I HOPE EVERYBODY GOT SOME FOOD, GOT TO TAKE A BREAK. HOPEFULLY YOU ARE WELL FED, HAD HAD A NICE LUNCH BUT ARE STILL ENERGIZED TO TALK ABOUT PKU BECAUSE IT'S YOUR JOB TO TELL US WHAT NEEDS TO BE DONE AND WHAT CAN BE DONE AND WE'RE GOING TO START OFF WITH HAVING REPORTS BACK FROM THE BREAKOUT SESSIONS. SO EACH GROUP WILL SPEND ABOUT FIB MINUTES REVIEWING THE SAILIENT POINTS FROM THE DISCUSSION AND WE'LL HAVE HOPEFULLY AN OPPORTUNITY FOR A LITTLE BIT OF QUESTION AND ANSWER. AND THEN WE'LL TAKE IT FROM THERE AND THEN WE'LL MOVE ON IT OUR FINAL PRESENTATION AND DEVELOPMENT OF RESEARCH JEOPARDY. SO WE DECIDED IN THE INTEREST OF FAIRNESS TO GO IN THE REVERSE ORDER FROM THE INITIAL PREPARATIONS OF THE WORKING GROUPS AND SO THE MOLECULAR TESTING GROUP GETS TO GO FIRST. >> THE OTHER PART IS THAT I HAVE TO BE AWAKE FOR THIS SO IF WE WAIT ABOUT 15 MINUTES INTO THIS, I GET MY POST PRANDIAL DROWSYIES AND YOU DON'T WANT TO HEAR ME SNORING. DO WE HAVE THE SLIDES COMING UP? PUSH A BUTTON. THERE THEY ARE. THEY'RE UP. OKAY, WELL, WE HAD FIVE QUESTIONS SO IT GIVES ME A MINUTE FOR QUESTIONS. TESTIFY TALK FAST. QUESTION ONE YOU CAN SEE IS WHAT'S THE BEST WAY TO LOCATE A SITE ABLE TO PERFORM GENEOTYPING, ISSUES ABOUT INSURANCE, AND MEDICAID, OR DOES ONE HAVE TO PAY FOR TESTING INDIVIDUALLY, TRY TO COLLECT INSURANCE AFTERWARDS, AND IS THE GENE FOR PKU PATENTSED AND IF SO, DOES THIS PRESENT A RESTRICTION IN TESTING? THIS WAS KIND OF A BROAD QUESTION, AND I THINK THE ANSWER WAS ALSO VERY BROAD. THE PKU ALLIANCE DOES SEND OUT QUESTIONNAIRES TO KEEP TRACK OF SERVICES AND WHERE THEY CAN BE OBTAINED, THAT INCLUDES THE MOLECULAR TESTING. OF COURSE, YOU CAN ALWAYS USE GENE TESTS FOR THAT. AND WE REALLY ANTICIPATED OUR EXPECTED THAT ALL PKU CLINICS SHOULD KNOW ABOUT THESE. IF THEY DON'T, THEY REALLY FEED TO$ THE FEDERALLY FUNDED CENTERS ACCEPT ALL INSURANCE PRODUCTS, BUT MANY TIMES, BOTH FOR HEM AND IN THE PRIVATE CLINIC SETTING, ONE HAS TO SPEND A LOT TIME UPFRONT DOING PREAUTHORIZATION OR ELSE YOUR PATIENT GETS STUCK WITH THE BILL. SO THAT TAKES A LOT OF TIME AND A LOT OF EFFORT. THERE IS -- YOU SHOULD NEVER SAY NEVER, I GUESS. THE INCLUSION OF GENETIC COUNSELING AS PART OF GENETIC TESTING IS NOT REALLY EXPLICIT. IT'S ALWAYS IMPLICIT AND SO DIFFERENT CENTERS HANDLE THAT DIFFERENTLY. BUT THE MONEY THAT'S GOING TO THE COMPANY THAT'S GOING TO THE TESTING LAB OR YOUR PATHOLOGY DEPARTMENT THAT'S NOT COMING TO YOUR CLINIC, YOU'RE STILL THE ONE THAT HAS TO PROVIDE THE SERVICE. SO THAT'S JUST THE WAY IT IS, FOLKS. SUCK IT UP. BECAUSE THEY DO SUCH A HIGH VOLUME OF TESTING THAT THEY'VE CONCENTRATED THAT AS MUCH AS POSSIBLE TO A SINGLE LABORATORY AND SO THEY GET REVERY STEEP DISCOUNTS ON A LOT OF THEIR TESTING, JUST A POSSIBILITY TO KEEP IN MIND. THE IDEA ABOUT HOW YOU GET AN INSURANCE COMPANY TO PAY FOR GENEOTYPING REALLY COMES DOWN TO PLEADING, AND TYPICALLY, IT INVOLVES, IF YOU GET A COUNCIL OR A -- COUNSELOR OR A DIETIX -- DIETIX -- DIETICIAN, IF YOU TALK TO A MEDICAL DIRECTOR AND THEY HAVE THE DISCRETION TO APPROVE THE REQUEST, ALMOST ALL THE TIME YOU CAN GET THAT DONE BECAUSE YOU CAN CONVINCE THEM THAT IT'S WORTH DOING MEDICALICALLY AND HAVING THAT OUT THERE FROM THIS CONFERENCE WILL BE HELPFUL. HOWEVER, THERE ARE SOME POLICY THAT'S JUST FLAT OUT SAY NO D.N.A. TESTING, NO EXCEPTIONS, IT'S JUST NOT COVERED AND UNDER THOSE CIRCUMSTANCES YOU'RE DEAD IN THE WATER. SO I THINK THAT WAS ABOUT IT. PKU IS NOT A PATENTED GENE. SO REALLY, THIS COMES DOWN TO KNOWING THE RESOURCES THAT THE LINES OF SUPPLY THAT YOUR INSTITUTION USES FOR MOLECULAR TESTING AND WORKING WITH THEM AS BEST YOU CAN. QUESTION TWO, GENEOTYPING IN MANY SITUATIONS CAN BE PREDICTIVE ABOUT RESPONSES TO SAPARTARIN AND THE QUESTION WAS EVEN IF YOUR GENEOTYPE PREDICT YOU NOT TO BE RESPONSIVE, SHOULD IT BE DONE? SO WE JUST REITERATED THE QUESTION AS AN ANSWER AND SAID MANY GENEOTYPES REALLY ARE PREDICTIVE OF SAPARTARIAN RESPONSE AND THERE ARE MANY REPRESENTED MANY, MANY TIMES IN THE MUTATIONS REPRESENTED MANY TIMES IN THE DATABASES THAT HAVE NEVER BEEN ASSOCIATED WITH RESPONSIVENESS. BUT WE ALSO FELT THAT LEAVING A LITTLE WRIGGLE ROOM OPEN WAS WARRANTED AND SO THE WAY WE ENDED UP PUTTING THAT WAS THE INEVITABLE DOUBLE NEGATIVE. SO AT THIS TIME THERE IS NOT EVIDENCE TO PROHIBIT A TRIAL OF SAPARTARIAN IN A PATIENT WITH AN UNFAVORABLE GENEO-TYPE. IF YOU HAVE A FAMILY THAT DESPERATELY WANTS THAT TO SORT OF FEEL THEY HAVE TURNED OVER EVERY STONE AND ARE READY TO DO THE THERAPIES AS YOU ARE PROSCRIBING THEM, THEN IT'S CERTAINLY REASONABLE TO DO. AND OF COURSE, WHEN WE'RE TALKING ABOUT A IS NOT AR TARIAN RESPONSE, WE'RE TALKING WITH A PHE RESPONSE SO WE KNOW NOTHING ABOUT GENEO-TYPE, PHENOTYPE PREDICTIONS ON -- FOR OTHER EFFECTS, NOR DO WE REALLY KNOW IF THERE ARE OTHER EFFECTS OF SAP AR TARIAN ON ANY OTHER SYSTEM AND THAT'S THE ROLE OF CLINICAL TRIALS. QUESTION, CAN INFORMATION BE USEFUL AND WHAT CUTOFFS VB USED? THE SHORT ANSWER IS YOU SHOULDN'T RELY ON YOUR NEWBORN SCREENING. ALL NEWBORN SCREENING SHOULD BE FOLLOWED UP WITH TESTING AND THAT'S HOW YOU SHOULD BE THINKING ABOUT CLASSIFYING PATIENTS, THAT IF YOU ARE LOOKING AT THE ABSOLUTEQ;j TEST. . . THE MOTHER AND CERTAINLY WE ARE SEEING MORE IMMIGRANTS IN THIS COUNTRY FROM COUNTRIES THAT DON'T HAVE NEWBORN SCREENING AND SO THEY MAY ACTUALLY HAVE SOME ISSUES WITH PKU. THE NEXT QUESTION WE DISCUSSED WAS WITH LOWER BLOOD PHENOLNINE LEVELS CLOSE TO THE PHYSIOLOGIC NORMAL CONCENTRATIONS LEAD TO BETTER OUTCOMES? WE CLEARLY DID NOT HAVE A LOT OF DATA REGARDING THIS QUESTION. THERE IS A NEED FOR RESEARCH TO DETERMINE THE OPTIMAL ADULT PHENOLNINE LEVELS AND PREGNANCY PHENOLNINE LEVELS BECAUSE OF THE PHYSIOLOGIC CHANGES OF PREGNANCY MAY BE A LITTLE BIT DIFFERENT AND ARE THEY DIFFERENT ENOUGH TO RECOMMEND DIFFERENT LEVELS? AGAIN, THESE ARE ALL QUESTIONS THAT NEED TO BE ANSWERED. AND IT'S UNCLEAR WHAT THE ACTUAL PHENOLNINE CONCENTRATIONS MIGHT BE IN THE FETUS WHEN WE MODIFY PHENOLNINE LEVELS IN THE MOTHER AND STUDIES COULD BE DONE RELATED TO TRANSPORT IN THE PLAS ENTA AND PHENOLNINE LEVELS PERHAPS USING GUINEA PIGS BECAUSE THEY HAVE A PLACENTA SIMILAR TO HUMANS OR AM BILLICAL SAMPLING, WHICH MAY NOT BE TOTALLY APPROPRIATE BECAUSE OF THE RISK INVOLVED BUT IT WOULD BE A METHOD TO GET INFORMATION WITH RESPECT TO PHENOLNINE ON THE FETAL SIDE. WE ALSO DISCUSSED THAT THE HUMAN STUDIES ARE LACKING AND WE CAN'T DO RANDOMIZED CONTROL TRIALS IN HUMANS BUT WE DO HAVE TO COLLECT INFORMATION ON METABOLIC AND OTHER FACTORS IN WOMEN WHO ARE PREGNANT WITH PKU. AND WE NEED TO DO THIS PROSPECTIVELY AND IT WOULD BE GREAT IF WE COULD BE ON THE SAME PAGE WITH RESPECT TO WHAT WE ARE COLLECTING. CERTAINLY, BIOMARIN HAS A P KUDOS REGISTRY THAT THEY HAVE TO MAINTAIN FOR THE STUDY OF KUFBAN. BUT IN TEN YEARS THAT REGISTRY IS GOING TO GO AWAY AND THERE MIGHT BE SOME WAY THAT WE CAN MAINTAIN SOME DEGREE OF A REGISTRY OR DEVELOP A REGISTRY FOR MOTHERS WITH PKU OR WOMEN WITH PKU WHO ARE PREGNANT. WHAT MATERNAL BLOOD PHENOLNINE CONCENTRATION IS TOO LOWER DURING PREGNANCY AND WHAT ARE THE BEST LEVELS PER PREGNANCY? -- FOR THE PREGNANCY? SO THERE WAS A SORT OF A GENERAL CONSENSUS THAT THE LOWER THE BETTER. BUT THAT WAS A GENERAL CONSENSUS, NOT BEST BASED ON SPECIFIC DATA BUT EXTRAPOLATING FROM EXISTING DATA. AND HOWEVER, THERE ARE RISKS TO HAVING A VERY LOW PHENOLNINE LEVEL AND THOSE RISKS ARE NUTRITIONAL DEFICIENCY. THERE ARE MOTHERS WHO ALMOST STARVE THEMSELVES BECAUSE THEY WANT THEIR PHENOL NYPD TO BE LOW IN PREGNANCY, NOT QUITE STARVATION BECAUSE THEN THE PHENOLNINE WOULD GO UP BUT NOT GETTING QUITE AS MUCH PROTEIN TO MAKE THE BABY OF NORMAL SIZE AND SO THEY RISK RESTRICTION AND POTENTIALLY SOME NUTRITIONAL DEFICIENCIES IN THEIR NEWBORN. THIS IS AN AREA THAT RESEARCH IS NEEDED. WE ALSO NEED TO EMPHASIZE THAT IT CAN BE VERY DIFFICULT DURING PREGNANCY, ESPECIALLY IN THE FIRST TRIMESTER, WHERE CAT BOLISM IS VERY OFTEN OCCURS EVEN IN MOTHERS WHO DON'T COMPLAIN OF NAUSEA AND VOMITING. IF YOU DO A CAREFUL STUDY OF THEIR CAROLIC INTAKE, THEY ARE REALLY IN A CATABOLIC PHASE AND THEIR PHENOLNINE WILL BE ELEVATED. BETTER MATERNAL EDUCATION TENDS TO LEAD TO BETTER OUTCOMES AND THE QUESTION WAS ALSO RAISED, PARTICULARLY IN WOMEN WHO HAVE SEVERE -- IF I CAN USE THAT TERM -- PKU, THAT THEY OFTEN HAVE MORE VARIABILITY IN THEIR PHENOLNINE LEVELS DURING PREGNANCY AND OUTSIDE OF PREGNANCY AND DOES THAT VARIABILITY ACTUALLY IMPACT OUTCOMES IN MATERNAL PKU? HOW CAN WE OPTIMIZE MATERNAL AND NEWBORN HEALTH DURING LACTATION AND THE POST PARTUM PERIOD? ? IN SUMMARY WE HAVE VERY LITTLE INFORMATION IN THIS AREA. THE CHALLENGES, BECAUSE OF LIMITED DATA AVAILABLE, THERE ARE FLUCTUATING PHENOLNINE LEVELS DURING THIS TIME. THERE IS CAT BOLISM IN THE WOMAN, IN THE IMMEDIATE POST PARTUM PERIOD SO THAT INFLUENCES -- THE PHENOLNINE LEVEL. WE KNOW SOME OF THE NUTRITIONAL DEMANDS IN THE POST PARTUM PERIOD BUT IT VARIES DEPENDING ON MR. YOU ARE BREAST FEEDING FULL-TIME OR PART-TIME, BREAST FEEDING NOT AT ALL. THERE ARE CLEARLY DEMANDS OF PARENTING, HORMONAL CHANGES THAT OCCUR. POST PARTUM DEPRESSION, WHICH IS NOT AN UNCOMMON FINDING FOR A WOMAN WHO DOESN'T HAVE PKU. WE FEEL IT'S PROBABLY EXACERBATED WITH HIGH PHENOLNINE LEVELS. AND THE POST PARTUM PERIOD EVERYBODY SORT OF SAYS OKAY, OUR WORK IS DONE. WE HAVE THIS BABY AND THE BABY'S FINE AND THE WOMAN SORT OF GETS DEEMPHASIZED BUT WE NEED TO MAINTAIN CLOSE CONTACT TO THAT WOMAN IN THE POST PARTUM PERIOD PROBABLY WEEKLY JUST LIKE WE DO IN THE ANTEPARTUM PERIOD. WE ALSO WOULD LIKE BETTER TURN AROUND TIMES FOR PHENOLNINE LEVELS, PARTICULARLY IN PREGNANCY BECAUSE WE DO HAVE TO MAKE THOSE DIETARY CHANGES ON SOMETIMES A WEEKLY BASIS. AGAIN, AN AREA OF A LARGE RESEARCH GAP. AND WE DIDN'T GET TO NUMBER FOUR. SO I'LL END THERE. DOES ANYONE HAVE ANY QUESTIONS OR DOES ANYONE ELSE IN THE GROUP HAVE ANYTHING ELSE THAT I MISSED? THANK YOU. [APPLAUSE] >> SO OUR WORK GROUP COMPLETELY IGNORED WHAT EVERYONE ELSE DID AND WHAT WE WERE TOLD TO DO AND DECIDED WE WANTED TO GATHER OUT OF OUR BREAKOUT TIME WAS TWO THINGS. FIRST OF ALL, WE WANTED TO GET FEEDBACK ABOUT THE GRID THAT WE PUT TOGETHER AND WE WANTED TO HEAR FROM PEOPLE IN THE ROOM WHAT THEY THOUGHT WERE KEY RESEARCH QUESTIONS AND SO THAT'S WHAT WE SPENTS OUR TIME DOING. AND RATHER THAN ANSWERING QUESTIONS THAT WE ALREADY HAD. SO AS THIS COMES UP, I WILL TELL YOU THAT WE HAVE EIGHT SLIDES HERE. HENRIETTA AND MICHELLE DID A GREAT JOB OF KEEPING TRACK OF WHAT EMP SAID. WEST LOST TRACK OF THEY WILL. I CAN'T POSSIBLY GO THROUGH ALL OF TIME BUT I AM GOING TO TELL YOU ABOUT A COUPLE KEY THINGS. SO THE FIRST IS THAT WE THOUGHT IT WAS PRETTY STRAIGHTFORWARD THAT EACH OF THE DOMAINS THAT WE CHOSE IMPLIED ISSUES THAT WERE IMPORTANT TO INDIVIDUALS WITH PKU. SO FOR EXAMPLE, EXECUTIVE FUNCTION. BUT JUST ABOUT EVERYTHING WE BROUGHT UP WAS IN FACT, A RESEARCH QUESTION BECAUSE THERE WAS A FAIR AMOUNT OF DISAGREEMENT IN THE ROOM ABOUT WHAT REALLY WAS UNIQUE TO POUK -- PKU, WITH AND WHAT MIGHT BE MORBIDITY. SO IN SOME WAYS MANY ARE RESEARCH QUESTIONS. THIS MAKES IT REALLY PRETTY DIFFICULT BECAUSE OUR