WELCOME TO OUR WORKSHOP SMALL AND LARGE COMPANIES ACROSS THE WORLD. AND AS OF 2020 SHE JOINED AS A CHIEF MEDICAL OFFICER. HER EXPERIENCE AND EXPERTISE CROSSES MULTIPLE DISEASE AREAS SPECIFICALLY EPILEPSY, ALS PARKINSON'S, PAIN AND M.S. AND CHILD AND ADULT NEUROLOGY. SO THANK YOU AMY. MOVING TO BOB HE IS A PROFESSOR OF ANESTHESIOLOGY AND NEUROLOGY AND PSYCHIATRY AND PROFESSOR IN THE CENTER OF HEALTH AND TECHNOLOGY AT THE UNIVERSITY OF RODCHESTER SCHOOL OF MEDICINE AND DENTISTRY. BOB'S MAJOR RESEARCH INTERESTS ARE METHODOLOGIES FOR ANALGESIC TRIALS AND PREVENTION AND ACUTE NEUROPATHIC AND MUSCULOSKELETAL PAIN AND WORKS IN ASSAY SENSITIVITY AND CLINICAL TRIAL DESIGN TO LOOK AT ACTIVE AND PLACEBO CONTROL AND TREATMENT. AN ILLUSTRATIVE CAREER AND HAS A PUBLIC-PARTNERSHIP WITH THE FDA AND PROMOTE INNOVATIVE ACTIVITIES. WE'RE FORTUNATE TO HAVE HAD BOTH AMY AND BOB HELP US ON THE OUTSIDE TO THINK OF WHAT IS MEANING IT WILL TO BRING THE COMMUNITY TOGETHER AND BETTER PLAN AHEAD FOR END POINT CLINICAL TRIALS. AND I WOULD LIKE TO THANK OUR COLLEAGUES. I'D LIKE TO WITH THOSE WHO RECENTLY JOINED US TO LEAD THE PLATFORM SCREENING PROGRAM AND REBECCA HUMMER WHO IS ALSO PROJECT MANAGER WITHIN THE DIVISION OF CLINICAL RESEARCH AND MOSTLY I WANT TO THANK JENNIFER AND MARA WHO HAS BEEN COORDINATING ALL OF US AND LAUNCHING WHAT I WOULD EXPECT TO BE A REALLY AMAZING TWO-DAY WORKSHOP. PRIVILEGED TO INTRODUCE DR. MENA SHORE AT THE INSTITUTE OF NEUROLOGICAL DISORDER AND STROKE AND JOINED AS A DEPUTY DIRECTOR SHE HAD BEEN A CHAIR IN THE DEPARTMENT OF PEDIATRICS AND CHIEF OF THE CHILDREN'S HOSPITAL SINCE 2006. PRIOR TO THAT SHE SPENT 20 YEARS AT THE UNIVERSITY OF PITTSBURGH AND ASSOCIATE DEAN FOR MEDICAL STUDENT RESEARCH AT THE MEDICAL SCHOOL. HER RESEARCH INTERESTS HAVE BEEN IN NEUROBLASTOMA AND SPENT A GOOD PORTION OF HER CAREER UNDERSTANDING THE TUMOR BIOLOGY AND STRATEGIES. WITH THAT I'D LIKE TO ASK NINA TO START US OFF. >> THREW TO THE COMMITTEE AND -- >> THANK YOU TO EVERYONE AND EVERYONE WHO SUPPORTED US AND THANK YOU FOR EVERYONE NO MATTER THE TIME ZONE AND I KNOW IT WILL A FRUITFUL AND VIGOROUS CONVERSATION AND JUST THE BEGINNING OF WHAT I HOPE WILL LAUNCH A MANY YEAR EFFORT TO DEVELOP NEW THERAPIES FOR PAIN, PARTICULARLY NON-ADDICTING THERAPIES FOR PAIN. SO IF I CAN HAVE THE NEXT SLIDE. THIS IS A VIEW OF HEAL INITIATIVE HELPING END ADDICTION LONG TERM. IT INVOLVES MANY INSTITUTES AND MORE THAN 20 DISTINCT PROGRAMS. SOME OF THEM VERY MUCH TARGETED TO PARTICULAR KINDS OF PAIN POPULATIONS ADDICTED TO PAIN MEDICATIONS. IT'S LED BY A GROUP OF NIH INSTITUTES AND CENTERS THAT COLLABORATE WITH ONE ANOTHER. IT WAS FUNDED BY CONGRESS THROUGH AN INITIATIVE AIMED AT RIDDING THE WORLD, REALLY, OF ADDICTION AND CHRONIC PAIN AND THE PROBLEMS ASSOCIATED WITH THE MEDICATIONS CURRENTLY AVAILABLE TO DEAL WITH PAIN. THE NEXT SLIDE GIVES A PICTORIAL VIEW OF THIS AND TO BE SUCCESSFUL ON THE ONE HAND TO DEAL WITH CHRONIC PAIN AND RID THE WORLD WITH CURRENTLY AVAILABLE THERAPIES. WE'LL NEED TO IDENTIFY ROBUST TARGETS WE CAN AIM OUR THERAPIES AND WILL NEED TO TARGET THOSE ENTITIES RESPONSIBLE FOR PAIN. WE'LL NEED TO DEVELOP THERAPEUTIC END POINTS THAT SAY, YES WE HAVE MADE A DENT IN THIS PAIN AND WE HAVE QUANTITATIVE MEASUREMENTS FOR THE PAIN AND NEED VALIDATED MEASURES TO ALLOW TO US SAY, PATIENTS ARE FUNCTIONING BETTER AND FEELING BETTER AS A RESULT OF CHANGING THE QUANTITATIVE PARAMETERS. WE'RE GOING TO FOCUS ON WHAT WE WANT AS THE QUANTITATIVE END POINTS AND WHAT WILL THIS MEAN QUALITATIVELY FOR THE LIVES FOR THE PATIENTS TO WHOM THE AGENT ARE GIVEN. AND THEY'RE TWO SIDES OF EXACTLY THE SAME COIN BUT WITHOUT EITHER ONE OF THEM WE BELIEVE IT LACKS THE SCIENTIFIC EVIDENCE WE NEED TO VALIDATE THERAPIES OR WILL LACK THE PATIENT POPULATIONS THAT WILL BE THE BENEFICIARIES OF THIS WORK WE'LL DO IN THE NEXT DAY OR SO. THE NEXT SLIDE IS A DEFINITION I FEEL LIKE I'M BRINGING COALS TO NEWCASTLE BUT THE CLINICAL OUTCOMES ARE THE DIRECT MEASURES OF WHICH I JUST SPOKE. THE MEASURES THAT SAY WE HIT THE TARGET AND THE MEASURES WE GET FROM THOSE PATIENTS AND SAYING THEIR LIVES ARE BETTER AND MORE PAIN FREE AND END POINTS GIVE THE VALIDATION OF THE SUBJECTIVE MEASURES WE MAKE IN OUR CLINICAL OUTCOMES THAT IS TO SAY ARE THERE SIGNAL TRANSDUCTION PATHWAYS FOR EXAMPLE THE EFFECTERS OF WHICH CHANGE RELIABLY IN QUANTITATIVE WAYS WHEN A PATIENT FEELS BETTER AND ARE THERE THINGS WE CAN MEASURE AND VALIDATE FOR US A CHANGE IN THE RESPONSE OF A PARTICULAR TARGET. WE ARE NOT THE FIRST TO TRY TO TRY TO MEASURE THE IMPACT WE'RE HAVING ON PAIN. FOR SURE IN THE NOT TOO DISTANT PATH WE HAVE USED INSTRUMENTS AND TRIED TO QUANTITATE WHAT HAS BEEN A QUALITATIVE AND SUBJECTIVE MEASURE. WHAT YOU SEE DEPICTS HERE ARE TOOLS TO MEASURE THRESHOLD FOR PAIN OR TOLERANCE TO PAIN BUT THEY'RE NOT ENDOGENOUS PAIN AND HAVEN'T TARGET WHAT'D TROUBLES PATIENTS. ON THE NEXT SLIDE YOU SEE WHAT THE FIELD HAS TRADITIONALLY DONE WITH THIS AND WHAT I'VE DONE TAKING CARE OF PATIENTS. I'VE TRIED TO TURN SOMETHING SUBJECTIVE AND QUALITATIVE INTO EXPECT I CAN QUANTIFY. HOW BAD IS THE CHARACTER OF THE PAIN AND WHAT MAKES IT BETTER AND WORSE AND WHAT COMES WITH IT? THESE ARE END POINTS BUT VERY DIFFICULT TO QUANTIFY FROM ONE PATIENT TO THE NEXT WE SAID IS THE PAIN CHRONIC ENOUGH, DISABLING ENOUGH IT CAUSES FRUSTRATION OR DEPRESSION OR THAT IT CAUSES YOU INABILITY TO FUNCTION IN YOUR EVERY DAY LIFE. THAT IS TO SAY CAN WE QUANTITATE THE IMPACT THIS PAIN HAS ON THE DAY YOU GO ABOUT YOUR EVERYDAY LIFE. AGAIN, THIS IS NOT QUANTITATIVE IN ANY SYSTEMATIC SENSE. DIFFICULT TO STANDARDIZE AND EQUA EQUATE BETWEEN COHORTS OR THERAPIES. QUE SAID ARE THERE ENTITIES INVOLVED IN THE MECHANISM OF PAIN THAT RELIABLY CHANGE WITH PATIENT FUNCTION OR WITH PATIENT CHARACTERIZATION OF OUTCOME. AND WE'VE HAD PROBABLY MORE SUCCESS WITH TURNING THIS IN TO SOMETHING QUANTITATIVE BUT WHEN YOU GO BACKWARDS AND SAY DOES THIS QUANTITATION MEAN SOMETHING FOR THE PATIENTS WE TREATED YOU'RE UNABLE TO DO THIS AND SAY THESE NUMBERS MEAN ANYTHING AS FAR AS THE PATIENTS WE'RE TRYING TO TREAT. AGAIN, THIS LOOKS QUANTITATIVE BUT DOES IT HELP US ACHIEVE OUTCOMES? PROBABLY NOT. THE NEXT SLIDE GIVES A SENSE OF WHAT THE FDA HAS DONE IS SAID MAYBE WE NEED TO DO IS ASK HOW MUCH MEDICATION DO YOU HAVE TO TAKE AND HOW ADDICTING OF MEDICATION DO YOU HAVE TO TAKE? HOW LONG DO YOU HAVE TO TAKE IT AND HOW BIG A DOSE AND HOW MUCH RELIEF DO YOU GET FROM THIS? AGAIN, THIS IS NOT STANDARDIZABLE FROM PATIENT TO PATIENT. THE BIOAVAILABILITY OF DIFFERENT MEDICATION MAY BE QUITE DIFFERENT FROM PATIENT TO PATIENT. AGAIN WE GET INTO THE PROBLEM OF STANDARDIZATION AND MAKING SOMETHING MEANINGFUL FOR OUTCOMES FOR PATIENTS OUT OF REGULATORY MEASURES OF THE IMPACT WE'RE HAVING. YOU SEE WHAT WE'RE TRYING TO ACHIEVE THE WAYS OF MEASURING THERAPIES OF PAIN HAVE BEEN UNABLE TO AFFORD US. WHAT WE HOPE TO ACHIEVE PARTLY AS A RESULT OF THE CONVERSATION THAT'S GOING TO HAPPEN OVER THE NEXT FEW HOURS IS STANDARDIZATION OF MEASUREMENT AND PRE-HOC SO IF FIVE GROUPS DO A STUDY THEY'RE ALL SPEAKING THE SAME LANGUAGE WHEN THEY COME OUT WITH RESULTS OF THE STUDY SO WE CANNOT HAVE TO HARMONIZE RESULTS AFTER THE STUDIES ARE COMPLETED. WE NEED STAKE HOLDERS INCLUSION AND NEED VIGOR AND DESCRIPTIVE TRANSPARENCY AND CONSISTENT TERMINOLOGY. I MUST SAY THIS HAS BEEN A BIG PROBLEM IN EVERY FIELD OF MEDICINE WHEN TWO PHYSICIANS OR SCIENTISTS OR TWO PHARMACOLOGISTS OR PHARMACIES TALK ABOUT THE SAME OUTCOME AND USE DIFFERENT LANGUAGE. WHAT DO YOU MEAN IMPROVEMENT IN PAIN DO YOU MEAN THE PATIENT CAN GO TO WORK EVERY DAY OR DOESN'T FEEL DISCOMFORT OR DO YOU MEAN THEY DON'T HAVE TO TAKE ANY MEDICATION TO FEEL BETTER? YOU NEED ACCOUNTING FOR THE NATURAL HISTORY OF THE PAIN AND CHRONIC BECAUSE OF THE ETIOLOGY AND WILL PAIN IMPROVE ON ITS OWN AND HOW DO YOU ACCOUNT FOR THAT WHETHER YOU ASK WHETHER A MEDICATION HAS OR HAS NOT MADE A DENT IN THAT CONDITION. THEN AN IMPORTANT THING IS THE FUNCTIONAL SIGNIFICANCE FOR THE PATIENT'S AFFECTED BY THE PAIN IS CRITICALLY IMPORTANT. WHAT DIFFERENCE HAS THIS MADE FOR THE EVERYDAY LIVES IN THE PEOPLE WE'RE SERVING. YOU'LL SEE THE MARCHING ORDERS FOR THE WORKSHOP AND THEY'RE NO SMALL TASK. THAT'S WHY WE'VE ENGAGED SUCH A DIVERSE AND WONDERFULLY ACCOMPLISHED GROUP OF PEOPLE AS YOU. WE HOPE THIS WORKSHOP EMBRACES DIVERSE VIEW POINTS. PEOPLE WHO COME AT THE PROBLEM OF SOLVING PAIN WITHOUT CAUSING ADDICTION THAT ALL OF YOU AND EACH OF YOU REPRESENT DIFFERENT APPROACHES TO THIS ISSUE AND DIFFERENT TOOLS WE CAN BRING TO BEAR ON THIS ISSUE. WE HOPE THERE WILL BE A FREE AND OPEN DISCUSSION THAT INVOLVES SHARING OF ALL OF THESE TOOLS AND ALL OF THESE APPROACHES THAT WILL REALLY IDENTIFY OPPORTUNITIES TO CHANGE THE OUTCOMES OF THERAPEUTICS FOR PATIENTS AND FAMILIES. WE'LL EXPLORE THE STATE OF SCIENCE AND IDENTIFY GAPS WE CAN HELP FILL AND THAT NIH CAN HELP PLAY A ROLE IN FILLING THOSE GAPS AND THEN REVIEW END POINTS THAT ARE CURRENTLY BEING USED IN PHASE 1 AND PHASE 1 STUDIES THAT PERHAPS WE DON'T HAVE TO START FROM SQUARE 1 WHEN WE DEVELOP OUTCOME MEASURES FOR THE ONGOING STUDIES. THE NEXT SLIDE IS WHAT WE HOPE WE'LL GET AT THE END OF THIS. WE'RE HOPING TO CREATE RECOMMENDATIONS FOR OUTCOME MEASURES TO BE DEVELOPED FOR CLINICAL TRIALS. NOT JUST OF DRUGS BUT OF DEVICES AS WELL. WE CAN COME OUT WITH RECOMMENDATIONS FOR APPROACHES THAT WILL DEVELOP INONGOING FASHION OUTCOME MEASURES THAT HAVE EVER MORE USEFUL AND PRACTICAL, MEANINGFUL TO THE PATIENTS WE SERVE AND THAT WE WILL BE ABLE TO PUBLISH THIS AND GUIDE THE FIELD AND THOSE NOT PART OF THIS DISCUSSION AS THEY GO ON TO DO CLINICAL TRIALS AS WELL. FINALLY, WE WANT TO THANK YOU. WE'RE GRATEFUL FOR YOUR INPUT AND DIVERSE EXPERIENCE AND THE WAY IN WHICH YOU HAVE GIVEN OF YOUR TIME YOUR EFFORT AND EXPERTISE AT A CHALLENGING TIME FOR ALL OF US. I THINK IT'S NOT LOST ON ANY OF US AT NINDS YOU HAVE COMPETITION FOR YOUR TIME AND EFFORT AND SO GRATEFUL FOR YOU BEING WITH US OVER THE NEXT DAY THANK YOU TO THE ORGANIZING COMMITTEE FOR ALLOWING ME TO SPEND TIME TALKING WITH YOU. THANKS A LOT. >> THANK YOU, NINA. HELLO, EVERYONE. I'D LIKE TO WELCOME YOU ON BEHALF OF MY CO-CHAIR BOB AND MYSELF. I'D ALSO LIKE TO GIVE A HUGE THANK YOU TO THE ORGANIZERS, FACILITATORS AND PARTICIPANTS IN THIS WORKSHOP AS YOU KNOW IT TAKES A GREAT DEAL OF PLANNING AND ORGANIZING TO PUT A WORKSHOP LIKE THIS TOGETHER. A BIG THANKS TO THOSE WHO CONTRIBUTED TO THAT EFFORT. AS NINA POINTED OUT HEAL HAS THE DIRECTIVE OF NEW MEDICATIONS AND DEVICES PARTICULARLY NON-OPIOID. TO THAT END HEAL HAS HAD TWO PREVIOUS WORKSHOP. ONE IN PRECLINICAL END POINTS AND ANOTHER ADDRESSING BIOMARKERS AND THIS IS THE THIRD WHERE WE TALK ABOUT MEANINGFUL CLINICAL END POINTS. WE HOPE YOU'LL BE AS CREATIVE AS POSSIBLE WE WANT THESE END POINTS TO BE ACCEPTABLE TO REGULATORS. SHORT OF THAT WE WANT YOU TO BE CREATIVE AND HOPEFULLY COME UP WITH INTERESTING AND NEW CLINICAL END POINTS. SO ONE OF OUR GOALS WAS TO ASSEMBLE A DIVERSE GROUP OF STAKEHOLDERS AND IF YOU LOOKED AT THE LIST OF ATTENDEES YOU'LL AGREE WE'VE DONE THAT. WE HOPE TO IDENTIFY SCIENTIFIC GAPDZ AND DEVELOPMENT -- GAPS AND DEVELOPMENT TRIALS THROUGH THE PROCESS. WE WANT TO DISCUSS DIFFERENT MEANS OF STUDYING ACUTE, SUBACUTE AND CHRONIC PAIN CONDITIONS. WE WANT TO ADDRESS WAYS TO DEAL WITH HETEROGENEITY AND VARIABILITY IN PAIN PATIENT POPULATIONS AND TO IDENTIFY NOVEL APPROACHES TO STUDY PAIN. SO WE HAD SEVERAL DELIVERABLES FOR THE WORKSHOP. WE WANT SUGGESTIONS FOR NOVEL END POINT MEASURES AND CLINICAL TRIALS. WE WANT TO REVIEW AND DISCUSS GUIDELINE FOR ESTABLISHING IMPROVED OUTCOME