>> Craig Hales: GOOD MORNING.
I'M DR. CRAIG HALES.
DIRECTOR OF NIDDK.
ALONG WITH STRAVROULA OS
GAINIAN AND DR. SUSAN YANOVSKI,
WHO IS NOW RETIRED, I WOULD
LIKE TO WELCOME YOU TO THE
WORKSHOP ON "CAN DATA SCIENCE
AND A.I. DELIVER ON ITS PROMISE
FOR SECTION CHIEF,
BIOSTATISTICS DIRECTOR, TITE
--
I WOULD LIKE TO RECOGNIZE ALL
THE MEMBERS OF THE FEDERAL
PLANNING COMMITTEE WITH
REPRESENTATIVES FROM INSTITUTES
AND OFFICES, AS WELL AS CDC AND
FDA.
THANK YOU FOR PROVIDING YOUR
VALUABLE INPUT WHICH HELPS
SHAPE THE AGENDA, SPEAKER
SELECTION AND WORKSHOP TOPICS.
THE BROAD RANGE OF
REPRESENTATIVES ON THE PLANNING
COMMITTEE AFFECTS WIDE-RANGING
EFFECTS OF GLP-1 BASED
THERAPIES TO DEEPEN OUR
UNDERSTANDING OF THE REAL WORLD
BENEFITS AND RISKS.
AS WE BEGIN THE WORKSHOP I HAVE
THE PLEASURE OF INTRODUCING DR.
GRIFFIN RODGERS, DIRECTOR OF
THE NATIONAL INSTITUTE OF
DIABETES AND DIGESTIVE AND
KIDNEY DISEASES OR NIDDK.
WILL PROVIDE SOME WELCOMING
REMARKS.
DR. RODGERS?
>> Griffin Rodgers: THANK YOU.
AS THE DIRECTOR OF NATIONAL
INSTITUTE OF DIABETES AND
DIGESTIVE AND KIDNEY DISEASES I
WOULD LIKE TO WELCOME TO THIS
IMPORTANT WORKSHOP ON
LEVERAGING REAL-WORLD EVIDENCE
TO ASSESS GLP-1 THERAPIES.
THEY ARE CURRENTLY APPROVED FOR
OBESITY AND TYPE 2 DIABETES,
MAJOR CARDIOVASCULAR EVENTS,
DIABETIC NEPHROPATHY AND
OBSTRUCTIVE SLEEP APNEA.
GROWING EVIDENCE SUGGESTS THE
POTENTIAL FOR THE PREVENTION OR
TREATMENT OF MULTIPLE CHRONIC
DISEASES, RANGING FROM
METABOLIC DYSFUNCTION STEATO
DPHHS HEPATITIS, OSTEOARTHRITIS
OF THE KNEE, ALZHEIMER'S
DISEASE, PARKINSON'S DISEASE,
SUBSTANCE OR ALCOHOL ABUSE.
THE INFORMATION IS INCREASE
WITH POSSIBLE OF EXPANDED
INDICATIONS IN THE FUTURE.
THE POTENTIAL PATIENT POOL FOR
GLP-1 DRUGS IS VERY LARGE.
THERE'S A CRITICAL NEED TO
MONITOR FOR SERIOUS ADVERSE
EVENTS THAT ARE RARE OR TAKE
YEARS TO DEVELOP.
SUCH AS ACUTE PANCREATITIS,
BOWEL OBSTRUCTION, MEDULLARY RY
THYROID CANCER, SUICIDAL
IDEATION OR ACUTE KIDNEY INJURY.
MANY QUESTIONS REMAIN ABOUT THE
USE OF GLP-1 BASED THERAPIES IN
THE REAL WORLD SETTINGS.
SUCH AS TREATMENT PATHWAYS FOR
SUSTAINABLE CARE, SAFETY AND
EFFECTIVENESS IN SUP
POPULATIONS, HETEROGENEITY OF
TREATMENT RESPONSE, ADHERENCE
CHALLENGES AND USE OF BROADER
RANGE OF CLINICAL SETTINGS AND
PRESENTATIONS THAN IN CLINICAL
TRIALS.
AND IMPACT THAT HELP FORM
POLICY DEVELOPMENT SUCH AS
COVERAGE DECISIONS.
REAL-WORLD DATA SOURCES
INCLUDING ELECTRONIC HEALTH
RECORDS AND CLAIMS OFF THE
POTENTIAL TO ANSWER MANY OF
THESE QUESTIONS.
CHALLENGES UNIQUE TO GLP-1
BASED DRUGS, SUCH AS INADEQUATE
INSURANCE COVERAGE, MEDICATION
SHORTAGES, COMPOUNDED
MEDICATIONS OBTAINED OUTSIDE OF
THE HEALTH CARE SYSTEM AND
OFF-LABEL USES REQUIRE SPECIAL
CONSIDERATION.
GIVEN THESE CHALLENGES AND
OPPORTUNITIES, WE ARE BRINGING
TOGETHER SCIENTISTS FROM
VARIOUS DISCIPLINES TO IDENTIFY
GAPS IN OUR KNOWLEDGE OF THE
BENEFITS AND RISK OF GLP-1
BASED THERAPIES AND HOW THEY
CAN BE ADDRESSED USING REAL
WORLD EVIDENCE TO INFORM POLICY
IN CLINICAL PRACTICE DECISIONS.
I WOULD LIKE TO THANK THE
DISTINGUISHED SPEAKERS FOR
TAKING THE TIME TO COME HERE AS
YOUR COLLECTIVE EXPERTISE AND
EFFORTS WILL HELP ADVANCE
PROGRESS ON PREVENTION AND
TREATMENT ON A RANGE OF CHRONIC
DISEASES THAT REPRESENT
PRIORITIES NOT ONLY FOR NIDDK
BUT MANY INSTITUTES AND OFFICES
ACROSS NIH.
WE LOOK FORWARD TO AN
ENLIGHTENING AND PRODUCTIVE
WORKSHOP ON THIS VERY IMPORTANT
TOPIC.
AND WITH THAT, LET ME TURN IT
BACK OVER TO DR. HALES.
THANK YOU.
>> Craig Hales: THANK YOU, DR.
RODGERS FOR YOUR INTRODUCTION
OF THE WORKSHOP.
TO MEET THE GOALS DR. RODGERS
JUST OUTLINED WE HAVE ARRANGED
AN EXCITING AGENDA OF SPEAKERS
WITH AMPLE TIME FOR Q&A AND
MODERATED DISCUSSION.
SO BY THE END OF THE WORKSHOP
PARTICIPANTS WILL HAVE
IDENTIFIED GAPS AND
OPPORTUNITIES FOR FUTURE
RESEARCH ON USING REAL-WORLD
EVIDENCE AND CLINICAL DECISION
MAKING AND CLINICAL GUIDELINE
DEVELOPMENT.
USING REAL-WORLD EVIDENCE FOR
REGULATORY AND HEALTH CARE
POLICY DECISION MAKING.
BEST PRACTICES FOR STUDY
DESIGNS ON GLP-1 BASED
THERAPIES USING REAL-WORLD DATA
AND ANALYTIC METHODS TO ADDRESS
ISSUES SPECIFIC TO GLP-1.
THE AGENDA BEGINS WITH TWO
KEYNOTE PRESENTATIONS TO HELP
SET THE STAGE.
AFTER THE KEYNOTES THERE WILL
BE A 15-MINUTE BREAK AND WE
WILL CONTINUE WITH SESSION ONE
ON REAL-WORLD EVIDENCE TO
INFORM REGULATORY DECISIONS AND
CLINICAL PRACTICE.
WE WILL BREAK FOR LUNCH AT
12:20 UNTIL 1:10 P.M. EASTERN
TIME.
THEN SESSION 2, WE WILL HEAR
ABOUT USING REAL WORLD IFRDS
FOR PUBLIC PRIVATE PAYER
PERSPECTIVES.
AND AFTER THE BREAK WE WILL
CONTINUE WITH SESSION 3 ON
METHODOLOGIC APPROACHES TO
REAL-WORLD EVIDENCE GENERATION
FOR GLP-1 BASED THERAPIES.
WE PLAN TO ADJOURN AT 4:45.
TOMORROW WE WILL BEGIN AT 10:00
A.M. EASTERN TIME.
SESSION 4, BEST PRACTICES FOR
STUDYING GLP-1 BASED THERAPIES
DEFINING EXPOSURE AND OUTCOMES.
WE WILL BREAK FOR LUNCH
12:35-1:15 EASTERN TIME.
AFTER LUNCH SESSION LED BY
CO-CHAIRS WHO WILL SUMMARIZE
RESEARCH GAPS AND OPPORTUNITIES
AND MODERATE A DISCUSSION WITH
ATTENDEES.
THE MEETING TOMORROW WILL
ADJOURN AT 2:00 P.M. EASTERN
TIME.
NOW FOR SOME HOUSEKEEPING
ANNOUNCEMENTS.
THE MEETING IS BEING RECORDED
AND WILL BE POSTED TO THE NIH
WEBSITE.
DANIELLE JOHNIKIN IS THE
MEETING HOST SO PLEASE EMAIL
WITH ANY TECHNICAL ISSUES.
USE THE Q&A FUNCTION TO ENTER
QUESTIONS FOR THE SPEAKERS AT
ANY TIME DURING THE
PRESENTATIONS OR MODERATED
DISCUSSION.
ATTENDEES CAN UPVOTE QUESTIONS
IN THE Q&A.
QUESTIONS WILL BE ANSWERED
DURING THE MODERATED DISCUSSION
FOR EACH SESSION.
IF YOUR QUESTION IS SELECTED BY
THE MODERATOR, THE MEETING HOST
WILL ENABLE YOUR UNMUTE BUTTON
SO YOU CAN UNMUTE YOURSELF AND
ENGAGE WITH THE SPEAKERS, IF
YOU WISH.
THE CHAT IS DISABLED FOR THIS
WORKSHOP AND THE RAISE HAND
FEATURE WILL NOT BE USED.
PLEASE USE THE Q&A FUNCTION
INSTEAD.
NOW I WOULD LIKE TO INTRODUCE
AND THANK THE CO-CHAIRS OF THE
WORKSHOP.
DR. DAVID ARTERBURN, LESLIE
CURTIS AND DARREN TOH BRING A
WEALTH OF EXPERIENCE, OF
EPIDEMIOLOGY, PRAGMATIC
RESEARCH, DESIGN AND
COMPARATIVE RESEARCH USING
REAL-WORLD DATA AND WERE
INSTRUMENTAL DEVELOPING THE
GOALS AND AGENDA TOPICS.
DR. DAVID ARTERBURN IS SENIOR
INVESTIGATOR, MANAGER
INVESTIGATIVE SCIENCES DIVISION
AT KAISER PERMANENTE IN
WASHINGTON HEALTH RESEARCH
INSTITUTE.
OUTCOMES OF OBESITY TREATMENT,
AND IMPLEMENTATION OF SHARED
DECISION MAKING TOOLS.
DR. LESLIE CURTIS IS CHAIR AND
PROFESSOR IN THE DEPARTMENT OF
POPULATION HEALTH SCIENCES AND
MEDICINE AT THE DUKE SCHOOL OF
MEDICINE.
RHODE ISLAND SEARCHER DR.
CURTIS USES MEDICARE AND
MEDICAID OUTCOMES FOR RESOIP.
SHE PLAYS A LEADING ROLE IN
NATIONAL EFFORTS TO IMPROVE
DATA QUALITY.
DR. DARREN TOH IS A PROFESSOR
AT HARVARD MEDICAL SCHOOL AND
HARVARD PILGRIM HEALTH CARE
INSTITUTE.
HE IS AN EPIDEMIOLOGIST,
DEVELOPING AND APPLYING
PRIVACY, TO CONDUCT
MULTI-CENTER STUDIES AND
DISTRIBUTE DATA NETWORKS.
IT'S BEEN A PLEASURE TO WORK
WITH THESE THREE SCIENTISTS
PLANNING THIS WORKSHOP.
NEXT WE WILL HEAR OPENING
REMARKS BY DR. ARTERBURN.
>> David Arterburn: THANK YOU,
DR. HALES, I'M AT KAISER
PERMANENTE SEATTLE.
IT'S A GREAT OPPORTUNITY TO
ADDRESS YOU, I WANT TO THANK
YOU FOR THE WARM WELCOME, DR.
HALES AND ALSO, THANK YOU ON
BEHALF OF OUR CO-CHAIRS, DARREN
TOH FROM HARVARD PILGRIM,
HARVARD MEDICAL SCHOOL AND
LESLIE CURTIS FROM DUKE
UNIVERSITY.
I ALSO WANT TO THANK DR. OS
GAINIAN AND YANOVSKI AND THE
WHOLE CO-CHAIR TEAM FOR THE
HARD WORK OVER THE PAST YEAR,
HELPING US DESIGN THIS VERY
ENGAGING PROGRAM, WHICH I THINK
WILL ENLIGHTEN ALL OF US AND
INSPIRE US TO TAKE THE NEXT
STEP IN EVALUATING THE
LONG-TERM AND REAL-WORLD
EFFECTIVENESS OF GLP-1
MEDICATIONS.
I THINK THE GLP-1 MEDICATIONS
ARE CLEARLY USHERING IN A
PARADIGM SHIFT IN TREATMENT OF
MANY CHRONIC DISEASES.
MOST NOTABLY OBESITY, WHICH HAS
A VERY DIFFICULT TIME
IDENTIFYING MEDICATIONS THAT
COULD INFLUENCE THE LONG-TERM
HEALTH AND PRA JECT RY OF
PATIENTS WITH THAT CHRONIC
DISEASE.
BEFORE I DIVE INTO THE HISTORY
OF GLP-1'S AND IMPACT, AND
BEFORE WE GET INTO THE TOPICS
AND CONVERSATION TODAY, I
WANTED TO TAKE A LOOK BACK AT A
PRIOR NIH WORKSHOP AND IMPACT A
DAY LIKE TODAY AND TOMORROW
WILL HAVE ON THE FIELD AND IN
HELPING US MOVE THE NEEDLE
FORWARD.
I HAD THE PLEASURE OF
CO-CHAIRING A WORKSHOP IN 2013
WITH ANITA KIRK LASS FROM
UNIVERSITY OF PITTSBURGH ON THE
LONG TERM OUTCOMES OF BARIATRIC
SURGERY.
THIS LED TO AN ARTICLE IN JAMA
BUT HAD MANY OTHER IMPACTS
BEYOND THAT CONFERENCE.
NEXT SLIDE, PLEASE, DR. HALES.
ONE OF THE OUTCOMES OF THAT
MEETING WAS A SPECIFIC NIH
FUNDING ANNOUNCEMENT THAT
EMERGED.
WE GATHERED TOGETHER TO TALK
ABOUT LONG-TERM OUTCOMES OF
BARIATRIC SURGERY AND THE GAPS
IN REAL-WORLD EVIDENCE, AS WELL
AS OTHER TYPES OF STUDIES THAT
COULD INFLUENCE OUR
UNDERSTANDING OF LONG-TERM
OUTCOMES AND NIDDK AND NIDA
ALSO RELEASED THIS FUNDING
ANNOUNCEMENT, WHICH LED TO
SEVERAL RO1 GRANTS EVALUATING
THE LONG-TERM EFFECTIVENESS OF
BARIATRIC SURGERY LOOKING AT
VARIOUS HEALTH OUTCOMES FROM
SUBSTANCE AND ALCOHOL ABUSE,
DEPRESSION, LONG-TERM IMPACTS
ON CARDIOVASCULAR DISEASES.
SO NUMEROUS STUDIES CAME OUT
AND PAPERS THAT HAD A HIGH
IMPACT EVALUATING THE LONGER
TERM OUTCOMES OF BARIATRIC
SURGERY AS A RESULT OF THAT
WORKSHOP.
AS WE ARE THINKING OF THE
POTENTIAL IMPACT OF TODAY, I
WANT TO ENCOURAGE OUR NIH
COLLEAGUES TO THINK ABOUT
WHETHER AN OUTCOME LIKE A
WORKSHOP LIKE THIS THAT COULD
HELP MOVE THE WORLD FORWARD OF
EVALUATING THE REAL-WORLD
EFFECTIVENESS OF GLP-1
MEDICATIONS.
NEXT SLIDE, PLEASE.
ANOTHER KEY OUTCOME OF THIS
WORKSHOP WAS THE FORMATION OF A
UNIQUE COLLABORATION CALLED THE
ALLIANCE OF RANDOMIZED TRIALS
OF MEDICINE VERSUS METABOLIC
SURGERY IN TYPE 2 DIABETES, THE
ARMMS-T2D CONSORTIUM.
ENROLLING 262 PARTICIPANTS FROM
FOUR SEPARATE RANDOMIZED
CONTROL TRIALS *F BARIATRIC
SURGERY AGAINST OTHER
INTERVENTIONS FOR OBESITY AND
TYPE 2 DIABETES AND FOLLOWED UP
UP TO 12 YEARS AFTER
RANDOMIZATION.
THEY EXTENDED THE LONG-TERM
FOLLOW-UP OF RANDOMIZED
LONG-TERM CLINICAL TRIALS,
INITIALLY SHORTER TERM
EVALUATIONS.
INCLUDED CLEVELAND CLINIC,
JOSLYN DIABETES CENTER IN
BOSTON, UNIVERSITY OF
PITTSBURGH, UNIVERSITY OF
WASHINGTON, KAISER PERMANENTE
AND PENNINGTON BIOMEDICAL.
THIS GRAPH SHOWS A 12-YEAR
FOLLOW-UP DATA ON LONG TERM
IMPACTS ON BODY WEIGHT IN THOSE
WHO RECEIVED METABOLIC SURGERY
AND THOSE WHO RECEIVED
INTENSIVE LIFESTYLE MEDICAL
THERAPY.
IT EVALUATED LONG-TERM OUTCOMES
ON WEIGHT LOSS, GLYCEMIC
CONTROL, DIABETES REMISSION AND
RELAPSE, BLOOD PRESSURE, HDL
AND LDL CHOLESTEROL, TRY
GLYCERIDES, ADVERSE EVENTS
QUALITY OF LIFE AND SOCIAL
DETERMINANTS OF HEALTH.
I THINK THIS REPRESENTS THE
KIND OF INNOVATIVE
OUT-OF-THE-BOX THINKING THAT
COULD EMERGE FROM A MEETING
LIKE TODAY, WHERE WE THINK WHAT
ARE THE POTENTIAL OPPORTUNITIES
TO HELP MOVE THIS FORWARD AND
TO UNDERSTAND LONG-TERM
OUTCOMES OF GLP-1 MEDICATIONS.
NEXT SLIDE, PLEASE, CRAIG.
ANOTHER WAY OF MEASURING IMPACT
IS TO TAKE A LOOK AT THE
PUBLICATIONS THAT EMERGED
FOLLOWING THAT CONFERENCE.
AND SO I TOOK A LOOK AT PUBMED
AND DID A SEARCH ON BARIATRIC
AND OBSERVATIONAL STUDIES WHICH
WAS A KEY COMPONENT OF THE
STUDIES MANDATE WAS TO LOOK AT
REAL-WORLD AND OBSERVATIONAL
DATA AND ABILITY TO LOOK AT
THOSE STUDIES FOR IMPACTING
BARIATRIC SURGERY OUTCOMES.
BARE
SINCE THE INCEPTION OF PUBMED
THERE HAVE BEEN OVER 1800
PUBLICATIONS BUT 1600 OF THOSE,
OR 89% OCCURRED AFTER THIS 2013
WORKSHOP.
AND SO THIS WAS BEGINNING, THIS
SORT OF WORKSHOP BEGAN AT THIS
SORT OF IMPORTANT JUNCTION,
JUST BEFORE THERE WAS THIS
REALLY LARGE AMOUNT OF WORK
BEING DONE TO HELP CLARIFY THE
LONG-TERM OUTCOMES OF BARIATRIC
SURGERY USING OBSERVATIONAL
STUDY DESIGNS.
AGAIN, WE ARE ON THIS
PRECIPICE, NEXT SLIDE, PLEASE,
CRAIG.
IF WE DO THE SAME SEARCH ON
GLP-1'S IN OBSERVATIONAL
STUDIES, WHAT YOU WILL SEE IS
THERE'S ALREADY, IN 2024 A HUGE
SPIKE IN THE NUMBER OF
OBSERVATIONAL STUDIES THAT HAVE
BEEN CONDUCTED, INVOLVING GLP-1
MIDCATIONS.
MUCH LARGER THAN THERE WERE IN
2023.
AND ALREADY, AS OF THIS MONTH,
IN 2025, WE HAVE ALREADY
PUBLISHED AS MANY ARTICLES,
OBSERVATIONAL STUDIES IN THIS
SPACE AS THERE WERE ALMOST IN
2023.
ANOTHER KEY THING TO NOTE IS
THAT THERE'S ALREADY 751
RESULTS FOR OBSERVATIONAL
STUDIES, COMPARED TO 1800 OVER
THE WHOLE INCEPTION, THIS
LONGER TIMEFRAME FOR BARIATRIC
SURGERY.
IT'S BEEN A BUSY YEAR.
IT'S HARD TO KEEP UP.
THERE ARE SO MANY STUDIES
COMING OUT IN THIS SPACE.
IT'S REALLY INSPIRING, THIS
GROUP OF SCIENTISTS AT NIH TO
COME TOGETHER AND FORM THIS
WORKSHOP TO HELP ADVANCE THE
FIELD AND SET STANDARDS IN THE
FIELD AROUND WHAT ARE THE BEST
PRACTICES THAT WE CAN USE AS
SCIENTISTS TO MOVE THIS FIELD
FORWARD.
BECAUSE AS WE WORK WITH
REAL-WORLD OBSERVATIONAL DATA,
AS WE HAVE CONDUCT PRAGMATIC
TRIALS,THERE ARE BEST PRACTICES
THAT WE CAN ALL ADOPT TO HELP
ENSURE THE HIGHEST RIGOR AND
QUALITY OF THE STUDIES THAT ARE
BEING GENERATED.
SO IT'S NOT JUST ABOUT VOLUME,
IT'S REALLY ABOUT QUALITY OF
THE SCIENCE WE ARE GENERATING.
THERE ARE SO MANY DATABASES
AVAILABLE.
SO MANY OPPORTUNITIES FOR
PEOPLE TO ENGAGE IN SCIENCE
LIKE THIS, BUT WE REALLY NEED
RIGOR TO HELP MOVE THE FIELD
FORWARD.
AND WE NEED TO ASK THE
QUESTION, WHAT ARE THE BEST
QUESTIONS THAT REAL-WORLD DATA
CAN ANSWER, OR WHAT ARE THE
CHALLENGES AND LIMITATIONS TO
ANSWERING THOSE QUESTIONS WITH
REAL-WORLD DATA.
THAT'S WHAT THIS WORKSHOP IS
FOCUSED ON.
I THINK AT THE END YOU WILL
HAVE A CLEAR PICTURE WHAT THE
MAJOR GAPS ARE, OPPORTUNITIES
FOR RESEARCH IN THIS SPACE.
AND WE WILL HAVE A CLEARER
PICTURE OF NEXT STEPS WE CAN
ALL BEGIN TO TAKE.
I WILL SAY THERE'S ALSO A LOT
OF RESEARCH ONGOING.
NIH THERE ARE AT LEAST 15
DIFFERENT REAL-WORLD, OR
OBSERVATIONAL ORIENTED STUDIES
THAT ARE INVESTIGATING GLP-1'S
ACROSS A VARIETY OF HEALTH
CONDITIONS.
THE WORK IS ALREADY GOING, IT
WILL BE CONTINUING.
AND IT WILL BE QUITE A RIDE
OVER THE COMING DECADE.
AND LOOKING BACK TOWARDS
BARIATRIC SURGERY TO SEE WHAT
HAPPENS WITH GLP-1'S AS WE MOVE
FORWARD.
NEXT SLIDE, PLEASE, CRAIG.
ONE THING I WANTED TO SAY, IN
CASE YOU'RE NOT AWARE OF THIS,
IF YOU ARE TRYING TO KEEP UP
WITH THIS SPACE, ONE THING I
FOUND TO BE VERY HELPFUL IS YOU
CAN GET DAILY UPDATES ON GLP-1
PUBLICATIONS THROUGH NCBI.
IF YOU GO TO PUBMED AND ENTER
IN YOUR SEARCH TERMS, SAY
SEMIGLUTIDE OR TIRZAPIDE.
THAT WILL TAKE YOU TO A SEARCH,
IF YOU DON'T ALREADY HAVE A
PROFILE.
THERE'S FIVE-TEN RELATED
SEMAGLUTIDE OR
TIRZEPATIDE-RELATED STUDIES.
OVER THE PAST YEAR THERE'S BEEN
AT LEAST ONE, IF NOT TWO
REAL-WORLD EVIDENCE STUDIES
THAT HAD BEEN GENERATED ALMOST
EVERY WEEK.
THAT HAVE HAD A SIGNIFICANT
IMPACT.
AND SO KEEPING ABREAST OF THE
FIELD WILL BE REALLY IMPORTANT
AS WE ALL MOVE FORWARD.
NEXT SLIDE, PLEASE, CRAIG.
SO ONE, TWO QUICK SLIDES I
WANTED TO ILLUSTRATE OF THIS,
THAT WERE RECENT EXAMPLES WAS
THIS PAPER BY KIM ET AL.
COLLEAGUES PUBLISHED JUST LAST
WEEK USING EPIC COSMOS DATASET,
AMONG 39,000 ILLABLE ADULTS,
887,000 RECEIVED PRESCRIPTIONS
FOR SEMAGLUTIDE OR TIRZEPATIDE
FOR OBESITY.
REALLY FROM 2023-2024.
BUT THERE'S MAJOR LIMITATIONS
TO DATA LIKE THIS, WHICH ARE
THE IMPORTANCE OF THIS
CONFERENCE TODAY TO THINK ABOUT
WHAT ARE LIMITATIONS TO VARIOUS
REAL-WORLD DATASETS.
EPIC COSMOS ONLY HAS THEIR
PARTICIPATING ORGANIZATIONS.
THEY HAVE NO ONLINE PHARMACIES
FOR PRESCRIPTIONS THEY WERE
TRACKING THERE.
THEY WERE LOOKING AT ONLY
PRESCRIPTIONS AND NOT
MEDICATION FILLS.
AND BRANDED MEDICATIONS ONLY
NOT OFF-LABEL USE.
NEXT SLIDE, PLEASE, CRAIG.
ANOTHER INTERESTING STUDY OR
PAPER SUMMARY PUBLISHED BY
DANIEL DRUCKER LAST WEEK, WHICH
IS AN OVERVIEW OF GLP-1-BASED
THERAPIES FOR DIABETES, OBESITY
AND BEYOND.
IT INCLUDED THIS FIGURE, WHICH
I THINK IS A GOOD TOUCH STONE
FOR THE BEGINNING OF THE
CONFERENCE.
ON THE TOP BOX IT DESCRIBES ALL
THE GLP-1 ACTIONS THROUGHOUT
THE BODY.
AND THEY ARE NUMEROUS.
AND THE OTHER PIECE THEY
ESTABLISH INDICATIONS LIST
WHICH KEEPS GROWING.
ON THE LEFT-HAND SIDE OF THIS
FIGURE.
ON THE RIGHT-HAND SIDE OF THE
FIGURE IS THE LARGE LIST OF
INVESTIGATIONAL INDICATIONS OF
GLP-1'S.
DR. RODGERS SPOKE OF THIS
EARLIER, BUT THERE'S SOME
CONDITIONS IN HERE I DIDN'T
KNOW WERE CURRENTLY BEING
STUDIED RELATED TO GLP-1, LIKE
PSORIATIC ARTHRITIS.
THERE'S AN OPPORTUNITY FOR
MULTI-DISCIPLINARY RESEARCH IN
THIS FIELD TO HELP MOVE THE
NEEDLE FORWARD.
NEXT SLIDE, PLEASE.
AS WE MOVE AHEAD TOGETHER AS A
GROUP, WE ARE WANTING TO GET
FEEDBACK FROM YOU TO HELP US
COMPILE THE LIST OF THE MOST
IMPORTANT MAJOR GAPS AND
OPPORTUNITIES FOR MAJOR
RESEARCH IN GLP-1'S USING
REAL-WORLD DATA.
I WOULD LIKE YOU TO BEGIN USING
OUR Q&A FEATURE.
IF YOU FIND THE Q&A BUTTON ON
THE TOP BAR, DEPENDING THE WAY
YOUR TEAMS IS LAID OUT, FIND
THE Q&A FEATURE AND BEGIN
PUTTING YOUR SUGGESTIONS IN THE
Q&A ABOUT WHAT YOU THINK ARE
THE MAJOR GAPS AND
OPPORTUNITIES FOR FUTURE
RESEARCH ON GLP-1'S.
AND THEN AS THOSE START
EMERGING FROM THIS
CONVERSATION, WE WOULD
ENCOURAGE YOU TO DO THAT OVER
THE COMING MINUTES, AS WE ARE
BEGINNING TO LAUNCH THE
CONFERENCE THIS MORNING.
AS YOU SEE THOSE COME UP, YOU
CAN UPVOTE THOSE SUGGESTIONS
MADE BY OTHERS BY CLICKING ON
THE LIKE BUTTON OR ACTUALLY
THERE'S AN UPVOTE BUTTON WHICH
IS AN UP ARROW.
IF CLICK ON THE UP-ARROW THAT
WILL PROVIDE FEEDBACK TO US
ABOUT WHAT ARE THE HIGHEST
PRIORITY GAPS AND OPPORTUNITIES
IN THE FIELD.
AND SO, PLEASE BEGIN PUTTING IN
YOUR SUGGESTIONS FOR MAJOR GAPS
AN OPPORTUNITIES FOR RESEARCH.
WE LOOK FORWARD TO PULLING
THOSE TOGETHER AND SHARING THEM
BACK WITH YOU AS THE CONFERENCE
GOES ON.
AT THIS POINT IT'S MY GREAT
PLEASURE TO INTRODUCE OUR FIRST
MODERATOR FOR TODAY'S KEYNOTE
SESSIONS, THAT'S DR. KIMBERLY
NARAIN FROM UCLA.
KIMBERLY, THANK YOU FOR YOUR
MODERATION TODAY AND I TURN IT
OVER TO YOU.
>> KIMBERLY NARAIN: HELLO, GOOD
MORNING, IT'S MY PLEASURE TO BE
HERE TO HAVE THE OPPORTUNITY TO
INTRODUCE OUR FIRST SPEAKER.
DR. DAVID
D'ALESSIO.
HE IS A RESEARCHER AT DUKE
SCHOOL OF MEDICINE.
HE HAS BEEN AT THE BEGINNING
CONDUCTING RESEARCH THAT HAS
ALLOWED US TO UNDERSTAND THE
WAY THAT THESE THERAPIES WORK
IN THE BRAIN.
HE ALSO REALLY HAD A FRONT-ROW
SEAT AS THIS KNOWLEDGE HAS
REALLY TRANSLATED FROM THE
BENCH TO THE BEDSIDE.
SO FROM THAT VANTAGE POINT HE
IS REALLY THE PERFECT PERSON TO
TALK TO US ABOUT THE WAY THESE
THERAPIES WORK AND TO GIVE US
SOME INSIGHT INTO WHAT WE CAN
EXPECT WITH THESE THERAPIES IN THE FUTURE.
TAKE IT AWAY DR. D'ALESSIO.
>> David D'Alessio: THERE, CAN
PEOPLE HEAR ME NOW?
>> YES.
>> David D'Alessio: MY SLIDES
ARE UP?
>> YES.
>> David D'Alessio: KIM, THANK
YOU VERY MUCH, THAT WAS A KIND
INTRODUCTION.
I WAS ASSUMING I WAS INVITED
HERE BECAUSE I'M OLD AND WAS A
FELLOW WHEN GLP-1 FIRST CAME
OUT.
I HAVE BEEN AROUND FOR A LONG
TIME BUT IT'S ACTUALLY BEEN A
VERY INTERESTING TO BE PART OF
WHAT'S BEEN I THINK A REAL
REVOLUTION AND TREATMENT *F
METABOLIC DISEASE.
SO WHAT I'M GOING TO DO IS GIVE
YOU A SORT OF BACKGROUND.
THIS WILL BE REALLY A SIDELINE
TO THE MAJOR TOPICS OF THIS
WORKSHOP.
BUT I WILL TALK ABOUT THE
HISTORY OF THE INCRETIN EFFECT,
WHERE THEY CAME FROM.
AND THEN TALK ROUGHLY THROUGH
THE EVOLUTION OF THE DRUGS,
INTRODUCE THE CONCEPT OF
MULTI-RHODE ISLAND --
RECEPTOR AGONISTS WHICH I THINK
WILL BE TIMELY GOING FORWARD
AND GIVE YOU A COUPLE OPINIONS
ON THE FUTURE.
PEOPLE KNEW FOR A LONG TIME
THAT IF YOU INTRODUCED GLUCOSE
IN THE GUT, THE BLOOD SUGAR
RESPONSE WAS DIFFERENT THAN IV.
THE TERM INCRETIN WAS JOINED IN
19 29 BY A GENTLEMAN NAMED
LABAR.
THEY COULD GIVE GUT EXTRACTS TO
DOGS IN LOWER BLOOD SUGAR, IT
WORKED BY STIMULATING INTERNAL
SECRETIONS OF THE PANCREAS,
WHICH WAS INCRETIN.
IN THE 60'S WHEN THE ASSAY FOR
INSULIN BECAME AVAILABLE.
IF YOU GAVE GLUCOSE, THE
INSULIN RESPONSE WAS HIGHER
WHEN THE GLUCOSE CAME FROM THE
GUT.
THE ASSUMPTION WAS THE GUT WAS
MAKING PEPTIDES AND THE HUNT
WENT IMMEDIATELY TO TRY TO FIND
THESE PEPTIDES.
BECAUSE THAT SEEMED LIKE AN
INTERESTING PHYSIOLOGY.
IN 1970 BROWN AND PETERSSON AT
UNIVERSITY OF BRITISH COLUMBIA
EXTRACTED KILOGRAMS AND PASSED
IT THROUGH COLUMNS AND CAME UP
WITH A MOLECULE THAT WAS
INSULIN ATROPIC.
GIP.
A DECADE LATE HE WHEN IT WENT
TO CLONING, THE PROGLUCAGON
GENE WAS FOUND.
DOWNSTREAM IT LOOKED LIKE TWO
NEW MOLECULES ALSO ENCODED IN
THAT PRO-HORMONE, THE FIRST WAS
LABELED GLUCAGON 1.
THAT HAD INSULIN A TROPIC
PROPERTIES AND THAT WAS THE
SECOND INCRETIN.
SINCE 1984 LOTS OF PEOPLE
LOOKED FOR OTHER INCRETINS BUT
IT'S STILL GL P&G IP.
THEY ARE SECRETED WHEN
NUTRIENTS GO THROUGH THE GUT.
GLUCOSE AND FAT BEING MORE
POTENT THAN PROTEIN.
IF YOU INFUSE THESE TO HUMANS
DUR A GLUCOSE TOLERANCE TEST
YOU SEE GLUCOSE ALONE
STIMULATES INSULIN.
IF YOU ADD G.
I. P. YOU DOUBLE IT, IF YOU ADD
GLP-1 YOU QUADRUPLE IT.
THIS WAS THE PAPER THAT
LAUNCHED A LOT OF RESEARCH INTO
GLP-1.
THIS DEMONSTRATION THESE
INCRETINS COULD BE PURIFIED,
GIVEN TO HUMANS AND HAVE THESE
STRIKING RESPONSES.
NOT ONLY ON INSULIN SECRETION
BUT TO LOWER GLUCOSE.
SO BASED ON THIS, THIS IS THE
INCRETIN AXIS AS WE TEACH
MEDICAL STUDENTS.
THAT WHEN A HUMAN BEING OR MOST
MAMMALS EAT, NUTRIENTS ARE
ABSORBED THROUGH ANEROCITES AND
INTRODUCED IN THE BLOOD.
L-CELLS AND K-CELLS ARE
STIMULATED TO RELEASE GI P&G LP.
THEY INTERACT WITH RECEPTORS,
GIP AND GLP.
WITH A HIGH DEGREE OF HEMOLOGY.
BETA CELLS END UP STIMULATING
INSULIN SECRETION.
A KEY COMPONENT OF THIS AND
WHAT DIFFERS FROM A LOT OF
SYNTHETIC DIABETES DRUGS IS
THEY ONLY STIMULATE INSULIN
SECRETION WHEN BLOOD SUGAR IS
ELEVATED.
THAT WAS ONE OF THE APPEALING
FEET YOUS FEATURES, THE RISK
OF HYPOGLYCEMIA VERY LOW.
IN 1993 A COUPLE STUDIES CAME
OUT, DR. NAUCK, HE BROUGHT IN
PEOPLE WITH BLOOD SUGARS OF 220.
ONE DAY HE GAVE THEM SALINE AND
ANOTHER DAY TURNED ON AN
INFUSION OF GLP-1.
THE BLOOD SUGAR DODDLES IN
SALINE BUT NORMALIZED IN THE
DIABETIC PATIENTS.
IT BROUGHT THEIR BLOOD SUGARS
DOWN TO AN AVERAGE OF ABOUT 95.
PART OF THIS WAS STIMULATION OF
INSULIN SECRETION BUT PART MAY
HAVE BEEN SUPPRESSION OF
GLUCAGON.
BUT NEVERTHELESS, THESE WERE
EYE-OPENING SORTS OF STUDIES.
I THINK THIS IS WHERE THE
PHARMACOLOGIC IN INCRETIN
LAUNCHS.
JOHN TURNER'S GROUP IN 1997
OBSERVED TYPE 2 DIABETICS WHO
WERE HYPER GLYCEMIC OVERNIGHT
AND INTOLERANCE WITH BREAKFAST
AND LUNCH.
HOOKED THEM UP TO GLP-1,
NORMALIZED BLOOD SUGAR
OVERNIGHT.
IT LOOKED LIKE IT SORT OF CURED
DIABETES.
WHAT WAS INTERESTING IN THIS
STUDY, THEY REPEATED THE GLP
ARM AND NORMALIZED BLOOD SUGAR
OVERNIGHT.
BUT THEN WHEN THEY TURNED OFF
THE INFUSION, EVERYTHING FELL
APART IN MINUTES.
IT TURNS OUT NATIVE GLP-1 IS
RAPIDLY METABOLIZED IN THE
CIRCULATION, IT HAS A HALF-LIFE
OF A MINUTE OR MINUTE AND A
HALF, SO IT WASN'T GOING TO BE
THE DRUG IN ITS NATIVE FORM.
BUT THE TARGET WAS THERE, THE
GLP RECEPTOR LOOKED LIKE A
GREAT TARGET AND A LOT OF
PEOPLE STARTED CHASING THAT
RIGHT AWAY.
HERE IS THE TIMELINE, INCRETINS
DISCOVERED IN 1985.
EXENATIZE, REPTILIAN, CHEMISTS
LIKE TO LOOK AT SNAKE AND
REPTILE VENOM BECAUSE THEY ARE
FULL OF PEPTIDES.
ONE AGONIST, ONLY PARTIALLY
HOMOLOGOUS.
YOU COULD MODIFY THIS PEPTIDE
INTO AN ANTAGONIST AND THAT
HELPED RESEARCH.
YOU START HAVING FDA-APPROVED
DRUGS, A THE FIRST DRUG ON THE
MARKET.
COULD SEE A STUDY STREAM OF
DRUG DEVELOPMENT IN THIS SPACE
STARTING IN 2005.
BECAUSE GLP IS A PEPTIDE AND
ITS RECEPTOR IS ACCESSIBLE TO
THAT STRUCTURE OF MOLECULE, ALL
THE EARLY DRUGS WERE
PEPTIDE-BASED.
THAT IS MAKING PEOPLE WANTED TO
MAKE SMALL MOLECULES COULDN'T
FIGURE OUT HOW TO DO IT.
SO PEPTIDE-BASED DRUGS NEED TO
BE INJECTED.
THAT'S BEEN THE MODE OF GLP
THERAPY EVER SINCE.
THEY ARE INSULIN A TROPIC,
GLUCOSE DEPENDENT, THEY DON'T
STIMULATE INSULIN WHEN THE
BLOOD SUGAR IS NORMAL OR LOW
AND HAVE A WELL KNOWN SIDE
EFFECT PROFILE.
WHEN WE INFUSE GLP-1 IN
RESEARCH STUDIES WE CAN FIND A
CEILING TO THE EFFECT THE
PATIENT STARTS TO SAY ALL
RIGHT, I'M GETTING QUEASY, YOU
BETTER STOP.
THAT TRANSLATED TO THE DRUGS.
WHAT WE SAW WITH NATIVE GLP-1
TRANSLATED TO THE SYNTHETIC
GLP, FARM CO THERAPEUTICS AND
SIDE EFFECTS, NAUSEA, VOMITING,
DIARRHEA WERE THE KNOWN AND
ACCEPTED SIDE EFFECTS.
A TOLERANCE TENDS TO OCCUR OVER
TIME AND THEY ARE BETTER
TOLERATED.
CAN TITRATE AND BETTER MITIGATE
THE SIDE EFFECTS.
THERE'S TWO GENERATIONS.
THE FIRST WERE DAILY INJECTIONS,
BYETTA THEN VICTOZA.
THEN WE GET TO TERZ TIED.
THE FIRST STIMULATION OF
GLUCOSE STIMULATED INSULIN
SECRETION.
ONCE PEOPLE STARTED DOING
CLINICAL TRIALS THEY NOTICED
OBSERVATIONS IN HUMANS
PARALLELED WHAT WE SAW IN RATS
AND MICE.
THESE DRUGS MADE YOU EAT LESS
AND THERE WAS SOME WEIGHT LOSS.
WITH THE FIRST DRUGS WE HAD A
REDUCTION OF A1C OF ABOUT 1%
WHICH WAS GOOD, STANDARD FAIR
FOR THE EARLY DECADE, THAT'S
WHAT YOU EXPECTED FROM A
DIABETES DRUG AND PEOPLE WOULD
LOSE 2-4 KILOGRAMS OF BODY
WEIGHT.
THAT DOESN'T SOUND LIKE A LOT,
BUT THOSE DAYS WHEN WE HAD
THOSE TREATMENTS AND ALL THOSE
DRUGS LOWERED BLOOD SUGAR AND
CAUSED WEIGHT GAIN, TO TELL
SOMEBODY YOU WEREN'T GOING TO
GAIN WEIGHT AND MAYBE LOSE A
LITTLE WEIGHT WAS QUITE
APPEALING IN THE CLINIC.
SO AGAIN, THIS NOTION THAT
GLP-1 SUPPRESSES FOOD INTAKE
CAUSED US TO RETHINK THE WHOLE
PHYSIOLOGY.
THE RECEPTOR HAD BEEN CLONED
FROM BETA CELLS AND WE GOT INTO
GLP-1 PHYSIOLOGY IN
THERAPEUTICS AS A WAY TO
STIMULATE INSULIN SECRETION.
BUT ONCE IT WAS APPARENT RATS
AND HERE HUMANS GIVEN GREATER
DOSES OF GLP-1 WILL DECREASE
CONSUMPTION OF A STANDARDIZED
MEAL, THEN PEOPLE STARTED TO
LOOK FOR BIOLOGY IN THE BRAIN.
THAT'S WHERE FOOD INTAKE AND
ENERGY BALANCE IS CONTROLLED.
TURNS OUT THE GLP-1 RECEPTOR IS
EXPRESSED IN THE HIND BRAIN AND
HYPOTHALAMUS.
BEING IMPORTANT, THE AREA THERE
POSTDREMA OUTSIDE THE
BLOOD-BRAIN BARRIER.
ONE OF THE PLACES IN THE BRAIN,
HYPOTHALAMUS BEING THE OTHER,
WHERE CIRCULATING MOLECULES,
WHETHER THEY BE ENDOGENOUS LIKE
GLP-1 OR EX OJ JUS HAVE ACCESS
TO NEURONS.
THINGS THAT ENTER CIRCULATION
CAN ACTUALLY INFLUENCE CNS
FUNCTION.
AND THAT'S WHERE THE SATIETY
WEIGHT LOSS AND NAUSEA WEIGHT
LOSS EFFECTS PLAY OUT.
MANY DIFFERENT FLAVORS OF
GLP-1 LIKE I SAID, EITHER FROM
THE REPTILE DESCENDANT OR.
LIXISENATIDE, EXENATIDE.
THEN CAME LIRAGLUTIDE AND
SEMAGLUTIDE.
THESE ARE SIMILAR TO NATIVE
GLP-1 BUT THEY AREN'T
METABOLIZED AND ACTIVATED IN
THE CIRCULATION AS MUCH.
THESE DRUGS LIXI AND EXENATIDE
ARE PRETTY MUCH OB SOLETE THOSE
THAT HAVE LOUSY INSURANCE, AND
FORMULARY INSIST YOU USE THESE
FIRST.
THESE TWO ARE THE PLAYERS RIGHT
NOW.
LIRAGLUTIDE AND DULAGLUTIDE
DON'T LOWER ENOUGH.
IF PATIENTS HAVE ACCESS TO
THIS, THIS IS WHAT YOU GO TO
NOW.
SEMAGLUTIDE HAD COMPARATIVE
EFFICACY WAY BEYOND WHAT YOU
SAW WITH DULA OR LIRAGLUTIDE.
AND THE A1C'S DROPPED 2%.
IF YOU WOULD HAVE TOLD ME IN
2010 THERE'S A SINGLE DRUG THAT
WOULD DROP A1C 2% I WOULD HAVE
SAID PIGS COULD FLY.
USING SEMAGLUTIDE AT THE
HIGHEST DOSES CAUSED
UNPRECEDENTED AMOUNTS OF WEIGHT
LOSS, WHEREAS THE FIRST
GENERATION GLP-1'S GAVE YOU 2-4
KILOGRAMS THESE DRUGS STARTED
TO GIVE YOU 10, 15, EVEN MORE
BODY WEIGHT THAN THAT, WITH
AVERAGE PERCENTAGES IN SOME OF
THESE CLINICAL TRIALS OF OVER
15%.
NOW 15% ISN'T WHAT YOU GET WITH
A GASTRIC BYPASS, I USUALLY
THINK THAT'S 30%.
BUT IT WAS COMPARABLE TO WHAT
YOU SAW WITH GASTRIC BANDING.
AGAIN IN THE EARLY PART OF THE
CENTURY STILL IN VOGUE.
THIS WAS WAY MORE THAN WHAT WE
HAD ON THE MARKET FOR WEIGHT
LOSS.
I THINK THAT'S WHERE IN THE
CLINIC THINGS CHANGED AND
PATIENTS STARTED COMING IN WITH
INTERNET FOLDERS OF DATA ON
THIS NEW DRUG.
AND ASKED FOR OZEMPIC BY NAME
AND STARTED BEING BESIEGED BY
ALL THE COMMERCIALS AND LOUSY
JINGLES AND ALL THAT STUFF.
THAT'S WHERE IT MOVES FROM A
DRUG FOR ENDO CINOLOGISTS TO A
DRUG THAT ALL THE POPULATION IS
ENTRANCED WITH.
SEMAGLUTIDE, I WOULD SAY IS THE
A POJ YOE SIS OF GLP RECEPTOR
AGONIST.
THE MOST POTENT, THE ONE IN
MOST USE, THE ONE WHERE WE HAVE
THE MOST DATA.
BUT OF COURSE, PEOPLE ALWAYS
SAY, ONCE THE BAR IS SET, YOU
WANT TO GO OVER THE BAR.
SO PEOPLE STARTED TALKING
ABOUT, CAN WE MAKE BETTER
INCRETIN-BASED DRUGS?
CAN WE MAKE THINGS MORE POTENT
THAN SEMAGLUTIDE?
AND THE CONCEPT OF
MULTI-RECEPTOR AGONIST WAS SORT
OF STUMBLED UPON BY
SERENDIPITY, A CHEMIST NAMED
RICHARD DEMARKY WAS TRYING TO
MAKE A SOLID GLUE CON, HE WAS
FLIPPING TO TRY TO GET IT TO BE
A BETTER DRUG FOR HYPOGLYCEMIA
AND LO AND BEHOLD HE FOUND IT
NOT ONLY ACTIVATED THE GLUCAGON
BUT GLP-1 RECEPTOR.
WHAT WE TEACH EVERYBODY IS A
PEPTIDE IS VERY SPECIFIC TO A
TYPE OF RECEPTOR, GLP WITH THE
GLP AND GIP WITH ONLY THE GIP.
BUT TURNS OUT YOU CAN BIND A
MOLECULE WITH MULTI-RECEPTOR
AGONISTS.
THOUGH WE DON'T KNOW EXACTLY
THE PHARMACOLOGY HOW THEY WORK,
YOU CAN SHOW THEY WILL HIT MORE
THAN ONE RECEPTOR SIGNALING
SYSTEM.
AND YOU MAKE A MULTI-RECEPTOR
AGONIST BY WHAT'S CALLED
ITERATIVE CHEMICAL REFINEMENT,
OR BLACK BOX, TRIAL-AND-ERROR.
IN THE CASE OF TIRZEPATIDE, FOR
GIP, YOU KNOW YOU WANT TO GET
SOME ACTIVITY AT THE GLP.
YOU GET A SINGLE PEPTIDE YOU
CAN SHOW HAS A DOSE-DEPENDENT
EFFECT IN MICE TO LOWER GLAOD
SUGAR.
BLOOD SUGAR.
IT WILL WORK IN MICE THAT HAVE
THE RECEPTOR KNOCKED OUT AND
RESPOND TO DUAL AGONIST AND GIP.
THOSE THAT DOESN'T HAVE A GLP.
IT LOOKS LIKE THIS COMPOUND
ACTUALLY WORKS THROUGH BOTH
RECEPTORS.
THIS IS A STUDY MY COLLEAGUES
AT DUKE DID WITH HUMAN EYELETS.
THEY WOULD GIVE AND LAYER ON
TERZ TIED.
THEY CAN BE ACTIVATED BY ONE
PEPTIDE MOLECULE.
THEY SHOWED IT TO A GROUP OF
PATIENTS, SOME OF WHOM GOT
SEMAGLUTIDE AND SOME OF WHOM
GOT PLACEBO.
YOU SEE THE WEIGHT LOSS PRETTY
REMARKABLE OVER THE 28 WEEKS OF
STUDY.
I SAID DAYS BUT I MEANT WEEKS.
THE LOSS OF WEIGHT WAS IN THE
FAT FRACTION.
THERE WAS LITTLE CHANGE IN THE
GROUPS WHAT THE LEAN TISSUE
ENDED UP BEING AT THE END OF
THE EXPERIMENT.
USUALLY WHEN WE LOSE WEIGHT WE
LOSE 30% LEAN, 70% FAT.
THAT SEEMS TO BE WHAT HAPPENED
IN THE INCRETIN-BASED DRUG
DOLLARS WITH THE LIMITED
INFORMATION WE HAVE SO FAR.
WHEN THEY LOOK AT ONE THAT GOT
SEMAGLUTIDE AND ONE THAT GOT
TIRZEPATIDE, COMPARED TO
PLACEBO, THE DIABETIC SUBJECTS
SECRETED MORE.
THE DOSING IS IMPORTANT WHEN
YOU TALK ABOUT RELATIVE
POTENCIES.
I THINK MOST PEOPLE AND MOST
PUBLISHED LITERATURE SUPPORTS
THE DUAL AGONIST BEING MORE
POTENT THAN THE SINGLE.
IF YOU GAVE A HIGHER DOSE OF
THE SINGLE AGONIST YOU MIGHT
CATCH UP SOMEWHAT.
SO WHAT ABOUT CLINICAL TRIALS?
TZP IN PATIENTS WITH DIABETES.
WHAT YOU SEE RELATIVELY SHORT
STUDY OF 40 WEEKS.
BUT THE A1C GOING DOWN MORE
THAN 2% FROM ABOUT 8.5% TO 6
AND FREQUENTLY AT THE HIGH DOSE
UNDER 6%.
AND THE CHANGE IN BODY WEIGHT.
IN LONGER CLINICAL TRIALS,
THESE DRUGS, MULTI-RECEPTOR
AGONISTS START TO APPROACH 20%
WEIGHT LOSS ON AVERAGE.
SO AGAIN, VERY POTENT EFFECTS
TO CAUSE WEIGHT LOSS AND
GLUCOSE LOWERING.
SO REALLY GOOD DIABETES DRUGS.
I'M NOT GOING TO GO THROUGH ALL
THE CLINICAL TRIALS, BUT JUST
TO SUMMARIZE, THE FDA REQUIRES
IF INTRODUCE A NEW DIABETES
DRUG TO THE MARKET YOU DO A
CARDIOVASCULAR SAFETY TRIAL TO
PROVE IT DOESN'T CAUSE
CARDIOVASCULAR EVENTS.
AND WITH SEMAGLUTIDE AND NOW
WITH TIRZEPATIDE THERE'S DATA
THAT SUGGESTS IF YOU TREAT
PEOPLE AT RISK FOR HEART
DISEASE WITH THESE DRUGS AND
COMPARE WITH PLACEBO, THE
EVENTS GO DOWN.
THERE SEEMS TO BE SOME
PROTECTIVE EVENT FOR FURTHER
CARDIAC DISEASE.
THERE'S ALSO DATA NOW ON RENAL
FAILURE.
IF TAKE PATIENTS WITH RENAL
FAILURE AND TREAT WITH
SEMAGLUTIDE THEY HAVE SLOWER
PROGRESSION IN RENAL DISEASE,
THIS HAPPENS WITH PATIENTS WHO
DON'T HAVE DIABETES.
IT'S EXPANDED FROM INSULIN
SECRETAGOGS, TREATING WEIGHT
LOSS AND NOW CARDIO-RENAL
ADVERSE EVENTS THAT ARE REALLY
THE MORBIDITY OF DIABETES.
SO IT'S JUST STRIKING.
THE DATA KEEPS ACCUMULATING.
TIRZEPATIDE IS REALLY EFFECTIVE
IN RESOLVING OBSTRUCTIVE SLEEP
APNEA.
AND BOTH TIRZEPATIDE AND
SEMAGLUTIDE HAVE IMPACTS ON
METABOLIC LIVER DISEASE,
NON-ALCOHOLIC, AT LEAST BY
DECREASING STEATOSIS AND
HEPATIC FIBROSIS.
THE POINT DR. ARTERBURN MADE AT
THE BEGINNING OF THESE HAVING A
BROAD EFFECT ON THE HEALTH
RELATED TO DYSMETABOLISM IS
BORNE OUT BY REASONABLY SOLID
AND REPEATED STUDIES.
SO WHAT'S THE FUTURE HOLD?
WELL, I CAN TELL YOU THAT THIS
IS AN AREA THAT DOESN'T SEEM
CAPPED OUT RIGHT NOW.
THERE'S JUST A LOT OF ACTIVITY
IN THE FIELD FROM SMALL PHARMA
TO BIG PHARMA.
EVERYBODY IS LOOKING FOR NEW,
MORE POTENT GLP-1'S.
AND THE mRNA CONCEPT HAS
BLOSSOMED AND PEOPLE ARE
PLAYING AROUND WITH MULTIPLE
APPROACHES TO MULTI-RECEPTOR
AGONISM.
SMALL MOLECULE AGENTS BEING
DEVELOPED.
SO ORAL AGENTS CAN BE TAKEN
ALSO ACT THROUGH THE SYSTEM.
OF COURSE SMALL MOLECULES ARE
WAY CHEAPER TO MAKE THAN
PEPTIDES AND DON'T REQUIRE PEN
INJECTORS AND NEEDLES AND ALL
THAT STUFF.
WE CONTINUE TO GENERATE A
DEEPER UNDERSTANDING OF THE
RELEVANT BIOLOGY.
A LOT OF THIS IS BACK FILLING.
WE HAVE DRUGS THAT ARE VERY
EFFECTIVE AND NOW WE ARE TRYING
TO FIGURE OUT WHY THEY ARE
EFFECTIVE.
