SO WELCOME BACK TO DAY 2 OF
THE PAIN IN ANIMALS WORKSHOP
MEETING.
TODAY IS DEDICATED TO
SUGGESTIONS ON MERVE SURING
OUTCOMES IN CLINICAL
APPROACHES.
THE FIRST UP IS JENNIFER
GEWANDTER FROM THE UNIVERSITY
OF ROCHESTER AND WILL TALK TO
US ABOUT APPROACHES TO
DEFINING CLINICALLY MEANINGFUL
CHANGE IN TRIAL OUTCOME
MEASURES.
>> OKAY, THANKING THE
ORGANIZERS FOR INVITING ME TO
SPEAK TODAY AND THANK YOU TO
YOU ALL FOR COMING TO THE
EARLY-MORNING SESSION.
SO A LITTLE OVERVIEW OF MY
TALK TODAY.
AS MENTIONED, I WILL BE
TALKING ABOUT HOW WE IDENTIFY
PAIN OUTCOMES IN HUMANS AND I
WILL ALSO TOUCH A LITTLE ON A
COUPLE OTHER TOPICS INCLUDING
WHY WE WANT TO DO THIS AND
LIMITATIONS ON DOING THIS,
WANT TO MENTION BRIEFLY
UNINTENDED CONSEQUENCES OF
APPLYING THESE CUTOFFS AND
APPLICATION OF THESE IDEAS TO
ANIMALS.
OKAY, SORRY.
SO FIRST THE APPROACHES, OF
MEANINGFUL DIFFERENCE.
THE FIRST THING I WILL TALK ON
IS THE PUBLISHED RESOURCE OF
INCORPORATING CLINICAL OUTCOME
ASSESSMENTS IN ENDPOINTS FOR
REGULATORY DECISION-MAKING.
AND THERE ARE TWO CUTOFFS,
THIS IS CALLED THE ANCHOR
BASED METHOD.
THERE ARE TWO OUTCOMES WE USE
PRIMARILY FOR TRIALS AND
COMPARE IT TO ANCHOR BASED
OUTCOMES THAT ARE PLAINLY
UNDERSTOOD, EASIER TO
UNDERSTAND FOR THE OUTCOME
ITSELF AND IT SHOULD BE A
TARGETED OUTCOME.
SO THE PATIENT GLOBAL
IMPRESSION OF CHANGE, THEY
WOULD ASK PEOPLE AT THE
BEGINNING OF THE STUDY HOW
WELL YOUR OVERALL BEING OR
PAIN HAS CHANGED AND WE HAVE
THESE ANCHORS INCLUDING VERY
MUCH IMPROVED, MUCH IMPROVED,
MINIMALLY IMPROVED, NO CHANGE
OR OF COURSE IT COULD HAVE GOT
TEN WORSE AS WELL.
THEN THERE IS THE PATIENT
GLOBAL IMPRESSION OF SEVERITY
WHICH HAS ANCHORS FOR NOT
PAINFUL, MILDLY PAINFUL,
MODERATELY PAINFUL, VERY
PAINFUL OR EXTREMELY PAINFUL.
SO FOR OUTCOMES, WE HAVE THESE
ANCHORS TO MOVE PATIENTS FROM
ONE BUCKET TO ANOTHER AND OF
COURSE IT CAN CHANGE BUT THIS
IS HOW IT WORKS IN GENERAL.
SO THIS EXAMPLE, A PAPER BY
Dr. JOHN FARER, THEY TOOK
MULTIPLE PAIN STUDIES OF
PEOPLE AND PLOTTED THE PERCENT
CHANGE IN THE NOS SCORE VERSUS
THE MUCH IMPROVED, AND AS YOU
CAN SEE THE PAIN IS HIGHLY
COORDINATED WITH THESE
ANCHORS.
NOTE/FARRAR.
>> SO I WILL DRAW YOUR
ATTENTION TO THE BOTTOM HERE,
THIS IS A PERCENT DATA.
AND YOU CAN SEE WHEN USING
DATA AND DID R OC ANALYSIS TO
IDENTIFY THE CUTOFF THAT WOULD
GIVE THE BEST SPECIFICITY OF
SOMEONE WHO IS VERY MUCH
IMPROVED MORE THAN ANYTHING
ELSE, THEIR CUTOFF WAS 46.51
SO IF YOU USE THE IMPROVEMENT
OF 46.51 YOU COULD PRETTY MUCH
BUCKET PEOPLE ON WHETHER THEY
WERE MUCH IMPROVED.
AND FOR VERY MUCH IMPROVED
THAN ANYONE ELSE, THE CUTOFF
IS 46.51.
THIS IS THE ANALYSIS THAT
WOULD SUPPORT THOSE
CONCLUSIONS AND THESE TYPES OF
STUDY HAVE BEEN REPEATED
MULTIPLE TIMES WITH PRETTY
SIMILAR RESULTS BUT THIS IS
THE METHOD WHICH WE USE O
IDENTIFY TO -- TO IDENTIFY
WHAT THE CUTOFFS SHOULD BE.
THE OTHER WAY WE DO THIS IS TO
JUST ASK PEOPLE SO I WILL GO
BACK TO FARRAR AND WHAT HIS
GROUP IS CURRENTLY WORKING ON
AND THIS IS AN ACUTE PAIN
SETTING AND I WILL GIVE A
GENERAL EXAMPLE OF HOW THEY
USE THE STOP WATCH METHOD.
IN THIS CASE, FOR EXAMPLE, YOU
CAN INCLUDE PATIENTS WHO ARE
GETTING A THIRD MOLAR
EXTRACTION AND YOU ASK WHAT IS
YOUR PAIN RIGHT NOW AND THE
SCALE IS HERE, AND THEY SAY A
7 AND YOU SAY AS SOON AS YOU
CAN FEEL ANY PAIN YOU NOTICE,
HIT YOUR STOP WATCH AND THEY
DO THAT AND IT IS A 7.
SO THAT IS A 40 PERCENT
IMPROVEMENT.
AND THEN THEY ASK IT AGAIN AND
YOU CAN EASE THESE OUTCOMES TO
SEE WHAT PERCENT IMPROVEMENT
WOULD BE MINIMALLY IMPORTANT
TO PEOPLE OR CLINICALLY
MEANINGFUL TO PEOPLE AND YOU
CAN GET A SIMILAR R OC
ANALYSIS TO CONSIDER WHAT
WOULD BE THE CUTOFF IN AN
ANALYSIS FOR ACUTE PAIN
SETTING.
AND YOU COULD DO SOMETHING
SIMILAR IN THE CHRONIC PAIN
SETTING WHERE YOU COULD SAY
SINCE A CHILD, DO YOU HAVE
MEANINGFUL PAIN RELIEF.
AND BECAUSE THIS IS ANCHOR
BASED, YOU LOSE SOME
PARTICIPATION WITH THE
ANCHORS.
ANOTHER WAY TO DETERMINE
WHETHER IT IS MORE HELPFUL IS
THE PATIENT INTERVIEW METHOD
AND THIS IS JUST ASKING THEM
WHAT THEY CONSIDER MEANINGFUL
AND WHY.
THIS IS VERY IMPORTANT BECAUSE
YOU CAN GET RICH DATA AND THAT
IS GOOD ON THE LEVEL.
THE LIMITATIONS IS YOU ARE
ASKING PEOPLE ABOUT
HYPOTHETICAL SITUATIONS SO YOU
WOULD SAY SOMETHING LIKE LAST
TIME YOU TOOK YOUR PAIN
MEDICINE, DID IT IMPROVE YOUR
PAIN, WAS IT MEANINGFUL TO
YOU, BUT SINCE YOU ARE TALKING
ABOUT THE PAST, IT COULD BE
NONANALOGOUS.
THESE ARE SMALL SAMPLE SIZES
SO GENERALIZABILITY IS AN
ISSUE AND IT COULD BE
DIFFICULT TO DIRECTLY
TRANSLATE THE RESULTS YOU GET.
BUT THESE COULD BE USED IN A
QUANTITATIVE SURVEY THAT COULD
BE USED TO GET MORE
QUANTITATIVE NUMBERS.
SO THOSE ARE THE TWO METHODS
WE USE TO OBTAIN MININGFUL
CUTOFFS.
SO NOW I WILL SHIFT AND TALK
ABOUT WHY WE WANT TO DO THIS
IN HUMANS AND FOR THOSE OF YOU
WHO DON'T THINK ABOUT THIS A
LOT, WE WANT TO DO THIS
BECAUSE IT WILL HELP RESPONDER
ANALYSIS OR ANALYSIS THAT
COMPARE THE PROPORTION OF
PARTICIPANTS WHO HAVE A
MEANINGFUL OUTCOME BETWEEN THE
TWO GROUPS AND THESE ARE
EASIER TO INTERPRET BETWEEN
PEOPLE.
SO IF YOU ARE CONSIDERING THE
PAIN OF I DON'T YOU ARE
GRANDMOTHER WHO -- PAIN OF
YOUR GRANDMOTHER WHO IS ON
PAIN MEDICATION, YOU CAN TRY
THIS AND THIS IS SOMETHING
WHERE PEOPLE CAN WRAP THEIR
HEAD AROUND THE DIFFERENCE
WITH A DRUG.
AND ANOTHER METHOD IS TO ASK
ABOUT THE LIMITATIONS.
SO IS IT REALLY THAT
STRAIGHTFORWARD? AND I WANT
TO ARGUE A LITTLE FOR
DISCUSSION PURPOSES, MAYBE NOT
AND I THINK WHAT IS REALLY
IMPORTANT TO CONSIDER IS THERE
IS A LOT OF VARIABILITY IN
WHAT IS MEANINGFUL AND IT CAN
CHANGE FOR A LOT OF THINGS.
SO BROAD THINGS FOR EXAMPLE IS
THE TREATMENT.
THE TREATMENT IS RISKY IF IT
CAN CAUSE IRREPUTABLE DAMAGE,
CAUSE YOUR JOINTS TO BE
REPLACED IF YOU THINK ABOUT A
DRUG RECENTLY PUT UP FOR
APPROVAL.
OR CONSIDERING NAUSEA,
VOMITING, THESE MAY BE
REVERSIBLE BUT FOR PEOPLE TO
CONSIDER CONTINUING TO TAKE A
DRUG, IT MAY HAVE TO BE
CONSIDERED TO WHETHER THE DRUG
IS MEANINGFUL FOR THEM OR
WORTH IT.
AND THEN TALKING ABOUT
SURGERY, THINGS THAT COST A
LOT OF MONEY TO THE PATIENTS
AND SOCIETY AT LARGE, YOU
WOULD EXPECT TO SEE A BIGGER
DIFFERENCE IN WHETHER IT IS
CLINICALLY MEANINGFUL.
ON THE FLIP SIDE OF THAT, YOU
HAVE THE CHRONIC PAIN AND IF
YOU CAN FIND ANYTHING THAT
MIGHT MOVE THE NEEDLE A LITTLE
BIT, THAT MIGHT BE MEANINGFUL
FOR THEM.
THERE ARE A LOT OF DRUGS THEY
COULD TRY THAT COULD GIVE THEM
A MODERATE MOVEMENT IN THEIR
PAIN.
AND THEN THERE IS THE
IDEOSYNCRACY BETWEEN PEOPLE.
I WILL TELL YOU A STORY OF A
TRIAL I AM DEVELOPING AT MY
SITE AND A WOMAN CAME IN AND
TOLD MY COORDINATORS THIS ONLY
WORKS FOR ME FOR ONE HOUR BUT
WORKS WELL FOR ME FOR ONE HOUR
AND ALLOWS ME TO WALK MY DOG
AND THAT IS A GOOD THING FOR
ME.
SO TWO HOURS OUT OF 24, MY
PAIN IS STILL A 5 THE OTHER
TIMES SO THAT WOULDN'T REALLY
CHANGE ON THE NRS.
SO FOR HER, A TINY IMPROVEMENT
ON THE NRS MIGHT BE HAVING A
HUGE IMPACT ON HER LIFE SO WE
TRY TO GET IT TOWN TO ONE --
DOWN TO ONE NUMBER AND THEN
SAY WELL, NOT ALL THE PEOPLE
RESPONDED, WE HAVE TO CONSIDER
THE CUTOFFS IN OUR ABILITY TO
TREAT PEOPLE AND MAKE THAT
CLEAR.
SO ONE THING TO CONSIDER WHEN
YOU ARE DOING PAPERS OR
PRESENTING DATA, THIS IS A
LITTLE COMPLICATED AND I WILL
TRY NOT TO FUMBLE THROUGH IT
BUT WHAT YOU SAW ON THE Y AXIS
IS THE PROPORTION OF
PARTICIPANTS AND ON THE X
AXIS, THE MINIMUM PERCENT
IMPROVEMENT IN PAIN.
SO WHEN YOU GET TO ABOUT
10 PERCENT IMPROVEMENT IN
PAIN, YOU SEE A HIGHER
PROPORTION OF PEOPLE IN THE
ACTIVE GROUP RESPONDING ALL
THE WAY UP TO 75 PERCENT OF
PAIN.
SO YOU LOOK AT THESE AT ANY
CUTOFF YOU CONSIDER
MEANINGFUL, THERE IS A
SEPARATION WHERE THIS OCCURS
SO REGARDLESS OF THE CUTOFF,
THIS DRUG CAN LOOKS REALLY
MEANINGFUL.
AND IN THIS CASE THERE IS
REALLY A BIG SEPARATION
BETWEEN THE PROPORTION OF
PARTICIPANTS WHO SAY THEY ARE
20 PERCENT IMPROVED OVER THE
ACTIVE PLACEBO GROUP BUT
ANYTHING OVER 25 PERCENT IS
ALMOST ON TOP OF EACH OTHER.
SO YOU LOOK AT THIS AND SAY
WELL I DON'T KNOW, THIS ISN'T
REALLY USEFUL.
BUT IF YOU LOOK AT THE DATA
THIS WAY AND NOT LOOKING AT A
SINGLE CUTOFF BUT ALL THE
CUTOFFS, YOU CAN SEE THE
DIFFERENCE IN THE TREATMENT.
SO ONE MORE, THIS IS MY SOAP
BOX PAPER, I SEE THIS ALL THE
TIME, AS A REVIEWER, I SEE
THIS AND I WANT TO SAY THIS AS
MUCH AS POSSIBLE.
A CLINICAL MEANINGFUL
DEFINITION OF A PATIENT IS
USEFUL FROM BASELINE.
AND IT IS NOT EQUAL TO THE
GROUP DIFFERENCE.
THERE IS A LOT OF VARIABILITY
IN RESPONSE AND THERE IS A
PLACEBO GROUP AND WE DON'T
HAVE THE TOOL TO DO MECHANISM
BASED DEVELOPMENT WHERE
EVERYONE IS RESPONDING
ACCORDINGLY.
AND WE REALLY WILL LIMIT THE
ABILITY TO IDENTIFY TREATMENTS
THAT ARE ACTUALLY MEANINGFUL
FOR PATIENTS THAT THEY CAN TRY
IN THE REAL WORLD IF WE HOLD
OURSELVES TO THE STANDARD OF
HAVING TO SEE A 2-POINT
DIFFERENCE IN GROUPS.
AND IF YOU THINK OF DRUGS FOR
PAIN, NONE OF THEM WILL GIVE
YOU THE 2 PERCENT DIFFERENCE
IN A CLINICAL TRIAL SO IT IS
REALLY IMPORTANT THAT WE DON'T
USE THIS WAY WHEN WRITING
PAPERS.
THE CHALLENGE IS'BECOMES -- IT
BECOMES REALLY DIFFICULT WHEN
ASKING PATIENTS OF THE
MEANINGFUL BASELINE, WHEN
ASSESSING DRUGS.
TO SAY YOUR PAIN WILL BE FROM
A 6 TO 3 AND THEY SAY WELL, IT
IS ACTUALLY 6 TO 4.
SO THE SIGNIFICANT DIFFERENCE,
THESE ARE ACTUAL IMPROVEMENTS
OVER THE ACTIVE GROUP WITH
PLACEBO AND THEN THE CHANGES
SHOULD BE LOOKED AT FOR EACH
ONE.
SO TO CONCLUDE, IF ANY OF THIS
IS USEFUL FOR ANIMAL RESEARCH,
WHAT I JUST SAID TO YOU, AND
AS AN APOCK HREUPZ --
APOCALYPSE, YOU CAN'T ASK
ANIMALS WHAT IS IMPORTANT OR
MEANINGFUL TO THEM BUT IF THEY
ARE A PET OWNER, YOU COULD
DETERMINE THAT.
AND THEN WHAT IS THE HOLISTIC
OUTCOMES OF AN EQUIVALENT
ANCHOR BASED METHOD IN
ANIMALS?
THE RELATIONSHIPS BETWEEN
TYPICAL INDUCED PAIN OUTCOMES
NEED HOLISTIC OUTCOMES WITH
CLEARLY DIFFERENTIATED
CATEGORIES AND THAT CAN COME
FROM PEOPLE WHO KNOW MORE
ABOUT ANIMALS THAN I DO AND
THEN I WONDER THAT FROM A
PRECLINICAL PERSPECTIVE, I
WOULD THINK THE GOAL WOULD BE
TO TO IDENTIFY CLINICALLY
MEANINGFUL THRESHOLDS IN
ANIMALS TO INCREASE SUCCESSFUL
TRANSLATION TO CLINICAL
TRIALS.
SO MEDICALLY, THERE IS A
DIFFERENCE BETWEEN HUMANS AND
THE ANCHOR BASED METHODS WHEN
ASKING PEOPLE ABOUT THEIR
EXPERIENCE.
IT IS VARIABLE AMONG PEOPLE SO
WE NEED TO USE CAUTION WHEN WE
PRESENT THEM TO THE WORLD AND
THEN MCI D FOR AN INDIVIDUAL
PATIENT OR ANIMAL SHOULD NOT
BE USED TO INFORM
INTERPRETATION OF WHAT IS
CLINICALLY MINGFUL --
MEANINGFUL DIFFERENCES BETWEEN
GROUPS AND TRANSLATION OF
THESE CONCEPTS WILL REQUIRE
CREATIVITY.
SO WITH THAT, I WOULD LIKE TO
THANK MY COLLEAGUES AND
DOCTORS FARRAR AND Dr.
LANGFORD WHO HELPED ME THINK
ABOUT MY RESEARCH.
[APPLAUSE]
>> EXCELLENT PRESENTATION,
THANK YOU VERY MUCH AND THE
PERFECT SEGUE TO THE NEXT
PRESENTATION, IT IS MY
PLEASURE TO INTRODUCE MY
FRIEND JOHN INNES WHO IS FROM
UNIVERSITY OF LIVER POOL AND
ENDED UP OPENING UP A PRACTICE
IN MOVEMENT REFERRALS.
JOHN HAS COME OVER FROM THE UK
AND MAY HAVE A BUG IN HIS
POWERPOINT THAT HE BROUGHT
OVER FROM THE UK SO WE WILL
JUST HOOK UP HIS COMPUTER
DIRECTLY.
AND JOHN CAN TALK ABOUT THE
MCI D FOR TWO OUTCOME BASED
MEASURES HE HAS BEEN INVOLVED
IN DEVELOPING FOR LOAD.
>> THANK YOU, REALLY NICE TO
BE HERE AND LIKE TO THANK THE
ORGANIZING COMMITTEE AND
STAKEHOLDER SPONSORS FOR
PUTTING THIS MEETING TOGETHER,
IT IS REALLY IMPORTANT AND
GREAT TO BE HERE.
SO JENNIFER'S TALK JUST NOW
WAS A PERFECT SEGUE FOR THIS
TALKING ABOUT THINGS DONE WITH
ANIMALS AND I WILL TALK WITH
THINGS THAT HAVE BEEN DONE
THAT ARE RELEVANT TO WHAT SHE
IS TALKING ABOUT.
THE MINIMAL CLINICALLY
IMPORTANT KITCHENS FOR LOAD
AND THIS IS MOVEMENT REFERRALS
FROM UNIVERSITY OF LIVER POOL.
PATIENT HISTORY IS HUGE WITH
MEDICINE AND WE USE DIFFERENT
TERMS FOR ANIMALS AND CLINICAL
METROLOGY AND WHEN I SAY THAT,
PEOPLE LOOK AT ME BLANKLY ON
WHAT THESE MEANS SO THE CLIENT
REPORTED OUTCOME MEASURES
RELATE TO PATIENT OUTCOMES.
AND ARE NOT ALWAYS EXPLICIT.
HUMAN OUTCOMES ARE OFTEN MORE
MEANINGFUL IF THEY HAVE
REPORTED OUTCOMES, FOR EXAMPLE
IN ENGLAND, A HIP OR KNEE
REPLACEMENT IS NOT COUNTED IF
THERE IS NO REPORTED UTCOME --
OUTCOME.
SO THERE WAS A TALK YESTERDAY
ON THIS TALKING ABOUT CROM
VALUE VALIDATION PROCESS AND
THESE HAVE BEEN COMPARED TO
EACH OTHER AND ALSO TO
OBJECTIVE MEASURES THAT WE
HAVE SOME MEASURE THE CRITERIA
AND ACCEPTED GOLD STANDARD.
BUT I JUST THOUGHT I WOULD
HOPEFULLY SHOW YOU A COUPLE OF
VIDEOS.
THIS IS THE REAL WORLD,
REALLY.
I USED TO BE IN ACADEMIA,
SPENT 22 YEARS THERE, DESCRIBE
MYSELF AS A RECOVERING A
ACADEMIC NOW AND I GO TO A
MEETING EVERY FEW WEEKS TO
TALK TO OTHERS IN ACADEMICS
BUT IT IS THE REAL WORLD WHEN
IT COMES TO CLINICAL TRIALS.
I GUESS JUST WATCH THIS VIDEO
FOR A SECOND AND THIS IS NOT
PARTICULARLY VALID FOR THIS
DOG, JUST ASSESS THIS DOG'S
MOBILITY AND WE SPENT ABOUT A
HALF DAY GETTING THE SCORE ON
ITS LIMBS AND TELLING US AN
OBJECTIVE MEASURE OF MOBILITY
WHERE THE OWNER GAVE A LOWER
SCORE.
AND COMPARE THAT DOG TO THIS
ONE AND YOU IMMEDIATELY SEE A
DIFFERENCE.
AND YESTERDAY WE HAD A TALK
THAT MENTIONED THE FATIGUE OF
CHRONIC PAIN IN HUMANS AND SO
I THINK THESE DOGS SHOW
FATIGUE OF CHRONIC PAIN IN
THIS DOG, 15.2 SO THIS DOG IS
LESS LAID BUT THE LOAD SCORE
IS 23 AND YOU MAY KEEP IN YOUR
OWN MIND WHICH DOG HAS MORE
MOBILE WILT ISSUES.
THE LOAD SCORE IS OBJECTIVE
AND NOT ALWAYS THE TRUTH, IF
YOU WILL.
SO WE SEE THE DEVELOPMENT IN
THIS REVIEW AND THAT
INSTRUMENTS CAN BE USED IN
DOGS WITH OSTEOARTHRITIS BUT
THERE WAS FURTHER WORK TO DO
AND WE DIDN'T HAVE CLINICALLY
IMPORTANT DIFFERENCES FOR LOAD
OR OTHER INSTRUMENTS FOR THAT
MATTER.
SO IN THIS STUD STUDY WE
PUBLISHED LAST YEAR WITH A
COLLEAGUE OF MINE, MARK
MORTON, WE LOOKED AT THE
CLINICALLY IMPORTANT
DIFFERENCES IN THE LIVER POOL
AS YO ARTHRITIS IN DOGS AND
CANINE ORTHOPEDIC INDEX AND
THERE WERE OUTCOMES WITH THAT.
SO AS JENNIFER DESCRIBED, THE
SCORE RECEIVED BY THE CLIENT
CAN BE SEEN AS BENEFICIAL COME
FIRED THOSE WHO RECEIVE NO
CHANGE AND WE NEED TO KNOW
THIS ESTIMATE BECAUSE THEY ARE
USED IN CLINICAL TRIALS AND
REGULAR LAKES CLINICAL TRIALS
THAT CAN BE USED AS A
THRESHOLD OR NOT THRESHOLD AND
CAN BE USED IN THE CLINIC IN
RESPONSE TO INTERVENTION AND
AS JENNIFER STRIPED, WE CAN
USE ANCHOR OR DISTRIBUTION
BASED METHODS BASED ON THE
UNDERLYING STATISTICAL
FEATURES OF THE GROUP.
NOW, WE TOOK A OPPORTUNITY
WITH THE RCVS KNOWLEDGE CANINE
CRUCIATE REGISTRY, WE HAVE THE
NATIONAL PROGRAM THERE AT THE
COLLEGE TO IMPROVE OUTCOMES
AND THIS INCLUDES PATIENTS WHO
SIGN UP THEIR CANINE CRUCIATES
TO GET DATA AND THERE ARE NOW
THOUSANDS OF CLIENTS
SUBMITTING DATA TO THAT
PROGRAM AND WITHIN THE
REGISTRY, THE TWO INSTRUMENTS
WE USE ARE THE LOAD AND CANINE
ORTHOPEDIC INDEX BUT THERE IS
ALSO AN ANCHOR QUESTION BUILT
IN WHICH IS COMPARED TO
SURGERY, HOW IS YOUR DOG NOW
AND JENNIFER USED THAT
CONCEPT.
THERE ARE A RANGE OF RESPONSES
AND WE'RE NOT PARTICULARLY
INTERESTED IN THIS STUDY WITH
THE CRUCIATE STUDY BUT WE WILL
GO AROUND THE INSTRUMENT
PROCESSES TO ASSESS THAT.
I WON'T BORROW YOU WITH THE
DETAILS HERE, THIS IS
PUBLISHED IN MCI-1.
THERE ARE DIFFERENT METHODS TO
LOOK AT THE METHODS OF MCI D
SO WE LOOK AT THE AVERAGE
CHANGE CORRESPONDING TO THE
MEAN CHANGE IN THE SCORE OF
THE SOMEWHAT BETTER GROUP, WE
LOOK AT THE MINIMUM DETECTABLE
CHANGE, THE SMALLEST CHANGE
THAT COULD BE CONSIDERED
BEYOND THE MEASUREMENT ERROR
WITH A 95 PERCENT CONFIDENCE
INTERVAL THRESHOLD.
THE CHANGE DIFFERENCE IS
DEFINED AS THE DIFFERENCE IN
THE AVERAGE CHANGE IN SCORE
BETWEEN THE SOMEWHAT BETTER
GROUP AND THE SAME GROUPS AND
THEN WE USE A OPERATING
CHARACTERISTIC CURVE USED TO
DISCRIMINATE BETWEEN THE
MINIMAL CHANGE AND NO CHANGE
GROUPS.
WE ALSO LOOKED AT THE
DISTRIBUTION METHOD, THE
EFFECT SIZE AND THAT IS
GENERALLY AGREED TO BE A SMALL
EFFECT SIZE SO WE CAN JUST
APPLY THAT TO BIGGER -- TO THE
STATISTICAL DATA WE HAVE AT
BASELINE.
AND THEN WE HAVE THE STANDARD
ERROR OF MEASUREMENT THAT THE
CLIENT POINTED OUT IN THE
SCORE, INDEPENDENT OF THE
PATIENT COHORT OF THE STUDY
AND AN INTRINSIC PROPERTY OF
THE ASSESSMENT TOOL BUT TO DO
THAT, YOU NEED AN ASSESSMENT
OF RELIABILITY FOR A TOOL AND
TO DO THAT, THAT WAS POOH HE
WASLY PUBLISHED BUT WE DIDN'T
HAVE THAT FOR THE CANINE
INDECKS.
THIS IS THE BASELINE OF THE
STUDY.
WE HAD 125 SUBJECTS, NOT HUGE
NUMBERS, AND THESE ARE THE
PREOPERATIVE AND BASELINE
SCORES AND THEY WERE
SIGNIFICANTLY DIFFERENT.
THAT IS HOW THE DATA WAS
DISTRIBUTED ACROSS THE GROUPS
AND AS JENNIFER SHOWED, IT
CORRELATES WITH THE ANCHOR
CATEGORY CORRELATED WITH THE
MEASURES EXCEPT FOR ONE
INDIVIDUAL IN THE SOMEWHAT
WORSE CATEGORY, THOUGHT THEY
WERE SOMEWHAT WORSE ON BOTH
INMENTS BUT SCORED LITTLE
BETTER AND IF WE LOOK AT THE
SAME GROUPS AND SOMEWHAT
BETTER GROUPS, THERE WERE
SIGNIFICANT DIFFERENCES SO
THAT ALLOWS US TO GO ON AND
DESCRIBE ESTIMATES FOR
MINIMALLY IMPORTANT
DIFFERENCES.
SO IF YOU LOOK AT THESE
NUMBERS, THESE ARE THE SIX
DIFFERENT METHODS ACROSS THE
TOP, THE ANCHOR BASED AND
DISTRIBUTION BASED METHODS AND
WE GOT THOSE ASSESSMENTS FOR
LOAD AND CANINE INCONNECTION
AND YOU CAN SEE -- INDEX AND
YOU CAN SEE THERE ARE SMALLER
LOADS AND PEOPLE ARGUE THE
ANCHOR BASED METHODS ARE MORE
CLINICALLY MEANINGFUL.
TO I GUESS THE SUMMARY FROM
THE FIRST STUDY IS WE
RECOMMENDED A WORKING CHANGE
IN LOAD OVER FOUR POINTS AND
FOR THE CANINE ORTHOPEDIC
INDEX, WE SUGGESTED A WORKING
MCI D OF 14.
AND I HAD THE OPPORTUNITY TO
COLLABORATE WITH ALMP VERY
MUCH ORPHAN SERVE AND AGO
WO*RB ETCH L WILL -- WITH
ALVES AND HE IS WORKING WITH
296 DOGS WITH BILATERAL HIP
ARTHRITIS AND HERE WAS AN
OPPORTUNITY TO GENERATE MCI D
ESTIMATES IN A MORE RELEVANT
PATIENT POPULATION WHICH IS
OSTEOARTHRITIS.
AND AGAIN, I WON'T LABOR YOU
WITH THE NUMBERS HERE.
THIS WAS PUBLISHED LAST WEEK
IN PLUS ONE SO YOU CAN LEAD TO
AT YOUR LEISURE IF YOU ARE
HAVING PROBLEMS SLEEPING.
296 DOGS HERE SO A REASONABLE
POPULATION FOR THE STUDY AND
YOU SEE THE BASELINE THERE AND
AGAIN, THERE WERE DIFFERENCES
BETWEEN THE SAME GROUP AND THE
SOMEWHAT BETTER GROUP SO THAT
ALLOWED US TO GO FORWARD AND
GENERATE ESTIMATES FOR MCI D.
AND INTERESTINGLY, THE
ESTIMATES CAME OUT VERY
SIMILAR TO THE FIRST STUDY SO
OUR CONCLUSION IN THAT PAPER
THAT WAS PUBLISHED LAST WEEK
WAS AGAIN WE WOULD RECOMMEND
AT THE MOMENT AN MCI D OF 4
FOR LOAD AND 14 FOR CANINE
ORTHOPEDIC INDEX.
BOTH STUDIES SHOWED WITH THE
CURVE, IT WAS HIGHER THAN WITH
THE CANINE ORTHOPEDIC INDEX
SHOWING AN ABILITY TO
DISCRIMINATE BETWEEN THE SAME
GROUPS OR SOMEWHAT BETTER
GROUP.
THESE SHOULD BE USEFUL FOR
RESEARCH STUDIES INVOLVING
TO*GS WITH OSTEOARTHRITIS AND
BY REGULATORS FOR PIVOTAL
STUDIES AND BY CLINICIANS.
THERE ARE FURTHER PARAMETERS
THAT WOULD BE USEFUL TO HAVE
ESTIMATES OF SUCH AS THE
CLIENT ACCEPTABLE CLINICAL
STATE WHERE THE CLIENT IS
LIKELY TO DEFINE THE OUTCOME
AS SATISFACTORY.
THIS IS A PARAMETER USED IN
PATIENT REPORTED OUTCOMES IN
HUMAN MEDICINE.
AND THEN A SUBSTANTIAL BENEFIT
WOULD ALSO BE USED TO
UNDERSTAND AND THAT IS THE
CLINICAL VALUE THAT THE CLIENT
CONSIDERS A SUBSTANTIAL
IMPROVEMENT.
SO AGAIN, THERE'S FURTHER WORK
TO DO TO PROVIDE OTHER
FEATURES AROUND THESE
PARTICULAR MEASURES.
SO I THINK WE NOW HAVE THREE
CLIENT REPORTED OUTCOMES IN
CANINE OSTEOARTHRITIS FOR
REGULATED TRIALS AND THE CBPI
HAS BEEN USED FOR SOMETIME
WITH WORK ON STEROIDALS AND
THE OUTCOME SLIGHTLY DIFFERENT
THAN I MEASURED FOR YOU TODAY
BUT FURTHER WORK IS REQUIRED
TO UNDERSTAND THE FEATURES OF
THESE OUTCOMES IN DIFFERENT
CONTEXTS.
AND THEN OF COARSE WE NEED TO
DIFFERENTIATE BETWEEN PONDERS
AND NONRESPONDERS AS
ACCURATELY AS POSSIBLE FOR
CLINICAL TRIALS.
AND JUST A BIT OF REFLECTION
REALLY TO FINISH UP WITH OF
HAVE WE GOT THIS RIGHT?
SO WITH CANINE BENEFITS,
SUCCESS CAN BE DESCRIBED AS
INCREASE OF 1 POINT OR MORE
AND OR WITH THE PIS, IF THERE
IS AN INCREASE OF 2 PERCENT OR
MORE.
AND THIS IS FROM A STUDY WITH
DOGS WITH PLACEBOS AND YOU CAN
SEE THE RATE IS HIGHER AT
53 PERCENT.
YOU GO BACK TO THE STUDY THAT
DUNCAN LASCELLES DID,
TREATMENT WAS ABLE TO SHOW
SUCCESS IN 14 AND 28 DAYS
WHEREAS IN THE CANINE INDEX,
THE PAIN WAS DESCRIBED AS
NULL.
SO I THINK WE NEED TO REFLECT
ON THESE CUTOFF VALUES.
MY CLINICAL EXPERIENCE, WE
HAVE HAD THIS IN THE UK FOR
ABOUT TWO YEARS NOW AND A
LITTLE LONGER IN THE U.S.
THE INITIAL RESPONSE RATE FROM
CLIENTS SAY THEIR T.J. IS
IMPROVED IN ANY DEGREE AROUND
18 PERCENT.
IN THE TYPICAL STUDY GROUP,
THEY RESPOND AT SAY 50 PERCENT
SO I THINK FOR THE MOMENT THAT
CDRI CUTOFF TO ME IS A LITTLE
BIT HARSH AND PERHAPS FURTHER
WORK WILL HELP US TO
UNDERSTAND THAT A LITTLE BIT
MORE.
SO I GUESS A PASSION OF MINE
NOW THAT I AM BACK IN CLINICAL
PRACTICE IS TO ACTUALLY EMBED
THESE TOOLS IN CLINICAL
PRACTICE, NOT JUST WITHIN THE
RESEARCH ARENA.
AND WE DEVELOPED SOME WORK IN
ONE OF THESE BIG CORPORATE
GROUPS AND ONE OF THE THINGS
WE DID WAS DEVELOP WORK FLOWS
THERE SO WE ALSO HAD A MEASURE
OF PATIENT REPORTED OUTCOME
MEASURES AND THIS IS NOT JUST
FOR PAIN OR ARTHRITIS BUT
AVAILABLE NOW FOR A RANGE OF
CONDITIONS WITH VETERINARY
MEDICINE.
AND VETERINARY MEDICINE IS
VERY MUCH IN RESPONDER MODE.
WE WAIT TORE A -- FOR A CLIENT
TO RAISE AN ISSUE AND DEAL
WITH THAT AND HOPE IT GOES
AWAY FOR THE NEXT TIME BUT
PERHAPS BEING MORE PROACTIVE
WITH MEASUREMENTS OF DATA
OUTCOMES TO IMPROVE OUR CARE
AND THERE ARE VARIOUS WAYS TO
DO THAT IN THE CLINIC AND I
PUBLISHED A PRACTICE LAST YEAR
ON THIS PARTICULAR TOPIC.
SO ONE OF THE WORK FLOWS WE
DEVELOPED IN MY LAST POSITION,
IN THE PRACTICE MANAGEMENT
SYSTEM, THAT WOULD TRIGGER A
E-MAIL TO THE CLIENT ASKING
THEM FOR CONSENT TO
PARTICIPATE IN THE SURVEYS.
IF THEY CONSENT, THEY REPORT
THE CLIENT OUTCOME MEASURES,
THEY HAVE CONSENTED TO THAT
AND THOSE WOULD COME INTO THE
PRACTICE SYSTEM AND DEPENDING
WHAT THE TREATMENT WAS, THAT
WOULD TRIGGER REPEAT SURVEYS
AT MAYBE TWO WEEKS, SIX WEEKS,
26 YEARS AND -- WEEKS AND THEN
YEARLY AFTER.
SO IN THIS WAY WE WERE ABLE TO
COLLECT ASSESSMENTS FROM THE
TEAM.
AND REPORTED OUTCOME MEASURES
WERE COLLECTED ACROSS THE
GLOBE AND THIS IS JUST A SHOT
OF THE PLATFORM.
THESE ARE DOGS THAT RECEIVED
ARTHROSCOPY FOR ELBOW DATA AND
JUST SUPPLIESD -- SPLICED AND
DICED THE DATA ON THAT GRAPH.
SO I THINK THESE TOOLS ARE
IMPORTANT IN CLINICAL PRACTICE
AND MANY HERE ARE HERE FOR
PRACTICE AND HOPEFULLY WE'RE
GETTING THERE IN THIS REGARD.
SO WITH THAT, I WOULD SAY
THANK YOU VERY MUCH AND THANK
YOU AGAIN FOR INVITING ME.
[APPLAUSE]
>> THANKS VERY MUCH, JOHN,
THIS IS A REALLY IMPORTANT
CONVERSATION.
AS WE DEVELOP OUTCOME MEASURES
AND UNDERSTANDING HOW WE
CONVERT CHANGES INTO
UNDERSTANDING WHAT IS
MEANINGFUL AND THEN ON IN TO
SUCCESS FAILURE ANALYSIS AND
THAT BRINGS ME TO THE NEXT
PRESENTATION, DOTTIE BROWN,
BECAUSE OF A RECENT CHANGE IN
JOBS, NOW WORKS FOR MARS
HEALTHCARE, HAD A CONFLICT
THAT COULDN'T BE RESOLVED SO
SHE IS IN LONDON AT THE
MOMENT, COULD NOT BE HERE BUT
HAS RECORDED A PRESENTATION
AND SHE WILL TALK ABOUT HER
APPROACH OF DEFINING
SUCCESS-FAILURE ANALYSIS AND
REMEMBER HAVE YOUR QUESTIONS
READY FOR THE PANEL SESSION
WHEN WE WILL GET EVERYONE
TOGETHER AND DISCUSS THESE
TOPICS.
>> GOOD MORNING, THIS MORNING
I WILL SHARE THE SUCCESS
PROCESS WE USE FOR THE SUCCESS
FAILURE ANALYSIS AND THIS WEIR
NARROW IS GIVEN TO THE OWNER
TO IDENTIFY THE SEVERITY AND
CHRONIC PAIN OF THEIR DOGS
OSTEOARTHRITIS.
SO WHEN WE START LOOKING AT
WHAT THE CONTROLS LOOK LIKE,
WE SEE THE PLACEBO DATA IS IN
BLUE AND THE NONSTEROIDAL
INTERVENTION ANIMALS ARE IN
RED.
AND WE EXPECT TO SEE MORE BLUE
ON THE LEFTHAND SIDE OF THE
CURVE WHERE THERE IS
DETERIORATION OR MINIMAL
IMPROVEMENT IN CHANGE SCORE
AND EXPECT TO SEE MORE RED ON
THE RIGHTHAND SIDE OF THE
CURVE WHERE THERE IS
SIGNIFICANT IMPROVEMENT IN THE
CHANGE SCORE OVER TIME AND WE
NOTICE A LOT OF OVERLAP
BETWEEN THESE TWO CURVES SO WE
SEE A LOT OF PURPLE ON THE
GRAPH.
AND MOST COMMONLY, THIS IS HOW
THE DATA IS HANDLED.
THE DATA IS ORDINAL MEANING
THE ORDER OF RESPONSE OPTION
IS MEAN ILLFUL.
SO IF -- MEANINGFUL.
SO IF THE OWNER CHOSES A 2 AND
THEN A 9 LATER ON DOWN THE
ROAD THEY ARE IDENTIFYING MORE
PAIN IN THEIR DOG OVER TIME
BUT IT IS NOT MEANINGFUL.
MOVING FROM A 2 TO 4 DOES NOT
MEAN A DOG IS IN DEVICE AS
MUCH PAIN, FOR EXAMPLE.
