>> LET'S GET STARTED. I THINK WE WERE JUST TALKING ABOUT THE LUNCHTIME, IT WAS A NICE OPPORORTUNITY FOR PEOPLE TO GET BETTER INFORM -- GET TOGETHER INFORMALLY AND TALK ABOUT THE COMMITTEE AND OTHER THINGS. SO WORKED OUT FINE. WE'RE GOING TO NOW MOVE TO DR. ROBERT CONLEY, THAT'S GOING TO TALK AND UPDATE US ON THE PROGRESS IN DEVELOPING RESOURCES TO ENHANCE BIOMARKERS AND INCLUSION IN EARLY PHASE TRIALS. >> THANK YOU. CAN EVERYBODY HEAR ME? I APPRECIATE THIS OPPORTUNITY TO CTAC. THIS IS THE SECOND TIME I HEARD ABOUT THIS PROGRAM. THE LAST TIME WE HAD NOT BEEN RUNNING AND THIS TIME WE HAVE BEEN RUNNING ABOUT A YEAR. THE OTHER THING I WOULD LIKE TO SAY IS KEEPING WITH THE THEME OF THIS MEETING CAN BE A PROGRAM USED TO ENHANCE EARLY PHASE TRIALS BUT IT'S NOT RESTRICTED TO THAT. WHY DID THE CLINICAL ASI DEVELOPMENT PROGRAM -- ASSAY PROGRAM GET STARTD? IT IS A PILOT AT THIS TIME. AND IT'S BEEN TALKED ABOUT A LITTLE BIT TODAY BUT BASICALLY WE DO GET CLINICAL TRIAL PROTOCOLS AND SEE THEM IN THE LITERATURE. THEY OFTEN DO INCLUDE MARKERS WHICH WE CALL INTEGRAL MARKERS THAT LOOK FOR ELIGIBILITY, STRATIFICATION OR TREATMENT ASSIGNMENT. AND THESE ARE BASICALLY IN VITRO DIAGNOSTIC TYPE MARKERS. HOWEVER THE ASSAYS USED IN THE PAST TO DETERMINE MARKERS DONE MEET STANDARDS REQUIRED FOR CLINICAL DECISION MAKING IN THE MODERN ERA AND CERTAINLY WITH PUSH TOWARD COMPANION DIAGNOSTIC S WE WANT TO DEVELOP DIAGNOSTICS MOST HELPFUL FOR DRUG DEVELOPMENT AS WELL AS FURTHER DOWN THE LINE. SO PREDICTIVE MARKERS AN ROBUST MEANS TO MEASURE ARE URGENTLY NEEDED IN CLINIC. SO TO GO OVER A LITTLE BIT WHY ARE WE CONCERNED? FIRST THE ANALYTIC PERFORMANCE, ANALYTICAL VALIDITY NEEDS TO BE FIT FOR THE PURPOSE YOU WANT TO USE IT FOR. THE ANALYTICAL VALIDATION REVOLVES AROUND HOW THE TEST CAN TEST THE ANOLYTE OF INTEREST. THE CLINICAL VALIDITY THEN MEANS HOW WELL DOES THIS TEST RESULT CORRELATE WITH OUTCOME YOU'RE INTERESTED IN, WHATEVER THE OUTCOME YOU MIGHT BE INTERESTED IN. THE CLINICAL UTILITY BASICALLY REFERS TO IF YOU USE THIS TEST DOES THAT HELP YOU DECIDE A TREATMENT FOR PATIENT BETTER THAN IT COULD WITHOUT IT IN SOME WAY. ASSAY QUALIFICATION IS USED TO LINK A BIOMARK WE ARE A BIOLOGIC PROCESS AN CLINICAL END POINTS TO SHOW IT'S FIT FOR USING IT FOR THAT PURPOSE. THE CLINICAL ASSAY DEVELOPMENT PROGRAM IS NOT A GRANT. IT DOES PROVIDE RESOURCES SO IN THAT WAY WE'RE SIMILAR TO NEXT PROGRAM. WE HAVE PROCESSES AND SERVICES THAT HELP DEVELOP DIAGNOSTIC TESTS AND ADDRESS CLINICAL NEEDS INCLUDING CO-DEVELOPMENT OF TARGETED AGENTS AND PREDICTIVE MASHERS. THE ASSAYS DEVELOPED SHOULD MEET PERFORMANCE STANDARDS THAT ARE RIGOROUS AND IDEALLY SHOULD SPEED MOLECULAR GUIDED THERAPIES COMPONENTS OF THIS PROGRAM CONSISTS OF CONTRACTS AND?-i STANDING PROGRAM RESOURCES. CONTRACTS ARE CLINICAL ASSAY DEVELOPMENT NETWORK. ISLE GO OVER THAT LATER. THE SPECIMEN RETRIEVAL SYSTEM. WE HAVE IN HOUSE STATISTICAL EXPERTISE. MANY OF YOU KNOW DR. MCSHANE, SOMNODR. POLY AND WE HAVE CANCER DIAGNOSIS PROGRAM AND OTHER PROGRAMS WITHIN THE DIVISION AND WE ARE ALSO BLESSED WITH A PROJECT MANAGER DR. PHYLLIS ROHAN. SO THE CLINICAL ASSAY DEVELOPMENT NETWORK IS A CONTRACT PROGRAM THAT WAS COMPETITIVELY AWARDED IN 2010. THE FUNCTION OF THESE LABS ARE ALL KLIA ACCREDITED LABS THAT ARE THERE FOR ASSAY OPTIMIZATION AND VALIDATION. YOU HAVE DONE THIS BEFORE, THEY HAVE UP AND RUNNING OR HAVE PROCESSES IN PLACE FOR VARIOUS ASSAYS THAT MIGHT BE USEFUL FOR BRINGING DIAGNOSTICS INTO CLINICAL TRIALS. SO THESE ARE WHO THEY ARE. WE HAVE THE MOLECULAR CHARACTERIZATION LABORATORY AND NCI FREDERICK HEADED BY DR. WILLIAMS OVER THERE. WE HAVE 8 CONTRACTS WITH OUTSIDE INSTITUTIONS AND YOU CAN LEAD THEM THERE. LOTS ARE COMPANIES, THE REST ARE ACADEMIC INSTITUTIONS. WE ALSO HAD IN PLACE AND HAVE A PLACE A SPECIMEN RETRIEVAL SYSTEM, THE THOUGHT WAS IN CLINICAL VALIDITY YOU WOULD NEED SOME PARAFFIN-EMBEDDED SAMPLES THAT HAD -- THAT COULD BE TIED TO OUTCOME ANONYMOUSLY. SO WE HAD -- HAVE A CONTRACT WITH KAISER PERMANENTE NORTHWEST WHICH IS A LARGE PLAN WITH STABLE MEMBERSHIP AS WELL AS ELECTRONIC MEDDLECAL RECORDS AND WE USED NATURAL LANGUAGE PROCESSING TOOL FROM HARVARD TO SCRUB IDENTIFIABLE DATA FROM THESE SAMPLES. WE HAVE THREE RECEIPT DATES. MISSION DEADLINES ARE THERE FOR 2012. AND JUST TO BE EMPHASIZED, WE REALIZE THAT CERTAINLY THE ACADEMIC COMMUNITY BUT EVEN SMALL BIOTECH DON'T HAVE ALL THE DATA NECESSARY TO BRING FORWARD A DIAGNOSTIC OTHERWISE WHY WOULD A PROGRAM LIKE THIS BE NECESSARY. THE EARLIEST POINT OF ENTRY, WORKING PROTOTYPE ASSAY HAS BEEN DEVELOPED. IT WORKS IN HUMAN TISSUE. AND THE INTEND USE CLARIFIED. WHAT DO YOU WANT TO USE THIS DIAGNOSTIC ASSAY FOR. BE NICE IF THERE WAS PREVALENCE DATA AND SOME PRELIMINARY CLINICAL VALIDATION DATA. SO WHAT HAPPENS IS THE SUBMITTERS PROPOSE THESE ASSAY, THEY MAY WANT TRANSFER TO A QUALITY ENVIRONMENT, CLIA FROM A RESEARCH BENCH ASSAY. THEY MAY WANT TO PERFECT THE ANALYTICAL PERFORMANCE AND INTENDED USE CONTEXT. THERE MAYBE CUT POINTS THAT NEED TO BE REFINED AND THEY MAY WANT CLINICAL VALIDITY IN A RETROSPECTIVE SPECIMEN SET. AGAIN ANY WORKING PROTOTYPE ASSAY BUT A CLEARLY DEFINED INTENDED CLINICAL USE FOR CANCER PROGNOSIS OR PREDICTION OF TREATMENT EFFICACY. OF COURSE, IF THE ASSAY IS FURTHER DOWN THE ROAD BUT NEEDS ADDITIONAL VALIDATION, IT'S ALSO ELIGIBLE. DOWN THE ROAD ASSAY MAY NEED TRANSFORMATION. MIGHT WANT TO MIGRATE THE PLATFORM, IT'S DEVELOPED IN FRESH FROZEN AND YOU THINK IT'S NOT GOING TO WORK IN A CLINICAL TRIAL WE NEED TO TRANSFER IT TO SOMETHING THAT CAN WORK IN PARAFFIN EMBEDDED, MAY NEED VALIDATION OF ANALYTIC PERFORMANCE, MAY NEED STATISTICAL CONSULTATION AND QUITE A FEW PEOPLE NEED HELP WITH APPROPRIATE SPECIMENS TO REFINE CUT POINTS FOR OTHER REASONS. AND SOME ASSISTANCE WAS TR -- WITH TRANSPORTABILITY, SAY THE CLINICAL TRIAL BEING PLANNED IS DONE AT SEVERAL SITES AND THEY ALL HAVE TO PERFORM THE ASSAY THE SAME WAY. APPLICATION PROCEDURES ARE SUCH THAT THERE IS A SPECIAL EVALUATION PANEL, SPECIAL EMPHASIS PANEL FOR THIS ACTIVITY AS WELL. THERE'S INTERNAL REVIEWS, ONCE YOU GET THE RECOMMENDATIONS FROM THE OUTSIDE REVIEWERS WE HAVE TO UNDERSTAND IF WE HAVE THE RESOURCES TO SUPPORT THE ASSAY, DOES IT FIT WITHIN