MEASURES AND END POINTS FOR CLINICAL TRIALS AND ULTIMATELY WE'D LIKE TO PUBLISH A WHITE PAPER SUMMARIZING THE WORKSHOP FINDINGS AND RECOMMENDATIONS. AS NINA SAID THIS IS A LOT TO BITE OFF IN TWO DAYS BUT HOPEFULLY WE CAN GET A GOOD START AND WITH THAT I'LL TURN THINGS OVER TO BARBARA KARP AND SMITRI IYENGAR. >> THIS IS A LITTLE BIT OF OVERLAP WITH WHAT NINA SHOWED YOU EARLIER. THERE'S MORE THAN 25 HEAL RESEARCH PROGRAMS INVOLVING 20 NIH INSTITUTES AND CENTERS ALL COLLABORATING ON THE STUDIES WITH A TRANS-NIH GOVERNANCE STRUCTURE. IT'S A PARTNERSHIP ACROSS GOVERNMENT COMMUNITIES AND PRIVATE SECTOR WITH A RAY OF RESEARCH SPAN FROM IDENTIFICATION EARLY DEVELOPMENT ALL THE WAY THROUGH CLINICAL TRIALS AND LATE-PHASE TRIALS INCLUDING EFFECTIVENESS BASED RESEARCH. THIS IS WHERE WE SIT WE'RE IN THE PAIN MANAGEMENT SPACE. I WANT TO TALK ABOUT EPIC NET. THAT'S THE CLINICAL TRIALS NETWORK WHERE WE'RE ALSO INTERESTED IN TRYING TO OPTIMIZE OUR CLINICAL TRIALS FOR PAIN AND THAT PROVIDED PART OF THE SETTING FOR THE WORKSHOP. THE EARLY PHASE PAIN NETWORK IS FOCUSSED ON ACCELERATING EARLY PHASE CLINICAL TRIALS OF NON-ADDICTIVE PAIN THERAPEUTICS AND NOT FOCUSSED ON ANY PARTICULAR TYPE OF THERAPEUTIC. WE'RE INTERESTED IN SMALL MOLECULES, BIOLOGICS AND DEVICES AND ALSO NOT FOCUSSED ON ANY PARTICULAR TYPE OF PAIN. WE'RE OPEN TO CONSIDERATION OF THERAPEUTICS FOR ANY PAIN INDICATION. THE GOALS OF EPIC NET INCLUDING PROVIDING ACADEMIC AND EXPERTS WITH EXPERT PAIN AND CLINICAL TRIAL INFRASTRUCTURE. AND THAT INFRASTRUCTURE INCLUDES A DATA CENTER AND COORDINATING CENTER AND HUBS AND SPOKES WHERE THE RESEARCH WILL BE CONDUCTED. THE HUBS AND SPOKES ARE ACADEMIC PAIN RESEARCH CENTER WITH ACCESS TO A BROAD RANGE OF PATIENTS BUT DIVERSE IN RACE, ETHNICITY AND DEMOGRAPHICS AND IN TERMS OF PAIN CONDITIONS. WE TAKE IN APPLICATION IN MANY DOMAINS AND AFTER A ROBUST THREE-STEP REVIEW PROCESS IF IT'S ACCEPTED IN THE NETWORK WE DESIGN AND RUN THE CLINICAL TRIAL FOCUSSED ON PHASE 2. SO WE'RE LOOKING AT PHASE 2 CLINICAL TESTING OF NON-ADDICTIVE PAIN THERAPEUTICS FOR CONDITIONS OF UNMET NEED. PART OF OUR MANDATE IS TESTING AND VALIDATION OF BIOMARKERS RELATIVE TO THE PAIN CLINICAL TRIALS AND WE'RE INCORPORATING AND PHENOTYPING PAIN POPULATIONS. PART OF THE MANDATE IMPORTANT TO THE OUTCOME OF THE WORKSHOP IS CHARGED WITH EXPLORING INNOVATIVE PAIN DESIGNS AND WE'RE INTERESTED IN DEVELOPING OUR CLINICAL OUTCOME ASSESSMENTS. AS AMY MENTIONED WE HAVE WORKSHOP DELIVERABLES AND RECOMMENDATIONS FOR NOVEL MEASURES AND END POINTS FOR DRUG AND DEVICE PAIN THERAPEUTICS. RECOMMENDATIONS AND GUIDELINES FOR APPROACHES TO IDENTIFYING THESE IMPROVED OUTCOME MEASURES AND END POINTS AND PUBLICATION OF A WHITE PAPER SUMMARIZING WORKSHOP GUIDELINES. I'D LIKE TO TURN IT OVER TO SMRITI TO PROVIDE INFORMATION ON THE AGENDA OVER THE TWO DAYS OF THE WORKSHOP. >> THANK YOU, BARBARA AND ALL FOR YOUR PARTICIPATION. AS MENTIONED, OUR WORKSHOP IS FOCUSSED ON KEY OUTCOME MEASURES AND END POINTS AND TO THAT END WE WILL BEGIN WITH PAIN ON THE DEVELOPMENT PATHWAY BEING CHAIRED BY PANELISTS FROM THE NAD IT WILL BE FOLLOWED BY A PAIN THERAPEUTICS DEVELOPMENT PANEL AND THAT. AND THAT WILL BE FOLLOWED BY THE THIRD PANEL WHERE WE WILL LOOK AT END POINT LANDSCAPE AND THAT WILL BE CHAIRED ALSO. THEN WE'LL BREAK INTO BREAKOUT SESSIONS AND WE WILL WRAP UP AT 3:30 AND THEN BRING THE OUTCOME FROM THAT ON OCTOBER 15. ON DAY TWO, WE WILL BRING BACK FEEDBACK FROM TODAY'S DISCUSSION AND HOPEFULLY IT WILL LEAD TO A WHITE PAPER. TODAY'S SESSION WILL BEGIN WITH THE PAIN REGULATORY DEVELOPMENT PATHWAY. AND AS MENTIONED EARLIER DR. HERTZ BEEN THE MODERATOR. IT WILL BE FOLLOWED BY THE DEVELOPMENT PATHWAY. AND THE PANELS WILL INCLUDE THE FOLLOWING: [LISTING PANELISTS] . WE LOOK FORWARD TO YOU WILL THE DISCUSSIONS -- TO ALL THE DISCUSSIONS. THAT WILL BE FOLLOWED BY THE BREAKOUT SESSIONS. THERE'S THREE BREAKOUT SESSIONS. THE ACUTE PAIN BREAKOUT SESSION IS BEING CHAIRED. THE ACUTE TO CHRONIC PAIN SESSION IS MODERATED BY DR. ROBERT EDWARDS AND THE FOLLOWING: [LISTING] >> THE CHRONIC PAIN SESSION IS MODERATED BY DR. ARNOLD AND THE LAISON WILL BE ME. THE STAFF WILL BE SERVING TO MONITOR THE CHAT. IF YOU HAVE SPECIFIC QUESTIONS, PLEASE SUBMIT THESE QUESTIONS IN ZOOM INTO THE CHAT BOX OTHERWISE RAISE YOUR HAND. AND SO IF IF IT IS APPROPRIATE YOU'LL BE INVITED TO SPEAK. IF NOT, WE WILL COLLATE ALL THE QUESTION AND FEED THEM TO THE VARIOUS PANELS AND BREAKOUT SESSIONS. THANK YOU. DURING THE MEETING PLEASE ADDRESS ANY WORKSHOP QUESTIONS TO JENNIFER OR IF YOU HAVE I.T. QUESTIONS ADDRESS THEM TO DRECK RICHARDS AND THEIR -- DIRECT THEM TO GREGORY RICHARDS. WITH THAT WE'RE ALMOST READY TO BEGIN THE WORKSHOP SO I WILL INVITE THE PAIN REGULATORY DEVELOPMENT SESSION AND DR. DR. SHARON HERTZ TO BEGIN IN THE NEXT COUPLE MINUTES. THANK YOU. >> THANK YOU VERY MUCH FOR INVITING ME TO PARTICIPATE IN THIS MEETING. I APPRECIATE IT GREATLY. I'M INTERESTED IN NOT ONLY TO MODERATE THE PANEL BUT IN LISTENING TO AND PARTICIPATING IN THE DISCUSSION THROUGHOUT TODAY AND TOMORROW. TODAY DISCUSSION IS THIS TOPIC OF PAIN REGULATORY DEVELOPMENT PATHWAY AND I HOPE EVERYONE HAS HAD THE OPPORTUNITY TO LISTEN TO THE FIVE EXTREMELY WELL-DONE TALKS THAT OUR PANELISTS HAVE ALREADY PRE-RECORDED. I'M GOING TO START OFF WITH A LITTLE BIT OF BACKGROUND. I RETIRED FROM FDA IN DECEMBER BUT I WAS DIVISION DIRECTOR FOR THE DIVISION OF ACHE IS THEE THAT AND -- ANAESTHESIA AND ANALGESIA AND I WORKED WITH MANY OF THE PANELISTS. WE HAVE HEATHER FITTER FROM THE DEPARTMENT OF NEUROLOGY AND WE HAVE CHRIS LEPTAK FROM THE CENTER FOR DRUG EVALUATION. WE HAVE NAOMI CHLOE THE DEPUTY DIRECTOR OF MY FORMER DIVISION WE HAVE DR. PAPADOPOLOUS AND WE HAVE PAR CLOSE -- -- CARLOS PENA. AND BASED ON THE DISCUSSIONS AND PRESENTED YOU HEARD DO ANY OF YOU HAVE QUESTIONS FOR ONE ANOTHER? IF NOT WE HAVE A BUNCH OF QUESTIONS READY FOR YOU AND A FEW THAT HAVE COME IN THROUGH THE PROGRAM. >> YOU DESCRIBED THE TIMES WHEN A BIOMARKER CAN BE USED WHEN THE WAY A PATIENT SURVIVES IS NOT AVAILABLE AND ARE YOU AWARE OF SETTINGS WHEN BIOMARKERS ARE USED IN PLACE OF DIRECT PATIENT REPORTED OUTCOMES WHEN AVAILABLE? >> THANK YOU FOR THE INVITE. IN THE BIOMARKER SPACE THE OPPORTUNITY OF HAVING A BIOMARKER IMPACT IN A POSITIVE WAY IN A DRUG DEVELOPMENT EFFORT GOES ABOVE AND BEYOND END POINTS. THE MAJORITY OF OUR BIOMARKERS ARE USED AS INCLUSION TO IDENTIFY THE APPROPRIATE PATIENT POPULATION OR LOOK AT POTENTIAL SAFETY ISSUES. THERE'S MANY USES OUTLINED. WITH RESPECT TO THE END POINT QUESTION, CERTAINLY THE FIELD FUNCTION FOR DRUG APPROVAL IS PROBABLY NOT THE BIOMARKER SPACE. THE BIOMARKER SPACE IS MORE AROUND THE FUNCTIONALITY OF A PATIENT FOR SOME LIKE ARTHRITIS END POINTS HAVE BEEN AROUND ACTIVITY TO LOOK AT THE FUNCTIONALITY OF THE PATIENT INDEPENDENT OF HOW THEY FUNCTION GLOBALLY IF THEY HAVE KNEE ARTHRITIS HOW MUCH CAN THEY FLEX THE KNEE AND IS THERE A WAY TO MITIGATE THE INFLAMMATION AND SCARRING IN THE KNEE FOR DOWN STREAM EFFECT? THOSE ARE THE OPPORTUNITIES. IIF YOU GOOGLE FDA SURROGATE END POINTS YOU'LL SEE WHAT CAN BE UFRD FOR TARGETED OR TRADITIONAL APPROVAL AND YOU CAN SEE THERE'S ULTIMATELY HUNDREDS OF DISEASES WHERE BIOMARKERS HAVE BEEN USED AT SOME POINT. AGAIN IF ANY PANELISTS HAVE QUESTIONS FEEL FREE TO PARTICIPATE IN REAL TIME. THE WHOLE IDEA OF BIOMARKERS IS INTERESTING AND THERE'S INTEREST IN THE PAIN COMMUNITY ON A VARIETY OF BIOMARKERS FOR DIFFERENT REASONS INCLUDING AS YOU'VE SAID TO FURTHER CATEGORIZE PATIENT POPULATIONS WERE. SOUTHBOUND. . MANY COMPANIES HAVE COME IN FOR DEVELOPMENT PROGRAMS FOR A VERY LONG TIME. THE QUESTION IS WHAT EXTENT OF SEPARATION IS CONSIDERED A CLINICALLY MEANINGFUL STANDARDS WITH ONSET OF ANALGESIA AND WHAT IS NEEDED IN A CLINICAL TRIAL FOR LABELLING PURPOSES. I'D LOVE TO HEAR YOUR THOUGHTS ON THAT. >> SHARON, CAN YOU HEAR ME? >> GREAT. THANK YOU FOR HAVING ME ON THE PANEL TODAY. SO WE HAVE HAD THE MOST EXPERIENCE WITH THE DOUBLE STOP WATCH METHOD AND THAT'S A SUBJECTIVE MEASURE WHEN A PATIENT FEELS MEANINGFUL PAIN RELIEF BUT THERE'S PIT FALLS AND THERE'S TIMES WHEN PATIENTS FORGET TO CLICK THE STOP WATCH AND FALL ASLEEP AND THEY MAY BE LEFT WITH GAPS IN THE DATA AND IT CAN BE UNCLEAR WHETHER A PARTICULAR PATIENT FORGOT BECAUSE THEY DIDN'T HAVE MEANINGFUL PAIN RELIEF. WE'RE OPEN TO WAYS TO UNDERSTAND HOW QUICKLY AN ANALGESIC WORK. THE SEPARATION OF CURVE IS A DIFFERENT LOOK AT THE SAME TYPE OF INFORMATION AND LOOKING AT THE CHARACTERISTIC OF THE DRUG FROM A DIFFERENT ANGLE AND THE STOP WATCH DATA AND THE TWO SUPPORT EACH OTHER. WE DON'T HAVE A SET IN STONE TIME EVEN FOR MEANINGFUL PAIN RELIEF FOR THE STOP WATCH METHOD. WE ALSO NEED TO LOOK AT THE PROPOSED CONTEXT OF USE. THERE MAY BE SITUATIONS WHERE A DRUG CAN BE SAFELY USED. AN EXAMPLE IS IN SOME POST SURGICAL SETTINGS WHERE THERE CAN BE RESIDUAL ANALGESIC FROM SURGERY AND THERE'S FACTORS TO CONSIDER AND IT'S NOT SURPRISING WE DON'T HAVE A SPECIFIC CRITERIA FOR WHAT IS CLINICALLY MEANINGFUL. WE WANT TO THINK OF HOW CRITICAL IS THE ONSET OF ACTION AND IF WE'RE TALKING ABOUT AN OPIOID WE'D WANT TO SEE A SEPARATION AT EARLY TIME POINTS OTHER WISE WE MAY NOT SEE THE SUPPORT OF THE DRUG AND WOULD LIKE TO SEE THE SEPARATION MAINTAINED. >> I THINK ONSET IS MORE OF A DESCRIPTIVE TERM AND HASN'T NECESSARILY RELIED ON STATISTICALLY SIGNIFICANT SEPARATION BECAUSE THERE'S A LOT OF THINGS THAT GO IN TO IT. ONE OF THE THINGS I'D LIKE TO KNOW IF YOU'RE CONSIDERING MIGHT BE TO HAVE SOME COMPANIES ESTABLISH A CORRELATION BETWEEN THE DOUBLE STOP WATCH AND THE SEPARATION TO GIVE EVERYONE A SENSE IF THERE'S A MORE REGULAR RELATIONSHIP THAT CAN BE USED TO DEFINE THE CLINICALLY MEANINGFUL SEPARATION. >> I AGREE. WE'D LOVE TO GET TO THE POINT WHERE WE KNOW THE MEASURES DO SUPPORT EACH OTHER. INSTEAD OF PRECISE TIME OF THE STOP WATCH THE CURVES WOULD OTHERWISE SUPPORT THAT PRECISE TIME TO MEANINGFUL PAIN RELIEF AND WE HAVE ACCEPTED IT AND DESCRIBED IT BUT WE THINK THERE'S PROBABLY OTHER GOOD OPTIONS AS WELL AND WE WOULD ENCOURAGE COMPANIES TO COME WITH THOSE OPTIONS BUT AGAIN THOSE MEASURES WOULD ALL BE TO SUPPORT EACH OTHER. >> I AGREE AND I WANT TO PUT A PERHAPS CHALLENGE OUT TO COLLEAGUES IN INDUSTRY TO DO SOME OF THAT WORK AND COME IN TO THE FDA AND BRING SOME PACKAGES WHERE SOME OF THAT WORK IS DONE TO HELP -- I DON'T WANT TO STEP ON THE WORDS THAT CROSSOVER BEYOND MY AREA OF EXPERTISE BUT TO VALIDATE OR QUALIFY AND CREATE THE MORE STANDING RELATIONSHIP SO WHEN THAT COMES IN WE HAVE MORE OF A DATABASE AND ANALYSIS. I THINK THAT WOULD BE A NICE CHALLENGE TO PUT OUT THERE. >> WE MAY FEEL WIDE VARIETIABILITY IN WHAT PATIENT -- VARIABILITY IN WHAT PATIENTS EXPERIENCE BUT WE WANT AN UNDERSTANDING OF HOW A DRUG STARTS TO WORK AND THIS IS CRITICAL IN THE ACUTE PAIN SETTING AND IT'S NOT ONLY AN EFFICACY ISSUE BUT CAN BE A SAFETY ISSUE. >> I KNOW YOU'RE GOING TO THINK I'M PICKING ON YOU BUT I WANT TO ASK ANOTHER QUESTION AND IT GOES A LITTLE BIT BEYOND YOUR TALK BUT I THINK IS IMPORTANT. YOU DEFINED ACUTE PAIN AS A SUMMED INTENSITY PAIN AND IT'S THOUGHT TO BE USEFUL IN ACUTE PAIN SETTINGS AND WHAT STANDS OUT DIFFERENT IS THE VALUES WERE INCLUDED IN THE LABELLING THAT'S A RECENT APPROVAL OF A NOVEL ANALGESIC BUT HADN'T BEEN INCLUDED IN LABELLING FOR PRODUCTS WITH ACUTE PAIN AND THE INJECTION YOU MENTIONED. WE USUALLY HEAR OF MORE PAIN NOW. WE'RE WONDERING WHAT'S BEHIND THE CHANGE IN THE APPROACH AND HOW YOU THINK THAT INFORMATION MAYBE USEFUL FOR CLINICIANS. I DO NOTE THAT ALSO THE PAIN OVER TIME CURVE'S LOOKING DIRECTLY AT PAIN INTENSITY ARE ALSO INCLUDED WHICH IS