSE
SCHEDULE BEFORE CONSIDERING
MAKING ANY RECOMMENDATIONS FOR
THE 9-VALENT, RECOMMENDING THE
9-VALENT AS A THREE-DOSE
SCHEDULE SO GOING BACK TO A
THREE-DOSE SCHEDULE OR
RECOMMENDING THE 9-VALENT AT THE
TWO-DOSE SCHEDULE WITH NO DATA.
MOST OF THE WORK GROUP MEMBERS
THOUGHT WE SHOULD CONTINUE TO
REVIEW AND CONSIDER THE 9-VALENT
AS A THREE-DOSE SCHEDULE AND TO
CONSIDER TWO-DOSE SCHEDULES WHEN
DATA FROM THE TWO VERSUS THREE
WERE AVAILABLE.
THERE WERE DEFINITELY A MINORITY
OPINION.
NOW I JUST WANT TO END THIS TALK
REVIEWING DATA ON COVERAGE IN
THE U.S.
I KNOW ALL ACIP MEMBERS ARE VERY
FAMILIAR WITH THIS GRAPH WHICH
SHOWS NATIONAL COVERAGE LEVELS
AMONG ADOLESCENTS FROM 2006 TO
'12 FOR ALL OF OUR ADOLESCENT
VACCINES AND SHOWING TDAP AND
MENINGOCOCCAL.
33% HAD RECEIVED ALL THREE
DOSES.
AND IN THE LAST THREE YEARS
THERE'S BEEN VERY LIMITED
INCREASE IN COVERAGE AND NO
INCREASE BETWEEN 2011 AND '12.
ONE OF THE INTEREST IN THE
2-DOSE SCHEDULES IS TO
FACILITATE THE SCHEDULES
ALTHOUGH WE HAVE NO DATA THAT
SIMPLIFIED SCHEDULES THEMSELVES
WOULD INCREASE VACCINE
INITIATION.
AND HERE WHAT'S GRAPHED ARE
COVERAGE FOR AT LEAST ONE DOSE,
AT LEAST TWO DOSES AND ALL THREE
DOSES FROM 2007 TO 2012 IN
FEMALES.
YOU CAN SEE ALL THESE HAVE A
SIMILAR TRAJECTORY.
54% RECEIVED AT LEAST ONE DOSE,
43% AT LEAST TWO AND 33% THREE
AND THERE'S A SIMILAR DROPOFF
BETWEEN 1 AND 2 AND 2 AND 3
DOSES.
SO JUST TO JUST EXTEND THE TIME
LINE DR. BOCCHINI SAID, THIS IS
OUR CURRENT SCHEDULE.
IN FEBRUARY OF COURSE WE HAD THE
PRESENTATIONS ALREADY DISCUSSED.
TODAY WE HEARD THE CLINICAL
TRIAL DATA AND IN OCTOBER WE
WOULD HAVE GRADE ECONOMIC
ANALYSIS.
HERE THE IMMUNOGENICITY AND
PRERCHT RECOMMENDATION OPTIONS.
FEBRUARY WOULD BE THE ESTIMATED
EARLIEST POSSIBLE VOTE ON THE
9-VALENT AND OCTOBER 15 WOULD BE
THE EARLIEST POTENTIAL DAY THAT
WE WOULD HEAR ON THE 9-VALENT
TWO DOSE TRIAL THAT WOULD BE
AVAILABLE.
I WANT TO THANK EVERYONE WHO
HELPED ME.
I PARTICULARLY WANT TO THANK
EILEEN DUNNE WHO WILL BE
TO THAILAND.
THANK YOU.
>> THANK YOU VERY MUCH.
OPEN FOR QUESTIONS AND COMMENTS.
YES, DR. MERM MAN.
HAVE ANY OF TOUNTRIES
THAT HAVE SWITCHED TO THE 2-DOSE
SCHEDULE SIGNALED WHAT THEY
MIGHT DO WITH THE 9-VALENT
VACCINE?
>> I'VE HAD SOME INFORMAL
DISCUSSIONS WITH PEOPLE ABOUT
THAT.
I THINK EVERYONE'S GRAPPLING
WITH THE SAME ISSUE.
DR. DUCHIN.
>> THANK YOU FOR THAT
COMPREHENSIVE REVIEW.