AND THIS DATA IS OFTEN
POSITIVELY SKEWED MEANING
THERE IS A TAIL TO THE RIGHT
AND THE MEDIAN AND MEAN AND
LOW DO NOT LINE UP THE WAY
THEY NORMAL NORMALLY WOULD IN
A DISTRIBUTE INPOPULATION SO
WE NORMALLY COMPARE SCORES
BETWEEN GROUPS.
AND THIS IS AN IDEALIZED
VERSION OF WHAT THE SHAPE
WOULD LOOK LIKE.
THE CURVE WOULD VARY QUITE A
BIT PARTICULARLY WHEN WE'RE
DEALING WITH RELATIVELY SMALL
CONCENTRATIONS OF PATIENTS AT
CLINICAL TRIALS.
WHEN YOU HAVE A OUTLIER LIKE
THIS, THE CONCERN IS LARGE
IMPROVEMENTS IN A SMALL NUMBER
OF DOGS WITHIN A GROUP COULD
POTENTIALLY MASK A LACK OF
IMPROVEMENT OR MINIMAL
IMPROVEMENT OF MANY DOGS IN
THAT GROUP.
SO THIS IS JUST ONE OF THE
REASONS WHY THERE MAY BE AN
IMTUGS TO SHIFT THE FOCUS TO
LOOKING AT THE DATA AT THE
INDIVIDUAL ANIMAL LEVEL AS
OPPOSED TO COMPARING OVERALL
DIFFERENCES BETWEEN SCORES AND
GROUPS.
SO WITH THE GOAL TO ASSIST
WHETHER THE TREATMENT HAS A
MESH MEASURABLE EFFECT FOR A
ANALYTIC STUDY, THE CRITERIA
FOR THE TREATMENT OF EACH
PATIENT WITH SOME SORT OF
CUTOFF NEEDS TO BE PREDEFINED.
SO THE SUCCESS OR FAILURE CAN
BE ASSIGNED AT THE R AT THE
END OF THIS STUDY AND THEN THE
NUMBER OF TREATMENT FAILURES
AND SUCCESSES IN EACH GROUP
CAN BE COMPARED.
AND AGAIN THERE ARE LOTS OF
DIFFERENT WAYS TO DO THIS SO I
AM SHARING WHAT WE DID FOR THE
PCBI AND IN THIS CASE, WE HAVE
TWO DIFFERENT DOMAINS TO
CONSIDER.
WE HAVE A CUTOFF IN THE CHANGE
OF THE PAIN SEVERITY SCORE AND
CHANGE IN THE INTERFERENCE
SCORE AND HOW THOSE TWO
CUTOFFS MAY WORK TOGETHER.
SO FOR THIS STUDY WE PULLED
TWO INDEPENDENT DATASETS
THROUGH CLINICAL STUDY
DESIGNS.
THESE WERE BOTH PLACEBO
MINIMIZED TRIALS WHERE
CARPROFEN WAS USED AS A
CONTROL.
AND THE DOGS RECEIVED
CARPROFEN ON DAY 4 AND THEN
AGAIN ON DAY 14.
ONE WAS SETTING THE CRITERIA
AND DEFINING TREATMENT SUCCESS
AS A REDUCTION OF 1, 2 AND 3
FOR THOSE SCORES.
SO THERE IS A LOT GOING ON IN
THIS SLIDE BUT THE IMPORTANT
THING TO NOTE IS WE BROKE THE
DATA DOWN IN THREE POPULATIONS
AND EACH OF THEM HAVE A
SEPARATE BOX ON THE SLIDE SO
WITH EACH BOX, WE VARIED THE
SUCCESS CRITERIA FOR EACH OF
THE TWO GIVING SCORED.
SO ULTIMATELY POPULATION 1
WHICH IS IN THE YELLOW BOX
INCLUDES 137 DOGS THAT HAD A
BASELINE SEVERITY OR
INTERFERENCE SCORE GREATER TO
OR EQUAL TO ONE.
BASELINE WAS 160 DOGS WITH AN
INTERFERENCE SCORE GREATER
THAN OR EQUAL TO 2.
AND DOGS IN THE AQUA BOX WERE
87 DOGS WHICH HAD A SEVERITY
SCORE OR BASELINE AT 3.
AND IN EACH OF THESE CRITERIA,
WE VARIED THE REDUCTION IN
SCORE AS 1, 2 AND 3 FOR ONE OR
BOTH OF THE SEVERITY OR PAIN
MEDICATION SCORES.
AND EACH POPULATION OR SUCCESS
CRITERIA, THE NUMBERS WERE
SUMMARIZED FOR SUCCESSES OR
FAILURES WITHIN EACH TREATMENT
GROUPS AND THEN THE
DIFFERENCES BETWEEN THE GROUPS
WERE EVALUATED FOR SUCCESS AND
AGAIN THE LINE WAS CALCULATED
FOR FAILURE OR SUCCESS.
SO FOR BOX NUMBER 2, THESE ARE
REDUCTIONS GREATER TO OR EQUAL
TO 1 IN THE PAIN SEVERITY
SCORE AND GREATER THAN OR
EQUAL TO 2 IN THE PAIN
INTERFERENCE SCORE AND THEN IN
POPULATION 3, A SIMILAR
SCHOOL, 64.7 WAS OBTAINED WITH
THAT SAME SUCCESS CRITERIA.
FOR POPULATION 3, THERE WERE
SOME ALTERNATE SUCCESS
CRITERIA THAT YIELDED SIMILAR
OR HIGHER POWER VALUES.
AND WE ALSO WANTED TO LOOK AT
THE POOL DATA IN THE WAY THE
ORIGINAL DATASETS WERE
ANALYZED TO MAKE SURE WE WERE
SEEING CONSISTENT RESULTS.
SO TO EVALUATE THE SAME DATA
ON THE BASIS OF MEDIAN SCORES
AS DONE PREVIOUSLY, THE
BASELINE OF 137 DOGS WITH
CARPROFEN AND THE POPULATION
1, 2 AND 3 AS CALCULATED.
THE CHANGES FROM BASELINE TO 4
WAS SIGNIFICANTLY DIFFERENT
BETWEEN CARPROFEN AND BASEBO I
WANTED KATEING THE IMPROVEMENT
IN THE CARPROFEN-TREATED DOGS
OVER THE PLACEBO DOGS WHICH WE
WOULD EXPECT.
SO OVERALL THE CHANGE IN SCORE
USING CHANGE IN MEAN SCORES
USED PREVIOUSLY OR BY LOOKING
AT THE NUMBER OF BE A ANIMALS
CATEGORIZED AS SUCCESSES BASED
ON PREDEFINED PAIN SEVERITY
CRITERIA AND IDENTIFYING
REDUCTIONS GREATER THAN OR
EQUAL TO ONE IN THE PAIN
SEVERITY SCORE AND GREATER
THAN OR EQUAL TO 2 IN THE PAIN
INTERFERENCE SCORE YIELDED THE
HIGHEST POWER FOR BOTH
POPULATION 2 AND POPULATION 3.
SO DOGS WITH BASELINE SCORES
GREATER THAN OR EQUAL TO 3.
SO THIS WAS USED IN THE CBI
APPROVAL STUDY FOR GALAPRANT
IN 2016 AS WELL AS THE SCORES
FOR ANOTHER DRUG USED IN THE
U.S.
NOTE/GALLIPRANT.
SO THIS IS THE REDUCTION LINE
TO DETERMINE HOW EFFECTIVE THE
TKR*UG IS AND THIS HAS BEEN
CARRIED FOR -- FORWARD IN
FUTURE STUDIES.
[APPLAUSE]
>> GREAT, PLENTY OF FOOD FOR
THOUGHT THERE.
HOPEFULLY WILL STIMULATE SOME
GREAT QUESTIONS DURING THE
PANEL DISCUSSION.
WE'RE GOING TO TAKE A
15-MINUTE BREAK HERE.
WE WILL COME BACK AT 10: 10,
SO STRETCH YOUR LEGS, GRAB
SOME COFFEE, COME BACK AT
10:10 A.M.
WE WILL HAVE GREATER
DISCUSSIONS ON SPECIES AND
OUTCOME MEASURES AND EXPLORE
THE AREA OF CURVE ANALYSIS
APPROACH VERSUS INDIVIDUAL
TIME POINTS SO SEE YOU BACK
HERE IN 15 MINUTES AT 10:10
>> NEXT WE HAVE PROFESSOR LUNA
WHO WORKS AT SAN PALO IN
BRAZIL AND HAS REALLY BEEN THE
DRIVER OF A LOT OF WORK
PARTICULARLY IN PRODUCTION
ANIMALS AROUND THE ASSESSMENT
OF PAIN AND DEVELOPING OUTCOME
PERSONNURES AND WILL TALK TO
US NOW AND HE IS WITH US OVER
ZOOM, THIS IS A RECORDED
PRESENTATION, HE WILL BE NOT
HERE BUT WITH US FOR THE
DISCUSSION FORUM.
>> I WOULD LIKE TO THANK Dr.
INNES AND ORGANIZERS.
ON THIS YOU WILL FIND THE
SCALES USED BY USERS --
[INDISCERNIBLE]
I HAVE SOME INTERESTS IN
RELATION TO THE PRESENTATION
AND ACTUAL COMMITTEES AS SHOWN
HERE.
A SUCCESSFUL SCALE IS ONE WITH
THE HIGHEST SPECIFICITY.
ANOTHER WAY TO IDENTIFY
SUCCESS IS INTRAREPEATABILITY
AND INTER-RATER RELIABILITY OR
REPRODUCIBILITY.
THIS CAN BE SHOWN BY THE
CUTOFF SCORE AND THE CONSENSUS
BASED STANDARDS FOR SELECTION
OF HEALTH MEASUREMENT
INSTRUMENT.
AFTER A REVIEW, THE PAIN SCALE
HAS ALSO BEEN PUBLISHED.
THIS HAS BEEN PUBLISHED FOR
CATTLE, AND THE CO SMIN SCALE
WAS DEVELOPED FOR ASSESSING
POSTOPERATIVE PAIN IN COWS.
THE ORIGINAL UCAPS WAS
DEVELOPED AND NEXT STEP WAS TO
DEVELOP CLINICAL VALIDATION IN
BULLS AND IN HOSPITAL
ENVIRONMENTS.
BOTH WERE DEVELOPED FOR
SPECIFICITY.
THE UCAPS, CPS AND UNIT AND
THERE WAS NO DIFFERENCE IN THE
SCORES BETWEEN BREEDS.
THIS SPECIFICITY OF SHOWING
PAIN.
THIS COULD BE USED CLINICALLY
NOT ONLY FOR PROVIDING
INFORMATION ON SURGERY BUT
ALSO TO MAKE SURE THAT IT IS
PLAUSIBLE.
SO THERE WAS PAIN ASSESSMENT
IN PAIN-FREE CATTLE AND IN
OTHERS FOR SURGERY.
BECAUSE SHEEP ARE USED FOR
TRANSLATIONAL MEDICINE AND USA
PS USED FOR POSTOPERATIVE
SURGERY IN SHEEP.
IT WAS ONLY LAPAROTOMY AND
FIELD CONDITIONS.
PAIN SCORES INCREASED AFTER
SURGERY.
THE PAIN WAS SIMILAR TO THE
ORIGINAL STUDY.
THIS IS THE NEW PAIN SCALE
COVERAGE FROM OUR GROUP.
THEY SCALED FOR PEOPLE AND
ABSENCE OF BEHAVIORS EXPRESSED
AND FOR GOATS IS IT WORKED
VERY WELL.
THE BOTTOMUCATU GOAT SCORE
MEASURED RESPONSIVENESS AND
CONSTRUCT VALIDITY IN ZONE 3
FOR PAIN-FREE GOAT AND
UNDERGOING PAIN.
A NEW STUDY CLINICALLY VALUE
VALIDATES THE PIG SCALE FROM
NORTH CAROLINA STATE
UNIVERSITY AND SHOWS A SIMILAR
RESULT TO INDEX.
RELIABILITY OF PAIN SYSTEM AS
SHOWN IN GOATS.
THIS IS AN EFFICIENT TOOL FOR
INTEROBSERVER RELIABILITY AND
USED TO MEASURE PAIN IN SWINE.
THE IMPLICATIONS AND
CONCLUSIONS, THE UPAPS WAS
USED TO MEASURE SENSITIVITY
AND PAIN AND IN ORDER OF
POURS -- IMPORTANCE.
FOR EXAMPLE, IN CATTLE, PAIN
WAS SHOWN IN THE WALL OF --
[INDISCERNIBLE]
, THE SAME TYPE OF BEHAVIOR.
THE BEHAVIOR ON THE TOP IS
SUFFICIENT TO 1.65.
WE DID THE SAME THING WITH
SWINE AND GOATS TO BETTER
UNDERSTAND THE BEHAVIORS FOR
PAIN TIGERS.
AND THESE GIVE US BETTER
UNDERSTANDING OF IMPORTANCE OF
EACH BEHAVIOR FOR PAIN
DIAGNOSIS.
IT IS A STEP TOWARDS AN
APPLICATION CAPABLE OF
AUTOMATICALLY ESTIMATING THE
PROBABILITY OF ANIMAL NEEDING
ANA LG ESIA OR NOT.
BASED ON A PAIN RECOGNITION
USING FACIAL AREA AND BODY
POSTURE TO AN ACCURACY OF
87 PERCENT AND FOR THE MOST
RECENT MODEL, USING AI FOR
AUTHOMATIC PAIN DETECTION.
WE ARE DEVELOPING NEW STUDY
FOR ACCURACY OF PAIN MEASURE
BASED ON THE UPAPS -- USA PS
AND SHEEP FACIAL EXPRESSION
FOR SCORING.
MACHINE OUTPERFORMS HUMAN
EXPECT IN SHEEP PAIN
VALIDATION.
WHAT IS NEXT?
ARE THE RESULTS PRODUCIBLE
WHEN USED BY UNTRAINED
SUBJECTS?
WE NEED TO MODIFY THE SCALE
FOR DIFFERENT AGE, SEX, OTHER
TYPES OF PAIN AND IMPLEMENT
ALGORITHMS.
ARTIFICIAL INTELLIGENCE CAN BE
INSERTED IN APPLICATIONS FOR
VET PAIN.
THANKS A LOT FOR YOUR
PATIENCE.
[APPLAUSE]
>> THANKS FOR THAT AND SO WHAT
WE HAVE HEARD SO FAR JUST AS A
QUICK RECAP IS DIFFERENT
APPROACHES TO DEFINING SUCCESS
FAILURE.
WE HAVE THE ANCHOR BASED
METHOD THAT WAS DESCRIBED.
A STATISTICAL APPROACH TO
PAUSING PARSING OUT HOW WE
SEPARATED GROUPS AND THEN
PRESENTED DATA BASED ON RESCUE
OR INTERVENTION SO NOW WE WILL
CONTINUE THE THEME AND IT IS
MY PLEASURE TO INTRODUCE MIKE
CONZEMIUS FROM THE UNIVERSITY
OF MINNESOTA AND HAS DRIVEN
THE REACTION FORCES IN PAIN
PATIENTS.
HE RECENTLY STARTED HIS OWN
PRACTICE IN ARIZONA,
UNFORTUNATELY LIKE PROFESSOR
LUNA, UNABLE TO JOIN US
PHYSICALLY SO HE IS JOINING US
OVER ZOOM.
MIKE, OVER TO YOU.
>> IS YOUR ZOOM TURNED UP?
>> SORRY?
>> WE COULDN'T HEAR YOU FOR A
SECOND BUT WE CAN HEAR YOU
NOW.
>> THANK YOU.
THIS IS ABOUT GROUND REACTION
FORCES AND MANY OF YOU MAY BE
UNFAMILIAR WITH GROUND
REACTION FORCES SO BRIEFLY
WHEN YOU STEP ON A SCALE IT
SAYS, YOU KNOW, 160 POUNDS,
THAT IS A GROUND REACTION
FORCE.
SO WE ARE MEASURING IN DOGS,
WHAT THIS TALK IS ABOUT, IN
DOGS ALTHOUGH THIS COULD BE
TRANSLAID -- TRANSLATED TO
OTHER SPECIES WHERE WE'RE
MEASURING GROUND REACTION
FORCES.
SO THIS IS PARALLEL TO THE
FLOOR AND VERY SENSITIVE AND
COMPLICATIONAL AND YOU MEASURE
A NUMBER OF OTHER THINGS OF
MOTION DATA ALONG WITH THAT.
SO THAT IS WHAT GROUND
REACTION FORCES ARE AND WHEN
-- THE REASON WE DO THAT, FOR
ME, ANY WAY THE REASON I DO
IT, IS ONE, IT GENERATES SOME
OBJECTIVE NUMBER.
AND IT IS A NUMBER GENERATED
BY THE ACTUAL PATIENT OR THE
STUDY SUBJECT, IF YOU WILL, AS
OPPOSED TO A PERSON LOOKING AT
AN ANIMAL AND GENERATING A
NUMBER.
DOGS I DO FOR ONE OF TWO
REASONS.
THEY LIMP BECAUSE A LIMB PUTS
OR A -- LIMB HURTS OR A LIMB
DOESN'T WORK CORRECTLY, LIKE
POINTED IN THE WRONG DIRECTION
OR SOMETHING LIKE THAT.
SO INTUITIVELY, THERE IS AN
INJURY THAT WOULD CAUSE PAIN
AND THEY ARE LIMITING AND THEN
I THINK WE CAN MEASURE,
QUANTIFY, THAT AMOUNT OF
DISCOMFORT.
SO DISCLAIMER, DISCLOSURE,
REALLY GOT NOTHING TO HIDE.
AND SO I AM GOING TO BE
SHARING THINGS FROM A PAPER WE
PUBLISHED, OH, GEEZ, ABOUT A
YEAR OR TWO, YEAR AND A HALF
OR SO AGO OF BEST PRACTICE FOR
GROUND REACTION FORCES IN THE
DOGS.
IT WAS MYSELF AND A SERIES OF
OTHER AUTHORS THAT HAVE A LOT
OF EXPERTISE USING THIS AND
THE REASON WHY WE DID IT,
REALLY, IS ONE, BECAUSE OF THE
PAWS GROUP THAT WAS A BIT OF A
MOTIVATING FACTOR, BUT ALSO
BECAUSE PEOPLE START CUTTING
CORNERS, TRYING TO COME UP
WITH SOMETHING THAT CAN MAYBE
BE SIMILAR TO THE GOLD
STANDARD, IF YOU WILL, AND
WHEN THEY CUT THOSE CORNERS,
THEY KIND OF, LIKE ANY TOOL
THAT IS REALLY GOOD, PEOPLE
GET IN THE WAY OF IT.
AND SO IT ADDRESSES -- THIS
PAPER ADDRESSES STANDARD
OPERATING PROCEDURES, QUALITY
ASSURANCE, HOW YOU PICK
SUBJECTS, DATA NORMALIZATION,
SO FORTH.
SO ONE PART OF THAT IS
ACTUALLY HOW TO MEASURE THINGS
AND WHAT IS QUANTIFIABLE, WHAT
IS THE DIFFERENCE THAT
MATTERS.
SO FIRST OF ALL, WHAT GROUND
REACTION FORCE DATA SHOULD BE
USED AND ONE THING THAT WE
WENT BACK AND FORTH ABOUT, AND
THERE IS A LOT OF DATA OUT
THERE IN THE LITERATURE THAT,
FOR EXAMPLE, USES THIS BUT NOT
THAT.
AND, WELL, I THINK WHAT I AM
SAYING IS WHEN YOU GET
TOGETHER IN A ROOM OF EXPERTS
AND DEBATE WHAT YOU HAVE TO DO
OR WHAT IS THE GOLD STANDARD,
SOMETIMES YOU HAVE TO GIVE UP
SOME OF YOUR OWN PUBLICATIONS
AND THAT IS WHAT ALL OF US HAD
TO DO AT ONE POINT OR ANOTHER
THROUGHOUT THIS.
SO REALLY A MINIMUM AMOUNT OF
DATA SHOULD BE CONSIDERED TO
INCLUDE VELOCITY,
ACCELERATION, PEAK MOVEMENT
AND VI.
SO THIS IS USED TO GENERATE
USABLE, RELIABLE DATA.
VELOCITY AND ACCELERATION ARE
SUPER IMPORTANT AND THE REASON
FOR THAT IS NOT EVERY PATIENT
IS THE EXACT SAME SIZE AND A
PEAK VERTICAL FORCE AND VI
RESPOND DIFFERENTLY TO
VELOCITY.
SO YOU COULD EITHER, WHEN YOU
MEASURE VELOCITY, MEASURE
TORSO VELOCITY OR MEASURE
CONTACT TIME, HOW MUCH TIME
THE FOOT IS IN CONTACT WITH
THE GROUND.
WELL, THOSE THINGS CHANGE
DEPENDING ON HOW TALL YOU ARE.
SO IF YOU CAN KIND OF IMAGINE
IF I AM WALKING NEXT TO
SOMEONE THAT IS HALF MY HEIGHT
AND WE ARE WALKING AT THE SAME
TORSO VELOCITY, OUR FEET WILL
BE MOVING AT DIFFERENT
VELOCITIES.
SO OUR TORSO VELOCITY IS THE
SAME BUT OUR FOOT VELOCITY AND
CONTACT TIME WITH THE ACTUAL
FLOOR IS DIFFERENT.
SO REALISTICALLY WHEN I AM
WALKING FAST, THE PERSON WHO
IS HALF MY HEIGHT MAY ACTUALLY
BE JOGGING.
SO WE ACTUALLY GENERATE
DIFFERENT FORCES, DIFFERENT
GROUND REACTION FORCES.
SO YOU HAVE TO MEASURE
VELOCITY, YOU HAVE TO REPORT
VELOCITY, THERE ARE WAYS TO
NORMALIZE IT AND THE DETAILS
WITH RESPECT TO THAT WITH OUR
PATIENTS IS BY WEIGHT AND
HEIGHT AND THAT IS MENTIONED
IN THAT PAPER.
YOU HAVE TO NOTICE PEAK
VERTICAL FORCE AND VI AND THEY
RESPOND DIFFERENTLY TO
VELOCITY AND ACCELERATION.
THERE ARE A NUMBER OF PAPERS
IN THE VETERINARY LITERATURE
FOR EXAMPLE, GOSH, I WOULD SAY
YOU COULD PULL OUT HALF OF
THEM THAT WOULD RECORD ONLY
PEEK VERTICAL FORCE AND SOME
OF THEM DON'T MEASURE
ACCELERATION AND SOME DON'T
MEASURE VELOCITY.
SO IT IS KIND OF LIKE I AM
GOING TO PRESCRIBE MYOCEMIA AS
BROWN HAIR AS OPPOSED TO
SAYING BROWN HAIR, 160 POUNDS,
5'10" AND WEARING PINK ON
WEDNESDAYS.
NOT A RULE, JUST A RULE I
FOLLOW.
SO YOU HAVE SOME EXAMPLES HERE
AND LOOK AT IS THE PEAK CHANGE
FROM VERTICAL VELOCITY
RECORDED IN A INDIVIDUAL OR
GROUP OF WALKING DOGS TREATED
FOR OSTEOARTHRITIS OVER TWO
MONTHS CLINICALLY IMPORTANT?
WELL, IF YOU PUT THOSE DATA
POINTS TOGETHER AND DIVIDE BY
TWO, WE HAVE A 10 PERCENT
IMPROVEMENT IN GROUND REACTION
FORCES AND WHAT I WOULD TELL
YOU IS DEPENDING ON THE
DISEASE, IF THIS WAS
OSTEOARTHRITIS, THAT WOULD BE
A VERY IMPRESSIVE MOVEMENT.
SO LET'S LOOK AT WHAT THE PEAK
VERTICAL FORCE.
SO 37 TO 40 AND VI FROM 14 TO
12.5, JUST THE OPPOSITE.
SO IT IS ACTUALLY A DECREASE
OF 10.1 PERCENT.
IF YOU AVERAGE THOSE TWO, THE
NET GROUND REACTION FORCE
ACTUALLY DECREASED BY
1 PERCENT.
SO THIS IS A VERY DIFFERENT
FINDING THAN WHAT OCCURRED IN
THE FIRST EXAMPLE.
THIS IS WHY YOU HAVE TO RECORD
VELOCITY AND ACCELERATION AND
WHY YOU HAVE TO REPORT GROUND
REACTION FORCES TOGETHER.
YOU CAN'T CARRY FORWARD AND
REPORT JUST ONE.
SO I FEEL LIKE WHEN YOU ARE
LOOKING AT GROUND REACTION
FORCES, OBVIOUSLY IT IS NOT
ONLY THE SUBJECT BUT IF YOU
WANT TO SAY WHAT IS A
CLINICALLY MEANINGFUL
DIFFERENCE, THE DISEASE
MATTERS AND IF IT IS DOGS WITH
A CRANIO CRUCIATE
LIGAMENTMENT, LIKE A ACL TEAR,
THAT IS VERY DIFFERENT THAN
OSTEOARTHRITIS.
SO FOR THE PURPOSES OF THIS
TALK, FOCUSING ON
OSTEOARTHRITIS AND CHRONIC
PAIN, SO YOU NEED TO HAVE
PLACEBO DATA FROM A RANDOMIZED
PLACEBO CONTROLLED TRIAL.
WE HAVE PRETTY GOOD
INFORMATION ON OSTEOARTHRITIS
AND THE PROCEDURE ON THE RIGHT
WAS FROM A FDA CLINICAL TRIAL
THAT WAS OBVIOUSLY A CLINICAL
CONTROL TRIAL.
AND THE DASH LINE ON THE TOP
IS THE GROUND REACTION FORCES
AND THE OTHER LINE THAT
IMPROVES AND GETS BETTER AND
GETS BETTER IS THE
QUESTIONNAIRE.
ONE BIT OF DISCLOSURE, THIS IS
THE OWNER QUESTIONNAIRE USED
HERE.
IT IS NOT AS ANALYTICAL AS THE
ONES THAT HAVE BEEN REPORTED
ON TODAY, FOR EXAMPLE, LIKE
THE CANINE PAIN REPORT.
BUT NEVERTHELESS, THIS IS THE
DATA.
AND IF YOU LOOK AT THE AVERAGE
DATA OF THESE PLACEBO DOGS
WITH OSTEOARTHRITIS, TREATED
WITH THE PLACEBO DO, NOT
CHANGE OVER TIME, THE GROUND
REACTION OF THE DOGS DOESN'T
CHANGE.
BUT THE OWNERS' INTERPRETATION
OVER THE TRIAL DID CHANGE.
IF YOU CATEGORIZE THINGS, ONE
THING WE TRY TO DO IS SEE WHAT
IS CLINICALLY DIFFERENT.
SO THE MEAN DATA DID NOT
CHANGE.
IF THERE WAS A 12 PERCENT
INCREASE IN GROUND REACTION
FORCES SEEN IN DOGS AND A 5 TO
10 PERCENT DECREASE IN 8.6
DOGS AND THIS WAS 60 DOGS
PLACEBO TREATED, ONE DOG HAD A
DECREASE IN 10 PERCENT SO NO
DOG IMPROVED MORE THAN 10
SPERSE REALISTICALLY, IT WAS
UNUSUAL.
THERE CAN BE SOME WAXING AND
WANING BUT IT IS UNUSUAL TO
SEE IMPROVEMENT OF GREATER
THAN 5 PERCENT AND RARE TO SEE
AN IMPROVEMENT OF GREATER THAN
10 PERCENT.
SO THAT IS ONE WAY TO KIND OF
LOOK AT THIS.
SO IF WE CAN LOOK AT THAT THAT
WAY AND THAT IS KIND OF WHERE
WE SAY OH, 5 PERCENT, PRETTY
IMPRESSIVE IMPROVEMENT IF YOU
ARE GOING TO LOOK AT A GROUP
OF DOGS.
YOU CAN ALSO COMPARE AVERAGE
GROUP LOOKING AT PREVIOUSLY
PUBLISHED DATA WE THINK IS
VERY RELIABLE.
FOR EXAMPLE, WE BELIEVE
ANTI-INFLAMMATORY TREATMENT
FOR OSTEOARTHRITIS WORKS AND
OMEGA-3 FATTY ACID DIETS
SHOWING CHANGES OF IMPROVEMENT
OVER TIME, THOSE STUDIES
RANGING FROM 3.5 TO 6 PERCENT,
AGAIN THE CHANGES IN THOSE
NUMBERS, MAYBE 5 PERCENT IS
THE MINIMUM.
THE OTHER WAY TO ADDRESS IT IS
ADDRESS THE PROBABILITY OF
CHANGE IN THE PLACEBO VERSUS
THE OTHER GROUP, IN DOGS WITH
OSTEOARTHRITIS, A CHANGE IN
BOTH PVF AND VI OVER A SHORT
PERIOD OF TIME PERIOD OF
3.5 PERCENT IS THE MINIMUM
VALUE THAT SHOULD BE
CONSIDERED CLINICALLY
IMPORTANT.
SO THE NUMBER OF DOGS IN EACH
GROUP THAT HAVE A CHANGE IN
GROUND REACTION FORCES GREATER
THAN 5 PERCENT IS A GOOD
MEASURE.
SO THAT IS ALL I HAVE FOR YOU
AND THANKS FOR YOUR TIME
TODAY, REALLY APPRECIATE IT.
[APPLAUSE]
>> THANKS VERY MUCH, MIKE, SO
LOTS EVER FOOD FOR THOUGHT
THERE, THINKING ABOUT HOW WE
DEFINE CLINICALLY IMPORTANT
CHANGE, HOW WE DEFINE SUCCESS
FAILURE AND WE WILL BE HAVING
A PANEL DISCUSSION SO LOOK
FORWARD LIVELY INTERACTION
THEN, WE WILL HAVE ALL THE
PRESENTERS OTHER THAN Dr.
BROWN AVAILABLE.
SO LET'S MOVE ON TO, SORT OF A
CHANGE IN DIRECTION BUT
FOCUSING ON TODAY'S THEME OF
LOOKING AT ANALYTICAL
APPROACHES AND CAN WE ADVANCE
THAT.
IT IS MY PLEASURE TO INTRODUCE
Dr. JIM CAMPBELL, A FRIEND
AND MENTOR TO ME, A LONG
CAREER AT JOHNS HOPKINS AS A
NEUROSURGEON AND PAIN
RESEARCHER AND HE IS NOW THE
CHIEF SCIENTIFIC OFFICER AT
CENTREXION THERAPEUTICS AND
WILL TALK TO US ABOUT ANOTHER
CONTROVERSIAL TOPIC ON WHETHER
TO USE THE AREA UNDER THE
CURVE AS AN ANALYSIS OR SINGLE
POINTS IN TIME.
JIM, TAKE IT AWAY.
>> GOOD TO SIGH EVERYBODY --
SEE EVERYBODY, THANKS TO THE O
ORGANIZERS AND DUNCAN FOR
HAVING ME HERE AT THE MEETING.
TUCK CAN AND I HAVE HAD MANY
DISCUSSIONS ABOUT THE TOPIC
AND ONE POINT TO MAKE HERE IS
IS WE SPEND BILLIONS AND
BILLIONS ON TRIALS IN ANIMALS
LOOKING TO COME UP WITH BETTER
THERAPY.
AND RELATIVELY SPEAKING, WE
SPEND VERY LITTLE ON CLINICAL
TRIAL TIME.
SO WE'RE LIKE GIVING A
PHYSICIST A THING OR TWO BUT
DON'T GIVE HIM A GOOD
TELESCOPE NECESSARILY ARE OR
WE DON'T TALK ABOUT THE
TELESCOPE CAPITUALLY.
SO THE MEASURE WE USE ARE
REALLY SO IMPORTANT AND I
THINK IT IS TERRIFIC TO SEE
THIS MEETING BECAUSE IT REALLY
BRINGS UP THE ANALYTIC TOOLS
THAT WE HAVE, THAT WE USE IN
CLINICAL TRIALS AND IT IS JUST
SO IMPORTANT.
I AM GOING TO SPEAK ABOUT A
PARTICULAR ASPECT OF THIS,
NAMELY HE IS ESSAY SENSITIVITY
AND THIS IS SOMETHING THAT I
HAVE THOUGHT WITH QUITE A LOT
OVER TIME.
DUNCAN AND I HAVE HAD MANY
CONVERSATIONS ABOUT THIS AND
DUNCAN HAS PROMPTED ME TO DO
SOME EVEN FURTHER, MORE
SERIOUS THINKING ABOUT THIS,
AND I DO. TO ACKNOWLEDGE AT
THE OUTSET THAT I AM INVOLVED
AT CENTREXION IN MULTIPLE WAYS
THAT CREATES A POTENTIAL
CONFLICT OF INTEREST.
THIS SLIDE MAKES THE FURTHER
POINT ABOUT THE IMPORTANCE OF
ESSAY SENSITIVITY WHEN WE DO
TRIALS.
SO E-- ASSAY SENSITIVITY, WHAT
IS IT REALLY, IT IS THE
ABILITY TO DETECT EFFICACY
WHEN IN FACT, IN THIS CASE, A
DOCTOR, IS TRULY EFFICACIOUS.
IT IS THE ABILITY TO
DISTINGUISH AN ACTIVE
TREATMENT FROM AN INACTIVE
TREATMENT AND COULD BE SAID
THAT A TRIAL THAT LACKS ASSAY
SENSITIVITY LACKS INTERNAL
VALIDITY.
THERE ARE MANY FACTORS THAT
AFFECT ASSAY SENSITIVITY,
TRIALS DESIGN AUTHORIZE RELY,
TRIAL CONDUCT, SELECTION OF
ENDPOINTS BUT WHAT I WANT TO
FOCUS ON IN THE NEXT FEW
MINUTES IS THE ANALYSIS PLAN.
SO TO BEGIN, LET'S JUST LOOK
AT SOME SIMULATED DATA.
IN THIS CASE, MY COLLEAGUE
JAMES CONNOLLY WORKED WITH ME
TO PUT TOGETHER AN ARBITRARY
DATASET.
WE HAD 170 SUBJECTS AND
IMAGINED HERE THE BLUE LINE
BEING THE PLACEBO GROUP WITH
170 SUBJECTS STUDY OVER A
1-WEEK -- 12-WEEK PERIOD OF
TIME AND THEN THE TEST COULD
BE INJECTION THERAPY, A DAILY
DRUG THAT IS GIVEN AND LOOKING
AT THE DECREASE IN PAIN ON THE
RATING SCALES AND LOOKING AT
THIS OVER TIME OUT TO 12
WEEKS.
SO I INVITE YOU TO THINK ABOUT
THIS.
IS THIS A THERAPY THAT LET'S
SAY IS SAFE, IS THIS SOMETHING
OF INTEREST, SOMETHING THAT
SHOULD BE LOOKED AT AS A DRUG
TO CARRY FORWARD AND DOES IT
WORK IMPORTANTLY AND THE FACT
IS THIS IS AN EXAMPLE OF A
FAILED TRIAL.
AND WHY IS THIS A FAILED
TRIAL?
BECAUSE IF YOU LOOK AT THIS,
IT IS REASONABLY CONVINCING
DATA AT DIFFERENT TIME POINTS
BUT SEEMS THAT AT WEEK 12,
THESE TWO DOGS ARE TOO CLOSE
TOGETHER AND WHAT IS THE
CONVENTION OF DOING THE
ANALYSIS OF THE TRIAL AND
SPECIFICALLY THE PRIMARY
ENDPOINT IS ORDINARILY
DIRECTED AT WHAT HAPPENS IN
THE LAB WEEK, THE 12TH WEEK IN
THIS CASE AND THIS IS REFERRED
TO AS A LANDMARK ANALYSIS AND,
AGAIN, IT IS WHAT THE DEVICE
AT THE FDA REQUIRES OF MOST OF
US IN DOING DRUG TRIALS.
AND IT IS INTERESTING IN THAT
WE HAVE LOTS OF DATA IN THIS
TRIAL BUT IN PRINCIPLE, I
MEAN, AND WE COULD LOOK AT ALL
THE DATA OF COURSE BUT IN
TERMS OF THE PRIMARY ENDPOINT,
THE ENDPOINT ANALYSIS LARGELY
IGNORES THE RICH DATASET AND
FOCUSES ON THE 12TH WEEK.
NOW, THIS CAN BE DONE IN
ANCOVA ANALYSIS OR MORE
MONTHLY, AN N MR M ANALYSIS
COULD BE DONE AND THERE IS
CONSIDERATION OVER OTHER TIME
POINTS BUT THE PRIMARY
COMPARISON IS STILL AT WEEK
12.
♪/M MR M.
WE COULD ASK THEREFORE, IS
THERE AN ALTERNATIVE AND
INTERESTINGLY, WE JUST
HAPPENED TO TALK A COUPLE OF
MINUTES AT THE BREAK AND HE
WAS TELLING ME ABOUT THINGS HE
IS DOING TO LOOK AT ACUTE PAIN
AND IT TURNS OUT AN ACUTE
PAIN, THE ANALYSIS IS ENTIRELY
DIFFERENT.
IT IS NOT A LANDMARK ANALYSIS
BUT GENERALLY IS THE SO-CALLED
SPID.
THERE ARE THOSE THAT ARGUE A
PAIN RELIEF SCALE IS MORE
SENSITIVE AND I AM NOT SURE
THAT THAT DISCUSSION HAS BEEN
PLAYED OUT SUFFICIENTLY.
AND THERE ARE MAYBE SOME
ARGUMENTS AGAINST THAT BUT I
AM NOT SURE THAT THOSE
ARGUMENTS ARE NECESSARILY
VALID.
BUT IN ANY CASE, LET'S FOCUS
ON THE SPID.
SO WHAT IS THIS?
IT STANDS FOR SUM OF PAIN
INTENSITY DIFFERENCE AND FOR
EACH TIME INTERVAL, ONE
SUBTRACTS THE PAIN INTENSITY
AT BASELINE FROM THE PAIN
INTENSITY AT THAT SPECIFIC
INTERVAL AND THEN ONE CAN TAKE
A SUM OF THE VALUE FOR EACH
SUBJECT, TIME WEIGHTING CAN BE
APPLIED TO ADJUST INTERVALS
AND THEN CUMULATIVE PAIN OVER
TIME AT THE ENDPOINTS FOR EACH
SUBJECT AND ONE COMES UP WITH
THE AREA UNDER THE CURVE
ANALYSIS ESSENTIALLY.
SO WHY CAN'T WE USE SIMILAR
TYPE OF ANALYSIS IN CHRONIC
PAIN?
LET'S TALK A LITTLE MORE ABOUT
AREA UNDER THE CURVE.
SOMETIMES IT IS REFERRED TO AS
AREA UNDER EFFECT.
IF ONE LOOKS INTEREST THIS
WITH REGARD IT CHRONIC PAIN
TRIALS, THERE IS VERY, VERY
LILLITH CHEWER -- LITTLE,
LILLITH CHEWER -- LITERATURE
AND IT IS STRIKING HOW LITTLE
THAT HAS BEEN DISCUSSED AS AN
ALTERNATIVE MEASURE.
IT IS CONDITION FUSING BECAUSE
WHAT ONE IN OUR FIELD
GENERALLY COMES UP WITH THE
AUC COMMON IN PK STUDIES, AND
THAT IS VERY SIMPLY THE
INTEGRAL OF THE CURVE OVER
TIME.
ONE CAN PLAY WITH THIS A BIT
AND DO TIME WEIGHTING.
ACTUALLY THIS IS PROBABLY A
NOVEL AREA FOR CONSIDERATION
SO HERE WE ARE WITH OUR
SIMULATED DATA AND THIS IS HOW
THIS WOULD LOOK.
WE HAVE RECTANGLES HERE BUT
PROPERLY THESE SHOULD BE
TRAPEZOIDS TO CAPTURE THE
INTEREST GRASS MORE ACCURATE
-- INTEREST INTEGRALS MORE
RELIABLY.
IF YOU LOOK AT THE ANALYSIS AT
WEEK 12 AND THIS IS JUST A
SIMPLE TEA TEST BUT WE SEE
HIGHLY SIGNIFICANT RESULT
OUTCOMES AND QUITE
SUBSTANTIALLY DIFFERENT AS
OPPOSED TO WHAT HAPPENED AT
WEEK 12.
SO THIS IS A SIMULATED CASE,
DOESN'T HAPPEN IN REAL LIFE
AND I THINK IT WOULD BE VERY
INTERESTING TO PURSUE LOOKING
ACROSS STUDIES WHERE AUC
ANALYSES ARE AVAILABLE AND TO
COMPARE THESE WITH LANDMARK
ANALYSES.
ONE STUDY THAT STUCK IN MY
MIND OVER TIME IN AN AREA OF
INTEREST OF MINE AND THAT IS
LOOKING AT ADJUSTING THERAPIES
FOR OSTEOARTHRITIS PAIN WITH A
REPORT FOR A DRUG NOW APPROVED
WHICH IS A NOVEL EXTENDED
RELEASE MICROSPHERE
FORMULATION OF TRIAMCINOLONE.
IGNORE THE MIDDLE LINE.
IT IS A DISTRACTION AT THE
MOMENT AND LOOK AT THE BOTTOM
LINE AND THE PLACEBO CURVE.
AND AT EACH OF THESE TIME
POINTS, WE SEE AN INCREASE IN
PAIN BETWEEN PLACEBO AND
ACTIVE BUT IT TURNS OUT THE
PRIMARY ENDPOINT WAS WEEK 12.