ALSO A LITTLE BIT MORE DIRECT INFORMATION. >> WHO SAYS NO ONE READS LABELS. WE FIRST RECOGNIZE FDA LABELLING HAS EVOLVED OVER THE YEARS AND WILL CONTINUE TO EVOLVE. AND SUPPORTED APPROVALS IN TIMES PAST PERHAPS THE LABEL JUST HAD A "P" VALUE AND WE'VE MADE THEM MORE USEFUL AND CLEARLY COMMUNICATE INFORMATION TO PRESCRIBERS. OF COURSE IT IS RELEVANT DATA TO INCLUDE AND WE COMPLETELY ALONE MAY NOT GIVE THE FULL STORY. THE QUESTION YOU ARE ASKING IS WHAT DO THE NUMBERS MEAN TO CLINICIANS. AND I THINK THAT'S A FAIR QUESTION. I THINK THE HOPE IS AS WE START INCLUDING THEM WE ACTUALLY HOPE BY GIVING PRESCRIBERS THAT ADDITIONAL PIECE OF INFORMATION THAT THE CURVES DO NOT. AND OVER TIME I HOPE THE ADDITIONAL PIECE OF DATA WILL EDUCATE THOSE WHO ARE INTERESTED IN THESE NUMBERS AND SERVE TO COMPLIMENT THE OTHER INFORMATION. IN TIME TAKING DAILY ANALGESICS WOULD BE WITHIN THE POPULATION OF CHRONIC MIGRAINE. PATIENTS WITH CHRONIC MIGRAINE OFTEN AREN'T INCLUDED IN OUR ACUTE TREATMENT TRIALS. FOR ELIGIBILITY WE USUALLY IS FOR A RANGE OF MED ACHES FOR A MONTH. IT COULD BE LIKE TWO TO EIGHT OR FOUR TO EIGHT AND THE REASON IS WE WANT TO TRACK 48 HOURS AFTER THE USE OF THE DRUG AND WE DON'T WANT ONE MIGRAINE OR HEADACHE TO COALESCE WITH ANOTHER. AND FOR THE PREVENTIVE TREATMENT OF MIGRAINE TRIALS WE HAVE TRIALS FOR MIGRAINE TREATMENTS AND THEY MAY HAVE MEDICATION OVER THESE AS WELL. >> I SUSPECT THESE MAY BE IT AS WELL AND CARLOS YOU MENTIONED AND WITH THE DEVICE TRIALS ARE THEY GENERALLY CONDUCTED IN PATIENTS WHO FAILED DRUG THERAPIES. I ASKED THAT BECAUSE IF STUDY POPULATIONS FREQUENTLY CONSISTENT OF PATIENTS INADEQUATELY MANAGED WITH DRUGS IT COULD REPRESENT A POPULATION DIFFICULT TO TREAT HOW DO YOU TAKE THAT IN TO ACCOUNT WHILE REVIEWING THE TRIALS? >> GREAT QUESTION AND I APPRECIATE BEING PART OF THIS DISCUSSION WITH ALL OF YOU HERE. SO A COUPLE COMMENTS ON TRACKING THE TREATMENTS. ONE IS THERE'S A VARIETY OF DEVICE TYPES THAT MAY VARY IN DEGREE OF RISK AND WHILE SOME DEVICES ARE MORE APPROPRIATE TO ONLY PERMIT USE IN TREATMENT REFRACTORY PATIENT POPULATIONS THERE MAY BE OTHER DEVICES LESS RISKY AND HAVE LESS AN ADVERSE EVENT PROFILE AND MAY BE WORTH STUDYING IN NAIVE PATIENTS. THAT'S ONE CONSIDERATION WE WALK THROUGH WHEN WE LOOK AT ANY GIVEN DEVICE SUBMISSION THAT COMES IN. AND TWO, WE WANT TO MAKE SURE THE RIGHT PATIENTS ARE STUDIED. WE'LL ASK IN GENERAL HE WILL GABLT -- ELIGIBILITY QUESTIONS IN HOW THE PATIENTS AND THE ULTIMATE REVIEW THE DEVICE IS TARGETED WHETHER REFRACTORY OR NAIVE PATIENTS WILL DEPEND ON THE SPONSOR'S DECISION OF WHAT THEY BELIEVE THEIR PRODUCT TO TARGET IN A PATIENT POPULATION. AND TWO ADDITIONAL POINTS, THIRD, WE'LL LOOK AT IF ONE PATIENT POPULATION'S STUDIED WITH SOME LEVEL OF REFRACTORY OR USE OF FAILED DRUG THERAPIES AFTER THE STUDY'S DONE WE'LL ASK, WELL, IT'S BEEN USED IN THIS PATIENT POPULATION WITH MAYBE NAIVE PATIENTS HOW GENERALIZABLE IS THE DATA SET TO OTHER SUBGROUPS OF PATIENTS WITHIN THIS CONDITION. FOUR, WE'LL ASK ABOUT THE SAFETY OF THE DEVICE AND ADVERSE EVENT PROFILE WHEN IT WAS STUDIED DURING THE TRIAL WHICH CAN ALSO BE RELATED TO THE TYPE OF PATIENT POPULATION BEING STUDIED AND THE AMOUNT OF REFRACTORY -- HOW NAIVE THEY ARE WITH REGARD TO DRUG THERAPIES. IT ALL LEADS TO THE TYPES OF QUESTIONS THAT SHOULD BE SUBMITTED TO US IN THE PRE-SUBMISSION AND WOULD HATE TO GIVE ADVICE BEFORE A SUBMISSION BEFORE THE REVIEW TEAM THAT TALKS ABOUT THE PROPOSED PATIENT POPULATION AND DEVICE TECHNOLOGY IN THE PRIOR STUDIES AND OUS DATA SETS. ALL THE QUESTIONS INCLUDING THE USE OF COMPLEMENT MEDICATIONS SHOULD BE DATA AND PART OF THE DISCUSSIONS WE LIKE TO HAVE WITH INVESTIGATORS WITH DEVICES WHEN THE STUDY'S CONDUCTED. IT'S EASIER TO LAY OUT HOW WE PLAN TO ADDRESS WHETHER OR NOT DRUG THERAPIES ARE INCORPORATED IN TO STUDY BEFORE IT'S STARTED THAN HAVING THE DATA SET COME TO US AND SAYING THIS DEVICE TARGETS NAIVE PATIENTS AN US HAVING TO WORK BACKWARDS AND FIGURE OUT HOW MUCH DO THE DRUGS IMPACT THE OUTCOMES AT THE END OF THE STUDY. SO DRUG THERAPY COMPLEMENT MEDICATIONS IS SOMETIMES A CHALLENGING COMPONENT OF MEDICAL DEVICE DESIGN THAT HOPEFULLY WE ALL HAVE DISCUSSIONS BEFORE THE STUDY STARTED ON WHAT PATIENT POPULATION'S BEING STUDIED BEFORE WE DO THE STUDY. >> I THINK THESE ISSUES AND HOW YOU ADDRESS THEM ARE IMPORTANT AND MAKING SURE THEY'RE PLANNED FROM THE START EVEN THOUGH PERHAPS THE RISK INVOLVED IS NOT KNOWN IN THE BEGINNING AND PERHAPS A MORE CONSERVATIVE THERAPY OR APPROACH WOULD BE STARTED WITH THE INITIAL TRIALS BUT I THINK IT'S CRITICALLY IMPORTANT FOR COMPANIES AND SPONSORS TO COME IN EARLY AS YOU SAID SO THAT TIME AND RESOURCES AREN'T WASTED ON CLINICAL TRIALS THAT ULTIMATELY DON'T ADDRESS THE NEED. I THINK THIS IS PROBABLY TRUE FOR EVERYWHERE. I JUST WANT TO CHECK IN -- WERE YOU GOING TO SAY SOMETHING? >> ONE MORE COMMENT, FOLKS I THINK WILL LIKE TO HEAR THIS. WHEN THERE ARE DEVICE STUDIES TA MAY USE DRUG THERAPIES ON LABEL OR OFF LABEL WE'LL USUALLY COORDINATE WITH HEATHER AND NAOMI ON THOSE TYPES MUCH STUDIES FROM DEVICES TO CENTER FOR DRUGS. WE ALSO WANT TO INCLUDE THE RIGHT PEOPLE TO DO THAT WE HAVE TO ALL WORK IN ADVANCE AND GET THE SUBMISSIONS IN EARLY. THERE'S A LOT OF COORDINATION BEHIND THE SCENES MANY PEOPLE DON'T REALIZE BUT IF THERE ARE DRUG STUDIES THAT INCORPORATE DEVICES, IT'S GOOD TO HAVE THE EARLY DIALOGUE BECAUSE WORKING WITH THEM DOESN'T HAPPEN MAGICALLY. WE NEED TIME TO DO WORK ON THE INSIDE WITHIN THE WALLS OF FDA. >> THANK YOU FOR THAT. I WANT TO GO BACK TO THIS A LITTLE BIT MORE IN TERMS OF HOW THE PATIENT POPULATION FACTORS IMPACT CLINICAL TRIAL DESIGN BUT BEFORE WE DO THAT I WANT TO MAKE SURE I HAVE TIME TO GO ON TO A COUPLE MORE QUESTIONS. I WANT TO ASK ELECTRA WHO I CAN'T SEE BUT I HOPE YOU'RE ON, WHAT ARE SOME OF THE MOST COMMON HURDLES -- THERE YOU ARE. GOOD TO SEE. WHAT ARE THE COMMON HURDLES OF GROUPS TRYING TO DEVELOP NOVEL INSTRUMENT TO EVALUATE PAIN? >> THANK YOU FOR THE QUESTION AND FOR THE OPPORTUNITY TO TALK WITH YOU TODAY. I'M LEARNING A LOT. I WILL PREFACE THESE ARE MY OWN VIEWS AND NOT NECESSARILY THAT OF THE FDA, OF COURSE. WHAT I WILL SAY IS THAT AS WE ALL KNOW COA DEVELOPMENT OF ANY KIND CAN BE TIME AND RESOURCE INTENSIVE. IF IT IS TO BE SUFFICIENTLY RIGOROUS TO SUPPORT OUR DECISION MAKING. IN FACT WE'RE TRYING TO HELP STAKEHOLDERS IN THIS REGARD THROUGH SOME OF THE WORK THAT WE'RE DOING WITH OUR PATIENT-FOCUSSED DRUG DEVELOPMENT GUIDANCE SERIES WHICH IS ONGOING UNDER 21st CENTURY CURES LEGISLATION. THIS IS ALSO WHY WE HAVE PROGRAMS SUCH AS OUR DRUG DEVELOPMENT TOOL QUALIFICATION PROGRAM TO ENCOURAGE THIS PRETTY COMPETITIVE COLLABORATION TO LOWER BARRIERS TO DEVELOPMENT. AS MENTIONED EARLIER IN THE CONFERENCE, PAIN IS REALLY A MULTI FACETED EXPERIENCE THAT CAN AFFECT INDIVIDUALS IN MANY WAYS. TO ASSESS INVESTS WE NEED TO START -- TO ASSESS END POINTS WE NEED TO LOOK AT WHAT MATTERS TO THE PATIENTS AND WITH REGARD TO PAIN AND INDIVIDUALS SUFFERING FROM PAIN, THERE'S A VARIETY OF CLINICAL ASSESSMENT TIMES CAN BE INFORMATIVE. SO WE MIGHT LOOK AT HOW DO PATIENTS COPE WITH CHRONIC PAIN. WE HAVE INTEREST IN USE OF WEARABLE ACCELEROMETERS TO EVALUATE PHYSICAL ACTIVITY IN PATIENTS WITH CHRONIC PAIN AND ONE PROJECT IN PARTICULAR WE HAVE IN OUR QUALIFICATION PROGRAM IS LOOKING AT PATIENTS WITH OSTEOARTHRITIS OF THE KNEE. TO THE PAIN ITSELF AND THE IMPACT FROM MULTIPLE STANDPOINTS CAN BE VERY USEFUL. IN ASSESSING PAIN ITSELF WE HAVE A LOT OF EXPERIENCE WITH PAIN SCALES. FOR PATIENTS ABLE TO RELIABLY REPORT ON BEHALF OF THEMSELVES SO WE CAN ALWAYS BUILD ON PAIN SCALES THAT HAVE BEEN USED TO ALSO POTENTIALLY LEAD TO NEW PAIN SCALES UNDERSTANDABLE TO PATIENTS THAT REALLY BALANCE THE SENSITIVITY WITH THE EASE OF USE FOR PATIENTS AND SO I THINK WE REALLY NODE TO CHALLENGE OURSELVES -- NEED TO CHALLENGE OURSELVES TO THINK ABOUT OUR PATIENT POPULATION AS A WHOLE. SO A WIDE RANGE OF PATIENTS FROM DIFFERENT DIVERSE DEMOGRAPHIC GROUPS AND GEOGRAPHICALLY DIVERSE GROUPS OF INDIVIDUALS. THOSE ARE SOME OF THE CHALLENGES. ONE FINAL THING I'LL SAY IS ONE OF THE MOST CHALLENGING AREAS IS ASSESSING PEDIATRIC PATIENTS OR PATIENTS UNABLE TO PROVIDE SELF-REPORT AND AS A GNOME -- NAOMI STATED WE CAN LOOK FOR EXTRAPOLATION FOR OLDER PATIENTS BUT FOR YOUNGER PATIENTS WE NEED GOOD INSTRUMENTATION AND GOOD CLINICAL OUTCOME ASSESSMENTS AND THIS TYPICALLY WILL BE IN USING REPORTED OUTCOMES. WE HAVE A PROJECT ONGOING IN CEDAR'S PILOT PROGRAM SUPPORTING STANDARD CORE CLINICAL OUTCOME ASSESSMENTS AND END POINTS. WORK IS OUT OF DUKE UNIVERSITY AND ZIMMERMAN AND OTHERS AND MAYBE WE'LL TALK TO THICK LATER IN THE CONFERENCE -- TO THIS LATER IN THE CONFERENCE AND ONE KEY ISSUE WITH CHALLENGES IS WITH PEDIATRICS AND PATIENTS WHO CAN'T EXPRESS THEMSELVES VERBALLY WE HAVE TO LOOK AT THINGS WE CAN OBSERVE. THE CHALLENGES THAT THE STRESS CAUSED BY PAIN LOOKS A LOT LIKE THE STRESS DUE IT OTHER CAUSES. WE'RE TRYING TO LOOK AT WAYS TO DISTINGUISH THAT TO MORE ACCURATELY ASSESS PAIN IN THE YOUNG PATIENTS. >> THANK YOU. >> IF I CAN JUST PIGGY BACK ON TO THAT QUESTION AS WELL BECAUSE ONE OF THE THINGS THE GROUP DISCUSS A LOT INTERNALLY IS A BIG CHALLENGE IS ACCESS TO DATA. AS GROUPS ARE GATHERING INFORMATION FOR THEIR OWN OBJECTIVES MANY TIMES THE DATA IN AND OF ITSELF IS NOT SUFFICIENT FOR BROADER QUESTION AND PAIN IS NO DIFFERENT THAN OTHERS IF THERE ARE STAKEHOLDERS AND MANY ARE REPRESENTED IN THE CONFERENCE FROM ACADEMIA AND PATIENT GROUPS, ETCETERA. IF YOU COULD WORK ON WHAT ARE THE CHALLENGES EVERYONE IS FACING AND TRY TO PUT TOGETHER PROJECT PLANS HOW THAT'S MITIGATED WITH OR DEALT WITH AND CONSENSUS DEFINITION OF COMPONENTS PATIENT POPULATIONS ARE FACING HELPS MAKE THE DATA THAT IS COLLECTED BY VARIOUS GROUPS HAVE IT TO BE INTEGRATED TO ANSWER THE BROADER QUESTIONS BUT IF EVERYBODY IS USING THEIR OWN FAVORITE DEFINITION OF SOMETHING IT'S REALLY LIMITING THEM ON THE ABILITY TO PULL DATA ACROSS GROUPS. >> THANK YOU. I THINK THAT'S AN IMPORTANT POINT. WITH THE AMOUNT OF INFORMATION COMING IN TO THEATION AGENCY IT -- IN TO THE AGENCY IT WOULD BE GREAT TO GET A MER -- MORE STANDARD GREAT APPROACH TO GET DATA TO AFFORD THE EFFORTS TO DEVELOP EITHER BIOMARKERS OR OUTCOME ASSESSMENTS OR TO UNDERSTAND THE DIFFERENT RESPONSES ACROSS DIFFERENT POPULATIONS WITHIN A DISEASE OR SYMPTOM CATEGORY. THANK YOU FOR THAT. NAOMI, I'M SURE PEOPLE ON THE CONFERENCE ARE INTERESTED IN THE NEW GUIDANCE. THE OLD PAIN GUIDANCE WAS TAKEN DOWN AND THE DRAFT GUIDANCE WRITTEN SOME TIME LATER IS NOT CURRENTLY ACTIVE. I KNOW YOU CAN'T TELL US SPECIFICS UNTIL THINGS ARE PUBLISH BUT CAN YOU TELL POTENTIAL FOR THE NEW GUIDANCES FOR INSTANCE DESCRIBED IN SOME OF THE LEGISLATION THAT'S BEEN PASSED IN THE PAST FEW YEARS? >> I SORT OF ANSWERED THE QUESTION ALREADY I CAN'T GIVE SPECIFICS I CAN SAY THEY'RE FORTHCOMING WITHOUT GIVING EXCUSES. IT'S BEEN A VERY BUSY TIME BUT WE HAVE BEEN ACTIVELY WORKING ON THEM. IN 2018 THE COMMISSIONER DESCRIBED WHAT WOULD BE COMING OUT AND WE'RE ACTIVELY WORKING ON THAT AND THE TOPICS DISCUSSED IN THE GUIDANCES ARE IN MY PEER-REVIEWED TALK AND WITH AN EMPHASIS ON NON-OPIOID ALTERNATIVES IN THE CHRONIC PAIN SPACE PIPPEN COURAGE EVERYONE TO PLEASE BE PATIENT. THEY'RE FORTHCOMING AND WE'LL LOOK FORWARD TO GETTING EVERYONE'S FEEDBACK ON THAT ONCE THEY'RE PUBLISHED THE DRAFT GUIDANCES. >> I WOULD LIKE TO SAY THAT IN THE PAST WHEN GUIDANCES HAVE COME OUT FOR COMMENTS IT'S BEEN INTERESTING TO SEE WHAT COMMENTS HAVE COME IN AND SO I ENCOURAGE FOLKS PARTICIPATING HERE IF THEY DON'T ALREADY CONSIDER LOOKING AT SOME OF THE DRAFT GUIDANCES TO PROVIDE