WHAT WAS THE REASON THAT THE 2
DOSE WAS SOUGHT IN SO MANY
COUNTRIES AND NOT HERE?
I THINK WE CAN -- I'D LIKE TO
TURN THAT OVER TO THE
MANUFACTURERS IF THEY WANT TO
ADDRESS THAT.
GO AHEAD.
>> DEVELOPING THE PRODUCTS AND
CONTRIBUTING TO THE EVIDENCE
BASE THAT INFORMS POLICY
DECISIONS.
THE LEVEL OF INTEREST IN THE
2-DOSE REGIMEN HAS VARIED FROM
COUNTRY TO COUNTRY.
IN EUROPE THERE WAS SIGNIFICANT
INTEREST AND SO WE DID PROVIDE
THE DATA THAT WAS USED, BOTH BY
REGULATORS AND POLICY MAKERS TO
LEAD TO THAT DISCUSSION.
YOU KNOW, THAT BEING SAID, AS
YOU'VE SEEN FROM THE
PRESENTATIONS BY DR. MARKOWITZ
AND OTHERS, YOU KNOW, WE HAVE
BEEN INVOLVED IN GENERATING DATA
THAT ARE RELEVANT TO THE
DELIBERATIONS THAT YOU'LL BE
CARRYING OUT AND AS WE HAVE
FOCUSED ON, AS YOU'VE HEARD, THE
DEVELOPMENT OF THE 9-VALENT
VACCINE WHICH YOU CAN TELL IS A
VERY COMPLICATED PROGRAM IN AND
OF ITSELF AND WANTING TO MAKE
SURE THAT THE TRANSITION FROM
THE QUADREY VALENT TO 9-VALENT
IS SMOOTH AND EFFECTIVE FROM
BOTH A SMOOTH AND MEDICAL HEALTH
PERSPECTIVE AS POSSIBLE, WE FELT
THAT IN THE U.S. OUR EFFORTS
WERE BEST FOCUSED ON DELIVERING
THE 9-VALENT VACCINE WITH THE
STRONGEST DATA SET TO SUPPORT
IT.
IN THE MEANTIME WE ARE
GENERATING TWO DOSES ON THE
9-VALENT.
GENERATING THE 2 DOSE
INFORMATION DIDN'T SEEM LIKE THE
BEST INVESTMENT OF RESOURCES OR
TIME.
>> DR. FREED.
LEONARD FREED FROM GSK.
WE HAVE SUBMITTED AND APPROVED
2-DOSE IN OVER 71 COUNTRIES AND
IT'S RECOMMENDED AS PART OF THE
IMMUNIZATION RECOMMENDATIONS IN
A NUMBER OF COUNTRIES TO USE THE
TWO DOSE IN THEIR PROGRAM.
IN THE UNITED STATES THIS STORY
IS SLIGHTLY DIFFERENT BECAUSE.
SLOW UPTATE WITH SERVER PROGRAM.
IN OTHER COUNTRIES AROUND THE
WORLD, PARTICULARLY IN
DEVELOPING COUNTRIES WHERE
THERE'S A GREATER OPPORTUNITY
FOR THE USE OF THE PRODUCT,
PARTICULARLY AROUND HELPING WITH
ADHERENCE AND COMPLIANCE WITH
THE SCHEDULE.
THANK YOU.
>> DR. KARRON?
SO I WAS ACTUALLY WONDERING
WHAT THE 2-DOSE SCHEDULE IS THAT
MERCK IS STUDYING FOR THE
9-VALENT VACCINE?
IS IT A 0-6 MONTH SCHEDULE OR IS
IT --
I THINK I --
>> YOU MEAN IT'S ON THE SLIDE
HERE?
OKAY.
SO 0-6 AND THE 0-9.
>> 0-12.
0-126789 EXCUSE ME.
>> MS. PELLY GREEN ANY.
WE'VE GIVEN A LOT OF
ATTENTION TO THE 3 DOSE VERSUS
THE 2 DOSE.
I WANT PEOPLE TO PAY PARTICULAR
ATTENTION TO THE INTERVAL.
I'LL PUT IN A PLUG FOR FAMILIES.
THE CURRENT INTERVALS OF 0, 2, 6
ARE INCREDIBLY CHALLENGING FOR
FAMILIES, RIGHT?
