>> GOOD MORNING, EVERYBODY. WELCOME TO THE SPECIAL IND TRAINING COURSE. MY NAME IS JOHN GALLIN, DIRECTOR OF THE CLINICAL CENTER. AND I WANT TO WELCOME EVERYBODY HERE FOR WHAT I THINK IS AN EXAMPLE OF WHY IT'S GREAT TO BE WORKING HERE, TO GET ACCESS TO SOME REALLY SPECIAL THINGS RIGHT AT THE BEGINNING, AND TODAY'S COURSE IS ONE OF THOSE. SO THIS SESSION WILL BE ON INVESTIGATIONAL NEW DRUG APPLICATIONS AIMED AT EDUCATING ALL OUR STAFF, CLINICAL INVESTIGATORS, TRAINEES AND ALL THE SUPPORT STAFF ON THE RELEVANT FDA REGULATIONS AND THE PROCESS OF PREPARING AND SUBMITTING AN IND APPLICATION. SO IT IS CRITICAL IF YOU WANT TO DO WORK ON DRUG DISCOVERY, THAT YOU NEED TO UNDERSTAND THE REGULATORY REQUIREMENTS, THE ETHICAL MANDATES, AND THE MECHANISMS AVAILABLE TO INTERACT WITH OUR COLLEAGUES AT THE F.D.A. SO THAT'S WHAT WE'RE HERE TO DISCUSS THIS DAY. TO THIS END, A JOINT TASK FORCE OF THE CLINICAL CENTER AND THE CENTER FOR DRUG EVALUATION AND RESEARCH WAS ESTABLISHED IN EARLY 2012, WITH THE PURPOSE OF THAT TASK FORCE TO PROMOTE EARLY ENGAGEMENT OF FDA REGULATORY SCIENTISTS AND NIH INVESTIGATOR PLANNING TO SUBMIT AN IND APPLICATION AND TO DEVELOP TOOLS AND EDUCATIONAL SESSIONS ON IND APPLICATIONS TO THE BENEFIT OF OUR CLINICAL INVESTIGATORS AND TRAINEES AND ALSO TO EXPORT THIS BROADLY THROUGHOUT THE COUNTRY. OF PARTICULAR INTEREST ARE THE IND-ENABLING PRE-CLINICAL DATA THAT MUST BE PROVIDED IN ORDER TO INITIATE A STUDY IN HUMAN SUBJECTS WITH BENEFIT AND RISK ASSESSMENT BEING A PRIMARY CONSIDERATION, BOTH FOR RESEARCH AND DRUG DEVELOPMENT AND ALSO FOR THE TREATMENT OF PATIENTS WITH RARE DISEASES WITH NO ALTERNATIVE THERAPIES AVAILABLE. AS YOU KNOW, THE CLINICAL CENTER IMPLEMENTS A VERY SIGNIFICANT NUMBER OF PHASE I STUDIES, INDEED 34% OF THE APPROXIMATELY 700 CLINICAL TRIAL PROTOCOLS WE HAVE, 34% ARE PHASE I OR FIRST-IN-HUMAN STUDIES. TODAY'S COURSE WHICH WILL BE FOCUSED ON IND APPLICATIONS IS AN IMPORTANT PRODUCT OF THE WORK OF THE TASK FORCE THAT WAS PUT TOGETHER IN 2012, AND THIS COURSE TOGETHER WITH THE LAUNCH OF AN IND WEB NAVIGATIONAL TOOL LAST MONTH, WE BELIEVE, PROVIDES IMPORTANT RESOURCES FOR EVER EVERYONE. SO TODAY, I THINK WE CAN ALL LOOK FORWARD TO SOME VERY VALUABLE PRESENTATIONS, BOTH BY THE NIH AND FDA STAFF AND AN EQUALLY VALUABLE AND PRODUCTION DISCUSSION OF BEST PRACTICES IN THIS IMPORTANT PIECE OF CLINICAL RESEARCH. BEFORE I END, I WANT TO THANK DR. JANET WOODCOCK, DIRECTOR OF CENTER FOR EVALUATION AND RESEARCH AND JOHN GENERAL SINCE, HERE TODAY, DIRECTOR OF THE OFFICE OF NEW DRUGS AT THE CENTER, FOR THEIR LEADERSHIP IN CREATING THIS COLLABORATION. I ALSO WANT TO ACKNOWLEDGE DAVID HENDERSON, THE DEPUTY DIRECTOR FOR CLINICAL CARE AT THE CLINICAL CENTER FOR HIS WORK IN HELPING TO ESTABLISH THE JOINT TASK FORCE AND TO ANNE PARIASA, THE ASSOCIATE DIRECTOR IN THE CDER CENTER. I WANT TO THANK JUAN LERTORA, DIRECTOR OF THE CLINICAL PHARMACOLOGY PROGRAM, CO-CHAIRING THE TASK FORCE AND ALSO FOR BEING THE CO-LEADER, ALONG WITH DR. LARISSA LAPTEVA, OF TODAY'S SESSION. DR. LAPTEVA IS IN THE RARE DISEASES PROGRAM AT THE FDA'S CENTER FOR DRUG EVALUATION AND RESEARCH AND THE OFFICE OF NEW DRUGS. SO MANY THANKS TO ALL OF THEM, AS WELL AS TO ALL THE SPEAKERS YOU'RE GOING TO HEAR FROM TODAY, AND I WISH YOU ALL A SPECIAL COURSE AND WE LOOK FORWARD TO YOUR FEEDBACK SO THAT FUTURE GENERATIONS OF THIS COURSE WHICH WILL BE POSTED ON THE WEB FOR FUTURE GENERATIONS OF THE COURSE CAN BE IMPROVED. I UNFORTUNATELY AM GOING TO HAVE TO LEAVE, I HAVE TO DO SOMETHING IN BUILDING ONE. BUT I WILL BE BACK AND GET FEEDBACK AS WELL, SO THANKS A LOT AND HAVE A GREAT DAY. LET ME INTRODUCE JUAN LERTORA, WHO IS GOING TO GIVE YOU SOME DETAILS. [APPLAUSE] >> THANK YOU VERY MUCH, DR. GALLIN. AND WELCOME, EVERYONE. WE LOOK FORWARD TO A VERY EXCITING SESSION TODAY. A SPECIAL WELCOME TO COLLEAGUES FROM THE FOOD AND DRUG ADMINISTRATION. AND TO MY EVENT CO-CHAIR TODAY, DR. LARISSA LAPTEVA. I WANT TO ALSO BEGIN BY ACKNOWLEDGING ALL THE MEMBERS OF THE JOINT TASK FORCE THAT WAS ESTABLISHED IN EARLY 2012, THE SLIDE SHOWS THE MEMBERSHIP FROM THE CENTER FOR DRUG EVALUATION AND RESEARCH, AND IN THE NEXT SLIDE, YOU HAVE THE MEMBERS OF THE TASK FORCE HERE AT NIH REPRESENTING SEVERAL OF THE NIH INSTITUTES, AND, AGAIN, OUR THANKS TO DR. DAVID HENDERSON FOR HELPING IN THE ORGANIZATION OF THIS TASK FORCE A COUPLE OF YEARS AGO. SO, WE WILL HAVE A NUMBER OF SESSIONS FOLLOWED BY QUESTIONS AND ANSWERS, AND SOME DISCUSSION PANELS, AS WE MOVE ALONG DURING THE DAY. AND WE HAVE SOME PRINTED PROGRAMS IN THE BACK, IF YOU WANT TO GET ONE, TO FOLLOW THE GENERAL AGENDA, BUT OF COURSE YOU HAVE THE PROGRAM, VIA THE REGISTRATION SITE, I AND THE WEBSITE FOR THE COURSE. LET ME NOW INTRODUCE DR. LARISSA LAPTEVA, WHO WILL MAKE SOME REMARKS AND THEN WE'LL BEGIN WITH THE PROGRAM. >> THANKS, VERY MUCH, JUAN. I'M LARISSA LAPTEVA AND I WORK IN THE OFFICE OF NEW DRUGS IN THE CENTER AT THE DRUG EVALUATION AND RESEARCH. IT'S A GREAT PLEASURE TO BE HERE AND CO-CHAIR THIS EDUCATIONAL ACTIVITY WITH JUAN LERTORA. COMPLETEDER NIH-ER, MEET THE RHEUMATOLOGY FELLOWSHIP, AND WORKED IN THE ROLE OF CLINICAL INVESTIGATOR FOR SEVERAL YEARS, WAS A LEAD INVESTIGATOR AND CO-INVESTIGATOR IN A NUMBER OF NIH-BASED PROTOCOLS AND HAD TO SUBMIT AND IND APPLICATION AT THE TIME AND ALSO DID I KNOW THAT I WOULD END UP WORKING THERE, NIN THAT WAS ABOUT NINE YEARS AGO. THIS EXPERIENCE IN BEING BOTH ON THE STANDING END AND RECEIVING END OF THE IND APPLICATION PROCESS HAS REALLY TURNED OUT TO BE QUITE HELPFUL IN THE ORGANIZATION OF THIS COURSE, BECAUSE WE WANTED THIS EDUCATIONAL ACTIVITY TO BE INFORMATIVE, AS WELL AS USEFUL TO THE NIH INVESTIGATIONORS IN THE CLINICAL RESEARCH COMMUNITY SO WHEN IT'S TIME FOR YOU TO ASSEMBLE AN IND APPLICATION AND PUT IT TOGETHER, AND WHEN YOU NEED TO WORK WITH THE REGULATORY AGENCY, NO ORDER TO MOVE YOUR RESEARCH FORWARD YOU KNOW HOW TO DO IT. SO WE HAVE EIGHT SESSIONS TODAY. EACH SESSION IS STRUCTURED TO HAVE ONE NIH PRESENTER AND ONEMDA PRESENTER, ALL THE M DA PRESENTERS HAS PRACTICAL HANDS-ON EXPERIENCE IN REVIEWING AND ASSESSING IND APPLICATIONS AND PROVIDING FEEDBACK ON APPLICATIONS, SO WE INVITE YOU TO TAKE ADVANTAGE OF THEM BEING HERE, ENGAGING CONVERSATIONS, ASKING QUESTIONS, ON THE TOPICS THAT ARE OF INTEREST TO YOU. WELL, SO WITHOUT FURTHER ADO, OUR FIRST SPEAKER IS IS DR. JOHN JENKINS, DIRECTOR OF THE OFFICE OF NEW DRUGS AND CENTER OF DRUG EVALUATION AND RESEARCH AND HE WILL BE TALKING ABOUT NDA ENTER TECA PERSPECTIVE AND FDA EXTRA SIEGIC BY REPORTS FOR DEVELOPMENT OF PRODUCTS FOR THE TREATMENT OF RARE DISEASES. >> GOOD MORNING. THANKS, LARISA, FOR THAT INTRODUCTION. IT'S GREAT TO BE HERE BECAUSE THIS IS REALLY A PROJECT THAT'S BEEN GOING ON FOR A COUPLE YEARS TO GET TO THIS POINT, A GREAT EXAMPLE OF COLLABORATION BETWEEN THE FDA AND NIH CLINICAL CENTER TO TRY TO ADVANCE CLINICAL RESEARCH. SO THIS IS WHAT I'D LIKE TO TALK ABOUT TODAY, A LITTLE BIT MORE IN DETAIL ABOUT THE ORIGINS AND GOALS OF THE CLINICAL CENTER AND NIH-FDA TASK FORCE, TO GIVE YOU A HIGH LEVEL INTRODUCTION TO WHO FDA IS AND THE ROLE OF THE CONDUCT OF CLINICAL RESEARCH AND ETHICAL UNDERPINNINGS OF THE OVERSIGHT, I'D LIKE TO GIVE YOU A VERY HIGH LEVEL VIEW OF EXPANDED ACCESS OR COMPASSIONATE USE YOU MAY HAVE HEARD ABOUT INVESTIGATIONAL DRUGS, DESCRIBE KEY POINTS WE THINK ARE IMPORTANT FOR YOU TO KEEP IN MIND AS YOU GO THROUGH THE TRAINING SESSION TODAY AND THEN VERY HIGH LEVEL OVERVIEW OF TODAY'S MEETING. SO THE TASK FORCE WAS FORMED TWO YEARS AGO, WE RECOGNIZE THERE WERE SOME CHALLENGES IN THE INTERACTION BETWEEN THE CLINICAL CENTER STAFF AND FDA STAFF, AS FAR AS IND'S AND TRANSLATIONAL RESEARCH. AS YOU SAW THE TASK FORCE HAS BROAD REPRESENTATION FROM NIH AS WELL AS CDER AND F.D.A. WE STARTED WITH GOALS TO IMPROVE COMMUNICATION ON IND PROTOCOLS AND TRANSLATIONAL RESEARCH. WE WANTED TO IDENTIFY AND TRY TO FIND SOLUTIONS TO RECURRING ISSUES. ONE OF THOSE RECURRING ISSUES WAS THAT WE OCCASIONALLY WERE PLACING YOUR IND'S IN CLINICAL HOME, YOU COULDN'T DO YOUR INVESTIGATIONS BECAUSE WE DIDN'T THINK THEY MET THE REGULATORY REQUIREMENTS OR THAT PATIENTS WEREN'T BEING ADEQUATELY PROTECTED IN THOSE IND'S, AND OBVIOUSLY THAT LED LED TO LET WITH CLINICAL CENTERS AND REGULATORS BECAUSE YOU WANTED TO DO TRIALS AND WE WANTED TO MAKE SURE THEY MET THE REGULATORY REQUIREMENTS AND ADEQUATELY PROTECTED PATIENTS. WE WANTED TO TRY TO FIND WAYS TO SOLVE RECURRING ISSUES SO THAT WE WEREN'T AT ODDS WITH EACH OTHER UNNECESSARILY. WE ALSO DECIDED THAT A WAY TO GET TO THAT POINT WAS TO ACHIEVE EARLY ENGAGEMENT. TO HAVE EARLY INTERACTION, CLINICAL CENTER INVESTIGATORS AND FDA, SO HE COULD UNDERSTAND WHAT WE WOULD NEED TO ALLOW YOUR IND TO PROCEED SO THAT WHEN YOU CAME TO US WITH YOUR IND, YOU WOULD NOT GO ON CLINICAL HOLD. THE OUTCOMES OF THAT PARTNERSHIP SO FAR HAVE BEEN TRAINING MATERIALS, INCLUDING TODAY'S SESSION, YOU HEARD ABOUT THE ONLINE TOOL CHEST THAT'S AVAILABLE NOW TO HELP YOU AS YOU'RE NAVIGATING THROUGH, DEVELOPING AND SUBMITTING YOUR IND, WE'VE HAD MEETINGS AND SCIENTIFIC EXCHANGES INCLUDING PRE-PRE-IND MEETINGS WHERE WE MEET WITH YOU VERY EARLY TO UNDERSTAND WHAT YOU'RE INVESTIGATING, WHAT YOUR GOALS ARE, SO WE CAN HELP YOU UNDERSTAND WHAT YOU NEED TO COME TO US WITH TO ENABLE THE INITIATION OF THAT IND. WE'VE DESCRIBED THE ONLINE TOOLS. AND WE'VE ALSO ESTABLISHED A PROCESS FOR RAPID COMMUNICATION WHEN ISSUES ARISE, FOR EXAMPLE IF YOU SUBMIT AN IND AND WE PUT THAT ON CLINICAL HOLD, BUT YOU THINK IT'S VERY CRITICAL THOSE PATIENTS BE TREATED, WE'VE ESTABLISHED A PROGRAM BY WHICH THERE COULD BE RAPID COMMUNICATION TO TRY TO RESOLVE THOSE ISSUES VERY QUICKLY. WE RECOGNIZE IN THIS PARTNERSHIP THAT WE HAVE SHARED GOALS. WE WANT TO IMPROVE PUBLIC HEALTH THROUGH RESEARCH AND DEVELOPMENT, WE WANT TO ADDRESS UNMET MEDICAL NEEDS FOR PATIENTS, FIND TREATMENTS FOR SERIOUS AND LIFE-THREATENING DISEASES, INCLUDING RARE DISEASES AND THOSE UNDERSERVED POPULATIONS. SO WE DO HAVE SHARED PUBLIC HEALTH GOALS. FDA IS RESPONSIBLE FOR ENSURING THAT PRODUCTS THAT ARE MARKETED ARE SAFE, EFFECTIVE AND HIGH QUALITY, BUT WE ALSO HAVE A VERY IMPORTANT ROLE IN OVERSEEING THE CLINICAL TRIAL PROCESS. SO THAT'S ONE OF THE PLACES WHERE WE'RE GOING TO INTERFACE WITH YOU THE MOST, WE HAVE A RESPONSIBILITY TO PROTECT SUBJECT AND CLINICAL TRIALS, SUBJECT TO FDA REGULATION, BY OVERSEEING THOSE TRIALS. SOME OF THE STRATEGIC PRIORITIES WE HAVE IN THE OFFICE OF NEW DRUGS AND CENTER FOR DRUGS IS TO FACILITATE DRUG DEVELOPMENT FOR RARE DISEASES, SERIOUS LIFE-THREATENING DISORDERS WITH UNMET MEDICAL NEEDS. WE DO THIS BY ENGAGING STAKEHOLDERS, INCLUDING PATIENTS AND RESEARCHERS, TO HELP THEM UNDERSTAND AND HELP US HELP THEM UNDERSTAND THE DRUG DEVELOPMENT PROCESS, AND WE ALSO HAVE A CRITICAL PATH INITIATIVE WHICH IS RELATED TO TRYING TO IMPROVE THE TRANSLATIONAL SCIENCE TO GO FROM BENCH TO BEDSIDE, TO FACILITATE DRUG DEVELOPMENT. THIS IS ABOUT A 90,000-FOOT VIEW OF WHO FDA IS. WE'RE ORGANIZED INTO CENTERS, BASED ON THE TYPE OF PRODUCT THAT IS BEING UTILIZED IN PATIENTS OR APPROVED FOR USE IN PATIENTS. SO WE'RE IN THE CENTER FOR DRUG EVALUATION AND RESEARCH, WE REGULATE AND REVIEW ALL DRUGS, SMALL MOLECULES AND THERAPEUTIC MODULES SUCH AS ENZYME REPLACEMENT THERAPY, HORMONES, AND IN THE OFFICE OF NEW DRUGS WE'RE ABOUT A THOUSAND PEOPLE, WE HAVE ABOUT 350 PHYSICIANS, ORGANIZED INTO 18 THERAPEUTIC REVIEW DIVISIONS BY THE TYPE OF INDICATION THAT YOU'RE SEEKING. SO FOR EXAMPLE IF YOU'RE STUDYING A DRUG FOR CARDIAC DISEASE, THAT'S GOING TO BE REVIEWED BY EXPERTS IN OUR CARDIO-RENAL DIVISION. A PULMONARY DRUG WILL BE IN OUR PULMONARY DRUGS DIVISION. SO WE HAVE A LOT OF CLINICAL EXPERTSE, REGULATORY EXTRA SEES, PHARMACOLOGY AND FOX TOXICOLOGY, STA STATISTICIANS, A WHOLE TEAM OVERSEEING DRUGS AND THERAPEUTIC AND BIOLOGIC AND ULTIMATELY MAKE DECISIONS ABOUT WHAT'S APPROVED. FDA HAS A CENTER FOR BIOLOGICS, SOME ON THE NIH CAMPUS, REVIEWING BIOLOGICS, BLOOD PRODUCTS, TISSUE DRUG BIOLOGIC PRODUCTS, STEM CELL AND GENE LOGIC A DEVICE AND RADIO LOCKIC CENTER, COMPANION TESTS, A CENTER FOR FOOD SAFETY AND APPLIED NUTRITION, WHICH OVERSEES THE REGULATION OF FOODS AND DIE CENTE DIETARY SUPPLEMENTS EXCEPT WHEN BEING INVESTIGATED FOR DRUG USE. IF YOU HAVE A DIE CENTE DIETARY SUPPLEMENT BUT SEEKING A CLAIM FOR A DRUG THOSE ARE REGULATED BY CDER. OUR OVERSIGHT OF INVESTIGATIONS IN HUMANS GENERALLY BEGINS AT THE FIRST INTRODUCTION OF THAT DRUG, OF AN INVESTIGATIONAL DRUG INTO HUMAN SUBJECTS. WE HAVE A LEGAL RESPONSIBILITY AND MORAL AUTHORITY FOR PROTECTING THE RIGHTS AND SAFETY AND WELFARE OF HUMAN SUBJECTS ENROLLED IN FDA-REGULATED CLINICAL INVESTIGATIONS. AND ALSO PROTECTING PUBLIC HEALTH FOR ASSURING THE SCIENTIFIC CREDIBILITY OF FDA FDA-REGULATED INVESTIGATIONS. WE LOOK AT THE SAFETY OF THE HUMAN SUBJECTS ENROLLING IN THE TRIALS TO MAKE SURE THEY ARE NOT UNREASONABLY HARMED BY ENROLLING IN THE TRIAL AND WE LOOK TO MAKE SURE THAT THE INVESTIGATIONS ARE OF HIGH QUALITY SO THAT THEY CAN BE INTERPRETED SO THAT WE'RE NOT WASTING THAT HUMAN CAPITAL, SO TO SPEAK, BY ALLOWING PATIENTS TO ENROLL IN CLINICAL TRIALS TO DON'T LEAD TO INTERPRETABLE RESULTS. THERE ARE REQUIREMENTS FOR THE CONDUCT OF HUMAN EXPERIMENTATION DESTRIVED FROM SHARED PRINCIPLES, CODIFIED INTO LAW THROUGH REGULATION IN 21 CFR 2312, THEE AND THEY HAVE ROOTING IN HISTORICAL EVENTS. A LOT OF REGULATION AND OVERSIGHT OF DRUGS HAS BEEN ROOTED IN TRAGEDIES. THAT'S WERE THESE ARE CODIFIED INTO THE REGULATORY FRAMEWORK TO AVOID THE HISTORICAL EVENTS. THOSE PRINCIPLES BROADLY STATE THAT MEDICAL RESEARCH MUST CONFORM TO GENERALLY ACCEPTED SCIENTIFIC PRINCIPLES WHICH WE REFER TO AS GOOD CLINICAL PRACTICES, BASED ON THOROUGH UNDERSTANDING OF SCIENTIFIC INFORMATION FROM RELEVANT SOURCES SUCH AS RESULTS OF ANIMAL AND OTHER EXPERIMENTATION ADEQUATE TO SUPPORT POST CLINICAL TRIALS AND OF SUFFICIENT QUALITY TO ASSURE THE RESULTS ARE CREDIBLE AND ACCURATE. SO THESE TRIALS ARE LIKELY TO GENERATE DATA THAT ARE GOOD FOR THE SOCIETY. BEFORE A TRIAL IS INITIATED THERE MUST BE A CAREFUL ASSESSMENT OF FORESEEABLE RISKS TO PATIENTS ENROLLED IN THE TRIAL WEIGHED AGAINST ANTICIPATED BENEFITS FOR STUDY SUBJECT AND CONDUCTED IN A WAY TO MINIMIZE THOSE RISKS. THE CONDUCT OF EACH STUDY MUST BE CLEARLY DESCRIBED IN THE PROTOCOL THAT YOU SUBMIT TO US FOR REVIEW. WHEN WE RECEIVE A PROTOCOL FOR AN IND STUDY WE REVIEW IT WITH THOSE PRINCIPLES IN MIND. WE LOOK AT THE STUDY DESIGNS BECAUSE WE REALIZE THEY ARE EXPECTED TO VARY DEPENDING UPON MANY FACTORS SUCH AS THE NOVELTY OF THE DRUG, ANY PRIOR EXPERIENCE WITH THAT DRUG OR THAT CATEGORY OF DRUGS, AND WHAT DEVELOPMENTAL PHASE THE STUDY IS OCCURRING IN SUCH AS PHASE I, PHASE II, PHASE III. WHEN WE LOOK AT PROTOCOL WE EXPECT IT WILL GENERALLY CONTAIN AT A MINIMUM ANIMAL PHARMACOLOGY AND TOXICOLOGY STUDIES SO WE CAN UNDERSTAND WHAT DOES THE DRUG DO PHARMACOLOGICALLY AND WHAT ARE THE OBSERVED TOXICITIES WHEN THAT DRUG IS GIVEN TO ANIMALS SO THAT WE CAN PREDICT TOXICITIES THAT MAY OCCUR IN HUMANS AND TRY TO MITIGATE THOSE OR PREVENT THOSE. WE NEED ADEQUATE INFORMATION ON THE MANUFACTURING OF THE DRUG THAT YOU PLAN TO ADMINISTER TO THE PATIENTS. SO IT'S NOT ADEQUATE JUST TO BUY A CHEMICAL FROM SIGMA AND DECIDE TO GIVE IT INTRAVENOUSLY TO HUMAN SUBJECTS. WE NEED TO UNDERSTAND WHAT EXACTLY THE MANUFACTURING PROCESS WAS, WHAT ARE THE INACTIVE INGREDIENTS AND IMPURITIES IN THAT PRODUCT THAT YOU OBTAINED FROM WHEREVER YOU'VE RECEIVED IT AND IN PARTICULAR IF YOU'RE GIVING IT PARETNERAR, INTRAVENOUSLY, SUBCUTANEOUS WE'RE LOOKING AT WHETHER IT'S SAFE TO BE ADMINISTRATE TO HUMAN SUBJECTS. WE ALSO LOOK AT WHETHER THE CLINICAL PROTOCOL IS ADEQUATE TO ACHIEVE ITS OBJECTIVES AND PROTECT THE PATIENTS AND WHETHER THE INVESTIGATOR IS QUALIFIED TO BE DOING THAT INVESTIGATION. NOW, THAT MAY NOT BE APPLICABLE TO THOSE OF YOU HERE AT THE CLINICAL CENTER BUT WE DO RECEIVE IND'S FROM ALL OVER THE COUNTRY AND ALL OVER THE WORLD AND WE HAVE TO ASSURE THAT THE INVESTIGATORS ARE QUALIFIED TO BE ADMINISTERING THE DRUG TO PATIENTS ASSESSING FOR FO TOXICITY AND MEETING REGULATORY REQUIREMENTS. PLEASE KEEP IN MIND THAT THE SAME ETHICAL AND STUDY DESIGN CRITERIA PRINCIPLES APPLY TO DRUGS FOR RARE DISEASES AS WELL AS THOSE FOR SERIOUS AND LIFE-THREATENING UNMET MEDICAL NEEDS. SO WE HAVE FLEXIBILITY IN HOW WE APPLY OUR REGULATORY STANDARDS BUT THERE IS NO LOWER BAR PER SE JUST BECAUSE YOU'RE STUDYING A DISEASE THAT IS RARE OR WHERE THERE'S A SERIOUS UNMET MEDICAL NEED. THERE'S STILL CERTAIN BASIC ETHICAL PRINCIPLES THAT MUST BE APPLIED IN ALL THOSE SITUATIONS. SOME OF THE COMMON CONCERNS WE SEE ARE OCCURRING IN THE EARLY PRE-IND FACE, AND THESE ARE USELY SAFETY RELATED. WHEUSUALLY SAFETY RELATED. WE'RE LOOKING AT DO YOU HAVE ANIMAL DATA TO ASSESS TOXICOLOGY AND PHARMACOLOGY, DO YOU KNOW INFOR ENOUGH ABOUT THE PRODUCT THAT IT'S SAFE TO ADMINISTER TO PATIENTS. IF YOU DON'T HAVE THAT INFORMATION WE PLACE THE IND ON CLINICAL HOLD, CLINICAL HOLD MEANS YOU'RE NOT ALLOWED TO ADMINISTER THE DRUG TO HUMAN SUBJECTS IN THAT CLINICAL TRIAL. SO YOU'RE PROHIBITING FROM PROCEEDING AND OBVIOUSLY THAT'S NOT A GOOD OUTCOME FOR YOU AND WE WOULD LIKE TO TRY TO AVOID THAT AS MUCH AS WE CAN. THE CRITERIA WE MOST COMMONLY USE TO DECIDE WHETHER TO PUT AN INITIAL IND ON HOLD IS THE SUBJECT WOULD BE EXPOSED TO AN UNREASONABLE RISK AND SIGNIFICANT RISK OF ILLNESS OR INJURY, OR, AND THIS HAPPENS COMMONLY I, THERE'S NOT ENOUGH INFORMATION TO MAKE A REASONABLE DETERMINATION ABOUT THE RISK TO THE PATIENTS. IF YOU ADVANCE IN YOUR TRIALS AND GET TO A LATER STAGE OF DEVELOPMENT, SAY PHASE II OR PHASE III WE LOOK FOR THE SAME SAFETY CONCERNS BUT WE ALSO THEN START PAYING MORE ATTENTION TO THE STUDY DESIGN TO MAKE SURE THAT THE DESIGN OF THE STUDY CAN ACHIEVE ITS STATED OBJECTIVES, BECAUSE AGAIN WE DON'T WANT TO SUBJECT HUMAN SUBJECTS TO ENROLLING IN INVESTIGATIONAL STUDIES THAT CAN'T BE INTERPRETED AND AREN'T PROVIDING VALUABLE DATA TO THE SCIENTIFIC ADVANCEMENT. WE APPLY THE THEORY OF THE ETHICAL PRINCIPLE OF DO NO HARM. THERE HAVE BEEN SOME IMPORTANT CASES THAT YOU SHOULD BE AWARE OF, WHERE PATIENTS HAVE BEEN SERIOUSLY HARMED IN INITIAL IND INVESTIGATIONS, AND WE ARE AWARE OF THESE AND KEEP THESE IN MIND, AS WE'RE CAREFULLY ASSESSING PROTOCOLS. THERE'S A PATIENT NAMED JESSE WHO DIED IN A CLINICAL TRIAL FOR GENE THERAPY IN 1999. A LATER INVESTIGATION INTO THAT PROTOCOL REVEALED MANY CONCERNS ABOUT THE WAY THE STUDY WAS CONDUCTED, HOW IT WAS REPORTED, NONCLINICAL SAFETY TESTING THAT LED UP TO THAT STUDY, THE INFORMED CONSENT AND OTHER CONCERNS. SO THIS WAS -- MANY OF YOU MAY NOT BE OLD ENOUGH TO REMEMBER 1999 THIS WASIN 199 THIS WAS A A BIG DEAL WHEN GENE THERAPY WAS VIEWED AS A CUTTING EDGE OF MEDICINE, A COLLUSION TO MANY PROBLEMS, AND JESSE DIED UNFORTUNATELY WHEN HE RECEIVED THAT GENE THERAPY. INVESTIGATIONAL RESEARCH AGENT. A FEW YEARS AGO THERE WAS A TRUCK TGN 1412 WITH ANTIHUMAN TD ANTIBODY, IT HAD AN ORPHAN DESIGNATION IN EUROPE, FOR TREATMENT OF MALIGNANCIES, IT WENT INTO A PHASE I CLINICAL PHARMACOLOGY STUDY IN THE U.K. WITH SIX SUBJECTS, ENROLLED, ALL SIX HAD NEAR FATAL SIDE EFFECTS IN THE INITIAL STUDY DIE TO CYTOCINE STORM. WHEN THE DRUG WAS INFUSED THEY HAD ESSENTIALLY CIRCULATORY COLLAPSE FROM CYTOKINE STORM. THE EUROPEAN MEDICINE AGENCY, THE COUNTERPART IN EUROPE TO THE FDA, SUBSEQUENTLY DEVELOPED A GUIDELINE FOR HOW TO INITIATE EARLY TRIALS IN BIOLOGIC AGENTS. ONE OF THE PROBLEMS WITH THIS STUDY, ALL SITUATION SUBJECTS WERE DOSED AT THE SAME TIME, THAT LEADS TO A PRINCIPLE WE APPLY A LOT WHICH IS YOU DOSE ONE SUBJECT AT A LOW DOSE AND SEE HOW THEY DO, BEFORE YOU ADVANCE TO A HIGHER DOSE OR EXPAND TO MORE SUBJECTS. HERE ALL SIX WERE DOSED AT THE SAME TIME AND THEY ALL HAD NEAR FATAL ADVERSE REACTIONS. NOW, WE HEAR A LOT ABOUT EXPANDED ACCESS AND DESIRE TO HAVE INVESTIGATIONAL USE OF DRUGS FOR PATIENTS, BUT OUR THEORY IS THAT THE BEST ACCESS FOR PATIENTS IS AN APPROVED DRUG. SO THAT'S WHAT WE'RE ALWAYS FOCUSING ON, HOW CAN WE DEVELOP THE EVIDENCE THAT'S NEEDED TO SUPPORT APPROVING THAT DRUG BECAUSE THAT'S THE BEST WAY FOR PATIENTS TO GET ACCESS TO PROVEN SAFE AND EFFECTIVE TREATMENTS. FOR MARKETING APPROVAL, WE APPLY A STATUTORY STANDARD THAT REQUIRES A DEMONSTRATION OF WHAT'S CALLED SUBSTANTIAL EVIDENCE, OF EFFICACY, SAFETY AND PRODUCT QUALITY. AND THAT SUBSTANTIAL EVIDENCE IS DEFINED AS EVIDENCE DERIVED FROM ADEQUATE AND WELL-CONTROLLED TRIALS, HISTORICALLY TRIALS HAS BEEN PURPOSELY INTERPRETED TO BE PLURAL, MEANING YOU NEED TO REPLICATE YOUR FINDINGS, THERE ARE CERTAIN CIRCUMSTANCES WHEN WE WILL ACCEPT A SINGLE TRIAL FOR DEMONSTRATION OF EFFICACY. AND THE DEFINITION OF ADEQUATE AND WELL-CONTROLLED IN THE STATUTE IS THAT ON THE BASIS OF WHICH IT COULD BE FAIRLY AND RESPONSIBLY CONCLUDED THAT THE DRUG WILL HAVE THE EFFECT IT PURPORTS TO HAVE UNDER THE CONDITIONS OF USE. SO THIS IS A STA STATUTORY STANDARD WE'RE REQUIRED TO APPLY FOR ALL DRUGS WHEN WE DETERMINE WHETHER THEY SHOULD BE APPROVED, AND AGAIN THIS APPLIES TO ALL DRUGS, INCLUDING DRUGS FOR RARE DISEASES, SERIOUS AND LIFE-THREATENING DISEASES, UNMET MEDICAL NEEDS. GOING FURTHER INTO THE DEFINITION OF ADEQUATE AND WELL-CONTROLLED TRIAL, WE INTERPRET THAT TO MEAN THAT THE TRIAL HAS BEEN DESIGNED, WELL ENOUGH, SO AS TO BE ABLE TO DISTINGUISH THE EFFECT OF THE DRUG FROM OTHER INFLUENCES SUCH AS SPONTANEOUS CHANGE, PLACEBO EFFECT, OR BIASED OBSERVATION. AND RANDOMIZED CONTROLLED CLINICAL TRIALS GENERALLY PLACEBO CONTROLLED ARE CONSIDERED THE GOLD STANDARD, NOT ALWAYS POSSIBLE IN CERTAIN SIXES BUT IN GENERAL THE CONTROLLED TRIAL FRAMEWORK IS THE WAY WE OPERATE IN EVALUATING FOR THE SAFETY AND EFFICACY OF DRUGS, THE CONTROL DOES NOT ALWAYS HAVE TO BE CONDITION CURRENT. THERCONCURRENT. IN CERTAIN CIRCUMSTANCES IT CAN BE HISTORICAL CONTROL IF THE NATURAL COURSE OF THE DISEASE IS WELL KNOWN. FOR EXAMPLE, WE COMMONLY APPROVE DRUGS TO TREAT CANCER WITHOUT A CONTROL GROUP BECAUSE WE'RE USING A HISTORICAL CONTROL GROUP WE KNOW FROM EXPERIENCE THAT TUMORS DON'T SPONTANEOUSLY REGRES REGRESS IN THE VAST MAJORITY OF CASES, SO IF WE SEE THE DRUG CAUSED A TUMOR TO SHRINK, THAT IS A CONTROLLED TRIAL USING A HISTORICAL CONTROL. I MENTIONED EARLIER EXPANDED ACCESS. SOMETIMES REFERRED TO AS COMPASSIONATE USE. THIS IS A PROGRAM WE HAVE AT FDA THAT ALLOWS PATIENTS TO RECEIVE INVESTIGATIONAL DRUGS FOR TREATMENT OF THEIR DISEASE, THIS IS NOT REALLY AN INVESTIGATION OF THE DRUG, THIS IS ABOUT ALLOWING PATIENTS TO HAVE ACCESS TO THOSE DRUGS FOR TREATMENT OF THEIR CONDITION, IT'S GENERALLY LIMITED TO PATIENTS WITH SERIOUS OR LIFE-THREATENING CONDITIONS, AND SITUATIONS WHERE THEY HAVE NO AVAILABLE COMPARABLE OR SATISFACTORY A ALTERNATIVE TREATMENTS, AND THIS IS A SPECIAL CASE. THIS INCLUDES SEVERAL DIFFERENT TYPES OF ACCESS, SOMETHING CALLED EMERGENCY IND'S, THE SITUATION WHERE WE AS IT SAYS, THE PATIENT HAS A LIFE-THREATENING CONDITION, AND IN THE OPINION OF THE INVESTIGATOR, IF THEY DON'T RECEIVE THE DRUG THEY WILL BE SUBJECT TO, YOU KNOW, FURTHER HARM OR DEATH. AND THE INVESTIGATOR DETERMINES THAT THE RISK OF THE DRUG IS NOT OUTWEIGHED BY THE RISK OF THE -- OUTWEIGHS THE -- THE RISK OF THE DRUGS DOES NOT WEIGH THE RISK OF USING THE DRUG IN THE PATIENT BECAUSE OF THEIR CONDITION. TEASE ARE SITUATIONS WHERE WE CAN GRANT THE ABILITY TO USE THE DRUG IN TREATMENT VERY RAPIDLY. WE ALSO HAVE SINGLE PATIENT IND'S WHICH ARE LESS EEMERGENCIENT SITUATION WHERE YOU WANT TO USE INVESTIGATIONAL DRUG TO TREAT A PATIENT OUTSIDE A TRIAL AND THE ABILITY TO HAVE LARGER GROUPINGS AND TREATMENT PROTOCOLS. SKPAFPDEEXPANDED AX SAYS PROVIDES ACCESS TO PATIENTS WITH LIFE-THREATENING CONDITIONS WITH NO SATISFY ALTERNATIVES, THESE IND'S GENERALLY DO NOT GENERATE USEFUL DATA ABOUT THE SAFETY OR EFFICACY OF THE DRUG BECAUSE THEY ARE NOT DESIGNED WITH USUAL PROTOCOL CONTROLS. AN IMPORTANT FACTOR TO KEEP IN MIND, BY REGULATION, EXPANDED ACCESS CANNOT INTERFERE WITH THE INITIATION, CONDUCT OR COMPLETION OF CLINICAL INVESTIGATIONS THAT COULD SUPPORT MARKING APPROVAL, OR OTHERWISE COMPROMISE THE POTENTIAL DEVELOPMENT OF THAT DRUG. WHAT THIS MEANS, WE CAN'T HAVE AN EXPANDED ACCESS PROGRAM WHERE EVERYONE WHO WOULD BE ELIGIBLE FOR THE CLINICAL TRIAL IS TAKING THE DRUG UNDER EXPANDED ACCESS, SUCH THAT WE'RE NOT LEARNING WHETHER THE DRUG IS ACTUALLY SAFE AND EFFECTIVE. THAT CAN BE A REASON FOR US TO PUT ACCESS TRIALS ON HOLD, IF THEY ARE INTERFERING WITH THE ACTUAL INVESTIGATION OF THE DRUG TOWARDS APPROVAL. SO I A FEW KEY POINTS TO END WITH, AGAIN, THE BEST ACCESS FOR PATIENTS TO EFFECT SAFE DRUGS IN OUR VIEW IS APPROVAL. SO THAT'S WHY WE FOCUS WHEN WE'RE REVIEWING THE INVESTIGATIONAL PHASE ON TRYING TO ENSURE THAT IT'S PROCEEDING TOWARDS A PLACE WHERE WE CAN HAVE ADEQUATE INFORMATION TO ESTABLISH THE DRUG IS SAFE AND EFFECTIVE, TO MEET THE APPROVAL STANDARD. FOR RARE DISEASES, AS I'VE SAID SEVERAL TIMES, THE STANDARDS ARE THE SAME BUT WE HAVE A GREAT DEAL OF FLEXIBILITY. WE RECOGNIZE THAT GIVEN THE LIMITED NUMBER OF PATIENTS YOU OFTEN ONLY GET ONE CHANCE TO GET IT RIGHT. SO IT'S VERY IMPORTANT WHEN YOU'RE STUDYING A DRUG FOR A RARE DISEASE TO CAREFULLY ASSESS THE NATURAL HISTORY, THE DESIGN OF A STUDY, AND HAVE FREQUENT COMMUNICATION WITH FDA SO THAT WE CAN MAKE SURE THAT WE'RE, TO THE BEST OF OUR ABILITY, GETTING IT RIGHT THE FIRST TIME BECAUSE WE MAY NOT HAVE A CHANCE TO GO BACK AND REPEAT THOSE STUDIES. THIS IS A KEY POINT FOR THOSE OF YOU WHO ARE INITIATING CLINICAL TRIALS, IS THAT IND-ENABLING AND FOUNDATIONAL SCIENCE SUCH AS TRANSLATIONAL RESEARCH AND DISEASE NATURAL HISTORY REALLY MUST BE CRITICAL CONSIDERED IN DESIGNING AND INITIATING SUCCESSFUL CLINICAL TRIALS. AND THE PROPOSED CLINICAL PLAN NEEDS TO BE SUPPORTED BY INFORMATION IN THE IND SUBMISSION. YOU'LL HEAR MORE ABOUT THAT TODAY, ABOUT WHAT DO WE NEED TO ALLOW AN INITIAL IND TO PROCEED SUCH AS THE ANIMAL DATA, AND MANUFACTURING DATA, AND THE DESIGN OF THE PROTOCOL, CONSENT FORM, ET CETERA. SO THIS IS VERY HIGH LEVEL OVERVIEW OF THE TOPICS YOU'RE GOING TO HEAR ABOUT TODAY. YOU WILL HEAR ABOUT CONTENTS AND SUPPORTING INFORMATION REQUIRED TO INITIATE AN IND, AND WHAT REGULATORY TOOLS ARE AVAILABLE TO HELP YOU IN THAT. YOU HEAR ABOUT THE INVESTIGATOR RESPONSIBILITIES, INCLUDING THE IRB OVERSIGHT, INFORMED CONSENT, SPECIAL CONSIDERATIONS THAT MUST BE TAKEN INTO ACCOUNT FOR VULNERABLE POPULATIONS SUCH AS A STUDY IN PEDIATRIC PATIENTS. YOU'LL HEAR ABOUT THE IND ENABLING INFORMATION, CHEMISTRY MANUFACTURING CONTROLS INFORMATION TO AL LA ALLOW US TO CONCLUDE YOUR PRODUCT IS SAFE TO ADMINISTER TO HUMANS, PHARMACO TOXICOLOGY THEY WERE, TO GIVE US SOME UNDERSTANDING WHAT THE DRUG WILL DO AND WHAT TOXICITIES WE SHOULD BE CONCERNED ABOUT AND WHETHER IT'S REASONABLY SAFE TO ALLOW HUMANS TO BE EXPOSED TO THAT DRUG AND HELPS YOU TO T SET A STARTING DOSE FOR CLINICAL TRIALS, HOW TO SUBMIT PROTOCOLS FOR REVIEW INCLUDING THE SAFETY INFORMATION, YOU LEARN MORE ABOUT CLINICAL HOLDS, HOW WE MAKE DECISIONS ABOUT CLINICAL HOLDS AND WHAT THAT MEANS TO YOU AS THE INVESTIGATOR. YOUR OBLIGATION TO REPORT SAFETY INFORMATION, IF YOU'RE NOT ON CLINICAL HOLD AND YOU'RE DOING THE INVESTIGATION, YOU'RE OBLIGATED AS THE INVESTIGATOR TO REPORT TO US IMPORTANT INFORMATION ABOUT SAFETY EVENTS THAT OCCUR IN THE TRIAL, AND YOU'LL HEAR IN MORE DETAIL ABOUT EXPANDED ACCESS PROTOCOLS. SO I HOPE YOU'LL FIND TODAY'S SESSION VERY INFORMATIVE, IT'S A GREAT COLLABORATION THAT WE'VE HAD GOING FOR THE LAST COUPLE OF YEARS, I THINK THE SUCCESS OF THAT PROGRAM IS THE FACT WE HAVE SO MANY PEOPLE ENROLLED IN THE COURSE TODAY. BUT ALSO THAT THE INTERACTIONS WE'VE BEEN HAVING WITH CLINICAL CENTER INVESTIGATORS FOR THE LAST COUPLE OF YEARS HAVE BEEN MUCH MORE POSITIVE THAN THEY WERE BEFORE WE STARTED THIS COLLABORATION. SO I WISH YOU WELL AS YOU GO THROUGH THE COURSE TODAY. IF YOU HAVE QUESTIONS FOR ME I CAN STAY FOR A COUPLE MINUTES OR WE CAN MOVE ON WITH THE PROGRAM. THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH, DR. JENKINS, FOR THAT VERY EXCELLENT OVERVIEW. WE MOVE ON NOW TO THE FIRST SESSION, BUT BEFORE I BEGIN I WANT TO REMIND THE AUDIENCE THAT TH SESSIONS ARE BEING WEBCAST AT NIH AND ALSO THEY ARE BEING RECORDED FOR THE BENEFIT OF FUTURE GENERATIONS OF INVESTIGATORS AND TRAINEES, AND SO IF YOU HAVE QUESTIONS, AFTER A LECTURE OR RATHER AFTER A SPEAKER PRESENTATION, AND DURING SOME OF THE PANEL DISCUSSION, PLEASE USE THE MICROPHONES IN THE AISLES. AND ALSO, AT THIS POINT, I WANT TO ACKNOWLEDGE THE ADMINISTRATIVE SUPPORT OF THE OFFICE OF CLINICAL RESEARCH, TRAINING AND MEDICAL EDUCATION, AND DR. FREDERICK OGNIBE AND HIS STAFF IN TERMS OF LEADING TO THE IMPLEMENTATION OF THE CONFERENCE TODAY. LET ME INTRODUCE DR. HEL HELP LAPTEVA, FORMERLY AT NOTIFY BUT FOR SEVEN YEARS WORKED IN THE OFFICE OF NEW DRUGS, IN THE CENTER FOR DRUG EVALUATION AND RESEARCH, WHERE SHE PARTICIPATES IN THE REVIEW OF CLINICAL TRIALS AND PROVIDES REGULATORY AND SCIENTIFIC ADVICE FOR CLINICAL DEVELOPMENT PROGRAMS, WITH INVESTIGATIONAL DRUGS AND BIOLOGICAL PROVIDES. SHE LED THE EFFORT TO CREATE THE WEB NAVIGATIONAL TOOL PERTAINING TO IND'S THAT SHE WILL DEMONSTRATE AND SOME OF YOU MAY HAVE SEEN ALREADY IN THE FDA WEBSITE, TO ASSIST BOTH NIH INVESTIGATORS AND ACADEMIC INVESTIGATORS ACROSS THE COUNTRY WITH THE SUBMISSIONS OF THEIR OND APPLICATIONS. LARISA, WELCOME. >> WELL, THANK YOU. GOOD MORNING, AGAIN. I PROMISE THIS IS THE LAST -- WELL, NO, THIS IS NOT THE LAST TIME, I'LL BE MODERATED A FEW MORE SESSIONS HERE TODAY. SO BECAUSE WE HAVE A LONG DAY AHEAD OF US AND MANY SPEAKERS WILL BE COVERING VARIOUS ASPECT OF OF IND APPLICATION PRESENTATION ISPARENTHESES