IF A DUAL AGONIST, IF A GLP GIP
IS GOOD, WOULD IT BE BETTER TO
ADD A GLUCAGON?
RETATRUTIDE CAUSES ON AVERAGE
CLOSE TO 25% BODY WEIGHT LOSS.
A QUARTER PATIENTS LOSE 30% OF
BODY WEIGHT, WHICH IS NOW
BARIATRIC-LEVEL WEIGHT LOSS.
IF YOU LOOK AT TRY AGONIST IT
DROPS A1C, DECREASES TRY
GLYCERIDE, CHOLESTEROL.
WE SEE WITH THE INCRETIN-BASED
DRUGS.
THEY ARE EXPECTED GIVEN THE
AMOUNT OF WEIGHT LOSS THESE
DRUGS CONFER.
THE SMALL MOLECULE AGENTS, YOU
KNOW, CAN SHOW YOU CAN MAKE A
SMALL MOLECULE THAT SITS IN THE
GLP-1 RECEPTOR BINDING POCKET,
GIVES YOU A DOSE RESPONSE.
AGAIN, SINGLE PILL, DROPS THE
A1C ALMOST 2%.
JUST MIND BLOWING IF YOU HAVE
BEEN TREATING DIABETES AS LONG
AS I HAVE.
THE WEIGHT LOSS EFFECT, 10
KILOGRAMS WITH A SINGLE PILL.
THERE'S LOTS MORE WHERE THIS
COMES FROM, THIS IS A VERY HOT
AREA.
EVERYBODY WOULD LIKE TO CONQUER
THE SMALL MOLECULE SPACE.
SO WHAT ARE THE DOWN SIDES OF
THE REVOLUTION HERE.
YOU CAN READ ABOUT SOME OF
THESE IN THE HUMAN INTEREST
SECTION OF THE "NEW YORK TIMES".
I WILL GIVE YOU MY TAKE.
THEY DO HAVE GI TOXICITY, IT'S
PREDICTABLE.
ABOUT HALF OF PEOPLE ARE GOING
TO GET NAUSEA, SOME WILL GET
VOMITING, SOMETIMES DIARRHEA,
SOMETIMES CONSPACING.
CONSSTI PACING.
STI CONSTIPATION.
QUESTIONS ABOUT PANCREATITIS, I
DON'T THINK BORNE OUT.
SOMETIMES DEHYDRATION FROM GI
TOXICITY AND DECREASE IN RENAL
FUNCTION.
LOW RATES OF DRUG PERSISTENCE,
WE ARE TALK ABOUT THIS.
VARIABLE ACCESS.
I HAVE A LOT OF PEOPLE WHO CALL
THESE RICH PEOPLE DRUGS, IF YOU
DON'T HAVE GOLD PLATED
INSURANCE OR MONEY IN THE BANK
OFTEN TIMES YOU HAVE TROUBLE
GETTING THESE DRUGS.
WE DISAPPOINT HAVE LONG-TERM
OUTCOME STUDIES.
LIMITED UNDERSTANDING OF
MECHANISMS.
THEY ARE EXPENSIVE TO PRODUCE,
SHIP AND STORE.
AND AS MORE AND MORE DRUG COSTS
ARE PASSED ONTO PATIENTS THEY
ARE VERY EXPENSIVE FOR THEM.
>> Darren
--
>> Kimberly Narain: DR., TWO
MINUTES LEFT.
>> David D'Alessio: OKAY, THANK
YOU.
THESE ARE PATIENTS GIVEN
SEMAGLUTIDE FOR 20 WEEKS AND
HALF THE GROUP WAS SWITCHED TO
PLACEBO AND HALF THE GROUP
CONTINUED.
YOU COULD SEE THE WEIGHT LOSS
CONTINUES BUT AS SOON AS YOU
STOP THE DRUGS THE WEIGHT COMES
BACK.
THAT RAISES THE QUESTION, ARE
THESE FOREVER TREATMENTS OR IS
IT POSSIBLE THEY WOULD CHANGE
SORT OF BODY WEIGHT REGULATION
INTERNALLY AT SOME POINT.
THE JURY IS OUT.
BUT THESE KIND OF DATA ARE
DISCOURAGING.
THIS TALKS ABOUT ADHERENCE.
THIS IS JUST A BUNCH OF WEIGHT
LOSS DRUGS.
SOME LIKE SEMAGLUTIDE THAT ARE
EFFECTIVE, SOME LIKE ORLISTAT,
NOT EFFECTIVE.
THE NUMBER OF PATIENTS RENEWING
PRESCRIPTIONS OVER TIME GOES
DOWN STEADILY.
THIS HAS BEEN BORNE OUT, SEEMS
PERSISTENCE WITH PRESCRIPTION
REFILLS AT A YEAR IS ABOUT 50%.
IT'S BETTER THAN PATIENTS WITH
TYPE 2 DIABETES THAN WITHOUT.
BUT AGAIN, IT'S REALLY
SURPRISING BECAUSE PEOPLE COME
IN ASKING FOR THESE DRUGS BUT
AFTER A WHILE THEY STOP THEM.
THIS STUDY PUBLISHED THIS YEAR,
THEY LOOKED FOR FEATURES, OLDER
PEOPLE STOPPED, MORE PEOPLE WHO
HAD PERSISTENT G.
I. SIDE EFFECTS STOPPED THEM
MORE.
THERE WAS AN EFFECT OF YOUR
INCOME AT HOME BUT IT DIDN'T
FAVOR DISCONTINUATION.
MY BET IF THIS WAS STRATIFIED
BY CO-PAY RATHER THAN INCOME IT
WOULD BE OVER HERE.
BECAUSE THESE DRUGS ARE
EXPENSIVE.
SEMAGLUTIDE, $1500 A MONTH.
TIRZEPATIDE $1200.
TIRZEPATIDE CAME OUT WITH
PATIENT-FRIENDLY PRICING IF
YOUR INSURANCE DOESN'T COVER IT.
BUT LOOK AT THESE MONTHLY
CHARGES.
THESE ARE LUXURY GOODS FOR A
LOT OF THE POPULATION.
SO IN TERMS OF THE PLEA TROPIC
EFFECTS.
YOU COULD SEE ARTICLES THAT
TALK ABOUT THE BENEFITS.
WE KNOW HEART AND KIDNEY, THESE
ARE BENEFICIAL.
ON THE OTHER HAND, WE REALLY
KNOW THAT THE RECEPTORS ARE IN
THESE TWO PLACES.
IT'S HARD TO FIND CONVINCING
EVIDENCE THAT THESE OTHER
TISSUES ARE DIRECTLY AFFECTED.
THE QUESTION IS HOW MUCH
PLEIOTROPY IS THERE, WHAT ARE
THE MECHANISMS AND IS IT
POSSIBLE THESE ARE BRAIN DRUGS
AND ALL THE BENEFICIAL EFFECTS,
EVEN ON INSULIN SECRETION ARE
MEDIATED BY THE BRAIN.
THE CLINICAL QUESTIONS ARE WE
NEED MORE LONG-TERM DATA.
IS IT HARMFUL TO STOP AND START?
BECAUSE THAT'S WHAT HAPPENS.
YOUR INSURANCE COVERS A WHILE,
THEN STOPS THEN YOU RESTART.
UP AND DOWN BODY WEIGHT, IS
THAT GOOD?
THEN WHAT'S THE PROPER
ALLOCATION OF THESE DRUGS.
THE INCRETIN EFFECT IS NOW
ABOUT 100 YEARS OLD AND
UNDERSTANDING IT OPENED THE
DOOR TO AN IMPORTANT NEW CLASS
OF THERAPEUTICS.
THE GLP-1 R SYSTEM IS A GREAT
DRUG TARGET.
I DON'T THINK WE ARE CLOSE TO
MAXIMIZING THE IMPACT OF THESE
DRUGS BECAUSE THE TOXICITY DOES
LOOM ONCE YOU GET TO A CERTAIN
DOSE.
I THINK THIS IS STILL A DYNAMIC
AREA OF DRUG DEVELOPMENT AND
THERE WILL BE A LOT OF ACTIVITY
IN THE NEXT DECADE AS NEW DRUGS
ARE DEVELOPED.
BUT I THINK TO BEND THE CURVES,
TO ACTUALLY CHANGE THE
INCREASING RATES OF DIABETES
AND OBESITY IN THE U.S. AND THE
WORLD WE HAVE TO HAVE DRUGS
THAT HAVE GREATER AVAILABLITY
AND EXPANDED ACCESS TO THE MANY
WHO NEED THEM.
WE DON'T HAVE THAT IN THE
CURRENT GENERATION OF DRUGS.
THANKS VERY MUCH.
HAPPY TO TAKE ANY QUESTIONS.
>> Kimberly Narain: THANK YOU
FOR THAT, REALLY JUST AMAZING
TALK, DR. D'ALESSIO.
BEFORE WE JUMP IN THE Q&A
PORTION, A QUICK REMINDER,
PLEASE PUT YOUR QUESTIONS IN
THE Q&A SECTION.
I WILL TAKE THE LIBERTY OF
ASKING THE FIRST QUESTION,
BECAUSE I CAN.
WHEN I WAS GOING BACK THROUGH
SOME OF YOUR PAPERS, IN THE
EARLY 2000'S YOU AND YOUR TEAM
PUBLISHED A PAPER WHERE YOU
GUYS IDENTIFIED THERE WERE SOME
GLP-1 RECEPTORS THAT COULD BE
STIMULATED TO PRODUCE ANOREXIA,
BUT NOT PRODUCE A SIGNIFICANT
AMOUNT OF GASTROINTESTINAL
UPSET.
TALK TO ME ABOUT WHEN AND HOW
YOU FIGURED OUT THAT DISCOVERY
HAD THE POTENTIAL TO HELP
REVOLUTIONARY THE WAY THAT WE
MANAGE OBESITY?
>> David D'Alessio: YEAH.
THAT WAS PROMPTED, I MEAN WHEN
I GOT AN IND TO GIVE NATIVE GLP
TO HUMANS WHEN I WAS JUST
STARTING OUT.
WE WITH PLAYING AROUND WITH THE
DOSES.
WE COULDN'T GET TO A MAXIMUM OF
INSULIN SECRETION BECAUSE
PEOPLE GOT NAUSEATED BEFORE WE
HIT THAT.
THEN IT BECAME APPARENT IF YOU
PUSH THE THERAPEUTIC WINDOW AND
GIVE HIGH DOSES YOU NEED TO TRY
TO UNDERSTAND THE NAUSEA ISSUE.
AND YOU KNOW, IN EARLY 2000'S
THERE WERE TWO SCHOOLS OF
THOUGHT.
ONE WAS THAT NAUSEA WAS
MEDIATED BY A DISTINCT GROUP OF
NEURONS IN THE HINDBRAIN AND
SATIETY IN ANOTHER GROUP.
ANOTHER GROUP OF SCIENTISTS
SAID NO IT'S THE SAME GROUP OF
NEURONS, YOU WON'T BE ABLE TO
SEPARATE THAT.
OUR DATA WAS OKAY IN DOING
THAT, WE WERE CONVINCED, I
THINK A LOT OF PEOPLE WERE.
THERE HAVE BEEN NICE PAPERS BY
HIGH END NEUROSCIENTISTS IN THE
TECHNOLOGY AVAILABLE TO THEM
THAT MAKES A CLEAR CASE THAT
THE SATIETY IS MEETED AT A
DIFFERENT SITE IN THE BRAIN
THAN NAUSEA AND YOU CAN
SEPARATE THEM, IN TERMS OF
NEURO CIRCUITRY, NOW WHETHER
THAT COULD BE TAKEN ADVANTAGE
OF WITH THESE DRUGS TO TARGET
ONE OVER THE OTHER IS THE
QUESTION, THAT WOULD TAKE A LOT
MORE WORK.
THE ONE THING I WOULD SAY,
THERE'S SOME NOTION THAT GIP,
WHICH ALSO WORKS IN THE BRAIN
AND IN THE SAME AREAS AS GLP,
THERE'S SOME PRE-CLINICAL DATA
THAT SUGGESTS GIP ACTUALLY
MITIGATES NAUSEA OF GLP-1 AND
ONE ARGUMENT WITH TIRZEPATIDE
IS MORE POTENT IS YOU CAN PUSH
THE DOSE HARDER BECAUSE YOU
DON'T GET AS MUCH NAUSEA.
THERE'S NO HEAD-TO-HEAD THAT'S
REALLY DEMONSTRATED THAT.
BUT WHEN I TALK TO MY
COLLEAGUES IN THE CLINIC, THE
YOUNGER DOCS USE MORE OF THIS
STUFF THAN I DO, THEY FAVOR
THAT.
THEY THINK TIRZ TIRZEPATIDE
MIGHT BE BETTER TOLERATED.
I THINK THERE'S SOME PRECEDENT
THAT BY MANIPULATING THESE
DRUGS YOU MAY BE ABLE TO FAVOR
EFFICACY OVER TOXICITY AND
WIDEN THE THEY'RE THERAPEUTIC
WINDOW AND THAT WOULD BE
HELPFUL.
ANOTHER THING, A PREAMBLE TO
THIS WORKSHOP, THIS IS VERY
TIMELY.
REAL-WORLD EVIDENCE AND THIS
LINE OF ANALYSIS IS WHAT IS
LACKING.
WHEN I LIST THE DOWN SIDES
THESE ARE THE KINDS OF THINGS I
THINK COULD BE REALLY
IMPORTANTLY ADDRESSED BY THE
SORTS OF QUESTIONS THAT ARE
GOING TO COME OF THIS MEETING.
SO I WAS REALLY DELIGHTED TO BE
INVITED.
I HOPE TO LEARN A LOT.
>> David
>> Kimberly Narain: I THINK
MAYBE WE HAVE TIME FOR ONE MORE
QUESTION.
I'M LOOKING IN THE CHAT.
I'M SEEING MOSTLY COMMENTEDS
ABOUT EVIDENCE GAPS.
I WILL ASK AN ADDITIONAL
QUESTION.
I WILL BE A LITTLE BIT SELFISH
HERE.
US JUNIOR RESEARCHERS TEND TO
BE VERY IN THE WEEDS WHEN WE
ARE THINKING ABOUT OUR RESEARCH
AND VERY FOCUSED ON WHAT'S
RIGHT IN FRONT OF US AND NOT
NECESSARILY THE PRACTICAL STEPS
THAT IT WOULD TAKE TO SEE THE
KNOWLEDGE WE ARE TRYING TO
PRODUCE TRANSLATED INTO THE
REAL IMPACT THAT WE SEEK.
THAT DIDN'T HAPPEN WITH YOU,
YOU WERE THERE TO TAKE THAT
JOURNEY TO SEE IT TRANSLATED
INTO THE BEDSIDE THERAPIES.
HOW DID YOU POSITION YOURSELF
TO DO THAT?
>> David D'Alessio: I WOULD SAY
BLIND LUCK.
BUT THE REALITY IS A COUPLE OF
THE EARLY STUDIES WE DID, WE
GOT RESULTS THAT WE DIDN'T
EXPECT.
SO WE WERE GIVEN GLP-1
EXPECTING TOO SEE EFFECTS ON
INSULIN SECRETION AND
SENSITIVITY.
WE DIDN'T SEE EFFECTS ON
SENSITIVITY EVEN THOUGH THE
GLUCOSE DISPOSAL WAS QUICK.
THERE WAS AN INSULIN EFFECT AND
INSULIN-DEPENDENT EFFECT.
THAT IS IN THE WEEDS.
BUT THAT SPOKE TO OTHER, MUST
BE OTHER MECHANISMS.
AND A LOT OF PEOPLE WERE
TELLING US OUR METHODS WERE
FLAWED AND THIS WAS AN ARTIFACT.
WE JUST KEPT AT IT, WHAT THAT
TOOK US TO WAS FROM THE EYELET
TO THE BRAIN.
WHAT WE WERE CALLING EXTRA
PANCREATIC EFFECT WAS BRAIN.
AT THE SAME TIME LOTS OF OTHER
PEOPLE, PROPER NEUROSCIENCE
WERE DOING THIS WORK AND IT
JUST MERGED.
WHAT I ALWAYS TELL OUR YOUNG
PEOPLE, IF YOU BELIEVE YOUR
DATA IS NOT TOO NOISY OR
ARTIFACTUAL YOU HAVE TO TELL.
I'M MORE EXCITED WHEN IT'S 180°
FROM WHAT I EXPECT.
I WAS WITH A GOOD GROUP AND WE
SUPPORTED EACH OTHER AND DIDN'T
BACK DOWN.
WE KEPT PUSHING FORWARD.
MOST OF THE TIME WHEN YOU LOOK
BACK, LIKE I SEE A BUNCH OF
OPPORTUNITIES I HAD THAT I
DIDN'T TAKE.
LIKE A GUY WAS ASKING ME BRING
SOME OF THAT GLP-1 DOWN AND
I'LL USE IT IN MY FOOD INTAKE
MODELS AND I NEVER GOT AROUND
TO IT.
SOMEBODY ELSE DID THAT.
IT'S JUST THE WAY IT GOES.
>> Kimberly Narain: THANK YOU
SO MUCH FOR THAT.
>> David D'Alessio: YEAH,
THANKS FOR ASKING.
>> Kimberly Narain: OKAY, I
THINK WE ARE GOING TO HEAD TO
OUR NEXT PRESENTATION AT THIS
POINT.
MR. MACIEJEWSKI, HE IS A
RESEARCHER AT DUKE AS WELL.
HE IS REALLY A PIONEER WHEN IT
COMES TO USING REAL-WORLD DATA
SOURCES.
HE HAS E SINTLY LEVERAGED THE
ENTIRE SPECTRUM OF REAL-WORLD
DATA SOURCES AND ACTUALLY
GENERATED SOME NEW ONES IN
ORDER TO HELP US UNDERSTAND,
ESSENTIALLY, THE ACCESS, THE
COST, AND THE HEALTH
IMPLICATIONS OF INTERVENTIONS
FOR CARDIO METABOLIC DISEASE.
HE HAS STUDIED AN ARRAY OF
INTERVENTIONS INCLUDING BUT NOT
LIMITED TO BARE BARIATRIC
SURGERY.
HE IS THE ONE TO TALK TO US
ABOUT THE LANDSCAPE OF
REAL-WORLD AND BENEFITS AND
TRADE-OFFS OF USING THESE
DIFFERENT DATA SOURCES.
AND ABOUT METHODOLOGICAL.
TAKE IT AWAY, MR. MACIEJEWSKI.
>> Matthew Maciejewski: THANK
YOU VERY MUCH.
I APPRECIATE THE OPPORTUNITY TO
PRESENT TO YOU ALL TODAY.
I WILL PROVIDE AN OVERVIEW OF
TOPICS THAT WILL BE DISCUSSED
IN GREATER DEPTH LATER TODAY
AND TOMORROW.
I CAN SHARE MY OWN SLIDES IF
NOBODY IS GOING TO BE PUTTING
THEM UP.
HOPEFULLY YOU CAN SEE MY SLIDES.
SO I WANT TO DISCLOSE, MY
DISCLOSURES.
HERE IS WHERE WE ARE GOING.
WE WILL SORT OF DESCRIBE REAL
WORLD EVIDENCE AND REAL WORLD
DATA AND TALK ABOUT THE DATA
PUZZLES AND DATA TYPES TO
GENERATE THAT EVIDENCE.
AND CONCLUDE WITH ISSUES ON THE
VARIOUS STUDY DESIGNS WE MIGHT
BRING TO BEAR TO ADDRESS
IMPORTANT QUESTIONS IN THIS
SPACE.
REAL-WORLD DATA, IF YOU ARE NOT
AWARE, IS DATA AROUND PATIENT
HEALTH STATUS IN THE DELIVERY
OF CARE THAT IS ROUTINELY
COLLECTED.
LEVERAGING DATA FROM EHR'S
REGISTRIES AND CLAIMS,
BASICALLY.
REAL WORLD EVIDENCE IS EVIDENCE
ABOUT THE USAGE AND POTENTIAL
BENEFITS OR RISKS OF MEDICAL
PRODUCTS AND SERVICES DERIVED
FROM THIS REAL-WORLD DATA.
AND TO FILL GAPS WE WILL HAVE
TO LEVERAGE A FULL SPECTRUM OF
DESIGNS I WILL TALK ABOUT.
IN THE IDEAL WORLD THE DATA
AVAILABLE TO US FOR GLP-1
EVALUATION WOULD BE DATA THAT
IS ROUTINELY AVAILABLE, THE
REAL-WORLD DATA IN BLACK HERE.
AND IDEAL DATA THAT IS RARELY
AVAILABLE IN THE RED.
SO NOT ONLY WOULD WE HAVE THE
ANTI-OBESITY MEDICATION OR AOM
ORDERS AND FILLS BUT WE WOULD
ALSO HAVE INFORMATION ON THE
COMPOUNDED INFORMATION THAT WE
KNOW PATIENTS ARE GETTING THEM,
WE JUST DON'T KNOW TO WHAT
EXTENT.
WE WOULD IDEALLY HAVE NOTES
FROM EVERY CLINIC VISIT THAT IS
INCREASINGLY AVAILABLE.
INFORMATION ON HEALTH SYSTEM
AND PATIENT BEHAVIOR
INFORMATION IN THE BOTTOM PART
OF THE RED TEXT.
HAVING THIS ADDITIONAL DATA IN
RED WOULD HELP US ENRICH OUR
ABILITY TO CHARACTERIZE
INCLUSION AND EXCLUSION
CRITERIA.
CO-VARIANTS FOR PREDESCRIPTIVE
PURPOSES, REGRESSION
ADJUSTMENTS AND TO BE ABLE TO
ADDRESS COMPETING HYPOTHESES
FOR WHY WE ARE SEEING OUTCOMES
IF WE KNEW OF PEOPLE'S USE OF
GYMS AND POOLS AND SUCH AND
RIDING BIKES AND WOULD HELP US
ENRICH OUR OUTCOME MEASUREMENT.
THERE IS A BROAD ARRAY OF
STRUCTURED AND UNSTRUCTURED
DATA THAT MIGHT BE USEFUL IN A
BIG DATA WORLD.
THIS IS CHARACTERIZED NICELY IN
THIS NICE 2014 PAPER IN JAMA
THAT WOULD CAPTURE AN ARRAY OF
DOMAINS OR TYPES OF DATA IN THE
ROWS HERE ON THE LEFT.
SOME OF WHICH I WILL DESCRIBE
NOW.
EHR DATA IS ROUTINELY AVAILABLE
IN A NUMBER OF DOMAINS.
THOSE THAT ARE AVAILABLE ACROSS
ALL THE HR'S MORE OR LESS, IS
REPRESENTED BY THE GREEN X'S,
AND THOSE THAT ARE SOMETIMES
AVAILABLE IN SOME EHR'S AND NOT
OTHERS ARE YELLOW, LIKE
SOCIOECONOMIC STATUS, MORTALITY
OR HEALTH BENEFITS.
EHR'S HAVE A NUMBER OF
LIMITATIONS, HOWEVER, DUE TO
THEIR LACK OF INTEROPERABILITY.
SUPPOSE I'M HERE IN NORTH
CAROLINA IN THE TRIANGLE.
SAY THERE'S TWO PAYERS,
MEDICARE IS PAYER ONE, BLUE
CROSS, BLUE SHIELD OF NORTH
CAROLINA IS PAYER TWO.
OVER TIME, PATIENTS WILL BE
COVERED BY DIFFERENT PAYERS.
AND DUE TO THE PROVIDER
NETWORKS ALLOWED IN THOSE
DIFFERENT PAYERS PATIENTS MAY
APPEAR, DISAPPEAR AND REAPPEAR
IN DIFFERENT OUTPATIENT AND
INPATIENT EHR'S.
THE DUKE EHR OUTPATIENT EHR A
AND B, AND UNC OUTPATIENT AND
EHR C AND D OVER TIME.
THERE ARE SOME HEALTH SYSTEMS
THAT ARE FAIRLY UNIQUE BECAUSE
THEY ARE RELATIVELY CLOSED
SYSTEMS.
AND NOT ONLY A PAYER BUT ALSO
THE PROVIDER OF CARE, LIKE V.A.
AND KAISER PERMANENTE WHERE YOU
MAY HAVE PERFECT OVERLAP OF THE
PAYER CLAIMS IN THE YELLOW
CIRCLES AND EHR'S IN THE GREEN
AND BLUE CIRCLES THAT
COMPLETELY OVERLAP BECAUSE THEY
ARE ENTIRELY CLOSED SYSTEMS AND
PAYERS AND PROVIDERS OF CARE.
OTHERWISE IN MOST COMMERCIAL
INSURANCE, THERE'S LOTS OF
TURNOVER, SO PEOPLE ARE
APPEARING AND DISAPPEARING AND
REAPPEARING IN THESE DIFFERENT
SOURCES OF DATA BECAUSE THEY
ARE CHANGING INSURANCE COVERAGE
AND CHANGING THEIR USUAL
PROVIDER OF CARE THAT MAY BE
DRIVING WHICH SYSTEMS AND EHR'S
THEY APPEAR IN.
SO THEY MAY BE BOUNCING BETWEEN
SAY DUKE AND UNC.
AND THIS APPEARING REAPPEARING
PHENOMENON PROBABLY OCCURS IN
OTHER HEALTH CARE SYSTEMS
DEPENDING ON THE SYSTEMS
OPERATING.
EHR'S HAVE OTHER LIMITATIONS,
INCLUDING CLINICAL NOTES MAY
NOT BE AVAILABLE.
WITH NLP CHANGING, BUT THEY ARE
NOT UNIFORMLY AVAILABLE.
UNSTRUCTURED DATA IS JUST
INHERENTLY CHALLENGING.
EHR'S ARE OFTEN HIGHLY
CUSTOMIZED WHILE UNC AND DUKE
MAY HAVE COMMON DOMAINS THERE
MAY BE DOMAINS AVAILABLE IN THE
DUKE EHR NOT AVAILABLE IN THE
UNC, AND REVERSE, THERE MAY BE
DOMAINS AVAILABLE IN UNC NOT IN
THE DUKE.
IF A PATIENT WENT TO UNC
YESTERDAY AND DUKE TODAY, THERE
MAY BE DIFFERENT VALUES OF
BLOOD PRESSURE FOR PERFECTLY
REASONABLE REASONS, BLOOD PRESS
YOUS CAN CHANGE HOUR TO HOUR,
BUT THERE MAY BE TYPOS THAT MAY
CAUSE DATA THAT SHOULD BE
SIMILAR TO APPEAR DIFFERENTLY.
PRAF PRAFT
THE LACK OF INTEROPERABILITY
MAY RESULT IN COUNTING OF
COVARIATES.
COLLEAGUE AT DUKE, BHAVSAR.
WHETHER YOU RELY ON DATA FROM A
SINGLE EHR OR POOL ACROSS
DIFFERENT EHR'S YOU COULD SEE
THE PREVALENCE OF HYPERTENSION
IS SIGNIFICANTLY UNDER COUNTED
IF JUST RELYING ON A SINGLE
EHR, COMPARED TO CHARACTERIZING
HYPERTENSION DIAGNOSE
DIAGNOSES ON ALL THREE.
THE INCIDENTS OF THESE
IMPORTANT CARDIOVASCULAR
OUTCOMES IS SIGNIFICANTLY UNDER
COUNTED IN A SINGLE EHR.
SO FOR EXAMPLE, USING AT
COMPOSITE STROKE AND HEART A
FAILURE, THERE'S ALMOST
UNDERCOUNT OF 6.4% COMPARED TO
WHEN YOU TRACK THAT ACROSS ALL
EHR'S UP TO 9%.
THERE ARE NETWORKS NOW OF
REAL-WORLD DATA THAT HAVE BEEN
COMPILED IN FEDERATED FORMS AN
CENTRALIZED FORMS.
IN A CENTRALIZED NETWORK ALL
THE DATA IS SORT OF BROUGHT TO
A CENTRALIZED HUB AND DATA
COULD BE LEVERAGED IN LARGE
SAMPLES THAT WAY.
OR A FEDERATED VERSION WHERE
THE DATA SITS IN EACH OF THE
SYSTEM AND THERE'S DISTRIBUTED
DATA ANALYSIS THAT'S DONE.
THIS SLIDE SHOWS ATTRIBUTES OF
THESE DIFFERENT NETWORKS AND
CONCRETE EXAMPLES OF THEM.
RINDISTRIES.
-- REGISTRIS.
IF THEY HAVE DIFFERENT EHR'S,
UNDERLYING DATA STRUCTURES
REGISTRIES ARE FOR PEOPLE WITH
RARE CONDITION OR COMMON
DISEASE.
OR CERTAIN PROCEDURES.
DUKE HAS BEEN INVOLVED IN
COMPILATION OF NUMEROUS
CARDIOVASCULAR PROCEDURE
REGISTRIS.
SO REGISTRIES COULD POTENTIALLY
BE USEFUL SOURCE FOR EVALUATION.
THEY SHARE COMMON DOMAINS OF
EHR'S BUT THEY HAVE UNIQUE
DOMAINS THAT MAY NOT BE IN THE
EHR'S LIKE FOLLOW-UP TIMES
SINCE CARDIOVASCULAR REGISTRIS
ARE VERY INTERESTED IN
UNDERSTANDING PATIENT OUTCOMES
IN THE MEDIUM AND LONG TERMS.
SO CHARACTERIZING AT TIME
POINTS IS IMPORTANT IN
REGISTRIS.
AND THEN THERE'S CLAIMS DATA,
MEDICARE OR OTHER, THAT HAVE
DOMAINS SIMILAR FROM EHR'S AND
REGISTRIES BUT ALSO HAVE UNIQUE
DATA ELEMENTS.
LIKE PAYMENTS AND REIMBURSEMENT.
SO IN MEDICARE CLAIMS YOU KNOW
WHAT MEDICARE HAS PAID FOR EACH
VISIT, EACH MEDICATION, EACH
HOSPITALIZATION AND YOU ALSO
KNOW ENROLLMENT BECAUSE THE
DATA CONTAINED IS ONLY ON THOSE
COULD HAVED BY THE PARTICULAR
PAYER.
SO CLAIMS DATA HAD PARTICULAR
BENEFITS IT'S CHARACTERIZING
THE CARE THAT'S BEEN REIMBURSED
WITHIN A PARTICULAR REGION,
SUCH AS KAISER PERMANENTE,
WASHINGTON WHERE DAVID
ARTERBURN IS, OR DUKE OR
MEDICARE.
BUT IT'S AGAIN LIMITED.
IT ONLY INCLUDES PEOPLE WHO ARE
COVERED BY THAT PAYER.
IF YOU ARE INTERESTED IN
UNDERSTANDING GLP-1 USE IN
MEDICAID THERE'S ONLY A CERTAIN
NUMBER OF STATES, MAYBE TEN
RIGHT NOW THAT COVER GLP-1'S.
IF ARE IN A STATE LIKE NORTH
CAROLINA WHERE MEDICAID DOESN'T
COVER, WON'T HAVE THAT
INFORMATION.
NONE OF THE CLAIMS DATA HAVE
INFORMATION ON COMPOUNDED
GLP-1'S.
SO THAT CHARACTERIZES A RANGE
AT A HIGH LEVEL OF DATA SOURCES
THAT MIGHT BE AVAILABLE FOR
GLP-1 EVALUATION.
NOW WE WILL PIVOT TO STUDY
DESIGNS THAT MIGHT LEVERAGE
THESE DATA TO BE ABLE TO
PROVIDE OR GENERATE REAL-WORLD
EVIDENCE.
THERE'S THREE BASIC DESIGNS I
WILL TALK ABOUT.
HIGHLY-CONTROLLED RANDOMIZED
TRIAL.
PRAGMATIC, AND QUASI
EXPERIMENTAL STUDY THAT COULD
EMULATE TRIALS USING TARGET
TRIAL PRINCIPLES.
IF YOU ARE INTERESTED IN
PRAGMATIC TRIAL METHODS AND
ISSUES I RECOMMEND YOU STICK
AROUND FOR ANJA'S AND LESLIE'S
TALK LATER.
IF YOU ARE INTERESTED IN THE
OTHER WORK, MIGUEL HERNAN, I
RECOMMEND YOU STICK AROUND FOR
HIS TALK LATER TODAY.
FUNDAMENTAL ISSUE REGARDLESS OF
THE STUDY DESIGN IS WHAT
COMPARITOR ARE YOU GOING TO BE
USING.
ANOTHER MEDICATION, OR ACTIVE
NON ANTI-OBESITY MEDICATION,
SGLT-2 OR DPP-4I.
OR BARIATRIC SURGERY OR CPAP OR
USUAL CARE.
IT AFFECTS THE CONFOUNDING THAT
MIGHT BE RELEVANT IN YOUR
NON-RANDOMIZED STUDY.
AND WHAT PARTICULAR SOURCE OF
CONFOUNDING THAT MIGHT BE
IMPORTANT.
FOR EXAMPLE, IF WE WANT TO DO A
STUDY COMPARING SEMAGLUTIDE TO
TIRZEPATIDE, YOU KNOW, THE
DEGREE OF CONFOUNDING IS
PROBABLY RELATIVELY UNIFORM
BECAUSE THESE ARE TWO COHORTS
OF PATIENTS WHO ARE ACTIVELY
SEEKING TREATMENT FOR WEIGHT
LOSS, PRESUMABLY.
AND THEY ARE EQUALLY OPEN TO
SIMILAR MODES OF RECEIVING THAT
TREATMENT.
WHEREAS, IF YOU ARE DOING
COMPARISON OF PATIENTS WHO ARE
HAVING SEMAGLUTIDE VERSUS
PEOPLE GETTING BARIATRIC
SURGERY, YOU ARE GOING TO BE
COMPARING PEOPLE WHO ARE ALSO
SEEKING WEIGHT LOSS TREATMENT
BUT MAYBE THERE'S DIFFERENCE IN
WILLINGNESS TO INJECT
MEDICATION.
AND DIFFERENT OPENNESS.
VERSUS SAY A COMPARISON OF
SEMAGLUTIDE TO SGLT-2'S, MAY BE
THE PATIENTS RECEIVING SGLT-2'S
AREN'T ACTIVELY SEEKING WEIGHT
LOSS TREATMENT, THEY ARE
SEEKING TREATMENT FOR MANAGING
OF THEIR DIABETES, WHEREAS
PEOPLE RECEIVING SEMAGLUTIDE
ARE INTERESTED IN THE WEIGHT
LOSS BENEFITS.
THE SECOND IMPLICATION WHICH
MAY BE SUPER OBVIOUS, THE
RESEARCH QUESTION AND CLINICAL
DECISION MAKING YOU ARE TRYING
TO INFORM CHANGES AS THE
COMPARATOR CHANGES.
IF YOU ARE COMPARING THE
SEMAGLUTIDE AND TIRZEPATIDE YOU
ARE TRYING TO INFORM THE
CLINICAL DECISION, WHICH GLP-1
SHOULD A GIVEN PROVIDER PROVIDE
CONSIDER PROVIDING AND WHAT ARE
THE TRADE-OFFS OF THAT.
COMPARED TO DECISION MAKING
AROUND PHARMACOTHERAPY VERSUS
SURGERY.
IF YOU WANT TO HEAR A LOT MORE
ABOUT THIS, I SUGGEST YOU STICK
AROUND FOR KRISTINA LEWIS'S
TALK TOMORROW.
AND THEN LET ME NOW TURN TO AN
ILLUSTRATION OF THE POTENTIAL
VALUE IN SAMPLE RESTRICTION
WHEN THINKING ABOUT MEDICATION
EVALUATION AND IT'S EFFECTS ON
CLINICAL OUTCOMES.
IN THIS CASE MORTAL.
ITY.
BASED ON 2007 PAPER BY
SEBASTIAN KNEE WISE, USE OF
STATIN IN ONE-YEAR MORTALITY,
OLDER ADULTS IN PENNSYLVANIA.
THEY RECOGNIZED THAT THE CHOICE
OF COMPARATOR CAN FUNDAMENTALLY
CHANGE YOUR ESTIMATED RATE
RATIO SHOWN IN THE RED AND
BLACK TEXT TO THE RIGHT.
AND THAT THERE MAY BE VALUE IN
TRYING TO, THROUGH STUDY DESIGN
AND SAMPLE RESTRICTION, IMPROVE
THE INTERNAL VALIDITY BY
REDUCING CONFOUNDING IN YOUR
CHOICE OF COMPARATOR.
INITIALLY IN THE FIRST LINE
THEY WERE COMPARING STATIN
USERS AND NON-USERS.
IN LARGE COHORTS.
BUT THEY WERE WORRIED THAT THE
NON-USERS HAD A HETEROGENEOUS
GROUP OF NON-USERS ALL ELIGIBLE
FOR STATINS BUT QUITE VARIED IN
THEIR SOURCE OF CONFOUNDING.
SO THEY WANTED TO REDUCE THE
SOURCE OF CONFOUNDING WHICH
WERE QUITE DIFFUSE THROUGH
SAMPLE RESTRICTION.
YOU COULD SEE HOW THE SAMPLE
SIZES DROPPED AS THEY IMPOSE
ADDITIONAL RESTRICTIONS.
TO MAKE THEM MORE HOMOGENOUS
AND REDUCE CONFOUNDING THE
AUTHORS FIRST RESTRICTED TO
INCIDENT USERS.
THEY BASICALLY KICKED OUT THE
PREVALENT USERS FROM THE FIRST
ROWS OF THE TABLE TO THOSE WHO
ARE INCIDENT USERS.
AND THEY FURTHER RESTRICTED TO
THOSE WHO HAD SIMILAR INDEX
DATES, THAT IS ENTRY INTO THE
COHORTS TO BEGIN FOLLOW-UP TO
ADDRESS 1B SECTION OF THIS.
SO THEY MATCHED PATIENTS WHO
SORT OF ENTERED THE COHORT AT
SIMILAR DATES BASED ON
MEDICATION OR VISIT DATES.
THAT WAS REALLY TO ADDRESS
IMMORTAL TIME BIAS.
THEY FURTHER RESTRICTED TO NOT
ALL OF NON-USERS BUT THOSE WHO
WERE INITIATING GLAUCOMA
MEDICATIONS WHICH WAS AN
ATTEMPT, SINCE GLAUCOMA
MEDICATIONS HAVE NO KNOWN
PATHWAY TO MORTALITY, IT WAS IN
EFFECT A PLACEBO BUT ACTIVELY
TAKING SOME TYPE OF MEDICATION.
YOU COULD SEE AS THE
RESTRICTION TO THIS COHORT WENT
ON AND ON, RESTRICTING THE
SAMPLE SIZES, THE EFFECT
ESTIMATE BASED ON RATE RATIOS
DROPPED WERE THE BIAS AWAY FROM
THE NULL GRADUALLY WAS
RESTRICTED FROM RATE RATIO 0.62
DOWN TO THE FINAL ANALYSIS IN
LINE 5 AT THE BOTTOM TO A RATE
RATIO OF 0.79 WHICH MIMICKED
THE PROSPER TRIAL THEY WERE
USING AS AN ANCHOR FOR THE
VALIDITY OF THIS OBSERVATIONAL
STUDY.
SO THE POINT OF ALL THIS IS TO
SAY WITH THROUGH THOUGHTFUL
COHORT RESTRICTION, YOU CAN
IMPROVE THE INTERNAL VALIDITY
OF YOUR REAL-WORLD IFRDS BY
TRYING TO ADDRESS CONFOUNDING
IN THE COMPARATOR YOU ARE
CHOOSING.
I REALIZE THAT'S A LOT.
BUT I WANTED TO HIGHLIGHT THIS
AS A NICE ILLUSTRATION OF
SAMPLE AND HOW IT CAN ADDRESS
CONFOUNDING.
WITH THAT, LET ME TURN TO THE
TRADE-OFFS IN THE DIFFERENT
STUDY DESIGNS.
STARTING WITH HIGHLY CONTROLLED
RANDOMIZED TRIALS.
WE KNOW DOES A GOOD JOB OF
ADDRESSING CONFOUNDING THROUGH
RANDOMIZATION, IT BALANCES IN
OUR TABLE ONE, ALL OBSERVED
CHARACTERISTICS AND CONFOUNDING
SO WHAT WE END UP WITH IS
EFFICACY ESTIMATE WITH STRONG
INTERNAL VALIDITY.
BECAUSE IT'S A PROSPECTIVE
DESIGN, THE MEASUREMENTS CAN BE
TAILORED OR RESEARCH QUESTION
IN A COUPLE WAYS.
WE CAN CHOOSE THE OUTCOMES THAT
WE WANT TO ADDRESS, THE
BASELINE MEASUREMENTS WE WANT
TO ASSESS IN OUR SURVEYS AND
DIRECTLY HAVE THOSE AVAILABLE
IF THEY ARE NOT ROUTINELY
AVAILABLE IN WHATEVER EHR DATA
OR CLAIMS WE ARE USING TO HELP
IDENTIFY ELIGIBLE PATIENTS.
AND WE CAN TIME THE
MEASUREMENTS OF OUTCOMES AT THE
TIMING WE THINK ARE IMPORTANT
TO OBSERVE EFFECTS.
BUT THERE ARE A NUMBER OF
LIMITATIONS TO HIGHLY
CONTROLLED TRIALS.
THEY MAY NOT GENERALIZED THE
REAL WORLD IF THEY ARE IN
ACADEMIC MEDICAL CENTERS.
THEY MAY NOT SPEAK TO THE
CLINICAL DECISIONS THAT ARE
PARTICULARLY RELEVANT TO
CLINICIANS IN THE FIELD IF
PLACEBO IS THE COMPARATOR.
ACTIVE COMPARATORS COULD BE
USED HERE.
THE EVIDENCE GENERATED MAY NOT
BE RELEVANT TO THE FULL ARRAY
OF PATIENTS RECEIVING THESE
TREATMENTS AS IS TYPICALLY DONE
IN THESE TRIALS, PREGNANT
WOMEN, OLDER ADULTS, CHILDREN,
ADOLESCENTS ARE EXCLUDED.
IF IT'S SMALL THEY MAY NOT HAVE
THE POWER TO SPEAK TO EVENTS OR
IDENTIFY SUBGROUPS WHO HAVE
PARTICULAR BENEFITS OR HARMS.
TO HELP ADDRESS THIS PRAGMATIC
TRIALS HAVE BEEN DONE MORE
INCREASINGLY TO ADDRESS SOME OF
THE LIMITATIONS OF THESE
HIGHLY-CONTROLLED TRIALS.
THEY HAVE THE BENEFITS OF
ADDRESSING CONFOUNDING THROUGH
RANDOMIZATION AS WELL.
THEY ALSO HAVE THE ABILITY TO
IMPROVE GENERALIZED ABILITY BY
BEING IMPLEMENTED IN EMPLOYER
SETTINGS, CHURCHES, GYMS,
YMCA'S AND OTHER CONTEXT
OUTPATIENT CLINICS NOT JUST
MEDICAL SENT CENTERS.
THEY MAY BE MORE GENERALIZABLE.
THIS IS ILLUSTRATED IN THE
FIGURE TO THE RIGHT WHICH IS AN
ATTEMPT TO SUMMARIZE
HYPOTHETICAL RESPONSE TO
TREATMENT BY THE ELIGIBLE
POPULATION.
THAT'S THE TOP CURVE.
THE BELL-SHAPED CURVE AT THE
TOP, REPRESENTING THE
POPULATION, WHICH CAN, SOME OF
THEM IN THIS HYPOTHETICAL
EXAMPLE ARE HARMED BECAUSE THE
NET BENEFIT IS NEGATIVE, BELOW
ZERO AND THERE ARE SOME
PATIENTS WHO DERIVE GREAT
BENEFIT FROM THE TREATMENT, NET
BENEFIT OF 1.25 OR 2, BUT THE
NET BENEFIT IS 0.5.
HIGHLY CONTROLLED TRIAL
REPRESENTED BY THE TIGHTLY
BOUND BELL-SHAPED CURVE
CENTERED AT 0.5, BECAUSE OF THE
RESTRICTIVE INCLUSION,
EXCLUSION AREA IT DOESN'T CLUE
THE FULL DISTRIBUTION OF
RESPONSES IN THE POPULATION.
WHEREAS PRAGMATIC TRIAL BEING
LESS RESTRICTIVE CAPTURES MORE
DISTRIBUTION OF RESPONSES IN
NET BENEFIT BUT NOT FULLY TO
THE TAIL BEYOND NEGATIVE 0.1 OR
ALL THE WAY TO TWO.
BUT IT DOES REPRESENT A MORE
COMPLETE DISTRIBUTION OF
PATIENT RESPONSES.
BY BEING A PROSPECTIVE DESIGN
YOU CAN HAVE THE SAME
MEASUREMENT BENEFITS AS THE
HIGHLY CONTROLLED TRIAL.
THE POWER TO EVALUATE RARE
EVENTS AND SUBGROUPS MAY BE
LIMITED IF THE SAMPLE SIZE IS
SMALL.
BUT BECAUSE IT'S REPRESENTING
MORE POPULATION DISTRIBUTION
AND RESPONSES IF YOU ARE ABLE
TO DO, YOU MAY BE ABLE TO PICK
UP HARMS IF THEY EXIST AND
HETEROGENEITY IF THEY EXIST.
AND THEN TRIAL EMULATION, IN
OUR QUASI EXPERIMENT OR
NON-RANDOMIZED STUDY.
AND MIGUEL WILL TALK ABOUT THIS
IN GREAT DEPTH.
THE GOAL IS TO OUTLINE,
FORMALIZE WHAT WOULD BE THE
IDEAL DOMAIN.
TREATMENT STRATEGIES, START-END
OR FOLLOW-UP, CAUSAL CONTRASTS.
AND EMULATE IN THE ABSENCE OF
RANDOMIZATION.
IN PARTICULAR, THIS LAST ONE,
HOW ARE WE GOING TO DEAL WITH
BASELINE/TIME-VARYING
CONFOUNDING TO TRY TO ADDRESS
SOURCES OF CONFOUNDING AND
SELECTION BIAS?
THERE ARE TRADE-OFFS IN TRIAL
EMULATION DESIGNS.
THERE ARE REAL BENEFITS OF
GENERALIZABILITY BECAUSE WE
WILL OBSERVE GENERALLY IN THE
GLP-1 WORLD PATIENTS GETTING
THEM ON AND OFF LABEL.
BECAUSE SO MANY PEOPLE ARE
GETTING THESE MEDICATIONS WE
PRESUMABLY WILL HAVE LARGE
SAMPLES SO WE MAY HAVE
STATISTICAL POWER TO MITIGATE
RARE OUTCOMES AND SUBGROUP
EFFECTS AND WE MAY BE ABLE TO
EVALUATE A BROAD ARRAY OF
COMPARATORS.
THERE'S UNOBSERVED CONFOUNDING
THAT MAY BE PROBLEMATIC MAYBE
WE CAN DETECT WITH NEGATIVE
CONTROL OUTCOMES I WILL MENTION
IN A MINUTE.
IF THEY AREN'T CAPTURED IN
ROUTINE WE WON'T HAVE THEM.
AND THERE MAY BE MISSING DATA
BECAUSE THE MEASUREMENTS ARE
CONTINGENT ON PATIENTS GETTING
CARE.
THIS COULD BE A WAY OF
DETECTING POTENTIAL CONFOUNDING
OR OTHER VALIDITY THREATS.
WHAT WE ARE TYPICALLY DOING, WE
WANT TO LOOK AT OUTCOMES WE
THINK WILL BE IMPROVED OR
CHANGED BY OUR TREATMENT OF
INTEREST.
SO WE ARE TESTING WITH A TEST.
BRINGING OTHER OUTCOMES AND
LAMP POSTS WE MAY NOT BE
LOOKING UNDER, IT SETS A HIGHER
THRESHOLD FOR THE HYPOTHESIS
THAN IF STUDIES DON'T HAVE.
BECAUSE THE NULL HYPOTHESIS
THAT GLP-1'S DON'T AFFECT
OUTCOME CAN ONLY BE IMPACTED IF
IT CHANGES OUTCOMES AS EXPECTED
AND IT DOESN'T CHANGE OUTCOMES
WE DON'T EXPECT TO BE AFFECTED.
I DID A STUDY IN EARLY 2010'S
LOOKING AT EFFECT OF ADHERENCE
FOR INSURANCE.
GENERICS IN THIS CONTEXT FOR
TREATING DIABETES, HYPER
LIPIDEMIA.
ARB'S AND CAI.
WE EXPECTED IMPROVEMENT IN THE
SIX CLASSES WHERE THERE WERE NO
GENERICS BUT NO CHANGES IN THE
TWO CLASSES WHERE THERE WERE
NOT GENERICKS.
WE BELIEVE THE VBID PROGRAM OF
COST-SHARING REDUCTIONS DID
IMPROVE ADHERENCE, BECAUSE WE
SAW CHANGES IN THE SIX CLASSES
WHERE WE EXPECTED THEM AND WE
DIDN'T SEE CHANGES IN THE TWO
CLASSES WHERE WE DIDN'T EXPECT
CHANGES.
SO THE COMBINATION GAVE US
GREATER CONFIDENCE THE VBID
EFFECTS WERE REAL.
IF WE SAW JUMPS IN THE ARB'S
AND CAI THAT WOULD BE A SIGNAL
THERE'S SOME CONFOUNDING
RUNNING THROUGH THE DRUG
CLASSES WE HADN'T ACCOUNTED FOR.
SO THEY COULD BE A USEFUL
DESIGN FEATURE TO ADD.
ANOTHER THING IS IN RANDOMIZED
TRIALS CAN ONLY CONDITION
ENROLLMENTS ON MEASUREMENTS YOU
HAVE UP TO AND ON THE DAY OF
RANDOMIZATION.
YOU CAN'T CONDITION THE SAMPLE
ON FUTURE INFORMATION.
IN RETROSPECTIVE CO-HORTON
THERE IS TREATMENT INFORMATION
THAT SHOULD NOT BE CONDITIONED
ON IN THIS RECENT STUDY, THE
AUTHORS DID CONDITION ON
POST-INITIATION EXCLUSIONS
RELATED TO CANCER PREGNANCY AND
BARIATRIC SURGERY BUT YOU CAN'T
DO THAT IN THE TRIAL SO
SHOULDN'T DO IT SO DON'T DO
THIS IN YOUR RETROACTIVE --
>> Kimberly Narain: THERE'S
ABOUT THREE MINUTES LEFT.
>> David >> Matthew
Maciejewski: LET ME COMMENT,
HOW MUCH NON ADHERENCE WE ARE
SEEING IN THE REAL WORLD ON
GLP-1'S.
TO COMPLEMENT OUR ITT ANALYSES
COULD BE USEFUL TO UNDERSTAND
DIFFERENTIAL NON ADHERENCE OF
TREATMENT GROUPS, MAYBE THE
TYPE OF GLP-1'S.
HELP US UNDERSTAND
DOSE-DEPENDENT EFFECTS AND HELP
US UNDERSTAND THE LONG TERM
EFFECTS, WHAT ARE THE BENEFITS
AND HARMS OF 20-YEAR CONTINUOUS
ADHERENCE TO [BEEP]'S.
-- GLP-1'S.
SINCE THE TIME OF HIPPOCRATES
AS A REAL ISSUE.
C. EVERETT KOOP REINFORCED THAT.
THE STUDY FOUND MEDICAL AND
NON-MEDICAL REASONS FOR
DISCONTINUATION.
OUT OF POCKET COSTS OF THEM,
PEOPLE SWITCHING MEDICATION
COVERAGE THAT DOES AND DOESN'T
COVER IT AND OTHER REASONS
NON-MEDICAL WE NEED TO
UNDERSTAND BETTER THAN WE DO
NOW.
REAL WORLD EVIDENCE SUGGEST
DISCONTINUATION RATES IN THE
TRIALS ARE NOT TRANSPORTED INTO
THE REAL WORLD.
IN REAL WORLD, NON-ADHERENCE
RATES ARE VERY HIGH,
DISCONTINUATION ARE HIGH BOTH
FOR SEMAGLUTIDE AND TIRZEPATIDE.
THIS IS AN AREA WE NEED MORE
WORK.
IN CONCLUSION, THERE'S AN
URGENT NEED FOR REAL-WORLD
EVIDENCE OF GLP-1 WITH STRONG
INTERNAL VALIDITY, BROAD
GENERALIZABILITY AND PRINCIPLED
SUBGROUP EFFECT ESTIMATION.
WE WILL NEED THE FULL SPECTRUM
OF STUDY DESIGNS TO DOUGH THIS.
THEY ALL HAVE TRADE OFFS BUT
TARGET TRIALS MAY BE
PARTICULARLY IMPORTANT, THE
LARGE SAMPLES LET US LOOK AT
RARE EVENTS, SUBGROUP, OFF
LABEL AND CHARACTERISTICS AND
OUTCOMES FOLLOWING
DISCONTINUATION.
THERE'S A NUMBER OF DATA
SOURCES TO DO THIS WORK.
BECAUSE THIS IS SO COMPLICATED
I THINK TEAM SCIENCE IS THE
ONLY WAY FORWARD.
THERE ARE IMPORTANT GAPS AND
OPPORTUNITIES WE ALL KNOW IN
THIS SPACE AND WE WILL HELP
SURFACE IN THE NEXT DAY AND A
HALF.
SOME OF WHICH I TALKED ABOUT.
AND WITH THAT, I WILL STOP AND
TAKE QUESTIONS.
>> Kimberly Narain: THANK YOU
FOR THAT.
I AM JUST GOING TO SAY A QUICK
REMINDER TO PUT YOUR QUESTIONS
IN THE Q&A.
IF THE QUESTION IS FOR THE
SPEAKER AND NOT IN REFERENCE TO
A GAP, PLEASE PUT THE SPEAKER'S
NAME THERE, JUST TO HELP US
IDENTIFY.
AND SO THIS QUESTION COMES FROM
JAIME MOORE, I BELIEVE.
AND THE QUESTION IS, WHAT ARE
THE KEY CONSIDERATIONS TO
CREATE A SYSTEM THAT
SPECIFICALLY TAKES A LIFE
COURSE LENS TO TRACK OUTCOMES
FOR INDIVIDUALS WITH GLP-1 R.A.
EXPOSURE FROM CHILDHOOD THROUGH
ADULTHOOD?
>> Matthew Maciejewski: WELL,
THAT'S A GREAT QUESTION.
WE NEED TO DO DATA LINKAGES,
SINCE PATIENTS CHANGE HEALTH
SYSTEMS AND INSURANCES OVER THE
COURSE OF THEIR LIFESTYLES SO
WE NEED, WE CAN STITCH TOGETHER
POTENTIALLY WHAT MIGHT BE A
SINGLE-PAYER SYSTEM IF WE HAVE
LOTS OF RESOURCES AT OUR
DISPOSAL.
I THINK IT'S VERY IMPORTANT TO
POSTULATE WHAT WOULD BE THE
IDEAL DATA STRUCTURE.
WE TRY TO FIGURE OUT WAYS IN
WHICH TO BUILD THE DREAM.
I DON'T THINK SUCH A THING
EXISTS AT SCALE RIGHT NOW.
>> Kimberly Narain: I HAVE
ANOTHER QUESTION HERE.
THIS COMES FROM PAULINA KAREVA,
I BELIEVE.
IT SAYS HAVE YOU USED TRINET
REAL WORLD DATA NETWORK, HOW
DOES IT COMPARE TO THE OTHERS?
>> Matthew Maciejewski: I'M
SORRY TO SAY I HAVE NOT.
SO I CAN'T SPEAK TO THAT.
>> Kimberly Narain: WHAT ELSE
DO WE HAVE COMING HERE?
OKAY.
SO THIS IS FROM PATRICK
SWAOEGERT.
IS TRIAL EMULATION FEASIBLE FOR
GLP-1 VERSUS BARIATRIC SURGERY
QUESTIONS USING REAL-WORLD DATA?
OR IS THE UNMEASURED
CONFOUNDING TOO GREAT?
>> Matthew Maciejewski: YEAH,
THAT'S A GREAT QUESTION.