IF WE COULD GO TO SOMETHING LIKE
A 0, 12, 24 AND ALIGNTH A
WELL TEENAGER VISIT I THINK THE
UPTAKE WOULD INCREASE
DRAMATICALLY.
GETTING A TEENAGER TO THE DOCTOR
THREE TIMES IN SIX MONTHS IS
ALMOST IMPOSSIBLE.
>> OTHER QUESTION OR COMMENT?
A QUICK QUESTION FOR DR.
MARKOWITZ.
MAYBE YOU COVERED THIS, BUT?
TERMS OF GOING FOR PREVIOUSLY
FULLY IMMUNIZED INDIVIDUALS WITH
THREE DOSES OF HPV 4, ARE THERE
CONSIDERATIONS OTHER THAN THREE
DOSES OF HPV 9 FOR CATCHING UP?
AND I'M THINKING AKIN TO WHEN
THE SWITCHOVER WENT FROM PCV 7
TO 13.
THERE WAS KIND OF AN ALGORITHM
TO USE.
NOT EVERYBODY WOULD GET THE FULL
COMPLIMENT.
>> YEAH, I -- FIRST OF ALL, FOR
PCV 13 THEY DID THAT STUDY AND
LOOKED AT GIVING A SINGLE DOSE
TO PEOPLE WHO HAD HAD A PREVIOUS
VACCINATION.
WE DON'T HAVE THOSE DATA AND SO,
YOU KNOW, WE'RE IN A DIFFERENT
SITUATION AND ALSO THE AGE GROUP
WAS DIFFERENT THAT THEY WERE
CONSIDERING SO WE WON'T HAVE
DATA FOR THAT AND WE WILL BE
LOOKING AT WHAT DATA ARE
AVAILABLE AND THAT WILL
OBVIOUSLY BE SOMETHING THAT WE
WILL BE GRAPPLING WITH, THE
ISSUE OF REVACCINATION.
>> ANY OTHER COMMENT?
I WANT TO CONGRATULATE THE
WORK GROUP FOR COVERING SUCH
COMPLICATED INFORMATION AND
CUING THIS UP FOR THE COMMITTEE.
LAURI, COULD YOU MOVE BACK TO
YOUR NEXT STEPS?
LAURI LAID OUT THE TIME LINE
THAT SHE ANTICIPATES THE WORK
GROUP BRINGING DATA BACK TO THE
FULL COMMITTEE AND THIS ENTIRE
TIME LINE REFERS TO THE 9-VALENT
SCHEDULE.
I THINK IT WOULD BE HELPFUL TO
HEAR COMMITTEE INPUT ABOUT WHAT
YOU WANT TO CONSIDER ABOUT THE
INTERVALS IN 2-DOSE IN ADVANCE
OF OTHER FORMULATIONS
POTENTIALLY BEING AVAILABLE
BECAUSE I THINK IF ONE IS
HEADING TOWARDS A FEWER DOSE
SCHEDULE, CHANGING THE INTERVAL
SOONER IS BETTER THAN CHANGING
THE INTERVAL LATER.
SO JUST GIVING SOME FEEDBACK SO
THE WORK GROUP KNOWS WHAT YOU'D
LIKE TO SEE I THINK WOULD BE
HELPFUL.
>> DR. CAMPBELL.
YEAH.
ALONG THOSE LINES, IT'S CLEAR
RIGHT NOW THEY'RE SEEING -- THE
DATA IS VERY STRONG THAT WE
SHOULD GO TO 0-6 OR 0-12.
THE ONLY PROBLEM IS THAT WHEN
9-VALENT COMES ALONG ARE WE
WILLING TO DO THAT WITH THE
9-VALENT WITHOUT THOSE DATA?
AND -- I MEAN, IT'S A LITTLE BIT
OF AN UNCOMFORTABLE SITUATION.
IT'S ALMOST AS IF THE 9-VALENT
WERE COMING ALONG WE WOULD RIGHT
NOW CHANGE THE INTERVAL.
AND YET EVERYBODY RECOGNIZES THE
PROBLEM WITH HAVING TO MAKE
PRETTY RAPID ADJUSTMENTS IN
PRIMARY CARE.
THING
TO DO.