SO WHAT WAS REPORTED IN THE
PRESS, FAILED TRIAL, DID NOT
MEET ITS PRIMARY ENDPOINT.
WHEN YOU LOOK AT THE DATA,
HOWEVER, IT WAS SIGNIFICANT AT
WEEK 11 AND IT WAS SIGNIFICANT
AT WEEK 13 AND THEN THERE WAS
A WANITTHAING EFFECT
CONSISTENT WITH THE BIOLOGY
AND STRO*EUD EFFECT.
THEY STRIKING THAT THE COMPANY
HAD TO REPORT TO INVESTORS IT
FAILED AT TRIAL.
AND WE HAVE HAD SOME BITTER
EXPERIENCE WITH THIS AS WELL.
THIS IS A DOUBLE BLIND PLACEBO
CONTROL PHASE 3 TRIAL THAT WE
UNDER TOOK WITH ONE MILL GRAM
OF CENTREXION INTO THE KNEE
FOR PATIENTS WHO HAD MODERATE
TO SEVERE ARTHRITIS PAIN.
SO WE DO THE INJECTION AND
LOOK AT THE RATING SCALE,
DECREASE IN PAIN VERSUS THE
PLACEBO.
AND WE MISSED THE PRIMARY
ENDPOINT WHICH AGAIN WAS WEEK
12 AND SO HAPPENED BY THE WAY
HAD WE DECLARED A WHICH WAS
PAIN WITH WALKING ON PRIMARY
ENDPOINT, IT WAS STATISTICALLY
SIGNIFICANT AT WEEK 12.
SO WE WERE QUITE LUCKY AND IT
WAS A TOSS-UP WHETHER WE WOULD
USE ONE VERSUS THE OTHER AT
PRIMARY ENDPOINT.
IT WAS REALLY -- THERE WAS NO
COMPELLING RATIONAL TO USE ONE
OVER THE OTHER.
BUT WHEN YOU LOOK AT THESE
DATA, PRETTY SIMILAR
DIFFERENCE, EVEN OUT TO WEEK
20, 25, 26, THERE IS A WANING
EFFECT IN THE LAST WEEKS OF
THE TRIAL.
ABOUT YOUR MANY OF THESE TIME
POINTS ARE IN FACT SIGNIFICANT
IN THE M MR M ANALYSIS.
AND WHEN WE DO A AUC ANALYSIS,
SAME DATA, THIS WAS
PRESPECIFIED SO THIS IS ONE OF
THE DECLARED SECONDARY
ENDPOINTS IN OUR STUDY, THE
AREA UNDER THE CURVE FOR THIS
SAME DATASET IS POSITIVE.
AND THE ANALYSIS SPAN GOING
FROM TIME ZERO TO WEEK 12 SO
HAD THAT BEEN THE ENDPOINT, WE
WOULD HAVE DECLARED THAT A
SUCCESSFUL TRIAL.
SO WHY THIS MIGHT NOT BE THE
PRIMARY ENDPOINT IF IT HAS
BETTER ASSAY SENSITIVITY.
THE WHOLE ISSUE OF THE
PATIENT'S IMPRESSION OF LOCAL
PAIN HAS COME UP BEFORE IN
JENNIFER'S TALK AND I THINK A
VERY IMPORTANT SCALE TO THINK
ABOUT AND I WILL COME BACK TO
THIS A LITTLE BIT MORE BUT WE
ALSO DID A -- AND THERE IS
SOME CONTROVERSY WHETHER YOU
COULD REPEAT THE STUDY BUT WE
DID THAT -- OR REPEAT THE
MEASURE OVER THE COURSE OF THE
TRIAL.
AND WE DID THAT RIGHT ALONG.
AND WE LOOKED AT THE
PERCENTAGE OF SUBJECTS WHO
REPORTED BEING MUCH BETTER OR
VERY MUCH BETTER WHICH IS THE
TOP OF THE SCALE, I WILL GO
BACK, A 7-POINT SCALE WHERE
SUBJECTS CAN REPORT FEELING
DIFFERENT OR WORSE AS WELL BUT
THE SIGNIFICANT DATA SHOWS THE
PRESPECIFIED ANALYSIS PLAN FOR
DATA AT EVERY TIME APPOINTED
THAT WE EXAMINED WITH VALUES
GOING FROM .01 TO .05.
SO ONE COULD ARGUE THAT THESE
DIFFERENCES WERE CLINICALLY
MEANINGFUL.
WE HAD ANOTHER PAID TRIAL THAT
WAS NEARLY IDENTICAL IN STEIN
AND ENDPOINTS AND ALL THE
OTHER NEUTRAL COMPONENTS AND
WE HAD A SIMILAR OUTCOME AND
BECAUSE THE TRIALS WERE
INTEGRATED, WE COMBINED THEM
SO HERE WE ARE GOING OUT TO 26
WEEKS AND THIS IS THE COMBINED
ANALYSIS.
IN THIS CASE, THE NMRM
ANALYSIS WAS APPLIED AND FOR
EVERY ONE OF THE WEEKS, AND
THIS IS WEEK 11 WHICH HAPPENED
NOT TO BE SIGNIFICANT, ABOUT
YOUR THERE WERE LATER TIME
POINTS THAT WERE SIGNIFICANT,
EVEN DOWN TO A POINT OF 001
AND THEN PROBABLY A WANING
EFFECT ONCE ONE GETS PAST WEEK
20, 21.
SO THIS ANALYSIS SADLY DOESN'T
APPEAR TO ACCOUNT AS A
CONTRIBUTOR TO A NDA BECAUSE
IT IS A COMBINATION OF TWO
OTHER TRIALS.
AND SO IS THIS KIND OF PAIN
MEANINGFUL SO WE LOOK T AT --
LOOKED AT THIS KIND OF
ANALYSIS IN POINT IN TIME
ANALYSIS, WEEKS 1, 2, 3 AND
WHAT ONE WOULD EXPECT, AN
INJECTION OF CAPAICIN, WHEN
ONE LOOKS AT THE CHANGE, THE P
VALUES START TO GET MORE
IMPRESSIVE IN TERMS OF THE
NUMBER OF SERIOUS AND AGAIN,
RACES THE QUESTION ABOUT WELL
WHAT IS THE SCALE HERE THAT
HAS THE BEST ETHICAL
SENSITIVITY?
I HAVE ALREADY SHOWN YOU THE
AREA UNDER THE CURVE MAY BE
MORE RELIABLE THAN THIS IN THE
FUTURE ALTHOUGH WE HAVEN'T
REALLY DISCUSSED THAT THAN THE
EXAMPLE I AM SHOWING YOU WITH
GREATER EFFICACY.
SO LET ME GO BACK TO THIS
POINT BEFORE I CLOSE ABOUT
GLOBAL ASSESSMENT.
I THINK FOR ME IN THIS JOURNEY
LOOKING AT AUC, THIS WAS A
SIDE ISSUE AND WOULD I DO --
JOHN'S WORK WAS REFERRED TO BY
EARLIER AND SPI ID REFERRED TO
AS THE GOLDEN STANDARD AND LED
ME TO THINK MAYBE THIS SHOULD
BE THE ENDPOINT AND IF IT IS
THE GOLD STANDARD, WHY NOT USE
THE GOLD STANDARD?
AND THERE ARE SOME ISSUES WITH
THAT.
ONE IS, IS IT REALLY A MEASURE
OF PAIN AND IS GLOBAL THE
RIGHT WORD?
[ CLEARING THROAT ]
PARDON ME.
I HAVE WOEFRTD IF WE SHOULD
INSTEAD TALK ABOUT PATIENT
CHANGE IN PAIN AND WE DO
INCLUDE RECALL BUT MAYBE
PATIENTS DO RECALL WHAT THEY
WERE LIKE BEFORE AND HOW THEY
ARE NOW?
THAT OBJECTION CAN BE RAISED
BY I DON'T KNOW IF IT HAS
REALLY BEEN STUDIED AS A FATAL
FAULT.
AND WE CAN TALK ABOUT THIS
LATER IF WE HAVE A CHANCE.
AND WHY IN FACT DO WE
NECESSARILY HAVE TO TAKE DAILY
PAIN RATINGS?
WE DON'T REALLY USE THE DATA
NECESSARILY AND THIS ADDS TO
THE COST FOR CERTAIN.
SO FOR CONSIDERATION, WE COULD
DO PATIENT IMPRESSION OF
CHANGE IN PAIN OVER SEVERAL
WEEKS INSTEAD OF DOING THESE
THINGS EVERY DAY.
I WILL MENTION BE A AREA UNDER
THE CURVE, ANALYSIS, COULD BE
MISLEADING IN A SITUATION
WHERE PAIN DRUG HAS A WANING
EFFECT AS MAY OCCUR, FOR
EXAMPLE, AS AN OPIOID, SO WE
MAY NOT WANT TO CALL THIS AUC
THEN.
THE WAY TO GET AROUND THIS IS
AS A TOOL USED IN OTHER
SITUATIONS, ECONOMIC,
FINANCIAL ANALYSIS, USE A
FUNCTION CALLED SUSPENSION
WAITING AND THIS DESERVES TO
BE CONSIDERED.
SO LET ME GO TO MY COLLUSION,
I WOULD SAY -- CONCLUSION, I
WOULD SAY THE ENDPOINT
ANALYSIS A FLAWED ENDPOINT AND
ACROSS THE ANALYSIS REALLY IS
A BETTER INTEGRATED TRIAL THAN
UNDULY WAITING FOR THE RESULTS
OVER A SINGLE WEEK.
ACUTE PAIN CAN BE USED IN
CHRONIC PAIN AND I WOULD SAY
ACUTE PAIN UNDER THE CURVE
COULD BE A PRIMARY ENDPOINT IN
PAIN STUDIES BOTH IN ANIMAL
AND HUMAN STUDIES AND WITH
THAT, I WILL CLOSE OUT.
THANK YOU.
[APPLAUSE]
>> THANKS VERY MUCH, JIM,
PROVOCATIVE THOUGHTS THERE.
SO WE WILL MOVE TO THE PANEL
DISCUSSIONS NOW AND I COULD
ASK ALL THE SPEAKERS FROM THIS
MORNING TO COME UP AND TAKE
SEATS, PLEASE.
AND JUST A VERY QUICK CHECK,
MIKE, STELIO, CAN YOU HEAR US?
STELIO?
OKAY, GREAT.
YOU WOULD THINK WITHIN FOUR
YEARS OF PLAYING WITH ZOOM, WE
WOULD ALMOST HAVE THIS FIGURED
OUT.
OKAY, ON TO QUESTIONS.
ANYONE HAVE QUESTIONS FOR THE
SPEAKERS?
IF NOT I CAN --
[OVERLAPPING SPEAKERS]
-- KICK OFF WITH ONE TO START
WITH.
OVER ZOOM, CAN YOU GUYS BOTH
MUTE IF YOU ARE NOT SPEAKING?
A LITTLE BIT OF FEEDBACK
OCCURRING.
GREAT, LET'S TRY THAT.
SO MAYBE THIS IS AN OPEN ENDED
QUESTION SO --
>> I DON'T MEAN TO INTERRUPT,
I AM SORRY.
SUPER FASCINATING, REALLY
ENJOYED THIS ONE, MY NAME IS
SUSAN WITH THE FDA IN
BIOLOGICS.
COULDN'T HELP BUT NOTICE THE
MEASURED REQUIREMENT IN
ARTHRITIS PAIN, THE FIRST
THING I THOUGHT ABOUT WAS
DERMATOLOGY.
I HAVE A DOG WITH AFRACTORY
DERMATITIS, AND THERE IS A
FOUR-PAGE OUTCOME, HOW MUCH
ASK -- DOES HE ITCH, ET
CETERA.
SO THE QUESTION IS AS FAR AS
THE PAIN KRELS -- CONTROLS IN
CLINICAL DESIGN, HAVE REPORTED
OUTCOMES AS IN PETS BECAUSE I
KNOW FROM MY OWN PETS THE
REPORTED OUTCOME IS FOR
IMPROVEMENT.
>> ANYONE LIKE TO PICK THAT
UP?
YES.
SO I GUESS IT IS ME.
THERE ARE VALIDATED TOOLS IN
EXISTENCE.
I THINK WOULD CAN CHAT TO ONE
OF THE DEVELOPERS, UNIVERSITY
OF BRISTOL AND I THINK THE
DEVELOPER WOULD, IN AUSTRALIA
AND HE HAS NO INTEREST IN THAT
SCALE FOR SOME REASON.
SO I AM SURE, I THINK THE RULE
DISCIPLINES THAT HAVE BEEN
MADE IN VETERINARY MEDICINE
AND HUMAN MEDICINE SHOULD COME
TOGETHER FOR BETTER CLINICAL
OUTCOMES.
THAT WOULD BE GREAT BECAUSE IT
IS A BIT SILENT AT THE MOMENT.
THERE ARE INCREASINGLY
OUTCOMES OUT THERE AND COULD
BE USED TO IMPROVE EACH OTHER
SO I AGREE WITH THAT.
>> SO COULD I INTERRUPT?
DUPIXEN IS NOW VERY STRIKINGLY
USEFUL THERAPY FOR ATOPIC
DERMATITIS AND THERE IS A
FLOOD OF THEATRES APPEAR --
OTHERS THAT APPEAR TO MAYBE
WORK AS WELL AND WE'RE
CERTAINLY SEEING A HUGE
DEVELOPMENT.
IN THE CHRONIC PAIN FIELD,
WE'RE LOOKING WITH ENVY ON
WHAT IS HAPPENING WITH ATOPIC
DERMATITIS WHICH IS HARDLY
RECOMMENDED.
MY WIFE IS A DERMATOLOGIST AND
20 YEARS AGO THIS WAS A
NUISANCE SYNDROME BUT NOW ALL
OF A SUDDEN THAT THERE IS A
TREATMENT, IT IS OF GREAT
INTEREST.
IN THE PAIN FIELD, THE
FRUSTRATION HAS BEEN THAT WE
HAVE REALLY NOT SEEN ANY
INNOVATION FOR OVER 20 YEARS
AND IT'S QUITE STRIKING WITH
DRUGS WE KNOW WORK, LIKE
GABAPENTON, PREABALIN, THOSE
DRUGS WORK AND SOMETIMES THE
HELP IT CONFERS TO A PATIENT
IS CLINICALLY VERY STRIKING,
ALTHOUGH OFTEN WITH SIDE
EFFECTS BUT IN DOING TRIALS,
IT HAS BEEN POINT OUT IN THE
ANALYSIS THAT MANY OF THE
TRIALS OUTRIGHT FAILED AND THE
STANDARDIZED EFFECTS ARE ALL
OFFER THE PLACE GOING FROM
NEGATIVE TO POSITIVE IN
VARIOUS LEVELS OF POSITIVITY.
SO ONE REASON FOR THAT COULD
BE THAT WE JUST DON'T KNOW IN
CHRONIC PAIN HOW OPTIMALLY TO
DO THE TRIALS AND THAT IS A
REAL SHAME BECAUSE WE ARE
LOOKING AT A NUMBER OF
PROMISING THERAPIES AND IF WE
DON'T HAVE OUR TOOLS NAILED
DOWN PROPERLY, WE ARE AT RISK
OF LOSING OUT ON INNOVATION
BECAUSE WE WON'T APPRECIATE
THAT THE DRUG TRULY WORKS FOR
NOW.
>> THANKS FOR THAT AND I AM
GOING TO BRING IN MIKE.
MIKE, I THINK YOU HAVE
SOMETHING TO SAY ABOUT THAT
QUESTION?
>> YES, I THINK IT IS A GREAT
QUESTION.
OBVIOUSLY WE HAVE TO HAVE AN
OPEN MIND.
ONE THING THAT I THINK IS
STARTING TO CHANGE IS, YOU
KNOW, SO WHEN IT COMES TO
PAIN, THE PATIENT CAN CHANGE
DRAMATICALLY DEPENDING ON
THEIR ENVIRONMENT THAT THEY
ARE IN.
AND YOU BRING A PATIENT INTO A
VETERINARY HOSPITAL, YOU KNOW,
IT IS QUITE COMMON FOR ME FOR
EXAMPLE, FOR AN OWNER TO SAY
OH, WELL LIKE I DON'T SEE MUCH
VALIDITY AND THEN THEY SHOW ME
A VIDEO AT HOME AND IT IS
QUITE OBVIOUS.
SO I DO THINK YOU HAVE TO
THINK ABOUT THE ENVIRONMENT
THEY ARE IN AND HOW THAT SKIS
MAY OR -- DISEASE MAY OR MAY
NOT BE IMPACTED BY THAT
PARTICULAR ENVIRONMENT.
THE ONE THING WE SHOULD WORK
FOR, MANY OF US HAVE WORKED
FOR, IS MEASURING THE PATIENT
IN THEIR NATURAL ENVIRONMENT,
WHICH IS AT HOME, VIA ACTIVITY
MONITORING WHICH IS A TRICKY
SCIENCE BUT THERE ARE SOME
AVOCATIONS THAT HAVE COME OUT
RECENTLY THAT SORT OF DESCRIBE
HOW WE CAN GET TO THE END OF
MEASURING THE PATIENT AT HOME
WHICH I THINK TRANSLATED WELL
IN MEASURING CHRONIC PAIN IN
THE PATIENT'S NATURAL
ENVIRONMENT.
SO THAT IS MY TAKE ON ONE OF
THE THINGS ABOUT
QUESTIONNAIRES.
>> GREAT, THANKS.
LETS HE GO TO THE NEXT
QUESTION OVER ON THE RIGHT
HERE.
>>
[INDISCERNIBLE]
IN HANOVER, I HAVE A QUESTION
OR MAYBE COMMENT RELATED TO
CAREGIVER ASSESSMENT BECAUSE
WE KNOW PAIN AND ALSO THE
RELATING OF PROXY, VERY
DEPENDENT ON THE CULTURE, YOUR
UPBRINGING.
ARE THERE ANY STUDIES THAT
LOOKED AT THE INFLUKES OF
THE -- INFLUENCE OF THE
PATIENT ON DISEASE AND
CAREGIVER ASSESSMENT?
BECAUSE I THINK WHEN WE LOOKED
AT THE DATA IN THE EUROPEAN
UNION AND MIDWEST, THERE WAS
QUITE A BIG DIFFERENCE IN THE
PLACEBO EFFECT BECAUSE OF THE
MUCH HIGHER PLACEBO EFFECT IN
THE U.S -- I MEAN EUROPEANS,
ACTUALLY SO MAYBE THE
EUROPEANS ARE MORE GRUMPY AND
A LITTLE LESS EFFECTIVE AND SO
THERE COULD BE A DIFFERENCE
BETWEEN THE AMERICAN AND
EUROPEAN CULTURE AND SO HAVE
YOU NOTICED ANY DIFFERENCES
WITH THE ANIMAL OR SAY A
CHILD?
>> GREAT QUESTION AND DO WE
NEED TO IMPLEMENT CULTURAL
FAILURES OR SUCCESSES?
JENNIFER, CAN YOU KICK US OFF
ON THIS ONE?
>> I DON'T KNOW, I MEAN, I
DON'T KNOW, I WOULD HAVE TO
LOOK AT THAT BUT I THINK IT IS
DEFINITELY TRUE, RIGHT, AS
THERE ARE SO MANY THINGS THAT
GO INTO A PLACEBO RESPONSE
WITH EXPECTATIONS AND THAT
WOULD BE REALLY INTERESTING TO
LOOK TO SEE IF SIMILARATICALLY
THERE IS A DIFFERENCE IN THE
STUDY AND I THINK THE BEST WAY
TO DO THAT IS AN INTERNATIONAL
STUDY LOOKING AT THE SAME
TYPES OF PAIN AND COMPARE
THAT.
>> ANYONE ELSE LIKE TO COMMENT
ON CULTURAL DIFFERENCES AND
PAIN AND HOW TO COMPARE THOSE
IN, MIKE?
>> REAL QUICK, I CAN IT IS --
I THINK IT IS AN EXCELLENT
POINT BUT A LITTLE BIT OF A
RAT HOLE.
I THINK IF YOU LOOK AT PLACEBO
DATA, THERE ARE PUBLISHED
EFFECTS WHERE THERE IS
DIFFERENCES IN RELIGION, HAS
AN EFFECT ON PLACEBO EFFECT,
GENDER AND AGE HAVE A MACABLE
BO EFFECT SO THERE ARE
PUBLICATIONS THAT LOOK AT
CAREGIVER PLACEBO EFFECTS AND
OUTSIDE INFLUENCES, I DON'T
SPECIFICALLY RECALL, YOU KNOW,
WHAT COUNTRY OF ORIGIN BUT I
THINK IT IS NOT ONLY COUNTRY
OF ORIGIN BUT YOU KNOW FOR
EXAMPLE IS AS I GET A LITTLE
OLDER, COULD SAY THOSE KIDS
WITH THAT ROCK AND ROLL MUSIC,
THE WA I THINKEN TIPPER PAIN
IN DOGS IS ALL WRONG.
SO I THINK THERE'S OTHER
FACTORS AS WELL SO I WOULDN'T
BE SURPRISED IF THERE ARE
OTHER INFLUENCING FACTORS AND
ONE OF THE THINGS YOU HAVE TO
ADDRESS IN YOUR STUDIES.
>> OKAY.
>> COULD I MAKE ONE COMMENT?
>> THEN I WILL COME TO YOU,
CELIA, ONE SECOND.
>> SO CAN YOU THINK -- DUNCAN,
YOU ARE VERY FAMILIAR WITH
THIS, WE ARE DOING EXPLORATORY
WORK IN THE U.S. AND LOOKING
AT OUTCOMES FOR DOGS IN A
ARTHRITIS MODEL AND WHAT WAS
STRIKING WAS TO SAY THE
DIFFERENCES.
IT HAPPENED IN -- ONE OF THE
STATES WAS RUN BY DOTTIE BROWN
WHEN SHE WAS AT THE UNIVERSITY
OF PENNSYLVANIA.
AND THE EFFECTS SIDE,
DIFFERENTIATION OF PLACEBO AND
EFFECTIVE IN A BLINDED TRIAL
WAS REMARKABLE AND VERY LITTLE
PLACEBO WAS OBSERVED.
BUT AT OTHER SITES WITHIN THE
U.S., THERE WAS AN ENORMOUS
PLACEBO EFFECT AND ONE WOULD
NEVER BE ABLE TO SHOW THAT A
DRUG TRULY WORKED OR NOT IF
THE PLACEBO EFFECT IS SO LARGE
THAT IT WIPES OUT THE ABILITY
TO MEASURE.
SO I AM NOT SCHUMER IT IS
JUST -- NOT SURE IT IS JUST
CULTURAL.
I THINK IT IS THE
SOPHISTICATION TRAINING OF THE
SITE AND HOW ONE INTERACTS
WITH THE CLIENT, THE OWNER OF
THE PET, FOR EXAMPLE, OR IN
THE CASE OF CHRONIC PAIN, THE
CONDITIONS OF THE RELATIONSHIP
WITH THE SUBJECTS, I THINK ARE
MORE LIKELY, EVEN THOUGH --
AND IT IS CHALLENGING WHETHER,
IN THE UK, THEY DO SPEAK A
FOREIGN LANGUAGE SO MAYBE THAT
IS IT.
>> I COULD CHIP IN TO SAY
BRITISH ENGLISH IS DEFINITELY
DIFFERENT FROM AMERICAN
ENGLISH.
COULD I BRING YOU IN NOW, OFF
STATEMENT FOR THE PANELISTS?
>> YES, SO THIS MIGHT BE A BIG
BANK BUT WE HAVE STUDIES IN
FIVE LANGUAGES SO IT PROVES A
POINT BUT COULD BE THAT THE
EFFECTS ARE SIMILAR --
[INDISCERNIBLE]
>> MAYBE THAT SPEAKS TO THE
QUALITY THAT THE ASSESSMENT
TOOL DOES WORK IN DIFFERENT
SETTINGS.
KATHLEEN, GO AHEAD.
>> KATHLEEN, UNIVERSITY OF
IOWA.
EVERYBODY HAS THAT UNIQUE
PERSPECTIVE, OH, WOULD HAVE
BEEN MORE EFFECTIVE IF I HAD
PICKED A DIFFERENT OUTCOME AND
JENNIFER HAS THIS CLAUSE OF
SHOULD WE PICK THE BENEFIT FOR
THE OUTCOME.
BUT I WONDER IF WE SHOULD
COMPARE THE OUTCOME TO OUR
PURPOSE?
IN OTHER WORDS, IS PAIN MORE
IMPORTANT OR SHOULD WE BE
LOOKING AT MULTIPLE UTCOMES,
AND I KNOW WE WILL TALK ABOUT
THIS LATER, OR SHOULD WE MAKE
OUR BEST GUESS AND THEN BE
TOLD AT A CLINICAL TRIAL THAT
YOU FAILED BECAUSE YOUR GUESS
IS WRONG, IT IS HARSH.
AND SO JENNIFER IS THE
CLINICAL EXPERT AND THAT WOULD
BE GREAT BUT LIKE TO GET A
THOUGHT ON THIS, ARE WE
LOOKING AT THINGS IN THE WRONG
WAY, SHOULD WE BE THINKING
ABOUT CLINICAL TRIALS AND
EXPANDING ON THE METHODOLOGY
IN A DIFFERENT WAY.
>> JENNIFER, PLEASE?
>> OH, WELL, WHAT A QUESTION.
I DON'T THINK I HAVE ANSWERS.
I THINK THERE ARE SO MANY
FACTORS THAT GO INTO DECIDING
WHAT YOUR PRIMARY OUTCOMES
SHOULD BE AND I LOVE THE IDEA
OF PERSONALIZING OUTCOMES AND
ACTUALLY THINKING ABOUT THIS
IN TERMS OF PAIN QUALITY,
MEASURING THE ACTIVE PAIN,
ASKING PEOPLE WHAT IS THE MOST
IMPORTANT PAIN QUALITY TO
THEM, ASSESS THE PAIN QUALITY
AND I AM DOING A STUDY TO LOOK
AT THAT.
I THINK THERE ARE A COUPLE OF
CHALLENGES.
THE FIRST ONE IS IF YOU GIVE
PEOPLE THE OPPORTUNITY TO
CHOOSE WHAT IS IMPORTANT TO
THEM AT BASELINE, THE OUTCOME
HAS TO BE SOMEWHAT UNIFORM.
IF IT IS MEASURED ON 0 TO 10,
YOU CAN COMBINE THOSE THINGS,
IF IT IS NOT, THEN YOU CAN'T
AND THAT IS ONE THING TO THINK
ABOUT.
THE OTHER THING WITH REGARD TO
BENEFIT RISKS THAT BECOMES A
LITTLE MORE COMPLICATED, I
THINK FOR ME, THE REASON I GOT
INTO PAIN RESEARCH IS I HAD A
MOM WHO WAS IN CHRONIC PAIN
HER WHOLE ADULT LIFE BUT I
WANTED TO MAKE IT AS EASY AS
POSSIBLE TO GET DRUGS WHEN
THEY DO TRULY WORK.
AND WHEN YOU BRING IN BENEFIT
RISK IN AN ASSESSMENT, YOU
RISK BEING ARE ABLE TO SHOW IT
WORKS.
SO I THINK IT HELPS PEOPLE
DECIDE WHICH OF THESE TWO
DRUGS SHOULD I TRY FIRST OR
WOULD BE BETTER FOR ME IS A
GOOD OUTCOME.
TO RAISE THE BAR AND SAY IN
ORDER TO GET APPROVED YOU HAVE
TO HAVE A HIGH BENEFIT RISK
PROFILE, WE HAVE TO BE VERY
CAREFUL ABOUT THAT AND THEN
LOOK AT THE NEGATIVE RISK AS A
BENEFIT OF THAT SO I THINK I
JUST RAM BUILD A LOT OF
THINGS.
>> ANYONE ELSE WANT TO COMMENT
ON INDIVIDUALIZING OUTCOME
MEASURES?
>> MAYBE WE WILL GET INTO THIS
A LITTLE BIT WHEN WE HAVE OUR
DISCUSSIONS ABOUT COMBINING
OUTCOMES AND MIGHT BE ABLE TO,
WITH COME POSSIBLE COMPOSITE
MEASURES, TAP INTO THIS.
I THINK A COMPLEXITY IS HOW DO
YOU WRITE THE LABEL AND I
THINK IT'S A TERRIFIC IDEA
THAT FOR ONE PERSON, PAIN IS
IMPORTANT AND IN ANOTHER
PERSON, MAYBE IT IS FUNCTION
BUT THEN WHEN YOU ARE WRITING
YOUR LABEL, HOW DO YOU WRITE
THE APPROVAL?
SO THIS DRUG IS APPROVED FOR
IMPROVING FUNCTION AND FOR
PATIENTS WHO HAPPEN TO HAVE
OSTEOARTHRITIS, THAT WOULD BE
OBVIOUSLY DIFFERENT THAN
SAYING THE DRUG WOULD BE
APPROVED AS A PAIN KRUG AND --
DRUG AND YOU HAVE A SP-PBS TO
THAT?
>> HOW DO YOU WRITE THE LABEL
IF IT IS A TREATMENT FOR THE
CONDITION?
NOT A FUNCTION OF THE PAIN BUT
THE CONDITION AND SO THAT IS
SOMETHING WE HAVE TO WRITE
WITH THEM IF WE'RE GOING TO DO
THIS.
AS WE ALL KNOW, ALL PEOPLE
DON'T RESPOND TO OUR PRIMARY
COUNCIL BUT YOU GET DIFFERENT
RESPONDERS TO DIFFERENT
OUTCOMES, LIKE THEY DON'T ALL
RESPOND TO THE SAME OUTCOME SO
I WONDER IF WE CAN CHANGE HOW
THEY THINK ABOUT IT BUT THAT
IS A REGULATORY IS HE AND I
DON'T KNOW --
>> I THINK ANOTHER WAY IT
LOCK AT IT IS COULD THE
OUTCOME CHANGE THE MEASURE AND
IT MIGHT HAVE AN EFFECT ON
SENSIBILITY BECAUSE THERE WILL
BE A LOT OF VARIABILITY.
LIKE LETTING PEOPLE USE
ASTRAMYACIN FOR CRAMPING OR
PAIN AND THE MORE CONCEPTS YOU
BRING IN, THE LESS SENSITIVITY
YOU WILL HAVE AND I THINK FOR
A CHILD TO BALANCE FLEXIBILITY
AND PAIN, AND WHAT ARE THE
PLUSES AND MINUSES OF THOSE
TWO THINGS.
>> YEAH, I WOULD ADD THAT A
LOT OF THESE RESULTS CAN ONLY
BE RESOLVED BY DOING STUDIES.
SO AGAIN MY OPENING THEME IS
IT IS REMARKABLE TO ME THAT WE
SPENT MILLIONS IN DRUG
TREATMENT AND DON'T NOTICELY
KNOW WHAT THE TOOLS SHOULD BE.
AND ONE WAY THIS COULD BE AN
APPROACH PROBABLY WITH NIH
FUNDING IS TAKE DRUGS THAT ARE
KNOWN TO WORK AND THAT COULD
BE GABAPENTIN WHERE IT PRETTY
CLEARLY IS OPENFUL AND TEST
DIFFERENT WAYS OF MEASURING
OUTCOME AND LOOK AT SOME OF
THESE IDEAS WITH DATA.
SO I THINK WE SPEND A LOT OF
TIME SPECULATING IN A LOT OF
OUR JUDGMENTS ABOUT HOW TO
DESIGN TRIALS AND WHAT
ENDPOINTS TO USE, IS BASED ON
COMMON SENSE AND DISCUSSION
BUT WE REALLY, I THINK NEED TO
GET INTO EMPIRICAL DATA TO
OPTIMIZE AND ADDRESS THESE
ISSUES.
>> THANK YOU, ALL RIGHT LET'S
MOVE ON TO ANOTHER QUESTION.
>> SIMONE FROM -- JUST READ
SOME PAPERS ABOUT PAIN
MANAGEMENT AND THERE ARE
QUESTIONNAIRES ABOUT THIS AND
PEOPLE LOOKING UP TO THE
ANIMALS AS FARMERS AND FOR
INSTANCE THEY SAW THIS YOU
WERE YOUNGER OR OLDER THAN 24
YEARS THE WAY YOU PERCEIVE
PAIN IS DIFFERENT AND THEN
THERE'S A DIFFERENCE TO IF YOU
HAVE MORE THAN A THOUSAND
PEOPLE IN YOUR STABLE OR LESS.
AND THEN WE HAVE SEEN OUTCOME
FROM THE U.S. THAT THEY ARE
RELYING ON PERSONAL EXPERIENCE
AND INTERESTINGLY WHEN I FELT
WHEN THEY GOT MORE TRAINING
AND EFFECTIVENESS OF THE DRUG,
THE MORE TRAINING, THE LESS
CONCERN ABOUT SIDE EFFECTS SO
IT IS LIKE HAVING A BIAS THE
OTHER WAY AROUND.
SO I WAS WONDERING IF
OBSTETRICIANS SAW THIS LIKE IT
IS IMPLEMENTED IN FARM ANIMALS
AND YOU CAN KIND OF USE IT
WITHOUT HAVING TO BE OVER THE
AGE OF 24?
THANK YOU.
>> SO STELIO, PERHAPS YOU
WOULD LIKE TO COMMENT ON THAT?
THERE ARE SOME STATEMENTS
THERE ABOUT HOW A NUMBER OF
FACTORS CAN INFLUENCE A NUMBER
OF OPTIONS AND YOU HAD A SLIDE
THAT SAID AI IS BETTER THAN
PEOPLE.
YOU WANT TO EXPLAIN WHAT YOU
MEAN BY THAT?
>> WELL, AI IS BETTER BECAUSE
THE AUC, AREA UNDER THE CURVE
WAS BETTER WITH INITIAL PAIN
BECAUSE BASICALLY WHAT WE HAD
WAS SURGERY AND AV SURGERY --
AFTER SURGERY AND THERE WAS
THE GROUND TRUTH OF THE SHEEP
FEELING PAIN AFTER SURGERY SO
THEY WERE ABLE TO SAY THEY
WERE PAINFUL BETTER THAN
HUMANS AND THIS IS BASED ON
THE VARIOUS DISEASES USED IN
THE ORIGINAL WORK.
WE DID THE SAME THING WITH THE
RAT BUT DIDN'T COMPARE THAT TO
THE HUMAN.
I THINK THE FIRST ONE IS
COMPARING HUMAN VERSUS MACHINE
BUT I THINK THERE IS STILL A
LOT OF WORK TO DO.
I STILL BELIEVE IN THE
WELL-TRAINED TEST AND WHAT
RELATES TO PEOPLE SO THEY CAN
LEARN, ARE THEY OBSESSING IN
PAIN STATE OR THEY CAN HAVE A
LOT OF PAIN --
[INDISCERNIBLE]
-- MAKE SURE HE IS WELL
TRAINED BEFORE HE STARTS DOING
THE ASSESSMENT.
BUT THERE ARE STUDENT FOR
ASSESSMENT MAY BE FEELING PAIN
IN THE STABLE, SO PAIN IS VERY
IMPORTANT.
>> THANK YOU FOR THOSE
COMMENTS AND I MIGHT ADD SOME
MEDICAL EVENT TRAINING ITSELF
ALTERS THE WAY WE SEE PAIN AND
NOT NECESSARILY IN A POSITIVE
DIRECTION.
JOHN?
>> JOHN FROM UNIVERSITY OF
PENNSYLVANIA, I THINK THAT
THERE'S A KEY ISSUE HERE AND
AS JIM KNOWS, I LOVE DATA AND
I LOVE TO LOOK AT DATA AND I
COMPLETELY AGREE YOU SHOULD BE
USING MORE THAN JUST THE
ENDPOINTS OF OUR TRIALS, TO
UNDERSTAND WHAT IS IN THE
TRIAL AND THE AREA OF PAIN.
WITH YOU SOME OTHER THINGS,
WHAT WE'RE TRYING TO DO WITH
RESEARCH IS APPROXIMATE TRUTH
AND WE DON'T REALLY KNOW HOW
TO GET THERE, AS YOU WERE
SUGGESTING.
I AM NOT SURE LOOKING AT A
MULTITUDE OF DATA IS
NECESSARILY GOING TO HELP US
GET THERE.
I THINK THERE ARE SOME
PRINCIPLES WE IMPOSE ON WHAT
WE DO TO BETTER UNDERSTAND IT.
FOR EXAMPLE, THE 0 TO 10 SCALE
IS AN ABSOLUTELY TERRIBLE
SCALE WHEN IT COMES TO
UNDERSTANDING WHETHER YOU HAVE
A HEADACHE THAT SAY IS AT A
FIVE, THEN TO SAY IT HAS GONE
FROM FIVE TO SEVEN, I DON'T
KNOW WHAT THAT MEANS.
BUT ON THE OTHER HAND, ON A
CLINICAL TRIAL AND WE GO FROM
FIVE TO SEVEN, I CAN SAY THAT
THERE WAS SOME BENEFIT.
AND IN A TRIAL SITUATION, IT
COMMUNICATES WELL ACROSS
CULTURE AND OTHER THINGS BUT I
THINK WHAT WE'RE STUCK WITH IS
REALLY UNDERSTANDING HOW TO
BEST GET THE DATA OUT OF THAT
PARTICULAR SCALE OR ANY SCALE,
AND DIFFERENT PATIENTS ARE
GOING TO RESPOND IN VERY
DIFFERENT WAYS.
AND WHAT WE NEED TO COME UP
WITH, AND I COULDN'T AGREE
WITH YOU MORE, A MECHANISM
THAT IS SPECIFIC WITH THE
QUESTION IS ASKS AND WHAT IS
BEST TO LOOK AT THAT.
USUALLY CLINICAL TRIAL MAKES
SENSE, SECONDARY OUTCOMES
MAKES SENSE, PERHAPS TRAINING
PEOPLE IN THE USE OF THIS
SCALE, ESPECIALLY IN THE
OBVIOUS MODE WITH A PARENT
LOOKING AT A CHILD OR AN OWNER
LOOKING AT A DOG AND
UNDERSTANDING THE CULTURE
MIGHT BE VERY IMPORTANT IN
DOING THAT.
BUT AT THE END OF THE DAY, A
MEASURE WORKS IF PEOPLE ARE
CONSISTENT ABOUT USING IT.
SO IF SOMEBODY STARTS AT 7 AND
GOES DOWN OR STARTS AT A 5 AND
GOES DOWN, THEN THAT IS A
NUMBER IN THE TRIAL BUT I
WOULD ARGUE THAT IT WILL BE
VERY DIFFERENT DEPENDING ON
THE QUESTION WE'RE ASKING AND
WILL BE DIFFERENT IN DIFFERENT
POPULATIONS.
SO I THINK THERE WILL BE
COMMON SENSE THAT GOES INTO
THIS.
ADDING DATA TO IT IS A REALLY
GREAT IDEA BUT AT THE END OF
THE DAY WHAT WE ARE STUCK WITH
IS HOW TO ANSWER THE QUESTIONS
IN TERMS OF BENEFITS SO I
WOULD STOP THERE.
THE QUESTION I WOULD HAVE WITH
REGARD TO ALL OF THIS IS, YOU
KNOW, WE HAVE BEEN STRUGGLING
A LITTLE BIT TO THINK ABOUT
HOW HUMANS AND ANIMAL RESULTS
ARE DIFFERENT AND I WOULD ASK
MY ANIMAL COLLEAGUES, WHAT IS
IMPORTANT FOR THE ANIMAL?
AND WHEN YOU SAY A SHEEP IS IN
PAIN OR A COW IS IN PAIN, I AM
ALL IN FAVOR OF PREVENTING
THAT.
BUT HOW DO YOU DECIDE SORT OF
WHAT IS ENOUGH FOR WHAT
BENEFIT IS THERE?
WE CAN COME UP WITH NUMBERS,
LIKE WE CAN LOOK AT THE FORCE
THEY PUT ON THEIR PAW AND SO
ON BUT AT SOME POINT -- IN THE
HUMAN I SAY HOW ARE YOU DOING
BUT FOR THE ANIMAL I AM HAVING
TROUBLE UNDERSTANDING AT WHAT
POINT DO YOU CONSIDER THE PAIN
IS GOOD ENOUGH AND I THINK IT
COMES DOWN TO THAT.
>> I JUST HEARD FROM JOHN ON
THE BBC THAT WE HAVE JUST A
MINUTE LEFT SO ANY COMMENTS ON
THAT, HOW DO WE DEFINE WHAT IS
ACTUALLY IMPORTANT TO AN
ANIMAL TO MOVE FORWARD TO
FINDING AN IMPORTANT CHANGE IN
AN OUTCOME MEASURE.
>> SO I WOULD LIKE TO SAY
SOMETHING, MY OPINION AND A
BOLD PICKUP POINT IS THE
PAINFUL STATE AND A NONPAINFUL
STATE, SO WHAT I WOULD
CONSIDER IN TREATMENT.
