I WILL OPEN THE MEETING I AM THE
PROGRAM OFFICER HERE AT
FOCUSED ON THE MICRO BIOME AND I
ALSO SERVE AS THE INSTITUTE
POINT OF CONTACT FOR MICRO BIOME
RESEARCH WHICH IS 1 OF THE
REASONS WHY I WILL BE MODERATING
TODAY'S MEETING.
HAVE A FEW SLIDES THERE ARE
MEMBERS IN THE AUDIENCE.
AND NICKY IS THE THAN FROM THE
CENTER FOR DISEASE CONTROL.
>> SO THIS IS HOW THE MEETING
WILL BE RUN.
I AM A MODERATOR TODAY I WILL BE
KEEPING TIME.
I'M NOT VERY IMPOSING BUT I WILL
STAND UP WHEN YOU ARE OUT OF
TIME.
WILL TRY TO KEEP EVERYTHING
PRETTY TIGHT TODAY.
DEPENDING ON THE SESSION 10 OR
15 MINUTES FOR Q&A OBVIOUSLY IN
PERSON QUESTIONS SO THE VIRTUAL
ATTENDEES ARE JOINING BY ZOOM.
AND THEN THE Q&A COMES TO THE
CHAT BOX.
IN THE VIDEOCAST IS LIVE RIGHT
NOW AND WILL ALSO BE ARCHIVED.
SO THIS IS JUST LOGISTICS WITH
VIRTUAL ATTENDEES.
AND IF YOU ARE LOOKING TO
PRESENT THERE IS A POINT OF
CONTACT FOR YOUR PRESENTATION
FILES.
THIS IS THE MOST IMPORTANT SLIDE
IN ALL SERIOUSNESS WE HAVE NO
FOOD ON-SITE.
WE HAVE ORGANIZED A MENU.
IT IS IMPORTANT THIS IS THE ONLY
SOURCE OF FOOD.
IF YOU DON'T FIND ANYTHING YOU
WOULD LIKE HERE THERE ARE OTHER
OPTIONS.
JUST COMMON ASK ME WE HAVE 1
HOUR 15 MINUTES FOR LUNCH.
SO WE JUST NEED TO USE THE QR
CODE.
MAKE SURE THAT YOU PURCHASE AND
IF YOU DON'T GET THAT E-MAIL THE
SEASON YOU DID NOT DO IT RIGHT.
OTHERWISE YOUR LUNCH WILL NOT BE
THERE BUT THEY WILL BE DELIVERED
AT 1145 THROUGH THE DOORS AND
INTO THE CAFETERIA.
MY ROLE HERE AS A MODERATOR.
SO THE PRESENTATION WILL BE BY
DOCTOR DAVID KASLOW A MEMBER OF
THE ORGANIZING COMMITTEE.
A RELATIVELY RECENTLY MINTED
DIRECTOR AT THE CENTER FOR
BIOLOGICS EVALUATION AND
RESEARCH AND WILL TALK TO US
ABOUT LIVE FILE THERAPEUTIC
PRODUCTS.
>> ON BEHALF OF US FDA LET ME
GIVE ME WELCOME TO THE WORKSHOP
SPEAKERS HERE ON PERSON AND
ONLINE ALSO THANK YOU TO
COLLEAGUES FROM CDC AND NIH.
I WILL START BY SAYING ALL OF MY
COMMENTS TODAY COME WITH THE
EXPLICIT DISCLAIMER THAT THEY
NEITHER BIND NOR OBLIGATE THE
FDA WITH NO COMPLEX OF
DISCLOSURES.
SO MY ASSIGNMENT IN THE NEXT 20
MINUTES OR LESS IS TO SET THE
STAGE FOR TODAY'S MEETING FROM A
REGULATORY PERSPECTIVE.
I WOULD JUST LIKE TO QUICKLY
WALK THROUGH TODAY'S AGENDA.
AND WE ARE TRYING TO SET THE
STAGE FOR THE WORKSHOP THROUGH
EPIDEMIOLOGY AND THE NUTRITIONAL
ASPECTS OF LOW BIRTH WEIGHT
INFANTS.
THAT IS FOLLOWED BY A 2 TALKS
CRITICAL FOR CLINICAL
INVESTIGATION THAT IS THE NET
CASE DEFINITION OF POTENTIAL
SAFETY SIGNALS OF SPECIAL
INTEREST.
AFTER Q&A WE WILL OPEN PUBLIC
COMMENT SESSION WITH 3 REQUESTED
PRESENTATIONS AFTER LUNCH WE
WILL HAVE 2 SESSIONS AND THE
FIRST IS A DEEPER DIVE INTO THE
CLINICAL TRIAL DESIGN WITH NEC
AND THEN WE'LL FOCUS ON THE
CHALLENGES AND OPPORTUNITIES.
AND WITH THE REGULATORY OVERVIEW
WITH A COMMONLY USED TERMS.
AND WITH A LIVE BIO THERAPEUTIC
PRODUCT.
AND THESE CONTAIN ORGANISMS SUCH
AS BACTERIA.
WITH THE PREVENTION AND
TREATMENT OR CONDITION OF HUMAN
BEINGS AND IS NOT A VACCINE.
I WILL HIGHLIGHT 3 COMMONLY USED
TERMS YOU WILL HEAR THROUGHOUT
THE COURSE OF THE DAY FIRST IS
BIOLOGICAL PRODUCTS ALSO KNOWN
AS BIOLOGICS.
THESE ARE REGULATED BY FDA AND
IS USED TO
DIAGNOSE, PREVENT, TREAT OR CURE
DISEASES AND MEDICAL
CONDITIONS.
IT IS A DIVERSE CATEGORY OF
PRODUCTS OF GENERALLY LARGE
COMPLEX MOLECULES INCLUDING
MICROORGANISMS.
PROBIOTICS ARE NOT DEFINED AS A
REGULATORY PRODUCT CATEGORY.
THAT WOULD BE FOOD DRUGS AND
BIOLOGICS DEPENDING ON THE
INTENDED USE OF THAT PRODUCT AND
DESPITE HOUSES IS A TERM PRONE
TO MISINTERPRETATION AND MISUSE
IS PRONE TO MISINTERPRETATION
AND WE AVOID THAT TURN AND TO A
SITUATION TERMINOLOGY THAT IS
MEANT TO ACTUALLY HIGHLIGHT THE
FUNCTION OF THE MICRO BIOME SUCH
AS DYSFUNCTIONAL OR DISEASE
PROMOTING.
NEXT I WOULD LIKE TO START WITH
THE PROPOSED AND CERTAINLY OPEN
FOR DISCUSSION, A STRATEGIC
INTENT STATEMENT.
AND THAT IS THE INTENT IS TO
DISCUSS A WELL-DEFINED PATHWAY
TO DEMONSTRATE THE EVIDENCE OF
SLEEP THE INEFFECTIVENESS AND
QUALITY OF LIFE THERAPEUTIC
PRODUCTS ARE VERY LOW BIRTH
WEIGHT INFANTS TO PREVENT NEC
THAT MEET STATUTORY STANDARDS.
BUT I WOULD ALSO LIKE TO DO IS
WITHIN THE STRATEGIC AND A
STRATEGIC INTENT IS A PROPOSED
PROBLEM STATEMENT IS A VERY LOW
BIRTH WEIGHT INFANTS AND REMAINS
A SIGNIFICANT PUBLIC HEALTH
PROBLEM.
FDA HAS NOT APPROVED ANY
PRODUCTS FOR NEC VARIOUS
PRODUCTS MARKETED AS PROBIOTICS
HAVE BEEN USED IN EFFORTS TO
PREVENT THIS SERIOUS AND
LIFE-THREATENING DISEASE HOWEVER
THESE PRODUCTS HAVE NOT BEEN
MADE USING PHARMACEUTICAL GOOD
MANUFACTURING PRACTICES.
SUBSTANTIAL EVIDENCE OF
EFFECTIVENESS HAS NOT YET BEEN
DEMONSTRATED WITH SERIOUS
ADVERSE OUTCOMES INCLUDING DEATH
HAVE BEEN REPORTED FOLLOWING THE
USE OF THESE PRODUCTS.
I WAS NEXT LIKE TO TURN SOME
TOPICS IN KEY UNDERLYING
ASSUMPTIONS TO GAIN SOME
ALIGNMENT DURING THE COURSE OF
TODAY'S WORKSHOP.
AND THAT IS TO ALIGN ON THE
BIOLOGICAL PRODUCT THAT CONTINUE
MICROORGANISMS SUCH AS BACTERIA
WITH THE INTENDED USE TO PREVENT
A SURE A VERY LOW BIRTH WEIGHT
INFANTS OR REGULATED AS
BIOLOGICS AND THEN TO PRESSURE
TEST 2 KEY UNDERLYING
ASSUMPTIONS THAT ADEQUATE AND
WELL-CONTROLLED CLINICAL
INVESTIGATIONS TO ESTABLISH
SAFETY AND EFFECTIVENESS IN THE
VERY LOW BIRTH WEIGHT INFANTS TO
MAKE THE STATUTORY REQUIREMENTS
FOR ETHICAL AND FEASIBLE.
AND SECOND LBP CAN BE
MANUFACTURED CONSISTENTLY AND IN
COMPLIANCE WITH GOOD
MANUFACTURING PRACTICE
REGULATIONS.
WITH THAT INTRODUCTION NEXT I
WOULD LIKE TO PROPOSED THE PICO
QUESTION BUT THE FOCUS OF THE
WORKSHOP OBVIOUSLY THIS IS OPEN
FOR DISCUSSION IS IT IS MEANT TO
IDENTIFY THE TARGETED GROUP THE
CONTROL INTERVENTION AND
INTERVENTIONS EXPECTED RESULTS
AND TO GET US STARTED.
OPEN FOR DISCUSSION AND TO
PROPOSE THE FOCUS OF THIS
WORKSHOP AND IN THAT WE FOCUS ON
THE BIO THERAPEUTIC PRODUCTS.
SO TO TURN THE ATTENTION TO THE
REGULATORY PATHWAYS THAT ARE
AVAILABLE IT IS IMPORTANT TO
EMPHASIZE THAT THERE IS THE
EXISTING LEGAL FRAMEWORK WE MUST
OPERATE AND THAT STARTS WITH
LAWS AND STATUTES THAT ARE
TRANSLATED INTO REGULATIONS
PARTICULARLY THE CLOSE AND THOSE
ARE TRANSLATED INTO GUIDANCE AND
GUIDANCE DOCUMENTS.
SO WITH THAT FRAMEWORK IN MIND
FOR BIOLOGIC PRODUCTS, THERE ARE
6 ACCESS AVENUES.
THROUGH THE LICENSE APPLICATIONS
AND THE EMERGENCY USE
AUTHORIZATION AND ALSO THROUGH
INVESTIGATIONAL NEW DRUG
COMPLICATIONS.
OF THOSE 6 AND FOR TODAY'S
DISCUSSION ON LBP I SUGGEST WE
FOCUS ON 4 OF THESE ACCESS
AVENUES THAT ARE RELEVANT.
THE 2 ON THE TOP OR THROUGH
APPROVED PRODUCTS TRADITIONAL
AND ACCELERATED APPROVAL AND
THEN THE 2 INVESTIGATIONAL
ACCESS AVENUES EXPANDED AND
INVESTIGATIONAL NEW DRUG
APPLICATION.
I HIGHLIGHTED ON THE RIGHT-HAND
SIDE WHAT NEEDS TO BE
ESTABLISHED IN TERMS OF
SUBSTANTIAL EVIDENCE IT IS
THROUGH DIRECT MEASURES OF
CLINICAL BENEFIT OR VALIDATED
WELL-ESTABLISHED AND POINTS THAT
PREDICT CLINICAL BENEFIT.
TALKING ABOUT ACCELERATED
APPROVAL, THIS IS A SURROGATE OR
INTERMEDIATE CLINICAL AND POINT
THAT WILL PREDICT CLINICAL
BENEFIT AND I WANT TO DRAW YOUR
ATTENTION TO THE EXPANDED ACCESS
PATHWAY IN THE REQUIREMENTS AND
RECORD -- -- CRITERIA THAT WILL
BE MET IN ORDER TO ACCESS THAT
PATHWAY.
SO BASED ON THE PROPOSED PICO
QUESTION VERY LOW BIRTH WEIGHT
INFANTS THE INTERVENTION FROM
LIVE BIO THERAPEUTIC PRODUCTS
WITH INTENDED OUTCOME OF
REDUCTION OF INCIDENTS OF
NEC, BASED ON THAT, THAT PRODUCT
WOULD FALL UNDER A BIOLOGICAL
LICENSE WITH REGULATIONS AND
JUST TO BE CLEAR WHAT THAT
REQUIRES IS DEMONSTRATION OF A
PRODUCT SAFETY PURITY AND
POTENCY THAT IS MEANT TO BE
EFFECTIVENESS.
IT ALSO REQUIRES THE FACILITY
NEEDS TO ASSURE NOT JUST
LICENSURE BUT THE PRODUCT
CONTINUES TO BE SAFE AND PURE
AND ONLY THOSE THAT ARE
DEMONSTRATED TO BE SAFE AND
EFFECTIVE AND CAN BE
MANUFACTURED IN A CONSISTENT
MANNER WILL BE LICENSED BY THE
FDA.
SEVERAL EXPEDITED PROGRAMS ARE
AVAILABLE.
THESE APPLY TO INVESTIGATIONAL
PRODUCTS THAT ADDRESS A SERIOUS
CONDITION TO PROVIDE THE
ADVANTAGE OVER AVAILABLE THERAPY
AND TO ADDRESS THE UNMET MEDICAL
NEED.
AND FOR THE FAST TRACK
BREAKTHROUGH THERAPY AND
PRIORITY REVIEW THE FAST TRACK
BREAKTHROUGH AND THAT PROVIDES
ACTIONS DESIGNED TO EXPEDITE THE
DEVELOPMENT AND THE VIEW OF
THESE PRODUCTS.
IT IS SIGNIFICANTLY MORE
INTENSIVE INTERACTIONS WITH THE
FDA.
AND SOME OF THE FORMAL
MECHANISMS MEETING WITH FDA
THROUGH THE LIFECYCLE OF THE
PRODUCT.
AND EMPHASIZED A SHARED PUBLIC
HEALTH GOAL OF SAFE AND
EFFECTIVE KEYS THROUGH EFFECTIVE
COMMUNICATION WITH SPONSORS AS
SHOWN ON THE BOTTOM OF THE
SLIDE.
I WOULD LIKE TO EMPHASIZE OUR
COMMITMENT TO EXPEDITE THE
REVIEW PROCESS FOR THOSE
PRODUCTS THAT ADDRESS THE
SERIOUS CONDITION AND
DEMONSTRATE THE POTENTIAL TO BE
A SIGNIFICANT IMPROVEMENT OF
SAFETY AND EFFECTIVENESS AND
RATHER THAN THE 12 MONTH REVIEW
TIMELINE YOU SEE AT THE TO
TOP, PRIORITY REVIEW SHORTENS
THE REVIEW TIME BY 1 THIRD BY 4
MONTHS WITH THE INTENSIVE
SIX-MONTH REVIEW.
SO TO BRIEFLY SUMMARIZE
CONSIDERING NEC IN VLBW A
SIGNIFICANT PUBLIC HEALTH
PROBLEM AND GIVING THE PROPOSED
PICO QUESTION THE PRODUCTS WOULD
BE CATEGORIZED AS LBP THERE ARE
SEVERAL PATHWAYS WHAT THOSE THAT
EXIST TO FACILITATE ACCESS TO
LBP AND 1 OF THE GOALS OF
TODAY'S WORKSHOP IS TO DISCUSS
THE KEY UNDERLYING ASSUMPTIONS
TO PREVENT NEC IN VLBW INFANTS.
>> I HOPE THAT SET THE STAGE SO
THE NEXT SPEAKER, KAREN PUOPOLO
A PROFESSOR OF PEDIATRICS
UNIVERSITY OF PENNSYLVANIA
SCHOOL OF MEDICINE AT THE
CHILDREN'S HOSPITAL OF
PHILADELPHIA.
THAT IS WITH NEC AND VLBW BABIES
IN THE NICU.
>> GOOD MORNING.
I AM STARTING OUT THIS
CONFERENCE AND HOPEFULLY OVER
THE NEXT 25 MINUTES HE WILL SEE
WHAT YOU PROBABLY ALREADY KNOW
THAT NECK IS UNFORTUNATELY
COMMON COMPLICATION OF
PREMATURITY WITH TERRIBLE
SHORT-TERM AND LONG-TERM LIFE
IMPLICATIONS.
I HAVE NO CONFLICTS RELATIVE TO
THE PRESENTATION AND THIS IS
WHAT WE WILL SPEAK ABOUT TODAY
AND THE DEMOGRAPHICS THAT I CAN
DESCRIBE IN THE ASSOCIATIONS AND
THEN WHAT ARE THE CONSEQUENCES
BOTH WITH
SURVIVAL, GROWTH, NEURODEVELOPMT
AND LONG-TERM IMPACTS.
THESE ARE THE THINGS THAT I WILL
NOT DISCUSS BUT OTHER SPEAKERS
WILL ADDRESS THIS TODAY.
NEC DOES OCCUR PRIMARILY ALONG
-- -- AMONG LOW BIRTH WEIGHT
BABIES.
MRS. DATA FROM THE DATABASE AND
IT COMPRISES DATA FROM ALMOST
1 MILLION INFANTS BORN OVER THE
PAST 24 YEARS IN THE UNITED
STATES AND IT SHOWS OVER THE
TIME APPROXIMATELY 5 TO
6 PERCENT OF VLBW BABIES
SUFFERED NEC.
WITH A RANGE.
AND HER SOME INCREASES AND
DECREASES OVER TIME.
AND LOOKING AT THE DISTRIBUTION
THIS IS DATA THAT IS VERY RECENT
2 OR 3000 INFANTS AND HERE AGAIN
THE MAIN 5 PERCENT SUFFERED
NEC.
BUT THERE IS A PROFOUND IMPACT
AND A DIFFERENTIAL AROUND THE
LOWEST GESTATION AROUND
10 PERCENT OF KIDS BORN AT 23
WEEKS SUFFERING THE
COMPLICATION.
AND THEN A LOWER RISK WITH
GESTATION.
I TRIED TO LOOK AT WHAT HAS
CHANGED ARE TRYING TO CHANGE
THINGS FOR THE BETTER.
AND RECENTLY LOOKING AT A NUMBER
OF OUTCOMES AT THE DATABASE TO
SEE WHAT HAS GOTTEN BETTER AND
WORSE AND DID SOME SOPHISTICATED
CALCULATION AND LOOKING AT THE
WAY NEC HAS CHANGED IN THE
POPULATION.
AND YOU CAN SEE HERE THERE WAS
SOME TIME PERIOD WHERE WE MADE
SIGNIFICANT IMPROVEMENTS WITH
TRULY STATISTICAL SIGNIFICANT
CHANGES BUT I HIGHLIGHT HERE IN
YELLOW THAT IN RECENT YEARS
THERE HAS BEEN NO ADVANCEMENTS
IN THE POPULATION.
WITH THE RESEARCH NETWORK ALSO
PROVIDES WITH THE REACH DATA SET
AND THIS IS DATA FROM THE
NETWORK ALMOST 10000 AND LOW
GESTATION INFANTS BECAUSE THE
FOCUS IS ON THE LOWEST GESTATION
HERE YOU CAN SEE AN AVERAGE OF
ALMOST 9 PERCENT OF INFANTS BORN
IN THE RANGE OF SUFFERED NEC
WITH PROFOUND DIFFERENCES BY THE
LOWEST GESTATION.
HERE IN THIS DATA SET 15 PERCENT
BORN THE 23rd WEEK SUFFERED
THIS COMPLICATION AND HER OWN
DATA SET WITH OVER 40 PERCENT OF
THE INFANTS WHO SUFFERED NEC
UNDERGO SURGERY AND THAT IS FOR
THE MOST SEVERE FORMS OF THE
DISEASE.
THE NEONATAL RESEARCH NETWORK
DID SOME COMPARATIVE STATISTICS
WHERE THE MEAN WAS HIGHER IN
THERE WAS A STATISTICALLY
SIGNIFICANT SLIGHT IMPROVEMENT
IN THE RATE BETWEEN THE 2 TIME
PERIODS.
SO THE AGENCIES GOT TOGETHER TO
WROTE THE WHITE PAPER ON NEC.
AND THAT REVIEWED THE MULTIPLE
FURTHER ASSOCIATIONS THAT CAN BE
SOUGHT WHO IS AT HIGHEST RISK
AND WHAT COULD BE MODIFIED.
AND THAT IS SLIGHTLY LOWER RISK
OF NEC IS ASSOCIATED WITH RISK.
AND THEN TO LARGELY COME DOWN
INCREASED EXPOSURES TO HYPOXIA.
NONE OF THIS THAT WE CAN
MODIFY.
WE SPEND A LOT OF TIME IN OUR
FIELD WITH PRACTICE AND WHAT IS
UNDER OUR CONTROL.
MEDICATIONS, TRANSFUSION
PRACTICES, OXYGEN SATURATION
TARGETS.
SO I WILL START WITH
ANTIBIOTICS.
ESSENTIALLY THIS WAS A KICK IN
THE BUTT TO US WITH ANTIBIOTICS
WITH VLBW BABIES AND IT LOOKS AT
DETAIL OF ANTIBIOTIC PRACTICE
BABIES BORN UNDER 1000 GRAMS AND
NOW IT IS A 25 EURO DATA SET.
AND IT SHOWED OVER 50 PERCENT OF
THE BABIES WERE RECEIVING
ANTIBIOTICS FROM BIRTH IN THE
ANY ABSENCE OF INFECTION 1 OF
THE THINGS THAT CAME OUT THE
WORK WAS A DIFFERENTIAL AND THE
USE RIGHT AFTER BIRTH AND THE
SUBSEQUENT OUTCOME IN THIS PAPER
WAS ESTIMATED THERE WAS A
7 PERCENT INCREASE FOR EVERY
ADDITIONAL DAY OF ANTIBODIES
GIVEN DESPITE RISK OF INFECTION
BUT NOT EVIDENCE.
THERE IS A SIMILAR STUDY AND
LOOKED QUANTITATIVELY AT THE
RISK BETWEEN INCREASING NUMBERS
OF ANTIBIOTICS STARTING FROM
BIRTH AND ESTIMATED THAT WITH
EACH ADDITIONAL DAY GIVEN THERE
WAS AN INCREASED ODDS WITH THE
THREEFOLD INCREASE GREATER THAN
10 DAYS OF EXPOSURE.
SOME THINGS HAVE GOTTEN BETTER I
WOULD LIKE TO ARGUE THAT WE HAVE
STARTED TO FOCUS ON PROPER USE
OF ANTIBIOTICS AND FROM THE
PREMIER DATA SET AND SHOWING
THAT OVER TIME IN 2009 THROUGH
2015 THERE HAVE BEEN SOME
DECREASES IN STATISTICALLY
SIGNIFICANT USE OF ANTIBIOTICS
AND LOW BIRTH WEIGHT BABIES
AMONG THE HIGHEST RISK.
DOING SOME WORK IN THE MORE
CONTEMPORARY DATA SET LOOKING AT
WHETHER WE CONTINUE AND THE
WIDESPREAD EARLY EXPOSURES AND
FOUND THAT OVER TIME OF 22014 AT
35 PERCENT GETTING PROLONGED
ANTIBIOTICS AT BIRTH AND WITH
THESE IMPROVEMENTS OF TARGETED
ANTIBIOTICS WE DO SEE A LESSER
ASSOCIATION WITH NEC THAT AS WE
HAVE CLEANED UP OUR ACT PERHAPS
WE ARE CONTRIBUTING LESS TO THE
RISK.
OF COURSE WE ARE WORRIED ABOUT
INFECTION IS WHY WE GIVE
ANTIBIOTICS AND PEOPLE HAVE DONE
ENORMOUS AMOUNTS OF WORK TO FIND
THE INFECTIOUS SMOKING GUN.
LIKE TO SHOW THIS TABLE.
AND YOU SEE THAT EACH INDIVIDUAL
BACTERIA AND VIRUSES HAVE
MULTIPLE REFERENCES ATTACHED.
BUT IN FACT IN THE END SPECIFIC
MICROBES ARE ASSOCIATED WITH NEC
IN SINGLE SITE RARE OUTBREAKS
AND CERTAINLY IT IS POSSIBLE
THAT INFECTIONS ARE ASSOCIATED
OR CAUSED OF THE COLONIZATION
AND THEY COULD ALIGN WITH THE
PATHOGENS CERTAINLY IN
ACTIVATION OF THE TLR PATHWAY
AND SOMETIMES AND COINCIDENT
THAT IS PART OF THE SPECTRUM BUT
IT IS FAIR TO SAY THE ROLE OF
SPECIFIC SPECIES DESPITE MANY
EFFORTS REMAINS UNCLEAR.
ANOTHER AREA WHERE WE DON'T HAVE
CLARITY ALTHOUGH WE ARE GETTING
SOME IS IN THE MANY
OBSERVATIONAL STUDIES THAT
SUGGEST A RELATIONSHIP BETWEEN
THE ADMINISTRATION OF RED BLOOD
CELLS AND NEC IT HAS BEEN HIGHLY
DEBATED AND PEOPLE IN OUR FIELD
HAVE MADE ALL SORTS OF
TRANSFUSION PRACTICES TO REDUCE
THE RISK.
BUT THE TRANSFUSION THE
PREMATURITY STUDY COMPARED TO
DIFFERENT A HEMOGLOBIN AND
THRESHOLDS AMONG THE LOWEST
BIRTH WEIGHT INFANTS.
AND THE PRIMARY OUTCOME DID NOT
FIND A DIFFERENCE BUT THE STUDY
PARTICIPANTS DID ACHIEVE
DIFFERENT HEMOGLOBIN LEVELS
DURING THE STUDY AND FEWER UNITS
OF BLOOD CELLS TRANSFUSED WITHIN
HALF OF THE PARTICIPANTS.
DESPITE THIS DIFFERENCE THE RATE
OF NEC WAS NOT DIFFERENT IT WAS
ABOUT THE 10 PERCENT WE HAVE
SEEN IN PRIOR EPIDEMIOLOGIC
STUDIES AND TO A RECENT
SECONDARY ANALYSIS WITH
TRANSFUSIONS GIVEN WITHIN THE
STUDY ALSO FOUND NO ASSOCIATION
THROUGH THE EVENT OF NEC.
SO WE WILL GO INTO DETAIL THAT
THIS IS THE PIECE OF THE
PRACTICE TRULY UNDER OUR CONTROL
AND HAS BEEN STUDIED IN MANY
DIFFERENT CENTERS AND DIFFERENT
WAYS AND I WILL POINT OUT THAT
MOST OF THE STUDIES ARE
ASSOCIATE - - ASSOCIATIONS AND
DISCUSSIONS OF PRACTICE AND NOT
TRIALS AND THIS IS 1 OF THE
FIRST OUT OF THE MOUNTING
HEALTHCARE SYSTEM WHERE ON A
QUEUE I BASIS COMPARING THE
RATES OF NEC AND THE SAME SYSTEM
HAVING MANY OF THE SAME
POSITIONS AND RESOURCES AND THEY
OBSERVED AS YOU CAN SEE CENTER A
HAD A 14 PERCENT RATE OF NEC AND
THE OTHER 2 HAD MARKEDLY LOWER
RATES.
THE AUTHORS LOOKED AT MULTIPLE
FACTORS STARTING WITH AN INFANT
- - INFANTS AT THE CENTERS
LOOKING AT MULTIPLE PRACTICES
LOOKING AT WHETHER THE OUTCOME
OF INFANTS WHO DID GET NICK --
-- NEC WAS DIFFERENT IT WAS NOT
BUT IT SHOWS A STRIKING
DIFFERENCE OF FEEDING PROTOCOLS
AND MOST IMPORTANTLY STRIKING
DIFFERENCES IN THE USE MOTHER'S
MILK VERSUS PRETERM FORMULA FOR
FEEDING.
SO THERE'S A LOT TO BE SET ON
THE TOPIC BUT I WILL POINT OUT
THE RECENT TRIAL WHICH WAS
RANDOMIZED CONTROLLED STUDY OF
INFANTS BORN UNDER 29 WEEKS OR
THE BIRTH WEIGHT OF UNDER
1000 GRAMS WERE RANDOMIZED TO
USE OF DONOR MILK OR PRETERM
FORMULA TO SUPPLEMENT.
THE STUDIES PRIMARY OUTCOME
WHICH IS A MEASURE OF COGNITIVE
FUNCTION WITH THE SCALES OF
INFANT DEVELOPMENT IS NOT
DIFFERENT THE MORTALITY WAS NOT
DIFFERENT BUT THE RATE OF NEC
WAS DIFFERENT IN STATISTICALLY
SIGNIFICANT AND HIGHLIGHTING 1
OF THE MANY COMPLICATIONS OF THE
TOPIC.
BUT WE WILL HAVE A MORE DETAILED
DISCUSSION.
WHAT DO WE KNOW ABOUT NEC?
IN MY CENTER OVER THE PAST 5
YEARS WE HAVE QUITE DRACONIAN
ANTIBIOTIC STEWARDSHIP GOING ON
WITH FEEDING PROTOCOLS AND WIDE
AVAILABILITY OF DONOR MILK TO
SUPPORT MOTHER AND IT HAS BEEN
3 PERCENT OVER 5 YEARS IT HAS
BEEN IN STATISTICALLY LOWER THAN
THE NATIONAL AVERAGE.
SO I WORK CLINICALLY AS MANY AS
YOU DO TWIN INFANTS WERE BORN AT
28 WEEKS THIS YEAR.
MOM WAS COMPLETE 1 WAS GROWTH
RESTRICTED THE AGA TWIN WAS
LARGELY MAINTAINED AND THEN GOT
ANTIBIOTICS AND THE BASIS ONLY
AFTER 24 HOURS AND WAS NEVER FED
ANYTHING OTHER THAN MOTHER'S
MILK AND DONOR MILK AND HUMAN
MILK.
CORRECTED GESTATIONAL AGE
PRESENTED LETHARGY APNEA WITH A
FULL EVALUATION AND EVENTUALLY
DIAGNOSED WITH NEC AND SHOWING
WIDESPREAD HEMATEMESIS.
TREATED AND RECOVERED AND
EVENTUALLY WENT HOME.
BUT HE HAD A TWIN BROTHER WHO
WAS GROWTH RESTRICTED WAS ALWAYS
SECURE AT A HIGHER OXYGEN
REQUIREMENT ULTIMATELY GETTING
TREATMENT AND THE BABY NEVER
DEVELOPED NEC AND ALSO
EVENTUALLY WENT HOME.
SUCCESS STORY PROBABLY BUT WE
HAVE LEARNED A LOT AND WE KNOW
VERY LITTLE.
WHAT ARE SOME OF THE
CONSEQUENCES IF YOU DO GET NEC?
I WILL SHOW A SERIES OF STUDIES
THAT IS A NEONATAL RESEARCH
NETWORK THAT HAS BEEN ABLE TO
HARNESS THE POWDER POWER OF
CLINICAL DATA WITH A DETAILED
FOLLOW-UP DATA.
THIS IS WORK OUT OF OUR OLD
COHORT 1995 TO 1998 WITH A BIRTH
WEIGHT UNDER 1000 GRAMS ALMOST
5000 INFANTS AS COLLEAGUES AND
COMPARED INFANTS THAT DID NOT
SUFFER NEC AND THOSE WHO GOT
MEDICAL NEC OR SURGICAL NEC AND
THE GROWTH DURING THE NICU TIME
ENDING AT 2 YEARS AND AS YOU CAN
SEE THERE WERE SIGNIFICANT
IMPACTS, NEGATIVE IMPACTS ON
BOTH WEIGHT, LENGTH AND HEAD
CIRCUMFERENCE WITH THE RISK OF
BEING AT LESS THAN TENTH
PERCENTILE STATISTICALLY
SIGNIFICANTLY GREATER WHEN YOU
COMPARE INFANTS TO HAD NO NEC
VERSUS SURGICAL NEC ALTHOUGH
INTERESTINGLY NOT SIGNIFICANT
DIFFERENCE BETWEEN THOSE WHO HAD
MEDICAL NEC.
IN ADDITION TO THESE
INVESTIGATORS LOOK AT TWO-YEAR
NEURODEVELOPMENT OUTCOME AND
WITH A LITTLE BIT OF AN OLDER
DEFINITION COMPARED TO WHAT WE
USE NOW, THESE INVESTIGATORS CAN
SHOW SIGNIFICANT DIFFERENCE IN
THE COMBINED RATE OF DEATH OR
SURVIVAL WITH MODERATE TO SEVERE
NEURODEVELOPMENT IMPAIRMENT WHEN
COMPARING THOSE THAT HAVE NO NEC
TO SURGICAL NEC.
I REALLY WANT TO CALL OUT THIS.
IT'S EASY TO GET LOST IN
DEFINITIONS AND ADJUSTMENTS OF
STATISTICS.
LOOK AT DEATH AND THIS COHORT IF
YOU WERE A BABY BORN UNDER
1000 GRAMS AND DID NOT SUFFER 1
OUT OF 5 DIED BEFORE DISCHARGE
IF YOU HAD ANY NEC THE RISK WAS
TWICE AS HIGH OF 40 PERCENT IF
YOU HAD SURGICAL NEC IT WAS EVEN
HIGHER THAN MEDICAL.
WITH A DEVASTATING COMPLICATION
OF PREMATURITY.
AS OF THE PARTICULAR ASSOCIATION
WITH SURGICAL NEC MANY STUDIES
FOCUSED ON THE GROUP THAT HAS
HAD SURGERY FOR NEC THIS IS A
LITTLE MORE CONTEMPORARY
FOCUSING ON THOSE BORN UNDER
1000 GRAMS COMPARING THOSE WHO
HAD NO NEC OR SPONTANEOUS
INTESTINAL PERFORATION.
AND WITH A COMBINED OUTCOME AND
HERE WE CAN SEE ALL OF THE
COMPARISONS SURGICAL NEC VERSUS
NO NEC WERE MARKEDLY HIGHER
RATES OF OVER 80 PERCENT OF
NEURODEVELOPMENTAL IMPAIRMENT.
>> YOU NEVER KNOW WHEN SOMETHING
WILL SHOW UP SO THERE WAS A
COMPARISON LOOKING AT THE
OUTCOMES ASSOCIATED IF THEY HAD
GOT IN BETTER.
AND ON THE ADJUSTED ANALYSIS
2012 THROUGH 2016 THERE IS
ACTUALLY NO IMPROVEMENT IN
NOTHING GOOD HAS CHANGE.
AND USING MORE CONTEMPORARY
DEFINITIONS OF IMPAIRMENT AT
90 PERCENT OF INFANTS.
THEY SUFFER DEATH OR
NEURODEVELOPMENTAL IMPAIRMENT.
WITH THOSE CONSEQUENCES OF
HAVING NEC OR SURGICAL NEC WHICH
IS SHORT BOWEL SYNDROME AND THE
OUTCOMES OF THAT THOSE BORN LOW
GESTATION COMPARING THOSE THOSE
THAT HAD HERE WE CAN SEE THE
COMBINED OUTCOME WAS MORE COMMON
AMONG THOSE WHO HAD SHORT BOWEL
SYNDROME AND EVERY MEASURE OF
SURVIVAL WAS STATISTICALLY
SIGNIFICANTLY WORSE.
IF YOU SURVIVED.
THE FAMILY IS BEING THERE LIVES
WITH THE CONDITIONS AT THE LEAD
THE NICU.
AND BASED ON A CONVENIENCE
SAMPLE AND HAS MANY LIMITATIONS
THAT STUDIES DO PARTICULARLY THE
FOLKS WHO RESPONDED TO THE
SURVEY WERE NON-HISPANIC WHITE.
AND I WAS INTERESTED TO KNOW IT
WASN'T ALWAYS THE TINY LOW
GESTATION INFANTS.
THOSE THAT WHO HAD SURVIVED NEC
AS WELL AS WELL AS ADULT
SURVIVORS THAT RESPONDED AND I
KNOW YOU CANNOT READ A LOT OF
THIS BUT I WOULD RECOMMEND YOU
LOOK AT THIS PAPER.
