>> WELCOME TO THE SPRING 2021 MEETING OF THE SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS. OR SACHRP. I'M JERRY MENIKOFF, OHRP DIRECTOR. IT GIVES ME GREAT PLEASURE TOLL WELCOME DOUG DIEKEMA. DOUG IS ATTENDING PHYSICIAN FOR THE TRUMAN CAT CENTER AT SEATTLE CHILDREN'S RESEARCH INSTITUTE AND DEPARTMENT OF PEDIATRICS AT THE UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE. HE RECEIVED HIS M.D. FROM UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE AND NPH FROM UNIVERSITY OF WASHINGTON SCHOOL OF PUBLIC HEALTH. BEYOND ALL OF THE FORMAL ROLES AND TITLES, PEOPLE WORKING IN THE FIELD OF BIOETHICS ARE ALREADY FAMILIAR WITH HIM AS VERY, VERY INFLUENTIAL VOICE OF BIOMETRICS. THERE IS A VARIETY OF WAYS TO MEASURE THINGS, I WOULD LOVE TO GIVE AN ANECDOTE IN TERMS OF PUBLICATIONS. WE HAVE DATA SHOWING HOW MANY ONE ARTICLE OR ANOTHER IS USED. GIVEN HOW MUCH COMPETITION FOR READERS IN PARTICULAR, THERE ARE PERHAPS A HANDFUL, MAYBE A HUNDRED, MAYBE A FEW HUNDRED VIEWS. IT IS INTERESTING TO SEE WHEN DOUG IS A CO-AUTHOR ON AN ARTICLE, EVEN IF MANY ARTICLES DON'T HAVE THAT MANY VIEWS, THE ARTICLE CAN HAVE A THOUSAND, PERHAPS EVEN MANY THOUSANDS OF VIEWS. JUST A SENSE OF HOW IMPORTANT PEOPLE THINK IT IS TO GET HIS VOICE AND HIS TAKE ON THINGS. AT OHRP, WE VERY MUCH LOOK FORWARD TO HIS STEWARDSHIP IN SACHRP, IN CONTINUITY WITH THE PAST STEWARDS OF THIS COMMITTEE, MOST CURRENTLY STEPHEN ROSEN FIELD. A VERY, VERY WARM WELCOME, DOUG, OVER TO YOU. >> THANKS FOR THAT KIND INTRODUCTION, JERRY. IT IS A PLEASURE AND AN HONOR TO BE CHAIR OF THIS COMMITTEE AND I'VE GOT BIG SHOES TO FILL WITH STEVE'S GREAT LEADERSHIP IN THE PAST. WE HAVE A BUSY AGENDA FOR OUR TWO DAY SACHRP MEETING THIS MARCH 2021 MEETING. SOME VERY INTERESTING TOPICS. TODAY WILL BE LARGELY DEVOTED TO THE TOPIC OF MANDATORY EXPLORATORY BIOPSIES IN RESEARCH. WE WILL HAVE SEVERAL PANEL PRESENTATIONS RELATED TO THAT AND THEN TOMORROW WE WILL TAKE UP, AGAIN, THE TOPIC OF JUSTICE AS AN ETHICAL CONCEPT IN 45CFR46. I KNOW THE SUBCOMMITTEES HAVE BEEN WORKING HARD OF MANY OF THEIR PROJECTS, BUT JUSTICE IN PARTICULAR. AND WE ARE HOPING TO POTENTIALLY FINALIZE THAT PRODUCT. AND THEN SEVERAL OTHER TOPICS FOR TOMORROW. SO IT SHOULD BE AN INTERESTING MEETING AND I'M LOOKING FORWARD TO THE DISCUSSION AND WELCOME EVERYBODY AND THANK THE COMMITTEE AND THE SUBCOMMITTEES FOR THEIR HARD WORK. I'D LIKE NOW TO CALL THE ROLL AND SO I WILL RUN THROUGH OUR LIST. BRIEFLY INTRODUCE OR SAY WHO YOU ARE AND HAVE YOU SIGNIFY PRESENTATION SO WE CAN GET THAT FOR THE MINUTES. SO WHY DON'T WE START WITH JODY -- >> HI. >> GO AHEAD, JODY. YOU ARE PRESENT. JODY IS THE DIRECTOR OF CLINICAL RESEARCH -- AND INSTRUCTOR IN THE DEPARTMENT OF PEDIATRICS AT THE UNIVERSITY OF SOUTH DAKOTA SCHOOL OF MEDICINE. LINDA COLEMAN. I'M PRESENT. GOOD MORNING. >> LINDA IS THE DIRECTOR OF HUMAN RESEARCH PROTECTION PROGRAM IN THE OFFICE OF RESEARCH AT YALE UNIVERSITY. JANET FREEMAN DAILEY. >> I'M HERE. AND JANET IS OUR PATIENT REPRESENTATIVE. SKIP NELSON. >> GOOD MORNING. >> SENIOR DIRECTOR AND PEDIATRIC DRUG DEVELOPMENT AT -- IN THE CHILD HEALTH INNOVATION LEADERSHIP DEPARTMENT AT JOHNSON & JOHNSON. LET'S GO TO KEVIN WEINFORT. >> GOOD MORNING. >> CHAIR OF RESEARCH IN POPULATION RESEARCH. CONSUELO WILKINS. CONSUELO, ARE YOU WITH US? >> DOUG, SHE IS GOING TO BE JOINING US ABOUT 15 MINUTES LATE. >> OKAY. SO CONSUELO WILL BE JOINING US EVENTUALLY. SHE IS THE EXECUTIVE DIRECTOR OF THE MEHARRY VANDERBILT ALLIANCE. LESLIE WOLFE. >> GOOD MORNING. >> LESLIE IS THE DIRECTOR FOR THE CENTER OF LAW HEALTH AND SOCIETY AT GEORGIA STATE UNIVERSITY. AND I THINK WALTER STRAUS, ARE YOU ON YET? I THINK WALTER WAS ALSO GOING TO BE LATE. HE IS THE VICE PRESIDENT FOR CLINICAL RESEARCH FROM MO DERNA. EXOFFICIO OFFICERS. ANYBODY FROM THE FDA. >> THIS IS JoANNE LESS AND THERE IS ANOTHER GENTLEMAN, PABLO. >> GOOD MORNING, PABLO MORALES FROM THE FDA. # >> HOW ABOUT THE NIH. >> GOOD MORNING, THIS IS LYDIA KLINE. >> ANYBODY ELSE FROM NIH? OCS? >> GOOD MORNING, PAYTON ISAAC IS ON. >> AND ANY OTHER EXOFFICIOS? OKAY. JERRY, BACK TO YOU FOR ANY ADDITIONAL COMMENTS YOU HAVE. >> OKAY. THANK YOU, DOUG. FIRST OF ALL, I WOULD LIKE TO THANK EVERYONE FOR ALL THE WORK THAT HAS TAKEN PLACE PRIOR TO THIS MEETING PARTICULARLY THE SUBCOMMITTEE CHAIRS AND SUBCOMMITTEE MEMBERS AND EXOFFICIOS AND OTHERS WHO HAVE BEEN WORKING ON THESE ISSUES. I WOULD LIKE TO THANKS THE OHRP STAFF, JEWULIA GORY, FOR HER SKILLFUL SHEPHERDING OF THE COMMITTEE. I WANT TO PICK UP A LITTLE BIT ON SOME THINGS, DOUG, YOU SAID ABOUT OUR SESSION. DURING THESE TWO DAYS SACHRP WILL BE ADDRESSING A NUMBER OF IMPORTANT TOPICS. I WOULD LIKE TO HIGHLIGHT TWO OF THOSE TOPICS IN PARTICULAR. A RESEARCH STUDY THAT HAS A MANDATORY BIOPSY AS ONE OF ITS PROCEDURES AND THAT THIS BIOPSY IMPOSES SIGNIFICANT RISKS AND NO BENEFIT TO A PARTICIPANT. IMAGINE THE STUDY HAS A TREATMENT NOT AVAILABLE IN A STUDY. WENT IS IT APPROPRIATE TO FORCE PARTICIPANTS TO UNDERGO THE BIOPSY TO GET ACCESS TO THE NEW TREATMENT BEING OFFERED IN THE STUDY. THIS IS AN IMPORTANT AND DIFFICULT QUESTION THAT GOES TO THE HEART OF RESEARCH ETHICS. YOU ARE GOING TO HEAR A GREAT DEAL ABOUT THIS IMPORTANT ISSUE SHORTLY. AND TO PICK UP ON ONE MORE TOPIC. JUSTICE. WE ARE CURRENTLY LIVING IN A TIME WHEN ISSUES RELATING TO JUSTICE, WHICH GROUPS ARE BEING INAPPROPRIATELY DENIED THEIR FAIR SHARE OF THE BENEFITS OF SOCIETY, WHICH ARE INAPPROPRIATELY ASSUMING MORE OF THEIR FAIR SHARE OF THE RISKS OF EVERYDAY LIFE. THESE ISSUES PERMEATE CURRENT POLICY DEBATES. TO BE MORE SPECIFIC, JUSTICE WITH REGARD TO HOW CLINICAL TRIALS ARE CONDUCTED IS IN THE HEART OF THE ISSUE IN THE HEADLINES EVERY DAY NOW. VACCINES FOR COVID-19. THE RESULT OF THE RESEARCH AND AS WE TRY TO REACH HERD IMMUNITY IMMUNITY, PUBLIC TRUST OF THE COVID-19 VACCINES HAS BECOME AN ISSUE OF UTMOST IMPORTANCE. IT IS HARD TO THINK OF A MORE IMPORTANT ISSUE THAT SACHRP CAN TACKLE. WE LOOK FORWARD TO THESE TWO DAYS OF DISCUSSION. ON THE OHRP END, I'M GLAD TO LET PEOPLE KNOW ABOUT NATALIE KLINE, DIVISION OF POLICY AND ASSURANCES DIRECTOR. WE ARE THRILLED TO HAVE HER IN THAT POSITION AND LOOK FORWARD TO HER FUTURE WORK AT OHRP. BACK TO YOU, DOUG. >> THANKS. OUR NEXT ITEM OF BUSINESS IS TO APPROVE OUR MINUTES FROM THE OCTOBER 20th MEETING IN 2020. DO ANY OF OUR MEMBERS HAVE CHANGES TO THOSE MINUTES? IF NOT, DO I HAVE A MOTION TO APPROVE THOSE MINUTES? >> SO MOVED. >> IS THERE A SECOND TO THAT MOTION? >> SECOND. >> ALL IN FAVOR OF APPROVING THE OCTOBER 20, 2020 MINUTES SAY AYE. >> AYE. >> AYE. >> AYE. >> ANY OPPOSED. ANY ABSTENTIONS? ALL RIGHT. OUR NEXT ITEM OF BUSINESS WHICH WE WILL BE WORKING ON FOR THE NEXT HOUR OR SO IS GOING TO BE LED BY MARK BARNES, WHO IS THE CO-CHAIR OF THE SUBCOMMITTEE ON HARMONIZATION. MARK, YOU ARE GOING TO TAKE US THROUGH THE SUBCOMMITTEE'S WORK ON INTERACTIONS BETWEEN SPONSORS CLINICAL TRIAL SITES AND SUBJECTS. >> YEAH. THANK YOU, DOUG. CAN YOU HEAR ME ALL RIGHT? >> YES. >> YES. >> OKAY. GREAT. SO GOOD MORNING, EVERYBODY. NICE TO BE HERE. I AM THE CO-CHAIR OF THE SUBCOMMITTEE ON HARMONIZATION. I CO-CHAIR WITH DAVID FORRESTER. I THINK YOU WILL HEAR FROM DAVID FORRESTER, DAVID BOROWSKI, AND MICHELE RUSSELL-EINHORN. WHAT WE ARE GOING TO TALK ABOUT FOR THE NEXT FEW MINUTES IS A DRAFT DOCUMENT THAT WE IN THE SUBCOMMITTEE SPENT A GOOD DEAL OF TIME CONSIDERING AND PUTTING TOGETHER. AND IT BASICALLY RELATES -- AND JULIA, IF YOU CAN PUT THIS UP ON THE SCREEN SOON, NOT RIGHT NOW, BUT IN A MINUTE, THAT WOULD BE GREAT, OR WHOEVER IS MANAGING THIS. THE ISSUE HERE IS THE FOLLOWING. IN MANY OF OUR INTERACTIONS WITH IRBs, WITH RESEARCH SUBJECTS, WITH INVESTIGATORS, WITH RESEARCH SPONSORS AND THAT INCLUDES INDUSTRY SPONSORS OF RESEARCH AS WELL AS ACADEMIC MEDICAL CENTER OR EMERGENCY CENTER RESEARCH WHEN IS AN INVESTIGATOR STUDY. WHAT WE HAVE SEEN OVER THE PAST FEW YEARS IS AN INCREASING RELATIONSHIP IN BOTH INTENSITY AND FREQUENCY BETWEEN SPONSORS OF RESEARCH ON THE ONE HAND AND THE RESEARCH SUBJECTS AND RESEARCH SUBJECT FAMILIES AND DISEASE ADVOCACY GROUPS ON THE OTHER. AND THIS HAS LED TO A NUMBER OF QUESTIONS ABOUT SORT OF WHAT IS THE APPROPRIATE ROLE OF A SPONSOR, AN INDUSTRY SPONSOR OR ACADEMIC MEDICAL SPONSOR IN THE COURSE OF INTERVENTIONAL CLINICAL RESEARCH WITH LIVING, BREATHING SUBJECTS. AND SO WE PUT THIS DOCUMENT TOGETHER BASICALLY TRYING TO ASSESS WHAT THE CURRENT PROBLEMS ARE NOW THAT OUR RESEARCHERS, IRBs AND SUBJECTS AND OTHERS HAVE RUN INTO. THE GOAL OF THIS DOCUMENT IS TO PROVIDE SOME -- IS TO ASSESS THE SITUATION AND IDENTIFY SOME OF THE ISSUES THAT HAVE ARISEN, BUT ALSO TO LOOK AT ARTICULATING SOME PRINCIPLES WE HOPE ULTIMATELY COULD FIND THEIR WAY INTO GUIDANCE DOCUMENTS AT AGENCIES THAT FUND AND SPONSOR CLINICAL RESEARCH. SO THAT IS THE PURPOSE OF THIS. THERE IS INITIAL FDA GUIDANCE ON THIS ISSUE, WHICH RELATED LARGELY TO TWO ISSUES. ONE IS THAT IN ITS BASIC GUIDANCE DOCUMENT OF THE ROLE OF IRBs AND INDUSTRY SPONSORS, THIS IS QUITE OLD, 25 YEARS OLD, FDA INDICATED IF A SPONSOR IS GOING BE INVOLVED, FOR EXAMPLE, IN RECRUITMENT ACTIVITIES, DIRECTLY ASSISTING SITES, THOSE RECRUITMENT ACTIVITIES MUST BE SET FORTH IN THE INVESTIGATION PLAN AND REVIEWED AND APPROVED BY THE IRP, UNLESS THEY ARE NOT SPECIFIC TO A PARTICULAR STUDY AND SIMPLY THE SPONSOR POSTING AVAILABLE STUDIES THAT IT SPONSORS ON ITS WEBSITE WITH NO MORE, NO LESS INFORMATION CONTAINED IN THE CLINICALTRIAL.GOV POSTINGS. ANY ELSE, ANY OTHER SIGNIFICANT CONTACT WITH SUBJECTS AND THE POTENTIAL -- THE COMMUNITY CONTAINING PEOPLE WHO ARE POTENTIALLY -- COULD BE POTENTIALLY CONSIDERED SUBJECTS AND MAY WISH TO SEEK ENROLLMENT AS SUBJECTS NEED TO BE SUBJECT TO IRB REVIEW AND APPROVAL. THE OTHER DOCUMENT I HAD NOT BEEN PREVIOUSLY AWARE. I THANK FDA AND MS. LESS BRINGING TO US. IN THE DEVICE AREA. PARTICULARLY DEVICE MANUFACTURERS -- THESE GUIDANCE DOCUMENTS ARE CITED IN THE FOOTNOTES. FOOTNOTE ONE IN THE DRAFT. THERE IS A GUIDANCE DOCUMENT FROM FDA ADDRESSING THE SITUATION IN WHICH DEVICE -- INDUSTRY DEVICE COMPANY SPONSORS OF RESEARCH WHICH TO BROADCAST OR OTHERWISE RECORD ON VIDEO PARTICULAR SURGICAL INTERVENTIONS THAT ARE PART OF AN INTERVENTIONAL TRIAL IN WHICH A SURGEON OR IT COULD BE A CARDIOVASCULAR INTERVENTIONAL -- CARDIOVASCULAR -- INTERVENTIONAL CARDIOLOGIST INTRODUCE AND USE A TEST DEVICE UNDER AN IDE IN AN OPERATING ROOM THEATER. THE PURPOSE OF THE BROADCAST IS TO ACQUAINT THE LARGER COMMUNITY, FOR EXAMPLE, OF INTERVENTIONAL CARDIOLOGISTS OR ORTHOPEDISTS OF A TEST OF THE DEVICE BEING USED. THE FDA WAS FACED WITH REQUESTS -- THIS IS IN THE COURSE OF A TRIAL -- THIS IS A SUBJECT WHO WAS ALSO A PATIENT UNDERGOING AN INTERVENTIONAL PROCEDURE ALSO A SUBJECT IN A TRIAL AND THE SPONSOR IS WANTING THE INVESTIGATOR WHO IS MOST LIKELY THE SURGEON ACTUALLY TO PARTICIPATE IN THIS KIND OF EDUCATIONAL SESSION OR FOR DIFFERENT PURPOSES, I SUPPOSE, BUT PARTICULARLY FOR PROFESSION EDUCATION. FDA WAS FACED WITH SITUATIONS IN WHICH COMPANIES WANTED TO DO THIS. AND FDA EXPRESSED CONCERN, AND THIS IS SET FORTH IN THE DOCUMENT IN WHICH A LINK IN FOOTNOTE ONE OF THIS DRAFT, IN REGARD TO THE CONSENT PROCESS FOR THESE PATIENTS, THESE PATIENT SUBJECTS, THE NEED TO PROTECT THE IDENTITY OF THESE PATIENT SUBJECTS IN THE COURSE OF A FILMING LIKE THIS AND THE ISSUE, YOU KNOW, SORT OF OVERARCHING ISSUE OF WHETHER THE PROCESS OF FILMING AN INTERVENTION LIKE THIS, A SURGICAL TRIAL INTERVENTION MIGHT INCREASE RISK TO THE SUBJECT BECAUSE THE SURGEON AND THE OPERATING TEAM COULD BE PERHAPS DISTRACTED BY THE PROCESS OR MAYBE THE WHOLE PROCESS MAY BE MADE MORE COMPLICATED BY THE PROCESS OF FILMING. FDA PUT FORTH A DOCUMENT SAYING FDA AND THE IRB SHOULD BE APPROACHED WHEN SUCH -- BEFORE SUCH A FILMING MIGHT OCCUR. AND THEN SET FORTH A NUMBER OF CONSIDERATIONS IN REGARD TO CONSENT AND SAFETY. THERE IS THE ISSUE OF UNDUE INFLUENCE OR COERCION. A SURGEON APPROACHING A PATIENT SUBJECT TO ASK FOR THIS SHOULD ONLY DO IT IN AS AT LEAST COERCIVE AS POSSIBLE. WE HAD THESE TWO FDA DOCUMENTS, BUT MUCH ELSE OF THE LEARNING IN THIS AREA HAS REALLY BEEN OURSELVES ON A CASE BY CASE, STUDY BY STUDY BASIS. HOW TO UNDERSTAND THE PRINCIPLES OF IRB APPROVE AND ETHICS REVIEW AND APPROVAL OF OVERSIGHT AND MONITORING OUGHT TO BE APPLIED TO THESE SITUATIONS. THERE ARE A FEW EXAMPLES IN THE INTRODUCTION TO THIS DOCUMENT. I WON'T READ THEM TO YOU. I HOPE YOU HAVE BEEN ABLE TO AT LEAST REVIEW THEM BRIEFLY, BUT FOR EXAMPLE, AND WE ARE NOT JUST TALKING ABOUT INDUSTRY SPONSORS OF STUDY, BUT ACADEMIC. PHASE ONE OF ONE OR TWO PATIENTS, SAY EIGHT PATIENTS ENROLLED IN THE STUDY, AN ENROLLMENT IS NOT YET COMPLETE BECAUSE THE COME PLMT IS 10. THE FIRST INTERVENTIONS HAVE BEEN SUCCESSFUL, TO REDUCE OR ELIMINATE THE DISEASE BURDEN. THE ACADEMIC MEDICAL CENTER, THE SPONSOR OF THIS STUDY, UNDER AN IND, WOULD LIKE THE INVESTIGATOR TO APPROACH THE SUBJECTS OR PERHAPS THE INSTITUTION WOULD LIKE TO APPROACH THE SUBJECTS THEMSELVES TO ASK IF THEY WOULD UNDERGO INTERVIEWS ABOUT WHAT THE STUDY WAS ABOUT. HOW THEY FARED IN THE STUDY. THIS IS BEFORE THE STUDY HAS COMPLETED ENROLLMENT AND WHILE THE STUDY IS ONGOING AND DATA COLLECTION MAY BE ONGOING. IN GENE THERAPY STUDIES THERE IS A LENGTHY FOLLOW-UP PERIOD FOR COLLECTION OF DATA. THE DATA SET IS NOT COMPLETELY LOCKED UNTIL YEARS LATER. AND SO IN THE FILM IS SHOWN. THE PERSON, THE SUBJECT SAYS, OH, GOSH, I ENROLLED IN THE STUDY. IT WAS FOR X CONDITION I HAD MY ENTIRE LIFE AND NOW I MADE A MIRACULOUS RECOVERY. IS IT TO BE USED FOR PHILANTHROPIC FUND RAI RAISING, TO ENTICE OTHERS TO BE SCREENED FOR THE STUDY. THAT IS ONE EXAMPLE. ANOTHER EXAMPLE WHICH WE SEE A LOT OF THESE DAYS IS INDUSTRY SPONSORS SECURING THE SERVICES OF THIRD PARTY VENDORS WHO IN TURN PROVIDE RECRUITMENT SERVICES. AND THE -- THERE ARE DIFFERENT WAYS THIRD PARTY VENDORS DO THIS. THEY MAY HAVE THEIR OWN DATA BASES OF POTENTIALLY ELIGIBLE SUBJECTS. THE ORIGINS OF THESE DATABASES ARE QUESTIONABLE. THEY HAVE THE DATABASES. THE CIRCUMSTANCES UNDER WHICH THEY HAVE SECURED THE DATABASE. THE OTHER POSSIBILITY IS THE THIRD PARTY VENDOR THOUGH UNDER CONTRACT TO THE SPONSOR, MAY BE SERVING AS A BUSINESS ASSOCIATE OR [INDISCERNIBLE] OF SITES. THERE IS A WORK PLAN OF WHICH THERE IS UP WITH OF THESE HIPAA THEORIES OR A PATIENT RECORD SET AT THE HIPAA COVERED ENTITY MEDICAL SUBSTITUTION AND PHARMACY, FOR EXAMPLE, THEY COMB THESE RECORDS TO TRY TO IDENTIFY POTENTIALLY ELIGIBLE SUBJECTS WHO THEN WOULD BE EITHER APPROACHED BY THEIR TREATING PHYSICIANS, THE INVESTIGATOR, AND IN SOME PLANS THE THIRD PARTY VENDOR MIGHT APPROACH THESE INDIVIDUALS THEMSELVES UNDER THE WAIVER OF AUTHORIZATION OR UNDER A BUSINESS ASSOCIATE AGREEMENT. SO THESE ARE SITUATIONS -- AND THERE ARE MANY OF THESE SITUATIONS THAT HAVE CROPPED UP. WE HAVE HAD -- THERE REALLY IS A LACK OF GUIDANCE IN THIS AREA. THE POINT OF THIS DOCUMENT IS TO TRY TO UNDERSTAND THE PROBLEMS AND SITUATIONS THAT MIGHT ARISE, DISCUSS THEM AND COME UP WITH POTENTIAL PRINCIPLES TO HOPEFULLY ANIMATE THE REGULATORY GUIDANCE DECISION MAKING BY THE RELATIVE AGENCIES. ANOTHER SITUATION WE HAVE SEEN, ESPECIALLY IN THE RARE DISEASE IN THE PEDIATRIC AREA. WE SEE MEDICAL DIRECTORS AND SOME CASES INVESTIGATORS THEMSELVES, DEVELOP A STRONG RELATIONSHIP WITH PATIENT ADVOCACY GROUPS. SUCH STRONG RELATIONSHIPS THAT THEY GIVE NOTICE TO THE ADVOCACY GROUPS AND THE FAMILIES IN AN ADVOCACY GROUP ABOUT POTENTIAL STUDY ENROLLMENT, ABOUT THE OPENING OF A STUDY. AND THE LINES BETWEEN ADVISING OR GIVING INFORMATION TO A DISEASE ADVOCACY GROUP VERSUS BECOMING AN ADVOCATE FOR PEOPLE AFFILIATED WITH THE ADVOCACY GROUP TO GET FIRST PRIORITY FOR PHASE 1 OR PHASE 2 TRIAL CAN ITSELF BE PROBLEMATIC. THIS IS NOT -- THESE EXAMPLES THAT I'M GIVING YOU ARE SANITIZED REAL LIFE EXAMPLES I HAVE DEALT WITH IN ADVISING MEDICAL CENTERS AND INDUSTRY AND IRBs ABOUT THESE THINGS. I HAVE TO TELL YOU, WE HAVE MANY PEOPLE ON THE SUBCOMMITTEES FOR SACHRP, THEY HAVE HAD SIMILAR EXPERIENCES AND PROBLEMS. SO, FOR EXAMPLE, ONE OF THE MEMBERS OF A SUBCOMMITTEE WHO I WILL NOT NAME BECAUSE THE INSTITUTION WOULD BE IDENTIFIABLE. THAT MEMBER OF THE SUBCOMMITTEE SAID, THIS DOCUMENT SETS FORTH THE MOST PROBLEMATIC AREAS OF MY PROFESSIONAL LIFE FOR THE LAST FEW YEARS IN TERMS OF TRYING TO ADVISE IS INVESTIGATORS WHAT TO DO AND OUR CONTRACTING OFFICE HOW TO DEAL WITH SPONSORS WHO WANT TO UNDERTAKE THESE KINDS OF ACTIVITIES. IT IS NOT A RARE SITUATION. SO, YOU KNOW, I THINK PROBABLY THE MOST IMPORTANT THING AND WE CAN GO -- WE CAN TALK ABOUT ANY OF THE DETAILS OF THIS DOCUMENT THAT PEOPLE MAY WANT TO TALK ABOUT AND I WILL BE QUIET AFTER A FEW MORE MINUTES. THE PRINCIPLES ARE THERE NEEDS TO BE TRANSPARENCY WITH THE IRBs, INVESTIGATORS AND SUBJECTS. THERE NEEDS TO BE A COMMITMENT TO NONCOERCION. THERE NEEDS TO BE CAREFUL ANALYSIS OF THE POTENTIALLY COERCIVE ELEMENTS AND THE POTENTIAL DATA INFLUENCE UNCONSCIOUS INFLUENCE ON DATA COLLECTION THAT OCCURS WHEN PEOPLE ARE -- WHEN SUBJECTS ARE APPROACHED IN A MIDDLE OF A TRIAL, STILL PARTICIPATING IN A TRIAL, THERE IS THE LESSER ISSUE OF WHEN THE INDIVIDUAL COMPLETED ITS STUDY VISITS BUT THE TRIAL CONTINUES TO BE OPEN AND THESE SUBJECTS ARE CHATTING WITH EACH OTHER IN SOCIAL MEDIA AND THEIR OWN DISEASE ADVOCACY GROUPS. THERE NEEDS TO BE IRB REVIEW AND APPROVAL OF THESE KINDS OF APPROACHES AND OF INTERVENTIONS WITH SUBJECTS AND THEIR FAMILIES. AND THEN IN REGARD TO THE HIPAA ISSUES, THERE IS A SECTION IN THIS DOCUMENT ABOUT THE USE OF BUSINESS ASSOCIATE AGREEMENTS AND WAIVERS OF AUTHORIZATION TO ALLOW THIRD PARTY VENDORS TO PERFORM THESE SERVICES. THERE IS A USE OF BUSINESS ASSOCIATE AGREEMENTS FOR THIS PURPOSE, PRIMARILY BECAUSE A BUSINESS ASSOCIATE AGREEMENT BETWEEN A HEALTH CARE PROVIDER AND THIRD PARTY VENDOR HAS VERY DEFINED PROTECTIONS FOR SUBJECTS AND SETS FORTH IN GREAT DETAIL THE DUTIES AND OBLIGATIONS FOR THE THIRD PARTY VENDOR AND POTENTIALLY CONTACTING PATIENTS. A WAIVER AUTHORIZATION IS ONLY A WAIVER AND IS ONLY AS GOOD AS THE WAY IN WHICH THE RECRUITMENT PROCESS, THE RECORD REVIEW PROCESS IS DESIGNED AND THE CONTRACTUAL OBLIGATIONS BETWEEN THE THIRD PARTY VENDOR AND THE SPONSOR PAYING FOR THE THIRD PARTY VENDOR SERVICES. I WILL STOP THERE AND BE HAPPY TO TALK ABOUT ANY OR ALL OF THIS THAT YOU'D LIKE. >> OKAY. >> DOUG, I'M RELINQUISHING IT BACK TO YOU. >> THANKS, MARK. ARE THERE GENERAL COMMENTS FROM THE COMMITTEE? ABOUT MARK'S DOCUMENT? DO WE WANT TO GO THROUGH THIS PARAGRAPH BY PARAGRAPH? HOW ABOUT IF WE START WITH GENERAL COMMENTS. >> DOUG, THIS IS KEVIN, I'M SORRY, WHAT IS OUR PROTOCOL? DO WE SHOUT OUT OR DO HAND RAISES OR WHAT SHOULD WE DO? I AM HAPPY WITH YOU SHOUTING OUT AS LONG AS WE ARE NOT TALKING OVER EACH OTHER. >> OKAY. WELL JUST QUICKLY, I HAVE A COUPLE MORE SPECIFIC THINGS, BUT I REALLY APPRECIATED THIS DOCUMENT. IT CERTAINLY IS TIMELY BECAUSE MORE AND MORE COMPANIES WE KNOW ARE WORKING, ESPECIALLY IN THE RARE DISEASE SPACE AND ARE BEING ENCOURAGED TO BE IN CLOSER CONTACT WITH THE PATIENTS AND SO -- WHICH IS A TERRIFIC THING SO THIS GUIDANCE IS REALLY NEEDED. I REALLY APPRECIATE THE ATTENTION TO DETAIL AND THE COMPREHENSIVENESS OF IT. I THOUGHT IT WAS TERRIFIC. I WILL HAVE MORE SPECIFIC DETAILS LATER. >> ANY OTHER COMMENTS GENERALLY? IF NOT, WE CAN GO THROUGH THIS PARAGRAPH BY PARAGRAPH AND SEE WHAT SPECIFIC CHANGES PEOPLE MIGHT WANT TO THIS PARTICULAR DOCUMENT. MARK, DO YOU WANT TO TAKE US THROUGH PARAGRAPH BY PARAGRAPH? >> I WOULD PROBABLY PREFER IF, I MEAN, I WILL DO WHATEVER YOU ALL WANT TO DO. I THINK PERHAPS THE BEST USE OF THE TIME WOULD EITHER TO BE TO GO RIGHT TO THE -- >> TO THE RECOMMENDATIONS. >> THE CASE EXAMPLES OR JUST TO GO TO THE ROIMECOMMENDATIONS. >> I WILL DO WHATEVER YOU ALL WANT TO DO. IF KEVIN HAS SOME SPECIFIC COMMENTS THAT ARE GROUP THEMEATICALLY, HAPPY TO HEAR THOSE. >> WE WILL DO WHATEVER YOU THINK IS MOST VALUABLE, MARK, TO GET THIS SORT OF TOWARD FINALIZATION. >> LET'S DO THIS, DOUG. WHY DON'T I REVIEW THE RECOMMENDATIONS QUICKLY. >> YEP. >> AND THEN WE WILL GO TO SPECIFIC COMMENTS PEOPLE HAVE ON ANY OF IT. HOW DOES THAT SOUND? >> THAT SOUNDS GREAT. >> JULIA, CAN YOU GO TO THE PENULTIMATE PAGE. JULIA, YOU HAVE TO PUT ONE PAGE UP AT A TIME BECAUSE THERE IS NO WAY I CAN READ THIS ON MY COMPUTER. >> I AM NOT QUITE SURE, FRANKLY, HOW DO IT ONE PAGE AT A TIME. >> I'M SEEING TWO PAGES. IF I'M HAVING TROUBLE SEEING IT, OTHER PEOPLE MAY BE HAVING TROUBLE. >> IT IS AWKWARD WHEN YOU ARE SHARING YOUR SCREEN BECAUSE I CAN'T SEE THE FULL MENU. >> IF YOU SEE THE SLIDER MINUS TO PLUS THAT WILL DO IT. >> HOW IS THAT? >> GREAT. SO MUCH BETTER. >> I ASSUME YOU WANT CONCLUSIONS I WANT TO REMIND EVERYONE THAT THE SACHRP MATERIALS ARE PUBLICLY POSTED. REGULATIONS.GOV AND SEARCH FOR HHS-OPHS-2021-0007. AND ALL THE SACHRP MATERIALS SHOULD BE THERE. THANK YOU. >> SO JULIA, IF YOU COULD BLOW THAT PAGE UP, THAT WOULD BE GREAT. >> YOU ARE NEVER SATISFIED MARK. >> MY POOR EYES CAN ONLY TAKE SO MUCH. A LITTLE BIGGER SHOULD BE FINE. >> OH, DEAR GOD. >> OKAY, THANK YOU, JULIA. LET ME REVIEW THESE BRIEFLY AND GIVE YOU THE UNDERPINNING FOR EACH ONE AND, DOUG, LET'S TAKE INDIVIDUAL COMMENTS AND THINGS, OKAY? >> YEAH. >> THE FIRST BULLET POINT IS ADDRESSING A SITUATION SPONSORS AS PART OF RECRUITMENT ACTIVITY SET UP SCREENING CENTERS STAFFED