>> THANKS FOR THAT STUDY AND
IF YOU HAD BEHAVIORALLISTS
HERE, I THINK THEY WOULD
PROBABLY COMMENT ON THE STUDY
WITH ANIMALS WHERE THEY HAVE
TO PAY A COST FOR BENEFIT AND
YOU CAN LOOK HOW HARD THEY
WORK TO GAIN THAT BENEFIT AS A
MEASURE OF HOW IMPORTANT THAT
BENEFIT IS, IF THAT MAKES
SENSE.
>> CONDITION BY PREFERENCE?
>> YES, THOSE SORTS OF ASSAYS
THAT CAN LOOK AT HOW MOTIVATED
AN ANIMAL IS TO REMOVE ITSELF
FROM AN ADVERSE EFFECT OR
POTENTIAL TREATMENT.
I THINK THERE MAY BE WAYS OF
GETTING TO THAT, LABORIOUS
WAYS.
[LAUGHTER]
>> OKAY, WITH THAT, DO I HAVE
TIME FOR ONE MORE?
OKAY, ONE LAST QUESTION.
>> THANK YOU ALL, I AM
CURIOUS WHAT YOUR THOUGHTS
WOULD BE THAT WE TAKE TO THE
PET OWNER, WHAT ASK IT LOOK
LIKE TO -- DOES IT LOOK LIKE
TO ACTUALLY PUT IT IN THEIR
HANDS FOR THE PRACTICE WE'RE
TALKING ABOUT IN THE CLINICAL
STUDY, MAKING IT USEFUL.
AS FAR AS THE GAIT ANALYSIS IS
GREAT IN RESEARCH BUT NOT
PRACTICAL FOR VETERINARIANS TO
HAVE THAT IN A PRACTICE.
SO WHAT DOES IT LOOK LIKE TO
MAKE IT MORE AVAILABLE AND PUT
IT OUT THERE.
>> THAT IS A LEAD-IN FOR YOU,
I GUESS.
>> WELL, I DID MY TALK LEADING
TO WAYS TO TRY AND DO THAT AND
IN MANY WAYS WE'RE SCARFING
THE SURFACE OF THAT AT THE
MOMENT.
A LOT OF WORK PUT INTO PATIENT
OUTCOMES IN MEDICINE AND
LOOKING AT HOW EFFECTIVE THAT
CAN BE BUT THERE ARE BARRIERS.
YOU CAN PROVIDE GREAT TOOLS TO
PATIENTS BUT THERE ARE THINGS
THAT GET IN THE WAY SUCH AS
LIFE AND HAVING A JOB.
SO ONE OF THE BIGGEST FACTORS
THAT INFLUENCES WHERE PATIENTS
REPORT THEIR OUTCOMES.
IN THE UK, WHETHER YOU HAVE
THE FORM OR NOT.
SO WE HAVE A LOT TO THINK
ABOUT HOW TO ROLL THESE TOOLS
OUT TO THE OWNER BUT IF WE
EVEN REACH A SMALL PERCENTAGE
OF THEM, THAT WOULD BE GREAT
PROGRESS BECAUSE FOR THE
MOMENT THEY ARE LOCKED OUT.
>> GREAT, THANKS FOR THOSE
COMMENTS.
I THINK WITH THAT WE WILL DRAW
THE MORNING TO A CLOSE.
WE WILL COME BACK HERE AT 12:
30:00 P.M. FOR THE NEXT
SESSION, LUNCH IS JUST OUT THE
DOOR BUT PLEASE, HELP ME JOIN
ALL OF OUR SPEAKERS FROM THIS
MORNING.
THANKS.
>> GOOD AFTERNOON.
WE'LL GET STARTED FOR OUR
AFTERNOON SESSION.
I'M CHERYL JOHNSON FROM THE
CENTER OF VETERINARY MEDICINE.
FIRST I'D LIKE TO INTRODUCE
DR. JOHN FARRAR.
HE IS A PROFESSOR OF
EPIDEMIOLOGY, NEUROLOGY GEE AND
ANESTHESIA AT THE UNIVERSITY OF
PENNSYLVANIA AND THE PRESIDENT
OF THE US ASSOCIATION FOR THE
STUDY OF PAIN.
HE'S BEEN INVOLVED IN CLINICAL
RESEARCH FOR 30 YEARS AND FOCUS
IS ON THE MEASUREMENT AND
MEANING OF PAIN AND RELATED
SYMPTOMS, STUDY DESIGN, CONDUCT,
ANALYSIS AND INTERPRETATION OF
STUDIES OF THE EFFICACY OF PAIN.
DR. JOHN FARRAR.
>> SO, GOOD AFTERNOON AND IT'S
ALWAYS DANGEROUS TO SPEAK RIGHT
AFTER LUNCH.
POST-PRANNIAL SYMPTOMS BEING
WHAT THEY ARE BUT I WILL TRY AND
KEEP YOU INTERESTED IN WHAT I'M
GOING TO BE TALKING ABOUT.
MY ROLE HERE TODAY IS TO
INTRODUCE THE TOPIC THIS MORNING
AND TO TALK A LITTLE BIT ABOUT
HOW WE THINK ABOUT OUTCOMES AND
WHAT WE DO WITH THEM.
SO, THE FIRST THING -- THE FIRST
THING THAT I WANT TO REMIND
EVERYBODY IS THAT OBVIOUSLY,
CLINICAL TRIALS IS WHAT WE ARE
TRYING TO DEAL WITH HERE AND A
CLEAR STATEMENT OF WHAT THE
QUESTION IS WE'RE TRYING TO
ANSWER IS OBVIOUSLY THE BIGGEST
ISSUE IN TRYING TO DECIDE HOW WE
DO THE STUDY, WHAT WE STUDY,
WHAT POPULATION WE STUDY.
BUT THERE ARE OTHER FACTORS THAT
GO INTO THAT AND I JUST DON'T
WANT US TO FORGET THE FACT THAT
THE IT'S NOT ALL ABOUT OUTCOMES.
IT'S ABOUT HOW THE STUDY IS
CONDUCTED AND WHAT GOES ON WITH
THAT.
AND THAT PARALLEL RANDOMIZED
DESIGNS IS THE GOLD STANDARD BUT
THERE ARE NEW ADAPTIVE WAYS OF
DEALING WITH CLINICAL TRIALS AND
YOU'RE GOING TO HEAR MORE ABOUT
THAT TODAY AS WELL.
I'LL SPEAK ABOUT IT BRIEFLY.
TYPES OF TRIAL ENDPOINTS,
SINGLE, MULTIPLE ENDPOINTS,
COMPOSITE ENDPOINTS, AND I'M
GOING TO TALK BRIEFLY ABOUT THE
ROLE OF SURROGATE ENDPOINTS AND
THE ROLE OF BIOMARKERS, WHICH
ARE OBVIOUSLY A KEY AND
IMPORTANT THING TO THINK ABOUT
THE DEVELOPMENT OF NEW PRODUCTS.
HOW DO WE HANDLE MULTIPLE
ENDPOINTS?
LET'S START WITH THAT.
IF YOU HAVE GOT FIVE DIFFERENT
THINGS YOU WANT TO MEASURE, YOU
CAN MEASURE EACH OF THEM
SEPARATELY AND THEN YOU CAN
ANALYZE EACH OF THEM SEPARATELY.
IF YOU DO THAT KIND OF THING,
THEN YOU NEED TO CORRECT FOR THE
MULTIPLE COMPARISONS ISSUE,
WHICH IS THAT IF YOU STUDY
ENOUGH THINGS, ONE OF THEM WILL
TURN OUT TO BE STATISTICALLY
SIGNIFICANT.
THE ADAGE I LIKE IS IF YOU
TORTURE THE DATA ENOUGH, IT WILL
CONFESS.
AND YOU GOT TO BE CAREFUL
BECAUSE THIS IS SOMETHING THAT
HAPPENS ON A REGULAR BASIS, LESS
IN THE CURRENT ENVIRONMENT THAN
IT DID BEFORE.
AND THERE ARE A BUNCH OF
DIFFERENT WAYS TO HANDLE
MULTIPLE ENDPOINTS.
YOU'LL HEAR PERHAPS MORE ABOUT
THIS IN THE STATISTICS ISSUES,
BUT THE SEQUENTIAL REJECTION
PROCEDURE WHERE YOU LOOK FIRST
AT ONE AND THEN AT THE SECOND
AND THEN AT THE THIRD AS YOU GO
DOWN IN TERMS OF IMPORTANCE.
THERE ARE COMBINED ENDPOINTS AND
I WOULD REMIND YOU THAT A
QUESTIONNAIRE, A
PATIENT-REPORTED OUTCOME IS A
COMBINED ENDPOINT.
YOU'RE TAKING SIX QUESTIONS AND
YOU'RE DOING SOMETHING TO THEM.
YOU'RE ADDING THEM UP OR
MULTIPLYING THE RESULTS OR
DIVIDING THEM BY WHO KNOWS WHAT.
IF YOU WANT A REAL EXAMPLE OF
HOW COMPLICATED IT CAN GET, GO
LOOK AT THE SF36 AND HOW THOSE
QUESTIONS ARE ANALYZED.
.46 TIMES THAT AND .82 TIMES
THAT AND IF IT'S TUESDAY,.73
TIMES THAT ONE.
IT'S COMPLICATED I VE TO HAVE A
WAY TO DO IT.
THE QUESTION THAT COMES UP IS
WHO GETS TO DECIDE HOW THEY ARE
PUT TOGETHER AND WHAT'S
IMPORTANT?
THEN THERE ARE OTHER WAYS OF
THINKING ABOUT THINGS.
WE HEARD THIS MORNING ABOUT THE
GLOBAL MEASURES AS WELL AND I'M
A BIG FAN OF THE IDEA THAT YOU
CAN USE A GLOBAL BUT WHAT YOU
REALLY WANT TO DO AT LEAST IN
HUMANS, IS TO MAKE SURE THAT
THEY ARE THINKING ABOUT THE
THINGS THAT YOU WANT THEM TO
CONSIDER WHEN THEY ANSWER THAT
GLOBAL QUESTION.
AND THE GLOBAL QUESTION CAN BE
ABOUT GENERAL THINGS.
IT CAN ALSO BE ABOUT PAIN AND
FATIGUE AND SPECIFICS.
SO WE CAN DO THESE.
THE PRINCIPLES OF COMBINED ENDS
POINTS, OBVIOUSLY WHEN YOU
COMBINE ENDPOINTS, THEY
OBVIOUSLY HAVE TO HAVE A
CLINICAL RELEVANCE TO EACH
OTHER.
THEY NEED TO BE RELATED.
THEY NEED TO BE PROSPECTIVELY
IDENTIFIED.
YOU CAN'T IDENTIFY THEM LATER.
I MEAN, YOU CAN BUT THEN IT'S A
HYPOTHESIS GENERATING A
HYPOTHESIS PROVING STUDY.
SO THE PRECISION OF MEASUREMENT
AND VALUES F ONE OF THEM IS
HIGHLY VARIABLE AND THE OTHER
ONE IS VERY SPECIFIC, PROBABLY
DON'T WANT TO COMBINE THEM
BECAUSE YOU'RE GOING TO MITIGATE
THE ABILITY TO DETECT A
DIFFERENCE.
THERE SHOULD BE LITTLE
THERAPEUTIC INTERACTION BETWEEN
THEM, AND I'LL TALK A LITTLE BIT
MORE ABOUT SOME OF THAT.
BUT THE IDEA IS THAT IT
SHOULDN'T BE MEASURING FIVE
THINGS THAT ARE ALL THE SAME.
BECAUSE YOU'RE NOT NECESSARILY
GOING TO BENEFIT FROM THAT.
AND IT'S BEST IF THE MEASURES
ARE EQUALLY SENSITIVE OR
RESPONSIVE TO THE THERAPY.
I MEAN IF SOME ARE LESS
RESPONSIVE AND SOME ARE MORE,
THEN AGAIN YOU ADD VARIABILITY.
AND THEN THERE ARE CERTAIN
PROPERTIES THAT ARE LISTED HERE
I WON'T SPEND TIME TALKING
ABOUT, BUT THEY ARE THERE FOR
YOU TO LOOK AT.
ONE OF THE STRENGTHS THAT
GENERATES A SINGLE SCORE FOR THE
CONCEPT, SO YOU'RE INTERESTED IN
QUALITY OF LIFE, YOU COME UP
WITH FIVE OR SIX DIFFERENT
QUESTIONS AND COMBINE THEM INTO
A SCORE AND YOU GET A SINGLE
OUTCOME YOU CAN MEASURE.
YOU DON'T HAVE TO DEAL WITH THE
MULTIPLE OUTCOMES AND ISSUES
RELATED TO THE STATISTICS.
SO IT AVOIDS THE MULTIPLE
COMPARISONS.
THERE ARE MULTIPLE QUESTIONS
THAT MAYBE BETTER, THE
DEFINITION OF THE OUTCOME OF
INTEREST, RIGHT?
WE CAN'T NECESSARILY AGREE ON
WHAT QUALITY OF LIFE MEANS TO US
BUT WE HAVE A GENERAL CONCEPT OF
WHAT IT MEANS TO A POPULATION
AND BY COMBINING MEASURES, WE
CAN CREATE THAT LATENT CONSTRUCT
OF QUALITY OF LIFE.
ALLOW MULTIPLE WAYS TO ACHIEVE A
SCORE.
AND THIS IS A BIG ISSUE I'LL
TALK ABOUT IN A MINUTE WHEN WE
TALK ABOUT COMPOSITES.
IF YOU'RE TESTING SOMETHING THAT
COULD MANIFEST IN FOUR-FIVE
DIFFERENT WAY, YOU MAY GET A
BETTER ANSWER OR A MORE ROBUST
ANSWER IF YOU LOOK AT ALL OF
THOSE PARTICULAR OUTCOMES
TOGETHER.
BUT THE WEAKNESSES ARE OBVIOUSLY
THERE AS WELL.
DEPENDS ON THE STRENGTH AND
VALIDITY OF THE MEASURE.
IT DEPENDS ON THE RESEARCHER OR
WHO DESIGNED THE STUDY.
IF YOU ASK A QUALITY OF LIFE
MEASURE AND YOU ASK TWO ABOUT
PHYSICAL FUNCTION AND ONE ABOUT
EMOTIONAL, YOU'RE GETTING
PHYSICAL FUNCTION TWICE THE
WEIGHT COMPARED TO EMOTION.
UNLESS YOU DO SOME MANIPULATIONS
TO MAKE THAT WORK OUT.
YOU NEED A JUSTIFICATION TO SAY
WHAT MOST IMPORTANT FOR THE
PARTICIPANTS AND THE QUESTION
THAT WAS ASKED EARLIER TODAY IS,
WHAT ABOUT THE FACT THAT PEOPLE
HAVE DIFFERENT VIEWS OF THE
WORLD?
AND THINGS THAT ARE IMPORTANT TO
ONE PERSON MAY NOT BE IMPORTANT
TO ANOTHER.
HOW CAN WE INCORPORATE THAT?
IT'S NOT AN EASY QUESTION TO ASK
AND I'M HAVE TO TALK ABOUT IT
MORE IN THE DISCUSSION.
AND THEN THERE ARE CONCEPTS AND
LANGUAGE THAT NEED TO BE
APPROPRIATE.
AND OBVIOUSLY WHEN WE'RE USING
WORDS, WE HAVE TO THINK ABOUT
THOSE WORDS AS THEY APPLY TO
PEOPLE WHO EVEN SPEAK THE
LANGUAGE IN THE UNITED STATES,
FOR INSTANCE, PEOPLE COME FROM
MANY, MANY DIFFERENT CULTURES.
AND WE ALL SPEAK ENGLISH, AT
LEAST IN PART.
BUT OUR INTERPRETATION OF THOSE
WORDS MAY BE DIFFERENT.
SO IT'S NOT JUST THAT WE HAVE TO
TRANSLATE THEM IN A DIFFERENT
LANGUAGE, BUT WE HAVE TO THINK
ABOUT HOW THEY APPLY.
SO, SWITCHING, AND I UNDERLINED
COMPOSITE.
THERE IS NO STRICT DEFINITION OF
MULTIPLE OR COMBINED OR
COMPOSITE.
AND THESE WORDS GET USED A
LITTLE BIT INTERCHANGEABLY.
WHAT I'M TALKING ABOUT HERE
ABOUT A COMPOSITE IS, OUTCOMES
THAT ARE SIMILAR AND MEASURING
SIMILAR THINGS THAT YOU PUT
TOGETHER, NOT AN SF36 QUALITY OF
LIFE MEASURE, WHICH I TALKED
ABOUT BEFORE.
SO CHRONIC DISEASE MANIFESTS
THEMSELVES IN MANY WAYS.
WE HEARD ABOUT A VERY
DERMATOLOGIC DISEASE THAT CAN
OCCUR AS DIFFERENT KINDS OF
RASHES AND AFFECT THE BODY AS A
WHOLE AND CAUSE JOINTS TO HURT.
THERE ARE DIFFERENT WAYS TO
MANIFEST.
EXAMINING THE TREATMENT IN SUCH
CASES REQUIRES MEASURING
OUTCOMES RELATED TO ALL
APPROPRIATE DISEASE
MANIFESTATIONS.
IF YOU'RE INTERESTED IN HOW THE
DRUG THAT YOU'RE USING WORKS,
YOU OUGHT TO KNOW AND LOOK AT
ALL OF THOSE VARIOUS OUTCOMES AS
INDIVIDUAL OUTCOMES.
PROBABLY AS SECONDARY.
AND THEN SOME SORT OF COMBINED
OUTCOME TO GIVE YOU YOUR
PRIMARY.
AND THE EXAMINATION OF SINGLETON
OUTCOMES CAN BE MISLEADING OR
MISSING IMPORTANT CONCEPTS.
IF YOU'RE ONLY INTERESTED IN
RASH AND THE MANNEST STATION OF
LUPUS IN SOME OTHER FEATURE OF
THAT DISEASE, THEN YOU'RE GOING
TO MISS THE OUTCOME OF INTEREST.
COMPOSITE ENDPOINTS EXAMPLES.
CONSTRUCTED FROM TWO OR MORE
CLINICALLY RELEVANT SINGLETON OR
COMPONENT ENDPOINTS, MULTIPLE
MEASURES OF THE SAME PHENOMENON.
MEASURES OF SEQUENTIAL EVENTS
CAN BE USEFUL.
MEASURES OF DIFFERENTIAL
PHENOMENON THOUGHT TO BE OF THE
SAME MECHANISM.
SOME EXAMPLES ARE, IF YOU'RE
INTERESTED IN VASCULAR DECIDE
AND WHAT MIGHT LEAD TO VASCULAR
DISEASE, YOU'RE NOT JUST GOING
TO STUDY HEART.
YOU'RE GOING TO STUDY PROBABLY
HEART AND YOU WANT TO THE STUDY
BRAIN WITH REGARDS TO STROKE.
YOU WANT TO KNOW ABOUT HOW THE
KIDNEYS ARE FUNCTIONS.
ING.
BECAUSE VASCULAR DISEASE WILL
EFFECT ALL OF THOSE AND
DIFFERENT PATIENTS MAY MANIFEST
DIFFERENT OUTCOMES.
YOU WANT TO COMBINE THOSE.
YOU CAN COMBINE BY SAYING, ANY
ONE OF THESE, YES/NO.
OR YOU COULD SAY I'M INTERESTED
BECAUSE SOMETIMES PEOPLE HAVE
WORST VASCULAR DISEASE AND I'M
GOING TO ADD THEM UP.
I'M GOING TO GET 1, 2, 3,
CARDIAC STROKE, KIDNEY DISEASE.
OBVIOUSLY THE ISSUE OF
CARDIOVASCULAR DISEASE ITSELF,
ANGINA, MI, SUDDEN DEATH,
ALLERGIC RESPONSES AND
SNEEZING -- COUGHING OR ASTHMA
AND YOU MIGHT WANT TO LOOK AT
ALL OF THOSE.
THE STRENGTHS THAT CAN IMPROVE
RESOLVING ABILITY BECAUSE YOU'RE
MEASURING ALL THREE IN VASCULAR
DISEASE, YOU'RE GOING TO BE
BETTER AT DETECTING DIFFERENCES
IN CHANGE AND SO IT'S GOING TO
INCREASE THE EFFECT SIZE.
IT MAY IMPROVE THE EFFICIENCY,
MAY GIVE A MORE EFFICIENT TRIAL
WITH LESS PATIENTS, MORE
ACCURATELY ANSWER THE BIOLOGICAL
QUESTION BECAUSE IF THE QUESTION
IS ABOUT WHAT HAPPENS IN THE
VASCULATURE, THIS EN THAT IS
GOING TO EFFECT ALL THE ORGANS F
YOU'RE INTERESTED IN WHAT
HAPPENS TO MYOCARDIUM WHEN IT'S
MADE AKNOCKSIC, THAT'S A
DIFFERENT QUESTION AND YOU
WOULDN'T OBVIOUSLY WANT TO STUDY
STROKE AS PART OF THAT OR KIDNEY
DISEASE.
AND THEN IT MAY HELP PREVENT
ACCIDENTAL INCORRECT
INTERPRETATION OF SINGLETON
ENDPOINTS THAT OCCUR BY CHANCE.
OKAY, NOW THERE ARE PROBLEMS,
RIGHT?
COMPOSITE ENDPOINTS CAN BE
COMPLICATED TO CONSTRUCT.
YOU GOT TO BE ABLE TO
DEMONSTRATE THAT THEY ARE
ACTUALLY RELATED.
THEY CAN BE COMPLICATED TO
INTERPRET.
IF YOU LOOK AT VASCULAR DISEASE
FOR THE THREE ORGANS THEN HOW DO
YOU DEAL WITH THE FACT THAT THEY
ARE DIFFERENT?
OBVIOUSLY A SECONDARY WAY OF
LOOKING AT THAT WOULD BE TO LOOK
AT THEM SEPARATELY AND THAT
WOULD BE ONE WAY TO DO THAT.
ENDPOINTS THAT ARE TO BE
COMBINED MUST BE BALANCED IF
RELATED.
YOU GOT TO BE ABLE TO MEASURE
WHAT YOU'RE ACTUALLY LOOKING
FOR.
AND SO THEY MUST MAKE BIOLOGIC
SENSE.
THIS IS JUST HORSE SENSE, RIGHT?
YOU GOT TO HAVE SOME IDEA ABOUT
HOW THIS IS ALL RELATED.
SO LET'S CONSIDER TWO EXAMPLES
HERE.
ONE OF THEM, IN BOTH CASES WE'RE
INTERESTED IN FATAL AND
NON-FATAL MIs.
AND IF WE JUST LOOK AT TREATMENT
1 AND TREATMENT 2, IN THIS CASE,
TREATMENT 1, IF YOU ADD THEM
TOGETHER, THERE ARE MORE EVENTS
IN TREATMENT 1 THAN IN TREATMENT
2 SO OBVIOUSLY THAT WORKS
BETTER.
BUT ON THE OTHER HAND, THE
NON-FATAL MIs ARE MORE THAN
THE NON-FATAL MIs IN TREATMENT
ONE.
SO DEPENDS ON THE QUESTION
YOU'RE ASKING.
IF YOU WERE STUDYING JUST
NON-FATAL MIs, YOU PROBABLY
WOULD GET THE WRONG ANSWER HERE.
AND HERE IS AN EXAMPLE WHERE IF
YOU ADD THEM TOGETHER, THEY BOTH
HAVE EXACTLY THE SAME NUMBER OF
EVENTS BUT TREATMENT 2 HAS MORE
NON-FATAL THAN FATAL MIs SO IS
TREATMENT 2 BETTER THAN
TREATMENT 1?
ONE COULD ARGUE NON-FATAL IS
PROBABLY BETTER THAN FATAL.
BUT IT'S DIFFERENT THAN THE
OTHERS, RIGHT?
OKAY, SO, LET'S SWITCH NOW TO
THINKING ABOUT PRIMARY END
POINTS IN CLINICAL TRIALS AND
I'M A BIT OF A RADICAL ABOUT
THIS.
FROM MY PERSPECTIVE IN HUMAN
BEINGS, THERE ARE ONLY THREE
PRIMARY OUTCOMES.
ONLY.
ONE, YOU GOT TO BE BORN, GOT TO
JOIN THE PARTY TO PLAY.
SECOND, DEATH, WE ARE TRYING TO
PREVENT THAT MOSTLY.
AND EVERYTHING ELSE IS ALL OF
YOUR LIFE.
EVERYBODY AGREES, RIGHT?
YES.
WE'LL HEAR ABOUT THIS LATER.
BUT I WOULD ARGUE THAT THE ONLY
REASON WE TREAT EVERYTHING ELSE
IS TO MAKE PEOPLE'S LIVES
BETTER.
NOW THAT INCLUDES KEEPING THEIR
GLUCOSE UNDER CONTROL SO THEY
DON'T DEVELOP ALL THE SIDE
EFFECTS OF DIABETES.
IT MEANS MAKING SURE THAT THEIR
HEART INJECTION FRACTIONS ARE
IMPROVED SO THEY CAN DO THE
THINGS THEY WANT TO DO.
BUT HONESTLY THINKING, I THINK
THAT'S A REASONABLE WAY OF
APPROACHING IT.
AND IN ANIMALS, I WAS A LITTLE
BIT STUCK.
YOU GOT TO BE BORN TO BE PART OF
THE PARTY.
THERE IS DEATH WHICH WE ARE
TRYING TO PREVENT OR MAKE IT
HAPPEN LATER.
AND I WAS WASN'T SURE WHAT
QUALITY OF LIFE IN ANIMALS
CONSISTED OF SO I CALLED IT
REDUCED SUFFERING.
I'M WELCOME INPUT FROM ALL OF
YOU.
THE OTHER THING I ADDED HERE IS
PRODUCT.
SO MEAT OR EGGS OR MILK.
BECAUSE CLEARLY IN ANIMALS THOSE
ARE IMPORTANT ISSUES THAT NEED
TO BE CONSIDERED AS PRIMARY
OUTCOMES.
AND THE FDA DEFINES CLINICALLY
MEANINGFUL AS HOW THE ANIMALS
FEEL, FUNCTION OR SURVIVE.
AGAIN, I DON'T KNOW IF THAT IS
TRUE BUT I WOULD PUT THAT IN.
AND I WOULD ARGUE THAT ALL THE
REST OF THEM ARE SURROGATE
ANIMALS.
EVERYTHING ELSE.
SO WHEN YOU DEAL WITH A
SURROGATE, THERE ARE SOME ISSUES
YOU HAVE TO THINK ABOUT.
NOW SURROGATE OUTCOMES ARE AN
INDICATOR OR SIGN USED IN PLACE
OF ANOTHER TO TELL IF THE
TREATMENT IS WORKING.
SURROGATE ENDPOINTS MIGHT
INCLUDE SHRINKING OF THE TUMOR
OR LOWER BIOMARKER LEVELS, RIG
RIGHT?
AND IT GOES ON TO SAY THAT THE
BENEFITS USED INSTEAD OF STRONG
INDICATORS SUCH AS LONGER
SURVIVAL OR IMPROVED QUALITY OF
LIFE, BECAUSE THE RESULTS OF THE
TRIAL MAY BE MEASURED SOONER.
AND THIS IS ABSOLUTELY TRUE.
THAT'S WHY WE USE MARKERS AND
BIOMARKERS AND SURROGATES TO TRY
TO GET A ANSWER SOONER.
THE RISK IS THAT THE SURROGATE
ENDPOINTS ARE NOT ALWAYS
INDICATORS OF THE OUTCOME.
THEY MUST BE IN THE CAUSAL
PATHWAY TO BE A SURROGATE, IN
THE PATHWAY, NOT JUST RELATED TO
THE PATHWAY.
AND THERE MUST BE AN UNDERLYING
SCIENTIFIC BASIS FOR THEM.
SO EVIDENCE TO INFER CAUSATION,
THERE IS A BUNCH OF
CONVERSATIONS ABOUT THIS OUTSIDE
OF THIS AREA.
EXPOSURE MUST PRECEDE THE
OUTCOME.
EXPOSURE MUST PRECEDE THE
OUTCOME.
YOU WOULD BE SURPRISED HOW MANY
ARTICLES THERE ARE WHERE THE
EXPOSURE CAME LATER.
A PERSON MOVED INTO AN AREA
WHERE THERE IS HIGH RADIATION
AND THEN TWO YEARS LATER
DEVELOPED A TUMOR.
FINE, BUT YOU FORGOT THAT THEY
WERE LIVING NEXT TO A
RADIOACTIVE DUMP BEFORE THEY
EVER GOT THERE.
SO DID THE HIGH-TENTION WIRES
CAUSE THE TUMOR?
I DOUBT IT.
STRENGTH OF ASSOCIATION
OBVIOUSLY NEEDS TO BE THERE.
PLAUSIBLE EXPLANATION FOR
CAUSATION HAS TO MAKE SENSE AND
THERE SHOULD BE, HOPEFULLY, SOME
SORT OF DOSE RESPONSE.
NOT ALL ASSOCIATIONS ARE CAUSAL.
IF YOU LEARN ONE THING IN
EPIDEMIOLOGY, EVER IN YOUR LIFE,
IT'S THAT ASSOCIATION DOES NOT
PROVE CAUSATION.
AND GOOD SURROGATES ARE
GENERALLY NOT MARKERS OF DISEASE
SEVERITY.
THAT'S A TOUGHER ONE AND WE CAN
TALK MORE ABOUT THAT.
SO HERE IS A DIAGRAM, THE
INTERVENTION SHOULD WORK ON THE
SURROGATE.
YOU'LL NOTICE THE ARROWS POINT
IN ONE DIRECTION TOWARDS THE
OUTCOME.
SO THE SURROGATE IS IN THE
CAUSAL PATHWAY.
EXAMPLES, PHYSIOLOGIC, PLOP,
OXYGENATION, HEMOGLOBIN A1C,
PATHOLOGY, TUMOR SIZE, HEALTH
SERVICES, SELVAGE, CHEMOTHERAPY,
A BUNCH OF WAYS TO THINK ABOUT
WHAT COULD BE SURROGATES.
WHY USE SURROGATE ENDPOINTS?
THEORETICALLY THEY SHORTEN THE
TIME HORIZON AND CAN INCREASE
THE POWER OF YOUR STUDY AND SAVE
MONEY.
SO AS AN EXAMPLE, YOU GOT A RISK
OF DEATH OF 10% AND THE RISK OF
THE PRIMARY OUTCOME THAT YOU
CHOOSE REDUCES THE DEATH BY 20%.
THEN LOOKING FOR A CHANGE IN 20%
OF YOUR POPULATION VERSUS 10% IS
GOING TO SAVE YOU IN TERMS OF
EFFICACY.
SO, IF THE ADVANTAGES OF THE
OUTCOME THAT YOU PICK IS A
CONTINUOUS VARIABLE AS OPPOSED
TO DICHOTOMOUS, DEATH IS
DICHOTOMOUS.
IN THIS CASE, IN THIS EXAMPLE,
THE MEAN IS 60 AND STANDARD
DEVIATION IS 20.
AND THE OBSERVATIONAL EVIDENCE
IS THAT A 10.INCREASE IN THE
MARKERS ASSOCIATED WITH 20%
INCREASE IN THE RISK OF DEATH,
OR ODDS RATIO 1.2.
WHEN WE LOOK AT THE RESULTS,
WHAT YOU CAN SEE IS THAT IF YOU
STUDY MORTALITY, AND THE
DIFFERENCES ARE FROM 10% TO 8%,
OR 10-4, THE NUMBERS YOU GET ARE
ABSOLUTELY HUGE.
IF YOU LOOK AT THE SURROGATE
MARKER, AND SAY WE'RE GOING TO
AFFECT THE SURROGATE DOWN BY
10%.
WHICH IS IT GOING TO EFFECT THAT
BY 20%.
THE NUMBERS NEEDED ARE 123 DOWN
TO 32 AND UP, DEPENDING ON WHICH
GROUP YOU PICK.
SO, THERE ARE WAYS TO LOOK AT
THIS THAT ARE OBVIOUSLY GOING TO
INCREASE YOUR ABILITY TO LOOK.
THE PROBLEM IS, YOU NEED TO BE
CLEAR THAT YOUR SURROGATE IS
RELATED TO THE OUTCOME.
AND THAT IS UP TO YOU TO DEFEND.
SO, THIS IS WHAT I WAS JUST
SAYING.
IN TERMS OF NUMBER 2, IF WE LOOK
HERE AT DEATH AND THE
COMPLEMENTARY -- OTHER MEASURE
YOU'RE GOING TO USE, OBVIOUSLY
THE NUMBER OF PEOPLE WHO DIE,
PART OF THEM ARE GOING TO HAVE
THIS VALLEY AND PART WILL NOT.
SO YOU WANT TO THINK ABOUT HOW
YOU'RE GOING IT DEAL WITH IT.
WHEN YOU DO THE MATH, YOU FIND
THAT THERE IS AN ODDS RATIO OF
ABOUT ONE.5.
IF YOU HAVE THE MARKER, VERSUS
IF YOU DON'T IN TERMS OF WHETHER
YOU'RE GOING TO DIE.
WHEN YOU CALCULATE THE SAMPLE
SIZES BASED ON JUST MORTALITY
AND THIS IS A STUDY WHERE YOU
HAVE TO STUDY PEOPLE A LONG TIME
TO SEE ANY DIFFERENCE AT ALL,
YOU NEED 56,000 PEOPLE TO STUDY
MORTALITY, WHEREAS IF YOU USE
THE SURROGATE, AND DROP THE
SURROGATE FROM .3 TO 1.5, THEN
YOU ONLY NEED 268 PATIENTS.
THE ASSUMPTION HERE IS THAT THIS
SURROGATE PREDICTS THE MORTALITY
IN SOME WAY.
IF YOU CAN'T PROVE THAT, THEN
THE SURROGATE IS NOT GOING TO BE
USEFUL TO YOU.
WHAT ARE THE RISKS OF SURROGATE?
THEY ARE NOT REALLY IN THE
CAUSAL PATHWAY AND IT'S
SOMETIMES REALLY HARD TO KNOW.
OTHER CAUSAL MECHANISMS EXIST.
EXPOSURE IS RELATED TO THE
OUTCOME IN OTHER WAYS AND YOU
HAVE TO HAVE A LEVEL OF
CONFIDENCE.
TO RUN THROUGH A YOU TOO, THIS
IS WHAT WE WERE TALKING ABOUT.
YOU NOTICE THE ARROWS GOING IN
ONE DIRECTION.
NOT THIS.
SURROGATES A CONFOUNDER HERE IF
YOU WANT TO BE SPECIFIC.
IT HAS AN INDEPENDENT
RELATIONSHIP WITH THE DISEASE
AND THE OUTCOME AND THE
MECHANISM FROM THE DISEASE TO
THE OUTCOME IS DIFFERENT.
THIS ONE IS WHERE IN FACT THE
SURROGATE IS THE IN THE PATHWAY
BUT IT'S ONLY A SMALL PART OF
THE OUTCOME.
THE LIKELIHOOD THAT THE
SURROGATE IS GOING TO HELP YOU
IS MINIMAL BECAUSE YOU'RE MOSTLY
NOT MEASURING THAT PARTICULAR
PATHWAY.
THE INTERVENTION COULD WORK
DIRECTLY ON THE OUTCOME AND SKIP
THE SURROGATE.
SO MEASURING THE SURROGATE IS
NOT GOING TO HELP YOU.
AND YOU CAN COME UP WITH A LOT
OF DIFFERENT EXAMPLES.
NOW LET'S TALK ABOUT UNINTENDED
CONSEQUENCES OF SURROGATES IS
ABOUT.
SO THERE IS ISSUES OF SUDDEN
DEATH, AND WE KNOW THAT IN
CARDIAC DISEASE THAT TREATING
IRREGULAR HEARTBEATS INCREASED
MORTALITY IN MOST CASES.
AND THAT'S JUST REPRESENTED
HERE.
SO WE HAVE TO BE VERY CAREFUL
ABOUT WHAT WE DO.
THIS IS ANOTHER EXAMPLE WHICH
I'M GOING TO GO QUICKLY THROUGH
SINCE I'M OVER TIME.
BUT THIS IS A GROWTH HORMONE
TREATMENT AND JUST TO MAKE THE
POINT HERE THAT IT TERPS OUT
THAT PEOPLE THOUGHT THIS IS HOW
GROWTH HORMONE WOULD EFFECT
STRENGTH AND IMMUNE FUNCTION TO
MAKE EVERYBODY BETTER.
THEY FORGOT THAT IT CAUSED FLUID
RETENTION, HYPOGLYCEMIA AND
INFECTIONS AND MADE PEOPLE
WORSE.
SO THE WHOLE POINT WAS THAT THE
SURROGATE THAT THEY CHOSE TO
LOOK AT WAS NOT REFLECTIVE OF
THE TOTALITY OF THE DISEASE THAT
WAS THERE.
SO, ARE SURROGATES ACCEPTABLE?
NOT REALLY.
IN PHASE III THEY CAN BE
ACCEPTABLE IN PHASE II AND THEY
CAN BE VERY USEFUL IN THE
INITIAL STUDIES OF OUTCOMES BUT
YOU HAVE TO DO SOME WORK TO
FIGURE OUT HOW THEY WORK.
I'M GOING TO END WITH THIS,
WHICH SOMEBODY ELSE IS GOING TO
TALK ABOUT, WHICH IS THAT THE
FDA HAS A GUIDANCE FOR INDUSTRY
NUMBER 268, THAT TALKS ABOUT THE
USE OF MEASURES AND ADAPTIVE
TRIALS.
AND WILL THERE ARE WAYS IN WHICH
WE CAN INCORPORATE SURROGATES
AND OTHER THINGS INTO ADAPTIVE
TRIALS THAT ARE USEFUL.
MEASURE SURROGATES BECAUSE YOU
CAN MEASURE THEM QUICKLY BUT
KEEP FOLLOWING PATIENTS AND LOOK
TO SEE IF THE RESPONSE HAPPENS
IN YOUR SURROGATE AS YOU'RE
MEASURING THE REST OF THE
PATIENTS EVENTS.
IF THE SURROGATE DOESN'T SHOW
YOU ANYTHING, YOU CAN STOP THE
TRIAL.
IF THE SURROGATE SUGGESTS THAT
THERE MIGHT BE AN OUTCOME OF
INTEREST, YOU MIGHT GO ON TO
MEASURE THE PRIMARY OUTCOME AND
CONTINUE THE TRIAL FOR ANOTHER
YEAR OR TWO IF THAT IS WHAT IT
WOULD TAKE.
AND I THINK THE MAIN FEATURE
HERE IS THAT ANY BIOMARKER THAT
IS USED MUST HAVE CLINICAL
SENSITIVITIES, SPECIFICITY,
POSITIVE AND NEGATIVE PREDICTIVE
VALUES TO BE USED TO DETERMINE
THE PATIENT POPULATION THAT YOU
WANT TO WORK WITH.
AND IT IS VERY IMPORTANT YOU
LOOK AT WHAT BIOMARKERS MEAN.
AND JUST A REAL QUICK COMMENT
ABOUT BIOMARKERS.
IT TURNED OUT THAT THEY LOOKED
AT STUDIES 1885,000 OF THEM, AND
BIOMARKERS MADE ALMOST NO
DIFFERENCE IN THOSE STUDIES.
WHY IS THAT?
GOT TO REMEMBER THAT HUMANS ARE
COMPLEX ANIMALS.
THERE ARE OVER 20,000
PROTEIN-CODED GENES AND THERE
ARE ALMOST 300,000 NON-REDUNDANT
PEPTIDES.
SO YOU PICK ONE AND YOU SAY,
THIS IS THE BEST THING SINCE
SLICED BREAD.
IT MIGHT BE.
BUT YOU GOT A LOT OF PROVING TO
BE ABLE TO USE AND FIGURE OUT
HOW THAT WORKS.
SO I'LL END WITH THIS,
COMPOSITES AND COMBINED
ENDPOINTS NEED TO BE CAREFULLY
DEFINED.
SURROGATE ENDPOINTS CAN
POTENTIALLY INCREASE THE
EFFICIENCY OF CLINICAL TRIALS.
THERE ARE SEVERAL KNOWN THREATS
THAT MUST BE ADDRESSED BEFORE
YOU IMPLEMENT THIS.
PHASE III TRIALS SHOULD BE
POWERED FOR THE PATIENT-CENTERED
OR ANIMAL-CENTERED ENDPOINT.
AND DECISION ANALYSIS CAN LINK
TRIAL EVIDENCE TO OBSERVED IN
DATA.
YOU CAN USE OBSERVATIONAL DATA
TO DECIDE ON WHAT THE OUTCOMES
ARE YOU SHOULD USE AND IMPROVE
THE WAY TO INTERPRET OUR
SURROGATE ENDPOINTS.
AND I'LL STOP THERE.
[ APPLAUSE ]
>> THANK YOU VERY MUCH DR. JOHN
FARRAR.
NEXT I'D LIKE TO INTRODUCE MY
COLLEAGUE, DR. CLAIRE RUBERMAN.
A MATHEMATICAL STATISTICIAN IN
THE OFFICE OF NEW ANIMAL DRUG
EVALUATION FOR VETERINARY
MEDICINE IN FDA.