IT IS A GOOD DESCRIPTION USING
QUALITATIVE SURVEY METHODS TO
REFLECT THE REALITY OF LIVING
AFTER THE DIAGNOSIS OF NEC.
MANY OF THE ITEMS THAT STOOD OUT
TO ME INCLUDED THE LONG-TERM
PHYSICAL EFFECTS WITH CONSTANT
WORRIES OF G.I. FUNCTION AND
GROSS THE SOCIAL IMPLICATIONS OF
BEING A TEENAGER WHO IS CONSTANT
WORRIES WHERE THE BATHROOM IS
AND INTERESTINGLY THE LACK OF
INFORMATION AROUND NEC AND THE
EXTENT TO WHICH THE FEW ADULT
SURVIVORS FELT THEY HAD TO
REPEATEDLY DISCUSS THIS AND TELL
THEIR PEDIATRICIAN THAT THEY ARE
NOT IMAGINING THEIR SYMPTOMS
ESPECIALLY WHEN THEY
TRANSITIONED INTO ADULT CARE.
LOOKING AT A FEW SPECIFIC
OUTCOMES THE RATE OF ANY
LONG-TERM IMPLICATION WAS
60 PERCENT ON THE SURVEY.
IT WAS ONLY A QUARTER OF THE
RESPONDENTS AND 17 PERCENT WERE
STILL RECEIVING INTRAVENOUS
SUPPLEMENTAL MUCH NUTRITION.
AT NEGATIVELY IMPACTED THE
HEALTH OF THE PARENTS 74 PERCENT
OF THE RESPONDENTS SAID THAT IT
DID.
FOR THE REST OF THE DAY YOU CAN
TAKE ON THIS MESSAGE.
NEC IS A TERRIBLE COMPLICATION
OF EXTREME PREMATURITY AND
OCCURS BETWEEN 5 THEIR 6 PERCENT
BORN UNDER 1500 GRAMS 10 PERCENT
UNDER 1000 GRAMS.
THERE HAVE BEEN SOME DECREASES
IN NEC OVER THE PAST 20 TO 30
YEARS ALTHOUGH IMPROVEMENTS HAVE
PLATEAUED OVER THE LAST 5 TO 10
YEARS AND THAT CONTINUES TO
OCCUR DESPITE MANY EFFORTS TO
IDENTIFY BEST PRACTICES.
APPROXIMATELY TWOFOLD RISK OF
DEATH INCREASED ASSOCIATED WITH
SURGICAL NEC A GOOD 1.5 PERCENT
OF NEURODEVELOPMENTAL IMPAIR
IMPAIRMENT.
THE OUTCOMES ARE MOST SEVERE
AMONG THOSE WITH SURGICAL NEC
AND THOSE WITH SHORT BOWEL
SYNDROME.
WE ARE ONLY BEGINNING TO
UNDERSTAND THE LIFELONG IMPACTS
OF THE COMPLICATIONS AND I AM
HAPPY TO BE AT A CONFERENCE THAT
IS TRYING AS HARD AS WE CAN TO
CONTINUE TO PREVENT THIS
TERRIBLE COMPLICATION.
THANK YOU.
[APPLAUSE]
>> THANK YOU.
I APPRECIATE THAT.
OUR NEXT SPEAKER DOCTOR PATEL
PROFESSOR OF PEDIATRICS IN THE
DIVISION OF NEONATOLOGY
UNIVERSITY SCHOOL OF MEDICINE
CHILDREN'S HEALTHCARE OF
ATLANTA.
TAKE IT AWAY.
>> THANK YOU TO FDA AND NIH I
LIKE TO ECHO THE COMMENTS ON THE
STAKEHOLDERS BRING IN THOSE
TOGETHER TO ADDRESS A TERRIBLE
DISEASE.
I WILL TALK ABOUT THE
NUTRITIONAL APPROACHES AND
SUPPLEMENTATION PRACTICES AMONG
LOW BIRTH WEIGHT INFANTS AND
WHEN THE THINGS I WAS TALK ASKED
TO TALK ABOUT WITH THE
RECOMMENDATIONS OF CARE SO I
WILL TALK ABOUT CURRENT
RECOMMENDATIONS OF CARE AS WELL
AS EVIDENCE.
A FEW DISCLOSURES THE CONTRACT
RESEARCH ORGANIZATION FOR TRIAL
THERAPEUTICS AND THE CONSULTANT
I WILL DISCUSS THAT AS WELL
TODAY AND BRIEFLY DISCUSSING
PROBIOTICS THIS IS NOT FOR THE
PREVENTION OF DISEASES AND I'M
ALSO SPEAKING HERE ON BEHALF OF
MYSELF AND NOT ANY ORGANIZATION
THAT COULD BE AFFILIATED.
MY GOAL TODAY IS TO TALK ABOUT
THE RECOMMENDATIONS BUT CURRENT
GUIDANCE IN TERMS OF NUTRITIONAL
SUPPLEMENTATION PRACTICES AS IT
RELATES TO LOW BIRTH WEIGHT
INFANTS AND HIGHLIGHTS THE
EVIDENCE OF WHAT I CAN IN THE
TIME THAT WE HAVE OF THE
EVIDENCE OF IMPACT NUTRITION ON
NEC FOR VLBW INFANTS AND THEN
THE SUPPLEMENTATION PRACTICES
AND WHAT ARE THOSE IN THE
NEONATAL INTENSIVE CARE UNITS.
SO TO BEGIN WITH WHAT ARE SOME
GUIDANCE ON NUTRITIONAL
APPROACHES IN SUPPLEMENTATION'S
AS IT RELATES TO THE TOPIC TODAY
FOR PROBIOTICS THAT ARE RELEVANT
FOR PRACTICING CLINICIANS IN THE
US AND ELSEWHERE?
SO I WILL START WITH GUIDANCE
AND HERE IS A CLINICAL REPORT ON
THE GUIDANCE FOR HUMAN MILK
TITLED PROMOTING HUMAN MILK AND
BREASTMILK FOR THE LOW BIRTH
WEIGHT INFANTS AND AS IT RELATES
TO NEC WITH OPTIMAL NUTRITION IT
DECREASES THE RISK OF
SIGNIFICANT COMPLICATIONS OF
PREMATURITY AND FEEDING IS
RECOMMENDED FOR LOW BIRTH WEIGHT
INFANTS AND IS INSUFFICIENT OR
CONTRAINDICATED.
THERE ARE RACIAL AND ETHNIC
DISPARITIES FOR VERY LOW BIRTH
WEIGHT INFANTS AND FREQUENTLY
REQUIRES FORTIFICATION TO MEET
THE NEEDS OF THE INFANTS.
IN ADDITION WITH GUIDANCE
PUBLISHED IN 2021 THERE ARE 4
KEY POINTS AND I COPY THESE
VERBATIM AND THE FIRST IS THAT
THE CURRENT EVIDENCE IT DOES NOT
SUPPORT PARTICULARLY THOSE WITH
A BIRTH WEIGHT OF LESS THAN
1000 GRAMS.
IT ALSO GOES ON TO GIVE SPECIFIC
RECOMMENDATIONS FOR CENTERS THAT
ARE MAKING THE DECISION TO
ADMINISTER PROBIOTICS BUT IF
THEY DO THAT THEY SHOULD DISCUSS
THE RISKS AND BENEFITS SO THEY
SHOULD CONSIDER A CONSENT
PROCESS AND SHOULD DEVELOP LOCAL
GUIDELINES FOR THOSE TO ASSESS
LOCAL IMPACTS AND THE CLINICIAN
SHOULD BE AWARE OF THE LACK OF
REGULATORY STANDARDS AND YOU
HEARD AN EXCELLENT INTRODUCTION
ON LBP'S AND THE REGULATION OF
THESE.
THEN FOR ADVERSE EVENT AND
SAFETY.
BUT THEN THE WHO HAS GUIDELINES
THAT WERE BROADENED FOR THE
GLOBAL COMMUNITY TO HIGHLIGHT AS
IT RELATES TO THE TOPIC OF
NUTRITIONAL PRACTICES AND
SUPPLEMENTS THE RECOMMENDATIONS
FOR THE CARE OF LOW BIRTH WEIGHT
INFANTS SOME OF THESE WERE
CONTINUING DISCONTINUATIONS 11
ARE STRONG RECOMMENDATIONS BUT
THEN SEVERAL NEW RECOMMENDATIONS
THAT AS 1 THAT WERE CONDITIONAL
THAT WE WILL TOUCH ON THIS
BRIEFLY AS IT IS RELEVANT TO THE
AREAS OF NUTRITION AND
SUPPLEMENTATION BUT ALSO THE
AMERICAN ACADEMY OF PEDIATRICS.
THE W JOE RECOMMENDS FEEDING
MOTHERS MILK THAT IS A STRONG
RECOMMENDATION IN MY MOTHER'S
OWN MILK IS NOT AVAILABLE THOSE
THAT IS CONSIDERED FOR FEEDING
IS CONSIDERED RECOMMENDATION
ALSO FORTIFICATION SPECIFICALLY
FOR THE POPULATION FOR VERY LOW
BIRTH WEIGHT INFANTS TO BE
CONSIDERED AND WHEN MOTHER'S OWN
MILK ARE NOT AVAILABLE THERE IS
A RECOMMENDATION FOR PRETERM
FORMULA.
VERY PRETERM BUT THE SUPPLEMENTS
THERE ARE A NUMBER OF
RECOMMENDATIONS FOR IRON AND
ZINC VITAMIN A SUPPLEMENTATION
BUT THESE ALSO MIRROR GUIDANCE
FROM THE AMERICAN ACADEMY OF
PEDIATRICS THEN FINALLY THE WHO
HAS A NEW RECOMMENDATION FOR
2023 PROBIOTICS COULD BE
CONSIDERED FOR HUMAN MILK WITH
PRETERM INFANTS THIS IS BASED ON
OTHER EVIDENCE AND WITH
SUPPLEMENTS THE NEXT STUDY ALSO
HAS GUIDANCE NOTED AS A STRATEGY
TO HELP THE DEUCE NEC AND DEATH
AND LOW BIRTH WEIGHT INFANTS
THERE IS A GROWING INTEREST IN
FAMILY SHOULD BE BETTER INFORMED
OF RISKS AND BENEFITS CLINICIAN
SHOULD BE PREPARED TO HAVE
PARENTS UNDERSTAND THE RATIONALE
AND THEN DETAILED IMPLEMENTATION
AND CAREFUL DATA COLLECTION ARE
ESSENTIAL TO CONTINUOUSLY TRACK
AND UNDERSTAND PROBIOTIC USE OR
THE LACK THEREOF AND THEN
FINALLY AS IT RELATES TO
GUIDANCE HERE IN THE UNITED
STATES GASTRIN ELEGY ASSOCIATION
IN 2020 TALKED ABOUT LESS THAN
37 WEEKS OF GESTATION AND THEN
WE SUGGEST THEY PROVIDE CERTAIN
TYPES OF PRODUCTS WITH DIFFERENT
TYPES OF BACTERIA THAT ARE
LISTED HERE WITH A
RECOMMENDATION FOR THE
PREVENTION AND THIS WAS A
CONDITIONAL RECOMMENDATION BASED
ON HIGH CERTAINTY OF EVIDENCE
WITH EUROPEAN SOCIETY FOR
GASTROENTEROLOGY AND NUTRITION
THAT ALSO HAS CONDITIONAL
RECOMMENDATIONS SO I JUST WANT
TO START THEIR 1 OF THE THINGS I
WAS ASKED TO TALK ABOUT OF
RECOMMENDED CARE WITH THE
GUIDANCE THAT CLINICIANS
PRACTICING IN UNITS RELATING TO
VERY LOW BIRTH WEIGHT UNITS IS
EXPRESSED TO TALK ABOUT THE
EVIDENCE OF THE NUTRITIONAL
APPROACHES AND YOU HEARD SOME OF
THIS FROM THE EXCELLENT
PRESENTATION AND I WILL REPEAT
SOME OF THIS BUT IT IS IMPORTANT
MANY OF THE SNOW THE BENEFITS OF
HUMAN MILK THIS WAS PUBLISHED IN
2009 FROM THE RESEARCH NETWORK
LOOKING AT OVER TIME ON THE X
AXIS LOOKING AT THE
PROPORTIONATE INFANTS WHO
SURVIVE FREE OF ANY CNA
CORRESPOND TO THE PROPORTION OF
HUMAN MILK INTAKE IN THE FIRST
14 DAYS OF LIFE THAT THEY
RECEIVE EXCLUSIVELY ALL HUMAN
MILK 75 PERCENT, 50 AND
25 PERCENT WITH THE TAKE-HOME
MESSAGE HUMAN MILK IS A VERY
IMPORTANT FACTOR WITH THE IMPACT
ON NEC THE HIGHER THE DOORS --
-- THE DOSE TO LOWER THE RISK.
OF COURSE RECOMMENDATIONS ARE
FOR MOTHERS ON MILK.
SO RANDOMIZING DESIGNS ON TRIALS
TO THE MOTHER'S OWN APPEARANCE
THIS IS WHY OBSERVATION DATA CAN
BE USEFUL TO QUANTIFY THE DATA.
WHAT ABOUT ODOR MELT - - DONOR
MELT?
IS NOT ALWAYS AVAILABLE THIS IS
A REVIEW THAT HIGHLIGHTS THE
DATA FROM RECENT CLINICAL TRIALS
ON THE EFFECTIVE DONOR HUMAN
MILK AND WHEN IT SHOWS THAT THE
USE OF DONOR HUMAN MILK RESULTED
IN A REDUCTION OF ABOUT
53 PERCENT AND THAT IS BASED ON
HIGH CERTAINTY EVIDENCE 11
STUDIES OF 2200 INFANTS INVOLVED
BUT IF THERE IS NO SIGNIFICANT
EFFECTS OF LATE ONSET INFECTION
-- -- INFECTION OF THE
ANALYSIS.
1 OF THE LARGEST TRIALS
CONTRIBUTING TO THAT ANALYSIS IS
THE RESEARCH NETWORK MILK TRIALS
MULTI- SET OF RANDOMIZED CONTROL
TRIALS INVOKING INFANTS WITH THE
BIRTH WEIGHT LESS THAN
1000 GRAMS SO THIS WAS DONE FROM
SEPTEMBER 2012 THROUGH
MARCH 2019 IT TOOK A NUMBER OF
YEARS BUT AN IMPORTANT TRIAL IT
IS IMPORTANT POPULATION THOSE
THAT ARE HIGHEST RISK SOMETIMES
THEY DO TAKE A WHILE TO ENROLL
WITH THE PURPOSE OF THE TRIAL
WAS TO LOOK AT THE EFFECTS OF
DONOR HUMAN MILK WITH COGNITIVE
OUTCOME THERE WAS NO SIGNIFICANT
DIFFERENCE THAT WE LOOKED AT THE
TRIAL AND THE REDUCTION AND WAS
DEFINED TO GREATER WITH A
5 PERCENT ABSOLUTE RISK
REDUCTION CORRESPONDING TO WHAT
YOU WOULD EXPECT BASED ON THE
PRIOR SYSTEMATIC REVIEW ABOUT A
50 PERCENT REDUCTION OF AN
EASY.
SO WHAT ABOUT OTHER NUTRITIONAL
PRACTICES?
THERE ARE THINGS AS IT RELATES
TO ENTERAL FEEDING AND NUTRITION
I WANT TO HIGHLIGHT A RECENT
WORKGROUP IN AUGUST OF THIS YEAR
THAT CONVENED A WORKGROUP OF THE
NATIONAL ADVISORY COUNCIL OF
HEALTH AND HUMAN DEVELOPMENT.
1 OF THE THINGS THEY WERE TASKED
WITH WAS TO CITE THE SCIENTIFIC
EVIDENCE AND THEN TO INCREASE
THE RISK.
BUT THEN TO HIGHLIGHT THE
FINDINGS FROM THIS REPORT I
THINK ARE RELEVANT FOR
NUTRITIONAL PRACTICES AS IT
RELATES TO THE OUTCOME WE ARE
INTERESTED IN TODAY.
THESE ARE SOME OF THE POINTS AND
YOU CAN LOOK BELOW BUT THE
RELATIONSHIP THE FEEDING AND
DEVELOPMENT OF NEC IS NOT CLEAR
BUT EVIDENCE TODAY SUPPORTS THE
HYPOTHESIS THE ABSENCE OF ANY
HUMAN MILK IS THE HIGH RISK AND
WE KNOW FROM STUDIES DISCUSSED
AS PART OF THE STUDY THERE'S A
NUMBER OF COMPONENT OF ASPECTS
AND A NUMBER OF COMPONENTS THAT
HAVE BEEN STUDIED THAT CONFIRM
BENEFIT AND THERE IS A NEED FOR
ADDITIONAL RESEARCH UNDERLYING
MECHANISMS THAT CAUSE THE
SPECIFIC COMPONENTS TO HELP
PREVENT IT AND WE NEED MORE
STUDIES TO DETERMINE WHY HUMAN
MILK AND NEC USE HAS A PERTINENT
EXAMPLE.
THIS TALK ALSO TOUCHES ON OTHER
ASPECTS LIKE TO USE THE STANDARD
OBSERVATIONAL STUDIES AS WELL AS
SOME OF THE DISCUSSIONS ON THE
APPROACHES TO FORTIFICATION IN
THE IMPACT BUT I WILL NOT GET
INTO THAT TODAY.
FINALLY I WILL TOUCH ON THE
EVIDENCE FOR SUPPLEMENTATION AND
PRACTICES OF LOW BIRTH WEIGHT
INFANTS IF YOU THINK OF THIS IN
TERMS OF THE SCOPE OF
SUPPLEMENTATION AND PRACTICES
THIS IS A BROAD SUPPLEMENTATION
AND THIS IS A REVIEW THAT LOOKS
AT SUPPLEMENTATION THAT MIGHT
HAVE AN IMPACT ON MICRO BIOME
HEALTH AND IT SEEMS THAT THE
TERMINOLOGY MAY BE DIFFERENT
THAN THOSE MENTIONED EARLIER
FROM THOSE PRODUCTS BUT AS WELL
AS OTHER NUTRITIONAL SUPPLEMENTS
THAT SOME OF THESE ARE ROUTINELY
ADMINISTERED WITH LOW BIRTH
WEIGHT INFANTS BUT TO TOUCH ON
THE ASPECTS OF SUPPLEMENTATION.
THINK OF NUTRITIONAL
SUPPLEMENTATION PROBIOTICS ARE
SELECTIVE TO HOST MICROORGA
MICROORGANISMS.
AND HUMAN MILK CAN SUPPORT OR BE
UTILIZED BY THOSE MICROORGANISMS
THOSE BIO BIOTICS THAT HAVE BEEN
STUDIED IN SPECIFIC TRIALS AND
SOME STUDIES HAVE MIXTURES AND
THEN NOT YET TO MY KNOWLEDGE
HAVE BEEN EVALUATED TO DATE IN
TERMS OF NONVIABLE PRODUCTS THAT
HAVE BEEN WITH THE LOW BIRTH
WEIGHT POPULATION THAT ALSO
COULD BE A STRATEGY THAT ABOUT
THE SUPPLEMENTATION?
THIS IS A SNAPSHOT I WAS A IS
NOT REFLECTIVE OF THE CURRENT
STATE BUT THIS IS DATA THAT IS
PUBLISHED REPORTS AND THE FIRST
IS ON THE LEFT PUBLISHED
2020, GROUP AT DUKE THAT
UTILIZED THE WAREHOUSE WHICH IS
DATA FROM A NUMBER OF UNITS
LOOKING AT TRENDS AND YOU CAN
SEE THE INCREASE AFTER 2014
THERE WAS AN INCREASE OF
PROBIOTIC YOU SUPPLEMENTATION
AND BASED ON THE 2022 SURVEY
PUBLISHED LAST YEAR ABOUT 1
THIRD REPORTED USE IN A GROUP OF
CHILDREN'S HOSPITAL UNITS AS
WELL AS MANAGED BY THE
PROBIOTICS GROUP THERE WAS SOME
GUIDANCE ABOUT 30 PERCENT OF
UNITS AND ABOUT 1 THIRD AT THE
TIME WERE CONSIDERING FOR
INITIATION AND A VARIETY OF
COMMERCIALLY AVAILABLE
SUPPLEMENTS THAT WERE USED IN
THE NICU AND I HIGHLIGHT THIS
YEAR WITH THE SURVEY THAT WAS
PUBLISHED SOME OF THESE ARE NO
LONGER AVAILABLE ON THE MARKET.
AS PART OF ROUTINE USE YOU HEARD
ABOUT THE NETWORK THESE GROUPS
HAVE HAD A CHANCE TO
CHARACTERIZE THE EXPERIMENTS THE
EXPERIENCE OF THE IMPLEMENTATION
AND PRACTICE I WILL NOT GET INTO
MUCH MORE DETAIL WE WILL TALK
ABOUT THIS AFTER LUNCH IN TERMS
OF EVIDENCE BUT I HIGHLIGHT THIS
BECAUSE 1 OF THE THINGS AS IT
RELATES TO HUMAN MILK AND
FEEDING PRACTICES IS THE ABILITY
TO LOOK AT THE POTENTIAL THE
ASSOCIATION ROUTINE
SUPPLEMENTATION AND THOSE WHO
DID NOT RECEIVE HUMAN MILK.
SIMILARLY GROUPS HAVE BEEN ABLE
TO CHARACTERIZE THE ASSOCIATION
BETWEEN ROUTINE SUPPLEMENTATION
OF THESE PRODUCTS IN THE NICU
AND THE PRODUCT THAT IS SHOWN ON
THE RIGHT FOR EXAMPLE A LOWER
REDUCTION THAT IS REPORTED FROM
2020.
AND FINALLY THE NUTRITIONAL
SUPPLEMENTATION AND PRACTICES
ARE A VARIETY OF DIFFERENT
SUPPLEMENTS AND I WILL NOT GO
INTO DETAIL ON EACH BUT THE
SUPPLEMENTS THAT ARE USED AND
THESE ARE SOME OF THE
EXAMPLES, VITAMIN A WAS A TRIAL
LAID BY THE NEONATAL RESEARCH
UNIT IN 1999 SHOWING
INTRAMUSCULARLY REDUCED
DYSPLASIA THAT IS ROUTINELY USED
VITAMIN D AND IRON INCLUDING FOR
THE PREVENTION OF RICKETS AND
VITAMIN A SUPPLEMENTATION IS NOT
ROUTINE BUT HAS BEEN STUDIED
PREVIOUSLY FOR HEMORRHAGE BUT IS
NOT USED OF SOME CONCERNS OF
SEPSIS AND THEN THERE ARE
STUDIES TO SUPPLEMENT DHA AND
STUDIES SHOW AN INCREASE OF
COMPLICATIONS SUCH AS DYSPLASIA
OR LUNG DISEASE IMPROVING
COGNITIVE OUTCOME.
BEGINNING WITH THE WHO
SUGGESTION OF ROUTINE
SUPPLEMENTATION OF ZINC COULD
REDUCE MORTALITY AND THEN SOME
SMALL CLINICAL TRIALS SHOW THAT
COULD HAVE A POTENTIAL
REDUCTIONS SO WITH THOSE
SUPPLEMENTS AND THEN TO BE
EVALUATED SO WITH A SNAPSHOT
WORD ARE THE PRACTICES AND WITH
MANY OF THE DATA THAT WE
DISCUSSED THIS FAR BETWEEN
INFANTS AT 20 WEEKS OF GESTATION
AND THIS IS DATA FROM 2013
THROUGH 2018 AND WHEN WE LOOK AT
HUMAN MILK USE OF THE FIRST 20
DAYS OF BIRTH IF YOU LOOK AT THE
DENOMINATOR BABIES THAT ARE FED
MOST CURRENTLY IF YOU LOOK AT
THE PRACTICE OF RECEIVING MILK
IS PART OF ROUTINE CARE AND THE
SUPPLEMENTATION COHORT IS ABOUT
10 PERCENT THEY ARE RECEIVING
SUPPLEMENTATION ABOUT 25 PERCENT
OF THE CENTERS I WON'T GO INTO
TOO MUCH DETAIL BUT TO SAY THE
RISK OF NEC IS 9 PERCENT LOOKING
AT SEPSIS BUT THEN I HIGHLIGHT
THE NUMBERS THIS IS JUST 15
CENTERS OVER THE PERIOD OF TIME
THAT MEANS 890 BABIES DEVELOPED
AND HAD TO HAVE SURGERY ALMOST
2000 WITH LATE ONSET SEPSIS.
SO WHEN WE TALK ABOUT
PERCENTAGES THIS REFLECTS REAL
PATIENCE AND THAT IS IMPORTANT
TO THINK ABOUT THE DATA THESE
ARE REAL PATIENTS IMPACTED BY
THESE DISEASES.
AND THEN LOOK AT MORTALITY AS WE
THINK OF THE CAUSE OF DEATH IN
BETWEEN 2 WEEKS AND 2 MONTHS OF
LIFE IT IS A SINGLE CAUSE OF
DEATH IT REALLY ACCOUNTS FOR THE
MAJORITY BETWEEN 2 WEEKS AND 2
MONTHS OF LIFE AND THEN OF
COURSE SOME OF THESE IT COULD
CONTRIBUTE TO MORBIDITIES THAT
COULD BE A CAUSE OF DEATH SO
THAT MEANS A TRAGIC DISEASE AND
GLAD WE ARE HERE TODAY TO
IMPLEMENT AND WITH THE
APPEARANCE OF MELCHOR DONOR MILK
AND ALTHOUGH GUIDANCE FOR
DIFFERENT GROUPS HUMAN MILK
FEEDING I THINK IT IS AN
IMPORTANT FACTOR IMPORTANT
AGAINST THE RISK AND A VARIETY
OF SUPPLEMENTS INCLUDING
PROBIOTICS HAVE BEEN EVALUATED
AND THEY ARE ROUTINELY USED HERE
IN THE UNITED STATES.
THANK YOU.
>> I WOULD LIKE TO INVITE OUR
SPEAKERS UP.
WE HAVE PLENTY OF TIME FOR
QUESTIONS.
PLEASE REMEMBER TO USE THE
MICROPHONE.
>> I AM WITH THE FDA AND ALSO
THE OFFICE OF VACCINE RESEARCH
AND REVIEW.
I HAVE A QUESTION YOU MENTIONED
THAT HUMAN MILK HAS A BIG IMPACT
ON THE INCIDENCE OF NEC FEEDING
EITHER MOTHERS OR DONOR MILK I
NOTICED THE DONOR MILK IS
PASTEURIZED.
IS THERE ANY DIFFERENCE BETWEEN
DONOR MELCHOR MOTHERS MILK?
>> MOTHERS MILK IS IDEAL
PASTEURIZATION DOES ALTER THE
CHARACTERISTICS LIKE THAT
MICROBES OR THE OTHER COMPONENTS
SOME ARE SUSTAINED SOUND YOU
LOOK AT THE BIOLOGIC DIFFERENCES
EFFECTIVE WITH PASTEURIZATION TO
REDUCE THE RISK OF INFECTION
THERE ARE SOME STUDIES SOMETIMES
THEY ARE OBSERVATIONAL AND
LIMITED THEY ARE CONFOUNDING BY
THOSE INDIVIDUALS THERE IS
PROVISION OF MOTHER ZONE MILK
THAT THEY MAY POTENTIALLY HAVE A
GREATER IMPACT OF MOTHER ZONE
MILK BUT THE TRIALS THAT YOU
JUST SHOWED HAVE A CLEAR AND
SIGNIFICANT EFFECT WHEN IT'S
LARGELY THE OWNER OF DIETS WITH
THE REDUCTION OF 50 PERCENT.
>> THAT IS MY QUESTION.
SO WITH THE PASTEURIZATION
PROCESS DOES THAT DEGRADE THE
ANTIBODIES THAT ARE TRANSMITTED
THROUGH COLOSTRUM?
>> AND WITH THE SPECIFIC
ANTIBODIES THERE IS SOME AFFECT.
>> IT DOES HOLD THE
PASTEURIZATION IT DOES NOT
ENTIRELY DEGRADE ANTIBODIES.
IT IS THE NON- SPECIFICITY SO
MOTHER'S OWN MILK PRESENTS THE
INFANT WITH ANTIBODIES DIRECTED
LARGELY TO THE MATERNAL
INFECTIOUS EXPERIENCE IDEALLY
MOTHER HAS TRANSMITTED THEIR OWN
MICRO BIOME AND SO THERE IS A
FIT BETWEEN THE ANTIBODY AND
MOTHER ZONE MILK.
1 COULD ARGUE DONOR MILK SO
THERE COULD BE WIDER EXPOSURE
AND LESS SPECIFIC AND DEPENDING
ON PREPARATION AND FREEZING
THERE COULD BE SOME DEGRADATION
OF ANTIBODY BUT NOT ENTIRELY.
>> A QUESTION IN THE CHAT.
MOST REQUIRE ALL ULTIMATE GROWTH
WITH BOVINE MILK.
>> .
>> THERE HAVE BEEN CLINICAL
TRIALS BUT THE 2 MOST RECENT 1
THAT WAS PUBLISHED IN EUROPE AND
1 IN CANADA AS WELL AS THE
JENSEN CHILD THEY LOOKED AND
THEN COMPARED FORTIFICATION AND
THEN THERE IS A COMPARISON OF
BOVINE BASED fortification base
based fortification Based fortin
WHICH WAS ON THE BASE SIDE OF
HUMAN MILK AND THOSE CLINICAL
TRIALS THERE WAS NO SIGNIFICANT
EFFECT ON EITHER TRIAL.
I DO THINK THERE ARE THOSE THAT
WILL TRY TO SYNTHESIZE BUT THEY
ARE STILL ONGOING.
SO TO RECEIVE HUMAN MILK AND THE
BENEFIT WITH THE ADDITIONAL
EFFECTIVE FORTIFICATION IS LESS
CERTAIN IN TERMS OF THE EFFECT
ON NEC.
>> I WORD ADD A COMMENT TO DONOR
MILK IS MATURE MILK WE WOULD NOT
HAVE COLOSTRUM WHICH IS QUITE
DIFFERENT THAT WILL ALWAYS COME
FROM THE BABY'S MOTHER WE WOULD
NEVER HAVE COLOSTRUM AS A DONOR
PRODUCT AND HOW IMPORTANT THAT
IS I GUESS WE THINK IS IMPORTANT
BUT WE DON'T KNOW.
ALSO FOR DOCTOR KASLOW THE LINE
BETWEEN PROMOTING HEALTH AND
HEAT TO MITIGATE PREVENT AND
TREAT DISEASE IS MURKY WITH THIS
TOPIC 8 YOU DID NOT TOUCH ON A
SPECIFIC FROM A REGULATORY
STANDPOINT ALSO THOSE GENERALLY
REGARDED AS SAFE AND HOW DO YOU
THINK THIS TOPIC FITS IN THOSE 2
POOLS?
>> I THINK WE HAVE SOME
COLLEAGUES THAT CAN ADDRESS STAY
AWAY FROM THE FOOD SITE AND
FOCUS ON THE DRUGS WHICH IS
CLEARLY REGULATED AND I WENT
THROUGH WHAT THOSE REGULATIONS
ARE.
WE COULD POTENTIALLY BE WE
REALLY NEED TO PAY ATTENTION WHY
I HIGHLIGHTED PICO WHICH IS THE
POPULATION IN ADDITION TO THE
INTERVENTION AND THE OUTCOME.
WHAT WE ARE TALKING ABOUT I
THINK ARE UNHEALTHY INDIVIDUALS
AND I THINK WE LOOK AT THAT
DIFFERENTLY AND WE LOOK AT SOME
OF THESE FOODS OF OTHERWISE
HEALTHY INDIVIDUALS.
I DON'T KNOW IF ANYONE WANTS TO
COMMENT FURTHER.
I HAVE MY BRAIN TRUST IN THE
BACK ROW FROM THE OFFICE AS A
NEWLY MINTED DIRECTOR OF THE
OFFICE BUT I DON'T KNOW IF
ANYBODY ELSE WANTS TO CHIME IN
ON THAT?
>> I CAN COMMENT ON THE FACT
FOOD IS SOMETHING THAT YOU TAKE
FOR NUTRITION, TASTE AND AROMA.
SO WHAT WE ARE TALKING ABOUT
HERE IS INTERVENTION TO PREVENT
THE DISEASE SO IT'S FROM WHAT IS
CONSIDERED TO BE A DRUG BUCKET
AND AS SUCH CONSIDERING THE
POPULATION I THINK IN THIS ROOM
WE WOULD ALL STRIVE TO HAVE A
PRODUCT THAT IS MANUFACTURED
ACCORDING TO PHARMACEUTICAL
GRADE AND ALSO HAS SHOWN TO BE
EFFECTIVE IN THIS VERY
VULNERABLE POPULATION.
>> CAN YOU OUTLINE THE EFFECT OF
DIFFERENT SUPPLEMENTS AND OF THE
DIFFERENT SUPPLEMENTS?
>> BUT THEY ARE ALSO MEDICATIONS
THERE HAS BEEN CONCERNED SOME
BABIES COULD BE SUBJECTED TO A
HIGHER RISK.
THERE'S NOT A GOOD DEED ABOUT
THE SPECIFICS BUT THAT HAS BEEN
THE CONCERN THAT COULD ALSO
RELATE TO INTRO FEEDING IN THE
CONCENTRATIONS AND TO HAVE
FORTIFIED FEEDINGS COULD BE IN
THE CONTRIBUTIONS OF HIGHLY
POSSIBLE NUTRITION DONOR.
>> THERE HAS BEEN ATTENTION TO
THE TOPIC AND I DEFER TO THE
NUTRITIONIST IN THE NICU TO
ADVISE US ON THE DIFFERENTIAL
CONTRIBUTIONS OF SUPPLEMENTS AND
ADVANCEMENT OF FEEDING IT MAKES
A SIGNIFICANT DIFFERENCE WHEN IT
DOESN'T AND OVER TIME IT APPEARS
THE CHANGES ARE LESS THAN 20 OR
30 YEARS AGO AS PRODUCTS HAVE
BEEN REFINED IN DIFFERENT WAYS.
BUT I DO THINK WE NEED A
NUTRITION EXPERT TO QUANTIFY
THAT.
>> HELLO.
THIS IS A QUESTION FOR DOCTOR
KASLOW.
I APPRECIATE THE FRAMING OF THE
GOALS FOR TODAY AND IT SOUNDS
LIKE YOU ARE PUSHING TO IDENTIFY
THE RIGHT QUESTIONS AND STEPS
WITH THE APPROVAL PATHWAY THAT
YOU HAVE IN MIND BUT WITH THESE
PUBLIC WORKSHOPS AS AN IMMUNE NO
- - SO WHAT HAPPENS NEXT AFTER
TODAY?
AT THE END OF THE DAY WHAT IS
THE PATHWAY THAT MIGHT COMES
AFTER THIS WORKSHOP AND
DISCUSSIONS?
>> WE HAVE TO LEAVE THAT TO THE
DEVELOPERS.
BUT OUR OFFICE IS WILLING READY
AND ABLE TO ACCEPT MISSIONS AND
REVIEWS OF INVESTIGATIONAL DRUG
APPLICATIONS THAT IDENTIFY THE
PATHWAY FOR DEMONSTRATING
SUBSTANTIAL EVIDENCE OF
EFFECTIVENESS BUT ALSO SAFETY
AND PRODUCT QUALITY.
I THINK THOSE ARE ALL SPELLED
OUT AND I TRIED TO PROVIDE
GUIDANCE DOCUMENTS TO DIRECT YOU
TO THAT.
BUT WE ARE WILLING READY AND
ABLE TO REVIEW SUBMISSIONS.
>> IN LOW AND MIDDLE INCOME
COUNTRY WE USE IT WITH FORMULA
AND YOU HAVE ANY OPINION ON THAT
AFFECT?
>> I AM OUT OF LINE TO COMMENT
ON THE UNIQUE CONTEXT AND
CIRCUMSTANCES THAT THE
CLINICIANS WOULD PRACTICE IN LOW
INCOME COUNTRIES.
>> OFTEN WE DO AND A SPECIFIC
GESTATIONAL AGE AT BIRTH OR
CORRECTION DID -- -- CORRECTION
AGE WE ARE COUNSELED TO TRANSFER
TO FORTIFICATION WITH FORMULA
POWDER.