INTENDED TO GIVE YOU A GENERAL VIEW OF AN IND APPLICATION, AND THE PROCESS WITH SUBMISSION AND SUCH AND A GENERAL SENSE OF WHY YOU EVEN NEED TO SEND SOMETHING THAT'S CALLED AN INVESTIGATIONAL NEW DRUG TO THE F.D.A. WE'LL ALSO GO THROUGH THE MAIN PARTS OR COMPONENTS OF AN IND APPLICATION, AND TIME AND TECHNOLOGY PERMITTING, AT THE END OF THE SLIDE PRESENTATION, I SHOULD BE ABLE TO SHOW YOU THE WEB NAVIGATIONAL TOOL WHICH WE DEVELOPED UNDER THE AUSPICES OF THE NIH-NDA TASK FORCE WITH THE GOAL TO ASSIST CLINICAL INVESTIGATORS AND ACADEMIC INVESTIGATORS WITH SUBMITTING IND APPLICATIONS. WITH THAT, LET ME START. BEFORE I DELVE INTO THE NUTS AND BOLTS OF THE IND SUBMISSION LET MESION LET ME SHOW YOU THE BIGGER PICTURE OF PHARMACEUTICAL PRODUCT DEVELOPMENT WHERE YOU SEE IND APPLICATION IS JUST PART ON THE CONTINUUM OF THE LIFE CYCLE, SO TO SPEAK, OF A PHARMACEUTICAL PRODUCT. AND IND APPLICATION IMPORTANTLY IS A MECHANISM FOR INFORMATION EXCHANGE BETWEEN AN IND APPLICANT, WHETHER IT'S A LARGE PHARMACEUTICAL COMPANY, SMALL PHARMACEUTICAL COMPANY, OR AN INDIVIDUAL INVESTIGATOR ON ONE END, AND THE REGULATORY BODY, FDA, ON THE OTHER END, ABOUT THE INVESTIGATIONAL DRUG, BECAUSE THE MISSION AND THE JOB OF THE REGULATORY AGENCY IS TO PROTECT AND PROMOTE PUBLIC HEALTH AND TO ASSURE THAT INVESTIGATIONAL DRUGS, MEANING DRUGS WITH YET UNPROVEN HE CAN CASEFFICACY AND NOT FULLY DEFINED, SOMETIMES UNDEFINED SAFETY, ARE NOT USED, ADMINISTERED OR SOLD INAPPROPRIATELY. AND FOR THAT REASON, THE FOOD, DRUG AND COS COSMETIC ACT THAT GOVERNS PHARMACEUTICAL DEVELOPMENT WHEN EXTENDED TO THE CODE OF FEDERAL REGULATIONS TELLS US ANY USE IN THE UNITED STATES OF A DRUG OR BIOLOGICAL PRODUCT NOT PREVIOUSLY AUTHORIZED FOR MARKING I MARKED ACCOUNT M ARKETING IN THE U.S. REQUIRES SUBMISSION TO THE F.D.A. YOU'RE HEARD ABOUT THE ETHICAL ASPECTS OF USING INVESTIGATIONAL DRUGS AND YOU'LL HEAR MORE IN SUBSEQUENT SESSIONS. PUT IT IN OTHER WORDS, ANY HUMAN RESEARCH STUDY MUST BE IND IF ITUNDER AND INDIAN INVOLVES A DRUG, IF IT'S A CLINICAL INVESTIGATION AND NOT EXEMPTED FROM THE IND APPLICATION REQUIREMENT. THERE IS A SET OF EXEMPTION FROM REQUIREMENTS AND I KNOW THAT NIH HAS A PROGRAM THAT'S CALLED IND WITHERED. WHAT IT DOES IS ASKING YOU TO PUT THE PARAMETERS OF YOUR RESEARCH IN THE SYSTEM AND THEN TO CHECK WHETHER YOUR CLINICAL STUDY MEETS OR DOESN'T MEET THE CRITERIA FOR IND EXEMPTION AND AT THE END GIVES YOU THE ANSWER WHETHER YOU DO OR DO NOT NEED TO SUBMIT AND IND APPLICATION. SO TO EXPAND ON THIS MORE, I'LL JUST GIVE YOU SOME DEFINITIONS HERE BECAUSE WE'RE TRYING TO LAY THE BACKGROUND FOR THE FUTURE OF EDUCATIONAL SESSIONS HERE TODAY. NOW, DRUGS, DEFINED IN THE FOOD, DRUG AND COSMETIC ACT IS AN ARTICLE INTENDED IN THE DIAGNOSIS, CURE, MITIGATION, TREATMENT OR PREVENTION OF A DISEASE. IT IS ALSO CONSIDERED TO BE AN ARTICLE THAT'S INTENDED TO AFFECT THE STRUCTURE OR ANY FUNCTION OF THE BODY. AS WAS MENTIONED PREVIOUSLY, BIOLOGICAL PRODUCTS SUCH AS, FOR EXAMPLE, ANTIBODIES OR FUSIONS RECEPTOR PROTEINS, OR BISPECIFIC ANTIBODIES THAT TARGET MORE THAN ONE MOLECULAR SITE ARE CONSIDERED DRUGS UNDER THIS DEFINITION BECAUSE THEY ARE INVESTIGATED OR USED FOR MITIGATION, TREATMENT, OR PREVENTION OF A DISEASE. CLINICAL INVESTIGATION, ON THE OTHER HAND, IS AN EXPERIMENT IN WHICH A DRUG IS ADMINISTERED OR DISPENSED TO OR USED INVOLVING ONE OR MORE HUMAN SUBJECTS, EXCEPT FOR THE USE OF A MARKETED DRUG IN THE COURSE OF CLINICAL PRACTICE. AND THIS LAST CLAUSE HERE IS REALLY ABOUT RARE SITUATIONS WHICH DO EXIST WHEN CERTAIN PRODUCTS MAY NOT BE APPROVED FOR CERTAIN CONDITIONS, YET CONSTITUTE STANDARD OF CARE AND SO FOR YOU NOT TO SUBMIT AND IND APPLICATION EVERY TIME FOR THAT, THAT'S EXACTLY WHERE THE CLAUSE COMES IN. AND AN EXAMPLE PERHAPS WOULD BE USE IN THE TREATMENT OF LUPUS, NEPHRITIS USED IN THE STANDARD OF CARE. WHAT WE'VE LEARNED SO FAR WHEN YOU'RE USING INVESTIGATIONAL PRODUCTS, YOU WOULD NEED TO COMMUNICATE WITH FDA ABOUT YOUR USE OF INVESTIGATIONAL PRODUCTS IN THE FORM OF THE IND APPLICATION. AND YOU MAY CHOOSE TO USE IT FOR YOUR CLINICAL STUDIES. IN THAT CASE YOUR INDIAN APPLICATION WOULD SUPPORT CLINICAL VACCINATIO INVESTIGATION OR CHOOSE TO USE IT FOR THE PURPOSE OF CLINICAL TREATMENT FOR YOUR PATIENTS. IN THAT CASE, YOUR IND APPLICATION WOULD SUPPORT CLINICAL TREATMENTS. AND WHAT YOU SEE ON THE RIGHT SIDE OF THE SLIDE HERE IS EXACTLY THE USE OF INVESTIGATIONAL DRUGS FOR CLINICAL TREATMENT, THAT'S THE EXPANDED ACCESS PROGRAM. I WON'T SPEND MUCH TIME ON THIS, WE'LL TALK MORE ABOUT IT LATER ON TODAY. OUR LAST SESSION IS ENTIRELY DEDICATED TO EXPANDED ACCESS, IND APPLICATION. ON THE LAST SIDE YOU SE SLIDE YOU SEE IND APPLICATIONS SUBMITTED FOR THE PURPOSE OF CLINICAL RESEARCH OR CLINICAL INVESTIGATION. WHEN WE LOOK AT IND APPLICATIONS, WE USUALLY MAKE AN APPROXIMATION WHETHER THIS IS A NOVEL PRODUCT, NEVER BEEN APPROVED, IT MAY BE IN DEVELOPMENT OR OTHER INDICATIONS, OTHER THAN WHAT YOU'RE INVESTIGATING IT IN. OR YOU MAY BE THE FIRST ONE TO INVESTIGATE THE PRODUCT ALTOGETHER. ANOTHER KIND OF IND APPLICATION THAT ARE SENT TO US FOR THE PURPOSE OF CLINICAL RESEARC RESEARCH ARE IND APPLICATIONS WITH PRODUCTS THAT ARE REPURPOSED. REPURPOSEED PRODUCTS MAY BE PRODUCTS THAT ARE ALREADY APPROVED AND ON THE MARKET BUT YOU'RE TRYING TO INVESTIGATE IT IN A DIFFERENT CONDITION AND IN THAT CASE THE DRUG WOULD STILL BE CONSIDERED INVESTIGATIONAL DRUG, IT IS INVESTIGATIONAL IN THE CONDITIONS IN WHICH YOU'RE INVESTIGATING IT. THAT'S THE REPURPOSED PRODUCT. SOMETIMES REPURPOSED PRODUCTS MAY BE PRODUCTS THAT HAVE UNDERGONE A WHOLE DEVELOPMENT PROGRAM, MAY NOT HAVE BEEN APPROVED YET, BECAUSE THE DEVELOPMENT PROGRAM WAS ABANDONED FOR PERHAPS REASONS OF INSUFFICIENT EFFICACY OR POOR SAFETY, YET THE PRODUCT CAN STILL BE REPURPOSED FOR OTHER INDICATIONS. SO THE OBJECTIVE OF OUR SESSION TODAY IS TO TRY TO ENABLE YOU TO KNOW AND RECOGNIZE THE MAIN PARTS OF AN IND APPLICATION. AND I KNOW THAT SOME OF YOU HAVE PROBABLY HAD THE EXPERIENCE OF ASSEMBLING AND SENDING IND APPLICATIONS TO FDA, SO I MADE THIS SLIDE INTERACTIVE. FEEL FREE TO SAY OUT LOUD ANY COMPONENTS OF AN IND APPLICATION THAT YOU KNOW. COME ON, WAKE UP. CMC, GOOD. ANY OTHER? CMC IS NOT THE FIRST ON MY LIST BUT I'LL SHOW YOU THE OTHERS. CLINICAL PRODUCT, THAT'S THE BREAD AND BUTTER. ANY OTHER? INVESTIGATOR QUALIFICATIONS. INVESTIGATOR'S BROCHURE, THAT'S RIGHT. ANYTHING ELSE? THAT'S CORRECT. PREVIOUS HUMAN EXPERIENCE. OKAY. WELL, SO I'LL JUST GO THROUGH THEM HERE ON THE SLIDE. WELL, THE FIRST THINGS YOU WOULD DO IS OBVIOUSLY YOU WOULD HAVE A COVER LETTER OR COVER SHEET FOR YOUR IND APPLICATION, AND THAT COVER LETTER SHOULD BE ADDRESSED TO THE DIRECTOR OF THE REVIEW DIVISION IN THE OFFICE OF NEW DRUGS, AND THE REVIEW DIVISION IS IN THE THERAPEUTIC AREA YOU'RE TRYING TO INVESTIGATE THE DRUG. THE COVER LETTER WOULD EXPLAIN WHAT THE INVESTIGATIONAL DRUG IS ABOUT. IT WOULD TELL US THE ROUTE OF THE ADMINISTRATION, FORMULATION, WHAT IS THE ORIGIN OF THE DRUG YOU'RE TRYING TO USE. IT WILL ALSO TELL US ABOUT THE INVESTIGATION ITSELF, WHAT YOU'RE TRYING TO ACHIEVE, WHAT KIND OF STUDY YOU'RE DOING AND WHAT PATIENT POPULATION. A TABLE OF CONTENTS, THAT'S ABOUT ORGANIZATION OF YOUR PACKAGE. AND, YES, THAT IS A PART OF AN IND APPLICATION. INTRODUCTORY STATEMENTS AND A GENERAL INVESTIGATIONAL PLAN, THIS IS SOMETHING THAT COULD BE VERY BRIEF. IT IS USUALLY USED TO HELP US TO PUT YOUR INVESTIGATION IN PERSPECTIVE AND TO LET US KNOW WHETHER THE PRODUCT IS BEING INVESTIGATED AND PERHAPS OTHER PHYSICIANS ARE IN THE LARGER CLINICAL PROGRAM. INVESTIGATORS BROCHURE, SOMEBODY POINTED THIS OUT CORRECTLY, AND THIS IS VERY IMPORTANT BECAUSE IF YOU'RE GETTING A PRODUCT FROM A DRUG COMPANY, THEN THEY SHOULD SEND YOU THE INVESTIGATOR'S BROCHURE, BECAUSE THE BROCHURE IS A COMPILATION OF INFORMATION ABOUT THE EFFECTS OF THE PRODUCTS, IT INCLUDES CHEMISTRY MANUFACTURING AND CONTROL INFORMATION, IT INCLUDES PRODUCT MECHANISM, IT MAY INCLUDE STUDIES IN ANIMALS UP TO DATE AND IMPORTANTLY DESCRIPTION OF THE EFFECTS OBSERVE AND ANTICIPATED EFFECTS OF THE PRODUCT AND ESSENTIALLY WE CONSIDER THE PROTOTYPE OF THE PRODUCT LABELED AT THE INVESTIGATIONAL STAGE AND BEFORE YOU USE YOUR DRUG, IN CLINICAL TRIALS, YOU WOULD ABSOLUTELY NEED TO BE FAMILIAR WITH THE CONTENTS OF THE INVESTIGATOR'S BROCHURE. CLINICAL PROTOCOLS, CHEMISTRY MANUFACTURING AND CONTROL INFORMATION, PHARMACOLOGY AND TOXICOLOGY INFORMATION, AND THAT'S THE ANIMAL STUDIES. AND NOTE THESE ARE NOT THE ANIMAL STUDIES IN MICE OR DISEASE MODELS WHERE YOU LOCK AT THE MECHANISM OF YOUR INVESTIGATIONAL DRUG AND CONSIDER THAT THIS MAY WORK IN A DISEASE X. THAT'S NOT WHAT IT IS. THIS IS A STANDARD SET OF TOXICOLOGY STUDIES THAT IS DONE IN NORMAL HEALTHY ANIMALS, SPECIFICALLY WITH THE GOAL TO INVESTIGATE THE TOXICOLOGICAL UNDESIRABLE EFFECTS OF THE INVESTIGATIONAL DRUG. YOU WILL HEAR ABOUT IT MORE DURING ONE OF OUR SESSIONS TODAY. A SUMMARY OF PREVIOUS HUMAN EXPERIENCE WITH THE INVESTIGATIONAL PRODUCT, ANY ADDITIONAL INFORMATION THAT MAY BE SPECIFIC TO THE DRUG THAT YOU'RE GOING TO USE, SAY, IT MAY BE DEPENDENCE IN ABUSE POTENTIAL, PSYCHOTROPIC DRUGS OR CERTAIN INFORMATION RELATED TO RADIOACTIVE DRUGS, AND THEN ANY OTHER RELEVANT INFORMATION YOU MAY REFER TO EXISTING IND APPLICATIONS THAT COULD ALREADY BE ON FILE WITH FDA IF YOU KNOW THEIR NUMBERS. AND KNOW ADDITIONAL INFORMATION ABOUT SUCH APPLICATIONS. SO SOME OF THE INFORMATION THAT WE'VE JUST DISCUSSED MAY BE SUBMITTED IN THE SUCCINCT FORM AS PART OF THE FORM THAT ARE EXPECTED TO BE SENT WITH ANY IND APPLICATION AND HERE ARE THE MAIN FORMS THAT WE USUALLY RECEIVE WITH EACH OF IND APPLICATIONS, SO WE RECEIVE THESE DAYS, SOME OF YOU MAY BE FAMILIAR WITH THESE FORMS. 1571, WHICH IS A COMPILATION OF INFORMATIONAL PIECES ABOUT YOUR SPECIFIC IND APPLICATION. 1572, WHICH IS INVESTIGATORS STATEMENT, CONTAINS INFORMATION ABOUT THE INVESTIGATOR, THEIR CONTACT INFORMATION, QUALIFICATIONS, AND IMPORTANTLY THE STATEMENT THAT THEY WOULD NOT START THE CLINICAL RESEARCH STUDY UNTIL THEY HAVE RECEIVED NOTIFICATION FROM THE FDA THAT THEIR STUDY IS SAFE TO PROCEED. AND FORM 3674 WHICH WAS ADDED RELATIVELY RECENTLY, THAT'S A CERTIFICATION OF COMPLIANCE WITH REQUIREMENTS OF CLINICAL TRIALS, AND I PUT THE LINKS TO EACH ONE OF THESE FORMS. THEY ARE EASILY ACCESSIBLE FROM THE FDA.GOV WEBSITE. YOU CAN FIND THEM THERE ALONG WITH THE INSTRUCTIONS ON COMPLETION OF THIS FORM. WHEN YOU SEND YOUR IND APPLICATION WE EXPECT TO RECEIVE IT IN TRIPLICATE, IT TAKES ABOUT 30 DAYS. SO WITHIN 30 DAYS, WE'RE SUPPOSED TO REVIEW THE APPLICATION, SEE IF THERE ARE ANY DEFICIENCIES IN THAT APPLICATION, RESOLVE THE DEFICIENCIES WITH YOU, TALK TO YOU, PERHAPS SEND YOU INFORMATION REQUESTS, RECEIVE INFORMATION FROM YOU, REVIEW IT AGAIN, AND THEN MAKE YOU HAPPY AT THE SAME TIME. SO IT IS VERY CRITICAL FOR US TO HAVE THE APPLICATION AS COMPLETE AS POSSIBLE BY THE TIME WHEN YOU SUBMIT IT AS YOUR INITIAL SUBMISSION. BECAUSSO LET'S LOOK AT THE IND APPLICATION CONTENTS AGAIN, BUT WITH A GOAL TO TRY TO FIGURE OUT FOR YOU AS AN NIH INVESTIGATOR WHICH PARTS YOU CAN GENERATE YOURSELF AND WHICH PARTS YOU COULD POTENTIALLY OBTAIN SOMEWHERE ELSE. NOW, GRANTED YOU'RE AN ACADEMIC INVESTIGATOR AT NIH. OFTEN TIMES WHEN YOU RUN YOUR CLINICAL STUDIES, YOU PROBABLY HAVE AN AGREEMENT WITH THE MANUFACTURING OF THE PRODUCT, AND YOU DON'T NECESSARILY HAVE TO PRODUCE OR GENERATE CERTAIN INFORMATION. YOU DON'T HAVE THE MANUFACTURING INFORMATION OF THE DRUG. THOSE NECESSARILY DO THE NONCLINICAL TOXICOLOGY STUDIES INVESTIGATING THE TOXIC EFFECTS OF THE PRODUCT. AND THAT IS WHY, HERE IS MY COLOR-CODED PIECES THAT YOU MAY OBTAIN SOMEWHERE ELSE. SPECIFICALLY, YOU MAY OBTAIN THEM FROM THE MANUFACTURER OF THE PRODUCT. AND HERE YOU HAVE THE INVESTIGATOR'S BROCHURE. CHEMISTRY MANUFACTURING AND CONTROL INFORMATION, PHARMACOLOGY AND TOXICOLOGY INFORMATION, PERHAPS A SUMMARY OF PREPARE HUMAN EXPERIENCE, MAYBE ANY ADDITIONAL SPECIFIC INFORMATION ABOUT THE PRODUCT. IF YOU ASK THE MANUFACTURER TO SEND THIS INFORMATION TO YOU, THE LIKELIHOOD THAT THEY WILL SEND IT TO YOU BECAUSE IT'S THEIR PROPRIETARY INFORMATION AND THEY MAY NOT NECESSARILY WANT TO SHARE IT WITH YOU, SO WHAT'S THE SHORT PART IN THAT SITUATION? THE REGULATORY MECHANISM THAT IS AVAILABLE TO YOU IS TO OBTAIN A LETTER OF AUTHORIZATION FROM THE MANUFACTURER OF THE PRODUCT, BECAUSE THE LIKELIHOOD THAT THEY ALREADY HAVE AN IND APPLICATION ON FILE ARE US, AND WHEN THEY GIVE YOU THE LETTER OF AUTHORIZATION, THAT LETTER GRANTS YOU THE ABILITY TO REFERENCE PREVIOUSLILY SUBMITTED TO US INFORMATION IN YOUR APPLICATION. AND IT GRANTS US THE ABILITY TO REVIEW THAT INFORMATION THAT'S ALREADY ON FILE WITH US AND DECIDE WHETHER IT WOULD BE SUPPORTIVE OF YOUR PROPOSED CLINICAL INVESTIGATION GRANTING US THE ABILITY TO REFERENCE THE INFORMATION THAT'S ALREADY AVAILABLE. YOU WON'T NECESSARILY SEE IT, BUT WE WOULD BE ABLE TO DECIDE WHETHER IT WOULD SUPPORT YOUR CLINICAL INVESTIGATION. SO JUST A FEW WORDS ABOUT THE IND APPLICATIONS, ESSENTIALLY THE REGULATORY MECHANISM THAT ALLOWS TO FACILITATE AVAILABILITY OF PROMISING NEW DRUGS, CURE PATIENTS WITH SERIOUS AND IMMEDIATELY LIFE-THREATENING CONDITIONS AND DISEASES, WHEN THERE ARE NO COMPARABLE OR SATISFACTORY ALTERNATIVE THERAPIES TO DIAGNOSE, MONITOR OR TREATMENT THE DISEASE OR CONDITION, THAT'S QUITE USUALLY WELL UNDERSTOOD BY PEOPLE. WHAT'S IMPORTANT THOUGH IS THAT YOU WILL HAVE TO MAKE A JUDGMENT CALL AS A CLINICIAN AND A TREATING PHYSICIAN WHEN YOU ARE CONSIDERING TO USE AN INVESTIGATIONAL DRUG IN YOUR PATIENT, IS WHETHER THE POTENTIAL PATIENT BENEFIT WOULD JUSTIFY THE POTENTIAL RISK OF THE TREATMENT AND THE POTENTIAL RISK WOULD NOT BE UNREASONABLE IN THE CONTEXT OF THE DISEASE THAT YOU'RE TREATING. AND SO THAT JUSTIFICATION WOULD ALSO NEED TO BE DISCUSSED IN YOUR IND APPLICATION, WHEN YOU'RE SENDING IT TO US. YET ANOTHER POINT HERE IS THAT THE EXPANDED ACCESS USE FOR THE REQUESTED TREATMENT SHOULD NOT INTERFERE WITH THE INITIATION, CONDUCT OR COMPLETION OF CLINICAL INVESTIGATIONS. THEY COULD POTENTIALLY SUPPORT MARKETING APPROVAL OF THE PRODUCT. IN OTHER WORDS, IF THERE'S A CLINICAL TRIAL GOING SOMEWHERE ELSE FOR THE CONDITION IN WHICH YOU'RE TRYING TO USE THIS DRUG FOR YOUR SINGLE PATIENT, IT IS PROBABLY BEST TO SEND THE PATIENT TO PARTICIPATE IN THE CLINICAL TRIALS, UNLESS FOR SOME REASON THEY JUST ABSOLUTELY CAN'T PARTICIPATE AND THEN YOU COULD TRY TO TREAT THEM UNDER A SINGLE IND APPLICATION YOU SENT TO US. OTHERWISE IT WOULD BE BETTER TO SEND THEM PARRO PARTICIPATING IN A CLINICAL TRIAL. CONTENTS OF THE CLINICAL PROTOCOL FOR IND APPLICATION SEND UNEXPANDED ACCESS WOULD BE DIFFERENT OBVIOUSLY FROM CONTENT OF A CLINICAL PROTOCOL WHEN YOU'RE TRYING TO DO A CLINICAL STUDY. AND THE CONTENTS ARE SPECIFIED IN THE CODE OF FEDERAL REGULATIONS, HERE THEY ARE ON THE SLIDE. ALL OF THIS INFORMATION YOU WOULD NEED TO PUT TOGETHER IN CASE YOU DECIDE TO SEND US AN IND APPLICATION FOR CLINICAL TREATMENT. SO THAT'S THE RATIONALE FOR THE INTENDED, INCLUDING FAILED THERAPEUTIC OPTIONS, AND FOR SINGLE PATIENT PROTOCOL YOU NEED TO INCLUDE PATIENT'S RECENT MEDICAL HISTORY AND PREVIOUS TREATMENT AND FOR PROTOCOLS INTENDED TO TREAT GROUPS OF PATIENTS YOU WOULD NEED TO SPECIFY INCLUSION AND EXCLUSION CR CRITERIA FOR WHOM THE TREATMENT WOULD BE APPROPRIATE IN YOUR JUDGMENT, AND YOU WOULD NEED TO SPECIFY THE PROPOSED METHOD OF ADMINISTRATION, DOSE AND DURATION YOU'RE SPENDING TO TREAT YOUR PATIENT FOR, AND OF COURSE DESCRIPTION OF THE CLINICAL PROCEDURES AND ANY LABORATORY TESTS OR ANY OTHER MONITORING THAT WOULD BE NECESSARY TO EVALUATE BOTH THE EFFECTS, THE FAVORABLE EFFECTS, THE TREATMENT BENEFIT, AS WELL AS THE EFFECTS THAT WOULD BE UNDESIRABLE AND ALSO HOW YOU WOULD MINIMIZE THE RISK TO YOUR TREATED SUBJECTS. IN SOME SITUATIONS, AGAIN, AS MENTIONED PREVIOUSLY, YOU WOULD PROBABLY NEED TO USE INVESTIGATIONAL DRUGS IN EMERGENCIES. AND IN THAT CASE, THE PEOPLE WHERE PIECE IS ELIMINATED FROM THE PROCEDURE, AND YOU COULD GIVE US A CALL, OR BY ANY OTHER RAPID MEANS OF COMMUNICATION EXPLAIN TO US THAT YOU WOULD NEED TO TREAT A PATIENT WITH AN INVESTIGATIONAL DRUGS AND FOR WHAT REASON, AND IN THAT CASE YOU WOULD STILL BE RESPONSIBLE FOR MAKING SURE THAT THE PHARMACEUTICAL COMPANY IS AGREEABLE AND IS GOING TO GIVE YOU THE PRODUCT. AND TYPICALLY SUCH AUTHORIZATION WHEN FDA GIVES THE AUTHORIZATION TO TREAT WOULD BE CONDITIONED ON THE APPLICANT'S OR YOUR SENDING A COMPLETE IND APPLICATION SUBMISSION OBVIOUSLY AS SOON AS PRACTICAL BUT NO LATER THAN 15 DAYS, AND THERE IS A SPECIFIC TIME LINE FOR THAT. I WILL SHOW YOU THIS TIME LINE IN THE AND A HAL NAVIGATIONAL TOOL IN A FEW MINUTES. NOW WE'VE COME TO THE DEMONSTRATION OF THE TOOL THAT'S AVAILABLE TO YOU ON THE WEBSITE. ESSENTIALLY IT PROVIDES THE REGULATORY INFORMATION TO ENABLE IND SUBMISSIONS. WE HOPE THIS PROMOTES UNDERSTANDING OF IND SUBMISSION PROCESSES AND THAT YOU COULD SEE OR MAYBE HAVE SEEN ALREADY IT PROVIDES CONCISE EXPLANATIONS AS WELL AS LINKS TO AVAILABLE GUIDANCE DOCUMENTS IN THE FDA FORMS AND LINED REFERENCES YOU MAY NEED TO USE PUTTING TOGETHER OR SUBMITTING IND APPLICATIONINGS. LET'S SEE IF I CAN WORK THROUGH THIS. EXCELLENT, THANK YOU. OKAY. ALL RIGHT. THIS IS HOW IT LOOKS LIKE. I HOPE YOU SEE -- OKAY, YES. THERE ARE FOUR COLUMNS TO IT, AND AS WE'VE JUST DISCUSSED, THE FIRST COLUMN CONTAINS THE INFORMATION THAT YOU WOULD NEED TO PUT TOGETHER FOR IND APPLICATIONS, THAT WOULD SUPPORT CLINICAL INVESTIGATIONS. AND THE COLUMN ON THE FAR RIGHT IS ABOUT AN IND APPLICATIONS, AND THE INFORMATION NEEDED FOR SUCH APPLICATIONS WHEN YOU'RE TRYING TO TREAT YOUR PATIENT. WHAT'S IN THE MIDDLE ARE ALL THE PROCEDURES THAT RELATE TO IND APPLICATIONS, AND THAT'S IND APPLICATION REPORTING, AND THE IND APPLICATION PROCEDURES. WHAT YOU CAN FIND IN THE PROCEDURES WOULD BE THE SITUATIONS FOR EXEMPTION FROM IND REQUIREMENT, FIND RECOMMENDATIONS ON HOW YOU WOULD INTERACT WITH NDA,ENED INVESTIGATOR'S RESPONSIBILITIES. THERE'S REPORTINGS, INCLUDING SAFETY REPORTINGS UNDER THE IND APPLICATION REPORTINGS. IF YOU CAN'T RECALL ANYTHING THAT WE'VE DISCUSSED TODAY, YOU COULD GO AND OPEN THE CONTENTS OF AN IND APPLICATION NEEDED FOR CLINICAL INVESTIGATION, AND HERE YOU WOULD BE ABLE TO FIND THE INVESTIGATOR'S CHECK LIST, WHICH IS DESIGNED SPECIFICALLY FOR YOU SO YOU COULD HAVE ALL THE PIECES THAT ARE NEEDED FOR YOU AND FOR YOUR APPLICATION, AND HAVE THEM PUT TOGETHER WHEN YOU ARE SENDING AN APPLICATION TO US. OKAY. WHAT YOU COULD FIND HERE UNDER THE REGULATORY AND ADMINISTRATIVE COMPONENTS WOULD BE A TABLE THAT BRIEFLY EXPLAINS THE INFORMATION THAT NEEDS TO BE PUT INTO THESE PIECES. AND REFERS YOU TO VARIOUS GUIDANCE DOCUMENTS AND ALL THE NEEDED INFORMATION TO ENABLE YOU TO PUT TOGETHER AN APPLICATION. NOW, WHAT I ALSO WANTED TO SHOW YOU TODAY IS THE ALGORITHM FOR SUBMITTING EMERGENCY IND APPLICATION. SO HERE IS THE TREATMENT OF A SINGLE PATIENT IN AN EMERGENCY SETTING. THAT'S SOMETHING THAT WE'VE HEARD PEOPLE NEED A LOT, PARTICULARLY AT NIH, AND SO WE TRY TO HELP AND PUT SUFFICIENT INFORMATION FOR EMERGENCY IND APPLICATIONS HERE ON THE LINE. WHAT YOU SEE HERE ARE PHYSICIANS CHECK LIST FOR AN IND APPLICATION FOR EMERGENCY TREATMENT. AND YOU COULD ESSENTIALLY COMPLETE THIS FORM AND FAX IT TO US. IT'S A TW TWO-PAGE FORM THAT CAN PROVIDE EVERYTHING NEEDED FOR THE ENERGY APPLICATION FOR THE INVESTIGATIONAL PRODUCT. NOW, WHEN YOU'RE DECIDING WHETHER YOUR SITUATION, WHEN YOU'RE TRYING TO USE THE DRUG, IS IN FACT ELIGIBLE FOR AN EMERGENCY INDP A INDICATIO, YOU COULD TAK E A LOOK AT THE ELIGIBILITY TOOL HERE, AND IT'S A BRIEF ALGORITHM THAT WALKS YOU THROUGH VARIOUS SITUATIONS AND THEN YOU DECIDE WHETHER YOUR PARTICULAR SITUATION APPLIES AND WHETHER YOU COULD SUBMIT AN IND APPLICATION IN THAT CASE. WE ALSO HAVE HERE A TIME LINE THAT ALLOWS YOU TO SEE BY WHICH DAY WHAT PIECE OF AN IND APPLICATION IS DUE AND WHEN YOU NEED TO NOTIFY YOUR IRB ABOUT EMERGENCY USE OF THE INVESTIGATIONAL DRUG. AND THEN IT GIVES YOU THE RECOMMENDATIONS FOR REPORTING OF WHAT'S HAPPENING IN YOUR IND APPLICATION. SO WHEN IT'S TIME FOR YOU TO PUT TOGETHER AN IND APPLICATION, AND SEND IT TO US, WE HOPE YOU USE THIS TOOL, THAT YOU FIND IT HELPFUL, AND WE WILL BE HAPPY TO HEAR ANY FEEDBACK FROM YOU ABOUT IT, AND IF YOU HAVE ANY QUESTIONS, I'LL BE HAPPY TO TAKE THEM TODAY, AND I WOULD LIKE TO THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> WELL, THANK YOU VERY MUCH, LARISA. WE HAVE A QUESTION. >> JUST ONE QUESTION. I WAS ON THE SITE YESTERDAY, TRYING TO GET INFORMATION ABOUT EXISTING IND'S. AND I COULDN'T FIND A SEARCH TOOL FOR EXISTING IND'S, AND I'M WONDERING IF THAT EXISTS AND IF NOT, WHY NOT? >> WELL, YOU WOULD NOT BE ABLE TO FIND EXISTING IND'S, BECAUSE EXISTING IND'S ARE PROPRIETARY INFORMATION, OF THE SPONSORS WHO SEND US THEIR IND APPLICATIONS. THIS IS THE INFORMATION THAT'S NOT AVAILABLE ONLINE. IF A DRUG COMPANY GIVES YOU A PRODUCT, AND THEY ARE WILLING TO SHARE THE INFORMATION ABOUT THEIR EXISTING IND AND THEIR EXISTING IND NUMBER WITH YOU, THEN THAT'S A DIFFERENT STORY. NOW, THERE IS NO COMPILATION OR REGISTRY OR DATABASE FOR EXISTING IND APPLICATIONS THAT WOULD COME OUT OF FDA BECAUSE ESSENTIALLY ALL THE IND APPLICATIONS ARE PRODUCTS IN DEVELOPMENT AND THEY ARE PROPRIETARY INFORMATION. >> THAT'S TRUE EVEN IF THE DRUG IS ALREADY APPROVED AND THE IND IS FOR REPURPOSING? >> THAT'S TRUE, EVEN IF THE DRUG IS ALREADY APPROVED AND IND IS FOR REPURPOSING. WHEN THE DRUG IS APPROVED, ALL THE INFORMATION ABOUT THE DRUG IS OUT THERE ANYWAY. IF THERE IS ANOTHER IND APPLICATION OPEN FOR REPURPOSING, THAT'S, AGAIN, A PRODUCT IN DEVELOPMENT AND THAT'S PROPRIETARY INFORMATION. >> THANK YOU VERY MUCH FOR THE QUESTIONS. AND NOW TO CONTINUE WITH THIS SESSION, AND TO DISCUSS INVESTIGATOR'S RESPONSIBILITIES, WE WILL HAVE DR. RACHEL HARTFORD FROM THE OFFICE OF NEW DRUGS, RACHEL IS A TEAM LEADER OF THE OFFICE OF NEW DRUGS ENHANCED COMMUNICATIONS TEAM. THIS TEAM IDENTIFIES AND DISSEMINATES BEST PRACTICES, SERVES AS A POINT OF CONTACT FOR GENERAL AND JURISDICTIONAL QUESTIONS AND IS A SECONDARY CONTACT FOR ANYONE ENCOUNTERING COMMUNICATION ISSUES. PRIOR TO SEARCHIN SERVING IN THIS ROLE SHE WAS A PROJECT MANAGER FOR INSULIN PRODUCTS IN THE VISION DIFFERENCE OF METABOLISM AND CRITICAENDOCRINE PRODUCTS.D WELCOME. >> THANK YOU. GOOD MORNING. GIVE ME A MOMENT JUST TO ORIENT HERE REAL QUICK. ALL RIGHT. THE FIRST THING WE'RE GOING TO LOOK AT BEFORE WE GET TO RESPONSIBILITIES ARE YOUR ENGAGEMENT PATHWAYS, OPTIONS OR OBTAINING INFORMATION AND ASSISTANCE THROUGH FDA CDER. THERE ARE FIVE MAIN ENGAGEMENT PATHWAYS. THE FIRST ONE WE'RE GOING TO LOOK AT IS THE OFFICE OF NEW DRUGS REVIEW DIVISION. THE TOOL YOU SAW EARLIER, THERE IS A LINK TO ALL THE DIVISION-SPECIFIC MAIN TELEPHONE LINES AND THEIR NAMES AND SOME OF THE PRODUCTS THAT THEY COVER. THOSE LINES SHOULD BE COVERED FROM 8:30 IN THE MORNING TILL 4:00 IN THE AFTERNOON. SO I'M NOT GOING TO REPEAT THAT INFORMATION. OND'S MISSION IS TO ENSURE SAFE AND DRUGS AND BIOLOGICS ARE AVAILABLE TO THE AMERICAN PEOPLE. THIS IS HOW WE MEET THAT MISSION. WE PROVIDE REGULATORY OVERSIGHT FOR INVESTIGATION ALSTUDIEAL STUD JIGS, MAKE DECISIONS FOR PRODUCTS, AND WE PROVIDE GUIDANCE TO REGULATED INDUSTRY ON A WIDE VARIETY OF CLINICAL, SCIENTIFIC AND REGULATORY MATTERS. THE NEXT PATHWAY WE'RE GOING TO LOOK AT IS THE SMALL BUSINESS ASSISTANCE. YOU MAY THINK WHAT DOES THAT HAVE TO DO WITH YOU? FIRST OF ALL, YOU ARE THE VERY DEFINITION OF A SMALL BUSINESS. YOU HAVE 500 OR LESS EMPLOYEES OR AFFILIATES, THEY ARE AN EXCELLENT RESOURCE FOR ADDITIONAL INFORMATION OF HOW THE FDA WORKS AND HOW TO HANDLE THINGS IN A MEETING, THEY HAVE NEWS LETTERS, THEY ARE JUST VERY WELL PREPARED TO DEAL WITH SMALL GROUPS. SO THEY PROMOTE PRODUCTIVE INTERACTION WITH REGULATED INDUSTRY, BY ASSISTING WITH DOMESTIC AND INTERNATIONAL SMALL PHARMACEUTICAL BUSINESSES SEEKING TIMELY AND ACCURATE INFORMATION RELATING TO THE DEVELOPMENT AND REGULATION OF HUMAN DRUG PRODUCTS. AND THESE ARE THE LATEST RESOURCES, THE E-MAIL UPDATES ARE HELPFUL. THEY HAVE A LARGE LIST SERVE. THEY PUT OUT A LOT OF VERY GOOD INFORMATION, TO THOSE WHO WOULD LIKE TO FOLLOW THEM ON TWITTER AND FACES R FACEBOOK, YOU CAN, AND THEY HAVE A WIDGET AS WELL. THIS IS HOW TO CONTACT THEM DIRECTLY AND YOU CAN CHECK OUT THEIR WEB PAGE. SO THE NEXT PATHWAY WE'RE GOING TO LOOK AT IS THE CDER OMBUDSMAN. YOU CAN SEE WHAT THEIR MISSION STATEMENT IS HERE. THEY ARE INFORMAL AND CONFIDENTIAL AND THEY DO PROVIDE A NEUTRAL ENVIRONMENT. SO WHAT ARE THEIR FUNCTIONS? THEY PRIMARILY RECEIVE AND INVESTIGATE COMPLAINTS FROM INDUSTRY REPRESENTATIVES, LAW FIRMS, CONSUMERS. CDER EMPLOYEES ARE WELCOME TO CONTACT THE HOME BUTT OMBUDSMAN'S OFFICE IF THEY ARE HAVING DIFFICULTY WITH INTERACTION WITH OR CO CONSUMERS, AND YOU CAN CONTACT THEM IF HAVE YOU QUESTIONS ABOUT ANY OF CDER'S DISPUTE RESOLUTION MAPS. THIS IS THEIR CONTACT INFORMATION AND LINK TO THEIR WEB PAGE. SO THE NEXT THING WE'RE GOING TO LOOK AT IS THE ENHANCED COMMUNICATION TEAM WHICH WAS CREATED A IN THIS FISCAL YEAR AND FDA PROMOTES INNOVATION THROUGH ENHANCED COMMUNICATION BETWEEN FDA AND SPONSORS DURING DRUG DEVELOPMENT. I REALLY LIKE THE WAY OUR PHILOSOPHY IS WORDED. THE TIMELY INTERACTIVE COMMUNICATION WITH RESPONSIBLE STORES DURING DRUG DEVELOPMENT IS A CORE ACTIVITY TO HELP ACHIEVE OUR MISSION TO IS A SILFACILITATE CONTACT BY MAKING NEW, SAFE AND EFFECTIVE DRUGS AVAILABLE TO THE AMERICAN PUBLIC IN A TIMELY MANNER. SO HANDLING ENHANCED COMMUNICATION THROUGH EXISTING MANUFACTURERS ASSISTING AND TECHNICAL TRAINING BRANCH, WE WANTED TO MENTION THEIR CONTACT INFORMATION. CDER CHOSE TO ADDRESS ENHANCED COMMUNICATION BY CREATING ENHANCED COMMUNICATION TEAM. IT'S OUR WHE WEB PAGE AND CONTACT INFORMATION, AND YOU YO HEARD WHAT WE DO. THIS IS WHAT WE'RE MADE OF. IT'S COMPRISED OF INDIVIDUALS WHO ARE EXPERIENCED AND KNOWLEDGEABLE ABOUT THE DRUG REVIEW PROCESS. AND WE ENTER ACT REGULARL INTERACT WITH R EVIEW STUFF AND APPLICANTS AND THE F.D.A. SO WHAT'S NOT CHANGING? THE REGULATORY PROJECT MANAGER REMAINS THE PRIMARY CONTACT FOR APPLICATIONS SPECIFIC, TECHNICAL AND SCIENTIFIC QUESTIONS. THE REASON FOR THIS IS THE RPN IS THE CO-LEADER OF THE REVIEW TEAM, THEY HAVE KNOWLEDGE OF DRUG CLASS, HISTORY AND RELATED MATTERS. THE RPM IS THE PRIMARY RESOURCE TO NEGOTIATE THE TIMELY RESOLUTION OF TECHNICAL, SCIENTIFIC, AND REGULATORY QUESTIONS, CONFLICTS, OR PROBLEMS. SO WHEN DO YOU COME TO US? THE ENHANCED COMMUNICATION TEAM? IF YOU HAVE A GENERAL QUESTION, THE INFORMATION MAY BE AVAILABLE ON THE WEBSITE, YOU MAY ASK ME WHERE YOU CAN FIND IT ON THE WEBSITE. YOU MAY WANT TO KNOW THE MAILING ADDRESS FOR REGULATORY SUBMISSION. YOU DON'T HAVE A PROJECT MANAGER, CONTACT THE ENHANCED COMMUNICATION TEAM. WE'RE ALSO SET UP TO IDENTIFY AND DISSEMINATE BREAS DISSEMINATE BEST PR ACTICES, WHERE I REALLY ASK YOU TO CONTACT ME IF YOU HAVE A CONCEPT OR AN IDEA OF A BEST PRACTICE, AN EXAMPLE, PLEASE CONTACT US AND LET US KNOW. E-MAIL US, CALL AND LEAVE A MESSAGE, YOU GET TO HELP SHAPE THIS PROCESS. WE'RE A SECONDARY POINT OF CONTACT FOR COMMUNICATION FOR SPONSORS WHO ARE ENCOUNTERING PRODUCTS COMMUNICATING WITH THE REVIEW TEAM FOR THE IND. WE DO NOT NECESSARILY PROVIDE THE ANSWER. WE FACILITATE THE ANSWER FROM THE DIVISION. SO AN EXAMPLE WOULD BE WHEN YOU HAVE NOT RECEIVED A RESPONSE TO YOUR REQUEST WITHIN A REASONABLE TIME FRAME. REASONABLE VARIES. IF IT'S FOR AN EMERGENCY IND, THAT MIGHT BE THE MATTER OF AN HOUR. IF IT'S FOR SUBMISSION THAT YOU PLANNED TO MAKE IN THE NEXT MONTH, GIVE YOUR PROJECT MANAGER A COUPLE OF DAYS TO GET BACK TO YOU. WHEN YOU HAVE NOT RECEIVED A RESPONSE TO A SIMPLE OR CLARIFYING QUESTION, OR BEEN REFERRED TO THE FORMAL MEETING PROCESS WITHIN 30 DAYS CALL AND LET US KNOW. WE'LL TAMP FACILITATE THAT. SO WHAT SHOULD YOU DO IF YOUR RPMS THAT NO HAS NOT RESPONDED? YOU SHOULD FOLLOW UP WITH THE REVIEW DIVISION MANAGEMENT, NUMBERS ARE LISTED IN THE TOOLS WE SAW EARLIER. AND THEY ARE ALSO LISTED ON THE ENHANCED COMMUNICATION TEAM PAGE. THAT WOULD BE THE CHIEF PROJECT MANAGEMENT STAFF FIRST, THEN THE DIVISION DIRECTOR DEPUTY, OR DIVISION DIRECTOR AS NEEDED. SO HERE WE GET TO THE NEXT SECTION WHICH IS THE RESPONSIBILITIES OF IND APPLICANTS. THIS IS WHERE THE RESPONSIBILITIES CAN BE FOUND IN THE CODE OF FEDERAL REGULATIONS, THIS IS A LINK THAT WILL TAKE YOU DIRECTLY THERE. SO WE'RE GOING TO LOOK AT THE GENERAL RESPONSIBILITIES OF SPONSORS AND INVESTIGATORS. I INCLUDE ALL THE RESPONSIBILITIES THERE FOR REFERENCE. THE KEY THING TO REMEMBER IS THAT A SPONSOR INVESTIGATOR ASSUMES BOTH INVESTIGATOR AND RESPONSIBILITIESLE BUILTS AS OUTLINED IN THE C CFR, SELECTING, MAINTAINING AN EFFECTIVE IND WITH RESPECT TO THE INVESTIGATION AND ENSURING FDA AND PARTICIPATING INVESTIGATORS ARE PROMPTLY INFORMED OF SIGNIFICANT NEW ADVERSE EFFECTS OR RISK WITH RESPECT TO THE DRUG. THE GENERAL RESPONSIBILITIES OF INVESTIGATORS ARE ENSURING INVESTIGATION IS CONDUCTED ACCORDING TO THE SIGNED INVESTIGATOR STATEMENT, THE INVESTIGATIONAL PLAN AND APPLICABLE REGULATIONS. FOR PROTECTING THE RIGHTS, SAFETY AND WELFARE OF SUBJECTS UNDER THE INVESTIGATOR'S CARE, WHICH INCLUDES OBTAINING INFORMED CONSENT AND INTERACTIONS WITH THE IRB, RESPONSIBLE FOR THE CONTROL OF DRUGS UNDER INVESTIGATION. AN INVESTIGATOR SHALL IN ACCORDANCE WITH THE PROVISIONS OF PROTECTION OF HUMAN SUBJECTS OBTAIN INFORMED CONSENT OF EACH HUMAN SUBJECT TO WHOM THE DRUG IS ADMINISTERED, EXCEPT AS PROVIDED, IN THE EXCEPTION FROM GENERAL REQUIREMENTS, OR EXCEPTION FROM INFORMED CONSENT REQUIREMENT FOR EMERGENCY RESEARCH OF THIS CHAPTER. ADDITIONAL