THE PORTFOLIO, DOES IT REALLY MAKE SENSE. WE ATTAIN THE RESOURCES AND WE ARE WORKING WITH PROJECT MANAGEMENT. SO WHO SON THE SPECIAL EMPHASIS PANEL? THOSE OF YOU WHO ARE USED TO THIS MAY KNOW THERE'S SPECIAL EMPHASIS PANEL NOT A STANDING GROUP, SO IT DOES GIVE US THE OPPORTUNITY TO SEE WHAT COMES IN EVERY ROUND AND TAYLOR THIS PANEL TO WHAT'S COMING63; IN, WHAT EXPERTISE WE MIGHT NEED. BUT IN GENERAL WE HAVE AB TWO PEOPLE FROM INDUSTRY, DIAGNOSTIC, PHARMA, PHARMA WORKING WITH BIOMARKERS, SEVERAL DIFFERENT FIELDS OF CLINICAL RESEARCH DEPENDING ON WHAT'S COMING IN. WE HAVE ONE OR TWO PATIENT ADVOCATES WHO HAVE BEEN VERY HELPFUL TO US, PATHOLOGISTS AND LABORATORIANS AND ALSO STATISTICIANS, MOST WHOM HAVE BEEN FROM THE COOPERATIVE GROUPS. THESE APPLICATIONS ARE EVALUATED WHETHER OR NOT HYPOTHESIS IS FOUND AND WHAT CLINICAL UTILITY COULD BE ENVISIONED FOR THIS. IS IT FEASIBLE FOR THE INTENDED USE? WHAT IS IMPACT OR CLINICAL NEED. WHAT IS INTENDED USE. AGAIN, THIS IS KEY, IS THIS A NOVEL INSIGHT, DOES IT ADD TO WHAT'S OUT THERE OR IS THIS A ME TOO KIND OF ASSAY KIND OF THING. WHAT IS THE PATH TO CLINICAL IMPLEMENTATION. ONCE THE ASSAY IS ACCEPTED INTO THE PROGRAM, THEN CONTRACTS ARE ARRANGED WITH OUR CONTRACTORS THEN WE FINE TISSUES. THE PROJECT MANAGEMENT TEAM IS THE SUBMITTER. THE CLINICAL ASSAY DEVELOPMENT LAB FROM THE NETWORK AS WELL AS NCI PERSONNEL. TIME LINE, MILESTONES AND GO NO GO DECISIONS ARE IMPLEMENTED, MANY, MANY M CONFERENCE CALLS ARE IMPLEMENTED. AND THEN THE ASSAY IS ACTUALLY RETURNED TO THE SUBMITTER TO PROCEED WITH WHATEVER THEY HAD IT FOR IN THE FIRST PLACECH ROUND 3 OF APPLICATIONS. WE HAD 16 APPLICATIONS AND 15 APPLICANTS. ONE CAME BACK IN AGAIN. ONE PROJECT IS IN PROJECT MANAGEMENT CURRENTLY, EXPECTED TO WIND UP DURING THIS YEAR. THIS IS A PROJECT WITH TWO ASSAYSCH ONE FORKS IDH 1 AND 2 MUTATIONS, IT IS A COMPANION DIAGNOSTIC FOR A SMALL COMPANY WORKING ON IDH INHIBITOR. THAT DID PROVIDE US WITH A CHALLENGE BECAUSE INTENDED USE WAS FOR LEUKEMIA AND BRAIN TUMORS. BUT WECIAL ABLE TO AS CERTAIN SAMPLES FROM THAT AND CONTRACT INDIVIDUALLY TO GET THOSE SAMPLES. ONE IS READY FOR TASK ORDER. THIS IS INTENDED TO BE PREDICTIVE AND IS AN RT PCR ASSAY FOR ALK EXPRESSION. SO IT'S AGNOSTIC TO WHATEVER THE TRANSLOCATION PARTNER IS. AND INTENDED TO BE USED WITH ALK INHIBITORS. ONE IS UNDER CONSIDERATION CURRENTLY, INTENDED TO BE A PREDICTIVE AND OR PROGRESS NOISIC ASSAY FOR THE EFFECTIVENESS OF RADIATION THERAPY. THERE ARE ALSO TWO WE KNOW THAT HAVE PLANS TO RESUBMIT THEIR ASSAY AFTER CONSULTATION. WHAT HAVE WE FOUND OUT? NUMBER ONE, ON GOING EDUCATIONAL NEED CERTAINLY IN THE COMMUNITY. WHEN ASSAYS ARE SUBMITTED FROM ACADEMIC WORLD OR SMALL COMPANY, THE BASIC TWO, THE INTENDED CLINICAL USE IS MORE OFTEN THAN NOT, NOT EXACTLY CLEARLY STATED. MORE THAN ONE INTENDED USE TO BE PROPOSED. THE CLINICAL NEED AND IMPACT, MOST CAN MAKE A REASONABLE CASE FOR THAT. BIOLOGIC RATIONAL BY ITSELF MANY ARE STILL TOO EARLY FOR THAT. MANY DON'T HAVE PREVALENCE DATA FOR MARKER IN ANY CONFIDENCE-GAINING WAY. THE NEED IS GREAT FOR SPECIMENS AND WE HAVE FOUND OUT POSSIBLY THAT ALTHOUGH WE HAVE FORMALIN FIXED PARAFFIN EMBEDDED SPECIMENS THOSE ARE NOT ADEQUATE FOR NEEDS WE'RE SEEING COMING IN. SO WE NEED TO BE CREATIVEN'T THAT. THERE IS A GREAT NEED FOR STATISTICAL EXPERTISE IN THE DEVELOPMENT PLAN OF THIS POTENTIAL DIAGNOSTIC. PLAN FOR FURTHER DEVELOPMENT GETTING THIS OUT FOR USE IS USUALLY NOT VERY WELL DEVELOPED BUT ONE COULD EXPECT THAT FOR THE EARLY DIAGNOSTIC DEVELOPMENT. SO WE MADE A FEW ADJUSTMENTS. WE WORK WITH A LOT OF APPLICANTS PRIOR TO THEM BEING E VATS WAITED AND ENCOURAGE PEOPLE TO COME TALK TO US ABOUT DIAGNOSTIC, HOW WE'RE GOING TO DEVELOP IT, HOW THEY WANT TO DEVELOP IT, WHAT IS THEIR REAL INTENDED USE. WE FIND WE NEED MORE STATISTICAL CONSUL STATION SO -- CONSULTATION O SO WE PROVIDED STATISTICIANS TO SEGREGATE TIME FOR THIS AND GENERALLY AS WELL, TELECONFERENCES. AND WE'RE WORKING ON ACQUIRING TISSUE RESOURCES AND WE MAY OR MAY NOT WANT STANDING RESOURCES THAT WAY. IT'S A DIFFERENT ACTIVITY AND A LOT OF PEOPLE DON'T KNOW WHAT TO DO WIT YET. WE PRESENTED TO THE IDSC. WE HAD CONFERENCE CALLS WITH THE SPORES, WE HAVE A CANCER CENTERS WEBINAR IN MARCH. WE PRESENTED AT NCCN MEETING LAST YEAR, WE PRESENTED AT VARIOUS AACR ASCO AND MARKER MEETINGS. WE HAD ADS OUT IN JOURNALS AND WE KEEP OUR EAR TO THE GROUND AND TRY TO INDIVIDUAL LYNNETTE WORK WITH PEOPLE WE KNOW ARE DEVELOPING DIAGNOSTICS. SO I'M OPEN FOR QUESTIONS RIGHT NOW BUT I WOULD LIKE INPUT AS TO HOW COULD WE BETTER ASSIST NCI CLINICAL TRIALS EFFORTS BECAUSE I DON'T THINK WE HAVE QUITE PENETRATED THAT AND IT WOULD BE NICE IF WE ALL WORKED IN CONCERT FOR THAT. DO WE NEED NEW OR DIFFERENT RESOURCES? NEW OR DIFFERENT COLLABORATIONS OR ANY OTHER SUGGESTIONS WOULD BE APPRECIATED. >> THANK YOU VERY MUCH. QUESTIONS OR COMMENTS, GEORGE? >> COUPLE OF QUESTIONS. ONE HOW DO YOU HANDLE IP AND TWO, WHICH GETS BACK TO YOUR LAST POINT, IN YOUR DECISION PROCESS DO YOU EXPLICITLY OR IMPLICITLY LOOK AT THE PHASE 1 PHASE 2 PORTFOLIO OF THE NCI IN TERMS OF HELPING TO MAKE DECISIONS WHICH DIAGNOSTICS TO DEVELOP? >> THE ANSWER TO THE FIRST IS A QUESTION ABOUT IP. WE WERE AWARE THIS MIGHT BE AN ISSUE. WHEN WE FIRST DEVELOPED THE PROGRAM. SO THE CONTRACTS ARE ACTUALLY OUT OF SAIC AND THEY DO NOT -- THE CONTRACTORS ARE NOT SUBJECT TO THE BIDOLE. SO THEY DON'T GET TO KEEP THE IP. ANYTHING WITHIN THAT IS NEGOTIABLE BUT THE IP BROUGHT IN REMAINS WITH THE SUBMITTER. THE OTHER QUESTION IS DO WE TAKE ACCOUNT OF THE PORTFOLIO. THAT IS THE PURPOSE OF THE SENIOR ADVISORY COMMITTEE. TO BE ABLE TO LOOK AT WHAT IS OUT THERE, NO WE HAVEN'T. A DELUGE OF DIAGNOSTICS TO BRING FORE THUS FAR SO IT'S EASY FROM THAT POINT OF VIEW BUT DEFINITELY WE DO KNOW WHAT'S GOING ON IN THE NEXT AND EARLY TRIALS PROGRAMS AS WELL AS WHAT MIGHT BE USEFUL ACROSS THE CLINICAL TRIALS SPECTRUM. >> I GUESS RELATED TO THAT, WE DONE ENCOURAGE DEVELOPMENT OF SPECIFIC DIAGNOSTICS, IS THAT CORRECT? >> AT THIS POINT WE HAVE NOT DIRECTED IF THAT'S WHAT YOU MEAN WE WANT CERTAIN DIAGNOSTICS BUT IT HAS BEEN BROUGHT UP IN CONVERSATION THAT MAY BE WE SHOULD ENCOURAGE PEOPLE TO DEVELOP THEM BUT CONSIDERING