SO THERE IS A TIME IN US CARE
THAT IS ALSO PRACTICED.
I AGREE I HAVE NO EXPERTISE TO
COMMENT ON WHAT IS DONE IN OTHER
SETTINGS.
>> AS A CLINICIAN 1 OF THE
PROBLEMS THAT WE SEE WITH DONOR
MILK IS POOR GROWTH IN THE
REQUIREMENT WITH
SUPPLEMENTATION.
JUST COMING BACK TO SOMETHING I
HEARD THIS SUMMER WAS THERE IS
SOME EVIDENCE OF THE MATURATION
PROCESS OF THE MOTHER'S OWN MILK
WITH THE DEVELOPMENT OF THE BABY
AND WE HEARD THAT COMMENT HERE
THAT DONATED MILK TENDS TO MORE
MATURE?
>> ANY MILK TRIAL WHERE BABIES
WERE RANDOMIZED THERE WAS
EVIDENCE LOWER WEIGHT GAIN
GROWTH COMPARED TO PRETERM
FORMULA SO THAT IS 1 OF THE
THINGS THAT HAS BEEN NOTED AND
HAS BEEN SHOWN AS MENTIONED
EARLIER MILK DONORS CAN BE
DIFFERENT IN TERMS OF
CHARACTERISTICS SOME MAY BE
DONATING AFTER THE BIRTH OF THE
TERM INFANT AND IT MAY BE MANY
MONTHS POSTPARTUM AND THAT TENDS
TO BE LOWER CALORIC DENSITY OR
LOWER PROTEIN.
A DONOR MAY HAVE DONATED CLOSER
TO POSTPARTUM OR AFTER PRETERM
DELIVERY WHERE CALORIC OR
PROTEIN INTAKE MAY BE HIGHER.
BUT SOME MILK BANKS ALLOW FOR
SELECTION OF PARTICULAR TYPES
THAT COULD HAVE DIFFERENCES IN
THE NUTRITIONAL CHARACTERISTICS.
THERE ARE GROUPS THAT USE THOSE
CALORIC CALORIES TO MEET TARG
TARGETS.
EVEN THOUGH THE GROWTH OF THE
TRIAL THERE IS NO DIFFERENCE OF
LONG-TERM OUTCOME ALSO QUESTION
HOW CLINICALLY SIGNIFICANT IS
THE LOWER GROWTH THAT IS A
SIGNIFICANT DECREASE OF NEC.
>> THERE IS A RICH DISCUSSION
GOING ON IN THE CHAT WITH
REFERENCES GIVEN.
>> THANK YOU FOR ALL THE
QUESTIONS.
WE DO WANT TO HAVE INTERACTION
WITH ONLINE PARTICIPANTS THIS IS
A GOOD EXAMPLE.
THANK YOU FOR ALL OF THE
SPEAKERS FROM THE FIRST SESSION
SO WE WILL TAKE A BREAK.
>> 1 ADDENDUM TO MY RESPONSE AND
I THINK THIS IS SOMETHING THAT
CAN HAPPEN TOMORROW 1 OF THE
SLIDES I REVIEWED WAS THE FORMAL
COMMUNICATION AND MEETING
MECHANISM IN 1 PLACE TO START
WHAT REALLY GETS THE REGULATOR
MANUFACTURE ON THE SAME PAGE IS
WHERE THE DEVELOPER CAN SUBMIT
SOME SPECIFIC QUESTIONS TO THE
ISSUES OF CLINICAL STUDIES AND
GET A FORMAL RESPONSE BACK FROM
THE AGENCY.
I WOULD SAY TOMORROW THERE IS A
WHOLE MECHANISM FOR DOING THAT
AND I ENCOURAGE YOU TO READ THE
GUIDANCE DOCUMENT.
>> WE ARE BACK IN THIS ROOM AND
10 MINUTES AT 1030.
THANK YOU.
OUR FIRST SPEAKER IS DOCTOR
JOSEPH NEU FROM THE UNIVERSITY
OF FLORIDA.
HE WILL GIVE US TO TALKS.
AND THE FIRST 1 IS ON CHALLENGES
WITH THE CURRENT CASE
DEFINITIONS FOR NEC.
THE STAGE IS YOURS.
>> I ALSO WANT TO THANK THE
ORGANIZERS WERE PUTTING TOGETHER
THIS VERY IMPORTANT MEETING
THERE IS SO MUCH CONTROVERSY IN
THESE AREAS THAT JUST TO GET
TOGETHER TO TALK ABOUT IT.
IT'S A VERY IMPORTANT ASPECT.
SO LET ME START WITH A
DISCLOSURE AND I WORK WITH
INDUSTRY AND I HAVE SOME FUNDING
FROM NATIONAL INSTITUTES OF
HEALTH AND THE MAIN DISCLOSURE
AND TO HEAR MORE ABOUT THIS
LATER TODAY THE AREA THAT I WANT
TO TALK ABOUT STARTS HERE I
RECEIVED AN E-MAIL SO HE ASKED
ME IF I WAS AWARE OF THE RECENT
MEETING THAT THEY HAD AND NOW WE
HAVE THIS FANTASTIC OPPORTUNITY
TO DO MORE RESEARCH OF
NECROTIZING ENTEROCOLITIS.
AND RECOMMENDING STRATEGIES FOR
RESEARCH.
WITH THIS PREMATURE BABY AND
HERE IS THE WEBSITE AND I WAS
VERY EXCITED THAT IT WILL BE
FUNDING SOME WORK IN THIS AREA.
AND THERE IS A REASON FOR THAT.
AND THE REASON FOR THAT IS IF
YOU ARE DIGGING YOURSELF DEEPER
INTO A HOLE, FIRST THING YOU DO
IS PUT DOWN A SHOVEL.
WE HEARD THIS MORNING THAT
NUMEROUS STUDIES OF NECROTIZING
ENTEROCOLITIS.
THERE ARE FUZZY STUDIES THERE IS
A LOT OF ASSOCIATIONS WE DON'T
KNOW MUCH ABOUT THIS PROBLEM WE
CALL IT A DISEASE AND I QUESTION
IF THERE IS A DISTINCT DISEASE
WITH A QUIZ AND I WANT YOU TO
THINK ABOUT THIS AS WE GO
THROUGH.
PLEASE DEFINE NECROTIZING
ENTEROCOLITIS.
2 YEARS AGO I WAS ON THE PHD
COMMITTEE.
SO PLEASE DEFINE NECROTIZING
ENTEROCOLITIS AND G.I.
DEVELOPMENT.
DO BABIES WITH BELLS STAGE 1 OR
2 NEC HAVE INTESTINAL NECROSIS?
IF THEY DON'T AND WE ARE CALLING
IT NECROTIZING ENTEROCOLITIS
ISN'T THAT A MISNOMER?
DO WE HAVE A CLEAR UNDERSTANDING
OF THE PATH OF PHYSIOLOGY -- --
PATHOPHYSIOLOGY?
DO WE HAVE ACCURATE BIOMARKERS
FOR NEC?
ARE THERE PREVENTATIVE
STRATEGIES AND WITH THESE
DYSFUNCTIONS THAT WE ARE CALLING
THEM AND I WILL MAKE A CASE FOR
THIS.
IN 1965, ALEXANDER SCHAEFER
DISEASES OF THE NEWBORN.
IT WAS WRITTEN IN THE BOOK ABOUT
NEC.
NOTHING WAS WRITTEN AND THEN 6
YEARS LATER DISEASE OF THE
NEWBORN A FEW SENTENCES MAY BE
THE PARAGRAPH OF NECROTIZING
ENTEROCOLITIS.
AND TO RECOGNIZE THERE WAS
SOMETHING THEY ARE CALLING
NECROTIZING ENTEROCOLITIS.
AND THEN THE BABY GETS BETTER
AFTER A COUPLE OF WEEKS AND THEN
SUDDENLY DEVELOPS OR A DISTENDED
ABDOMEN AND GOES TO SURGERY THE
ENTIRE BOWEL IS DEAD AND THE
BABY DIES.
THIS IS DEVASTATING AS YOU SAW
IN PREVIOUS LECTURES THEY DIED.
IT IS A TERRIBLE PROBLEM.
BUT AS YOU ALSO SAW FOR THE LAST
60 YEARS WE HAVE NOT HAD VERY
MUCH PROGRESS.
THERE ARE SEVERAL REASONS FOR
THIS.
AND HERE IS 1 OF THEM.
AND CALLING THIS INTO THE SAME
DATA SET.
WE HAVE ANIMAL MODELS THAT DO
NOT CORRECTLY REPRESENT WITH THE
INDIVIDUAL PATHWAYS RATHER THAN
SYSTEMS.
AND IN 2011 DOCTOR WALKER AND I
WROTE AN ARTICLE ON NECROTIZING
ENTEROCOLITIS.
AND THAT THERE WERE PROBABLY
SEVERAL ENTITIES THAT WE WERE
CALLING NECROTIZING
ENTEROCOLITIS AND AT THAT TIME
BEGINNING TO RECOGNIZE SPUN TIME
-- -- SPONTANEOUS PROLIFERATION
IS SOMETHING WE WERE CALLING
NECROTIZING ENTEROCOLITIS BUT IT
WAS A DIFFERENT ENTITY.
AND THERE WAS SUGGESTIONS THAT
THERE WERE SEVERAL DIFFERENT
ENTITIES THAT WE WERE CALLING
NECROTIZING ENTEROCOLITIS.
WITH THE PREMATURE BABY WITH A
DISTENDED ABDOMEN.
SO THIS BABY GOT WORSE WENT TO
THE OPERATING ROOM AND HAD PIECE
OF NECROTIC INTESTINE.
THAT IS WHAT WE WERE CONSIDERING
CLASSIC NECROTIZING
ENTEROCOLITIS.
SO NOW IN 2024.
TO HAVE A CLASSIC NECROTIZING
ENTEROCOLITIS.
THE SAME REVIEW ARTICLE WE
THOUGHT THERE WAS A CERTAIN PATH
OF PHYSIOLOGY THAT WAS COMMON IN
BABIES WITH NECROTIZING
ENTEROCOLITIS.
AND HERE IS A PICTURE THAT WE
SHOWED ON THE ARTICLE WITH A
COMBINATION OF
PREMATURITY, GENETIC
PREDISPOSITION.
AND CAUSES THE INFLAMMATORY
RESPONSE AND THAT ENDS UP BEING
NECROSIS.
IT'S THE ONLY POTENTIAL PATHWAY
AS WELL.
AND IT WAS RECOGNIZED IN THE
1970S FIRST WE HAVE TO LEARN
ABOUT HYPOXIA ISCHEMIA.
WE WERE CONVINCED IN THE
SEVENTIES THAT NECROTIZING
ENTEROCOLITIS THIS MODEL WAS
DEVELOPED THIS IS AN UNDER -- --
AN ANIMAL MODEL THAT RELIES ON
AND HYPOXIA ISCHEMIA.
THEY PUT THEM IN THE PLASTIC BAG
AND CLOSE IT UP FOR 7 OR 8
MINUTES THEY TURN BLUE AND GAS
-- -- GASP.
THEN YOU PUT THEM INTO A
REFRIGERATOR.
AND THEN YOU TAKE THEM OUT OF
THE REFRIGERATOR THEN FEED THEM
SOMETHING TOTALLY DIFFERENT BUT
THEN THE BABY ANIMALS FOR A FEW
DAYS.
AND THERE ARE OVER 200 PAPERS
SHOWING THIS MODEL IS CALLED A
MODEL OF NECROTIZING
ENTEROCOLITIS.
IS THIS REALLY A GOOD MODEL?
BUT IS IT A MODEL OF WHAT WE SEE
IN THE BABIES?
AND THIS OCCURS BETWEEN 28
THROUGH 31 WEEKS OF CORRECTED
GESTATIONAL AGE WHERE WE SEE THE
PEAK.
IF THEY HAD SEVERE HYPOXIA AT
BIRTH WE WOULD SEE A LOT OF
BABIES WITH LOW APGAR SCORES
DEVELOPING NECROTIZING
ENTEROCOLITIS AFTER BIRTH BUT
THAT'S NOT WHAT WE ARE SEEING.
SO WHAT HAPPENS DURING THIS
PERIOD OF TIME?
NOT WITH RETINOPATHY PRIOR TO
MATURITY SO THERE IS
MICROVASCULAR CHANGES GOING ON
THAT THE BARRIER IS STILL
IMMATURE AT THIS TIME AND
DEVELOPMENTAL PATTERN CHANGES
THAT IN THE MID- SECOND
TRIMESTER THE RECEPTORS ARE AT
THEIR HIGHEST DENSITY AND THIS
IS WHEN YOU HAVE THE EXPOSURE TO
MICROBES.
THIS SETS UP THE PERFECT STORM
FOR INFLAMMATORY'S.
WE ARE NOT SURE THIS IS WHAT IS
GOING ON WITH ALL BABIES.
SO WE WROTE THIS ARTICLES
PUBLISHED IN 2017.
AND TAKING THE DATA FROM
NEONATAL INTENSIVE CARE UNITS.
AND THEN TO GET DATA TO PUT THIS
TOGETHER AT BAYLOR UNIVERSITY.
AND THE DATA FROM THE MICROBIAL
DNA.
HERE WHAT WE ARE SEEING ON THE
LEFT SIDE OF THE SLIDE IS
BETWEEN 24 AND 36 WEEKS
GESTATION AND WE SEE RELATIVE
ABUNDANCE OF MICROBES.
WHEN WE LOOK AT THE RIGHT SIDE
WE SEE DIFFERENCES IN THE COLORS
WHAT ARE THE DIFFERENCES WE ARE
SEEING AND THE BABIES THAT WE
DEVELOP COMPARED TO THE CONTROL
BABIES?
WE SEE AN INCREASE OF PRO- DEAL
BACTERIA OVER TIME AND ALMOST
WHAT DOES THIS MEAN IT HAS A LOT
OF LBS IN THEIR CELL WALL.
AND THEY ARE DECREASING OF THE
MORE POSITIVE MICROBES TO HAVE A
BIOREACTOR THAT THEY PRODUCE
FATTY ACID SOME ARE WHICH
THOUGHT TO BE VERY IMPORTANT
WITH INTEGRITY.
AND WITH THESE COMPONENTS THAT
STIMULATE THE CELLS TO HELP AND
DIFFERENTIATE THE T CELLS INTO T
CELLS AND THIS PARTICULAR
BACTERIA DIFFERENTIATES INTO
COLONIZING T CELLS BUT WE SEE
THE DECREASE SO THIS IS A VERY
INTERESTING ASSOCIATION BUT IT
DOESN'T TELL US CAUSALITY JUST
LIKE SEVERAL OF THE OTHER
STUDIES.
WE HAVE A LOT OF ASSOCIATIONS.
IT IS A GUMBALL MACHINE.
WE ARE SEEING DIFFERENT
GUMBALLS, COLORS AND FLAVORS.
HERE IS THE ANALOGY.
BECAUSE IT IS SO MANY DIFFERENT
PROBLEMS WE HAVE A DIMINISH OF
PROBLEMS AND THAT IS 1 OF THE
MAJOR PROBLEMS THAT WE HAVE TO
SAY THIS PARTICULAR AGENT
PREVENTED NECROTIZING
ENTEROCOLITIS WITH CURRENT
DIFFICULTIES AND OPPORTUNITIES.
THESE 8 DIFFERENT DEFINITIONS DO
WE HAVE A DEFINITION?
I DON'T THINK SO.
HERE ARE SOME OF THE PROBLEMS WE
ARE CALLING NET.
THIS IS A STAGING CRITERIA IN
THE LATE SEVENTIES IN KANSAS AND
THIS WAS NOT MEANT TO DEFINE
NECROTIZING ENTEROCOLITIS BUT TO
GIVE SOME IDEA WHAT IS GOING ON
WITH THE DEGREE OF ILLNESS AND
STAGE I 2024 IS TOTALLY
MEANINGLESS ALMOST ALL OF THE
TINY BABIES HAVE SOME DISTENTION
AND SOME INSTABILITIES.
THAT WOULD ALL BE CONSIDERED
STAGE I ADVERTISING.
STAGE II.
USUALLY RADIOGRAPHIC EVIDENCE
HELPS WITH STAGE II AND I WILL
GIVE YOU STAGE II INFORMATION
SHORTLY WITH -- -- INTESTINAL
PREPARATIONS I THINK NOW WE ARE
CONVINCED THAT IS A DIFFERENT
DISEASE ENTITY AND NEC BUT
HIGHLY PROBLEMATIC IS THAT WHERE
THE BABIES DEVELOP THE PROBLEM
SURGEONS PUT IN THE DRAIN AND WE
DON'T HAVE A GOOD CODE FOR
SPONTANEOUS INTENTIONAL -- --
INTESTINAL PREPARATIONS WAS PUT
INTO THE MEDICAL RECORDS IS NEC.
SO THAT TELLS US THE MEDICAL
RECORDS ARE NOT THAT HELPFUL AND
IN FACT IF YOU HAVE THESE IN THE
MEDICAL RECORDS THIS IS HIGHLY
PROBLEMATIC BABIES WITH
CARDIOGENIC ISCHEMIA.
THOSE HAVE INTERRUPTED AORTIC
ARCH THAT IS A TOTALLY DIFFERENT
PROBLEM.
SO JUST TO GIVE YOU SOME IDEA WE
HAVE THIS CONDITION OF PROBLEMS
THAT WE ARE ALL CALLING NEC.
HERE IS AN INTERESTING EXAMPLE
THIS IS AN X-RAY TAKEN OF THE
BABY WHO ACTUALLY HAD NO REAL
CONSIDERATIONS OF ANYTHING IN
THE G.I. TRACT.
THE RADIOLOGIST SAID THERE IS
SOMETHING IN THIS WRITE UP AND I
DON'T REALLY KNOW WHAT THIS IS
IT COULD BE IT COULD BE STAGE TO
NEC.
NORMAL PHYSICAL EXAMINATION THIS
IS JUST TOO WILL IN THE
GASTROINTESTINAL TRACT WE SEE
THIS VERY OFTEN AND HAS BEEN
RECORDED IN THE CHART AS HAVING
NEC AND MANY OF THESE BABIES
ALSO HAVE 7 DAYS OF ANTIBIOTICS
AND ARE PLACED IN PO AND IT IS
HIGHLY PROBLEMATIC.
HERE WE HAVE ANOTHER BABY
OUTSIDE OF THE BOWEL WALL AND
THE BABY WENT TO SURGERY AND
THIS IS WHAT THEY SAW.
A SMALL PERFORATION.
NECROSIS.
THIS IS CALLED SPONTANEOUS
PERFORATION THIS IS NOT
NECROTIZING ENTEROCOLITIS BUT
AGAIN MANY OF THESE BABIES ARE
CODED IN THEIR CHART AS HAVING
NEC.
A FRIEND WROTE THIS COMMENTARY A
COUPLE OF YEARS AGO THE
DEFINITIONS OF NEC.
WHAT ARE WE DEFINING AND HIS
MACHINE LEARNING THE ANSWER?
IT'S INTERESTING THIS ARTICLE
CAME OUT ABOUT THE SAME TIME WE
WERE DOING SOME YOU GET THE
UNIVERSITY OF FLORIDA TRYING TO
DIFFERENTIATE BEING ABLE TO USE
SOME EARLY FEATURES TO
DIFFERENTIATE SPONTANEOUS
PERFORATION FROM NECROSIS OF THE
BOWEL PERK WE HAVE THIS PICTURE
FROM BEFORE AND HERE IS
NECROTIZING ENTEROCOLITIS.
WE HAD BABIES IN OUR DATA SET
THAT ACTUALLY WENT TO THE
OPERATING ROOM WHERE THEY SAW IT
EITHER TRUE NECROSIS OF THE
INTESTINE OR INSTANTANEOUS
PERFORATION AND WE USE TO REVISE
MACHINE LEARNING TO SEE IF WE
COULD DIFFERENTIATE BETWEEN THE
2 BEFORE THE EVEN HAPPENED.
THERE WERE 2 DIFFERENT
ALGORITHMS THAT WERE USED AND
UNDER THE CURVE AND HERE ARE
SOME OF THE FEATURES THAT WERE
HIGHLY RELATED TO TELL THE
DIFFERENCE BETWEEN THE 2.
AND A MAJOR INTEREST IS THE
INSTANTANEOUS PERFORATIONS
OCCURRED VERY EARLY IN THE MOST
PREMATURE BABIES.
NOW IF WE HAVE SUPERVISED
MACHINE LEARNING WHAT ABOUT
UNSUPERVISED?
WE CAN ACTUALLY UTILIZE
UNSUPERVISED TO TAKE THE GUMBALL
MACHINE AND SEPARATE OUT THOSE
THINGS IN THE GUMBALL MACHINE
HERE I'M USING A DIFFERENT
ANALOGY WITH DIFFERENT KINDS OF
FRUIT.
WE HAVE A BASKET OF FRUIT WE
WANT TO SEPARATE INTO
STRAWBERRIES, BANANAS AND
ORANGES WE CAN USE UNSUPERVISED
APPROACH.
THAT TAKES FEATURES THAT ARE
CLOSELY RELATED TO 1 ANOTHER AND
PUTS THEM TOGETHER THEN BATCHES
AND CLUSTERS THEM.
THAT IS WHAT WE DID WITH 200
BABIES FROM THE NEONATAL
INTENSIVE CARE UNIT.
AND THIS IS FROM A PAPER THAT WE
PUBLISH FROM PEDIATRIC RESEARCH
AND 2024.
THIS IS THE DIFFERENT BABIES AND
Y AXIS YOU CANNOT READ THIS VERY
WELL BUT THESE ARE DIFFERENT
FEATURES AND WE COULD FIND 5
DIFFERENT CLUSTERS OF INTESTINAL
INJURY ON THIS GROUP OF.
WE ARE NOT LABELING THEM AS ANY
PARTICULAR DISEASE.
BUT WE HAVE 1 CLUSTER THAT
NEEDED TO GO TO SURGERY.
ANOTHER CLUSTER WITH ANOTHER
LEUKOCYTE PSYCHOSIS ANOTHER
PREMATURE BABIES WITH EARLY
INTESTINAL INJURY.
THIS IS 1 WAY WE COULD ACTUALLY
LOOK AT THESE DIFFERENT
INTESTINAL INJURIES IN THE
BABIES.
NOW I JUST WANT TO SHOW YOU
THIS.
IT IS COMMENTARY WRITTEN FROM
STUDIES IN KANSAS RELATED AND
ARTIFICIAL INTELLIGENCE TO
CLASSIFY ACQUIRED INTESTINAL
INJURY AND PRETERM NEONATES A
NEW PERSPECTIVE.
I WILL BE THIS TO VERY QUICKLY.
IN CONCLUSION THE STUDY
REPRESENTS A PROMISING AND NEWER
APPROACH TO REDEFINING
INTESTINAL DISEASES.
WITH THE QUEST FOR BETTER
CLASSIFICATION OF ACQUIRED
DISEASES AND THE INTENT TO
DEVELOP TOOLS THAT CAN BE
APPLIED IN THE CLINICAL RESEARCH
SETTING SHOULD BE PARAMOUNT AND
THIS ENDEAVOR TO THE PATH OF
THEOLOGICAL MECHANISMS WHICH IN
TURN PROVIDES THERAPY.
WHAT ABOUT THESE MECHANISMS HOW
DO WE FIGURE OUT WHAT IS GOING
ON IN THESE CLUSTERS?
JUST HAVING THESE IS NOT ENOUGH
WE WANT TO KNOW WHAT IS GOING ON
AND TO DIFFERENTIATE IN 1
CLUSTER VERSUS THE OTHER.
1 WAY TO DO THIS IS CALLED
MULTI- ALL MIX.
I AM SURE YOU ARE AWARE OF THE
PARABLE OF THE 6 BLIND MEN ALL
TRYING TO LOOK AT THE STRUCTURE
AND THEY DON'T COLLABORATE.
1 OF THE THINGS THAT YOU CAN DO
WITH MULTIOMICS APPROACH NOT
JUST TAKE THE MICRO BIOME BUT
THE MULTIOMICS APPROACH TO
INTEGRATE THAT AND WITH THAT YOU
CAN FIND A SYSTEMS BIOLOGY
MECHANISM THAT GIVES YOU AN IDEA
WITH EACH 1 OF THOSE CLUSTERS.
HERE IS A STRATEGY FOR THE
FUTURE AND 1 POSSIBLE APPROACH.
GO BACK TO 1965 OR 1971 AND
MAKE-BELIEVE THE TERM
NECROTIZING ENTEROCOLITIS NEVER
EXISTED.
EVALUATE LARGE DATA SETS OF
PRETERM INFANTS WITH VARIOUS
FORMS OF FEEDINGS AND PERFORMED
UNSUPERVISED CLUSTERS AND THEN
PROSPECTIVELY CLUSTER THESE WITH
UNSUPERVISED AI AND THEN THE
INTEGRATED MULTIOMICS WHAT IS
GOING ON AND THEN THE BIOMARKERS
FOR EARLY DETECTION AND THEN
DEVELOP PREVENTATIVE AND
THERAPEUTIC MEASURES BASED ON
THE PATHOPHYSIOLOGICAL
MECHANISMS WITHIN EACH CLUSTER
BUT THEY WILL ALL HAVE DIFFERENT
NAMES THAN NECROTIZING
ENTEROCOLITIS.
THANK YOU FOR YOUR ATTENTION.
[APPLAUSE]
>> OUR NEXT SPEAKER TALK VERY
PROVOCATIVE AS THE MEDICAL
EPIDEMIOLOGIST THE NATIONAL
CENTER OF INFECTIOUS DISEASES
AND KRIS WILL TALK ABOUT CASE
DEFINITIONS OF PRODUCTS MARKETED
AS PROBIOTICS AND IN VERY LOW
BIRTH WEIGHT INFANTS.
>> THANK YOU.
GOOD MORNING PERK I HAVE BEEN
ASKED TO TALK ABOUT SAFETY
SIGNALS AS WELL AS CASE STUDIES
TALKING ABOUT VLBW INFANTS AND
LOOK AT THE 2 FORMS OF PUBLIC
HEALTH TO FIND THE INFORMED
APPROACH.
I HAVE NO DISCLOSURES THAT THESE
ARE MY OWN VIEWS AND DO NOT
NECESSARILY REPRESENT THOSE SO
WE HAVE A FAIRLY BUSY AGENDA
TODAY.
WE HAVE MANY DIFFERENT TOPICS.
AND A VERY BUSY DISCUSSION ON
THERAPEUTIC PRODUCTS THAT CAN
EXPAND THAT I HAVE A SHORT TIME
HERE TO DELVE INTO THE
THERAPEUTIC PRODUCTS AS SEEN
THROUGH THE LENS OF HEALTH AND
TO HAVE LIVE BIO THERAPEUTIC
PRODUCTS AND THAT INCLUDES DATA
SHOWING THE EFFECT AND THEN
HIGHLIGHTING EFFORTS IT HAS BEEN
REPORTED TO LITERATURE AND THEN
SUMMARIZING CURRENT
RECOMMENDATIONS BY PROFESSIONALS
AND OTHER ORGANIZATIONS.
MOST IMPORTANTLY I HOPE TO
PROVIDE A PICTURE OF THE NATURAL
HISTORY OF THE LBP USE WITHIN
THE UNITED STATES AND ABROAD
SOME OF THIS HAS BEEN COVERED BY
SPEAKERS ALREADY AND OTHERS I
WILL BE FORESHADOWING GIVING
ADDITIONAL DETAIL.
THE FIRST THING I WANT TO DO IS
PROVIDE A FEW DEFINITIONS AND
I'M REFERRING TO DIFFERENT TERMS
TO DESCRIBE NEWBORNS AT
DIFFERENT GESTATIONAL AGES SO
HERE ARE A FEW OF THE
DEFINITIONS IF YOU ALREADY SAW
AND HEARD SOME OF THESE BUT THE
AVERAGE DURATION OF PREGNANCY OR
THE TERM IS 40 WEEKS THAT IS THE
MORE IMMATURE THE TIME OF
DELIVERY AND THE MORE VULNERABLE
THEY ARE TO PHYSIOLOGICAL STRESS
INCLUDING INFECTION.
PRETERM OFFENSE FOR LESS THAN 28
WEEKS OFTEN HAVE THE HIGHEST
RISK.
THE SAME GOES FOR BIRTH WEIGHT
BEING ABOUT 7 POUNDS WITH
3200 GRAMS HOWEVER WE HAVE
HIGHER RISK NEONATES THAT ARE
BORN AT 1500 GRAMS OR VERY
LITTLE BIRTH WEIGHT OVER THOSE
THAT ARE AT EXTREMELY LOW BIRTH
WEIGHT AT 1000 GRAMS OR LESS.
I ALSO WANT TO BE UP FRONT ABOUT
MY USE OF THE TERM LBP.
THEY CAN BE REFERRED TO AS
PROBIOTICS BUT AS MENTIONED
EARLIER THOSE ARE NOT ALWAYS
EASY TO DEFINE.
LBP ARE PRODUCTS THAT CONTAIN
ORGANISMS AND USE TO PREVENT OR
CURE IDS OR CONDITION AND ALSO
NOT CONSIDERED TO BE A VACCINES
ARE CURRENTLY WE DO NOT HAVE ANY
LBP'S FOR US AND I WILL USE THAT
FOR MY PRESENTATION SO NOW THAT
WE HAVE THE DEFINITIONS OUT OF
THE WAY I WANT TO TALK ABOUT THE
IMPACT AND HOW IT AFFECTS VERY
LOW BIRTH WEIGHT UNITS AND
SHOWING THIS FROM THE NEXT
SOCIETY BECAUSE DIGITALLY IT
SHOWS THE IMPACT BETTER THAN I
CAN DESCRIBE IT.
WE HEARD EARLIER THIS MORNING
ABOUT THE DEVASTATING EFFECT ON
BOTH NEONATES AND FAMILIES AND
NOT TO REHASH WHAT HAS BEEN
DISCUSSED BUT TO SUMMARIES WE
ESTIMATE BETWEEN 3500 NEONATES
ARE DIAGNOSED EACH YEAR AND THAT
LEADS TO 1 BABY DYING FROM NEC
EACH DAY IT HAS A
DISPROPORTIONATELY HIGHER RATE
OF BLACK INFANTS AND YOU CAN SEE
INCIDENCE OF NEC THAT HAS
DECREASED OVER TIME.
BUT WE HAVE MORE WORK TO DO TO
KEEP THE HIGHLY VULNERABLE
INFANT SAFE SUCH A DEVASTATING
DISEASE RESEARCHERS HAVE BEEN
LOOKING FOR WAYS.
1 OF THE WAYS TO PREVENT THIS AS
IT PROVIDES PROTECTIVE BENEFITS
TO THE NEONATE AND THE MICRO
BIOME 1 OF THE FIRST REPORTS IS
BEING PROTECTIVE SEEING IN THE
REPORT THEY SHOW THE CHOICE
PLAYED A PART IN THE ASSOCIATION
OF THE DEVELOPMENT AND CONFIRMED
CASES WERE 6 TIMES HIGHER AMONG
INFANTS AS COMPARED TO INFANTS
WHO RECEIVED MILK PRODUCTS FOR
HUMAN MILK PROMPTED PRODUCTS.
HAVING PROTECTED BENEFITS THAT
WE HEARD ABOUT THIS MORNING
INCLUDING WE AFFIRMING THE
FINDINGS AFTER CONVENING THE
WORKSHOP HHS FDA CDC GAVE A
JOINT STATEMENT BASICALLY SAYING
THERE IS NO CONCLUSIVE EVIDENCE
THAT CONCLUDES AND THAT THERE IS
STRONG EVIDENCE THAT HUMAN FOCUS
PROTECTED AGAINST THAT.
IT IS NOT COMPLETELY PROTECTED
RESEARCHERS HAVE WAYS OF THE
HIGHER RISK NEONATES THAT IS
CONSIDERED A POTENTIAL WAY TO DO
THAT AND THE THOUGHT WAS TO HAVE
A FAVORABLE MICRO BIOME.
AS WELL AS SUBSEQUENT DAMAGE SO
THERE'S A NUMBER OF TRIALS AND
STUDIES AND THE OVERALL EFFECT
ON SEPSIS NECROTIZING
ENTEROCOLITIS AS WELL AS
MORTALITY AND THE FIRST STUDY
WAS IN 1999 AND THE SLIDE ONCE
WE WILL GO OVER LATER BUT I WANT
TO HIGHLIGHT THESE STUDIES HAVE
MIXED RESULTS OVER TIME.
SOME FAVOR THE USE WHILE OTHERS
SO LITTLE OR NO STATISTICAL
SIGNIFICANCE FOR THEIR ROLE.
INCLUDING THE MOST RECENT
SHOWING LBP'S COULD REDUCE THE
VERY LOW BIRTH WEIGHT NEONATES
THIS IS DUE TO THE QUALITY OF
EVIDENCE THAT WERE USED AS WELL
AS OTHER FACTORS.
AND THEN WE HAVE REPORTS
INCREASED SEEING USE OVER TIME
OF VERY LOW BIRTH WEIGHT INFANTS
HOWEVER ON SEPTEMBER 29 ISSUED A
DEAR HEALTHCARE PROVIDER LETTER
AFTER AN INVESTIGATION INTO THE
DEATH OF AN INFANT THAT HAS
ADMINISTERED 1 OF THESE PRODUCTS
THE INFANT WAS PRETERM AND
EXTREMELY LOW BIRTH WEIGHT AND
WAS GIVEN L BT AS WELL AS THE
OIL AND THAT BECAME SEPTIC AND
THE ORGANISM WAS CULTURED FROM
THE INFANTS BLOOD AND THE
CULTURE BACTERIA WITH SEQUENCING
MATCH THAT WAS CONTAINED IS 1 OF
THE REASONS WE ARE HERE TODAY.
AND THIS LETTER THE FDA REMINDED
PROVIDERS THERE IS NO PROBIOTICS
FOR USE AS A DRUG OR BIOLOGIC
PRODUCT IN INFANTS AND THERE
COULD BE A SERIES OF ADVERSE
EFFECTS WITH THESE PRODUCTS.
CONTAINING LIVE ORGANISMS AND IF
THEY ESCAPE OUT OF THE
INTESTINES THERE IS THE
POTENTIAL IT CAN CAUSE AN
INFECTION.
THERE HAVE BEEN REPORTS OF SUCH
CASES IN MEDICAL LITERATURE FOR
AN EXAMPLE OF THIS REPORT
DESCRIBING HOW THE NICU IN
NORWAY BEGAN USING AS A
PROPHYLAXIS AT 28 WEEKS OF
GESTATION.
THEY ADMINISTERED LBP'S TO 290
INFANTS THROUGH 2015 AND
DESCRIBED 3 THAT DEVELOPED
SEPSIS WHICH IS THE SAME AS LBP
GIVEN TO THE FENCE.
SO I HAVE THE ADDITIONAL
CHARACTERISTICS SHOWN ON THE
TABLE ON THE RIGHT.
THE AUTHORS HERE POINTED OUT
THEY DON'T KNOW WHETHER THE
ORGANISM OR THE CULTURE WAS A
CONSEQUENCE OF NECROTIZING
ENTEROCOLITIS ITSELF AND HAVING
THE OUTCOMES FOR THESE AND YOU
WILL SEE FROM THE NICU.
SO I JUST MENTIONED
TRANSLOCATION I THOUGHT IT WOULD
BE HELPFUL TO BRIEFLY RECAP WHAT
THAT IMPLIES OR MEANS SO BEAR
WITH MY ART SKILLS.
I KNOW THEY ARE NOT GREAT BUT
THE DRAWING ON THE LEFT IS
REPRESENTED IN THE NEONATAL AND
ON THE RIGHT IT WAS DAMAGED BY
EITHER INFLAMMATION OR SOME
OTHER TYPE OF INTESTINAL
INJURY.
IT IS VERY SIMPLISTIC BUT IS
SOME OTHER TYPE OF INSULTS.