CLINICAL FOLKS IN THE ROOM -- AND YOU HEARD THIS IN THE QUESTIONS YESTERDAY -- ALREADY FEEL OVERWHELMED. THE VISIT IS TOO SHORT. WE ARE NOT GETTING PAID AND WE DON'T HAVE THE STAFF AND THIS IDEA TAWE CAN ADD MANY MORE THINGS INTO IT'S ERUPT VISITS IS REALLY ASKING TOO MUCH. SO IN SOME WAYS WE'RE STUCK BETWEEN WANTING TO DO A SORT OF RAPID, FAST, EASY STRAIGHTFORWARD SCREENING THAT EMP CAN DO ALL THE TIME AND ON THE OTHER HAND, A BEAUTIFUL, PERFECT COMPREHENSIVE RESEARCH DATABASE FROM WHICH WE CAN ANSWER ALL THE QUESTIONS THAT WE HAVE AND THOSE TWO ARE INCOMPATIBLE. AND WHAT OUR GROUP HAS TRIED TO DO IS FIND SOME BALANCE IN BETWEEN AND WE GOT A LOT OF FEEDBACK FROM THE BREAK OUTGROUPS THAT HELPED US DISTINGUISH THAT. THAT'S THE MAIN ISSUES THAT CAME UP AND I AM GOING TO RETURN TO THEM IN A MINUTE. AND I WANTED TO REITERATE THIS FRAMEWORK WAS THE NEWBORN RESEARCH NETWORK AND RESEARCH COLLABORATEIVES. WE DO THINK THAT THE WORK WE'RE DOING IS GOING TO BE IN SOME WAYS IMPLEMENTED AND THIS IS GOING TO BE PART OF THE FUTURE. PRETTY EXCITING. AS A RESULT TO GO THROUGH A COUPLE OF THE DOMAINS BECAUSE I THINK WE'RE ALREADY SEVEN MINUTES PAST OUR TIME. SHOULD WE BE CHECKING BONE DENSITY EARLIER AND PART OF THE IDEA IS THERE IS NOT RESEARCH NOW TO MAKE A CLINICAL GUIDELINES RECOMMENDATION. NO ONE CAN TELL YOU WHAT YOU NEED TO DO. IF WE CAN GET MOST FOLKS TO DO THIS IN THEIR CLINICICAL WORLD, THEN WE WILL BEGIN TO ANSWER THE QUESTION OF WHETHER IT NEEDS TO BE DONE AND FOR WHOM. IN THE NEUROLOGICAL DOMAIN, FOR EXAMPLE, CAME UP THAT YES, WE ALL SEEM TO SEE TREM ODORS, YET NO ONE HAS DONE RESEARCH TO SHOW THE CONNECTION. IS IT HIGH OR LOW PHE OR A GOOD MARKER OF WHAT'S GOING ON CLINICALLY? A LOT OF DISCUSSION ABOUT THE COGNITIVE MEASURES. ON ONE HAND, I QM IS FAIRLY POTEENT MEASURES AND GIVES US A GOOD SENSE OF WHAT'S GOING ON OVERALL. WE ALL AGREE IN SOME WAYS THIS HAS BEEN A SUCCESS STORY OF NEWBORN SCREENING AND IN FACT, IT'S MORE SUBTLE COGNITIVE ISSUES THAT REALLY MATTER. AND THERE ARE A WHOLE HOST OF ISSUES. NO ONE GETS PAID TO DO IT AND FAMILIES DON'T HAVE THE TIME. THERE ARE SOME OTHER ISSUES THAT CAME UP. ARE THERE DIFFERENT THINGS BEING DONE IN DIFFERENT PLACES? WHAT DO YOU DO WHEN YOU FIND A RESULT OF SORT OF A BIG ISSUE? THE PEOPLE IN THE TRENCHES ARE SAYING WE DON'T WANT TO DO A BUMP OF TESTS, FIND RESULTS AND A, NOT HAVE THE RESOURCES OR N•D– KNOW HOW TO INTERPRET OR NOT HAVING ANYTHING TO DO AT ALL AND IT'S INAPPROPRIATE TO EXAMINE THEM AND NOT FOLLOW UP. ONE OF THE ISSUES THAT CAME UP AS WELL WAS SORT OF AN INTERESTING QUESTION OF WHETHER WITH ALL THE DIFFERENT SCREENINGS AND DOMAINS, SHOULD WE JUST TAKE CERTAIN ITEMS FROM CERTAIN SCREENING TOOLS AND VALIDATE IT AS A SO-CALLED PKU SCREEN? DOES THERE NEED TO BE A SEPARATE SET OF QUESTIONS AND THIS IS SOMETHING OUR GROUP WILL HAVE TO DEAL WITH. EXECUTIVE FUNCTION ALSO CAME UP AS WELL. IS THERE A REAL CONNECTION WITH PKU AND WHAT IS THE FUNCTIONAL SIGNIFICANCE OF IT AND WHAT SHOULD WE BE DOING ABOUT IT? ARE THE NEUROCOGNITIVE OUTCOMES REVERSIBLE? DO WE NEED TO LOOK MORE CLOSELY TO SEE WHETHER IT NEEDS TO BE TREATED? CLASSIFICATIONS, ARE THEY STILL MEANINGFUL? AND DOES VULNERABILITY DECREASE WITH AGE? WE'VE HEARD THIS OVER THE LAST TWO DAYS. TO SUMMARIZE, THERE ARE A FEW KEY ISSUES. ONE IS WHETHER PERHAPS THERE SHOULD BE FACT TWO GRIDS. ONE MIGHT BE WHAT'S THE BARE MINIMUM FRUGAL SCREENING TOOLS THAT HOPEFULLY EVERYBODY CAN IMPLEMENT BECAUSE THEY'RE EASY, PAST, CHEAP AND GIVE US GOOD INFORMATION, AND WHAT MIGHT BE THE NEXT LEVEL UP? IT MIGHT BE ANOTHER LEVEL THAT SOME FOLKS COULD DO? AND THEN PROCESS QUESTIONS, TOO. WHO SHOULD BE DECIDING THAT? ARE THE FOLKS PUTTING TOGETHER THE RESEARCH COLLABORATEIVES INVOLVED IN DECIDING WHAT MEASURES ULTIMATELY GET CHOECH? WE'VE HEARD THAT SAID MANY TIMES THAT THE PERFECT IS THE ENEMY. GOOD AND WE KNOW THAT THERE ARE MANY CHOICES FOR THESE MEASURES IF WE CAN ALL AGREE ON ONE SET OF THEM AND LITTLE BY LITTLE WE CAN START TO ANSWER SOME OF OUR RESEARCH QUESTIONS. ONE OF THE THINGS THAT MAY SAVE US IS TEMG. THERE ARE PRODUCTS OUT THERE. ONE OF THEM IS CALLED CHATUS IN WHICH FAMILIES HAVE DIRECT ACCESS TO THESE SCREENING MEASURES AND SO YOU CAN EMAIL THE FAMILY AHEAD OF TIME OR TEXT THEM AND SAY GO TO THIS SECURE WEBSITE AND YOU CAN HAVE ANY NUMBER OF TOOLS FOR THE FAMILY TO ANSWER AND GATHER CLINICAL DATA THAT GOES INTO YOUR ELECTRONIC DATABASE SO BY THE TIME THEY CALM IT'S -- COME TO THE VISIT, YOU ALREADY HAVE THE INFORMATION AND CHARTING IS ALREADY DONE AND TIE INTO THE TRANSLATIONAL RESEARCH NETWORK DATABASE. YOU'VE DONE THAT, TOO. SO DATA ENTRY BY FAMILIES EVEN BEFORE THEY COME TO THE VISIT MIGHT RELIEVE A LOT OF THE PRESSURE THAT CLINICS FEEL AND GIVE US MUCH MORE POWERFUL INFORMATION. AND THE LAST TWO BIGGS BIG THINGS IS WHETHER WE SHOULD BE ADDING A HEALTH-RELATED QUALITY LIFE MEASURE. AND FAMILY MEASURES AS WELL? THERE ARE SO MANY RESEARCH ACROSS THE BOARD, NOT JUST IN PKU BUT CHARACTERISTICS OF FAMILIES THAT DETERMINE A LOT OF THE OUTCOMES. AND ALL THE SCREENING TOOLS ARE CHILD-FOCUSED. SO ONE OF THE BIG ISSUES IS WE NEED TO THINK ABOUT AT LEAST ONE FAMILY MEASURE. THAT'S SOME OF THE STUFF THAT CAME UP IF OUR WORK GROUP AND THANK YOU VERY MUCH. [APPLAUSE] >> GREAT IDEAS THAT CAME OUT OF THE BREAKOUT SESSION, SO THANK YOU ALL FOR YOUR HARD WORK. I'D LIKE TO INTRODUCE OUR LAST FORMAL SPEAKER OF THE TAI ANN, THE ACTING ASSOCIATE DIRECTOR FOR RARE DISEASES IN THE OFFICE OF NEW DRUGS AT THE F.D.A. AND SHE'S GOING TO TALK TO US ABOUT THE CASE FOR CLINICAL STUDIES, A PERSPECTIVE FROM THE FOOD AND DRUG ADMINISTRATION. SO ANN, GO AHEAD. >> THANK YOU, MELISSA. AND THANK YOU TO THE ORGANIZERS FOR CONVENING THIS MEETING. IT HAS REALLY BEEN A PLEASURE TO GET REAQAPTED WITH ALL THE WORK THAT HAS BEEN DONE. IT'S BEEN SO TRANSFORMATIVE AND IT'S REALLY A PLEASURE TO BEERE. I AM GOING TO GIVE THE F.D.A. PERSPECTIVE. BUT LISTENING OVER THESE PAST TWO DAYS TO THE PRESENTATIONS AND THE COMMENTS, I DON'T THINK THEY ARE WIDELY DIFFERENT FROM WHAT YOU HAVE BEEN HEARING. JUST TO START, I'D LIKE TO RETURN TO THE ARC REPORT OR THE EPC -- I'LL BE REFERRING TO IT AS THE ARC REPORT AND THE IMPRESSIONS FROM READING AND HEARING ABOUT THIS REPORT. AND I THINK MY OVERRIDING IMPRESSIONS FROM THIS AND IT'S CONSISTENT WITH WHAT I'VE BEEN HEARING IS THAT DESPITE 50 YEARS OF THE ABILITY TO IDENTIFY PATIENTS AND TO INTERVENE WITH AN HE HAVE CAESIUS TREATMENT THAT THE QUANTITY AND AVAILABILITY OF GOOD QUALITY DATA FROM ADEQUATE AND WELL-CONTROLLED STUDIES IS SOMEWHAT LACKING. ALTHOUGH THERE IS CONVINCING EVIDENCE FOR THE IMPROVED NEWER LOGIC OUTCOMES, ESPECIALLY IN CERTAIN GROUPS, THE EVIDENCE FOR OTHER WELL-DEFINED CLINICAL OUTCOMES, ESPECIALLY IN SOME POPULATIONS NEARLY IS NOT AS COMPELLING OR AS WELL DEFINED AND THAT THERE REMAINS SIGNIFICANT GAPS IF OUR UNDERSTANDING OF THE DISEASE, THE POPULATIONS, THE RESULTS AND THE INTERVENTIONS. AND REALLY TAKEN ALL TOGETHER, I DO BELIEVE IT PROVIDES EVIDENCE AS A CALL FOR MORE RESEARCH. CAN YOU HEAR ME OKAY? OKAY. SO THE PURPOSE OF RESEARCH IS TO FIND TRUTH. BUT I SUPPOSE MORE REALISTICICALLY IS POSING QUESTIONS AND TRYING TO CONDUCT WELL-DESIGNED STUDIES AROUND THAT TO TRY TO ANSWER THOSE QUESTIONS BY GENERATING GOOD EVIDENCE. AND FOR INTERVENTIONAL TRIALS, THE GOLD STANDARD IS TYPICALLY THE RANDOMIZED CONTROL TRIAL, ALTHOUGH BY NO MEANS IS IT LIMITED TO THAT AND THERE IS CONSIDERABLE FLEXIBILITY AROUND THIS. BUT WHY IS THIS GOOD EVIDENCE SO IMPORTANT IS BECAUSE THESE RESULTS WILL BE USED TO INFORM PUBLIC HEALTH DECISIONS. CERTAINLY THERE ARE APPROVAL AND NON-APPROVAL DECISIONS FROM REGULATORY AGENCIES. BUT IT REALLY IS MUCH MORE THAN THAT. WHO SHOULD BE TREATED WITH WHAT AT WHAT DOSE FOR HOW LONG AND WHAT ARE THE RISK BENEFITS? HOPEFULLY, THE END RESULT IS WE'RE DOING MORE GOOD THAN HARM. BUT THERE ARE A LOT OF OTHER COSTS AND SUBSTANTIAL IMPACTS. WITH WE MAKE THESE PUBLIC HEALTH DECISIONS, IT DOES IMPACT INDIVIDUALS. BUT I THINK AS WE HEARD SO ELOQUENTLY FROM PARENTS THIS MORNING, IT IMPACTS THE WHOLE FAMILY AND THE COMMUNITY AS WELL. SO WE REALLY DO NEED THAT GOOD INFORMATION. BUT ALSO, A VERY IMPORTANT FUNCTION OF THIS IS TO IDENTIFY THE GAPS AND WHERE IS A NEED FOR ADDITIONAL STUDY AND ADDITIONAL INTERVENTION AND WE'VE HEARD A LOT ABOUT THAT THESE PAST COUPLE OF DAYS. I'D LIKE TO RETURN TO THE SAPARTARIAN EXPERIENCE BECAUSE I THINK IT HAD A NUMBER OF POINTS IN THERE THAT I THINK ARE RELEVANT AS WE TRY TO MOVE FORWARD. AND THEN ALSO AS DR. WHITLEY SAID JUST A SHORT WHILE AGO FROM THE REPORT OF THE PHARMACOLOGIC INTERVENTION GROUP, CAN WE DRAW FROM OTHER RARE DISEASES THAT ARE INFORMATIVE TO PKU AND I THINK THE ANSWER IS YES AND I'D LIKE TO PRESENT A COUPLE OF THINGS THERE. THE ORPHAN DRUG ACT WAS ENACTED IN THE U.S. IN 1983. PRIOR TO THAT THERE WAS VERY LIMITED EXPERIENCE, REALLY A COUPLE OF DOZEN DRUGS, IF THAT, AT THE TIME AND SINCE THAT TIME WE NOW HAVE ALMOST 400 APPROVED DRUGS IN THE U.S. THIS IS FOR ABOUT 250 UNIQUE DISEASES, AND THERE IS A CONSIDERABLE EXPERIENCE THERE TO LEARN FROM. WITH ANY RARE DISEASE, WE HAVE TO USE EVERY OPPORTUNITY WE HAVE TO LEARN. SO WE'LL JUST LOOK AT THE OLD ORPHANS AND NEWER ORPHANS AND COMPARE AND CONTRAST AND THEN TO TAKE A LOOK AT WHERE DO WE NEED TO GO FROM HERE. SO I THINK THIS WAS EXPLAINED IN DETAIL IN THE PHARMACOLOGIC INTEVENGS GROUP AND I BRING IT UP AGAIN BECAUSE OF HOW IMPORTANT IT WAS TO THE SAPARTARIAN PROGRAM. THERE WAS A CLEAR UNDERSTANDING OF TERO HYDRO BIOOPZRIN WHAT THE EXPECTED INTERVENTION WAS AND THAT TURNED OUT TO BE A VERY IMPORTANT FACTOR IN HOW THE CLINICAL TRIALS WERE DESIGNED. WHAT DID WE KNOW WHEN WE STARTED. IT WAS APPROVED IN 2007 AND CLINICAL DEVELOPMENT STARTED SEVERAL YEARS BEFORE THAT AND FROM THE BEGINNING, JUST KNOWING THE DRUG AND HOW IT IS EXPECTED TO IMPACT, WE KNEW NOT EVERYONE WAS GOING TO RESPOND. IT'S A -- ONLY SOME OF THE OTHER MUTATIONS. SO THAT WAS AN IMPORTANT FACTOR IN CONSIDERING THE DESIGN. THERE IS ALSO -- THIS IS VERY UNUSUAL FOR RARE DISEASES. MOTE OF THE TIME WE DON'T HAVE A -- MOST OF THE TIME WE DON'T HAVE A LOT OF INFORMATION. BUT THERE WAS CONSENSUS ON A SHORT TERM BIOMARKER THAT ESSENTIALLY A SURROGATE THAT WE CAN RELY UPON AND GOOD EVIDENCE THERE FROM LONG TERM PROSPECTIVE NATURAL HISTORY STUDIES. AND WE ALSO KNEW THAT THE LONG TERM NEUROCOGNITIVE EFFECT WOULD TAKE YEARS, MAYBE EVEN A DECADE TO REALLY SEE IMPACT. AND I DO RECALL THAT THE REPORT ALSO SAYS THERE IS NO STANDARD OR CONSISTENCY AMONG THE U.S. CENTERS. THE PREVALENCE IS WELL-DESCRIBED AND THIS IS ALSO UNUSUAL FOR RARE DISEASES. WE OFTEN DON'T HAVE A VERY GOOD IDEA OF THE PREVALENCE. BUT WITH NEWBORN SCREENING, PRETTY MUCH EVERY PATIENT WAS IDENTIFIED, AND HIGHLY EXPERIENCED TREATMENT CENTERS. AND THESE WERE ALL CONSIDERABLE ADVANTAGES TO PUTTING A PROGRAM TOGETHER. OF COURSE, WE'VE HEARD A LOT ABOUT EXISTING DIETARY RIGORS AND THE REALITY OF DIET AND TREATMENT. AND THE MAGNITUDE OF THE NON-ADHERENCE IN THE OLDER PATIENTS. AND OF COURSE, SPECIAL CONSIDERATIONS FOR SOME OF THE SUBPOPULATIONS. AND THEN THERE