FIRST LET ME ASK ARE THERE ANY PUBLIC COMMENTS ON THIS PROTOCOL? ANYBODY ON THE LINE? SO LET ME READ FOR YOU THE PROPOSED RECOMMENDATIONS TO THE INVESTIGATORS AND HAVE THEM RESPOND IF THEY WANT TO. SO FROM THE CLINICAL STANDPOINT, IT WOULD BE HELPFUL TO ADD HLA TYPING TO THE PROTOCOL SO THAT IF THERE IS AN ANTI-AAV CAPSID T CELL RESPONSE THIS WOULD BE CORRELATED WITH ALA PROFILE. NUMBER TWO YOU SHOULD STRONGLY CONSIDER INCLUDING CRITERIA FOR STARTING IMMUNOSUPPRESSION WHEN THERE IS A RISE IN LIVER ENZYMES THAT MAY INDICATE THE LIVER RESPONSE -- GENERAL GUIDELINES REGARDING AN IMMUNOSUPPRESSIVE REGIMEN THAT SUPERVISE SOME ROOM FOR INDIVIDUALIZED CLINICAL CARE. FROM AN ETHICAL LEGAL AND SOCIAL STANDPOINT, THE SCREENING INFORMED CONSENT DOCUMENT SHOULD INCLUDE ADDITIONAL DATA ON THE TRIAL, INCLUDING THE TIME COMMITMENT, PROPOSED CHANGES IN THERAPY IF ONE ENTERS THE TRIAL AND THE SAFETY-RELATED ISSUES FOR THIS PROTOCOL. IT IS IMPORTANT TO HAVE THIS IN THE DOCUMENT THAT SOME OF THE SCREENING WILL NOT BE DONE AT THE MAIN TRIAL SITES. NUMBER TWO, THE SECTION OF THE INFORMED CONSENT DISCUSSES THE RISKS OF GOING OFF THE CHOLESTEROL THERAPY PRIOR TO THE STUDY SHOULD INCLUDE FURTHER DISCUSSION OF THEIR CONTINUED MONITORING OF THEIR CHOLESTEROL LEVELS AND THAT THEIR CLINICAL CARE REMAIN THE PRIORITY. SO THOSE ARE THE THINGS THAT WE HAVE INCLUDED IN THE DOCUMENT. ANY OTHER THINGS THAT RAC MEMBERS FEEL STRONGLY ABOUT INCLUDING? ANY RESPONSE FROM THE INVESTIGATORS? >> I THINK WE AGREE WITH ALL OF THAT. WE APPRECIATE THE RECOMMENDATIONS AND ACTUALLY THEY HAVE BEEN VERY HELPFUL TO US SO WE AGREE. >> AGAIN WE THANK ALL THE INVESTIGATORS FOR BEING WITH US TODAY AND THE REVIEWERS FOR THEIR FINE JOB. THANK YOU. JEFF, LET'S TAKE A VOTE ON THIS PRETTPROTOCOL. ANY MOTION FOR A VOTE? DR. CHATTERJEE. ANY SECOND? GOOD. LET'S TART. COKE YES, STROME YES, MOLINO YES. [INDISCERNIBLE] >> YOU HAVE TO TURN OFF YOUR MICROPHONES. ONLY TWO CAN BE ON AT ANY ONE TIME. FONG YES. >> DRESSER EPSTEIN, YES. >> [INDISCERNIBLE] YES. >> [INDISCERNIBLE], YES. >> THANK YOU VERY MUCH. >> [INDISCERNIBLE] >> MASTROIANNI, YES. >> OH, YES. >> [INDISCERNIBLE] >> FOSS, YES. >> ANYBODY ELSE ON THE -- DR. BUCKMEYER? OKAY. NEXT WE HAVE A COMMENT FROM DR. GRAHAM FROM THE NIAID WHO WILL ADDRESS US WITH A PUBLIC COMMENT. >> YES, THANK