THE INTESTINES ARE FILLED WITH
MICROBES IT IS ESTIMATED WITHIN
THE FIRST MONTH OF LIFE NEONATES
HAVE BILLIONS OF INTESTINAL
CONTENT AND THEN WE ATTEMPT TO
INFLUENCE THE MICROBIAL MAKE UP
OF THE INTESTINES WHEN THE GUT
IS HEALTHY MICROBES CONTINUE
WITHIN THE GUT HOWEVER WITH
INJURY OR INFLAMMATION COULD
ALLOW THESE ORGANISMS TO RECAP
THE INTESTINES AND GOING INTO
THE LYMPHATIC TISSUE OR INTO THE
BLOODSTREAM IF THEY ARE NOT
FOUND AND KILLED BY THE IMMUNE
SYSTEM AS POSSIBLE THEY COULD
MULTIPLY AND CAUSE SEPSIS OR
ANOTHER FORM OF INFECTION.
IT IS A BASIC DESCRIPTION BUT
CONSIDERED TO BE A LIKELY WAY
WHEN IT IS ADMINISTERED.
IT'S NOT JUST BACTERIA WE NEED
TO BE CONCERNED ABOUT.
ALSO FUNGI HAVE BEEN REPORTED AS
A CAUSE OF SEPSIS.
THERE IS A STUDY WHERE THE
AUTHORS OF THE STUDY DESCRIBED.
>> IT WAS FOR THE HOSPITAL
PROTOCOL TO NEONATES BECAME
SEPTIC.
AND THE AUTHORS COMPARED THE
FUNGI USED IN SEQUENCING, THEY
FOUND THE FUNGI WAS ROUGHLY
90 PERCENT SIMILAR LEADING THEM
TO THE CONCLUSION THE RECOVERED
STRINGS MATCH THE ADMINISTERED
PRODUCT THEY ALSO SUSPECTED
TRANSLOCATION OR ENVIRONMENTAL
CONTAMINATION AS A CONTRIBUTING
FACTOR THEY DID DIE
UNFORTUNATELY BUT THE AUTHORS
ATTRIBUTED THE DEATH TO MAJOR
UNDERLYING CARDIAC MALFORMATIONS
THE OTHER INFANT DID RECOVER AND
WAS DISCHARGED FROM THE NICU.
THERE IS SOME EVIDENCE THOSE
THAT CAN NEVER BE PRESCRIBED AND
AN EXAMPLE OF THIS IS A HOSPITAL
IN ITALY BEGAN ADMINISTERING IN
2017.
ONLY 1 OF THESE NEONATES
ACTUALLY RECEIVE THE LVT
HOSPITAL PROTOCOL.
TO OTHER NEONATES THAT WERE
NEVER GIVEN THE LBP STAYED IN
THE SAME ROOM AS IS INFANT AND
THE RESEARCH TEAM ANALYZED THE
SIMILARITY OF ORGANISMS
RECOVERED FROM THE 3 NEONATES
AND THAT THEY ARE ALL THE SAME
AS ADMINISTERED PRODUCT.
THEY STATE THERE ARE SEVERAL
DIFFERENT MODES OF TRANSMISSION
FOR THE CONTAMINATION FROM THE
LBP ITSELF AND ON THE HANDS OF
HEALTHCARE PROVIDERS.
WE TAKE THIS HYPOTHESIS A STEP
FURTHER.
PUBLISHING A STUDY FROM THE TIME
THE PACKET WAS OPENED.
I HAVE SOME OF THE SAMPLING
RESULTS ON THE TABLE ON THE
RIGHT-HAND SIDE THE SURFACE THE
LEAD IS SAMPLED IS IN THE
LEFT-HAND COLUMN IN THE COLONY
FORMING UNITS ARE DETECTED IN
THE RIGHT-HAND COLUMN AND YOU
CAN SEE THE PACKET WAS OPENED IN
THIS ORGANISM WAS RECOVERED FROM
THE IMPACTED AREA AND SING IT
WAS MASSIVE AIR CONTAMINATION
ALTHOUGH IT DID CLEAR AND NO
FURTHER ORGANISMS WERE DETECTED
AFTER 1 HOUR.
ALSO WITH THAT DISPERSION OF THE
ORGANISM OF NEARBY ENVIRONMENTAL
SERVICES THOSE THAT WERE
DETECTED WITHIN 2 HOURS.
THEY ALSO SAW THAT CANCER
TECHNICIANS WHO OPENED THE
PACKET HAD SIGNIFICANTLY
CONTAMINATED THEIR HANDS PRIOR
TO WATCHING THEM THIS WAS
EVIDENCED BY WHAT WAS CULTURED
EVEN AFTER VIGOROUS HANDWASHING
57 SEE IF USE WERE DETECTED
AFTER THEY WASH THEIR HANDS OF
THIS SUGGEST LBP'S CAN LEAD TO
INADVERTENT TRANSMISSION OF
ORGANIZED ORGANISMS THROUGH
SERVICES OR THROUGH HEALTHCARE
PROVIDERS WHICH CONTINUES TO
REINFORCE HIGH-QUALITY INVENTION
AND PREVENTION PRACTICES WITH
GOOD ENVIRONMENTAL CLEANING
SERVICES FOR SHARED MEDICAL
EQUIPMENT AND THEN HYGIENE FOR
HEALTHCARE PROVIDERS.
LBP'S ARE INTENTIONALLY NOT A
STERILE PRODUCT AND NEED TO
CONTINUE WITH LIVING ORGANISMS
TO HAVE THEIR EFFECT AND THAT
OPENS THE POSSIBILITY THEY CAN
BECOME CONTAMINATED WITH
UNINTENDED ORGANISMS THAT THEY
ARE NOT METICULOUSLY FOLLOWED.
1 EXAMPLE IS DURING AN
INVESTIGATION FDA CDC IN
CONNECTICUT DEPARTMENT OF HEALTH
AFTER A FETAL INFECTION AND A
PRETERM INFANT IN 2014 THIS WORD
IS ADMINISTERED MANUFACTURER TO
HAVE THE INFANT HAD SURGICAL
RECEPTION OF THE INTESTINES AND
PATHOLOGIC SPECIMENS SHOWED A
HEAVY BURDEN THE PRODUCT
INCLUDING UNOPENED BOTTLES WAS
TESTED THAT COULD HAVE BEEN
CONTAMINATION AND WHEN IT WAS
TESTED THEY IDENTIFIED WITHIN
THE UNOPENED BOTTLES OF THE
PRODUCT SO THE MAP ON THE RIGHT
SHOWS THOSE IN GREEN WAS WIDELY
DISTRIBUTED ACROSS THE US SO
CONTAMINATION WITH UNINTENDED
ORGANISMS LEADING TO
COLONIZATION AS WELL AS POSSIBLE
INFECTION AND SERVES AS A
REMINDER THE QUALITY AND SAFETY
OF THE THERAPIES NEED TO BE
INSURED FOR THE SAFETY OF OUR
PATIENTS.
THERE ARE MANY MORE STUDIES THAN
I HAVE TIME TO DISCUSS THEY WANT
TO BRING YOUR ATTENTION TO THE
SYSTEMATIC REVIEW WHICH IS 16
ARTICLES AND INCLUDES 32
REPORTED CASES OF NEONATAL
SEPSIS.
THE PIE CHART HERE SHOWS THE
BREAKDOWN THAT IS ADMINISTERED
TO THE INFANTS AND YOU CAN SEE
THESE VERY AMONG THE DIFFERENT
REPORTS I HAVE SUMMARIZED
DETAILS LIKE GESTATIONAL
AGE, BIRTH WEIGHT AND SIGNS OF
INFECTION BUT INTERESTINGLY THE
ONLY 1 THAT WAS REPORTED LIKELY
RELATED TO THE UNDERLYING
CARDIAC ISSUES DISCUSSED EARLIER
IT ALSO DOES NOT INCLUDE FROM
THE HEALTH CARE PROVIDER LATER
OR THE NEONATE FROM THE
CONTAMINATED PRODUCT BUT I DO
WANT TO HIGHLIGHT MANY OF THESE
DID REQUIRE SURGICAL RESECTION
OF THE BOWEL AND HAD LINES
REMOVED TO IMPAIR ACCESS OR HAD
AN INCREASE OF RESPIRATORY
SUPPORT NEEDS.
THEY ALSO RECEIVED AT LEAST 1
ANTIMICROBIAL DRUG AS WELL AND
ALL THESE CONTRIBUTE DOWN THE
ROAD TO SIGNIFICANT MORBIDITIES
FOR THE INFANTS AS WE HEARD
ABOUT EARLIER.
WHILE A SERIES OF EVENTS LIKE
THESE NEED TO BE INVESTIGATED
FURTHER AND SHOULD NOT BE TAKEN
LIGHTLY WE HAVE 32 CASES OF
SEPSIS RELATED TO LBP
ADMINISTRATION ACCORDING TO
MEDICAL LITERATURE DESPITE
HAVING THESE PRODUCTS
ADMINISTERED WORLDWIDE EVERY DAY
ON A GIVEN BASIS.
SO WITH ALL OF THIS IN MIND I
WANT TO CLOSE BY TAKING A LOOK
THAT YOU HEARD EARLIER FROM
DOCTOR PATEL BUT IF YOU LOOK AT
THE US STARTING WITH THE
AMERICAN ACADEMY OF PEDIATRICS
AS A LEADER AND BACK IN 2021 AND
THEY PUBLISH THEIR STANCE
CURRENT EVIDENCE WITH UNIVERSAL
ADMINISTRATION OF PROBIOTICS
PARTICULARLY THOSE BORN
EXTREMELY LOW BIRTH WEIGHT.
WE FOLLOWED THAT WITH THE
AMERICAN AND GASTRO- SAID
ASSOCIATION THAT RECOMMENDS
STRAINS IN COMBINATION FOR USE
OF PRETERM AND LOW BIRTH WEIGHT
INFANTS.
IF WE TRANSITION TO LOOK AT
INTERNATIONAL ENTITIES THEY
SUGGEST LBP'S COULD REDUCE RACE
-- -- RATES OF SEPSIS AND
MORTALITY BUT CAUTION SHOULD BE
USED.
SIMILARLY THE WHO HAS ADDITIONAL
RECOMMENDATION FOR LBP DUE TO
THE BALANCE OF EVIDENCE FOR
DECREASED MORTALITY AND INVASIVE
INFECTION WITHOUT EVIDENCE OF
HARM BUT NO RECOMMENDATION WAS
GIVEN TO THE FORMULATION DOES OR
TIMING OR DURATION OF USE BUT I
DO WANT TO HIGHLIGHT THE
STATEMENT SAYS IT IS ESSENTIAL
FOR THIS TO BE INCLUDED AS
SHARED DECISION-MAKING AND THAT
REQUIRES A NATIONAL REGULATORY
APPROVAL AND CLEAR INSTRUCTIONS
FOR SAFETY.
AS ANYWHERE ELSE IN MEDICINE WE
NEED TO CARE FOR SUCH A
VULNERABLE POPULATION.
AND FINALLY BEFORE I CONCLUDE I
WANT TO LOOK AT THE CURRENT
PRACTICES IN THE US AND DOCTOR
PATEL SPOKE ABOUT THIS EARLIER
AND I BELIEVE IT IS A DIFFERENT
STUDY THAT I HAVE HIGHLIGHTED
HERE.
ALTHOUGH NOT FORMALLY TRACKED WE
DO HAVE AN IDEA OF LBP'S AND A
FEW DIFFERENT ARTICLES.
SURVEY OF 500 NICU SHOWS TO LOW
BIRTH WEIGHT INFANTS AND
REMEMBER THIS IS AROUND THE TIME
SEVERAL STUDIES STARTED TO SHOW
THE BENEFIT OF PREVENTING THAT.
IF WE FAST-FORWARD 2023 AND
ANOTHER SURVEY SHOWED 29 PERCENT
ADMINISTERED LBP TO PREMATURE
NEONATES AND IT WAS REPEATED IN
2023 AFTER THE PROVIDER LETTERS
WITH A MUCH LOWER RESPONSE RATE
THAN THEY DID PREVIOUSLY AND
ONLY 16 PERCENT OF FACILITIES
RESPONDED TO THE SECOND SURVEY
BUT THEY DID FIND ONLY 2 NICU
RESPONDED WITH CONTINUED USE AND
IT ALSO FOUND MOST WORD USE FDA
APPROVED EVEN ONLY BY 10 OR
20 PERCENT SO SIMILAR TO THE
LAST SLIDE THEY HIGHLIGHT THERE
IS A SEVERITY AND THAT THERE IS
DESPERATION FOR CAREGIVERS AS
WELL AS FAMILIES TO HAVE A
SOLUTION FOR THESE PATIENTS.
SO TO SUMMARIZE LBP'S HAVE
POTENTIAL BENEFITS REDUCING
WASTE THE SEPSIS AND PREVENTING
NEC IN THE HIGHLY VULNERABLE
POPULATION BUT THE VERDICT IS
OUT BASED ON THE ORGANISMS THAT
ARE USED IN THE DOSAGES AND THE
TIMING AND DURATION LEADING TO
MULTIPLE AND SOME USE.
LOOK AT THIS THROUGH THE LENS OF
PUBLIC HEALTH AND THEN TO
BALANCE THE RISK OF HARM WHILE
USING THE PRODUCTS APPROPRIATELY
AND THIS REQUIRES STANDARDIZING
RESEARCH PROTOCOLS AND
MANUFACTURING PRACTICES AS WELL
AS EQUITABLE USE OF
INTERVENTIONS.
FDA APPROVAL OF PRODUCT FIGURES
PROMINENTLY WITH FORMAL
RECOMMENDATIONS I'M VERY GLAD WE
ARE JOINED BY OUR ADVOCACY
GROUPS AND PROFESSIONAL
SOCIETIES TO ENSURE FAMILIES ARE
INVOLVED IN THE SHARED
DECISION-MAKING OF THE HIGHLY
VULNERABLE PATIENTS.
THANK YOU FOR YOUR TIME.
[APPLAUSE]
>> WE HAVE A COUPLE OF QUESTIONS
IN THE CHAT AND ALSO TO JUST
SUGGEST YOU DON'T HAVE TO BE
APPEAR TO ANSWER QUESTIONS IF
YOU HAVE QUESTIONS TO ANSWER
JUST OPEN YOUR MIKE.
>> I SHARE MANY OF THE THINGS IN
TERMS OF THE CHALLENGE AND THE
DIAGNOSIS I THINK SOME OF THOSE
THAT THE CORE GROUP DID
HIGHLIGHT GOES TO IMPROVE
DEFINITION AS WELL AS BIOMARKERS
TO HELP AID AND DIAGNOSE.
BUT MY COMMENT IS IF YOU COULD
ADDRESS THE OBVIOUS ISSUES
EXCLUDING STAGE I OR LOWER STAGE
AND THE CHALLENGES VERSUS ENTRY
AND THE CHALLENGE WHICH IS FOCAL
INTESTINAL PERFORATION IMPACTS
LARGELY THE TRIALS AND WHY THAT
NOISE OR MISCLASSIFICATION MAY
BIAS THE FINDINGS.
>> IF YOU ADDRESS THOSE OBVIOUS
THINGS AND USE THE APPROACH THAT
YOU SUBJECTED AND YOU TAKE THIS
DISEASE THAT IS 5 PERCENT
BREAKING IT INTO 5 CLUSTERS OF
1 PERCENT, HOW DO PEOPLE ACHIEVE
THE TYPES OF TRIALS WE ARE
ADVOCATING FOR TO MAKE THE'S
TRIALS THAT ALL OF A SUDDEN
BECOME VERY CHALLENGING AND
VISIBLE?
>> THAT IS STILL TO BE
DETERMINED OBVIOUSLY.
BUT THERE ARE SEVERAL ASPECTS OF
YOUR QUESTION AND 1 IS THAT YOU
MENTIONED NEC AGAIN AS A
DISCRETE ENTITY AND THIS IS 1 OF
THE CONCERNS I HAD ABOUT THAT
REPORT AND THE EMPHASIS GOING
FORWARD WITH STUDIES THAT WE ARE
LOOKING AT 8 DISCRETE ENTITY AT
LEAST WITH ITS NAME AND WHAT WE
HAVE TO DO IS MAYBE YOU GET AWAY
FROM THAT TO TALK ABOUT THE
DIFFERENT FORMS OF INTESTINAL
INJURY AND THEN SAY WE WILL
DISSECT OUT THE DIFFERENT FORMS
OF INTESTINAL INJURY THAT IS 1
WAY TO LOOK AT THIS AND THEN
LOOK AT THE DIFFERENT CLUSTERS.
WE MAY NOT NEED TO LOOK AT ALL
OF THESE CLUSTERS BUT IF YOU
FIND CLUSTERS AND 1 THAT IS VERY
DANGEROUS WHERE YOU REALLY SEE A
LOT OF MORTALITY AND MORBID
MORBIDITY, YOU CAN COMPARE THAT
TO JUST 1 OTHER CLUSTER AND GET
A MUCH HIGHER POTENTIAL FOR
STATISTICALLY SIGNIFICANT
RESULTS.
>> THIS IS A COMMENT AND A
QUESTION.
WHAT YOU PRESENTED WAS 3
DIFFERENT SCENARIOS.
1 IS THAT YOU ARE INFECTED WITH
WHAT YOU ARE COLONIZED WITH
THERE IS A PHYSIOLOGIC
BACKGROUND AND AN OPPORTUNITY
FOR AN ACTION HEAVILY COLONIZED
AND THEN THE SECOND SCENARIO AND
THIRD IS WHAT WE WORRY ABOUT
THAT LBP HAS PROMOTED THAT THERE
IS A CONTAMINATION AND THAT IS
SOMETHING NOT UNIQUE TO LBP SO
DOES CDC HAVE A PLAN TO PERFORM
SURVEILLANCE TO LOOK
PARTICULARLY AT THE SECOND
SCENARIO WHETHER THERE IS A
DIFFERENTIAL RISK OF INFECTION
IF YOU ARE HEAVILY COLONIZED
WITH THE ADMINISTERED LBP VERSUS
THE WORLD COLONIZING YOU?
THAT IS THE KEY QUESTION TO ME.
>> I STAYED AWAY FROM TRYING TO
MAKE CORRELATIONS BETWEEN
WHETHER OR NOT THE ADMINISTERED
PROBIOTIC IS THE CAUSE OR JUST
ASSOCIATED WITH IT.
I THINK THAT IS STILL A MAJOR
NEED FOR RESEARCH TO UNDERSTAND
WHAT THAT TIMING IS OR WHAT THE
CORRELATION IS.
IN TERMS OF WHAT CDC HAS DOWN
THE ROAD IT IS CHALLENGING TO DO
THIS IN PEDIATRIC HOSPITALS
THERE MAY BE WAYS TO DO THAT IN
THE FUTURE AND HEARING WHAT THE
CONSENSUS IS AS WELL AS WORKING
TOGETHER WITH FDA AND NIH
COLLEAGUES CAN HELP DETERMINE
WHAT THAT CAN BE DOWN THE ROAD
RIGHT NOW I DON'T KNOW IF WE
HAVE THE CAPABILITY BUT THAT CAN
BE SOMETHING TO BUILD ON IN THE
FUTURE.
>> JUST 1 QUICK QUESTION.
HAVE YOU LOOKED AT THE IMMUNE
SYSTEM MATURITY PRETERM NORMAL
BASICALLY THE IDEA OF LOOKING AT
THE IMMUNE SYSTEM DEVELOPMENT AS
A METRIC?
>> ABSOLUTELY THERE ARE BIG
DIFFERENCES THAT OCCUR IN THE
INTESTINAL MUCOSAL DURING
DEVELOPMENT.
AND IF YOU LOOK AT GOBLET CELLS
AND MUCUS PRODUCTION AND TINY
PREMATURE BABIES THERE IS VERY
LITTLE OF THAT.
THEY ARE NOT WELL-FORMED THE
INTESTINAL IGA IS NOT YET
PRESENT.
THERE IS NUMEROUS DEVELOPMENTAL
FACTORS THAT ARE UNDERGOING
DEVELOPMENT.
SO THE PRETERM WITH THE MUCOSAL
IMMUNE SYSTEM ARE HIGHLY
VULNERABLE.
SO NOW BETWEEN 1 BABY VERSUS
ANOTHER THERE IS A HIGH AMOUNT
OF VARIABILITY BETWEEN BABIES
AND TO BE ABLE TO DISSECT OUT IN
ANY GROUPS OF BABIES, THAT WILL
REQUIRE A LOT OF EFFORT THAT AT
THIS JUNCTURE WE DON'T HAVE MUCH
OF THAT.
PUT TOGETHER THE MICRO BIOME
THAT IS THE CONCEPT OF THE
MULTIOMICS AND TYING THEM
TOGETHER AND INTEGRATING THEM
THAT WILL BE VERY IMPORTANT IN
THE FUTURE BUT WE DON'T HAVE
THAT YET.
>> WE HAVE 2 MINUTES LEFT.
>> WITH THE SAFETY COMPONENTS 1
OF THE THINGS THAT IS EMERGING
IS DISCUSSION AROUND MULTI-
DRUG-RESISTANT ORGANISMS AND THE
TRANSFER OF ANTIBIOTIC
RESISTANCE GENES IT COULD GO
EITHER WAY TO DECREASE THE STUDY
AND ANY EVIDENCE OF ANTIBIOTIC
RESISTANCE IN THE REVIEW OF
LITERATURE?
>> CAN I CLARIFY YOUR NAME AND
ASSOCIATION?
LBP PROBIOTIC USE.
I WILL SAY I WAS LOOKING FOR
THAT AND I DID NOT COME ACROSS
ANY THAT I WAS ABLE TO IDENTIFY.
BUT IF OTHERS IN THE AUDIENCE
HAVE EVIDENCE OTHERWISE I'M
HAPPY TO HEAR IT.
TO MY KNOWLEDGE THAT IS A
THEORETICAL RISK THERE IS THE
POTENTIAL FOR GENE TRANSFER TO
ORGANISMS ADMINISTERED THAT
COULD HAPPEN AT THE TIME OF
MANUFACTURING OR LATER WHEN THE
BACTERIA GETS INTO THE
ENVIRONMENT.
BUT TO MY KNOWLEDGE AT THIS TIME
WE HAVE NOT SEEN THAT HAPPEN.
>> THIS QUESTION IS DIRECTED AT
JOE.
I APPRECIATE THE DISCUSSION
ABOUT AND TYPING INTESTINAL
INJURIES.
DO YOU THINK WE KNOW ENOUGH
ABOUT THE PATH THE BIOLOGY WITH
THESE DIFFERENT TYPES TO
UNDERSTAND IF THERE IS ANY
OVERLAP OR NO OVERLAP?
>> THERE -- -- THAT'S A VERY
GOOD QUESTION BECAUSE I MAY NOT
HAVE MADE THAT POINT CLEAR
ENOUGH.
THE CLUSTERING WOULD OCCUR FIRST
AND WE DON'T HAVE THAT YET
AMONGST SEVERAL DIFFERENT
NEONATAL INTENSIVE CARE UNITS
THE NETWORK DOES NOT HAVE THE
GRANULARITY FROM THE INFORMATION
I HAVE AVAILABLE FROM THE
NEONATAL NETWORK TO DO THAT
TALKING TO THE KOREAN NETWORK
AND THEY DO HAVE THE GRANULARITY
TO DO THAT SO WE HAVE STARTED
WORKING ON GETTING THE DIFFERENT
CLUSTERS.
A MUCH LARGER POPULATION.
>> AND WE CAN START LOOKING AT
CLUSTERS.
>> WE PUT THAT CLUSTER A WITH
CLUSTER B AND CLUSTER C.
>> THAT'S ALL WE HAVE TIME FOR
THIS SESSION WE ENCOURAGE YOU TO
REACH OUT IN PERSON AND ASK
QUESTIONS.
NOW WE ARE MOVING INTO THE ORAL
COMMENTS PERIOD.
THANK YOU VERY MUCH.
[APPLAUSE]
OPEN PUBLIC COMMENTS 1130
THROUGH 1135 EACH INDIVIDUAL
WILL HAVE 5 MINUTES TO SPEAK AIR
IN PRIOR WHO IS REPRESENTING THE
NEXT SOCIETY.
>> THANK YOU FOR THE OPPORTUNITY
TO SPEAK TODAY IN THE RESEARCH
DIRECTOR THROUGH THE NEXT
SOCIETY THE WORLD'S LEADING
NONPROFIT ORGANIZATION DEDICATED
TO THE PREVENTION AND TREATMENT
NECROTIZING ENTEROCOLITIS
THROUGH RESEARCH AND EDUCATION
AND ADVOCACY.
UNDERSTAND THE DEVASTATING
OUTCOMES THAT RESULT FROM THE
LACK OF PREVENTION AND TREATMENT
OPTIONS FOR NEC.
WE APPRECIATE THE CONVENING AND
THE RECOGNITION BY THE CDC, FDA
AND NIH OF THE COMPLEXITIES
SURROUNDING THE USE FOR THOSE AT
RISK OF NEC WE SUPPORT THE
INTENTIONAL FOCUS ON THE SAFETY
OF THERAPEUTICS FOR THIS
VULNERABLE POPULATION.
THE NEXT SOCIETY FOUNDED IN 2014
AFTER HER SON WAS LOST DUE TO
COMPLICATIONS BEFORE HIS FIRST
BIRTHDAY.
EXPERIENCING A SUDDEN DIAGNOSIS
THERE WAS LITTLE INFORMATION
AVAILABLE ON THE
RISKS, TREATMENTS OR POTENTIAL
CAUSES OF NEC.
SHE HAS SINCE HARNESSED AND
EMPOWERED AN INTERNATIONAL
NETWORK OF CLINICIANS AND
SCIENTIST WORKING TOGETHER TO
BUILD A WORLD WITHOUT THIS CRUEL
DISEASE.
THE CURRENT PREVENTION AND
TREATMENT OPTIONS ARE INADEQUATE
AND FAILING OUR COMMUNITY.
ALTHOUGH MORE RESEARCH IS NEEDED
TO UNDERSTAND AND ELIMINATE NEC
CURRENT EVIDENCE DEMONSTRATES
CARE PRACTICES CAN MEANINGFUL
INFLUENCE MORE SPECIFICALLY
RESEARCH HAS DEMONSTRATED
PROBIOTICS COULD BE AN EFFECTIVE
TOOL TO PREVENT NEC AND DEATH
AND VERY LOW BIRTH WEIGHT
INFANTS.
A NEXUS I DEVELOPED AND RELEASED
A TOOLKIT A RESOURCE TO BETTER
UNDERSTAND PROBIOTICS USE AND
INFORM THE DECISION-MAKING
PROCESS AND FOSTER DISCUSSION
AMONG KEY STAKEHOLDERS SPECIFIC
TO EACH UNIT IT INCLUDES A
COMPREHENSIVE REVIEW OF
AVAILABLE EVIDENCE, GUIDANCE
FROM WORLDWIDE PROFESSIONAL
ORGANIZATIONS AND TIPS AND TOOLS
AND MITIGATION STRATEGIES FOR
HEALTHCARE TEAMS AND PATIENT
FAMILIES TO NAVIGATE THE RISKS
AND BENEFITS.
IN 2023 AS YOU HAVE HEARD
30 PERCENT OF NICU RAISING
PROVIDED DASH PROBIOTICS IT IS
IN, AND MUCH OF THE WORLD BUT
VIRTUALLY HALTED IN THE US AFTER
THE FDA WARNING OF THE EXTREMELY
RARE RISK OF SEPSIS
COMMUNICATION AND COLLABORATION
AMONG CLINICIANS AND FAMILIES
AROUND PROBIOTICS HAVE STOPPED
BECAUSE THERE ARE NO LONGER
OPTIONS AVAILABLE.
IT IS IMPERATIVE WE SUPPORT
CLINICIANS AND PATIENT FAMILIES
WORKING IN CONCERT TO EVALUATE
THE RISKS AND BENEFITS OF
VARIOUS TREATMENTS INCLUDING
PROBIOTICS.
WE MUST HAVE A VOICE OF WHAT IS
CONSIDERED THE ACCEPTABLE RISK
OR BENEFIT IN THE NICU AND
FAMILIES MUST HAVE ACCESS.
WE CAN WORK SIMULTANEOUSLY AND
IMPROVE SAFETY AND PREVENTION
STRATEGIES AS WE DO WITH ALL
NICU CARE PRACTICES.
TODAY, RIGHT NOW AS WE HAVE THIS
MEETING BABIES ARE DYING FROM
NEC.
WE HEAR TRAGIC STORIES FROM
FAMILIES EVERY DAY AS THESE
DISCUSSIONS REVOLVE AROUND
PROBIOTIC USE WE NEED A SEAT AT
THE TABLE WE ARE HERE TO ENGAGE
IN HAVING A REFINED PATHWAY WITH
DEMONSTRATED SAFETY OF IMPROVED
OUTCOMES FOR NEONATES THEY NEED
MORE INFORMATION HOW THEY CAN
PROTECT THEIR NEWBORNS HEALTH
AND THE ABILITY OF CLINICIANS TO
PROVIDE ACCURATE INFORMATION AND
DISCUSS PERFECTIVE CARE OPTIONS
IS BEING HINDERED EVEN SLIGHT
VARIATIONS TRANSLATE INTO
PROFOUND CONSEQUENCES FOR
PATIENT FAMILIES AND CAN BE THE
DIFFERENCE BETWEEN A CHILD
DEVELOPING A SEVERE LIFE
ALTERING OR FATAL DISEASE OR
GOING AT HOME WITH THEIR
FAMILY.
JUST AS HISTORY CHANGING CARE
PRACTICES IT CARRIES ITS OWN
RISK OF SUBJECTING PATIENTS TO
THE DISEASE THAT COULD BE
PREVENTED.
CRITICAL TO RECOGNIZE THE
SHATTERED FAMILIES WHO WILL
NEVER AGAIN HOLD THEIR CHILDREN
IN THEIR ARMS AND THE URGENCY OF
IMPLEMENT TEAM PREVENTION
STRATEGIES WHILE CONSIDERING THE
RISKS.
THANK YOU.
[APPLAUSE]
>> THANK YOU WE APPRECIATE THOSE
COMMENTS UP NEXT FROM THE
AMERICAN ACADEMY OF PEDIATRICS.
>> I WOULD LIKE TO SPEAK.
I AM IN FULL SUPPORT OF
EVERYTHING THAT WAS JUST SAID.
THANK YOU FOR THIS TIME I AM
SPEAKING TO YOU ON BEHALF OF THE
AMERICAN ACADEMY OF PEDIATRICS A
NONPROFIT PROFESSIONAL
ORGANIZATION OVER 67000
PEDIATRICIANS COMMITTED TO THE
OPTIMAL HOPE OF ALL CHILDREN AND
WE WENT TO ADD HER THANKS TO THE
ORGANIZERS TO BRING TOGETHER
IMPORTANT PERSPECTIVES ON THIS
TOPIC I SERVE AS THE CHAIR OF
THE AP SECTION THE PROFESSIONAL
HOME FOR ANY APOLOGIST SENSITIVE
WARNING WAS ISSUED IN 23 WE HAVE
HEARD FROM MANY MEMBERS
REGARDING THE IMPACT OF THEIR
STATEMENT OF PRETERM INFANTS IS
3 TUMMY MESSAGES WE WOULD LIKE
TO SHARE FIRST WE BELIEVE AS WE
HEARD THERE IS A SUBSTANTIAL
LIKELIHOOD PROBIOTICS
CONTRIBUTED TO POSITIVE OUTCOMES
IN PRETERM INFANTS AND WE WILL
HEAR MORE THIS AFTERNOON THERE
ARE MANY REPORTS OF TRIALS AND
OBSERVATION STUDIES AND ANALYSIS
EXAMINING PROBIOTICS SEVERAL
HAVE FOUND SIGNIFICANT
REDUCTIONS OF NEC AND MORTALITY
WHILE THE OVERALL CERTAINTY OF
EVIDENCE IS MIXED IN THE OPTIMAL
DOSE REMAINS UNDER INVESTIGATION
THE LIKELIHOOD PROBIOTICS
CONTRIBUTES TO POSITIVE OUTCOMES
SEEMS HIGH.
SECOND AP POLICIES SUPPORTS THE
USE OF PROBIOTICS FOR PRETERM
ELEMENTS WITH THE ELEMENTS OF
THE 2021 AP POLICY STATEMENT HAS
IT LISTED ALREADY BUT THE 2023
MORNING LEAVES THE MISS
IMPRESSION IT OPPOSES ALL USE
WHILE THE WARNING HIGHLIGHTED
THE CONCLUSION THAT "CURRENT
EVIDENCE DOES NOT SUPPORT THE
ROUTINE UNIVERSAL ADMINISTRATION
OF PROBIOTICS FOR PRETERM
INFANTS"IT DOES NOT ADDRESS
OTHER KEY COMPONENTS OF THE
STATEMENT FROM AS WE HEARD
EARLIER AND ACKNOWLEDGES THAT
SOME CENTERS MAY CHOOSE TO
ADMINISTER PROBIOTICS AND OFFERS
GUIDANCE HOW IT CAN BE DONE
APPROPRIATELY.
IT INCLUDES DISCUSSION OF RISKS
AND BENEFITS FOR FAMILIES
CONSIDERATION OF INFORMED
CONSENT AND CAREFUL MONITORING
OF OUTCOMES AND ADVERSE EVENTS.
LASTLY AS WE HAVE HEARD
PROBIOTIC USE IN THE NICU HAS
PRECIPITOUSLY DECLINED SINCE THE
FDA WARNING.
THERE ARE OTHER REPORTS WE HAVE
SEEN INDICATE BY 1 THIRD OF NICU
USING PROBIOTICS A SIMILAR
SURVEY CONDUCTED THIS MONTH IS
DIFFERENT SHOWN PROBIOTIC USE
HAD ALMOST STOPPED IN ALL CASES
THE DECISION TO STOP PROBIOTIC
USE IS BASED ON THE FDA WARNING.
ESTIMATED IT HAS BEEN CLEAR NOT
TO INSTRUCT CARE IN PRETERM
OFFENSE BUT THE RESULT HAS BEEN
A LARGE REDUCTION OF THE USE OF
PROBIOTICS IN THE NICU.
WE RESPECT AND APPRECIATE THE
REGULATORY OVERSIGHT OVER
DIETARY SUPPLEMENTS AND WE KNOW
THE SUPERVISION IS ESSENTIAL FOR
SAFE HEALTHCARE IN THE UNITED
STATES.
HOWEVER NEONATOLOGIST ARE
STRUGGLING WITH THIS ISSUE WITH
THE CURRENT REGULATORY AND LEGAL
UNCERTAINTY MOREOVER WE ARE
CONCERNED THE WARNING HAS
NEGATIVELY IMPACTED THE PRACTICE
OF MEDICINE AND MAY ADVERSELY
IMPACT OF PRETERM INFANTS.
FIRST AS IS DOING WE ASK FEDERAL
HEALTH AGENCIES TO EXTRADITE
STEPS NEEDED TO PERFORM
EVALUATION FOR PROBIOTICS FOR
PRETERM INFANTS.
THE IT INDICATES TO MITIGATE
CURE OR PREVENT A DISEASE OR
CONDITION SUCH AS NEC WITH AN
INVESTIGATIONAL NEW DRUG
APPLICATION AND ALSO TO PURSUE
THE IND IS NOT REALISTIC FOR
MEMBERS WE URGE THE FDA AND
OTHERS TO WORK WITH THE
SCIENTIFIC COMMUNITY AND
MANUFACTURERS TO EXPEDITE TRIALS
AS MUCH AS POSSIBLE.
PERHAPS SCIENCE CAN BE USED TO
FACILITATE THE PARTICIPATION IN
WITH NEEDED EVIDENCE MORE
QUICKLY.
SECOND WE ENCOURAGE THE FDA TO
EXERCISE ENFORCEMENT DISCRETION
TO ALLOW INDIVIDUAL CLINICIANS
IN PRETERM INFANTS IT IS BASED
IN PART ON THE PERCEIVED USE OF
PROBIOTICS WITH THE INTENT TO
MITIGATE THE USE UP HOWEVER
THERE ARE MANY REASONS PROVIDERS
INCLUDING REDUCING MORTALITY
REDUCING DURATION.
THE AP REPORT FROM 2021 HAS
DETAILED GUIDANCE FOR PRETERM
INFANTS AND IT COULD BE A
CRITERIA UNDER WHICH THE FDA
COULD ALLOW ENFORCEMENT
FLEXIBILITY.