WERE OTHER FACTORS AND UNCERTAINTIES THAT WEREN'T WELL-DESCRIBED AT THE TIME GENEO-TYPE, PHENOTYPE, LARGE AMINO ACIDS AND SOME OTHER CONSIDERATIONS. ALL OF THIS WAS CONSIDERED VERY CAREFULLY AT THE TIME. THERE WAS CATIONAL BACK BACK-AND-FORTH AND ENGAGEMENT ON THIS PROGRAM, AND I THINK AS YOU ALL KNOW, THERE WERE FOUR STUDIES THAT SUPPORTED THE APPROVAL OF SAPARTARIAN AND THIS HAS BEEN GONE OVER. BUT JUST TO GO OVER SOME OF THE FEATURES JUST TO HIGHLIGHT A FEW POINTS. THE FIRST STUDYS WITH AN OPEN LABEL SINGLE ARM TRIAL. EVERYBODY GOT TREATED FOR EIGHT DAYS AND THE WHOLE POINT OF THIS WAS TO IDENTIFY RESPONDERS. AND THEN THE RESPONDERS WHO WERE IN AGE GREATER THAN EIGHT AGE. THE MEAN AGE WAS ABOUT 22) AND MOSTLY OLDER AT LESSENTS AND YOUNG ADULTS. DECREASE IN PHENOLNINE OF 30%. AND RESPONDENTS OF THIS TRIAL WERE INCLUDED IN THE TRIAL THAT WAS FOR SIX WEEKS. AND THERE WERE 89 RESPONDERS AND 88 OF THEM PARTICIPATED IN STUDY NUMBER TWO. I THINK THE IMPORTANT CONSIDERATION HERE IS THERE HAD NOT BEEN THE REALLY THE ENRICHMENT TRIAL IN STUDY ONE THAT INFORMED STUDY TWO, STUDY TWO WOULD HAVE HAD TO HAVE BEEN A WHOLE LOT BIGGER BECAUSE THERE WOULD HAVE BEEN A LOT OF PEOPLE WHO WOULDN'T HAVE RESPONDED. AND THIS MADE SENSE OF WHAT WE KNEW ABOUT THE DRUG AND HOW IT WOULD IMPACT. AND STUDY THREE WAS AN EXTENSION BUT IT WAS TO TRY TO GET MORE INFORMATION ON A DOSE-RESPONSE HE CAN'T. AND THEN STUDY -- EFFECT. AND STUDY FOUR WAS IN CHILDREN. THESE WERE WELL-CONTROLLED ON DIET AND CERTAINLY ETHICAL ISSUES HERE, WHY YOU WOULDN'T WANT TO TAKE CHILDREN OFF THEIR DIET AND IT STARTED AT A HIGHER DOSE BUT ESSENTIALLY A VERY SIMILAR DESIGN. THIS WAS THE OPEN RUN-IN PHASE AND THE RESPONDERS WERE ENTERED INTO THE RANDOMIZED CONTROLLED TRIAL. THE RESULTS MAY BE A LITTLE HARD TO SEE BUT THE RESPONDERS ABOUT 20% OF THE PEOPLE WHO ENTERED AND THE MEAN DECREASE IN PHE WAS ABOUT 10 PERCENT BUT THE ZERO LINE IS RIGHT HERE, SO ESSENTIALLY THE NORMAL CURVE SHIFTED TO THE LEFT AND IT WAS APPROXIMATELY THESE PATIENTS HERE THAT MET THAT 30 PERCENT RESPONDER MARK WHO WERE THEN OFFERED ENROLLMENT IN PART TWO. AND HERE IS PART TWO OF THE STUDY THAT WAS PLACEBO PLACEBO-CONTROLLED AND DOUBLE BLIND AND IT WAS RELATIVELY A SMALL NUMBER OF PATIENTS -- 88 -- BUT THE RESPONSE WAS QUITE LARGE. IT WAS A MEAN CHANGE OF ABOUT 240 IN THE SAPARTARIAN SAPARTARIAN-TREATED GROUP. OR ABOUT A 30% DECREASE AND HIGHLY STATISTICICALLY SIGNIFICANT AND THIS MAGNITUDE OF RESPONSE WAS FELT TO BE CLINGICALLY MEANINGFUL FROM WHAT WAS KNOWN ABOUT THE DISEASE. AND STUDY THREE, IN ADDITION TO THE LONG TERM MAINTENANCE -- SINCE THIS IS A CHRONIC DISEASE, TO DEMONSTRATE MAINTENANCE OF EFFECT. THERE WAS THE DOSE TITRATION, WHICH DID DEMONSTRATE DOSE RESPONSE GOING FROM FIVE TO TEN TO 20. AND THEN IN CHILDREN, VERY SIMILAR RESULTS. HIGHER DOSE OF SAPARTARIAN, ABOUT A 56 PERCENT RESPONSE RATE. OVERALL TOTAL EXPOSURE WAS ABOUT 379 PATIENTS BUT MOST OF THESE WERE TREATED FOR ONE WEEK, RELATIVELY A SMALL NUMBER OF PATIENTS AND EVEN SMALLER TREATED LONGER THAN THAT. AND THE AGE RANGE WAS FOUR TO 49. SO WHAT WERE THE FINDINGS AND FEATURES WILL ABOUT THIS PLAN? WAS IT A PERFECT PLAN? NO, IT WASN'T. BUT DID IT ANSWER A BUNCH OF VERY IMPORTANT QUESTIONS? AND I THINK THAT IT DID. THE CLINICAL PLAN WAS LARGELY INTENDED TO DEMONSTRATE THE PHARMACODYNAMIC EFFECT OF THE DRUG ON THE PHE LEVELS. THAT WAS KNOWN UPFRONT AND THAT WAS PLANNED FOR UPFRONT. AND THE SHORT TERM EFFICACY WAS BASED ON A SUPPORTED SURROGATE BASED ON CONSIDERABLE EVIDENCE THAT CAME FROM YEARS BEFORE. AND IT WAS ALWAYS INTENDED AS WELL TO BE CONSIDERED A PHARMACOLOGIC AJUNT TO DIETARY THERAPY. AND WHAT ENDED UP IN THE LABELING AND IN THE INDICATION WAS THAT IT WOULD NOT ELIMINATE THE NEED FOR DIETARY MANAGEMENT. AND THAT IS A POINT THAT HAS I THINK, COME UP OVER AND OVER AGAIN. AND ALSO, AT THE TIME IS THERE REALLY WASN'T ANY CLEAR WAY OF RECOGNIZING WHO WAS GOING TO RESPOND OTHER THAN TO GIB PEOPLE A TRY. AND THAT'S HOW THE LABELING CAME TO BE. SO WHAT WERE THE LIMITATIONS FROM THIS? AND I THINK WE WERE ALL VERY AWARE OF WHAT THEY WERE. THERE IS NO ASSESSLET OF THE LONG TERM NEUROCOGNITIVE CLINICAL OUTCOMES AND THEY WEPT OUT TO ABOUT 26 WEEKS. IT WAS NEVER EXPECTED THAT WE WERE GOING TO BE ABLE TO MAKE A MEANINGFUL ASSESSMENT THERE. GENEO-TYPE CORRELATIONS ARE MAYBE MORE IMPORTANTLY. THERE WERE NO AT THE TIME -- AN EFFORT WAS MADE BUT THERE WAS NO OBVIOUS CORRELATION WITH GENEO-TYPE ABOUT WHO WAS GOING TO RESPOND. DIETARY MANAGEMENT AND THIS IS WHAT WE HEARD FROM THE COMMUNITY. THERE WAS QUITE A BIT OF CONCERN THAT THIS WOULD BE SEEN AS A SUBSTITUTE FOR DIETARY MANAGEMENT AND WE TOOK THAT VERY SERIOUSLY. AND THERE WAS NO EXPOSURE IN THE YOUNGEST CHILDREN AND RELATIVELY SHORT TERM ADMINISTRATION FOR A DRUG. A PLAN WAS THEN PUT IN PLACE AT THE TIME HOW WERE WE GOING TO ADDRESS THESE? SO THIS WAS ALL NEGOTIATED WITH THE DRUG DEVELOPER AT THE TIME OF THE APPROVAL. AND MANY OF THESE THINGS WERE ACTUALLY ONGOING AT THE TIME OF APPROVEAL OR STARTED SHORTLY THEREAFTER. THAT INCLUDED A PLAN TO STUDY THE YOUNGER CHILDREN, LONG TERM STUDY IN CHILDREN WHO WERE LESS THAN EIGHT AT THE TIME THEY STARTED, PARTICULARLY FOR NEUROCOGNITIVE AND GROWTH OUTCOMES, LONG TERM SAFETY, AND THEN THE ESTABLISHMENT OF THE REGISTRY, WHICH IS NOW UP AND RUNNING AND HAS BEEN NOW HAVE ABOUT 1,000 PATIENTS REGISTER ASKED THIS INCLUDES THE MATERNAL SUBSTUDY. I THINK THESE THINGS ARE WELL-KNOWN. BUT WHAT MAY NOT BE KNOWN IS THERE IS ALSO A PHE GENE SPECIMEN REQUIREMENTS AS WELL AND THIS IS SOMETHING THAT'S USUALLY DONE PREMARKETV BUT GIVEN THE UNMET MEDICAL NEEDS, THIS WAS DEFERRED TILL POST MARKETING. AND JUST TO SAY ANOTHER WORD OR TWO ABOUT THE REGISTRY, THIS IS A VOLUNTARY REGISTRY, AS MOST REGISTRIES ARE. OBSERVATIONAL AND NOT INTERVENTIONAL AND THIS PARTICULAR REGISTRY IS LIMITED TO PATIENTS WHO EITHER HAVE RECEIVED SAPARTARIAN OR ARE RECEIVING SAPARTARIAN SO IT'S NOT EVERYBODY. AND ONLY 20 TO 50 PERCENT OF PESHTS RESPOND. SINCE IT IS VOLUNTARY, YOU TRY TO INCORPORATE THIS INTO PRACTICES AS MUCH AS POSSIBLE, TRY TO CLAW DRAW ON -- DRAW ON THINGS SO THAT WE DO GET GOOD PARTICIPATION AND GOOD DATA COLLECTIONS. SO THEY HAVE TO BE VERY CAREFUL ABOUT WHAT YOU FEEL ARE MOST IMPORTANT TO INCLUDE. SO I THINK, JUST LIKE TO SIDE STEP A LITTLE BIT THEN TO THE EARLY ORPHANS. AS WE MENTIONED, THERE IS QUITE A BIT OF ORPHAN DRUG EXPERIENCE NOW, AND I THINK AS WE HAVE GAINED EXPERIENCE, WE HAVE REALLY MADE A VERY CONCERTED EFFORT TO REALLY LEARN FROM OUR EXPERIENCE. F.D.A. SINCE 1983 AND WHEN THE ORPHAN DRUG AGO WAS PASSED. BUT THE F.D.A. CENTER FOR DRUGS HAS START AID RARE DISEASE PROGRAM. THE WHOLE PURPOSE IS TO TRY TO SUPPORT ALL ORPHAN DRUG OR RARE DISEASE DRUG DEVELOPMENT. SO WHAT WE ARE DOING IS WE ARE ANALYZING VERY CLOSELY OUR PREVIOUS EXPERIENCE AND TRYING TO FIGURE OUT HOW WE CAN FEED THIS INTO CLINICAL TRIALS AS WE MOVE FORWARD. AND I THINK THERE IS A FEW THINGS HERE I THINK THAT MAY BE RELEVANT TO PKU, AS WE TRY TO FAST FORWARD. THE EARLY ORPHANS IN 198LE3, WHEN YOU TALK TO THE PEOPLE THAT WERE INVOLVED IN NEGOTIATING THE ORPHAN DRUG ACT AND WHAT IT CONTAINED, A PREVAILING THOUGHT AT THE TIME WAS THAT GIVEN THE SMALL POPULATIONS AND THE RAREITY, IT WASN'T GOING TO BE POSSIBLE TO DO RANDOMIZED CONTROLLED STUDIES AND WERE PROBABLY GOING TO RELY ON OPEN SINGLE LABELING TRIALS AND MANY THEM WERE CONTROLLED FROM LITERATURE. IT'S WHAT WE REFERRED TO OFTEN AS THE WHAT EVERYBODY KNOWS THEORY. AND SINCE THEN WHAT WE FOUND OUT IS THAT CAN BE INACCURATE AND IT CAN SEND US DOWN THE WRONG PATH. WHAT TENDS TO GET PUBLISHED IS OFTEN THE OUTLIERS AND IT DOESN'T REPRESENT THE WHOLE SPECTRUM OF DISEASES, ESPECIALLY PHENOTYPEIC VARIABILITY IS EXPECTED. THERE WAS ALSO A TENDENCY TO APPROVE AND MOVE ON AND JUST THE NEED AT THE TIME WAS SO GREAT THAT ONCE YOU HAD A THERAPY, THE TENDENCY WAS TO HAVE IT IN PLACE AND MOVE ON. AND THAT LEFT A LOT OF GAPS, AND MANY YEARS LATER SOMETIMES HAVE A WAY OF COMING BACK TO HAUNT YOU. FOR EXAMPLE, THERE ARE SOME EARLY BIOLOGIC PRODUCTS THAT APPROVED. SNF THEM COULD BE HUMAN OR ORIGIN AND WITH THE ADVENT OF COMMON THERAPIES OR TECHNOLOGIES, PERHAPS MANUFACTURING CONSIDERATIONS MIGHT CHANGE. BUT IF THERE IS NO GOOD INFORMATION TO COMPARE IT TO, THAT REALLY KIND OF LEAVES YOU IN A WINED AND THAT CAN BE A MAJOR PROBLEM. SO AS WE'VE LOOKED BACK AT THESE, I THINK THE PREVAILING THOUGHT IS REALLY -- HAS REALLY SHIFTED QUITE A BIT. AS WE CAN -- OUR FEELING REALLY IS WE CAN BETTER SERVE PATIENTS THROUGH SCIENTIFIC RIGOR. THE EVIDENCE DEVELOPED FROM THESE STUDIES DOES CARRY A LOT OF WEIGHT IN DECISION MAKING FOR OUR PATIENTS AND WE REALLY FEEL WE OWE IT TO THE PATIENTS TO GET THE BEST INFORMATION POSSIBLE. BUT THERE IS A LOT OF FLEXIBILITY AND SCIENTIFIC JUDGMENT IN HOW THAT IS ACHIEVED. THESE ARE VERY DIVERSE DISEASES. NO ONE SIZE FITS ALL. AND EVEN WITHIN A DISEASE, IT WILL DEPEND ON WHAT IS A DRUG AND HOW DO YOU EXPECT IT TO INTERVENE IN THE DISEASE? AND I THINK THE SAPARTARIAN EXAMPLE THERE GIVES SOME OF THOSE CONSIDERATIONS. NATIONAL ORGANIZATION FOR RARE DISORDERS ALSO PUBLISHED A PAPER LAST YEAR WHERE THEY WEPT BACK AND LOOKED AT ALL THE NON-APPROVALS SINCE 1983. AND THEY DOCUMENTED CONSIDERABLE FLEXIBILITY OF TWO THIRDS OF THE PROGRAM WERE DESCRIBED AS NON-TRADITIONAL, MEANING DIDN'T USE THE USUAL TWO RANDOMIZED CONTROL TRIALS. USED A HUGE VARIETY OF STUDY DESIGNS, AND THIS IS WHERE THIS ENGAGEMENT AND NEGOTIATION STRATEGY REALLY COMES IN. AND WE ALWAYS SAY PLEASE COME IN EARLY AND OFTEN AND TALK TO US AND WE WILL WORK WITH YOU TO TRY TO FIND A PATH FORWARD. SO ANOTHER THING WE ALWAYS TELL PEOPLE IS TO DESCRIBE THE NATURAL - AS EARLY AS POSSIBLE AND THAT WAS VERY IMPORTANT IN THE PKU EXPERIENCE. CLEARLY IT'S BEEN IN OTHER PROGRAMS AS WELL. ONCE YOU DO THAT, KEEP GOING, ESPECIALLY IF THERE IS AN INTERVENTION. THE DISEASE COURSE WILL CHANGE, AND OFTEN YOU'RE IN UNCHARTERED WATERS. I WAS TALKING TO A COUPLE OF PEOPLE YESTERDAY AND THEY WERE DESCRIBING HOW PATIENTS IN THEIR 40S NOW ARE COMING BACK INTO CLINIC AND MAYBE HADN'T BEEN SEEN IN A WHILE AND THEY ARE BRINGING UP SYMPTOMS AND THIS IS REALLY -- THESE ARE THINGS THAT REALLY MAYBE HAVEN'T BEEN DESCRIBED. PATIENTS WITH EARLY INTERVENTIONS ARE NOW GOING BACK, WHICH WE MAY NOT HAVE SEEN IN THE COURSE OF THE DISEASE. IT'S IMPORTANT TO CAPTURE THAT AND FIND WAYS TO INCORPORATE THIS LEARNING AS WE MOVE FORWARD. IN ADDITION TO THE PRIMARY DEFECT, WITH SO MANY OF THESE GENETIC DISEASES, IT'S ALSO SECONDARY FACTORS CASCADE AND VERY IMPORTANT AND WE'RE GOING TO NEED COMBINATION THERAPIES AS WELL. MAY NOT BE JUST THE ONE INTERVENTION. AND WE ALSO HAVE A LOT MORE TOOLS THAN WE USED TO. BIOMARKERS HAS COME UP SEVERAL TIMES. THINGS LIKE COMPUTEATIONAL MODELING AND ANIMALS. JUST TO GIB ONE EXAMPLE, OUR GROUP ALPHA WAS APPROVED IN 2006 FOR POM PAY DISEASE, WHICH IS A RARE PROGRESSIVE, MUSS COLLAR DISORDER, AND IT WAS APPROVED BASED ON A SINGLE STUDY IN 18 PATIENTS AND THIS WAS HISTORICALLY CONTROLLED. BUT THIS WAS FORMALLY DONE. IT WAS A RETROSPECTIVE DRUG REVIEW