THE WAY THE PROGRAM IS RIGHT NOW, PEOPLE HAVE TO HAVE SORT OF PROTOTYPE ASSAY TO BEGIN WITH. BEFORE BRINGING INTO DEVELOPMENT AND IT'S IDEAL IF THEY HAVE A KNOWN CLINICAL TRIAL THEY WANT TO GO INTO AFTER THAT. IS THERE A POSSIBILITY PEOPLE CAN BRING TO YOU AN ASSAY THAT WITH SOME CLINICAL DATA TO POTENTIALLY VERY USEFUL BUT RIGHT NOW LET'S SAY CELLULAR AN EXPENSIVE BUT SOME OTHER SUBSTITUTE FOR IT CAN BE DEVELOPED PERHAPS WITHIN YOUR PROGRAM WITH SOME EXPERTISE THAT YOU MIGHT GATHER AROUND THAT PROBLEM? A SUBSTITUTE MORE AN MORE EFFECTIVE. >> CURRENTLY DESIGNED, THE FUTURE IS OPEN BUT CURRENTLY DESIGNED WE HAVE REQUIRED SOMEBODY PUT IT INTO A TISSUE OF INTEREST. AND THE ASSAY WORKS IN THAT TISSUE. EVEN IF IT COMES FROM CELLULAR. FOR EXAMPLE, PEOPLE SUBMITTED BASED ON CELL LINES FOR EXAMPLE, THEY HAVE AN EXPRESSION PROFILE FOR EXAMPLE, BUT THEN THEY HAVE SAMPLES THAT THEY FOUND IT COULD WORK IN HUMAN SAMPLES. WE HAVE TO THIS POINT ASKED SUBMITTERS TO MAKE SURE IT WORKS IN HUMAN SAMPLES BEFORE BRINGING IT INTO THE PROGRAM. >> I'M TAKEN ABACK BY THE SLIDE WHERE YOU SAY FOR MOST APPLICATIONS THAT YOU HAVE GOTTEN THUS FAR THE CLINICAL USE IS NOT CLEARLY STATED THE STATISTICAL TALK ISN'T THERE THAT MANY PEOPLE CONFUSE PROGNOSTIC FOR PREDICTIVE, NOT MUCH PLANS FOR DEVELOPMENT. WHAT ARE YOU ENVISIONING OVER THE NEXT COUPLE OF YEARS OF MONITORING AN EVALUATING THIS TO SEE WHETHER IT'S GETTING -- GOING IN THE RIGHT DIRECTION OR WHETHER IT REALLY ISN'T DOING WHAT YOU INTENDED IT TO DO ORIGINALLY AND THOSE RESOURCES SHOULD BE PUT INTO OTHER AREAS. >> RIGHT NOW THE PROGRAM IS FUNDED ON ARRA SO IT HASN'T. IT HAS AN END POINT BUT I HAVE GIVEN A LOT OF THOUGHT TO THIS PARTICULAR INSTANCE AND WHEN WE GET DIAGNOSTICS INTO CLINICAL TRIALS I THINK THAT COULD BE CONSIDERED THE SUCCESS. WE AT LEAST THE CANCER DIAGNOSTICS PROGRAM REALIZED FOR A LONG TIME MANY PEOPLE DONE KNOW HOW TO DEVELOP DIAGNOSTICS.< CROT WE'RE ALONE IN THAT. THE PHARMACEUTICAL INDUSTRY HAS BEEN STRUGGLING WITH THE SAME ISSUE. WE DON'T ASK FOR THE ASSAY TO BE FAR ALONG. IT'S OFTEN DIFFICULT TO GET EXPERTISE IN ACADEMIA OR SMALL COMPANY. AS FAR AS INTENDED CLINICAL USE I THINK THIS IS WE MOSTLY GET THAT ISSUE FROM ACADEMIA. ONE NEEDS TO FOCUS ON ONE INTENDED USE SO INTENDED TO IDENTIFY ELIGIBLE PATIENTS OR INTENDED TO MONITOR THEM OR INFORM ABOUT WHICH PATIENTS HAVE A WORSE PROGNOSIS OR WHATEVER. BUT NOT ALL THREE. AND MANY PEOPLE FEEL THAT MAYBE RIGHTLY ALL THREE COULD BELONG TO THIS DIAGNOSTIC. BUT FOR BRINGING SOMETHING FORWARD WE FOCUS ON ONE TO START WITH. THAT'S PART OF THE EDUCATION. THAT DOESN'T PRECLUDE US SUPPORTING SOMETHING IF THE INTENDED USE IS ALL OVER THE PLACE. WE'D LIKE FOR THEM TO HONE IT DOWN BUT THAT MAY MEAN WE HAVE TO GO BACK AND TALK WITH THEM AND HAVE AN UNDERSTANDING OF WHERE THEY WANT TO DEVELOP IT FIRST. THEY MAY TWEAK IN BETWEEN. WE'RE FAIRLY FLEXIBLE IN THAT POINT. >> CLARIFICATION. CAN YOU CLARIFY WHETHER THE AGENT HAS TO BE ACCEPTED INTO ONE OF THE NCI PROGRAMS OR IF SOMETHING CAN CAN COME IN FOR THE DIAGNOSTIC? THE QUESTION IS CAN YOU TALK ABOUT THE TIME LINES FROM THE INITIAL DISCUSSION TO APPLICATION TO REVIEW AND DEVELOPMENT OF SOMETHING THAT CAN INGO PATIENTS. >> SURE. THANK YOU FOR THOSE QUESTIONS. IT'S NOT STRICTLY A COMPANION DIAGNOSTIC ISSUE. WE ARE INTERESTED IN PREDICTIVE AND DIAGNOSTIC DIAGNOSTICS FOR EVEN THINGS IN COMMON USE, NOT SUBJECT OF INVESTIGATION OF NEW DRUG APPLICATIONS AT THIS POINT. SO NO, IT DOESN'T HAVE TO COME IN WITH SOMETHING THAT NCI IS DOING. WE WOULD LIKE A LITTLE MORE OF THAT AS THINGS GO ON. BUT WE'RE IN ONE YEAR. WE'RE NOT VERY FAR ALONG THIS. IDEALLY ONCE THIS GETS UP AND RUNNING THESE THINGS WILL BE ON CONCERT. I FORGOT YOUR SECOND QUESTION. THE TIME LINE. >> THE TIME LINE BUT JUST A POINT BECAUSE THAT CAN BE AN ISSUE BECAUSE IF YOU HAVE TO GO THROUGH THE NEXT PROGRAM, YOU HAVE DISCUSSION, YOU GO THROUGH THE REVIEW PROCESS AN IT CAN TAKE A PERIOD -- PEOPLE NEED TO KNOW IF THEY CAN BE TALKING TO YOU ABOUT DIAGNOSTICS SEPARATE IF IT DOESN'T GET APPROVED FOR -- IF YOU HAVE LIMITED (INAUDIBLE). >> IT COULD BE -- IT'S A THEORETICAL PROBLEM AT THIS POINT. >> POTENTIALLY NOBLG. >> WE WOULD LOVE TO HAVE THIS PROBLEM. ALL WOULD BE UNDER CONSIDERATION WHETHER OR NOT DEVELOPED BY NCI OR NOT. RIGHT NOW WE HAVEN'T MADE IT MANDATORY THAT IT WILL BE NCI DEVELOPEDDED TRIAL. TIME LINES, WE -- SO WE HAVE TRIED TO HAVE A TIME LINE FROM SUBMISSION TO PROJECT START OF FOUR MONTHS. ACCEPTED PROJECT. NOW WE HAVEN'T MET THAT YET BUT A LOT IS DUE TO MTAs EXECUTED, THAT KIND OF THING. AND THEN WE TAKE INTO ACCOUNT THE TIME LINE OF THE SUBMITTER FOR OUR CURRENT 2HG AND IDH PROJECT, THEY WANT TO BE IN THE CLINIC THE THIRD OR FOURTH QUARTER OF 2012. SO WE STARTED WORKING WITH THEM EIGHT MONTHS AGO AND THINK WE'RE GOING TO MEET THAT TIME LINE. >> I HAVE CURE CURIOSITY IN TERMS OF INTENDED CLINICAL USE AND PERHAPS (INAUDIBLE) CAN COMMENT, I DON'T KNOW IF HE'S STILL HERE. SOME DRUGS HAVE BEEN APPROVED NOW WITH PARTICULAR DIAGNOSTIC TESTS. FOR EXAMPLE (INDISCERNIBLE) HAS BEEN APPROVED FOR THE PARTICULAR TEST YOU HAVE TO DO TO GET REIMBURSEMENT IN INSURANCE YOU HAVE TO DEMONSTRATE THAT. SO YOU ARE ENTERTAINING Ax ASSAY FOR ALK. HOW DO YOU INCORPORATE LONG TERM, HOW DO YOU INCORPORATE NEW ASSAYS FOR THINGS THAT HAVE BEEN APPROVED BASED ON ONE PARTICULAR ASSAY? SOME FLEXIBILITY REGARDING THAT OR NOT? >> FOR THAT ONE, LET ME TELL YOU OUR THOUGHT PROCESS ON THAT ONE. WE AND OTHERS ARE NOT SURE THE APPROVED ASSAY CATCHES EVERYBODY IT NEEDS TO CATCH. SO YOUR FALSE NEGATIVE RATE MIGHT BE HIGHER THAN WE DESIRE IT TO BE. THE FDA HAS PROCEDURES FOR OTHER TESTS TO COME AND BE APPROVED. FOR SUCH USE. THE LABELING IF I'M NOT MISSEN SAYS N FDA -- AN FDA APPROVED TEST. >> PETER. >> IF I MISSED IT, ALONG THOSE LINES DO YOU HAVE REGULAR REGULATORY SUPPORT FOR IDE FILINGS? MANY OF THESE ACTUALLY REQUIRE IDE. >> MANY WILL. WHAT WE DO IS HAVE A NICE WORKING RELATIONSHIP WITH CDRH AND WE DO A GO BETWEEN KIND OF MATCH MAKING SITUATION WITH THEM. SO IT'S NOT TECHNICALLY REGULATORY SUPPORT AT THIS TIME, NOT TECHNICALLY FUNDED TO FILE THE PAPERWORK. BUT WE DO HELP WITH THE CONVERSATIONS AS TO WHAT YOU NEED AND CERTAINLY WHEN