I KNOW THERE ARE EVALUATIONS
ONGOING, DO TARGET TRIAL
EMULATION IN THAT EXACT SPACE.
I THINK IT IS POSSIBLE TO DO SO
WITH SOME QUALIFICATIONS.
THE FIRST IS THAT BARIATRIC
SURGERY AT LEAST, WHICH I HAVE
DONE A LOT OF WORK IN, WITH
DAVID ARTERBURN AND OTHERS,
OFTEN IN TRIALS AND IN ROUTINE
CLINICAL PRACTICE, THERE ARE
PSYCHIATRIC REFERRALS TO
DETERMINE IF A PATIENT IS A
GOOD CANDIDATE.
AND THE INFORMATION ON THE
SEVERITY OF PEOPLE'S MENTAL
HEALTH CONDITIONS IF THEY ARE
PREVALENT ARE TYPICALLY NOT
OBSERVED.
SO WE CAN'T APPLY EXCLUSIONS TO
OUR COMPARATOR, NON-SURGICAL
COMPARATOR, IN ORDER TO
IDENTIFY, BECAUSE WHAT YOU
WOULD WANT TO DO IS COMPARE
PEOPLE WHO ARE ELIGIBLE FOR
BOTH INTERVENTIONS.
AND NOT ALL INCLUSION/EXCLUSION
CRITERIA ARE OBSERVABLE IN
ROUTINELY-COLLECTED DATA.
IN MENTAL HEALTH CONDITIONS,
SEVERITY IS ONE OF THEM.
WE DON'T OBSERVE THE LIFESTYLE
MODIFICATIONS OF BOTH DIET AND
EXERCISE THAT PEOPLE MAY OR MAY
NOT BE DOING AFTER INITIATION
OF THESE TREATMENTS AND THAT'S
A SOURCE OF CONFOUNDING.
AND SO I THINK THAT IS A
LIMITATION.
BUT IT IS, I THINK, GIVEN THAT
THE WEIGHT LOSS AND OTHER
HEALTH EFFECTS OF THESE
INTERVENTIONS ARE SO GREAT, I
DON'T BELIEVE THAT THE
BEHAVIORAL CHANGES THAT WE'RE
MISSING THAT WE CAN OBSERVE ARE
GOING TO COMPLETELY SWAMP THE
EFFECTS OF THOSE TREATMENTS ON
OUTCOMES.
SO I'M CAUTIOUSLY OPTIMISTIC
THAT CAN BE DONE.
>> Kimberly Narain: OKAY.
THIS IS FROM ARAVA CUACA.
ON THE NOTE OF YOUR HEALTHY
ADHERERS AND STOPPERS OF THE
MEDS IS THERE ANALYSIS IN
VARIOUS GROUPS OF POPULATIONS?
>> Matthew Maciejewski: I THINK
IT'S A VERY ACTIVE AND OPEN
AREA OF INVESTIGATION.
TO BE ABLE TO UNDERSTAND THE
REASONS FOR NON-ADHERENCE OR
DISCONTINUATION, YOU PROBABLY
NEED TO DO PRIMARY DATA
COLLECTION OF SOME KIND TO
SURVEY PATIENTS, BASICALLY.
I THINK THERE ARE A FEW, THE
GASSOIAN THAT DAVID SHOWED AND
I REFERENCED, BUT I THINK THIS
IS A VERY OPEN AREA FOR WORK.
>> Kimberly Narain: ANOTHER
QUESTION IS COMING FROM, LET'S
GIVE SOMEONE ANOTHER
OPPORTUNITY HERE.
KHADIR, DO WE STILL THINK IN
THE UPCOMING FEW YEARS OLDER
ANTI-OBESITY DRUGS WILL STILL
BE SUITABLE ALTERNATIVES IN
TARGET STUDIES OF GLP-1'S?
>> Matthew Maciejewski: YEAH,
THAT'S A GREAT QUESTION.
THIS AREA IS SO DYNAMIC AND NEW
TECHNOLOGIES ARE COMING ON SO
FAST THAT IT IS HARD TO PREDICT
THE FUTURE.
BUT PHENTERMINE IS A FAIRLY
EFFECTIVE MEDICATION THAT, THIS
IS PERSONAL OPINION, MIGHT BE A
POTENTIAL FIRST-LINE OPTION,
SINCE IT'S REALLY INEXENSIVE.
SINCE ITS, I BELIEVE, GENERIC.
IT COULD BE, IF THERE'S
EVENTUALLY TRIALS OF STEP
THERAPY WHERE YOU GET PEOPLE TO
TRY BEHAVIORAL INTERVENTION AND
TRY THEM ON SOMETHING
INEXPENSIVE LIKE PHENTERMINE
AND IF THEY DON'T SUCCEED, YOU
SWITCH THEM TO ONE OF THESE
MORE EXPENSIVE GLP-1'S, I CAN
SEE THAT BEING USEFUL IN THIS
CONTEXT.
IF WE REALLY WANT TO TAKE A
POPULATION-BASED APPROACH TO
WEIGHT MANAGEMENT, WE ARE GOING
TO NEED THE FULL ARRAY OF
BEHAVIORAL, PHARMACOLOGIC AND
SURGICAL INTERVENTIONS AND THE
OPTIMAL MIX IN A PORTFOLIO OF
INTERVENTIONS IS TOTALLY
UNKNOWN.
>> Kimberly Narain: I THINK
THIS WILL BE OUR LAST QUESTION
HERE.
THIS IS PAULINA KHUKEVA.
WHAT DO YOU THINK OF USING A.
I. METHODS IN ADDITION?
>> Matthew Maciejewski: A.
I. METHODS CAN BE USEFUL FOR,
IF ARE DOING WEIGHTING OR
MATCHING METHODS, BOOSTED
GRADIENT FORESTS AND SUCH
METHODS HAVE BEEN USEFUL FOR
GENERATING PROPENSITY-BASED
KIND OF MODELS THAT PREDICT WHO
GETS TREATMENT, VERSUS NOT
TREATMENT, OR TREATMENT A,
VERSUS TREATMENT B.
THEY ARE BEING USED IN SUBGROUP
IDENTIFICATION METHODS, CAUSAL
FOREST BY SUSAN ATHY AND OTHERS.
SO I THINK A.
I. IS GOING TO BE USEFUL IN
THOSE PARTICULAR CONTEXTS AND
MAYBE OTHERS.
BUT A.
I., FUNDAMENTALLY, WE NEED A
GOOD , RICH DATASETS.
IT CAN'T MAGICALLY SOLVE CAUSAL
INFERENCE, CONFOUNDING
PROBLEMS, IF YOU ARE IN A
REALLY SPARSE DATASET.
AND THAT REMINDS ME OF A QUOTE,
WHICH IS SOMETHING LIKE, YOU
CAN'T MAKE RIGHT BY STATISTICS
WHAT YOU HAVE DONE WRONG BY
DESIGN.
>> Kimberly Narain: THANK YOU.
I THINK THAT'S A GREAT PLACE TO
END OUR DISCUSSION.
>> Matthew Maciejewski: THANKS
VERY MUCH.
>> Craig Hales: GREAT, THANK
YOU SO MUCH FOR THAT KEYNOTE
PRESENTATIONS TO GET US KICKED
OFF.
WE WILL GO AHEAD AND TAKE A
BREAK NOW.
AND WE WILL RECONVENE AT 11:00.
HAS BEEN AT THE FDA FOR THE
LAST 11 YEARS, SHE LEADS FDA'S
ADVANCING REAL WORLD EVIDENCE
PROGRAM AND LEADS A PORTFOLIO
OF EXTERNALLY CONDUCTED
REAL-WORLD EVIDENCE PROJECTS
AND SHE IS ALSO CONTRIBUTES TO
GUIDANCE DEVELOPMENT.
DR. BRADLEY WILL BE SPEAKING ON
THE USE OF REAL-WORLD EVIDENCE
FOR REGULATORY DECISION MAKING.
DR. BRADLEY?
>> THANKS, CHRISTINA, I WILL
SHARE MY SLIDES, CAN YOU HEAR
ME OKAY?
YEAH?
OKAY, GREAT.
CAN EVERYBODY HEAR ME AND SEE
MY SLIDES?
PERFECT.
SO AS CHRISTINA SAID, I'M HERE
TODAY MOSTLY TO TALK ABOUT THE
FDA, REAL-WORLD EVIDENCE
PROGRAM AND SOME WORK WE ARE
DOING ON THE SAFETY OF GLP-1'S.
THIS SPEECH REFLECTS MY VIEWS
AND NOT THE VIEWS OF FDA AND
SHOULDN'T BE CONSTRUED TO
REPRESENT FDA'S VIEWS OR
POLICIES, I HAVE NO CONFLICTS
OF INTEREST.
PRODUCTS SHOULDN'T BE CONSTRUED
AS ENDORSEMENT *.
WE WILL GO THROUGH FDA REAL
WORLD EVIDENCE.
THE CURES ACT OF 2016 FDA SHALL
ESTABLISH A PROGRAM TO EVALUATE
THE POTENTIAL USE OF REAL-WORLD
EVIDENCE TO SUPPORT NEW
INDICATION FOR A DRUG APPROVED
UNDER SECTION 505C AND SATISFY
POST-APPROVAL STUDY
REQUIREMENTS.
AND SHALL ESTABLISH A DRAFT
FRAMEWORK, DESCRIBE SOURCES OF
EVIDENCE, GAPS IN DATA
COLLECTION ACTIVITIES PD ET
CETERA.
FDA SHALL ISSUE DRAFT GUIDANCE
FOR INDUSTRY AND OTHER
STAKEHOLDERS WHICH WOULD FIND
APPROPRIATE STANDARDS, DATA
SOURCES, THINGS LIKE THAT.
AND SO, IN 2018, FDA PUT OUT
THEIR DECEMBER 2018 PUT OUT
FRAMEWORK FOR DRUGS AND
BIOLOGICS.
THIS APPLIES TO CENTER FOR
DRUGS AND BIOLOGICS ON THE
ONCOLOGY CENTER FOR EXCELLENCE.
REAL WORLD EVIDENCE, IT'S A
MULTIFACETED PROGRAM WHICH
INCLUDES THINGS LIKE INTERNAL
AGENCY PROCESSES.
WE HAVE A REAL-WORLD EVIDENCE
SUBCOMMITTEE THAT GETS TOGETHER
WITH SENIOR LEADERSHIP TO
DISCUSS ISSUES PERTINENT TO
REAL-WORLD EVIDENCE AT THE
AGENCY.
AND WE INVITE EXTERNAL PARTIES
TO PRESENT ON THE REAL-WORLD
EVIDENCE SUBCOMMITTEE AND WHERE
THEY CONSULT ON ADMISSIONS FOR
REAL-WORLD DATA.
WE DO EXTENSIVE EXTERNAL
ENGAGEMENT.
WE DO THINGS LIKE WHAT I'M
DOING TODAY AND WE TALK WITH
PANELS, WE GO TO CONFERENCES
AND MEETINGS.
AND AS I MENTIONED WE BRING
EXTERNAL PARTIES TO HEAR SOME
OF THEIR IDEAS.
AND LARGE DEMONSTRATION
RESEARCH PROJECTS REHATED --
RELATED TO THE METHODOLOGIC.
AND CONSIDERATIONS WHEN USING
REAL-WORLD DATA AND EVIDENCE IN
REGULATORY DECISION MAKING.
I THINK THE LAST PRESENTATION
COULD HAVED THESE DEFINITIONS,
JUST TO ARTICULATE THESE ARE
THE OFFICIAL FDA DEFINITIONS OF
BOTH REAL-WORLD DATA AND
REAL-WORLD EVIDENCE.
REAL-WORLD DATA ARE CONSTRUED
AS DATA THAT ARE ROUTINELY
COLLECTED.
SOMETIMES IF YOU HAVE
POTENTIALLY A REGISTRY SET UP
BY A SPONSOR FOR THE PURPOSES
OF CONDUCTING A POST-MARKETING
REQUIREMENT THAT WAS PUT
TOGETHER A PROTOCOL, THAT
WOULDN'T REALLY FALL --
SOURCES OF REAL-WORLD DATA AS
WE HEAR FROM THE LAST
PRESENTATION, ELECTRONIC HEALTH
RECORDS, MEDICAL CLAIMS DATA
AND PRODUCT AND DISEASE
REGISTRIS.
THE EVIDENCE DERIVED FROM
VARIOUS STUDY DESIGNS COVERED
BY THE LAST PRESENTATION ON
TRIALS, PRAGMATIC, EXTERNALLY
CONTROLLED AND OBSERVATIONAL
STUDIES.
SO MY COLLEAGUES PUBLISHED THIS
PAPER IN 2024 IN
PHARMACOEPIDEMIOLOGY AND DRUG
SAFETY.
WHEN CAN REAL-WORLD DATA, IT
HAS MANY USES AND CERTAINLY THE
SCIENCE AND HEALTH CARE SPACE.
JUST TO GIVE AN IDEA WHEN FDA
CAN GENERATE REAL-WORLD
EVIDENCE.
I INCLUDED A DATA TABLE.
FOR EXAMPLE, COULD HAVE AN
INTERTEN VUN SHL STUDY YOU
MIGHT USE REAL-WORLD DATA TO
SELECT TRIALS TO IDENTIFY
POTENTIAL PARTICIPANTS.
THAT WOULD NOT BE WHAT WE
CONSIDER REAL-WORLD EVIDENCE
FOR THE PURPOSES OF REGULATORY
DECISION MAKING.
CONVERSELY, IF THEY USED
REAL-WORLD DATA FOR ITS
ENDPOINT IT WOULD BE DEEMED TO
HAVE GENERATED REAL-WORLD
EVIDENCE THAT COULD BE
CONSIDERED IN REGULATORY
DECISION MAKING.
SIMILARLY, IN EXTERNALLY
CONTROLLED TRIALS, MIGHT HAVE
AN EXTERNAL CONTROL ARM THAT
USES REAL-WORLD DATA FROM A
DATA SOURCE THAT WOULD BE
DEEMED TO HAVE REAL-WORLD
EVIDENCE AND OBVIOUSLY ON THESE
INTERVENTIONS, DESIGNS LIKE AN
OBSERVATION ALICO HORTON,
REAL-WORLD EVIDENCE IS THE
TOPIC OF THE STUDY, TYPICALLY.
NEXT I WANTED TO TOUCH ON SOME
OF OUR GUIDANCES, AS I
MENTIONED WE PUBLISH A SUITE OF
EIGHT DIFFERENT GUIDANCES.
FIVE ARE FINAL VERSIONS AND
THREE ARE IN DRAFT.
ACCORDING TO STAKEHOLDER
COMMENTS.
THEY ARE CATEGORIZED A CCORDING
TO THEIR CONTENT.
WE PUT GUIDANCE ON THE USE OF
REGISTRIS.
IN TERMS OF IF YOU ARE
CONSIDERING USING THESE DATA
SOURCES, THESE ARE THE THINGS
THAT FDA NEED YOU TO CONSIDER
AND VARIOUS RECOMMENDATIONS
AROUND DATA, SO THESE DATA
SOURCES AND MOVING ONTO THE
DESIGN PHASE WE PUT OUT
RECOMMENDATIONS FOR THE USE OF
EXTERNALLY CONTROLLED TRIALS
WHICH ACTUALLY DIDN'T INCLUDE
HIGH --
WE PUT OUT GUIDANCE CONCERNING
DESIGN CONSIDERATIONS FOR RCT'S
AND CLINICAL PRACTICE SETTINGS,
WHICH AGAIN WAS MENTIONED IN
THE LAST PRESENTATION.
WHERE YOU KNOW, WE ARE USING
SORT OF MORE PRAGMATIC ELEMENTS
WITHIN THE HEALTH CARE SYSTEM
TO CONDUCT THE RCT'S.
WE ALSO PUT OUT VARIOUS
PROCEDURAL GUIDANCE ON WHERE TO
SUBMIT DATA AND REGULATORY
CONSIDERATION WHEN USING THESE
DATA FOR SUBMISSION TO SUPPORT
REGULATORY DECISION MAKING.
THE LINK ON THIS SLIDE WILL
GIVE AN OVER VIEW MORE IN
DEPTH, YOU DON'T HAVE TO GO
THROUGH ALL EIGHT, IF ANYONE
HAS ANY FURTHER INTEREST IN
THAT.
RECENTLY CDER CENTER FOR REAL
WORLD EVIDENCE INNOVATION
LAUNCHED.
IT WAS A NICE PUBLIC MEETING IN
DECEMBER 2024.
CCRI, THE AIM IS TO PROMOTE
CONSISTENT SIGHIVEIC REVIEW AND
KNOWLEDGE MANAGEMENT ACROSS THE
GRIPS THAT ARE CONSIDERING THIS
TYPE OF DATA FOR REGULATORY
DECISION MAKING.
IN TERMS OF ENSURING CONSISTENT
ASSESSMENT OF THE ADEQUACY OF
REAL-WORLD DATA AND RELATED
STUDY DESIGNS FOR REGULATORY
DECISION MAKING, THE CENTER
WILL ALSO BE CONCERNED WITH
PROMOTING CONSISTENT SCIENTIFIC
REVIEW ACROSS OTHER CENTERS AND
FDA AND RELATE DEVELOP
KNOWLEDGE MANAGEMENT AND
RESOURCES FOR STAFF.
ANOTHER AIM IS TO DRIVE-IN
NOVATION IN THE SPACE BY
CONTINUING TO ADDRESS GAPS IN
REGULATORY SCIENCE AND POLICY.
SO THE FOCUS AREAS FOR CCRI ARE
SCIENTIFIC REVIEW AND POLICY,
AGAIN, MAINTAINING AND
EXTENDING OUR COORDINATED
OUTREACH ENGAGEMENT WITH
PARTIES OF THE AGENCY.
ADVANCING RESEARCH INITIATIVES
AND DEVELOPING KNOWLEDGE
MANAGEMENT REPOSITORIES.
INTERNALLY.
NOW I WANT TO TALK ABOUT FDA
APPROACH TO EVALUATING
SUBMISSIONS RELATED TO
REAL-WORLD EVIDENCE.
THE STANDARD FOR ASSESSING
THESE SUBMISSIONS DOESN'T
CHANGE.
THE FOUNDATIONAL CONCERN ARE
DATA FIT FOR USE.
FIT FOR USE COMPRISES TWO
CONSIDERATIONS.
RELEVANCE.
DOES THE POTENTIAL DATA SOURCE
BEING CONSIDERED CONTAIN THE
RELEVANT INFORMATION ON THE
STUDY ELEMENTS YOU NEED TO
ANSWER YOUR STUDY QUESTION.
DOES IT CAPTURE YOUR EXPOSURES
AND COVARIATES IN AN ADEQUATE
MANNER.
DO YOU ALLOW THE STUDY TO
HAPPEN.
THE RELIABILITY ON THE OTHER
HAND MAY OR MAY NOT BE QUESTION
AGNOSTIC.
HOWEVER RELIABLE ARE THE DATA,
HOW ACCURATE, CAN THE DATA
THAT'S MEASURED BE COMPARED
WITH A SOURCE OF TRUTH AND WHO
COMPLETED YOUR DATA?
IF YOU ONLY HAVE CLAIMS DATA,
ARE YOU MISSING IMPORTANT
CONFOUNDERS THAT MIGHT BE
SUPPORTED.
WITHIN DATA SOURCES WHAT ARE
THE EX TINT AMPLE TEND OF
MISSING THE CONFOUNDER
PRINCIPLES.
AND TRACEABILITY, SOMETIMES
THESE PRIVACY AND DATA CAN GO
THROUGH VARIOUS ITERATIONS, IS
YOUR DATA TRACEABLE TO THE
SOURCE DATA AND THE RELIABILITY
AROUND THAT.
THE SECOND CONSIDERATION OF
COURSE IS THE STUDY DESIGN YOU
HAVE CHOSEN TO ANSWER YOUR
QUESTION.
CAN IT GENERATE ADEQUATE
SCIENTIFIC EVIDENCE.
TO HELP ANSWER REGULATORY
QUESTION.
OBVIOUSLY THERE'S A VERY HIGH
BAR FOR ASSESSING SUBMISSIONS
THAT SUPPORT A REGULATORY
DECISION.
AND WHETHER STUDY CONDUCT MEETS
FDA REGULATORY REQUIREMENTS.
THERE ARE SEVERAL REQUIREMENTS
AROUND DATA SUBMISSION THAT
NEED IN ORDER THAT THE DATA CAN
BE CONSIDERED.
I WILL BRIEFLY TOUCH ON A
COUPLE EXAMPLES OF WHERE
REAL-WORLD EVIDENCE HAS
CONTRIBUTED SUBSTANTIALLY TO
REGULATORY DECISIONS.
THE FIRST AND PROBABLY ONE OF
THE MORE WELL-KNOWN IS
TACROLIMUS, PROGRAF FOR LIVER
TRANSPLANT.
BASED ON EVIDENCE FROM RCT'S.
THERE WERE NO RCT'S FOR LONE
TRANSPLANT SO SPONSOR PROPOSE
APPLICATION FOR THAT.
AND THE STUDY DATA AND DESIGN
WERE EVALUATED A CODING TO FDA
STANDARDS AND IT WAS GRANTED
APPROVAL IN JULY 2021 FOR
PREVENTING INFECTION IN
TRANSPLANTS.
IT WAS A VERY WELL KNOWN AND
RIGOROUS MAINTAINED DATABASE OF
REGISTRY OF LUNG TRANSPLANT.
THE PATIENT LEVEL DATA FROM THE
REGISTRY WAS PROVIDED TO FDA AS
PART OF THE REVIEW PROCESS.
AND IT WAS A
NON-INTERVENTIONAL
OBSERVATIONAL TREATMENT GROUP.
COMPARED TO HISTORICAL CONTROLS.
OF NOTE IN THIS SITUATION, THE
OUTCOMES ARE VIRTUALLY CERTAIN
WITHOUT THERAPY, DRAMATIC
EFFECT CONCERNS ABOUT BIAS IN
THIS CASE.
THE SECOND EXAMPLE FOR A DRUG
USE IN THE TREATMENT OF
COVID-19 TOCILIZUMAB, TREATMENT
IN ADDITION TO CORTICOSTEROIDS
AND REQUIRING SUPPLEMENTAL
OXYGEN, NON-INVASIVE OR
INVASIVE MECHANICAL VENTILATION
OR EXTRA CORPOREAL MEMBRANE
OXYGENATION.
THE SORT OF REAL-WORLD DATA
COMPONENT OF THE RCT, THE
PRIMARY ENDPOINT WAS OBTAINED
FROM NATIONAL DEATH RECORDS.
THEN THE LAST ONE WAS A SAFETY
RELATED ISSUE FOR LACOSAMIDE,
WHICH IS USED FOR SEIZURES.
THE POINT HERE WAS TO PROPOSE
ALTERNATE LOADING DOSE FOR
INITIATION OF LACOSAMIDE
TREATMENT IN PARTIAL ON SET
SEIZURE FOR PATIENTS IN DHIRN.
THE ALTERNATE DOSES PRESENTED NO
ADVERSE EVENTS SO THAT LED TO
THE CHANGE IN THE LOAD AND DOSE
IN THAT PRODUCT.
AND USE FOR ELECTRONIC HEALTH
RECORDS.
THERE ARE SEVERAL CHALLENGES
WITH REAL-WORLD EVIDENCE.
YOU DON'T HAVE TIME TO GO INTO
ALL OF THEM, I THINK THE LAST
PRESENTER COULD HAVED SOME OF
THESE WELL.
DATA RELIABILITY AND CLINICAL
RELEVANCE AND IT'S REALLY ON
THE SPONSOR TO DEMONSTRATE THIS
TO THE AGENCY.
SOMETIMES, YOU KNOW, IT MAY BE
NOT EASY TO DEMONSTRATE
RELIABILITY IN THE ABSENCE OF
THRESHOLD OR MEASURES OF WHAT
IS GOOD ENOUGH, AND THAT IS
SOMETHING WE ARE EXPLORING.
THE POSSIBILITY TO ACTUALLY
CAPTURE THE OUTCOME AND DATA
SOURCE, IF NOT, CHALLENGES WITH
LINKAGE FOR OTHER DATA SOURCES
CAN BE PROBLEMATIC IN TERMS OF
GETTING PATIENT CONSENT IF
THAT'S NOT ACHIEVED BEFORE.
AND THE COST OF THESE THINGS.
IN TERMS OF DESIGN AND
INTERPRETATION, CONFOUNDING IS
FREQUENTLY INITIATED IN
NON-RANDOMIZED STUDIES.
PROBLEMS WITH INAPPROPRIATE
SPECIFICATION OF THE ENDPOINT.
USING NON-COMPARATOR.
FOR US, CONDUCT IS VERY
IMPORTANT.
MAKING SURE EVERYTHING IS
PRE-SPECIFIED AND FULLY
REVIEWED BY REVIEW TEAM AT FDA
IS REALLY A MAJOR CONCERN FOR
US.
ALSO THAT, NO ONE ELSE UNTIL
APPROVAL HAS BEEN APPROVED AND
ACCESS TO PATIENT-LEVEL DATA
AND ABILITY TO INSPECT
REAL-WORLD DATA SOURCES IS A
MAJOR CONCERN AND COULD BE
CHALLENGING FOR A SPONSOR WHO
POTENTIALLY DOESN'T OWN THAT
DATA.
I WANTED TO MOVE ONTO SOME
SPECIFIC CHALLENGES RELATED TO
THE DIABETES AND OBESITY SPACE.
IF YOU ARE USING HEALTH CARE
CLAIMS DATA, BUT THERE ARE
SPECIFIC CHALLENGES IN THIS
AREA, MEASURE CONFOUNDING
PARTICULARLY BMI, DIABETES
SEVERITY, HBA1C OFTEN CLAIMS
THEY DIDN'T HAVE ACCESS TO
LABORATORY DATA.
THERE IS LIKE A PROXY FOR
DIABETES SEVERITY AND ADAPTED
DIABETES SEVERITY INDEX YOU CAN
GUILT -- GET FROM CLAIMS
DATA BUT ONLY A PROXY.
THIS GLP-1 AREA CAN BE VERY
DIFFICULT TO IDENTIFY THE
INDICATION FOR GLP-1 USE,
ESPECIALLY IF IT'S WEIGHT LOSS.
IT'S VERY DIFFICULT TO IDENTIFY
INDICATION IN CLAIMS DATA, BUT
SOMETHING LIKE DIABETES IS A
LITTLE BIT EASIER TO ASSUME AND
TRY TO IDENTIFY OBESITY THE AND
DIAGNOSIS CODES LACKS
SENSITIVITY.
THERE ISN'T ANOTHER CHRONIC
WEIGHT MANAGEMENT PRODUCT THAT
IS A SUITABLE COMPARATOR FOR A
STUDY IN GLP-1'S AND NOT POSE
AS CHALLENGES IF YOU WANT TO DO
STUDIES IN THE WEIGHT LOSS
POPULATION.
BECAUSE OBVIOUSLY, IF YOU ARE
USING A NON-USER GROUP THEY
COULD BE VERY DIFFERENT AND
COULD LEAD TO IMBALANCE AND
SORT OF BASELINE
CHARACTERISTICS BETWEEN THE TWO
GROUPS.
NEXT I JUST WANT TO TALK
BRIEFLY ABOUT SOME STUDIES THAT
FDA HAVE DONE IN THE SENTINEL
SYSTEM, A LONG DISTRIBUTOR
NETWORK THAT IS FOCUSED ON SORT
OF ACTIVE SURVEILLANCE OF
APPROVED PRODUCTS IN MONITORING
SAFETY.
THIS WAS ACTUALLY A TREE SCAN
BASE SIGNAL IDENTIFICATION
STUDY DONE FOR OZEMPIC BETWEEN
JANUARY 2018 AND FEBRUARY 2022.
COMPARED TO ANOTHER DIABETES
AGENT.
THEY HAD 134 MATCHED PAIRS WITH
CONVENTIONAL AND SLIGHTLY LESS
ON THE SCORE METHODS.
SEMAGLUTIDE USERS YOUNGER HAD A
LOT MORE HEALTH CARE
UTILIZATION AND HISTORY OF
OBESITY AND INSULIN USE.
THEY WERE EITHER LABELED
ADVERSE EVENTS LIKE NAUSEA,
VOMITING, CONSTIPATION,
DIARRHEA.
THERE WERE NO NEW SAFETY
SIGNALS FOR OZEMPIC AND MORE
LIKELY CO MORBID AND NONE OF
THE ALERTS REQUIRED FURTHER
FOLLOW-UP.
I KNOW I'M GOING A BIT OVER
TIME HERE.
FDA ARE CURRENTLY INTERESTED IN
THE RISK OF INTENTIONAL
SELF-HARM WITH GLP-1 DRUGS.
THERE ARE TWO STUDIES ONGOING,
DESCRIPTIVE ANALYSIS THAT
LOOKED AT UNADJUSTED RATES OF
INTENTIONAL SELF-HARM AMONG
ADULT USERS BETWEEN 2015-2023
TO GET IDEA OF PSYCH HISTORY,
PSYCHOLOGICAL DISORDERS,
MEDICAL HISTORY AND HEALTH CARE
UTILIZATION AMONG THOSE WITH
OBESITY, RECEIVING ANY WEIGHT
LOSS PRODUCT.
THE INFERENTIAL STUDY UNDER WAY
WAS EVALUATING THE ASSOCIATION
BETWEEN THE USE OF GLP-1'S AND
POTENTIAL SELF-HARM AND USERS
OF OTHER DIABETES DRUGS.
INCIDENT USERS WITH TYPE II
DIABETES BETWEEN 2015-2023.
AND SECONDARY POPULATION CO
MORBID TYPE II DIABETES AND
OBESITY.
INTENTIONAL SELF-HARM
IDENTIFIED USING SENTINEL.
INVERSE PROBABILITY USING
ICD-10 DIAGNOSIS CODES.
AND INVERSE PROBABILITY OF
TREATMENT WEIGHTING TO ADJUST
FOR CONFOUNDING.
THESE STUDIES AREN'T AVAILABLE
YET SO UNFORTUNATELY I DON'T
HAVE THAT INFORMATION TO SHARE,
BUT SURELY THEY WILL BE OUT
SOON ENOUGH, SO PLEASE KEEP AN
EYE OUT FOR THEM.
IN SUMMARY OUR PROGRAM IS
ADVANCING AS OUTLINED IN OUR
FRAMEWORK, GUIDANCE AND OTHER
INTERESTED PARTIES ARE
INTERESTED IN CURRENT
CHALLENGES AND CHALLENGE WITH
GENERATING REAL-WORLD EVIDENCE,
CDER AND CCRI IS CONTINUING TO
ADVANCE THE USE OF RWE AND
DRIVE-IN NOVATION IN THE SPACE.
HOPEFULLY THE RESULTS WILL BE
AVAILABLE SOON.
I WANT TO ACKNOWLEDGE MY TEAM
AND ANALYTIC TEAM AND
COLLEAGUES IN DIVISION OF
EPIDEMIOLOGY AND DIVISION OF
PHARMACOVIGILANCE AND OFFICE OF
SURVEILLANCE WITH HELP WITH THE
SLIDES.
SO THANK YOU SO MUCH.
WE HAVE REAL-WORLD EVIDENCE
MAILBOX IN MY CENTER.
SO IF ANYONE HAS ANY QUESTIONS
YOU CAN OF COURSE ASK ME OR
REACH OUT VIA OUR EMAIL HERE.
THANK YOU FOR YOUR TIME.
>> CHRISTINE WEE: THANK YOU
VERY MUCH.
OUR NEXT TWO PRESENTERS WILL
SPEAK ON ASSESSING STRENGTH OF
REAL-WORLD EVIDENCE FOR
PRACTICE AND GUIDELINES
DEVELOPMENT.
DR. JOHN WONG IS CHAIR FOR
ACADEMIC AFFAIRS CHIEF OF DLIN
CAL DECISION MAKING AND PRIMARY
CARE INTERNIST AT TUFTS MEDICAL
CENTER AND VICE CHAIR TASK
FORCE, AND EDITOR FOR RESEARCH
ANNALS OF INTERNAL MEDICINE.
USING DECISION ANALYSIS.
JOINED BY DR. ASHLEY SKINNER,
HEALTH ANALYSIS RESEARCHER AND
POPULATION HEALTH SCIENCES AT
DUKE UNIVERSITY.
SHE A RECOGNIZED EXPERT IN
OBESITY AND CONTRIBUTED TO THE
AMERICAN ACADEMY PEDIATRIC
WHICH HAS HELPED SHAPE STANDARD
FOR CARE IN PEDIATRIC OBESITY.
WE WILL START WITH DR. JOHN
WONG FOLLOWED BY DR. SKINNER.
>> JOHN WONG: THANKS, DR. WEE.
BUILDING ON THE EXCELLENT TALKS
ABOUT THE STRENGTHS AND
LIMITATIONS OF RANDOMIZED
VERSUS NON-RANDOMIZED EVIDENCE
AND HOW IT INFORMS REGULATORY
DECISIONS.
I'M HOPING TO SPEAK BRIEFLY
WITH YOU ALL ABOUT HOW THE
TRANSLATION OF THAT EVIDENCE
INTO RECOMMENDATIONS FOR
CLINICAL CARE PRACTICE VARIES,
SO THAT YOU CAN COMPARE AND
CONTRAST THE IMPLICATIONS AND
STRENGTHS AND LIMITATIONS OF
THAT.
I HAVE NO FINANCIAL
DISCLOSURES, AS MENTIONED I'M A
VICE CHAIR OF PREVENTIVE
SERVICES TASK FORCE, THIS
PRESENTATION DOES NOT
NECESSARILY REPRESENT THE
VIEWS, PROCESSES,
RECOMMENDATIONS AND POLICIES OF
THE USPSTF.
NOR DO THE VIEWS EXPRESS IN
THIS PRESENTATION, THEY SHOULD
NOT BE CONSTRUED AS OFFICIAL
POSITION OF AHRQ OR DEPARTMENT
OF HEALTH AND HUMAN SERVICES.
WE ARE SCIENTIFICALLY
INDEPENDENT GROUP OF VOLUNTEERS.
WE HAVE EXPERIENCE AND
EXPERTISE IN PRIMARY CARE,
DISEASE PREVENTION AND
EVIDENCE-BASED MEDICINE.
WE MAKE RECOMMENDATIONS ABOUT
PREVENTIVE SERVICES, SCREENING,
COUNSELING AND PREVENTIVE
MEDICATIONS FOR PEOPLE WITHOUT
SYMPTOMS OR SIGNS OF DISEASE.
OUR MISSION AND WORK IS TO
IMPROVE THE HEALTH OF PEOPLE
NATIONWIDE OF
BRIEFLY OUR DEVELOPMENT PROCESS
CONSISTS OF REVIEWING TOPIC
NOMINATION WHICH COULD BE
SUBMITTED BY ANYONE, ANY
PERSON, OR ORGANIZATION.
WE PRIORITIZE THOSE NOMINATIONS
AND WORKING WITH OUR AHRQ
EVIDENCE BASED REVIEW TEAMS WE
DRAFT A RESEARCH PLAN THAT THEN
GOES OUT FOR PUBLIC COMMENT.
ANYONE, ANY ORGANIZATION CAN
MAKE COMMENTS.
WE REVIEW EACH AND EVERY ONE OF
THOSE COMMENTS AND FINALIZE OUR
RESEARCH PLAN.
THE EVIDENCE-BASED PRACTICE
CENTER THEN GOES OUT AND DOES
THE EVIDENCE SEARCH AND RETURNS
IT BACK TO THE TASK FORCE.
THE TASK FORCE THEN REVIEWS THE
EVIDENCE AND DEVELOPS DRAFT
RECOMMENDATIONS STATEMENT, THAT
AGAIN, GOES OUT FOR PUBLIC
COMMENT.
AND AGAIN, WE READ EACH AND
EVERY SINGLE PUBLIC COMMENT AND
REVISE RECOMMENDATION STATEMENT
AND IN FACT HAVE A SEPARATE
SECTION ABOUT IT IN OUR FINAL
SUBMISSION THAT IS SUBMITTED
BOTH PUBLICLY FROM THE AHRQ WIB
WEBSITE OR JAMA.
THE USPSTF IS AN EXEMPLAR
EXAMPLE NATIONAL ACADEMIES
MEDICINE 2011 RECOMMENDATION
FOR GUIDELINE PROCESSES, CALLED
CLINICAL GUIDELINES WE CAN
TRUST.
WHAT DO OUR RECOMMENDATION
GRADES LOOK LIKE?
THEY DEPEND ON TWO ELEMENTS.
THE FIRST IS CERTAINTY FROM LOW
TO HIGH.
I WANT TO HIGHLIGHT YOU CAN
ONLY HAVE MODERATE OR HIGH
CERTAINTY IF YOU HAVE RCT
EVIDENCE THAT AFFECTS A HEALTH
OUTCOME.
I WILL SAY A WORD ABOUT THAT IN
THE NEXT SLIDE.
THE OTHER DIMENSION IS THE
MAGNITUDE OF NET BENEFIT.
WE ARE CONSIDERING THE
POPULATION BENEFIT VERSUS THE
POPULATION HARM.
AND IF THAT NET BENEFIT IS
EITHER SUBSTANTIAL OR MODERATE,
WE GIVE IT AN A OR B
RECOMMENDATION GRADE.
AND YOU CAN THINK OF THAT AS
BASICALLY SOMETHING THAT SHOULD
BE DONE AT THE POPULATION
LEVEL.
WE HAVE AT LEAST MODERATE
CERTAINTY, OF AT LEAST MODERATE
MAGNITUDE OF NET BENEFIT.
GENERALLY THAT SHOULD BE
INCORPORATED INTO CLINICAL
DECISIONS.
IF THE NET BENEFIT IS SMALL, WE
GIVE IT A GRADE OF C.
YOU COULD THINK OF THE C AS A
CHOICE IN WHICH A CLINICIAN
EXPLAINS THE OPTIONS AND THE
PATIENT SHARES THEIR
PREFERENCES AND VALUES, AND
TOGETHER MAKE A DECISION
THROUGH SHARED DECISION MAKING
AS TO WHETHER OR NOT THAT
PREVENTIVE INTERVENTION IS
APPROPRIATE FOR THEM.
IF THE NET BENEFIT IS EITHER
ZERO OR NEGATIVE WE GIVE IT A D
GRADE.
CAN THINK OF "D" AS "DON'T".
WITH LOW DEGREE, THAT'S AN I
STATEMENT.
BASICALLY INDICATES THERE'S
INSUFFICIENT EVIDENCE, IT'S
STILL AN IMPORTANT INTERVENTION
AND NOT FOR OR AGAINST, WE JUST
DON'T HAVE ENOUGH EVIDENCE TO
MAKE A RECOMMENDATION.
AND BASICALLY IT'S A CALL FOR
FURTHER RESEARCH.
A WORD ABOUT HEALTH VERSUS
INTERMEDIATE OUTCOMES.
A HEALTH OUTCOME FOR THE TASK
FORCE INVOLVES SYMPTOMS,
FUNCTIONAL LEVELS AND
CONDITIONS THAT PATIENTS CAN
FEEL OR EXPERIENCE AND ARE
DEFINED BY MEASURES OF PHYSICAL
OR PSYCHOLOGICAL WELL-BEING.
INTERMEDIATE OUTCOMES ARE
PATHOLOGIC, OR PHYSIOLOGICAL,
PSYCHOLOGICAL, SOCIAL OR
BEHAVIOR MEASURES AND OTHER
STUDY ENDPOINTS RELATED TO
PREVENTIVE INTERVENTION.
EXAMPLES BLOOD PRESSURE, SERUM
CHOLESTEROL OR WEIGHT.
I WANT TO HIGHLIGHT THE FACT
THAT A PREVENTIVE SERVICE HAS A
PROVEN EFFECT ON AN
INTERMEDIATE OUTCOME DOES NOT
NECESSARILY ESTABLISH THAT IT
CAN IMPROVE OUTCOMES THAT ARE
PERCEPTIBLE TO PATIENTS.
BECAUSE WE ARE FOCUSED ON
PATIENTS WHO DON'T HAVE
SYMPTOMS OR SIGNS, WE DON'T
MAKE RECOMMENDATIONS FOR
PATIENTS, SAY, WHO HAVE A
PARTICULAR DISEASE, SUCH AS
DIABETES.
WE VIEW THAT AS THE PURVIEW OF
DISEASE MANAGEMENT
ORGANIZATIONS SUCH AS THE
AMERICAN DIABETES ASSOCIATION,
FOR THOSE WHO HAVE TYPE I OR
TYPE II DIABETES.
I WANT TO SHARE WITH YOU WHAT
WE DID IN 2018, WHICH IS OUR
LATEST RECOMMENDATION STATEMENT.
JUST AS AN EXAMPLE OF OUR
PROCESSES AND PROCEED YOUS.
PROCEDURES.
BEHAVIORAL AND PHARMACOTHERAPY
WEIGHT LOSS INTERVENTIONS TO
PREVENT OBESITY-RELATED
MORBIDITY AND MORTALITY IN
ADULTS.
WE DO NOT ADDRESS THESE
PHARMACOTHERAPY INTERVENTIONS
FOR INDIVIDUALS WITH TYPE II
DIABETES.
THIS PARTICULAR EVIDENCE
REPORTS STARTS WITH ADULTS ON
THE LEFT WHO ARE OVERWEIGHT OR
HAVE OBESITY.
IF THAT INVOLVES A PRIMARY CARE
ASSESSMENT FOR CANDIDATES FOR
WEIGHT LOSS OR WEIGHT LOSS
MAINTENANCE INTERVENTIONS.
AND THAT'S BASICALLY THOSE WHO
ARE OBESE OR OVERWEIGHT.
WHAT YOU SEE THEN IS AN
INTERVENTION.
BEHAVIORAL OR PHARMACOTHERAPY
INTERVENTIONS.
AND YOU CAN SEE THE NUMBER ONE
GOES DIRECTLY TO THE RIGHT TO
HEALTH OUTCOMES.
IN AN RCT DO THOSE
INTERVENTIONS AFFECT AND
MEASURE MORBIDITY, MORTALITY OR
QUALITY OF LIFE FOR FUNCTIONING.
THAT'S OUR DIRECT EVIDENCE LINK.
INDIRECT GOES THROUGH #2,
RANDOMIZED TRIALS MIGHT
DEMONSTRATE WEIGHT LOSS OR
WEIGHT LOSS MAINTENANCE OR
EFFECT ON INCIDENCE OR
PREVALENCE OF OBESITY-RELATED
CONDITIONS.
YOU SEE A DASHED LINE.
THE QUESTION, DOES THAT LEAD
THAT INDIRECT EVIDENCE CHAIN
LEAD TO IMPROVEMENT IN HEALTH
OUTCOMES.
AND FOR ALL OUR RECOMMENDATION
STATEMENTS YOU COULD LOOK AT
#3, WE ARE ALWAYS LOOKING AT
THE ADVERSE EFFECTS OF THE
INTERVENTIONS.
SO IN 2018, LOOKING AT THE
EVIDENCE AS WE DO, WHAT DID
THAT FIND FOR FARM CO THERAPY?
WE FOUND 32 RANDOMIZED CONTROL
TRIALS FOR WEIGHT LOSS OR
WEIGHT LOSS MANAGEMENT.
WE FOUND FOR LIRAGLUTIDE,
LORCASERIN, NALTREXONE,
BUPROPION, ORLISTAT AND
PHENTERMINE-TOPIRAMATE ALL WITH
BEHAVE YOAL COUNSELING.
WE FOUND IN 14 STUDIES
INVOLVING OVER 22,000 PATIENTS.
BUT HERE IS THE RIB.
WHEN WE LOOKED AT INCLUSION
CRITERIA REQUIRED DEMONSTRATION
OF MEDICATION ADHERENCE,
REQUIRED MEETING WEIGHT LOSS
GOALS OR BOTH BEFORE
ENROLLMENT, NARROW ELIGIBILITY
OF THOSE, THERE BY LIMITING
APPLICABILITY.
MORE OVER TRIAL COMPLETION
RANGED FROM 10-93%, MOST 50-70%.
THERE WERE FEW RCT'S PER DRUG
AND VARIABILITY IN THE OUTCOME
REPORTING.
WE ALSO LOOKED AT QUALITY OF
LIFE.
AGAIN, WE FOUND EVIDENCE THESE
MEDICATIONS WITH BEHAVIORAL
COUNSELING IMPROVED QUALITY OF
LIFE.
THE EFFECTS WERE SMALL AND
CLINICAL SIGNIFICANCE OF THOSE
EFFECTS WERE UNCERTAIN.
MORE OVER THERE WAS A DROP OUT
RATE THAT WAS 35% OR HIGHER IN
5 OF THE 10 STUDIES.
WE ALSO LOOKED AT WHETHER OR
NOT IT DECREASED INCIDENT
DIABETES.
THAT WAS FOR TRIALS WITH NEARLY
10,000 PATIENTS.
BUT AGAIN, WE SAW THAT HIGH
DROP OUT RATE.
WITH REGARD TO WEIGHT LOSS
MAINTENANCE THERE WERE THREE
STUDIES WITH A LITTLE OVER
1,000 PATIENTS, NONE OF THEM
REPORTED HEALTH OUTCOMES.
SO IN CONTRAST TO THAT TITLE
FROM OUR EVIDENCE REVIEW TEAM,
YOU SEE OUR FINAL
RECOMMENDATION STATEMENT
DOESN'T EVEN MENTION
PHARMACOTHERAPY, AND WHY NOT?
WE WERE UNCLEAR ABOUT HOW WELL
PATIENTS TOLERATE THESE
MEDICATIONS AND WHETHER THE
FINDINGS ARE APPLICABLE TO THE
GENERAL U.S. PRIMARY CARE
POPULATION.
MORE OVER WE FOUND DATA WERE
LACKING ABOUT THE MAINTS NANS
OF IMPROVEMENT AFTER
DISCONTINUATION OF
PHARMACOTHERAPY.
AS A RESULT, THE USPSTF
ENCOURAGES CLINICIANS TO
PROMOTE BEHAVIORAL
INTERVENTIONS AS THE PRIMARY
FOCUS OF EFFECTIVE
INTERVENTIONS FOR WEIGHT LOSS
IN ADULTS.
THAT WAS OUR B RECOMMENDATION
IN 2018.
HOW WE THINK OF THE EVIDENCE
AND OUTCOMES AND THE PATIENT
POPULATION FOR WHICH WE MAKE
OUR RECOMMENDATIONS.
WHILE COMPARE AND CONTRAST OUR
2018 TO THE MOST RECENT
AMERICAN DIABETES ASSOCIATION
ANNUAL STANDARDS OF CARE IN
DIABETES.
SO THIS IS WHAT THEY DO
ANNUALLY IN JANUARY, BASED ON
THE EVIDENCE THEY GARNER.
THE ADA'S EVIDENCE-GRADING
SYSTEM, AS ARTICULATED IN THEIR
METHODS RANGES FROM LEVEL A, B,
C AND E, WHERE A IS CLEAR OR
SUPPORTIVE WELL-CONDUCTED
ADEQUATELY POW HE HAD RCTS.
LEVEL B IS SUPPORTIVE WELL
CONDUCTED COHORT OR CASE
CONTROL STUDIES.
C IS POORLY CONTROLLED OR
UNCONTROLLED AND E IS EXPERT
OPINION.
I WANT TO HIGHLIGHT THAT ALL
RECOMMENDATIONS FOR THEM
RECEIVE A RATING FOR THE
STRENGTH OF THE EVIDENCE AND
NOT THE STRENGTH OF THE
RECOMMENDATION.
YOU CAN THINK OF THE STRENGTH
OF RECOMMENDATION PERHAPS AS
THE MAGNITUDE OF NET BENEFIT.
SO WHAT DID THEY FIND WHEN THEY
DID THE EVIDENCE REVIEW?
PRETTY MUCH SIMILAR TO WHAT WE
FOUND FOR MEDICATIONS.
A WEIGHT LOSS PERCENTAGE THAT
RANGES FROM ROUGHLY 5% TO 10%
FOR PRE-GLP-1 RECEPTOR AGONIST.
GLP-1
DUAL THEY FOUND OVER 10%,
ROUGHLY 13% REDUCTION IN WEIGHT
LOSS.
SO HOW DID THIS TRANSLATE WHEN
THEY MADE THEIR OBESITY
RECOMMENDATIONS?
AGAIN, I'M FOCUSING ON OBESITY
BECAUSE IT WOULD BE MOST
COMPARABLE TO OUR 2018
RECOMMENDATION.
SO IN 8.5, CHAPTER ON OBESITY
SAID WEIGHT LOSS OF 3-7% OF
BASELINE WEIGHT IMPROVES GUY
SEMIA AND OTHER IMMEDIATE
CARDIOVASCULAR RISK FACTORS,
THEY GAVE THAT AN A.
SUSTAINED LOSS OF MORE THAN 10%
OF BODY WEIGHT USUALLY CONFERS
GREATER BENEFITS, INCLUDING
DISEASE MODIFYING EFFECTS AND
POSSIBLE REMEIGS OF TYPE II
DIABETES AND MAY IMPROVE LONG
TERM CARDIOVASCULAR OUTCOMES
AND MORTALITY.
THEY WENT ONTO CONCLUDE
PREFERRED FARM CO THERAPY
SHOULD BE GLP-1 IN PARTICULAR
BECAUSE OF WEIGHT INDEPENDENT
BENEFITS SUCH AS GLYCEMIC AND
CARDIO METABOLIC BENEFITS.
SO TO COMPARE AND CONTRAST WHAT
I HOPE YOU TAKE AWAY FROM THAT,
THE USPSTF THINKS ABOUT HIGH OR
MODERATE CERTAINTY, RCT
EVIDENCE THAT IS EITHER
SUBSTANTIAL OR MODERATE IN NET
BENEFIT ON HEALTH OUTCOMES FOR
THEIR A OR B RECOMMENDATIONS.
THOSE HEALTH OUTCOMES INVOLVE
SYMPTOMS, FUNCTIONAL LEVELS
THAT PATIENTS CAN FEEL OR
EXPERIENCE.
AND WHEN WE THINK ABOUT
REAL-WORLD EVIDENCE FOR HARMS,
BENEFITS, EPIDEMIOLOGY
MODELING, WE DO INCORPORATE OR
THINK ABOUT THEM IN OUR
CONSIDERATIONS.
IN PARTICULAR, WE VALUE
PRAGMATIC STUDIES, WHICH HELP
US THINK ABOUT FEASIBILITY AND
APPLICABILITY.
AND THUS IMPROVING ON EXTERNAL
VALIDITY AS COMPARED TO
INTERNAL VALIDITY OF RCT'S.
TO THEN LOOK AT THE ADA AND
THEIR STANDARDS OF CARE THAT'S
UPDATED ANNUALLY, THEY
INCORPORATE RCT DATE -- WELL
CONDUCTED COHORT OR CASE
CONTROL STUDIES FOR A OR B
LEVELS.
OUTCOMES, 3-7% WEIGHT LOSS ON
GLYCEMIA AND CARDIOVASCULAR
RISK AND POSSIBLE WEIGHT
INDEPENDENT BENEFITS OF
GLP-1-1R OR GLP-1.
I WANT TO CONCLUDE WITH
RESEARCH GAPS AND NEEDS.
THE TASK FORCE RECOMMENDS
FURTHER RESEARCH TO EXAMINE
EFFECTS OF INTERVENTIONS FOR
OBESITY ON LONGER TERM WEIGHT
AND HEALTH OUTCOMES, SUCH AS
CARDIOVASCULAR OUTCOMES,
PSYCHOSOCIAL, QUALITY OF LIFE
AND PATIENT-CENTERED OUTCOMES.
FOR THE 2025 ADA, SUSTAINED
LOSS OF MORE THAN 10% PROVIDES
POSSIBLE REMISSION OF TYPE II
DIABETES AND MAY IMPROVE
LONG-TERM CARDIOVASCULAR
OUTCOMES AND MORTALITY.
THEY HIGHLIGHT THE GROWING GAPS
IN DIABETES CARE, QUALITY AND
OUTCOMES AND CALL FOR URGENT,
SUBSTANTIAL AND MULTI-SECTORIAL
SYSTEM LEVEL IMPROVEMENT TO
HEALTH CARE.
AND WITH THAT, I'M GOING TO
STOP SHARING AND TURN THE
SCREEN OVER TO MY COLLEAGUE.
>> CHRISTINE WEE: THANK YOU,
DR. WONG.
NEXT WE WILL HAVE DR. SKINNER
WHO WILL SHARE HER PERSPECTIVE
IN GUIDELINES FOR PEDIATRIC
OBESITY.
>> DR. SKINNER: THANK YOU,
EVERYBODY FOR THE OPPORTUNITY
TO PRESENT HERE.
I WILL FOLLOW JOHN WITH LOOKING
AT SOME OF THE REAL-WORLD
EVIDENCE AND THE PRACTICE
GUIDELINES WE HAVE FOR CHILDREN
RELATED TO PHARMACOTHERAPIES,
SPECIFICALLY GLP-1'S.
I WILL START WITH I HAVE NO
CONFLICTS OF INTEREST OR
FINANCIAL RELATIONSHIPS.
I DID SERVE AS LEAD
METHODOLOGIST.
IN JANUARY 2023, AMERICAN
ACADEMY OF PEDIATRICS PUBLISHED
FIRST EVER CLINICAL PRACTICE
GUIDELINE FOR EVALUATION AND
TREATMENT OF CHILDREN AND
ADOLESCENTS WITH OBESITY.
PRIOR TO THIS THERE WAS ONLY
EXPERT OPINIONS, NO GUIDELINES.
JOHN DESCRIBED HOW THE USPSTF
GRADES THEM AND ADA.
AAP USES SIMILAR GRADING SYSTEM
AS FAR AS GRADING, WITH A, B,
C, ET CETERA.
I WILL PRESENT THE FINAL
TREATMENT ALGORITHM THAT WAS
ULTIMATELY DEVELOPED.
AND IT RECOMMENDS MOTIVATIONAL
INTERVIEWING AND INTENSIVE
HEALTH BEHAVIOR AND LIFESTYLE
TREATMENT FOR CHILDREN WITH
OBESITY.
DEFINITELY FOR AGES 6 AND OLDER.
THIS IS NOT UNEXPECTED AT ALL.
HOWEVER, WE ALSO RECOMMENDED
FOR CHILDREN WITH OBESITY AT
THE AGE OF 12 OR OVER TO
CONSIDER WEIGHT LOSS
PHARMACOTHERAPY AND THAT SHOULD
BE OFFERED TO THOSE CHILDREN.
AS WELL AS BARIATRIC SURGERY.
SO GLP-1'S HAVE A PARTICULARLY
UNIQUE PLACE IN PEDIATRICS, AND
THAT'S BECAUSE CHILDREN REALLY
DON'T LIKE NEEDLES AT ALL.
WE HAVE EVIDENCE OF
PHENTERMINE, SOMEWHAT EFFECTIVE.
AND WE ALSO KNOW SEMAGLUTIDE IS
MORE EFFECT ITCH.
EFFECTIVE.
WHEN FAMILIES ARE MAKING THE
DECISION, IT'S WHETHER OR NOT A
CHILD IS INTERESTED IN
INTERESTING AN INJECTION.
IT'S LESS PROBLEMATIC WITH
SEMAGLUTIDE BECAUSE ITS WEEKLY.
ONE THING THAT'S REALLY
IMPORTANT IS WE ARE STILL
BUILDING THE PLANE WHILE WE ARE
FLYING IT.
WE HAVE RELATIVELY LITTLE
EVIDENCE BEYOND THE TRIALS THAT
WERE USED.
WE HAVE ONE STRONG SEMAGLUTIDE
TRIAL, THE TIRZEPATIDE TRIAL IS
STILL UNDER WAY.
WE DON'T EVEN HAVE FDA APPROVAL
FOR THAT IN ADOLESCENCE.
PHYSICIANS ARE REALLY JUST
TRYING TO MAKE A LOT OF
DECISIONS AS THEY GO, BASED ON
THEIR CURRENT CLINICAL JUDGMENT.