WE ARE CONCERNED WITHOUT THIS TO
REDUCE THE BURDEN OF SERIOUS
OUTCOMES WOULD BE HAMPERED WITH
THE OFFICIAL POLICY ALLOWING THE
USE OF PROBIOTICS FOR THE
PROMOTION OVERALL HEALTH.
THANK YOU FOR HOLDING THE
MEETING.
[APPLAUSE]
>> .
>> GRATEFUL FOR THE COMMENTS
THAT WE WERE HEARING BEFORE FROM
THE SPEAKERS PROFESSIONAL
CONFLICT OF INTEREST BUT I WILL
BE DISCUSSING PROBIOTICS THAT
ARE NOT APPROVED AS A MEDICATION
BY THE FDA.
SO WITH SOME CONTACT THE MEDICAL
GROUP IS AFFILIATED PHYSICIANS
WITH A LARGE FOOTPRINT IN
NEONATOLOGIST.
WE MADE FROM ACCUSED TO
CHILDREN'S HOSPITAL 100,000
BABIES PER YEAR AND WE HAVE 5500
BABIES AND THAT IS ABOUT ROUGHLY
20 PERCENT OF US NEONATOLOGY AND
THE GOOD NEWS IS THAT IS FED
INTO A DATA SET.
IT'S NOT PERFECT BUT ALLOW SOME
UNIQUE HERE NEED -- -- LEARNING
FROM THE NEONATAL CONSORTIUM
EACH WITH DIFFERENT STRENGTHS
AND WEAKNESSES.
SO OUR AFFILIATED PHYSICIANS
RESPECT THE WORK OF THE FDA AND
CHAIR -- -- SHARE THE WARNING
LETTER REGARDING USE OF
PROBIOTICS WITH AFFILIATED
CLINICIANS WE VIEW NEC HAS A
DREADED COMPLICATION OF
PREMATURITY THAT IS MORE
APPROPRIATELY TERMED DISEASE
THAT IS NOT BETTER UNDERSTOOD
THAT HAS NEED TREATMENTS AND
PREVENTATIVE MEASURES.
WE HAVE COLLABORATED PREVIOUSLY
AND WE COMMIT TO COLLABORATE
GOING FORWARD.
SO TO GIVE SOME PEDIATRIX IS 1
OF THE LARGEST DATA SETS IN THE
WORLD AND INCLUDING 20
SPECIFICALLY RELATED TO NEC
AND/OR PROBIOTICS.
HAVE TIME TO GO THROUGH THESE
BUT A COUPLE HAVE BEEN
MENTIONED.
SO WHAT ARE WE SEEING?
PROBIOTIC USE WAS INCREASING
PRIOR TO THE WARNING LETTER
ABOUT 1 THIRD OF VLBW INFANTS IN
THE NETWORK WERE RECEIVING
PROBIOTICS SO ABOUT 2 THIRDS AND
MORE THAN 50 PERCENT OF THE
UNITS WERE NOT USING PROBIOTICS
BUT A SIGNIFICANT PROPORTION OF
THE BABIES WERE BUT THE WARNING
LETTER CAME OUT BUT OUR BABIES
ARE CAPTURED ON DISCHARGE DAY SO
THOSE BORN IN THESE QUARTERS ARE
NOT DISCHARGED UNTIL THE
SUBSEQUENT QUARTER AFTER THE
WARNING LETTER BUT THE SPIGOT
HAS BEEN TURNED OFF.
1 OF THE CONCERNS THAT BROUGHT
FORTH IN THE WARNING LETTER IF
WE LOOK IN OUR NETWORK AT 29
WEEKS GESTATION BABIES OVER A 6
YEAR WINDOW A LITTLE OVER 9000
BABIES EXPOSED TO PROBIOTICS
WITH 11 DOCUMENTED INFECTIONS
WITH BLOOD OF THE SPINAL FLUID.
AND INTO OF THOSE THEY WERE
REPORTED AS CONTAMINANT POSSIBLY
A FALSE POSITIVE AND IN 9
PATIENTS POSSIBLY A TRUE
INFECTION 7 DISCHARGE HOME 1
TRANSFERRED TO ANOTHER HOSPITAL
AND IS UNKNOWN AND 1 DIED
APPROXIMATELY 40 DAYS LATER.
IS NOT CLEAR THE ATTRIBUTION OF
DEATH FROM OUR DATA SET.
WHEN WE LOOK AT JUST NEC AND
MORTALITY THOSE BORN IN THE SAME
6 YEAR WINDOW IT IS 44000 BABIES
ABOUT 1854 WERE DIAGNOSED AT 4.2
PERCENT A LITTLE OVER 1000 THOSE
THAT WERE DIAGNOSED WITH MEDICAL
NEC AS THE THE DIAGNOSIS CAN BE
COMPLICATED I KNOW 139 OR
13 PERCENT DIED AND THAT IS
SLIGHTLY A UNDERESTIMATE AS
ALMOST 1 THIRD WAS IN THE BIRTH
HOSPITAL SENT TO ANOTHER
INSTITUTION FOR HIGHER LEVEL OF
CARE.
LOOK AT THOSE WITH SURGICAL NEC
AND 44 PERCENT DIED WHICH IS
LIKELY IN UNDERESTIMATE AS THEY
WERE TRANSFERRED ELSEWHERE.
JUST LOOKING AT ALL DEATHS OF
BABIES NOT JUST NEC RELATED THAT
IS 5098 DEATHS AND 9.4 PERCENT
WERE BABIES THAT HAD NEC MEDICAL
OR SURGICAL AND I AM REMISS TO
TALK ABOUT AND VALUES HERE THOSE
ARE REAL HUMAN BABIES IF YOU ARE
CLINICIAN THAT WORKS ON THE
FRONT AND THESE ARE
HEARTBREAKING BECAUSE OFTEN THEY
HAVE GOTTEN THROUGH MANY OF THE
SCARY THINGS IN THEIR EARLY
COURSE ONLY TO BE SNAKE BIT BY
THE TERRIBLE DISEASE.
SO TO SHORT COMMENTS WE ANALYZE
THE IMPACT OF THE CESSATION OF
PROBIOTIC USE OF HEALTH OUTCOMES
OF HIGH RISK PRETERM IN SINCE
IT'S TOO EARLY TO LOOK AT THAT
ASSOCIATION YET AND THE LINE OF
DEMARCATION SEEKING TO MITIGATE
OR TREAT DISEASE IS MURKY.
SO WHAT CAN BE DONE TO
FACILITATE CLINICAL TRIALS IN
THIS AREA AND YOU SEEK TO
REGULATE OTHER NUTRITIONAL
PRODUCTS USED IN THE NICU
SIMILAR FOR USE OF PROBIOTICS?
THANK YOU FOR HAVING ME.
>> THANK YOU FROM ALL THE
SPEAKERS FROM THE 2 SESSIONS I
APPRECIATE YOU SHARING YOUR
THOUGHTS AND BEING ON TIME ALSO
THANK YOU TO THE 3 MEMBERS OF
THE PUBLIC TO SHARE THEIR
THOUGHTS.
WE WILL ADJOURN UNTIL 1:00 P.M.
I WILL MEET YOU HERE AT 1:00 WE
HAVE LUNCH BREAK 1 HOUR 15
MINUTES IF YOU PURCHASED A LUNCH
STRAIGHT THROUGH THE DOUBLE
DOORS AND INTO THE
NONFUNCTIONING CAFETERIA.
YOU'RE MORE THAN WELCOME THERE
IS SEATING THERE ALSO OUTSIDE IF
YOU DID NOT OR DON'T HAVE A
LUNCH THERE ARE LUNCH OPTIONS
OUT THE FRONT DOOR OUT THE LIGHT
PASS A LIGHT MAKE SURE YOU TAKE
YOUR BADGE OTHERWISE YOU WILL
NOT COME BACK IN.
WE WILL SEE YOU HERE AT 1:00
P.M.
THANK YOU.
>> THANK YOU TO THE ORGANIZERS
AS A FASCINATING AND CHALLENGING
TOPIC.
I'M HAPPY TO HAVE THESE IN-DEPTH
DISCUSSIONS STARTING LONG
COLLABORATIONS.
NO DISCLOSURES.
THE WORKER WILL PRESENT HAS BEEN
FUNDED BY NIAID.
I AM THE CHAIR OF THE AGA
SCIENTIFIC ADVISORY BOARD FOR
THEIR MICRO BIOME CENTER BUT ALL
OF MY DISCUSSIONS ARE MY OWN
PERSONAL OPINION AND NO OTHER
FINANCIAL SUPPORT.
SO WE ALL KNOW WHAT THE PROBLEM
IS BY NOW.
NECROTIZING ENTEROCOLITIS
UTTERLY CATASTROPHIC ILLNESS
DISPROPORTIONATELY WITH CHILDREN
BORN LESS THAN 1500 GRAMS AND
AFFECTED MORE SEVERELY WEIGHING
LESS THAN 1000 GRAMS.
THEY ARE UNIQUELY SUSCEPTIBLE TO
DISEASES OF GOT ORIGIN QUITE
LIKELY MICROBIAL THAT HAS BEEN
PRECIPITATED OR PERPETUATED IN
THIS TALK I WOULD LIKE TO TOUCH
ON SEVERAL POINTS HOW GET
MICROBIAL OPTIONS CHANGE OVER
TIME AND TRY TO LOOK AT WHAT
MIGHT DRIVE SOME OF THESE
COMPOSITIONAL CHANGES.
TRY TO THE TERM IN SOME
LITERATURE OUT THERE AND SOME
COHORT STUDIES LINKING WHAT IS
IN THE GUT OR THE MICROBES IN
THE GUT OR THE DISEASE IS INPUT
TOGETHER NECROTIZING
ENTEROCOLITIS AND EXPLORING
KNOWLEDGE OF GUT MICROBES TO BE
HARNESSED WITH ENDPOINTS FOR
STUDIES.
AND WITH THAT I WILL GO INTO
THIS AS WE ALL HAVE LEARNED AS
THE TEMPORARY INTEREST TO BE
COLONIZED PRENATALLY THE GUT THE
CHILDREN ARE BORN WITH STERILE
INTESTINES ALMOST NO EVIDENCE OF
VIABILITY OF MICROBES IN INFANT
GETS.
SOON AFTER BIRTH THE MECONIUM
WILL PASS OUT AND THE HUMAN
BEGINS A LIFELONG CONNECTION TO
MICROBES OF DIVERSE CONSTITUENCY
COMPOSITION FUNCTIONALITY AND
THOSE WILL CHANGE OVER LIFE IN
RESPONSE TO ILLNESS AND MAY BE
AS A CAUSE OF ILLNESS.
FROM INFANTS IN MANY WAYS ARE
DIFFICULT TO STUDY BECAUSE OF
LIMITATIONS ON SAFETY OF
INTERVENTIONS ON THE OTHER HAND
WITH THE MICRO BIOME THEY ARE
UNIQUELY SUITABLE FOR
HIGH-FREQUENCY TO RESIDE IN
ENVIRONMENTS WHERE THERE'S NOT A
LOT OF IN AND OUT MAYBE GO OFF
THE FLOOR FOR THE X-RAY STUDY
BUT LARGELY IN 1 GEOGRAPHIC
SPACE AND THE ECOSPHERE IS
FAIRLY WELL-MANAGED.
NO PETS RELATIVELY LIMITED
NUMBER OF HANDLERS AND FEW ORAL
ANTIBIOTICS.
IT IS A GOOD OBSERVATIONAL
ECOLOGICAL STUDY HOW DOES THE
BACTERIA GET IN THERE WHERE DO
THEY COME FROM AND EXPAND AND
HOW MIGHT THEY HAVE THE ABILITY
TO INFLUENCE OUTCOMES WITHIN THE
SEVERAL MONTHS THAT THEY LIVE IN
THE NICU?
FURTHERMORE 1 OF THE GOOD SIDES
OF MEDICAL RECORDS CAPTURES A
LOT OF DATA THAT IS CONCEIVABLY
MINEABLE AS YOU TRY TO CORRELATE
ECOLOGICAL CHANGES WITH
INTERVENTIONS AND ENVIRONMENTAL
INFLUENCE.
ABOUT 16 YEARS AGO IN RESPONSE
TO THE MICRO BIOME PROJECT, WE
WERE FUNDED TO STUDY PRETERM TO
FIND MICROBIAL DETERMINANTS OF
NECROTIZING ENTEROCOLITIS.
I WOULD LIKE TO GIVE
ACKNOWLEDGMENT TO NIAID TO GET
INTO THIS SPACE THERE WERE NO
INFECTIONS INVOLVED WE STARTED
OUT SO IT WAS A GAMBLE SO I
REALLY WANT TO THANK THEM FOR
FUNDING OUR 2 VALIDATION COHORTS
BEING ASSEMBLED AT 2 OTHER
CENTERS SIMULTANEOUSLY GIVING
MORE CREDENCE TO THE
OBSERVATIONAL STUDY AT ST. LOUIS
CHILDREN'S HOSPITAL.
SO THE FIRST ROUND OF DATA THAT
WE GENERATED WAS A STUDY NONE OF
THEM DEVELOPED NECROTIZING
ENTEROCOLITIS.
WAS A SMALL COHORT I DON'T THINK
THERE WAS A SINGLE POSITIVE
BLOOD CULTURE AND ALL BLOOD
STOOLS -- -- ALL STOOLS HAD
SEQUENCING THIS IS ALREADY
ANCIENT HISTORY THROUGH DAY 30
AND THEN EVERY 3 DAYS AFTER.
922 STOOLS AND 7000 ON AVERAGE
PER STOOL SO THE FIRST ROUND THE
DATA WE FOUND WERE IMMUNE THE
CONFRONTED WITH MARKEDLY DIVERSE
POPULATION YOU CAN SEE THE
DISTRIBUTION OF DIFFERENT
CLASSES OF BACTERIA ALMOST ALL
OF THEM THE MAJORITY OF
MICROBIAL BACTERIA A RANDOM
STOOL WITH THE SEQUENCES OVER
HALF WOULD BE GRAHAM NEGATIVE
BACILLI.
IN THERE BUT NOT YET PREDOMINANT
AS IT WOULD BE THE ADULT STOOL.
SO WE ARE ALREADY DEALING WITH
SOME SEVERE OUTCOMES.
THAT SOUNDS GOOD BUT ON THE
OTHER HAND LOOK AT THIS ON THE
INDIVIDUAL LEVEL IT IS 1
PARTICIPANT AND THE FIRST THING
YOU SEE IS YOU ARE OBLIGATED TO
TAKE WHATEVER YOU CAN GET WITH
THE STOOL YOU CANNOT SCHEDULE SO
IF YOU CAN MOVE THE NUMBERS IT
IS QUITE IRREGULAR AND WE
CALCULATE WE WOULD GET A STOOL
ON AVERAGE ABOUT ONCE EVERY 2
AND HALF DAYS SO IS NOT
CONTINUOUS MONITORING ALTHOUGH
NOT PERFECT IT IS RISK-FREE
SPECIMENS AND NOT A BIG DEAL TO
COLLECT IT AND THEN WE STARTED
SEQUENCING.
THIS SINGLE PATIENT DID FAIRLY
WELL BUT YOU CAN SEE THE
PROGRESSION OF MICROBES.
EARLY ON IN THE FIRST WEEK OR 2
OF LIFE THE BLUE PART OF THOSE
COLUMNS REPRESENT GRAM-POSITIVE.
THE RED OR THE PINK IS
GRAM-NEGATIVE AND YOU CAN SEE
THERE IS BLUE THERE ARE DAY TO
DAY INSTABILITIES BUT OVERALL
YOU CAN SEE THE TREND WHEN YOU
PUT IT TOGETHER YOU WILL COME UP
WITH A RECOGNIZABLE PATTERN WITH
THE BACTERIA THAT WILL BE
PRESENT AND WILL PREDOMINATE FOR
A FEW WEEKS AND THEN THEY WILL
BE REPLACED BY ANAEROBES AND FOR
THE REST OF THE HEALTHY LIFE
THAT WILL PREDOMINATE.
AND THEN DAY TO DAY DISRUPTIONS
WE DON'T KNOW WHAT CAUSES THEM
AND WE DON'T KNOW THE
IMPLICATIONS BUT YOU CAN IMAGINE
IF YOU DO A SINGLE CASE-CONTROL
STUDY IT WILL BE A PROBLEM IF
YOU'RE TRYING TO RELATE
SOMETHING LIKE THIS TO AN
OUTCOME YOU CANNOT JUST TAKE 1
SPECIMEN DASH SPECIMEN TO
CHARACTERIZE 1 PERSON VERSUS
ANOTHER AND THE WAY WE HANDLED
IT TO SMOOTH THAT OVER WITH A
LOT OF CHILDREN AND SPECIMENS
THIS IS A SINGLE PATIENT
STARTING OFF WITH GRAM-POSITIVE
AND THEN THE NEXT DAY IS
DOMINATED BY GRAM-NEGATIVE
BACTERIA AND THEN YOU SEE IT
INCHING UP DAY BY DAY STOOL
SEQUENCE NOT THE WHEN I SHOWED
BEFORE AND THEN WHERE THE
PATIENT WILL HARBOR A POPULATION
OF BACTERIA.
THERE WAS A VERY TELLING
DIFFERENCE BETWEEN CHILDREN'S
PROGRESSION OF THE MICROBES
DEPENDING ON THEIR GESTATIONAL
AGE AT BIRTH SO RIGHT HERE YOU
CAN SEE THIS CLUSTER RISING AT
THIS RATE IT IS SLOWER THAN
THOSE RISING AT THIS RATE AND
THE STATISTICIAN WAS IMPRESSED
WITH THE SIGNIFICANCE OF THIS
CLEARLY A DIFFERENT POPULATION
THAN THIS AND THESE CHILDREN
WERE BORN BETWEEN 25 AND 28
WEEKS OF GESTATION AND BORN JUST
SHORT OF GESTATION SO IT IS A
SLOWER EVOLUTION -- -- EVOLUTION
TO GET TO THAT MORE ADULT LIKE
FORMATION WE RAN A LOT OF
ANALYSIS WITH THE COMMUNITY
STRUCTURE YOU CAN SEE THAT IT
DOES SUGGEST THAT THE MOST
PRETERM HAS A SLOWER
DEVELOPMENTAL PACE BUT AT
APPROXIMATELY THE SAME TIME IF
YOU RELATE THE CHILD'S AGE TO
POST MENSTRUAL AND THEN IT DOES
NOT AFFECT ANY MICROBIAL CONTENT
AND THE DELIVERY DOES NOT HAVE
MUCH INFLUENCE THERE EITHER.
HOWEVER IN A FOLLOW-ON STUDY IN
THE LAB TECHNOLOGY IS ADVANCING
AS META- GENOMIC SEQUENCING AND
SHE LOOKED AT THE SAME COHORT
MANY OF THE SAME STOOLS TO FIND
WHEN YOU BREAK IT OUT WITH
DIFFERENT ANTIBIOTICS TO REDUCE
DIVERSITY OF THE MICROBIAL
CONTENT ALL IN AGGREGATE SOME
ACTUALLY INCREASED DIVERSITY
LIKE ERYTHROMYCIN AND ALSO SHE
DID FUNCTIONAL SCREENING LOOKING
FOR ANTIBIOTIC RESISTANCE
CONFIRMED ELEMENTS AND FOUND A
REASONABLE NUMBER AND THIS IS ON
THE PEAK AND THEY WERE NOT FOUND
IN THE DATABASE OF ANTIMICROBIAL
RESISTANCE.
THE PROBLEM STILL PERSISTS.
SO WE ARE PROBABLY MISSING MORE
THAN WE NO. SO WE EXTENDED THE
INITIAL ROUND OF COMPARISONS TO
CHILDREN WHO HAVE NECROTIZING
ENTEROCOLITIS ALL STOOLS ALL THE
TIME GO BACK TO THE FREEZER AS A
WHAT DID WE HAD PRIOR TO THE
EVENT?
166 PATIENTS WERE IN THE STUDY
AND MATCH THEM TO CONTROLS WITH
THE GESTATIONAL AGE OF BIRTH AND
BIRTH WEIGHT.
3500 DIFFERENT STOOLS WERE
SEQUENCED 6000 MEANS PER 12 THIS
IS 2012 IN TERMS OF TECHNOLOGY
BUT NOW WE CAN HAVE A REASONABLE
DATABASE TO SAY WHAT IS
DIFFERENT PRIOR TO THE
DEVELOPMENT OF NEC COMPARED TO
CONTROLS THAT DO NOT.
SO BASICALLY THEY DEVELOP NEC
AFTER 30 DAYS OF AGE HAVE A FREE
EVENT SURGE OF GRAM-NEGATIVE
BACTERIA THOSE THAT ARE
PROTECTED SEEM TO START ON THE
PATH TO HOLDING ONTO NURSE
SHARING AND HANGING ONTO
ANAEROBES.
THESE ARE THE GRAM-NEGATIVE'S
BUT WE DON'T SEE THAT FOR THE
KIDS THAT DEVELOP NEC ON OR
BEFORE DAY 30.
AGAIN WE SUBJECTED THIS TO A
VARIABLES STUDY THE STATISTICIAN
TELLS US THAT FOR ALL
GESTATIONAL AGES DRIVEN FOR
CHILDREN BORN TO THE 427 WEEKS
GESTATION WE HAVE SIGNIFICANTLY
MORE BACTERIA THAT ARE
DEVELOPING NEC AND SIGNIFICANTLY
WE WERE NEGATIVE ACTIVITIES.
CHILDREN BORN AFTER 27 WEEKS DID
NOT SEE A SIGNAL.
THEN LOOK AT THE VALIDATION
COHORTS WE HAVE THE SAME
ASSOCIATION WITH ST. LOUIS WHERE
THE RISK OF DEVELOPING NEC THAT
CHIEFLY THOSE WITH THOSE LESS
THAN 27 WEEKS NOT THOSE BORN
AFTER 27 WEEKS.
THIS LINES UP WITH NECROTIZING
ENTEROCOLITIS THE SHORTER THE
GESTATION THE CHILD HAS A LATER
THEY DEVELOP NEC IF THEY DO.
WITH THE DIFFERENT BACTERIA WITH
GAMMA PROTEIN BACTERIA E. COLI
THEN SUBSETS WITH SPECIFIC
STRAINS IT IS ALWAYS POPPING UP
BUT IF YOU LOOK AT THE DIFFERENT
PIE CHARTS THERE IS A LOT OF
VARIABILITY THESE PIE CHARTS
REPRESENT THE GRAM-NEGATIVE
OVERREPRESENTED WITH THE
AGGREGATE BUT NOTHING IS JUMPING
OUT IN SOME CENTERS E. COLI IS
PREDOMINANT BUT ON THE OTHER
HAND AMONG THE CHILDREN CONTROLS
THE NEGATIVE PROCLIVITIES IT
SEEMED TO BE THE SAME SO WE TALK
ABOUT CAUSALITY IN 1 CENTER BUT
IT MAY JUST REFLECT THAT CENTER
BUT THE COMMON DENOMINATOR OF
THE OFFENSIVE POPULATION MAY NOT
BE AT THE GENUS OR SPECIES LEVEL
BUT A SHARED TRAIT LEVEL.
AS WE HEARD A LITTLE BEFORE
ABOUT POLYSACCHARIDE TO BE
UPREGULATED IN INFANTS AFTER
BIRTH SO AT LEAST IT IS A
WORKING HYPOTHESIS.
BUT I'D LIKE TO GET BACK TO
THIS.
YES IT IS TRUE YOU ARE AT
GREATER RISK BUT IT IS NOT
CATEGORICAL IT IS TWOFOLD OR
THREEFOLD AND IT IS HARD TO SAY
YOU CAN JUST DOUBLE OR TRIPLE A
PROPORTION OF AN ORGANISM YOU
HAVE A CATASTROPHIC OUTCOME THAT
WILL KILL THE DIGESTIVE SYSTEM
SO WHILE THERE IS THE
ASSOCIATION I AM NOT SURE THE
SINGLE ORGANISM INJURY THE
PARADIGM THAT WE HAVE LEARNED
WITH INFECTIOUS DISEASES WILL
HOLD WE HAVE THESE POPULATIONS
THAT TILT BUT ARE FAR FROM
CATEGORICAL.
THEN WITH A DEEPER DIVE THE
STUDY KEEPS GOING SAME COHORT
AND SPECIMENS AND FREEZERS AND
DATABASE AND A POSTDOC RECENTLY
PUBLISHED A STUDY AGAIN WITH THE
SAME COHORT 236 INFANTS THIS
TIME STARTING OUT WANTING TO
DEFINE IN GREATER DETAIL THE
PROFESSIONAL MICROBES AND THEN
OF COURSE BLOOD.
2500 STOOLS 500 PER SAMPLE YOU
CAN SEE TECHNOLOGY IS MARCHING
FORWARD AND SOME INTERESTING
SETS OF DATA CAME OUT.
BACTERIA IN THE AGGREGATE OR
ASSOCIATED THAT SEEMS TO BE
PROTECTIVE THEY FOUND THE
COUPLING DAY OF LIFE 40 NOT 30
BUT IT IS SIMILAR TO WHAT WE ARE
INFERRING FROM THE FIRST STUDY
AND THE APPEAL DB LOGIC DATA.
BUT ALSO WE FOUND THE FIRST TIME
WE REALLY LOOKED AT PRESSERS AND
A FEW OTHER NON- ANTIBIOTIC
DRUGS.
BUT IN THIS STUDY ROBERT PULLED
OUT ALL OF THE MEDICATIONS GIVEN
TO THE CHILDREN WITH CONTROL SO
NOT SURPRISINGLY ANTIBIOTICS
TENDED TO REDUCE THE DENSITY AND
THE PAPER HAS THE COLOR CODE
SOMETIMES THEY INCREASE THE
DENSITY BUT THESE DRUGS ARE NOT
ANTIBIOTICS.
VITAMIN D IS ON THEIR IRON IS ON
THERE.
THAT COULD ALTER A POPULATION
AND REALLY WE DO NOT LOOK AT
NON- ANTIBIOTIC DRUGS AS
INFLUENCING MICROBIAL CONTENT
BUT PROBABLY I SHOULD.
THERE IS SOME DATA FROM OLD
LITERATURE NOT JUST ANTIBIOTICS
THAT AFFECT THE MICROBES.
A COUPLE OTHER SPINOFF SETS OF
DATA.
WHAT I SHOWED YOU WITH THE
ABRUPTNESS THAT IS A RISK FACTOR
WERE A CHILD HAS WHERE NICK --
-- NEC WAS CUT LIKELY TO FOLLOW
AND THE SHIFTS SEEM TO BE
PRECIPITATED BY ANTIBIOTICS NOT
THAT SURPRISING THE EPISODE OF
NEC OCCURS 15 DAYS LATER AND
WHEN BUGS ARE REPOPULATED AFTER
SHIFT THERE IS MUCH MORE
RESISTANCE TO GENES IN THEM.
IS NOT JUST REPLACING IT NOT
JUST KNOCKING DOWN E. COLI AND
COMING BACK NOW YOU ARE REPLACED
BY MORE RESISTANT BUGS WHETHER
OR NOT THEY ARE PATHOGENS THAT
DEPENDS ON YOUR DEFINITION
HAVING BACTERIAL TRANSCRIPTION
COMPONENT IT DID ADD A LITTLE
MORE SENSITIVITY TO THE GENOMIC
COMPONENT IN THAT STUDY IN TERMS
OF RISK BUT IT WAS NOT MAJOR DNA
MUCH LESS EXPENSIVE TO SEQUENCE
THE AND RNA IS A GOOD
APPROXIMATION OF A POPULATION.
THIS WAS FASCINATING WITHIN
CENTERS WHAT WAS ISOLATED IT WAS
ISOGENIC YEAR AFTER YEAR AFTER
YEAR.
AND IN ST. LOUIS AND IN
LOUISVILLE AND OKLAHOMA HAVE
THEIR OWN UNIQUE.
STAFF WAS IDENTICAL BETWEEN
CENTERS ALMOST NO NUCLEOTIDE
DIFFERENCE BETWEEN THE STAFF AND
THE STOOL IN ST. LOUIS OR IN
OKLAHOMA.
NOW SENSE EVERYTHING IS NEW I DO
WANT TO SHOW 1 LITTLE HISTORICAL
FINDING THERE WAS A GROUP IN
ST. LOUIS SOME OF YOU MAY
RECOGNIZE THESE NAMES LIKE THE
PEDIATRIC INFECTIOUS DISEASES
DOCTOR INTO PEDIATRIC SURGEONS
CULTURED STOOL IN THE LATE
SEVENTIES FROM CHILDREN WITH NEC
AND I AM CERTAIN AND
EPIDEMIOLOGIST WOULD HAVE A
HEART ATTACK WHEN THEY SAW THIS
IS NOW A HIGH FREQUENCY OF
OCCURRENCE IN THE NICU AND THEN
NO CASES AND THEN TO STUDY THIS
1 AND THE DETAILS ARE GETTING
VAGUE BUT I THINK THEY WERE JUST
SWAPPING THE COLONIES.
IN PERIOD A GASTRIC JUICE AND A
LOT OF E. COLI.
B NONE IN THE STOMACH SOME IN
THE STOOL AND THEN BACK HERE
AGAIN THEY FIND SOMETHING.
IT IS HARD TO KNOW BUT WE WERE
NOT THE FIRST GROUP IN ST. LOUIS
TO ASSOCIATE GAMMA UP RODEO
BACTERIA WITH NECROTIZING
ENTEROCOLITIS.
I WANT TO RUN THROUGH THE
BLOODSTREAM INFECTIONS.
CHILDREN WHO HAVE A VERY HIGH
FREQUENCY OF BLOODSTREAM
INFECTIONS AND WHILE WE ARE
GATHERING ENOUGH STOOLS FOR THE
NEXT STUDY WE SAID LET'S DO A
PRELIMINARY BLOODSTREAM
INFECTION STUDY THIS WAS RUN BY
A MEDICAL STUDENT WHO MAJORED IN
BACTERIOLOGY IN COLLEGE AND JUST
TOOK TO THE PROJECT AVIDLY.
WE KNOW THIS CHILD HAS STREP IN
THEIR BLOOD LATE ON STREAM
INFECTIONS WHAT WE HAVE IN THE
FREEZER?
TWENTY STOOLS AND HE WOULD FIND
A DAY OR 2 BEFORE THE CHILD HAD
THE CLINICAL COLLAPSE TO CAUSE
THE BLOOD CULTURE GROUP B STREP
AS THE INFECTION THE CHILD DID
NOT LOOK SICK WITH NO LINES THEN
A SIMILAR STORY.
E. COLI THE CHILDREN HAD SEVERE
DETERIORATION 2 OR 3 WEEKS OF
AGE EVERY 1 OF THEIR STOOLS IN
THE FREEZER WAS FULL OF THE
EXACT SAME E. COLI AND WE HAVE
STOOL FROM 1 OF THEIR MOTHERS
AND THAT WAS ALSO FULL OF THE
EXACT SAME E. COLI.
SO NOW THIS IS A PARADIGM OF
BLOODSTREAM INFECTION IT MAY NOT
BE COMING FROM THE LINES ARE THE
VENTILATORS BUT IT COULD BE
COMING FROM THE GUT.
SO VERY BRIEFLY DURING HIS
FELLOWSHIP IN THE LAB SAID I
WILL DO THIS BETTER SO ON THE
LEFT IS WHAT MIKE DID CLASSIC
TIGER BIOLOGY YOU END UP WITH AN
ORGANISM AT THE END THAT IS VERY
SATISFYING AND SAID I WILL
SEQUENCE THIS AND FIND IT MYSELF
THROUGH STOOL CULTURE AND HE DID
EXTENDED IT TO 19 CASES OF
BLOODSTREAM INFECTION, 499
STOOLS AND WHEN HE HAD THE
BLOODSTREAM ISOLATE AND THE
SIGNAL EVIDENCE, EACH OF THE
ISOLATES WERE SEQUENCED AND
ISOGENIC SO HE CERTAINLY
CONFIRMED THE FINDINGS WITH VERY
GOOD TECHNOLOGY WITH 19
BLOODSTREAM INFECTION PATIENTS
COLONIZED IN THE STOOL THAT IS
THE ULTIMATE BIOMARKER THE
PATHOGEN GETS IN AND HANGS
AROUND AND THE PERSON GETS SICK
AND TOLD A CRASH INTERESTINGLY
11 OF THOSE 19 PATIENTS HAD 4
MORE THAT CARRIED THE
BLOODSTREAM AGENT POST ILLNESS
THEY WERE TREATED AND DID WELL
AND STILL HAVE THE PATHOGEN IN
THEIR STOOL.
THERE WERE A REASONABLE NUMBER
OF CONTROLS READ THE SAME
ORGANISM INCLUDING CHILDREN WHO
WERE BORN AND LIVED IN THE NICU
1 OR 2 YEARS EARLIER AND DID NOT
OVERLAP MAY BE INDIGENOUS
BACTERIA IN THESE UNITS AND
FINALLY NOTICING STATISTICALLY
INFECTIONS WERE INVERSELY
ASSOCIATED IN THE STOOL.
THEY JUST NOTED THIS CURIOUSLY
IN MARTY'S PAPER HE HAD A
QUOTATION THAT I COULD NOT GET
YESTERDAY OR I WOULD HAVE WENT
BACK TO THE SOURCE.
HE QUOTED A GROUP FOR THE PAS
SOCIETY 1977 WHERE A GROUP
CALLED STANLEY'S GROUP SAID
COLONIZATION IN THE STOOL IS
ASSOCIATED WITH INCREASED RISK
OF NECROTIZING ENTEROCOLITIS
WHILE COLONIZATION WAS
ASSOCIATED WITH DECREASED
INCIDENCE.
AND THERE IS SOME DATA FROM
HARVARD TO HAVE 2 UNRELATED
SPECIES INFLUENCING EACH OTHER
IN A MICROBIAL POPULATION.
I HAVE TIME TO TALK ABOUT
STRUCTURE OR FUNCTION CLAIMS OF
PROBIOTIC THE GASTROENTEROLOGY
FIELD WE LIKE TO COMMENT NOW WE
HAVE A NEW ORGAN IN OUR BODY WE
NEVER HAD UNTIL THE MICRO BIOME
DATA CAME OUT AND IT MAY BE IN
YEARS TO COME FOR THE BIOME
RESPONSES WILL BE A FUNCTION
THAT YOU CAN MEASURE BIOTICS
AGAINST.
THANK YOU.
[APPLAUSE]
>> SO THE NEXT SPEAKER WILL TALK
TO US ABOUT THE CURRENT STATE OF
EVIDENCE BUT THE USE OF PRODUCT
MARKETED AS PROBIOTICS.
>> I'M HERE TO TALK ABOUT THE
ELEPHANT IN THE ROOM.
MILLER FROM WASHINGTON
UNIVERSITY TALKING ABOUT THE
CURRENT STATE OF EVIDENCE FOR
PROBIOTICS AND A CLINICAL
IMMUNOLOGIST I LOVE ALL THINGS
MICRO BIOME.
NO DISCLOSURES OR CONFLICTS OF
INTEREST AND BRIEFLY MY GOAL
TODAY IS TO DO A SHORT
EXAMINATION OF THE PROBIOTICS
WITH THE MICRO BIOME THAT IN AND
OF ITSELF COULD BE A WHOLE
SERIES OF TALKS I WILL FOCUS ON
THE ISSUE DO THEY REALLY GET IN
THERE AND STAY AND THEN WHAT IS
THE INTERACTION IN THE CONTEXT
OF THIS IDEA OF TRAJECTORY THAT
WE JUST HEARD TO TALK ABOUT?
AND TO HIGHLIGHT THE IMPORTANCE
OF SPECIES THAT ARE USED TO
SUMMARIZE THE CLINICAL STUDIES
OF PROBIOTICS AND MAY BE A SHORT
LOOK AT THE FUTURE.
>> HERE JUST TO PRESENT THE DATA
I WILL BE FOCUSING ON THE HUMAN
DATA SO THE FIRST IDEA OF
ENGRAFTMENT ARE THE ORGANISMS
GETTING IN THERE AND STAYING
ALIVE SO THIS GOES BACK TO
STUDIES AT THE VERY BEGINNING OF
PROBIOTIC USE THE FIRST STUDY IS
PRESENTED HERE.