COMMENTS TO THE AGENCY. THE AGENCY DOES LOOK AT THOSE COMMENTS AND VERY CAREFULLY TO SEE TO MAKE SURE THE GUIDANCES ARE ADDRESSING THE NEEDS OF THE COMMUNITY THAT ARE BEING GUIDED WITH THE ADVICE. >> IT'S NOT LIP SERVICE. WE LOOK AT ALL THE COMMENTS THAT COME IN AND IT'S NOT JUST A MATTER OF LOOKING AT THEM BECAUSE WE'RE REQUIRED TO BECAUSE WE'RE NOT ACTUALLY REQUIRED TO LOOK AT EVERY COMMENT AND ADDRESS THEM BUT IT'S A COMPLICATED SPACE AND WE DO WANT TO HEAR FROM FOLKS WHAT THEY THINK AND NOT JUST IN OUR DIVISION BUT ANOTHER DIVISION WHERE WE SPECIFICALLY CALL OUT AREAS IN WHICH WE DO WANT HELP. WE DEFINITELY ECHO THAT ENCOURAGING FOLKS TO PLEASE MAKE COMMENTS ONCE THOSE ARE OUT. >> AND SHARON, THERE'S A FEW QUESTIONS THAT HAVE COME IN. >> DOES ANYBODY ON THE PANEL HAVE QUESTIONS FOR ONE ANOTHER AT THIS POINT IF NOT I WOULD LIKE IT HEAR SOME OF THE ADDITIONAL QUESTIONS AND HAVE FOLKS ADDRESS THEM. >> THERE'S A QUESTION FROM DR. AMY CHAPPELL THERE'S A PRECEDENT IN THE EPILEPSY FIELD FOR APPROVAL FOR A STUDY ON HYSTERICAL CONTROLS. DO YOU SEE THIS AN OPTION IN PAIN REGULATORY TRIALS AND THIS IS DIRECTED TO NAOMI. >> I DIDN'T CATCH PART OF THE QUESTION. COULD YOU REPEAT IT. >> THERE'S A PRECEDENT IN THE EPILEPSY FIELD FOR APPROVAL BASED ON A STUDY USING HYSTERICAL CONTROLS. DO YOU SEE THIS AS AN OPTION IN PAIN REGULATORY TRIALS? SO I THINK THE AGENCY HAS BEEN PRETTY CLEAR IN GUIDANCE AS TO WHEN WE DO AND DO NOT ACCEPT HISTORICAL CONTROLS. THERE'S SPECIFIC SITUATIONS AND I'M NOT GOING TO GO THROUGH ALL THE SCENARIOS NOW. WE DO ACCEPT THEM IN AREAS IN WHICH THERE'S BEEN ESTABLISHED TREATMENT EFFECT WHEN THE EFFECT IS VERY OBVIOUS. CERTAINLY IN AREAS OF CERTAIN INFECTIOUS DISEASE LIKE HEPATITIS IN WHICH THE VIRUS DOESN'T NECESSARILY GO AWAY ON ITS OWN. WE CAN ACCEPT HISTORICAL CONTROLS. I THINK THE EVIDENCE FOR ACCEPTING IT IN PAIN ISN'T NECESSARILY THERE. AS OF NOW IT'S NOT SOMETHING WE HAVE ACCEPTED. >> AND I THINK TO BUILD ON THAT JUST A TAD, IN FACT BECAUSE OF A NUMBER OF FACTORS WITH PAIN STUDIES IN FACT DOESN'T THE AGENCY STILL REQUIRE SOME MEASURE OR DEMONSTRATION OF SUPERIORITY AND NOT JUST A NON-INFERIORITY OUTCOME? >> ABSOLUTELY. THERE'S ISSUES OF PLACEBO RESPONSE IN PAIN TRIALS AND SOMETIMES SMALL EFFECT SIZES. THERE ARE -- WE HAVE NOT HISTORICALLY ACCEPTED NON NON-INFERIORITY TRIALS AND SUPERIOR TRIALS ARE WHAT WE HAVE ACCEPTED BECAUSE OF ALL OF THE PITFALLS IN THE SPACE IN PARTICULAR WITH ACCEPTING NON-INFERIORITY. >> THERE'S A COMMENT FROM PETER GOTSBY. IT SAYS MBS PRE SELECTS CHILDHOOD NAUSEA AND PHOBIA AND ANOTHER SYMPTOM MAY BE MORE BOTHERSOME LIKE VERTIGO AND OTHERS AND THERE MAY BE AN ARGUMENT TO THINK ABOUT MBS MORE BROADLY. DO YOU WANT TO COMMENT ON THAT? >> THAT'S AN INTERESTING POINT. WE HAVE LOOKED AT THE MIGRAINE ASSOCIATED WITH SYMPTOMS OF MIGRAI MIGRAI MIGRAINE PHONOPHOBIA AND OTHERS AND WE'RE LOOKING AT IF OTHER BOTHERSOME SYSTEMS MAY BE INCORPORATE THE BUT AT THIS POINT THESE ARE THE MOST BOTHERSOME TREATMENTS WE'VE LOOKED AND HAVE BEEN ABLE TO LOOK AT TREATMENT EFFECTS WITH THAT. >> THERE'S A COMMENT IN TERMS OF NOVEL OUTCOMES. AND REVISITING ON SITE MEASURES SOUNDS LUKE A LOW PRIORITIES IN TERMS OF THE GOALS. I DON'T KNOW IF PAUL HAS A SPECIFIC QUESTION AROUND HIS COMMENTS AND IF YOU CAN PUT THAT IN THE CHAT BOX WE CAN BRING THAT BACK IN AND THEN WE HAVE A QUESTION. HOW IS QUALITY CONTROL PLANNED FOR MEDICAL CANNABIS AND HOW DOES FDA REGULATE IT AND WHAT END POINTS CAN BE USED FOR STUDIES OF MEDICAL CANNABIS. >> I THINK THAT COULD BE FOR ANY IN THE GROUP HERE BUT I'LL REPHRASE IT WILL THE USE OF MEDICAL CANNABIS FOR DIFFERENT TYPES OF PAIN SYNDROMES OR CAUSES WHO YOU CONSIDER CHANGES IN THE OUTCOMES USED OR DO YOU HAVE ADDITIONAL ONES TO ADD? ALL RIGHT. I'M GOING START PICKING ON PEOPLE. HEATHER, ANYTHING IN YOUR AREA? >> I THINK THE KEY QUESTION IS WHAT ARE THEY USING THE PRODUCT FOR? WHAT'S THE INDICATION THEY WANTED TO USE IT FOR? IF THEY WANT IT TO USE TO PREVENT MIGRAINE OR FOR MIGRAINE I BELIEVE WE USE THE SAME END POINTS BUT IF THERE'S SOMETHING ELSE THEY WERE TARGETTING WE HAVE TO WORK WITH THE SPONSOR IN DETERMINING WHAT THE END POINT MIGHT BE. >> IT DEPENDS ON THE CHRONIC PAIN INDICATION OR A SPECIFIC ONE? IT DEPENDS WHAT THEY'RE LOOKING AT. ONCE WE KNOW THAT FROM AN EFFICACY PERSPECTIVE WE'D TREAT IT AS ANY OTHER ANALGESIC AS FAR AS END POINT. >> AND THERE MAY BE INTEREST IN SOME CANNABINOIDS. CARLOS, DO YOU HAVE ANYTHING THAT MAY BE STRUCTURED THAT WAY? >> NOT ON THIS LINE OF DISCUSSION. I'M STILL THINKING ABOUT THE HISTORICAL CONTROLS. ON THE DRUG SIDE OF THE HOUSE THERE MAY BE SPECIFIC REQUIREMENTS ON HOW HISTORICAL CONTROLS ARE VIEWED. ON THE DEVICES SIDE PART OF OUR REGULATIONS REQUIRES US TO LOOK AT WHAT WE CALL VALID SCIENTIFIC EVIDENCE INCLUDING HISTORICAL CONTROLS AS AN EVIDENCE DATA SET TO SUBMIT IN A MARKETING APPLICATION. IT MAY OR MAY NOT BE SUFFICIENT FOR AN APPROVAL DECISION BUT I THINK HISTORIC CONTROL TO GO BACK TO THE PREVIOUS DISCUSSION, HISTORICAL CONTROLS THEY'RE A LITTLE MORE DETAILED ON THE DATA SET. IF A HISTORICAL CONTROL INCLUDED DEVICE PARAMETERS OF A PRIOR DEVICE WE KNOW IS SAFE AND EFFECTIVE WOULD THOSE CONTROLS BE SATISFACTORY TO COMPARE TO? THOSE ARE SOME OF THE DEVICE SIDE CHALLENGES WE'D HAVE TO WALK THROUGH. THERE'S AREAS BEST SERVED IN A DETAILED DISCUSSION OF SOMETHING WE NEED BEFORE US TO MAKE DECISIONS. >> WE HAVE TWO OR THREE MINUTES LEFT. THERE'S A COUPLE OTHER QUESTIONS. IS THERE ANYTHING ELSE YOU WANT TO ASK THE PANEL? >> UP ALL FAIRNESS TO THE PANELISTS I DON'T THINK I HAVE ANYTHING THAT COULD BE ADEQUATELY ADDRESSED IN TWO MINUTES. ARE THERE ANY OTHER QUICK QUESTIONS YOU'VE GOT? >> ONE QUICK QUESTION. HOW DOES THE STOP WATCH CORRELATE WITH PSYCHOLOGICAL MEASURES? >> I HEARD HOW DOES IT CORRELATE WITH FUNCTIONAL MEASURES AND WHAT WAS THE SECOND? >> PAIN RELATED PSYCHOLOGICAL MEASURES. >> WE'RE MOSTLY USING THE METHOD TO UNDERSTAND THE ONSET OF ANALGESIA. AS FAR AS I KNOW WE DON'T HAVE CORRELATIONS WITH OTHER FUNCTIONAL MEASURES. >> I THINK THAT'S RIGHT. BECAUSE IT'S TRYING TO DETERMINE ONSET OF ACTION, REALLY MOSTLY IN ACUTE SETTINGS IT'S HARD TO KNOW HOW TO IN COR OPERATE THAT WITH OTHER -- INCORPORATE THAT WITH OTHER FACTORS. >> OKAY. SO WE JUST HAVE A MINUTE LEFT BEFORE WE MOVE ON TO THE NEXT PANEL DISCUSSION. I WOULD LIKE TO THANK EVERYONE ON THE PANEL, ALL THE FDA MEMBERS AND DR. HERTZ FOR TAKING THE TIME. I'D LIKE TO TURN THIS OVER TO THE NEXT SESSION. THIS IS BEING LED BY DR. AMY CHAPPELL AND AMY, PLEASE START YOUR PANEL. AMY WILL TALK ABOUT THE PAIN THERAPEUTIC DEVELOPMENT PATHWAY CHANNEL AND SHE AND HER PANELISTS WILL HAVE THE FLOOR FOR THE NEXT SESSION. >> I HAVE A DISTINGUISHED PANEL CONSISTING OF NADINE ATTAL AT THE UNIVERSITY OF VERSAILLES AND SHE'S IS GOING TO ADDRESS THE EUROPEAN PERSPECTIVE ON THE PAIN THERAPEUTICS DEVELOPMENT PATHWAY. NEXT WE'LL HAVE DAVID HEWITT. DAVID IS REPRESENTING THE INDUSTRY PERSPECTIVE. DAVID, AS MOST OF YOU KNOW HAS A DISTINGUISHED CAREER IN PHARMA. MOST RECENTLY HE IS SENIOR VICE PRESIDENT FOR CLINICAL DEVELOPMENT AT NURA BIO AND WE'LL HAVE LYNN MATALLANA TO GIVE THE PATIENT PERSPECTIVE. SHE'S A PATIENT HERSELF AND MUCH MORE THAN THAT BUT FOR THE PURPOSES OF THIS CLINICAL SHE IS REPRESENTING THE PATIENT PERSPECTIVE AND SHE'S ALSO A PATIENT ADVOCATE. YOU CAN READ MUCH MORE OF THEIR BIOS ON THE WORKSHOP WEBSITE. WE'LL START WITH QUESTIONS FROM THE PANELISTS TO ONE ANOTHER. AND I'M GOING START WITH NADINE. I THINK YOU HAD A COUPLE QUESTIONS FOR THE OTHER PANELISTS. >> ABSOLUTELY. FIRST, THANK YOU FOR KINDLY INVITING ME TO THIS VERY IMPORTANT MEETING. I I THINK IT'S INTERESTING TO BE HERE AND I'M HONORED I REPRESENT IN A WAY THE EUROPEAN PERSPECTIVE ON CLINICAL END POINTS FOR PAIN CLINICAL TRIALS. I HAD SOME QUESTIONS FOR PROFESSOR HEWITT REGARDING HIS PRESENTATION. IF YOU AGREE I'M GOING TO ASK THEM NOW. SO YOU DISCUSSED GENERAL PAIN INDICATIONS AND SAID WHICH ARE IMPORTANT AND STATED GENERAL PAIN INDICATION REQUIRED MULTIPLE STUDIES AND SUBINDICATIONS AND I AGREE WITH YOU DAVID HEWITT THIS MAY BE A BARRIER FOR THE DEVELOPMENT OF ANALGESICS BUT IN EUROPE AND THIS WAS TOPIC OF MY TALK AND THERE'S INDICATIONS FOR PAIN SUCH AS NEUROPATHIC PAIN WHICH IS ONE OF MY FEARS IN PARTICULAR REQUIRE POSITIVE STUDIES IN ONLY TWO DISTINCT CHALLENGES FOR MULTIPLE PAIN BUT MULTIPLE CONDITIONS MAY INDUCE PAIN. I'D LIKE TO KNOW WHETHER THIS EUROPEAN PERSPECTIVE ON INDICATIONS IN THIS CONTEXT MAY ULTIMATELY IMPACT FDA PERSPECTIVE? >> THANK YOU. FIRST, LET ME THANK EVERYONE FOR INVITING ME AND BEING HERE TO PARTICIPATE. I DO THINK THERE'S A NUMBER OF BARRIERS THAT I THINK EXIST TO THE DEVELOPMENT OF ANALGESICS. AND ONE OF THE THINGS WE'RE SEEING RIGHT NOW AND OBVIOUSLY THIS PANEL IS PART OF THIS IS THAT I THINK THE UNMET NEED WE ALL RECOGNIZE IS NOT MET COMMENSURATE WITH THE RESOURCING GOING IN TO DEVELOPMENT OF ANALGESICS. AND THE FACT THERE'S BEEN MECHANISMS AND MOLECULES ASSESSED AND FAILURES IN THE PRFTS -- IN THE PROCESS AND THIS IS AN UNDERSTANDING THERE'S DIFFERENT UNDERLYING PATHOPHYSIOLOGIES TO UNDERLYING PAIN. IT MAKES SENSE. FROM HAVING TO DO REPLICATE STUD STUDIES AND REPLICATIONS THERE'S A HIGH PLACEBO AFFECT AND WE GET NEGATIVE STUDIES. SO MY CONCERN IS INDUSTRY CAN GIVE UP PRETTY QUICKLY ONCE THEY HIT A NEGATIVE STUDY. YOU MAY HAVE AN INDICATION OF POSTNEUROAT POSTNEUROATIC NEURALGIA AND THEY WON'T INVEST FURTHER. HOW MANY WHAT YOU NEED TO HAVE IN A PARTICULAR INDICATION TO GET NEUROPATH INDICATION OR OTHER INDICATIONS SHOULD BE RE RE-EXAMINED AND DISCUSSED AND THE EUROPEAN MODEL IS VALID. >> IN THE UNITED STATES YOU HAVE INDICATIONS FOR CHRONIC PAIN IN GENERAL WHICH WE DON'T HAVE IN EUROPE AND REGARDING SOME PAIN CONDITIONS SUCH AS NEUROPATHIC PAIN. THIS THIS SEEMS TO BE PUZZLING. ON ONE HAND THERE'S SPECIFIC SUB CAUCUSES WITH THIS AND OTHERS SUCH AS CHRONIC PAIN WHICH WE DON'T HAVE EXCEPT FOR OPIOIDS OF COURSE BUT WE DO HAVE OTHER TIPS OF DRUGS. >> EXACTLY. I THINK THAT'S RIGHT. THE CHALLENGE HERE IS THAT SOMETHING MEME TALK ABOUT ALL THE TIME IT'S NOT THE DISEASE THAT MAY MATTER AT ALL BUT THE UNDERLYING PATHOPHYSIOLOGY AND HOW IT MAY EXIST ACROSS DIFFERENT PAIN INDICATIONS. AND CONFOUNDING IT MORE IS WE ENTER THE WORLD OF PERSONALIZED MEDICINE AND THE FACT THAT IT MAY HAVE MORE TO DO WITH THE GENETICS OF THE INDIVIDUAL OR THE PHARMACO GENOMICS OF THE INDIVIDUAL THAN THE UNDERLYING PAIN PATHOPHYSIOLOGY AND DISEASE. IT'S COMPLICATED. THE BENEFIT OF A PANEL LIKE THIS IS WE START TO EXPLORE OTHER WAYS OF THINKING ABOUT WHAT'S BEEN IN SOME WAYS AN INTRACTABLE PROBLEM. >> AMY, DO YOU THINK YOU CAN ASK QUESTIONS? >> GO AHEAD. >> THESE ARE MY QUESTIONS BUT I THINK THERE'LL BE OTHERS. I HAVE ANOTHER QUESTION ABOUT DISEASE MODIFYING AGENT FOR CHRONIC PAIN. MENTIONED IN YOUR PRESENTATION THE FACT THIS IS MODIFYING AGENT WILL BE PROBABLY MORE RELEVANT THAN ONGOING SYMPTOMATIC AGENT. DO YOU HAVE ANY EXCEPTIONS OR EXAMPLE TO GIVE BECAUSE WE HAVE LITTLE DISEASE MONDAY -- MODIFYING AGENT FOR DISEASE IN THE MARKET. >> ONE INTERESTING THING THIS GIVES UP AND I APPRECIATE THE BIOMARKER AND IN SOME WAY PAIN IS A BIOMARKER OF DISEASE. WE HAVE TALKED ABOUT PAIN AND CHRONIC PAIN SPECIFICALLY AS A CHRONIC ILLNESS, WHICH IT IS, AND THAT'S IMPORTANT BECAUSE IT'S HELP LEGITIMIZE PAIN AND TREAT PAIN AGGRESSIVELY BUT IT DOESN'T CHANGE THAT PAIN IS A BIOMARKER AND AS LYNN GAVE IN HER PRESENTATION, WHICH IS GOOD, PATIENTS WANT TO KNOW THE UNDERLYING CAUSE OF THEIR DISEASE. WHY AM I IN PAIN? IT'S CHRONIC PAIN AND A DISEASE ISN'T ENOUGH FOR A LOT OF PEOPLE. FOR INSTANCE, IN