RECEIVED HER PH.D. FROM THE
JOHNS HOPKINS BLOOMBERG SCHOOL
OF PUBLIC HEALTH AND BA IN
MATHEMATICS.
DR. RUBERMAN.
[ APPLAUSE ]
>> GOOD AFTERNOON, EVERYONE.
SO, TO START I'LL GIVE YOU A
LITTLE BIT OF A ROADMAP ABOUT MY
PRESENTATION TODAY.
THERE IS DEFINITELY A LOT OF
OVERLAP SO THANK YOU DR. JOHN
FARRAR FOR A LOT OF REALLY
IMPORTANT INTRODUCTIONS.
SO I'LL GIVE MORE BACKGROUND AND
THEN TALK ABOUT DIFFERENT TYPES
OF ENDPOINTS FROM A STATISTICAL
PERSPECTIVE.
BEFORE I GET INTO ENDPOINTS I
WANT TO NOTE THAT OUR
STATISTICAL CONSIDERATIONS
REALLY DEPEND ON THE TYPE OF
STUDY AND THE OBJECTIVE OF THE
STUDY.
SO I'LL DISTINGUISH BETWEEN
EXPLORATORY STUDIES WHERE OUR
GOAL IS TO GENERATE NEW
HYPOTHESES, TYPICALLY SMALLER,
MORE FLEXIBLE STUDIES WHERE WE
MAY EMPLOY STATISTICS AND FORMAL
MODELS, BUT WE DON'T NECESSARILY
PRE-DEFINE OUR PRIMARY ENDPOINTS
OR OUR METHODS.
IN CONTRAST, IN CONFIRMATORY
STUDIES, OUR GOAL IS TO TEST THE
VALIDITY OF AN ALREADY
ESTABLISHED HYPOTHESIS.
TYPICALLY THESE STUDIES ARE
DESIGNED WITH KNOWLEDGE ABOUT
PREVIOUS STUDIES OR OTHER
INFORMATION.
IN THESE CASES, IN A CONFIRM
TORE YOU STUDY, WE SUSPECT OUR
STATISTICAL METHODS AND MODELS
AS WELL AS A BASIS FOR THE STUDY
CONCLUSIONS ARE PRE-SPECIFIED.
SO, IN A CONFIRMATORY STUDY, WE
DEFINE OUR PRIMARY ENDPOINTS.
SO THE PRIMARY ENDPOINT OR IN
SOME CASES, THE FAMILY OF
PRIMARY ENDPOINTS ARE THE
ENDPOINTS UPON WHICH WE MAKE OUR
STUDY CONCLUSIONS.
SO THOSE CAN BE SINGLE, WHICH IS
PRETTY SELF EXPLANATORY.
AND WE HAVE A COUPLE OF
DIFFERENT OPTIONS AS WE HAVE
SEEN ABOUT MULTIPLE PRIMARY
ENDPOINTS.
ONE OPTION IS WE HAVE CO-PRIMARY
ENDPOINTS WHERE WE SAY THAT THE
SUCCESS OF THE STUDY DEPENDS ON
A POSITIVE OUTCOME IN ALL OF THE
END POINTS.
SO IN A PAIN STUDY, WE THINK
THAT IT'S CLINICALLY RELEVANT
THAT WE SHOW SUCCESS ACROSS ALL
THESE DIFFERENT FACETS OF PAIN.
IN CONTRAST, IN MULTIPLE PRIMARY
ENDPOINTS FOR THE PURPOSE OF
THIS TALK, I'M TALKING ABOUT
MULTIPLE ENDPOINTS WHERE IF WE
HAVE A TREATMENT EFFECT ON AT
LEAST ONE OF THESE ENDPOINTS,
THAT'S SUFFICIENT TO CONCLUDE
STUDY SUCCESS.
SO WE HAVE MANY DIFFERENT
AVENUES OR MULTIPLE AVENUES IN
WHICH TO SHOW SUCCESS.
AND THEN THE THIRD OPTION IS TO
DEFINE A COMPOSITE ENDPOINT
WHERE WE TAKE OUR MULTIPLE
ENDPOINTS AND WE COMBINE THEM
INTO SOME SINGLE VARIABLE AND
HAVE JUST ONE STATISTICAL
HYPOTHESIS.
SO BEFORE I GET INTO MORE
DETAILS, I WANT TO RECALL SOME
KEY STATISTICAL CONSIDERATIONS
IF WE ARE TALKING ABOUT JUST A
SINGLE HYPOTHESIS.
SO THE GENERAL FRAMEWORK THAT
WE'RE TALKING ABOUT WITH
HYPOTHESIS TESTING IS THAT WE
HAVE A NULL HYPOTHESIS ABOUT OUR
POPULATION.
OFTEN THIS IS SIMPLEST CASE NO
DIFFERENCE BETWEEN TWO GROUPS.
WE COLLECT DATA FROM A RANDOM
SAMPLE OF OBSERVATIONS THAT WE
HOPE IS REPRESENTATIVE OF OUR
POPULATION OF INTEREST.
WE CALCULATE SOME TEST
STATISTICS, THIS MAYBE SOMETHING
LIKE A MEAN OR DIFFERENCE IN
MEANSING AND COMPARE THE
OBSERVED RESULTS TO THE EXPECTED
RESULTS UNDER THE NULL
HYPOTHESIS.
SO WE LOOK AT THE DISTRIBUTION
OF THE TEST STATISTIC IF THE
NULL HYPOTHESIS WERE TRUE AND
THEN MAKE A DECISION EITHER TO
REJECT THE NULL AND ACCEPT THE
ALTERNATIVE, OR WE FAIL TO
REJECT THE NULL IF WE DON'T HAVE
SUFFICIENT EVIDENCE.
SO THERE ARE TWO WAYS IN WHICH
WE CAN MAKE A MISTAKE.
THIS TABLE WILL PROBABLY LOOK
FAMILIAR TO MANY FOLKS HERE.
BUT THIS IS A TWO BY TWO TABLE.
IN THE TOP LEFT, WE REJECT THE
NULL WHEN THE NULL HYPOTHESIS IS
ACTUALLY TRY.
SO THAT'S A TYPE I ERROR.
AND THE SIGNIFICANCE LEVEL,
ALPHA, IS THE THRESHOLD BELOW
WHICH THE TYPE I ERROR RATE
SHOULD BE CONTROLLED.
OFTEN WE SEE ALPHA STATUS .05.
AND THEN IN THE BOTTOM RIGHT, WE
HAVE THE ERROR WHERE WE FAIL TO
REJECT THE NULL HYPOTHESIS
BUT -- THE NULL, BUT THE NULL IS
ACTUALLY FALSE.
SOLE WE HAVE A FALSE NEGATIVE.
THE CONVERSE OF THAT IS THE
POWER.
SO THAT'S WHEN WE CORRECTLY
REJECT THE NULL.
SO POWER IS 1 MINUS THE TYPE II
ERROR.
SO WHAT HAPPENS WHEN WE MOVE TO
MULTIPLE TESTING?
SO INTUITIVELY IF WE HAVE
MULTIPLE HYPOTHESES THAT WE'RE
TESTING AND WE CAN CONCLUDE
STUDY SUCCESS, BASED OFF OF ANY
OF THESE HYPOTHESES, THEN WE
HAVE MORE CHANCES TO GET IT
WRONG.
SO THIS CONCEPT IS REFERRED TO
AS MULTIPLICITY.
THIS IS OUR HIGHER-THAN INTENDED
OVER ALL TYPE I ERROR RATE WHEN
CONDUCTING MULTIPLE TESTS
WITHOUT MAKING ANY STATISTICAL
ADJUSTMENTS.
AND THE FAMILY WISE ERROR RATE
IS THE PROBABILITY OF MAKING ONE
OR MORE TYPE I ERRORS.
SO THIS IS A SIMPLE EXAMPLE
SHOWING HOW THE FAMILY WISE
ERROR RATE CAN BE INFLATED AS WE
INCREASE THE NUMBER OF
ENDPOINTS.
HERE WE ARE STARTING WITH AN
ALPHA LEVEL OF .05 AND I'LL
ASSUME JUST IN THE SIMPLE
EXAMPLE WE HAVE UNCORRELATED
ENDPOINTS.
THE NUMBERS WILL CHANGE
DEPENDING ON THE CORRELATION.
WHEN YOU SEE THAT IF WE INCREASE
THE NUMBER OF ENDPOINTS, THE
FAMILY WISE ERROR RATE INCREASES
QUITE DRAMATICALLY.
SO WE HAVE A COUPLE OF OPTIONS
FOR HOW TO ADDRESS THIS.
ONE IS THAT WE DEFINE CO-PRIMARY
ENDPOINTS WHERE WE HAVE TO
ACHIEVE SIGNIFICANTS FOR EACH
INDIVIDUAL ENDPOINT.
OFTEN THE CHOICE AND DECISION TO
USE CO-PRIMARY ENDPOINTS CAN BE
DRIVEN BY CLINICAL FACTORS SO I
WON'T SPEND TOO MUCH TIME ON
THIS.
BUT I WANT TO NOTE THAT IF WE
HAVE CO-PRIMARY ENDPOINTS, WE NO
LONGER HAVE TO WORRY ABOUT
MULTIPLICITY BECAUSE WE ARE
REQUIRING STATISTICAL
SIGNIFICANCE FOR EACH ENDPOINT
INDIVIDUALLY.
HOWEVER, ON THE OTHER SIDE OF
THE EQUATION, THE POWER CAN BE
NEGATIVELY AFFECTED.
IT CAN BE HARDER TO CONCLUDE
THAT A STUDY SUCCESSFUL BECAUSE
WE HAVE TO OVERCOME MULTIPLE
HURDLES.
ANOTHER OPTION IS WE CAN GO BACK
TO THE FRAMEWORK OF MULTIPLE
PRIMARY ENDPOINTS WHERE YOU CAN
ACHIEVE STUDY SUCCESS WITH ANY
ONE INDIVIDUALLY.
BUT WE HAVE STATISTICAL
ADJUSTMENTS TO DEAL WITH THE
INFLATED TYPE I ERROR RATE.
AND I'LL SPEND SOME TIME TALKING
ABOUT SOME OPTIONS THAT WE HAVE.
AND THEN THE THIRD OPTION IS TO
CREATE A COMPOSITE ENDPOINT.
SO NOW WE HAVE TAKEN OUR
MULTIPLE ENDPOINTS AND BACK DOWN
TO ONE SINGLE ENDPOINT AND WE'RE
ONLY TESTING ONE HYPOTHESIS.
AND DR. JOHN FARRAR GAVE NICE
EXAMPLES OF THOSE AND I'LL TALK
A LITTLE BIT MORE ABOUT A COUPLE
OF ADDITIONAL STATISTICAL
CONSIDERATIONS.
SO THERE IS A NICE GUIDANCE FROM
INDUSTRY PUBLISHED BY OUR
COLLEAGUES AT CDER AND SEEBER.
AND THEY GIVE A NUMBER OF
DIFFERENT OPTIONS FOR
CONTROLLING THE FAMILY WISE
ERROR RATE.
I WON'T GO THROUGH ALL OF THE
OPTIONS BUT I WANT TO NOTE THAT
IN A CONFIRMATORY STUDY, IT'S
REALLY CRITICAL THAT IN ADDITION
TO PRE SPECIFYING OUR PRIMARY
ENDPOINTS AND THE OUR MODELS, IF
WE'RE GOING TO BE USING
STATISTICAL METHODS FOR
ADJUSTMENTS, THOSE METHODS
SHOULD ALSO BE PRE-SPECIFIED.
THE SIMPLEST METHOD WE CAN USE
IS THE BON FERONY METHOD.
WE DIVIDE OUR .05 BY THE NUMBER
OF CHOSEN ENDPOINTS, IN THE
SIMPLEST CASE.
SO WE HAVE 5 COPRIMARY
ENDPOINTS.
FOR EACH INDIVIDUAL ENDPOINT
WE'RE LOOKING AT WHETHER THE
P-VALUE IS LESS THAN .01.
WE CAN ALSO THINK ABOUT A
WEIGHTED BON FERONY WHERE WE UP
WEIGHT SOME OF THEM AND DOWN
WEIGHT OTHERS.
THIS IS A VERY SIMPLE METHOD.
IT DOESN'T REQUIRE ANY
ASSUMPTIONS ABOUT OUR DATA OR
HOW THE ENDPOINTS ARE
CORRELATED.
IT ONLY TAKES ONE STEP.
BUT THE DOWNSIDE IS THAT IT'S
VERY CONSERVATIVE.
SO WE SEE WE MAY HAVE OR OFTEN
HAVE A LOSS OF POWER USING THE
BON FERONY METHOD.
AND WE WANT TO BE CAREFUL
ESPECIALLY WITH A LOT OF
ENDPOINTS.
SO, I WON'T GO THROUGH THIS
SLIDE IN DETAIL BUT I WANT TO
NOTE THAT THERE ARE A NUMBER OF
DIFFERENT STATISTICAL METHODS.
SOME OF THEM MAKE ASSUMPTIONS
ABOUT HOW THE DATA IS
DISTRIBUTED OR WHETHER OR NOT
END POINTS ARE CORRELATED.
SOME OF THEM LOOK AT ALL
ENDPOINTS EQUALLY WHEREAS IN
OTHER CASES, YOU CAN TEST THE
ENDPOINTS IN A PRE-DEFINED ORDER
WHERE YOU START WITH THE MOST
CLINICALLY-RELEVANT ENDPOINTS.
SO THERE ARE A NUMBER OF
DIFFERENT OPTIONS AND IT'S
CRITICAL THAT THE STATISTICIAN
WORK WITH THE CLINICIAN TO
IDENTIFY WHAT METHOD MAY BE MOST
APPROPRIATE.
SO GOING BACK TO AN EXPLORATORY
STUDY, WE DON'T HAVE THE SAME
TYPE I ERROR CONCERN BECAUSE
WE'RE ASSUMING THAT AN
EXPLORATORY STUDY WILL BE
FOLLOWED UP WITH A CONFIRMATORY
STUDY.
HOWEVER, THERE IS STILL A RISK
THAT IF WE DO AN EXPLORATORY
STUDY, AND WE GET A REALLY LOW
P-VALUE, THAT WE OVERINTERPRET A
DIFFERENCE.
AND THIS IS REFERRED TO AS
SELECTIVE INFERENCE.
SO THIS IS A SLIDE, THIS PICTURE
FROM ERIC GIBSON OF NOVARTIS,
WHERE HE IS DEMONSTRATING THE
ISSUE WITH SELECTED INFERENCE
WHERE WE'RE DRAWING THE TARGET
AROUND THE ARROW.
AND THIS CAN LEAD TO PROBLEMS OF
LOW REPLIC ABILITY WHERE WE OVER
INTERPRET SOME DIFFERENCE AND
ARE UNABLE TO REPLICATE IT IN A
LATER STUDY.
AND THIS CAN BE QUANTIFIED WITH
THE FALSE DISCOVERY RATE, WHICH
IS THE EXPECTED PROPORTION OF
FALSE POSITIVE FINDINGS AMONG
ALL POSITIVE.
SO AMONG ALL REJECTED
HYPOTHESES.
AND THE FAMILY WISE ERROR RATE
WAS FIRST INTRODUCED IN THE
90s IN THE CONTEXT OF GENOME
WIDE STUDIES WHERE CONTROLLING
THE FAMILY WISE ERROR RATE WAS
FOUND TO BE TOO CONSERVATIVE
WHEN YOU HAVE A LARGE NUMBER OF
HYPOTHESES.
AND OFTEN YOU MIGHT -- THERE IS
A RISK YOU MIGHT MISS SOMETHING
IF YOU CONTROL THE FAMILY WISE
ERROR RATE.
SO A BIG GENOME-WIDE STUDY OR
EXPLORATORY STUDY WHERE YOU
DON'T WANT TO LOSE A ENDPOINT,
CONTROLLING THE FALSE DISCOVERY
RATE MIGHT BE A MORE APPROPRIATE
OPTION.
AND THIS SLIDE, THIS TABLE,
GIVES YOU SOME IN TUITION THAT
AS YOU INCREASE THE NUMBER OF
TESTS WHETHER BECAUSE OF AN
INCREASE IN ENDPOINTS OR PERHAPS
BECAUSE OF ADDITIONAL SUBGROUPS
OR DOSES, FOR ANY FIXED POWER
LEVEL, AS INCREASE THE NUMBER OF
TESTS, THE FALSE DISCOVERY RATE
WILL INCREASE QUITE
DRAMATICALLY.
AND I HAVE INCLUDED AT THE
BOTTOM A REALLY -- THE
RELATIONSHIP BETWEEN THE FALSE
DISCOVERY RATE AND THE FAMILY
WISE ERROR RATE.
AND SIMILAR TO HAVING A NUMBER
OF METHODS FOR CONTROLLING THE
FAMILY WISE ERROR RATE, WE ALSO
HAVE SOME STATISTICAL OPTIONS
FOR CONTROLLING THE FALSE
DISCOVERY RATE.
AND I'LL NOTE THAT THESE METHODS
ARE LESS CONSERVATIVE.
ANY METHOD THAT CONTROLS THE
FAMILY WISE ERROR RATE WILL ALSO
AUTOMATICALLY CONTROL THE FALSE
DISCOVERY RATE.
AND SO SOME OF THE METHODS ARE
THE BEN YAMENEY AND -- [
INAUDIBLE ]
METHOD.
AND THEN THERE HAS BEEN A LOT OF
LITERATURE AND WORK BY JOHN
STORY AND OTHERS TO INTRODUCE
ALTERNATIVE METHODS LIKE THE
POSITIVE FALSE DISCOVERY RATE.
THERE IS ADDITIONAL STATISTICAL
LITERATURE INTRODUCING THE OTHER
METHODS TO THIS.
SO SIMILAR TO THE FAMILY WISE
ERROR RATES, IT DEPENDS ON WHAT
DATA YOU HAVE AND YOUR
ASSUMPTIONS.
SO I'LL SWITCH GEARS A LITTLE
BIT AND TALK ABOUT COMPOSITE
ENDPOINTS FOR A FEW MINUTES.
SEWED AS MENTIONED BEFORE,
COMPOSITE ENDPOINTS IS WE DON'T
NEED TO CHOOSE A PRIMARY.
WE ALSO DON'T NEED TO ADJUST FOR
MULTIPLE TESTING.
HOWEVER, CLINICAL RELEVANCE AND
INTERPRETABILITY IS REALLY KEY
FOR NOT ONLY THE ENDPOINT AS A
WHOLE BUT ALSO THE INDIVIDUAL
COMPONENTS.
WE CAN THINK ABOUT WEIGHTING
WITH COM POSILATE ENDPOINTS IN A
NUMBER OF DIFFERENT WAYS --
COMPOSITE -- ONE IS IF WE ARE
COMBINING SCORES THAT ARE ON
MULTIPLE SCALES, SAY ONE SCALE
IS 0-3 AND THE OTHER IS 0-100.
IF YOU ADDED THE SCORES TOGETHER
THE ONE ON THE MUCH HIGHER SCALE
WOULD BE UP WEIGHTED.
SO WE WANT TO TAKE THAT INTO
ACCOUNT WHEN WE'RE CONSTRUCTING
OUR ENDPOINTS POTENTIALLY AT OUR
OWN WEIGHTS TO COUNTER ACT THAT.
WE CAN ALSO THINK ABOUT WEIGHTS
TO ACCOUNT FOR OUR
DIRECTIONALITY OF DIFFERENT
COMPONENTS AS WELL AS CLINICAL
IMPORTANCE AND SEVERITY.
AND AS A STATISTICIAN, I WANT TO
POINT OUT IF WE DO ANALYSIS ON
OUR COMPOSITE ENDPOINT, AND
STATISTICAL INFERENCE AND
CONCLUSIONS APPLY TO THAT
COMPOSITE ENDPOINT AS A WHOLE
AND WE CAN'T MAKE CONCLUSIONS
ABOUT THE INDIVIDUAL COMPONENTS.
SO THERE ARE OFTEN CASES WHERE
WE MIGHT WANT TO LOOK AT
SECONDARY ANALYSIS THAT LOOK AT
THE INDIVIDUAL COMPONENTS AFTER
WE MADE A CONCLUSION ABOUT THE
COMPOSITE AS A WHOLE.
SO I'LL CLOSE OUT WITH A COUPLE
OF ADDITIONAL THOUGHTS DEPENDING
ON THE TYPE.
COMPOSITE ENDPOINT -- SO WITH
CONTINUOUS DATA OFTEN OUR
ANALYSIS IS LOOKING AT A
DIFFERENCE IN GROUP MEANS WHICH
CAN BE INTERPRETED NICELY FOR AN
INDIVIDUAL AS WELL AS FOR A
GROUP.
I THINK DR. BROWN MADE A REALLY
IMPORTANT POINT IN HER TALK
EARLIER TODAY THEY WANT TO
REITERATE THAT IF WE HAVE
ORDINAL SCORES, THE SUM OR THE
MEAN OF THOSE SCORES IS NOT
INTERPRETABLE.
SO WE CAN'T ASSUME THAT
DISTANCES BETWEEN INTERVALS OR
CHANGES IN SCORES ARE EQUAL WHEN
WE'RE LOOKING AT TOGETHER.
AND THEN A DOWNSIDE WITH
CONTINUOUS COMPOSITE ENDPOINTS
AND DATA IN GENERAL IS THAT
EARLY WITHDRAWLS OFTEN MEAN
MISSING DATA THAT WE WANT TO
THINK ABOUT.
WE HAVE SEEN TODAY SOME NICE
EXAMPLES OF BINARY COMPOSITE END
POINTS DEFINING TREATMENTS,
SUCCESS OR FAILURE.
OR ANALYSIS ARE OFTEN LOOKING AT
DIFFERENCES IN PROPORTIONS AND I
WANT TO POINT OUT THAT WITH
BINARY DATA IN GENERAL, OUR
POWER IS PARTICULARLY SENSITIVE
TO VARIABILITY OF TREATMENT
EFFECTS BETWEEN SITES AND
BALANCES AND THE NUMBER OF
ANIMALS AT EACH SITE AS WELL AS
THE PLACEBO EFFECT.
THAT IS A CONSIDERATION IF WE
ARE TAKING CONTINUOUS DATA AND
TRANSFORMING IT INTO
SUCCESS/FAILURE.
THE POSITIVE BINARY COMPOSITE
ENDPOINTS OR DATA IN GENERAL, IS
THAT OFTEN WHEN WE PRE SPECIFIED
OUR OUTCOME WE CAN ACCOUNT FOR
EARLY WITHDRAWLS IN OUR
ANALYSIS.
SO THEY ARE NOT NECESSARILY
MISSING DATA.
THEY MAY BE ABLE TO BE INCLUDED
AS A TREATMENT FAILURE, FOR
EXAMPLE.
AND THEN FINALLY, THE THIRD KEY
POINT IS TIME TO EVENT DATA
WHERE STATISTICAL ANALYSIS IS
LOOKING AT SURVIVAL ANALYSIS
METHODS.
WE CAN ALSO LOOK AT THINGS LIKE
THE WIN RATIO IN WHICH CASE WE
CAN PRIORITIZE THE MOST
IMPORTANT ENDPOINTS.
THESE ARE REALLY NICE BECAUSE IF
WE HAVE A RARE OUTCOME, WE CAN
INCREASE THE NUMBER OF EXPECTED
EVENTS AND THEREFORE INCREASE
OUR POWER AND WE CAN ALSO LIKE
BINARY DATA, INCORPORATE EARLY
WITHDRAWLS.
SO, AGAIN, I JUST WANT TO
CONCLUDE BY SAYING THAT OUR --
AS SAID A LOT TODAY, WE WANT TO
BALANCE OUR STATISTICAL
CONSIDERATIONS WITH CLINICAL
CONSIDERATIONS.
WE LOOK - I MENTIONED P VALUES
AND SIGNIFICANCE BUT WE WANT TO
LOOK AT THE EFFECT SIZE AND
INTERPRETATION OF THE EFFECT
SIZE IN ADDITION TO THE P-VALUE.
IT'S REALLY IMPORTANT THAT WE IN
A CONFIRMATORY STUDY WE
PRE-SPECIFY OUR COMPOSITE
ENDPOINTS OR CO-PRIMARY
ENDPOINTS, AS WELL AS METHODS WE
MIGHT USE FOR OUR ADJUSTING FOR
MULTIPLE COMPARISONS.
AND WE ARE LES STRINGENT WITH
PRE-SPECIFICATION IN EXPLORATORY
STUDIES BUT WE WANT TO BE
CAREFUL WITH INTERPRETING
MULTIPLE STATISTICAL TESTS.
SO IT'S IMPORTANT TO THINK ABOUT
WHAT METHODS WE MIGHT WANT TO DO
TO COUNTER ACT THIS.
SO THANK YOU ALL FOR YOUR
ATTENTION.
[ APPLAUSE ]
>> GOOD AFTERNOON, I'M EMILY
SUBMIT AT THE FDA CENTER FOR
VETERINARY MEDICINE.
OUR NEXT SPEAKER IS DR. HANS
COETZEE FROM KANSAS STATE
UNIVERSITY THE ASSOCIATE DEAN
FOR RESEARCH.
HE EARNED HIS BACHELOR OF
VETERINARY SCIENCE DEGREE FROM
SOUTH AFRICA AND ALSO WAS
AWARDED A SPECIAL CERTIFICATE IN
PRODUCTION FROM THE ROYAL
COLLEGE OF VETERINARY SURGEONS.
HE ALSO EARNED A DOCTORATE IN
VETERINARY MICROBIOLOGY AND
HOLDS DUAL BOARD CERTIFICATION,
THE AMERICAN COLLEGE OF
VETERINARY CLINICAL PHARMACOLOGY
AND THE AMERICAN COLLEGE OF
ANIMAL WELFARE AND A EUROPEAN
SPECIALIST IN ANIMAL WELFARE
SCIENCE.
I'D LIKE TO WELCOME HIM TO
DISCUSS EXAMPLES OF MULTIPLE AND
COMPOSITE ENDPOINTS.
[ APPLAUSE ]
>> THANK YOU VERY MUCH,
EVERYONE.
I APPRECIATE YOU HANGING IN
THERE FOR THE AFTERNOON SESSION.
THIS IS A PHOTOGRAPH OF THE LAB
FROM A FEW YEARS AGO AS
DR. DAVID ANDERSON WITH THE
CAMERA SHOOTING EXIT SPEED
DEVICE TO MEASURE HOW FAST THE
ANIMALS ARE LEAVING THE SHOOT.
AND THEN THERE IS ALSO THE
UBIQUITOUS FLYPAPER YOU REQUIRE
EVERY TIME YOU DO FOOD ANIMAL
RESEARCH TO GET THE FLIES OFF
THE COW.
IT'S PRETTY EVENTFUL OUT THERE
IN THE BARN.
SO GET READY TO SEE SOME COWS.
WE HAVE PLENTY OF COW EXAMPLES
COMING UP HERE.
JUST MY CURRENT DISCLOSURES.
I CONSULT FOR A NUMBER OF
DIFFERENT COMPANIES.
MOST OF THE WORK YOU'LL SEE
PRESENTED TODAY WAS FUNDED BY
THE USDA AND THEN I ALSO HAVE
RECEIVED ETHICAL OVERSIGHT FOR
ALL STUDIES WE WILL BE REPORTING
HERE THIS AFTERNOON.
SO MOST OF THE INFORMATION I
HAVE IN TERMS OF DEFINITIONS
COMES FROM THESE TWO SOURCES,
ONE ALREADY REFERENCED HERE BY
DR. RUBERMAN IN TERMS OF
DISCUSSING THE MULTIPLE
ENDPOINTS IN CLINICAL TRIALS
GUIDANCE FROM FDA AND THE OTHER
IS A PAREN THAT WAS PUBLISHED
SEVERAL YEARS AGO AND INCREDIBLE
USEFUL RESOURCE ON ANALYZING
MULTIPLE ENDPOINTS IN CLINICAL
TRIALS OF PAIN.
SO WE'LL TALK ABOUT THE
DEFINITIONS, THAT'S WHERE THEY
COME FROM.
I WANT TO VERY BRIEFLY COVER THE
DEFINITIONS.
I HAVE BEEN WELL SET UP BUT WHEN
I TALK ABOUT A PRIMARY ENDPOINT,
I'M TALKING ABOUT VARIABLES
CAPABLE OF PROVIDING THE MOST
CLINICALLY RELEVANT AND
CONVINCING EVIDENCE.
WHAT IS THAT?
THAT'S WHAT WE ARE TRYING TO
FIGURE OUT NOW FOR 15 YEARS.
I RECALL 15 YEARS AGO MICHELLE
INVITED ME TO THE FDA TO PRESENT
A STAFF COLLEGE ON PAIN
ASSESSMENT IN FOODANCE MALLS AND
WE ARE STILL WRESTLING ON WHAT
CONSTITUTES THAT CLINICALLY
RELEVANT AND CONVINCING EVIDENCE
FOR PROVING THIS.
MULTIPLE ENDPOINTS.
THESE ARE SIGNIFICANT RESULTS
TYPICALLY REQUIRED FOR SEVERAL
PRIMARY ENDPOINTS TO BE
CONSIDERED A TRIAL POSITIVE.
AND REQUIRING EACH OF THESE
ENDPOINTS TO BE SIGNIFICANT DOES
HAVE IMPACT IN TERMS OF THE
STATISTICAL POWER AS CLARED HAS
ALREADY TALKED ABOUT THIS
AFTERNOON.
-- CLAIRE -- IN TERMS OF
SECONDARY ENDPOINTS, THESE
PROVIDE BACKGROUND AND A GREATER
UNDERSTANDING OF PRIMARY
ENDPOINTS.
THEY SEPARATE COMPONENTS OF
COMPOSITE ENDPOINTS.
THEY ARE IMPORTANT GIVEN THE
TREATMENTS OBJECTIVES BUT FOR
WHICH THE STUDY MAY NOT HAVE
ADEQUATE POWER.
THEY CAN AID IN THE
UNDERSTANDING OF THE MECHANISM
OF ACTION OF THE TREATMENT.
THEY RELATE TO THE SECONDARY
HYPOTHESIS ANOTHER MAJOR
OBJECTIVE OF THE TREATMENT AND
ARE INTENDED TO BE USED FOR
EXPLORATORY NAN SIS.
ANALYSIS.
AND THEN ALREADY DISCUSSED,
THERE ARE EXPLORATORY ENDPOINTS
AS WELL.
THESE SHOULD BE PRE-SPECIFIED,
OCCASIONALLY WE'LL DO SOME
POST-HOC ANALYSIS BUT PRE
SPECIFYING THE EXPLORATORY
ANALYSIS IS CRITICAL AND THESE
ARE NOT DIRECTLY RELATED TO THE
PRIMARY OBJECTIVE SO THEY ARE
HYPOTHESIS GENERATED.
AND THEN THE COMPOSITE
ENDPOINTS, MULTIPLE ENDPOINTS
COMBINED INTO A SINGLE VARIABLE
AND I'LL SHOW AN EXAMPLE AT THE
END OF THE PRESENTATION.
THIS IS USEFUL WHEN A DISEASE
HAS MANY CLINICALLY-IMPORTANT
MANIFESTATIONS AND THIS APPROACH
TYPICALLY INCREASES THE
STATISTICAL POWER AS HAS ALREADY
BEEN DISCUSSED.
HOPEFULLY THAT WILL SET US UP IN
TERMS OF BEING ON THE SAME PAGE
IN TERMS OF WHAT WE ARE TALKING
ABOUT WHEN WE TALK ABOUT THESE
DIFFERENT ENDPOINTS AND THEIR
APPLICATION.
SO WHY DO WE CARE ABOUT MULTIPLE
OR COMPOSITE ENDPOINTS IN PAIN
STUDIES?
IF THERE IS NOTHING ELSE YOU'RE
TAKING AWAY FROM THIS MEETING,
PAIN IS COMPLICATED.
WE VIOLENT YET FIGURED OUT THE
SINGLE ENDPOINT THAT WORKS
RELIABLY EVERY TIME.
WE TRY TO MEASURE PAIN IN THE
FOOD ANIMAL.
MOST OF THE TRIALS WE CONDUCT
HAVE MULTIPLE ENDPOINTS TO TRY
TO ASSESS PAIN AND ANALGESIC
DRUG EFFICACY.
WHEN WE HAVE MORE THAN ONE
ENDPOINT AND MORE THAN ONE
ENDPOINT IS ANALYZED IN A SINGLE
TRIAL, WE HAVE THIS INCREASED
LIKELIHOOD OF HAVING A FALSE
CONCLUSION ABOUT THE DRUG SO WE
HAVE TO MAKE THAT ADJUSTMENT FOR
THE MULTIPLICITY ISSUE.
AND SO THE GREATER THE NUMBER OF
THE STATISTICAL TESTS WE
PERFORM, THE HIGHER PROBABILITY
THAT ONE OR MORE OF THEM WILL
YIELD THE STATISTICALLY
SIGNIFICANT RESULTS BY CHANCE
ALONE.
SO I REALLY APPRECIATE THE FIRST
TWO SPEAKERS IN SETTING UP THIS
ASPECT OF THE PRESENTATION.
I WENT THROUGH THOSE PRETTY
QUICK BECAUSE THAT'S A RECAP OF
WHAT HAS ALREADY BEEN TALKED
ABOUT.
SO THE BIG DIFFERENCE IN FOOD
ANIMALS, OUR DOMAINS ARE
DIFFERENT.
A LOT HAS BEEN SAID TODAY AND
YESTERDAY ABOUT DOMAINS.
IN HUMAN MEDICINE, GENERALLY
ACCEPTED THAT THERE ARE SIX CORE
DOMAINS FOR ASSESSING CHRONIC
PAIN.
PAIN ITSELF, PHYSICAL
FUNCTIONING, EMOTIONAL
FUNCTIONING, PARTICIPANT RATINGS
OF GLOBAL IMPROVEMENT, SYMPTOMS
AND ADVERSE EFFECTS AND THEN
PARTICIPANT DISPOSITION.
BUT ON THE FOOD ANIMAL SIDE AS
MENTIONED YESTERDAY, WE TALK
ABOUT THESE THREE PRIMARY
DOMAINS WHICH ARE ALSO THE
DOMAINS WE ASSESS WHEN ASSESSING
ANIMAL WELFARE.
THOSE ARE BASIC HEALTH AND
FUNCTIONING, NATURAL LIVING AND
THE EFFECT OF STEPS.
EARLIER TODAY, IT WAS TALKED
ABOUT THE COMPOSITE SCALES AND
SEVERAL OF THOSE HAVE ALREADY
BEEN DESCRIBED.
AS TALKED ABOUT YESTERDAY, THE
PAIN SCALE AND FACIAL GRIMACE
SCALES ARE ALSO SCALES WE USE TO
TRY TO ASSESS THE BEHAVIORAL
OUTCOMES OF THOSE EFFECTIVE
STATES.
WE ALSO ASSESS NEUROENDOCRINE
OUTCOMES AND PHYSIOLOGICAL
OUTCOMES AS WELL.
WHEN WE TALK ABOUT FOOD ANIMALS,
PARTICULARLY IN ACUTE PAIN
SETTING AND THESE THREE PRIMARY
DOMAINS, HEALTH AND FUNCTIONING,
EFFECTIVE STATES AND THE NATURAL
LIVING.
SO IN TERMS OF HOW WE ASSESS
THOSE, THIS IS OUR FIRST EXAMPLE
OF A COM POSILATE SCALE THAT IS
QUITE COMMONLY USED NOW IN TERMS
OF TRYING TO ASSESS PAIN.
THIS IS THE COW PAIN SCALE
DESCRIBED FROM THE UNIVERSITY OF
IN COPENHAGEN.
SIX ENDPOINTS THAT THE COME OUT
OF THIS SCALE.
THE FIRST TWO OF THEM ARE
MEASURED ON A 0-1.
SO BINARY OUTCOME AND THEN THE
REMAINING FOUR OUTCOMES ARE
MEASURED ON A 3-POINT SCALE.
SO WHEN YOU ADD UP THOSE
TOGETHER, YOU END UP WITH A
COMPOSITE SCORE OUT OF 10.
THAT'S ONE OF THE SCALES THAT
FOLKS TRIED TO USE TO ASSESS
ANALGESIC DRUG EFFICACY.
THIS IS THE FIRST POINT OF
CHALLENGE FOR US FROM THE FOOD
ANIMAL SIDE IS WE HAVE REALLY
STRUGGLED TO REPRODUCE THESE IN
DIFFERENT SETTINGS.
SOMETIMES WE SAID, MAYBE IT'S A
SPECIFIC THING, MAYBE IT'S JUST
THE WAY WE RAISE CATTLE IN THE
UNITED STATES VERSUS EUROPE.
WE HAVE REALLY STRUGGLED TO GET
THESE ENDPOINTS AND SCALES TO BE
REPRODUCED RELIABLY EVERY TIME
WE TRY TO USE THEM.
WE ARE DOING MORE WORK IN THAT
AREA BECAUSE THERE IS MORE WORK
WARRANTED.
MY COLLEAGUE WHO IS HERE, FIRST
DESCRIBED THIS FACIAL GRIMACE
SCALE IN PIG LETS AND THIS IS
ANOTHER INCREDIBLY USEFUL SCALE
IN TERMS OF TRYING TO ASSESS
PAIN USING A BEHAVIOR SCALE IN
PIGS.
THE CHALLENGE WITH THIS IS
HAVING ALL THE TESTERS, WE
STRUGGLE TO RECRUIT STUDENTS IN
THE NYE LAB BECAUSE NO ONE LIKES
WATCHING THE VIDEOS WHEN LOOKING
AT DIFFERENT ENDPOINTS.
THESE SCALES ARE VERY, VERY TIME
CONSUMING TO ANALYZE AND I WAS
ENCOURAGED BY THE DISCUSSION
ABOUT MACHINE LEARNING YESTERDAY
THAT THERE MAY BE SOME MACHINE
LEARNING OPPORTUNITIES FOR US TO
BE ABLE TO AUTOMATE THESE
SCALES.
BUT ABI'S WORK IS OUT STANDING
IN MOVING THE SCALE FORWARD IN
TERMS OF UNDERSTANDING HOW WE
MIGHT BE ABLE TO MEASURE PAIN IN
PIG LETS BUT IT SURE WOULD BE
GREAT IF WE COULD AUTOMATE THAT.
THEN IN TERMS OF SOME OF THE
OTHER SCALES THAT ARE OUT THERE.
THE SCALE THAT IS USED MOST
COMMONLY BY -- THE ONE WE PUT IN
THE HANDS OF FARMERS AND SAID,
USE THIS SCALE, IS WHAT IS KNOWN
AS THE [ INAUDIBLE ]
SYSTEM.
THIS WAS DESCRIBED IN THE
JOURNAL OF THEORY GENEALOGY.
IT HAS NOTHING TO DO WITH ANIMAL
WELFARE BUT WAS DESCRIBED
SEVERAL YEARS AGO AND WIDELY
ADOPTED BY THE DAIRY INDUSTRY
AND A 5-POINT SCALE FOCUSING ON
THE BACK OF THE ANIMAL AND WHAT
ITS FEET ARE DOING.
IF THEIR BACK ARCHES, THE FIRST
SIGN OF TROUBLE IN TERMS OF
LAMENESS.
IF THE BACK ARCHES AND THE
ANIMAL STARTS TO WALK WITH A
SHORT STRIDE, WE SEE PROGRESSION
IN LAMENESS AND THEN WHEN WE SEE
THE ANIMAL FAVORING THE LIMB AND
SCORES 4-5, THAT'S WHEN WE RUN
INTO ISSUES AND 5 IS WHERE THE
ANIMAL IS NON-WEIGHT BEARING.
THIS IS A SCALE THAT HAS BEEN
EASIEST FOR IMPLEMENT ON FARMS
BECAUSE IT'S VERY
STRAIGHTFORWARD.
WE BASICALLY LOOK AT THE BACK,
LOOKING AT THE STRIDE LENGTH AND
THE FEET AND WE'RE DONE.
SO, THAT'S BEEN REPRODUCED
SEVERAL TIMES IN DIFFERENT
STUDIES AND HAS BEEN USED SOME
IN ANALGESIC STUDIES AS I WILL
SHOW IN A MOMENT.
THIS THE IS A SCALE THAT
DR. LUNA TALKED ABOUT.
THIS WAS THE ONE DEVELOPED AND
LOOKING AT LOCOMOTION BEHAVIORS,
ACTIVITY, APPETITE,
MISCELLANEOUS ACTIVITIES AND
GIVING COMPOSITE SCORE OUT OF 10
WHEN YOU ADD THE CATEGORIES
TOGETHER.
THESE SCORES ARE SIMILAR.
THIS IS THE UCPS IS ON THE LEFT
AND CPS IS ON THE RIGHT AND THE
BEHAVIORS ARE SUMMARIZED IN THE
COLUMN TO YOUR RIGHT.
AND YOU'LL NOTICE THAT MOST OF
THE FOCUS IN BOTH SCORING
SYSTEMS ARE BASED ON THE
ATTENTION AND INTERACTION THAT
THE ANIMAL HAS WITH ITS
ENVIRONMENT BACK POSITION IS
IMPORTANT AND THESE TWO SCORES
AS WELL.