BY PEOPLE, IN SOME CASES NURSES OR EMTs, OR NO CLINICAL TRAINING AND ACT AS A RESOURCE AS STUDY COORDINATORS SO PATIENTS AND FAMILIES CAN CALL IN AND DESCRIBE THEIR PERSONAL MEDICAL SITUATION AND GET AN INITIAL ASSESSMENT OF WHETHER THEY MIGHT BE ELIGIBLE FOR THE STUDY. THERE ARE SITUATIONS -- THE IDEA HERE, THE IDEAL SITUATION IS THAT THE SPONSOR WOULD IDENTIFY PEOPLE WHO WOULD CALL INTO A CALL CENTER OR INTERNET CHAT ROOM THAT THE SPONSOR HAS SET UP THROUGH A PUBLIC WEBSITE POSTING OF SOME PORT. THE SPONSOR ACCEPTS QUESTIONS. IF THE SPONSOR FINDS THERE IS A PERSON WHO MAY BE ELIGIBLE FOR THE STUDY AND WOULD LIKE TO BE CONSIDERED WITH ELIGIBILITY, THE SPONSOR, WITH THE CONSENT OF THE GIVEN ELECTRONICALLY, GIVES THE INFORMATION TO FOLLOW UP AT THE SITE. ANOTHER ITERATION, SPONSORS HAVE A HELP DESK LIKE THIS. NOT ONLY DO THEY RECEIVE INQUIRIES FROM POTENTIALLY ELIGIBLE SUBJECTS, BUT THEY ALSO SOLICIT FROM THE SUBJECTS COPIES FROM THE MEDICAL RECORDS. THEY WILL ASK SUBJECTS TO SIGN A HIPAA AUTHORIZATION TO ALLOW THE SPONSOR'S HELP DESK OR RUN BY A THIRD PARTY VENDOR TO THE SPONSOR TO APPROACH THE EXISTING HEALTH CARE PROVIDERS TO GET FULL COPIES TO MEDICAL RECORDS TO ASSESS ELIGIBILITY. WHAT WE ARE TRYING TO SAY HERE IS ULTIMATELY THE ELIGIBILITY DECISIONS OUGHT TO BE MADE BY THE INVESTIGATORS AND SPONSORS SHOULD BE CAREFUL ABOUT SHARING INFORMATION, YES, FACILITATING CONTACT BETWEEN POTENTIALLY ELIGIBLE SUBJECTS IN THE SITES, BUT NOT MAKING FINAL ELIGIBILITY DETERMINATIONS. WE DON'T GET MORE SPECIFIC THAN THAT IN THE RECOMMENDATION OR DOCUMENT. THAT IS WHAT THIS IS TRYING TO ADDRESS IN GENERAL, THAT PARTICULAR SITUATION. THE NEXT IS THAT -- PREMISED -- OOPS. GO BACK, JULIA. >> DOUG, DO WE WANT TO TALK ABOUT THESE ONE AT A TIME? >> YEAH. IF YOU HAVE COMMENTS, WHY DON'T WE GO THERE. SO GO AHEAD, SKIP >> YEAH, SO, MARK, I AGREE WITH THE GENERAL DIRECTION. I GUESS I HAVE TWO COMMENTS. SO DEPENDING -- I MEAN, LET'S IMAGINE A TRIAL IS OPEN 18-65 AND SOMEONE WHO IS A PARENT CALLS OF SOMEONE WHO IS 16 OR SOMEONE WHO IS 66 CALLS. THAT IS PRETTY STRAIGHT FORWARD. SO I GUESS, WHICH IS A LOT DIFFERENT THAN ASKING FOR THE COMPLETE MEDICAL RECORD AND DYEING -- DIVING INTO THE LABORATORIES AND ALL THAT STUFF. >> RIGHT. I GUESS MY QUESTION IS WHERE IS THAT APPROPRIATE LINE AND WHAT IS IT THAT IS DRIVING THE CONCERN ABOUT CROSSING IT? IS IT PRIVACY? IS IT INVESTIGATOR ROLE? CAN YOU GIVE ME SOME CLARITY. >> I CAN GIVE YOU SOME EXAMPLES. ONE IS PRIVACY. WE HAVE SEEN SITUATIONS IN WHICH INDIVIDUALS WHO HAVE TRIED TO CALL INTO THESE CALL CENTERS OR INTERACT ARE NOT QUITE -- THEY ARE SURPRISED, EVEN THOUGH THEY MAY HAVE SIGNED FORMS, THEY ARE SURPRISED THE ACCESS OF THE SPONSOR TO THEIR MEDICAL RECORDS. THAT IS ONE THING THAT HAS HAPPENED. ANOTHER THING THAT HAS HAPPENED AND I HAVE HAD TO PERSONALLY UNRAVEL STICKY SITUATIONS, THE SPONSOR RECEIVED INFORMATION, THEY WANT QUICK, RAPID STUDY ENROLL. . THE PEEL WHO CALL IN MAY BE EXISTING PATIENTS OF THE INVESTIGATOR IN THE STUDY. THE INVESTIGATOR IS ANGRY AT THE SPONSOR IN INTERFERING WITH CONVERSATIONS THAT THE GOURMET WANT TO HAVE WITH PATIENTS WHO MAY BE ELIGIBLE FOR THE STUDIES. THE SPONSOR AGENTS HAVE INSISTED THE PERSON CALLED IN BE CONSIDERED FOR THE STUDY, BUT THEIR OWN PHYSICIAN WHO IS AN INVESTIGATORS IN THE STUDY SAYS I LOOKED AT THIS AND THE PERSON IS NOT ELIGIBLE. THERE ARE VERY INFLAMMATORY SITUATIONS. WE ARE PURPOSELY VAGUE IN THIS DOCUMENT ABOUT EXACTLY WHAT THE LINE SHOULD BE. WHAT WE ARE TRYING TO SAY, THOUGH, IS THESE ARE THE KINDS OF THINGS THAT OUGHT TO BE CONSIDERED IN A SPONSOR AND INVESTIGATOR DESIGNING WHAT WOULD BE AN APPROPRIATE SPONSOR ROLE. >> AND THE CASES YOU DESCRIBE ARE COMPELLING, BUT THE AND I THINK IN THE TEXT YOU GIVE NUANCE, BUT THE WAY THIS TEXT READS IT IS THE SIMPLEST QUESTION. IS THERE A WAY OF NOT DRAWING THE LINE TO GET INTO SPECIFIC CASES, AS YOU MENTIONED, BUT -- AND MAYBE THE DISTINCTION IS ANSWERING A SIMPLE QUESTION ABOUT ELIGIBILITY. ARE YOU THE RIGHT AGE? DO YOU HAVE THE DISEASE? VERSUS SOMETHING THAT REQUIRES GETTING INTO A MEDICAL RECORD. I'M WONDERING IF A LINE CAN BE DRAWN THAT IS ABLE TO DISTINGUISH BETWEEN WHAT WOULD BE A FAIRLY SIMPLE QUESTION TO ANSWER WITHOUT THE NEED TO KNOW SOMEONE'S MEDICAL HISTORY VERSUS A MORE DETAILED KNOWLEDGE. >> ALL RIGHT, WELL, LOOK, ANY COMMENTS THAT YOU GUYS HAVE ON CHANGING THIS DOCUMENT, IT IS FINE. IT IS YOUR DOCUMENT. IT IS NOT MY DOCUMENT. THAT IS FINE. THE WAY THIS IS PHRASED HERE IS I THINK -- MY INTERPRETATION OF THE WAY IT IS CURRENTLY PHRASED IS THAT A SPONSOR WEBSITE OR CALL CENTER COULD SAY TO THE PARENT, GOSH, YOU SAY YOUR CHILD IS 16, BUT 18 IS THE ELIGIBILITY DETERMINATION, SO THAT PERSON WOULD PROBABLY NOT BE ELIGIBLE. YOU CAN CALL THE SITE IF YOU WANT TO. IF YOU WANT, I WILL FORWARD THE INFORMATION, BUT THE ELIGIBILITY AGE IS REALLY 18. >> MM-HMM. I SEE. >> THAT IS AN EXAMPLE. THAT IS CONTEMPLATED BY THE WAY THIS IS PHRASED. >> SO THAT IS WHAT YOU MEAN BY SHARE AND DISCUSS STUDY ELIGIBILITY INFORMATION, BUT NOT GETTING INTO YOUR SPECIFICS? OKAY. >> SO THIS IS JANET. SO SOMETHING I DON'T SEE IN HERE -- I'M SORRY. I'M GETTING AN ECHO. >> WE CAN HEAR YOU OKAY, JANET. >> SOMETHING THAT DOES COME UP IS INCLUSION OF NONPROFIT OR PATIENT GROUPS WHEN THE OFFICERS ARE THEMSELVES PATIENTS. WHAT ARE THE ETHICS OF A PERSON WHO MIGHT POTENTIALLY BE ON THE TRIAL DISCUSSING WITH THE SPONSOR POTENTIAL TRIAL DESIGN OR SITE LOCATIONS? OR TALKING TO THE SPONSOR TO TRY AND HELP IDENTIFY AN APPROPRIATE SITE LOCATION FOR A PATIENT WHO DOESN'T HAVE THE TRIAL IN THEIR COUNTRY. I REALIZE THAT SACHRP IS ONLY DEALING WITH THE U.S., SO IN THE INSTANCE OF AN ORGANIZATION IN THE U.S., THEY ARE TRYING TO HELP A CANADIAN PATIENT ACCESS A TRIAL, GIVEN THE PERSON HAS THE RESOURCES TO DO SO, WHERE ARE THE BOUNDARIES, AN OFFICER OF A NONPROFIT, BUT ALSO A PATIENT TALKING TO A SPONSOR ABOUT A TRIAL THEY MIGHT PARTICIPATE IN? >> WELL, I MEAN, YOUR COLLEAGUES MAY HAVE ANSWERS TO THAT QUESTION. I THINK THE SPONSOR SHOULD BE CAREFUL IN THAT SITUATION, YOU KNOW, NOT TO PROMISE ENROLLMENT TO A PERSON WHO IS KIND OF BASICALLY A KEY OPINION LEADER IN A PATIENT ADVOCACY ORGANIZATION, BUT RATHER TO REFER THEM LIKE ANYBODY ELSE ON THE STREET WHO MAY HAVE THAT DISEASE OR CONDITION, TO A STUDY SITE AND INVESTIGATOR FOR A FULL CONVERSATION ABOUT IT. I THINK WHERE WE RUN INTO TROUBLE SOMETIMES IS WE HAVE AN OVERIDENTIFICATION BETWEEN A SPONSOR REPRESENTATIVE AND PARTICULAR PEOPLE OR FAMILIES WITHIN A DISEASE ADVOCACY GROUP LEADING TO PROMISES THAT ARE MADE BY A SPONSOR THAT REALLY ARE THE SUBJECT OF ISSUES THAT SHOULD BE DISCUSSED BETWEEN THE INVESTIGATOR AND THE FAMILY. >> SO AS LONG AS NO PROMISES ARE MADE, YOU DON'T SEE A PROBLEM WITH A PERSON CONSULTING ON DESIGN OF A TRIAL OR POTENTIAL SITES OF A TRIAL WHEN THEY ARE A POTENTIAL PARTICIPANT OF THE TRIAL? >> WELL, I THINK THAT PARTICULAR ISSUE IS A REAL ISSUE. I DON'T THINK IT IS REALLY -- THAT IS NOT ADDRESSED SPECIFICALLY IN THIS DOCUMENT. IT IS NOT INAPPROPRIATE, IT SEEMS TO ME, FOR INDUSTRY SPONSOR TO TALK TO THESE PEOPLE ABOUT WHO ARE THE MOST RESPONSIBLE CLINICIANS, WHO ARE THE CLINICIANS WITH WHOM THE GROUP AND THE INDIVIDUALS IN THE GROUP HAVE HAD THE BEST EXPERIENCE WHO IS RESPONSIVE? WHO HAS DONE OTHER STUDIES? THAT INFORMATION IS PROBABLY VABLG TO THE SPONSOR ANYWAY THROUGH CT.GOV, EVEN IF IT IS A COMPETITOR. THE PRIMARY PROBLEM IS MAKING SURE IF SOMEONE IS ADVISING A COMPANY AND BEING PAID FOR IT THAT THE COMPANY SHOULD BE CAREFUL ABOUT APPEARING TO BE PAYING FOR AN ENDORSEMENT, ESSENTIALLY. >> WELL, IN A LOT OF THESE CASES THE PATIENTS ARE NOT BEING PAID FOR IT. >> I KNOW. IN SOME CASES THEY ARE THROW. >> YEAH. THANK YOU. >> IT IS CONSUELO. I'M STRUGGLING A LITTLE BIT WITH THE ROLE OF ADJUDICATING TRIAL ELIGIBILITY. AND MAYBE THIS IS HAPPENING MORE THAN I WOULD IMAGINE, BUT I IMAGINE THAT WHAT IS HAPPENING IN MANY CASES IS THE ELIGIBILITY CRITERIA ARE DIFFICULT TO INTERPRET, SO, YOU KNOW, LIFE EXPECTANCY, YOU HAD TO HAVE BEEN DIAGNOSED IN CERTAIN PERIOD OF TIME. DIAGNOSIS WAS VAGUE, INCONSISTENT. THERE ARE THOSE KINDS OF ISSUES THAT PERHAPS MAKE IT MORE OF A DISCUSSION AS OPPOSED TO -- AND ADVOCACY AS OPPOSED TO TRYING TO REALLY DETERMINE TRIAL ELIGIBILITY. SO I GUESS I'M NOT SURE HOW THAT FIRST BULLET WOULD BE ACTUALLY IMPLEMENTED OR HOW WE WOULD DISTINGUISH BETWEEN THESE PRACTICALLY. >> WELL, I THINK, CONSUELO, THAT -- I MEAN, IF THERE WERE KIND OF INDETERMINANT -- IF THERE WERE NOT LAB VALUES, BUT INSTEAD FOR EXAMPLE SYMPTOMOLOGY IS PART OF THE ELIGIBILITY CRITERIA, THAT IS EXACTLY THE KIND OF THING THAT OUGHT NOT TO BE ADJUDICATED BY A SPONSOR REPRESENTATIVE WHO MAY NOT BE CLINICIAN, BUT RATHER IF THE PERSON HAD BASIC ELIGIBILITY, HAS THE DISEASE, HAS A DIAGNOSIS OF THE DISEASE, THAT PERSON WOULD BE REFERRED ON TO A SITE TO HAVE A REAL CONVERSATION WITH A CLINICIAN ABOUT IT. I WOULD THINK THAT IS THE WAY THIS WOULD WORK OUT. >> IS YOUR SENSE THAT IS NOT HAPPENING NOW? AGAIN, THAT IS WHAT I WOULD PRESUME IS ALREADY HAPPENING. >> WELL, I'VE SEEN IT HAPPEN AND I'VE SEEN IT NOT HAPPEN. NOT JUST ME, BUT I THINK OTHERS HAVE SEEN MANY DIFFERENT ITERATIONS OF SPONSOR INVOLVEMENT LIKE THIS. SOME ARE CABINED AND COMPARTMENTALIZED AND CLEAR LINES AND OTHERS IT HAS BEEN A MORE EXPANSIVE ROLE. . >> OTHER COMMENTS ON THIS PARTICULAR POINT? >> IF YOU HAVE PARTICULAR LANGUAGE YOU WOULD LIKE ADDED TO THIS, I'M HAPPY TO DO IT AS LONG AS EVERYBODY ELSE AGREES WITH IT. THAT IS NOT A PROBLEM. >> MARK, HEARING THIS DISCUSSION, I'M WONDERING IF THE WORD ADJUDICATING IS THE RIGHT TERM. I MEAN, IT SEEMS TO ME TO SOME DEGREE THE SPONSOR OR THIRD PARTY VENDOR ADJUDICATED IN THE SENSE THAT THEY PROBABLY HAVE DEVELOPED THE INCLUSION AND, COLLUSION CRITERION AND THEY SHOULD PROBABLY BE IN A POSITION TO SAY, NO, EVEN THOUGH THE CLINICIAN THINKS THIS PATIENT IS ELIGIBLE, THEY ARE REALLY NOT. BUT WHAT I -- WHAT I'M HEARING YOUR INTENT HERE TO BE IS THAT THE SPONSOR SHOULD NOT BE TELLING A CLINICIAN, FOR EXAMPLE, THAT HIS OR HER PATIENT SHOULD BE IN THE TRIAL WHEN THE CLINICIAN THINKS THEY SHOULD NOT BE. DO I HAVE THAT RIGHT? IS IT REALLY MORE THE LATTER? >> NO. I THINK, I MEAN, I THINK IT IS BOTH -- >> ARE YOU HEARING THE SAME BACKGROUND NOISE I AM. >> CAN EVERYONE MUTE OTHER THAN THE PEOPLE TALKING. EVERYONE SHOULD BE ON MUTE OTHER THAN THE SPEAKERS. THANK YOU. >> THERE WE GO. IT IS BETTER NOW. >> I THINK, DOUG, IT WORKS BOTH WAYS. I THINK THAT A SPONSOR -- BY THE WAY, THESE ARE -- THESE ISSUES IN MANY CASES ARE LESS OF A PROBLEM WITH BIG PHARMA OR MODERATE SIZE PHARMA WITH ROBUST COMPLIANCE INFRASTRUCTURES AND MORE THE CASE IN THE SMALL BIOTECH AND THE SMALL KIND OF STARTUP PHARMA COMPANIES THAT DON'T HAVE COMPLIANCE INFRASTRUCTURE AND TRYING TO WORK AS QUICKLY AS POSSIBLE. THAT IS WHEN MANY OF THESE ISSUES ARISE. I THINK WHAT WE ARE SAYING IS THAT THE -- IS THAT THERE CAN BE A MECHANISM FOR HANDING OUT INFORMATION TO PEOPLE, BUT SPONSORS ARE NOT THE ONES WHO ENROLL SUBJECTS. IT IS SITES AND INVESTIGATORS WHO ENROLL SUBJECTS. NO MATTER WHAT A SPONSOR'S HELP DESK SAYS, ULTIMATELY IT NEEDS TO BE CLEAR TO THE POTENTIAL INTERESTED PARTY AND FAMILY AS WELL AS TO THE CLINICIAN THAT IT IS THE CLINICIAN WHO IS MAKING THE ELIGIBILITY DETERMINATION. IF THE CLINICIAN MAKES AN INACCURATE ELIGIBILITY DETERMINATION, THAT SHOULD BE DETECTED IN THE MONITORING PROCESS AND THE PERSON LATER EX EXCLUDED FROM THE STUDY, THE DATA EXCLUDED. >> CAN YOU CLARIFY SOMETHING FOR ME? I'M NOT AS KNOWLEDGEABLE ABOUT TRIALS AS YOU ARE. ALL OF THE INVESTIGATORS HAVE TO SUBMIT EVERY POTENTIAL PARTICIPANT TO THE SPONSOR TO BE ADJUDICATED ANYWAY, CORRECT? >> IN SOME CASES THAT IS DONE. IN SOME CASES, ESPECIALLY IN PHASE 1 OR GENE THERAPY STUDIES, BUT THE SPONSOR FOLKS WHO ARE DOING THAT ELIGIBILITY ARE CLINICAL PEOPLE IN MEDICAL AFFAIRS OFFICE OR CLINICAL OPERATIONS. THEY ARE NOT A VENDOR PERFORMING A SCREENING SERVICE ON THE PHONE. THOSE ARE TWO DIFFERENT GROUPS OF PEOPLE WITHIN MOST COMPANIES. >> BUT IF THEY ARE TALKING DIRECTLY TO THE SPONSOR RATHER THAN A VENDOR. I REALIZE A LOT OF PHARMA COMPANIES HAVE TO SEPARATE THEIR ARMS BETWEEN MEDICAL AND ADVOCACY AND THAT IS PART OF THE ISSUE. BUT THE COMPANIES THAT I WORK WITH, USUALLY THE ADVOCACY PERSON SAYS I HAVE TO TALK TO MEDICAL AND GET BACK TO YOU. SO THAT IS STILL PART OF THE ADJUDICATION PROCESS THE SAME AS IF YOU WEPT THROUGH A PI. IS THERE ROOM FOR THAT TO HAPPEN? >> BUT, JANET, IT IS NOT. ON THE PHONE, ONE IS NOT DOING A PHYSICAL EXAMINATION. >> [INDISCERNIBLE] >> WHAT YOU ARE DESCRIBING AS A SECOND CHECK ON THE ELIGIBILITY OCCURS AFTER A FULL DISCUSSION BETWEEN THE PATIENT, SUBJECT AND THE CLINICIAN AND A REVIEW BY THE CLINICIAN AND THE CLINICIAN INVESTIGATOR HAS MADE A DETERMINATION HE OR SHE THINKS THE PERSON IS ELIGIBLE AND THEY FILL OUT THE ELIGIBILITY CRITERIA FORM AND THAT IS SENT TO THE SPONSOR. THAT IS A MORE COMPREHENSIVE PROCESS THAN A HELP DESK, SO -- >> YEAH. PROPS I'M CONFUSING THAT -- PERHAPS I'M CONFUSING WITH WHAT WE HAVE TO DO WITH INTERNATIONAL PATIENT POPULATIONS. SOMETIMES A PATIENT NEEDS TO FIND OUT WHETHER OR NOT THEY HAVE A CHANCE TO ENROLL BEFORE THEY MAKE THE TIME AND EFFORT TO TRAVEL TO A DISTANT SITE. THAT HAPPENS, AGAIN, IN RARE POPULATIONS. THEY WOULD WANT TO KNOW AND THEY USUALLY END UP CALLING THE PHARMA NUMBER. FROM THE CLINICALTRIALS.GOV. IS THAT STILL ALLOWED? >> YES. DEFINITELY ALLOWED. AND THE FOLKS ON -- YES, THAT IS ALLOWED. YES. AND UNDER THIS RECOMMENDATION, WHICH IS NOT PROSCRIPTIVE, IT IS BASICALLY SAYING, OF COURSE, SHARING INFORMATION IS ALLOWED. OF COURSE ANSWERING QUESTIONS IS ALLOWED, BUT ULTIMATELY, WHAT WOULD HAPPEN IN THAT SITUATION, OPTIMALLY, I WOULD THINK, THAT IS THE SPONSOR'S HELP DESK WOULD SAY TO THE PATIENT, GOSH, WHO IS YOUR TREATING PHYSICIAN IN TASH TASHKENT. YOU SHOULD HAVE THEM GET IN TOUCH WITH THIS PERSON, THE LEAD OF THE STDY AT EMRY OR BAYLOR. THEY COULD HAVE A CONVERSATION ABOUT YOUR POTENTIAL ELIGIBILITY. >> EVEN IN THE U.S. THAT DOESN'T HAPPEN. I HAVE BEEN AT A COMMUNITY HOSPITAL THAT DIDN'T KNOW ANYTHING ABOUT THE CLINICAL TRIAL. THEY DON'T HAVE CLINICAL TRIALS AT THEIR SITES, SO THEIR DOCTORS ARE JUST AS CLUELESS AS THE PATIENTS OF HOW TO GET ENROLLED IN A CLINICAL TRIAL WITH A CONDITION THEY DON'T KNOW ANYTHING ABOUT. THOSE CONVERSATIONS USUALLY DON'T HAPPEN. THE PATIENT IS TOLD TO LOOK IT UP FOR YOURSELF. >> THAT IS NOT A GOOD OUTCOME. I DON'T THINK THIS CONCLUSION PRECLUDES THE ASSISTANCE A SPONSOR COULD OFFER IN THAT SITUATION. >> OKAY. THANK YOU. >> SHOULD WE MOVE ON TO THE SECOND PRINCIPLE? >> THE SECOND IS TALKING ABOUT, AFTER A SITUATION IN WHICH -- ESPECIALLY IN A STUDY THAT REQUIRES FEW SITES AND SIGNIFICANT TRAVEL AND SIGNIFICANT PERIODS OF TIME SPENT BY THE INDIVIDUAL SUBJECT AND POTENTIALLY THEIR FAMILY MEMBERS AWAY FROM HOME, WE HAVE SPONSORS AND SPONSOR VENDORS THAT BEGIN TO TAKE ON RESPONSIBILITIES FOR ARRANGING TRAVEL AND ARRANGING FOR EVEN PAYMENTS TO SUBJECTS FOR SORT OF DAILY LIVING EXPENSES AND THEY ARRANGE FOR A HOTEL, A FREE HOTEL ROOM OR OTHER ACCOMMODATION FOR THE INDIVIDUAL AND THEIR FAMILY. THERE IS NOTHING WRONG WITH THAT, NECESSARILY, AS LONG AS IT IS MADE CLEAR IN THE APPLICATION FOR THE STUDY AS TO WHAT THE SPONSOR'S ROLE IS AND WHAT IT SHOULD BE DOING AND AGREED TO DO AND NOT DO. THERE NEEDS TO BE TRANSPARENCY TO THE SUBJECTS ABOUT WHAT THE SPONSOR IS DOING AND THE LIMITS OF WHAT THE SPONSOR IS GOING TO DO AND ABLE TO DO. I THINK THAT ONE OF THE PROBLEMS WE HAVE SEEN IN THESE SITUATIONS IS THAT THE SPONSOR REPRESENTATIVE, WHO MAY BE A THIRD PARTY VENDOR OR MAYBE SOMEBODY FROM THE SPONSOR ITSELF, THEY END UP ACTING AS EFFECTIVELY AS AN INTERFACE BETWEEN THE INVESTIGATOR AND THE RESEARCH SITE ON ONE HAND AND THE SUBJECT AND THE FAMILY ON THE OTHER. AND SO -- AND THE SUBJECTS BECOME OVERLY IDENTIFIED WITH THE WELFARE OF THE COMPANY. AJD THE -- AND SO IN SITUATIONS, FOR EXAMPLE, IN WHICH THE IMPROVEMENT OF SYMPTOMS IS A SELF- -- SELF-REPORTED IMPROVEMENT OF SYMPTOMS IS A, ACTUALLY A SECONDARY END POINT OR DATA COLLECTED DURING THE STUDY, THERE IS A RISK THERE. WHAT THIS BULLET POINT IS TRYING TO SAY IS THOSE KINDS OF INTERACTIONS SHOULD BE TRANSPARENT, SHOULD BE CONSENTED CONSENTED, AND THERE SHOULD BE CARE GIVEN BY THE SPONSOR IN TERMS OF BUILDING A THERAPEUTIC ALLIANCE WITH THE PATIENT, WITH THE PATIENT SUBJECT AND THE PATIENT SUBJECT'S FAMILY. SO THAT IS WHAT THAT IS ABOUT. >> MARK, I'M NOT ENTIRELY CLEAR WHAT YOU MEAN BY IRB APPROVED CATEGORIES OF INTERACTION. >> WELL, WHAT I MEAN BY THAT IS THAT WHEN THE STUDY DESIGN HAS BEEN CLEAR AND THE APPLICATION HAS BEEN CLEARED, THAT THE SPONSOR WILL DO X, Y, AND ZED, FOR THE INDIVIDUALS ENROLLED IN THE STUDY. THE SPONSOR SHOULD NOT WITHOUT IRB APPROVAL AND INVESTIGATOR APPROVAL AND UNDERSTANDING GO AHEAD AND ASSUME THE OBLIGATIONS OF A, B, AND C, AS WELL. >> MARK, THIS IS KEVIN. YOU KNOW, GIVEN THIS IS TRYING TO ADDRESS PLACES WHERE PEOPLE ARE A BIT FUZZY ON THE BOUNDARIES, I'M WONDERING WHETHER SPECIFYING WHAT IS MEANT BY THERAPEUTIC ALLIANCES WOULD HELP TO REMOVE SOME OF THAT FUZZINESS. I THINK I KNOW WHAT'S MEANT BY THAT, BUT I'M JUST WONDERING WHETHER IN OUR FORMAL RECOMMENDATIONS WHETHER THE USE OF THAT TERM MIGHT BE INTRODUCING SOME AMBIGUITY FOR READERS. >> THAT IS A GOOD SUGGESTION, KEVIN. I CAN WORK ON THE WORDING ON THAT AND THE IRB CATEGORIES OR INTERACTION TO BE CLEARER ABOUT WHAT IS MEANT THERE. >> I THINK THAT WOULD BE HELPFUL. >> OKAY. >> ANYBODY ELSE HAVE A COMMENT ON THIS SECOND PRINCIPLE? IF NOT, WE CAN MOVE TO THE THIRD. >> THE THIRD IS BASICALLY SAYING -- THERE IS A LONG TREATMENT OF THIS IN THE TEXT, BUT IT BASICALLY SAYS THAT THE SPONSOR AND SPONSOR VENDOR INTERACTIONS, THEY NEED TO BE PAINFUL AWARE OF THE PRIVACY OBLIGATIONS IN REGARDS TO THE PEOPLE CALLING IN. THEY NEED TO UNDERSTAND WHAT THEY ARE ALLOWED TO DO AND NOT ALLOWED TO DO, BY APPLICABLE LAW, NOT ONLY HIPAA, IN MANY CASES THE SPONSOR OR SPONSOR VENDORS ARE NOT BOUND BY HIPAA, BUT STATE PRIVACY LAWS, GENERAL MEDICAL PRIVACY LAWS THAT WOULD APPLY TO WHAT THEY ARE DOING AND LAWS THAT ARE SPECIFIC, FOR EXAMPLE, GENETIC INFORMATION, HIV INFORMATION, MENTAL HEALTH AND MENTAL HYGIENE INFORMATION. THE INTERACTIONS WITH THE ELIGIBLE SUBJECTS AS WELL AS PROVIDERS AND SITES ARE CONSISTENT WITH THE PRIVACY OBLIGATIONS. I THINK THIS IS IN HERE, AS I SAID, THERE IS A LONG TREATMENT OF THIS IN THE TEXT, I THINK THE REASON THIS IS IN HERE IS BECAUSE MANY OF US ON THE COMMITTEE HAVE HAD SITUATIONS IN WHICH THERE IS A COMPLETE LACK OF CLARITY ON THE PART OF THE SPONSOR AND SPONSOR VENDORS ABOUT WHAT IS GOING ON AND WHAT THEY ARE AWE ALLOWED TO DO AND NOT ALLOWED TO DO. >> THIS IS JANET. IT SEEMS LIKE IT MIGHT BE WORTH, ADDING A SENTENCE STATES THE SPONSOR'S OBLIGATION TO NOTIFY THE PATIENTS ABOUT HOW THE INFORMATION THEY ARE SHARING WILL BE USED DURING THEIR INTERACTION. WHILE THAT MIGHT BE CALLED OUT SPECIFICALLY IN PRIVACY REGULATIONS, THEY ARE BOUND BY, I THINK IT NEEDS TO BE EMPHASIZED. >> THAT IS FINE. I THINK THAT IS COMPLETELY CONSISTENT WITH THE TEXT THAT SUPPORTS THIS RECOMMENDATION. I'M HAPPY TO PUT THAT IN HERE AS AN ADDITIONAL SENTENCE. >> THANK YOU. >> JUST A POINT OF CLARITY, MARK, THE CLAUSE AFTER THE COMMA, I'M NOT SURE WHAT THAT BELONGS TO OR WHAT THAT IS REFERRING TO AS WELL AS PATIENT AND SUBJECTS' HEALTH CARE PROVIDERS. ARE WE TALKING ABOUT THE PRIVACY RIGHTS >> WE ARE ARE TALKING ABOUT THE PRIVACY OBLIGATIONS OF A SPONSOR AS WELL AS PATIENTS. THE APPLICABLE PRIVACY OBLIGATIONS OF A PATIENT'S HEALTH CARE PROVIDER. THAT IS WHAT IT IS MODIFYING. >> OKAY. >> MAYBE IT WOULD BENEFIT FROM ADDING IN AS WELL AS THE PRIVACY OBLIGATIONS OF -- >> YEAH. THAT'S FINE. >> YEAH. >> ANY OTHER COMMENTS -- GO AHEAD. >> WHAT WE WANT TO AVOID HERE IS A SPONSOR OR SPONSOR VENDOR CALLING SOMEONE'S HEALTH CARE PROVIDER AND REQUESTING RECORDS OVER THE PHONE, RIGHT? THAT IS NOT APPROPRIATE. IF THERE IS GOING TO BE THAT KIND OF CONTACT, THE PATIENT NEEDS TO BE -- THE CALLER NEEDS TO BE INFORMED OF IT AND THE CALLER INSIDES TO HAVE EXECUTED A HIPAA AUTHORIZATION TO DIRECT THEIR PROVIDER TO RELEASE RECORDS. THAT IS AN EXAMPLE OF WHAT IS REFERRED TO HERE. >> OKAY. THE EXAMPLE IS HELPFUL. WE MAY WANT TO THINK ABOUT PUTTING THAT RIGHT THERE WITH THE POINT. >> OKAY. THE NEXT BULLET POINT IS IN REGARD TO THE SITUATION IN WHICH THE MEDICAL CENTER OR THE UNIVERSITY IS THE -- IS ACTUALLY THE EMPLOYER OF THE INVESTIGATOR AND SERVES EFFECTIVELY AS THE KIND OF SPONSOR OF A STUDY. AND THE -- WHAT THIS IS RESPONDING TO IS A SITUATION LIKE ONE THAT WE REFERRED TO IN MY OPENING REMARKS ABOUT EXAMPLES, OF AN INVESTIGATOR GETTING A CALL FROM THE SPONSOR WHO IS ACTUALLY THE ACADEMIC MEDICAL CENTER, EMPLOYER OF THE INVESTIGATOR, SAYING, GOSH, GIVE ME THREE PATIENTS. THE FIRST THREE PATIENTS IN YOUR GENE THERAPY STUDY. WE WANT TO INTERVIEW THEM FOR OUR PUBLICITY THIS WEEK OR FOR OUR PLANNED PUBLICITY CAMPAIGN. AND WHAT THIS IS SAYING IS THAT WE NEED TO BE CAREFUL ABOUT THE -- ABOUT COMPROMISING THE INDEPENDENCE OF THE INVESTIGATOR IN THAT SITUATION AND THE NEED FOR THE INVESTIGATOR TO REALLY ACT AS THE PROTECTOR OF THE SUBJECTS AND THEIR FAMILIES. IN ADDITION TO, IN ANOTHER SITUATION, INVOLVING