SPECIFIC RESPONSIBILITIES OF CLINICAL INVESTIGATORS ARE SET FORTH IN REVIEW BOARDS OF THIS CHAPTER. WHAT ARE OUR RESPONSIBILITIES? SUBMIT AN IND APPLICATION ACCORDING TO CONTENT AND FORMAT SPECIFIED IN REGULATIONS. SUBMIT INFORMATION ABOUT THE TRIALS, CLINICAL TRIALS.GOV, RESPOND TO ALL FDA INQUIRIES, CORRESPONDENCE AND COMMUNICATION, SUBMIT SAFETY REPORTS IN THE LIFE CYCLE, MAINTAIN THE IND APPLICATION THROUGH ITS LIFE CYCLE, AND KEEP ALL RECORDS RELATED TO YOUR IND APPLICATION. FOR A PERIOD OF TWO YEARS FOLLOWING THE DATE OF APPROVAL FOR MARKETING, OR UNTIL TWO YEARS AFTER OF THE INVESTIGATION IS DISCONTINUED. THANK YOU. WE SHOULD BE CLOSE TO ON TIME. [APPLAUSE] >> OKAY. SO OUR NEXT SESSION IS REGARDING NIH PERSPECTIVE ON THE INVESTIGATOR'S RESPONSIBILITY, THAT'S GOING TO BE THREE TOPICS, IRB REVIEW, INFORMED CONSENT, AND A SPECIAL PERSPECTIVE ON POPULATIONS IN PARTICULAR CHILDREN. THE FIRST PRESENTER IS DR. RICHARD CANNON, TALKING ABOUT THE IRB PERSPECTIVE OF REVIEW, DR. CANNON IS SENIOR INVESTIGATOR IN CARDIOLOGY, FORMER DIRECTOR OF THE HEART LUNG BLOOD INSTITUTE, INITIALLY APPOINTED TO THE NHLBI IRB IN 1992, A CHAIR SINCE 2012. I'LL LET HIM TELL YOU MORE ABOUT THE INVESTIGATAL REVIEW BOARDS. >> THANK YOU. GOOD MORNING. I WANT TO START WITH A QUOTATION FROM 200 YEARS AGO, NOTHING FOCUSSINGS THE MIND LIKE A HANGING, REFERRING TO ONE'S OWN HANGING RATHER THAN SOMEONE ELSE. HE SAID IT MUCH MORE ELEGANTLY BUT YOU GET THE IDEA. I WOULD PARAFREEZ PARAPHRASE THIS TO SAY NOTHING FOCUS LIKE THE REVIEW OF A RESEARCH PROPERT RESEARCH RESEARCH P ROTOCOL BECAUSE THE STAKES ARE HIGH. ON ONE HAND WE HAVE INVESTIGATORS THAT ARE ENTHUSIASTIC ABOUT THEIR NEW DRUG, OR BIOLOGICAL PRODUCT, THEY MAY BE HOPING THIS WILL BE A SIGNIFICANT ADVANCE FOR PATIENTS AND MANY OF WHOM HAVE SERIOUS DISEASES WITH VERY FEW OR MAYBE NO THERAPEUTIC OPTIONS, SO WE HAVE THAT ENTHUSIASM ON THE ONE HAND. AND THEN WE HAVE THE SOBER EXPERIENCE OF THE IRB THAT THINGS DON'T OFTEN TURN OUT AS ANTICIPATED OR EXPECTED. AND SOMETIMES HARMS CAN COME TO WEREESEARCH SUBJECTS THAT NOT INTENDED OR ANTICIPATED. WE'VE GOT TO BE VERY SURE WE DO OUR JOB WELL, THAT WE UNDERSTAND TO THE EXTENT POSSIBLE THAT THE RISKS OF RESEARCH AND THAT THE PROTOCOL IS SUFFICIENTLY DESIGNED TO IDENTIFY UNANTICIPATED RISKS, WE CAN CHANGE THE PROTOCOL OR MODIFY THE PROTOCOL OR MAYBE SUSPEND OR TERMINATE THE PROTOCOL TO PROTECT HUMAN SUBJECTS. WE HAVE TO LIVE UNDER ANOTHER SET OF REGULATIONS SO WE HAVE TITLE 45 THAT REGULATES ALL HUMAN SUBJECTS RESEARCH WITHIN IND, FDA REGULATED RESEARCH, TITLE 21, A WHOLE NEW SET OF REGULATIONS INCLUDING THE POSSIBILITIES OF AUDIT IF WE DON'T DO OUR JOB RIGHT. WE TAKE THIS EVEN MORE SERIOUSLY THAN WE ORDINARILY TAKE OUR RESPONSIBILITIES TO OVERSEE HUMAN SUBJECTS RESEARCH. SO ONE OF THE FIRST THINGS THAT WE MIGHT HAVE TO CONSIDER WHEN A PROTOCOL IS SUBMITTED TO THE IRB IS WHETHER AN IND IS EVEN REQUIRED. THIS HAS BEEN REFERRED TO ON SEVERAL OCCASIONS, BUT THE FDA DOES ALLOW THE IRB TO MAKE THAT DETERMINATION, AND WE FOCUS PRIMARILY ON WHAT'S HIGHLIGHTED IN YELLOW, AND THAT IS THE INVESTIGATION DOES NOT INVOLVE A ROUTE OF ADMINISTRATION, PATIENT POPULATION OR OTHER FACTOR THAT SIGNIFICANTLY INCREASES RISK OR DECREASES ACCEPTABILITY OF RISK ASSOCIATED WITH USE OF A DRUG PRODUCT. SO IF THE INVESTIGATOR CAN MAKE THE CASE THAT THAT SEEMS TO BE TRUE AND OKAY, WE MAY ALLOW EXEMPTION FROM IND. IF WE HAVE ANY QUESTIONS OR CONCERNS, WE'LL REQUIRE THE INVESTIGATOR ACTUALLY SUBMIT AN IND APPLICATION TO THE F.D.A. WE HAVE SEVERAL PROCEED COMES ARE REPURPOSED, USE OF A DRUG ALREADY APPROVED FOR ANOTHER INDICATION, THE USE OF A TORVA STAT INT IN, TO LOWER EXAMINATION, BUT BEING USED FOR PATIENTS WITH LUNG DISEASE. THE IF AN IND IS REQUIRED THE SPONSOR WILL PROVIDE THE IRB WITH DOCUMENTATION IN THE FORM OF DATED WRITTEN COMMUNICATION FROM THE FDA, THE IND GOES INTO EFFECT 30 DAYS AFTER THE FDA ASSIGNS THE IND APPLICATION NUMBER, UNLESS THE FDA NOTIFIES THE SPONSOR THE INVESTIGATION IS SUBJECT TO A CLINICAL HOLD, OR IF THE FDA SENDS A SAFE TO PROCEED LETTER IN WHICH CASE IT CAN START SOONER THAN 30 DAYS. SO AN IMPORTANT QUESTION THAT WE ADDRESS IN THE IRB IS, IS THE RESEARCH SCIENTIFICALLY SOUND? IF IT'S NOT GOOD SCIENCE, IT'S UNETHICAL TO DO THE RESEARCH. IN THE INTRAMURAL RESEARCH PROGRAM, AS YOU KNOW, THERE'S A REQUIREMENT ALL PROTOCOLS UNDERGO INDEPENDENT SCIENTIFIC AND STATISTICAL REVIEW. OFTEN PRIOR TO THAT THERE'S A REVIEW AT THE BRANCH LEVEL OR LABORATORY LEVEL, SO OFTEN THERE HAVE BEEN SEVERAL REVIEWS OF THIS PROTOCOL BEFORE IT COMES TO THE IRB. FROM THE FDA, IF THERE WEREFROM ISSUES THE FDA HAD WITH THE PROTOCOL, WE WANT TO NOW HOW INVESTIGATORS RESPONDED TO CONCERNS AND THAT WOULD HELP WITH OUR DETERMINATION. THE IRB WILL REVIEW THE INVESTIGATOR'S BROCHURE, WE WANT TO KNOW PARTICULARLY FOR FIRST-IN-HUMAN CLINICAL TRIAL, AND WE WANT TO MAKE SURE WE HAVE APPROPRIATE EXPER EXPERTISE, SIGN ACTIVIVE, BIOETHICS, SOMETIMES WE MIGHT INVITE A CONSULTANT TO GIVE US INFORMATION TO REVIEW THE PROTOCOL IN A RESPONSIBLE MANNER. IS THE INVESTIGATOR CAPABLE OF CONDUCTING THE PROPOSED RESEARCH? YOU'VE HEARD THIS PREVIOUSLY, THIS IS A MATTER OF CONCERN NOT ONLY TO THE FDA BUT TO THE IRB BECAUSE THE STUDY WILL BE DONE HERE AT THE CLINICAL CENTER. WE WANT TO MAKE SURE THE INVESTIGATOR IS QUALIFIED BY EDUCATION, TRAINING AND EXPERIENCE, AND THAT THE INVESTIGATOR UNDERSTANDS AND IS WILLING TO CONDUCT THE RESEARCH CONSISTENT WITH GOOD CLINICAL PRACTICE. YOU'VE HEARD GOOD CLINICAL PRACTICE PREVIOUSLY. IT'S WORTH REPEATING IT'S THE INTERNATIONAL STANDARD FOR THE DESIGN, CONDUCT, OVERSIGHT, MONITORING, THE ANALYSIS, REPORTING OF A STUDY THAT INVOLVES HUMAN SUBJECTS, THAT PROVIDES ASSURANCE THAT THE DATA ARE CREDIBLE, THAT THEY ARE ACCURATE, AND THAT HUMAN SUBJECTS HAVE BEEN PROTECTED. SO WE WANT TO MAKE SURE THAT INVESTIGATORS KNOW THAT. THE INTRAMURAL RESEARCH PROGRAM, IT'S NOW A REQUIREMENT ALL INVESTIGATORS, PRINCIPAL AND ASSOCIATE, COMPLETE REQUIRED TRAINING. WE WANT TO KNOW IF THE INVESTIGATOR HAS THE NECESSARY RESOURCES HERE AT THE CLINICAL CENTER TO COMPLETE RESEARCH WITH APPROACH REALL APPROPRIATE DELEGATIO N OF RESPONSIBILITIES. IT REQUIRES A LOT OF PEOPLE. WE WANT TO MAKE SURE PEOPLE HAVE THE RIGHT SKILLS TO DO THE RIGHT THINGS IN THE PROTOCOL. WE WANT TO MAKE SURE THE INVESTIGATOR IS CAPABLE OF IDENTIFYING ADVERSE EVENTS, PROVIDING MEDICAL CARE TO RESEARCH SUBJECTS. DOES THE PROTOCOL DESIGN ALLOW US TO IDENTIFY, OR DOSE ESCALATION, WHAT KINDS OF OVERSITE, WILL A DSMB BE REQUIRED, THE ANSWER IS ALMOST ALWAYS YES. AND THEN THIS IS VERY IMPORTANT TO US, IS THERE A CREDIBLE RECRUITMENT PLAN, CAN THEY RECRUIT SUBJECTS NEEDED, IMPORTANT FOR PHASE II WHERE IT SWITCHES FROM SAFETY TO EFFICACY. ARE THEY GOING TO BE ABLE TO ACCRUE ENOUGH SUBJECTS TO COMPLETE THE STUDY? IF THEY CAN'T, SADLY THIS OFTEN HAPPENS, THEY ARE UNABLE TO RECRUIT ENOUGH SUBJECTS, WE LEARN VERY LITTLE FROM THE STUDY AND AGAIN THAT RAISES ETHICAL ISSUES ABOUT THE CONTINUATION OF THE PROTOCOL. DOES THE INVESTIGATOR UNDERSTAND THE RESPONSIBILITIES OF CONDUCTING IND RESEARCH? SOME OF THIS HAS BEEN TOUCHED UPON PREVIOUSLY OR WILL BE DISCUSSED THIS AFTERNOON. SO ACCOUNTABILITY AND USE OF INVESTIGATIONAL PRODUCTS AND STORAGE INVOLVES THE CLINICAL CENTER PHARMACY, YOU'LL HEAR FROM GEORGE GRIMES LATER ON ABOUT THIS. WE ALSO WANT TO MAKE SURE THERE'S A PLAN TO EDUCATE RESEARCH SUBJECTS, HOW THEY ARE GOING TO TAKE THIS DRUG, ARE THEY AWARE OF THE SIDE EFFECTS OF THE DRUG, IF THEY HAVE TO TAKE IT AT HOME, DO THEY UNDERSTAND HOW THEY ARE TO TAKE IT AT HOME, IS THERE PROVISION THEY TAKE IT THE RIGHT WAY? WE WANT TO MAKE SURE THAT OUR INVESTIGATORS UNDERSTAND THE REPORTING REQUIREMENTS FOR ADVERSE EVENT, WE'LL TALK ABOUT THAT IN DETAIL IN JUST A MOMENT, BUT ALSO THE NEED FOR ANY CHANGE IN THE PROTOCOL REQUIRING NOTIFICATION OF THE IRB IN THE FORM OF AMENDMENT, CONTINUING REVIEW RESPONSIBILITIES ON AN ANNUAL BASIS OR SOONER, ANNUAL REPORTS TO THE F.D.A. AGAIN, THE IRB NEEDS TO APPROVE ANY CHANGE IN THE PROTOCOL. NOW, SOMETIMES THIS CAN BE SPA EXPEDITED IF IT'S MINOR, THIS CAN BE DONE RAPIDLY, IT DOESN'T HAVE TO GO FOUGHT FUL TO THE IRB, SUBSTANTIVE CHANGES REQUIRES THE FULL IRB. RECORD KEEPING, IN ADDITION TO REGULATORY BINDER AND CASE REPORT FORMS, WE WANT TO MAKE SURE THEY UNDERSTAND THE NEED TO PROTECT AND RETAIN THE DATA. THIS IS JUST MENTIONED A MOMENT AGO. AND IN FACT IN THE CLINICAL CENTER THERE'S EFFORT TO TRY TO RETAIN DATA FOREVER, BY USE OF BEATRICE, SO THE DATA CAN BE REUSED AT A FUTURE TIME WITH APPROPRIATE SAFE GUARDS. WE WANT TO MAKE SURE THEY UNDERSTAND THE REQUIREMENTS FOR SAMPLE STORAGE AND FOR THE MONITORING AND THE ADMINISTRATION OF SAMPLE STORAGE THAT IS REQUIRED BY THE INTRAMURAL RESEARCH PROGRAM AT THE NIH. THERE'S A POLICY FOR THAT. WE WANT TO MAKE SURE THEY HAVE APPROPRIATE LEGAL DOCUMENTS IN PLACE, FOR COLLABORATIONS WITH SPONSOR AND OTHER COLLABORATORS PARTICULARLY THOSE OUTSIDE THE NIH. WE WANT TO MAKE SURE THE MONITORING IS SATISFACTORY. IS THERE APPROPRIATE QUALITY ASSURANCE, QUALITY CONTROL? IS THERE GOING TO BE MONITORING THROUGHOUT THE STUDY? WHO IS GOING TO PROVIDE IT, THE SPONSOR OR SOMEONE IN THE INSTITUTE, IS THERE A MON DR. ? MONITOR? A DSNC MONITOR, MOST CASES THERE WILL BE. WE WANT TO MAKE SURE THE FDA MAY INSPECT THE STUDY AT ANY TIME OR PERFORM AN AUDIT. AND THEN THE NEED FOR FINAL REPORT TO BOTH THE FDA AND THE IRB. OKAY. SAFETY REPORTING REQUIREMENTS, VERY IMPORTANT. INVESTIGATORS ARE REQUIRED TO REPORT ADVERSE EVENTS TO THE SPONSOR UNLESS EXEMPTED IN THE PROTOCOL. INVESTIGATORUDING SPONSORS, HERE AT THE CLINICAL CENTER MANY SPONSORS ARE INVESTIGATOR SPONSORS, THEY MUST NOTIFY THE IRB AND FDA WITHIN 15 DAYS, 7 DAYS IF SERIOUS, OF ADVERSE EXPERIENCE WITH THE DRUG THAT IS UNEXPECTED, BASED ON INFORMATION IN THE PROTOCOL, INVESTIGATOR BROCHURE, AND/OR THE CONSENT, AT LEAST POSSIBLY RELATED TO THE RESEARCH AND SUGGEST A SIGNIFICANT RISK OF HUMAN SUBJECTS. THAT'S WHAT'S CONSIDERED AN UNANTICIPATED PROBLEM. WHEN WE RECEIVE A REPORT OF AN UNANTICIPATED REPORT WE HAVE TO CONSIDER THE APPROPRIATE ACTION THAT MAY BE TO MODIFY THE STUDY IN SOME WAY, MAYBE TO CHANGE THE DOSING ADMINISTRATION, IT MAY BE TO ADD SOMETHING TO THE CONSENT, TO INFORM A SUBJECT OF A NEW ADVERSE EVENT THAT WASN'T APPRECIATED WHEN THE STUDY WAS FIRST DESIGNED AND APPROVED, OR IT MAY BE A MORE SUBSTANTIVE ACTION, IT MAY BE WE'LL SUSPEND ENROLLMENT UNTIL SOMETHING IS WORKED OUT, SOMETHING IS DA DRAMATICALLY CHANGED OR THERE'S CONVERSATION WITH THE FDA, OR WE MAY TERMINATE THE PROTOCOL THAT WE DO NOT FEEL THAT IT'S SAFE TO CONTINUE THE PROTOCOL. ALL THIS IS REPORTED TO THE FDA AND THEY MAY TAKE THEIR OWN ACTION, PUT IT ON CLINICAL HOLD OR TERMINATE THE PROTOCOL. SO SAFETY REPORTING, VERY IMPORTANT, IN HUMAN SUBJECTS RESEARCH. ALSO IMPORTANT IS PROTOCOL DEVIATION REPORTING. PROTOCOL DEVIATION IS ANY CHANGE, DIVERGENCE OR DEPARTURE FROM THE IRB-APPROVED RESEARCH PROTOCOL, CONSIDERED SERIOUS IF IT COMPROMISES SAFETY, WELFARE OR RIGHTS OF SUBJECTS. ALL PROTOCOL DEVIATIONS ARE REVIEWED BY THE IRB, SERIOUS PROTOCOL DEA DEVIATIONS ARE REPORTED TO THE FDA, THE ACTIONED MIGHT BE TO MODIFY OR SUSPEND OR TERMINATE PROTOCOL, PARTICULARLY IF WE FEEL INVESTIGATORS ARE NOT CAPABLE OF CONDUCTING THE RESEARCH. HERE IS A HINT. IT'S NOT IN THE REGULA REGULATIONINGS, TO AVOID FREQUENT REPORTING OF NONSERIOUS REPORTING, BECAUSE ALL DEVIATIONS HAVE TO BE REPORTED TO THE IRB, SO TO AVOID FILING NONSERIOUS PROTOCOL REPORTS PROVIDE FOR FLEXIBILITY. MAYBE A WINDOW OF HOURS OR DAYS FOR TESTING REQUIRED IN THE PROTOCOL, IF APPROPRIATE. BECAUSE SOMETIMES PATIENTS DON'T SHOW UP ON THE DAY WHEN THEY ARE SUPPOSED TO SHOW UP, OR THE LAB MISPLACES A SPECIMEN OR SOMETHING HAPPENS AND THEY CAN'T COLLECT THAT DATA POINT. PROVIDE FLEXIBILITY WITH PROTOCOL. AN IMPORTANT RESPONSIBILITY TO THE IRB IS REVIEW CONSENT DOCUMENT AND THE CONSENT CONSENT ISW COULD BE SENT IS OBTAINED. DR. GRADY WILL TALK ABOUT THIS IN JUST A BIT. IS THE CONSENT DOCUMENT UNDERSTANDABLE? THE REQUIREMENTHERE ARE NO TERMS, ABBREVIATIONS, LANGUAGE CONFUSING TO A RESEARCH SUBJECT. A LOT OF RESEARCH SUBJECTS ARE ILL, THEY MAY HAVE SERIOUS DISEASES, AND THEY MAY JUST -- THEIR EYES MAY GLAZE WHEN THEY SEE A 15-PAGE CONSENT THAT DOESN'T PROVIDE THE INFORMATION THEY NEED TO MAKE A DECISION ABOUT WHETHER OR NOT TO PARTS ANYTIME IPARTICIPATE IN THE STUDY. WE HAVE TO MAKE SURE THE CONSENT DOCUMENT IS ACHIEVING ITS INTENDED PURPOSE. DOES THE CONSENT PROVIDE A FAIR DESCRIPTION OF RISKS AND BENEFITS? WE DO NOT WANT INVESTIGATORS TO OVERSELL THE POTENTIAL BENEFITS OF A AN INVESTIGATIONAL DRUG OR PRODUCT BECAUSE IF THE BENEFITS -- THERE MAY BE NO BENEFITS, AND CERTAINLY THE RISKS COULD OUTWEIGH POTENTIAL BENEFIT AND WE NEED TO BE AWARE OF THAT. AND ARE THERE OPTIONS TO PARTICIPATION, IS THERE SOMETHING ELSE THEY COULD DO? WE DON'T REQUIRE INVESTIGATORS TO LIST EVERY OTHER RESEARCH PROTOCOL OUT THERE, SUBJECT CAN GO TO CLINICALTRIALS.GOV AND DO THAT BUT IF THERE ARE REASONABLE ALTERNATIVES, OPTIONS FOR FDA APPROVED PRODUCTS OR TREATMENTS, THEN PATIENTS SHOULD BE -- RESEARCH SUBJECTS SHOULD BE MADE AWARE OF THAT. SPECIAL SITUATIONS, WE'RE GOING TO HEAR FROM DR. PORTER IN A BIT BUT IF THEY ARE CHILDREN, PREGNANT WOMEN, IMPAIRED SUBJECTS, WE HAVE TO HAVE SAFE GUARDS TO PROTECT THOSE SUBJECTS. WHO WILL OBTAIN CONSENT? WE WANT TO KNOW WHO IS GOING TO OBTAIN CONSENT? THE INVESTIGATORS HAVE TO BE IDENTIFIED IN THE PROTOCOL. WE'VE GOT TO MAKE SURE THEY HAVE HAD TRAINING TO OBTAIN CONSENT BECAUSE CONSENT, AS DR. GRADY WILL EMPHASIZE, IS A PROCESS. WE WANT TO BE SURE THAT PROCESS WILL BE FOLLOWED. DOES THE CONTENT DESCRIBE THE EXTENDED OR FUTURE USE OF DATA? THIS IS IMPORTANT BECAUSE DATA BEATRICES OR YOUE 'TIS MAY COMBINE THEM WITH OTHER STUDIES, OR PUT THEM IN A PUBLIC DATABASE IN THE FUTURE, AND WE WANT TO MAKE SURE THE CONSENT ALLOWS FOR THAT. ARE CONFLICTS OF INTEREST IDENTIFIED, IS THERE PROVISION OF TRAVEL AND LODGING, COMPENSATION, ADVERTISEMENTS, OR RECRUITING MATERIALS, WE NEED TO SEE AND APPROVE THOSE. SUBJECT WITHDRAWAL, VERY IMPORTANT. IF A SUBJECT WITHDRAWS OR IS WITHDRAWN FOR GOOD REASON, FROM AN IND STUDY, THE DATA COLLECTED TO THE TIME OF WITHDRAWAL REMAINS PART OF THE STUDY DATABASE AND MAY NOT BE REMOVED. IF A PATIENT SAYS I'M OUT OF HERE, I'M DONE WITH THIS, I WANT YOU TO DESTROY MY DATA, CAN'T DO THAT. YOU HAVE TO KEEP THE DATA UP TO THE TIME THE SUBJECT WITHDRAWS FROM THE STUDY, THAT SHOULD BE STATED IN THE CONSENT. THE SUBJECT MAY BE ASKED TO PROVIDE FOLLOW-UP DATA COLLECTION, THEY MAY STOP THE INVESTIGATIONAL TREATMENT BUT THEY MIGHT BE WILLING TO COME TO THE CLINIC ON SEVERAL OCCASIONS TO MAKE SURE THINGS ARE GOING WELL, AND ALLOW FOR THAT DATA COLLECTION. SO STATE THAT IN THE CONSENT AS WELL OR THERE'S GOING TO BE THE REQUIREMENT FOR AN ADDITIONAL CONSENT FOR THE FOLLOW-UP WHEN THEY DROPPED OUT OF THE STUDY. SO THESE SPECIAL SITUATIONS FOR USE OF INVESTIGATE JAAL DRUGS HAVE LAPTEVA AND YOU'LL HEAR MORE THE EMPHASIS IS ON TREATMENT, NOT RESEARCH. I JUST MENTION THIS JUST TO POINT OUT THE IRB'S ROLE IN THIS, FOR AN EXPANDED ACCESS TO INVESTIGATIONAL DRUG THERE HAS TO BE A PROTOCOL APPROVED BY IRB. FOR EMERGENCY USES OF A TEST ARTICLE WHERE TIME IS OF ESSENCE, THE IRB DOES NOT APPROVE THE TEST ARTICLE. THE FDA IS ALERTED. THERE NEEDS TO BE APPROVAL BUT IT DOES NOT GO BEFORE THE FULL IRB. HOWEVER, THERE HAS TO BE A SUBMISSION, NOTIFICATION OF THE SUBMISSION FORM TO THE IRB WITHIN FIVE DAYS, BUT THE IRB DOES NOT APPROVE THE EMERGENCY USE. SO FINALLY, THIS LOOKS LIKE A DAUNTING PROCESS, AND IT IS. I'VE BEEN THROUGH THIS MANY TIMES MYSELF, AS HAVE SEVERAL OF YOU IN THE AUDIENCE. SO YOU KNOW THAT IT IS A DAUNTING PROCESS. HOWEVER, IT'S CLEAR THE FDA IS GOING TO GREAT LENGTHS TO MAKE THIS AN EASIER PROCESS AND THAT'S A GOOD THING. HOWEVER, IT'S IMPORTANT TO GET HELP. IF YOU'VE NEVER DONE THIS BEFORE, IF YOU'VE NEVER GONE THROUGH THE APPLICATION PROCESS OR CONDUCTED AN IND-REGULATED RESEARCH, GOOD TO GET MENTORS, AND THERE ARE PLENTY OF MENTORS. LEARN THROUGH INVESTIGATORS WHO HAVE BEEN THROUGH THE CLINICAL PROCESS. RESUE SOP I 15. EVERYTHING I'VE SHOWN YOU TODAY EXCEPT FOR THE BIT ABOUT THE HANGING SYMPTOMS FRO COMES FROM SOP 15. READ IDENTIFY CAREFULLY. ALSO YOUR INSTITUTE OR CENTER SHOULD HAVE AN IRB OR PROTOCOL SERVICES OFFICE, THEY CAN BE A TREMENDOUS RESOURCE. THERE MAY BE A REGULATORY AFFAIRS EXPERT IN THAT OFFICE, PROTOCOL NAVIGATORS, WHO CAN HELP NAVIGATE THE PROCESS, AND YOU CAN GO TO THE IRB CHAIR, HOPEFULLY THAT PERSON CAN BE A SOURCE OF INFORMATION. AS WE HEARD THIS MORNING, YOU'LL HEAR AS THIS TRAINING SESSION GOES ON, THE FDA IS WILLING TO HELP. PHONE CONVERSATIONS, PRE-IND OFTINGS, THE FDA AT THE END THE DAY, WE ALL WANT THE RESEARCH TO PROCEED, WE WANT IT TO PROCEED THOUGH IN A RESPONSIBLE MANNER. THANK YOU. APPLAUSE >> THANK YOU, DR DR. CANNON. THAT WAS GREAT. I'M HEATHER BRIDGE WITH THE OFFICE OF HUMAN SUBJECTS RESEARCH PROTECTION, WE'LL TELL YOU MORE ABOUT THAT. I'M GOING TO INTRODUCE DR. CHRISTINE GRADY, THE CHIEF OF THE CLINICAL CENTER AND BIOETHICS DEPARTMENT, AND ONE OF HER AREAS OF RESEARCH IS INFORMED CONSENT AND SHE'S GOING TO TELL US MORE ABOUT THAT TOPIC. >> GOOD MORNING. YOU'VE HEARD ALREADY ABOUT INVESTIGATOR RESPONSIBILITIES TO COMMUNICATE WITH THE FDA, WITH THE IRB, WITH THE SPONSOR. I'M GOING TO TALK ABOUT INVESTIGATOR'S RESPONSIBILITY TO COMMUNICATE WITH THE SUBJECT. AND THAT'S USUALLY ONE MAIN PIECE IS INFORMED CONSENT. IT'S NOT THE ONLY TIME BUT IT'S A VERY IMPORTANT PART OF ENROLLING AND RETAINING PEOPLE IN RESEARCH IS TO GIVE THEM THE INFORMATION THEY NEED TO UNDERSTAND WHAT THE STUDY IS ABOUT. SO I'M GOING TO START BY REMINDING US CONSENT ITSELF IS A MORAL AND LEGAL PROTECTION FROM UNAUTHORIZED INVASION OF ONE'S BODY OR ONE'S PROPERTY. THAT'S A GENERAL STATEMENT ABOUT WHAT CONSENT IS. IT HAS A POWERFUL MORAL FACILITATIVE POWER. IF I GIVE YOU CONSENT TO BORROW MY CAR, IT'S FINE FOR YOU TO TAKE THE CAR AND DRIVE IT. IF YOU TAKE IT WITHOUT MY CONSENT, YOU'VE STOLEN IT. IF I GIVE YOU CONSENT TO DRAW MY BLOOD YOU CAN TAKE MY BLOOD. IF YOU TAKE MY BLOOD WITHOUT MY CONSENT, IT COULD BE YOU A SALT AND BATTERY, IT'S A STRONG POWER. IN THE CONTEXT OF RESEARCH AND HEALTH CARE, WE ACTUALLY DON'T JUST TALK ABOUT CONSENT. WE TALK ABOUT INFORMED CONSENT. SO IT'S NOT JUST GIVING PERMISSION. BUT IT'S GIVING PERMISSION OR AUTHORIZATION OF SOMETHING BASED ON UNDERSTANDING WHAT THAT ACTIVITY IS. OR WHAT THAT ACTIVITY ENTAILS. IT IS A LEGAL, REGULATORY AND ETHICAL REQUIREMENT FOR ALMOST ALL HEALTH CARE TRANSACTIONS AND CLINICAL RESEARCH, NOT ONLY IN THE UNITED STATES BUT MOST PLACES AROUND THE WORLD. IN RESEARCH, BECAUSE WE'RE ESPECIALLY IN IND RESEARCH PERHAPS, WE'RE ASKING PEOPLE TO TAKE ON RISKS TO HELP US ANSWER A QUESTION ABOUT SOMETHING WE DON'T KNOW. WHETHER OR NOT THIS DRUG WORKS IN A CERTAIN CONTEXT. THEREFORE, PEOPLE SAY THAT THIS SORT OF INJUNCTION AGAINST USING PEOPLE FOR THE BENEFIT OF SOMEBODY ELSE IN RESEARCH REQUIRES A LITTLE BIT MORE ATTENTION TO INFORMED CONSENT THAN YOU MIGHT GIVE IT IN A CLINICAL CARE ENVIRONMENT. AND ALL OF THE CODES AND REGULATIONS THAT GOVERN ETHICAL AND CLINICAL RESEARCH TALK ABOUT CONSENT AND THEY NOT ONLY TALK ABOUT INFORMED CONSENT, BUT THEY TALK ABOUT VOLUNTARY CONSENT. SO YOU ARE ALL FAMILIAR I'M SURE WITH THE NURENBERG CODE AND STATEMENT, VOLUNTARY CONSENT OF THE HUMAN SUBJECT IS ABSOLUTELY ESSENTIAL. ALL ITERATIONS FROM HELSINKI HAVE DETAILS ABOUT HOW IMPORTANT INFORMED CONSENT IS. THE LAST BULLET ON THIS SIDE IS FROM BOTH THE FDA REG'S AND THE COMMON RULE, AND BASICALLY THEY BOTH SAY NO INVESTIGATOR MAY INVOLVE A HUMAN BEING AS A SUBJECT IN RESEARCH COVERED BY THESE REGULATIONS, UNLESS THE INVESTIGATOR HAS OBTAINED LEGAL EYLEGALLY EFFECTIVE INFORMED CONSENT OF THE SUBJECT OR REPRESENTATIVE. IT'S A STRONG STATEMENT, IT'S IN THE REGULATIONS THAT GOVERN ALL OF THE RESEARCH WE DO. AS DR. CANNON MENTIONED ALREADY, EVERYONE IN THIS ROOM KNOWS, INFORMED CONSENT IS NOT JUST A PIECE OF PAPER, IT'S NOT JUST A BOX THAT YOU CHECK OFF WHEN YOU'RE DOING YOUR RESEARCH. I'M GOING TO DO RESEARCH, NOW THE CONSENT PART. IT'S A PROCESS OF GIVING PEOPLE INFORMATION ABOUT THE STUDY SEE THEY CAN MAKE A CHOICE, INFORMED AND VOLUNTARY CHOICE, ABOUT WHETHER OR NOT THEY WANT TO PARTICIPATE AND WHETHER OR NOT THEY WANT TO CONTINUE TO PARTICIPATE THROUGHOUT THE DURATION OF THE STUDY. MOST PEOPLE AGREE THIS PROCESS INVOLVES SEVERAL STEPS. IT INVOLVES DISCLOSURE OF INFORMATION TO THE PERSON. THEY ARE UNDERSTANDING WHAT THE INFORMATION IS ABOUT. AND BEING IN A POSITION TO DELIBERATE ABOUT IT. THEY ARE BEING ABLE TO MAKE A VOLUNTARY DECISION ABOUT WHETHER OR NOT THEY WANT TO PARTICIPATE OR CONTINUE TO PARTICIPATE. THEN AUTHORIZING THAT DECISION IN SOME WAY AND THEN DOCUMENTING. AUTHORIZATION AND DOCUMENTATION ARE OFTEN THE SAME THING. SIGNING A PIECE OF PAPER. THERE ARE TIMES WHEN CONSENT IS DONE IN A DIFFERENT WAY BESIDES SIGNING A PIECE OF PAPER. WHAT ABOUT DISCLOSURE? DISCLOSURE OF INFORMATION IS USUALLY DONE IN TWO WAYS. THERE IS A WRITTEN CONSENT DOCUMENT, THERE ARE ALSO DISCUSSIONS WITH THE P.I. AND OTHER MEMBERS OF THE RESEARCH TEAM AND THE PARTICIPANT OR THE POTENTIAL PARTICIPANT. AS YOU ALL KNOW, A SIGNED CONSENT FORM IS REQUIRED BY FEDERAL REGULATIONS IN ALMOST EVERY CASE, CERTAINLY UNDER AN IND IT IS. THERE ARE SOME EXCEPTIONS WHICH WE CAN TALK ABOUT IF YOU WANT. UNFORTUNATELY, WRITTEN CONSENT FORMS FOR RESEARCH ARE OFTEN LONG, COMPLEX, WRITTEN AT A HIGH LEVEL, AND DIFFICULT TO READ AND UNDERSTAND. IN FACT, DATA SUGGESTS THEY ARE GETTING LONGER, MORE COMPLEX, AND MORE DIFFICULT TO READ OVER TIME RATHER THAN LESS. SO HOW DO YOU WRITE A CONSENT FORM? BASICALLY, YOU WANT TO WRITE A SUMMARY OF THE INFORMATION ABOUT A STUDY, THAT THE PERSON NEEDS TO KNOW TO MAKE A CHOICE. AND SO THE GOAL IS INFORMED DECISION MAKING. THE REGULATIONS ARE VERY CLEAR ABOUT THE ELEMENTS, KINDS OF INFORMATION THAT NEED TO BE INCLUDED IN THE WRITTEN DOCUMENT AND IRB REVIEWS TO MAKE SURE THEY ARE NOT ONLY THERE BUT ADEQUATE. AND THOSE ELEMENTS, THIS IS A VERY BRIEF PARASURPRISE I'LL SHOW YOU ON THE NEXT SLIDE THE DETAILS IN THE REGS, BUT YOU WANT TO EXPLAIN IT IS RESEARCH, THE PURPOSE OF THE RESEARCH, THE PROCEDURES THAT ARE INVOLVED IN THE RESEARCH AND HOW THEY ARE DIFFERENT FROM WHAT MIGHT OCCUR IN THE CLINICAL ENVIRONMENT, THE RELATED RISKS AND FORESEEABLE DISCOMFORT, POSSIBLE BENEFITS, ALTERNATIVES, AND THEN SOME THINGS ABOUT THE RIGHTS THAT THE PERSON HAS IF THIS I, THAT THIS IS A VOLUNTARY CHOICE AND WE WILL DO EVERYTHING TO PROTECT CONFIDENTIALITY. DECISIONIS INFORMED DIGS MAKING. AS DR. CANNON MENTIONED, THE DOCUMENT AND WHO WILL COUL OBTAIN CONSENT ARE APPROVED BY THE IRB WHO HAS THE FINAL AUTHORITY OF ENSURING ADEQUACY OF INFORMATION. IMPORTANTLY, ADVERTISEMENTS, FLYERS, BROCHURES, ET CETERA, ARE CONSIDERED PART OF THE INFORMED CONSENT PROCESS. IT'S NOT JUST THE DOCUMENT THAT PEOPLE SIGN AND GET TO PUT IN THEIR RECORD. THIS IS THE WORDING FROM THE REGULATIONS FOR THE ELEMENTS THAT I JUST WENT THROUGH IN A FEW WORDS, THEY ARE IMPORTANT TO KNOW AND PROBABLY YOU'VE ALL READ THEM. IF YOU HAVEN'T, YOU SHOULD. BUT IT'S COMMON SENSE, THIS IS RESEARCH, HERE IS THE PURPOSE, HERE IS THE PROCEDURES, RISKS AND BENEFITS, ALTERNATIVES. SO I WANT TO SPEND THE REST OF MY MINUTES TALKING ABOUT A LITTLE BIT ABOUT SOME OF THE DETAILS IN THIS PHRASE. THIS COMES OUT OF THE FDA REGULATIONS AND ENTITLE 21 CFR 5020 PROVIDED IN 5023, UNLESS THE INVESTIGATOR HAS OBTAINED THE LEGALLY EFFECTIVE AND INFORMED CONSENT OF THE SUBJECT OR AUTHORIZEDEGAL EY LEGALLY ORDERED REPRESENTATIVE AND AN INVESTIGATOR SHALL SEEK CONSENT ONLY UNDER CIRCUMSTANCES THAT PROVIDE PERSPECTIVE SUBJECT OR REPRESENTATIVE SUFFICIENT OPPORTUNITY TO CONSIDER WHETHER OR NOT TO PARTICIPATE AND MINIMIZE THE POSSIBILITY OF COERCION OR UNDUE INFLUENCE. I'LL TALK ABOUT THOSE TWO THINGS. FINALLY THE INFORMATION THAT IS GIVEN TO THE SUBJECT OR REPRESENTATIVE SHALL BE IN LANGUAGE UNDERSTANDABLE TO THE SUBJECT OR THE REPRESENTATIVE. NOW, I COULD TALK ABOUT THESE THINGS ALL DAY LONG, I HAVE ABOUT FIVE MINUTES TO DO THE REST. I WANT TO SAY A LITTLE BIT WILL LEGALLY EFFECTIVE AND INFORMED CONSENT. A VERY IMPORTANT BOOK WRITTEN 20 YEARS AGO NOW, TALKED ABOUT TWO SENSES OF INFORMED CONSENT. THE FIRST IS AUTONOMOUS AUTHORIZATION THAT YOU'RE GIVING SOMEBODY THE INFORMATION WITH WHICH THEY CAN MAKE AN INFORMED AND VOLUNTARY DECISION, AND THEY AUTONOMOUSLY AUTHORIZE THEIR DECISION FOR YOU. THAT'S THE GOAL OF INFORMED CONSENT. IN THIS BOOK, THEY DISTINGUISH THIS FROM WHAT SOMETIMES ARE THE SOCIAL RULES OF CONSENT, WHAT LOOKS LIKE A LEGALLY EFFECTIVE AUTHORIZATION, BUT MIGHT NOT BE A REAL AUTONOMOUS AUTHORIZATION. SO THE STRINGS MIGHT B DISTINCTION MIGHT BE YOU HAVE A PARTICIPANT WHO YOU GIVE THE INFORMATION TO, THEY HAVE THE OPPORTUNITY TO THINK ABOUT IT. THEY TALK TO THEIR FAMILY OR THEIR PRIMARY CARE PROVIDER, THEY ASK QUESTIONS, THEY SAY OKAY, I'M NOT SO HAPPY ABOUT THIS YOU ABOUT BUT I WANT TO DO THIS, THEY SIGN THE CONSENT, THAT'S AUTONOMOUS AND A SOCIALLY EFFECTIVE WRITTEN DOCUMENT OF INFORMED CONSENT. DISTINGUISH THAT, FOR EXAMPLE, FROM SOMEONE FOR WHOM THE INFORMATION IS VERY HARD TO UNDERSTAND, THEY DON'T RECEIVE IT AHEAD OF TIME, YOU GIVE THEM FIVE MINUTES TO READ A COMPLICATED DOCUMENT AND ASK THEM TO SIGN IT, THAT SOMETIMES HAPPENS. THEY MAY ACTUALLY SIGN IT, AND THEREFORE IT LOOKS LIKE LEGALLY EFFECTIVE INFORMED CONSENT BUT IS NOT AUTONOMOUS AUTHORIZATION BECAUSE THEY DIDN'T HAVE TIME TO UNDERSTAND AND MAKE A DECISION BASED ON IT. WHAT ABOUT SUBJECT OR SUBJECTS LEGALLY AUTHORIZED REPRESENTATIVE? IN MOST CASES, WE ASK THE SUBJECT TO GIVE CONSENT FOR RESEARCH THEY ARE GOING TO PARTICIPATE IN. ONLY IF THEY ARE NOT LEGALLY ABLE TO GIVE CONSENT OR THEY DON'T HAVE THE CAPACITY TO GIVE CONSENT WOULD WE GO TO SOMEBODY ELSE. AND THEN THE REGULATIONS ALLOW FOR A LEGALLY AUTHORIZED REPRESENTATIVE, THIS IS THE REGULATORY LANGUAGE, LEGALLY AUTHORIZED REPRESENTATIVE DEFINED AS AN INDIVIDUAL OR JUDICIAL OR OTHER BODY AUTHORIZED UNDER APPLICABLE LAW TO CONSENT ON BEHALF OF A PROSPECTIVE SUBJECT TO THE SUBJECT'S PARTICIPATION IN THE PROCEDURES INVOLVED IN RESEARCH. SO WHO ARE LEGALLY AUTHORIZED REPRESENTATIVES? PARENTS ARE FOR CHILDREN. PEOPLE WHO HAVE BEEN NAMED LEGAL GUARDIANS BY A COURT OF LAW ARE LEGALLY AUTHORIZED REPRESENTATIVES. AND PREVIOUSLY APPOINTED DURABLE POWER OF ATTORNEYS BY THE PARTICIPANT HIM OR HERSELF EFFECTIVELY ARE LEGALLY AUTHORIZED REPRESENTATIVES. THEY CAN ALL GIVE PERMISSION FOR A SUBJECT WHO CANNOT CONSENT FOR HIMSELF. WE AT THE NIH AND INTRAMURAL PROGRAM HAVE A DETAILED POLICY ABOUT THE KINDS OF RESEARCH PEOPLE WHO CAN'T CONSENT, ADULTS WHO CAN'T CONSENT FOR THEMSELVES, CAN PARTICIPATE IN. AND THE PROCESS BY WHICH THAT ENROLLMENT CAN OCCUR. AND WE ALSO HAVE A WONDERFUL I THINK RESOURCE HERE AT THE NIH, CALLED THE ABILITY TO CONSENT ASSESSMENT TEAM WHICH YOU CAN CALL ANYTIME AND WE, I'M PART OF THIS TEAM, WILL HELP YOU EVALUATE THE CAPACITY OF AN INDIVIDUAL TO CONSENT, WE'LL HELP YOU EVALUATE THE APPROPRIATENESS OF A SURROGATE THAT THEY HAVE NAMED, WE'LL HELP YOU EVALUATE WHETHER OR NOT THE INDIVIDUAL WHO CANNOT GIVE CONSENT FOR HIM OR HERSELF FOR THE RESEARCH MIGHT STILL RETAIN THE CAPACITY TO ASSIGN THE SURROGATE TO GIVE PERMISSION FOR THEM. THOSE ARE THE KINDS OF THINGS WE OFFER HERE AT THE NIH. WHAT ABOUT CIRCUMSTANCES THAT PROVIDE THE PROSPECTIVE THE SUN OPPORTUNITY TO DECIDE WHETHER OR NOT TO PARTICIPATE AND MINIMIZE COERCION OR INDUE INFLUENCE? CERTAINLY SOME OF THE COMMON SENSE SELF EVIDENT THINGS ARE EFFICIENT OPPORTUNITY, MEANS, TIME TO READ THE DOCUMENT, TIME TO LISTEN TO THE DISCUSSION, TIME TO THINK ABOUT IT, TIME TO ASK QUESTIONS, THOSE SEEM SO OBVIOUS AND YET WE DON'T ALWAYS DO A GOOD JOB ABOUT THAT. THE OTHER PART OF THIS PHRASE IS MINIMIZING THE POSSIBILITY OF COERCION AND UNDUE INFLUENCE, IMPORTANT CONCEPTS IN RESEARCH. OOPS, I'M GOING TO COME BACK TO THAT IN A SECOND. SUFFICIENT OPPORTUNITY TO CONSIDER INCLUDES IS THE PARTICIPANT IN A POSITION TO HEAR AND UNDERSTAND THE INFORMATION AND DELIBERATE. SO NOT ONLY GIVING THEM THE TIME BUT MAKING SURE THAT THEY ARE IN A SETTING OR IN A STATE OF MIND WHERE THEY CAN ACTUALLY RECEIVE INFORMATION AND DELIBERATE ABOUT IT. SOMETIMES PEOPLE WHO ARE VERY SICK, WHO ARE, YOU KNOW, TAKING ANALGESICS, WHO ARE FEELING DESPERATE, WHO ARE FEELING PRESSURED, WHO ARE FEELING IN A HURRY, THOSE ARE DIFFICULT SITUATIONS AND VERY DIFFICULT TIMES TO TAKE IN INFORMATION AND DELIBERATE ABOUT INFORMATION. THE SAME QUESTION SHOULD BE ASKED ABOUT VOLUNTARINESS, IS THE PARTICIPANT ABLE TO MAKE A VOLUNTARY CHOICE? THIS IS A COMPLICATED NOTION, NO CHOICE THAT WE EVER MAKE IN LIFE IS FREE OF OTHER INFLUENCES. I THINK THAT'S A FAIR STATEMENT TO MAKE. BUT WE WANT TO BE SURE THAT THE PERSON IS IN A POSITION TO MAKE A SUFFICIENTLY FREE CHOICE. NOBODY'S PRESSURING THEM, NOBODY'S FORCING THEM, NOBODY'S COERCING THEM, NOBODY'S TELLING THEM THEY HAVE TO DO THIS OR THEY ARE NOT GOING TO GET SOMETHING ELSE THAT THEY FEEL LIKE THEY NEED. THOSE ARE THE KINDS OF DECISIONS, I MEAN THE KINDS OF THINGS WE SHOULD THING ABOUT IN TERMS OF VOLUNTARINESS. PEOPLE WHO ARE PARTICULARLY IN DIFFICULT POSITIONS ARE PEOPLE WHO ARE IN DEPENDENT POSITIONS, PROFESSORS WHO ASK STUDENTS TO VOLUNTEER FOR A STUDY, OR MILITARY OFFICERS WHO ASK THE PEOPLE UNDER THEM, OR THE NAVY DOCTORS WHO ASK THEIR OWN PATIENTS. THERE ARE LOTS OF WAYS WE COULD THINK ABOUT WHAT IS A POSITION IN WHICH A PERSON CAN ACTUALLY