YOU. I'M BARNEY GRAHAM, I'M THE CHIEF OF THE CLINICAL TRIALS COURT THE VACCINE RESEARCH CENTER HERE ON CAMPUS. I'VE BEEN HERE FOR TEN YEARS. BEFORE THAT I WAS AT VANDERBILT UNIVERSITY FOR 22 YEARS AND I'VE BEEN INVOLVED IN CLINICAL VACCINE TRIALS SINCE 1997. I WANT TO MAKE A BRIEF COMMENT ABOUT THE TOPIC YOU'LL DISCUSS TOMORROW AFTERNOON AT 1:30 AND UNFORTUNATELY I WON'T BE AVAILABLE AFTER THAT, BUT IT'S TO DISCUSS A PROPOSAL THAT NAIAD IS MAKING TO THE RAC HOW TO DEAL WITH DNA OR -- VECTORS DELIVERING VACCINE ANTIGEN GENES. SO WE'VE BEEN INVOLVED IN GENE DELIVERY VACCINE STUDIES SINCE THE LATE 80'S. AND THE PROPOSAL IS THAT AS OVA HAS PROVIDED AN APPENDIX M FOR MEANING THAT VACCINE VECTORS THAT EXPRESS AN ANTIGEN THAT WILL INDUCE AN IMMUNE RESPONSE IS NOT GOING TO EXIST BECAUSE OF REPLICATION, INTEGRATION OR SHEDDING ARE EXEMPT FROM CRACK REVIEW. WE HAVE DONE THESE STUDIES OVER DECADES AND THERE'S NOW BEEN TENS OF THOUSANDS OF PEOPLE IMMUNIZED WITH THESE TYPE OF VECTORS. OUR PROPOSAL IS THAT, AND RECENTLY AROUND ALMOST 10 YEARS AGO, A NEW RECOMMENDATION WAS MADE THAT EACH OF THESE CLINICAL PROTOCOLS ON THESE VECTORS, DNA VACCINES WOULD REQUIRE ABC REVIEW. FLUSH EVEN THOUGH THEY WERE EXEMPT FROM RAC REVIEW. AND SINCE WE NOW HAVE DATA ON TENS OF THOUSANDS OF PEOPLE AND HAVE NOT SEEN ANYTHING THAT'S ALARMING AND SINCE THE FDA GAME OUT WITH NEW GUIDANCE ON DNA VACCINES IN 2007 THAT REPLACED THEIR 1899 1996 RECOMMENDATIONS AND HAVE ADOPTED A POSITION THAT EVEN A LOT OF TIMES YOU DON'T HAVE TO REPEAT YOUR CLINICAL TOXIC IF YOU'RE CHANGING OUT THE INSERT, EVEN THOUGH IF YOU'RE USING THE SAME VECTOR BACKBONE. OUR PROPOSAL FOR POLICY CHANGES THAT THE RAC ADOPT THE SAME EXEMPTION CRITERIA THAT THEY USE IN APPENDIX M FOR IBC REVIEW OF THE CLINICAL PROTOCALLS. AT THE STAGE OF THE CLINICAL PROTOCOLS. THESE PRODUCTS HAVE BEEN REVIEWED BY IBC'S AT THE BENCH LEVEL, AT THE PRECLINICAL TESTING LEVEL AND BY THE TIME THEY HAVE GOTTEN TO THE CLINICAL TRIAL LEVEL, THEY'VE BEEN REVIEWED PROBABLY ON MORE THAN ONE OCCASION BY AN IBC. AT THE CLINICAL TRIAL LEVEL, THERE IS AN IRB REVIEW, THERE'S AN FDA REVIEW, THERE'S A SPONSOR REVIEW, THERE'S A NUMBER OF THINGS IN PLACE AT EACH SITE TO MAKE SURE THE STUDY IS BEING DONE IN A GOOD, IN A JUICY P TYPE OF MANNER. AND SO OUR PROPOSAL IS, IS THAT