THEY GAVE PROBIOTIC STRAIN FOR 2
WEEKS AND THEN THEY CULTURE THAT
ORGANISM FROM THE STOOL AND THEY
HAD USE VERY SPECIFIC ANAEROBIC
CULTURES TO GET ACCURATE DATA
AND FOUND THAT YES LIVE BACTERIA
ARE IN THERE AND STAY IN THERE
FOR A LITTLE WHILE BUT THEN THEY
GRADUALLY DECREASE AFTER THE
INTRODUCTION OF ANTIBIOTICS.
WE HAVE ALL MOVED WELL BEYOND
THE USE OF CULTURES BUT THERE IS
BIAS IN ANY METHODOLOGY THAT YOU
HAVE SO FOR THE CULTURE -BASED
METHODS THOSE VERY OFTEN
ANAEROBES ARE HARD TO CULTURE
THEY ARE HARD TO PROCESS SO IT
IS PRONE TO NOT FINDING THINGS
AND WITH THE USE OF CULTURE
INDEPENDENT SEQUENCING THAT ALSO
HAS SOME BIAS ASSOCIATED 1 OF
THE QUESTIONS EARLY ON HIS ARE
WE JUST MEASURING DEAD?
IS THERE SOMETHING REALLY GOING
ON?
I THINK OVER TIME GIVEN THE FACT
WE SEE SUCH AN IMPACT ON BOTH
COMMUNITY STRUCTURE AND FUNCTION
AND THE ENGRAFTMENT THAT HAS
BEEN SHOWN TO CONTINUE ON PAST
THE USE OF ANTIBIOTICS WITH THE
ORGANISM YOU ARE USING CAN STAY
BEYOND THE STATE FOR MANY
MONTHS.
SO I WOULD SAY IN SUMMARY THEY
ARE ALIVE AND KICKING AND
STICKING IN THERE.
WHAT ARE THEY DOING?
HOW DO THEY IMPACT THIS
TRAJECTORY AND THIS PATTERN THAT
WE JUST HEARD PHIL TALK ABOUT?
THERE IS A LITTLE BIT OF
VARIATION IN THE DATA AND NOW IN
THE LAST FEW YEARS, AGAIN IT MAY
VARY DEPENDING ON THE ORGANISM
YOU ARE LOOKING AT THAT THERE IS
A THEME THAT YOU HEAR THROUG
THROUGHOUT.
BUT OVERWHELMINGLY THE DATA
SHOWS THAT IT DOES ADVANCE
MATURATION.
THEY TEND TO BE THE DRIVERS OF
THAT AND ACCELERATE PROGRESSION
OF THE MATURATION OF THE GUT
MICRO BIOME.
THERE IS SOME DATA THAT SAYS IT
DOES NOT ADVANCE MATURATION IT
MOVES THINGS AROUND AND CHANGES
SPECIFIC BACTERIA BUT THAT
PATTERN OF PROGRESSION CONTIN
CONTINUES.
I WILL GIVE YOU 1 EXAMPLE.
IT'S BUSY BUT IT IS AN EXAMPLE
OF THE MATURATION AFFECT.
CHRISTOPHER STEWART'S GROUP OUT
OF THE UK JUST RECENTLY
PUBLISHED AND THEY TOOK 123 VERY
LOW BIRTH WEIGHT BABIES WITH NO
PATHOLOGY.
IN FACT THEY WERE STUDYING OVER
A 10 YEAR PERIOD ALL BABIES IN
THE NICU.
FROM THAT GROUP PULLING 123
CASES OF SEPSIS TOOK ADVANTAGE
OF A NATURAL EXPERIMENT GOING ON
AT THE TIME.
THROUGH 2011 AND 2013 THEY DID
NOT USE ANY ANTIBIOTIC -- -- IN
A BIOTICS 2014 THROUGH 16 THEY
INTRODUCED TO ORGANISMS AND THEN
WHEN THAT PRODUCT WAS NO LONGER
AVAILABLE THEY MOVE TO
ADDITIONAL PRODUCT AND ADDED ON
THE SAME TO BASIS BUT THEN THE
FINAL PRODUCT ADDED A VERY
SPECIFIC ADDITIONAL SPECIES TO
WHAT THEY WERE SEEING SO THEN
THEY FOLLOWED THE INFANTS OVER
THE COURSE OVER THE FIRST 69
DAYS 0 THROUGH 69 COLLECTING
STOOL SAMPLES.
THEY FIRST TOOK ALL OF THE STOOL
SAMPLES AND WERE ABLE TO
CLASSIFY THE COMMUNITY TYPES
INTO 5 DISTINCT COMMUNITY
TYPES.
AND THEN THEY LOOKED AT THE
INFANTS AND HOW OVER TIME THEY
DEVELOP THEIR GUT MICROBIAL
COMMUNITY ACROSS ALL OF THE
DIFFERENT TIME COMPONENTS THE
INFANT STARTED OUT WITH THE
COMMUNITY TYPE I AND THAT IS
WHAT WE SAW THAT PHIL TALKED
ABOUT A LOT OF THE GRAM-POSITIVE
BACILLI WITH THE STAFF SPECIES
THAT WERE PRESENT AND IN THE
KNOW PROBIOTIC AREA THE INSTANCE
MATURED INTO A COMMUNITY TYPE
THAT IS DOMINATED BY GAMMA
BACTERIA.
AND THEN THEY INTRODUCED INTO
THE POPULATION THE USE OF
PROBIOTICS YOU CAN SEE A SHIFT
OF HOW THE INFANTS MOVE THROUGH
COMMUNITY MEMBERSHIP TOWARD THE
COMMUNITY TYPE 5 AND THIS IS
DISCRIMINATED BY THE PRESENCE OF
BACTERIA THAT WAS NOT EVEN
PRESENT IN THE PRODUCT THAT THEY
USE THEY TRY TO CULTURE THAT OUT
BUT IT'S NOW PRESENT AS WELL AS
INTO CAUCUS AND BYRON ELLA NOW A
LITTLE BIT CLOSER TO THE TERM
BREAST-FED BABY STOOL AND THEN
THEY FINALLY INTRODUCED THE
THIRD PRODUCT, THE COMMUNITY
PROFILE MOVED TOWARD A MORE
DOMINANT TYPE WHICH IS MUCH
GREATER DIVERSITY OF BACTERIA
AND LACTOBACILLI WHICH WAS MUCH
CLOSER STATISTICALLY TO A TERM
INFANT BEING FED BREASTMILK.
I THINK YOU CAN SAY THE
EVOLUTION OF THE GUT MICROBIAL
COMMUNITY VARIES BY THE PRODUCT
YOU ARE USING NOT ONLY GENUS BUT
SPECIES AND STRAIN IS VERY
IMPORTANT IN THE PROCESS AND IT
ACCELERATED MATURATION CLOSER TO
A TERM PROFILE.
SO REALLY WE ARE TALKING ABOUT
THIS TERRIBLE DISEASE
NECROTIZING ENTEROCOLITIS WHAT
DOES THAT HAVE TO DO WITH NEC?
I WILL GO BACK TO THE EARLIER
INFORMATION THAT WAS MENTIONED
ABOUT THE DIFFERENT SURVEYS AND
A COUPLE OF PEOPLE HAVE TALKED
ABOUT THE SURVEYS AS WELL.
THIS IS FROM 2023 A LOT OF
DIFFERENT PRODUCTS HE SAW WERE
BEING USED SO ON THE X AXIS IS A
DIFFERENT PRODUCT AND THEN THE
NUMBER OF NICU.
A LOT OF VARIATION AS TO WHAT
PRODUCTS ARE BEING USED.
LOOK AT THE TOP 3 TAKE A CLOSER
LOOK THE MOST COMMON IS A
COMBINATION OF FACTORS THE
SECOND THE VARIATIONS IN
ADDITION TO VARIATIONS OF
PRODUCTS LOTS OF VARIATION IN
ADMINISTRATION.
SOME OF THE NIC GAVE IT TO ALL
BABIES UNDER 35 WEEKS YOU CAN
SEE THE DISTRIBUTION BY WEEKS
SUMMIT 34, 33, 32 LOTS OF
VARIATIONS.
THE DIFFERENCES IN TERMS OF THE
FEEDING TYPE SOME GAVE IT TO
EVERYBODY SOME WAS JUST
BREASTMILK OR FORMULA AND SOME
PLACES GAVE IT AND PO ALSO
DIFFERENCES OF TIMING.
WHEN YOU TAKE THE TOP 3 LOOK AT
THE DATA FOR THE INDIVIDUAL
SPECIES THOSE INDIVIDUAL
PRODUCTS AND WE ARE LOOKING NOW
AT CLINICAL DATA AND LOOKING FOR
RANDOMIZED CONTROL TRIALS AND
GOOD EPIDEMIOLOGIC STUDIES THAT
DATA IS LESS ROBUST THAN WE WILL
SEE AND META-ANALYSIS.
IT DOES NOT MEAN THERE IS NOT
ADDITIONAL SAFETY DATA OUT THERE
OR ENGRAFTMENT DATA BUT THIS IS
PARTICULARLY FOCUSED ON THE
CLINICAL TRIALS.
SO IN THE FIRST CATEGORY THE
MOST COMMONLY USED THE LARGEST
RANDOMIZED CONTROLLED TRIALS FOR
THE USE OF PROBIOTICS IS OVER
1000 BABIES AND IT SHOWED A
54 PERCENT REDUCTION OF THE NEC
GREAT A VERY LOW BIRTH WEIGHT
BABIES.
IN THE SECOND TYPICALLY IT WAS
USED IN COMBINATION WITH 57
STUDIES USED IN VARIOUS
COMBINATIONS AND THERE IS A
STUDY A RETROSPECTIVE ANALYSIS
FROM 2014 WHICH HAD A HIGH
NUMBER OF BABIES ALMOST 500 THAT
SHOWED A DECREASE OF NEC ALONG
-- -- AMONG THE VLBW GROUP.
I KNOW 1 OF THOSE AUTHORS ARE
HERE SO THAT MAY COME UP LATER.
THEN THE THIRD MOST COMMON IS A
COMBINATION OF VARIOUS
COMBINATION OF CLINICAL STUDIES
THERE WAS 1 RANDOMIZED
CONTROLLED TRIAL IN 2022 WHICH
IS A VERY HIGH RISK RATIO BUT
VERY LARGE CONFIDENCE
INTERVALS.
ALSO ADDITIONAL STUDIES THAT
SHOW DECREASES OF RATES.
SO THE DATA IS VARIABLE ON A
SPECIFIC FORMULATION SO 1 OF THE
THINGS THAT WE DO IN THAT CASE
IS TRIED TO PULL THE DATA AND
LUMP IT TOGETHER TO GET
ADDITIONAL INFORMATION.
SO LOOKING AT THE SYSTEMATIC
REVIEWS OF META-ANALYSIS MANY
HAVE BEEN DONE AS THIS GRAPH
DEMONSTRATES AND THERE ARE LOTS
OF VERY GOOD STUDIES THROUGH
THIS ANALYSIS OVER THE YEARS
PARTICULARLY THE LAST FEW
YEARS.
I WANT TO USE OUR PLATFORM THAT
IS RELATIVELY CURRENT AND
INCLUSIVE OF ALL THE DIFFERENT
VARIOUS PROBIOTIC COMPONENTS
THAT EVALUATED FOR BIAS AND ALSO
INCLUDED A SENSITIVITY ANALYSIS
PULLING OUT JUST THE HIGHEST
QUALITY STUDIES.
SO I WILL USE THE REVIEW AS THE
BASE TO GET THROUGH SOME OF
THESE CLINICAL TRIALS.
JUST PUBLISHED 2023 IT MET ALL
MY CRITERIA AND VERY
SPECIFICALLY LOOKED AT ISSUES OF
DESIGN QUALITY AND STUDY
MUTATIONS USING THE 6 DIFFERENT
COMPONENTS SELECTION AND
NUTRITION BIAS AND IT INCLUDES
60 TRIALS WITH OVER 11000
BABIES.
A LOT OF BABIES.
I THINK WE HAVE SEEN THE SUMMARY
SLIDE EARLIER.
LOOKING AT NEC MORTALITY LATE
ONSET INFECTIONS AND FIRST
DESCRIBES IT IN TERMS OF THE
ABSOLUTE EFFECT SO 60 PER 1000
IS A RISK OF 6 PERCENT VERSUS
THE PROBIOTIC GROUP OF
3.3 PERCENT SO IN TERMS OF
GETTING AN IDEA OF WHAT THAT
RISK DIFFERENCES IN THE
MAGNITUDE OF THAT SOMETIMES THAT
IS HARD TO TELL IN THE RISK
RATIO.
IT IS 2.7 PERCENT WHICH WHEN THE
NUMBERS ARE FAIRLY LOW OVERA
OVERALL, CAN BE A FAIRLY
SIGNIFICANT IMPACT.
SHOWING A RISK RATIO OF
0.5436 PERCENT REDUCTION IN THE
RATE OF NEC FOR ALL CAUSE
MORTALITY AND THEN ON THE FAR
LEFT THAT RISK DIFFERENCES
1.5 PERCENT AND IT IS ABOUT 12
OR 23 PERCENT DECREASE IN RATE
AND AGAIN MUCH LOWER ONCE AGAIN
FOR LATE ONSET SEPSIS.
QUALITY OF THE EVIDENCE VARIED
AND THE OFFICE CONCLUSION IS
THAT PROBIOTICS MAY REDUCE THE
RISK OF NEC WITH LOW CERTAINTY.
IT PROBABLY REDUCES THE OVERALL
MORTALITY WITH MODERATE
CERTAINTY AND IT PROBABLY HAS
LITTLE OR NO EFFECT ON THE RISK
OF LATE ONSET SEPSIS WITH
MODERATE CERTAINTY.
SO HOW COULD IT BE WE HAVE 11000
BABIES ENROLLED IN THE STUDIES
AND WE HAVE ONLY HAVE THAT
CERTAINTY IN TERMS OF THE EFF
EFFECT?
ONE OF THE CONCERNS RAISED WAS
THE CONCERN AROUND PUBLICATION
BIAS AND THE BOTTOM LINE IS IT
IS SUPPOSED TO BE SYMMETRIC IF
THERE'S NO EVIDENCE OF
PUBLICATION BIAS IT DOES HAVE A
SYMMETRY FAVORING PUBLICATION OF
POSITIVE STUDIES THAT SHOWED THE
TREATMENT EFFECT COMPARED TO THE
CONTROLS.
YOU CAN DO STATISTICAL ANALYSIS
AND THAT WAS SIGNIFICANT.
SO NOW LET'S TAKE A LOOK AT THE
LUMPING OF THESE DIFFERENT
PRODUCTS BY A GENUS LEVELS.
SO I WILL FOCUS ON THE 3 MOST
COMMONLY USED AND WHAT I HAVE
DONE AT THE TOP I JUST MADE IT
EASIER FOR ALL OF US TO SHOW A
COMPARISON BETWEEN THE PROBIOTIC
AND THE CONTROL THE NUMBERS OF
NEC CASES AND THE NUMBER OF
BABIES AND THE FINAL COMPILED
RISK RATIO AND FOR A COMBINATION
OF BACTERIA SPECIES THE RISK
RATIO WAS 0.36 WHICH WAS
SIGNIFICANT AND INCLUDED THIS
OTHER TRIAL AND WE WILL TALK
ABOUT THAT IN MORE DETAIL THE
SECOND MOST IS THE BACTERIA
SPECIES IN ISOLATION AS A SINGLE
ORGANISM PROBABLY DOUBLE THE
NUMBER OF SUBJECTS AND SHOWED
ALMOST 30 PERCENT DECREASE OF
NEC RISK AND STILL WAS
SIGNIFICANT AND IT CONTAINS THIS
PIPS TRIAL SO I POINT OUT THE
TRIALS PRIMARILY BECAUSE OF THE
QUALITY THEY PROVIDED THEY WERE
THE HIGHEST CASE NUMBERS OVER
1000 IN EACH SO IF YOU ARE ALL
GREEN YOU DON'T HAVE ANY
IDENTIFIED BIAS IN YOUR STUDY
YELLOW IS NOT SO GREAT AND
YELLOW IS PRETTY BAD THERE ARE
SOME SMALLER STUDIES THAT ARE
PRETTY GREEN BUT MUCH SMALLER
COMPARED TO THESE 2 SO LET'S
TAKE A CLOSER LOOK SO THIS IS
FROM THE UK USING DIFFERENT
BACTERIA 1 WAS IN AUSTRALIA AND
NEW ZEALAND USING A COMBINATION
THE PRIMARY OUTCOME OF PIPS WAS
FOCUSED ON A COMPOSITE OUTCOME
WHERE AS THOSE THAT WERE LOOKING
AT LATE ONSET SEPSIS WAS THE
PRIMARY OUTCOME THE PIPS TRIAL
FOUND NO DIFFERENCE EITHER IN
THE PRIMARY OUTCOME OR NEC THERE
WAS NO DIFFERENCE OF LATE ONSET
SEPSIS OR MORTALITY BUT THEY DID
FIND A DECREASE OF NEC YOU CAN
SEE THAT FOR VERY LOW BIRTH
WEIGHT BABIES AGAIN IT WAS SEEN
WITH THE META-ANALYSIS AND FOR
THE EXTREME LOW BIRTH WEIGHT
BABIES THEY WERE ABLE TO HAVE NO
SIGNIFICANT DIFFERENCE WITH
ENCOMPASSING AND THEY HAD OVER
500 BABIES ARE NEARLY 500 AND
EACH OF THE STUDIES.
1 OF THE THINGS WE HEARD A
LITTLE BIT ABOUT EARLIER IN THE
DAY IS CROSSOVER THAT WHEN YOU
GIVE THE PROBIOTIC NOT ONLY
OTHER TREATED GROUPS GOING TO
HAVE A BIT YOU WILL HAVE IT IN
THE CONTROLS AS WELL AND IN THE
PIPS STUDY 35 PERCENT OF THE
CONTROLS WERE COLONIZED WITH THE
ORGANISM.
THIS IS THE ONLY STUDY I FOUND
THAT ACTUALLY TRIED TO ADDRESS
THIS ISSUE AND WE CATEGORIZE THE
CHILDREN BY THEIR COLONIZATION
STATUS.
AND THEY FOUND NO DIFFERENCE IN
THE RISK OF NEC.
SO THEN THE LAST CATEGORY OF
ORGANISMS COMBINED WITH
LACTOBACILLUS SHOWS A
SIGNIFICANT DECREASE FOR NEC.
NO EFFECTS ON THE REMAINING
ORGANISMS UP ON THE SLIDE IF YOU
TAKE THE STUDIES AND PUT THEM
TOGETHER FOR VERY LOW BIRTH
WEIGHT BABIES THOSE WITH ALMOST
A 50 PERCENT RISK OF AN EC THEN
YOU CAN SEE THOSE INTERVALS AND
IT IS SOMEWHAT REASSURING THAT
THE OVERALL AVERAGE RATE OF NEC
WAS 16 WHAT ARE THE CRITICISMS
IS THAT THE CONTROL GROUP HAS
SUCH A HIGH RATE OF NEC - - OF
NEC THEY WERE NOT MEASURING IT
CORRECTLY BUT AT LEAST IN THIS
COMBINED ANALYSIS IT IS SIMILAR
TO WHAT WE WOULD HAVE EXPECTED.
SO NOW THEY PULLED OUT ALL THE
STUDIES THAT WERE HIGHEST
QUALITY AND THEY LOOKED AT THOSE
AND NOW THEY ARE COMBINING ALL
THE DIFFERENT PROBIOTICS AND THE
IMPACT DROPS BUT IT DOES REMAIN
SIGNIFICANT WITH THE RISK RATIO
OF 0.7.
AND FOR MORTALITY OVERALL
MORTALITY VERY LOW BIRTH WEIGHT
I DID HAVE A 23 PERCENT DECREASE
WHICH WAS LOST IN SENSITIVITY
ANALYSIS AND NOT EVIDENT WITH
LOW BIRTH WEIGHT BUT LATE ONSET
SEPSIS NO SINGLE 1 GROUP SHOWING
AND AFFECT THE OVERALL DECREASE
WAS 11 PERCENT LOSS TO THE
SENSITIVITY ANALYSIS NOT EVIDENT
IN THE EXTREMELY LOW BIRTH
WEIGHT AND IN THIS GROUP OF
STUDIES NO ADVERSE EVENTS WERE
REPORTED.
LET'S PULL OUT THE EXTREMELY LOW
BIRTH WEIGHT BABIES BECAUSE WHO
GETS NEC UNDER 1000 GRAMS THEY
HAVE THE HIGHEST RATE NOT JUST
HAVING NEC BUT THE HIGHEST RATE
OF MORTALITY.
WHEN YOU LOOK AT THE STUDIES AT
EACH GENUS EVALUATED THERE WAS
NO SIGNIFICANT IMPACT ON NEC AND
WHEN YOU PUT THEM TOGETHER THE
RISK RATIO IS 0.92 WITH THE
CONFIDENCE INTERVAL OF 1 SO FOR
EXTREMELY LOW BIRTH WEIGHT
BABIES UNDER 1000 GRAMS NO
EFFECT LATE ONSET SEPSIS OR
MORTALITY.
NOW I WILL GO BACK TO THE REAL
WORLD OUT OF THESE CONTROL
TRIALS BACK TO A STUDY PUBLISHED
OUT OF THE VERMONT OXFORD
NETWORK OVER 300,000 BABIES AND
THEY LOOKED AT THE YEAR 2012
THROUGH 2019 AND THEY WERE
COMPARING ESTIMATES OF CHANGE OF
ANY SEE OUTCOME BY YEAR IN
HOSPITALS THAT ADOPTED
PROBIOTICS AND THOSE THAT DID
NOT.
AND OF THE OUTCOMES NEC
MORTALITY IN LATE ONSET SEPSIS
THE ONLY 1 THAT YOU CAN SEE
GRAPHICALLY IS A DECREASE OF NEC
RATES AND 18 PERCENT AND EACH OF
THESE ARE REGRESSION
COEFFICIENTS ACCOUNTING FOR 6
DEFECTS OF HOSPITAL, TIME AND
THE CHARACTERISTICS THEY DID NOT
ACCOUNT FOR TEMPORAL CHANGES IN
HOSPITAL.
THE ASSUMPTION WAS THAT IF
PROBIOTICS WERE NOT INTRODUCED
THEN THEY WOULD HAVE MAINTAINED
THE SAME TRAJECTORY OVER THAT
TIME PERIOD.
WE COULD ARGUE IF THAT IS TRUE
OR FALSE BUT THEY DID INDICATE
THESE TRENDS OVER TIME WERE
RELATIVELY STABLE PRIOR TO THE
USE OF PROBIOTICS AND THEY FOUND
THE ODDS RATIO 0.82 AND NO
IMPACT OF SEPSIS OR MORTALITY.
TO MAKE IT EASIER TO COMPARE
THERE IS CONVERSION TO RISK
RATIO THE NUMBERS ARE A LITTLE
DIFFERENT AND THE REVIEW RISK
RATIO FOR VERY LOW BIRTH WEIGHT
BABIES IS 0.5 FOR THE
SENSITIVITY ANALYSIS IS 0.7 AND
AN EXTREMELY LOW BIRTH WEIGHT
BABIES 0.92 IN THE VERMONT
OXFORD STUDY THE RISK RATIO WAS
MORE SIMILAR TO WHAT WAS
REPORTED ON THE SENSITIVITY
ANALYSIS AND ON THE COMBINED LOW
BIRTH WEIGHT OUTCOME ANALYSIS.
AND AGAIN NO DIFFERENCE FOUND
FOR EXTREMELY VLBW BABIES SO THE
BENEFIT WAS SMALLER THAT WAS
REPORTED IN META-ANALYSIS.
IT WAS SIMILAR TO WHAT WAS
EVIDENT IN THE SENSITIVITY
ANALYSIS.
BUT THE EVIDENCE FOR EXTREMELY
VLBW BABIES WAS WE CANNOT
SIGNIFICANT.
IT ALSO HIGHLIGHTS THE NEED TO
MONITOR PROBIOTICS AS THEY MOVE
OUT OF THESE TIGHTLY CONTROLLED
CLINICAL TRIALS TO CONTINUE TO
EVALUATE THEIR EFFICIENCY AND
EFFECT.
SO WHAT IS COMING UP?
WENT TO CLINICAL TRIALS.GOV AND
I PULLED OUT NOT EVERY SINGLE
STUDY THAT AT LEAST HAD TO POST
IN THE LAST 10 YEARS THEY WERE
RECRUITING ARE NOT YET STARTING
TO RECRUIT OR RECENTLY COMPLETED
THESE ARE THE STUDIES THAT WERE
PRESENT AND THE LARGEST STUDY
1600 BABIES IS IN THE
NETHERLANDS AND SPECIFICALLY
TARGETS BABIES BETWEEN 22 AND 28
WEEKS THE END DATE IS SLATED
2026.
THERE IS AN ADDITIONAL STUDY IN
PAKISTAN WITH SAFETY AND
TOLERABILITY STUDY.
IN ADDITION THERE ARE MANY
PRIVATE COMPANIES AS WELL AS
ACADEMIC CENTERS WORKING ON
ENGINEERING WHICH YOU DON'T HAVE
TIME TO GO INTO THE POTENTIALLY
ARE SAFER AND MORE EFFECTIVE.
I WILL SKIP MY SUMMARY FOR THE
SAKE OF TIME.
WE HAVE ALL HEARD IT.
WEIGH THE RISKS AND BENEFITS SO
I WILL END WITH THE THANK YOU
FOR ALL OF THE FAMILIES WHO HAVE
PARTICIPATED.
WITHOUT THEM WE WOULD KNOW
NOTHING AND YOU REALLY DO MAKE
IT BETTER FOR THE NEXT
GENERATION OF BABIES TO COME.
THANK YOU.
[APPLAUSE]
>> THANK YOU DOCTOR WARNER WE
APPRECIATE YOUR PRESENTATION OF
NEXT PROFESSOR OF PEDIATRICS
DIVISION OF INFECTIOUS DISEASE
AT THE SCHOOL OF MEDICINE AND WE
WILL TALK ABOUT CLINICAL TRIAL
DESIGN CONSIDERATIONS IN THE
NICU.
>> THANK YOU VERY MUCH AND TO
THE ORGANIZERS FOR THIS
OPPORTUNITY.
SINCE MY TIME WAS CHANGED I TOOK
THE LIBERTY OF CHANGING THE
TITLE.
HOPEFULLY IN THE NEXT 20 MINUTES
I CAN CONVINCE YOU OF THE
CHALLENGES AND MANY OF THEM HAVE
ALREADY BEEN DISCUSSED AS WELL.
AS MENTIONED I HAVE THE
PRIVILEGE OF WORKING WITH
MR. PATEL FOR MANY YEARS AND
ALSO 1 OF THE INFECTIOUS DISEASE
FELLOWS SO WE ARE PROUD OF HIS
ACCOMPLISHMENTS.
AND I WILL TALK ABOUT 2 THINGS
ABOUT DOING CLINICAL TRIALS IN
THE NICU AND ALSO PREPARING FOR
JOE'S TALK OF THE CHALLENGES OF
USING LIVE BIOTHERAPEUTICS AND
DOING STUDIES WITH THOSE.
DISCLOSURES RECEIVING TRAVEL
SUPPORT THE ASSOCIATION FOR
PROBIOTICS AND PREBIOTIC'S AND
THAT RELATIONSHIP HAS ENDED AS
WITH OTHER SPEAKERS THE VIEWS
EXPRESSED ARE MY OWN AND DO NOT
REPRESENT THOSE OF MY EMPLOYER.
AND SO WE HAVE REALLY LEARNED
WHAT WE REALLY NEED IS TO HELP
INFORM DECISION-MAKING.
OFTEN TIMES GETTING THAT CAN BE
CHALLENGING AND THAT HAS BEEN
EXPRESSED.
AND ALSO TO HAVE A STUDY DESIGN
FLEXIBILITY 1 OF THE MESSAGES
THEY WANT TO LEAVE YOU WITH.
AND TO THINK OF THE GOLD
STANDARD AND DEVELOPING
INFORMATION AND IT IS EXCITING
WITH NEW LIFE BIOTHERAPEUTICS
PRODUCTS ALSO ABOUT NEW AND
CHALLENGING WAYS OF DOING
STUDIES.
OFTEN TIMES ENROLLMENTS ARE TIME
SENSITIVE UNFORTUNATELY YOU HAVE
A VERY COMPLEX INFORMED CONSENT
PROCESS THAT CAN BE VERY
CHALLENGING FOR FAMILIES AS
WELL.
AND THEN WE DO HAVE THE
PRIVILEGE OF FOLLOWING BABIES
FOR A LONG PERIOD OF TIME SO WE
COULD LOSE TOUCH AFTER THEY ARE
TRANSFERRED FROM CENTER TO
CENTER THAT ALSO RELATES TO
LONG-TERM FOLLOW-UP.
AND WITH THE ENDPOINTS.
AND THOSE STATISTICS ARE
CHALLENGING AND THEN ANOTHER
HUGE CHALLENGES ADVERSE EVENT
ADJUDICATION.
AND SOMETHING THAT TRANSPIRES AS
THE ADVERSE EVENT OR IS IT
SOMETHING THAT IS RELATED TO THE
UNDERLYING POST?
WE SPENT A LOT OF TIME TALKING
ABOUT DEFINITIONS SO WHEN WE ARE
CONDUCTING STUDIES IT'S
IMPORTANT TO KNOW THE IMPORTANCE
OF USING THERAPEUTIC THAT HAS
DIFFERENT IMPACTS.
AND WITH THE MEASUREMENT
APPROACHES IN TERMS OF
OUTCOMES.
AND THEN WHAT WE WANT TO SHOW IS
A THERAPEUTIC BENEFIT AND THAT
REQUIRES INVALIDATED EFFICACY.
AND THERE IS SOME HOPE SO I WANT
TO MENTION SPECIFICALLY RELATED
TO ADVERSE EVENTS WHICH SEEMS TO
BE AN IMPORTANT CHALLENGE AND
THE ADVERSE EVENTS WAS DEVELOPED
IN 2019 BY THE INTERNATIONAL
NADEL CONSORTIUM AND BASICALLY
IT WAS A SCALE DEVELOPED WITH
THE VALIDATION AND BASICALLY TO
ASSESS THE IMPACT OF VARIABILITY
AND WHAT THEY DID WAS DEVELOP
THIS TO ASSESS RELIABILITY THAT
IS SHOWN WITH THE NICU
INTERNATIONALLY.
AND WITH THE TRIAL PROTOCOLS BUT
IT'S NOT COMPLETE THE PLANS TO
FURTHER REFINE AND STANDARDIZE
WITH ADDITIONAL COVERAGE.
THIS SLIDE YOU SHOWS A
SCREENSHOT TO HAVE A DEFINITION
OF NECROTIZING ENTEROCOLITIS FOR
ADVERSE EVENTS SO THIS IS FROM
THE ORIGINAL PUBLICATION IN 2019
BUT THERE IS AN EVOLUTION GOING
ON MORE AND MORE ADVERSE EVENTS
ARE BEING ADDED.
WITH THE STRUCTURE OF
REPORTING.
AND MEASURING EFFICACIES SO WITH
THE CHARACTERISTICS OF THE
POPULATION THERE IS LOTS OF
VARIABILITY AND THAT IS
DEVELOPING BETTER CARE AND WHEN
YOU HAVE TO ACCOUNT FOR SOME OF
THOSE CHANGES IN DOING STUDIES
AND DOING ANALYSIS AND CHANGES
OF REFERENCE AND HOW DO WE
MEASURE A MEANINGFUL CLINICAL
BENEFIT?
AND IT FEELS FUNCTIONS AND THEN
NEONATAL POPULATION WE DO HAVE
SOME OPPORTUNITIES TO ASSESS
FUNCTION AND SURVIVAL AND THEN
MORTALITY AND MORBIDITY OUTCOMES
ARE FREQUENTLY LOOKED AT BUT
HOPEFULLY THAT IS OVER A PERIOD
OF TIME SO 1 OF THE THINGS WE
CAN DO AND THINKING ABOUT IT
CLINICIANS AND FAMILY MEMBERS
AND OTHER STAKEHOLDERS THAT ARE
CLINICALLY RELEVANT.
LOOKING AT COMPOSITE OUTCOMES.
AND THEN TO ADDRESS THE
OUTCOMES.
AND LOOKING AT THE NET BENEFIT
OF THERAPY AND ANOTHER BENEFIT
STATISTICALLY ESPECIALLY WITH
MISSING DATA OR INDIVIDUAL
COMPONENTS SO IF YOU EQUALLY
WAGE THE COMPONENTS BUT THE
EQUAL WEIGHTING YOU NEED TO
CONSIDER THAT AS WELL.
AND THEN THOSE ARE MUCH MORE
CHALLENGING.
WHAT CAN WE DO TO OPTIMIZE
EFFICIENCY?
THIS IS GETTING US AWAY AND THEN
HOW WE CAN DESIGN TRIALS TO
PRESENT WITH MEANINGFUL
BENEFITS.
CAN WE ADOPT MONSTER PROTOCOLS
TO REINVENT THE WHEEL TO ADAPT
PROTOCOLS THAT HAVE BEEN
RELEASED.
CENTRALIZING IRB A NUMBER OF
LOCATIONS AND ACTUALLY FEDERAL
RESPONSIVE STUDIES AND THEN
USING REAL-WORLD DATA TO
GENERATE REAL-WORLD EVIDENCE.
SOME TRIAL DESIGN STRATEGIES
THAT ARE NOT NEW ANY MORE
SOMETHING THAT HAS BEEN LOOKED
AT VERY CLOSELY BUT THAT IS THE
APPROACH OF PRIOR PROBABILITIES
THAT THE EVENT WILL OCCUR AND
THE ADVANTAGE OF USING
STATISTICS THAT YOU CAN FORMALLY
INCORPORATE RESULTS THAT HAVE
BEEN DONE ON OTHER STUDIES AND
YOU CAN ACTUALLY UPDATE AS THE
EVIDENCE ACCRUES AND THAT HELPS
YOU WITH THE WEIGHTS OF BENEFITS
AND HARMS THAT IS WHAT WE
TRADITIONALLY THINK ABOUT AND 1
OF THE CHALLENGES WITH THIS
APPROACH AND THERE IS SOME
ARBITRARY THRESHOLDS THAT HAVE
TO BE DECIDED UPON AT THE
TRIAL.
I CANNOT EMPHASIZE THIS ENOUGH.
TO ENGAGE STAKEHOLDERS AND
PARENTS AND CAREGIVERS AND
ADVOCACY GROUPS ARE CRITICAL
THIS IS SOMETHING WE WANT TO DO
AT THE TIME TO THINK ABOUT
ENGAGING NURSES OR PSYCHOLOGISTS
IT COURSE THE REGULATORY FUNDING
AGENCIES AND INDUSTRY
PARTNERSHIPS WHICH IS SO
CRITICAL.
WAS STATISTICIANS NEED TO BE
INVOLVED FROM THE BEGINNING AND
INCLUDING THE MAD ASSIST WITH A
TREMENDOUS AMOUNT OF DATA TO PUT
TOGETHER IN SOME MEANINGFUL WAY
WHETHER THE USE OF ARTIFICIAL
INTELLIGENCE OR OTHER MACHINE
LEARNING REALLY INVOLVING TO BE
VERY BENEFICIAL.
ALL OF THIS ENGAGEMENT HELPS TO
INFORM TRIAL DESIGN WITH
MEANINGFUL AND POINTS WITH
ENGAGEMENT IN RECRUITMENT AND
THEN ALSO HOPEFULLY WILL HELP US
PREDICT BARRIERS TO OVERCOME IN
ADVANCE OF IMPLEMENTING THE
TRIAL AND RESOURCES.
>> I JUST WANT TO HIGHLIGHT THE
INTERVENTION WHICH I THINK IS
INTERESTING.
AND THIS WAS AN INTERVENTION
MAPPING.