SAY NO. IF THEY WANT TO. COERCCOERCION IS ACTUALLY SOMETHING THAT WE DON'T IN THIS COUNTRY AND MAYBE ESPECIALLY IN THIS BUILDING SEE VERY OFTEN IN RESEARCH. I DON'T THINK WE COERCE PEOPLE. AND THE REASON I SAY THAT IS BECAUSE COERCION MEANS YOU SORT OF FORCE SOMEBODY TO DO SOMETHING OR YOU MAKE THEM WORSE OFF IF THEY SAY NO. THAT DOESN'T HAPPEN IN THIS BUILDING, AT LEAST IN MY EXPERIENCE. UNDOUNDUE INFLUENCE IS VAGUER OR SOFTER. MOST AGREE IT'S THE KIND OF NOTION YOU'RE PROVIDING AN INFLUENCE TO PARTICIPATE THAT THE PERSON CAN'T RESIST, AND THEY REALLY ARE TAKING ON SOMETHING THAT THEY WOULDN'T TAKE ON OTHERWISE, RISKS THEY KIND OF AGREE TO, THE DINED PURPOSE THEY WOULDN'T AGREE TO BUT THEY ARE SO OVERINFLUENCED BY WHAT THEY ARE OFFERING THEY CAN'T MAKE A CLEAR DECISION. YOU CAN SEE HOW COMPLICATED THAT COULD BE TO SORT OUT BUT THAT'S THE TASK WE AS INVESTIGATORS HAVE TO FIGURE OUT. AND MY CARTOON, IT SHOULDN'T LOOK LIKE THAT. I DON'T THINK IT DOES VERY OFTEN. WHAT ABOUT THE PHRASE, INFORMATION SHALL BE IN A LANGUAGE UNDERSTANDABLE TO THE SUBJECT OR REPRESENTATIVE? THIS IS AGAIN A COMPLEX NOTION. HOW MUCH INFORMATION SHOULD BE DISCLOSED? WE LOOKED AT THE ELEMENTS OF WHAT NEEDS TO BE INCLUDED IN A CONSENT DOCUMENT, KINDS OF THINGS PEOPLE NEED TO KNOW TO MAKE A DECISION. BUT THERE ARE WAYS AND WAYS TO PRESENT THAT INFORMATION. SO YOU CAN TALK ABOUT THE PURPOSE OF A STUDY, IN A VERY CLEAR, STRAIGH STRAIGHTFORWARD SENTENCE PEOPLE UNDERSTAND WHO DON'T HAVE SCIENTIFIC BACKGROUND AND TALK ABOUT THE PURPOSE OF A STUDY IN A THREE-PAGE SCIENTIFICALLY COMPLEX DESCRIPTION. SO THOSE ARE DECISIONS THAT EACH OF US INVESTIGATORS HAVE TO MAKE WHEN WE'RE DECIDING HOW MUCH INFORMATION TO DISCLOSE. HOW SHOULD THE INFORMATION BE PRESENTED? IT SHOULD BE IN A WRITTEN DOCUMENT, SHOULD BE AT AN EIGHTH GRADE READING LEVEL, AS DR. CANNON MENTIONED, DESCRIBED TO PEOPLE IN DISCUSSIONS AS WELL, THIS SHOW THIS SHOWS SHOULD SHOWS B E ONE ON ONE, GROUP EXECUTION DISCUSSIONS OR WITH MEMBERS OF THE TEAM, SHOULD THEY BE REPEATED DISCUSSIONS, IN THE CONFERENCE ROOM, IN THE WAITING ROOM, SHOULD THEY BE IN THE EXAM ROOM? THOSE ARE ALL DECISIONS THAT NEED TO BE MADE. WHAT FACTORS MIGHT AFFECT UNDERSTANDING? CERTAINLY EDUCATION LEVEL, COGNITIVE CAPACITY, THEIR ABILITY TO PAY ATTENTION, BASED ON A NUMBER OF FACTORS, ALL OF THOSE AND MANY OTHERS COULD AFFECT. AGE COULD AFFECT SOMEBODY'S UNDERSTANDING. I THINK ONE UNDERAPPRECIATED ASPECT OF CLINICAL RESEARCH IN ALL CONTEXTS IS HOW DO WE ASSESS WHETHER OR NOT PEOPLE UNDERSTAND, AND WHEN YOU LOOK ACROSS THE BOARD, MOST OF THE TIME I THINK PEOPLE JUST SAY DO YOU HAVE ANY QUESTIONS? OR DO YOU UNDERSTAND? AND THE QUESTION MIGHT BE IS THAT ADEQUATE? CERTAINLY IN CERTAIN CASES IT'S PROBABLY NOT. WE GO THE WHOLE EXTREME TO SOME KINDS OF STUDIES AND ESPECIALLY THE MORE RISKY STUDIES WHERE PEOPLE GIVE WRITTEN TESTS. THEY GIVE A QUIZ. AND THE PERSON CANNOT ENROLL IN THE STUDY UNLESS THEY HAVE ACHIEVED A CERTAIN SCORE ON THAT QUIZ. THERE'S AN ONGOING DEBATE ABOUT HOW MUCH THE SUBJECT HAS TO UNDERSTAND IN ORDER TO GIVE VALID CONSENT. CERTAINLY THINGS LIKE THEY ARE DOING THINGS IN THE CO CONTEXT OF RESEARCH THAT ARE NOT COMPLETELY FOR THEM BUT FOR UNDERSTANDING THE ANSWER TO A QUESTION, AND THAT THERE ARE CHANCES OF BENEFIT THAT NEED TO BE CLEAR AND HOW MUCH RISK THEY ARE UNDERTAKING NEEDS TO BE CLEAR. THIS IS A STATEMENT FROM THE FDA INFORMATION SHEET FOR INVESTIGATORS THAT SAYS A LITTLE BIT MORE ON THIS TOPIC, CONSENT DOCUMENTS SHOULD NOT CONTAIN UNPROVEN CLAIMS OF EFFECTIVENESS, OR CERTAINTY OF EXPLICIT ORHER EXPRESS IT IMPLICIT, OVERLY OPTIMISTIC REPRESENTATIVATIONS ARE MISLEADING, AS WELL AS REQUIREMENTS TO MINIMIZE THE POSSIBILITY OF COERCION, THIS SPEAKS TO THE KINDS OF WORDS YOU CHOOSE TO PUT IN WRITTEN DOCUMENTS AND HOW THEY -- WHAT KIND OF MESSAGE THEY GIVE PEOPLE, AND WE KNOW WORDS ARE POWERFUL. THIS IS JUST A COUPLE THINGS I PULLED OFF THE GOOGLE IMAGES, YOU CAN SEE THE LINK. BUT SOME OF THESE ARE ACTUALLY REALLY INTERESTING. DO WE CALL PEOPLE PATIENTS OR PARTICIPANTS? DO WE TALK ABOUT DOCTORS OR STUDY DOCTORS OR RESEARCHERS? DO WE TALK ABOUT TREATMENT IN THE CONSENT DOCUMENT OR STUDY DRUG OR INVESTIGATIONAL DRUG? THESE ARE EXAMPLES OF THE WORDS WE CAN CHOOSE THAT MAKE A IN HOW PEOPLEPOW PEOPLE UNDERSTAND. LASTLY WHAT SHOULD SUBJECTS UNDER? MOST PEOPLE AGREE THAT AS THE STUDY THAT'S BEING PRESENTED TO SOMEBODY IS INCREASINGLY RISKY, OR INCREASINGLY NOVEL, OR INCREASINGLY DISTANT FROM WHAT THEY MIGHT EXPERIENCE IN A CLINICAL SETTING, THEN THE THRESHOLD GOES UP A LITTLE FOR WHAT THEY NEED TO UNDERSTAND, THEY NEED TO UNDERSTAND RISKS AND DIFFERENCES. I'VE ALREADY TALKED ABOUT HOW WE DON'T UNDERSTAND -- HOW WE KNOW. INTERESTINGLY, INCREASINGLY AVAILABLE DATA ABOUT INFORMED CONSENT IN THE CONTEXT OF RESEARCH SHOWS RESEARCH SUBJECTS MISUNDERSTOOD VARIOUS ASPECTS OF RESEARCH IN WHICH THEY PARTICIPATE. THERE ARE DETAILS I COULD GO INTO AT A DIFFERENT TIME BUT I THINK THE FACT IS THAT THERE'S A LOT OF MISUNDERSTANDING. THE QUESTION WE MIGHT ASK OURSELVES TODAY IS WHY? WHY DON'T THEY UNDERSTAND WHAT WE'RE DOING? I THINK THERE ARE AT LEAST FOUR REASONS. ONE IS THAT THE DISCLOSURE OF INFORMATION IS EITHER INADEQUATE OR MISLEADING. WE SAY THIS IS GOING TO BENEFIT YOU, THIS IS A TREATMENT THAT'S GOING TO BENEFIT YOU AND THEY SORT OF UNDERSTAND THIS IS A TREATMENT THAT'S GOING TO BENEFIT ME. WHEN THAT MAY BE NOT WHAT WE'RE SUPPOSED TO BE SAYING. IF WE DO A GOOD JOB OF WRITING OUR CONSENT DOCUMENT AND IRB'S DO A GOOD JOB REVIEWING THEM, THAT PROBLEM SHOULD BE MINIMIZED, ALTHOUGH WHAT WE DON'T CONTROL IS THE DISCUSSION THAT HAPPENS OUTSIDE OF THOSE DOCUMENTS. ANOTHER POSSIBILITY IS POOR RECALL. PEOPLE ARE IN A SITUATION WHERE THEY CAN'T REALLY TAKE IN INFORMATION, OR SOMETHING ELSE IS DISTRACTING THEM, THEY MAY NOT REMEMBER WHAT YOU TOLD THEM. THEY MAY NOT REMEMBER WHAT THEY READ IN THE DOCUMENT THAT YOU WENT OVER SO CAREFULLY AND THEY ACTUALLY SIGNED. AND SO THEY DON'T HAVE A WAY OF UNDERSTANDING WHAT THEY DON'T REMEMBER. I THINK ALSO IMPORTANTLY IS THE UNDERSTANDING THE CONTEXT AND EXPECTATIONS OF INDIVIDUALS IN RESEARCH, MANY ARE PEOPLE WHO ARE ILL, MANY ARE PEOPLE WHO ARE ILL LOOKING FOR TREATMENT OPTIONS, AND EXPECTATIONS MIGHT BE DIFFERENT THAN WHAT WE'RE ACTUALLY OFFERING THEM. AND WE NEED TO BE COGNIZANT OF THAT POSSIBILITY, AND I THINK AWARE THAT SOME PEOPLE END UP ENROLLING IN RESEARCH UNDER WHAT MANY REFERRED TO AS A MISCONCEPTION. THEY UNDERSTAND THAT THEY ARE ENROLLING IN RESEARCH BECAUSE THIS IS THE BEST TREATMENT OPTION THAT THEY HAVE. IT MIGHT BE. BUT IT STILL NEEDS TO BE UNDERSTOOD THAT IT'S NOT SIMPLY TREATMENT. SO TO END WITH WHAT IS THE THERAPEUTIC MISCONCEPTION? THE COMMONLY REACHED TO PHENOMENON IN CLINICAL RESEARCH BECAUSEICALLY COINED BY AND I BASICALLY COINED BY PAUL APPLE,BAUM AND COLLEAGUES, AN INDIVIDUAL INTERPRETS OR DISTORTS THE INFORMATION TO MAINTAIN THE VIEW EVERY ASPECT OF THE RESEARCH PROJECT TO WHICH HE OR SHE CONSENTED WAS DESIGNED TO BENEFIT HIM DIRECTLY. THEY DON'T UNDERSTAND THAT THIS IS RESEARCH, THAT THIS IS DIFFERENT THAN WHAT THEY MIGHT GET IF THEY WENT TO THEIR DOCTOR DOWN THE STREET. THEY FAIL TO RECOGNIZE HOW PERSONAL CARE, THAT IS THE OBLIGATION OF THE PHYSICIAN TO MAKE MEDICAL DECISIONS BASED SOLELY ON THEIR BEST INTERESTS, MIGHT BE DIFFERENT IN THE CONTEXT OF RESEARCH AND COMPROMISED BY PARTICIPATING IN SOME CASES IN RESEARCH. PAUL APPLEBAUM AND COLLEAGUES CAME THIS IS A COMMON PHONE PHENOMENON AND PEOPLE WHO ACTUALLY SUFFER FROM A MISCONCEPTION, THERAPEUTIC MISCONCEPTION, CANNOT GIVE VALID CONSENT. THAT'S THE THIRD BULLET. THEY CLAIM THAT IT INVALIDATES CONSENT.O GIVE CON SEVEN. A FELLOW AND I WROTE A PAPER ARGUING MISUNDERSTANDING IS MORE COMPLICATION, PEOPLE DO SUFFER A THERAPEUTIC MISCONCEPTION BUT SOME UNDERSTAND, THEY GET IT, THEY UNDERSTAND THEY ARE ENROLLED IN RESEARCH BUT THEY STILL MIGHT OVERESTIMATE THE BENEFITS. EITHER BECAUSE -- THERE ARE LOTS OF POSSIBLE REASONS THEY MIGHT MISESTIMATE BENEFITS OR RISK. SOME PEOPLE ARE JUST OPTIMISTS. I KNOW YOU TOLD ME LESS THAN 5% OF PEOPLE WILL BENEFIT. I'M GOING TO BE ONE OF THOSE! I'M GOING TO BE THAT ONE! SO WE HAVE TO BE ABLE TO DISTINGUISH WHETHER IT'S TRULY A MISCONCEPTION, A MISESTIMATION, WE WE CAN CORRECT, OR JUST OPTIMISM WHICH WE DON'T WANT TO DEFLATE BUT MAKE SURE IT'S INFORMED. THAT'S IT. >> THE LAST PRESENTER FOR THIS SESSION IS DR. DENNY PORTER, A SENIOR INVESTIGATOR IN THE INTRAMURAL RESEARCH PROGRAM OF THE DEVELO DEVELOPMENTAL ENDOCRINOLOGY PROGRAM OF THE EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT, NICHD, DR. PORTER IS DIRECTOR FOR NICHD. I WILL LET HIM SPEAK. >> THIS MORNING, WHAT I'D LIKE TO DO IS TAKE A FEW MINUTES TO DISCUSS REALLY THE ETHICAL AND REGULATORY CONSIDERATIONS THAT HAVE TO BE TAKEN AND CONSIDERED WHEN DEALING WITH PEDIATRIC RESEARCH SUBJECTS. IN TEN MINUTES WE'RE NOT GOING TO DELVE INTO WHAT THE HISTORY -- WE'RE NOT GOING TO -- YOU COULDSCUSS SHALL DID - SPEND OURS DISCUSSING MINIMAL RISK OR MINIMAL INCREMENT BUT I WANT TO GIVE YOU THE FRAMEWORK ABOUT THINKING ABOUT PEDIATRIC SUBJECTS IF YOU'RE CONSIDERING CLINICAL RESEARCH. SO ALSO TO GIVE IT RATHER THAN JUST THE ETHICAL AND REGULATORY BACKGROUND, YOU HAVE TO CONSIDER CHILDREN DESERVE SAFE AND EFFECTIVE THERAPY. CHILDREN ARE NOT SMALL ADULTS. WE CAN'T JUST SIMPLY CONDUCT RESEARCH IN ADULTS AND EXTEND IT TO CHILDREN. THERE ARE PHYSIOLOGICAL DIFFERENCES. CHILDREN HAVE DEVELOPING SKELETAL SYSTEMS, DEVELOPING BRAINS. WE JUST CAN'T SIMPLY EXTRAPOLATE BASED ON SIZE. CHILDREN ALSO HAVE DIFFERENT DISEASES. JUST AS AN EXAMPLE, INBORN AIRS METABOLISM, USUALLY EXPAND FROM CHILDREN TO ADULT BUT IN CHILDREN, THE DISEASES ARE MUCH MORE SEVERE, ADULTS FREQUENTLY ATTENUATED. IN CONTRAST TO DRUG USE IN ADULTS OR DRUG APPROVAL IN ADULTS MAJORITY OF DRUGS ARE USED OFF LABEL. WE AS PEDIATRICIANS ARE PRESCRIBING DRUGS NOT APPROVED BY THE FDA FOR THAT PURPOSE IN THE PEDIATRIC POPULATION. TO GIVE YOU AN IDEA OF THE MAGNITUDE LOOKING AT A NUMBER OF RECENT ARTICLES, IT'S BEEN ESTIMATED ABOUT 80% OF HOSPITALIZED CHILDREN ARE TREATED WITH WITHIN OR MORE OFF LABEL DRUGS, WHEN YOU GET INTO THE PEDIATRIC INTENSIVE CARE UNIT DEPENDING ON AGE, IT'S 96-100% OF CHILDREN TREATED DURING ADMISSION WITH A DRUG THAT'S NOT APPROVED FOR USE IN THE PEDIATRIC POPULATION. IN CONSIDERATION OF THE RISK CONSIDERATIONS, THE RISK NEEDS TO BE BALANCED WITH THE RISKS OF THE DISEASE. OKAY. SO WHAT IS THE REGULATORY FRAMEWORK THAT WE NEED TO CONSIDER AS THE PREVIOUS SPEAKERS MENTIONED, WE HAVE THE REGULATORY FRAME WORE OF HUMAN RESEARCH THE CODE OF REGULATION 45 AND ALSO THE ASPECTINGS THAT GUIDE THE FDA IN REGULATION 21. CAN REGARDS TO RISK CONSIDERATION IN PEDIATRICS, TWO SEGMENTS REALLY COINCIDE THE LANGUAGE IS THE SAME. I'M PUTTING IT IN THE CONTEXT OF REGULATION 46. THAT'S HOW INVESTIGATORS USUALLY DEAL DIRECTLY WITH IRB'S. WHAT ARE THE RISK CATEGORIES? AND THERE ARE FOUR OF THEM. THEY ARE IN INCREASING ORDER OF RISK. SO A 46-404 IS RESEARCH NOT INVOLVING GREATER THAN MINIMAL RISK. OBVIOUSLY THE CONCEPT OF MINIMAL RISK IS SOMETHING THAT AN IRB HAS TO CONSIDER, BUT FOR EXAMPLE A CHILD IN WHICH YOU'RE OBTAINING A URINE SAMPLE OR OBTAINING A BLOOD DRAW, THAT WOULD BE IN MOST CIRCUMSTANCES CONSIDERED MINIMAL RISK. 405 LEVEL, THIS IS PROBABLY THE CATEGORY THAT IF YOU'RE CONSIDERING AN IND, RESEARCH WILL FALL INTO, BUT IT'S RESEARCH INVOLVING GREATER THAN MINIMAL RISK, BUT PRESENTING THE PROSPECT OF A DIRECT BENEFIT, SO THE PATIENT OR PARTICIPANT IN THE RESEARCH MAY BENEFIT DIRECTLY FROM WHAT YOU'RE DOING. THE 406 CATEGORY IS RESEARCH INVOLVING GREATER THAN MINIMAL RISK, BUT WITHOUT THIS DIRECT PROSPECT OF A BENEFIT. HOWEVER, THE RESEARCH IS DESIGNED TO YIELD INFORMATION FOR WHICH CHILDREN WITH THE SAME DISEASE OR SIMILAR DISEASE MAY BE ABLE TO BENEFIT. AN EXAMPLE MIGHT BE SOME OF THE NATURAL HISTORY STUDIES DEPENDING ON HOW COME FOR ARE.PLE THECOMPLEX THEY MAY NOTAL PARTICIPANT MATE NOT HAVE THE DIRECT PROSPECT OF BENEFIT DEPENDING ON PROCEDURES THERE, BUT OTHERS WITH THAT DISEASE IN THE FUTURE, IF THAT RESEARCH WOULD ENABLE YOU TO DEVELOP THERAPIES OR COME UP WITH THE POTENTIAL OUTCOME MEASURES, MAY BE ABLE TO BENEFIT FROM THAT. THAT WOULD BE AN EXAMPLE OF 406. 407 IS A LEVEL I HAVE NOT SEEN A PROTOCOL RISE TO. IT ACTUALLY IS RESEARCH THAT IS NOT APPROVABLE UNDER THE PRIOR THREE CATEGORIES, AND IT HAS TO BE RESEARCH THAT WILL HAVE A BENEFIT FOR THE HEALTH OR WELFARE OF CHILDREN BUT TO GIVE YOU AN UNDERSTANDING WHY WE DON'T SEE THOSE, THOSE HAVE TO GO TO THE DEPARTMENTAL LEVEL FOR APPROVAL. LET ME GO TO THE 405 CATEGORY BECAUSE THAT'S THE ONE THAT REALLY IS RELEVANT TO MOST PROTOCOLS THAT REQUIRE AN AN IND. UNDER THE MAJOR HEADINGS, THERE ARE OTHER CRITERIA THAT MUST BE MET, AND THAT'S WHAT I'M TO EXPLORE WITH RESPECT ARE THE 405 CATEGORY. AGAIN, THIS IS MORE THE MINIMAL RISK PRESENTING THE PROSPECT OF A DIRECT BENEFIT. FIRST OF ALL, RISK IS JUSTIFIED BY ANTICIPATED BENEFIT TO THE SUBJECT. IT'S A RISK BENEFIT ANALYSIS. THERE HAS TO BE ENOUGH OF A PROSPECT THAT THIS DRUG MIGHT WORK AND MIGHT BENEFIT THE PATIENT, TO JUSTIFY THE DEGREE OF RISK THAT YOU HAVE INCLUDED IN YOUR PROTOCOL. SECOND, THE RELATION OF THE ANTICIPATED BENEFIT TO THE RISK IS AT LEAST AS FAVORABLE TO THE SUBJECT AS THAT PRESENTED BY ALTERNATIVE -- AVAILABLE ALTERNATIVE THERAPIES, OFTEN NOT THE CASE WITH RESEARCH BEING DONE HERE, IT'S BEING DONE IN RARE DISEASES THAT DON'T HAVE ANY THERAPIES, SO IF YOU'RE TRYING TO DEVELOP A THERAPY FOR A LETHAL DISEASE THAT DOES NOT HAVE A KNOWN TREATMENT, THAT'S DIFFERENT THAN DEVELOPING AN ANTIBIOTIC TO TREATMENT O OTITIS MEDIA WHERE YOU'RE DRYING TO IMPROVE ON THE CURRENT SITUATION. AND THEN FINALLY ADEQUATE PROVISIONS ARE MADE FOR THE ASSENT, THESSENT AND THE PERMISSION IS PROVIDED BY GUARDIANS, ASCEN ASSENT BY THE CHILD. RISK IS JUSTIFIED BY ANTICIPATED BENEFIT TO THE SUBJECT. YOU AS THE INVESTIGATOR REALLY NEED TO TAKE THE LEAD. YOU ARE PROBABLY THE WORLD'S EXPERT IN THE DISEASE. YOU KNOW MUCH MORE ABOUT THE DISEASE AND RESEARCH YOU WANT TO DO. THEN. IRB, THEN THE FDA WHO WILL NECESSARILY BE REVIEWING. THIS IS ESPECIALLY DREW I TRUE IN RARE DISEASES. YOU NEED TO DEFINE THE RISK OF DISEASE. OFTEN THIS MEANS YOU HAVE TO KNOW THE NATURAL HISTORY OF THE DISEASE. YOU HAVE TO KNOW THE HETEROGE, INERAHETEROGENADE OF YOUR POPULATION. WHY DO YOU WANT TO DO IT? WHAT EVIDENCE DO YOU HAVE THIS MIGHT ACTUALLY WORK AND PROVIDE A BENEFIT TO YOUR PATIENT? YOU HAVE TO DEFINE THE RISK OF THE RESEARCH, WHAT PROCEDURES ARE YOU GOING TO DO? WHAT IS THE REAL RISK OF THOSE PROCEDURES? YOU NEED TO WORK TO MITIGATE THE RISK OF THE RESEARCH INTERVENTION. OFTEN MINOR THINGS CAN DECREASE THE RISK IN PEDIATRICS. FOR EXAMPLE, WE THINK OF BLOOD DRAWS AS BEING DONE EVER DAY. WE GO TO THE DOCTOR AND GET THEM. PUT A CREAM ON A CHILD, IT DECREASES SIGNIFICANTLY THE RISK AND DISCOMFORT TO THAT CHILD. THE MAJOR DIFFERENCE, BUT A MINOR INTERVENTION YOU NEWED TO NEED TOOUT. THINK ABOUT AND MAXIMIZE THE POTENTIAL OF PROTOCOL TO DEMONSTRATE BENEFIT. THIS GETS AT THE CONCEPT MENTIONED A NUMBER OF TIMES. IT'S GOT TO BE GOOD SCIENCE. FINALLY, THE NEXT ONE IS THE RELATION OF THE ANTICIPATED BENEFIT TO THE RISK IS AT LEAST AS FAVORABLE TO THE SUBJECTS AS THAT FOR ALTERNATIVE APPROACHES, AND I THINK THAT THAT ONE REALLY IS INTUITIVELY OBVIOUS. YOU CAN'T TRY TO DEVELOP A NEW THERAPY IF YOU DON'T THINK IT'S GOING TO BE BETTER THAN THE EXISTING THERAPY. AND THEN I THINK A MAJOR ISSUE IN PEDIATRIC RESEARCH IS THIS IDEA OF ASSENT AND CONSENT. YOU NEED TO GET PERMISSION TO DO THAT, IT'S THE LEGAL GUARDIAN'S OS OR PARENTS THAT PROVIDE PERMISSION OR CONSENT TO DO THE RESEARCH. IN THE 405 LEVEL OF RESEARCH, THE REGULATIONS SPECIFY YOU SHOULD GET TWO PARENTS' CONSENT, OR THE IRB, YOU CAN ASK THE IRB TO ALLOW YOU TO MAKE A DETERMINATION THAT YOU CAN GET ONE PARENT TO SIGN. PREVIOUSLY WE HEARD ABOUT THE CONSENT PROCESS. IN PEDIATRICS WE HAVE WHAT WE CALL ASSENT. THE CHILD IS ALSO A PARTICIPANT. THIS ISN'T ALWAYS EASY. IF YOU'RE DOING A STUDY THAT'S INVOLVING LET'S SAY 15-YEAR-OLDS THAT ARE COGNITIVELY NOR NORMAL, YOU HAVE TO WORK WITH PEOPLE BUT IT'S FAIRLY EASY TO WRITE AN ASSENT OR FIGURE OUT AN ASSENT THAT WOULD APPLY TO THAT GROUP. IF YOU'RE DEALING WITH A RARE DISEASE OR A HETEROGENEOUS DISEASE THAT SHOWS DIFFERENT PROGRESS, HAS COGNITIVE IMPAIRMENT, YOU MIGHT HAVE A 12-YEAR-OLD WHERE YOUR CONSENT IS JUST FINE. YOU HAVE A 17-YEAR-OLD THAT IS ISN'T GOING TO UNDERSTAND ANYTHING THAT YOU'RE ABLE TO PUT DOWN ON PAPER. SO YOU HAVE TO WORK WITH YOUR IRB TO TRY TO DETERMINE WHAT IS A GOOD WAY OF ASKING THE CHILD AT AN APPROPRIATE LEVEL, IS IT OKAY FOR US TO DO THIS? AND TO GET BACK A REALISTIC RESPONSE. SO THE IRB SHALL DETERMINE ADEQUATE PROVISIONS ARE MADE FOR SOLICITING ASSENT OF THE CHILDREN WHEN IN THE JUDGMENT OF THE IRB THE CHILDREN ARE CAPABLE OF PROVIDING ASSENT, AND THEY CAN TAKE INTO ACCOUNT THE AGE, MATURITY AND PSYCHOLOGICAL STATE OF THE CHILDREN INVOLVED. AND THE JUDGMENT DOESN'T HAVE TO BE ONE ASSEN ASSENT FITS ALL. JUDGE. MENT CA CAN BE FOR THE GROUP IF IT'S HOMO GENOUS, OR YOU HAVE TO APROVIDE ASSENT BUT CAN TAILOR IT TO THE CHILD SPECIFICALLY. OKAY. SO JUST SORT OF TO SUMMARIZE THIS, ALL CLINICAL RESEARCH INVOLVES RISK. PEDIATRIC RESEARCH INVOLVES RISK. BUT THERE'S A NEED. THE CONCERN ABOUT RISK SHOULD NOT PRECLUDE THE DEVELOPMENT OF SAFE AND EFFECTIVE THERAPIES FOR CHILDREN. THE RISK NEEDS TO BE COMMENSURATE WITH THE DISEASE, AND THE POTENTIAL THERAPY. AND WHAT CAN YOU AS INVESTIGATORS DO? YOU NEED TO DEFINE THE RISK OF THE DISEASE, YOU NEED TO DEFINE THE RISK OF THE PROPOSED INTERVENTION, YOU NEED TO MITIGATE THE RISK TO THE PROPOSED CLINICAL TRIAL, YOU NEED TO DEFINE THE CLINICAL BENEFIT OR POTENTIAL CLINICAL BENEFIT, AND NEED TO MAXIMIZE THE POTENTIAL CLINICAL TRIAL. SO THE FACT OF INCLUDING CHILDREN SHOULD NOTE PRECLUDE RESEARCH BUT YOU NEED TO WORK WITH THE IRB AND FDA TO PUT YOUR RESEARCH IN THE CONTEXT OF THE DISEASE AND THE THERAPY THAT YOU'RE PROPOSING. [APPLAUSE] >> WE ARE A LITTLE BIT BEHIND OUR SCHEDULE, AND IN ORDER TO STAY WITH THE REST OF THE PROGRAM WITHOUT A MAI MAJOR DELAY I WOULD PROPOSE IF ANYONE HAS A PRESSING QUESTION NOW, PLEASE APPROACH THE MICROPHONE. OTHERWISE, I THINK WE'RE GOING TO HAVE TO DISPENSE WITH WHAT WE HAD THOUGHT WOULD BE A PANEL DISCUSSION FOLLOWING THIS SESSION, AND THEN WE'LL TAKE A 10-MINUTE BREAK AND RESUME -- I'M SORRY, DR. LAPTEVA IS SAYING FIVE MINUTES BREAK AND LET COME BACK PLEASE. OKAY? THANK YOU ALL VERY MUCH. THANK YOU TO THE SPEAKERS SO FAR THIS MORNING. OUR NEXT SESSION TODAY IS DEDICATED TO PRODUCT QUALITY ISSUES AND INFORMATION ABOUT CHEMISTRY, MANUFACTURING, AND CONTROLS THAT NEEDS TO BE INCLUDED IN IND APPLICATIONS. WE HAVE TWO SPEAKERS, THREE PARTICIPANTS IN THE PANEL DISCUSSION AT THE END OF THE SESSION WHICH WE HOPE TO HAVE. SO OUR FIRST SPEAKER IS DR. KHAIRUZZAMAN, OVER FIVE YEARS HE'S BEEN REVIEWS INVESTIGATIONAL DRUG APPLICATIONS AND NEW DRUG APPLICATIONS, PRIOR TO JOINING JOINING FDA IN 2008 HE WORKED FOR THE PHARMACEUTICAL INDUSTRIES FOR SEVEN YEARS, EARNED A MASTER AND Ph.D. DR. KHAIRUZZAMAN, PLEASE. >> THANK YOU. GOOD MORNING, EVERYONE. SO IN THE NEXT 15 MINUTES WHAT I WOULD LIKE TO DO IS WALK YOU THROUGH THE FUNDAMENTALS OF CNC, REQUIRED TO SUBMIT UNDER IND. THIS IS WHAT MY PRESENTATION SCHEME LOOKS LIKE. THERE ARE SIX MAJOR BULLET POINTS I WOULD LIKE TO COVER TODAY. THE FIRST I WOULD LIKE TO GIVE YOU A VERY BRIEF CMC REGULATORY PERSPECTIVE, AND THEN INTRODUCE YOU CAN CTD MODEL, A COMMON TECHNICAL DOCUMENTS MODEL AND LEAD MY DISCUSSION TOWARDS UNDERSTANDING WHAT PRODUCT QUALITY INFORMATION IS EXPECTED IN AND IND APPLICATION AND RECOGNIZE WHEN CMC PART OFFED A LEADINGON IS ADEQUATE PLEASING TO SAFETY RELATED CONCERNS. THERE ARE SEVERAL GUIDANCES, I WILL CITE A FEW AND THEN CITE A COUPLE EXAMPLES FOR BETTER UNDERSTANDING. CFR 21 PART 312 TALKS ABOUT IND BUT THERE ARE SUBPARTS, 23, AND SUBPART 7, VERY CLEARLY MENTION ABOUT THE CMC REQUIREMENT FOR INVESTIGATE REQUIREMENT. UNDER SUB PART 7 THERE ARE FIVE SECTIONS, TALKING ABOUT THE REQUIREMENT THAT SHOULD BE SUBMITTED, B FOR DIRECT PRODUCT, C PLACEBO, D FOR ABLING AND E FOR REQUIREMENT. SUB PART 7 SAYS SUFFICIENT CMC INFORMATION IS REQUIRED TO ENSURE IDENTITY OF THE INVESTIGATAL DRUG QUALITY, PURITY AND STRENGTH, AMOUNT OF INFORMATION MAY VARY DEPENDING ON THE FACE, TYPE AND DURATION, YOU HEARD EARLIER FROM THE EARLIER SESSION THAT ONCE IND IS FILED, 30 DAYS ARE ALLOWED FOR DETERMINATION OF SAFETY BY THE AGENCY. THIS IS NOT A GRAPHICAL REPRESENTATION, JUST TO SHOW YOU HOW THE AMOUNT OF CMC INFORMATION COMES FACE TO FACE, AS YOU SEE UNDER PHASE I THE AMOUNT OF CMC INFORMATION IS MINIMAL, AND TOTALLY LINKED WITH THE SAFETY RELATED CONCERN. AS THE INVESTIGATION MOVES ON, PHASE II AND III JUMPS BECAUSE OF EFFICACY COMING INTO THE PICTURE AND WE HAVE MORE CMC INFORMATION AND FINALLY WHEN IT REACHES TO NDA, THE LEVEL REACHES A PLATEAU AND IT IS PURELY A QUALITY-RELATED FACTOR WHICH IS LINKED WITH THE SAFETY, EFFICACY. LEFLEVEL OF CMC DEPENDS ON MANUFACTURER, LEVEL H OF PHASE, I, II, OR III, OR PRODUCT IMPURITIES. LENGTH OF STUDY, NUMBER OF SUBJECT, PATIENT POPULATION, AND PREVIOUS HUMAN EXPERIENCE, LEFT OF CMC INFORMATION DEPENDS ON TYPES OF DRUGS, FOR EXAMPLE BOTANICAL OR SYNTHETIC, AND KNOWLEDGE OF IT, WHETHER IT'S A NEW MOLECULE OR ENTITY OR THE MOLECULE IS OLD, OR PRODUCTS SITUATION. ROUTE OF ADMINISTRATION IS IMPORTANT, WE'RE TALKING ABOUT IF IT IS A PARENTAL PRODUCT, LEVEL OF RISK IS HIGH VERSUS TOPICAL THEN THE LEVEL IS LOW. LEVEL OF CMC AND ITS RELATIONSHIP WITH IND TYPE, WHAT I MEAN HERE BY IND TYPE WHAT TYPE OF INVESTIGATIONAL DRUG WOULD BE USED IN THE INVESTIGATION. THERE ARE SIX DIFFERENT SCENARIOS, THE FIRST ONE IS THE MOLECULE COULD BECOME NEW, NEW CHEMICAL ENTITY. SECOND SCENARIO IS MOLECULE COULD BE OLD BUT DOSAGE IS NEW OR A NEW DELIVERY FOR A NEW INDICATION. THE THIRD SCENARIO IS PRODUCT IS APPROVED IN THE MARKET AND SIMPLY THE IND IS USING THE PRODUCT FOR THE RESPECTIVE INVESTIGATION, OR THE PRODUCT IS APPROVED BUT THERE'S SOME SORT OF REFORMULATION IN THE LAB INVOLVED, FOR EXAMPLE CRUSHING A TABLET, MIXING WITH SOME OTHER INGREDIENT, PUTTING IT IN CAPSULES. EXAMPLE FIVE IS FOR BOTANICAL DRUGS, OR RADIO LEVEL PRODUCTS. SO WHY FOR CMC IN PHASE I STAGE, SAFETY IS PRIMARY. ANY INFORMATION WE VIEW FROM SAFETY REGULATIONS ISSUES. SECOND REASON IS A SMALL NUMBER OF PATIENTS, SUBJECT INVOLVED IN PHASE I STUDIES, TRIALS CONDUCTED UNDER A CONTROLLED SETTING WHICH MEANS ADVERSE EVENTS CAN BE MONITORED. LIMITED NUMBER OF BATCHES OF PHASE I STAGE, A NUMBER OF DRUGS AND BATCHES MANUFACTURED, VERY LIMITED CMC INFORMATION, MANUFACTURING PROCESS ARE NOT YET DEFINED, NOT VALIDATED AT THAT STAGE, AND PROCESS CONTROLS AT EARLY STAGE. THIS IS WHAT THE CTD, COMMON TECHNICAL MODELS LOOK LIKE. THERE ARE FIVE. I'M NOT GOING TO COVER ALL OF THEM. OUR FOCUS IS QUALITY WHERE ALL THE INFORMATION GOES IN AND THE QUALITY MODEL IS FURTHER DIVIDED, WHAT'S IMPORTANT HERE IS 3.2, 3.2 PRODUCTS, ALL THE INFORMATION GOES INTO THAT. THE DRUG SUBSECTION IS FURTHER DIVIDED. HERE IS -- WE SHOULD TAKE A LOOK AT WHAT INFORMATION WE'RE LOOKING INTO. S-1 PROVIDES THE GENERAL INFORMATION OF THE MOLECULE, FOR EXAMPLE THE STRUCTURE, NO, MA'ANOMENCLATURE. NUMBER TWO PROVIDES THE INFORMATION OF THE MANUFACTURER, NAME OF THE MANUFACTURER SOMETIMES REQUIRING THE MANUFACTURER TO ISSUE AND HAVE SOME PROBLEMS, AND THEN WE HAVE ISSUES. SISYNTHESIS PROCESS, S-3 PROVIDES INFORMATION OF THE CHARACTERIZATION, IT'S VERY IMPORTANT FOR NEW DRUGS OR NEW MOLECULES, STRUCTURAL DETERMINATION, AND THE IMPURITIES PRESENT AT THE END OF SYNTHESIS. THEN WE HAVE A CONTROL, THE INFORMATION OF A SPECIFICATION, WE'RE NOT EXPECTING DETAILED DESCRIPTION. BATCH ANALYSIS DATA, PARTICULARLY TOXICOLOGICAL BATCH, ANALYTIC BATCH AND CLINICAL BATCH TO BE USED IN THE INVESTIGATION. S-5, UNDER THIS SECTION THERE'S A REFERENCE STANDARD INFORMATION, IT MAY NOT BE NECESSARILY FOR ALL THE CASES, CASE BY CASE, STABILITY, WE'RE NOT LOOKING FOR THE WHOLE LOT OF STABILITY DATA, ONLY SUFFICIENT TO COVER THE DURATION OF THE INVESTIGATION. THE SEVEN SUBSECTION INFORMATION, WE EXPECT TO SEE THIS, IF THE DRUG IS OLD THEN MAYBE THERE COULD BE ESTABLISHED DRUG DIFFERENCE, OR IF IT'S BOTANICAL, NEW LEVELS OF ISOTOPES, THEN WE EXPECT TO SEE THIS INFORMATION. DRUG PRODUCT SUBSECTION IS DIVIDED INTO SEVEN SECTIONS, FORMULATION, COMPOSITION IS IMPORTANT. WE WOULD LIKE TO SEE THE PRODUCT FORMULATION. PRODUCT LEVEL EVENT WE DON'T EXPECT TO SEE THAT, THE DECISION IS OKAY. BUT THE MANUFACTURER, WE WOULD LIKE TO SEE THE MAIN PROCESS DESCRIPTION OF THE DRUG PRODUCT'S MANUFACTURER. AND CONTROL, THIS SUBSECTION IS VERY IMPORTANT, THE CONTROL OF THE DRUG PRODUCT SUCH AS SPECIFICATION MATTERS TO DETERMINE IDENTITY, QUALITY, SO THOSE INFORMATIONS ARE ESSENTIAL. BATCH ANALYSIS, DOING DOING DEGRADATION, IMPURITY, THAT INFORMATION WE WOULD LIKE TO SEE THAT. THE REFERENCE STANDARD, IT IS NOT REQUIRED ACTUALLY AT IND STAGE, A BRIEF DESCRIPTION IS NECESSARY. STABILITY, AGAIN, ONLY TO COVER THE CLINICAL TRIAL PERIOD. SO WHY DO WE NEED ALL THIS CMC INFORMATION IN PHASE I? WHAT IS THE LINK? THESE ARE THE QUESTIONS WE TYPICALLY ASK. DO WE KNOW THE STRUCTURE OF THE COMPONENT? IF WE DON'T KNOW WHAT THE STRUCTURE OF THE COMPOUND IS, SAFETY DETERMINATION COULD BE MISLEADING. DO WE KNOW THE PHYSICAL PROPERTIES OF THE DRUG COMPOUND? ARE THERE MULTIPLE POLYMERS? SOME POLYMERS COULD BE LESS VIABLE, SOME OTHER POLYMERS COULD BE HIGHER LEVELS, AND THEN MODEL WE'RE USING THE LESS VIABLE POLYMER IN CLINICAL STUDIES, TEN TIMES HIGHER LEVELS OF POLYMER, THAT COULD BE AN ISSUE. SO DO WE KNOW WHAT COMPOSITE BOTANICAL EXTRACTS ARE? WE UNDERSTAND BOTANICALS COULD HAVE MULTIPLE DIFFERENT COMPONENTS, IF THEY ARE NOT ABSOLUTELY IDENTIFIED IN THE INITIAL STAGE. AT LEAST DO WE HAVE AN IDEA HOW THE BOTANICAL EXTRACTION PROCEDURE IS DONE? BECAUSE THEY ARE SOMETIMES HARMFUL, USED IN EXTRACTION PROCEDURE. IS THERE A POTENTIAL INSOLVENCY? WE NEED TO KNOW THAT. IS THERE GENETIC IMPURITIES IN THE SUBSTANCE DERIVED FROM THE ENTITY PATHWAY? THAT'S IMPORTANT INFORMATION FROM THE POINT OF VIEW. ARE THERE ANNUAL IT CA ANALYTICAL MATTERS APPROPRIATE TO DETECT IMPURITIES OR IDENTITIES? DO WE KNOW THE IDENTITY AND POTENCY OF THE DRUG? I COVERED THAT. DO WE KNOW THE COMPARATIVE PICTURE OF THE IMPURITIES USED IN THE TOX BATCH AND CLINICAL BATCH? GENERALLY IN THE TOX BATCH THE LEVEL OF IMPURITY IS MUCH HIGHER AND CLINICAL MUCH IS MUCH PUR PURIFIED. DO WE HAVE THE CLINICAL BATCH USED IN THE INVESTIGATION? DO WE KNOW THE PATHOGENESIS OF THE DRUG SUBSTANCE TO BE USED DIRECTLY FOR INTRAVENOUS TRIAL AND GO FOR INJECTION? IS THE STABILITY DATA SUFFICIENT TO ENSURE STABILITY FOR THE CLINICAL TRIAL DURATION? SO WHAT ARE ARE THE SAFETY-RELATED PRODUCTS? THE FIRST THING I WOULD LIKE TO MENTION, THE FIRST TIME IT'S BEING USED IN HUMANS, IF IT'S NOT, ALL OTHER INACTIVE INGREDIENTS, WE HAVE A WEBSITE AND IT IS ACCESSIBLE BY THE PUBLIC. IS THERE ANY ANIMAL ORIGIN IN THE FORMULATION AND IF THERE IS WHETHER THAT COMPLIES WITH REGULATIONS, DO WE HAVE IMPURITY INFORMATION OF THE DRUG PRODUCT TO BE USED FOR THE CLINICAL PRODUCT? IS THERE POTENTIAL HARMFUL DEGRADATION COUNT COMPOUNDS FORMING? IS THE STABILITY INFORMATION SUFFICIENT TO COVER THE CLINICAL TRIALS? THESE ARE THE DIRECT RELATED PORTION WE SHOULD ASK WHILE PREPARING THE CMC SECTION. THIS IS SOME EXAMPLES OF HOW -- WHAT ARE THE COMMON CMC DEFICIENCIES RELATED TO SAFETY RELATED CONCERNS? NO CMC PACKAGE, NO CERTIFICATE OF ANALYSIS FOR BATCHES TO BE USED IN THE INVESTIGATION. NO STABILITY INFORMATION, NO INFORMATION ON IMPURITIES, HOW THEY ARE CONTROLLED, WHAT ARE THE LEVELS IN THE HUMAN CLINICAL TRIAL BATCHES? IMPURITY PROFILES OF CLINICAL BATCHES, DIFFERENT THAN TOX BATCH, AND AS I MENTIONED DIFFERENT MEANS OF IMPURITY LEVELS HIGHER IN CLINICAL THAN TOX BATCH AND ANALYTICAL INFORMATION, IF THERE'S NO INFORMATION ABOUT THAT, THEN, YOU KNOW, IT CLEARS DOUBT ABOUT THE QUALITY, PURITY AND IMPURITY OF THE INVESTIGATIONAL DRUG. THESE ARE SOME USEFUL GUIDES ON THE INTERNET. THERE ARE MANY OTHERS BUT WHAT I WOULD LIKE TO HIGHLIGHT IS THE CONTENT AND FORMAT, SIMILAR GUIDANCE IS THERE FOR SMALL MOLECULES. THE SECOND ONE IS TH ONE, AND THE THIRD ONE IS VERY IMPORTANT. IND FOR PHASE II AND PHASE III, AND THEN'S CGNP FOR PHASE I VOICAL DRUG AND IMPURITIES, HIGHLY VALUABLE FOR IND APPLICANTS. SO THERE ARE A COUPLE EXERCISES I WOULD LIKE TO SAY. RESEARCH FROM NIH CAUSES TO ASK WHETHER A STUDY PLANNING TO CONDUCT WOULD NEED AN IND. THE STUDY WILL INVOLVE THE USE OF A CRANBERRY CONCENTRATE FORMED INTO A TABLET ANDED A PH-RLADMINISTERED ORALLY, PREVENTING URINARY TRACT INFECTION, DOES SHE NEED AN IND? THE ANSWER IS YES. ANOTHER RESEARCHERS CALLS TO STUDY INVOLVINGUDY HE'S THE USE OF DRUG X CURRENTLY MARKETED IN THE U.S., HOWEVER THERE IS A NEED TO CRUSH THE TABLET AND MIX WITH OTHER DILUTANTS AND PUT IT INTO A CAPSULE SHELL IS AN IND NEEDED? THE FIRST IS YES. BRIEF STABILITY DATA, ALL OF THE ABOVE, NONE OF THE ABOVE, THE ANSWER IS ALL OF THE ABOVE. WE HAVE AN E-MAIL ADDRESS, CHEMISTRY-RELATED INQUIRY FOR IND, WE HAVE DESIGNATED PEOPLE WHO WILL GET BACK TO YOU. THANK YOU. THANK YOU VERY MUCH. [APPLAUSE] >> THE SPEAKER IS DR. GEORGE GRIMES WHO DOES NOT NEED AN INTRODUCTION IN THIS FACILITY, WORKED AT THE NIH PHARMACY SINCE 1973, HE'S BEEN SUPERVISING PRODUCT DEVELOP UNIT SINCE 1979, AND HAS BEEN THE CHIEF OF THE PHARMACEUTICAL DEVELOPMENT SECTION SINCE 2003. DR. GRIMES. >> OKAY. WHAT I'M SHOWING HERE