DIRECTING THE INVESTIGATOR TO BE INVOLVED AND NOT EVEN SO MUCH OF IDENTIFYING POTENTIAL PATIENTS AND ABOUT BEING FILMED FOR AN INTERVIEW, INVOLVING THE INVESTIGATOR IN AN ONGOING STUDY AND FAVORABLE PUBLICITY INFORMATION AND CRAFTING PUBLICITY MESSAGES FOR THE SPONSOR ACADEMIC MEDICAL CENTER ABOUT THE STUDY. WE HAVE SEEN OVERSTEPPING. SOME OF YOU WHO ARE INVESTIGATORS MAY HAVE BEEN SUBJECT TO THIS YOURSELF. THERE HAVE BEEN COUNTLESS TIMES I HAVE BEEN CALLED UPON BY LEADING ACADEMIC MEDICAL CENTERS TO LOOK AT THEIR PR. THEY INCLUDE INTERVIEWS WITH INVESTIGATORS AND ONGOING STUDIES THAT, IN MY MIND AT LEAST, CROSSED THE LINE BETWEEN EXPLAINING WHAT THE STUDY IS AND THE PROMISE OF A STUDY VERSUS TALKING ABOUT THE PRELIMINARY RESULT TS. -- RESULTS. >> ANY COMMENTS ON THIS ONE? WE HAVE ABOUT 10 MINUTES, SO IF THERE ARE NOT COMMENTS, LET'S KEEP MOVING. >> SORRY, DOUG, THIS IS LESLIE. AND MY ONLY QUESTION AND I DON'T HAVE A PARTICULAR RESPONSE RIGHT AT THE MOMENT, MARK, AND I APOLOGIZE FOR NOT HAVING SPENT AS MUCH TIME WITH THIS DOCUMENT AS I OUGHT TO HAVE. IT ALMOST SEEMS THAT WE ARE NOT ASKING ENOUGH OF THE INSTITUTIONS HERE, THAT IT IS SORT OF DON'T INTERFERE WITH THE OBLIGATIONS OF THE INVESTIGATOR ARE WITHOUT GOING BACK TO FIRST PRINCIPLES -- THE INSTITUTION HAS ITS OWN RESPONSIBILITIES WITH RESPECT TO RESPONSIBLE CONDUCT OF RESEARCH AND THE APPROPRIATE TREATMENT OF HUMAN SUBJECTS. SO IT IS NOT JUST ABOUT THE RELATIONSHIP BETWEEN THE INVESTIGATOR, BUT THAT THOSE SORT OF CLEAR LINES AS YOU WERE JUST TALKING ABOUT OF MAKING SURE THAT WE ARE NOT, YOU KNOW, UNDERMINING THE INTEGRITY OF THE RESEARCH, EXPLOITING THE PARTICIPANTS, OR FALSELY RAISING HOPE WHEN WE KNOW THE WHOLE POINT OF DOING THIS IS TO FIND OUT WHETHER OR NOT IT IS GOING TO WORK. I WOULD BE HAPPY TO THINK A LITTLE MORE IF WE ARE GOING TO BE COMING BACK TO THIS DOCUMENT, TO SEE IF I COULD SUGGEST SOMETHING. IT IS NOT WRONG TO ALSO THINK ABOUT THAT RELATIONSHIP AND HOW AN INVESTIGATOR MIGHT BE UNDULY PRESSURED WITH THE EMPLOYER, BUT TO CALL ON THE BETTER AND BIGGER OBLIGATIONS THERE. >> OKAY. IT IS A GOOD POINT, LESLIE. TO THE EXTENT THERE WAS, JUST SO YOU KNOW, TO THE EXTENT THERE WAS CRITICISM AND DISSATISFACTION WITH THESE PRINCIPLES IN THE SUBCOMMITTEE, IT WAS BECAUSE THEY DIDN'T GO FAR ENOUGH. IT WASN'T BECAUSE THEY WERE TOO PROSCRIPTIVE. SO I THINK THAT IS AN EXAMPLE. WE CAN ADD THAT. EVEN IF I DON'T HEAR FROM YOU, I WILL TRY TO ADD IT. >> OKAY. THANKS, MARK. >> YEAH. THANKS, LESLIE. THE NEXT, SO I WILL JUST HURRY THROUGH THESE, DOUG. THE NEXT ONE IS, IT SEEMS OBVIOUS. IT SAYS SPONSORS PLANNING CONTACT OR INTERACTIONS WITH ENROLLED SUBJECTS DURING A STUDY HAVE TO BE TRANSPARENT WITH THE PLANS WITH INVESTIGATORS AND IRBs AND HAVE TO TELL THEM WHAT IS GOING ON. AND THERE NEEDS TO BE CLEAR UNDERSTANDING AND FRANKLY APPROVAL OF THE IRB IF THAT IS GOING TO HAPPEN. THERE MAY BE NECESSARY EXCEPTIONS. FOR EXAMPLE, IF IT IS CLEAR IN THE PROTOCOL THAT THE SPONSOR OR HIS OR HER, ITS VENDOR IS GOING TO ASSIST IN TRAVEL ARRANGEMENTS, FOR EXAMPLE, THERE MAY BE THINGS CONTACT ASSOCIATED WITH ADVERSE EVENT FOLLOW-UP. THE SPONSOR HAS AN OBLIGATION TO PAY FOR THE MEDICAL EXPENSES INJURED AS A RESULT OF HIS OR HER PARTICIPATION IN THE STUDY. THE INVESTIGATORS AND THE SITE NEED TO INTERACT WITH THE SUBJECTS DURING THE STUDY. GO ON DOWN A LITTLE BIT, PLEASE, JULIA. THE NEXT BULLET POINT ALSO SEEMS -- THIS COMES UP TO A LITTLE BIT OF WHAT YOU WERE SAYING, LESLIE. SPONSORS, NOT ONLY INDUSTRY SPONSORS, BUT RESEARCH INSTITUTION SPONSORS SHOULD INTERACT WITH SUBJECTS LEAST INTRUCE I, RESPECTFUL OF THE RELUCTANCE TO GAING IN INTERACTIONS. APPROACHING SUBJECTS THROUGH THE INVESTIGATOR INITIALLY SPONSORS MIGHT BE MINDFUL OF THE POSSIBLY SUBJECT AND FAMILIES HAVE LITTLE MEANINGFUL ABILITY TO REQUEST. LIKE IN THE SITUATION THE FDA ADDRESSED A COUPLE OF YEARS AGO. I WILL GO THROUGH THE NEXT TWO, DOUG, AND IF WE HAVE COMMENTS. THE NEXT IS SPONSORS AND INVESTIGATORS ASKING SUBJECTS AND FAMILIES TO ENGAGE IN PUBLIC RELATIONS ACTIVITIES INCLUDING, FOR EXAMPLE, FILMING, THOSE REQUESTS SHOULD BE CONFINED TO THE PERIOD AFTER THE SUBJECT HAS COMPLETED THEIR CONTROL SITUATION. NOT WHILE THEY ARE A SUBJECT. OPTIMALLY, THAT ENTIRE THING SHOULD OCCUR AFTER A TRIAL HAS COMPLETELY ENDED, NOT JUST FOR THAT SUBJECT, BUT FOR ALL SUBJECTS. BEWE ARE NOT PROSCRIPTIVE HERE ON ANY POINT EXCEPT SUBJECTS CURRENTLY ENROLLED IN TRIAL AND NOT FINISHED WITH THEIR PARTICIPATION, SHOULD NOT BE APPROACHED OF THOSE KINDS OF ACTIVITIES. AND FINALLY, THE USE OF INTERVIEWS WITH SUBJECTS OR SUBJECT TESTIMONIALS FOR ONGOING TRIAL RECRUITMENT. THEY SHOULD NOT TOUT THE INVESTIGATIONAL THERAPIES AS TREATMENT AND NOT APPEAR TO OFFER CURATIVE INTERVENTIONS WHICH ACCURATELY PORTRAY CLINICAL STUDY AS THE USE OF UNPROVEN, BUT PROMISING EXPERIMENTS OR PROCEDURES. THIS SEEMS OBVIOUS. OFF LABEL OR PRELABEL, PREAPPROVAL PROMOTION, ET CETERA, BUT WE HAVE SEEN THE LINE CROSSED. AND THIS IS WHY IT IS HERE. REMEMBER THAT MOST OF THE GUIDANCE ABOUT THIS THAT IS FORMAL IS NOT ABOUT SUBJECTS AND SUBJECT PARTICIPATION IN THESE ACTIVITIES, IT IS ABOUT INDUSTRY DOING OR A SPONSOR DOING PARTICULAR THINGS. HERE WE ARE SIMPLY TRYING TO MAKE CLEAR WHAT THE OBVIOUS IMPLICATION OF WHAT THOSE PRINCIPLES WOULD BE. DOUG, I WILL STOP THERE BECAUSE THOSE ARE THE RECOMMENDATIONS. >> MARK, COULD I JUST CLARIFY? SO BY TESTIMONIALS DO YOU MEAN SOMETHING OTHER THAN WHAT APPEARS IN THE PREVIOUS BULLET, WHICH IS TO ENGAGE IN MEDIA AND PUBLIC RELATIONS ACTIVETIVE? THE NEXT TO THE LAST BULLET WOULD SEEM TO PRECLUDE DOING THESE TESTIMONIALS FOR RECRUITMENT AT ALL UNLESS THEY ARE SEPARATE ACTIVITACTIVITIES. DO YOU SEE WHAT I MEAN? THE NEXT TO THE LAST BULLET SUGGESTS WE SHOULDN'T BE CRUISING SUBJECTS AND FAMILIES FOR MEDIA UNTIL ALL ENROLLED SUBJECTS HAVE COMPLETED STUDY VISITS. >> THAT'S RIGHT. DOUG, I WILL TELL YOU HOW THIS ARISES, IT IS SLIGHTLY DIFFERENT, THE LAST BULLET FROM THE NEXT TO THE LAST. THE WAY IT IS DIFFERENT IS WHAT SOMETIMES HAPPENS IS THERE A PHASE TWO STUDY. THE PHASE TWO STUDY IS OVER AND THE SUBJECT IS APPROACHED TO DO A MEDIA INTERVIEW THAT BASICALLY IS ASKING SOFTBALL QUESTIONS ABOUT HOW WONDERFUL THE PHASE TWO RESULTS WERE FOR THAT PERSON. AND THAT IS GOING TO BE USED TO RECRUIT FOR THE PHASE THREE STUDY. >> OKAY. >> THAT IS REALLY WHAT WE'RE -- I THINK THAT IS A COMMON PROBLEM. >> GOT IT. >> MARK. THIS IS SKIP. QUICK QUESTION -- QUICK COMMENT ON THE SECOND TO LAST BULLET, WHICH I THINK IS AN EASY FIX. JUST TO POINT OUT THAT OFTEN TRIALS HAVE AN LONG-TERM EXTENSION. PEDIATRICS COULD BE ON LONG-TERM EXTENSION FOR MARKETING, WHICH COULD BE YEARS. >> RIGHT. >> GETS SPECIFICITY OF WHAT IT MEANS TO COMPLETE PARTICIPATION. REGISTRATIONAL TRIAL. OTHERWISE THERE WOULD BE NO CONTACT UNTIL THE MARKETING APPLICATION. >> I THINK THAT IS A GOOD POINT, SKIP. IT IS A GOOD THING FOR GENE THERAPY STUDIES BECAUSE THEY ARE FOLLOWED FOR 15 YEARS. WE CAN FIX THAT WITH A SENTENCE. >> YEAH. >> THIS IS JANET. YEAH, WE NEED TO HAVE SOMETHING ON THAT ALSO BECAUSE IN THE CASES OF THESE RARE DISEASES WHEN THEY'LL NEVER GET TO A PHASE THREE TRIAL, THE PHASE TWO TRIAL HAS TO CONTINUE BEYOND DRUG APPROVAL. AND YET -- SO IF SOMEONE IS HAVING A GOOD RESPONSE AND THEY HAVE BEEN ON THAT DRUG FOR YEARS AND THE DRUG HAS BEEN APPROVED, IS THERE REALLY AN ETHICAL ISSUE IF THEY SHARE THEIR EXPERIENCE? >> NO. I THINK NOT. I THINK, JANET, THAT KIND OF THING COULD BE INCORPORATED IN THE SENTENCE TO CLARIFY >> OKAY. THANK YOU. >> DOUG, DID WE WANT TO -- I KNOW THAT KEVIN -- I DON'T KNOW IF KEVIN HAD SOME SPECIFIC COMMENTS THAT ARE OTHER THAN WHAT HAS BEEN COVERED IN THE DISCUSSION. >> ONE OF THEM WAS ALREADY ANSWERED OR JUST SLOPPY READING ON MY PART, THE OTHER IS A MINOR EDITORIAL. COMMENT. IT WAS LINE 205, THAT SECTION YOU LAY OUT A VERY HELPFUL SET OF FOUR QUESTIONS. THAT MOTIVATED THAT SECTION. I WAS JUST GOING THROUGH SORT OF KEEPING SCORE. WHEN I GOT TO THE END OF THAT SECTION, I WASN'T SURE QUESTION TWO HAD BEEN ADDRESSED. THE MORE I READ QUESTION TWO, I WASN'T EXACTLY SURE WHAT IT WAS ASKING. THAT WAS AT LINE 205. SO NOT A BIG SUBSTANTIVE COMMENT. I LIKE THOSE QUESTIONS. THEY GUIDED THE TEXT REALLY WELL, BUT WHEN I WENT BACK TO QUESTION TWO, I WAS HAVING TROUBLE SEEING HOW THAT ONE HAD BEEN ANSWERED. AND THE MORE I READ IT, I WAS A LITTLE UNSURE ABOUT EXACTLY WHAT IT WAS ASKING. THAT IS ALL. >> OKAY. THAT IS FINE, KEVIN. I KNOW WE DON'T HAVE TO BELABOR THIS NOW, I WILL TRY TO LOOK THROUGH THIS AND REFINE THE QUESTION. IF IT IS A QUESTION, MAKE SURE IT IS ANSWERED, OKAY. >> GREAT. THANK YOU. OTHERWISE, EVERYTHING IS SO INCREDIBLY CLEAR AND EASY TO FOLLOW. I APPRECIATE THE GROUP WORK. >> THANKS. I THINK THE SUBCOMMITTEE, I MEAN, WE WORKED ON THIS A LONG TIME. AND I THINK THAT MANY OF THE SUBCOMMITTEE MEMBERS FELT LIKE THIS WOULD BE AN INCREDIBLY HELPFUL DOCUMENT IN THE REAL LIFE OF AN IRB AND INVESTIGATORS. AND SPONSORS, TOO, BECAUSE IT LEADS TO PREDICTABILITY AS THESE THINGS. >> DOUG, WHAT I AM GOING TO TRY TO DO, I WILL TRY THIS EVENING TO INCORPORATE THESE COMMENTS AND HOPEFULLY WE CAN COME BACK TOMORROW AND REVIEW THE CHANGES. >> OKAY. THAT IS WHAT WE DO IF THERE ARE NOT MASSIVE CHANGES TO A DOCUMENT, REFINE IT OVER THE COURSE OF A TWO-DAY MEETING AND PRESENT IT AGAIN >> THAT SOUNDS LIKE A REASONABLE PLAN. I'M NOT HEARING ANY MAJOR CONCERNS >> NO. I THINK THAT WOULD BE FINE. LET ME PROVIDE NUANCE TO SECOND TO LAST BULLET. I'M NOT SURE YOU NEED TO ADD A SENTENCE IN THAT BULLET, BUT A MORE NUANCED DISCUSSION WHERE YOU TALK ABOUT ACTIVE PARTICIPANTS NOT BEING RECRUITED. IT IS THE SECTION ON LINE, LET ME JUST FIND IT. BASICALLY, I HIGHLIGHTED IT. WHERE IT IS. LINE 314. ADDING DISCUSSION THERE. I'M NOT SURE YOU HAVE TO NECESSARILY BURDEN THE RECOMMENDATION WITH THAT DISCUSSION. >> THAT IS A GOOD POINT. I WILL DO THAT, SKIP. >> YEAH >> OKAY. THANKS TO BOTH YOU AND YOUR SUBCOMMITTEE, MARK, FOR THIS IMPORTANT DOCUMENT. WE WILL TRY TO GET BACK TO IT TOMORROW AFTERNOON. AFTER A FEW CHANGES HAVE BEEN MADE. >> THANKS FOR THE DISCUSSION. >> OKAY. NEXT WE ARE GOING TO TURN OUR ATTENTION TO THE TOPIC THAT WILL TAKE UP THE REST OF OUR DAY, WHICH IS MANDATORY EXPLORATORY BIOPSIES. WE'LL TAKE A BREAK IN ABOUT AN HOUR. THE NEXT PHASE OF OUR MEETING WILL BE A SERIES OF PANEL DISCUSSIONS AND WE'LL SORT OF BREAK IN THE MIDDLE OF THOSE. BUT I'M GOING TO TURN IT OVER NOW TO MICHELE RUSSELL-EINHORN KORKS CHAIR OF SUB PART A SUBCOMMITTEE WHO CAN INTRODUCE US TO THIS TOPIC AND INTRODUCE OUR PANELISTS. OVER TO YOU, MICHELE. >> THANK YOU, DOUG. CAN YOU HEAR ME OKAY? >> YES. >> SO WELCOME, EVERYBODY. EXCITED TO GET US STARTED ON THIS CONVERSATION. ADDS DOUG SAID. IF YOU LOOK AT THE AGENDA WE ARE GOING TO BE SPENDING A LOT OF TIME TALKING ABOUT MANDATORY EXPLORATORY BIOPSIES. I DID PREPARE A VERY DRAFT SUMMARY OF THE -- I HAVE TO APOLOGIZE, I GUESS THERE IS A BIT OF AN ECHO GOING ON. THE DRAFT DOCUMENT REALLY WAS TO GIVE THE MEMBERS SOME SENSE OF THE ISSUES JUST TALKING ABOUT THE SUMMARY OF THE IRB ARE VIEW CRITERIA. A REVIEW OF THE ISSUES ADDRESSED IN ANASCO OF ARTICLE GENERALLY SOME COMMENTS ABOUT MANDATORY BIOPSIES THAT IT IS NOT UNCOMMON YOU SEE THEM IN PHASE ONE RESEARCH. THERE ACTUALLY IS AN OLD OHRP LETTER I UNEARTHED. IT WENT BACK FROM 2012 AND TALKED ABOUT A RESEARCH PROTOCOL AT THE UNIVERSITY OF MICHIGAN THAT INCLUDED A REQUIREMENT FOR PARTICIPATION IN FUTURE RESEARCH. THE REASON I INCLUDED IT WAS TO THE EXTENT THAT IT ADDRESSES THE ISSUE OF INCLUDING PARTICIPATION IN OTHER ACTIVITIES AS INTEGRAL TO PARTICIPATING IN THE RESEARCH. AND THEN AT THE END, JUST, YOU KNOW, RAISE THE ISSUE THAT SACHRP HAS BEEN ASKED TO CONSIDER, GUIDANCE DOCUMENT ON THE ISSUE OF MANDATORY BIOPSIES WOULD BE AN APPROPRIATE AND USEFUL TOOL. I GUESS I'M NOT CLEAR ON WHAT WE COULD DO ON THIS TOPIC. IT IS EXCITING WE HAVE SO MANY PANELISTS IN THE NEXT COUPLE OF DAYS, TODAY AND TOMORROW, TO HELP INFORM THIS ISSUE. SO LET ME START BY SAYING THAT WE HAVE, ONE, TWO, THREE, FOUR, FIVE, SIX INDIVIDUALS WHO WILL BE PROVIDING US WITH SOME BACKGROUND INFORMATION ON THE ETHICS OF MANDATORY RESEARCH BIOPSIES IN CLINICAL TRIALS. I ASKED THEM TO ADDRESS FOUR QUESTIONS. AND, YOU KNOW, I'M VERY HUMBLE HERE AND YOU ALL MIGHT THINK PERHAPS I MISSED A QUESTION THAT SHOULD HAVE BEEN ADDRESSED. SO KEEP THAT IN THE BACK OF YOUR MIND. HOPEFULLY WE WILL HAVE TIME FOR SOME QUESTIONS TO THEM. THE OVERARCHING QUESTION I ASKED AND YOU'LL SEE IN THESE PRESENTATIONS IS THERE A NEED FOR GUIDANCE TO ASSIST IRPs IN THEIR RESEARCH THAT INCLUDES MANDATORY BIOPSIES? IS THERE A PERCEIVED GAP IN THE MANDATORY REGULATORY? IS THERE GUY DAN AND TO HELP IRBs APPLYING THE CRITERIA. IS THERE SPECIFIC EXPERTISE IRBs SHOULD ACCESS? IF THERE IS AN ISSUE, IF THE ISSUE, IN PART, REVOLVES AROUND WHETHER A MANDATORY BIOPSY IS INTEGRAL TO THE RESEARCH, IS THERE GUIDANCE TO HELP IRBs DETERMINE WHAT IS OR IS NOT INTEGRAL TO THE MAIN RESEARCH. WHAT WE ARE TRYING TO DO AT THIS MEETING IS FLESH OUT WHAT THE ISHSZ ARE. SO WITH ALL OF THAT BACKGROUND SAID, I'D LIKE TO MOVE US TO OUR PANEL PRESENTATIONS. WE HAVE TWO INDIVIDUALS FROM THE NATIONAL INSTITUTES OF HEALTH, JAMES DOROSHOW AND PERCY IVY. I THINK -- SO I'M A LITTLE CON -- CONFUSED. WE ARE DOING TWO SEPARATE PRESENTATIONS AND DR. DOROSHOW IS STARTING, RIGHT, JULIA? >> NO. >> GO AHEAD, JULIA. >> I BELIEVE IT IS ONE PRESENTATION JOINTLY PRESENTED BY PERCY AND DR. DOROSHOW. >> GOT IT. IS DR. DOROSHOW GOING FIRST? >> NO. THE PRESENTATION IS GOING TO BE MADE BY DR. IVY. >> ALL RIGHT. THANK YOU FOR THE CLARIFICATION. I'LL INTRODUCE BOTH OF THEM. DR. IVY WILL BE LEADING THE CONVERSATION. DR. IVY IS THE ASSOCIATE CHIEF OF THE INVESTIGATIONAL DRUG BRANCH PART OF CANCER THERAPY AT NCI. SHE HAS BEEN THERE SINCE 1997. I FOOL LIKE IT WAS OPRR IN THE LATE 90s. THE NAME HAS BEEN IN MY ARENA, MY LANDSCAPE. SO LET ME ALSO INTRODUCE DR. JAMES DOROSHOW, THE DEPUTY DIRECTOR OF [INDISCERNIBLE] CANCER INSTITUTE SINCE -- YOU SHOULD HAVE THEIR BIOGRAPHIES, WHICH HAVE A LOT OF SUPER INFORMATION ABOUT THEIR BACKGROUNDS. DR. IVY, I WILL LET YOU TAKE IT AWAY. >> ALL RIGHT. LET ME GET MY SLIDES UP. >> ON BEHALF OF THE WHOLE KWHEET, WE THANK YOU FOR TAKING TIME OUT TO PREPARE THE SLIDES YOU PREPARED TO GO OVER WITH US TODAY AND DO THIS PRESENTATION. >> ALL RIGHT. SO I WANTED TO THANKS ALL OF YOU FOR THE OPPORTUNITY TO PRESENT TO YOU. I'LL BE PRESENTING A GENERAL PERSPECTIVE ON HOW THE NCI APPROACHES BIOPSIES AND BIOMARKERS IN THE CONTEXT OF CLINICAL TRIALS. AND LET ME SEE, HOW TO ADVANCE THE SLIDES HERE. THEY ARE NOT ADVANCING. ALL RIGHT. SO I THINK THE FIRST QUESTION WE WANTED TO ADDRESS IS WHY A BIOMARKER STUDY INCLUDEDED IN EARLY PHASE CRITICAL TRIALS AND WHEN ARE BIOPSIES USEFUL OR REQUIRED? NEXT SLIDE. SORRY. I CAN ADVANCE THEM. SO WHEN WE, AT THE NCI, THINK OF BIOMARKER STUDIES WHY DO WE WANT TO DO THEM? I THINK FOR US THE MOST IMPORTANT REASON IS THEY WE ARE CHARGED WITH DOING CLING CAL TRANSLATION OF RESEARCH AND CANCER BIOLOGY. A LOT OF OUR WORK MOVES FROM THE BENCH TO THE BEDSIDE AND BACK AGAIN. WE ARE LOOKING TO TEST PATIENTS ELIGIBLE FOR EARLY STAGE CLINICAL TRIALS. WI CAN DO THAT THROUGH A VARIETY OF OBSERVATIONS. WE WOULD LIKE TO ANALYZE THEIR TUMOR OR OTHER TISSUES FOR PATHWAY ACTIVATIONS OR PRESENCE OF BIOMARKERS. WE CAN DO THAT USING DIFFERENT ACTIONS. BASED ON THAT, A PATIENT WOULD BE ASSIGNED TO A TRIAL. THAT WOULD BE BASED ON GENOTIPPIC INFORMATION. WE ATTEMPT PATIENT MONITORING. BY THAT I MEAN DURING THE COURSE OF A CLINICAL TRIAL WE MAY WANT TO FURTHER ASES HOW WELL THE TARGET WAS ENGAGED, WAS IT COMPLETELY SUPPRESSED? USING FARM LOGICAL DYNAMIC MARKERS ARE WE SEEING WHAT WE EXPECT TO SEE? IN OTHER WORDS, DO WE HAVE A PROOF OF CONCEPT THIS IS ENGAGING A SPECIFIC TARGET. AND TO MONITOR PATIENTS POST TREATMENT IN PARTICULAR TO EVALUATE THEM FOR THE EMERGENCE OF [INDISCERNIBLE] OR IN SOME INSTANCES WHEN IT IS APPROPRIATE TO MONITOR THEM OR BIOPSY THEM TO ASSESS WHETHER OR NOT THEY ARE, I WILL CALL THEM SUPER OR SECTIONAL RESPONDERS. USING THAT KREE TIER YEAH, WE TRIED TO MOVE FORWARD TO OUR CLINICAL TRIALS. WHAT DO THESE BIOMARKERS DO? INNERLY, THEY ARE PHARMACO-DYNAMIC OR DESCRIPTIVE. WE ARE LOOKING FOR TREATMENT MODULATION OF A TARGET, DISCOVERING THINGS THAT ARE HAPPENING, BUT MAINLY QUALITATIVE AND QUANTITATIVE CHANGES. IN LATER PHASE STUDY, WE ARE TAKING THE BIOMARKERS, IDENTIFYING EARLIER CHANGES AND TRYING TO DETERMINE IF THEY ARE PROGNOSTIC OR PREDICTIVE BIOMARKERS. I WILL TALK NEXT ABOUT BIOMARKER STUDIES IN EARLY PHASE TRIALS. WE HAVE TWO DESCRIPTIONS. THE FIRST IS INTEGRAL BIOMARKER STUDIES. IT IS DEFINED USING ASSAYS OR TESTS WITH A BIOPSY THAT MUST BE PERFORMED FOR THE TRIAL TO PROCEED. INTEGRAL STUDRIES ARE INHERENT TO THE DESIGN OF THE TRIAL. THEY MUST BE PERFORMED ON ALL PARTICIPANTS TO ACHIEVE THE PRIMARY OBJECTIVE OF THE TRIAL. SOME EXAMPLES OF THIS ARE THINGS LIKE DETERMINING ELIGIBILITY OR TEST TO ASSIGN PATIENTS TO A SPECIFIC TREATMENT ARM OR STRATIFICATION OR RANDOMIZATION. ON TESTS WHOSE RESULTS SERVE AS THE PRIMARY END POINT OF THE TRIAL. THESE BIOMARKERS MAY REQUIRE A CLI A-CERTIFIED LABORATORY TO BE RUN. WHAT IS IMPORTANT FOR WHICH EACH BIOPSY MUST BE NEEDED, THE ASSAY MUST BE ASSESSED FOR ACCURACY, REPRODUCTABILITY AND FITNESS FOR PURPOSE. OUR GOAL REMAINS TO MAXIMIZE OR OPTIMIZE EACH PATIENT'S CONTRIBUTION TO THE SCIENCE AND DRUG DEVELOPMENT IN A SAFE AND EFFECTIVE FASHION. WE HAD ANOTHER GROUP OF BIOMARKER STUDIES THAT ARE BEGRATED BIOMARKER STUDIES. THEY ARE PART OF THE TRIAL. THEY HAVE HIGH PRIORITY IN TERMS OF ANSWERING CONSTRUCT OR QUESTIONS IN THE CONTEXT OF A TRIAL. THEY HAVE BEEN PERFORMED ON ALL PARTICIPANTS OR ON A PRE-DEFINED SUBSET OF PATIENTS. YOU NEED SUFFICIENT PRELIMINARY DATA TO MAKE SURE SCIENTIFIC VALIDITY RESULTS FROM THE TRIAL. WE ARE TRYING TO DEFINE CAREFULLY BASED ON THE STUDY, HOW CRITICAL IS THE BIOMARKER? WHEN WE LOOK AT THIS, IT IS IMPORTANT TO SAY MANDATORY BIOPSIES, A SINGLE BIOPSY FOR NO OTHER PURPOSE FOR AN EXPLORATORY BIOMARKER IS NOT ACCEPTFUL. MANDATORY BIOPSY FOR FUCHB SPECIFIED RESEARCH IS NOT ACCEPTABLE. BIOPSIES FOR INTEGRAL ASSAYS ARE MANDATORY AND ARE ACCEPTABLE. WE WENT OVER THE REASONS. THEY ESTABLISH ELIGIBILITY. TO DETERMINE THE PRIMARY END POINT, THE PATIENT MUST CONSENT TO THE BIOPSY TO PEARNS. IF THE PATIENT IS UNWILLING TO BE BIOPSIED, THEY MAY NOT PARTICIPATE IN A TRIAL. IF AT ANY TIME DURING THE STUDY THE PATIENT MAY WITHDRAW FROM THE STUDY FOR FURTHER BIOPSIES, THEY MAY DO TO. MANDATORY BIOPSIES FOR INTEGRATED BIOMARKER ARE ACCEPTABLE WITH CAVEATS, SO THEY REQUIRE SOME DISCUSSION. SO THE BIOMARKER DEFINITIONS WE USE BROADLY, I SPOKE ABOUT INTEGRAL AND INTEGRATED. I'M GOING TO MOVE ON TO EXPLORATORY BIOMARKER. THESE ARE IN GENERAL RESTRICTIVE. THEY MAY NOT BE VALIDATED OR FIT FOR THE PURPOSE OF THE STUDY. SO THEY MAY BE EVALUATING SOMETHING THAT IS CONCEPTUAL OR MAYBE OF INTEREST, BUT THEY ARE NOT PART OF THE STUDY. AN EXAMPLE MIGHT BE A STUDY OF CROSSTALK -- BIOMARKER AND THE NEED FOR BIOPSIES, WE THINK OF THEM AS A METHOD OF VALIDATION. THE FIRST STEP IN ANY OF OUR THOUGHTS IS HOW DO WE RELEGATE. EARLY IN SIMPLE TRIALS WE ARE DOING EXEMPLOYER VALIDATION AND THEN WE ARE DOING ADVANCED METHOD VALIDATION. YOU DO THIS THROUGHOUT THE COURSE OF ALL PHASES OF STUDY. SO YOU ALL OBVIOUSLY KNOW THAT. THE OTHER THING THAT IS DONE AND IT IS ALSO DONE FOR EARLY, PRECLINICAL MAY BE PHASE 0, IS DIAGNOSTIC BIOMARKER DEVELOPMENT. THAT IS USUALLY WITH A BINARY END POINT, THERE IS VALIDATION, TESTED FOR INTENDED USE, CLINICAL UTILITY AND FINAL VALIDATION AS A SELECTED BIOMARKER. SO BIOPSY BENEFIT AND THE TYPE OF BIOPSY. I ADAPTED FROM THE RISK SLIDES SO I COULD PRESENT IT IN A FASHION THAT WOULD BE FAMILIAR TO THOSE ON THIS PANEL. SO WHEN WE SPEAK OF MANDATORY BIOPSIES AND LOOK AT RISK VERSUS BENEFIT BASED ON THE BIOMARKER TYPE AND PURPOSE, WE GENERALLY THINK OF EXPLORATORY BIOMARKERS AND NOT BEING ACCEPTABLE AT ANY LEVEL OF RISK. THE ONLY TIME ANY OF THEM ARE ACCEPTABLE IF THEY ARE USING RESIDUAL TISSUE FROM A BIOPSY THAT HAS A HIGH -- HIGH RISK MANDATORY BIOPSIES MAY BE ACCEPTABLE, WE HANDLE THAT ON A PROTOCOL BY PROTOCOL BASIS AND WE WANT TO REVIEW THE SAFETY ISSUES IN CONSULTATION WITH THE ZUDY WHICH INCLUDES THE STUDY AND THE INTERVENTIONAL RADIOLOGIST. OPTIONAL BIOPSIES ARE IN A DIFFERENT CATEGORY. SO WE ONCE AGAIN ARE LOOXING AT PLORATORY EXPLORATORY, INTEGRATED OR INTEGRAL AND TROISK THE PATIENT. EXPLORATORY ARE NOT ACCEPTABLE. LOW RISK NAY MAY BE ACCEPTABLE ON A PROTOCOL TO PROTOCOL BASIS. FOR INTEGRATED BIOPSIES THAT ARE OPTIONAL, IF THEY ARE HIGH RISK THEY ARE NOT ACCEPTFUL. IF THEY ARE MODERATE, THEY ARE ACCEPTABLE ON A PROTOCOL BY PROTOCOL BASIS. THAT REQUIRES A SPECIAL. LOW RISK BIOPSIES MAYBE ARE ACCEPTABLE. CLINICAL BIOMARKERS ARE THOSE THAT ARE MODERATE RISK. HIGH RISK ARE ACCEPTABLE BUT MAY REQUIRE REVIEW ON PROTOCOL BY PROTOCOL ISSUES AND REVIEW OF SAFETY ISSUES IN CONSULTATION WITH THE STUDY. SORRY ABOUT THE RINGING PHONE IN THE BACKGROUND. I KEEP TRYING TO HANG UP. WHEN WE THINK ABOUT BIOMARKER, WE DEVELOP A BIOMARKER PLAN FOR EACH PROTOCOL. I WANT TO TALK REALLY QUICKLY ABOUT WELL DEVELOPED FIT FOR PURPOSE BIOMARKER PLANS. I WANT TO SHOW