BUT THE SYSTEMATIC PROCESS TO
LOOK AT A PROTOCOL AND THEN THE
KEY POINT ABOUT THIS BRIEF
INTERVENTION WITH RESEARCH TEAM
MEMBERS TO GET FEEDBACK AND THE
APPROACH INCLUDING FEEDBACK FROM
FAMILY MEMBERS ABOUT THE UTILITY
OF VARIOUS COMPONENTS TO BE
PERCEIVED AND OPTIMIZE AND IT IS
OUTSIDE OF THE REALM OF WHAT WE
TRADITIONALLY THINK ABOUT AND
THAT CAN BE REALLY HELPFUL
ESPECIALLY IF THERE ARE
CHALLENGES IN THE MOMENT.
TAKE ADVANTAGE AND LEVERAGING
THE NEONATAL NETWORKS AND THERE
ARE MANY MORE AND AND THEN
ACROSS THE GLOBAL BORDERS AND
SOME OF THESE GROUPS IN THE
RESEARCH NETWORKS COULD BE
EXTREMELY BENEFICIAL HOPING TO
WORK THROUGH INFRASTRUCTURE
ISSUES.
AND WITH THOSE CHALLENGES OF
CLINICAL DESIGN THERE IS A LOT
OF VARIABILITY AND REPORTING OF
OUTCOMES AND THEN DESCRIBE THAT
WITH THAT META-ANALYSIS WITH A
HAS BEEN DEVELOPED IS THE
NEONATAL OUTCOMES THAT AND
BASICALLY THIS IS A SET OF
OUTCOMES AGREED-UPON FOR OTHER
INDIVIDUALS CLINICALLY IMPORTANT
THAT SHOULD BE ASSESSED AND THEN
NEONATAL TRIALS.
IN THE SEPTEMBER EDITION OF
PEDIATRICS THAT RELATE TO THE
NEONATAL OUTCOME AND HOW THEY
CAN BE USED AND 1 OF THE
MANUSCRIPTS TOOK 36 NEONATAL
TRIALS OR THE 100 PARTICIPANTS
FROM 2015 THROUGH 2020 AND THEY
APPLIED THE CONSORT OF THE
OUTCOMES AND GUIDANCE TO EACH 1
OF THE TRIALS AND SUBDIVIDED
THEM INTO DIFFERENT OUTCOME
CATEGORIES SHORT-TERM NEONATAL
COMPLICATIONS AND THEN WHAT THE
MANUSCRIPT DOES IS EMPHASIZE
WHICH STUDIES HAVE DONE THIS AND
HOW THEY MANAGE SO ONCE AGAIN
THIS IS ANOTHER TOOL IN THE
TOOLBOX WE CAN USE TO HELP
STANDARDIZED OUTCOMES.
AND WITH THOSE TRIALS THERE ARE
MANY CHALLENGES SO JUST IN
GENERAL WITH HUMAN CLINICAL
TRIALS AND TO TALK ABOUT THE
DIFFERENT COMPARISON GROUPS THE
SAMPLE SIZE DIFFERENCES AND SOME
OF THIS HAS PROGRESSED OVER THE
LAST DECADE AND THOSE THAT
REMAIN AND WHAT IS NEEDED AND
WHEN DO WE NEED TO STRATIFY?
IT IS IMPORTANT TO DO THAT IF WE
HAVE DIFFERENCE JUST TO GO
BETWEEN THE 2 GROUPS AT
BASELINE.
ENDPOINT SELECTION.
WE REFER TO THAT CAN WE USE THE
ENDPOINT ON THE GOOD ONES WITH
GOOD PREDICTIVE VALUE AND HOW DO
THEY REMAIN IN THINKING THROUGH
THAT CAN USE AS AN EARLY
INDICATOR OF DYSFUNCTION AND IF
YOU DO USE LABORATORY FOR WHAT
IS NORMAL AND WHAT IS THE
REFERENCE.
FOR THE CHALLENGES AND BENEFITS
AS WELL.
SO THE OTHER POINT I ALSO WANT
TO EMPHASIZE THAT WE TALKED
ABOUT IS STANDARDIZATION OF
INTERVENTION WITH LBP AND IT IS
SPECIFIC OF THE STRAIN THAT HAS
BEEN USED IN DESCRIBING THE
NOMENCLATURE SO EVERYONE IS
AWARE OF THE PRODUCT THAT HAS
BEEN USED AND THEN THE SCHEMATIC
THAT WAS PUBLISHED QUITE A WHILE
AGO BUT RANGES TRUE TODAY THAT I
THINKING ABOUT THE PRODUCT WHAT
IS HAPPENING TO THE PRODUCT AS
IT GOES TO THE HOST AS IT IS
STORED AND ADMINISTERED AND EVEN
GOING BACK TO ACTUAL
PRODUCTION.
THESE ARE ALL KEY ISSUES THAT
NEED TO BE SPECIFIED
SPECIFICALLY WHEN CONDUCTING A
TRIAL SO THERE IS AN
UNDERSTANDING.
AND THEN ADHERENCE WHICH IS
ALWAYS A CHALLENGE.
SO WITH NEONATES THAT MAY NOT
ALWAYS BE POSSIBLE SO IS THERE A
WAY OR OTHER WAYS TO MIMIC
DIRECTLY IN THE NON-
HOSPITALIZED INDIVIDUAL AND THE
STOOL ASSESSMENTS ELECTRONIC
MONITORING AND THEN THE VALUE OF
SELF-MONITORING AS WELL ARE WAYS
WE CAN ASSESS ADHERENCE AND SO
THEN WE GET A COMPOSITE IDEA OF
WHAT ADHERENCE IS.
SAFETY ASSESSMENT REALLY
REPORTING IN A STANDARDIZED WAY
TO PRE- SPECIFY WHAT SEVERITY IS
WITHOUT ASSOCIATION MANY STUDIES
UNFORTUNATELY SAY NO SAFETY
EVENTS WERE OBSERVED IN THAT CAN
BE VERY CHALLENGING BECAUSE HOW
YOU DEFINE THE SAFETY EVENT AND
WHAT IS THE OBSERVATION?
SO TO BE VERY INTENTIONAL OF
SAFETY ASSESSMENTS.
1 OF THE APPLICATION THAT I
DESCRIBED WHEN WE ARE THINKING
ABOUT SAFETY EVENTS FOR LBP.
AND FINALLY I JUST WANT TO AND
WITH SOME OPPORTUNITIES I
PRESENTED A LOT OF CHALLENGES.
ALTHOUGH THERE ARE TOOLS IN THE
TOOLBOX SO THINKING PROACTIVELY
WHEN WE ARE DESIGNING TRIALS TO
BE VERY INTENTIONAL.
THINKING OF HOW WE CAN BE
ADAPTIVE AS WE DESIGN STUDIES
AND HOW WE CAN HAVE A RIGOROUS
STUDY WITH REAL-WORLD
APPLICATIONS AND I CANNOT
EMPHASIZE THE IMPORTANCE OF THAT
AND I HAVE COME TO VALUE THE
GUIDANCE FROM NOT ONLY
PARTICIPANTS AND FAMILY MEMBERS
AS WELL AS THINKING ABOUT
LONGER-TERM OUTCOMES THINKING
ABOUT BEHAVIORAL PSYCHOLOGY AND
SOCIAL WORKERS TO BE ENGAGED IN
MANY STUDIES AND THAT IS AN
EXAMPLE VERY WELL OF ENGAGING
THE COMMUNITY.
AND EFFICIENTLY AS POSSIBLE
RELATED TO OPERATIONS TO
OPTIMIZE OUR SCIENTIFIC
DISCOVERY.
UNFORTUNATELY WE ARE CHALLENGED
BY THE OPERATIONAL LIMITATION.
IF WE CAN GET BEYOND THAT TO
THINK ABOUT FOCUSING ON THE
SCIENTIFIC DISCOVERY THAT WOULD
HELP WITH THE COLLECTION AND THE
ANALYSIS.
AND THEN FINALLY WITH PRODUCT
DEFINITIONS AND COMPOSITIONS AND
REGULATORY GUIDANCE.
THANK YOU VERY MUCH FOR YOUR
ENGAGEMENT.
[APPLAUSE]
>> WE HAVE 15 MINUTES FOR Q&A
AND PLENTY OF TIME TO UNPACK
WHAT WAS SAID ALWAYS TO
ENCOURAGE THE ONLINE
PARTICIPANTS WITH THE QUESTIONS
IN THE CHAT.
>> FOR DOCTOR WARNER THANK YOU
FOR YOUR PRESENTATION VERY
INTERESTING.
I WAS WONDERING ISN'T BREASTMILK
A PROBIOTIC AND ITSELF AND HOW
DOES THAT COMPARE TO YOUR MICRO
COMMUNITIES AND WHERE THOSE KIDS
BREAST-FED ARE NOT?
AS WE ARE HEARING THAT SEEMS TO
HAVE SOME EFFECTIVENESS OF
TREATING NEC.
>> BREASTMILK HAS ITS OWN
MICROBIAL COMMUNITY AND IT
INTERFACES WITH THE GOT
MICROBIAL COMPONENTS THAT
DEVELOPS THERE AS WELL SO BY
DEFINITION PERHAPS IT IS A
PROBIOTIC THAT IS INDIVIDUALIZED
FOR EACH BABY MOTHER NATURE IS
PRETTY SMART.
BUT THE QUESTION PERHAPS IS HOW
DOES THAT INTERFACE SUBSEQUENT
EFFECTS THAT YOU SEE?
THAT IS THE QUESTION.
IT DEFINITELY DOES.
WE ARE JUST STARTING TO PAY
ATTENTION TO THAT.
AND I DO WONDER WHY ARE WE
SEEING SUCH AN EFFECT UNDER
1000 GRAMS?
IS IT BECAUSE OF THE MICROBIAL
COMMUNITY THAT IS PRESENT IN ANY
1 PARTICULAR MICROBE OR HOW THAT
WORKS SO THE MATERNAL ACT WILL
IMPACT THE OUTCOMES OF THE
STUDY.
>> THINKING ABOUT IT AS A
PRODUCT OR A DRUG WOULD IT BE
SOMETHING YOU WOULD WANT TO KNOW
MORE ABOUT?
TAKING THAT AS PART OF THE
TRIAL?
>> WE KNOW THAT MICROBE
INTERACTIONS AND THOSE
COMMUNITIES DO NOT ALWAYS PLAY
WELL TOGETHER IN THE SANDBOX
WITH THOSE DRUG INTERACTIONS IN
A TRIAL.
>> ABSOLUTELY I WOULD GO BACK TO
SOME OF THE CHALLENGES OF DOING
THE STUDIES IN THE NICU.
PARTICULARLY EARLY ON.
YOU WANT TO CAPTURE EVERY SINGLE
THING AND PULL THAT UP
AT.1 MICROLITERS CC TO GIVE ORAL
IMMUNOTHERAPY.
THAT'S 1 OF THE CHALLENGES.
I'M NOT A BIG BREASTMILK FAN BUT
THE CHALLENGE IS TO OBTAIN THE
PRODUCT OVER TIME.
IT CAN BE DONE FROM A PRAGMATIC
STANDPOINT AND ADDS TO THE COST
IT'S NOT NECESSARILY EASY TO
ANALYZE THE COMPONENTS.
THERE IS A LOT OF FAT IN IT
THOSE ARE CHALLENGES.
BUT I WOULD AGREE IDEALLY WITH
THEM A TABLEAU - - A TABLEAU X
STUDY 1 OF THE COMPONENTS TO
LOOK AT.
>> AS A FOLLOW-UP QUESTION, IN
TERMS OF THE VARIATION OF THE
PROBIOTIC USED WHAT IS KNOWN
SPECIFICALLY QUANTITATIVELY OF
THE PRODUCT OVER TIME AND WITH
THAT CONSISTENCY IN THE
COMPOSITION AND STABILITY IN THE
STUDIES THAT YOU DESCRIBE.
>> CERTAINLY IN SOME OF THE
EARLIER STUDIES UNFORTUNATELY IT
SHOWED VERY LITTLE PRODUCT FROM
WHAT WAS PRESENT I THINK THAT
HAS CHANGED AND IN PARTICULAR
SOME MANUFACTURERS THEY ARE
FAIRLY STRINGENT IN WHAT IS
PRODUCED.
I AM CERTAINLY NOT A PRODUCTION
SPECIALIST TO THINK THE
PHARMACEUTICALS WOULD KNOW
BETTER INFORMATION HOW THEY
APPROACH THAT BUT THERE IS THAT
VARIATION EVEN IN BETWEEN THE
PRODUCTS WITH THE SAME PRODUCT
OVER TIME I THINK WE ARE GETTING
BETTER BUT THAT'S MORE OF THE
CHALLENGES THAT WE FACE.
HOW DO YOU ACCOUNT FOR THAT?
>> SO WITH THE IDEA OF BEING A
LIVING ORGANISM AND WHAT HAPPENS
TO THE PRODUCT AFTER IT IS GIVEN
AND HAS THE POTENTIAL TO CROSS
CONTAMINATE OR AT LEAST
INTERFACE WITH CONTROLS SO JUST
THINKING ABOUT HOW THIS HAS
TAKEN AS WELL AS VERIFYING.
>> A LARGE TRIAL AFTER BEING
ADMINISTERED BY THE STATE WE
TEST EVERY 6 MONTHS THE THIRD
BATCH WE EFFECTIVELY HAD IT
ANALYZED 2 WAYS AT THE OUTCOME
AND BETWEEN THEM COUNTRYWIDE OR
THEY DIDN'T UNFORTUNATELY IT DID
NOT MAKE A DIFFERENCE BUT YOU
HAVE TO HAVE GOOD MICROBES IN
MOST INTERVENTIONS YOU AUTHORIZE
DO NOT REPLICATE OR STOP
REPLICATING.
>> MAYBE THAT'S WHERE WE GET
HELP FROM GOVERNMENT
COLLEAGUES.
>> THANK YOU.
INFORMATION ABOUT THE TRIALS AND
IDEALS IS TERRIFIC.
BUT HOW DO WE GET THERE?
DOES IT TAKE INVESTIGATORS OR
COMPANIES TO PROPOSE THESE NEXT
STEPS OR IS IT SOMETHING YOU
HAVE TO ASK THE CDC TO SAY WE
NEED A BETTER TRIAL IN THIS AREA
WITH MULTIPLE FOLKS INVOLVED?
>> THAT'S A GREAT QUESTION.
1 OF THE THINGS IS
COLLABORATION.
THAT IS IMPORTANT ALSO DEPENDS
ON WHAT WE WILL USE THE TRIAL TO
DETERMINE IF IT'S THE APPROVAL
OF A PRODUCT THEN YOU NEED TO
INVOLVE REGULATORY INDUSTRY AS
WELL BUT THEN THINKING
CREATIVELY WHAT WE CAN CONSIDER
AS APPROPRIATE EVIDENCE.
AND TRIALS ARE 1 EXAMPLE BUT
THANKFULLY NOW THERE ARE SOME
IMPORTANT INFORMATION ON THE FDA
WEBSITE HOW TO USE THE STUDIES
AND SET THEM UP FOR VARIOUS
PRODUCTS.
ONCE AGAIN IT IS COMMUNICATION
AND CORROBORATION SO I THINK 1
OF THE CHALLENGES IS IT SEEMS
OVERWHELMING YOU AS AN
INVESTIGATOR ARE TRYING TO START
SOMETHING NEW AND FOR THE
NETWORK AS AN EXAMPLE FINDING
OUT WHAT HAS ALREADY BEEN DONE
AND SOME OF THE OTHER NETWORKS I
LISTED AS WELL OR THE
OPPORTUNITY TO WORK TOGETHER AND
COLLABORATE.
>> AS A -- -- I WAS THINKING AS
YOU WERE SPEAKING THAT JOURNALS
THEMSELVES HAVE BECOME SO
STRINGENT AS YOU WRITE UP THE
STUDY TO MEET THE CRITERIA MAYBE
THEY COULD REQUIRE THAT FOR A
PUBLICATION THAT COULD BE
MOTIVATION TO BRING IT FORWARD.
>> THAT WAS ACTUALLY SOMETHING I
WAS TRYING TO BRING OUT WITH THE
RECENT PUBLICATION AND
PEDIATRICS WHERE THEY TOOK THE
STUDIES AND PUT THEM UP AGAINST
THE 2 GUIDELINES SO WHICH ONES
ADHERED AND EMPHASIZED THE
ASPECTS OF THE GUIDANCE THAT ARE
POSITIVE AND THAT WE WOULD LIKE
TO SEE MORE OF AND TO SEE
INTERPRETING THE RESULTS.
>> I HAVE 2 QUESTIONS.
GIVEN EVERYTHING WE HAVE HEARD
TODAY AND THE POTENTIAL SPREAD
DO WE THINK AN INDIVIDUAL
PATIENT CONSENTED RANDOMIZED
STUDY CAN BE DONE VERSUS A
CENTER CROSSOVER?
THE OTHER QUESTION WHICH IS
PROMPTED BY THE PRESENTATION IS
GIVEN AND WHAT YOU HAVE LEARNED
ABOUT THE CHANGES OVER TIM
TIME, WHAT IS THE TIMING OF THE
INTERVENTION AND SHOULD THAT BE
FROM BIRTH OR OTHER TRIGGERS FOR
THE INTERVENTION?
>> THAT IS INTERESTING BECAUSE
IF YOU WENT TO TARGET THE GROUP
AT THE HIGHEST INCIDENTS AND THE
WORST OUTCOME YOU SHOULD
PROBABLY WAIT A FEW WEEKS AND
THEN RANDOMIZE INTERESTINGLY THE
ORAL NOT ABSORBABLE ANTIBIOTICS
TRIALS WHAT START GIVING THEM AT
BIRTH GIVING THEM FOR A COUPLE
WEEKS RIGHT BEFORE CHILDREN
WOULD DEVELOP NEC.
SO THERE ARE ISSUES WHICHEVER
WAY YOU CHOOSE I WOULD LIKE TO
ASK INDUSTRY IN THE ROOM I HEARD
FROM SOMEBODY WHO WAS
CONSIDERING A NEW MOLECULE TO
PREVENT NEC AND WAS ENCOUNTERING
A LOT OF OPPOSITION IN THE NICU
AND GOVERNMENT TO RANDOMIZING
BECAUSE MOST OF THEM WANT TO GET
THAT CAN THEY ARE SUCH A
VULNERABLE POPULATION AND IT IS
SUCH A NEW DRUG IS THERE
PROFOUND A VERSION?
ABOUT 100 PEOPLE IN THIS ROOM AT
5 OF US WERE GOING TO HAVE IN
THE NEXT 60 DAYS A CATASTROPHIC
ABDOMINAL EVENT WE WOULD ALL BE
LINING UP TO BE RANDOMIZED.
BUT THERE SEEMS TO BE THE
APPROACH AVOIDANCE TO DOING
TRIALS WITH INFANTS?
AM I PERCEIVING THIS CORRECTLY?
>> I WOULD SAY DEPENDING ON THE
RISK PROFILE OF THE PRODUCT.
IF THERE'S NOT A LOT OF RISK
THEN YOU COULD DO IT.
IT REALLY GOES BACK TO
EVERYTHING YOU DO IN NEONATOLOGY
WITH THE RISK RATIO.
>> YOU RAISE AN EXCELLENT POINT
AND 1 OF THE THINGS I DO FOR FUN
IS INFECTION PREVENTION SO I AM
ACUTELY AWARE OF SOME OF THE
CHALLENGES OF INADVERTENT
COLONIZATION AND TRANSMISSION
AND IN SOME WAYS WE COULD USE
THAT TO OUR BENEFIT BUT I DO
THINK THAT HAVING RANDOMIZED
STUDIES IS SOMETHING WE SHOULD
LOOK MORE TOWARDS IT HELPS US
WITH NUMBERS.
BUT THE CHALLENGE IS WITH INBORN
AND OUTBOARD MAKE SURE YOU HAVE
A GOOD STATISTICIAN ON SPEED
DIAL TO HELP YOU THINKING
THROUGH THOSE ISSUES BUT SOME OF
THE STUDIES THAT SHOW THERE IS
COLONIZATION OF A PRODUCT WHEN
THAT WAS NOT ADMINISTERED IS
IMPORTANT AND SHOWS US WHAT IS
POSSIBLY REALLY HAPPENING WITH
HYGIENE IN THE NICU.
>> THERE ARE SOME QUESTIONS IN
THE CHAT.
DID ANY OF THE RCT SHOW A CASE
THE PROBIOTIC SEPSIS TO
CALCULATE?
AND THEN THE NUMBER NEEDED TO
TREAT EFFICACY BEFORE THERE IS A
CASE OF SEPSIS.
I WILL JUST MENTIONED THIS WE
TALKED ABOUT THIS WE HAVE
CULTURE NEGATIVE SEPSIS.
WITH THE ANAEROBES THEY ARE
DIFFICULT TO GROW.
YOU GET ANAEROBIC AND AEROBIC
CULTURES.
BUT THAT WOULD NOT BE A PROBLEM
FROM A LABORATORY STANDPOINT I
AM GUESSING IT WOULD BE IN THE
HUNDREDS.
>> BASED ON VERY LITTLE
STATISTICS.
>> SO YOU MENTIONED THE TRIAL
DESIGNS AND APPROACHES THAT
ALLOWS YOU TO CONSIDER PRIOR
EVIDENCE WITH THAT TREATMENT
EFFECT AND THE OUTCOME SO THERE
IS PRIOR EVIDENCE GOING DOWN
VERY SPECIFIC FOR A PRODUCT
BEING STUDY BUT YOU HAVE
THOUGHTS ON WHAT IS AVAILABLE TO
BE CONSIDERED IN TERMS OF USE OF
TRIAL DESIGNS GOING FORWARD AS
IT RELATES TO THE APPROACH IN
TERMS OF CONSIDERING?
>> AT LEAST AREA LOOK AT THE
PRIOR EVIDENCE TO SEE WHAT I CAN
ESTIMATE TO DO ANALYSIS.
I WILL ASK FOR HELP ON THIS 1.
I THINK MORE INFORMATION IS
BETTER.
I WILL SAY FOR SOME POPULATIONS
NOW GOING DOWN AT 2022, 23, I
DON'T THINK THERE IS ANY PRIOR
EVIDENCE FOR THOSE POPULATIONS
WHO ARE THE HIGHEST POPULATIONS
AT RISK.
>> I'M NOT SURE I WILL ANSWER
YOUR QUESTION BUT THE OTHER
ADVANTAGE IS AS YOU ARE GOING
THROUGH YOU CAN MAKE CHANGES
WITH THE DATA YOU ARE ACCRUING
SO IT MIGHT NOT HELP IN EVERY
SITUATION BUT WE NEED TO TAKE A
LOOK AT WHAT WE HAVE AND ASSESS
THAT AND APPLY IT IS MUCH AS
POSSIBLE TO MOVING FORWARD.
>> THIS WAS RELATED HOW HAS THE
FDA APPROACHED STATISTICS AND
DESIGNS FOR DRUG TRIALS?
>> AND THAT HAS BEEN APPROACHED.
>> I COULDN'T REALLY HEAR THE
ENTIRE QUESTION BUT THE GIST OF
IT WAS FDA USING STATISTICS AND
THE APPROVAL OF OTHER PRODUCTS?
THE ANSWER IS YES AND IN FACT
YOU CAN FIND THAT IN 1 OF THE
FNT PRODUCTS
STATISTICS TO HELP WITH THE
EFFICACY ANALYSIS.
LOOK AT THE PRESCRIBING
INFORMATION OF SECTION 14 WILL
FIND THE DISCUSSION.
>> THERE WAS ADDITIONAL
LEARNINGS AND IT AS WELL.
SO WE WILL TAKE A BREAK THERE IS
A 10 MINUTE BREAK AT 2:40 P.M.
THANK YOU FOR YOUR
PARTICIPATION.
OKAY.
WILL COME BACK FROM THE BREAK.
WE HAVE 2 MORE PRESENTATIONS.
AND THEN WE WILL WRAP UP WITH
THE Q&A AND WE WILL HAVE SOME
CLOSING REMARKS THE FIRST TALK
IS FROM DOCTOR JOSEPH NEU
TALKING ABOUT CHALLENGES AND
OPPORTUNITIES OF CONDUCTING THE
CLINICAL TRIAL WITH THE LDV WE
HAVE HEARD ABOUT THAT IN THE
PAST SESSION.
>> JUST TO START I WANT TO THANK
ANDY FOR SETTING THE STAGE FOR
THIS FANTASTIC JOB OF THE
POTENTIAL CHALLENGES AND
OPPORTUNITIES SO HERE I WILL
TALK ABOUT AND ACTUAL TRIAL
WHERE WE WENT THROUGH SOME OF
THESE CHALLENGES AND
OPPORTUNITIES I WILL GET MY
DISCLOSURE SLIDE THE NAME OF THE
TRIAL IS CALLED THE CONNECTION
TRIAL I JUST WANT TO GIVE YOU A
HISTORICAL PERSPECTIVE WITH A
CONNECTION TRIAL.
THIS WAS INITIATED 12 YEARS
AGO.
SOME OF THE BASIS OR REASONS FOR
THIS WAS THE DATA THAT WE HAD AT
THE TIME WAS UNCLEAR WITH
SEVERAL ANALYSIS THAT WAS
PUBLISHED IN PEDIATRICS IN 2010
WHICH REALLY RAISED A LOT OF
INTEREST AND IN FACT IT WAS A
COMMENTARY ASSOCIATED WITH THAT
THAT SAID IF IT IS NOT UNETHICAL
IF WE DO NOT USE PROBIOTICS.
THAT WAS 2010.
SO IN 2013 OUR COLLEAGUES FROM
IBT HAD SOME DISCUSSIONS WITH
THE FDA AND INITIATION OF PHASE
2 TRIAL STARTED UNDER IMD 8
YEARS AGO.
THERE WERE A LOT OF SAFETY
CONCERNS ABOUT OTHER AGENTS AND
YOU HAVE HEARD THIS AND SEVERAL
LECTURES THE SAFETY CONCERNS AND
THE TRANSLOCATION OF THE
BACTERIA AND SOME BABIES
ACTUALLY DYING OF ASSOCIATED
WITH THE PROBIOTICS AND ALSO
SOME OF THE PRODUCTS BEING
CONTAMINATED AND MICRO- SIS WAS
1 OF THESE AND THEN MOST
RECENTLY FDA WARNINGS AFTER
SEPSIS AND DEATH.
STARTING ENROLLMENT PHASE III
SEVERAL YEARS AGO.
AND NOW THIS IS COMPLETED IN
AUGUST 2024.
I WILL SHOW YOU A LITTLE BIT OF
DATA ON THIS.
THE OBJECTIVES WAS TO EVALUATE
WHICH IS A LACTOBACILLUS SCREEN
VERSUS STERILE WATER PLACEBO IN
VLBW INFANTS.
WE LOOKED AT SAFETY AND
PREVENTION OF NECROTIZING
ENTEROCOLITIS, IMPROVED
SUSTAINED FEEDING INTOLERAN
INTOLERANCE, DECREASE OF
SEVERITY IN NEC AND REDUCTION OF
DEATH DUE TO ANY CAUSES AND
LENGTH OF HOSPITALIZATION OR
GROWTH OR OTHER MORBIDITIES.
NOW THE 2 PRIMARY OUTCOMES WERE
PREVENTION OF NEC AND IMPROVED
SUSTAINED FEEDING TOLERANCE AND
WE ADDED THE IMPROVED SUSTAINED
FEEDING TOLERANCE A FEW YEARS
BACK AFTER DISCUSSING THIS WITH
FDA AND WE DECIDED TO ADD THE
SECOND PRIMARY OUTCOME.
HERE IS THE PATIENT ENROLLMENT
IT IS A LARGE STUDY ALMOST 100
DIFFERENT INTENSIVE CARE UNITS
IN 10 DIFFERENT COUNTRIES 2186
BABIES SCREENED AND THEN THERE
WERE SOME EXCLUSIONS AND WE CAN
JUST GO THROUGH THE REASONS FOR
NOT BEING TREATED WITH THE
DISCONTINUATION OF TREATMENT AND
THEN WHEN YOU GET DOWN TO THE
BOTTOM YOU HAVE 925 BABIES
COMPLETED AND 892 IN THE PLAC
PLACEBO.
SO OPERATIONALLY IT IS
CHALLENGING.
A SHORT TIME WINDOW TO OBTAIN
INFORMED CONSENT.
48 HOURS.
A LOT OF BABIES WERE BEING
TRANSFERRED AND WERE TRANSFERRED
OUT OF THE ORIGINAL INTENSIVE
CARE UNITS.
THERE WERE HETEROGENEOUS WAYS OF
WORKING AND CARE PRACTICES
BETWEEN COUNTRIES AND UNITS SO
JUST TO GIVE YOU AN EXAMPLE FOR
SUSTAINED FEEDING TOLERANCE WE
PROVIDED ALL OF THE UNITS WITH
THE RECOMMENDATIONS AND FEEDING
GUIDELINES.
IT WAS VERY INTERESTING HOW THE
DOGMA AND TRADITION OF THE
VARIOUS NEONATAL INTENSIVE CARE
UNITS WERE OVERWRITING THOSE
RECOMMENDATIONS.
IN ENROLLMENT OF PRETERM INFANTS
IN A VERY STRESSFUL SITUATION
AND ESPECIALLY WHEN YOU GET TO
THE INFANTS YOU HAVE FREQUENT
SERIOUS EVENTS AND THEY ARE
DIFFICULT TO SEPARATE FROM WHAT
IS USUALLY THERE IN THE FRAGILE
POPULATION OR IF THERE IS
ACTUALLY SOMETHING OR A SIGNAL
FROM THE AGENT.
SO ELIGIBILITY AGAIN BODY WEIGHT
BETWEEN 550 AND 100 GRAMS
GESTATIONAL AGE OF 22 THROUGH 23
WEEKS STARTING LESS THAN 48
HOURS OF AGE AND WE ALSO HAVE
PRETERM BIRTH WITHOUT IMMINENT
RISK OF DEATH TO WHOM ONLY
COMFORT CARE IS GIVEN.
EARLY SEPSIS ONLY INCLUDING
THOSE WITH BACTERIA IN THE BLOOD
OR MOTHERS WITH HIV CHROMOSOMAL
ABERRATIONS PLANNED
ADMINISTRATION OF OTHER
BACTERIAL PRODUCTS OR
PROBIOTICS.
JUST A LITTLE BIT OF INFORMATION
ABOUT LACTOBACILLUS A SINGLE
DOSE WAS GIVEN WITHIN 48 HOURS
OF BIRTH FROM POST MENSTRUAL AGE
OF 34 WEEKS PLUS 6 DAYS WITH 9
DAYS OF DOSING WITH A FOLLOW-UP
AT 40 WEEKS.
EACH DOSE WAS GIVEN THROUGH
GASTROINTESTINAL TUBE RANDOMIZED
TREATMENT AGAINST A STERILE
WATER PLACEBO AND DOUBLE-BLIND
NEITHER INTENSIVE CARE STAFF NOR
SPONSOR WAS INFORMED OF WHO GETS
WHAT AND WHO GOT WHAT WAS AFTER
THE LAST PATIENT WAS AFTER THEY
LEFT THE STUDY WE DID NOT DO THE
UNWINDING AND TELL LAST AUGUST.
BUT WE ENDED UP HAVING 551
INFANTS BETWEEN 50749 GRAMS 1351
INFANTS 750 THROUGH 1000 GRAMS
AND 215 FEMALES 50 PERCENT
CAUCASIANS 50 PERCENT BLACK
AFRICAN AMERICANS 27 PERCENT
C-SECTION 77 PERCENT.
AND THE GROUPS WERE WELL
BALANCED.
AND WITH THE OUTCOMES THIS IS
SOMETHING I JUST WANT TO MENTION
VERY BRIEFLY THE OUTCOMES HAVE
NOT BEEN YET SUBJECTED TO PEER
REVIEW.
HOPEFULLY WE WILL GET THIS
SUBMITTED AND YOU ARE SEEING
SOME OF THESE RESULTS FOR THE
FIRST TIME.
NO DIFFERENCE IN TERMS OF SAFETY
BETWEEN PLACEBO AND SEPSIS
ABDOMINAL DISTENTION AND
RESPIRATORY FAILURE AND
METABOLIC GOAL BALANCES.
HYPER OR HYPOGLYCEMIA, PULMONARY
HEMORRHAGE.
THIS IS THE INTENTION TO TREAT.
YOU CAN SEE THE AGENT VERSUS THE
PLACEBO.
THE P VALUE 0.248 THAT IS
SIGNIFICANT.
NEC DIAGNOSED AFTER 14 DAY
DAYS.7 PERCENT WITH THE P VALUE.
FROM THE PERSPECTIVE OF WHAT
HAPPENS IS FIRST COUPLE OF WEEKS
NUMBER 1 ONLY STARTING TO GIVE
THE AGENT IN THE FIRST COUPLE OF
WEEKS.
PLUS THE OTHER PROBLEM IS YOU
HAVE A LOT OF BABIES WITH
SPONTANEOUS INTESTINAL
PERFORATION THE NEW AGE OF
SPONTANEOUS INTESTINAL
PERFORATION AND FREQUENTLY THAT
IS DIAGNOSED AS NEC SO WHEN WE
TAKE THOSE BABIES OUT AND LOOK
AT THE 14 DAYS WE SEE A
DIFFERENCE TO LOOK AT THE BABIES
DIAGNOSED AS HAVING NEC BY X-RAY
WE SEE NO DIFFERENCE NOW HERE
ARE SOME SUB GROUPINGS I WILL
REPEAT A LITTLE OF WHAT I SAID.
FORCED -- -- POST 14 DAYS OR
SEEMS TO BE A DIFFERENCE FROM
THE ENTIRE GROUP.
LOOK AT X-RAY POST 14 DAYS.
REALLY NO DIFFERENCE.
THEN LOOK AT SURGICAL NEC.
THOSE WHO HAD TO GO TO SURGERY.
YOU SEE A SLIGHT SUGGESTION OF
THE P VALUE OF 1.2 6 PERCENT
POST 14 YOU SEE A VALUE OF 0.46
FAVORING THE SUBJECTS.
IF YOU LOOK AT NEC SURGERY OR
NEC DEATH OR POST 14 DAYS, WE
SEE A STATISTICAL
SIGNIFICANCE.018.
SAY FEEDING TOLERANCE SO WHAT IS
THE SUSTAINED FEEDING
TOLERANCE?
THERE IS SO MANY DEFINITIONS WE
ENDED UP MAKING OUR OWN
DEFINITION BUT WE MADE A VERY
STRICT DEFINITION MAY BE TOO
STRICT.
SO THE WAY WE DEFINED SUSTAINED
FEEDING TOLERANCE IS THE DEFINED
TIME FROM THE FIRST PERIOD OF 10
CONSECUTIVE DAYS WITH ENTERAL
FEEDINGS GREATER THAN
120 MILLILITERS WITH NO
NUTRITION AND 100-GRAM BODY
WEIGHT INCREASE.
AND THE ASTERISKS HERE THE
STATISTICIANS WANTED TO MAKE
SURE THAT WE PUT THIS INTO
CONTEXT OF COMPETING RISK
ANALYSIS TO UNEQUAL NUMBERS OF
DEATHS PRIOR TO REACHING
SUSTAINED FEEDING TOLERANCE AND
I WILL SHOW YOU ABOUT THE DEATH
SHORTLY.
BUT WHEN YOU LOOK AT THE
SUSTAINED FEEDING TOLERANCE IN
THE ENTIRE GROUP THERE IS A
DIFFERENCE OF ABOUT 2 DAYS WITH
A P VALUE 2076 WITH LESS THAN
750 GRAMS THE P VALUE.035 WITH
THE GROUP AND THEN THE OTHER 2
GROUPS 750 THROUGH 999 AND
1500 GRAMS NOT STATISTICALLY
SIGNIFICANTLY DIFFERENT.
MORTALITY.
THIS IS A CURVE THAT SHOWS THE
MORTALITY DIFFERENCES THE BLUE
WAS THE TREATMENT THE SINGLE IS
THE RED AND IN THE FIRST 2 WEEKS
WE SEE VERY LITTLE DIFFERENCE
BUT THEN WE START TO SEE
DIVERGENCE IT ENDS UP BEING
27 PERCENT DIFFERENCE IN
MORTALITY WITH -- -- BETWEEN THE
2 GROUPS.
SO WHAT MIGHT BE DRIVING THIS
MORTALITY?