IS AN EXAMPLE OF A CMC SUBMISSION THAT AKM WAS JUST TALKING ABOUT, AND THIS IS WITH PERMISSION FROM DR. LORENZO IN NIAAA, A REAL ONE WE SENT IN EARLIER THIS YEAR, AN INJECTION OF APEPTIDE, AND THIS PATTERN IS WHAT YOU WOULD SEE ON ALL OF THE CMC'S WE SEND TO INVESTIGATORS HERE. AM I TOO - -- OKAY. THE FIRST THING WE DO IS CHECK THE RAW MATERIAL, AND THE MOST IMPORTANT THING IN OUR MINDS WHEN WE ENCOUNTER A NEW DRUG IS THAT WE WANT TO GET A RAW MATERIAL THAT'S GNP GRADE, AND SOMETIMES WE CAN BUY IT AND SOMETIMES WE GET IT FROM DRUG COMPANIES, AND DO THE FORMULATION WORK. SOMETIMES WE HAVE TO GO OUT AND HAVE IT SYNTHESIZED. THE GMP GRADE IS SOMETIMES HARD TO GET. IT'S ALWAYS MORE EXPENSIVE. WHEN YOU HAVE TO BUY IT. THERE ARE SOME SITUATIONS WHERE WE END UP TALKING WITH THE FDA ABOUT WHEN IT'S VERY DIFFICULT TO DO,TO MAKE AN EXCEPTION, AND, YOU KNOW, UNDER CERTAIN CIRCUMSTANCES, IN WHICH CASE WE WOULD DO MORE OF THE ANALYTICAL WORK THAT YOU SEE IN THE FIRST SECTION OF THE SUBMISSION. SO ONE OF THE FIRST THINGS WE DO IS LOOK AT THE CERTIFICATE OF ANALYSIS, FOR THE COMPOUND. THAT GIVES US AN IDEA OF SOME OF THE THINGS AKM WAS JUST GOING OVER, LIKE WHAT SOLVE ARE INVOLVED, WHAT THINGS WE HAVE TO LOOK OUT IN TESTS FOR. AND WE ALWAYS PROVIDE A COPY OF THE LABEL, AND WE DO SOME IDENTITY TESTING, THAT'S WITH THE I-R TRACING IS AND OTHER THAT DOESN'T SO, HPSC ASSAY WAS DONE ON THIS COMPOUND INITIALLY, AS WELL. AND IN THE BOTTOM, PHARMACEUTICAL INGREDIENT SEND, RAW MATERIAL SPECIFICITY SHEET. WE MAKE OUR OWN SHEET. SOMEWHAT IN ADVANCE OF DOING OUR ANALYTICAL WORK, AND SOMETIMES WE ADD THINGS OR SUBTRACT THINGS AS WE GO ALONG BUT THE ANALYTICAL DATA SHEET IS RAW MATERIAL SPECIFIC TAKES SHEET IS BASICALLY THE SAME AS THE CERTIFICATE OF ANALYSIS, WE REPEAT A LOT OF THE TESTS. AND JUST TO BE SURE THAT THERE ARE NO MISTAKES, AND SOMETIMES WE DO GET MISTAKES. WE'VE GOTTEN BOTTLES OF POWDER OR LIQUID THAT DON'T MEET THE SPECIFICATIONS. WE HAVE TO SEND IT BACK. WE'VE GOTTEN THINGS THAT HAD THE WRONG THING IN THE BOTTLE. THE FAIRLY UNIQUE THING THAT HAPPENED A COUPLE MONTHS AGO, WE GOT THE SUPPLY WITH THE RIGHT THING IN THE BOTTLE BUT THE WRONG LABEL. SO THAT HAD TO BE SENT BACK AS WELL. THOSE ARE SOME OF THE REASONS WHY WE DO THESE TESTS. IN THE DRUG PRODUCT SECTION, THE FIRST THING WE DO IS SHOW THE MANUFACTURING PROCEDURE, A RECIPE IN EFFECT THAT SHOWS ALL OF THE INGREDIENTS AND WE USE THE LOT NUMBERS, THE AMOUNTS, EXPIRATION DATES AND STEP BY STEP PROCEDURE OF HOW TO MAKE THE DRUG. AND AT THE END OF OUR MANUFACTURING PAGES IS BASICALLY ALL OF THE TESTS THAT THE ITEM HAS TO PASS BEFORE WE WOULD RELEASE IT OUT OF QUARANTINE. AND THE TEST INVOLVES THINGS LIKE ASSAY AND STERILITY, GENERAL SAFETY TESTS, ANY NUMBER OF TESTS AND INCLUDESSED ADMINISTRATIVE THINGS LIKE THE PROTOCOL HAS TO BE APPROVED. OUR ISSUES WITH FDA HAVE TO BE RESOLVED. AND IT'S A VERY SIMPLE NEA NEAT AND DONE CHECK LIST. NEXT SECTION IS ASSAY PROCEDURE. WE ARE NOT PROUD, WE WILL TAKE AN ASSAY PROCEDURE AND USE IT JUST AS IT IS GIVEN TO US, IF IT'S ADEQUATE. WE HAVE FIVE VERY GOOD CHEMISTS WITH AVERAGE OF ABOUT 20 YEARS EXPERIENCE EACH IN THIS GROUP AND THEY CAN MAKE THEIR OWN ASSAYS, PROCEDURES, IF NEEDED. THE VALIDATION OF THE ASSAY PROCEDURE IS AN IMPORTANT PART. WE STRESS THE DRUG TO MAKE SURE THAT WE CAN TELL, WE'VE MIXED IT WITH ACID, MIXED IT WITH BASE, MIXED IT WITH PEROXIDES, AND HOLD IT AT HIGH TEMPERATURES, JUST TO SHOW THAT THE ASSAY PROCEDURE THAT WE'RE USING WILL TELL SOMETHING HAS GONE BAD, IF IT'S GONE BAD. THEN OF COURSE WE DO STERILITY TESTS, AND USUALLY IN THE CASE WHEN WE'RE MAKING A CMC SECTION, IT'S THE FIRST TIME WE'VE DONE SOMETHING WITH THE DRUG, SO STABILITY, SUITABILITY TESTS HAVE TO BE DONE VERY SIMILAR TO THE ENVIRONMENTAL ASAY PROCEDURE.F THE SAMPLES ARE INNOCULATED WITH A RANGE OF BUGS, FIVE OR SIX DIFFERENT TYPES OF BUGS, AND THE SYSTEM HAS TO SHOW THAT IF THERE WAS A BUG IN THERE, THAT IT WOULD SHOW UP IN THE STERILITY PROCEDURE. THIS CAUSES A LOT OF SUPPLY BECAUSE WE MIGHT NEED AS MANY AS 80 VIALS OF AN INJECTION TO DO THIS PROCEDURE. ALLELE RESULTS, ENDOUG ENDOTOXIN, A TEST WITH INJECTS, FINISHED PRODUCT SPECIFICITY SHEET IS AGAIN LIKE A CERTIFICATE OF ANALYSIS FOR THE RAW MATERIAL, WE HAVE A CERTIFICATE THAT WE CALL FINISHED PRODUCT SPECIFICATION SHEET FOR THE FINAL PRODUCT, IT LISTS ALL THE TESTS THAT ARE DONE, LISTS THE ACCEPTANCE RANGES, AND THE ACTUAL VALUES. THAT'S A VERY IMPORTANT PART OF THE SUBMISSION. THEN ANOTHER VERY IMPORTANT PART IS THE -- I'VE GOT TO PUSH A BUTTON. STABILITY MONITORING PLAN. YOU DON'T WANT TO GET TO THE END OF THE STUDY AND FIND OUT THAT THE DRUG EXPIRED SIX MONTHS AGO, SO WE'RE ALWAYS MONITORING THESE SUPPLIES. SOMETIMES IT REQUIRES US TO MAKE NEW BATCHES IF THE STABILITY IS NOT WHAT WE HOPED FOR. AND WE DO IT NOT ALWAYS IN EVERY CONDITION, AS IS SHOWN HERE, IN THE MINUS 80, MINUS 20, REFRIGERATE AND ROOM TEMPERATURE CONDITIONS. BUT THIS ONE WE KNEW NOT VERY MUCH ABOUT IN THE BEGINNING, SO IF IT'S A DRUG WE KNOW A LOT ABOUT IT, IT MIGHT BE ONE CONDITION, WHERE IT'S STORED. THE STABILITY MONITORING GOES BEYOND JUST MEASURING THE DRUG. SOMETIMES WE NEED TO BE MINDFUL OF SOME OF THE EXCIPIENTS LIKE THE MICRO BIOLOGICAL PRESERVATIVES, WE NEED TO KNOW IT SURVIVES THE SHELF LIFE AS WELL AS THE DRUG. SOME STABILITY MONITORING PLANS ALSO INCLUDE THE TESTING OF THE IMPURITIES, WHEN WE HAVE THE SPECIFIC PROBLEM WITH THE IMPURITY. PRODUCT LABEL AND ACCOUNTABILITY PLAN IS ALWAYS PART OF THE PROCESS. THE PRODUCT LABEL HAS TO HAVE A CAUTION NEW DRUG LEGEND, AND WE PUT THAT ON EVERYTHING THAT COMES OUT OF THE PHARMACY. THANK YOU. [APPLAUSE] >> THANK YOU, DR. GRIMES. I WOULD LIKE TO INVITE BOTH PRESENTERS TO SIT AT THE TABLE SO WE HAVE AN OPPORTUNITY TO OFFER OUR AUDIENCE TO ASK QUESTIONS. SO OUR THIRD PANELIST TODAY IS DR. PRASAD PARI WHO IS THE BRANCH CHIEF IN THE OFFICE OF QUALITY ASSURANCE, HE HAS EXPERIENCE IN PHARMACEUTICAL INDUSTRY AND FDA WORK AND HIS WORKED AT FDA SINCE 1999 IN LEADERSHIP POSITIONS. SO HERE WE HAVE OUR PANEL DISCUSSION. ANY QUESTIONS? >> MY QUESTION RELATES TO BIOCOMPATIBILITY STUDIES, FOR PHASE I STUDY OR ASSAYS, DO THEY NEED TO BE QUALIFIED OR VALIDATED? >> PLEASE SPEAK INTO THE MICROPHONE. >> OKAY. ARE YOU TALKING ABOUT USB 87, 88 STUDIES? >> RIGHT. >> TYPICALLY WE WOULDN'T EXPECT TO SEE THEM DURING PHASE I. IT DEPENDS ON THE TYPE OF TRIAL, HOW LONG THE CONTACT TIME IS. IF IT IS OF COURSE AN IMPLANTED DEVICE WE WOULD EXPECT TO SEE ALL THAT INFORMATION IN THE PHASE I IND. IF IT IS NOW LIKE A MOUTHPIECE OF AN MDI, WE WOULD EXPECT TO SEE THAT AT A LATER PHASE OR MAYBE AN IND STAGE. >> THANK YOU VERY MUCH. >> ANOTHER QUESTION PLEASE? >> WADE ATKINS. I HAVE SOME -- WOULD LIKE TO GET YOUR OPINION ON THE UTILIZATION OF A DRUG MASTER FILE IF THERE ARE SEVERAL IND'S THAT HAVE COMPARABLE MANUFACTURING OR RELEASE CRITERIA FROM THE PERSPECTIVE OF AGENCY USING THAT APPROACH AND MULTIPLE INVESTIGATORS WHO MAY USE A COMMON MANUFACTURING CYCLE. >> I THINK IF THERE'S MULTIPLE IND, IF THERE'S ONE DMF, WHAT WE EXPECT TO SEE IS THE DMF REFERENCE FIRST AND DMF AUTHORIZATION LATER. I MEAN, ALL THE CMC INFORMATION DOESN'T HAVE TO BE IN THE IND APPLICATION AS LONG AS THERE'S APPROPRIATE REFERENCE. THANK YOU. >> OKAY. NEXT QUESTION PLEASE? >> I HAVE A QUESTION ABOUT IF THE MANUFACTURING COMPANY IS NOT LOCATED IN THE U.S., ARE THERE SPECIFIC REQUIREMENTS THAT NEED TO BE FILED IN TERMS OF THE CMC? >> YEAH, I GUESS THE ANSWER WOULD BE IT DEPENDS ON WHAT TYPE OF INFORMATION YOU HAVE ACCESS TO, AN APPROVED PRODUCT, FOR THE FIRST THING WE WOULD WANT TO SEE IS THE LABEL OF THAT AND SEE WHAT EXIPIENTS ARE THERE. IF THE TRIAL IS FOR U.S. PURPOSES, AND YOU DON'T HAVE ANY CMC INFORMATION ON THAT, I GUESS THAT WOULD DEFINITELY BE A WHOLE ISSUE, YEAH. >> THANK YOU. >> ANY OTHER QUESTIONS? >> LET ME ADD, WE DO MAKE THINGS FROM PRODUCTS THAT COME FROM OVERSEAS, AND FOR US, IT'S PRETTY MUCH, YOU KNOW, JUST A MORE DISTANT SUPPLIER, AND BUT WE DO HAVE TO GET CERTIFICATES AND ALL THE SAME THINGS WE WOULD REQUIRE FROM THE U.S. SUPPLIER AND THEY HAVE TO BE SATISFIED AND CHECKED OUT BY OUR CHEMISTS. >> MAYBE I'LL ADD TO THAT, SOMETIMES YOU HAVE SEEN PRODUCTS THAT ARE ACTUALLY MARKETED OVERSEAS THAT ARE BEING USED FOR TRIALS, EVEN THOUGH THERE'S A U.S. APPROVED MARKET FOR THAT, IN THAT CASE WE WOULD GENERALLY ASK THE RATIONALE FOR USING THE OVERSEAS PRODUCT. ALSO THERE IS AN INCOMPARABLE ANALYSIS OR SOME MAYBE ATTRIBUTES COMPARING THE TWO DIFFERENT PRODUCTS USING A CERTIFICATE OF ANALYSIS OR SOME SORT OF CMC INFORMATION BRIDGE. >> ALL RIGHT. IF THERE ARE NO OTHER QUESTIONS, THEN -- OH, OKAY, ONE MORE. JUAN? >> OH, I WANTED TO ASK, WHEN WE GO INTO A PHASE II OR PHASE III TRIAL WE OFTEN HAVE PLACEBO CONTROLS, AND I WANTED TO ASK YOU AND DR. GRIMES IN TERMS OF WHAT WE DO HERE IN THE PHARMACEUTICAL DEVELOPMENT EDITION OF THE PHARMACY DEPARTMENT, WHAT STANDARDS, IF YOU WILL, ARE APPLICABLE TO PLACEBO FORMULATIONS? >> I THINK THE PLACEBO FORMULATION, EVEN IF IT IS IN PHASE I, I THINK THE INFORMATION, LEVEL OF INFORMATION, MANUFACTURING, QUALITY, AND PARTICULARLY THE EXIPIENTS BECAUSE THERE'S NO DRUG, WE DON'T EXPECT TO SEE API REGULATED CMC INFORMATION. ALL WE LOOK FOR, HOW THEY ARE MANUFACTURED, THE GMP STANDARD AND QUALITY CONTROL OF EXIPIENTS USED IN THE FORMULATION. DO YOU WANT TO ADD ANYTHING? >> THE PLACEBOS HERE, WE CONSIDER THEM TO BE DRUGS, AND WE DO ALL THE NECESSARY TESTS. THE INITIAL ASSAY IS VERY SIMPLY TO SHOW THAT THERE'S NO DRUG IN THERE. BUT SOME OF THE PLACEBOS DO HAVE EXIPIENTS LIKE PRESERVATIVES, THEY HAVE TO BE MAINTAINED, SO WE TREAT THEM AS AND WE GIVE THEM EXPIRATION DATES LIKE ANY OTHER DRUG. >> MAYBE ALL JUST ADD TYPICALLY FOR A PHASE I OR PHASE II IND IF WE DON'T EXPECT TO SEE CERTIFICATES OF ANALYSIS FOR A PLACEBO AS LONG AS THERE'S A GRADE, IF YOU CAN REFERENCE A USB OR NF GRADE OR EUROPEAN PHARMCOPIA GRADE FOR LACTOSE OR MICRO CRYSTALLINE, AS WE FOE FORWARD TO PHASE III AT THAT POINT ADEQUATE DOCUMENT FOR THAT EXIPIENT USED IN THE USINGO, ALSO IF YOU'RE SUING BE A CAPSULE YOU NEED TO PROVIDE CERTIFICATION FOR THAT AS WELL. >> ALL RIGHT. SO I WOULD LIKE TO THANK DR. KHAIRUZZAMAN AND GRIMES, WE'RE READY TO CONTINUE WITH OUR PROGRAM, AND THE NEXT SESSION IS ABOUT PHARMACOLOGY AND TOXICOLOGY INFORMATION. >> THANK YOU VERY MUCH FOR THOSE VERY INTERESTING PRESENTATIONS. NOW WE CONTINUE WITH PHARMACOLOGY AND TOXICOLOGY. WE HAVE TWO SPEAKERS AND A PANEL. THE FIRST PRESENTER WOULD BE DR. TODD BOURCIER, DESCRIBING AN OVERVIEW OF PHARMACOLOGY AND TOXICOLOGY DATA. THIS IS IN IND-ENABLING INFORMATION, AND PRE-CLINICAL PHARMACOLOGY ARE IND ENABLING INFORMATION. DR. BOURCIER RECEIVED HIS PHARMACOLOGY FROMSOMETHING NEW YORK MEDICAL COLLEGE AND CONTINUED HIS HE CA IN BRIGHAM AND YOUNG WHERE HE INVESTIGATED IMMUNOLOGICAL PATHWAYS OF CARDIOVASCULAR INJURY AND JOINED THE FDA IN 2004, AND A PHARMACOLOGY AND TOXICOLOGY DRUG REVIEWER, TEAM LEADER IN THE INFORMATION OF METABOLIC AND ENDOCRINE PRODUCTS, OVERSEEING THE MAJOR AREAS LIKE DIABETES, OBESITY AND OTHER ENDOCRINE DISORDERS. >> I'M PLEASED TO BE HERE TO PARTICIPATE IN THE CLAN COLLABORATIVE PROGRAM. I'M A TEAM LEADER, IT'S A BUSY DIVISION, WE HAVE QUITE A DIVERSE PROFILE OF DRUGS UNDER OUR PURVIEW FROM THE RARE GROWTH HORMONE TO OBESITY AND DIABETES AND EVERYTHING METABOLIC IN BETWEEN. WE RECEIVE QUITE A NUMBER OF INVESTIGATOR IND'S, IN FACT INVESTIGATOR OR SPONSOR INITIATED IND'S COMPRISE NEARLY A THIRD OF ALL IND'S THAT WE SEE IN THE METABOLIC AND ENDOCRINE DIVERSE AND DIVERSE. SO I THOUGHT IT MIGHT BE USEFUL IF WE START OUT BY LISTING WHAT I VIEW AS THE TOP THREE PHARM-TOX ISSUES, I'LL REFER TO IT AS THAT. THE TOP THREE PHARM-TOX ISSUES THAT TEND TO LEAD TO THE MOST DIFFICULTY IN FRO FRUSTRATION FOR FDA REVIEWER AND THE APPLICANT AND HAVE IN THE PAST LED TO CLINICAL FOLDS, AND IN NO PARTICULAR ORDER, THEY ARE NUMBER ONE, IND RESEMBLES, AND I GET NOSTALGIC BECAUSE I WROTE A FEW IN THE PAST, IT'S NOT RIGHT FOR AN IND COMPLETE WITH SPECIFIC AIMS ONE, TWO AND THREE. OR THE IND INCLUDES ONLY PROOF OF CONCEPT STUDIES, BY THAT I MEAN STUDIES IN EFFICACY MODEL OF DISEASE IN AN ANIMAL MODEL OF DISEASE. AND YOU'LL SEE WHY THAT'S AN ISSUE LATER. OR THE IND LACKS A NONCLINICAL SECTION ENTIRELY. SO AS I GO THROUGH MY BRIEF TALK I HOPE YOU'LL UNDERSTAND OR APPRECIATE WHY THESE PARTICULAR ISSUES DO TEND TO PRESENT DIFFICULTY FOR US AND HOW THOSE ISSUES CAN BE AVOIDED. AVOIDED IN PUTTING TOGETHER YOUR IND. TO FIRST FRAME OUR DISCUSSION LET ME FRAME THE QUESTION, WHAT IS THE INTENT AND USE OF PHARM-TOX DATA IN DRUG DEVELOPMENT? THE ANSWER TO THE QUESTION DEPENDS, YOU MIGHT GET DIFFERENT ANSWERS, DEPENDING WHO YOU ASK BUT FROM WHERE I SIT, FROM THE FDA PERCH, THE INTENT OF PHARM-TOX DATA IS TWO-FOLD, FIRST TO ESTABLISH THE PHARMACOLOGICAL PROPERTIES OF THE COMPOUND TO A REASONABLE DEGREE OF SPECIFICITY. SECONDLY, IT'S TO UNDERSTAND THE TOXICOLOGICAL PROFILE OF THE COMPOUND BEING INVESTIGATED, REGARDING TARGET ORGANS, EXPOSURE RESPONSE RELATIONSHIPS, REVERSE BUIL REVERSIBILITY . WHEN IT'S FILTERED THROUGH CONDITIONS OF USE IT CAN SET OR HELP GUIDE SELECTION AND CLINICAL TRIALS RANGING MOST IMPORTANTLY IN THE FIRST IN FIRST-IN-HUMAN TRIALS AND PHASE II AND III AND CAN GUIDE CLINICAL MONITORING BEYOND SAFETY ASSESSMENTS COMPONENTS OF ALL CLINICAL TRIALS AND IDENTIFIES AND PREDICTS RISKS THAT CAN'T BE CA CAPTURED IN A CLINICAL TRIAL LIKE ASSESSING CANCER RISK IN A SHORT DURATION TRIAL, OR FOR REASONS THAT ETHICAL, USING A DRUG IN THE COURSE OF PREGNANCY. WHAT IS THE SCOPE OF WHAT WOULD BE CONSIDERED A "COMPLETE PHARM-TOX" PACKAGE? IT'S WORTH LOOKING OVER IN THE NEXT COUPLE SLIDES, I'LL HAVE BULLET POINTS WHICH ARE ESSENTIALLY TAKEN STRAIGHT FROM THE REVIEW TEMPLATES THAT THE PHARM-TOX STAFF USES WHEN REVIEWING YOUR IND'S. THE FIRST OF THESE IS THE PHARMACOLOGY. IT'S A BROAD TOPIC. AT A MINIMUM WE'RE LOOKING FOR INFORMATION ON TARGET SPECIFICITY OF THE DRUG, PRIMARY AND SECONDARY SPECIFICITY. PROOF OF CONCEPT STUDIES, THE ONES I JUST MENTIONED, ANIMAL MODELS OF DISEASE AND RELEVANT INFORMATION SUITABLE FOR YOUR PURPOSE. PHARMACO-I CAKINETICS, INFORMATION ON THE B ABSORPTION AND DISTRIBUTION, METABOLISM AND EXCRETION OF THE DRUG. GENERAL TOXICOLOGY, AND THAT'S VERY MUCH A -- PROBABLY THE MOST IMPORTANT PART OF PHARM- TOX INFORMATION IN AN IND, AS A DEFAULT WE GET THIS FROM STUDIES IN ONE RODENT AND ONE NECROPSYEDENT RODENT AND NECK OPSY EVALUATION AND DRUG-FREE RECOVERY TPRAOEFD PERIODS. AND STUDIES ARE CONDUCTED ACCORDING TO GOOD LABORATORY PRACTICE, GOOD GLP, FOR ANIMAL STUDIES. IT CAN BE AN ISSUE FOR SOME PEOPLE. CONTINUING ON, WE'RE LOOKING FOR INFORMATION ON GENETIC TOXICOLOGY USUALLY ASSESSED THROUGH INVITRO AND INVIVO, EVIDENCE OF CARCINOGENICITY, UP TO TWO-YEAR STUDIES AT A MILLION AND A HALF A POP, WE ASK FOR TWO. INFORMATION ON REPRODUCTIVE TOXICOLOGY, ALSO DEGRE TOUCHING FOR FERTI LITY AND FETAL DEVELOPMENT. THERE ARE PRODUCT-SPECIFIC ASSESSMENTS WHICH ARE PRODUCT SPECIFIC, IT DEPENDS ON YOUR PARTICULAR SITUATION BUT THESE COULD TAKE THE FORM OF JUVENILE ANIMAL STUDIES, FEE PEDIATRIC POPULATIONS, IF THERE'S A CONCERN IT COULD CAUSE PANCREATIC DAMAGE AND SO FORTH. SO I THINK YOU COULD APPRECIATE THAT'S AN AWFUL LOT OF INFORMATION. IT'S ALSO IMPORTANT TO REALIZE THAT COMPLETE PHARM-TOX INFORMATION IS NOT ALWAYS NEEDED AND CERTAINLY IS NOT EXPECTED ALL AT THE SAME TIME, ALL AT ONCE. IT DEPENDS GREATLY ON THE SCOPE OF THE POST CLINICAL TRIAL YOU'RE PUTTING INTO YOUR IND. ANI'LL COME BACK TO THIS QUICKLY. BUT RIGHT NOW I WANT TO POINT OUT THIS PARTICULAR GUIDANCE, ICM M 3R 2, I HOPE YOU'RE FAMILIAR WITH THOSE SETS OF GUIDANCES, IT DISCUSSES THE TIMING AND SCOPE OF NONCLINICAL STUDIES AND HOW THEY SUPPORT CLINICAL PROGRAMS. EACH OF THE NONCLINICAL SAFETY TOPICS I WENT OVER IN THE PRIOR TWO SLIDES HAS AT LEAST ONE, USUALLY MORE THAN ONE, ICH GUIDANCE DEDICATED TO THE SAFETY TOPIC. WE DO CONSIDER ALL THE PHARM-TOX TOPICS I MENTIONED IMPORTANT SAFETY ISSUES, THEREFORE THERE IS AN EXPECTATION ALL NONCLINICAL TOPICS BE ADDRESSED. AGAIN, IN A MANNER APPROPRIATE FOR THE SCOPE OF YOUR CLINICAL PROGRAM. THERE'S GREAT, AS DR. JENKINS MENTIONED, GREAT FLEXIBILITY IN THE TIMING AND TYPE OF SUPPORTIVE NONCLINICAL STUDIES AND MANY FACTORS THAT DETERMINE THE FLEXIBILITY THAT WE HAVE AT THE FDA. AND I WANT TO PRESENT THREE OF THEM AS THESE ARE PROBABLY THE LARGEST FACTORS CONTRIBUTING TO THAT FLEXIBILITY. THE FIRST I'VE ALREADY MENTIONED, SCOPE OF PROPOSED CLINICAL STUDY. FOR EXAMPLE, IF YOU'RE PROPOSING A SHORT DURATION TRIAL, THREE MONTHS OR LESS, THEN WE DON'T NEED REALLY INFORMATION ON CARCINOGENICITY, JUST SHORTER ABRIE ABBREVIATED INFORMATION. SECOND, WE OFTEN SEE THOSE ELICITED HERE. THE PEDIATRIC POPULATION, MORE OR DIFFERENT STUDIES MIGHT BE REQUIRED THAN WHAT I LISTED. THOSE WITH ADVANCED CANCER, ICHS-9, ANOTHER GUIDANCE DOCUMENT, DESCRIBES DIFFERENT NEEDS THAN WHAT I DESCRIBED IN THE LAST TWO SLIDES. REPRODUCTIVE TOXICOLOGY, PROBABLY ISN'T ALL THAT IMPORTANT IF YOU'RE PROPOSING TO STUDY A POPULATION IN THE ELDERLY OR POST-MENOPAUSAL GROUPS. IN RARE DISEASES, IT'S MORE DIFFICULT BECAUSE THERE'S RATHER QUITE A BIT OF HETEROGENAITY. THERE'S NO RULE OF THUMB I CAN GIVE YOU YET. THE THIRD ISSUE THAT DETERMINES FLEXIBILITY AND PROBABLY THE MOST IMPORTANT OR APPLICABLE TO THIS AUDIENCE IS THE REGULATORY STATUS OF THE DRUGS THAT YOU'RE INVESTIGATING. BY THAT, I MEAN THE DRUG EITHER HAS OR HAD FDA MARKETING APPROVAL, OR THE DRUG NEVER HAD AND DOESN'T HAVE FDA MARKETING APPROVAL. IF YOUR DRUG DOES HAVE OR HAD FDA APPROVAL, THEN AN NDA OR PDA MUST EXIST. WE CAN FIND IT. IF THIS FITS YOUR SITUATION, REFERENCE THE APPROVED DRUG LABEL IN THE IND. IT WOULDN'T HURT TO INCLUDE A COPY OF THE DRUG LABEL AS WELL. IT IS IMPLICIT IN THAT APPROVED DRUG LABEL THE NONCLINICAL PROGRAM WAS ADEQUATE TO SUPPORT THE APPROVED DOSE DURATION AND INDICATION STATED IN THE LABEL. DEPENDING ON THE PROPOSAL THAT YOU'RE PROPOSING, THE APPROVED REFERENCE LABEL MOST LIKELY PROVIDES SUFFICIENT NONCLINICAL INFORMATION TO SUPPORT WHAT YOU WANT TO DO IN THE IND. AND THEN YOU'RE DONE. SO AGAIN IF THE SITUATION FITS TO WHAT YOU WANT TO DO, ALL YOU REALLY NEED TO DO IN YOUR IND IS FOCUS ON CHANGES FROM THE APPROVED LABEL REGARDING DOSE, DURATION AND DRUG SOURCE OF FORMULATION AND CLINICAL POPULATION. WHAT'S THE DIFFERENCE THAT YOU WANT TO DO FROM WHAT THE DRUG IS APPROVED FOR? ANY DIFFERENCES THAT RESULT IN A SUBSTANTIAL CHANGE TO THE RISK BENEFITS MAY REQUIRE ADDITIONAL NONCLINICAL INFORMATION AND THAT INFORMATION MIGHT COME FROM A LETTER OF AUTHORIZATION THAT YOU'RE ABLE TO OBTAIN FROM THE NDA HOLDER. IF THAT'S NOT A POSSIBILITY, NEW STUDIES MIGHT BE CALLED FOR OR THERE MIGHT BE SUPPORTIVE LITERATURE THAT'S ADEQUATE TO BRIDGE THE DIFFERENCES FROM THE APPROVED DRUG LABEL. THEN THERE'S THE OTHER REGULATORY STATUS WHERE YOUR DRUG DOES NOT HAVE FDA APPROVAL. IN THAT CASE, THIS BRIEF SCHEMATIC MIGHT BE OF SOME HELP FOR YOU. FIRST ASK THE QUESTION, IS THE DRUG OR THE PRODUCT THE SUBJECT OF ANOTHER IND? AND I UNDERSTAND IT MIGHT BE DIFFICULT TO KNOW HOW TO DO THAT BUT THERE ARE WAYS. IF THE ANSWER TO THAT QUESTION IS YES, THEN IT IS CRITICAL TO OBTAIN A LETTER OF AUTHORIZATION FROM THE IND HOLDER, THAT ALLOWS THE FDA REVIEWER TO ACTUALLY OPEN THAT IND AND USE THE NONCLINICAL INFORMATION IN THAT IND TO SUPPORT YOUR APPLICATION. WE CAN'T DO THAT WITHOUT THE LETTER OF AUTHORIZATION BECAUSE IT'S PROPRIETARY, AS WE HEARD PREVIOUSLY. ONCE YOU HAVE THE LOA ALL ONE NEEDS TO DO IS ADDRESS DIFFERENCES FROM THE REFERENCED IND. WE SHOULD HAVE SOME INFORMATION AS TO WHAT THAT IND IS THERE FOR. AND INCLUDE ANY OTHER RELEVANT INFORMATION AND YOU SHOULD BE GOOD TO GO. IF YOU DON'T KNOW OR THE THE DRUG IS NOT THE SUBJECT OF -- ANOTHER IND, THINGSTHE GET MORE DIFFICULT. ONE CAN INCLUDE RELEVANT LIT FEWER OR NEEDLITERATURE OR INCLUDE STUDIE S I MENTIONED EARLIER. THIS IS WHERE THE REGULATORY INVENTORY OF PRE-IND ADVICE COMES INTO PLAY. WE CAN DISCUSS THAT AT THE PANEL, BUT IT'S HIGHLY RECOMMENDED ONE GET PRE-IND ADVICE IF YOU FALL IN THAT CATEGORY. IN EITHER CASE, THE FDA REVIEWS THE APPLICANTS AND REFERENCED IND AND DETERMINE ADEQUACY FOR SUPPORT, AND AS YOU HEARD PREVIOUSLY, THERE'S A 30-DAY REVIEW CLOCK, FROM WHICH THE END OF WHICH TIME YOU'LL HEAR FROM US, USUALLY THE REVIEW TIME IS NOT 30 DAYS, WE NEED TO HAVE A DECISION WITHIN 20 DAYS BECAUSE OF INTERNAL PROCESSES, SO THAT'S ONE LITTLE ADDITIONAL NUANCE I WANTED TO ADD TO THE 30-DAY MAGIC NUMBER. I DID WANT TO POINT OUT QUICKLY THREE RESOURCES. THE FIRST IS THE ORANGE BOOK. IT'S ON THE FDA WEBSITE. THIS IS A SEARCHABLE CAT DATABASE OF CURRENT AND FORMER FDA APPROVED PHARMACEUTICALS. IF YOU WONDER WHAT'S THIS DRUG'S REGULATORY STATUS, FDA APPROVED, THIS IS WHAT YOU WANT TO GO. LARISA NICELY WENT THROUGH THE WEBSITE, THE NEGOTIATOR INITIATED WEBSITES, THE FIRST TIME I SAW FULL DEMONSTRATION. THERE'S A LOT OF GOOD INFORMATION ON THAT. IT PROVIDES A HIGH LEVEL GUIDE TO THOSE IND COMPONENTS. OR INVESTIGATORS. AND THE ICH WEBSITE IS THERE FOR YOU, THIS IS THE REPOSITORY OF ALL ICH GUIDANCES TO DEVELOPING PHARMACEUTICALS WORLDWIDE. IF YOU'RE NOT FAMILIAR WITH THEM, YOU NEED TO BE. SO TO SUMMARIZE, I RECOMMEND DEDICATE A SECTION IN YOUR IND TO PHARM-TOX, IT DOESN'T HAVE TO BE LONG, NECESSARILY. EXPLICITLY STATE THE SOURCE OF THE PHARM-TOX INFORMATION THAT'S BEING USED TO SUPPORT SAFETYD, ADDRESS THOSE TOPICS AND ADDRESS GAPS BETWEEN SUPPORTIVE DATA AND BRIDGE THE GAPS WHERE IT'S CLINICAL AND MEANINGFUL. I'LL STOP THERE AND THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU VERY MUCH, DR. BOURCIER. WE'RE GOING TO MOVE THEN TO THE NEXT SPEAKER, DR. ALAN REMALY, WHO IS A MEDICAL OFFICER IN THE PUBLIC HEALTH SERVICE OF THE NATIONAL INSTITUTES OF OF HEALTH. HEALTH. GRADUATED FROM THE UNIVERSITY OF PITTSBURGH WITH M.D. AND Ph.D. IN BIOCHEMISTRY AND JOINED THE NATIONAL INSTITUTE OF HEALTH IN 1990. DR. REMALY. >> THANKS FOR THE KIND INTRODUCTION AND INVITATION TO BE HERE TODAY. YOU'RE PROBABLY READY FOR LUNCH SO I WAS TOLD TO KEEP IT SHORT. WE THOUGHT WE WOULD GIVE AN EXAMPLE OF A RECENT CLINICAL TRIAL FACILITATED BY THE JOINT NIH-FDA TASK FORCE AND I'D LIKE TO COMMENT ON HEI RARE DISEASES, IT'S A LOT OF WHAT WE DO HERE. I WILL BEGIN WITH A CRASH COURSE ON THE ENZYME CHOLESTEROL, I I'LL TRY TO GO THROUGH IT QUICKLY AND BACKGROUND TELL YOU ABOUT THE PHASE I STUDY WHICH IS IMPORTANT, FOR PATIENTS WITH GENETIC. THE PART WILL TH ON THE LEFT IS NEWLY DISCREETED, THE PROTEINS STABILIZE IT. IT'S A MINOR COMPONENT, IT'S MOST ACTIVE IN PULLING CHOLESTEROL FROM CELLS, HOW IT'S LARGELY BENEFICIAL BY REMOVING EXCESS CHOLESTEROL. ONCE REMOVED IT'S STORED INSIDE THE PARTICLES, THIS IS PARTICLE ON THE RIGHT, THE SPEAKE SPHERICAL. AND THE KEY ENZYME ATTACHES THE FATTY ACID TO CHOLESTEROL. IT'S AN ENZYME PRODUCED IN LIVER PRODUCED INTO THE PLASMA. IT GENERATES LYSO-PC, BUT THE MAIN PRODUCT IS CHOLESTEROL-ESTHER. CHOLESTEROL IS A HYDRO PHOBIC MOLECULE, ONCE YOU HAVE THE FATTY ACID APATCH. IT'S HYDROPHOBIC AND TRAPPED ON THE HDL PARTICLE, THE PATHWAY BY WHICH HDL IS BELIEVED TO BE BENEFICIAL, TWO GRAMS ARE REMOVED AND RETURNED TO THE LIVER, AND ONCE THE CHOLESTEROL IS TRAPPED ON THE HDL 90% GOES BACK TO THE LIVER. WE WERE INTERESTED IN THIS PATHWAY, THERE'S SEVERAL CLINICAL TRIALS WHERE YOU INFUSE THE MASON PARTICLES ONCE A WEEK FOR FOUR TO FIVE WEEKS, REMARKABLE REDUCTION IN PLAQUE, EQUIVALENT TO TWO YEARS OF STATIN TREATMENT. WE WERE INTERESTED IN WHETHER YOU COULD INFUSE THE ENZYME AND MAKE THE ENDOGENOUS HDL WORK MORE EFFICIENTLY. THAT'S HOW WE STARTED, THIS IS THE PHASE I STUDY, USED IN PATIENTS WITH STABLE CORE ANOTHER ARTERY DISEASE. I'M GOING TO TALK ABOUT THE DEFICIENCY, PATIENTS MISSING THE ENZYME. THE MAIN PROBABLY IS RENAL DISEASE. SO THIS DISEASE, THE WORLD'S EXPERT IN THIS DISEASE, MANY PATIENTS COME FROM OKLAHOMA, MENNINITES. MOST PEOPLE REMEMBER THE FISH EYE. THIS IS THE EXAMPLE OF THE FISH EYE. THEY HAVE A DEPOSIT OF CHOLESTEROL THROUGHOUT THE CORNEA AND ON THE PERIPHERY. IF YOU HAD THE PARTIAL DEFICIENCY YOU HAVE A FISH EYE DISEASE. IF YOU HAVE LESS THAN 10% EFFICIENCY, YOU HAVE FULL BLOWN, THE MAIN PROBLEM IS END STAGE RENAL DISEASE. THEY HAVE NO HDL. THEY HAVE VERY UNUSUAL PARTICLES, LPX PARTICLES. I SHOWED YOU HDL BEFORE. YOU SEE A VESICAL. THIS IS VERY RICH IN FREE CHOLESTEROL, A NET POSITIVE CHARGE, IT GETS TRAPPED IN THE KIDNEY. THESE PARTICLES GET TRAPPED AND THE LABORATORY HAS HONE SHOWN THEY TRIGGER INFLAMMATION. IAND MICE CAN GET THE DISEASE IF YOU INJECT THEM. WE DEVELOPED A SMALL PHARMACEUTICAL COMPANY IN MICHIGAN, AND THEY DEVELOPED A VERY SUFFICIENT EXPRESS SYSTEM FOR MAKING THE RECOMBINANT ENZYME IN CLINICAL TRIALS. THE FIRST STUDY, THE PHASE I STUDY, WE'RE INTERESTED IN SAFETY, THE COMPANY WAS INTERESTED IN INDICATION FOR ACUTE CORONARY SYNDROME. THIS WORKED REMARKABLY WELL, NO SAFETY ISSUES IN THE STUDY. AND WE HAD LIKE OUR MODELS, REMARKABLE INCREASE IN HDL, 40 TO 50%, CONSISTENT FOR SEVERAL DAYS. WE WERE PLEASED WITH THE PHASE I STUDY WHICH WE COMPLETED LAST SUMMER. AND AFTER THE STUDY WAS OVER WE HAD LEFTOVER ENZYME. THE OTHER INDICATION WAS L-CAP DEFICIENCY, THE COMPANY WAS IVE BUT DIDN'T HAVEDIDN'T HAVE RESOURCES. THEY CONTACTED FDA AND THIS WAS APPROVED BASED ON A MONKEY STUDY, A TOX STUDY, TEN INFUSIONS WERE SAVED BUT WE DIDN'T HAVE SIX MONTHS SAFETY DATA AT THE TIME. WE WERE STARTING TO RECRUIT PATIENTS FOR AN L-CAT DEFICIENCY STUDY. IT WAS REFERRED BY ERNIE SCHAEFFER IN BOSTON, THE PATIENT WAS DETERMINED TO GET TREATED. WE HAD SOME PRELIMINARY DISCUSSIONS WITH THE FDA, THERE WAS CONCERN IT WAS SUCH A RARE DISEASE IF WE START TREATING PATIENTS OFF PROTOCOL, BUT THIS PATIENT HAD ADVANCED DISEASE, IT WASN'T CLEAR HE WOULD BE A SUBJECT THAT WE WOULD TREAT BECAUSE OF THE RENAL DISEASE, IT WAS RECOMMENDED HE GO ON DIALYSIS. WE TALKED TO THE FDA. THEY RECOMMENDED US TO DO A SINGLE PATIENT IND STUDY FOR THIS PATIENT. SO WE SUBMIT THAT, LAST NOVEMBER, IT TOOK 20 DAYS TO COME BACK AND THEY PUT IT ON HOLD. AND THIS WAS WHERE THE COLLABORATION BETWEEN NIH AND FDA IS HELPFUL. IT'S INTIMIDATING. I DIDN'T KNOW THE OTHER PARTIES GOT ON THE PHONE AND TALKED ABOUT THE ISSUES. WE DID NOT HAVE THE LONG-TERM SAFETY DATA. THE COMPANY STARTED A SIX-MONTH STUDY IN MICE, PART OF THE REASON IT WAS DELAYED, THEY REQUESTED THE STUDY BE DONE IN KNOCKOUT MICE. AND THE COMPANY STARTED IT BUT THREE MONTHS UNTIL THE DATA WAS RELEASED. THEY WANTED TO SEE THE DATA BUT THEY WERE HAPPY IT WAS STARTED BUT THE GREATER CONCERN WAS THE RELEVANCE IN REGARD TO THE PHASE I STUDY. WE WERE DISAPPOINTED BECAUSE WE THOUGHT BASED ON RESULTS OF THE PHASE I STUDY WE PROVED IT WAS SAFE AND THIS COULD BE USED IN PATIENTS WITH DEFICIENCY AND THEY RAISED THE POINT THEY WERE CONCERNED THAT THE PATIENTS PERHAPS WOULD HAVE A DIFFERENT RESPONSE TO THE L-CAT, INCREASED BUILDUP TO PRECURSORS AND MORE L-CAT, THEY COULD GENERATE MORE CHOLESTEROL-S. SO WE ACTUALLY SHARED WITH THEM SOME DATA FROM ANIMAL STUDIES AND POINTED OUT THESE PATIENTS HAVE VERY LOW CHOLESTEROL, THEY HAVE NO HDL, SO WHEN WE INFUSE THE L-CAT WE EXPECTED TO NOT GET MUCH RESPONSE BASED ON OUR ANIMAL STUDIES. SO AFTER SHARING SOME OF THE PRE-CLINICAL ANIMAL DATA AND SOME DATA SHOWING THE ADDITION OF L-CAT TO WHOLE BLOOD, THEY APPROVED OUR PROTOCOL AND I WOULD LIKE TO CONCLUDE WITH TWO SLIDES. THE PATIENT WAS TREATED APPROXIMATELY OVER TWO WEEKS SINCE JANUARY, HE'S DONE VERY WELL. HE HAD ONE SERIOUS ADVERSE EVENT THAT WAS NOT ATTRIBUTED TO THE DRUG, HE HAD A LONG HISTORY OF AFIB A-FIB BUT NO SITE REACTION, NO TOXICITY. HDL WAS UNDETECTABLE, BUT YOU CAN SEE IT WAS ALMOST NORMAL. HE HAD A DROP IN CHOLESTEROL, LD L WENT UP. YOU SEE THE LDL WHICH WAS QUITE LOW, WENT UP TO NORMAL LEVEL, THE MOST IMPORTANT THING, THE CHOLESTEROL ESTHER, IF YOU MAINTAIN CHOLESTEROL ESTHER AT 30 PER CENT YOU DON'T DEVELOP LPI, WE WERE ABLE TO KEEP IT IN THE NORMAL RANGE FOR A WEEK. HE WAS TREATED EVERY WHO WEEKS, HDL GOES UP AND DOWN BUT CHOLESTEROL STAYED UP. WE THINK THE THERAPY MAY BE POTENTIALLY BENEFICIAL FOR PATIENTS. THE PATIENT HAD ADVANCED DISEASE. WE WERE NOT CERTAIN WHETHER IT WOULD HELP. HE DID SHOW MODEST IMPROVEMENT IN EVEN MA EVEN RENAL TESTS BUT BASICALLY STABILIZED. WE HAVE YOUNG PATIENTS WE WOULD LIKE TO TREAT IN THE FUTURE BEV BEFORE THEY DEVELOP ADVANCED DISEASE. ONE OF THE PROBLEMS IS YOU HAVE CHOLESTEROL-RICH RED CELLS. IT WAS ACQUIRED BY AS EXTRTRA-ZENECA THIS YEAR. I MENTIONED BOB, WHO WAS THE P.I., P.I.SOPINION -- THE >> [APPLAUSE] >> THANK YOU FOR SHARING THE DATA AND OUTCOME OF YOUR CONSULTATION WITH THE FOOD AND DRUG ADMINISTRATION. WE HAVE A PANEL DISCUSSION NOW, I WOULD INVITE THE SPEAKERS TO COME TO THE FRONT AND ALSO INVITE DR DR. JOHN McKEW FROM THE NATIONAL CENTER FOR ADVANCEMENT OF TRANSLATIONAL SCIENCES, A VERY ACTIVE INVESTIGATOR IN RARE DISEASES, AND HAS ALSO PRIOR PHARMACEUTICAL INDUSTRY EXPERIENCE IN TERMS OF DRUG DEVELOPMENT AND DR. ANNE PARISSER WHO READS THE RARE DISEASE PROGRAM IN THE OFFICE OF NEW DRUG AT CDER. WE OPEN THE PANEL FOR QUESTIONS, HOPEFULLY -- I BEG YOUR PARDON, DR. BILL GAHL, LAST BUT NOT LEAST, DR. BILL GAHL. YES. THANK YOU SO MUCH FOR COMING. DR. BILL GAHL IS THE CLINICAL DIRECTOR OF THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE HERE AT TH THE CLINICAL CENTER AND ALL NIH ANDHERE, BOTH FROM FDA POINT OF VIEW I HAVE EXPERIENCE IN DEALING WITH IND SUBMISSIONS, DEALING WITH ISSUES THAT EMERGE IN THE CON TEXCONTEXT OF IND YOU SUBMISSION AND HAD A VERY INTERACTIVE PRODUCTION IN ITEMS OF CONSULTATION AND IN TERMS OF