THE IBC REVIEW IS NO LONGER NECESSARY. IT DOESN'T ADD ANYTHING TO THE SAFETY AND IT TAKES A LOT AWAY FROM IN TERMS OF TIME AND ATTENTION TO OTHER THINGS THAT THE IBC COULD I THINK BE OCCUPIED WITH. SO OUR PROPOSAL IS THAT IBC REVIEWS NOT BE REQUIRED ANYMORE FOR GENE IN BASED VECTORS, EITHER DNA OR REPLICATION DEFECTIVE VECTORS THAT ARE EXPRESSING VACCINE ANTIGEN, THEY'RE GOING TO BE CLEARED. AND SO WE DON'T THINK IT REPRESENTS A HARM TO THE ENVIRONMENT OR TO THE PERSONNEL OR TO THE VACCINE VOLUNTEER. AND SO THAT IS THE BASIC PROPOSAL. THERE'S A HANDOUT BRIEFLY EXPLAINING THAT PROFESSIONAL OVER HERE WE -- PROPOSAL OVER HERE WE CAN GIVE YOU. I THINK THAT'S WHAT'S GOING TO BE DISCUSSED TOMORROW. IN PARTICULAR, THERE'S A PARTICULAR BURDEN WHEN A TRIAL, EVEN AFTER A PHASE ONE TRIAL, ON THE SECOND PHASE ONE TRIAL OR ON THE EXPANDED SET OF TRIALS, YOU GO TO PHASE TWO OR THREE, EVEN IN MULTICENTER STUDIES, EVERY TIME A NEW STUDY IS STARTED, YOU GO BACK TO IBC REVIEW. SO IT'S AN ENORMOUS WASTE OF RESOURCES, BASICALLY. AND EVEN ON THE SAME EXACT DNA PLASMID IF WE STARTED A NEW ANYWAYS ONE TRIAL WE GO BACK TO IBC REVIEW FOR THE SAME VECTOR, FOR THE SAME BASIC STUDY. SO I JUST WOULD LIKE YOU TO CONSIDER THE NAIAD PROPOSAL FOR HOW TO DEAL WITH THESE REPLICATION EFFECTIVE VECTORS USED FOR VACCINES. >> THANK YOU VERY MUCH. SO THE POLICY PROPOSAL IS BEING CIRCULATED. WHAT I'M GOING TO READ FOR YOU ARE THE PUBLIC COMMENTS THAT HAVE COME ACROSS BY E-MAIL TO THE SITE. AGAIN, WE'RE USING THIS FORMAT FOR THE VERY FIRST TIME, SO AGAIN, I APOLOGIZE FOR THESE HICCUPS THAT HAPPEN OVER THE NEXT TWO DAYS. THE FIRST COMMENT IS FROM -- WE ALL KNOW DR. -- AND SHE WRITES I STRONGLY DISAGREE WITH THE FOLLOWING MOTION OF THE ISCGT BOARD OF DIRECTORS. THE RACs WOULD TERMINATE REVIEW OF INDIVIDUAL CLINICAL PROTOCOLS AND WOULD INSTEAD IDENTIFY NEW AREAS OF RESEARCH THAT REQUIRE A PUBLIC FORUM FOR DISCUSSION AND REVIEW. IN ITS REVIEW OF CLINICAL PROTOCOLS, THE RAC SERVES AS A VALUABLE FUNCTION TO AUGMENT SAFETY FOR GENE TRANSFER CLINICAL TRIAL PARTICIPANTS. IN ADDITION, THE RAC PROVIDES A PUBLIC FORUM FOR DISCUSSION OF PLANNED CLINICAL TRIALS AND FOR DISCUSSION AND IF NEEDED IN-DEPTH REVIEW OF ADVERSE EVENTS. THE BOARD OF DIRECTORS ARGUMENT THAT GENE TRANSFER NEITHER LEADS TO GERMA GERMLINE TRANSMISSION NEAR