THERE'S A COUPLE UNIQUE FACTORS.
IT'S TRUE FOR ADULTS.
BUT PARTICULARLY WITH CHILDREN
BECAUSE THE LEVEL OF MEDICAID
COVERAGE IS SO HIGH.
THE MAP HERE IS DEMONSTRATING
THE LEVEL OF MID EDICAID
COVERAGE FOR GLP-1'S.
EITHER LIRAGLATIDE OR
SEMAGLUTIDE.
MOST HAVE NO COVERAGE OR ARE
COVERED WITH RESTRICTIONS.
SOME HAVE OTHER LIMITATIONS.
I DON'T THINK THERE'S A SINGLE
STATE WHERE IT'S ACTUALLY JUST
OPENLY COVERED.
BUT WHAT'S ALSO REALLY
IMPORTANT IS THIS CHANGES ALL
THIS MONTH-TO-MONTH.
FOR EXAMPLE, NORTH CAROLINA NOW
DOES COVER THEM WITH FEWER
LIMITATIONS BUT MINNESOTA HAS
NOW STOPPED COVERING.
AND IT'S POSSIBLE THAT'S
CHANGED SINCE THE LAST TIME I
READ THAT.
SO WHAT WE HAVE, AND WHAT THAT
RESULTS IN, WE HAVE A
POPULATION OF CHILDREN WHO ARE
OFTEN GOING ON AND OFF THESE
MEDICATIONS.
THIS IS A REAL OPPORTUNITY TO
USE SOME OF THESE REAL-WORLD
EVIDENCE TO SEE WHAT HAPPENS,
IF A CHILD HAS HAD A LOT OF
SUCCESS, WHAT HAPPENS WHEN THEY
THEN DISCONTINUE.
THAT'S ACTUALLY ONE OF THE
BIGGEST QUESTIONS THAT WE HAVE.
WHAT DO WE NEED TO KNOW?
WE HAVE VERY LITTLE EVIDENCE ON
WHAT THE BEST CLINICAL
MANAGEMENT IS IN CHILDREN.
SIMILAR TO WHAT JOHN MENTIONED
THERE ARE A LOT OF LIMITATIONS
ON THE POPULATIONS INCLUDED IN
THE TRIALS.
AND WE HAVE EVEN FEWER TRIALS
THAN EXIST FOR ADULTS.
MEANING THERE'S FEWER CO
MORBIDITIES, ET CETERA.
IT'S NOT CLEAR HOW THIS
TRANSLATES INTO THE GENERAL
POPULATION.
ONE OF THE MORE DIFFICULT
THINGS AND OFTEN IMPORTANT FOR
KIDS BECAUSE IT'S DIFFICULT FOR
FAMILIES TO CONSIDER TAKING
THEIR CHILDREN AND PUTTING THEM
ON A LIFE-LONG MEDICATION.
AND SO THE QUESTION IS, WHEN DO
YOU DISCONTINUE?
HOW DO YOU DISCONTINUE?
WHAT IS THE RISK OF REGAIN?
HOW DO WE LIMIT THAT.
THERE ARE QUESTIONS WHO WE
SHOULD BE ABLE TO TREAT.
IN PARTICULAR BECAUSE TRIALS
EXCLUDE THOSE WITH DISORDERED
EATING OR MENTAL HEALTH
DIAGNOSES.
SAME WITH MENTAL HEALTH
DIAGNOSES.
WE KNOW THAT MENTAL HEALTH
DIFFICULTIES ARE STRONGLY
ASSOCIATE WITH OBESITY AND IT'S
VERY UNCLEAR WHICH DIRECTION
THAT GOES.
THERE'S ALSO SOME REALLY
CRITICAL OUTCOMES THAT ARE
EITHER POORLY ASSESSED IN
TRIALS OR THAT OCCURRING AT
PRETTY LOW FREQUENCIES SO IT'S
HARD TO PICK THEM UP IN
RELATIVELY SMALL TRIALS HERE.
ONE IS MENTAL HEALTH RISKS.
SO THIS IS IN ADDITION TO WHAT
I THINK ABOUT THE GENERAL
MENTAL HEALTH RISK OF OBESITY,
BUT THE MENTAL HEALTH RISK OF
CHANGING BODY SIZE,
PARTICULARLY FOR ADOLESCENT WHO
ARE A UNIQUE TIME AND THEIR
UNDERSTANDING OF THEMSELVES.
THERE'S A LOT OF CONCERN ABOUT
THE DEVELOPMENT OF EATING
DISORDERS.
AND INDEED, GLP-1'S CERTAINLY
LIMIT INTAKE OF FOOD.
BUT WHETHER THAT IS RESTRICTIVE
INTAKE IN TERMS OF WHAT IS
DRIVING THAT REDUCED INTAKE MAY
OR MAY NOT BE SOMETHING WE
THINK OF AS AN EATING DISORDER.
THERE'S ALSO REALLY IMPORTANT
CONCERNS ABOUT SOCIAL
DEVELOPMENT.
MANY OF THESE CHILDREN WILL
BENEFIT HEALTH-WISE FROM
SIGNIFICANT WEIGHT LOSS,
ESPECIALLY AS A TRAJECTORY INTO
ADULTHOOD.
BUT THEY ARE A PART OF COMPLEX
ADOLESCENT SOCIAL GROUPS AND
WHAT HAPPENS TO THEIR SOCIAL
DEVELOPMENT.
IS THAT GOOD OR BAD?
WE DON'T REALLY KNOW.
A FEW CAUTIONS, AS WE THINK
ABOUT USING EVIDENCE OUTSIDE OF
THESE TRIALS.
ONE IS A REALLY IMPORTANT
UNOBSERVED EXPOSURE.
WE KNOW THAT COMPOUNDING IS
RELATIVELY PREVALENT FOR ADULTS.
IT'S LESS COMMON IN CHILDREN,
BUT WE KNOW IT'S HAPPENING.
HOW MUCH IT'S HAPPENING IS
ALMOST ENTIRELY ANECDOTAL
EVIDENCE THERE.
EVEN THOUGH THAT IS PROBABLY
LESS LIKELY TO BE A PROBLEM
MOVING FORWARD, WE HAVE 2-3
YEARS, IF WE ARE LOOKING FOR
EXAMPLE, EHR DATA WHERE
COMPOUNDING MIGHT BE SOMETHING
THESE KIDS ARE USING, SO WE
WOULDN'T BE ABLE TO IDENTIFY
THOSE EXPOSURES.
THERE'S ALSO JUST SO MUCH OTHER
UNOBSERVED INFORMATION.
KIDS MOVE IN AND OUT OF
TREATMENT A LOT.
THERE'S ALSO VERY FEW
PRESCRIBERS OF GLP-1'S FOR
ADOLESCENTS SO THEY ARE OFTEN
NOT IN THE SAME SYSTEM AS THEIR
PRIMARY CARE PHYSICIAN.
WHICH MEANS YOU LOSE A LOT OF
DATA IF THOSE SYSTEMS ARE NOT
TALKING TO EACH OTHER.
FOR EXAMPLE, WHERE WE ARE, WE
HAVE TWO VERY LARGE MEDICAL
CENTERS NEXT TO EACH OTHER.
ONLY ONE OF THOSE HAS AN
OBESITY TREATMENT PROGRAM.
AND THAT PROGRAM IS THE ONLY
ONE WE ARE AWARE OF THAT
ACTUALLY PRESCRIBES GLP-1'S TO
ADOLESCENTS.
SO HALF OF THE POPULATION MAY
BE SEEN IN ONE SYSTEM BUT COME
TO ANOTHER SYSTEM TO RECEIVE
THESE MEDICATIONS.
AND AS IS TRUE FOR ADULTS, AS
WELL AS CHILDREN, OBESITY IS
JUST AFFECTED BY SO MANY THINGS
OUTSIDE THE HEALTH CARE SYSTEM.
THERE ARE SO MANY EXPOSURES WE
JUST ARE NOT EVER GOING TO BE
ABLE TO MEASURE IN THE WAY WE
TYPICALLY USE REAL-WORLD
EVIDENCE.
SO WHAT ARE THE MAJOR GAPS AND
OPPORTUNITIES HERE?
ONE IS TO UNDERSTAND LONG-TERM
OUTCOMES.
WE HAVE OUTCOMES UP TO, I
BELIEVE, 62 WEEKS AT THIS POINT.
WE DO KNOW THAT WEIGHT REGAIN
HAPPENS QUICKLY UPON
DISCONTINUATION.
BUT WE DON'T KNOW WHAT HAPPENS
IF CHILDREN ARE ON THESE FOR A
VERY LONG TIME.
AND YOU KNOW, THAT IS ONE OF
THE BIGGEST CONCERNS THAT
PARENTS OFTEN HAVE WITH THIS.
WE ALSO DON'T KNOW MUCH ABOUT
MANAGEMENT OVER TIME.
LOOKING AT WHAT ACTUALLY
HAPPENS IN CLINICAL PRACTICE,
WHERE YOU KNOW, CHILDREN DO
START AND THEN PERHAPS STOP.
OR MAYBE THERE'S A DIFFERENT
DOSE ESCALATION CHOSEN BY THE
CLINICIAN FOR WHATEVER REASON,
WE MIGHT BE ABLE TO LEARN A LOT
ABOUT DIFFERENT APPROACHES THAT
CAN PROVIDE EFFECTIVENESS WHILE
LIMITING HARMS.
AND BEING ABLE TO ASSESS THOSE
HARMS IS ONE OF THOSE GAPS AND
OPPORTUNITIES AS WELL.
THERE'S SOME THAT ARE
PARTICULARLY UNIQUE TO
CHILDREN, HAVING TO DO WITH THE
SOCIAL DEVELOPMENT IN ADDITION
TO SOME CONCERNS OF EATING
DISORDERS AND WHAT THEY LOOK
LIKE IN TEENAGERS.
SO JUST TO SUMMARIZE AND END
HERE, THERE'S A LOT OF
EVIDENCE, A LOT OF
OPPORTUNITIES FOR THE USE OF
REAL-WORLD EVIDENCE, EVEN
THOUGH IN THE CPG MOST RECEPTLY
PUBLISHED WE HAD TO FOCUS ON
RANDOMIZED TRIALS BECAUSE
THAT'S ALL THAT WAS AVAILABLE.
I EXPECT MUCH OF THIS DATA WILL
BE MUCH MORE USEFUL AS WE MOVE
FORWARD.
>> Christina Wee: THANK YOU, SO
NOW WE WILL GO TO THE QUESTION
AND ANSWER SECTION OF OUR
PRESENTATION.
I HAVE A COUPLE QUESTIONS IN
THE CHAT DIRECTED AT DR.
BRADLEY.
THE FIRST QUESTION HAS TO DO
WITH HOW THE FDA SELECTS
TOPICS, IN TERMS OF USING
REAL-WORLD EVIDENCE?
>> Marie Bradley: THAT'S A GOOD
QUESTION.
FOR RESEARCH INITIATIVES,
USUALLY COME UP WHEN WE ARE
REVIEWING SUBMISSIONS.
WE ALSO RELY HEAVILY ON
FEEDBACK FROM EXTERNAL PARTIES
THAT COME TO US AND SAY THESE
ARE THE ISSUES WE ARE FACING.
AND ALSO THE LITERATURE, RIGHT?
ANY KIND OF ISSUES THAT MIGHT
BE RAISED IN THE LITERATURE
THAT COULD BE RELEVANT TO THE
USE OF REAL-WORLD DATA AND
REGULATORY SUBMISSIONS.
IF WE ARE CONCERNED, HAVE
SPECIFIC CONCERNS WE CAN PUT
OUT REQUESTS FOR PROPOSALS.
WE WOULD DO THAT THROUGH
POTENTIALLY SOLICITED FOR --
MECHANISMS.
WE CURRENTLY HAVE FOUR, OR
THREE, WE FUNDED FOUR IN 2023
AND ONE HAS WRAPPED UP.
AND INVESTIGATING VARIOUS
METHODOLOGIC CHALLENGES WITH
DECISION MAKING.
WE HAVE FIVE CENTERS FOR
EXCELLENCE IN REGULATORY
SCIENCE.
SO WE CAN PUT OUT REQUESTS FOR
PROPOSALS IF WE HAVE SPECIFIC
TARGETED INTERESTS.
WE ALSO, AT THE AGENCY, HAVE
WHAT WE CALL A BROAD
ANNOUNCEMENT.
THAT'S MUCH MORE BROAD WE WOULD
INVITE INTERESTED PARTIES TO
SUBMIT PROPOSALS AND PROJECT
IDEAS FOR THINGS THEY THINK ARE
VERY PERTINENT IN THE AREA.
SO USING THOSE KIND OF
MECHANISMS.
ALSO IF THERE IS SOMETHING MORE
PRESSING WE NEED TO INVESTIGATE
IN A MORE SPEEDILY MANNER,
ESPECIALLY THINGS LIKE DURING A
PANDEMIC SITUATION, WE WOULD
HAVE INTERNAL FUNDING WE CAN
FUND SOME OF OUR OWN STAFF TO
DO THAT RESEARCH AS WELL.
AND WE HAVE OUR SENTINEL SYSTEM
FOR SAFETY-RELATED INQUIRIES.
THAT'S KIND OF HOW IT WORKS,
MOSTLY.
>> Christine Wee: GREAT, I HAVE
A FOLLOW-UP QUESTION.
YOU MENTIONED IN YOUR TALK
AREAS IN THE GLP-1'S YOU WERE
COLLECTING DATA ON.
AND I WONDER WHETHER THERE IS
AN ACTIVE MONITORING OF
LITERATURE.
BECAUSE SOME OF THE TOPICS, I
CAN IMAGINE THERE ARE OTHER
INVESTIGATIVE, INDEPENDENT
REGULATORY ASKING AND ANSWERING
AND HOW MUCH OF THAT IS
OVERLAPPING AND DO YOU EXTRACT.
OR DO YOU WAIT FOR RESEARCHERS
TO SORT OF SUBMIT IT TO YOUR
ATTENTION?
>>
Marie Bradley: THAT'S A GOOD
QUESTION.
YEAH, THE RESEARCH I'M TALKING
ABOUT THROUGH THE BROAD AGENCY
ANNOUNCEMENTS WILL BE A LITTLE
SEPARATE TO THE REVIEW SYSTEM.
SO THE WAY IT WOULD WORK IN
FDA, IF THERE'S A CONCERN WITH
A REGULATED PRODUCT,
POTENTIALLY THERE'S A FEW
STUDIES IN THE LITERATURE, WE
WOULD HAVE TEAMS OF
EPIDEMIOLOGISTS RUN THOROUGH
SYSTEMATIC REVIEWS TO SUMMARIZE
THAT EVIDENCE, TO LOOK AT THE
QUALITY OF THE STUDIES, AND TO
SEE IF THAT IS SOMETHING THAT
WE SHOULD MOVE FORWARD WITH
EITHER DOING OUR OWN STUDY,
MAYBE ASKING A SPONSOR TO DO A
STUDY OR PUT SOME SORT OF SEW
SOLICITATION FOR PROPOSAL.
CERTAINLY WE KEEP ABREAST TO A
PROPOSAL IF IT'S RELATED TO A
PRODUCT.
>> Christine Wee: THANKS, NEXT
I HAVE A QUESTION FOR JOHN AND
MAY ALSO BE RELEVANT TO ASHELEY.
YOU BRING UP THE ISSUE OF HIGH
ATTRITION WITH PHARMACOLOGIC
TREATMENTS FOR OBESITY AND THE
RESTRICTED ELIGIBILITY
CRITERIA, WHICH SORT OF SPEAKS
TO GENERALIZABILITY.
BUT I WOULD POSIT, AN ANALOGOUS
CONCERN AND ISSUE ARISES ALL
THE TIME WITH THE EVALUATION OF
EVIDENCE FOR BEHAVIORAL
INTERVENTIONS.
BECAUSE WHILE SOME OF THOSE
HAVE HIGH ATTRITION RATES, AND
EVEN IF THEY DON'T, AS A
CLINICIAN WE SORT OF KNOW UP
FRONT YOU ARE REALLY STUDYING A
TINY SLIVER OF THE MOST
HIGHLY-MOTIVATED FOLKS.
THERE'S A SENSE RESULTS FROM
THESE RCT'S ARE REALLY
EXAGGERATED AND OVERLY
OPTIMISTIC AND NOT REAL WORLD.
HOW DO YOU TAKE THAT INTO
CONSIDERATION IN YOUR
EVALUATION PROCESS?
>> John Wong: THE A REALLY
INTERESTING QUESTION.
WE LOOK FOR CONSISTENCY IN THE
BENEFIT.
IN BEHAVIORAL INTERVENTIONS
ALONE WITHOUT PHARMACO, 65
DEMONSTRATED WEIGHT LOSS.
THE OTHER PIECE I WILL MENTION,
THERE WAS CONSISTENCY IN TERMS
OF COMPONENTS OF THOSE
BEHAVIORAL INTERCONVENIENT --
INTERVENTIONS WITH REGARD TO
ENERGY BALANCE, WITH REGARD TO
HEALTHFUL DIETARY PATTERNS.
THEY EMPLOYED STANDARD
BEHAVIORAL CHANGE TECHNIQUES.
NOW, HAVING SAID THAT, THERE
WERE LIMITATIONS THAT ARE
EVIDENCE REVIEW TEAM
IDENTIFIED, WHICH IS THE NUMBER
OF TIMES AN INTERVENTION
OCCURRED, THE LENGTH OF TIME.
THOSE INTERVENTIONS OCCURRED.
AND THE DURATION OF TIME.
NONETHELESS, YOU KNOW, WE FOUND
THIS CONSISTENT BENEFIT THERE.
WE FELT WE HAD STRONG INTERNAL
HAVE VALIDITY FROM RANDOMIZED
CONTROL TRIALS.
THEY DID FIND, THE EVIDENCE
REVIEW TEAM HIGH VARIABILITY IN
TERMS OF REPORTING AND WE
RECOMMENDED MORE CONSISTENT USE
OF OUTCOME REPORTING USING
EITHER A CHECKLIST OR A
FRAMEWORK.
BUT WE APPRECIATE AND TOTALLY
UNDERSTAND YOUR COMMENT.
>> Christine Wee: I GUESS A
FOLLOW-UP, NOT SO MUCH INTERNAL
VALIDITY BUT EXTERNAL
GENERALIZED, YOU COULD HAVE 65
STUDIES BE CONSISTENT BUT THAT
DOESN'T ADDRESS THE BIGGER
ISSUE.
I WONDER IF, DR. SKINNER, IF
YOU WOULD LIKE TO WEIGH IN, I
IMAGINE THE SAME WITH KIDS.
>> DR. SKINNER: MOST ASSUREDLY
THE SAME ISSUE.
I AGREE WITH EVERYTHING JOHN
SAID.
I THINK WE HAVE GOOD INTERNAL
VALIDITY, BUT LIKE EVERY
DISEASE, YOU ARE ONLY GOING TO
FIND SUCCESSFUL TREATMENT
AMONGST PEOPLE WHO WANT
TREATMENT AND WANT TO ENGAGE IN
TREATMENT.
AND I THINK OBESITY IS A UNIQUE
ONE THAT THERE ARE OFTEN PEOPLE
WHO JUST DON'T WANT TO ENGAGE
IN TREATMENT.
SO TO TAKE A STUDY OF PEOPLE
WHO ARE HIGHLY MOTIVATED AND
WANT TO BE PART OF TREATMENT
AND ASSUME THAT WILL WORK FOR
PEOPLE WHO DON'T WANT TO ENGAGE
IN TREATMENT, OF COURSE THAT'S
NOT GOING TO TRANSLATE IN THE
SAME WAY.
IN TERMS OF RIGHT POPULATIONS
WHO CAN BENEFIT FROM THIS, I
THINK THE CONSISTENCY WE SEE,
ESPECIALLY IN LIFESTYLE
TREATMENT, FOR PEOPLE WHO WANT
IT, IT CAN BE EFFECTIVE.
>> CHRISTINE WEE: THANK YOU.
I WOULD ALSO BE CAUTIOUS ABOUT
MAKING SURE WE AREN'T INFERRING
THAT JUST BECAUSE SOMEONE CAN'T
COMPLY BECAUSE, YOU KNOW, THESE
INTENSIVE TREATMENTS ARE VERY
TIME CONSUMING DOESN'T MEAN
THEY DON'T WANT IT, IT'S JUST
MAYBE THEY DON'T HAVE THE
RESOURCES OR THE TIME.
THERE'S A QUESTION IN THE CHAT
FOR YOU, DR. WONG, BY ONE OF
THE ORGANIZERS, SO I DON'T HAVE
THE IDENTITY OF THE PERSON.
YOU MENTIONED THE USPSTF CITED
LACK OF DATA OF IMPROVEMENT
AFTER DISCONTINUATION OF
PHARMACOTHERAPY AS A CONCERN.
I GUESS I WOULD ALSO CONCUR
WITH THIS QUESTIONER ABOUT, ARE
WE REALLY HOLDING OBESITY
PHARMACOLOGIC THERAPY TO A
HIGHER STANDARD THAN WE WOULD
WITH ANY OTHER TREATMENT FOR
CHRONIC DISEASE?
WE DON'T ASK THE QUESTION ARE
WE CONCERNED IF WE STOP THIS
BLOOD PRESSURE MEDICATION THERE
WOULD BE RETURN OF HYPERTENSION
OR DIABETES.
SO WHY ARE WE SETTING A
DIFFERENT BAR?
>> JOHN WONG: I WOULDN'T SAY
THAT'S NOT THE REASON WE DIDN'T
HAVE EVIDENCE.
WE DIDN'T HAVE HEALTH OUTCOME
FOR THAT, THAT WAS THE
RATIONALE FOR THAT.
I WILL ADD, JUST TO SUPPORT
SOME OF THE SUBSEQUENT
SPEAKERS, YOU KNOW, AS I
MENTIONED WE HIGHLY VALUE
PRAGMATIC TRIALS TO HELP WITH
EXTERNAL VALIDITY.
THE OTHER POINT I WOULD MAKE
IS, WE HAVE USED TRIAL
EMULATION STUDIES AS PART OF
EVIDENCE, WHEN WE DON'T HAVE
ANY RANDOMIZED CONTROL TRIALS.
AND SO, OUR EVIDENCE REVIEW
PRACTICE TEAMS HAVE RECENTLY
PUBLISHED RECOMMENDATIONS FOR
HOW TO INCORPORATE
NON-RANDOMIZED STUDY
INTERVENTIONS INTO EVIDENCE.
EVEN WHEN WE MAY HAVE SOME
RANDOMIZED CONTROL TRIAL
EVIDENCE.
I THINK THOSE ARE ALL HELPFUL,
POTENTIALLY HELPFUL FOR HELPING
US BRIDGE THAT INTERNAL TO
EXTERNAL VALIDITY.
AS A PRACTICING CLINICIAN I'M
WELL AWARE OF.
BUT NONETHELESS IF WE FIND
INTERNAL VALIDITY, IT'S WORTH
MENTIONING TO PATIENTS.
>> CHRISTINE WEE: WE HAVE A
QUESTION IN THE CHAT FOR DR.
SKINNER FROM VIRGINIA RAY, WHAT
DO YOU THINK ARE THE MAIN
REASONS PCP'S ARE SO RELUCTANT
TO PRESCRIBE IN ADOLESCENCE?
>> DR. SKINNER: YEAH, I THINK
FOR THE MOST PART, AND THIS IS
ALL ANECDOTAL EXPERIENCE, AND
I'M NOT A CLINICIAN, THIS IS ME
WATCHING CLINICIANS.
THEY FEEL THE SITUATION SHOULD
BE MANAGED BY A SPECIALIST.
THERE'S A LOT OF CONCERN ABOUT
THEY DON'T LIKE PRESCRIBING AN
INJECTION.
THEY WOULD RATHER HAVE A CHILD
RECEIVING THESE MEDICATIONS
ALSO BE PART OF INTENSIVE
LIFESTYLE TREATMENT WHICH
USUALLY DOESN'T HAPPEN WITHIN
THE PRIMARY CARE OFFICE.
IT HAPPENS IN SOME OTHER AREA.
I THINK THEY ARE REALLY NEW.
OUR SEMAGLUTIDE TRIAL IS ONLY
2-3 YEARS OLD AND WE DON'T HAVE
ONE FOR TIRZEPATIDE YET.
FOR ADOLESCENCE, THAT'S A REAL
ISSUE.
AND THE LACK OF INFORMATION
ABOUT HOW TO MANAGE IT
LONG-TERM AS A CHRONIC
CONDITION, I THINK IS REALLY
CONCERNING FOR PEDIATRICIANS.
IN GENERAL, PEDIATRICIANS ARE
MUCH MORE CAUTIOUS WITH
MEDICATIONS THAN OFTEN INTERNAL
MEDICINE OR OTHER ADULT
PHYSICIANS CAN BE.
BUT THAT'S MY EXPERIENCE.
>> CHRISTINE WEE: I THINK THAT
MAKES SENSE.
SO I HAVE A QUESTION YOU
MENTIONED AND DR. BRADLEY DID
TOO, YOU MENTIONED THE LACK OF
HIGH QUALITY REAL-WORLD
EVIDENCE IN KIDS BECAUSE OF
JUST THE REALITIES OF COVERAGE
AND PRACTICE TRANSITIONS AND SO
FORTH.
WHAT DO YOU THINK ARE SOME, YOU
KNOW, IF YOU COULD HAVE
ANYTHING ON YOUR WISH LIST,
WHAT DO YOU THINK WE WOULD
REALLY NEED TO SORT OF BRIDGE
THAT GAP?
DO YOU SEE A ROLE FOR
STAKEHOLDERS, HEALTH PAYERS TO
PRODUCE OR PROVIDE INCENTIVES
FOR THE COLLECTION OF THIS
DATA, WHETHER IT BE REG
-REGISTRIES?
>> DR. SKINNER: REGISTRIES ARE
A PARTICULARLY STRONG IDEA HERE.
I THINK CERTAINLY AT LEAST
RIGHT NOW, GIVEN THE COSTS OF
THESE MEDICATIONS THERE SHOULD
BE INCENTIVES FOR INSURERS TO
IDENTIFY WHO WOULD BENEFIT FROM
THESE MEDICATIONS.
ARE THERE POPULATIONS WE SHOULD
BE MORE HESITANT ABOUT, OR
SHOULD FACILITATE ACCESS TO
MORE RATHER THAN USING THE LACK
OF THEIR INCLUSION IN A TRIAL
AS A REASON TO PREVENT THEM
THERE.
I THINK, YOU KNOW, MORE
FOLLOW-UP BY THE POST-MARKETING
SURVEILLANCE BY THE
PHARMACEUTICAL COMPANIES COULD
BE PARTICULARLY USEFUL AND
COULD BENEFIT THEM.
IT COULD HELP THEM DETERMINE
WHICH POPULATIONS THAT'S USEFUL
FOR.
I'M NOT ENTIRELY SURE, BUT I
SUSPECT THE APPROACH TO THAT
MIGHT BE DIFFERENT IN
PEDIATRICIANS, VERSUS ADULT
MEDICINE AND WHAT THAT MIGHT
LOOK LIKE EXACTLY.
>> CHRISTINE WEE: JUST TO
FOLLOW-UP WITH DR. BRADLEY.
I DIDN'T SEE THAT LISTED AS
PART OF THE PORTFOLIO.
IS THAT SOMETHING THE FDA IS
DOING, IF YOU CAN ANSWER THAT
QUESTION.
>> MARIE BRADLEY: YOU MEAN
MONITORING IN KIDS?
YEAH, I'M NOT AWARE THERE'S
ANY, THE TWO SAFETY STUDIES
THAT ARE CURRENTLY ONGOING, I'M
NOT AWARE OF MANY OTHER EFFORTS
IN MONITORING SAFETY.
BUT I DON'T WORK IN THE OFFICE
OF SCIENCE AND EPIDEMIOLOGY SO
I'M NOT AWARE OF ANY PLANS FOR
THAT RIGHT NOW.
>> CHRISTINE WEE: WE HAVE A
QUESTION DIRECTED TO DR. WONG
FROM SUE YANOVSKI.
REGARDING THE TASK FORCE
RECOMMENDATIONS WHICH I THINK
WERE PUBLISHED IN 2018.
THERE'S MORE EVIDENCE ON
CARDIOVASCULAR ENDPOINTS.
DO YOU HAVE ANY INDICATION WHEN
THERE MIGHT BE AN UPDATE TO
THOSE GUIDELINES?
>> JOHN WONG: WE ARE DEFINITELY
UPDATING OUR BEHAVIORAL
RECOMMENDATION STATEMENT.
I WILL JUST EMPHASIZE, IT'S
RECOMMENDATIONS AS OPPOSED TO A
GUIDELINE.
AND WE DO INTEND, WE PULLED OUT
PHARMACOLOGIC INTERVENTIONS,
RECOGNIZING THE RAPID EVIDENCE
GENERATION WITHIN TLP-R1A AND
DUAL THERAPY AND WE WILL BE
LOOKING AT THAT IN THE FUTURE.
I WAS AMAZED AT DAVID
ARTERBURN'S DAILY UPDATE FOR
NEW PUBLICATIONS AT 10 PER DAY.
I FEEL FAIRLY DAUNTED IN TERMS
OF TRYING TO DO THE EVIDENCE
REVIEW OF THAT, BUT I CAN
PROMISE YOU WE WILL BE DOING
THAT IN THE FUTURE.
I DON'T HAVE A DATE FOR IT.
>> CHRISTINE WEE: HOW DO YOU
SEE REAL-WORLD EVIDENCE PLAYING
A ROLE?
I THINK YOU FOCUSED A LOT ON
RCT'S.
>> JOHN WONG: YOU KNOW,
HISTORICALLY,WE HAVE FOCUSED ON
REAL-WORLD EVIDENCE IN THE
ABSENCE OF RCT DATA.
AND I'LL SAY THAT OUR EVIDENCE
REVIEW PROCEDURES
RECOMMENDATIONS SHOULD COME OUT
OF THE ARHQ EFFECTIVE HEALTH
PROGRAM AND SCIENTIFIC RESOURCE
CENTER CAME UP WITH, RECOGNIZED
THAT NRS OI,'S NON RANDOMIZED
STUDIES OF INTERVENTIONS CAN
PROVIDE COMPLIMENTARY DATA.
WHERE WE HAVE FOUNDATIONAL
EVIDENCE, SUCH AS THE BENEFITS
OF MAMMOGRAPHY, THOSE RCT'S
WERE ALL DONE FROM THE 1970s UP
TO THE 1990s, YET THINGS HAVE
CHANGED SINCE THEN.
AND NONE OF THEM INCLUDED
PATIENTS WHO WERE 75 AND OLDER.
AND CONSEQUENTLY, WE HAVE USED
TRIAL EMULATION STUDIES TO TAKE
A LOOK AT THAT AS WELL AS
MODELING, JUST AS ONE EXAMPLE,
AT LEAST FROM THE TASK FORCE
STANDPOINT, AS WELL AS OUR
EVIDENCE-REVIEW TEAMS, THEY ARE
LOOKING AT OUTSIDE OF
TRADITIONAL RANDOMIZED CONTROL
TRIALS.
>> CHRISTINE WEE: WE HAVE
ANOTHER QUESTION IN THE CHAT
FROM ONE OF THE ORGANIZERS
REGARDING GUIDELINES.
THE QUESTION IS DO WE NEED
STUDIES TO BE COMPARING
GLP-1'S, VERSUS LIFESTYLE
INTERVENTIONS TO INFLUENCE
GUIDELINES OR ARE WE AT THE
STAGE WHERE THE STUDIES ARE
MOST INTERESTED ARE REALLY
COMPARING DIFFERENT
PHARMACOLOGIC THERAPIES?
>> JOHN WONG: THAT'S A FABULOUS
QUESTION, FROM OUR TASK FORCE
STANDPOINT, ANYTHING THAT WOULD
IMPROVE HEALTH OUTCOMES IS WHAT
WE FOCUS ON, IN TERMS OF
BENEFITS AND HARMS.
OBVIOUSLY, CURRENTLY THERE ARE
DIFFERENCES IN COSTS.
BUT AT LEAST FROM THE TASK
FORCE PERSPECTIVE, WE DON'T
THINK ABOUT THAT.
WE ARE STRICTLY FOCUSED ON WHAT
WILL HELP PEOPLE.
AND SO, IN THAT SENSE, A
COMPARISON OF INTERVENTIONS
OTHER THAN PHARMACOLOGIC, I
THINK WOULD BE HELPFUL FOR US
TO UNDERSTAND THAT CHOICE FOR
PATIENTS, AND WHETHER OR NOT
ARE THERE FACTORS THAT MIGHT
PREDISPOSE TO ONE OVER THE
OTHER.
ARE THE BENEFITS COMPARABLE?
AND THIS QUESTION OF DURABILITY
OF THE BENEFIT AND WHETHER OR
NOT YOU COULD TRANSITION ONCE
YOU HAVE LOST WEIGHT LOSS, OR
WHETHER OR NOT THE INITIAL
THERAPY IS WHAT'S REQUIRED AND
HOW DURABLE IS IT.
BECAUSE MOST OF THESE STUDIES
HAVE ONLY GONE OUT 12-18 MONTHS.
AND YOU AND I KNOW WEIGHT LOSS
IS A DAILY SORT OF
CONSIDERATION FOR OUR LIFESTYLE
HABITS.
I THINK THOSE WILL BE IMPORTANT
CONSIDERATIONS AS WELL AS THE
POTENTIAL LIFE-LONG
CONSEQUENCES THAT WE JUST ARE
PROLONGED DURATION OF THESE
MEDICATIONS THAT WERE
ARTICULATED WELL EARLIER TODAY.
WE JUST DON'T KNOW YET.
>> CHRISTINE WEE: SO FINAL
QUESTION THAT I'M GOING TO ASK,
DIRECTLY PRIMARILY TO ASHELEY
BUT ALSO JOHN.
AS AN EDITOR I HAVE SEEN POORLY
DESIGNED AND EXECUTED STUDIES
THAT USE REAL-WORLD DATA AND
OFTEN MISINTERPRETED OR UNDER
INTERPRETED AND THEY GET
PUBLISHED AND THE ASSUMPTIONS
ARE INCORRECT, BASED ON THE
QUALITY OF THE STUDY DESIGN.
WE KNOW THAT SYSTEMATIC REVIEWS
THAT COMPILE, THIS IS LARGELY
REAL-WORLD EVIDENCE WILL PULL
RESULTS FROM HIGH AND POOR
QUALITY DATA.
BASED ON YOUR EXPERIENCE, I
DIRECT IT TO DR. SKINNER,
BECAUSE I ASSUME YOU RELY MORE
ON REAL-WORLD EVIDENCE BECAUSE
OF LACK OF RCT DATA, HOW DO
GUIDELINE COMMITTEES SORT OF
NAVIGATE WEIGHING, GOING
THROUGH THE LITERATURE, THE
QUITE VAST LITERATURE ON THE
TOPIC?
>> DR. SKINNER: YES, QUITE VAST
IS AN UNDER STATEMENT.
SO IN OUR, IN THE CPG FOR
CHILDREN AND ADOLESCENCE, WE
ACTUALLY DID NOT INCLUDE
SYSTEMATIC REVIEWS IN THAT.
THAT'S ONE OF THE WAYS WE
APPROACH THAT, THAT WAY WE CAN
ENSURE THAT THE EVIDENCE THAT
WE ARE USING THAT WE GRADE EACH
OF THOSE STUDIES BASED ON THEIR
RISK OF BIAS.
AND THAT WAY WE KNOW WE ARE
DOING THAT WITH THE ORIGINAL
STUDY.
SO THAT'S ONE OF THE APPROACHES
WE HAVE USED.
I THINK THAT IT'S PART OF A
CONVERSATION THAT HAPPENS WITH
WE ARE SITTING AROUND THE TABLE
ABOUT WHAT RECOMMENDATIONS WE
ARE GOING TO MAKE.
IT'S OFTEN NOT AN EXACT BLACK
OR WHITE SCIENCE HERE OF WHAT
YOU DO WITH THAT.
BUT YOU KNOW, I THINK
DEFINITELY IDENTIFYING THOSE
STUDIES THAT ARE NOT DOING A
VERY GOOD JOB, OR PARTICULARLY
IN MOST CONCERNING THOSE THAT
ARE OVER INTERPRETING THE
EFFECTIVENESS OR LACK OF HARM
OR SOMETHING OF THAT NATURE.
>> CHRISTINE WEE: JOHN, DO YOU
WANT TO ADD ANYTHING TO THAT?
>> JOHN WONG: YOU KNOW, WE HAVE
EXPERTS IN THE CENTERS.
THEY LOOK AT THREE SOURCES FOR
THE QUALITY OF EVIDENCE, IN
TERMS OF THEIR CLINICAL
APPROPRIATENESS FOR COMBINING
ANALYSIS.
ALWAYS DO A SYSTEMATIC REVIEW.
THE QUESTION IS SHOULD YOU DO A
QUANTITATIVE SYNTHESIS OR NOT.
THEY THINK OF CLINICAL HETERO
GENESTITY, INCLUSION OR
EXCLUSION, OUTCOMES, THE TYPES
OF PARTICIPANTS, THE FOLLOW-UP
TIME, THE OUTCOMES THEY ARE
CONSIDERING.
THEY THINK OF METH DO LOGIC
ISSUES.
THEY THINK A LITTLE BIT
OBVIOUSLY ABOUT STATISTICAL
HETEROGENEITY AND WHETHER IT'S
APPROPRIATE TO INCLUDE AND THEY
HAVE AN ALGORITHM THEY WORK
THROUGH.
SO FROM A QUALITY STANDPOINT,
AND THEN THE TASK FORCE ITSELF
THINKS OF APPLICABILITY,
FEASIBILITY IT THEY ARE DONE IN
OTHER COUNTRIES IS IT
TRANSPORTABLE TO UNITED STATES.
THOSE ARE ALL THINGS THAT GO
INTO OUR RECOMMENDATION
STATEMENTS.
I AGREE WITH YOU, THERE'S HIGH
HETEROGENEITY AND WHETHER OR
NOT TO POOL DEPENDS ON THE
STRENGTHS AND LIMITATIONS WE
HEARD ABOUT THIS MORNING.
>> CHRISTINE WEE: I THINK THE
REAL CHALLENGE WITH
OBSERVATIONAL STUDIES AS
OPPOSED TO RCT'S IS REALLY
IDENTIFYING WHAT I WOULD SAY
FATAL LIMITATIONS.
LIKE CONFOUNDING.
WHICH OFTEN, THE METHODOLOGIST
WHO MAY NOT BE CONTENT EXPERTS
MAY NOT EASILY BE ABLE TO
IDENTIFY.
I'M REASSURED, DR. SKINNER, THE
TASK FORCE, OR YOUR COMMIT HE
IS DOING THAT REVIEW YOURSELF.
WE HAVE TWO MINUTES.
I THINK I WILL ASK THE LAST
QUESTION IN THE CHAT, WHICH IS
DIRECTED TO DR. SKINNER.
HOW DO YOU APPROACH
CONVERSATIONS ABOUT GLP-1'S
WITH PEDIATRIC PATIENTS AND
THEIR PARENTS GIVEN CURRENT
LIMITATIONS WITH THE EVIDENCE?
>> WELL I'M NOT A CLINICIAN, SO
I DON'T HAVE TO APPROACH THESE
CONVERSATIONS.
BUT OBVIOUSLY WORK VERY CLOSELY
WITH THOSE WHO DO.
IN GENERAL, I THINK THEY ARE
VERY HONEST ABOUT THE EVIDENCE
WE DO HAVE, WHAT WE DON'T KNOW.
MOST OF THE CHILDREN I HAVE
EXPOSURE TO THROUGH THE
CLINICIANS ARE IN AN OBESITY
TREATMENT PROGRAM SO THEY ARE
OFTEN SIGNIFICANT, SEVERE
OBESITY WITH COMORBIDITIES SO
THAT CHANGES WHAT THOSE
DISCUSSIONS LOOK LIKE.
I THINK THAT'S THE BEST WE CAN
DO WITH ANY PATIENT OR ANYBODY.
HERE IS WHAT WE KNOW AND WHAT
WE DON'T KNOW.
SUPPORT THEM IN MAKING
DECISIONS.
I THINK WE CERTAINLY COULD USE
BETTER INFORMATION ABOUT HOW TO
HELP THEM MAKE THOSE DECISIONS.
>> CHRISTINE WEE: THANK YOU
VERY MUCH.
THIS IS SUCH A GREAT DISCUSSION
AND YOUR THREE DISCUSSIONS WERE
VERY ENLIGHTENING.
I GUESS WE WILL BREAK NOW FOR
LUNCH.
>> Craig Hales: THAT'S RIGHT,
THANKS.
>> CHRISTINE WEE: MAYBE REMIND
EVERYBODY WHEN WE ARE SUPPOSED
TO TUNE BACK IN.
>> Craig Hales: SURE, WE WILL
BREAK FOR LUNCH AND START AGAIN AT 1:10 P.M. EASTERN TIME.
THANK YOU.
>> Craig Hales: THANK YOU.
>> I WANT TO GO OVER
HOUSEKEEPING RULES BEFORE THE
NEXT SESSION, THE MEETING IS
BEING RECORDED, POSTED TO THE
NIH WEBSITE.
DANIELLE FROM SCIENTIFIC
CONSULTING GROUP IS THE MEETING
HOST.
E-MAIL HER WITH ANY TECHNICAL
ISSUES.
USE THE Q&A FUNCTION TO ENTER
QUESTIONS FOR THE SPEAKERS AT
ANY TIME DURING THE
PRESENTATIONS OR MODERATED
DISCUSSION.
ATTENDEES CAN UPVOTE QUESTIONS
IN THE Q&A, ANSWERED DISCUSSION
FOR EACH SESSION.
THE CHAT IS DISABLED AND THE
"RAISE HAND" FEATURE WILL NOT BE
USED.
USE THE Q&A FUNCTION INSTEAD.
NOW I'D LIKE TO WELCOME DR.
DAVENE WRIGHT, MODERATOR FOR
SESSION 2-RBGS REAL WORLD
EVIDENCE FOR PUBLIC AND PRIVATE
PAYER COVERAGE DECISIONS.
DR. WRIGHT?
>> THING YOU FOR JOINING US.
I'M DAVENE WRIGHT, ASSOCIATE
PROFESSOR AT HARVARD MEDICAL
SCHOOL, PLEASED TO MODERATE THIS
SESSION ON THE REAL WORLD
EVIDENCE FOR PUBLIC AND PRIVATE
PAYER COVERAGE DECISIONS, EACH
OF OUR THREE SPEAKERS WILL SPEAK
FOR 20 MINUTES, FOLLOWED BY
30-MINUTE MODERATED DISCUSSION
WITH ALL SPEAKERS.
PLEASE POST AND UPVOTE QUESTIONS
IN THE Q&A BOX ON TEAMS,
INDICATE WHICH SPEAKER YOUR
QUESTION IS FOR.
FIRST UP DR. ANAND PAREKH, CHIEF
MEDICAL ADVISER OF THE
BIPARTISAN POLICY CENTER, A
BOARD CERTIFIED INTERNAL
MEDICINE PHYSICIAN, INCOMING
CHAIR OF ROUNDTABLE ON OBESITY
SOLUTIONS NATIONAL ACADEMIES OF
SCIENCES, ENGINEERING, AND
MEDICINE, FORMERLY AN HHS DEPUTY
ASSISTANT SECRETARY FOR HEALTH,
DEVELOPED AND IMPLEMENTED
NATIONAL INITIATIVES ON
PREVENTION AND CARE MANAGEMENT,
DR. PAREKH WILL PROVIDE A
NATIONAL AND PUBLIC PAYER
PERSPECTIVE ON COVERAGE OF GLP-1
THERAPIES.
TAKE IT AWAY.
>> THANK YOU FOR THE
INTRODUCTION, TO CRAIG, AND
NIDDK FOR THIS WORKSHOP.
I'LL SHARE MY SCREEN HERE AND
SLIDES.
LET'S SEE.
ALL RIGHT.
CAN FOLKS SEE THE SLIDES?
>> YES, THEY LOOK GOOD
>> GREAT.
WONDERFUL.
JUST A LITTLE BIT OF DISCLOSURES
AT THE OUTSET, THE BIPARTISAN
POLICY CENTER, WE'RE A THINK
TANK IN WASHINGTON, D.C. THAT
TRIES TO TAKE THE BEST IDEAS
FROM BOTH SIDES TO PROMOTE
HEALTH SECURITY AND OPPORTUNITY,
WE WORK ON VARIETY OF HEALTH
POLICY ISSUES AS WE THINK OF
THREE-LEGGED STOOL, ISSUES THAT,
ONE, WE THINK ARE IMPORTANT
HEALTH POLICY ISSUES; TWO, BOTH
SIDES NEED TO BE EDUCATED;
THREE, THERE'S A POLICY WINDOW.
SO AT THE FEDERAL LEVEL CONGRESS
OR EXECUTIVE BRANCH CARES ABOUT
THIS.
WHEN WE TALK ABOUT OBESITY, 40%
OF ADULTS, 100 MILLION
AMERICANS, CHILDREN AS WELL, AND
GLP-1-BASED THERAPIES, A
CRITICAL POLICY ISSUE SO IT'S
BEEN A SPACE WE'VE ACTIVELY BEEN
ON.
IN 2022, WE DID PUBLISH A
REPORT, TITLED EXPANDING ACCESS
TO OBESITY TREATMENTS IN OLDER
ADULTS, AND WHAT WE DID IS
ESSENTIALLY CONDUCT A SYSTEMATIC
REVIEW OF 21 RANDOMIZED
CONTROLLED TRIALS EVALUATING
WEIGHT LOSS INTERVENTION OF ONE
YEAR IN DURATION NOT CURRENTLY
COVERED BY MEDICARE, SO A NUMBER
OF FDA-APPROVED PHARMACEUTICALS
INCLUDING TWO GLP-1s, GLUTIDE
AND SEMI GLUTIDE, AND THE
CONCLUSION, BACK IN 2022 GIVE
THAN OBESITY IS RECOGNIZED AS
CHRONIC DISEASE, THERE ARE
FDA-APPROVED MEDICATIONS FOR
OBESITY, THAT POLICYMAKERS
SHOULD REMOVE STATUTORY
PROHIBITION ON MEDICARE PARK D
COVERAGE FOR FDA-APPROVED
ANTI-OBESITY MEDICATIONS.
WE'LL DISCUSS THAT IN A MOMENT.
WE CONCLUDED FURTHER STUDIES IN
THE OLDER ADULT POPULATION
HELPED IN CONSIDERATION FOR
TREATMENTS AND SUBSEQUENTLY OUR
SISTER ORGANIZATION, BPC ACTION,
DID ENDORSE AND WE'LL TALK ABOUT
THIS THIS BILL IN CONGRESS TO
TREAT AND REDUCE OBESITY THAT
WOULD ALLOW FOR MEDICARE
COVERAGE OF THESE MEDICATIONS,
SO JUST A COUPLE DISCLOSURES AS
WE START ABOUT THE ORGANIZATION
AS WELL AS OUR WORK.
I WANT TO COVER MEDICARE IF HE
-- █AT THE FEDERAL LEVEL, WHAT
DOES DoD DO, AND COVER
MEDICAID, AND HONE IN ON WHERE I
THINK WE NEED SOME MORE REAL
WORLD EVIDENCE.
SO, LET'S START WITH MEDICARE.
MEDICARE CURRENTLY DOES COVER
GLP-1 DRUGS FOR TYPE 2 DIABETES.
IT ALSO COVERS GLP-1 DRUGS FOR
SLEEP APNEA WITH OBESITY, SO
MODERATE TO SEVERE SLEEP APNEA
WITH OBESITY AND COVERS GLP-1
FOR CARDIOVASCULAR DISEASE WITH
OBESITY, SPECIFICALLY REDUCE THE
RISK OF MAJOR CARDIAC EVENTS IN
NON-DIABETIC ADULT WAS
ESTABLISHED CARDIOVASCULAR
DISEASE AND YOU HAVE TO BE
OVERWEIGHT OR OBESE.
SO IN SELECT CASES, WITH
OBESITY, MEDICARE CURRENTLY
COVERS THESE DRUGS.
BUT OVERALL, MEDICARE CURRENTLY
DOES NOT COVER ANY ANTI-OBESITY
MEDICATION FOR OBESITY, OBESITY
ALONE, DUE TO STATUTORY
PROHIBITION OF COSMETIC WEIGHS
LOT DRUGS THAT PREDATES
ENACTMENT OF MEDICARE PART D IN
2003 AND SO ESSENTIALLY THE
SOCIAL SECURITY ACT ALLOWS
EXCLUSION OF, QUOTE, ANY AGENT
WHEN USED FOR ANOREXIA, WEIGHT
LOSS, OR WEIGHT GAIN, AND FOR
THE LAST TWO DECADES, UP TILL
LAST NOVEMBER, CMS INTERPRETED
THAT FOR MEDICARE AS ESSENTIALLY
PRECLUDING THE COVERAGE OF
ANTI-OBESITY MEDICATIONS,
INCLUDING GLP-1s.
THERE WAS LEGISLATION.
THERE HAS BEEN OVER THE LAST
SEVERAL YEARS IN CONGRESS,
BIPARTISAN LEGISLATION, WITH
HUNDREDS OF SPONSORS, DEMOCRAT
AND REPUBLICAN, CALLED TREAT AND
REDUCE OBESITY ACT I WOULD WHICH
WOULD ALLOW COVERAGE AGAIN FOR
THE TREATMENT OF OBESITY OR FOR
WEIGHT LOSS MANAGEMENT FOR
INDIVIDUALS OVERWEIGHT.
ESSENTIALLY COVERAGE OF ANY
FDA-APPROVED MEDICATION FOR
OBESITY.
THIS BILL HAS NOT MOVED
SIGNIFICANTLY IN ITS OWN RIGHT,
MODIFIED VERSION OF THIS BILL
ACTUALLY DID MOVE LAST YEAR IN
THE HOUSE WAYS AND MEANS
COMMITTEE, PASSED AN AMENDED
VERSION THAT WOULD SORT OF BREAK
THIS DOWN OR CUT THIS DOWN TO
THE EXTENT THAT ONLY INDIVIDUALS
STARTING ON MEDICARE PREVIOUSLY
ON GLP-1s OR ANTI-OBESITY
MEDICATION FOR A YEAR PRIOR TO
STARTING ON MEDICARE WOULD BE
COVERED.
SO OBVIOUSLY A MUCH SMALLER SIZE
OF THE MEDICARE POPULATION, YOU
KNOW, THAT RAISES EQUITY AND
OTHER CONCERNS BUT THIS IS A
BILL CURRENTLY STILL IN
CONGRESS, HAS NOT BEEN PASSED BY
CONGRESS.
AND ONE OF THE CHIEF REASONS WHY
EVEN THOUGH WE'RE STILL ACCRUING
EVIDENCE ON THE BENEFITS,
LONG-TERM BENEFITS OF GLP-1s,
ONE OF THE MAIN REASONS WHY IT
HASN'T MOVED IS BECAUSE OF THE
FISCAL IMPACT TO THE FEDERAL
BUDGET.
AND YOU'LL HEAR ABOUT THIS MORE
IN A FEW MINUTES FROM NOELIA BUT
LAST OCTOBER THE CONGRESSIONAL
BUDGET OFFICE RELEASED ON REPORT
ON HYPOTHETICALLY IF YOU DID
EXPAND COVERAGE OF ANTI-OBESITY
MEDICATIONS IN THE MEDICARE
PROGRAM WHAT WOULD BE THE
POTENTIAL FISCAL IMPACT AND
CONCLUSION AS YOU'LL HEAR FROM
THAT REPORT WAS LOOKING AT A
VARIETY OF -- MAKING A VARIETY
OF ASSUMPTIONS ON CRITICAL
FACTORS, NET INCREASE IN FEDERAL
SPENDING BY ABOUT $35 BILLION
OVER NINE YEARS WITH ASSUMPTIONS
SUCH AS UPTAKE RATES INCREASING
FROM 2% TO 14% OVER THAT TIME
PERIOD.
SO OBVIOUSLY WHATEVER YOU MAKE
OF THESE ASSUMPTION THAT CAN
THEN CHANGE THE ULTIMATE FEDERAL
ESTIMATED SPENDING AMOUNT, THAT
WAS THE REPORT IN OCTOBER.
VERY SHORTLY THEREAFTER IN
NOVEMBER, CMS FOR THE FIRST TIME
PROPOSED REINTERPRETING THAT
LONGTIME EXCLUSION THAT READING
OF THE SOCIAL SECURITY ACT THAT
I MENTIONED BUT GIVEN THAT
OBESITY IS NOW RECOGNIZED AS A
DISEASE, CMS PROPOSED PART D
COVERAGE OF ANTI-OBESITY
MEDICATIONS FOR INDIVIDUALS,
BENEFICIARIES WITH OBESITY, NOT
OVERWEIGHT BUT JUST OBESITY, AND
ALSO PROPOSED APPLYING THAT TO
THE MEDICAID PROGRAM.
AND WE'LL GET TO THE MEDICAID
PROGRAM IN A SECOND BUT IT'S
ALWAYS BEEN OPTION FOR MEDICAID
PROGRAM, THAT REINTERPRETATION
WAS IN A PROPOSED RULE THAT
CMS'S ESTIMATES WERE IT WOULD
INCREASE COSTS BY $15 BILLION
DUE TO EXPANDED MEDICAID
COVERAGE, ESTIMATED UPTAKE
3.4 MILLION MEDICAL CARE AND 4
MILLION MEDICAID BENEFICIARIES.
THERE WERE ABOUT 25,000 COMMENTS
THAT CAME IN TO CMS OVER SEVERAL
MONTHS, ULTIMATELY DURING THE
NEW ADMINISTRATION, CURRENT
TRUMP ADMINISTRATION, IT WAS
DECIDED JUST EARLIER THIS MONTH
THAT PROPOSAL WAS NOT INCLUDED
IN THE FINAL RULE SO IT WILL NOT
BE MOVING FORWARD AT THIS TIME.
MOST PEOPLE KNOW MEDICARE NOW
HAS ABILITY TO NEGOTIATE
PRESCRIPTION DRUG PRICES, AND
THE FIRST LIST OF 10 DRUGS THAT
OCCURRED IN THE LAST YEAR, THE
NEXT SET OF DRUGS DOES INCLUDE
SEMAGLUTIDE, SO MEDICARE WILL
NEGOTIATE WITH THE INCLUSION
WITH A TWO-YEAR LAG PERIOD.
THAT'S ON THE MEDICARE SIDE.
THAT'S GREAT, THAT'S FOR THE 60
MILLION MEDICARE BENEFICIARIES
BUT WHAT ABOUT OTHER AMERICANS
ON FEDERAL GOVERNMENT INSURANCE
PROGRAMS?
THINK ABOUT THE MILITARY AND
DEPARTMENT OF DEFENSE AND
TRICARE, COVERAGE OF GLP-1s
FOR DIABETES
AND FOR WEIGHT MANAGEMENT PRIOR
AUTHORIZE AS, MEET BIM CRITERIA,
UNDERGO SIX MONTHS OF BEHAVIORAL
MODIFICATION AND DIETARY
RESTRICTION AS WELL AS THREE
MONTHS OF USING OTHER
ANTI-OBESITY MEDICATIONS SO
GENERIC ALTERNATIVE MEDICATIONS,
ANNUAL OWN THEN ARE YOU -- IS IT
COVERED, ARE GLP-1s COVERED
FOR WEIGHT MANAGEMENT, SIMILARLY
THE VETERANS DEPARTMENT COVERS
GLP-1s FOR TYPE 2 DIABETES FOR
FOR WEIGHT MANAGEMENT AND
OBESITY YOU NEED TO PASS THROUGH
SIGNIFICANT PRIOR AUTHORIZATION,
BMI, PARTICIPATION IN
COMPREHENSIVE LIFESTYLE
INTERVENTION PROGRAM AND EITHER
FAILURE OF GENERIC ALTERNATIVES,
AND THAT MEANS NOT MEETING AT
LEAST 5% REDUCTION IN BODY
WEIGHT, WHICH CLINICALLY IS
ASSOCIATED WITH ALL THOSE
PARAMETERS THAT WE CARE ABOUT
WEIGHT AND BLOOD PRESSURE AND
CHOLESTEROL, AS WELL AS OTHERS.