THE HEAD POSITION IS ALSO
EXAMINED IN THE TWO SCORING
SYSTEMS AND MOVEMENT WITH OR
WITHOUT STIMULATION IS REALLY
THE FOURTH AREA THAT IS
SUMMARIZED.
SOME OF THE BEHAVIORS THAT ARE
NOT CONSERVED ACROSS THE TWO
SCORING SYSTEMS, BUT ALL OF THIS
DISTILLS DOWN TO THE MAIN
ENDPOINTS.
WHAT IS THE ANIMAL DOING?
HOW IS IT BEHAVING IN ITS
ENVIRONMENT?
DOES IT MOVE WITHOUT
STIMULATION?
WHAT'S THE HEAD POSITION?
THOSE ARE THE AREAS WE FOCUS ON.
THE ONE WE USED QUITE COMMONLY
IN MY LAB HAS BEEN BASICALLY
DOING A VAS SCORE.
SO THERE ARE TWO CALFS.
PEN A AND PEN B.
AND THE ONCE YOU CAN ACCLAMATE
TO THE SEA SICKNESS OF THE
CAMERA MOVING UP AND DOWN, YOU
MIGHT BE ABLE TO HAVE A LOOK AT
THOSE TWO PENS OF CALFS AND
FAIRLY QUICKLY PERHAPS PROVIDE
AN ASSESSMENT FOR ME.
THE INTERACTIVE PART HERE.
WHO BELIEVES THAT PEN A RECEIVED
AN ANALGESIC DRUG BEFORE THEY
WERE CASTRATED?
SHOW OF HANDS.
NON RESPONDERS?
PEN B.
ANY TAKERS FOR PEN B?
NOT VERY MANY TAKERS.
ONE FOR PEN B.
THE DIFFERENCE WITH PEN B, A LOT
OF THOSE ANIMALS ARE NOT COMING
UP TO THE GATE TO SEE WHAT THE
PERSON WITH THE CAMERA IS DOING.
WE SEE A LOT OF ARCHED BACKS IN
PEN B.
PEN B IS THE GROUP THAT DIDN'T
GET ANY ANALGESIA.
THOSE ANIMALS ARE NOT SUPER
INTERACTIVE.
PEN A ALTHOUGH THERE ARE A FEW
ANIMALS STANDING WITH ABNORMAL
GATE, MAJORITY OF COMING UP AND
REALLY INTERESTED IN THE PERSON
TAKING THE VIDEO.
AND SO WE WERE ABLE TO SCALE
THIS ON A 0-10 LINE AND THAT
GIVES US A CONTINUOUS SCALE
OUTCOME THAT WE CAN THEN ANALYZE
USING A MIXED MODEL.
THESE ARE SOME OF THE BEHAVIORAL
ENDPOINTS WE MEASURED AND SOME
OF THOSE LEND THEMSELVES TO
BEING EITHER PART OF MULTIPLE
ENDPOINTS ANALYSIS OR THEY CAN
BE PART OF A COMPOSITE ANALYSIS
THEMSELVES.
IN TERMS OF THE ENDPOINTS, WE
COMMONLY MEASURE, THIS IS JUST A
SNAPSHOT OF SOME OF THE
ENDPOINTS THAT WE FOCUS ON WHEN
WE TRY TO ASSESS PAIN IN COWS.
SO ON THE TOP LEFT CORNER, THAT
IS INFRARED.
IF YOU LOOK AT THAT CALF AND
WATCH THE VIDEO FOR A LITTLE
BIT, YOU'LL SEE THAT THERE IS A
POINT WHERE THE COLOR CHANGES
FROM BRIGHT RED COLORS
INDICATING VERY GOOD PROFUSION
OF THE SKIN TO GREENS AND
YELLOWS, WHICH JUST HAPPENED IN
THAT VIDEO.
AND THAT'S THE POINT OF SURGICAL
CASTRATION.
WHAT WE ARE MEASURING THERE IS
EPINEPHRINE RELEASE CAUSING
PHASEO CONSTRUCTION RESULTS THE
BLOOD FLOW MOVING AWAY FROM THE
SKIN, CAUSING THE SKIN TO COOL.
WE CAN CAPTURE THAT AND MODEL
THOSE DATA USING SOME RESEARCH
SOFTWARE.
AND SO THE IRT IS PROVEN TO BE
QUITE A USEFUL TOOL IN SOME OF
THESE MULTIPLE ENDPOINT STUDIES.
AND WE HAVE MECHANICAL
THRESHOLD, ALL RIGHT RATE,
SUBSTANCE P ANALYSIS,
ACCELEROMETERS, DATA ANALYSIS
FOR THE PRESSURE MAP WE'LL TALK
ABOUT.
MEASURING SPEED AT WHICH THEY
LEAVE THE SHOOT WITH BARREL
RACING TIMERS.
SO YOU HAVE TO BE IN KANSAS FOR
THAT.
THIS IS TWO BARREL RACING TIMERS
SET UP TO MEASURE THE SPEED THE
ANIMAL IS LEAVING THE SHOOT.
WE MEASURE CORTISOL AND DONE
WORK WITH EEGs AS WELL.
LOTS OF ENDPOINTS WE MEASURE IN
FOOD ANIMALS SO THAT IS WHAT OUR
BOARD LOOKS LIKE.
WE THESE HAVE ALL HELPED US TO
GENERATE HYPOTHESES.
SO THE COLOR-CODING HERE IN A
SCALE OF THINGS THAT REALLY
HAVEN'T SERVED US WELL IN TERMS
OF MULTIPLE ENDPOINT STUDIES,
AND THEN THINGS THAT ARE USEFUL
AND THINGS THAT ARE PROVEN
USEFUL AS PRIMARY ENDPOINTS,
THERMOGRAPHY AND PRESSURE MAT
ANALYSIS.
THERE ARE LOTS OF WORK TO BE
DONE IN THIS SPACE STILL IN
TERMS OF TRYING TO REFINE THE
MEASUREMENT OF THESE ENDPOINTS.
IT HAS ELECTRODERMAL ACTIVITIES
NOT BEING USEFUL.
EXIT SPEED HASN'T EITHER AND
GROWTH AND PERFORMANCE IS NOT
USEFUL EITHER.
SO IN TERMS OF HOW WE DETERMINE
THE OPTIMAL PRIMARY ENDPOINT,
THIS WAS MENTIONED YESTERDAY IN
A PRESENTATION.
THIS IS WORK DONE THAT USED ROC
CURVES TO OPTIMIZE THE ENDPOINTS
WE COULD MEASURE IN TERMS OF
ASSESSING PRIMARY ENDPOINTS.
FOR CASTRATION, DEHORNING AND
MAINTENANCE, PLASMA CORTISOL
STILL CAME OUT ON TOP.
WE ROLE OUR ICE ON CORTISOL
BECAUSE IT'S NOT REALLY PAIN
SPECIFIC, IT IS VERY, VERY
SUSCEPTIBLE TO THE EFFECTS OF
ANALGESIC DRUG AND GIVES US
PRETTY GOOD SENSITIVITY AND
SPECIFICITY ACROSS DIFFERENT
STUDIES THAT WE ASSESSED.
FOR ABDOMINAL STUDY, IRT PROVED
TO HAVE THE HIGHEST AUC UNDER
THE RAW CARVE AT .73.
WE STILL HAVE SOME WORK TO DO IN
TERMS OF REFINING ENDPOINTS.
CORTISOL IS STILL THE MOST
WIDELY REPORTED ENDPOINT IN FOOD
ANIMAL MEDICINE IN TERMS OF
MEASURING PAIN.
TO SWITCH TO THE BEST EXAMPLE OF
A MULTIPLE ENDPOINT SCENARIO WAS
THE APPROVAL OF BANT MEAN
TRANSDERMAL.
OR TRANSDERMAL FORMULATION FOR
SYSTEMIC ABSORPTION THROUGH THE
SKIN.
SO THIS IS GUIDANCE 123 FROM FDA
IN WHICH SECTION 6 ON LABELING
SPECIFIES THE USE OF VALIDATED
METHODS OF PAIN ASSESSMENT IN
THE TARGET SPECIES THAT ARE
ENCOURAGED AND RECOMMENDED FOR
THE ASSESSMENT OF PAIN.
SO PRIOR TO 2017, WE STRUGGLED
TO COME UP WITH THESE VALIDATED
METHODS OF PAIN ASSESSMENT.
BUT THEN THERE WAS THIS APPROVAL
AND I'LL WALK YOU THROUGH THAT
THAT GAVE US SOME GUIDANCE IN
TERMS OF HOW WE MIGHT USE
MULTIPLE ENDPOINTS IN PAIN
STUDIES IN FOOD ANIMALS.
SO THAT'S THE FOI AND THAT'S
WHAT THE DRUG LOOKS LIKE.
IT'S A PINK LIQUID APPLIED
TOPICALLY TO THE BACK AND THEN
ABSORBED THROUGH THE SKIN OF THE
ANIMAL AND THIS DRUG IS LABELED
FOR THE ALLEVIATION OF PAIN
ASSOCIATED WITH FOOT ROT IN
CATTLE.
SO THIS IS A GCP STUDY.
TWO DIFFERENT SITES AT WHICH THE
STUDY WAS CONDUCTED.
15 ANIMALS IN EACH TREATMENT
GROUP.
30 ANIMALS AT EACH SITE.
AND BASICALLY THE OVERALL DESIGN
OF THE STUDY IS THAT THERE WAS A
LAMENESS INDUCTION THAT OCCURRED
AT ABOUT 48 HOURS BEFORE
TREATMENT WAS EXPECTED TO OCCUR.
LAMENESS WAS INDUCED WITH THE
INJECTION.
AT APPROXIMATELY 48 HOURS AFTER
THE INJECTION, THOSE ANIMALS MET
THE ENTRY CRITERIA IF THEY HAD
LAMENESS SCORE AT 3.
A LESION SCORE OF 2-3 AND A
SWELLING SCORE OF 2-3.
AND AT THAT POINT IN TIME, THE
ANIMALS THAT MET THOSE INCLUSION
CRITERIA WERE RANDOMIZED TO
TREATMENT AND THEY RECEIVED
EITHER THIS OR A DYE.
AT SIX HOURS AFTER TREATMENT,
THE OUTCOME MEASURES WERE TAKEN
AT THAT POINT IN TIME.
SO TWO PHASES TO THIS STUDY.
THE INITIAL INDUCTION PHASE
WHERE THE ANIMALS WERE EXPOSED
TO THE BACTERIUM AND BECAME
LAME.
ONCE THEY MET THE ENTRY CRITERIA
FOR LAMENESS, THEY WERE
RANDOMIZED INTO TREATMENT GROUPS
AND THE OUTCOME MEASURES WERE
TAKEN AT SIX HOURS AFTER.
SO THE LAMENESS SCORING SYSTEM
IS WHAT I DESCRIBED PREVIOUSLY.
IT LOOKS SPECIFICALLY AT THE
ANIMALS WALKING OR STANDING WITH
A STRAIGHT BACK OR ARCHED BACK
AND THEN AT THE HEAD, NOT WEIGHT
BEARING OR FAVORING A LIMB.
SO THE SAME 5-POINT SCALE.
THE OTHER ENDPOINT THAT WAS
MEASURED HERE WAS THE DATA
ANALYSIS THAT WAS PERFORMED WITH
THE PRESSURE MAT.
LAMENESS WAS SCORED PRIOR TO
INDUCTION AND THEN A DAY AFTER
PRIOR TO ENROLLMENT.
SO APPROXIMATELY 48 HOURS AFTER
INDUCTION.
AND THEN THE ANIMALS WERE
TREATED AND LAMENESS WAS SCORED
AGAIN AT 6 HOURS AFTER
TREATMENT.
AND SO THIS REALTIME DATA
ANALYSIS SYSTEM WAS USED TO
EVALUATE THE MAXIMUM FORCE
APPLIED TO THE LAME FLOOR AND
THEN THE CONTACT AREA AT THE
TIME OF THE MAXIMUM FORCE
APPLIED.
THIS IS AN EXAMPLE HERE.
NOT FROM THIS STUDY BUT THIS IS
ANIMAL CROSSING OVER THE
PRESSURE MAT SHOWING THE FOOT
FALLS USED TO ASSESS THE MAXIMUM
TOTAL FORCE IN THE CONTACT AREA.
SO THE TREATMENT SUCCESS
CRITERIA STATISTICALLY
SIGNIFICANT DIFFERENCE OF
TREATMENT SUCCESS BETWEEN
TREATED AND CONTROLLED GROUPS
WAS ASSESSED SIX HOURS AFTER
TREATMENT AND THE TWO OUTCOMES
THAT WERE REQUIRED WAS
IMPROVEMENT IN THE LAMENESS
SCORE AND THEN IMPROVEMENT IN
TOTAL FORCE AND CONTACT AREA.
SO THEY USED BOTH THE VISUAL
SCORING SYSTEM OF LAMENESS AND
THE PRESSURE MAT SCORES TO TRY
TO ASSESS WHETHER THERE WAS AN
EFFECT OF TREATMENT IN THIS --
IN THESE ANIMALS.
THESE ARE THE OUTCOME FROM THE
FOI.
LAMENESS SCORE IMPROVEMENT 15-15
ANIMALS IMPROVED WITH THE
TRANSDERMAL AT SIX HOURS AFTER
TREATMENT.
ONLY ONE-15 ANIMALS IMPROVED IN
THE CONTROL GROUP FOR LAMENESS
SCORE.
AND THEN IN TERMS OF THE TWO
OUTCOMES MEASURED ON THE
PRESSURE MAT THE MAXIMUM FORCE
AND THE CONTACT AREA AT SITE 1
SHOWED STATISTICALLY SIGNIFICANT
DIFFERENCE AFTER TREATMENT FOR
BOTH FORCE AND CONTACT AREA.
AND SIMILAR OUTCOMES WERE
MEASURED IN THE CONTROL GROUP AT
THE SECOND SITE.
SO STATISTICALLY SIGNIFICANT
IMPROVEMENTS SEEN IN THESE
ANIMALS, BOTH IN THE LAMENESS
SCORE AND ALSO IN THE PRESSURE
MAT OUTCOMES.
SO ACROSSIC EXAMPLE OF A
MULTIPLE ENDPOINT STUDY.
-- A CLASSIC EXAMPLE.
SO EFFECTIVE PAIN CONTROL WAS
DEMONSTRATED AT SIX HOURS AFTER
TREATMENT.
THE PAIN ASSESSMENT OCCURRED
WITH MULTIPLE ENDPOINTS WHICH
WAS BOTH LAMENESS SCORE AND
CONTACT AREA AND FORCE.
AND THIS WAS REPLICATED AT TWO
LOCATIONS SHOWING THAT THIS
EXPERIMENTAL MODEL WAS AN
EFFECTIVE MODEL IN INDUCING
LAMENESS AND DEMONSTRATING THAT
THE USE OF THESE MULTIPLE
ENDPOINTS WAS USEFUL IN TERMS OF
ASSESSING ANALGESIC EFFECTS IN
FOOT ROT.
SO TO FINISH UP, JUST SOME WORK
IN PROGRESS.
MY GRADUATE STUDENT TRIED TO
DEVELOP A COMPOSITE ENDPOINT
SCALE FOR THESE PHYSIOLOGICAL
OUTCOMES BY NORMALIZING THE DATA
USING NORMALIZATION EQUATION.
SO HE WAS TRYING TO GET DATA ON
TO A 0-10 SCALE WITH X BEING THE
INDIVIDUAL VALUE EACH ANIMAL.
THE X MAX BEING THE MAXIMUM
RESPONSE AND THE X MIN BEING THE
MINIMUM RESPONSE WE OBSERVED.
ENDPOINTS WERE CORTISOL,
MECHANICAL THRESHOLD, OCULAR
THERMOGRAPHY, THE DIFFERENCE IN
TEMP BETWEEN A HORN AND THE EYE
AND HEART RATE AND WE HAD 185
CALFS AND THEY WERE RANDOMIZED
INTO GROUPS AND THERE WAS ALSO A
SHAM GROUP THAT WAS NOT EXPOSED
TO THE DE-HORNING PROCEDURE.
ALL THE DRUGS WERE ADMINISTERED
IN TWO MILLIGRAMS PER KILO GRAM.
SO WHEN WE ANALYZED THESE DATA
USING CONVENTIONAL STATISTICS,
WE DIDN'T SEE ANYTHING THAT WAS
SUPER EXCITING.
SO THE GREEN AND THE RED ARE
SIGNIFICANTLY DIFFERENT AND THE
YELLOW WERE NOT SIGNIFICANTLY
DIFFERENT FROM THE OTHER GROUPS.
AND SO, FOR THE SAME CHANGE IN
HEART RATE, WE SAW A SIGNIFICANT
DIFFERENCE BETWEEN THE ANIMALS
THAT RECEIVED -- AND SHAM GROUP
COMPARED WITH THE OTHER GROUPS
IN THE STUDY.
WE DIDN'T SEE ANYTHING
SIGNIFICANT EXCEPT THIS GROUP
FOR THE SAME CHANGE IN OCULAR
DEMORNING TEMPERATURE.
MECHANICAL THRESHOLD NO
DIFFERENCE BETWEEN THE TREATMENT
GROUPS.
THERE WAS ONLY A DIFFERENCE
BETWEEN TREATMENT AND SHAM AND
THEN AVERAGE DAY-TO-DAY NO
DIFFERENCE ACROSS-THE-BOARD.
WHEN MAT DID HIS ADJUSTMENTS OF
THE DATA, HE DID OBSERVE THERE
WAS SEPARATION THAT OCCURRED
BETWEEN THE DIFFERENT GROUPS.
THE PLACEBO AND THE GROUP THAT
RECEIVED THE -- HAD THE HIGHEST
PAIN STRESS INDEX WHEN HE DID
THE NORMALIZATION PROCEDURE AND
THAT WAS SIGNIFICANTLY DIFFERENT
AT 4 AND 8 HOURS COMPARED WITH
THE OTHER GROUPS.
AND THEN OF COURSE THE SHAM
GROUP WAS SIGNIFICANTLY
DIFFERENT FROM ALL OF THEM
THROUGHOUT THE STUDY.
BUT THAT DIFFERENCE WAS LAST
AFTER 24 HOURS.
SO THE TAKE HOME MESSAGE IS
THERE ARE SOME OPPORTUNITIES FOR
US TO PERHAPS REFINE THESE
COMPOSITE SCORES IN THE FUTURE
IN A WAY THAT MAKES SENSE FOR US
TO BE ABLE TO ANALYZE THESE
PHYSIOLOGICAL ENDPOINTS.
SO APPRECIATE YOUR TIME AND
ATTENTION TODAY.
THE CONCLUSIONS THAT WE STILL
NEED THESE ANALGESIC DRUGS IN
FOOD ANIMALS BECOMING CRITICALLY
IMPORTANT FOR US IN TERMS OF
MEETING SOME OF THE CONSUMER
CONCERNS ABOUT HOW CATTLE ARE
BEING RAISED AND PIGS.
CONSIDERABLE PROGRESS IS BEING
MADE IN VALIDATING THESE METHODS
AND WE STILL HAVE OPPORTUNITIES
TO THE REFINE THEM AND
PARTICULARLY IN TERMS OF
VALIDATION.
SO THAT'S ALL I HAVE.
I ACKNOWLEDGE MY FUNDING
AGENCIES TODAY AND THANK YOU FOR
YOUR TIME AND ATTENTION.
APPRECIATE IT.
[ APPLAUSE ]
>> THANK YOU.
I REMEMBER 15 YEARS AGO WHEN YOU
CAME AND TALKED TO FDA.
I'M SURPRISED IT HAS ALREADY
BEEN 15 YEARS.
BUT THANK YOU FOR SHOWING US ALL
THE PROGRESS YOU HAVE MADE.
OUR NEXT SPEAKER IS ANOTHER
COLLEAGUE FROM FDA CENTER FOR
VETERINARY MEDICINE, DR. QIAO
ZHANG.
AND DR. QIAO ZHANG IS A
BIOSTATISTICIAN IN THE OFFICE OF
NEW ANIMAL DRUG EVALUATION.
SHE RECEIVED HER PH.D. IN
STATISTICS AT STONY BROOK
UNIVERSITY IN LONG ISLAND,
NEW YORK.
AND I'D LIKE TO WELCOME HER TO
TALK ABOUT ADAPTIVE AND OTHER
INNOVATIVE PAIN MEASUREMENT
STUDY DESIGNS.
[ APPLAUSE ]
>> GOOD AFTERNOON, EVERYONE.
THANK YOU FOR STAYING FOR THE
LAST TALK.
IT WON'T BE LONG, I PROMISE.
SO I'M GOING TO TALK ABOUT
ADAPTIVE AND NORMATIVE PAIN
MEASUREMENTS STUDY DESIGNS.
SO I WILL START WITH
INTRODUCTION ABOUT THE
DEFINITIONS FOR THE ADAPTIVE
DESIGN AND ENRICHMENT DESIGN
ACCORDING TO THE GUIDANCE 268.
AND THEN I WILL TALK ABOUT TWO
EXAMPLES IN ADAPTIVE DESIGN AND
ONE EXAMPLE IN ENRICHMENT
DESIGN.
AND FINALLY I WILL WRAP UP WITH
SOME TAKE-HOME MESSAGES.
SO THE GUIDANCE, GFI268 PROVIDES
SOME RECOMMENDATIONS AND
CONSIDERATIONS FOR DIFFERENT
TYPES OF ENORMATIVE DESIGNS.
SO ACCORDING TO THE GUIDANCE,
THE ADAPTIVE DESIGN REFERS TO
THE CLINICAL EFFECTIVENESS STUDY
DESIGN THAT ALLOWS FOR
PROSPECTIVELY PLANNED
MODIFICATIONS.
AND THE MODIFICATIONS MAY IMPACT
THE SAMPLE SIZE OR THE DURATION
OF THE STUDY.
THE ENDPOINT AND OTHER STUDY
FEATURES AS WELL.
THE ENRICHMENT DESIGN REFERS TO
PROSPECTIVE USE OF ANY
CHARACTERISTIC TO SELECT A STUDY
POPULATION.
AND IT IS MORE LIKELY TO DETECT
THE DRUG EFFECT IN THAT SELECTED
POPULATION THAN THE UNSELECTED
POPULATION.
FOR EXAMPLE, THE HIGH PLACEBO
EFFECT IS ALWAYS A CONCERN IN
THE PAIN MEASUREMENT STUDIES AND
WE WOULD LIKE TO SELECT THOSE
PATIENTS NOT RESPONDING TO THE
PLACEBO AND EXPECT TO DETECT A
HIGHER -- IN THIS POPULATION.
I'LL TALK MORE ABOUT THIS
EXAMPLE WHEN I INTRODUCE THE
PLACEBO DESIGN.
SO I THINK THE COMMON KEYWORD
FOR THESE TWO DESIGNS ARE
PROSPECTIVE.
SO THAT MEANS ALL THE ADAPTATION
OR ENRICHMENT FEATURES NEED TOUR
PRE SPECIFIED IN THE PROTOCOL
AND THIS IS ALSO POINTED OUT IN
THE GUIDANCE.
SO IN THE PROTOCOL, I NEED TO
SPECIFY THE NUMBER AND TIMING OF
THE INTERIM ANALYSIS.
THE STATISTICAL ANALYSIS METHODS
AND THE ADAPTATION CRITERIA AND
ALGORITHM GOVERNING FOR
ADAPTATION DECISIONS.
SO AS DR. RUBERMAN INTRODUCED,
THE EXPLORATORY STUDY AND THE
CONFORM TERRI STUDY MAY HAVE
DIFFERENT PURPOSE.
SO THEREFORE THEY MAY REQUIRE
DIFFERENT STATISTICAL JUDGMENTS.
SO THE GUIDANCE 268 PROVIDES
GENERAL RECOMMENDATIONS FOR THE
CONFIRMATORY STUDIES.
SO -- THE TALK I'M GOING TO GIVE
TODAY ALSO FOCUS ON CONFIRMATORY
STUDIES ONLY.
BUT ALL THE METHODS WE DISCUSS
TODAY AND IN THE GUIDANCE ARE
ALSO APPLICABLE TO THE
EXPLORATORY STUDIES JUST WITH
FEWER RESTRICTIONS ON THE
ADJUSTMENTS FOR MULTIPLICITY.
HERE IS DIAGRAM TO SHOW YOU A
STANDARD ADAPTIVE DESIGN.
SO ALL THE KEY DESIGN FEATURES
NEEDS TO BE PRE SPECIFIED
CHOOSING THE HYPOTHESIS, THE
POWER, THE SAMPLE SIZE, TIMING
AND RULES FOR THE INTERIM
ANALYSIS, IA.
AND THEN AFTER THE STUDY IS
INITIATED AND ALL THE PATIENTS
ARE ENROLLING, THE INTERIM
ANALYSIS WILL BE CONDUCTED AT A
PLANNED TIME POINT AND BASED ON
THE INTERIM ANALYSIS RESULTS, WE
MAY MAKE ADAPTATIONS ON SAMPLE
SIZE OR TO STOP THE STUDY EARLY
FOR FEW UTILITY OR STOP THE
STUDY EARLY FOR EFFECTIVENESS OR
SOME OTHER ADAPTATIONS BY
DESIGN.
AND IF THE STUDY IS NOT STOPPED
FOR ANY REASON, IT WILL JUST
CONTINUE TO THE END AS PLANNED
AND A FINAL ANALYSIS WILL BE
CONDUCTED AND DRAW CONCLUSIONS.
TO ILLUSTRATE THE IDEA, I WILL
SHOW ONE INTERIM ANALYSIS HERE
BEING PRACTICED.
YOU MAY CONDUCT MORE THAN ONE
INTERIM ANALYSIS BUT MULTIPLE
INTERIM ANALYSIS MAY GIVE RISE
TO THE CONCERN OF THE STUDY
INTEGRITY DUE TO THE OPERATIONAL
BIAS.
SO -- MAY BE APPLIED
ACCORDINGLY.
THIS IS JUST SOMETHING YOU MAY
NEED TO KEEP IN MIND WHEN
DESIGNING ADAPTIVE DESIGN STUDY.
AND ALL THESE ADAPTATIONS MAY
APPLY TO ANY STUDY WITH
DIFFERENT TYPES OF ENDPOINTS.
IN TERMS OF THE PAIN MEASUREMENT
STUDIES, I CONSIDER THE
ADAPTATION IN SAMPLE SIZE AND
ADAPTATION TO STOP THE STUDY
EARLY FOR FEW UTILITY MAY BE
MORE FEASIBLE AND MORE
BENEFICIAL THAN THE OTHER TYPES
OF ADAPTATIONS.
SO NOW I'M GOING TO INTRODUCE
THE FIRST EXAMPLE.
THE SAMPLE CISORY ESTIMATION.
IT GIVES US A CHANCE TO MODIFY
AND EMPHASIZE DURING THE
UNDERGOING STUDY.
WE CALL IT BLINDED VERSUS
UNBIDDED.
IN THE BLINDED SSR, FOR EXAMPLE,
IN ONCOLOGY STUDY, THE NUMBER OF
EVENTS IS THE KEY FACTOR TO
DETERMINE THE POWER.
SO, WE WOULD LIKE TO MONITOR THE
EVENT RATE DURING THIS STUDY AND
IF THE EVENT RATE IS SMALLER
THAN EXPECTED, WE MAY WANT TO
INCREASE TOTAL SAMPLE SIZE TO
ACHIEVE THE TARGET NUMBER OF
EVENTS.
SO THAT'S A BLINDED DESIGN.
I THINK IN THE PAIN MEASUREMENT
STUDIES, IT'S LESS COMMONLY
USED.
BUT ONE ADVANTAGE OF BLINDED SSR
IS THAT IT IS GENERALLY BELIEVED
TO HAVE LIMITED OR NO IMPACT ON
THE FAMILY WISE ERROR RATE,
WHICH YOU MAY RECALL IS THE
PROBABILITY OF MAKING ONE FALSE
POSITIVE DECISION AMONG ALL THE
HYPOTHESIS TESTED.
SO ON THE OTHER HAND, THE
UNBLINDED SAMPLE SIZE ESTIMATION
ALLOWS TO ESTIMATE DURING THE
STUDY, HOWEVER THAT WOULD
INFLATE THE FAMILY WISE ERROR
RATE BECAUSE YOU DO USE THIS
REPEATEDLY.
SO APPROPRIATE METHOD SHOULD BE
APPLIED TO CONTROL THAT ERROR.
HERE IS ONE EXAMPLE.
THE CONDITION POWER.
THIS IS THE PROBABILITY THAT THE
FINAL STUDY RESULT WILL BE
STATISTICALLY SIGNIFICANT GIVEN
THE DATA OBSERVED SO FAR.
FOR EXAMPLE, IF WE WOULD LIKE TO
COMPARE THE TREATMENT ARM AND
CONTROL ARM, COMPARED TO SUCCESS
RATE BETWEEN TWO GROUPS, THE
INTERIM ANALYSIS WE OBSERVED 30%
THAT WE MAY ASK WHAT IS THE
PROBABILITY OF STATISTICAL
SIGNIFICANCE BY THE END OF THE
STUDY?
SO THAT MEANS WE ARE USING WHAT
WE HAVE OBSERVED SO FAR TO
PREDICT A RESULT BY THE END OF
THE STUDY.
GIVEN THE ASSUMPTION THAT THIS
WILL HOLD TRUE FOR THE REST OF
THE STUDY.
SO, THERE ARE SEVERAL
STATISTICAL METHODS THAT WE CAN
USE TO DO THE CALCULATION.
WE APPLY ONE OF THEM AND ACHIEVE
A RESULT OF 65%.
SO WHAT DOES THAT MEAN?
HOW ARE WE GOING TO MAKE
DECISIONS BASED ON THE
OBSERVATION?
THE BOTTOM GIVES YOU A SERIES OF
DECISION RULES THAT YOU MAY
APPLY IN THE STUDY.
BEFORE THE INTERIM ANALYSIS IS
CONDUCTED, WE WOULD LIKE TO
PRE-SELECT A MINIMUM CONDITIONAL
POWER AND TARGET CONDITIONAL
POWER.
THE CP MINIMUM IS A THRESHOLD
SUCH THAT IF THE OBSERVED
CONDITIONAL POWER IS SMALLER
THAN THIS NUMBER, WE CONSIDER
THE STUDY TO BE NOT PROMISING
AND HAS SMALL CHANCE TO SUCCEED.
SO IN THIS CASE, WE PROBABLY
WILL STOP THE STUDY FOR
FUTILITIY.
BUT IF IT IS OBSERVED BETWEEN
THE TWO NUMBERS, WE MAY CONSIDER
THE STUDY IS PROMISING BUT MAYBE
UNDER POWERED.
SO IN THIS CASE, WE MAY INCREASE
THE SAMPLE SIZE TO ACHIEVE THE
TARGET POWER.
AND LAST, IF THE OBSERVED
CONDITIONAL POWER IS LARGER THAN
YOUR TARGET POWER, THEN THE
STUDY SHOULD CONTINUE TO
ORIGINAL SAMPLE SIZE WITHOUT ANY
MODIFICATIONS.
SO, I THINK SSR IS QUITE
SELF-EXPLANATORY.
IT CAN HELP AVOIDING THE UNDER
POWERING ISSUE, LIKE IF YOU
OBSERVE LIKE A HIGHER PLACEBO
EFFECT IN A STUDY AND MAYBE
OVERESTIMATE AN EFFECT AND IN
THIS CASE YOU MAY HAVE A CHANCE
TO SAVE THE STUDY BY INCREASING
THE SAMPLE SIZE.
BUT ALSO, WE NEED TO CONSIDER
THE CONTROL OF ERRORS AND
BIASES.
THE FIRST ONE IS THE FAMILY WISE
ERROR RATE BECAUSE YOU DO
CONDUCT TESTING DURING THIS
PROCESS.
ALSO OVERPOWERING THE STUDY.
THAT MEANS YOU SELECT A SAMPLE
SIZE THAT CAN POWER A TEST OR
DETECT -- SO SMALL IT IS NO
LONGER CLINICALLY RELEVANT.
I THINK YOU MAY ADJUST THIS
ISSUE BY PRE SPECIFYING A
CLINICALLY-MEANINGFUL EFFECT
INSTEAD OF JUST COMPARING THE
RESULT TO ZERO BY DEFAULT.
ALSO ADAPTATIONS MAY BRING BIAS
INTO THE STUDY AND SO IN THIS
CASE, SOME STRAT GEWILL NEED TO
BE APPLIED TO MAINTAIN THE STUDY
INTEGRITY AND VALIDITY.
FOR EXAMPLE, YOU MAY WANT TO
CONSULT A THIRD STATISTICIAN TO
ASSESS THE ADAPTATION AND ALSO
YOU WILL LIKE TO MINIMIZE THE
BIAS AND MAINTAIN MASKING WHEN
YOU COMMUNICATE THE ADAPTATION
RESULTS.
AND ALSO TIMING IS VERY
IMPORTANT.
IF YOU CONDUCT THE ADAPTATION
TOO EARLY, YOU MAY BE MISGUIDED
BY THE UNRELIABLE ESTIMATES DUE
TO THE HIGHLY-VARIABLE SAMPLES.
AND IF YOU CONDUCT ADAPTATION
TOO LATE, THEN THERE IS A VERY
LIMITED WINDOW TO ADAPT A STUDY.
SO I THINK SSR WILL BE MORE
BENEFICIAL TO A STUDY WITH
RELATIVELY LONG ENROLLMENT
PROCESS, BUT SHORT OBSERVATION
WINDOW.
FOR EXAMPLE IF YOU HAVE A STUDY
PROBABLY WE NEED ABOUT AT LEAST
A YEAR TO FINISH ENROLLMENT BUT
YOUR ENDPOINT OBSERVATION WILL
BE LIKE ON DAY 30, PROBABLY IT
MAY BE WORTH TO TAKE A LOOK AT
THE STUDY AND THE RESULTS AND
SEE IF YOU NEED TO JUSTIFY THE
SAMPLE SIZE.
ALSO LAST CRASH IS STATISTICAL
METHODS.
ALTHOUGH THERE ARE SOME EXISTING
STATISTICAL METHODS TO CONDUCT
SSR, BUT THOSE METHODS MAY NOT
BE DIRECTLY APPLICABLE TO THE
ANIMAL STUDIES -- SORRY, ANIMAL
CLINICAL TRIALS, WHICH WE HAVE
DIFFERENT STUDY DESIGN STANDARDS
HUMAN CLINICAL TRIALS.
SO DESIGNING STUDY WITH SSR, ALL
THESE CONCERNS SHOULD BE TAKEN
INTO CONSIDERATION.
THE NEXT EXAMPLE WE TALK ABOUT
IS THE GROUP SEQUENTIAL DESIGN.
THIS DESIGN GIVES YOU A CHANCE
TO PROSPECTIVELY COMPARE THE
RESULTS AND WITH THE OPPORTUNITY
TO STOP THE STUDY EARLY FOR
EFFECTIVENESS.
AGAIN, YOU WILL NEED TO PRE
SPECIFY THE TIMING TO THE KEY
STUDY FACTORS AT A PLANNED
STAGE.
AND AFTER THE STUDY IS
INITIATED, YOU WILL LIKE BY THE
TIME OF THE FIRST INTERIM
ANALYSIS, YOU CONDUCT HYPOTHESIS
TESTING AND COMPARE THE P-VALUE
OBTAINED FROM THE TESTING TO A
PRE SPECIFIED ALPHA LEVEL,
CALLED ALPHA 1 HERE.
IF THE P-VALUE IS SMALLER THAN
THE ALPHA LEVEL, THAT MEANS THE
EFFECT YOU OBSERVED SO FAR IS
QUITE PROMISING AND YOU MAY STOP
THE STUDY FOR EARLY FOR
EFFECTIVENESS.
BUT IF IT'S LARGER THAN ALPHA 1,
YOU WILL NEED TO CONTINUE THE
STUDY UNTIL THE NEXT INTERIM
ANALYSIS.
AND THIS WHOLE PROCESS CAN BE
REPEATED UNTIL EITHER THE STUDY
IS STOPPED FOR EFFECTIVENESS
EARLY OR YOU CONTINUE TO THE END
AS PLANNED.
AND THEN A FINAL ANALYSIS SHOULD
BE CONDUCTED.
I WOULD LIKE TO DRAW ATTENTION
TO THE ALPHA LEVELS HERE.
ALPHA 1 AND ALPHA F.
ALL ARE SELECTED SUCH THAT THE
FAMILY WISE ERROR RATE IS
CONTROLLED.
SO, USUALLY THEY ARE MUCH
SMALLER THAN ALPHA LEVEL OF .05.
I GIVE YOU EXAMPLE IN THE NEXT
SLIDE.
SO THE GROUP SEQUENTIAL DESIGN
PROVIDES A CHANCE TO STOP THE
STUDY EARLY.
SO IT GENERALLY WILL REDUCE
EXPECTED SAMPLE SIZE AND THE
DURATION OF THE CLINICAL TRIALS.
BUT IN TERMS OF THE CONCERNS,
THE FIRST IS THE FAMILY WISE
ERROR RATE.
YOU'RE CONDUCTING MULTIPLE
TESTING, SO OF COURSE THE FAMILY
WISE ERROR RATE WILL BE
INFLATED.
IN THIS CASE, YOU WOULD NEED TO
ADJUST THE ALPHA LEVEL YOU WOULD
LIKE TO USE FOR EACH TEST.
HERE AT THE TABLE, IT SHOWS YOU
THE RELATIONSHIP BETWEEN THE
ALPHA LEVEL AND THE NUMBER OF
TESTING YOU WOULD LIKE TO
CONDUCT.
FOR EXAMPLE, IF YOU LIKE TO
CONDUCT TWO INTERIM ANALYSIS AND
ONE FINAL ANALYSIS, AND WOULD
LIKE TO USE THE SAME ALPHA LEVEL
FOR EACH TEST, THEN YOU NEED TO
COMPARE THE P-VALUE TO .022 FOR
EACH TEST.
AND AS THE NUMBER OF TESTS
INCREASES, THE ALPHA LEVEL FOR
EACH TEST WILL DECREASE
ACCORDINGLY.
SO THIS ALPHA LEVEL SHOULD BE
PRE SPECIFIED AS THEY NOT ONLY
JUST IMPACT THE FAMILY WISE
ERROR RATE, IT DEFINITELY IMPACT
YOUR POWER.
SO WE NEED THIS CRITERIA TO
CONDUCT THE POWER CALCULATION
FOR YOUR STUDY.
THE TIMING OF THE GROUP
SEQUENTIAL DESIGN IS IMPORTANT.
YOU WOULD LIKE TO TIME THIS SUCH
THAT IF THE TEST IS SIGNIFICANT,
STATISTICAL SIGNIFICANT.
YOU STILL HAVE SUFFICIENT SAMPLE
SIZE TO GENERALIZE YOUR RESULTS
TO THE TARGET POPULATION.
ALSO YOU WOULD LIKE TO HAVE
SUFFICIENT SAMPLE SIZE TO
ACHIEVE INDEPENDENT EVIDENCE AND
ALSO PROVIDE RELIABLE ASSESSMENT
OF SAFETY VARIABLES.
SO, THE STATISTICAL SIGNIFICANCE
HERE IS UNNECESSARY BUT NOT
SUFFICIENT.
THE CLINICAL RELEVANCE PLAYS A
VERY IMPORTANT ROLE TO DECIDE
WHETHER THE STUDY SHOULD BE
STOPPED FOR EFFECTIVENESS.
NOW LET'S SWITCH GEARS TO THE
ENRICHMENT DESIGN.
SO THE PLACEBO LEAD IN DESIGN IS
QUITE SELF-EXPLANATORY BY ITS
NAME.
SO ALL THE ELIGIBLE PATIENTS
WILL RECEIVE PLACEBO AND THEY
WILL BE OBSERVED FOR SOME
PERIOD.
WE CALL THIS PLACEBO-LEAD IN
PERIOD.
BY THE END OF THE PERIOD, EACH
PATIENT WILL BE CATEGORIZED AS
EITHER THE PLACEBO RESPONDER OR
NON RESPONDER BASED ON
CLINICALLY RELEVANT CRITERIA.
AND ONLY NON RESPONDERS WILL BE
OFFICIALLY ENROLLED INTO THE
STUDY AND WILL BE RANDOMIZED TO
EITHER THE TREATMENT ARM OR THE
PLACEBO ARM.
AND IN A STANDARD DESIGN TO
RESPONDERS WILL NOT BE FOLLOWED
ANYMORE.
SO THE EXPECTATION OF USING THIS
METHOD IS TO MITIGATE A PLACEBO
EFFECT.
HOWEVER, THIS BENEFIT IS QUITE
DEBATABLE.
ACCORDING TO A META-ANALYSIS
BASED ON 101 DEPRESSION STUDIES,
THIS PLACEBO EFFECT WAS NOT
DECREASED AS EXPECTED.
SO IT COULD BE DUE TO THE
LEAD-IN PERIOD WAS TOO SHORT.