RELEASE OF RECOMBINANT INTO THE GENERAL PUBLIC TAKES A NARROW VIEW OF THE RISKS OF GENE TRANSFER ESPECIALLY REGARDING FUTURE PROTOCOLS THAT MAY AIM TO MODIFY REGULATORY DNA SEQUENCES. SECOND COMMENT COMES FROM -- FROM THE WISTAR ON THE RACS ROLE. IN REGARD TO PUBLIC SAFETY I THINK THE RAC SHOULD CONTINUE TO REVIEW AND MAKE DECISIONS FOR ALL CLINICAL TRIALS IN HUMAN GENE THERAPY FIELD. SO THOSE ARE THE COMMENTS THAT HAVE COME IN TODAY. I'M EXPECTING MANY MORE TOMORROW. AND SO THAT'S THE START. MOVING ON TO THE NEXT AGENDA ITEM. REGARDING THE MINUTES OF THE RAC FROM DECEMBER 13TH DR. BADLEY AND DR. ROSS HAS REVIEWED THE MINUTES IN DETAIL. >> I'M HERE. >> DR. ROSS? >> YES, I'M HERE ON THE PHONE. >> I'M HERE AS WELL. >> OKAY. WOULD EITHER ONE OF YOU LIKE TO COMMENT ON ANY NEEDS FOR CHANGES OR PROPOSED THAT IT BE ENTERED INTO RECORD. >> I PROPOSE THAT THEY BE ENTERED INTO THE RECORD. I FOUND THAT THEY WERE SATISFACTORY. >> OKAY, VERY GOOD. ANY COMMENTS FROM ANY OTHER MEMBERS OF RAC? >> SATISFACTORY. >> VERY GOOD. SO WE NOW MOVE TO THE NEXT AGENDA ITEM WHICH IS THE REPORT OF THE GENE TRANSFER SAFETY ASSESSMENT BOARD. DR. YANKASKAS. >> EXCUSE ME, SOMEONE ON THE PHONE I THINK YOU HAVE YOUR WEBCAST VOLUME UP, IF YOU CAN SHUT IT DOWN BECAUSE WE'LL GET SOME FEEDBACK FROM THAT GIVEN THE DELAY. >> THANK YOU. GENE TRANSFER SAFETY ASSESSMENT BOARD INCLUDES SEVEN MEMBERS OF THE RAC WHO SERVE ON THE SUPPLEMENTAL COMMITTEE AND I'LL GIVE THE QUARTERLY REPORT. IN THE FIRST QUARTER OF THIS CALENDAR YEAR, THERE WERE 12 TOTAL SUBMISSIONS. THE DISEASE INDICATIONS INCLUDED 12 CANCERS, HEMOPHILIA OR THE DISEASE INDICATIONS FOR THE NON-PROTOCOLS THAT WERE NOT SELECTED FOR IN-DEPTH REVIEW HAD SEVEN ON CANCER, ONE ON HEMOPHILIA AND ONE ON HEART FAILURE. THE VECTORS FOR THOSE NON-SELECTED PROTOCOLS WERE THREE WITH PLASMIDS, TWO WITH ADENO VIRUS, TWO WITH ARE RETRO VIE RUSSIAN, ONE WITH A TRANSPOSE ON AND ONE WITH AAV. SERIOUS ADVERSE EVENTS WERE REVIEWED, THERE WERE 15 REPORTS REVIEWED FROM 9 PROTOCOLS INCLUDING BOTH INITIAL AND FOLLOW UP REPORTS. NONE OF THE EVENTS REVIEWED THIS QUARTER REQUIRED DISCUSSION AT TODAY'S MEETING. 