>> GOOD AFTERNOON AND WELCOME TO OUR OPEN SESSION OF THE ADVISORY SUBCOMMITTEE. IT'S REALLY A PLEASURE TODAY TO TALK ON THE TOPIC OF IMPORTANT INTEREST FOR OUR TRANSPLANTATION PROGRAM TO BE REVIEWED FROM A VARIETY OF PERSPECTIVES. I WANT TO MAKE A COUPLE OF COMMENTS ABOUT THE DIVISION. THOSE OF YOU WHO WERE AT THE OPENING SESSION OF COUNCIL, HEARD DR. FAUCI MENTION THE RETIREMENT OF DR. PLAUTS? IT WAS A REAL PLEASURE WORKING WITH MARSHAL OVER THE YEARS AND AS YOU HEARD, HE WAS IN GOVERNMENT SERVICE FOR 27 YEARS AT NIH AND YEARS AT CDC, BRINGING UP TO 30 YEARS OF BRINGING HIS EXPERTISE TO MANY IMPORTANT PROBLEMS IN ALLERGY AND IMMUNOLOGY. SO IT'S WITH SOME REGRET THAT WE HAD TO SAY GOODBYE TO MARSHAL BUT HE WILL BE CONTINUING WITH US PART-TIME AS A DIRECTOR AND WE'LL LOOK FORWARD TO THOSE FUTURE INTERACTIONS THE SESSION WE HAD PLANNED FOR THIS AFTERNOON IS GOING TO FOCUS ON BRINGING THERAPEUTICS TO THE CLINIC, AND NANCY BRIDGES WAS GOING TO SPEAK ON HUMAN TRANSPLANTATION, BRINGING A CELLULAR THERAPY TO THE CLINIC. SHE UNFORTUNATELY, IS NOT ABLE TO BE HERE TODAY. JONAH ODOM HAS AGREED TO GIVE A SIMILAR OVERVIEW BUT WITH A SLIGHTLY BROADER FOCUS AT A HIGH LEVEL, ON WHAT THE INSTITUTE IS DOING IN CELLULAR THERAPEUTICS IN GENERAL. T-REGS, DC REGS, E-REGS, MESENCHYMAL STEM CELLS AND OTHER APPROACHES, AND IN A VARIETY OF CLINICAL TRIALS THAT YOU'LL HEAR ABOUT. FOLLOWING THAT, BERNARD HERRING WILL BE TALKING ABOUT PHASE III TRIAL OF HUMAN ISLET TRANSPLANTATION THAT WAS COMPLETED SEVERAL YEARS AGO AND PUBLISHED. SOME MAJOR BREAKTHROUGHS CAME OF THAT TRIAL IN UNDERSTANDING HOW ISLET TRANSPLANTATION COULD BE SUCCESSFUL. AND JUST THIS YEAR, A FOLLOW-ON PAPER LOOKING AT SOME SECONDARY AIMS, WAS PUBLISHED SHOWING VERY STRIKING QUALITY OF LIFE IMPROVEMENTS USING SEVERAL VALIDATED INSTRUMENTS. AND THEN BRUCE SCHNEIDER WILL BE SPEAKING ABOUT REGULATORY CONSIDERATIONS IN CELL THERAPY TRIALS. AND JONAH WILL INTRODUCE BERNARD AND BRUCE IN A LITTLE MORE DETAIL THAN I HAVE ALREADY. FOLLOWING THAT, WE HAVE FIVE CONCEPT CLEARANCES FOR COUNCIL CONSIDERATION, AND HOPEFULLY WE'LL WRAP UP BY 3:30 ON TIME, AND THOSE OF YOU WHO HAVE TO CATCH FLIGHTS, SHOULDN'T HAVE ANY TROUBLE OTHER THAN WEATHER. SO, THANK YOU. WHILE JONAH IS COMING UP, I WANT TO MAKE ONE BRIEF COMMENT, WHICH IS THAT THIS IS THE TYPE OF WORK YOU'RE GOING TO HEAR ABOUT THIS AFTERNOON THAT REALLY REQUIRES AND EXEMPLIFIES THE THINGS THAT WE CAN DO WITH SET ASIDE DOLLARS FOCUSED ON A CHALLENGING CLINICAL PROBLEM THAT WOULD NEVER PROCEED AS SUCCESSFULLY WITHOUT THOSE DEDICATED RESEARCH DOLLARS AND THE DEDICATION OF NIH STAFF AND ACADEMIC INVESTIGATORS AND THE FDA, ALL WORKING COLLABORATIVELY TO MAKE SOMETHING HAPPEN THAT WOULDN'T OTHERWISE BE THE CASE. AND YOU'LL GET A SENSE OF THAT THIS AFTERNOON, BUT I DON'T THINK THAT WE CAN GO TOO FAR IN JUST THANKING AND COMMENDING THE PEOPLE WHO ARE INVOLVED IN THIS THROUGHOUT THE HHS AND ACADEMIA FOR BRINGING US TO THE POINT WE ARE AT NOW. >> JONAH: THANK YOU, DAN. CELL THERAPY REPRESENTS AN EXCITING AND EMERGING NEW AREA IN BASIC AND CLINICAL RESEARCH, TRANSPLANTATION PORTFOLIO. AND WHILE ORGAN TRANSPLANTATION HAS RESTORED HEALTH AND EXTENDED LIFE TO THOUSANDS OF OUR PATIENTS OVER THE LAST HALF CENTURY WITH END-STAGE ORGAN DISEASE, IT STILL HAS NOT PRESERVED NORMAL HEALTH OR NORMAL LIFE EXPECTANCY, LARGELY RELATED TO ON-GOING, SMOLDERING ALLOGRAFT INJURY, AS WELL AS THE TOXICITIES AND SIDE EFFECTS OF THE IMMUNOSUPPRESSIVE DRUGS. AND NEWER CELL THERAPY APPROACHES, WHICH PROMISE TO BE MORE TARGETED AND RELY ON LOCAL ENVIRONMENTAL NEEDS, HAVE THE POTENTIAL TO MINIMIZE IMMUNOSUPPRESSIVE DRUGS, PERHAPS ELIMINATING THEM, AND PROMOTING ALLOGRAFT TOLERANCE. HOWEVER, ONE OF THE MAJOR HURDLES IN TRANSLATING SOME OF THESE PROMISING PRE-CLINICAL RESEARCH IN ANIMAL STUDIES, IS COMING UP WITH A GMP CELL PRODUCT THAT CAN BE CONSISTENTLY CHARACTERIZED IN TERMS OF THE PHENOTYPE, THE POTENCY, REPRODUCIBILITY, AND SAFETY. AND FINALLY, WITH A CELL PRODUCT, HOW DOES ONE GET THIS TO LICENSURE AND TO OUR PATIENTS FOR THEIR BENEFITS? CLEARLY OVER THE LAST COUPLE OF DECADES, IMMUNOSUPPRESSIVE DRUGS ARE ESSENTIAL FOR SHORT-TERM GOOD EXCELLENT OUTCOMES WE SEE IN TRANSPLANTATION, BUT AT A TREMENDOUS COST IN TERMS OF THE LONG TERM, NOTABLY KIDNEY DAMAGE FROM THE NEVER TOXICITY OF THE DRUGS, ACCELERATEY CARDIOVASCULAR DISEASE, DIABETES AND ONGOING GRAFT INJURY THE NEWER DRUGS ARE NEEDED TO AVOID LONG TERM IMMUNOSUPPRESSION AND ACHIEVE ALLOGRAFT TOKERRANCE. SO AS A BRANCH, WE FEEL THESE GOALS, ALTHOUGH CHALLENGING, YET PROMISING TO PURSUE. IN THE REGULATORY T-CELL SPACE, IN BOTH KIDNEY AND LIVER TRANSPLANT RECIPIENTS, THERE ARE A NUMBER OF TRIALS LED BY SANDY FENG AND FLAVIO VINCENTE AT UCSF, LOOKING AT POLEY CLONAL AND DONOR-DERIVED ANTIGEN-SPECIFIC T-REGS AND OUTCOMES IN THIS POPULATION. DR. ALLAN KIRK IS ABOUT TO EMBARK ON SIMILAR TYPES OF TRIAL LOOKING AT MESENCHYMAL STROMAL CELLS IN THE KIDNEY CONTEXT. DR. ANGUS THOMPSON IS ALSO ABOUT TO EMBARK ON A TRIAL LOOKING AT REGULATORY DENDRITIC CELLS AS THE INDIGESTIONAL CELL PRODUCT IN ADULT KIDNEY TRANSPLANT POPULATIONS. SO THIS IS CERTAINLY A FAST AND EMERGING AREA FOR US IN THE CLINICAL SECTION AND THERE ARE BASIC INVESTIGATIONS IN OUR BASIC SECTION LOOKING AT PRE-CLINICAL MODELS OF CELLULAR THERAPY IN TRANSPLANTATION. NOW THIS AFTERNOON, THE PRIMARY FOCUS WILL ADDRESS ISLET CELL TRANSPLANTATION, NAMELY CELL THERAPY FOR TYPE I DIABETES, AND OUR SPEAKERS WILL HIGHLIGHT THE JOURNEY TOWARDS THIS FIRST NIAID-SUPPORTED CELL THERAPEUTIC APPROACH AND PRODUCT THAT IS NOW READY FOR LICENSURE, AND ULTIMATELY FOR PATIENTS. THE WORK WAS ACCOMPLISHED IN ONE OF OUR ESTABLISHED NETWORKS, THE CLINICAL ISLET TRANSPLANTATION CONSORTIUM, AND THIS HAS BEEN WORK THAT HAS OCCURRED OVER THE LAST 10 YEARS. DR. NANCY BRIDGES, THE TRANSPLANTATION BRANCH CHIEF, WAS INSTRUMENTAL IN DESIGNING THE TRIAL AND SERVED AS ITS MEDICAL MONITOR. TOM, ALONG WITH NANCY, WAS THE SCIENTIFIC CO-DIRECTOR OF THE CIT CONSORTIUM WHICH CONDUCTED EIGHT CLINICAL TRIALS. AND SPECIAL CONSIDERATION REALLY GOES TO ALISYN, THE PROJECT MANAGER FOR THIS EFFORT, FOR HER DAY-TO-DAY WORK, AND JULIA GOLDSTEIN AND CHRISTINE, WHO DIVIDES THE REGULATORY STRATEGY AND PARTICULARLY JULIA, WHO PROVIDED THE OVERSIGHT OF THE MANUFACTURING PROCESS. NOW PREPARING A LICENSE-ENABLING TRIAL WAS ESSENTIALLY NEW TERRITORY FOR US AT DAIT, REQUIRED HARMONIZING AND MANUFACTURING PROCESSES AMONG FOUR DIFFERENT MANUFACTURING SITES TO CREATE A COMMON MANUFACTURING PROTOCOL, THAT ALL THE SITES ADHERED TO. THERE WAS VALIDATION OF ALL THE REAGENTS USED IN THE MANUFACTURING PROCESS, AND THIS TOOK ACTUALLY A LITTLE OVER TWO YEARS BEFORE ONE COULD ACTUALLY BEGIN TO DO ANY WORK. ALL THE FACILITIES REQUIRED AUDITING AND THERE WAS ONGOING DIALOGUE WITH THE FDA ABOUT THE EVIDENCE REQUIRED FOR THIS TRIAL. I WOULD LIKE TO TURN OVER THE PODIUM TO THE MORE IMPORTANT SPEAKERS THIS AFTERNOON. OUR FIRST SPEAKER DR. BERNARD HERRING, IS PROFESSOR OF MEDICINE AND EXECUTIVE DIRECTOR OF THE SHULTZ DIABETES INSTITUTE AT THE UNIVERSITY OF MINNESOTA. HE WILL REVIEW THE CLINICAL TRIAL THAT LED TO THIS PRODUCT. HE IS ALSO THE LEADER OF THE CONSORTIUM WHO BROUGHT THIS EFFORT TO FRUITION. WE ARE VERY FORTUNATE TO HAVE AMONG US OUR FINAL SPEAKER AND DISCUSSANT, DR. BRUCE SCHNEIDER, FROM THE FDA, AND HE HAS A LONG-STANDING INTEREST IN THE DEVELOPMENT OF CELL THERAPIES, AND WE LOOK FORWARD TO HIS KEEN INSIGHT AND GUIDANCE RELATED TO THESE REGULATORY ISSUES. AND WITH THAT, I'LL ASK BERNARD TO COME UP AND TAKE IT AWAY. >> BERNARD: THANK YOU FOR THE PRIVILEGE OF PRESENTING THIS STUDY ON BEHALF OF THE CLINICAL ISLET TRANSPLANTATION CONSORTIUM. THIS HAS BEEN A TREMENDOUS COLLABORATIVE EFFORT AMONG ACADEMIC CENTERS AND WE REALLY APPRECIATE THE SUPPORT WE HAVE RECEIVED ALONG THE WAY, AND WE FEEL PROUD AS A GROUP TO HAVE VERY ACCOMPLISHED SOMETHING OUT OF ACADEMIC LABS WITHOUT INVOLVEMENT OF A COMPANY AND AN ARMY OF PROFESSIONALS THAT USUALLY TAKE ON SUCH A CHALLENGE. AND THE SUPPORT WE RECEIVED WAS NOT LIMITED TO FINANCIAL SUPPORT SUPPORT, BUT REGULATORY EXPERTISE AND MANUFACTURING EXPERTISE, AND EXPERTISE IN A NUMBER OF DIFFERENT AREAS, REALLY CONTRIBUTED TO THE OUTCOME OF THE STUDY. SO I WILL, ON BEHALF OF NANCY AND TOM AND THE ENTIRE CONSORTIUM, REVIEW THIS STUDY, AND CLINICAL AND QUALITY OF LIFE OUTCOMES OF HUMAN ISLET TRANSPLANTATION. I REPRESENT THE CONSORTIUM AND WE WILL ALSO TALK ABOUT SEVERE HYPOGLYCEMIA. THIS WAS THE INDICATION, AND THEN REALLY PRESENT IN DETAIL THE TRIAL AND AT THE END, DISCUSS BRIEFLY THE BIOLOGICS LOGICS APPLICATION AND IMPLICATIONS FOR SUBSEQUENT STUDIES. THE CONSORTIUM REALLY INCLUDED CLINICAL AND MANUFACTURING SITES HERE AND INSTITUTIONS IN NORTH AMERICA, AND ALSO OUR CLINICAL TRIALS CENTERS AND DATA MANAGEMENT CENTER AT THE UNIVERSITY OF IOWA. AND THE FIRST HALF WAS TO ESTABLISH PROCEDURES FOR MANUFACTURING OF A COMPLEX CELLULAR PRODUCT. AND EIGHT CENTERS CURRENTLY DEVELOPMENTED AND IMPLEMENTED A HARMONIZED PROCESS AND MANUFACTURING WAS CONTROLLED BY BATCH RECORD, STANDARD OF PROCEDURES, THAT INCLUDED ACCEPTANCE FOR ORGANS AND CRITICAL PRODUCT SPECIFICATIONS, CERTIFICATE OF ANALYSIS AND TEST METHODS. AND THE PROCESS WAS COMPLIANT WITH. AND