THE AREA OF I'M INTERESTED IN NOW WHICH ARE SYMPTOMS THAT'S A MECHANISM INVOLVED IN DEGENERATION AND MAY PLAY A ROLE IN A NUMBER OF AREAS INCLUDING A LOT OF NEURODEGENERATION AND IT'S THE UNDERLYING CAUSE. ONE COULD SEE, FOR EXAMPLE, A DRUG AND THERE ARE OTHER MECHANISMS AS WELL IN THE AREA THAT ARE FOCUSSED ON DEGENERATION THAT FIXING AND ADDRESSING THE INJURY OR UNDERLYING MECHANISM AND PREVENT IG IT LIKE YOU DO WITH KNOCKOUTS TO SAR 1 PRESENT IN THIS CASE THE ELEVATION OF NEUROFI NEUROFILLIMENT LIGHT CHANGE AND AS WE ADDRESS THE NEURODEGENERATION AND STUDIES FUNCTIONAL OUTPUTS MAY NOT BE WHAT WE'RE LOOKING FOR OR FIBER DENSITY MAY NOT BE THE END POINT WE'RE LOOKING AT THOUGH IT WOULD BE AND THE MORE RELEVANT END POINT ARE THE DRUGS WORKING ON AXONAL INJURY PREVENTION MAY BE ANALGESIC IN AND IF IT SELF. THE INHIBITOR MAY BE ANALGESIC AND THAT MAY BE THE END POINT YOU HAVE TO LOOK AT. >> WE HAVE SO MANY AGENT FOR CHRONIC PAIN. >> I SAW DISCUSSION CLINICAL RELEVANT END POINTS AND WE'RE DEALING WITH NEW END POINTS OR BETTER END POINTS. YOU STATE IN YOUR PRESENTATION THE CURRENT LINEAR PAIN END POINTS SUCH AS THE 0 TO 10 NUMERICAL SCALE WHICH IS STANDARD IN MOST CLINICAL TRIALS MAY NOT ALWAYS BE CLINICAL AND MEANINGFUL. AND WHAT DO YOU THINK ABOUT THIS AND DO YOU THINK END POINTS SUCH AS THE PROPORTION OF RESPONDERS ARE MORE SUITABLE THAN OUTCOMES FOR CLINICAL TRIALS BECAUSE THE LINEAR PAIN END POINT IS IN THE VAST MAJORITY OF CLINICAL TRIALS FOR PAIN. POINTS. ONE OF MY HANGUPS WITH THE LINEAR PAIN SCALE IS WHEN I WAS TREATING PATIENTS AND ASKED HOW MUCH PAIN THEY HAD AND THEY'D PUSHBACK ON 20 OUT OF 10 AND THEY WERE TRYING TO CONVEY THEY DIDN'T HAVE MUCH RESPECT FOR THE PAIN SCAN I WAS USING WHICH WAS ING TO ME AND EXPRESSED TO ME THERE WAS AN EMOTIONAL COMPONENT OF THE PAIN DRIVING THIS IDEA OF PAIN. AND I REMEMBER ONE PATIENT WHEN I ASKED ABOUT HER NEUROLOGIST AND SHE SAID THAT'S WHEN I WALKED IN IT WAS A 6 BUT WHEN YOU TALK ABOUT MY NEURALGIA JUST TALKING ABOUT IT MAKES IT GO UP TO A 10. AND THERE'S AN EMOTIONAL ASPECT. GOING BACK TO THE PREVIOUS TALK AND BASICALLY THERE WAS A NEW YORK TIMES ARTICLE ABOUT IT AND EVEN IN POST OPERATIVE PAIN A CHILD'S MOTHER IN THE ROOM WILL INFLUENCE THE PAIN RATING SCALE IS IMPACTFUL. AND LOOKING AT THE COMPLEXITY AND MULTIPLE LEVELS OF PAIN WHICH HAD BEEN PREVIOUSLY DONE IN THE CHAT SECTION. PEOPLE BROUGHT UP OTHER END POINTS THAT PROMISED THAT. IT'S NOT SOMETHING NEW. I JUST DON'T THINK IT'S BEEN INCORPORATED IN TO HOW WE DO CLINICAL TRIALS FROM A REGULATORY APPROVAL STANDPOINT. >> I'M GOING INTERRUPT YOU AND BRING LYNN IN TO THE CONVERSATION. LYNN, I HAD A QUESTION FOR YOU, WE HEARD IN HEATHER'S PRESENTATION IN MIGRAINE STUDIES THE MOST BOTHERSOME SYMPTOM IS BEING USED AS A CO-PRIMARY. I WONDERED SINCE THERE'S SO MANY COMORBIDITIES AND SYMPTOMS IN FIBROMYALGIA PATIENTS DO YOU SEE THAT AS A POTENTIAL CO-PRIMARY IN STUD OZ -- STUDIES OTHER THAN MIGRAINE? YOU'RE ON MUTE, LYNN. >> SORRY. FIRST, THANK YOU FOR ALLOWING ME TO BE HERE AND REPRESENT THE MILLIONS OF S DEALING WITH CHRONIC PAIN. I WANT TO THANK THE DOCTORS FOR THEIR REALLY EXCELLENT INSIGHTS AND ABILITY TO REALLY TRY TO UNDERSTAND WHAT THE PATIENT IS GOING THROUGH. I THINK IT'S AN AREA I WAS INTERESTED IN WHEN WE WERE LOOKING AT THE SUBSETS OF PEOPLE DOING CLINICAL TRIALS IS THAT WE AREN'T LOOKING AT PATIENTS THAT ARE ALIKE AND SO IF YOU HAVE AN ILLNESS LIKE FIBROMYALGIA MAYBE TAKING THE ATTENTION AND PEOPLE DEALING WITH OTHER PAIN ISSUES LIKE MIGRAINE HEADACHES OR IRRITABLE BOWEL OR LOWER BACK PAIN THOSE THINGS ARE BEING IGNORED BUT THEY'RE HAVING AN AFFECT ON THEIR OVERALL PAIN. AND AS DR. HEWITT MENTIONED THERE'S THE EMOTIONAL COMPONENTS AS WELL. SAY YOU'RE INVOLVED WITH A DIVORCE OR JUST HAD A BABY AND TRYING TO DEAL WITH SLEEPLESS NIGHTS. THERE'S SO MANY COMPONENTS THAT GO INTO AN INDIVIDUAL'S EXPERIENCE OF PAIN AND WHEN WE TRY TO BRING THESE DOWN IN TO BLACK AND WHITE NUMBERS OR WAYS OF EVALUATING THE INDIVIDUAL, IT CAN BE VERY DIFFICULT. I KNOW MANY OF THESE CONDITIONS LIKE MIGRAINE HEADACHES OR IRRITABLE BOWEL AND THINGS THAT WE HAVE STILL CONTINUED TO LOOK AT AS SUBSETS OF OTHER ILLNESSES, THAT'S NOT FAIR TO THE PATIENTS BECAUSE WHAT THEY'RE EXPERIENCING IS EXTREMELY REAL. AND IT MAY NOT HAVE ANYTHING TO DO WITH THE OTHER CONDITIONS THAT THEY'RE EXPERIENCING. SO I CAN UNDERSTAND WHY THEY WOULD FEEL MAYBE UNDER REPRESENTED OR UNABLE TO FOCUS ON THAT PARTICULAR EXPERIENCE OF PAIN THEY ARE HAVING. >> THANK YOU, LYNN. DO YOU HAVE QUESTIONS FOR NADINE OR DAVID? >> I JUST WANTED TO REINFORCE WHAT DR. HEWITT SAID ABOUT THE RANKING OF PAIN. THE SURVEY I DID SHOWED STRONGLY PATIENTS WANT TO BE ABLE TO EXPRESS MORE. I THINK THE IDEA OF THAT PAIN IS BOTH A PHYSICAL AND EMOTIONAL EXPERIENCE MAYBE WE NEED TO LOOK AT THOSE TWO THINGS AS DIFFERENT SCALES OF EXPERIENCE. SO IF SOMEONE SAYS TO YOU, WHAT IS YOUR PAIN RIGHT NOW IF YOU'RE IN A SITUATION WHERE YOU ARE UNCOMFORTABLE YOU MAY SAY 30 OUT OF 10 ON AN EMOTIONAL SCALE. BUT HOW DO YOU FEEL WE CAN HELP THE PATIENT TO UNDERSTAND AND PARTS IN CLINICAL TRIALS -- PARTICIPATE IN CLINICAL TRIALS WHERE THEY CAN ACCEPT PAIN IS PHYSICAL AND EMOTIONAL? I KNOW YOU'VE DONE A LOT OF RESEARCH AND HOW DO YOU TEAL WITH THAT FROM THE PATIENT'S PERSPECTIVE SO THEY DONE FEEL PEOPLE THINK THEY'RE CRAZY OR NOT BEING HEARD. >> PAIN IS A COMPLEX PHENOMENON. THE PAIN IS ONLY A BIOMARKER. I WANT TO MAKE CLEAR IN MY TRAINING WHEN A PERSON HAD A NUANCE OF PAIN, WE THOUGHT THE NUANCE OF PAIN IS POTENTIALLY PROGRESSION OF THEIR DISEASE OF A CANCER. THAT'S WHAT I MEANT. TO THOSE WHO DO MIGRAINE WE KNOW IF A PERSON HAS A NEW MIGRAINE HEADACHE AFTER THE AGE OF 50, THEY DO DESERVE IMAGING BECAUSE THAT'S A BIOMARKER THAT MAY HAVE A BRAIN TUMOR. THAT'S NOT TO SAY PAIN IS NOT A BIOMARKER OF THAT BUT IT'S DISTRESS AND WHY I QUOTED THE ISP DEFINITION THAT ITS AN EMOTIONAL EXPERIENCE. HOW WE GO FORWARD ON THIS I THINK THE WORK YOU DID, THAT SURVEY AND IT'S BEEN INVOLVED IN PARKINSON'S DISEASE AND OTHER NEUROLOGY AREAS AND WE DON'T KNOW WHAT THE PATIENTS ARE DOING LIKE THE ALZHEIMER'S PATIENT STARTS READING THE NEW YORK TIMES TO DO THE CROSS WORK PUZZLE OR PEOPLE WHO HAVE PARKINSON'S START DOING THE TANGO OR TAI CHI BUT IF WE DON'T CONTROL FOR THAT IT'S PROBLEMATIC. I THINK WE NEED TO TALK TO PATIENTS MORE AND DO WHAT YOU DID IN A VERY MORE EVOLVED WAY. AS I TALK ABOUT THE PAIN SCALE I THOUGHT IT WAS INTERESTING A LOT OF PATIENTS DIDN'T LIKE THE ZERO TO -- 0 TO 10 PAIN SCALE AND WHAT WOULD SPEAK TO THEIR EXPERIENCE MORE? AND I TALK ABOUT PAIN BEING THE DECIBEL OR SCOVAL MACHINE. IT'S ONE IDEA WAS A PAIN CONE. AND IT COULD BE 0 AND GET LARGER. I WOULD BE CURIOUS AND MAYBE OTHERS ONLINE KNOW THIS, ARE THERE BETTER SCALES OUT THERE THAT MAY BE MORE SENSITIVE THAN THE LINEAR SCALE? AND IT WOULD BE NICE TO NOT HAVE TO DO THE CONVERSION AND HAVE A CLINICALLY MEANINGFUL SCALE AND TALKING TO PATIENTS. >> THERE WAS A QUESTION SUBMITTED PRIOR TO THE MEETING. IT SAID THE SLIDE SPOKE TO EMOTIONAL PAIN AND WOULD YOU CONSIDER THIS AN INDEPENDENT PRIMARY OUTCOME MEASURE AND IF SO IS THERE A SENSITIVE SCALE YOU'D RECOMMEND? >> A CANCER PATIENT HAD WIDELY METASTATIC DISEASE WOULD RATE THEIR PAIN AS A 6. AND SOMEONE WITH FIBROMYALGIA RATED THEIR PAIN 15 OUT OF 10. THERE IS THE SHORT FORM OF THE McGILL PAIN QUESTIONNAIRE. FOR THE PURPOSES OF THIS WORKSHOP, ONE MAY CONSIDER DEVELOPING NEW OUTCOME MEASURES LIKE A MISERY INDEX OR SOME SORT OF MEASURE OF THE EMOTIONAL EXPERIENCE OF PAIN AND SOME MEASURES SEEM TO BE A BIT INADEQUATE. THEY'RE ALL PSYCHO METRICS AND NOT MY AREA OF EXPERTISE. IN TERMS OF COULD IT BE A GOOD END POINT, YEAH, FOR CERTAIN MEDICATIONS TO ME IT'S POSSIBLE LIKE A CANNABINOID MAY HAVE A GREATER AFFECT THAN THE DISCRIMINATORY PAIN BECAUSE THEY'RE DIFFERENT BRAIN AREAS INVOLVED. THE GYRUS FOCUSES IN ON THE PAIN AND LIMBIC AREAS LOOK AT THE EMOTION. IT CAN BE CONSIDERED AND DISCUSSED. >> DAVID, YOU'VE BEEN IN THE HOT SEAT FOR A WHILE. DO YOU HAVE PATIENTS FOR THE OTHER PANELISTS? >> >> THERE'S MEASURES OUT THERE AND DIFFERENT MEASURES CAN BE USED. THE QUESTION I HAD FOR HER WAS DO YOU THINK WE SHOULD RESTUDY SOME OF THE DRUGS THAT HAVE BEEN APPROVED TO TRY TO DETERMINE OUTCOME MEASURES TO HELP ENRICH CERTAIN POPULATIONS. AND LOOKING AT THE NOTES, PEOPLE HAVE MENTIONED ENRICHMENT MAYBE EVEN EXCESSIVE ENRICHMENT. WE CAN TALK ABOUT THAT. I LIKE THE IDEA OF FINDING THE RIGHT DRUG FOR THE RIGHT PERSON AND DECREASING THE NUMBER OF CLINICAL TRIALS AND TRIALS AND PUTTING THE PATIENT THROUGH. >> THANK YOU FOR ASKING THE QUESTION. IT'S QUITE RELEVANT TO THE FIELD BECAUSE INDEED THERE'S NOW AN INITIATIVE CALLED IMI2 A PUBLIC-PRIVATE PARTNERSHIP WITH MANY EUROPEAN LABS PARTNERSHIP AND ONE THOSE INVOLVED IN THE PARTNERSHIP IS TO TAKE THESE AND LOOK AT PATIENT-REPORT THE OUTCOME MEASURES SUCH AS THOSE DEVELOPED AND SEE IN EVEN NEGATIVE TRIALS WHETHER WE CAN BETTER ASSESS OR PREDICT THE RESPONSE AND TARGET BETTER THE PATIENT'S PHENOTYPES RESPONDING TO SUCH A DRUG. IT'S NOW ONGOING AND THE LEADERS ARE IN GERMANY AND THEY'RE WORKING ON IT AND IT'S IMPORTANT. IT CAN BE ONE OF THE STEPS AND ONE IMPORTANT STEP TOWARDS BETTER RESPONDING TO SUCH AND SUCH THERAPY IN A BETTER PERSONALIZED TREATMENT. >> VERY GOOD. HAVE AN ANOTHER QUESTION AND GO BACK TO THE AFFECT AND ASPECT. THERE'S A QUITE A NUMBER OF SCALES AND THE SCALES THAT COULD BE USED FOR REGULATORY APPROVAL PURPOSE. AND I THINK TE QUESTION IS WHETHER WE NEED NEW SCALES BASED ON THE DISCUSSIONS FROM A WORKING GROUP LIKE THIS THAT MAY HELP US GET THERE. I WANT TO ASK LYNN, I LOVE THAT RESEARCH THING YOU DID AND THIS IS ALWAYS A BIG THING FOR US IN THE PHARMACEUTICAL INDUSTRY BECAUSE WE'RE TRYING TO RECRUIT PATIENTS FOR TRIAL IS THIS QUESTION, IT COMES IN PARKINSON'S AND ALZHEIMER'S DISEASE SHOULD REGULATIONS EXIST TO GET PATIENTS ENROLLED? IT'S ALWAYS TELLING THAT PATIENTS WANT TO PARTICIPATE IN CLINICAL TRIALS BUT NOT NECESSARILY MADE AWARE OF THEM THROUGH THEIR PHYSICIANS OR WHATEVER REASON AND MAYBE THIS IS AN AREA TO WORK ON. >> WE HAVE MANY PATIENTS WHO CONTINUE TO BE CLINICAL TRIAL ADDICTS AND THERE'S A LOT OF THEM AND THE RECENT RESEARCH SHOWED A LOT OF PEOPLE AREN'T BE REACHED. I THINK PART OF THE PROBLEM IS WE NEED TO LOOK AT THE PATIENT AND REALIZE THE VALUE IN THE CLINICAL TRIALS AND GET THE FEEDBACK THEY FELT LIKE A GUINEA PIG. AND YOU TALKED ABOUT THE IMPORTANCE OF MAKING THE PATIENT FEEL A PART OF THE STUDY AND THAT MEANS INCREASED COMMUNICATION BETWEEN THE PEOPLE DOING THE RESEARCH AND THOSE THAT ARE PARTICIPATING. MAYBE THERE'S COGNITIVE PROBLEMS OR CHALLENGE WITH TECHNOLOGY REQUIREMENTS AND WE NEED TO HELP THEM TO DO THE BEST POSSIBLE JOB SO THE OUTCOMES WILL BE BETTER. AS FAR AS A REGISTRY, I KNOW THE NATIONAL FIBROMYALGIA ASSOCIATION THIS PAST YEAR HAS PARTICIPATED IN DIFFERENT RESEARCH STUDIES IN HELPING Ph.D. STUDIES, UNIVERSITY STUDIES AND EVEN PHARMACEUTICAL STUDIES. AND WE'RE ABLE TO REACH A BROADER MARKET OF PEOPLE POSSIBLE PARTICIPANTS THAT HAVEN'T BEEN REACHED BEFORE BUT THE PROBLEM IS WE'RE NOT BEING COMPENSATED IT'S COSTING THE NONPROFITS TIME AND MONEY AND THERE'S A VALUE THERE. I THINK BUSINESSES SHOULD BE A PART OF THIS AND ACADEMICS SHOULD BE A PART OF THIS AND NEEDS TO BE ONE OF THE PRE-QUESTIONS IS DO WE NEED AN ADVOCACY SYSTEM TO BE ABLE TO AND NOT NECESSARILY AN ADVOCACY SYSTEM BUT ONE THAT CAN CONNECT THE RESEARCHERS AND PATIENTS SO WE HAVE A BETTER WAY OF HELPING ONE ANOTHER TO UNDERSTAND AND TO MAKE SURE WE DON'T HAVE SHORTFALLS ARE PATIENTS AREN'T AWARE OF WHAT THE PROTOCOLS ARE AND