YOU A QUICK EXAMPLE OF PART OF WHAT WE DO. IN EVERY PHONE CALL WE HAVE A BIOMARKER PLAN TABLE THAT THE INVESTIGATORS KNOW ABOUT. I HOPE YOU CAN SEE IT IN THE SLIDE. THEY HAVE TO PRIORITIZE EACH [INDISCERNIBLE] BECAUSE YOU RUN OUT OF SPECIMEN BEFORE YOU RUN OUT OF BIOMARKERS AN INVESTIGATOR WANTS TO DO. YOU MUST PRIORITIZE THEM. THEY MUST ALSO STATE IN THEIR OPINION WHETHER OR NOT THEY ARE MANDATORY OR OPTIONAL AND THEN WE, AS A PROGRAM, BASED ON THE BIOMARKER REVIEW AND WHETHER OR NOT IT IS MANDATORY AND WHAT KIND OF BIOMARKER IT IS AND HOW MUCH IS KNOWN ABOUT IT, WE WILL REVIEW IT BY BIOMARKER REVIEW COMMITTEE. WE ARE LOOKING AT THE INITIAL STATUS OF THE TERM IN THE ORIGINAL AND RECORDED WHEN WE REVIEWED THE WHOLE PROPERTY CAL AND UPDATE THIS PERIODICALLY. THE OTHER THING THAT IS INCLUDED IN ALL OF OUR PROTOCOLS IS A SUMMARY TABLE FOR INTERVENTIONAL RADIOLOGY. TO COVER EXACTLY WHAT THEY ARE COLLECTING D BIOPSY SPECIMEN FOR AND HOW MANY SPES MINES ARE NEEDED AND WHAT IS THE RIGHT PRIORITIZATION. INTERACTION, CONSULTATION AND EXPRESSION PRIOR TO THE PROCEDURE AND WHICH INFORMS THE RADIOLOGIST OF THE PURPOSE OF EACH BIOPSY. PREBIOPSY ASSESSMENTS ARE RECORDED AND TRACKED THROUGH TRIAL SPECIFIC CASE REPORT FORMS. THE BIOMARKER REVIEW COMMITTEE AS THE CANCER THERAPY EVALUATION PROGRAM WAS ESTABLISHED BY THE NCI VEK DIRECTOR TO ENSURE THAT INVESTIGATIONAL INTEGRAL BIOMARKERS AND INTEGRATED RESEARCH BIOMARKERS ARE FIT FOR PURPOSE. THAT WILL DETERMINE HO HOW WE LOOK AT APPROACHING OBTAINING THE BIOPSY. THE SBE GRATH GRAL BIOMARKER MUST BE MEASURED IN ON ALL TRIAL PARTICIPANTS TO CONDUCT THE TRIAL AND DETERMINE THE PRIMARY OUTCOME. INTEGRATED BIOMARKERS MAY JUSTIFY RESEARCH BIOPSIES OR INTERINVASIVE PROCEDURES TO OBTAIN SAMPLES. HOW DOES THE BRC LOOK AT NEW CLINICAL TRIAL PROPOSALS? THE TRIAL DESIGN MUST DEFINE THE PURPOSE FOR EACH BIOMARKER. IS IT TO SELECT PARTIALS TO CORRELATE MESH YURMS AT BASELINE AND OUTCOMES FOLLOWING TREATMENT OR MEASURE PHARACODYNAMIC EFFECT. WHETHER IT HAS BEEN SHOWN TO HAVE PERFORMANCE CHARACTERISTICS THAT FIT THE PURPOSE. THEY HAVE TO HAVE PREDIGGS AND DYNAMIC RANGE IDENTIFIED. SO AS WE HAVE THOUGHT ABOUT THIS, OVERALL, THE RECOMMENDATIONS, WE WOULD LIKE TO SHARE WITH THIS GROUP. I REVIEWED THIS TABLE ONCE SO I AM NOT GOING TO REVIEW IT LINE BY LINE EXCEPT TO SAY THERE ARE SITUATIONS MANDATORY BIOPSIES ARE ACCEPTABLE AND THAT IS DIFFERENT FROM THE SITUATION IN THEY ARE NOT. SO EXPLORATORY BIOPSIES IN GENERAL FOR A SINGLE REASON ARE NOT ACCEPTABLE. THEY CAN IF THEIR TISSUE IS OBTAINED USED. [INDISCERNIBLE] BIOMARKERS ARE ACCEPTABLE IF THERE IS HIGH RISK, OUR RISK BENEFIT/ANALYSIS IS PERFORMED IN DISCUSSION WITH THE STUDY PI AND THE INTERVENTIONAL RADIOLOGIST TO DETERMINE THIS BENEFITS VALUE OF OBTAINING THE BIOPSY. IF IT IS UNACCEPTABLY HIGH, THEY DON'T PROCEED WITH THE BIOPSY. SO IT IS AN ONGOING DISCUSSION WITH THE STUDY TEAM. >> DR. IVY, I'M SO SORRY TO STOP YOU. CAN YOU PUT YOUR SLIDES IN PRESENTATION MODE SO THEY WILL BE MORE FULL SCREEN. >> OH, SURE. LET ME SEE HERE. >> FROM MY VIEW, I'M -- >> SWAP DISPLAY. >> IS THAT BETTER? >>> CAN YOU SEE IT NOW? >> YES. OKAY. SO OPTIONAL BIOPSIES, I THINK THE IMPORTANT THING IS THAT WITH EXPLORATORY BIOMARKERS, ONLY MINIMAL OF ALL RISK IS ACCEPTABLE AND EVEN THAT REQUIRES DISCUSSION. IN OTHER INSTANCES, OPTIONAL BIOPSIES MAY BE ACCEPTABLE IF THE END POINT IS LOW RIFBLG FOR AN INTEGRAL OR INTEGRATED OR OF MODERATE RISK FOR INTEGRAL OR INTEGRATED BIOPSY, ONCE AGAIN, NOT ACCEPTABLE FOR EXPLORATORY BIOMARKERS. SO OUR OVERALL RECOMMENDATIONS IS TO LIST THE TYPE OF BIOMARKER WE ARE EVALUATING. THAT LISTS THE BIOMARKERS IN OUR CLINICAL TRIALS AND DETERMINE WHETHER OR NOT THE BIOPSY IS MANDATORY OR OPTIONAL, DEPENDING ON THE GOALS OF THE TRIAL AND THEN TO SIMPLY REFER TO THIS KIND OF TABLE TO DETERMINE WHETHER OR NOT THE RISKS OF THE BIOPSY WILL OUTWEIGH THE BENEFITS AND FOR MANDATORY BIOPSIES IF THEY ARE EXPLORATORY, THEY ARE NOT ACCEPTABLE. OPTIONAL BIOPSIES ARE NOT ACCEPTABLE FOR INTEGRAL BIOMARKERS. THEY MUST BE DONE. ALL OF THE REST ARE ACCEPTABLE, BUT ON A PROTOCOL BY PROTOCOL BASIS AND IN CONSULTATION WITH THE STUDY TEAM WHICH IS THE RADIOLOGIST. I THINK THAT IS MY LAST SLIDE. I CAN STOP HERE AND TAKE QUESTIONS OR I CAN MOVE ON. I HAD ATTACHED TO THIS PRESENTATION A NUMBER OF EXAMPLES WHERE THE USE OF BIOPSIES IN CLINICAL TRIALS WAS CRITICAL FOR ANALYZING THE RESULTS OF THE STUDY OR DETERMINING THE RECOMMENDED DOSE DOERMING THE TARGETS EFFECT. SO PLEASE LET ME KNOW IF YOU WOULD LIKE ME TO PROCEED WITH THE EXAMPLES OR WE CAN STOP HERE FOR QUESTIONS. >> THIS IS MICHELE. I THINK YOU SHOULD GO AHEAD AND PRESENT THESE. >> I WILL ASK DR. DOROSHOW IF -- WE WERE LOOKING AT AKT AND MKS EK INHIBITION TO EVALUATE FEEDBACK COMPENSATION FOR SINGLE AGENTS, CLEARLY ENHANCE EFFICACY FOR COMBINATION INHIGGS AND LACK OF EFFICACY IN STANDARD PHASE ONE ASSOCIATED WITH RASH, RHETTAL ABNORMALITIES AND LFT INCREASES. THIS WAS THE PROTOCOL. THIS WAS THE DRUG ADMINISTRATION. PATIENTS WITH ADVANCED COLO-RECTAL CANCER. THEY HAD A DNA BASED ANALYSIS. THEY HAVE EVALUATING THE PATHWAYS. [INDISCERNIBLE] USING HIGHLY SENSITIVE ELIZA ASSAYS. AND EXAMINE THE DEGREE OF TARGET INHIGGS. -- INHIBITION. THE GOAL OF THE STUDY IS DEGREE, PER TU BAGS OF FEEDBACK AND CORRELATION WITH CLINICAL OUTCOME. SO WITH RESPECT TO PHOSPHORYLATION IS SHOWN ON THIS TABLE. THESE HIGHLY ACCURATE TECHNICALLY BIOMARKERS ARE ACCURATE, SENSITIVE BIOMARKERS NEEDED TO DETERMINE IF DOSING IS COMPROMISE COMPROMISED. I WILL GO ON UNLESS YOU HAVE QUESTIONS. JIM, WOULD YOU LIKE TO ADD TO THAT DESCRIPTION? >> NO. THAT IS GREAT, PERCY, KEEP GOING. >> SO NEXT WE LOOKED AT THE DIFFERENTIAL EFFECTS USING ABT-888, A PAR INHIBITOR, AND ANOTHER DRUB CONSIDERED TO BE A PAR INHIBITOR AND HAD A VERY POSITIVE RANDOMIZED SPACE, TOO, BUT ABSOLUTELY NEGATIVE PHASE THREE STUDY. BASED ON THE COMPARISONS AND JUST THE EVALUATIONS, THEY LOOKED AT BSI-201 AND ITS TWO METABOLITES AND THEY DO NOT INHIBIT PARP. THAT IS WHY THIS FAILED IN A LARGE PHASE 3 TRIAL. THIS WAS NOT KNOWN. BETTER EVALUATION OF THE BIOMARKERS IN EARLY CLINICAL TRIALS USING THESE KINDS OF ASSAYS, HAVE STOPPED MOVING FORWARD WITH THE RANDOMIZED PHASE THREE IF THERE HAD BEEN MORE INFORMATION IN THE EARLIER FA PHASES OF STUDY THAT COULD HAVE BEEN OBTAINED USING BIOPSIES. THIS IS THE PHARMACODYNAMIC BIOMARKERS, IMPACT ON NCI DEVELOPMENT PORTFOLIO. WHAT WE WERE LOOKING FOR IS DEMONSTRATION IS TREATMENT WITH VELIPARIB, NIRAPARI AND THEY WERE ABLE TO SHOW TREATMENT WITH VELLPARB DID NOT LEAD TOP DISCONTINUATION OF THE TRIAL. THESE WERE USEFUL PHARMACODYNAMIC RESULTS UNLIKELY WITHOUT. YOU NEED A BIOMARKER TO DO A BIOMARKER IN CLINICAL TRIAL AND THUS NEED A BIOPSY. THEY ACTUALLY DEMONSTRATE CLINICAL PROOF OF MECHANIC SIMPLE ESSENTIAL TOLL DEMONSTRATE LATE STAGE DEVELOPMENT. THAT IS MY LAST SLIDE. THAT WAS ONE EXAMPLE. I THINK THERE IS ONE MORE. SO THE LAST EXAMPLE THAT WAS PUBLISHED IN JCO, WAS SIGNIFICANT RATES OF BIOPSIES THAT HAD INSUFFICIENT TUMORS. THE CLINICAL TRIALS, THE CRITERIA WERE THREE IMAGES OF BIOPSIES. AND THE PERCENTAGE [INDISCERNIBLE] IN THE FIRST TRIAL. SO AS YOU LOOK DOWN THE TABLE, YOU CAN SEE THAT THE ABILITY TO ACQUIRE HIGH QUALITY BIOPSIES IS OFTEN QUITE CHALLENGING. SO LET ME SEE IF THERE IS ANYTHING ELSE I WANTED TO SAY ABOUT THIS. SO OUT OF ALL OF THESE, THE TUMOR WAS ONLY AVAILABLE FOR NINE OF THE PATIENTS. THIS IS A CHALLENGE. THE OTHER CHALLENGE IS THE ABILITY TO ACTUALLY GET PEER BIOPSY SPECIMENS WHEN YOU ARE TRYING TO LOOK FOR PHARMACODYNAMICFECT YOU WANT TO LOOK AT THE DEGREE OF CHANGE. LAST BUT NOT AT LEAST YOU CAN SEE THE GREEN BOX THAT SHOWS THE AREA WHERE THE TUMOR. THE REST OF THE BIOPSY DOES NOT HAVE TUMOR IN IT OR MINIMAL AMOUNTS OF TUMOR THAT WOULD REQUIRE LASER CAPTURE MICRODEFLECTION TO LOOK AT THEM. SO WHAT ARE THE REASONS FOR BIOPSY INSUEFFICIENCY? [INDISCERNIBLE] THERE WERE MORE TUMOR -- 17%, LOW TUMOR CONTENT SO THAT WAS 720% OF THE SPES MINES. THE MAIN REASON FOR INSUFFICIENCY IS LOW TUMOR CONTENT. ABOUT 45% OF LIVER BIOPSIES ARE INSUFFICIENT DUE TO DECREASED TUMOR CONTENT AND TWO TRIAL SAMPLE SETS SHOWED A TREND IN DECREASED TUMOR CONTENT IN THE POST BODOSE BIOPSY. THE CONCLUSIONS WERE IMPORTANT ONES, THAT IS THAT WE NEEDED VERY EXPERIENCED INTERVENTIONAL RADIOLOGISTS THAT WERE DEDICATED TO THE CONDUCT OF THIS TRIALS AND COULD HELP AND WORK WITH US, WHICH IS WHAT WE ASKED FOR IN OUR NEW SET OF TRIALS THAT THERE BE A DEDICATED INTERADVANTAGEOUSAL RADIOLOGIST FOR THE TRIAL IS SUBMITTED TO COMPLETING THE WORK ON THAT TRIAL AND THAT ACTUALLY MARKEDLY IMPROVED THE ABILITY TO ACQUIRE SUFFICIENT TUMORS TO CONDUCT THE ANALYSES WE WANTED TO PERFORM. THERE ARE TWO REFERENCES THAT CAN BE USED TO IMPROVE BIOPSY QUALITY AND HOW WE CAN IMKBROOUFT-- IMPROVEMENT. THAT IS HIGHLY INTERDISCIPLINARY APPROACH. THE REST OF MY SLIDES ARE JUST EXAMPLES OF HOW WE TRACK DIFFERENT KINDS OF BIOMARKERS AND THE STATUS OF DEVELOPMENT FOR OUR BIOMARKER ASSAYS. I THINK I CAN CONCLUDE AND TAKE ANY QUESTIONS. I WILL ASK DR. DOROSHOW IF HE WOULD LIKE TO MAKE ANY SUMMARY COMMENTS? >> NO. HAPPY TO TAKE QUESTIONS. >> JULIA, THIS IS MICHELE. IS IT OKAY IF WE TAKE A FEW QUESTIONS NOW? I WAS THINKING WE WOULD ASK PAUL NADLER TO MOVE HIS PRESENTATION TO AFTER THE BREAK. >> THAT IS FINE. >> OKAY. SO I'M GOING TO TIME US BECAUSE WE ARE SUPPOSED TO TAKE A BREAK AT 1:15. SO LET'S SPEND A FEW MINUTES FOR QUESTIONS. JULIA, I THINK I CAN'T SEE HANDS UP. YOU MAY BE NEEDING TO MANAGE THE QUESTIONS. >> OKAY. >> IT IS WALTER. I WONDER IF I COULD ASK A QUESTION. SO I FOLLOW THE LOGIC, THIS RISK-BASED APPROACH, DR. IVY, I WONDER IF YOU COULD SPEAK TO THE ISSUE OF CATEGORIZING THE RISK ASSOCIATED WITH BIOPSY COLLECTION? I'M A FORM EER GASTROENTEROLOGIST. WHERE WE TALK ABOUT THE THRESHOLD FOR RISK, WHAT IS THE SOURCE OF THE REFERENCE? CENTERS THAT ARE WITHIN THE NCI HAVE GREAT EXPERTISE IN OBTAINING BIOPSIES WHEREAS OTHER CENTERS MAY ACTUALLY HAVE LOWER PERFORMANCE AND I WONDER IF YOU CAN SPEAK ABOUT THAT ISSUE? >> I CAN SPEAK ABOUT OUR APPROACH, WHICH MIGHT BE THE MOST HELPFUL. WE FORMED A SMALL CONSORTIUM AMONGST ALL OF THE SITES THAT HAVE CLINICAL TRIALS. INTERVENTIONAL RADIOLOGISTS AT EACH SITES THAT HAD BEEN DEDICATED TO PARTICIPATING IN EARLY PHASE CHRISTIAN CAL TRIALS. USING THAT INTERVENTIONAL RADIOLOGY GROUP, WE DEVELOPED A GROUP OF RISK BASED ASSESSMENTS THAT ANY INTERVENTIONAL RADIOOLOGIST COULD DETERMINE THE RISK BENEFIT. THAT OCCURS IN CONSULTATION WITH THE WHOLE STUDY TEAM, BUT AS A PERSON WHO [INDISCERNIBLE] AND SHE WAS EXTREMELY HELPFUL TO US IN SETTING UP THE RISK CRITERIA, SO IT WOULD BE EASY FOR AN INTERVENTIONAL TO UNDERSTAND HOW THEY CONDITION INPUT AND THE OTHER ISSUE THAT COMES UP IS MANY TRIALS WILL REQUIRE SOMETIMES SOME REQUIRE FOUR OR SIX BIOPSIES AROUND A -- NEEDLE AND HOW TO APPROACH THAT. AND HOW TO PRIORITIZE WHAT IS THE MOST IMPORTANT SES MEN TO GET? SO TO GIVE THE INTERVENTIONALIST SOME DALE WE HAVE HAD A SERIES OF WEBINARS WITH ALL OF OUR INVESTIGATORS -- I'M SORRY? INCLUDING THE INTERVENTIONAL RADIOLOGIST. AND GIVEN A SERIES OF SEMINARS ON HOW TO APPROACH THIS RISK-BASED OR RISK EVALUATED BIOPSY ASSESSMENT. WE ARE HOPING OVERALL THAT WILL HELP US IN IMPROVING THE QUALITY OF THE BIOPSY USED IN OUR CLINICAL TRIALS. >> OKAY. YEAH. THANK YOU. MY OBSERVATION IS REALLY THAT THE RISK IS KIND -- THE REFERENCE RISKS ARE A FUNCTION OF THE OPERATORS. AND THEY ARE REPRESENTATIVE OF THE OPERATORS. IN SOME CASES THEY MAY ACTUALLY BEST CASE EXAMPLES. >> YEAH. WELL, I AGREE WITH YOU. THE OTHER THING I WOULD SAY IS THAT WE ARE COLLECTING THE INFORMATION ON THE RISK ASSESSMENTS. SO THEY HAVE TO -- IT IS A SIMPLE CASE FORM. IT IS QUICK TO FILL OUT. A SERIES OF CHECKED BOXES THAT THEY HAVE TO RECORD THE AMOUNT OF RISK THEY FELT FOR CONCERN, HIGH, INTERMEDIATE OR LOW, THEY HAVE TO TLOORECORD THAT IN THE CASE FORM. AS WE ACQUIRE ENOUGH DATA WE WILL GO BACK AND REVIEW ALL OF THAT. [INDISCERNIBLE] WE ARE STARTING WITH A QUALIFIED ASSAY AND THEY OBTAIN A BIOPSY, [INDISCERNIBLE] TUMOR AND ARE THEY ABLE TO ANALYZE THE TUMOR IN THE FUTURE? IS IT VIABLE TUMOR TISSUE. WE ARE ALSO FEEDING THAT INFORMATION BACK TO THE INTERVENTIONALIST SO THEY CAN DO A "BETTER JOB" PICKING REGIONS TO BIOPSY BASED ON RADIOGRAPHY CHARACTERISTICS. >> VERY GOOD. THANK YOU. >> ARE THERE ANY OTHER QUESTIONS? SO THIS IS MICHELE. DR. IVY, I HAVE A QUESTION. DO YOU FEEL THAT THE LINE BETWEEN EXPLORATORY BIOPSIES AND INTEGRAL BIOPSIES CAN BE BLURRY? >> WELL, I DON'T THINK OF THE BIOPSY OR PROCEDURE AS EXPLORATORY. I THINK OF THE BIOMARKER THEY ARE ASSESSING OR EVALUATING AS EXPLORATORY. SO WE STRUGGLE A BIT WITH NOMANCLATURE, BIOMARKERS ARE INTEGRATED OR EXPLORATORY AND THEN WE TALK ABOUT WHETHER OR NOT THE BIOMARKER IS CRITICAL FOR THE STUDY AND REQUIRES A BIOPSY TO OBTAIN THE RESULTS. SO THE BLURRY LINES, I THINK, COME ON THE EDGES OF THE -- LET ME GO BACK TO -- SORRY. I HOPE I WON'T MAKE ANYBODY TOO DIZZY. THE BLURRY LINES GO ACROSS THE SLIDE. WHERE WE ARE ASKING FOR AN ASSESSMENT. AND THIS IS WHERE THE STUDY CHAIN AND THE INTERVENTIONAL RADIOLOGIST NEED TO WORK TOGETHER TO ASSESS RISK AND WHETHER THE RISK IS WORTH IT. SO LET US USE THE EXAMPLE OF AN INTEGRAL BIOMARKER. IT IS A PRIMARY END POINT FOR THE STUDY AND THEY NEED THE TISSUE TO DETERMINE WHETHER OR NOT THE PATIENT CAN GO ON A CLINICAL TRIAL. SO AT THAT POINT IN TIME, THE INTERVENTIONALIST WILL GIVE THEIR OPINION ON WHETHER OR NOT THEY SHOULD PROCEED OR THEY THINK IT IS WORTH IT TO TAKE THE RISK AND THE PI WOULD ALSO GIVE THEIR ASSESSMENT OR THE ONCOLOGIST FOR THE PATIENT ON THE STUDY AND THEY MAY NOT THINK IT IS WORTH THE RISK. THERE IS THIS BALANCE. I THINK THAT IS WHERE THE FINE LINES OR GRAY AREAS COME IN. THE ART AND PRACTICE OF MEDICINE AND HOW YOU DETERMINE WHAT IS BEST FOR YOUR PATIENT. I GAVE YOU ONE EXAMPLE WHERE THE ONCOLOGIST MAY NOT HAVE THOUGHT IT WAS ACCEPTABLE AND THE INTERVENTIONALIST THOUGHT THEY COULD DO IT, BUT THERE WAS INCREASED RISK. THE OTHER EXAMPLE IS WHEN THE ONCOLOGIST THINKS IT IS CRITICALLY IMPORTANT AND PUSH THE INTERVENTIONIST TO DO A HIGH RISK BIOPSY. THEY HAVE TO REACH CONSENSUS. IT IS A COLLABORATIVE PROCESS. IT CAN'T BE DICTATED BY A CHART. IT HAS TO BE A DISCUSSION BETWEEN THOSE PERFORMING THE PROCEDURE AND THE PURPOSE OF THE BIOMARKER. THE PLACE THIS BECOMES MURKIER, IS WHEN THE BIOMARKER IS NOT INTEGRAL. WHEN YOU MOVE TO INTEGRATED THERE ARE GOOD REASONS TO DO INTEGRATED BIOMARKERS, BUT THEY ARE NOT NECESSARILY CRITICAL DO THE ANALYSIS OF THE STUDY AND SO YOU HAVE TO ONCE AGAIN DECIDE HOW IMPORTANT IT IS. AND SO I THINK THAT'S WHERE WE COME INTO THIS AREA OF CLINICAL JUDGMENT. ON THE PART OF THE ONCOLOGIST AND ON THE PART OF THE INTERVENTIONAL RADIOLOGIST. I THINK THE CHALLENGING THING IS TO SIMPLIFY DESCRIPTION OF WHAT IN GENERAL WHEN IRB LOOKED AT A STUDY THAT IS USING CERTAIN TYPES OF BIOMARKERS AND WHAT KIND OF BIOPSY THEY ARE REQUIRING. AND THERE ALSO HAS TO, I THINK, BE SOME ACCEPTANCE THAT IT IS A CLINICAL TRIAL AND REQUIRING CLINICAL JUDGMENT TO MAKE THESE DECISIONS. ONCE AGAIN, THEY ARE AN OUTSIDE PARTY, LOOKING AT WHAT THE TEAM IS DOING AND ASKING, IS THE RISK VERSUS THE BENEFIT TO THE PATIENT TO PARTICIPATE IN THIS PARTICULAR TRIAL APPROPRIATE? AND SO THAT'S WHY I TRIED TO DEVELOP THIS SIMPLIFIED TABLE THAT MIGHT BE EASIER FOR AN IRB, AS THEY START TO THINK ABOUT THIS GLOBALLY, WHAT IS IT THEY THINK SHOULD BE DONE? WHAT IS THE BEST THING TO DO AND HOW TO DO IT? >> GREAT. THANK YOU VERY MUCH. REALLY APPRECIATE YOUR PRESENTATION. JULIA, JUST WANT TO CONFIRM WE SHOULD MOVE ON TO PAUL NADLER'S? >> IF PAUL IS READY TO GO, THAT IS TERRIFIC. OTHERWISE, I THINK WE COULD ALSO CALL FOR THE BREAK RIGHT NOW. SO I THINK IT IS REALLY UP TO PAUL, UNLESS, DOUG, YOU HAVE A PREFERENCE? >> NO. IF PAUL IS READY, WE CAN DO HIM AND BREAK AFTER THAT. >> OKAY. PAUL IS READY, IT APPEARS. >> THANK YOU. >> OKAY. SO I'M GOING TO -- GOOD AFTERNOON. I'M GOING TO ANSWER THE QUESTIONS THAT WERE SENT OUT TO US BY MICHELE. THE QUESTION SHE RAISED FOR US ARE IS THERE A NEED FOR GUIDANCE TO ASSIST INSTITUTIONAL REVIEW BOARDS TO -- >> PAUL, I'M SO SORRY. BEFORE YOU LAUNCH IN, COULD YOU, AGAIN, JUST INTRODUCE YOURSELF TO THE GROUP, PLEASE. >> SURE. I'M PAUL NADLER, A PHYSICIAN. I'M AN ONCOLOGIST N AND CLINICAL IMMUNOLOGIST. TRAINED AT NCI. I HAD TO LAUGH WHEN DR. IVY SAID SHE GOT THERE IN 1997, I LEFT IN 82, HAVING GOTTEN THERE IN 1982. I'M AN OLD NCIER. I WORKED IN INDUSTRY, BIG PHARMA, SMALL BIOTECH PDL AND CLINICAL RESEARCH CONSULTING, REGULATORY CONSULTING WITH MULTIPLE CLINICAL RESEARCH COMPANIES IN PHASE ONE AND PHASE TWO ONCOLOGY TRIALS. AT TIMES PEOPLE HAVE INSISTED WE WORK IN OTHER FIELDS LIKE AUTOIMMUNE INFLAMMATORY DISEASES I'M TRAINED IN AND VIROLOGY, BUT WE DO CANCER AS A PRIMARY BUSINESS. I'M SURE THE REASON I'M HERE IS BECAUSE -- SUGGESTED I COME. FOUR QUESTIONS THAT MICHELE OUTLINED, THE NEED TO ASSIST IRBs IN RESEARCH THAT INCLUDES MANDATORY BIOPSIES. IS THERE A PERCEIVED CAP IN THE REGULATORY CRITERIA THAT INHIBITED ADEQUATE REVIEW OF RESEARCH THAT INCLUDES MANDATORY BOB BIOPSIES, THERE IS HELP TO APPLY THE CRITERIA TO RESEARCH INVOLVING MANDATORY BIOPSIES. IS THERE SPECIFIC IRBs SHOULD ACCESS IN QUESTIONS ABOUT MANDATORY BIOPSIES AND IF THE ISSUE REVOLVES AROUND MANDATORY BIOPSY IS INTEGRAL TO THE RESEARCH TO HELP IRBs DETERMINE WHAT IS AND NOT INTEGRAL TO THE MAIN RESEARCH. REFERRING BACK TO DR. IVY'S PRESENTATION, OBVIOUSLY, NCI, IN THEIR INTRAMURAL AND EXTRA MURAL STUDIES HAS DONE THIS WORK. DETERMINING WHAT IS INTEGRAL AND NOT INTEGRAL. THERE IS NO FRAMEWORK IN PHARMA OR THE EXTRAMURAL WORLD OUTSIDE OF NCI. SPECIFICALLY TO DO THIS. SOME SCIENTIFIC REVIEW COMMITTEES AND INDIVIDUAL INSTITUTIONS MAY HAVE THIS, BUT IN GENERAL, I DON'T BELIEVE PHARMA OR BIOTECH GO THROUGH THIS PROCESS NOR DO I BELIEVE MOST INVESTIGATORS OR INSTITUTIONS SPONSORING THEIR OWN RESEARCH GO THROUGH THIS PROCESS. FIRST QUESTION, IS THERE A CRITERIA. I THINK, ALTHOUGH THERE WERE OTHERS THAT WERE PROVIDED TO US. THERE ARE ELEMENTS IN THE CODE OF FEDERAL REGULATIONS IN REGARD TO IRB MEMBERSHIP. EACH IRB SHOULD INCLUDE ONE MEMBER OF PRIMARY CONCERN IN SCIENTIFIC YA AREA, AT LEAST ONE NONSCIENTIFIC, MORE IMPORTANT IRB IN ITS DISCRETION MAY INVITE INDIVIDUALS WITH COMPETENCE TO ASSIST IN ISSUES WITH EXPERTISE. THIS IS VERY IMPORTANT. THE LATTER PART, CLAUSE E, WHILE EACH MEMBER MAY BE A SIGN HITS, THEY COULD BE A -- OR A CLINICIAN WHERE THEY DO NINGS ALLERGY, BUT BIOPSIES ARE NOT NECESSARILY INVOLVED AND THOUGHT ABOUT THIS AREA NOR ARE THEY EXPERT IN A SPECIFIC SCIENTIFIC AREA. IN THIS PARTICULAR APPLICATION, IN THIS CASE ONCOLOGY, WE ARE PRIMARILY TALKING ABOUT IS THE BIOPSY REASONABLE, MANDATORY, SCIENTIFICALLY VALIDATE AND WITHOUT THE BIOPSY THE STUDY SHOULDN'T OR COULDN'T BE DONE. EVEN IF AN IRB HAS AT LEAST ONE MEMBER WITH A SCIENTIFIC FOCUS, IT IS NOT GUARANTEED THIS INDIVIDUAL WILL HAVE REQUISITE EXPERTISE TO WEIGH THE MANDATORY BIOPSY REQUIREMENT. ONLY AT NCI OR RESEARCH CENTER HAVE THE POP -- PEOPLE TO DO THAT. CLAUSE E PROVIDES A DIRECTION IN WHICH THIS ISSUE COULD BE ADDRESSED. THERE IS NO RIGHT NOW, I SEE SPECIFIC MECHANISM FOR IRBs TO IDENTIFY AND INVOLVE SOME OR ALL OF THE RELEVANT EXPERTISE NECESSARY TO ADJUDICATE THE QUESTION OF NECESSITY OF MANDATED BIOPSIES. SO LET'S TALK ABOUT INTERNAL IRBs. CLEARLY THEY MAY OR MAY NOT HAVE, A PLACE LIKE MARK, INSTITUTE OF CHICAGO, KNOWING HE CAN REACH OUT TO FACULTY AND FINDING THEM TO PROVIDE EXPERT EXPERTI EXPERTISE. FOR A CENTRAL IRB THAT MAY OR MAY NOT BE AVAILABLE AT THE DEPTH VIABLE AT A MAJOR CANCER CENTER. THERE IS NO SPECIFIC MECHANISM FOR IRB TO DO THIS. THAT IS A LACKING. I DON'T KNOW THAT YOU CAN FILL THAT WITH REGULATORY GUIDANCE. BUT THERE IS SUFFICIENT GUIDANCE IN THE IRB REGS TO SEE IF IT IS SCIENTIFICALLY JUSTIFIED. THERE IS NO SPECIFIC MECHANISM TO GET THAT EXPERTISE. THERE IS NO PERCEIVED CAP IN THE GUIDANCE ITSELF, BUT RATHER QUESTIONS REGARDING HOW TO OBTAIN THE SPECIFIC INFORMED UNBIASED INPUT NECESSARY TO MAKE SUCH DECISIONS. THE NEXT QUESTION WAS GUIDANCE FOR IRBs IN APPLYING REGULATORY CRITERIA. AN IRB SHOULD REVIEW AND APPROVE, REQUIRE MODIFICATION. WOULD DISAPPROVE ALL RESEARCH ACTIVITIES COVERED BY THIS POLICY INCLUDING EXEMPT ACTIVITIES. THEY HAVE THE RIGHT TO SAY YEA OR NAY TO ANY BIOPSY, MAPD TERRY OR OTHERWISE BASED ON THIS REGULATORY GUIDANCE. IRB SHOULD NOTIFY INSTITUTION IN WRITING TO APPROVE OR DISAPPROVE THE MODIFICATIONS REQUIRED TO SECURE THEIR APPROVAL AND THAT RESEARCH CANNOT GO ON WITHOUT THE IRB ACCEPTING IT AND APPROVING THE STUDY TO GO FORWARD AT AN INSTITUTION. FINALLY THE IRB SHOULD CONDUCT CONTINUING RERUE OR RESEARCH. THE IRB HAS TO REVIEW IT INITIALLY, BUT IN ADDITION IN RESEARCH AND GETTING SAFETY INFORMATION EVERY YEAR, THEY COULD COME ACROSS A NEW RISK THAT HASN'T BEEN CAPTURED IN THE CONSENT NOR THE MATERIAL OF INCREASED RISK FOR THESE BIOPSIES WHICH MAY CHANGE THE RISK/BENEFIT RATIO. THE REGULAR LEIGHS PROVIDE THE AUTHORITY FOR MODTY FICATIONS OR -- INCLUDING MANDATORY AND VOLUNTARY BIOPSIES. THERE IS NO SPECIFIC GUIDANCE ON HOW TO EVALUATE BIOPSIES ARE SCIENTIFICALLY AND THEREFORE ETHICALLY JUSTIFIED. SO EXPERTISE OF IRB. GENERALLY THE MEMBER