THERE WAS NO ADVERSE EVENTS RECOGNIZED TO THE ATTRIBUTED PRODUCT AND NO CASES OF PRIMARY NON FUNCTION WERE OBSERVED IN ANY ONE OF THE 48 PATIENTS PARTICIPATING IN THIS STUDY REALLY INDICATING THAT THE MANUFACTURING PROCESS WAS WELL DEVELOPED. AND THIS WAS REPORTED TWO YEARS AGO IN DIABETES BY THE CONSORTIUM. AND THIS PROCESS INVOLVES REALLY PREPARING THE PANCREAS, ASSOCIATING THE PANCREAS WITH A DEFINED ENZYME BLEND AND THEN YOU SEE ISOLATED AND ISLETS OBTAINED HERE IN THE RED AND THE TISSUE AND THEN ISLETS ARE SEPARATED FROM TISSUE ON CONTINUOUS DENSITY GRADIENTS TO ACHIEVE A HIGHLY-PURIFIED CULTURE PRIOR TO IMPLANTATION. AND IMPLANTATION IS ACHIEVED USING A MINIMALLY INVASIVE, MOST MOSTLY A INTERVENTIONAL RADIOLOGICAL APPROACH. AND HERE YOU SEE A CATHETER IN THE VEIN AND THE CORRECT LOCATION OF THE CAT TERIS DEMONSTRATED BY CONTRAST PRIOR TO INFUSION -- THE CATHETER IS -- THE CONSORTIUM CONDUCTED PHASE II TRIALS TO ADVANCE THE FIELD WITH INNOVATIVE APPROACHES TO ISLET TRANSPLANTATION AND THEN CONDUCTED ALSO TWO PHASE III LICENSURE TRIALS, ONE CIT06 IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND CIT07 IN PATIENTS WITH TYPE I DIABETES COMPLICATED BY HYPOGLYCEMIA. AND I WANT TO SHARE A FEW NOTES ON THE SEVERE HYPOGLYCEMIA WITH YOU. SEVERE HYPOGLYCEMIC EPISODES ARE DEFINED TO ACTIVE ADMINISTER OTHER MEDICATIONS. AND PROBLEMATIC HYPOGLYCEMIA IS A CONDITION IN WHICH THESE EPISODES ARE UNPREDICTABLE AND CANNOT EASILY EXPLAIN OR PREVENT IT. CAUSES MAJOR FEEL AND MALADAPTIVE BEHAVIOR -- MAJOR FEAR -- HAVE A SIGNIFICANT IMPACT ON HEALTH AND QUALITY OF LIFE. AND SEVERE HYPOGLYCEMIA EFFECTS ALL ASPECTS OF LIFE FOR PEOPLE WITH DIABETES. IT CAN DISRUPT EVERY DAY ACTIVITIES AND CAN HAVE A PROFOUND IMPACT ON CONFIDENCE, CAREERS, RELATIONSHIPS, AND CAUSE EMBARRASSMENT, SOCIAL ISOLATION, EMPLOYMENT DISCRIMINATION, LOSS OF EMPLOYMENT. AND ALSO CASHEDIAC ARRHYTHMIA AND -- CARDIAC -- AND SOMETIMES DEATH. SO MUCH LESS RECOGNIZED COMPARED WITH MICROVASCULAR CHRONIC IMPLICATIONS SUCH AS KIDNEY FAILURE OR. AND WHEN YOU TALK TO PATIENTS WITH TYPE I DIABETES, THE FEAR OF HYPOGLYCEMIA IS RATED WITH THE SAME DEGREE OF CONCERN AS THE DEVELOPMENT OF SITE-THREATENING NEUROPATHY. PATIENTS ARE AFRAID TO STAY ONE NIGHT ALONE AT HOME BECAUSE THEY KNOW THEY COULD EXPERIENCE SEVERE HYPOGLYCEMIA AND COULD BE FOUND DEAD IN THE BED THE NEXT MORNING. AND FOR THIS REASON, SEVERE HYPOGLYCEMIA REMAINS A MAJOR OBSTACLE TO REMOVE DIABETES AND DESPITE THE NOVEL WIDESPREAD USE OF SENSORS, THE FREQUENCY OF HYPOGLYCEMIA AND ITS IMPLICATIONS HAS NOT TRAUMICALLY CHANGED OVER THE PAST DECADES. AND IT IS NOT A RARE CONDITION. 66% OF PATIENTS WHOSE TYPE I DIE BEAT CEASE COMPLICATED BY AWARENESS OF HYPOGLYCEMIA. AND 50% OF ALL EPISODES IN THE UNITED STATES. THERE ARE NEW TECHNOLOGIES, DIABETES TECHNOLOGIES AND HERE IS SHOWN MET TRONNICS, INSULIN PUMP, THAT TOGETHER WITH A SENSOR AND A PREDICTIVE LOW GLUCOSE SUSPEND CAPABILITY, HAS BEEN STUDIED. AS OFTEN PATIENTS WITH A HISTORY OF HYPOGLYCEMIA AND SEVERE HYPOGLYCEMIC EVENTS, WERE EXCLUDED FROM PARTICIPATION IN THE STUDIES. THIS I SHOULD SAY IS ONE EXCEPTION AND THAT IS A RECENT STUDY THAT WAS REPORTED IN THE LANCIT, TES TESTING THIS SENSOR IN PATIENTS IN WHOM DIABETES WAS COMPLICATED BY SEVERE HYPOGLYCEMIA. BUT WHEN N A METANALYSIS, THE FIELD AND THE INTERVENTIONS AND THIS SUBGROUP OF PATIENTS WERE REVIEWED, VERY LIMITED STUDIES, ONLY 18 RANDOMIZED CONTROL TRIALS IDENTIFIED AND NONE OF THE INTERVENTIONS THAT WERE EFFECTIVE IN ALL PATIENTS, AND FOR INTERVENTIONS TO BE EFFECTIVE, PATIENTS HAD TO ACCEPT MUCH HIGHER TARGET HEMOGLOBIN A1C. SO COMPROMISED GLYCEMIC CONTROL FOR THE PURPOSE OF PREVENTING SEVERE HYPOGLYCEMIA, WHICH INDICATES THAT IS THERE A VERY NARROW THERAPEUTIC WINDOW, AND WITH DIABETES TECHNOLOGIES AWARENESS, AT BEST WAS ONLY PARTIALLY RESTORED. AND THIS STUDY WAS CONDUCTED BY TENTIOUSY DIABETES CARE -- TERS RE-- WITH A FOCUS ON HYPOGLYCEMIA AND INCLUDING A SPECIALIST HYPOGLYCEMIA SERVICE. ANOTHER 25% COULD ACHIEVE CLINICAL IMPROVEMENT BUT THERE IS A SUBGROUP OF ABOUT 25% THAT ACCORDING TO THEIR JUDGMENT, REQUIRED A TRANSPLANTATION DESPITE HAVING ACCESS TO ALL THE OTHER THERAPIES SO THAT IS THE GROUP OF PATIENTS WE WANTED TO TARGET AND A GROUP IS NOT SERVED& WELL BY ALL OTHER AVAILABLE THERAPIES. AND ACCORDINGLY, THE OBJECTIVE OF THE PHASE III TRIAL WAS TO DETERMINE THE EFFECTIVENESS AND SAFETY OF A STANDARDIZED HUMAN ISLET PRODUCT IN TYPE I DIABETIC PATIENTS IN WHOM IMPAIRED AWARENESS OF HYPOGLYSEMIA AND SEVERE HYPOGLYCEMIA PERSISTED DESPITE OPTIMIZED MEDICAL TREATMENT. AND DR. SNYDERER IS HERE AND HE WAS INSTRUMENTAL IN DESIGNING THIS STUDY TOGETHER WITH NIAID AND NIDDK AND THE INVESTIGATORS. IT WAS DESIGNED AS A PHASE III STUDY AND NIAID WAS THE IND SPONSOR. IT WAS ASSIGNED AS A PERSPECTIVE SINGLE-ARM MULTI-CENTER STUDY AND DR. SNYDER WILL COMMENT ON THE DESIGN IN HIS PRESENTATION. 48 PATIENTS WERE ENROLLED. AND PATIENTS RECEIVED UP TO THREE INFUSIONS OF PURIFIED HUMAN PANCREATIC ISOLATES. AND PATIENTS WERE 18-65 YEARS OF AGE. TYPE I DIABETES FOR AT LEAST FIVE YEARS AND NO REMAINING C PEPTIDE WAS DOCUMENTED, SEVERE HYPOGLYCEMIA IN THE PREVIOUS YEAR. AND DOCUMENTED REDUCED AWARENESS AWARENESS. AND THERE WERE SEVERAL EXCLUSION CRITERIA. AND THE UM IMMUNOSUPPRESSIVE THERAPY INCLUDED INDUCTION WITH A POLO CLONAL T-CELL ANTIBODY, RAPID ATG AND A SOLID TNF RECEPTOR, AND MAINTENANCE THERAPY. AND THE PRIMARY ENDPOINT IS VERY UNIQUE AND I THINK VERY WELL THOUGHT OUT AND AGAIN, THANKS TO DR. AND I'DER FOR HIS SUGGESTIONS. WE DEBADED -- SNYDER -- WHETHER IF SHOULD BE INSULIN DEPENDENT OR OTHER ENDPOINTS BUT DR. SNYDER CONVINCED US IN THIS POPULATION, THE MOST CLINICALLY-RELEVANT ENDPOINT WOULD BE A COMPOSITE ENDPOINT, INCLUDING HEMOGLOBIN A1C LESS THAN 7% AND COMPLETE PROTECTION FROM SEVERE HYPOGLYCEMIA ON DAY 28, 365, FOLLOWING THE FIRST ISLET TRANSPLANT, AS THIS IS ALMOST IMPOSSIBLE TO ACHIEVE AND MAINTAIN IN PATIENTS WITH A HISTORY OF SEVERE HYPOGLYCEMIA. AND THEN THERE WERE MULTIPLE SECONDARY ENDPOINTS FOR SAFETY AND EFFICACY, INCLUDED AS WELL. AND GETTING TO THE RESULTS, 87.5% MET THE PRIMARY ENDPOINT AT ONE YEAR AT BASELINE WAS 0% AND 71% AT TWO YEARS AFTER THE ISLET TRANSPLANT. AND HEMOGLOBIN A1C IMPROVED AND NORMALIZED WITH THE MEDIAN LEVELS BEING BELOW 6, THAT IS NORMAL, AS QUICKLY AS DAY 75 AND CONTINUING DAY 365 AND DAY 730. AND THE NUMBER OF PATIENTS WITH SEVERE HYPOGLYCEMIC EPISODES REDUCED FROM 100% AT BASELINE TO ABOUT 5% AT ONE AND TWO YEARS AFTER TRANSPLANTATION. AND THE NUMBER OF EPISODES PER PATIENT ALSO REDUCED SIGNIFICANTLY AND THE MEDIAN NUMBER WAS ZERO AT ONE AND TWO YEARS AFTER TRANSPLANTATION, SO HIGHLY EFFECTIVE RESOLUTION OF SEVERE HYPOGLYCEMIA. THE SCORE DETERMINES AWARENESS OF HYPOGLYCEMIA. AND THE SCORE OF 0 INDICATES FULL AWARENESS, AND 7 IS INDICATING LOSS OF AWARENESS. SO THE MEDIAN SCORE WAS 6 AT BASELINE AND BECAME 0 AND REMAINED 0 AT TWO YEARS AFTER TRANSPLANTATION, DEMONSTRATING RESTORATION OF HYPOGLYCEMIA AWARENESS, WHICH REALLY EXPLAINS WHY PATIENTS WERE SO PROTECTED. SO INSULIN INDEPENDENTS WAS NOT THE PRIMARY ENDPOINT. IT WAS ACHIEVED IN 50% OF PATIENTS AT ONE YEAR AFTER TRANSPLANTATION, MAINTAINING 25% OF PATIENTS. BUT THE INSULIN REQUIREMENTS WERE VERY LOW. AND AS YOU CAN SEE HERE, THE MEDIAN REQUIREMENTS WERE AT DAY 75 WITH.015 UNITS AND LATER 0 UNITS PER KILOGRAM PER DAY WITH A FEW PATIENTS REQUIRING HIGHER DOSES OF INSULIN. AND THE MEAN CONTINUOUS GLUCOSE MONITORING RESULTS SHOW IMPROVED GLYCEMIC CONTROL THROUGHOUT THE PERIOD. WE THEN RECENTLY REPORTED QUALITY OF LIFE STUDIES AND LOOKED PREDOMINANTLY AT TWO MEASURES, ONE REFERRED TO AS THE DIABETES-RELATED DISTRESS TOTAL SCORE. AND YOU SEE IMPROVED SIGNIFICANTLY AND REMAINED LOW POST TRANSPLANTED. AND THE SECOND INSTRUMENT THAT IS VERY RELEVANT INCLUDED THIS STUDY POPULATION, IS THE HYPOGLYCEMIA FEAR SCORE THAT WAS VERY HIGH IN ALL PATIENTS AT BASELINE AND IMPROVED SUBSTANTIALLY THROUGHOUT THE STUDY I WANT TO PRESENT THE ADVERSE EVENTS THAT WERE EXPERIENCED. 