MAYBE WE HAVE END POINTS OUTCOMES FROM THE STUDIES THAT AREN'T SATISFACTORY. I WANT TO SNEAK IN ONE MORE THING. THE COMMENT ABOUT RE-DOING CLINICAL TRIALS AND WE SET CERTAIN END POINTS. FOR EXAMPLE, WITH THE PHARMACEUTICAL PRODUCTS FOR FIBROMYALGIA, WE SAID WE WANTED 30% IMPROVEMENT BUT WHAT WE DIDN'T LOOK AT WAS 30% IMPROVEMENT OF WHAT GROUP OF PEOPLE WITHIN THAT POPULATION OF PEOPLE. SO A LARGE GROUP OF PEOPLE THAT COULDN'T REACH THE IMPROVEMENT AND OFTEN HAD BAD SIDE EFFECTS AND BECAUSE OF THAT THERE WAS A LET DOWN IN THE FIBROMYALGIA AND OTHER POPULATIONS OF PEOPLE THAT HAD EXPECTATIONS OF WHAT THESE DRUGS WERE GOING TO DO. I THINK IT'S REALLY IMPORTANT THAT WE UNDERSTAND BOTH AS THE PATIENTS AND AS THOSE PEOPLE DOING THE RESEARCH WHAT WE'RE TRYING TO ACCOMPLISH AND FOR WHAT SUBSET OR GROUPS OF PEOPLE WITHIN THE PAIN POPULATION. >> CAN I ASK ONE MORE QUESTION FOR LYNN OR DO YOU WANT TO GO ON? >> ONE MORE. >> THE OTHER QUESTION IS 40%, 6% OF PATIENCE YOU SAID DON'T WANT TO TAKE A PILL. THAT I THOUGHT WAS REALLY TELLING. THE IDEA THEY'RE NOT TRYING TO FIND AN ANSWER IN A PILL IS INTERESTING. >> I'VE WORKED WITH CHRONIC PAIN PATIENTS AND MYSELF AM ONE. BACK IN THE EARLY 2000s, 90% WANTED A PILL. THAT'S WHEN WE WENT FORWARD AND STARTED WORK THE PHARMACEUTICAL COMPANIES AND TOOK ALMOST 10 YEARS TO GET TO A PLACE THAT WAS HELPING BUT MANY SIDE EFFECTS HAVE BEEN DETERRENTS TO PEOPLE. AND I THINK THE PAIN COMMUNITY AND NOW GOING THROUGH THE OPIOID CRISIS WHERE MEDICATIONS THEY HAVE BEEN USING FOR A LONG TIME AND I KNOW THE RISKS OF OPIOIDS BUT THERE'S PEOPLE WHO HAVE HAD BENEFITS FROM THEM AND NOW NOT BEING ABLE TO HAVE ACCESS TO THEM. I THINK THEY'RE FEELING LIKE THEY'RE KIND OF ON THEIR OWN. WE HEAR THE IDEA OF SELF-MANAGEMENT AS SOMETHING THAT THEY WANT TO TAKE CONTROL BACK IN A LOT OF WAYS. WE HAD SO MANY NEW THINGS OUT THERE TOUTED AS WAYS OF IMPROVING HEALTH AND PAIN SUCH AS NUTRITION, SLEEP, EXERCISE, ALL THESE THINGS, I THINK PATIENTS ARE FINALLY SAYING WAIT A MINUTE AND ALSO THE COST OF PAIN. WE SAID FOR A LONG TIME PATIENTS ARE SPENDING OVER $5,000 A YEAR AVERAGE OUT OF POCKET FOR SUPPLEMENTS AND CHIROPRACTORS AND ALL THESE THINGS. IT'S TIME WE HELP THE PATIENT BY UNDERSTANDING WHAT CAN THESE THINGS DO FOR THEM. YOU MENTIONED A PERSONALIZED APPROACH. I THINK RESEARCH CAN HELP CUT DOWN THAT FEELING OF BEING A GUINEA PIG AND MAKING SURE PEOPLE FEEL SECURE IN THE MEDICATIONS AND THEY'RE BEING APPROPRIATELY PRESCRIBED TO THEM AND NOT JUST HERE'S SOMETHING THAT SOUNDS LIKE IT MAY BE HELPFUL. I KNOW WE'RE A WAYS OFF ON SOME THINGS BUT THEY COULD BE BENEFICIAL. >> DO YOU HAVE A QUESTION? >> SHE MENTIONED NOT ONLY THE PATIENTS LESS AND LESS WILLING TO TAKE DRUGS IN CLINICAL TRIALS AND SOME TAKE THEM FOR UNSPECIFIC REASONS. SO AS YOU MENTIONED PREVIOUSLY PATIENTS ADDICTED TO TRIALS AND WONDERING IF THERE'S POSSIBILITIES IN HOW TO DETECT THEM AND THIS IS A CONCERN. >> WILL I'VE KNOWN A LOT OF ORGANIZATIONS WITH CLINICAL TRIAL SITES AND IT BECOMES DIFFICULT TO FIND PEOPLE SO THEY HAVE A RAPPORT WITH A GROUP OF PEOPLE AND KEEP BRINGING THEM BACK. OFTEN TIMES PEOPLE FEEL IT'S A WAY TO BE HEARD AND FIND AN ANSWER. SOME DON'T HAVE THE ECONOMIC SITUATION TO HAVE INSURANCE AND THINGS. IT'S WAY TO TRY SOMETHING THAT WOULD HELP THEM. OFTEN TIMES THOSE PEOPLE WHO PARTICIPATE IN CLINICAL TRIALS ARE DESPERATE. IN OUR SCREENING WE NEED TO EVALUATE SOME OF THESE FACTS AND NEED TO EXPAND THE NUMBERS AND KINDS OF PEOPLE PARTICIPATING AND MANY AREN'T WORKING AND THOSE THAT ARE WORKING DON'T HAVE THE TIME OR THE ABILITY TO TAKE TIME OFF AND IF THEY'RE A MOTHER AND HAVE CHILDREN THEY CAN'T TAKE TIME OFF AND THERE'S A PSYCHOLOGICAL COMPONENT OF THOSE TRYING AND THEY'RE DESPERATE AND WE NEED TO BE AWARE OF THESE SITUATIONS. WE NEED TO EXPAND OUR ABILITY TO INCLUDE OTHER TYPES OF PEOPLE IN THE CLINICAL TRIALS. I THINK I USE THE WORD ADDICTED AND THAT'S PROBABLY STRONG BUT PEOPLE WHO FEEL THEY GET SOMETHING OUT OF BEING APART OF A CLINICAL TRIAL. OFTEN TIMES WE'RE GETTING THE SAME PEOPLE WITH THE SAME PROBLEMS IN THE SAME SYMPTOM AND THINGS LIKE THAT THAT ARE PARTICIPATING. AND I HAVE BEEN THRILLED OVER THE LAST 20 YEARS HOW THE MEDICAL COMMUNITY HAS EMBRACED THE OPINION OF THE PATIENTS AND GIVEN THEM SO MUCH MORE CREDENCE IN BEING ABLE TO PARTICIPATE AND HAVE GOOD INSIGHTS THAT ARE GOING TO HELP MAKE RESEARCH BETTER AND HELP HEALTH CARE PROVIDER DO A BETTER JOB. I FEEL THE MORE WE CAN BRIDGE THE GAP AND WORK TOGETHER THE BETTER WE'LL BE OVERALL. DOCTORS WILL BE HAPPIER BECAUSE THEY'LL BE ABLE TO HELP THE PATIENTS AND THE PATIENTS ARE GOING TO GET BETTER. >> THANKS, LYNN. THAT'S A GOOD CAUTIONARY TALE OF WHAT WE CALL PROFESSIONAL PATIENTS AND DAVID IT BRINGS UP THE IMPORTANCE OF LIFESTYLE MEASUREMENTS AND MAKE SHUSH THERE'S NOT HUGE SHIFTS DURING THE COURSE OF THE TRIAL WHICH COULD IMPACT THE OUTCOME. THANK YOU. >> WE WANT TO ENCOURAGE PEOPLE TO USE THE RAISE THE HAND FUNCTION. WE ONLY HAVE A FEW MORE MINUTES LEFT SO I'M SURE -- AND ONE GREAT INTEREST TO ME IS THERE'S OVER 100 PAIN CONDITIONS ASSOCIATED. UNFORTUNATELY MANY ARE KNOWN CONDITIONS HOW DO WE ENCOURAGE THE COMMUNITY TO TREAT OTHER CONDITIONS NOT WITHIN THE WELL DEFINED SPACE? WHAT IS IT NIH CAN DO TO HELP FACILITATE THE TRIALS? >> WE'RE WHERE WE WERE 10 YEARS AGO IN STUDYING RARE DISEASES. THE PHARMACEUTICAL INDUSTRY WAS CONCERNED THEY WOULDN'T HAVE A GOOD RETURN ON INVESTMENT BUT IT'S TRUE AND RARE DISEASES AREN'T THAT RARE AND THEY'VE GARNERED INTEREST FROM THE PHARMACEUTICAL COMPANIES AS YOU KNOW. SAME IS TRUE WITH THE PAIN CONDITIONS. THE PAIN CONDITIONS THERE ARE SOME RARE PAIN CONDITIONS AND THE ISSUE IS REGULATORY GUIDANCES. THAT'S AN IMPORTANT ASPECT OF THE WORKSHOP AS I SEE COMMENTS THERE'S BEEN A LOT OF SCALES AND INITIATIVES GONE ON IN THE LAST 20 YEARS. THEY HAVEN'T ALWAYS TRANSLATED TO CHANGE IN THE WAY WE LOOK AT OUR DRUGS. WE NEED TO BE THINKING ABOUT RARE DISEASES AND NEED TO ENCOURAGE UNSPORTSMANLIKE COMPANIES TO LOOK AT TELL -- PHARMACEUTICAL COMPANIES TO LOOK AT THEM. AND SOME ARE FOCUSSED ON NEUROPATHIC PAIN AND SOME NEED TO MOVE AWAY FROM THAT AND FIBROMYALGIA. LET ME STOP THERE. >> LYNN? >> OFTEN TIMES WE FIND THINGS THAT WILL HELP THE BROADER POPULATION FROM LOOKING AT SMALLER POPULATIONS. BEING A PAIN ADVOCATE I HEAR THINGS ALL THE TIME THAT MAYBE AREN'T GETTING ATTENTION. WHEN I STARTED OUT, FIBROMYALGIA NO ONE HEARD THE WORD AND I DIDN'T KNOW IF IT WAS A REAL CONDITION OR WHAT IT WAS. IT ENDED UP BEING IT WAS SOMETHING THAT AFFECTS MILLIONS OF PEOPLE. I THINK WE DON'T JUST LET ECONOMICS PLAY A PART IN WHAT WE'RE TRYING TO DO AND ACCOMPLISH. >> THANK YOU. >> CAN I SQUEEZE IN ONE MORE QUESTION? YOU'VE ALL DISCUSSED THE IMPORTANCE OF UNDERSTANDING PAIN DEVELOPMENT IN DEVELOPING THERAPEUTICS WE'RE IN A PRECISION MEDICINE ERA, HOWEVER, THE MECHANISMS UNDERLYING MANY FORMS OF PAIN ARE NOT WELL UNDERSTOOD. WHAT ARE YOUR RECOMMENDATIONS IN SUCH CASES? >> WELL, MAYBE I CAN RESPOND TO THIS. IN THE FIELD IN PARTICULAR OF NEUROPATH YOU CAN PAIN BUT IT'S NOT SPECIFIC TO THE FIELD THERE'S BEEN A LOT OF ATTEMPTS TO DEVELOP SOME TOOLS, I WOULD SAY QUESTIONNAIRES OR MEASURES SUCH AS QUANTITATIVE TESTING TO EXPLORE THE MECHANISM WHICH MIGHT BECOME SURROGATES OF SOME MECHANISMS. THIS IS FAR FROM BEING PERFECT BUT THERE'S INDICATIONS FROM CLINICAL TRIALS IN SOME CASES IT WORKS AND THESE MEASURES I SURROGATE OF MECHANISM CAN BETTER PREDICT TO A RESPONSE TO A DRUG THERAPY OR NON-DRUG THERAPY. >> AND QUANTITATIVE SENSORY TESTING HAS NOT CAUGHT ON IN THE UNITED STATES AS WELL AS I THOUGHT IT WOULD HAVE AS IT'S MORE POPULAR IN THE E.U. AND THERE'S WAYS OF LOOKING AT THE UNDERLYING PATH OF PHYSIOLOGY OF PAIN AND FUNCTIONAL IMAGING. WE DON'T HAVE TIME TO GO IN TO IT WITH TOO MUCH DEPTH. >> ONE MORE QUICK QUESTION FOR LYNN. YOUR SURVEY INDICATED 65% OF THE RESPONDERS WISHED THEY RESPONDED IN A TRIAL DID THEY ASK WHETHER THEY DIDN'T HAVE AN OPPORTUNITY OR WERE EXCLUDED? >> THAT NUMBER WAS FOR PEOPLE INTERESTED IN LIFESTYLE AND COMPLIMENTARY AND ALTERNATIVE TREATMENTS. NOT DISTINCTLY FOR PAIN MEDICATIONS BUT THE MAIN REASON WAS THEY HADN'T BEEN CONTACTED. THEY DIDN'T KNOW ABOUT THEM. >> AN QUICK QUESTIONS? >> I THINK WE HAVE ONE MORE MINUTE LEFT AND THAT'S GOOD FOR A TRANSITION. >> THANK YOU. >> THE NEXT IS A BREAK, RIGHT, JENNIFER? >> YEAH. >> WE'LL SEE YOU AT 12:45. >> WE'LL NOW MOVE TO THE THIRD PANEL LED BY BOB DWORKIN. >> FIRST, I'D LIKE TO THANK OUR THREE PANELISTS FROM DUKE UNIVERSITY AND ROBERT EDWARDS FROM HARVARD AND PETRA SCHWEINHARDT FROM THE UNIVERSITY OF ZURICH. I'M PLEASED WE HAVE SUCH DISTINGUISHED PANELISTS. WE'LL DO IT DIFFERENTLY. I'VE ASKED EACH PRESENTERS TO GIVE TO NO MORE THAN A THREE TO FIVE-MINUTE HIGHLIGHT KEY POINTS OF THEIR LONGER PRESENTATIONS AVAILABLE ONLINE FOR DAYS JUST SO IF ANY YOU HAVEN'T SEEN THE PRESENTATIONS YOU HAVE A QUICK RECAP AND AFTER THOSE THREE AND AND IN THE LAST 10 MINUTES WE'LL ASK BARBARA KARP FACILITATING THIS SESSION FROM NIH TO ASK ANY QUESTIONS THAT HAVE COME ALIVE SO DIFFERENT FROM THE SESSIONS EARLIER THIS MORNING AND WE'LL SEE HOW IT GOES. LET'S START WITH BRYCE REEVE FROM DUKE UNIVERSITY. >> THANK YOU FOR ALLOWING ME TO COME UP AND TALK TO YOU TODAY AND WHEN YOU SAY THREE TO FIVE MINUTES I GUESS THAT MEANS 15 TO 20 MINUTES. BRIEFLY, I DON'T WORK EXCLUSIVELY IN THE FIELD OF PAIN. I PROBABLY WORK ACROSS A RANGE OF ADULT AND PEDIATRIC POPULATIONS AND I HAVE HEARD THROUGH SESSIONS THIS MORNING THAT THERE ARE RANGE A TYPE OF WAYS WE CAN ASSESS PAIN WHETHER IT BE BIOMARKERS OR THROUGH CLINICAL OUTCOME ASSESSMENTS. AN WE'LL GET MORE SPECIFIC IN TO PAIN THAN WHAT I'LL BE COVERING TODAY AND FOR THE CLINICAL OUTCOME ASSESSMENTS WE ALL RECOGNIZE AND THINK OF THE PATIENTS ACTUALLY DIRECT VOICE IS THE GOLD STANDARD. WE TRY AS MUCH AS POSSIBLE TO CAPTURE THE MEASURES OF PAIN. WE ALSO KNOW THERE ARE TIMES WHEN THE PERSON MAY EITHER BE TWO YOUNG OR ILL OR DON'T WANT TO COMPLETE A QUESTIONNAIRE AND THAT CAN INCLUDE A MEASURE FROM A CAREGIVER. AND THERE'S INTEREST TO USE DIGITAL MEASURES AND WHAT WE THINK OF WHEN PAIN IS LIMITED HOW TO GET CONTINUOUS MEASURE I LIKE THIS QUOTE THAT SAYS WHAT IS OBSERVED IS NOT NATURE BUT NATURE EXPOSED AND A LOVE THIS QUOTE. IT RESONATES WITH ME AND THIS IS AND WE NEED TO RECOGNIZE THAT WE NEVER GET A PERFECT ASSESSMENT OF WHAT A PERSON'S PAIN LEVEL IS. IT'S RENDERING OF A LIFE SPAN FRAMEWORK FOR A FEW TALKS. AND THE YELLOW ARROW IS SUPPOSED TO REPRESENT THE LIFE SPAN FROM BIRTH ALL THE WAY TO AN OLDER ADULT. AND WE NEED TO RECOGNIZE IN THE FRAMEWORK AND WHAT'S THE SOURCE OF INFORMATION AND WHEN WE LOOK ABOVE THE YELLOW LIFE SPAN WE NEED TO HAVE CONVERSATIONS ON WHAT IS THE PAIN CONSTRUCT IS THIS THE PAIN SEVERITY OR HOW OFTEN IT OCCURS AND HOW MUCH IT INTERFERES. WE TALKED ABOUT THE PHYSICAL AND SOMATIC AND AFFECTIVE TYPES OF PAIN. AND WE NEED TO THINK ABOUT HOW THE CONCEPTS CHANGE OVER THE COURSE OF THE LIFE SPAN. WHEN WE THINK OF PAIN INTERFERENCE WHEN WE TALK ABOUT PAIN INTERFERENCE IS IT DIFFERENT FROM WHAT A CHILD VERSUS WHAT AN OLDER ADULT WAS. AND THERE'S THE TYPES OF MEASURES WE CAN DO AND WE HAVE TO RECOGNIZE DEPENDING ON HOW OLD THE INDIVIDUAL IS AND IN THE EARLIER SESSION THEY WERE FOCUSSED IN THE TOUGH AREA FROM BIRTH TO AGE 3 YEARS OF AGE. AND HOWEVER WE DO KNOW THERE'S A BIAS WHEN YOU ARE ASKED TO REPORT WHAT SOMEONE ELSE'S PAIN LEVEL IS AND COMPARING CHILD VERSUS THE CAREGIVER REPORT AND REPORT THE LEVEL OF PAIN AND WHAT WAS INTERESTING IS ONE FACTOR THAT DETERMINED THE LEVEL OF AGREEMENT OR DISAGREEMENT WAS THE PARENT HAD MORE PAIN