AND COLLECTED THE EXPERIENCE IN PATIENTS AND IT WAS SOMETHING WE FELT WE WOULD HAVE A GOOD CONFIDENCE ON. THERE WERE COMMITMENTS WITH THIS AS WELL AND THERE WAS A REGISTRY FORMED AND THE REGISTRY NOW HAS OVER 1,000 PATIENTS AND THIS IS REMARKABLE FOR A VERY RARE DISEASE. AND TO GET AN EXPERIENCE LIKE THAT IS JUST NEVER REMEMBER BEEN SEEN BEFORE. BARRY BURN AND KIRSCH NANI SUMMARIZED THEIR FIRST FIVE YEARS OF EXPERIENCE IN 2011 AND ESSENTIALLY WHAT THIS DID IS REDEFINED THE PHENOTYPES FOR THE DISEASE AND WHY THAT WAS SO IMPORTANT, IT TURNED OUT TO BE INFORMATIVE FOR PATIENT CARE AND FOR MAKING TREATMENT DECISIONS. THESE THINGS CAN HAVE AN ENORMOUS IMPACT AND BE A VERY IMPORTANT LEARNING TOOL AND HELP US A LOT, BE NOT JUST IN PATIENT CARE BUT ALSO IN FINDING THE GAPS FOR RESEARCH AND FORMING OTHER RESEARCH PROGRAMS AS THEY COME UP. SINCE THIS WAS AN ENZYME, THE RESULTS WERE CONSIDERABLE IMMUNOJENITY AND THIS IS SOMETHING ELSE THAT WAS POST MARKETING COMMITMENT AND THEY MADE A LOT OF PROGRESS HERE AND ACTUALLY HAVE SOME INTOLERANCE REGIMENTS THAT ARE STARTING TO BE USED AND HAD A VERY BIG IMPACT FOR SOME OF THE PATIENTS, ESPECIALLY THE MORE SEVERE PHENOTYPES. AND PSYCHODISORDERS, OM A FEW EXAMPLES. I THINK THESE REGISTRIES HAVE BEEN ENORMOUSLY USEFUL IN MANY CASES. AND SOME OF THESE ARE RUN BY THE DRUG DEVELOPERS AS CONDITION AF PROFLES BUT SOME OF THEM ARE ALSO RUN BY ACADEMIC CENTERS AND BY ADVOCACY GROUPS. AND IT DOESN'T SEEM TO MATTER, AS LONG AS THEY ARE WELL-CONSTRUCTED AND THEY CONTINUOUSLY TWEET. RETURNING TO THE ARC REPORT, CLEARLY A THOROUGH COMPREHENSIVE AND HAD A LOT OF THOUGHT AND WORK THAT WEPT INTO IT AND CONGRATULATE ALL THE AUTHORS ON ALL THE WORK THEY DID FOR THIS AND I THINK THE QUESTIONS THAT WERE ASKED WERE VERY INFORMATIVE. THIS IS THE ONE THING THAT STRUCK ME. THIS IS THE TABLE FROM THE EXECUTIVE SUMMARY BUT APPEARED AGAIN IN THE BODY OF THE REPORT AND THIS WAS SHOWING THAT THE SEARCH AND A NUMBER OF ARTICLES AND THEN WHERE WE ENDED UP WITH AT THE END AND IT TURNED OUT TO BE ABOUT 66 ARTICLES HERE THAT FORMED AND MOST OF THE INFORMATION AND FOR SOME OF THESE KEY QUESTIONS THEY'RE AT ZERO, WHICH I THINK WAS IMPRESSIVE. AND THE NUMBER OF GOOD STUDIES ATTRIBUTED BY THE AUTHORS WERE ALSO A SMALL NUMBER OF THOSE. SO I THINK THE CONCLUSIONS THAT CERTAINLY THAT I DREW FROM THIS WAS THAT, WHILE IT CERTAINLY SUPPORTS THE GOALS STWRRK AS WE'VE HEARD MANY TIMES, THE INFORMATION FROM THIS IS IDENTIFIED BY MANY OF THE GAPS WHERE THE DATA ARE REALLY LACKING AND PERHAPS A CALL TO ACTION OF HOW TO MOVE FORWARD AND STRONGLY SUPPORTED NEED FOR ADDITIONAL RESEARCH. THE HIGH-PRIORITY RESEARCH AREAS AND I THINK WE'VE HEARD OVER AND OVER AGAIN CONSIST-EY OF TOOLS, DATA COLLECTION ACROSS THE ENTIRE POPULATION, A COMPREHENSIVE PUBLIC HEALTH PLAN, AND PERHAPS MOST IMPORTANTLY, THAT ALL-IMPORTANT DATA THAT IS GOING TO ALLOW PATIENTS AND CAREGIVERS TO MAKE INFORMED CHOICES. AND SO WHERE ARE WE NOW? AND THIS WAS REALLY JUST TIME PLY WE ARE I THINK MORE IN THE MIDDLE. WE HAVE A LOT OF INFORMATION, BUT CERTAINLY THERE ARE A LOT OF GAPS. SO WHERE DO WE GO FROM HERE? AND I'VE BEEN WORKING ON RARE DISEASES FOR A LONG TIME, AS I KNOW MANY OF YOU HAVE -- AND I AM DATING MYSELF HERE. BUT PROBABLY REVIEWED THOUSANDS OF APPLICATIONS, CLINICAL DEVELOPMENT PROGRAMS EARLY THROUGH LATE PHASES SO MY THOUGHTS ON HERE. THESE ARE NOT F.D.A. POLICY, BUT JUST SOME THOUGHTS. I THINK THE SINGLE BIGGEST PROBLEM IS ALWAYS DECIDING ON END POINTS. WHAT ARE WE GOING STOUSE FOR THE END POINTS IN THIS SITUATION WITH THIS DRUG FOR THIS INTERVENTION? IS IT RELIABLE? IS IT EITHER GOING TO PREDICT A CLINICAL OUTCOME THAT WE WANT TO KNOW ABOUT OR IS IT THE OUTCOME ITSELF THE CLINICAL OUTCOMES AND REALLY THE IMPORTANT ISSUE FOR PATIENTS? AND IN THIS SITUATION, I THINK WHAT'S REALLY NEEDED HERE ARE THE INTERMED OUTCOMES. WE HAVE THE SHORT TERM PHENOLNINE LEVELS AND WE HAVE THE LONG TERM IQ TESTING AND THERE HAS BEEN DISCUSSION ON THIS. BUT I THINK WHERE THE CRITICAL NEED HERE IS THE INTERMED OUTCOMES THAT TAKE EITHER MONTHS OR A YEAR OR TWO TO GET TO AND CAN BE MEANINGFUL TO PATIENTS AND PERHAPS THE GREATEST LACK IS IN THE OLDER PATIENTS, OLDER, MEANING ADD LESSENT, YOUNG ADULTS. THE PREDICTIVE PROGRESS NOSTICS AND RESPONSE CHARACTERISTICS SUCH AS GENE GENEO-TYPE BEING THE PREDICTED VALUE, I THINK IT'S IMPORTANT RIGHT NOW PARTICULARLY WITH SAPARTARIAN BUT FROM WHAT WE'VE HEARD DR. HARDING YESTERDAY, IT IS GOING TO BE MORE IMPORTANT IN THE FUTURE AS WELL. WHO SHOULD BE TREATED? THERE ARE CERTAIN GENEOTYPES MORE LIKELY TO SPEND OR WILL THERAPIES NEED TO BE TAILORED DEPENDING ON THESE THINGS AND I THINK THAT'S GOING TO BECOME A MUCH MORE IMPORTANT QUESTION AS WE MOVE FORWARD. AND INVESTIGATIONAL AGENTS MOVE FORWARD. ADEQUATE CONTROLLED TRIALS ARE VERY IMPORTANT. HOPEFULLY NOT TOO LONG WHERE THERE WILL BE MULTIPLE THERAPEUTIC CHOICES AND PATIENTS WILL BE ASKING US WHICH ONES SHOULD THEY USE AND WE NEED GOOD INFORMATION TO INFORM THOSE DECISIONS. WHAT WOULD BE HELPFUL AS WELL FOR THE LONG TERM ASSESSMENT ESPECIALLY IS TO TRY TO DECREASE SOME OF THE NOISE. EVEN IF THE PUT TOGETHER LARGER EXPERIENCE, IT STILL IS A RELATIVELY LARGE POPULATION AND THE NOISE HAS A WAY OF RANDOMIZING ITSELF OUT, BUT SMALLER POPULATION, THAT DOESN'T ALWAYS HAPPEN. AND THAT CAN REALLY CAUSE A LOT OF PROBLEMS IN TRYING TO INTERPRET RESULTS. SO OUR COMMON STANDARD PRACTICE POSSIBLE. I DON'T KNOW. I THINK THAT'S YOUR DECISIONS. BUT IT WOULD BE, I THINK, REAL HELPFUL FOR THESE LONG TERM ASSESSMENTS. SO I THINK I'VE GONE OVER THESE BEFORE. BUT COMPREHENSIVE PLAN I THINK IS VERY, VERY IMPORTANT. AND DRAWING FROM EXPERIENCE ON AND OTHER DISORDERS, CYSTIC FIBROSIS FOUNDATION STARTED IN 1955. VERY SHORTLY AFTER THAT THEY PUT TOGETHER A PATIENT REGISTRY AND THE PRIMARY GOAL AT THAT POINT IT WAS UNUSUAL FOR A CHILD TO SURVIVE TO SCHOOL AGE. AND WHAT THEY WERE LOOKING FOR WERE BEST PRACTICES AND CENTERS OF EXCELLENCE TO CARE FOR THE CHILDREN TO IMPROVEN THEIR -- IMPROVE THEIR SURVIVAL. THAT HAS EVOLVED OVER THE YEARS AND NOW HAVE ABOUT 60 YEARS OF EXPERIENCE IN A REGISTRY. AS A PRIORITY SHIFTED TO DATA COLLECTIONS SHIFTED AS WELL AND THEY HAVE A BODY OF EVIDENCE THAT IS REMARKABLE AND IT'S REALLY PAYING OFF. LAST MONTH THERE WAS AN APPROVAL FOR A DRUG TARGETED TO THE GENETIC DEFECT FIRST TIME EVER IN CYSTIC FIBROSIS AND IT WAS A RESULT. EARLIER WORK THAT WENT INTO THAT AND IT'S VERY IMPORTANT AND THEY HAVE A NUMBER OF THINGS IN THE PIPELINE AS WELL. SO I THINK THESE ARE VERY EXCITING TIMES. ANOTHER EXAMPLE, A LITTLE BIT DIFFERENT WOULD BE THE MUSS COLLAR DISTROPHIES. ABOUT TEN YEARS AGO THEY ACTUALLY IN THEIR WORDS THEY SAID THEY WERE NOWHERE AND SO WHAT THEY DID IS PUT TOGETHER A TEN-YEAR PLAN, A MULTI-PRONG ADD APPROACH TO GO AFTER PATIENT CARE BIOMARKERS, GENETIC TYPING, IDENTIFICATION OF POTENTIAL AGENTS. THEY WENT OUT WITH A NUMBER OF DIRECTIONS AND ONCE AGAIN, INCREASE IN KNOWLEDGE IF IN WHAT IS A RELATIVELY SHORT PERIOD OF TIME HAS BEEN RATHER REMARKABLE. I THINK THE ESTABLISHMENT OF THESE COMPREHENSIONIVE PLANS OVER THE LONG TERM ESTABLISHING PRIORITIES, COMING AT THIS WITH A NUMBER OF DID I FACTORS BECAUSE IT REALLY IS A CONTINUUM. WE NEED THE PATIENT CARE. WE NEED THE NATURAL HISTORY TO INFORM THE CLINICAL TRIAL DESIGNS AND FORM THE PRODUCTS AND THE INTERVENTIONS AND THINGS LIKE BIOMARKERS AND OUTCOME ASSESSMENTS. WE NEED THESE TO MEASURE INTERVENTION. SO IT'S VERY IMPORTANT, I THINK, TO LOOK AT THESE ALL TOGETHER F AT ALL POSSIBLE. AND ESTABLISH LONG TERM PERSPECTIVE DATA COLLECTION IS ANOTHER THING WE FOUND TO BE VERY, VERY USEFUL. THIS CAN BE A NATURAL FORMAL NATURAL HISTORY STUDY OR VOLUNTARY REGISTRY AND PROBABLY SHOULD SAY LARGER EXPERIENCE RATHER THAN LARGE EXPERIENCE BECAUSE IT'S ALL RELATIVE. BUT THE SMALLER THE POPULATION THE GREATER THE GAIN. FROM 18 TO 15 PATIENTS JUST AN EXTRAORDINARY OPPORTUNITY. 18 PATIENTS TO 1,000 PATIENTS. THEN TO TRY TO BUILD DELIBERATE FEEDBACK WITH THE EVOLVING HISTORY OF THE DISEASE AND TO CONSTANTLY BE FILLING IN THE GAPS AND LOOKING FOR AREAS AND NEEDS FOR IMPROVEMENT. WELL-DESIGNED CLINICICAL DEVELOPMENT PROGRAMS ARE OF COURSE ESSENTIALLY -- SOCIAL WE CAN INFORM PATIENTS PROPERLY. BUT NO ONE STUDY IS GOING TO ANSWER THIS ALL AND IT'S USUALLY WITH A SERIES OF STEPS AND WITH SAPARTARIAN NEED TO ANSWER THOSE QUESTIONS PREMARKET. I THINK THIS HAS BEEN TOUCHED ON A NUMBER OF TIMES. BUT THOSE OUTCOME MEASURES USUALLY TAKE A LOT OF DISCUSSION AND A LOT OF WORK. AND OTHER FACTORS COME UP IN DIAGNOSTICS, DEVICES. RAPID GENETIC TESTING, ALSO MAKING OTHER AREAS TO LOOK TO. SO IN SUMMARY, THESE ARE POINTS THAT HAVE BEEN MADE MANY TIMES OVER THE PAST TWO DAYS AND I THINK I AM GLAD THAT IT'S CONSISTENT WITH WHAT'S BEEN SAID. BUT COMPREHENSIVE PLAN IS ESSENTIAL. ALL STAKEHOLDERS REALLY DO NEED TO BE INVOLVED EVERY STEP THE WAY. WHEN WE COLLABORATE, THINGS WORK A LOT MORE EFFICIENTLY AND A LOT BETTER. WELL-DESIGNED PROGRAMS ARE ESSENTIAL FOR GENERATING GOOD QUALITY DATA THAT WILL THEN BE USED TO INFORM PUBLIC HEALTH DECISIONS. PARTICIPATION WILL BE VERY VALUABLE IF HELPING US TO MAKE THESE GOALS AND PRIORITIES. AND BUILDING THOSE PROCESSS AND PROCEDURES TO INCORPORATE THE KNOWLEDGE TO MOVE FORWARD ON A CONTINUOUS BASIS WOULD BE VERY, VERY USEFUL. SO I WILL STOP THERE. [APPLAUSE] >> I'VE GOT ONE PRACTICAL QUESTION. I KNOW WHEN THE DRUG SAP TAR TARIAN WAS FIRST TESTED, THE CLINICAL TRIAL LOOKED PRIMARILY AT 10 MILLIGRAMS PER KILOGRAM AND I THINK A DOSE OF MAYBE 30 MILLIGRAM PER 30 KILOGRAM. BUT WHAT HAPPENS IN PRACTICE CAN BE QUITE DIFFERENT THAN THAT. HOW DOES THE F.D.A. PREPARE THE COMMUNITY FOR USE OF A DRUG IN TERMS OF THINGS LIKE DOSING? ARE THERE RECOMMENDATIONS? DOES THE LABEL CARRY MUCH LEGAL OR PRACTICAL IMPACT ON THOSE THINGS? >> WELL, THE GOAL IS TO TRY TO DESIGN THE CLINICAL DEVELOPMENT PROGRAMS WITH AN EYE TO HOW IT WILL BE USED IN THE CLINIC. THE WHOLE POINT IS TO PUT THAT INFORMATION INTO THE HANDS OF THE TREATING PHYSICIANS SO THAT THEY WILL HAVE A GOOD IDEA OF HOW THE DRUG WILL BEHAVE AND WHAT THEY NEED TO DO. BUT DEVIATING WHAT FR WHAT'S IN THE LABEL IS NOT AT ALL UNCOMMON AND WAYOU ARE DESCRIBING FALLS ON PRACTICE OF MEDICINE AND IT'S A DECISION MADE BY THE DOCTOR, THEIR FEELING THE BEST NEEDS OF THE PATIENT IN FRONT OF THEM. AND IT'S REALLY THAT BECOMES YOUR DECISION AND WE DON'T INTERFERE. >> AND I AM NOT QUITE SURE HOW TO ASK THIS QUESTION. AS A PRACTICE MATTER AND I'M THINKING OF ANOTHER DRUG -- LUMIZYME FOR TREATMENT OF POMP PAY DISEASE. THE LABEL DESCRIBES USE PRIMARILY IN CHILDREN AND OF COURSE, INSURANCE COMPANIES COME BACK AND DECLINE USE IN OTHER CIRCUMSTANCES LIKE OLDER PATIENTS, DIFFERENT AGE GROUPS. SO DOES THE F.D.A. LABEL OR THE PROCESS -- DOES THE F.D.A. UNDERSTAND HOW THAT IMPACTS THE APPLICATION AND SEEK TO GUIDE THAT IN ANY WAY? >> YES. AND THAT WAS A LITTLE BIT OF AN UNUSUAL SITUATION. THERE ARE TWO PRODUCTS ON THE MARKET. THERE ISOMYAZYME, WHICH DOESN'T HAVE AN AGE RESTRICTION AND LUMIZYME AND THE CUTOFF IS AGE EIGHT AND THE YOUNGER PATIENTS RIGHT NOW ARE SUPPOSED TO