30 STUDY-RELATED ADVERSE EVENTS, PROCEDURE-RELATED 5 OF 75 PROCEDURES WERE ASSOCIATED WITH BLEEDING. FOLLOWING PER CUTANEOUS CANNULAITION OF PORTAL VEIN. NOT A SINGLE EVENT OF PLEADING BUT A DIFFERENT APPROACH. IMMUNOSUPPRESSION-RELATED TRANSIENT NUTROPAENIA AND CYTOKINE RELEASE, ELEVATED LFTs. AND HYPOGLYCEMIA IN 4. NONE REQUIRED EXPEDITED REPORTING TO THE FDA, INDICATING INDICATING. NEOPLASMS WERE DIAGNOSED, THIS IS -- LET ME SKIP THIS. -- FOLLOWING PANEL-REACTIVE ANTIBODIES AND DONOR-SPECIFIC ANTIBODIES, IN A SUBSET OF PARTICIPANTS. ONE SUBJECT HAD A HUGE KIDNEY INJURY OF UNCLEAR ETIOLOGY. BY DAY 365, THE GFR HAD RISEN TO 63. SO TO NEAR NORMAL. AND INITIATION OF IMMUNOSUPPRESSION WAS ASSOCIATED WITH A SMALL NON-STATISTICALLY SIGNIFICANT DROP IN GFR AND A FURTHER SIGNIFICANT DROP AT DAY 365, COMPARED WITH BASELINE STATUS. SO IN SUMMARY, THE PRIMARY ENDPOINT, NEAR-NORMAL HEMOGLOBAL A ONE C LEVELS OF LESS THAN 7% AND PROTECTION FROM SEVERE HYPOGLYCEMIA WAS MET BY 88% AT ONE YEAR AND 71% AT TWO YEARS. AWARENESS OF HYPOGLYCEMIA WAS RESTORED AS INDICATED BY A NORMAL CLARK SCORE OF 0. THERE WAS SIGNIFICANT IMPROVEMENTS IN OTHER MEASURES OF GLYCEMIC CONTROL AND IN HEALTH-RELATED QUALITY OF LIFE ASSESSMENTS. NO STUDY-RELATED DEATH OR DISABILITY OCCURRED. BLEEDING OCCURRED IN 5-75 PROCEDURES BUT IS AVOIDABLE WITH A DIFFERENT ACCESS TO THE PORTAL VEIN. THE GFR DECREASED SIGNIFICANTLY ON IMMUNOSUPPRESSION. IN CONCLUSION, THE TRANSPLANT ISLET RESTORED GLYCEMIC CONTROL, HYPOGLYCEMIA AWARENESS AND PROTECTION FROM SEVERE HYPOGLYCEMIC EPISODES IN TYPE I DIABETIC PATIENTS WITH INTRACTABLE IMPAIRED AWARENESS OF HYPOGLYCEMIA AND SEVERE HYPOGLYCEMIC EPISODES. SAFETY EVENTS OCCURRED, INCLUDING BLEEDING AND INCREASED RENAL FUNCTION. ISLET IS TESTED AND SHOULD BE CONSIDERED FOR PATIENTS WITH TYPTYPETYPE I DIE BEAT ICE AND IAH IN WHOM OTHER, LESS-INVASIVE CURRENT TREATMENTS HAVE BEEN INEFFECTIVE IN PREVENTING SHE. THESE STUDIES WERE REPORTED IN DIABETES CARE, AND IS IMPORTANT THAT THIS STUDY REPRESENTS THE VERY FIRST PHASE III TRIAL OF A CELL THERAPY PRODUCT IN DIABETES. AND ESTABLISH A NEW EFFICACY BENCHMARK IN DIABETES CARE AND HAS ALREADY CREATED MOMENTUM FOR SCALABLE ISLET REPLACEMENT THERAPIES. AND THE STUDY ON IMPROVED HEALTH-RELATED QUALITY OF LIFE WAS ALSO REPORTED IN DIABETES CARE IN 2018, AND PARTICIPANTS REPORT CONSISTENT AND STATISTICALLY SIGNIFICANT AND CLINICALLY-MEANINGFUL IMPROVEMENTS IN CONDITIONS-SPECIFIC HEALTH-REALITY QUALITY OF LIFE, AS WELL AS SELF Q OF OVERALL HEALTH. LET ME BRIEFLY TOUCH ON THE IMPORTANCE OF A BIOLOGICS LICENSE. NIHIMATION IS SCIENCE IN PURSUIT OF FUNDAMENTAL KNOWLEDGE ABOUT THE NATURE AND BEHAVIOR OF LIVING SYSTEMS AND ALSO THE MISSION IS ON THE APPLICATION OF THAT KNOWLEDGE TO EXTEND HEALTHY LIFE AND REDUCE THE BURDENS OF ILLNESS AND DISABILITY. ONLY A LICENSE WILL MAKE THIS AVAILABLE TO PATIENTS IN THE U.S. AND A LICENSE WILL ALSO PROMOTE CONTINUED RESEARCH ON ISLET TRANSPLANTATION AS ROUTINE MEDICAL COSTS OF LICENSED PRODUCTS ARE REIMBURSED AND MAKING RESEARCH SO MUCH MORE AFFORDABLE AND THE LICENSE WILL CREATE FURTHER MOMENTUM FOR A SCALABLE ISLET PRODUCT NEXT GENERATION TECHNOLOGY SUCH AS STEM CELL-DERIVED OR ISLET PRODUCTS. AND JUST TO GIVE YOU EXAMPLE OF WHERE THIS SHOULD GO, AS I POINTED OUT, THE NON IMMUNOLOGICAL SIDE EFFECTS OF IMMUNOSUPPRESSION INCLUDING ISLET AND RENAL TOXICITY, LIMIT THE APPLICABILITY OF ISLET TRANSPLANTATION AND THERE ARE SEVERAL NOVEL SELECTIVE IMMUNOTHERAPIES, INCLUDING ANTAG NESTIC ANTIBODIES OR ANTI-CD40 LIGAND ANTIBODIES NOW BECOMING AVAILABLE FOR CLINICAL INVESTIGATION. THESE BIOLOGICS ARE EXPECTED TO ALLOW EVEN BETTER ISLET FUNCTION TO BE EXPERIENCED BY PATIENTS WITHOUT CAUSING RENAL TOXICITY, WHICH AS I THINK I POINTED OUT, AND WANTED TO EMPIFIES, IS CLINICALLY THE MOST CONCERNING ADVERSE EVENT OBSERVED IN THIS STUDY. SO I WANTED TO AGAIN EXPRESS MY SINCERE THANKS TO NIH, TO NIAID AND NIDDK FOR HAVING SUPPORTED THIS STUDY IN MANY INSTRUMENTAL WAYS. I WANTED TO THANK THE PATIENTS AND FAMILIES, THE CLINICAL AND MANUFACTURING SIDES OF OUR CLINICAL TRIALS. AND REGULATORY EXERTS AND PROJECT MANAGERS FOR THEIR CONTRIBUTIONS. THANK YOU. [ APPLAUSE ] I'M HAPPY TO TAKE A FEW QUESTION QUESTIONS. >> COULD YOU COMMENT ON THE DEGREE OF RENAL FAILURE IN -- [ LOW AUDIO ] >> BERNARD: SO I THINK THIS IS AN IMPORTANT QUESTION. NOW THE DECLINE IN KIDNEY FUNCTION AS MEASURED BY THE GFR, WAS SIGNIFICANT BUT WAS STABLE. WE ALSO KNOW THAT IN PATIENTS WITH POOR GLYCEMIC CONTROL, THE FUTURE GLYCEMIC CONTROL CAN BE HYPERFILTRATION. IF YOU NOW PROVIDE IMPROVED GLYCEMIC CONTROL, YOU CAN JUST NORMALIZE HYPERFILTRATION AND LOWER THE GFR AND BRING IT BACK INTO A NORMAL RANGE, WHICH I THINK COULD HAVE BEEN A BENEFIT OF THE STUDY RATHER THAN AN ADVERSE EVENT. WE ALSO KNOW THAT IN THOUSANDS OF PATIENTS, YES THERE IS A DROP IN KIDNEY FUNCTION, AN EXPECTED ADVERSE EVENT BUT AS REVIEWED NOT TOO LONG AGO, THIS IS NOT A PROGRESSIVE DECLINE IN RENAL FUNCTION ONCE YOU HAVE YOUR NEW LEVEL FAIRLY SOON, ACCORDING TO THE ONE VERY LARGE DETAILED STUDY, OVER THE NEXT 10-20 YEARS, IT REMAINS AT THIS LEVEL. SO WE DON'T KNOW WE HAVE NO DATA TO PROVE THAT IN OUR ISLET POPULATION BUT THERE IS REASON TO BELIEVE THAT THERE IS NO PROGRESSIVE DECLINE IN KIDNEY FUNCTION, WHICH OF COURSE IS VERY, VERY RELEVANT IN THIS PATIENT GROUP. AND WITH NEW IMMUNOTHERAPIES, WE CAN AVOID RENAL TOXICITY ALL TOGETHER. AND THAT OF COURSE WOULD BE FANTASTIC. PLEASE? >> BERNARD, SOUNDS LIKE -- [ LOW AUDIO ] >> BERNARD: YES, THAT IS ALSO CLINICALLY, A VERY RELEVANT QUESTION. SO WE HAVE FOR THIS REASON, EXCLUDED PATIENTS WITH CHRONIC KIDNEY DISEASE FROM PARTICIPATION BECAUSE WE DIDN'T KNOW HOW COMMONLY WE SEE PANEL REACTIVE ANTIBODIES, BUT WE SAW ONLY IN TWO SUBJECTS, WE SAW DONOR-SPECIFIC ANTIBODIES AND SENSITIZATION-INDUCED BY THE GRAFT. WE KNOW THAT IS A VERY RELEVANT AND WE BELIEVE THE RISK IS LOWER THAN PREVIOUSLY REPORTED IN OTHER ISLET STUDIES AND IN RENAL TRANSPLANT STUDIES, BUT IT IS A VERY SIGNIFICANT ONE AND IS PART OF THE CONSENT PROCESS WHEN YOU ASSIST PATIENTS IN REALLY EVALUATING THEIR PARTICIPATION IN A STUDY. PLEASE. >> WHY WERE STUDYING DEVICES EXCLUDE THIS PARTICULAR GROUP OF PATIENTS -- [ LOW AUDIO ] >> BERNARD: YOU SEE THAT HAS TO DO WITH THE REGULATORY STRATEGY. AND MAYBE THE TIME TO MARKET IS SHORTEST IF YOU SELECT A POPULATION IN WHICH EFFICACY CAN BE DEMONSTRATED AND EFFICACY CAN BE DEMONSTRATED IN LOWERING HEMOGLOBIN A1C LEVELS WITHOUT AN ASSOCIATED INCREASE IN SEVERE HYPOGLYCEMIA. THAT CANNOT BE EASILY ACCOMPLISHED IN THE MOST CHALLENGING PATIENT POPULATION. THAT IS WHY AS THOSE STUDIES GET PLANNED, THOSE PATIENTS ARE MORE OR LESS ALWAYS EXCLUDED FROM PARTICIPATION. THERE ARE A FEW EXAMPLES WHERE INVESTIGATORS AND COMPANIES HAVE FOCUSED ON THE SAME PATIENT POPULATION, AND HERE YOU SEE YOU CAN NOT COMPLETELY AVOID SEVERE HYPOGLYCEMIA LIKE WE DO. AT LEAST AVOID IN 95% OF PATIENTS, AND WITH DIABETES TECHNOLOGIES, YOU CAN THE NOT RESTORE AWARENESS OF HYPOGLYCEMIA, WHICH IS VERY HELPFUL IN AVOIDING HYPOGLYCEMIA, SUBSEQUENT HYPOGLYCEMIA. AND WE CAN, WITH A TRANSPLANT, WE CAN PROTECT FROM HYPOGLYCEMIA, WE CAN RESTORE AWARENESS AND WE CAN RESTORE NORMAL GLYCEMIC CONTROL. AND WITH THOSE TECHNOLOGIES, YOU HAVE TO MAKE A COMPROMISE AS A PATIENT. YOU HAVE TO ACCEPT ELEVATED GLYCEMIC TARGETS FOR OTHER TECHNOLOGIES TO WORK. SO THE QUESTION ALWAYS IS, WHEN THIS IS A VERY SIGNIFICANT CLINICAL PROBLEM, AND MAYBE WE HAVE 200,000 PEOPLE IN THE UNITED STATES OR MORE WHO ARE REALLY AFFECTED, WHEN WILL THE TECHNOLOGIES BE READY TO REALLY COMPARE THEM HEAD-TO-HEAD AND KNOW WHO IS THE PATIENT, AT WHAT POINT IN TIME, WHO WOULD REALLY BENEFIT THE MOST AND DO YOU HAVE EVIDENCE? SO THAT IS A QUESTION THAT AS ISLET TRANSPLANTATION CONTINUES TO EVOLVE AND DIABETES TECHNOLOGIES CONTINUE TO EVOLVE, IT'S NOT AN EASY ANSWER. >> I THINK YOU RAISE AN INTERESTING TOPIC EITHER FOR CONVERSATION NOW OR AFTER BRUCE SPEAKS, WHICH IS, THESE TRIALS TAKE A LONG TIME TO DESIGN, AND TO CONDUCT. AND IT IS VERY CHALLENGING TO COME UP WITH A DESIGN THAT WILL BE CONVINCING AND COMPELLING 5-8 YEARS LATER WHEN THE TECHNOLOGIES BOTH IN THE TRANSPLANTATION FIELD AND THE IMMUNOSUPPRESSION REGIMENS ARE LIKELY TO HAVE CHANGED AND THE DEVICE TECHNOLOGIES HAVE CHANGED. SO, IT'S A VERY CHALLENGING ISSUE THAT YOU MAY WANT TO COMMENT ON OR BRUCE MIGHT. THE OTHER POINT I'D LIKE TO HEAR YOUR PERSPECTIVE ON IS, MANY OF THE INVESTIGATORS WHO ARE WORKING WITH THE DEVICES, HAVE COMMENTED INFORMALLY AT LEAST, IN THEIR CENTERS ABOUT A YEAR OR SO AFTER GOING ON DEVICES, UP TO 50% OF PEOPLE MAY NOT BE HAPPY WITH THE DEVICES AND HAVE ABANDONED THEM. I DON'T KNOW WHETHER THAT IS COMPLETELY ACCURATE OR REPRESENTATIVE STORY. BUT YOU MAY WORK WITH MANY OF THOSE PEOPLE AND TOM MAY ALSO, YOU MIGHT WANT TO COMMENT. >> I THINK THAT'S ANOTHER VERY RELEVANT POINT. WE HAVE MONITORED PATIENTS FOR TWO YEARS AND WE HAVE OFFERED TO ALL PATIENTS, THE POSSIBILITY OF PARTICIPATING IN A LONG-TERM FOLLOW-UP STUDY. SO WE WILL HAVE SOON 5-YEAR DATA TO REPORT. NIDDK IS HERE IN THE ROOM, IS A RESPONSIBLE PROGRAM OFFICER FOR THE COLLABORATIVE ISLET TRANSPLANT REGISTRY AND WE ARE ABOUT TO SUBMIT A MANUSCRIPT THAT PRESENTS 5-YEAR FOLLOW-UP DATA. ON ISLET TRANSPLANTATION. WHEN YOU LOOK AT DIABETES TECHNOLOGIES AND YOU MAY KNOW BETTER THAN ANYONE HERE IN THE ROOM, BUT AS FAR AS I CAN TELL, MOST STUDIES HAD A FOLLOW-UP OF HALF A YEAR ON NEW DIABETES TECHNOLOGY. OR MAYBE SOME ONE YEAR. I SAW RECENTLY THERE WAS ONE STUDY THAT INCLUDED A 4-YEAR FOLLOW-UP. THAT IS MAYBE NOT A COMMON STUDY DESIGN. SO I THINK IT IS FAIR, YOU SEE, CAN YOU REALLY HAVE SUSTAINED ACHIEVEMENT OF CLINICALLY-RELEVANT ENDPOINTS WITH THOSE TECHNOLOGIES AS YOU CAN HAVE WITH ISLET TRANSPLANTATION. AND ISLET TRANSPLANTATION, WE ALSO HAVE PEOPLE WHO DROP OUT AND BUT I THINK WE WILL SOON BE ABLE TO REPORT ON LONG TERM OUTCOMES AND WE WILL BE ABLE TO SHOW THAT IN PATIENTS WITH SEVERE HYPOGLYCEMIA AND NEGATIVE C PEPTIDE AT BASELINE, AND PATIENTS WHO HAVE RECEIVED A PARTICULAR INDUCTION IN MAINTENANCE REGIMEN, 96% REMAIN COMPLETELY PROTECTED FROM SEVERE HYPOGLYCEMIA FOR THE NEXT FIVE YEARS, AND I THINK THAT IS DIFFICULT TO BEAT FOR ANY TECHNOLOGY. AND YES, IT COMES WITH IMMUNOSUPPRESSION, BUT WE HAVE ALSO GOOD DATA TO INDICATE THAT IMMUNOTHERAPY CAN BE IMPROVED OR EVEN TOLERANCE CAN BE INDUCED. SO THAT IS WHY DAN EMPHASIZED, IT'S SO DIFFICULT TO FIND THE RIGHT