PRE-IND ENGAGEMENT, IF YOU WILL, THAT WE CERTAINLY WANT TO ENCOURAGE. THE PANEL IS OPEN. PLEASE COME TO THE MICROPHONES FOR QUESTIONS. AND OTHERWISE THE PANEL MEMBERS FEEL FREE TO MAKE YOUR COMMENTS REGARDING THE DISCUSSION SO FAR. >> I'M SCATTERED THUNDERSTORM INSURE STEWED.FROM THE ALCOHOL INSTITUTE. GIVE US INFORMATION ON PREPARING FOR THE IND BEFOREHAND, ARE WE EXPECTED TO ASK QUESTIONS OR IS THE FDA COUNTERPART ASKING US QUESTIONS. >> THE PRE-IND IS FIRST REQUESTED TO THE DIVISION THAT'S APPROPRIATE FOR INDICATION THAT YOU'RE PURSUING. AND USUALLY WITH THAT REQUEST COMES SOMETIMES A BRIEF TWO, THREE, FOUR-PAGE SUMMARY OF WHAT IT IS THAT YOU WANT TO DO, WHAT QUESTIONS YOU MIGHT HAVE, AND THAT'S USUALLY FORWARDED TO THE TEAM LEADERS IN THE INFORMATION TO DECIDE WHETHER OR NOT A PRE-IND MAKES SENSE IN THAT PARTICULAR CASE. AND IF SO, IF ONE IS GRANTED, THEN IT'S EITHER A FACE-TO-FACE MEETING OR WE COULD SIMPLY PROVIDE WRITTEN RESPONSES TO QUESTIONS THAT YOU PROVIDE. SO AT THAT POINT, A BACKGROUND PACKAGE IS PREPARED BY THE APPLICANT, BY YOU, AND IF -- IT DEPENDS WHO IS ASKING THE PRE-IND. MERCK ASKED FOR PRE-IND'S, WE HAVE A CERTAIN EXPECTATION OF WHAT WE ENTERTAIN FROM THEM VERSUS A PERSON WITH A RARE DISEASE FROM NIH WHO WANTS TO ASK CERTAIN QUESTIONS. SO IF, FOR EXAMPLE, THE QUESTION IS WITH A BACKGROUND, WELL, WE HAVE THIS KIND OF INFORMATION, NOT CLINICAL INFORMATION, TO SUPPORT A PHASE I SINGLE DOSE STUDY, DO YOU THINK THAT'S ADEQUATE TO SUPPORT THAT SINGLE SENDING DOSE STUDY? NOT IN TERMS OF YES OR NO ANSWER BUT WE MIGHT BE ABLE TO SAY, WELL, WE THINK THIS PAPER AND THAT PAPER YOU'RE PULLING FROM THE LITERATURE MIGHT BE SUPPORTIVE, OR, NO, WE DON'T THINK THAT'S ENOUGH TO SUPPORT IT. THAT'S THE KIND OF QUESTION I THINK THAT I HOPE THAT WE WOULD BE ABLE TO ENTERTAIN FROM AN INDIVIDUAL INVESTIGATOR. THERE ARE CERTAIN QUESTIONS PRE-IND'S THAT ARE NOT HELPFUL TO ANYBODY, LIKE WHAT DO I NEED TO GET THIS DRUG APPROVED? WELL -- >> THE LABEL. >> WHAT WILL MY LABEL READ, YES. PREMATURE AND BASICALLY OUR RESPONSE. QUESTIONS THAT ARE PERTINENT TO WHAT YOU WANT TO DO, AT STEP ONE, ARE THE MOST PERTINENT QUESTIONS DO ASK. IF WE DO HAVE QUESTIONS, WE WILL CERTAINLY ASK THEM. IF THERE ARE QUESTIONS THAT WE THINK SHOULD HAVE BEEN ASKED, BUT WEREN'T ASKED, WE WILL BRING THOSE ISSUES UP IN OUR RESPONSES. SO THE GOAL OF THE PRE-IND IS TO AVOID CLINICAL HOLDS WHEN THE IND COMES IN. SOMETIMES THEY ARE SUCCESSFUL AND FRUITFUL. OTHER TIMES WE'RE NOT SURE WHY THEY ASKED FOR A PRE-IND. >> I'LL JUST ADD TO WHAT TODD SAID. THERE'S ALSO GUIDANCE AVAILABLE ON THE WEBSITE. GUIDANCE CALLED FORMAL MEETINGS WITH FDA. SO THAT HAS SOME INFORMATION ON THE PROCESS INVOLVED AND GIVES A LITTLE BIT OF BACKGROUND ON WHAT SHOULD BE INCLUDED IN YOUR PACKAGE. AND AS TODD SAID, WHAT YOU REALLY ARE TRYING TO DO IS FIGURE OUT HOW TO GET THE CLINICAL TRIAL OPEN. SO THE BIG THREE TOPICS WOULD BE PHARMACO TOXICOLOGY, IF ADEQUATE, WHAT DO YOU HAVE AND PROVIDE BACKGROUND OF WHAT YOU HAVE OR WHAT YOU'RE THINKING OF DOING. THE CMC INFORMATION, MUCH LIKE YOU HEARD IN PREVIOUS TALKS, WHAT YOU HAVE AND YOU'RE ASKING IS THIS ADEQUATE, AND THEN IF YOU COULD PUT A SYNOPSIS OF WHAT YOU'RE THINKING ABOUT FOR THE CLINICAL TRIAL, WHAT THAT WOULD LOOK LIKE AND WHY THE INFORMATION YOU HAVE IS SUPPORTING SAFETY, YOU WANT US TO COMMENTS ON I COMMENT ON IS THIS OKAY TO MOVE FORWARD. IF YOU FORGET TO ASK QUESTIONS, MOST OF THE TIMES OF THE REVIEW DIVISION WILL ANSWER IT ANYWAY. >> I WOULD LIKE TO SAY ON THE WEB NAVIGATIONAL TOOL THAT I SHOWED YOU EARLIER, THERE IS A LINK CALLED INTERACTIONS WITH NDA, THERE WOULD BE PROCEDURES ON HOW TO REQUEST A MEETING WITH NDA, A PRE-IND MEETING OR ANY OTHER MEETING, THAT WE COULD SET UP TO HAVE A DISCUSSION WITH YOU RELATED TO YOUR INVESTIGATION. ALTHOUGH AVAILABLE GUIDANCE DOCUMENTS INCLUDING THE ONE THAT DR DR. PARISER MENTIONED WOULD BE A LINK. >> MY QUESTION RELATES TO THE RARE DISEASES, IN READING THROUGH SOME OF THE WEB PAGE INFORMATION, I'M A BIT CONFUSED ABOUT THE DESIGNATION, LET'S SAY A SINGLE SPONSOR GETS FOR A SPECIFIC RARE DISEASE. IS THAT THE ONLY AUTHOR THAT CAN PURSUE THAT INDICATION? OR MULTIPLE CAN? AND HOW DOES THAT DEAL WITH THE APPROVAL SUBSEQUENTLY? >> YOU'RE REFERRING TO ORPHAN DESIGNATION, CORRECT? >> YES. >> ORPHAN DESIGNATION WAS INTENDED TO PROVIDE FINANCIAL INCENTIVES THAT MAKE ORPHAN DRUG FINANCIALLY VIABLE. IT'S A COMPLETELY SEPARATE PROCESS FROM THE IND PROCESS AND GOING THROUGH DIFFERENT STUDIES. IT DOESN'T SET ANY STANDARDS OR TELL YOU WHAT YOU NEED TO DO. IT'S REALLY ABOUT FINANCES. SO WHOEVER HOLDS THE ORPHAN DESIGNATION AND IF THEY APPLY FOR MARKETING APPLICATION, THEY WILL GET ALL THE FINANCIAL BENEFITS OF THAT. AS LONG AS IT'S NOT AN APPROVED DRUG AND YOU HAVE ACCESS TO THE DRUG, THEN YOU CAN GO AHEAD AND SUBMIT AN IND, WHETHER OR NOT YOU HAVE AN ORPHAN DESIGNATION OR NOT. YOU CAN ELSE GET MULTIPLE ORPHAN DESIGNATIONS BY DIFFERENT PEOPLE FOR SIMILAR OR SAME DRUGS, THE DIFFERENCE IS ONCE IT GETS APPROVED WITH MARKET EXCLUSIVITY, IT'S FOR SEVEN YEARS AFTER. >> YOU CAN HAVE AS MANY HORSES IN THE RACE BUT WHOEVER GETS THERE FIRST GETS THE ACTUAL FINANCIAL ADVANTAGE? >> YES, BUT THERE'S A LOT OF CAVEATS DEPENDING EXACTLY WHAT IT IS. YOU CAN STILL SUBMIT YOUR APPLICATION AND STUDY THE DRUG. >> THANK YOU. MY SECOND QUESTION ACTUALLY IS SOMETHING I'M RELATIVE NEW TO. WHEN WE TALK ABOUT DRUG LABEL OR PRODUCT LABEL, YOU HAD MENTIONED ON SOME OF THE SLIDES WHAT THE CONTENT IS, I WAS WONDERING IF YOU COULD GIVE US AN EXAMPLE OF A DRUG LABEL FOR YOUR PRODUCTS, PERHAPS THE ONE THAT WAS DESCRIBED. >> YEAH, A DRUG LABEL WOULD BE FOR A DRUG THAT'S APPROVED. INSERTAT PACKAGE INSERT USUALLY STUCK TO THE BOX IN NUMBER FOUR FRONT WIT FONT FOR APPROVED DRUGS. IF YOU'RE USING SOMETHING THAT'S APPROVED YOU CAN USE THAT AS SUPPORTING INFORMATION. >> THEY CAN BE FOUND AT FDA.GOV, YOU PUT IN -- IT'S A SEARCHABLE DATA BECAUSE FOR APPROVED DRUGS. TYPICALLY THEY WILL HAVE THE FDA LABEL, MOST RECENT LABELLISTLIED THERE. LABEL LABEL LISTED THERE. WEBSITE.HE NIH WEB SIDE. >> DAILY MED. >> YOU CAN SEE THE FDA APPROVED LABEL. IF IT IS -- I DON'T KNOW IF IT WOULD BE PARTICULAR LIP INSTRUCTFUL BUT I CAN GIVE AN EXAMPLE OF HOW A DRUG LABEL SUPPORTS INVESTIGATOR B'S IND. PHENERMINE IS OLD AND OUT OF DATE BUT APPROVED FOR "A FEW WEEKS USE." AND THERE'S A LOT OF INTEREST IN PURSUING PHENERMINE IN COME COMBINATION WITH OTHER DRUGS AND THE LABEL IS BEING CITED, WHICH IS FINE, IT'S AN APPROVED DRUG. AS I MENTIONED, ONE NEEDS TO REFER TO AT TH THE THE APPROVED DRUG. CHRONIC TREATED AS A CROTCHIC CONDITION. FOR A FEWAPPROVED FOR A YOU WEEKS SO THE LABEL CAN ONLY PROVIDE PARTIAL SUPPORT FOR WHAT THEY WANT TO DO TODAY. WHEN I MENTION RISK BENEFITS, THIS IS AN EXAMPLE WHERE AN APPROVED DRUG LABEL IS NOT SUFFICIENT, NOT ENTIRELY SUFFICIENT, TO SUPPORT THE NEW IND'S COMING IN, AND THOSE DIFFERENCES NEED TO BE BRIDGED SOMEHOW. >> THANK YOU. >> AREN'T WHETHER O AND WHETHER OR NOT TH ERE'S A HUGE AMOUNT OF LITIGATION SURROUNDING THAT. THE COMPANY SPENT $17 MILLION ON PHEN-FEN WHEN THEY TRIED TO GO DOWN THAT ROAD, A COMPANY I USED TO WORK WITH. >> SO THIS BRINGS UP A QUESTION, I DIDN'T HAVE THE PROPER UNDERSTANDING, BUT IF THERE'S AN IMPROVED DRUG AND YOU WANT TO DO A STUDY FOR THE USE OF THAT DRUG OFF LABEL, AND YOU WANT TO GET AN IND OR YOU NEED TO GET AN IND BECAUSE YOUR INSTITUTION LIKE THE NIH TELLS YOU TO GET ONE, OR AN IRB DOES, YOU APPLY, YOU CAN USE WHAT'S ON THE LABEL AS YOUR DRUG MASTER FILE, AND YOU DON'T HAVE TO ASK THE COMPANY TO WRITE A LETTER OPENING THEIR DRUG MASTER FILE FOR THAT IND, IS THAT RIGHT? >> THAT'S CORRECT. >> OKAY. >> RIGHT? >> YEAH, IT'S CORRECT, BUT I GUESS THE ANSWER IS ALWAYS GOING TO BE THAT DEPENDS ON WHAT YOU'RE PROPOSING TO DO. IF YOU'RE VASTLY EXCEEDING THE APPROVED DOSE, OR YOU'RE GOING INTO A HIGHER RISK POPULATION, THAT MAY NOT BE COVERED BY THAT BUT YOU CAN CERTAINLY USE THE INFORMATION THAT IS AVAILABLE IN ADDITION TO PERHAPS THERE ARE SOME GAPS THAT NEED TO BE BRIDGED. >> AND OCCASIONALLY THERE ARE EXAMPLES, WHAT'S APPROVED ON THE DRUG LABEL IS NOT ALL THE INFORMATION AVAILABLE FOR THAT. FOR THAT PARTICULAR DRUG. SO THAT IT IS -- I CAN ENVISION A SITUATION IF ONE GETS A LETTER OF AUTHORIZ AUTHORIZATION FROM THE NDA HOLDER WHICH ALLOWS US TO OPEN THE NDA THERE MIGHT BE A STUDY OR TWO IN THERE RELEVANT TO WHAT YOU WANT TO DO IN YOUR IND. >> YEAH, THAT MAKES SENSE. THERE'S A SORT OF COROLLARY QUESTION, WHICH IS IF WE WANT TO KNOW IF WE NEED AN IND OR NOT THERE'S CERTAIN GUIDANCE IN THERE, YOU NEED AN IND IF IT'S GOING TO BE USED LATER ON FOR AN NDA AND YOU DON'T OTHERWISE, OR YOU MAY NOT OTHERWISE, BUT IN ORDER TO FIND OUT FROM THE FDA, WHETHER YOU NEED AN IND OR SUCH AND SUCH, MY UNDERSTANDING IS YOU HAVE TO APPLY FOR THE IND? >> NOT ALWAYS. YOU CAN CONTACT THE REVIEW DIVISION USUALLY BY LETTER AN TELL THEM WHAT YOU WANT TO DO. THE FIRST STEP IS TO GO THROUGH CRITERIA FOR EXEMPTION, IF YOU THINK YOU QUALIFY, IT SEEMS LIKE YOU DO, THEN YOU CAN PROCEED. IF YOU'RE NOT SURE, YOU CAN TRY CONTACTING THE REVIEW DIVISION AND SOMETIMES BE ABLE TO LOOK AT THE INFORMATION AND SAY YOU DON'T NEED IT OR YOU DO. BUT SOMETIMES THERE MAY NOT BE ENOUGH INFORMATION AND THEY WILL TELL YOU TO SUBMIT. >> WE'VE SEEN THAT KIND OF QUESTION COME IN PRE-IND PACKAGES, DO WE NEED AN IND? SO THAT'S ALSO ANOTHER AVENUE THAT AN INVESTIGATOR CAN HAVE PUTTING TOGETHER A PRE-IND PACKAGE IS LESS DAUNTING THAN AN IND PACKAGE. SO IT CAN RANGE THEN FROM SIMPLY CONTACTING THE PROGRAM MANAGER AND ASKING THIS IS WHAT I WANT TO DO, SHE WILL GIVE YOU INSTRUCTIONs HOW TO PROCEED NEXT, OR SUBMIT A PRE-IND INCLUDING THAT QUESTION. DOES FDA THINK THAT AN IND IS NECESSARY FOR WHAT IT IS THAT WE WANT TO DO? AND YOU'LL GET AN ANSWER ON THAT. >> WELL, THANK YOU VERY MUCH TO ALL THE SPEAKERS AND THE PANEL MEMBERS. WE APPRECIATE THEIR PRESENTATIONS AND THEIR INPUT IN THIS DISCUSSION. NOW WE'RE GOING TO TAKE A LUNCH BREAK. WE'LL START AGAIN PROBABLY AT 12:30 P.M., SO PLEASE COME BACK ON TIME. AND WE WILL CONTINUE WITH SEVERAL OTHER INTERESTING SESSIONS THIS AFTERNOON. >> ALL RIGHT. WE'RE GOING TO START OUR AFTERNOON PART OF THE PROGRAM. CLINICAL PROTOCOLS IN IND. DR. JAMES GULLY AUTHORED OVER 20 STUDIES WITH IND APPLICATIONS INCLUDING MANY FIRST-IN-HUMAN STUDIES AND HAS BEEN AN HAV INVESTIGATOR ON 60 CLINICAL TRIALS. HE'S ESPECIALLY INTERESTED IN IMMUNOTHERAPY FOR CANCER PROVIDING INSIGHT INTO UNIQUE ISSUES WITH BIOLOGICS, HIGHLIGHTING THE IMPORTANCE OF EARLY COMMUNICATION WITH NDA FOR FIRST-IN-HUMAN STUDIES. DR. GULLEY, PLEASE. >> THANK YOU VERY MUCH. I'M REALLY HAPPY TO BE ABLE TO BE HERE TO GIVE YOU SOME IDEA OF WHAT WE'VE DONE, AND GIVE YOU REALLY AN EXAMPLE OF I WOULD SAY HOW NOT TO DO THINGS. FIRST OF ALL, WE'LL GO THROUGH INGREDIENTS OF A CLINICAL PROTOCOL, AND WE'LL GO THROUGH A PATHWAY FOR DEVELOPMENT, AND THEN LIKE ELEANOR ROOSEVELT SAID, IT'S BEST TO LEARN FROM OTHER PEOPLE'S MISTAKES BECAUSE YOU WON'T LIVE LONG ENOUGH TO MAKE THEM ALL YOURSELF. THERE'S SOME SPECIAL CONSIDERATIONS FOR BIOLOGICS I WANTED TO GO INTO. FIRST OF ALL, CLINICAL PROTOCOL INGREDIENTS, WELL, IN THE CLINICAL TRIAL DOCUMENTS, I THINK CERTAINLY EVERYONE WOULD AGREE THE BACKGROUND IS VERY IMPORTANT. IT CAN PROVIDE THE SCIENTIFIC RATIONALE OF WHY YOU WANT TO DO THE STUDY AS WELL AS GIVE SAFETY CONSIDERATIONS ABOUT THE PRODUCT THAT YOU'RE USING. CLINTON CACLINICAL TRIAL DESIGN IS IMPORTANT WITH PRIMARY AN SECONDARY POINTS. ELIGIBILITY CRY TEAR CRITERIA SHOULD BE OUTLINED IN THE CLINICAL TRIAL AND STATISTICAL CONSIST O CONSIDERATION OF THE STUDY DESIGN. PATHWAY OF GETTING FROM A CONCEPT TO AN OPEN APPROVED ACCRUING CLINICAL STUDY IS AS FOLLOWS. FIRST, YOU NEED TO DO THE PRE-CLINICAL WORK TO JUSTIFY THIS, INCLUDING TOXICOLOGY, PHARMACOLOGY, MECHANISM IMPACTION AND EFFICACY STUDIES AND ASSIMILATE THAT AND PLAN THE POTENTIAL CLINICAL TRIAL DESIGN. SO ONCE YOU GET ALL THAT TOGETHER, WHAT I WANT TO EMPHASIZE HERE IS THERE IS OPPORTUNITY FOR A PRE-IND CONSULTATION WITH THE AGENCY AND WE'LL COME BACK TO THAT IN A LITTLE BIT. THEN YOU -- AFTER GETTING ALL YOUR INFORMATION TOGETHER, YOU WRITE UP THE CLINICAL TRIAL, YOU OBTAIN THE SCIENTIFIC INPUT, AND THE SAFETY INPUT FROM THE VARIOUS COMMITTEES HERE AT THE NIH, YOU HAVE A SEPARATE -- SORRY, SCIENTIFIC REVIEW AND SEPARATE IRB AND THERE MAY BE OTHER ISSUES FOR BIOLOGIC SUCH AS INSTITUTIONAL BIOSAFETY COMMITTEE AND OFFICE OF BIOLOGIC ACTIVITIES, FOR VACCINES, THAT INCLUDE HUMAN GENETIC MATERIAL. SO ONCE THAT IS ALL DONE, THEN YOU CAN FILE THE IND. THERE'S A 30-DAYTIME FRAME FOR ANY CLINICAL HOLD ISSUES TO BE IDENTIFIED. WHEN THAT'S PAST AND ALL APPROVALS ARE IN PLACE YOU CAN OPEN THE TRIAL AND START ACCRUING PATIENTS. I WANT TO HONE DOWN ON THE IND PACKAGE FOR SUBMISSION, BECAUSE WE'RE GOING TO TALK ABOUT THAT IN THE EXAMPLE IN A LITTLE BIT. PLEA CLINICAL PHARMACOLOGY AND TOXICOLOGY STUDIES SHOULD INCLUDE PRE-CLINICAL DATA AND PREVIOUS CLINICAL EXPERIENCE THAT COULD COME FROM STUDIES DONE OUTSIDE OF THE U.S., FOR INSTANCE. THERE'S ALSO THE CLINICAL TRIAL PROTOCOL THAT WE ALREADY DISCUSSED, AND INVESTIGATE INFORMATION, AND CHEMISTRY MANUFACTURING AND CONTROL SECTION. SO WHAT I'D LIKE TO SHARE WITH YOU NOW IS KIND OF A STORY OF A CLINICAL TRIAL THAT WE HAVE ONGOING HERE, AND KIND OF SOME OF THE HICCUPS WE WENT INTO WHEN WE FIRST STARTED THIS STUDY. THIS IS A TRIAL OF A DRUG CALLED NHS-IL 12, A HUMAN ANTIBODY, THE NHS COMPONENT, TUMOR NECROSIS TARGETING ANTIBODY CONJUGATED WITH AL-12. THIS IS A SCHEMATIC WITH A HUMAN ANTIBODY WITH TWO IL-12'S BOUND TO IT. NOW, OBVIOUSLY, TESTING IN A PRE-CLINICAL SETTING HAS SEVERAL INTERESTING CAVEATS THAT ONE SHOULD BE AWARE OF. SO WHEN WE'RE TESTING CHEMOTHERAPIES, OFTEN THOSE ARE TESTED IN KEEN O XENOGRAPHS WITH HUMAN TUMORS IN SKID MICE, AND THERE'S NO ISSUES WITH IMMUNOGENECITY WITH SKID MICE, BUT YOU NEED AN INTACT IMMUNE SYSTEM IN THE ANIMAL TO TEST, AND YOU CAN DEVELOP SIGNIFICANT ANTIDRUG ANTIBODIES. SO JUST A LITTLE BIT ABOUT THIS NHS-IL-12. LET'S SEE IF I CAN GET THE POINTER. YES. YOU CAN SEE HERE THE INJECTION SITE AND THE ACCUMULATION OF THE DRUG WITHIN THE TUMOR SITE. DOWN IN THE OTHER PANEL HERE, YOU HAVE A SIMILAR ANTIBODY, IT'S AGAINST FIBRONECTIN CON JECONJUGATED WITH IL-12, THERE APPEARS TO BE BETTER PHARMACO-I CAPHARMACO-KINETIC PROPERTIES. AS PREAC PREVIOUSLY MENTIONED, SOME DATA USED FOR THE IND SUBMISSION CAN COME FROM OTHER STUDIES INCLUDING FOREIGN STUDIES OF THE DRUG OR SIMILAR DRUGS FROM OUTSIDE OF THE U.S SO THIS TUMOR NECROSIS-TARGETING ANTIBODY HAS BEEN TESTED WITH AN I-131 CON CONJUGATE IN CHINA, APPROVED FOR THE TREATMENT OF APPROVED LUNG CANCER. YOU CAN SEE THE TARGETING OF THIS LUNG LESION, AND YOU CAN SEE ALSO THERE'S SOME UPTAKE HERE IN A SITE OF KNOWN MA FAST CYST OMETASTASIS OF THE LUNG CANCER. SO I'M GOING TO PUT THE DRUG A LITTLE BIT ON HOLD WHILE WE TALK ABOUT GUIDANCE FOR INDUSTRY, AND THEN WE'LL COME BACK TO IT. GUIDANCE FOR INDUSTRY ARE BASICALLY DOCUMENTS THAT REPRESENT THE FDA THINKING ON A TOPIC, AND PROVIDE GREATER TRANSPARENCY AS YOU'RE GETTING READY FOR THE IND SUBMISSION. NOW, WITH BIOLOGICS, THERE'S SOME UNIQUE ISSUES THAT WE MENTIONED. THESE BIOLOGICS, WHEN YOU'RE TESTING AN INTACT IMMUNE SYSTEM, IN PRE-CLINICAL BODIES THE XENO ANTIGENS CAN BE IMMUNOGENIC, DIFFICULT TO FIND AN APPROPRIATE ANIMAL MODEL. HERE IS DATA LOOKING AT IL-12 IN THIS MODEL, THE SAME HUMAN ANTIBODY NHS, WHAT YOU CAN SEE IS A VERY NICE INCREASE IN GAMMA INTERFERON, WHICH YOU WOULD EXPECT FOLLOWING ADMINISTRATION OF THE NHS-IL-12. WITH THE SECOND DOSE THERE'S NO DEFECTION OF GAMMA INTERFERON. MAYBE WE'RE SHOOTING BLANKS, AFTER THE SECOND DOSE, BECAUSE YOU'RE DEVELOPING ANTIDRUG ANTIBODIES. WE LOOKED AT THIS ALSO IN DOGS. YOU CAN SEE WITH THE FIRST DOSE, VERY NICE AREA UNDER THE CURVE FOR BOTH MALE, FEMALE DOGS, AT ALL THE DOSES TESTED. BUT WHEN YOU GIVE THE SECOND DOSE, DAY EIGHT HERE, THE UNDER UNDER THE CURVE IS MARKEDLY DIMINISHED, THIS IS ACTUAL MEASUREMENT OF THE ANTIBODY ITSELF, PHARMACO KINETIC MEASUREMENT. INDEED YOU SEE THAT'S ASSOCIATED WITH THE PRODUCTION OF ANTIBODIES TO DRUG. SO THEN WE LOOKED IN NONHUMAN PRIMATES. THIS IS ANOTHER SERUM CYTOCITE, IP-10. AFTER THE FIRSTED A ADMINISTRATION OF THE IL-12, A NICE INCREASE IN THE SERUM IP-10, TRANSIENT, BUT BY THE THIRD DOSE THE INCREASE IN IP-10 WAS SIGNIFICANTLY MUTED. SO WHAT IS THE GUIDANCE FOR INDUSTRY SAYING ABOUT THESE TYPES OF ISSUES? WELL, FOR BIOLOGICS, FO TOXICITY STUDIES MAY BE MISLEADING AND ARE DISCOURAGING. WE SAID THAT'S ENCOURAGING. THE DETECTION OF ANTIBODIES SHOULD NOT BE THE SOLE CRITERIA UNLESS THE IMMUNE RESPONSE NEUTRALIZED PHARMACOLOGICAL EFFECT. THERE IS DECREASE BASICALLY FROM THE FIRST TIME WE GIVE A DOSE UNTIL WE GIVE THE SECOND OR THIRD DOSE, THERE'S A SIGNIFICANT DECREASE. SO PROBABLY APPLIES HERE. IT APPEARS TO US THAT THE FIRST THREE ANIMAL MODELS REALLY WEREN'T GREAT ANIMAL MODEL TOES TOES -- NODELS T NOD MODELS TO BE TESTING THIS IN. WE GOT THE IND PACKAGE AND FILED THE IN. WE HAD DATIND. WE HAD DATA THAT INFLUENCED OUR THINKING FROM OTHER STUDIES THAT HAD BEEN DONE, PRE-CLINICAL STUDIES. THERE WAS A STUDY PERFORMED BY INDUSTRY WITH A POX VIRUS VACCINE THAT CONTAINED CEA, AND WAS ALSO GIVEN WITH HUMAN GMCFS, ALL OF THESE LAST SO THAT THE THREE MOLECULES WERE ALL HUMAN PROTEINS IN A NONHUMAN PRIMATE. SO THERE WAS NO CLINICAL TOX ISSUES HERE BUT THERE WERE IMMUNE CONJUGATES AT MEMBE NECROPSY SEEN IN THE KIDNEYS OF MANY NONHUMAN PRIMATES TREATED AT THE HIGHEST DOSE. BASED ON THAT, WE THEN HAD TO AMEND OUR ONGOING TRIALS WITH A SIMILAR AGENT, AND TIGHTEN OUR ELIGIBILITY CRITERIA TO REALLY LOOK TO SEE, IS THIS A REAL CLINICAL ISSUE OR IS THIS JUST SOMETHING THAT WAS AS A RESULT OF A IRRELEVANT FINDING IN A MODEL THAT PROBABLY WASN'T IDEAL. AFTER MUCH TESTING IT APPEARED TO BE NO CLINICAL RELEVANCE TO THE FINDINGS ON THE STUDIES. ALSO, WITH THE IL-15 STUDY THAT WAS INITIATED HERE, IN THE LAST COUPLE OF YEARS, IN PRE-CLINICAL TESTING IN NONHUMAN PRIMATES THERE WAS SOME TOXICITY SEEN, BUT IT WAS LARGELY TRANSIENT, AND AT DOSES UP TO 200, AND WHAT THEY STARTED AT WAS A DOSE OF 3 MICRO GRAMS PER KILL O PER KILO GRAM WITH EXCESS TOXICITY AND HAD TO BE DEESCALATED. IN THE FIRST, YOU HAVE POTENTIAL TOXICITY SEEN IN NONHUMAN PRIMATES THAT WASN'T PRESENT IN HUMANS. IN THE SECOND ONE YOU SEE NO TOXICITY IN NONHUMAN PRIMATES WHERE THERE WAS TOXICITY IN HUMANS. SO THERE CAN BE ISSUES WHEN YOU DEAL WITH BIOLOGICS THAT MAY NOT BE APPARENT AND MAY BE UNIQUE TO THE BIOLOGICS. SO WE FILED THE IND. HOWEVER, WHAT WE -- WHEN WE WENT TO THE MEETING WITH THE FDA WE REALIZEELED THE STUDIES WERE NOT FULL GLP STUDIES, AND WE ONLY HAD TWO ANIMALS PER GROUP RATHER THAN THREE TO FIVE. WE SAID, WELL, PROBABLY THESE ARE NOT REALLY -- NONE OF THE ANIMAL MODELS THAT WE LOOKED AT, WE DIDN'T THINK THEY WERE GOOD ENOUGH, BUT ATHIN I THINK APPROXIMATE WE HAD A PRE-IND CONSULTATION WITH THE FDA WE WOULD HAVE ISSUES AND BEEN FURTHER AAHEAD. THE FDA DID APPROVE WITH A PARTIAL CLINICAL HOLD TO TREAT PATIENTS WITH A SINGLE DOSE OF THE IL-12 AND DID GO AHEAD WITH THE FULL GLP TOX STUDY ON NONHUMAN PRIMATES, AND THIS DID ALLOW US EVENTUALLY TO PROCEED WITH A MULTIPLE ASCENDING DOSE STUDY WHICH JUST STARTED. JUST SOME QUICK UPDATES ON THE GLP STUDY, THIS IS LOOKING AT THE IMMUNOGENECITY ON 32 NONHUMAN PRIMATES, AND YOU CAN SEE IN THE CONTROL ANIMALS, BY WEEK 29, NO ANTIBODIES, THERE WAS ONE OUT OF FIVE FEMALES HAD ANTIBODIES AT WEEK 15, BUT IN ALL OF THE ANIMALS THAT RECEIVED THE NHS-IL 12 ALL HAD ANTIBODY BY WEEK -- BY DAY 15 THAT REMAINED BY DAY 29. IF YOU TAKE THE HIGHEST COAST AND LOOK AT GAMMA ENTIRE FEARON BIG INCREASES AT THE FIRST TREATMENT. AT THE SECOND VERY LITTLE TO NO INCREASE, AND THIRD TREATMENT AGAIN VERY LITTLE CHANGE IN THE GAMMA INTERFERON LEVELS. SO I THINK THESE ANTIBODIES SUGGEST THESE ANTIBODIES THAT WERE MADE WERE LIMITING THE AMOUNT OF ACTIVITY OF THE DRUG IN PHARMACODYNAMIC PARAMETERS. SO DESPITE THE FACT THAT THESE ANIMALS HAD NO SIGNIFICANT TOXICITY DUE TO THE ADVERSE DRUG -- SORRY, OF THE ANTIDRUG ANTIBODIES, YOU CAN'T RELY ON THE NO OBSERVED ADVERSE EFFECT LEVEL. WE DID TEST MUCH HIGHER DOSES, SOMETIMES ONE CAN OVERCOME BY GOING TO HIGHER DOSES, ONE CAN ACTUALLY PUSH THROUGH THE ANTIDRUG ANTIBODIES BUT WE WERE TESTED AT DOSES UP TO 6 MILLIGRAMS PER KILO GRAM IN THE .1HUMAN PRIMATE STARTING AT MICRO GRAM PER KILOGRAM. WE OPENED THE TRIAL FOR DOSE LEVEL FOUR, 2 MICROGRAMS PER KILOGRAM. CONCERNS IS TONELS OF THE ASSURE IF DATA IS SAFE FOR I WOULD SUBMIT BASED ON OURUMANS. EXPERIENCE AND ASK THAT YOU LEARN FROM OUR MISTAKES AND TO CONSULT THE FDA EARLY AND AS OFTEN AS NEEDED WITH A PRE-IND CONSULTATION, THE ISSUES ARE NOT ALWAYS STRAIGHTFORWARD. SOMETIMES YOU MIGHT THINK THIS IS THE RIGHT THING TO DO OR THE RIGHT WAY TO GO BUT CONSULTATION WITH THE FDA IS I THINK VERY HELPFUL, AND IMPORTANTLY THEY DO HAVE THE TIME SAY. THEY HAVE A LOT OF EXPERIENCE WITH THIS, AND THEY HAVE THE REGULATORY AUTHORITY, SO BECAUSE OF THAT I THINK, AGAIN, TO CONSULT EARLY AND AS OFTEN AS NEEDED. THANK YOU VERY MUCH. [APPLAUSE] NOW WE'VE COME TO THE HEART OF OUR PROGRAM. AND THAT'S THE SESSION ON CLINICAL HOLD. NOBODY WANTS THEIR PROTOCOL BE PLACED ON HOLD. DR. ALIZA THOMPSON IS THE MEDICAL OFFICER AND TEAM LEADER IN THE OFFICE OF NEW DRUGS, RECEIVED HER MEDICAL DEGREE FROM JOHNS HOPKINS UNIVERSITY AND COMPLETED INTERNAL MEDICINE AND NEPHROLOGY TRAINING AT COLUMBIA UNIVERSITY IN NEW YORK. SHE HOLDS A MASTER OF SCIENCE IN BIOSTATISTICS FROM THE COLUMBIA UNIVERSITY AND JOINED THE DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS IN 2007, AND SHE HAS BEEN INVOLVED IN MANY AND PERSONALLY I WOULD LIKE TO SUBMIT MANY COMMERCIAL INVESTIGATIONAL NEW DRUG APPLICATIONS. HER TEAM FOCUSES ON PRODUCTS BEING DEVELOPED FOR RENAL-RELATED INDICATIONS AND REVIEWS PRODUCTS THAT ARE DEVELOPED FOR OTHER INDICATIONS. DR. THOMPSON PLEASE. >> I'M JUST GOING TO MAKE SURE I KNOW HOW TO DO THIS, LARISSA, AND MAYBE I DON'T. OKAY. CAN EVERYONE HEAR ME? WELL, THANKS SO MUCH FOR INVITING ME. THANK YOU TO ALL OF YOU FOR STICKING AROUND. I KNOW YOU'VE HAD A LONG DAY SO FAR OF LECTURES AND IT'S PROBABLY HARD TO SIT FOR THAT LONG. I THINK THIS MORNING AS I UNDERSTAND YOU GOT A NUMBER OF LECTURES WHICH FOCUSED ON THE CRITICAL ELEMENTS TO INCLUDE AND IND SUBMISSION. I'M GOING TO DISCUSS A LES HAPPY TOPIC, WHAT HAPPENS IF A REVIEW DIVISION GETS YOUR APPLICATION AND THEY DECIDE THAT THE PROPOSED STUDY CAN NOT ACTUALLY PROCEED. OVER THE COURSE OF THIS SHORT PRESENTATION I'M GOING TO FOCUS ON THREE TOPICS, START WITH TERMINOLOGY, WHAT IS A CLINICAL HOLD, FROM THERE BRIEFLY DISCUSS GROUNDS FOR IMPOSING A CLINICAL HOLD AND MOVE TO THE FIND TOPICS, WHAT MUST BE DONE TO RESUME CLINICAL INVESTIGATIONS AFTER A CLINICAL HOLD HAS BEEN PLACED. SO AS YOU'RE ALL WELL AWARE, AFTER YOU SUBMIT AN IND APPLICATION, THE REVIEW DIVISION HAS 30 DAYS TO REVIEW IT. WHAT A CLINICAL HOLD IS, AN ORDER WHICH IS ISSUED BY FDA TO AN IND SPONSOR, SOMEONE DELAYS A PROPOSED CLINICAL INVESTIGATION OR SUSPEND AN ONGOING INVESTIGATION. EVEN THOUGH I HIGHLIGHTED THE FACT THAT WE HAVE THE 30-DAY INITIAL PERIOD TO REVIEW NEW IND APPLICATIONS, WE REALLY HAVE THE AUTHORITY TO ISSUE A CLINICAL HOLD AT ANY PHASE OF DEVELOPMENT. SO WHAT ARE TYPES OF CLINICAL HOLDS? GENERALLY THEY COME IN TWO VARIETIES. WHAT'S CALLED A COMPLETE CLINICAL COLD, HOLD, A DELAY OR SUSPENSION, AND THEN THERE'S A PARTIAL CLINICAL HOLD, A DELAY OR SUSPENSION OF PART OF THE UNDER THE IND.NTHE INDIAN. PROTOCOL OR PART OF THE PROTOCOL IS NOT ALLOWED BUT OTHER PARTS OF PROTOCOLS WOULD BE A ALLOWED TO PROCEED. EFFECTS, WE MAY PROPOSE A STUDY WITH A SINGLE ASCEND DOSE PHASE FOLLOWED BY A MULTIPLE AND YOU MAY DECIDE WE'RE ONLY COMFORTABLE WITH YOU PROCEEDING WITH ONE PART OF IT. IT MAY BE THAT WE'RE UNHAPPY WITH THE DOSE THAT YOU'RE PROPOSING AND WE WANT YOU TO START AT A LOWER DOSE. OR UNHAPPY WITH THE TRIAL DURATION NOT JUST AS RELATES TO MULTIPLE DOSES BUT MAYBE WE'RE CONCERNED YOU DON'T HAVE SUFFICIENT DATA TO SUPPORT DOING IT FOR THE NUMBER OF WEEKS THAT YOU'RE DOING IT. ANOTHER ISSUE WHICH I THINK WAS SORT OF RAISED IN THE PRIOR TALK WAS THE STUDY POPULATION, YOUR DRUG MAY HAVE SIGNIFICANT TOXICITY ASSOCIATE WITHED, IT'S IT'S NOT REASONABLE OR ETHICAL TO EXPOSE PEOPLE TO THE RISK. WE WANT YOU TO DO THE STUDY IN A DISEASED POPULATION. THE REGULATIONS LAY THIS OUT. PHASE I STUDIES, SOME GROUNDS FOR IMPOSING A CLINICAL HOLD INCLUDE FIRST HUMAN SUBJECTS WOULD BE EXPOSED TO ILLNESS IF THEY PARTICIPATE. THE CLINICAL INVESTIGATORS NAMED ARE NOT QUALIFIED BY REASON OF THEIR SCIENTIFIC TRAINING AND EXPERIENCE TO CONDUCT THE INVESTIGATION. AND THAT WILL NEVER APPLY TO HOPEFULLY YOU GUYS. ANOTHER ISSUE COULD BE THE INVESTIGATOR BROCHURE IS MISLEADING, ERRONEOUS OR INCOMPLETE OR THE IND DOES NOT ACTUALLY CONTAIN SUFFICIENT INFORMATION TO ASSESS RISKS OF THE SUBJECTS. IN MY DIVISION IN SPECIFICALLY MY THEY ARE MUTE ISSU PAOUTD THEY ARE PAO UTD THEY ARE THERAPEUTIC, MOST ARE IN THIS CATEGORY. WHAT ABOUT PHASE II OR PHASE III? IT'S ALL THE SAME REASONS FOR PHASE I BUT HERE IT'S EXPANDED A LITTLE BIT, NOT JUST TO SAFETY BUT THE WHOLE IDEA THAT THE PLAN OR PROTOCOL IS SO DEFICIENT IN THE DESIGN TO MEET STATED OBJECTIONS WE DON'T THINK IT'S REASONABLE TO PROCEED. I'VE NEVER BEEN INVOLVED IN A HOLD PLACED FOR THIS REASON. BUT THEORETICALLY WE COULD PUT IT ON HOLD IF WE THOUGHT THE STUDY WAS ABSOLUTELY USELESS. SO I WANT TO EMPHASIZE TO YOU, I DON'T KNOW IF YOU'VE EVER PLAYED THE GAME RED LIGHT, GREEN LIGHT. WE DON'T VIEW THIS AS A GAME. WE TAKE THIS VERY SERIOUSLY, CLINICAL HOLDS. AND IF YOU EVEN LOOKED AT THE REGULATIONS THEMSELVES, THEY REQUIRE THAT WHEN WE CONCLUDE THAT THERE MAY BE GROUNDS FOR IMPOSING A CLINICAL HOLD AS A FIRST STEP WE'LL ATTEMPT TO RESOLVE THE MATTER BEFORE ISSUING THE CLINICAL HOLD. FREQUENTLY WE'LL HAVE A CALL WITH THE SPONSOR OR CALLS WHERE WE STATE WHERE OUR CONCERNS ARE AND THEY WILL SEE IF THEY CAN ACTUALLY PROVIDE DATA NEEDED TO ADDRESS THE ISSUE, MAYBE THEY DO HAVE THE CHEMISTRY DATA WE'RE LOOKING FOR, OR MAYBE IT'S AN ISSUE OF MODIFYING THE TRIAL DESIGN. SO THAT WE FEEL MORE CONFIDENT WE'RE ENSURING THE SAFETY OF THE STUDY SUBJECTS. AGAIN, IN MY EXPERIENCE, 'EM EMPHASIZING WE TAKE THE DECISION SERIOUSLY, IT'S REALLY JUST A LAST RESORT WHEN, YOU KNOW, THE SPONSOR REALLY IS NOT ABLE TO SUPPLY WHAT WE NEED TO CONCLUDE THE STUDY IS IN FACT SAFE TO PROCEED. SO I'M GOING TO PAUSE FOR A SECOND. LARISSA MENTIONED MY THERAPEUTIC AREA IS RELATED TO THE KIDNEY. I JUST WANT TO MAYBE ASK THE QUESTION TO THE AUDIENCE, AS I UNDERSTAND ALL OF YOU ARE INVOLVED IN PHASE I OR PHASE II STUDIES, I WANT TO CONFIRM BY PEOPLE RAISING THEIR HANDS, ARE YOU ALL IN FACT, OR MANY OF YOU, INVOLVED? OKAY, SO A NUMBER. DO YOU KNOW SOMEONE INVOLVED IN A PHASE I OR PHASE II STUDY? OKAY, PEOPLE ARE LAUGHING AND SMILING. I'M GOING TO ASSUME THAT'S YES. I'M GOING TO SAY MY THERAPEUTIC AREA, THAT CLINICAL HOLDS ARE THE EXCEPTION RATHER THAN THE RULE. I'M GOING TO THROW BACK OUT TO SEEMS YOUINCE IT'S SYME'S YOU AT KNOW SOMEONE, HOW MANY OF YOU KNOW SOMEBODY WHO HAD THEIR IND PLACED ON CLINICAL HOLD? UH-OH. IF ANYTHING, I'M SAYING IT'S RARE, I'M SEEING A LOT OF HANDS GO UP. MAYBE IT'S NOT HOW I WANTED TO DO THE STATISTIC. HOLDS,D ASK HOW MANY POLLED OF BUT IT'S SOMETHING YOU'VE SEEN AND THAT'S UNFORTUNATE. HOPEFULLY THOSE STUDIES WERE ABLE TO OVERCOME THE HOLD AND MOVE ON. BUT JUST IN TERMS OF, AGAIN, IT'S PROBABLY DEPENDING ON THERAPEUTIC AREA, SOME OF YOU EXPERIENCED DIFFERENT THAN WHAT I'M PUTTING UP HERE. I WANT TO NOTE AT LEAST IN MY DIVISION, MY THERAPEUTIC AREA, MANY CLINICAL HOLDS WE IMPOSE ARE BASED ON PRODUCT QUALITY ISSUES. SO WHAT ARE EXAMPLES OF THIS? IT COULD BE THAT THERE'S A KNOWN DOIN DEGRADANT TO YOUR DRUG AND YOU DIDN'T MONITOR FOR IT IN STABILITY STUDIES. IT COULD BE THAT AS PART OF YOUR DRUG SYNTHESIS PATHWAY YOU DIDN'T ASSESS FOR IT, YOU'RE PLACED ON HOLD UNTIL YOU CAN PROVIDE DATA SHOWING THAT THE DRUG SUBSTANCE BATCHES AND BATCHES YOU'RE PLANNING TO USE IN THE CLINICAL TRIAL DON'T ACTUALLY CONTAIN A RESIDUAL LEVEL OF THAT POTENT GENOTOXIN. IN TERMS OF OTHER REASONS I'VE SEEN AUTHO FOR CNC CLINICAL HOLDS OR WHAT CONTRIBUTED TO THE DECISION, THERE'S NOT SUFFICIENT INFORMATION PROVIDED ON POTENTIAL IMPURITIES AND SPECIFICALLY THE ASSAYS OR METHODS USED TO TRY TO IDENTIFY THE POTENTIAL IMPURITIES WERE NOT SUFFICIENTLY SENSITIVE. TO GIVE YOU A FLAVOR OF SOME REASONS A APPLICATIONS GET PUT ON HOLD FOR CNC ISSUES, YOU HAD LECTURES BASED ON PRODUCT QUALITY, MAYBE THEY SPOKE ABOUT OTHER ISSUES THAT CAN ARISE WITH APPLICATIONS. BONBEYOND THAT I WOULD ARGUE MOST ISSUES WE COME ACROSS CAN ADDRESSED PRIOR TOSSED AND THE STUDY STARTING OR 30-DAY DEADLINE. FREQUENTLY AND FORTUNATELY WE DON'T HAVE TO PUT SPONSORS ON HOLD. WITH THAT SAID I WANT TO POINT OUT SOME ISSUES THAT COME UP THAT SOMETIMES NEED TO BE RESOLVED. SO THE SPONSOR COMES IN, THEY MAY PROPOSE A OF THE EXTRAING STARTING DOSE AND WE DON'T THINK A SUFFICIENT SAFETY MARGE MARGIN AND SHOULD START LOWER OR BECAUSE OF THE STEEPNESS OF TOXICITY WE MAY WANT THEM TO ASCEND MORE GRADUALLY IN THE STUDIES. WE MAY NOT THINK THAT THE THEIR MONITORING IS ADEQUATE OR FREQUENT FOR A PARTICULAR FOX TOXICITY AND MAYBE TO GIVE YOU MORE CONCRETE EXAMPLES THROW OUT THE FOLLOWING THE. YOU HAVE A DRUG MAYBE BEING DEVELOPED IN ANOTHER INDICATION, IN ONCOLOGY, RIGHT? MAYBE THEY SAW CASES OF LIVE INJURY. THEY ARE HARD TO INTERPRET BECAUSE OF THE UNDERLYING POPULATION, MAYBE OTHER MEDICATIONS THEY