THE TEST IS DEVELOPED WE MAKE SURE THAT WHAT IS NEEDED FOR THE IDE IS IN THE VALIDATION. SO IT CAN GO FORWARD. >> THAT WAS ANY QUESTION. >> YOU SAY THIS IS FUNDED BY ARRA MONEY AND THERE ARE NO MORE FUNDS, IS THAT RIGHT? ARE THESE LAST SUBMISSIONS OR HOW IS THAT GOING TO WORK? >> THAT'S ABOVE MY PAY GRADE. THAT'S -- THIS IS KIND OF UNDER DISCUSSION AT THE MOMENT. >> >> DEPEND ON INTENDED USE WE THINK THIS IS A MAJOR GAP IN TERMS OF HOW ACADEMICS SIMPLY DON'T HAVE THE RESOURCES TO GO FROM 200 CONVENIENT SAMPLES IN FREEZER TO GETTING TO THE POINT WHERE THEY HAVE AN ASSAY APPROPRIATE FOR A REAL RANDOMIZED TRIAL VALIDATION. THIS IS A WAY TO GET THOSE RESOURCES IN SUCH A WAY THAT IT WOULD IMMEDIATE FDA GUIDELINES. THE ISSUE -- WE HAVE ENOUGH MONEY FOR ANOTHER YEAR, TWO YEARS IN ARRA TO SUPPORT THIS AND AT THE END OF THE TIME WE HAVE TO SEE HOW MUCH PEOPLE REALLY REQUIRE IT, IF THEY DO, GREAT. IF THEY DON'T, NO. >> I DIDN'T KNOW ABOUT THIS PROGRAM BUT IT'S AN EXTRAORDINARILY IMPORTANT PROGRAM. PARTICULARLY SINCE I DON'T THINK SUCH ISSUES AS ANALYTIC PERFORMANCE ARE THINGS MOST ACADEMICS AND MOST SMALL BIOTECH COMPANIES UNDERSTAND AT ALL. SO IT IS BRINGING VALUE TO THE EQUATION OF CLINICAL TRIALS THAT IS VERY IMPORTANT AND IS CURRENTLY LACKING. SO I WANT TO SAY HOW ENTHUSIASTIC AIM FOR A PROGRAM I HADN'T HEARD ABOUT UNTIL TODAY. >> I'LL FOLLOW-UP ON THAT. DO YOU HAVE PLANS FOR A BROADER EDUCATION EFFORT? IN OTHER WORDS MOST AROUND THE TABLE ARE FAMILIAR WITH DRUG DEVELOPMENT BUT PROBABLY MUCH LESS FAMILIAR WITH COMPANION DIAGNOSTIC OR DEVELOPMENT OF A PROGNOSTIC TEST. YOU HAVE SAY PLANS PERHAPS IN CONJUNCTION WITH FDA OR OTHERS TO TRY TO MORE BROADLY EDUCATE THE COMMUNITY ABOUT HOW TO DO THIS, HOW TO ACCOMPLISH THIS? WHETHER THAT MIGHT BE SOMETHING YOUR OFFICE WOULD TRY TO WORK WITH AND PERHAPS PARTNERING WITH THE FDA AROUND SOMETHING LIKE THAT. >> YEAH. I -- JIM, I THINK THAT'S A WONDERFUL SUGGESTION AND FDA, WE HAVE BEEN DISCUSSING SOMETHING AROUND THAT. WE HAVE A FEW CONSTRAINTS AS FAR AS RESOURCES FOR THAT. I GUESS IT'S TIME FOR A PLUG. BUT WE DID A WORKSHOP ON GENOMICS AND WHAT WE NEED FOR GENOMICS INTO CLINICAL TRIALS LAST JUNE. WHEN WE GET A MIGHT BE WE'LL -- MINUTE WE'LL HAVE THE REPORT OUT N. MAY, MAY 3 AND 4 WE HAVE A NEXT GEN WORKSHOP A SUGGESTION INTO THE CLINIC. SOME OF THOSE ISSUES GET DISCUSSED IN THOSE THINGS. WHAT YOU WHA DO YOU DO WITH THE OTHER THINGS, THE SINGLE ANOLYTE T ONE TO SIX ANOLYTE KIND OF THING. I THINK MICKEY IS WANTING TO CHIME IN HERE. (OFF MIC) SO ONE OF THE ISSUES THAT WE HAVE BEEN CONSIDERING IS LOOKING FROM THE POINT OF VIEW OF THE PATIENT AND WE HAVE THESE TARGETED THERAPIES AND ALL CLINICAL TRIALS EARLY. SO THE PATIENT DOESN'T WANT TO GIVE 27 SAMPLES, WOULDN'T IT BE BETTER IF WE THOUGHT OF SOME WAY TO JUST DO A MULTI-ANOLYTE TEST AND THEN GO FROM THERE. WE ARE TRYING TO SEE WHAT THE HURDLES ARE THERE. CEDAR HAD A COUPLE OF ISSUES. ONE CONCERN THEY HAVE IS IF THESE -- WHAT WE'RE GETTING IS PEOPLE WANT TO DO THESE UMBRELLA TRIALS BUT IN ACADEMIC INSTITUTION. HOW DO PEOPLE GET ACCESS TO THIS? THE ACADEMIC INSTITUTION IS DOING THEIR RESEARCH, THEY DON'T HAVE THE CAPABILITY AND REFERENCE LAB FOR THE WORLD. HOW DO YOU DO THAT? IF YOU USE SOME OTHER TEST AFTER THAT, IT'S IMPORTANT TO SAIMP SAMPLES FROM THE FIRST TEST SO YOU CAN RECOMMEND YOU'RE READING THE SAME ANOLYTE CORRECTLY. >> PART OF MY QUESTION IS WHETHER OR NOT SOME OF THE PATIENTS ARE GOING TO BE ABLE TO HAVE MULTIPLE TESTS DONE ON TISSUE SAMPLE, YOU ALSO MENTION THAT THERE IS AN INADEQUATE SUPPLY OF SPECIMEN. I IMAGINE THOSE TWO FIT TOGETHER. YOU SAID THERE ARE SOME CREATIVE WAYS THAT YOU'RE LOOKING FOR TISSUE OR FINDING WAYS, CAN YOU TALK ABOUT THAT A LITTLE BIT? >> WE PARTNERED WITH AN INSTITUTION IN ARIZONA WHO DOES BRAIN TUMORS, THEY HAD A BANK AND ARE ABLE TO SUPPLY THAT AND SOME OF THE LEUKEMIA CENTERS HAVE LEUKEMIA. WE DON'T NEED A DROVE, THAT'S WHY WE NEED STATISTICIANS TO FIGURE OUT HOW DO WE REALLY NEED TO VALIDATE THE0U– TEST. WE CAN'T PREDICT WHAT'S GOING TO COME UP SO ABSENT A PROSPECTIVE TRIAL WHICH IS ONE OF THOSE OPTIONS, WE DO KEEP ONE PART OF OUR PROGRAM IS RESOURCES DEVELOPMENT BRANCH AND THE SPECIMEN RESOURCE LOCATER FIRST, WHICH ACTUALLY HAS SOME HINTS TO WHERE SAMPLES MIGHT BE. FOR TEST VALIDATION WE DON'T NEETD NEED OUTCOME DATA. WE NEED TO KNOW WHAT THE PATHOLOGY WAS. HOW MUCH TUMOR THERE IS IN A SAMPLE. IN ORDER TO DETECT THE ANOLYTE ACCURATELY WE MIGHT NOT NEED A LOT OF OUTCOME DATA. SO I THINK SO FAR SO GOOD. IF WE GET 20 TESTS AT A TIME WE MIGHT HAVE AN ISSUE BUT RIGHT NOW WE'RE NETWORKING IT. >> QUESTIONS? IF NOT, THANK YOU VERY MUCH. EXCELLENT. SO OUR FINAL SPEAKER THIS AFTERNOON IS EVA SZABO FROM PREVENTION. EVA IS GOING TO TALK ABOUT CONSORTIA FOR EARLY PHASE PREVENTION TRIALS AND THINK THIS IS AN IMPORTANT TOPIC BECAUSE WE SPENT A LOT OF DISCUSSIONS HERE TALKING ABOUT THERAPEUTIC TRIALS BUT THERE IS A VERY LARGE INITIATIVE ON PREVENTION THAT WE NEED TO ALSO KEEP A CLOSE EYE ON. AND PROVIDE HELP FOR NCI AND PROVIDE SOME DIRECTION. >> ALL RIGHT. CAN EVERYBODY HEAR ME OKAY? THANK YOU FOR THIS OPPORTUNITY. IT'S A MIXED BLESSING WHEN YOU FOLLOW THE TREATMENT DESCRIPTIONS. SO THAT'S WHY I HAVE THE FIRST SLIDE TO ORIENT PEOPLE. CANCER IS CARCINOGENOSIS AS A PROCESS THAT OCCURS OVER MANY YEARS AND WE'RE NOW FOCUSING OVER THOSE EARLY PARTS OF THE PROCESS. THAT BRINGS UNIQUE CHALLENGES. ALL THE CHALLENGES THAT YOU HEARD FROM DR. DOROSHOW AND IVY, CONLEY TODAY, KEEP THOSE IN MIND AND ADD ON A FEW OTHERS. THAT'S GOING TO BE THE FOCUS OF MY PRESENTATION. OUR PROGRAM IS ONE PROGRAM FOR EARLY PHASE -- ANYTHING BEFORE PHASE 3 CLINICALLY. THE CHALLENGES COME IN TWO VARIETIES. SCIENTIFIC AS WELL AS LOGISTIC LOGISTICAL. TARGET SELECTION, AGENT SELECTION BECAUSE YOU'RE TRYING TO PREDICT WHAT'S THE PATHWAY THAT LEADS TO INVASIVE CANCER BEFORE YOU HAVE THAT INVASIVE CANCER. SO IDENTIFYING THOSE TARGETS IS FAIRLY CHALLENGING AND I WILL SHOW YOU WHAT WE HAVE BEEN USING FOR OUR CRITERIA. A SECOND CHALLENGE RISK BENEFIT IS OF COURSE ALWAYS A VERY IMPORTANT ISSUE IN CLINICAL TRIALS BUT WHERE THAT GOLDEN POINT IS IS SHIFTED IN A MAYOR WAY IN PREVENTION TRIALS BECAUSE THE AMOUNT OF RISK ONE