TIME, AND THE RIGHT DESIGN FOR RANDOMIZED STUDY, BECAUSE EVERYTHING IS EVOLVING FAIRLY QUICKLY. >> WHAT ABOUT THE AVAILABILITY OF ORGANS FOR TRANSPLANTATION? >> YES, SO THAT OF COURSE IS A LIMITING FACTOR. MAYBE WE HAVE 2000 SUITABLE ORGANS PER YEAR AND THEN WE HAVE LOGISTICAL CHALLENGES ON TOP OF THAT. I THINK WHAT IS FAIR TO SAY AT THE VERY, VERY LEAST, ONE IMPACT THIS STUDY WILL HAVE, AS IT WILL DEMONSTRATE THAT CELL THERAPY CAN BE VERY EFFECTIVE IN TREATING TYPE I DIABETES AND IT CAN REALLY, LIKE I SAID, FURTHER CREATE MOMENTUM FOR DEVELOPING STEM CELL DERIVED OR PIANO TRANSPLANT THERAPIES AND MAYBE WITH HUMAN ISLET TRANSPLANTATION, WE CAN ONLY REALLY HELP A SMALL SUBSET OF PATIENTS BUT WE CAN SHOW PROOF-OF-CONCEPT VERY CLEARLY AND A LOT OF INTEREST IS REALLY IN THIS FIELD RIGHT NOW. SO IT HAS THIS IMPACT AS WELL. AND I THINK WHAT WE LEARNED ABOUT ISLET DELIVERY SITES, METABOLIC MONITORING, AND ABOUT ALL OF THOSE KEY ELEMENTS, WILL HAVE RELEVANCE TO THE DEVELOPMENT OF NOVEL CELL THERAPY PRODUCTS, BECAUSE THEY NEED TO BE INFUSED OR DELIVERED SOME WAY, NEED TO BE MONITORED AND SO I THINK IT WILL HAVE AN IMPACT ABOVE AND BEYOND THE 2000 PATIENTS WE MAY BE ABLE TO SERVE A YEAR. YOU'RE RIGHT. >> JONAH: THANK YOU BERNARD, I'M GOING TO CALL BRUCE UP TO THE TABLET HERE. I DON'T THINK HE HAS ANY SLIDES SO HE WILL PRESENT HIS REMARKS. >> DUE TO LAST-MINUTE SCHEDULING AND I GUESS ABOUT A WEEK AGO I DETERMINED WHAT I WAS SUPPOSED TO BE TALKING ABOUT, ASIDE FROM WRITING A BLA AND GIVEN THE FACT THAT IT GENERALLY TAKES ABOUT 3-4 WEEKS TO GET SLIDES CLEARED AT MY AGENCY, I HAVE NO SLIDES. I ALSO JUST ONE DISCLAIMER WHAT I'M ABOUT TO SAY, THESE OPINIONS ARE MY OWN AND DON'T REPRESENT FDA OPINION. I WANT TO GIVE YOU OUR THINKING ABOUT THE ISLET DEVELOPMENT PROGRAM AND THIS TRIAL IN PARTICULAR AND ALSO SOME OF OUR THINKING ABOUT HOW WE SHOULDN'T GET PAST THIS LOG JAM OF GETTING A BLA. FIRST OF ALL, THIS IS AN EXTREMELY EXCITING TIME IN CELLULAR AND GENE THERAPY. WE HAVE MANY NEW EXCITING PROGRAMS, SOME OF WHICH, GENE THERAPY ONES, WILL PROBABLY CURE A BUNCH OF TERRIBLE PEDIATRIC DISEASES THAT ARE WELL IN ADVANCE OF DEVELOPMENT AND THE PROSPECTS OF THE FIELD ARE VERY, VERY EXCITING FOR CELL THERAPY PARTICULARLY FOR ISLET TRANSPLANTATION OR IN GENERAL TERMS FOR BETA CELL REPLACEMENT, THERE ALSO HAS BEEN TREMENDOUS ADVANCES IN ADDITION TO WHAT BERNARD HAS JUST DESCRIBED IN DEVELOPMENT OF EMBRYONIC STEM-CELL DERIVED BETA CELLS AND IPS CELLS AND ISOLATES. AND WHAT IS HOLDING THAT FIELD UP, IS THE PROBLEM OF ENCAPSULATION OF GETTING THE CELLS INTO PATIENTS AND KEEPING THEM AND PROTECTING THEM. SO WHAT I'D LIKE TO DESCRIBE NOW IS HOW WE LOOK AT THIS PROGRAM IN ISLET CELL TRANSPLANTATION. ISLET CELLS ARE ALLOGENEIC CELLS ARE REGULATED A A 351 CELLULAR PRODUCT, UNDER THE IND-BLA PATHWAY, REGULATED IN OUR OFFICE AND CENTER FOR BIOLOGICS EVALUATION AND RESEARCH AT FDA AND, AND THE NEW NAME OF OUR OFFICE IS OFFICE OF TISSUES AND ADVANCED THERAPY. WE STILL REGULATE THE SAME CELL AND GENE THERAPY PRODUCTS. BECAUSE OF THE NATURE OF THE NEW PRODUCTS IN PARTICULAR ALLOGENEIC ISLET CELLS, THE TRADITIONAL PATHWAYS FOR CLINICAL TRIALS MAY NOT BE PRACTICAL. THE TRADITIONAL PATHWAY FOLLOWING OF COURSE THE GOLD STANDARD OF A RANDOMIZED CONTROL, DOUBLE-BLIND CLINICAL TRIAL AND THAT OF COURSE REMAINS THE GOLD STANDARD, IT JUST TURNS OUT THAT OFTENTIMES IT JUST CAN'T BE DONE, FOR EXAMPLE FOR PEDIATRIC OR RARE PEDIATRIC DISEASES. PARENTS OR CAREGIVERS ARE UNWILLING TO RANDOMIZED CHILDREN INTO A TRIAL WHERE THEY MAY BE IN A CONTROLLED GROUP OR THE POPULATION WILL BE SO SMALL THAT EVEN IF YOU RANDOMIZED IT, IT WOULD BE SUCH STATISTICAL IMBALANCES AT BASELINE IT MAY NOT WORK ANYWAY. SO 12-13 YEARS AGO -- IT TURNED OUT OF COURSE THAT ALLOGENEIC ISOLATES PRESENTED US WITH ABOUT THE SAME PROBLEM BUT IT TURNED OUT THAT THE SOLUTION WAS EASIER AND 12-13 YEARS AGO, I STARTED WORKING ON THIS AND THINKING ABOUT HOW TO ORGANIZE AND DESIGN CLINICAL TRIALS FOR ISLET TRANSPLANTATION AND AT THAT TIME, IT WAS BROODED ABOUT THERE WAS GOING TO BE FUNDING, I BELIEVE, FOR A RANDOMIZED CONTROL TRIAL FOR ISLET AFTER KIDNEY AND I THINK THERE WAS FUNDING FOR IT BUT IT NEVER CAME ABOUT BECAUSE PREDICTIVELY, PEOPLE WOULD NOT AGREE TO BE RANDOMIZED INTO SUCH A TRIAL. AND GOING OVER THE FIGURES, ASIDE FROM THE SAFETY DATABASE, THERE REALLY IS NO REASON TO, GIVEN THE OUTCOMES OF THE VERY ROBUST OUTCOMES OF TRIALS WITH ALLOGENEIC ISOLATES. AND THE REASON FROM THE EMERGING DATABASE FROM THE COLLABORATIVE ISLET TRANSPLANT REGISTRY AT THE TIME, AND THE OUTCOMES OF WHICH ARE SIMILAR TO WHAT POSSIBLY NOT AS ROBUST BUT SIMILAR TO WHAT DR. HERRING HAS JUST DESCRIBED, AND THE REASON I THOUGHT A TRIAL WAS NOT NECESSARY, WAS BECAUSE FIRST OF ALL, IF THE OUTCOMES WERE THAT ROBUST, THE TREATMENT AFFECT SIZE WAS SO BIG, AND PROBABLY DIDN'T NEED TO, AND I'LL ADDRESS THAT IN A MOMENT. AND THEN IF YOU ARE GOING TO LOOK FOR PROGRESSION OF MICROVASCULAR COMPLICATIONS, WE RECALL THAT THE DCCT TRIAL REQUIRED ABOUT 1500 YOUNGER PEOPLE WITH EARLY DISEASE TO SHOW THE AFFECTS OF TYPE HEMOGLOBIN GLUCOSE CONTROL ON NEUROPATHY AND RETINOPATHY. THIS WOULD BE PRACTICAL FOR THAT REASON IN ANY CASE. THE SAFETY DATABASE IS ANOTHER STORY BUT WE HAVE A LOT OF SAFETY DATA FROM SIDER AND YOU HEARD THE SAFETY OUTCOMES OF THIS PARTICULAR TRIAL. THIS WAS OUT FOR PUBLIC COMMENT AND EVERYBODY LIKED IT AND IT WENT OKAY. BUT THE OVERALL DESIGN OF THIS IS THE SINGLE-ARM TRIAL IN WHICH YOU HAVE A HISTORICAL CONTROL, OR HYPOTHETICAL CONTROL, OR CONTROL ALSO BASED ON WHAT THE PATIENT'S BASELINE WAS, BUT HYPOTHETICAL CONTROL WOULD BE THE NUMBER OF PATIENTS WITH PORTION OF SUBJECTS IN THE TRIAL WHO WOULD TRANSITION TO A STATE OF EITHER COMPLETEINS LET INDEPENDENCE, WHICH IS THE CASE OF TYP TYPE I DIABETES, WHICH IS SOMETHING LIKE 0. OR WOULD ACHIEVE THE COM POSIS END POINT, WHICH WE THOUGHT WAS A REALLY GOOD CLEANINGFUL MEANINGFUL ENDPOINT, THAT IS ADEQUATE CONTROL OF HEMOGLOBIN A1C IN THE ABSENCE OF SHE, AND WITH THE USE OF SIMPLIFIED INSOLENT REGIMENS, SO EVEN IF YOU NEEDED A LITTLE INSULIN, THIS IS A HUGE ENDPOINT CLINICALLY. SO THE STRUCTURE OF SUCH A TRIAL IS TO PROJECT A RESPONSE RATE OF X, THE POINT ESTIMATE OF LET'S SAY 70% OF PEOPLE WOULD RESPOND, AND THEN THE TRIAL IS POWERED SO THAT THE LOWER BOUNDARY OR THE 95% CONFIDENCE INTERVAL AROUND THAT POINT SNAT IS GREATER THAN 50%. AND THEN FOR THE COMPARATOR, YOU MAKE UP SOME NUMBER. IF IT'S ZERO, LET'S SAY FOR INSULIN INDEPENDENTS, THEN THAT'S EASY. AND WHAT WE REALLY WRESTLED WITH ALONG WITH THE CIT FOLKS, WAS THE CONSTRUCTING A HYPOTHETICAL. SO WHAT WE IF IS WE CAME UP WITH A VERY CONSERVATIVE NUMBER LIKE 27%, WHICH OF COURSE IT JUST DOESN'T HAPPEN FOR PEOPLE WHO ACHIEVE THE COMPOSITE ENDPOINT, AND THE UPPER BOUNDARY FOR THEM IS UNDER 50%. THAT IS BASICALLY THE STRUCTURE OF THIS TRIAL AND IT TURNED OUT THAT IT WORKED. IN FACT, IT WORKED VERY WELL. SO, THE KEY ELEMENT IN DESIGNING SUCH A TRIAL IS THE TREATMENT AFFECT SIZE. I MEAN, IT IS VERY HARD TO DO THIS IF YOU ARE LOOKING AT A SMALLER AFFECT SIZE, LET'S SAY 10% IMPROVEMENT. BUT IF YOU'RE LOOKING FOR OUTCOME THAT VIRTUALLY NEVER OCCURS IN NATURE, AS PART OF THE NATURAL HISTORY OF DISEASE, THEN THE JOB IS EASIER. SO THAT IS THE RATIONAL. SO, EVERYTHING THAT WAS DONE BASICALLY IN DESIGNING THIS TRIAL AND EXECUTING IT AND ANALYZED -- WE HAVEN'T ANALYZED THE DATA YET, BUT IN JUST DISCUSSING PROBLEMS, WAS DONE IN COLLABORATION WITH US AND WITH THE CIT GROUP. SO THIS IS REALLY A GOOD EXAMPLE OF COLLABORATION BETWEEN REGULATORY AUTHORITY AND THE INVESTIGATORS. SO, THE ISSUE IS NOW, WE HAVE SEEN THE DATA.& WE HAVEN'T GOTTEN THE BLA APPLICATION YET, AND I'LL ADDRESS THAT IN A MOMENT, BUT THE LESSONS LEARNED, I THINK FOR THIS, WHEN WE REANALYZED, NOT THESE DATA, BUT DATA FROM CIDR, WE PUBLISHED A PAPER 5 YEARS AGO IN THE AMERICAN JOURNAL OF TRANSPLANTATION USING STATISTICAL MODELING. IF TURNED OUT IF YOU TAKE ALL THE PEOPLE WHO ACHIEVE THE PRIMARY ENDPOINT FROM THE ENTIRE CIDER DATABASE AND YOU DO A KAPLAN MIRE SURVIVAL ANALYSIS FOR MAINTENANCE OF THAT COMPOSEIT ENDPOINT, LOSS OF THAT END POINTED IS DRIVEN ALMOST ENTIRELY BY THE HEMOGLOBIN A1C COMPONENT. IF YOU HAVE A LANDMARK ANALYSIS OF ONE YEAR OR TWO YEARS, AND YOU HAVE AN A1C OF 6 1/2 OR 7.0 AND YOU GET ONE BLIP, AT THAT LANDMARK, THEN THE PATIENT IS NOW CONSIDERED A NON-RESPONDER. SO WE ARE NOW WORKING ON OTHER KINDS OF TRIAL DESIGNS TO ELIMINATE THAT PROBLEM. AND ONE OF THEM IS A MODEL THAT I HAVE BEEN WORKING ON JUST TO SCORE THE AMOUNT OF TIME OVER A 3-YEAR PERIOD THAT IS SPENT IN A CLINICALLY BENEFICIAL STATE AND THERE CAN BE REVERSIBLE TRANSITIONS AMONG CLINICALLY PREDEFINED STATES AND THERE ARE SEMI--MARK OFF MODELS THAT ACCOUNT FOR THAT. IT GETS COMPLICATED BUT I THINK IF A TRIAL LASTS, LET'S SAY THREE YEARS AND THERE ARE MULTIPLE -- FOR SOME PATIENTS, MULTIPLE ISLET TRANSPLANTS, THAT MAY BE THE BETTER WAY TO LOOK AT THE OUTCOMES. THE OTHER THING THAT IS BASICALLY THE OTHER THING THAT IS REALLY UNACCOUNTED FOR UNSCORED, IS WHETHER OR NOT THERE REMAINS OR -- THE REMAINS SO-CALLED METABOLIC MEMORY. IF YOU TAKE SOMEBODY WHO IS 50 YEARS OLD WHO IS A TYPE I DIABETES FOR MANY YEARS AND YOU NORMALIZE