WITH SCIENTIFIC EXPERTISE WILL NOT HAVE THE SPECIALIZED KNOWLEDGE TO ADJUDICATE THE QUESTIONS REGARDING MANDATORY BIOPSIES. HAVING BEEN IN AN ACADEMIC SETTING, USUALLY NOBODY WANTS TO BE ON THE IRB. AND SO IT IS A -- YOU ARE ON IT FOR A TIME. SOMETIMES YOU GAIN EXPERTISE TO DEAL WITH THESE ISSUES. SOMETIMES PEOPLE ARE DOING IT, EXCUSE MY EXPRESSION, BECAUSE THEY HAVE TO AND IS REQUIRED BY THEIR DIVISION. MEDICAL AREA EXPERTISE OF IRB MEMBERS MAY NOT BE SUFFICIENT FOR SPECIFIC PROTOCOLS, AND MAY HAVE AN INTEREST IN THE STUDY. IN ADDITION, AN IRB MEMBER AT A LOCAL INSTITUTION MAY HAVE INNATE INTERNAL BIAS IN TERMS OF BEING SUPPORTIVE OF THE STUDY AND THE BIOPSIES BECAUSE OF THEY ARE IN THE GROUP, IN THE DIVISION, THEY KNOW THE INVESTIGATOR OR THERE COULD BE CONSEQUENCES OF THEM NOT BEING SUPPORTIVE. SCIENTIFIC REVIEW COMMITTEES PRESENT AT LARGE CANCER CENTERS HAVE AN SUBSTITUTION INTEREST IN CLINICAL TRIALS. BUT IRBs MAY ASSUME THEIR APPROVAL INCLUDED A CRITICAL REVIEW OF BIOPSY REQUIREMENTS. IN ADDITION, IRBs MAY ASSUME THAT FDA IS ANOTHER LEVEL OF CRITICAL SCIENTIFIC REVIEW OF THE RATIONAL FOR ETHICS AND MAN AND DIARY BIOPSIES. THEY MAY THINK THE SCIENTIFIC COMMUNITY DID IT AND ASSUME THE FDA HAD DONE THIS REVIEW AND THEY MAY THINK BY THOSE PRIOR REVIEWS THAT, OF COURSE, THE BIOPSY HAS BEEN VALIDATED, APPROVED BY OTHERS. SO THEY MAY JUST FALL ON THAT. IX RBs ARE FREE TO ASK FOR EXTERNAL INPUT BUT MAY NOT HAVE THE EXPERTISE TO IDENTIFY OR COMPENSATE THEM. WITHIN AN INSTITUTION, THAT MAY NOT BE AN ISSUE OUTSIDE OF AN INSTITUTION IT MY BE AN ISSUE. NEXT ONE IS WHAT GUIDANCE IS THERE FOR IRBs TO DRM WHAT IS INTEGRAL. RIGHT NOW THERE IS NO SPECIFIC IRB GUIDANCE TO ASSIST WHETHER THE BIOPSY IS INTEGRAL TO THE CLINICAL TRIAL. I DO NOT THINK MOST SPONSORS OUTSIDE OF THE NCI, GO THROUGH THIS RIGOROUS APPROACH TO CATEGORIZING THE BIOMARKERS ARE INTEGRAL OR NOT OR INTEGRATED OR NOT OR ET CETERA. POSSIBLE RESOURCES IS TO SEE WHETHER IT IS MANDATORY WOULD BE THE PROTOCOL BACK GROUBD, RATIONAL FOR THE TRIAL, INVESTIGATOR'S BROCHURE, AND LABORATORY MANUAL IF AVAILABLE. THEY CAN REQUEST IT. NEW GUIDANCE MAY BE YUSZFUL, BUT RESOURCES EXTERNAL TO MANY EXISTING IRBs MAY BE NEEDED, AND THIS MAY PROLONG THE TIME FOR IRB REVIEW OF CERTAIN PROTOCOLS. NOT THAT IS A BAD THING. THIS MAY BE A LONGER REVIEW. HOW MAY IT IMPROVE THE PROCESS? I THINK WE CAN REASSESS THE PROCESS AND REQUIRE THAT PROTOCOLS INCLUDE A RATIONAL FOR BIOPSIES IN GENERAL AND FOR MANDATORY BIOPSIES SPECIFICALLY. I THINK DR. IVY SAID THERE ARE IN CASES THEY ARE. IT IS IMPORTANT IF A TUMOR IS EXCEEDING -- [INDISCERNIBLE] PATHOGENS COULD BE ONE SBE CELLULAR TARGET OR DOWN THROUGH PATHWAY. THE EFFECTS OF THE PARAMETERS THAT COULD REQUIRE RESISTANCE. ARE THERE ESTABLISHED ASSAYS RELATIVE TO THE EXPERIMENTAL THERAPY ON THE TARGETS NECESSITATING A MANDATORY BIOPSY AND ALTERNATIVE METHODS TO INTERROGATE THE POTENTIAL TARGETS. MOST OF US LOOK FOR OTHER TISSUES WHERE THE TARGET IS EXPRESSED. YOU CAN MITIGATE THE RISKS TOWARD ASSESSING TARGETS, BUT UNFORTUNATELY MANY TARGETS OR MOST TARGETS ARE UNDER THE EXPRESSED WEEKLY OR NOT ACTIVATED IN PERIPHERAL TISSUES SO YOU CAN'T DO THAT IN MANY CASES. ALTERNATIVE TECHNIQUES TO ASSESSFECTS OF THERAPY. WE HAD A CASE WHERE WE ARE INTERROGATING CD30 BIOPSY AND HODGKINS LYMPHOMA, AND NOW IT IS UNKNOWN, A SURROGATE FOR CD30 TUMOR SILLS AFTER BRUTUXIMAN THERAPY. THERE ARE CLEARLY WAYS THAT NEED TO BE EXPLORED BEFORE ONE GETS INTO DOING BIOPSIES POTENTIALLY DANGEROUS TO THE PATIENT AND MAN AND -- MANDATED BY THE PROTOCOL. REASSESS THE PROCESS OF PROTOCOL REVIEW AND APPROVAL AT MULTIPLE LEVELS. IT SHOULD INDICATE ACCEPTANCE OF RATIONAL AND NECESSITY FOR MANDATORY BIOPSIES AND WHAT PROVISIONS HAVE BEEN TAKEN TO MINIMIZE THE RISK. IT IS NOT JUST GENERALLY DONE IN PROTOCOLS. THIS ISN'T SOMETHING WHERE THE SITE IS SPECIFIC. WE SHOULD INCLUDE SPECIFIC RATIONAL, SPECIFICALLY THOSE THAT CONFER A SIGNIFICANT RISK TO PATIENTS. IN BOTH THE FDA AND SCIENTIFIC REVIEW OF PROTOCOLS, MORE DIVERSE SCIENTIFIC EXPERT IS FEASIBLE, AT THIS POINT, I UNDERSTAND THE FDA DOESN'T NECESSARILY DO THIS, BUT I THINK IT IS CERTAINLY FROM MY VANTAGE POINT WITHIN THEIR PURVIEW AND WITHIN THE PURVIEW OF SCIENTIFIC REVIEW COMMITTEES WHERE THEY EXIST FOR PROTOCOLS FOR INSTITUTIONS. WE MIGHT, IF THAT IS NOT FEASIBLE, CREATE A CENTRAL IRB WITH PARALLEL CENTRALS. PERHAPS IT IS TIME FOR THE SANCTUARYS HAVE THEIR OWN PARALLEL SRCs, THE GOAL TO ELIMINATE THE POTENTIAL FOR BIAS AT SITES AND ADDRESS THE LACK OF EXPERTISE WITHIN SOME INSTITUTIONAL IRBs FOR SOME OF ALL TRIALS IN ONCOLOGY. WE SPENT A LOT OF TIME WORKING WITH CENTRAL IRBs AND INSTITUTIONAL IRBs AND CLEARLY SUBSTITUTIONAL IRBs HAVE THEIR OWN FOCUS AND WHAT HAVE YOU, ULTIMATELY THE LACK OF BIAS, CENTRAL IRBs, PARALLEL SRCs AND ACCESS TO RESOURCES WHILE VERY, VERY LARGE UNDERTAKING MIGHT BE AN INTERESTING SOLUTION TO THIS PROBLEM IN A MORE GENERAL FASHION. SO IF THE RESPONSIBILITIES OF IMPROVING THE PROCESS, IF RESPONSIBILITIES REMAIN WITH IRB, THERE NEEDS TO BE IMPLEMENTATION OF A CENTRALIZED SRC OR ACCESS TO RELEVANT EXPERTS NOT INVOLVED IN THE INSTITUTION OR TRIAL AND NOT AFFILIATED WITH THE SPONSOR SHOULD BE CONSIDERED. WE NEED TO HOLD SPONSORS RESPONSIBLE FOR REPARATION AND REVIEW OF DOCUMENTS TO PROVIDE ADD ADEQUATE GUIDANCE TORI Bs TO EVALUATE THE POTENTIAL UTILITY OF BIOPSIES AND TO ASSESS WHETHER THEY SHOULD BE MANDATORY. MARK HAS BEEN PRYING TO PROMULGATE THIS DISCUSSION, THIS IS NOT A RIGOROUS PROCESS THAT PEOPLE GO THROUGH AND MAYBE IT SHOULD BE. I THINK IT SHOULD BE. SO WE MAYBE NEED TO GO IN THAT DIRECTION. OKAY. SO JUST SOME FINAL THOUGHTS. FIRST OF ALL, WE DON'T KNOW EVERYTHING WE NEED TO KNOW IN BEGINNING DRUG DEVELOPMENT. IT IS FREQUENTLY THE EXCEPTION RATHER THAN THE RULE THAT WE HAVE VALIDATED BIOMARKER ASSAYS OR WE KNOW WHAT THE RIGHT BIOMARKERS ARE FOR ALL TYPES OF TARGETS. SO I THINK CONSIDERATIONS ON MANDATORY BIOPSIES MAY VARY WITH THE TYPE OF BIOMARKER BEING EVALUATED. FOR INSTANCE, THE INITIAL BIOPSY TO DETERMINE CELL SURFACE EXPRESSION OF THE ANT GENERAL TARGET OF AN ANTIBODY FOR A NOVEL TARGET MAY BE JUSTIFIED AT THE BEGINNING OF THE DRUG DEVELOPMENT. SOMETIMES IT HASTENS DRUG DEVELOPMENT TO A GO-NO GO DECISION. DR. IVY HIT ON THIS, HITTING IN TARGETS. IN PHARMA AND BIOMARKER AND NCI AS WELL IS USED MOST OF THE TIME. DEPENDING WHETHER YOU HIT THE TARGET OR NOT, YOU MAY NOT SEE OBJECTIVE RESPONSES IN PHASE ONE OR DETERMINE THE RIGHT TUMOR TYPES TO EVALUATE LATER. SOMETIMES DOCUMENTATION, THIS IS MORE MUNDANE, HITTING THE TARGET IS REQUIRED FOR FUND-RAISING AT EARLY STAGE BIOTECH KNOWLEDGE COMPANIES. IT HAS BEEN AMAZING OVER THE LAST 20 PLUS YEARS, BUT WITHOUT THERE HAVING DATA, THE TARGET HAS BECOME INCREDIBLY IMPORTANT FOR EARLY STAGE COMPANIES FOR VALIDATION AND LARGE PHARMA COMPANIES LIKE NOVARTIS, THEY HIT THE TARGET OR DON'T GO ON AS WELL. MAKES A LOT OF SENSE. FINALLY, THE EXPERT AND KNOWLEDGE TO DESIGN EARLY STUDIES EXPLORING PHARMACODYNAMICS TARGET ENGAGEMENT AND MARKERS OF RESISTANCE IS NOT UNIFORMLY AVAILABLE, PARTICULARLY IN THE BIOTECH COMPANIES. IS THERE A PERCEIVED GAP IN THE REGULATORY CRITERIA TO GUIDE,RI Bs? NO. IS THERE GUIDANCE THAT COULD HELP APPLY THE IRB CRITERIA? NO SPECIFIC AT PRESENT BUT THEY HAVE THE RIGHT TO SEEK THAT OUTSIDE EXPERTISE. SPECIFIC EXPERTISE, YES, BUT THEY HAVE TO IDENTIFY IT AND HAVE THE RESOURCES TO DO SO. IN THE ISSUE INVOLVES AROUND A MANDATORY BIOPSY IS INTEGRAL, NO SPECIFIC GUIDANCE IS NEEDED SINCE THEY ARE EMPOWERED TO MAKE THESE DETERMINATIONS. BY EXISTING GUIDANCE. IT IS UNCLEAR HOW TO CREATE A GUIDANCE CRITERIA TO SUFFICE IN ALL CASES. IT JUST OCCURRED TO ME, THERE COULD BE AND THIS IS JUST A FORM OF WHAT MIGHT BE CONSIDERED OF A QUESTIONNAIRE THAT THE SCIENTISTS, EXTERNAL OR INTERNAL ON AN IRB MIGHT HAVE TO ACCEPT OR REJECT AS ADEQUATE RATIONAL TO SUPPORT THE BIOPSIES? THERE IS A STRONG RATIONAL TO MAKE THEM MANDATORY? IS THERE A CLEAR STATEMENT TO THE ANALYTICAL PLAN? IS THERE VERIFICATION THAT AN ASSAY HAS BEEN DEVELOPED OR WILL BE AVAILABLE? IS THERE DOCUMENTATION THAT ALTERNATIVE, LESS-INVASIVE APPROACHES WOULD NOT ADDRESS THE QUESTIONS BEING ASKED. IS THERE DOCUMENTATION THAT SIMILAR BIOPSY STUDIES HAVE NOT ALREADY BEEN DONE. I WOULD SAY PARENTHETICALLY, YOU DON'T WANT TO DO EGFR, PHOSO ARELATION ASSAYS NOW FOR SMALL MOLECULE -- INHIBITORS IF SIMILAR HAS BEEN DONE AND IS THERE A MAN TO MINIMIZE COMPLICATIONS EXPERIENCE CENTERS, LITTLING THE SITES TO BIOPSY, ET CETERA? AND I'LL STOP THERE. >> A VERY THOUGHTFUL PRESENTATION AND THE REVIEW QUESTIONNAIRE AT THE END OF IT IS A REALLY NICE WRAP UP. SO I THINK WE'RE GOING TO BREAK WELCOME BACK, EVERYBODY. WE'RE GOING TO HAVE OUR NEXT PANELIST ON MANDATORY BIOPSIES, WE WELCOME GUATAM MEHTA, A DIVISION OF ONCOLOGY IN THE FDA AND LIAISON FOR THE ADULT NEUROONCOLOGY. WE'RE EXCITED TO HAVE HIM WITH US. GUATAM, THE STAGE IS YOURS. >> THANK YOU MICHELLE AND THANK YOU TO THE COMMITTEE FOR HAVING US PARTICIPATE. CAN YOU SEE MY SLIDES HERE? >> YES. >> IS THAT WORKING? >> NO. >> OKAY. GREAT. >> NO. I CANNOT SEE. >> SORRY IT IS MY -- >> I'M A NEURO SURGICAL ONCOLOGIST IN THE DIVISION OF ONCOLOGY IN THE OFFICE OF NEW DRUGS AT CEDAR. LIKE SEVERAL OF THE OTHERS HERE I TRAIN AT THE NIH AND NB ANDERSON AND WAS IN PRACTICE AT THE HOUSE CLINIC BEFORE MOVING TO FDA. BECAUSE THE FDA COMPLIMENTS OUR REVIEW INVESTIGATION PROTOCOLS LIKE THE ONES BEING DESCRIBED TODAY WE WANTED TO PROVIDE THE COMMITTEE SOME CONTEXT AND BACKGROUND ON OUR REGULATORY REVIEW PROCESS TO FRAME THIS DISCUSSION ON MANDATORY BIOPSIES. I'M GOING TO TAKE A FEW MINUTES TO DESCRIBE THIS PARTICULARED AS IT RELATES TO INVESTIGATIONAL AND RENEWED DRUG APPLICATIONS. I HAVE NO DISCLOSURES TO REPORT. SO OUR MISSION AT THE FDA ENSURES THE SAFETY, EFFICACY AND SECURITY OF DRUGS AND BIOLOGIC DEVICES. THEY NEED TO BE PROVEN SAFE AND EFFECTIVE TO THE FDA BEFORE THEY CAN BE MARKETED. IN OUR REVIEW WE DO NOT TAKE INTO ACCOUNT -- SORRY. I GOT A LITTLE WINDOW. IS IT STILL SHOWING MY SCREEN? >> YES, IT SHOWS YOUR SCREEN. >> IT IS FOR ME. >> OKAY. SORRY. OKAY. SORRY ABOUT THAT. AND SO, AGAIN, IING -- THE DRUGS AND BIOLOGICS WE REGULATE NEED TO BE PROVEN SAFE AND EFFECTIVE TO THE FDA BEFORE THEY CAN BE MARKETED. DURING OUR REVIEW PROCESS WE DO NOT TAKE INTO ACCOUNT ANY ISSUES RELATED TO EITHER COST OR PAYMENT AND WE DO NOT REGULATE THE PRACTICE OF MEDICINE. AS MANY OF YOU KNOW, REGULATORY REVIEW AT THE FDA SPANS THE BREADTH OF DRUG DEVELOPMENT AND STARTS WITH THE INVESTIGATIONAL NEW DRUG OR IND APPLICATION PROCESS. THIS APPLICATION IS TYPICALLY REQUIRED BEFORE THE START OF ANY CLINICAL TRIAL IN THE U.S. AND ITS PURPOSE IS TO PROTECT CLINICAL TRIAL PARTICIPANTS WITH THE FOCUS ON SAFETY THROUGHOUT THE CLINICAL DEVELOPMENT PROGRAM. SPONSORS MAY MEET WITH THE F.D.A. PRIOR TO IND SUBMISSION TO SEEK ADVICE AT A PRE-IND MEETING AS WELL AS THROUGHOUT THE DEVELOPMENT PROGRAM. AFTER THIS APPLICATION PHASE THEN THEY ALSO SUBMIT PROTOCOL AND AMENDMENTS THAT WE HAVE TO REVIEW ON A ROLLING BASIS. SO WE'RE QUALIFIED FOR AN IND. THE PROTOCOL FIRST MUST BE INVESTIGATIONAL AND INCLUDE AN EXPERIMENT IN WHICH THE DRUG IS ADMINISTERED TO ONE OR MORE HUMAN PARTICIPANTS. IN SOME CASES PREVIOUSLY APPROVED DRUGS MAY BE EXEMPT FROM A REVIEW. SO IN GENERAL, THE DRUG THAT WE'RE REVIEWING IN THE APPLICATION IS NEW. AND THEN FINALLY THE DRUG SHOULD BE RECOGNIZED IN THE PHARMAPEDIA IN INTENDED TREATMENT. THIS CAN INCLUDE SOME FOOD AND DIETARY TREATMENTS IF IT MEETS THE ABOVE CRITERIA. THE IND REVIEW IN ONCOLOGY IS GROUNDED IN A MULTIDISCIPLINARY APPROACH. INCLUDING PROJECT MANAGERS FOR POINT OF IMPACT DURING AND AFTER APPLICANT SUBMISSION. EXPERTS IN THE PRODUCT QUALITY AND MANUFACTURING AS WELL AS CLINICAL PHARMACOLOGISTS. AND CLINICIANS, SUCH AS MYSELF, THAT MAY HAVE VARYING SPECIFIC SPECIALTIES INCLUDING ONCOLOGY, RADIATION ONCOLOGY AND SURGERY. AND FINALLY, BIO STETTITIONS THAT HAVE EXPERTISE IN CLINICAL TRIAL DESIGN. IN CASES WHERE COMPANION DIAGNOSTIC IS BEING USED WE TYPICALLY CONSULT THE CENTER FOR DEVICES AND RULING IC -- RAID DEE I DON'T LOGIC HELP FOR THEIR EXPERTISE. IT UNDERGOES A 30 DAY REVIEW PROCESS THAT IS REALLY FOCUSED ON SAFETY. AT THE END OF THE REVIEW, THE FDA THROUGH THE MULTI MULTIDISCIPLINARY TEAM MAKES A DETERMINATION WHETHER SAFE TO PROCEED OR PLACED ON HOLD. AND IN THIS PROCESS WE REVIEW THE IND TO MAKE SURE THAT IT DOESN'T POSE ANY INREASONABLE RISK OF INJURY TO ANY OF THE PARTICIPANTS AND THE STUDY IS ADEQUATELY DESIGNED TO MEET ITS SUBJECTIVES. TO QUICKLY TIE THINGS IN TO THE DISCUSSION OF BIOPSIES I WANT TO MAKE A COUPLE OF QUICK POINTS TO GIVE A FRAMEWORK FOR HOW BIOPSIES SPECIFIC TO BIOMARKERS WHICH WE DO REVIEW FIT INTO THIS PROCESS. THIS IS DIFFERENT THAN EXPLORATORY BIOPSIES THE OTHER SPEAKERS ARE DESCRIBING. IN THIS CASE, WE REFER DISH FOR RISK DETERMINATION. AND IN MANY CASES THESE BIOMARKERS WE SEE ARE SELECTION BIOMARKERS FOR ENROLLMENT ON A TRIAL. IN TERMS OF LOOKING AT THE RISK BENEFIT OF THESE, WITH CANCERS THAT ARE INCURABLE, WE LOOK AT THE RISK OF SELECTION BIOMARKERS WITHIN THE CONTEXT OF THE DISEASE, THERAPIES AND PATIENT POPULATION BEING STUDIED. SOME PATIENTS MAY HAVE NO ACCEPTABLE ALTERNATIVE THERAPIES THAT PROVIDE MEANINGFUL BENEFIT. OR PATIENTS WHO DO COULD DELAY SUCH THERAPIES UNTIL AFTER A CLINICAL TRIAL. THE ACCEPTABILITY OF ANY SUCH BIOPSY IS REALLY DEPENDENT ON PATIENTS BEING ADEQUATELY CONSENTED AS TO THE RISKS AND BENEFITS OF A PROCEDURE. WE TYPICALLY REQUEST AND REVIEW THE INFORMED CONSENT DOCUMENT DURING IND SAFETY REVIEW TO ENSURE THAT THE RISKS ARE ADEQUATELY DISCLOSED. SO THAT IS ALL I WANTED TO GO OVER. I JUST WANTED TO ACKNOWLEDGE THE FOLLOWING PEOPLE AND PROVIDE OUR CONTACT INFORMATION IF YOU HAD ANY FURTHER QUESTIONS. THANK YOU. >> THANK YOU. >> MICHELLE, DO WE STILL HAVE YOU? MICHELLE ARE YOU THERE? ALL RIGHT. I'M GOING TO SHOOT HER AN E-MAIL AND SHE SEEMS TO BE HAVING ISSUES. AT THE SAME TIME, DR. MARK RATAIN WOULD YOU LIKE TO PROCEED? >> WOULD BE HAPPY TO. WELL, THANK YOU. LET ME FIRST INTRODUCE MYSELF. I'M MARK RATAIN. I'M A MEDICAL ONCOLOGIST AND CLINICAL ONCOLOGIST AT THE UNIVERSITY OF CHICAGO. AND I SPEND MOST OF MY CAREER IN DRUG AND DIAGNOSTIC DEVELOPMENT. AND MOST OF MY CAREER DOING EARLY CLINICAL TRIALS ESPECIALLY PHASE ONE TRIALS. I'VE ALSO STUDIED THE ETHICS OF PHASE ONE CLINICAL TRIALS LARGELY COLLABORATION WITH CHRIS DOHERTY OUR IOB CHAIR. SO I'M VERY FAMILIAR WITH THE SCIENTIFIC AND ETHICAL ISSUES AROUND EARLY CLINICAL TRIALS. AND I ALSO WAS VERY INVOLVED IN THE ASCO WORKSHOP THAT YOU'RE GOING TO HEAR ABOUT IN LAURA LEVIT OUR NEXT SPEAKER. AND I VERY MUCH APPRECIATE THE ISSUE OF SKARP DISCUSSING THIS ISSUE, WHICH IS GREAT CONCERN TO ME PERSONALLY FOR MANY YEARS. NOW, YOU HUEARD A LOT ABOUT THE SCIENCE. AND I THINK IT REQUIRES A LITTLE MORE EXPLANATION. AND THERE'S REALLY BEEN -- THERE'S REALLY THREE GENERAL CATEGORIES OF THE HYPOTHETICAL SCIENTIFIC VALUE OF TUM TUMOR BIOPSIES IN ONCOLOGY TRIALS. LET'S START WITH THE FIRST ONE TO DEVELOP A COMPANION DIAGNOSTIC. DR. MEHTA WAS JUST DISCUSSING THAT AND HE WAS DISCUSSING THE POTENTIAL RISK OF THE DIAGNOSTIC. AND JUST TO BE CLEAR, AND THAT WAS THE FIRST INDICATION FOR THE DRUG WAS ENROLLED IN THE TRIAL. AND THE TRIAL HAD MANDATORY BIOPSIES. A MANDATORY BIOPSIES BEFORE TREATMENT AND AFTER TREATMENT. IT W IT WAS COMPLICATED BY RESPIRATOR ARREST AND DEATH 24 HOURS LATER. EVEN THOUGH THE DRUG HAS GONE ON TO DEAD APPROVAL IN BOTH THE U.S. AND EUROPE. THIS PATIENT OBVIOUSLY NEVER HAD A CHANCE TO BENEFIT FROM THE DR DRUG. NOW, LET'S LOOK AT A MORE RECENT STUDY. AND THIS COMES FROM MD ANDERSON CANCER CENTER. A PLACE WITH TREMENDOUS EXPERTISE IN CANCER CLINICAL TRIALS AND INTERVENTIONAL RADIOLOGY. AND THE FIRST AUTHOR OF THE STUDY IS MICHAEL OWNERMAN, A REVIEW OF THE BIOPSY COMPLICATIONS AT MD ANDERSON. AND HE ANALYZE D 745 BIOPSIES OF WHICH 211, 28% OF INTRATHORACIC, 25% INTRAABDOMINAL. AND OTHERS SKIN BIOPSIES OR BREAST BIOPSIESES. IF YOU LOOK AT MAJOR COMPLICATIONS IT DOESN'T LOOK TOO BAD. YOU SEE 6 OUT OF 745. YOU FOCUS IN ON JUST THE INTRA-THOR RASSICK, YOU FIND OUT OF 211, 2%. BUT THEN YOU SEE THE MINOR COMPLICATIONS WHICH ARE STRIKING STRIKINGLY HIGH IN THE SUB POPULATION, AROUND UNDERGOING INTRATHORACIC BIOPSIES, WITH 31 PATIENTS HAVING MINOR COMPLICATIONS. NOW, WHAT ARE THESE MINOR COMPLICATIONS. WELL, TO UNDERSTAND THIS, YOU HAVE TO LOOK AT THE COMMON TOXICITY CRITERIA THAT HAVE BEEN DEVELOPED BY THE NATIONAL CANCER INSTITUTE. SO THERE ARE -- THERE IS SUCH A THING AS A GRADE 1 AND GRADE 2 PNEUMOTHORAX. GRADE 3 SAYS HOSPITALIZATION IS INDICATED AND A GRADE 4 SAYS IT IS LIFE-THREATENING. A GRADE 2 PNEUMOTHORAX IS SYMPTOMAT SYMPTOMATIC AND INTERVENTION IS INDICATED. THIS IS NOT A SNIFFLE AND A GRADE 1 IS SA PNEUMOTHORAX THAT IS ASYMPTOMATIC AND ONLY REQUIRES OBSERVATION, OBSERVATION TO MAKE SURE IT DOESN'T BECOME LIFE-THREATENING. SO THIS IS VERY DIFFERENT THAN OTHER GRADE 1 AND 2 TOXICITIES. MOST IRB'S AND ONCOLOGISTS HEAR ABOUT GRADE 1 AND 2 TOXICITIES WE THINK OF MILD TO MODERATE SYMPTOMS. IN FACT, RIGHT UNDER THESE ADVERSE EVENTS IN THE CHART, ARE POST NASAL DRIP AND SNEEZING. AND SO A SYMPTOMATIC PNEUMOTHORAX HAS THE SAME DEGREE OF SEVERITY AS MODERATE SNEEZING OR MODERATE POST NASAL DRIP REQUIRING PRESCRIPTION OR SOME INTERVENTION SUCH AS AN ANTIHISTAMINE DROP. THERE'S A LITTLE DISPARITY IN THE GRADING THAT MAKES THIS A LITTLE CONFUSING. BUT WHEN YOU READ THE OBERMAN PAPER, YOU SEE 17% OF PATIENTS HAD COMPLICATIONS. 34 PNEUMOTHORAX, ONE SUBCUTANEOUS EMSPEAKSEMIA AND ONE INTUBATION AND 9% OF CHEST TUBES. IF THIS WERE A DRUG DELIVERED TO PATIENTS WITH THIS COMPLICATION RATE THIS WOULD ONLY BE ACCEPTABLE IF IT WAS A VERY HIGHLY EFFECTIVE DRUG. SOMETHING SUCH AS CARD T CELL THERAPY RELEADING TO SITO CONDO RELEASE SYNDROME. BUT NOW WE'RE TALKING ABOUT DRUGS BEING ADMINISTERED TO PATIENTS OF UNKNOWN BENEFIT AND REGARDLESS OF THE DOSE OF THE DRUG AND THE EFFICACY OF THE DRUG IF YOU UNDERGO AN INTRATHORACIC BIOPSIES YOU'RE UNDERGOING 17% RISK OF COMPLICATIONS AND 4 TO 3, FOUR BIOPSIES SCIENTIFIC PURPOSES OF THE STUDY, THE RISK IS OBVIOUSLY EVEN HIGHER. AND THEN THE INCREMENTAL KNOWLEDGE FROM EXPLORATORY BIOPSIES HAS BEEN INFREQUENT. AGAIN YOU HEARD DR. IVY'S PRESENTATION WHERE HE HIGHLIGHTED TWO CONTRIBUTIONS FROM THE NCI TRIALS WHERE SHE EXPLAINED HOW THE BIOPSIES INFORMED WHY THERAPIES DIDN'T WORK WE DID AN ANALYSIS THAT WE PUBLISHED IN 2016 OF ALL PHASE 1 CLINICAL TRIALS IN WHICH THERE WAS POST TREATMENT BIOPSIES DURING THE PERIOD 2003 TO 2010. WE FOUND 72 STUDIES IN THE LITERATURE, THIS IS IN PUB MED. OF COURSE IT WOULD BE UNPUBLISHED STUDIES AS WELL. AND WE COUNTED UP THE BIOPSIES IN THESE 72 STUDIES THERE WERE MORE THAN 1800 BIOPSIES THAT WERE REPORTED FOR SOME OF THEM THE EXACT NUMBER NOT KNOWN SO THIS IS A MINIMUM ESTIMATE. THIS WAS OVER A 8 YEAR PERIOD. AND THERE WERE 12 SIGNIFICANTLY BIOMARKER RESULTS MANY OF THE STUDIES LOOKED AT BIOMARKERS. SO 12 RESULTS MET THE CRITERIA FOR STATISTICAL SIGNIFICANCE. AND OF THE 12 BIOMARKER RESULTS THEY INCITED IN 54 ARTICLES FIVE OF THE 12 BIOMARKERS HAVE BEEN CITED. AND THE BIOMARKERS NEVER CITED AS THE BASIS FOR DOSE OR SCHEDULE SELECTION. SO, IN FACT, NOT ONLY IS INCREMENTAL KNOWLEDGE BEEN INFREQUENT BUT IN FACT THE IMPACT ON SUBSEQUENT DRUG DEVELOPMENT WAS 0 IN THIS ANALYSIS THAT WE CONDUCT. AND AGAIN IT WAS LIMITED TO THE 2003, 2010 PERIOD. SO IT LEADS THE QUESTION, WHAT SHOULD IRB'S DO AND HOW CAN IRB'S ASSESS THE RISK AND SOCIETAL BENEFIT OF THESE BIOPSIES. SO FROM THE STAND POINT OF RISK, ARE THE BIOPSIES LIMITED TO SKIN AND SOFT TISSUE OR DO THEY INCLUDE HIGHER RISK BIOPSIES ESPECIALLY INTRATHORACIC. ARE THE BIOPSY METHODS CONSISTENT WITH USUAL CLINICAL PRACTICE OR ADDITIONAL RISKS? SUCH AS ADDITIONAL PASSES REQUIRED. IS THERE A PROCESS FOR EXCLUDING POTENTIAL PARTICIPANTS WITH UNACCEPTABLE BIOPSY RISK PRIOR TO INFORMED CONSENT AT THE CLINICAL TRIAL? BECAUSE IF NOT, THE PATIENTS SIGN UP FOR THE TRIAL AND THEN FIND THEMSELVES DOWN IN INTRAVENTIONNAL RADIOLOGY GETTING CONSENTED FOR THE BIOPSY THAT RADIOLOGY GISTS MAY BE CONCERNED, FOR EXAMPLE, THAT THE PATIENTS HAVE GONE THIS FAR THEY NEED TO GO AHEAD. IF I WERE TO COME UP WITH AN ANALOGY, IT WAS YOU JUST SPENT AN HOUR AT THE GROCERY STORE AND YOU GET TO THE CHECK-OUT LINE AND YOU FIND A 20% SURCHARGE ON YOUR BILL AND YOU FIND OUT THAT IS FOR MANDATORY PURCHASE OF LOTTERY TICKETS IN ADDITION TO YOUR BILL AND YOU'RE TOLD, WELL, YOU MIGHT WIN, THAT'S WHY WE'RE BILLING YOU FOR THIS. AND YOU ARE GIVEN LOTTERY TICKETS THAT YOU DIDN'T WANT. AND THEN FINALLY, WHAT IS THE HISTORICAL COMPLICATION RATE OF RESEARCH BIOPSIES AT THE INSTITUTION? SO THE IRB'S CAN MAKE THIS ASSESSMENT. I THINK THAT IF GIVEN THE DATA, AND THE METHODS, I THINK THE IRB'S ARE ABLE TO MAKE THIS ASSESSMENT. THESE ARE THE KINDS OF ISSUES IRB'S ARE USED TO DEALING WITH, IF GIVEN THE INFORMATION. I THINK THESE -- THE BENEFIT SIDE IS MUCH MORE COMPLICATED, AS DR. NADLER HAS INDICATED. ONE, WILL THE DATA BE MADE PUBLICLY AVAILABLE IN A TIMELY MANNER. THAT WOULD CERTAINLY BE A CRITERIAION FOR SOCIAL BENEFIT. ARE THE SCIENTIFIC METHODS SOUND? YOU SEE INCREMENTAL SCIENTIFIC VALUE OF THE BIOPSIES WELL ARTICULATED AS