AND THEN THE OFFICE OF PERSONNEL
MANAGEMENT REQUIRES, IF YOU'RE A
FEDERAL GOVERNMENT EMPLOYEE,
EVERY CARRIER TO COVER AT LEAST
ONE GLP-1 DRUG FOR WEIGHT LOSS
SINCE EARLY 2023.
AND SO I THINK FROM A BIGGER
PICTURE PERSPECTIVE WHAT I HOPE
YOU START TO APPRECIATE IS EVEN
THOUGH WE HAVE SORT OF ONE
FEDERAL GOVERNMENT, AND
DEPENDING ON THE INSURANCE
PROGRAM THAT YOU'RE ON, WHETHER
IT'S MEDICARE, WHETHER IT'S A
FEDERAL EMPLOYEE HEALTH BENEFIT
PROGRAM OR DoD, HOW THE
GOVERNMENT APPROACHES COVERAGE
OF GLP-1s FOR OBESITY AND
WEIGHT MANAGEMENT DIFFERS
DEPENDING ON THE PROGRAM.
MEDICAID IS A FEDERAL/STATE
PROGRAM AND PARTNERSHIP,
STATUTORY DEFINITION IS FOR
OBESITY MEDICATIONS, QUOTE,
AGENTS WHEN USED FOR ANOREXIA,
WEIGHT LOSS, OR WEIGHT GAIN MAY
BE EXCLUDED.
SO HERE MEDICAID AND STATES GET
THE CHOICE OF PARTICULARLY FOR
ADULTS, 40% OF MEDICAID
BENEFICIARIES HAVE OBESITY,
STATES HAVE THE PREROGATIVE TO
DECIDE WHETHER THEY WANT TO
COVER ANTI-OBESITY MEDICATIONS
AND GLP-1s, TECHNICALLY FOR
KIDS, ALL ANTI-OBESITY
MEDICATIONS SHOULD BE COVERED
UNDER WHAT'S CALLED EPSDT
BENEFITS, EARLY PERIODIC
SCREENING DIAGNOSTIC AND
TREATMENT PROGRAM, BUT WHEN YOU
DIG UNDERNEATH AND TRY TO FIND
THE DETAILS, VERY FEW ACTUALLY
DO COVER THE SECOND WAY THEY ARE
SUPPOSED TO DO IT BUT FOR ADULTS
WE'RE AT 13 OR 14 STATES
NATIONALLY THAT ARE COVERING
THESE DRUGS.
WHEN I SAY COVERING, THEY COME
IN ALL SORT OF SIZES AND SHAPES,
JUST LIKE WE TALKED ABOUT, V.A.
AND DoD, MANY OF THESE STATES
HAVE SIGNIFICANT PRIOR
AUTHORIZATIONS, WE'LL GIVE A
COUPLE EXAMPLES LIKE
MISSISSIPPI, INITIAL IS BASED ON
BMI AND COMORBID CONDITIONS BUT
EVERY SIX MONTHS HAS TO BE
REAUTHORIZATION BASED ON
PROGRESS TOWARDS OVERCOMING
OBESITY.
IN VIRGINIA, AUTHORIZATION
INCLUDES YOU HAVE TO BE IN A
COMPREHENSIVE LIFESTYLE
INTERVENTION, PROVIDERS HAVE TO
ATTEST THAT THE PATIENCE'S
OBESITY IS DISABLING AND
LIFE-THREATENING.
PATIENTS HAVE TO TRY A NON-GLP-1
AGONIST FOR WEIGHT LOSS IN THE
PREVIOUS SIX MONTHS, AND NOT BE
PROGRESSING, SO SIGNIFICANT
PRIOR AUTHORIZATION, MICHIGAN,
YOU HAVE TO FAIL LOSING 5% OF
BASELINE WEIGHT, GO THROUGH A
NUMBER OF HOOPS BUT AT LEAST 13
TO 14 MEDICAID PROGRAMS IN SOME
CAPACITY ARE COVERING GLP-1s.
AND STATE EMPLOYEE HEALTH PLANS,
I'M FOCUSING ON FEDERAL BUT
PUBLIC SIDE FOR STATES THERE ARE
WILL 16 STATE EMPLOYEE HEALTH
PLANS THAT ARE COVERING
GLP-1s, A COUPLE NOTABLE ONES
RECENTLY IN THE NEWS WHO
REVERSED, THEY SAW ASTRONOMICAL
INCREASES IN COST AND REVERSED.
COLORADO, WEST VIRGINIA COME TO
MIND, NORTH CAROLINA COMES TO
MIND AS WELL.
SO WEIGHING BENEFITS VERSUS COST
IS VERY DIFFICULT DECISION FOR
REALLY ALL 50 STATES, BOTH FOR
MEDICAID PROGRAMS AS WELL AS
STATE EMPLOYEE HEALTH PLANS.
BACK TO MEDICAID, KAISER DID AN
IMPORTANT RECENT SURVEY ASKING
FOR THOSE WHO ARE COVERING IT
WHY ARE YOU COVERING IT?
YOU SEE SOME OF THE MAIN REASONS
ON THE RIGHT THERE.
FOR THOSE NOT COVERING IT, WHAT
ARE THE REASONS YOU'RE NOT
COVERING IT?
NO SURPRISE THAT COST REALLY
TWO-THIRDS OF STATES NOTED COST
AS THE NUMBER ONE BARRIER FOR
NOT COVERING OBESITY MEDICATION.
OTHER REASONS WERE POTENTIAL
SIDE EFFECTS, ADHERENCE
CONCERNS, NEED FOR LEGISLATIVE
ACTION, A NUMBER OF REASONS BUT
COST IS I WOULD SAY THE BIG
ISSUE.
I WANT TO SPEND A COUPLE MINUTES
ON A REALLY THINK NICE WHITE
PAPER THAT CAME OUT FROM THE
INSTITUTE FOR CLINICAL AND
ECONOMIC REVIEW IN THE LAST FEW
WEEKS.
AGAIN, WITH THE WHOLE GOAL BEING
WE KNOW ABOUT THE PROMISE AND
BENEFITS THAT WE'RE STILL
LEARNING ABOUT LONG-TERM
BENEFITS OF GLP-1s, BUT HOW DO
WE ENSURE AFFORDABLE AND
EQUITABLE ACCESS FOR NEW OBESITY
MEDICATIONS, AND WHAT KAISER DID
WAS LIFT OUR WHAT ARE SOME OF
THE MARKET STRATEGIES BEING
UTILIZED RIGHT NOW OR COULD BE
UTILIZED, WHAT ARE SOME FEDERAL
ACTIONS BEING CONTEMPLATED RIGHT
NOW, OR COULD BE IMPLEMENTED IN
THE FUTURE, AGAIN, TO ENSURE
AFFORDABLE AND EQUITABLE ACCESS,
YOU KNOW, A COUPLE ONES HERE
JUST TO LIST OFF, ON THE MARKET
STRATEGY SIDE WHAT CAN
PURCHASERS DO, THEY CAN
TEMPORARILY DENY COVERAGE AND
SAY WE NEED MORE REAL WORLD
EVIDENCE OF THAT PERSISTENCE.
WE NEED TO WAIT FOR COSTS TO
COME DOWN THROUGH MARKET
COMPETITION OR NEGOTIATION.
LET'S HOLD OFF.
ANOTHER STRATEGY IS TO IDENTIFY
ARE THERE SOME SUBPOPULATIONS OR
ARE THERE SOME WAYS WHERE WE CAN
ALLOW THE POPULATION HEALTH
BENEFIT FROM GLP-1s TO START
TO BE REALIZED THROUGH ENHANCED
PRIOR AUTHORIZATION, SO THERE
ARE A LOT OF INTERESTING IDEAS
HERE FROM NARROWING COVERAGE
THROUGH BMI AND CLINICAL
COMORBIDITY RESTRICTION, WE NEED
SOME REAL WORLD EVIDENCE FOR
THAT.
DO YOU REQUIRE LIFESTYLE
MANAGEMENT AS PRE-RECOLLECT
WHICH PREREQUISITE OR
CONCOMITANT, SHOULD WE LIMIT
DURATION OF TREATMENT, THROUGH
ANECDOTAL EXPERIENCE IN ENGLAND
AND CLAIMS BY COMPANIES THAT
SUGGEST SOME PATIENTS CAN
MAINTAIN WEIGHT LOSS AFTER
DISCONTINUATION OF GLP-1s, DO
WE NEED REAL WORLD EVIDENCE
THERE?
SHOULD THERE THERE BE STEP
THERAPY, THERE'S SOME EVIDENCE
THIS SUGGESTS SOME PATIENTS
DON'T NEED GLP-1s YOU ABOUT
COULD MEET WEIGHT TARGETS WITH
LESS EXPENSIVE MEDICATIONS AND
COULD YOU STRUCTURE A BENEFIT
SUBSET, YOU ONLY GET TO GLP-1s
AS WE'VE SEEN A LOT OF STATES, I
JUST MENTIONED V.A. AND DoD
DOING, ONLY IF YOU'RE NOT ABLE
TO LOSE OR MEET WEIGHT TARGETS
WITH LESS EXPENSIVE MEDICATION.
SO A NUMBER OF WAYS YOU COULD
USE PRIOR AUTHORIZATION AND
FORMULARY MANAGEMENT, PROVIDER
NETWORK MANAGEMENT, YOU ALLOW A
BROADER ARRAY OF PROVIDERS,
PRIMARY CARE PROVIDERS, TO
PRESCRIBE GLP-1s BUT WITH
TIGHT UTILIZATION VERSUS DO YOU
JUST ALLOW OBESITY SPECIALISTS
AND NARROW PANEL TO PRESCRIBE
THESE MEDICATIONS WITHOUT
UTILIZATION MANAGEMENT,
DIFFERENT MARKET STRATEGIES OUT
THERE CURRENTLY BEING THOUGHT
OF.
ON THE FEDERAL ACTION SIDE,
CERTAINLY A NUMBER OF THINGS
BEING DISCUSSED FROM EXPANDING
MEDICARE COVERAGE, WE SAW CMS
DECIDED NOT TO CURRENTLY MOVE
FORWARD WITH THE PROPOSED RULE
TO EXPAND COVERAGE, COULD THEY
REVISIT THAT RULE?
COULD THERE BE A NEW CENTER FOR
MEDICARE AND MEDICAID INNOVATION
MODEL THAT TESTS EXPANSION OF
GLP-1s?
COULD ACCESS BE MANDATED THROUGH
U.S. PREVENTIVE SERVICE TASK
FORCE, WHICH AS YOU KNOW IS AN
INDEPENDENT BODY THAT RATES
CLINICAL PREVENTIVE SERVICES,
THOSE RATED A AND B THROUGH THE
AFFORDABLE CARE ACT MUST BE
COVERED, IN MOST CASES, BY
PRIVATE INSURERS WITHOUT COST
SHARING.
COULD GLP-1s AND ANTI-OBESITY
MEDICATIONS BE CONSIDERED
THROUGH THAT, PROBABLY NOT
LIKELY EVEN THOUGH THERE ARE --
THERE WAS PRECEDENT FOR THAT AS
WELL, HIV MEDICATION, BUT MORE
FOR PRIMARY PREVENTION AS
OPPOSED TO TREATMENT.
SHOULD THERE BE MORE AGGRESSIVE
NEGOTIATION OF PRICES, WE TALKED
ABOUT SEMAGLUTIDE FOR 2027, AND
SOME OTHER OPTIONS THAT I THINK
ARE PROBABLY LESS REALISTIC BUT
PROVIDING FEDERAL SUBSIDIES TO
COMMERCIAL INSURERS, LICENSING
TO GENERIC MANUFACTURERS, SO
THERE'S MORE -- IT'S MORE
AFFORDABLE FOR PUBLIC PLAYERS,
ALL HAVE PROS AND CONS BUT A
HELPFUL FRAMEWORK TO START
THINKING ABOUT COVERAGE OF
GLP-1s.
I WANTS TO END ON GAPS AND
OPPORTUNITIES.
THE BIGGEST TWO OPPORTUNITIES,
THE FIRST IS FOR MICROSIMULATION
RESEARCH, THE SECOND IS REAL
WORLD EVIDENCE RESEARCH.
THE FIRST BULLET HERE ON
MICROSIMULATION, WE HOSTED A
MEETING OF THE BIPARTISAN POLICY
CENTER SIX MONTHS AGO TRIED TO
BRING TOGETHER ACROSS THE
COUNTRY LEADING MICROSIMULATION
RESEARCH EXPERTS WHO ARE FOCUSED
ON TRYING TO EXAMINE WHAT ARE
THE FISCAL IMPACTS TO PUBLIC
PROGRAMS IN PARTICULAR FOR
COVERAGE OF ANTI-OBESITY
MEDICATION, CBO WAS THERE, MANY
FOLKS PROBABLY PARTICIPATING IN
TODAY'S WORKSHOP IN THAT
MEETING.
AND WE WENT THROUGH MANY OF THE
ASSUMPTIONS IT TAKES TO ESTIMATE
THE FISCAL IMPACT.
YOU GOT TO FIGURE OUT, WELL,
WHAT'S THE N, HOW MANY MILLIONS,
HOW MANY WANT TO TAKE IT, WHAT'S
THE ADHERENCE, WHAT ARE THE
PRICE OF MEDICATIONS, WITH
REBATES, NET PRICE, HOW MIGHT
NEGOTIATION IMPACT THIS, HOW
COULD MARKET COMPETITION IMPACT
THIS, WHAT ARE THE HEALTH
BENEFIT OFFSETS?
HOPEFULLY THIS WILL REDUCE
PREVENTIBLE HEALTH CARE
UTILIZATION, IMPROVE HEALTH,
WHAT ARE THE HEALTH BENEFITS,
WHAT ARE SOME OTHER ASSUMPTIONS,
SO A LOT OF THAT RESEARCH, A LOT
OF PLACES AROUND THE COUNTRY ARE
LOOKING AT THAT.
THERE'S A CITATION HERE FROM A
NICE STUDY THAT JUST CAME OUT
TWO WEEKS AGO IN JAMA HEALTH
FORUM, RESEARCHERS FROM CHICAGO
AND TUFTS AND MICHIGAN WHO
LOOKED AT THIS, AGAIN, LOOKING
AT DIFFERENT ASSUMPTIONS, THAT
WORK NEEDS TO CONTINUE.
AND THEN FINALLY IDENTIFYING
SUBPOPULATIONS WITH OBESITY FOR
WHOM INCREASED ACCESS TO
GLP-1s ARE MOST BENEFICIAL,
AND WE NEED A LOT OF REAL WORLD
EVIDENCE.
NOT JUST THE SUBPOPULATIONS, NOT
JUST FOR WHOM, IT'S HOW DO YOU
USE IT.
SO FOR WHOM, WITH WHAT, BACK TO
LIFESTYLE MODIFICATION PROGRAMS,
FOR HOW LONG, SO BACK TO
LIFESTYLE.
WHAT ARE THOSE LIFESTYLE AND
WEIGHT MANAGEMENT PROGRAMS MOST
EFFECTIVE AND COMPLEMENTING
GLP-1 DRUGS?
AND THEN FOR HOW LONG.
AND THIS IS REALLY NO PUN
INTENDED SORT OF THE MONEY
QUESTION.
IS THERE A CLINICALLY EFFECTIVE
SUSTAINABLE OFF-RAMP PATHWAY FOR
GLP-1s, ONCE SOMEBODY GETS TO
TARGET WEIGHT LOSS, ONCE
SOMEBODY ACHIEVES CLINICAL
IMPACT, WHERE WHETHER IT'S SIX
MONTHS OR A YEAR OR TWO YEARS
WHERE YOU CAN SAFELY COME OFF
THESE MEDICATIONS AND THEN YOU
MAY NEED -- MAYBE YOU NEED OTHER
NON-GLP-1 MEDICATIONS, LIFESTYLE
AND DIET MANAGEMENT, THE
OFF-RAMP PATHWAY THAT'S
SUSTAINABLE, THESE AREAS WOULD
BENEFIT FROM URGENT NEED FOR
REAL WORLD EVIDENCE THERE.
SO I WILL STOP THERE AND REALLY
LOOKING FORWARD TO THE
DISCUSSION AFTER THE NEXT FEW
PANELISTS.
THANK YOU FOR ALLOWING ME THE
OPPORTUNITY TO PRESENT TO YOU.
>> GREAT.
THANK YOU SO MUCH.
FANTASTIC.
I ALREADY HAVE A NUMBER OF
QUESTIONS.
WE'LL DO OUR Q&A AT THE END.
NEXT SPEAKER, I'D LIKE TO
INTRODUCE DR. NOELIA DUCHOVNY,
CONGRESSIONAL BUDGET OFFICE, 20
YEARS OF EXPERIENCE CONDUCTING
HEALTH POLICY RESEARCH ON
POLICIES RELATED TO POPULATION
HEALTH CONCERNS LIKE OBESITY AND
SUBSTANCE USE, ON THE FEDERAL
BUDGET.
DR. DUCHOVNY WILL SHARE FROM TE
CONGRESSIONAL BUDGET OFFICE
REGARDING COVERAGE OF
MEDICATIONS TO TREAT OBESITY.
>> LET ME SHARE MY SLICES -- SL
PERFECT.
THANK YOU.
GOOD AFTERNOON.
I'M GOING TO BE SPEAKING ABOUT
MY WORK AT THE CONGRESSIONAL
BUDGET OFFICE, AND I WILL BE
MAKING -- I WANT TO TOUCH ON
THREE ASPECTS OF THE WORK.
FIRST, I WOULD LIKE TO TELL YOU
ABOUT THE WORK THAT WE DO AT THE
CONGRESSIONAL BUDGET OFFICE, IN
CASE YOU'RE NOT VERY FAMILIAR
WITH OUR OFFICE.
I WANT TO TALK ABOUT THE REPORTS
THAT WE PUT OUT IN LAST OCTOBER,
THAT ANAND MENTIONED.
THEN I'M GOING TO TALK ABOUT THE
MAJOR AREAS OF UNCERTAINTY.
ALL THESE TOPICS WILL SOUND VERY
FAMILIAR BECAUSE THEY HAVE
ALREADY BEEN DISCUSSED BY PRIOR
SPEAKERS.
SO I HAVE NO CONFLICTS OF
INTEREST.
SO LET ME START BY TALKING ABOUT
THE POLICY MAKING PROCESS.
TIMES OF INFORMATION CBO
GENERALLY PROVIDES TO CONGRESS
INCLUDES BASELINE PROJECTIONS,
THOSE ARE PROJECTION OF FEDERAL
SPENDING AND REVENUE UNDER
CURRENT LAW TO HELP FORMULATE
BUDGET.
AS AN EXAMPLE, MY COLLEAGUE WHO
DOES PROJECTIONS FOR MEDICARE
ENROLLMENT AND SPENDING FOR THE
NEXT TEN YEARS.
AND THEN CONGRESSIONAL BUDGET
OFFICE IS ALSO CHARGED WITH
DOING COST ESTIMATES OF
LEGISLATIVE PROPOSALS, AND THOSE
LEGISLATIVE PROPOSALS ARE
MEASURED AGAINST BASELINE
PROJECTIONS.
WE -- THE AGENCY ALSO LOOKS AT
ESTIMATES OF ECONOMIC AND
BUDGETARY EFFECTS OF DIFFERENT
POLICY OPTIONS.
AND IMPORTANTLY, CBO IS STRICTLY
NONPARTISAN AND DOES NOT MAKE
POLICY RECOMMENDATIONS.
GOING BACK TO THE COST
ESTIMATES, THOSE ESTIMATES HAVE
CERTAIN CHARACTERISTICS.
FOR THE MOST PART THEY FOCUS ON
THE NEXT TEN YEARS, BUT
SOMETIMES LOOK 20 YEARS OR MORE
INTO THE FUTURE.
THIS IS ESPECIALLY IMPORTANT IN
CERTAIN POLICIES, FOR EXAMPLE,
RELATED TO PREVENTION AND YOU
MIGHT EXPECT THAT THE COST OF
COVERING A NEW PREVENTIVE
SERVICE MIGHT COME EARLY IN THE
BUDGET WINDOW, THIS TEN YEARS,
BUT THE BENEFITS WON'T COME
UNTIL MUCH LATER.
SO IT'S IMPORTANT FOR US TO --
WHEN WE CAN, WE ESTIMATE EFFECTS
IN NOT ONLY TEN YEARS BUT TWENTY
YEARS, AND AT THE VERY LEAST TRY
TO GIVE THE CONGRESS
INFORMATION, SUPPLEMENTAL
INFORMATION, ON WHAT HAPPENS
AFTER THE FIRST DECADE.
ESTIMATES REFLECT MIDDLE OF
DISTRIBUTION OF LIKELY OUTCOMES.
THEY INCORPORATE BEHAVIORAL
RESPONSES TO THE EXTENT
POSSIBLE, THAT MEANS WE RELY ON
AVAILABLE EVIDENCE.
ESTIMATES MAY BE UPDATED IF NEW
INFORMATION BECOMES AVAILABLE,
AND CAN CHANGE AS A RESULT.
AND WHEN WE PUT OUT ESTIMATES,
WE INCLUDE EXPLANATIONS OF THE
ANALYSIS TO THE EXTENT POSSIBLE.
SO ASSESSMENTS ARE BASED ON
DETAIL ANALYSIS, INCLUDING DEEP
UNDERSTANDING OF FEDERAL
PROGRAMS AND REVENUE RESOURCES,
EXAMINATION OF RELEVANT RESEARCH
LITERATURE AND ANALYSIS OF DATA
REPORTED BY FEDERAL AGENCIES.
WE RELY HEAVILY ON OUTSIDE
EXPERTS IN ACADEMIA, THINK
TANKS, INDUSTRY GROUPS, PRIVATE
SECTOR, FEDERAL, STATE, AND
LOCAL AGENCIES.
AND YOU'LL SEE ALL OF THESE
REFLECTED WHEN I TALK ABOUT OUR
ESTIMATE OF COVERAGE OF
ANTI-OBESITY MEDICATIONS.
WE ALSO HAVE TWO PANELS, ONE IS
MORE TARGETED TO MACROECONOMIC
ISSUES, AND THERE'S A SECOND
PANEL OF HEALTH ADVISORS.
NOW TURNING TO THE ESTIMATE OF
MEDICARE COVERAGE OF
ANTI-OBESITY MEDICATIONS, ANAND
DISCUSSED THIS BUT JUST BRIEFLY
MEDICARE DOES COVER SOME
TREATMENTS FOR OBESITY THAT
INCLUDES BARIATRIC SURGERY,
COUNSELING AND OBESITY
SCREENINGS, BEHAVIORAL THERAPY.
PART D PROHIBITED FROM COVERING
PRESCRIPTION DRUGS OR AOMs FOR
WEIGHT LOSS BUT CAN COVER THOSE
MEDICATIONS FOR THINGS LIKE TYPE
2 DIABETES AND CARDIOVASCULAR
DISEASE.
SO AS I MENTIONED IN LAST
OCTOBER WE PUBLISHED A REPORT
LOOKING AT POLICY THAT WOULD
AUTHORIZE MEDICARE PART D TO
COVER ANTI-OBESITY MEDICATIONS,
AND THAT REPORT CONCLUDED THAT
THAT COVERAGE WOULD COST THE
FEDERAL GOVERNMENT MORE THAN IT
WOULD SAVE FROM REDUCING OTHER
HEALTHCARE SPENDING LEADING TO
OVERALL INCREASE IN THE DEFICIT.
SO THIS TABLE SHOWS THE EFFECT
ON THE DEFICIT WHICH OVER TEN
YEARS THAT'S THE TOTAL, THE VERY
LAST COLUMN, WOULD INCREASE
DEFICIT BY $35.5 BILLION, AND
THAT'S COMBINATION OF DIRECT
COST OF POLICY WHICH WOULD
INCREASE DEFICIT BY ALMOST $39
BILLION, OVER THOSE TEN YEARS,
AND SAVINGS FROM IMPROVED HEALTH
THAT WOULD REDUCE BY
$3.4 BILLION.
SO LESS THAN 10% OFFSET IN
INCREASE.
SHOULD BE NOTED FUTURE ESTIMATES
OF THE SAME POLICY COULD DIFFER
BECAUSE OF DIFFERENT POLICY
SPECIFICATIONS, CHANGES IN
BASELINE PROJECTIONS, ABILITY OF
NEW EVIDENCE AND IMPROVEMENT IN
CBO'S ESTIMATING POLICY.
ESTIMATED METHODOLOGY, SORRY.
SO, LET ME BREAK DOWN AND TALK
ABOUT THE DIFFERENT COMPONENTS
THAT WENT INTO COMING UP WITH
THOSE ESTIMATES.
AND THE SOURCES OF DATA THAT WE
USED TO GET AT SPECIFIC
PARAMETERS.
SO, DIRECT COSTS THAT OUTLINE IN
THE PREVIOUS TABLE ARE
DETERMINED BY TWO FACTORS.
THE USE OF THE MEDICATIONS AND
THE PRICE OF THE MEDICATIONS.
USE IS IN TURN A FUNCTION OF THE
NUMBER OF ENROLLEES ELIGIBLE FOR
COVERAGE OF AOMs, TAKEUP OF
THOSE MEDICATIONS AND DURATION
OF THE TREATMENT.
LET ME TAKE EACH ONE OF THESE
FACTORS AND GIVE YOU A LITTLE
MORE DETAIL.
TO ESTIMATE THE NUMBER OF
ENROLLEES ELIGIBLE FOR COVERAGE
WE STARTED WITH THE TOTAL NUMBER
OF ENROLLEES WITH OBESITY OR
THAT FELL IN THE OVERWEIGHT
CATEGORY AND HAD CO-MORBIDITIES,
AND WE PUT THAT I THINK ALMOST
ABOUT 30 MILLION ENROLLEES, USED
SURVEY DATA WHICH WE WERE ABLE
TO IDENTIFY PEOPLE IN MEDICARE,
PEOPLE ENROLLED IN MEDICARE,
WITH SELF-REPORTED BMI AND
MEDICAL CONDITIONS.
FROM THAT, WE SUBTRACTED THE
NUMBER OF PEOPLE WITH DIABETES,
BECAUSE THOSE PEOPLE WOULDN'T BE
NEWLY ELIGIBLE UNDER THE POLICY,
THEY ARE ALREADY ELIGIBLE.
AND WE HAVE TO THINK, DEDUCTED
NUMBER OF PEOPLE WITH
CARDIOVASCULAR INDICATIONS, AND
HAD TO THINK ABOUT NOT ONLY
WHAT'S HAPPENING RIGHT NOW BUT
ALSO WE HAD TO HAVE INDICATIONS
TO BE COVERED IN THE NEXT TEN
YEARS, LOOKED AT ONGOING
CLINICAL TRIALS AND, YOU KNOW,
WE SAID IN THE NEXT TEN YEARS
THERE'S PROBABILITY NEW
INDICATION MIGHT BE COVERED, SO
THAT REDUCES THE NUMBER OF
PEOPLE NEWLY ELIGIBLE TO RECEIVE
MEDICARE COVERAGE, THESE
MEDICATIONS FOR WEIGHT LOSS
ONLY.
SO I THINK JUST TO GIVE A SENSE
IN 2025, ABOUT 30% OF PEOPLE
EITHER WITH OBESITY OR
OVERWEIGHT AND CO-MORBIDITIES
CAN GET ACCESS TO MEDICATIONS
BECAUSE THEY ALSO HAVE DIABETES
OR CARDIOVASCULAR INDICATIONS.
BY THE END OF THE BUDGET WINDOW,
SO IN YEAR 10 OF THE POLICY, WE
SAID THAT 50% OF PEOPLE AMONG
THIS GROUP OF MEDICARE ENROLLEES
EITHER WITH OBESITY OR
OVERWEIGHT AND COMORBIDITIES
WOULD BE ELIGIBLE UNDER CURRENT
LAW.
WE ALSO HAD TO IS SPECIFY
TAKEUPS OF MEDICATIONS AMONG
PEOPLE NEWLY ELIGIBLE, AND WE
USED SOME RELATED DATA.
WE TALKED TO EXPERTS.
AND I THINK ANAND ALSO MENTIONED
THIS, WE CAME UP WITH AN
ESTIMATE THAT ABOUT 2% OF PEOPLE
NEWLY ELIGIBLE TO RECEIVE THESE
MEDICATIONS WOULD TAKE IT UP IN
THE FIRST YEAR OF THE POLICY, IN
2026, GROWING TO 14% BY THE END
OF THE BUDGET WINDOW.
AND THEN WITH DURATION OF
TREATMENT, AGAIN, WE USED SOME
AVAILABLE DATA, AND OVER TIME WE
SEE PEOPLE STAYING ON THE
MEDICATION FOR LONGER.
SO THAT'S USE.
IN TERMS OF PRICE, LIST
PRICES -- I THINK THIS IS STILL
TRUE, JUST OVER A THOUSAND
DOLLARS, FEDERAL GOVERNMENT PAID
LESS THAN THAT BECAUSE OF
REBATES; COST SHARING AND OTHER
FACTORS.
IN TERMS OF FUTURE PRICES ANAND
MENTIONED THERE WILL BE PRICE
NEGOTIATION STARTING IN 2017, WE
EXPECT THAT THERE WILL BE
SPILLOVERS AND THE PRICE WILL
ALSO GO DOWN AND GOING FORWARD
WE EXPECT GENERIC COMPETITIONS
WHICH WOULD DRIVE DOWN PRICES,
AND NEW PRODUCTS THAT COULD BE
MORE EFFICIENT AND EXISTING
PRODUCTS MIGHT HAVE HIGHER
PRICES, SO THERE'S SOME PUSH AND
PULL HERE, AND -- OKAY.
SO, IN TERMS OF OFFSETTING
BUDGETARY SAVINGS, CBO IS NOT
AWARE OF EMPIRICAL EVIDENCE THAT
DIRECTLY LINKS AOM USE TO
REDUCTION IN HEALTH CARE
SPENDING FROM IMPROVED HEALTH.
SO, WE INSTEAD LOOKED AT TWO
COMPARABLE TYPES OF RESEARCH.
THE FIRST CAME FROM
OBSERVATIONAL STUDIES THAT
LOOKED AT EFFECTS OF BARIATRIC
SURGERY ON HEALTHCARE SPENDING
AND SECOND ONE THAT ALREADY BEEN
MENTIONED IS MICROSIMULATION
STUDIES, WE LOOKED AT TWO.
LET ME START BY TELLING YOU
ABOUT THE OBSERVATIONAL STUDIES
ON BARIATRIC SURGERY.
EVIDENCE IS MIXED.
STUDIES SHOW THAT BARIATRIC
SURGERY INCREASES SPENDING OVER
TIME.
THERE'S SOME THAT SHOW NO
CHANGE, SOME THAT SHOW LOWER
SPENDING.
SO WE TOOK THOSE STUDIES.
WE MADE SOME ADJUSTMENTS BECAUSE
THOSE STUDIES AT LEAST SOME OF
THEM, MAYBE ALL OF THEM, WERE
BASED ON PRIVATE PAYERS, SO WE
HAD TO CONVERT PRICES TO
MEDICARE PRICES.
WE LOOKED AT THE STRENGTH OF THE
STUDY DESIGN, SO WE BASICALLY
GAVE EACH OF THE STUDIES THE
WEIGHT, AND STUDIES WITH BETTER
CONTROL, BETTER MATCHING BETWEEN
GROUPS THAT DID AND DID NOT
UNDERGO BARIATRIC SURGERY HAD
HIGHER WEIGHT, STUDIES THAT HAD
LOWER ATTRITION HAD HIGHER
WEIGHT, AND VICE VERSA.
AND FROM -- YOU KNOW, AFTER
MAKING THOSE ADJUSTMENTS WE CAME
UP WITH A STREAM OF NUMBERS
SHOWING IMPACT FROM IMPROVED
HEALTH, THE YEAR AFTER PEOPLE
HAD BARIATRIC SURGERY, YEAR ONE
THROUGH YOU'RE TEN AND TOOK INTO
ACCOUNT THE FACT THAT HAVING
BARIATRIC SURGERY IS DIFFERENT
FROM TAKING OR GETTING AN
INJECTION.
YOU DON'T HAVE ALL THE
COMPLICATIONS THAT YOU MIGHT
HAVE FROM BARIATRIC SURGERY, SO
WE KIND OF TRIED TO ZERO THAT
OUT.
SO THERE ISN'T AN INCREASE IN
SPENDING FOR EXAMPLE FROM
COMPLICATIONS.
SIMILARLY FOR MICROSIMULATION WE
LOOKED AT TWO MICROSIMULATION
STUDIES.
ONE FROM KAISER AND ONE FROM THE
UNIVERSITY OF SOUTHERN
CALIFORNIA.
AND THOSE STUDIES, WE AVERAGED
THEM.
WE AVERAGED THE RESULTS TOGETHER
AND AGAIN CAME UP WITH STREAM OF
SAVINGS FOR PEOPLE TAKING THE
MEDICATION FOR ONE YEAR, TWO
YEARS, THREE YEARS AND SO FORTH.
TEN YEARS.
AND WE COMBINED EVIDENCE FROM
MICROSIMULATION STUDIES AND
OBJECTSAL STUDIES AND EACH YEAR
FOR THE TEN-YEAR PERIOD I SHOWED
YOU IN THE TABLE EARLIER WE HAVE
BASICALLY IN YEAR ONE EVERYBODY
HAS TAKEN THE MEDICATION FROM
ONE YEAR OR LESS.
IN YEAR TWO, YOU HAVE PEOPLE
THAT HAVE EITHER JUST STARTED
TAKING THE MEDICATION OR HAVE
TAKEN IT FOR TWO YEARS.
AND SO FORTH.
SO, OBSERVED FOR ESTIMATED
SAVINGS TAKING INTO ACCOUNT THE
MIX OF PEOPLE SOME OF WHOM HAVE
TAKEN THE MEDICATION FOR A VERY
SHORT PERIOD OF TIME AND SOME
FOR A VERY LONG TIME.
SO MOVING ON TO WHAT NEW
RESEARCH WOULD BE ESPECIALLY
USEFUL, I DON'T THINK YOU'LL BE
SURPRISED BY ANY OF THIS.
I THINK I WAS ABLE TO SHOW YOU
AND EXPRESS THERE'S UNCERTAINTY
IN OUR ESTIMATES AND THERE'S NEW
INFORMATION COMING OUT DAILY.
I DON'T HAVE PubMed
NOTIFICATION BUT I DO HAVE A
NOTIFICATION FROM GOOGLE
SCHOLAR, YOU KNOW, EVERY DAY
THERE ARE A LOT OF NEW STUDIES
AND NEW INFORMATION COMING UP.
SO, I THINK THAT WE WOULD BE
ESPECIALLY INTERESTED IN MORE
INFORMATION ABOUT USE OF THESE
MEDICATIONS, TAKEUP RATE AND
PATIENT ADHERENCE, AND SAVINGS
FROM IMPROVED HEALTH BASED ON
DIRECT EVIDENCE WOULD BE
ESPECIALLY VALUABLE.
EXPECTATION OF PRICES OF NEW
OBESITY MEDICATIONS,
EXPECTATIONS WITH OTHER
CONDITIONS THESE MEDICATIONS
WILL BE APPROVED TO TREAT.
AND ALSO EFFECTS OF WEIGHT LOSS
ON MORTALITY.
AND THAT -- THOSE AREAS OF
RESEARCH CAN BE -- SPECIFIC
AREAS OF RESEARCH INCLUDE
SPECIFICALLY FOR THE HEALTH
SAVINGS, ASSOCIATED WITH HEALTH
IMPROVEMENT, NOT ONLY SHORT TERM
BUT ALSO LONG-TERM EFFECTS, WE
WOULD BE INTERESTED IN EFFECTS
BY ADHERENCE TIMES, EFFECTS FOR
DIFFERENT SUBGROUPS, SO
SUBGROUPS CAN INCLUDE INSURANCE
COVERAGE, INITIAL BMI, AND AGAIN
EFFECTS OF MORTALITY AND
DISABILITY WOULD BE HELPFUL AS
WOULD ANY INFORMATION ON HOW USE
OF ANTI-OBESITY MEDICATIONS
AFFECT EMPLOYMENT.
THERE'S TYPES OF STUDIES, I
THINK THIS HAS BEEN DISCUSSED
BUT RANDOMIZED CONTROLLED TRIALS
ESPECIALLY ONES WITH LONGER
FOLLOW-UP PERIODS WOULD BE
HELPFUL.
NATURAL EXPERIMENTS THAT USE
EXOGENOUS VARIATION IN AOM
COVERAGE, OUTCOMES WITH AND
WITHOUT THAT COVERAGE WOULD BE
HELPFUL, AND OBSERVATIONAL
STUDIES THAT COMPARE OUTCOMES
AMONG PEOPLE WHO DID AND DO NOT
TAKE THESE MEDICATIONS AND ARE
ABLE TO ADJUST FOR DIFFERENCES
BETWEEN GROUPS THAT COULD ALSO
HAVE EFFECTS ON HEALTH AND
HEALTH CARE SPENDING WOULD BE
USEFUL AS WELL.
SO THAT'S THE END OF MY
PRESENTATION.
THANK YOU.
I LOOK FOR WORD TO YOUR
QUESTIONS.
>> THANK YOU VERY MUCH.
APOLOGIES FOR GOING SLIGHTLY OUT
OF ORDER.
NEXT SPEANINGER -- SPEAKER IS
DAVID HINES, YEARS OF EXPERIENCE
ADVISING THE STATE OF TENNESSEE,
NASHVILLE PUBLIC SCHOOLS IN
NASHVILLE, LED THE ESTABLISHMENT
OF INTEGRATED HEALTH AND
WELLNESS FACILITIES, CURRENTLY
WORKING ON EXPANSION OF
VALUE-BASED CARE INCLUDING
BUNDLED PAYMENT PROGRAM FOR
MEDICAL AND SURGICAL WEIGHT
LOSS, WILL BE SHARING STATE AND
PRIVATE PAYER PERSPECTIVE ON
COVERAGE OF GLP-1 THERAPIES.
>> IF MR. HINES CAN PUSH THE
RIGHT BUTTONS HE WILL.
LET ME SHARE MY SCREEN.
YEAH, GET TO THE RIGHT PLACE.
>> YOU ARE NOT PRESENTING YET
BUT WE CAN SEE A PRESENTATION.
>> OH, IS IT IN SLIDE SHOW?
>> IT'S NOT IN THE SLIDE SHOW.
>> OKAY.
LET ME SWAP THESE.
I'M SORRY.
SOMEBODY ELSE IS MUCH BETTER AT
THIS THAN I AM.
>> YOU'RE GOOD AT MANY OTHER
THINGS THOUGH.
>> LET ME SEE.
>> NOW WE'RE SEEING THE WRONG
SCREENS.
GO TO DISPLAY SETTINGS AND
SWITCH.
PERFECT, GOOD TO GO.
>> GREAT.
FOLKS, IT'S GREAT TO BE WITH
YOU.
I DON'T KNOW HOW I GOT DRUG INTO
THIS, Y'ALL ARE A HECK OF A LOT
SMARTER THAN I AM.
I'VE BEEN IN THE WEEDS FOR
YEARS, TRYING TO GET THINGS TO
WORK, WHERE I TAKE CARE OF
PEOPLE I'M SUPPOSED TO TAKE CARE
OF.
METRO NASHVILLE SCHOOLS, I'VE
GOT 6500 ACTIVE TEACHERS I TAKE
CARE OF, 3,000-PLUS RETIREES, I
TAKE CARE OF 18,000 COVERED
LIVES.
IT'S A GOOD GROUP.
IT'S AN INTERESTING GROUP THAT I
HAVE.
I TAKE CARE OF TEACHERS.
I LOOK AT MY EMPLOYEE
POPULATION, I KNOW THAT
BASICALLY THEY ARE ALL COLLEGE
EDUCATED, MOST MASTER'S AND
BEYOND.
I KNOW THEY ALL LIVE AND WORK IN
NASHVILLE, TENNESSEE.
AND BASICALLY I KNOW I HAVE TO
HAVE A LONG-TERM VIEW OF WHAT
GOES ON WITH THIS POPULATION
BECAUSE WHAT I'VE LEARNED IS
I'VE LOOKED IN THE DATA OF THIS
GROUP, IF I HAVE A TEACHER FOR
ABOUT YEAR 4 OR 5, I'LL PROBABLY
HAVE THEM INTO RETIREMENT, UNTIL
THEY ARE NO LONGER WALKING THE
EARTH WITH US AT THIS POINT.
TO DO THAT AND UNDERSTAND WHAT'S
GOING ON WITH THE POPULATION, I
DO A LOT WITH ON-SITE MEDICAL,
SINCE 2009.
I WORK CLOSELY WITH UNIVERSITY
MEDICAL CENTER HERE, STAFF AND
MANAGE.
ALSO GIVE MEDICAL MANAGEMENT AND
HELPS ME UNDERSTAND WHAT GOES
INTO THE WORLDS OF MEDICINE, I
HAVE A MEDICAL DIRECTOR I WORK
WITH.
I HAVE A PRETTY ROBUST DATASET
THAT I DEAL WITH.
I RECEIVE ALL MY MEDICAL CLAIMS,
PHARMACY CLAIMS, BUT ON TOP OF
THAT WILL TAKE A PAYROLL
EXTRACT, DROP IT OUT THERE SO I
CAN SEE WHO THESE PEOPLE ARE,
SEE THE IMPACTS, WHAT WE DO ON
TIME AND ATTENDANCE, RETENTION.
I ALSO TAKE RACE AND ETHNICITY,
DROP IT OUT THERE SO I CAN TRY
TO UNDERSTAND WHAT'S HAPPENING
THERE.
ALSO I UNDERSTAND -- I KNOW
WHERE THEY WORK AND WHERE THEY
LIVE AND I KNOW WHERE THEY ARE
NOT IN AREAS OF HIGH NEED, LOW
NEED.
AND ON TOP OF THAT I PULL EMR
FEEDS FROM OUR MEDICAL CENTERS.
ALSO LABCORP AND QUEST TO
UNDERSTAND WHAT'S GOING ON WITH
THE POPULATION.
YOU DO A LOT OF WORK TO
RESEARCH, I UNDERSTAND THE DRUGS
DRUGS AND IMPACT, I'M TRYING TO
UNDERSTAND HOW IT IMPACTS MY
PEOPLE LOCALLY.
TO MAKE MODIFICATIONS AS I NEED.
I'M SUPPOSED TO BE TALKING ABOUT
PRIVATE PAYER PERSPECTIVE, THIS
IS A PRIVATE PAYER, PEOPLE TELL
ME I'M THE ODDTITY.
MOST PEOPLE DON'T HAVE THE DATA,
RESEARCH AND SUPPORT, I'VE TAKEN
A LOT OF APPROACHES
IN MY AREAS DEALING WITH PRETTY
NASTY STUFF WHEN IT COMES TO
HEALTHCARE COST IN THE LAST FEW
YEARS.
COMING OUT OF COVID HAS BEEN A
BIZARRE TIME.
IF YOU THINK ABOUT THE COST AND
IMPACTS OF HANDLING GLP-1s,
THE FRAMEWORK, WHAT ELSE WE'RE
DEALING WITH, YOU KNOW, WE HAD
DELAYED CARE, WE THINK SPIKED A
LOT OF COSTS FOR US.
ON TOP OF THAT, THERE'S
SOMETHING THAT'S HAPPENED, WITH
COVID, THAT MADE PRICES RISE.
AND BEYOND THAT AS WELL
PROVIDERS BASICALLY HAD TO
RE
RENEGOTIATE AND COME BACK MAKING
UP FOR LOSSES OUT OF COVID.
OUR MARKETPLACE HAS BEEN SEEING
EIGHT, NINE, TEN, ELEVEN PERCENT
INCREASES, PASSED ON TWO YEARS
OF PREMIUM INCREASES, HOPING I'M
FINALLY CLOSING THE GAPS.
THERE SEEMS TO BE A NEW FORM, A
LOT DRIVEN BY CATASTROPHIC
CLAIMS.
TYPICALLY WHAT WE'VE SEEN IN THE
MARKETPLACE IS THAT, YOU KNOW,
WE CONSIDER CATASTROPHIC CLAIM
THE COMBINED COST GOING OVER
$100,000.
REMOVING THAT MARK, IT'S GOING
TO BE TWO TO TWO-FIFTY, IDENTIFY
TRUE CATASTROPHIC CLAIM, JUST
THE VOLUME IS TOO HIGH WHEN WE
USE THE HUNDRED THOUSAND MARK TO
UNDERSTAND WHAT'S GOING ON.
SO IT'S BEEN A TOUGH FEW YEARS,
HOPEFULLY WE'LL HAVE SOME
SUNSHINE BUT BASICALLY THE
QUESTION THAT PEOPLE IN MY
POSITION, CAN WE AFFORD WHAT TO
ME LOOKS LIKE ANOTHER 3 TO 4%
INCREASE WHEN ALREADY DEALING
WITH AROUND A 10% INCREASE
WITHOUT GLP-1.
THE OTHER QUESTION COMES BACK
INTO THIS STING, TALKING ABOUT
OUR EXPERIENCE BECAUSE I DID
TRACK THIS GLP-1s, AND ONE
GROUPS THAT HAD TO PULL BACK
FROM IT, BECAUSE BASICALLY WE
INVESTED TODAY HOPING TO GET
THAT RETURN BUT THAT RETURN
COMES FARTHER DOWN FIELD THAT WE
CAN AFFORD TO HOLD OUT FOR.
A LOT OF FOLKS, IF WE OPEN AND
HAVE GLP-1 COVERAGE, TAKE CARE
OF AOMs AND WEIGHT LOSS ARE WE
GOING TO KEEP THESE PEOPLE WE
SPEND THE MONEY OR ARE WE FIXING
THEM UP TO GO ELSE THERE AND
LOSE THE RESOURCE WE INVESTED
HIGHLY IN.
SOME THINGS THAT CONCERN US, IS
THERE EVER AN END TO BEING ON
GLP-1s IN STUDIES AREN'T
SHOWING THAT BUT I WONDER ALSO
THESE STUDIES ARE THEY SHOWING
GLP-1s IN COMBINATION WITH
LIFESTYLE PROGRAMS AND COE
APPROACH, ARE WE LOOKING AT DRUG
FOR DRUG'S SAKE, OPEN THE DOOR,
LET PEOPLE GET ON THE DRUGS,
COMPARE THAT TO SEE IF THEY
BASICALLY WITHOUT OTHER
MODIFICATIONS, IS THERE SUCCESS,
LOOK AT MORE OF A CONTROLLED
PROGRAM TO WHERE, YOU KNOW, DO
WE UNDERSTAND IF GLP-1s
COMBINED WITH VERY ROBUST
LIFESTYLE PROGRAM WILL GET US
RESULTS WE NEED.
LONG-TERM SIDE EFFECTS NOT
KNOWN, WE REMEMBER WHEN PHEN-FEN
WAS ON THE MARKET, WE REMEMBER
THAT.
FOR THOSE THAT NEED IT, NOT
COSMETIC PURPOSES.
WE SAID WE'RE GOING TO PAY FOR
ANTI-OBESITY MEDICATION BACK IN
THE DAY, THE THOUGHT WAS THIS IS
COSMETIC, BEHAVIORAL ISSUE.
SCIENCE HAS CHANGED.
MORE INVOLVED AND MORE ENGAGED
AT THIS POINT BUT WE STILL WANT
TO MAKE SURE THAT THOSE THAT
TRULY NEED IT ARE GETTING IT,
AND WHEN I LOOK AT MY POPULATION
ANOTHER THING WE UNDERSTAND IS
WE GET INTO THE RACE AND
ETHNICITY, I LOOK AT MY
PROFILES, LARGE VARIATIONS BY
RACIAL LINES IN THE WORLD OF
OBESITY WHICH CONCERNS ME
BECAUSE WE NEED TO TAKE CARE OF
FOLKS, TAKE CARE OF FOLKS WELL.
I'LL LOOK AT MY POPULATION.
I KNOW THAT ABOUT HALF THAT
POPULATION LIVES IN AREAS OF
HIGH NEED.
I KNOW THAT ON TOP OF THAT, 30%
GREATER CHANCE YOU'RE A MINORITY
LIVING IN THAT AREA OF HIGH
NEED.
I WANT TO LOOK AT OBESITY IN MY
POPULATION, 37%, WHAT THAT HID
IS MY BLACK POPULATION, 55%,
WHITE AND OTHER POPULATION
RUNNING LOW 30s.
THERE'S A DISPARITY THERE THAT I
THINK WE NEED TO -- YOU TALK
ABOUT MEETING PEOPLE WHERE THEY
ARE, TRYING TO HELP OUT, IT'S A
REAL NEED, A REAL ISSUE.
ANOTHER FACT IN THE BLACK
POPULATION, CANCER, LIVING AND
WORK IN THE AREA OF HIGH NEED.
I HAVE TO UNDERSTAND SCHOOLS ARE
WHERE OUR STUDENTS ARE,
REGARDLESS OF WHAT'S GOING ON,
IN A VERY URBAN DISTRICT.
ALSO COMES THE ISSUE OF
ADHERENCE, WHAT CONCERNS US,
PAYING FOR A PRESCRIPTION OR TWO
OR THREE PRESCRIPTIONS, THEY
JUST FALL OFF OF IT.
AND DON'T GET ANYWHERE.
HOW CAN WE ENSURE THE RIGHT
FOLKS ARE ON IT AND STAY ON IT
AND NEED TO?
AND WHAT'S NEXT?
YOU KNOW, SOONER OR LATER WILL
BE THE GLP-1 PILL, THAT WILL
BASICALLY TAKE -- BRING A NEW
WAVE OF INTEREST FROM FOLKS THAT
DIDN'T WANT TO GIVE THEMSELVES A
SHOT.
ARE WE GOING TO SEE LOWER COST
WITH THE NEW ONES IN THE
PIPELINE, WILL WE SEE THINGS
BETTER THAN THAT?
ANOTHER THING WE DON'T
UNDERSTAND IS TRUE COST BECAUSE
REBATE DOLLARS FLOW BACK THROUGH
PBMs AND WE DON'T SEE WHAT
THAT REBATE IS PER DRUG.
WE JUST KNOW IN GENERAL OUR
REBATE AMOUNTS ON THE DIFFERENT
MEDICATIONS.
AND SO THE TRUE COSTS OF THESE
MEDICATIONS ARE HIDDEN FROM US
AND WE SHOULD BE ABLE TO SEE PER
DRUG, PER LINE, WHAT THE TRUE
COST IS.
BUT WITH ALL THOSE CONCERNS AND
EVERYTHING ELSE, THERE'S STILL
CHANGES GOING ON WITHIN THE
INDUSTRY.
AS YOU CAN SEE, THIS IS A STUDY
THAT CAME OUT RECENTLY TALKING
ABOUT EMPLOYER'S PARTICIPATION
IN GLP-1s, OPENING UP FOR
ANTI-OBESITY MEDICATION, SMALL
COMPANIES ARE NOT THERE.
ONLY 16%.
A THOUSAND TO FIVE THOUSAND
WORKERS, ALMOST 25%.
VERY LITTLE PENETRATION IN THE
MARKETPLACE BECAUSE A LOT OF
THINGS WE'RE HEARD, IT'S THE
COST, AND THE SCARES THE DICKENS
OUT OF SO MANY OF US.
SO MUCH HAS ALREADY BEEN
MENTIONED, EVEN THOSE OF US THAT
HAVE JUMPED ON THE BANDWAGON
HAVE HAD TO PULL BACK, MANY OF
US HAVE.
AS YOU CAN SEE ON THERE, FROM
KAISER PERMANENTE, MAKING SOME
CHANGES, BLUE CROSS, BLUE CROSS
OF MICHIGAN.
AND THEN SOME CHANGES EVEN WITH
REDUCTION IN COVERAGE ON THE FEP
PROGRAM.
PEOPLE HAVE PULLED BACK.
I DON'T THINK THE PUSH IS
ASTRONG AS -- AS STRONG TO OPEN
UP, AND COMPANIES INTO GLP-1s
ARE THE LARGER COMPANIES WHO
HAVE TO BASICALLY DO MORE TO TRY
TO BRING IN, YOU KNOW, BATTLE
FOR EMPLOYEES, THAT COMPETITION
THAT'S OUT THERE.
IT'S GOING TO BE MORE YOUR HIGH
TECH GROUPS, MORE OF THE RICHER
ORGANIZATIONS AND COMPANIES.
PUBLIC SECTORS WILL LAG BEHIND.
ON TOP OF WHAT WE HAVE GOING ON
WITHIN THE OVERALL COST, PUBLIC
SECTOR HAS TO WORRY ABOUT BEING
THE PUBLIC PERSPECTIVE --
PERCEPTION OF THINGS.
WHY ARE YOU PROVIDING THIS
MEDICATION WHEN I CAN'T AFFORD
TO HAVE IT AND I'M YOUR TAXPAYER
TYPE SITUATION.
SO A LITTLE BIT DIFFERENT
PERSPECTIVE THAT GOES ON.
IN MY OWN STATE, BEEN INDICATED
EARLIER, TENNESSEE BENEFIT OPEN
PLANS OPENED UP AND COVERED
AOMs IN 2017.
THEY APPLIED PRIOR AUTHORIZATION
REQUIREMENT TO IT, AS YOU CAN
SEE.
HAVE TO HAVE A CERTAIN BMI, ALSO
GET MEDICATION INITIALLY
PARTICIPATE IN A COMPREHENSIVE
WEIGHT MANAGEMENT PROGRAM FOR
SIX MONTHS, USE IT WITH REDUCED
CALORIE AND DIET AND EXERCISE.
THEN YOU HAVE TO LOSE A CERTAIN
PERCENTAGE OF BODY WEIGHT TO
CONTINUE THERAPY.
FOLKS THAT MANAGE THAT PLAN ARE
GOOD FRIENDS.
THEY STRUGGLE WITH THIS.
THEY TRY TO BASICALLY CONTROL
THE COST BUT ACTUALLY TAKE CARE
OF THE FOLKS THAT NEED IT.
AND I ADMIRE THEM FOR WHAT THEY
HAVE DONE.
BUT ONE OF THE CHANGES THAT HAS
COME ABOUT IS BASICALLY ON THEIR
CONSUMER-DRIVEN HEALTH PLAN,
REMOVED AOMs, NOW SUBJECT TO
DEDUCTIBLE.
COST-SAVING MOVE ON THEIR BEHALF
DUE TO COST OF THE DRUG.
BUT ONE OF THE THINGS THAT FOLKS
IN MY CHAIR THINK ABOUT IS
WHAT'S GOING TO HAPPEN ONE DAY
WHEN AOMs DO HIT THE
PREVENTIVE DRUG LIST THAT
APPLIES TO EVERYBODY.
AND WE'LL BE MANDATED TO CHANGE
AT THAT POINT, CAN WE BEAR THE
WEIGHT OF WHAT'S GOING ON,
SHOULD THAT HAPPEN, WHEN THAT
HAPPENS.
IT'S BEEN POINTED OUT THAT
TENNESSEE HAD LIMITED COVERAGE
FOR AOMs OR GLP-1s IN
MEDICAID POPULATION, KIND OF
INTERESTING.
THAT POPULATION, PROVIDE AOMs
FOR THOSE UNDERSTOOD 21, IF OVER
21 IT'S THE SAME BASIC ROUTINE.
DIABETICS AND THOSE WITH HEART
DISEASE.
THAT'S EVEN IN LIGHT OF 2022,
TENNESSEE ASSEMBLY HAD A CHRONIC
WEIGHT MANAGEMENT TASK FORCE
THAT RECOMMENDED ELIMINATION OF
THAT RESTRICTION, OPEN UP THE
GLP-1s TO ALL.