RECEIVEOMYAZYME AND NOT THE LUMIZYME. MOOF THE TIME, THOUGH, FOR RARE DISEASES, UNLESS THERE IS A CONTRAI REPEAT INDICATION FOR SOME REASON, THERE ISN'T AN AGE RESTRICTION BECAUSE OF THE REASON THAT YOU STATE, NOT INTENDING TO RESTRICT ACCESS UMS THERE IS A REALLY GOOD REASON FOR IT. UNLESS. >> YOU GAVE US A LOT OF REALLY GOOD ADVICE AND RECOMMENDATIONS OF WHAT WE CAN TRY TO DO. FOR INSTANCE, VOLUNTARY REGISTRY, COLLECT DATA, COLLECT DATA IN MANY DIFFERENT WAYS, WHICH IS VERY GOOD ADVICE. BUT YOU ALSO I AM SURE UNDERSTAND THAT COLLECTING DATA REQUIRES PEOPLE'S TIME AND EFFORTS. MAYBE THE PATIENTS CAN VOLUNTEER TO REGISTER -- PUT DATA IN THE REGISTRY. BUT THE PEOPLE WHO NEED TO ANALYZE THE DATA, COLLECT THE DATA WILL BE -LNEED TO BE SUPPORTED. AND BASICALLY IT SOUNDS LIKE THE SUGGESTION OF DOING A LONGITUDENAL STUDY OF PKU PATIENTS. THOSE ARE BIG AND EXPENSIVE STUDIES. NOT EASILY PULLED OFF AND NOT WITHOUT ANY MONEY WHATSOEVER, RIGHT? DID YOU HAVE ANY THOUGHTS ON THAT? >> YEAH. AND THAT IS A VERY IMPORTANT POINT. AND I THINK THIS IS SOMETHING THAT WE'RE ALL PAINFULLY AWARE OF AND IT WOULD CERTAINLY BE OF GREAT UTILITY IN PKU AND GREATLY -- GREAT UTILITY IN ALL RARE DISEASES. ONE OF THE BIGGEST THING WE FACED IN A DISEASE SO THEN TRYING TO DESIGN A CLINICAL DEVELOPMENT PROGRAM AROUND THAT ONCE YOU HAVE CANDIDATE THERAPEUTIC BECOMES VERY, VERY DIFFICULT. IF I HAD MY WAY, THERE WOULD BE MONEY AND FUNDING FOR NATURAL HISTORY STUDIESIFER ALL RARE DISEASES BUT OBVIOUSLY THAT'S A MASSIVE UNDERTAKING. SO DO I HAVE THE ANSWER TO THAT. I DON'T. AND YOU'RE ABSOLUTELY RIGHT. WE NEED RESOURCES TO DO THIS AND IF ANYBODY HAS ANY GOOD IDEAS, WE'D BE GLAD TO HEAR THEM. >> GARY HARDING. AND EVEN MORE EDITORIAL COMMENT IS EVEN IF WE HAD A WAY OF COLLECTING ALL THE DATA RIGHT NOW, AT LEAST IN THE U.S., WHAT DRIVES TREATMENT DIFFERENCES HAS A LOT MORE TO DO WITH WHO PAYS FOR WHAT. AND UNLESS THOSE ARE DEALT WITH, WE'LL NEVER COME TO A CONSENSUS ABOUT WHAT CAN BE DONE. [APPLAUSE] >> THANK YOU VERY MUCH. >> AND I JUST WANTED TO NUT A PLUG -- IN A PLUG. THERE IS GOING TO BE A CONFERENCE ON NATURAL HISTORY STUDIES THAT MAY BE OF INTEREST AND THAT'S GOING TO BE HELD IN MAY. JIPTLY SPONSORED BY NIH AND BY F.D.A.. JOINTLY. AND I DON'T REMEMBER THE DATES OFF THE TOP OF MY HEAD. DO YOU? OKAY. MAY 15 AND 16. I THINK WE ALL RECOGNIZE THE NEED FOR QUALITY NATURAL HISTORY STUDIES AND HOW DIFFICULT THEY ARE TO DO AND TO GET FUNDED. WE HOPE THIS WILL BE A REALLY PRODUCTIVE WORK SHOP TO HELP PEOPLE DEVELOP STRATEGIES FOR SUPPORTING THOSE STUDIES. SO I KNOW THAT IT SAYS THAT IT'S BREAK TIME BUT WE WANT TO FINISH BY 4:00 BECAUSE SOME OF YOU ARE GOING TO BE LEAVING. SO I'D LIKE TO PROPOSE RIGHT NOW THAT WE GO AHEAD AND MOVE ON TO OUR ATTEMPT TO DEVELOP A RESEARCH AGENDA. SO THIS IS REALLY WHERE WE NEED TO HEAR FEEDBACK FROM YOU ABOUT WHAT ARE THE MOST IMPORTANT NEEDS, PRIORITIES, AND NEXT STEPS FOR RESEARCH IN PKU? AND THIS IS REALLY VITALLY CRITICAL TO NIH AND OUR MISSION AND IT'S ALSO VERY IMPORTANT TO ADVANCE DIAGNOSTICS AND TREATMENT FOR INDIVIDUALS WITH PKU. SO WE REALLY OWE IT TO THE PATIENTS AND THEIR FAMILIES TO DEVELOP ROBUST STRATEGIES FOR WHAT WE THINK ARE THE NEXT IMPORTANT ELEMENTS. AND SO I'VE ASKED MELISSA MCPHEETERS FROM THE HRQ EPC COMMITTEE AT VAPIDER BILT TO HELP ME LEAD THIS SESSION AND WE ARE GOING TO SEE HOW IT GOES. VANDER BIMENT -- VANDERBILT. ONE OF THE REASONS WHY I THINK THIS IS IMPORTANT -- COME ON UP. IT'S OKAY. THEY WON'T BITE. [LAUGHTER] ONE OF THE REASONS WHY I THINK THIS IS SO IMPORTANT IS BECAUSE WE HAVE THIS MISSION AT NIH TO REALLY PROMOTE RESEARCH, BUT I ALSO WANT TO -- CAN I SAY THIS PUBLICLY THAT YOU ALL ARE GOING TO BE DOING A RESEARCH NEEDS? THE EPC COMMITTEE THAT PUT TOGETHER THE HRQ REPORT HAS ALSO BEEN CHARGED WITH DEVELOPING A FUTURE RESEARCH NEEDS DOCUMENT AS WELL. WE'RE HOPING TO GET DOUBLE INPUT FOR BOTH OF OUR AGENDAS FROM THE AUDIENCE HERE AND FROM THE EXPERTISE THAT IS GATHERED HERE. AND WE THOUGHT THAT IT WOULD BE HELPFUL JUST TO LET YOU KNOW ABOUT SOME OF THE CONSIDERATIONS WHEN YOU ARE THINKING ABOUT A RESEARCH AGENDA, WHAT IS IMPORTANT FOR STARTERS IN TERMS OF HOW WE THINK ABOUT THE IMPORTANCE OF QUESTIONS AND HOW WE PRIORITIZE THOSE. SO ONE OF THE FIRST QUESTIONS IS IS WHAT WE'RE TALKING ABOUT A GAP IN OUR KNOWLEDGE OR IS IT A METHOD LOGIC ISSUE AND SHE IS MUCH MORE OF AN EXPERT ON THIS THAN I AM. BUT I THINK YOU WILL SEE AS WE GO THROUGH MYSTERY IDEAS THAT WE POSED HERE TO GET YOUR FEEDBACK FROM, IS THAT SOME REALLY CLEARLY ARE GOSH, WE JUST DON'T KNOW ANYTHING ABOUT THAT PARTICULAR ISSUE VERSUS OTHER ISSUES ARE ONES WHERE IT'S SORT OF WE NEED TO DEVELOP BETTER METHODOLOGIES TO MEASURE SOME OF THESE THINGS AND IT'S MUCH MORE OF A SORT OF APPROACH ISSUE. THE TIMEFRAME IS REALLY IMPORTANT, AND THIS IS NOT JUST BECAUSE FUNDING DECISIONS ARE BASED ON TIME PERIODS, BUT BECAUSE IT REALLY HELPS US FIGURE OUT WHAT IS DOINGDOABLE VERSUS THE INTERMED-TERM VERSUS THE LONG-TERM AND DIVIDED THIS SHORT TERM BEING THREE YEARS OR LESS, AND WE REALIZED THAT MAY BE OPTIMISTIC BUT WE'D RATHER HAVE AMBITIOUS GOALS THAN PUT THINGS OFF SO FAR IN THE FUTURE THAT WE NEVER REACH THEM. THIRDLY, ARE THE RESOURCES THAT WOULD FACILITATE ANSWERING EACH OF THESE QUESTIONS AND THIS INCLUDES BIOPARKERS, REGISTRIES, WHICH WE JUST TALKED QUITE A BIT ABOUT. SERVICES, WHAT KINDS OF RESOURCES WOULD BE HELPFUL FOR ANSWERING THOSE QUESTIONS? I THINK THAT IN PARTICULAR, WHEN WE'RE FACING A TIGHT FUNDING CLIMATE, WHICH WE ARE THESE DAYS, THAT PARTNERSHIPS ARE EVEN MORE IMPORTANT AND LEVERAGES RESOURCES IS ESSENTIAL. WHAT HAPPENS WHEN MONEY IS TIGHT IS THAT PEOPLE FIGURE OUT CREATIVE WAYS TO GET THE WORK DONE AND WE HOPE THAT THAT WILL ALSO BE THE CASE IN THIS FUNDING CLIMATE. FOURTH, WHAT ARE THE HIGHEST PRIORITIES? WHAT IS THE POTENTIAL FOR SIGNIFICANT HEALTH IMPACT OR THE POTENTIAL FOR NEW KNOWLEDGE AND WHERE SHOULD WE PUT OUR MONEY FIRST ESSENTIALLY, AND FEASIBILITY I THINK IS ALSO TIGHTLY LINKED TO PRIORITYIZATION. SO WHAT CAN WE REASONABLY DO? WHAT DO WE HAVE THE RESOURCES TO DO RIGHT NOW, WHAT DO WE HAVE THE INFRASTRUCTURE TO ACCOMPLISH? KEEP THOSE ISSUES IN MIND AS WE THROW OUT SOME IDEAS AND GET YOUR FEEDBACK. SO AND THESE HAVE BEEN PULLED OVER THE DISCUSSION OVER THE PAST TWO DAYS IS WHAT SOME OF THE WORKING GROUPS PUT TOGETHER IN THEIR BREAKOUT SESSIONS. WE TALKED ABOUT -- I AM NOT SURE WHETHER WE WANT TO CALL IT THE GRID OR THE UNIFORM ASSESSMENT METHOD. BASICALLY THE WORK GROUP TRIED TO DEVELOP AN APPROACH WHICH THEY'VE NOW DECIDED TO SORT OF RETHINK AS OF AN HOUR AGO. BUT ESSENTIALLY ARE SOME OF THOSE MEASURES THAT THEY PROPOSED? CAN THEY BE USED TO TEST THE EFFECTS OF TREATMENT? AND IF NOT, WHAT IS MISSING? OR HOW CAN THESE BE VALIDATED AS OUTCOME MEASURES AND THAT LEADS CLOSELY TO RECURRING THEM NUMBER TWO. WHAT ARE THE APPROPRIATE LONG TERM AND SHORT TERM MEASURES AND THE CLINICAL OUTCOME ASSESSMENTS? WE'RE USING THOSE TERMS INTERCHANGEABLY THAT CAN HELP US IDENTIFY INTERVENTION WITH REGARD TO COG IN ADDITION, BEHAVIOR, PSYCHIATRIC SYMPTOMS? MANY OF YOU HAVE RECOGNIZED THAT THE CMS ASPECTS AND NEWER LODGEUAL AND CENTRAL NERVOUS SYSTEM TYPES OF EFFECTS OF PKU ARE WHAT WE WANT ULTIMATELY IMPROVE AND AIMMEDIATELYIO RATE. IF THIS IS ONE OUR AREAS OF FOCUS OF PKU, WHAT ARE THE APPROPRIATE OUTCOME MEASURES TO IDENTIFY THOSE CHANGES THAT WE SO WANT TO MEASURE? AND WE ALSO HAVE TO KEEP IN MIND THAT THEY HAVE TO HAVE RELEVANCE TO PATIENT OR THEY ARE NOT GOING TO GET SUPPORT FROM SKPRIJDS FAMILIES. THOSE ARE TWO -- -- INDIVIDUALS AND FAMILIES. SO THE THIRD ONE IS ARE THERE ANY PROMISING BIOMARKERS ON THE HORIZON THAT MIGHT BE VALUABLE FOR MORE ON THING PKU IN RESPONSE TO THERAPY? MIGHT THERE BE INSIGHTS FROM DISORDERS TO BH 4 METABOLISM? I WAS INTRIGUED BY SOME OF THE STUDIES THAT DR. BLAU MENTIONED THAT CARRIE HARDING MENTIONED ABOUT SOME OF THE SIMILARITIES IN SYMPTOMS THAT WE BE ABLE TO LEARN FROM OTHER DISORDERS THAT WILL HELP US IDENTIFY SENSITIVE BIOMARKERS IN PKU. AND THEN THE FOURTH ISSUE WHAT ARE THE SOCIAL SUPPORT SYSTEMS THAT MIGHT FACILITATE THE BEST CLINICAL OUTCOMES FOR INDIVIDUALS WITH PKU AND WHAT STRATEGIES CAN BE USED TO OVERCOME BARRIERS AND IMPROVE ADHERENCE TO TREATMENT IF ALL PHASES OF LIFE? WE HEARD ABOUT ISSUES AT ADOLESCENCE AND PREGNANCY AND ADULTHOOD AND THE ELDERLY INDIVIDUALS ON DIET MANAGEMENT AND THEY MAY HAVE UNIQUE ISSUES AS WELL. WHAT ARE THOSE SORT OF SUPPORT SYSTEMS THAT CAN PROMOTE ADHERENCE? HOW CAN THEY BE MEASURED AND WHAT ARE MOST SENSEIB TO TREATMENTS? LET'S START WITH THESE FOUR THEMES AND I WOULD REALLY LIKE TO HEAR FROM YOU ALL WHETHER YOU THINK WE'RE HITTING THE RIGHT TARGETS OR WHETHER THERE ARE OTHER PRIORITIES TANEED TO BE CONSIDERED STTD OF THESE. -- TARGETS THAT NEED TO BE CONSIDERED INSTEAD OF THESE? AND YOU ARE GOING TO BE HELD HOSTAGE UNTIL YOU SPEAK UP. [LAUGHTER] >> SINCE I PROPOSED WITH DESIREEY THAT FIRST ONE, I THOUGHT I COULD SAY ONE TH5 ABOUT IT. I DON'T THINK IT REALLY MATTERS WHICH EXACT MEASURE WE MIGHT USE OF ADAPTIVE BEHAVIOR OR EVEN DEPRESSION OR ANXIETY. THE POINT IS WE SHOULD ALL USE THE SAME ONE. AND THE MEASURES ARE GENERALLY IF THEY'VE BEEN VALIDATED IN THE GENERAL POPULATION, THEY'VE ALSO BEEN CORRELATED WITH EACH OTHER AND IN ORDER TO BE CONSIDERED VALID HAS TO HAVE THE SAME CONCEPT. SO I AM NOT MARRIED TO THOSE. THOSE WERE CHOSEN BY TEN PSYCHOLOGISTS AND A PSYCHIATRIST MANY YEARS AGO AND WE'VE BEEN WORKING ON THEM SINCE. SO IT DOESN'T REALLY MATTER. WHAT MATTERS IS THAT WE DO THE SAME THING. >> SO MY QUESTION BACK TO YOU THEN WOULD BE SINCE WE'RE NOW IN THE RESEARCH AGENDA PART OF THE MEETING, AWHAT WOULD BE THE RESEARCH PROCESS OR QUESTION OR PROJECT THAT COULD HELP US GET TO THAT DECISION ABOUT WHICH ONES SHOULD BE USED? IS THAT SOMETHING THATUT -- OUGHT TO BE ON THE RESEARCH AGENDA? WHAT I HEAR YOU SAYING IS THERE IS LOTS OF POTENTIALLY VALID MEASURES AND THERE ARE. SO WHAT'S THE RESEARCH QUESTION THAT WOULD GET US TO THE NEXT STEP? >> FOR SELECTING WHICH ONE? >> THIS IS ONE OF THE HUGE ISSUES IS GETTING TEN PSYCHOLOGISTS TO AGREE ON WHICH MEASURE THEY WANT TO USE. >> I WOULD SUGGEST THAT WE DO TWO POSSIBILITIES. ONE WOULD BE A PILOT STUDY WHERE WE EXPAND ON WHAT I -- WHERE WE GIVE VERY GOOD NEUROPSYCHOLOGY TESTING FULL RANGE WITH NOT JUST THESE MEASURES BUT SOME OTHER MEASURES AND SEE WHICH ARE BEST CORRELATED. A SECOND HOPGS -- OPTION THAT HAS BEEN RECOMMENDED BY PEOPLE AND I AM NOT SURE IS THE BEST IDEA IS TO GET A PKU-SPECIFIC SCREENING MEASURE. BUT I THINK WHAT -- AGAIN, WE HAVE TWO QUESTIONS HERE. THERE IS THE CLINICAL NEED AND THERE WE JUST NEED A SCREENING MEASURE. IT DOESN'T MATTER. FOR RESEARCH, I THINK WE REALLY NEED TO BE CAREFUL ABOUT WHAT WE DO. AND TO DO THAT, THEN WE PROBABLY WOULD WANT TO HAVE MAYBE A SMALLER STUDY, WHERE THEY GET A FULL NEUROPSYCHE AND WHERE THEY GET AND WHERE WE REALLY ALSO DON'T GET STUCK ON JUST WHAT CAN BE DONE THROUGH A SCREENING MEASURE. SPEED OF PROCESSING HEPATOBEEN TALKED ABOUT AT ALL AND THAT MAY BE AS PORP AS ATTENTION AND EXECUTIVE FUNCTION. IMPORTANT. I THINK