I REMEMBER IT WAS SEVEN DAYS AND
SOME RESPONDERS MAY NOT HAVE
SUFFICIENT TIME TO SHOW THEIR
RESPONSE.
ALSO, IT COULD BE DUE TO THE
PATIENTS AND THE INVESTIGATORS
WERE NOT WELL HAVOCKED TO THE
STUDY FUTURE.
SO THERE WERE SEVERAL UPDATED
VERSIONS OF THIS PLACEBO LEAD-IN
DESIGN.
FOR EXAMPLE, MOST OF THE
PATIENTS AND THE INVESTIGATORS
ARE MASKED TO THE DURATION OF
THE LEAD-IN PERIOD SO THEY WILL
HAVE EXPECTED EXPECTATIONS ABOUT
THE RESPONSE.
AND ALSO, IN SOME STUDIES, THE
PLACEBO RESPONDERS WILL STAY IN
THE STUDY TO MAINTAIN MASKING.
SO SOME STRATEGIES MAY BE USED
TO IMPROVE THE DESIGN.
ONE ADVANTAGE OF USING THE
PLACEBO LEAD-IN DESIGN IS THAT
THE ENRICHMENT WAS CONDUCTED
BEFORE THE RANDOMIZATION AND
THIS WILL NOT REQUIRE A FORMAL
ALPHA ADJUSTMENT.
BUT I THINK THE MAIN CONCERN FOR
THIS METHOD IS THAT IT MAY NOT
BE GENERALIZABLE TO TARGET
POPULATION.
FOR EXAMPLE, IF THE RESULT WE
OBTAINED BASED ON THE PLACEBO
NON-RESPONDERS, MAY NOT BE THE
SAME AS THE RESPONDERS.
SO THEREFORE THE RESULTS MAY NOT
BE GENERALIZABLE TO THE WHOLE
POPULATION.
SO THEREFORE WE MAY NEED TO HAVE
LABELING IMPLICATIONS OR HAVE A
NARROWER INDICATION TO REFLECT A
SUB POPULATION STUDY.
TO WRAP IT UP, I THINK THE
KEYWORD FOR THIS TOPIC IS
PROSPECTIVE.
SO IF YOU WOULD LIKE TO USE ANY
ADAPTATION OR ENRICHMENT IN YOUR
STUDY, YOU WILL NEED TO
PROSPECTIVELY SPECIFY ALL THE
KEY FEATURES OR ADAPTATION RULES
AT A PLANNED STAGE.
ALSO THE STATISTICAL HYPOTHESIS
TESTING METHODS SHOULD BE
APPLIED TO PUBLICLY CONTROLLED
FAMILY WISE ERROR RATE.
ALSO WE MAY NEED TO PAY EXTRA
ATTENTION TO THE
GENERALIZABILITY OF THE
EFFECTIVENESS DATA -- RESULTS.
SO IF YOU PLAN TO PLAN A STUDY
WITH ANY ADAPTATIONS OR
ENRICHMENT, I HIGHLY ENCOURAGE
THE EARLY INVOLVEMENT OF A
STATISTICIAN BECAUSE IT WOULD
FACILITATE A WHOLE PROCESS AND
MAKING THE COMMUNIQUESES MORE
EFFICIENT.
AND HERE ARE THE REFERENCES I
USED.
AND THANK YOU FOR YOUR
ATTENTION.
[ APPLAUSE ]
>> THANK YOU VERY MUCH TO ALL OF
OUR SPEAKERS.
I'D LIKE TO INVITE OUR SPEAKERS
UP FOR THE PANEL DISCUSSION.
>> WHAT MIGHT BE SOME
CONSIDERATIONS FOR ADAPTIVE
SELECTION OF A PRIMARY ENDPOINT
AMONG MULTIPLE CANDIDATE POINTS.
>> THAT'S A HARD QUESTION.
REALLY.
SO THERE IS SUCH A DESIGN AS
ADAPTIVE ENDPOINT SELECTION
DESIGN.
IN THIS DESIGN IT BASICALLY
IS -- WE'LL START WITH MULTIPLE
ENDPOINTS AND THEN AFTER THE
FIRST STAGE THEN SOME
ADAPTATIONS WILL BE APPLIED AND
YOU WILL CHOOSE THE FINAL
ENDPOINT BASED ON THIS DESIGN.
I THINK ALONG WITH THE OTHER --
LIKE ALL THE OTHER ADAPTATIONS,
AGAIN ALL THE RULES, ADAPTATION
RULES AND STUDY DESIGN AND
STATISTICAL METHODS, SHOULD BE
PRE SPECIFIED.
BUT ALONG WITH THAT, THE AAT
THAT POINTIVE SELECTION IN
ENDPOINTS ACTUALLY WILL INFLATE
THE FAMILY WISE ERROR RATE DUE
TO TWO REASONS.
ONE IS THE MULTIPLE TESTING,
BECAUSE YOU HAVE MULTIPLE
ENDPOINTS AND ANOTHER ONE IS THE
SELECTION PROCESS.
SO THAT BASICALLY WILL REQUIRE
EVEN MORE RIGOROUS CONTROL OF
THE FAMILY WISE ERROR RATE.
AND SOMETIMES THE MULTIPLE
TESTING STRATEGIES ARE SO
COMPLICATED AND IT MAKES IT SO
VERY HARD TO COMMUNICATE WITH
THE CONDITIONS ABOUT THE PROCESS
AND THE RESULTS AND SOMETIMES
THESE MAY BE EVEN DIFFICULT TO
COMMUNICATE WITH THE
STATISTICAL -- AS WELL.
SO IF THIS IS THE METHOD YOU
WOULD LIKE TO USE IN YOUR STUDY,
A MORE EXTENSIVE DISCUSSIONS AND
COMPUTATIONS WILL BE REQUIRED TO
PLAN THE STUDY.
>> SO IF I COULD JUST SAY ONE
THING.
BOTH OF YOU COMMENTED ON THE
DIFFERENCE BETWEEN THE
EXPLORATORY AND CONFIRMED
TRIALS.
AND I THINK IN AN EXPLORATORY
SETTING, ADAPTIVE CHOICE OF
OUTCOMES CAN BE A USEFUL TOOL,
MEANING YOU START OUT WITH
THREE-FOUR, AS I SUGGESTED
BRIEFLY AT THE END OF MY TALK.
YOU MIGHT USE A BIOMARKER AND
YOU'RE LOOKING TO SEE WHEN YOU
ADMINISTER YOUR TREATMENT
WHETHER THE BIOMARKER RESPONDS
IN THE WAY YOU EXPECT IT TO
RESPOND.
AND YOU'RE THEN MEASURING OTHER
FUNCTIONAL OUTCOMES AND OTHER
OUTCOMES AS YOU MOVE FORWARD.
IF YOU FIND THAT THE BIOMARKER
THAT YOU ARE CONVINCED IS
ACTUALLY SHOULD RESPOND TO THE
TREATMENT THAT YOU'RE GIVING,
YOU'RE GETTING A THYROID
MEDICINE AND THE TSH CAN CHANGE,
FOR INSTANCE.
I'M USING A RIDICULOUS EXAMPLE.
BUT THE POINT IS, IF YOU FIND
YOUR BIOMARKER DOESN'T, THAT
MEANS THAT MAYBE THE TREATMENT
ISN'T GETTING TO WHERE IT NEEDS
TO BE.
IT ISN'T BEING ABSORBED.
SOMETHING IS GOING ON WITH IT
AND THEN YOU CAN ABANDON THE
CONTINUED MONITORING OF THE
TRIAL BECAUSE IT'S NOT CAUSING
THE EFFECT THAT YOU THINK.
THAT'S PROBABLY NOT APPLICABLE
TO A CONFIRMATORY TRIAL BUT YOU
PROBABLY WANT, IF YOU HAVE A
BIOMARKER, TO ASSESS WHETHER THE
TREATMENT IS ACTUALLY DOING WHAT
YOU THINK IN THE ANIMAL OR THE
HUMAN.
IT'S PROBABLY A REASONABLE THING
TO INCLUDE IN CONFIRMATORY
TRIALS JUST TO BE SURE THAT THE
LOTS ARE REASONABLE.
THAT THE DRUG DIDN'T GET LEFT IN
THE SUN AND BAKED TO DEATH.
SO YOU CAN MAKE SURE THAT YOU'RE
DOING WHAT YOU THINK.
>> ONE OF THE DISCUSSIONS WE
HAVE ON THE FOOD ANIMAL SIDE
ALWAYS IS HOW LONG THE
CLIMATIZATION PERIOD SHOULD BE
AND WHETHER THE CLIMATIZATION
PERIOD IS BEING SUFFICIENT AND
EFFECTIVE TO BE ABLE TO GIVE US
MEANINGFUL DATA WHEN WE PULL THE
TRIGGER ON THE STUDY ITSELF.
SO I THINK MEASURING SOME OF OUR
PROSPECTIVE ENDPOINTS IN THESE
ANIMALS ON ARRIVAL AND THEN
RE-MEASURING THEM CLOSER TO THE
START OF THE STUDY TO SEE
WHETHER THEIR POPULATIONS WITHIN
OUR POPULATION THAT HAVEN'T
ACCLIMATED WELL TO OUR FACILITY,
THAT COULD MAKE OUR TRIALS MORE
POWERFUL BY BEING ABLE TO HAVE
THAT ASSESSMENT TOOL IN TERMS OF
MAKING BETTER DECISIONS WITH THE
STUDY POPULATION.
>> JUST IN HUMANS, WHAT THAT
MEANS IS WE MEASURE PAIN FOR
SEVEN DAYS BEFORE YOU ENROLL
THEM IN THE TRIAL.
WE ARE LOOKING TO SEE THAT
PATIENTS ARE ABLE TO DO WHAT WE
ARE ASKING OF THEM.
AND THERE IS A RUN-IN PROCEDURAL
RUN-IN THAT IS VERY, VERY
EFFECTIVE IN MAKING SURE THAT
YOU GET PATIENTS WHO CAN
ACTUALLY DO WHAT YOU'RE THINKING
ABOUT.
BECAUSE WHEN YOU ENROLL PEOPLE
IN TRIALS, THEY TEND TO GET
BETTER IN PAIN STUDIES IN
PARTICULAR, AND WE CAN TALK
ABOUT THE PLACEBO RUN-IN.
I HAVE TO SAY, I DISAGREE WITH
THAT PROCESS.
BUT THE ISSUE IS THE SAME HERE.
WE WANT TO CLIMATIZE PEOPLE TO
THE PROCEDURES THAT WE'RE DOING
AND MAKE SURE THEY ARE WILLING
TO DO THEM BEFORE YOU RANDOMIZE
THEM.
SO IT'S THE SAME KIND OF THING.
>> THANK YOU.
THANK YOU VERY MUCH FOR THE
PRESENTATIONS.
I HAD JUST A COUPLE OF QUESTIONS
IF YOU DON'T MIND, STATISTICALLY
RELATED.
SO IN PAIN STUDIES, WHAT'S THE
FAVORED WAY, BEST WAY -- I'D
LIKE YOUR THOUGHTS ON HOW TO
HANDLE MISSING DATA.
SHOULD WE BE LOOKING AT LAST
OBSERVATION CARRIED FORWARD,
USING A MEAN OF THE REST OF THE
SUBJECTS IN THAT GROUP AT THAT
TIME POINT?
MANY STATISTICAL PACKAGES WANT A
COMPLETE DATASET.
>> THAT'S A GREAT QUESTION.
I THINK PROBABLY THE ANSWER
DIFFERS A LITTLE BIT BETWEEN
ACADEMIC AND REGULATORY SETTING.
I THINK OFTEN IN A REGULATORY
SETTING, WE AREN'T USING AS MANY
IMPLEMENTATION METHODS.
SO WE MAY BE LOOKING AT -- IF WE
HAVE THE BINARY END POINT,
LOOKING AT THE DEFINED TREATMENT
FAILURES POTENTIALLY FOR ANIMALS
WHO ARE WITHDRAWN EARLY AND
LOOKING TO MINIMIZE MISSING
DATA.
BUT IT CERTAINLY -- I THINK IT'S
HARDER TO IMPROSECUTE THE
STUDIES WE'RE LOOKING AT.
>> I THINK AT LEAST IN HUMAN
STUDIES, THERE IS A DIFFERENCE
BETWEEN DIFFERENT KINDS OF
MISSING DATA.
IF YOU MISS A COUPLE OF POINTS
IN MEASURING THE DATA OR YOU
LOSE SOME DATA, BY THE END YOU
HAVE FOLLOW-UP DATA.
THAT'S A SITUATION WHERE
IMPLEMENTATION IS VERY OFTEN
USED TO GET A SENSE OF WHAT
WOULD HAVE HAPPENED IN BETWEEN.
YOU DON'T REALLY HAVE TO DO
THAT.
YOU CAN JUST USE THE DATA THAT
IS AVAILABLE IN THOSE
CIRCUMSTANCES.
IT'S WHY PATIENTS DROP OUT OR
YOU STOP COLLECTING DATA.
THERE IS A STRONG ARGUMENT FOR
NOT HAVING THEM DROP OUT FROM
THE COLLECTION OF THE DATA BUT
JUST DROP OUT FROM USING THE
DRUG.
AND YOU CAN INFER THINGS ABOUT
THE PATIENTS RELATED TO THAT.
THERE IS A NATIONAL ACADEMY OF
SCIENCE PIECE THAT TALKS ABOUT
THAT IN SPECIFIC AND BASICALLY
MIXED MODELING IS WHAT IS DONE
TO TRY TO USE ALL THE DATA THAT
IS AVAILABLE TO YOU.
IN TERMS OF DRAWING GRAPHS AND
OTHER THINGS, YOU HAVE TO DO
SOMETHING AND IT CAN GET VERY
COMPLICATED THERE.
BUT THERE ARE SOME VERY
STRAIGHTFORWARD WAYS OF TRYING
TO HANDLE IT.
THE BOTTOM LINE IS, IF YOU HAVE
GOT 20% MISSING DATA, YOU'RE
PROBABLY OKAY.
IF YOU HAVE GOT 40% OR SOMETHING
HIGHER, THEN YOU'RE DONE.
AND THE LAST COMMENT IS THAT IF
YOU DO A RESPONDER ANALYSIS, AND
WE TALKED A LOT THIS MORNING
ABOUT THAT, THEN MISSING --
PEOPLE WHO DROP OUT ARE NON
RESPONDERS BY DEFINITION.
SO THERE ISN'T ANY MISSING DATA
IN THAT SENSE.
AND SO, THE NICE THING ABOUT A
RESPONDER ANALYSIS IS THAT IT
DOESN'T EXPLAIN WHY THEY DROPPED
OUT AND SIDE EFFECTS AND LACK OF
EFFICACY.
BUT IT DOES ACCOUNT FOR THE FACT
THAT THEY ARE NOT THERE ANYMORE.
>> THANK YOU.
I HAVE ONE MORE QUESTION.
SO YOU MENTIONED RESPONDER
ANALYSIS.
WE TALKED ABOUT SUCCESS FAILURE.
AND AS WE SEE MORE OF THESE
RESULTS COMING OUT IN STUDIES,
WE CAN SEE THE DELTA VARIES
QUITE A BIT.
SUCCESS FAILURE DELTAS AND
OBVIOUSLY INCREASED SAMPLE SIZE.
YOU CAN GET THAT P-VALUE WHERE
YOU WANT IT, BUT ANY THOUGHTS ON
WHAT IS AN APPROPRIATE DELTA
BETWEEN SUCCESS IN THE TREATMENT
AND PLACEBO GROUP?
HOW SEPARATED DO THEY NEED TO
BE?
IS THERE A DEGREE OF SEPARATION
THAT GIVES YOU BETTER FEELING
COLLECTIVELY ABOUT THE
THERAPEUTIC?
>> SO, I WANT TO BE VERY CLEAR
ABOUT SOMETHING THAT JEN WATERS
SAID, WHICH IS THAT THE
CLINICALLY-IMPORTANT DIFFERENCE
OR THE MINIMALLY-IMPORTANT
DIFFERENCE, WHATEVER, IS
APPLICABLE TO THE INDIVIDUAL.
IT'S NOT APPLICABLE TO THE
STUDY.
AND SO WHAT WE'RE DOING IS
CONVERTING INDIVIDUALS FROM A
NUMBER TO A RESPONDER OR NON
RESPONDER.
YOU THEN CALCULATE THE
PROPORTION OF PEOPLE WHO RESPOND
OR DON'T RESPOND.
THE DIFFERENCE BETWEEN THE
GROUPS IS NOT AN IDENTIFIABLE --
THERE ISN'T A WAY OF DETERMINING
WHAT THAT IS ABSENT
UNDERSTANDING THE DISEASE.
IF I TREAT HEADACHE AND I HAVE A
5% DIFFERENCE IN RESPONSE
BETWEEN TWO DRUGS, I WOULD SAY
THAT IS PROBABLY NOT
SIGNIFICANT.
IF I AM TREATING SEXIST OR
CARDIAC FAILURE AND I HAVE A 5%
CHANGE IN MORTALITY, I'D SAY
THAT'S PRETTY GOOD DIFFERENCE.
SO IT REALLY IS DEPENDENT ON
WHAT YOU'RE LOOKING AT.
AND I DON'T KNOW HOW TO
INTERPRET THAT WITH ANIMALS BUT
I THINK THE POINT IS, IT'S GOING
TO VARY TREMENDOUSLY.
THE PROBLEM THAT WE ARE PLAYING
WITH HERE AND WE WERE TALKING AT
LUNCH, IF YOU HAVE A DRUG THAT
CURES PAIN, JUST YOU TAKE ONE
PILL AND YOU'RE DONE, NO MORE
PAIN, ALL OF THIS IS MOOT.
YOU JUST GIVE PEOPLE THE THING
AND SEE WHAT HAPPENS.
THE TROUBLE IS, WE'RE NOT DOING
THAT.
WE ARE LOOKING AT CHANGES IN 10
OR 10 OR 30%.
AND WHEN WE GET INTO THAT LEVEL,
IT'S VERY HARD TO KNOW WHAT IS
GOING TO BE RELEVANT.
>> THANK YOU.
>> HI, KANSAS STATE.
THIS RESPONDER-NON-RESPONDER AND
EFFECT SIZE ISSUE IS KIND OF
A -- I'M INTERESTED TO HEAR HOW
HOW YOU PULL THESE THINGS APART.
THE LAST SPEAKER MENTIONED
PARSING THE PLACEBO GROUP INTO
RESPONDERS AND NON RESPONDERS,
WHICH I THOUGHT WAS REALLY AN
INTERESTING POINT.
BUT THE QUESTION IS, WHEN YOU
LOOK AT THE RESPONSE TO A DRUG
AND YOU HAVE THE UNIMODAL SHIFT,
YOU CAN INTERPRET.
WHAT HAPPENS WHEN YOU HAVE TWO
MODES?
YOU HAVE A RESPONDING GROUP THAT
IS QUITE SHIFTED FROM THE
NON-RESPONDING GROUP.
DO ANY OF OUR DESIGNS ACCOUNT
FOR THAT KIND OF CONDITION WHERE
THERE IS A CLEAR
RESPONDER/NON-RESPOND RENNER
GROUP?
>> LET ME TRY TO UNDERSTAND YOUR
QUESTION.
SO YOU MEAN, THE TREATMENT GROUP
AND PLACEBO GROUP, THEY HAVE
DIFFERENT TYPES OF DISTRIBUTION?
SORRY.
CAN YOU REPEAT THAT PART?
>> YES, SORRY IF IT'S UNCLEAR.
WHEN YOU GIVE THE DRUG AND YOU
HAVE PATIENTS THAT RESPOND TO
THE DRUG AND PATIENTS THAT DON'T
RESPOND TO THE DRUG -- SO
INSTEAD OF HAVING TA SKEWED
UNIMODAL DISTRIBUTION, YOU HAVE
A BI-MODAL DISTRIBUTION OF
RESPONDERS AND NON RESPONDERS.
THAT IS WHAT I'M ASKING ABOUT.
BECAUSE MOST OF OUR STATISTICAL
ANALYSIS, I MEAN, WE USE THE
UNIMODAL DISTRIBUTION.
>> SO I CAN START THERE.
THERE ARE SOME VERY KEY FEATURES
TO THE STUDY OF PAIN THAT I
THINK ARE IMPORTANT.
IN A GRAPH THAT JENNIFER WAS
NICE ENOUGH TO SHOW, WHICH WAS
SHOWING THE RESULTS IN MULTIPLE
DIFFERENT DISEASES, CRON LOW
BACK PAIN, ET CETERA, THERE WAS
A VERY TIGHT RELATIONSHIP
BETWEEN THE CHANGE IN PAIN AND
THE LEVEL ON THE GLOBAL SCALE.
WHAT ALSO WE TESTED IN THAT
STUDY WAS WHETHER IT MADE A
DIFFERENCE WHETHER YOU GOT THE
PLACEBO OR NOT.
AND IT TURNED OUT THAT THE
PEOPLE WHO RESPONDED IN THE
PLACEBO GROUP HAD EXACTLY THE
SAME CURVE, WHICH WAS REALLY
IMPORTANT BECAUSE IT MEANT THAT
WE WEREN'T DIFFERENTIATING
BETWEEN PEOPLE IN THE TREATMENT
AND PLACEBO GROUP BY DESIGNATING
PEOPLE AS RESPONDERS.
YOUR POINT, AND I'M NOT SURE
THIS IS YOUR QUESTION BUT I'M
GOING TO ANSWER THE QUESTION I
WANT TO ANSWER.
NO MATTER WHAT WE USE, THERE IS
A CERTAIN PERCENTAGE OF PEOPLE
THAT DON'T RESPOND, EVEN WITH
THE VERY BEST THERAPY.
THERE IS A GROUP THAT DON'T
RESPOND.
IT IS INHERENT TO WHAT WE WANT
TO DO IN MEDICINE, AS WE BEGIN
TO PERSONALIZE IT TO TRY AND
UNDERSTAND WHAT THAT GROUP IS
BEFORE.
AND SO BEING ABLE TO DETECT A
GROUP OF PEOPLE IN THE TREATMENT
GROUP WHO DON'T RESPOND IS A KEY
FEATURE OF TRYING TO TREAT
PEOPLE MORE APPROPRIATELY AND
PREVENTING THEIR PAIN.
IN A STUDY WE ARE CONDUCTING OR
FINISHING UP AT THE UNIVERSITY
OF PENNSYLVANIA, WE ARE LOOKING
AT PATIENTS AFTER THE THIRD
MOLAR EXTRACTION WHO GET
IBUPROFEN.
80% OF THEM RESPOND BUT 20%
DON'T.
AND IT TURNS OUT THAT THERE ARE
SOME DIFFERENCES IN BLOOD
MEASURES AND BIOMARKERS THAT
MIGHT HELP US TO IDENTIFY THIS.
THIS IS NOT FINAL BY ANY MEANS
BUT IT TURNS OUT THAT LEUCOCYTE
ACTIVATION, WHICH IS AN
INDICATION OF INFLAMMATORY
PROCESS, IS -- AND PEOPLE WHO
HAVE A LIKE OOCYTE THAT IS VERY
ACTIVATED, THEY RESPOND BETTER
TO THE ANTI-INFLAMMATORY.
AND THE ONES WHO DON'T HAVE A
LOT OF LEUCOCYTE ACTIVATION
DON'T RESPOND AS WELL.
THAT SORT OF MAKES SENSE.
I'M NOT SAYING IT'S TRUE.
I'M JUST SAYING IT MAKES SENSE
FROM THE PERSPECTIVE THAT IF YOU
HAVE GOT A LOT OF
INFLAMMATION -- WOULD WORK.
AND THIS IS A KEY QUESTION.
THAT'S WHY I THINK THE RESPONDER
ANALYSIS APPROACH IS SO
IMPORTANT.
LOOKING FOR THAT BIMODALITY,
LOOKING FOR THE GROUPS THAT
DON'T RESPOND, IDENTIFYING
GENOTYPES OF THOSE PEOPLE,
HOPEFULLY IN ADVANCE, WOULD BE
JUST A BOOM TO OUR TREATMENT OF
ALL DISEASES, FRANKLY.
>> AND JUST TO THINK ABOUT, IF
YOU TALK ABOUT STATISTICAL
METHOD, JUST LIKE THE PLACEBO
DESIGN -- TREATMENT WITHDRAWAL
DESIGN.
IT'S LIKE THE OPPOSITE, EVERYONE
IS RECEIVING THE TREATMENT AND
THE RESPONDERS ARE NON
RESPONDERS WILL BE SEPARATED
AFTER THE LEAD-IN PERIOD AND
THEN ONLY THE RESPONDERS WILL BE
CONTINUED THROUGH THE STUDY AND
SOME OF THEM WILL BE
RERANDOMIZED TO THE PLACEBO
GROUP AND THEN THE ANALYSIS WILL
BE BASED ON THESE PATIENTS ONLY.
I THINK THE SAME ISSUE AS THE
PLACEBO LEAD-IN DESIGN.
HOW ARE YOU GOING TO INTERPRET
THE RESULTS AND HOW ARE YOU
GOING TO GENERALIZE THE RESULTS?
IT WILL BE SOMETHING TO CONSI
CONSIDER.
>> THANK YOU.
DO WE KNOW ABOUT IMPORTANCE OF
PLACEBO EFFECT IN PAIN AND
CLINICAL TRIAL?
IF WE CHOOSE RATHER A COMPOSITE
CRITERIA RATHER THAN -- CRITE
CRITERIA.
FOR THE SAME CLINICAL TRIAL, IF
YOU SELECT A COMPOSITE ENDPOINT
RATHER THAN A MULTIPLE ENDPOINT,
WHAT IS THE PLACEBO EFFECT
IMPORTANCE?
DO WE SEE SOME DIFFERENCE OR
NOT?
BEYOND THE FACT THAT AS IT HAS
BEEN EXPLAINED REGARDING
STATISTICAL APPROACH, THERE IS
PRO AND CONS FOR THE COMPOSITE
OR MULTIPLE.
BUT REGARDING SPECIFICALLY THE
PLACEBO EFFECT, WHAT DO WE KNOW
ABOUT THIS?
>> I THINK THIS IS AN IMPORTANT
QUESTION THAT HAS NOT BEEN
COMPLETELY ANSWERED YET.
BUT, FOR EXAMPLE, IF YOU WERE TO
LOOK AT PHYSICAL FUNCTION VERSUS
REPORT OF PAIN AND DO SOME SORT
OF COMPOSITE WHERE YOU LOOK AT
PAIN PLUS PHYSICAL FUNCTION, THE
ISSUE THERE IS THAT IT MAY BE
THAT PEOPLE SAY, OH, YES, I'M
FEELING BETTER.
BUT THEY DON'T HAVE ANY CHANGE
IN THEIR WALKING ABILITY.
BECAUSE THE PAIN IS STILL THERE
AND THEY ARE STILL LAME BY IT.
SO THERE IS THE POSSIBILITY THAT
IF YOU PICK MORE FUNCTIONAL
MEASURES OR OTHER THINGS, YOU
MIGHT HAVE A SMALLER DEGREE OF A
PLACEBO EFFECT.
NOW, THE REASON THAT THAT IS
CONTROVERSIAL IS BECAUSE WHEN
PEOPLE THINK THEY DON'T HAVE
MORE PAIN, THEY TURN ON THEIR
ENDOGENOUS SYSTEMS AND THEY
DON'T HAVE MORE PAIN AND SO
THEIR PHYSICAL FUNCTION ACTUALLY
GETS BETTER.
IT IS NOT A DONE DEAL BY ANY
MEANS, BUT LOOKING AT THE
DIFFERENT OUTCOMES, I THINK IS
AN IMPORTANT ONE.
I'LL TAKE THE OPPORTUNITY TO SAY
ONE THING ABOUT THE PLACEBO
RUN-IN TRIAL.
I HAVE TO SAY THAT I ACTUALLY
DISAGREE WITH THE CONCEPT OF A
PLACEBO RUN-IN TRIAL.
PRIMARILY BECAUSE IT'S NOT A
PLACEBO RUN-IN TRIAL.
IT'S A PLACEBO-TREATED GROUP RUN
OF-IN TRIAL.
WHAT HAPPENS IN ANY GROUP THAT
YOU TREAT THERE IS NATURAL
HISTORY OF DISEASE.
SOME PEOPLE GET BETTER.
THERE IS REGRESSION TO THE MEAN.
PEOPLE WHO START AT A HIGH LEVEL
ARE GOING TO GO TO A LOW-LEVEL.
AND THEN THERE IS THE MIND/BODY
PLACEBO EFFECT.
THE TROUBLE WITH RUN-IN TRIAL IS
THAT YOU'RE EXCLUDING PEOPLE WHO
HAVE NATURAL VARIATION IN THEIR
DISEASE.
THOSE ARE EXACTLY THE ONES YOU
WANT IN YOUR TRIAL.
BECAUSE THEY HAVE NATURAL
VARIATION AND YOU WANT TO SEE IF
THAT CHANGE GETS BETTER OR
WORSE.
THE 101 TRIALS FOR DEPRESSION,
THEY FOUND THAT THE PLACEBO
RUN-IN DID NOT EFFECT THE
OUTCOMES.
AND THE SAME HAS BEEN FOUND IN
SEVERAL PAIN TRIALS AS WELL.
AND SO THE CONCEPT OF EXCLUDING
PEOPLE WHO RESPOND TO PLACEBO IS
JUST NOT A GOOD ONE.
HOWEVER, WE WERE TALKING ABOUT
THIS BEFORE.
PHENOTYPING YOUR PATIENTS, YOUR
ANIMALS, BEFORE YOU PUT THEM IN
YOUR TRIAL, WE KNOW THAT IN MICE
THERE IS THE WIMP SPECIES AND --
THE WIMP GROUP AND THE STOIC
GROUP.
IT TURNS OUT BLACK 6, THE ONE
MOST COMMONLY USED IS RIGHT IN
THE MIDDLE, WHICH IS LUCKY.
WE KNOW IN HUMANS, IT'S THE
SAME.
THERE ARE PEOPLE WHO RESPOND
REALLY WELL WITH PAIN.
THERE ARE THOSE WHO DON'T
RESPOND WELL TO PAIN.
AND WE NEED TO HAVE A PHENOTYPE
BEFORE WE START OUR TRIAL.
IN ANIMALS YOU WERE TALKING
ABOUT BEING ANXIOUS AFTER
TRAVELING HUNDREDS OF MILES AND
THEN TESTING THEM ALL OF A
SUDDEN.
IT'S LIKELY IN COWS AND SHEEP
AND ALL THE REST, THAT THEY ARE
GOING TO BE STOIC ANIMALS AND
NON-STOIC.
YOU MIGHT WANT TO DO SOME SORT
OF EXPERIMENTAL TEST,
EXPERIMENTAL PAIN, JUST A LITTLE
BIT OF HEAT OR SOMETHING, TO SEE
WHO RESPONDS TO THE PAIN BEFORE
YOU GO ENROLLING THEM UNTIL A
TRIAL.
SO THE PHENOTYPING OF PEOPLE
BEFORE YOU ENROLL THEM, I THINK
IS A VITAL ISSUE.
BUT I THINK THAT THE PLACEBO
RUN-IN IS PROBABLY NOT THE RIGHT
WAY TO DO THAT.
DID THAT ANSWER YOUR QUESTION?
>> I HAVE A QUESTION FOR THE
PANEL.
WHAT ARE THE STAT ACTIVITY CALL
AND CLINICAL CONSIDERATIONS --
STATISTICAL -- ASSESSING A
SINGLE ENDPOINT AT MULTIPLE
POINTS VERSUS MULTIPLE ENDPOINTS
AT A SINGLE TIME POINT?
>> GOING BACK TO YOUR POINT
ABOUT PAIN WAXING AND WANNING
AND POTENTIALLY NOT KNOWING WHEN
A DRUG IS GOING TO TAKE INTO
EFFECT, HAVING A SINGLE ENDPOINT
THAT YOU ASSESS AT MULTIPLE
TIMES IS A REALLY GREAT WAY TO
THINK ABOUT THIS.
A NICE POINT ALSO IF WE HAVE ONE
ENDPOINT WE LOOK AT AT MULTIPLE
TIME POINTS IS THAT WE CAN
ANALYZE POTENTIALLY IN A SINGLE
MODEL AND GAIN SOME POWER FROM
ONE ANALYSIS.
SO USING SOME INFORMATION FROM
THE OTHER TIME POINTS.
THE DOWNSIDE, THOUGH, IF WE HAVE
A MODEL WITH A TREATMENT EFFECT
AS WELL AS LOOKING AT THE
TREATMENT BY TIME INTERACTION,
IT CAN SOMETIMES BE DIFFICULT TO
MAKE CONCLUSIONS IF YOU SEE, FOR
EXAMPLE, THAT THERE IS A
SIGNIFICANT TREATMENT EFFECT AT
ONE TIME POINT AND THEN THE DRUG
DOESN'T WORK AT ANOTHER.
IT'S HARDER TO KNOW WHAT TO DO.
AND THEN I THINK POINTS ABOUT
WHETHER OR NOT TO HAVE MULTIPLE
ENDPOINTS AT A SINGLE TIME
POINT -- IF YOU'RE MORE
CONFIDENT ABOUT THAT BEING A
GOOD CHOICE OF TIME POINTS, BUT
PERHAPS THERE ARE MULTIPLE
DIFFERENT ASPECTS OF PAIN THAT
YOU WANT TO ANALYZE.
>> I THINK FOR US, IT BECOMES A
QUESTION OF WHETHER YOU'RE
STUDYING INTEROR
INTRAINDIVIDUALS VARIATION,
BECAUSE WE ONLY HAVE SO MUCH
TIME AND SO MANY ANIMALS AND SO
MUCH HELP.
AND WHEN YOU START RUNNING
ANIMALS THROUGH THE SHOOT
REPEATEDLY, YOU'RE LIMITING THE
NUMBER OF ANIMALS YOU HAVE ON
TRIAL.
SO IT BECOMES AN
INTRA-INDIVIDUAL VARIABILITY
STUDY AND THEN YOU RUN INTO THE
RISK OF HABITATION.
THE ANIMALS GET USED TO THAT
FACILITY AND THAT IMPACTS THE
ENDPOINTS AS WELL BECAUSE THEY
HAVE SEEN IT ALL BEFORE.
IF YOU BRING IN A LARGE NUMBER
OF ANIMALS BUT YOU ONLY RUN THEM
THROUGH A COUPLE OF TIMES, YOU
GET MORE INTEREST-INDIVIDUAL
VARIATION ASSESSED BUT YOU'RE
THEN RUNNING INTO THIS ISSUE OF
THOSE ANIMALS AREN'T HABITUATING
EITHER SO THEY ARE BASICALLY --
IT COULD BE A POSITIVE OR A
NEGATIVE THING.
>> AND IF I COULD JUST MAKE ONE
QUICK COMMENT.
WE MENTIONED ABOUT THE FACT THAT
PAIN, AT LEAST, VARIES OVER
TIME.
AND IF YOU IMAGINE THAT THE PAIN
IS VARYING IN YOUR TREATMENT
GROUP AND YOUR PLACEBO GROUP BUT
IT'S VARYING AT A SLIGHTLY
DIFFERENT FREQUENCY, THERE WILL
BE SOMETIMES WHEN THEY COME
CLOSER TOGETHER AND SOMETIMES
WHEN THE LINES BECOME FURTHER
APART.
AND SO I THINK JIM CAMPBELL'S
DISCUSSION THIS MORNING, WHICH
WAS TO LOOK AT ALL OF THE DATA
OVER TIME, IS MUCH STRONGER
INDICATION OF THE -- WHAT'S
GOING ON WITH THE GROUPS AND
WITH THE PATIENTS INDIVIDUALLY.
AND SO, I'M VERY MUCH IN FAVOR
OF MEASURING PAIN THROUGHOUT THE
STUDY AND IN FACT, THERE IS SOME
STUDIES THAT ARE 12 WEEKS LONG
AND THEY MEASURE EVERY DAY.
I DON'T KNOW HOW THEY DO THAT.
BUT THE POINT IS, YOU JUST GET A
LOT OF DATA TO BE ABLE TO LOOK
AT IT AND IT GIVES YOU MORE
POWER TO DIFFERENTIATE BETWEEN
GROUPS.
I THINK THAT WILL BE MY CHOICE.
MULTIPLE MEASURES ALWAYS A GOOD
IDEA RIGHT AT THE BEGINNING.
GET EVERYTHING RIGHT AT THE
BEGINNING AND AT THE END.
>> ONE MORE QUESTION.
>> THANK YOU.
I WAS WONDERING IF WE ARE
LOOKING AT THE BINARY OUTCOME
MEASUREMENT OF SUCCESS VERSUS
FAILURE, WE SEE THAT NOW
SOMETIMES USED IN STUDIES BUT
I'M WONDERING -- BECAUSE
SOMETIMES EVEN DO NOT PROVIDE
THE INITIAL DATA ANYMORE.
FOR EXAMPLE, [ INAUDIBLE ]
WONDERING IF THIS -- I REALLY
DON'T LIKE THIS.
BUT I WAS WONDERING WHAT YOUR
OPINION IS ABOUT THIS.
>> CAN YOU REPEAT THE PART?
SO YOU'RE WONDERING ABOUT BINARY
ENDPOINTS IF THE THEY DON'T
PROVIDE WHAT?
>> THE ORIGINAL DATA.
SO THEY GO FROM CONTINUOUS DATA,
FOR EXAMPLE, SUCCESS AND FAILURE
AND IMPROVEMENT AND -- I WAS
WONDERING WHAT YOUR OPINION IS
ABOUT THAT?
NOT GIVING THE ORIGINAL
CONTINUOUS DATA ANYMORE BUT ONLY
PROVIDING THE SUCCESS RATE.
>> THAT'S A GREAT QUESTION.
I THINK THAT THERE IS OFTENTIMES
WHERE IT CAN BE HELPFUL TO LOOK
AT THE ORIGINAL DATA AS PERHAPS
SOMETHING AS A SECONDARY OUTCOME
THAT YOU DON'T NECESSARILY HAVE
A FORMAL ANALYSIS BUT YOU HAVE
SOME STATISTICS.
I THINK IT CAN GIVE A LOT OF IN
TUITION AS TO HOW THE OUTCOME
WAS CONSTRUCTED.
>> FELLOWS THAT WORK WITH ME
KNOW THAT THE ANSWER TO ANY
QUESTION ABOUT SHOULD I DO THIS
OR SHOULD I DO THAT IS, BOTH.
AND SO I THINK YOU HAVE THE
DATA.
YOU SHOULD LOOK AT IT BOTH WAYS.
OR IN MANY DIFFERENT WAYS, TO
TRY TO UNDERSTAND IT.
THE TROUBLE IS, YOU HAVE TO PICK
ONE AS THE PRIMARY.
AND AS DR. CAMPBELL SUGGESTED,
SOMETIMES WE GET THE WRONG ONE.
AND EVERYTHING ELSE IS POSITIVE
BUT YOU JUST CAN'T DEAL WITH IT.
THE LAST THING I WOULD SAY IS
THAT THE ISSUE ABOUT
DICHOTOMIZING DATA GOING FROM A
CONTINUOUS TO A DIE COT MISSCALE
IS YOU OBVIOUSLY LOSE POWER IN
THE PROCESS -- DICHOTOMOUS
SCALE -- IF YOU MEASURE THAT
OVER TIME AND WE ARE ABOUT TO
PUBLISH A PAPER ON THIS, IF YOU
MEASURE THAT OVER TIME YOU
REGRAIN ALMOST ALL THE POWER OF
LOOKING AT 50% OVER A LONG
PERIOD OF TIME.
THERE ARE WAYS TO THINK ABOUT
TAKING DATA AND MANIPULATING IT
IN A WAY SO THAT YOU DON'T LOSE
A TREMENDOUS AMOUNT OF POWER BUT
YOU STILL ARE ABLE TO LOOK AT
THE DIFFERENT OUTCOMES.
I THINK THE OUTCOMES PROVIDE YOU
DIFFERENT INFORMATION AND THEY
ARE BOTH IMPORTANT.
>> I THINK THE CHALLENGE HERE IS
WE OFTEN GET A DISCONNECT
BETWEEN THE CLINICAL AND
RESEARCH SETTING AS WELL.
FROM A FOOD ANIMAL SIDE, OUR
PRODUCER WILL SAY THE COW GOT
BETTER OR SHE DIDN'T.
THERE IS NO IN BETWEEN
CONTINUOUS SCALE.
BUT FROM A RESEARCH SIDE, THE
CONTINUOUS SCALE WORKS BEST.
BUT AT THE END OF THE DAY, OUR
CLIENTS ARE LOOKING AT IT FROM A
DICHOTOMOUS, YES THEY GOT
BETTER, NO THEY DIDN'T.
IT'S TRANSLATING IT INTO A
LANGUAGE THEY UNDERSTAND AND
THAT ANIMAL LOOKS BETTER BECAUSE
IT GOT AN ANALGESIC.
THAT IS EVENTUALLY WHERE WE WILL
BE IN TERMS OF HOW THESE DRUGS
ARE USED.