IT WAS RECOMMENDATION BUT
DEFINITELY WASN'T ACTED ON.
AS NOTED RECENTLY IN THE NEWS
THAT OUR TENNCARE SUBMITTED
BUDGET REQUEST FOR $118 MILLION
TO COVER THE COST OF GLP-1s
ALONE.
OUR STORY, I'VE GOT DATA, I LOVE
MY DATA AND KEEP IT WITH UP.
WE'VE BEEN WORKING IN THIS AREA
OF DIABETES.
THERE'S A LOT OF MONEY, ALL YOU
FOLKS KNOW, SPENT ON DIABETICS,
NOT NECESSARILY THE COST OF
DIABETES ALONE BUT TOTAL
HEALTHCARE SPEND WITH
COMORBIDITIES WITHIN THAT
POPULATION.
WHAT WE'VE NOTICED IN OUR
POPULATION, AND WORK WE'VE DONE,
OVER THE YEARS, WE'VE BEEN
KEEPING OVERALL TOTAL HEALTH
CARE FOR DIABETIC POPULATION
RELATIVELY FLAT.
LOOKING INTO DIABETIC SPENDS
SPECIFICALLY WHAT'S OF INTEREST
IS THIS ISSUE THE TOP PART IS
GLP-1 UTILIZATION, OF THAT
POPULATION, ORANGE, ALL OVER
PHARMACY, BLUE BAND IS MEDICAL.
THE LINE IS INCREASE IN
CONTINUOUS GLUCOSE MONITORING
UTILIZATION IN THE POPULATION.
WHAT WE'VE NOTICED IS AS THE
GLP-1 UTILIZATION HAS INCREASED
TO OFFSET THE MAJORITY OF THAT
INCREASE, WITH DECREASES IN
OTHER PHARMACY SPEND AND MEDICAL
SPEND OF THAT POPULATION.
LIKE I SAY, OVERALL WE'RE
KEEPING IT STEADY.
WHAT'S OF INTEREST, LOOKING
INSIDE THE NUMBERS, DIABETIC
POPULATION, LOOKED AT INSULIN
USE.
WE'VE SEEN REDUCTION IN VOLUME
OF INSULIN USE THAT COMES ABOUT
BY BASICALLY NUMBER OF UNITS AND
NUMBER OF PATIENTS SO WE'RE
SEEING A DOWNWARD TREND IN
DIABETICS, IN OUR POPULATION.
HOWEVER, THE OTHER THING TRYING
TO PUSH BACK THE OTHER DIRECTION
IS WE'RE SEEING INCREASED NUMBER
OF PEOPLE BEING DIAGNOSED WITH
DIABETES AND THEY ARE GOING FROM
GOING ALMOST DIRECTLY TO
GLP-1s NOW, SO THE LAG BETWEEN
DIAGNOSIS AND APPLICATION OF
GLP-1s HAS BEEN REDUCED.
I MENTIONED WE WERE THE ONES
THAT TRIED THIS AND HAD TO STOP.
I'VE BEEN WORKING WITH THE
MEDICAL CENTER FOR YEARS DOING
DIFFERENT VALUE-BASED BUNDLES,
STARTING WITH MATERNITY.
WE'VE MOVED INTO ONCOLOGY
PATHWAYS AT THIS POINT.
A FEW YEARS AGO WE STARTED WITH
OUR FIRST WEIGHT LOSS BUNDLE, A
BARIATRIC SURGERY, AS LONG AS
YOU WENTZ TO A CENTER OF
EXCELLENCE, ALL SERVICES AT NO
CHARGE, SO GIVING AWAY BARIATRIC
SURGERY.
I TOLD THE FOLKS THAT RAN THAT
PROGRAM IF I'M GOING TO CUT
SOMEBODY TO LOSE WEIGHT I'LL PAY
THEM TO TAKE A PILL OR SHOT AS
WELL.
I WAS LOOKING AT GLP-1s AND
POTENTIAL OUTCOMES THAT WOULD
COME, WE DID WHAT YOU FOLKS
TALKED ABOUT, LOOKED AT RESULTS
THAT CAME AROUND ON THE
BARIATRIC SURGERY, AND RETURN ON
INVESTMENT THAT COULD COME FROM
THE WEIGHT LOSS AND PERCENTAGE
OF WEIGHT LOSS, USED THAT AS
VALIDATION OF THE POTENTIAL
COST, SAVINGS OF THAT PROGRAM.
WE LAUNCH THE MEDICAL WEIGHT
LOSS SURGERY.
I KEPT ANTI-OBESITY SURGERY
COVERED, OPENED ON THE MEDICAL
SIDE AS PART OF THE PROGRAM, RAN
IT THROUGH OUR OWN CLIENT
SPECIFIC NETWORK.
RESULTS WERE GREAT.
PEOPLE WERE LOSING WEIGHT, BLOOD
PRESSURE DROPPED, GLUCOSE
DROPPED, A1c DROPPED, LDL
DROPPED, GOOD RESULTS.
AS WE LAUNCHED THE PROGRAM
INITIALLY, WE HAD BASICALLY
LIMITATIONS IN THE MARKETPLACE
ON GETTING THE GLP-1 -- THE
MARKET WAS TIGHT.
SUPPLY WAS NOT MEETING DEMAND.
IT PUT ITS OWN TYPE OF CAP ON
UTILIZATION, AS THE MARKET GOT
BETTER AND FLOW OF GLP-1s GOT
STRONGER VOLUME INCREASED.
AT THE ENDS OF THE DAY, HALF A
MILLION A MONTH, AT THE ENDS OF
THE DAY, ON THAT PROGRAM.
THE OTHER GROUP ON THAT PROGRAM
BUNDLE WAS THE MEDICAL CENTER
ITSELF FOR THEIR EMPLOYEES.
I HAD BASICALLY SET UP THIS
FIRST INITIAL CAP THAT CAME BY
UTILIZATIONI ACTUALLY CONTROLLED
THE SPIGOT, I COULD CONTROL THE
COST BUT THEY DID NOT.
THEY ENDED UP BASICALLY
INVESTING A LOT MORE IN THE
BUNDLE THAN I DID TYPE
SITUATION, AND CAME TO THE POINT
FINANCIALLY THEY BASICALLY COULD
NOT AFFORD TO DO IT ANYMORE.
SO THEY DECIDED TO SHUT DOWN THE
PROGRAM, BASICALLY IF THEY ARE
NOT GOING TO DO IT FOR
THEMSELVES ARE NOT GOING TO DO
IT FOR ANYONE ELSE.
AND I ARGUED WITH THEM, FUSSED A
LITTLE BIT, REALITY I KNEW I
COULDN'T AFFORD IT EITHER.
BUT IT'S WHAT I'VE DONE AT THIS
POINT, RAN THIS PROGRAM FOR TWO
YEARS, 18 MONTHS IN DURATION.
WE HAD 80% RETENTION AT THAT
18-MONTH PERIOD.
WE STILL HAVE PEOPLE IN THE
PROGRAM BECAUSE IT TWILIGHTED IN
DECEMBER, SO WE FRONT-LOADED
PAYMENT ON THE PROGRAM SO
ANYBODY THAT MADE IT IN DISEASE
HAD THE OF -- IN DECEMBER HAD
THE FULL 18 MONTHS OF COVERAGE,
FIRST WAS WORKING YOURSELF UP,
LATTER PART WAS HOW DO YOU
REDUCE YOUR DEPENDENCY ON IT.
AND WE HAD GOOD RESULTS,
OVERALL, IN THE APPLICATION.
22.5, WHAT'S GOING ON, NOT
GETTING ROI QUICK ENOUGH HAD TO
TERMINATE.
POST-PROGRAM THOSE THAT
GRADUATED OUT 60 OF PATIENTS
HELD WEIGHT STABLE, 24% AVERAGE
WEIGHT LOSS RAN 23 POUNDS
OVERALL WEIGHT FOR THE
POPULATION INCREASED BY 2.8 SO
WE'VE SEEN SUSTAINING EVEN
WITHOUT GLP-1s IN THE PROGRAM
AND WE'VE SEEN EVEN BETTER
IMPROVEMENTS FOR THE DIABETIC
GROUP.
GOOD PARTICIPATION.
ANOTHER THING OF NOTE THAT WE
FOUND WE RAN A GOOD HEALTH
PROGRAM, BASICALLY
GASTROINTESTINAL HEALTH PROGRAM,
HIGH OVERLAP OF THOSE WITHIN THE
MEDICAL WEIGHT LOSS PROGRAM AND
G.I. PROGRAM WHICH HELPED US A
LOT WITH OUR RETENTION NUMBERS
PROBABLY.
SO, WHAT ARE THE KEY KNOWLEDGE
GAPS THAT NEED TO BE ADDRESSED?
COVERAGE ACCESS TO GLP-1
THERAPY, YOU KNOW, WE BELIEVE IN
THE VALUE OF GLP-1s, YOU CAN'T
DENY IT, YOU SEE THE RESULTS,
PEOPLE LOSING WEIGHT AND THINGS
IMPROVE.
WHEN IT COMES TO OBESITY,
THERE'S NOT MANY OF US BASICALLY
ARGUING OBESITY IS NOT A
DISEASE.
WE BELIEVE IT IS A DISEASE AND
SHOULD BE TREATED AS SUCH AND
JUST IRRITATES THE HELL OUT OF
ME, I'VE GOT A DISEASE AND A
RELATIVE CURE BUT I CAN'T AFFORD
TO APPLY IT.
WE'VE RUN INTO DILEMMAS
SOMETIMES, A LOT OF TIMES AN
AREA OF FERTILITY AND FERTILITY
BENEFITS.
PRECURSOR TO THIS TYPE OF
SITUATION.
THE FACT IF YOU LOOK AT STANDARD
FERTILITY COVERAGE, PAY TO
DIAGNOSE, TO FIND OUT WHY THEY
CAN'T HAVE A BABY BUT DON'T PAY
TO CREATE IT.
A FEW OF US STEPPED OUT MORE AND
MORE TO ADD FERTILITY COVERAGE,
TO HELP PEOPLE HAVE A
FAMILY-TYPE SITUATION.
THOSE THAT HAVE NOT DONE THAT,
IT'S BEEN THE SAME THING, COST
ISSUES.
SOME DO STRUGGLE TO UNDERSTAND
SOME PEOPLE CAN'T SUCCEED
WITHOUT MEDICAL AND SURGICAL
INTERVENTIONS.
ONE OF THE THINGS WE NOTICE IS
WHAT HAPPENS ON THAT BMI CHART,
YOU CAN BASICALLY NEED TO
UPDATE, MORE AGGRESSIVE TYPE
SITUATION.
USED TO BE EVERYBODY THOUGHT IT
WAS BEHAVIORAL.
LIKE I SAID, WITH THE NEW
KNOWLEDGE, THERE'S MORE AND MORE
ACCEPTANCE IT GOES BEYOND.
BASICALLY WE NEED LOWER PRICES
AND INTEGRATED WEIGHT LOSS
PROGRAM.
I DON'T WANT TO OPEN UP THROUGH
MY PHARMACY BENEFIT WITHOUT IT
BEING ATTACHED TO SOMETHING.
WE WANT TO HELP PEOPLE SUCCEED,
NOT JUST TAKE A MEDICINE AND
WHEN IT DOESN'T WORK OR THEY
HAVE ISSUES, STOP TAKING
MEDICINE.
EVERYTHING SHOULD BE TIED
TOGETHER WITH HOW YOU CAN MODIFY
YOUR LIFESTYLE AND BASICALLY
HAVE THESE DRUGS TO HELP YOU.
AND BASICALLY NEED MEANS TO
ENHANCE ADHERENCE, BETTER
SCREENING, SHORTER TIMELINE FROM
INVESTMENT TO RETURN.
ANOTHER ONE OF THE HATS I WEAR
HEAD UP THE TENNESSEE COALITION,
BASE COALITION OF HEALTH, HEALTH
CARE TENNESSEE, PART OF THE
NATIONAL ALLIANCE OF PURCHASER
COALITIONS, ALL THESE COALITIONS
FROM THE MIDWEST TO HOUSTON, TO
ST. LOUIS, ET CETERA, BASICALLY
ARE PART OF THIS LARGER
COALITION ACTIVITY THAT WE HAVE.
COALITION CAME OUT WITH
BASICALLY A POSITION STATEMENT,
WHEN IT CAME TO OBESITY AND
WEIGHT LOSS, WHICH WAS WORTHY.
BASICALLY POINTS OUT OR
ACKNOWLEDGES THAT OBESITY IS
COMPLEX, MULTI-FACETED,
AFFECTING MORE THAN 40% OF THE
POPULATION.
ALL THESE DISEASES, RECOGNIZING
MOST EMPLOYERS AND MOST ARE
COMMITTED TO A WHOLE PERSON
HEALTH APPROACH FOR EMPLOYEES
AND THEIR FAMILIES, INCLUDES
OPTIMIZATION OF HEALTHCARE
RESOURCES, ACKNOWLEDGE URGENCY
AND LONG-HELD STIGMAS AND BIASES
ASSOCIATED WITH IT.
AND THAT WE SHOULD CONSIDER THE
FULL SPECTRUM.
WE'D LOVE TO CONSIDER THE FULL
SPECTRUM FROM LIFESTYLE TO OTHER
OBESITY MANAGEMENT STRATEGIES TO
GLP-1s TYPE SITUATION.
WE DO KNOW THAT TRADITIONAL
APPROACHES HAVE FALLEN SHORT.
AND THESE -- BASICALLY WHAT WE
BELIEVE IS THIS ENGAGING THROUGH
OBESITY SCIENCE, I'M GLAD YOU
FOLKS ARE PUSHING THAT FORWARD,
BUT WE ALSO HAVE TO DESIGN FOR
AFFORDABLE, EQUITABLE,
SUSTAINABLE IMPACT.
WE'VE GOT TO AFFORD THE ANSWER,
AFFORD THE CURE.
WE BELIEVE IN PERSONALIZED
SHARED DECISION-MAKING AND
RESPONSIBILITY.
YOU CAN'T JUST -- IT'S NOT ONE
SIZE FITS ALL.
WE WATCHED OBESITY PROGRAMS IN
OUR ORGANIZATION, THROUGH THE
NET-WIDE UNDERSTANDING ONE THING
A PERSON MIGHT REACT TO ONE
PROGRAM, ANOTHER PERSON WON'T,
BUT THEY WILL REACT TO SOMETHING
ELSE.
OVERALL WE HAVE TO BE BETTER
INTO INTEGRATING CARE INTO THIS
CULTURE OF HEALTH AND
WELL-BEING, BASICALLY IT WILL
HELP US ALL WITH BOTTOM LINE AND
PRODUCTIVITY.
THAT IS IT.
THANK YOU FOLKS.
>> GREAT.
THANK YOU SO MUCH.
I ASK FOR ALL THE SPEAKERS TO
COME ON THE CAMERA.
WE HAVE SEVERAL QUESTIONS IN THE
CHAT.
I'VE DIVIDED THEM INTO THREE
CATEGORIES.
ONE AROUND LONG-TERM COST
EFFECTIVENESS, NEXT AROUND COST
AND PRICE NEGOTIATION, THIRD AND
DEMANDS.
I'LL START WITH COST
EFFECTIVENESS.
THERE'S A QUESTION IN THE CHAT
FROM BYRON REGARDING HOW COST OF
THESE MEDICATIONS MAY BE OFFSET
WITH REDUCTIONS TO COMORBIDITIES
IN THE LONG RUN, MANY QUESTIONS
ALONG THESE LINES.
ANAND, YOU MENTIONED WORKING
WITH MICROSIMULATION MODELS, AND
RESEARCHERS, WHAT IS THE SCOPE
THAT SHOULD BE CONSIDERED IN
TERMS OF THE TIME HORIZON MODEL
AND COMORBIDITIES CONSIDERED IN
TERMS OF OBESITY-RELATED HEALTH
IMPROVEMENTS, BEST PRACTICE
RECOMMENDATIONS, CONSIDERING A
LIFETIME HORIZON, WHAT'S
REALISTIC FOR PAYERS?
>> THANKS FOR THAT QUESTION.
I'M NOT SURE IF THERE'S A
ONE-SIZE-FITS-ALL RESPONSE FOR
THAT.
AND SOME -- DAVID SHOULD COMMENT
ON THE PRIVATE SECTOR SIDE WHERE
THERE'S PROBABLY MORE PRESSURE
TO REALIZE SAVINGS IN A SHORTER
TIME FRAME, MEDICAID IS
CHALLENGING BECAUSE OF THE
CHURN.
I THINK FOR MEDICARE, SINCE A
LOT OF PAYERS FOLLOW MEDICARE,
GIVEN THE SITUATION THAT WE'RE
IN RIGHT NOW NOELIA SHOULD WEIGH
IN, GIVEN CMS DOESN'T TAKE
ACTION, CONGRESS IS GOING TO
LOOK AT CBO, CBO LOOKS AT
TEN-YEAR SCORING WINDOW,
SOMETIMES BEYOND THAT BUT
USUALLY TEN-YEAR SCORING WINDOW.
CERTAINLY FOR MICROSIMULATION
PROVIDING MORE DATA TO CBO, OF
WHAT ARE POTENTIAL HEALTHCARE
COSTS, OFFSETS OR BENEFITS
WITHIN TEN YEARS WOULD BE VERY
HELPFUL TO CBO STAFF AND SO
MINIMUM THAT IS IMPORTANT.
BUT, BOY, I THINK OTHERWISE ON
THE PRIVATE SECTOR SIDE, YOU
KNOW, I DON'T THINK PEOPLE HAVE
TEN YEARS TO WAIT, RIGHT?
AND YOU HAVE MAYBE A YEAR OR
TWO, THREE, OTHERWISE, YOU KNOW,
IF COSTS ARE REALLY HIGH,
THERE'S NOT A LOT OF -- YOU
KNOW, THERE'S NOT A LOT OF
CUSHION THERE, AND THAT'S WHY I
THINK, AGAIN, STARTING WITH
THOSE HIGH RISK POPULATIONS,
SUBPOPULATIONS WITHIN OBESITY,
YOU CAN DEMONSTRATE WITHIN A FEW
MONTHS AND WITHIN A YEAR SO THAT
YOU'RE PREVENTING EXPENSIVE
HEALTHCARE UTILIZATION AND
EMERGENCY ROOM VISITS AND
INPATIENT HOSPITALIZATIONS AND
YOU CAN DEMONSTRATE THAT ROI.
YOU WON'T DEMONSTRATE ON AVERAGE
INDIVIDUAL WITH OBESITY BUT
THOSE -- YOU KNOW, WITH
COMORBIDITIES AND HIGHER RISK,
SO AGAIN REAL WORLD EVIDENCE TO
IDENTIFY THAT SUBPOPULATION
WOULD BE MOST HELPFUL FOR THOSE
WHO DON'TS HAVE TEN YEARS TO
WAIT FOR THE RETURN ON
INVESTMENT.
SO I THINK DAVID AND NOELIA WILL
HAVE SOME THOUGHTS.
>> TOTALLY AGREE.
IN MY WORLD, WE'RE LOOKING FOR
RETURN IN THE FIRST YEAR.
I HEAR FEEDBACK, AM I COMING
THROUGH?
>> I'M ALSO HEARING FEEDBACK BUT
YOU'RE COMING THROUGH.
>> MY WORLD, WE LOOK AT PUTTING
IN PROGRAMS, EVERYBODY IS
SELLING US SOLUTIONS NOWADAYS.
WITH THIS PUSH, WHAT WE WANT TO
SEE AT LEAST INITIALLY, SOME
REDUCTION IN THE PHARMACY SPEND
IS AN EARLY INDICATOR OF WHAT'S
GOING ON, ARE WE MAKING GAINS.
THEN MORE ON THE MEDICAL SIDE OF
THE EQUATION.
WE WANT TO SEE SOME SUCCESSES
WITHIN YEAR ONE.
YEAR TWO, BETTER START SEEING
THAT KIND OF SOLIDIFY.
YEAR THREE WE SHOULD BE GOLDEN
AT THAT POINT.
>> NOELIA?
>> SEEMS LIKE WE CANNOT HEAR
YOU.
>> I'M HEARING FEEDBACK, THE
SAME STATEMENT OVER AND OVER
AGAIN.
CAN YOU TRY SPEAKING AGAIN?
I'M NOT ABLE TO HEAR YOU.
WHY DON'T WE TAKE A MINUTE AND
MAYBE YOU CAN CALL INTO THE
PHONE NUMBER, OR OTHERWISE
TROUBLESHOOT.
I'M GOING TO CONTINUE WITH
QUESTIONING, WHICH IS COMING
FROM PATRICK IN THE CHAT WHO
ASKED HOW CAN WE RECONCILE THE
UP-FRONT COST OF GLP-1 USE WITH
LONG-TERM COST SAVINGS?
FOR EXAMPLE WILL COMMERCIAL
PAYERS BEAR THE BRUNT WHILE CMS
REALIZES COST/BENEFITS AS
PATIENTS AGE CAN OBESITY-RELATED
EXPENSES?
MAYBE, DAVID, YOU CAN START WITH
THAT ONE.
>> COULD YOU REPEAT THE
QUESTION?
I'M SORRY.
>> THE QUESTION IS HOW CAN WE
RECONCILE THE UPFRONT COST OF
GLP-1 USE WITH LONG-TERM COST
SAVINGS, WILL COMMERCIAL PAYERS
BEAR THE BRUNT OF THE COST WHILE
CMS REALIZES COST-BENEFIT AS
PATIENTS AGE WITH
OBESITY-RELATED EXPENSES?
>> YEAH, WE'RE ALWAYS WORRIED
ABOUT COST SHIFTING THAT GOES ON
IN THE POPULATION, WHETHER
THROUGH MEDICARE OR MEDICATION
POPULATION.
BASICALLY THEY HAVE MORE POWER
TO NEGOTIATE SAVINGS FOR ONE
THING, BASICALLY FOR EVERYBODY
LOOKS TO PROFIT IT COMES OFF THE
COMMERCIAL SIDE OF THE EQUATION,
WHAT I END UP GETTING CHARGED AT
THE END OF THE DAY.
BUT, YEAH I THINK THERE'S A VERY
GOOD POINT EVEN IN THAT TIME LAG
SITUATION, A LOT OF THINGS
ESPECIALLY IN THE CARDIOVASCULAR
DISEASE AREAS, COMORBIDITIES
COME ON, IT'S GOING TO HAPPEN IN
LATER AGES.
I'VE BEEN PAYING ALONG TO HELP
THEM BUT LOSE CONTROL, BASICALLY
LOSE THE BENEFIT AT THE END.
GOOD POINT.
>> PLEASE WEIGH IN.
>> I'LL ADD I THINK IT IS AN
INTERESTING POINT, THIS WAS ALSO
IN THAT REPORT THAT THE HIGHER
THE COMMERCIAL UPTAKE OF THIS,
YOU KNOW, THEORETICALLY THE
HEALTHIER THE POPULATION SHOULD
BE AS THEY AGE INTO MEDICARE AND
IT SHOULD BENEFIT THE MEDICARE
PROGRAM AS WELL.
AND SO SHOULD THERE BE
INCENTIVES, IT SHOULD HELP WITH
THE MEDICARE POPULATION, OR THE
PROGRAM, IN TERMS OF SOLVENCY.
>> CAN YOU HEAR ME NOW?
>> YES, WE CAN HEAR YOU!
>> OKAY.
>> WEIGH IN ON EITHER OF THE
EARLIER QUESTIONS, JUST THINKING
ABOUT THE COST EFFECTIVENESS IN
THE LONGER RUN.
>> SURE.
I THE CONGRESSIONAL BUDGET
OFFICE IS A HEAVY USER OF
MICROSIMULATION MODELS, LUCKY
RESEARCHERS RUNNING MODELS ARE
ENGAGED WITH US AND ANSWER MANY,
MANY QUESTIONS FROM US.
SO, YOU KNOW, AGAIN, THE BENEFIT
OF THOSE MODELS IS THAT THEY CAN
LOOK BEYOND LIKE ONE OR TWO
YEARS, THEY CAN LOOK, YOU KNOW,
WELL INTO THE FUTURE.
AS OPPOSED TO SOME OF THE
RANDOMIZED CONTROLLED TRIALS,
THEY INCLUDE EFFECT OF WEIGHT
LOSS NOT JUST ON CARDIOVASCULAR
CONDITIONS BUT, YOU KNOW, A
WHOLE SET OF MEDICAL CONDITIONS,
SO BECAUSE OF THAT THE EFFECT
FROM IMPROVED HEALTH ARE
BROADER.
THEY ARE ABLE TO SAY, YOU KNOW,
ON AVERAGE THESE ARE THE HEALTH
CARE SPENDINGS, THE CHANGE IN
HEALTH CARE SPENDING FOR THE
AVERAGE USER BUT THEY ALSO HAVE
ABILITY OF SAYING, WELL, WHAT IF
ALL THESE PEOPLE MORBIDLY OBESE
TAKE THESE MEDICATIONS WHAT IS
THE OFFSET THERE?
YOU KNOW, THEY CAN ALSO LOOK,
YOU KNOW, WHAT IF LIKE EVERYBODY
WHO IS LIKE JUST ABOVE 30, BMI
OF 30, TAKE THE MEDICATIONS, YOU
MIGHT SEE DIFFERENT EFFECTS SO
WE'RE ENGAGING IN THAT, WITH
THAT RESEARCH ALL THE TIME.
>> I WANT TO ASK A SPECIFIC
QUESTION.
YOU MENTIONED YOU CONSIDERED
PRODUCTIVITY IMPROVEMENTS AS
PART OF YOUR COST ESTIMATES, IS
THAT RIGHT?
>> NOT QUITE.
>> OKAY.
>> SO THE COST ESTIMATES HAVE
LIKE VERY SPECIFIC GUIDELINES,
AND THEY NORMALLY DON'T INCLUDE
PRODUCTIVITY IMPROVEMENTS.
HOWEVER, YOU KNOW, WE DO PROVIDE
THE CONGRESS WITH SUPPLEMENTAL
INFORMATION.
SO, YOU KNOW, IF THERE WAS
EVIDENCE THAT, YOU KNOW,
PRODUCTIVITY WOULD IMPROVE, LIKE
THAT'S SOMETHING WE WOULD WANT
THE CONGRESS TO KNOW SO THAT
THEY HAVE A FULLER SET OF
OUTCOMES AND INFORMATION AS THEY
CONSIDER LEGISLATION.
IT'S NOT JUST, YOU KNOW, THESE
MEDICATIONS ARE SUPER EXPENSIVE
AND, YOU KNOW, SO THEY CAN LOOK
AT THE BROADER EFFECT OF THE
ECONOMY.
>> GREAT.
THANK YOU.
IN THE INTEREST OF TIME I WANT
TO MOVE TO TALKING ABOUT COST
AND PRICE NEGOTIATION.
SO IN THE CHAT JAMIE MOORE ASKS
CAN YOU DESCRIBE IN MORE DETAIL
WHAT MEDICARE PRICE NEGOTIATIONS
FOR SEMAGLUTIDE MIGHT LOOK LIKE
AND DO THESE NEGOTIATED PRICES
TICKLE DOWN TO THE OTHER FEDERAL
PROGRAMS YOU SPOKE ABOUT?
>> I CAN START.
I THINK THE SHORT ANSWER IS WE
DON'T KNOW, JUST BECAUSE THIS
PROGRAM IS SO NEW.
LAST YEAR WAS THE FIRST YEAR
WHERE TEN DRUGS WERE NEGOTIATED
BY MEDICARE, AND THAT ACTUALLY
WON'T GO INTO EFFECT UNTIL 2026.
SO WE DON'T QUITE KNOW WHAT THE
ULTIMATE EFFECT WILL BE, WILL IT
BE 10%, 20%, 30% REDUCTION?
THESE ARE ALSO REDUCTIONS IN
LIST PRICES, AS WELL, WHICH ARE
OFTEN DIFFERENT FROM SOME SORT
OF NET PRICES.
SO, TO WHAT EXTENT, AND HOW
MUCH, AND HOW QUICKLY, CERTAINLY
WON'T HAPPEN UNTIL 2027 SO WE
STILL HAVE A COUPLE OF YEARS.
IT'S HARD TO SAY.
NOW, AT THE SAME TIME ALL THIS
IS GOING ON, THERE'S MARKET
COMPETITION ONGOING.
SO THERE'S A PIPELINE OF DRUGS
THAT COULD COME OUT NEXT COUPLE
YEARS AND BECOME FDA APPROVED.
HOW MIGHT THAT THEN REDUCE
PRICES AS WELL?
THERE WE DON'T KNOW BECAUSE A
LOT OF THESE DRUGS EVEN THEY ARE
SIMILAR MAY DIFFER IN TERMS OF
THE CLINICAL BENEFIT AND HOW
E
EFFECTIVE THEY ARE, SIDE
EFFECTS, WHETHER YOU CAN TAKE
ORALLY, NOT THROUGH SUBCU.
SO THERE ARE A NUMBER OF FACTORS
THAT WILL TERM WHETHER THAT
MARKET COMPETITION, HOW MUCH IT
WILL REDUCE THE PRICE AND HOW
QUICKLY, AND THERE'S THE
NEGOTIATION SIDE AS WAS ASKED IN
THE QUESTION.
SO, I'M NOT SURE EXACTLY WHAT WE
KNOW.
WE DO KNOW THAT CURRENTLY NET
PRICES FOR GLP-1s ARE IN THE
EIGHT TO NINE THOUSAND DOLLAR
RANGE.
OTHER COUNTRIES ARE ALWAYS CITED
AS A BENCHMARK, OTHER COUNTRIES
PARTICULARLY IN EUROPE, THESE
SAME DRUGS ARE A THOUSAND
DOLLARS OR TWO THOUSAND DOLLARS,
SO THE DELTA IS PRETTY BIG
THERE.
HOW MUCH WE'LL BE ABLE TO GET
THERE, HOW QUICKLY WE GET THERE
I JUST DON'T THINK WE KNOW THE
ANSWER TO THAT.
BUT, DAVID AND NOELIA MAY HAVE
THOUGHTS.
>> I'LL JUST SAY IN OUR 2024
REPORT, WE DO SHOW SIGNIFICANT
REDUCTION IN ANNUAL NET FEDERAL
COSTS IN MEDICARE.
BUT EVEN, YOU KNOW, WITH THOSE
PRICES RELATIVE, YOU KNOW, THE
PRICES ARE STILL PRETTY HIGH,
AND YOU HAVE A LOT OF PEOPLE
TAKING THE MEDICATIONS SO
RELATIVE TO MULTIPLYING TWO
NUMBERS, STILL A REALLY BIG
NUMBER.
SO I THINK THERE WAS A QUESTION
IN THE Q&A ABOUT HOW LOW THESE
MEDICATIONS -- HOW LOW WOULD
NOTE PRICE -- NET PRICE HAVE TO
BE TO COMPLETELY OFFSET EACH
OTHER OR HAVE, YOU KNOW, EVEN
SAVINGS.
I THINK WE HAVEN'T DONE THAT
CALCULATION.
WE COULD, BUT THEY WOULD HAVE TO
BE MUCH, MUCH LOWER.
>> YEAH, I WILL SAY THERE ARE
THREE QUESTIONS IN THE CHAT
RELATED ABOUT HOW LOW THE PRICE
HAS TO BE, ONE THOUSAND DOLLARS
A MONTH DOES NOT SEEM
SUSTAINABLE, ALSO ARE THERE NOT
POLICIES TO ADDRESS WHAT
COMPANIES ARE ALLOWED TO CHARGE,
WE COULD FIND ANSWERS IN THE
WHITE PAPER THAT CAME OUT IN
APRIL, ICER STANDS FOR THE
INSTITUTE FOR CLINICAL AND
ECONOMIC REVIEW, HOW DO YOU
DETERMINE THE ICER PAPER AFTER
YOU LOOKED AT IT?
>> I CAN START, ONE OF THE
SLIDES SUMMARIZED SOME OF THE
KEY OPTIONS THERE.
AGAIN, I DON'T THINK THERE'S ANY
MAGIC BULLET BUT I DO THINK SORT
OF PICTURING THAT SLIDE NOW BUT
I THINK IT'S THE COMBINATION,
AGAIN, OF IDENTIFYING
SUBPOPULATIONS THROUGH REAL
WORLD EVIDENCE AND WHILE WE'RE
IN THIS SORT OF MURKY TIME,
ALONG WITH AGGRESSIVE PRICE
NEGOTIATION, I THINK IT'S THAT
COMBINATION, THAT'S WHAT'S
REALLY NEEDED AT THIS POINT.
YOU KNOW, UNFORTUNATELY
EVERYBODY WHO COULD BENEFIT IS
NOT GOING TO IMMEDIATELY GET
ACCESS, BUT WHO ARE THOSE THAT
WE CAN IDENTIFY THROUGH REAL
WORLD EVIDENCE WITH ASSOCIATED
AS DAVID HAS EMPHASIZED
LIFESTYLE MANAGEMENT, AND THEN
FOR HOW LONG, AGAIN, REAL WORLD
EVIDENCE, HOW DO THEY NEED TO BE
ON THE DRUGS, IF WE COULD GET
THOSE DRUGS IN WHILE MARKET
COMPETITION AND DRUGS
NEGOTIATION SIGNIFICANTLY REDUCE
PRICES AT LEAST BY HALF IN THE
NEXT COUPLE YEARS I THINK THAT'S
SORT OF A PATH FORWARD.
>> I'LL JUST ADD THAT QUICKLY,
YOU KNOW, PART OF OUR ESTIMATE
INCLUDES PEOPLE WHO ARE TAKING
THE DRUGS FOR SHORT PERIODS OF
TIME, WHICH ACCRUES COST, BUT
YOU DON'T SEE THE BENEFITS.
SO I THINK, YOU KNOW, OVER TIME
LIKE ADHERENCE CAN GO UP, YOU
KNOW, THAT INCREASES COST, BUT,
YOU KNOW, IF THE PRICES ARE
LOWER IT DOESN'T INCREASE COST
SO MUCH.
THERE'S DEFINITELY A DANCE HERE.
YOU KNOW, I'LL ALSO SAY THAT,
YOU KNOW, WE -- CONGRESSIONAL
BUDGET OFFICE LIKE BY, YOU KNOW,
IT'S OUR MANDATE TO LOOK AT
COSTS, BUT THERE ARE MANY
BENEFITS PROVEN BY MANY PEOPLE
IN THE VIRTUAL ROOM IN REGARDS
TO HEALTH.
WE'RE LOOKING AT A VERY LIKE
NARROW, YOU KNOW, VERY NARROW
FOCUS.
>> ON THE SUBJECT OF ADHERENCE,
I WANT TO TALK ABOUT DEMAND AND
PUT DAVID IN THE HOT SEAT.
SO, YOU MENTIONED THE CHALLENGE
OF INCREASE HEALTHCARE COSTS,
BEING PASSED TO EMPLOYEES.
THIS IS A QUESTION FROM THE
CHAT.
HAVE YOU ASKED TEACHERS WHETHER
THEY WOULD BE WILLING TO ACCEPT
A 3 TO 4 INCREASE TO COVER FOR
WEIGHT LOSS?
>> I HAVE NOT.
I HAD TO GO THE OPPOSITE LATELY.
I REPORT TO A BOARD OF TRUSTS,
HALF UNION, HALF MANAGEMENT TYPE
THING.
I HAVE THE UNION PRESIDENT AND
VICE PRESIDENT SIT THERE ON MY
BOARD OF TRUST.
WHEN WE HAD TO STEP AWAY FROM
GLP-1s, THEY WERE LOOKING AT
PREMIUM INCREASES 11 TO 12% TYPE
SITUATION.
IT WAS LIKE WE WERE DOING
EVERYTHING WE COULD TO BASICALLY
REDUCE, WHAT'S GOING ON IN THE
CATASTROPHIC WORLD WE'VE STEPPED
INTO AND THEY REALIZE THE NEED.
BASICALLY TO TAKE CARE OF THE
POPULATION AS A WHOLE.
AND DO WHAT WE COULD DO TO KEEP
PRICES IN LINE TO TAKE CARE OF
TEACHERS BUDGET THE BEST WE
COULD.
WHEN IT COMES TO COST INCREASE,
25% OUT OF THEIR POCKET, 75% OUT
OF THE SCHOOL BOARD POCKET
SITUATION.
I RECEIVED SUPPORT, OF THE FOLKS
KNOWING WHAT THE IMPACT WAS AND
WHAT WE NEEDED TO GAIN TO STAY
SUSTAINABLE.
>> MY LAST QUESTION FOR
EVERYONE, WHAT DATA ON LIKELY
OBESITY TREATMENT UPTAKE AND
DEMAND WOULD BE THE MOST -- BEST
TO INFORM CARE AND DECISION
MAKING?
IN ORDER TO ASSESS HOW MUCH OF A
HIT PEOPLE WILL TAKE WE NEED TO
KNOW HOW MUCH PEOPLE ARE GOING
TO BE INTERESTED IN THESE DRUGS
REALISTICALLY.
>> I THINK IN MEDICARE, YOU
KNOW, WE'RE IN A LITTLE BIT OF A
PICKLE BECAUSE MEDICARE DOESN'T
COVER THE DRUGS.
SO, YOU KNOW, BY VIRTUE OF THAT,
WE CAN'T GO TO MEDICARE, YOU
KNOW, CLAIMS AND SEE HOW MANY
PEOPLE ARE TAKING IT UP.
SO, BUT WE COULD, YOU KNOW, DRAW
ON MAYBE LIKE MEDICARE ADVANTAGE
CLAIMS, OR INFORMATION THERE,
OR, YOU KNOW, LIKE -- SO I THINK
THAT'S DEFINITELY A CHALLENGE.
YOU KNOW, I THINK SO TAKING
INFORMATION FROM OTHER CLAIMS
WHERE YOU LOOK, YOU KNOW, YOU'RE
LOOKING AT DIFFERENT POPULATION,
MUCH YOUNGER POPULATION,
POSSIBLY POPULATION THAT HAS
MUCH FEWER COMORBIDITIES OR, YOU
KNOW, MAYBE THEY ARE TAKING MUCH
FEWER MEDICATIONS, SO DOCTORS
MIGHT BE MORE WILLING TO
PRESCRIBE ANTI-OBESITY
MEDICATION, I THINK WE HAVE TO
BE CAREFUL ABOUT HOW WE
TRANSLATE THAT EVIDENCE INTO
EVIDENCE FOR THE MEDICARE
POPULATION.
>> GREAT.
ANAND AND DAVID IN 30 SECONDS
YOUR THOUGHTS HOW WE GET GOOD
DEMAND DATA?
>> I THINK WE CAN TAKE A LOOK
AT THE REQUIREMENTS AND
UNDERSTAND WHAT YOUR BMIs ARE,
DIFFERENT COMORBIDITIES ARE
WITHIN YOUR POPULATION.
AND TRY TO FACTOR IN, YOU KNOW,
WHAT KIND OF PERCENTAGE OF THAT
POPULATION WOULD ACTUALLY GET
ENGAGED WITH THIS.
BUT IT'S -- YOU THINK YOU KNOW,
BUT THERE'S A LOT OF UNKNOWNS IN
THE POPULATION WHEN IT COMES TO
WHAT'S TRULY GOING ON.
YOU'RE NOT GOING TO HAVE ALL THE
STATISTICS ON EVERYBODY TYPE
SITUATION.
BUT I DON'T KNOW.
TAKE A LOOK AT THE OBESITY
PERCENTAGE OF THE POPULATION,
WORK YOUR WAY BACKWARDS TYPE
THING.
COME UP WITH A PERCENTAGE.
DIFFERENT TODAY VERSUS WHAT WILL
HAPPEN TOMORROW AS WE GO TO PILL
FORM.
I'M SORRY.
>> YEAH, I'LL ADD YOU'RE NEVER
GOING TO HAVE 100% UPTAKE.
THERE WILL BE REASONS, SIDE
EFFECTS, COST, NOT WANTING TO
TAKE A MEDICINE, AND THAT'S WHY
A LOT OF MICROSIMULATION
STUDIES, THEY ARE ASSUMING NOT
EVEN 50 OR 7 5 BUT LOWER, TWO,
FIVE, TEN, FIFTEEN, 20% UPTAKE
RATES BASED ON, AGAIN, PAST DATA
AND LOOKING AT OTHER MEDICATIONS
AND SO I'LL JUST GO BACK TO
CONCLUDING THOUGHT, AGAIN, SO
MANY PLACES JUST IN THIS
DISCUSSION WHERE REAL WORLD
EVIDENCE WOULD BE SO IMPORTANT,
WHAT ARE SUBPOPULATIONS, HOW DO
YOU FIT IN LIFESTYLE MANAGEMENT,
WHAT'S THE OFF-RAMP FOR
MEDICATION?
ALL OF THAT, YOU KNOW, IF WE CAN
START TO STUDY THAT USING EHR
AND REAL WORLD DATA THAT WOULD
BE REALLY HELPFUL.
>> FANTASTIC.
THANK YOU, EVERYONE, FOR YOUR
PRESENTATIONS, YOUR COMMENTARY,
AND EVERYONE IN THE AUDIENCE FOR
QUESTIONS.
I WILL PASS IT BACK TO DR.
HAILS.
>> THANK YOU FOR THE ENGAGING
DISCUSSION.
WE'RE GOING TO TAKE JUST ABOUT A
10-MINUTE BREAK, BACK AT 2:55:00
P.M. EASTERN TIME.
>> OUR LAST SESSION FOR DAY 1 OF
THE WORKSHOP, I'D LIKE TO
WELCOME DR. DARREN TOH,
MODERATOR, PHO METHODOLOGIC
PRIECHS TO REAL WORLD EVIDENCE
GENERATION FOR GLP-1 THERAPIES.
DR. TOH?
>> THANK YOU.
I'M DARREN TOH, PROFESSOR HERE
IN THE DEPARTMENT OF POPULATION
MEDICINE AT HARVARD MEDICAL
SCHOOL AND PILGRIM HEALTH CARE
INSTITUTE.
WE HAVE THREE EXCELLENT SPEAKERS
TODAY.
WE'LL HEAR FROM THEM FIRST AND
THEN WE'LL FOLLOW THEIR
PRESENTATION BY MODERATED
DISCUSSION AND Q&A SESSION.
I'LL BRIEFLY INTRODUCE THE
SPEAKERS BECAUSE IT WOULD TAKE
TOO MUCH TIME IF I LISTED
ACCOMPLISHMENTS.
PLEASE GO TO THE WORKSHOP
WEBSITE FOR BIOSKETCHES.
FIRST IS DR. ANNA JESTREBOFF,
FOUNDING DIRECTOR OF YALE
OBESITY RESEARCH CENTER, HAS LED
AND PUBLISHED SEVERAL SEMINAR
TRIALS ON GLP-1 AND
MULTI-RECEPTOR AGONISTS, SOME
WERE HIGHLIGHTED IN EARLIER
SESSIONS TODAY.
WE WILL SHARE SOME OF THE REAL
WORLD PATIENT CASES TO HIGHLIGHT
THE NEED FOR MORE AND BETTER
TRIALS AND REAL WORLD DATA
STUDIES.
>> THANK YOU FOR THE PRODUCTION.
IT'S MY PLEASURE TO BE HERE
TODAY.
I'VE LEARNED SO MUCH.
I'LL BE GIVING A DIFFERENT
PERSPECTIVE AND PRESENT A COUPLE
PATIENTS.
THESE ARE MY DISCLOSURES.
I SERVE ON SCIENTIFIC ADVISORY
BOARDS AND LEAD CLINICAL TRIALS
WITH OUR INDUSTRY PARTNERS WHO
ARE DEVELOPING THESE
THERAPEUTICS.
I WILL BE MENTIONING OFF LABEL
USE OF OLDER MEDICATIONS THAT
HAVE BEEN MENTIONED TODAY.
SO, MY TALK IS SLIGHTLY
DIFFERENT.
IT FOCUSES ON WHY WE'RE ALL HERE
TODAY.
WE'RE ALL HERE TODAY BECAUSE WE
WANT TO HELP OUR PATIENTS.
BECAUSE WE WANT TO HELP PEOPLE
LIVING WITH OBESITY.
AND IN ORDER TO DO THAT WE NEED
TO KNOW WHAT GAPS ARE AND WHAT
THE QUESTIONS ARE.
WHO BETTER TO INFORM US THAN OUR
PATIENTS AND PARTICIPANTS, THEY
TEACH US EVERYTHING.
SO, I'LL START WITH TWO CASES.
ONE IS A PATIENT WHO ACTUALLY
WAS IN ONE OF OUR CLINICAL
TRIALS AND THEN TRANSITIONED TO
BE IN MY CLINIC, AND THE SECOND
A CLINIC PATIENT I'VE SEEN FOR
MANY YEARS.
SO THIS FIRST PATIENT IS A
49-YEAR-OLD FEMALE, AND THE
FIRST THING THAT I DID WHEN SHE
CAME TO SEE ME IN CLINIC WAS
LOOK AT HER EMR.
AND I LOOKED AT HER BMI
TRAJECTORY.
AS YOU CAN SEE OVER THE HOURS OF
SEVERAL YEARS SHE LOST WEIGHT
SUCCESSFULLY.
THAT WAS NOT THE PROBLEM.
THE PROBLEM WAS SHE GAINED IT
BACK.
HER BIOLOGY WAS EXTREMELY
STRONG.
SO SHE WAS EXTREMEL ADHERENT TO
DIET AND CAME TO US FOR HELP.
SHE ENCONTROLLED IN TRIALS.
THIS IS WHAT HAPPENED OVER THE
COURSE OF ONE YEAR.
WITHIN A YEAR SHE LOST OVER 90
POUNDS, CAME TO ME AND WAS SO
SURPRISED BECAUSE SHE SAID, YOU
KNOW, I'M DOING EVERYTHING THAT
I WAS DOING BEFORE I STARTED THE
TRIAL, TRACKING MY FOOD,
EXERCISING EVERY DAY, THE ONLY
THING THAT CHANGED IS MY WEIGHT.
SO TRULY THIS MEDICINE WAS
IMPACTING HER BIOLOGY, THE
BIOLOGY AND THE BRAIN YOU HEARD
ABOUT THIS MORNING.
WHAT HAPPENED WHEN SHE FINISHED
THE TRIAL?
WELL, UNFORTUNATELY SHE BEGAN TO
REGAIN WEIGHT.
WE DO SEE THIS.
THERE'S VARIABILITY BUT HER WAS
QUITE RAPID.
AND SO SHE CAME TO SEE ME IN
CLINIC, WE STARTED SEMAGLUTIDE
TO SLOW DOWN THE WEIGHT GAIN.
SHE WAS WAKING UP HUNGRY,
CRAVING, COULD NOT STOP HERSELF
FROM EATING SECONDS, THE PULL
WAS SO STRONG, SHE WAS
EXPERIENCING FOOD NOISE.
IT DID SLOW DOWN WAIT REGAIN,
MAINTAINED HALF OF WHAT SHE LOST
IN THE TRIAL AND HER BMI WAS
STILL CREEPING UP, ABOUT 28 TO
29, WE STARTED ONE OF THE OLDER
MEDICATIONS WHICH LEVELED HER
OUT, SHE STARTED TO LOSE WEIGHT
AGAIN.
SO WHAT HAPPENED THEN IS IT WAS
COMMERCIALLY AVAILABLE, WHICH IT
WASN'T AT THE END OF THE TRIAL
BECAUSE THE FDA NEEDED TO REVIEW
DATA, WE TRANSITIONED AND
STOPPED SEMAGLUTIDE.
SHE CONTINUES, DOES NOT REQUIRE
HIGHEST DOSE, AND SHE'S DOING
QUITE WELL WITH BMI AROUND 25.
WHAT DOES SHE TEACH US?
SHE HAD TO MEET SPECIFIC
INCONTRIBUTION CRITERIA WHICH
SHE DID, AND SHE KNEW SHE HAD A
1 IN 4 CHANCE OF BEING ON
PLACEBO BUT WANTED TO ENROLL.
PROTOCOLIZED TREATMENT THIS IS
REALLY IMPORTANT, IF YOU NOTICED
HER WEIGHT TRAJECTORY IN TERMS
OF WEIGHT LOSS WAS VERY FAST,
SHE CAME DOWN TO BMI OF 20.
SHE DID NOT FEEL COMFORTABLE AT
A BMI OF 20 NOR DID SHE WANT TO
BE THERE BUT WAS SO COMMITTED TO
FINISHING THE TRIAL THAT SHE
DID.
SHE'S MUCH MORE COMFORTABLE, AND
FEELS HEALTHIER AT THIS BMI
WHERE SHE'S CURRENTLY.
AFTER THE TRIAL SHE SOUGHT
CLINICAL CARE WITH ME, WE
PRESENTED WEIGHT GAIN AND KEPT
HER TO A HEALTHY WEIGHT.
SHE ALSO HAD ACCESS AND
AVAILABILITY TO THESE THERAPIES
AND TOOK SOME TIME TO GET HER TO
WHAT HAD WORKED FOR HER IN THE
FIRST PLACE.
NOW, THE SECOND PATIENT,
39-YEAR-OLD, THAT I'VE SEEN FOR
ALMOST A DECADE NOW.
BEFORE SHE CAME TO SEE ME SHE
ACTUALLY HAD BARIATRIC SURGERY,
LOST 50 POUNDS, 20% OF HER BODY
WEIGHT.
UNFORTUNATELY SHE BEGAN TO
REGAIN WEIGHT AND MAY HAVE BEEN
DISEASE PROGRESSION OR OTHER
FACTORS AND REGAINED ABOUT 5%
QUICKLY BY 12 MONTHS OUT.
SHE ASKED HER CARE PROVIDER IF
SHE COULD START A MEDICATION, AT
THAT TIME NO MEDICATION WAS
STARTED, SEVERAL MONTH LATER
ASKED AGAIN, NALTREXONE
BIPRUPRPABE WAS STARTED.
WE CONTINUED, PLATEAUED, ADDED
PHENTERMINE, ADDED RECEPTOR
AGONIST, LOST WEIGHT, PLATEAUED,
AN SEMAGLUTIDE BECAME AVAILABLE
AND WE SWITCHED OUT FOR
SEMAGLUTIDE AND SHE CONTINUED TO
LOSE WEIGHT, DID EXPERIENCE SIDE
EFFECTS, WE DIDN'T TITRATE,
ADDED METFORMIN, LOST MORE
WEIGHT, PLATEAUED AGAIN, G.I.
SIDE EFFECTS RESOLVED, CONTINUD
TO TITRATE SEMAGLUTIDE.
SHE LOST 75 ADDITIONAL POUNDS,
WITH SURGERY AND MEDICATION LOST
OVER 100 POUNDS.
ONCE WE WERE ABLE TO TITRATE UP
THE SEMAGLUTIDE WE WERE ABLE TO
STOP THE PHENTERMINE, AND THE
OTHERS, SHE REMAINS ON
SEMAGLUTIDE TODAY.
I SHARED THIS PATIENT WITH YOU
TO DEMONSTRATE THAT THINGS CAN
BE VERY COMPLICATED, AND THE
PATIENTS THAT WE CARE FOR AND
TREAT AND BECOME PARTICIPANTS IN
OUR RANDOMIZED CONTROLLED TRIALS
ARE NOT LIKE THIS.
WE REALLY, REALLY NEED TO
UNDERSTAND HOW TO CARE FOR
PATIENTS THAT RECEIVE THIS TYPE
OF REAL WORLD CARE.
SO, WHAT HAPPENS IN THE REAL
WORLD?
WE USE COMBINATION THERAPY,
WHETHER MEDICATION COMBINATION
THERAPY OR WITH SURGERY.
PATIENTS EXPERIENCE INSURANCE
BARRIERS, SHE WAS FORTUNATE TO
HAVE THE INSURANCE COVERAGE.
WE USE OLDER MEDICATIONS, THOSE
CAN OFTEN BE COST EFFECTIVE.
THERE IS MEDICATION INITIATION
AND DISCONTINUATION, I'LL TOUCH
ON THAT IN JUST A SECOND.
THERE'S DISEASE PROGRESSION, SO
JUST AS IN DIABETES WE ADD
MEDICATIONS, WE SHOULDN'T BE
SURPRISED THAT WE NEED TO ADD
MEDICATIONS OVER LONG-TERM
FOLLOW-UP AND CARE OF THESE
PATIENTS.
SO WHAT CAN WE LEARN FROM OUR
PATIENTS AND WHAT CAN REAL WORLD
STUDIES REALLY HELP US TO DO?
OF COURSE LONG-TERM
TOLERABILITY, SAFETY, EFFICACY
IS KEY, REALLY WHAT WE WANT TO
ADDRESS.
THERE'S MANY THINGS WITHIN THAT,
SO LOOKING AT EXTERNAL BARRIERS,
HOW THEY IMPACT BOTH TREATMENT
AS WELL AS LET OUTCOMES IN OUR
PATIENTS WHICH HAS COME UP
TODAY.
IN TERMS OF SIDE EFFECTS I WANT
TO SPEND A MOMENT ON THIS.
THIS IS BECAUSE IN THE TRIALS,
THE MEDICATIONS ARE TITRATED UP
ON A VERY CONCRETE SCHEDULE,
THERE'S SOME FLEXIBILITY IN
TRIALS, NOW, BUT IT IS MUCH MORE
FLEXIBLE IN REAL WORLD.
MOST COMMON SIDE EFFECTS ARE
GASTROINTESTINAL.
IF SOMEBODY IS HAVING NAUSEA WE
DON'T GO UP, IF THEY HAVE VOMIT
WE GO GO DOWN.
THERE'S NO REQUIREMENT TO GO UP
ONCE A MONTH ON THE DOSE,
STARTING LOW AND GOING SLOW CAN
MITIGATE.
DEPENDING ON PROVIDER OR
SETTING, DEPENDING HOW QUICKLY
THE MEDICATION IS TITRATED THIS
WILL IMPACT YOUR SIDE EFFECTS,
WE HAVE NO IDEA HOW THAT OCCURS
IN THE REAL WORLD.
THERE'S ALSO STRATEGIES FOR
PATIENTS, DIETARY STRATEGIES
THEY CAN EMPLOY THAT I LISTED
OUT.
THERE'S VERY FEW STUDIES LOOKING
AT HOW NUTRITION AND PHYSICAL
ACTIVITY CAN BE PAIRED WITH
THESE MEDICATIONS TO OPTIMIZE
THOSE TOLERABILITIES AS WELL AS
HEALTH OUTCOMES.
NOW, WHAT ARE OTHER THINGS?
WHAT IMPACTS WEIGHT EFFICACY
RESPONSE AND MAINTENANCE, WHAT
ARE IMPACTS?
WHAT IMPACTS LONG-TERM
ADHERENCE?
IN TERMS OF ADHERENCE THIS HAS
COME UP TODAY, ALSO VERY
IMPORTANT.
WE SEE THAT COST OF COURSE IS A
VERY SIGNIFICANT BARRIER,
ACCESS, DO YOU HAVE ACCESS TO
PROVIDERS, TOLERABILITY I JUST
MENTIONED, THAT WILL IMPROVE
OVER TIME.
THE LACK OF UNDERSTANDING OF THE
BIOLOGY OF OBESITY.
SO THE MOST COMMON QUESTION WE
GET FROM PATIENTS, I LOST
WEIGHT, I CAN STOP THE MEDICINE?
AND IT'S INTERESTING BECAUSE FOR
BLOOD PRESSURE OUR PATIENTS MAY
STOP THE MEDICINE BUT THEY DON'T
GENERALLY ASK US THIS QUESTION.
SO IF A MEDICATION IS STOPPED
FOR HIGHER TENSION, BLOOD
PRESSURE GOES UP, WE'RE NOT
SURPRISED.
BUT THEN WHEN WE SHOW THE SAME
EXACT FIGURE FOR OBESITY, WE
STOP THE MEDICINE, WE'RE
SURPRISED WHEN OUR PATIENTS MAY
GAIN BACK THE WEIGHT.