THEM, EVEN AFTER THE ISLET TRANSPLANT FAILS, HOW LONG DOES -- WHAT IS THE LONG TERM AFFECT ON PROGRESSION OF RETINOPATHY OR NEUROPATHY? WE REALLY DON'T KNOW. AND THESE KINDS OF INVESTIGATIONS WERE DONE IN THE EDITH TRIAL THAT FOLLOWED DCCT AND THE THEY WERE QUITE REVEALING. SO, BASICALLY, THAT IS REALLY THE MESSAGE THAT I WANTED TO GIVE ABOUT HOW WE LOOK AT THESE TRIALS. WE ARE OPEN TO THE DEVELOPMENT OF NOVEL CLINICAL TRIAL DESIGNS, ALWAYS OF COURSE MAINTAINING STANDARDS FOR DEMONSTRATION OF SAFETY AND EFFECTIVENESS THROUGH QUOTE/UNQUOTE, ADEQUATE AND WELL-CONTROLLED TRIALS OF ONE OR MORE. I MUST ALSO SAY THAT IN THE BACKGROUND, I'M VERY MUCH INDEBTED TO THE DATA THAT WERE PROVIDED BY CIDR, THE COLLABORATIVE TRANSPLANT REGISTRY, BECAUSE THEY REALLY HELPED GUIDE OUR THINKING AS AS TO YOU WHAT TO EXPECT, AND SO EVEN THOUGH WE, ON THE FACE VALUE OF THESE RESULTS ARE STRIKING, AND ROBUST, THEY AREN'T REALLY THE ONLY RESULTS. IT'S NOT LIKE THIS CAME OUT OF THE BLUE. IT'S AS THOUGH THEY WERE DONE ON THE HEELS OF MULTIPLE PHASE II SMALL TRIALS BY MULTIPLE INVESTIGATORS WHO WITH SMALL CLINICAL POPULATIONS WILL SAY 6, 8, 12, SUBJECTS IN THE TRIAL, WHO CAME UP WITH SIMILAR RESULTS. SO, WE REALLY ADD TO THE KEDGENCEY OF THESE RESULTS. THAT THE POINT, WE HAVE GREAT PROOF-OF-CONCEPT. WE HAVE A PRODUCT WHICH IS THE ONLY PRODUCT ON BETA CELL REPLACEMENT PRODUCT AVAILABLE THAT CAN DO WHAT DR. HERRING DESCRIBED. THIS IS ONE AREA THAT DEPENDENT COME UP IN OUR PLANNING. THIS SHOULD BE PROBABLY ADDED TO THE TARGETED PRODUCT PROFILE LIKE WE USED TO GUIDE PHARMACEUTICAL DEVELOPMENT IN WHICH THE PHARMACEUTICAL SPONSORS ARE ASKED TO -- IF IT'S A VOLUNTARY DOCUMENT, BUT THE PRINCE SPELL YOU WRITE THE LABEL BEFORE YOU GO DO THE EXPERIMENT. SO THEN YOU CAN DESIGN ALL THE EXPERIMENTS THAT WOULD SUPPORT THE LABEL AND CLAIM, AND I THINK PROBABLY WE SHOULD HAVE DONE SOMETHING LIKE THAT IN THIS SITUATION. RIGHT NOW, LET ME AGAIN FOR THOSE OF YOU WHO MAYBE ARE UNFAMILIAR WITH THIS. WRITING A BLA IS NOT LIKE WRITING A PAPER. EVEN FOR GCI OR NEW ENGLAND JOURNAL OR SOMETHING, OR EVEN A PH.D. THESIS T IS VERY COMPLICATED. IT HAS GENERALLY CONSISTS OF THOUSANDS OF PATIENTS WITH ZILLIONS OF DATA BITS AND MUST BE SUBMITTED IN ELECTRONIC FORMAT SO WE CAN REVIEW IT APPROPRIATELY. AND SO THIS TAKES GENERALLY SOME OUTSIDE ORGANIZATION, I GUESS BIG DRUG COMPANIES HAVE THOSE FACILITIES, BUT IT'S THE KIND OF THING I HAVE BEEN AT FDA FOR MANY YEARS AND I COULDN'T DO IT. I COULD WRITE A PH.D. THESIS BUT I COULD NEVER WRITE A BLA. SO AND IT COST MONEY. IT MUST COST A MILLION DOLLARS OR SOMETHING LIKE THAT SIMPLY TO WRITE THIS THING. IN THIS CASE IT IS POSSIBLE OR LIKELY THAT THAT THIS PRODUCT AND SITUATION WOULD QUALIFY FOR A WAIVER OF THE USER FEE. THIS IS NOT AN OFFICIAL ANNOUNCEMENT BUT IT IS A SMALL QUOTE COMPANY AND LIMITED RESOURCES AND PUBLIC RESOURCES AND REASONS FOR THAT. TWO THINGS NEED TO GET DONE WITH THIS PROJECT. ONE IS, AND BERNARD AND I WERE DISCUSSING THIS EARLIER. ONE IS TO TRY TO FIGURE OUT WHETHER WE COULD DO THIS WITH ONE BLA, COVERING EVERYTHING, OR WHETHER HEAVEN FORBID, SEVEN BLAs FOR THE ISLET ALONE PROJECT AND SEVEN FOR THE ISLET AFTER KIDNEY PROJECT, THE THE 07 AND 06 TRIALS. AND I DON'T KNOW IF I HAVE ENOUGH REVIEWERS ON MY TEAM TO REVIEW 14BLAs IF THEY ALL COME AT THE SAME TIME. SO WE'LL HAVE TO FIGURE THAT OUT AND WE ARE GOING TO HAVE TO WORK THE CIT GROUP TO DEVISE SOME STRATEGY BECAUSE WITHOUT A BLA, AS DR. HERRING SAID, THERE WILL BE PROBLEMS IN BRINGING THIS TO MARKET AND HELPING THIS FIELD ADVANCE. SO IF THERE ARE ANY QUESTIONS AND ANYBODY MUST SPEAK INTO THE MICROPHONE, I'M GLAD TO ENTERTAIN ANYTHING. >> I HAVE A QUESTION HERE. SO, I KNOW THAT -- I DON'T KNOW HOW FECAL TRANSPLANTS ARE BEING CONSIDERED, WHETHER THEY ARE ORGAN TRANSPLANTS, BUT I KNOW THEY ARE BEING CONSIDERED AS QUASI-DRUGS. HOW IS THE FDA GOING TO REGULATE THAT? >> SOME OF THIS IS UNRESOLVED. I DON'T KNOW THE ANSWER -- [ LOW AUDIO ] -- CLASSIFICATION OF THIS ISSUE. THAT I CAN'T EVEN DRESS. I MEAN, UNDER THE PRESENT CIRCUMSTANCES -- I'M NOT SURE THAT WOULD BE HELPFUL. UNLESS THE ENTIRE PARADIGM IS CHANGED AND WILL BE REGULATED ACCORDING TO SOME ORGAN TRANSPLANT PARADIGM. >> I DO BELIEVE THAT FECAL TRANSPLANTS WILL BE REGULATED BY THE FDA. I THINK A YEAR OR TWO AGO, THERE WAS SOME INSTRUCTION TO THE COMMUNITY WHO WANT TO DO THIS, THAT THEY NEED TO GO TO THE FDA SO THEY CAN REVIEW WHAT IS IN THE POOP. >> CAN A GOVERNMENT AGENCY SUBMIT A BLA? OR DOES IT HAVE TO BE -- >> I DON'T KNOW. WHAT WOULD HAPPEN SHEAR IT WOULDN'T BE SUBMITTED BY A GOVERNMENT AGENCY, IT WOULD BE SUBMITTED BY THE INDIVIDUAL INVESTIGATORS. DR. HERRING WOULD BE THE HOLDER OF THAT BLA. >> I DON'T KNOW IF THERE IS ANY LAW AGAINST THAT. >> SO I UNDERSTAND FROM THE NEW ENGLAND JOURNAL, A RECENT EDITORIAL IN THE NEW ENGLAND JOURNAL FROM THE FDA, THAT THE ENVIRONMENT MAY HAVE CHANGED IN SOME SUBTLE WAYS DUE TO 21ST CENTURY CURES ACT AND REGENERATIVE MEDICINE AGAINST THERAPY. AND ONE OF THE THINGS THAT SORT OF RESONATED WITH YOUR DISCUSSION WAS, THAT SEEMED TO BE A WAY TO FORMERLY INCORPORATE EVIDENCE SUCH AS REGISTRY DATA THAT NORMALLY MIGHT NOT BE ON BLA APPLICATION. WASN'T SURE WHETHER YOU WANT TO COMMENT ON THE -- [ LOW AUDIO ] >> BRUCE, COULD YOU KNOWLEDGE KATE ME? I DON'T KNOW -- COULD YOU EDUCATE ME? I DON'T KNOW WHAT THE PRECEDENT IS FOR ACADEMIC CENTERS APPLYING FOR BLA AND WHAT THE DOWNSTREAM CONSEQUENCES OF OWNING A BLA REGARDS TO LEGAL ISSUES AND FINANCES. >> WHAT HAPPENS IN ALMOST ALL THE GENE THERAPIES, SOMETIMES THEY ARE INITIATED BY AN ACADEMIC CENTER. BUT BY THE TIME THEY GET TO BLA TO SUBMITTING A BLA, THEY HAVE ALREADY BEEN TAKEN OVER BY A DRUG COMPANY, A NEW BIOTECH START UP OR PERHAPS EVEN AN ESTABLISHED PHARMACEUTICAL COMPANY THAT IS DEVELOPING THESE THINGS. THIS IS UNIQUE THIS SITUATION. THERE SHOULDN'T BE ANYTHING -- BASICALLY, THE WAY I SEE, THERE ARE REALLY TWO ISSUES AS I MENTIONED, ONE IS COMING UP WITH THE MONEY TO HAVE SOMEBODY WRITE THIS THING AND THE OTHER IS TO REDESIGN THE WHOLE BLA APPLICATION STRATEGY AS WE DISCUSSED EARLIER. THAT IS -- FRANKLY MY OWN VIEW IS I'D LIKE TO SEE ONE BIG BLA AND THE PEOPLE TO CONTRIBUTE TO IT WOULD EACH HAVE THEIR SHARE OF IT F IT TURNS OUT THAT UNDER REVIEW, THAT EVERY CENTER HEADS BEEN SUCCESSFUL. AND THOSE MAY BE EXCLUDED. THERE MAY BE APPROACHES TO THIS. AND THIS IS NOT APPROACH THE CMC ISSUES, WHICH WOULD BE THE CHEMISTRY MANUFACTURING CONTROL ISSUES WHICH IS NOT REGULATED BY OUR CLINICAL GROUP AND THEY WOULD HAVE TO MAKE SOME KIND OF DETERMINATION AS TO WHETHER OR NOT ALL OF THESE PROCESSES YIELDED ESSENTIALLY THE SAME PRODUCT. SO SCIENTIFICALLY, I DON'T SEE THESE PROBLEMS AS BEING INSURMOUNTABLE. WHEN SOMEBODY COMES UP WITH A MILLION DOLLARS TO WRITE THIS THING. >> SO MAYBE BRUCE OR BERNARD COULD COMMENT ON ANOTHER ISSUE RELATED TO THAT. YOU ALLUDED TO THE COST OF BLA. BASICALLY WE HAVE NO GRANT FUNDING MECHANISM TO SUPPORT DEVELOPMENT AND SUBMISSION OF THE BLA AND AS YOU COMMENTED, IT'S NOT LIKE WRITING A PAPER AFTER THE GRANT HEADS TERMINATED WHERE WE EXPECT -- GRANT HAS TERMINATED WHERE WE EXPECT PEOPLE TO BE ABLE TO DO THAT WITH MINIMAL SUPPORT. THE OTHER ISSUE IS THAT AS YOU POINTED OUT IN THE CANCER IMMUNOTHERAPY, GENE THERAPY ARENA, A LOT OF THIS GETS HANDED OFF TO BIOTECH OR START UPS, SPUN OUT OF ACADEMIA. IT'S PERFECTLY CONCEIVABLE THAT THE BLAs OR ISLETS WOULD BE FILED BY ACADEMIC SPINOFFS BUT THERE IS ANOTHER ELEMENT TO THIS THIS, WHICH IS THE WHOLE UNOS POLICIES ON CHARGING FOR OUR PROHIBITION ON CHARGING FOR ORGAN DONATION AND SUPPLY ORGANS FOR THE FORESEEABLE FUTURE IS THROUGH UNOS. MAYBE WE'LL HAVE ISOLATES THROUGH OTHER TECHNOLOGIES AT SOME POINT. ISOLATES -- BUT THERE ARE COST CONSIDERATIONS FOR A BIOTECH SPINOFF THAT ARE UNIQUE TO THIS FIELD. AND MAYBE THE TWO OF YOU COULD COMMENT ON THAT. [ LOW AUDIO ] >> COULD YOU COMMENT ON WHAT COULD A COMPANY CHARGE FOR THIS PRODUCT? AND UNDER CURRENT POLICIES AND LAW -- [ MULTIPLE SPEAKERS ] >> THE COSTS ARE SUBSTANTIAL. HERE IN THE U.S., WE PAY ALL THE PROCUREMENT ORGANIZATIONS NOW 50 50, 60,000 DOLLARS TO REIMBURSE ORGAN ACQUISITION FEES. THAT IS NOT ONLY FOR A PRISTINE DONOR, IT CAN BE A DONOR WITH MULTIPLE CO-MORBIDITIES AND SO FORTH. SO IN CANADA, THIS IS A WHOLE DIFFERENT SYSTEM. THERE ARE NO FEES. AND THERE IS NO REGULATION. AND EVERYTHING WAS PRETTY MUCH APPROVED 10-15 YEARS AGO BY APPROACHINS AND THE NEXT PROVINCE. SO HERE FOR A COMPANY TO SEE POSSIBLE RETURN ON INVESTMENTS, I THINK IT CANNOT COME FROM THIS FIRST PRODUCT. I THINK A COMPANY COULD POSSIBLY BE ENTICED TO PARTICIPATE IF ONE COULD MAKE THE POINT. YOU CAN BUILD AN IDENTITY IN CELL THERAPY FOR DIABETES OR YOU CAN HAVE INFRASTRUCTURE. YOU CAN BUILD EXPERTISE. YOU CAN TRAIN YOUR STAFF. WHAT YOU ARE SAYING IS ALSO IMPLYING THAT ANYONE WHO WANTS TO REALLY GO FORWARD AND WANTS TO CONSIDER THIS, REALLY NEEDS TO PUT A BUSINESS PLAN TOGETHER AND NEEDS TO LOOK AT THE NUMBERS HOW MANY PATIENT DOSES NEED TO BE PLACED AND NEED TO BE DELIVERED IN A YEAR FOR THIS ORGANIZATION TO BREAK-EVEN AT LEAST. SO IN YOUR FACILITY YOU HAVE ALL THE REGULATORY EXPERTISE THAT YOU NEED. AND YOU HAVE ALL THE ACQUISITION FEES AND YOUR SUPPLIES AND ENZYMES AND OTHER THINGS. SO