CAN TAKE ON IS OBVIOUSLY A LOT LESS T. COHORT SELECTION ISSUE IS A MAJOR ISSUE. YOU HEARD THE STATEMENT THAT YOU HAVE TO SCREEN TEN PEOPLE TO FIND ONE WITH THE APPROPRIATE MOLECULAR ABNORMALITY DEPENDING ON THE FREQUENCY, WHILE AGAIN YOU HAVE TO SCREEN MORE PEOPLE TO FIND THE PRE-NEOPLASIA OR THE RISK ASSESSMENT MARKER THAT WILL PREDICT FUTURE CANCER. IT'S MORE THAN TEN TO ONE IN OUR STUDIES. THAT'S JUST LIFE. IMPERFECT ASSESSMENT OF PHASE 3 TRIALS MAYBE IN PREDICTING PHASE 3 EFFICACY, IT'S MORE SO AT THE PREVENTION STAGE WHERE BUILT INTO YOUR CLINICAL TRIALS YOU DON'T HAVE AN EASILY MEASURABLE IMAGEABLE MARKER ON THE MACRO SCALE. A LOT OF THINGS ARE ON THE MICROSCOPIC OR MOLECULAR SCALE. THEN THERE'S LOGISTICAL COMPONENTS OF THIS. ALL THESE STUDIES ARE BIOMARKER. THEY REQUIRE SOME FORM OF TISSUE OR BIOLOGIC FLUID AND SO WE HAVE BEEN STRUGGLING WITH THIS CONCEPT OF NEEDING TO OBTAIN INVASIVE TISSUE SAMPLING FOR A LONG TIME AND FOR PAYING FOR THISSISH THE SHOE SAMPLING AND IT ALMOST ALWAYS PRE AND POST AT+o THE MINIMUM. THERE ARE LIMITED FUNDING OPPORTUNITIES FOR EARLY PHASE STUDIES THE GRANT PORTFOLIO IS QUITE POOR IN SUPPORTING THE STUDIES. PHARMA IS NOT AN EGGER PARTNER -- EEGER PARTNER USUALLY. SO WE HAVE NEED TO -- ONE REASON WE HAVE A CONTRACT PROGRAM IS TO FILL IN THE HUGE GAP BECAUSE OTHERWISE THERE'S LITTLE THAT MOVES FORWARD. THE ELEPHANT IN THE ROOM IS PHASE 3 STUDIES THAT WOULD FLOW FROM EARLY PHASE STUDIES ARE HUGE, THEY ARE LONG, FUNDING AND RESOURCES REQUIRED ARE SOMETIMES DAUNTING. FORGIVE ME FOR BEING BASIC. I KNOW PEOPLE KNOW THIS BUT I WASN'T SURE WHETHER ALL IS IN THE AUDIENCE, SO FORGIVE ME. WE REALLY DO THESE RISK BENEFIT CALCULATIONS FROM THE GET GO, REALLY AT THE PRE-CLINICAL LEVEL. BENEFIT WHICH IS EFFICACY IN PREVENTING CANCER AND ASSOCIATED MORBIDITY AND MORTALITY AND THE RISK. THE RISK IS NOT JUST BIG SIDE EFFECT, THE CARDIOVASCULAR END POINT, WHICH ARE LIKELY TO OCCUR IN THE SMALL NUMBER BUT ALSO A TOLERABILITY BECAUSE AGENTS HAVE TO BE TAKEN FOR LONG PERIODS OF TIME. SO WHAT MIGHT BE GRADE 1 OR 2 DIARRHEA WHICH PERHAPS YOU CAN DEAL WITH, IN A TREATMENT AND PREVENTION SETTING FOR YEARS, THAT'S A NO GO. HOW HAVE WE BEEN MOVING AGENTS TO CLINICAL TRIALS? I THINK THESE ARE MAJOR AREAS OF INVESTMENT CURRENTLY AND FUTURE. IF YOU KNOW THE MECHANISM YOU'RE GOLDING BEEN FOR MOST CANCER, LIQUID AND SOLID WE DON'T KNOW. HPV STORY IS -- AND CERVICAL CANCER IS THE POSTER CHILD BUT IT'S ONE OF ONE RIGHT NOW. SO WE OFTEN DO RELY ON PRE-CLINICAL MODELS THROUGH CELL LINES AND OTHER IN VITRO MODELS, ANIMAL, CARCINOGENOSIS AND TRANSGENIC MODELS. AND WE HAVE GOOD PROOF THAT THEY ARE PREDICTIVE BUT IN OTHER CASES WE DONE HAVE THESE DEFINITIVE STUDIES. WE HAVE EPIDEMIOLOGY, COHORT AN CASE CONTROL STUDIES AND SOME TUMOR SYSTEMS THESE HAVE BEEN VERY GOOD IN PREDICTING EFFICACY IN A TRUE PREVENTION TRIAL BUT THOSE DATA ARE LACKING FOR MOST CASES. THEN SOMETHING WE HAVE BEEN LOOKING AT AGGRESSIVELY IS TO LOOK AT THE SECONDARY END POINT FROM OTHER CLINICAL TRIALS. THIS IS HOW TO TAMOXIFEN RA LOCK FEEN HAVE COME INTO PREVENTION ARENA FOR BREAST CANCER BUT THOSE AGAIN, ONGOING PIECE OF WORK. BOTTOM LINE IS IT'S ALL ABOUT OPTIMIZING THE RISK AND THE BENEFIT, KNOWING WHAT THE BENEFIT IS LIKELY TO BE AND IDENTIFYING THE INDIVIDUALS WHO ARE MOST LIKELY SHORT TERM WHO ARE HIGHEST RISK WHO HAVE THE PROPER PHARMACOGENETICS MAKE UP TO BE ABLE TO RESPOND TO THE DRUGS WITHOUT THE INTERVENTIONS. IT'S THIS FIGURE WHICH TELLS YOU THE DILEMMA OF THE FIELD WHICH IS THE MORE FURTHER ALONG IN THE CAR SIN YEN SI PROCESS THE FEWER NEEDED TO TREAT BUT IN THOSE EARLY PHASES YOU DONE KNOW WHO IS GOING ON TO CANCER, YOU NEED TO TREAT MANY MORE. OUR PROGRAM IS FOCUSED ON EARLY PHASE CLINICAL TRIALS WHICH IS FROM ZERO TO PHASE 2 BUT WITH A MAJOR EMPHASIS ON PHASE 2. FEW ZERO AND PHASE 1 STUDIES. THIS IS THE WHOLE DCP DRUG DEVELOPMENT PROGRAM, IT IS SUBSTANTIALLY SMALLER THAN WHAT YOU HEARD ABOUT TODAY. WE HAVE A PRE-CLINICAL PROGRAM THAT MY COLLEAGUE RUNS WHICH IDENTIFIES AGENTS. YOU PROGRAM, THE ONE I'M TALKING ABOUT TODAY IS THE PRIMARILY THE PHASE 2 TO A LESSER EXTENT PHASE 1 AND OCCASIONAL PHASE ZERO TRIAL THIS, TEASE SAFETY AND PRELIMINARY EFFICACY DATA THAT ARE MEANT TO THEN PHASE 3 STUDIES GENERALLY PERFORMED (INDISCERNIBLE) AND THE COOPERATIVE GROUPS. WE DO TRY TO INTERFACE WITH OTHER NCI PROGRAMS BECAUSE BIOMARKERS ARE SUCH A RELEVANT AN IMPORTANT COMPONENT OF HOW WE DETERMINE EARLY EFFICACY EDRN IS MAJOR RESOURCE WE HOPE TO WORK WITH EVEN MORE IN THE FUTURE. NOTICE THAT MY ARROW GOES BOTH WAYS BETWEEN THE EARLY PHASE -- BETWEEN CONSORTIA AND PRE-CLINICAL PROGRAM BECAUSE WE DO IN FACT GO BACK TO LOOK AT ANIMAL MODELS TO DO BIOMARKER DEVELOPMENT WORK FURTHER AND TO EXTEND WHAT WE HAVE LEARNED IN THE PHASE 1 AND 2 STUDIES. THE OBJECTIVE IS TO FURTHER AGENTS FOR FURTHER CLINICAL DEVELOPMENT, PRIMARY PRELIMINARY EFFICACY STUDIES AN THIS IS A FAIRLY NEW FIELD STILL IN THE BIG PICTURE, WE ALSO HAVE GOALS OF OPTIMIZING CLINICAL TRIAL DESIGNS AND WE TRY MANY DIFFERENT WAYS DOING THESE STUDIES AND OF COURSE TO GET A BETTER HANDLE ON BIOMARKERS PREDICTIVE OF SUBSEQUENT PHASE 3 EFFICACY. THE PROGRAM IS RIGHT NOW IN THE PROCESS OF RECOMPETITION WITH APPLICATIONSxD ALREADY HAVING BEEN RECEIVED SO WE'RE SORT OF IN THE MIDDLE AND WHICH WILL BE HEARING ABOUT IS A HUE BRID OF WHAT WE HAVE DONE AND -- HYBRID WHAT WE HAVE DONE AND WHERE WE HOPE TO GO. THIS IS A MAP OF WHERE WE HAVE BEEN IN THE MOST RECENT ITERATION OF THE PROGRAM, WE HAVE SIX MAIN CONTRACTORS WHO SUBCONTRACT WITH MANY DIFFERENT ADDITIONAL SITES, AGAIN TO PERFORM THESE STUDIES. AND THINK ARE ESSENTIALLY THROUGHOUT UNITED STATES WITH SOME SITES IN EUROPE AS WELL. IT'S A CONTRACT DRIVEN PROGRAM, SO WE WORK PRIMARILY WITH THOSE SIX CONTRACTORS. THE LEAD ORGANIZATION AS WE CALL THEM, CLOs, WHO THEN CONTRACT WITH ADDITIONAL PARTICIPATING SITES SO ALL THOSE REGULATORY HURDLES THAT YOU HEARD ABOUT, MULTIPLE IRBs, SUBCONTRACTS, THOSE ARE MAJOR ISSUES FOR US. IN THE ITERATION THAT IS COMING UP, WE WILL HAVE A STEERING COMMITTEE COMPOSED OF THE PIs, THE MAIN PIs FOR THE LEAD ORGANIZATION AS WELL AS SELECT DCP STAFF TO HELP THE GENERAL INTERNAL WORKINGS AND AS