>> AND THAT'S A KEY ISSUE.
CLINICAL DECISION-MAKING IS
DICHOTOMOUS.
I'M GOING TO GIVE THEM A DRUG.
I'M NOT.
THEY ARE GOING TO GET BETTER,
THEY ARE NOT.
SO YOU HAVE TO CONVERT WHATEVER
YOU DO INTO DICHOTOMOUS TO BE
USEFUL CLINICALLY.
>> THANK YOU.
>> I'D LIKE TO THANK OUR PANEL
VERY MUCH --
>> JUST ONE QUESTION.
I THINK EVERYTHING THAT ALL OF
YOU HAVE SAID HERE IS VERY
VALUABLE.
MY NAME IS DEBRA AND I WORK WITH
BIOTREES ED (?) AND PHENOTYPING
IN ADVANCE OF STUDIES I THINK IS
REALLY WHERE IT'S AT.
AND I ALSO BELIEVE THAT YOU,
DR. JOHN FARRAR MENTIONED OUR
MOVE TOWARDS PRECISION MEDICINE.
AND IN LISTENING TO THAT, AND I
THINK JUST LACKING STATISTICAL
KNOWLEDGE LIKE SOME OF OUR TOWN
MEMBERS WHO ARE OBVIOUSLY VERY
TALENTED, WHAT I'M CURIOUS ABOUT
IS, IF WE PHENOTYPE AT THE
BEGINNING OF A STUDY AND THEN WE
LOOK AT THOSE DIFFERENT GROUPS,
IS IT BEST TO LOOK AT THE
STATISTICAL ANALYSIS AS
SUBGROUPS OR TO THEN TAKE THOSE
PHENOTYPES AND THEN STRAT FINEM
INTO YOUR RANDOMIZATION?
-- STRATIFY -- I'M NOT QUITE
SURE HOW THAT WOULD WORK OUT
STATISTICALLY BUT I KNOW IT'S
KEY TO PAIN AND HOW PAIN WORKS.
>> I'M NOT BASHFUL.
IF YOU HAVE THE MONEY TO RUN ALL
OF THE GROUPS BUT TO POWER IT
FOR THE PHENOTYPE THAT YOU THINK
IS VALID, THEN MORE POWER TO
YOU.
DO IT ALL.
THE TROUBLE IS, THAT WE DON'T
GENERALLY HAVE THAT.
SO PHENOTYPING THE IDEA, IS TO
STUDY ONLY THE ONES THAT YOU
THINK ARE GOING TO RESPOND AND
NOT STUDY THE OTHERS.
IF YOU ARE IN FACT STUDYING A
POPULATION AND TRYING TO
UNDERSTAND WITHIN THAT
POPULATION AND TO RETRO FIT
PHENOTYPES, THEN YOU END UP WITH
SUBGROUP ANALYSIS AND SUBGROUP
ANALYSIS HAVE ALL THE PROBLEMS
THAT GO WITH THAT.
MULTIPLE COMPARISONS AND OTHER
KINDS OF ISSUES.
BUT IT IS FROM AN EXPLORATORY
PERSPECTIVE.
EVERY TIME I TALK TO A GROUP
THAT IS TRYING TO DO A STUDY, I
SAY LOOK TO THE ONES WHO DON'T
RESPOND.
GO FIND THE ONES WHERE SOMETHING
ISN'T WORKING AND LET'S TRY TO
FIGURE OUT WHAT THAT IS AND
TRIED TO FIGURE OUT HOW TO MAKE
IT BETTER FOR THEM.
AND THEN FIGURE OUT HOW CAN I
IDENTIFY THE ONES AND HOW IT
WORKS?
STOW LOOKING AT IT, STRATIFY IT
AND SUBGROUPS ARE BOTH VALID.
I TOLD YOU, BOTH.
THEY ARE BOTH VALID WAYS OF
LOOKING AT IT.
THE PRIMARY OUT AND HAS TO BE
FOCUSED ON THE STUDY GROUP
YOU'RE LOOKING AT.
>> AND I JUST DID, LISTENING TO
EACH OF YOU SPEAK AS WELL, I
THINK THAT ONE KEY FINDING, AND
I BELIEVE WHAT YOU SAID AS WELL,
THE EXEXSPORE TORY DESIGN IS A
GOOD ROUTE.
AND LOSE AND LOSE EARLY.
LOSE WELL AND LOSE EARLY.
BECAUSE THEN YOU CAN DEFINE WHAT
YOUR PARAMETERS ARE TO WIN.
PAIN IS COMPLEX.
>> THANK YOU VERY MUCH.
AND THANK YOU TO OUR PANEL.
[ APPLAUSE ]
>> ALL RIGHT, WHAT GREAT
DISCUSSION.
I'M JUST GOING TO TAKE A COUPLE
OF MINUTES HERE TO WRAP THINGS
UP.
WE WILL COME BACK TO FUTURE
PLANNING IN A SECOND.
FIRSTLY I WANT TO THANK ALL OF
YOU, ALL OF THE ATTENDEES, THE
ENGAGEMENT YOU HAVE ALL SHOWN,
THE DISCUSSION I KNOW HAS BEEN
GOING ON.
I HAVE BEEN LISTENING AND THERE
IS GREAT DISCUSSION OUT THERE
AND ALSO, THANK ALL OF THE
SPEAKERS FOR SHARING THEIR
KNOWLEDGE AND ENGAGING IN THE
DISCUSSION.
SO THANK YOU, EVERYONE.
AND THEN THIS SLIDE IS PRETTY
IMPORTANT.
WE COULD NOT COME TOGETHER OR
HAVE THIS MEETING WITHOUT OUR
SPONSORS.
SO SINCERE THANKS TO THE MAY DAY
FUND FOR REALLY SHORING UP THE
MAJORITY OF THE SPONSORSHIP WE
NEEDED TO PUT THIS EVENT ON.
AND I'D ALSO DUE THANKS TO THE
NIH, PARTICULARLY MARIE GILL,
MIKE LA SHIN SKI, FOR THEIR
SUPPORT, BOTH WITHIN THE NIH
BEING ADVOCATES FOR THE CORE
MEETING AND THEN ALSO TO
EVERYONE ELSE, ALL THE OTHER
STAFF BEHIND-THE-SCENES WHO
WORK.
THANK YOU.
THOSE WHO WORK AT THE NIH TO
HELP MAKE THIS HAPPEN.
[ APPLAUSE ]
AND THEN ALSO THANKS TO THE
MORRIS ANIMAL FOUNDATION AND THE
COMPARATIVE PAIN RESEARCH AND
EDUCATION CENTER FOR THE THE
ADDITIONAL SUPPORT.
I WANT TO ACKNOWLEDGE -- DON'T
WORRY.
I WANT TO ACKNOWLEDGE THE
ORGANIZING COMMITTEE.
YOU'LL FIND THE LIST OF EVERYONE
WHO IS IT ON THE ORGANIZING
COMMITTEE IN THE PROCEEDINGS.
AND ALSO THANK DANE JOHNSON,
JOHN COLE AND THE REST OF THE
TEAM AT THE NORTH CAROLINA STATE
UNIVERSITY CONTINUING EDUCATION
UNIT WHO HAVE HELPED DO ALL THE
ORGANIZATION AND BRING THIS
TOGETHER.
JUST A COUPLE OF OTHER THINGS.
A NUMBER OF PEOPLE ASKED ABOUT
WHETHER THE SLIDES WILL BE
AVAILABLE.
THEY WILL BE AVAILABLE IN PDF
FORMAT AND ALL ATTENDEES WILL BE
COMMUNICATED WITH BY DANE,
INDICATING WHERE YOU'LL BE ABLE
TO PICK UP THOSE PDFs OF THE
SLIDES.
AND DON'T FORGET THE
PROCEEDINGS, YOU SHOULD HAVE HAD
A LINK SENT TO YOU FOR THE
PROCEEDINGS.
WHAT HAS BEEN DISCUSSED IN THIS
MEETING WILL BE WRITTEN UP, A
COMBINATION OF THE COMMITTEE,
THE SPEAKERS GETTH TOGETHER TO
WRITE IT UP, WHETHER ONE
DOCUMENT OR A COUPLE, BUT WE ARE
ALL ONBOARD ABOUT DOING THAT,
AREN'T WE?
YES?
WE WILL START NEXT WEEK.
IT'S A LOT OF WORK.
IT'S A VERY IMPORTANT THING TO
BE DOING.
AND SO WITH THAT, THEN, IT JUST
REMAINS FOR ME TO SAY, I THINK
MICHELLE WHO WAS INVOLVED IN THE
INITIAL PLANNING OF THIS
MEETING, WOULD HAVE BEEN PROUD
OF THIS MEETING.
AND WHEREVER YOU ARE, MICHELLE,
THANK YOU FOR EVERYTHING THAT
YOU HAVE DONE IN THE PAST TO
MAKE THESE MEETINGS A SUCCESS,
INCLUDING THIS ONE.
AND WITH THAT -- I KNOW WE ARE
PAST 2:30 HERE AND PEOPLE MAY
HAVE TO LEAVE.
I WANT TO HAVE AN OPEN
DISCUSSION, IF ANYONE HAS ANY
THOUGHTS THEY'D LIKE TO SHARE
ABOUT THEMES FOR FUTURE
MEETINGS?
THE CORE MEETING ORIGINALLY WAS
SET UP TO DISCUSS THE
MEASUREMENT OF PAIN IN ANIMALS
WITH THE JEWELLISM OF IMPROVING
HUMAN HEALTH THROUGH PROVING OUR
ABILITY TO USE AND UNDERSTAND
ANIMAL MODELS AND ALSO IMPROVING
VETERINARY SPECIES HEALTH BY
IMPROVING OUR ABILITY TO MEASURE
AND THEREFORE TREAT PAIN.
SO THAT'S THE OVERARCHING THEME.
IF YOU HAVE OTHER IDEAS, PLEASE
SHARE THOSE.
AND YOU DON'T HAVE TO DO IT NOW,
BUT IF YOU HAVE COMMENTS YOU'D
LIKE TO SHARE WITH EVERYONE NOW
ABOUT THE POTENTIAL CONTENT,
THEMES OF FUTURE MEETINGS,
PLEASE DO.
OTHERWISE JUST REACH OUT TO
ANYONE ON THE ORGANIZING
COMMITTEE.
IT LOOKS LIKE WE HAVE --
>> I'LL MENTION A COUPLE OF
THINGS.
CORNELL UNIVERSITY.
I'M NOT A PAIN EXPERT BUT I
FOCUS ON ARTIFICIAL
INTELLIGENCE.
I WANT TO MAKE A COUPLE OF
POINTS, OBSERVATIONS AND TO
SHARE FOR POTENTIAL THOUGHTS.
THE FIRST THOUGHT I HAD WAS JUST
THE WHOLE ISSUE OF METROLOGIY
AND HOW WE MEASURE THINGS.
AND I THINK THAT THERE CERTAINLY
IS SPACE WHERE THERE ARE
CHALLENGES IN SORT OF MEASURING
SOMETHING.
BUT THEN THERE ARE OTHER AREAS
WHERE YOU CAN REALLY MEASURE
SOMETHING VERY WELL AND
ACCURATELY AND PRECISELY.
THOSE ARE THE KINDS OF THINGS
THAT YOU HAVE A LOT OF CONTROL
OVER.
SO I HEAR THERE WAS SOME TALKS
ABOUT SENSORS TO MEASURE CERTAIN
THINGS.
NOW THESE THINGS WE CAN CONTROL
VERY WELL AND MEASURE.
WE CAN STANDARDIZE THESE THINGS.
WE CAN CALIBRATE THEM.
WE CAN PERFORM QUALITY ASSURANCE
ON THESE THINGS.
AND THIS IS CRITICAL FOR US TO
BE ABLE TO ENSURE THAT WE HAVE
APPLES-TO-APPLES COMPARISONS
WHEN WE DO -- WHEN WE REPORT OUR
DATA.
THAT WAS MY FIRST OBSERVATION
WAS TO WHAT EXTENT WE MIGHT BE
ABLE TO STANDARDIZE A LOT OF OUR
QUANTITATIVE DATA?
THE SECOND ONE IS KIND OF LINKED
TO THE WHOLE ARTIFICIAL
INTELLIGENCE QUESTION.
IN THAT PARTICULARLY WITH
MEDICINE, WE HAVE SERIOUS
CHALLENGES WITH DATA
HARMONIZATION AND DATA
STANDARDS.
IF YOU ARE SICK, YOU GO TO A
HOSPITAL.
YOU DEMANDED TO HAVE YOUR CT
SCANS.
YOU CAN GET THEM ON A DISK AND
IT HAS VERY SPECIFIC FORMAT THAT
IS RECOGNIZED INTERNATIONALLY.
THERE ARE STANDARDS FOR THESE
THINGS.
THERE IS INTEROPERABILITY FOR US
TO BE ABLE TO ACCESS THAT DATA
AND UNDERSTAND WHAT THE PIXELS
MEAN AND IN A RICH DEGREE OF
METADATA THAT HAS BEEN CURATED
BY A SERIES OF EXPERTS.
AGAIN, THEY MAKE THE DATA
TRANSPARENCY, EASY FOR US TO
UNDERSTAND WHAT THAT DATA IS.
I THINK THAT THAT IS A REALLY
CRITICAL CHALLENGE FOR FOLKS IN
VETERINARY MEDICINE WHERE WE
HAVE VERY DIFFERENT SYSTEMS.
THEY HAVE DIFFERENT FORMATS OF
THE DATA AND SOME OF THEM DON'T
HAVE ANY METADATA AT ALL.
SO FOR EVEN -- EVEN IF WE ARE
THINKING ABOUT AI AS BEING A
PANACEA TO SOLVE ALL OF OUR
PROBLEMS, I HAVE NEWS FOR YOU.
THAT IS IF WE DON'T HAVE DATA
STANDARDS, THERE IS NO WAY FOR
US TO BE ABLE TO REALLY BUILD
MULTIEL-PLATFORM,
MULTI-INSTITUTIONAL DATASETS FOR
US TO REALLY LEARN FROM THE
DATA.
THAT WAS AN IMPORTANT THINGS.
AND THEN THE FINAL POINT WAS
SORTAVE -- SOMETHING MY PH.D.
ADVISER WOULD SAY TO ME.
THAT WAS RELATED TO THE GENERAL
IDEA THAT IF YOUR TOOLS AREN'T
WORKING, FIND A BETTER TOOL.
BUT THE WORST THING YOU WANT TO
DO IS BUILD MORE RULES FOR THE
TOOLS THAT ARE NOT WORKING.
IN OTHER WORDS, IF WE'RE FINDING
THAT WE HAVE THESE DEVICES THAT
REQUIRE SO MUCH ENERGY AND
EFFORT TO BE ABLE TO EXTRACT
USEFUL INFORMATION FROM, THEN WE
REALLY HAVE TO ASK OURSELVES, IS
THIS THE RIGHT THING WE'RE
DOING?
AND ARE THERE BETTER
TECHNOLOGIES OR TECHNIQUES WE
CAN USE TO HELP QUANTIFY AND
CREATE THE KINDS OF LATITUDE
THAT WE NEED IN OUR DATASETS TO
CREATE THE POWER WE ARE LOOKING
FOR IN OUR STUDIES.
SO THOSE ARE THE THREE THINGS I
THOUGHT TO SHARE WITH THIS
GROUP.
>> THANK YOU.
TWO GREAT IDEAS AND ONE WARNING.
WE WILL BUST OUR BUBBLE IF WE
DON'T FIGURE OUT DATA
COMPATIBILITY.
THANK YOU.
>> SO, I'LL MAKE MINE QUICK.
I THINK SOMETHING THAT COULD
REALLY ADD TO THE CONVERSATION
IS A DISCUSSION OF THE
NEUROGENETICS OF PAIN.
FOR INSTANCE, WE KNOW OF MANY
MEN DEALING IN MONOGENETIC
TRAITS, CONTROLLED ION CHANNELS.
THERE IS NATURAL VARIATION AMONG
HUMAN BEINGS AND AMONG NON-HUMAN
MALLS AND I THINK TALKING ABOUT
THIS GENETIC DIMENSION OF
WELFARE COULD BE A REALLY
INTERESTING ANGLE AND IF YOU'RE
INTERESTED, I COULD MAYBE EVEN
HELP PUT TOGETHER A PANEL OF
SCIENTISTS IF YOU WANTED TO DO
LIKE A SPECIAL SESSION ON THIS.
SO THANKS FOR ORGANIZING THIS.
THIS WAS WONDERFUL AND I REALLY
ENJOYED IT.
>> THANK YOU FOR THOSE THOUGHTS.
>> HI, LATARSHA CRAWFORD
UNIVERSITY OF WISCONSIN, SCHOOL
OF VETERINARY MEDICINE.
THANK YOU VERY MUCH.
I ENJOYED THIS REALLY SINCE DAY
ONE SEVERAL YEARS AGO.
ONE THING I DID WANT TO JUST
KIND OF COMMENT ON THAT I THINK
COULD BE REALLY INFORMATIVE FOR
THIS GROUP OF FOLKS IS PERHAPS A
BETTER UNDERSTANDING OR A MORE
CLEAR DISCUSSION OF SOME OF THE
PERIPHERAL MECHANISMS OF PAIN.
SO THERE IS A LOT OF TALK ABOUT
CENTRAL SENSITIZATION AND HOW
INTERESTING AND COMPLEX THAT IS.
BUT I THINK THAT JUST BECAUSE
PAIN IS CHRONIC OR MULTI-FOCAL
OR JUST BECAUSE THERE ARE AREAS
OF SECONDARY HYPERALGESIA OR
THAT SORT OF THING, DOESN'T MEAN
IT'S SOLELY CENTRAL IN TERMS OF
THE LONG TERM EFFECTS THAT ARE
HAPPENING OR THE WAYS IN WHICH
THE SENSORY SYSTEM IS CHANGING.
AND I THINK THAT MAYBE SOME
FURTHER DISCUSSION ABOUT
PERIPHERAL MECHANISMS AND
PLASTICITY THAT LIES WITHIN THE
PERIPHERY IS ALSO PROBABLY WORTH
OUR UNDERSTANDING AND PERHAPS
DIVING A LITTLE BIT DEEPER INTO
IT.
AND I'M HAPPY TO BE A PART OF
THAT DISCUSSION.
>> LOVELY, THANK YOU.
I'M WRITING ALL OF THESE DOWN.
THIS IS GREAT AND SAVING US A
LOT OF HOMEWORK.
>> HI, ABI, KANSAS STATE
UNIVERSITY.
SO I'M A LARGE ANIMAL PAIN
RESEARCHER.
AND I HEARD A LOT THE LAST
COUPLE OF DAYS ABOUT US TALKING
ABOUT SELF REPORT BEING THE GOLD
STANDARD AND I CERTAINLY FEEL
THAT WAY WHEN I'M DEALING WITH
MY PIGS T WOULD BE FANTASTIC IF
THEY COULD JUST TELL ME THAT
THEY ARE IN PAIN.
BUT SOMETHING THAT STRUCK ME IN
JUST SITTING AND HEARING THE
HUMAN HEALTH PERSPECTIVE IS THAT
I AM NOT WORRIED THAT MY PIGS
ARE GOING TO BE MOTIVATED TO
SHOW THAT THEY ARE IN MORE PAIN
WHEN THEY ARE NOT NECESSARILY IN
PAIN.
MY SIGNIFICANT OTHER IS A FAMILY
MEDICINE PHYSICIAN IN RURAL
KANSAS AND SOMETHING HE DEALS
WITH A LOT IS PEOPLE
SELF-REPORTING HIGH AMOUNTS OF
PAIN TO GAIN ACCESS TO CERTAIN
DRUGS.
AND HE SEES PEOPLE THAT ARE ON
SUCH HIGH DOSES OF OPIOIDS THAT
HONESTLY WOULD TAKE A
RHINOCEROS.
AND I THINK THERE IS JUST THIS
CONCERN NOW THAT PERHAPS SELF
REPORT IN HUMAN MEDICINE IS NOT
NECESSARILY THE GOLD STANDARD
BECAUSE PEOPLE ARE MOTIVATED IN
CERTAIN CASES TO SUFFER HIGHER
LEVELS OF PAIN TO GAIN ACCESS TO
CERTAIN DRUGS.
THAT MIGHT BE A NICE PIECE TO
THIS DISCUSSION OF HOW WE KIND
OF DEAL WITH THIS SORT OF OPIOID
CRISIS WE ARE SEEING IN PEOPLE
SAYING THAT THEY ARE IN CERTAIN
LEVELS OF PAIN TO BE MOTIVATED
FOR OTHER REASONS.
SO THAT WAS JUST MY TWO CENTS.
>> GREAT.
THANK YOU VERY MUCH FITS IN THE
WITH THE WHOLE HEAL INITIATIVE.
>> SORRY TO STAND UP IN THE WAY
OF OTHERS.
I DIDN'T REALIZE.
A COUPLE OF THOUGHTS.
IN TERMS OF DATA
STANDARDIZATION, FOR ANYBODY
THAT HAS SUBMITTED DATA TO THE
FDA, YOU UNDERSTAND THAT THERE
ARE REQUIREMENTS AS TO WHAT
FORMAT THAT DATA SHOULD TAKE.
I DON'T HONESTLY KNOW IF THE
ANIMAL DATA IS AS RESTRICT AS
HUMAN.
BUT HAVING JUST WORKED WITH THE
DART SYSTEM AND 40 OR 45
DIFFERENT STUDIES.
THERE IS A STANDARD APPROACH TO
RECORDING OF THAT DATA.
AND MAYBE THERE ISN'T A NEED TO
RE-CREATE THE WHEEL.
IT'S AN STDM FORMAT, C DISK
PROCESS.
SOMEWHAT CUMBERSOME BUT IT
WORKS.
AND SO MAYBE IF THAT WERE
ADOPTED IN AT LEAST LARGER
MEDICAL CENTERS THAT DO
RESEARCH, DATA COULD BE IN A
MORE STANDARDIZED FORMAT.
OBVIOUSLY, IN HEALTH CARE WE
HAVE OUR STANDARDIZED FORMAT.
DATA IS BEING TRANSITIONED INTO
OMAL AND THE A BUNCH OF OTHER
INITIALS I DON'T CLAIM TO
UNDERSTAND.
AND THAT KIND OF SYSTEM CAN ALSO
WORK AND AI CAN HELP IN THE
TRANSITION OF DATA TO THAT
PERSPECTIVE.
WITH REGARDS TO THE LAST
SPEAKER, AS SOMEBODY WAS TAKING
CARE OF PATIENTS FOR A VERY LONG
TIME, PAIN IS SELF REPORTED AND
WILL ALWAYS BE SELF REPORTED.
AND THERE JUST ISN'T ANY WAY
AROUND IT.
THE POINT MADE ABOUT
COMPLAINING, THAT IS CLEARLY AN
ISSUE IN CLINICAL CARE.
IN RESEARCH, I THINK THAT THAT
IS LESS OF A PROBLEM AS LONG AS
WE ARE CAREFUL ABOUT WHO WE
ENROLL IN TRIALS.
WITH REGARDS TO THE THIRD THING
THAT WAS MENTIONED, WHICH IS
MONITORS OR WAYS OF
UNDERSTANDING.
IN SMALL ANIMAL STUDIES, THEY
HAVE STARTED TO USE VIDEO
RECORDING OF MOTION AS A WAY OF
UNDERSTANDING.
AND THERE IS NO REASON WHY THAT
CAN'T BE ADOPTED TO COWS IN A
CORAL OR SHEEP IN A FIELD OR
OTHER THINGS.
SO UNDERSTANDING HOW TO EMPLOY
SOME OF THE TECHNOLOGY THAT IS
RAPIDLY BEING DEVELOPED, AND
THEN ANALYZED EITHER THROUGH AI
OR OTHER MECHANISMS TO NOT HAVE
TO PUT THINGS ON TO ANIMALS TO
SEE HOW THEY ARE MOVING, BUT
JUST OBSERVE THEM.
THE LAST THING IS, I AGREE WITH
YOU THAT WE PROBABLY KNOW IF
YOUR PIGS ARE IN PAIN, BUT IN
SMALL ANIMAL STUDIES, WE KNOW
THAT IF YOU PUT -- INJECT
SOMETHING INTO A MALE MOUSE AND
PUT IT IN WITH OTHER MALE MICE,
IT WILL NOT RESPOND WITH PAIN
BEHAVIOR AS STRONGLY.
BECAUSE THEY ARE AFRAID THE
OTHER MICE WILL COME BEAT IT UP.
WHEREAS IF YOU PUT THEM IN WITH
THE FEMALES, THEY ARE JUST
LICKING THEIR PAW UNTIL THEY
CAN'T STOP.
SO I WOULD ARGUE THAT IN FACT IN
LOOKING AT PIGS AND LOOKING AT
GOATS AND LOOKING AT ANIMALS,
MIXING THEM UP -- I A LOT OF
THESE ARE CASTRATED, BUT THE
BOTTOM LINE IS THAT I THINK
THERE MAY BE WELL BE DIFFERENCES
IN THE WAY ANIMALS RESPOND BASED
ON THEIR ENVIRONMENT.
SO WE KNOW THAT THE PLACEBO
EFFECT OCCURS IN PIGS AND
ANIMALS AND HORSES AND
EVERYWHERE.
SO, IT'S NOT THE SAME BUT IT IS
ALSO AN ISSUE.
IN TERMS OF WHAT MIGHT BE DONE
HERE, I THINK THAT MAYBE
COMBINING WHAT WE KNOW FROM
SMALL ANIMAL INTO LARGE ANIMAL,
AND WE TALKED ABOUT THIS BEFORE,
MIGHT BE AN INTERESTING WAY OF
SORT OF BRINGING TOGETHER GROUPS
THAT COULD LEARN FROM EACH
OTHER.
I LOVED THE PICTURES OF LAMBS
AND SHEEP THAT WERE IN PAIN.
JEFF MOGUL, 15 YEARS AGO, CAME
UP WITH A MOUSE SCALE -- I
HONESTLY CAN'T TELL THE
DIFFERENCE.
BUT I THINK THAT THAT COULD BE
EXPANDED.
AGAIN, AI AND OBSERVATIONAL FACE
RECOGNITION AND ALL OF THIS
STUFF.
SO, TWO THINGS.
ONE IS SMALL AND LARGE ANIMAL
TOGETHER AND THE OTHER ONE IS
THE TECHNOLOGY THAT WAS
SUGGESTED FOR ADVANCEMENT OF
WAYS TO MEASURE INTERACTIONS
BETWEEN ANIMALS OR RESPONSES TO
PAINFUL STIMULI MIGHT BE USEFUL.
>> GREAT.
THANK YOU FOR THOSE COMMENTS.
AND YOU'RE RIGHT.
THE FDA HAS FIGURED OUT HOW DATA
SHOULD BE PACKAGED UP AND IN
ORDER TO MAKE IT WORK AND BE
VERIFIABLE AND THE NIH HAS AN
ONGOING INITIATIVE TO MAKE DATA,
GOT TO GET THIS RIDE, FINDABLE,
SEARCHABLE.
>> RELIABLE.
>> BUT THAT'S A VERY IMPORTANT
PART OF SHARING DATA.
WE NEED TO MAKE SURE IT'S IN A
FORMAT THAT EVERYONE CAN USE AND
IN THE RIGHT PLACE.
YOUR COMMENTS ARE WELL TAKEN.
AI WILL NOT MOVE FORWARD UNLESS
THE DATA REPOSITORIES ARE THERE
IN A WAY THAT CAN BE READ.
I THINK THAT WILL BE A GREAT
THEME TO BRING PEOPLE TOGETHER
AND TALK ABOUT COLLABORATION,
HOW DO WE COLLABORATE TO CREATE
THOSE APPROPRIATE DATASETS.
THANK YOU.
>> I GREATLY ENJOYED THE PAST
FEW DAYS, THANK YOU.
I WOULD BE REMISS AND NOT
PLUGGING MAYBE AN ANALYSIS OF
MOLECULAR BASIS FOR PAIN,
MOLECULAR ALTERATIONS THAT
OCCUR.
THERE HAS BEEN SO MUCH WORK
USING RNA SEQUENCING AND IN SITU
HYBRIDIZATION LOOKING AT EVENTS,
CERTAINLY IN THE PERIPHERY AND
CENTRALLY.
I THINK WE COULD DO THAT.
AND JOHN, I REALLY LIKE THE IDEA
OF LOOKING AT ETHOLOGICAL KIND
OF EXPERIMENTAL DESIGNS, ANIMAL
INTERACTIONS.
YOU COULD PICK THINGS OUT.
THERE ARE SOME REALLY GREAT
STUDIES THAT HAVE BEEN DONE ON
MICE.
>> THAT WHOLE SOCIAL THING,
THAT'S A GREAT IDEA.
I MEAN, IT'S UNDERSTANDING THE
EFFECTS OF PAIN BEHAVIORS ON
SOCIAL INTERACTIONS AND ON
SOCIAL INTERACTIONS IS A AREA OF
MEASUREMENT THAT I DON'T THINK
HAS BEEN EXPLORED VERY MUCH.
>> I'M VERYING TROUBLE SEEING
AGAINST THE LIGHTS.
>> JAMES HARRIS.
FIRST TIME ATTENDING THIS
WORKSHOP.
THANK YOU VERY MUCH FOR PUTTING
THIS TOGETHER.
I APPRECIATED THE DUALITY OF THE
HUMAN WORK GOING TOWARDS HUMAN
AND HUMAN GOING TOWARDS ANIMAL.
WE HEARD A LOT ABOUT PAIN
ASSESSMENT COMING FROM THE HUMAN
WORLD.
THERE IS MORE A CLASSIFICATION,
LIKE WHAT IS THE PAIN GENERATOR?
WHICH DR. CRAWFORD POINTED OUT
PERIPHERAL.
FOR HUMAN WORK, THERE IS A LOT
OF DEVELOPMENT TO UNDERSTANDING
WHAT TYPE OF PAIN YOU'RE
TREATING WHETHER NEUROPATHIC, OR
NEUROSUSCEPTIVE.
AND THAT IS NEEDED FOR
REIMBURSEMENT, WHICH IS PRETTY
MUCH THE REASON THAT ALL
COMPANIES ARE DOING DEVELOPMENT.
SO, I APPRECIATE ALL OF THESE
PRODUCTION ANIMALS AND LIVESTOCK
STUDIES THAT I THINK COULD ALSO
BE HELPFUL TOL UNDERSTAND
CLASSIFICATION AND WE HAVE A
WIDE RANGE OF SMALL ANIMAL
MODELS.
APPRECIATE THE NIH FOR THE
FUNDING, BUT I THINK A MORE
DEVELOPED DISCUSSION ABOUT PAIN,
DIFFERENT PAIN GENERATORS AND
SOURCES AND CLASSIFICATION
BETWEEN HUMAN AND ANIMAL WORK
COULD BE REALLY HELPFUL.
>> SO YOU THINK THAT SPEAKS TO
PAIN PHENOTYPING?
LIKE REALLY UNDERSTANDING THE
PHENOTYPE AND THE ENDOTYPE.
THERE ARE COMMENTS ABOUT
PHENOTYPING IN ORDER TO
UNDERSTAND WHAT SUBJECTS WE'RE
BRINGING INTO STUDIES.
I'M THINKING YOUR CONCEPT ABOUT
WHAT IS DRIVING THE PAIN SPEAKS
TO THE ENDOTYPE.
WHAT EXACTLY IS GOING ON ON A
MOLECULAR AND CELLULAR BASIS.
>> I THINK THE WHOLE PAIN FIELD
IS STILL WORKING ON ENDOTYPE
VERSUS PHENOTYPE AS FAR AS WE DO
ALL OF OUR MEDICINE MOSTLY ON
SYMPTOMS ANYWAY BUT HOW DO WE
TRANSITION FROM WHAT WE SEE NOW
TO A DEEPER UNDERSTANDING SO
THAT WE CAN DO THIS
PERSONALIZATION OF PAIN
TREATMENT?
>> THANK YOU.
>> THIS HAS BEEN A GREAT DEAL OF
FUN.
I REALLY ENJOYED THIS.
JUST ONE COMMENT AND THEN MAYBE
AN IDEA FOR THE FUTURE.
AT FDA, I DON'T WORK FOR CDM BUT
I DO REVIEW NON-CLINICAL ANIMAL
DATA FOR HUMAN DRUGS.
I WILL SAY THAT SEND F THAT'S
WHAT YOU'RE REFERRING TO, IN A
STANDARDIZED FORMAT, RIGHT NOW I
WORK FOR THE CENTER FOR BY
LOGICS.
THE STANDARDIZED FORMAT IS
REQUIRED FOR ALL TOXICOLOGY DATA
FOR SMALL MOLECULES AS WELL AS
LARGE COMING INTO FDA.
THAT IS SOMETHING THAT IS MOVING
ALONG.
IT'S NOT REQUIRED FOR DISCOVERY
BUT CERTAINLY FOR SAFETY.
AND I WAS JUST THINKING, ONE OF
THE THINGS THAT SURPRISED ME
WHEN I CAME FROM CLINICAL
STARTING TO WORK IN REGULATORY,
THAT IS, I THINK A NICE ADD IS
THAT THE FDA WILL SOLICIT
PATIENT PERSPECTIVES WHEN IT AND
TO THE APPROVAL OF A NEW
PRODUCT.
SO WHEN I WAS LISTENING TO ONE
OF THE FORMER TALKS ABOUT WHAT'S
CONSIDERED GOOD?
LIKE WHAT'S CONSIDERED A
RESPONSE?
I THINK IT WOULD BE INTERESTING
TO HEAR PERSPECTIVES FROM
PRODUCERS AND OWNERS AND
STAKEHOLDERS IN ANIMAL
INDUSTRIES AS TO WHAT IS THE
BENCHMARK OF I'M GOING TO APPLY
THIS OR NOT AND IS THAT
DIFFERENT FROM THE ACADEMIC
CLINICIAN, THE RESEARCH
SCIENTIST AND HOW THOSE TWO
PERSPECTIVES WOULD HAVE TO COME
TOGETHER TO HAVE A SUCCESSFUL
OUTCOME.
>> SO, SPEAKING OF STAKEHOLDERS
TO FIND OUT WHAT WOULD BE
MEANINGFUL IN THEIR EYES IN
TERMS OF THE TYPE OF RESPONSE
THEY WANT TO SEE?
>> BECAUSE AT THE END OF THE
DAY, YOU COULD HAVE ALL THESE
PAPERS AND LIKE HIGH-IMPACT
JOURNALS BUT IF IT DOESN'T
IMFACT BOOTS ON THE GROUNDWORK
THAT IS ACTUALLY HAPPENING IN
WHATEVER SETTING, PRODUCTION
SETTING, CLINICAL PRACTICE, I
THINK THE GAIN IS LESS.
>> THANK YOU.
GREAT COMMENTS.
>> VERONICA SMITH, MEDICAL
ETHICS, AUSTRALIA.
THANK YOU FOR THE LAST TWO DAYS.
IT MADE OUR FLIGHT WORTH IT.
JUST A COUPLE OF -- JUST A
COMMENT AS SOMEONE WHO HAS BEEN
WORKING WITH ANIMALS FOR OVER 20
YEARS AND IS A FARMER AS WELL
FOR THE LAST 10.
IT IS FRUSTRATING TO HEAR
EVERYONE SAY SO MUCH ABOUT THE
ANIMALS AREN'T TELLING YOU.
YOU CAN'T TALK TO THEM.
THE ANIMALS REALLY ARE.
AND YOU ALL KNOW.
THEY ARE TALKING TO YOU EVERY
MINUTE AND TELLING YOU WHETHER
THEY ARE IN PAIN OR WHETHER THEY
ARE HAPPY.
AND THERE IS A WORD I LIKE TO
USE WHICH IS, WELL-BEING, RATHER
THAN WELFARE.
AND THAT'S ABOUT ANIMAL'S
QUALITY OF LIFE.
SO, I SORT OF WANT EVERYONE TO
STOP SAYING THAT THEIR ANIMALS
AREN'T TALKING TO THEM.
BECAUSE YOU KNOW THAT THEY ARE.
BUT, ALSO THAT LEADS TO FOR
FUTURE PLANNING.
MAYBE WE NEED TO BE DOING MORE
WORK IN WHAT IS NORMAL.
SO BEHAVIOR IN ANIMAL THAT IS IN
A HAPPY STATE, AND THEN THIS
WILL FREAK THE CVM PEOPLE OUT.
IS MAYBE RATHER THAN LOOKING AT
THEIR RESPONSE COMPARED TO A
PLACEBO, LOOK AT THEIR RESPONSE
COMPARED TO WHAT THAT
STANDARDIZED NORMAL SHOULD BE.
BUT THAT'S GOING TO ALSO HELP
OUR AI FRIENDS BECAUSE WE'LL
HAVE THAT BANK OF INFORMATION
ABOUT WHAT WE CONSIDER TO BE
NORMAL BEHAVIOR.
YES, WE'LL HAVE TO MEET AND
STUDY WITH DIFFERENT SEXUAL
SPECIES INTERACTIONS AND
ENVIRONMENTAL INTERACTIONS
AND -- ALL SORTS OF -- AND AGE
GROUP INTERACTIONS AS WELL.
SO THERE IS A LOT TO DO BUT
MAYBE THAT'S SOMETHING WE NEED
TO FOCUS ON.
>> GREAT COMMENTS.
THANK YOU.
>> MARK WISE, NICE TO MEET YOU.
REALLY ENJOYED THE MEETING AND
THESE COMMENTS.
WHAT I HEARD WAS, YESTERDAY WE
HEARD THE C SONG VERSUS THE LOAD
MEASURES.
AND WHAT IT SOUNDS LIKE THINGS
THAT WE'RE STRUGGLING WITH IS
THE METROLOGIY COMPONENT THAT
WAS BROUGHT UP EARLIER.
AND AND WE DON'T KNOW WHAT ARE
THE MOST SENSITIVE MEASURES AND
WE'RE DANCING AROUND THE
SENSITIVE MEASURES AND THEN
SCALING THESE MEASURES OR
NORMALIZING THESE MEASURES.
AND TODAY THE TALK ABOUT
MULTIDIMENSIONAL MEASURES AND
INTEGRATING OR PARSING THOSE.
SO I DON'T REALLY KNOW THE
ANSWER BUT I THINK THAT SOMEHOW
WE HAVE TO MAYBE THROUGH A
META-ANALYSIS OR SOME KIND OF
STATISTICAL ANALYSIS, DETERMINE
WHICH OF OUR TESTING IS THE MOST
SENSITIVE FOR US SO WE'RE NOT
MEASURING FIVE DIFFERENT, 10
DIFFERENT, 20 DIFFERENT WAYS.
OR EVEN MEASURING THE SAME THING
IN SLIGHTLY DIFFERENT FACETS OF
THE PRIMP.
SO MAYBE SOME KIND OF PULLING
TOGETHER THAT SO THAT WE COULD
HAVE A MORE UNIFIED MEASURE
RATHER THAN ALL OF THESE
DIFFERENT -- AND IT MAY BE
HELPFUL TO MOVE TO HEAR FROM THE
HUMAN SIDE OF THINGS, BECAUSE
THE ISSUE, ESPECIALLY THE
REGULATORY ISSUE THAT I HEAR IS,
WE START OFF WITH VERY NARROW
POPULATIONS THAT WE'RE TESTING
WITHIN AND WE CAN GENERALIZE AN
EFFECT SIZE BUT AS WE MOVE INTO
BROADER AND MORE DIVERSE
POPULATIONS, THE EFFECT SIZES
CHANGE OR WE HAVE RESPONDER AND
NON-RESPONDER POPULATIONS.
AND UNTIL WE GET TO THAT, THAT
WE CAN PHENOTYPE AND DO IT RIGHT
AND THEN SCALING FOR THE
APPROPRIATE PHENOTYPE,
EVERYTHING IS JUST FUZZ.
IT'S A HAZE.
SO I DON'T KNOW HOW DO YOU IT.
BUT SOMEHOW IT NEEDS TO GET
INTEGRATED BECAUSE THE
REGULATORY COMPONENT IS GOING TO
BE TOUGH TO OVERCOME BECAUSE AS
WE ENCOMPASS LARGER AND MORE
DIVERSE POPULATIONS AND THE
EFFECT SIZES IMPACTED, THEN HOW
DO WE REACH REGULATORY ENDPOI
ENDPOINTS?
THAT WAS VERY POORLY WORDED.
>> NOT AT ALL.
GREAT COMMENTS.
AND I THINK FROM ALL OF THE
COMMENTS AND EVERYTHING WE HEARD
IT'S CLEAR WE ARE MOVING IN THE
RIGHT DIRECTION.
IT'S ALL POSITIVE BECAUSE WE ARE
HAVING DISCUSSIONS AND COMING
TOGETHER TO MEET LIKE THIS AND
TO DISCUSS THESE DIFFICULTIES
AND HURDLES AND THESE
OPPORTUNITIES.
SO THANK YOU TO EVERYONE.
SAFE JOURNEY HOME.
AND SEE YOU NEXT TIME.
I DON'T KNOW WHEN THAT WILL BE.
[ APPLAUSE ]