IF MEDICATIONS ARE IMPACTING
NEUROBIOLOGY OF THE DISEASE,
THEN WE STOP TREATING THAT
DISEASE, WHY WOULD WE BE
SURPRISED THE WEIGHT IS
REGAINED?
AS THERE'S VARIABILITY IN WEIGHT
REDUCTION, THERE'S ALSO
VARIABILITY IN WEIGHT REGAINED.
THAT'S BECAUSE THERE'S DIFFERENT
TYPES OF OBESITIES, WE NEED TO
UNDERSTAND THAT BUT ON AVERAGE
OVER TIME PATIENTS TEND TO GAIN
BACK THE WEIGHT.
WHAT ABOUT IF WE CONTINUE THE
MEDICATION?
HERE'S A THREE-YEAR RCT WE DID,
OVER THREE YEARS THE WEIGHT IS
ACHIEVED AND MAINTAINED, YOU CAN
ALSO SEE THIS WITH OTHER HEALTH
BENEFITS, HERE I'M SHOWING
SYSTOLIC BLOOD PRESSURE, SAME
SAID FOR A1c.
WHAT IN THE MEDICATION IS
DISCONTINUED?
WEIGHT REGAIN ON AVERAGE THERE'S
WEIGHT REGAINED WHEN MEDICATION
IS STOPPED, AGAIN THERE'S
VARIABILITY IN THAT.
WHAT WE REALLY NEED DO IS LOOK
AT THIS LONG TERM BECAUSE SOME
PATIENTS CAN SUSTAIN SHORT TERM,
BUT LONG TERM GAIN BACK.
SAME THING WITH BLOOD PRESSURE.
VERY QUICKLY THAT STARTS TO GO
BACK UP.
NOT ONLY ARE WE LOSING THE
WEIGHT BENEFIT, WE'RE ALSO
LOSING THE BLOOD PRESSURE A1C
BENEFIT.
WITH OBESITY, ADHERENCE COULD BE
A SECRET WEAPON.
THE REASON I SAY THIS IS BECAUSE
IF YOUR PATIENT STOPS TAKING
BLOOD PRESSURE MEDICINE THEY
DON'T HAVE ANY IMMEDIATE
FEEDBACK THAT THEIR BLOOD
PRESSURE IS GOING UP.
SAME THING WITH HEMOGLOBIN A1C.
IF A PATIENT SYMPTOMS TAKING
ANTI-OBESITY MEDICATION AND IS
THAT RIGHT GAINING BACK WEIGHT,
THEY CAN IMMEDIATELY FEEL THAT
AND SEE THAT.
SO, I THINK ADHERENCE LONG TERM
ONCE WE ADDRESS COST AND ACCESS
WILL ACTUALLY BE A SECRET WEAPON
AND HOPEFULLY PATIENTS WILL COME
BACK TO YOUS, MOST OF MY
PATIENTS IF THEY STOP, THEY STOP
ONCE AND NEVER AGAIN.
SO, WHAT ARE A FEW OTHER THINGS?
WHAT ARE THE LONG-TERM SAFETY
OUTCOMES?
THIS IS REALLY KEY IN TERMS OF
DECADES OF DATA, NOT YEARS OF
DATA, AND WE DO HAVE THAT IN
PATIENTS WITH DIABETES IN TERMS
OF USE OF THESE MEDICATIONS BUT
NOT WITH OBESITY.
WHAT ARE THE POTENTIAL
ADDITIONAL EFFECTS?
WHAT ARE PATIENTS EXPERIENCING?
HOW IS THIS IMPACTING THEIR
QUALITY OF LIFE?
THIS IS ALL IMPORTANT, ONLY WAY
WE'LL KNOW THAT IF WE'RE GOING
TO ACTIVELY INCLUDE PATIENTS IN
THESE TRIALS IN TERMS, IN THESE
STUDIES WHAT WE'RE ADDRESSING
AND ACTING.
WHAT IS THE IMPACT OF PATIENT
CARE SETTING, PLACE THEY ARE
RECEIVING CARE AND WHAT IS BEING
DELIVERED THERE?
AND WHAT ROLE DOES SHARED
DECISION MAKING PLAY?
THIS IS IMPORTANT BECAUSE SO
MUCH OF THE TIME OUR PATIENTS
COME TO US ASKING FOR SPECIFIC
MEDICATION BECAUSE OF EVERYTHING
THEY HAVE SEEN ON SOCIAL MEDIA.
AND ALL OF THIS IS IMPORTANT
BECAUSE HOW DO WE BEST INFORM
STANDARDS OF CARE AND OPTIMIZED
HEALTH OUTCOMES?
I COME BACK TO OUR PATIENT, WITH
OBESITY, THAT PERSON THAT CAN
TEACH US EVERYTHING THAT WE NEED
TO KNOW, IDENTIFY THOSE GAPS,
GIVE US THE QUESTIONS, ALL WE
NEED TO DO IS FIGURE OUT HOW TO
ANSWER THOSE QUESTIONS.
SO WITH THAT I THINK THANK YOU
FOR YOUR ATTENTION AND I'LL HAND
IT OVER TO DR. CURTIS.
THANK YOU.
>> THANK YOU.
IT SET US UP WELL FOR THE NEXT
PRESENTATION BY DR. LESLEY
CURTIS.
SO, I WILL BRIEFLY THROUGH DR.
CURTIS, WHAT WEARS MANY HATS.
DR. CURTIS IS CURRENTLY CHAIR
AND PROFESSOR IN THE DEPARTMENT
OF DEPARTMENT
OF POPULATION HEALTH SCIENCE AND
MEDICINE AT DUKE.
CO-CHAIR OF THE WORKSHOP TODAY
AND WILL TALK ABOUT
OPPORTUNITIES AND CHALLENGES OF
USING PRAGMATIC TRIALS TO STUDY
GLP-1-BASED THERAPIES.
LESLEY?
>> THANKS SO MUCH, DARREN.
THANK YOU, ANIA, FOR SETTING
THIS TALK UP SO WELL.
FIRST OF ALL, MY DISCLOSURES, I
WANT TO SHARE THOSE.
WHAT I'LL BE TALKING ABOUT TODAY
THAT IS PRAGMATIC CLINICAL
TRIALS REALLY COMES FROM THE TEN
YEARS OR SO THAT I HAVE SPENT
WORKING IN THE NIH PRAGMATIC
TRIALS COLLABORATORY.
SO, FOR THOSE WHO MAY NOT BE
FAMILIAR WITH THE COLLABORATORY,
IT'S A GROUP OF ABOUT -- WE NOW
HAVE MAYBE 35 TRIALS THAT HAVE
EITHER BEEN PART OF THE
COLLABORATORY OR PART OF THE
COLLABORATORY PRAGMATIC TRIALS
THAT COME TOGETHER TO LEARN HOW
BEST TO DO PRAGMATIC TRIALS
EMBEDDED IN HEALTH CARE
DELIVERY.
THESE 35 TRIALS HAVE BEEN FUNDED
BY 14 I.C.s ACROSS THE NIH,
AND HAVE GENERATED JUST RICH,
RICH LESSONS ABOUT HOW BEST TO
DO PRAGMATIC TRIALS.
SO WHAT I'LL TALK ABOUT AT LEAST
IN THE FIRST PART REALLY
REFLECTS WHAT WE'VE LEARNED
TOGETHER.
IT'S HELPFUL TO THINK ABOUT
PRAGMATIC TRIALS IN TERMS OF
THREE KEY ATTRIBUTES.
THE FIRST IS THAT THE INTENT IS
ALMOST ALWAYS TO INFORM DECISION
MAKERS, AND THAT INCLUDES
PATIENTS, CLINICIANS,
POLICYMAKERS, PAYERS, MANY OF
WHOM WE'VE HEARD FROM TODAY.
IT'S NOT TO ELUCIDATE BIOLOGICAL
OR SOCIAL MECHANISMS.
THESE TRIALS ALSO AIM TO ENROLL
A POPULATION THAT'S REALLY
RELEVANT TO THE DECISION, AND
THAT DECISION IN CLINICAL
PRACTICE.
WE ALSO LOOK FOR THEM TO BE
REPRESENTATIVE OF BOTH THE
PATIENTS AND SETTINGS IN WHOM
THAT DECISION IS RELEVANT.
AND THEN FINALLY, A KEY
ATTRIBUTE IS JUST THE INTENT TO
REALLY SIMPLIFY PROCEDURES AND
DATA COLLECTION, SO THAT THE
TRIAL CAN FOCUS ON THE POWER
NEEDED TO ANSWER THE QUESTION,
ACROSS A BROAD RANGE OF
OUTCOMES.
NOW, YOU KNOW, WHEN WE THINK
ABOUT PRAGMATIC TRIALS, IT'S
REALLY IMPORTANT TO REMEMBER
THAT PRAGMATISM IS SOMETHING
THAT OPERATES ALONG A SPECTRUM.
THESE I SHOW HERE ON THIS
FIGURE, ELEMENTS OF THE PRESSIE
2 FRAMEWORK FOR EVALUATION OR
ASSESSING PRAGMATISM OF A TRIAL.
FOR THOSE FAMILIAR WITH IT
YOU'LL RECOGNIZE WE OFTEN THINK
ABOUT THAT IN TERMS OF
ELIGIBILITY, HOW WIDELY
AVAILABLE OR HOW ELIGIBLE, WHAT
DOES THE POPULATION LOOK LIKE IN
TERMS OF ELIGIBILITY, HOW
RESTRICTIVE ARE WE WITH
ELIGIBILITY CRITERIA, ARE WE
RECRUITING IN PRAGMATIC TRIALS,
WE COULD RECRUIT IN THE CARE
SETTING IN WHICH THE PATIENTS
ARE ACTUALLY SEEN.
YOU KNOW, THE SETTING MIGHT ALSO
BE A PRIMARY CARE PHYSICIANS
PRACTICE, RATHER THAN, SAY,
SPECIALTY CLINIC.
WE OFTEN HAVE TO THINK ABOUT THE
RESOURCES REQUIRED AT THE
ORGANIZATIONAL LEVEL TO SUPPORT
AND EXECUTE THE TRIAL.
SO WE'RE TALKING ABOUT CHANGING
CLINICAL WORKFLOWS MUCH LESS
PRAGMATIC THAN SOMETHING THAT
HAS A VERY LIGHT TOUCH.
OTHER CONSIDERATIONS WITH
RESPECT TO FLEXIBILITY OF
INTERVENTION AND HOW FLEXIBLE WE
ARE WITH ADHERENCE TO THE
INTERVENTION.
HOW WE'RE FOLLOWING UP THE
PARTICIPANTS, WHETHER THE
OUTCOMES ARE SURROGATE OUTCOMES,
WHICH ARE USED IN EXPLANATORY
TRIALS, OR PATIENT FOCUSED.
THE KEY THING TO REMEMBER HERE
IS THAT PRAGMATIC IS AN
ADJECTIVE BUT NOT A BINARY
INDICATOR OF THE TRIAL.
YOU KNOW, AGAIN, WE CONDUCT
THESE BECAUSE THEY HAVE SUCH
POTENTIAL TO INFORM POLICY AND
PRACTICE WITH TRULY HIGH QUALITY
EVIDENCE.
AND OFTEN WE CAN DO IT AT A
REDUCED COST WITH HIGHER
EFFICIENCY COMPARED TO A
TRADITIONAL TRIAL.
IN THE COLLABORATORY WE'VE COME
UP WITH THE FIVE Rs THAT
EXPLAIN WHY WE WOULD DO A PCT.
I'VE TOUCHED ON SOME OF THESE ON
THE EARLIER SLIDES, BUT I THINK
IT REALLY STARTS WITH THE
QUESTION, RIGHT?
THE QUESTION DICTATES WHETHER
WE'RE DOING A PRAGMATIC TRIAL OR
NOT, AND IT HAS TO BE A PRESSING
ONE THAT THE HEALTHCARE SYSTEM,
LEADERS, PATIENTS, FRONTLINE
CLINICIANS, WHERE THEY CARE
ABOUT THE ANSWER.
THAT'S IMPORTANT BECAUSE
PRAGMATIC TRIALS EVEN THE MOST
PRAGMATIC ONES OFTEN TOUCH THOSE
DIFFERENT STAKEHOLDERS AND THEIR
BUY-IN IS ESSENTIAL.
WE DO THEM BECAUSE WE WANT TO
TEST AN INTERVENTION IN A REAL
WORLD SETTING WHICH OF COURSE
WE'VE BEEN TALKING ABOUT ALL DAY
TODAY.
WE WANT TO MAKE SURE WE'RE
FOCUSED ON A REPRESENTATIVE
POPULATION, SO THAT THE RESULTS
OF THE TRIAL REALLY INFORM THE
IMPLEMENTATION MORE BROADLY THAN
IN THE TRIAL.
AND ACCELERATE UPTAKE OF
SUCCESSFUL INTERVENTIONS.
WE'RE OFTEN LOOKING TO RELY ON
ROUTINELY COLLECTED DATA
WHEREVER POSSIBLE.
AGAIN, TO MAXIMIZE EFFICIENCY,
AND MINIMIZE ADDITIONAL COST.
AND, YOU KNOW, PERHAPS THE MOST
IMPORTANT REASON TO DO A
PRAGMATIC TRIAL VERSUS OTHER
REAL WORLD APPROACHES IS BECAUSE
SOME QUESTIONS REALLY NEED
RANDOMIZATION IN ORDER FOR THEM
TO BE ANSWERED IN A WAY THAT
TRULY INFORMS THE DECISION
MAKER.
SO, WITH THAT KIND OF OVERVIEW
OF PRAGMATIC TRIALS, LET ME JUST
TOUCH ON A FEW CONSIDERATIONS
FOR PRAGMATIC TRIALS THAT WOULD
BE USING GLP-1 BASED THERAPIES.
FIRST, WITH RESPECT TO EQUIPOISE
AND RECRUITMENT, AND WE'VE HEARD
SOME ABOUT THIS TODAY ALREADY,
YOU KNOW, CONSIDER A TRIAL THAT
RANDOMIZES PATIENTS OR
PARTICIPANTS TO A GLP-1-BASED
THERAPY AND A NON-GLP-1 ARM,
GIVEN WHAT WE KNOW ABOUT THE
EFFICACY OF GLP-1-BASED
THERAPIES, YOU COULD IMAGINE
THAT CLINICIANS MIGHT REALLY BE
UNWILLING OR UNINTERESTED IN
REFERRING PATIENTS TO A TRIAL
WHERE THE RANDOMIZATION INCLUDES
THAT NON-GLP-1 ONE ARM.
HERE MAKES SENSE TO THINK ABOUT
WHERE COMPARATIVE EFFECTIVENESS
TRIALS OR HEAD-TO-HEAD TRIALS
COULD BE MORE LIKELY TO SUCCEED.
AND THAT MAY BE SOMETHING THAT
WE WILL TALK ABOUT TODAY.
ALSO IMPORTANT TO THINK ABOUT
THE PARTICIPANT PERSPECTIVE
HERE, AND THEY MIGHT BE
UNWILLING TO RISK BEING ASSIGNED
TO A COMPARATOR ARM, RIGHT?
SO, SOMETIMES THERE'S AN
ASSUMPTION OR OFTENTIMES THERE
MAY BE ASSUMPTION THAT TRIAL
PARTICIPATION GIVES THEM ACCESS
TO THE DRUG, WHEN IN FACT OF
COURSE THEY COULD BE RANDOMIZED
TO A DIFFERENT ARM.
I THINK A TAKEAWAY HERE,
SOMETHING WE'VE SEEN TIME AND
AGAIN IN THE COLLABORATORY, IS
THAT CLINICIAN AND PATIENT
ENGAGEMENT IN THE DESIGN IS
TRULY ESSENTIAL TO MAKE SURE
THAT THE TRIAL CAN BE
EFFECTIVELY UNDERTAKEN, PATIENTS
AND CLINICIANS WILL WANT TO
PARTICIPATE.
WE'VE HEARD TODAY ABOUT THE
RAPIDLY SHIFTING LANDSCAPE, DAVE
IN HIS FIRST TALK REALLY LAID
OUT NICELY HOW QUICKLY THE
LANDSCAPE HAS ACCELERATED OVER
THE LAST FEW YEARS EVEN.
THINK ABOUT A TRIAL THAT MIGHT
COMPARE A GLP-1-BASED THERAPY TO
SOME KIND OF USUAL CARE ARM.
WELL, THAT MAY NOT REPRESENT THE
STANDARD OF CARE AS THE TRIAL
PROGRESSES.
DOES LEAD US TO THINK ABOUT
ADAPTIVE OR PLATFORM DESIGNS
WITH FLEXIBILITY, ALSO GENERALLY
LESS PRAGMATIC AND A LITTLE BIT
MORE COMPLICATED, THESE ARE
CONSIDERATIONS, RIGHT?
THERE ARE CHALLENGES AND THERE
ARE SOLUTIONS BUT THEY DO ADD
SOME COMPLEXITY.
ECHOING PRIOR SLIDE IT'S
IMPORTANT TO INVOLVE PAYERS AND
REGULATORS EARLY TO MAKE SURE
THAT AGAIN WE'RE DEFINING
MEANINGFUL COMPARATORS, GIVEN
THIS EVOLVING LANDSCAPE SO THAT,
AGAIN, AT THE END OF THE STUDY
WE'RE STILL INFORMING AN
IMPORTANT DECISION.
IN ADDITION TO THE EVOLVING
STANDARD OF CARE IT'S ALSO THE
CASE THAT OVER TIME WE'RE JUST
SEEING NEW INDICATIONS FOR THESE
THERAPIES.
YOU COULD IMAGINE, YOU KNOW, A
PATIENT MIGHT -- A PARTICIPANT
OVER THE COURSE OF THE TRIAL
MIGHT ACTUALLY BECOME ELIGIBLE
FOR THE THERAPY BY VIRTUE OF A
NEW APPROVED INDICATION FOR THE
THERAPY.
SO IT IS A COMPLICATED
LANDSCAPE, BOTH IN TERMS OF THE
STANDARD OF CARE AND HOW THAT'S
EVOLVING BUT ALSO IN TERMS OF
THE GROWING NUMBER OF
INDICATIONS FOR WHICH THESE
THERAPIES HAVE BEEN APPROVED.
WE'VE TALKED A LOT ABOUT
ADHERENCE AND DISCONTINUATION.
WHAT WE HAVEN'T TOUCHED ON YET
IS CONTAMINATION.
MAYBE JUST WITH RESPECT TO
ADHERENCE AND DISCONTINUATION, I
THINK IN ANY TRIAL, PRAGMATIC
TRIAL EVEN, WE WANT TO BE ABLE
TO USE EXISTING DATA TO MONITOR
EARLY SIGNS OF DISCONTINUATION.
AND EVEN CONSIDER STRUCTURED OR
REALTIME CAPTURE OF
DISCONTINUATION REASONS.
I THINK SEVERAL SPEAKERS HAVE
NOTED THE IMPORTANCE OF REALLY
GATHERING ADDITIONAL INFORMATION
ABOUT WHAT'S DRIVING
DISCONTINUATION.
YOU KNOW, CONTAMINATION IS A
REAL ISSUE AS WELL BECAUSE
PARTICIPANTS WERE RANDOMIZED TO
NON-GLP-1 ARM MAY SEEK OUT THE
DRUG INDEPENDENTLY.
AND THAT THAT CAN CERTAINLY
HAPPEN AND WE'RE SEEING THAT.
YOU KNOW, SEVERAL HAVE MENTIONED
THE CHALLENGE OF COST AND
COVERAGE BECAUSE IN THE REAL
WORLD AS WE'VE HEARD, IT'S JUST
ACCESS IS HIGHLY VARIABLE.
SO, IN FACT ANIA SHARED WHAT IN
A LOOKS LIKE TO THE PATIENT WHEN
THEY RECEIVE THEM IN THE TRIAL
BUT MIGHT NOT RECEIVE THEM
AFTERWARDS.
THERE'S OPTIONS FOR TEMPORARY
COVERAGE FOR PARTICIPANTS, BUT
IT'S -- THIS IS A REAL CHALLENGE
I THINK THAT WE FACE AS WE THINK
ABOUT HOW TO DESIGN THESE
STUDIES.
AND THEN, YOU KNOW, IT'S
IMPORTANT TO REMEMBER THAT WE'VE
GOT SOME REAL -- I WOULD CALL IT
STAKEHOLDER MISALIGNMENT HERE.
MANUFACTURERS MAY BE VERY
RELUCTANT OR UNWILLING TO FUND
OR SUPPORT TRIALS THAT HAVE THE
POTENTIAL TO REVEAL LIMITED REAL
WORLD EFFECTIVENESS.
THINK ABOUT THE HEAD-TO-HEAD
TRIAL THAT WE MIGHT LONG FOR,
AND THERE'S A REAL RISK TO THE
MANUFACTURERS OF BOTH THERAPIES
AND SO THINKING ABOUT HOW WE
ALIGN THE VALUES, PERSPECTIVES
AN NEEDS OF STAKEHOLDERS IS
IMPORTANT.
HEALTH SYSTEMS OFTEN DON'T HAVE
OR DON'T REALLY HAVE INCENTIVES
TO PARTICIPATE IN PRAGMATIC
TRIALS, AND SO, AS PEOPLE WHO DO
PRAGMATIC TRIALS WE TALK ABOUT
IMPORTANCE OF ENGAGING HEALTH
SYSTEM TO UNDERSTAND LIKE WHERE
THE VALUE IS FOR THEM IN THE
ANSWER AND MAKING SURE THEN THAT
THE TRIAL ANSWERS THAT QUESTION.
AND PAYERS, WE'VE TALKED ABOUT
THIS BEFORE TODAY, HAVE A SHORT
TIME HORIZON SO THEY MAY NOT
REALIZE THE LONG-TERM BENEFITS
AND WOULD ALSO BE RELUCTANT TO
SUPPORT THESE TRIALS.
IN THE END, JUST TO WRAP THIS
UP, YOU KNOW, THINK AS WE'VE
HEARD TODAY THERE ARE MANY, MANY
QUESTIONS RELATED TO GLP-1
THERAPIES FOR WHICH WE NEED
ANSWERS, AND WE NEED THEM IN THE
REAL WORLD.
I WOULD ARGUE THAT SOME OF THOSE
QUESTIONS MAY BE ALMOST
IMPOSSIBLE TO ANSWER WITHOUT
RANDOMIZATION, OTHERS MAY HAVE
DIFFERENT PERSPECTIVES BUT
ACTUALLY THE QUESTION ABOUT, YOU
KNOW, HOW TO REDUCE USE, HOW TO
TITRATE IT DOWN OVER TIME, MAYBE
IN COMBINATION WITH LIFESTYLE
INTERVENTIONS, THOSE KINDS OF
QUESTIONS TAPERING QUESTIONS CAN
BE VERY CHALLENGING TO ANSWER IN
EVEN AN EXQUISITELY
WELL-DESIGNED OBSERVATIONAL
STUDY.
AS WE THINK ABOUT THE KINDS OF
QUESTIONS THAT NEED ANSWERS,
IT'S IMPORTANT TO REMEMBER THAT
PRAGMATIC TRIALS ARE REALLY
IMPORTANT TOOL, IF YOU WILL, IN
OUR METHODOLOGICAL TOOLBOX.
AND WITH THAT I WILL STOP
SHARING.
>> THANK YOU, LESLEY.
THAT WAS GREAT.
NEXT SPEAKER IS DR. MIGUEL
HERNAN, HARVARD CHAN SCHOOL OF
PUBLIC HEALTH.
I CANNOT THINK OF A BETTER
PERSON TO SPEAK ABOUT THE TOPIC
OF EMULATION THAN MIGUEL, HE'S
THE PERSON THAT DEVELOPED,
REFINED, AND APPLIED A FRAMEWORK
AND CONVENED EVERYONE THAT THIS
IS REALLY SOMETHING WE SHOULD
CONSIDER TO IMPROVE RIGOR OF
REAL WORLD DATA STUDIES, TALKING
ABOUT USING TRIAL EMULATION
FRAMEWORK TO STUDY GLP-1-BASED
THERAPY USING REAL WORLD DATA.
MIGUEL?
>> THANK YOU VERY MUCH.
ARE MY SLIDES UP?
CAN YOU HEAR ME?
>> YES.
>> FANTASTIC.
SO, YEAH, LET'S TALK ABOUT OUR
REAL WORLD DATA AND LESLEY HAS
PRESENTED IN SUCH A WAY THIS
FLOWS VERY NICELY FROM HER
PRESENTATION.
SO, THIS IS MY OTHER RELEVANT
ENGAGEMENTS, AND I'M GOING TO
START BY SAYING SOMETHING THAT
WE KNOW HERE, WHICH IS NONE OF
THE TRIALS CAN ANSWER ALL
QUESTIONS, WE'RE TALKING ABOUT
OBSERVATIONAL AND REAL WORLD,
SOME TOO EXPENSIVE, NOT ETHICAL,
SOME NOT PRACTICAL, SOME WILL BE
DONE AT SOME POINT, BUT NOT YET.
AND WE NEED TO MAKE DECISIONS
NOW.
ALSO, AS LESLEY MENTIONED,
SOMETIMES THERE'S MISALIGNMENT
OF INCENTIVES AND SOME TRIALS,
ESPECIALLY HEAD-TO-HEAD TRIALS
WHICH WOULD BE VERY IMPORTANT
FOR GLP-1-BASED THERAPIES ARE
NOT DONE BECAUSE MANUFACTURERS
DON'T HAVE INCENTIVE TO PAY FOR
THEM AND THE PAYERS AND HEALTH
SYSTEMS MAY NOT BE SET UP
APPROPRIATELY FOR RESEARCH.
THE CASE WITH THAT, THE NUMBER
OF QUESTIONS THAT WE HAVE IS
ALWAYS GOING TO BE GREATER THAN
THE NUMBER OF TRIALS THAT AS A
SOCIETY WE CAN CONDUCT.
SO YOU THINK ABOUT ALL THE
QUESTIONS WE HAVE FOR EVERY
POSSIBLE COMBINATION OF
TREATMENTS, FOR DIFFERENT
OUTCOMES, OVER DIFFERENT TIME
PERIODS, FOR DIFFERENT SUBGROUPS
BASED ON CLINICAL
CHARACTERISTICS SO WE'RE NOT
GOING TO BE ABLE TO CONDUCT
TRIALS TO ANSWER ALL QUESTIONS
THAT WE MAY HAVE IN A PRECISE
WAY.
THAT'S REALLY WHY WE NEED TO
TALK ABOUT -- THIS IS NOT
SOMETHING THAT IS AN OPTION THAT
WE HAVE.
IT'S WHAT WE WILL HAVE TO BE
USING EVEN ONCE YOU USE HUMAN
DATA TO INFORM SOME OF THE
DECISIONS THAT WE MAKE.
PHARMACOTHERAPY, GLP-1-BASED
THERAPIES IN PARTICULAR.
THE QUESTION, THE QUESTION IS
NOT WHETHER TO USE OBSERVATIONAL
DATA BUT HOW TO USE IT
CORRECTLY.
AND WE'VE HEARD ABOUT DIFFERENT
TYPES OF OBSERVATIONAL DATA,
SOME OF THESE DATASETS ARE
ASSEMBLED SPECIFICALLY FOR
RESEARCH PURPOSES, COHORTS, SOME
CASES CONTROL STUDIES, SO
BECAUSE THESE DATASETS HAVE BEEN
DESIGNED FOR RESEARCH, MEANING
THAT INVESTIGATORS HAVE CONTROL
OVER THE DATA THAT ARE BEING
GENERATED.
THEY TEND TO HAVE SOME
ADVANTAGES THAT OTHER TYPES OF
DATA NOT GENERATED FOR RESEARCH,
AND OF COURSE THOSE STUDIES
WE'VE BEEN TALKING ABOUT HERE A
LOT DURING TALKS, DATA THAT ARE
GENERATED FOR CLINICAL PURPOSES
LIKE ELECTRONIC HEALTH RECORDS
OR FOR INSURANCE PURPOSES LIKE
CLAIMS, ET CETERA.
ALL THESE DATABASES THAT WOULD
HAPPEN TO FIND IN THE REAL WORLD
BUT WE AS INVESTIGATORS HAVE NO
POSSIBILITY OF DESIGNING IN A
WAY FOR OUR RESEARCH, THIS IS
WHAT IS KNOWN AS REAL WORLD DATA
FROM OBSERVATIONAL POINT OF
VIEW.
WE SOMETIMES CALL IT SOUND DATA.
DATA WE FIND IN THE REAL WORLD
AND WE TRY TO REPURPOSE FOR
RESEARCH.
NOW, WE HAVE A LOT OF THIS TYPE
OF REAL WORLD DATA.
AND WE HAVE THESE DATA FOR A
VERY LONG TIME.
THIS IS NOT NEW.
PHARMACO EPIDEMIOLOGISTS WERE
USING DATABASES OF ELECTRONIC
HEALTH RECORDS IN THE 1970s,
AND '80s.
AND WHAT IS DIFFERENT IS THAT
MORE OF THEM NOW, WE HAVE MORE
DATA NOW.
IT'S VERY COMMON NOW TO HAVE
DATABASES WITH MILLIONS OF
PEOPLE, THAT WASN'T THAT COMMON
IN THE '70s OR '80s, AND
THERE IS DETAILED INFORMATION ON
A LOT OF THINGS THAT WE'RE GOING
TO BE USING FOR OUR RESEARCH
LIKE THERAPIES, ET CETERA.
THIS IS VERY PROMISING, AND YET
IF YOU READ THE MEDICAL
LITERATURE FOR THE LAST FEW
DECADES, IT'S FULL OF
SPECTACULAR FAILURES OF CAUSAL
INFERENCE FROM OBSERVATIONAL
DATA.
I'M GOING TO BRIEFLY MENTION
TWO, BUT I COULD TALK ABOUT MANY
MORE AND I'M SURE MOST OF YOU
KNOW OF MANY MORE TOO.
SO, I WANT YOU TO TALK ABOUT ONE
BASED ON RESEARCH DATA AND ONE
ON FOUND DATA, REAL WORLD DATA.
THE STUDY WAS PUBLISHED IN 1996,
AND CLAIM HORMONE THERAPY
PREVENTS CORONARY HEART DISEASE
IN POSTMENOPAUSAL WOMEN.
RESULTS AND CONCLUSIONS OF THIS
STUDY WAS THAT THERE WAS A
MARKED DECREASE IN RISK OF MAJOR
CORONARY HEART DISEASE AMONG
WOMEN WHO TOOK IT AS OPPOSED.
NOW, SEVEN YEARS LATER,
RANDOMIZED TRIAL WAS PUBLISHED,
IN THE SAME JOURNAL, THAT IT WAS
WRONG, HORMONE THERAPY DOES NOT
PREVENT CORONARY HEART DISEASE
IN POSTMENOPAUSAL WOMEN.
AND THESE ARE CONCLUSIONS, DO
NOT CONFER CARDIAC PROTECTION.
AND MAY INCREASE RISK OF
CORONARY HEART DISEASE.
THIS IS ONE EXAMPLE.
ANOTHER EXAMPLE WAS THE EXAMPLE
OF THERAPY WE'VE STUDIED AND
RISK OF COLORECTAL CANCERS, A
STUDY PUBLISHED AGAIN IN THE
SAME JOURNAL IN 2005, AND
CONCLUSION WAS USE OF STUDIES
WAS ASSOCIATED WITH 50%
REDUCTION IN RISK OF COLORECTAL
CANCER.
A FEW MONTHS LATER, AGAIN, THERE
WAS EVIDENCE FROM RANDOMIZED
TRIALS SHOWING THAT WAS WRONG.
IN FACT, THERE WAS NO EFFECT ON
CANCER OR CANCER DEATH
ESTABLISHED.
THIS IS TWO EXAMPLES FROM A VERY
LONG LIST OF WHY HISTORY SHOWS
US WE CANNOT TRUST CAUSAL
INFERENCE BASED ON OBSERVATIONAL
DATA.
AND IT IS ALSO JUST A SIDE
COMMENT, NONE OF THESE
CATASTROPHIC FAILURES HAVE BEEN
RETRACTED IN JOURNALS, WE KNOW
THEY ARE WRONG AND KNOW THEY ARE
WRONG.
THE QUESTION IS PRECISELY THAT,
WHY?
WHY SO MANY OBSERVATIONAL
ANALYSES ARE BIASED?
THERE ARE TWO POSSIBLE
EXPLANATIONS TO THAT QUESTION.
ONE POSSIBLE EXPLANATION IS THAT
OBSERVATIONAL DATASETS ARE NOT
BAD, AND THE OTHER POSSIBLE
EXPLANATION IS THAT
OBSERVATIONAL DATASETS ARE NOT
USED WELL.
THOSE ARE VERY DIFFERENT
EXPLANATIONS WITH DIFFERENT
IMPLICATIONS FOR USES THAT WE'RE
DISCUSSING HERE TODAY BECAUSE
IT'S POSSIBLE THAT OBSERVATIONAL
DATASETS DON'T HAVE ENOUGH DATA
TO ANSWER THE QUESTIONS THAT WE
WANT TO ANSWER.
MAYBE TOO MUCH CONFOUNDING, NOT
ENOUGH INFORMATION IN THE
DATASET TO ADJUST FOR
CONFOUNDERS OR MEASUREMENT
ERROR, BIASES WE'LL HAVE IN
CAUSAL INFERENCE THAT WOULD BE
DUE TO LIMITATIONS OF THE DATA,
COMMON DATA BIASES.
THE OTHER POSSIBILITY IS THAT
THESE OBSERVATIONAL DATASETS ARE
NOT BEING USED WELL.
NOT THAT THE DATA ARE
INEFFICIENT, THAT WE'RE NOT
DOING WITH THE DATA WHAT WE'RE
SUPPOSED TO DO WITH THE DATA.
AND WE DESIGN OUR OBSERVATIONAL
ANALYSIS IN SUCH A WAY THAT IT
CREATES BIAS, THAT IS CALLED
DESIGN BIAS.
OKAY.
LET'S TALK ABOUT THE DESIGN
BIASES FIRST.
HOW DO WE MAKE SURE THAT THESE
BIASES DON'T HAPPEN?
WELL, WE CAN THINK ABOUT
RANDOMIZED TRIALS.
WE KNOW HOW TO DESIGN AND
ANALYZE RANDOMIZED TRIALS AND WE
HAVE HEARD A LITTLE BIT ABOUT
THAT HERE ALREADY.
THERE ARE SOME THINGS THAT WE
KNOW, SOME BASIC PRINCIPLES FROM
TRIALS THAT WE KNOW LIKE, FOR
EXAMPLE, WE DON'T START THE
FOLLOW-UP OF INDIVIDUALS IN THE
TRIAL UNTIL THEY HAVE BEEN
ASSIGNED TO A TREATMENT THERAPY.
IN FACT, WE START THE FOLLOW-UP
AT THE TIME THEY ARE ASSIGNED TO
A TREATMENT THERAPY.
SEEMS SO OBVIOUS WE NEVER TALK
ABOUT THAT WHEN WE'RE CONDUCTING
A TRIAL.
WE NEVER SAY, OH, MAKE SURE THAT
YOU START THE FOLLOW-UP AT THE
TIME OF RANDOMIZATION.
THAT IS WHAT WE DO.
TURNS OUT MANY OBSERVATIONAL
ANALYSIS DON'T DO THAT.
PROBLEMS OF PREVIOUS EXAMPLES OF
HORMONE THERAPY, THE STUDY I
GAVE YOU, BECAUSE OF FAILURE TO
FOLLOW BASIC PRINCIPLES OF THE
STUDY DESIGN THAT WE FOLLOW BY
DEFAULT IN ALL TRIALS.
SO, THAT'S REALLY WHAT WE CAN --
HOW WE CAN THINK ABOUT CAUSAL
INFERENCE FROM OBSERVATIONAL
DATA.
WE WANT TO ESTIMATE CAUSAL
EFFECT USING OBSERVATIONAL DATA
THEN WE CAN THINK OF WHAT THE
HYPOTHETICAL RANDOMIZED TRIAL IS
THAT WE WOULD LIKE TO CONDUCT.
AND THEN WE STRUCTURE AND
ANALYZE OBSERVATIONAL DATA AS IF
IT WAS COMING FROM THAT TRIAL
BECAUSE THAT HYPOTHETICAL TRIAL
IS THE TARGET OF CAUSAL
INFERENCE, WHAT WE WOULD LIKE TO
DO RATHER THAN USING REAL WORLD
DATA.
TARGET TRIAL IS REALLY ONE WAY
OF THINKING ABOUT WHAT WE'RE
DOING WITH OBSERVATIONAL DATA.
WE SAY, OKAY, THIS IS THE TRIAL
THAT WE WOULD LIKE TO CONDUCT,
THIS IS HOW I'M GOING TO
ORGANIZE MY DATA TO TRY TO
EMULATE THAT TRIAL.
BY DOING THAT I'M GOING TO
FOLLOW THE BASIC PRINCIPLES OF
STUDY DESIGN AND ANALYSIS THAT
WE KNOW HOW TO USE FOR TRIALS.
THIS ACTUALLY MEANS THAT EVERY
TIME WE'RE USING OBSERVATIONAL
DATA FOR CAUSAL INFERENCES WE'RE
ATTEMPTING TO EMULATE TARGET
TRIAL.
SOMETIMES THAT IS NOT EXPLICIT,
BUT THE FACT THAT SOME PEOPLE
DON'T MAKE IT EXPLICIT DOESN'T
MEAN THEY ARE NOT TRYING TO
EMULATE TARGET TRIAL.
THEY SHALL JUST -- THEY ARE JUST
NOT TELLING US.
IT'S BETTER TO MAKE IT EXPLICIT,
WE CAN HAVE A MORE EFFICIENT
CONVERSATION ABOUT PROS AND CONS
OF THAT PARTICULAR ANALYSIS.
IT GOES BOTH WAYS BECAUSE IF
SOMEONE IS ANALYZING
OBSERVATIONAL DATA AND WE ASK,
HEY, CAN YOU TELL US WHAT YOUR
TARGET TRIAL IS AND THEY CAN NOT
SPECIFY, PROBABLY THAT'S
OBSERVATIONAL DATA, IS NOT VERY
GOOD, DOESN'T KNOW THE ACTUAL
QUESTION THAT IS TRYING TO
ANSWER.
THIS CONCEPT OF TARGET TRIAL IS
IT'S A VERY OLD, NOT THE LABEL,
THE LABEL TARGET TRIAL IS
SOMETHING THAT WE CAME UP WITH,
BUT THE CONCEPT ITSELF HAS BEEN
USED AT LEAST FROM THE 1950s,
DORN, FROM NIH, WAS WRITING
ABOUT THIS IN 1953, WOLD WAS AN
ECONOMICICIAN IN SWEDEN, AND
COCHRANE AND GRADUATE STUDENTS,
RUBIN AND OTHERS IN THE '70s
AND '80s, AS IF YOU WERE
COMING FROM A TRIAL.
WE HAD TO WAIT UNTIL 1996 THAT
JAMIE ROBBINS HAD A GENERAL
THEORY THAT HAD THE TARGET TRIAL
AT THE CENTER AND THAT WAS
GENERAL BECAUSE COULD BE USED
FOR TIMELINE TREATMENTS AS
OPPOSED TO TREATED, NOT TREATED,
BECAUSE WHEN WE SAY WE WANT TO
ESTIMATE THE EFFECT OF A
GLP-1-BASED THERAPY WE DON'T
MEAN TAKING ONE PILL, WE TALK
ABOUT THE EFFECT OF TAKING THE
PILL OVER TIME AND AS WE'VE
HEARD MAYBE WITH DIFFERENT DOSES
OVER TIME DEPENDING ON THE
CLINICAL RESPONSE.
SO GENERAL THEORY OF CAUSAL
INFERENCE FOR TIME IS WHAT
ROBINS DEVELOPED IN 1986.
SO, THIS CONCEPT OF TARGET TRIAL
LEADS TO A WAY OF THINKING ABOUT
CAUSAL INFERENCES FROM
OPERATIONAL DATA INTO STEPS.
FIRST ONE IS WE HAVE TO ASK THE
CAUSAL QUESTION.
SECOND IS THAT WE HAVE TO ANSWER
THE CAUSAL QUESTION.
AND HOW DO WE ASK A CAUSAL
QUESTION?
WELL, ONE NATURAL WAY IS TO
DESCRIBE THE PROTOCOL OF TARGET
TRIAL.
WE CAN SPECIFY THE PROTOCOL OF
TARGET TRIAL, THEN WE CAN --
THAT IS ONE NATURAL WAY OF
ARTICULATING CAUSAL QUESTION
THAT WE'RE ASKING.
AFTER THAT WE EITHER CONDUCT
TARGET TRIAL, IF WE CAN, OR WE
USE OBSERVATIONAL DATA TO
EXPLICITLY EMULATE EACH OF THE
COMPONENTS OF THE PROTOCOL OF
THE TARGET TRIAL AND EXPLICITLY
IS REALLY THE KEY WORD.
SO, WHAT I'M SAYING IS THE FIRST
THING WE DO WHEN WE'RE USING
REAL WORLD DATA, USING
OBSERVATIONAL DATA, TO DESIGN A
RANDOMIZED TRIAL.
AND THEN ONCE WE KNOW WHAT IS
THE TARGET TRIAL WE'RE TRYING TO
EMULATE THEN WE CAN MOVE TO WORK
WITH OBSERVATIONAL DATA.
WHEN I SAY WE SPECIFY PROTOCOL
OF TARGET TRIAL WE SPECIFY EACH
OF THE BASIC COMPONENTS OF THE
PROTOCOL OF ANY RANDOMIZED TRIAL
WE HAVE TO DESCRIBE ELIGIBILITY
CRITERIA, TREATMENT STRATEGIES,
ASSIGNMENT, OUTCOMES, CAUSAL
CONTRASTS, ET CETERA.
AND THEN ONCE WE HAVE OUR
PROTOCOLS, THEN WE GO TO THE
OBSERVATIONAL DATA AND DESCRIBE
HOW WE MAP EACH OF THESE
COMPONENTS INTO THE
OBSERVATIONAL DATA.
NOW, BY DOING THIS, WE WILL
ELIMINATE THE DESIGN BIASES.
BY DOING THIS WE MAKE SURE THERE
ARE NOT BIASES DUE TO SELECTION
OF PREVALENT USERS OR IMMORTAL
TIME, THEY DISAPPEAR IF WE DO
THIS PROCESS WELL.
WE'RE LEFT WITH DATA BIASES.
IF THERE ARE NOT ENOUGH
CONFOUNDERS, THOSE THINGS CANNOT
BE USING THE TARGET TRIAL
FRAMEWORK.
WHAT IS THE IMPORTANCE OF
ELIMINATING THE DESIGN BIASES?
WELL, LET ME JUST GIVE YOU AN
EXAMPLE OF WHAT HAPPENS TO THE
PREVIOUS TWO CASES, HORMONE
THERAPY AND STATIN THERAPY
CASES, WHEN WE APPLY THE TARGET
TRIAL FRAMEWORK TO THE
OBSERVATIONAL DATA.
IN BOTH CASES, NOW WE FIND
RESULTS FULLY COMPATIBLE WITH
THOSE OF THE RANDOMIZED TRIALS
BOTH FROM HORMONE THERAPY AND
STATINS AND CANCER WHERE BARBARA
DICKERMAN LATER STUDIED USING
RECORDS THAT SHOWED USING THE
OBSERVATIONAL DATA WE ALSO FIND
THE EFFECTS OF STATINS ON
CANCER, BECAUSE THE TWO EXAMPLES
HAVE MOSTLY BIASES DUE TO
INCORRECT DESIGN, NOT DUE TO
INSUFFICIENT INFORMATION IN THE
OBSERVATIONAL DATA.
SO, THE PROBLEM IN THESE TWO
EXAMPLES THAT I GAVE YOU WASN'T
LACK OF RANDOMIZATION.
THE PROBLEM WAS INCORRECT DESIGN
OF THE OBSERVATIONAL ANALYSIS,
ESSENTIALLY THE FOLLOW-UP WAS
NOT STARTED, TIME ZERO WAS NOT
TIME OF ASSIGNMENT OR THERE WAS
INFORMATION THAT WAS NOT KNOWN
AT TIME ZERO, AND THAT WAS USED
TO CLASSIFY PEOPLE INTO ONE
GROUP OR THE OTHER GROUP, THINGS
LIKE WE WOULD NEVER DO IN A
RANDOMIZED TRIAL.
SO NOTHING WRONG WITH THE
OBSERVATIONAL DATA IN THIS CASE,
AND IN MANY OTHERS, THE PROBLEM
WAS HOW THE DATA WERE USED.
OKAY.
SO, DESIGN BIASES ARE BAD.
BUT WE KNOW HOW TO ELIMINATE
THEM.
WE CAN EXPLICITLY EMULATE TARGET
TRIAL.
WE'RE LEFT WITH DATA BIASES,
SPECIFICALLY CONFOUNDING DUE TOE
LACK OF RANDOMIZATION.
HOW BAD IS THAT?
AND THE FIRST POINT IS TO ANSWER
THAT QUESTION, WE NEED TO SOLVE
THE DESIGN BIASES.
WE CANNOT ASK ABOUT CONFOUNDING
IN AN OBSERVATIONAL STUDY THAT
IS NOT DESIGNED WELL BECAUSE TO
GET BIAS THAT CANNOT BE
ADJUSTED, STUDIES HAPPEN WITH
THE DESIGN BIAS, SO THEY ARE SO
STRONG AND DUE TO STRUCTURE, NO
POSSIBILITY OF ADJUSTING FOR
THEM IN MOST CASES.
SO WE FIRST EMULATE TARGET
TRIAL, EXPLICITLY, AND
CONFOUNDING, THAT IS ONE OF THE
ADVANTAGES OF THE EXPLICIT
EMULATION OF A TARGET TRIAL THAT
WE CAN FOCUS ON CONFOUNDING, ON
THE DATA, WITHOUT HAVING TO BE
DISTRACTED BY ALL THE OTHER
BIASES THAT ARE REALLY
SELF-INFLICTED BIASES.
THEY HAVE NOTHING TO DO WITH THE
QUALITY OF THE DATA.
AND THEN THERE ARE MANY EXAMPLES
OF TARGET TRIAL -- OF USE OF
OBSERVATIONAL DATA TO EMULATE A
TARGET TRIAL IN WHICH RESULTS
ARE SIMILAR TO THOSE FROM THE
TRIALS.
THERE ARE ALSO MANY EXAMPLES, I
DON'T HAVE TIME TO GO OVER SOME
OF THEM HERE, IN WHICH
OBSERVATIONAL EMULATIONS HAPPEN
BEFORE THE TRIALS WERE CONDUCTED
AND THEN THE TRIAL ESSENTIALLY
IS CONFIRMED, OBSERVATIONAL
STUDIES ARE DONE.
SO THERE ARE MANY CASES IN WHICH
WE HAVE -- WE CAN NOW DOCUMENT
IN WHICH THE REAL WORLD DATA
WHEN USED WELL IN CASES IN WHICH
CONFOUNDING IS NOT MASSIVE, OR
THERE'S VERY GOOD DATA ON
CONFOUNDERS OR BOTH, THEN OF
COURSE THIS IS THE IDEAL
SCENARIO FOR THE USE OF REAL
WORLD DATA.
SO LET ME GIVE JUST ONE QUICK
EXAMPLE, FOR GLP-1-BASED
THERAPIES.
AND A FEW YEARS AGO WE SENT WITH
THE HELP OF COLLEAGUES FROM
PCORI I WROTE A WHITE PAPER ON
HOW TO USE OBSERVATIONAL DATA TO
EMULATE TARGET TRIALS OF
DIABETES THERAPIES.
AND THEN SEVERAL GROUPS AROUND
THE COUNTRY WERE FUNDED BY PCORI
TO CONDUCT STUDIES THAT OF
COURSE INVOLVED GLP-1-BASED
THERAPY.
SO LET ME DESCRIBE ONE OF THOSE
STUDIES.
FIRST LET ME TELL YOU WHAT THE
TARGET TRIAL IS BECAUSE THE
FIRST THING IS TO DESIGN TARGET
TRIAL, THEN WE TALK ABOUT THE
OBSERVATIONAL DATA.
THIS IS THE SUMMARY OF THE
PROTOCOL OF TARGET TRIAL IN
WHICH WE TAKE PEOPLE WITH
DIABETES, WHO ARE ON METFORMIN
AND NEED SECOND THERAPY AND
THOSE PEOPLE WOULD BE RANDOMIZED
TO ONE OF THOSE FOUR THERAPIES,
EITHER GLP-1 R.A. OR OTHERS,
FOLLOWED TO ESTIMATE RISK OF
MAJOR CARDIAC EVENTS.
THIS PCORI STUDY, WHICH COMBINED
DATA FROM PATIENT HEALTH SYSTEMS
AND INSURANCE PROVIDERS AROUND
THE U.S., THAT'S ABOUT 5 MILLION
PEOPLE WITH DIABETES THAT
DE-DUPLICATED BECAUSE OF COURSE
AS WE HAVE HEARD BEFORE SOME
PEOPLE MAY APPEAR IN MORE THAN
ONE SYSTEM OVER TIME.
THEY WERE LINKED TO NATIONAL
INDEX, MOSTLY ELECTRONIC HEALTH
RECORDS, THIS IS VERY RICH
CLINICAL DATA.
THERE ARE MEASUREMENTS OF HBA1C
AND MANY OTHER LAB INDICATORS.
AFTER APPLYING ELIGIBILITY
CRITERIA OF THE TARGET TRIAL,
75,000 INDIVIDUALS IN THIS
DATASET THAT MET CRITERIA,
15,000 ON GLP-1 THERAPIES.
AND THIS IS A SUMMARY OF THE
RESULTS, AS YOU CAN SEE THE RISK
OF IS LOWEST FOR GLP-1s, AND
SGLT2s, COMPARED WITH SHUL
PHON UREAS, THERE ARE MANY OTHER
EXAMPLES WITH THE DATABASE FOR
RENAL OUTCOME, ET CETERA.
ANOTHER EXAMPLE OF THE USE OF
OBSERVATIONAL DATA IN WHICH
RESULTS ARE NOT AS CONCLUSIVE,
NOT AS INFORMATIVE LET ME
MENTION USE OF RECORDS IN THIS
CASE FROM THE V.A. TO ESTIMATE
EFFECTS BARIATRIC SURGERY ON
CARDIOVASCULAR EVENTS, USING
EXPLICIT TARGET TRIAL EMULATION.
AND YOU MAY NOTICE AT THE END OF
THE TITLE OF THIS PAPER IS A
QUESTION MARK BECAUSE THAT'S
REALLY WHAT WE'RE TRYING TO
DETERMINE HERE, IS IT POSSIBLE
TO USE OBSERVATIONAL DATA FROM
ELECTRONIC HEALTH RECORDS TO
ESTIMATE EFFECT OF BARIATRIC
SURGERY?
THERE ARE MANY OBSERVATIONAL
STUDIES THAT HAVE BEEN PUBLISHED
IN THE PAST, AND THEY TEND TO
FIND SOMETIMES A SURPRISINGLY
BIG EFFECT OF BARIATRIC SURGERY
ON CORONARY HEART DISEASE.
IN THIS ANALYSIS WE WENT OVER
THE PREVIOUS STUDIES.
WE FOUND PLACES IN WHICH THEY
DEVIATED FROM WHAT THE TARGET
TRIAL WOULD HAVE DONE.
WE DID WHAT THE TARGET TRIAL
WOULD HAVE DONE AND WE CONCLUDED
THERE WAS NOT MUCH EVIDENCE OF
STRONG EFFECT ON CARDIOVASCULAR
DISEASE OF BARIATRIC SURGERY, SO
HERE THIS IS AN EXAMPLE THAT I
WANTED TO SHOW BECAUSE THE
ANSWER IS WE DON'T REALLY TRUST
THE OBSERVATIONAL DATA HERE
BECAUSE THERE'S NOT ENOUGH
INFORMATION TO REALLY EMULATE
TARGET TRIAL.
WE HAD TO MAKE A LOT OF
DECISIONS BECAUSE FOR EXAMPLE WE
DON'T KNOW WHEN A PERSON GOES TO
THE DOCTOR AND WHEN THAT PERSON
IS ASSIGNED TO THE PROCESS THAT
MAYBE A YEAR LATER WILL END UP
WITH SURGERY.
WHAT HAPPENS IN MANY STUDIES IS
THEY COMPARE THOSE WHO HAVE
SURGERY AND THOSE WHO DON'T HAVE
SURGERY BUT THOSE ARE THE
PREVIOUS SIX MONTHS OF THOSE
PEOPLE ARE VERY DIFFERENT AND
THAT IS NOT TAKEN ACCOUNT IN THE
OBSERVATIONAL ANALYSIS, MOST
OBSERVATIONAL ANALYSIS.
THIS IS AN EXAMPLE TO SAY, LOOK,
DOESN'T SEEM LIKE THERE'S MUCH
EFFECT, WHAT WE'LL DO IN A
TRIAL, BUT WE REALLY NEED
RANDOMIZED TRIAL.
IF WE WANT TO ANSWER THIS
QUESTION, WE'LL HAVE REACHED THE
LIMITS OF OBSERVATIONAL DATA.
THERE ARE TOO MANY ASSUMPTIONS
HERE.
THE GOOD THING IS THAT IT
PROVIDES EQUIPOISE FOR A TRIAL,
IF A TRIAL IS NOT ETHICAL
BECAUSE BARIATRIC SURGERY LOWERS
RISK OF HEART DISEASE, WELL,
ACTUALLY IT'S NOT CLEAR.
WE NEED THAT TRIAL.
MY POINT IS THAT OBSERVATIONAL
DATA ANALYSIS ARE NOT
NECESSARILY HOPELESS, MANY TIMES
CAN PROVIDE ACTIONABLE
INFORMATION.
AND SOMETIMES THEY CAN'T.
BUT AT LEAST THEY CAN HELP US
DECIDE WHEN A TRIAL IS THE ONLY
WAY TO GO.
NOW, THERE'S ALWAYS A KEY
QUESTION HERE, WHICH IS FINE.
WE USE THE TARGET TRIAL
FRAMEWORK.
WE DON'T HAVE DESIGN, BUT WE
STILL MAY HAVE CONFOUNDING, HOW
DO WE KNOW WE HAVE SUCCEEDED IN
ADJUSTING FOR CONFOUNDING?
WE CAN NEVER KNOW FOR SURE AND
THAT'S THE PROBLEM.
THAT'S WHY ALL THE THINGS BEING
EQUAL WE PREFER RANDOMIZED TRIAL
OVER OBSERVATIONAL EVOLUTION OF
THE RANDOMIZED TRIAL.
AND BUT THERE ARE SOME WAYS IN
WHICH WE CAN PROVIDE EMPIRICAL
EVIDENCE THAT THE OBSERVATIONAL
ANALYSIS IS NOT -- ONE WAY IS BY
USING NEGATIVE CONTROLS AND WE
HAVE HEARD ABOUT THAT THIS
MORNING.
FOR EXAMPLE, FOR DIABETES
THERAPIES, ONE POSSIBLE NEGATIVE
CONTROL OUTCOME IS THE RISK OF
CORONARY HEART DISEASE IN THE
FIRST THREE MONTHS OF TREATMENT.
WE DON'T EXPECT THAT THE
TREATMENTS WILL HAVE AN EFFECT,
A VERY SHORTENED EFFECT, IF WE
FIND SOMETHING THAT LOOKS LIKE A
VERY SHORT THERAPY EFFECT,
PEOPLE GETTING GLP-1 BASED
THERAPIES, AND THAT'S WHERE
WE'RE FINDING THIS.
THE OTHER IS BENCHMARKING, A
TWO-STAGE THINGS.
FIRST WE USE EFFECT ESTIMATE
FROM EXISTING TRIALS TO
BENCHMARK THE EFFECT ESTIMATED
FROM THE OBSERVATIONAL AND TRY
TO EMULATE.