WELL EXTERNAL ADVISORY COMMITTEE, NOT THE ONLY COMMITTEE THAT ADVISES ON DRUG DEVELOPMENT BUT THIS WILL BE SPECIFICALLY FOR THE EARLY PHASE CLINICAL TRIALS. AND THIS ORGANIZATION ALLOWS HIM TO DO MULTIPLE STUDIES AT THE SAME TIME IN MULTIPLE ORGAN SYSTEMS. WE ACCEPT -- WE SOLICIT SPECIFIC STUDIES BUT ALSO ACCEPT VISITOR INITIATED STUDIES WITHIN THIS PROGRAM. A STUDY MAYBE OPEN AT ONE SITE OR AT MULTIPLE SITES DEPENDING ON THE NEED, IT COULD BE AT THE LEAD ORGANIZATION BUT DOESN'T HAVE TO BE SO WE HAVE THE ABILITY TO REACH MANY DIFFERENT SITES IF THEY HAVE A SPESKS EXPERTISE. WE HOPE TO DO MORE INTERCONSORTIA IN THE FUTURE. WE ONLY HAD ONE IN THE CURRENT CLINICAL TRIAL. SO TO GIVE YOU A SENSE OF THE COMPLEXITY OF DOING CLINICAL TRIALS FOR PREVENTION PURPOSES, I WILL TELL YOU TWO STORIES OUTLINING HOW STORE DIS HAVE BEEN DONE AND PERHAPS YOU CAN ADVISE HOW TO DO THE IT IN THE FUTURE. THIS IS A GLUCOSE ISOMER THAT COMES FROM DIETARY SOURCES, AND HAS BEEN STUDIED IN A VARIETY OF HEALTH RELATED CONDITIONSCH IT IS THE SURS OF SEVERAL MOLECULES. BUT THE MECHANISM OF ACTION IN THE PAST HAS NOT BEEN KNOWN. WHY ARE WE INTERESTED? IT'S THE WORK OF THE GRANDADDY, FATHER OF CANCER CHEMOPREVENTION. AND IN A VARIETY OF ANIMAL MODEL SYSTEMS THIS DRUG IS SHOWN TO INHIBIT CARCINOGEN INDUCED TUMORS, LUNG TUMOR, IN A VARIETY OF SETTINGS INCLUDING MAINSTREAM AND SIDE STREAM SMOKE EXPOSURE. AND IN TERMS OF SAFETY, I'M TELLING YOU ESSENTIALLY ALL THAT WAS KNOWN WHEN WE STUDIED THIS DRUG IN THE MID 2000s, EARLY 2000sISH SAY. IN TERMS OF SAFETY, IT IS GENERALLY REGARDED AS SAFE. SO IT'S ON FDA MASTER LIST, A HUGE BENEFIT IN THE SETTING. SO STEVEN LIMB WHO HELD ONE OF OUR CONTRACTS AT THE TIME PERFORMED A PHASE 1 STUDY TO LOOK AT THE MAXIMUM TOLERATED DOSE. AND ALSO DID BRONCHOSCOPY LOOKING FOR REGRESSION OF DYSPLASIA. SO ALL HAD TO HAVE BRON KEEL DYSPLASIA TO BEGIN WITH -- BRON AND THERE WAS REDUCTION IN DYSPLASIA. THIS WAS NOT A RANDOMIZED STUDY, IT WAS PHASE 1. ONE OTHER INTERESTING THING IS THERE WAS A DECREASE IN BLOOD PRESSURE, NOT A CLINICALLY WORRISOME DECREASE BUT MORE LIKE 130 TO 115 KIND OF MODE. DOSE WAS IDENTIFIED. IN THIS SETTING DR. LIMB HAD THE FORE SITE TO DO NORMAL BRONCHIAL BRUSHINGS FROM NORMAL SITES DURING BRON CHOSSCOPIES -- BRONCHOSCOPIES AND (INDISCERNIBLE) AT BOSTON UNIVERSITY EXPRESSION AND ABILITY TO PREDICT SUBSEQUENT CANCER LOOK AT SPECIMENS AND DID A SERIES OF STUDIES BASED ON SAMPLES FROM OUR STUDIES AS WELL AS OTHERS AND FOUND THAT LOOKING AT GENE EXPRESSION PATTERNS THAT THE PI-3 KINASE PATHWAY APPEARS ACTIVATED IN SMOKERS WITH DYSPLASIA, AND IN LUNG CANCER PATIENT BUS NOT HEALTHY SMOKERS WITHOUT DYSPLASIA, NOT IN COPD PATIENTS WITHOUT DYSPLASIA. TAKING SPECIMENS FROM THE SMALL TRIAL HE SHOWED (INAUDIBLE) REVERSED THIS PI-3 PHASE SIGNALING PATHWAY ACTIVATION. THIS IS NOW NORMAL BRONCHIAL AIRWAYS IN SMOKERS WHO REGRESSED BY HISTOLOGIC CRITERIA. SO THIS TO US IS INTERESTING FOR MANY REASONS BECAUSE IT TAKES US TO THE 21st CENTURY IN TERMS OF HOW WE CAN NOW LOOK AT STUDIES. IN THE PAST WE HAVE LOOKED AT PRE-NEOPLASTIC LESIONS OFTEN, SOMETIMES IN EXPRESSION OF VARIOUS MARKERS IN THE NORMAL EPITHELIUM IN AT RISK PATIENTS, AT RISK SUBJECTS. NOW WE HAVE TWO QUESTIONS THAT THIS DATA RAISED. IS PI-3 KINASE ACTIVATION THE -- A MARKER THAT IDENTIFIES SMOKERS TRULY AT RISK IF YOU FIND IT EARLY IN PEOPLE DYSPLASIA, IN TUMORS AND NOT APPARENTLY IN EARLIER PHASES. IT IS SOMEWHAT EASIER TO GET BRUSHINGS THAN TO TRY TO IDENTIFY MULTIPLE AREAS OF DYSPLASIA WHICH THOUGH DONE WITH AUTOFLUORESCENCE BRONCHOSCOPY ARE A SOMEWHAT BLIND WAY LOOKING FOR HISTOLOGIC ABNORMALITIES. THERE'S POTENTIAL TO ALLOW A COHORT AND ASKS QUESTIONS ABOUT IS THIS A BETTER CLINICAL TRIALS MODEL. YOU CAN DO PATHWAY ANALYSIS, IT'S MORE A GLOBAL LOOK AT THE RISK. YOU CAN GO WITH SMALLER NUMBERS OF PARTICIPANTS, SHORTER INTERVENTIONS. THESE ARE HYPOTHESIZE FOR THE NEXT PHASE. IT WILL ALLOW US TO IDENTIFY MECHANISMS OF POTENTIALLY ALLOW US TO IDENTIFY MECHANISMS FOR INTERVENTIONS AND PERHAPS GET TO THAT MORE PERSONALIZED WAY OF ADDRESSING CHEMOPREVENTION. SO WE HAVE ONGOING A PHASE 2D STUDY, THIS IS A FAIRLY CLASSIC, IF I CAN SAY THAT, IN QUOTE LUNG BRONCHIAL DYSPLASIA MODEL SYSTEM, SMOKERS WITH DYSPLASIA, ABOUT 100, 110 TO BE EXACT SLATED TO BE ENROLLED. THEY WANT BRONCHOSCOPY AND SPIECIAL CT TREATMENT FOR SIX MONTHS AND REGRESSION OF BRONCHIAL DYSPLASIA. THAT'S THE CLASSIC MODEL. WHAT YOU DON'T HAVE ON THIS SLIDE IS TO FINE THOSE 110 SMOKERS WITH DYSPLASIA WE'LL WIND UP DOING BROS COSCOPY IN 5 OR 600 SMOKERS IF NOT MORE. VERY RESOURCE INTENSE. BUT WOULD WE -- WHAT WE HAVE DONE HERE IS WE WILL LOOK WHETHER OR NOT IN FACT THOSE SMALL NUMBERS FROM DR. SPEAR'S DATA CAN BE VALIDATED IN A PRELIMINARY FASHION IN THIS LARGER TRIAL SO THERE WILL BE GENE EXPRESSION ANALYSIS DONE IN BOTH PLACEBO AND THE TREATED SITES, SO WE HAVE THREE SITES ONGOING AND WE'RE ALMOST HALFWAY THERE. I'M GIVING YOU TWO EXAMPLES FROM LUNG HEAD AND NECK BECAUSE THAT'S WHAT I DO. SO I'M MOST FAMILIAR WITH THE DATA, IT'S NOT TO MEAN THAT THIS IS DIFFERENT FOR ANY OTHER TARGET ORGAN SITE. SO A SECOND TYPE OF STUDY THAT WE'RE DOING THAT'S CURRENTLY ONGOING FOCUSES ON THE DRUG AN ANTI-DIABETIC AGENT, A PPAR GAMMA AGONIST. THE RATIONALE HERE COMES BOTH FROM PRE-CLINICAL DATA AND ANIMAL MODELS, AS WELL AS SOME VERY LIMITED EPIDEMIOLOGY. THE ANIMAL MODELS SHOW THAT IN CARCINOGEN-TREATED RAT TONGUE MODEL THE INCIDENCE AND MULTIPLICITY OF TUMORS IS GREATLY DECREASED. THERE WERE ONE GROUP HAS LOOKED AT THE VA DATABASE LOOKING AT LUNG CANCER AND DIABETICS TREATED WITH A GROUP OF DRUGS THIS IS A MEMBER OF THE (INAUDIBLE) AND FOUND A SIGNIFICANT DECREASE IN DIABETICS. WHO TREATED WITH TZDs IN TERMS OF LUNG CANCER OR HEAD AND NECK CANCER, NOT IN COLON OR PROSTATE CANCER. LIMITED DATA DATABASE, THAT'S THE DATA THAT ARE OUT THERE. WE PERFORMED A SMALL STUDY PHASE 2A WITH 22 PARTICIPANTS. AND THERE WAS THIS IS AN ORAL LEUKOPLAIKIA, PRECURSOR TO ORAL CANCER. IN THIS STUDY, FRANK ANDRE UNIVERSITY OF MINNESOTA, THERE WAS 80% RESPONSE RATE IN THIS SMALL COHORT AT THE PHASE 2A OPEN LABEL STUDY WITH ABOUT 80% DECREASE IN SIZE OF THE LESION. VERY SHORT INTERVENTION. THAT WE TOOK AS A SIGNAL THERE ARE ADDITIONAL ANIMAL MODEL THAT WOULD SUGGEST THAT IN LUNG CANCER YOU MAY HAVE BENEFITS AS WELL. BUT THESE DATA ARE MORE LIMITED, THIS IS A TREATMENT MODEL ON RIGHT SHOWING XENOGRAPH TUMOR VOLUME IS DECREASED BY TZDs AND THERE'S A DELAY IN THE GROWTH OF TUMOR USING (INAUDIBLE) CARBONATE TREATED MICE THAT DEVELOP ADINOCARCINOMA IN A WILE TYPE STATE AND IN A P-53 MUTANT STATE WHAT YOU SEE THERE TUMOR BURDEN. IF YOU START TREATMENT AFTER SMALL LESIONS ALREADY PRESENT, PRE-MALIGNANT LEAGUES. WE HAVE TWO STUDIES ONGOING IN THE CURRENT ITERATION OF CONTRACT PROGRAM, A MORE CLASSIC PHASE 2B ORAL LEUKOPLAIKIA STUDY. 