SO I GUESS I'D LIKE TO HEAR FROM
THE OTHER COMMITTEE MEMBERS
WHETHER THERE WOULD BE ANY
CHANCE OF US GOING -- YOU KNOW,
STICKING ON THAT KIND OF A --
ESSENTIALLY AN OFF LABEL
RECOMMENDATION FOR THAT
INTERVAL.
ANYBODY WILLING TO TAKE THAT
ON?
I HAVE TO REFLECT ON MS.
PELLEGRINI'S COMMENTS THAT IN A
PRIMARY CARE SETTING WE'RE DOING
ATROCIOUSLY IN TERMS OF GETTING
HPV COVERAGE OUT THERE.
THAT'S -- THAT'S BEEN SHOWN NOW
OVER, WHAT, EIGHT YEARS?
WE'RE DOING POORLY.
AND PART OF THAT IS JUST DEALING
WITH ADOLESCENTS IN PRIMARY
CARE, AND THEY DO NOT COME IN
FOR A FOLLOW-UP IN A MONTH TO
TWO MONTHS.
AS A PARENT OF A 2-DOSE SON
RIGHT NOW WHO WAS IMMUNIZED ON A
0-12 MONTH, I CAN ATTEST TO HOW
DIFFICULT IT IS TO GET SOMEBODY
IN.
SO I'M GUILTY AS CHARGED, BUT
REALLY LOOKING AT THE REALITIES
OF PRACTICE HERE I THINK IS
INCREDIBLY IMPORTANT IN TERMS OF
IMPLEMENTING A VERY GOOD
VACCINE.
DR. ENGWALD.
>> I GUESS REFLECTING BACK AND
THE STANDARD OF EVIDENCE THAT
THE COMMITTEE SEEMED TO WANT, I
AM DUBIOUS THAT -- I'M NOT QUITE
SURE WE WOULD HAVE ANY MORENVIN
CANCER DOWN THE LINE BASED ON
GOING FROM A 3-DOSE TO 2-DOSE
THAN WE DID FOR THE PNEUMOCOCCAL
VACCINE.
I DON'T THINK THE DATA WOULD BE
ANY BETTER.
I'M NOT CONVINCED BASED ON THAT
DISCUSSION THAT THE COMMITTEE IS
READY TO DO THAT.
>> DR. BENNETT?
WELL, I HATE TO SAY THIS
COMING FROM ME, BUT I HAVE TO
SAY THAT I THINK THE DATA ARE
BETTER HERE BECAUSE
ACTUALLY COMPARATIVE TRIALS AND
WE DON'T HAVE THAT FOR
WE HAVE TWO DOSE VERSUS -- THREE
DOSE VERSUS -- WE HAVE FOUR DOSE
VERSUS NOTHING BUT WE DON'T HAVE
THREE VERSUS FOUR AND THERE ARE
SOME TWO DATA HERE.
>> IMMUNOGENICITY, BUT IF YOU
LOOK AT THE DATA WITH CLINICAL
OUTCOMES, THE RELATIVE RISKS FOR
THE TWO-DOSE SCHEDULE ARE NOT
VERY IMPRESSIVE.
CERTAINLY THEY DON'T LOOK
COMPARABLE TO THE THREE-DOSE
SCHEDULE.
>> HOWEVER, THOSE WERE ALL 0-2,
RIGHT?
AM I RIGHT ABOUT THAT?
THAT DID NOT COMPARE 0-6 OR 0-12
SO WE REALLY HAVE NO DATA ON
THAT.
>> I WANT TO SHOW THE EFFICACY
DATA BECAUSE I THINK THERE'S A
FEELING THAT WE WILL HAVE A LOT
OF EFFICACY DATA TO POSSIBLY
INFORM BUT I THINK THE EFFICACY
DATA WILL BE VERY DIFFICULT NOT
BECAUSE OF SCHEDULES BUT BECAUSE
OF THE CATCHUP POPULATION THAT'S
DONE AND THE DIFFERENCES BETWEEN
TWO AND THREE-DOSE VAC CINES.
IT'S INTERESTING TO SEE THE
DATA.
I'M NOT SURE HOW INFORMATIVE IT
IS FOR OUR DELIBERATIONS.
>> I THINK YOU HAVE TO TELL US
WHAT THE OTHER FACTOR IS.
I DO HAVE A SCREENING TEST IN MY
PRACTICE FOR CERVICAL CANCER AND
I DO NOT FOR INVASIVE
PNEUMOCOCCAL DISEASE.