MAYBE IF YOU PAY -- 50,000 FOR ORGAN ACQUISITION FEES AND THEN MAYBE YOUR NET COST IS 25,000 A PRODUCT, THE MANUFACTURE OF ONE PRODUCT, IT COULD BE A BIT HIGHER. AND THEN YOU HAVE IMMUNOTHERAPY AND ADMISSION AND THEN WHAT ALL BECOMES PART OF THE COST AND IT WILL BE SUBSTANTIAL. ON THE FLIP SIDE, IF THERE WAS ONE COMPANY AND MAYBE ONE GROUP THAT COULD REALLY YOU TAKE THIS O THAT GROUP PROBABLY WOULD ALSO HAVE SOME NEGOTIATION LEVERAGE MAYBE WORTH ORGAN PROCUREMENT ORGANIZATIONS AND MAYBE WITH OTHER SUPPLIERS AND BECAUSE IT WOULD BE PRETTY MUCH THE ONLY GROUP THAT COULD BE ONE OR TWO OR THREE GROUPS AT THE END OF THE DAY WHO DO IT AND MAYBE THAT IS THE ONLY GROUP OR ORGAN PROCUREMENT ORGANIZATIONS TO TALK TO BECAUSE THERE IS NOBODY ELSE TO TAKE THOSE. YOU HAVE TO LOOK FOR ALL THE IMPLICATIONS. >> SUPPOSE THE ROUTE WE ARE PLANNING TO DO, SIMPLIFYING THE -- LET'S SAY THERE IS ONE BLA, SO THEN YOU HAVE 7 SITES OR 6 OR 5 EVEN. THEN THEY COULD SHARE THE COST OF THIS THING WHICH IS A FEW HUNDRED,000 DOLLARS. A FEW HUNDRED THOUSAND DOLLARS, ASSUMING THERE WOULDN'T BE USER FEES. I DON'T THINK THERE WOULD BE. SO THE ORIGINAL INTENT WOULD HAVE BEEN ACHIEVED. >> BECAUSE OF THE AFFECTS OF THE MODEL USED, IT WOULD HAVE TO BE REVIEWED OVER AND OVER AGAIN IN THE ENTIRETY. AND SO AT LEAST THE EFFECTIVENESS STANDPOINT, I DON'T SEE ANYTHING THAT WOULD BE LOST IN TERMS OF SCIENTIFIC RIGOR. >> THIS IS ONE STRATEGY. I THINK I WAS DISCUSSING WITH YOU OVER LUNCH ANOTHER STRATEGY WHERE REALLY THE FOCUS OUGHT TO BE ON THE CLINICAL STUDY REPORTS AND NIAID HAS NOW PRETTY MUCH COMPLETED AND WE ARE LOOKING AT 15,000 PAGES AND REPORTS. AND THAT IS WHAT THE DATA WILL NOT CHANGE. SO NOW YOU COULD HELP SIDES THAT APPLY BY BEING INNOVATIVE IN THE FORMAT THAT IS REQUIRED TO SUBMIT BUT IT WILL, AT THE END OF THE DAY, COME DOWN TO THE VERY SAME CLINICAL STUDY REPORTS THAT ALREADY WITH THE FDA HAS BEEN SUBMITTED AND MAYBE THE INDIVIDUAL SIDES WOULD NEED TO DEMONSTRATE THEIR READINESS REGARDING CMC WITH FACILITIES AND SO FORTH. SO THAT COULD BE A MUCH MORE MANAGEABLE APPROACH AND COULD SUBSTANTIALLY REDUCE THE COSTS ASSOCIATED WITH FIND FIGHTING ASSUMING YOU WILL RAISE WAIVE THE OTHER FEES ALREADY. SO WHETHER THAT IS A REALISTIC -- I KNOW YOU WILL HAVE TO CONSULT YOUR GROUP, BUT WE HAVE TO REALLY BE INNOVATIVE IN HOW WE GET TO THE FINISH LINE. >> FROM OUR STANDPOINT, I DON'T SEE A PROBLEM -- [ LOW AUDIO ] IT'S EASIER TO DO IT UNDER ONE UMBRELLA. I THINK THE ONLY POTENTIAL BLOCK IS CMS -- [ LOW AUDIO ] >> I HAVE ONE QUESTION, IF THERE IS TIME. >> VERY BRIEF. >> OKAY. SO THOSE OF US WHO ARE NAIVE CAN ASK NAIVE QUESTIONS. WE DON'T HAVE FDA APPROVAL ON OUR COMPANY DOING BONE MARROW TRANSPLANTS. THESE WERE DONE IN HOSPITAL INSTITUTIONS. WHY ISN'T THIS JUST THE HOSPITAL-BASED PROGRAM AT CENTERS THAT HAVE THE EXPERTISE TO DO IT? UNTIL WE HAVE A DRUG, WHICH MAY BE CELL LINE AND COMMERCIALIZED, BUT IN THIS CASE, IT'S DONOR DERIVED. WHY ISN'T THIS DONE IN A HOSPITAL-BASED FASHION? >> I THINK, AND YOU MAY WANT TO COMMENT, YOU SEE, ISLETS AS A CELLULAR PRODUCT WERE REGULATED IN A DIFFERENT WAY FROM THE BEGINNING. AND YOU SEE THAT PATH WAS NOT AVAILABLE TO ISLET TRANSPLANTATION. THAT IS MY UNDERSTANDING. >> I THINK THERE IS ALSO THE ELEMENT THAT INITIALLY, BONE MARROW TRANSPLANTS WERE DONE WITHOUT SUBSTANTIAL PROCESSING.& AND AS THE DEVICES FOR PROCESSING SELECTING CELLS THROUGH MAGNETIC TECHNOLOGIES AND OTHERS, ANTIBODY-BASED TECHNOLOGIES, CAME INTO PLAY, THOSE DEVICES GOT LICENSED AS DEVICES. BUT THE WHOLE PROCEDURE AND OPERATION IS SUBJECT TO THE SAME CONCERNS WE HAVE HERE. >> PART WHAT HAVE GOES INTO THIS DECISION IS SOMETHING AS A 351 REGULATED PRODUCT. -- [ LOW AUDIO ] >> THANK YOU ALL THREE OF YOU FOR VERY INTERESTING AND WORTHWHILE DISCUSSION. WE NEED TO MOVE ON TO THE FISCAL YEAR 2020 RESEARCH CONCEPT CLEARANCES AND WE ARE A LITTLE BIT BEHIND SCHEDULE BUT I THINK IN THE INTEREST OF TIME, I WILL ASK EACH OF OUR STAFF MEMBERS TO INTRODUCE THEMSELVES AND THE CONCEPT CLEARANCES, DISCUSS THE BACKGROUND AND THE RATIONAL BRIEFLY AND ENTERTAIN QUESTIONS AND AS WE HAVE DONE IN THE PAST, IF OUR IMPRESSION IS THAT THE QUESTIONS AND COMMENTS ARE NOT EXPRESSING SERIOUS CONCERNS, I'LL ASK FOR A NON-BLOCK RECOMMENDATION AT THE END FOR ALL OF THE CONCEPT CLEARANCES F THERE ARE CONCEPT CLEARANCE THAT IS SEEM TO GENERATE SPECIFIC CONCERNS TO REQUIRE MORE CONVERSATION, I'LL ASK FOR A RECOMMENDATION FOR THAT ONE FAVORABLE OR NOT INDEPENDENTLY. SO STACY, YOU'RE FIRST. AND TRY TO KEEP THINGS BRIEF. I HOPE WE DON'T LOSE COUNCIL MEMBERS ON THE WAY TO THE AIRPORT. >> FOR THOSE WHO DON'T KNOW ME, I'M STACY FERGUSON, I HANDLE THE B-CELL BASIC IMMUNOLOGY PORTFOLIO AND IT INCLUDES ANTIBODY FUNCTION, WHICH IS ACTUALLY A GAP IN MY PORTFOLIO, AND THAT IS THE NATURE OF THIS INITIATIVE. THIS IS A NEW INITIATIVE FOR œI'LL EXPLAIN.REEMENT, WHICH THE GOALS ARE TO ELUCIDATE MECHANISMS OF FC, FC RECEPTOR INTERACTING AND DEENDENT ANTIBODY MEDIATED FUNCTION. THE LONG TERM GOAL IS TO PREDICT THE EFFICACY OF MONOCLONAL ANTIBODY THERAPEUTICS AND TO INFORM DEVELOPMENT OF THESE THERAPEUTICS, NEW ONES, IN VACCINES DESIGNED TO PROMOTE F C' MEDIATED KILLING. JUST AS A BACKGROUND. MONOCLONAL ANTIBODIES IS A RAPIDLY GROWING CLASS FOR CANCER, IMMUNE DYSREGULATION AND INFECTIOUS DISEASE. IN-VITRO ASSAYS TO DEFINE KILLING MECHANISMS IS MISLEADING. IT'S COMMON TO DO NK ASSAYS IN-VITRO AND IMPORTANT TO RECOGNIZED THAT ANTIBODIES ARE POLYFUNCTIONAL AND EFFECTOR CELLS OPTIMIZED FOR IN-VITRO KILLING MAY NOT WORK IN-VIVO AND MAY NOT WORK BY THE SAME MECHANISMS. THE FC RECEPTOR EXPRESSION PATTERNS OF EFFECTOR CELLS CAN DEPEND ON THE CELL TYPE, LOCATION OF THOSE CELLS AND MACRO NATION OF LUNG MAY NOT EXPRESS THE SAME FC RECEPTORS AS THEY DO IN THE GUT OR IN THE LIVER. IT CAN DEPEND ON THE DEVELOPMENTAL STAGE OF THAT CELL AND ALSO A PLASTICITY IN FC RECEPTOR GLYCOSYLATION. THERE IS A LOT OF WORK DONE ON THEMSELVES BUT NOT AS MUCH ON FC RECEPTORS. SO LAST YEAR, WE HAD A WORKSHOP ON FC-MEDIATED KILLING AND JUST TO GIVE YOU A QUICK EXAMPLE OF HOW COMPLICATED THIS IS, THIS IS ONE OF THE STUDIED EPITOPES FOR KILLING AND ALL OF THESE MECHANISMS, WHETHER DIRECTED AT APOPTOSIS, MEDIATED KILLING, ADCCM KILLING MECHANISMS, CAN BE DEMONSTRATED IN-VITRO. AND THAT STILL DOESN'T GIVE YOU AN IDEA OF WHAT IS GOING IN-VIVO, WHICH IS DEFINITELY COMPLICATED AND I WON'T -- MOST PROBABLY KNOW THAT. IF YOU HAVE QUESTIONS, I'M HAPPY TO GO INTO IT MORE. WE DON'T REALLY HAVE TIME FOR AN EXTENSIVE DESCRIPTION. SO THE TYPE OF STUDIES WE ANTICIPATE HERE ARE BOTH MECHANISTIC AND DESCRIPTIVE STUDIES ON EFFECTOR CELL AVAILABILITY, FREQUENCY PHENOTYPES, AT DIFFERENT SITES. AND LOOKING AT THE RELEVANT KILLING MECHANISMS. FC RECEPTORS PATTERNS AND THESE ARE GOING TO BE OFTEN DESCRIPTIVE STUDIES. CHARACTERISTIC OF OPTIMAL EPITOPES. WE KNOW THAT LIKE FORRA TUX IN, THERE ARE ONLY 50 AMINO ACIDS THAT MOST OF THE ANTIBODIES RECOGNIZE YET THEY COMPETE WITH EACH OTHER AND HAVE DIFFERENT EFFECTOR CELL FUNCTIONS AND THE SAME FC VEILANCE, DENSITY OF ANTIBODIES. CONFORMATIONAL REQUIREMENTS OF ANTIBODIES FOLLOWING TO THE TARGETTANT JEB ON THE TARGET CELL. -- TARGET CELL. IF YOU HAVE ANY QUESTIONS I'M HAPPY TO TAKE THEM. >> SET ASIDE FOR THE U01 PART? >> YES. >> GOOD AFTERNOON, EVERYONE. I'M GOING TO PRESENT A PROGRAM ANNOUNCEMENT WE ARE PROPOSING FOR 2020 LOOKING AT PROCESSING AND PRESENTATION OF NON-CONVENTIONAL MHC LIGANDS. SO THE GOAL, SPECIFICALLY IS TO CHARACTERIZE ANTIGEN PROCESSING AND PRESENTATION MECHANISMS THAT ARE USED IN A GENERATION OF NOVEL PEP TITTIC AND NON-PEP TITTIC LIGANDS PRESENTED BY CLASSICAL AND NON CLASSICAL MHC1 AND 2 MOLECULES. THE IDEA BEING, WE DON'T UNDERSTAND HOW MUCH THEY CONTRIBUTE TO PROTECTIVE IMMUNE RESPONSES TO INFECTIOUS PATHOGENS AND VACCINES, PATHOGEN-ASSOCIATED IMMUNE PATHOGENESIS AND OTHER IMMUNE-MEDIATED DISEASES. SO SOME OF THE TOPICS THAT WE CAN LOOK AT WITH THIS FOR THE R01 AND R21 MECHANISM, INCLUDE BUT ARE NOT EXCLUSIVELY LIMITED TO, WHEN THERE IS TRANSLATION FROM A NON-TRADITIONAL STARTING CODON, WHEN WE ARE HAVING PEPTIDES THAT DERIVED FROM NON-CONTIGUOUS SEQUENCES SUCH AS HYBRID PEPTIDES, NEOANTIGENS WHICH CAN BE VERY IMPORTANT IN AUTOIMMUNITY, AND THEN IS THERE THE WHOLE CATEGORY OF PEP TIDDIC AND NON-PEPTIDIC LIGANDS FOR HLAEF OR G OR MEAT-DERIVED CD1 EPITOPES AND WE'LL ALSO LOOK AT TECHNOLOGIES. THIS WILL BE A CSR REVIEW. THERE IS NO SET ASIDE FOR THIS. DATE AND DAIDS ARE PARTICIPATING IN THIS AND HOPING TO STIMULATE RESEARCH INTEREST IN THIS. SO PERHAPS 5-7 APPLICATIONS PER CYCLE WITH 1-3 AWARDS PER YEAR PAYLINE IN THIS AREA. ANY QUESTIONS? OTHERWISE I'LL TURN IT OVER TO JOE. >> [ OFF MICROPHONE ] >> THAT COULD BE PART OF IT. SO IN THE FIRST AREA WHERE WE ARE LOOKING AT WHETHER IT IS A TRADITIONAL START OR NON-START. -- >> [ OFF MIC ] >> THAT IS SOMETHING THAT AN INVESTIGATOR CAN COME IN WITH AN APPLICATION AND SURE, WE WOULD DEFINITELY LOOK AT THAT. >> SO I WONDER, WOULD THAT BE CONSIDERED MAYBE A NEO-ANTIGEN? COULD IT BE CONSIDERED UNDER THE NEO-ANTIGEN CATEGORY? NOW YOU CHANGED THE STRUCTURE OF WHAT SHOULD BE A CELL - -- [ LOW AUDIO ] >> ARE YOU TALKING LIKE HUMANIZING A ANTIBODY, CHANGING AMINO ACID SEQUENCE? >> ANY PROTEIN. >> THAT WOULD