SUBSTANTIVE? IS THE SCIENTIFIC VALUE THE BIOPSIES INDEPENDENT THE PRIMARY OBJECTIVE OF THE STUDY. LET ME TAKE YOU THROUGH THESE. SO YOU UNDERSTAND THE COMPLEXITY OF THESE QUESTIONS. SO WILL THE DATA BE MADE PUBLICLY AVAILABLE? WELL, IF IT IS A PRIMARY OR SECONDA SECONDARY OBJECTIVE, YES, IN THEORY, IF IT IS A EXPLORATORY OBJECTIVE, THE ANSWER IS GENERALLY NO. ALTHOUGH COMPANIES ARE NOW REQUIRED TO PUT PHASE ONE TRIALS AND CLINICAL TRIALS.GOV THEY GENERALLY DO FOR THE PURPOSE OF PUBLIC SIZING THE TRIAL BUT THE RESULT OF EXPLORATORY OBJECTIVES ARE NOT REQUIRED TO PUT INTO CLINICAL TRIALS.GOV AND THEN SPONSORS USE THE LOOPHOLE FOR LACK OF A BETTER TERM TO BURY THE DATA OF RELATED TO BIOPSIES. ARE THE SCIENTIFIC METHODS SOUND? WELL, IF IT IS WELL DETAILED IN THE DOCUMENTS AND ACCOMPANIED BY INDEPENDENT SCIENTIFIC REVIEW AND INDEPENDENT OF THE SPONSOR AND THE BI AND DR. NADLER HAS SUGGESTED SOMETHING SIMILAR, YES. IF THEY'RE -- IF THE DETAILED METHODS ARE IN THE LABORATORY MANUAL WHICH IS NOT AVAILABLE TO THE IRB AND NO SCIENTIFIC REVIEW IS AVAILABLE, NO. IS THE INCREMENTAL SCIENTIFIC VALUE THE BIOPSIES WELL ARTICULATED AND SUBSTANCE. THIS IS A SCIENTIFIC QUESTION THAT REQUIRES AN INDEPENDENT SCIENTIFIC REVIEW. OFTEN YOU SEE LANGUAGE IN THE PROTOCOL THAT IT IS EITHER JUST EXPLORATORY OR THAT IT IS STATED IN STIATISTICAL LANGUAGE. THAT IT HAS THE POWER TO DETECT THE DEVATION IN BIOMARKER X. IT MAY HAVE THAT POWER BUT IT IS UNCLEAR WHAT THE VALUE OF THAT BIOMARKER IS AND WHAT A 0.75 STANDARD DEVIATION DIFFERENCE MEANS. I THINK YOU SEE A LOT OF PROTOCOLS WRITTEN WITH THIS KIND OF STATISTICAL PLAN AND THEN QUITE FRANKLY UN INTERPRINTERPRETTAL NOT ONLY A MEMBER BUT SOMEONE WITH YEARS OF EXPERIENCE IN EARLY CLINICAL TRIALS AND ONCOLOGY. FINALLY IS THE SCIENTIFIC VALUE OF THE BIOPSIES INDEPENDENT OF THE PRIMARY OBJECTIVE OF THE STUDY? IT IS A SCIENTIFIC QUESTION THAT REQUIRES SCIENTIFIC REVIEW. MORE OFTEN YOU SEE SOMETHING TO THE AFFECT OF WE LIKE TO CORRELATE BIOMARKER FINDINGS WITH THERAPEUTIC SUCCESS. IN FACT, MANY CLINICAL TRIALS TYPICALLY THOSE RUN BY THE COOPERATIVE GROUPS TALK ABOUT CORE RELATIVE SCIENCE WHICH MEANS HAVE YOU TO SEE THERAPY THERAPEUTIC SUCCESS IN ORDER TO HAVE ANY CHANCE WHATSOEVER OF SCIENTIFIC SUCCESS OF THE BIOPSIES. IF YOU'RE DEALING WITH A TRIAL OF A NEW DRUG AND HAVE NO IDEA WHETHER YOU WILL EVER SEE THERAPEUTIC SUCCESS, IT IS FAIRLY FARFETCHED TO THINK THAT THESE BIOPSY RESULTS WILL HAVE SCIENTIFIC VALUE FROM THE PURPOSE CORRELATED TO THE PATIENT. SO HERE ARE MY SUGGESTED TO SAC SACRP. I'M NOT A MEMBER OF THE COMMITTEE. I WAS ASKED BY MICHELLE TO COME UP WITH SUGGESTIONS. ONE, ALL REQUIRE INDEPENDENT REVIEW, PRIOR TO DECISION, THAT ADDRESSES THE SCIENCE STATISTICAL METHODS AND B THE INCREMENTALS OF THE BIOPSIES. ONLY TALKING ABOUT MANDATORY BIOPSIES. I V HAVE HAVE NO OBJECTION TO OPTIONAL BIOPSIES AND NO CONCERN OF OPTION OPTIONAL BIOPSIES, ALTHOUGH IT WOULD BE NICE TO CLEAR INDICATION OF THE PATIENT. TWO, ALL MUST DIRECTLY RELATE TO ONE PRIMARY OR SECONDARY OBJECTIVE. SO IF YOU CAN'T FIND ANY EVIDENCE OF THAT, THERE'S NO SOCIAL VALUE IN IT. AND AN EASY DECISION IN THEORY FOR THE IRB IF IT IS ONLY EXPLORATORY, IT CAN'T BE MANDATORY. AND THEN FINALLY AND I THINK HAD HAD -- THINK THIS IS AN IMPORTANT ONE AND SOME INSTITUTIONS DO THIS BUT NOT NECESSARILY BECAUSE OF THE IRB. ALL DIRECT COMPLICATIONS IN RESEARCH BIOPSIES MUST BE TRACKED TO THE INSTITUTIONAL LEVEL AND REPORTED TO THE IRB OF RECORD. IDEALLY THESE WOULD ALSO BE REPORTED TO THE SPONSOR AND IDEALLY ALSO REPORTED TO THE FDA. BECAUSE THEY ARE COMPLICATIONS OF THE CLINICAL TRIAL. BUT CERTAINLY THE IRB NEEDS THIS FOR THE PURPOSE OF ASSESSING RISK OF ONGOING STUDIES AS WELL AS RISKS OF FUTURE STUDIES. SO THANK YOU FOR YOUR ATTENTION. AND I LOOK FORWARD TO YOUR QUESTIONS. >> GREAT. THANKS SO MUCH, MARK. CAN YOU ALL HEAR ME? CAN YOU HEAR ME, MARK? ANYBODY? >> YES. >> BECAUSE I KNOW I GOT DROPPED OFF BEFORE. SO OUR NEXT SPEAKER IS LAURA LEVIT. LAURA, ARE YOU HERE? I SEE YOU. >> I'M HERE. I'M JUST -- >> LAURA DIRECTOR OF RESEARCH AND ANALYSIS AND PUBLICATIONS AT THE AMERICAN SOCIETY FOR CLINICAL ONCOLOGY, ASCO. AND SHE'S GOING TO TALK TO US AGAIN ABOUT THIS ISSUE AND THE ASCO PUBLICATION. LAURA IT IS ALL YOURS. >> THANK YOU MICHELLE AND THANK YOU SACHRP FOR HAVING ME TODAY. AS MICHELLE SAID, I'M GOING TO DISCUSSING A FRAMEWORK, FOR ONCOLOGY CLINICAL TRIALS. AND JUST AS A DISCLAIMER, MY BACKGROUND IS IN LAW, NOT IN MEDICINE. BUT I WAS THE STAFF LEAD ON THE GROUP THAT DEVELOPED THIS FRAMEWORK. SO ASCO'S CONCERN RELATED TO RESEARCH BIOPSIES STEM FROM THE FACT THAT THESE BIOPSIES AS WE HEARD ARE INCREASINGLY COMMON IN ONCOLOGY CLINICAL TRIALS. AND THEY'REs THERE'S CONCERN ABOUT WHETHER THERE'S A SCIENTIFIC JUSTIFICATION FOR THE BIOPSIES LIKE MARK WAS JUST SAYI SAYING, IS THE SCIENCE FEASIBLE, IS IT IMPORTANT? ASCO HAS MANY CONCERN OF THE SAFETY OF THE BIOPSIES AND WHETHER THE RISKS ARE BEING MINIMIZED OR EVEN ASSESSED AND THEN ISSUES OF INFORMED CONSENT RELATED TO MANDATORY BIOPSIES AND THE POTENTIAL FOR UNDUE INFLUENCE. SO ASCO'S PROCESS FOR DEVELOPING THE FRAMEWORK THAT I'M GOING TO PRESENT, WE STARTED BY COLLABORATING WITH THE FDA TO HOST A STAKEHOLDER MEETING. IT WAS AN INTERNAL INVITATION MEETING THAT ASCO AND THE GOALS IN MEETING WERE TO IDENTIFY WHAT THE SCIENTIFIC ETHICAL ADMINISTRATIVE CONCERNS RELATED TO RESEARCH BIOPSIES. AND WE PULLED TOGETHER RESEARCHERS, PATIENT ADVOCATES, BIO HE IS CITY CYSTS REPRESENTS FROM THE INDUSTRY AND REGULATORS AND FOLLOWING THE MEETING ASCO PUT TOGETHER TASK FORCE AND THEIR CHARGE WAS TO DEVELOP THE FRAMEWORK IF HOW WHEN RESEARCH BIOPSIES SHOULD BE INCLUDED IN CLINICAL TRIALS. SO QUICKLY I WANTED TO RECOGNIZE THE TASK FORCE MEMBERS. LED BY MARK RATAIN, WHO WE JUST HEARD FROM, BUT ALSO INCLUDED THE OTHER PEOPLE LISTED HERE, WHICH INCLUDED EXPERTISE IN ETHICS, INTERVENTIONAL RADIOLOGY AND A PATIENT REPRESENTATIVE. AND THE WORK OF THIS GROUP WAS PUBLISHED IN AN ASCO RESEARCH STATEMENT IN THE JOURNAL OF CLINICAL ONCOLOGY IN 2019. AND THIS STATEMENT IS REALLY GOING TO FORM THE BASIS OF MY REMARKS TODAY. SO THE ASSUMPTIONS THAT ASCO MADE IN DEVELOPING ITS FRAMEWORK WERE THAT WE NEED DIFFERENT GUIDELINES BASED ON THE SCIENTIFIC CONTRIBUTIONS OF THE BIOPSIES. I THINK WE HAVE HEARD A LOT ABOUT THIS. BUT THE RULES SHOULD BE DIFFERENT FOR BIOPSIES THAT SUPPORT EXPLORATORY ANALYSIES VERSUS SECONDARY END POINTS VERSUS PRIMARY END POINTS OR END POINTS FOR STRATIFICATION OF THE TRIAL. WE THINK THERE NEEDS TO BE DIFFERENT GUIDELINES BASED ON THE TIMELINE OF SIGNIFICANT RISKS. RISK BY THE SITE OF THE BIOPSY, THE SKILL, THE INSTITUTION AND CLINICIAN PERFORMING, MANY THINGS. AND THEN WE THINK THAT THERE NEEDS TO BE DIFFERENT GUIDELINES FOR OPTIONAL VERSUS MANDATORY BIOPSIES. AND WE DEFINE OPTIONAL BIOPSIES AS THOSE THAT ARE NOT A CONDITION OF ENROLLMENT IN THE STUDY. THIS MEANS THAT PATIENTS COULD ENROLL IN THE STUDY AND RECEIVE THE INVESTIGATIONAL TREATMENT BUT NOT GET THE BIOPSY. VERSUS MANDATORY BIOPSIES WHERE THEY DID HAVE -- PATIENTS DO HAVE TO AGREE TO THE BIOPSY TO ENROLL IN THE STUDY. >> LAURA. I'M SO SORRY. THIS IS JULIA. WE'RE SEEING A GRAY BOX ON THE SCREEN. WHICH I BELIEVE YOU'RE SEEING AS THE PARTICIPANT'S PANEL. CAN YOU JUST MOVE THAT OUT OF THE FIELD OF VIEW. THERE YOU GO. MUCH BETTER. >> IS THAT BETTER? >> YES. I THINK SO. THANK YOU. >> SURE. OKAY. SO THE NEXT TWO SLIDES PRESENT ASCO'S GENERAL RULES FOR OPTIONAL AND MANDATORY BIOPSIES AND THESE LOOK SIMILAR TO WHAT CHRISSY IVY PRESENTED I THINK THE RULES ARE DIFFERENT I THINK MAYBE SHE TOOK THE SLIDE AND MODIFIED IT. THESE ARE THE ACTUAL WHAT ASCO RECOMMENDED. WE DECIDED FOR OPTIONAL BIOPSIES THAT THEY ALWAYS ARE ACCEPTABLE. THE IDEA HERE IS THAT COMPETENT ADULTS CAN DECIDE WHETHER THEY WANT TO CONSENT TO RESEARCH BIOPSIES OR NOT. WHERE THE RISK TO -- WHERE THE RISK TO THE PARTICIPANTS WAS HIGH, SO THE BOTTOM ROW, WE THOUGHT THIS DID REQUIRE AN EXTRA LEVEL REVIEW EITHER BY REGULATORS OR IRB'S. LOOKING AT THE STUDY DESIGNED THE CONSENT FORMS. AND THE EXCLUSION CRITERIA, TO MAKE SURE THEY'RE -- THE RISK TO -- RISK TO PARTICIPANTS IS MINIMIZED TO THE EXTENT POSSIBLE. MY SCREEN SEEMS TO BE FROZEN NOW. SO THEN THIS TABLE LOOKS -- BUT IT IS THE FOR MANDATORY BIOPSIES. HERE AGAIN, THE ASCO FRAMEWORK RAISE THE RISK TO THE PARTICIPANT FROM THE BIOPSIES AGAINST THE UTILITY TO THE SOCIETY. I'M GOING TO TALK THE EXPECTED UTILITY TO SOCIETY. SO RESEARCH BIOPSIES THAT SUPPORT PRIMARY END POINTS. THE FRAMEWORK FOUND THAT OR PARTICIPANT SAYS THAT THEY'RE ALWAYS ACCEPTABLE. BUT WHERE THE RISK TO PARTICIPANTS IS HIGH, THAT, AGAIN, THE NEXT LEVEL REVIEW BY IRB'S AND REGULATORS IS IMPORTANT. AND THEN THE MIDDLE COLUMN WHERE THE EXPECTED UTILITY TO SOCIETY IS POTENTIAL, SUCH AS FOR SECONDARY END POINTS, WE THOUGHT THAT THE -- THEY'RE ACCEPTABLE WHERE THE RISK IS LOW, WHERE THE RISK IS MODERATE, THERE SHOULD BE AN EXTRA LEVEL OF REVIEW AND THEY SHOULD NOT BE DONE WHERE THE RISK IS HIGH TO THE PARTICIPANT. AND THEN FOR UNKNOWN OR EXPLORATORY BIOPSIES, WE THOUGHT THAT THEY SHOULD NOT BE DONE AT ALL, WHERE THERE'S MODERATE OR HIGH RISK TO THE PARTICIPANT AND EVEN WHERE THE RISK IS LOW, THERE SEEMS TO BE AN EXTRA LEVEL OF REVIEW. SO IN ADDITION TO THE FRAMEWORK I JUST PRESENTED ASCO ALSO CAME UP WITH A NUMBER OF RECOMMENDATIONS DIRECTED AT SPECIFIC STAKEHOLDERS WITH SOME SUGGESTIONS HOW TO IMPROVE THE ETHICS OF RESEARCH BIOPSIES. AND I'M GOING TO QUICKLY GO THROUGH THOSE BECAUSE I THINK THERE MIGHT BE SOME RELEVANT IDEAS FOR SACHRP TO CONSIDER AS THEY WORK ON THIS ISSUE. THEY ORGANIZED THREE GOALS FOR IMPROVING THE ETHICS OF RESEARCH BIOPSIES. THESE ARE MAXIMIZE D SCIENTIFIC UTILITY, MINIMIZE PARTICIPANT RISK, AND IMPROVE OVERSIGHT OF RESEARCH BIOPSIES. SO THE FIRST TWO RECOMMENDATIONS RELATE TO MAXIMIZING SCIENTIFIC UTILITY. SO RECOMMENDATION ONE PRESENTED HERE IS TO IMPROVE THE SCIENTIFIC RATIONALNAL FOR CONDUCT DURING RESEARCH TRIALS. HERE WE ASKED THAT INVESTIGATORS INCLUDE STATISTICAL ANALYSIS PLANS FOR ALL SECONDARY OBJECTIVES WE THOUGHT MORE INFORMATION COULD BE PROVIDED BY INVESTIGATORS RELATED TO BIO BANKING HOW IT IS STORED, ARCHIVED, HOW THE DATA WILL BE SHARED AND THE JUSTIFICATION WHY THE BIOMARKER MIGHT THINK IT LEAD TO SOMETHING BENEFICIAL. WE CALLED FOR SCIENTIFIC REVIEW COMMUNITIES AND IRB'S TO INCLUDE MORE EXPERTISE IN THE SPECIALTIES NECESSARY TO EVALUATE RESEARCH BIOPSIES. SO THIS MAY INCLUDE PATHOLOGY GISTS AND INTERGENERALIZATIONNAL RULI RULINGISTS AND THEN ADDRESSED THE ISSUE OF MUCH OF THE DETAILS OF RESEARCH -- ARE AVAILABLE IN THE MANUALS. WE ASKED THAT SPONSORS INCLUDE THESE LAB MANUALS AS PART OF THE TRIAL PROTOCOL SO THAT THE INFORMATION ABOUT RESEARCH BIOPSIES CAN BE REVIEWED BY IRB'S AND OTHERS. AND THEN THE INSTITUTIONS THAT CONDUCT RESEARCH BIOPSY SHOULD CONDUCT STANDARD OPERATING PROCEDURES FOR THEIR LABORATORIES. RECOMMENDATION 2 ALSO RELATES TO MAXIMIZING SCIENTIFIC UTILITY. THIS RECOMMENDS THE TARGET TO BETTER TARGET THE PUBLISH AND DISSEMINATE RESEARCH INFORMATION. WE CALLED ON JOURNALS TO -- ON THE NUMBER COMPLICATIONS, SUCCESS RATE AND RESULT OF THE BIOPSIES, THE METHODS THAT THEY USED TO DO THE BIOPSIES AND THEN WHEN THEY PUBLISH THE CLINICAL TRIAL PROTOCOLS TO INCLUDE THE LAB MANUAL. RECOMMENDATIONS 3 AND THE NEXT SEVERAL RECOMMENDATIONS RELATE TO MINIMIZING PARTICIPANT RISK. THE SECOND GOAL OF THE RECOMMENDATIONS. AND THIS RECOMMENDATION CALLS FOR DEVELOPING AND PROMOTING BEST PRACTICES IN THE CONDUCT OF RESEARCH BIOPSIES. 38 TARGET SPONSORS INVESTIGATORS AND ASKED THEM TO DESIGN TRIALS THAT MINIMIZE THE TISSUE REQUIRED, USES THE SAFEST PROCEDURES TO COLLECT SUFFICIENT TISSUE TO MEET THE RESEARCH OBJECTIVES, DEVELOPS THE APPROPRIATE ELIGIBILITY CRITERIA FOR THE BIOPSIES AND THEN TRACKS THE ADVERSE EVENTS THAT RESULT FROM THE BIOPSIES. SIMILARLY 3B RELATES TO BEST PRACTICES, AGAIN, IN CONDUCTING RESEARCH BIOPSIES, BUT TARGETS THE INSTITUTIONS. THAT IN TRIALS THAT INCLUDE RESEARCH BIOPSIES AND WE THOUGHT THAT INSTITUTION SHOULD INCLUDE CLINICAL GUIDELINES. REQUIRE PREVIOUS COLLECTED SAMPLES WHEN AVAILABLE OR SAMPLES BE TAKEN AT THE SAME TIME AS CLINICAL PROCEDURES. THOUGHT THAT MORE INFORMATION SHOULD BE PROVIDED TO PROCEDURALISTS ABOUT STUDY GOALS, RESEARCH NEEDS AND RESEARCH TISSUE REQUIREMENTS. AND THAT INSTITUTIONS HAVE A RESPONSIBILITY TO ENSURE THAT A TRAINING AND SKILL OF CLINICIAN PERFORMING THE RESEARCH BIOPSIES. RECOMMENDATION FOR, AGAIN, ALSO RELATES TO MINIMIZING PARTICIPANT RISK. HERE WE'RE CALLING FOR BETTER COLLECTION OF SERIOUS ADVERSE EVENTS FROM RESEARCH BIOPSIES. AND REALLY WE THOUGHT THAT RESEARCH BIOPSIES SHOULD BE TREATED ADVERSE EVENTS FROM RESEARCH BIOPSIES SHOULD BE TREATED TO OTHER SERIOUS ADVERSE EVENTS IN CLINICAL TRIALS SO WE CALLED ON REGULATORS TO CONSIDER SAE STUDY RELATED AND THAT SPONSOR SHOULD REQUIRE PARTICIPATING INVESTIGATORS TO REPORT TO THEM SERIOUS ADVERSE EVENTS THAT RESULT FROM THE RESEARCH BPTSIOPSIES. RECOMMENDATION NUMBER FIVE RELATES TO MINIMIZING THE PARTICIPANT RISK. THIS RECOMMENDATION CALLS FOR IMPROVING THE INFORMED CONSENT PROCESS FOR TRIALS WITH RESEARCH BIOPSIES. WE HAVE RECOMMENDATIONS FOR MANDATORY BIOPSIES. WE THOUGHT THAT INFORMED CONSENT FORMS COULD DO A BETTER JOB OF DEFINING THE CONDITIONS FOR PARTICIPANTS IDENTIFYING RISK. AND THEN MAKING VERY CLEAR, FOR NOT IN A GIRL'S RESEARCH BIOPSIES THERE'S NO CLINICAL BENEFITS FOR THE PARTICIPANTS. AND THEN FOR INFORMED CONSENT FOR OPTIONAL BIOPSIES, WE THOUGHT THAT THESE COULD DO A BETTER JOB MAKING IT CLEAR THAT THE BIOPSIES ARE OPT IN CH. AND FINALLY THE SIXTH RECOMMENDATION THAT ASCO MADE RELATES TO IMPROVING THE OVERSIGHT OF RESEARCH BIOPSIES AND HERE THERE MIGHT BE SOMETHING PARTICULARLY RELEVANT TO SACHRP. SO FIRST -- AS WE HEARD THE FDA AND OTHER REGULATORS WHEN THEY ARE REVIEWING NEW IUD'S ISSUES STUDIES MAY RECEIVE LETTERS AND WE THOUGHT THE LETTER COULD DOCUMENT WHETHER THE RESEARCH BIOPSY WAS REVIEWED. I THINK WE HEARD THAT LIKELY THIS IS ONLY -- IF THEY ARE ONLY RENEWED, IF THEY'RE SELECTION BIOMARKERS, NOT OTHER TYPES OF BIOMARKERS. AND THIS NEEDS TO CLEAR IN EVERYBODY IN THE PROCESS WHAT THE FDA ACTUALLY LOOKED AT. WE THOUGHT THAT SCIENTIFIC REVIEW COMMITTEES SHOULD REVIEW THE SCIENTIFIC OF RESEARCH BIOPSIES AND MAKE SURE THE INFORMATION IS PROVIDED TO THE IRB'S AND IN THEIR REVIEWS OF THE STUDY. IRB'S SHOULD REVIEW SAFETY AS PART OF THE OVERALL REVIEW OF THE PROPOSED RESEARCH STUDY. I THINK WE HEARD THAT IRB'S HAVE THE JURISDICTION TO DO THIS. WE'RE JUST ASKING FOR A MORE ROBUST REVIEW HERE. AND THAT PERHAPS HARDSHIP ISSUE GUIDANCE OW IRB'S COULD REVIEW HIGH RISK BIOPSIES. SO IN CONCLUSION, I THINK RELEVANT TO TODAY, IT WOULD BE GREAT IF OHARP ISSUED -- HOW TO REVIEW BIOPSIES. I THINK THAT IRB'S SHOULD TAKE A CLOSE LOOK AT RESEARCH BIOPSIES AS THEY LOOK AT STUDIES. AND I THINK MAYBE THE TABLES WITHIN THE ASCO FRAMEWORK COULD PROVIDE GUIDANCE TO THEM HOW TO WEIGH THE BENEFITS AND RISKS TO THE BIOPSIES. THEY SHOULD HAVE THE APPROPRIATE EXPERTISE AVAILABLE TO UNDERSTAND THE RISKS AND BENEFITS OF RESEARCH BIOPSIES SO MAYBE INCLUDING RADIATION ONCOLOGIS ONCOLOGISTS, OR AT LEAST HAVING EXPERTS AVAILABLE TO CONSULT AS NEEDED. IRB SHOULD MAKE SURE THEY GET THE LAB MANUALS AS PART OF THE TRIAL PROTOCOLS. THE DETAILS OF THE RESEARCH BIOPSIES ARE SOUGHT OUT IN THESE DOCUMENTS. I THINK THERE'S ROOM FOR IRB'S TO LOOK MORE CLOSELY AT THE CONSENT FORMS THAT ARE ALLOWING RESEARCH BIOPSIES TO PROCEED ONE POTENTIALLY TO LOOK AT THE TEMPLATE RELATED TO RESEARCH BIOPSIES. AND THEN AS I MENTIONED THE FDA CAN MAKE IT CLEAR IN THEIR STUDY WHETHER OR NOT THEY EVEN LOOKED AT THE RESEARCH BIOPSY. WITH THAT, I'LL THANK YOU FOR YOUR ATTENTION AND WRAP UP. >> HI LAURA. THIS IS MICHELLE. MY VIDEO DOESN'T SEEM TO BE WORKING. CAN YOU HEAR ME? >> YES. I CAN HEAR YOU. >> OKAY. SO WHY DON'T WE OPEN IT -- THANK YOU VERY MUCH. AND THANK YOU TO ALL OF OUR OTHER PANELISTS -- AHH, THERE I AM. WE CAN TAKE QUESTIONS NOW. SO DOES ANYBODY HAVE QUESTIONS FOR OUR PANELISTS? >> THIS IS JANUAEJANET. THANK YO EXCUSE ME. SO I'M NOT QUITE SURE WHO TO ADDRESS THIS TO. BUT ONE OF THE ISSUES THAT COMES UP, IS RELATED TO A COMMENT THAT WAS MADE ABOUT IRB'S MAY NOT HAVE ACCESS TO THE SCIENTIFIC KNOWLEDGE TO BE ABLE TO VET A PARTICULAR BIOPSY. AND THIS IS COMPLICATED IN THE CASE OF BASKET TRIALS FOR RARE DISEASES, WE HAVE HAD CASES WHERE THE PI AT A PARTICULAR FACILITY IS A SPECIALIST IN ONE TYPE OF CANCER THAT IS BEING TESTED BUT NOT THE OTHERS. AND THE PATIENT WILL HAVE ISSUES THAT DEVELOP AND THAT PI IS NOT AWARE OF HOW THAT PATIENT MIGHT BE IMPACTED. BECAUSE THEY DON'T KNOW THAT PARTICULAR TYPE OF CANCER. FOR INSTANCE, THE PI MIGHT BE A SPECIALIST IN BLADDER CANCER, BUT THE PATIENT IS A LUNG PATIENT. AND THE BIOPSIES CONCERNS ARE DIFFERENT. SO I THINK WE NEED TO ALSO ADDRESS THAT ISSUE. IN TERMS OF A PARTICULAR SITE'S IRB REVIEWING THINGS. >> THANKS JANET. ANYBODY WANT TO MAKE A COMMENT? >> I'M HAPPY TO RESPOND. IT IS NOT CLEAR TO ME WHAT THE QUESTION IS, THOUGH. >> WELL, PERHAPS DON'T UNDERSTAND THE PROCESS. WHEN YOU HAVE GOT A BASKET TRIAL PERHAPS THERE'S A CENTRAL IRB THAT IS DOING THE REVIEW RATHER THAN INDIVIDUAL SCIENCE. BUT IF THE PI HAD A SITE THAT IS NOT FAMILIAR WITH HOW BIOPSY MIGHT IMPACT LUNG CANCER PATIENT BECAUSE THEY SPECIALIZE IN A DIFFERENT TYPE OF CANCER. THE IRB MIGHT THINK THAT THEY HAVE AN EXPERT WHO CAN COMMENT BUT THEY MAY NOT BE FAMILIAR WITH THE IMPACT ON ALL OF THE CANCERS THAT ARE BEING STUDIED BY A PARTICULAR BASKET TRIAL? HOW DO WE ADDRESS THAT? >> I THINK ONCOLOGISTS PEDIATRIC ADULTS, PEDIATRIC ONCOLOGISTS, PEDIATRICI PEDIATRICIANS, BEFORE US. THE RISK OF LIVER BIOPSY, THE RISK OF LUNG BIOPSY CAN BE ASSESSED REGARDLESS IF YOUR SUBSPECIALTY IN ONCOLOGY. >> THANK. SKIP. >> I HAVE A QUESTION. SO I IN THE PRESENTATION BY NCI. AND BY ASCO ON THE SLIDE THAT HAD SORT OF THE SIX BOXES RANKING SORT OF RISK AND BENEFIT AND WHETHER BIOPSIES WERE ACCEPTABLE OR UNACCEPTABLE, I THINK THERE WERE SOME IMPORTANT DIFFEREN DIFFERENCES IN HOW ONE EVALUATED THE TRADE OFF BETWEEN RISK AND THE DEGREE TO WHICH THE INFORMATION WAS INTEGRAL OR IMPORTANT TO THE SCIENTIFIC VALUE OF THE PROTOCOL. AND WHAT I'VE HEARD -- THIS IS LEADING UP TO A QUESTION -- BUT WHAT I HEARD BEHIND THE ASCO PRESENTATION IS THAT THEY BASICALLY MADE THE DECISION THAT A COMPETENT ADULT CAN MAKE A DECISION TO EXPOSE THEMSELVES TO THAT RISK. WHEREAS THE -- NCI RECOMMENDATIONS ACTUALLY LOOKING STRANGELY LIKE THE WAY PEDIATRIC PEOPLE THINK ABOUT RISK, IN TERMS OF MINIMAL RISK, THE LOW RISK, ET CETERA. WHICH DOESN'T NECESSARILY PRIVILEGE CONFORMED -- INFORMED CONSENT. WHAT I'M INTERESTED IN HEARING NOT SO MUCH THE DIFFERENCES IN THE RISK CLASSIFICATION BECAUSE WE CAN ALWAYS UNPACK THAT, BUT WHETHER OR NOT IN THIS AREA IT IS APPROPRIATE, IN FACT, TO ASSUME THAT INFORMED CONSENT OUGHT TO SERVE IN QUITE THAT STRONG A ROLE IN TERMS OF POTENTIAL SUBJECTS FULLY UNDERSTANDING THE IMPLICATIONS OF THE BIOPSIES AND SO ON AND SO FORTH, SHOULD INFORMED CONSENT AS IT APPEARS TO FUNCTION IN THE ASCO RECOMMENDATIONS BE IN THAT STRONG OF A POSITION RELATIVE TO WHAT IS ACTUALLY GOING ON IN THE -- IN THE ACTUAL ENROLLMENT PROCE PROCESS? THAT'S MY QUESTION. >> I'M HAPPY TO TAKE THAT, LAURA. UNLESS YOU -- >> YEAH, I MEAN, I GUESS. I CAN START. I MEAN, THE ASCO COMMITTEE I THINK DID HAVE DISCUSSIONS ABOUT THAT ISSUE. BUT DEFINITELY ENDED UP, AS I PRESENTED ON THE SIDE, THAT INFORMED CONSENT COULD SERVE IN THAT ROLE AND COMPETENT ADULTS COULD DECIDE FOR THEMSELVES WHETHER WHETHER TO TAKE ON THE RISK. I THINK IN THE TABLE I SHARED IT DID SHOW WHERE THE RISK TO PARTICIPANTS IS HIGH, WE ARE ASKING FOR THAT EXTRA LEVEL OF REVIEW LOOKING AT THE STUDY DESIGN, ELIGIBILITY, CRITERIA, AND THE INFORMED CONSENT FORM. SO HOPEFUL THAT WILL WOULD PREVE PREVENT, YOU KNOW, INAPPROPRIATE OPTIONAL BIOPSIES FROM BEING INCLUDED IN TRIAL PROTOCOLS. YOU KNOW, MARK, DID YOU HAVE SOMETHING TO ADD? >> WHAT I WAS GOING TO SAY WAS -- AND THAT I CAME INTO THAT ASCO MEETING FEELING THAT I ALSO HAD CONCERNS ABOUT OPTIONAL BIOPSIES THAT WERE HIGH RISK. AND I WAS CONVINCED BY ACTUALLY THE PATIENT REPRESENTATIVES PRESENT THERE THAT PATIENTS WANTED TO HAVE THE RIGHT TO PARTICIPATE IN BIOPSIES STUDYIES, EVEN OF UNCERTAIN VALUE, THAT IF THERE WAS ANY CHANCE THAT IT COULD BE SCIENTIFICALLY USEFUL, THEY WANTED TO NOT BE PREVENTED HIS FROM DOING SO. SO THAT WAS -- I THINK THAT WAS A VERY STRONG OPINION THAT WAS PRESENTED BY OUR PATIENT REPRESENTATIVES. AND THAT'S HOW IT ENDED UP IN OUR RECOMMENDATIONS. >> I HAVE A COMMENT FROM THE NCI PERSPECTIVE. FIRST OF ALL, I DEVELOPED MY RISK -- IF YOU WILL, BASED ON T THE MATRIX, SO THEY AT LEAST LOOKED SIMILAR FAMILIAR TO PEOPLE. SO IT MIGHT BE EASIER TO COMPARE THE TWO. AND WE DID NOT ADDRESS SO MUCH THE PATIENT CONSENT AND THE WILLINGNESS TO ACCEPT THE RISK. BUT WE'RE ASKING THE QUESTION ABOUT WHETHER THE PROFESSIONAL PLANNING TO PERFORM THE PROCEDURE, THE BIOPSY, FELT THAT THERE WAS A LEVEL OF RISK IN THEIR ABILITY TO OBTAIN THE BIOPSY. NOT THE WILLINGNESS OF A PATIENT TO CONSENT TO THE BIOPSY. BUT THE RISK OF ACTUALLY PERFORMING THE PROCEDURE. SO THAT, I THINK, IS ONE DIFFERENT AND -- DIFFERENCE IN HOW THIS WAS PRESENTED. AND