100 PARTICIPANTS, MULTIPLE SITES, 11 SITES, PERFORMING THE STUDY WITH A CLINICAL AND PATHOLOGIC END POINT BUT NO GENE EXPRESSION ANALYSIS REALLY MORE STANDARD IMMUNOHISTOCHEMICAL ANALYSES TO BE DONE ON THOSE SAMPLES. WE ALSO HAVE A PILOT STUDY IN A NON-SMALL CELL LUNG CANCER SETTING. PEOPLE WHO ARE AWAITING SURGERY WILL GET A SHORT TREATMENT, 2 TO 6 WEEKS PRIOR TO DEFINITIVE SURGERY, SMALL NUMBER OF PARTICIPANTS, THESE ARE ALL BIOMARKER END POINTS AND THERE WE WILL LOOK AT GENE EXPRESSION ANALYSIS AS WELL AS MORE STANDARD IMMUNOHISTOCHEMICAL ANALYSES IN TUMOR, PRE AND POST TREATMENT AS WELL AS NORMAL BRONCHIAL EPITHELIUM. SO THESE ARE HOW WE HAVE BEEN DOING STUDIES IN THE PAST. THIS IS NOT APPROXIMATE EXHAUSTIVE LIST BY NO MEANS OF THE AGENT WE LOOK AT BUT I WANTED TO POINT OUT A COUPLE OF THINGS THAT WE HAVE BEEN TRYING TO DO IN THIS PROGRAM. YOU SEE ON THERE METFORMAN WHICH IS THE SUBJECT OF A LOT OF ENTHUSIASM RECENTLY FOR CANCER PREVENTION BASED ON A VARIETY OF DATA. WE DO HAVE SEVERAL STUDIES, PILOT STUDIES FAIRLY SMALL LOOKING IN VARIOUS ORGAN SYSTEMS. WE HAVE SOME PHASE 1 STUDIES WHICH COME THROUGH PROGRAMS SUCH AS RAPID, OUR VERSION OF RAID IN ITS PREVIOUS LIFE NOW THE PREVENT PROGRAM AND THE REASON I POINT THEM OUT IS UAB 30 IS A REXNOID DOES NOT HAVE LIVER THE TRIGLYCERIDE TOXICITY THAT PLAGUED THE FIELD OF RETINOID AN REXNOID. WE FOCUS ON EGFR INHIBITORS THAT ARE TOO TOXIC BUT DOSE ESCALATION STUDIES TRYING TO IDENTIFY A DOSE THAT DOES HAVE PHARMACODYNAMIC IMPLICATIONS. YET IS TOLERABLE. SO IN OUR NEW ITERATION OF THIS PROGRAM WHICH AS I SAY WE DON'T HAVE OUR CONTRACTS IN PLACE YET. WE'RE IN THE MIDDLE OF THE PROCESS. THOUGH THE APPLICATIONS HAVE BEEN RECEIVED AND REVIEWED. THE NEW EM FASIS IS TO UNDERSTAND THE BIOLOGY OF THIS PROCESS. REMEMBER, THIS IS NOW SPREAD OVER MANY DIFFERENT ORGAN SYSTEMS AND THE AMOUNT OF MONEY WE HAVE IS EQUIVALENT TO WHAT THE PHASE 1 PROGRAM THAT YOU HEARD ABOUT FROM DR. DOROSHOW. WE ARE LOOKING TO EXPAND TO NEW SIGN SCIENTIFIC AREAS SUCH AS IMMUNOPREVENTION, A DIVISIONAL GOAL. BUT BECAUSE WE REALLY ARE NOT LOOKING TO DEVELOP HUGE NUMBER OF DRUGS FROM ANIMAL TO FIRST IN MAN WE'RE LOOKING TO REPURPOSE OLD DRUGS WHERE WE KNOW WHAT THE TOXICITY PROFILE IS AND WHERE PERHAPS YOU CAN EFFECT MULTIPLE CHRONIC DISEASES. THAT'S WHERE NSAIDS OR ASPIRIN I SHOULD SAY ATTRACTIVE AGENT BECAUSE YOU HAVE CARDIOVASCULAR COMPONENT THAT'S WHERE THE ANTI-DIABETIC AGENTS ARE ALSO OF GREAT INTEREST BECAUSE SOME INCLUDING MET FORKSORMAN AND SMALLER EXTENT (INAUDIBLE) HAVE BEEN SHOWN TO STAVE OFF DIABETES IN PEOPLE WITH METABOLIC SYNDROME, PRE-DIABETES GLUCOSE INTOLERANCE. INTERMEDIATE YATIATE END POINTS HAS TO TO REMAIN A CRITICAL GOAL BECAUSE THAT IS MOW WE LEARN WHETHER WE'RE EFFECTIVE. IT'S A WORK IN PROGRESS. AGAIN, COLLABORATION WITH EDRN AND OTHER PROGRAMS ARE KEY THERE. WE HAVE BEEN AND WILL CONTINUE TO FOCUS ON RISK ASSESSMENT STRATEGIES AND INTEGRATING THEM EARLY ON SO THAT WE CAN FOCUS ON THOSE HIGH THROUGH PUT POPULATIONS WHO ARE AFTERALL WHO WE WANT TO TARGET ULTIMATELY WHEN THESE STRATEGIES GO INTO DELIVERY TO THE GENERAL PUBLIC. COMBINATIONS YES. HARDER IN PREVENTION THAN TREATMENT BUT THERE HAVE BEEN SOME STUDY, ALTERNATIVE WAYS TO DO DRUG DELIVERY. PULSE TILE TREATMENT, WE NOW MODEL THAT IN MICE. AND ACTUALLY CAN BE FAIRLY EFFECTIVE. PERHAPS GIVING PEOPLE A BREAK, MAYBE YOU DONE NEED FIVE YEARS OF A DRUG, MAYBE YOU CAN DO IT IN VARIOUS WAYS. THAT OBVIOUSLY NEEDS TO BE WORKED OUT. WE HAVE A BIOREPOSITORY, IT WAS VIRTUAL RIGHT NOW IN THE SPECIMENS AT THE SITES THAT HAVE COLLECTED THEM BUT WE HOPE TO CENTRALIZE THAT, MONEY IS NEEDED FOR THAT. THAT'S ALL I WANTED TO SAY AND BE HAPPY TO HEAR YOUR THOUGHTS ABOUT WHAT YOU DO AND WHAT WE SHOULD DO. >> THANK YOU, QUESTIONS. >> IN TERMS OF THE DECISION DOSING FOR TRIALS HOW ARE YOU -- THE QUESTIONS COMING IN TERMS OF HOW DO YOU FIGURE OUT YOU'RE NOT GIVING TOO MUCH, WE'RE CHOOSING BASED ON WHAT PEOPLE CAN TOLERATE. >> RIGHTCH THIS IS WHERE GOING FROM DRUGS THAT ARE AROUND ALREADY IS HELPFUL. YOU CAN DO THE EXPECTED EQUIVALENT DOSE FROM ANIMALS TO PEOPLE THAT'S HARD THING TO DO. SO I'LL TELL YOU HOW WE HAVE BEEN DOING IT, OR HOW I HAVE BEEN DOING IT, OFTEN YOU GO WITH THE MAXIMUM DOSE THAT IS IN USE AND TOLERABLE, IF YOU CAN DO DOSE DEESCALATION STUDIES. IF DOING A 100 STUDY IS HARD, OR 50 PERSON STUDY, PLACEBO IS RESOURCES. THE FIRST PASS WILL BE THE HIGHEST APPROVED DOSE, AND KNOW THAT'S NOT -- NO, THAT'S NOT THE BEST WAY TO DO IT. >> ONCE YOU SEE YOUR MAXIMUM DOSE THEN DO THE DEESCALATION THE NEXT STEP TRYING TO DO LARGER TRIALS. >> RIGHT. THAT'S EXACTLY RIGHT. LIKE ONE PHASE 2 STUDY DOESN'T BUY YOU A PHASE 3 IN TREATMENT, IT CAN'T IN PREVENTION EITHER. THIS IS WHERE I HOPE IF YOU CAN SHOW IMPACT OF THE DRUG ON TARGETS, AND THE EPITHELIUM, IN A SHORTER TIME FRAME WITHOUT A FULL-FLEDGED PHASE 1, 2B, WHICH IS A BIG STUDY, WE CAN DO THAT STUDY ONCE WE HAVE DOSE OPTIMIZATION. THAT'S WHERE WE WOULD LIKE THE GO, YES. >> I WAS WONDERING IF THERE IS A CLEAR MECHANISM FOR MOVING POTENTIAL PREVENTION AGENTS THAT HAVE ADEQUATE EFFICACY AND DECENT SAFETY TOWARD PHASE 3. YOU HAVE A RELATIONSHIP TW DISEASE SITE COMMITTEES OR PREVENTION COMMITTEES AN RESEARCH GROUPS TO DO THAT? THE DISEASE SITE COMMITTEES CAME IN TO BEING AFTER WE HAD AGENTS FOR PHASE 3 PREVENTION STUDIES, FEW AND FAR BETWEEN, ESPECIALLY THESE DAYS WITH THE FUNDING THAT IS THERE. SO THIS ISN'T DOING -- SO I HAVE TO DO -- I'M SORRY. SO THAT HAS NOT BEEN TESTED YET. IN THE PAST WHEN PHASE 3 STUDY WERE DONE, LESLIE CAN SPEAK TO THAT AS