DR. BOCCHINI.
I WAS GOING TO SAY I THINK
THE OPPORTUNITY FOR THE TWO-DOSE
WAS VERY DIFFERENT IF YOU'RE
LOOKING FOR A 9-VALENT VACCINE.
IT'S IN THE NEXT SIX MONTHS.
SO THAT WOULD CREATE A SITUATION
WHERE WE WOULD BE MAKING
MULTIPLE CHANGES IN IMMUNIZATION
RECOMMENDATIONS WITHIN A VERY
THINK COULD MAKE IT VERY
DIFFICULT FOR THE PRACTITIONER
TO FOLLOW THOSE RECOMMENDATIONS
OR TRUST THEM IF THEY ARRIVE.
>> DOCTOR?
THIS MIGHT HAVE GONE BY TOO
FAST FOR ME, BUT COULD YOU
REMIND US, LAURI, WHAT TYPE OF
LICENSURE WE'RE EXPECTING,
APPLICATION WE'RE EXPECTING FOR
MALES FOR THE 9-VALENT IN TERMS
OF AGE GROUPS AND SO FORTH?
BECAUSE THERE WAS A DISCUSSION
OF OFF LABEL INTERVALS AND SO
FORTH.
SO -- AND DR. DUNNE REVIEWED
THIS.
THE FIRST LICENSURE, WHICH
YOU'RE EXPECTING AT THE END OF
THIS YEAR WILL BE FOR FEMALES
9-26 AND FOR MALES 9-15.
THE DATA ON THE 16-26-YEAR-OLDS
OR THE 15-26-YEAR-OLDS, WE WILL
HAVE THAT IN OCTOBER.
SO WE WILL HAVE THOSE DATA.
WE'LL BE ABLE TO SEE THOSE DATA
EVEN THOUGH THEY WILL NOT HAVE
BEEN SUBMITTED YET TO FDA.
SO THE FEELING OF THE WORK
GROUP, IT WOULD BE VERY HARD
PROGRAMMATICALLY TO HAVE THE
QUADREY VALENT VACCINE
RECOMMENDED FOR THE OLDER MALES
BUT THE 9-VALENT VACCINE
RECOMMENDED FOR FEMALES 9-26 AND
MALES 9-15.
SO THE PROPOSAL IS TO MOVE
FORWARD WITH THE RECOMMENDATION
FOR 9-26 -- YOU KNOW, FOR THE
FULL AGE GROUP OF FEMALES AND
MALES EVEN THOUGH IT WOULD BE
TECHNICALLY OFF LABBEL FOR THE
15-26-YEAR-OLD MALES.
WE WILL HAVE DATA THAT WE'LL BE
ABLE TO SEE BEFORE THAT TIME.
DR. PICKERING.
>> DR. LUXEMBOURG SAID THAT WE
WOULD HAVE 2-DOSE DATA AT THE
END OF NEXT YEAR.
WHAT TYPE OF DATA WILL THIS SNB
AND SECONDLY, ARE THE ANTIBODY
LEVELS AND KINETICS OF THE FIVE
STRINGS THAT ARE IN THE NEW
VACCINE SIMILAR TO 16 AND 18?
>> SO THE FIRST QUESTION, THE
DATA WILL BIMMUNOBRIDGING
DATA, COMPARISON OF
IMMUNOGENICITY AT THE PEAK,
WHICH MEANS ONE MONTH AFTER THE
LAST DOSE VERSUS THE SECOND
DOSE.
IN TERMS OF KINETICS, WE'VE
LOOKED AT KINETICS AFTER THREE
DOSE, YOU KNOW, IN THE ONGOING
STUDIES AND THE KINETICS
SIMILAR BETWEEN THE ADDITIONAL
TYPES AND THE ORIGINAL TYPES,
WHICH MEANS PEAK ONE MONTH AFTER
THE DECREASE BY APPROXIMATELY
70%, 12 MONTH AND, YEAH,
APPROXIMATELY 80, 90% LATER
REACHING A PLATEAU.
>> ANY FURTHER QUESTIONS OR
DISCUSSION?
IF NOT, I THINK WE WILL LIMIT
THINGS TO ABOUT A 10-MINUTE
BREAK.