THEMSELVES THEY TEND TO OVER REPORT THE CHILD'S PAIN LEVEL IS AND WE NEED TO RECOGNIZE WHAT WE CAN DO TO CORRECT THEM. AND I'VE TAKEN MY FIVE MINUTES AND GONE A SLIGHTLY BIT OVER. WHAT WE NEED TO UNDERSTAND IS WHILE THERE'S DIFFERENT PAIN MEASURES OUT THERE THERE'S OPPORTUNITIES TO REVISIT THE WAYS YOU ASK SOME PAIN QUESTIONS AND LOOK AT THE RESPONSE OPTIONS. IN MY PRESENTATION I TALKED ABOUT SOME OF THE LIMITATIONS FROM WHAT I SEE IS A NUMERIC RANGE SCALE IN THE TYPES OF QUESTIONNAIRES. AS YOU HEARD FROM THE FDA, THERE'S A MOVEMENT TOWARDS DEVELOPING AND IDENTIFYING WHAT WOULD BE CORE OUTCAMPAIGN MEASURE ASSESSMENTS AND OUR GROUP IS FOCUSSED ON THE PEDIATRIC AREA. WE NEED INTEGRATE THE MORE DIGITAL TYPES OF ASSESSMENTS LIKE ECOLOGICAL MOMENTARY SYSTEMS TO CUT PAIN MORE OFTEN AND SEE HOW IT DEVELOPS THROUGHOUT THE WEEK. WE NEED TO LOOK AT USING DIFFERENT TYPES OF INFORMATION AND PAIN ATTRIBUTES AND DEVELOP COMPOSITE MEASURES AND STRENGTHS AND LIMITATIONS OF THOSE AND RECOGNIZE WE ALWAYS NEED TO INCLUDE PATIENT POPULATIONS IN BOTH THE DEVELOPMENT AND EVALUATION OF OUR PARTICULAR PAIN MEASURE AND IMPORTANTLY WE NEED TO UNDERSTAND WHAT ASPECTS OF PAIN ARE MOST IMPORTANT TO THEM AND WITH THAT I'LL TURN IT BACK OVER TO YOU. >> OUR NEXT SPEAKER LET'S SEE IF YOU CAN BE MORE SUCCINCT THAN BRYCE WAS. >> I'LL GIVE IT A SHOT. THANKS FOR INVITING ME. ROB EDWARDS PAIN PSYCHOLOGIST AT BRIGHAM AND WOMEN'S. FOR THE SEVEN WHO WATCHED MY FULL TALK, THANK YOU. I HOPE YOU LEARNED SOMETHING GOOD. YOU GUYS CAN TAKE A THREE MINUTE NAP AROUND NOW AND FOR THE REST OF YOU IN A COUPLE MINUTES I'LL TELL YOU EVERYTHING YOU NEED TO KNOW FROM THAT TALK. I'M GOING TO SAY NEXT SLIDE A LOT BECAUSE I HAVE FALLEN IN LOVE WITH ANIMATIONS ON POWER POINT SLIDES AND MANY ARE THREE OR FOUR ADDITIONS THAT WILL COME IN. AS MIKE ROBINSON AND OTHERS HAVE NOTED NICELY IN THE CHAT WE HAVE A BUNCH OF WELL VALIDATED WIDELY USED PATIENT REPORT THE OUTCOME MEASURES FOR PAIN AND IMPACT AND ACTION OF OTHER ORGANIZATIONS HAVE DONE A NICE JOB SUMMARIZING WHAT ARE THE RECOMMENDED MEASURES WE SHOULD BE USING FOR CLINICAL TRIALS FOR PAIN. YOU SEE THE RECOMMENDATIONS FOR EMOTIONAL FUNCTIONING ETCETERA. AND YOU CAN SEE WHEN WE'RE REPORTING TRIAL OUTCOMES WE DO A GOOD JOB OF REPORTING PAIN INTENSITY USED AS A PRIMARY OUTCOME, REPORTING SYMPTOMS AND PARTICIPANT DISPOSITION. THEY'RE ALL OVER 50% REPORTED IN CLINICAL TRIALS AND ALL THE OTHER IMPORTANT OUTCOMES TO PATIENTS ARE REALLY UNDER REPORTED. WELL UNDER 50% FOR MOST OF THEM. STICKING TO THE REALM OF PATIENT-REPORTED OUTCOMES MEASURES THERE'S PROBABLY SOME CONDITIONS WHERE WE MIGHT THINK HARD OUTCOMES AND CONDITIONS LIKE OSTEOARTHRITIS WHERE POST THE PAIN IS EVOKED BY SPECIFIC ACTIVITIES IN CONDITIONS LIKE OSTEOARTHRITIS WE CAN BETTER REPRESENT PATIENTS IF WE USE ACTIVITY SPECIFIC MEASURES OR EVOKED PAIN MEASURES. IF YOU LOOK AT THE LAST COLUMN IN THE TABLE ON THE BOTTOM FOR KNOWN EFFICACIOUS TREATMENT AND WHAT YOU CAN SEE THE EFFECT SIZE FROM NAPROXIN YOU GET THIS OUTCOME AND LARGER EFFECT SIZES FOR MORE TIP CAP PAIN AT -- TYPICAL PAIN AT REST TYPES OF MEASURES. AND STREAMING PROGRAMS STUDIED AND THIS ONE USES CALIBRATED NOXOSTIMULI AND THIS AVOIDS LOGICAL ERRORS IN RATING WHERE FOR EXAMPLE THE AVERAGE PAIN IS RATED AS MORE INTENSE OR WORSE THAN THE WORSE PAIN. THE ERRORS IF I CAN CALL THEM THAT TYPICALLY GO TO CLINICAL TRIALS AND YOU CAN CUT THEM DOWN WITH TRAINING PROGRAMS. THERE'S ALSO QUITE A BIT OF INTEREST IN COMPOSITE OUTCOMES. PART OF THE REASON FOR THAT IS THAT OUR TREATMENTS OFTEN EFFECT ALL SORTS OF PARAMETERS AND WE'RE TALKING ABOUT THINGS LIKE PAIN INTENSITY AND PHYSICAL FUNCTION. THERE'S OFTEN A MODEST, AT BEST, RELATIONSHIP BETWEEN THOSE THINGS. SOMETIMES NO RELATIONSHIP AT ALL. PEOPLE CAN IMPROVE IN FUNCTION BUT NOT PAIN AND VICE VERSA. SO COMPOSITE OUTCOMES THAT COMBINE THESE SORTS OF DOMAINS WHERE FOR EXAMPLE YOU CAN BE A RESPONDER IF YOU HAVE A SUBSTANTIAL IMPROVEMENT IN PAIN INTENSITY OR IN PHYSICAL FUNCTION OR TOGETHER EVEN BETTER. THOSE SORTS OF COMPOSITE OUTCOMES OFTEN OFFER GREATER ASSAY SENSITIVITY. YOU GET LOWER NUMBERS NEEDED TO TREAT WITH THOSE COMPOSITE OUTCOMES AND BETTER REPRESENT THE PATIENT EXPERIENCE. THERE'S A TON OF INTEREST IN NEW OUTCOME MEASURES EVERYTHING FROM ACCELEROMETER METERS AND THE SPACIAL EXTENT OF PAIN IN AND THERE ARE GROUPS WORK ON NEW OUTCOME MEASURES INCLUDING THINGS LIKE RANGE OF MOTION METRICS AND OTHER PATIENT-REPORTED DOMAINS THAT ARE IMPORTANT TO PEOPLE BUT UNDER STUDIED THINGS LIKE SPIRITUALITY AND WE'RE DESIRING TO ASSESS THE AFFECTS OF OUR TREATMENTS ON THOSE IMPORTANT DOMAINS. THAT'S ALL I'VE GOT. THANKS VERY MUCH. >> NEXT IS PETRA SCHWEINHARDT AND I SHOULD SAY SHE SHOULD GET EXTRA MINUTES BECAUSE SHE SET ASIDE HER DINNER PLANS. >> GOOD MORNING, GOOD DAY OR GOOD NIGHT I GUESS. I'LL TRY TO KEEP THIS BRIEF. OBVIOUSLY THERE'S A LOT OF THAT COULD BE SAID ABOUT ALL THESE TOPICS BUT I FIND IN PARTICULAR THERE'S BRAIN-BASED BIOMARKERS BECAUSE IT'S EXCEEDINGLY COMPLEX ISSUE. I WOULD LIKE TO START BY SAYING IT RELATES TO THE PREVIOUS DISCUSSION IN THE PANEL IF YOU CONSIDER PAIN THE PRIMARY PROBLEM SOME PEOPLE MAY CALL IT A DISEASE WHICH ARGUABLY MAY BE THE CASE IN CERTAIN CHRONIC PAIN CONDITIONS THEN IT SEEMS LIKE AN OBVIOUS FUNCTION WE SHOULD LOOK AT THE BRAIN BECAUSE AT THE END OF THE DAY THE SENSATION OF THE BRAIN IS A CAUSE OF BRAIN FUNCTION. IN THE MORE EXTENDED TALK YOU CAN PROBABLY LISTEN TO AFTER THE MEETING I PRESUME, I WILL ALSO MAKE THE CASE WHERE THERE MAY BE SOME INSTANCES WHERE IT'S NOT EFFICIENT OR MAYBE DANGEROUS. REALLY, EVEN IN CHRONIC PAIN WE HAVE TO THINK ABOUT WHAT OUR ISSUES AT HAND IS, IS IT THE PAIN OR SOMETHING ELSE OR STILL A SYMPTOM LONG-TERM ACUTE PAIN BUT THAT'S A DIFFERENT DISCUSSION. ANYWAY, I WANT TO BE CAUTIOUS HERE. ALSO BECAUSE I THINK BRAIN IMAGING GETS HYPED A LOT AND HOPES ARE THERE AND I DON'T WANT TO BE NEGATIVE AND I DON'T THINK THEY'RE COMPLETELY UNJUSTIFIED BUT I WANT TO MAKE THE POINT IT'S RELATIVELY EARLY DAYS WITH BRAIN-BASED BIOMARKERS. AND OTHER PEOPLE IN THE COMMUNITY WILL TELL YOU THE OPPOSITE OF WHAT I'M SAYING. EVERYTHING WE DO IN SCIENCE I THINK WE HAVE TO BE VERY CAREFUL IN DEFINING WHAT OUR AIM IS AND WHAT WE WOULD BE LIKE TO USE THIS BIOMARKER FOR. SO LET'S START WITH MAYBE THE MOST SIMPLISTIC CONCEPT AND THAT'S BEEN PUSHED A LITTLE BIT IN THE COMMUNITY TO USE IT AS A DIAGNOSTIC BIOMARKER. SO FOR THE DETECTION OF PAIN ALSO THE ONLY THING THAT MATTERS IS WHAT THE PATIENT FEELS AND IF THEY DON'T FEEL PAIN THERE'S NO POINT TO THE TREATMENT OR INTERVENTION. ONE CAN MAKE THE CASE OF THE POPULATIONS AND YOUNG CHILDREN AND PEOPLE WHO CANNOT SELF-REPORT IT'S NOT THE MAJORITY OF THE PAIN POPULATION. IF YOU WANTED TO USE IT AS A DIAGNOSTIC BIOMARKER REPLACING WHAT THE PATIENT IS TELLING US THEY HAVE PAIN IN MY MIND THE IMPORTANT PREREQUISITE FOR THE BIOMARKER IS IT'S MORE SENSITIVE THAN THE REPORT. AND I DO BELIEVE THERE'S REASON TO BELIEVE THAT MIGHT BE THE CASE BECAUSE IF YOU THINK ABOUT IT IF YOU AGREE ON PERCEPTION OF PAIN BEING A BRAIN FUNCTION LOOKING AT THE BRAIN'S ACTIVITY IN THE GIVEN MOMENT IS SORT OF CLOSER TO THAT SENSATION THAN HAVING AND IT'S CLOSER TO THE SENSATION AND EXPERIENCE OF THE PATIENT THAN HAVING THEM REPORTING ON IT. IN THAT SENSE IT MAY BE MORE SENSITIVE THAN THE REPORT. AND THERE'S BEEN WORK ON THIS TOPIC AND IN 2015 THEY PUBLISHED I KNOW THE FIRST INDICATION THAT MAY BE THE CASE WHAT THEY DID IN THE STUDY IS THEY HAD SEVEN KNOWN ANALGESICS WITH PAIN AND SEVEN OF THOSE STUDIES THERE WAS A CHANGE IN THE BRAIN RELATED ACTIVATION BUT ONLY FIVE OUT OF THOSE STUDIES THERE WAS ALSO CHANGE IN PAIN REPORT. YOU COULD ARGUE THE BRAIN-BASED BIOMARKER WAS SENSITIVE AND IN MY MIND THE JURY'S STILL OUT THERE. OTHER TYPE OF BIOMARKER BRAIN IMAGING MAY BE USEFUL FOR AND SOMETHING I TERM HERE MECHANISTIC BIOMARKER ACCORDING TO A TERMINOLOGY NOT AN OFFICIAL BIOMARKER FOR ME IT'S HELPFUL IN TRYING TO UNDERSTAND THE CONCEPT. LET'S PURSUE AND WE HEARD FROM TWO PEOPLE TWO BRAINS WITH EXPERIENCE TO PAIN TO A CERTAIN DEGREE AND THEY REPORT TO US THERE'S SIMILAR PAIN INTENSITY AND THEY ALSO USE MORE SOPHISTICATED ASSESSMENT AND WE ASK THEM HOW UNPLEASANT IT IS AND IT ALL LOOKS SIMILAR IN THEIR REPORT. YOU CAN THINK OF DIFFERENT BRAIN ACTIVATION PATTERNS AND WHAT MAY BE UNDERLYING THE SAME OUTCOME REPORTED BY THE PATIENT. THIS IS SOMETHING THAT IN PSYCHIATRY HAS CAUGHT UP AS TERMED AS DIFFERENT ENDOPHENOTYPES LEADING TO THE SAME SYMPTOMS. THERE'S SOME INDICATION THAT SOMETHING LIKE THIS EXISTS AGAINST BUT THAT'S A WAY WHERE BRAIN IMAGING MAY BE ABLE TO PROVIDE ADDITIONAL INFORMATION WE CAN'T GET FROM PATIENT-REPORTED OUTCOMES. AND WITH THIS I'LL PRESENT WITH MY TAKE HOME MESSAGES. I MADE IT CLEAR IN THE SHORT TIME THAT THE BIOMARKER TO CHOOSE DEPENDS A LOT ON THE TERM. I DISCUSSED THE TYPE OF BIOMARKER AND DISCUSSED THERE'S A MECHANISM OF THE TREATMENT IS PROBABLY IMPORTANT FOR THE SELECTION AND I ALLUDED TO SOME OF THE KEY QUESTIONS I STILL HAVE WHEN THE BRAIN-BASED BIOMARKERS ARE MORE SENSITIVE THAN THE PAIN RECORD WHETHER THEY CAN DIFFERENTIATE BETWEEN DIFFERENT PAIN PHENOTYPES AND WHETHER THEY CAN DIFFERENTIATE DIFFERENT TREATMENT MECHANISMS. >> SO WE HAVE ABOUT A DOZEN OR MORE EXCELLENT QUESTIONS THAT HAVE ALREADY COME IN FOR THE THREE PANELISTS AND WE'LL SPEND TIME GOING THROUGH SOME OF THEM I DOUBT WE'LL GET THROUGH ALL OF THEM AND WE'LL FIND OUT IF ADDITIONAL QUESTIONS CAME IN THROUGH CHAT. I'D LIKE TO START WITH BRYCE, THE QUESTION IS DISCUSSING THE DEVELOPMENT OF NEW OUTCOME MEASURES. GIVEN YOUR VAST EXPERIENCE IN THIS AREA, WHAT DO YOU THINK ARE THE MOST IMPORTANT STEPS TO REQUIRE AND VALIDATE A NOVEL OUTCOME AND WHAT'S KEY IN THE VALIDATION PROCESS? >> THANK YOU. I THINK THE KEY THING AND I HEARD THIS EMPHASIZED IN EARLIER SESSIONS TODAY IS DIRECTLY INVOLVING THE PATIENT AND PATIENT ADVOCATES IN THE DEVELOPMENT AND EVALUATION OF THE MEASURE. AND IT STARTS NOT JUST AS THE PATIENT'S AS PARTICIPANTS IN THE TRIAL OR STUDY THERE, THE EXTENT THAT YOU CAN INCLUDE PATIENT ADVOCATES AS FELLOW RESEARCH TEAM MEMBERS TO IDENTIFY WHAT IS THE MOST IMPORTANT RESEARCH QUESTION WE SHOULD BE ADDRESSING. WHAT WE THINK CAN CONCEPTUALIZE PAIN AND HOW TO CONDUCT THE EVALUATION PROCESS IN A WAY THAT THE HIGHEST QUALITY RESULT. IN ADDITION TO THAT WHAT WE'VE DONE WITH OTHER MEASURES I'VE BEEN INVOLVED WITH AND WITH OTHER PAIN MEASURES AS WELL IS UP FRONT CONVERSATIONS LIKE INTERVIEWS WITH PATIENTS WHERE YOU ALLOW US TO GO MORE IN DEPTH WITH PATIENTS WITH CHRONIC PAIN OR ACUTE PAIN AND UNDERSTANDING WHAT IT MEANS TO BE IN THE PAIN AND WHAT'S A MEANINGFUL CHANGE OVER TIME INCLUDING PATIENT DO COGNITIVE TESTING OF THE QUESTIONNAIRES AND SURVEYS. AND I THINK IN MANY WAYS WHEN WE LOOKED AT SOME OF THE EXISTING PAIN MEASURES AND ASKED PATIENTS TO TALK ABOUT WHAT PAIN IS TO THEM IT'S A WIDELY VASTLY DIFFERENT INTERPRETATION. ANY EXTENT WE CAN DEVELOP MORE CONCRETE AND UNDERSTANDABLE TYPES OF END POINTS OR RESPONSE CATBURY THAT SHOW INTERVAL RESPONSES MAY HELP -- AND CONTINUING TO USE PATIENTS AND MEMBERS AND PARTICIPANTS WILL HOPEFULLY YIELD SOME IMPROVED MEASURES IN THE FUTURE. >> THERE'S A QUESTION ABOUT KEY STEPS AND VALIDATING OUTCOME MEASURE. >> CAN YOU REPEAT THAT? I MISSED THE QUESTION. >> ANYTHING TO ADD TO WHAT BRYCE SAID? HE EMPHASIZED CONTENT VALIDITY ARGUABLY THE FIRST STEP. ANYTHING YOU'D LIKE TO ADD TO WHAT ELSE IS CRITICAL AND SANCTIONED REALLY IN THE VALIDATION OF A NOVEL OUTCOME MEASURE? >> NO, I THINK BRYCE HIT ALL THE HIGHLIGHTS INCLUDING MAKING SURE TO ENGAGE PATIENTS