WELL AND LORI (INDISCERNIBLE) AS WELL THEY HAD SPECIAL REVIEWS BEFORE THE PHASE 3 STUDIES WERE DONE F. AND WHEN TO MOVE ON TO A PHASE 3 STUDY THAT MECHANISM WILL KNEE TO BE INCREASED. >> VERY NICE PRESENTATION. OBVIOUSLY IN PREVENTION IS KEY. BUT AS YOU POINT OUT RISK BENEFIT AND TOXICITY PROFILE CHANGES DRAMATICALLY AND THE RISK GOES UP. THE BULLET DOWN THERE INTEGRATING AND DEVELOPING THE HIGHEST RISK POPULATION O TO SAY WHATEVER TECHNOLOGY MOLECULAR EPIDEMIOLOGIST WOULD CHANGE PROTOCOLS AN TYPES OF TRIALS YOU'LL BE DOING. SO THE INTEGRATION WITH THE OTHER PROGRAMS ON GOING TO HELP DEVELOP THAT? >> SO WE'RE TRYING, EDRN IS THE NATURAL PARTNER. OBVIOUSLY THEY DO THINGS THAT COME UP THROUGH THEIR OWN PIPELINE. THIS IS WHERE WE TRY TO UP IN THE FIELD INTEGRATE WHATEVER IT LOOKS LIKE MAYBE EFFECTIVE. >> TO UNDERSTOOD SCORE A COUPLE OF THINGS THAT EVA SAID. THIS IS THE ONLY MECHANISM THAT I KNOW OF THAT SUPPORTS EARLY PHASE PREVENTION, COMPANIES AREN'T INTERESTED IN THIS FOR VARIOUS REASONS. IT'S CRITICAL. THE ASPECT OF PERSONALIZED PRERENGS IS SOME AGENTS THAT ARE REPURPOSED BUT WE HAVE A FEEL FOR THE TARGET WHETHER P-3K OR METFORMIN IS GOING TO LEAD PERSONALIZED PREVENTION, TARGETING HIGH RISK IS IMPORTANT. IT IS A DIFFICULT FIELD. THIS IS A CRITICAL MECHANISM TO KEEP THE WORK GOING. THE CANCER DRUG DEVELOPMENT MODEL IS THE WRONG MODEL WE ARE ON OUTLIER WHEN IT COMES TO DRUG DEVELOPMENT AND ONCOLOGY, NO AREA DEVELOPS DRUGS THE WAY WE DO. MOST MEDICINE DEALS WITH CHRONIC ADMINISTRATION AS FAR AS BIG DRUGS THE ANTI-HYPERTENSIVES, YOU NAME IT, THOSE MODELS ARE DIFFERENT. THEY DON'T PURSUE, THEY DON'T GO TO PHASE 3, THE PHASE 3 TRIAL IS A CONFIRMATORY TRIAL. I'LL SURE YOU THOUGHT ABOUT THIS MORE, YOU CAN LEARN FROM OTHER DRUG DEVELOPMENT AREAS OTHER THAN ONCOLOGY, WHICH ARE MORE APPROPRIATE MODELS AND SORT OF WHAT WE DO. >> YOU'RE ABSOLUTELY RIGHT THAT'S WHY I HESITATED TO SAY THAT WE START IN A PHASE 2 SETTING WITH THE MAXIMAL APPROVED DOSE. BUT WHEN PUSH COMES TO SHOVE YOU HAVE TO MAKE A DECISION. WHAT WILL I DO AND HOW MUCH HOW MANY RESOURCES DO I USE RIGHT UP FRONT. AND I AGREE WITH YOU 100% THAT DOSING IS CRITICAL BOTH FOR TOLERANCE BUT ALSO FOR EFFICACY. >> IN ALMOST EVERY AREA, NO ONE WOULD DO A SINGLE DOSE PHASE 2 STUDY, THEY'RE RANDOMIZED DOSES OUT OF THE GATE IN PHASE 2. >> RIGHT. SO WHAT WE HOPE TO DO ARE SMALLER STUDIES, NOT FULL PHASE 2, FOR US PHASE 2 IS OFTEN 100 -- A BLINDED STUDY. WHICH IS A LOT OF RESOURCES. IT IS A BIG STUDY SO WE HOPE TO DO SMALLER ONES TO GET A MORE SENSE OF DOSE BEFORE GOING INTO THESE BIGGER ONES THAT I'M SHOWING YOU. HOW MANY TRIALS AN DISCRETE AGENTS ARE CURRENTLY IN THE PIPELINE IN DEVELOPMENT THROUGH THE MECHANISM YOU HAVE IN PLACE? >> YEAH, SO IN THIS MECHANISM, 2003, WE HAVE AROUND 60 TRIALS THAT HAVE BEEN DONE OR ARE ONGOING AND SO 40 SOME ODD DIFFERENT AGENTS. SO IT'S REALLY QUITE SMALL. IS THE BOTTOM LINE. >> ADDITIONAL QUESTIONS, SCOTT? >> I HAVE BEEN INVOLVED IN THIS MECHANISM MORE SO IN THE PAST BUT ANOTHER REALLY NICE ASPECT IS THAT EVEN THOUGH AGENTS COME FROM DCPA, THEY ALLOW INVESTIGATOR INITIATED STUDIES WITH GOOD SCIENCE TO TAKE. SO IT HAS -- IT IS A DYNAMIC SYSTEM AND HAS THAT BALANCE TO IT AS WELL WHICH I THINK IS REALLY IMPORTANT. THERE ARE GOOD EXAMPLES WHERE PEOPLE USE THESE FUNDS LEVERAGED WITH OTHER FUNDS TO DO MOLECULAR STUDIES THAT WE HAVE DONE AT ANDERSON USING THIS MECHANISM TO LEVERAGE OTHER FUNDS FOR PROFILING WORK. SO IT'S A NICE MECHANISM THAT HAS FLEXIBILITY TO ALLOW THESE INVESTIGATOR INITIATED MOLECULAR CORRELATES. >> ADDITIONAL QUESTIONS, COMMENTS? OKAY. THANK YOU, VERY MUCH. SO JUST IN CLOSING, I THINK WE'RE DONE BASICALLY WITH OUR AGENDA FOR TODAY. AND I WANT TO THANK EVERYBODY FOR COMING AND STAYING THE ENTIRE TIME AND ALSO FOR PARTICIPATING IN THE DISCUSSION. COUPLE OF THINGS THAT I WANTED TO MENTION ON OUR AGENDA AS WE GO FORWARD, FIRST OF ALL, SHEILA AND I ARE TRYING TO CONTINUE TO ENCOURAGE PEOPLE TO GET INVOLVED IN THE AGENDA SETTING EFFORTS. I THINK WE DIDN'T DO THAT MUCH OF IT THIS TIME BECAUSE WE WANT WANT TO FOCUS THIS TIME ON THE EARLY ASPECTS OF THE NCI PORTFOLIO FROM THERAPEUTICS TO PREVENTION TO BIOMARKERS. BUT IF THERE ARE TOPICS THAT PEOPLE ARE INTERESTED IN HEARING MORE ABOUT OR O OTHER TOPICS, PLEASE LET US KNOW. WE'LL MAKE SURE THAT PEOPLE HAVE AN OPPORTUNITY TO PARTICIPATE IN THE TELECONFERENCE WHERE WE SET THE AGENDA. WE STILL GOING TO BE A MORE DETAILED PORTFOLIO ANALYSIS OF OVERALL NCI SPENDTURES ON CLINICAL TRIALS, THAT'S SOMETHING WE HEARD ABOUT AS A COMMITTEE MAYBE A YEAR, YEAR AND A HALF AGO AND WE WANT TO BRING THAT BACK FOR FURTHER DISCUSSION, ESPECIALLY SINCE WE HAVE NEW MEMBERS. WE'RE ALSO PLANNING TO HAVE SOME SESSIONS ON OVERALL ACCRUAL AS WELL AS MINORITY ACCRUAL TO CLINICAL TRIALS AND SEE WHERE WE ARE AND TRY TO UNDERSTAND SOME OF THE CHALLENGES AND HOW THOSE MIGHT BE OVERCOME GOING FORWARD. SO THOSE ARE TWO AGENDA ITEMS THAT CAME UP IN THE PAST AND THAT WE HAVE NOT COMPLETELY -- WE HAVEN'T FORGOTTEN ABOUT. ONE OTHER THING I WOULD LIKE TO MENTION IS WE ARE -- AGAIN, WE HAVE A NUMBER OF NEW MEMBERS AN SHEILA IN PARTICULAR HAS BEEN WORKING ON ORIENTATION BOOK TO HELP NEW MEMBERS GET ORIENTED TO THE COMMITTEE AND WE ALSO I HAVE HEARD FROM A NUMBER OF COMMITTEE MEMBERS THAT PEOPLE WOULD LIKE TO HAVE SOME TIME TO TALK AS A COMMITTEE ABOUT COMMITTEE OPERATIONS AN ISSUES HOW WE MIGHT BE -- MIGHT DO A BEAR JOB HELPING NCI. SO WE'RE PLANNING TO HAVE THE NEXT MEETING A SESSION LASTING 45 MINUTES FROM 8:15 TO 9 A.M. WHICH WOULD BE A LITTLE BIT MORE PRIVATE WITH THE COMMITTEE AND THE NCI STAFF, SHEILA, JIM AND PROBABLY DR. GRAY. AND KIND OF AN ORIENTATION SESSION. BUT IT -- WE'LL ALSO HAVE AN OPPORTUNITY TO TALK ABOUT COMMUNITY OPERATIONS AT THAT TIME. AND IT'S BASICALLY OFFLINE, NOT PART OF THE FORMAL MEETING BUT IT WILL BE FOR US TO HELP THE COMMITTEE DO THEIR JOB BETTER. I THINK IS WHAT I'M ENVISIONING. SO PLEASE PUT THAT IN THE BACK OF YOUR HEAD BECAUSE WE WILL PROBABLY START A LITTLE BIT EARLIER NEXT TIME AND HAD AN OPPORTUNITY TO TALK AS A COMMITTEE HOW WE THINK WE'RE DOING AND PERHAPS DO BETTER. SO IF THERE ARE ANY OTHER COMMENTS OR THOUGHTS? QUESTIONS? IF NOT, WE'RE ADJOURNED AND