I THINK IT IS ULTIMATELY EASILY RESOLVABLE. I THINK ALL PATIENTS IN THE ENDS WILL CONSENT TO THE PROCEDURE. AND AT THE TIME THEY MAY NOT KNOW -- WHEN THEY PROVIDE CONSENT THEY MAY NOT KNOW THE RISK OF THE BIOPSY IS, BECAUSE THEY WILL NOT HAVE FULLY AND COMPLETELY EVALUATED BY THE INTERVENTIONAL RADIOLOGYIST, FOR EXAMPLE, SO YOU HAVE TO GO BACK AND REDISCUSSED THAT WITH THE PATIENT. BUT THAT ONCE AGAIN TO ME IS A MORE COMPLEX PROCESS. YOU'RE FIRST TALKING ABOUT ABOUT -- BETWEEN THE PERSON WHO IS VYING THE TRIAL AND THE PERSON PERFORMING THE PATIENT AND THE PHYSICIAN PERFORMING THE PROCEDURES AND THEN YOU HAVE TO PRESENT THAT INCREASED RISK TO THE PATIENT AND ASK WHETHER IT IS ACCEPTABLE TO THEM. SO WE MAY DECIDE AS A PHYSICIAN, THIS SEEMS TOO HIGH RISK. AND WE WOULD LIKE TO SUGGEST TO THE PATIENT, THAT, YOU KNOW, THESE ARE ALL OF THE OPTIONS IN FRONT OF THEM, AND THIS MAY BE OUR RECOMMENDATION. SO I AGREE WITH YOU, WE HAVE TAKEN A SOMEWHAT MORE CONSERVATIVE APPROACH,. HAVING SAID THAT, I ALSO THINK THAT A PART OF THIS RELATES BACK TO THE RATHER EXTENSIVE WORK WE DO AND ALSO MAKING SURE THAT THE BIOMARKERS ON OUR STUDY ARE CLEARLY -- FOR THE PURPOSE THEY WERE DESIGNED FOR TO BE USED WITHIN THE STUDY. AND SHOW WE HAVE EXPERT RESEARCH PATHOLOGISTS MOLECULAR BIOLOGISTS AND A NUMBER OF PEOPLE THAT CAN ON EVERY SINGLE BIOMARKER THAT IS GOING TO BE PERFORMED IN A STUDY. AND THEY ACTUALLY REACHED THE CONCLUSION AS INDEPENDENT REVIEWERS THAT THE ASSAY IS, QUOTE, READY FOR THE PRIME TIME, IF YOU WILL. IT WOULD BE ACCEPTABLE AS AS -- WE'LL SAY IN A BIOMARKER, WANTS THEIR PATIENT SELECTION. SO WE HAVE DONE ALL OF THIS. AND IN DOING THAT, IT IS FROM THERE THAT WE MAKE A DETERMINATION ON WHETHER OR NOT WE THINK THE BIOPSY ITSELF SHOULD BE MANDATORY OR OPTIONAL. OR IF IT IS EVEN OF ANY VALUE IN THE YOU HAD IS -- STUDY AT ALL. AND THAT IS A DIFFERENT PROCESS FROM SENDING DOWN THE PATIENT -- THE PATIENT DOWN TO INTERVENTIONAL RADIOLOGY AND ASKING THAT THEY AND THEIR X-RAY BE EVALUATED FOR THE RISK OF OBTAINING THE TISSUE. SO THEY'RE DIFFERENT THINGS AND I THINK PERHAPS WE WOULD BENEFIT FROM SOMEWHAT MORE STANDARDIZED NOMENCLATURE SO WE AREN'T CONFUSING -- OR AT LEAST CONFUSES ME, I'LL PUT IT THAT WAY. THE BIOPSY ITSELF TO ME IS NOT EXPLORATORY. WHAT IS EXPLORATORY IS THE BIOMARKER. THAT IS DETERMINED BY THE CONTEXT OF THE STUDY. SO THAT TO ME IS HOW I PERSONALLY FLUSH THAT OUT. I HOPE THAT ANSWERS YOUR QUESTION. >> YEAH, I DON'T KNOW IF THIS IS HELPFUL BUT THE ASCO STATEMENT IS FOCUSED ON REVIEWING THE TRIAL DESIGN. BUT WE DO NOTE IN THE STATEMENT THAT YOU HAVE TO ASSESS THE RISK OF THE BIOPSY FOR EACH INDIVIDUAL PERSON. SO SO THESE ARE KIND OF GENERAL GUIDELINES FOR HOW YOU THINK ABOUT KIND OF THE OVER ARCHING DESIGN IN ELIGIBILITY CRITERIA BUT NOT WHETHER AN INDIVIDUAL PATIENT SHOULD GET A BIOPSY IN A GIVEN CONTEXT. >> AGREED. I THINK THEY'RE REALLY -- WE'RE REALLY IN THE SAME PLACE. WE MIGHT BE USING SLIGHTLY DIFFERENT DESCRIPTIONS BUT I THINK OUR WHOLE IS TO PROVIDE A SUFFICIENT GUIDANCE THAT REASONABLY WELL EDUCATED IRB WOULD BE ABLE TO MAKE A DETERMINATION ABOUT THE STUDY DESIGN, THE BIOMARKERS BEING USED AND WHETHER OR NOT IT IS APPROPRIATE TO ASK FOR MANDATORY BIOPSIES VERSUS ALLOWING THEM TO BE OPTIONAL. ALLOWING THE PATIENTS TO OPT IN OR OPT OUT. SO IT REALLY IS TO ASSIST IN DECISION MAKING, AS OPPOSED TO BEING DESCRIPTIE DESCRIPTIVE -- PRESCRIPTIVE. >> THIS IS JANET AGAIN. I SEE SOME SIMILARITIES BETWEEN THIS AND THE DISCUSSIONS WE HAVE HAD REGARDING PROTOCOLS FOR TRANSPLANTS. WHEN WE WERE SAYING, WELL, DOES THE PATIENT REALLY WANT TO TAKE THIS RISK. AND THE PATIENTS ARE SAYING, WE DON'T HAVE ANY OTHER CHOICE. YOU KNOW, WE'RE -- IT IS EITHER THIS OR WE DIE. AND SOMETIMES IN CASES, THE PATIENT MAY BE PRESENTED WITH A HIGH RISK BIOPSY. BUT THEIR LIFE MAY BE SO DIFFICULT OR THEIR PROGNOSIS MIGHT BE SO BAD THAT THEY'RE WILLING TO TAKE THAT RISK. AND THEY SHOULD BE -- IT IS ALREADY STATED THAT THE PATIENT SHOULD BE GIVEN THE OPTION AS LONG AS THEY HAVE COMPLETE INFORMATION. >> SO -- >> I AGREE WITH THAT STATEMENT. I THINK THAT IS REASONABLE. >> SO JANET, LET ME RESPOND. BECAUSE I THINK YOU'RE -- I THINK WE'RE IN AGREEMENT THAT MANY OF THE PATIENTS -- MANY OF THE POTENTIAL PARTICIPANTS FOR THESE EARLY CLINICAL TRIALS FEEL THEY HAVE NO CHOICE BUT TO SEEK AN INVESTIGATIONAL DRUG. AND THEREFORE, YOU KNOW, AGREED TO THESE MANDATORY BIOPSIES AS PART OF THE PROTOCOL BECAUSE THEY HAVE NO CHOICE. NOW IF THESE SAME BIOPSIES WERE NOT MANDATORY, MOST SUBJECTS DON'T AGREE TO HIGH RISK BIOPSIES ON AN OPTIONAL BASIS. THEY JUST DON'T. WHICH IS WHY SPONSORS HAVE MADE THESE MANDATORY BECAUSE THEY GO OTHERWISE PARTICIPANTS WON'T AGREE TO IT. BUT OF COURSE FROM THE -- WHAT THE PARTICIPANT USES, THE BENEFIT OF THE TRIAL, THE DIRECT MEDICAL BENEFIT, THE BIOPSIES PROVIDE NO INCREMENTAL MEDICAL BENEFIT. AND ALSO PROVIDED EVIDENCE OF NOT EVEN NECESSARILY SOCIAL BENEFITS. SO I THINK THAT IS -- THAT IS THE CRUX OF THE ISSUE. >> I THINK PRIMARILY WHEN I'M THINKING OF THIS. I'M THINKING OF BIOPSIES REQUIRED TO BE ENTERED THE TRIAL IN CASE YOU HAVE TO IDENTIFY WHETHER OR NOT THE PERSON HAS THE BIOMARKER. IN THOSE CASES -- >> YEAH -- >> THAT'S A LITTLE DIFFERENT. >> THAT'S VERY DIFFERENT. NOT THE SOURCE OF DISAGREEMENT. I DON'T THINK THERE'S ANY REAL DISAGREEMENT ABOUT THAT. >> SKIP, DID YOU HAVE A QUESTION? PUT YOU ON THE SPOT. >> I WAS GOING TO MAKE THE SAME COMMENT. I THINK IT IS -- YOU KNOW, YOU MAY NOT HAVE A CHOICE. THE QUESTION IS DO WE OFFER -- SHOULD YOU BE PUT IN A POSITION OF HAVING TO MAKE A CHOICE FOR A MANDATORY BIOPSIES THAT IN FACT HAS NO RELATIONSHIP TO THE INTERVENTION -- TO GET THE INTERVENTION. I THINK THAT IS THE CRUX OF THE MATTER. YOU KNOW, I'D HAVE TO GO BACK AND LOOK THROUGH THE NCI SLIDES. I THOUGHT THEY DID TAKE A DIFFERENT VIEW COMPARED TO ASCO ABOUT PRECISELY THAT ISSUE. THAT INFORMED CONSENT IN THAT CONTEXT WOULD BE SUFFICIENTLY VOLUNTARY TO ALLOW ONE TO DO THAT. I HAVE MY DOUBTS THAT WE SHOULD CONSIDER THAT VOLUNTARY, IF IN FACT THE ONLY WAY YOU CAN GET ACCESS IS THROUGH A BIOPSY THAT HAS NO RELATIONSHIP TO THE INTERVENTION. BUT I MAY HAVE OVERMISINTERPRETED THE SLIDES BY NCI OR BY ASCO, IF I'M OVERREADING THAT DIFFERENCE. >> WELL, I HAVE THAT SAME QUESTION, SKIP. AND I'D KIND OF LIKE THEM -- THE PANELISTS TO ADDRESS THE DIFFERENCE BETWEEN THE NCI AND THE SACO FRAMEWORKS. IF PRIMARY DIFFERENCE BEING NCI WOULD NOT FIND ANY -- ANY MANDATORY EXPLORATORY BIOPSIES ACCEPTABLE. BUT ASCO WOULD FIND THEM ACCEPTABLE, IF THEY'RE LOW RISK. AND OF THOSE THAT FALL INTO THE SECONDARY END POINT CATEGORY, THE HIGH RISK ONES NCI CONSIDERS ACCEPTABLE ON A PROTOCOL TO PROTOCOL BASIS. BUT AS SCOW WOULD NOT. SO THOSE ARE THE TWO PRIMARY DIFFERENCES BETWEEN THE TWO FRAMEWORKS AND I'D BE INTERESTED IN IN THE REASONS THAT YOU WENT IN ONE DIRECTION VERSUS THE OTHER. >> I THINK THE LATTER, THE INTERIM BIO, MAKER THAT MAY OR MAY NOT REQUIRE A MANDATORY BIOP BIOPSY, IS SOMETHING THAT WOULD BE OPEN FOR DISCUSSION. AND IT MIGHT BE HELPFUL FOR THE GROUP TO TALK IN ALL ASPECTS OF THAT SO WE CAN REACH CONSENSUS. WE TOOK A NEUTRAL A PHYSICIAN AS WE THOUGHT WE COULD. AND ALLOWED FOR DISCUSSION AMONGST ALL OF THOSE PERFORMING THE STUDY ABOUT THE RISK BENEFIT ANALYSIS AND HOW TO APPROACH THAT. SO THAT'S WHY WE DID THAT. WE WANTED THE OPPORTUNITY TO ASSURE, AS BEST WE CAN, PATIENT'S SAFETY. AND TO CLEARLY DEFINE THE NEED OF -- FOR THE BIOMARKER AND THE CONTEXT OF THE STUDY BEING PERFORMED. I TOTALLY AGREE WITH MARK. IF THIS NEVER COMES TO PUBLIC LIGHT, THEN WE SHOULDN'T BE DOING IT. WE REALLY SHOULDN'T BE DOING IT. SO FOR US IT IS CRITICALLY IMPORTANT THAT THEY PUBLISH ANYONE WHO PERFORMS A TRIAL, PUBLISH THE RESULT OF THEIR BIOMARKER STUDIES AND THAT WITHIN THE CONTEXT OF THEIR PROTOCOL THEY HAVE A STATISTICAL DESIGN TO ANALYZE THE BIOMARKER END POINTS. AND WE REALLY TRY VERY HARD NOT TO MOVE FORWARD WITHOUT THOSE KINDS OF ASSURANCES. BUT AM I -- I THINK -- I'M OPEN TO ANY KIND OF SUGGESTION ON THAT. I THINK WE CAN DEFINE IT PERHAPS MORE TIGHTLY. I GUESS I FELT LIKE SOME MODEST AMOUNT OF WIGGLE ROOM WAS A REASONABLE WAY TO GO RATHER THAN BEING ABSOLUTELY CONCISE IN HOW WE WOULD INSIST ON SOMETHING. >> DEB, LET ME RESPOND TO YOUR QUESTION. I THINK THIS MAY BE A CASE OF PERFECT BEING THE ENEMY BEING GOOD TRYING TO GET CONSENSUS. WE'RE LOOKING AT ONE IRB THAT REVIEWS THESE TRIALS FOR Ns NCI'S EARLY CLINICAL TRIALS COMMITTEE. AND IT IS ALSO THE ONLY IRB THAT REVIEWS TRIALS FROM ONLY ONE SPONSOR. THESE ARE TRIALS SPONSORED BY THE NATIONAL CANCER INSTITUTE INVESTIGATI INVESTIGATIONAL DRUG RAMPS. THAT'S A ONE OFF SITUATION. AND I THINK YOU REALLY SHOULD ENCOURAGE OR ENCOURAGE SACHRP ON IRB'S AT LARGE RATHER THAN THE EARLY CLINICAL TRIALS COMMITTEE IS GOING TO RE DO WHEN REVIEWING TRIALS FROM ONE SPONSOR THAT EFFECTIVELY A POINT OF THIS IRB FOR THE PURPOSE OF REVIEWING THEIR TRIALS. WE DON'T HAVE ANYBODY FROM THAT IRB ON THIS PANEL BUT I THINK THAT IS THE SITUATION. >> WELL, THEIR -- NCI HAS THREE CENTRAL IRB'S, ONE -- >> LIKE THE ONE EARLY -- >> AND THERE'S ONE FOR EARL A. AND THERE'S ONE FOR, QUOTE, PEDIATRIC, GENERAL, AND EARLY. SO TECHNICALLY THEY'RE QUOTE, TWO CENTRAL IRB'S THAT REVIEW EARLY STAGE TRIALS FROM PEDIATRIC AND SOME ADULTS. AND FOR ME THAT WOULD BRING ME BACK TO THE QUESTION I WANTED TO ASK PAUL, WHICH IS, IS THERE A ROLE FOR CENTRAL IRB'S WITH CERTAIN EXPERTISE THAT COULD ASSIST IN THE REVIEW OF THESE KINDS OF BIO, MAKERS. AND IS THERE A WAY TO NATIONALLY IMPLEMENT THAT AS A BODY WE ARE ASSURED THAT THEY ARE EVALUATING THE VALUE OF THE RESEARCH BIOMARKERS TO THE STUDY. AND THE ROLE OF THE BIOPSY IN THAT STUDY AND SHOULD IT BE MANDATORY OR OPTIONAL? AND GIVEN THE IRB'S ASSISTANCE IN THEIR REVIEW, WITH A PANEL THAT HAS EXPERTISE IN THESE AREAS. BECAUSE CERTAINLY LOCAL IRB'S MAY OR MAY NOT HAVE THAT EXPERTISE. HOW COMMERCIAL IRB'S LIKE THE WEST TO BE ERB -- IRB APPROACHES THIS ISSUE IS ANOTHER ISSUE. SO THERE'S ALL DIFFERENT FLAVORS OF IRB'S AND THEY'RE ALL CHARGED WITH THE SAME THING. AND HOW DOES ONE APPROACH THAT AND PROVIDE GUIDANCE FOR THAT MORE GLOBALLY? THAT QUESTION ON PAUL, YEAH. >> I THINK FOR MOST CLINICAL TRIAL PROTOCOLS, THE CENTRAL IRB'S ARE QUITE CAPABLE OF HANDLING THEM AND HANDLING ALL OF THE ISSUES. IN WELL THERAPEUTIC AREAS WITH SOME EXCEPTIONS. AND THOSE EXCEPTIONS MAY BE FOR SOME ONCOLOGY STUDIES AND FOR SOME HIGH LY INTERVENTIONAL STUDIES. SO I DON'T KNOW WHAT I WOULD DO SOME ASTHMA EXPERIMENT SOMEBODY WANTS TO DO. I THINK THAT RAISES THE SAME ETHICAL QUESTIONS THAT OUR BIOPSY STUDIES DO. I THINK CENTRAL IRB'S HAVE A LOT OF ADVANTAGES. THEY TEND TO HAVE NO PARTICULAR BIAS. AGAIN, ANY INDIVIDUAL CAN BE BIAS. BUT THEY DON'T HAVE ANY INSTITUTIONAL BIAS OR NEED TO SAY YES TO A STUDY OR IN A NEED YOUR FASHION. I'M SAYING THIS TO MARK ON THE CHICAGO IRB. MARK IS THE UNIQUE INDIVIDUAL WITH NO IRB'S AND IS OUT THERE, YOU KNOW, EVALUATING EVERYTHING. I THINK A LOT OF PEOPLE -- YOU KNOW, IRB'S DON'T TAKE IT QUITE AS SERIOUSLY AS THEY SHOULD ON ACADEMIC IRB'S ANYWAY I CAN SAY THAT ON THE QUESTIONS WE RECEIVE ON PROTOCOLS. MAYBE MISSED THE POINT. I THINK CENTRAL IRB'S ARE LESS TURN OVER AND MORE MOTIVATED. I'M NOT SPEAKING HERE FOR CAPITALISM. BUT IF YOU'RE A HIGH POWERED ACADEMIC, WHETHER CLINICAL OR NONCLINICAL, IN AN ACADEMIC MEDICAL CENTER, BEING AN EASTBOUIRB IS EXCELLENT FOR A WHILE BUT NOT SOMETHING YOU WANT TO SPEND TWO YEARS DOING EVERY WEEK, OR TWICE A WEEK, OR ONCE A MONTH. WITH SOME EXCEPTION. THERE MAY BE SOMEONE SUPREME LY INTERESTED, BUT MOST AREN'T. EVEN IF THEY ARE AND DOING A GREAT JOB THEY DON'T HAVE THE TIME TO DO A REALLY IN DEPTH RESEARCH TO THE AREA OF SIMILAR PROTOCOLS HOW THEY WERE HANDLED ET CETERA. BUT I THINK THE IDEA OF A CENTRAL SCIENTIFIC REVIEW COMMITTEE, IF IT WERE FEASIBLE, WOULD PAY OFF. AND IF WE COULD PARALLEL CENTRAL IRB'S THAT I THINK WORK RAPIDLY AND WELL. IT MIGHT BE A GOOD THING. I DON'T KNOW HOW TO SET IT UP, THOUGH. THE PROTOCOL YOU NEED, YOU KNOW, YOU COULD SET IT UP WITH THE INTERVENTIONAL RADIOLOGISTS HAVING THEIR SPECIAL AREAS. IF YOU HAD 5 OR 10 RADIOLOGY GISTS TO CALL UPON, YOU COULD COVER THE FIELD AND CIRCULATE. THEY'RE EXTREMELY BUSY. THE SAME WOULD BE FOR SURGICAL BIOPSIES. SOME OF THESE BIOPSIES HAVE TO BE DONE SURGICALLY. THE PATHOLOGIST COULD BE -- YOU COULD SET IT WITH THE PATHOLOGY GIST AS WELL. THE QUESTION IS TO GET THE SCIENCE EXPERTISE BETWEEN THE BASIC SCIENCE AND POLITICAL SCIENCE WHERE THE RUB COPS IN. LET'S BE HONEST. I'VE DONE STUDIES THE LAST TEN YEARS ON DCR MIX, THE KATINA PATHWAY, AND YOU KNOW, RASPIES AND AGFR. YOU KNOW, THOSE ARE VERY DIFFERENT. AND THEY'RE DIFFERENT FOR FOR -- BIOLOGY. THOSE PEOPLE ARE EASY TO IDENTIFY, THOUGH. IT IS NOT LIKE YOU CAN'T FIND THE CLAMORING EXPERTS. WE KNOW WHO THEY ARE. I THINK IT CAN BE DONE. BUT WE TO HAVE THE PEOPLE IDENTIFIED FROM CALLING CONSULTANTS WHEN YOU IDENTIFY A TARGET. I THINK IT CAN BE DONE. BUT WHO IS GOING TO SET IT UP, HOW WILL IT BE PAID FOR, I THINK SPONSORS AUTO WOULD HAVE TO PAY FOR IT. JUST LIKE SPONSORS PAY FOR WESTERN IRB AND WHAT HAVE YOU. BUT I THINK TO ME HONESTLY THERE MIGHT BE CONSIDERABLE LOCAL RESISTANCE TO THIS, I THINK THINK -- AT TIMES I THINK I AM TO GIVE THE INSTITUTIONS A BREAK AND ABANDON THEIR IRB'S, TYPICALLY IF THEY ARE -- I THINK IT IS REDUNDANT AND THEY DON'T HAVE THE EXPERTISE THEY NEED. >> YEAH, I WANT TO ECHO WHAT PAUL JUST SAID. ALL NCI DESIGNATED CANCER CENTER CENTE CENTERS MUST HAVE A SCIENTIFIC REVIEW COMMITTEE PROCESS IN PLACE. AND SO THEY'RE NOT GOING TO BE ABLE TO DELEGATE THAT JUST LIKE MOST ACADEMIC INSTITUTIONS DON'T DELEGATE THE IRB TO AN OUTSIDE IRB UNLESS MANDATED TO. SO I THINK IT WOULD BE VERY DIFFICULT TO DO SO. BUT I AGREE THAT IT IS FEASIBLE TO DO SOMETHING. AND I THINK THE SCIENTIFIC EXPERTISE -- I'M NOT SURE EVERY PROTOCOL NEEDS TO BE REVIEWED NECESSARILY MULTIPLE TIMES FOR SCIENTIFIC VALUE. BUT IN THEORY THERE SHOULD BE SOME REAL SCIENTIFIC REVIEW PROCESS OF A PROTOCOL JUST LIKE WHEN PAPERS ARE PUBLISHED THERE'S SCIENTIFIC REVIEW OF THE RESULTS. WHY DON'T WE HAVE BETTER SCIENTIFIC REVIEW BEFORE THE STUDY STARTS IF THE STUDY IS RESULTING IN SIGNIFICANT RISK THAT IS UNRELATED TO ANY DIRECT MEDICAL BENEFIT. SO I THINK THAT IS ANOTHER OPTION. >> NOW IF YOU GO BEYOND THE QUESTION OF BIOPSIES. >> YEAH. >> HOW MANY SEEDING STUDIES ARE DONE -- WE DON'T WANT TO GO THERE IN THIS MEETING BUT THERE ARE A LOT OF CANCER STUDIES THAT SUCK UP PATIENTS FOR NO EARTHLY REASON. >> I'D LIKE TO ADDRESS ANOTHER ISSUE THAT HAS COME UP. WHETHER OR NOT SOMETHING IS CONSID CONSIDERED VALID AS A MANDATORY BIOPSY IF THE BIOPSIES RESULTS ARE NOT SHARED. IN A LOT OF THE BIOMARKER TRIALS IN LUNG CANCER WHICH IS WHAT I'M MOST FAMILIAR WITH, WE ALL KNOW ON TKI'S WE'RE EVENTUALLY GOING TO PROGRESS. AND DON'T UNDERSTAND ALL OF THE MECCA SIMPLES OF RESISTANCE THAT DEVELOP ON VARIOUS TKI'S. SO OBVIOUSLY WE HAVE TO BIOPSY AT SOME POINT TO FIND OUT WHAT GOING ON IN THOSE PARTICULAR CELLS. BUT GENERALLY IF THERE'S ANY MANDATORY BIOPSY IN A TRIAL AFTER THE PATIENT HAS BEEN ON THE DRUG, THE DRUG COMPANIES HOLD ON TO THOSE. I'M NOT SURE THAT IS NECESSARILY A BAD THING BECAUSE THEY'RE TRYING TO FIND OUT WHAT ANOTHER NEW DRUG MIGHT BE TO BE ABLE TO ADDRESS THOSE MECHANISMS OF RESIS STANCE. AND THEY'RE PUTTING IF EFFORT INTO IT, BUT THAT IS SOMETHING THAT NEEDS TO BE ADDRESSED. I DON'T THINK JUST BECAUSE THEY HOLD ON TO THE BIOPSIES THAT THAT IS A BAD THING. SPEAKING AS A PATIENT I WANT ANOTHER DRUG AFTER MY TKI STOPS WORKING AND I WANT THE DRUG COMPANIES TO DEVELOP THAT. I'M NOT SURE RELEASING THOSE BIOPSIES OUT INTO THE WILD IS THE BEST APPROACH. IS. COULD YOU TALK A LITTLE MORE ABOUT WHAT YOU MEAN WHEN SENDING THE BIOPSIES OUT INTO THE WILD? >> ARE WE GOING TO REQUIRE PHARMA COMPANIES TO COMPLETE A THOROUGH ANALYSIS OF THE BIOPSIES AND SHARE THAT DATA WITH ANY RESEARCHER WHO IS INTERESTED? >> WELL, I THINK THEY SHOULD PUBLISH THOSE RESULTS SO THEY'RE PUBLICLY AVAILABLE FOR REVIEW AND CONSIDERATION. WHETHER OR NOT THEY RELEASE THE BIOPSY STUFF ARRESTED -- AND REFER TO FUTURE STUDIES I THINK IS A SLIGHTLY DIFFERENT QUESTION FROM THAT ONE. I JUST WANTED CLARITY AROUND WHETHER OR NOT THAT IS WHAT YOU MEANT. >> I WOULD AGREE RELEASING THE TISSUE IS A SEPARATE ISSUE. BUT THEY DON'T ALWAYS ANALYZE THE ISSUE FROM RESISTANCE RIGHT AWAY. THEY MIGHT WAIT A WHILE FOR A SPACE ON THE DOCKET FOR THAT. ARE WE GOING TO ADDRESS WHAT THEY HAVE TO DO WITH THOSE BIOPSIES? I THINK THAT WOULD -- WOULD -- POTENTIALLY BENEFIT FUTURE PATIENTS. >> YEAH, I THINK THERE'S A LOT OF ISSUES HERE. SO WE'RE A LITTLE BIT BEYOND OUR TIME FOR THE PANEL CONVERSATION. AND I WANTED TO ASK IF ANYBODY HAS ANY FINAL QUESTIONS TO ASK AND THEN I'LL RELEASE OUR KIND PANELISTS FROM THE MEETING TODAY. SO ONE LAST CALL FOR QUESTIONS ON REALLY -- ANYWAY, ONE LAST CALL FOR QUESTIONS? NOPE. ALL RIGHT. WELL I WANT TO THANK ALL OF YOU FOR THE TIME YOU SPENT ON THINKING ABOUT THIS DEVELOPING YOUR SLIDES, SHARING YOUR INFORMATION WITH US. IT IS A REALLY IMPORTANT TOPIC AND WE VERY MUCH APPRECIATE ALL OF THE WORK THAT YOU HAVE DONE AND ARE DOING ON THIS ISSUE. SO THANK YOU VERY MUCH. >> THANK YOU. >> THANKS. >> JULIA, CAN OUR GUESTS -- >> THANK YOU. >> LEAVE OUR MEETING? >> THEY ARE WELCOME TO. I THINK THEY'RE WELCOME TO HERE -- STAY AND HEAR DISCUSSION. IT IS A PUBLIC MEETING. IF THEY WANT TO STAY, THEY'RE WELCOME TO. >> GOT IT. OKAY. >> IT IS THEIR CHOICE. >> SO LET ME TURN US TO A MORE GENERAL CONVERSATION ABOUT THIS ISSUE. SO I THINK THAT WE NEED TO FIGURE OUT WHETHER SACHRP COULD PROVIDE USEFUL GUIDANCE, USEFUL RECOMMENDATIONS TO THE SECRETARY REGARDING GUIDANCE THAT WOULD BE USEFUL TO INSTITUTIONAL REVIEW BOARDS IN REVIEWING RESEARCH WITH MANDATORY BIOPSIES. A AND. >> SORRY, JODY -- >> SORRY. GO AHEAD. >> I JUST HAD ONE COMMENT. WHEN WE DISCUSSED THIS TOPIC AT THE SUBCOMMITTEE LEVEL, WE WANTED TO HEAR THE OTHER SIDE OF THE STORY FROM NCI. >> RIGHT. >> AND I DON'T KNOW OR MAYBE OTHERS DO, I DON'T KNOW IF I -- I -- HAVE COME TO ANY CONCLUSION AFTER HEARING THE OTHER SIDE. OF THE STORY. SO I JUST WANTED TO BRING THAT UP AND SEE IF -- WHAT ARE PEOPLE PEOPLE'S THOUGHTS ON THAT? >> I THINK THAT IS A GOOD WAY TO GET THE DISCUSSIONS STARTED. THANK YOU. SO LET ME OPEN IT UP. TO -- I THINK DOUG ACTUALLY RAISED THE ISSUE OF WHAT WERE THE DIFFERENCES BETWEEN NCI AND THE AS AS SCOW. AND IT DEFINITELY SEEMED LIKE NCI WAS VERY MUCH THE MANDATORY BIOPSIES ARE MOSTLY IMPORTANT. THEYCO. AND IT DEFINITELY SEEMED LIKE NCI WAS VERY MUCH THE MANDATORY BIOPSIES ARE MOSTLY IMPORTANT. THEY DRAW A LINE THAT SEEMED TO BE BLACK AND WHITE. I DIDN'T THINK IT WAS AS EASY AS SHE WAS DESCRIBING IT AND MARK RATAIN DEFINITELY HAS A DIFFERENT VIEW. AND I -- SO I THINK YOU'RE RIGHT, IT IS NOT -- WE WANTED TO HEAR WHAT NCI HAD TO SAY. NOT EXACTLY CLEAR WHAT THE ISSUES ARE AND HOW THAT PLAYS INTO WHETHER WE COULD PROVIDE USEFUL GUIDANCE FOR IRB'S. THANKS FOR PUSHING THAT. LET ME OPEN IT UP. FRJ>> ZACK, I'LL PUT YOU ON THE SPOT. WHAT DO YOU THINK? >> YEAH, I WILL I -- I THINK IT IS A GOOD QUESTION AS TO WHETHER THERE'S SOMETHING HERE WE CAN OFFER. YEAH, I MEAN TO ME THIS IS ACTUALLY A HARDER QUESTION THAN THE PEDIATRIC ARENA. WHE WHERE, YOU KNOW, THE DECISION -- THE INFORMED CONSENT IS COMING FROM A DIFFERENT PARTY. AND IT IS BEING REQUIRED. BECAUSE I DO -- I THINK ASCO'S FRAMEWORK IN MY MIND IS A USEFUL ONE. WHETHER WE NEED TO ENDORSE THAT IN SOME WAY, I DON'T KNOW, AS SACHRP. >> I WILL SAY, I REALLY LIKED PAUL NADLER'S QUESTIONS. IF YOU MAY RECALL AT THE VERY END OF HIS POWER POINT, HE HAD SEVEN -- SEVEN QUESTIONS. IS THERE ADEQUATE RATIONAL TO SUPPORT BIOPSIES IS THERE A STRONG RATIONAL TO -- VAFSHGS OF THE ASSAY AND SO ON. YOU KNOW, I MEAN, I'M SURE WE COULD READ THROUGH AND FINE-TUNE IT. BUT IT ALMOST SEEMED LIKE TO ME, LIKE, WHY NOT? LIKE THESE QUESTIONS ACTUALLY HELP FRAME THE ISSUE WHEN THERE'S A PROTOCOL THAT INVOLVES MANDATORY BIOPSIES. IT HELPS THE FOCUS. AND I THINK IT CAN HELP WITH THE IRB RATIONALE FOR AN IRB PUSH BACK. YOU KNOW, IN OTHER WORDS, INSTEAD OF JUST SAYING, YOU KNOW, IT JUST DOESN'T FEEL RIGHT. THIS MANDATORY BIOPSY DOESN'T SEEM INTEGRAL TO THE RESEARCH. IF YOU TAKE THESE SEVEN QUESTIONS, IT ACTUALLY MIGHT BE THAT YOU CAN PUT A HOOK ON ONE OF THEM AND THAT CAN BE THE REASON WHY AN IRB SAYS THAT IT IS IN FACT. YOU KNOW, I LOOKED AT THOSE QUESTIONS AND I THOUGHT, YES, SOMETHING LIKE THAT COULD BE VERY USEFUL. BUT JUST MY VIEW, OPEN IT UP TO OTHER PEOPLE'S THOUGHTS. >> I AGREE, THOSE QUESTIONS ARE VERY USEFUL. BUT THEN THAT STILL BEGS THE QUESTION WHERE DOES THE IRB FIND THE ANSWERS TO THE RESEARCH THOSE QUESTIONS? >> I HAVE TO SAY WE ASK QUESTIONS LIKE THIS ALL OF THE TIME. YOU KNOW IRB'S REVIEW MOST IRB'S REVIEW A BROAD RANGE OF PROTOCOLS DEVICE PROTOCOLS INVESTIGATIONAL DRUG PROTOCOLS, YOU KNOW, SPECIMEN RESEARCH AND WHATEVER. AND THERE'S A LOT OF QUESTIONS THAT TEND TO GO BACK AND FORTH, MAYBE AT DIFFERENT POINTS IN TIME IN THE REVIEW PROCESS. BUT THIS -- THESE QUESTIONS TO ME ARE NOT UNUSUAL. >> I UNDERSTAND IRB'S HAVE A LOT OF DIFFERENT TRIALS TO LOOK AT AND THEY HAVE A LOT OF BACKGROUNDS. I'M COMING FROM THE VIEWPOINT IN LUNG CANCER, WHERE THE NUMBER OF BIOMARKERS AND THE NUMBER