17 PLOAT CALLS NOTIFIE PROTOCOLS -- FIVE O F THESE 17 WERE REVIEWED AT PREVIOUS PUBLIC MEETINGS. REVIEW THE HIGHLIGHTS OF THE RESPONSES ON THOSE FIVE PROTOCOLS. PROTOCOL NUMBER 878 IS A PILOT FEASIBILITY STUDY OF -- AND GENETICALLY MODIFIED NEURO STEM CELLS EXPRESSING E COLI -- FOR THE TREATMENT OF RECURRENT HIGH GRADE GLEE OWE MAS. THIS REWAS REVIEWED IN OUR DECEMBER 2007 MEETINGS. PRECLINICAL STUDIES WERE DOWN A MODEL WITH PRIOR RADIATION TO ASSESS WHETHER RADIATION COULD ALTER THE TUMOR ENVIRONMENT AND MAKE THE NEURAL STEM CELLS WHICH HAVE BEEN TRANSFORMED WITH A C -- ONCOJEAN TO PRODUCE TUMORS. THE EFFECT OF RADIATION ON THE ABILITY OF THE CELLS TO M MIGRATE TO THE TUMORS WAS ALSO EVALUATED. RADIATION DID NOT CHANGE THE SAFETY PROFILE OF THE CELLS IN THESE MODELS. ANIMAL AND CELL MIGRATION STUDIES ALSO DETERMINED THAT -- DID NOT ARGUMENT EITHER THE TUMOR GENICITY OR THE -- OF THE STEM CELLS. DEXAMETHASONE IS A COMMONLY USED DRUGS IN PATIENT WITH LEO MAS. PROTOCOL NUMBER 989 IS A PHASE ONE OPEN LABEL ESCALATING DOSE STUDY OF THE SAFETY INTOLERABLITY OF SINGLE DAILY DOSES OF CEQ508 AN RNA-BASED THERAPY FOR -- THIS WAS REVIEWED BY THE RAC IN SEPTEMBER OF 2009. THE RESPONSE NOTES THAT IMMUNE RESPONSES TO -- ONE OF THE BACTERIAL COMPOUNDS OF THE STUDY AGENT WHICH IS CEQ508 HAS NOT BEEN SEEN IN PRECLINICAL STUDIES OR IN A PREVIOUS PHASE ONE TRIAL. THE MUTATIONS SEEN IN THIS DISEASE LEADS TO INCREASE DATA -- WHICH LEADS TO UP REGULATIONS OF GENES INVOLVED IN SELF PROLIFERATION INCLUDING THE -- ONCOGENE. ADDITIONAL ANALYSIS OF CORRELATIONS BETWEEN ONCOGENES -- AND CLINICAL OUTCOMES IS BEING CONSIDERED. LASTLY ONLY SUBJECTS WITH A DUMPEDOCUMENTEDMUTATION -- WILL BE ENROLLE D IN THE STUDY. PROTOCOL NUMBER 10 THIS IS LIPO DEPLETION PLUS ADAPTER CELL TRANSFER WITH A CXR2 AND NGFR TRANSDUCED T CELLS FOLLOWED BY HIGH DOSE INTERLEUKIN TWO IN PATIENTS WITH -- MELANOMA. THIS WAS REVIEWED BY THE RAC IN MARCH 2010. THIS STUDY WILL EMPLOY AN APPROACH TO THE PHASE ONE DOSE ES CALCULATIOESCALATION SO DOSING COHORTS CAN BE INFORMED BY THE PRIOR COHORTS FOR THE TRANSDUCE TUMOR INFILTRATING LIMB FIGHTS WHICH MAY EXPAND -- LYMPHOCYTES WHICH MAY EXPAND -- OR ELIMINATED. GIVEN THE RECENT DATA THAT THE CT4 POSITIVE T CELLS MAY BE CRITICAL TO ANTI-TUMOR ACTIVITY. IN ADDITION TO EXAMINING THE TUMOR FOR THE PRESENCE OF CXCR2 TRANSDUCED TILs THEY WILL EXAMINE WHETHER CD4 POSITIVE T CELLS ARE PRESENTED. FINALLY THE AGE LIMIT FOR PEDIATRIC PATIENTS HAS BEEN CLARIFIED TO