BE DIFFERENT THAN OPTIMIZING CODON USAGE. >> WOULD THIS APPLY MAINLY FOR INFECTIOUS DISEASES OR AUTOIMMUNE DISEASES? WHAT IS THE APPLICATION? >> DIFFICULTY BOTH. DEFINITELY BOTH. >> I THINK THE HYBRID PEPTIDE IDEAS COULD BE HUGE ENOUGH IMMUNITY. I'M CURIOUS, HOW DO YOU -- WHEN THERE IS NO SET ASIDE MONEY, HOW DO YOU ACHIEVE YOUR GOALS FROM YOUR PROGRAM? >> THAT IS AN INTERESTING QUESTION. ULTIMATELY WE'LL BE MONITORING TO SEE HOW MANY APPLICATIONS COME IN AND HOW MANY WE ARE ABLE TO FUND. WE'LL HOPEFULLY BE ABLE TO SUPPORT A NUMBER 2 PAY LINE. IF WE ARE NOT GETTING THE GOALS, THEN MAYBE IT'S SOMETHING WE CAN REVISIT FOR A FUTURE INITIATIVE WHERE WE PUT SOME SET ASIDE ASIDE. THAT WOULD BE AFTER WE SEE IF THIS IS A SUCCESSFUL MECHANISM FOR GENERATING THE INTEREST AND GETTING IN THE APPLICATION. >> MY NAME IS JOAN BREEN. I'M SECTION CHIEF FOR THE IMMUNOREGULATIONS SECOND IN THE BASIC IMMUNOLOGY BRANCH AND I WANT TO TELL YOU ABOUT THIS PROPOSED INITIATIVE THAT THE PROGRAM WHICH I CURRENTLY MANAGE WITH TIM GUNNEDDER, WHO YOU JUST HEARD FROM, SO THIS IS THE CURRENT PROPOSAL IS CALLED, COMPUTATIONAL MODELS IN IMMUNITY, THE CURRENT PROGRAM THIS WERE CALLED MODELINGNS OF- IMMUNITY FOR BIODEFENSE, AND THE PROGRAM GOALS REALLY HAVEN'T CHANGED, ALTHOUGH WE CHANGED THE MECHANISMS, THE WAY WE HAVE DONE THIS. AND THAT IS TO DEVELOP NEW AND IMPROVED COMPUTATIONAL MODELS OF IMMUNE RESPONSES, AND AS ITS NAME IMPLIES, IT'S BASED ON BIODEFENSE WITH THE REQUIRED CATEGORY PATHOGENS AND THEN ADDITION OF EMERGINMERGINGMERGING AND REIMMERGING INFECTIOUS DISEASES OVER TIME. IT'S CORE, WHAT WE ARE REALLY TRYING TO ADHERE IS VALIDATION AND IMPROVEMENT OF MODELS USING EXPERIMENTAL MANIPULATION AND IMMUNOLOGICAL EXPERIMENTATION, COUPLED TO COMPUTATIONAL AND INFORMATICS TECHNOLOGIES. AND REALLY TRYING TO MARY THOSE TWO AREAS. AND IT'S BEEN A CHALLENGE -- MARRY THOSE TWO AREAS. -- AND ALSO WE HAVE SEEN REWARDS AND I'LL TELL YOU A LITTLE BIT ABOUT THAT BRIEFLY. ONE EMPHASISES IS TO MAKE MODELS AS WELL AS DATA GENERATED PUBLICLY-AVAILABLE. PARTICULARLY WHEN THE PROGRAM WAS BEGUN, WE ALWAYS HAD SUMMER SCHOOLS AND IMPOSIA EACH SUMMER TO BRING THE COMMUNITIES OF IMINOLOGYISTS AND COMPUTATIONAL FOLKS TOGETHER TO SYNERGIZE AND BRING THE TOOLS FROM EACH COMMUNITY. SO SOME OF THE ACCOMPLISHMENTS OF THE PROGRAM IN ABOUT 10 YEARS, THE CENTERS OF WHICH WE HAD FOUR EACH AWARD, HAVE 143 PEER-REVIEWED PUBLICATIONS. I HAVE HERE LISTED SOME OF THE TOOLS THAT THEY HAVE GENERATED. I COULD HAVE EASILY PULLED OUT SOME OF THE PAPERS AS WELL. IT'S FROM DIVERSE AREAS OF SCIENCE AND I'LL POINT OUT ONE, THE FOURTH BULLET, THIS WAS THE FIRST AGENT-BASED MODEL FOR SIMULATING IMMUNITY, IN 24 CASE, A GASTROINTESTINAL INFECTION BY A GROUP AT VIRGINIA TECH. IT'S NOT IN OUR POOL BUT THIS WAS THE PREVIOUS ITERATION OF THE PROGRAM. AND THESE TOOLS ACTUALLY THEY ARE STILL AVAILABLE, AND THEY NOWADAYS UNLIKE WHEN THE PROGRA STARTED, ALL OF THESE ARE DEPOSITED WHEN THESE FOLKS PUBLISHED THEIR PAPERS AND ARE PUT INTO COMMON ELEMENTS WHERE THEY CAN BE FOUND BY THE REST OF THE COMMUNITY. SO THE CURRENT PROGRAM, THAT WAS AWARDED IN LATE 2014, ACTUALLY, ARE FOUR CENTERS, AND COINCIDENTALLY, THEY ARE WORKING ON INFLUENZA ALTHOUGH THAT WASN'T THE ORIGINAL DESIGN. THEY JUST TURNED OUT TO BE THE TOP APPLICATIONS. THEY ARE WORKING ON THINGS LIKE EVOLUTION OF IMMUNE RESPONSES TO FLU, REALLY USING ADAPTIVE IMMUNE RESPONSE, COUPLED TO A STRONG COMPUTATIONAL GROUP AT EMORY. SOMETHING WE DIDN'T EXPECT BUT TURNED OUT TO BE A STRENGTH IS A STRUCTURE-BASED DESIGN OF ANTIBODY ANTIGEN INTERACTIONS WITH A GROUP FROM JAMES CROW AND A WHOLE BUNCH OF REALLY STRONG STRUCTURAL IMMUNOLOGISTS, AS WELL AS COMPUTATIONAL FOLKS. EARLY IMMUNITY STUDIES BY STEWART AT ALBERT EINSTEIN, AND TOM KEPLER AND GARNET, WHO ARE MONITORING AFFINITY MATURATION AND THESE WERE U19 PROGRAMS. THE KIND OF WORK THAT THEY ARE DOING, I JUST WANTED TO GIVE YOU A SNAPSHOT, AND IT TERPS OUT THAT IT WAS FORITUTE US THAT THIS WAS BEFORE THE RECENT PUBLICATIONS OF THE UNIVERSAL VACCINE APPROACH FOR INFLUENZA. ONE PROBLEM THAT IS BEING ATTACKED IS BASICALLY THE LACK OF A BOOST WITH SUCCESSIVE VACCINES FOR HA ANTIBODIES. AND BASICALLY THERE IS VERY LITTLE NAIVE POPULATION, OF COURSE, AND WHAT THIS IS GROUP FROM THE EMORY GROUP FOR THE HEAD AND THE STEM, WHAT CAN YOU SEE IN THE FIGURE THAT THERE IS NO BOOST. YOU CAN MAKE AN ARGUMENT THERE IS A BOOST FOR THE HEAD BUT THAT'S NOT SUCH A STRONG ARGUMENT AND THERE IS CLEARLY NO BOOST FOR THE STEM AND THAT IS UNFORTUNATE BECAUSE THE STEM IS AN AREA THAT IS BEING TARGETED AGGRESSIVELY BECAUSE YOU MAY BE ABLE TO DESIGN A UNIVERSAL APPROACH USING THE STEM. SO THIS GROUP IS TRYING TO MODEL AND UNDERSTAND WHY WE ARE GETTING A LACK OF BOOST AND WHY WE ARE NOT GETTING B-CELL ACTIVATION. AND REALLY HOW IN THE DOWNSTREAM TO DESIGN A BETTER APPROACH TO DO THIS SINCE WE HAVE BEEN AS WE STATED, NOT TERRIBLY SUCCESSFUL OVER THE LAST 30 YEARS. I'M GOING TO SKIP THAT FOR TIME. ANOTHER APPROACH IS BY THE VANDERBILT GROUP WHERE THEY ARE REALLY DOING MODELING OF ANTIBODIES THAT THEY PULL OUT OF PEOPLE IN A VACCINE CLINIC WHO HAVE BEEN IMMUNIZED AGAINST FLU TO TRY TO UNDERSTAND THE ANTIBODY INTERACTIONS, TRYING TO LOOK AT THE STEM VERSUS HEAD IN A STRUCTURAL WAY, TO TRY AND THEN ANALYZE THOSE INTERACTIONS AND THEN IMPROVE THEM POTENTIALLY GENERATE THERAPEUTIC ANTIBODIES THAT WOULD BE USED PERHAPS EVEN IN LIEU OF A VACCINE. AND THIS HAS BEEN A SUCCESSFUL PROGRAM. IT'S NOT WHAT WE HAD IN MIND FOR COMPUTATIONAL IMMUNOLOGY, BUT IT HAS BEEN A REALLY STRONG CENTER. WHAT WE PROPOSED HERE FOR FY20, IS TO RECOMPETE THE PROGRAM WHERE MAJOR CHANGES. WE WOULD LIKE TO USE A Y01 MECHANISM. SO WE REALLY WANT AN INTEGRATED IMMUNOLOGY COMPUTATIONAL PROJECT RIGHT OUT-OF-THE-GATE WORKING ON NIAID PRIORITIES OF COURSE, NOT GOING TO SPECIFICALLY CALL OUT CATEGORY A-C PATHOGENS AND HOPE TO SUPPORT 4 OF THESE IN FY20. I'M HAPPY TO TAKE QUESTIONS. THANK YOU. >> SO I'M THE PROGRAM OFFICER FOR THE PORTFOLIO. WHAT I WANT TO PRESENT IS A NEW CONCEPT CALLED MOLECULAR AND GENETIC CHARACTERIZATION OF INBORN IMMUNITY AND WE WILL SEE BOTH APPLICATIONS. THE EXISTING PORTFOLIO CONTAINS A COLLECTION OF PROGRAM ANNOUNCEMENTS THAT SOLICIT R01 AND R31s AND R33s IN RESEARCH WITHOUT ANY RESTRICTION IN THE TOPIC. AND ALSO AN RFA WHICH IS A U24, AND THIS AIMS TO BUILD RESOURCES FOR INVESTIGATORS IN THE PRIMARY IMMUNE DEFICIENCY FIELD TO ASSIST IN THEIR RESEARCH. WHAT WE PROPOSE TO DO IS TO REPLACE THIS RFA, THIS U24, WITH A NEW INITIATIVE. SO, WHAT I WANT TO DO IS JUST IN THE NEXT TWO SLIDES GIVE YOU A BRIEF OUTLINE OF WHAT THE RESOURCE PROGRAM IS ALL ABOUT. AND MAYBE COMMUNICATE SOME OF THE REASONS WHY WE WANT TO REPLACE WITH A NEW INITIATIVE. SO THIS IS COOPERATIVE AGREEMENT. AND IT IS CALLED THE UNITED STATES IMMUNE DEFICIENCY NETWORK. AND IT'S BUILT TO BUILD AND MAINTAIN THREE TYPES OF RESOURCES. THE FIRST IS A REGISTRY OF CLINICAL DATA FROM INDIVIDUALS WITH PRIMARY IMMUNE DEFICIENCIES DEFICIENCIES. PURPOSE OF BEING ABLE -- THE SCIENTISTS IN THE FIELD TO BE ABLE TO QUERY THIS DATA AND RETRIEVE INFORMATION THAT IS RELEVANT TO PRIMARY IMMUNE DEFICIENCIES. SO THE NEXT RESOURCE IS TO BUILD REPOSITORY OF CELLS AND OTHER MATERIALS FROM SUCH PATIENTS AND THIS HAS BEEN NOT AS WIDELY USED. THE LAST SAMPLE DEPOSITED WAS 2009. SO IT'S BEEN A WHILE. WE HAD A NEW SAMPLE DEPOSITED. WE HAVE WHAT IS THE -- ALREADY IN THE REPORT IS BEING USED TO SOME DEGREE BUT IT'S NOT OUTSTANDING. AND THE LAST RESOURCE IS TO BUILD EDUCATIONAL OPPORTUNITIES SUCH AS TRAINING AND DISSEMINATION OF INFORMATION FOR FELLOWS WHICH WE INTEND TO SUPPORT. WE ARE VERY SUPPORTIVE OF THIS AND WE WILL SUPPORT USING OTHER MECHANISMS. IN THE NEXT SLIDE I WANT TO BRIEFLY OUTLINE WHAT THE PROBLEM HAS DONE -- PROGRAM HAS DONE DURING THE LAST ITERATIONS, SINCE THE BEGINNING OF 2015. IN TOTAL, WE HAVE ABOUT 5000 REGISTRY ENTREES AND THIS IS SINCE 1992 IN TOTAL. SO NOT A LOT OF ENTREES AND WE HAVE MORE THAN 40 RECRUITMENT CENTERS. SO DESPITE THE LARGE NUMBER OF CENTERS THAT THEY ARE AVAILABLE AND SIGNED UP TO ENTER OR REGISTER DATA INTO THE REGISTRY, WE DON'T HAVE A WHOLE LOT OF EXCITEMENT FROM THE FIELD IN ENTERING DATA AS THIS. THIS YEAR THE REGISTRY WAS MOVED TO THE CLOUD WHICH WAS A BIG ADVANCEMENT IN TERMS OF USABILITY AND STABILITY OF THE REGISTRY. SINCE 2015, WE HAD ABOUT APPROXIMATELY 140 QUERIES, WHICH LED TO APPROXIMATELY 30 POSTERS OR PRESENTATIONS, MOST OF THEM OUR POSTERS. AND THE PUBLICATIONS ARE USUALLY DESCRIPTIVE IN NATURE AS EXPECTED FROM A REGISTRY. WE HAVE A REASONABLE SUCCESS WITH THE TRAINING ASPECT OF THE GRANT. WE HAD ABOUT 40 TRAVEL GRANTS TO FELLOWS. ABOUT 19 VISITING PROFESSORS THAT GO TO DIFFERENT MEDICAL INSTITUTIONS TO GIVE GRAND ROUNDS AND WE HAD ABOUT 10 VISITING FELLOWS FROM 1-2 WEEK VACATION AT DIFFERENT CENTER. AND AGAIN I WANT TO MAINTAIN WE WILL MAINTAIN THE TRAINING ASPECT USING OTHER RESOURCES. AND FINALLY THE COLLABORATIONS THAT ARE MEANT TO BE BUILT FROM THIS PROGRAM HAVE BEEN -- COULD HAVE BEEN BETTER. THE FOLLOWING INFANTS WITH LOW LYMPHOCYTES IS A COLLABORATION WITH UCSF AND IT IS A REGISTRY BUILT TO FOLLOW-UP INFANTS WITH LOW LYMPHOCYTES AND IT IS COLLECTING LONGITUDINAL DATA, WHICH IS IMPORTANT. BUT