OF TRIALS HAS PROLIFERATED SO MUCH THAT WE HAVE DOCTORS THAT NORMALLY TREAT LUNG CANCER PATIENTS WHO ARE COMPLETELY UNAWARE OF THE BIOMARKERS. THINGS ARE MOVING REALLY FAST. I'M NOT SURE THAT EVERY IRB HAS ALL OF THE EXPERTISE THEY NEED. >> I WOULD JUST SAY I THINK THAT IS A DIFFERENT -- THAT'S A LARGER DIFFERENT ISSUE WHAT DOES IT MEAN FOR AN IRB IN TERMS OF ITS COMPOSITION AND EXPERTISE. I THINK IT WOULD BE HELPFUL IF WE COULD FOCUS IN ON, YOU KNOW, DO WE THINK AS A COMPLETE WE COULD IDENTIFY RECOMMENDATIONS USEFUL TO THE IRB. MAYBE IT IS ACTUALLY RECOMMENDING THAT WHERE THERE'S A QUESTION THAT AN IRB REACH OUT FOR INTERVENTIONAL RADIOLOGIST CONSULT. WHICH IS NOT AN UNUSUAL SITUATION. IRB'S REACH OUT ALL OF THE TIME FOR AD HOC ADDITIONAL EXPERTISE. BUT, AGAIN, OTHER PEOPLE? >> I HAVE -- >> I'M SORRY. I'M JUST NOTICING THAT SKIP'S HAND HAS BEEN UP FOR A BIT. I DON'T KNOW IF THAT IS OLD OR DOES SKIP KNOW THAT YOUR HAND. >> MY HAND? YEAH, NO, I HAVE IT UP. BUT I'M FINE WAITING -- I DON'T HAVE TO TALK NOW. I CAN WAIT A LITTLE BIT. >> ALL RIGHT. HOW ABOUT LINDA? >> I HAD A QUESTION BECAUSE I WANTED TO UNDERSTAND WHAT ONE OF THE SPEAKERS SAID. THEY TALKED ABOUT THE ROLE OF THE REVIEW COMMITTEE WHICH IS MANDATORY FOR CERTAIN TYPES OF -- FOR CANCER. >> CANCER RESEARCH, YEAH. >> AND I JUST DIDN'T -- CAN SOMEONE CLARIFY FOR ME WHAT THAT PERSON'S POSITION WAS? WAS IT THAT BECAUSE WE HAVE PROTOCOL REVIEW COMMITTEES AND PRESUMABLY LOOKING AT THE ISSUES THAT IRB JUST LIKE ANY OTHER TYPE OF STUDY, THEY CAN SEEK GUIDANCE FROM THEM? OR -- I DIDN'T UNDERSTAND THAT PERSON'S ARGUMENT. CAN SOMEONE HELP ME -- COULD SOMEONE CLARIFY THAT FOR ME? I'M NOT SURE IF YOU REMEMBER THE COMMENT ABOUT THE PROTOCOL REVIEW COMMITTEE PIECE OF IT AND HOW THAT PLAYS INTO THIS. IF NOT, THAT IS OKAY, IT IS FINE I'LL -- >> I AM INTERESTED IN IT AS -- BECAUSE THE PROTOCOL IS GOING THROUGH A SCIENTIFIC REVIEW PRIOR TO THE IRB REVIEW. THE IRB DID NOT FEEL COMPEL LED OR HAD THE PRESSURE TO TO REVIEW IT FROM THAT PERSPECTIVE. THEY WERE MORE FOCUSED ON THE ETHICS PART IS HOW I UNDERSTOOD THAT. >> OKAY. >> I THOUGHT IT WAS PART OF DR. IVY'S PRESENTATION TOO IN THAT -- SHE SAYS WE HAVE THIS RIGOROUS REVIEW PROCESS AND BIOPSIES REVIEW PROCESS AND SCIENTIFIC REVIEW PROCESS AND WE'RE NOT GOING TO LET THESE THINGS GO THROUGH. SHE MADE A COMMENT NOT TODAY BUT IN A PREVIOUS CALL ABOUT THERE BEING NO FIT -- A REQUEST FOR MANDATORY BIOPSIES WAS NOT A FISHING EXPEDITION AND THAT NCI IS VERY CAREFUL WITH WHENEVER THERE'S A MANDATORY BIOPSY INCLUDED IN RESEARCH. AND LINDA, I TOOK THE BASIS FOR HER STATEMENT TO BE THAT, YOU KNOW, WE HAVE THESE COMMITTEES THAT DIG IN TO THE IT AND I THINK PAUL NADLER KIND OF BUILT ON THAT BY SAYING, YOU KNOW, YOU SEE THOSE COMMITTEES IN THE CANCER ARENA, BUT YOU DON'T NECESSARILY SEE IT IN OTHER PLACES. WHICH, AGAIN, IS -- THAT'S NOT ANOTHER ISSUE, RIGHT, WHICH IS DOES THAT JUST MEAN THAT IRB'S DON'T HAVE SCIENTIFIC EXPERTISE PERIOD, RIGHT? SO YOU ALWAYS NEED A PEER REVIEWED SCIENTIFIC REVIEW COMMITTEE. IF THAT IS NOT -- I'M NOT SURE THAT'S WHERE WE ARE, BUT -- >> OKAY. THANK YOU. >> SKIP, YOU'RE WELCOME TO TALK NOW. >> YEAH, JUST ONE COMMENT ON THAT. THERE IS A TENSION HERE BETWEEN HISTORICALLY WHAT WAS A DIVISION BETWEEN SCIENTIFIC REVIEW AND ETHICAL REVIEW. WHICH I THINK IS FUNDAMENTALLY CONCEPTUALLY IMPOSSIBLE TO MAINTAIN. YOU CAN'T DO AN ETHICAL REVIEW WITHOUT A SCIENTIFIC REVIEW. IT IS ALSO TRUE YOU CAN'T HAVE AN EXPERTISE IN EVERYTHING. AND SO YOU IN COMPLICATED AREAS ARE BY DEFAULT DEPENDENT UPON THE INFORMATION THAT IS PROVIDED TO YOU BY THE APPROPRIATE EXPER EXPERTS. AND YOU NEED TO BE IN A POSITION TO JUDGE THAT INFORMATION, EVEN IF YOU DON'T HAVE THE EXPERTISE ABOUT THAT INFORMATION. SO THERE'S A BIT OF A TENSION. SO I DO AGREE, I LIKE THE QUESTIONS -- THE QUESTIONS THAT WERE PRESENTED AS A WAY OF TELLING THE IRB, YOU HAVE A RIGHT TO ASK THESE QUESTIONS. YOU MAY NOT BE ABLE TO ANSWER THEM YOURSELF. BUT HAVE YOU A PERFECT RIGHT TO THAT THERE BE A AN ANSWER TO THE QUESTION AND EVALUATE THAT WHETHER THOSE ANSWERS HAVE A CERTAIN CREDIBILITY TO IT. WHAT I FIND -- I MEAN, I DIDN'T HEAR MUCH DIFFERENCE OF OPINION, FRANKLY, IN ANYBODY'S PRESENTATION. I GOT THE IMPRESSION THAT MARK WAS MAINLY QUESTIONING WHETHER THE CLAIM THAT THERE'S ALWAYS A SCIENTIFIC JUSTIFICATION IS JUST -- IS APPROPRIATE AT ALL TIMES MORE ON A SCIENTIFIC ISSUE BUT NOT THE FRAMEWORK AROUND ONE WOULD MAKE THOSE DISTINCTIONS. I DIDN'T HEAR ANYBODY SAY THAT MANDATORY BIOPSIES HAVE ABSOLUTELY NO SCIENTIFIC PURPOSE BECAUSE THEY'RE FISHING EXPEDITION IS A GOOD THING, BUT YET WHEN THIS TOPIC FIRST CAME UP AS A POSSIBILITY, PEOPLE WERE SAYING, WELL, THAT IS HAPPENING ALL OF THE TIME. SO I -- YOU KNOW, I MEAN, I -- I HAVE NO PROBLEM OFFERING ADVICE AND THE ADVICE THAT WAS PACKAGED FOR US WOULD BE PRETTY EASY TO OFFER UP WITH SOME MODIFICATIONS. BUT I'M STILL NOT CLEAR -- I MEAN, WHERE THERE'S SMOKE THERE MUST BE FIRE. BUT I HAVEN'T SEEN A WHOLE LOT OF DATA. NOR PEOPLE ARGUING THAT MANDATORY BIOPSIES THAT HAVE NO VALUE ARE PERFECTLY FINE. >> SO THE OTHER COMMENT THAT WAS MADE EARLY ON WAS SOME CONCERN THAT IRB'S DIDN'T NECESSARILY FEEL THAT THEY HAD THE ABILITY TO PUSH BACK ON MANDATORY BIOPSIES. SO THAT IS PART OF THE QUESTION. THAT IS THE QUESTION. YOU KNOW, IS THERE A GAP IN THE IRB REVIEW CRITERIA OR A PERCEIVED GAP OR, YOU KNOW, SOMETHING WHERE IRB'S DON'T FEEL THAT THEY CAN REQUIRE ADDITIONAL VERIFICATION TO JUSTIFY A SITUATION WITH MANDATORY BIOPSIES. I DIDN'T GET THAT SENSE FROM ANY OF THE PRESENTATIONS. I MEAN, I THINK THAT WE COULD, YOU KNOW, WE COULD OFFER SOME RECOMMENDATIONS. I THINK WE COULD ALWAYS OFFER RECOMMENDATIONS. THERE'S ALWAYS THINGS ONE COULD SAY. THE QUESTION IS, IS IT A PLACE WHERE SACHRP WANTED SUSPENDED TIME. I COULD BE A PRO VOLCANO CATURAND SAYING, OKAY, I THINK IT HAS BEEN A GREAT DISCUSSION. I DON'T THINK THERE'S ENOUGH MEAT THERE FOR SACHRP TO OPINE ON IT. WAS THE BEST THING WE CAN DO. WITH THAT, HOW DO WE CABLE THIS RIGHT NO NOW -- GREAT DISCUSSION. LIKED A LOT. ISN'T MEAT THERE FOR SACHRP TO WORK ON. >> WHAT YOU'RE BASICALLY SAYING IS ABSENCE NEEDS A CLEAR ANALYSIS, DO WE SPEND THE TIME ADDRESSING THIS? EVEN THOUGH WE HEARD GREAT PRESENTATIONS AND SOLUTIONS TO THE PERCEIVED PROBLEM. I THINK THAT IS REASONABLE WHERE WE DON'T SEE THE NEED. IT IS NOT CLEAR TO ME WHY EVERYBODY HAS GONE TO ALL OF THE TROUBLE AND SEEING AS COMPANY AND EVERYBODY TO PUT OUT THE RECOMMENDATIONS. WHY WERE THEY SO READY TO PUT THIS ALL TOGETHER. THERE MUST HAVE BEEN A PROBLEM AND MAYBE THE FIRE IS ALREADY OUT. BUT WHAT -- I MEAN, THERE'S THERE'S -- THERE MUST HAVE BEEN AN ISSUE THAT CAUSED EVERYBODY TO THINK WE HAVE TO DO THIS. >> IF I COULD JUST ADD TO SKIP'S COMMENTS. I TOO FOUND TOO FOUND A LOT MORE CONSENSUS THAN DISAGREEMENT AMONG THE SPEAKERS. AND IT DOES >> OFTEN THE PROFESSIONAL ASSOCIATION STATEMENTS, >> I WONDER WHETHER -- THE STATEMENT SEEMED VERY SENSIBLE, UNLIKE THE ASCO POSITION PAPER AND THAT SEEMS REASONABLE TO ME AS WELL SO I DO WONDER A LITTLE BIT ABOUT WHAT -- CAN ADD. >> WOMAN: MEMORY SUCKS. DOES ANYBODY REMEMBER IN THE PRESENTATIONS WE HAVE SEEN IN THE WORKING GROUPS WHETHER THE EXAMPLES THAT WERE OFFERED WERE IN THE FIELD OF ONCOLOGY OR OTHERS, OTHER PLACES? >> WOMAN: OFF THE TOP OF MY HEAD, I CANNOT REMEMBER. >> MAN: THEY CERTAINLY OCCUR IN OTHER PLACES. YOU KNOW, GENETICS, RHEUMATOLOGY, IMMUNOLOGY, DERMATOLOGY WHERE THEY WERE ASKING -- ONE ONE OF THE REQUESTS WE GET FREQUENTLY IS FOR EXTRA LIVER BIOPSY SPECIMENS OR EXTRA G.I. SPECIMENS THAT ARE BEING USED FOR EXPLORATORY PURPOSES. THEY CERTAINLY OCCUR OUTSIDE OF THE CANCER REALM. THE SENSE I HAVE IS THAT WHAT BOTHERS MANY PEOPLE ABOUT THE MANDATORY PORTION IS THAT MANY OF THESE PATIENTS ARE DESPERATE TO ENROLL IN THE TRIAL AND THAT IS A FORM OF UNDUE INFLUENCE. I DON'T KNOW THAT THAT WAS REALLY EXPLICITLY ADDRESSED BY THE PANELISTS. AND -- I HAVE A SENSE THAT IRBS TO SOME DEGREE WANT TO BE EMPOWERED TO SAY "NO" IN THAT SETTING AS OPPOSED TO FEELING LIKE IT IS A MULTICENTER TRIAL ANYWAY SAID NO, THEY WILL GO TO ANOTHER INSTITUTION. SO MAYBE IF SAC -- RENDERED AN OPINION WE WOULD HAVE MORE GROUNDS TO SAY MANDATORY BIOPSIES IN THIS SITUATION, MAY BE ALIGNED WITH WHATEVER ASCO HAS SUGGESTED ARE NOT OKAY. >> MAN: DOUG, I SHARE YOUR INTUITION AND THAT IS PARTLY WHY I ASKED THE QUESTION THAT I ASKED. FOR US TO GO THERE WOULD BE A MUCH MORE COMPLEX ASSESSMENT OF VOLUNTARINESS, CHOICE, CONSENT. THAT WILL BE MORE THAN JUST SAYING TAKE A QUICK LOOK AT THE BIOPSY AND MAKE SURE IT IS SCIENTIFICALLY USEFUL; IT WOULD BE A MUCH MORE COMPLICATED ENDEAVOR TO UNPACK VOLUNTARY CHOICE IN THE CONTEXT OF -- YOU KNOW -- EARLY PHASE CLINICAL TRIALS AND SITUATIONS WHERE CHOICES ARE EXTREMELY LIMITED, THAT WILL BE QUITE A CHALLENGE. >> I COMPLETELY AGREE SKIP. BUT I GUESS THAT IS WHY I AM NOT ENTIRELY CONVINCED THAT NOT ADDRESSING THE QUESTION BUT ADDRESSING THESE OTHERS IS REALLY GOING TO HELP IRBS ALL THAT MUCH. IT SHOULD BE ANSWERED BY IRBS THEMSELVES AND THAT IS WHY I THROW IT OUT THERE, I THOUGHT IT WOULD BE EASY. >> WOMAN: I THINK IT IS ALSO IMPORTANT TO ADDRESS THE FACT THAT REQUIRING SOMEONE TO HAVE A MANDATORY BIOPSY TO ENTER A TRIAL IS IN SOME WAYS NO WORSE THAN SAYING YOU HAVE TO TRAVEL CROSS-COUNTRY FROM CALIFORNIA TO BOSTON BECAUSE THAT IS THE ONLY SITE OR YOU HAVE TO STOPAND NOT TAKE THE NEXT POSSIBLE TKI THAT YOU MIGHT HAVE BECAUSE THAT WOULD DISQUALIFY YOU FROM THE TRIAL SO YOU HAVE TO TAKE CHEMO IF YOU WANT TO GET INTO THIS TRIAL. THERE IS A LOT OF UNDUE INFLUENCE IS THE PATIENT'S HAVE TO GO THROUGH WHEN THEY ARE INTERESTED IN CLINICAL TRIALS. >> MAN: I'M NOT HEARING STRONG CONSENSUS AT THIS POINT AS TO WHETHER THE SUBCOMMITTEE SHOULD PROCEED TO WRITE SOMETHING OR WHETHER WE SHOULD ABANDON THIS AND THAT IS PROBABLYDECISION WE SHOULD MAKE TODAY. >> WOMAN: SO THIS IS LESLIE. THE ONE QUESTION I HAVE IS REALLY ABOUT WHETHER THERE NEEDS TO BE A BRIDGE BETWEEN THE RECOMMENDATIONS FROM ASCO TO THE REGULATED COMMUNITY, AND THAT WILL BE THE ONE PLACE WHERE I THINK -- WE TALKED ABOUT THIS EARLIER, DOES THERE NEED TO BE SOME SORT OF AN ENDORSEMENT OF THIS IS A HELPFUL WAY OF LOOKING AT THINGS. AND YOU MAY WANT TO ASK ADDITIONAL QUESTIONS GIVEN THAT PERMISSION TO PUSH BACK. AND I DID WONDER AS YOU LISTENED TO THE PRESENTATIONS YOU SAW A BEAUTIFUL LITTLE CHART THAT LOOKS THERE ARE SIMILAR ACROSS NCI AND ASCO, IS IT ACCEPTABLE? DOES THAT MEAN I DON'T GET ASKED THE QUESTION THAT CONCERNS THIS PARTICULAR POPULATION FOR SOME REASON? OR THE NUMBER OF THEM OR OTHER THINGS? THERE MAY BE SOME VALUE IN NOT A VERY LENGTHY DOCUMENT BUT SOMETHING THAT AT LEAST COMMUNICATES, THERE HAS BEEN CAREFUL CONSIDERATION AND HERE ARE SOME OTHER THINGS YOU MAY WANT TO THINK ABOUT RATHER THAN JUST SAY OH, ASCO SAID IT MUST BE ACCEPTABLE AND MUST BE ACCEPTABLE IN ALL CASES BUT YOU CAN STILL AFTER QUESTION. >> WOMAN: CAN WE APPLY ASCO AND NCI DOCUMENTS TO NON-ONCOLOGY SETTINGS? >> ALSO A GOOD POINT. >> MAN: YEAH. IN SOME WAYS THAT WILL BE VALUE-ADDED, TO TAKE WHAT IS DESIGNED FOR A CANCER SETTING AND ADAPT IT TO ALL SETTINGS THAT AN IRB MIGHT ENCOUNTER IN A MANDATORY BIOPSY SITUATION. I DON'T THINK IT WOULD REQUIRE A LOT OF ADAPTATION; ASCO SPEAKS TO ONCOLOGISTS AND HEMATOLOGISTS AND NOBODY ELSE PROBABLY KNOWS WHAT THEY ARE DOING. (CHUCKLES) >> WOMAN: I THINK THAT THE DISCUSSION IS A LITTLE FLAT ON THE TOPIC; THERE IS PROBABLY SOMETHING WE CAN ALWAYS SAY ABOUT IT JUST NOT SURE -- I DON'T THINK I HEAR A ROUSING CHORUS OF POSITIVE THOUGHTS OR COMMENTS ABOUT MOVING FORWARD WITH THIS TOPIC. >> MAN: KEVIN, WERE YOU GOING TO SAY SOMETHING? >> FOLLOWING UP TO LESLIE'S COMMENT. IS THAT KIND OF A DOCUMENT THAT SACOR (SOUNDS LIKE) COULD PRODUCE? I DON'T HAVE THAT MUCH EXPERIENCE; THERE IS CLEARLY SOME PROBLEM IN SOME DIFFICULTY IN INTERPRETATION AND A GAP. AND I AGREE. IT DOES NOT SEEM LIKE WE HAVE HEARD A GOOD ARGUMENT FOR SOMETHING THAT IS RESPONSIVE TO THE TYPE OF A THING; AT THE SAME TIME, IT SOUNDS LIKE IT COULD BE HELPFUL BUT I DON'T KNOW THAT IS WITHIN SACOR'S SCOPE OR NOT? TO DO THAT KIND OF DRAWING ATTENTION TO MAKING AWARE OF >> WOMAN: THAT IS A JULIA QUESTION. >> ARE THERE OTHER TOPICS AROUND ONCOLOGY? >> THIS IS JULIA. I WOULD REITERATE THAT SACHRP REALLY EXISTS IN ORDER TO MAKE RECOMMENDATIONS TO THE SEC.; THOSE RECOMMENDATIONS AND TAKE VARIOUS FORMS, THEY CAN TAKE THE FORM OF FAQS FOR EXAMPLE, THEY COULD TAKE THE FORM OF RECOMMENDATIONS, FOR SPECIFIC DRAFTS. I THINK YOU WOULD NEED TO ASK YOURSELVES WHETHER IT IS HELPFUL TO THE COMMUNITY IF THE SUBSTANCE OF YOUR RECOMMENDATION IS REALLY JUST GOING TO BE IN EFFECT HIGHLIGHT OTHER MATERIALS THAT ALREADY EXIST. >> RIGHT, EXACTLY. >> >> WOMAN: IS IT SAFE TO ASSUME THAT IRBS WOULD ALL BE AWARE OF THOSE MATERIALS THEY DON'T DEAL WITH ONCOLOGY THAT OFTEN? DO ALL IRBS HAVE SOME EXPOSURE TO ONCOLOGY? >> MAN: I'LL SPEAK FROM MY IRB. 50% OF OUR PROTOCOLS ARE ONCOLOGY, I DON'T THINK UNTIL I JOINED THIS COMMITTEE THAT I KNEW ABOUT ASCO'S GUIDELINES. WITHOUT SOMEBODY SAYING HEY, THERE ARE SOME GUIDELINES THE IRBS WOULD NOT NECESSARILY KNOW THAT. >> WOMAN: I THINK IF AN IRB SAW AN ISSUE WITH THE MANDATORY BIOPSIES IN A NONONCOLOGY TRIAL AND DID SOME RESEARCH AND FIND THE ASCO GUIDANCE, JUST LIKE THEY WOULD FIND THE OTHER ARTICLES ON MANDATORY BIOPSIES I WOULD NOT SAY THAT IT IS JUST BECAUSE IT'S ASCO IRBS WOULD NOT KNOW ABOUT IT BECAUSE THERE IS SOME RESEARCH GOING ON TO MAKE SURE THAT IRBS ARE EDUCATED ABOUT DIFFERENT ISSUES. LIKE I SAID, DON'T FORGET IRBS DEAL WITH SO MANY DIFFERENT ISSUES THAT THERE IS ALWAYS SOMETHING AROUND EDUCATION GOING ON. >> WOMAN: (OFF MIC) -- >> MAN: THERE ARE VAST DIFFERENCES BETWEEN THE IRBS AND THE [NOT UNDERSTOOD]-- IF WE WROTE SOMETHING THERE WILL BE SOME PEOPLE THAT WILL FIND HELPFUL AND OTHERS NOT. >> WOMAN: I AM DISPLAYING MY IGNORANCE ON IRBS HERE. IS THERE A CENTRAL SITE WHERE AN IRB COULD GO TO FIND ONE PLACE ALL THE REFERENCE DOCUMENTS THEY WOULD FIND HELPFUL IN MAKING DECISIONS? >> MAN: NO. I MEAN -- THE OHRP WEBSITE IS ONE PLACE WHETHER LOOK FOR GUIDANCE. >> WOMAN: WOULD IT BE UNREASONABLE TO SUGGEST THAT WE RECOMMEND TO OHRP TO MAKE THE ASCO AND NCI DOCUMENTS AVAILABLE ON THAT WEBSITE? >> FOR [NOT UNDERSTOOD], IT HAS TO GO THROUGH THE GUIDANCE PROCESS FOR OHRP -- AS A FORMER REGULATOR, TO POST SOMETHING THAT YOU THEN PUT YOUR IMPRIMETEUR ON, IT HAS TO GO THROUGH SOME SORT OF GUIDANCE PROCESS. THEY COULD SPEAK FOR THEMSELVES BUT I SUSPECT THAT WOULD BE PROBLEMATIC. >> WOMAN: THANK YOU SKIP, I THINK THAT WAS WELL SAID. I THINK IT WILL BECOME COMPLICATED, THAT IS NOT THE TYPE OF THING THAT SACHRP SHOULD DO. >> MAN: OKAY HOW ARE WE GOING TO MAKE THIS DECISION? >> YOU ARE SUPPOSED TO TELL US, YOU ARE THE CHAIR. >> LIKE -- I AM NOT SENSING A GREAT DEAL OF ENTHUSIASM. I GUESS I SHOULD HEAR FROM COMMITTEE MEMBERS WHO DO THINK WE SHOULD HAVE SOMETHING IN WRITING ABOUT THIS TOPIC. >> MAN: WHETHER THERE REALLY IS SOME SORT OF BURNING PLATFORM, WE COULD ASK THE SUBCOMMITTEE TO GO BACK AND DETERMINE WHETHER THERE IS INDEED SUCH A BURNING PLATFORM. I DIDN'T -- NONE OF US SEEM TO HAVE HEARD IT -- MAKES IT UNCLEAR WHAT IS DRIVING THE DISCUSSION WE HAD TODAY. >> WHAT DO YOU THINK ABOUT THAT? YOU WANT TO ASK THE SUBCOMMITTEE TO SEE IF THEY CAN FIND A FIRE? >> SURE, I'LL DO THAT. >> WE ARE NOT KICKING IT DOWN THE ROAD BUT IT DOES SEEM THERE IS AN EXTENSIVE DISCUSSION ON THIS ISSUE TODAY AND WE ARE MISSING THE DRIVER AND THE MOTIVATION BEHIND IT. >> WOMAN: SO I'M HAPPY TO TAKE IT BACK TO THE SUBCOMMITTEE AND HAVE MORE OF A CONVERSATION. >> MAN: I THINK WE CAN PROBABLY CONVEY TO THE SUBCOMMITTEE THAT THE SENSE OF NEED WAS NOT THERE. IF THEY KNOW SOMETHING THAT WE DON'T, MAYBE IT IS WORTH PURSUING BUT IF THEY ARE NOT FINDING A COMPELLING NEED FOR A DOCUMENT, MAYBE WE SHOULD DROP IT. >> THE THREE OF US OF US ARE ON THE SUBCOMMITTEE, SKIP, LINDA AND MYSELF. >> MAN: I'M THINKING ABOUT THE COMPLEXITY OF DOING THIS ASSESSMENT. TWO THOUGHTS COME TO MIND. IS THIS A PROBLEM OR NOT? AND MY NEXT THOUGHT WAS, NO ONE ON THIS CALL CAN REACH OUT AS PART OF THEIR FEDERAL CAPACITY TO DO THAT BECAUSE IF THEY ASK MORE THAN NINE PEOPLE THEY VIOLATED THE PAPERWORK REDUCTION ACT I THINK. (CHUCKLES) YEAH, IT'S A THING. SOMEBODY IN THEIR PRIVATE CAPACITY WOULD HAVE TO DECIDE AND DO A NEEDS ASSESSMENT BY PUTTING SOMETHING IN THE IRB FORM OR PUTTING A QUESTIONNAIRE WITH A LINK TO IT. HEY, IS THIS A PROBLEM OR NOT? IT IS NOT AS IF SACHRP -- I'M ASSUMING ALSO A SUBCOMMITTEE OF SACHRP COULD IN ANY WAY GO OUT AND DO A FORMAL NEEDS ASSESSMENT EXCEPT ASKING A FEW PEOPLE IF THEY KNOW IF THIS IS A PROBLEM. I'M NOT SURE WHAT I WOULD DO WITH A REQUEST FOR NEEDS ASSESSMENT FRANKLY. >> MAN: I DON'T KNOW THAT HE WOULD NEED TO BE A FORMAL NEEDS ASSESSMENT. IF YOU THINK ABOUT OUR DISCUSSION EARLIER TODAY, YOU KNOW THE PIECE MARK WORKED ON, HE HAD A NUMBER OF IMPORTANT EXAMPLES ON THE DOCUMENT THAT DEMONSTRATED THE NEED FOR THIS AND THAT IS WHAT WE HAVE NOT HEARD. I HAVE NOT HEARD A GOOD CASE EXAMPLE. >> THERE IS PROBABLY NO LAW FIRMS THAT HAVE CLIENTS COMING TO THEM WITH BIOPSIES, OTHERWISE WE WOULD HAVE SUCH CASES SO I DO NOT KNOW HOW WE WOULD FIND THE FIRE. I THINK OTHER PEOPLE HAVE AN IDEA BUT I DO NOT KNOW HOW WE WOULD FIND A FIRE. >> WELL THAT IS GOOD QUESTION. WE ALSO HAVE SEVERAL PEOPLE WHO DOIRB WORK AND I HAVE NOT HEARD EXAMPLES FROM THOSE FOLKS EITHER AS TO WHETHER GUIDANCE WOULD BE IMPORTANT OR USEFUL. I MEAN, LINDA YOU'RE ONE OF THOSE PEOPLE. I DON'T KNOW IF YOU HAVE THOUGHTS. >> LINDA: THE ONLY THING I WOULD SAY IS SIMILAR TO WHAT LESLIE SAID, BECAUSE GUIDANCE IS SO FOCUSED ON ONCOLOGY, AND SINCE JULIA MENTIONED, WE DO NOT NECESSARILY HAVE TO DO A LONG, NARRATIVE DOCUMENT. WE COULD DO SOMETHING VERY SHORT, MORE LIKE A REMINDER TO THE IRB THAT THEY DO HAVE THE AUTHORITY TO PRESCRIBE SOME OF THESE THINGS AND HERE ARE SOME THINGS YOU MAY WANT TO LOOK AT AND HERE'S SOME USEFUL GUIDANCE YOU MIGHT BE ABLE TO USE IN ANOTHER AREA. I AM NOT SURE HOW THAT WOULD LOOK LIKE AND THAT WOULD BE THE ONLY THING I PROBABLY WOULD RECOMMEND ABSENT SOMETHING MORE SPECIFIC BECAUSE I DON'T RECALL ANY -- EVEN SOME OF THE EXAMPLES DISCUSSED THAT ROSE TO THE LEVEL OF HAVING SOME SORT OF CONFLICT. I CAN SEE THE POWERPOINT BUT THAT IS WHERE I AM LANDING AND WHAT I'M SAYING IS I CAN GO EITHER WAY. IF WE HAVE A SITUATION, WE ARE GOING TO GO AHEAD AND DOING DEPENDENT RESEARCH AND MAKE ANY OTHER AREA WHERE WE DON'T HAVE CERTAIN ETHNICITIES, WE ARE GOING TO GO OUT AND SEEK IT, THAT IS HOW OUR IRB WOULD APPROACH THIS. >> WOMAN: I WOULD SAY THAT [NOT UNDERSTOOD] IT HAS NOT BEEN AN ISSUE. THERE ARE TIMES WHETHER MANDATORY BIOPSIES IN RESEARCH AND THE IRB CAN PUSH BACK AND GET MORE INFORMATION, HOW THOSE GET RESOLVED I CANNOT SAY FOR SURE BUT I DO KNOW THAT THERE ARE LOTS OF TIMES WHEN THEY ASKED FOR MORE INFORMATION AND I WILL SAY THAT IT WAS MY TIME AT DANA FARBER (SOUNDS LIKE) WERE MANDATORY BIOPSIES WERE MORE OF AN ISSUE, WHEN THEY WERE IN NCI COOPERATIVE RESEARCH WHERE WE HAD TO RELY ON THE NCI IRB, AND IN THOSE TRIALS THERE WAS A HUGE AMOUNT OF PUSHBACK FROM THE INSTITUTION, FROM THE INVESTIGATORS BECAUSE WE WERE NOT SERVING AS THE IRB, AND THEY DID NOT WANT TO HAVE THE MANDATORY BIOPSIES, JUST AS AN INTERESTING SITUATION ESPECIALLY GIVEN WHAT THE NCI PRESENTATION. >> SO WE SHOULD PROBABLY WRAP THIS UP. CAN WE DO AN INFORMAL SHOW OF HANDS? AND I AM GOING TO ASK OF THE COMMITTEE MEMBERS IF YOU THINK THAT IT WOULD BE USEFUL FOR THE SUBCOMMITTEE TO DEVELOP SOMETHING? WHETHER FAQS OR SOME BASIC GUIDANCE THAT MAY BE REFLECT THE QUESTIONS THAT WERE PRESENTED TO US ALONG WITH SOME MODIFICATION OF ASCO. JUST RAISE YOUR HAND AND WILL GET A SENSE OF HOW MANY PEOPLE THINK THIS IS WORTH PURSUING. I AM NOT SEEING ANY HANDS. THAT WOULD SUGGEST A MERE LACK OF ENTHUSIASM TO PURSUE THIS ANY FURTHER. DOES THAT SOUND OKAY MICHELLE? >> FINE WITH ME. >> OKAY. >> MICHELLE: I THINK IT'S BEEN A GREAT DISCUSSION AND A GREAT LEARNING EXPERIENCES AND I APPRECIATE GETTING TO KNOW THE PANELISTS AND WE GET TO MOVE ONTO ANOTHER TOPIC. >> ALRIGHT SO WE HAD NO PUBLIC COMMENTS THROUGHOUT THE DAY. WE DO NOT HAVE THAT TO DEAL WITH. AND I WILL JUST WRAP UP TODAY'S MEETING BY ONCE AGAIN THANKING EVERYBODY FOR YOUR PARTICIPATION AND CONTRIBUTION AND TIME. AS WELL AS THE SUBCOMMITTEE CHAIRS FOR ALL THEIR TIME AND EFFORT AND WORK THAT GOES INTO PREPARING FOR THIS MEETING. AND TOMORROW WE'VE GOT ANOTHER BUSY AGENDA. WE ARE GOING TO TRY TO CARVE OUT SOME TIME TO GO BACK TO THE INTERACTIONS BETWEEN SPONSORS, CLINICAL TRIALS IN SUBJECTS AND WE WILL DO THAT BY STEALING A LITTLE TIME AS WE GO THROUGH THE AGENDA TOMORROW. OTHERWISE, ANY LAST ANNOUNCEMENTS JULIA? ANYTHING WE NEED TO SAY BEFORE WE LET FOLKS GO? >> JULIA: THANK YOU DOUG. I ALSO WANT TO COME IN FOR THE RECORD THAT WE DID NOT RECEIVE ANY PUBLIC COMMENT IN ADVANCE OR DURING THE MEETING. TOMORROW WILL START PROMPTLY AT 11. I WOULD ASK MEMBERS AND SPEAKERS TO PLEASE DIAL IN BY 10:45. SO MY HEART DOES NOT STOP THINKING I NOT HAVE A QUORUM, OKAY? PLEASE DIAL IN BY 10:45, I WOULD VERY MUCH APPRECIATE IT. THAT IS REALLY ALL FOR ME AND I THANK YOU ALL VERY, VERY MUCH. >> THANKS EVERYBODY. >> BYE. >> THANK YOU. >> UNTIL TOMORROW.