GOT. BUT YOU ALSO KNOW THAT THE PHARMACOLOGIC CLASS HAS BEEN ASSOCIATED OR THERE HAVE BEEN FATAL CASES OF LIVER TOXICITY WITH OTHER MEMBERS OF THE PHARMACOLOGIC CLASS. MAYBE SETTINGS LIKE THAT, WE WOULD WANT THAT INFORMATION INCLUDED IN THE INVESTIGATOR'S BROCHURE, THE APPLICANT MAY NOT HAVE NOT IT WAS RELEVANT BUT WE WANT IT DESCRIBED. THAT MAY BE AN EXAMPLE OF OUR CONCERNED ABOUT AN IND AND SOMEBODY THAT COULD BE WORKED OUT PRIOR TO THE 30-DAY DEADLINE. IN TERMS OF OTHER ISSUES, IT COULD BE YOU HAVE A DRUG, BIOLOGIC. YOU GIVE IT -- EVEN AFTER A SINGLE DOSE, A RELEVANT SPECIES, YOU SEE INFLAMMATION IN THE JOINT. SO MAYBE IN THE SETTING WE MIGHT TELL YOU THAT IT'S FINE TO DO YOUR SINGLE ASCENDING DOSE STUDY BUT WHAT WE WANT IS YOU TO PAUSE OR AT LEAST WAIT, YOU KNOW, FOR SOME PERIOD BETWEEN INITIAL DOSING AND INITIAL SUBJECTS IN THE COHORT JUST TO ALLOW ENOUGH TIME FOR THE TOXICITY TO POTENTIALLY MANIFEST BEFORE YOU GO ON TO THE NEXT SUBJECT AS OPPOSED TO DOSING ALL PEOPLE IN THE COHORT AND ONCE AND DISCOVERING THEY DIDN'T TOLERATE IT WELL. THOSE MIGHT BE EXAMPLES OF ISSUES THAT WE WANT OR MODIFICATIONS WE THINK NEED TO BE MADE TO A PROTOCOL OR STRESS INVESTIGATOR BROCHURE BUT MODIFICATIONS THAT CAN BE WORKED OUT. SOMETIMES THERE'S A BACK AND FORTH. WE SAY, OH, WHAT YOU PROPOSE IS INSUFFICIENT, MAYBE WE SUGGEST SOMETHING, MAYBE THE SPONSOR GETS AT THE PRIMARY ISSUE, MAKING SURE WE'RE ADEQUATELY ENSURING THE SAFETY OF STUDY SUBJECTS. AGAIN, I WANTED TO ALSO MAKE THE POINT THAT WHAT I'M DESCRIBING IS THE EXPERIENCE IN MY DIVISION, THE BASIS FOR HOLDS AND USE OF CLINICAL HOLDS MAE VARY DEPENDING UPON THE THERAPEUTIC AREA YOU'RE WORKING IN. MAYBE I IMAGINE YOU ALL REPRESENT A NUMBER OF THERAPEUTIC AREAS. I KNOW SOMEONE FROM THE KIDNEY SPACE IS OUT THERE BUT I'M GUESSING OTHER SPACES AS WELL. I WANT TO MAKE A NOTE ABOUT PRE-CLINICAL DATA. I UNDERSTAND YOU GOT A LECTURE THIS MORNING ON PRE-CLINICAL DATA, WHAT IMPORTANT ELEMENTS TO INCLUDE IN THE IND SUBMISSION. CLEARLY, ESPECIALLY FOR YOUR FIRST-IN-HUMAN STUDY, IT'S CRITICAL TO HAVE SUFFICIENT PRE-CLINICAL DATA SO THE REVIEW TEAM CAN ASSESS WHETHER A PRODUCT IS REASONABLY SAFE FOR INITIAL TESTING IN HUMANS. AS I THINK ALSO CAME OUT IN THE LAST LECTURE, NOT ONLY ARE THERE AGENCY GUIDANCE OUT THERE TO GIVE YOU A SENSE OF NECESSARY PRE-CLINICAL STUDIES, PHARMACOLOGY AND TOXICOLOGY, BUT ALSO I WANT TO EMPHASIZE PRE-IND CONSULTATIONS ARE CRITICAL AND VERY IMPORTANT AND I THINK VERY VALUABLE TO ENSURE THAT WHEN YO YOUR IND COMES IN, IT'S NOT LIKELY TO GO ON CLINICAL HOLD BECAUSE OF A LACK OF PRE-CLINICAL DATA. NOT JUST THE STANDARD PRE-CLINICAL DATA BUT SOMETIMES SPECIAL PRE-CLINICAL DATA THAT MAY BE NEEDED GIVEN WHAT'S BEEN OBSERVED WITH YOUR PRODUCT. SO TO THROW OUT AN EXAMPLE, SPONSOR CAME IN FOR PRE-IND MEETING FOR A DRUG THAT HAD IMPORTANT VASCULAR INJURY IN ANIMALS, AND THE RESPONSIBLE TORE HAD HYPOTHESIZED AND THOUGHT THEY UNDERSTOOD THE MECHANISM AND BASED THE MONITORING STRATEGY INTRALLY HUMANS BASED ON THAT BUT THERE WANTEDUGH CONCERNING O KERN CONCERN THEY ENT WITH ADDITIONAL STUDIES WITH THE SPONSOR DID.TORE WHERE THE IND SUBMISSION THEY RESOLVED THE MES MECHANICKIC MECHANICKIST IC ISSUES, USE THAT, ESPECIALLY IF YOUR DRUG APPEARS TO HAVE IMPORTANT TOXICITIES YOU'RE CONCERNED ABOUT IN THE CLINICAL SETTING. WHAT HAPPENS WHEN AN IND IS ISSUED? IT'S NEVER A HAPPY MOMENT FOR ANYONE. BUT WHAT WILL USUALLY HAPPEN IS WE'LL CALL YOU AND INDICATE THAT YOUR IND IS BEING PUT ON HOLD. USUALLY IT'S NOT GOING TO COME AS A SURPRISE BECAUSE, AGAIN, THERE'S GOING TO BE A BACK AND FORTH RULE. ROLE. YOU MAY TRY TO PROVIDE THE DATA WE'RE LOOKING FOR TO RESOLVE THE ISSUE. WHEN WE PUT YOU ON CLINICAL HOLD, WE'RE GOING TO TELL YOU WHICH STUDIES THE HOLD APPLIES TO. WE'RE ALSO GOING TO OF COURSE EXPLAIN THE BASIS FOR PUTTING YOU ON THE HOLD. BEYOND THIS INITIAL CALL YOU SHOULD EXPECT TO GET WITHIN 30 CALENDAR DAYS A WRITTEN EXPLANATION OF THE REASON WHY YOU'RE BEING PUT ON CLINICAL HOLD AND HOPEFULLY THE STEPS NECESSARY TO RESOLVE THE HOLD SO YOU KNOW WHAT TO DO NEXT. AND HOW DO YOU GET THE GREEN LIGHT? WELL, WHAT YOU NEED TO DO IS SUBMIT SOMETHING THAT WE'VE REFERRED TO AS A COMPLETE RESPONSE. ESSENTIALLY THE IDEA OF THE COMPLETE RESPONSE IS THE RESPONSE IN WHICH ALL OF THE CLINICAL HOLD ISSUES THAT HAVE BEEN IDENTIFIED BY THE DIVISION HAVE BEEN ADEQUATELY ADDRESSED. AND THAT MEANS EITHER THAT DEFICIENCYTHE DEFICIENT OR SATISFIED US THAT IT'S REASONABLE AND PROCEED WITH THE ORIGINAL OR SOME MODIFICATION OF THAT INVESTIGATION. AND ONCE WE REVIEWED THAT, AND IN FACT CONCLUDED THAT YOU'VE ACTUALLY ADDRESSED ALL THE DEFICIENCIES, WE WILL LIFT THE CLINICAL HOLD. AND WE ARE REQUIRED OR WE SHOULD RESPOND TO YOU WITHIN 30 CALENDAR DAYS OF YOU SUBMITTING THE COMPLETE RESPONSE, BUT INDICATES REGARDLESS YOU REMAIN ON HOLD UNTIL WE ACTIVELY DO SOMETHING AND COMMUNICATE THAT YOU'RE IN FACT OFF. BUT AGAIN, GOOD LUCK. I HOPE WHOEVER GIVES THE LECTURE IN ANOTHER YEAR OR FIVE YEARS, NO ONE WILL RAISE THEIR HAND WHEN ASKED IF THEY KNOW SOMEONE WHO HAS BEEN ON CLINICAL HOLD. [APPLAUSE] >> THANK YOU VERY MUCH, DR. THOMPSON. PLEASE DON'T LEAVE BECAUSE THERE MAY BE SOME QUESTIONS TO YOU HERE. FIRST QUESTION? >> THANK YOU VERY MUCH FOR THAT NICE PRESENTATION. NOW, ONE QUESTION I HAVE RELATES TO A MECHANISM THAT I'VE SEEN IN A FEW LOCATIONS WHERE TOWARD THE END OF THE 30-DAY SAFETY REVIEW PERIOD, SAY DAY 28 OR 29, YOU KNOW, THE CONCERNS ARISE TO A LEVEL THAT THEN YOU CALL THE INVESTIGATOR AND PRETTY MUCH WARN THEM THAT THEY MAY BE PLACING A CLINICAL HOLD AND THEN, YOU KNOW, IF THE ISSUES ARE COMPLEX ONE OPTION THAT I SAW OFFERED TO THE INVESTIGATOR WAS WITHDRAW THE IND. SO TECHNICALLY IF YOU WITHDRAW THE IND YOU'RE NOT PLACED ON CLINICAL COLD HOLD BUT TAKE ADVANTAGE OF THE DISCUSSION, IF YOU WILL, AND EXCHANGES THAT WENT ON PRIOR TO THAT TIME, AND MODIFY YOUR APPLICATION WITH A NEW SUBMISSION. HOW OFTEN IS THAT MECHANISM USED AND DOES IT REALLY PLACE THE INVESTIGATOR IN A BETTER POSITION OR DOES IT MAKE A DIFFERENCE? >> I DON'T THINK, YOU KNOW KNOW, CLINICAL HOLDS ARE NOT IDEAL BECAUSE IT MEANS YOU CAN'T START YOUR INVESTIGATION. AND THAT SLOWS DOWN RESEARCH, AND THAT'S NOT GOOD. I THINK FOR PEOPLE WHO ARE IN IN A COMMERCIAL SETTING, IT COULD ALSO HAVE IMPLICATIONS FOR THEIR ABILITY TO RAISE FUNDS AND GENERATE SOME PROBLEMS. SO I WOULD SAY THAT YOU'RE RIGHT, YOU CAN WITHDRAW AN IND, SO THAT YOU DON'T EVER GET ACTUALLY PUT ON CLINICAL HOLD. THAT SAID, IN TERMS OF WHEN YOU START BACK UP YOUR INVESTIGATION, OR ULTIMATE IMPLICATIONS, THE FACT THAT YOU'VE WITHDRAWN PUTS YOU IN THE SAME PLACE WHICH IS THAT YOU CAN'T DO A STUDY. AND NOT UNTIL YOU HAVE ACTUALLY RESOLVED ISSUES. IN MY EXPERIENCE WHEN SPONSORS HAVE WITHDRAWN THEIR APPLICATIONS, SO THEY CAN AVOID GETTING PUT ON HOLD, WE STILL PUT ALL THE DEFICIENCIES IN THE LETTER TO THEM, AND AGAIN WHEN THEY COME BACK IN THEY ARE STILL GOING TO NEED TO ADDRESS THEM. SO I DON'T KNOW IF SOME OF IT IS WINDOW DRESSING, MAYBE IT'S IMPORTANT IF YOU HAVE A COMMERCIAL IND AND YOU'RE TRYING TO GET INVESTORS. IF YOU'RE NOT IN THAT SETTING I DON'T KNOW IF IT MATTERS MUCH. BUT THAT IS, WAS YEAH, AS YOU NOTED, IT'S HOW SOME PEOPLE ADDRESS THE ISSUE. >> THANK YOU. ANY OTHER QUESTIONS? ALL RIGHT. IT SEEMS LIKE THIS WAS VERY CLEARMENT OUR NEX. THANK YOU, DR. THOMPSON. OUR NEXT SESSION IS MODERATED BY HEATHER BRIDGE. SHE IS HERE. >> THANK YOU, LARISSA. IND APPLICATION SAFETY REPORTING, OUR FIRST PRESENTER IS DR. DMITRI IARIKOV. AND HE'S GOING TO PRESENT FROM THE FDA PERSPECTIVE, HE JOINED IN 2005 IN THE DIVISION OF ANTIINEFFECTIVE PRODUCTS, CENTER FOR DRUG EVALUATION AND RESEARCH, AND HE HAS WORKED AS A STAFF PHYSICIAN IN, HE'S AN NIH-ER. AND HE COMPLETED A FELLOWSHIP THERE INFECTIOU INFECTIOUS DISEASE AT TUFTS. WITHOUT FURTHER ADO. >> GOOD AFTERNOON. TODAY WE'LL DISCUSS IND SAFETY REPORTING REGULATIONS TO HELP YOU TO COMPLY WITH IND SAFETY REPORTING AND REQUIREMENTS. IN DOING THIS PRESENTATION ABOUT SAFETY REPORTING, RELEVANT DEFINITIONS, REPORTING RESPONSIBILITIES, REPORTING TIME FRAMES, AND BASICALLY DISCUSSING SAFETY REPORTING. IND SAFETY REPORTING INCLUDING CELL AND GENE THERAPIES, THERE ARE TWO CATEGORIES OF SAFETY REPORTING. TODAY WE'LL TALK ABOUT EXPEDITED REPORTING. IN SEPTEMBER OF 2010, A FINAL RULE WAS PUBLISHED ON EXPEDITED SAFETY REPORTING TO REGULATIONS, AND UNDER THE FORMER REGULATIONS, THE SPONSORS WERE REQUIRED TO REPORT EVENTS WITH A REASONABLE POSSIBILITY THAT THE EXPERIENCE MIGHT HAVE BEEN CAUSED BY THE DRUG. AS A RESULT, MANY EVENTS THAT WERE IN TH -- THEY WERE REPORTED, FOR EXAMPLE MORBIDITY AND MORTALITY RELATED TO UNDERLYING DISEASE OR STATIC POPULATIONS SUCH AS MYOCARDIAL INFARCTION IN THE ELDERLY OR POINTS REPORTED AS EVENTS AND IN GENERAL WHEN REPORTED INDIVIDUALLY THIS ANALYSIS OF THIS EVENT DOES NOT HELP TO UNDERSTAND SAFETY OF THE DRUG PRODUCTS, AND RATHER THESE EVENTS SHOULD BE REPORTED IN AGGREGATE ANALYSIS. AND NEW IND SAFETY REPORTING REQUIREMENTS WERE DEVELOPED TO REDUCE THE NUMBER OF UNINFORMATIVE EVENT AND REGULATIONS EMPHASIZE THE IMPORTANCE OF EVIDENCE AND THE EVENT. THESE REGULATIONS BECAME EFFECTIVE IN MARCH OF 2011 AND SUBSEQUENTLY THE AGENCY ISSUED GUIDANCE ON NEW SAFETY REPORTING REQUIREMENTS IN DECEMBER OF 2012. IMPORTANTLY, NO CHANGES EMULATING IMPORTANT REQUIREMENTS TO IND SAFETY REPORTING. RELEVANT DEFINITIONS, INVESTIGATORS AND INDIVIDUALS UNDER WHOSE DIRECTION THE DRUG IS ADMINISTERED, TAKING RESPONSIBILITY FOR AN ISSUED CLINICAL INVESTIGATION AND IMPORTANTLY THE SPONSOR RATHER THAN THE INVESTIGATOR IS RESPONSIBLE FOR SAFETY REPORTING TO THE FDA AND IF ONE INDIVIDUAL BOTH INITIATES AND CONDUCTS THE INVESTIGATION, THE SPONSOR INVESTIGATOR. ADVERSE EVENT IS AN UNTOWARD MEDICAL OCCURRENCE. SUSPECTESUSPECTEDDED ADVERSE REACTION, AN Y ADVERSE EVENT WITH EVIDENCE OR CAUSAL RELATIONSHIP TO THE DRUG, AND THERE' ADVERSE REACTION IS THE EVENT THAT CAUSED BY A DRUG. AND THIS DIAGRAM DEPICTS A CONTINUUM OF ADVERSE EVENTS. I'M SORRY. OKAY. AS YOU CAN SEE HERE, ADVERSE REACTIONS AT THE CENTER OF THE CONTINUUM OF THAT ADVERSE EVENT. IT IMPLIES THEY HAVE THE MOST, THE GREATEST CAUSATIVE RELATIONSHIP TO THE STUDIED DRUG. EXPEDITED SAFETY REPORTING, IMPORTANTLY, THE EVIDENCE IS THE KEY ELEMENT RELEVANT TO EXPEDITED SAFETY REPORTING, ONLY SERIOUS AND UNEXPECTED SUSPECTED ADVERSE REACTIONS NEED TO BE REPORTED EX-PA EXPEDITIOUSLY AND IN ACCORDANCE WITH REQUIREMENTS. LET'S TALK ABOUT THIS TERM, SUSPECTED SERIOUS AND UNEXPECTED. SUSPECTED ADVERSE REACTION, PROBABLY THE MOST CRITICAL FOR EXPEDITED SAFETY REPORTING. SO SUSPECTED ADVERSE REACTION MEANS ANY EVENT FOR WHICH YOU HAVE EVIDENCE FOR CAUSALITY IN TERMS OF ASSOCIATION BETWEEN THE DRUG AND ADVERSE EVENT. AND THE SPONSOR IS RESPONSIBLE FOR -- RATHE THAN THE RATHER THAN RATHER THAN THE INVESTIGATOR IS RESPONSIBLE FOR CAUSALITY JUDGMENT.THE SINGLE MOST COMMON EVENT KNOWN TO BE ASSOCIATED WITH THE DRUG, HEPATIC INJURY SHOULD BE DEFINED AS A SUSPECTED ADVERSE REACTION. UNCOMMON EVENTS, BUT EVENTS NOT COMMONLY ASSOCIATED WITH THE DRUG, WITH DRUG EXPOSURE, BUT IN EVENTS THAT OTHERWISE ARE UNCOMMON IN THE STUDIED POPULATION AND CLASSICAL EXAMPLE, TENDON RUPTURE OR EVENTS THAT OCCURRED MORE FREQUENTLY IN THE TREATMENT GROUP AS REVEALED BY AGGREGATE ANALYSIS, POINTING TO RELATIONSHIP BETWEEN THE DRUG AND THE EVENT AND THIS EVENT WOULD MEET REQUIREMENTS FOR SUSPECTED ADVERSE REACTION DEFINITION. SERIOUS EVENTS RESULT IN DEATH, LIFE-THREATENING, HOSPITALIZATION OR PROLONGATION OF EXISTING HOSPITALIZATION, RESULTING IN SUBSTANTIAL DISRUPTION OF THE ABILITY TO CONDUCT NORMAL LIFE FUNCTION AND IN AABNORMALTY, OR EVENTS THAT DO NOT RESULT DIRECTLY IN ALL THESE OUTCOMES BUT ENTAIL MEASUREMENTS TO PREVENT THEM. UNEXPECTED, THIS DEFINITION IS ENTIRELY DEPENDENT ON THE EVENT IN THEE EVENT AND BROCHURE OR IF IT'S A SINGLE INVESTIGATOR BROCHURE IT'S NOT AVAILABLE, IN THE APPLICATION. SO EVEN NOT ONLY THE LISTING BUT ACTUALLY THE DEGREE OF EVENT IS IMPORTANT. FOR INSTANCE, IF LIVER ENZYME ELEVATION IS LISTED BUT THE CVENT IS ACTUALLY HEPATIY FAILURE, THIS WOULD BE UNEXPECTED. IF IT'S TO A CLASS, NOT TO A PARTICULAR DRUG UNDER INVESTIGATION, WE STILL CONSIDER THIS EVENT AS UNEXPECTED, BECAUSE IT'S NOT SPECIFICALLY MENTIONED IN THE APPLICATION. AND LET'S TALK ABOUT EXPEDITING REPORTING RESPONSIBILITIES. SO THE DECISION TO EXPEDITIOUSLY REPORT THE EVENT TO THE AGENCY IS ULTIMATELY BECAUSE THE ON THE CAUSALITY EVENT BY THE SPONSOR REGARDLESS OF THE INVESTIGATOR. ALL SERIOUS ADVERSE REACTIONS TO BE REPORTED TO THE SPONSOR AND JUDGMENT ABOUT CAUSALITY AND SERIOUSNESS, BUT ONCE AGAIN THIS IS THE SPONSOR WHO IS RESPONSIBLE FOR EXPEDITED REPORTING, IMPORTANTLY INVESTIGATOR SHOULD BE AWARE OF INDIVIDUAL REQUIREMENTS REGARDING SAFETY REPORTING. OTHER SPONSOR REPORTING RESPONSIBILITIES, SPONSOR SHOULD DEVELOP A PLAN, PRE-DEFINED PLAN DURING PROTOCOL DEVELOPMENT WHERE THE SPONSOR WILL DEFINE EVENTS THAT WILL BE MONITORED AND EXPECTED BUT MONITORS FOR AGGREGATE ANALYSIS TO REPORT EXPEDITIOUSLY IF THESE ANALYSIS FINDS THE OH HAVEN'T OCCURRED AT THE HIGH RATE IN THE ACTIVE FORM. WHEN SUSPECTED, YOU SEE ,NEXPECTED ADVERSE REACTION IS IDENTIFY IN THE SAFE REPORT. SEND THE INFORMATION WITHIN 15 CALENDAR DAYS. AS I MENTIONED BEFORE, SPONSORS SHOULD MONITOR FOR THE FREQUENCY OF EXPECTED ADVERSE EVENTS DURING THE INVESTIGATION. THIS SLIDE SUMMARIZES ASSESSMENT AND REPORTING RESPONSIBILITIES FOR SERIOUS UNEXPECTED ADVERSE REACTION. AS YOU SEE, BOTH SPONSOR AND INVESTIGATOR ASSESS SERIOUSNESS AND CAUSALITY, SPONSOR DEFINES THE EVENT AS UNEXPECTED. IF SPONSOR OR INVESTIGATOR CAN SEE THERE'S EVENTS SERIOUS, THE SPONSOR WILL ASSESS IF IT'S NEEDS TO BE REPORTED EXPEDITIOUSLY BUT IT'S THE REPORT OR NOT REPORT.IBILITY TO WHAT ABOUT SERIOUS ADVERSE EVENTS? ONCE AGAIN, IF IT'S A SINGLE EVENT BUT CAUSALITY IS STRONGLY SUGGESTED BY THE NATURE OF EVENTS, FOR INSTANCE ANAPHYLAXIS, LIVER FAILURE, IT NEEDS TO BE REPORTED. OR IF IT'S EXPECTED ADVERSE REACTIONS BUT ONCE AGAIN AGGREGATE ANALYSIS FOUND THE HIGH FREQUENCY OF THIS EVENT THAT NEEDS TO BE -- THEY NEED TO BE OF TH REPORTED EXPEDITIOUSLY. HOW TO SUBMIT IND SAFETY REPORTS, YOU HAVE TO SUBMIT THEM IN A RELEVANT AGENCY, NARRATIVE FORM, ON THIS SLIDE THEY CAN BE FOUND ON THE WEB, USUALLY SPONSOR USES THIS FORM, 3500-A. AND IF YOU SUBMIT YOUR REPORTS, YOU SHOULD USE A NARRATIVE FORM, THE EASIEST ONES, REPORTING TIME FRAME, NONFATAL OR LIFE-THREATENING, SERIOUS SUBMITTED WITHIN 15 DAYS AS WELL AS DATA FROM AGGREGATE ANALYSIS AND FATAL AND LIFE-THREATENING EVENTS ARE SUBMITTED WITHIN 7 CALENDAR DAYS. OTHER SOURCES FOR EXPEDITED SAFETY REPORTING INCLUDE CLINICAL TRIALS UNDER IND, NONCLINICAL, U EPIDEMIOLOGICAL, LIVER STUDIES, REPORTS FROM FOREIGN AUTHORITIES, MARKETING EXPERIENCE, REGARDLESS OF WHETHER THESE REPORTS AND STUDIES ARE CONDUCTED BY THE SPONSOR OR NOT. ONCE AGAIN, ALL POSSIBLE SCIENTIFIC INFORMATION THAT MIGHT POINT TO SAFETY ISSUES FOR THE PARTICULAR INVESTIGATION. OTHER ISSUES, CASES THAT WILL NOT COMPROMISE THE INTEGRITY OF THE STUDY, IT'S IMPORTANT TO HELP WITH MANAGEMENT OF THE EVENT, SO IF SERIOUS UNEXPECTED ADVERSE EVENTS OCCUR, IT SHOULD BE -- THE SUBJECT SHOULD BE UNBLINDED AND IN GENERAL IF IT OCCURS THAT THE SUBJECT WAS RECEIVING PLACEBO YOU SHOULD NOT REPORT THE EVENT BECAUSE THERE'S A REASON FOR THE CAUSAL RELATIONSHIP BETWEEN THE STUDIED DRUGS IN THIS CASE PLACEBO IN THE EVENT IT'S MINIMAL. BRIEFLY, THEY HAVE TO SUMMARIZE ALL ADVERSE EXPERIENCE DURING THE PAST YEAR, THE ADVERSE EXPERIENCE, BUT IT'S NOT POINT OF OUR DISCUSSION. IN SUMMARY, THE CAUSALITY DETERMINES WHETHER TO REPORT THE EVENT TO US, EXPEDITIOUSLY. THE INDIVIDUAL EVENT SHOULD BE REPORTED ONLY FOR SERIOUS UNSUSPECTED AND SUSPECTED ADVERSE REACTION AND EXPECTED ADVERSE EVENTS REPORTED IN ANING A ANING A AGGREGATE ANALYSIS. THE SPONSOR DETERMINES CAUSE A LITTLCAUSALITY AND REPORTS TO THE FDA TO NOTIFY ALL INVESTIGATORS AS WELL. AND THIS SLIDE CONCLUDES MY PRESENTATION AND PROVIDES YOU WITH RELEVANT REFERENCES TO THE SUBJECT. [APPLAUSE] QUESTIONS? NOBODY? OKAY. >> THANK YOU. OUR NEXT PRESENTER IS NICOLE GRANT, DIRECTOR O OF THE NCI, C.C.R OFFICE, SHE MANAGES OVER 70 IND'S AN. CCR IS RESPONSIBLE FOR ALL SUBMISSIONS TO THE FDA, AND ALL COMMUNICATIONS WITH THE FDA ON BEHALF OF CCR. SO HERE IS NICOLE. >> HELLO. SO MY SLIDES HAVE A LITTLE BIT OF OVERLAP. I'LL BE SKIMMING THROUGH SOME OF THE BEGINNING OF THESE SLIDES FOCUSING ON HANDS-ON PRACTICAL TIPS FOR HOW YOU FIGURE OUT WHAT YOU'RE SUPPOSED TO REPORT AND HOW TO DO IT ON TO THE FDA IF YOU'RE THE SPONSOR. I'LL SKIP THE DEFINITION. WHY DO WE MONITOR FOR ADVERSE EVENTS? WE HAVE TO IDENTIFY EVENTS THAT CAN AFFECT THE SAFETY OF THE PATIENTS. ENSURING THEY ARE NOT HURT. WE NEED TO INFORM REGULATORS, INVESTIGATORS, WHERE I OF THE NEW AND IMPORTANT INFORMATION ABOUT THE EVENT. AND THEN WE HAVE TO PROVIDE A SUMMARY OF THE ADVERSE EXPERIENCES IN ORDER TO DEVELOP THE DRUG OR REGIMEN TOXICITY PROFILE IF YOU'RE TRYING TO DEVELOP THIS DRUG FURTHER. SO WE ALREADY COVERED THE ADVERSE EVENT DEFINITIONS. AND OF COURSE THERE'S LOTS OF TERMS OUT THERE FOR ADVERSE EVENTS BUT THESE ARE NOT AN ADVERSE EVENT. , THSERIOUS ADVERSE EVENT, I'LL SAY I THINK AS INVESTIGATORS WE ARE USED TO REPORTING SAE'S, THAT'S BEEN DRILLED INTO US FROM WHEN YOU WERE FIRST IN MEDICAL SCHOOL OR NURSING SCHOOL IF YOU'RE ASSESSING THEM AS A NURSE, AND I THINK THAT HERE AT THE NIH EVERYONE KNOWS WE'VE RECENTLY TRANSITIONED TO REPORTING UNANSWE UNANTICIPATED PROBLEMS TO THE IRB AND WHAT WE WERE DOING WAS REPORTING JUST SAE'S, THAT'S WHAT WAS HAPPENING TO THE FDA. EVERYBODY WAS REPORTING SAE'S, AND THAT CREATES A LOT OF WHITE NOISE FOR THE FDA TO FIGURE OUT AND IRB'S. SO THEY REVISED THEIR DEFINITIONS. THE FDA REVISED THEIR SAFETY REPORTING REQUIREMENTS. IT'S KIND OF SIMILAR TO A SUSAR, WHAT THE FDA WANTS. SUASAR'S. THEY DON'T WANT TH S AE'S. IT'S SIMILAR. I CAN'T THINK OF A SITUATION WHERE IT WOULD NOT BE ONE OR THE OTHER, OFF THE TOP OF MY HEAD, AT LEAST. HOW DO YOU FIGURE OUT IS THIS A SUSAR OR A UP IN YOU'V U P? YOU HAVE TO ASSESS, EVEN IF THE SPONSORATOR IS NOT THE TO DETERMINE WHAT THE EVENT IS CALLED, HOW SERIOUS IS IT, AND THE MOST IMPORTANTLY, WHAT IS THE ATTRIBUTION. MEDRA IS USED INTERNATIONALLY. SO THE MEDRA IS THE MOST CON VALIDATED MEASUREMENT FOR NAMING AN ADVERSE EVENT, DEVELOPED BY THE ICH, MANAGED BY THE MSSO, USED IN THE U.S., EUROPEAN UNION, AND JAPAN, FOR SAFETY REPORTING, IT'S NOT MANDATED IN THE UNITED STATES BUT IT IS MANDATED IN EUROPE AND JAPAN. SO ANOTHER VERY COMMON TERMINOLOGY THAT'S USED, I WORK IN CANCER, AND SO WE USE THE CTCAE, AND THIS WAS DEVELOPED IN A BRANCH OF THE NCI TO AID IN THE RECOGNITION AND GRADING OF SEVERITY OF ADVERSE EVENTS ON CHEMOTHERAPY. WHAT ESSENTIALLY YOUR PROTOCOL SHOULD DEFINE WHAT TERMINOLOGY YOUR USING, IN CANCER STUDIES WE SAY THIS IS THE TOXICITY CRITERIA WE'RE GOING TO USE. I WOULD ASSUME THAT NONCANCER STUDIES SHOULD LIST WHATEVER TOXICITY CRITERIA THEY ARE GOING TO USE, SO REFER TO YOUR PROTOCOL. SO THEN HOW SEVERE IS THIS? AGAIN, THERE ARE A VARIETY OF SEVERITY RATING SCALES. WHY DO WE HAVE THEM? THEY PROVIDE A SCALE TO MEASURE IMPACT ON THE PARTICIPANT, PROMOTES CONSISTENCY ACROSS ALL AE'S AND PROVIDES GUIDANCE IN EVALUATION AND DOCUMENTATION OF SEVERITY OF THE ADVERSE EVENT AND FACILITATES A COMMON UNDERSTANDING OF THE DATA WHEN YOU SHARE IT ACROSS REGULATORY ENTITIES. SO THIS IS A GENERIC ONE THAT IS USED FOR CLINICAL TRIALS, MILD, MODERATE, SEVERE. WORLD HEALTH ORGANIZATION DEVELOPED THEIR OWN SEVERITY SCALE, ZERO THROUGH FOUR, CONSISTENT WITH MEDRA TERMS, TRANSLATED ACROSS MANY LANGUAGES. FDA HAS A VERY SPECIAL SEVERITY SCALE FOR PREVENTION VACCINE TRIALS, THEY HAVE A GUIDANCE ABOUT IT. AGAIN, YOUR PROTOCOL SHOULD LIST WHAT SEVERITY SCALE YOU ARE USING. AND THEN YOU HAVE TO DETERMINE THE ATRIBUTEION, CA CONSIDER WHAT IS KNOWN ABOUT THE DRUGS, THE THERAPY, INTERVENTION, EXPECTEDNESS, WHAT IS KNOWN ABOUT THE DISEASE YOU'RE STUDYING ACTUALLY? IS THERE A TEMPORAL RELATIONSHIP OF ADVERSE EVENT TO THE STUDY INTERVENTION? IF IT HAPPENED 100 DAYS AFTER THEY GOT THE STUDY AGENT, WELL, WAS IT PROBABLY RELATED? MAYBE NOT, ESPECIALLY IF THE HAD A SHORT HALF-LIFE, PROBABLY NOTE. DOES IT DISAPPEAR WHEN THE AE IS DISCONTINUE AND DOES IT REAPPEAR AT THE SAME SEVERITY WITH THE SAME TIME POINT IF REINTRODUCED? CONSIDER THE FOLLOWING WHEN YOU CONSIDER THE ATTRIBUTION, IS THE A E RESULT OF EXISTING DISEASE OR BASELINE SIGNS OR SYMPTOMS? IS IT A RESULT OF UNDERLYING MEDICAL CONDITIONS THE PERSON HAS? OR UNDERLYING CONCURRENT MEDICATIONS THEY ARE TAKING? SO, AGAIN, YOUR PROTOCOL SHOULD SPECIFY WHAT KIND OF ATTRIBUTION SCALE YOU'RE USING. USUALLY THE DATABASE IS SET UP TO CAPTURE THIS, IT'S RELATED OR NOT RELATED, THE MOST SIMPLE. BUT MOST PROTOCOLS AT LEAST IN MY EXPERIENCE LIKE TO GIVE THIS RANGE, BECAUSE INVESTIGATORS OFTEN DON'T LIKE TO DECLARE RELATED OR NOT RELATED. SO THEY HAVE A RANGE OF UNRELATED UP THROUGH DEFINITE, SO ANYTHING FROM POSSIBLE, PROBABLE OR DEFINITE WOULD BE CONSIDERED A SUSAR, SUSPECTED. SO THE TRICK IS FILLING IN THE BLANKS. WHAT IS IT? WHEN YOU ARE REPORTING TO IRB, THEY ARE LOOKING FOR RELATEDNESS TO RESEARCH, THAT'S THE ENTIRE RESEARCH THAT COULD BE OCCURRING FOR THE PATIENT, FOR EXAMPLE THEY GOT A PIC LINE PUT IN AND HAD A CLOT BECAUSE OF THE PIC LINE, THAT WASN'T BECAUSE OF THE STUDY DRUG. THAT WAS BECAUSE OF THE RESEARCH THAT THEY WERE PARTICIPATING IN. FDA IS LOOKING FOR RELATEDNESS TO THE IND AGENT. SO IF THIS EVENT DID NOT HAVE A TEMPORAL RELATIONSHIP WITH THE IND AGENT, THE FDA DOES NOT WANT YOU TO REPORT IT. THERE MIGHT BE A SITUATION WHERE YOU'RE GOING TO REPORT TO THE FDA, NOT REPORT TO THE FDA BUT REPORT TO IRB BUT I CAN'T THINK OF ANYTIME YOU WOULD REPORT TO THE FDA AND NOT THE IRB BECAUSE THE IND AGENT IS RELATED TO RESEARCH. YOUR SPONSOR COULD WANT ANY OF THESE THINGS. FIGURING THIS OUT WILL HELP YOU DECIDE WHETHER OR NOT YOU NEED TO SEND THIS REPORT TO THESE DIFFERENT REGULATORY GROUPS. WE HAVE TWO DIFFERENT TYPES OF ADVERBS EVENT REPORTING, ROUTINE OR EXPEDITED, A VARIETY OF REGULA REGULATORY GROUPS TO REPORT TO. IF YOU'RE THE SPONSOR YOU HAVE TO REPORT TO THE IBC IF IT INVOLVES GENE THERAPY AND ALSO THE SPONSOR IF YOU'RE THE INVESTIGATORO OR IF YO, OR IF YOU'RE THE SPONSOR TO THE FDA. ROUTINE FDA REPORTING, SO YOU CAN DO A NARRATIVE OR TABULAR SUMMARY, HE REFERRED TO THIS ALREADY ABOUT THE ANNUAL REPORT. I'LL SKIP THAT. AGAIN, IF YOU ARE THE INVESTIGATOR REPORTING TO THE SPONSOR, YOU NEED TO REPORT ANY SAE, WHETHER OR NOT IT IS CONSIDERED RELATED TO THE DRUG. IT'S UP TO THE SPONSOR TO DECIDE WHETHER OR NOT IT GETS SUBMITTED TO THE FDA. AND LET'S SEE. THE SPONSOR HAS TO NOTIFY THE FDA AND ALL PARTICIPATING THEM VIATORS AND THEY NOVEMBER THE IND SAFETY REPORT, THIS WAS ALREADY PRETTY MUCH COVERED, AGAIN, WITHIN 15 DAYS. WHAT IS YOUR SAFETY RECORD INCLUDING? ALL SERIOUS, UNEXPECTED SUSPECTED ADVERSE REACTIONS, FINDINGS, SIGNIFICANT RISK IN HUMANS, INCREASED RATE OF OCCURRENCE OF THE SUSPECTEDDED ADVERSE REACTION. BEFORE YOU SUBMIT THIS REPORT TO THE FDA, YOU NEED TO MAKE SURE THAT THE EVENT MEETS ALL THREE DEFINITIONS. SUSPECTED ADVERSE REACTION, SERIOUS, UNEXPECTED. IF IT'S A FATAL OR LIFE-THREATENING, YOU HAVE SEVEN DAYS TO REPORT IT FROM WHEN YOU'RE NOTIFIED OF THE EVENT. HOW DO YOU REPORT IT? A MANDATORY MED WATCH OR NARRATIVE. -- I'M GOING TOK US ON THE MED FOCUS ON THE MED WATCH. WE'RE SPONSORS, WE DON'T HAVE OVERALL FINDINGS OR POOLED ANALYSIS, WE DON'T HAVE MULTIPLE PROTOCOLS WE'RE ANALYZING UNDER ONE IND. THIS IS AN OLD MED WATCH FORM I FOUND ON THE INTERNET, I COULDN'T PULL OFF THE CURRENT ONE BECAUSE IT'S A PDF PROTECTED FILE. YOU HAVE A MED WATCH. I GAVE YOU ON THE BACK, I DON'T KNOW IF YOU COULD PICK IT UP ON YOUR WAY OUT, HERE IS A CHEAT SHEET WE GIVE INVESTIGATORS WITH TRICKS ON HOW TO FILL OUT THE MED WATCH AND WHAT TO PUT IN THE DIFFERENT BLOCKS. THEY DO GIVE INSTRUCTIONS OF COURSE ON THE MED WATCH FORM. BUT THIS HOPEFULLY WOULD HELP YOU FURTHER. WHAT IS IMPORTANT THAT YOU PUT ON THERE? FIRST OF ALL, THE REPORTER INFORMATION, SUBJECT DEMOGRAPHICS, INFORMATION ABOUT THE STUDY AGENT, DATES GIVEN, DOSE, RATE OF ADMINISTRATION, EVENT, ATR ATTRIBUTE AND NARRATIVE SUMMARY. THE PERSON READING THIS FORM DOESN'T KNOW ANYTHING ABOUT THE PATIENT AND HIS OR HER HISTORY. THIS PART OF THE NARRATIVE SUMMARY PROVIDES THE BACKGROUND INFORMATION NECESSARY TO ASSESS THE EVENT AND SUPPORT TH THE ATTRIBUTION. GIVE INFORMATION THAT DESCRIBES THE EVENT, GIVE THE TIMING RELATIVE TO PRODUCT ADMINISTRATION. SO THE MED WATCH FORM DOESN'T SPECIFICALLY ASK YOU THESE QUESTIONS. YOU HAVE TO REMEMBER TO PUT IT ALL IN A NARRATIVE SUMMARY, THAT'S HARD TO REMEMBER. PUT IN THE ATTRIBUTION. IT DOESN'T ASK WHAT IT IS, SO YOU NEED TO REMEMBER TO PUT THAT IN THE SUMMARY. GIVE REALLY SANT RELEVANT SUBJECT HISTORY . WHERWHEN YOU LIST CON COME CONCOMITANT ME DS, DON'T USE WHAT TREATED THE EVENT, THIS IS LOOKING FOR UNDERLYING MEDICATIONS THAT COULD CONTRIBUTE TO THE EVENT. WHAT DO YOU DO IF ONLY LIMITED INFORMATION IS AVAILABLE? WHAT IF YOU'RE CONTACTED BY THE PATIENT'S LOCAL PHYSICIAN AND THE PERSON WENT HOME IN BETWEEN CYCLES OF THERAPY AND YOU'RE IN NORTH DAKOTA AND THIS PERSON GOT ADMITTED, IT'S LIFE-THREATENING, YOU'VE GOT SEVEN DAYS TO FILE THE REPORT, I'M THE SPONSOR, GET AS MUCH INFORMATION AS YOU CAN, DOCUMENT ALL THE AND SUBMIT WHAT YOU HAVE ANDIONS PROVIDE A PLAN AND SUMMARY OF THE EVENT AND TREATMENT TO DATE. WHEN ADDITIONAL INFORMATION BECOMES AVAILABLE, THEN YOU SUBMIT AN AMENDED REPORT. DON'T THINK, OH, I'VE GOT TO WAIT UNTIL I GET ALL THE INFORMATION TO SUBMIT THIS IN THREE WEEKS. NO. SUBMIT WITHIN THE SEVEN DAYS. AND THEN SUBMIT AN AMENDED REPORT. SO AS A GENERAL RULE, FOLLOW-UP IS REQUIRED WHEN THERE'S A CHANGE IN CAUSE OR RELATEDNESS OF EXPERIENCE, FOR EXAMPLE, NEW INFORMATION ON A DEATH BECOMES AVAILABLE. WHAT IF YOU SENT IN A REPORT BECAUSE SOMEONE DIED AND DID AN AUTOPSY AND TWO MONTHS LATER HAVE THE RESULTS, NOW YOU SEE IT WAS ACTUALLY RELATED TO DISEASE ROCK PRESS AN PROGRESSION AND NOT OAR DRUGS, YOU SUBMIT AN AMENDED REPORT WITH THE AUTOPSY REPORT WITH REDACTION, OF COURSE, OR IF THE FDA REQUESTS MORE INFORMATION, THEY MAY. SO YOU DON'T HAVE TO SUBMIT A FOLLOW-UP REPORT WHEN YOUR. YOUR A E RESOLVES. IF IT RESOLVE ALSO AT DAY 28 DOESN'T MEAN YOU HAVE TO FILE ANOTHER REPORT BECAUSE YOU'LL PUT THAT IN YOUR MEDICAL REPORT AND REPORT THAT EVENT ALSO IN YOUR ANNUAL REPORT. SO REMEMBER, EXPEDITED EVENTS ARE A SUBSET OF EXPEDITED EVENTS, THE OTHER THING TO REMEMBER, ANYTHING THAT YOU PUT ON YOUR EXPEDITED ADVERSE EVENT FORM ON YOUR MED WATCH MUST BE PRESENT IN SOURCE DOCUMENTS. EVERYBODY SHOULD BE IN YOUR SOURCE DOCUMENTS, ALSO REPORTED ON YOUR CASE REPORT FORMS. IF THE FDA EVER COMES TO DO AN INSPECTION, THEY ARE GOING TO WANT TO SEE ALL THE SOURCE DOCUMENTS THAT SUPPORT WHAT YOU'VE SUBMITTED TO THEM. APPLICABLE REALL REGULATIONS ALSO. [APPLAUSE] >> ANY QUESTIONS FOR NICOLE? >> I DO HAVE A QUESTION. THE RELATIONSHIP BETWEEN AN INVESTIGATOR AND SPONSOR IS SOMETHING I DON'T SEE MUCH OF. I DON'T HAVE A FEEL FOR IT WORKING AT FDA. SO MY QUESTION IS TO THE INVESTIGATORS IN THE AUDIENCE, AND TO YOU, IF YOU FILL OUT A MED WATCH FORM AND YOU THINK OR YOU CONCLUDE AS THE INVESTIGATOR THAT IT IS PROBABLY OR POSSIBLY RELATED TO THE STUDY DRUG, AND YOU SUBMIT THAT TO THE SPONSOR, OF COURSE, WHERE DO THINGS -- HOW DO THINGS TYPICALLY GO FROM THERE? WHAT'S THE INTERACTIONS BETWEEN THEN THE SPONSOR AND THE INVESTIGATOR? FOR EXAMPLE, IS THE SPONSOR ABSOLUTELY OBLIGATED TO PASS ON THAT MED WATCH FORM WHEN THE INVESTIGATOR BELIEVES THAT IT'S RELATED TO DRUG, OR CAN THE SPONSOR JUST DISAGREE AND MAKE THEIR OWN CONCLUSION? HOW IS THAT DYNAMIC WORK? >> THE SPONSOR CAN DISAGREE AND MAKE THEIR OWN CONCLUSION BECAUSE THEY ARE ULTIMATELY RESPONSIBLE FOR REPORTING THAT TO THE FDA AND OTHER INVESTIGATORS STUDYING THAT STUDY DRUG AND ULTIMATELY ADDING TO THE INVESTIGATOR BROCHURE. HERE WE HAVE KIND OF AN INTERESTING DYNAMIC BECAUSE ON SOME OF OUR IND'S, OUR DIVISION, THE CENTER FOR CANCER RESEARCH, ACTS AS A SPONSOR FOR INVESTIGATORS HERE. IN SOME CASES THE SPONSOR IS THE INVESTIGATOR. THE SPONSOR IS THE INVESTIGATOR, THEY CAN DO WHATEVER THEY WANT, RIGHT? BECAUSE THEY ARE THE SPONSOR AND THE INVESTIGATOR. BUT OTHERWISE, IF THE INVESTIGATOR IS HERE, AND THEY SUBMIT A REPORT TO US AS THE CCR, AS THE SPONSOR, THE PHYSICIAN WHO ESSENTIALLY IS THE NAME ON THE IND AS THE SAR GETS TO DECIDE IF HE THINKS IT MEETS CRITERIA TO REPORT TO THE FDA. SOMETIMES HE DOES NOT. HE WILL TELL THE INVESTIGATOR HERE WE'RE NOT GOING TO SUBMIT THIS. WE DON'T THINK IT'S RELATED. AND THEN IT'S DONE. >> I COULD JUST OFFER A PERSPECTIVE FOR INTERACTION WITH INDUSTRY SPONSORS. WHAT TYPICALLY HAS HAPPENED IN OUR CASE IS WHEN WE SUBMIT THE REPORT TO THE SPONSOR THAT GENERATES AN ALMOST IMMEDIATE PHONE CALL FROM THE MEDICAL DIRECTOR OF THE SPONSOR TO INTERACT WITH US, TO ASK QUESTIONS, TO GET MORE DETAIL. TO THEN MODIFY THEIR REPORT THAT THEY SENT ON. I CAN'T THINK OF MANY EXAMPLES OR ANY EXAMPLES WHERE THEY HAVE NECESSARILY DISAGREED, BUT THEY HAVE ASKED QUESTIONS ABOUT RELATEDNESS IN OTHER DETAILS TO MAKE SURE THAT WE'VE REPORTED OUT ACCURATE INFORMATION IN IT. >> I'LL ADD ONE MORE THING ABOUT THE MED WATCH IN TERMS OF THE SPONSOR REQUESTING MORE INFORMATION. OFTEN TIMES, WE SUBMIT INCOMPLETE REPORTS TO OUR SPONSORS. SO THEY DO NEED MORE INFORMATION. BUT ALSO WHEN YOU DO SUBMIT A REPORT, HAVE ANOTHER PERSON READ IT. KIND OF LIKE THE PERSON THAT SAID WRITE THE PROTOCOL, HAVE