FOR RESEARCH AGENDA, I WOULD LIKE TO SEE IT GO A STEP FURTHER AND DO THAT. I THINK ANOTHER OPTION WOULD BE TO USE THE NATIONAL PKU ASSOCIATION AND TRY SOME OF THE COMPUTERIZED ONES WHERE PARENTS ARE RESPONDING AND COMING INT MAY NOT BE AS REPRESENTATIVE OF THE SAMPLE BUT IT'S A BIG SAMPLE AND THAT MIGHT HELP US TO SEE HOW DOES THAT WORK AND MAYBE THAT COULD LEAD TO A WAY TO LOOK AT OUTCOMES. USING SOME OF THESE MEASURES OR A SELF-CREATED ONE. I THINK IN THE LONG RUN WE'RE BETTER OFF USING A VALIDATED MEASURE BECAUSE THEN IT COULD WORK FOR OTHER METABOLIC DISORDERS. >> RIGHT. >> TOAD A -- TO ADD. IN FAVOR OF USING SOMETHING THAT'S ALREADY VALIDATED, THAT MEANS WE CAN DO REALLY COOL THINGS THAT ARE VERY USEFUL LIKE COMPARED TO DIABETES AND LEARN FROM LEVERAGE FROM OTHER DISORDERS. AND I WOULD ALSO ADD THAT WHATEVER YOU DO, THINK ABOUT THE COST AND THE LIGHTENING BECAUSE FOR THOSE FOLKS WHO ARE ALREADY DOING ALL OF THESE MEASURES, IT'S A LOT SIMPLER TO PICK AND CHOOSE WHAT YOU'VE GOT AND FOR SOMEBODY LIKE ME THAT'S DOING A STUDY WHERE WE NEEDED TO ACTUALLY DO SOMETHING COMPARABLE, WE HAD TO ACTUALLY GO AND FIND A PSYCHOLOGIST. AND SO THINKING OF MAYBE GOING BACK TO PARTNER WITH THE ADVOCACY GROUPS OR SOMETHING THAT YOU CAN LEVERAGE EITHER THROUGH OUR COLLEAGUES WHO ARE PSYCHOLOGISTS OR SOMETHING THAT COULD BE SUPPORTED NATIONALLY IS CAN THERE BE A LICENSE THAT WE CAN USE? IF YOU WANT TO GET EVERYBODY DOING THE SAME THING, DOES EVERYBODY HAVE TO GO TO THE IRB AND GET PERMISSION AND BUY THE LICENSE? CAN THERE BE A CENTRAL CORE WHERE WE GET THIS AND THEN WE TURN IT OVER TO SOMEBODY AND THEY GIVE US BACK A SCORE? >> THANK YOU. >> GO AHEAD. >> UNIVERSITY OF WOIPS. I'D LIKE TO SUGGEST -- WISCONSIN. I'D LIKE TO SUGGEST IF WE HAD BETTER RESEARCH IN THE PKU AREA, THIS WOULD BETTER INFORM CLINICAL PATIENTS AND I'D LIKE TO SUGGEST TWO AREAS. THE MECHANISM OF THE TOXICITY OF PHENOLNINE IN THE BRAIN IS UNKNOWN. THERE ARE THREE MAIN HYPOTHESIS, NEUROTRANSMITTERS, THIRD ONE ESCAPED ME.„i AND MYELENATION AND NEUROTRANSMITTERS, AS WELL AS THE OBSERVATION THAT REALLY WE'RE USING BLOOD PHENOLNINE LEVELS AS A SURROGATE FOR BRAIN PHENOLNINES SO THE METHODOLOGY TO MEASURE PHENOL NYPD IN THE BRAIN, AS HAS BEEN SUGGESTED BY DR. BARRY IS THE FIRST EXAMPLE. THE SECOND EXAMPLE IS TO USE BASIC SCIENCE. THE ETIOLOGY OF THIS IS COMPLETELY UNKNOWN BUT COULD BE INVESTIGATED IN ANIMAL MODEL. THE MOST BAKE QUESTION IS -- THE MOST BASIC QUESTION IS IS IT A FUNCTION OF THE GENE GENEOTYPE OR THE DIET, THE TREATMENT, THE DISEASE? AND I HAVE FOUND AS A PERSON THAT DOES TRANSLATIONAL WORK, CLINICAL STUDIES IN PKU THAT YOU DON'T KNOW WHERE TO GO AT NIH. THE BONE EXAMPLE WHERE YOU COULD MAYBE NIDDK. IT'S REALLY VERY DIFFICULT BECAUSE THERE ARE NO SPECIFIC RFAS RELATED TO SOME OF THE BASIC SCIENCE QUESTIONS IN PKU. >> AND I WANT TO COMMENT ON YOUR COMMENTS. THAT ACTUALLY HAS BEEN A RECURRING THEME TODAY, TOO, AT LEAST WITH REGARD TO YOUR FIRST BASIC SCIENCE QUESTION. I HAVE TRIED TO CAPTURE NUMBER 13 HERE ARE YOU WHAT ARE THE MECHANISMS FOR MEASURING THE EFFECTS OF IT ON THE BRAIN AND I AGREE THAT SEEMS TO BE A VERY IMPORTANT BASIC SCIENCE QUESTION THAT STILL REMAINS UNANSWERED. AND A COMMENT IN RESPONSE TO WHERE TO GO WITH SOME OF THESE PERHAPS NON-CMS-RELATED SYMPTOMS IN TERMS OF RESEARCH OR GUIDANCE AT NIH. I CAN TELL YOU BECAUSE TINA WORKS VERY CLOSELY WITH ME THAT TINA IRV IN THE DISABILITIES BRANCH AT NICHD AND WE HAVE A RESEARCH PROGRAM IN NEWBORN SCREENING AND FOR STARTERS YOU CAN CAC US AND WE CAN HELP GUIDE YOU IN TERMS OF SPECIFIC PROGRAM OFFICERS OR PROGRAMS TO SEE WHERE YOUR RESEARCH ISSUES RIGHT MIGHT FIT BEST AT NIH. PLEASE USE THAT. TINA, WHERE ARE YOU? DID YOU ALREADY DISAPPEAR ON ME? GO AHEAD. >> HI. NICOLE COLOGNE FROM THE CANADIAN PKU NONPROFIT. I JUST WANTED TO HIGHLIGHT A RESEARCH INCIDENCE THAT I THINK IS IMPORTANT. IMMEDIATE CARE FOR PATIENTS AND IMPROVED CARE FOR PATIENTS AS WELL AS A WAY TO HELP INFORM SOME OF THESE OTHER RESEARCH PROJECTS THAT WE NEED TO DO. AND THAT IS THAT A HOME MONITOR-TYPE SYSTEM, WHICH WE'RE GRATEFUL THAT OBAMA PUT SOME MONEY INTO IT AND DISAPPOINTED THAT IT'S BEEN FOUND NOT TO WORK VERY WELL AT THIS POINT. BUT I THINK IT'S REALLY, REALLY IMPORTANT BECAUSE EVEN THOUGH I THINK THE TURN AROUND TIME FOR THOSE RESULTS HAVE PROBABLY IMPROVED GREATLY OVER THE LAST 20 YEARS, SOME SUCH AS MYSELF LIVE IN AREAS THAT ARE QUITE FAR AWAY FROM OUR CARE FACILITY AND OUR RESULTS OFTEN TAKE ABOUT TEN DAYS. THE INFORMATION WHEN WE GET THAT BACK IS VIRTUALLY USELESS. IT'S GREAT FOR HISTORICAL BUT WE'RE ADAPTING FOR DIET BASED ON A TEN DAY-OLD RESULT. ,000 IT -- I THINK IF WE HAD A SYSTEM LIKE THAT, IT WOULD ALSO BE VERY HELPFUL WHEN YOU ARE STARTING TO SKBUS LOOK AT DIFFERENT TREATMENTS SUCH AS KUFBAN AND G MPS. IT WOULD HELP US EVALUATE THOSE THINGS. I THINK THERE IS A GREAT BENEFIT TO THE PATIENT IMMEDIATELY, AS WELL AS TO THE SCIENCE THAT WE NEED TO GATHER. >> THANK YOU. >> ONE MORE POINT, TOO. I THINK RELYING ON INDUSTRY TO DO SOMETHING LIKE THAT IS NOT -- I DON'T THINK IT'S FEASIBLE THAT MANY COMPANIES ARE GOING TO PUT IN THAT MUCH MONEY AND EFFORT INTO SOMETHING THAT IN REALITY IS NOT GOING TO PROBABLY MAKE THEM ANY MONEY BACK. SO I THINK THAT FIND OF -- KIND OF INITIATIVE NEEDS TO COME MORE FROM THE -- I DON'T KNOW SOMEBODY, PLEASE. >> SOUNDS LIKE WHAT YOU ARE SAYING IS WE NEED A SECTION OF THIS RESEARCH AGENDA THAT FOCUSES ON SYSTEMS AND CARE AND HOW TO PUT THIS IN A WAY THAT'S EFFECTIVE FOR THE FAMILIES. >> AND I THINK IT ALSO SORT OF REFLECTS PERHAPS A BROADER CATEGORY OF IMPLEMENTATION SCIENCE TOO, WHICH IS REALLY HOW DO YOU FULLY TRANSLATE FROM THE BENCH TO THE BEDSIDE AND THEN INTO THE COMMUNITY SO THAT THESE ARE PRACTICAL INTERVENTION THAT'S REALLY MAKE A DIFFERENCE IN THE LIVES OF INDIVIDUALS? AND I THINK WE'VE SEEN SOME STRIKING AND SOBERING EXAMPLES OF HOW DIFFICULT EVEN ACCESSING SOME OF THESE TREATMENTS HAS BEEN. AND IF THERE WERE RESEARCH THAT REALLY DEMONSTRATED THAT HAVING THE OPPORTUNITY TO HAVE HOME MOANING, HAVING ACCESS TO THESE TREATMENTS, MADE A DRAMATIC IMROMT IN QUALITY OF LIFE, THE ARGUMENT CAN BE MADE ALL THE MORE COMPELLING FOR COVERAGE AND CONTINUING PURSUING OF THOSE THERAPIES. >> WASHINGTON UNIVERSITY. I WANT TO FOLLOW UP A LITTLE BIT ON SOME OF THE EARLIER COMMENTS THAT SUSAN MADE, BUT IT SORTS OF SEGUING WHAT BOB JUST SAID AS WELL. I THINK AS WE DEVELOP THESE MEASURES FOR SCREENING, FOR REFERRAL, TO GATHER HISTORICAL INFORMATION TO LOOK FOR CHANGE WITH TREATMENT, WE NEED TO BE CAREFUL THAT WE'RE NOT A GOOD STARTING POINT IS PSYCHOLOGISTS AND PSYCHIATRISTS SITTING AND COMING TO SOME CONSENSUS ABOUT MEASURES. I THINK AS A NEXT STEP WE WANT TO CONDUCT RESEARCH THROUGH ITEM ANALYSES TO DETERMINE WHICH OF THE MEASURES AND ITEMS POTENTIALLY ARE EXACTLY RIGHT FOR THIS POPULATION. AND IN THAT WAY IF WE CAN EASE THE BURDEN AND LET THE CLINIC ADMINISTER. IF THERE ARE FIVE QUESTIONS RATHER THAN 250 QUESTIONS THEY CAN ADMINISTER TO BEGIN TO DETERMINE WHEN TO REFER OR AT LEAST WHICH OF THOSE ITEMS OUT OF THE 250 TO REMEMBER PAY ATTENTION TO. I THINK THAT'S GOING TO BE THE MOST HELPFUL. AND THE OTHER PIECE TO THAT IS THEN WHERE DO WE GO TO LOOK FOR FUNDING MECHANISMS TO SUPPORT THE KIND OF I GUESS INFRASTRUCTURE FOR LACK OF A BETTER TERM, TO PRODUCE THESE TYPES OF MEASURES AND PUT THEM TOGETHER IN A WAY THAT CLINICS CAN ACTUALLY MAKE USE OF THEM? INSTEAD OF FEELING GUILTY THAT THEY DON'T HAVE TIME TO MAKE USE OF THEM? >> GOOD COMMENTS. I WANTED TO COMPLIMENT THE GROUP FOR RECOGNIZING THIS SORT OF TENSION BETWEEN CLINICAL CARE AND RESEARCH AND I THINK WE ALL RECOGNIZE THAT WHEN WE ARE DEALING WITH RARE POPULATIONS THAT THAT IS A FUZZY LINE IN MANY RESPECTS. JERRY SAID IT YESTERDAY WHEN HE SAID EVERY PATIENT I SEE IN A SENSE IS A RESEARCH SUBJECT. AND THAN WE'RE VIEWING INDIVIDUALS WITH THESE RARE CONDITIONS AS JUST GUINEA PIGS BUT BECAUSE IT'S RARE, WE REALLY NEED TO TAKE ADVANTAGE OF ALL THE DATA WE CAN COLLECT AND IF THAT MEANS TAKING CLINICAL INFORMATION AND USING THAT IN A RESEARCH STUDY, THAT'S WHERE WE HAVE TO BE THINKING PRACTICALLY FOR SOME OF THESE DEVELOPMENTAL MEASURES AND DEVELOPMENT OF OUTCOMES. WE ALWAYS NEED TO KEEP THAT TENSION IN MIND AND REALLY TRY TO FIND A MIDDLE GROUND BETWEEN CLINICAL SCREENING TOOLS BUT ALSO THAT ARE GOING TO HAVE SOME RESEARCH UTILITY. JERRY? >> BARRY. TAKEN TOGETHER ALL THE DATA SUGGEST AT THE PATHOPHYSIOLOGY AND PKU REPRESENTS A CONTINUUM AND IT GOES FROM THE PATIENT WHO IS MANIFESTING EXECUTIVE CONTROL ABNORMALITIES, ANXIETY, DEPRESSION, ALL THE WAY TO RELATIB NON-HARD-WIRED PROBLEMS LIKE DOPAMINE DEFICIENCY, WITH ADVERTISE TONIA IS A MAN FEGS OF OTHER PROBLEMS. TREMOR AND THEN CORTCO SPINAL TRACT INVOLVEMENT WITH HYPERFLEXIA. IT'S NOT CLEAR WHETHER THAT IS REALLY A CONTINUUM, BUT IT CERTAINLY WOULD BE A REASONABLE HYPOTHESIS TO STATE ONCE AGAIN, I THINK THE REASONABLE QUESTION WOULD BE TO ASK IS ONE OR MORE OF THOSE ELEMENTS ALL WAIT FROM EXECUTIVE FUNCTION CONTROL ABNORMALITIES TO CORTICOSPINAL TRACT INVOLVEMENT -- IS THAT RELATED IN A CAUSE-AND-EFFECT WAY TO THE MAGNITUDE OF ELEVATION IN PHENOLNINE? OR MORE SPECIFICALLY TO PHENOL NYPD AND BRAIN? AND I THINK WE KEEP TALKING ABOUT THAT BUT I THINK IT'S THE MAIN ISSUE HERE AND IT'S ALSO PROBABLY AS A WAY THAT MODIFIER GENES MAY BE ABLE TO PLAY A ROLE IN CAUSING THE PHENOTYPE TO BE EXPRESSED DIFFERENT IN SOME INDIVIDUALS COMPARED TO OTHERS. AND I THINK THIS IS WHERE THE BIG PROBLEMS IS IN TERMS OF MONEY AND METHOD LOGICAL PROBLEM. I THINK THE CAPABILITY EXISTS RIGHT NOW TO BE ABLE TO USE SEVEN TESTABLE RESEARCH MAGNETS TO DO THIS. BUT IT ALSO TAKES THE PROPER PHYSICIST WHO IS GUIDING THAT AND IT'S NOT FOR EVERY CENTER TO DO THAT. BUT THE RIGHT PERSON CREATING THE RIGHT ALGARITHMS I THINK CAN ALLOW FOR THE PHENOL NYPD TO BE QAUPTIFIED PROPERLY IN BRAIN. QUANTITYIFIED AND THEN TO CORRELATE THAT WITH BLOOD LEVELS AND I SEE THAT AS JUST AN ISSUE OF PARAMOUNT IMPORTANCE. AND THEN THE NEXT ISSUE IS THAT THERE ARE WAYS OF LOOKING AT NEUROTRANSMITTER AND RELATE IT TO ELEMENTS LIKE THE RECEPTORS USING PET SCAN ORGANIZE SOME OTHER TECHNIQUES WITH ISOTOPICALLY LABELED MATERIALS AND THIS ALSO MAY BE A VERY ELEGANT WAY OF TRYING TO DETERMINE WHETHER THE BRAIN THAT HAS BEEN POISONED WITH HIGH PHE LEVELS FOR SOMETIME IS GIPG TO SHOW THE EVIDENCE -- BEGINNING TO SHOW THE EVIDENCE OF DYSFUNCTION. THAT MIGHT BE A WONDERFUL BIOMARKER TO LOOK AT IN TERMS OF REAL OUTCOME. I THINK EVEN THOUGH MONEY IS LIMITED THAT IT MIGHT REALLY BE A VERY WORTHWHILE TO INVEST IN THIS WITH THE RIGHT INDIVIDUALS WHO HAVE THE TECHNICAL CAPABILITIES TO ANSWER THIS RATHER THAN JUST EMBARKING ON A MULTICENTER STUDY WHERE IT WOULD FOCUS ON A FEW MODALITIES AND A GOOD DATABASE. I THINK WHAT WE REALLY NEED HERE ARE MECHANISMS OF DISEASE TO GET AT THE REAL ISSUES OF PATHOPHYSIOLOGY, OTHERWISE WE'LL CONVENE AGAIN IN ANOTHER TEN YEARS AND WE'LL BE ASKING THE SAME QUESTIONS. >> THANK YOU. VERY INSIGHTFUL COMMENTS. >> MOSLEY, UNIVERSITY OF SOUTHERN CALIFORNIA. I THINK THAT A LOT OF THIS RESEARCH IS