AND RELEVANT STAKEHOLDERS IN THE VALIDATION PROCESS. AND EMPHASIZING THE FACT THAT REALLY WHAT WE'RE INTERESTED IN IS PATIENT REPORT OF THEIR STATE OF PACIFIC, SYMPTOMS, EFFECTS OF THEIR PAIN, ETCETERA. AND I THINK BRYCE NICELY EMPHASIZED THAT. >> AND I CAN ADD SOMETHING IN A SLIGHTLY DIFFERENT DIRECTION BUT RELATED AND I SAW IT CAME UP IN THE CHAT AS A QUESTION. THE QUESTION ON BRAIN PRIORITIES PRIORITIES -- BIOMARKER IS HOW DO YOU VALIDATE IT IN AT THE END OF THE DAY WE CARE ABOUT THE EXPERIENCE OF THE PATIENT. SO IN MY MIND IT'S LIKE A STATISTICAL PROBLEM. IT COULD BE FIRST OF ALL THE EFFECT SIZE YOU MEASURED WITH THE BRAIN IMAGE AND YOUR TRUE MEASURES GO IN ONE DIRECTION BUT THE OTHER IS CONSISTENT AND THEN ALSO SOMETHING I THINK THAT IS POTENTIALLY HELPFUL FOR CLINICAL TRIALS IS LET'S SAY I IMAGINE A SCENARIO WHERE THE BRAIN-BASED BIOMARKER WOULD RESPOND FIRST AND THEN DOWN THE LINE THE PATIENT REPORT CATCHES UP WITH THAT SO TO SPEAK WHICH ALSO SPEAKS TO LARGE EFFECT SIZES OF THE BIOMARKER. IT'S A CONUNDRUM IN A WAY BECAUSE THE TWO THINGS HAVE TO CORRELATE OTHERWISE THERE'S NO CONTENT VALIDATION OF THE BRAIN-BASED BIOMARKER. THERE'S WAYS AROUND THIS BUT IT'S AN IMPORTANT QUESTION. >> BOTH PATIENTS AND CLINICIANS HAVE ARGUED FUNCTION IS AS IMPORTANT AS PAIN INTENSITY. SO THE QUESTION FOR YOU AND BRYCE AND PETRA IS ALMOST EVERYBODY THINKS FUNCTION IS CRITICALLY IMPORTANT IN THE PERSON EXPERIENCING PAIN. WHAT IS THE PRIMARY OUTCOME IN CLINICAL TRIALS AND IF IT'S NOT THE PRIMARY OUTCOME WHY ISN'T IT THE CO-PRIMARY TREATMENT SO IF THE TREATMENT ISN'T CONSIDERED EFFICACIOUS UNLESS THERE'S STATISTICALLY SIGNIFICANT DIFFERENCES ON FUNCTION AND PAIN OUTCOME? >> FANTASTIC QUESTION. THE FIRST PART OF MY ANSWER IS I THINK THERE'S BEEN A MOVEMENT IN THE LAST 5 OR 10 YEARS OR SO AND YOU WOULD PROBABLY KNOW ABOUT THIS BETTER THAN ALMOST ANYONE TO MAKE FUNCTION THE PRIMARY OUTCOME FOR SOME TRIALS OF SOME TREATMENTS AND SOME CONDITIONS. SO FOR EXAMPLE I BET A LOT OF PEOPLE IN THE MEETING ARE FAMILIAR WITH THE SPACE TRIAL. THE TRIAL THAT COMPARED OPIOID TO NON-OPIOID TREATMENT OF MUSCULOSKELETAL PAIN. A FUNCTION WAS THE PRIMARY OF THAT TRIAL IF I REMEMBER CORRECTLY LIKE PAIN INVENTORY AND WE CONSIDER THAT A FUNCTIONAL MEASURE OF PAIN IMPACT. I THINK MORE AND MORE TRIALS ARE INCORPORATING FUNCTION MEASURES AND AT LEAST CONSIDERING USING THEM AT PRIMARY OUTCOMES. I BET WE HAVE A LONG DISCUSSION AND IT WOULD PROBABLY USE UP THE REST OF TIME, WHICH I PROMISE I WON'T DO, ON THE RELATIVE MERITS ON PICKING PAIN INSENCE INTENSITY AS -- INTENSITY AS CO-OUTCOMES AND PAIN INTENTION AN AND FUNCTION ASSESSMENT WE CAN USE TO DEFINE RESPONDERS. I THINK THERE'S ADVANTAGES AND DISADVANTAGES TO EACH AND I ENCOURAGE AND I BET YOU DO TO PEOPLE PLANNING CLINICAL TRIAL TO IN CORM RATE A FUNCTION -- INCORPORATE A FUNCTION MEASURE AS A PRIMARY OUTCOME OR COMPOSITE MEASURE OR EVEN IN THE CASE WHERE YOU SUSPECT OTHERS THERE'S GOOD AND WELL VALIDATED PATIENT-REPORTED OUTCOP -- OUTCOME MEASURES WHETHER DISEASE SPECIFIC OR GENERAL. >> CAN I ADD SOMETHING? >> SURE, PETRA. >> I FULLY AGREE. SO WHY NOT WHETHER IT SHOULD BE AN IMPORTANT OUTCOME MEASURE BUT WHY IT IS NOT. SO TO ANSWER THAT QUESTION, BOB, I THINK IT'S MOSTLY OUR OWN BIAS BECAUSE IT'S VERY INTERESTING IF YOU LOOK AT OTHER PROFESSIONS LIKE PHYSICAL THERAPISTS FOR EXAMPLE AND YOU MENTIONED A CONDITION THAT'S THEIR PRIMARY OUTCOME IN MANY INSTANCES AND THEY DON'T USE THE ICD THEY USE THE INTERNATIONAL CONDITION OF FUNCTION. IT HAS TO DO WITH OUR FIELD AND BACKGROUND AND BIASES AND WHETHER IT'S USEFUL OR NOT. >> THIS IS BRYCE. I AGREE WITH PETRA AND ROB. AGAIN IT GETS BACK TO THE FIRST QUESTION WE NEED TO ASK WHAT'S THE MOST IMPORTANT ASPECT FOR YOU. IS IT JUST TO REDUCE THE PAIN SEVERITY BY SOME FRACTION OR NUMBER OVERALL OR IS IT ABLE TO GO BACK AND DO THE WORK AND THE DAILY ACTIVITIES THERE AND I IMAGINE YOU WOULD FIND FOR MANY PATIENTS WHEN THEY TALK ABOUT THEIR PAIN OR FATIGUE, THEY'RE DEFINING IT IN TERMS OF WHAT THEY'RE ABLE OR NOT ABLE TO DO BECAUSE OF THE PAIN. I EXPERIENCE CHRONIC PAIN MYSELF. I'VE HAD IT MOST OF MY LIFE AND I FEEL PAIN EVERY DAY, EVERY SECOND BUT FOR ME WHEN THE PAIN BECOMES INTOLERABLE IS WHEN I'M NOT ABLE TO FOCUS OR TALK OR DO THE WORK SO THE FACT THAT FUNCTIONING COULD BECOME THE PRIMARY MEASURE MAY BE SOMETHING THAT MAY BE THE MOST IMPORTANT PART OF MANAGING PAIN. >> WE CAN COME BACK TO THIS AFTER PETRA. PE PETRA, PEOPLE WERE INTRIGUED ON YOUR PRESENTATION AND GOING BEYOND THAT AND TALK ABOUT WHETHER A TRAIT VERSUS DISTINCT AND MRI INTENDED TO IDENTIFY PLACEBO SO A DISTINCTION FOR PAIN AND PLACEBO RESPONSE AND PARTICULARLY WITH RESPECT TO THAT FMRI. I KNOW THAT'S A LOT. >> I WILL TRY. THE FIRST PART I THINK IS RELATIVELY STRAIGHTFORWARD THE SECOND PART TOO BUT WE'LL SEE IF I CAN DISTRACT YOU ALONG THE WAY. RIGHT, SO FOR THOSE WHO HAVE NOT WATCHED OUR PRESENTATIONS, SO THE KEY POINT HERE IS REALLY THAT THERE'S BEEN QUITE A FEW STUDIES DOING WHAT IS CALLED RESTING STATE FUNCTION MAGNETIC IMAGING YOU LIE IN THE SCANNER AND DO NOTHING TO THEM AND THEY'RE SUPPOSED TO DO NOTHING, WHATEVER THAT MEANS DOING NOTHING AND YOU RECORD THEIR BRAIN ACTIVITY. THEN YOU SEE HOW DIFFERENT PARTS OF THE BRAIN ARE CONNECTED DURING THIS TIME. THEN IT'S IT'S BEEN REPORTED OVER AND OVER THE BRAIN THE SO-CALLED FUNCTION CONNECTIVITY BETWEEN PATIENTS WITH CHRONIC PAIN LOOKS DIFFERENT THAN PEOPLE WITHOUT CHRONIC PAIN AND WE LOOKED AT CHRONIC PAIN PATIENTS THAT HAD PAIN IN THE SCANNER AND CHRONIC PAIN PATIENTS WHO HAPPENED NOT TO HAVE PAIN IN THE SCANNER. WE SOMETIMES ACT AS IF CHRONIC PAIN PATIENTS HAD PAIN 24/7 AND IT MAY BE FLUCTUATING AND NOT BE OFF SOMETIMES. IT MAY BE ESPECIALLY FOR THE PREVALENT CONDITIONS IT'S OFTEN MOVEMENT EVOKED SO IT'S NOT A PAIN CONDITION EVEN IF IT'S CHRONIC BECAUSE IT'S BEEN THERE A LONG TIME. THE CHRONIC PAIN PATIENTS WHO DIDN'T HAVE PAIN IN THE SCANNER WE FOUND MINUTE CHANGES OF THE RESTING STATE. AND IT LOOKED AS IF MOST OF THESE BRAIN CHANGES THAT HAVE BEEN DESCRIBED MIGHT ACTUALLY BE RELATED TO THE FACT THAT PEOPLE HAVE PAIN IN THE SCANNER WHICH GOES BACK TO LOOKING FOR BIOMARKER OF THE EXPERIENCE OF PAIN BUT IT WOULD NOT SPEAK TOWARDS BRAIN ALTERATIONS IN CHRONIC PAIN CONDITIONS. THE BRAIN IS PROCESSING PAIN AND WE HAVEN'T BEEN ABLE TO IMAGE THAT BECAUSE PATIENTS DIDN'T HAVE BRAIN IN THE SCANNER BUT THE QUESTION IS IF THERE'S ALTERATIONS RELATED TO SOME OTHER CHARACTERISTIC OF THE CHRONIC PAIN CONDITION THAT DON'T RELATE TO HAVING PAIN IN THE SPECIFIC MOMENT IF YOU KNOW WHAT I MEAN SO COULD BE DISEASE BURDEN AND DURATION OF PAIN AND THAT'S A CORRELATION WE FOUND AND THAT'S THE DIFFERENTIATION. FOR ANYONE DOING FUNCTIONAL IMAGING THAT DIFFERENTIATION IS HUGELY IMPORTANT BECAUSE IF IT'S PAIN IS DETECTED IN A BRAIN SCANNER OR EEG THE BRAIN SCANNER WILL LOOK DIFFERENT TO NOT HAVING PAIN. AND THE SECOND IS REGARDING PLACEBO. >> WE ONLY HAVE SIX MINUTES LEFT AND THE PERSON WHO ASKED A QUESTION SAID LOOKING AT RESILIENCE AND PROTECTIVE FACTORS WE SPEND TOO MUCH TIME LOOKING AT DEPRESSION, ANXIETY, CATASTROPHIZING. SHUNT WE LOOK AT -- SHOULDN'T WE LOOK AT POSITIVE FACTORS LIKE RESILIENCE. PETRA COULD YOU USE IT TO WEED OUT PATIENTS AND THAT IS AN OVERVIEW OF WHAT WE'LL BE TALKING ABOUT THE NEXT HOUR IF BARBARA GAVE US ANOTHER HOUR BUT I DON'T THINK SHE WILL AND SO I'LL HAND IT TO HER TO ASK ANY FINAL QUESTIONS. >> WE DO HAVE ONE RAISED HAND. DO YOU WANT TO ASK YOUR QUESTION? WE'RE GOING TO UNMUTE YOU. >> SO WE DISCUSSED MULTIPLE END POINTS AND COMBINATIONS OF BIOMARKERS AND PATIENT-RELATED OUTCOMES AND WONDERING WHY WE DIDN'T ADDRESS 2 AND 3. THERE'S STRICT STATISTICAL LIMITS AND PEOPLE DISCUSSED THE BROAD SPECTRUM OF OUTCOMES YOU COULD USE. WOULDN'T IT MAKE SENSE TO PROMOTE ADDITIONAL SECONDARY OUTCOMES IN PHASE II TO THEN INFORM PHASE III. THIS IS FOR THE ENTIRE PANEL. >> I AGREE, IT'S IN EARLY FACED STUDIES YOU CAN EXPLORE NUMBER OF ASSESSMENTS AND OUTCOMES. YOU CAN GET A SENSE OF WHICH ONE IS GOING TO HAVE THE BIGGEST BANG FOR THE BUCK TO EVALUATE A TREATMENT'S EFFICACY IN THE PHASE III. >> AND ONE HAS TO TAKE INTO ACCOUNT PATIENT BURDEN. WE CAN'T HAVE A TWO-DAY BASELINE VISIT WITH MEASURES OF RESILIENCE AND PROTECTIVE FACTORS. PHASE 2 -- PHASE II IS A GREAT WAY TO LOOK AT EXPLORATORY END POINT. ROB, DO YOU WANT TO ADD ANYTHING? >> PHASE II SEEMS LIKE AN IDEAL TIME TO INCLUDE A NUMBER OF OUTCOME MEASURES ACROSS MULL PAL DOMAINS IF THERE'S POTENTIAL BIOMARKERS THAT COULD BE ASSESSED WITHOUT TOO MUCH OF A BURDEN IT'S GREAT TO INCLUDE THEM AS WELL AND YOU CAN DO THINGS LIKE LOOK AT THE RELATIVE ASSAY SENSITIVITY OF OUTCOMES AND DOMAINS AND LOOK AT SUBGROUPS WITH BIOMARKER DATA OR OTHER DATA AND GET AN IDEA IN PHASE II WHICH PARTICIPANTS ARE LIKELY TO RESPOND AND THEY CAN BE NUMBER TIF. >> THAT'S RELATED TO A QUESTION THAT CAME IN WHICH IS FACING THIS HOW DO YOU GO ABOUT PRIORITIZING AND CHOOSING WHICH SCALES OR RATINGS YOU'LL INCLUDE IN STUDIES ESPECIALLY LIMITED BY PATIENT BURDEN? >> WE HAVE TO THINK ABOUT WHAT WE TRY TO DO AND WHAT PATIENT POPULATION AND WA WE KNOW ABOUT THE PAIN AND WHAT THE MECHANISM OF TREATMENT IS. WE DO THAT TOO LITTLE. I DON'T WANT TO BE NEGATIVE BUT WE NOW FIND OUT AN OSTEOARTHRITIS MOVING IS A MEASURE AND IF YOU HAD SPOKEN TO PHYSICAL THERAPISTS YEARS AGO WE WOULD HAVE FIGURED THAT OUT. I THINK THAT WOULD BE MOST INFORMATIVE. >> ONE QUESTION THAT CAME IN AND PETRA RELEVANT TO YOU WHAT ABOUT THE APPLICABILITY OF THE BRAIN MEASURES AND EVERY E -- EEG AND PEDIATRIC AND OTHER POPULATIONS WHERE YOU DON'T HAVE A SUBJECTIVE PAIN RATING TO GO AGAINST? >> IT'S SOMETHING THAT COMES UP THAT IS WORTH BEING EXPLORED. ALONG THOSE LINES IN THE MRI SCANNER AND WHAT IS THINKABLE WE START TO DEVELOP MARKERS STARTING WITH FMI AND THEN EEG IS MORE PATIENT AND SUBJECT FRIENDLY. WE LEARN SOMETHING ABOUT BRAIN USING MORE SOPHISTICATED OR COMPLEX MEASURES AND SOMETHING USABLE AND CHEAPER AND MORE FRIENDLY AND CHILDREN OFTEN HAVE TO BE SEDATED AND WE DON'T WANT THAT. >> IT SEEMS FOR MOST CLINICAL TRIALS HAVE YOU TWO KEY OUTCOMES, PAIN AND FUNCTION. ONE OR THE OTHER COULD BE THE PRIMARY END POINT OR COULD BE CO-PRIMARY END POINTS OR ONE MIGHT VALIDATE A COMPOSITE MEASURE OF PAIN AND FUNCTION. AND THAT TAKES CARE OF EVERYTHING. DEPENDING ON THE TREATMENT AND TRIAL, PAIN AND FUNCTION ARE EITHER PRIMARY, CO-PRIMARY OR ELEMENTS OF A COMPOSITE. DO WE ALL FIVE OF US AGREE WITH THAT? BARBARA MAY NOT BE ABLE TO SAY BECAUSE SHE WORKS FOR THE GOVERNMENT. I'LL TAKE SILENCE AS AGREEMENT. >> THERE'S NO STRONG OPPOSITION. >> THIS IS ROB, JUST 30 SECONDS. I AGREE WITH YOU CLOSE TO 100% ON MOST THINGS. I'M NOT SURE I CAN GET TO 100% HERE. LET'S SAY I HAVE DESIGNED THIS PATIENT NON-PHARMACOLOGIC TREATMENT FOR MUSCULOSKELETAL PAIN I THINK WILL IMPROVE A PATIENT'S EMOTIONAL FUNCTIONING AND GENERAL RATINGS OF QUALITY OF LIFE BUT I DON'T THINK WILL HAVE BIG IMPACTS ON THEIR DAILY PAIN INTENSITY OR GENERAL FUNCTION AND SAY IT BENEFITS SLEEP AS WELL. AND IN MOST SURVEYS THOSE ARE IMPORTANT MODIFICATIONS WITH PAIN AND IF I HAVE A TREATMENT AND WANT TO MAKE SOME OF THOSE SOME OF THE CO-PRIMARY OUTCOME MEASURES AND IGNORE TREATMENT AND FUNCTION BECAUSE MY TREATMENT DOESN'T IMPACT THAT I'M HOPING THAT WILL BE OKAY AND I'M HOPING TO DO THAT. THAT MAY MAYBE VIOLATES ONE OR MORE PRINCIPLES OF WHAT YOU JUST ANNUNCIATED. >> PHYSICAL OR EMOTIONAL FUNCTION AND THEN WE'RE ON THE SAME PAGE. I THINK I'LL LOSE MY JOB IF I DON'T GIVE IT TO BARBARA TO GO TO THE NEXT SESSION. >> WE'RE A COUPLE MINUTES OVER. THANK YOU ALL, IT WAS A GREAT SESSION.