AGE 7 AND OLDER RATHER THAN RELYING ON QUOTE INTELLECTUAL AGE, END QUOTE. THE NEXT PROTOCOL 1049 IS PHASE ONE PHASE TWO OPEN LABEL SINGLE CENTER MULTIPLE DOSE, DOSE ESCALATION STUDY TO EVALUATE THE SAFETY INTOLERABLITY OF SNSO1T ADMINISTERED BY INTRAVENOUS INFUSION IN PATIENTS WITH RELAPSE THE OR REFRACTORY MULTIPLE MYELOMA. SNSO1T IS A PARTICLE PLASMID COMPLEX CONTAINING A GENE FOR TRANSLATION INITIATION VECTOR 5A PROTEIN AND AN SIRNA AGAIN OF THE SAME NATIVE EIF5A. IN MYELOMA CELLS THE EIF5A IS -- AND THIS PROMOTES CELL GROWTH. THIS IS THE TARGET OF THE SIRNA. -- THAT MAY BE MADE BY THE PLASMIDS SHOULD THEN PROMOTE APPEAR TOASTS. PRECLINICAL MODELS REVIEW AT THE RAC COMMITTEE EMPLOYED SUBCUTANEOUS INJECTION. HOWEVER THE RESULTS OF TOXICOLOGY STUDIES DEMONSTRATE THAT INTRAVENOUS ADMINISTRATION LEADS TO PLASMID DNA IN THE BONE MARROW. THE CLINICAL TRIAL WILL THEN EXAMINE BONE MAYOR SAMPLES TO DETERMINE IF APPEAR TOASTS IS OCCURRING IN MYELOMA CELLS. ON THE SAME PROTOCOL, A CONCERN WAS RAISED REGARDING WHETHER THE STUDY COULD ARGUMENT THE EXPRESSION OF THE YEW CARIOTIC TRANSLATION INITIATION FACTOR 5A LIKE 1 WHICH MAY BE ON -- GENE. DATA PRESENTED THAT EIFAL1 APPEARS TO BE A SIT GENE AND NOT EXPRESSED IN THE MYELOMA CELL LINE. MOREOVER GIVEN THE SEQUENCE HOMOLOGY BETWEEN EIF5AL1 AND EIF5A WOULD BE SILENCED BY THE SIRNA. THE LAST PROTOCOL IS 1101, A RANDOMIZED DOUBLE BLIND PHASE THREE EPI TRIAL ARE PROSPECT WHETHER OR WITHOUT -- ASYMPTOMATIC OR MINIMALLY SYMPTOMATIC METASTATIC CASTRATE RESISTENT PROSTATE CONFERENCE. THAT WAS REVIEWED BY THE RAC IN 2011678. ADDITIONAL INFORMATION WAS ADDED FOR THE RATIONAL OF THE USE OF AN EMPTY -- VECTOR RATHER THAN A -- VIRUS VECTOR WHICH IS THE BACKBONE OF THE STUDY AGENT AS THE PLACEBO CONTROL. DETAILED CONSTRUCTIONS AND PRECAUTIONS WILL BE PROVIDED TO THOSE INDIVIDUALS WHO WILL PREPARE THE STUDY AGENT FOR INJECTION, ORANGE RACK WITH SUBJECTS IN ORDER TO ENSURE THAT THE VECTORS HANDLED IN A SAFE MANNER AND THAT HEALTHCARE WORKERS ARE INFORMED OF THE POTENTIAL RISKS. THAT'S THE END OF OUR REPORT. ARE THERE ANY QUESTIONS? >> THANK YOU VERY MUCH. WE ARE GOING TO TAKE A BREAK OF ABOUT 10 MINUTES AND THEN WE'RE GOING TO CONDUCT A DISCUSSION OF THE IBC ISSUES THAT WE'VE BEEN DOING BY PHONE AND WE CAN DO IN PERSON. SO RETURN IN ABOUT TEN MINUTES