DEFINITELY, DEFINITELY NEEDED. BUT THE BIGGER PROBLEM RIGHT NOW IS HOW TO GETHE PRODUCT TO THE INDIVIDUALS. MY CLINIC COULDN'T PROBABLY PARTICIPATE IN A STUDY WITH ADULTS BECAUSE I ALWAYS HAVE THIS BREAK OF TWO WEEKS OR A MONTH WAITING FOR AUTHORIZATION TO GET THEIR PRODUCTS. SO IT'S A BIG PROBLEM WITH ADULTS IN CALIFORNIA AND ALL OVER THE NATION AND A LOT OF ADD LENTS TO DO DCH -- ADOLESCENTS, TOO. AND AS MUCH AS I WANT THIS RESEARCH TO HAPPEN, WE NEED HELP FROM THE NIH OR THE F.D.A. OR WHATEVER TO TRY TO GET THE PRODUCTS TO THESE INDIVIDUALS SO THAT WE CAN GET GOOD STUDIES. [APPLAUSE] >> SO BASICALLY IN ADDITION TO THERE BEING A RESEARCH GAP AND THE RESEARCH WE NEED TO DO, THERE ARE PROCESS ISSUES WE NEED TO IDENTIFY IN THIS TO SUPPORT BOTH OF THOSE. AND I JUST WANT TO MAKE A COMMENT ABOUT THAT. I KNOW MANY OF YOU ARE INVOLVED IN -- HAVE BEEN INVOLVED WITH REGARD TO SOME OF THE ESSENTIAL HEALTH BENEFITS, ASPECTS OF THE AFFORDABLE CARE ACT AND NIH IS NOT ALLOWED TO LOBBY THE GOVERNMENT BECAUSE WE ARE PART OF THE GOVERNMENT. THIS IS REALLY AN AREA WHERE WE FEEL YOUR PAIN AND SOMETIMES OUR¨oI HANDS ARE TIED. BUT I THINK THAT THE DIALOGUE NEEDS TO CONTINUE AND CONTINUE AND CONTINUE AND MAKE SURE THAT PEOPLE UNDERSTAND THE ISSUES. I THINK THAT KNOWLEDGE AND EDUCATION IS REALLY ESSENTIAL TO MOVE FORWARD WITH THESE AREAS ASPECTS OF ACCESS. RONNIE? >> ONE OF THE THINGS WE HAVE FAILED TO BRING UP SO FAR IS THE VALIDATION OF NUTRITION TOOLS WHEN WE COLLECT THE NUTRITION DATA. STILL THE WAY WE ARE COLLECTING THE INFORMATION HAS NOT BEEN VALIDATED AND I WOULD URGE THAT WE INVEST SOME RESOURCES IN DOING THAT BEFORE GATHERING DATA. AND SECOND PIECE I WANTED TO ECHO WHAT DR. BARRY JUST SAID IN TERMS OF UNDERLYING MECHANISMS IS ALSO INVESTING IN SOME OTHER MARKERS LIKE THE SEROTONIN AND DOPAMINE WHICH WOULD HELP US LEARN THE UNDERLINING MECHANISMS. >> AND RONNIE, DO YOU HAVE SPECIFIC IDEAS FOR METHODS TO VALIDATE SOME OF THE NUTRITION INTERVENTIONS? >> I THINK WE NEED TO STANDARDIZED THE -- STANDARDIZE THE TOOL WE ARE USING FOR DATA ANALYSIS, WHICH IS THE NATIONAL DATA TOOL WHICH IS USED FOR RIP. I THINK WE NEED TO VALIDATE THAT AND THE THREE-DAY DIET RECORDS USING THAT METHOD VERSUS FOOD FREQUENCY AND WITH THE LARGER SAMPLE SIZE TO ENSURE THAT THE DATA COLLECTED. >> SPEAKING OF DIET RECORDS, I WANT TO MAKE A COMMENT. I DON'T REMEMBER WHICH CONFERENCE I WAS ATTENDING BUT SOMEONE TALKED ABOUT ONE WAY TO REALLY GET AT DIETARY RECORDS IS TO HAVE PARTICULARLY FOR ADOLESCENTS AND YOUNG ADULTS WHO HAVE THEIR CELL PHONES WITH THEM ALL THE TIME IS HAVE THEM TAKE A PHOTO OF THE MEAL THEY ARE ABOUT TO EAT AND AFTER THEY ARE DONE AND SEND THAT QUICKLY AS A RECORD TO THE DIETICIAN. IT WOULD CERTAINLY TAKE ADVANTAGE OF MEDIA AND MIGHT BE SOMETHING APPEALING TO THE GENERATION. >> I THINK WE SHOULD BE THINKING ALONG THOSE LINES IN TERMS OF TECHNOLOGY FOR FUTURE DATA COLLECTION. WE SHOULD BE RIGHT THERE. >> PICTURES -- A PICTURE IS WORTH A THOUSAND WORDS, RIGHT? >> THE IPHONE APP WOULD DO THE ANALYSIS FOR YOU. >> THERE YOU GO. >> I WANT TO GO BACK TO YOUR COMMENT ABOUT NOT BEING ABLE TO LOBBY BECAUSE OF THE POSITION YOU'RE IN. HOWEVER, YOU CAN TRY TO CHOOSE TO NOT DO HARM AND I AM VERY MUCH WORRIED THAT WHEN WE POINT OUT ALL THE GAPS IN THE KNOWLEDGE THAT THAT'S NOT HELPING OUR CASE FOR GETTING UNIFORM COVERAGE OF WHAT WE KNOW WORKS AND I DON'T KNOW HOW TO PREVENT THAT. BUT THAT'S A BIG CONCERN FOR ME. >> AND I THINK BOTH IN THE ARC REPORT AND IN THE DOCUMENTS THE CONSENSUS DEVELOPMENT CONFERENCE THAT PRODUCED PRODUCED THE DOCUMENT, I THINK WE DO NEED TO CERTAINLY CELEBRATE AND RECOGNIZE THE VALUE OF DIETARY INTERVENTION AND THE VALUE OF THE NEWER THERAPEUTIC INTERCONVINCINGS SUCH AS SAPARTAR TWRAN BECAUSE THAT ACTUALLY IS VERY IMPORTANT. YOU'RE RIGHT. WE DON'T WANT TO BE NEGATIVE ABOUT THIS. WE DEFINITELY NEED TO PAINT -- WE HAVE TO CELEBRATE THE POSITIVE AFFECTS -- ASPECTS BUT RECOGNIZE THERE IS STILL WORK TO BE DONE AND AGAIN IT'S FINDING THAT RIGHT BALANCE. >> CAROL, I HOPE YOU DON'T MIND. YOUNG FERGUSON. I DIRECTED THE CONSENSUS PROGRAM HERE FOR 11 YEARS. I'D LIKE TO SAY THAT EVEN THOUGH WE ALWAYS TOLD OUR PANELS NOT TO ADVISE OTHER GOVERNMENT AGENCIES WHAT TO DO, THERE WERE THREE TIMES WHERE THE PANEL DECIDED THAT THEY WANTED TO DO THAT ANYWAY AND THEY DID MAKE RECOMMENDATIONS TO BOTH HIPSA, AT THE TIME CMS NOW AND TO THE F.D.A.. SO IT'S HAPPENED BEFORE. I THINK FOR ANY OF THE PANELS. IT CAME CLOSE. AFTER THE CONSENSUS CONFERENCE ON LIVER TRANSPLANTATION, WHICH THE PANEL WORKED VERY WELL. IT TOOK ABOUT A YEAR AND THEN CMS STARTED TO PAY FOR LIVER TRANSPLANTS. SO IT DOES HAPPEN. >> THANK YOU. CAROL? >> FIM, YOU ASKED A -- FIRST OF ALL, YOU ASKED A QUESTION AT THE BEGINNING. DID YOUR QUESTIONS CAPTURE ANOTHER BIG GAP AND I'D LIKE TO START BY SAYING I THINK YOUR QUESTIONSoL YOUR FOUR QUESTIONS REALLY COVER IT VERY WELL AND IT SOUNDS LIKE YOU'RE ASKING FOR HOW TO HONE IN ON THEM. >> I THINK WE MISSED SOME IMPORTANT ELEMENTS. >> SORT OF RELATED TO WHAT WEIBE BEEN TALKING ABOUT. IF YOU GO BACK TO YOUR QUESTION FOUR, WHICH I THINK IS A RATHER IMPORTANT ONE, FIRST OF ALL, WHEN YOU ARE DOING THE REPORTS AND OBVIOUSLY YOU ARE GOING TO HAVE AN OPPORTUNITY TO SAY THAT A RECURRING THEME WAS THAT WE WANT SOMETHING BETTER THAN DIET BUT WHEN PEOPLE COMPLY WITH DIET, IT WORKS. SO IT'S A HUGE SUCCESS STORY AND YOU HAVE AN OPPORTUNITY TO AFFIRM THAT. IN YOUR QUESTION NUMBER FOUR, I THINK ONE OF THE STUDIES I PERSONALLY WOULD LIKE TO SEE IS TO LOOK AT THE SERVICE DELIVERY AND COMPARE WITH OTHER COUNTRIES AND LOOK AT ACCESS. DO PEOPLE WHO HAVE ACCESS HAVE BETTER OUTCOMES? DO PEOPLE BY DEFINITION HAVE ACCESS IN COUNTRIES WHERE ACCESS IS JUST UNIFORMLY THERE? HAVE BETTER OUTCOMES? I THINK WE SERM THINK THEY HAVE BETTER -- ONLY 30 OF OURS ARE COMING TO CLINIC. AND THEN WE CAN EXPLORE WHATEVER THE FACTORS THAT, IF ALL OTHER THINGS ARE EQUAL, THEN WHAT ARE THE FACTORS THAT AFFECT COMPLIANCE? THAT'S ONE. AND I THINK THAT SITS VERY NICELY INTO YOUR NUMBER FOUR AND THAT'S A STUDY THAT CAN BE DONE, COULD BE FUNDED, COULD BE COLLABORATIVE. I SUSPECT THE PKU ALLIANCE COULD PLAY A KEY ROLE AND CERTAINLY MGCI BUT I'D BE SHOCKED IF THEY WEREN'T HAPPY TO HELP. WITH THAT SAID, ANOTHER THING I THINK I WOULD LIKE TO SEE AS A TOOL FOR GETTING A LOT OF THIS DONE IS I THINK WE NEED SOMETHING ON THE ORDER OF GUIDELINES, BUT THIS EPIPHANY I HAD, IF WE COULD PLEASE TRY TO MAKE THE GUIDELINES -- THIS IS THE NUMBER OR THIS IS THE TOOL BUT SOME FLEXIBILITY, SOME -- THIS IS THE CEILING AND THIS IS THE FLOOR AND WITHIN THERE YOU HAVE TO CHOOSE AND MAKE SOME PROVISION SO THAT WE CAN COMPARE ACROSS CLINICS BUT WITH ENOUGH FLEXIBILITY SO THAT WE CAN EACH MAKE IT WORK FOR EACH INDIVIDUAL PATIENT AND SHRINK AND STILL BE ABLE TO COMPARE A CLINIC. BUT IF WE DON'T HAVE FLEXIBILITY IN THERE, WE'RE JUST GOING TO IGNORE THE GUIDELINES. SO GUIDELINES WOULD BE USEFUL WITH SOME FLEXIBILITY AND I AM SURE -- I KNOW GMDI ARE WORKING ON GUIDELINES. AND DIET GUIDELINES AND IF THERE IS ANY WAY THAT THE FEDERAL AGENCIES CAN HELP FACILITATE THAT, REALIZING THAT IT MAY BE A CLINICAL GUIDELINE BUT IT'S GOING TO BE A REMEMBER PORN RESEARCH TOOL. >> -- IMPORTANT RESEARCH TOOL. >> THANK YOU. I WANTED TO MAKE MY COMMENT AND ASK A QUESTION. I THINK THAT WE REALLY SEE THE IMPORTANCE OF UPDATING THE GUIDELINES AND I THINK WE APPRECIATE THE NEED TO HAVE SOME SORT OF FLEXIBILITY. AND I THINK THAT EFFORTS ARE ALREADY UNDER WAY TO BRING THOSE GROUPS TOGETHER, BOTH THROUGH MDI AND ANY OTHER GROUPS THAT WANT TO WEIGH IN BECAUSE I THINK THE VALUE IN HAVING GUIDELINES IS PARTIALLY THE WEIGHT THAT IS PUT BEHIND IT AND THE NUMBER OF GROUPS THAT AGREE THAT THIS IS VALUABLE. SOUNDS LIKE WE MAY EVEN GET THE CANADAIANS ON BOARD, TOO. AND PARTNER WITH OUR EUROPEAN COLLEAGUES AS WELL. SO I THINK WE'RE HEARING THE MESSAGES THAT ARE COMING ACROSS AND WE WILL CERTAINLY DO WHAT WE CAN AT NIH TO FACILITATE BRINGING THE APPROPRIATE PARTIES TOGETHER EVEN THOUGH WE ARE NOT OFFICIALLY IN THE DOMAIN OF ISSUING GUIDELINES. AND I WANTED TO ASK MELISSA IF SHE HAD ANY ADDITIONAL COMMENTS ABOUT THIS ISSUE OF SOCIAL SUPPORT SYSTEMS IN RESEARCH THAT CAN ADDRESS THIS AND IF YOU HAVE ANY THOUGHTS FROM HAVING RECEIVED LITERATURE NOT ONLY FOR PKU REPORTS THAT MIGHT HELP SOME OF THE INVESTIGATORS HERE IN DESIGNING STUDIES TO LOOK AT THOSE ACCESS THEM AND HOW TO STUDY THOSE IN ROBUST WAYS? >> SURE. WHEN WE STARTED THE PROJECT FOR THE REVIEW, THAT WAS ONE OF MY FIRST QUESTIONS, ACTUALLY, WAS DO WE NEED TO INCLUDE THIS REVIEW IN THE REPORT-TYPE INTERVENTION? IT ENDED UP BEING NOT ONE OF THE KEY QUESTIONS BUT I LOOK THE LIBERTY TO LOOK AT THE LITERATURE BECAUSE I WAS INTERESTED AND THERE WASN'T A LOT OF SOLID INTERVENTION-TYPE RESEARCH. CLEARLY A RECOGNITION FOR PREGNANT WOMEN, ESPECIALLY AS THE NEED TOR THAT TYPE. I THINK THAT THAT BRINGS A GREAT OPPORTUNITY TO DO WHAT THIS GROUP DOES REALLY WELL, WHICH IS REACH BEYOND TRADITIONAL BOUNDARIES OF I AM A DIETICIAN AND I DO THIS TYPE OF IT RESEARCH AND I HAVE I AM A PHYSICIAN BUT TO ALSO REACH OUT TO OUR SPECIAL COLLEAGUES WHO HAVE A LOT OF EXPERIENCE IN DOING RESEARCH AROUND THINGS LIKE SOCIAL SUPPORT, SOCIAL NETWORK AND HOW THAT WORKS AND HOW THAT SUPPORTS AND THAT'S A TREMENDOUS OPPORTUNITY ESPECIALLY FOR A POPULATION WORKING IN A RARE DISEASE. THAT WOULD BE MY SUGGESTION AND ENCOURAGEMENT AND I THINK THAT WOULD BE REALLY EXCITING. >> JUST WONDERING IF -- >> WHEN I LOOK ACROSS TO THE EDUCATION SECTOR, AND OF COURSE THE PSYCHOLOGY COLLEAGUES, THEY CAN GIVE US GREAT INSIGHTS INTO STUDY DESIGN AND HOW TO DO THAT. >> WE'RE GOING FOALLOW CAROL TO INTERJECT ONE MORE TIME. >> SORRY. I THINK THAT'S GREAT AND -- BUT YOU CAN REACH OUT VIA TWITTER AND FACEBOOK AND WHATEVER IF YOU ARE ALLOWED TO AND ENCOURAGE PEOPLE TO COME BACK TO KPLIPG PARTICIPATE. BUT CLINIC BUMENT IF THEY DON'T HAVE -- BUT IF THEY DON'T HAVE INSURANCE, THAT DOESN'T DO MUCH. THAT'S TERRIFIC AND I'D BE INTERESTED TO BE INVOLVED BUT I AM STILL THINKING BASICALLY LET'S COMPARE TO US ENGLAND OR LET'S COMPARE PATIENTS WHO HAVE INSURANCE, WHO DON'T HAVE INSURANCE AND GET GOOD OUTCOME STUDIES. I AM MEANING, DO YOU HAVE INSURANCE? DO YOU HAVE A CLINIC? >> THAT'S A QUESTION OF WORKING WITH OUR HEALTH POLICY FOLKS. AND DO REALLY STRONG HEALTH SERVICES RESEARCH AND I THINK THAT'S GREAT WITH YET ANOTHER PART OF OUR FRAMEWORK, WHICH IS A HEALTH SERVICES RESEARCH KIND OF AGENDA. >> MY COMMENT WAS ABOUT THIS DILEMMA AS WELL. WE IN THE FIELD OF MEDICAL DISEASE ARE A RELATIVELY SMALL GROUP AND WE TEND TO DO THINGS IN AN ISOLATED WAY. BUT IT IS SO DEPRESSING, AND IT'S SO DIFFICULT TO FACE THOSE PATIENTS IN THE CLINIC. IF THE ADULT COMES IN AND THEY DON'T HAVE THE MONEY TO GET THE FOOD, THEY DON'T KNOW WHAT TO DO. WE DON'T HAVE THE ANSWER. WE FEEL LIKE A FOOL WHEN THIS GOES ON AND IT'S EVEN WORSE WHEN IT'S A PREGNANT WOMAN. MAYBE WE'RE NOT PARTNERING WITH THE RIGHT -- WITH THE RIGHT AGENCIES. WHAT I AM THINKING ABOUT IS MAYBE IT'S WRONG FOR US TO GO THIS ALONE WITH REGARD TO PATIENTS WITH PKU. PEABODY WE SHOULD LOIN OURSELVES