ANOTHER PERSON READ IT. HAVE SOMEONE READ THAT ADVERSE EVENT REPORT BEFORE YOU SUBMIT IT TO THE SPONSOR OR FDA TO MAKE SURE THE STORY MAKES SENSE AND ALL THE INFORMATION IS THERE. >> I THINK IT'S A GOOD QUESTION, SOMETIMES IT'S COMPLEX, FOR INSTANCE, ONE SPONSOR AND MORE THAN TWO OR THREE INVESTIGATORS ON EACH SIDE, THE SIDES COULD BE HEADED IN MANY COUNTRIES. I MEAN, IT WOULD BE VERY HARD FOR US AND FOR THE INVESTIGATOR TO DECIDE WHAT TO SUBMIT AND WHEN AND HOW. IT'S REASONABLE TO EXPECT THE SPONSOR TO FILTER AND BIGGER PICTUREI CAN ABOUTER OF WHAT TO PASS TO THE AGENTS AND TO SEE WHAT'S GOING ON THERE. >> THANK YOU. ANY OTHER QUESTIONS? OKAY. WE HAVE A 15-MINUTE BREAK SO OUR LAST SESSION TODAY IS ABOUT THE LONG AWAITED EXPANDED ACCESS PROGRAM. EXPANDED ACCESS TO INVESTIGATIONAL DRUGS. THAT WOULD RELATE TO IND APPLICATIONS SUPPORTING CLINICAL TREATMENTS. AND OUR FIRST SPEAKER TODAY IS COLLEEN LOCICERO, SHE'S THE ASSOCIATE DIRECTOR IN REGULATORY AFFAIRS IN THE OFFICE OF DRUG EVALUATION ONE, IN THE OFFICE OF NEW DRUGS, SHE'S BEEN IN THAT POSITION SINCE 2002, PRIOR TO THAT WORKED AS A PROJECT MANAGER IN THE DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS, AND SHE'S BEEN WITH FDA SINCE 1998. SO, COLLEEN, IN FACT WORKED IN THE DEVELOPMENT OF THE PROPOSED RULE AND FINAL RULE RELATED TO EXPANDED ACCESS TO INVESTIGATIONAL DRUGS, FOR TREATMENT USE, AND THE FINAL RULE WAS ISSUED IN AUGUST OF 2009. SHE HAS ALSO WORKED ON THE DEVELOPMENT OF THE GUIDANCE FOR EXPANDED ACCESS TO INVESTIGATIONAL DRUGS FOR TREATMENT USE, QUESTIONS AND ANSWERS, GUIDANCE AVAILABLE ONLINE THROUGH THE FDA.GOV WEBSITE. HER ACTIVE PARTICIPATION IN THE EXPANDED ACCESS PROGRAM AND ITS IMPLEMENTATION BROUGHT HER THE IDENTIFICATION AS THE REGULATORY CONTACT FOR QUESTIONS REGARDING ANYTHING THAT HAS TO DO WITH EXPANDED ACCESS. COLLEEN, WE'RE READY TO HEAR YOU. >> OKAY. THANKS, LARISSA. I APPRECIATE THE INTRODUCTION. I'M COLLEEN LOCICERO FROM THE OFFICE OF DRUG EVALUATION ONE AND INVOLVES OF NEW DRUGS,ED A CDER AT FDA. I'M GOING TO TALK ABOUT EXPANDED ACCESS TO INVESTIGATIONAL DRUGS FOR TREATMENT USE. YOU CAN ALCAN YOU ALL HEAR ME? OKAY. I'LL START WITH BACKGROUND. IN THE PAST WE'VE HAD TO DO THIS THROUGH INFORMAL MEMBER MECHANISMS BECAUSE REGS FAILED TO KEEP UP WITH PRACTICE IN HOV, ONCOLOGY, THERE'S NO EXPLICIT MENTION OF TREATMENT USE AND EXPANDED ACCESS, USED INTERCHANGEABLE, BUT INVESTIGATIONAL DRUGS WERE MADE AVAILABLE THROUGH INFORMAL MECHANISMS, YOU MAY HAVE HEARD SOME OF THESE TERMS, COMPASSIONATE USE, SINGLE PATIENT PROTOCOL, EXCEPTIONS. NOW THAT WE HAVE SOLID REGULATIONS WE TRY TO AVOWED OF THOSE TERMS BECAUSE THEY CAN LEAD TO CONFUSION BUT I WANT TO THE MENTION THEM BECAUSE YOU'RE PROBABLY FAMILIAR WITH THEM. A VAST MAJORITY OF ACCESS WE FILL OUT OVER THE YEARS IS FOR INDIVIDUAL PATIENTS, IN 1987 THE AGENCY FORMIZED REGULATION AND TREATMENT IND AND EMERGENCY IND MECHANISMS BUT BECAUSE THAT DIDN'T REALLY CAPTURE ALL OF THE TYPE OF ACCESS THAT WE ALLOWED, WE REVISED REGULATIONS IN 2009 IN THE FINAL RULE, EXPANDED ACCESS, TO INVESTIGATIONAL DRUGS FOR TREATMENT USE. SO THE 2009 REGULATIONS ACTUALLY REFLECT PROVISIONS FROM SECTION 561, OF THE 1997 FOOD AND DRUG ADMINISTRATION ACT. SECTION 5 61 PROVIDES ACCESS TO INVESTIGATIONAL DRUGS, IN EMERGENCY SITUATIONS, FOR INDIVIDUAL PATIENTS, OR SMALL GROUPS OF PATIENTS IN NONEMERGENCY SITUATIONS, AND THEN FOR WIDESPREAD ACCESS THROUGH TREATMENT IND'S AND TREATMENT PROTOCOLS. AS LARISSA MENTIONED, THE FINAL RULE WAS PUBLISHED IN AUGUST OF 2009 AND WENT INTO EFFECT OF OCTOBER THAT YEAR RECOGNIZING THE PRIMARY GOAL OF ACCESS IS TREATMENT AS OPPOSED TO PRIMARY GOAL OF OTHER CLINICAL TRIALS WHICH ARE TO GENERATE INFORMATION ABOUT THE DRUG. THE SERIOUSNESS OF THE DISEASEEASES AS DECREASES AND NUMBER OF PATIENTS TO BE EXPOSED INCREASES. IN OTHER WORDS, FDA NEEDS MORE EVIDENCE OF SAFETY AND EFFICACY TO ALLOW A TREATMENT IND WHERE THERE'S A POTENTIAL FOR WIDESPREAD EXPOSURE TO AN INVESTIGATIONAL DRUG FOR A SERIOUS BUT NOT LIFE-THREATENING DISEASE, THEN WE DO TO ALLOW A SINGLE PATIENT ACCESS PROGRAM FOR A PATIENT WITH A LIFE-THREATENING DISEASE TO PROCEED. SO THE ACCESS REGULATIONS THEN DESCRIBE THREE TREATMENT USE SCENARIOS BASED PRIMARILY BUT NOT SOLELY ON THE NUMBER OF PATIENTS TO BE TREATED, BUT ALLOW FOR RIGOROUS REQUIREMENTS WITH INCREASING EXPOSURE. THE REGS TRY TO BALANCE THE COMPETING INTERESTS THAT ARE INHERENT TO ALLOWING ACCESS TO INVESTIGATIONAL THERAPIES. THAT IS TO ALLOW ACCESS TO TOESTIGATIONABLE THERAPIES PATIENTS WITH SERIOUS OR LIFE-THREATENING DISEASES, TO IMPEDE MARKETING BY ENTIRE FEARING WITH CLINICAL TRIALS BY COMPETING FOR PATIENTS, PATIENTS, IF GIVEN THE CHOICE, A LOT OF TIMES WOULD OPT FOR OBTAINING ACCESS THROUGH AN ACCESS PROTOCOL AS OPPOSED TO RIGORS REQUIRED OF PARTICIPATION IN A CLINICAL STUDY. AND MINIMIZING RISK TO PATIENTS. THIS IS JUST AN OVERVIEW OF WHERE THE ACCESS REGS ARE LOCATED. THE GENERAL ACCESS REGS START OUT BY, AGAIN, EMPHASIZING THAT EXPANDED ACCESS IS FOR THE TREATMENT OF PATIENTS AND NOT TO GATHER INFORMATION ABOUT THE DRUG. IT ALSO EXPLAINS IT CAN BE USED TO PROVIDE ACCESS TO APPROVED DRUGS WHERE THE AVAILABILITY OF THAT DRUG IS LIMITED, FOR PATIENTS WHO DON'T MEET CRITERIA PROVIDED THEY MEET CRY CRITERIA FOR ACCESS. WE MUST MAKE A DETERMINATION THAT THE POTENTIAL BENEFIT JUSTIFIES THE POTENTIAL RISKS, AND THAT THE POTENTIAL RISKS ARE NOT UNREASONABLE IN THE CONTEXT AND ACCESS WILL NOT INTERFERE WITH THE CLINICAL TRIALS TO SUPPORT APPROVAL OF THAT EXPANDED ACCESS USE. THE SUBMISSION REQUIREMENTS ARE ON SLIDE A, I'M NOT GOING TO GO THROUGH ALL OF THEM. WE DO RECOGNIZE IN THE REGS MUCH OF THE REQUIRED INFORMATION CAN BE SUPPLIED BY REFERENCING AN EXISTING APPLICATION, FOR EXAMPLE A COMMERCIAL IND, PROVIDED SPONSOR OF THE EXISTING APPLICATION GRANTS THE RIGHT OF REFERENCE TO THE ACCESS SPONSOR. WE SEE QUITE A LOT OF THAT WITH IT, IN PARTICULAR OUR SINGLE PATIENT IND'S. THE REGS SPECIFY THAT THE EXPANDED ACCESS SUBMISSIONS ARE TO BE PLAINLY MARKED. THE REASONS ARE WE WANT TO MAKE SURE THEY GET PROMPT ATTENTION, AND ALSO WE GET AN AWFUL LOT OF INQUIRIES ABOUT THE NUMBER OF ACCESS REQUESTS WE RECEIVE AND THE NUMBER THAT WE ALLOW TO PROCEED, AND IF THEY ARE PLAINLY MARKED IT FACILITATES OUR TRACKING, ENABLES US TO RESPOND TO QUESTIONS. HERE WE ACTUALLY UPDATED OUR 1571 FORM WITHIN THE PAST I WOULD SAY 18 MONTHS, TO INCLUDE ALL THE DIFFERENT TYPES OF EXPANDED ACCESS WE WE HOPE INVESTIGATORS CHECK THEM TO FACILITATE OUR TRACKING. THE SAFE GUARDS THAT APPLY TO ALL TYPES OF EXPANDED ACCESS, INFORMED CONSENT MUST BE OBTAINED. THERE MUST BE IRB REVIEW AND APPROVAL OF THE PROGRAM. ALL ACCESS PROGRAMS WITH SUBBED TO IND REQUIREMENTS AND CLINICAL HOLD PROVISION, THE SPONSOR MUST PROVIDE AN INVESTIGATORSBORO SURE TO PROVIDED ONE EXISTS FOR THE DRUG. NOW, THE CRITERIA AND SUBMISSION REQUIREMENTS THAT I JUST MENTIONED APPLIED TO ALL THE DIFFERENT TYPES OF ACCESS, BUT THERE ARE SOME CRITERIA AND SAFE GUARDS UNIQUE TO THE SARASOTAOUS TYPES OF ACCESS. VARIOUS TYPES OF ACCESS. THE FIRST IS SINGLE PATIENT ACCESS, UNDE THIS IS ACCESS FOR ONE PATIENT. THE CRITERIA UNIQUE TO INDIVIDUAL PATIENT ACCESS IS PHYSICIAN MUST DETERMINE THE PROBABLE RISK FROM THE DRUG DOES NOT EXCEED THAT FROM THE DISEASE, AND FDA MUST DETERMINE THE PATIENT CANNOT OBTAIN ACCESS UNDER ANOTHER IND OR PROTOCOL. THE SAFEGUARDS THAT ARE UNIQUE, TREATMENT IS LIMITED TO ONE COURSE, THAT DOES NOT PRECLUDE TREATMENT FOR AN EXTENDED DURATION, FOR EXAMPLE THE TREATMENT OF A CHRONIC DISEASE. IF THE EVIDENCE SUPPORTS THAT. IT JUST MEANS THAT WE WANT TO MAKE SURE THERE'S DISCUSSION BETWEEN FDA AND THE SPONSOR AS TO THE DURATION OF THE TREATMENT AND THE SPONSOR JUST DOESN'T GO OFF AND TREAT THE PATIENT FOR AN UNSPECIFIED DURATION. IF WE DO AUTHORIZE ACCESS FOR AN EXTENDED DURATION, WE MAY REQUIRE SPECIAL MONITORING. FOR ALL INDIVIDUAL PATIENT OR SINGLE PATIENT ACCESS PROGRAMS, WE REQUIRE WRITTEN SUMMARY AT THE END OF THE TREATMENT. NOW, IF WE GET A SIGNIFICANT OR CONSIDERABLE NUMBER OF REQUESTS FOR SINGLE PATIENT ACCESS, FOR THE SAME DRUG, FOR THE SAME USE, WE -- IT'S IN MOST EVERYBODY'S BEST INTEREST IF WE APPROACH THE DEVELOPER OF THE DRUG AND ASK THEM TO CONSIDER TO CONSOLIDATE ALL OF THE SINGLE PATIENT ACCESS INTO AN INTERMEDIATATE SIZE ACCESS PROGRAM WHICH I'LL TALK ABOUT NEXT. THAT MAKES IT EASIER ON US ADMINISTRATIVELY AND MAKES IT EASIER ON ANY SUBSEQUENT PHYSICIANS WHO WANT ACCESS TO THAT DRUG, THEY DON'T HAVE TO SUBMIT THEIR OWN IND AND MAINTAIN AN IND. IT'S ACTUALLY IN THE BEST INTEREST OF THE DEVELOPER AS WELL BECAUSE IT CONSOLIDATES ANY INFORMATION THAT THEY MIGHT BE ABLE TO GET FROM ACCESS WHICH IS LIMITED, BUT IT'S POSSIBLE INTO A SINGLE PROGRAM RATHER THAN A BUNCH OF DIFFERENT PROGRAMS UNDER DIFFERENT SPONSORS. SO THEN AS PART OF THE INDIVIDUAL PATIENT REGULATIONS THERE'S AN EMERGENCY PROVISION. AND THAT ALLOWS FOR EMERGENCY ACCESS, SO IT'S A SUBSET OF INDIVIDUAL PATIENT ACCESS BECAUSE IT APPLIES TO SINGLE PATIENTS ONLY. YOU CAN'T GET EMERGENCY ACCESS TO INVESTIGATIONAL DRUGS FOR MULTIPLE PATIENTS. IT'S TO BE USED ONLY IN A TRUE EMERGENCY, WHEN THE PATIENT NEEDS TREATMENT BEFORE WRITTEN SUBMISSION CAN BE MADE. EMERGENCY USE CAN BE AND GENERALLY IS AUTHORIZED OVER THE PHONE. A FOLLOW-UP WRITTEN SUBMISSION MUST BE MADE TO THE FDA WITHIN 15 DAYS, IF THEY HAVE TELEPHONE AUTHORIZATION. AN ENTER MADATE SIZ ENTER INTERMEDIATATE ARE FOR MORE THAN ONE PATIENT WILL YOU LESS THAN WE WOULD EXPECT FOR -- BUT LESS THAN TREATMENT PROTOCOL WHICH HAS THE POTENTIAL TO BE THOUSANDS OF PATIENTS. AND BECAUSE WHEN THE REGS IN 2009 CAME OUT, THIS WAS THE FIRST TIME WE HAD ARTICULATED AND PUT IN WRITING ANYTHING ABOUT THIS TYPE OF ACCESS, IT STARTS WITH SOME EXAMPLES OF SCENARIOS WHERE WE THINK AN INTERMEDIATE ACCESS PROGRAM MIGHT BE APPROPRIATE. A DRUG NOT BEINGRUG NOD BEING DEVELOPED, A DISEASE SO RARE YOU CAN'T DESIGN A TRIAL TO DECIDE WHETHER THE DRUG IS SAFE AND EFFECTIVE BUT YOU WANT TO ALLOW PATIENTS WHO MIGHT BENEFIT FROM THE DRUG ACCESS TO IT YOU MIGHT ALLOW IT UNDER AN ENTIRE IMMEDIATEAT SIZE ACCESS PROGRAM. IF YOU HAVE A DRUG THAT'S BEING DEVELOPED BUT YOU HAVE A CONSIDERABLE NUMBER OF PATIENTS WHO ARE NOT ELIGIBLE FOR ONE REASON OR ANOTHER, WE MIGHT AUTHORIZE ACCESS TO THOSE ENTIRES UNDER AN ENTIRE POPULATION PROGRAM. IF YOU HAD A DRUG THAT WAS APPROVED AND ON THE MARKET, AND THEN WAS WITHDRAWN FOR A SAFETY REASON, BUT YOU HAD A SUB-POPULATION OF GENERAL PATIENT POPULATION FOR WHICH WE FELT THE BENEFITS CONTINUE TO OUTWEIGH THE RISKS, WE MIGHT ALLOW ACCESS TO THAT DRUG TO THOSE PATIENTS UNDER AN INTERMEDIATE ACCESS PROGRAM. OR IF WE HAD A DRUG SHORTAGE, IN THIS COUNTRY, AND WE'RE ABLE TO GET A EUROPEAN VERSION, AND IMPORT IT. WE MIGHT ALLOW ACCESS TO THE PATIENTS WHO NEED THAT DRUG UNDER AND INTERMEDIATATE SIZE ACCESS PROGRAM. THERE MUST BE ENOUGH EVIDENCE IF THE DRUG IS SAFE TO JUSTIFY THE SIZE AND PRELIMINARY EVIDENCE OF AN EFFECT. THE SUBMISSION REQUIREMENTS, THE SUBMISSION IS TO INCLUDE A STATEMENT WHETHER THE DRUG IS BEING DEVELOPED OR NOT DEVELOPED, A DESCRIPTION OF THE PATIENT POPULATION, AND EXPLANATION OF WHY THE DRUG CANNOT BE DEVELOPED OR WHY THESE PATIENTS CANNOT BE ENROLLED IN THE CLINICAL TRIAL. THE SAFE GUARDS INCLUDE AN FDA ANNUAL REVIEW AND ASSESSMENT OF WHETHER TREATMENT USE SHOULD CONTINUE, WHETHER IT MIGHT BE POSSIBLE TO CONDUCT A STUDY, IF IT'S NOT BEING DEVELOPED, OR IF IT IS BEING DEVELOPED WHETHER ACCESS IS INTERFERING WITH DEVELOPMENT. WHETHER ACCESS UNDER TREATMENT IND OR PROTOCOL MIGHT BE MORE APPROPRIATE AT THIS POINT IN TIME. THERE'S ALSO A REQUIREMENT FOR MONITORING TO ENSURE THAT THE LICENSED PHYSICIANS ARE COME PRICE WITH THCOMPLYING WITH PROTOCOL AND REGULATIONS. THE REG TALK ABOUT TREATMENT IND OR PROTOCOL, BEING DEVELOPED FOR MARKETING APPROVAL, THE POTENTIAL FOR THOUSANDS OF PATIENTS TO GET ACCESS UNDER THIS TYPE OF ACCESS PROGRAM. THE CRITERIA ARE THAT THE DRUG IS BEING INVESTIGATED IN CLINICAL TRIALS, OR THE TRIALS ARE COMPLETED AND THE COMPANY IS ACTIVELY PURSUING MARKETING APPROVAL. SO TREATMENT IND'S AND TREATMENT PROTOCOLS ARE DIFFERENT FROM SINGLE PATIENT ACCESS AND INTERMEDIATATE ACCESS IN THAT THE DRUG HAS TO BE BEING DEVELOPED. THERE MUST BE SUFFICIENT EVIDENCE OF SAFETY AND EFFECTIVENESS, AND THE EVIDENCE REQUIREMENTS DIFFERS WHETHER THE USE IS FOR A SERIOUS OR LIFE-THREATENING DISEASE. AND THEN THE SAFEGUARDS INCLUDE A 30-DAY POST SUBMISSION WAIT, BEFORE INITIATING TREATMENT FOR BOTH TREATMENT IND'S AND PROTOCOLS, FOR SINGLE PATIENT AND INTERMEDIATE SIZE PROTOCOLS SUBMITTED TO AN EXISTIN EXISTING IND BUT FOR NO 30-DAY WAIT, LIKE TREATMENT PROTOCOLS BECAUSE OF THE POTENTIAL TO EXPOSE SO MANY PATIENTS, WE IMPOSED A 30-DAY GOTOD TO MAKE SURE WE'VE WE ADEQUATE TIME AND MONITORING TO ENSURE THE PHYSICIANS ARE COME PRICE WITCOME -- COMPLYING WITH PROTOCOLS AND REGS. WHAT TO EXPECT FROM FDA IF YOU SUBMIT AN ACCESS -- MAKE AN ACCESS SUBMISSION? EXPECT A LETTER THAT REMINDS YOU OF THE 30-DAY WAIT. FOR ALL ORIGINAL IND'S, TREATMENT WITH THE INVESTIGATIONAL DRUG CAN BEGIN 30 DAYS AFTER FDA RECEIVES THE IND, OR ON EARLIER NOTIFICATION BY FDA. I HAVE UNDERLINED THAT BECAUSE A LOT OF OUR DIVISIONS THAT RECEIVE A LOT OF SINGLE PATIENT ACCESS PROGRAMS WILL AUTOMATICALLY GO AHEAD AND WAIVE THE 30-DAY SAFETY PERIOD, THEY WILL NOTIFY THE SPONSOR THAT THEY CAN PROCEED WELL BEFORE 30 ARE UP. IF THE DIVISION DOESN'T AUTOMATICALLY DO THAT, YOU CAN REQUEST A WAIVER OF THE 30 DAY SAFETY PERIOD, AND HOPEFULLY THEY WILL GRANT IT TO YOU. THE EXCEPTION FOR THE 30-DAY WAITING PERIOD BESIDES THE WAIVER IS THE EMERGENCY IND TREATMENT USE CAN BEGIN WHEN THE TREATMENT IS AUTHORIZED BY THE FDA OFFICIAL OVER THE PHONE. NOW, WHAT YOU MIGHT EXPECT TO GET FROM FDA IS YOU MIGHT GET A STUDY MAY PROCEED LETTER, BUT THAT'S NOT REQUIRED, BECAUSE IF YOU DON'T HEAR FROM FDA WITHIN 30 DAYS, YOU CAN GO AHEAD AND START REGARDLESS. UNLESS OF COURSE THE IND IS PUT ON CLINICAL HOLD, IN THAT CASE THE NOTIFICATION YOU WOULD GET IS NOTIFICATION OF CLINICAL HOLD, THAT'S GENERALLY DONE OVER THE PHONE WITH THE FOLLOW-UP CLINICAL HOLD LETTER AND THE TREATMENT CAN'T PROCEED UNTIL THE HOLD IS RESOLVED OR LIFTED. NOW, FOR AN EMERGENCY IND THE ONLY THING TO EXPECT FROM FDA IS AN ACKNOWLEDGEMENT LETTER THAT REMINDS THE SPONSOR OF THE REQUIREMENT FOR THAT FOLLOW-UP WRITTEN SUBMISSION. FOR INTERMEDIA SIZE PATIENT POPULATION AND TREATMENT IND'S, PRETTY MUCH THE SAME THING. AN ACKNOWLEDGEMENT LETTER REMINDING THE SPONSOR OF THE 30-DAY WAIT, OPTIONAL CORRESPONDENCE MAY BE A STUDY MAY PROCEED LETTER AND IF ACCESS PROGRAM IS PUT ON HOLD THEN NOTIFICATION OF THE CLINICAL HOLD WITH THE FLIP FOLLOW-UP CLINICAL HOLD LETTER. THESE SLIDES PROVIDE SOME RESOURCES THAT YOU MIGHT BE INTERESTED IN, THAT TALK ABOUT ACCESS, THE REGULATIONS, THE RULES. THE MAP ON TREATMENT IND'S AND PROTOCOLS, DRAFT GUIDANCE, AND THE OFFICE HAS A GOOD WEBSITE PARTICULARLY GOOD FOR INDIVIDUAL INVESTIGATORS. THANK YOU FOR YOUR TIME. [APPLAUSE] >> THANK YOU, COLLEEN. OUR NEXT SPEAKER IS DR. KEN OLIVIER, TOP CLINICIAN IN THE CLANNER TO OF CLINICAL INFECTIOUS DISEASES IN.THE NIAID, INVESTIGATOR OF SEVERAL TREATMENT PROTOCOLS AND LOCAL NEUTRAL HISTORY COHORT, PATHOGENESIS ON CHRONIC AIRWAY DISEASE. HE WILL SHARE HIS PERSPECTIVE ON EXPANDED ACCESS IND APPLICATIONS. >> THANK YOU FOR THE INI INVITATION. I WORK PRIMARILY IN RARE AND NEGLECTED INFECTIONS THAT INVOLVE THE LUNG, AND MANY OF THEM DON'T HAVE A LINE OF INDUSTRY SPONSORS WAITING AT THE DOOR TO DEVELOP DRUGS, AND TO FIND TREATMENTS FOR SOME OF THESE PATIENTS IT'S REQUIRED A BIT OF IMAGINATION AND ESPECIALLY WHEN TREATMENT FAILURE HAS OCCURRED, I HAVE KNOCKED ON THE FDA'S DOOR SEVERAL TIMES IN THE PAST. NOT ALL OF THESE EXAMPLES HAVE FIT NEEDLY INTO THESE EXPANDED NEATLY INTO THEFEETLY INTO THE EXPANDED CATEGORIES. ONE DRUG WAS DEVELOPED IN 1970'S AS A TREATMENT FOR TUBERCULOSIS, IN THE '80s IT WAS FOUND TO BE USED FOR THE TREATMENT OF HEL LEPROSY AND HAS AN INDICATION FOR TREATMENT OF LEPROSY, THE MANUFACTURER OF THE DRUG TOOK IT OFF THE MARKET IN 2004, AND IT WAS RECOGNIZED IT ALSO HAD ACTIVITY AGAINST A NUMBER OF OTHER NONTUBERCULOSIS MICRO BACTERIA, A PROGRAM ALLOWED INDIVIDUAL USE IND APPLICATIONS TO OBTAIN THE DRUG. IS THESE NONTUBERCULI INFECTIONs BECAME MORE PREVALENT, IND ACCESS BECAME MORE FREQUENT. WE WERE ASKED BY THE FDA AFTER 2009 TO TRY TO CONSOLIDATE OUR PATIENTS INTO AN ENTIR ENTIRE INTERMEDIATE GROUP EXPANDED ACCESS PROGRAM THAT WAS DIFFICULT FOR A NUMBER OF REASONS. THE SPONSOR WAS NOT INTERESTED IN PURSUING THIS OUTSIDE OF THE LIMITED USE OF THE DRUG THAT WAS AVAILABLE, BUT WE DID GO THROUGH THE STEPS OF TRYING TO PUT THAT TOGETHER. WE'VE HAD OTHER EXPERIENCES WITH DRUGS THAT ARE MANUFACTURED OUTSIDE OF THE U.S. FOR RARE DISEASES, RARE INFECTIONINGS NOT PREVALENT IN THE U.S. AND HAVE UTILIZED THIS PROGRAM TO OBTAIN THOSE DRUGS WHEN THEY HAVE BEEN REFERRED INTO THE NIH FOR TREATMENT. HOWEVER, IN THE NEXT FEW MINUTES I'D LIKE TO TALK ABOUT AN EXAMPLE THAT INVOLVED A DRUG THAT WAS A BIT OUT SIDE OF MY AREA OF EXPERTISE BUT I'D LIKE TO WALK YOU THROUGH OUR EXPERIENCE USING THE EMERGENCY ACCESS PROGRAM FOR THIS. MY BIGGEST DISCLOSURE IS THAT I'M NOT AT ALL AN EXPERT ON THIS TOPIC. I'VE RELIED ON THE RESOURCES THAT ARE LISTED HERE AND I THINK THAT ONE OF THE NICE THINGS ABOUT BEING HERE AT THE CLINICAL CENTER IS THAT WE HAVE A WEALTH OF RESOURCES AND A NUMBER OF PEOPLE WITH CONSIDERABLE EXPERIENCE THAT WHILE THEY MAY NOT EXACTLY KNOW YOUR PARTICULAR INTEREST OR DESIRE FOR OBTAINING THE DRUG, THEY ARE VERY GOOD AT POINTING IN THE RIGHT DIRECTIONS TO GET YOU WHERE YOU NEED TO GO. SO FOR THIS PARTICULAR CASE, WE CONSULTED PRIMARILY THE PUBLISHED LITERATURE, AND I'LL TALK ABOUT THAT. WE RELIED HEAVILY ON THE NIH CLINICAL CENTER PHARMACY AND I CAN'T SAY ENOUGH GOOD THINGS ABOUT THE PEOPLE IN THE INVESTIGATIONAL DRUG SERVICE THERE AND THEIR WILLINGNESS TO HELP OUT, ESPECIALLY IN AN EMERGENCY SITUATION. WE WERE VERY FORTUNATE TO HAVE A DRUG MANUFACTURER THAT WAS HAPPY TO WORK WITH US ON THIS. I AM ALSO VERY FORTUNATE THAT OUR IRB CHAIR'S OFFICE IS RIGHT NEXT DOOR TO MINE. SO THAT WAS VERY HELPFUL IN GETTING GUIDANCE IN ITEMS OF GETTING THIS THROUGH THE IRB, AND THEN WE ALSO HAVE THE ASSISTANCE OF THE REGULATORY GROUP AND ALSO A LOT OF FROMHE FDA ALONG THE WAY. I'D LIKE TO TELL YOU ABOUT THIS CASE AND HOW THIS EVOLVED. OUR INITIAL INTENT WITH THIS CASE WAS TO USE THE EMERGENCY ACCESS PROGRAM. THERE WERE SOME EXTENUATING CIRCUMSTANCES THAT ENDED UP GIVING US MORE TIME THAN WE THGHT WE HAD, SO WE KIND OF DID A HYBRID OF BOTH OF THESE WHICH I'LL DESCRIBE, BUT I FOLLOW A FAIRLY LARGE COHORT OF PATIENTS WITH A CONDITION WHERE THE AIRWAYS ARE DILATE AND RESULT IN CHRONIC AND RECURRING INFECTION THAT SAID UP CONSIDERABLE INFLAMMATION AND RESULTS IN FORMATION OF NEW BLOOD VESSELS IN THE LUNG THAT HAVE VERY WEAK WALLS AND ARE PRONE TO BLEEDING. IN THIS 60-YEAR-OLD PATIENT WITH THIS CONDITION DEVELOPED AN ASPERGOLOMA, WITHIN THE CAVITY IN THE LEFT LOBE THERE'S AN ODDLY SHAPED BALL SITTING WITHIN THIS. IF YOU ROTATED THIS PATIENT AROUND, THIS WOULD BASICALLY SETTLE OUT WHERE GRAVITY IS, SO THIS IS A FUNGUS BALL IN THE CAVITY. FOR WHATEVER REASON, HAVING THAT COLLECTION OF INFLAMMATORY CELLS AND MOLD WITHIN THE CAVITY SETS UP THIS CONDITION OF BEING PREDISPOSED TO SIGNIFICANT BLEEDING. THIS PATIENT HAD RECURRENT MASSIVE BLEEDING FROM THE LUNG THAT WAS LIFE-THREATENING. AT THE POINT THAT WE BEGAN THIS PROCESS, SHE NEEDED URGENTS ATTENTION. WE HAD STABILIZED THE BLEEDING BY HAVING THE RADIOLOGIST GO IN AND BASICALLY BLOCK A MAJOR BLOOD VESSEL TO THE AREA, BUT THAT WAS NOT FELT TO BE A PERMANENT SOLUTION. SHE HAD VERY SIGNIFICANT UNDERLYING LUNG DISEASE, AND WAS NOT A SURGICAL CANDIDATE. THE TREATMENT OF CHOICE WOULD HAVE BEEN TO REMOVE THIS AND REMOVE THE SOURCE OF BLEEDING, AND WE TURNED OUT INTERVENTIONAL RADIOLOGIST WHO PROPOSED A C-T GUIDED CATHETER-BASED TREATMENT OF THIS. WE THEN LOOKED IN THE LITERATURE AND THERE WERE SEVERAL PUBLISHED PAPERS ON TRYING THIS TYPE OF INTERVENTION AS A METHOD OF CONTROLLING BLEEDING. MANY OF THOSE HAD OUTCOMES THAT WERE A BIT SCARY IN TERMS OF EITHER COMPLICATIONS OR FAILED ATTEMPTS, THIS PARTICULAR PAPER FROM FRANCE WAS ACTUALLY THE LARGEST PUBLISHED SERIES AND HAD A FAIR AMOUNT OF DETAIL NOT ONLY ON HOW THEY DID THE PROCEDURE BUT WHAT THE SOLUTION WAS OR THE COMPOUND WAS THAT WAS USED TO PUT INTO THIS CAVITY. ONE OF THE PROBLEMS WITH THIS TECHNIQUE IS THAT INJECTING THINGS INTO THE CAVITY GENERALLY RESULTS IN THE SUBSTANCE BEING PUSHED OUT INTO THE AIR WAY AND NOT REMAINING IN PLACE. BUT THIS PARTICULAR COMPOUND WAS THE WAY TO BASICALLY HAVE IT LIQUID AT ROOM TEMPERATURE, AND HAVE IT CONGEAL OVER TIME AT BODY TEMPERATURE AND REMAIN IN PLACE. SO IT WAS FELT THAT THE PARTICULAR FORMULA THAT WAS USED IN THIS PAPER WAS VITAL TO THE OUTCOMES THAT WERE REPORTED. AND ONE OF THE COMPONENTS OF THIS, IN ADDITION TO THE ANTIFUNGAL AGENT, WHICH IS READILY AVAILABLE HERE, THEY USED A RADIO-CONTRAST DIE THAT HAD PROPERTIES THAT ALLOWED IT TO NOT REMAIN IN A LIQUID FORM AND TO BE EASILY VISUALIZED OVER TIME TO FOLLOW THE PROGRESS OF THIS. IT WAS MANUFACTURED IN FRANCE, IT WAS APPROVED FOR USE IN FRANCE, AND WAS NOT APPROVED BY THE U.S. FDA FOR USE IN THE U.S SO THE INITIAL DESIRE WAS TO OBTAIN THIS IN A RAPID FASHION, TO BE ABLE TO USE IT AS A COMPONENT OF THIS LIQUID PASTE THAT WOULD BE INJECTED INTO THIS CAVITY TO MORE PERMANENTLY FIX THE BLEEDING PROBLEM. SO WE INITIALLY TURNED TO THE CLINICAL CENTER PHARMACY. THEY HELPED US WITH OBTAINING THE LABEL, THE PACKAGE INSERT FOR THIS PARTICULAR PRODUCT. THAT GAVE US INFORMATION ABOUT THE MANUFACTURER. IT ALSO TOLD US INFORMATION ABOUT THE POTENTIAL SIDE EFFECTS THAT WE WOULD NEED IN PUTTING OUR REQUEST FORWARD TO THE FDA ABOUT THE POTENTIAL RISKS THAT MAY BE INVOLVED WITH THE USE OF THE COMPOUND, AND ABOUT OTHER USES AND ITS INDICATED USE. WE ALSO RECOGNIZED THAT THERE WAS AN IND PACKAGE ON FILE WITH THE FDA AFTER CONTACTING THE COMPANY. THEY WERE MORE THAN HAPPY TO COOPERATE. THEY GAVE US ADDITIONAL INFORMATION ABOUT THE DRUG. THEY GAVE US INFORMATION ABOUT THEIR LOCAL U.S.-BASED ARM THAT WAS PROVIDING A GREAT DEAL OF HELP, AND WAS AT THE READY TO PROVIDE THE DRUG AS SOON AS WE GOT APPROVAL TO USE IT. WE THEN PUT TOGETHER A PACKAGE, WENT TO THE FDA, I CALLED DR. DWAYNE REEVES IN THE RADIOPHARMACEUTICAL BRANCH, WHO I EXPLAINED THE SITUATION. HE GAVE APPROVAL FOR IMMEDIATE USE OF THE DRUG. DUE TO CIRCUMSTANCES OF THE PATIENT'S CONDITION, WE WEREN'T ABLE TO PERFORM THE PROCEDURE RIGHT AWAY WHICH GAVE US TIME TO PUT THE PAPERWORK TOGETHER THAT WAS INVOLVED. WE USED A PROCESS AT THAT TIME WHICH NO LONGER ACTUALLY EXISTS WHERE WE ATTACHED THIS TO AN EXISTING NATURAL HISTORY PROTOCOL THROUGH SOMETHING CALLED A SPECIAL EXEMPTION FROM RESEARCH PROTOCOL BUT BASICALLY OUTLINED WHAT WE WERE PROPOSING TO DO, HOW WE WERE PROPOSING TO DO IT. IT GAVE INFORMATION ABOUT THE DRUG THAT WE WERE PROPOSING TO USE, AND SIDE EFFECTS AND INDICATIONS FOR THAT DRUG. WE PUT TOGETHER A CONSENT FORM THAT WAS TAILORED TO THIS PARTICULAR PATIENT'S CONDITION. AND EXPLAINED OUR REASONS FOR WANTING TO USE THIS COMPOUND. IT EXPLAINED CLEARLY IT WAS NOT APPROVED FOR USE IN THE U.S AND THAT WE WERE REQUESTING APPROVAL TO USE IT FROM THE U.S. FDA IN THIS EMERGENCY SITUATION. SOME OF THE FORMS THAT WERE MENTIONED, WE FILLED OUT. I THINK THIS IS PROBABLY AN OLDER VERSION OF WHAT COLLEEN JUST SHOWED, BUT WE FILLED OUT THE INVESTIGATIONAL NEW DRUG APPLICATION FORM, 1571, INCLUDED INFORMATION ABOUT THE DRUG AND MANUFACTURER, I INCLUDED INFORMATION ABOUT MYSELF AND ABOUT THE OPERATOR AND INTERVENTIONAL RADIOLOGY, ABOUT THE SETTING, UNDER WHICH THIS WOULD BE PERFORMED. AND WE BOTH PROVIDED EVIDENCE OF OUR EXPERTISE AND THE UNDERLYING DISEASE AND THE USE OF THE TECHNIQUE THAT WOULD BE INVOLVED IN THE USE OF THIS AGENT. AS I MENTIONED, WE CONTACTED THE PHARMACEUTICAL COMPANY AND WITHIN A RELATIVELY SHORT PERIOD OF TIME THEY PROVIDED THIS LETTER OF AUTHORIZATION, WHICH GAVE US THE CROSS REFERENCE FOR INFORMATION REGARDING THE CHEMISTRY MANUFACTURING AND OTHER INFORMATION ON THE PRODUCT. WHICH WE THEN PASSED ALONG TO THE FDA. AND I WAS ABLE TO PREPARE THIS LETTER THAT INCLUDED ALL OF THOSE ATTACHMENTS ALONG WITH THE AUTHORIZATION THAT WAS FAXED OVER, AND I ACTUALLY GOT WORD BACK FROM DR. REEVES WITHIN SEVERAL HOURS OF RECEIVING THAT PACKET. IF IT WASN'T A SUCCESS, I WOULDN'T BE TELLING THE STORY. BUT THIS PATIENT BASICALLY PRESENTED WITH LIFE-THREATENING BLEEDING FROM FU FUNGUS BALL IN THE LUNG. THIS IS A CT RECONSTRUCTION AFTER THE PROCEDURE WAS PERFORMED. THE CAVITY HAS DECREASED IN SIZE. THE FUNGUS BALL WAS EXTRUDED DURING THE COURSE OF HER TREATMENT AND CLINICAL COURSE. AND SHE'S -- THIS WAS IN 2011. SHE'S HAD NO SIGNIFICANT RECURRENT BLEEDING SINCE THAT TIME. THIS ALLOWED THE APPROVAL TO USE THE DESIRED IMAGING AGENT AS PART OF THE CATHETER-BASED TREATMENT. THIS APPROVAL WAS OBTAINED VERY RAPIDLY, AND THE PATIENT WAS TREATED, AS I MENTIONED, WITHOUT RECURRENCE OF BLEEDING. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU VERY MUCH FOR THE GREAT EXAMPLE, REPRESENTING EXACTLY WHAT WE'RE LOOKING FOR, BOTH REGULA CLINICAL AND REGULATORY, DONE ACCORDING TO THE REGS AND CORRECTLY. ANY QUESTIONS TO COLLEEN LOCICERO AND DR. KEN OLIVIER? ALL RIGHT. WE HAVE A QUESTION. >> THANK YOU SO MUCH. THE PROGRAM HAS BEEN WONDERFUL. TO THE TWO SPEAKERS, WHEN YOU HAVE A SINGLE OR INTERMEDIATE, AND THE MANUFACTURER OF THE DRUG IS NO LONGER INTERESTED OR THEY ARE NOT MANUFACTURING ANYMORE, HOW DO YOU HANDLE THOSE SITUATIONS? >> JUST COME DOWN, DR. OLIVIER. >> I CAN SPEAK TO OUR PARTICULAR EXPERIENCE WITH CLOFAZIMINE. WHAT ENDED UP HAPPENING, WHEN YOU'RE WORKING WITH RARE DISEASES, FREQUENTLY AND FORTUNATELY THERE'S A PATIENT ADVOCACY GROUP BEHIND THAT DISEASE, AND THAT GROUP ACTUALLY WENT TO CONGRESS AND LOBBIED TO HAVE THAT DRUG BE MADE MORE WIDELY AVAILABLE AND I THINK THAT FACILITATED SETTING UP A PROGRAM WITH THE FDA THAT THE MANUFACTURER WENT ALONG WITH AND THAT HAS BEEN PERPETUATED FOR SEVERAL YEARS NOW TO ALLOW THAT TO HAPPEN. THERE MAY BE OTHER ROUTES AS WELL THAT ARE A LITTLE LESS UNCONVENTIONAL BUT THAT WAS THE EXPERIENCE THAT WE HAD. >> YES, THIS IS A GOOD EXAMPLE, BUT JUST TO EMPHASIZE, IF THE MANUFACTURER ISN'T WILLING TO GIVE YOU THE PRODUCT, FDA CANNOT REQUIRE THEM TO GIVE YOU THE PRODUCT. WE HAVE NO AUTHORITY MAKING THEM TO GIVE YOU THE PRODUCT. WE MAY TRY TO TALK TO THEM, YOU WOULD PROBABLY TALK TO THEM AS WELL. PATIENT ADVOCACY GROUPS COULD TALK AND TRY TO CONVINCE THEM THIS IS THE PRODUCT THAT IS ABSOLUTELY NEEDED FOR YOUR TREATMENT SITUATION. THERE ARE NO REQUIREMENTS TO MAKE THEM GIVE YOU THE DRUG. >> ANY ADDITIONAL COMMENTS? DR. LEMERY, YOUR DIVISION HAS A LOT OF EXPANDED ACCESS, IND APPLICATIONS, AND YOU WANTED TO SHARE YOUR EXPERIENCES WITH US. >> I CAN SAY THE ONE THING I DON'T KNOW IF IT WAS STRESSED WITH EMERGENCY INDIAN'S INDS, IND'S, YOU CAN GIVE THE DRUG BEFORE IRB APPROVAL. OUR PRIVILEGE I PREFERENCE IS THE IRB ROUTE, AND WE TRY TO GET THEM IN 24 HOURS, BUT IF IT DOESN'T MEET THE CRITERIA OF EMERGENCY, EVEN IF THE PATIENT IS VERY SICK, IN OUR CASE, CANCER, WE STILL GO THE SINGLE PATIENT IND ROUTE OR EXPANDED ACCESS FOR A SINGLE PATIENT AND WE GET IT DONE QUICKLY AND WITHIN 24 OR 48 HOURS TO ACCOMMODATE THE PATIENT WITH A LIFE-THREATENING DISEASE. WE TRY TO GET IT DONE QUICKLY. WE RECOGNIZE THAT. >> OKAY. THANK YOU. ANY OTHER COMMENTS OR QUESTIONS? ALL RIGHT. WELL, IT HAS BEEN A LONG DAY. AND WE WOULD LIKE TO THANK YOU ALL FOR YOUR PARTICIPATION, BOTH THE PARTICIPANTS WHO WERE PRESENT IN THE ROOM AND ALL OF WE HOPE THE COURSE WAS HELPFUL AND INFORMATIVE. ALL THE REGULATORY INFORMATION THAT WAS PRESENTED TODAY IS AVAILABLE ONLINE AND YOU CAN FIND IT THROUGH THE WEB NAVIGATIONAL TOOL. AND THE ADDITIONAL REFERENCES THAT ARE LINKED TO THAT TOOL AND IF AT THE END OF THE DAY WE WERE ABLE TO MAKE YOUR NEXT IND SUBMISSION A LITTLE EASIER AND MORE UNDERSTANDABLE, AND A LITTLE LESS COUNCILMA CUMBERSOME, WE ACHIEVED WHAT WE WANTED TO ACHIEVE. IF YOU STILL HAVE QUESTIONS OR NEED ADDITIONAL CLARIFICATION WE'LL LEAVE OUR CONTACT INFORMATION HERE AND YOU CAN FIND IT ONLINE. JUAN LERTORA HAS ALSO BEEN EXTREMELY HELPFUL AND INSTRUMENTAL IN COMMUNICATIONS ISSUES WITH US. SO THANK YOU. [APPLAUSE] >> WELL, THANK YOU VERY MUCH, LARISSA, FOR THE EXCELLENT JOB YOU DID THROUGHOUT THE PROCESS OF DEVELOPING THIS EDUCATIONAL PROGRAM, AND THE IND NAVIGATIONAL TOOL THAT YOU DEMONSTRATED FOR US EARLIER TODAY. AND I THINK WE HAD A VERY PRODUCTIVE DISCUSSION FROM MY PERSPECTIVE. I WANT TO ALSO THANK ALL THE SPEAKERS FROM THE CENTER FOR DRUG EVALUATION AND RESEARCH AT THE FDA, AND THE NIH INVESTIGATORS AND IRB CHAIRS AND STAFF THAT PARTICIPATED TO PRESENT THE PERSPECTIVE FROM NIH. WE HAVE RECORDED THESE SESSIONS. AT SOME FUTURE POINT WE HOPE TO MAKE THESE AVAILABLE AS A RESOURCE, EDUCATIONALLY, AND THAT WILL ALSO INCLUDE PDF FILES OF THE SLIDES OR THE PRESENTATIONS THAT YOU HEARD TODAY. SO STAY TUNED. IF YOU WANT TO REFER BACK TO THIS MATERIAL, OR TO SHARE THE INFORMATION WITH SOME OF YOUR COLLEAGUES IN THE FUTURE. AND IN CLOSING, I ALSO WANT TO THANK OUR STAFF HERE AT NIH, THAT DEALT WITH THE RECORDING OF THE SESSIONS HERE AT THE EVENTS MANAGEMENT DIVISION AND CENTER FOR INFORMATION TECHNOLOGY THAT HELPED US WITH THE WEBCAST. AGAIN, I WANT TO THANK ALL OF YOU IN ATTENDANCE HERE AT LIPSETT AND THOSE THAT FOLLOWED OUR PROCEEDINGS VIA THE WEBCAST MECHANISM. THANK YOU VERY MUCH TO ALL. [APPLAUSE]