STILL HAVING TROUBLE RECRUIT RECRUITING MORE SUBJECTS. AND WE HAD A FEW GRANTS FROM INDUSTRY. IF YOU HAVE ANY QUESTIONS ON THIS PART BEFORE I CONTINUE TO DESCRIBE THE NEW INITIATIVE? YES? >> WONDERING IT SEEMS LIKE A GREAT IDEA TO HAVE A REPOSITORY FOR THESE TYPE OF PATIENTS. WHAT IS THE CHALLENGE? WHY DO YOU THINK NO SAMPLES HAVE BEEN DEPOSITED FOR SO LONG? >> THE BIOREPOSITORIES IS ONE ASPECT OF THE PROGRAM AND THE REGISTRY DATA IS ANOTHER ASPECT OF THE PROBLEM. ARE YOU ASKING FOR THE BY ONE REPOSITORY OR REGISTRY OF THE DATA? >> BOTH. >> BOTH. OKAY. SO ONE OF THE ISSUES IS THAT THAT THERE ARE A LOT OF REGULATIONS IN PLACE IN TRANSFERRING MATERIAL FROM ONE INSTITUTION TO WHEREVER THE SAMPLE SIZE IS. SO THERE NEEDS TO BE AGREEMENTS IN PLACE AND LAWYERS GETTING INVOLVED. NOBODY HAS THE TIME TO DO THAT T JUST DOESN'T HAPPEN. THE REGISTRY OF CLINICAL DATA HAS IT NEEDS TO BE ENTERED MANUALLY. AND THAT CARRIES ITS OWN ISSUES OF ACCURACY AND TIME INVOLVEMENT. AND EVEN THOUGH WE OFTEN FOR THE USE TO ENTER DATA FOR CENTERS, WE STILL DON'T GET MANY OFFICER. SO I DON'T REALLY KNOW. WHAT I WOULD SAY IS MAYBE THERE IS NOT MUCH INTEREST DESPITE THE FACT THAT THE COMMUNITY -- THIS PROGRAM IS 25 YEARS OLD. THIS HAS BEEN GOING ON SINCE 1992. WE MANAGE TO GET 5000 ENTRIES. SO IT TAKES A LONG TIME TO ENTER THE DATA. IT'S MANUAL. AND PEOPLE ARE JUST NOT PUTTING IN THE TIME. YOU CAN MAKE YOUR OWN ASSESSMENT BUT THAT IS THE FACT THAT WE CAN'T GET A LOT OF EXCITEMENT OUT OF IT. WE CAN'T GET INVESTIGATORS TO BE VERY EXCITED IN GETTING INVOLVED INTO THE REGISTRY. WE HAVE MORE THAN 40, ABOUT 45 CENTERS WITH IRBs IN PLACE. AND WE JUST DON'T. AND WE OFTEN THE STUFF TO TO THE SITES AND ENTER DATA THERE OR GET THE DATA MAILED AND ENTER THE DATA THERE. BUT WE HAVE NOT FOUND A WAY TO GET THE COMMUNITY INTERESTED. SO FOR THOSE REASONS, AND ALSO BECAUSE THERE IS NEW TECHNOLOGY AVAILABLE TODAY WITH THE GENOMICS AND I THINK THE DIAGNOSIS HAS BEEN THAT WE HAVE WAYS TO DIAGNOSE AND TREAT THEM SO MUCH MORE RAPIDLY AND EFFECTIVELY THAT I THINK PEOPLE'S EFFORTS ARE GOING ELSEWHERE. AND THIS IS THE REASON FOR PROPOSING THE NEW INITIATIVE THAT I WILL DESCRIBE. SO AS I SAID, IT'S CALLED THE MOLECULAR AND GENETIC CHARACTERIZATION OF IMMUNITY. ALSO CALLED PRIMARY IMMUNE -- AND AS WAY OF INTRODUCTION BRIEFLY, THESE ARE MONOGENEIC AND RECENTLY DIGENEIC AND THERE ARE MORE THAN 350 OF THEM IDENTIFIED SO FAR AND THE NUMBER INCREASES VERY RAPIDLY. THEY ARE CHARACTERIZED BY HIGHLY DIVERSE PHENOTYPES SUCH AS INFECTION OR INFLAMMATION. THEY REVEAL NEW CONCEPTS AND PATHWAYS AND THEY PAVE THE WAY FOR PRECISION MEDICINE. AND THIS IS THE REASON FOR PROPOSING THIS TODAY. BECAUSE WE BELIEVE THE WORK I'M GOING TO PROPOSE WILL LEAD TO PRECISION MEDICINE FOR THESE DISORDERS. THE BIOCHEMICAL AND MOLECULAR CHARACTERIZATION OF GENETIC DEFLECT CAUSE INBORN ERRORS OF IMMUNITY ARE DIVIDED INTO TWO VERY BASIC GENERAL STEPS. THE FIRST STEP IS THE GENETIC VARIANT DISCOVERY WHICH IS DONE THROUGH NEXT-GEN SEQUENCING AND COMPUTATIONAL ANALYSIS AND OUT OF THOUSANDS AND THOUSANDS OF VARIANTS THAT IDENTIFIED THROUGH NEXT-GEN SEQUENCING, THE COMPUTATIONAL ANALYSIS WILL MEDIATE A PROCESS OF SELECTION AND PRIORITIZATION OF THESE VARIANTS AND YOU COME DOWN TO A FEW, MAYBE 10 OR 15 OF EITHER CODING OR NON CODING VARIANTS WHO ARE VERY LIKELY TO CAUSE DISEASE. AND THE BOTTLENECK IN GENOMIC RESEARCH TODAY IS TO GO FROM THIS GENOMIC VARIANCE, GO THROUGH THEIR BIOCHEMICAL VALIDATION AND DEMONSTRATE DISEASE CAUSALITY AND ELUCIDATE THE MOLECULAR MECHANISM OF THE DISEASE. SO WHAT THIS INITIATIVE WANTS TO DO, IT WANTS TO CONCENTRATE ON THE SECOND STEP, THE BIOCHEMICAL VALIDATION, AND SORT OF FEED INTO THE BOTTLENECK OF THIS PROCESS AND TRY TO SUPPORT SOME OF THIS IDENTIFICATION OF NEW DISEASES AND IMMUNE DISORDERS. SO, WHAT WE REQUIRE FOR THIS NEW CONCEPT IS THE VARIANT SELECTION AND PRIORITIZATION TO BE FINALIZED. ALL VARIANTS ARE ACCEPTABLE EXCEPT SOMATIC VARIANTS. SINGLE NUCLEOTIDE VARIANTS AND DILUTIONS AND -- [ READING ] ARE ALL ACCEPTABLE. THE DISEASE PHENOTYPE BOTH AT THE CLINICAL OR CELLULAR LEVELS WILL BE WELL DEFINED THE INFORMATION ABOUT THE COHORT OR PEDIGREE SHOULD BE AVAILABLE. STUDIES AND SINGLE PATIENTS ARE ACCEPTABLE AS LONG AS THEY FOLLOW THE ESTABLISHED GUIDELINES. I JUST WANT TO SAY THAT THERE IS A WAY -- OUR EXISTING PROGRAM DOES SUPPORT NEXT GENERATION SEQUENCING FOR PIDs. IT'S NOT THAT WE DON'T SUPPORT THIS RESOURCE. WE DO. FOR THIS PARTICULAR INITIATIVE, WE WANT THE NEXT GENERATION SEQUENCING TO BE FINALIZED BECAUSE IT IS USED IN THIS CASE AS A DIAGNOSTIC. AND THIS IS OR HAVE LISTED 3 EXAMPLES OF PRIMARY IMMUNE DEFICIENCIES IDENTIFIED IN 5-6 PATIENTS. VERY FEW. AND THE WAY IT WORKED OUT, THEY HAD A PEDIGREE OF A FAMILY OF TWO WITH A VERY SIMILAR CLINICAL PHENOTYPE, THEY KNEW THEY HAD A PID. THEY CAME UP WITH A VARIANCE AND DID THE PRELIMINARY DATA AND THEY IDENTIFIED THE POTENTIAL DEFECT BEHIND IT. AND SO THIS IS THE TYPES OF APPLICATIONS WE WANT TO SOLICIT. BECAUSE THIS IS THE TYPE OF WORK WHICH IS GOING TO LEAD TO PRECISION THERAPY FOR THESE SPECIFIC DISORDERS. FOR EXAMPLE, IN THE FIRST ONE, THE FIRST EXAMPLE, THE ISG15 AND THE USB18 DEFICIENCY, THESE ARE TWO GENES THAT ARE ONLY GENES SO FAR THAT HAVE BEEN INVOLVED IN THE NEGATIVE REGULATION OF TYPE I INTERFERONS. VERY SIGNIFICANT. AND SO, THEY WILL DESIGN TARGETED THERAPIES FOR THESE 2 GENES TO ENHANCE BOTH ANTIVIRAL RESPONSES AND ALSO TO AUTOIMMUNE DISEASES WITH ELEVATED TYPE I INTERFERON RESPONSES. THE SECOND DEFICIENCY IS WHAT CAUSES ER STRESS AND RESULTS IN A COMBINED IMMUNODEFICIENCY AND SUSCEPTIBILITY TO INFECTION. SO PROVIDES OPPORTUNITY TO HAVE A THEY WERE THEY TARGETS THE ER STRESS AND TO TREAT INFECTIOUS DISEASES. HIGHLY SIGNIFICANT. SO WE HOPE THE OUTCOMES OF THIS INITIATIVE IS TO IDENTIFY THE DISEASE THAT WILL LEAD TO EARLY AND ACCURATE DIAGNOSIS. IT WILL ELUCIDATE THE MOLECULAR MECHANISM OF DISEASE AND LEAD TO PRECISION MEDICINE THERAPEUTICS. AND ASIDE FROM THE PRIMARY IMMUNE DEFICIENCY FIELD, IN GENERAL, IMNOUNALY, IT WILL PROVIDE INSIGHTS FOR THE FUNDAMENTAL MECHANISM OF HUMAN IMMUNITY AND IT WILL OF COURSE REVEAL NEW CONCEPTS AND PATHWAYS AND THAT IS ALL I HAVE. IF YOU HAVE ANY QUESTIONS. >> HELLO, EVERYONE. I'M LANAN PEREZ. I'M A PROGRAM OFFICER WITH THE RADIATION AND NUCLEAR COUNTERMEASURES PROGRAM. AND TODAY I'M GOING TO TELL YOU ABOUT RENEWED INITIATIVE. SO THE INITIATIVE WE ARE TRYING TO RENEW IS GOING TO BE USING A BOTTLE MECHANISM AND THE REASON WHY WE WANT TO USE THAT IS IT GIVES MORE FLEXIBILITY AND CONTROL AS TO WHAT WE DO WITH THE CONTRACTS. WE EXPECT APPLICATIONS AND WE ARE HOPING TO FUND ABOUT 1-2, 3-YEAR AWARD CONTRACTS. AND IN THE PAST WE HAD SUCCESS WITH ABOUT FUNDING 2-3 AND I'LL TELL YOU MORE ABOUT THAT. THE GOALS ARE COUNTERMEASURES OF RADIATION INJURY AND TO SUPPORT PROOF OF CONCEPTS IN THE USE OF UNMET NEED IN THE LUNG AND GI AND ACUTE RADIATION AREAS. THIS WILL HELP US SUPPORT STUDIES FOR FDA LICENSURE OF MEDICAL ISSUES THAT COME INTO OUR SPACE SINCE MANY ARE AT DIFFERENT LEVELS OF DEVELOPMENT. AND SO, WE ARE HOPING TO FUND THOSE AND SO, JUST TO GIVE YOU A LITTLE BIT OF A BACKGROUND, WE HAVE SOME DRUGS HAVE BEEN APPROVED WITH THE HEMATOPOIETIC ACUTE RADIATION SYNDROME, IN ALASKA THANKS TO THE HARD WORK OF OUR PROGRAM AND CHAPERONING AND PUSHED THROUGH BY BARDA, OUR SISTER AGENCY IN THIS EFFORT. PREVIOUS PROGRAMS TO ADJUST RADIATION INJURY SPAN DIFFERENT MECHANISMS. ONE BEING COOPERATIVE AGREEMENTS AND OTHER GRANT MECHANISMS AND THOSE ARE MORE FOR BASIC-LEVEL RESEARCH SUPPORT AND A FEW OF THOSE HAVE BEEN IN THE AREAS OF CELLULAR THERAPEUTICS AND OTHER MEDICAL COUNTERMEASURES WITHIN SPECIFIC INJURIES AS WELL AS VASCULAR INJURIES AND TECHNOLOGIES. WE ALSO HAD SBIRs AND DEVELOPMENT OF MEDICAL COUNTERMEASURES AND TECHNOLOGIES IN OUR SPACE. WE HAVE RENEWAL IN FISCAL YEAR SEVENTEEN AND 18, WE HAD THE 17 WASN'T UNDER OMNIBUS, THE NEXT ONE WAS UNDER THE OMNIBUS AND SUPPORTED TWO DIFFERENT AREAS. ONE WAS WITH MEDICAL COUNTERMEASURE SPACE AND ONE SUPPORTING THE BIODISSYMMETRY BIOMARKERS AND DEVICES SPACE. AND WE WERE ABLE TO SUPPORT TWO APPLICATIONS THAT CAME IN THROUGH THE MEDICAL COUNTERMEASURE AREA. AND THOSE ARE ADDRESSING LUNG INJURY WHICH IS GOOD BECAUSE THAT IS ONE OF THE AREAS THAT IS IN NEED RIGHT NOW. THE BIODISSYMMETRY APPLICATIONS, UNFORTUNATELY WERE NOTLY NOT UP TO THE LEVEL OF RESEARCH WE NEED TO SUPPORT UNDER CONTRACT MECHANISMS. SO WE DIDN'T FUND THOSE AND WE ARE HOPING TO GO BACK AND FUNNED THOSE THROUGH ANOTHER MECHANISM. SO IF YOU HAVE ANY QUESTIONS, I CAN ANSWER THEM. THANK YOU. >> JIM, I TAKE IT YOU JUST ENTERTAINED TO MARK SOME OF THE ADVANTAGES OF THIS? GOOD. WITH THAT, NOW WE ARE CLEAR AND SO A FEW QUESTIONS AND COMMENTS. SECOND TO APPROVE GOING AHEAD WITH THESE CONCEPT CLEARANCES. OKAY. FOR UNBLOCKED RECOMMENDATIONS, WE ARE FREE TO GO AHEAD WITHOUT CONFLICTS, UNLESS YOU THINK IT IS PARTICULARLY SERIOUS. IF NOT, WE CAN GET A SECOND FROM ONE OF THE OTHER COUNCIL MEMBERS MEMBERS. DONE. WITH THAT, YOU'LL HEAR FROM -- YOU NEED TO VOTE ON LINE. SO WE ARE ALL FINISHED. ACTUALLY WE ARE A LITTLE AHEAD OF SCHEDULE. LET ME THANK YOU ALL FOR A PRODUCTIVE DISCUSSION THIS AFTERNOON AND WE WISH YOU SAFE TRAVELS HOME.