WITH SOME OTHER TYPE OF AGENCY AND TRY TO CHANGE THE NATURE OF WHAT -- THIS IS A CHRONIC DISEASE SO WHY SHOULD THE PATIENTS WITH CYSTIC FIBROSIS WHO SEEM TO HAVE MORE SUPPORT -- WHY SHOULD THEY GET BETTER TREATMENT AND GET MORE FUNDS THAN THE PATIENTS WITH PKU? ARE WE MAKING A MISTAKE IN THE WAY THAT WE ALIGN OURSELVES? IS THERE SOMETHING NOVEL THAT WE CAN DO BETTER? JUST COMPLETELY UNEXPECTED. SOMETHING THAT DOESN'T FIT WELL BUT IT WORKS BECAUSE I THINK REALLY WHAT WE NEED TO DO IS WE NEED TO GET THE PATIENTS THE MEDICAL FOOD AND BE ABLE TO TREAT THE PREGNANT WOMAN PROPERLY. NO MATTER WHAT IT TAKES TO DO IT. EVEN IF IT MEANS MOVING OUTSIDE OF OUR FIELD. ARE THERE SOME THOUGHTS ABOUT THIS OR NOVEL THINGS THAT WE COULD DO? >> WHAT I WAS TRYING TO SAY ALONG SIMILAR LINES 10 TO 15 YEARS AGO, PKU RESEARCH [INDISCERNABLE] EVEN OUTCOME OF H.R.Q AND THERE TRULY IS A RESEARCH NEED. OBVIOUSLY, STUDY SECTIONS WOULD HAVE TO CHANGE THEIR OPINION ALSO, RIGHT? BECAUSE IF YOU SAY THERE IS A RESEARCH NEED STILL NOT MOVE FORWARD AND YOUNG PEOPLE THAT HOPE TO MOVE -- YOUR RESEARCH WILL STILL FALTER AND NOT SUCCEED AND TURN SOMEWHERE ELSE. AND CERTAINLY ANOTHER THEME IS RARE DISEASE RESEARCH. NICHD LUCKILY OR DOES UNDERSTAND THAT RARE DISEASES NEED RESEARCH BUT THERE IS ALSO ALWAYS THE PEOPLE WHO DO RESEARCH ON RARE DISEASES HAVE TO DEPEND WHY THEY THINK THAT SO MUCH MONEY IS SUPPOSED TO BE ATTRIBUTED TO SUCH QUOTE UNQUOTE SMALL POPULATION OF PATIENTS. MAYBE ALIGNING WITH A TOTALLY DIFFERENT GROUP AND SAYING WE ARE THE MODEL SYSTEM, TAKE US IN IS ONE WAY TO GO. BUT IN REALITY, WE ARE FACING ALL THOSE ISSUES WHEN WE ARE APPLYING FOR GRANTS TO ANSWER BASIC RESEARCH QUESTIONS. >> THE MAJORITY OF NIH FUNDING GOES TO INVESTIGATE OR-INITIATED PROPOSALS, AND SO THAT MEANS THAT WE CAN DO WHAT WE CAN TO SOLICIT PARTICULAR TYPES OF PROPOSALS BUT IT'S STILL THE INVESTIGATORS WHO ARE COMING UP WITH THE HIGHEST QUALITY, THE MOST ROBUST STUDIES THAT FOR THE MOST PART GET FUNDED. AND SO JUST WANT TO ENCOURAGE YOU TO CONTINUE TO MAKE YOUR CASE FOR WHY IT'S IMPORTANT THAT WE FUND IT AND TO CONTINUE TO WRITE QUALITY APPLICATIONS. BUT I ALSO THINK THAT NIH IS NOT THE ONLY SOURCE OF FUNDING FOR STUDIES OF THIS NATURE AND THAT THERE ARE OTHER WAYS IN WHICH TO SUPPORT RESEARCH IN SOME OF THESE SCIENCES AS WELL AS APPLY IN SERVICES-ORIENTED ARENAS. >> I THINK YOU HIT IT RIGHT ON THE HEAD THAT THIS CONFERENCE, THE EPC REPORT, PRODUCTS LIKE THAT AND FUTURE RESEARCH NEEDS PRODUCT THAT WE'LL BE CREATING ARE OPPORTUNITIES AND TOOLS TO CELEBRATE WHAT IS POSITIVE AND THE GREAT RESEARCH THAT IS THERE AND ALSO TO POINT OUT THE RESEARCH AGENDA AND MAYBE TO PROVIDE RESEARCHERS WITH A BACKGROUND PIECE TO POINT TO TO SAY THIS IS CLEARLY A NEED AND IT'S BEEN LAID OUT IN A VERY SYSTEMATIC WAY TO SUPPORT THE GRANT APPLICATIONS. >> CHRISTINE BROWN AND MOTHER OF TWO CHILDREN WITH PKU. AND I KNOW THAT WE'VE BEEN TALKING ABOUT THESE ISSUES AND WHAT IS ON THE GROUND AND WHAT IS THE REALITY FOR CHILDREN AND ADULTS LIVING WITH PKU IN THIS COUNTRY, AND I WANT TO GIVE YOU THE VOICE OF WHAT I HEAR FROM OUR COMMUNITY AND GIVING YOU VOTES. WHEN WE WERE LOOKING AT PUTTING TOGETHER A NATIONAL CONFERENCE IN DECIDING ON WHAT TOPICS WE WERE GOING TO ADDRESS AT OUR CONFERENCE, WE DID A SURVEY OF THE COMMUNITY TO SEE WHAT THEY WANTED TO HEAR ABOUT, WHAT WERE THEIR CONCERNS AND TOOLS DID THEY NEED IN ORDER TO MANAGE THEIR PKU BETTER? AND I'M AMAZED THAT THE BIGGEST RESPONSE WAS PKU TREATMENT UPDATES. BUT INSURANCE RIM BRURMENT ISSUES -- REIMBURSEMENT ISSUES RANK HIGHER THAN DIET MANAGEMENT, RESEARCH FOR A CURE, NEUROCOGNITIVE ISSUES, BONE DENSITY, MATERNAL PKU -- EVERYTHING. INSURANCE REIMBURSEMENT WAS OUR SECOND MOST REQUESTED TOPIC. THE REALITY AND THE VOICE THAT I KNOW ALL OF YOU KNOW SO WELL FROM THE PATIENTS IS RESEARCH AND INNOVATION ARE WONDERFUL, BUT IF YOU CAN'T HAVE ACCESS BECAUSE YOU CAN'T GET SOMEONE TO PAY FOR IT, IT'S NOT REALLY HELPING THE PEOPLE THAT YOU ARE TRYING TO HELP. >> THANK YOU. >> THANK YOU SO MUCH FOR THAT. I WOULD SAY THERE IS A RESEARCH AGENDA TO BE HAD AROUND ACCESS AND HEALTH SERVICES RESEARCH AND IT'S DOING THAT KIND OF RIGOROUS RESEARCH THAT GIVES YOU THE INFORMATION THAT YOU NEED TO ACTUALLY MAKE CHANGES HAPPEN. >> I JUST WANT TO BRING UP SOMETHING THAT I HEARD FROM ONE OF MY COLLEAGUES SITTING NEAR ME THAT MAKES A WHOLE LOT OF SENSE. ONE REASON WHY WE'RE HAVING PROBLEMS IS REIMBURSEMENT OF MEDICAL FORMULA IS BECAUSE -- I DON'T WANT TO STIR UP -- IT'S BECAUSE IT'S A MEDICAL FORMULA AND I DON'T REALLY UNDERSTAND A WHOLE LOT ABOUT IT, BUT ISN'T IT MEDICINE? THERE IS A HUGE DISCONNECT BETWEEN THE NECESSITY OF MEDICAL FORMULA AND FOOD AS FAR AS THE INSURANCE COMPANIES ARE CONCERNED. AND THAT'S SOMETHING WE GOT TO GET THROUGH. THE OTHER PROBLEM THAT IS VERY SEVERE IS THAT EVEN THOUGH WE TRY TO RALLY THE TROOPS -- AND THERE ARE LOT OF FAMILIES THAT ARE ACTIVE IN THIS AREA -- IT IS VERY TRUE THAT THIS IS VERY TIME TIME-CONSUMING AND THESE FAMILIES ARE ALREADY OVERLOADED. SO THAT'S ANOTHER REASON WHY WE NEED HELP. SO THINK ABOUT THAT. I DON'T THINK THERE IS ANY BETTER WORD OR TERM FOR MEDICAL FORMULA, IN MY OPINION. BUT THAT'S GONE THROUGH SEVERAL GENERATIONS, AND AGAIN, IT SUPPORTS THE FACT THAT THIS IS ONE OF THE MAIN PROBLEMS IS REIMBURSEMENT OF MEDICAL FORMULA AND OTHER THINGS RELATED TO PKU. >> MIKE? >> MIKE WATSON FROMACK MG. IN RESPONSE TO BOTH JERRY AND CAROL, I THINK WE'RE VICTIMS PROBABLY OF A POLITICAL PROBLEM. THERE ARE HALF A DOZEN DISEASES, VERY SPECIFICALLY NAMED IN LEGISLATION. THEY HAVE CENTERS THAT BUILD ALL THE SAME KINDS OF TOOLS THAT WE NEED FOR THE OTHER 6,900 DISEASES AND I BET HALF OF THE PEOPLE IN THIS ROOM WOULD BE AT ANY OTHER NUMBER OF MEETINGS LIKE THIS. BUT THIS WHOLE IDEA OF BUILDING THE TOOLS AND RESOURCES THAT ALLOW US TO SUPPORT RESEARCH ACROSS A BROAD RANGE OF THINGS THAT WOULD ACCOMMODATE PKU AND MANY OTHER DISEASES IS I THINK CENTRAL TO THE PROBLEM. AND SO THINKING MUCH MORE ABOUT THOSE KINDS OF SYSTEMS AND TOOLS THAT SUPPORT ALL THESE RARE DISEASES OR AT LEAST A LARGE NUMBER OF THEM IS REALLY SOMETHING WE SHOULD FOCUS ON AND I DON'T KNOW IF IT CAN BE SAID IN REPORTS LIKE THIS, BUT GETTING AWAY FROM THE ONE DISEASE, GETTING AUTHORIZATION LANGUAGE AND VAST RESOURCES, WHICH IS WHAT HAPPENED WITH THE SITIC FIBROSIS AND OTHERS AND LOOKING AT THIS BROAD RANGE OF THE OTHER 6,990 DISEASES I THINK IS WHERE WE HAVE TO PUT A LOT OF FOCUS. FIXING PKU WOULD BE WONDERFUL. BUT DEALING WITH THE BROAD RANGE OF THEM WOULD BE EVEN BETTER I THINK. >> LET ME ASK YOU ONE QUESTION IN FOLLOWUP TO THAT. AS WE MOVE FORWARD IN OUR FUTURE RESEARCH FEPDS NEEDS AGENDA AND GATHER MORE INFORMATION, IT SOUNDS LIKE WE'VE TALKED ABOUT IDENTIFYING WHAT ARE THE GAPS AND ISSUES AND IT WOULD BE HELPFUL TO IDENTIFY WHAT IS FUK SKPEK WHAT MIGHT BE SORT OF CROSS-CONDITION? WILL THAT BE A HELPFUL THING IN THIS? >> YEAH. THAT'S REALLY THE CENTRAL PROBLEM. I HAVE A BIAS IN THAT I DIRECT THE NEWBORN SCREENING TRANSLATIONAL NETWORK FOR NICHD THAT'S TRYING TO BUILD DATABASES, IT, INFORMATICS AND THINGS THAT SUPPORT THESE KINDS OF RESEARCH. YOU HEAR ABOUT THE OTHER KINDS OF NATIONAL COOPERATIVE GROUPS THAT GET AT THIS DINED OF STUFF AND THEY COMPETE FOR INDIVIDUAL EXPERTS THAT MIGHT DEAL WITH THE SPECIFIC ISSUES THAT YOU MIGHT NEED FOR CERTAIN KINDS OF STUDIES THAT CAN DRAW THE VERY BEST PEOPLE IN BUT THEY TEND TO HAVE THE CENTRAL CORES OF PEOPLE WHO ARE AT THE LEVEL TO TALK ABOUT. LUMENTLY WHEREVER THE DATA COMES FROM, THERE IS A SUBSET OF PEOPLE WOEVALUATE THAT DATA, MAKE RECOMMENDATIONS BASED ON IT AND SORT OF THE GOOD NEWS AND THE BAD NEWS IS THERE IS VERY FEW PEOPLE IN THE METABOLIC FIELD AND YOU COULD PROBABLY DIVIDE 150 OF THEM UP IN THE UNITED STATES AND PUT THEM ALL TO WORK IN THESE KINDS OF STUDIES. IT WILL BE HARD TON OVERBURDEN THEM. BUT I THINK SPREADING THEM OUT INSTEAD OF CENTRALLY FOCUSING ON A SINGLE DISEASE WOULD BE THE KEY. I WOULD LOOK HARD ACROSS NOT JUST THE THINGS THAT NIH ARE BUILDING BUT LOOK AT THE BROADER RANGE OF THINGS THAT ARE GOING TO BE NEEDED TO SUPPORT THIS KIND OF RESEARCH. >> AND I THINK JUST TO BUILD UPON THAT, THERE IS A REAL EFFORT TO DEVELOP COMMON DATA ELEMENTS TO RARE DISEASES. RESEARCH HAS BEEN ENGAGED IN WITH REGARD TO BUILDING THE REGISTRY AND I THINK THERE IS POWER IN NUMBERS. THERE ARE CERTAIN COMMON THEMES AND CERTAIN ELEMENTS THAT CAN REALLY BENEFIT FROM LEVERAGING SOME OF THOSE RESOURCES THAT COULD BE AFFORDED TO THE RARE DISEASE COMMUNITY AS A WHOLE. SO I THINK IT'S IMPORTANT TO KEEP THOSE THINGS IN MIND. CAROL AND THEN KATHY AND WE'RE GOING TO CLOSE. WE'RE ALMOST DONE. >> THERE IS A LOT OF EFFORTS AND THAT WOULD BE WONDERFUL AND ANOTHER THING TO SOME EXCEPT ALREADY IN PROGRESS IS A BIG BARRIER THAT H HMS COULD HELP WITH AND THAT'S THE PROBLEM OF MULTIPLE IRBS AND I KNOW THERE IS A BIG MPR FOR HUMAN SUBJECTS PROTECTION, BUT TO HAVE TO TAKE EVERYTHING THROUGH EVERYBODY'S IRB TAKES ABOUT A YEAR AND A HALF TO TWO YEARS TO GET A MULTICENTER PROJECT OFF THE GROUND AND THAT IS A BIG PROBLEM THAT YOU GUYS COULD HELP SOLVE. HHS. >> AND NICHD IS DEVELOPING SOME FEDERATED MODELS AND THERE IS REAL HOPE THAT THAT SORT OF FRAMEWORK AND MODEL WILL BE INCORPORATED MORE BROADLY SO THANK YOU FOR RAISING THAT. >> I WANTED TO MENTION THAT THE NIH IS ALSO WORKING ON ANOTHER INITIATIVE THAT INCLUDES SOME OF THE COMPONENTS THAT DR. WATSON MENTIONED REGARDING NUTRITION AND DIETARY SUPPLEMENT AND SOME OF YOU IN THIS ROOM ATTENDED OUR WORKSHOP IN DECEMBER AND WE ARE MOVING FORWARD WITH THE STRUCTURE FOR THAT INITIATIVE AND YOU WILL BE HEARING FROM US AGAIN. WE WILL -- WE ARE HOPING AND EXPECTING THAT THE METABOLIC COMMUNITY WILL STEP UP TO THE PLATE WITH SOLVING SOME OF THESE VERY CRITICAL ISSUES. I WANTED TO REMIND PEOPLE OF THAT INITIATIVE THAT'S ONGOING. THANKS. >> AND THIS INITIATIVE HAS ITS OWN ACRONYM. NUTRITIONAL AND DIETARY SUPPLEMENTS FOR INBURN METABOLISM AND MANY OF YOU ARE ENGAGED IN THOSE ACTIVITIES, TOO. ANOTHER EFFORT TO BRING PEOPLE TOGETHER AROUND COMMON THEMES. THIS IS GOING TO CLOSE OUR CONFERENCE ON PKU. I WANT TO THANK EVERYBODY FOR COMING, FOR BEING SO ENGAGED AND SO ENERGIZING AND CONTRIBUTING TO THE REALLY RICH DISCUSSION. WE HAVE A LOT NOW TO WORK WITH IN PULLING THIS ALL TOGETHER FOR PUBLICATIONS AND FOR NEXT STEPS AND BELIEVE ME THERE WILL BE NEXT STEPS. MANY OF YOU WILL BE HEARING FROM ME OR OTHERS. THIS PLEASE BE OPEN AND BE WILLING TO REVIEW THINGS FOR US AND GIVE US FEEDBACK. WE SERM WOULD APPRECIATE THAT. A PHYM THANK YOU TO OUR CONFERENCE PLANNERS. THE LADIES WHO SAT OUT AT THE DESK IN FRONT DID A FANTASTIC JOB OF BRINGING US ALL TOGETHER SO WE OWE THEM A HUGE DEBT OF GRATITUDE. [APPLAUSE] THANK YOU. A THANK YOU TO OUR AV TEAM. YOU PROBABLY DIDN'T SEE MUCH BUT BELIEVE ME. HE KEPT EVERYTHING MOVING SMOOTHLY AND A THANK YOU FOR THE WORKING GROUP MEMBERS, COCHAIRS AND THE FIVE COORDINATORS THAT I'VE WORKED WITH SO CLOSELY OVER THE LAST FIVE YEARS AND THANK YOU SO MUCH. OUR FURNDS, NICHD ANDODS. EVERYBODY, SAFE TRAVELS AND GOOD LUCK AND KEEP THE FAITH. [APPLAUSE]