IF WE CAN BENCHMARK THE EFFECT
FROM OBSERVATIONAL STUDIES TO
THOSE FROM TRIALS WE CAN GO TO
THE SECOND STAGE, USE THE
OBSERVATIONAL DATA TO EXTEND THE
INFERENCES, TWO THINGS THE TRIAL
COULD NOT ANSWER.
MULTIPLE EXAMPLES AT OUR GROUP
AND OTHER GROUPS HAVE BEEN
WORKING ON.
THIS IS NOT AN EASY PROCESS TO
BENCHMARK BECAUSE MANY TRIALS
ONLY PUBLISH INTENTION TO TREAT
EFFECT ESTIMATES BUT CANNOT BE
BENCHMARKED BECAUSE ESTIMATES
ARE AFFECTED BY ADHERENCE, AND
ADHERENCE PATTERNS MAY BE
DIFFERENT.
MANY TIMES THE BENCHMARKING WILL
REQUIRE A REANALYSIS OF TRIAL
FROM THE DATA TO BE ABLE TO
COMPARE THAT TO AN OBSERVATIONAL
DATA.
AND TO FINISH HERE WITH THIS
MESSAGE TRIALS AND OBSERVATIONAL
EMULATIONS ARE COMPLEMENTARY
APPROACHES.
WE CAN USE OBSERVATIONAL DATA
FOR MAKING UNTIL WE HAVE TRIALS,
CAN USE THE TRIAL TO DESIGN
BETTER OBSERVATIONAL STUDIES,
FOR EXAMPLE WITH BENCHMARKING,
AND CAN USE OBSERVATIONAL
EMULATION TO ANSWER QUESTIONS
THE TRIAL COULDN'T.
THIS IS NOT A COMPETITION.
THIS IS NOT A COMPETITION
BETWEEN RANDOMIZED TRIALS AND
REAL WORLD DATA.
THERE IS A ROLE FOR BOTH TO PLAY
IF WE KEEP THE RIGHT BALANCE
HERE.
PLEASE KEEP IN MIND THE
TWO-STAGE PROCESS, FIRST ASK THE
QUESTION, THEN ANSWER IT.
DON'T JUMP INTO THE
OBSERVATIONAL DATA LANGUAGE.
NO, FIRST WE NEED TO KNOW WHAT
IS THE EFFECT THAT WE'RE TRYING
TO ESTIMATE.
THEN WE DESIGN OUR OBSERVATIONAL
ANALYSIS AROUND THAT.
AND IF ANYTIME SOMEONE PROVIDES
YOU WITH EXACT ESTIMATES FROM
OBSERVATIONAL DATA ASK THEM WHAT
IS YOUR TARGET TRIAL.
IF THEY KNOW THE TARGET TRIAL
YOU'RE GOING TO HAVE A FRUITFUL
CONVERSATION.
IF THEY DON'T, YOU ARE GOING TO
HELP THEM A LOT.
SO THANK YOU VERY MUCH.
AND THESE ARE WHAT I THINK ARE
OUR FUNDERS.
>> THANK YOU, MIGUEL.
NOW I WOULD LIKE TO WELCOME BACK
ALL THE SPEAKERS.
WE HAVE A LOT OF QUESTIONS.
I HOPE I CAN GO THROUGH ALL OF
THEM.
IF YOU CAN STOP SHARING YOUR
SLIDES AND WE CAN HIGHLIGHT ALL
THE SPEAKERS.
SO I'LL START WITH AN EASY ONE.
THIS QUESTION IS FOR ANIA, MAYBE
FOR LESLEY AS WELL.
THERE'S A QUESTION ABOUT SORT OF
REASONABLE COMPARATORS IN THE
PRAGMATIC TRIALS, THE QUESTION
IS WHETHER ALL ARE REASON ENABLE
A PRAGMATIC TRIAL.
DO WE NEED A TRIAL TO COMPARE
THE MOST POTENT DRUG VERSUS
LEAST POTENT, OR SHOULD WE FOCUS
ON DRUGS THAT ARE SIMILAR
EFFICACY?
SO WHAT ARE YOUR THOUGHTS ABOUT
HOW TO BEST USE PRAGMATIC TRIAL
SORT OF APPROACH TO STUDY
MEDICATIONS?
LESLEY,
>> LESLEY, DO YOU WANT TO GO
FIRST?
>> QUICK ANSWER, WHAT IS THE
QUESTION, THE DECISION WE'RE
TRYING TO INFORM, RIGHT?
AND THAT WOULD GUIDE THE CHOICE
OF COMPARATORS.
I'LL TURN IT OVER TO ANIA TO
GIVE A CLINICAL ANSWER.
>> I MEAN, I AGREE, IF YOU DON'T
KNOW THE QUESTION IT'S HARD TO
SAY HOW THE TRIAL SHOULD BE
DESIGNED OR STUDY SHOULD BE
DESIGNED.
YOU KNOW, RIGHT NOW I THINK THE
INTEREST IS IN TERMS OF THE NEW
HIGHLY EFFECTIVE MEDICATIONS,
AND I THINK WHAT I TRIED TO SHOW
IS WE'RE USING OLDER MEDICATIONS
AND NEED TO SEE HOW THEY WORK
BUT MAY NEED TO USE MORE THAN
ONE.
IF AVERAGE EFFICACY IS 5% OR
MAYBE 7 OR 8% AND NEWER
MEDICATIONS IS 15 OR 20%, THEN
IT'S VERY DIFFERENT.
MECHANISMS ARE ALSO VERY
DIFFERENT.
NOT EVERYBODY WILL RESPOND TO
SOMETHING THAT HAS A GLP-1
COMPONENT, THERE ARE RARE
INDIVIDUALS WHO HAVE TROUBLE
TOLERATING EVEN WHEN WE GO UP
SLOWLY, VERY RARE, BUT IT DOES
HAPPEN.
AND I THINK WE HAVE TO KEEP IN
MIND THERE'S NOT ONE TYPE OF
OBESITY.
SO, THERE ARE MANY DIFFERENT
OPTIONS IN TERMS OF HOW DO WE
FIGURE OUT WHAT WORKS BEST FOR
WHICH PATIENT, AND WHO MAY
GARNER THE MOST BENEFIT.
>> THANK YOU.
SO, THIS QUESTION COULD BE VERY
LONG BUT IT'S IMPORTANT.
MIGUEL AND LESLEY MAKE THE POINT
ABOUT THE NEED FOR RANDOMIZATION
FOR CERTAIN QUESTIONS.
BUT WHAT STRUCK ME IS THAT WHEN
I THINK ABOUT COMPARISONS THAT
REQUIRE RANDOMIZATION IT'S USUAL
THROW COMPARE DIFFERENT
MODALITIES, RIGHT? COMPARING
ONE AOM VERSUS ANOTHER EVEN
THOUGH IT'S DIFFICULT AS WE JUST
DISCUSSED IT'S EASIER TO
COMPARED TO PAIRING WITH
BARIATRIC SURGERY OR WITH
LIFESTYLE BEHAVIORAL TREATMENTS.
BUT AT THE SAME TIME, IT'S HARD
TO RECRUIT PATIENTS.
IN THIS CASE, REAL WORLD DATA
STUDY MIGHT NOT BE FEASIBLE,
PRAGMATIC TRIAL IS ALSO
CHALLENGED, TRYING TO FIGURE OUT
IF THERE'S AN INTEREST TO
COMPARE TREATMENT MODALITIES,
LET'S SAY DRUG VERSUS NON-DRUG
TREATMENT HOW DO WE DO THIS?
THE QUESTION IS FOR EVERYONE.
>> I'LL START AND SAY, MIGUEL, I
APPRECIATED THE WAY YOU ENDED BY
TALKING ABOUT LIKE THERE ARE A
COUPLE STEPS HERE, RIGHT?
I THINK WHAT YOU HIGHLIGHTED IN
THE PAPER THAT YOU SHOWED
COMPARING BARIATRIC SURGERY TO
MEDICATION THERAPY WAS LIKE
THAT'S WHERE A TARGET TRIAL
EMULATION STUDY CAN REALLY LAY
THE GROUND WORK FOR A RANDOMIZED
TRIAL AND DEMONSTRATE LIKE TURNS
OUT WE ACTUALLY HAVE EQUIPOISE,
RIGHT?
I THINK THAT WAS AN ELEGANT WAY
OF SHOWING HOW ONE CAN INFORM
THE OTHER.
>> RIGHT.
AND THE CHOICE BETWEEN GROUPS
HERE IS REALLY DICTATED BY WHAT
THE QUESTION IS.
IF THE QUESTION HAS BEEN ASKED
FOR CLINICAL REASONS, BASED ON
DOCTORS, THEY HAVE NO INTEREST
IN COMPARING TWO THINGS THAT
THEY ARE NEVER GOING TO CONSIDER
AS ALTERNATIVE THERAPY, IF THE
QUESTION IS ASKED BY REGULATOR
SIMILAR CONSIDERATIONS APPLY.
YOU DON'T WANT TO COMPARE ONE
TREATMENT VERSUS PLACEBO WHEN
REALLY THERE IS AN EXISTING
TREATMENT THAT WORKS WELL, THEN
IT HAS TO BE TO HAVE COMPARISON,
THAT'S THE ONLY THING THAT MAKES
SENSE FROM CLINICAL POINT OF
VIEW, EVEN THOUGH IT'S NOT
ALWAYS LIKE THAT EVEN FROM A
REGULATORY POINT OF VIEW, WE
SHOULD CONSIDER SOME CHANGES
THERE.
BUT THIS IS SOMETHING THAT
APPLIES TO ANY TYPE OF STUDY
DESIGN BECAUSE THAT IS OF COURSE
A QUESTION OF INTEREST, WE CAN
DISCUSS WHETHER IN THE REAL
WORLD THOSE THINGS ARE REALLY
ALTERNATIVES.
IF THEY ARE NOT CONSIDERED
ALTERNATIVES BY DOCTORS AND
YOU'RE GIVING TREATMENT A AND B
TO DIFFERENT PATIENTS DIFFICULT
TO ANSWER WITH OBSERVATIONAL
DATA.
THIS MORNING WE HEARD ABOUT
EXAMPLE FOR COVID, TRIALS SHOWED
IT WORKED VERY WELL, BUT
OBSERVATIONAL STUDY PUBLISHED
SIX MONTHS BEFORE THE TRIAL WAS
FINISHED.
SAME THING, THAT WAS A PERFECT
EXAMPLE BECAUSE THERE WAS
CONFOUNDING.
DOCTORS HAD NO IDEA WHETHER IT
WORKED OR NOT, USING MORE OR
LESS RANDOM, SOME HOSPITALS
USING IT ONLY WHEN THEY HAD IT.
THAT'S PERFECT SETTING FOR
OBSERVATIONAL STUDY.
WHAT THE TRIAL DID WAS CONFIRM
WHAT OBSERVATIONAL STUDIES
FOUND.
IT WAS IMPOSSIBLE, VERY
CONFOUNDING IN THAT CASE.
THAT'S ONE EXTREME.
THE OTHER EXTREME IS COMPARING
TWO THERAPIES WITH DIFFERENT
INDICATIONS REALLY, THERE'S NO
WAY WE CAN DO IT WITH
OBSERVATIONAL DATA.
>> AND I'LL JUST ADD IN TERMS OF
PATIENTS AND THEIR PREFERENCE
FOR TREATMENT, OBVIOUSLY A LOT
OF TIME PATIENTS WILL KNOW, AND
OBVIOUSLY THOSE TREATMENTS WILL
BE DIFFERENT WHETHER A
MEDICATION OR SURGERY.
WITHIN CLINICAL CARE WE OF
COURSE DEMONSTRATE AND DISCUSS
WITH PATIENTS THAT CONTINUUM OF
CARE, THEY MAY REQUIRE ONE
TREATMENT AT ONE POINT IN THEIR
LIFE, ANOTHER TREATMENT AND ITS
ADDITIVE.
IF YOU ARE COMPARING OR LOOKING
AT TWO TREATMENTS THAT ARE, YOU
KNOW, QUITE DIFFERENT, IT'S
REALLY IMPORTANT TO KNOW WHAT
YOU'RE MEASURING REGARDLESS OF
WHAT TYPE OF TRIAL YOU'RE
LOOKING AT BECAUSE, FOR EXAMPLE,
IF YOU WANT TO LOOK AT IMMEDIATE
ANTI-INFLAMMATORY EFFECTS COMING
ABOUT AND WE'RE SEEING
POTENTIALLY WITH THESE NEW
MEDICATIONS, IF WE'RE NOT
MEASURING THAT WE CAN'T COMPARE
THAT.
WHAT IS HAPPENING IN BARIATRIC
SURGERY, RIGHT?
AND WHAT DEGREE OF THE EFFECT IS
FROM THE WEIGHT REDUCTION
ITSELF, RIGHT?
BECAUSE WE SEE WEIGHT REDUCTION,
SIGNIFICANT DEGREES WITH SURGERY
AND MEDICATION.
BUT WHERE THE ADDITIONAL EFFECT
OF THE AGENTS THEMSELVES THAT
MAY NOT BE HAD WITH BARIATRIC
SURGERY ALONE, FOR EXAMPLE,
DIRECT EFFECTS ON THE BETA CELL
OR ISLET WHICH IMMEDIATELY OCCUR
WITH THE NEW CLASS OF MEDICATION
SO I THINK IT'S INCREDIBLY
IMPORTANT A PRIORI TO REALLY
KNOW WHAT YOU'RE GOING TO
MEASURE AND, AGAIN, THAT COMES
BACK TO WHAT IS YOUR QUESTION,
YEAH.
>> YES, YES, YES.
AS YOU REMEMBER, MIGUEL TELLING
ME ASKING THE RIGHT QUESTION IS
50% OF THE BATTLE IF NOT MORE
.
ALL THREE OF YOU MENTIONED
STAKEHOLDER ENGAGEMENT.
ANIA, YOUR EXAMPLE HELPED US
CRYSTALLIZE THIS NOTION WE'RE
NOT DEALING WITH DATA, SO FOR
MANY OF US, IT'S EASY TO FORGET
THIS IS AN IMPERFECT REFLECTION
OF PATIENTS' LIVED EXPERIENCES.
DO YOU HAVE ANY EXAMPLES WHICH
STAKEHOLDER ENGAGEMENT HAS
WORKED WELL, MEANING NOT ONLY
INFORMED THE QUESTION WE SHOULD
BE ASKING BUT ALSO HELP US
DESIGN THE STUDY SO THAT THE
STUDY CAN REALLY ANSWER THE
QUESTION.
THIS AGAIN IS FOR ALL THREE
SPEAKERS.
>> I WILL BRING FORWARD THE
EXPERIENCE WE HAD WITH THE
ADAPTABLE TRIAL, WHICH WAS
COMPARING HIGH DOSE VERSUS LOW
DOSE ASPIRIN FOR SECONDARY
PREVENTION OF CARDIOVASCULAR
EVENTS.
THAT WAS A PCORI-FUNDED STUDY
WHERE WE ENGAGED PATIENTS AS
REAL PARTICIPANTS, AND THAT
GROUP OF PATIENTS WAS ENGAGED
FROM THE BEGINNING.
THEY HELPED US WITH DESIGN.
THEY HELPED US WITH THINKING
ABOUT HOW TO RECRUIT.
I MEAN, TRULY EVERY ASPECT OF
THE STUDY THEY WEIGHED IN ON,
INCLUDING LIKE HOW TO EXPLAIN
THE RESULTS, RIGHT?
HOW TO REPORT THE RESULTS.
SO THAT'S OFTEN THE EXAMPLE THAT
WE USE IN THE PRAGMATIC TRIAL
SPACES.
THAT WAS AN EARLY EXAMPLE.
THERE ARE MANY, MANY THAT HAVE
ACCUMULATED OVER TIME AS WE'VE
REALLY EXPERIENCED THE VALUE OF
BRINGING THOSE PERSPECTIVES IN.
I'M SURE, YOU KNOW, ANIA, YOU
AND MIGUEL HAVE PLENTY OF
EXAMPLES TOO.
>> YEAH, I MEAN, I AGREE AGREE.
IF THAT'S THE ONLY TAKEHOME FROM
THE TALK, TO ENGAGE PATIENTS AS
PARTICIPANTS REGARDSLESS OF THE
TRIAL WE'RE DOING BECAUSE
ULTIMATELY WE CAN ONLY INFER
FROM THEIR LIVED EXPERIENCES AND
WHAT THEY ARE ACTUALLY
INTERESTED IN.
I REALLY DON'T THINK THAT WE DO
THAT ENOUGH.
AND WHAT BRINGS OUR PATIENTS
BACK IS WHAT THEY ARE
EXPERIENCING, QUALITY OF LIFE IS
WHAT THEY REALLY -- OF COURSE
IT'S HEALTH AND EVERYTHING BUT
HOW ARE THEY ABLE TO LIVE THEIR
LIFE TO THE FULLEST WITH THE
CARE THAT WE PROVIDE SO I
COULDN'T AGREE MORE.
>> ALONG THESE LINES WE HAVE A
PCORI-FUNDED PROJECT, WE ENGAGE
PATIENTS, HOW SHOULD WE ANALYZE
DATA?
AND SO WE HAVE FOCUS GROUPS WITH
PATIENTS, AND WE -- FROM THE
HOSPITALS AROUND HERE, WE TAUGHT
THEM THE PROTOCOL EFFECT, WE
EXPLAIN WHY PEOPLE WANT TO USE
INTENTION TO TREAT EFFECTS FOR
TRIALS AND THEY UNDERSTOOD.
WE USED A NON-TECHNICAL LANGUAGE
BUT WE UNDERSTAND, BUT THAT'S
NOT WHAT WE WANT BECAUSE YOU
WEREN'T GIVING US THE EFFECT IN
THE STUDY WHICH 20%, 30% OF
PEOPLE, 40% ARE NOT TAKING A
DRUG, CONTAMINATED EFFECT, YEAH,
BUT PEOPLE SAY THAT'S A
REFLECTION OF WHAT HAPPENS IN
REAL LIFE.
YES, BUT AS A PATIENT, THAT'S --
I DON'T CARE, I WANT TO KNOW IF
I TAKE THE TREATMENT.
DON'T GIVE ME THE EFFECT OF
STUDYING 40% OF PEOPLE THAT
DIDN'T TAKE THE TREATMENT.
WHAT IF I TAKE IT?
SO THIS IS ONE OF THE REASONS
ACTUALLY THAT WE USE TO PROPOSE
THAT IN ALL TRIALS WE EXAMINE
PROTOCOL EFFECT, A LITTLE BIT
MORE SOPHISTICATED.
SO, YES, HAVING THIS INPUT IS
VERY HELPFUL FOR ALL OF US.
>> THANK YOU.
NEXT QUESTION AGAIN IS FOR ALL
SPEAKERS.
AGAIN, JUST TRYING TO RECONCILE
DIFFERENT THINGS THAT WE HEARD
TODAY.
SO, ON ONE HAND WE ALL RECOGNIZE
THAT WE NEED STUDIES THAT LOOK
AT LONG-TERM OUTCOMES.
ON THE OTHER HAND, WE ALSO
RECOGNIZE THAT THE LANDSCAPE IS
SHIFTING VERY QUICKLY IN THIS
AREA.
SO HOW DO WE MAKE SURE THAT
STUDY OR PRAGMATIC TRIALS AT THE
END OF THE STUDY THE RESULT WILL
BE RELEVANT OR HOW DO WE MAKE
SURE THAT WE INCORPORATE THE
CHANGING LANDSCAPE IN OUR
DESIGN?
AND, YOU KNOW, THERE'S ALWAYS
THIS THING ABOUT HAVING TO
REGISTER YOUR TRIAL OR PROTOCOL
BEFORE YOU DO THE STUDY,
AMENDMENTS DOWN THE ROAD, SO
HELP US FIGURE OUT HOW TO DO A
STUDY THAT'S ROBUST FOR
LONG-TERM OUTCOMES BUT
ACCOMMODATING RAPIDLY CHANGING
LANDSCAPE?
>> I DON'T THINK IT'S POSSIBLE.
I THINK IN THE BACKGROUND
THERAPIES KEEP CHANGING, YOU
HAVE TO KEEP DOING STUDIES.
THAT'S HOW I'D SAY IT.
OF COURSE, THAT IS -- THAT MAY
BE -- YOU COULD HAVE FASTER
REACTION, WHERE YOU'RE USING
OBSERVATIONAL STUDIES, WHEN
YOU'RE DOING TRIALS.
BUT THERE'S ALSO THIS
POSSIBILITY THAT WE DISCUSSED
WHEN WE TALK ABOUT BENCHMARKING,
WHEN SOMETHING THAT WE COULD
CONSIDER IS HAVING AN ORGANIZED
SYSTEM IN WHICH THE TRIAL, TYPE
OF TRIAL, LESLEY WAS STUDYING,
MAYBE HAS ONE YEAR OF FOLLOW-UP.
SO, WE CAN DO MORE OF THOSE.
AND FASTER.
AND THEN WE USE THE REAL WORLD
DATA TO BENCHMARK TO ONE YEAR.
IF WE GET THE SAME RESULT FOR
ONE YEAR WE CAN USE THE
OBSERVATIONAL DATA TO EXTEND TO
THREE OR FIVE YEARS.
SO THAT WE DON'T HAVE TO DO
FIVE-YEAR TRIALS ALL THE TIME.
WE CAN DO SHORTER TRIALS, USE
THEM AS BENCHMARK FOR THE REAL
WORLD DATA AND USE THE REAL
WORLD DATA FOR LONGER FOLLOW-UP.
AND IF WE CAN DO THAT IN SOME
WAY THAT IS NOT JUST HAPHAZARD,
THAT SOMEONE DOES A TRIAL, A
DIFFERENT PERSON DOES REAL WORLD
STUDY, IF WE CAN HAVE GROUPS OF
PEOPLE, TEAMS OF INVESTIGATORS
WITH EXPERTISE IN ALL OF THESE
AREAS THAT CAN WORK TOGETHER AND
DESIGN THE PROCESS IN THIS WAY,
WE PROBABLY WILL BE MORE
EFFICIENT.
>> I'LL ADD THAT THIS IS THIS
MAY BE SIMPLISTIC BUT IN TERMS
OF REGISTRIES, OF COURSE EUROPE
DOES A MUCH BETTER -- I'M NOT
GOING TO SAY BETTER BUT THEY DO
IT DIFFERENTLY, RIGHT?
SO THAT WOULD BE I THINK
INCREDIBLE TO HAVE A ROBUST
SYSTEM BECAUSE IT'S GOING TO
CONTINUE TO CHANGE INCREDIBLY
RAPIDLY.
JUST THE OTHER DAY I WAS, YOU
KNOW, SPEAKING WITH A COLLEAGUE,
AND WE WERE LIKE, CAN YOU
BELIEVE FIVE YEARS AGO, YOU
KNOW, AND I'VE BEEN DOING THIS
FOR ALMOST 20 YEARS, IT'S
AMAZING HOW IT'S GONE FROM
OBESITY NOT A DISEASE, CLEARLY A
DISEASE, TO WE HAVE THINGS THAT
CAN HAPPEN TO WOW WE HAVE THINGS
THAT IMPACT BIOLOGY.
WE'VE HAD BARIATRIC SURGERY BUT
NOT MEDICATIONS, IT'S CHANGING
SO RAPIDLY.
WE'RE IN OUR INFANCY.
SO IF IT'S CHANGING THIS RAPIDLY
NOW, I MEAN, MULTIPLY.
THERE'S HUNDREDS OF MEDICATIONS
IN DEVELOPMENT.
WE'RE ONLY TALKING ABOUT ONE
CLASS TODAY.
THERE ARE MULTIPLE OTHER CLASSES
THAT ARE BEING DEVELOPED.
SO, ANYWAY, IF THERE'S A WAY NOT
JUST TO CAPTURE MOMENTS IN TIME
WHICH IS WHAT WE DO WITH RCTs,
IF THERE'S A WAY TO CAPTURE
MOMENTS IN TIME AND CONTINUOUS
MOVING PICTURE, EVOLVING
PICTURE, THAT WOULD BE IDEAL.
>> I WOULD JUST UNDERSCORE
ACTUALLY BOTH OF THESE POINTS,
MIGUEL, THE POINT ABOUT
COORDINATED EFFORTS, RIGHT?
I'VE BEEN STRUCK OVER THE COURSE
OF THE ENTIRE DAY ABOUT THE
SHEER VOLUME OF QUESTIONS OF
GAPS THAT NEED TO BE FILLED.
AND THE WORST CASE SCENARIO,
EVERYONE TRIES TO DO THAT
INDIVIDUALLY.
MIGUEL MAKES AN IMPORTANT POINT,
LET'S BE COORDINATED THINKING
HOW TO DO REALLY IMPORTANT
LONG-TERM STUDIES.
ANIA, TO YOUR POINT, I AGREE
LIKE REGISTRIES HAVE TO BE A
COMPONENT OF THIS.
THERE'S, YOU KNOW, NO OTHER WAY,
I THINK.
>> SO THE NEXT FEW QUESTIONS ARE
FOR SPECIFIC SPEAKERS.
IF YOU DON'T GET A QUESTION TAKE
A MENTAL BREAK FOR 30 SECONDS.
ANIA, YOU MENTIONED THAT
ADHERENCE IS THE SECRET WEAPON,
PATIENTS POP IN AND REGAIN
WEIGHT, MAYBE THEY WILL TAKE THE
DRUG AGAIN, SO YOU ARE IN THIS
CLINICAL SPACE.
AND DO YOU KNOW IF THERE'S ANY
MOVEMENT ON JUST DEVELOPING SORT
OF EVEN MORE EXTENDED RELEASE
REGIMENS, ASSUMING THAT PATIENT
TOLERATED WELL, MAYBE YOU'LL
HAVE INJECTION THAT EVERY SIX
MONTHS, I NOTICED THE FIELD
MOVING TO ORAL MEDICATION FOR
GOOD REASON BUT ON THE FLIP SIDE
IS THERE ANY DEVELOPMENT ON THE
FRONT JUST TO FURTHER IMPROVE
ADHERENCE, IF WILL YOU?
>> YES.
SO GREAT QUESTION.
AND THERE'S MULTIPLE APPROACHES
TO MAINTENANCE.
AND I DO FULLY BELIEVE THAT
ADHERENCE IS GOING TO BE THE
SECRET WEAPON.
WHAT I DO CLINICALLY, I GIVE
PATIENTS, IF THEY WANT TO STOP,
I SAY LET'S DECREASE THE DOSE
AND SEE WHAT HAPPENS.
IF WE DECREASE THE DOSE AND
THEIR WEIGHT IS STABLE WE CAN
DECREASE AGAIN.
MOST OFTEN WHAT HAPPENS IS THAT
WE END UP INCREASING DOSE BACK
UP BECAUSE THEY ARE REGAINING
WEIGHT OR STRUGGLING.
SOMETIMES WE CAN DECREASE THE
DOSE FOR SOME TIME OR SPACE OUT
THE DOSE, SO PATIENTS DON'T TAKE
IT ONCE WEEKLY BUT MAYBE EVERY
OTHER WEEK AND THEN AFTER A YEAR
AND A HALF OR SO THEY INCREASE
BACK UP.
SO IT JUST DEPENDS ON THE
PATIENT.
WE DON'T HAVE ENOUGH
INFORMATION.
TO YOUR POINT IN TERMS OF
SPACING OUT THE DOSE FOR
MAINTENANCE, NOT JUST EVEN
SPACING OUT THE DOSE BUT
OPPORTUNITIES FOR THINGS THAT
ARE LESS FREQUENT THERE ARE A
FEW AGENTS IN DEVELOPMENT THAT
ARE MONTHLY, AND THERE'S ONE
CALLED MARITIDE, MONTHLY OR LESS
FREQUENT, WE'LL HAVE TO SAY
WHETHER THOSE MEDICATIONS, THAT
ONE AND ANY OF THE OTHERS IN
DEVELOPMENT, CAN ACTUALLY BE
TAKEN EVEN LESS FREQUENTLY THAN
WHEN ONCE A MONTH BUT IMAGINE
TAKING SOMETHING ONCE A MONTH,
SO 12 TIMES OR LESS A YEAR AND
TREATING OBESITY.
SO I THINK LOTS TO LOOK TOWARDS
AND THEN AS YOU MENTIONED, DAILY
ORAL MEDICATIONS COMING AS WELL.
AND ORAL SEMAGLUTIDE HIGHER DOSE
HAS BEEN INVESTIGATED, AND
LOOKED AT, AS POTENTIAL
TREATMENT FOR OBESITY SO WE'LL
AWAIT FDA EVALUATION AND THEN
THE NEXT ONE, A SMALL MOLECULE
ORAL DAILY.
AGAIN, THERE'S SO MUCH TO
ANTICIPATE.
THERE'S MANY ORAL -- DAILY ORALS
IN DEVELOPMENT AS WELL.
>> YES, ABSOLUTELY.
SO INSTEAD OF TEN PAPERS A DAY,
--
>> YES, EXACTLY.
NEXT QUESTION FOR MIGUEL.
TALKING ABOUT THE FEASIBILITY OF
STUDYING OFF-LABEL USE, SO
THERE'S A QUESTION ABOUT HOW DO
YOU ACTUALLY ASSEMBLE THE STUDY
POPULATION?
SO HAVE YOU USED TARGET TRIAL
EMULATION FRAMEWORK FOR
OFF-LABEL MEDICATION, NOT
NECESSARILY GLP-1 THERAPIES.
>> THAT IS ONE OF THE MAIN
ADVANTAGES, HAVING OBSERVATIONAL
DATA THAT YOU CAN DO THAT TYPE
OF THINGS.
MANY TIMES WHEN THE OUTCOME IS
NOT THE OUTCOME FOR WHICH THE
TREATMENT IS INDICATED,
CONFOUNDING, MAGNITUDE OF CON
FOUNDER IS SMALLER.
YES, WE DO THIS ALL THE TIME.
FOR EXAMPLE, WE'RE KNOW LOOKING
AT STARTING THERAPIES, NOT WHAT
IT IS INDICATED FOR.
WE'RE WORKING WITH THE
INVESTIGATORS TO TRY TO DO THE
COORDINATED EFFORT THAT LESLEY
WAS MENTIONING, AND FOR GLP-1
THERAPIES OF COURSE WE CAN LOOK
AT OUTCOMES THAT WERE NOT THE
OUTCOMES FOR WHICH THIS WAS
INDICATED, MANY PEOPLE ARE DOING
NOW.
YES, THIS IS ONE OF THE MAIN
USES OF THE REAL WORLD DATA.
THIS CAN BE THE FOUNDATION FOR
RANDOMIZED TRIALS LATER.
>> SO, THIS QUESTION FOR LESLEY.
WE SPOKE EARLIER ABOUT MEDICARE
NOT CURRENTLY COVERING THESE
DRUGS FOR OBESITY OR CHRONIC
WEIGHT MANAGEMENT.
IN THAT CASE IF WE STILL WANT TO
STUDY EFFECT OF THIS DRUG IN THE
ELDERLY POPULATION, HOW DO WE
USE REAL WORLD DATA TO
ACCOMPLISH THAT?
>> SO, IF I HAD LIKE A MAGIC
WISH WAND, MY MAGIC WAND WOULD
SAY LET'S USE COVERAGE WITH
EVIDENCE DEVELOPMENT, RIGHT?
WHERE AS WE MAKE THE DRUG
AVAILABLE FOR THE PURPOSES OF
STUDYING, THESE DRUGS AVAILABLE
FOR PURPOSES OF STUDYING,
QUANTIFYING THE EFFECT, AND
ANSWER THE IMPORTANT QUESTIONS
SO WE CAN BEGIN TO ACTUALLY
DEMONSTRATE OR EVALUATE NOT JUST
EFFECTIVENESS IN THAT
POPULATION, TO BEGIN TO LOOK AT
COST EFFECTIVENESS, A REAL
DRIVER.
CLEARLY THAT'S NOT A
CONSIDERATION FOR MEDICATION BUT
IT'S A CONSIDERATION FOR OTHER
PAYERS WHO WOULD LOOK TO
MEDICARE RESULTS, OR WOULD LOOK
TO THAT STUDY TO INFORM THEIR
DECISIONS.
>> A FEW MINUTES LEFT.
THIS IS OUR LAST QUESTION.
FOR ALL THE SPEAKERS.
WE SPOKE ABOUT -- MIGUEL SAID
OBSERVATIONAL STUDIES AND TRIALS
ARE COMPLEMENTARY.
ANIA MENTIONED REGISTRY DATA
FROM OTHER COUNTRIES.
LESLEY NICELY SAID, WELL, MAYBE
THERE'S SOMETHING THERE.
SO JUST INTERESTED IN YOUR
THOUGHT ABOUT HOW TO MAKE THAT
HAPPEN.
HOW DO WE HAVE A MORE ROBUST
EVIDENCE GENERATION PLATFORM TO
STUDY GLP-1 THERAPIES?
>> I'M GLAD YOU ENDED WITH AN
EASY QUESTION.
YOU KNOW, LET ME THROW OUT
OPTIMISM, AT THE END OF A DAY OF
A MEETING.
I DO THINK THAT AS WE LOOK AT
WHAT HAS HAPPENED, WHAT IS
HAPPENING IN TERMS OF ELECTRONIC
HEALTH RECORD DATA AND SOME
STANDARDIZATION EFFORTS, RIGHT?
THERE ARE TOOLS, WHETHER FHIR,
USCDI, STANDARDIZED PUMPS TO
MOVE DATA AROUND, I FEEL LIKE
WE'RE POTENTIALLY APPROACHING A
POINT WHERE THE KINDS OF DATA
THAT WE NEED TO ANSWER THESE
QUESTIONS ARE EXISTING AND COULD
BE PUT TOGETHER FOR THIS.
I WOULD LOVE TO THINK ABOUT
POTENTIALLY, YOU KNOW, THESE
QUESTIONS AS A DRIVING USE CASE
FOR HOW WE MIGHT DEVELOP SUCH A
PLATFORM, RIGHT?
SO WE COULD DO THE WORK THAT
WE'VE BEEN TALKING ABOUT ALL
DAY.
SO THERE'S MY OPTIMISTIC
RESPONSE.
>> LET ME ADD TO THAT OPTIMISM
TOO.
I THINK THAT WE ARE SEEING AN
INCREASING NUMBER OF EXAMPLES
AROUND THE WORLD HOW TO DO THIS,
IN PRINCIPLE THERE'S A REASON
WHY IT'S GOING TO HAPPEN IN THE
U.S. TOO.
IF YOU THINK FOR EXAMPLE DURING
THE PANDEMIC THE U.K. GAVE US A
LESSON HOW YOU CAN DO TRIALS
WITH LOTS OF PEOPLE, PRECISE
ESTIMATES LINKED TO ELECTRONIC
HEALTH RECORDS.
SO THAT'S ONE WAY IN WHICH YOU
CAN COMBINE BOTH SOURCES OF
INFORMATION.
WE HAVE PROJECTS IN SWEDEN IN
WHICH THEY ARE NATIONAL REG
REGISTRIES USED AS SOURCE FOR
TRIALS, WHICH MEANS YOU HAVE THE
REAL WORLD DATA AND TRIAL DATA
COMING FROM THE SAME PEOPLE.
AND YOU CAN DO BENCHMARKING,
SOMETIMES WE'VE DONE IT, DONE
THE BENCHMARKING OF TRIALS THAT
HAVEN'T BEEN FINISHED YET SO WE
CAN EXTEND THE RESULTS AFTER
THEY ARE FINISHED.
HERE IN THE U.S. THERE ARE A FEW
EXAMPLES, MOST PROMINENT MAY BE
THE V.A., THE LARGEST HEALTH
CARE SYSTEM IN THE COUNTRY.
VERY RICH DATA, INFRASTRUCTURE
ON THOUSANDS EVER INVESTIGATORS
THAT CAN ACCESS THE DATA BUT ARE
A SOURCE OF RANDOMIZED TRIALS,
DONE WITHIN THE HEALTH SYSTEM.
ONCE YOU HAVE THE SETTING,
TRIALS ARE DONE AS PART OF --
WITHIN THE HEALTH SYSTEM AND YOU
HAVE THE REAL WORLD DATA, COMING
FROM THE SAME PEOPLE WITH THE
SAME QUALITY, A LOT OF
OPPORTUNITIES OPEN, STARTING TO
HAPPEN, I HOPE TO SEE MUCH MORE
OF IT.
>> I'M ALSO AN OPTIMIST.
I'LL ADD OBESITY AFFECTS A
BILLION PEOPLE.
IN THOSE BILLION PEOPLE, OBESITY
IS RELATED OR CONTRIBUTES TO OR
PRIMARY CAUSE OF HUNDREDS OF
OTHER DISEASES, OVER 200.
AND SO NOT ONLY IS THIS AN
AMAZING OPPORTUNITY BUT IT'S
SOMETHING THAT I THINK HAS TO BE
DONE, SO MAYBE THIS IS THE
IMPETUS TO DO IT.
GIVEN SO MANY PEOPLE ARE
AFFECTED, WE CAN TRANSFORM
HEALTH IF WE CAN UNDERSTAND HOW
BEST TO TREAT THIS ONE DISEASE.
>> GREAT.
THERE'S A GOOD END TO OUR
FANTASTIC DISCUSSION.
THANK YOU ALL FOR THE VERY
EXCELLENT PRESENTATIONS.
I LEARNED A LOT FROM YOUR
PRESENTATIONS TODAY.
WITH THAT WE'RE READY TO MOVE TO
THE NEXT SESSION.
THAT'S FOR THE CO-CHAIRS.
THANK YOU.
>> FANTASTIC SESSION.
JUST REALLY IN AWE OF ALL THE
PRESENTERS TODAY.
IT'S BEEN A SPECTACULAR DAY.
I'VE LEARNED SO MUCH, REALLY
FEEL INSPIRED BY THE QUESTIONS
BEING ASKED AND ENGAGEMENT FROM
EVERYONE ATTENDING.
WE WANTED TO TRY TO SPEND A
LITTLE TIME SUMMING UP WHAT
WE'VE HEARD ABOUT MAJOR GAPS AND
OPPORTUNITIES.
I DID PULL TOGETHER SLIDES TO
TRY TO HELP KICK US OFF.
I WANT TO PUT A CHALLENGE OUT TO
THE ATTENDEES TO ENGAGE IN A
CONVERSATION ABOUT YOUR MAJOR
TAKEHOMES FROM TODAY SO FAR.
AND SORT OF I LIKE WHERE WE WERE
ENDING AROUND OUT-OF-THE-BOX
THINKING ABOUT WHAT'S IT GOING
TO TAKE TO MOVE THE FIELD
FORWARD RAPIDLY, CHANGES IN HOW
WE'RE AGGREGATING DATA OR
THINKING BOLDLY ABOUT HOW WE
USES GLP-1s IN USE CASE AROUND
DATA ACCESS, LONGITUDINAL, ET
CETERA, KICKING THAT OFF.
I WILL SHARE MY SCREEN AND BRING
UP SLIDES TO LOOK AT.
SO, WE KICKED OFF THE DAY BY
TALKING ABOUT THE GAPS IN OUR
KNOWLEDGE THAT WE NEEDED TO
ADDRESS.
AND THAT WAS THE MAIN FOCUS OF
THE CONFERENCE TODAY.
OUR GOAL IS TO IDENTIFY GAPS AND
OPPORTUNITIES ON REAL WORLD
EVIDENCE FOR CLINICAL DECISION
MAKING AND GUIDELINE
DEVELOPMENT, WE HEARD AROUND
REGULATORY HEALTH CARE DECISION
MAKING, BEST PRACTICES FOR STUDY
DESIGNS, LAST SESSION WAS GREAT
FOR THAT, AND THE SESSION
EARLIER THIS MORNING AS WELL AS
ANALYTIC METHODS TO ADDRESS
SPECIFIC ISSUES, WE HEARD SOME
ABOUT THAT TODAY.
WE'LL HEAR MORE ABOUT THAT
TOMORROW.
I WANTED TO SUM UP KEY IDEAS
THAT I HEARD FROM EACH OF THE
SESSIONS
WHAT I WAS STRUCK BY IS THE
SMALL MOLECULES AND THEY ARE
EMERGING, MANY MORE OF THEM,
INTERESTING TO SEE CAN WE
OBSERVE REAL WORLD EFFICACY IS
COMPARABLE WITH SMALL MOLECULES
COMPARED TO INJECTABLES.
I WAS INTERESTED IN THE
STATEMENT ABOUT HEALTH BENEFITS
OF GLP-1s, SEEM TO REQUIRE
CONTINUOUS LONG-TERM TREATMENT.
SO ARE THERE ALTERNATIVE
TREATMENT PROTOCOLS THAT CAN
HELP SOME LONG-TERM MAINTENANCE?
IS IT OPEN TO ONGOING QUESTIONS?
AND MANY PEOPLE SPOKE ABOUT
ADHERENCE ISSUES.
ADHERENCE AS DAVE DESCRIBED IN
REAL WORLD DATA, DESPITE
TREATMENT EFFECTS, WE DO NEED TO
UNDERSTAND WHY AND IS IT DRIVEN
MOSTLY BY ACCESS AND
AFFORDABILITY OR OTHER ISSUES AT
PLAY?
I WAS STRUCK BY DAVE'S LAST
SLIDE WHICH PROPOSED CLINICAL
PRIORITIES FOR HOW WE THINK
ABOUT USING GLP-1s WITH TYPE 2
DIABETES FIRST, TARGETING
POPULATIONS FOR WEIGHT LOSS, WHO
HAVE CHRONIC DISEASE SUCH AS
CARDIOVASCULAR DISEASE, SLEEP
APNEA, BROAD PATIENT POPULATION
SUCH AS OBESITY WITHOUT CHRONIC
CONDITIONS, AND POPULATION
PREVENTIVE HEALTH.
WONDERING IF THIS IS THE RIGHT
SELECTION, DOES SEEMS TO BE HOW
MEDICARE IS OPERATING BUT IS
THAT THE RIGHT WAY TO MOVE
FORWARD AND SHOULD WE HAVE MORE
DEBATE WHAT CLINICAL PRIORITIES
SHOULD BE AND IS THERE RESEARCH.
AND COMMENTS WHETHER OR NOT
BENEFITS FROM CLINICAL TRIALS
TRANSLATE.
WE'LL WORLD EVIDENCE CAN INFORM
THAT GAP.
AND I WAS STRUCK BY THE
STATEMENT WE NEED TO FULL
SPECTRUM OF STUDY DESIGN TALKING
ABOUT TRADEOFFS OF REAL WORLD
STUDY DESIGN AND THERE'S
TRADEOFFS FOR EACH, IT'S HAVING
THIS COLLECTION OF THEM AND
MULTI-DISCIPLINARY EVIDENCE
GENERATION PROCESS THAT LEADS US
IN THE DIRECTION OF HAVING
BETTER KNOWLEDGE OVER TIME, SO
THERE WON'T BE SOME SUPERIORITY
OF OTHER STUDIES OVER SOME
OTHERS BUT I THINK WE NEED MANY
STUDIES AND DATABASES TO
TRIANGULATE THE TRUTH.
AND MATT POINTED TO ALSO THE
OUTCOMES OF PATIENT EXPERIENCE
AFTER DISCONTINUATION WITHOUT
RESTART, UNDERSTANDING WHEN
PATIENT STOPS WHAT ARE LONG-TERM
OUTCOMES?
NEXT SESSIONS, SESSION 1, DR.
BRADLEY, I WAS STRUCK BY THE
ONGOING WORK AND GUIDANCE THEY
PUBLISHED.
I WANTED TO REEMPHASIZING
INFLUENCING FDA POLICY.
SO FOR THOSE WHO WANT TO THINK
ABOUT HOW CAN I INFLUENCE FDA
POLICY, THEY HAVE A ROADMAP FOR
THAT.
AND THEY EMPHASIZED ONGOING FDA
EVALUATIONS ARE HAPPENING
PARTICULARLY AROUND SUICIDAL
THOUGHTS AND ACTIONS, ARE THEY
MORE COMMON WITH PATIENTS
TREATED WITH GLP-1s, LOOKING
FOR WARD TO THOSE RESULTS.
AND WE HEARD FROM DR. WONG AND
DR. SKINNER, SO LITTLE EVIDENCE
IS IS THERE FOR CHILDREN AND WE
NEED A LOT OF DATA THERE AND
REAL WORLD DATA CAN BE ONE WAY
TO BEGIN TO FILL THOSE GAPS AND
ADDRESS THOSE NEEDS.
THERE'S OPPORTUNITY TO
INVESTIGATE HARMS, MENTAL HEALTH
RISKS, EATING DISORDERS, SOCIAL
DEVELOPMENT, LONGER-TERM WEIGHT
AND HEALTH OUTCOMES, QUALITY OF
LIFE, PATIENT-REPORTED OUTCOMES;
REDUCING GAPS AND CARE QUALITY
AND OUTCOMES.
NOT JUST EVALUATING INDIVIDUAL
THERAPIES BUT EVALUATING SYSTEM
LEVEL DECISIONS THAT THEY ARE
MAKING HOW TO ROLL MEDICATION
OUT AND LOOKING AT THE NATURAL
EXPERIMENT IN REAL WORLD HEALTH
SYSTEMS.
NEXT THINKING ABOUT ANAND AND
DAVID'S PRESENTATIONS ABOUT
PUBLIC AND PRIVATE PAYER
PERSPECTIVES, MICROSIMULATION
RESEARCH THAT WAS MENTIONED,
FOLLOW-UP WINDOW TO HELP INFORM
MEDICARE POLICY SEEMED REALLY
IMPORTANT FOR US TO THINK ABOUT
AS WE DESIGNED FUTURE
MICROSIMULATION RESEARCH.
AND THEN TWO COMMENTS ABOUT OR
IDEAS ABOUT SUBPOPULATIONS WITH
OBESITY, IDENTIFY THOSE WHO ARE
MOST LIKELY TO BENEFIT BUT ALSO
THE POINT WAS EMPHASIZED BY
DAVID HINES WE NEED TO ENSURE
THAT POPULATIONS WITH HIGHEST
NEED GET ACCESS.
SO THOSE MIGHT NOT BE THE SAME
POPULATIONS, THOSE MOST LIKELY
TO BENEFIT AND WITH HIGHEST
NEEDS, COULD BE DEFINED
DIFFERENTLY SO LOOKING AT BOTH
THOSE QUESTIONS SEPARATELY.
COMBINING DOESN'T LEAD TO
GREATER BENEFIT.
DO WE NEED TO PAY FOR BOTH?
OR WHAT'S THE MINIMUM NECESSARY
IN TERMS OF LIFESTYLE SUPPORT TO
COMBINE AOMs SO WE CAN REDUCE
COST FOR PAYERS AS THEY ARE
TRYING TO EXPAND COVERAGE AND
ACCESS FOR THESE.
NOELIA MENTIONED REAL WORLD
OBJECTIVES TO SUPPORT ECONOMIC
EVALUATION FOR CONGRESSIONAL
BUDGET OFFICE, LONG-TERM
EFFECTS, ADHERENCE, SUBGROUPS,
MORTALITY, DISABILITY,
EMPLOYMENT.
MENTIONED NATURAL EXPERIMENTS
THAT EXAMINE THE VARIATIONS IN
COVERAGE AND COMPARED OUTCOMES
FOR PEOPLE WITH AND WITHOUT
COVERAGE.
THAT'S REALLY INTERESTING TO
THINK ABOUT USING THOSE ACROSS
HEALTH SYSTEMS OR DIFFERENT
TYPES OF DATA TO TRY TO
TRIANGULATE SOME COVERAGE AND
POLICY DECISIONS THAT ARE
HAPPENING.
OBSERVATIONAL STUDIES COMPARING
OUTCOMES OF PEOPLE WHO DO AND DO
NOT TAKE AOMs ADJUSTING FOR
DIFFERENCES BETWEEN THE GROUPS,
WE TALKED ABOUT HOW CHALLENGING
THAT CAN BE TO COMPARE THOSE
KINDS OF GROUPS WITH UNMEASURED
CONFOUNDING AND TARGET TRIAL
EMULATION PROCESS COULD HELP US
SPECIFY WHEN THAT MIGHT BE A
GOOD SET TIME TO DO THAT OR NOT
BUT IT'S IMPORTANT TO NOTE
PAYERS WANT TO KNOW THE ANSWER
TO THESE QUESTIONS.
AND THEN IN SESSION 3,
INTERESTING IDEAS COMING OUT OF
ANIA AND LESLEY'S CONVERSATION
AND PRESENTATION ABOUT OTHER
ALTERNATIVE TITRATION PROTOCOLS
THAT COULD BE USED TO REDUCE
SIDE EFFECTS AND IMPROVE
LONG-TERM ADHERENCE, AND HOW DO
WE PAIR NUTRITION AND PHYSICAL
ACTIVITY TO IMPROVE
TOLERABILITY, ADHERENCE,
OUTCOMES.
AND MOST PATIENTS THAT STOP
AOMs STOP ONCE AND THEN
RESTART AND NEVER STOP AGAIN.
I'M INTERESTED TO SEE CAN WE SEE
THAT IN REAL WORLD DATA?
AND CAN WE STUDY THAT?
WHAT'S THE DURATION OF STOPPING,
WHAT'S THE HEALTH IMPACT OF
STOPPING, AND THEN SORT OF
WHAT'S THE PATTERN OF ADHERENCE
WHEN THEY RESTART?
PRAGMATIC TRIALS, THEY ARE
RELEVANT, WE TALKED ABOUT IT,
COMPARING ALTERNATIVES HEAD TO
HEAD, TESTING STRATEGIES FOR
TAPERING AOMs, USING-TERM
AOMs, ANTI-OBESITY MEDICATION,
WITH LIFESTYLE INTERVENTIONS.
TESTING STRATEGIES HEAD TO HEAD
IN PRAGMATIC SETTINGS MIGHT BE
BETTER THAN TARGET TRIALS.
THERE WAS NOTES THAT WERE
IMPORTANT ABOUT REAL CHALLENGES
IN COMPARING AGAINST USUAL CARE
AND NON-AOM TREATMENTS, MIGHT
NOT BE WELL RECEIVED AND USUAL
CARE KEEPS CHANGING RAPIDLY,
DEFINING USUAL CARE NOW BUT A
YEAR FROM NOW USUAL CARE GROUP
LOOKS DIFFERENT.
LOTS OF CHALLENGES.
CLOSING UP WITH MIGUEL'S
CONVERSATION, HE WAS POINTING
TOWARD TARGET TRIAL EMULATION
APPROACH, HIGHLY VALUABLE AND
SPECIFYING AND THIS KIND OF
CLARITY AROUND ASSUMPTION THAT
GO INTO A TARGET TRIAL, AND IT'S
IMPORTANT TO THINK THAT IN THIS
RAPIDLY CHANGING LANDSCAPE WE
COULD HAVE FASTER REACTION TIME,
FASTER EVIDENCE GENERATION, WITH
REAL WORLD DATA STUDIES, PERHAPS
IN PRAGMATIC TRIALS.
SO, I THOUGHT THAT WAS AN
INTERESTING COMMENT THAT HE
MADE.
HE COMMENTED THAT WE DON'T HAVE
TO DO FIVE-YEAR PRAGMATIC
TRIALS.
LET'S THING ABOUT SHORTER
PRAGMATIC TRIALS THAT SORT OF
GIVE US CLEAR INITIAL EVIDENCE
AND THAT HELPS US INFORM WHAT
THE FUTURE LONGER-TERM PRAGMATIC
TRIALS MIGHT BE.
BUT THE TARGET TRIALS WERE ALSO
REALLY GOOD FOR EXAMINING OFF
LABEL USE OF MEDICATIONS, AND SO
I THOUGHT THAT WAS ANOTHER
IMPORTANT POINT FOR US TO BE
THINKING ABOUT WHERE THIS SWEET
SPOT IS FOR TARGET TRIALS.
THAT'S MY QUICK SUMMARY.
I WANTED TO TURN TO OVERALL
DISCUSSION BETWEEN THE CO-CHAIRS
AND THEN WE CAN WRAP UP FOR THE
DAY AND TALK ABOUT THE AGENDA
FOR TOMORROW.
WHAT ELSE WOULD YOU ADD FROM
YOUR REFLECTIONS ON THE DAY,
DARREN AND LESLEY?
>> I THOUGHT THAT WAS AN
AMAZING SUMMARY, DAVID.
I DON'T HAVE MUCH TO ADD.
I ENCAPSULATED THE KEY -- MANY
KEY POINTS PEOPLE MADE.
THANK YOU.
DARREN?
>> NO, I AGREE.
IT'S REMARKABLE SO MANY
UNANSWERED QUESTIONS BUT AT THE
SAME TIME THERE ARE SEVERAL
THINGS THAT CONSISTENTLY
MENTIONED THROUGHOUT THE DAY,
RIGHT?
SO I JOTTED DOWN SOMETHING NOT
COMPREHENSIVE, LONG-TERM
OUTCOMES, ADHERENCE, HOW TO PAY
FOR THIS, AND WHETHER OR HOW TO
EITHER TAPER OFF OR STOP THE
TREATMENT.
SO MANY OF THESE ARE MENTIONED
BY MULTIPLE SPEAKERS AS KEY GAP
AREAS TO THE FIELD, POTENTIALLY
FILLED BY REAL WORLD DATA
ANALYSIS.
I'M STRUCK BY THE FACT WE
COVERED SO MANY BASES AND THEN
THERE'S ALSO A SET OF THEMES
THAT KEEP OCCURRING BY DIFFERENT
SPEAKERS AND BY THE ATTENDEES OF
THE WORKSHOP.
>> GREAT.
THANK YOU, DARREN.
THANK YOU, LESLEY, AS WELL.
AND THANK YOU, EVERYONE WHO
STUCK WITH US THROUGHOUT THE DAY
TODAY.
I'M SURE YOU WON'T MIND IF WE
GIVE YOU FOUR MINUTES BACK IN
THE SCHEDULE.
WE HAVE ANOTHER FUN DAY TOMORROW
PLANNED.
LET ME SHARE MY SCREEN AND GIVE
YOU A QUICK OVERVIEW OF WHERE
WE'RE GOING WITH THAT.
TOMORROW WE'RE BE TALKING ABOUT
BEST PRACTICES FOR STUDYING
GLP-1 THERAPIES.
DEFINING EXPOSURES AND OUTCOMES,
GETTING INTO THE WEEDS OF SOME
OF THE NITTY-GRITTY CHALLENGES
OF HOW YOU DO REAL WORLD
STUDIES, USING GLP-1-BASED
THERAPY.
DEFINE EXPOSURE, DEFINING
OUTCOMES, FOCUS IN ON VERY
SPECIFIC HEALTH CONDITIONS AND
CHALLENGES OF DOING REAL WORLD
DATA STUDIES THERE.
WE'LL END WITH A MODERATED
DISCUSSION ABOUT THE KEY
RESEARCH GAPS AND OPPORTUNITIES,
BRINGING TOGETHER EVERYTHING
ACROSS BOTH DAYS AND TRYING TO
PUT TOGETHER KEY THEME AREAS FOR
US TO TAKE AWAY AND HOPEFULLY
BUILD ON THE EVIDENCE BASE AS WE
MOVE FORWARD.
I WANT TO THANK MY CO-CHAIRS,
FOR THE HELP IN PREPARING THE
SESSION, AND EVERYONE INVOLVED
AS SPEAKERS.
GREAT DAY.
WE'LL SEE YOU AGAIN TOMORROW
MORNING.
>> THANK YOU FOR THE EXCELLENT
SUMMARY.
THANK YOU FOR LEADING US THROUGH
THAT.
WE'LL ADJOURN FOR DAY 1.
PLEASE COME BACK TOMORROW
MORNING.
THANKS FOR GIVING US A PREVIEW
OF WHAT WE'RE GOING TO SEE
TOMORROW.
TOMORROW'S SESSION STARTS AT 10
A.M., EASTERN TIME.
SEE YOU THEN.
HAVE A GOOD EVENING.