WE ARE STILL NOT SURE BUT WE
HAVE BEEN DOING SOME SPECULATION
AND HERE WHEN WE LOOK AT THE
INTESTINAL PERFORATION'S WE SEE
6 IN THE IBP GROUP.
THIS IS NECROTIZING
ENTEROCOLITIS WITH INTESTINAL
PERFORATION AND 18 AND THE
PLACEBO GROUP.
SO THERE IS MORE IN THE PLACEBO
GROUP ALMOST TWICE AS MORE AND
CHOICES MANY HERE WHEN WE LOOK
AT CARDIORESPIRATORY PROBLEMS
SUCH AS DYSPLASIA WE SEE LESS
DYSPLASIA OF THE IBP GROUP THAN
THE PLACEBO GROUP.
INTRACRANIAL HEMORRHAGE IS NOT
DIFFERENT PULMONARY EMBOLI AND
AMMONIA THESE ARE NOT DIFFERENT
BUT IT IS OF INTEREST THAT THE
DYSPLASIA OF THE SEVERE
INTESTINAL INJURIES ARE
DIFFERENT AND SUGGESTING PERHAPS
A ROLE OF THE IBP SYSTEMIC
INFLAMMATORY RESPONSE OF THE
GASTROINTESTINAL TRACK AND THE
G.I. TRACT.
I WOULD LIKE TO CONCLUDE THIS IS
THE LARGEST STUDY EVER OF THE
LIFE BIO THERAPEUTIC PRODUCT IN
PREMATURE INFANTS.
IT IS TO BENEFIT NEC AND
SUSTAINED FEEDING TOLERANCE.
BUT REMEMBER IT IS AN AMBIGUOUS
CLINICAL DIAGNOSIS AND LESS A
LAPAROTOMY OR AUTOPSY ARE
PERFORMED.
THE SUSTAINED FEEDING TOLERANCE
WERE HAMPERED TO ADVOCATED AND
FEEDING PROTOCOLS A SIGNIFICANT
REDUCTION OF THE RISK OF DEATH
FROM ANY CAUSE.
AT THIS JUNCTURE WE HAVE NO
CONCERNS AS TO SAFETY.
AND LACTOBACILLUS WAS NEVER
FOUND IN CLINICAL SUSPICION FOR
SEPSIS SO WE KNOW THERE IS A
POSITIVE BENEFIT TO RISK FOR
PREMATURE INFANTS BORN WITH A
VERY LOW BIRTH WEIGHT.
THANK YOU FOR YOUR ATTENTION.
[APPLAUSE]
>> WHAT A POWERFUL
PRESENTATION.
THANK YOU THE NEXT PRESENTATION
IS BY DOCTOR STEFFAN STROMBERG.
HE WILL TALK TO US ABOUT
HIGHLIGHTS IN PRODUCT
DEVELOPMENT AND DIFFERENTIATING
FROM DRUGS AND DIETARY
SUPPLEMENTS.
>> THANK YOU.
I AM THE TENTH SPEAKER ON FRIDAY
AFTERNOON.
I WILL TELL YOU ABOUT WHY I AM
HERE.
I REPRESENT THE COMPANY.
THE FIRST THING YOU SHOULD KNOW
IS WE ARE A COMPANY CALLED IBT
AND WHEN WE STARTED THE COMPANY
IN 2013.
WE DID THAT BECAUSE WE WANTED TO
DEVELOP LIVE LBP.
I WAS WORKING FOR A COMPANY TO
DO DIETARY SUPPLEMENTS.
SO THEN WE CAN WORK THERE.
SINCE 2016 WE'VE BEEN ON THE
NASDAQ STOCK EXCHANGE.
IT ALL STARTED WITH THE
PUBLICATION FROM 2012.
HE HAD CONDUCTED A STUDY WITH
PLACEBO AND ACTED THERE'S
5 PERCENT NEC IN THE PLACEBO AND
THEN A 3 PERCENT SO THEN READING
A LITTLE BIT ALSO 2012 AND THIS
IS A HISTORIC CONTROLLED TRIAL
HERE WE SAW 15 PERCENT NEC AND
THEN THEY INTRODUCED AND THEN A
2 PERCENT NEC SO THEN I ASK
MYSELF WHAT IT IS NEC AND WHAT
IS PRETERM?
REMEMBER I AM THE ONLY 1 AND I'M
NOT AN MD.
SO THEN I SAW PICTURES OF NEC
AND PRETERM INFANTS AND I SAID
THIS LOOKS SEVERE SO I TOOK AN
AIRPLANE FOR THE FIRST TIME IN
2012 AND I ASKED EVERYTHING I
COULD ABOUT NECROTIZING
ENTEROCOLITIS.
AND THEN I CONTINUED TO READ
MORE AND AT THE END OF SAID FROM
NEC AND A TELL YOU BECAUSE YOU
ARE THE EXPERTS.
SO I CONCLUDE MY FINDINGS IN THE
TEXT AND I'M SAYING PRETERM
INFANTS NEED HELP AND ALSO THAT
THEY DON'T NEED MORE PROBLEMS.
THANK YOU AGREE WITH THAT.
I HOPE WE DO.
AND THAT MADE ME INTRIGUED TO GO
ON.
I THEN WAS THINKING ABOUT THE
CAUSE OF DEATH AND HERE YOU SEE
COLORS AND HOW THEY ARE CHANG
CHANGING.
IN THE BEGINNING OF LIFE ON THE
LEFT YOU CAN SEE THE BABIES ARE
DYING EARLY IN LIFE.
THE FIRST 12 HOURS IN THE FIRST
WEEK IT IS BLUE.
THEN LATELY YOU SEE OTHER COLORS
INCLUDING PURPLE FOR NEC.
THAT I AM THINKING OKAY THERE IS
SOMETHING IN THE BEGINNING AND
THEN SOMETHING AFTER THE FIRST
WEEK AND THEN BLUE.
BLUE BABIES THEY NEED
CIRCULATION AND OXYGEN IN THE
BEGINNING OF LIFE.
ONCE THEY HAVE ESTABLISHED THAT
THEN THEY NEED
ENERGY, NUTRITION, THEY NEED TO
BE FED.
SO THE COMPLICATIONS AND THE
REASONS WHY SHIFTED AFTER A WEEK
OR 2.
I KEPT READING A LITTLE BIT AND
SINCE KENNEDY AND THE SIXTIES
AND TELL TODAY AND SEEING
SEVERAL BREAKTHROUGHS WITH THE
INCUBATOR AND BREAST-FEEDING
SURFACTANTS AND OTHER FACTORS
HAVE BEEN ADDED BUT I WAS
SITTING DOWN AND THINKING MAYBE
IT IS TIME TO ACTUALLY PRODUCE
IBP 9414.
AND HAVE AN EFFECT ON GUT
FUNCTION AND MAYBE IF WE HAVE
THAT GOING BACK TO THIS PICTURE
IF WE IMPROVE GUT FUNCTION MAYBE
WE REDUCE MORTALITY.
SO THEN REMEMBER I WAS WORKING
FOR THE COMPANY IT IS A DIETARY
SUPPLEMENT COMPANY AND THEN WE
REALIZE THERE ARE NO THERAPIES
AVAILABLE FOR MEDICAL NEED AND
THEN WE WERE THINKING GO TO
DIETARY SUPPLEMENT I WILL
DISCUSS THAT TODAY IT SHOULD BE
CONSIDERED SOME PEOPLE SAY YES
SOME SAY NO BUT WE LOOKED AT THE
PRETERM INFANTS THESE ARE THE
POPULATION THAT WE WILL TREAT
AND WE JUST SAY THEY ARE
EXTREMELY VULNERABLE AND TOOK A
POSITION.
THE IBT POSITION WAS AND REMAINS
CLEAR PHARMACOLOGICAL
DEVELOPMENT IS THE RIGHT PATH
FORWARD.
THAT IS SUBJECTIVE THINKING.
BUT THIS IS WHAT WE DO AT IBT
SINCE I AM THE CEO I REPRESENT
THE COMPANY IN FULL.
EVERYBODY SAYS I CANNOT SPEAK
FOR THE ORGANIZATION BUT I CAN
SO WE DO DEVELOPMENT SO WHAT IS
IBP?
I FORWARD THIS SO WE LOOK AT
THIS IT ONLY HAS 3 LEGS AND
THERE IS A REASON FOR THAT AND
THE LEGS FOR SAFETY PRODUCTION
WE CAN CALL THEM OTHER THINGS
BUT THEY ARE EQUALLY IMPORTANT
IF YOU BREAK OFF 1 LEG THE STOOL
WILL TIP.
AND THEN WE DO CLINICAL TRIALS.
PUBLISHED IN THE NEW ENGLAND
JOURNAL.
AND IT IS ALL ON EFFICACY.
WE WANT THAT.
IT IS GREAT TO HAVE AN EFFECT.
THAT'S WHAT WE WANT.
I WANT TO GIVE YOU EFFICACY SO
YOU BUY MY PRODUCT.
BUT I ALSO NEED TO LOOK AT
SAFETY ABSOLUTELY WE WILL COME
BACK TO THAT BUT I WANT TO
HIGHLIGHT PRODUCTION.
BECAUSE IF I A DOCUMENT THE
EFFECTS AROUND EFFICACY AROUND
CLINICAL TRIALS AND THAT CREDIT
IS CHANGING WITH TIME THEN IS
NOT RELEVANT ANYMORE IT IS OLD
DATA IF MY PRODUCT IS CHANGING
WITH TIME THE PRODUCT THAT I AM
OFFERING YOU.
WE NEED TO LOOK AT THAT
PRODUCTION THERE ARE OTHER
ASPECTS FOR EXAMPLE THE
PRODUCTION INVOLVES A MISTAKE
AND LET'S SAY SALMONELLA.
THAT IS SAFETY YOU READ AND THE
PUBLICATIONS AND THE JOURNALS WE
DON'T SEE SIDE EFFECTS BUT THAT
WAS FOR THE PRODUCT THAT DID NOT
CONTAIN THE SALMONELLA.
SO THAT IS NOT TRUE ANYMORE AND
THEREFORE WE NEED TO PAY VERY
MUCH ATTENTION TO THE PRODUCTION
AND ALSO WE KNOW IT IS ALIVE THE
L STANDS FOR LIVE AND I KNOW
THAT IT DIES AND WATER.
SO IF I PRODUCE IT IN A WAY WITH
A LITTLE BIT OF WATER IS ENTERED
INTO THE PRODUCT, I AM NOT
GIVING YOU LIVE BIO THERAPEUTIC
PRODUCT IT IS DEAD.
AND THEN THE EFFICACY DOESN'T
WORK SO I WANT TO HIGHLIGHT
BECAUSE I KNOW FDA AND OTHERS
THEN YOU LOOK AT THIS FROM THE 3
LEGS PRINCIPAL THAT IS GOOD FOR
EVERYBODY WHO WANTS TO USE THE
PRODUCT SO LOOK AT SAFETY AND
THIS IS THE REASON WE STARTED
LBP WE COULD NOT SEE IF THEY HAD
PICKED UP THE SAFETY SIGNALS AND
I JUST READ SOMETHING FROM THE
TOOLKIT THAT WAS PUBLISHED LAST
YEAR.
THEY SAY MOST OF THE TRIAL IS
DONE ON PRETERM INFANTS DO NOT
FULLY MONITOR OR REPORT SIDE
EFFECTS.
I AGREE BUT I ALSO READ THE
PAPERS.
WHAT DOES IT MEAN?
BUT I AM JUST LOOKING AT THE
PICTURE OF THE ICEBERG YOU SEE
WHAT YOU SEE BUT BENEATH THE
SURFACE THERE MIGHT BE MORE.
SO THEREFORE I THINK IT'S
IMPORTANT THAT YOU TRY TO LOOK
BENEATH THE SURFACE TO SEE WHAT
THE ICEBERG HOLDS UNDERNEATH THE
SURFACE.
SO PHARMACEUTICALS IN GENERAL WE
TRIED TO BALANCE THE RISK AND
BENEFITS AND IF THEY OUTWEIGH
THE RISK IT IS GOOD THE DRUG IS
GOOD OR IS GOOD TO PRESCRIBE THE
DRUG IT IS GOOD IF THE RISKS
OUTWEIGH THE BENEFITS THEN IT IS
BAD.
WE SHOULD NOT USE IT AND THEN WE
USE SCALE OVER AND OVER.
I'M NOT BUT I THINK FDA IS USING
IT AND CDC AND DOCTORS USE IT
EVERY DAY.
YOU LOOK WHEN YOU APPROVE A DRUG
IT FDA LOOK AT THE RISK AND
BENEFIT AND THEN YOU DECIDE.
?
SO THEN TO THINK WHAT SHOULD WE
SAY?
ANTIBIOTICS IS A GROUP IT IS
VERY GOOD IF SOMEONE HAS AN
INFECTION BUT IT'S VERY BAD IF
WE USE THEM EVERY DAY SO ARE
THEY GOOD OR BAD?
IT DEPENDS.
AND THEN WHEN PRESCRIBED I KNOW
WHAT THE PACKAGING SAID AND YOU
READ ALL THE WARNINGS AND THE
TEXT FROM FDA AND THE
MANUFACTURERS AND THEN YOU
DECIDE I THINK I WILL PRESCRIBE
THIS AND THEN THE BABY OR
PATIENT COMES BACK YOU MAY
CHANGE THE MEDICATION FOR SIDE
EFFECTS.
SO AGAIN WHAT IS OUR ROLE?
IT IS PRETTY SIMPLE.
WE WANT TO WITH THE BABIES
LOOKING OVER AT DOCTOR PATEL AND
YOU CAN SEE THAT WE WANT TO TAKE
OUT THE REASONS TO REDUCE THE
DEATH OF THE BABIES WE ARE
TRYING NOT TO REMOVE THE SIDE
EFFECTS OR SAFETY CONCERNS BUT
WE ARE TRYING SO REALLY I WOULD
LIKE TO RAISE THAT ICEBERG OUT
OF THE WATER SO WE CAN ALL LOOK
AT WHAT THE DRUG IS DOING.
LAST TALKING ABOUT PRODUCTION
AND I MADE A VERY SIMPLE PICTURE
WE WANT TO KEEP THE LIVING
BACTERIA INSIDE THE PRODUCT BUT
KEEP THE PATHOGENS ON THE
OUTSIDE THAT'S IMPORTANT.
SO 12 YEARS AGO WE STARTED THIS
IS A SUMMARY OF 12 YEARS WE HAVE
BEEN WORKING IN 15 COUNTRIES AND
WE HAVE ENROLLED OVER 2000
PATIENTS IN THE TRIAL AND THE
COST IS $110 MILLION SO FAR.
SO WHEN I WAS INVITED TO SPEAK
THE CDC ASKED ME TELL ME ABOUT
THE CHALLENGE.
I'M HAPPY TO DO SO.
AND THIS IS NOT PART OF YOUR
JOB.
YOU DIDN'T EVEN DO ANYTHING
ABOUT THIS I'M JUST TELLING YOU
WHY.
BUT FIRST WHEN WE DO CLINICAL
STUDIES AT HIGH QUANTITY IT COST
A LOT OF MONEY.
AND IBT DOES NOT SELL ANYTHING.
WE HAVE NO INCOME.
IF WE WANT TO SPEND MONEY WE
NEED TO HAVE THE MONEY.
IT'S NOT THAT EASY YOU CAN SEE
WHAT WE HAVE DONE PEOPLE HAVE
GIVEN US MONEY SO WE START WITH
THE ORPHAN DRUG RESIGNATION AND
THEN WITH $5 MILLION AND THEN IT
HAS CONTINUED THROUGH THE
DEVELOPMENT.
IS A THAT HITS THE X AXIS IT IS
OVER.
SO IT'S MY JOB TO KEEP A LINE ON
- - KEEP AN EYE ON THE GREEN
LINE HOW WE RELATE TO THE
INVESTORS.
THIS IS MY EVERYDAY WORK NOTHING
TO DO A SCIENCE OR BABIES
RUNNING A COMPANY.
SO ANOTHER FACTOR OF WHAT I
WOULD SAY IS OUTSIDE OF OUR
CONTROL AND LOOKING AT COVID AND
DEATH DUE TO COVID AND WHAT YOU
CAN SEE THE BLUE LINE THAT
RECRUITMENT INTO THE STUDY IS
PRETTY MUCH STANDING STILL WHEN
WE HAVE PEAKS OF COVID
OUTBREAKS.
WHY IS THAT?
HOSPITALS HOW DO WE GET FULL
CONSENT?
WE THOUGHT THE STUDY WOULD TAKE
2 YEARS BUT IT TOOK 5 YEARS.
NUMBER 3 HAS TO DO WITH
PRODUCTION AGAIN AND THAT IS IN
A SIMPLE WAY YOU CAN DIVIDE
DRUGS INTO 2 TYPES ORAL DRUGS
AND INJECTABLE DRUGS AND ORAL
DRUGS YOU TAKE WITH YOUR HAND
AND INJECTABLES WE INJECT AND IF
YOU LOOK BEHIND THE SCENES INTO
THE MANUFACTURING THEY CAN BE
MANUFACTURED IN DIFFERENT WAYS.
AND TO THE LEFT I HAVE MAN WHO
IS LOOKING OR HANDLING THE
PRODUCTS IN OPEN SETTING.
IF WE NEED A STERILE PRODUCT IT
DOESN'T WORK.
BECAUSE IN THIS CASE PATHOGENS
MIGHT COME OR BUGS COULD COME IN
CONTACT WITH THE PRODUCT ALSO
WATER COULD COME IN CONTACT AND
REMEMBER I SAID L. REUTERI WILL
DIE WITH WATER SO WE DON'T WANT
TO HAVE THIS OPEN HANDLING WE
WENT CLOSED HANDLING SO THEN WE
SEE THE GLOVEBOX AND THE PERSON
MANIPULATING SOMETHING BUT NOW
THE RULES SAY THAT IF YOU'RE
INTO STERILE INJECTABLE
MANUFACTURING YOU NEED TO SHOW
THE REGULATORS YOU ARE IN
CONTROL BUT THIS IS FREE FROM
BUGS AND THESE MANUFACTURERS
THEY PRACTICE EVERY DAY AND THEY
TRY TO STAY IN CONTROL OF THE
EQUIPMENT THEY HAVE TO BUT THEN
WE COME AND HELLO?
I HAVE A BUG I WOULD LIKE TO
BRING THAT INTO YOUR STERILE
ENVIRONMENT.
HOW DO YOU FEEL ABOUT THAT?
WHAT DO THEY SAY?
NO THANK YOU.
WILL YOU BUY A LOT?
YES I THINK I WILL ORDER SOME
MATERIAL I HOPE.
IS IT IS SO MUCH WORK FOR US AS
A COMPANY THAT I JUST WANT TO
TELL YOU THIS TODAY.
WHY ARE WE DOING THIS?
WHY DO WE GO THROUGH ALL OF
THESE CHALLENGES?
I THINK THE IMPORTANT THING TO
SAY IS WE DON'T NEED TO DO
THAT.
WE DO IT BECAUSE WE WANT TO
BECAUSE WE WANT TO HELP THE
BABIES THERE IS NO REGULATION
AND NOTHING FORCING US TO DO
WHAT WE ARE DOING.
WE DO THIS OUT OF FREE WELL.
AND WHAT WE WANT IS TO SEE
OURSELVES THAT IF YOU COMBINE A
PICTURE FROM DOCTOR PATEL'S
PUBLICATION AND YOU LOOK AT THE
EFFECTS ON THE MORTALITY AFTER
14 DAYS I CAN ALREADY SEE THE
BLUE AND THE RED ARE SEPARATED
AND THIS IS ALL MORTALITY AND
THIS MAKES US VERY HAPPY AND WE
ARE PROUD AND SAY THAT THIS IS A
WONDERFUL THING WE HAVE BEEN
WORKING WITH THE LAST 12 YEARS.
SO THE NEXT STEP IS TO PREPARE.
AND YOU CAN SEE TO THE LEFT THE
PICTURE IS OLD BUT THIS IS WHAT
IT LOOKS BACK HOME IN SWEDEN AS
WE GATHER THE REPORTS IN THE
DATA AND PUTTING THEM TOGETHER.
AFTER THAT HOPEFULLY FDA WILL
LOOK AND COME OUT AND SAY
SOMETHING POSITIVE.
THEN WE HAVE A PRODUCT WE CAN
GIVE.
I HAVE IT SOMEWHERE.
IT IS EMPTY.
BUT WE WANT TO GIVE THAT PRODUCT
TO PEOPLE WHO WERE LOOKING FOR
THE PRODUCT THIS IS A WHOLE
THING WE ARE DOING.
THIS IS WHY WE ARE DOING THE
TRIAL.
THANK YOU SO MUCH.
>> QUESTIONS?
>> FROM PEDIATRICS THIS IS A
QUESTION FOR DOCTORS JOSEPH NEU
WE TALK ABOUT THINGS AND HAVING
STRICT PROTOCOL BUT AS A
CLINICIAN YOU ALSO KNOW THAT
EVERYTHING IS CONTEXTUAL FROM
PLACE TO PLACE TALK ABOUT PEOPLE
IN YOUR TRIAL BEING LOYAL TO
THEIR ALGORITHM AND WHEN I LOOK
AT THE CENTERS THAT HAVE GOOD
EXCELLENCE TAKING CARE OF THE
MOST PREMATURITY THE GERMANS AND
THE JAPANESE I HAVE EXTREMELY
DIFFERENT STRATEGIES
DIAMETRICALLY OPPOSED BUT YET
THEY ALL GET GOOD OUTCOMES.
SO AS SOMEBODY WHO IS A TRIAL
LIST ALSO, THIS JUST SEEMS LIKE
A COMPLICATED THING BECAUSE WE
KEEP COMING DOWN TO THE VERY
NARROW DISEASES BUT LIVE IN A
COMPLICATED WORLD JUGGLING MANY
BALLS OF RISK AND HOW YOU
ACCOUNT FOR THAT IN THE TRIALS
WERE CONTEXT MATTERS EVEN WITH A
PRODUCT THAT IS PROVEN TO BE
EFFICACIOUS IN A SETTING.
>> I 100 PERCENT AGREE IT HAS TO
BE CONTEXTUALIZED AND JUST TO
GIVE YOU AN EXAMPLE, WHEN YOU
LOOK AT THE SUSTAINED FEEDING
TOLERANCE AND COMPARE EUROPE TO
THE UNITED STATES AND IN THE
UNITED STATES THERE IS A
SIGNIFICANT DIFFERENCE AND IN
EUROPE THERE IS NOT BUT THE
PRODUCT VERSUS PLACEBO AND
EXACTLY WHY?
WE DON'T KNOW BUT THERE ARE
DIFFERENCES ACROSS THE POND WITH
PRACTICES TRADITIONAL
DIFFERENCES AND I THINK THAT
SOME OF THOSE INGRAINED
DIFFERENCES MAY BE A PART OF
THAT.
ABSOLUTELY I COULD NOT AGREE
MORE.
>> SO FROM THE RESUME A QUESTION
DOES IT CAUSE MORTALITY A
DIFFERENT OPINION ON THE USE OR
EXCLUSIVE MOSTLY ON HUMAN MILK
VERSUS PRETERM FORMULA?
>> THAT'S A REALLY GOOD
QUESTION.
WE HAVE NOT DISSECTED THAT OUT
AND IT IS SOMETHING WE NEED TO
LOOK AT.
THANK YOU.
>> DOCTOR JOSEPH NEU WHAT IS
YOUR RECOMMENDATION TO FDA AFTER
THIS TRIAL?
I READ THAT QUESTION BECAUSE I
ASSUMED IT WAS THE OUTCOME FROM
HIS PREVIOUS TALK.
>> IT IS NOT UP TO ME TO DECIDE.
>> JUST QUICKLY TO TOUCH ON THE
QUESTION OF FORMULA.
>> SO THIS IS SOMETHING ME HAVE
A VERY RICH DATA SET AND AT THIS
JUNCTURE THERE IS SO MANY THINGS
WE STILL NEED TO DISSECT AND
THAT IS 1 OF THEM.
THE TYPE OF FEEDING THAT THESE
BABIES HAVE RECEIVED.
>> YOU ARE A DOCTOR SO WHERE DO
YOU END UP ON THIS?
>> IT'S A GOOD QUESTION.
WE ARE PRODUCING IT IN EUROPE
AND THE REASON IS BECAUSE WE
HAVE TO STAY VERY CLOSE TO
MANUFACTURERS AND SINCE WE ARE
BASED IN EUROPE WE HAVE
MANUFACTURING IN EUROPE.
>> WAS IT IN A TRADITIONAL SMALL
MOLECULE MANUFACTURER?
CAN YOU SAY MORE ABOUT THAT?
>> I CAN'T SPEAK ABOUT IT
BECAUSE IT COMES FROM THE
DIETARY SUPPLEMENT COMPANY AND I
WAS VISITING THE CURRENT
PRODUCERS AND SINCE I AM NEXT
REGULATOR AND WORKING WITH THE
LARGE COMPANIES I FELT THAT IT
WAS RIGHT FROM THE BEGINNING AND
I DO NOT USE ANY LBL
MANUFACTURERS AND HAD TO START
FROM SCRATCH AND PEOPLE THAT
WERE DOING PHARMACEUTICALS NOT
DOING FOOD PRODUCTS.
A VERY HIGH COST I MUST SAY TO
DO THE SWITCH.
>> CAN YOU PLEASE REPEAT THE
QUESTION?
>> TALK ABOUT L. REUTERI AND TO
GIVE THAT AS A MOLECULE TO THE
BABIES IS THE QUESTION.
WE THOUGHT YOU COULD DO THIS BUT
WHY CHANGE THE SYSTEM THAT COMES
FROM MOTHERS?
WE HAVE SOURCED THE STRAIN FROM
LACTATING WOMEN IN HUMANS AND SO
THEREFORE WE HAVE TAKEN FROM THE
BREAST MILK THAT'S WHAT WE ARE
GROWING IN THE FACTORY SO WE
THOUGHT EVERYBODY LIKES
BREASTMILK IT IS PROBABLY VERY
SAFE TO GIVE SOMETHING THAT THEY
NORMALLY GET WERE NOT SAYING
THAT'S THE REASON TO GET IT
APPROVED BUT IT IS A GOOD
STARTING POINT.
>> WHAT IS IT?
>> SO THERE IS A QUESTION AND A
HAS TO DO WITH THE WAY THE
ANALYSIS IS DONE WITH THE MODERN
TREATMENT WITH THE DOUBLE-BLIND
FOR ALL CAUSE MORTALITY.
>> SO THE MODIFICATION LARGELY
WAS IN DISCUSSION WITH THE
STATISTICIAN AND IF YOU DO
STRAIGHT INTENTION TO TREAT AND
IF YOU HAVE ABSOLUTELY NO DRUG
BEING GIVEN TO THE INDIVIDUAL IT
JUST DOESN'T MAKE SENSE TO
INCLUDE THAT.
SO I THINK IT MADE A LOT OF
SENSE TO HAVE THAT MODIFICATION
WHERE IN THE DRUG GROUP AT LEAST
THEY HAVE RECEIVED 1 DOSE OF THE
DRUG.
>> FOLLOWING UP ON A PREVIOUS
QUESTION CAN YOU TALK MORE HOW
THE MANUFACTURING OF THE
PHARMACEUTICAL LEVEL PRODUCT
DIFFERS FROM THE FOOD GRADE
PRODUCT?
>> IT IS A GOOD QUESTION.
HOW MUCH YOU KNOW ABOUT
PHARMACOPEIA?
>> THE PACKET WE USE IN MED
SCHOOL?
[LAUGHTER]
>> IT IS A VERY LONG ANSWER.
I DON'T KNOW WHERE TO START BUT
FOR EXAMPLE EVERY BATCH SHOULD
BE TESTED SO YOU DON'T HAVE
PATHOGENS DO YOU SEE THAT
GLOVEBOX I WAS SHOWING?
WHAT HAPPENS IF THERE WAS A
LEAKAGE OR SOMEBODY HAS A LONG
FINGERNAIL AND THERE IS A
WHOLE?
WE WANT TO DETECT THAT ERROR
PRIOR TO GIVING YOU THEIR
PRODUCTS WITH THE UNDOCUMENTED
RISK.
SO WE WILL TEST EVERY BATCH AND
LOOK FOR ERRORS.
>> DOES THAT TESTING NOT HAPPEN
WITH FOOD SUPPLEMENTS?
>> I DON'T WORK IN FOOD
SUPPLEMENTS.
AND I KNOW FROM THE COST REASON
THEY CANNOT APPLY THE THINGS
THAT WE APPLY.
THAT IS THE POLITICALLY CORRECT
ANSWER I THINK.
>> I WILL PUT YOU ON THE SPOT TO
DOVETAIL THAT.
IF IBT PRODUCT IS EVENTUALLY
APPROVED IN THE US IS THERE AN
ESTIMATED PRICE POINT COMPARED
TO THE PRODUCTS FOR USE QUICK.
>> LOOKING AT THE COST OF
PRODUCTION IS MUCH HIGHER BUT
THAT IS 1 PIECE INVESTING
$110 MILLION IN A DEVELOPMENT
PROGRAM IS 1 PIECE AND VERY MUCH
ABOUT THE EFFICACY.
IF WE SAY THIS HAS NO EFFECT AND
THE COST OF THE PRICE WILL BE 0
AND IT'S OKAY IF I DON'T SAY
ANYTHING BUT IF I WANT TO SAY TO
PREVENT DEATH OR SOMETHING THEN
IT BECOMES A DRUG THAT WE HAVE
LABELED CLAIMS WITH THE FDA IN
THE COUNTRY AND LET'S SEE WHERE
IT LAST.
AFTER THAT WE CAN DISCUSS
PRICE.
>> WE HAVE JUST A COUPLE OF
SECONDS LEFT.
THANK YOU FOR THE PRESENTATION
THANK YOU FOR PARTICIPATING.
WE HAVE 1 MORE SECTION AND
CLOSING COMMENTS BUT I WANT TO
TAKE A MOMENT TO THANK THE TEAM
FOR PUTTING EVERYTHING TOGETHER
OBVIOUSLY IT'S VERY IMPORTANT TO
HAVE EVERYBODY'S INPUT ALSO
THANK YOU TO ALL THE NIAID FOLKS
AS WELL AS THE SUPPORT FROM MY
BRANCH AND SECTION CHIEF.
LUSCIOUS WHAT I WANTED TO DO BUT
THEN ASKS SECTION IS A CLOSING
REMARKS.
HE WILL BE SENT OFF WITH SOME
WISDOM.
HE HAS A LOT OF NOTES.
I SAW HIM TYPING.
>> SO MY ASSIGNMENT IS TO
ATTEMPT A BRIEF SUMMARY
RECOGNIZING I AM BETWEEN YOU AND
FRIDAY RUSH HOUR ON THE CAPITAL
BELTWAY.
I WILL TRY TO KEEP IT SHORT.
HOPEFULLY FOUND THE PUBLIC -- --
THE OPEN PUBLIC WORKSHOP TODAY
ON THE CURRENT STATE OF
EPIDEMIOLOGY, NUTRITIONAL
ASPECTS OF NEC AND USE OF LBP TO
PREVENT NEC ON THE CURRENT
LITERATURE AND CLINICAL DESIGNS
AND ON MANUFACTURING OF THESE
PRODUCTS.
WE MAY NOT BE LEAVING WITH ALL
OF THE QUESTIONS ANSWERED BUT I
DO THINK WE COLLECTED SOME
ADDITIONAL QUESTIONS TODAY THAT
WILL BE HELPFUL IN REVISING AND
REFINING THE STRATEGIC ATTEMPT
OF WHAT WE ARE TRYING TO DO BUT
ALSO THE PROBLEM STATEMENT SO ON
THE NEXT COUPLE OF SLIDES I WILL
GO BACK TO A SLIDE PRESENTED
DURING THE INTRODUCTION AND TRY
TO CAPTURE SOME OF THE
ADDITIONAL QUESTIONS THAT MAY
HAVE COME OUT OF THE DISCUSSION
TODAY.
SO ON THE FIRST SLIDE THIS HAS
TO DO WITH BIOLOGICAL PRODUCTS
WITH THEY WERE TO MAKE THE
ASSERTION BUT 1 THING THAT CAME
UP IN DISCUSSION THAT IS
CRITICALLY IMPORTANT IS WHAT IS
THE RECOGNIZE DISEASE OR
CONDITION THAT WE ARE ASSUMING
THIS PRODUCT ADDRESSES?
DO WE NEED TO TAKE A LOOK AT
NECROTIZING ENTEROCOLITIS AS A
RECOGNIZE DISEASE OR CONDITION
AND IS THERE SOMETHING ELSE THAT
SHOULD BE DEFINED?
I WILL LEAVE THAT AS AN OPEN
QUESTION.
SO WHERE DO WE LAND TODAY WITH
RESPECT TO ADEQUATE CLINICAL
INVESTIGATION TO ESTABLISH
SAFETY AND EFFECTIVENESS TO ME
STATUTORY REQUIREMENTS?
AND I THINK THERE WAS A PRETTY
LONG LIST OF QUESTIONS THAT CAME
UP FOR EXAMPLE THE ROLE FOR
PROPOSED RISK FACTORS WITH THE
STRATIFICATION AND SUBGROUP
ANALYSIS AND STANDARDS OF
STEWARDSHIP IN THE CLINICAL
TRIALS DO WE NEED STOOL
BIOMARKERS LIKE THE MICROBIAL
COMMUNITY PROFILES IN THE
CLINICAL INVESTIGATIONS?
>> 1 OF THE THINGS POINTED OUT
GIVEN THE POTENTIAL FOR
CROSS-CONTAMINATION DO WE NEED
TO LOOK AT ALTERNATIVE CLINICAL
DESIGNS AND WHAT WORK DO WE HAVE
TO DO ON DEFINING STANDARD OF
CARE INCLUDING MEDICATIONS OF
BOTH OF THE CONTROL GROUP AND
THE INVESTIGATIONAL GROUP DURING
THE TRIAL IS THERE A NEED FOR
ACCEPTED CASE DEFINITIONS AS
WELL AS ADDITIONAL WORK ON THE
MECHANISTIC UNDERSTANDING OF
WHAT IS CAUSING THE DISEASE AND
THE CONDITION AND WHAT MAY
ACCOUNT FOR THE ABILITY THAT HAS
BEEN OBSERVED IN THOSE DISEASE
STATES AND CONDITIONS?
AND THAT IS A LONG LIST OF
QUESTIONS BUT WHAT ARE THE
IMPLICATIONS ON BOTH THE DESIGN
AND FEASIBILITY?
AND FINALLY THE NEED FOR
COMPLETION FOR A SPECIFIC
ADVERSE EVENT DEFINITION AND
RELATED TO THE SAFETY RISK AND
HARM AND THE USE OF ADJUDICATION
WITH CLINICAL INVESTIGATION.
FINALLY WHERE DO YOU LAND IN
TERMS OF MANUFACTURING?
HIGHLIGHTING SOME OF THE
PRODUCTION CHALLENGES 1 OF WHICH
IS INCLUDING AND ENSURING
RELIABILITY OF ALL THE THINGS
THAT IT COULD BE EXPOSED TO WHEN
IT LEAVES THE FACTORY FLOOR AND
GETS TO THE INFANT IN THE NICU.
A COUPLE OF OTHER THINGS THAT
CAME UP RELATED TO THE PRODUCT
AS PART OF THE INVESTIGATION
WOULD BE REALLY HELPFUL TO HAVE
A CLEAR DEFINITION OF WHAT IS
THE COMPOSITION TO FACILITATE
CLINICAL INVESTIGATIONS AND THEN
ALSO HOW DO WE CHARACTERIZE WHAT
ACTUALLY HAPPENS TO A PRODUCT
DURING THE CLINICAL
INVESTIGATION?
I WILL AND THERE I WILL ECHO
AGAIN A HUGE THANKS TO THE
SPEAKERS AND PRESENTERS IN
PERSON PARTICIPANTS AND THOSE
ONLINE PARTICULARLY MY
COLLEAGUES AT CDC AND NIH I WILL
MISS THE MONDAY AFTERNOON
MEETINGS.
I WILL END.
THANK YOU.
[APPLAUSE]